Synthesis and Reactions of Enan-tiopure 1-Acyl-2-[triaryl(alkyl)silyl]- 2,3-dihydro-4-pyridones

Abstract

The addition of triphenylsilyl-or dimethylphenylsilymagnesium bromide to certain chiral 1-acylpyridinium salts affords C-2 silylated dihydro-4pyridones in good yield and high diastereoselectivity (84 -96% de).Reduction and substitution reactions of these heterocycles were examined to explore their utility as chiral building blocks.Several highly stereoselective transformations were observed.For several years we have been exploring the utility of enantiopure N-acyl-2,3-dihydro-4-pyridones as chiral building blocks for the stereocontrolled synthesis of various alkaloids and natural products. 1 These dihydropyridones are prepared by the addition of Grignard reagents or metallo enolates to chiral 1acylpyridinium salts. 2 For example, the reaction of enantiopure 1-acylpyridinium salt (1), prepared in situ from 4-methoxy-3-triisopropylsilylpyridine and the chloroformate of (-)-trans-2-(αcumyl)cyclohexanol (TCC), 3 with aliphatic Grignard reagents provides dihydropyridones (2) in high yield and 85-95% de (Scheme 1).Dedicated to Professor A. I. Meyers in celebration of his 70 th birthday.N OMe TIPS CO 2 R* Cl N O CO 2 R* R TIPS 1) R-Met 2) H 3 O + R* = cyclohexyl-based chiral auxiliaries 2 1 2 Scheme 1The absolute stereochemistry at C-2 of the major diastereomer (2) was shown to be the (R) configuration.Interestingly, in contrast to carbanions, silicon nucleophiles add to the corresponding 1-acylpyridinium salts (3) from the opposite face to give the dihydropyridones (4) with the (S) configuration at C-2 (Scheme 2). 4 Reported herein is a study of this unique asymmetric reaction and synthetic transformations of the resulting silylated dihydropyridones (4).The reaction of triphenylsilylmagnesium bromide 5 with various chiral 1-acylpyridinium salts to give dihydropyridones (6) was investigated (Scheme 3).The pyridinium salts were prepared from 4methoxypyridine, 4-methoxy-3-trimethylsilylpyridine, 6 4-methoxy-3-tributylstannylpyridine 2 or 4methoxy-3-triisopropylsilylpyridine, 2 and the chloroformate of (-)-menthol (Men) or (-)-8-phenylmenthol (8-PhMen). 2The results of this study are shown in Table 1.Poor de's were observed when (-)-menthol was the chiral auxiliary (Entries 1-3).When the corresponding 8-phenylmenthol-derived pyridinium salts were used, excellent de's were obtained for most reactions.It was interesting that pyridine (5c), which gives the best results with Grignard reagents, 2 afforded product (6c) with a low de (Entry 4).When the TIPS group was replaced with a TMS or Bu 3 Sn group or a proton, an excellent degree of asymmetric induction was observed (Entries 5-8).In contrast to