Chiral acetals diastereoselective

Chiral acetals/ketals derived from either (R,R)- or (5,5 )-pentanediol have been shown to offer considerable advantages in the synthesis of secondary alcohols with high enantiomeric purity. The reaction of these acetals with a wide variety of carbon nucleophiles in the presence of a Lewis acid results in a highly diastereoselective cleavage of the acetal C-0 bond to give a /1-hydroxy ether, and the desired alcohols can then be obtained by subsequent degradation through simple oxidation elimination. Scheme 2-39 is an example in which H is used as a nucleophile.97... 

Extensive investigations have been directed toward the development of chiral ester enolates that might exhibit practical levels of aldol asymmetric induction. Much of the early work in this area has been reviewed (111). In general, metal enolates derived from chiral acetate and propionate esters exhibit low levels of aldol asymmetric induction that rarely exceed 50% enantiomeric excess. The added problems associated with the low levels of aldol diastereoselection found with most substituted ester enolates (cf. Table 11) further detract from their utility as effective chiral enolates for the aldol process. Recent studies have examined the potential applications of the chiral propionates 121 to 125 in the aldol condensation (eq. [94]), and the observed erythro-threo diastereoselection and diastere-oface selection for these enolates are summarized in Table 31. For the six lithium enolates the threo diastereoselection was found to be... 

Early efforts using a chiral auxiliary, such as a chiral acetal or 2-phenylcyclohexanol, resulted in modest diastereoselectivity. - ... 

Asymmetric induction in the cyclopropanations of unsaturated substrates with methylene has been extensively investigated. A propensity of the Simmons-Simth and related reagents to make coordination to basic atoms is most frequently exploited. Treatment of a,/J-unsaturated aldehyde acetals derived from the aldehydes and chiral dialkyl tartrates or 2,4-pentanediol, with diiodomethane/diethylzinc in hexane, produces cyclopro-panecarboxaldehyde acetals with high diastereoselectivity (equation 69)109 110. Uniformly good diastereoselectivity has also been realized in the cyclopropanations of chiral acetals... 

Aldol coupling of chiral acetals. The acetals (2) prepared from an aldehyde and (2R,4R)-pentanediol react with a-silyl ketones orenol silyl ethers in the presence of TiCI, to form aldol ethers 3 and 4 with high diastereoselectivity (>95 5). Removal of the chiral auxiliary usually results in decomposition of the aldol, but can be effected after reduction... 

Reaction with chiral acetals. The chiral ketals derived from (2R,4R)-( - )-2,4-pentanediol (1) can be cleaved with high diastereoselectivity by aluminum hydride reagents, in particular DIB AH, C12A1H, and Br2AlH. Oxidative removal of the chiral auxiliary affords optically active alcohols. This process provides a useful method for highly asymmetric reduction of dialkyl ketones.3... 

Diastereoselective, copper-catalyzed propargylic substitution by Grignard reagents to yield optically active allenes has been reported for substrates having a chiral acetal moiety [Eq. (72) 138] [10,148]. 

Chiral acetals can be used as auxiliaries in the diastereoselective reactions of Grignard reagents with acyclic as well as cyclic a-keto acetals. Nucleophilic addition to the monoprotected diketone (69 equation 18) occurs with excellent stereoselectivity to generate the corresponding tertiary alcohol (70) as the major product, usually with greater than 95 5 selectivity. Removal of the ketal yields a-hydroxy ketones of high optical purity. In most examples, enantiomeric excesses of 95% and higher are observed in the resultant keto alcohols. Table 17 represents the results of additions to cyclic and acyclic substrates. 

Asymmetric halogenation of chiral acetals has been realized by C. Giordano (refs. 2-7). Using alkyl esters of optically active tartaric acids as chiral auxiliaries, a high diastereoselectivity is obtained even at room temperature. The results are best explained by a fast electrophilic addition of bromine on the electron rich enol ether, originating from an acid-catalyzed equilibrium with the chiral acetal. If (2R, 3R)-tartaric acid is involved, a S-configuration prevails at the new stereogenic center. Finally, cautious hydrolysis provides a set of 2-bromo alkyl aryl ketones, which can be obtained in enantiomerically pure form after crystallization (Fig. 2) ... 

Chiral acetate (204) shows excellent diastereofacial selectivity and has obvious utility as a reagent for asymmetric aldol reactions. As shown in equation (122), reaction of (204) with benzaldehyde provides diastereomers (205) and (206). As shown in Table 23, entry 1, the diastereoselectivity is 83% if the lithium enolate is formed in the conventional manner and the aldol reaction is carried out in THF at -78 C. A significant improvement is obtained by using the magnesium enolate (Table 23, entry 5), and diastereoselectivity of up to 98% is obtained by the use of very low reaction temperatures (Table 23, entries 10-13). 

Ethynylsilanes react with the chiral acetal in Scheme 52 with good diastereoselection, providing a route to enantiomerically enriched alcohols to rival the Midland method. 

Six-membered chiral acetals, derived from aliphatic aldehydes, undergo aldol-type coupling reactions with a-silyl ketones, silyl enol ethers," and with silyl ketene acetals " in the presence of titanium tetrachloride with high diastereoselectivities (equation 41) significant results are reported in Table 20. This procedure, in combination with oxidative destructive elimination of the chiral auxiliary, has been applied... 

Cyclic exo-methylene compounds bearing a chiral acetal function prove to be excellent dieno-philes in the noncatalyzed Diels-Alder reaction. Dioxolanones 8 react with cyclopentadiene (9) and acyclic dienes 12 and 15 to afford adducts with diastereoselectivities as high as 100% 28,29. The major adduct 16 from the addition of 8b to diene 15 has been applied to the synthesis of the top half of kijanolide30. 

Diastereoselective deprotonation has been observed with enantiopure complexes (e.g.,42) prepared by acetalization of benzaldehyde with asymmetric 1,2-diols (Fig. 3) [32,34,36,50,85,116,122,125]. A series of experiments with S-bu-tane-l,2,4-triol as a source of chiral acetal auxiliary failed to demonstrate synthetic utility [122]. 

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