2-Substituted furans 1a,b,c were found to be conveniently transformed into trans 4-oxo-2-enals 2a,b,c in 62-87% yields by using NBS/pyridine in THF-acetone-H(2)O (<-15 degrees C then rt) or NBS/NaHCO(3) in acetone-H(2)O (<-15 degrees C then rt after addition of pyridine). Further oxidation of the enals 2a-c using NaClO(2) led to the trans 4-oxo-2-enoic acids 3a-c in good yields. With this transformation in mind, we designed syntheses of (+)-aspicilin, (+)-patulolide, and (-)-pyrenophorin. In the synthesis of (+)-aspicilin as shown in Schemes 1 and 2, the pivotal intermediate 6 was prepared from olefin 7 in which 2-furyl group is attached. The AD reaction of 7 secured the C(5) and C(6) stereochemistry of aspicilin, and the subsequent transformation using the protocol described above afforded the ester 6. Stereocontrolled reduction of 6 followed by deprotection and the Yamaguchi macrocyclization furnished (+)-aspicilin. For the synthesis of (+)-patulolide (Scheme 3) and (-)-pyrenophorin (Scheme 4), the intermediates are the furans 38 and 44, which were prepared easily by the classical methods using furyllithium 33. The furan ring oxidations proceeded as well, furnishing acids 40 and 46 in good yields, acetalization of which afforded the known intermediates 41 and 47, respectively.

By using the convenient protocol for conversion of 2-substituted furans into 4-oxo-2-alkenoic acids ((i) NBS, (ii) NaClO(2)), macrosphelide B (2) was synthesized from furyl alcohol 5 (>98% ee) and acid 6 (99% ee). The protocol was first applied to the PMB ether of 5 to afford acid 13b. On the other hand, 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 the key ketone 17, which upon reduction with Zn(BH(4))(2) afforded anti alcohol 18 stereoselectively (15:1). After protection/deprotection steps, the furan 18 was converted to seco acid 3 by using the furan oxidation protocol mentioned above, and lactonization of 3 with Cl(3)C(6)H(2)COCl, Et(3)N, and DMAP afforded 22 (MOM ether of 2), which upon deprotection with TFA produced 2. Transformation of 22 to macrosphelide A (1) was then investigated. Although the chelation-controlled reduction of 22 should afford the desired anti alcohol 24, Zn(BH(4))(2) at <-90 degrees C gave a 2 approximately 1:1 mixture of anti/syn alcohols. On the contrary, reduction with NaBH(4) in MeOH at -15 degrees C produced the syn isomer 23 with >10:1 diastereoselectivity. Mitsunobu inversion of the resulting C(14)-hydroxyl group and deprotection of the MOM group with TFA afforded 1. Similarly, reduction of 2 with NaBH(4) afforded the C(14)-epimer of 1 stereoselectively. The observed stereoselectivity in the reductions of 22 and 2 could be explained on the basis of computer-assisted calculation, which showed presence of the low-energy conformers responsible for the stereoselective reduction. In addition, conversion of 2 to 1 was established, for the first time.

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