Mol Divers DOI 10.1007/s11030-013-9494-2
SHORT REVIEW
Recent advances in C-heteroatom bond forming by asymmetric Michael addition Majid M. Heravi · Parvin Hajiabbasi
Received: 10 April 2013 / Accepted: 2 December 2013 © Springer Science+Business Media Dordrecht 2013
Abstract In this review, we try to highlight the recently reported stereoselective Michael conjugate additions of heteroatom nucleophiles to electron-deficient alkenes. The topic is divided based on the nature of the nucleophile employed (nitrogen-, oxygen-, sulfur-, or phosphorus-centered) and then subdivided to distinguish between catalyst-controlled and substrate/reagent-controlled methods which is necessary to achieve asymmetric synthesis. Keywords Asymmetric synthesis · Michael addition · C-heteroatom bond formation · Enantioselectivity · Chiral catalyst · Chiral reagent
Introduction In the last decade many new bond-forming reactions have been reported and well established. Among them, the Michael addition could be considered distinct due to its significant atom economy for diastereoselective and enantioselective bond formation in asymmetric synthesis. Asymmetric C-heteroatom bond-forming reactions as a key step lead to many useful products such as biologically natural products that contain C–O bonds in the form of ether, ketone, or ester moieties in their structures, as well as the synthesis of pharmaceuticals that often contain C–N bonds, and heterocycles in which C–N, C–O, or C–S bonds are present in their ring structures. The catalytic asymmetric addition of phosphorus nucleophiles to electrophiles leads to C–P bond formation which is one of the most powerful methods to provide chiM. M. Heravi (B) · P. Hajiabbasi Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran e-mail: [email protected]
ral phosphorus-containing compounds as ligands for various metal-catalyzed asymmetric reactions. Alongside with the interest and literature reports for asymmetric C–C bond formation, herein we focus on an overview of asymmetric C-heteroatom bond-forming reactions involving conjugate additions with the hope that it will attract the attention of synthetic organic chemists. Some of the earliest examples of conjugate additions involve the C–C bond formation when Michael [1,2], after whom the Michael addition/reaction was named, investigated the addition of enolates of ketones and aldehydes to the β-carbon of α,β-unsaturated carbonyl compounds in 1887. Since then, asymmetric Michael reactions have attracted the attention of organic chemists. Various chiral substrates, reagents, and acids or bases as catalysts have been employed to develop this significant asymmetric reaction efficiently. In fact, the asymmetric Michael reaction started flourishing and thriving among synthetic organic chemists when Belokon et al. [3] for the first time reported a catalyzed asymmetric Michael reaction using chiral alkali metal alkoxides. In continuation of our interest concerning the recent applications of named reactions in organic synthesis [4–11], in this review we wish to highlight a number of recent and selected carbon–heteroatom bond formations via heteroatom Michael asymmetric addition as a key strategic step to produce various useful products, particularly in the total synthesis of natural products. Although the asymmetric aspects of the traditional Michael addition reaction have been thoroughly reviewed [12–17], heteroatom Michael additions have been less so [18–20], and asymmetric variants are even more limited [21–23]. Therefore, it is worthwhile to highlight recent and applicable examples in order to demonstrate the enormous potential of this method in organic chemistry and as an important synthetic tool for the synthesis of pharmaceutically relevant compounds.
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Mol Divers Scheme 1
C–N bond formation via asymmetric aza-Michael addition Nitrogen-containing heterocycles have broad applications in organic chemistry, material and life sciences [24–26]. C–N bond formation, accompanied by the generation of stereogenic centers, is found in the synthesis of many important biomolecules, such as amino acids [27] and glycosamines [28]. In the following section, we will introduce and highlight some typical processes for C–N bond forming. C–N bond formation using chiral catalysts Intermolecular processes An enantioselective Michael addition of ammonia (in the form of benzophenone imine 2) to nitroalkenes 1 was performed using thiourea 3 as an organocatalyst in heptane. A one-pot asymmetric aza-Michael addition–acidic hydrolysis protocol was performed with a number of aliphatic and aromatic nitroalkenes to achieve the synthesis of optically active β-amino nitro compounds with 60–80 % yields and 78–84 %ee (Scheme 1) [29]. (Note: newly formed C-heteroatom bonds are depicted in red; asterisk indicates location of chiral centers). The asymmetric aza-Michael addition of 1,2,4-triazole 6 to α,β-unsaturated ketone 5 was successfully carried out using a combination of primary amino thiourea 4 and 4-nitrobenzoic acid as organocatalyst to produce the desired product in high yield with moderate to excellent enantioselectivity. In addition, the application of the procedure for aryl and cyclic ketones 9 was shown by the reaction of cyclic enone 9, triazole 6, and amine thiourea 7 in the presence of 2-methoxybenzoic acid in toluene to preferably produce product 10 (Scheme 2) [30]. Mahé et al. [31] reported the enantioselective phasetransfer catalyzed synthesis of 3,5-diaryl pyrazolines 14 from
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chalcone derivatives 12 and N -aryl hydrazine 11 in a 1:1 ratio to give pyrazolines 14 as levo(−)-isomer (S). By using K3 PO4 (solid–liquid phase-transfer conditions) the enantiomeric excess was slightly improved; however, the reaction was slower and the yield was lower relative to those obtained when Cs2 CO3 was used. The chiral ammonium/amide ion pair generated by N -ortho-methoxybenzylquininium salt and N -acylhydrazines is used as catalyst in this protocol (Scheme 3). The enantioselective Michael addition of 1H -benzotriazole 15 to cyclic 19, acyclic 5, and enone (e.g., cyclohexenone) was accomplished using 9-amino-9-deoxyepiquinine 16 as an effective organocatalyst resulting in the preparation of desired products in high yields and with good to excellent enantioselectivities (Scheme 4) [32]. Fu et al. [33] prepared 2-substituted-1,5-benzodiazepine derivatives 25 from an enantioselective domino reaction involving O-phenylenediamine 23 and 2 -hydroxychalcones 22 using titanium complex with chiral ligand derived from (S)-BINOL and l-proline amide (Scheme 5). The presence of a 2 -hydroxy group in the α,β-unsaturated ketones was crucial for reactivity and high stereo induction in this protocol [33]. In the proposed catalytic cycle, the oxygen atom of the hydroxy group and the nitrogen atom of the imine moiety of this intermediate coordinate with the chiral titanium complex. The additions occur from the sterically less hindered side where an intramolecular hydrogen bond with the hydroxy group also causes the stabilization of an α,β-unsaturated ketimine intermediate [34]. β-Amino homopropargylic nitro compounds 28 are prepared by enantioselective Michael addition to nitroenynes 26 using P-spiro heterochiral arylaminophosphonium barfate · BArF 27 as chiral ionic Brønsted acid catalyst (Scheme 6) [35]. Michael adduct 32 and the product resulting from its amidation 33 was achieved by the enantioselective aza-Michael reaction of O-benzylhydroxylamine 30 and α,β-unsaturated
Mol Divers Scheme 2
Scheme 3
N -acyloxazolidinones 29 using samarium iodobinaphtholate 31 as an efficient catalyst (Scheme 7) [36]. As shown in Scheme 8, Lu and Deng [37] developed an enantioselective aza-Michael reaction using chiral bifunctional organocatalyst 36 and simple α,β-unsaturated ketones such as alkyl vinyl ketones 34 bearing both aryl and alkyl β-substituents. Enantiomerically enriched hydroquinolines 41 were successfully made in two steps: (1) an aza-Michael addition and (2) cyclization. Palladium-polarized aza-ortho-xylylenes 40 and 42 were intermediates generated by decarboxylation
produce hydroquinolines 41 with high diastereoselectivity (>99:1) (Scheme 9) [38]. 3H -Pyrrolo[1,2-a]indole-2-carbaldehydes 47 were synthesized by the Michael addition of 1H -indole-2carbaldehyde 44 to α,β-unsaturated aldehydes 45 under diphenylprolinol silyl ether 46 catalysis followed by an iminium/enamine activation mode. Indeed, this enantioselective domino reaction protocol can construct a tricyclic pyrrolo indole core which is a characteristic structural unit of many bioactive natural products in moderate to good yields (40–71 %) and high to excellent enantiomeric excesses (85
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Scheme 4 Scheme 5
to >99 %ee). This catalytic performance is demonstrated in Scheme 10 [39]. Aza-Michael adducts were prepared by the addition of substituted pyrazoles 49 and 50 to (E)-3-cyclopentylacrylaldehyde 48 using diarylprolinol silyl ether 51 as organocatalyst and were then converted to Janus kinase inhibitor INCB018424 (54). The use of benzoic acid or 4-nitrobenzoic
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acid as an acidic additive proved to increase the reaction rate by creating a stronger acidic media. It is worth mentioning that, in this reaction SEM and POM were used as protecting groups (Scheme 11) [40]. Enantioselective asymmetric Michael addition of aromatic amines 56 to N -alkenoyloxazolidinones 55 catalyzed by iodido(binaphtholato)samarium 57 afforded β-amino
Mol Divers Scheme 6
Scheme 7 Scheme 8
acid derivatives 58 as illustrated in Scheme 12. It was found that homochiral dimer [(R)-57–(R)-57] is more active and enantioselective than monomer (R)-57 in this protocol [41]. Chiral β-amino acid derivatives with a chiral center at the α-position of 62 projected to be useful in the field of medicinal chemistry [42] are synthesized using a combination of
bifunctional chiral Pd-μ-hydroxo complex 61 with aromatic amine salts 60. In this aza-Michael reaction a highly enantioselective protonation of enolate intermediates was performed in THF (Scheme 13) [43]. N -Tosylimines 64 and electron-deficient alkenes 63 reacted in the presence of chiral acid–base organocatalyst 65
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Scheme 9 Scheme 10
to afford 1,3-disubstituted isoindolines 66 (Scheme 14). The aza-MBH/intramolecular aza-Michael reaction described here are both diastereo- and enantio-selective. The optimal result (98 % yield, 92 %ee) was obtained when the reaction was performed in CHCl3 at 10 ◦ C in the presence of molec-
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ular sieves as an additive [44] to suppress the decomposition of moisture-sensitive N-tosylimines 64. Another enantio- and diastereo-selective domino asymmetric α-aminoxylation/aza-Michael reaction for the synthesis of functionalized tetrahydro-1,2-oxazines 70 was reported
Mol Divers Scheme 11
Scheme 12
by using amine catalyst 69 derived from acyclic substrates (Scheme 15) [45].
Intramolecular processes Over the last decade, phase-transfer catalysts have been utilized in the efficient enantioselective synthesis of pharmaco-
logically active compounds. Intramolecular N -alkylation of indoles esters 71 was performed using phase-transfer catalyst (PTC) 72 as illustrated in Scheme 16 to prepare dihydropyrazinoindolinones 73. In addition, synthesis of compound 75 was achieved using a combination of indolyl ester 74 and catalytic amounts of PTC in the presence of aqueous KOH. A computational study was carried out to elucidate a plausible reaction mechanism for this reaction [46].
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Scheme 14
Scheme 15
An enantioselective intramolecular Friedel–Crafts-type aza-Michael addition was developed via the asymmetric N -alkylation of indoles under acidic reaction conditions using catalytic amounts of chiral phosphoric acid 77 which is composed of organocatalysis and transition metal (Scheme 17) [47]. Enantioselective intramolecular aza-Michael reaction of 3,4-dihydropyrazino[1,2-a]indol-1(2H )-ones 79 was reported by Bandini et al. [48] to prepare polycyclic indolyl-
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based compounds 81 using phase-transfer catalysis 80 (Scheme 18).
Chiral reagents Applications of lithium amides as homochiral ammonia equivalents for the formation of C–N bonds through conjugate addition have been reviewed recently by Davies et al.
Mol Divers Scheme 16
Scheme 17
[18,19] and, therefore, we did not feel the need to cover this in this review. The key steps in the asymmetric synthesis of azadiospongin 84 containing a tetrahydropyran ring with two phenyl groups and three asymmetric centers are Mitsunobu inversion, cross olefin metathesis, and intramolecular azaMichael addition reaction. This is the first aza-analog of this
class of molecules that were synthesized via one-pot Boc deprotection and aza-Michael addition (Scheme 19) [49]. A double aza-Michael reaction was reported as part of a nine-step total synthesis of (−)-lentiginosine 88 from (3R,4R)-3,4-dihydroxy-1,5-hexadiene 85. Thus, 4-oxopiperidine 87 was prepared by the cyclization of the key compound 3-oxonona-1,4,8-triene 86, which was converted
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Mol Divers Scheme 18
Scheme 19
Scheme 20
to the indolizidine after ozonolysis and reductive amination (Scheme 20). It is found that diastereomeric ratio depends on the choice of solvent and temperature [50]. The enantioselective synthesis of the neurokinin substance P receptor antagonists aminopiperidine (+)-L-733,060 (89) and (+)-CP-99,994 (90) [C-3 epimer (−)-(2S,3R)-1] was achieved by a stereoselective Ireland–Claisen rearrangement
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and asymmetric Michael addition domino sequence (Fig. 1). Asymmetric Michael addition of Baylis–Hillman adducts 91 using chiral lithium amide (S)-92 afforded optically active γ -substituted δ-aminoacids 93 and subsequently afforded 2,3-disubstituted piperidines 94 (Scheme 21) [51]. The enantioselective synthesis of cis- and trans-piperidine dicarboxylic acid was performed using homochiral piperidin-
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Fig. 1 Structures of piperidine derivatives
edicarboxylic derivatives 95 and 96 (Fig. 2). The cinnamaldehyde double bond is a masked carboxylic functionality, and cerium(IV) ammonium nitrate (CAN) promoted monodebenzylation in this protocol (Scheme 22) [52,53]. The total synthesis of (+)-negamycin 106 and its 5-epiderivative was reported by Nishiguchi et al. [54] through 13 steps in an overall yield of 31 %. In this synthesis the key step is the asymmetric Michael addition of chiral amine (−)-104 [(1S, 2R)-(−)-2-methoxybornyl-10-benzylamine] into the α,β-unsaturated carbonyl moiety of intermediate 103 to generate the second chiral center in (+)-negamycin 106.
A similar process has been utilized to prepare 5-epinegamycin (Scheme 23) [54]. The enantioselective synthesis of 2,5-disubstituted pyrrolidines 108 was achieved by Gärtner et al. [55] using the following key reactions: an asymmetric iridium-catalyzed allylic amination, a Suzuki–Miyaura coupling, and an intramolecular aza-Michael addition. A total synthesis of alkaloids from amphibian skins has also been reported to show the importance of the asymmetric Michel addition as a decisive step (Scheme 24) [55]. An asymmetric reductive amination/aza-Michael sequence reaction of keto enones 109, p-anisidine 110, and a hydride source such as benzothiazolines 113 was performed using the Brønsted acid organocatalyst 111 to produce trans1,3-disubstituted tetrahydroisoquinolines 115 (Scheme 25) [56]. An asymmetric Brønsted acid 116-catalyzed reaction of nucleophile (NuH) 115 and bifunctional iminoenoates 114 containing an imine and Michael acceptor was reported by Enders et al. [57]. Subsequently, intramolecular aza-Michael addition into chiral amine 117 gave chiral 1,3-disubstituted isoindolines 118 (Scheme 26) [57]. Sequential Mannich–aza-Michael reactions were performed to synthesize 2,3,5-trisubstituted pyrrolidines 122 in
Scheme 21
Fig. 2 Structures of cis-(2S,3R)- and trans-(2S,3S)piperidinedicarboxylic acids
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Scheme 23 Scheme 24
high yields and excellent diastereomeric ratios [58]. In this protocol, l-proline catalyzed Mannich reaction, whereas the intramolecular aza-Michael reaction was controlled in basepromoted addition (Scheme 27). C–O bond formation via asymmetric oxa-michael addition Chiral catalysts The domino enantioselective oxa-Michael/carbocyclization synthesis of dihydrofurans 126 (75–77 % yield) was achieved by the reaction of propargyl alcohols 124 and enals 123 using
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a combination of transition metal and amine catalyst 125 (Scheme 28) [59]. Alemán et al. [60] reported the enantioselective synthesis of 4-amino-4H -chromenes 130 via organocatalytic oxa-Michael/aza-Baylis–Hillman tandem reactions between 2-alkynals 127 and tosylimines 128 (Scheme 29). A reasonable reaction mechanism is shown in Scheme 30. The first step is forming an iminium intermediate 131 using catalyst 129 which activates alkynal 127. Then, the oxaMichael addition of salicyl N -tosylimine 128, intramolecular reaction of alenamine intermediate 132, and imine lead to compounds 130. Catalyst 129 can also be recovered and reused in the last step [60].
Mol Divers
Scheme 25 Scheme 26
The enantioselective total synthesis of marine meroterpene (+)-conicol 137 was achieved via organocatalytic domino oxa-conjugate addition/Michael addition as a key step reaction. 2-((E)-2-nitrovinyl)benzene-1,4-diol 133 and α,β-unsaturated aldehydes 134 react to form intermediate 136 by an oxa-Michael addition (Scheme 31) [61]. Bifunctional catalysts 140, produced from the ion-pair assembly of pyrrolidines and available primary amino acids, were utilized in an oxa-Michael–Mannich reaction to prepare
tetrahydroxanthenones 141 by the reaction of salicylaldehydes 138 and cyclohexenones 139 (Scheme 32) [62]. The enantioselective synthesis of daurichromenic acid 147 and confluentin 146 as natural products was reported by Liu and Woggon [63] where the enantioselective domino aldol/oxa Michael reactions of farnesal 143 and 2-methoxy4-methylsalicylaldehyde 142 were the key steps (Scheme 33). The oxa-Michael/aldol tandem reaction (abnormal Baylis–Hillman) of salicylaldehydes 138 and alkynals 127
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Mol Divers Scheme 27
Scheme 28
Scheme 29
was performed to produce optically active 2,3-disubstituted 4-hydroxy-4H -chromenes 148 using silyl prolinol ethers 129 as catalyst to activate the reagents (Scheme 34) [64]. Chiral 3-nitro-2H -chromenes 151 were produced through a novel one-pot enantioselective organocatalytic tandem oxaMichael–Henry reaction where salicylaldehydes 149 reacted with nitro olefins 150 in the presence of chiral secondary amine organocatalyst 140 and salicylic acid as co-catalyst (Scheme 35). A plausible mechanism for this reaction is demonstrated in Scheme 36 [65]. The reaction of α,β-unsaturated aldehydes 153 and (E)-benzaldehyde oxime 154 as nucleophile and subsequent in situ reduction of the addition product was performed via
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a one-pot, organocatalytic oxa-Michael addition to produce β-diols 156 with >94 %ee (Scheme 37). An insect sex pheromone of Bactrocera cucurbitae and a glycerol kinase substrate were also synthesized utilizing this procedure [66]. Flavanone 158 was prepared by an enantioselective intramolecular oxa-Michael addition of activated α,β-unsaturated ketones 157 using a chiral N ,N -dioxide nickel(II) complex as a new chiral catalyst (Scheme 38) [67]. Commercially available diaryl-2-pyrrolidinemethanol derivative 160 catalyzed the reaction of nitroalkenes 159 and tert-butyl hydroperoxide as a nucleophile to produce optically active peroxides 161 with 59–70 % yield and >84 % enantioselectivity (Scheme 39) [68].
Mol Divers Scheme 30
Scheme 31
Scheme 32
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Scheme 33 Scheme 34
Scheme 35
In the following protocol pyrrolidine TG-bound catalysts or resin-bound hydroxyprolylthreonine derivatives 164 catalyzed asymmetric tandem Aldol/Michael reaction (Scheme 40). The first step involves the production of a resinbound enamine from catalyst and acetophenone 162 which undergoes diastereoselective equatorial attack onto the substituted cycloalkanone. Thus, resin-bound β-hydroxyketone loses its hydroxyl group and the resulting unsaturated iminium salt undergoes cyclisation with the remaining phenolic group with the retention of chiral memory to generate chromanone 167 [69]. As illustrated in Scheme 41, the enantioselective synthesis of biologically important natural 2,2-disubstituted chromanes 170 was promoted by guanidine 169 as a catalyst.
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The chromane skeleton containing a quaternary carbon chiral center was prepared via the intramolecular oxa-Michael addition of α,β-unsaturated esters to a 2-hydroxyaryl moiety at the C-5 carbon of 168. In this protocol the E/Z geometry of the α,β-unsaturated ester 168 was established by chiral HPLC and NMR [70]. Chiral monofluorinated flavanones 173 were achieved via an organocatalytic tandem intramolecular oxa-Michael addition/electrophilic fluorination reaction using quinidinederived 172 as bifunctional catalyst (Scheme 42) [71]. Polysubstituted furofuranes 177 containing four stereocenters were prepared by enantioselective organocatalytic domino oxa-Michael/aldol/hemiacetalization synthesis. Indeed, hexahydrofuro[3,4-c]furanes diastereo- and enantio-
Mol Divers Scheme 36
Scheme 37
selectivities synthesis proceeded via the formation of two C–O and one C–C bonds. β-Alkoxylation of α,β-unsaturated aldehydes 174 catalyzed by a secondary amine 176 takes place in this protocol (Scheme 43) [72]. The reaction mechanism is represented in Scheme 44. The enantioselective oxa-Michael addition to γ /δhydroxy-α,β-enones proceeded using a push/pull-type bifunctional organocatalyst. Complexation of the tertiary nitrogen to boron (the push) and coordination of the carbonyl by the thiourea (the pull) could enhance the nucleophilicity of the boronate oxygen (Fig. 3). The Michael addition to 179 in CH2 Cl2 media was completed in 16 h (Scheme 45) [73].
Chiral reagents A stereoselective synthesis of normethyl C1 –C13 fragment 188 of bistramide A is achieved via an asymmetric Sharpless epoxidation, a cross-metathesis reaction, and an intramolecular oxa-Michael reaction as the key step. Oxa-Michael intramolecular reaction of 187 afforded compound 188. The trans-2,6-disubstituted tetrahydropyran subunit 188 has been synthesized in an overall yield of 7 % with 96 %ee . The cis isomer, obtained in 47 % overall yield and 96 % enantiomeric excess, was also synthesized and reported (Scheme 46) [74].
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Mol Divers Scheme 38
Scheme 39
Scheme 40
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Mol Divers Scheme 41
Scheme 42
Scheme 43
As illustrated in Scheme 47 oxa-Michael cyclization approach is a part of the synthesis of E7389 C14 –C35 and Halichondrin C14 –C38 building blocks 191. The allylic alcohols 189 were subjected to the base-induced oxa-Michael reaction to provide the cyclization products in 90 % yield with excellent stereoselectivity [75].
The asymmetric total synthesis of (+)-scanlonenyne was performed by a general strategy for the construction of both 2,6-cis- and 2,6-trans-disubstituted tetrahydropyrans in 18 steps in 9 % overall yield from glycolate oxazolidinone and acrolein. The asymmetric intramolecular hetero-Michael addition of hydroxybutenolide 192 for the construction of
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Mol Divers Scheme 44
both the α,α -cis- and α,α -trans-pyranolactones 193 was the key step in this multistep synthesis (Scheme 48) [76]. An oxa-Michael reaction was used to close the C(8–12) tetrahydropyran ring in the asymmetric synthesis of the C(6– 18) bis(tetrahydropyran)spiroacetal fragment (Fig. 4) of the lituarine class of natural products. In fact, the stereochemical outcome in this transformation was understood to be thermodynamically controlled, leading to an equatorial CH2 CO2 Me substituent (Scheme 49) [77].
A retrosynthetic analysis of ring A and B subunits of bryostatins is illustrated in Fig. 5. Bryostatin ring B was synthesized by a Ru-catalyzed tandem alkene–alkyne coupling/Michael addition reaction using chiral reagent (Scheme 50) [78]. The synthesis of cortistatins (Fig. 6) was reported through an intramolecular Diels–Alder reaction (IMDA), oxidative de-aromatization, and an oxa-Michael addition reaction. The
Fig. 3 Asymmetric catalysis
Scheme 45
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Scheme 46
oxa-Michael addition reaction was applied to substrate 201 after a regioselective hydrogenation and proved to be a useful method for the formation of the oxa-bicyclo-[3.2.1]heptane core 202 (Scheme 51) [79].
C–S bond formation via asymmetric thia-michael addition In recent years, C–S bond formation via asymmetric thiaMichael addition has been limited exclusively to the use of chiral catalysts. Examples include asymmetric cascade reac-
tions of α-substituted and α,β-unsaturated aldehydes using the primary amine catalyst 206. In this case, the intermediate iminium/enamine cascade sequence led to the valuable precursors of the α-amino acids 207 with two adjacent stereogenic centers (Scheme 52) [80]. An organocatalytic asymmetric chemo-, diastereo-, and enantio-selective domino thia-Michael/aldol reaction was performed between 2-mercaptoacetophenone 208 and α,β-unsaturated aldehydes 209 to produce benzothiopyran derivatives or thiochromenes 210 with three contigous stereocenters, in high yields, up to >15:1 dr and 96 to >99 %ee (Scheme 53) [81].
Scheme 47
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Mol Divers Scheme 48
The organocatalytic asymmetric thia-Michael addition of arylmethyl mercaptans 213 to cyclic enones 212 using amino acid derivative S-triphenylmethyl l-cysteine 214 was reported by Yoshida et al. [82] with moderate to high enantioselectivity (Scheme 54). As illustrated in Scheme 55, the organocatalytic asymmetric thia-Michael/Michael addition reaction of thiols 213 with nitro olefin enoates 216 led to highly substituted chromans 218 with a quaternary stereocenter [83] where the external thiol reacted regioselectively with the nitroolefin in preference to the enoate. Enantioselective organocatalytic asymmetric Michael reaction of β,β-disubstituted nitroalkene 218 (Michael acceptor) opened a new gateway approach to β 2,2 -amino acids 221 synthesis with hetero-quaternary stereocenters (Scheme 56) [84]. This example highlights the fact that the nitro group dominates the directing effect of an ester group.
Fig. 5 Retrosynthetic analysis of bryostatins
C–P bond formation via asymmetric phospha-michael addition
Fig. 4 Natural products with the spiro[furan-2, 2’-pyrano[3,2-b] pyran] structural motif Scheme 49
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In recent years, C–P bond formation via asymmetric phosphaMichael addition has only been discussed in reactions involving chiral catalysts. The 1,4-phospha-Michael addition reac-
Mol Divers Scheme 50
tion between diethyl phosphite and enones bearing both aryl and alkyl β-substituents was reported to take place in the presence of a dinuclear Zn complex catalyst resulting in the production of β-oxophosphonates as biologically active phosphonates in high yields and with excellent enantioselectivities (up to 99 %ee) (Scheme 57) [85]. Zinc-mediated asymmetric phospha-Michael additions of dialkylphosphine oxides 225 to α,β-unsaturated ketones 226 was reported by Zhao et al. [86] using a catalyst based on Trost’s dinuclear catalyst with a beneficial effect of pyriFig. 6 Structures of steroidal natural product
Scheme 51 Scheme 52
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Mol Divers Scheme 53
Scheme 54
Scheme 55
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Mol Divers Scheme 56
Scheme 57
dine and 228 (Scheme 58). Excellent yields and enantioselectivities (up to >99 %ee) were obtained for a wide scope of enones employing this catalyst under mild conditions [86]. Zhu et al. [87] performed squaramide-catalyzed enantioselective phospha-Michael addition of diphenyl phosphite 230 to nitroalkenes 229 to obtain chiral β-nitro phosphonates 232, which are appropriate precursors for the synthesis of biologically active β-amino phosphonic acids (Scheme 59). The phospha-Michael addition of dialkyl phosphine oxide 225 to α,β-unsaturated N-acylpyrroles 233 was performed
to obtain the desired product 234 in excellent yields (up to 99 %) and enantioselectivities (94–99 %ee) (Scheme 60) [88,89]. Subsequently, the latter was readily reduced to chiral phosphines 235 using HSiCl3 .
Conclusions In this review, we highlight recent asymmetric heteroatom Michael reactions centered on C–N, C–O, C–S, and C–P
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Mol Divers Scheme 58
Scheme 59
Scheme 60
bond formations. A suitable chiral, non-racemic substrate, reagent, or catalyst is required to produce beneficial heteroatom Michael adducts enantioselectively and diastereose-
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lectively. These C-heteroatom bond formations can provide a platform for the construction of enantiomerically pure novel chemical entities for their explorations and applications in a
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broad range of scientific fields and especially in biology and medicine. Acknowledgment The authors are grateful to the Alzahra University Research Council for the supports.
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SHORT REVIEW
Recent advances in C-heteroatom bond forming by asymmetric Michael addition Majid M. Heravi · Parvin Hajiabbasi
Received: 10 April 2013 / Accepted: 2 December 2013 © Springer Science+Business Media Dordrecht 2013
Abstract In this review, we try to highlight the recently reported stereoselective Michael conjugate additions of heteroatom nucleophiles to electron-deficient alkenes. The topic is divided based on the nature of the nucleophile employed (nitrogen-, oxygen-, sulfur-, or phosphorus-centered) and then subdivided to distinguish between catalyst-controlled and substrate/reagent-controlled methods which is necessary to achieve asymmetric synthesis. Keywords Asymmetric synthesis · Michael addition · C-heteroatom bond formation · Enantioselectivity · Chiral catalyst · Chiral reagent
Introduction In the last decade many new bond-forming reactions have been reported and well established. Among them, the Michael addition could be considered distinct due to its significant atom economy for diastereoselective and enantioselective bond formation in asymmetric synthesis. Asymmetric C-heteroatom bond-forming reactions as a key step lead to many useful products such as biologically natural products that contain C–O bonds in the form of ether, ketone, or ester moieties in their structures, as well as the synthesis of pharmaceuticals that often contain C–N bonds, and heterocycles in which C–N, C–O, or C–S bonds are present in their ring structures. The catalytic asymmetric addition of phosphorus nucleophiles to electrophiles leads to C–P bond formation which is one of the most powerful methods to provide chiM. M. Heravi (B) · P. Hajiabbasi Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran e-mail: [email protected]
ral phosphorus-containing compounds as ligands for various metal-catalyzed asymmetric reactions. Alongside with the interest and literature reports for asymmetric C–C bond formation, herein we focus on an overview of asymmetric C-heteroatom bond-forming reactions involving conjugate additions with the hope that it will attract the attention of synthetic organic chemists. Some of the earliest examples of conjugate additions involve the C–C bond formation when Michael [1,2], after whom the Michael addition/reaction was named, investigated the addition of enolates of ketones and aldehydes to the β-carbon of α,β-unsaturated carbonyl compounds in 1887. Since then, asymmetric Michael reactions have attracted the attention of organic chemists. Various chiral substrates, reagents, and acids or bases as catalysts have been employed to develop this significant asymmetric reaction efficiently. In fact, the asymmetric Michael reaction started flourishing and thriving among synthetic organic chemists when Belokon et al. [3] for the first time reported a catalyzed asymmetric Michael reaction using chiral alkali metal alkoxides. In continuation of our interest concerning the recent applications of named reactions in organic synthesis [4–11], in this review we wish to highlight a number of recent and selected carbon–heteroatom bond formations via heteroatom Michael asymmetric addition as a key strategic step to produce various useful products, particularly in the total synthesis of natural products. Although the asymmetric aspects of the traditional Michael addition reaction have been thoroughly reviewed [12–17], heteroatom Michael additions have been less so [18–20], and asymmetric variants are even more limited [21–23]. Therefore, it is worthwhile to highlight recent and applicable examples in order to demonstrate the enormous potential of this method in organic chemistry and as an important synthetic tool for the synthesis of pharmaceutically relevant compounds.
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Mol Divers Scheme 1
C–N bond formation via asymmetric aza-Michael addition Nitrogen-containing heterocycles have broad applications in organic chemistry, material and life sciences [24–26]. C–N bond formation, accompanied by the generation of stereogenic centers, is found in the synthesis of many important biomolecules, such as amino acids [27] and glycosamines [28]. In the following section, we will introduce and highlight some typical processes for C–N bond forming. C–N bond formation using chiral catalysts Intermolecular processes An enantioselective Michael addition of ammonia (in the form of benzophenone imine 2) to nitroalkenes 1 was performed using thiourea 3 as an organocatalyst in heptane. A one-pot asymmetric aza-Michael addition–acidic hydrolysis protocol was performed with a number of aliphatic and aromatic nitroalkenes to achieve the synthesis of optically active β-amino nitro compounds with 60–80 % yields and 78–84 %ee (Scheme 1) [29]. (Note: newly formed C-heteroatom bonds are depicted in red; asterisk indicates location of chiral centers). The asymmetric aza-Michael addition of 1,2,4-triazole 6 to α,β-unsaturated ketone 5 was successfully carried out using a combination of primary amino thiourea 4 and 4-nitrobenzoic acid as organocatalyst to produce the desired product in high yield with moderate to excellent enantioselectivity. In addition, the application of the procedure for aryl and cyclic ketones 9 was shown by the reaction of cyclic enone 9, triazole 6, and amine thiourea 7 in the presence of 2-methoxybenzoic acid in toluene to preferably produce product 10 (Scheme 2) [30]. Mahé et al. [31] reported the enantioselective phasetransfer catalyzed synthesis of 3,5-diaryl pyrazolines 14 from
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chalcone derivatives 12 and N -aryl hydrazine 11 in a 1:1 ratio to give pyrazolines 14 as levo(−)-isomer (S). By using K3 PO4 (solid–liquid phase-transfer conditions) the enantiomeric excess was slightly improved; however, the reaction was slower and the yield was lower relative to those obtained when Cs2 CO3 was used. The chiral ammonium/amide ion pair generated by N -ortho-methoxybenzylquininium salt and N -acylhydrazines is used as catalyst in this protocol (Scheme 3). The enantioselective Michael addition of 1H -benzotriazole 15 to cyclic 19, acyclic 5, and enone (e.g., cyclohexenone) was accomplished using 9-amino-9-deoxyepiquinine 16 as an effective organocatalyst resulting in the preparation of desired products in high yields and with good to excellent enantioselectivities (Scheme 4) [32]. Fu et al. [33] prepared 2-substituted-1,5-benzodiazepine derivatives 25 from an enantioselective domino reaction involving O-phenylenediamine 23 and 2 -hydroxychalcones 22 using titanium complex with chiral ligand derived from (S)-BINOL and l-proline amide (Scheme 5). The presence of a 2 -hydroxy group in the α,β-unsaturated ketones was crucial for reactivity and high stereo induction in this protocol [33]. In the proposed catalytic cycle, the oxygen atom of the hydroxy group and the nitrogen atom of the imine moiety of this intermediate coordinate with the chiral titanium complex. The additions occur from the sterically less hindered side where an intramolecular hydrogen bond with the hydroxy group also causes the stabilization of an α,β-unsaturated ketimine intermediate [34]. β-Amino homopropargylic nitro compounds 28 are prepared by enantioselective Michael addition to nitroenynes 26 using P-spiro heterochiral arylaminophosphonium barfate · BArF 27 as chiral ionic Brønsted acid catalyst (Scheme 6) [35]. Michael adduct 32 and the product resulting from its amidation 33 was achieved by the enantioselective aza-Michael reaction of O-benzylhydroxylamine 30 and α,β-unsaturated
Mol Divers Scheme 2
Scheme 3
N -acyloxazolidinones 29 using samarium iodobinaphtholate 31 as an efficient catalyst (Scheme 7) [36]. As shown in Scheme 8, Lu and Deng [37] developed an enantioselective aza-Michael reaction using chiral bifunctional organocatalyst 36 and simple α,β-unsaturated ketones such as alkyl vinyl ketones 34 bearing both aryl and alkyl β-substituents. Enantiomerically enriched hydroquinolines 41 were successfully made in two steps: (1) an aza-Michael addition and (2) cyclization. Palladium-polarized aza-ortho-xylylenes 40 and 42 were intermediates generated by decarboxylation
produce hydroquinolines 41 with high diastereoselectivity (>99:1) (Scheme 9) [38]. 3H -Pyrrolo[1,2-a]indole-2-carbaldehydes 47 were synthesized by the Michael addition of 1H -indole-2carbaldehyde 44 to α,β-unsaturated aldehydes 45 under diphenylprolinol silyl ether 46 catalysis followed by an iminium/enamine activation mode. Indeed, this enantioselective domino reaction protocol can construct a tricyclic pyrrolo indole core which is a characteristic structural unit of many bioactive natural products in moderate to good yields (40–71 %) and high to excellent enantiomeric excesses (85
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Scheme 4 Scheme 5
to >99 %ee). This catalytic performance is demonstrated in Scheme 10 [39]. Aza-Michael adducts were prepared by the addition of substituted pyrazoles 49 and 50 to (E)-3-cyclopentylacrylaldehyde 48 using diarylprolinol silyl ether 51 as organocatalyst and were then converted to Janus kinase inhibitor INCB018424 (54). The use of benzoic acid or 4-nitrobenzoic
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acid as an acidic additive proved to increase the reaction rate by creating a stronger acidic media. It is worth mentioning that, in this reaction SEM and POM were used as protecting groups (Scheme 11) [40]. Enantioselective asymmetric Michael addition of aromatic amines 56 to N -alkenoyloxazolidinones 55 catalyzed by iodido(binaphtholato)samarium 57 afforded β-amino
Mol Divers Scheme 6
Scheme 7 Scheme 8
acid derivatives 58 as illustrated in Scheme 12. It was found that homochiral dimer [(R)-57–(R)-57] is more active and enantioselective than monomer (R)-57 in this protocol [41]. Chiral β-amino acid derivatives with a chiral center at the α-position of 62 projected to be useful in the field of medicinal chemistry [42] are synthesized using a combination of
bifunctional chiral Pd-μ-hydroxo complex 61 with aromatic amine salts 60. In this aza-Michael reaction a highly enantioselective protonation of enolate intermediates was performed in THF (Scheme 13) [43]. N -Tosylimines 64 and electron-deficient alkenes 63 reacted in the presence of chiral acid–base organocatalyst 65
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Scheme 9 Scheme 10
to afford 1,3-disubstituted isoindolines 66 (Scheme 14). The aza-MBH/intramolecular aza-Michael reaction described here are both diastereo- and enantio-selective. The optimal result (98 % yield, 92 %ee) was obtained when the reaction was performed in CHCl3 at 10 ◦ C in the presence of molec-
123
ular sieves as an additive [44] to suppress the decomposition of moisture-sensitive N-tosylimines 64. Another enantio- and diastereo-selective domino asymmetric α-aminoxylation/aza-Michael reaction for the synthesis of functionalized tetrahydro-1,2-oxazines 70 was reported
Mol Divers Scheme 11
Scheme 12
by using amine catalyst 69 derived from acyclic substrates (Scheme 15) [45].
Intramolecular processes Over the last decade, phase-transfer catalysts have been utilized in the efficient enantioselective synthesis of pharmaco-
logically active compounds. Intramolecular N -alkylation of indoles esters 71 was performed using phase-transfer catalyst (PTC) 72 as illustrated in Scheme 16 to prepare dihydropyrazinoindolinones 73. In addition, synthesis of compound 75 was achieved using a combination of indolyl ester 74 and catalytic amounts of PTC in the presence of aqueous KOH. A computational study was carried out to elucidate a plausible reaction mechanism for this reaction [46].
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Mol Divers Scheme 13
Scheme 14
Scheme 15
An enantioselective intramolecular Friedel–Crafts-type aza-Michael addition was developed via the asymmetric N -alkylation of indoles under acidic reaction conditions using catalytic amounts of chiral phosphoric acid 77 which is composed of organocatalysis and transition metal (Scheme 17) [47]. Enantioselective intramolecular aza-Michael reaction of 3,4-dihydropyrazino[1,2-a]indol-1(2H )-ones 79 was reported by Bandini et al. [48] to prepare polycyclic indolyl-
123
based compounds 81 using phase-transfer catalysis 80 (Scheme 18).
Chiral reagents Applications of lithium amides as homochiral ammonia equivalents for the formation of C–N bonds through conjugate addition have been reviewed recently by Davies et al.
Mol Divers Scheme 16
Scheme 17
[18,19] and, therefore, we did not feel the need to cover this in this review. The key steps in the asymmetric synthesis of azadiospongin 84 containing a tetrahydropyran ring with two phenyl groups and three asymmetric centers are Mitsunobu inversion, cross olefin metathesis, and intramolecular azaMichael addition reaction. This is the first aza-analog of this
class of molecules that were synthesized via one-pot Boc deprotection and aza-Michael addition (Scheme 19) [49]. A double aza-Michael reaction was reported as part of a nine-step total synthesis of (−)-lentiginosine 88 from (3R,4R)-3,4-dihydroxy-1,5-hexadiene 85. Thus, 4-oxopiperidine 87 was prepared by the cyclization of the key compound 3-oxonona-1,4,8-triene 86, which was converted
123
Mol Divers Scheme 18
Scheme 19
Scheme 20
to the indolizidine after ozonolysis and reductive amination (Scheme 20). It is found that diastereomeric ratio depends on the choice of solvent and temperature [50]. The enantioselective synthesis of the neurokinin substance P receptor antagonists aminopiperidine (+)-L-733,060 (89) and (+)-CP-99,994 (90) [C-3 epimer (−)-(2S,3R)-1] was achieved by a stereoselective Ireland–Claisen rearrangement
123
and asymmetric Michael addition domino sequence (Fig. 1). Asymmetric Michael addition of Baylis–Hillman adducts 91 using chiral lithium amide (S)-92 afforded optically active γ -substituted δ-aminoacids 93 and subsequently afforded 2,3-disubstituted piperidines 94 (Scheme 21) [51]. The enantioselective synthesis of cis- and trans-piperidine dicarboxylic acid was performed using homochiral piperidin-
Mol Divers
Fig. 1 Structures of piperidine derivatives
edicarboxylic derivatives 95 and 96 (Fig. 2). The cinnamaldehyde double bond is a masked carboxylic functionality, and cerium(IV) ammonium nitrate (CAN) promoted monodebenzylation in this protocol (Scheme 22) [52,53]. The total synthesis of (+)-negamycin 106 and its 5-epiderivative was reported by Nishiguchi et al. [54] through 13 steps in an overall yield of 31 %. In this synthesis the key step is the asymmetric Michael addition of chiral amine (−)-104 [(1S, 2R)-(−)-2-methoxybornyl-10-benzylamine] into the α,β-unsaturated carbonyl moiety of intermediate 103 to generate the second chiral center in (+)-negamycin 106.
A similar process has been utilized to prepare 5-epinegamycin (Scheme 23) [54]. The enantioselective synthesis of 2,5-disubstituted pyrrolidines 108 was achieved by Gärtner et al. [55] using the following key reactions: an asymmetric iridium-catalyzed allylic amination, a Suzuki–Miyaura coupling, and an intramolecular aza-Michael addition. A total synthesis of alkaloids from amphibian skins has also been reported to show the importance of the asymmetric Michel addition as a decisive step (Scheme 24) [55]. An asymmetric reductive amination/aza-Michael sequence reaction of keto enones 109, p-anisidine 110, and a hydride source such as benzothiazolines 113 was performed using the Brønsted acid organocatalyst 111 to produce trans1,3-disubstituted tetrahydroisoquinolines 115 (Scheme 25) [56]. An asymmetric Brønsted acid 116-catalyzed reaction of nucleophile (NuH) 115 and bifunctional iminoenoates 114 containing an imine and Michael acceptor was reported by Enders et al. [57]. Subsequently, intramolecular aza-Michael addition into chiral amine 117 gave chiral 1,3-disubstituted isoindolines 118 (Scheme 26) [57]. Sequential Mannich–aza-Michael reactions were performed to synthesize 2,3,5-trisubstituted pyrrolidines 122 in
Scheme 21
Fig. 2 Structures of cis-(2S,3R)- and trans-(2S,3S)piperidinedicarboxylic acids
123
Mol Divers Scheme 22
Scheme 23 Scheme 24
high yields and excellent diastereomeric ratios [58]. In this protocol, l-proline catalyzed Mannich reaction, whereas the intramolecular aza-Michael reaction was controlled in basepromoted addition (Scheme 27). C–O bond formation via asymmetric oxa-michael addition Chiral catalysts The domino enantioselective oxa-Michael/carbocyclization synthesis of dihydrofurans 126 (75–77 % yield) was achieved by the reaction of propargyl alcohols 124 and enals 123 using
123
a combination of transition metal and amine catalyst 125 (Scheme 28) [59]. Alemán et al. [60] reported the enantioselective synthesis of 4-amino-4H -chromenes 130 via organocatalytic oxa-Michael/aza-Baylis–Hillman tandem reactions between 2-alkynals 127 and tosylimines 128 (Scheme 29). A reasonable reaction mechanism is shown in Scheme 30. The first step is forming an iminium intermediate 131 using catalyst 129 which activates alkynal 127. Then, the oxaMichael addition of salicyl N -tosylimine 128, intramolecular reaction of alenamine intermediate 132, and imine lead to compounds 130. Catalyst 129 can also be recovered and reused in the last step [60].
Mol Divers
Scheme 25 Scheme 26
The enantioselective total synthesis of marine meroterpene (+)-conicol 137 was achieved via organocatalytic domino oxa-conjugate addition/Michael addition as a key step reaction. 2-((E)-2-nitrovinyl)benzene-1,4-diol 133 and α,β-unsaturated aldehydes 134 react to form intermediate 136 by an oxa-Michael addition (Scheme 31) [61]. Bifunctional catalysts 140, produced from the ion-pair assembly of pyrrolidines and available primary amino acids, were utilized in an oxa-Michael–Mannich reaction to prepare
tetrahydroxanthenones 141 by the reaction of salicylaldehydes 138 and cyclohexenones 139 (Scheme 32) [62]. The enantioselective synthesis of daurichromenic acid 147 and confluentin 146 as natural products was reported by Liu and Woggon [63] where the enantioselective domino aldol/oxa Michael reactions of farnesal 143 and 2-methoxy4-methylsalicylaldehyde 142 were the key steps (Scheme 33). The oxa-Michael/aldol tandem reaction (abnormal Baylis–Hillman) of salicylaldehydes 138 and alkynals 127
123
Mol Divers Scheme 27
Scheme 28
Scheme 29
was performed to produce optically active 2,3-disubstituted 4-hydroxy-4H -chromenes 148 using silyl prolinol ethers 129 as catalyst to activate the reagents (Scheme 34) [64]. Chiral 3-nitro-2H -chromenes 151 were produced through a novel one-pot enantioselective organocatalytic tandem oxaMichael–Henry reaction where salicylaldehydes 149 reacted with nitro olefins 150 in the presence of chiral secondary amine organocatalyst 140 and salicylic acid as co-catalyst (Scheme 35). A plausible mechanism for this reaction is demonstrated in Scheme 36 [65]. The reaction of α,β-unsaturated aldehydes 153 and (E)-benzaldehyde oxime 154 as nucleophile and subsequent in situ reduction of the addition product was performed via
123
a one-pot, organocatalytic oxa-Michael addition to produce β-diols 156 with >94 %ee (Scheme 37). An insect sex pheromone of Bactrocera cucurbitae and a glycerol kinase substrate were also synthesized utilizing this procedure [66]. Flavanone 158 was prepared by an enantioselective intramolecular oxa-Michael addition of activated α,β-unsaturated ketones 157 using a chiral N ,N -dioxide nickel(II) complex as a new chiral catalyst (Scheme 38) [67]. Commercially available diaryl-2-pyrrolidinemethanol derivative 160 catalyzed the reaction of nitroalkenes 159 and tert-butyl hydroperoxide as a nucleophile to produce optically active peroxides 161 with 59–70 % yield and >84 % enantioselectivity (Scheme 39) [68].
Mol Divers Scheme 30
Scheme 31
Scheme 32
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Mol Divers
Scheme 33 Scheme 34
Scheme 35
In the following protocol pyrrolidine TG-bound catalysts or resin-bound hydroxyprolylthreonine derivatives 164 catalyzed asymmetric tandem Aldol/Michael reaction (Scheme 40). The first step involves the production of a resinbound enamine from catalyst and acetophenone 162 which undergoes diastereoselective equatorial attack onto the substituted cycloalkanone. Thus, resin-bound β-hydroxyketone loses its hydroxyl group and the resulting unsaturated iminium salt undergoes cyclisation with the remaining phenolic group with the retention of chiral memory to generate chromanone 167 [69]. As illustrated in Scheme 41, the enantioselective synthesis of biologically important natural 2,2-disubstituted chromanes 170 was promoted by guanidine 169 as a catalyst.
123
The chromane skeleton containing a quaternary carbon chiral center was prepared via the intramolecular oxa-Michael addition of α,β-unsaturated esters to a 2-hydroxyaryl moiety at the C-5 carbon of 168. In this protocol the E/Z geometry of the α,β-unsaturated ester 168 was established by chiral HPLC and NMR [70]. Chiral monofluorinated flavanones 173 were achieved via an organocatalytic tandem intramolecular oxa-Michael addition/electrophilic fluorination reaction using quinidinederived 172 as bifunctional catalyst (Scheme 42) [71]. Polysubstituted furofuranes 177 containing four stereocenters were prepared by enantioselective organocatalytic domino oxa-Michael/aldol/hemiacetalization synthesis. Indeed, hexahydrofuro[3,4-c]furanes diastereo- and enantio-
Mol Divers Scheme 36
Scheme 37
selectivities synthesis proceeded via the formation of two C–O and one C–C bonds. β-Alkoxylation of α,β-unsaturated aldehydes 174 catalyzed by a secondary amine 176 takes place in this protocol (Scheme 43) [72]. The reaction mechanism is represented in Scheme 44. The enantioselective oxa-Michael addition to γ /δhydroxy-α,β-enones proceeded using a push/pull-type bifunctional organocatalyst. Complexation of the tertiary nitrogen to boron (the push) and coordination of the carbonyl by the thiourea (the pull) could enhance the nucleophilicity of the boronate oxygen (Fig. 3). The Michael addition to 179 in CH2 Cl2 media was completed in 16 h (Scheme 45) [73].
Chiral reagents A stereoselective synthesis of normethyl C1 –C13 fragment 188 of bistramide A is achieved via an asymmetric Sharpless epoxidation, a cross-metathesis reaction, and an intramolecular oxa-Michael reaction as the key step. Oxa-Michael intramolecular reaction of 187 afforded compound 188. The trans-2,6-disubstituted tetrahydropyran subunit 188 has been synthesized in an overall yield of 7 % with 96 %ee . The cis isomer, obtained in 47 % overall yield and 96 % enantiomeric excess, was also synthesized and reported (Scheme 46) [74].
123
Mol Divers Scheme 38
Scheme 39
Scheme 40
123
Mol Divers Scheme 41
Scheme 42
Scheme 43
As illustrated in Scheme 47 oxa-Michael cyclization approach is a part of the synthesis of E7389 C14 –C35 and Halichondrin C14 –C38 building blocks 191. The allylic alcohols 189 were subjected to the base-induced oxa-Michael reaction to provide the cyclization products in 90 % yield with excellent stereoselectivity [75].
The asymmetric total synthesis of (+)-scanlonenyne was performed by a general strategy for the construction of both 2,6-cis- and 2,6-trans-disubstituted tetrahydropyrans in 18 steps in 9 % overall yield from glycolate oxazolidinone and acrolein. The asymmetric intramolecular hetero-Michael addition of hydroxybutenolide 192 for the construction of
123
Mol Divers Scheme 44
both the α,α -cis- and α,α -trans-pyranolactones 193 was the key step in this multistep synthesis (Scheme 48) [76]. An oxa-Michael reaction was used to close the C(8–12) tetrahydropyran ring in the asymmetric synthesis of the C(6– 18) bis(tetrahydropyran)spiroacetal fragment (Fig. 4) of the lituarine class of natural products. In fact, the stereochemical outcome in this transformation was understood to be thermodynamically controlled, leading to an equatorial CH2 CO2 Me substituent (Scheme 49) [77].
A retrosynthetic analysis of ring A and B subunits of bryostatins is illustrated in Fig. 5. Bryostatin ring B was synthesized by a Ru-catalyzed tandem alkene–alkyne coupling/Michael addition reaction using chiral reagent (Scheme 50) [78]. The synthesis of cortistatins (Fig. 6) was reported through an intramolecular Diels–Alder reaction (IMDA), oxidative de-aromatization, and an oxa-Michael addition reaction. The
Fig. 3 Asymmetric catalysis
Scheme 45
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Mol Divers
Scheme 46
oxa-Michael addition reaction was applied to substrate 201 after a regioselective hydrogenation and proved to be a useful method for the formation of the oxa-bicyclo-[3.2.1]heptane core 202 (Scheme 51) [79].
C–S bond formation via asymmetric thia-michael addition In recent years, C–S bond formation via asymmetric thiaMichael addition has been limited exclusively to the use of chiral catalysts. Examples include asymmetric cascade reac-
tions of α-substituted and α,β-unsaturated aldehydes using the primary amine catalyst 206. In this case, the intermediate iminium/enamine cascade sequence led to the valuable precursors of the α-amino acids 207 with two adjacent stereogenic centers (Scheme 52) [80]. An organocatalytic asymmetric chemo-, diastereo-, and enantio-selective domino thia-Michael/aldol reaction was performed between 2-mercaptoacetophenone 208 and α,β-unsaturated aldehydes 209 to produce benzothiopyran derivatives or thiochromenes 210 with three contigous stereocenters, in high yields, up to >15:1 dr and 96 to >99 %ee (Scheme 53) [81].
Scheme 47
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Mol Divers Scheme 48
The organocatalytic asymmetric thia-Michael addition of arylmethyl mercaptans 213 to cyclic enones 212 using amino acid derivative S-triphenylmethyl l-cysteine 214 was reported by Yoshida et al. [82] with moderate to high enantioselectivity (Scheme 54). As illustrated in Scheme 55, the organocatalytic asymmetric thia-Michael/Michael addition reaction of thiols 213 with nitro olefin enoates 216 led to highly substituted chromans 218 with a quaternary stereocenter [83] where the external thiol reacted regioselectively with the nitroolefin in preference to the enoate. Enantioselective organocatalytic asymmetric Michael reaction of β,β-disubstituted nitroalkene 218 (Michael acceptor) opened a new gateway approach to β 2,2 -amino acids 221 synthesis with hetero-quaternary stereocenters (Scheme 56) [84]. This example highlights the fact that the nitro group dominates the directing effect of an ester group.
Fig. 5 Retrosynthetic analysis of bryostatins
C–P bond formation via asymmetric phospha-michael addition
Fig. 4 Natural products with the spiro[furan-2, 2’-pyrano[3,2-b] pyran] structural motif Scheme 49
123
In recent years, C–P bond formation via asymmetric phosphaMichael addition has only been discussed in reactions involving chiral catalysts. The 1,4-phospha-Michael addition reac-
Mol Divers Scheme 50
tion between diethyl phosphite and enones bearing both aryl and alkyl β-substituents was reported to take place in the presence of a dinuclear Zn complex catalyst resulting in the production of β-oxophosphonates as biologically active phosphonates in high yields and with excellent enantioselectivities (up to 99 %ee) (Scheme 57) [85]. Zinc-mediated asymmetric phospha-Michael additions of dialkylphosphine oxides 225 to α,β-unsaturated ketones 226 was reported by Zhao et al. [86] using a catalyst based on Trost’s dinuclear catalyst with a beneficial effect of pyriFig. 6 Structures of steroidal natural product
Scheme 51 Scheme 52
123
Mol Divers Scheme 53
Scheme 54
Scheme 55
123
Mol Divers Scheme 56
Scheme 57
dine and 228 (Scheme 58). Excellent yields and enantioselectivities (up to >99 %ee) were obtained for a wide scope of enones employing this catalyst under mild conditions [86]. Zhu et al. [87] performed squaramide-catalyzed enantioselective phospha-Michael addition of diphenyl phosphite 230 to nitroalkenes 229 to obtain chiral β-nitro phosphonates 232, which are appropriate precursors for the synthesis of biologically active β-amino phosphonic acids (Scheme 59). The phospha-Michael addition of dialkyl phosphine oxide 225 to α,β-unsaturated N-acylpyrroles 233 was performed
to obtain the desired product 234 in excellent yields (up to 99 %) and enantioselectivities (94–99 %ee) (Scheme 60) [88,89]. Subsequently, the latter was readily reduced to chiral phosphines 235 using HSiCl3 .
Conclusions In this review, we highlight recent asymmetric heteroatom Michael reactions centered on C–N, C–O, C–S, and C–P
123
Mol Divers Scheme 58
Scheme 59
Scheme 60
bond formations. A suitable chiral, non-racemic substrate, reagent, or catalyst is required to produce beneficial heteroatom Michael adducts enantioselectively and diastereose-
123
lectively. These C-heteroatom bond formations can provide a platform for the construction of enantiomerically pure novel chemical entities for their explorations and applications in a
Mol Divers
broad range of scientific fields and especially in biology and medicine. Acknowledgment The authors are grateful to the Alzahra University Research Council for the supports.
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