title: Development of an enantioselective synthetic route to neocarzinostatin chromophore and its use for multiple radioisotopic incorporation.
abstract: A convergent, enantioselective synthetic route to the natural product neocarzinostatin chromophore (1) is described. Synthesis of the chromophore aglycon (2) was targeted initially. Chemistry previously 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 highly oxygenated substrates 27 and 54. An alternative synthetic plan was therefore developed, based upon a proposed reduction of the epoxy alcohol 58 to form the aglycon 2, a transformation that was achieved in a novel manner, using a combination of the reagents triphenylphosphine, iodine, and imidazole. The successful 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 with > or =20:1 diastereoselectivity. The alcohol 22 was then converted into the epoxy alcohol 58 in 17 steps with an average yield of 92% and an overall yield of 22%. Key features of this sequence include the diastereoselective Sharpless asymmetric epoxidation of allylic alcohol 81 (98% yield); intramolecular acetylide addition 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 the chloroacetate protective group in situ to furnish the naphthoic acid ester 85 in 80% yield; and elimination of 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 the N-methylamino --> hydroxyl replacement analogue 3, an alpha-D-fucose derivative of neocarzinostatin chromophore, formed in 42% yield by a two-step Schmidt glycosylation-deprotection sequence. For the synthesis of 1, an extensive search for a suitable 2'-N-methylfucosamine glycosyl donor led to the discovery that the reaction of 2 with the trichloroacetimidate 108, containing a free N-methylamino group, formed the alpha-glycoside 114 selectively in the presence of boron trifluoride diethyl etherate. Subsequent deprotection of 114 under mildly acidic conditions then furnished the labile chromophore (1). The synthetic route was readily modified for the preparation of singly and doubly (3)H- and (14)C-labeled 1, compounds unavailable by other means, for studies of the mechanism of action of neocarzinostatin in vivo.
authors: Contribution from the Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Andrew G
authors: AG
authors: Myers
authors: Ralf
authors: R
authors: Glatthar
authors: Marlys
authors: M
authors: Hammond
authors: Philip M
authors: PM
authors: Harrington
authors: Elaine Y
authors: EY
authors: Kuo
authors: Jun
authors: J
authors: Liang
authors: Scott E
authors: SE
authors: Schaus
authors: Yusheng
authors: Y
authors: Wu
authors: Jia-Ning
authors: JN
authors: Xiang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D002250:Carbon Radioisotopes; D053281:Enediynes; D006031:Glycosylation; D007553:Isotope Labeling / Q000379:methods; D008958:Models, Molecular; D013237:Stereoisomerism; D014316:Tritium; D009353:Zinostatin / Q000031:analogs & derivatives / Q000138:chemical synthesis*
chemical_list: D000903:Antibiotics, Antineoplastic; D002250:Carbon Radioisotopes; D053281:Enediynes; D014316:Tritium; C032372:neocarzinostatin chromophore; D009353:Zinostatin