Development of an Enantioselective Synthetic Route to Neocarzinostatin Chromophore and Its Use for Multiple Radioisotopic Incorporation

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• 作者：Andrew G. Myers ; Ralf Glatthar ; Marlys Hammond ; Philip M. Harrington ; Elaine Y. Kuo ; Jun Liang ; Scott E. Schaus ; Yusheng Wu ; and Jia-Ning Xiang
• 刊名：Journal of the American Chemical Society
• 出版年：2002
• 出版时间：May 15, 2002
• 年：2002
• 卷：124
• 期：19
• 页码：5380 - 5401
• 全文大小：405K
• 年卷期：v.124,no.19(May 15, 2002)
• ISSN：1520-5126

文摘

A convergent, enantioselective synthetic route to the natural product neocarzinostatin chromophore (1) is described. Synthesis of the chromophore aglycon (2) was targeted initially. Chemistrypreviously developed for the synthesis of a neocarzinostatin core model (4) failed in the requisite 1,3-transposition of an allylic silyl ether when applied toward the preparation of 2 with use of the more highlyoxygenated substrates 27 and 54. An alternative synthetic plan was therefore developed, based upon aproposed reduction of the epoxy alcohol 58 to form the aglycon 2, a transformation that was achieved ina novel manner, using a combination of the reagents triphenylphosphine, iodine, and imidazole. Thesuccessful route to 1 and 2 began with the convergent coupling of the epoxydiyne 15, obtained in 9 steps(43% overall yield) from D-glyceraldehyde acetonide, and the cyclopentenone (+)-14, prepared in one step(75-85% yield) from the prostaglandin intermediate (+)-16, affording the alcohol 22 in 80% yield and withmages/entities/ge.gif">20:1 diastereoselectivity. The alcohol 22 was then converted into the epoxy alcohol 58 in 17 steps withan average yield of 92% and an overall yield of 22%. Key features of this sequence include thediastereoselective Sharpless asymmetric epoxidation of allylic alcohol 81 (98% yield); intramolecular acetylideaddition within the epoxy aldehyde 82, using Masamune's lithium diphenyltetramethyldisilazide base (85%yield); selective esterification of the diol 84 with the naphthoic acid 13 followed by selective cleavage of thechloroacetate protective group in situ to furnish the naphthoic acid ester 85 in 80% yield; and eliminationof the tertiary hydroxyl group within intermediate 88 using the Martin sulfurane reagent (79% yield).Reductive transposition of the product epoxy alcohol (58) then formed neocarzinostatin chromophore aglycon(2, 71% yield). Studies directed toward the glycosylation of 2 focused initially on the preparation of theN-methylamino mages/entities/rarr.gif"> hydroxyl replacement analogue 3, an mages/gifchars/alpha.gif" BORDER=0>-D-fucose derivative of neocarzinostatinchromophore, formed in 42% yield by a two-step Schmidt glycosylation-deprotection sequence. For thesynthesis of 1, an extensive search for a suitable 2'-N-methylfucosamine glycosyl donor led to the discoverythat the reaction of 2 with the trichloroacetimidate 108, containing a free N-methylamino group, formed themages/gifchars/alpha.gif" BORDER=0>-glycoside 114 selectively in the presence of boron trifluoride diethyl etherate. Subsequent deprotectionof 114 under mildly acidic conditions then furnished the labile chromophore (1). The synthetic route wasreadily modified for the preparation of singly and doubly ³H- and ¹⁴C-labeled 1, compounds unavailable byother means, for studies of the mechanism of action of neocarzinostatin in vivo.