Biomimetic entry to the sarpagan family of indole alkaloids: Total synthesis of (+)-geissoschizine and (+)-N-methylvellosimine

Article abstract of DOI:10.1021/ja0296024

A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, from D-tryptophan (19) was performed as a critical prelude to achieving the first biomimetic, enantioselective synthesis of the sarpagi

Full text of DOI:10.1021/ja0296024

Published on Web 03/20/2003
Biomimetic Entry to the Sarpagan Family of Indole Alkaloids:
Total Synthesis of (+)-Geissoschizine and
(+)-N-Methylvellosimine
Alexander Deiters, Kevin Chen, C. Todd Eary, and Stephen F. Martin*
Contribution from the Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
Received December 5, 2002; E-mail: sfmartin@mail.utexas.edu
Abstract: A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of
monoterpenoid indole alkaloids, from D-tryptophan (19) was performed as a critical prelude to achieving
the first biomimetic, enantioselective synthesis of the sarpagine alkaloid (+)-Na-methylvellosimine (5). The
approach to (+)-geissoschizine was designed to address the dual problems of stereocontrolled formation
of the E-ethylidene moiety and the correct relative configuration at C(3) and C(15). Key steps in the synthesis
involve a vinylogous Mannich reaction to prepare the carboline 22, which has the absolute stereochemistry
at C(3) corresponding to that in 1 and 5, and an intramolecular Michael addition that leads to the tetracyclic
corynantheane derivative 24, which possesses the correct stereochemical relationship between C(3) and
C(15). Compound 24 was then transformed into 27, the pivotal intermediate in the syntheses of 1 and 5,
by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction
of the lactam in 27 followed by removal of the C(5) carboxyl group by radical decarbonylation gave
deformylgeissoschizine (2) that was converted into (+)-geissoschizine (1) by formylation. The common
intermediate 27 was then converted via a straightforward sequence of reactions into the R-amino nitrile
39. The derived silyl enol ether 40 underwent ionization upon exposure to BF3‚OEt2 to give the intermediate
iminium ion 41 that then cyclized in a biomimetically inspired intramolecular Mannich reaction to deliver
(+)-Na-methylvellosimine (5). This transformation provides experimental support for the involvement of such
a cyclization as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids.
Introduction
The alkaloids of the indole family have arguably been subject
to more structural, pharmacological, biosynthetic, and synthetic
investigations than any other group of alkaloid natural products.1
The intense interest in the indole alkaloids derives from the
structural diversity and complexity of many of its members
coupled with the important physiological properties and me-
dicinal applications of some of these natural bases. As part of
our ongoing efforts to develop general strategies for the efficient
synthesis of members of the various subgroups of this family,
we have completed the total syntheses of a number of structur-
ally different indole alkaloids, including reserpine, tetrahydro-
alstonine, geissoschizine, rugulovasines A and B, setoclavine,
akuammicine, strychnine, and manzamine A.2 In designing
approaches to several of these, key steps for skeletal construc-
tion were inspired by proposals for their biogenesis.3 For
example, geissoschizine (1) is a known biosynthetic precursor
of akuammicine (3) and strychnine,4 and the pivotal step in our
synthesis of 3 involved the sequential oxidation and base-
(2) (a) Martin, S. F.; Ru¨eger, H.; Williamson, S. A.; Grzejszczak, S. J. Am.
Chem. Soc. 1987, 109, 6124. (b) Martin, S. F.; Benage, B.; Geraci, L. S.;
Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991, 113, 6161. (c) Martin,
S. F.; Clark, C. C.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236. (d) Ito,
M.; Clark, C. C.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem.
Soc. 2001, 123, 8003. (e) Liras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.;
Martin, S. F. J. Am. Chem. Soc. 2001, 123, 5918. (f) Humphrey, J. M.;
Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.;
Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584.
(1) For reviews, see: (a) Herbert, R. B. In The Monoterpenoid Indole Alkaloids;
supplement to Vol. 25, Part 4 of The Chemistry of Heterocyclic Compounds;
Saxton J. E., Ed.; Wiley: Chichester, 1994; Chapter 1. (b) Saxton, J. E. In
The Monoterpenoid Indole Alkaloids; supplement to Vol. 25, Part 4 of
The Chemistry of Heterocyclic Compounds; Saxton J. E., Ed.; Wiley:
Chichester, 1994; Chapter 8. (c) Saxton, J. E. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1998; Vol. 50. (d) Saxton, J. E.
In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1998;
Vol. 51, Chapter 1. (e) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998,
327-340 and references therein.
(3) For a review of some examples of biomimetic alkaloid synthesis, see:
Scholz, U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349.
9
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J. AM. CHEM. SOC. 2003, 125, 4541-4550
4541

A R T I C L E S
Deiters et al.
Scheme 1
Scheme 2
advanced to address this crucial issue. The first of these was
set forth in 1968 by van Tamelen, who suggested that the bond
between C(5) and C(16) was formed via an intramolecular
Mannich reaction of an intermediate such as 4,5-dehydro-
geissoschizine 7 (Scheme 1, path A).8 In support of this novel
hypothesis, van Tamelen and Olivier shortly thereafter reported
a biogenetic-type synthesis of ajmaline (15) in which the key
step was the conversion of 12 into a mixture of the epimeric
aldehydes 14 (Scheme 2).9 This remarkable cyclization to give
the pentacyclic sarpagan skeleton proceeded via the putative
iminium ion 13, which was produced by decarbonylation of an
activated form of the carboxyl group in 12. Compound 14 was
then elaborated into ajmaline (15) in a series of transformations.
Some 25 years after van Tamelen’s original report, the
cyclization of several 4,5-dehydrocorynantheane analogues of
13 was reinvestigated by Lounasmaa and co-workers.10 Al-
though they were able to transform compounds 16-18 into the
derived ∆4(5)-iminium ions via a Polonovski-Potier protocol,
they did not observe the expected “biogenetic-type” cyclization
of any of these iminium ions. On the basis of these findings,
Lounasmaa proposed an alternate biosynthetic pathway for
forming the sarpagan skeleton that would proceed via an
intramolecular Mannich reaction of the conformationally more
flexible iminium ion 9 (Scheme 1, path B). Cyclization of the
resultant aldehyde 10 would then furnish a pentacyclic inter-
mediate that would be converted into 11. If this proposal is
correct, then the biogenesis of the corynanthe and the sarpagine
alkaloids must follow different pathways.
induced skeletal reorganization of the closely related corynanthe-
type derivative 2.2d
The successful implementation of a biomimetic transforma-
tion as the last step in our synthesis of akuammicine led us to
examine the feasibility of preparing alkaloids of the sarpagine
family such as polyneuridine aldehyde (4) or Na-methyl-
vellosimine (5) from 1 along biogenetic lines. Na-Methyl-
vellosimine has been isolated from the root bark of Rauwolfia
nitida, which has been used in indigenous medicine as an emetic
and cathartic.5 Precedent for such a transformation derived from
the extensive work of Sto¨ckigt and co-workers, who elucidated
many of the details in the enzymatic transformation of stricto-
sidine (6), a key intermediate in the biosynthesis of monoter-
penoid indole alkaloids, into sarpagan-17-ol (11) via the
akuammidine aldehyde 8 (Scheme 1),6 This is a complex
sequence of reactions involving more than 10 steps that are
catalyzed by a number of different enzymes.
Although these studies elucidated many of the details of
indole alkaloid biosynthesis, the question of the timing of bond
construction between C(5) and C(16) to produce the sarpagan
skeleton remained,6f,7 and two different proposals have been
(4) (a) Battersby, A. R.; Hall, E. S. Chem. Commun. 1969, 793. (b) Scott, A.
I.; Cherry, P. C.; Qureshi, A. A. J. Am. Chem. Soc. 1969, 91, 4932. (c)
Heimberger, S. I.; Scott, A. I. J. Chem. Soc., Chem. Commun. 1973, 217.
(5) Isolation of Na-methylvellosimine: Amer, M. A.; Court, W. E. Phytochem-
istry 1981, 20, 2569.
(6) For reviews, see: (a) Sto¨ckigt, J. In The Alkaloids; Cordell G. A., Ed.,
Academic: San Diego, 1995; Vol. 47, p 115. (b) Sto¨ckigt, J. In Natural
Product Analysis; Schreiner, P., Herderich, M., Humpf, H.-M., Schwab,
W., Eds.; Vieweg: Braunschweig-Wiesbaden, 1998; p 313. See also: (c)
Pfitzner, A.; Sto¨ckigt, J. Tetrahedron Lett. 1983, 24, 1695. (d) Pfitzner,
A., Sto¨ckigt, J. Planta Med. 1983, 48, 221. (e) Pfitzner, A.; Sto¨ckigt, J. J.
Chem. Soc., Chem. Commun. 1983, 459. (f) Pfitzner, A.; Krausch, B.;
Sto¨ckigt, J. Tetrahedron 1984, 40, 1691. (f) Herbert, R. B. In The
Biosynthesis of Secondary Metabolites, 2nd ed; Chapman and Hall: London,
1989; 133. (g) Schmidt, D.; Sto¨ckigt, J. Planta Med. 1995, 61, 254.
(7) The atoms are numbered according to the “biogenetic numbering” of Le
Men and Taylor: Le Men, J.; Taylor, W. I. Experimenta 1965, 21, 508.
The diametrically opposed observations of van Tamelen and
Lounasmaa provided considerable impetus to our efforts to
explore a biomimetic synthesis of 5 and related compounds from
(8) (a) van Tamelen, E. E.; Haarstad, V. B.; Orvis, E. L. Tetrahedron 1968,
24, 687. (b) van Tamelen, E. E.; Yardley, J. P.; Miyano, M.; Hinshaw, W.
B., Jr. J. Am. Chem. Soc. 1969, 91, 7349.
(9) (a) van Tamelen, E. E.; Olivier, L. K. J. Am. Chem. Soc. 1970, 92, 2136.
(b) van Tamelen, E. E.; Olivier, L. K. Bioorg. Chem. 1976, 5, 309.
(10) Lounasmaa, M.; Hanhinen, P. Tetrahedron 1996, 52, 15225.
9
4542 J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003

(+)-Geissoschizine and (+)-N-Methylvellosimine
A R T I C L E S
Scheme 3
intermediates such as deformylgeissoschizine (2). There are, of
course, significant differences between the iminium ion 13 of
van Tamelen and the iminium ions of Lounasmaa that were
generated from 16-18, and we reasoned that these dissimilarities
might account for the divergent observations. In particular, the
nucleophilic sites on 13 and on the iminium ions derived from
16-18 are electronically and sometimes sterically different.
Moreover, we believed that the Z-ethylidene group in 16 and
17 would not favor conformations that could undergo cycliza-
tion, whereas the E-ethylidene moiety in compounds related to
2 would clearly favor those conformations.11,12
To explore new strategies for the enantioselective syntheses
of indole alkaloids of the corynanthe and sarpagine families,
we initiated a series of studies that culminated first in an efficient
synthesis of (+)-geissoschizine (1) and then in a biomimetic
synthesis of (+)-Na-methylvellosimine (5). Significantly, this
synthesis of 5 represents the first example of a biomimetic,
enantioselective synthesis of a member of the sarpagine alkaloid
family, and it also provides compelling support for van
Tamelen’s original proposal for the biogenesis of these and the
related ajmaline alkaloids. We now report the details of these
investigations.13
Results and Discussion
Geissoschizine (1), an indole alkaloid belonging to the
corynanthe family, has been isolated from a variety of plant
species.14 It is a known intermediate in the biogenesis of a
number of monoterpene indole alkaloids.6 Although 1 may also
be envisioned as a precursor of 5, there is presently no evidence
to support this conjecture. Inasmuch as 1 occupies a central
position in the area of indole alkaloids, it has been the subject
of numerous investigations that have culminated in its synthe-
sis.15,16 Our first approach to geissoschizine featured a vinylo-
gous Mannich reaction17,18 and an intramolecular hetero-Diels-
Alder reaction as key constructions.15e,g In this synthesis, the
challenging stereochemical problems of controlling the geometry
of the ethylidene side chain and the relative configuration at
C(3) and C(15) were effectively controlled. However, the
strategy could not be readily modified for an enantioselective
synthesis of 1 nor could it be adapted to provide intermediates
related to geissoschizine that could be chemically transformed
along biogenetic pathways into representative indole alkaloids
of the sarpagine and ajmaline groups. A novel entry to
geissoschizine that provided simultaneous solutions to both of
these problems was therefore developed.
(11) For a review, see: Lounasmaa, M.; Hanhinen, P. Heterocycles 1999, 51,
649.
(12) (a) Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron
1989, 45, 2683. (b) Jokelar, R.; Halonen, M.; Lounasmaa, M. Tetrahedron
1993, 49, 2567.
(13) For a preliminary account of the synthesis of (+)-geissoschizine, see:
Martin, S. F.; Chen, K.; Eary, C. T. Org. Lett. 1999, 1, 79.
(14) (a) Puisieux, F.; Goutarel, R.; Janot, M. M.; LeHir, A. C. R. Seances Acad.
Sci. Ser. 2 1959, 249, 1369. (b) Rapoport, H.; Windgasson, R. J., Jr.;
Hughes, N. A.; Onak, T. P. J. Am. Chem. Soc. 1960, 82, 4404. (c) Janot,
M.-M.; Tetrahedron 1961, 14, 113. (d) Mehri, H.; Sciamama, F.; Plat, K.;
Sevenet, T.; Pusset, J. J. Ann. Pharm. Fr. 1984, 42, 145.
Synthesis of the Key Corynantheane Intermediate 27. On
the basis of prior experience,2c we knew that vinylogous
Mannich reactions involving iminium ions related to the
dihydrocarboline 20, which was prepared from D-tryptophan (19)
in a single operation by modification of a known procedure,19
would proceed preferentially from the face opposite the carboxyl
moiety at C(5). Hence, 20 was allowed to react with the vinyl
ketene acetal 21 to produce 22 as the only isolable product
(Scheme 3). As expected, the nucleophilic attack of 21 onto 20
occurred with high diastereoselectivity from the si face,
establishing the correct absolute stereochemistry at C(3) of the
indole alkaloid targets. Although it was not necessary to esterify
the carboxyl function in 20 prior to executing the vinylogous
Mannich reaction, subsequent transformations would require
such protection of that group. Crude 22 was thus treated directly
(15) Syntheses of racemic geissoschizine: (a) Yamada, K.; Aoki, K.; Kato, T.;
Uemura, D.; van Tamelen, E. E. J. Chem. Soc., Chem. Commun. 1974,
908. (b) Hachmeister, B.; Thielke, D.; Winterfeldt, E. Chem. Ber. 1976,
109, 3825. (c) Wenkert, E.; Vankar, Y. D.; Yadav, J. S. J. Am. Chem. Soc.
1980, 102, 7971. (d) Banks, B. J.; Calverley, M. J.; Edwards, P. D.; Harley-
Mason, J. Tetrahedron Lett. 1981, 22, 1631. (e) Martin, S. F.; Benage, B.;
Hunter, J. E. J. Am. Chem. Soc. 1988, 110, 5925. (f) Wenkert, E.; Guo,
M.; Pesthanker, M. J.; Shi, Y. J.; Vanker, Y. D. J. Org. Chem. 1989, 54,
1166. (g) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore,
M. J. Am. Chem. Soc. 1991, 113, 6161. (h) Lounasmaa, M.; Jokela, R.;
Miettinen, J.; Halonen, M. Heterocycles 1992, 34, 1497. (i) Lounasmaa,
M.; Jokela, R.; Anttila, U.; Hanhinen, P.; Laine, C. Tetrahedron 1996, 52,
6803. (j) Bennasar, M.-L.; Jimenez, J.-M.; Sufi, B. A.; Bosch, J. Tetrahedron
Lett. 1996, 37, 9105. (k) Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi,
N. Tetrahedron Lett. 1997, 38, 5307. (l) Bennasar, M.-L.; Jimenez, J.-M.;
Vidal, B.; Sufi, B. A.; Bosch, J. J. Org. Chem. 1999, 64, 9605.
(16) Syntheses of (+)-geissoschizine: (a) Bohlmann, C.; Bohlmann, R.; Rivera,
E. G.; Vogel, C.; Manandhar, M. D.; Winterfeldt, E. Liebigs Ann. Chem.
1985, 1752. (b) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989,
111, 300. (c) Yu, S.; Berner, O. M.; Cook, J. M. J. Am. Chem. Soc. 2000,
122, 7827. See also ref 13.
(17) For a review of recent applications of vinylogous Mannich reactions to
alkaloid synthesis, see: Martin, S. F. Acc. Chem. Res. 2002, 35, 895.
(18) For other recent reviews on the Mannich reaction and its variants, see: (a)
Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. Engl. 1998,
37, 1045. (b) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
(19) Previero, A.; Coletti-Previero, M.-A.; Barry, L.-G. Can. J. Chem. 1968,
46, 3404.
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A R T I C L E S
Deiters et al.
Scheme 4
with isobutylene in the presence of sulfuric acid to give 23 in
59% overall yield from 20. Nb-Acylation of 23 with diketene
furnished an intermediate â-keto amide that underwent facile
cyclization via an intramolecular Michael reaction upon addition
of potassium tert-butoxide to give 24 (86%). This reaction
presumably proceeded under thermodynamic control to establish
the correct relative stereochemistry at C(3) and C(15).
The synthesis of 24 completed assembly of the corynantheane
framework, so the next phase of the endeavor required introduc-
ing the E-ethylidene side chain to enable access to 27. Toward
this end, hydride reduction of the C(19) carbonyl function in
24 gave the alcohol 25, the stereochemistry of which was
unambiguously proven by X-ray crystallographic analysis. The
stereochemical outcome of this reduction is also consistent with
that observed in closely related systems.2c,20 Stereoselective
dehydration of 25 proved to be somewhat more difficult than
anticipated. For example, several efforts to effect direct dehy-
dration of 25 by base-induced â-elimination gave only small
amounts of 27 together with the corresponding Z-isomer.
Elimination of the derived mesylate 26 with DBU produced a
mixture (ca. 1:1) of 27 and its Z-isomer, albeit in modest yield.
Preliminary attempts to equilibrate these E- and Z-geometric
isomers with iodine in refluxing benzene led to extensive
decomposition. On the other hand, heating a mixture of the
isomeric alkenes at 100 °C in the presence of DBU did improve
the E/Z-ratio up to 3.5:1, but again decomposition pathways
led to poor material balance. Eventually we discovered that
warming a solution of 25 and methanolic NaOMe at 50 °C led
to stereoselective elimination to give the desired ester 27 bearing
the E-ethylidene side chain together with variable amounts of
the corresponding acid 28, although none of the Z-isomer was
isolated. While the high stereoselectivity observed in this process
was somewhat surprising in light of our earlier results, we have
observed similar selectivities in related eliminations.21 The acid
28 was likely produced by saponification of the ester moiety in
either 25 or 27 by hydroxide ions generated in the elimination
step. Esterification of this acid could be simply performed in
situ by adding excess acetyl chloride to the basic reaction
mixture, thereby producing 27, a compound that would serve
as the common intermediate for the syntheses of (+)-geisso-
schizine (1) and (+)-Na-methylvellosimine (5), in 85% overall
yield from 24.
classical Barton protocols,24 but 2 was obtained in only low
and inconsistent yields ranging up to 25%. The radical de-
carboxylation of the benzophenone oxime ester derived from
30 was then examined,25 but this procedure was unsuccessful,
as were alternate methods involving generation and reduction
of the iminium ion formed by the reaction of 30 with phosphorus
oxychloride.26 Finally, we discovered that the acyl selenide that
was formed by the sequential reaction of 30 with isobutyl
chloroformate and then sodium phenylselenide,27 underwent
facile and efficient radical decarbonylation to give deformyl-
geissoschizine 2 in 79% overall yield from 30.28,29 Formylation
of 2 according to the procedure of Winterfeldt16a then delivered
(+)-geissoschizine (1) in 48% yield (96% yield based upon
recovered starting material) via a sequence requiring only 11
chemical operations from D-tryptophan (19). The synthetic (+)-
geissoschizine thus obtained was spectroscopically identical with
a sample of racemic 1 previously prepared in our group,15g
and its optical rotation corresponded closely with that reported
for natural 1 {[R]2D0 ) +109 (c ) 0.58, EtOH); [R]2D0 ) +113
(c ) 0.43, EtOH)16b}.
Biomimetic Synthesis of (+)-Na-Methylvellosimine (5).
At this juncture, we reasoned that Na-methylated iminium ions
of the general form 31 would constitute potentially viable
intermediates in a biomimetic synthesis of (+)-Na-methyl-
vellosimine. Such iminium ions differ structurally in two
important ways from those generated by Lounasmaa, who was
unsuccessful in efforts to induce the intramolecular Mannich
reaction of iminium ions generated from 16-18.10 Perhaps
most importantly, iminium ions 31 all possess an E-ethylidene
side chain that should favor those conformations of the DE-
ring system in which the substituent at C(15) is approximately
Enantioselective Synthesis of (+)-Geissoschizine (1). The
transformation of 27 into (+)-geissoschizine (1) was initiated
with the selective reduction of the lactam function according
to the Borch protocol to furnish 29 in 92% yield (Scheme 4).22
Cleavage of the tert-butyl ester moiety was conducted using
trifluoroacetic acid in the presence of thioanisole,23 an essential
cation scavenger, to provide the acid 30. Having served its role
as a stereochemical control element to set the absolute stereo-
chemistry at C(3) and C(15), it was now time to remove the
carboxyl group from C(5) of 30. This task, however, proved
to be more difficult than anticipated. We first explored the
radical decarboxylation of 30 according to several of the
(24) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem.
Commun. 1983, 939. (b) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry,
J. J. Chem. Soc., Chem. Commun. 1984, 1298. (c) Barton, D. H. R.; Crich,
D.; Herve, Y.; Potier, P.; Thierry, J. Tetrahedron 1985, 41, 4347.
(25) Hasebe, M.; Tsuchiya, T. Tetrahedron Lett. 1987, 28, 6207.
(26) (a) Dean, R. T.; Padgett, H. C.; Rapoport, H. J. Am. Chem. Soc. 1976, 98,
7448. (b) Johansen, J. E.; Christie, B. D.; Rapoport, H. J. Org. Chem. 1981,
46, 4914.
(27) For leading references to acyl selenides, see: (a) Boger, D. L.; Mathvink,
R. J. J. Org. Chem. 1992, 57, 1429. (b) Evans, P. A.; Roseman, J. D.;
Garber, L. T. J. Org. Chem. 1996, 61, 4880.
(28) (a) Pfenninger, J.; Heuberger, C.; Graf, W. HelV. Chim. Acta 1980, 63,
2328. (b) Ireland, R. E.; Norbeck, D. W.; Mandel, G. S.; Mandel, N. S. J.
Am. Chem. Soc. 1985, 107, 3285.
(29) For other examples of the radical decarbonylation of acyl selenides, see:
(a) Quirante, J.; Escolano, C.; Bonjoch, J. Synlett 1997, 179. (b) Stojanovic,
A.; Renaud, P. Synlett 1997, 181.
(20) (a) Winterfeldt, E.; Radunz, H.; Korth, T. Chem. Ber. 1968, 101, 3172. (b)
Winterfeldt, E.; Gaskell, A. J.; Korth, T.; Radunz, H.-E.; Walkowiak, M.
Chem. Ber. 1969, 102, 3558. (c) Naito, T.; Kojima, N.; Miyata, O.;
Ninomima, I. J. Chem. Soc., Perkin Trans. 1 1990, 1271.
(21) Martin, S. F.; Benage, B.; Williamson, S. A.; Brown, S. P. Tetrahedron
1986, 42, 2903.
(22) Borch, R. F. Tetrahedron Lett. 1968, 61.
(23) Evans, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1989, 111, 1063.
9
4544 J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003

(+)-Geissoschizine and (+)-N-Methylvellosimine
A R T I C L E S
Scheme 5
axially oriented. Such a disposition of this side chain would
minimize the distance between C(5) and C(16) in the ground
state, thereby favoring cyclization.11 The iminium ions 31,
like van Tamelen’s putative iminium ion intermediate 13,8 also
bear a Na-methyl group rather than the Na-Boc group that is
found in 16-18. Following the lead of van Tamelen, we would
employ the carboxyl moiety at C(5), which had already served
as a stereochemical control device to set the absolute stereo-
chemistry in intermediates leading to 1, as a functional handle
for the regioselective formation of the requisite ∆4(5)-iminium
ions 31.
Toward setting the stage for the key biomimetic cyclization
step, the lactam 27 was first reacted with NaH in DMF in the
presence of methyl iodide to give the Na-methylated lactam 32,
which was immediately reduced to the amine 33 in 90% overall
yield using the Borch procedure (Scheme 5).22 An alternative
route to 33 was briefly examined in which we attempted to effect
the selective alkylation of the Na-atom of 29; however,
concomitant methylation of the Nb-atom was observed as a
significant and unavoidable side reaction. Acid-catalyzed cleav-
age of the tert-butyl ester in 33 in the presence of methylthio-
anisole proceeded smoothly as before to give the acid 34 in
excellent yield.
The synthetic plan now required a suitable tactic for generat-
ing a ∆4(5)-iminium ion that would undergo efficient cyclization
to the sarpagine framework. The precedent of van Tamelen
notwithstanding,9 it occurred to us that the C(5) carboxylic acid
moiety might not be the optimal precursor function as the
somewhat harsh conditions required for generating the requisite
iminium ion did not seem compatible with the presence of
an enol derivative of the ester at C(16). This concern was
validated in several exploratory experiments. On the other hand,
it was well-known that R-amino nitriles could be transformed
into iminium ions under mild conditions.30 Consequently, 34
was transformed by an 1-(3-dimethylaminopropyl)-3-ethyl-
carbodiimide (EDCI) mediated coupling with NH4OH into
the corresponding amide 35 in 86% yield.31 Dehydration of
35 with trifluoroacetic acid anhydride then provided the nitrile
36 in 90% yield. With 36 in hand, we performed several
experiments directed toward cyclizing the ester enolate and
ketene acetal derived from 36, but these experiments did not
yield detectable amounts of Na-methyl-16-epi-pericyclivine
(37).32
of the cyano group by reaction with LiBH4 in THF (Scheme
6).33 When a large excess (10 molar equiv) of reducing agent
was used and the reaction was conducted in dilute solution (7.5
mM) for an extended period of time (43 h), the alcohol 38 was
obtained in a nearly quantitative yield. Attempts to accelerate
this reaction by heating, adding MeOH, or using Et2O as the
solvent merely led to decreased yields.34 Oxidation of the
primary alcohol group in 38 using the Dess-Martin periodinane
reagent buffered with pyridine gave the aldehyde 39 in 83%
yield.35
In contrast to our expectations, 39 exhibited no propensity
toward cyclization under (Lewis) acidic conditions (CF3CO2H,
TIPSOTf), even in the presence of silver salts (like AgBF4).36
We therefore decided to explore a modified tactic that involved
subjecting a preformed nucleophilic derivative of the aldehyde
to conditions that were known to lead to ionization of R-amino
nitriles. Hence, the morpholine enamine of 39 was prepared
first and treated with AgBF4 and (Lewis) acid (CF3CO2H,
TIPSOTf), but we were unable to isolate any of the cyclized
products 5 or epi-5.37 We then synthesized the silyl enol ether
40 (E:Z ) 61:39) by reacting 39 with TBDMSCl in the presence
of NaH. Gratifyingly, when 40 was treated with freshly distilled
BF3‚OEt2 in degassed benzene at room temperature, a diaster-
eomeric mixture (7:3) of (+)-Na-methylvellosimine (5) and 16-
epi-(+)-Na-methylvellosimine (epi-5) was isolated, presumably
Our inability to cyclize 36 inspired us to modify the nature
of the activating function attached to C(16). Toward this goal,
the carboxyl group in 36 was selectively reduced in the presence
(33) Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd
ed.; Seyden-Penne, J., Ed.; John Wiley & Sons: New York, 1997.
(34) For a review of aspects of borohydride reductions, see: (a) Brown,
H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567. (b) Periasamy, M.;
Thirumalaikumar, M. J. Organomet. Chem. 2000, 609, 137.
(30) Overman, L. E.; Ricca, D. J. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Ed.; Pergamon Press: 1991, 2, p 1007 and references
therein. See also ref 18a.
(31) Waldmann, H.; Schmidt, G.; Jansen, M.; Geb, J. Tetrahedron 1994, 50,
11865.
(32) Isolation of 37: Pinchon, T.-M.; Nuzillard, J.-M.; Richard, B.; Massiot,
G.; Le Men-Olivier, L.; Sevenet, T. Phytochemistry 1990, 29, 3341.
(35) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Meyer, S.
D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(36) Daub, G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron 1988, 44, 3919.
(37) Attempts of an intramolecular nucleophilic displacement of the cyano group
by metal enolates derived from 36 and 39 also failed. For a similar
cyclization, see: Herlem, D.; Flore´s-Parra, A.; Khuong-Huu, F.; Chiaroni,
A.; Riche, C. Tetrahedron 1982, 38, 271.
9
J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003 4545

A R T I C L E S
Deiters et al.
Scheme 6
Figure 1. NOESY experiment on 36 with the strong and illustrative NOEs
shown for the preferred conformation A. The preferred ground state
conformation of the C and D rings of (Z)-2 is shown in B, and the chair
conformation of the D ring of (E)-2 is shown in C.
the CD quinolizidine ring system, thus placing C(5) and C(16)
in close proximity for the cyclization.
To evaluate the correctness of this structural hypothesis, the
solution conformation of the closely related compound 36 was
studied in a series of IR and 1H NMR experiments, including a
NOESY experiment in which a number of close contacts were
observed (Figure 1). That the quinolizidine CD-ring is likely
cis-fused is supported by the absence of Wenkert-Bohlmann
absorption bands in the IR spectrum of 36.40 These bands should
be visible if the nitrogen lone pair were antiperiplanar to both
H(3) and H(21b), as is the case for the trans-quinolizidine
system of (Z)-deformylgeissoschizine [(Z)-2] as shown in B
(Figure 1).41 The cis-fusion is further supported by the NOE
between Na-CH3 and H(3) (see A in Figure 1); it is also
consistent with the preferred conformation of deformylgeisso-
schizine (2).11a The strong NOE contacts between H(5) and
H(21a) and the two small coupling constants of J5,6a ) 2.1 Hz
and J5,6b ) 5.1 Hz suggest that H(5) occupies an equatorial
position on the C-ring.
The assignment of a boatlike conformation for the D-ring of
36, which positions the ester side chain at C(15) in an axial
orientation, is consistent with the observed pairwise NOEs
between H(3)-H(21b), H(15)-H(18), H(19)-H(21a), and
H(19)-H(21b), as shown in A. The absence of any NOEs to
the methylene group of C(16) suggests that the D-ring has some
twist boat character. There is the possibility that the side chain
appended to C(15) is axial on a cis-quinolizidine system in
which the D-ring is a chair (see C, Figure 1).11,12a However,
this conformation is not in accord with the observed NOE
between H(3) and H(21b) that are both equatorial in C. Chair
conformations for D-rings in related Na-Boc-protected indolo-
quinolizidines have been previously discounted owing to the
steric interactions that would then result between the Na-CH3
and the C(14) methylene moieties.12b The available spectral
evidence and literature precedent thus support our hypothesis
that the D-ring of 36 resides in a boat-like conformation with
via cyclization of the iminium ion 41. This mixture was simply
exposed to aqueous KOH in MeOH to furnish the more stable
5 as the exclusive product in 54% yield (68% based upon
recovered aldehyde) from 39,38 thereby completing the first
biomimetic, enantioselective synthesis of a sarpagine alkaloid.
Other Lewis acids including TMSOTf or TBDMSOTf also led
to the formation of 5 and epi-5, albeit with diminished yields.
Upon treatment of 40 with AgBF4 in acetonitrile, no cyclization
product 5/epi-5 was detected. The synthetic (+)-Na-methyl-
1
vellosimine (5) was identical (TLC, H and 13C NMR, MS)
with a sample of ent-5, generously provided by Prof. James M.
Cook.39 The optical rotation of synthetic 5 {[R]2D0 ) +91 (c )
0.10, CHCl3)} was higher than that of natural 5 {[R]D ) +23
20
(c ) 0.01, CHCl3)5} but corresponded well with that of synthetic
ent-5 {[R]D20 ) -99 (c ) 0.40, CHCl3)39a}.
Our original belief that 40 would be transformed into 5 and
epi-5 was based upon the prediction that the intermediate
iminium ion 41 would reside preferentially in a ground state
conformation that was favorable for cyclization. Namely, owing
to A1,3 strain with the adjacent E-ethylidene side chain, the enol
ether substituent at C(15) in 41 should occupy an axial position
on the D-ring, as had been observed previously for 2 and related
compounds.11,12 One would also then anticipate the D-ring of
41 to reside in a boat-like conformation with a cis-fusion of
(40) (a) Bohlmann, F. Angew. Chem. 1957, 69, 641. (b) Bohlmann, F. Chem.
Ber. 1958, 91, 2157. (c) Wenkert, E.; Roychaudhuri, D. K. J. Am. Chem.
Soc. 1956, 78, 6417.
(41) (a) Wenkert, E.; Guo, M.; Pestchanker, M.; Shi, Y.-J.; Vankar, Y. J. Org.
Chem. 1989, 54, 1166. (b) Takayama, H.; Watanabe, T.; Seki, H.; Aimi,
N.; Sakai, S. Tetrahedron Lett. 1992, 33, 6831.
(38) Bartlett, M. F.; Sklar, R.; Taylor, W. I.; Schlittler, E.; Amai, R. L. S.; Beak,
P.; Bringi, N. V.; Wenkert, E. J. Am. Chem. Soc. 1962, 84, 622.
(39) (a) Total synthesis of ent-5: Liu, X.; Wang, T.; Xu, Q.; Ma, C.; Cook, J.
M. Tetrahedron Lett. 2000, 41, 6299. (b) Total synthesis of 5: Yu, J.;
Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543.
9
4546 J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003

(+)-Geissoschizine and (+)-N-Methylvellosimine
A R T I C L E S
(3S,5R)-3,4,5,6-Tetrahydro-3-(3-methoxycarbonylallyl)-1H-pyrido-
[3,4-b]indole-5-carboxylic Acid (22). A mixture of imine hydrochloride
20 (5.12 g, 20.5 mmol) and the vinyl ketene acetal 21 (13.2 g, 61.5
mmol) in anhydrous MeCN (100 mL) was stirred at 0 °C for 30 min
and then at room temperature for 4 h, during which time a clear yellow
solution resulted. The solvent was removed under reduced pressure to
give a thick yellow oil that was purified by flash chromatography eluting
with CH2Cl2 and MeOH/CH2Cl2 (1:9f4:6) to give 22 (6.50 g) as a
yellow solid, which was used in the next reaction without further
purification. An analytical sample was obtained by flash chromatog-
raphy eluting with MeOH/CH2Cl2 (15:85f20:80): 1H NMR (250 MHz,
MeOH-d4) δ 7.88 (s, 1 Η), 7.46 (d, J ) 7.7 Hz, 1 H), 7.32 (d, J ) 8.1
Hz, 1 H), 7.16-6.89 (comp, 3 H), 6.07 (d, J ) 15.7 Hz, 1 H), 5.12-
5.01 (m, 1 H), 4.12 (t, J ) 7.6 Hz, 1 H), 3.70 (s, 3 H), 3.37-2.94
(comp, 4 H); 13C NMR (62 MHz, MeOH-d4) δ 173.5, 167.9, 143.2,
138.5, 129.2, 127.4, 126.5, 123.5, 120.5, 119.2, 112.3, 107.7, 55.8,
52.2, 52.0, 36.4, 23.6; IR (neat) ν 3378, 2950, 1709, 1628 cm-1; HRMS
(CI) m/z 315.1333 [C12H19N2O4 (M + 1) requires 315.1345).
(3S,5R)-tert-Butyl 3,4,5,6-Tetrahydro-3-(3-methoxycarbonylallyl)-
1H-pyrido[3,4-b]indole-5-carboxylate (23). The crude acid 22 (6.5
g) from the preceding experiment was dissolved in 1,4-dioxane (150
mL) containing concentrated H2SO4 (10 mL), and isobutylene gas was
bubbled for 3 h at room temperature into the mixture through a
dispersion tube fitted with a glass frit; the volume of the solution
increased by about 20 mL during this period. The solution was
maintained at room temperature overnight, and then isobutylene gas
was bubbled into the mixture as before for 1 h. The mixture was again
allowed to stand overnight, whereupon it was slowly poured into a
mixture of ice (100 g), ammonium hydroxide (20 mL), and CH2Cl2
(300 mL). The pH of the aqueous phase was adjusted to 9 by the slow
addition of additional ammonium hydroxide. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 200 mL). The
combined organic layers were dried (MgSO4), and the solvents were
removed under reduced pressure. The residue was purified by flash
chromatography eluting with EtOAc/hexane (3:7f1:1) to give 4.45 g
(59% from 20) of 23 as a yellow foam: 1H NMR (250 MHz) δ 7.89
(s, 1 Η), 7.50 (d, J ) 7.3 Hz, 1 H), 7.30 (d, J ) 7.4 Hz, 1 H), 7.19-
7.01 (comp, 3 H), 5.97 (d, J ) 15.7 Hz, 1 H), 4.38 (t, J ) 6.7 Hz, 1
H), 3.81 (dd, J ) 7.8, 5.1 Hz, 1 H), 3.75 (s, 3 H), 3.07 (dd, J ) 15.4,
5.0 Hz, 1 H), 2.89 (dd, J ) 15.3, 6.9 Hz, 1 H), 2.67 (t, J ) 6.8 Hz, 2
H), 2.15 (br s, 1 H), 1.46 (s, 9 H); 13C NMR (62 MHz) δ 172.7, 166.6,
145.3, 136.0, 134.0, 127.0, 123.9, 121.9, 119.5, 118.2, 110.8, 108.0,
81.4, 52.9, 51.6, 49.7, 38.8, 28.0, 25.1; IR (neat) 3358, 2977, 1723,
1657 cm-1; HRMS (CI) m/z 371.1965 [C21H27N2O4 (M + 1) requires
371.1971].
the C(15) substituent in an axial orientation; it then seems
reasonable to surmise that a low-energy conformation for the
iminium ion 41 is similar.
Conclusion
A unified strategy for the enantioselective syntheses of the
corynanthe alkaloid (+)-geissoschizine (1) and the sarpagine
alkaloid (+)-Na-methylvellosimine (5) from D-tryptophan (19)
has been developed. The stereocenter in 19 sets the absolute
and relative stereochemistry at all stereocenters in 1 and 5.
Moreover, the carboxyl group in 19 enables the eventual,
regioselective generation of the requisite ∆4(5)-iminium ion for
the cyclization leading to 5. In these syntheses, the relative and
absolute stereochemistry between C(3) and C(15) and the
E-ethylidene double bond geometry in both 1 and 5 are
completely controlled, thereby addressing several important
problems in the area. Furthermore, the synthesis of (+)-Na-
methylvellosimine (5) features a biomimetic, intramolecular
Mannich reaction that provides persuasive support for a key
step in the proposed biosynthesis of the sarpagine and ajmaline
alkaloids from corynantheane intermediates. The absolute ster-
eochemistry at C(3) of both 1 and 5 was established at the outset
by a vinylogous Mannich reaction in which 22 was produced
as the only isolable product. A subsequent intramolecular
Michael reaction provided 24, thereby setting the correct relative
stereochemistry between C(3) and C(15). Base-induced dehy-
dration of the derived alcohol 25 cleanly introduced the requisite
E-ethylidene group and provided the pivotal intermediate 27.
Conversion of 27 into (+)-geissoschizine (1) completed a
concise enantioselective synthesis of this alkaloid by a sequence
that involved only 11 chemical operations from commercially
available D-tryptophan and proceeded in 17% overall yield,
based upon recovered 2 in the final step. Compound 27 was
also converted in eight steps into the key intermediate 40, which
underwent a facile intramolecular Mannich reaction to give (+)-
Na-methylvellosimine (5). Further applications of vinylogous
Mannich and biomimetic reactions as key steps in the syntheses
of complex alkaloids will be reported in due course.
Experimental Section
General Methods. Unless otherwise noted, solvents and reagents
were reagent grade and used without purification. CH2Cl2, i-Pr2NH,
and Et3N were freshly distilled from CaH2. THF and Et2O were passed
through two columns of neutral alumina. MeOH, CH3CN, and DMF
were passed through two columns of molecular sieves. Toluene was
passed through a column of neutral alumina and a column of Q5
reactant. Reactions involving air- or moisture-sensitive reagents or
intermediates were performed under an inert atmosphere of argon in
glassware that had been flame dried. Melting points are uncorrected.
Infrared (IR) spectra were recorded either neat on sodium chloride plates
or as solutions in CH2Cl2, as indicated, and are reported in wavenumbers
(cm-1). 1H and 13C NMR spectra were obtained as solutions in CDCl3
or C6D6, and chemical shifts are reported in parts per million (ppm)
downfield from (CH3)4Si (TMS). Coupling constants are reported in
hertz (Hz). Spectral splitting patterns are designated as follows: s,
singlet; br, broad; d, doublet; t, triplet; q, quartet; quin, quintet; m,
multiplet; and comp, complex multiplet. Signals in the 13C NMR that
could not be assigned are separated by slashes. Flash column chroma-
tography was performed using Merck silica gel 60 (230-400 mesh
ASTM) according to the method of Still.42
(3S,5R,15R,20S)-tert-Butyl 3,4,5,6,14,15,20-Heptahydro-20-acetyl-
15-methoxycarbonylmethyl-21-oxoindolo[2,3-a]quinolizine-5-car-
boxylate (24). A solution of the amino ester 23 (10.0 g, 27.0 mmol),
DMAP (200 mg, 1.64 mmol), and diketene (2.80 mL, 36.3 mmol) in
anhydrous toluene (200 mL) was stirred at room temperature for 2.5
h. The solution was diluted with toluene (150 mL) and cooled to -10
°C. Potassium tert-butoxide (5.80 g, 51.7 mmol) was added, and the
resulting suspension was vigorously stirred at -10 to -5 °C for 70
min. The reaction was quenched by adding 0.5 N HCl (100 mL), and
the resulting solution was diluted with EtOAc (300 mL) and water (100
mL). The layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 200 mL). The combined organic fractions were dried
(MgSO4), and the solvents were evaporated under reduced pressure.
The product was purified by flash chromatography eluting with CH2-
Cl2 and EtOAc/hexane (3:7) to give 10.5 g (86%) of 24 as a yellow
solid: mp 80-82 °C; 1H NMR (250 MHz) δ 8.07 (s, 1 Η), 7.52 (d, J
) 7.1 Hz, 1 H), 7.31 (dd, J ) 6.9, 1.1 Hz, 1 H), 7.22-7.09 (comp, 2
H), 5.86 (dd, J ) 6.1, 1.3 Hz, 1 H), 5.09 (d, J ) 10.4 Hz, 1 H), 3.69
(s, 3 H), 3.46-3.38 (comp, 2 H) 2.96 (ddd, J ) 8.4, 6.1, 2.1 Hz, 2 H),
2.62 (dt, J ) 12.9, 3.6 Hz, 1 H), 2.52-2.26 (comp, 3 H), 2.40 (s, 3 H),
1.28 (s, 9 H); 13C NMR (62 MHz) δ 204.0, 171.9, 169.2, 166.4, 136.5,
(42) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
9
J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003 4547

A R T I C L E S
Deiters et al.
131.1, 126.7, 122.4, 119.4, 118.4, 110.9, 107.1, 82.2, 61.5, 51.9, 51.2,
51.1, 38.5, 34.8, 30.3, 29.7, 27.9, 22.6; IR (CH2Cl2) 3312, 2976, 1731,
1633, 1621 cm-1; HRMS (CI) m/z 455.2174 [C25H31N2O6 (M + 1)
requires 455.2182].
4 H), 2.36-1.99 (comp, 4 H), 1.61 (d, J ) 6.8 Hz, 3 H), 1.34 (s, 9 H);
13C NMR (62 MHz) δ 173.7, 171.8, 136.0, 135.8, 134.1, 127.5, 121.3,
120.8, 119.2, 117.9, 110.9, 105.4, 81.8, 61.2, 55.1, 51.7, 49.0, 38.0,
32.4, 31.8, 28.1, 21.9, 12.7; IR (neat) 3377, 2975, 1729 cm-1; HRMS
(CI) m/z 425.2431 [C25H33N2O4 (M + 1) requires 425.2440].
(3S,5R,15R,19S,20S)-tert-Butyl 3,4,5,6,14,15,20-Heptahydro-20-
(1-hydroxyethyl)-15-methoxycarbonylmethyl-21-oxoindolo[2,3-a]-
quinolizine-5-carboxylate (25). A mixture of 24 (1.70 g, 3.86 mmol)
and NaBH4 (293 mg, 7.72 mmol) in anhydrous MeOH (60 mL) was
stirred at -10 °C for 25 min. Saturated NaHCO3 (40 mL) and CH2Cl2
(80 mL) were added, and the mixture was stirred at 0 °C for 5 min.
The organic layer was removed and the aqueous layer was extracted
with CH2Cl2 (3 × 40 mL). The combined organic layers were dried
(Na2SO4) and concentrated to give 1.68 g (95%) of 25 as a white
solid: mp 190-192 °C; 1H NMR (250 MHz) δ 7.90 (s, 1 Η), 7.52 (d,
J ) 7.2 Hz, 1 H), 7.31 (d, J ) 7.4 Hz, 1 H), 7.21-7.09 (comp, 2 H),
5.90 (d, J ) 4.4 Hz, 1 H), 5.04 (d, J ) 10.3 Hz, 1 H), 4.27 (br s, 1 H),
3.71 (s, 3 H), 3.44 (d, J ) 15.7 Hz, 1 H), 3.28 (br s, 1 H), 2.98 (ddd,
J ) 15.7, 6.0, 3.8 Hz, 1 H), 2.81-2.31 (comp, 5 H), 1.41 (d, J ) 6.4
Hz, 3 H), 1.25 (s, 9 H); 13C NMR (62 MHz) δ 172.6, 170.9, 170.0,
136.5, 131.5, 126.7, 122.3, 119.8, 118.3, 110.9, 107.1, 82.4, 70.7, 53.5,
51.7, 51.4, 50.6, 40.4, 36.7, 31.0, 27.8, 22.6, 21.3; IR (CH2Cl2) 3295,
2977, 1732, 1716, 1614 cm-1; HRMS (CI) m/z 457.2327 [C25H33N2O6
(M + 1) requires 457.2339].
tert-Butyl (20E)-[3S-(3r,5â,15r)]-3,4,5,6,14,15-Hexahydro-15-
methoxycarbonylmethyl-20-ethylidene-21-oxoindolo[2,3-a]quinoli-
zine-5-carboxylate (27). A cold solution of freshly prepared 0.1 M
NaOMe (20 mL, 2.09 mmol) was added to a flask containing crude
alcohol 25 (288 mg, 0.63 mmol) at 0 °C. After 20 min the mixture
was allowed to warm to room temperature and then heated at 50 °C
for 1.5 h. The solution was recooled to 0 °C and acetyl chloride (0.54
mL, 7.6 mmol) was slowly added. After 30 min the mixture was allowed
to warm to room temperature and stirred for a additional 2.5 h. Saturated
NaHCO3 (30 mL) and CH2Cl2 (30 mL) were added, and the organic
layer was removed. The aqueous layer was extracted with CH2Cl2 (3
× 30 mL), and the combined organic layers were dried (Na2SO4) and
concentrated. The crude concentrate was purified by flash chromatog-
raphy eluting with 30% EtOAc/hexane to give 239 mg (89%) of 27 as
a colorless oil that formed a foam under vacuum: 1H NMR (300 MHz)
δ 7.89 (s, 1 H), 7.55 (d, J ) 7.2 Hz, 1 H), 7.32 (d, J ) 7.2 Hz, 1 H),
7.15 (comp, 2H), 6.87 (q, J ) 6.1 Hz, 1 H), 5.81 (d, J ) 4.4 Hz, 1 H),
4.88 (d, J ) 10.5 Hz, 1 H), 3.68 (s, 3 H), 3.65 (d, J ) 15.4 Hz, 1 H),
3.45 (br s, 1 H), 3.1 (dd, J ) 5.9, 1.6 Hz, 1 H), 2.81-2.74 (m, 1 H),
2.63 (ddd, J ) 16.3, 10.6, 3.5 Hz, 2 H), 1.85 (d, J ) 7.3 Hz, 3 H),
1.75-1.65 (m, 1 H), 1.24 (s, 9 H); 13C NMR (75 MHz) δ 172.3, 170.1,
168.5, 136.6, 135.9, 133.5, 132.2, 126.7, 122.0, 119.6, 118.0, 110.9,
106.6, 81.7, 52.0, 51.6, 49.5, 40.0, 36.8, 29.6, 27.8, 23.2, 14.0; IR (neat)
3268, 2976, 1732, 1652, 1608 cm-1; HRMS (CI) m/z 439.2225
[C25H31N2O5 (M + 1) requires 439.2233].
(3S,5R,15R,20E)-tert-Butyl 3,4,5,6,14,15,21-Heptahydro-15-meth-
oxycarbonylmethyl-20-ethylideneindolo[2,3-a]quinolizine-5-carbox-
ylate (29). A slurry of 27 (0.843 g, 1.92 mmol) and trimethyloxonium
tetrafluoroborate (0.752 g, 5.08 mmol) in CH2Cl2 (60 mL) containing
2,6-di-tert-butylpyridine (1.27 mL, 5.60 mmol) was stirred at room
temperature for 22 h, during which time a homogeneous yellow solution
was produced. The reaction mixture was cooled to 0 °C, and anhydrous
MeOH (20 mL) was added. After 15 min, NaBH4 (0.750 g, 19.8 mmol)
was added, and the mixture was stirred at 0 °C for another 20 min.
Saturated NaHCO3 (50 mL) and CH2Cl2 (100 mL) were added and the
layers separated. The aqueous layer was extracted with CH2Cl2 (2 ×
60 mL). The combined organic fractions were dried (MgSO4), and the
solvents were removed under reduced pressure. The residue was purified
by flash chromatography eluting with EtOAc/hexane (2:8f3:7) to give
0.75 g (92%) 29 as a foam: 1H NMR (250 MHz) δ 8.37 (s, 1 Η), 7.45
(d, J ) 6.9 Hz, 1 H), 7.31-7.28 (m, 1 H), 7.13-7.02 (comp, 2 H),
5.42 (q, J ) 6.8 Hz, 1 H), 4.64 (br s, 1 H), 3.71 (dd, J ) 6.7, 4.6 Hz,
1 H), 3.65 (s, 3 H), 3.45 (br d, J ) 12.1 Hz, 1 H), 3.31-3.01 (comp,
(3S,5R,15R,20E)-3,4,5,6,14,15,21-Heptahydro-15-methoxycarbo-
nylmethyl-20-ethylideneindolo[2,3-a]quinolizine-5-carboxylic Acid
(30) To a solution of the ester 29 (0.709 g, 1.67 mmol) and thioanisole
(3.5 mL) in CH2Cl2 (4.0 mL) at 0 °C was added trifluoroacetic acid
(4.0 mL), and the solution was then stirred at room temperature for 5
h. The volatiles were removed under vacuum, and the residue was
purified by flash chromatography eluting with MeOH/CH2Cl2 (5:
95f20:80) to give 0.752 g (93%) of 30 as a foam: 1H NMR (250
MHz, MeOH-d4) δ 7.47 (d, J ) 7.7 Hz, 1 H), 7.35 (d, J ) 9.7 Hz, 1
H), 7.19-7.03 (comp, 2 H), 5.77 (q, J ) 6.8 Hz, 1 H), 5.27 (br s, 1
H), 4.12 (br s, 1 H), 3.88 (AB q, J ) 13.5 Hz, 2 H), 3.60 (s, 3 H),
3.54-3.31 (comp, 3 H), 2.49 (br s, 2 H), 2.36 (dd, J ) 15.5, 7.6 Hz,
1 H), 2.10 (dd, J ) 15.5, 7.9 Hz, 1 H), 1.70 (d, J ) 6.8 Hz, 3 H); 13
C
NMR (62 MHz, MeOH-d4) δ 173.6, 138.4, 131.0, 130.3, 128.5, 127.5,
123.6, 120.7, 119.2, 112.4, 105.5, 54.3, 53.6, 52.2, 37.4, 31.4, 28.0,
27.7, 21.6, 13.3; IR (neat) 3364, 3233, 2954, 1732, 1682, 1633 cm-1
;
HRMS (CI) m/z 369.1799 [C21H25N2O4 (M + 1) requires 369.1814].
(3S,5R,15R,20E)-3,4,5,6,14,15,21-Heptahydro-15-methoxycarbo-
nylmethyl-20-ethylideneindolo[2,3-a]quinolizine (2) To a solution of
acid 30 (240 mg, 0.652 mmol) in anhydrous THF (25 mL) at -10 °C
were added isobutyl chloroformate (0.10 mL, 0.771 mmol) and
N-methylmorpholine (85 µL, 0.771 mmol). The reaction mixture was
stirred at -10 °C for 15 min and at room temperature for 15 min,
whereupon it was recooled to -10 °C. A solution of sodium
phenylselenide in THF, which was prepared by reaction of benzene-
selenol (82 µL, 0.771 mmol) and sodium hydride (32 mg, 60%
dispersion in mineral oil, 0.80 mmol) in THF (10 mL) at 0 °C, was
then added through a cannula. The resulting mixture was stirred at -10
°C for 20 min and at room temperature for 30 min. The volatiles were
removed under reduced pressure, and the residue was dissolved in
benzene (20 mL). Neat Bu3SnH (0.70 mL, 2.60 mmol) and AIBN (20
mg, 0.12 mmol) were added, and the mixture was heated at 80 °C (oil
bath temp) with stirring for 4 h. The solvents were removed under
reduced pressure, and the residue was purified by flash chromatography
eluting with EtOAc/hexane (4:6) to give 167 mg (79%) of 2, which
gave spectroscopic data (1H and 13C NMR, IR, and MS) consistent
with those reported in the literature.16
(3S,5R,15R,20E)-tert-Butyl N-Methyl-3,4,5,6,14,15-hexahydro-15-
methoxycarbonylmethyl-20-ethylideneindolo[2,3-a]quinolizine-5-
carboxylate (33). A mixture of the indole 27 (615 mg, 1.40 mmol),
CH3I (105 µL, 1.68 mmol), NaH (60% suspension in mineral oil, 67
mg, 1.68 mmol), and DMF (15 mL) was stirred at 0 °C for 3 h and
then at room temperature overnight. H2O (20 mL) was added, and the
aqueous phase was extrated with CH2Cl2 (4 × 50 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo. The 1H
NMR spectrum of the crude product indicated a complete conversion
to 32. Hence, the residue was dissolved in CH2Cl2 (45 mL), and Me3-
OBF4 (627 mg, 4.20 mmol) and 2,6-di-tert-butylpyridine (1.04 mL,
4.62 mmol) were added. The reaction mixture was stirred at room
temperature for 20 h and cooled to 0 °C. MeOH (15 mL) was added,
and stirring continued for 15 min. NaBH4 (530 mg, 14.0 mmol) was
added and stirring was continued for 30 min. Saturated NaHCO3
(aqueous, 20 mL) was added, and the layers were separated. The
aqueous phase was extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure, and the crude product was purified by flash chromatography
on silica gel eluting first with hexane and then with EtOAc/hexane
(50:50) to give 550 mg (90% over two steps) of 33 as a yellow oil: 1H
NMR (300 MHz, CDCl3) δ 7.47-7.04 (comp, 4 H), 5.51 (q, J ) 7.5
Hz, 1 H), 4.36 (dd, J ) 4.1 Hz, 10.8 Hz, 1 H), 3.72 (d, J ) 12.6 Hz,
1 H), 3.64 (s, 3 H), 3.61 (s, 3 H), 3.63-3.55 (comp, 2 H), 3.34 (quin,
9
4548 J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003

(+)-Geissoschizine and (+)-N-Methylvellosimine
A R T I C L E S
J ) 6.5 Hz, 1 H), 3.15-3.03 (comp, 2 H), 2.72 (dd, J ) 7.2, 15.3 Hz,
1 H), 2.58 (dd, J ) 8.4, 15.3 Hz, 1 H), 2.41-2.33 (m, 1 H), 1.70 (d,
J ) 6.3 Hz, 3 H), 1.59-1.50 (m, 1 H), 1.32 (s, 9 H);13C NMR (125
MHz, CDCl3) δ 173.1, 172.6, 137.65, 137.0, 135.4, 126.6, 121.0, 120.9,
118.9, 117.9, 108.6, 104.8, 80.9, 60.4, 57.0, 51.5, 50.6, 40.1, 36.0, 31.8,
30.4, 28.1, 25.9, 13.0; IR (neat) 2922, 1731, 1470, 1368, 1152, 1011,
845 cm-1; HRMS (CI) m/ z 439.2604 [C36H25N2O8 (M + 1) requires
439.2597].
(ddd, J ) 2.7, 10.5 Hz, 12.9 Hz); 13C NMR (75 MHz, CDCl3) δ 172.9,
137.9, 136.0, 133.5, 126.1, 121.6, 121.2, 119.3, 118.0, 117.3, 108.9,
103.7, 57.6, 51.5, 51.1, 50.8, 40.6, 35.9, 31.1, 30.4, 26.0, 12.9; IR (CH2-
Cl2) 2922, 1732, 1470, 1378, 1149, 742 cm-1; HRMS (CI) m/z 364.2019
[C22H26N3O2 (M + 1) requires 364.2025].
(3S,5R,15R,20E)-N-Methyl-3,4,5,6,14,15-hexahydro-20-ethylidene-
15-(2-hydroxyethyl)indolo[2,3-a]quinolizine-5-cyanide (38). LiBH4
(8 mg, 0.38 mmol) was added to a stirred solution of 36 (20 mg, 0.06
mmol) in THF (8 mL). After 23 h, another portion of LiBH4 (5 mg,
0.23 mmol) was added and stirring was continued for 20 h. Saturated
aqueous NaHCO3 (1 mL) and brine (1 mL) were then added, and the
mixture was stirred for 15 min. The layers were separated, and the
aqueous phase was extracted with Et2O (3 × 2 mL). The combined
organic phases were dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash column chroma-
tography on silica gel eluting with Et2O to yield 18 mg of 38 (98%) as
a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J ) 7.8 Hz, 1
H), 7.26 (d, J ) 7.8 Hz, 1 H), 7.21 (dt, J ) 1.2, 8.4 Hz, 1 H), 7.11 (dt,
J ) 1.2, 7.4 Hz, 1 H), 5.55 (q, J ) 7.8 Hz, 1 H), 4.01 (dd, J ) 2.1, 5.1
Hz, 1 H), 3.87-3.72 (comp, 2 H), 3.66 (s, 3 H), 3.65-3.55 (m, 1 H),
3.48 (d, J ) 16.2 Hz, 1 H), 3.23 (ddd, J ) 2.1, 5.3 Hz, 15.0 Hz, 1 H),
3.16-3.00 (comp, 2 H), 2.58 (ddd, J ) 5.4, 9.6, 12.9 Hz, 1 H), 2.14-
2.02 (m, 1 H), 1.79-1.59 (comp, 2 H), 1.70 (dd, J ) 1.2, 6.9 Hz),
1.63 (ddd, J ) 2.7, 10.2, 10.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ 137.9, 136.2, 134.7, 126.2, 121.5, 120.9, 119.3, 117.9, 117.4, 108.9,
103.7, 61.3, 57.7, 51.2, 50.7, 39.1, 36.1, 31.1, 30.1, 25.9, 13.0; IR (neat)
3388 (br), 2920, 1470, 1378, 1326, 1150, 1055, 910, 7.39 cm-1; HRMS
(CI) m/z 336.2069 [C21H26N3O (M + 1) requires 336.2076].
(3S,5R,15R,20E)-N-Methyl-3,4,5,6,14,15-hexahydro-15-methoxy-
carbonylmethyl-20-ethylideneindolo[2,3-a]quinolizine-5-carboxyl-
ic Acid (34). CF3CO2H (0.7 mL) was added dropwise to a stirred
solution of the ester 33 (125 mg, 0.29 mmol) and thioanisole (0.6 mL)
in CH2Cl2 (0.7 mL) at 0 °C. Stirring was continued for 3.5 h, while
the solution was allowed to warm to room temperature. The solvents
were removed under reduced pressure, and the residue was purified by
flash chromatography on silica gel eluting with MeOH/CH2Cl2 (10:
90) to furnish 100 mg (90%) of the acid 34 as a yellow solid: mp
1
170-171 °C (from CH2Cl2); H NMR (300 MHz, DMSO-d6) δ 7.40
(d, J ) 7.8 Hz, 1 H), 7.34 (d, J ) 8.1 Hz, 1 H), 7.10 (t, J ) 7.8 Hz,
1 H), 6.99 (t, J ) 7.8 Hz, 1 H), 5.46 (q, J ) 7.0 Hz, 1 H), 4.37 (d, J
) 10.8 Hz, 1 H), 3.81-3.74 (comp, 2 H), 3.66-3.52 (comp, 2 H),
3.60 (s, 3 H), 3.55 (s, 3 H), 3.27 (quin, J ) 6.5 Hz, 1 H), 3.10-2.94
(comp, 2 H), 2.68-2.52 (comp, 2 H), 2.44-2.36 (m, 1 H), 1.64 (d, J
) 6.9 Hz, 3 H), 1.58-1.48 (m, 1 H); 13C NMR (75 MHz, DMSO-d6)
δ 173.2, 172.2, 137.2, 134.7, 125.8, 120.9, 118.7, 117.7, 109.2, 104.1,
59.2, 56.3, 51.2, 50.3, 34.8, 31.3, 30.3, 24.8,12.8; IR (CH2Cl2) 3401,
2918, 1731, 1681, 1199, 1017, 748 cm-1; HRMS (CI) m/z 383.1971
[C22H27N2O4 (M + 1) requires 383.1971].
(3S,5R,15R,20E)-N-Methyl-3,4,5,6,14,15-hexahydro-15-methoxy-
carbonylmethyl-20-ethylideneindolo[2,3-a]quinolizine-5-carboxam-
ide (35). 1-Hydroxybenzotriazole (HOBt) (244 mg, 1.81 mmol) and
EDCI (346 mg, 1.81 mmol) were added to a stirred solution of the
acid 34 (276 mg, 0.72 mmol) in DMF (15 mL). The reaction mixture
was stirred for 1 h, and NH4OH (2 mL) was added. Stirring was
continued overnight, whereupon brine (30 mL) and H2O (5 mL) were
added. The aqueous phase was extracted with EtOAc (3 × 20 mL),
and the combined organic phases were dried (MgSO4) and filtered.
The filtrate was concentrated under reduced pressure, and the residue
was purified by flash chromatography on silica gel eluting with EtOAc
to furnish 237 mg (86%) of the amide 35 as a white solid: mp 152-
154 °C (from EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.47-7.06 (comp,
4 H), 6.47 (br s, 1 H), 5.82 (brs, 1 H), 5.55 (q, J ) 7.0 Hz, 1 H), 4.25
(d, J ) 8.4 Hz, 1 H), 3.64 (s, 3 H), 3.61 (s, 3 H), 3.60-3.49 (comp,
2 H), 3.41 (d, J ) 12.3 Hz, 1 H), 3.29-3.33 (m, 1 H), 3.18 (dd, J )
5.5, 15.9 Hz, 1 H), 3.05 (dd, J ) 7.2, 15.9 Hz, 1 H), 2.51 (dd, J ) 5.4,
15.3 Hz, 1 H), 2.38 (dd, J ) 9.3, 15.3 Hz, 1 H), 2.18 (ddd, J ) 2.7,
(3S,5R,15R,20E)-N-Methyl-3,4,5,6,14,15-hexahydro-15-(2-oxo-
ethyl)-20-ethylideneindolo[2,3-a]quinolizine-5-cyanide (39). Dess-
Martin reagent (34, 0.08 mmol) was added to a stirred solution of the
alcohol 38 (18 mg, 0.05 mmol) and pyridine (9 µL) in CH2Cl2 (4 mL)
at 0 °C. The ice bath was removed, and stirring was continued for 40
min. Saturated aqueous NaHCO3 (1 mL) and saturated aqueous Na2S2O3
(1 mL) were then added, and the mixture was stirred for 10 min. The
layers were separated and the aqueous phase was extracted with Et2O
(3 × 2 mL). The combined organic phases were dried (MgSO4) and
filtered. The filtrate was concentrated under reduced pressure, and the
residue was purified by flash column chromatography on silica gel
eluting with EtOAc/hexane (30:70) to give 15 mg of 39 (83%) as a
colorless foam: 1H NMR (300 MHz, C6D6) δ 9.27 (s, 1 H), 7.50-
7.48 (m, 1 H), 7.29-7.20 (comp, 2 H), 6.98 (d, J ) 9.0 Hz, 1 H), 5.19
(q, J ) 6.9 Hz, 1 H), 3.64 (m, 1 H), 3.67-3.20 (comp, 3 H), 3.08 (q,
J ) 7.7 Hz, 1 H), 2.80 (dd, J ) 5.3, 15.6 Hz, 1 H), 2.72 (s, 3 H), 2.68
(d, J ) 15.6 Hz, 1 H), 2.38 (ddd, J ) 1.8, 6.8, 16.5 Hz, 1 H), 2.22 (dd,
J ) 7.2, 16.5 Hz, 1 H), 2.05 (ddd, J ) 6.0, 9.0, 13.4 Hz), 1.48 (d, J )
6.9 Hz, 3 H), 1.19 (ddd, J ) 2.1, 9.9, 13.4 Hz); 13C NMR (125 MHz,
C6D6) δ 199.8, 138.5, 136.1, 134.3, 126.8, 122.0, 119.8, 118.5, 117.1,
109.5, 104.1, 120.4, 57.8, 51.1, 51.0, 50.4, 36.0, 30.3, 28.0, 26.1, 12.9;
8.4, 13.8 Hz, 1 H), 1.82-1.72 (m, 1 H), 1.70 (d, J ) 7.0 Hz, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 175.8, 172.7, 137.8, 135.4, 134.9, 126.2,
123.3, 121.5, 119.2, 118.2, 108.8, 105.2, 62.0, 56.7, 51.6, 51.0, 38.3,
34.0, 33.1, 30.3, 24.3, 13.2; IR (CH2Cl2) 2952, 2860, 1732, 1691, 1568,
1470, 1160, 1012 cm-1; HRMS (CI) m/z 382.2140 [C22H28N3O3 (M +
1) requires 382.2131].
IR (neat) 2919, 2818, 2731, 1720, 1470, 1377, 1327, 1149, 743 cm-1
;
HRMS (CI) m/z 333.1838 [C21H23N3O (M + 1) requires 333.1841].
(+)-Na-Methylvellosimine (5). The aldehyde 39 (5 mg, 0.015 mmol)
was added to a suspension of NaH (60% suspension in mineral oil, 3.6
mg, 0.09 mmol) in THF (3 mL) at -78 °C. TBDMSCl (11.5 mg, 0.08
mmol) was then added, and the ice bath was removed. Stirring was
continued for 45 min, and the reaction mixture was concentrated under
reduced pressure to 0.5 mL. It was filtered through a plug of SiO2
eluting with Et2O/pentane (1:1), to give an inseparable diastereomeric
mixture of 40 {HRMS (CI) m/z 448.2781 [C27H38N3OSi (M + 1)
requires 448.2784]}. The E/Z ratio of 61:39 was determined from the
1H NMR spectrum by integration of the signals for C17-H [6.34 (d,
J ) 12.0 Hz, 0.61 H, C17-H(E)), 6.07 (dd, J ) 0.6, 5.7 Hz, 0.39 H,
C17-H(Z))]. Freshly distilled BF3‚OEt2 (4 µL, 0.030 mmol) was added
to a solution of 40 (7 mg, 0.015 mmol) in degassed benzene (0.7 mL)
and the reaction mixture was stirred at room temperature for 3.5 h.
The volatiles were removed under reduced pressure, and MeOH (3 mL)
(3S,5R,15R,20E)-N-Methyl-3,4,5,6,14,15-hexahydro-15-methoxy-
carbonylmethyl-20-ethylideneindolo[2,3-a]quinolizine-5-cyanide (36).
(CF3CO)2O (133 µL, 0.94 mmol) was added to a stirred solution of 35
(180 mg, 0.47 mmol) and Et3N (0.66 mL, 4.72 mmol) in CH2Cl2 (15
mL) at 0 °C, and the mixture was stirred for 75 min. The volatiles
were removed under reduced pressure, and the residue was purified by
flash column chromatography on silica gel eluting with EtOAc/hexane
(30:70) to give 155 mg (90%) of 36 as a pale yellow solid: mp 178-
179 °C (from EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.48-7.08 (comp,
4 H), 5.23 (q, J ) 6.7 Hz, 1 H), 4.03 (dd, J ) 2.1, 5.1 Hz, 1 H), 3.84
(dd, J ) 5.7, 10.5 Hz), 3.76 (dt, J ) 2.1, 13.2 Hz, 1 H), 3.64 (s, 3 H),
3.63 (s, 3 H), 3.48 (d, J ) 13.2, 1 H), 3.39-3.43 (m, 1 H), 3.24 (dd,
J ) 5.1, 15.3 Hz, 1 H), 3.06 (d, J ) 15.3 Hz, 1 H), 2.77 (dd, J ) 7.5,
15.3 Hz, 1 H), 2.68-2.55 (comp, 2 H), 1.70 (d, J ) 6.7 Hz, 3 H), 1.60
9
J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003 4549

A R T I C L E S
Deiters et al.
and aqueous KOH (0.5 M, 3 drops) were added. The solution was stirred
for 24 h, the solvent was removed under reduced pressure, and CH2-
Cl2 (5 mL) was added. The mixture was dried (MgSO4) and filtered,
and the filtrate was concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel eluting with
EtOAc/MeOH (9:1) to yield 1 mg (20%) of the aldehyde 39 and 2.5
mg (54%) of Na-methylvellosimine (5) as a pale yellow solid. The TLC,
1H and 13C NMR, and MS of synthetic 5 were identical with that of an
authentic sample of ent-5 obtained from Prof. James M. Cook:39 mp
1185, 1096, 752 cm-1; HRMS (CI) m/z 307.1807 [C21H23N3O (M +
1) requires 307.1810].
Acknowledgment. We thank the National Institutes of Health,
The Robert A. Welch Foundation, Merck Research Laboratories,
and Pfizer, Inc. for their generous support of this research. A.D.
gratefully acknowledges a Feodor-Lynen postdoctoral fellowship
from the Alexander von Humboldt Foundation. We also thank
Prof. James M. Cook (University of Wisconsin, Milwaukee)
for supplying a generous sample of ent-5. We thank Dr. Vincent
Lynch (Department of Chemistry and Biochemistry, The
University of Texas) for performing the X-ray crystallographic
analysis of 25.
236-240 °C (from CHCl3); [R]D ) +91 (c ) 0.10, CHCl3) {lit.5 mp
20
D
1
255-260 °C; [R]20 ) +23 (c ) 0.01, CHCl3)}; H NMR (500 MHz,
CDCl3) δ 9.64 (d, J ) 1.0 Hz, 1 H), 7.47 (ddd, J ) 1.0, 1.0, 7.5 Hz,
1 H), 7.30 (d, J ) 8.0 Hz, 1 H), 7.20 (ddd, J ) 1.0, 7.0, 8.0 Hz, 1 H),
7.09 (ddd, J ) 1.0, 7.0, 7.5 Hz, 1 H), 5.36 (q, J ) 7.0 Hz, 1 H), 4.27
(dd, J ) 2.5, 10.0 Hz, 1 H), 3.67-3.60 (comp, 3 H, C5-H), 3.65 (s,
3 H), 3.19-3.21 (m, 1 H), 3.14 (dd, J ) 5.0, 15.5 Hz, 1 H), 2.62 (dd,
J ) 1.5, 15.5 Hz, 1 H), 2.49 (d, J ) 7.5 Hz, 1 H), 2.13 (ddd, J ) 2.0,
9.5, 12.5 Hz, 1 H), 1.77 (ddd, J ) 2.0, 4.0, 12.5 Hz, 1 H), 1.62 (dt, J
) 2.0, 7.0 Hz, 3 H); 13C NMR (125 MHz, C6D6) δ 202.8, 137.4, 139.2,
134.4, 127.2, 121.1, 118.2, 119.0, 117.0, 108.8, 103.1, 54.9, 56.2, 50.6,
49.4, 32.4, 29.4, 26.6, 27.3, 12.6; IR (CH2Cl2) 2914, 2847, 1710, 1470,
Supporting Information Available: Copies of 1H NMR
spectra of 35, 36, 38, 39, synthetic (+)-5, and synthetic (-)-5
and X-ray data (CIF) for compound 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0296024
9
4550 J. AM. CHEM. SOC. VOL. 125, NO. 15, 2003