A convergent, enantioselective synthetic route to the natural product neocarzinostatin chro
mophore (
1) is described. Synthesis of the chro
mophore aglycon (
2) was targeted initially. Che
mistrypreviously 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 for
m the aglycon
2, a transfor
mation that was achieved ina novel
manner, using a co
mbination of the reagents triphenylphosphine, iodine, and i
midazole. Thesuccessful route to
1 and
2 began with the convergent coupling of the epoxydiyne
15, obtained in 9 steps(43% overall yield) fro
m D-glyceraldehyde acetonide, and the cyclopentenone (+)-
14, prepared in one step(75-85% yield) fro
m the prostaglandin inter
mediate (+)-
16, affording the alcohol
22 in 80% yield and with
![](/i<font color=)
mages/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 asy
mmetric epoxidation of allylic alcohol
81 (98% yield); intra
molecular acetylideaddition within the epoxy aldehyde
82, using Masa
mune's lithiu
m diphenyltetra
methyldisilazide 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 eli
minationof the tertiary hydroxyl group within inter
mediate
88 using the Martin sulfurane reagent (79% yield).Reductive transposition of the product epoxy alcohol (
58) then for
med neocarzinostatin chro
mophore aglycon(
2, 71% yield). Studies directed toward the glycosylation of
2 focused initially on the preparation of the
N-
methyla
mino
![](/i<font color=)
mages/entities/rarr.gif"> hydroxyl replace
ment analogue
3, an
![](/i<font color=)
mages/gifchars/alpha.gif" BORDER=0>-
D-fucose derivative of neocarzinostatinchro
mophore, for
med in 42% yield by a two-step Sch
midt glycosylation-deprotection sequence. For thesynthesis of
1, an extensive search for a suitable 2'-
N-
methylfucosa
mine glycosyl donor led to the discoverythat the reaction of
2 with the trichloroaceti
midate
108, containing a free
N-
methyla
mino group, for
med the
![](/i<font color=)
mages/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 chro
mophore (
1). The synthetic route wasreadily
modified for the preparation of singly and doubly
3H- and
14C-labeled
1, co
mpounds unavailable byother
means, for studies of the
mechanis
m of action of neocarzinostatin in vivo.