Directed aldol reaction retroaldolization

Direct aldol reactions on building block 49 appear to be much more straightforward, but are problematic because of the retroaldol problem. Nevertheless, two successful non-basic methods... 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

Diastereomer ratios were determined by gas chromatography. Since the aldol adduct undergoes retroaldol reaction on the column, it must be silylated prior to injection. Approximately 5 mg of the crude adduct is filtered through a short plug of silica gel to remove any trace metals. The material is taken up into 1-2 mL of dichloromethane in a 2-raL flask or small test tube. To this solution are added 4-5 drops of N,N-diethyl-1,1,1-trimethylsilylamine and a small crystal of 4-(N,N-dimethylamino)pyridine (Note 11), The solution is stirred for 2 hr and injected directly onto the column. (Column conditions 30 m x 0.32 mm fused silica column coated with OB 5, 14 psi hydrogen carrier gas, oven temperature 235°C). 

Phenyl-substituted oxiranes may be reduced in DMF akin to benzyl ethers by direct and indirect methods the regioselectivity is slightly higher in the indirect reduction [76]. Benzoyloxiranes can be reduced in MeCN to aldoles addition of acetic acid prevents a retroaldol reaction catalyzed by the EGB [77]. The ring opening is analogous to the reduction of 2-alkoxyacetophenone to acetophenone. 

Since it had been determined that ketone or aldehyde functionality was not directly accessible from chiral A/-acyloxazolidinones, the transamination-metal alkyl addition procedure provided a conveniently expeditious alternative. The first step, transamination, proceeded in high yield by introduction of the N-acyloxazolidinone into a solution of the aluminum amide in dichloromethane at -IS C. The reaction is favored by the presence of a-heteroatom substituents and by -alcohol functionality (aldol adducts). Acceleration of the transamination in the latter case is most likely due to formation of a chelated intermediate (5) which serves to activate only the exocyclic carbonyl towards attack (equation 4). Because of the indicated activation, these aldol adducts are often the best substrates for this permutation. The effectiveness of the transamination in the case of (4) is noteworthy, as retroaldol fragmentation of this substrate usually occurs under mild base catalysis. 

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