Enolates chiral, conformation

In this section are discussed aldol reactions of achiral aldehydes with chiral enolates. In previous sections, many such examples have already been given for enolates derived from rigid cyclic ketones, lactones and lactams. The emphasis here is on reactions of the enolates of conformationally flexible, achiral ketones, esters and amides. 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

With chiral enol species (/ )-silylketene acetal derived from (1 R,2S)-N-methyl ephedrine-O-propionate, both the aldehyde carbonyl and the ephedrine NMe2 group are expected to bind to TiCU, which usually chelates two electron-donating molecules to form ra-octahedral six-coordinated complexes.25 Conformational freedom is therefore reduced, and the C-C bond formation occurs on the six-coordinated metal in a highly stereoselective manner.18... 

One possible explanation for the diastereoface selection (AAGt -78°C 3 kcal/mol) observed for these chiral enolates is illustrated in Scheme 23. In the respective aldol transition states derived from conformers A and B leading to erythro diastereomers A and B, it may be assumed that developing imide resonance (118) will lock the chiral auxiliary in one of the in-plane conformations illustrated in products A or B. Based on an examination of models, it is projected that developing CHj R, allyhc strain steric interaction (37) disfavors that transition state leading to A. These steric considerations are largely attenuated in the transition state leading to the observed erythro adduct B. ... 

It should also be noted that there is a strong conformational bias for only one of the product chelate conformers. For example, erythro chelate D should be strongly disfavored by both 1,3-diaxial Rj L and CH3 Xq steric control elements. Consequently, it is assumed that the transition states leading to either adduct will reflect this conformational bias. Further support for these projections stems from the observations that the chiral acetate enolates derived from 149a exhibit only poor diastereoface selection. In these cases the developing Rj CH3 interaction leading to diastereomer A is absent. Similar transition state allylic strain considerations also appear to be important with the zirconium enolates, which are discussed below. 

The central point of Evans s methodology is the induction of a 7t-enantiotopic facial differentiation through a conformationally rigid highly ordered transition state. Since the dialkylboron enolates of AT-acyl-2-oxazolidinones exhibit excellent syn-diastereoselectivity syn.anti >97 3) when reacted with a variety of aldehydes, Evans [14] studied the aldol condensation with the chiral equivalents 32 and 38. which are synthesised from fS)-valine (35) and the hydrochloride of (15, 2R)-norephedrine (36) (Scheme 9.11), respectively, and presently are commercially available. 

In the course of examining the CAI effect of conformational restriction of the C3-side-chain, intermediate 24 was prepared. Shankar and co-workers (Shankar et al., 1996) demonstrated that 10, a key intermediate in the research synthesis could be accessed by Wacker oxidation of olefin 24 (Scheme 13.7). Additionally, an alternative chiral variant of the well-precedented addition of zinc enolates to imines was demonstrated. Treatment of the bromoacetate 25, derived from 8-phenylmenthol with zinc and sonication followed by imine addition afforded 26 in 55% yield with greater than 99% de. Ethyl magnesium promoted ring-closure followed by C3 alkylation with 28, intercepts the previously demonstrated route through formation of olefin 24 (Shankar et al., 1996). 

An unsaturated dicarboxylic acid is doubly esterified with a chiral diol, leading to the macro-cyclic diolidc 1. Sequential formation of both enolates and methylation proceeds with high diastereofacial selectivity, which is induced by the relatively rigid conformation of the 12-mem-... 

Substitution of a carbon monoxide ligand of complexes, such as 1, by the more electron-donating triphenylphosphane group (see Section 1.1.1.3.4.1.3.) provides chiral monophos-phane complexes, such as 3. Monophosphane complexes in general lack sufficient electrophilic-ity to react with amines or thiols, but react readily with amine anions at the /J-position, producing enolate anions such as 4, which may be quenched stereoselectively at the a-carbon by electrophiles46 (see Section 1.1.1.3.4.1.3.). The conformational and stereochemical issues involved are essentially identical to those already discussed in this section for the 1,4-additions of carbon nucleophiles. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Simple enols stabilized by bulky aryl groups have been reviewed.131 Amide enols, tip2C=C(OH)NR1R2 (tip = 2,4,6-triisopropylphenyl), can be generated by reaction of amines with ditipyl ketene, are observable by NMR, and slowly tautomerize. Vinyl alcohols with two or three bulky aryls have propeller conformations and are chiral, but are not easily resolved. 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

The stereochemistry of conjugate additions requires similar considerations to those used to predict nucleophilic attack on a carbonyl. Acyclic substrates may yield up to three contiguous chiral centres (Scheme 18). The relative stereochemistry of carbons C(l) and C(2) will depend upon the approach of the two reagents. The stereochemistry of carbon C(3) will depend upon the lifetime of the intermediate 30 if it has even a short lifetime it will take up the most stable conformation. For example, the base-catalysed additions of ethanol-d and 2-methyl-2-propanethiol-d to ethyl crotonate give a (2R, 3R )/(2R, 3S ) diastereoisomeric ratio of the addition products of approximately 10 190. The authors90 suggest the reaction proceeds in two steps and the protonation of the enolate determines the stereoselectivity. 

Ab initio methods also appear to be useful for predicting the M- to P-conformational transition barrier for reactive species, such as enolate 8. It is known that the presence of an (iS7-C3-substituent will favor the /17-con former in which the C-3 substituent adopts a pseudoequatorial arrangement. Consequently, deprotonation of C-3 at low temperature of certain benzodiazepines can result in single, conformationally chiral, nonracemic enolates locked in the /(/-configuration. The inversion barrier for enolate 8 at 195 K is calculated by DFT methods to be 17.5 kcal mol-1, which compares with 12.4 kcal mol-1 for the derivative where the N-l group is methyl instead of isopropyl <2003JA11482>. These results were used to explain the enantioselective C-3-alkylation method discussed in... 

Among several chiral cyclic and acyclic diamines, (R,R)-cyclohexane-l,2-diamine-derived salen ligand (which can adopt the gauche conformation) was most effective in providing high enantioselectivity [38]. Further, the introduction of substituents at the 3,4, 5 and 6 positions on the aromatic ring of catalyst 39c was not advantageous, and resulted in low enantioselectivity [32,37,39]. The metal ions from first-row transition metals - particularly copper(II) and cobalt(II) - that could form square-planar complexes, produced catalytically active complexes for the asymmetric alkylation of amino ester enolates [38]. 

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