Silyl ketene acetals, chiral diastereoselectivity

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

Unsaturated acyl derivatives of oxazolidinones can be used as acceptors, and these reactions are enantioselective in the presence of chiral to-oxazoline catalysts.321 Silyl ketene acetals of thiol esters are good reactants and the stereochemistry depends on the ketene acetal configuration. The Z-isomer gives higher diastereoselectivity than the Zf-isomer. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Denmark utilized chiral base promoted hypervalent silicon Lewis acids for several highly enantioselective carbon-carbon bond forming reactions [92-98]. In these reactions, a stoichiometric quantity of silicon tetrachloride as achiral weak Lewis acid component and only catalytic amount of chiral Lewis base were used. The chiral Lewis acid species desired for the transformations was generated in situ. The phosphoramide 35 catalyzed the cross aldolization of aromatic aldehydes as well as aliphatic aldehydes with a silyl ketene acetal (Scheme 26) [93] with good yield and high enantioselectivity and diastereoselectivity. 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

In a separate, elegant use of 165, Rychnovsky and coworkers have carried out a diastereoselective addition of methyl acetate-derived silyl ketene acetal to aldehyde 174 to afford adduct 175 in high diastereomeric purity (Scheme 15) [102]. Hydroxy ester 175 was subsequently employed as an intermediate in the total synthesis of the polyene macrolide antibiotic Roflamycoin. This work highlights a novel application of the chiral catalyst system in reagent-controlled coupling of chiral functionahzed substrates which by themselves display only mod-... 

Diastereoselective Aldol Additions of Chiral Silyl Ketene Acetals and Chiral Silyl Enol Ethers... 

Chiral silyl ketene acetals (Il)-(20) were recently introduced for diastereoselective aldol-type additions. Camphor derivatives (11)-(16) are conformationally rigid with one diastereotopic face of the enol silane sterically shielded. - A -Methylephedrine derivatives (17)-(20) are likely to bind to TiCU through the NMe2 group with consequent dramatic conformational constraint.As a result the Lewis acid mediated additions to C=X occur in a highly stereoselective way. The chiral auxiliaries can then be removed (and recycled) by reduction, saponification or displacement with various nucleophiles to give useful synthetic intermediates. 

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... 

In our synthesis [36] of spiruchostatin A, we followed Simon s procedure for the preparation of 3. We too were unable to achieve the Carreira aldol in good yield. Moreover, the reaction requires the preparation of three noncommercial materials the binaphthyl chiral aminophenol, the t-butyl salicaldehyde, and the silyl ketene acetal. Instead, we opted for a diastereoselective aldol with the Nagao auxiliary. For reasons that are not completely clear, the Nagao thiazolidinethione auxiliary exhibits high diastereoselectivity in acetate aldols unlike the more popular Evans oxazolidinone auxiliary. In this case, aldol adduct 7 was obtained in good yield (Scheme 12-3). Unlike the other syntheses, this was coupled directly to the peptide rather than hydrolyzed to the acid 5. 

For example, /3-ionone can be chlorinated selectively in the apposition by addition of NCS to the kinetic enolate (eq 1). With the appropriate chiral auxiliary, NCS chlorinates silyl ketene acetals with high levels of diastereoselectivity (eq 2) a-Chloro... 

To date the most general chiral auxiliary mediated asymmetric Ireland-Claisen rearrangement is that of Corey et al. (Scheme 4.44) [47]. They found that treatment of crotyl propionates and related esters afforded good yields, diastereoselectivities and enantioselectivities of the pentenoic acid products. The rearrangements also occurred at significantly lower temperature than the silyl ketene acetals. A key advantage of the chemistry is that the chiral auxiliary attachment, Ireland-Claisen rearrangement, and auxiliary removal all occur in one pot. 

Other reports deal with a pyrrolidine-catalysed homo-aldol condensation of aliphatic aldehydes (further accelerated by benzoic acid), a diastereoselective aldol-type addition of chiral boron azaenolates to ketones,the use of TMS chloride as a catalyst for TiCU-mediated aldol and Claisen condensations, a boron-mediated double aldol reaction of carboxylic esters, gas-phase condensation of acetone and formaldehyde to give methyl vinyl ketone, and ab initio calculations on the borane-catalysed reaction between formaldehyde and silyl ketene acetal [H2C=C(OH)OSiH3]. ... 

A large variety of propionic acid esters and higher homologs having a chiral alcohol moiety have been used in additions to aldehydes [56, 57]. It turned out, however, that the lithium enolates result in only moderate simple diastereoselectivity and induced stereoselectivity, in contrast with the corresponding boron, titanium, tin, or zirconium enolates and silyl ketene acetals, with which stereoselectivity is excellent. The same feature has been observed in enolates derived from chiral amides and oxazolidinones, as... 

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