3-Amino esters from chiral silyl ketene acetals

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Chiral silyl ketene acetals derived from (lS,2/ )-A/-methylephedrine (168), known to exhibit high levels of syn-anti and diastereofacial selectivities in the aldol condensation,131 have been used by Gennari et al. in TiCU-mediated imine condensations for the asymmetric synthesis of [3-lactams (Scheme 34) 132, 33 p.Amino esters (169) are produced in these reactions, and are characterized by their sub-... 

Azodicarboxylate esters are the reagents of choice for electrophilic A -amino aminadon leading to hydrazine derivatives. Besides Grignard reagents and alkyl or aryl lithiunt conqmunds, enolates and silyl enol ethers derived from ketones have been aminated by this method. In particular, di-r-butyl az icarboxylate has been reacted with a variety of chiral enolates (Scheme I9)i03.i04 chiral silyl ketene acetals (Schemes 20 and to afford a-hydrazino acid derivatives with high dia-... 

Akiyama and coworkers, who had pioneered BINOL-derived phosphoric acids, noticed that aldimines 365 available from 2-aminophenol and aromatic, heteroaromatic, and cinnamyl aldehydes can be activated by the chiral acid catalyst 367, so that they are electrophilic enough to react with silyl ketene acetals 366 in diastereoselective and enantioselective Mannich reactions. Thus, P-amino esters 368 are formed with a high preference for the syn-diastereomers that are obtained in high enantiomeric excess (Scheme 5.96) [182]. 

Examples of the Bronsted-acid catalysts and hydrogen-bond catalysts are shown in Figure 2.1. We have recently reported the Mannich-type reaction of ketene silyl acetals with aldimines derived from aromatic aldehyde catalyzed by chiral phosphoric acid 7 (Figure 2.2, Scheme 2.6) [12]. The corresponding [5-amino esters were obtained with high syn-diastereoselectivities and excellent enantioselectivities. 

Recently, Corey and coworkers prepared the cinchonidine-derived bifluoride 20 from the corresponding bromide by passage of a methanolic solution through a column of Amberlyst A-26 OH- form, and subsequent neutralization with 2 equiv. of 1 N HF solution and evaporation (the modified method C in Scheme 9.5). The catalytic activity and chiral efficiency of 20 (dried over P205 under vacuum) have been demonstrated by the development of a Mukaiyama-type aldol reaction of ketene silyl acetal 21 with aldehydes under mild conditions, giving mostly syw-P-hydroxy-a-amino esters 22 as the major diastereomer with good to excellent enantiomeric excesses (Table 9.4) [23],... 

Yamamoto and co-workers found that 27 is an excellent chiral promoter not only for the aza Diels-Alder reaction of aldimines [40] but also for the stereoselective aldol-type reaction of aldimines with ketene silyl acetals [55]. The reaction of (5)-benzyli-dene a-methylbenzylamine with trimethylsilyl ketene acetal derived from terf-butyl acetate in the presence of (R)-27 produces the (R) adduct in > 92 % diastereomeric excess (de), whereas reaction with (5)-27 gives the adduct in 74 % de. In a similar way, (5)-butylidene a-methylbenzylamine, an aliphatic imine, can be converted to the (R)-)3-amino ester in 94 % de by use of (R)-27 (Eq. 73). 

On the basis of these results, we have developed the first method for the enantiose-lective synthesis of chiral /3-amino acid esters from achiral imines and ketene silyl acetals using BLA 28. The enantioselectivity of the aldol-type reaction is dramatically increased by using sterically bulky A-substituents. Condensation of the imine derived from benzhydrylamine occurs with high enantioselectivity (90 % ee) (Eq. 80). Furthermore, the best result (96 % ee) is achieved by use of a 1 1 (v/v) mixture of toluene and dichloromethane as solvents. Thus, excellent enantioselectivity (95 % ee or better) has been achieved in reactions of aromatic aldehyde-derived imines... 

Imino aldol reaction of ketene silyl acetals with the chiral imine derived from tartaric acid 83 in the presence of a cation-exchange resin provided the corresponding /i-amino esters 84 in a good yield and high diastereose-lectivity [68]. The esters 84, thus obtained, were subjected to the Grignard reagent which promoted S-lactam formation. After a sequence of reactions compound 84 was transformed into the ester 85 [68] which in the past was... 

In the methodology developed by Oppolzer and Moretti18, closely resembling the Gen-nari, Colombo and Bertolini procedure15, the crude ketene silyl acetals 7, derived from the chiral esters 6, are reacted with di-tm-butyl azodicarboxylate (DBAD) to yield the adducts 8, and, via 9, the amino acids 10. 

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