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530 Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams Katherine M. Byrd Review Open Access Address: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive Lawrence, Kansas 66045-7582, USA Email: Katherine M. Byrd - [email protected] Keywords: α,β-unsaturated amides; α,β-unsaturated lactams; conjugate addition; Michael addition Beilstein J. Org. Chem. 2015, 11, 530–562. doi:10.3762/bjoc.11.60 Received: 28 January 2015 Accepted: 01 April 2015 Published: 23 April 2015 Associate Editor: J. N. Johnston © 2015 Byrd; licensee Beilstein-Institut. License and terms: see end of document. Abstract The conjugate addition reaction has been a useful tool in the formation of carbon–carbon bonds. The utility of this reaction has been demonstrated in the synthesis of many natural products, materials, and pharmacological agents. In the last three decades, there has been a significant increase in the development of asymmetric variants of this reaction. Unfortunately, conjugate addition reactions using α,β-unsaturated amides and lactams remain underdeveloped due to their inherently low reactivity. This review highlights the work that has been done on both diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams. 530 Introduction Conjugate (or 1,4- or Michael) additions [1-5] are some of the most powerful carbon–carbon bond forming reactions in the synthetic chemist’s toolbox. These reactions have been the key step in the syntheses of numerous natural products and pharma- ceutically relevant compounds [6-11]. A conjugate addition (CA) reaction involves the addition of a nucleophile to an elec- tron-deficient double or triple bond (Scheme 1). The addition takes place at the carbon that is β to the electron-withdrawing group (EWG), resulting in the formation of a stabilized carban- ion intermediate. At this point, the carbanion can be either protonated to form the β-substituted product or an electrophile can be added to form the α,β-disubstituted product. The latter operation is often referred to as a three-component coupling due to the combination of the original unsaturated compound, the nucleophile, and the electrophile. In 1883, Komnenos reported the first conjugate addition where he added the diethyl malonate anion to ethylidene malonate [12]. This reaction was not fully investigated until 1887, when Michael thoroughly studied this reaction using various stabi- lized nucleophiles and α,β-unsaturated systems [13]. Most of the early work, including Michael’s, involved the use of stabi- lized or “soft” [14] nucleophiles such as malonates and nitroalkanes. Mechanistically, one can imagine a 1,2-addition of the nucleophile occurring versus the 1,4-addition if the EWG is a carbonyl compound, but this is not observed when malonates

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  • 530

    Diastereoselective and enantioselective conjugate additionreactions utilizing ,-unsaturated amides and lactamsKatherine M. Byrd

    Review Open AccessAddress:Department of Medicinal Chemistry, University of Kansas, 1251Wescoe Hall Drive Lawrence, Kansas 66045-7582, USA

    Email:Katherine M. Byrd - [email protected]

    Keywords:,-unsaturated amides; ,-unsaturated lactams; conjugate addition;Michael addition

    Beilstein J. Org. Chem. 2015, 11, 530562.doi:10.3762/bjoc.11.60

    Received: 28 January 2015Accepted: 01 April 2015Published: 23 April 2015

    Associate Editor: J. N. Johnston

    2015 Byrd; licensee Beilstein-Institut.License and terms: see end of document.

    AbstractThe conjugate addition reaction has been a useful tool in the formation of carboncarbon bonds. The utility of this reaction has beendemonstrated in the synthesis of many natural products, materials, and pharmacological agents. In the last three decades, there hasbeen a significant increase in the development of asymmetric variants of this reaction. Unfortunately, conjugate addition reactionsusing ,-unsaturated amides and lactams remain underdeveloped due to their inherently low reactivity. This review highlights thework that has been done on both diastereoselective and enantioselective conjugate addition reactions utilizing ,-unsaturatedamides and lactams.

    530

    IntroductionConjugate (or 1,4- or Michael) additions [1-5] are some of themost powerful carboncarbon bond forming reactions in thesynthetic chemists toolbox. These reactions have been the keystep in the syntheses of numerous natural products and pharma-ceutically relevant compounds [6-11]. A conjugate addition(CA) reaction involves the addition of a nucleophile to an elec-tron-deficient double or triple bond (Scheme 1). The additiontakes place at the carbon that is to the electron-withdrawinggroup (EWG), resulting in the formation of a stabilized carban-ion intermediate. At this point, the carbanion can be eitherprotonated to form the -substituted product or an electrophilecan be added to form the ,-disubstituted product. The latteroperation is often referred to as a three-component coupling due

    to the combination of the original unsaturated compound, thenucleophile, and the electrophile.

    In 1883, Komnenos reported the first conjugate addition wherehe added the diethyl malonate anion to ethylidene malonate[12]. This reaction was not fully investigated until 1887, whenMichael thoroughly studied this reaction using various stabi-lized nucleophiles and ,-unsaturated systems [13]. Most ofthe early work, including Michaels, involved the use of stabi-lized or soft [14] nucleophiles such as malonates andnitroalkanes. Mechanistically, one can imagine a 1,2-addition ofthe nucleophile occurring versus the 1,4-addition if the EWG isa carbonyl compound, but this is not observed when malonates

    http://www.beilstein-journals.org/bjoc/about/openAccess.htmmailto:[email protected]://dx.doi.org/10.3762%2Fbjoc.11.60

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    Scheme 1: Generic mechanism for the conjugate addition reaction.

    Figure 1: Methods to activate unsaturated amide/lactam systems.

    are used as nucleophiles. It has now been well established thatsoft nucleophiles prefer a 1,4-attack whereas hard nucleo-philes such as organomagnesium and lithium reagents prefer a1,2-attack.

    Within the past couple of decades, there has been a focus on thedevelopment of asymmetric variants of the Michael reaction. Inearly studies, chemists relied on chiral auxiliaries [5], hetero-cuprates [15,16], or natural product-based [17] ligands to in-duce high to modest stereoselectivity. In 1991, Alexandre Alex-akis and co-workers reported the first asymmetric conjugate ad-dition reactions where they employed organocopper reagentsand chiral phosphorus-based ligands [18]. This breakthrough inthe field led to the development of different chiral ligands forasymmetric CA reactions. Another major advancementoccurred in 1997 when Feringas group developed the firstcatalytic, enantioselective tandem conjugate additionaldolreaction of cyclic enones [19]. While tandem conjugate addi-tion-functionalization reactions were well known prior toFeringas publication [20] (Scheme 1), this work was uniquebecause of the high enantioselectivity that was observedthrough the use of a chiral ligand. Since this publication, manygroups have developed methods to conduct tandem conjugateadditionalkylations, allylations and aldol reactions [21].Through the work of Alexakis, Feringa and others, the range ofMichael acceptors used in both CA and tandem CA-function-alization reactions have been expanded to include ,-unsatu-rated ketones, aldehydes, lactones, esters, nitroolefins, and to alesser extent ,-unsaturated amides and lactams.

    ReviewThe lack of development in the CA of ,-unsaturated amidesand lactams is not surprising because these substrates aresignificantly less reactive than other Michael acceptors. In orderto improve the reactivity of amides and lactams, they have beenmodified in the following manner: A) placing an EWG on thenitrogen [22], B) placing an EWG on the -carbon atom [23],C) converting the amide/lactam to a thioamide/lactam or D) ac-tivation by a Lewis acid [24] (Figure 1).

    Method A is the most common method for activating the amideor lactam system. Method B has been generally employed in thesynthesis of several natural products and pharmaceutical com-pounds [25]. When the starting substrate for the CA reaction isan unsaturated tertiary amide, the thioamide method is a usefulstrategy. Lewis acid activation (method D) has been usedcommonly for the 1,4-addition of stabilized nucleophiles, butthere are some exceptions. The need to activate amides andlactams adds a level of difficulty in developing asymmetric CA(ACA) reactions.

    Not surprisingly, a limited number of reviews focus on ACAreactions that are performed using ,-unsaturated amides orlactams as Michael acceptors. In the many reviews that havebeen published on CA reactions, there are only a handful ofexamples provided where ,-unsaturated amides or lactams areMichael acceptors. Since ,-unsaturated amides and lactamsare less reactive, the ACA reactions that have been developedfor ,-unsaturated ketones, esters and other substrates, would

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    Scheme 2: DCA of Grignard reagents to an L-ephedrine derived chiral ,unsaturated amide.

    not necessarily work well on ,-unsaturated amides andlactams. Therefore, the focus of this review is to highlight thework that has been done on the development of diastereoselec-tive and enantioselective conjugate addition reactions using ,-unsaturated amides and lactams. This is not an exhaustiveaccount of all ACA reactions that employ ,-unsaturatedamides and lactams as Michael acceptors. Instead, the reviewaims to highlight significant work in this area. Though, themajority of the review will focus on examples where carbon nu-cleophiles are utilized; there are examples where heteronucleo-philes are used throughout the review. There are only a coupleof examples of sulfa-Michael additions that are mentioned inthis review because this topic has recently been reviewed [26].In terms of the mechanisms of the CA reactions, only thosemechanisms that differ from the generally accepted ones will bediscussed [4,27]. Finally, the terms conjugate addition, Michaeladdition and 1,4-addition will be used interchangeably through-out this review.

    1 Diastereoselective conjugate additions(DCA)Though CA reactions had been studied for decades, significantprogress in the development of CA reactions using ,-unsatu-rated amides and lactams was not observed until the 1980s [28-31]. Initial efforts toward performing the asymmetric CA reac-tions focused on the development of diastereoselective CA reac-tions. These reactions were achieved by performing conjugateadditions to chiral Michael acceptors that blocked one face ofthe double bond from the incoming nucleophile, thus preferen-tially producing one diastereomer over the other. The chiralityof the Michael acceptors can be attributed to one of two factors:1) use of a chiral auxiliary attached to the nitrogen or 2) existingstereochemistry of the acceptor. In this section, we will brieflydiscuss the use of both types of chiral Michael acceptors inDCA of ,-unsaturated amides and lactams.

    1.1 DCA using chiral auxiliariesChiral auxiliaries have been useful tools to induce stereoselec-tivity in CC bond forming reactions [5,32-34]. Ideally, thesecompounds are stable, easily attached, removed and recover-able. One of the first examples of a DCA reaction using a chiralauxiliary was done by Mukaiyama and Iwasawa in 1981 [28].

    DCA reactions were performed on a series of ,-unsaturatedamides, which employed L-ephedrine as a chiral auxiliary(Scheme 2).

    Mechanistically, it was supposed that the Grignard reagentformed an internal chelate between the nitrogen and the oxygenon the auxiliary that locked the conformation of the molecule.The excess Grignard reagent would add to the double bondfrom the less sterically hindered side, thus leading to the diaste-reoselectivity. Note that when using Grignard reagents as nu-cleophiles in CA reactions, the possibility of the 1,2-addition ofthe carbonyl group is always a concern. In this case, the 1,2-ad-dition product was not observed. The authors concluded that the1,2-addition reaction did not occur because the magnesium saltsthat were present in the solution would be chelated strongly bythe oxygen in the chiral auxil iary and the oxygenof the resulting enolate of the CA reaction. This chelation tothe magnesium would retard the 1,2-addition reaction fromoccurring.

    Since the Mukaiyama publication, there have been many chiralauxiliaries studied in DCA reactions of ,-unsaturated amides[35]. Figure 2 highlights a few of the most common chiralauxiliaries that have been used.

    Like the Mukaiyama example, the Oppolzer auxiliary (4) wasused in DCA reactions with Grignard reagents [36,37]. Theadvantages of using this auxiliary are that it is readily availablefrom () or (+)-camphor-10-sulfonyl chloride, both the startingN-enoyl sultam and the product from the DCA reaction can bepurified by recrystallization, and the auxiliary is easilyremoved. Another sultam-based chiral auxiliary that has beenused is bicycle 5 [38]. The authors were able to demonstratethat use of auxiliary 5 in the DCA reaction of 11 provided anincrease in diastereoselectivity and a higher yield of the prod-uct after deprotection of the sultam group over the Oppolzerauxiliary (Scheme 3).

    The Evans auxiliary 6 has been used extensively in severalasymmetric transformations such alkylations, allylations andmost notably for aldol reactions [33,39]. It has also beenutilized in DCA reactions of ,-unsaturated amides [40-44].

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    Figure 2: Chiral auxiliaries used in DCA reactions.

    Scheme 3: Comparison between auxiliary 5 and the Oppolzer auxiliary in a DCA reaction.

    Scheme 4: Use of Evans auxiliary in a DCA reaction.

    One of the first examples was published by Hruby andco-workers, where they added Grignard reagents, in the pres-ence of a CuBr(CH3)2S complex, to a series of ,-unsatu-rated-N-alkenoyl-2-oxazolidinones [43] (Scheme 4).

    The diastereoselectivity of the reactions using the Evans auxil-iary is attributed to the ability of the Lewis acidic metal to forma complex between the two carbonyl oxygens (Figure 3).

    This Lewis acid complex locks the molecule into one con-formation, thus facilitating the diastereoselectivity. Though thestructure depicted in Figure 3 is considered the standard modelfor diastereoselectivity, there are examples where changes in theLewis acid, nature of the organocuprate, or choice of the chiralauxiliary can show a reversal in the diastereoselectivity of DCA

    Figure 3: Lewis acid complex of the Evans auxiliary [43].

    reactions [40,45]. Other auxiliaries such as trityloxymethyl--butyrolactam (7) [45,46], (4R,5S)-1,5-dimethyl-4-phenyl-2-imidazolidionone (8) [47] and ethyl (S)-4,4-dimethylpyrogluta-

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    Scheme 5: DCA reactions of ,-unsaturated amides utilizing (S,S)-(+)-pseudoephedrine and the OTBS-derivative as chiral auxiliaries.

    Scheme 6: An example of a tandem conjugate addition-alkylation reaction of an ,-unsaturated amide utilizing (S,S)-(+)-pseudoephedrine.

    mate (9) [48] have been used in DCA reactions with ,-unsatu-rated amides, though to a lesser extent than the Evans auxiliary.

    In recent years, (S,S)-(+)-pseudoephedrine has emerged as achiral auxiliary for the use in DCA reactions of ,-unsaturatedamides [49-54]. Bada and co-workers published a report wherethey performed aza-Michael additions to various ,-unsatu-rated amides attached to (S,S)-(+)-pseudoephedrine [51](Scheme 5).

    Interestingly, when the oxygen in (S,S)-(+)-pseudoephedrinewas protected, a reversal in diastereoselectivity was observed[54]. The authors attributed the difference in diastereoselectiv-ity to the fact that when unmodified (S,S)-(+)-pseudoephedrineis used, a lithium alkoxide is produced in the presence of thelithium amide nucleophile. This alkoxide is believed to directthe addition of the lithium amide through coordination(Figure 4). On the other hand, when the oxygen in pseu-doephedrine is TBS-protected (OTBS-15), this group stericallyblocks one side of the double bond, thus the nucleophile attacksthe opposite face.

    Prior to the development of the diastereoselective aza-Michaelreactions, (S,S)-(+)-pseudoephedrine had been used as a chiralauxiliary for the diastereoselective -alkylation of amides [55-57]. This literature precedent aided in the development of thetandem conjugate addition-alkylation reactions using (S,S)-(+)-pseudoephedrine as a chiral auxiliary [49,50] (Scheme 6).

    Figure 4: Proposed model accounting for the diastereoselectivityobserved in the 1,4-addition of Bn2NLi to ,-unsaturated amides at-tached to (S,S)-(+)-pseudoephedrine. Reprinted with permission fromJ. Org. Chem., 2005, 70, 87908800. Copyright 2005 American Chem-ical Society.

    These reactions proceeded with moderate to high yields(6396%) and high diastereoselectivities. The authors noted thatthe diastereoselectivity of the initial CA reaction does not affectthe stereochemical outcome of the alkylation step. In fact, theobserved diastereoselectivity of the alkylation step is in agree-ment with previous reports on the diastereoselective -alkyl-ation of amides using (S,S)-(+)-pseudoephedrine as a chiralauxiliary [49,50,57].

    ,-Unsaturated aminoalcohol-derived bicyclic lactams havebeen particularly useful in the synthesis of several natural prod-ucts and pharmaceuticals [25,58-61]. Meyers and co-workersprovided some of the first examples of DCA reactions utilizing

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    Scheme 7: Conjugate addition to an ,-unsaturated bicyclic lactam leading to (+)-paroxetine and (+)-femoxetine.

    Scheme 8: Intramolecular conjugate addition reaction to ,-unsaturated amide.

    these unsaturated lactams. They were able to obtain the 1,4-ad-dition product in moderate to high yields and high diastereose-lectivites [62,63]. Afterwards, Amat and co-workers utilizedthese unsaturated lactams in several DCA reactions. Anexample of these reactions is shown in Scheme 7 where theconjugate addition of 20 provided the corresponding productboth in high yield and diastereoselectivity (97:3) [64].Following a series of steps, the 1,4-addition products wereconverted to either (+)-paroxetine (R = p-FC6H4) or (+)-femox-etine (R = C6H5) (Scheme 7).

    1.2 DCA to inherently chiral Michael acceptorsWhen DCA reactions are performed using a chiral Michaelacceptor, the diastereoselectivity is dictated by the overall ste-reochemistry of the Michael acceptor. The advantage of this ap-proach over the use of a chiral auxiliary is that the addition andremoval of a group to induce diastereoselectivity is not re-quired, hence making this approach more atom economical. The

    disadvantage of performing DCA reactions using chiralsubstrates is that the overall stereochemistry of the Michaelacceptor may either produce the undesired diastereomer in highyield or a low diastereoselectivity may be observed. Due to thecomplex nature of the chiral starting material, structuralchanges that would enhance the diastereoselectivity are typi-cally difficult to execute. Despite this disadvantage, this ap-proach has been utilized in the synthesis of several natural prod-ucts [7,8,25,65-70]. The following section highlights a coupleexamples.

    In 1993, Evans and Gauchet-Prunet developed a method tosynthesize protected syn-1,3-diols by performing intramolec-ular conjugate additions to a series of ,-unsaturated esters andamides [71] (Scheme 8).

    Upon treatment of 24 with KHMDS and benzyaldehyde, ahemiacetal forms which provides the alkoxide nucleophile for

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    Scheme 9: Conjugate addition to an ,-unsaturated pyroglutamate derivative.

    the DCA reaction. These reactions proceeded in good yields(7184%) and high diastereoselectivities. This work has beenuseful because the syn-1,3-diol moiety is commonly observedin many natural products, most notably in polyol macrolideantibiotics [72-74].

    Performing CA reactions on chiral lactams has been a commonmethod to access several natural products and unnatural aminoacids [58,75-77]. For example, Oba and co-workers performedconjugate additions to an ,-unsaturated pyroglutamatederivative where the carboxylic acid was protected as a5-methyl-2,7,8-trioxabicyclo[3.2.1]octane (ABO ester) [66](Scheme 9).

    The authors were able to execute the conjugate addition of 26using a Gilman reagent in high yield. The diastereoselectivitywas not determined for the CA product. Instead, the authorsconverted the product to 3-methylglutamic acid 28 and theywere able to observe only one diastereomer.

    DCA reactions have been shown to be a useful method toperform asymmetric CA reactions. Initially, these reactionswere done using chiral auxiliaries, which have provided the 1,4-addition product in high yield and diastereoselectivity. The useof chiral auxiliaries in DCA reactions has been useful becausethey can be easily attached and removed or transformed into avariety of functional groups. Though the utility of chiral auxil-iaries in DCA reactions has been demonstrated in ,-unsatu-rated amides, this method has not been extensively applied to,-unsaturated lactams. Another drawback to this approach isthat a stoichiometric amount of the chiral auxiliary is requiredto induce diastereoselectivity. On the other hand, both ,-unsaturated amides and lactams have been utilized as chiralMichael acceptors in DCA reactions. These reactions, whichrely on the inherent stereochemical information of the Michaelacceptor, have been useful in the synthesis of a number ofnatural products and pharmaceutical agents.

    2 Enantioselective conjugate additions (ECA)Enantioselective conjugate addition (ECA) reactions, especiallycatalytic variants, address the limitations of DCA reactions.ECA reactions do not require the addition and/or removal of

    groups on the Michael acceptor in order to achieve good stereo-selectivity, which makes these reactions atom economical.Also, the low catalyst loading allows for the use of a variety ofchiral ligands. Herein, various types of ECA reactions arediscussed.

    2.1 Copper-catalyzed ECA reactionsDuring the early development of CA reactions, Grignardreagents were initially studied as potential nucleophiles forthese reactions. Unfortunately, mixtures of the 1,4-addition andthe acylation products were formed. Upon further investigation,it was discovered that the use of copper in CA reactions willpreferentially form the 1,4-addition product [1]. Since then,copper has been the most commonly used metal in DCA andECA reactions. In terms of the nucleophiles that are used,mainly alkyl organometallic reagents derived from zinc,aluminium, lithium and magnesium are used [1,3,4]. Alkenyl,alkynyl and aryl organometallic reagents have been used lessfrequently [78-84].

    Feringa and co-workers reported the first copper-catalyzed ECAreactions of ,-unsaturated lactams in 2004 [22]. They wereable to perform these reactions in high yields and enantio-selectivities by using a phosphoramide ligand [85]. Table 1highlights the different substrates and alkyl metal nucleophilesthat were studied in this work.

    Though the use of the Cbz group in the ECA reaction providedthe product in good yield and enantioselectivity (Table 1, entry1), entries 2 and 3 show that the best enantioselectivities wereobserved with the N-carboxyphenyl protecting group. Theauthors were also able to employ the more reactive alkylalu-minium reagents in this reaction, although there was a decreasein the enantioselectivity (Table 1, entries 5 and 6). When theECA of a 5-membered lactam was performed with anorganozinc reagent, the reaction proceeded with high conver-sion, but the product was isolated in low yield and enantio-selectivity (Table 1, entry 4). Alternatively, the authors tried touse the triethylaluminium reagent on the 5-membered lactam(Table 1, entry 7), but the enantioselectivity was worse thanusing diethylzinc. So far, this methodology is limited to using6-membered lactams.

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    Table 1: Copper-catalyzed ECA reactions of alkyl nucleophiles to ,-unsaturated lactams.

    Entry R/n RM Time (h) Conv. (yield) % ee (%)

    1 Bn/1 Et2Zn 3 100 (70) 752 Ph/1 Et2Zn 2 100 (65) 953 Ph/1 Bu2Zn 4 100 (52) >904 t-Bu/0 Et2Zn 4 90 (15) 355 Ph/1 Me3Al 2 100 (78) 686 Ph/1 Et3Al 1 100 (88) 287 t-Bu/0 Et3Al 2 95 (25) 3

    Table 2: Copper-catalyzed ECA reactions of alkenyl nucleophiles to an ,- unsaturated lactam.

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

    1 H n-Bu H 53 862 H n-Bu H 70 863 H Cy H 54 824 H t-Bu H 66 725 H (CH2)3Cl H 58 846 H Ph H 69 907 Me H H 54 748 n-Bu H H 30 519 H H CH2O-t-Bu 47 12

    In 2013, Alexakis and co-workers reported the copper-catalyzedenantioselective 1,4-addition of a variety alkyl- and alkenyl-alanes to N-protected 5,6-dihydropyrrolinones [86]. In theirreport, they applied the same system that they developed for theasymmetric 1,4-addition of alkenylalanes to N-substituted-2,3-dehydro-4-piperidones [78]. It is important to note that additionof trimethylaluminium as a coactivator was necessary for thesereactions to work [78,87] (Table 2).

    Overall, the reactions in Table 2 show that moderate to goodyields and good enantioselectivities can be achieved with a

    variety of alkenylalanes. Most notably, this methodology canbe applied to the addition of functionalized alkenyl groups(Table 2, entry 5).

    The authors also applied their methodology to the 1,4-additionof alkylalanes to an ,-unsaturated lactam (Table 3).

    As compared to Feringas work with alkylalanes, yields of thesereactions are lower, but the enantioselectivities are much higher.It is important to note that use of triethylaluminium in Alexakiswork and diethylzinc in Feringas work provided the desired

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    Table 3: Copper-catalyzed ECA reactions of alkylalane nucleophiles to an ,-unsaturated lactam.

    Entry R Yield (%) ee (%)

    1 Me 54 942 Et 45 963 iBu 42 864 Ph 51 86

    Table 4: Copper-catalyzed ECA of alkylzinc reagents to ,-unsaturated N-alkenoyloxazolidinones.

    Entry R Zn(alkyl)2 Mol % 37 Mol % Cu salt Time [h] Yield (%) ee (%)

    1 Me ZnEt2 2.4 1.0 1.3 95 952 Me Zn[iPr(CH2)3]2 5.0 1.0 12 61 933 Me Zn(iPr)2 2.4 0.5 15 95 764 n-Pr ZnEt2 2.4 1.0 3 86 945 n-Pr Zn[iPr(CH2)3]2 2.4 1.0 24 89 956 (CH2)3OTBS ZnEt2 2.4 1.0 6 95 >987 iPr ZnEt2 2.4 1.0 24 88 92

    1,4-addition product in comparable yield and enantioselectivity.Also, Alexakis and co-workers expanded the scope of this reac-tion by performing the 1,4-addition with triisobutylaluminiumand triphenylaluminium (Table 3, entries 3 and 4), whichprovided the products in moderate yields and high enanitoselec-tivities.

    So far, only copper-catalyzed ECA reactions of ,-unsaturatedlactams have been discussed. These reactions have also beenapplied to ,-unsaturated N-alkenoyloxazolidinones. Forinstance, Hird and Hoveyda developed the copper-catalyzedasymmetric 1,4-addition of alkylzinc reagents to ,-unsatu-rated N- alkenoyloxazolidinones [88]. The authors employed achiral triamide phosphane in order to induce stereoselectivity,

    which is quite different from other chiral ligands that have beenused in ECA reactions. The Hoveyda group has utilized aminoacid-based ligands, which were rapidly identified throughparallel screening methods [89,90], for ECA of a variety ofMichael acceptors [91-94]. Table 4 shows a series of ,-unsat-urated N-alkenoyloxazolidinones that were used in the copper-catalyzed asymmetric 1,4-addition.

    As shown in Table 4, these 1,4-addition reactions proceededwith good to excellent yields and enantioselectivities.

    In 2006, Pineschi and co-workers reported the copper-catalyzedasymmetric 1,4-addition of alkylzinc reagents to acyclic ,-unsaturated imides [95]. In this case, the authors used a phos-

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    Table 5: Copper-catalyzed asymmetric 1,4-additions of alkylzinc reagents to acyclic ,-unsaturated imides.

    Entry R Alkyl Yield (%) ee (%)

    1 Pr Et 80 842 Me iPr 78 603 iPr Et 75 954 Ph Et 78 985 p-CF3C6H4 Et 84 >996 p-OMeC6H4 Et 74 94

    Scheme 10: Cu(I)NHC-catalyzed asymmetric silylation of ,-unsaturated lactams and amides.

    phoramidite as the chiral ligand. They were also able to obtainthe 1,4-addition product for ,-unsaturated substrates that hadan aryl group on the -position, which was not achieved withthe methodology that was developed by Hird and Hoveyda.Table 5 highlights selected examples of this reaction.

    The reaction proceeded in moderate to high yield and with goodto high enantioselectivities.

    Though carbon nucleophiles are used in the majority of thecopper-catalyzed ECA reactions of ,-unsaturated amides andlactams, Procter and co-workers have expanded this method-ology to the addition of silicon [96]. This reaction is particu-larly useful because the silyl group can be transformed into a

    number of functional groups [97]. In Procters work, they useda Cu(I)NHC (N-heterocyclic carbene) system to catalyze theasymmetric transfer of silicon from PhMe2SiBpin [98,99] to,-unsaturated amides and lactams through activation of theSiB bond [96] (Scheme 10).

    Scheme 10 shows selected examples of the ,-unsaturatedlactams and amides that were used for the 1,4-silylation.Overall, the reactions were achieved in both high yields andenantioselectivities with a variety of substrates.

    In addition to silicon, much work has been done on the asym-metric 1,4-additon of boron to ,-unsaturated carbonyl com-pounds. Enantioenriched organoboron reagents are useful

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    Scheme 11: Asymmetric copper-catalyzed 1,4-borylation of an ,-unsaturated amide.

    Scheme 12: Asymmetric cross-coupling 49 to phenyl chloride.

    because they can be used in cross-coupling reactions [98,100]or they can be converted into the corresponding alcohol [101]while retaining the stereochemical information. Transitionmetals such as Cu [102-112], Rh [113-115], Ni [116,117], Pd[116,118] and Pt [119,120] have all been successfully used tocatalyze the 1,4-additon of boron to ,-unsaturated carbonylcompounds. Of the transition metals mentioned, copper is themost cost-effective and least toxic choice. Though there aremany examples of copper-catalyzed 1,4-additions of boron,most of the reports use bis(pinacolato)diboron (B2pin2) as asource of boron. In 2013, Molander and co-workers reported theasymmetric 1,4-addition of bisboronic acid (BBA) andtetrakis(dimethylamino)diboron to various ,-unsaturated car-bonyl compounds [121]. Use of bisboronic acid and tetrakis(di-methylamino)diboron provides boron sources that are moreatom economical than B2pin2. Scheme 11 shows an example ofthe asymmetric 1,4-borylation where the authors used an ,-unsaturated amide as the Michael acceptor.

    The authors were able to obtain high yields and enantio-selectivities for a variety of ,-unsaturated carbonyl com-pounds. Also, they cross-coupled the -borylated amideswith various aryl and heteroaryl chlorides to yield the-(hetero)arylated amides in high yields while maintainingstereochemical integrity. Scheme 12 shows an example of thiscross-coupling reaction.

    So far, there are not many examples of copper-catalyzed ECAreactions of ,-unsaturated amides and lactams. One limita-

    tion to the methodology that has already been reported is that1,4-addition of carbon nucleophiles to pyrrolinones have onlyresulted in low yields and enantioselectivities. Compared to thenumber of existing methods for copper-catalyzed ECA reac-tions of ,-unsaturated ketones and other substrates, there isdefinitely a need for additional research in this area.

    2.2 Rhodium-catalyzed ECA reactionsUnlike copper-catalyzed CA reactions, the analogous rhodium-catalyzed reactions have only been developed in the last coupleof decades. In 1997, Miyaura and co-workers reported the firstexamples of rhodium being used in 1,4-addition reactions. Inthis report, they used a rhodium(I) catalyst to perform 1,4-addi-tions of aryl- and alkenylboronic acids to ,-unsaturatedketones [122]. One year later, Hayashi and Miyaura reportedthe asymmetric variant of this reaction [123]. Since the publica-tion of these seminal papers, rhodium has been used exten-sively in ECA reactions [124-135].

    Rhodium-catalyzed ECA reactions have many advantages overthe copper variant: (1) The reactions can be performed in proticor aqueous solvents. (2) Aryl-, alkenyl- and alkynyl nucleo-philes are routinely used, where there are only limited exam-ples in the copper-catalyzed version. (Note: In contrast, therehave not been any rhodium-catalyzed CA reactions of alkyl nu-cleophiles.) Finally, (3) no 1,2-addition is observed in therhodium variant because the organometallic reagents that areused are less reactive than the organolithium and -magnesiumreagents used in the copper-catalyzed reactions [125].

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    Scheme 13: Rhodium-catalyzed asymmetric 1,4-arylation of an ,-unsaturated lactam.

    Scheme 14: Rhodium-catalyzed asymmetric 1,4-arylation of an ,-unsaturated amide.

    One of the first examples of a rhodium-catalyzed asymmetric1,4-addition of lactams was reported by Hayashi andco-workers [136]. They reported that the key to achieving highyields for this reaction was to use arylboroxines instead of aryl-boronic acids and the addition of 1 equiv of water to boron.Also, highest yields were obtained when the reaction was run at40 C, which differs from reports where the reactions had to berun at 100 C when other Michael acceptors were used[123,130,137-141]. In order to demonstrate the utility of thisreaction, Hayashi and co-workers performed the rhodium-catalyzed ECA of 51 to yield 4-arylpiperidinone 52. Compound52 is a key intermediate in the synthesis of the pharmaceuticalagent, ()-paroxetine [142] (Scheme 13).

    In 2001, Sakuma and Miyaura reported the first rhodium-catalyzed asymmetric 1,4-addition of ,-unsaturated amides[143]. They were able to obtain high enantioselectivities using acatalyst generated from Rh(acac)(C2H4) and (S)-BINAP. Unfor-tunately, the 1,4-addition products were only obtained inmoderate yields because of incomplete conversion of thestarting material. This problem could be rectified by the addi-tion of an aqueous base. According to their discussion, theaqueous base converted the Rh(acac) complex to the corres-

    ponding RhOH complex. Such RhOH complexes have beenproposed in the literature as active intermediates in the trans-metallation of organoboronic acids [122,144,145]. Scheme 14highlights an example of the rhodium-catalyzed asymmetric1,4-addition of amides.

    In seminal reports for the rhodium-catalyzed ECA reactions,BINAP or a BINAP derivative was used as the chiral ligand forthese reactions. Hayashi in 2003 [146] and Carreira in 2004[147] demonstrated that chiral bicyclic dienes can act as usefulchiral ligands for rhodium-catalyzed ECA reactions. InCarreiras report, they examined the effectiveness of their dieneligand on the conjugate addition of an ,-unsaturated amide(Scheme 15). They were able to obtain the 1,4-addition productboth in high yield and enantioselectivity. Since the publicationof these results, many different types of chiral dienes have beenused in rhodium-catalyzed ECA reactions [148,149].

    In 2011, Lin and co-workers reported the rhodiumdiene-catalyzed asymmetric 1,4-arylation of -lactams [150]. ThoughHe and co-workers previously reported a 1,4-arylation of-lactams, they obtained the product in moderate yields andgood enantioselectivities [151]. When Lin and co-workers were

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    Scheme 15: Rhodium-catalyzed asymmetric 1,4-arylation of an ,-unsaturated amide using a chiral bicyclic diene.

    Scheme 16: Synthesis of (R)-()-baclofen through a rhodium-catalyzed asymmetric 1,4-arylation of lactam 58.

    developing their 1,4-arylation procedure, they decided to use achiral diene because the literature had shown that these ligandsprovide higher reactivities and enantioselectivities than phos-phine ligands in rhodium-catalyzed asymmetric reactions[152,153]. Scheme 16 shows the rhodium-catalyzed asym-metric 1,4-arylation that was developed by Lin and co-workersand the subsequent transformation to the GABAB receptoragonist, (R)-()-baclofen.

    Much of the work that has been discussed so far has employedthe use arylboron reagents. In recent years, organosiliconreagents have emerged as key players in organic synthesis dueto the their stability, low cost, and nontoxicity. Like organo-boron reagents, organosilicon reagents are readily available,tolerant to functional groups, and easy to handle. Thoughorganosilicon reagents have been used in rhodium-catalyzedasymmetric 1,4-additions, many of them rely on the use ofmoisture-sensitive organotri(alkoxy)silanes or the addition of anacid or base in order to obtain the product in high yield andenantioselectivity [154]. These observations led Hayashi,Hiyama and co-workers to develop mild conditions for therhodium-catalyzed asymmetric 1,4-arylation and alkenylation[155]. They employed a series of organo[2-(hydroxymethyl)-phenyl]dimethylsilanes [156-158] as organosilicon reagents andthey also used these conditions for the 1,4-addition of ,-unsat-urated amides and lactams (Scheme 17).

    Reaction 1 (Scheme 17) shows the rhodium-catalyzed 1,4-aryl-ation of Weinreb amide 64 using phenyl[2-(hydroxymethyl)-phenyl]dimethylsilanes. The authors were able to obtain the 1,4-addition product in quantitative yield in only 4 hours which iscontrary to other reports of rhodium-catalyzed 1,4-arylation of,-unsaturated amides, where 20 hours were required for thecompletion of the reactions [130,154]. The authors expandedtheir methodology to an asymmetric version which is shown inthe second reaction 2 of Scheme 17. Again the 1,4-additionproduct was obtained in high yield and enantioselectivity.

    Though both electron-rich and electron-poor aryl nucleophileshave been successfully added in rhodium-catalyzed asymmetric1,4-arylations, heteroaryl nucleophiles have not been employedas extensively. Martin and co-workers expanded the scope ofthe rhodium-catalyzed asymmetric 1,4-addition by the develop-ment of conditions using 2-heteroaryltitanates and -zincreagents [159]. With these conditions they obtained the 1,4-ad-dition products in moderate to good yields and excellentenantioselectivities. The authors were also able to apply themethodology to an ,-unsaturated lactam (Scheme 18).

    Though Binap and bicyclic diene ligands have been highlightedin this section, several other ligands have been used in rhodium-catalyzed asymmetric 1,4-additions of ,-unsaturated amidesand lactams (Figure 5).

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    Scheme 17: Rhodium-catalyzed asymmetric 1,4-arylation of an ,-unsaturated amide and lactam employing organo[2-(hydroxymethyl)phenyl]di-methylsilanes.

    Scheme 18: Rhodium-catalyzed asymmetric 1,4-arylation of an ,-unsaturated lactam employing benzofuran-2-ylzinc.

    Figure 5: Further chiral ligands that have been used in rhodium-catalyzed 1,4-additions of ,-unsaturated amides and lactams.

    Besides the previously referenced examples, (S)-Binap has alsobeen used in the 1,4-addition of aryltrialkoxysilanes to a seriesof ,-unsaturated amides [154]. In 2005, Hayashi andco-workers developed conditions for the 1,4-arylation ofvarious Weinreb amides, which utilized (S,S)-75 as the chiralligand [130]. Xu and co-workers developed various N-sulfinylhomoallylic amines (76) [160] and N-cinnamyl sulfonamides

    (77) [161] ligands for the rhodium-catalyzed asymmetric 1,4-arylation of a variety of ,-unsaturated carbonyl compounds.Finally, in 2012, Franzn and co-workers designed an indole-olefin-oxazoline (78) ligand for the 1,4-addition of ,-unsatu-rated lactones and lactams [148]. With these ligands the desiredproducts were obtained in moderate to excellent yields andgood to excellent enantioselectivities.

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    Scheme 19: Palladium-catalyzed asymmetric 1,4-arylation of arylsiloxanes to a ,-unsaturated lactam.

    Scheme 20: SmI2-mediated cyclization of ,-unsaturated Weinreb amides.

    This section illustrates that much work has been done in thedevelopment of asymmetric 1,4-arylations of ,-unsaturatedamides and lactams. The 1,4-arylation products were obtainedin high yields and enantioselectivities through the use of avariety of chiral ligands and rhodium sources. Unfortunately,there are no examples of the rhodium-catalyzed ECA of alkenyland alkynyl nucleophiles to ,-unsaturated amides andlactams, which remains an area that is underdeveloped.

    2.3 Other transition-metal-catalyzed ECA reactionsThough the majority of the reports on ECA of ,-unsaturatedamides and lactams utilize copper and rhodium as catalysts,other transition metals have also been used in these reactions.For example, Minnaard and co-workers developed the palla-dium-catalyzed asymmetric 1,4-arylation of arylsiloxanes to,-unsaturated carbonyl compounds [162]. The authors discov-ered that it was necessary to add a fluoride source to the reac-tion mixture in order to suppress side reactions, which has been

    reported by others to result in the isolation of the saturated car-bonyl compound and phenol [163-166]. They were able toapply this methodology to the asymmetric 1,4-addition oflactam 79 to afford the 4-phenyl product in moderate yield andhigh enantioselectivity (Scheme 19).

    Molander and Harris developed the samarium(II) iodide-medi-ated cyclization of ,-unsaturated esters and amides [167](Scheme 20). Previous methods for the cyclization of alkylhalides and ,-unsaturated carbonyl systems include: (1) tin-mediated radical cyclization [168] or (2) nucleophilc cycliza-tion via a carbanion generated through a lithiumhalogenexchange [169-171]. The first method has limited utilitybecause toxic byproducts are produced in the reaction that canbe difficult to remove. The application of the second method islimited because the high reactivity of the lithium reagentsrestricts the functional groups that can be present in the startingmaterial. The SmI2-mediated method provides a useful alter-

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    Scheme 21: MukaiyamaMichael addition of thioester silylketene acetal to ,-unsaturated N-alkenoyloxazolidinones.

    native because this reagent is mild and highly tolerant of func-tional groups.

    Since it is well known that SmI2 causes the 1,4-reduction of,-unsaturated systems [172], nickel(II) iodide was added toretard this reaction by modifying the reduction potential ofSmI2 [173,174]. The authors were pleased that the cyclizationof Weinreb amides 81 and 83 proceeded in high yields and dias-teroselectivities. As the authors used 5 equiv SmI2 in their reac-tion and it is well documented that SmI2 reduces NO bonds[172,175], the 1,4-addition product was isolated as the amide,which resulted from the reduction of the N-OMe bond. Use ofsmaller quantities of SmI2 in the reaction produced only thereductive cleavage product (NH) with no cyclization.

    2.4 Lewis acid-catalyzed ECA reactionsThis section will focus on Lewis acid-catalyzed ECA reactions,which employ stabilized nucleophiles such as silyl enol ethersand amines. Chiral Lewis acids play a dual role in these reac-tions. They activate the Michael acceptors by coordinating withthe carbonyl oxygen and they provide a chiral environment forthe reaction to occur. The first part of this section will focus onthe asymmetric 1,4-addition of carbon nucleophiles and the nexttwo parts will discuss the addition of amines (aza-Michael addi-tion) and phosphorous compounds.

    2.4.1 Asymmetric 1,4-addition of carbon nucleophiles: Sinceits initial discovery [176,177], the MukaiyamaMichael reac-tion has emerged as a reliable alternative to the use of metalenolates as nucleophiles in Michael reactions. Katsuki andco-workers reported the first application of this reaction to ,-unsaturated amides [178]. Their reactions were promoted byeither a Sc(OTf)33,3-bis(diethylaminomethyl)-1,1-bi-2-naph-

    thol complex (85) or Cu(OTf)2(S,S)-2,2-isopropylidene-bis(4-tert-butyl-2-oxazoline) complex (86) (Figure 6).

    Figure 6: Chiral Lewis acid complexes used in theMukaiyamaMichael addition of ,-unsaturated amides.

    The latter bis(oxazoline) and its derivatives have becomecommon chiral ligands in Lewis acid-mediated reactions [179].The Evans group has developed several methods forDielsAlder and aldol reactions that employed chiral bis(oxazo-line) copper(II) complexes [180]. Starting in 1999, Evans andco-workers published a series of papers which reported theMukaiyamaMichael addition to various ,-unsaturatedMichael acceptors [181-184]. Evans and co-workers alsoexpanded their methodology for the development of asym-metric MukaiyamaMichael addition of ,-unsaturatedN-acyloxazolidinones [182] (Scheme 21).

    As shown in Scheme 21, these reactions proceed in high yieldsand enantioselectivities. Also, this scheme demonstrates that thegeometry of the enolsilane drastically affects the diastereoselec-tivity of the reaction.

    Up to this point in this review, the use of alkynyl nucleophilesin the asymmetric 1,4-addition of ,-unsaturated amides andlactams has not been discussed. Though alkynyl nucleophiles

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    Scheme 22: Asymmetric 1,4-addition of aryl acetylides to ,-unsaturated thioamides.

    Scheme 23: Asymmetric 1,4-addition of alkyl acetylides to ,-unsaturated thioamides.

    (in the form of metal alkynylides) have been used in bothcopper [185-187] and rhodium-catalyzed [188-191] 1,4-addi-tion reactions, this methodology has not been expanded to theuse of ,-unsaturated amides and lactams as Michael accep-tors. This is probably due to the combination of the low reactiv-ity of these Michael acceptors and the low inherent nucleophi-licity of the metal alkynylides. In 2010, Shibasaki andco-workers developed the asymmetric 1,4-addition of terminalalkynes to ,-unsaturated thioamides [192]. In order to achievethis reaction, Shibasaki and co-workers used a soft Lewis acid/hard Brnsted base/hard Lewis base cooperative catalysissystem, a strategy that has been used in other reactions [193-196] (Scheme 22).

    In the case of the reaction above, the alkynylide was generatedfrom [Cu(CH3CN)4]PF6, (R)-3,5-iPr-4-Me2N-MeOBIPHEP,and Li(OC6H4-p-OMe) [197,198]. The hard Lewis base in thisreaction was bisphosphine oxide 95, which was added toenhance the Brnsted basicity of Li(OC6H4-p-OMe) by coordi-nating to the lithium counterion. The authors were able toobtain the 1,4-addition products in high yields and enantio-selectivities when they used various aryl acetylides. Also, thismethodology was expanded to various alkyl acetylides. In orderto obtain high enantioselectivities, they varied the coppersource, ligand and the hard Lewis base (Scheme 23).

    The authors demonstrated the utility of this reaction by applyingit towards the synthesis of a potent GPR40 agonist AMG 837[199]. Shibasaki and co-workers expanded their application ofsoft Lewis acid/hard Brnsted base cooperative catalysis to theasymmetric vinylogous conjugate addition of ,-unsaturatedbutyrolactones to ,-unsaturated thioamides [200]. This reac-tion provides a method for producing enantioenriched buteno-lide units, which are found in many natural products [201-204](Scheme 24).

    The reactions in Scheme 24 demonstrate that the vinylogousconjugate addition of unsaturated butyrolactones to ,-unsatu-rated thioamides proceeded in high yields, enantioselectivitiesand diastereoselectivities.

    Starting in 2005, Shibasaki and co-workers reported both thegadolinium and strontium-catalyzed asymmetric 1,4-cyanationof ,-unsaturated N-acylpyrroles [205-207]. N-Acylpyrroleshave proven to be useful alternatives to Weinreb amides,because they share many of the same advantages butN-acylpyrroles are more reactive at the carbonyl unit and thetetrahedral intermediate is more stable than the Weinreb amides[208]. Based on their previous work on the Strecker reaction[209-211], Shibasaki and co-workers used a gadolinium-basedcatalyst for the 1,4-cyanation (Scheme 25).

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    Scheme 24: Asymmetric vinylogous conjugate additions of unsaturated butyrolactones to ,-unsaturated thioamides.

    Scheme 25: Gd-catalyzed asymmetric 1,4-cyanation of ,-unsaturated N-acylpyrroles [205].

    Scheme 26: Lewis acid-catalyzed asymmetric 1,4-cyanation of ,-unsaturated N-acylpyrazole 107.

    Overall, this reaction proceeded in good to excellent yields andhigh enantioselectivies, with Michael acceptors having aryl oralkyl groups on the -carbon.

    In 2014, Wang and co-workers reported a Lewis acid-catalyzedasymmetric 1,4-cyanation of ,-unsaturated amides andketones [212]. Though much work has been done in the devel-opment of 1,4-cyanations of ,-unsaturated compounds [213-218], there are limited examples that use ,-unsaturatedamides as Michael acceptors [219]. Thus, the authors expandedthe scope of this reaction by using a chiral Lewis acid as a cata-

    lyst. After screening many ligands, magnesiumBINOL com-plex was identified as suitable catalyst for the 1,4-cyanation of107. The authors obtained the 1,4-cyano products in bothmoderate to high yields and enantioselectivities for a variety of-aryl substituted N-acylpyrazoles (Scheme 26).

    In 2007, Shibasaki and co-workers reported the asymmetric 1,4-addition of dibenzyl malonate to ,-unsaturated N-acylpyrrolescatalyzed by a La(OiPr)3linked BINOL complex [220].Optimal yields and enantioselectivies were realized by adding1,1,1,3,3,3-hexafluoroisopropanol (HIFP) to the reaction mix-

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    Scheme 27: Lewis acid mediated 1,4-addition of dibenzyl malonate to ,-unsaturated N-acylpyrroles.

    Scheme 28: Chiral Lewis acid mediated 1,4-radical addition to ,-unsaturated N-acyloxazolidinone [224].

    ture and by placing steric bulk near the lanthanide metal. Theauthors were able to achieve the asymmetric 1,4-addition ofdibenzyl malonate in good yields and enantioselectivies underthese conditions (Scheme 27).

    Lewis acid catalysts have also been used to promote asym-metric 1,4-addition of radicals to ,-unsaturated amides.Though there were a few previous reports of this reaction [221-223], Sibi and co-workers reported some of the first examplesof the 1,4-radical addition to ,-unsaturated N-alkenoylox-azolidinones using a substoichiometric amount of a chiral Lewisacid [224,225] (Scheme 28).

    The authors were only able to decrease the catalyst loading to20% in order to obtain the product in yields and enantio-selectivities that were comparable to reactions that used a stoi-chiometric amount of the catalyst. Lowering the catalyst

    loading any further only led to longer reaction times anddecreased yields.

    2.4.2 Asymmetric aza-Michael additions: Aza-Michael addi-tions have emerged as a powerful tool to form functionalizedamines [226-228]. This reaction has been most commonly usedto produce -amino acids and their derivatives [229,230]. Notsurprisingly, only a small amount of work in this area hasutilized ,-unsaturated amides or other carboxylic acidderivatives. This section will focus on the most significant find-ings that have been reported on the Lewis acid catalyzed aza-Michael additions of ,-unsaturated amides and lactams[231,232].

    One of the first examples of an aza-Michael addition to ,-unsaturated amides was reported by Sibi and co-workers [233].In this work, they performed the 1,4-addition of O-benzylhy-

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    Scheme 29: Aza-Michael addition of O-benzylhydroxylamine to an ,-unsaturated N-acylpyrazole.

    Scheme 30: An example of the aza-Michael addition of secondary aryl amines to an ,-unsaturated N-acyloxazolidinone.

    droxylamine to pyrazole-derived ,-unsaturated amides using achiral Lewis acid derived from bisoxazoline 116 (Scheme 29).

    The authors obtained the 1,4-addition products in optimal yieldsand enantioselectivities when 30 mol % of the catalyst wasused. Interestingly, when the Lewis acid is switched to thelanthanide triflate, Yb(OTf)3 or Y(OTf)2, the opposite configur-ation of the product was obtained (the S enantiomer wasobtained vs. the R enantiomer that is obtained when MgBr2 isused).

    In 2001, the Jrgensen group reported the first aza-Michael ad-dition of secondary aryl amines [234]. The authors obtained the1,4-addition products in moderate to high yields and enantio-selectivities by using a nickelDBFOXPh [235,236] catalyst(Scheme 30).

    Other chiral ligands have been used in addition to chiral bisox-azolines for asymmetric aza-Michael additions. For example,Hii and co-workers reported the first example of the use of apalladium(II) complex for the aza-Michael additions of selected,-unsaturated N-alkenoyloxazolidinones [237] (Scheme 31).

    This reaction worked best when aniline was the aromatic aminethat was used for the addition. Though the use of 4-Cl-C6H4NH2 gave similar results as with the parent compound

    aniline, the 1,4-addition reaction proceeded in high yield butlow enantioselectivity when 4-OMe-C6H4NH2 was used as thenucleophile. This result revealed that these reaction conditionsonly work for electron-deficient anilines. Despite this limita-tion, Hii and co-workers expanded the methodology to other,-unsaturated N-alkenoylbenzamides [238] and carbamates[239,240] (Scheme 32).

    In order to find means to overcome the low enantioselectivitiesobserved when electron-rich anilines are used in their protocolfor aza-Michael additions, Hii and co-workers performed adetailed mechanistic study of this reaction [241]. Based on thisstudy, the rate-limiting step of the aza-Michael addition was thecoordination of the catalyst to the 1,3-dicarbonyl moiety of theMichael acceptor. They were also able to determine that theaniline competitively binds to the catalyst. In order to avoiddeactivation of the catalyst by the free aniline, the authors main-tained a low aniline concentration during the reaction by using asyringe pump to add the aniline over 20 hours. Scheme 33shows the difference in observed enantioselectivity of the aza-Michael addition using the previous protocol and the slow addi-tion protocol.

    In the report by Sodeoka and co-workers, the authors took adifferent approach to increasing the enantioselectivity of the1,4-addition of electron-rich anilines [242]. To circumvent the

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    Scheme 31: Aza-Michael additions of anilines to a ,-unsaturated N-alkenoyloxazolidinone catalyzed by palladium(II) complex 123.

    Scheme 32: Aza-Michael additions of aniline to an ,-unsaturated N-alkenoylbenzamide and N-alkenoylcarbamate catalyzed by palladium(II) com-plex 126.

    Scheme 33: Difference between aza-Michael addition ran using the standard protocol versus the slow addition protocol.

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    Scheme 34: Aza-Michael additions of aryl amines salts to an ,-unsaturated N-alkenoyloxazolidinone catalyzed by palladium(II) complex 133.

    Scheme 35: Aza-Michael addition of N-alkenoyloxazolidiniones catalyzed by samarium diiodide [244].

    issues raised by the Hii study [241], they added 1 equiv of triflicacid to 1.5 equiv of aniline to create the anilinium salt. The ad-dition of the acid, along with the use of 133 as the chiral Lewisacid complex provided the 1,4-addition products in good toexcellent yields and excellent enantioselectivities when bothelectron-deficient and -rich anilines were added (Scheme 34).

    In 2008, Collin and co-workers developed the asymmetric aza-Michael addition of N-alkenoyloxazolidinones catalyzed byiodo(binaphtholato)samarium [243]. This group had previouslyreported the use of samarium diiodide in the 1,4-addition of arylamines to N-alkenoyloxazolidinones [244]. In that report, theysometimes obtained a mixture of products, where one was thedesired 1,4-addition product and the other product resulted fromthe 1,4-addition and acylation of the amine (Scheme 35). Theside product was formed in higher amounts when electron-richaryl amines were used.

    In the asymmetric variant of this reaction, Collin andco-workers discovered that reducing the temperature to 40 C

    diminished, and in some cases, eliminated the formation of theundesired product (Scheme 36). Overall, this iodo(binaphtho-lato)samarium-catalyzed asymmetric aza-Michael additionprovided the 1,4-addition products in low to good yields andlow to moderate enantioselectivities.

    Collin and co-workers also expanded this methodology to the1,4-addition of O-benzylhydroxylamine [245] (Scheme 37).Like the previous reactions, the formation of the undesired sideproduct could be reduced by lowering the reaction temperatureto 40 C. Overall, the 1,4-addition products were produced inmoderate to high yields and enantioselectivities.

    Up to this point, aza-Michael additions, which use eitheranilines or O-benzylhydroxylamine, have been discussed.Gandelman and Jacobsen reported the first asymmetric 1,4-ad-dition of various N-heterocycles to ,-unsaturated imides[246]. This reaction represented a novel approach to synthe-sizing functionalized chiral N-heterocycles, which are studied inareas such as material science [247,248] and biological chem-

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    Scheme 36: Asymmetric aza-Michael addition of p-anisidine to ,-unsaturated N-alkenoyloxazolidinones catalyzed byiodido(binaphtholato)samarium [243].

    Scheme 37: Asymmetric aza-Michael addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones catalyzed by iodido(binaphtholato)samarium.

    Scheme 38: Asymmetric 1,4-addition of purine to an ,-unsaturated N-alkenoylbenzamide catalyzed by (S,S)-(salen)Al.

    istry [249-252]. In the past, the Jacobsen group has used chiral(salen)Al complexes [253] as catalysts for the asymmetric 1,4-addition of azide [254], cyanide [219], substituted nitriles [255]and oximes [256] to ,-unsaturated imides. The authors usedthese previous studies as the basis for the development of the1,4-addition of N-heterocycles to ,-unsaturated imides. Theyapplied both substituted and unsubstituted purines, benzotri-azole, and 5-substituted tetrazoles as nucleophiles to this

    reaction, which resulted in moderate to excellent yields andexcellent enantioselectivities of the 1,4-addition products(Scheme 38).

    As shown in Scheme 38, two 1,4-addition products wereisolated because purine exists as a tautomeric mixture (N-7Hand N-9H). Under the optimal reaction conditions, the N-9regioisomer was produced preferentially.

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    Scheme 39: Asymmetric 1,4-addition of phosphites to ,-unsaturated N-acylpyrroles.

    Scheme 40: Asymmetric 1,4-addition of phosphine oxides to ,-unsaturated N-acylpyrroles.

    2.4.3 Asymmetric 1,4-addition of phosphorous compounds:Optically active, phosphorous-containing compounds, mostcommonly phosphates, have been studied in the context ofbiology and medicine for decades. Due to the facile enzymaticcleavage of phosphates, phosphonates have been studied asphosphate mimics for many years [257,258]. Though the 1,4-addition of phosphites provides a direct route for accessingchiral phosphonates, there are only a few examples of this reac-tion [259-264]. In 2009, Wang and co-workers reported one ofthe first catalytic, enantioselective 1,4-addition of phosphites to,-unsaturated N-acylpyrroles [265] (Scheme 39).

    In their work, diethylzinc and 147 acts as a bifunctional cata-lyst system where the ,-unsaturated system is activatedthrough Lewis acid coordination and the catalyst acts as adirecting group for the phosphite. Overall the reaction proceedsin both high yield and enantioselectivity. In 2010, Wang andco-workers expanded their methodology to the 1,4-addition ofphosphine oxides. Similar to their previous work, this reactionprovided the products in high yields and enantioselecitives[266] (Scheme 40).

    2.5 ECA employing organocatalystsOrganocatalysts have become powerful alternatives to performreactions which have traditionally been carried out using metalor Lewis acid catalysts [267,268]. These reactions are simple to

    accomplish, and the catalysts are easy to handle and store. Also,many catalysts are commercially available or can be easilysynthesized from commercially available materials. Organocat-alysts can be placed into two catagories: 1) catalysts that cova-lently attach themselves to the starting materials (e.g., enamine[269] and iminium [270] catalysis) and 2) catalysts that interactwith the starting materials through non-covalent interactions(e.g., hydrogen bonding [271]). In this section, the examples ofECA reaction of ,-unsaturated amides and lactams will fit inthe latter category.

    Wang and co-workers developed conditions to rapidly accessstereochemically-enriched thiochromanes through a tandemMichael-aldol reaction of 2-mercaptobenzaldehydes and ,-unsaturated imides [272]. This reaction was catalyzed by anorgancatalyst that contains a thiourea group that is able tohydrogen bond with the imide moiety and a tertiary amine,which acts as an activating/directing group by hydrogenbonding to the thiol. Scheme 41 shows an example of this reac-tion. Overall, this reaction produced the thiochromenes in highyields, enantioselectivites and diastereoselectivities.

    One drawback of this work is that the authors only employed-aryl-substituted ,-unsaturated N-alkenoyloxazolidinones.Dong and co-workers expanded the scope of this reaction byusing both -aryl and alkyl-substituted Michael acceptors for

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    Scheme 41: Tandem Michael-aldol reaction catalyzed by a hydrogen-bonding organocatalyst.

    Scheme 42: Examples of the sulfa-Michaelaldol reaction employing ,-unsaturated N-acylpyrazoles.

    the sulfa-Michaelaldol reaction [273]. Also, they replaced theoxazolidinone with a pyrazole on the Michael acceptor whichled to obtaining the 1,4-addition product in high yields, enantio-selectivities and diastereoselectivities (Scheme 42).

    A couple years after Wangs report on the tandem sulfa-Michaelaldol reactions, Deng and co-workers reported the useof a cinchona alkaloid catalyst in the simple asymmetric 1,4-ad-dition of thiols to ,-unsaturated N-alkenoyloxazolidinones[274] (Scheme 43).

    Under these conditions, the authors obtained the 1,4-additionproducts in excellent yields and enantioselectivities. In 2011,Chen and co-workers applied their cinchona alkaloid-based

    squaramide catalyst to the asymmetric sulfa-Michael addition of,-unsaturated N-alkenoyloxazolidinones [275] (Figure 7).Unlike the previous example in Scheme 43, products wereobtained in excellent yields and enantioselectivies while thesereactions were carried out at room temperature. Also, the scopeof the thiols used was expanded to include various alkylderivatives.

    For the past few years, Hoveyda and co-workers have reportedon the development of a metal-free, NHC-catalyzed method forthe 1,4-addition of boron to carbonyl compounds [276,277]. In2012, this group reported a catalytic, enantioselective version ofthis reaction, which included the use of a variety of ,-unsatu-rated carbonyl compounds [278]. They included the 1,4-boryla-

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    Scheme 43: Example of the sulfa-Michael addition of ,-unsaturated N-alkenoyloxazolidinones.

    Table 6: Enantioselective 1,4-borylation of ,-unsaturated Weinreb amides.

    Entry R Temp (C) Conv. (%) Yield (%) er

    1 Ph 50 86 61 86.5:13.52 p-BrC6H4 50 >98 70 94:63 n-pentyl 50 77 74 95:54 (CH2)2OTBS 66 96 92 93:75 iBu 66 78 73 95:56 iPr 50 67 60 95:5

    Figure 7: Structure of cinchona alkaloid-based squaramide catalyst.

    tion of ,-unsaturated Weinreb amides. Overall, these reac-tions proceeded in good to excellent yields and excellent enan-tioselectivies (Table 6).

    In 2013, Takemoto and co-workers developed an organocata-lyst-mediated asymmetric intramolecular oxa-Michael additionof ,-unsaturated esters and amides [279]. Though oxa-Michael additions of ,-unsaturated esters and amides havebeen reported in the literature [280], Takemotos work providesmild conditions for the reaction, which will minimize unwanted

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    Scheme 44: Asymmetric intramolecular oxa-Michael addition of an ,-unsaturated amide.

    Scheme 45: Formal synthesis atorvastatin.

    side reactions in the presence of a base. Scheme 44 shows anexample of this reaction.

    The authors generally obtained the oxa-Michael addition prod-ucts in good to high yields and excellent enantioselectivities. Inorder to demonstrate the utility of this reaction, the authors usedisoxazolidine 163 in the formal synthesis of atorvastatin [281-283] (Scheme 45).

    Isoxazolidine 163 was converted to the -amino--hydroxy-ester 164 after transforming the benzyl amide to the benzyl esterand cleaving the NO bond. Then, compound 164 wasconverted to the -keto ester 165 through a cross-Claisen con-densation. Ester 165 can be converted to atorvastatin after aseries of steps [284].

    ConclusionAsymmetric conjugate addition reactions have becomepowerful tools for the formation of stereochemically enriched

    CC, Cheteroatom bonds. The utility of these reactions havebeen demonstrated through their use in the synthesis ofnumerous natural products and pharmaceutical agents. The lastcouple of decades have shown a significant increase in thedevelopment of asymmetric conjugate addition reactions, espe-cially in the catalytic, enantioselective variants of these reac-tions. Unfortunately, much of this work does not include the useof ,-unsaturated amides and lactams due to their inherentlylow reactivity. This review highlights the work of authors whowere able to overcome this low reactivity in order to developdiastereoselective and enantioselective conjugate additions of,-unsaturated amides and lactams.

    Although ACA reactions using ,-unsaturated amides andlactams have been underdeveloped in general, much progresshas been made in the last two decades. One of the most signifi-cant developments occurred in the mid-2000s when Feringa andHoveyda/Pineschi reported some of the first methods for thecatalytic, enantioselective 1,4-addtion of alkyl nucleophiles.

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    This represented a significant breakthrough because these reac-tions had previous been well developed for other ,-unsatu-rated compounds. Also, the use of a variety of carbon nucleo-philes such as alkenyl, alkynyl and aryl nucleophiles and het-eronucleophiles such as amines, silanes and alcohols have beenreported. Often these reactions afford the product in high yieldsand enantioselectivities, thus providing valuable tools to access-substituted carboxylic acid derivatives.

    While progress has been made in the development of ACAreactions utilizing ,-unsaturated amides and lactams, there isstill work that needs to be done. For example, rhodium-catalyzed asymmetric 1,4-additions of alkenes and alkynes to,-unsaturated ketones and other substrates have been wellestablished, yet these reactions have not been applied to ,-unsaturated amides and lactams. Another area for developmentis the limited utilization of 5-membered lactams in ACA reac-tions. The 1,4-addition products of these substrates can easilybe converted to unnatural amino acids and other key intermedi-ates in the synthesis of a natural product or pharmacologicalagent. Thus there is still a need to continue making progress inthe development of asymmetric 1,4-addition reactions that use,-unsaturated amides and lactams as Michael acceptors.

    AcknowledgementsI would like to thank Dr. Paul Helquist for critically reading andproviding suggestions for this manuscript.

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