Diastereoselectivity asymmetric Michael additions

Enantiocontrolled anti-selective Michael additions of the metalated ylides derived from a-(alkylideneamino)alkanoates are attractive as a new synthetic route to enantiomers of a-amino esters. Although there are a variety of chiral glycine equivalents available, only the enolates derived from 1,4-dihydropyrazine have been successfully applied to asymmetric Michael additions (Scheme 11.22) (103-105). In these reactions, the diastereoselectivities are high. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

Reagent 1 also undergoes asymmetric Michael additions with enolate ions. Michael additions with disubstituted lithium eno-lates proceed with almost complete tt-facial diastereoselectivity. Starting with these Michael additions, (—)-methyl jasmonate (eq 4) and (—)-estrone methyl ether (eq 5) can be obtained in high enantiomeric purities. 

Ester enolates. Oppolzer showed in 1983 that the Z(Gj-dienolate shown in Scheme 5.30a adds to cyclopentenone with 63% diastereoselectivity [160]. Additionally, the enolate adduct can be allylated selectively, thereby affording (after purification) a single stereoisomer having three contiguous stereocenters in 48% yield. The transition structure illustrated is not analogous to any of those illustrated in Scheme 5.29 because cyclopentenone is an s-trans-Z-enone, whereas the enones in Scheme 5.29 are s-cis-E. In 1985, Corey reported the asymmetric Michael addition of the EfOj-enolate of phenylmenthone propionate to -methyl crotonate as shown in Scheme 5.30b [161]. The product mixture was 90% syn, and the syn adducts were produced in a 95 5 ratio, for an overall selectivity of 86% for the illustrated isomer. The transition structure proposed by the authors to account for the observed selectivity is similar to that shown in Scheme 5.29c, but with the enone illustrated in an s-trans conformation. Intramolecular variations of these reactions were reported by Stork in 1986, as illustrated in Scheme 5.30c and 5.29d [162]. Two features of... 

Amide and imide enolates. Scheme 5.31 illustrates several examples of asymmetric Michael additions of chiral amide and imide enolates. Yamaguchi [163] investigated the addition of amide lithium enolates to -ethyl crotonate, but found no consistent topicity trend for achiral amides. The three chiral amides tested are illustrated in Scheme 5.31a-c. The highest diastereoselectivity found was with the C2-symmetric amide shown in Scheme 5.3Ic. Evans s imides, as their titanium enolates, afforded the results shown in Scheme 5.31d and e [164,165]. The yields and selectivities for the reaction with acrylates and vinyl ketones are excellent, but the reaction is limited to P-unsubstituted Michael acceptors P-substituted esters and nitriles do not react, and 3-substituted enones add with no selectivity [165]. 

The use of the carbanion derived from the chloroallylphosphonate (163) in the enantioselective synthesis of cyclopropanes (164) by Michael addition to a,P-unsaturated ketones has been the subject of a short review (Scheme 18). Denmark s group have published full details of the asymmetric Michael addition reactions of cyclic enones with carbanions derived from l,3,2-oxa2aphosphor-inane 2-oxides (165) and (167). y-Addition to give (166) predominates although the extent of this depends on the ring size of the Michael acceptor. The level of diastereoselectivity depends on the stereochemistry of the allylphosphonate used ... 

The chiral sulphoxide, (S)-(+)-2-(4-tolylsulphinyl)-2-cyclopentenone, has been used as a ring D component to effect an asymmetric Michael addition with 91-94% diastereoselectivity by reaction in the chelated form with the a,a-disubstituted lithium enolate from 2-bromo-6-methoxytetral-1-one while the (R)-(-) antipode reacts in a non-chelated form with the a-monosubstituted lithium enolate of 6-methoxytetralone (ref. 147). This synthesis makes use of earlier experience in the use of a-mono and a,a-disubstituted lithium enolates in the ethyl acetoacetate series with the non-chelated and chelated forms respectively of a p-ketosulphoxide (ref. 148). Eight futher steps were involved to produce (+)-estrone methyl ether in an overall yield of 6.3%. 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

Sugar-hased prolinamide 16m has also been employed as catalyst for the asymmetric Michael addition of cyclohexanones to p-nitroslyrenes. During optimisation of the reaction conditions, the authors found that the polarity of the solvent does not modify the yield or stereoselectivity, but the best ee was obtained under neat conditions at -20 °C. Ammonium ionic liquids 41a,b are also efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitro-olefins giving the adducts with excellent yields and enantioselectivities and modest to high diastereoselectivities. 

Ma and coworkers described the first organocatalytic asymmetric Michael addition of aldehydes to a,p-unsaturated thiol esters promoted by catalyst Cla. The reaction proceeded with good yields, diastereoselectivity and excellent enantioselectivity. 

Ley and coworkers also used tetrazole 5a to catalyse the asymmetric Michael addition of a ketone to an aromatic nitro-olefin in a 1 1 mixture of ethanol and isopropanol. The products obtained had moderate to good diastereoselectivities (up to >19 1 dr) and moderate enantioselectivities (up to 73% ee). Further, a homoproline tetrazole derivative (5b) was prepared and used for asymmetric Michael reaction. Catalysts 5a and 5b gave similar diastereoselectivities however, the catalyst 5b produced products with higher enantioselectivities in the Michael addition of ketones to aromatic nitro-olefins (Scheme 9.34). Ley and coworkers explained that the side chain of the homotetrazole was responsible for the increased enantioselectivity. 

In 2014, the group of Rahman reported the asymmetric Michael addition of aliphatic aldehydes and ketones to substituted tra s-(3-nitrostyrenes catalysed by aldo-ketoreductase mimicking peptides. A selected series of peptides, analogous to amino acid sequences of the enzyme, showed in all cases fair to excellent yields and diastereoselectivities with enantiomeric excesses of up to 71%. 

In contrast, Michael additions of a,a-disubstituted lithium enolates proceed, apparently via the chelated form of enone sulfoxides (Figure 5.2), with almost complete jt-facial diastereoselectivity [104]. This methodology has been used in the asymmetric synthesis of the pheromone, (-)-methyl jasmonate (121), from cyclopentenone sulfoxide (98b) [105] via the intermediate (120), which was formed in at least 98% enantiomeric purity upon asymmetric Michael addition of bis a-silylated a-lithioacetate to (98b). Addition of the a-bromo enolate (122) to enantiomerically pure (98a) and oxidation gives the product sulfone (123), with almost complete asymmetric -induction with respect to the sulfoxide. Sulfone (123) was then converted into the steroidal sex hormone, (+)-oestradiol (124) (Scheme 5.42) [106]. 

Subsequent studies demonstrated that the asymmetric Michael addition of trisubstituted carbon nucleophiles promoted by 6 -demethylated Cinchona alkaloids (CPD, CPN, RO-CPD and RO-CPN) could be efficiently achieved using a,p-unsaturated sulfones, enones and enals as Michael acceptors in a highly enantioselective and diastereoselective fashion. 

In the course of synthesising enantioenriched y-keto gem-bisphosphonates having anti-arthritic and anti-inflammatory activities, Barros and Phillips have finalised organocatalytic asymmetric Michael additions of cyclic ketones to vinyl gem-bisphosphonates. The reactions were performed in the presence of (iS)-( + )-l-(2-pyrrolidininylmethyl)pyrrolidine as an organocatalyst and benzoic acid as an additive, leading to the expected Michael products in high yields, excellent diastereoselectivities (> 98% de) combined with enantioselectivities... 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

A novel and effective organocatalytic system consisting in chiral pyrrolidi-nyl-thioimidazole and a thioureido acid additive was demonstrated by Xu et al. to efficiently promote the asymmetric Michael addition of ketones to nitro-olefins, affording the products with high diastereoselectivities of up to 98% de and excellent enantioselectivities of up to 99% ee (Scheme 1.49). Previously, these authors have shown that the use of salicylic acid as an additive to this catalyst in these reactions gave similar results but at a higher catalyst loading of 20 mol % instead of 5 mol % with the thioureido acid additive. ... 

Li and coworkers found that 20 mol% of catalyst 164 served as effective catalyst for the asymmetric Michael addition of cylcopentanone to chalcones [74b]. Moderate diastereoselectivities but excellent enantioselectivities were achieved with a range of chalcones. The reaction was proposed to occur via an enamine-iminium transition state (Scheme 5.46). 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

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