Biogenetically inspired approach to the Strychnos alkaloids. Concise syntheses of (±)-akuammicine and (±)-strychnine

Article abstract of DOI:10.1021/ja010935v

A linear synthesis of the indole alkaloid (±)-akuammicine (2) was completed by a novel sequence of reactions requiring only 10 steps from commercially available starting materials. The approach features a tandem vinylogous Mannich addition and an intramol

Full text of DOI:10.1021/ja010935v

J. Am. Chem. Soc. 2001, 123, 8003-8010
8003
Biogenetically Inspired Approach to the Strychnos Alkaloids. Concise
Syntheses of (()-Akuammicine and (()-Strychnine
Masayuki Ito, Cameron W. Clark, Michael Mortimore, Jane Betty Goh, and
Stephen F. Martin*
Contribution from the Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
ReceiVed April 11, 2001
Abstract: A linear synthesis of the indole alkaloid (()-akuammicine (2) was completed by a novel sequence
of reactions requiring only 10 steps from commercially available starting materials. The approach features a
tandem vinylogous Mannich addition and an intramolecular hetero Diels-Alder reaction to rapidly assemble
the pentacyclic heteroyohimboid derivative 8 from the readily available hydrocarboline 6. Oxidation of the E
ring of 8 gave the lactone 9 that was converted into deformylgeissoschizine (11). The subsequent elaboration
of 11 into 2 was effected by a biomimetically patterned transformation that involved sequential oxidation and
base-induced skeletal reorganization. A variation of these tactics was then applied to the synthesis of the
C(18) hydroxylated akuammicine derivative 36. Because 36 had previously been converted into strychnine (1)
in four steps, its preparation constitutes a concise, formal synthesis of this complex alkaloid.
Strychnine (1), which is found in large amounts in the Indian
poison nut (Strychnos nux Vomica) and Saint Ignatius' bean
(Strychnos ignatii), has a long and rich history as one of the
most notorious of the indole alkaloids.1,2 The renowned toxicity
of strychnine results from its interaction with the strychnine-
sensitive glycine receptor in the lower brain stem and the spinal
cord, thereby disrupting normal nerve cell signaling and leading
to overexcitation of the motor system and intense muscular
convulsions.3 Strychnine was first isolated in pure form by
Pelletier and Caventou in 1818.4 The extensive degradative and
structural studies that ensued finally culminated in 1946 when
Robinson first proposed the correct structure of strychnine.5 A
year later, Woodward independently suggested the same struc-
ture and referred to strychnine as the most complex substance
known for its molecular size.6 Given that a mere 24 skeletal
atoms are arrayed in seven rings with six contiguous stereogenic
centers in 1, this elite status arguably endures. The structure
and absolute configuration of strychnine were unequivocally
established by X-ray crystallography.7 The related alkaloid
akuammicine (2) was isolated from the seeds of Picralima
klaineana more than a century after the isolation of strychnine,8
and its structure was elucidated shortly after that of 1.9
The daunting structural complexity of 1 coupled with its
biological activity has served as the impetus for numerous
synthetic investigations. It is only fitting that the first total
synthesis of 1 was completed by Woodward in 1954, an event
that perhaps signaled the genesis of the modern era of complex
molecule synthesis.10 After Woodward’s pioneering achieve-
ment, there was considerable interest in the Strychnos alkaloids,1
but strychnine did not succumb again to total synthesis until
1992 when Magnus reported the synthesis of 1 via the Wieland-
Gumlich aldehyde.11 Shortly thereafter, Stork,12 Overman,13
Kuehne,14 Rawal,15 and more recently Bonjoch and Bosch16 and
(1) For leading reviews of Strychnos alkaloids, see: (a) Bosch, J.;
Bonjoch, J.; Amat, M. The Alkaloids 1996, 48, 75 and references therein.
(b) Bonjoch, J.; Sole´, D. Chem. ReV. 2000, 100, 3455.
(2) Creasey, W. A. In The Monoterpene Indole Alkaloids; Saxton, J. E.,
Ed.; Interscience: New York, 1983; p 800. (b) Franz, D. N. The
Pharmacological Basis of Therapeutics; Gilman, A. G., Goodman, L. S.,
Gilman, A., Eds.; Macmillan: New York, 1980. (c) Barron, S. E.; Guth, P.
S. Trends Pharm. Sci. 1987, 8, 204.
(3) Aprison, M. H. In Glycine Neurotransmission; Otterson, O. P., Storm-
Mathisen, J., Eds; John Wiley: New York, 1990; p 1.
(4) Pelletier, P. J.; Caventou, J. B. Ann. Chim. Phys. 1818, 8, 323.
(5) Robinson, R. Experientia 1946, 2, 28. (b) Holmes, H. L.; Openshaw,
H. T.; Robinson, R. J. Chem. Soc. 1946, 908. (c) Openshaw, H. T.;
Robinson, R. Nature 1946, 157, 438.
(8) Henry, T. A.; Sharp, T. M. J. Chem. Soc. 1927, 1950.
(9) Millson, P.; Robinson, R.; Thomas, A. F. Experientia 1953, 9, 89.
(b) Edwards, P. N.; Smith, G. F. J. Chem. Soc. 1961, 152.
(10) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker,
H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. (b) Woodward, R.
B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K.
Tetrahedron 1963, 19, 247.
(11) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.; Merritt,
A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403. (b) Magnus, P.; Giles,
M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt, A.; Kim,
C. S.; Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116.
(12) Stork, G. Reported at the Ischia Advanced School of Organic
Chemistry, Ischia Porto, Italy, September 21, 1992.
(13) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc.
1993, 115, 9293-9294. (b) Knight, S. D.; Overman, L. E.; Pairaudeau, G.
J. Am. Chem. Soc. 1995, 117, 5776.
(6) Woodward, R. B.; Brehm, W. J.; Nelson, A. L. J. Am. Chem. Soc.
1947, 69, 2250. (b) Woodward, R. B.; Brehm, W. J. J. Am. Chem. Soc.
1948, 70, 2107.
(7) Robinson, J. H.; Beevers, C. A. Acta Crystallogr. 1951, 4, 270. (b)
Peerdeman, A. F. Acta Crystallogr. 1956, 9, 824.
(14) Kuehne, M. E.; Xu, F. J. Org. Chem. 1993, 58, 7490. (b) Kuehne,
M. E.; Xu, F. J. Org. Chem. 1998, 63, 9427.
(15) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
10.1021/ja010935v CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/31/2001

8004 J. Am. Chem. Soc., Vol. 123, No. 33, 2001
Ito et al.
Scheme 1
Scheme 2
Vollhardt17 published their separate accounts of the total
synthesis of 1. It is noteworthy that each of these approaches
highlighted novel chemistry that was developed and applied to
solve specific problems or challenges associated with the
synthesis of this complex natural product. During the course of
their investigations in the Strychnos area, the groups of
Overman,18 Kuehne,19 and Bonjoch and Bosch20 also completed
the total synthesis of the related akuammicine (2) using strategies
and tactics similar to those they had successfully applied to 1.
In developing our own approach to alkaloids of the Strychnos
family, we were intrigued by the possibility of implementing a
novel strategy that owed its conception to a consideration of
their biogenesis.21,22 Feeding studies using the Corynanthe
alkaloid geissoschizine (4) have shown that it is a biosynthetic
precursor of strychnine and akuammicine.21g-i Several mecha-
nistic pathways have been proposed for the series of skeletal
reorganizations that interconnect the two respective alkaloid
families, but the key question we sought to address was whether
it would be possible to mimic one of these putative biosynthetic
pathways to convert either geissoschizine itself or related
corynantheoid compounds such as 5 (Z ) H, OR) into the
pentacyclic skeleton 3 (Scheme 1). We now report the details
of our concise, biomimetic syntheses of akuammicine (2) and
strychnine (1) that feature a cascade of reactions involving the
oxidation and rearrangement of the Corynanthe skeleton.23
Setting the Stage. We have had a longstanding interest in
developing short and efficient syntheses of complex indole
alkaloids, and some time ago we reported a concise and general
entry to the natural bases of the heteroyohimboid and corynan-
theoid families. The approach featured the vinylogous Mannich
reaction of 6 with 1-trimethylsilyloxybutadiene in the presence
of crotonyl chloride to give 7 followed by the intramolecular
hetero Diels-Alder reaction of 7 to give 8, thereby assembling
the pentacyclic heteroyohimboid skeleton in only four steps from
tryptamine (Scheme 2).24 Prior to examining the feasibility of
mimicking biosynthetic pathways according to Scheme 1, it was
first necessary to convert 8 into 10 and 11. Indeed, de-
formylgeissoschizine (11) is a key intermediate in numerous
syntheses of the Corynanthe alkaloids. Thus, hydration of the
enol ether moiety of 8 followed by a ruthenium-catalyzed
oxidation25 of the intermediate lactol furnished the lactone 9 in
79% yield. Although we briefly examined several known
methods for converting the dihydropyran D ring of 8 directly
into the requisite lactone using pyridinium chlorochromate
(PCC)26 and palladium-catalyzed oxidations,27 these procedures
failed to give usable quantities of 9 from 8. When 9 was exposed
to sodium methoxide, facile â-elimination ensued to give an
acid that was esterified in situ to deliver 10 in 92% yield.
Selective reduction of the amide moiety of 10 proceeded in 91%
yield to furnish synthetic 11, the spectral data of which were
identical to those reported in the literature.28
(16) Sole´, D.; Bonjoch, J.; Garc´ıa,-Rubio, S.; Peidro´, E.; Bosch, J. Angew.
Chem., Int. Ed. Engl. 1999, 38, 395. (b) Sole´, D.; Bonjoch, J.; Garc´ıa,-
Rubio, S.; Peidro´, E.; Bosch, J. Eur. J. Chem 2000, 6, 655.
(17) Eichberg, M. J.; Dorta, R. L.; Lamottke, K.; Vollhardt, K. P. C.
Org. Lett. 2000, 2, 2479.
(18) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, Jr., R. W.;
Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966.
(19) Kuehne, M. E.; Xu, F.; Brook, C. S. J. Org. Chem. 1994, 59, 7803.
(20) Sole´, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1996, 61, 4194. (b)
Sole´, D.; Bonjoch, J.; Garcia-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron
Lett. 1996, 37, 5213. (c) Bonjoch, J.; Sole, D.; Garcia-Rubio, S.; Bosch, J.
J. Am. Chem. Soc. 1997, 119, 7230.
(21) For a review of indole alkaloid biosynthesis, see: (a) Rahman, A.-
ur; Basha, A. Biosynthesis of Indole Alkaloids; Clarendon Press: Oxford,
U.K., 1983; p 45. See also: (b) Woodward, R. B. Nature 1948, 162, 155.
(c) Harley-Mason, J.; Waterfield, W. R. Tetrahedron 1963, 19, 65. (d)
Wenkert, E.; Wickberg, B. J. Am. Chem. Soc. 1965, 87, 1580. (e) Gaskelle,
A. J.; Joule, J. A. Tetrahedron 1967, 23, 4053. (f) Scott, A. I.; Qureshi, A.
A. J. Am. Chem. Soc. 1969, 91, 1, 5874. (g) Battersby, A. R.; Hall, E. S.
Chem. Commun. 1969, 793. (h) Scott, A. I.; Cherry, P. C.; Qureshi, A. A.
J. Am. Chem. Soc. 1969, 91, 4932. (i) Heimberger, S. I.; Scott, A. I. J.
Chem. Soc., Chem. Commun. 1973, 217.
First-Generation Approach. With the corynantheoid inter-
mediates 10 and 11 in hand, the stage was set for our exploration
(24) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore,
M. P. J. Am. Chem. Soc. 1991, 113, 6161 and references therein.
(25) Ishii, Y.; Osakada, K.; Ikariya, T.; Saburi, M.; Yoshikawa, S.
Tetrahedron Lett. 1983, 24, 2677.
(26) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron Lett. 1977,
39, 3483.
(27) Rodeheaver, G. T.; Hunt, D. F. J. Chem. Soc., Chem. Commun.
1971, 818. (b) Januszkiewicz, K.; Alper, H. Tetrahedron Lett. 1983, 24,
5159. (c) Alper, H.; Januszkiewicz, K.; Smith, D. J. H. Tetrahedron Lett.
1985, 26, 2263.
(22) For a review of some examples of biomimetic alkaloid synthesis,
see: Scholz, U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349.
(23) For a preliminary account of portions of this work, see: Martin, S.
F.; Clark, C. W.; Ito, M.; Mortimore, M. J. Am. Chem. Soc. 1996, 118,
9804.

Biogenetic Approach to the Strychnos Alkaloids
J. Am. Chem. Soc., Vol. 123, No. 33, 2001 8005
Scheme 3
Scheme 4
of tactics for effecting their rearrangement into the Strychnos
skeleton. Our initial plan was to evaluate a strategy reminiscent
of the biosynthetic pathway favored by Scott.21h We were
mindful of the failure of Winterfeldt, who first attempted to
induce a similar reorganization of a related corynantheoid
intermediate lacking the ethylidene moiety at C(20),29 but we
were not deterred as we envisioned several possible tactics that
had not yet been pursued. We also believed that an (E)-
ethylidene group at C(20) would play a key role and enable the
process by enforcing a conformation upon the D ring that would
orient the ester side chain in the axial orientation required for
cyclization to form a pentacyclic ring system (vide infra).
In our first experiments, the lactam 10 was first allowed to
react with tert-butyl hypochlorite, and solvolysis of the inter-
mediate chloroindolenine(s) in the presence of silver perchlorate
gave the spirocyclic oxindole 12, the structure of which was
established unequivocally by X-ray analysis (67% overall yield)
(Scheme 3).30 Only trace amounts of the C(7) epimeric
spiroindole were detected. A comparison of the structures of 1,
2, and 12 reveals that the stereochemistry at C(7) of 1 and 2 is
opposite that found in 12. This stereochemical issue did not
concern us unduly because it was well known that spiroindoles
related to 12 having amino, not amide, nitrogens in the D ring
undergo facile equilibration and epimerization at C(7).30,31 We
thus reasoned that the amino spiroindole obtained upon selective
reduction of the C(21) carbonyl group in 12 would readily
isomerize to give a compound having the correct configuration
at C(7).
in 16 and the oxindole carbonyl group are on opposite sides of
the D ring, it is not surprising that we were unable to cyclize
either of these compounds to generate the Strychnos skeleton.
The equilibration of spiro oxindoles related to 13 and 14 is
well known,30,31 and the epimerization at C(7) presumably
involves a reversible Mannich reaction that proceeds via the
intermediate 18, cyclization of which may produce either 13 or
14 (Scheme 5). However, it now appears that this equilibration
Scheme 5
To test this hypothesis, we selectively reduced the D ring
lactam in 12 (Me3OBF4, 4-Å molecular sieves; NaBH4, MeOH;
H3O+, ∆), but we found that the reaction was rather inefficient.
On the other hand, the oxidative rearrangement of the amine
11 proceeded in 68% yield to give a separable mixture of
oxindoles we initially believed to be 13 and 14 (Scheme 4).
After a series of unsuccessful attempts to cyclize the ester side
chain at C(15) onto C(2) of the oxindole we had presumed was
14, we more carefully scrutinized the basis for our original
structural assignments. A series of NOE analyses of the two
oxindoles derived from 11 suggested that these compounds were
in fact the isomeric oxindoles 15 and 16, and the structure of
15 was verified by X-ray analysis. A subsequent survey of the
literature revealed that Wenkert had previously prepared 15 and
1
16 by the oxidative rearrangement of 17, and the H and 13C
NMR spectral characteristics of our compounds were identical
with those reported.32 Inasmuch as the ester side chain at C(15)
(28) For example, see: (a) Overman, L. E.; Robichaud, A. J. J. Am.
Chem. Soc. 1989, 111, 300. (b) Wenkert, E.; Guo, M.; Pestchanker, M. J.;
Shi, Y.-J.; Vankar, Y. D. J. Org. Chem. 1989, 54, 1166. (c) Lounasmaa,
M.; Jokela, R.; Miettinen, J.; Halonen, M. Heterocycles 1992, 34, 1497.
(29) Gaskell, A. J.; Radunz, H.-E.; Winterfeldt, E. Tetrahedron 1970,
26, 5353.
(30) Martin, S. F.; Mortimore, M. Tetrahedron Lett. 1990, 31, 4557 and
references therein.
(31) Finch, N.; Taylor, W. I. J. Am. Chem. Soc. 1962, 84, 1318. (b)
Shavel, J.; Zinnes, H. J. Am. Chem. Soc. 1962, 84, 1320. (c) Awang, D. V.
C.; Vincent, A.; Kindack, D. Can. J. Chem. 1984, 62, 2667. (d) Stahl, R.;
Borschberg, H.-J.; Acklin, P. HelV. Chim. Acta 1996, 79, 1361.
(32) Wenkert, E.; Shi, Y.-J. Synth. Commun. 1989, 19, 1071.
is also accompanied by concomitant epimerization at C(3) in
normal oxindoles such as 13 and 14, which have an exocyclic
(E)-ethylidene moiety at C(20), to give the corresponding
pseudo diastereomers 15 and 16 as the preferred products. The
probable driving force for forming 15 and 16 is to relieve the
unfavorable A1,3-interaction between the ester side chain at
C(15) and the C(18) methyl group on the ethylidene moiety of
the D rings in 13 and 14, respectively. In this context, it is
perhaps noteworthy that all known oxindole alkaloids bearing

8006 J. Am. Chem. Soc., Vol. 123, No. 33, 2001
Ito et al.
alkyl substituents at C(20) have either the normal or allo
configurational relationships in which the hydrogens at C(3)
and C(15) are both R; the hydrogen at C(20) in these compounds
may be either R or â. To our knowledge, there are no natural
oxindoles having an ethylidene side chain at C(20).33
Scheme 6
Second-Generation Approach. The misfortunes of these
attempts notwithstanding, we were still attracted to the pos-
sibility of inducing a biomimetic reorganization of the corynan-
theoid ring system into the Strychnos skeleton. The mechanism
for the conversion of chloroindolenines such as 19 into
spiroindole derivatives is believed to involve the rearrangement
of the methanol or water adducts 20.31 An intriguing question
then arose: Would it be possible to initiate the skeletal
reorganization of the chloroindolenine 19 (X ) H2) with a
carbon nucleophile derived from enolization of the C(15) side-
chain ester moiety? Although the additions of carbon nucleo-
philes to the C(2) carbon of chloroindolenines are rare, such
transformations had been reported by Massiot (21 f 22, eq
1)34 and Rapoport (23 f 24, eq 2).35 In light of these promising
The precise mechanistic course of this novel biogenetically
patterned transformation has not been established, but we believe
that the basic features are summarized in Scheme 6. The initial
oxidation of the indole ring of 11 with electropositive halogen
to give the epimeric chloroindolenines 25a,b is well prece-
dented.30,31 Deprotonation of 25a,b at C(16) may envisioned to
give an enolate that could first cyclize onto C(2) to give 26a,b.
Subsequent skeletal reorganization would lead to 27 via 1,2-
migration of C(3) from C(2) to C(7), perhaps by an SN2-like
process; tautomerization of 27 would then furnish 2. An
alternative pathway entails cyclization of the enolate derived
from 25a,b onto C(7) to give 28, one epimer of which
corresponds to the alkaloid strictamine. The base-induced
rearrangement of strictamine into akuammicine is known,
although the reaction proceeds in poor yield under forcing
conditions.36 Because we did not have an authentic sample of
strictamine nor did we isolate any material having the spectral
properties of strictamine, we cannot offer any evidence sup-
porting this latter pathway.
precedents, we turned our efforts to evaluating the feasibility
of converting 11 directly into 2.
In our first experiments, 11 was chlorinated with tert-butyl
hypochlorite and the epimeric chloroindolenines 25a,b thus
obtained were exposed to excess lithium diisopropylamide
(LDA) to give a complex reaction mixture that was almost
intractable. However, we were fortunate to have an authentic
sample of 2 that had been generously provided by Overman,
and we were able to detect a faint spot on the TLC of the
reaction mixture that had an Rf corresponding to that of 2. After
some experimentation using a variety of bases to deprotonate
the intermediate chloroindolenines, we were eventually able to
isolate 2 in ∼10% yield. The synthetic 2 thus obtained was
The excitement associated with being able to achieve the first
biomimetic synthesis of 2 was tempered by the poor yield of
the overall transformation. Efforts were thus directed toward
improving the overall efficiency of the process. Examination
1
of the TLCs and the H NMR spectra of the crude reaction
mixtures obtained after the chlorination step and after treatment
of the intermediate chloroindolenines with base provided an
important clue: Two chloroindolenines were being formed in
ratios that ranged from approximately 4:1 to 10:1 depending
upon the conditions. It was the more polar chloroindolenine,
which was the minor product in our initial experiments, that
1
identical (TLC, H and 13C NMR) with an authentic sample.
(33) See: (a) Trager, W. F.; Lee, C. M.; Phillipson, J. D.; Haddock, R.
E.; Dwuma-Badu, D.; Beckett, A. H. Tetrahedron 1968, 24, 523. (b) Bindra,
J. S. In The Alkaloid, Chemistry and Physiology; Manske, R. H. F., Ed.;
Academic Press: New York, 1975; Vol. XIV, p 83.
(34) Vercauteren, J.; Massiot, G.; Le´vy, J. J. Org. Chem. 1984, 49, 3230.
(35) Feldman, P. L.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 1604
(36) Olivier, L.; Levy, J.; Lemen, J.; Janot, M.-M.; Budzikiewicz, H.;
Djerassi, C. Bull. Soc. Chim. Fr. 1965, 868. (b) Ahmad, Y.; Fatima, K.;
Rahman, A.; Occolowitz, J. L.; Solheim, B. A.; Clardy, J.; Garnick, R. L.;
Le Quesne, P. W. J. Am. Chem. Soc. 1977, 99, 1943.

Biogenetic Approach to the Strychnos Alkaloids
J. Am. Chem. Soc., Vol. 123, No. 33, 2001 8007
Scheme 7
Figure 1. Preferred conformation of 11 showing R-attack of electro-
positive chlorine from the convex R-face and from the more hindered
â-concave face.28b,37,38
was converted into akuammicine by the action of strong base;
the less polar, major spot remained primarily unchanged. In this
context, it is perhaps noteworthy that only one of the epimeric
chloroindolenines generated in the reaction depicted in eq 1
rearranged to give 22.34 In a number of other studies with closely
related compounds, the less polar chloroindolenine has been
shown to be the R-isomer, whereas the more polar one was the
â-isomer.31 These observations clearly suggested that the major
product formed upon reaction of 11 with tert-butyl hypochlorite
was the R-chloroindolenine 25a, and the more polar, minor
product was the requisite â-isomer 25b.
In light of the above analysis, we reasoned that if the
stereochemical course of the initial chlorination step could be
reversed to give 25b as the major product, the overall efficiency
of this biomimetic sequence to akuammacine might be signifi-
cantly improved. A possible basis for the stereoselectivity of
this chlorination step emerged upon consideration of the
preferred conformation of the starting 16-deformylgeissoschizine
(11), which has been proposed by Wenkert, Lounasmaa, and
Winterfeldt to correspond to that shown in Figure 1.,28b,37,38 In
this conformation, the D ring is forced into a chair conformation
in which the ester side chain at C(15) is positioned in an axial
orientation to relieve A1,3-strain between this side chain and
the C(18) methyl group in a manner reminiscent of the
conformational factors that helped drive the isomerizations of
the spirocyclic indoles 13 and 14 to give 15 and 16, respectively
(Scheme 5). The concave â-face is somewhat more hindered
than the convex R-face in this conformation, so chlorination
would be expected to occur preferentially from the R-face to
give 25a. Because the lone pair on the basic nitrogen atom is
projected on the R-face, we were intrigued by the possibility
that a Lewis acid might complex with this lone pair, thereby
reducing access to the R-face and leading to increased â-attack.
The correctness of this hypothesis notwithstanding, we were
delighted to discover that addition of Lewis acids gave increased
quantities of the desired â-chloroindolenine 25b. A number of
MDS, BuLi, tert-BuOK) to effect the skeletal reorganization
and found that LHMDS in THF was superior to other combina-
tions. In the optimized sequence, 11 was first treated with SnCl4
in toluene and the resulting complex allowed to react with tert-
butyl hypochlorite at -15 °C. Deprotonation of the crude 25b
thus obtained with LHMDS in THF at -15 °C delivered 2 in
52% overall yield from 11.
In view of the results of these experimental studies, it is now
possible to refine our initial view of the details associated with
transforming 11 into 2 (Scheme 6). The ester enolate of the
â-chloroindolenine 25b appears to cyclize first to give 26b, and
because of the anti relationship between the chlorine at C(7)
and C(3), facile 1,2-migration of C(3) to C(7) ensues to furnish
27. Although the analogous cyclization of the enolate derived
from 25a to form 26a seems plausible, the syn orientation
between the chlorine at C(7) and C(3) in 26a apparently
precludes its rearrangement to produce 27. Another pathway
for converting 25a into 2 would involve cyclization of the ester
enolate derived from 25a to generate 28, which would then
undergo base-induced rearrangement to provide 2 as discussed
previously. While it is therefore possible that any 25a formed
by the chlorination of 11 might be converted into 2, such a
process does not appear to be an efficient one.
.
Lewis acids (e.g., ZnCl2, MgCl2, BF3 OEt2, AgBF4, and TiCl4)
were examined, but SnCl4 was found to give the best results.
Hence, when the complex formed upon reaction of 11 with
SnCl4 was oxidized with tert-butyl hypochlorite, the desired
â-chloroindolenine was formed as the predominant product as
evidenced by TLC and 1H NMR of the reaction mixture;
generally only traces of the less polar R-isomer could be
detected. We surveyed a number of solvents (benzene, toluene,
THF, ether) and bases (NaH, KH, LHMDS, KHMDS, NaH-
Formal Synthesis of Strychnine (1). Having demonstrated
that the tetracyclic corynantheoid skeleton could be readily
rearranged to the pentacyclic Strychnos skeleton in the labora-
tory, we sought to apply this novel strategy to the formal
synthesis of strychnine from a hydroxylated derivative of 11
according to the plan outlined in Scheme 7. Hence, the
immediate objective was to prepare 18-hydroxyakuammicine
(36) as this compound had been previously converted into
strychnine.13
(37) Jokela, R.; Halonen, M.; Lounasmaa, M. Tetrahedron 1993, 49,
2567. (b) Lounasmaa, M.; Jokela, R.; Hanhinen, P.; Laine, C.; Anttila, U.
Heterocycles 1996, 43, 1699. (c) Lounasmaa, M.; Hanhinen, P. Heterocycles
1999, 51, 649.
(38) Bohlmann, C.; Bohlmann, R.; Rivera, E. G.; Vogel, C.; Manandhar,
M. D.; Winterfeldt, E. Liebigs Ann. Chem. 1985, 1752. (b) Winterfledt, E.;
Freund, R. Liebigs Ann. Chem. 1986, 1262. (c) Ninomiya, I.; Naito, T.;
Miyata, O.; Shinada, T.; Winterfeldt, E.; Freund, R.; Ishida, T. Heterocycles
1990, 30, 1031.
The issue that lay before us was the selection of a suitable
protecting group for the C(18) hydroxyl group. On the basis of
earlier work with related compounds,39 we anticipated that it
would be possible to remove an O-benzyl group from the C(18)

8008 J. Am. Chem. Soc., Vol. 123, No. 33, 2001
Ito et al.
Scheme 8
removed to furnish 36 in 22% (unoptimized) overall yield. The
synthetic 36 thus obtained gave spectral data (1H NMR, 13C
NMR, IR) identical with that of an authentic sample. Because
Overman had previously converted 36 into 1 in four steps,13 its
preparation constitutes a formal synthesis of 1.
Conclusions. Concise syntheses of the two complex indole
alkaloids 1 and 2 have been completed using a novel biomimetic
approach that features the skeletal reorganizations of the
tetracyclic corynantheoid derivatives 40 and 11, which were
quickly assembled by exploiting vinylogous Mannich and
intramolecular hetero Diels-Alder reactions as key steps. The
total synthesis of 2 required only 10 steps from commercially
available tryptamine and proceeded in an overall yield of 8%.
Notwithstanding the need to exchange hydroxyl-protecting
groups at an advanced stage in the formal synthesis of
strychnine, 36 was nevertheless prepared via a longest linear
sequence requiring only 12 steps and proceeding in 2.8% overall
yield from tryptamine. Other applications of vinylogous Man-
nich, Diels-Alder, and related biomimetic transformations to
the syntheses of indole alkaloids are currently being investigated
on a broad front, and the results of these investigations will be
reported in due course.
hydroxy group of an advanced intermediate by catalytic
hydrogenolysis, even in the presence of a trisubstituted eth-
ylidene moiety. Toward this end, benzyloxycrotonyl chloride
(29) was prepared in three steps by treating methyl bromocro-
tonate with benzyl alcohol in the presence of silver(I) oxide,
followed by ester saponification and reaction of the intermediate
acid with oxalyl chloride. The vinylogous Mannich addition of
1-trimethylsilyloxybutadiene to the N-acyl iminium ion that was
generated in situ upon reaction of 29 with 6 then delivered 30.
Heating 30 induced a facile intramolecular hetero Diels-Alder
reaction to give 31 in 67% overall yield from 6. The conversion
of 31 into amine 34 (46% overall yield) followed prior art,
thereby setting the stage for the key skeletal rearrangement.
Indeed, treatment of 34 with SnCl4 and tert-butyl hypochlorite
followed by reaction of the mixture of chloroindolenines thus
obtained with LHMDS gave 35 in 25-30% yield. To our
dismay, however, a number of preliminary attempts to effect
the selective O-debenzylation by catalytic hydrogenolysis or by
reaction with trimethylsilyl iodide were not promising, and we
elected to use another hydroxyl-protecting group.
The possibility of introducing alternative protecting groups
including tert-butyldimethylsilyl, p-methoxybenzyl, or meth-
oxymethyl on the hydroxy crotonyl acylating agent used at the
outset of the synthesis was explored. However, we encountered
difficulties arising from incompatibilities of these protecting
groups with the reaction conditions at various subsequent steps.
The expedient of replacing the benzyl group at a more advanced
stage of the synthesis was therefore examined. After testing
several possibilities, we concluded that this exchange of
protecting groups would be best performed on the lactone 32.
However, deprotection of 32 to give 37 by catalytic hydro-
genolysis also proved somewhat troublesome, as variable
quantities of the ring-cleaved product 38 were often obtained
(Scheme 8). Eventually we found that hydrogenolysis (1 atm
H2) of 32 in the presence of Pearlman’s catalyst in EtOAc/EtOH
(2:1) furnished 37 in 67% yield. Opening the lactone ring of
37 by base-induced â-elimination and acid-catalyzed formation
of the methyl ester, followed by protection of the primary
alcohol moiety as its tert-butyldimethylsilyl ether afforded 39
in 53% overall yield. Selective reduction of the lactam function
in 39 as before then provided the amine 40. Compound 40 was
subjected to the oxidation-rearrangement protocol previously
developed for 34, and the hydroxyl-protecting group was then
Experimental Section
(()-(19R,20R)-19-Methyloxayohimban-17,21-dione (9). A solution
of the cycloadduct 8 (1.616 g, 5.24 mmol) in a mixture of THF (28
mL) and H2O (8 mL) containing 70% aqueous HClO4 (6 drops) was
heated at 80 °C for 6 h. EtOAc (80 mL) was added, and the organic
layer was separated and washed with NaHCO3 (20 mL). The combined
aqueous phases were extracted with EtOAc (2 × 50 mL). The combined
organic extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was dissolved in toluene (80 mL) containing Et3N
(0.17 mL, 0.123 g, 0.64 mmol), 4-phenyl-3-butene-2-one (0.918 g, 6.28
mmol), and tris(triphenylphosphine)ruthenium(II) chloride (0.48 g, 0.50
mmol), and the resulting slurry was heated at 120 °C for 24 h. The
solvent was removed under reduced pressure, and the residue was
purified by flash chromatography eluting with MeOH/CH2Cl2 (1:50)
to give 1.34 g (79%) of 9 as a gray solid: mp 251-252 °C; 1H NMR
(DMSO-d6) δ 10.98 (s, 1 H), 7.40 (d, J ) 7.6 Hz, 1 H), 7.31 (d, J )
7.9 Hz, 1 H), 7.06 (t, J ) 7.2 Hz, 1 H), 6.97 (t, J ) 7.3 Hz, 1 H),
4.92-4.78 (m, 2 H), 4.67 (dd, J ) 7.7, 6.3 Hz, 1 H), 2.89 (td, J )
12.2, 4.0 Hz, 1 H), 2.77-2.41 (m, 6 H), 2.38 (m, 1 H), 1.61 (dt, J )
10.5, 2.3 Hz, 1 H), 1.41 (d, J ) 6.2 Hz, 3 H); 13C NMR (DMSO-d6)
δ 170.6, 167.1, 136.2, 133.8, 126.2, 121.1, 118.7, 117.8, 111.1, 107.0,
74.3, 52.2, 45.0, 37.2, 33.9, 32.5, 26.9, 21.3, 20.6; IR 3140, 1715, 1635
cm-1; mass spectrum (EI) m/z 324.1472 (C19H20N2O3 requires 324.1474),
324, 308 (base), 265, 237, 139.
(()-(19E)-19,20-Didehydro-21-oxocorynan-17-oic Acid, Methyl
Ester (10). A suspension of 9 (1.10 g, 3.40 mmol) in MeOH (25 mL)
containing NaOMe (0.724 g, 13.4 mmol) was stirred at room temper-
ature for 24 h. The solution was cooled to 0 °C, and oxalyl chloride
(2.42 mL, 3.52 g, 27.7 mmol) was added dropwise. The reaction mixture
was stirred at 0 °C for 1 h, warmed to room temperature, and stirred
for 5 h. CH2Cl2 (20 mL) and saturated NaHCO3 (20 mL) were added,
and the aqueous layer was separated and extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried (Na2SO4) and
concentrated, and the residue was purified by flash chromatography
eluting with MeOH/CH2Cl2 (1:50) to furnish 1.05 g (92%) of 10 as a
pale yellow solid: mp 210-211 °C; 1H NMR (300 MHz) δ 8.16 (s, 1
H), 7.51 (d, J ) 7.5 Hz, 1 H), 7.34 (d, J ) 7.5 Hz, 1 H), 7.19 (t, J )
7.5 Hz, 1 H), 7.14 (t, J ) 7.5 Hz, 1 H), 6.89 (q, J ) 7.4 Hz, 1 H),
5.14-5.07 (m, 1 H), 4.84 (t, J ) 5.4 Hz, 1 H), 3.58 (s, 3 H), 3.43
(ddd, J ) 16.0, 5.4, 4.9 Hz, 1 H), 3.03 (dd, J ) 11.4, 3.9 Hz, 1 H),
2.92 (ddd, J ) 11.4, 3.9, 2.0 Hz, 1 H), 2.86-2.78 (m, 1 H), 2.51 (dt,
J ) 11.4, 4.1 Hz, 1 H), 2.33 (dt, J ) 8.2, 3.1 Hz, 1 H), 2.27 (d, J )
16.4 Hz, 1 H), 2.11 (dd, J ) 16.4, 11.1 Hz, 1 H), 1.82 (d, J ) 7.3 Hz,
3 H); 13C NMR (75 MHz) δ 172.9, 165.8, 136.6, 134.7, 133.6, 133.2,
127.4, 122.3, 121.0, 118.5, 111.2, 109.8, 51.8, 51.6, 41.7, 38.1, 31.8,
(39) Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak, S. J.
Am. Chem. Soc. 1987, 109, 6124.

Biogenetic Approach to the Strychnos Alkaloids
J. Am. Chem. Soc., Vol. 123, No. 33, 2001 8009
1
30.0, 21.2, 13.8; IR 3460, 3080, 2970, 2940, 1725, 1660, 1605, 1440
cm-1; mass spectrum (CI) m/z 338.1623 (C20H22N2O3 requires 338.1630),
338 (base), 265, 237, 169.
236-238 °C; H NMR (300 MHz, CDCl3) δ 8.00 (s, 1 H), 7.42 (d, J
) 7.4 Hz, 1 H), 7.27-7.15 (comp, 6 H), 7.14-7.02 (comp, 2 H), 6.37
(dd, J ) 6.0, 1.0 Hz, 1 H), 5.09-5.04 (m, 1 H), 4.66 (dd, J ) 6.0, 5.1
Hz, 1 H), 4.63-4.60 (m, 1 H), 4.55 (d, J ) 11.9 Hz, 1 H), 4.49 (d, J
) 11.9 Hz, 1 H), 4.02-3.95 (m, 1 H), 3.88 (dd, J ) 10.8, 2.9 Hz, 1
H), 3.76 (dd, J ) 10.8, 7.2 Hz, 1 H), 2.83-2.76 (m, 2 H), 2.72-2.68
(m, 2 H), 2.56-2.50 (m, 1 H), 2.39 (td, J ) 13.6, 3.4 Hz, 1 H), 1.70-
1.58 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 167.0, 144.2, 138.0, 136.2,
132.7, 128.2, 127.8, 127.5, 126.6, 122.1, 119.7, 118.3, 111.0, 109.0,
102.1, 73.5, 72.3, 71.2, 53.6, 42.4, 40.5, 33.9, 27.8, 21.0; IR (CHCl3)
3470, 3064, 2925, 2247, 1636, 1433 cm-1; mass spectrum (CI) m/z
415.2024 (C26H27N2O3 requires 415.2021), 415, 397, 307.
(()-(19R,20R)-19-[(Phenylmethoxy)methyl]oxayohimban-17,21-
dione (32). A slurry of 31 (0.97 g, 2.2 mmol) in a mixture of THF (25
mL) and water (5 mL) containing 70% aqueous HClO4 (4 drops) was
stirred at 80 °C for 12 h. The mixture was cooled to room temperature
and then added to a separatory funnel containing CH2Cl2 (30 mL) and
saturated NaHCO3 (20 mL). The layers were separated, and the aqueous
phase was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layers were washed with brine (1 × 20 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by flash
chromatography eluting with MeOH/CH2Cl2 (1:20) to give 0.94 g (93%)
of anomeric lactols as an off-white mixture that was not characterized
but used immediately in the next step.
(()-(19E)-19,20-Didehydrocorynan-17-oic Acid, Methyl Ester
(11). To a solution of 10 (0.740 g, 2.19 mmol) in CH2Cl2 (20 mL) was
added trimethyloxonium tetrafluoroborate (0.811 g, 5.48 mmol) and
2,6-di-tert-butylpyridine (1.72 mL, 1.47 g, 7.66 mmol), and the resulting
slurry was stirred for 24 h at room temperature. The mixture was then
cooled to 0 °C, and anhydrous MeOH (30 mL) was added. Solid NaBH4
(0.495, 13.1 mmol) was then added, and the mixture was stirred at 0
°C for 10 min. The mixture was poured into saturated NaHCO3 (20
mL), and the resulting aqueous mixture was extracted with CH2Cl2 (3
× 20 mL). The combined organic extracts were dried (Na2SO4) and
concentrated, and the residue was purified by flash chromatography
(3% MeOH/CH2Cl2) to provide 0.646 g (91%) of 11 as a white foam
that gave spectral properties identical with those published.28
Akuammicine (2). A 1 M solution of SnCl4 in heptane (0.84 mL,
0.84 mmol) was added to a solution of amine 11 (248 mg, 0.76 mmol)
in toluene (25 mL) at -15 °C, and the resulting yellow solution was
stirred vigorously for 30 min. tert-BuOCl (125 µL, 1.09 mmol) was
added, and the reaction mixture was stirred for 10 min. The mixture
was poured into a saturated solution of K2CO3 (30 mL), and the biphasic
mixture was shaken vigorously until both layers were clear. The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (3
× 30 mL). The organic layers were combined, washed with NH4Cl
(50 mL) and brine (50 mL), dried (MgSO4), and evaporated under
reduced pressure. The oily residue was dried under high vacuum for
30 min and then dissolved in THF (50 mL). The solution was cooled
to -15 °C, and a 1 M solution of LHMDS in THF (2.3 mL, 2.3 mmol)
was added. The mixture was stirred for 2 h, and then saturated aqueous
NH4Cl (20 mL) was added. The layers were separated, and the aqueous
layer was back extracted with CH2Cl2 (3 × 30 mL). The organic layers
were combined, washed with brine (50 mL), dried (MgSO4), and
evaporated under reduced pressure. The crude material was purified
by flash column chromatography eluting with CHCl3/MeOH (70:1) to
A solution containing a portion of the mixture of the above lactols
(0.537 g, 1.19 mmol), 4-phenyl-3-butene-2-one (0.192 mg, 1.28 mmol),
Et3N (0.45 mg, 0.45 mmol), and tris(triphenylphosphine)ruthenium-
(II) chloride (82 mg, 0.08 mmol) in toluene (40 mL) was heated under
reflux for 24 h. The solvent was removed under reduced pressure, and
the residue was purified by flash chromatography eluting with MeOH/
CH2Cl2 (1:50) to give 0.422 g (79%) of lactone 32 as a gray solid: mp
1
210-212 °C; H NMR (300 MHz) δ 8.06 (s, 1 H), 7.50 (d, J ) 7.3
Hz, 1 H), 7.38-7.29 (comp, 6 H), 7.21-7.16 (m, 1 H), 7.15-7.10 (m,
1 H), 5.08-5.02 (m, 1 H), 4.89-4.84 (m, 1 H), 4.70 (dt, J ) 7.2, 2.6
Hz, 1 H), 4.60 (s, 2 H), 3.91 (d, J ) 2.6 Hz, 2 H), 3.22 (dt, J ) 7.0
Hz, 1 H), 2.98-2.91 (m, 1 H), 2.86-2.75 (comp, 3 H), 2.69-2.62 (m,
1 H), 2.43 (m, 2 H), 1.81-1.69 (m, 1 H); 13C NMR (75 MHz, DMSO-
d6) δ 171.1, 168.6, 139.1, 137.1, 134.7, 129.2, 128.3, 127.3, 127.1,
122.0, 119.6, 118.7, 112.1, 108.0, 78.0, 73.2, 72.7, 53.0, 40.5, 39.6,
35.0, 33.2, 27.9, 21.4; IR (CHCl3) 3468, 2925, 2868, 2247, 1740, 1640,
1434 cm-1; mass spectrum (CI) m/z 431.1969 (C26H27N2O4 requires
431.1970), 431 (base), 339.
1
give 128 mg (52%) of 2 that was identical (TLC, H and 13C NMR)
with an authentic sample.
(()-1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-1-(4-oxo-2-bute-
nyl)-2-[1-oxo-4-(phenylmethoxy)-2-butenyl]-, (E,E)- (30). To a solu-
tion of 4-(phenylmethoxy)-2-butenoic acid (3.34 g, 17.4 mmol) in
CH2Cl2 (35 mL) was added freshly distilled oxalyl chloride (7.6 mL,
11 g, 87 mmol). The reaction mixture was stirred at room temperature
for 24 h and then concentrated under reduced pressure to give the acid
chloride 29. A solution of crude 29 was dissolved in THF (25 mL)
and added dropwise to a solution of 6 (2.67 g, 15.7 mmol) and
1-trimethylsiloxybutadiene (13.5 g, 15.0 mL, 95.1 mmol) in THF (35
mL) at -78 °C. The reaction mixture was stirred 1 h at -78 °C, allowed
to warm to room temperature, and stirred at room temperature for 1 h.
The mixture was partitioned between CH2Cl2 (60 mL) and saturated
NaHCO3 (40 mL). The aqueous layer was separated and extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were dried (Na2-
SO4) and concentrated to give a gum that was purified by flash
chromatography eluting with CHCl3/EtOAc (3:1) to afford 5.13 g (79%)
(()-(19R,20R)-19-(Hydroxymethyl)oxayohimban-17,21-dione (37).
A solution of the ester 32 (200 mg, 0.465 mmol) in a mixture of EtOAc
(14.0 mL) and EtOH (7.0 mL) containing 20% Pd(OH)2/C (32 mg, 46
µmol) was stirred under H2 (1 atm) at room temperature until starting
material was consumed (∼5 h). The catalyst was removed by vacuum
filtration through Celite, and the filter pad w×88as washed with hot
MeOH (10 mL). The filtrate was concentrated under reduced pressure
to afford a yellow solid that was purified by flash chromatography
eluting with CHCl3/MeOH (20:1) to give 106 mg (67%) of 37 as a
white solid: mp 264-265 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.12
(br s, 1 H), 6.58 (d, J ) 7.6 Hz, 1 H), 6.49 (d, J ) 8.0 Hz, 1 H), 6.23
(m, 1 H), 6.14 (m, 1 H), 4.22 (t, J ) 5.8 Hz, 1 H), 4.11-4.06 (m, 1
H), 4.01-3.96 (m, 1 H), 3.72-3.67 (m, 1 H), 2.93-2.88 (m, 1 H),
2.87-2.80 (m, 1 H), 2.15-2.04 (comp, 2 H), 1.93-1.72 (comp, 4 H),
1.67-1.65 (m, 1 H), 1.48 (dd, J ) 16.4, 6.6 Hz, 1 H), 0.78-0.66 (m,
1 H); 13C NMR (75 MHz, DMSO-d6) δ 170.1, 168.0, 136.2, 133.7,
126.2, 121.0, 118.6, 117.1, 111.1, 106.9, 79.0, 63.2, 52.1, 40.3, 34.0,
32.0, 31.7, 26.8, 20.4; IR 3690, 3606, 3019, 2925, 2254, 1602, 1218
cm-1; mass spectrum (CI) m/z 341.1501 (C19H21N2O4 requires 341.1501),
341 (base), 199.
(()-(19E)-19,20-Didehydro-21-oxo-18-hydroxycorynan-17-oic Acid,
Methyl Ester. A suspension of 37 (75 mg, 0.22 mmol) in MeOH (10
mL) containing NaOMe (36 mg, 0.66 mmol) was stirred at room
temperature for 24 h. The solution was cooled to 0 °C, p-toluenesulfonic
acid (189 mg, 1.1 mmol) was added, and the mixture was stirred at 0
°C for 1 h and then at room temperature for 5 h. The reaction mixture
was transferred to a separatory funnel containing CH2Cl2 (20 mL) and
saturated NaHCO3 (20 mL), and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (3 × 20 mL), and the combined organic
1
of 30 as a pale yellow solid: mp 118-119 °C; H NMR (300 MHz)
δ 9.25 (d, J ) 7.9 Hz, 1 H), 9.10 (s, 1 H), 7.47 (d, J ) 7.5 Hz, 1 H),
7.39-7.35 (comp, 5 H), 7.32 (d, J ) 7.5 Hz, 1 H), 7.19-7.08 (comp,
2 H), 6.99 (dt, J ) 15.1, 3.8 Hz, 1 H), 6.82 (dt, J ) 15.6, 7.4 Hz, 1 H),
6.71 (d, J ) 15.1 Hz, 1 H), 6.09 (dd, J ) 8.3, 5.1 Hz, 1 H), 5.99 (dd,
J ) 15.6, 7.9 Hz, 1 H), 4.62 (s, 2 H), 4.25-4.22 (comp, 3 H), 3.49-
3.42 (m, 1 H), 2.98-2.78 (comp, 4 H); 13C NMR (75 MHz) δ 193.8,
166.2, 153.0, 142.9, 137.7, 136.3, 134.8, 132.4, 128.5, 127.8, 127.7,
126.4, 122.1, 119.7, 119.6, 118.1, 111.2, 108.1, 72.9, 69.0, 48.8, 40.7,
37.9, 22.2; IR (CHCl3) 3265, 3296, 3065, 3032, 2919, 2849, 2248,
1686, 1661, 1608, 1440 cm-1; mass spectrum (CI) m/z 415.2015
(C26H27N2O3 requires 415.2021), 415, 346 (base), 308, 290.
(()-(19R,20R)-16,17-Didehydro-19-[(phenylmethoxy)methyl]ox-
ayohimban-21-one (31). A solution of 30 (1.24 g, 3.00 mmol) in
mesitylene (150 mL) was degassed and heated at 160 °C in a sealed
tube for 72 h. The solvent was removed under reduced pressure, and
the residue was purified by flash chromatography eluting with hexanes/
EtOAc (1:1) to yield 1.05 g (85%) of 31 as a light yellow solid: mp

8010 J. Am. Chem. Soc., Vol. 123, No. 33, 2001
Ito et al.
layers were dried (Na2SO4) and concentrated. The residue was purified
by flash chromatography eluting with CH2Cl2/MeOH (20:1) to deliver
58 mg (74%) of product as a white solid: mp 337-339 °C; 1H NMR
(300 MHz) δ 8.28 (br s, 1 H), 7.50 (d, J ) 7.7 Hz, 1 H), 7.33 (d, J )
7.4 Hz, 1 H), 7.12-7.02 (comp, 2 H), 6.86 (t, J ) 6.4 Hz, 1 H), 5.10-
5.07 (m, 1 H), 4.86 (br t, J ) 5.3 Hz, 1 H), 4.36 (d, J ) 6.4 Hz, 2 H),
3.54 (s, 3 H), 3.53-3.48 (m, 1 H), 2.99-2.79 (comp, 3 H), 2.52 (dt,
J ) 14.3, 5.7 Hz, 1 H), 2.32-2.12 (comp, 3 H); 13C NMR (75 MHz)
δ 172.7, 168.3, 137.3, 136.3, 133.8, 133.1, 127.2, 122.3, 120.0, 118.4,
111.0, 109.7, 59.1, 51.7, 51.6, 41.8, 40.6, 38.1, 31.4, 30.1, 21.0; IR
(CHCl3) 3689, 3609, 3465, 2930, 2852, 2248, 1727, 1662, 1612, 1438
cm-1; mass spectrum (CI) m/z 355.1655 (C20H23N2O4 requires 355.1658),
355 (base), 323.
(()-(19E)-19,20-Didehydro-21-oxo-18-(tert-butyldimethylsilyloxy)-
corynan-17-oic Acid, Methyl Ester (39). A mixture of alcohol from
the preceding experiment (60 mg, 0.17 mmol) in pyridine (10 mL)
containing DMAP (100 mg, 0.84 mmol) and TBSCl (127 mg, 0.85
mmol) was stirred at room temperature for 24 h. The reaction mixture
was partitioned between CH2Cl2 (20 mL) and saturated NaHCO3 (20
mL). The aqueous layer was separated and extracted with CH2Cl2 (3
× 20 mL). The combined organic layers were dried (Na2SO4) and
concentrated, and the residue was purified by flash chromatography
eluting with MeOH/CH2Cl2 (1:20) to deliver 56 mg (71%) of 39 as a
white solid: mp 200-201 °C; 1H NMR (300 MHz) δ 7.96 (br s, 1 H),
7.50 (d, J ) 7.4 Hz, 1 H), 7.34-7.31 (m, 1 H), 7.22-7.10 (comp, 2
H), 6.85-6.80 (m, 1 H), 5.11-5.07 (m, 1 H), 4.87-4.83 (m, 1 H),
4.41 (dd, J ) 14.7, 7.1 Hz, 1 H), 4.31 (dd, J ) 14.7, 4.9 Hz, 1 H),
3.55 (s, 3 H), 3.45-3.40 (m, 1 H), 3.01-2.93 (comp, 2 H), 2.83-2.79
(m, 1 H), 2.53-2.46 (m, 1 H), 2.32-2.23 (comp, 2 H), 2.14 (dd, J )
16.6, 10.6 Hz, 1 H), 0.90 (s, 9 H), 0.09 (s, 6 H); 13C NMR (75 MHz)
δ 172.6, 165.0, 138.3, 136.3, 133.1, 132.8, 127.2, 122.2, 119.9, 118.3,
111.0, 109.6, 107.2, 59.7, 51.6, 41.6, 38.1, 31.2, 30.3, 25.8, 21.0, 18.3,
-5.3; IR (CDCl3) 3155, 2253, 1816, 1794, 1727, 1651, 1614, 1464,
1380, 1097, 912 cm-1; mass spectrum (CI) m/z 469.2511 (C26H37N2O4-
Si requires 469.2522), 469 (base), 453, 411.
(160 µL, 0.16 mmol) was added to a solution of amine 40 (65 mg,
0.15 mmol) in toluene (5.0 mL) at -15 °C, and the resulting solution
was stirred for 30 min. tert-Butyl hypochlorite (32 µL, 0.30 mmol)
was added, and the reaction mixture was stirred for an additional 30
min. The mixture was poured into a separatory funnel containing CH2-
Cl2 (20 mL) and saturated K2CO3 (10 mL). The layers were separated,
and the organic layer was dried (Na2SO4) and concentrated under
reduced pressure. The residue was dissolved in THF (5 mL) and cooled
to -15 °C. A 1 M solution of LHMDS in THF (620 µL of a 1.0 M
solution in THF, 0.62 mmol) was added, and the reaction was stirred
at -15 °C for 30 min and then at room temperature for 3 h. The mixture
was transferred to a separatory funnel containing CH2Cl2 (5 mL) and
saturated NaHCO3 (10 mL). The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 20 mL). The combined organics
were washed with brine (20 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by flash chromatog-
raphy eluting with CHCl3/MeOH (50:1) to give 17 mg (26%) of product
as an off-white residue: mp 147-149 °C; 1H NMR (300 MHz) δ 9.05
(br s, 1 H), 7.25 (d, J ) 7.6 Hz, 1 H), 7.16 (td, J ) 7.6, 0.8 Hz, 1 H),
6.90 (t, J ) 7.4 Hz, 1 H), 6.82 (d, J ) 7.7 Hz, 1 H), 5.43-5.41 (m, 1
H), 4.38 (dd, J ) 15.6, 6.2 Hz, 1 H), 4.18-4.12 (comp, 2 H), 4.00-
3.89 (comp, 2 H), 3.81 (s, 3 H), 3.36 (td, J ) 12.6, 5.6 Hz, 1 H),
3.08-2.98 (comp, 2 H), 2.53-2.41 (comp, 2 H), 1.87 (dd, J ) 12.6,
5.5 Hz, 1 H), 1.31 (m, 1 H), 0.89 (s, 9 H), 0.06 (s, 6 H); 13C NMR (75
MHz) δ 168.3, 167.4, 143.2, 138.4, 136.4, 127.6, 124.6, 121.3, 120.9,
109.6, 100.8, 67.5, 61.4, 57.4, 56.2, 55.9, 51.1, 45.8, 30.5, 29.8, 26.0,
18.3, -5.2; IR (CHCl3) 3469, 3332, 3022, 2954, 2930, 2857, 2426,
1730, 1640, 1463, 1328, 1258 cm-1; mass spectrum (CI) m/z 453.2561
(C26H37N2O3Si requires 453.2573), 453 (base), 395, 323, 263.
(()-(19E)-2,16,19,20-Tetradehydro-18-hydroxycuran-17-oic Acid,
Methyl Ester (36). A solution of protected alcohol from the preceding
experiment (17 mg, 38 µmol) in MeOH (3 mL) containing 2 N HCl (7
drops) was stirred overnight at room temperature. The reaction was
transferred to a separatory funnel containing 20% Na2CO3 (5 mL), and
the mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with brine (1 × 15 mL), dried (Na2SO4),
and concentrated under reduced pressure. The residue was purified by
flash chromatography eluting with CHCl3/MeOH (10:1) to afford 10.5
mg (83%) of 36 as an off-white solid that gave spectra identical with
that of an authentic sample.13
(()-(19E)-19,20-Didehydro-18-(tert-butyldimethylsilyloxy)corynan-
17-oic Acid, Methyl Ester (40). A mixture of 39 (0.56 g, 1.2 mmol)
in CH2Cl2 (15 mL) containing trimethyloxonium tetrafluoroborate (0.43
g, 3.1 mmol) and 2,6-di-tert-butylpyridine (1.1 mL, 0.83 g, 4.2 mmol)
was stirred for 24 h at room temperature, whereupon it was cooled to
0 °C and anhydrous MeOH (30 mL) added. Solid NaBH4 (0.23 g, 6
mmol) was added, and the mixture was stirred for 15 min. Saturated
NaHCO3 (20 mL) was added, and the mixture was extracted with CH2-
Cl2 (3 × 20 mL). The combined extracts were dried (Na2SO4) and
concentrated, and the residue was purified by flash chromatography
eluting with MeOH/CH2Cl2 (1:30) to provide 0.45 g (83%) of amine
Acknowledgment. We are grateful to the National Institutes
of Health (GM 25439) and The Robert A. Welch Foundation
for their generous support of this research program. We also
thank Professor Larry E. Overman (University of California,
Irvine) for supplying a generous sample of authentic (()-
akuammicine (2) and complete spectral data for 36.
1
40 as a yellow gum: mp 43 °C; H NMR (300 MHz) δ 8.48 (br s, 1
H), 7.48 (d, J ) 7.1 Hz, 1 H), 7.34 (d, J ) 7.3 Hz, 1 H), 7.17-7.07
(comp, 2 H), 5.54 (t, J ) 6.2 Hz, 1 H), 4.29-4.17 (comp, 3 H), 3.69
(s, 3 H), 3.57 (d, J ) 12.5 Hz, 1 H), 3.29-3.20 (m, 1 H), 3.14-3.06
(comp, 3 H, C5-H), 2.98 (d, J ) 12.5 Hz, 1 H), 2.70-2.62 (m, 1 H),
2.31-2.12 (comp, 4 H), 0.89 (s, 9 H), 0.07 (s, 6 H); 13C NMR (75
MHz) δ 173.5, 140.1, 138.5, 134.1, 128.7, 122.6, 121.3, 119.4, 118.5,
111.1, 108.0, 65.2, 53.0, 51.4, 51.0, 37.6, 33.2, 31.1, 25.8, 19.5, 18.1,
-4.1; IR (CHCl3) 3470, 3350, 3025, 3008, 2954, 2930, 2857, 1726,
1463 cm-1; mass spectrum (CI) m/z 455.2721 (C26H39N2O3Si requires
455.2730), 455 (base), 323.
Supporting Information Available: Experimental proce-
dures and complete characterization (1H and 13C NMR and IR
spectra and mass spectral data) for new compounds not included
in the Experimental Section. See any current masthead page
for ordering information and Web access instructions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(()-(19E)-2,16,19,20-Tetradehydro-18-(tert-butyldimethylsilyloxy)-
curan-17-oic Acid, Methyl Ester. A 1 M solution of SnCl4 in heptane
JA010935V