An enantioselective synthesis of patulolide A (1). patulolide B (2). and pdtulolide C (3) from ethyl (R)-3-bydroxybutanoate is described.
Recently Yamada and his co-workers isolated three new antimicrobial macrolides from the culture broth of Penicil- lium urticae mutant S11R59, named them patulolide A, B, and C and clarified their structures as depicted in formulas 1,2 and 3, re~pectively',~). They showed both antifungal and antibacterial activities. The gross structure 1 of patulolide A was confirmed by a synthesis of ( f)-14).
We became interested in synthesizing these new macrolides so as to show the utility of ethyl (R)-3-hydroxybutanoate',') (4) as a chiral building block. Our synthesis starting from 4 as shown in the Scheme enabled us to synthesize the naturally occurring enantiomers of patulolides A, B, and C.
Ethyl (R)-3-hydroxybutanoate (4, 100% e.e.) was converted into the iodide 5 in 86% overall yield as described previously7). Chain elongation of 5 to 6 was executed in 72% yield by treatment with a Grignard reagent in the presence of cuprous bromide according to Normant et al.8*91. Oxidation of 6 with pyridinium chlorochromate (PCC)"' gave 7. Treatment of 7 with ethyl lithiopropiolate"~'*) afforded 8 a in 82% yield from 6 as a diastereomeric mixture. The free hydroxy group of 8a was protected as 2-methoxyethoxymethyl (MEM) ethert3) to give 8 b in 84% yield. Subsequent removal of the tetrahydropyranyl (THP) protective group of 8 b furnished 8c in 82% yield. Hydrogenation of 8c over palladium/barium sulfate in the presence of quinoline gave the (Z)-olefinic ester 9a in 84% yield. Alkaline hydrolysis of 9 a with lithium hydroxide yielded the hydroxy acid 9b, the precursor for macrolactonization.
Lactonization of 9 b to 10 was accomplished by the method of Yamaguchi and his co-~orkers'~). Thus, 9 b was first treated with 2,4,6-trichlorobenzoyl chloride and triethylamine in THF to give a mixed anhydride whose dilute solution in toluene was slowly added to a refluxing solution of 4-(dimethy1amino)pyridine (DMAP) in toluene to give 10 in high yield (91 YO). Interestingly, the double bond of 10 was shown to be of (E) geometry as evidenced by its 'H-NMR spectrum with J = 16 Hz for the olefinic protons.