Furan ring oxidation strategy for the synthesis of macrosphelides A and B

By using the convenient protocol for conversion of 2-substituted furans int o 4-oxo-2-alkenoic acids ((i) NBS, (ii) NaClO2), macrosphelide B (2) was sy nthesized from furyl alcohol 5 (>98% eel and acid 6 (99% eel. The protocol was first applied to the PMB ether of 5 to afford acid 13b. On the other ha nd, DCC condensation of acid 6 with 5 gave 16 after deprotection of the TBS group. Condensation was again carried out between 13b and 16 to furnish th e key ketone 17, which upon reduction with Zn(BH4)(2) afforded anti alcohol 18 stereoselectively (15:1). After protection/deprotection steps, the fura n 18 was converted to seco acid 3 by using the furan oxidation protocol men tioned above, and lactonization of 3 with Cl3C6H2COCl, Et3N, and DMAP affor ded 22 (MOM ether of 2), which upon deprotection with TFA produced 2. Trans formation of 22 to macrosphelide A (1) was then investigated. Although the chelation-controlled reduction of 22 should afford the desired anti alcohol 24, Zn(BH4)(2) at <-- 90 degreesC gave a 2 similar to1:1 mixture of anti/s yn alcohols. On the contrary, reduction with NaBH4 in MeOH at -15 degreesC produced the syn isomer 23 with >10:1 diastereoselectivity. Mitsunobu inver sion of the resulting C(14)-hydroxyl group and deprotection of the MOM grou p with TFA afforded 1. Similarly, reduction of 2 with NaBH4 afforded the C( 14)epimer of 1 stereoselectively. The observed stereoselectivity in the red uctions of 22 and 2 could be explained on the basis of computer-assisted ca lculation, which showed presence of the low-energy conformers responsible f or the stereoselective reduction. In addition, conversion of 2 to 1 was est ablished, for the first time.