Auxiliary Nagao

Nagao, Y., Hagiwara, Y., Kumagai, T., Ochiai, M., Inoue, T., Hashimoto, K., and Fujita, E. (1986). New C4-chiral l,2-thiazolidine-2-thiones Excellent chiral auxiliaries for highly diastereocontrolled aldol-type reactions of acetic acid and a,b-unsaturated aldehydes. J. Org. Chem. 51, 2391-2393. 

Acyl-l,3-oxazolidine-2-thiones, chiral (1). Nagao and co-workers1 have prepared the chiral 3-acetyl-l,3-oxazolidine-2-thiones (la and lb) and used them to effect diastereoselective aldol reactions. The two chiral auxiliaries show, as expected, opposite diastereoselectivities, but contrast with the diastereoselectivities observed with chiral 4-alkyl-2-oxazolidones (11, 379-381). This aldol reaction has been used to prepare the chiral azetidinone 4 (equation I) and (-I- )-Prelog-Djerassi lactone. 

Many of the previously mentioned auxiliaries do not lead to high selectivity with unsubstituted enolates. In this case, the use of Nagao s acetate aldol methodology is frequently applied [30]. For example, in a recent synthesis of pate-amine A, two such aldol reactions of 46 were used, both of which proceeded with >95%ds (Scheme 9-15) [31]. 

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. 

SCHEME 10.28. Stereochemical models of aldol reactions using the Evans and Eujita-Nagao-Crimmins chiral auxiliaries. 

SCHEME 10.29. The use of the Fujita-Nagao-Crimmins chiral auxiliary in formal synthesis of... 

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