Chiral auxiliaries Michael addition

Various chiral auxiliaries and catalysts have been developed that allow diastereoface-and enantioface-selective Michael additions. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

Mainly sulfoxide groups are introduced as chiral auxiliaries for the modification of a,/J-unsat-urated enones (see Section D.1.5.3.5.). Chiral imine derivatives have also been used (see Section D.1.5.3.1.). Various chiral alcohols, and in particular 8-phenylmenthol, have been successfully used as auxiliaries, mainly in two-fold Michael additions to a,/ -unsaturatcd esters. 

Asymmetric Michael additions using chiral auxiliary containing donors have attracted widespread attention and various methods are now available that give high enantiomeric excess. 

An interesting approach to zr n.v-2,3-disubstituted cyeloalkanones is offered by auxiliary controlled intramolecular Michael additions. The diastereoselectivity depends on the chiral alcohol used193> l94. When the borneol derivative 7 was used as substrate, a single diastereomer of 8 resulted when the reaction was performed at 25 "C under thermodynamic control with a catalytic amount of sodium hydride in benzene. 

The application of auxiliary control in the asymmetric Michael addition of chiral enolates derived from ketones is rare the only example known is the use of (27 ,37 )-2,3-butancdiol as an auxiliary. The ketal of (27 ,37 )-2,3-butanediol with 3-methyl-l,2-cyclohexanedione reacts with 3-buten-2-one using as base a catalytic amount of sodium ethoxide in ethanol195. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Scheme 2.48. Results of the chiral auxiliary supported domino Michael addition/ Wittig reactions.

Specifically functionalized OZTs are helpful synthons10,21 which are emerging as new chiral auxiliaries with high potential in chirality transfer.56,80 The efficient Michael addition-reductive elimination process to produce... 

Diastereoselective conjugate additions to chiral Michael acceptors in which the part initially bearing the chiral information is removable (i.e., a chiral auxiliary) provides a means to synthesize enantiomerically pure conjugate adducts. Chiral auxiliaries should ideally be readily available in both enantiomeric forms. They should... 

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... 

High diastereofacial selectivities are observed in cycloadditions and Michael additions with ot,(3-unsaturated esters having chiral heterocyclic auxiliary at the p-position, as shown in Schemes 11.20, 11.21, and 11.25, and cannot be well-explained using Kozikowski s awfi-periplanar model (124,125) or Houk s inside alkoxy model (126,127). Both the anti-periplanar conformation and the syn-periplanar conformation of the acceptors participate in the transition structures, depending on nonbonding interactions in the dipole-chiral auxiliary pair (121). 

The use of oxazolines as chiral auxiliaries for asymmetric Michael additions has yielded mixed results. For example, Langlois group reported modest dia-stereoselectivities (up to 60% de) for cyanide addition to a number of chiral... 

Instead of introducing the (S)-proline-derived chiral auxiliary (206), its enantiomer in the Michael-addition, the authors obtained the enantiomeric product (208 ) having opposite optical rotation compared to (208). 

The bacteriostatic gliotoxin was prepared206 by a total synthesis involving an asymmetric Michael-addition. A chiral amino acid derivative served as chiral auxiliary in the key step. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Based on this gathered experience the diastereoselective alkylation of enantio-pure a-lithiated sulfonates was extended to the Michael addition with aliphatic nitroolefins [95]. Thus the Michael adducts 118 could be achieved in excellent yields (84-99%) with high diastereoselectivities de of 80-88% (84 to >98% after recrystallization or chromatography). Cleavage of the chiral auxiliary and treatment with diazomethane furnished the anti-configured a,j3-disubstituted y-nitro-methyl sulfonates 119 in overall yields of 41-70% and with excellent de- and ee-values (Scheme 1.1.32). 

The methyl group was introduced by a two-step procedure. Thus, the hydrazone Michael adducts 52 were converted into the enol pivaloates 53 in excellent yields and diastereomeric excesses de > 96%) by treatment with pivaloyl chloride and triethylamine. After treatment with lithium dimethylcuprate the chiral auxiliary was removed by addition of 6n HCl in order to obtain the 5-substituted 2-methylcyclopentene carboxylate 54 in good yields and with excellent stereoselectivity (de, ee > 96%). Finally, the asymmetric synthesis of dehydroiridodiol (55, R = Me, = H) and its analogues was accomplished by reduction of 54 with lithium aluminum hydride or L-selectride leading to the desired products in excellent yields, diastereo- and enantiomeric excesses (de, ee > 96%). 

The synthesis of substituted cysteines can be accomplished via Michael addition reactions,]67124-126] by nucleophilic displacement,]127] from racemic thiazolines,]128] via aziridine ring opening,]129 and by asymmetric synthesis using a chiral auxiliary.]130] The details for some of these methods are described. 

The chiral, nonracemic oxazepine derivative (46 Scheme 18) was studied as donor in the Michael addition to prochiral a,p-unsaturated carbonyl compounds.134-133 The products were obtained with 44-55% ee after removal of the chiral auxiliary group. With 1-nitrocyclohexene as acceptor, somewhat better se-lectivities (62% ee) were observed.136... 

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxiliary molecules which are released on work-up (equation 90 shows an example of such a reaction). 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

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. 

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