開催日: 2017/09/20 - 2017/09/22
Frondosin A (1), isolated from the marine sponge Dysidea frondosa by Freyer and co-workers,1 is a member of a family of five norsesquiterpenoid natural products. Frondosin A (1) was found to inhibit the binding of the interleukin-8 and exhibit anti-HIV activity. Recently, we reported that Rh2(S-TCPTTL)4 (5) is a highly effective catalyst for enantioselective tandem carbonyl ylide formation-cyclization reactions of α-diazo-β-ketoester with arylallene dipolarophiles, providing cycloadducts in good to high yields and with enantioselectivities of up to 99% ee as well as with perfect exo diastereoselectibity. In conjunction with our continuing interest in the carbonyl ylide cycloaddition strategy for the synthesis of natural products, we herein report catalytic asymmetric total synthesis of frondosin A (1) by exploiting Rh(II)-catalyzed intermolecular 1,3-dipolar cycloaddition as one of the key steps. The 1,3-dipolar cycloaddition of carbonyl ylide derived derived from α-diazo-β-ketoester 2a with 2 equiv of 2,5-dimethoxyphenylallene (3a) using 1 mol % of Rh2(S-TCPTTL)4 (5) afforded the exo-cycloadduct 4a in 78% yield with 82% ee. Reductive cleavage of the ether-bridge in iodoalcohol followed by protection of the primary alcohol as its TIPS ether and treatment of tertiary alcohol with LiHMDS and methyl chloroformate furnished allylic carbonate 17. Palladium-catalyzed regio- and stereoselective formate reduction of 17 provided 18 as a major product, which was transformed to allyl alcohol 9. 1,3-Transposition of primary allylic alcohol of 9 followed by oxidation gave enone 8, which was further converted to enol triflate 7 by 1,4-addition of alkylcopper reagent and subsequent triflation. Reductive Heck cyclization of 7 using Pd(OAc)2 and formic acid in the presence of diisopropylamine in N-methylpyrrolidone provided frondosin dimethyl ether (6) in good yield. Finally, oxidation of 6 and subsequent reduction of the corresponding quinone with zinc in acetic acid completed the total synthesis of frondosin A (1).