Studies on the synthesis of aphidicolin. The Diels–Alder route to spirocyclic intermediates

Abstract

The isopropylidene cyclohexylidenemalonates (6; R1= R2= H; R1, R2= OCH2CH2O; and R1, R2= SCH2CH2S) undergo cycloaddition with butadiene, 2-trimethylsilyloxybuta-1,3-diene, and 3-trimethylsilyloxypenta-2,4-diene to give the corresponding spirocyclic adducts (7; R1= R2= H), (11; R1, R2= OCH2CH2O; R1, R2= SCH2CH2S), and (23; R1, R2= OCH2CH2O; R1, R2= SCH2CH2S). The trimethylsilylenol ether (11; R1, R2= SCH2CH2S) was converted via compounds (12), (14), (15), (16), and (17) to the toluene-p-sulphonate (18) which undergoes base-catalysed intramolecular enolate alkylation to give the bicyclo[3.2.1 ]octanones (19) and (20) which serve as models for aphidicolin (1) and stemodine (2) synthesis. The adduct (23; R1, R2= SCH2CH2S) was converted via the trione (25) into the ester (27) whose enol ether derivative (28) is a promising precursor to the key aphidicolin intermediate (4).