triphenylphosphonium bromide in benzene in the presence
of potassium tert-butoxide. The Wittig reaction took place
in 90% yield. Hydroboration/oxidation was employed to
solve the problem of chemoselectivity between the olefinic
centers. It was felt the less hindered C16-C17 double bond,
relative to the C19-C20 site, would be attacked more readily
by selective hydroborating agents. It had been documented9
that the C19-C20 double bond of the enantiomer of 13
reacted with both BH3‚DMS and BH3‚THF, however, it did
not react with thexyl borane or 9-BBN. Certainly, a key issue
rested on the regiopreference for the desired attack at the
C16-C17 double bond in contrast to the C19-C20 bond.
Importantly, Magnus et al.4 had previously demonstrated that
C17 of the C16-C17 olefinic site could be selectively
hydroborated to provide the 16(S) alcohol in the synthesis
of (+)-koumine. From examination of the possible transition
states,10 attack from the convex face seemed more favorable,
although it would be difficult to distinguish the outcome
based solely on steric factors. Gratifyingly, (E)16-epiaffi-
nisine (1) was obtained as the only detectable diastereomer
when the hindered diisoamylborane or 9-BBN were em-
ployed as hydroborating agents, followed by oxidative
workup. Further oxidative cyclization of 1 effected by DDQ
in THF afforded dehydro-16-epiaffinisine (4) in 98% yield
in stereospecific fashion. Although the vinylogous iminium
ion 16 is depicted here as an intermediate, a number of
possible mechanisms for the generation of 4 are possible.11-20
The spectroscopic properties and optical rotations of synthetic
1 and 4 agree in all respects with those reported for the
natural products.1 Thus, a concise and stereospecific total
synthesis of 1 and 4 has been carried out from commercially
available D-(+)-tryptophan methyl ester (7) which involved
only seven reaction vessels for 1 (25% overall yield) and
eight reaction vessels for 4 (24% overall yield).
Scheme 4a
a Reagents and conditions: (a) PPh3CH3Br, KO-t-Bu, benzene,
rt, 4 h, 92%. (b) Sia2BH; NaOH/H2O2, rt, or 9-BBN; NaOH/H2O2,
rt, 75-80%. (c) DDQ, THF, reflux, 1 h, 95%.
With the E-ethylidene ketone 18 in hand, the synthesis of 2
was completed via a Wittig reaction coupled with a chemo-
specific, regiospecific hydroboration/oxidation (74% yield
for the two steps). (E)16-Epinormacusine B (2) was obtained
as the sole diastereomer from this procedure. Consequently,
(E)16-epinormacusine B (2) could be prepared in a short
synthetic sequence from D-(+)-tryptophan methyl ester (7)
in eight reaction vessels in 26% overall yield. The spectro-
scopic properties and optical rotation of synthetic 2 were in
complete agreement with the natural product.1 Finally,
oxidative cyclization of alcohol 2 by treatment with DDQ
in THF afforded the dehydro-16-epinormacusine B (5) in
95% yield (Scheme 4). The stereochemistry of the chiral
centers in both 4 and 5 was determined by 2D NOESY
experiments; they were present in the correct configuration
at C(3), C(5), C(6), C(15), and C(16) as depicted in Figure
2.
Recently, the synthesis of the E-ethylidene ketone 18 was
completed by Wang and Cook7 via an efficient enolate driven
palladium-catalyzed cyclization as a key step (Scheme 4).
This synthesis7 permitted the conversion of the Na-H, Nb-
benzyl tetracyclic ketone 17, which had been prepared in
two reaction vessels from D-(+)-trypotophan methyl ester
(7),21 into the E-ethylidene ketone 18 in only three steps.
(9) Liu, X. Ph.D. Thesis, University of Wisconsin-Milwaukee, 2002.
(10) Brown, H. C.; Keblys, K. A. J. Am. Chem. Soc. 1964, 86, 1791.
(11) Pinchon, T.-M.; Nuzillard, J.-M.; Richard, B.; Massiot, G.; Le Men-
Olivier, L.; Sevenet, T. Phytochemistry 1990, 29, 3341.
(12) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
(13) Oikawa, Y.; Yoshioka, T.; Kunihiko, M.; Yonemitsu, O. Hetreo-
cycles 1979, 12, 1457.
(14) Campus, O.; DiPerro, M.; Cain, M.; Mantei, R.; Gawish, A.; Cook,
J. M. Heterocycles 1980, 14, 975.
(15) Cain, M.; Mantei, R.; Cook, J. M. J. Org. Chem. 1982, 47, 4933.
(16) Wang, T.; Xu, Q.; Yu, P.; Liu, X.; Cook, J. M. Org. Lett. 2001, 3,
345.
(17) Walker, D.; Hiebert, J. D. Chem. ReV. 1967, 67, 153.
(18) Braude, E. A.; Jackman, L. M.; Linstead, R. P. J. Chem. Soc. 1954,
3548.
Figure 2. Selected NOESY’s of dehydro-16-epiaffinisine (4).
(19) Jackman, L. M. AdV. Org. Chem. 1960, 2, 329.
(20) Bergman, J.; Carlsson, R.; Misztal, S. Acta Chem. Scand. B 1976,
30, 853.
(21) (a) Yu, P.; Wang, T.; Yu, F.; Cook, J. M. Tetrahedron Lett. 1997,
38, 6819. (b) Wang, T.; Yu, P.; Li, J.; Cook, J. M. Tetrahedron Lett. 1998,
39, 8009. (c) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens,
D.; Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc. 1999, 121,
6998. (d) Yu, P.; Cook, J. M. J. Org. Chem. 1998, 63, 9160.
In conclusion, the first stereospecific total synthesis of (-)-
(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2),
and (+)-dehydro-16-epiaffinisine (4) has been accomplished
from commercially available D-(+)-tryptophan methyl ester
Org. Lett., Vol. 4, No. 26, 2002
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