Acetals aldol condensation, stereoselectivity

Largely stimulated by the synthesis of 3-lactam antibiotics, there have been widespread investigations into the stereochemical aspects of imine condensations, mainly involving reactions of enolates of carboxylic acid derivatives or silyl ketene acetals. In analogy to the aldol condensation, stereoselectivity of imine condensations will be discussed in terms of two types in this chapter (i) simple dia-stereoselectivity or syn-anti selectivity, when the two reactants are each prochiral (equation 12) and (ii) diastereofacial selectivity, when a new chiral center is formed in the presence of a pre-existing chiral center in one of the reactants (e.g. equation 13). The term asymmetric induction may be used synonymously with diastereofacial selectivity when one of the chiral reactants is optically active. For a more explicit explanation of these terms, see Heathcock s review on the aldol condensation. ... 

Stereoselective aldol-type condensation.1 Enol silyl ethers do not undergo aldol condensation with aldehydes or ketones in the presence of this triflate,. but the reaction occurs at —78° (4-12 hours) with the corresponding acetals or ketals (and certain orthoesters). Moreover the erythro-aldol is formed with high stereoselectivity. 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

In recent organic synthesis, stereoselective aldol condensations has been performed under two different conditions. Under the influence of acid, stabilized enol derivatives, enolsilanes (M = SiMe3), can condense with aldehydes or acetals in a stereoselective fashion [Eq. (12)]. In this reaction the role of the acid is to activate aldehydes or acetals. Alternatively, under basic conditions, the same process can be carried out directly with aldehydes and reactive, preformed metal enolates (M = Li, MgL, ZnL, AIL2, BL2, etc.) of defined geometry. 

The nucleophilic addition of a carbanion to an aldehyde or a ketone having a conjugated double bond and the subsequent dehydration sequence (Knoevenagei reaction) is a popular method for generating dienes and polyenes (equation 37). This reaction takes place efficiently and stereoselectively, when LDA is used as a base in the presence of chlorotrimethylsilane (equation 38). Knoevenagei condensation was a key reaction during many classical carotenoid syntheses. Recently, Seltzer and coworkers used the dimefiiyl acetal of acetylacetaldehyde for aldol condensation with a Cis-aldehyde, to generate the tetraenyl ketone acetal (equation 39). ... 

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to 3-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of 3-lactams from Reformatsky reagents and Schiff bases. Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations . ... 

S,3S,4R)-4-Amino-3-hydroxy-2-methylpentanoic acid (3), having three consecutive asymmetric centers, was prepared by the aldol condensation of (R)-2-aminopropionaldehyde derivative (15) and -boron enolate (16) (Fig. 11) [42]. The aldol product (17) was obtained in 35 1 stereoselectivity and used directly as an active ester for the subsequent peptide synthesis, i.e., the coupling with tripeptide S (18) facilitated by cupric acetate afforded tetrapeptide S (19) [43]. These studies were included in the first total synthesis of deglyco-BLM and BLM by Umezawa and his co-workers which included our group in 1982 [44, 45] and the synthesis by Hecht s group was completed in the same year [46, 47], proving the entire structure of BLM. 

Optically active -silyl acetic acid and siLylmethylamines have been made to determine chiral amines and acids respectively, ol-silyl esters and PhCHO used in cross aldoL condensation with moderate stereoselectivity, while... 

Aldol Condensation with Enol Silyl Ethers. The first example of an aldol condensation between an unactivated enolate and an electrophilically activated carbonyl substrate was accomplished using enol silyl ethers and acetals or orthoesters in conjunction with a catalytic amount of Trimethykilyl Trifluoromethanesul-fonate. The reaction proceeds very readily at —78 C and affords the eo /W-aldol product with high stereoselectivity. The use of 2,2-dimethoxypropane in this reaction affords p-methoxy ketones (eq 10). 

In other studies, analysis of the products of reaction between formaldehyde and guanosine at moderate pH shows a new adduct—formed by condensing two molecules of each reactant—which has implications for the mechanism of DNA cross-linking by formaldehyde,17 while the kinetics of the mutarotation of N-(/ -chlorophcnyl)-//-D-glucopyranosylamine have been measured in methanolic benzoate buffers.18 For a stereoselective aldol reaction of a ketene acetal, see the next section. 

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