kinugasa reaction: an `ugly duckling' of β-lactam...

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Tetrahedron 70 (2014) 7817e7844

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Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Tetrahedron report number 1050

Kinugasa reaction: an ‘ugly duckling’ of b-lactam chemistry

Sebastian Stecko, Bart1omiej Furman, Marek Chmielewski *

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

a r t i c l e i n f o

Article history:Received 3 March 2014Available online 19 June 2014

Keywords:b-LactamsNitronesAlkynesCycloadditionsRearrangementsCascade reactions

* Corresponding author. E-mail addresses: [email protected] (M. Chmielewski).

http://dx.doi.org/10.1016/j.tet.2014.06.0240040-4020/� 2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78172. Kinugasa reaction: the basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7819

2.1. Catalysts and ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78192.2. Other modifications of Kinugasa reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78222.3. Mechanism of Kinugasa reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7823

3. Stereocontrol in Kinugasa reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78253.1. Cis-trans selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78253.2. Asymmetric Kinugasa reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7825

3.2.1. Diastereoselective Kinugasa reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78263.2.2. Enantioselective Kinugasa reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7832

4. Application of Kinugasa reaction in synthesis of bioactive compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78375. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7841

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7841References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7841Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7844

1. Introduction

b-Lactams play an essential role in medicine and consequentlyin pharmaceutical industry.1,2 The discovery of penicillins1a,3 andcephalosporins (Fig. 1)1aec,4,5 was undoubtedly a milestone in thehistory of modern medicine, which led to the improvement ofhealth and life expectancy of man since the middle of the 20thcentury. Following the discovery of their value as clinically useful

[email protected], marek.chmie-

drugs against bacterial infections,6 the past few decades havewitnessed a remarkable growth in the field of b-lactam chemistryand biology.2,7 As a result, a variety of structurally diverse groups ofb-lactams were developed as presented in Fig. 1.

Last decade revealed interesting non-antibacterial propertiesof b-lactams including cholesterol-lowering effects,8e12 antifun-gal,13 anticancer,14 antiviral,15 and antihyperglycemic activity.16

Also available are numerous reports on serine protease17e19

(elastase,20 thrombin,21 or tryptase) inhibition by certain b-lac-tams as well as discovery of 2-azetidinones’ antagonism of va-sopressin V1a receptor22 and inhibition of HIV-1 protease23 andb-lactamase.24

Delta:1_given nameDelta:1_surnameDelta:1_given namemailto:[email protected]:[email protected]:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.tet.2014.06.024&domain=pdfwww.sciencedirect.com/science/journal/00404020http://www.elsevier.com/locate/tethttp://dx.doi.org/10.1016/j.tet.2014.06.024http://dx.doi.org/10.1016/j.tet.2014.06.024http://dx.doi.org/10.1016/j.tet.2014.06.024

Fig. 1. Major classes of b-lactams.

S. Stecko et al. / Tetrahedron 70 (2014) 7817e78447818

In addition to their clinical use as antibacterial agents, b-lactamshave also been used as highly useful synthons in preparation of var-ious compounds of biological significance (e.g., side chain oftaxol).1d,1f

The effectiveness of b-lactams against bacterial infections isuncontested. The irresponsible and uncontrolled widespread use ofthese agents has resulted, however, in the advent of an ever-increasing number of antibiotic-resistant bacterial strains. Asa consequence, the need for b-lactams with greater potency andbroader spectrum of action has become increasingly apparent. Thesearch for novel, highly active b-lactam antibiotics, as well as moreeffective b-lactamase inhibitors has motivated academic and in-dustrial laboratories to design new functionalized b-lactam struc-tures. Therefore, considerable attention is given to elaboration andupdate of b-lactam syntheses, based on either new or already

Scheme 1. Main strategies for the s

established methodologies, or else on the modification of preex-isting groups attached to the 2-azetidinone ring.

As a result of the long-standing interest in b-lactams inchemistry and medicine, many methodologies of stereoselectiveconstruction of the four-membered b-lactam ring were de-veloped.1,25,26 The most popular classical methods are ketene-eimine cycloaddition, also known as the Staudingerreaction,1,4,16,27e31 ester or amide enolate-imine condensa-tions1,16,32 and [2þ2] cycloaddition of isocyanates to vinylethers (Scheme 1).33 The majority of these reactions relies onchiral auxiliaries or enantiomerically defined starting materialsas a way to control of the stereoselectivity of those reactions.Another important group of reactions involves spi-rocyclopropane isoxazolidine ring contraction,34 formation ofthe b-lactam ring via N-acylation of b-amino acids and N-

ynthesis of 2-azetidinone ring.

S. Stecko et al. / Tetrahedron 70 (2014) 7817e7844 7819

alkylation of amides or hydroxamic acids by a b-leavinggroup.1b,1c,1e,1g,16,35 Formation of C3eC4 bond by direct C-al-kylation is very rare.1,16,36

On the other hand, direct, catalytic, asymmetric approaches areattractive alternatives to the above-mentioned classical strategiesand provide a general route toward greater diversity of b-lactamstructures. Among them, rhodium-catalyzed carbonylation ofaziridines,37 rhodium-catalyzed intramolecular CeH insertion ofdiazoamides38 and ligand-catalyzed ester enolate-imine conden-sations are the most significant ones.39

Among the different synthetic routes for the construction of b-lactams, there also exists an interesting, direct method for theirpreparation that has been discovered almost 40 years ago.40,41 Ina brief communication Kinugasa and Hashimoto40 reported thatthe reaction of copper(I) phenylacetylide (1) with nitrones (2aed),performed in dry pyridine, furnished (after hydrolysis) cis- or trans-b-lactams (3aed) in relatively good yields (Scheme 2).

Scheme 2. Original work by Hashimoto and Kinugasa.40

The classical, copper-free cycloaddition of nitrones to terminalalkynes proceeds under thermal conditions and leads to regioiso-meric isoxazolines 4a,b (Scheme 3).42 The presence of Cu(I)changes the overall outcome of this process; the reaction takesplace at room temperature, leading to 2-azetidinone products 3instead of isoxazolines 4.

Scheme 3. Thermal non-catalyzed alkyneenitrone cycloaddition reaction.42

There are two main advantages of Kinugasa reaction asa method of preparation of b-lactam compounds: (a) its high atomeconomy and (b) accessibility and stability of starting materials.

Numerous terminal alkynes with diverse substituents are eithercommercially available or readily available from a variety of pre-cursors. Moreover, in comparison with other hydrocarbons, acety-lenes are highly predisposed toward transformation into usefulintermediates and products due to their intrinsic reactivity that canbe selectively manipulated by transition metals.43

The same features can be found in their Kinugasa reactionpartnersdnitrones, which have been widely used in organic syn-thesis because of their multiple reactivity. Additionally, mostnitrones are stable and easy to prepare and handle.42 As will beshown later, Kinugasa reaction is known to be tolerant to thepresence of a wide range of functional groups (e.g., alcohols,amines, halides, and esters), which widens the spectrum of itspotential applications.

Despite the attractiveness of Kinugasa reaction, it is surprisingthat after the first reports in the 1970s,40 almost three decades hadto pass before it received more attention and has been explored indetail. It is particularly curious since the investigation of the re-activity of copper(I) acetylides goes back to the second part of the19th century and Glaser reaction44 along with its many

modifications has probably been one of the most studied examplesof these transformations. 1,3-Dipolar cycloaddition reactions havealso been the subject of intensive research, most notably by Huis-gen,45 whose efforts led to the formulation of their general con-cepts. Nowadays, dipolar cycloadditions have found widespreadapplication in organic synthesis and have been the subject of manyreviews.42,46 During that time, the paths of copper acetylides and1,3-dipoles, particularly nitrones, crossed rarely.47e49 The discoveryof exceptional reactivity of copper acetylides toward organic azides(copper-catalyzed alkyneeazide cycloaddition, CuAAC) has proba-bly been the turning point that led to the renaissance of Kinugasareaction.50e53 Both reactions show similarities, therefore familiar-ity with the CuAAC reaction can be of use in understanding Kinu-gasa reaction to some extent.

In this review, we present a comprehensive survey of Kinugasareaction from its discovery up to the present time. We will discussthe current progress in the asymmetric variant of the reaction, itsscope and limitations, recent mechanistic studies and reports on itsapplications in the synthesis of bioactive b-lactam compounds.

2. Kinugasa reaction: the basics

2.1. Catalysts and ligands

In the pioneering communication of Kinugasa and Hashimoto,40

a reaction of nitrone with copper(I) acetylide was performed in thepresence of pyridine as the base and the solvent. Following thereports of Ding and Irwin47 and Shandu,48 the copper acetyliderequired for Kinugasa cascade is generated in situ by directdeprotonation of the terminal alkyne with stoichiometric or cata-lytic amount of a copper(I) source in the presence of a base, simi-larly to how it takes place in the CuAAC reaction.

The following copper(I) salts: iodide, bromide, chloride, or ac-etate are commonly used. Tertiary (e.g., Et3N, i-Pr2NEt, Cy2NMe)and secondary amines (e.g., Cy2NH or i-Bu2NH) are typically used asbases.54,55 An inorganic base (e.g., K2CO3) can also be used.49b Useof bulky amines usually directs the reaction toward the formationof kinetic cis-2-azetidinones.55e57 Reactions are typically carriedout in MeCN or DMF, since these solvents offer good solubility ofcopper acetylides. Tang and co-workers55 performed detailedstudies on all of these factors. Very recently, Feng et al.58 demon-strated that Kinugasa reaction can be performed efficiently underso-called ‘on water’ conditions.

As it was demonstrated in the case of CuAAC reaction, copper(II)salts and their coordination complexes are not competent for thealkyne activation. Therefore, prior reduction of the Cu(II) ion to anactive Cu(I) ion is required. Introduction of a reducing agent to thereaction mixture, most commonly sodium ascorbate, developed byFokin et al.50 for CuAAC process, is regarded as a convenient andpractical alternative to the oxygen-free conditions required whenCu(I) salts are used. The combination of ascorbate with copper(II)salts, such as readily available CuSO4$5H2O or Cu(OAc)2, has be-come the method of choice for preparative synthesis of 1,2,3-triazoles. The same strategy has been applied to Kinugasa re-action by Basak et al.59 Reactions of diarylnitrones and propargylderivatives were conducted in the presence of CuSO4, or Cu(OAc)2and sodium ascorbate in DMF/water, t-BuOH/water or MeCN/watersolvent mixtures. The corresponding b-lactam products were ob-tained in moderate yields (50e65%) and with low selectivity (cis/trans 1:1 to 2:1).

In contrast to the reports of ineffectiveness of Cu(II) salts ascatalysts for CuAAC reactions,53 groups of Tang,55 Evans,57 Otani,54

and Feng58 showed examples of Kinugasa reactions catalyzed Cu(II)salts such as Cu(ClO4)2, CuBr2, and Cu(OTf)2, without a reducingagent such as sodium ascorbate. The origin of this phenomenon,

Scheme 5. Mechanism of Cu(OTf)2 catalyzed Kinugasa reaction proposed by Otaniet al.54


particularly the source of the required active copper(I) species, isnot clear.

Copper(II) is a well-known oxidizing agent for organic com-pounds.60 Alcohols, amines, aldehydes, thiols, and phenols can beoxidized by cupric ion, simultaneously reducing it to the catalyti-cally active Cu(I) species in the process. Particularly relevant areoxidative acetylene coupling reactions,61 including the earlier-mentioned Glaser coupling.44 Since terminal acetylenes are nec-essary substrates for Kinugasa reaction, their oxidation is an in-evitable side process, which in turn, produces the requiredcatalytically active Cu(I) species (Scheme 4).62 As a proof of concept,Tang55b evoked the experimental observations. In the reaction ofphenylacetylene with C,N-diphenylnitrone carried out in thepresence of Cu(ClO4)2$6H2O (10 mol %), TOX ligand, and 1 equivCy2NH under nitrogen atmosphere, a small amount of the couplingproduct diphenylbutadiyne was isolated. Feng and co-workersmade similar observations: [ . ]the combination of Cu(OTf)2, chi-ral diamine, and one equivalent of n-Bu2NH in water generated a blueprecipitate. Upon adding phenylacetylene, a yellow oil was generatedthat floated on top of the water, which indicated that copper(II) wasreduced in situ into copper(I) by phenylacetylene to form a copper(I)ephenylacetylide species.58

Scheme 4. Mechanism of Glaser coupling proposed by He et al.62

Otani and co-workers,54 who investigated Kinugasa reactioncatalyzed by IndaBOXeCu(OTf)2 complexes, suggested thatCu(OTf)2 and bis(oxazoline) ligand form complex 5. This complexactually acts as a chiral Lewis acid in the catalytic cycle to producecopper complex 6 by the reaction with acetylide formed by theaction of an amine (base) as shown in Scheme 5. Cationic complex 6is indeed the key species, reacting with the nitrone as a dipolar-ophile to furnish b-lactam together with the restored Lewis acidcatalyst.

Another explanation is also possible: copper(II) salts may becontaminated with Cu(0) and, therefore, the reaction can be cata-lyzed by Cu(I) ion supplied by the elemental copper acting as a re-ducing agent. This type of activation is well known in the case of

CuAAC reaction, where copper metal (wire or turnings) is oftenused.50,63 The patina onmetal surface, which contains copper oxideand carbonates, is sufficient to initiate the catalytic cycle. Addi-tionally, the presence of Cu(II) salts usually accelerates the wholeprocess.

A thorough understanding of the role of Cu(II) in Kinugasa re-action seems to be essential to sustain further development in thisarea. It is even more urgent since it was observed that in thepresence of copper(II) salts, Kinugasa reaction proceeds more


efficiently, usually effecting better enantioselectivity than the re-action with copper(I) salts under the same conditions (videinfra).54,55,57

Very recent report by Lei and co-workers64 seems to shed morelight on this discussion. On the basis of measurements of X-rayabsorption spectra and in situ electron paramagnetic resonance theAuthors provided evidence for the reduction of Cu(II) to Cu(I)species by both aromatic and aliphatic alkynes in the presence oftetramethylethylenediamine (TMEDA), in which TMEDA playsa dual role as both a ligand and a base. The structures of the startingCu(II) species and the resulting Cu(I) species were determined as(TMEDA)eCuCl2 and [(TMEDA)CuCl]2 dimer, respectively. The re-duction mechanism was proposed as shown in Scheme 6. Co-ordination of CeC triple bonds to Cu(II) leads to activation of theCeH bond and thus facilitates deprotonation in the presence of thebase and formation of CueC bonds. The subsequent inner sphereelectron transfer breaks the CueC bonds and forms the CeC bond.The attack of chloride anion on Cu(I) releases the homocoupling

Scheme 6. Proposed mechanism of reduction of Cu(II) to Cu(I) by terminal alkynes.64

product and forms [(TMEDA)eCuCl]2. Since the reported Cu(II)/TMEDA/alkyne reactant system is similar to catalytic systems usedby Tang,55 Evans,57 Otani,54 and Feng,58 it can be concluded thatformation of Cu(I) active species in Kinugasa reaction proceeds inthe same way. This conclusion is also supported by the above-mentioned observation of homocoupling products.55,58

Miura and co-workers49 provided another significant contri-bution to the studies on Kinugasa reaction. Under the reactionconditions shown in Scheme 7, the ratio of cis-3 to trans-3 isomersis dependent on the type of phosphorus- or nitrogen-containing

Scheme 7. Products of Kinugasa reaction observed by Miura et al.49

ligands employed. The group also reported formation of N-(1,3-diphenyl-2-propynylidene)aniline (7), N-benzylideneaniline (8),and phenylacetic acid (9), resulting from competing nitrone de-oxygenation and nucleophilic addition of copper acetylide.

When the reaction was performed in the presence of phos-phines such as PPh3, PBu3, dppe, or dppp (at 80 �C), trans-b-

lactam was isolated as the sole Kinugasa product, althoughformed in poor yield (6e36%), along with the imine 8, found asthe major product. In the presence of nitrogen-containing ligandssuch as pyridine or 1,10-phenanthroline, at room temperature,the yield of b-lactams was significantly higher (55e71%) pro-viding cis-3 and trans-3 azetidinones, in ratio of 2:1 for pyridineand 1:1.2 when 1,10-phenanthroline was employed as theligand.49b The same influence of nitrogen and phosphorus li-gands on Kinugasa reaction has also been observed by Zhao andLi.65 In that case the combination of 2,20-bipyridine (10 mol %)with CuCl (5 mol %) was reported as the most efficient catalyticsystem.

Based on the observation that in the presence of CuI/dppe thereaction required a higher temperature than a similar processcarried out with CuI/pyridine, it was concluded that phosphineligands suppressed the reaction progress, especially the cyclo-addition step. Miura postulated that one of the possible reasonsfor this situation could be the inherent properties of that kind of

ligand, which makes the terminal carbon of the acetylide in-termediate relatively negative and, therefore, less reactive to-ward the nitrone oxygen (Scheme 8).49b The coordination ofligand could also increase the nucleophilic character of the ter-minal carbon causing the intermediate to preferentially attackthe electrophilic carbon of nitrone to give 7, when arylacetylenesare employed as the starting materials. In the case of aliphaticterminal alkynes, however, the formation of 3 has not beendetected, while only 7 along with imine 8 were observed. Thiswould imply that copper alkylacetylides tend to act as nucleo-

philes rather than dipolarophiles, possibly because of their betterfrontier orbital interaction with nitrone.49b Deoxygenation of thenitrone by phosphine66 followed by a copper acetylide additionto the resulting imine to give a propargylic amine, which sub-sequently is transformed into 7 under basic conditions is anotherpossibility.67

Scheme 8. Ligand-controlled mechanism of reaction of nitrone with an alkyne.49b


Miura et al.49b also suggested that the isolated carboxylicacid 9 may be formed through oxygen insertion to copper(I)acetylide that leads to alkynoxide 10 and imine 8. Hydrolysis ofalkynoxide 10 leads to corresponding carboxylic acid 9(Scheme 9).

Scheme 9. Mechanism of forma

Scheme 10. Three-component synthesis of b-lactams from N-methy

2.2. Other modifications of Kinugasa reaction

Zhao and Li65 have demonstrated the synthesis of b-lactamsthrough Kinugasa cascade in a multicomponent fashion. The nitronewas generated in situ from corresponding aryl aldehyde and methylor benzyl hydroxylamine and subsequently reacted with alkynepresent in the reaction mixture (Scheme 10). One example of

tion of carboxylic acid 9.49b

l or N-benzyl hydroxylamine, aldehydes, and phenylacetylene.65


a synthesis of 2-azetidinone from C-pentyl-N-methyl nitrone in goodyield has also been reported.14 All reactions were conducted undersolvent-free conditions at 70 �C in the presence of 5 mol % of CuCl/2,20-bipyridine complex and AcONa as the base (K3PO4 providedcomparable results). Surprisingly, almost no desired product wasobserved when either Et3N or DBU were used as the base, whereasthe productswere obtained in lower yields when i-Pr2NEt and K2CO3were used.14

Pezacki et al.68 studied SDS micelle-promoted, copper-catalyzedmulticomponent Kinugasa reactions in aqueous media. The re-actions were performed ‘in a single pot’ for a series of C,N-diary-lnitrones generated in situ with Cu(I) phenylacetylide leading to b-lactams in yields of 45e85% (Scheme 11). The diastereoselectivity ofthe reaction was rather lowdthe cis/trans ratio varied from 1:1 to2:1. Moreover, together with the desired b-lactam products, theformation of unusual product 11was observed. Based on performedexperiments, it was concluded that the formation of amide 11 arosefrom decomposition of one of the intermediates of the cascade

Scheme 11. Micelle-promoted multicomponent Kinugasa reaction.68

rather than from the final b-lactam. The substituents influence thereaction progress either by accelerating the cycloaddition, or min-imizing the side reactions. Aryl aldehydes bearing electron-donating groups accelerated the reaction but simultaneously theyield of corresponding b-lactams was reduced, and the amount ofside product 11 was increased. The presence of electron-withdrawing groups in the benzaldehyde component caused anopposite effect.

Scheme 13. Mechanism of the Kinugasa reaction proposed by Tang et al.55

2.3. Mechanism of Kinugasa reaction

The first proposal of Kinugasa reaction mechanism has comefrom the research by Ding and Irwin.47 As illustrated in Scheme 12,the process consists of two-step cascade reaction involving 1,3-dipolar cycloaddition followed by a rearrangement. The initial cy-cloaddition step produces the copper-bound isoxazoline 12, whichsubsequently undergoes a rearrangement leading to the b-lactamring.

Scheme 12. Mechanism of Kinugasa reaction proposed by Ding and Irwin.47

It has been suggested that b-lactam formation proceeds througha highly strained bicyclic oxaziridinium intermediate 13 (Scheme12). While cis-azetidinone is formed under kinetic control, due toprotonation of isoxazoline intermediate 12 from the sterically lesshindered face, the formation of thermodynamically favorabletrans-product is likely a result of isomerization at C-3 under basicreaction conditions.

An alternate rearrangement pathway was proposed almost 30years later by Tang et al.,55 starting with the ring opening of iso-xazoline 12 leading to ketene 14, followed by an intramolecularacylation to afford enolate 15, which after protonation, furnishesfinal b-lactam 3 (Scheme 13). Again, the stereochemical outcome ofKinugasa reaction is dependent on the initial cycloaddition stepleading to isoxazoline derivative 12 (common for both mecha-nisms). The first step establishes the configuration at C-4, which inturn, influences the stereochemistry at C-3 since the formation ofkinetic cis-product is a result of protonation of enolate 15 from theless shielded side.

There are no doubts regarding the pathway of the cycloadditionstep of Kinugasa cascade. It is assumed that the process proceedssimilarly to the CuAAC reaction. A simplified catalytic cycle (basedon an early proposal for CuAAC50e53) has been put forward byChmielewski and co-workers (Scheme 14).69 Because the precisenature of the reactive alkynyl copper species in CuAAC, as well as inKinugasa reaction, has not been sufficiently documented, the realmechanism could be even more complicated.53 The main compli-cations are related to the tendency of these copper species to formpolynuclear compounds and great facility of ligand exchange at thecopper center. As a result, mixtures of Cu(I), terminal alkynes, andother ligands (including solvents) usually contain multiple orga-nocopper species, in rapid equilibrium. Moreover, kinetic studiesand DFT calculations indicated that at certain steps of CuAAC pro-cess a dinuclear copper(I) species may be involved.53

The course of rearrangement of copper isoxazoline 12 leading tothe b-lactam is also not clear. So far, there is no evidence to un-ambiguously prove or disprove the pathways presented in Schemes12 and 13. However, based on the arguments enumerated below, itcan be concluded that currently the second proposal seems moreplausible.

Scheme 14. Catalytic cycle of Kinugasa reaction.69


The mechanism involving ketene intermediate 14 seems to bemore convincing since it corresponds well with the work of DeShong and co-workers.70 They reported the formation of b-lactams17 via cycloaddition of nitrones with trimethylsilylacetylene fol-lowed by desilylation of 5-(trimethylsilyl)-isoxazoline 16 withfluoride anion (Scheme 15). Authors claimed that the rearrange-ment of isoxazoline 16 into b-lactam 17 proceeds through fluoride-mediated ring opening followed by subsequent cyclization of ke-tene amidate.

Scheme 15. Formation of b-lactams via cycloaddition/desilylation sequence reported by De Shong et al.70

Another indirect evidence of plausibility of Tang’s proposalcomes from a report of Shimizu et al.71 that describes the synthesisof b-lactams through thermal rearrangement of amino-cyclobutenones 18 (Scheme 16).

Scheme 16. Synthesis of b-lactams via thermal rearrangement ofaminocyclobutenones.71

Finally, Shintani and Fu72 demonstrated the possibility ofinterception of b-lactam enolate 15 by its reaction with anelectrophile. This certainly has been no trivial achievement,since the energetically favorable proton transfers often proceedwith remarkable facility in comparison to other bond formingreactions. However, in the presence of a proton trap and anexternal electrophile (allyl iodide), 2-azetidinones containinga quaternary stereogenic center at C-3 were obtained(Scheme 17).

Scheme 17. Formation of b-lactams bearing quaternary stereogenic center by trappingthe enolate intermediate with an electrophile.72

The scope of alkynes used in Kinugasa reaction is limited to ter-minal ones because only in these cases the cycloaddition reactionleads to copper-bound isoxazoline (12), which can undergo sub-sequent rearrangement to the 2-azetidinone. When non-terminalalkynes are employed, the process stops at the isoxazoline product,and its transformation into the b-lactam requires an additional NeObond breaking step. For example, Ishihara and co-workers73 trans-formed 1,3-dipolar cycloadducts, derived from nitrones and non-terminal alkynes, into b-lactams by reductive cleavage of the NeObond using SmI2 (Scheme 18).

Scheme 18. Ishihara’s b-lactam synthesis through 1,3-dipolar cycloaddition followed by reductive NeO bond cleavage.73


3. Stereocontrol in Kinugasa reaction

3.1. Cis-trans selectivity

Kinugasa reaction performed with non-chiral substrates usuallyleads to a mixture of isomeric cis- and trans-2-azetidinones. Theratio of the products depends on the reaction conditions and thestructure of reactants. As already discussed, the formation of cis-product is a result of protonation of intermediate 15 (or 13) fromthe less shielded side. Usually, this kinetic product is found as themajor component of the post-reaction mixture. The pathway of theformation of thermodynamic trans-isomers is not so straightfor-ward and may be strongly influenced by steric or electronic effectsor their combination. For example, the reaction of phenylacetylenewith C,N-diphenylnitrone leads to a mixture of cis and transproducts in a 85:15 ratio (Scheme 19).54 The replacement of phe-nylacetylene by a more electron-deficient alkyne, e.g., p-nitro-phenylacetylene leads mostly to the trans product (cis/trans18:82).54 Undoubtedly, in both cases the protonation of corre-sponding intermediates proceeds similarly, due to comparablesteric demands. Thus, in the case of the electron-poor alkyne, theformation of the trans product is a consequence of the isomeriza-tion of the initially formed cis-isomer facilitated by the increasedacidity of the proton at C-3 position. The use of evenmore electron-deficient acetylene, for instance ethyl propiolate, results in exclu-sive formation of the trans product.54

Scheme 19. The influence of alkyne electron properties on cis/trans selectivity of Ki-nugasa reaction.54

Scheme 20. Attempted epimerization at C-6 of carbapenams 19 and 21.76

The cis/trans selectivity of the reaction is also strongly influ-enced by the characteristics of the amine base used. Typically,bulkier amines tend to give better diastereoselectivity owing to theenhanced preference of protonation from the less shielded sideleading to the prevalent formation of cis-b-lactam. Conversely, theuse of more basic amines may accelerate the epimerization of thekinetic product and, in consequence, lead to decreased diaster-eoselectivity of the process.

The decrease of cis/trans selectivity depends also on the reactiontime. Extension of the reaction time increases the amount of trans-isomer formed since the cis-product is subjected to extended ex-posure to the action of the base.58,56,74

It has been reported that the isolated cis-2-azetidinone can beepimerized to the respective trans-isomer under basic conditions.

For example, Miura et al.49b isomerized cis-b-lactams by heating at80 �C in DMF in the presence of K2CO3, whereas Hsung et al.75 re-ported epimerization in the presence of DBU in boiling toluene. Theisomerization can also be achieved under milder conditions, forinstance DBU in CH2Cl2 at 0 �C,57 KHMDS in THF at �50 �C.76

Very recently, Feng et al.58 demonstrated highly trans-selectiveKinugasa reaction performed in water as the solvent. The increasedcontent of the trans isomer in this case was attributed to theisomerization at C-3 carbon atom under basic conditions.

We have found that in contrast to 3-aryl or 3-carbonylsubstituted cis-b-lactams, the 3-alkyl substituted analogs do notundergo detectable epimerization at room temperature in CDCl3solution in the presence of Et3N, or even tetramethylguanidine. Inthe presence of 2 equiv KHMDS in THF, cis isomer 19 could beepimerized at C-6 carbon atom of the carbapenam skeleton fur-nishing desired isomer 20 in 55% yield (Scheme 20), whereas cor-responding silyl protected compound 21 yielded eliminationproduct 22 with an exocyclic double bond (Scheme 20).76

3.2. Asymmetric Kinugasa reaction

Asymmetric Kinugasa cascade provides an entry to numerous b-lactam compounds with defined configuration and known or po-tential biological activity. However, due to the complex course ofthis process, its stereochemical outcome is not easy to predict. Asillustrated in Scheme 21, the first stereogenic center is formedduring the cycloaddition step of Kinugasa cascade. At this stageasymmetric induction can be achieved relatively easily providedthat the reaction is performed in one of the following manners:a chiral nitrone and/or chiral terminal alkyne are used, or a chiralligand designed for chelation of the Cu(I) ion is applied. Stereo-controlled formation of the second stereogenic center at C-3 de-pends on several factors. Its formation is undoubtedly stronglyrelated to the initially established center at C-4. Thus, in most casesthe kinetic cis-2-azetidinones are formed. In many instances,however, the influence of the neighboring stereogenic center in the

Scheme 21. The formation of new stereogenic centers during Kinugasa cascade.


side chain, which is also of kinetic origin, can be demonstrated. Theformer and the latter effect may create either a matched or mis-matched situation. Due to the relative acidity of H-3 proton, whichcan be additionally enhanced by certain types of substituents at C-3carbon atom, this center can also be epimerized under the basicreaction conditions.

3.2.1. Diastereoselective Kinugasa reaction. In 1995, Miura et al.49b

reported that the reaction of racemic alkyne 23 with nitrone 2aleads to the formation of four diastereomeric b-lactams cis-24,trans-24, cis-25, and trans-25 in ratio 60:11:12:17 (Scheme 22). Thestructural assignments were performed by the comparison of 1HNMR spectrum of the post-reaction mixture with NMR data re-ported previously.77 The (cisþtrans 24)/(cisþtrans 25) ratio of 71:29

Scheme 22. Reaction of alkyne 23 with nitrone 2a (overall yield not given).49b

indicated a high preference for the formation of both isomers oflactam 24 during the initial cycloaddition step of Kinugasa cascade.The stereochemical model shown in Fig. 2 can rationalize this ob-servation. Owing to the linear symmetry of triple bond, the nitronehas three possible trajectories to approach the dipolarophile inrelation to the acetylene stereogenic center. The proposed transi-tion state anticipates an approach of the nitrone between the smalland the medium substituent of the stereogenic center with both

Fig. 2. Stereochemical model for reaction of nitrone 2a with alkyne 23.

Scheme 23. Reaction of C,N-diarylnitrones with propyn

syn substituents at the C]N double bond, oxygen atom and N-phenyl group, directed toward the hydrogen atom.

Later, the same reaction under ‘click’ conditions (CuSO4$5H2O,sodium L-ascorbate, Et3N in MeCN/H2O), has been investigated byBasak and co-workers,59 and was found to give a cis/trans mixture(3:2) in 65% yield. The Authors, however, did not clarify, which cis/trans pair has been obtained.

The reactions of non-racemic propynes 26a,b bearing chiraloxazolidinone auxiliaries with C,N-diarylnitrones have been stud-ied by the Basak group (Scheme 23).78 The products cis-27 andtrans-27 were obtained in moderate yields. The absolute configu-ration of one of the obtained cis products was assigned by X-rayanalysis. As can be seen from Scheme 23, both chiral auxiliariesprovided full stereocontrol of the initial cycloaddition step, but the

formation of second stereogenic center proceeded with lowerstereoselectivity. Slightly better results were obtained in the case ofpropyne 26b bearing a phenylglycine-derived auxiliary. However,authors did not disclose any efforts to remove the chiral auxiliaryfrom cis-27a or b to produce the free, enantiomerically pure b-lactams. It was demonstrated that cis isomers underwent epime-rization to trans isomers upon treatment with n-BuLi at a lowtemperature.

In comparison to propynes 26a,b, chiral alkynes 28a,b provideda higher level of stereoselectivity of Kinugasa reaction with C,N-diarylnitrones.75 Hsung and co-workers75 obtained correspondingcis-3-amino-b-lactams in good yields and with dr up to >95:5(Scheme 24). During scope and limitation studies, it was found thatmore sterically encumbered auxiliaries (e.g., 28b) decreased thereaction rate. The same effect has been observed when less activeCuCl was used instead of CuI. In both cases a substoichiometricamount of copper(I) salt was used (20 mol %), in contrast to thepreviously reported examples, where at least 1 equiv of the catalystwas used. The high stereoselectivity of the reaction was explainedby the stereochemical model, which predicted that the chiral

es 26a,b bearing chiral oxazolidinone auxiliaries.78


oxazolidinone auxiliary controls not only the cycloaddition step,but also the subsequent protonation step leading to cis-29 productspredominantly.

Scheme 24. Reaction of C,N-diarylnitrones with non-racemic ynamides 28a,b.75

Table 1The Kinugasa reaction of chiral acetylene 33 and diarylnitrones 32aeda

Entry Nitrone dr (cis-37/trans-37)/(cis-38/trans-38)b

Yield of cis-37 isomer(overall yield)c [%]

1 32a (68:18):(7:7) 41 (61)2 32b (48:12):(40:0) 62d (95)3 32c (52:25):(13:10) 55e (62)4 2a (58:12):(13:17) 48 (82)

In contrast to the work of Basak group,78 Hsung et al.75 wenta step further and demonstrated the removal of the chiral auxiliarythat led to Boc-protected 3-amino-2-azetidinone cis-31(Scheme 25). Finally, the DBU-mediated epimerization of cis-30

Scheme 25. Transformation of b-lactams cis-30 and trans-30 into compounds cis-31and trans-31.75

Scheme 26. Reaction of nitrones 32aed w

gave compound trans-30, which subsequently was transformedinto azetidinone trans-31.

Chmielewski and co-workers74 investigated the stereo-selectivity of Kinugasa reaction of C,N-diarylnitrones 2d, 32aecwith non-racemic acetylenes 33e36. The reactions were performedin the presence of CuI (1 equiv) and tetramethylguanidine (2 equiv),which offered better yields and higher levels of stereoselectivitythan Et3N, which was used earlier. They proceeded with moderateyields and providedmixtures of four isomers cis-37, trans-37, cis-38,and trans-38 (Scheme 26, Table 1).56,69,76,7

a Standard conditions: nitrone (2 equiv), acetylene (1 equiv), CuI (1 equiv), TMG(2 equiv) in MeCN at rt.

b Determined by 1H NMR and HPLC.c The overall yield was determined by 1H NMR of crude reaction mixture in CDCl3

in the presence of trichlorethylene as an internal standard.d Inseparable mixture of cis-37 and trans-37 in ratio 3:1.e Mixture of isomers in ratio 7.3:2.5:1 (cis-37/trans-37/trans-38), cis-38 is more

polar and was lost during purification.

As indicated by the experimental data presented in Table 1, bothyield and stereoselectivity of these reactions are strongly related tothe electronic nature of the nitrone. The reaction with the nitronebearing a p-fluorophenyl substituent at the nitrogen atom (32c)proceeded with higher selectivity to afford predominantly corre-sponding cis-37 product, but with lower overall yield compared tothe analogous reaction involving nitrone 2a. On the other hand, thereaction of acetylene 33 with nitrone 32b bearing an electron-rich

ith non-racemic acetylenes 33e36.74

Fig. 3. Stereochemical model of the reaction of nitrone 39 and alkyne ent-33.79


aryl in the benzylidene fragment, proceeded with no selectivity toafford a mixture of cis- and trans-azetidinones (Table 1, entry 2) inhigh overall yield. For nitrone 32a both effects are additive, there-fore the reaction with this compound proceeded stereoselectivelybut with moderate yield only (Table 1, entry 1). The same stereo-chemical outcome has been observed for chiral acetylenes 35e36.

Based on the above-presented results of diastereoselectiveKinugasa reaction, it can be concluded that high level of stereo-selectivity can be achieved only when non-racemic acetylenebearing a stereogenic center next to the alkyne triple bond is usedand when the conformational lability around the stereogenic cen-ter is limited. Compounds 26a,b, 33e36 do not fulfill that re-quirement. Therefore, the asymmetric induction in thecycloaddition step is ineffective. In contrast, for ynamides 28a,b thechiral auxiliary is tightly bound to the acetylene moiety, Ph or i-Prgroups attached to the stereogenic center are in proximity to thetriple bond and the stereodifferentiation proceeds efficiently.

The stereochemical outcome of diastereoselective Kinugasacascade is changed when more rigid cyclic nitrones are applied.Chmielewski et al.79 demonstrated that the reaction of chiralacetylenes, for instance D-glyceraldehyde-derived compound ent-33 or L-lactic acid-originating acetylene 41, with achiral nitrone 39proceeded with excellent diastereoselectivity, affording corre-sponding carbapenams 40 and 42 in moderate yield (40e50%,Scheme 27). The observed direction of asymmetric induction wasrationalized using the stereochemical model presented in Fig. 3.79

In the cycloaddition step, the nitrone approaches from the lesshindered side of the acetylene, between the oxygen and hydrogenatoms, while the five-membered nitrone ring is directed toward thehydrogen atom (Fig. 2). The final protonation of enolate occurs toa great degree from the convex side of intermediate.

Scheme 27. Diastereoselective reaction of nitrone 39 with alkynes ent-33 and 41.79

Scheme 28. Reaction of nitrone

Analogous reactions with six-membered nitrone 43 proceededsimilarly but in very low yield, 20% and 10%, respectively(Scheme 28).80 For example, reactions between nitrone 43 andphenylacetylene or alkyne 44 proceeded with relatively good dia-stereoselectivity, affording corresponding racemic carbacephamscis-45a and cis-46a.

Interestingly, nitrone 47, derived from dihydroisoquinoline,displayed different reactivity than previously investigated cyclicnitrones (Scheme 29). Phenylacetylene did not afford any definedproduct, whereas more reactive 3,3-diethoxypropyne gave ex-pected b-lactams cis-48 and trans-48 in a ratio of about 2:1, ac-companied by adduct 49, which originated from oppositeregiochemistry of the first 1,3-dipolar cycloaddition step. In addi-tion, a minute amount of N-acyl-tetrahydroisoquinoline 50, whichwas probably formed as a result of a redox reaction involving thecopper acetylide and the nitrone, was also isolated.31,51 A morecomplex situation was observed for the same nitrone 47 in a re-action with alkyne 33.80 The expected Kinugasa products 51aecand racemic compound 53, consisting of two molecules of thenitrone and one acetylene, were obtained in only 29% yield anda ratio of about 5:7:1:2 (Scheme 30). In addition, compound 52(25% yield) was found in the post-reaction mixture.

Conversely, Basak reported that the same nitrone 47 in a re-action with ethyl propiolate in the presence of CuI/Et3N in DMFprovided trans-azetidinone 54 in 54% yield (Scheme 31).81

In 2008, we reported the use of non-racemic cyclic nitrones 55and 57, derived from (S)-malic and L-tartaric acid, respectively, indiastereoselective Kinugasa reaction leading to b-lactams withcarbapenam scaffolds (Scheme 32).56 The reactions were per-formed in MeCN, in the presence of CuI and Et3N as the base. cis-Carbapenams (e.g., cis-56, cis-58) were found as major products,and the use of bulkier amines (i-Pr2NEt or Cy2NMe) let to furtherincrease of their content in the post-reaction mixture.

Models shown in Fig. 4 explain the stereochemical pathway ofthe reaction. The initial 1,3-dipolar-cycloaddition step is highlystereoselective, involving the approach of copper acetylide exclu-sively anti to the tert-butoxy group of the nitrone. Subsequentprotonation proceeds from the less shielded convex side of thebicyclic enolate leading to the kinetic cis product. As shown in

43 with simple alkynes.80

Scheme 29. Kinugasa reaction of nitrone 47 with 3,3-dietoxypropyne.80

Scheme 30. Kinugasa reaction of nitrone 46 with alkyne 33.80

Scheme 31. Kinugasa reaction of nitrone 47 with ethyl propiolate.81

Scheme 32. Asymmetric Kinugasa reaction invol


Scheme 32, the location of t-BuO substituent is essential for highstereocontrol of the cycloaddition step. The shift of the tert-butylgroup from C-3 to C-4 carbon atom, as in nitrone 59, caused visiblereduction of selectivity (formation of two cis products 60 and 61).Nevertheless, a preference for approach of the acetylene anti to thenitrone substituent was observed.56

Interesting results have been noted for reactions where bothreactants, nitrone, and alkyne, were chiral (Scheme 33).79 For

ving non-racemic nitrones 55, 57, and 59.56

Fig. 4. Stereochemical model of reaction involving non-racemic nitrone 55.56


example, in the case of matched pair 55 and ent-33 only cis car-bapenam 62was obtained, whereas for the mismatched pair ent-55and ent-33 two stereoisomers cis-63 and trans-63 were formed ina 9:1 ratio.

Scheme 33. Double asymmetric induction in reaction of alkyne ent-33 with nitrones 55 and ent-55.79

The stereochemical outcome of those reactions where both re-actants (acetylene and nitrone) were chiral, was rationalized on thebasis of previous observations (Fig. 3).56 Similarly to additions in-volving non-chiral acetylenes, the initial 1,3-dipolar-cycloadditionstep proceeds almost exclusively anti to the tert-butoxy group ofthe nitrone. The stereogenic center of the nitrone reactant playsa decisive role in determination of the stereochemical outcome ofthis step. The influence of the stereogenic center in the acetylenecan be neglected. In the case of matched pair, the acetylene ster-eogenic center has an insignificant effect on the protonation step.Only in the case of mismatched pair the influence of acetylenestereogenic center is manifested by the formation of a smallamount of the trans isomer. Nevertheless, it is important to notethat since Kinugasa reaction proceeds in the presence of a base, theformation of thermodynamically most stable trans isomer by theepimerization at position a- to the b-lactam carbonyl group shouldnot be neglected. The reported cases of base-catalyzed epimeriza-tion, however, require a stronger base and usually a higher tem-perature.49b,75 Therefore, the stereochemistry of the protonation of

copper enolate should be considered as sensitive not only to theinfluence of the configuration at bridgehead carbon atom but alsoto the configuration of the stereogenic center in the side chain nextto C-6 carbon atom of the bicyclic skeleton.

Our group69 demonstrated that certain acetylenes display en-hanced reactivity in the investigated processes, providing corre-sponding 2-azetidinones in higher yield and therefore requiringa shorter reaction time (Table 2, acetylenes ent-33 and 44). Forexample, the reaction of nitrone 55 with glyceraldehyde-derivedacetylene ent-33 yielded cis-product 62 in 94% yield after 24 h(Scheme 33, Table 2). When the reaction was quenched after 2 hcompound 62 was isolated in 80% yield. High yield was also ach-ieved when the amount of the copper salt was decreased from100 mol % to 5 mol % (Scheme 33, Table 2).69 A similar effect wasobserved when 3,3-diethoxypropyne 44 was used.

Based on the analysis of acetylene structureeefficiency re-lationship in the context of Kinugasa reaction (Table 2), it wasconcluded that the high reactivity of compounds ent-33 and 44might have its origin in the specific structure of copper acetylidesformed by these molecules. It was suggested that the enhancementof the rate and yield of Kinugasa reaction for acetylenes derivedfrom glyceraldehyde ent-33 and propargyl aldehyde acetal 44 hasits origin in the formation of a highly reactive, rigid dinuclear

Table 2Acetylenes’ structure effect on Kinugasa reaction

Acetylene CuI [mol %] Time [h] Yield [%]

100 24 94 (60a)100 2 80 (47a)

5 24 785 2 80

100 24 75100 2 46

5 24 30

100 24 41100 2 n.d.

5 24 n.d.

100 24 40100 2 n.d.

5 24 n.d.

100 24 45 (55a)100 2 12

5 24 n.d.5 2 n.d.

100 24 72 (94a)100 2 62 (68a)

5 24 58 (97a)5 2 60a

100 24 31 (36a)100 2 10

5 24 n.d.5 2 n.d.

100 24 55 (55a)100 2 55

5 24 35 (36a)5 2 36

100 24 56 (30a)100 2 57

5 24 49 (31a)5 2 31

n.d.¼not determined.a In presence of 1,10-phenanthroline (100 or 5 mol %).


copper(I) complex in which each metal ion is coordinated to one orboth oxygen atoms in the acetylene molecule and to both triplebonds (Fig. 5).69

Fig. 5. Possible model of coordination of copper ions by alkynes ent-33 and 44.69

The rigid structure of the dioxolane ring stabilizes the confor-mation of the acetylide and enables optimal interaction of the ox-ygen atoms with the copper ion. Such coordination is less effectivein the case of more flexible structures (Table 2, compounds64e66).69

The existence of a specific coordination effect of the copper(I)ion seems to be confirmed by the reactions with an external ligand,for instance 1,10-phenanthroline. The significant increase of thereaction yield in the case of acetylene 64 may indicate the ap-pearance of a synergistic effect of both oxygen atoms and the N,N-ligand. In contrast, addition of phenanthroline ligand to the re-action of nitrone 55 with acetylene 67 or 68 causes only a slightenhancement of the yield. On the other hand, the opposite effect of1,10-phenanthroline in the case of ent-33 could be explained as-suming interference with the 1,3-dioxolane ring effect, probablydue to competitive coordination of the metal ion. A similar situa-tion, competitive coordination of Cu(I), can occur if an additionaloxygen atom is introduced (compare 67 and 68) to the acetylenemolecule. Such results again confirm the critical role of the oxygenatoms and their location in the acetylene molecule (compare ent-34, 69).69

It has also been demonstrated that a phenyl ring may replaceone of the oxygen atoms (compare alkyne 44 with 70 and 71) toprovide coordination of the copper ion by the aromatic sextet(Scheme 34). It should be noted, however that no less than twodonor centers are necessary for effective coordination of the copperion and, accordingly, activation of the triple bond for the cycload-dition reaction with the nitrone.

There is another important point emerging from those stud-ies.56,69,79 Due to multiple reactivity of nitrones, efficient synthesisof b-lactams through Kinugasa reaction can be performed onlywhen the desired process is faster than possible side reactions. It isparticularly important to enhance the reactivity of copper(I) ace-tylides by encouraging their polymeric aggregates to form smaller,more reactive species. As shown above, proper choice of the alkynestructure can be an important factor.

In a recent report, our group76 has shown that diastereoselectiveKinugasa reaction involving five-membered nitrones (e.g., 75, 77)derived from pentofuranoses and simple acetylenes (both chiraland non-chiral) provided an interesting entry to carbapenam an-tibiotics. The reactions proceeded in moderate to good yield anddisplayed high diastereoselectivity, affording mainly one dominantcis product, such as 76 and 78 (Scheme 35). In cases where twostereogenic centers in the cyclic nitrone (e.g., 79) would effectopposite asymmetric induction, the center located next to thedouble bond has played the decisive role in the stereochemicaloutcome of the process (Scheme 36).

As it has been previously reported, in cases when both reactantsused, the sugar-derived cyclic nitrone and the alkyne, were chiral,the stereochemical course of Kinugasa cascade was controlledmainly by the structure of the nitrone; the influence of the acety-lene configuration could be neglected.76

Recently, Khangarot and Kaliappan82 have used Kinugasa cas-cade for stereoselective synthesis of cis-carbapenams frompentose-derived nitrones and sugar-derived terminal alkynes(Scheme 37). Corresponding carbapenam products (e.g., 80) wereaccompanied by Glaser coupling products44 (e.g., 81), which mightindicate incomplete exclusion of oxygen during the reaction (for-mation of diacetylenes is usually dependent on the presence ofoxygen). The cis-carbapenam products were obtained in good yield(43e92%). However, no further transformations of these interestingbio-conjugates, nor evaluation of their bioactivity, were reported.

Jørgensen and co-workers83 reported an interesting example ofdiastereoselective synthesis of b-lactams via highly enantiose-lective Michael addition/intramolecular Kinugasa cascade, usinga one-pot protocol (Scheme 38). In the presence of 0.25 equiv CuI,

Scheme 34. Double asymmetric induction in reaction of alkynes 70 and 71 with nitrone ent-55.79

Scheme 35. Kinugasa reaction involving sugar-derived nitrones 75 and 77.76

Scheme 36. Competitive effect of substituents in nitrone 79 on the asymmetric induction of Kinugasa reaction.76

Scheme 37. A stereoselective synthesis of sugar-derived chiral b-lactams.82


b-lactam 84a was isolated in 58% yield and 88% ee from a reactionmixture of hexen-2-al (82a), malononitrile derivative 83, and N-phenylhydroxylamine. The relative configuration of 84a wasestablished by X-ray crystallography. Other aliphatic a,b-un-saturated aldehydes were also successfully transformed into cor-responding b-lactams 84b and 84c in comparably good yield (46and 51%) with excellent enantio- and diastereoselectivity (91 and

90% ee, dr >20:1). Furthermore, the presence of unsaturated sidechains was well tolerated, yielding 84d and 84e (52%, 90% ee, and52%, 88% ee).

3.2.2. Enantioselective Kinugasa reaction. Miura and co-workers49b

have reported that the reaction between diphenylnitrone (2a) andphenylacetylene proceeded not only with an excess of pyridine but

Scheme 38. Intramolecular synthesis of b-lactams via Michael addition/Kinugasa cascade.83


also in the presence of a catalytic amount of 1,10-phenanthroline.Based on this observation, it has been concluded that asymmetricinduction during formation of 3 should be possible, if the reactionwas carried out in the presence of a certain type of chiral ligands,particularly nitrogen-containing bidentate compounds. Followingthis assumption, a model reaction was conducted usingbisoxazoline-type ligands 85aec (Scheme 39, Table 3). The reactionof 2awith phenylacetylene at room temperature yielded 3 as a cis/trans mixture in 65:35 ratio. The enantiomeric excess was 40% forboth isomers. Treatment of the cis/trans mixture with K2CO3 inDMF at 80 �C gave trans-3 with 40% ee. Higher ee (68%) was ob-tained when the amount of CuI was increased to 1 equiv. Whenligands 85b and 85c were applied, enantiomeric excess of 67% and45% was obtained, respectively. (�)-Sparteine was found to bea relatively poor ligand yielding trans-3 with 23% ee only.

Scheme 39. First example of enantioselective Kinugasa reaction (absolute configura-tion of the product was not given).49b

Table 3Reaction of phenylacetylene (1 mmol) with C,N-diphenylnitrone (2a, 1 mmol) in thepresence of chiral ligands 85aec and (�)-sparteine (Scheme 38)49b

Entry Ligand CuI/ligand[mmol]

Time [h] Yield oftrans-3a [%]

eeb [%]

1 85a 0.1:0.2 5 5 n.d.2 85a 0.1:1.0 2 45 403 85a 1.0:1.0 1 54 684c 85a 0.1:0.2 2 50 575 85b 1.0:1.0 2 40 676 85c 1.0:1.0 2 40 457 (�)-Sparteine 0.1e1.0 2 47 23a Yield after isomerization of cis/trans mixture to trans isomer.b Determined by 1H NMR in the presence of Eu(tfc)3.c Acetylene was added to the mixture in 10 portions.

In 2002, Fu and co-workers,84 inspired by Miura’s pioneeringstudies, demonstrated enantioselective Kinugasa reactions cata-lyzed by copper(I) complex with C2-symmetric planar-chiralbis(azaferrocene) ligands (Table 4). In their initial studies, theutility of 86a during the coupling of phenylacetylene with C,N-diphenylnitrone under Miura’s conditions was examined but the

observed stereoselectivity was moderate. Subsequently, the ligandwas re-designed (86b) and the reaction conditions were optimized,culminating with an effective catalytic system (loading of only1 mol %), which generated b-lactams with good enantiomeric ex-cess and cis diastereoselectivity. Use of sterically demanding tri-alkylamine (1.0 equiv or less) as the base was identified as essentialto effect good cis selectivity of the reaction.

Since bicyclic and polycyclic b-lactams constitute important anddesirable targets, both as synthetic endpoints (e.g., penicillins andtribactams)1 and as synthetic intermediates,1d,1f,85 Fu and Shintani72

focused their attention on the development of intramolecularKinugasa reaction, which would ideally employ a chiral catalyst andtarget the preparation of enantioenriched bi- and polycyclic b-lac-tam scaffold. Disappointingly, planar-chiral bis(azaferrocene) 86b,whichhadbeen founduseful for the intermolecular processes (Table4), furnished the desired b-lactam 88 with poor enantioselectivityand in low yield (Table 5, entry 1). Alternative ligand architectures,such as chiral bisoxazoline 85a, afforded 88 with moderate stereo-selectivity and in modest yield (Table 5, entry 2).

When ligand 89a was used in copper-catalyzed intramolecularKinugasa reaction of alkyneenitrone 87, the desired b-lactam 88was produced with markedly improved stereoselectivity and yield.Ligand 89b, in which i-Pr group of the oxazoline moiety has beenreplaced with a t-Bu group, gave similar level of enantioselectivitybut lower yield (Table 5, entry 4). Finally, phosphaferrocene-eoxazoline 89a was identified as superior to the diastereomericligand 90with respect to both enantioselectivity and yield (Table 5,entry 3 vs entry 5). The latter results indicate that chirality ofoxazoline subunit is the dominant stereocontrol element and thatplanar chirality of phosphaferrocene subunit plays a subordinate,although not insignificant role.

The use of established Cu/phosphaferroceneeoxazoline cata-lysts 89a and 89b during the synthesis of tricyclic compoundscontaining a 6,4 or 7,4 ring systemwas explored by the same group(Scheme 40).72 The i-Pr-substituted ligand 89awas identified as theligand of choice for generation of b-lactams fused to a six-membered ring (86e90% ee), whereas for the seven-memberedrings the t-Bu-substituted analog 89b gave superior results(85e91% ee).

It has also been demonstrated that in the presence of a protontrap, the b-lactam enolate can be intercepted by an external elec-trophile to afford 2-azetidinone bearing a quaternary stereogeniccenter at the C-3 position.72

After a few attempts silyl enol ether was identified as the mostsuitable irreversible proton trap that can disable the usual pathwayof Kinugasa reaction. Thus, in the presence of CuBr/89a complex,silyl enol ether and KOAc as the base, compound 87 underwentcyclization followed by alkylation with good stereoselectivity (85%ee) to afford 91 in 76% yield (Scheme 41).72 As a result, two car-bonecarbon bonds, a carbonenitrogen bond, two new rings (in-cluding b-lactam), a carbonyl group, and adjacent tertiary andquaternary stereocenters can be generated in a single cycliza-tionealkylation sequence.

Table 4Enantioselective Kinugasa reaction catalyzed by chiral CuCl/86 complex84

Entry R1 R2 R3 Cis/trans %ee cis Isolated yieldcis isomer [%]

1 Ph Ph Ph 95:5 77 692 Ph Ph 4-(EtOOC)C6H4 95:5 67 (71a) 79 (91a)3 Ph Cy 4-(Me)OC6H4 95:5 83 (92a) 46 (65a)4 Ph PhCO Ph 90:10 90a 56a

a Run at �20 �C; Cy¼cyclohexyl.

Table 5Ligand effects for an intramolecular Kinugasa reaction72

Entry Ligand Yield [%] ee [%] Configuration

1 86b 30 6 (3S,4S)2 85a 39 62 (3R,4R)3 89a 74 88 (3S,4S)4 89b 47 90 (3S,4S)5 90 52 58 (3S,4S)

Scheme 40. Enantioselective synthesis

Scheme 41. Synthesis of b-lactams containing a quaternary stereocenter.72


Basak et al.86 attempted to utilize simple amino acids to effectthe enantiomeric enrichment in a reaction of C,N-diarylnitroneswith propargyl and homopropargyl alcohols. The reaction betweenC,N-diphenylnitrone 2a and propargyl alcohol in the presence ofCuI and L-proline (both 1 equiv) in DMF at room temperatureafforded essentially two products, cis-b-lactam 92 (15%) along with3-exomethylene b-lactam 93 (25%; Scheme 42). When DMSO wasused as the solvent, exomethylene b-lactam became the majorproduct (70%) accompanied by a small amount of cis-b-lactam (ca.10%). However, the enantiomeric enrichment of 93was rather poor(w15%). Other L-amino acids (e.g., L-tyrosine, L-tryptophan) werecompletely ineffective. The path leading to the formation of 93was

of 6,4- and 7,4-bicyclic b-lactams.72

Scheme 42. L-Proline mediated synthesis of 3-exomethylene-2-azetidinones.86


proposed as proceeding via L-proline-mediated elimination ofwater molecule at the stage of isoxazoline, before the formation ofb-lactam, rather than simple water elimination from azetidinone92 (Scheme 43).86

Scheme 43. The way of formation of 93 proposed by Basak et al.86

The most rewarding contribution to catalytic enantioselectiveKinugasa reaction has come from Tang’s laboratory.55 In an earlycommunication, authors reported that in the presence of a catalyticamount of pseudo C3-symmetric trisoxazoline ligand (TOX ligand)94a, Cu(ClO4)2$6H2O, and a small amount of Cu(I) salt to catalyzeKinugasa reaction between alkynes and C,N-diarylnitrones, desiredb-lactam 3 was obtained in moderate to good enantioselectivity(Scheme 44).55a In a subsequent full paper, a reaction modification,its scope and limitations, and the mechanism were disclosed indetail.55b

Scheme 44. Enantioselective Kinugasa reaction catalyzed by Cu(II)/TOX 94a chiral complex.55

Among Cu(I) and Cu(II) sources examined in combinationwith ligand 94a, the latter, particularly Cu(ClO4)2$6H2O, werefound to be good catalysts for the reaction and usually gavebetter enantioselectivity than copper(I) salts under the sameconditions.55 Regardless of the oxidation state of copper, pre-dominantly cis-b-lactams were obtained (dr >10:1).

Detailed studies showed that amines strongly influence dia-stereoselectivity, enantioselectivity, and reaction rate.55b Bulkieramines always gave better diastereoselection. Generally, tertiaryamines provided higher diastereoselectivity than secondary ones,and these were in turn better than primary amines. In comparisonwith tertiary and primary amines, secondary amines led to desiredproducts with higher enantioselectivity but lower diaster-eoselectivity. To obtain both better diastereoselectivity and enan-tioselectivity, a variety of secondary amines have beeninvestigated and it was found that the use of dicyclohexylamineled to the most satisfactory results (Scheme 44). In this case, thereaction of phenylacetylene with C,N-diphenylnitrone 2a gave 79%ee, comparable to the result reported by Fu84 with the use of 86a/CuCl as a chiral catalyst (see Table 4, entry 1). Analogously toprevious reports, MeCN has been found to be the preferredsolvent.55b

To improve the asymmetric induction, a variety of oxazolineligands (94e100) have been synthesized to study the effect of sucha ligand on the reaction.55b In comparison to bisoxazolines, the useof trisoxazolines led to higher reaction rates and better enantio-selectivity. This observation was rationalized proposing strongerchelation of copper center by the TOX ligand, which should inhibitthe coordination polymerization of copper acetylide. Further ex-periments demonstrated that the core bisoxazoline backbone wasessential to the process and the pendant oxazoline rarely influ-enced the enantioselectivity of Kinugasa reaction.

To understand the role of the sidearm oxazoline in 94a duringthis process, Tang and co-workers55b carried out detailed studiesusing 13C NMR. As it was previously demonstrated by Gade et al.,87

the pendant oxazoline of bisoxazoline-based tridentate ligand isdynamically coordinated to the copper ion and therefore it stabilizesthe catalytic species, and greatly improves the catalytic efficiency.The NMR experiments confirmed coordination of the copper ion byall three nitrogen atoms of ligand 94a (Scheme 45); without theCu(I) salt all three sp2 carbon atoms had different chemical shiftswhereas in the presence of an equimolar amount of CuCl all thesesignals merged into one. It was observed that following addition ofan equimolar amount of phenylacetylene and the base, the singlepeak of three sp2 carbon oxazolines split again into three separatepeaks. This result indicateddecoordinationof thependantoxazolinewhen the copper(I) phenylacetylide is formed. On the basis of NMRstudies, as well as the experimental results, Tang and co-workers55b

proposed a stereochemical pathway of the reaction to rationalizethe observed enantioselection (Scheme 45).

Under the optimal reaction conditions, Kinugasa reaction hasbeen investigated by employing a variety of structurally differentnitrones and alkynes.55b It has been found that the electroniccharacter of C-bound aromatic groups of nitrones affected both

yield and stereoselection. Electron-rich aromatic groups increasedenantioselectivity but decreased the yield whereas electron-deficient ones slightly decreased enantioselectivity but increasedthe reaction rate. The electronic properties of N-bound aromaticgroups of nitrones had almost no impact on the enantioselection.Both electron-deficient and electron-rich aryls afforded goodenantioselectivity and diastereoselectivity. Neither C-alkyl nor N-alkyl nitrone gave the desired product. Noticeably, both aryl andalkyl alkynes worked well to provide the desired b-lactams. In allcases cis-2-azetidinones were found as major isomers, with theexception of reactions involving ethyl propiolate where pre-dominately trans products were obtained, although the latter resultshould rather be attributed to base-induced isomerization.

In 2007, Guiry et al.88 used HETPHOX ligands 101e104 (incombination with CuCl and Cy2NMe) in Kinugasa reaction, andachieved poor to moderate levels of enantioselectivity (Scheme46). When Cu(II) salts were examined in subsequent experi-ments, high diastereoselectivity was observed but the reactionwas characterized by poor enantioselectivity and low overallconversion. Poor enantioselectivity was also observed when Cu(I)species were generated in situ, using copper(II) acetate and so-dium ascorbate (20 mol %), although the conversion was


satisfactory (75%). The highest enantioselectivity (up to 55% ee forcis isomer) was observed when ligand 102 was used, but theconversion was poor.

Recently, Evans et al.57 disclosed a highly stereoselectivecopper(II)-catalyzed coupling reaction of alkynes with nitronesusing IndaBOX ligands (105aej). Themost effective ligandwas 105j,

Scheme 45. Model of copper coordination by TOX ligand 94a and stereochem

Scheme 46. Enantioselective Kinugasa reaction ca

providing up to 97:3 dr and up to 98% ee with preference for C-alkylnitrones (Scheme 47). It was also confirmed that cis-b-lactamscould be converted into respective trans isomers by treatment withDBU in CH2Cl2 at 0 �C.

The IndaBOX ligands were also employed by Saito and co-workers.54 Although neither the chemical yield nor

ical model of Kinugasa reaction catalyzed by Cu(II)/94a chiral complex.55b

talyzed by CuCl/HETPHOX chiral complexes.88

Scheme 47. Enantioselective Kinugasa reaction catalyzed by CuBr2/IndaBOX chiral complexes.57


diastereoselectivity were improved, the highest level of enantio-selectivity was attained using Cu(OTf)2 complex along with simpleand readily available C2-symmetric IndaBOX ligand 105c. Selectionof optimal reaction conditions led to identification of s-Bu2NH asthe best amine and i-PrOAc as the best solvent. Very recently, Sierraet al.89 applied ligand 105c in a synthesis of b-lactams starting fromterminal alkynes substituted with metal fragments, includingsandwich, half-sandwich, and arene-tethered metal-carbenecomplexes, but the enantioselectivity of the process was rather low(90% ee and >90:10 dr. Incomparison, the earlier-discussed Cu(II) salts, such as Cu(OTf)2,were more active but less stereoselective (88% ee, dr 87:13). It isworth to note that CuOTf in combination with the IndaBOX ligandwas found to be an inactive catalytic system as reported by Otaniand co-workers.54

Very recently, Feng et al.58 demonstrated that the use of a catalyticsystemconsistingof chiral secondaryamine107andCu(OTf)2 resultedin a highly diastereoselective and enantioselective approach to trans-

b-lactams (Scheme 49). Interestingly, it has been found that the bestyield, diastereoselectivity, andenantioselectivitywereobservedwhensecondary, aliphatic, non-sterically-hindered bases, such as n-Bu2NHor Et2NH, were used. Throughout the initial experiments MeCN wasused as the standard solvent providing good yield and selectivity ofcorresponding b-lactams (Scheme 50). Notably, when the reactionwasperformedunder solvent-free conditions, bothgoodyield and theenantioselectivity were achieved with a slight loss of diaster-eoselectivity. Interestingly, reaction rate was accelerated by thepresence of a small amount of water (‘on water’ conditions), thusgenerating the b-lactamwith improved diastereoselectivity and yield(Scheme 49). Further experiments showed that the predominantformationof trans-b-lactams isa resultof fast isomerizationof initiallyformed cis-isomers under the reaction conditions.

4. Application of Kinugasa reaction in synthesis of bioactivecompounds

As mentioned in Introduction to this account, b-lactam com-pounds play a vital role in modern medicine as important anti-bacterial agents. Moreover, the growing number of recent studiesrevealed that compounds containing 2-azetidinone ring exhibitbioactivity extending well beyond the originally discovered anti-bacterial properties, thus significantly increasing the value of thisclass of compounds. In fact, development of novel methods of the

Scheme 49. Enantioselective Kinugasa reaction catalyzed by Cu(II)/107 chiral complex.58

Scheme 50. Solvent effect on Kinugasa reaction catalyzed by Cu(II)/107 complex.58


synthesis of 2-azetidinones is driven largely by the discovery oftheir new pharmaceutical applications. In this context, as well asdue to its inherent versatility, Kinugasa reaction is one of the mostuseful tools in the synthesis of structurally diverse b-lactams.

Basak and co-workers91 reported the synthesis of several chi-mera cis and trans b-lactam nucleobases 109 from correspondingN-propargyl nucleobases 108aec via Kinugasa reaction (Scheme 51).b-Lactams 109 were subjected to a preliminary screening for anti-bacterial activity against ampicillin-sensitive Escherichia coli. Theuracil-containing b-lactam has been found to be active against thestrain, with activity of about 20% of that of ampicillin.

Scheme 51. Synthesis of b-lactam nucleoside chimera via Kinugasa reaction.91

Scheme 52. Kinugasa reaction route to lactamdiynes.94

Since 1995, cyclic enediynes, the pharmacophore present inenediyne antitumor antibiotics, fused to a small ring (e.g., b-lactam)have become attractive targets as anticancer agents.92,93 The rea-sons for choosing a b-lactam scaffold was its bio-recognition and itsinherent strain. The advantage of using such construct as a molec-ular building block stems from the fact that, in addition to thestructural strain imparted on the fused enediyne moiety, the ringcan also be easily opened by a nucleophile (such as thiol) or anenzyme (such as transpeptidase or b-lactamase), or even underbasic conditions. Basak’s group94 demonstrated an approach to

lactamdiynes via intramolecular Kinugasa reaction (Scheme 52).This method was particularly attractive in regard to the class ofstructures that could not be easily obtained by other methods dueto the instability of corresponding starting materials.

Kinugasa reaction was also utilized to prepare a potential b-turn-based pharmacophore, peptidyl b-lactams, using propargyl-substituted ethyl pyroglutamate 110 and C,N-diphenylnitrone inthe presence of CuI and Et3N in MeCN solution (Scheme 53).95

The reaction produced three diastereomers: one trans-isomer111 and a pair of cis-isomers 111 and cis-112 (the ratio of ste-reoisomers was not reported). It appeared that only cis-112 iso-mer readily epimerized to the respective trans-compound duringthe reaction. The other cis-isomer, cis-111, was configurationallymore stable and therefore resistant to similar epimerization.Analysis of temperature coefficients observed for the chemicalshifts of two NH protons in the final tripeptide products 113e115indicated the presence of strong hydrogen bonding only forcompound 113 where the b-turn-like conformation seemed to bepreferred.

Asmentioned in Introduction, the last decade of research revealedseveral types of non-antibiotic bioactivity of b-lactams. Some aryl-substituted 2-azetidinones display activity as cholesterol absorption

Scheme 53. Synthesis of novel azetidinyl-substituted g-lactam-based peptides.95


inhibitors. Among them ezetimibe (116) has been found to be themost powerful agent used in modern hypercholesterolemia therapy.

A pioneering attempt to prepare the core of an anti-hypercholesterolemic b-lactam using Kinugasa reaction has beenreported by Basak et al. (Scheme 54).81 The proposed strategy in-volved the synthesis of cis-b-lactam (rac-117) via Kinugasa reactionfollowed by Swern oxidation and Wittig olefination to affordcompound rac-118. Following his earlier reports, Basak also sug-gested the possibility to prepare the corresponding trans isomer of

Scheme 54. Synthesis of antihypercholesterolemic b-lactams using Kinugasa reaction.81

rac-117 via base-mediated epimerization, as well as the formationof enantioenriched trans-117 through enzymatic kinetic resolutionof the racemate.96

In 2011, our group97 reported a formal asymmetric synthesis ofezetimibe (116) via diastereoselective Kinugasa reaction betweennitrone 119 and L-glyceraldehyde-derived acetylene 33 as a keystep. In the presence of CuI and tetramethylguanidine as the basethe mixture of b-lactams cis/trans-120 along with respective cis/trans-121 were obtained in moderate yield and in a ratio of about4.5:1, respectively (Scheme 55). The products were partially puri-fied by chromatography to afford adduct cis-120 with a smallamount of trans-120.

Two isolated b-lactams (cis-120 and trans-120), both displayingthe same absolute configuration at C-4 carbon atom as in target

molecule 116, underwent an acid-catalyzed deprotection of diox-olane fragment to afford diol 122 (along with its C-3-epimer).Glycolic cleavage of diol 122 with subsequent base-mediated epi-merization yielded aldehyde 123, which has been previouslytransformed into ezetimibe by the Schering-Plough Process group(Scheme 56).11

Thienamycin (124), imipenem (125), and penipenem (126) areexamples of the most potent types of antibacterial agents and areamong those used as the last resort weapon against the mostserious infections in clinical practice (Scheme 57). All of thempossess a bicyclic skeleton with a characteristic pattern of ab-solute configuration of the key stereogenic centers responsiblefor high antibiotic activity. Recently, our laboratory reported76

that diastereoselective Kinugasa reaction involving five-membered nitrones, such as 75, 77, and 79, derived from pen-tofuranoses, and simple non-chiral or chiral acetylenes providedan interesting entry to carbapenam antibiotics. The reactionsproceeded in moderate to good yield and displayed high dia-stereoselectivity affording predominantly one cis product. It

should be noted that the substitution and configuration of groupslocated next to either the double bond or the nitrogen atom ofthe nitrone could effectively control the configuration at thebridgehead carbon atom, which is essential for the biologicalactivity of the target antibiotic. For example, the copper(I)-catalyzed reaction between (R)-but-3-yn-2-ol and 2-deoxy-ri-bose-derived L-threo-nitrone 77 led to carbapenam product 19along with respective trans isomer 20, with the same configu-ration at bridgehead carbon atom of the carbapenam skeleton(Scheme 57). Bearing in mind the structure and configuration ofcarbapenam antibiotics, the use of nitrone 77 yields the mostattractive results, furnishing products with the desired sub-stitution in the pyrrolidine ring. This, in turn, enables in-troduction of the required side chains in subsequent steps of the

Scheme 55. Kinugasa reaction of nitrone 119 with alkyne 33.97

Scheme 56. A formal synthesis of ezetimibe 116.97

Scheme 57. Synthesis of carbapenem scaffold via Kinugasa reaction.76


synthesis, as well furnishing proper configuration both at thebridgehead carbon atom and within the side chain. It was dem-onstrated that the epimerization at C-6 of the carbapenamskeleton from cis to trans arrangement of the involved protonscould be easily accomplished in the presence of 2 equiv KHMDSto give the desired isomer 20 in 55% yield (Scheme 20).76

Recently, we have also presented98 a simple strategy for thepreparation of 2-azetidinone 132, which is known to be a directindustrial precursor of various commercially available carbapenem

antibiotics.99,100 The key step was Kinugasa reaction betweennitrone 127 and alkyne 128 derived from D-lactic acid. Corre-sponding b-lactam product 130 was obtained as a 3:1 mixture ofdiastereomers (Scheme 58). Subsequent debenzylation with so-dium in liquid ammonia and oxidation of intermediate 131 withlead tetraacetate furnished lactam 132. The actual reaction path-way is not fully understood. Initially formed Kinugasa copperenolate 129 undergoes either protonation anti to the benzylox-ycarbonyl group, a proton shift from C-4 to C-3 carbon atom and

Scheme 58. Synthesis of 2-azetidinone 132.98


subsequent epimerization, or protonation at C-4 carbon atom ofthe b-lactam.

Owing to the linear symmetry of triple bond, the nitrone ap-proaches the acetylene molecule between the small and the me-dium substituent. Since nitrones derived from glyoxalates exist asa mixture of both possible conformations, two syn substituents ofthe C]N double bond (oxygen atom and benzyloxycarbonyl, orbenzyl and benzyloxycarbonyl) are directed toward the hydrogenatom of the acetylene stereogenic center (Fig. 6). Proposed transi-tion state geometries should produce the same configuration at C-4carbon atom of the b-lactam ring for both conformations of thenitrone, which satisfactorily explains the observed high stereo-selectivity of Kinugasa cascade leading to final product 132.

Fig. 6. Possible transition states for the reaction of nitrone 127 and alkyne 128.

5. Conclusions

Our intention was to demonstrate that the reaction discoveredby Kinugasa and Hashimoto40 remains not fully explored andcontinues to offer attractive opportunities for progress in the syn-thesis of therapeutically useful b-lactam products. Further de-velopments in this area may potentially put this reaction in theranks of the most useful methodologies applicable for the con-struction of the b-lactam four-membered ring. In contrast with thepopular [2þ2]-cycloaddition as well as the enolateeimine con-densation, Kinugasa reaction, owing to the relatively well-definedtransition state of the 1,3-dipolar cycloaddition step, promises tooffer better stereocontrol of the process. Moreover, the wide ac-cessibility and relatively high stability of starting materials consti-tute an environment with few restrictions for the elaboration ofa wide variety of b-lactam compounds.

Acknowledgements

Financial support by the European Union within European Re-gional Development Fund, Project No. POIG.01.01.02.-14-102/09 isgratefully acknowledged.

References and notes

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