Synthesis of Sphingofungin D and Its Three Diastereomers

✍ Scribed by Ken Otaka; Kenji Mori

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 330 KB
• Volume: 1999
• Category: Article
• ISSN: 1434-193X
• DOI: 10.1002/(sici)1099-0690(199908)1999:8<1795::aid-ejoc1795>3.0.co;2-y

✦ Synopsis

Sphingofungin D [(2S,3R,4R,5S,14R)-1] and its three dia-epoxyoctane [(R)-7], 1-heptyne (8) and N-acetyl-Dmannosamine (9). stereomers were synthesized by starting from (R)-1,2-

In 1992 VanMiddlesworth et al. reported the isolation [1] and structure elucidation [2] of sphingofungins, a new family of antifungal metabolites produced by Aspergillus fumigatus ATCC 20857. These compounds are potent and specific inhibitors of serine palmitoyl transferase. The structures 1, 2 and 3 assigned to sphingofungins D, B and A, respectively, show their similarity to sphingolipids. Their stereochemistry at C-14 was not reported initially, [2] but in 1995, Chida et al. elucidated it to be (R) by examining the ozonolysis product of natural sphingofungin C (2, OAc instead of OH at C-5). [3] In continuation of our synthetic studies on sphingosine relatives, we undertook a synthesis of both the (14R) and (14S) isomers of 4. Because 4 derived from the natural sphingofungin C has been converted into sphingofungin D (1), B (2) and A (3), [2] the synthesis of 4 implies that of these three sphingofungins. In this paper, we will report the synthesis of four diastereomers of 4, and their conversion into sphingofungin D and its three diastereomers. [4] In 1996, a synthesis of sphingofungin B was reported by Kobayashi et al. [5] [6] Our retrosynthetic analysis as shown in Scheme 1 suggests that 4 may be synthesized by the coupling reaction of 5 (nonpolar part) and 6 (polar part). Optically active 5 will be derived from (R)-1,2-epoxyoctane (7) and 1-heptyne (8). On the other hand, preparation of 6 will be possible from N-acetyl--mannosamine (9).

Scheme 2 summarizes the preparation of the nonpolar building block 15. Cleavage of (R)-7 (91% ee; purchased from Japan Energy Co.) with the acetylide from 8 yielded 10 and 11. After separation by column chromatography, 10 was subjected to the acetylene zipper reaction [7] to give Scheme 1. Structures of sphingofungins and their retrosynthetic crystalline (R)-12, m.p. 42Ϫ43°C, [α] D 23 ϭ Ϫ0.86 (c ϭ 1.7 analysis in Et 2 O). The corresponding TBS ether (R)-13 was metal-[ ] Part XX: H. Takikawa, S. Muto, K. Mori, Tetrahedron 1998, lated with tri(n-butyl)tin hydride [8] to give the alkenylstan-54, 3141Ϫ3150. nane (R)-14, which furnished the alkenyl iodide (R)-15 by [a] Department of Agricultural Chemistry, The University of Tokyo, treatment with iodine in diethyl ether. [9] The overall yield Yayoi 1-1-1, Bunkyo-ku, Tokyo 113Ϫ8657, Japan of (R)-15 based on 7 was 61% after 5 steps. Mitsunobu in- [b] Research fellow on leave from Sumitomo Chemical Co.