efficient for the present system. Actually, starting from 3H-R
derivative 17, spiro-oxindole 20a was obtained in 49% yield
as a sole separable product. By contrast, from 3H-â derivative
18, the two diastereomeric oxindoles 21b and 21a were
produced in 69% and 5% yields, respectively. The stereo-
chemistry at the C7 position in compounds 20a, 21a, and
21b was unambiguously elucidated by extensive NMR
analyses. By irradiating H9 on the benzene ring, a clear NOE
was observed between the protons on C14 in 20a and 21b,
demonstrating that 20a and 21b have 7(S) and 7(R) con-
figurations, respectively. On the other hand, a clear NOE
between H9 and H3 was observed in the differential NOE
experiment of 21a, revealing its 7(S) configuration. The
predominant formation of diastereomeric oxindole derivatives
through the lead tetraacetate oxidation/solvolytic rearrange-
ment may be interpreted from the plausible mechanism
discussed in previous papers.13a,15b,c,16e In contrast, the facile
interconversion of rhynchophylline (3) and isorhynchophyl-
line (4) under acidic conditions is well-known.3b,14g,17 On the
basis of the mechanism in the literature, the concomitant
epimerization at C3 during the solvolytic rearrangement
above may be considered. To examine this possibility, the
oxindoles 20a, 21a, and 21b obtained by the above reactions
were treated under the conditions used for rearrangement
(one drop of acetic acid, aqueous methanol, reflux for 30
min). As a result, the oxindoles were recovered in their
completely intact forms, demonstrating that in the case of
the Nb-formyl derivatives, no isomerization at C3 or C7
occurs and the stereochemistry at C3 of the products is the
same as that of the starting materials.
derivative 2 in 82% overall yield from 20a. Synthetic 2 was
completely identical in all respects (chromatographic behav-
ior, mass, IR, UV, CD, 1H and 13C NMR, [R]D) with natural
Us-8. Therefore, the structure including the absolute con-
figuration of the chiral centers in 2 was established.
Next, for the completion of the total synthesis of Us-7,
3(R),7(S) isomer 21a was employed for the transformation
as above. However, surprisingly, product 1 was not identical
1
with natural Us-7 by comparison of their H and 13C NMR
spectra, although all spectral data including NOE data
indicated that the product possessed the molecular structure
of the reported Us-7 (1). As described in the introductory
section, the stereochemistry at the spiro position (C7) was
deduced by employing the empirical rule of the CD spectra
for common Corynanthe-type oxindole alkaloids. At this
stage, if we were to eliminate the information of the CD
spectral data, an alternative structure 22 could be considered
as a candidate structure for Us-7, which accounted for the
observed NOE correlation between H3 and H9 in the natural
product. Then, we shifted our synthetic target to oxindole
22 having the 3(S),7(R) configuration. To improve the
diastereoselectivity of the reduction of imine 16 with NaBH4,
the use of several reaction conditions and reagents was
attempted. When sodium tris[(S)-N-benzyloxycarbonylproly-
oxy]hydroborate19 was used for reducing imine 16, the
diastereomeric ratio of the amines was changed to ca. 1:1.
As described above, the oxidative transformation of 3(S)
isomer 17 using Pb(OAc)4 gave oxindole 20a with the 7(S)
configuration as the sole product. However, by employing
t-BuOCl instead of Pb(OAc)4, 7(R) isomer 20b was obtained
in 20% overall yield, together with 20a in 68% yield. The
structure including the stereochemistry at C7 in 20b was
elucidated by extensive 2D-NMR analysis and differential
NOE experiments (from H9 to H3) as above. The functional
group on the side chain in 20b was then converted into the
ketone to furnish target molecule 22 in 84% overall yield.
Synthetic 22 was completely identical in all respects
The final stage of the total synthesis is the conversion of
the functional group on the side chain in the oxindole
derivatives. First, oxindole 20a having the 3(S),7(S) config-
uration was used to complete the synthesis of Us-8. The
protecting group of the secondary hydroxyl group was
removed by hydrogenolysis, and the resulting alcohol was
oxidized with Dess-Martin periodinane18 to give ketone
1
(chromatographic behavior, mass, IR, UV, CD, H and 13C
(14) (a) Finch, N.; Taylor, W. I. J. Am. Chem. Soc. 1962, 84, 3871. (b)
Shavel, J., Jr.; Zinnes, H. J. Am. Chem. Soc. 1962, 84, 1320. (c) Hollinshead,
S. P.; Grubisha, D. S.; Bennett, D. W.; Cook, J. M. Heterocycles 1989, 29,
529. (d) Martin, S. F.; Mortimore, M. Tetrahedron Lett. 1990, 31, 4557.
(e) Stahl, R.; Borschberg, H.-J.; Acklin, P. HelV. Chim. Acta 1996, 79, 1361.
(f) Martin, S. F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem. Soc.
1996, 118, 9840. (g) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.;
Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003.
(15) (a) Van Tamelen, E. E.; Yardley, J. P.; Miyano, M.; Hinshaw, W.
B., Jr. J. Am. Chem. Soc. 1969, 91, 7333. (b) Pellegrini, C.; Strassler, C.;
Weber, M.; Borschberg, H. J. Tetrahedron: Asymmetry 1994, 5, 1979. (c)
Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am.
Chem. Soc. 1999, 121, 2147.
NMR, [R]D) with natural Us-7. Therefore, the structure of
Us-7 was revised as formula 22, and the absolute configu-
ration of the chiral centers in Us-7 was established.
The present study revealed that the empirical rule of the
Cotton effect used for the structure determination of common
Corynanthe-type oxindole alkaloids is not applicable to the
elucidation of the absolute stereochemistry at the C7 spiro
center of D-seco-type compounds.
(16) (a) Esmond, R. W.; Le Quesne, P. W. J. Am. Chem. Soc. 1980,
102, 7117. (b) Takayama, H.; Masubuchi, K.; Kitajima, M.; Aimi, N.; Sakai,
S. Tetrahedron 1989, 45, 1327. (c) Takayama, H.; Kitajima, M.; Ogata,
K.; Sakai, S. J. Org. Chem. 1992, 57, 4583. (d) Peterson, A. C.; Cook, J.
M. Tetrahedron Lett. 1994, 35, 2651. (e) Peterson, A. C.; Cook, J. M. J.
Org. Chem. 1995, 60, 120. (f) Wearing, X. Z.; Cook, J. M. Org. Lett. 2002,
4, 4237 and references therein.
(17) (a) Wenkert, E.; Udelhofen, J. H.; Bhattacharyya, N. K. J. Am. Chem.
Soc. 1959, 81, 3763. (b) Seaton, J. C.; Nair, M. D.; Edwards, O. E.; Marion,
L. Can. J. Chem. 1960, 38, 1035. (c) Phillipson, J. D.; Hemingway, S. R.
Phytochemistry 1973, 12, 2795. (d) Awang, D. V. C.; Vincent, A.; Kindack,
D. Can. J. Chem. 1984, 62, 2667. (e) Laus, G. J. Chem. Soc., Perkin Trans.
2 1998, 315.
Acknowledgment. The authors thank Professor Dr.
Kentaro Yamaguchi, Analysis Center of Chiba University,
for X-ray crystallographic analysis.
Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectral data for
compounds 13, 14, 17, 18, synthetic and natural Us-8 (2),
1, and synthetic and natural Us-7 (22), as well as X-ray data
(ORTEP) for compound 19. This material is available free
(18) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(19) Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc., Perkin Trans.
1 1983, 265.
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Org. Lett., Vol. 5, No. 16, 2003