recent advances in asymmetric [3,3]-sigmatropic rearrangements · 2017. 10. 24. · the claisen...

REVIEW 961

Recent Advances in Asymmetric [3,3]-Sigmatropic RearrangementsAsymmetric [3,3]-Sigmatropic RearrangementsUdo NubbemeyerInstitut für Organische Chemie und Abteilung für Lehramtskandidaten, Fachbereich Chemie und Pharmazie, Johannes Gutenberg-Universität, Duesbergweg 10–14, 55099 Mainz, GermanyFax +49(6131)3924533; E-mail: [email protected] 3 December 2002; revised 14 March 2003

Synthesis 2003, No. 7, Print: 20 05 2003. Art Id.1437-210X,E;2003,0,07,0961,1008,ftx,en;E08002SS.pdf. © Georg Thieme Verlag Stuttgart · New York

Abstract: The synthesis of new complex structures is still a chal-lenge in preparative organic chemistry. Focusing on the generationof defined stereogenic centers, the [3,3]-sigmatropic rearrange-ments are known as reliable reactions. Always, a highly orderedtransition state must be passed through, which allows the shift ofchiral information from the reactant into the nascent product. Gen-erally, the complete [1,3]- and, frequently, the [1,4]-chirality trans-fer enables one to predict the configuration of the new centers.

This review focuses on Claisen and Cope rearrangements, whichadopt the chiral information via a so termed asymmetric induction.This means, that the directing chiral subunit is placed outside of thesix centers of the rearrangement system being reorganized duringthe course of the [3,3]-sigmatropic reaction.

Reviewing the literature since 1995, enantioselective Claisen rear-rangements have been widely investigated. The unique sense of thereaction allows the conversion of an easily accessible C atom–het-eroatom bond into a new C–C bond making this rearrangement use-ful for constructing complex molecules. In contrast, the Coperearrangement is reversible. One crucial requirement is to force theprocess to completion with respect to the desired product. Hence‘enantioselective Cope rearrangements’ are always included as onestep in a reaction cascade to guarantee the unique sense of the pro-cess. Analyzing such reactions in more detail, the chirality-inducingstep is run prior to the Cope rearrangement. Thus, the [3,3]-sigma-tropic rearrangement is conducted under the well-known [1,3]-chirality transfer conditions.

1 Introduction2 Asymmetric Claisen Rearrangements: Classification3 Remote Stereocontrol in Claisen Rearrangements3.1 Stereogenic Center at C13.2 Stereogenic Center at C63.3 Stereogenic Center in Other Positions4 Auxiliary Control in Claisen Rearrangements4.1 Auxiliary Attached to Position X4.2 Auxiliary Attached to Position Y4.3 Auxiliary Attached to Position Z4.4 Miscellaneous5 Chiral Metal Complex Directed Claisen Rearrangements6 Enantioselective Catalyzed Claisen Rearrangements7 Asymmetric Cope Rearrangements7.1 Remote Stereocontrol in Cope Rearrangements7.2 Auxiliary Control in Cope Rearrangements7.3 Catalyst Control in Cope Rearrangements8 Summary

Key words: asymmetric Claisen rearrangement, Cope rearrange-ment, chiral auxiliary, chiral metal complex, chiral catalyst

1 Introduction

The efficient syntheses of complex molecules such as nat-ural and pharmaceutically important products are still achallenge in organic chemistry. Primarily, key com-pounds with a defined constitution and defined stereogen-ic properties have to be generated. Such intermediatesserve as starting materials for further synthetic efforts toproduce the desired targets.

The Claisen and the Cope rearrangements are known asreliable protocols to generate defined configured tertiaryand quaternary carbon centers as well as complicated Catom–heteroatom bonds.1 Regarding the Cope rearrange-ments, the reversibility has to be taken in account. Thelayout of the reactant should guarantee the unique sense ofsuch a process. Generally, the [3,3]-sigmatropic processesare characterized by the formation of highly ordered tran-sition states where repulsive interactions are minimized(Scheme 1). In combination with defined olefin geometry,the stereospecific bond reorganization of the reactant al-lows the prediction of stereogenic properties of the prod-uct.

Scheme 1 [3,3]-Sigmatropic rearrangements

Focusing on the syntheses of optically active compounds,four different strategies can be used to introduce the chiralinformation.

The simplest way to introduce chiral information is theresolution of target molecules. Generally, such a strategycan offer the advantage of a simple and short synthesis, nospecial requirements concerning the stereochemistry (ex-cept diastereoselectivities) have to be considered, but suchmethodology suffers from the fact, that 50% of product(the wrong enantiomer) has to be wasted.

A second strategy can be seen as an ex-chiral-pool processplacing the chiral information in the six centers that are re-organized during the course of the rearrangement. Easilyaccessible optically active allylic alcohols, amines, andthiols are converted into �,�-unsaturated carbonyl com-pounds (Claisen and hetero-Cope rearrangements). Thenewly generated chiral carbon atom gains the stereochem-

962 U. Nubbemeyer REVIEW

Synthesis 2003, No. 7, 961–1008 ISSN 1234-567-89 © Thieme Stuttgart · New York

ical information through a complete [1,3]-chirality trans-fer, i.e. from the reactant chiral C–X fragment and definedconfiguration of the double bonds. The success of the de-fined C–C bond formation strongly depends on the qualityof the reactant allyl system. Generally, such a fragmentshould be easily prepared by means of well known pro-cesses like Sharpless reactions,2 enantioselective reduc-tions of carbonyl compounds,3 and enzymatic processes.4

Until now, this strategy is mostly applied to [3,3]-sigma-tropic rearrangements to construct optically pure com-pounds.

The third strategy combines rearrangement and the intro-duction of the chiral information in a single step. The so-called external asymmetric induction requires the wellknown highly ordered transition state of the (achiral)[3,3]-sigmatropic system and, additionally, a defined ori-entation of the chiral subunit to achieve a maximal asym-metric induction. Considering the fact, that a majority ofthe [3,3]-sigmatropic processes are run at high tempera-tures, the latter prerequisite of a defined conformation isnot so easy to fulfil and stereoselective rearrangementsseem to be the exception. Hence, the development of ex-ternally directed asymmetric [3,3]-sigmatropic rearrange-ments remains a challenge.

High external asymmetric induction can be achieved in socalled diastereoselective rearrangements. Here, the origi-nal chiral information is placed in the core of the reactantand is maintained in the body of the molecule during therearrangement and beyond it – until the formation of thetarget molecule. In contrast, the rearrangements aretermed enantioselective since the original chiral informa-tion is placed in an auxiliary or a metal complex. Recentefforts are summarized in this review.

The fourth strategy can be understood as the high end ofan external controlled asymmetric induction. A chiral cat-

alyst can be used to introduce the chiral information dur-ing the course of the sigmatropic rearrangement. Untilnow, only a few examples of successfully enantioselectivecatalytic Claisen and Cope rearrangements has been re-ported. An excellent overview of catalyzed Claisen rear-rangements, has recently been published byHiersemann.1g

The first successful efforts are briefly summarized in thispaper.

2 Asymmetric Claisen Rearrangements: Clas-sification

The Claisen rearrangement is the most used [3,3]-sigma-tropic rearrangements, due to the ease of generation of theintermediate allyl vinyl system, along with the smoothand irreversible formation of the product, making this re-action applicable in numerous fields of organic synthesis.

Subdividing the asymmetric variants of the Claisen rear-rangements, diastereoselective reactions characterized byhigh remote stereocontrol generally place at the inducingchiral center adjacent to position one and six (Scheme 2).Additionally, several examples have been described em-ploying the crucial stereochemical information in anotherposition, alternatively more than one chiral center can in-fluence the outcome of the rearrangement.

Scheme 2 Remote stereocontrol

Udo Nubbemeyer was bornin Lengerich/Westfalen in1960. He studied chemistryat the University of Han-nover and received his di-ploma degree in 1986.Diploma and PhD theseswere undertaken in thegroup of Prof. Dr. E. Win-terfeldt (University of Han-nover), research interestsfocusing on stereoselectivespiropiperidine syntheses.After receiving his PhD in1989, he spent a postdoctor-al spell at the Ciba–GeigyLaboratory at the University

of Fribourg (Switzerland)with Prof. D. Bellus and Dr.B. Ernst (1989–1990), in-vestigating reactions ofketenes and allyl sulfides,and also the generation offunctionalized cyclobu-tanones. In 1991 he movedto the Freie Universität Ber-lin to begin his ‘Habilita-tion’ in the group of Prof.Dr. J. Mulzer; this was com-pleted in 1996. Since thenhe has been working as as-sistant lecturer at the FUBerlin. From 1999–2001 heheld a temporary professor-

ship of Organic Chemistryat the Technische Univer-sität in Dresden. In 2002 hestarted his current positionas associate professor of or-ganic chemistry at MainzUniversity. His major topicsof interest are olefin synthe-sis, aza-Claisen rearrange-ments, radical cyclizations,medium-sized rings, totalsynthesis of natural andpharmaceutically importantproducts, alkaloids,eicosanoids, steroids, andamino acids.

Biographical Sketch

REVIEW Asymmetric [3,3]-Sigmatropic Rearrangements 963


In the recent past, auxiliary controlled Claisen rearrange-ments have gained increasing interest. A systematic anal-ysis shows there are three general positions, X, Y, and Z,at which the chiral information can be attached to the allylvinyl core unit (Scheme 3).

The chiral subunit can be bound to position X, if X is a ni-trogen atom. In addition to the vinyl and the allyl substit-uent, a third substituent, a chiral center can be attachednext to the rearrangement core. Due to the close proximityof the chiral information to the rearrangement site thisshould result in maximum asymmetric induction.

The attachment of a chiral fragment at position Y can beachieved using an electronegative heteroatom Y. Predo-minantly, O and N are incorporated in such reactants.Here, ketene acetal and amide acetal reactions will be dis-cussed. The results of Ireland ester enolate rearrange-ments involving chiral metal complexes are summarizedin chapter 5.

Until now, the placing of a chiral substituent in position Zallowed for the most extensive variation, some overlapwith the remote stereocontrol part (inducing center placedadjacent to position 1) cannot be avoided. Generally, thechirality-inducing subunit should be simply attached to anoxygen or a nitrogen atom (Z = O, N), but in such a case,any potential rotation with respect to the C–Z–C bondshas to be suppressed to achieve high diastereoselectivity.Hence, metal chelates serve as efficient tools to fix de-fined transition state conformations and to maximizeasymmetric induction.

Scheme 3 Positions of covalently bound chiral auxiliaries

The use of chiral metal complexes for efficient asymme-tric induction is in the domain of ester and amide enolateClaisen rearrangements. Always, the reactant esters andamides are deprotonated at low temperature. After addinga Lewis acid metal salt and a chiral ligand, the [3,3]-sig-matropic rearrangement is started under mild conditions,allowing high levels of asymmetric induction to beachieved. The major disadvantage is, at least equimolaramounts of the metal salt and the chiral ligand must beused as the product represents a better ligand system forthe metal complex. Attempts at developing catalytic reac-tion conditions fails in most cases, a final hydrolysis isnecessary to separate rearrangement system and metal salt(Scheme 4).

Scheme 4 Chiral metal salts as chiral auxiliaries

Until now, real enantioselective catalytic Claisen rear-rangements are more or less exceptions. The first success-ful reactions reported involved the conversion of allylamidates into the corresponding carbamates employingchiral palladium catalysts.

Scheme 5 Catalyzed enantioselective rearrangements

First promising results building up new C–C bonds havebeen published recently.

3 Remote Stereocontrol in Claisen Rearrange-ments

With the intention of achieving maximum asymmetric in-duction via remote stereocontrol, the chiral informationshould predominantly been placed next to the nascent sig-ma bond formed during the course of the rearrangement,carrying the new chiral centers. Hence, the stereodirectingsubunit must be attached to position 1 and 6, respectively.Always, a single defined transition state conformationcauses a highly selective reaction. In the majority of rear-rangements, mild reaction conditions and low tempera-tures are thought to exploit weak electronic effects forobtaining diastereoselective conversions.

3.1 Stereogenic Center at C1

As a matter of principle, the arrangement of a stereodirect-ing center adjacent to C1 seems to be a simple approach.Analyzing such a plan more carefully, some restrictionsbecome obvious. On one hand, the vinyl double bondmust be assembled stereoselectively to avoid the forma-tion of mixtures of diastereomers. On the other hand, eas-ily accessible optically active C–X groups serve asefficiently directing subunits. In the present special case,the C–X bond occurs in the �-position with respect to thereactant carbonyl group. The formation of the vinyl dou-ble bond should suffer from some �-elimination as a com-peting process. Thus, only a few examples are publishedin this field.

Sreekumar reported the rearrangement of �-hydroxydithioketene acetals 1.5 Since the rearrangement withoutany catalyst gave a mixture of minor syn-2 and major anti-2 products, the rearrangement in the presence of a zeoliteresulted in the exclusive formation of the syn-dithioestersyn-2. The authors postulated an adsorption of the reactantonto the surface of the aluminum silicate in such a way,that the bulky R-group forced the attack of the allyl chainin a trajectory that minimized repulsive interactions, dur-ing the course of the rearrangement. Consequentially, the



syn-product syn-2 occurred as a single diastereomer inhigh yield. The reaction has not yet been tested with enan-tiopure material to exclude any intermediate condensa-tion/re-addition of H2O (Scheme 6).

Scheme 6

A related rearrangement has been described by Beslin.6

The conversion of (S)-allyl thioamide acetal 3 gave thecorresponding syn-thioamides 4 in a ratio of 98:2 andabout 70% yield. The stereochemical outcome was inter-preted as a stereoelectronic effect which favored the ar-rangement of the allyl subunit syn to the OH function.Again, the reaction was not carried out with optically ac-tive material (Scheme 7).

Scheme 7

Rizzacasa et al. tested an Ireland ester enolate rearrange-ment as a key step in the total synthesis of the phospholi-pase A2 inhibitor (–)-cinatrin B.7 Starting from D-arabinose, the furane carboxylic acid 5 was generated infive steps. The esterification with racemic side chain allylalcohol 6 delivered 7 and the subsequent Ireland–Claisenrearrangement gave the corresponding product 8 contain-ing the quaternary center. Carefully developed reactionconditions and the use of HMPA as a co-solvent were re-

ported to be necessary to suppress the competing �-elimi-nation while deprotonating the ester. The conversion wasfound to proceed with a high yield of 95%, but with a dis-appointing diastereoselectivity of about 43:57 8a/8b(dr 1.3:1). The use of enantiomerically pure allylalcohol6, increased the dr values to 2.7:1 [(S)-6] and 2.1:1 {(R)-6}. The result was explained by an incomplete [1,4]-chirality transfer. After the deprotonation, a mixture of E-and Z-ester enolates were formed through defined transi-tion states during the reorganization of the bond system.Obviously, the external stereodirecting power of the C1 in7 was too weak to overcome the selectivity determiningrequirements of the internal chirality transfer. However,the diastereomers 8a and 8b were separated and the envis-aged total synthesis was successfully completed(Scheme 8).

The synthesis of optically active 2,3-disubstituted succi-nates could be achieved starting from allylester 9.8 Afterdeprotonation and trapping of the enolate as TBS keteneacetal 10, the Ireland rearrangement gave the correspond-ing carboxylic acid 11 with 9:1 anti-diastereoselectivityand 55% yield. The intermediate E-ketene acetal wasforced to adopt a transition state conformation in whichallyl strain was minimized: the allyl group preferentiallyapproached from the ester face minimizing the repulsiveinteractions caused by the sp2 systems. The disfavoredsp3/sp2 combination represented by a close proximity ofallyl and i-Bu could be avoided. The Ireland rearrange-ment strategy allowed high anti-selectivity to be achieved,in contrast, the direct alkylation of the lithium ester eno-late by means of an intermolecular reaction led to thestereoinverted syn-product with a high selectivity. The re-actions were developed on a multi kilogram scale as ma-terial in pseudo peptide syntheses (metallo proteinaseinhibitor programs) (Scheme 9).

The construction of three consecutive chiral centers hasbeen developed by Yamazaki.9 A tandem sequence of an

Scheme 8



initial diastereoselective Michael addition of an imideenolate 12 to an allyl trifluoromethyl crotonate 13 gener-ated an intermediate Z-enolate (Z)-14, which underwent afinal palladium(II)-catalyzed Claisen–Ireland rearrange-ment to give 15 and some ester 14 (protonation of (Z)-14).The stereochemical outcome of the [3,3]-sigmatropic re-action was explained by the formation of a chair-like tran-sition state arranging the most electron rich substituent R1

anti with respect to the incoming nucleophilic doublebond. Replacing the trifluoromethyl group in 16(X = CF3) by CH3 (16: X = CH3) the rearrangementcaused an unselective reaction via E-17 to 18 due to thelack of the strong directing effect of the electron with-drawing CF3 substituent (Scheme 10). Detailed informa-tion is summarized in Table 1.

The tetracyclic sesquiterpenoid (–)-cyclomyltaylan-5-ol(22) was synthesized starting from (S)-(–)-Hajos–Wiechert ketone analogue 19.10 One major challenge ofthe synthesis was the diastereoselective generation of thequaternary center as the anchor atom of three rings. Thereactant, unsaturated cyclopentenone 20 was formed inten steps. First efforts to introduce the side chain by meansof an enolate allylation failed. In contrast, the O-allylationsucceeded once a potassium enolate was formed initially.Upon heating the O-allylenol ether to about 110 °C the

Claisen rearrangement proceeded smoothly to deliver thedesired �,�-unsaturated ketone 21 in 96% yield as a singlediastereomer. The reaction was thought to pass through achair-like transition state, the bicyclic ring environmentnext to C1 of the [3,3]-sigmatropic core system enforcedthe selective exo-attack of the allyl unit. However, a boat-like conformation would have led to the same result sincethe terminus of the allyl moiety was substituted symmet-rically. The total synthesis of 22 was completed by furthermanipulation of 21 (Scheme 11).

The stereogenic center at C1 could be replaced by astereogenic axis, as demonstrated by Krause in a prelimi-

Scheme 9

Table 1 Results of the Michael Addition-Ireland Rearrangement Tandem Reactions

Entry R1 R2 R3 Time (h) Catalyst Yield 15 (%) Yield 14 (%)

1 Me H H 4 Pd(II) 55 22

2 Me H H 6 Pd(II) 65 22

3 Me H H 6 – 44 45

4 Me H H 11 Pd(II) 47 16

5 Et H H 6 Pd(II) 63 32

6 i-Pr H H 6 Pd(II) 60 32

7 Me Me H 6 Pd(II) 65 21

8 Et Me H 6 Pd(II) 74 34

9 i-Pr Me H 6 Pd(II) 62 45

10 Me H Me 6 Pd(II) 0 79

Scheme 10



nary publication.11 The addition of Me2CuLi to an allyleneynoate 23 generated an intermediate chiral allenylenolate, which was trapped with bromo trimethylsilane atlow temperatures to deliver the Z-ketene acetal. Uponwarming-up to room temperature the Ireland rearrange-ment led to the formation of the ester 24 in a low yield ofabout 20%, however, the product consisted of a63:15:12:10 mixture of diastereomers showing a de-creased directing ability of the chiral axis in comparisonto the chiral center approach (Scheme 12).

Scheme 12

The replacement of the chiral carbon at C1 by a sulfoxidefragment opened the route to a new class of efficientstereodirecting groups.12 Dithioesters 25 (R2 = SMe) andthioamides 25 (R2 = NMe2) could be easily prepared byacylation of methylsulfoxides with trithiocarbonates andby condensation of chiral sulfinates with thioacetamide,respectively. Deprotonation followed by S-allylation al-lowed the exclusive generation of (Z)-thioketene acetals26, the choice of base (LDA and t-BuLi) was found to becrucial for a smooth reaction. Rearranging a series of S-al-lyl dithioacetals 26 at room temperature, gave the corre-sponding dithioesters 27a and 27b with a highdiastereoselectivity and an acceptable yield. The more sta-ble thioamide acetals 25 (R2 = NMe2) underwent Claisenrearrangements upon heating in THF at reflux without de-composition allowing the generation of optically activematerial. The stereochemical outcome was explained bythe formation of a defined transition state arranging the

lone pair of the sulfoxide as the most electron rich substit-uent anti with respect to the attacking allyl chain. Addi-tionally, the most bulky R1 side chain should have adoptedan exo-position (Scheme 13). Detailed information issummarized in Table 2. (For use of sulfoxides as chiralauxiliaries see chapter 4.3).

Scheme 13

3.2 Stereogenic Center at C6

In contrast to the preceding strategy, the placing of astereodirecting center adjacent to C6 does not cause simi-lar potential problems. Generally, no elimination shouldoccur and the configuration of the 5,6-double bond of the[3,3]-sigmatropic core system can be generated via well-known olefination methods before starting the rearrange-ment. The stereodirecting center can contain carbon

Scheme 11

Table 2 Rearrangement of Z-Thioketene Acetals

Entry R1 R2 R3 T (°C) Yield (%)

dr

112b Me SMe H r.t. 63 93:7

212b Me SMe Me r.t. 51 94:6

312b t-Bu SMe H r.t. 40 98:2

412b t-Bu SMe Me r.t. 50 >99:1

512b i-Pr SMe H r.t. 42 94:6

612b i-Pr SMe Me r.t. 50 >99:1

712b c-C6H11 SMe H r.t. 47 95:5

812b c-C6H11 SMe Me r.t. 60 >99:1

912a c-C6H11 NMe2 H r.t. 60 96:4a

1012a c-C6H11 NMe2 H 66 78 95:5a

1112a c-C6H11 NMe2 Me r.t. 51 >98:2a

1212a c-C6H11 NMe2 Me 66 76 100:0a

1312a c-C6H11 NMe2 Br r.t. 56 95:5a

1412a c-C6H11 NMe2 Br 66 58 96:4a

a Optically active material.



branches as well as defined C-atom–heteroatom bonds.The latter offers the advantage as a potential excellent ste-reodirecting subunit. Since the electron rich 1,2-vinyldouble bond should attack the allyl system at position 6,an adjacent C–X (nucleophilic X) bond should adopt ananti-arrangement with respect to the incoming donor. Inother words, the extended C–X-�* orbital is syn-coplanarwith respect to the attacking vinyl double bond. The tran-sition state is stabilized by additional delocalization ofsome electron density into the empty anti-bonding orbital.Such electronic effects should result in highly stereoselec-tive Claisen rearrangements. Again, mild reaction condi-tions and low temperatures lead to the best results.

Bellus et al. were the first to report such diastereoselectivereactions.13 Allyl mercaptanes 28 and electron deficientketene 29 underwent the so-called intermolecular ketene-Claisen rearrangement. The process was thought to pro-ceed in two steps. After an initial addition of the electro-philic ketene equivalent to the nucleophilic thio center ahypothetical intermediate zwitterion Z was formed, whichunderwent an immediate [3,3]-sigmatropic rearrangementto give the corresponding thioesters 30/31. The chargeneutralization served as an efficient driving force allow-ing the whole process to be carried out at low tempera-tures (0–35 °C). The mild reaction conditions resulted inhighly diastereoselective conversions placing chiral C–Oand C–N functions at C4 of the allyl system (stereogeniccenter adjacent to C6). The hypothetical zwitterion Z,should have adopted a chair conformation c-Z as knownfor acyclic [3,3]-sigmatropic rearrangements. Further-more, quasi 1,3-diaxial repulsive interactions should beminimized. Consequentially, the attacking trajectory ofthe thiuronium enolate onto the allyl system should beanti with respect to the best donor, the ether oxygen or theamide nitrogen attached to C4, respectively. Generally,the 1,2-asymmetric induction was found to be >90:10 infavor of the syn-product 31 for the oxygen substituted sys-tems (X = O).13a,c In contrast, most runs employing allylamides (X = NBn) gave only moderate diastereoselectivi-ties of 80:20 to 90:10 (31/30).13b Semi-empirical AM1calculations of representative systems implied that pre-dominantly chair-like transition states, c-Z, were formed,but in the case of the amides an energetically low compet-ing boat-like conformation b-Z seemed to be responsiblefor the formation of significant amounts of the anti-dias-tereomer 30. Detailed data are summarized in Table 3.

The thioesters 30 and 31 were converted into their corre-sponding defined configured di- and trisubstituted �-bu-tyrolactones 32 and 33 (X = O) and �-lactams (X = NBn),respectively, which are useful building blocks for pharma-ceutically important product syntheses. The variability ofR1 should be pointed out as a major advantage of themethod. Discussing the limitations, only electron-defi-cient ketenes 29 (at least one halide) could be employedsuccessfully, more electron rich ketenes gave [2+2]-cy-cloadditions resulting in the corresponding cyclobu-tanones. Furthermore, the simple diastereoselection in theassembly of C2 of the thioesters 30/31 was found to be

low indicating non-selective thiuronium enolate forma-tion in the hypothetical zwitterionic intermediate(Scheme 14, Table 3). These difficulties could be over-come by switching to the allylamine analogs (vide infa).

Scheme 14

Intending to develop a more general method for the rear-rangement of allyl systems with high remote stereocon-trol, the thioether function was replaced by an aminogroup as present in 34.14 In contrast to the ketene-Claisenrearrangement described above, the use of �,�-disubstitut-ed carboxylic acid halides 35 exclusively induced a socalled von-Braun degradation.15 Initially, the tertiaryamine 34 and the acid chloride 35 (X = Cl) formed anacylammonium chloride, which after nucleophillic attackby the chloride on the allyl ammonium subunit generatedallyl chlorides 36 and amides 37. Subjecting the ally-lamines 34 to �-monosubstituted acid halides 35 in thepresence of Lewis acids like trimethyl aluminium, the de-sired rearrangement dominated. Upon running the reac-tion at 0 °C, the degradation could almost be suppresseddepending on the substitution pattern in 34 and 35. Final-ly, the use of carboxylic acid fluorides 35 (X = F) in thepresence of trimethyl aluminium enabled the process torun in the absence of nucleophiles.14c In terms of stereose-lection for the conversion of 38�41, the 1,2-asymmetricinduction was found mostly to be >90:10 in favor of thesyn-product – even when nitrogen was used as the direct-ing function. The minor, anti-diastereomer only occurredin appreciable amounts if acetyl chloride was used as thesource of acid chloride. Furthermore, the simple diastere-oselectivity (internal asymmetric induction) was high al-lowing the diastereoselective generation of two newstereogenic centers in a single step bearing a variety offunctional groups. The so formed �,�-unsaturated amides38–41 represent useful intermediates for natural productsyntheses as demonstrated in the synthesis of (+)-dihydro-canadensolide 4214b and the formal synthesis of (–)-peta-sinecin 43 (44 = petasinecin) (Scheme 15).14c,16 Detailedinformation is summarized in Table 4.



The stereochemical outcome of the reaction could be ex-plained by the formation of a clearly preferred transitionstate. Generally, the ketene equivalent (from 35) and theallylamine 34 (R1: No 3) combined to form a hypotheticalintermediate acyl ammonium enolate with a defined Z-enolate geometry (in b-38, c-39, c-40), as is known foramide and acyl ammonium enolates. Adopting the chair-like conformations c, the anti-arrangement of the attack-ing enolate and the guiding heteroatom (N and O at C4)favored c-39 over c-40, the anti/syn-product 39 was iso-lated as the major compound. Surprisingly, R2-substitu-ents characterized by extended �-systems led to the syn/syn-products 38 selectively. Here, the high remote stereo-control must involve an alternative boat-like transitionstate conformation b-38. In Scheme 15 the hypothesesconcerning 34 (R1: No 3) are outlined. With respect to theinverted configuration of the directing center adjacent to

C6 in 34 (R1: No 1, 2, 4) 38–41 (R1: No 1, 2, 4), the enan-tiomer stereotriads of are formed.

In addition to C–C bond formation by means of a [3,3]-sigmatropic rearrangement, C–N bonds could be generat-ed stereoselectively using efficient remote stereocontrolcaused by a chiral center adjacent to C6. Planning such aprocess, one’s attention has to be turned on the drivingforce of the reaction. Since carbonic acid derivatives mustbe rearranged, the resulting system should be character-ized by some higher stability to direct the conversion to-wards the product avoiding an equilibrium occurring.Gonda employed thiocyanates 45 as a nitrogen source.17

Always, the suitable reactants have been synthesizedstarting from the corresponding allylalcohols by an initialmesylation and a subsequent substitution with potassiumthiocyanate. Rearranging acyclic S-allyl thiocyanates 45under thermal conditions for a short reaction time of 3

Table 3 1,2-Asymmetric Induction in Ketene-Claisen Rearrangements of Allylsulfides

Entry R1 X R2 R3 Yield (%)30+31

dr31/30

Yield (%)32+33b

32+33c

113a,c Me O TBS Cl 87 97:3 9090

213a,c Me O TBS Me 83 3/1:0/0a 71–89a

87a

313a,c i-Pr O TBS Cl 76 >95:5 81

413a,c TBSOCH2CH2 O TBS Cl 76 >95:5 45

513b Me NBn BOC Cl 91 81:19 90/95 (syn/anti)90/93 (syn/anti)

613b Me NBn Tos Cl 98.5 90:10 –80/78 (syn/anti)

a Mixture of C2 diastereomers. b Zn/HOAc incl. reductive dechlorination. c H+ deprotection only, entry 4: double deprotection.

Scheme 15



hours, a mixture of N-allyl isothiocyanate diastereomers46 and 47 were obtained indicating a poor 1,2-asymmetricinduction of about 60:40.17a,d In contrast, prolongation ofthe heating from 24 hours to 48 hours caused the exclusivecyclization of the syn-isocyanate 47. The intramolecularattack of the carbamate nitrogen at the isothiocyanategave the stable anti-imidazolidinthione 49 in an unidirec-tional reaction step, no syn-48 could be detected. Due tothe reversibility of the rearrangement under the conditionsreported, the reactant could be converted into the singlediastereomeric product 49. In addition, catalytic amountsof 2-pyridone were found to accelerate the formation ofthe anti-imidazolidinethione 49 allowing a remarkable re-duction of the reaction time (Scheme 17).

Investigating the 1,2-asymmetric induction, diacetoneglucose was found to serve as an efficient directing sub-stituent.17b The rearrangement of (E)- and (Z)-allyl thiocy-anates 50 under thermal conditions resulted in theexclusive formation of the �-isothiocyanate 51 in highyield and complete diastereoselectivity. No equilibriumbewteen 51 and 52 has been reported even though the tem-perature was only 70 °C and the reaction time was com-paratively short (3 h). Obviously, the open book shape ofthe acetonide-furanose bi-cycle allowed the generation of

tertiary C–N bonds with a defined configuration.18 The C4side chain was less important considering the stereoselec-tivity of the rearrangement since the variation of the pro-tecting groups caused no appreciable effect.

Analogous experiments on a galacto thiocyanate series 53led to similar observations, generating secondary C–Nbonds with a defined configuration.19a Upon heating (E)-and (Z)-allyl thiocyanate 53 to about 70 °C, the [3,3]-sig-matropic rearrangement led to the corresponding isothio-cyanates 54 and 55 in high yield and highdiastereoselectivity of 96:4 in favor of the �-product 54.Conducting the same reactions at 140 °C for a short time,both diastereomers were found in a ratio of 50:50. Heatingfor a longer period of time led to an excess of the �-isomer55. These latter experiments improved the reversibility ofthe process and showed, that the stereochemical outcomeof the reaction was strongly temperature- and time-depen-dent (Scheme 18).

Table 4 1,2-Asymmetric Induction in Zwitterionic Aza-Claisen Re-arrangements of Allylamines

Entry R1 R2 X Yield (%)

Ratio 38/39/40/41

114a 1 H Cl 84 –:1:2:–

214a 1 Me Cl 73 <1:<1:>15:<1

314a 2 H Cl 80 –:4:7:–

414a 2 Me Cl 74 <1:1:10:<1

514a 3 H Cl 82 –:3:2:–

614a 3 Me Cl 77 <1:9:1:<1

714b 3 ClCH2CH2 Cl 74 3:7:<1:<1

814a 3 i-Pr Cl 45 <1:97:<1:<1

914a 3 H2C=CH Cl 62 <1:97:<1:<1

1014a 3 H2C=CHCH=CH- Cl 60 97:<1:<1:<1

1114a 3 Ph Cl 52 97:<1:<1:<1

1214a 3 Cl Cl 82 2:96:<1:<1

1314a 3 OBn Cl 83 9:86:<1:4

1414c 4 Me F 78 <1:<1:>97:<1

1514c 4 Ph F 85 <1:<1:>97:<1

1614c 4 Cl Cl 24 <1:<1:>97:<1

1714c 4 Cl F 76 <1:<1:>97:<1

1814c 4 OBn F 68 <1:<1:>97:<1

Scheme 16 Hypothetical transition states of the zwitterionic aza-Claisen rearrangement: remote stereocontrol

Scheme 17



With the intention of developing a new route to the 5-azaribose core of the pyrimidine nucleoside peptide antibioticpolyoxin L, the above mentioned aza-Claisen strategy wastested starting from the ribo-thiocyanate 56.17c The ther-mal rearrangement (PhH, 70–80 °C, up to 5 h) led to vary-ing mixtures of diastereomeric isothiocyanates 57 and 58depending on the substituent R attached to C1 with goodyields. Unfortunately, the uridyl derived system gave thelowest selectivity of about 60:40. In contrast, the xylo-thiocyanates 59 rearranged to the corresponding isothio-cyanates 60 and 61 with satisfactory yields and a signifi-cantly higher diastereomeric excess (60/61 90:10–99:1).Obviously, the adjacent silylether protected C4 OH groupacted as an efficient directing group (Scheme 19).

Scheme 19

A second strategy to introduce a nitrogen via an aza-Clais-en rearrangement can be termed as the Overman variant.20

Initially, allylalcohols had to be converted into the corre-sponding trichloro acetimidates. Such acetic acid deriva-tives can undergo a [3,3]-sigmatropic-like reaction in thepresence of Pd(II) or Hg(II) catalysts resulting in aceta-mides.21 The formation of the C=O function starting fromthe C=N group is the major driving force of the reaction,making the whole process irreversible.

Gonda investigated this strategy intending to develop anew sequence to synthesize the carbohydrate core of theantibiotics lincomycin and clindamycin. In this specialcase all attempts to catalyze the [3,3]-sigmatropic rear-rangement failed.19a Thus, the thermal reaction was con-ducted heating the reactant 62 to about 200 °C in xylene.Disappointingly, the reaction of (E)- and (Z)-trichloroacetimidates 62 (X = Cl) suffered from a low yield and nodiastereoselectivity. In contrast, the conversion of the tri-fluoro acetimidates 62 (X = F) gave the desired products63 and 64 in 93–95% yield. The reactant bearing an E-double bond delivered poor diastereoselectivity of 42:5863:64. The best result was reported for the rearrangementof the Z-system, generating predominantly the �-amide 64with a dr of 9:91 (63:64, Scheme 20). However, the rear-rangement of the allyl thiocyanate 59 mentioned above(Scheme 19) served as a potential alternative.

Scheme 20

A highly selective non-catalyzed rearrangement has beendescribed by Isobe in the course of the total synthesis of(–)-tetrodooxin.22b,c The central tertiary amino group in 66was introduced by means of an Overman rearrangementof the acetimidates 65.21 The dioxolane subunit served asan efficiently directing function. The transition state po-tentially passed through could be described as a chair-likeconformation arranging the dioxolane in a pseudo-axial �-position. Thus, the amino group was forced to attack the�-face of the double bond generating the desired key com-pound 66 with complete diastereoselectivity and an ac-ceptable yield on a 20 g scale (Scheme 21).

In contrast to these findings, van Boom reported a suc-cessful catalyzed rearrangement as a key step in the syn-

Scheme 18



thesis of a conduramin derivative.22a The amidate 67 wasobtained starting from a galalacto pyranoside in eightsteps. The Overman rearrangement in the presence of aPd(II) catalyst gave the desired amide 68 diastereoselec-tively with anti-configuration in 73% yield. The stereo-chemical outcome could be explained by the argumentoutlined in Scheme 16 (chair-like transition state in anal-ogy to c-39). Finally, four further steps furnished the de-sired target 69 (Scheme 22).

Scheme 22

3.3 Stereogenic Centers in Other Positions

In addition to the 1,2-asymmetric induction strategies togenerate new stereogenic centers via Claisen rearrange-ment, several further reactions have been reported placingefficient directing chiral subunits in other positions. Gen-erally, several structural and conformational properties ofthe reactant influence the transition states of these reac-tions making a reliable prediction of the stereochemicaloutcome of the [3,3]-sigmatropic reaction more and moredifficult.

Boeckman reported on an enhancement of stereoselectiv-ity in Claisen rearrangements by remote stereogenic cen-ters in the presence of sterically demanding Lewis acids.23

In the course of the development of a synthetic access tosaudin, acyclic thermal [3,3]-sigmatropic reactions havebeen investigated. Starting from the bicyclic lactone 70the allyl side chain was introduced by an O-alkylation ofthe corresponding enolate 71. The so formed allyl vinylether was subjected to Claisen rearrangement conditionsto generate the cyclohexanones 72 and 73 bearing two ad-ditional stereogenic centers. The thermal rearrangements

were conducted at high temperatures. As expected, the drvalues of the products were low. Testing a range of Lewisacids showed that a significant reduction of the reactiontemperature and the reaction time could be achieved.Though several conversions did not go to completion thediastereoselectivities were found to be significantly en-hanced. The best results were reported for the methyl se-ries (R = Me, additional stereogenic center adjacent toC6) though the yield was moderate, the reactions were farfrom being optimized (Scheme 23). Detailed informationis given in Table 5.

Scheme 23

Magnus planned to employ a Claisen rearrangement as akey step in the total synthesis of taxol.24 Since the [3,3]-sigmatropic core system contained no stereogenic centers,the adjacent chiral A and C ring fragments should serve asefficient chiral inductors. Initially it was attempted to car-ry out the Claisen rearrangement as a ring contraction of a12-membered unsaturated lactone 74. The failure of thisprocess was presumed to be due to an overly constrainedtransition state, which would have to be formed, closingthe central B ring to 75. Alternatively, the 2,3-bond wasconstructed prior to the closure of the B ring starting fromester 76. This Claisen rearrangement proceeded with 57%yield to give acid 77. The new bond bore the correctlyconfigured stereogenic centers as found in the target mol-ecule taxol (Scheme 24).

Scheme 24

Scheme 21



Ishihara tested an esterification Ireland–Claisen rear-rangement sequence as a key step in a convergent synthe-sis of some azadirachtin model compounds to generate thehighly substituted C8–C14 bond.25 Initially, the ester 78was formed to connect both halves of the molecule. Then,the deprotonation/silylation at low temperature led to theintermediate ketene acetals, which rearranged upon heat-ing to 70 °C to give the acids 79 and 80 as mixtures of dia-stereomers separable by means of HPLC. The reactionwas found to be strongly dependent on the conditions em-ployed. Since the rearrangement should occur through achair-like transition state, the selective generation of inter-mediate ketene acetal was thought to be crucial. The useof TMSCl resulted in the E-configuration, E-c minimizesrepulsive interactions between the lactone and silyl group.Acid 80 was formed predominantly (55% yield, 3:1). Incontrast, the reaction employing Me2SiCl2 formed the Z-acetal, Z-c predominantly as a result of chelation of the si-lyl group to the lactone C=O and the enolate. Consequen-tially, the acid 79 was isolated as the major compound(87% yield, 4:1) with all stereogenic centers in the sameconfiguration as the natural product (Scheme 25).

Barrett developed an efficient synthesis of annulated �-lactam carboxylic esters 83.26 The key step was a tandemIreland–Claisen ring closing metathesis cascade. Thoughthe reactant �-lactam 81 was characterized by a definedstereogenic center, no chiral induction was observed inthe initial rearrangement step to 82. The product was ob-tained as 1:1 mixture of diastereomers (Scheme 26).

Medium-sized rings could serve as highly efficient frame-works to induce diastereoselective rearrangements withremote stereocontrol because of the restricted conforma-tional mobility of such systems. Investigating Bergman–Myers reactions of cyclic enediynes and eneyne allenes,Magriotis employed a Claisen rearrangement as a ringcontraction to force the termini of the �-systems to the ap-

propriate distance ready for the cyclo aromatization.27 Thering size was found to play a crucial role, since ten mem-bered rings containing an enedyine subunit were unstable.The eleven membered analogs could be obtained fromBergman cyclization by protecting one triple bond as a

Table 5 Remote Stereocontrol in Simple Claisen Rearrangements of Bicyclic Lactones

Entry R Lewis Acid mol Time (h) T (°C) Yield (%) Ratio

1 H – – 2 105 81 1:1

2 H i-Bu3Al 2 18 25 33a 1:2

3 H Me3Al 2 0.9 25 90 1:3

4 H MADc 4 2 25 88 2:5

5 H Et2AlCl–PPh3 2 1.5 -50 57a 1:4

6 H Et2AlCl–PPh3 2 0.5 25 94 1:5

7 Me – – 2 125 76 1:3

8 Me Me3Al 2 0.2 45 60b 1:24

9 Me MADc 4 2 25 43b 1:24

10 Me Et2AlCl–PPh3 2 0.5 25 39b 1:24

a Incomplete conversion. b Not optimized.c MAD = Bis(2,6-di-tert-butyl-4-methylphenoxy)methylaluminum.

Scheme 25

Scheme 26



Co-carbonyl complex during the course of the sigmatrop-ic reaction. Furthermore, any competing [1,3]-rearrange-ment as found in a non-protected system could besuppressed. Starting from the 15-membered lactones 84,treatment with LiHMDS and TIPSOTf at low tempera-tures gave the Z-enolate. After protection of the less hin-dered triple bond with Co2(CO)8, the ring strain of thesystem was dramatically reduced allowing an Ireland re-arrangement at ambient temperature. Finally, the oxida-tive deprotection of the triple bond gave the desiredeleven membered enediynes 85 in 50–60% yield overall.The process was found to be diastereoselective due to thehighly efficient transannular remote stereocontrol in sucha system (Scheme 27).

Scheme 27

Highly selective Claisen rearrangements of substrates 86bearing a defined configured sulfinyl moiety at C5 en-abled the creation of up to two asymmetric centers whilepreserving the useful vinyl sulfoxide functional group.28

The Johnson reaction conditions were found to be mostviable as long as the vinyl double bond could be generatedin a defined manner. Thus, the [3,3]-sigmatropic rear-rangements were run at about 130 °C using easily acces-sible vinylogous carbonates 86. Generally, a finaldecarboxylation gave the �,�-unsaturated aldehydes 87and 88. Maintaining the configuration of the sulfoxide, therelative arrangement of the allyl double bond and thestereogenic center C3 were varied. Consequentially, thestereochemical outcome of the rearrangements could besubdivided into a matched set delivering high selectivityand a mismatched set leading to decreased dr’s. The acy-clic architecture of all systems suggested chair-like transi-tion states to be passed during the course of the reaction.The sulfoxide and the 5,6-double bond should alwaysadopt a S-cis arrangement. Thus, the matched reactionspassed through a chair transiton state where 1,3-diaxial re-pulsive interactions are minimized, i.e. the small lone pairof the sulfoxide should have been placed in an endo-posi-tion ts-endo. In contrast, the mismatched series via ts-exosuffered from severe repulsion because of the endo orien-tation of the Ar unit of the sulfoxide causing decreased di-astereoselectivities. The influence of the chiral sulfoxide

was corroborated by the rearrangement of the sulfide ana-logs effecting a modified stereochemical outcome The E-and Z-vinyl sulfides gave predominantly Z-olefins. The E-reactants caused a high (93:7), the Z a significantly de-creased, diastereoselectivity (72:28). Removing thestereogenic center at C3, the sulfoxide was found to be ca-pable of inducing the generation of the new chiral centerwith a high diastereoselectivity. Finally, the ethoxy cyclo-hexene 89 was treated with an allyl alcohol. After ex-changing the carbinol groups the Claisen rearrangementproceeded in high yield and a high sulfoxide supported di-astereoselectivity to give the corresponding 2-substitutedcyclohexanones 90 and 91 bearing two new chiral centers(Scheme 28, Table 6).

Scheme 28

4 Auxiliary Control in Claisen Rearrange-ments

Auxiliary controlled [3,3]-sigmatropic rearrangementsrepresent an almost classical approach to introduce chiralinformation into a more complicated rearrangement sys-tem. The major advantage is that there is reliable controlover the stereochemical outcome of the reaction. All prod-ucts are diastereomers, e.g., the separation of minor com-pounds should be more or less easy and the well knownspectroscopic analyses will always be characterized bydefined and reproducible differences. However, the auxil-iary strategy requires two additional chemical transforma-tions: the attachment and the removal of the auxiliarymust be carried out in two steps. The efficiency of thesesteps influences the whole sequence. High yields, alongwith the avoidance of stereochemical problems are theprerequisite of each step. Furthermore, the synthesis andthe recycling of an auxiliary must be taken in account.Overall, a set of advantages and problems have to be con-sidered before deciding on an auxiliary strategy.



4.1 Auxiliary Attached to Position X

The setting of X = nitrogen enables a chiral auxiliary to beattached to this position via the third binding valence.Such a plan offered the advantage of the [3,3]-sigmatropicrearrangement system and the stereodirecting groupplaced in very close proximity. Unfortunately, the aza-Claisen rearrangements of amide enolates (OLi) werecharacterized by significantly higher reaction tempera-tures in comparison to their oxygen analogs because of themoderate driving force [moderate charge stabilizationenolate deprotonated amide RN(Li)C=O]. Thus, theadoption of a single transition state conformation turnedto be unlikely increasing the risk of poor efficiency of theauxiliary causing unselective reactions.

An aza variant of the Ireland rearrangement has been de-veloped by Tsunoda.29 The reaction is a key step in an (+)-antimycin A3 97 synthesis. Starting from (+) methylben-zylamine 92 as the chiral auxiliary, the amide 93 was ob-tained after four steps. A deprotonation/silylation gave theZ-ketene aminal, which underwent the [3,3]-sigmatropicrearrangement upon heating to 120 °C in a sealed tube(generally, the analogous o-ketene acetal Ireland rear-rangements are run at r.t. or below). The �,�-unsaturatedamides 94 and 95 were isolated as a mixture of four dia-stereomers. The major isomer 95 was obtained in 78%yield as an inseparable 82:18 mixture of isomers with theminor compound indicating a complete internal and amoderate external (auxiliary derived) asymmetric induc-tion. The high reaction temperature prevented the reactionfrom passing through a single transition state conforma-

tion. The cleavage of the amide 95 succeeded via iodo lac-tonization resulting in an enantiomerically enrichedlactone 96. The minor enantiomer could be finally re-moved after coupling with the second half of the targetmolecule. Finally, the (+)-antimycin A3 97 was generatedafter conducting several further steps (Scheme 29).

Two aspects must be considered when planning highly se-lective auxiliary directed aza-Claisen rearrangements. On

Table 6 Chiral Sulfoxide-Directed Diastereoselective Claisen Rearrangements

Entry Ar R1 R1� R2 R2� Yield (%) Yield (%) 87 Yield (%) 88 dr

1 p-Tol Ph H H n-Bu 79 100 –

2 p-Tol Et H H Me 78 100 –

3 1-Naph Ph H H n-Bu 79 100 –

4 p-Tol H Ph n-Bu H 74 88 8

5 2-MeO-1-Naph H Ph n-Bu H 77 100 –

6 p-Tol H Ph H n-Bu 73 23 70

7 p-Tol H Et H Me 76 26 73

8 1-Naph H Ph H n-Bu 71 29 63

9 p-Tol Ph H n-Bu H 74 24 73

10 2-MeO-1-Naph Ph H n-Bu H 77 – 100

11 1-Naph Me Me H n-Bu 80 99 1

12 1-Naph Me Me n-Bu H 78 88 14

13 2-MeO-1-Naph H Ph n-Bu H 80 99 1 98:2

14 2-MeO-1-Naph Ph H H n-Bu 75 100 0 100:0

Scheme 29



the one hand the reaction temperature had to be signifi-cantly lowered in comparison to Tsunoda’s conditions.On the other hand the conformational mobility of the po-tential transition state had to be restrained forcing the sys-tem to take a single reaction path. The zwitterionic aza-Claisen rearrangement seemed to fulfill both prerequisitesusing L-(–)-proline derivatives 98 as chiral auxiliaries.30

Several N-allyl pyrrolidines 101 were synthesized via aPd(0)-catalyzed amination of the corresponding allylme-sylates 99 and 100, respectively. The double bond was al-ways in the E-configuration. Treatment with chloro andsuitably protected �-amino acetyl fluorides 102, in thepresence of solid potassium carbonate and trimethyl alu-minum in chloroform at 0 °C led to the formation of thecorresponding �,�-unsaturated amides 103 and 104. Mostlikely, the charge neutralization served as an efficientdriving force allowing the reactions to be conducted atsuch low temperatures. The use of azido acetyl fluoride102 (R3 = N3) enabled a subsequent reductive cyclizationto generate D-proline L-proline dipeptides 105, allowing avariety of substituents to be introduced onto the new D-proline moiety (Schemes 30, 31).

The strategy for removing the auxiliary should be chosendepending on the auxiliary and the substitution pattern ofthe amide 103/104. Generally, the iodo lactonization asdescribed by Tsunoda29 led to the smooth cleavage of alltypes of amides. The prolinol auxiliaries(R1 = CH2OTBS) offered further advantages. In the pres-ence of acid stable substituents R2 and R3, a neighboringgroup assisted transesterification (R1 = CH2OTBS) withHCl/MeOH enabled the amides 103 to be converted intothe corresponding esters 107. Alternatively, the auxiliarycan be used as a leaving group in an intramolecular metalorganic reaction of 103 (R3 = CH2–Ar–Br) to generate acyclic ketone 108 without any loss of chiral information(Scheme 31).

Discussing the stereochemical outcome of the Claisen re-arrangements, two aspects have to be considered. On theone hand, the relative configuration of the new stereogen-ic centers was found to be exclusively syn in 103 and 104,indicating that the reaction passed through a chair-liketransition state c-� and c-�, respectively, which included aZ-acyl ammonium enolate structure (complete simple dia-stereoselectivity/internal asymmetric induction).

On the other hand the external asymmetric inductionstrongly depended on the chiral auxiliary. Careful analysisof the hypothetical zwitterionic intermediates c-� and c-�indicated the formation of a stereogenic ammonium cen-ter. In terms of the well known 1,3-chirality transfer of[3,3]-sigmatropic rearrangements, the present reaction al-lowed the chiral information to be shifted from the ammo-nium center (1) to the enolate C (3). The amide 103/104�-carbon atom had been constructed with a defined con-figuration after passing through the above mentionedchair-like transition state c-�/c-�, including defined olefingeometry and the equatorial arrangement of the bulky(chain branch) part of the auxiliary. Consequentially, thecrucial step of the whole process must have been the dia-

stereoselective addition of the ketene equivalent on gener-ating the zwitterionic intermediate. Thus, employing theauxiliaries bearing the small proline methyl ester substit-uent (R1 = CO2Me) in 101, the reaction with non-hinderedacid fluorides 102 gave the corresponding amides 103/104 with low or moderate diastereoselectivity indicatingunselective N-acylation. In contrast, conversions at lowertemperatures or with bulky substituted acid fluorides 102resulted in significantly higher selectivities (more selec-tive acylation). The use of reactant allylamines bearingthe bulky proline t-butylester and the OTBS prolinol aux-iliaries as R3, were characterized by a high auxiliary di-rected diastereoselectivity indicating a defined acylationrearrangement path via c-�. Presently, the OTBS prolinol(R1 = CH2OTBS) is the auxiliary of choice due to its easeof introduction, its high directed induction of chirality, itsstability under subesequent reactions, and its simplecleavage by the neighboring group assisted amide 103 togive ester 107. Detailed information is summarized inTable 7 (Schemes 30, 31).

Presently, the zwitterionic aza-Claisen rearrangement hasbeen developed as a reliable method to synthesize suitablyprotected non-natural �-amino acid derivatives, e.g. C-al-lyl glycines type 107 and 3-arylprolines type 105.

Scheme 30

4.2 Auxiliary Attached to Position Y

The attachment of a chiral auxiliary to position Y is not re-stricted to Y = nitrogen because only one binding valenceis occupied by the rearrangement system. Analyzing thesituation more carefully, the use of Y = O, S connecting acarbon bound auxiliary would have required Johnson-type rearrangement conditions to induce the thermal con-version of the intermediate ketene acetals. Such drasticconditions disable the passing of defined transition stateconformations, the products would have been formed asmixtures of diastereomers.31. Hence, a nitrogen atom hadbeen placed in position Y offering two additional bindingvalences to fix the chiral information much more effi-ciently.



An Eschenmoser-type rearrangement for the constructionof �,�-unsaturated amides required the generation of suit-able amide acetals. Conducting so called auxiliary con-trolled Ficini–Claisen rearrangements, the startingmaterial of choice was found to be N-alkynyl oxazolidino-ne (�109) and imidazolidinone.32 In contrast to the wellknown Eschenmoser and Johnson variants, the Ficini re-arrangement was characterized by carefully optimizedand significantly milder reaction conditions so as to avoidthe cleavage of the ynamides. The acid seemed to play acrucial role during the course of the process. Treatment ofthe ynamine derivatives 109 with allylalcohols 110 in thepresence of sub-stoichiometric amounts of p-nitroben-zenesulfonic acid at about 70–80 °C induced the initialacid mediated quasi-syn addition of the alcohol to the tri-ple bond. The alkynyl amide 109 was protonated to givethe N-acyl ketene iminium salt forcing the allylalcohol110 to attack syn with respect to the allenyl H. An inter-mediate E-amide acetal was formed, which underwent animmediate Claisen rearrangement to give the correspond-ing amides 111 with high yield and moderate to high ex-ternal (auxiliary directed) stereocontrol. Thestereochemical outcome could be compared to that of thewell-known Evans-aldol reactions. In the majority of re-actions, the major diastereomer was formed in a 80:20 to96:4 ratio with respect to all minor compounds. A set ofauxiliaries and allylalcohols was tested indicating the ef-ficiency of the so-called Sibi-oxazolidinone in 109.33 Fi-nally, the removal of the oxazolidinone subunitsproceeded via basic cleavage and a subsequent iodo lac-tonization. A 3:1 mixture of diastereomers 112 and 113was obtained indicating a moderate asymmetric inductionupon generating the lactones (Scheme 32).

Scheme 32

Considering the anionic Ireland–Claisen rearrangements,a chelate complex formed as an intermediate potentiallyaffected the chance for the reaction to pass through a sin-gle defined transition state conformation, which would ef-fect the selectivity of the reactions. Again, the drivingforce of such a process had to be taken into account be-cause the rearrangement had to be run at low tempera-tures.

Since the rearrangement of amide enolates (OLi) requiredhigh reaction temperatures of about 120 °C causing theformation of mixtures of diastereomeric products29 Metzinvestigated the corresponding imidates 115.34 Generally,the imido ester enolates (NLi) were more basic than theiroxygen analogs. Thus, the driving force on generating theproduct deprotonated amides [RN(Li)C=O] via rearrange-ment should have been increased (more stabilized productanion) allowing such processes to run at low tempera-tures. The auxiliary of choice was found to be an axiallychiral binaphthyl amino group.

The reactant imidates 115 were synthesized in two stepsstarting from the amides 114. Initially, the amides 114were treated with phosgene to form the intermediate imi-doyl chlorides, the subsequent addition of an allyl alcoholgave the corresponding ester 115 in high yield. Deproto-nation of the system with a strong base gave raise to a Z-enolate, which underwent the [3,3]-sigmatropic rear-rangement at 0 °C. The product amides 116 were formedas single diastereomers indicating complete internalasymmetric induction as well as the high directing abilityof the auxiliary. The stereochemical outcome could be ra-tionalized by the formation of a chair-like transition stateincorporating a lithium chelate including the methoxygroup of the auxiliary: such an arrangement should becharacterized by an efficient shielding of one face of theenolate by the �-hydrogen of the binaphthyl moiety forc-ing the allyl subunit to attack the less encumbered side.Detailed information is given in Table 8. The present

Scheme 31



method allowed the two new stereogenic centers in 116 tobe established with high selectivity. The removal of theauxiliary succeeded via the iodo lactonization/reductivecleavage developed by the same group.35 The �,�-unsatur-ated carboxylic acid 117 was obtained without anyepimerization of the �-carbon center, the auxiliary 118was recovered almost quantitatively (Table 8,Scheme 33).

A second strategy to enhance the driving force of theClaisen rearrangements involved thioamides. Thioamidesunderwent facile S-allylations to form the correspondingthioamide acetals and the sulfur was known to be a betterleaving group compared to the oxygen, on breaking theC–S bond during the rearrangement. Again, the fixing ofone favored transition state conformation was crucial fora selective reaction. Thus, preliminary results publishedby Welch suffered from moderate de of about 65%.36

The bicyclic rigid array introduced by Meyers allowed theauxiliary controlled generation even of quaternary stereo-genic centers.37 A �-ketocarboxylic ester and a 1,2 amino

Table 7 Auxiliary-Controlled Zwitterionic Aza-Claisen Rearrangements of Allylamines

Entry R1 R2 R3 T (°C) Yield (%) Ratio 103/104

130a H 3,4-Methylenedioxyphenyl Cl 0 36a 1:1

230a CO2Me 3,4-Methylenedioxyphenyl Cl 0 69 2:1

330a CO2tBu 3,4-Methylenedioxyphenyl Cl 0 50a >95:5

430a CH2OTBS 3,4-Methylenedioxyphenyl Cl 0 72 >95:5

530a CO2Me 3,4-Methylenedioxyphenyl N3 0 77 4:1

630a CO2Me 4-Methoxyphenyl N3 0 13a 1:1

730a CH2OTBS 3,4-Methylenedioxyphenyl N3 0 87 >95:5

830a CH2OTBS 4-Methoxyphenyl N3 0 57 >95:5

930a CH2OTBS Ph N3 0 91 >95:5

1030b CO2Me H NPht 0 74 1:1

1130b CO2Me H N3 20 77 4:1

1230b CO2Me H N3 0 77 7:1

1330b CO2Me H N3 –20 77 9.5:1

1430b CO2Me H (EtO)2CHCH2NBOC 20 73 15:1

1530b CH2OTBS H N3 0 77 >95:5

1630b CH2OTBS H HNBOC 0 6 –

1730b CH2OTBS H (EtO)2CHCH2NBn 0 0 –

1830b CH2OTBS H (EtO)2CHCH2NBOC 0 51b >95:5

1930b CH2OTBS H (EtO)2CHCH2NCbz 0 75 >95:5

2030b CH2OBn H (EtO)2CHCH2NBOC 0 47b >95:5

a Not optimized.b Yield including four further steps.

Table 8 Auxiliary-Controlled Imidate Enolate Rarrangementsa

Entry R1 R2 R3 X Yield (%)

dr

134a Me H Me H 78 97:3

234a Me H Et H 60 97:3

334a Et H Me H 59 97:3

434a Me Me Me H 56 96:4

534a Me Me Et H 45 96:4

634a Et Me Me H 47 >91:9

734b Me H Me Me 54 88:12

834b Me H Me Me 48 >98:2

a Rearrangement at –10 °C.



alcohol derivative were condensed to give a Meyers chiralbicyclic lactam 119. To date, a set of such chiral bicycliclactams has been used in thio-Claisen rearrangements(119a–d). Likewise, the �-position of the lactam 119could be alkylated using standard operations, the carbonylwas converted to a thiocarbonyl group by treatment witha Belleau-type reagent to give 120. The deprotonation ofthe thiolactam 120 and the subsequent allylation affordedthe S-allyl thioamide acetal 121. Upon heating to about30–140 °C (solvent depending) in a carefully chosen sol-vent, the system underwent Claisen rearrangement to gen-erate the �,�-unsaturated thioamide 122.37a Generally, theexo-diastereomer was the most favored product, howevera trisubstituted olefin with at least one bulky substituent atthe endo-position was required, otherwise, disappointingdiastereoselectivities were reported.37c Surprisingly, theClaisen rearrangement of sterically encumbered systems121 did not go to completion. In contrast, the process wasfound to be reversible, enforcing the separation of theproduct 122 and remaining reactant 121 after one rear-rangement cycle.38 However, the starting material 121was subjected to the reaction conditions for a second cycleenhancing the isolated yield of the desired product 122.The removal of the auxiliary was carried out upon treat-ment of the thioamide 122 with Meerweins salt and Red-Al to give rise to the corresponding aldeyde 123. The so-formed defined complex substances 123 bearing chiralquaternary centers were used for the investigating scopeand limitations of further C–C bond forming reactionssuch as olefin metatheses. Further manipulation of 123 ledto the natural product (–)-trichodiene 124 (Table 9,Scheme 34).

Pyrrolidine derivatives serve as suitable substitutents inposition Y as long as a C2 symmetric framework was em-ployed. A preliminary result published by Martensshowed, that the rearrangement of bicyclic pyrrolidinecarboxylic ester 125 (R1 � H) delivered a high diastereo-selectivity, the corresponding hydrogen derivative 125

(R1 = H) a comparatively low diastereoselectivity for theconstruction of 12639 (Scheme 35).

Scheme 35

Rawal investigated the stereodirecting properties of theC2 symmetric 2,5-diphenyl pyrrolidine 127.40 After con-version into the thioamide in two steps, the deprotonation/S-allylation sequence produced the crucial Z-thioamideacetals 128. The subsequent rearrangement at ambienttemperature or reflux conditions gave the �,�-unsaturatedthioamides 129 in high yield and excellent diastereoselec-tivity. The stereochemical outcome could be rationalizedby the formation of a chair-like transition state, arrangingthe allyl moiety anti with respect to the endo-positionedaryl group (c-�). The C2 symmetry of the auxiliary pre-cluded the adoption of different conformations causingmixtures of diastereomers. The method enabled the gener-ation of one and two novel adjacent stereogenic centerswith a high simple and a high auxiliary controlled dia-stereoselectivity in 129. Finally, the removal of the pyrro-lidine was effected by means of the Meyers sequence(activation–reduction), as mentioned above, providing al-cohol 130. The scope and limitations of this method arestill far from being exhausted. Detailed information is giv-en in Table 10 (Scheme 36).

Scheme 34

Scheme 33



N-Aryl-N-alkyl substituted thioamides 131 have been in-troduced by Metzner investigating nonoptically activebut, never the less diastereoselective thio-Claisen rear-rangements.41 A careful analysis of a set of such com-pounds gave a defined nearly perpendicular arrangementof the aryl group with respect to the amide function andthe preferential occurrence of the so termed E-amide 131.The attachment of an o-substituted aniline derivative in-duced a chiral axis along the N–C(S) bond. Since the fa-vored conformation was found to be stable upon heatingup to 140 °C, the chiral properties of the chiral axis wasexpected to serve as a diastereoselective inducing group ina Claisen rearrangement. After the initial deprotonation of131 with LDA at low temperatures the Z-enolate formed,which underwent S-allylation upon treatment with allylhalides to give the corresponding intermediate N,S-keteneacetals 132. A slow allylation at ambient temperature re-sulted in the mixture being heated at reflux. This inducedan immediate [3,3]-sigmatropic rearrangement giving riseto the �,�-unsaturated amides 133 in high yield. The dia-

Table 9 Meyers Thio Ketene Aminal Claisen Rearrangements

Entry R1 R2 R3’ R3 Solvent T (°C) Yield (%) dr

1a37d Me Me H H THF 25 71 3:1

2a37d Me H H Me THF 25 79 91:9

3a37d Me H H Ph Xylene 140 48 >99:1

4a37d Me H Me Me Xylene 140 68 >99:1

5a37a Me -(CH2)3- Me DMF 90 60a >99:1

6b37b allyl H Me H THF 65 72 9:1

7b37c allyl H CH2OTPS H THF 65 96 11:1

8b37c allyl H H CH2OTPS THF 65 57 10:1

9b37c allyl H CH2OPMB H THF 65 84 20:1

10b37c allyl H H CH2OPMB THF 65 85 14:3

11c37c TPSO(CH2)3-

H Me H THF 65 79 3:1

12c37c Me H H H THF 25 74 1.7:1

13c37c Me H Me H THF 65 70 1.8:1

14c37c Me H Me Me DMF 90 35 15:1

15d37c Me H H H THF 25 62 2:1

16d37c Me H Me H THF 65 40 1:1

17b37c TPSO(CH2)3-

H Me H THF 65 79 9:1

18b37c Me H H H THF 0 93 2:1

19b37c Me H Ph H PhMe 110 52 >95:5

20b37c Me H Me Me PhMe 110 55 >95:5

a Two cycles, 60% conversion, reversible rearrangement.

Scheme 36



stereomeric ratio was found to be about 80:20 (E/Z), withan optimal result of about 86:14 (E/Z) achieved using the2,4-di-(t-butyl)-anilide (R2 = t-Bu). The stereochemicaloutcome was presumed to be a result of the reaction pass-ing through a chair-like transition state c-�. The allyl moi-ety should attack the sterically less shielded face of theketene double bond anti with respect to the bulky o-sub-stituent of the anilide. Consequentially, the major productcould be termed as the (racemic) 2S,aS-diastereomer 133(E). Further studies are in progress (Scheme 37).

Scheme 37

4.3 Auxiliary Attached to Position Z

The attachment of a chiral auxiliary to positon Z allowedfor the most extensive variation of enantiomerically puresubstituents. Hence, C, O, N, and S-bound auxiliarieshave been tested in the recent past. Generally, all variantsof the Claisen rearrangement should be usable because thecentral heteroatoms in positions X and Y are arbitary. TheIreland rearrangement characterized by mild reaction con-ditions seemed to be the method of choice to achieve high-ly diastereoselective conversions. Especially, thepotential to create chelate controlled reactions thus mini-mizing conformational mobility during the course of thereaction promised a maximum efficiency from a chiralauxiliary. Preliminary results, published by Kallmerten in1986 conducting Ireland-type rearrangements in the pres-ence of a chiral benzyl ether function, were found to pro-vide moderate diastereoselectivity.42

Kazmaier investigated the rearrangement of glycine allyl-ester enolates during the course of the synthesis of non-natural amino acid derivatives.43 The rearrangement of O-allyl glycine derivatives 134 led to C-allyl glycines with adefined configuration at the �- and �-centers, through anIreland-type rearrangement. The chiral information couldbe introduced by means of a nitrogen bound auxiliary.With the intention of generating (di- and oligo-)peptides,another chiral �-aminoacid served as the chiral auxiliaryin 134 enabling C–C bond formation onto a peptide back-bone. Initially, the O-allyl glycine derivative 134 wasdeprotonated by at least two equivalents of a strong Li-base at low temperatures. After the addition of a chelatingLewis acidic metal salt, the reaction mixture was allowedto warm to room temperature. The [3,3]-sigmatropic rear-rangement led to the corresponding carboxylic acid,which was immediately converted into the methyl ester

Table 10 Thio Ketene Aminal Claisen Rearrangements Involving C2 Symmetric Auxiliaries

Entry R1 R2 R3 R3� T (°C) Yield (%) de

1 Me H H H 25 98 81

2 Me Me H H 25 100 77

3 Me H Me Me 65 89 >99

4 Me H -(CH2)5- 65 91 >98

5 Me H Me H 25 93 76

6 Me H H Me 65 92 >99

7 Me H Ph H 25 100 66

8 Me H H Ph 65 86 >99

9 Me H Et Me 65 81 >99

10 Me H Me Et 65 88 >99

11 Ph H Me Me 65 92 >98

12 OMe H Me Me 65 88 >98



135/136. One major advantage of such a procedure wasthe exclusive formation of E-enolate geometry during thedeprotonation/chelation step causing highly simple asym-metric induction. The crucial point was the directing qual-ity of the chiral auxiliary in combination with the Lewisacid. The use of ZnCl2 and a catalytic amount of a Pd(0)-complex resulted in moderate asymmetric induction andsome problems with the regiochemistry, namely rear-rangement of the substituted allyl system in 134. Optimaldiastereoselectivities were obtained when rearrangementof dipeptides 134 was carried out in the presence of Al(i-PrO)3 and Ti(i-PrO)4 but the chemical yields were low be-cause of the competing isomerization of the allyl ester 134into the corresponding vinyl derivative 137. Higher yieldsof 135 and 136 were obtained using MnCl2 during thecourse of the rearrangement of the crotyl ester (R1 = Me).However, the diastereoselectivity achieved was moderate.Some variation of the auxiliary amino acid and the protec-tive group gave no significant change in the externalasymmetric induction. Obviously, the N-terminal aminoacid of the dipeptide was not strong enough to effect a us-able auxiliary directed asymmetric induction. Consequen-tially, the peptide based Ireland reaction wasrecommended for the rearrangement of optically active al-lyl esters, any matched or mismatched effects during thecourse of such diastereoselective conversions could be al-most excluded (Scheme 38).

Scheme 38

An asymmetric variant of the Carroll rearrangement hasbeen investigated by Enders et al. employing successfullythe RAMP/SAMP auxiliary methodology.44 �-Ketoallyl-esters 138 were initially treated with SAMP and RAMP,respectively, to form the corresponding hydrazones 139 inhigh yield of >80%. The double deprotonation using LDAat low temperatures gave rise to the bis-anion, which un-derwent the Carroll rearrangement upon warming to roomtemperature. After reduction of the crude hydrazono es-ters with LiAlH4, the resulting alcohols 140 were obtainedin good yields and with high diastereoselectivities. The fi-

nal oxidative removal of the auxiliary gave the hydroxyketones 141 with excellent enantioselectivities(Scheme 39, Table 11). The appilicability of this se-quence was shown by conducting a short, enantio and dia-stereoselective total synthesis (142�143�144) of theantibiotic (–)-malyngolide 144 and related analogs via theRAMP route (Scheme 40).

Analyzing the stereochemical outcome of the rearrange-ment, the initial double deprotonation must form the eno-late with a high E-selectivity. Presuming a chelation of theLi cation by the enolate-O, the amide-N, and the oxygenof the methyl ether of the auxiliary, a tricyclic rigid arraycould be postulated forcing the allyl subunit to attack al-most exclusively the less shielded exo-face (parallel to the� hydrogen, Scheme 39). Consequentially, the definedenolate geometry caused the predominant syn-configura-tion of R2 and R3 (internal asymmetric induction) and theanti-orientation of the newly formed centers with respectto the directing auxiliary subunit (external asymmetric in-duction). Since a wide variety of substituents R1–R4 couldbe applied, the method was found to allow a variety of ter-tiary and quaternary centers to be generated with reliablehigh selectivity.

Additionally, the Carroll rearrangement could be run inthe presence of Lewis acids. In contrast to the bis-anionvariant, significantly lower diastereoselectivities werefound. The results were explained by the generation of anintermediate, containing a mixture of E- and Z-silylketeneacetals or by the formation of competing boat-like andchair-like transition states. However, the fixing (chelata-tion) of the chiral information during the course of the re-arrangement in such a way that a single preferredtransition state would have to be formed, failed. It is note-worthy, that the major diastereomer formed using theLewis acid promoted reaction exhibited the syn-orienta-tion of the newly formed centers with respect to the direct-ing auxiliary subunit (inverted external asymmetricinduction with respect to the bis-anion method, Table 11,entries15–21).

Scheme 39



Scheme 40

Chiral sulfoxide fragments have been described as highlyefficient stereodirecting groups that synthesize �-thio-amides and thioesters with a defined configuration via re-mote stereocontrol (chapter 2.1).12 The same sulfoxidehad been used as a chiral auxiliary for the rearrangementof (S)-crotyl (R = Me) and (S)-cinnamyl thioamide acetals(R = Ph) 145.

A deprotonation S-allylation allowed the exclusive gener-ation of the Z-thioketene amide acetals 146, the allyl moi-ety was assembled as an E/Z-mixture and a neat (E)-146and (Z)-146 system. Rearrangement of (Z)-146 at 66 °C,

resulted in the corresponding thioamide 147, which wasformed diastereoselectively with an acceptable yield. Sur-prisingly, the amide acetals (E)-146 (R = Ph) deliveredpreferentially the same diastereomer 147, the amide 148was generated as the minor compound. In contrast, (E)-146 (R = Me) gave favorably the expected diastereomer148. The stereochemical outcome of the Z-system rear-rangement was explained by formation of a defined tran-sition state b-Z as discussed above (Scheme 8). Thepreferred transition state of E-146 depended strongly onthe bulkiness of R: the adoption of a chair-like transitionstate c-E was destabilized by repulsive interaction bew-teen R and Cy. In the presence of R = Ph, a boat-like tran-sition state b-E seemed more likely to favor the formationof amide 147. Finally, the sulfoxide could be reduced withP4S10 to give the thioethers 149. The complete removal ofthe sulfoxide auxiliary was accomplished by SmI2 reduc-tion to generate the thioamides 150 with 76–80% ee. De-tailed information is given in Table 12 (Scheme 41).

Table 11 SAMP and RAMP as Chiral Auxiliaries in Carroll Rearrangements

Entry R1 R2 R3 R4 Yield (%) Yield (%) de 140 ee 141

1 -(CH2)3- n-Pr H 81 84 89 86

2 -(CH2)3- i-Pr H 73 89 96 94

3 -(CH2)3- i-Bu H 62 91 91 96

4 -(CH2)3- i-(CH2)4Me H 66 96 94 >98

5 -(CH2)3- c-Hex H 83 93 93 >96

6 -(CH2)4- n-Pr H 74 96 91 82

7 -(CH2)4- i-Pr H 69 95 89 >98

8 -(CH2)4- i-Bu H 59 92 88 94

9 -(CH2)4- i-(CH2)4Me H 64 98 88 98

10 -(CH2)4- c-Hex H 77 >99 88 98

11 -(CH2)3- -(CH2)4- 63 52 90 96

12 Me Me -(CH2)4- 75 57 >98 >96

13 -(CH2)3- n-Bu H 69 89 93 60

14 -(CH2)4- n-Bu H 59 90 90 74

15a -(CH2)3- n-Pr H 58 84 19 57

16a -(CH2)3- n-Bu H 76 89 20 57

17a -(CH2)3- i-Bu H 78 90 16 60

18a -(CH2)4- n-Bu H 59 86 5 67

19a -(CH2)4- i-Bu H 67 87 8 77

20a -(CH2)4- i-Pr H 70 90 25 71

21a -(CH2)4- i-(CH2)4Me H 66 87 41 76

a Lewis acid method via intermediate silyl ketene acetals. Major compound: syn-arrangement of auxiliary center and R2, R3.



Scheme 41

4.4 Miscellaneous

A special auxiliary controlled hetero-Claisen rearrange-ment has been developed by Langlois.45 Camphor oxazo-line N-oxides 152 were synthesized starting fromoptically active hydroxylamino isoborneol 151. Aftercondensation with suitable orthoesters, the intermediatenitrones 152 formed were easily O-acylated (153) bymeans of acid chlorides. Standing at room temperatureovernight effected the [3,3]-sigmatropic rearrangement,which gave the �-acyloxy oxazolines 154 in acceptableyield and up to 95% diastereoselectivity. Obviously, theauxiliary enforced the efficient exo-attack of the ester ox-ygen parallel to the hydrogen atoms at the ring junction.The product oxazolines 154 underwent a facile cleavageto 155 upon treatment with CbzCl. Finally, a two steptransesterification allowed the removal of the auxiliary togive the optically active �-hydroxy methyl ester 156(Scheme 42, Table 13).

Scheme 42

4-Diene tricarbonyl iron complexes could serve as chiralauxiliaries for Ireland–Claisen rearrangements.46 Uponcareful optimization of the reaction conditions, Roushfound, that treatment of acetates 157 and 158 (R = H) withKHMDS in THF/HMPA in the presence of TBSCl inter-mediate resulted in silyl ketene acetals, which underwentIreland rearrangement after warming up to room temper-ature. Always, a single diastereomer 159 (R = H) was ob-tained independently from the E- and Z-configured O allylester reactant 157/158. The nascent C–C bond was gener-ated diastereoselectively anti with respect to the iron tri-carbonyl moiety passing through a highly ordered chair-like transition state. The analogous reaction employingthe propionates 157 and 158 (R = Me) gave a high auxil-iary induced diastereoselectivity in 159 (R = Me), as ex-pected, but the simple diastereoselectivity (internalasymmetric induction) remained disappointingly low.Obviously, the ketene acetal formation delivered an E/Zmixture as the rearrangement passed through a chair-likeand a boat-like transition state. Finally, the 4-iron tricar-bonyl complex was removed by oxidative cleavage with

Table 12 Chiral Sulfoxide Fragments as Stereodirecting Chiral Auxiliaries

Entry R Ratio E/Z T (°C) Yield (%) Ratio 147/148

1 Me 86:14 20 43 15:85

2 Me 95:5 66 64 18:82

3 Me 0:100 66 53 100:0

4 Ph 100:0 20 30 70:30

5 Ph 100:0 66 53 90:10

6 Ph 96:4 66 45 100:0

Table 13 Camphor-Directed Diastereoselective Hetero-Claisen Re-arrangements

Entry R1 R2 Yield (%) de

1 Me Ph 64 92

2 Et Ph 46 >95

3 Et Me 41 92

4 Et OBn 38 32

5 Et Me 61 94

6 Bn Me 67 95

7 Ph Me 0 –

8 (CH2)2CO2Me Me 58 95



NMO to give the unprotected racemic butadienes withhigh yield. An enantioselective variant has still to be de-veloped (Scheme 43).

Scheme 43

5 Chiral Metal Complexes Directed Claisen Rearrangements

The classical auxiliary controlled [3,3]-sigmatropic rear-rangements were developed as a reliable method to intro-duce chiral information into a more complicatedrearrangement system. The major disadvantage of such astrategy is the requirement of two additional chemicaltransformations: the attachment and the removal of theauxiliary must always to be considered. The efficiency ofthese steps influences the usability of the whole sequence.

The careful analysis of the Claisen rearrangements point-ed out that the presence of a Lewis acid could effect a sig-nificant acceleration of such a reaction. Since acoordination of the Lewis acid metal salt at the core het-eroatoms of the [3,3]-sigmatropic system was a prerequi-site, the proximity of the Lewis acid ligands shouldinfluence the stereochemical outcome of the rearrange-ment. Hence, the use of chiral ligands should cause an ex-ternal chiral induction. In conclusion, a Lewis acidcarrying chiral ligands should serve as a chiral auxiliary.The separate attachment and the final removal of the aux-iliary could be avoided, the enantioselective Claisen rear-rangement arose as a more straight forward process.Generally, such a reaction should be run catalytically, butthe increased complexation ability of the product in com-parison to the reactants mostly inhibited the release of theLewis acid right after a rearrangement step until the aque-ous cleavage. The stereochemical properties of the prod-ucts had to be carefully analyzed using chiral GC, HPLC,and derivatization techniques.

First reports on Lewis acid-mediated chiral Claisen rear-rangements were published by Yamamoto.47,48 As an ex-tension of the trisaryloxy aluminum promoted conversionof allyl vinyl ethers 160 into the corresponding �,�-unsat-

urated aldehydes 161, chiral biaryl ligands were tested fortheir asymmetric induction ability. After treatment of theallyl vinyl ether 160 with the aluminum reagent at lowtemperatures for 10–40 hours, the chiral aldehydes 161were isolated in 63–97% yield with an ee of 63–92%. Theabsolute configuration of the products was determined viavarious methods (Scheme 44).

Scheme 44

Recently, Maruoka published the first results of a simpleClaisen rearrangement in the presence of a new chiralbis(organoaluminum) Lewis acid.49 The treatment of theallyl vinyl ether 160 with stoichiometric amounts of thebis aluminum reagent 162 and 163, respectively, indichloromethane at low temperatures for 4 hours gave thechiral aldehydes 161 in 50–92% yield with an ee of 51–85%. The absolute configuration of the products was de-termined via capillary GC (Scheme 45).

Scheme 45

Corey used a C2 symmetric chiral boron reagent 164 to ef-fect an almost complete enantioselectivity in Ireland–Claisen rearrangements as key steps in natural productsyntheses.50 The anti-inflammatory agent precursor (+)-fuscol 165 and the terpenoid (+)-�-elemene 166 were con-structed starting from the same precursor geranylester168.50b Upon treatment of ester 168 with equimolaramounts of bromo borane 164 in toluene in the presence



of an excess of triethylamine, the Ireland rearrangementgenerated the �,�-unsaturated acid along with a minor dia-stereomer in about 85% yield. A 3:1 mixture of diastereo-mers was separated after reduction to the correspondingprimary alcohols 169, the ee of both compounds was>99% (determined via chiral HPLC). The diastereoselec-tivity of the Ireland rearrangement was not optimized. Ob-viously, the internal asymmetric induction wasincomplete, this could have been the consequence of anunselective vinyl double bond formation or the formationof a competing boat-like transition state. Finally, severalfurther steps allowed the conversion of the key intermedi-ate into the desired target molecules 165 and 166.

The diastereoselectivity was found to be significantlyhigher when the lactone ring contraction was conductedby means of an enantioselective Ireland rearrangement.50a

The fifteen-membered lactone 170 was treated with thechiral diazaborolidine (L*)2BBr 164 in the presence ofBarton’s base.51 The ring contracted carbocycle 171 wasisolated in 86% yield with >97:3 diastereoselectivity and>98:2 enantioselectivity. Obviously, the medium sizedring framework enforced the generation of a defined eno-late geometry, which finally effected the high internalasymmetric induction. The so-obtained material served asa key compound in the synthesis of marine diterpenoiddolabellatrienone 167 (Scheme 46).

Scheme 46

Enantioselective aromatic Claisen rearrangements weredeveloped by Taguchi using the Corey diazaborolidine.52

Planning such a conversion additional complications hadto be considered. On one hand the reaction should be re-gioselective (ortho-selective), on the other hand so-calledabnormal Claisen rearrangements should be efficientlysuppressed. Various catechol monoallyl ethers fulfilledthese prerequisites. The formation of 3-allyl catechol de-rivatives 173 from 172 with complete regioselectivity andup to 99% ee using the p-tosylamide auxiliary 164 (2), the3,5-bis-(trifluoromethyl)-phenylsulfonamide 164 (1)gave more moderate results. The first step of the reactionwas thought to be the formation of the boron ester with thecatechol OH group effecting an intramolecular reaction.53

Since the Lewis acidity of the boron should be almostmaintained and a rigid five membered complex formed,the rearrangement should occur as the second step. Thestereochemical outcome could be rationalized by arrang-ing the phenylsulfonate next to the �-phenyl of the five-membered ring in such a manner, that the aryl substituentshielded one face of the catechol. Hence, the allyl groupattacked the opposite face, and the formation of a chair-like transition state led to the enantioselective generationof the new carbon center. The absolute configuration ofthe new stereogenic center in 173 was determined by theolefin geometry of the reactant 172 in the presence of thechiral auxiliary. The E-olefin caused one configuration,the Z-olefin caused the inverted absolute configuration ofthe nascent benzyl position of the product 173(Scheme 47).

Scheme 47

Considering the importance of fluorinated compounds inthe field of medicinal chemistry, the applicability of theenantioselective aromatic Claisen rearrangement has beenextended to aliphatic difluorovinyl allyl ethers 174.Again, the o-phenol function effected the formation of aboron ester leading to an intramolecular reaction. The so-formed six-membered complex should guarantee a highasymmetric induction but in the present case, the combi-nation of auxiliary 164, olefin geometry and substituent Rcaused an extended variation. However, the method al-lowed smooth generation of a set of optically active fluor-inated compounds 175. Until now, the removal of theanchor phenol group was very difficult (Scheme 48,Table 14).



Scheme 48

The Ireland variant is known to be one of the mildestClaisen rearrangements thus promising high stereoselec-tivities when generating new C–C bonds. Focusing on thereaction of �-hydroxy and �-amino acid allylesters the ini-tial deprotonation step led to the corresponding ester eno-late, whose geometry was directed towards the cis-arrangement of enolate O and �-heteroatom in the pres-ence of a chelating Lewis acid. Considering the fact thatthe Lewis acid offered at least two additional bindingsites, these positions could be occupied by a chiral biden-tate ligand. Hence, chiral information was placed next tothe sigmatropic rearrangement system optimizing thechance of inducing a high degree of asymmetric informa-tion into the nascent unsaturated carboxylic ester. TheKazmaier group investigated the scope and limitations ofsuch a strategy focusing on the syntheses of optically ac-tive non-natural amino acid derivatives 177.43a,54 Based onthe first findings in the field of rearrangements of O-allylglycine derivatives in the presence of metal salts,54h sever-al combinations of Lewis acids and chiral ligands havebeen tested for the chelate-Claisen rearrangement of N-tri-fluoroacetyl glycine crotylester.54g Generally, a chair-liketransition state was postulated, the defined enolate geom-etry led always to the anti-product as a result of the highinternal asymmetric induction. The variation of the chiralligand allowed the absolute configuration of the product

177 to be determined (Scheme 49). While the pair (–)-phenylglycinol/(–)-valinol failed to achieve any externalasymmetric induction, the pair (–)-ephedrine/(–)-pseudoephedrine resulted in the formation of both enantiomers,with only 10–30% ee. In contrast, the use of quinine/qui-nidine or chinchonidine/chinchonine was found to bemuch more effective: up to 86% ee in favor of the majorenantiomer 177 was achieved. A final re-crystallizationgave rise to the enantiopure product 177. The carefulchoice of the metal salt was mandatory in terms of a highenantioselectivity. Most Lewis acids (ZnCl2, BCl3,MgCl2, EtAlCl2, CaCl2) resulted in high chemical yieldsbut the ee was moderate. Best results were achieved con-ducting the reaction in the presence of Al(i-PrO)3 andMg(OEt)2. It was noteworthy, that the metal salt was ca-pable of accelerating the rearrangement in the absence ofthe chiral ligand, too. Thus, it was recommended to al-ways use an excess of the chiral auxiliary. Varying the N-protecting group, the initially employed trifluoro aceta-mides and the pentafluoro benzamides gave the best re-sults in terms of yield and enantioselectivity. The use ofCbz, BOC, Bz, Ac, and Ts were found to be less applica-ble. In summary, best results concerning yield and selec-tivity were achieved conducting the chelate-Ireland–Claisen rearrangement of 178 with LiHMDS as the base,TFA as protecting group, Al(i-PrO)3 as metal salt and thequinine/quinidine as the ligand, to generate one chiral C-allyl glycine 179 and, likewise, the corresponding anti-pode (Table 15). Finally, first attempts at generating ter-tiary amino acids 179 (R3 H, Table 15, entries 19–21resulted in a smooth reaction with a high diastereoselec-tivity. In contrast, the enantioselectivities were signifi-cantly decreased to about 10% in the acyclic example(entry 19) and to 33% for the rearrangement of the lactams(entries 20, 21) (Scheme 50).

Table 14 Chiral Diazaborolidine-Directed Claisen Rearrangements of Fluorinated Compounds

Entry Reactant Olefin R Yield (%) ee (%) Remarks

152b 1 E n-Pr 89 (88) 94 (88) (Borolidine 164)

252b 1 E n-Pr 97 93

352b 1 Z n-Pr 92 95 Enantiomer

452b 1 E n-Pr 80 86 Product cyclized

552b 1 E n-Pr 51 57 CO2H instead of OH

652a 2 E TMS 60 85

752a 2 E n-Pr 39 41

852a 2 Z n-Pr 55 55

952a 2 Z Et 58 43

1052a 2 Z c-C6H11 90 56

1152a 2 E (S)-5-(2,2-dimethyl-1,3-dioxolanyl) 47 67 de



Scheme 49

Suitable products have been tested in aminoacylase reac-tions.54d The asymmetric chelate Claisen rearrangementwas employed as a key step in a synthesis of isostatine,54e

and a non-natural 4-hydroxyproline derivative containingpeptide synthesis.54b,c

The so-called intermolecular Claisen rearrangement de-veloped by Bellus and Malherbe required the presence ofa Lewis acid to obtain satisfactory yields. The Lewis acidwas thought to activate the ketene fragment upon additionto the nucleopilic heteroatom of the allyl subunit and tostabilize the hypothetical zwitterionic intermediate, untilthe [3,3]-sigmatropic rearrangement gave rise to the prod-

Scheme 50

Table 15 Enantioselective Chelate Ireland Rearrangements

Entry R1 R2 R3 Yield (%) de (%) ee (%)

154f Me Me H 50 – 85

254f Et Me H 33 97 91

354f t-Bu Me H 23 98 93

454f Cy Me H 30 90 86

554f Me2C=C (CH2)2- Me H 51 98 85

654f Ph Me H 30 90 81

754f Naphthyl Me H 25 90 84

854f Naphthyl Me H 70 50 –

954f Bn Me H 16 95 76

1054f PhOCH2- Me H 12 95 81

1154f -(CH2)4- H 60 – 78

1254f -(CH2)5- H 70 – 86

1354f -(CH2)6- H 45 – 82

1454f -(CH2)7- H 33 – 79

1554b,d,e Me H H 90 (96, 79) 92 (99, 97) 87 (87, 88a)

1654b BnOCH2- H H 80 99 64

1754b H H H 98 – 77

1854b Ph H H 92 98 66

1954a Me H Me 86 (95) 85 (95) 9 (10b)

2054a Me H NCO (CH2)2- 58 75 28c

2154a Me H NCO (CH2)3- 98 95 33**

a Mg(OEt)2. b Pfp. c Replace N(tfa)/R3 by N–C(O)–(CH2)n-.



uct. Preferentially, zinc chloride (allyl sulfides and al-lylethers)13 and trimethyl aluminum (allyl amines)14 wereused. MacMillan55 investigated the intermolecular aza-Claisen rearrangements treating N-allyl morpholines 180with glycolic acid chlorides 181 in the presence of achiral-chelated Lewis acid. So termed ‘magnesium BOX’systems 183 and 184 gave the best results concerningyield (up to 95%)56 and chirality transfer (up to 97% ee)generating the amides 182. Usually, 2–3 equivalents ofthe chiral metal complex had to be employed to achievesatisfactory ee values. The glycolic acid frameworkseemed to play a crucial role in terms of asymmetric in-duction: a non-chelating �-oxygen substituent R3 pro-duced amides 182 with only moderate enantiomericexcess. In contrast, the use of benzyloxy acetyl chlorideallowed very high ee values to be achieved. It seemed rea-sonable, that this �-oxygen substituent enabled an effi-cient chelation of the chiral modified Lewis acid causingthe high level of external chirality transfer. The substitu-tion pattern of the allyl morpholine remained variable, theuse of E- and Z-olefins, led to the defined formation ofenantiomeric amides 182 with comparable asymmetric in-

duction. Scope and limitations have been outlined inTable 16. Until now, the catalytic enantioselective of theClaisen rearrangement involving sub-stoichiometricamounts of the chiral information has remained unknown(Scheme 51).

Scheme 51

Table 16 Chiral Magnesium BOX-Lewis Acids as Auxiliaries in the Rearrangement of N-Allyl Morpholines

Entry R1 R2 R2 R3 Equiv Yield (%) de (%) ee (%)

1 H H H Bn – 42 – –

2 H H H Bn 2.0 (1) 87 – 56

3 H H H Bn 2.0 (2) 88 – 83

4 H H H Bn 2.0 (3) 65 – 86

5 H H H Bn 0.5 (4) 81 – 42

6 H H H Bn 1.0 (4) 63 – 81

7 H H H Bn 2.0 (4) 80 – 91

8 H H H Ac 2.0 (4) 44 – 37

9 H H H TBS 2.0 (4) 67 – 38

10 H H H 4-ClPh 2.0 (4) 59 – 71

11 H H H Ph 2.0 (4) 48 – 78

12 H H H Me 2.0 (4) 28 – 80

13 Me H H Bn 3.0 (4) 78 – 91

14 Ph H H Bn 3.0 (4) 79 – 90

15 H CH2OBz H Bn 3.0 (4) 86 84 86

16 H 4-NO2Ph H Bn 3.0 (4) 82 98 97

17 H CO2Et H Bn 3.0 (4) 84 94 96

18 H Cl H Bn 3.0 (4) 95 96 91

19 H H Cl Bn 3.0 (4) 74 96 91

20 H CO2Et Me Bn 3.0 (4) 75 88 97



6 Catalytic Enantioselective Claisen Rear-rangements

Catalytic enantioselective Claisen rearrangements can beseen as the high end of a long period of extensive devel-opments of the [3,3]-sigmatropic reaction intending toachieve an efficient external asymmetric induction.57 Thefirst prerequisite is that the catalyst must act in at leastsub-stoichiometric amounts during the course of the pro-cess. A turn over number >1 required an efficient com-plexation directly to the reactant, a significant decrease ofthe activation energy of the sigmatropic reorganization ofthe bonds (to suppress non-catalyzed, racemic back-ground reactions and to enhance one diastereomorphic re-action path to achieve a high asymmetric induction), anda reliable decomplexation of the newly formed productenabling the catalyst to accelerate another rearrangement.As described in the previous chapter 5 it appeared ex-tremely difficult to fulfill all of these requirements. Espe-cially, as the more favored complexation of the productover the reactants turned out to be hard to circumvent.Hence, most rearrangements using chiral Lewis acid ar-rays were run stoichiometrically with respect to the acti-vating agent.

First catalytic processes including Claisen rearrangementshad been planned as tandem, domino, and consecutive re-actions: an initial enantioselectively catalyzed step gener-ated the allyl vinyl backbone for the consecutivesigmatropic rearrangement. Since the allyl subunit con-structed could have including a defined stereogenic cen-ter, the final rearrangement could profit from the well-known 1,3 chirality transfer.

First contributions were published by Nakai and Trost,who developed palladium-catalyzed allylation [3,3]-sig-matropic rearrangement reactions.58 The first step of thesequence was the formation of the allyl vinyl ether. Nakaireported an in situ enol ether exchange starting from allyl-alcohol 185 and naphthyl methyl ether 186. Vinylethersunderwent a palladium(II)/Brönsted acid-catalyzed allyl-ation. At room temperature palladium(II)-catalyzed animmediate [3,3]-sigmatropic rearrangement to form the�,�-unsaturated ketones 187. The stereochemical outcomecould be rationalized by the formation of a metal stabi-lized boat-like transition state generating the product anti-187. In the absence of any palladium, the well knownClaisen rearrangement (chair-like transition state) wasfound upon heating the intermediate to about 100 °C giv-ing syn-187.59 Employing an optically active allyl alcoholas reactant of the transetherification, the final Claisen re-arrangement delivered the ketone anti-187 via the wellknown 1,3 chirality transfer with 70% ee. Disappointing-ly, the 1,4-chirality transfer from 188 synthesizing 189was found to be very low (<2% ee) indicating an ineffi-cient internal asymmetric induction (Scheme 51).

The Trost group developed palladium-catalyzed enantio-selective allylations:60 phenol 190 and carbonate 191 werereacted in the presence of catalytic amounts of Pd(0) andthe ligand 192 to generate the allyl vinyl system 193 bear-

ing a defined stereogenic center. The Claisen rearrange-ment for the construction of 194 was carried out as anindependent second step profiting from a high degree of1,3-chirality transfer. Conducting aromatic Claisen rear-rangements, some loss of the chiral information was ob-served because of the facile breaking of the allyl O bondin 193 before creating the new C–C bond. The so formedintermediate cation tended to undergo racemization.61 Acareful optimization of the reaction conditions in combi-nation with the choice of a suitable Lewis acid system wasmandatory to obtain optimum results. Generally, the rear-rangements involving cyclic allyl ether subunits resultedin the formation of single stereoisomers, whereas the re-action involving the open chain allylether resulted a mix-ture of E- and Z-olefins (Scheme 53).

Scheme 53

3-Substituted 1,2-diketones 195 could serve as vinyl sub-units generating allyl vinyl ethers 198 and 201 via a palla-dium-catalyzed enantioselective allylation withcarbonates 196 and 200 in the presence of ligands 192 and197. The final Ho(FOD)3-catalyzed Claisen rearrange-ment gave the corresponding cyclopentenones 199 and202 with high yield and a high enantiomeric excess as aresult of efficient 1,3-chirality transfer. The method al-lowed ketones bearing an adjacent stereogenic chiral cen-ter with a defined configuration to be generated. Furthertransformation enabled highly substituted cyclic ketonesto be produced via this short sequence (Scheme 54).

Scheme 52



Scheme 54

Diazoketones 203 reacted with allylacohols 204 in thepresence of a rhodium(II)-catalyst.62 The reaction couldbe described as an addition of an alcohol to a carbenoidgenerating an intermediate Z-enol. The double bond ge-ometry arose from an intramolecular hydrogen shift fromthe attacking alcohol to the nascent enolate oxygen. Theso-formed allyl vinyl system underwent a final Claisen re-arrangement to give an �-alkoxy ketone 206.63 Due to theformation of a defined enol geometry, the use of an opti-cally active allyl alcohol 204 gave rise to the formation ofa chiral product ketone 206, too, via a chair-like transitionstate. Best yields and ee’s were obtained by reacting dou-bled stabilized �-diazo �-ketoesters 203, significantamounts of the ketone 205 were found, when the substitu-tion pattern of the allyl moiety effected a severe decelera-tion of the Claisen rearrangement. Monostabilized �-diazo ketones 203 and 208 (replacement of the CO2Meagainst other substituents as aryl, alkyl) underwent allylalcohol insertion Claisen rearrangement processes undersimilar conditions to allow the synthesis of a variety ofuseful substrates. One of these compounds was used as akey intermediate in a total synthesis of (+)-latifolic acid207. Additionally, propargyl alcohols 209 were testedconcerning their applicability in the insertion rearrange-ment sequence to synthesize chiral allenes 210 and 211.However, the reaction depended strongly on the condi-tions applied, competition of [2,3]- and [3,3]-sigmatropicrearrangement complicated the reaction concerning thestereochemical outcome (Scheme 55).

Recently, a reduction-Claisen rearrangement tandem pro-cess was published.64 Until now, no enantioselective vari-ant has been described, but the method exhibits somepotential in this regard. �,�-Unsaturated O-allyl esters 212underwent a chemoselective homogenous hydrogenation(hydrosilylation) in the presence of a Rh(II) catalyst. Theso formed intermediate silyl ketene acetal underwent a fi-nal Ireland rearrangement at room temperature. Since the

vinyl double bond of the ketene acetal was generated withE-geometry, the process produced the anti-product 213with high diastereoselectivity (Scheme 56).

Scheme 56

Exactly the opposite strategy of an initial aromatic Claisenrearrangement and a consecutive enantioselective car-boalumination was developed by Wipf as a new water-ac-celerated tandem process.65 Aryl vinyl ethers 214underwent aromatic trimethyl aluminum mediated [3,3]-sigmatropic rearrangements. In the presence of catalyticamounts of Erker’s chiral zirconocene derivative 215, theintermediate olefin 216 underwent an immediate enantio-selective methyl alumination. The so formed alkyl-metalspecies was finally oxidized (O2) to give the optically ac-tive carbinol 217. Stoichiometric amounts of water werefound to accelerate both, the rearrangement and the car-boalumination. A set of 3-aryl-2-methyl propanols 217was synthesized in 29–78% yield with 60–90% ee. Addi-tionally, the first ethylalumination was successfully car-ried out to give 3-aryl-2-ethyl propanol in 40% yield and92% ee (Scheme 57).

The first successful enantioselective catalytic Claisen re-arrangement for the construction of newly defined C–Cbonds was published by Hiersemann.66 Firstly, careful op-timization of a catalytic racemic analog was conductedconverting �-alkoxycarbonyl allylenol ethers 218 into thecorresponding unsaturated �-keto esters 219/220 (racem-ic) in the presence of a variety of Lewis acid systems.Since copper(II) triflate was found to be an effective cat-

Scheme 55



alyst, an asymmetric variant of the Claisen rearrangementwas tested with Cu(OTf)2/BOX systems (BOX = bis-ox-azoline). Upon treatment of suitable rearrangement sys-tems 218 with 0.5–10 mol% of Cu(II) BOX catalysts, theconversions gave the corresponding �-ketoesters 219/220with excellent chemoselectivity and a high catalyst de-rived enantioselectivity. The variation of the substituent X(t-Bu, Ph: attractive interactions between Ph and esterC=O) allowed the selective synthesis of ester 219 and 220.Furthermore, the competing 1,3-rearrangement productswere hardly detectable. The reaction conditions tolerateda variety of alkyl and alkenyl substituents. The stereo-chemical outcome could be explained by the formation ofa chair-like transition state arranging the Cu(II) as a che-late between allyl ether and side chain ester carbonyl ox-ygen. The C2 symmetric BOX ligand should force theallyl subunit to attack the face anti with respect to thenearest oxazoline-R causing the high external chiral in-duction as observed during the course of the process. Theinternal asymmetric induction was moderate due to rear-rangement of the E-allylethers. In contrast, the corre-sponding Z-systems led to remarkable syn-selectivityallowing the generation of two new neighboring stereo-genic centers by means of a catalyst controlled induction.Finally, the catalyst could be removed by a simple filtra-tion enabling an almost facile recycling. These findingsrepresented a very good basis for further developments ofenantioselectively-catalyzed Claisen rearrangements. De-tailed information is given in Table 17 (Scheme 58).

Starting from Z-neryl and E-geranyl enolether systems221, the enantioselective Claisen rearrangement generat-ed �-keto �,-unsaturated esters 222 as intermediates, in-corporating the highly efficient Cu(OTf)2/BOX systems.In the present case, the terminal olefin and the �-ketoestermoiety underwent a final Lewis acid-catalyzed carbonylene reaction to give the cyclohexane derivatives 223/224.Such a domino process was characterized by a high yield,an acceptable diastereoselectivity, and an excellent enan-tioselectivity overall (Scheme 59, Table 18).

Pioneering work in the field of enantioselective catalyticimidate rearrangements was reported by Overman.67

Since palladium(II) complexes were known as reliablecatalysts for O-allylimidate 225 and N-allylamide 228 re-

arrangements, such conversions were assayed in the pres-ence of chiral metal ligands 229–233. The reactionmechanism was a two-step process – initial complex for-mation of 226/235 through intramolecular amino pallada-tion of the double bond (oxidative addition) to give 227/236 and a final reductive elimination to generate theClaisen rearrangement type product amide 228. Extensivevariation of the catalysts and the reaction conditions im-proved the usability of chiral 1,2-diamines 229 preparedfrom L-(–)-proline. The activity of the complex was in-creased by exchanging one chloride counterion for themore easily removable tetrafluoroborate. Best resultswere obtained for the rearrangement of amidate 225 intoamide 228 in 69% yield with 55–60% ee by employing 5mol% of the palladium(II) catalyst. The elimination of theimidate especially in the presence of more basic catalystsand the [1,3]-rearrangement were considered as the majorcompeting processes.

Replacing the chiral 1,2-diamino ligand 229, by a ferroce-nyl methyl amino analog 230, the yield increased to 98%when the process was run at room temperature, but the eeobtained remained moderate (60 � 2%). The more easilyaccessible and more stable ferrocenyl imine derivatives

Scheme 57

Scheme 58

Scheme 59



231 gave a somewhat higher enantioselectivity of up to73% (counterion: trifluoro acetate), however, the yieldand the ee strongly depended on the preparation of the cat-alyst and tended to show some variability. Actually, thehigh end of catalytic enantioselective rearrangement of al-lyl imidates can be achieved using chiral oxazoline ferro-cenyl palladacycles 232 and 233 as activating metalcomplexes. Treatment of the standard E- and Z-imidates234 with 5 mol% of the catalyst in dichloromethane atroom temperature, provided S-amide 237 in 57% yieldand 79% ee (from E-234) and R-amide 237 in 67% yieldand 91% ee (from Z-234). Varying the aryl substituent aswell as the imidate substitution pattern, resulted in ee val-ues of up to 96%. Always, the Z-allylimidates gave the

Table 17 Copper BOX Catalysts in Enantioselective Claisen Rearrangements

Entry RZ RE R�(Z) R�(E) Mol% cat. (X)

Config. Yield (%) Syn/Anti ee (%) Config.3/4

1 Me H Me Me 5 (Ph) (S,S) 100 – 82 R/-

2 Me H Me Me 5 (Ph) (R,R) 100 – 82 S/-

3 H Me Me Me 5 (Ph) (S,S) 99 – 82 S/-

4 Me H Me Me 10 (t-Bu) (S,S) 47 – 88 S/-

5 Me H Me Me 10 (t-Bu) (S,S) 99 – 88 S/-

6 Et H Me Me 5 (Ph) (S,S) 99 – 84 R/-

7 i-Pr H Me Me 5 (Ph) (S,S) 98 – 78 R/-

8 i-Propenyl H Me Me 5 (Ph) (S,S) 100 – 86 R/-

9 Bn H Me Me 5 (Ph) (S,S) 99 – 76 R/-

10 Bn H Me Me 10 (t-Bu) (S,S) 7 – – –

11 Bn H Me Me 10 (t-Bu) (S,S) 94 – 84 S/-

12 Bn H Me Me 0.5 (Ph) (R,R) 100 – 76 S/-

13 Me H Me Me 5 (Ph) (S,S) 99 – 80 R/-

14 H Me H Pr 5 (Ph) (S,S) 100 86:14 82 S/R

15 Me H H Pr 5 (Ph) (S,S) 100 28:72 72 R/R

16 H Me Pr H 5 (Ph) (S,S) 99 3:97 88 S/S

17 Me H Pr H 5 (Ph) (S,S) 98 99:1 84 R/S

18 Bn H Pr H 5 (Ph) (S,S) 100 95:5 82 R/S

19 i-Propenyl H Pr H 5 (Ph) (S,S) 98 92:8 86 R/S

20 Me H Pr H 5 (Ph) (S,S) 100 96:4 76 R/S

21 H H H Ra 10 (Ph) (S,S) 98 89:11 99

22 H H H Ra 10 (Ph) (R,R) 92 89:11 99

23 H H Ra H 10 (Ph) (S,S) 93 19:81 99

24 H H Ra H 10 (Ph) (R,R) 93 20:80 99

a R = 4-Methyl-3-pentenyl.

Table 18 Enantioselectively Catalyzed Claisen Rearrangement Car-bonyl Ene Tandem Reactions

Entry 221 Cat. Config. Yield (%) Ratio 223/224 ee (%)

1 E (S,S) 98 89:11 99

2 E (R,R) 92 89:11 99 (ent)

3 Z (S,S) 93 19:81 99

4 Z (R,R) 93 20:80 99 (ent)



better results in comparison to their E-analogs, E- and Z-reactants 234 caused the formation of the opposite enanti-omeric products 237 using the same catalyst system.Though the removal of the N-aryl moiety remained stillsomewhat problematic, the process was applied to thesynthesis of a variety of optically active allyl amines. De-tailed information is given in Table 19 (Schemes 60, 61).

Recently, Kang introduced two new palladacycles 238and 239, which have been prepared from chiral ferroce-nyl-bis oxazolines in several steps.68 Rearrangement of al-lyl imidates 234 led to the corresponding amides 237,yield and ee of these conversions was found to be compa-rable or somewhat higher to that reported by the Overmangroup (Scheme 61, Table 20).

The promising preliminary results of the Overman groupstimulated further efforts concerning the asymmetric imi-date rearrangements focussing on ligand tuning.69

Leung synthesized three palladacycles 242–244, basingon chiral phenylethyl amine, which were tested on the re-arrangement of O-crotyl imidates 240 to amide 241. Ben-zyl 242 and naphthyl derivatives 243 gave disappointingenantioselectivities (4–13% ee). In contrast, the phenan-threne substituted material 244 allowed the correspondingamide 241 to be produced in up to 79% ee, when the rear-

rangement was carried out in benzene in the presence of10 mol% of the catalyst (Scheme 62).

Table 19 Enantioselective Palladacycles in Overman Imidate Rearrangements (1)a

Entry Imidate R1 R2 R3 Yield (%) ee (%) (config.)

1 E Ph 4-F3C-C6H4 n-Pr 57 79 (S)

2 Z Ph 4-F3C-C6H4 n-Pr 67 91 (R)

3 E Ph 4-MeO-C6H4 n-Pr 93 83 (S)

4 Z Ph 4-MeO-C6H4 n-Pr 83 91 (R)

5 Z Ph 4-MeO-C6H4 Me 96 75 (R)

6 Z Ph 4-MeO-C6H4 Bn 85 88 (R)

7 E Ph 4-MeO-C6H4 i-Bu 97 84 (S)

8 Z Ph 4-MeO-C6H4 i-Bu 89 96 (R)

9 Z o-Tol 4-MeO-C6H4 i-Bu 97 96 (R)

10 Z Ph 4-MeO-C6H4 H11C6CH2- 87 90 (R)

11 Z Ph 4-MeO-C6H4 neopentyl 35 92 (R)

12 Z Ph 4-MeO-C6H4 neopentyl 77 87 (R)

13 Z Ph 4-MeO-C6H4 i-Pr 59 86 (R)

14 E Ph 4-MeO-C6H4 Ph 59 63 (R)

15 Z Ph 4-MeO-C6H4 Ph 11 77 (S)

a Catalysts: 232 and 233.

Scheme 60



Uozumi and Hayashi tested a series of chiral oxazolinesubstituted ligands 246 in the palladium(II)-catalyzed re-arrangement of imidate 245. A diphenylphospinophenyloxazoline 246 was the most stereoselective species allow-ing chiral N-allylamides 247 to be obtained in 70% eestarting from the reactant 245 bearing a linear side chain(R = n-Pr) and up to 81% ee when the R group was iso-propyl. Consistent with the Overman results, basic cata-

lysts stimulated the competing elimination of the imidate248. A lower reaction temperature led to a slightly in-creased enantioselectivity (Scheme 63).

Scheme 63

Tridentate chiral ligands for palladium(II)-catalyzed imi-date rearrangements were introduced by Zhang. The bestresults were reported for the reaction of 249 in the pres-ence of 10% bisoxazoline palladium(II) complex 250 indichloromethane or dichloroethane generating amide 251.Extensive variation of the ligand as well as the reactionconditions led to lower yields, ee-values and to the forma-tion of side products (elimination, [1,3]-rearrangement)(Scheme 64).

Scheme 64

Optically active allyl thiols 254/255 could be synthesizedby means of a enantioselective catalytic thionester thiol-ester rearrangement using palladium(0) catalysts.70 Inanalogy to the imidate rearrangements chiral ligand sys-tems 192 (Scheme 47) effected an efficient external chiralinduction. Racemic O-allyl thiono carbamates 252 and253 were treated with 2.5–7.5 mol% of the catalyst systemto give the rearranged S-allyl carbamates 254/255 with up

Scheme 61

Table 20 Enantioselective Palladacycles in Overman Imidate Rear-rangements (2)a

Entry Imidate Catalyst Yield (%) ee (%) (con-fig.)

1 n-Pr (E) 238-1 30 49 (R)

2 n-Pr (E) 238-2 74 67 (R)

3 n-Pr (Z) 238-2 43 68 (S)

4 Ph (E) 238-2 69 40 (S)

5 n-Pr (E) 239-1 27 64 (R)

6 n-Pr (E) 239-2 83 87 (R)

7 n-Pr (Z) 239-2 73 82 (S)

8 n-Bu (E) 239-2 65 89 (R)

9 n-Bu (Z) 239-2 54 72 (S)

10 Ph (E) 239-2 63 67 (S)

11 n-Pr (E) 239-3 91 92 (R)

12 n-Pr (Z) 239-3 85 90 (S)

13 n-Bu (E) 239-3 74 95 (R)

14 n-Bu (Z) 239-3 70 86 (S)

15 Ph (E) 239-3 90 87 (S)

16 Me (E) 239-3 68 90 (R)

a R1 = Ph, R2 = 4-MeO-C6H4.

Scheme 62



to 93% yield and up to 92% ee. The reactions of a varietyof racemic cyclohexenol thionocaramates 253 (n = 1)were characterized by a somewhat higher yield and enan-tioselectivity, respectively, even in the presence of de-creased catalyst concentrations of 1.25–2.5%.Additionally, the rearrangement of the cycloheptenol de-rivative 253 (n = 2) proceeded in 94% yield and 92%ee.Details are outlined in Table 21. Since the carbamatefunction was known to be an easily removable protectinggroup, a variety of optically active allylthiols could beconstructed as usable chiral starting materials. The mech-anism of the reaction was explained as an initial formationof a symmetric palladium allyl cation complex. In thepresence of the chiral ligand the reorganization proceededby attack of the sulfide anion. The stereochemical out-come could be summarized as a catalyst-controlled de-symmetrization of a prochiral allylic cation forming thethio Claisen rearrangement type products 254/255. Acrossover experiment supported this postulated reactionpath: the rearrangement of a mixture of two differentthiono carbamates in the presence of the catalyst gave theexpected carbamates as well as the carbamates with ex-changed allyl moieties. Initial experiments improved theusability of the method in solid-phase reactions(Scheme 65).

Scheme 65

7 Asymmetric Cope Rearrangements

The extensive use of the Cope rearrangement suffers fromthe fact, that such a process is generally regarded as re-versible. This special character has always to be taken inaccount when planning a stereoselective conversion togenerate new stereogenic centers. Additional require-ments have to be considered to guarantee the unique senseof the process. The reaction can be directed by introducingan additional defined driving force: the loss of ring-strain,the ion stabilization in oxy- and aza-Cope reactions, andthe inclusion of the [3,3]-sigmatropic reaction as one stepin a domino process (such as aza-Cope–Mannich and al-dol-oxy-Cope and reverse)71 leading to a defined stableproduct.

Asymmetric variants of the Cope rearrangement have of-ten been conducted as one step in a cascade of consecutiveconversions. In most cases, the reactant right before the

rearrangement was characterized by at least one chiralcenter in the sigmatropic core system. Hence, the stereo-chemical outcome of the reaction was explained as the re-sult of the well-known [1,3]-chirality transfer originatingfrom the formation of a highly ordered (chair-like) transi-tion state. Consequentially, the asymmetric induction di-rected the formation of the reactant, the outcome of theCope rearrangement can be seen as an (indirect) after ef-fect. On the other hand, one crucial limitation should bementioned: analyzing the transition state in the absence ofsteric effects, little selectivity between the quasi-axial andquasi-equatorial positioned heteroatom anion (especiallyoxygen) was expected. This effect caused low levels ofstereoselectivity during the course of (oxy)-Cope rear-rangements. The aid of an additional stereodirecting sub-unit was recommended in such cases to achieve sufficientstereochemical results.72 Focussing the contents of this re-view strongly on asymmetric Cope processes, only a fewexamples remain to be considered. Hence, several tandemprocesses are included which incorporate the introductionof chirality and a Cope rearrangement in direct consecu-tive steps.

Table 21 Enantioselective Catalytic Thionester Thiolester Rear-rangement Using Palladium(0) Catalysts

Entry R R� Cat. (%)

Yield (%)

ee (%)

acyclic reactant 252

1a Me Me 2.5 92 91

2a Me Et 2.5 92 92

3a Me n-Pr 2.5 89 90

4a Me i-Pr 2.5 93 90

5a Me n-Bu 2.5 89 85

6a Me t-Bu 2.5 76 85

7a Et Me 7.5 92 91

8a Et i-Pr 7.5 86 86

9a Et t-Bu 7.5 91 64

acyclic reactant 253

10a – Me 1.25 94 97

11a – Et 1.25 96 95

12a – n-Pr 1.25 94 99

13a – i-Pr 1.25 92 92

14a – n-Bu 2.5 93 99

15a – t-Bu 1.25 92 97

16a – Bn 2.5 91 99

17b – Me 1.25 94 92

a n = 1.b n = 2.



7.1 Remote Stereocontrol in Cope Rearrange-ments

With the intention of achieving maximum asymmetric in-duction via remote stereocontrol, the chiral informationshould predominantly be placed in the neighborhood ofthe nascent chiral sigma bonds formed during the courseof the rearrangement. Always, the formation of a singledefined transition state conformation caused a highly se-lective reaction.73

Optically active strychnan- and aspidospermatan-type al-kaloids have been diastereoselectively synthesized byKuehne starting from an enantiopure tryptophan deriva-tive 256.74 The key sequence involved a cascade of a con-densation (256�a�b), a [3,3]-sigmatropic rearrange-ment (c�d) and a termination by a Mannich type cycliza-tion (e�f�257). The tryptophan stereogenic center di-rected the stereochemical outcome of the domino processby means of efficient remote control. The tetracyclicproduct was found as a single diastereomer 257 (variableR), respectively. Finally, the removal of the benzyl estergroup succeeded via hydrogenolytic cleavage, conversioninto the nitrile, elimination, and reduction of the iminiumsalt to give the enantiopure indole derivative 258.

The tetracyclic compound 258 served as a versatile opti-cally active key compound in the synthesis of (–)-20-epi-lochneridine and (–)-strychnine (Scheme 66).

The amino sugar 260 was synthesized starting from an N-galactosyl derivative 259.75 After an initial Lewis acid-mediated ring opening an iminium salt a formed whichunderwent an immediate aza-Cope rearrangement. Themost stable iminium salt b thus formed determined theunique sense of the process. The resulting chain elongatedsugar derivative 260 was obtained diastereoselectivelywith a high yield (99%) (Scheme 67).

Scheme 67

The synthesis of tryprostatin B involved an aza-Cope re-arrangement as one key step.76 After investigating the bestreaction conditions running test sequences in the racemicseries, the L-tryptophan derivative 261 was treated withBF3·OEt2. The product ester 262 was obtained in 61%yield without any racemization. The regiochemical out-come was formally rationalized as two consecutive [3,3]-and [3,5]-rearrangement steps.77 The product served as akey compound in a tryprostatine B synthesis describedearlier (Scheme 68).

Scheme 68

A tandem reaction of an initial Diels–Alder cycloadditionand a consecutive Cope rearrangement was published bySerrano.78 The manno and galacto -nitrocyclohexadienes263 and 266 underwent highly endo-selective Diels–Alder additions to cyclopentadiene 264. Continued heat-ing of the intermediates resulted in Cope rearrangementsto give the more stable tricyclic systems 265 and 267. Thesugar moiety could be removed by an oxidative cleavageto yield the corresponding aldehydes (Sc=CHO,Scheme 69).Scheme 66



Scheme 69

7.2 Auxiliary Control in Cope Rearrangements

By analogy to the strategy described for the Claisen rear-rangements, the auxiliary controlled [3,3]-sigmatropic-Cope reaction represented an almost classical approach tointroduce chiral information into a more complicated sys-tem. The major advantage is reliable control over thestereochemical outcome of the reaction: all products arediastereomers. However, the reversibility of the rear-rangement must be taken in account and the auxiliarystrategy requires two additional chemical transforma-tions. High yields and avoidance of stereochemical prob-lems are the prerequisite of each step. Furthermore, thesynthesis and the recycling of an auxiliary have to be tak-en in account. Overall, the advantages and disadvantagesmust be weighed up before deciding on an auxiliary strat-egy. Again, the unique sense of the reaction has to be care-fully planned: most Cope rearrangements have beenincorporated as one step in a tandem sequence.

An auxiliary directed aza-Cope rearrangement was de-scribed by Agami as a key step in the synthesis of (–)-al-lokainic acid 272.79 The R-alaninol derivative 268 wascondensed with glyoxal to give an intermediate N-allyliminium salt 269. The so induced aza-Cope rearrange-ment delivered an enolate 270, which then attacked thenewly formed iminium salt terminating the tandem pro-cess. The final Mannich type cyclization generated thepyrrolidine 271 ring bearing the correct configurations ofall stereogenic centers of the target 272 (Scheme 64).

An asymmetric menthone-monitored crotylation of alde-hydes was developed by Nokami.80 Upon treatment ofchiral menthone 274 with crotyl magnesium chloride 273,the Grignard adduct 275 was isolated in good yield froma mixture of diastereomers. This special crotyl donor 275was then reacted with 3-phenyl propanal (276)(R = PhCH2CH2) in the presence of a Lewis and a proticacid to give the homoallyl alcohol 280 in a good yield anda high ee. The reaction mechanism was rationalized as ini-tial formation of a hemi-acetal 277, after an acid catalyzeddehydration an oxonium ion 278 was generated, which re-arranged adopting a chair-like transition state in an oxo-nia-Cope type [3,3]-sigmatropic process.81 Finally, the

resulting more stable oxonium ion 279 was cleaved togive the menthone 274 and the optically active homoallylalcohol 280. Varying the side chains of the reactant alde-hyde 276, the scope and limitations of the process weretested. The reactions of benzaldehyde 276 (R = Ph) andsaturated aldeydes 276 gave good yields and excellentenantioselectivities. In contrast, �,�-unsaturated alde-hydes did not lead to the analogous alcohols 280(Table 22, entries 7, 8). However, initial efforts to createan asymmetric allylation involving the corresponding1-allyl menthol resulted in only moderate enantiomericexcess (Table 22, Scheme 71).

Scheme 71

The so called amino-Cope rearrangement was exploitedby the Allin group.82 The process could be described as acascade consisting of an initial [3,3]-sigmatropic reactionof an 3-amino 1,5-diene 282 to give an intermediateenamine 283, which was finally treated with an electro-phile to generate an �,-unsaturated aldehyde 284 (3,3).The second step made the whole process irreversible. Asa matter of principle, up to three consecutive asymmetriccenters could have been introduced with a high diastereo-selectivity and a high yield. While the thermal conversionof tertiary amines 281 (replace NH by NR) required hightemperatures of >180 °C, the corresponding secondaryamines 281 rearranged at room temperature after an initialdeprotonation with n-BuLi (anionic amino Cope rear-rangement).83 The reaction mechanism of the anionic

Scheme 70



variant seemed to be strongly dependent on the reactionconditions employed. Theoretical calculations gave a fa-vored two-step pathway for the rearrangement:84 initially,the anion 282 dissociated to give allyl anion 285 and an�,�-unsaturated imine 286, which recombined by meansof a Michael-type process to give the product 287. Thislatter dissociative mechanism was supported by the for-mation of equal amounts of the 3,3- and the 1,3-rearrange-ment products 284 in the reaction of diene 281. The 3,3/1,3-rearrangement product ratio formed depended on thesolvent system used, in a more polar system like THF andTHF–HMPA, the dissociation mechanism was favoreddelivering predominantly the 1,3-product 284 (1,3). Incontrast, in toluene and hexane, respectively, the 3,3-product 284 (3,3) was isolated as the major compound in-dicating a concerted pathway (Scheme 72).

Scheme 72

Focusing on asymmetric variants of the amino-Cope rear-rangements, the directing ability of bulky auxiliary aminesubstituents reacting chiral 3-amino 1,5-dienes 289 waschecked. After treatment of cinnamaldehyde 288 with anenantiopure 2-amino alcohol 289 an oxazolidine 290(equilibrium with 291) was formed which was immediate-ly allylated by means of allyl magnesium bromide to givethe 1,5-diene 292. The amino dienes 292 were obtained inhigh yields (60–78%) and high auxiliary derived dia-stereoselectivities of 82–97%. The final anionic amino-Cope rearrangement delivered the oxazolines 295 (via293 and 294) right after the work-up procedure. The aux-iliary amino alcohol could be removed by chromatogra-phy on silica gel to provide the desired aldehydes 296 in53–65% yield and up to 94% ee. Detailed information isoutlined in Table 23 (Scheme 73)

The �,-unsaturated aldehydes 296 obtained served asuseful precursors to synthesize optically active 2,5-disub-stituted tetrahydropyrans.

Scheme 73

The combination of a dienolate allylation and a consecu-tive Cope rearrangement gave rise to the formation of �,�-unsaturated �-chiral carboxyl compounds.85 In the firststep N-pentenoyl camphor sultams 297 and 298 weredeprotonated with a strong base and the so formed dieno-lates were subsequently treated with allyl bromide. The �-allyl �,�-unsaturated imides 299 and 300 were obtained

Table 22 Menthone-Directed Asymmetric Cope Rearrangements

Entry R Yield (%) ee (%)

1 Ph- 48 >99 (S)

2 BnO(CH2)5- 75 >99 (R)

3 PhCHCH3 64 >99 (S)

4 PhS(CH2)2- 78 >99 (S)

5 Et2CH- 71 >99 (S)

6 H2C=CH(CH2)8- 71 >99 (R)

7 Citronellal – –

8 H3C(CH2)4CH=CH- – –

9 PhCH2CH2- 71 >99 (R)

10 PhCH2CH2- 68 70 (R)a

a Replace Me of crotyl by H: allylation.

Table 23 Asymmetric Amino-Cope Rearrangements

Entry R Yield 292 (%)

de 292 (%)

Yield 296 (%)

ee 296 (%)

1 i-Pr 78 97 60 84

2 t-Bu 77 94 53 88

3 i-Bu 60 92 57 71

4 Ph 64 96 61 83

5 Bn 67 82 65 94



with a high auxiliary directed diastereoselectivity with re-spect to the newly formed stereogenic center, the �,�-dou-ble bond in 299 was preferentially Z-configured (Z/E 78:22, 88:12 after recrystallization). E-Derivativeswere selectively generated by converting the correspond-ing 298 into the allylated compound 300.86 The thermoly-sis of the 1,5-dienes, induced the Cope rearrangement.The unique sense of the reaction was guaranteed by con-structing the more stable �,�-unsaturated imides 301. Thestereochemical outcome could be explained by the forma-tion of a chair-like transition state, while the bulky auxil-iary containing substituent adopted the pseudo equatorialposition. The E-configured starting material 300 suppliedresulted in a single diastereomer (R)-301 in high yield. Incontrast, the diastereoselectivity upon rearrangement ofthe Z-olefin 299 gave rise to the formation of a 85:15 mix-ture of products (S)-301 and (R)-301. Obviously, the for-mation of the transition state including an axial positionedsubstituent caused lower selectivity. However, the materi-al so-obtained was used as a key compound in the synthe-sis of the side chain of zaragozic acid A (Scheme 74).

Scheme 74

In addition to the allylation-Cope rearrangement, Nakaiinvestigated an auxiliary directed aldol-silyloxy-Cope re-arrangement.87 Here, the deprotonated sultam imines 302and 303 were treated with croton aldehyde, to give the al-dol adducts 304 (OH) and 305 (OH), respectively with Eand Z double bonds in analogy to the allylations describedabove (chiral boron dienolate strategy). Subjecting thesematerials to thermal oxy-Cope rearrangement conditionsresulted in retro aldol processes predominating. Thus, thealdol adducts were converted into the corresponding silylethers 304 and 305 prior to the rearrangement. Upon heat-ing to about 210 °C the silyloxy-Cope rearrangement de-livered the corresponding �,�-unsaturated �,�-chiralimido aldehydes syn-306 and anti-306. The formation ofa chair-like transition state with minimal 1,3-diaxial re-pulsive interactions led to a high yield and an excellentdiastereoselectivity when the E-configured material 305reacted. In contrast, Z-304 delivered a somewhat loweryield as well as lower selectivity because of the formation

of a sterically more demanding transition state(Scheme 75).

Scheme 75

The auxiliary directed reaction of terminally unsubstitut-ed dienolates avoided any geometry problems with thedouble bond. Nakai as well as Black and Schneider suc-ceeded in generating diasteromerically pure oxazolidi-none 309 (A) and sultam imide derivatives 310 (B) via thealdol reaction with 307 and 308, respectively.88 The finalthermal oxy-Cope rearrangement enabled the synthesis of�,�-unsaturated �-chiral imides 311/312 in high yield andwith a high auxiliary induced diastereoselectivity. Again,any competing retro-aldol reactions could be suppressedprotecting the intermediate carbinols 309/310 as silylethers (Scheme 70).

Scheme 76

Paquette investigated the auxiliary directed 1,5 asymmet-ric induction when two equivalents of vinyl anions wereadded to squarate esters 313 synthesizing enantioenriched



bicyclo octanone derivatives 321.89 Generally, such con-secutive addition cascades with 314 and 315 gave rise tothe formation of 1,2-trans divinyl adducts. An electrocy-clic ring opening ring closure process and a final transan-nular addition gave the product enantiomers 321 in a 2:1ratio. An alternative pathway could occur via the interme-diate 1,2-cis-divinyl adducts 317 and 318: after additionof the dihydrofuran anion 314 to the squarate 313 the for-mation of the racemate 316 resulted. The consecutive ad-dition of the auxiliary derived anion 315 caused some syn-addition (Li-chelation effect of the ether oxygen). The so-formed cis-adducts 317 and 318 underwent a dianionicoxy-Cope rearrangement passing through a highly or-dered boat-like transition state to give 319 and 320, re-spectively. A final transannular ring closure delivered theenantioenriched products 321. The stereochemical out-come was carefully exploited by means of deuterium la-beling experiments. Depending on the auxiliary aminesubunit, up to 35% ee could be achieved via oxy-Cope andelectrocyclic reaction cascades, respectively(Scheme 77).

Scheme 77

8-Oxabicyclo[3.2.1]octene derivatives 324 served as use-ful intermediates for the total syntheses of a variety of nat-ural products such as nonactic acid, pyrrolizidinealkaloids, furane ethers, etc. An enantioselective access tothe core fragment was established as the Davies [3+4]-cy-cloaddition sequence.90 The cyclopropanation-Cope rear-rangement process could be directed either by means of achiral auxiliary or by a chiral catalyst to generate opticallyactive material. The auxiliary series started from vinyl di-

azo acetate 322 and furan 323. The choice of the auxiliaryXC [(S)-lactate or the (R)-pantolactonate] enabled the gen-eration of one bicyclooctene 324 and the enantiomer withrespect to the new stereogenic centers. The de values var-ied between 57% and 94%. The removal of the ester suc-ceeded by transesterification and reduction, respectively.Details are given in Table 24 (Scheme 78).

Scheme 78

7.3 Catalyst Control in Cope Rearrangements

Catalytic-enantioselective Cope rearrangements are stillfar from being exhausted. In analogy to the Claisen rear-rangements such external asymmetric induction requirescatalyst systems that act in at least sub-stoichiometricamounts during the course of the process.91 Consideringthe reversibility of Cope rearrangements, the situtation be-comes complicated since the catalyst might accelerate thereaction in both directions. Furthermore, a successfullycatalyzed-enantioselective step might be wasted by re-formation of the reactants and loss of all chiral informa-tion. Hence, the Cope rearrangement was usually em-ployed as one step in a cascade, to guarantee the uniquesense of the sequence. Until now, the chiral catalyst wasused to generate the rearrangement system, then, the Copereaction proceeded via the highly ordered transition statesallowing the generation of new centers by means of acomplete [1,3]-chirality transfer.

[3+4]-Cycloadditions represent an effective tool for thegeneration of carbocyclic and heterocyclic ring systems.Davies92 developed catalyst directed enantioselective se-quences, which coinsisted of an initial [2+1]-cycloaddi-tions, enabling the generation of optically active cis-1,2-divinyl cyclopropanes. A subsequent Cope rearrangementproceeded with an almost complete chirality transfer viahighly ordered boat-like transition states.93 Various lessconstrained seven-membered ring frameworks bearingdefined stereogenic centers were synthesized this way(Scheme 78).

As mentioned above (Scheme 79), the Davis cyclopropa-nation-Cope rearrangement process could be directed ei-ther by means of a chiral auxiliary or by a chiral catalystto generate optically active material.90 Intending to en-hance the optical purity of the bicycle 327, first tests wereconducted running the [3+4]-cycloaddition in the pres-ence of a chiral proline type catalyst {Rh2[(R)- and (S)-TBSP]4}. While the simple material 325 (XC = OMe)could be converted into the bicycle with 80% ee, the more



electron rich vinyl diazoacetate 325 (XC = OMe) gaveonly moderate selectivity. Upon treatment of the chiral di-azoesters 325 (XC � OMe) with furanes 326 in the pres-ence of the chiral catalyst, double stereoselection aspectscould be investigated. Unfortunately, no significant en-hancement of the diastereoselectivities could be achievedeven in the case of the matched combination. However,the isolated yield of 327 was increased up to 99%. Theformation of some side products such as a very labiletriene was completely suppressed (Table 25, Scheme 80).

Scheme 80

The syntheses of the higher homologues of tropanes couldbe achieved by means of a regio- and enantioselective

[3+4]-cycloaddition of vinyl diazo acetates 328 and pyri-dones 329 as well as dihydro pyridines 330. The auxiliarydirected conversions of simple vinyl diazo acetate 328[X = (S)-lactate, R = H] and N-methyl pyridone 329 gavea low yield and a low selectivity in the construction of331. Moderate yields and diastereoselectivities were ob-tained even using the matched combination of chiral cata-lyst [(R)-DOSP and (R)-,(S)-TSP] and auxiliary (X = S-lactate, R = H), respectively. Best results concerning theee were achieved involving the styryl diazo acetate(R = Ph) in the presence of a chiral catalyst, but the yieldremained disappointingly low (Table 26, entry 6). The useof the electron rich dihydropyridines 330 generating 332seemed to be more promising, but the regiochemistryproblem of the initial cyclopropanation had to be solved.Best results were obtained employing 4-substituted esters

Table 24 Diastereoselective Cyclopropanation-Cope Rearrangement Tandem Process

Entry XC R1 R2 R3 R4 Yield (%) de (%) Config. 324

1 S OTBS H H H 72 79

2 R OTBS H H H 82 94 ent

3 S OTBS Me H H 62 90

4 R OTBS Me H H 75 95 ent

5 S OTBS H Me H 81 75

6 R OTBS H Me H 91 83 ent

7 S OTBS Me Me H 91 84

8 R OTBS Me Me H 69 94 ent

9 S OTBS H COMe H 74 79

10 R OTBS H COMe H 65 94 ent

11 S OTBS Me COMe H 71 80

12 R OTBS H Me CO2Me 65 82 ent

13 S H H H H 63 57

Scheme 79 Cyclopropanation Cope rearrangement cascade

Table 25 Cyclopropanation-Cope Rearrangement Tandem Process in the Presence of Chiral Catalysts

Entry XC R1 L Yield (%)

de/ee (%)

1 OMe H (S)-TBSP 64 –/80

2 OMe OTBS (S)-TBSP 94 –/46

3 S H (S)-TBSP 51 68/

4 S H (R)-TBSP 44 –/–

5 S OTBS (S)-TBSP 99 53/–

6 S OTBS (R)-TBSP 97 80/–

7 R OTBS (S)-TBSP 83 20/–

8 R OTBS (R)-TBSP 67 70/–



328 (R � H, X = OMe) and a 5-functionalized dihydro py-ridine 330 in the presence of a chiral catalyst. Excellentregioselectivity was found using bulky chiral ligands,which directed the cyclopropanation to the double bondnext to the nitrogen. This effect was enhanced when thesubunit was placed in the 5-position of the dihydro pyri-dine 330. Some results are detailed in Table 26(Scheme 81).

Scheme 81

Intramolecular cyclopropanation-Cope rearrangementtandem processes led to annulated cycloheptadienes 335and 339 bearing up to three new stereogenic centers. Upontreatment of the all trans-diazoacetate (E)-333 with an op-tically active Rh(II) catalyst the corresponding carbocy-cles 335 (via 334) and 339 (via 338) were generated withexcellent diastereoselectivity and up to 50% ee. The abso-lute configuration of the ring junction was found to be de-pendant on the substitution pattern of the diene: themethyl compound (E)-333 (X = Me) delivered the (S)-335, the hydrogen analog (E)-333 (X = H) the R configu-ration in (R)-339. In contrast, a cis-configured diene moi-ety in (Z)-333 gave rise to the formation of the trans-1,2divinyl cyclopropane 336 unsuitable for a consecutiveCope rearrangement. However, the thermolysis inducedthe formation of the cycloheptadiene 339, too. Such anoutcome was explained by an epimerization prior to the fi-nal rearrangement. The cyclopropane underwent an initial

diradical ring opening (337) ring closure process to gener-ate the cis-system 338. Since one stereogenic center musthave been maintained during the course of the isomeriza-tion, the chiral information originating from the catalystdirected cyclopropanation was still present. Consequent-ly, the Cope rearrangement proceeded via the well knownboat-like transition state with complete [1,3]-chiralitytransfer and an ee up to 93% (Table 27, Scheme 82).

Scheme 82

The efficiency of the sequence was demonstrated in anenantioselective-catalyzed synthesis of the tremulaneskeleton 341. The three step cyclopropanation-epimeriza-tion-Cope rearrangement sequence provided the tricyclictarget molecule in 67% yield and 93% ee starting from

Table 26 Synthesis of Tropane Derivatives via Enantioselectively Catalyzed [3+4]-Cycloadditions

Entry R R� Diene X L Yield (%) de/ee (%)

1 H – 329 (S)-lactate OOct 33 40/–

2 H – 329 (S)-lactate 40 45/–

3 H – 329 (S)-lactate (R)-DOSP 32 60/–

4 Me – 329 (S)-lactate (S)-TPSP 78 51/–

5 H – 329 Me (S)-TPSP 17 –/10

6 Ph – 329 Me (R)-DOSP 33 –/60

7 H H 330 Me (R)-DOSP 32 –/50–60

8 H Me 330 Me (S)-TPSP 30 –/58

9 Me H 330 Me (S)-TPSP 48 –/65

10 Ph H 330 Me (S)-TPSP 68 –/82

11 Ph H 330 Me (R)-DOSP 63 –/80



(Z)-340. The corresponding E-ester (E)-340 gave 341with a moderate ee of 35% (Scheme 83).

Scheme 83

A variety of optically active cycloheptadienes 344 weresynthesized via the enantioselective-catalyzed cyclopro-panation-Cope rearrangement tandem process. With theintention of investigating the scope and limitations of thissequence, various combinations of acyclic and carbocy-clic vinyl diazo acetates 342 and a set of dienes 343 weresubjected to the enantioselective catalytic reaction condi-tions. Generally, the reactions proceeded with high regio-selectivity and a high catalyst-directed enantioselectivity.Details are summarized in Table 28 (Scheme 84).

Scheme 84

8 Summary

Since Claisen’s94 and Cope’s95 original reports on [3,3]-sigmatropic rearrangements, these reactions have gainedparticular importance in the field of preparative organicchemistry.

They are a powerful tool for constructing new C–C bondsof defined configuration, the development of a great num-ber of versions can be accommodated to a variety of syn-thetic requirements and applications.96 Even in the recentpast [3,3]-sigmatropic rearrangements have been used tosolve problems in total syntheses pointing to the reliabilityof these special transformations.97,98 Actually, the asym-metric variants of Claisen and Cope rearrangements aregaining an increasing interest. Hopefully, this review willnot only summarize the recent findings and synthetic ap-plications in this field but also have added some interest-ing perspectives, which provide a firm basis for furtherfruitful investigations.

Acknowledgment

I thank my co-workers and my students for their excellent collabo-ration. I thank the DFG the FCI and Schering AG for support of thisresearch.

References

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Table 27 Enantioselective Intramolecular Cyclopropanation-Cope Rearrangements

Entry 333 X R1 R2 yielda (%) eea (%)

1 E H H Me 74 24

2 E H H H 71 50

3 E H Me H 53 46

4 E Me H H 64 52b

5 Z H H Me 72 (74) 62 (24)

6 Z H H H 72 (71) 67 (50)

7 Z H Me H 44 (53) 67 (46)

a Stepwise synthesis (yield and ee via direct synthesis from 333). b Product 335.



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Table 28 Enantioselective Intermolecular Cyclopropanation-Cope Rearrangements

Entry R1 R2 R3 R4 R5 R6 R7 Yield (%) ee (%)

1 H Me H H Ph H H 87 98

2 H Ph H H Ph H H 83 98

3 H PhCH=CH H H Ph H H 84 93

4 H H2C=CH H H Ph H H 56 96

5 H H H H Ph H H 41 73

6 -(CH2)4- H H Ph H H 62 94

7 -(CH2)3- H H Ph H H 60 81

8 H Me -CH2- H H H 47 91

9 H Ph -CH2- H H H 77 93

10 H PhCH=CH -CH2- H H H 80 90

11 H H2C=CH -CH2- H H H 58 92

12 H H -CH2- H H H 70 63

13 Me H -CH2- H H H 74 62

14 OTBS H -CH2- H H H 97 74

15 H Ph H H OTBS H H 63 93

16 H Ph H H H H Cl 69 82

17 H Ph H H H Me Me 45 91

18 H PhCH=CH H Me Me H Me 87 97

19 -(CH2)4- -CH2- H H H 61 73

20 -(CH2)3- -CH2- H H H 66 74

21 H Ph H Me H H H 47 96

22 H PhCH=CH H Me H H H 62 98

23 H Ph H H Me H H 51 98

24 H PhCH=CH H H Me H H 82 95



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(18) A Johnson rearrangement involving such a system was found to be unselective: (a) Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. Chem Lett. 1985, 1925. (b) Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org. Chem. 1987, 52, 1201.

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(20) Overman, L. E. Angew. Chem., Int Ed. Engl. 1984, 23, 579; Angew. Chem. 1984, 96, 565.

(21) For the discussion of a stepwise reaction mechanism see chapter 6 and the literature cited therein.

(22) (a) Ovaa, H.; Codee, J. D. C.; Lastdrager, B.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1999, 40, 5063. (b) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Fukuda, Y.; Isobe, M. Tetrahedron 2001, 57, 3875. (c) Nishikawa, T.; Asai, M.; Isobe, M. J. Am. Chem. Soc. 2002, 124, 7847.

(23) (a) Boeckman, R. K. Jr.; Neeb, M. J.; Gaul, M. D. Tetrahedron Lett. 1995, 36, 803. (b) Boeckman, R. K. Jr.; del Rosario Rico Ferreira, M.; Mitchell, L. H.; Shao, P. J. Am. Chem. Soc. 2002, 124.

(24) Magnus, P.; Westwood, N. Tetrahedron Lett. 1999, 40, 4659.

(25) Fukuzaki, T.; Kobayashi, S.; Hibi, T.; Ikuma, Y.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877; further racemic examples of model compound rearrangements are given in this reference.

(26) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S. P. D.; Braddock, D. C.; Procopiou, P. A.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2000, 65, 3716.

(27) (a) Vourloumis, D.; Kim, K. D.; Petersen, J. L.; Magriotis, P. A. J. Org. Chem. 1996, 61, 4848. (b) For a preliminary communication see: Magriotis, P. A.; Kim, K. D. J. Am. Chem. Soc. 1993, 115, 2972.

(28) de la Pradilla, R. F.; Montero, C.; Tortosa, M. Org. Lett. 2002, 4, 2373.

(29) (a) Tsunoda, T.; Nishii, T.; Yoshizuka, M.; Yamasaki, C.; Suzuki, T.; Itô, S. Tetrahedron Lett. 2000, 41, 7667. (b) For preliminary publications see: Tsunoda, T.; Sakai, M.; Sasaki, O.; Sako, Y.; Hondo, Y. Tetrahedron Lett. 1992, 33, 1651. (c) Tsunoda, T.; Tatsuki, S.; Shiraishi, Y.; Akasaka, M.; Itô, S. Tetrahedron Lett. 1993, 34, 3297. (d) Tsunoda, T.; Tatsuki, S.; Kataoka, K.; Itô, S. Chem. Lett. 1994, 543. (e) Itô, S.; Tsunoda, T. Pure Appl. Chem. 1994, 66, 2071. (f) Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.; Yamamoto, H.; Itô, S. Tetrahedron Lett. 1996, 37, 2463.

(30) (a) Laabs, S.; Münch, W.; Bats, J.-W.; Nubbemeyer, U. Tetrahedron 2002, 58, 1317. (b) Zhang, N.; Nubbemeyer, U. Synthesis 2002, 242; for a preliminary result see ref. 14c.

(31) The Ireland-type rearrangements are characterized by metal enolates bearing chiral ligands. These reactions are discussed in chapter 5 (vide infra).

(32) (a) Mulder, J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383. (b) For a synthesis of alkynyl amides see: Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. A.; Hsung, R. P. Tetrahedron 2001, 57, 459.

(33) (a) Sibi auxiliary: Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163. (b) Evans asymmetric aldol reaction: Evans, D. A. Aldrichimica Acta 1982, 15, 23.

(34) (a) Hungerhoff, B.; Metz, P. Tetrahedron 1999, 55, 14941. (b) Hungerhoff, B.; Metz, P. J. Org. Chem. 1997, 62, 4442. (c) Hungerhoff, B.; Metz, P. GIT Fachz. Lab. 1996, 40, 690.

(35) Metz, P. Tetrahedron 1993, 49, 6367.(36) (a) Welch, J. T.; Eswarakrishnan, S. J. Am. Chem. Soc. 1987,

109, 6716. (b) Reddy, K. V.; Rajappa, S. Tetrahedron Lett. 1992, 33, 7957. (c) Jain, S.; Sinha, N.; Dikshit, D. K.; Anand, N. Tetrahedron Lett. 1995, 36, 8467.

(37) (a) Lemieux, R. M.; Meyers, A. I. J. Am. Chem. Soc. 1998, 120, 5453. (b) Lemieux, R. M.; Devine, P. M.; Mechelke, M. F.; Meyers, A. I. J. Org. Chem. 1999, 64, 3585. (c) Watson, D. J.; Lawrence, C. M.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 815. (d) For a preliminary publication see: Devine, P. M.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 2633. (e) For a palladium-catalyzed rearrangement (moderate stereoselectivity): Watson, D. J.; Devine, P. M.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 1363.

(38) The reversibility had been proven by subjecting the pure product to the reaction conditions resulting in the Claisen reactant and potentially some other diastereomers.

(39) Wilkens, J.; Wallbaum, S.; Saak, W.; Haase, D.; Pohl, S.; Patkar, L. N.; Dixit, A. N.; Chittari, P.; Rajappa, S.; Martens, J. Liebigs Ann. 1996, 927.

(40) He, S.; Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122, 190; additionally the commercially available C2-symmetric 2,5-bis-(methoxymethyl) pyrrolidine had been employed once resulting in a high yield and a high diastereoselectivity.

(41) Dantale, S.; Reboul, V.; Metzner, P.; Philouze, C. Chem.–Eur. J. 2002, 8, 632.

(42) (a) Kallmerten, J.; Gould, T. J. J. Org. Chem. 1986, 51, 1152. (b) For another chelate controlled racemic ester enolate Claisen rearrangement see: Krafft, M. E.; Dasse, O. A.; Jarrett, S.; Fievre, A. J. Org. Chem. 1995, 60, 5093.

(43) (a) Maier, S.; Kazmaier, U. Eur. J. Org. Chem. 2000, 1241. (b) Kazmaier, U. J. Org. Chem. 1994, 59, 6667.

(44) (a) Enders, D.; Knopp, M. Tetrahedron 1996, 52, 5805. (b) Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Liebigs Ann. 1996, 1095. (c) Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2278; Angew. Chem. 1995, 107, 2442.

(45) (a) Dalko, P. I.; Langlois, Y. Tetrahedron Lett. 1998, 39, 2107. (b) For a review concerning related rearrangements see: Kelly, T. R.; Arvanitis, A. Tetrahedron Lett. 1984, 25, 39.

(46) Roush, W. R.; Works, A. B. Tetrahedron Lett. 1997, 38, 351.(47) (a) Maruoka, K.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc.

1995, 117, 1165. (b) Racemic catalytic variant: Saito, S.; Shimada, K.; Yamamoto, H. Synlett 1996, 720. (c) For some early publications see: Maruoka, K.; Banno, H.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 7791. (d) Maruoka, K.; Yamamoto, H. Tetrahedron: Asymmetry 1991, 2, 647. (e) Maruoka, K.; Yamamoto, H. Synlett 1991, 793.



(48) For an early publication using a (IPC)2BOTf: Oh, T.; Wrobel, Z.; Devine, P. N. Synlett 1992, 81.

(49) Tayama, E.; Saito, A.; Ooi, T.; Maruoka, K. Tetrahedron 2002, 58, 8307.

(50) (a) Corey, E. J.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229. (b) Corey, E. J.; Roberts, B. E.; Dixon, B. R. J. Am. Chem. Soc. 1995, 117, 193.

(51) The use of Hünig’s base resulted in a disappointing yield of only 36%. Barton’s base: pentaisopropylguanidine.

(52) (a) Ito, H.; Sato, A.; Kobayashi, T.; Taguchi, T. J. Chem. Soc., Chem. Commun. 1998, 2441. (b) Ito, H.; Sato, A.; Taguchi, T. Tetrahedron Lett. 1997, 38, 4815.

(53) The boron ester formation was crucial for the Claisen rearrangement to proceed. In the absence of an o-OH group the reaction failed. The o-OH group could be replaced by a carboxylic acid function but such conversion resulted a lower yield and a decreased enantioselectivity. Additionally some p-product was isolated.

(54) (a) Kazmaier, U.; Mues, H.; Krebs, A. Chem.–Eur. J. 2002, 8, 1850. (b) Mues, H.; Kazmaier, U. Synthesis 2001, 487. (c) Mues, H.; Kazmaier, U. Synlett 2000, 1004. (d) Bakke, M.; Ohta, H.; Kazmaier, U.; Sugai, T. Synthesis 1999, 1671. (e) Krebs, A.; Kazmaier, U. Tetrahedron Lett. 1999, 40, 479. (f) Krebs, A.; Kazmaier, U. Tetrahedron Lett. 1996, 37, 7945. (g) Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 2012; Angew. Chem. 1995, 107, 2213. (h) Kazmaier, U.; Maier, S. J. Chem. Soc., Chem. Commun. 1995, 1991.

(55) Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 2911.

(56) However this special variant did obviously not suffer from any von Braun type degradation or from any [2+2]-cycloadditions as reported in previous publications and references cited therein).

(57) For potential catalysts see (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (b) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159.

(58) (a) Sugiura, M.; Nakai, T. Tetrahedron Lett. 1996, 37, 7991. (b) Sugiura, M.; Yanagisawa, M.; Nakai, T. Synlett 1995, 447.

(59) Reacting non-symmetric enol ethers the palladium-catalyzed version preferentially gave the less-substituted vinyl systems. The rearrangement passed through a boat-like transition state. In contrast the proton-catalyzed reaction gave the higher substituted vinylether and the thermal rearrangement (100 °C) passed through a chair-like transition state. Regio- and stereochemistry could be influenced by a careful choice of the reaction conditions. For the discussion of a two-step reaction mechanism see Overman amidate rearrangements.67

(60) (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000, 122, 3785. (b) Trost, B. M.; Toste, D. F. J. Am. Chem. Soc. 1998, 120, 815. (c) For a racemic version see: Gester, S.; Metz, P.; Zierau, O.; Vollmer, G. Tetrahedron 2001, 57, 1015. (d) For a potential racemization during aromatic Claisen rearrangements see: Bernard, A. M.; Cocco, M. T.; Onnis, V.; Piras, P. P. Synthesis 1997, 41.

(61) Generally such intermediate cations could suffer from so-called abnormal 1,3 Claisen rearrangements. A catalytic variant to generate polycyclic terpenoids has been investigated by: (a) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131. (b) For further 1,3 rearrangements (chirality transfer) see: Shiina, I.; Nagasue, H. Tetrahedron Lett. 2002, 43, 5837. (c) See also: Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Hagaa, K.; Uyeharaa, T. Tetrahedron Lett. 2002, 43, 3633.

(62) (a) Wood, J. L.; Moniz, G. A. Org. Lett. 1999, 1, 371. (b) Drutu, I.; Krygowski, E. S.; Wood, J. L. J. Org. Chem. 2001, 66, 7025. (c) For a direct allylation of diazoketones as a surrogate for catalyzed enantioselective Claisen rearrangements see: Davies, H. M. L.; Ren, P.; Jin, Q. Org. Lett. 2001, 3, 3587.

(63) The rhodium catalyst did not influence the Claisen rearrangement step.

(64) (a) Miller, S. P.; Morken, J. P. Org. Lett. 2002, 4, 2743. (b) For further tandem processes see: Diels–Alder/Claisen: Soldermann, N.; Velker, J.; Vallat, O.; Stoeckli-Evans, H.; Neier, R. Helv. Chim. Acta 2000, 83, 2266. (c) Frank, S. A.; Works, A. B.; Roush, W. R. Can. J. Chem. 2000, 78, 757.

(65) (a) Wipf, P.; Ribe, S. Org. Lett. 2001, 3, 1503. (b) The Claisen rearrangement is an ideal precursor for olefin converting consecutive processes such as metathesis dihydroxylations etc.

(66) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem. Int. Ed. 2001, 40, 4700; Angew. Chem. 2001, 113, 4835. (b) For catalyzed racemic rearrangements see: Hiersemann, M.; Abraham, L. Org. Lett. 2001, 3, 49. (c) Hiersemann, M. Synthesis 2000, 1279. (d) Kaden, S.; Hiersemann, M. Synlett 2002, 1999.

(67) (a) Calter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org. Chem. 1997, 62, 1449. (b) Kollis, T. K.; Overman, L. E. Tetrahedron Lett. 1997, 38, 8837. (c) Cohen, F.; Overman, L. E. Tetrahedron: Asymmetry 1998, 9, 3213. (d) Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 2933. (e) For the thermal and palladium-catalyzed racemic rearrangement see: Overman, L. E.; Zipp, G. G. J. Am. Chem. Soc. 1997, 62, 2288.

(68) Kang, J.; Yew, K. H.; Kim, T. H.; Choi, D. H. Tetrahedron Lett. 2002, 43, 9509.

(69) (a) Jiang, Y.; Lougmire, J. M.; Zhang, X. Tetrahedron Lett. 1999, 40, 1449. (b) Leung, P.-H.; Ng, K.-H.; Li, Y.; White, A. J. P.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1999, 2435. (c) Uozumi, Y.; Kato, K.; Hayashi, T. Tetrahedron: Asymmetry 1998, 9, 1065.

(70) Gais, H.-J.; Böhme, A. J. Org. Chem. 2002, 67, 1153.(71) For an aza-Cope–Mannich tandem process see: (a) Knight,

S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776. (b) For oxy-Cope-aldol tandem process see ref.1i

(72) Low stereoselectivities were observed in several anionic oxy-Cope rearrangements: Lee, Y.; Lee, Y. R.; Moon, O.; Kwon, O.; Shim, M. S.; Yun, J. S. J. Org. Chem. 1994, 59, 1444.

(73) For an example where a chiral chromium arene complex did not affect the stereochemical outcome of a Cope rearrangement see: (a) Mandal, S. K.; Sarkar, A. J. Chem. Soc., Perkin Trans. 1 2002, 669. (b) For an aza-Cope rearrangement via chromium carbene complexes see: Barluenga, J.; Tomas, M.; Ballesteros, A.; Santamaria, J.; Suarez-Sobrino, A. J. Org. Chem. 1997, 62, 9229.

(74) (a) Kuehne, M. E.; Xu, F. J. Org. Chem. 1997, 62, 7950. (b) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9427. (c) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9434.

(75) Deloisy, S.; Kunz, H. Tetrahedron Lett. 1998, 39, 791.(76) (a) Cardoso, A. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron

Lett. 2000, 41, 3611. (b) Depew, K. M.; Danishefsky, S. J.; Rosen, N.; Sepp-Lorenzino, L. J. Am. Chem. Soc. 1996, 118, 12463.

(77) The 3,5-rearrangement can be described as an iminium salt olefin addition and a subsequent fragmentation (cation stabilization). No new stereogenic center was constructed.

(78) Román, E.; Baños, M.; Higes, F. J.; Serrano, J. A. Tetrahedron: Asymmetry 1998, 9, 449.



(79) Agami, C.; Couty, F.; Puchot-Kadouri, C. Synlett 1998, 449.(80) (a) Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.;

Hussain, I.; Kataoka, K. J. Am. Chem. Soc. 2002, 123, 9168. (b) For preliminary publications see: Nokami, J.; Anthony, L.; Sumida, S. Chem.–Eur. J. 2000, 6, 2909; concept. (c) See also: Sumida, S.; Ohga, M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310. (d) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609. (e) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 3426. (f) For a recent publication (1,3 chirality transfer in 2-oxonia Cope rearrangements see: Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. Org. Lett. 2002, 4, 2389.

(81) The reversibility of the Cope rearrangement might cause some racemization – the avoiding of such a process was recommended. Alternatively a Prins cyclization could be discussed as the basic reaction mechanism. Cope rearrangements were found to be much faster than the Prins reaction. For the role of oxonia Cope rearrangements in Prins cyclizations see: (a) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815. (b) Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919.

(82) (a) Allin, S. M.; Baird, R. D.; Lins, R. J. Tetrahedron Lett. 2002, 43, 4195. (b) Allin, S. M.; Button, M. A. C.; Baird, R. D. Synlett 1998, 1117. (c) Allin, S. M.; Button, M. A. C. Tetrahedron Lett. 1998, 39, 3345–3348. (d) For preliminary publications see: Allin, S. M.; Button, M. A. C.; Shuttleworth, S. J. Synlett 1997, 725.

(83) n-BuLi was found to be the base of choice to induce the anionic amino Cope rearrangements. Experiments using alternative strong bases such as LDA and KHMDS failed.

(84) (a) Young Yoo, H.; Houk, K. N.; Lee, J. K.; Scialdone, M. A.; Meyers, A. I. J. Am. Chem. Soc. 1998, 120, 205. (b) Dobson, H. K.; LeBlanc, R.; Perrier, H.; Stephenson, C.; Welch, T. R.; Macdonald, D. Tetrahedron Lett. 1999, 40, 3119. (c) Allin, S. M.; Button, M. A. C. Tetrahedron Lett. 1999, 40, 3801.

(85) Tomooka, K.; Nagasawa, A.; Wei, S.-Y.; Nakai, T. Tetrahedron Lett. 1996, 37, 8899.

(86) In contrast to the Oppolzer sultams the corresponding Evans auxiliary gave only moderate chiral induction of about 50% de building-up the new stereogenic center.

(87) Tomooka, K.; Nagasawa, A.; Wei, S.-Y.; Nakai, T. Tetrahedron Lett. 1996, 37, 8995.

(88) (a) Schneider, C.; Rehfeuter, M. Tetrahedron Lett. 1998, 39, 9. (b) Black, W. C.; Giroux, A.; Greidanus, G. Tetrahedron Lett. 1996, 37, 4471.

(89) Paquette, L. A.; Tae, J. J. Org. Chem. 1998, 63, 2022.(90) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem.

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(93) For a mechanistic discussion concerning the stereochemical outcome of the asymmetric catalyzed cyclopropanation see the original references.

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