Sequential one-pot cyclizations: Concise access to the ABCE tetracyclic framework of strychnos alkaloids

Article abstract of DOI:10.1021/ol9004799

A sequential one-pot biscyclization route to the ABCE tetracyclic framework of Strychnos alkaloids has been developed. Specifically, the AgOTf-mediated spirocyclization of an appropriately functionalized indole 3-carbinamide afforded a stable spiroindolen

Full text of DOI:10.1021/ol9004799

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2085-2088
Sequential One-Pot Cyclizations:
Concise Access to the ABCE Tetracyclic
Framework of Strychnos Alkaloids‡
Gopal Sirasani and Rodrigo B. Andrade*
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
randrade@temple.edu
Received March 7, 2009
ABSTRACT
A sequential one-pot biscyclization route to the ABCE tetracyclic framework of Strychnos alkaloids has been developed. Specifically, the
AgOTf-mediated spirocyclization of an appropriately functionalized indole 3-carbinamide afforded a stable spiroindolenine intermediate; subsequent
addition of DBU to the reaction mixture effected an unprecedented intramolecular aza-Baylis-Hillman reaction, delivering a tetracyclic product
in 70% isolated yield.
The indole alkaloids strychnine (1)1 and akuammicine (2)2 are
characteristic members of the Strychnos family that continue
to capture the imagination of organic chemists (Figure 1).3Strych-
paper heralded the advent of modern organic synthesis,5
underscoring the utility of biogenetic hypotheses in guiding
strategy irrespective of ultimate veracity.6 Since then, many
groups have reported syntheses of strychnine (1),7 akuam-
micine (2), and related Strychnos alkaloids.8 To be sure, these
complex natural products remain excellent substrates for
showcasing methodologies aimed at rapidly assembling
polycyclic structures in both atom-9 and step-economical10
fashion.
(2) (a) Millson, M. F.; Robinson, R.; Thomas, A. F. Experientia 1953,
9, 89. (b) Edwards, P. N.; Smith, G. F. J. Chem. Soc. 1961, 152.
(3) (a) Bosch, J.; Bonjoch, J.; Amat, M. Alkaloids 1996, 48, 75. (b)
Saxton, J. E. Nat. Prod. Rep. 1993, 10, 349. (c) Aimi, N.; Sakai, S. In The
Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, 1989; Vol. 36, pp
1-68.
Figure 1. Representative Strychnos alkaloids strychnine (1) and
akuammicine (2).
(4) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis: Targets,
Strategies, Methods; Wiley: New York, 1996, pp 21-40.
(5) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker,
H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749.
nine (1) has occupied a special place in the history of
(6) Woodward, R. B. Nature (London) 1948, 162, 155.
synthetic organic chemistry.4 Woodward’s 1954 seminal
(7) For an excellent review of total and formal syntheses of strychnine
from 1954-2000, see:(a) Bonjoch, J.; Sole, D. Chem. ReV. 2000, 100, 3455.
For an excellent review of total and formal syntheses of strychnine from
2000-2007, see: (b) Shibasaki, M.; Ohshima, T. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: San Diego, 2007; Vol. 64, pp 103-139.
‡ Dedicated to Prof. Frank Davis on the occasion of his 70th birthday.
(1) Robinson, R. Experientia 1946, 2, 28.
10.1021/ol9004799 CCC: $40.75
Published on Web 04/21/2009
 2009 American Chemical Society

Both alkaloids possess a compact, ABCDE pentacyclic
core that harbors three distinct synthetic challenges: (1) the
C7 spirocyclic quaternary stereocenter, (2) the bridged CDE
framework, and (3) the alkylidene side chain.7 Herein we
report our solution to the first challenge that sets the stage
for addressing the remaining two in future work.
delivered iodoacetamide 6, setting the stage for the critical
spirocyclization. Examination of molecular models suggested
the cyclization of 6 would proceed stereoselectively to furnish
an intermediate mapping onto the C-ring of the Strychnos
alkaloids. In the event, treatment of iodoacetamide 6 with
AgOTf and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) in
toluene at room temperature for 1.5 h cleanly delivered
spiroindolenine 7 in 96% yield from 5 (dr ) 13:1). The use
of base was critical for the success of this reaction. Although
we screened other bases (e.g., 2,6-lutidine, pyridine, Et3N,
i-Pr2NEt), DTBMP gave the highest yield. Additionally, the
reaction proceeded in both THF and CH2Cl2. Stronger bases
(e.g., NaH, t-BuOK) also cyclized 6 in the absence of AgOTf
albeit at the expense of both yield and diastereoselectivity.19
Finally, the relative stereochemistry of spiroindolenine 7 was
secured from a NOE analysis of select hydrogens (C9TC3
Our strategy was inspired by Woodward, who set the C7
stereocenter (and C-ring) early in his synthesis. Taking
advantage of indole’s nucleophilicity at its C3 position,
cyclization of an activated Schiff base to form the C7-C3
bond of 1 furnished a 3,3-spiroindolenine intermediate.11 We
were intrigued at the prospect of also effecting a spirocy-
clization, albeit on an indole lacking substitution at C2 and
cyclizing via the C7-C6 bond.12 While previous syntheses
of Strychnos alkaloids have targeted this bond,13-15 there
were no examples of C-ring cylizations without the E-ring
already in place. Similar trends were found with the related
Aspidosperma alkaloids.19,16,17 It was during this latter
analysis that we found tactical inspiration from Heathcock’s
elegant synthesis of aspidospermidine wherein AgOTf was
employed to cyclize an iodoacetamide onto a tetrahydrocar-
bazole scaffold.18
1
and C2TC14) in the H NMR spectrum (Scheme 1).
With the C7 stereocenter and C-ring in place, attention
was directed at closing the E-ring. Ideally, our approach
would segue smoothly into D-ring closure. Rawal’s brilliant
use of the intramolecular Heck reaction to fashion the
D-ring20 struck us as a suitable candidate; moreover, our
route established the requisite C15-C16 olefin in the second
step. Cognizant of the electrophilic nature of the spiroindo-
lenine imine and the need for a C17 methylcarboxylate
to access targets 1 and 2, we envisioned the use of
an intramolecular aza-Morita21 or aza-Baylis-Hillman
(IABH)22 reaction of 7 tethered to an enoate (C15-C17) as
a viable tactic. To the best of our knowledge, this specific
transformation was unprecedented.23 Furthermore, we wanted
to consolidate a step by utilizing a bromoacetamide in place
of a chloroacetamide as the latter did not cyclize when
subjected to our optimized reaction conditions (i.e., AgOTf
and DTBMP).
To test our idea, we prepared a substrate that would be
amenable to further synthetic elaboration. Condensation of
commercially available indole-3-carboxaldehyde (3) with
benzylamine and allylation of the Schiff base afforded
homoallylic amine 4 in 90% over two steps (Scheme 1).
Scheme 1. Synthesis of Spiroindolenine 7
To realize this goal, we acylated 4 with bromoacetyl
chloride to furnish bromoacetamide 8 in 94% yield (Scheme
2). A cross-metathesis reaction was recruited to install the
Scheme 2. Synthesis of Enoate-Tethered Spiroindolenine 10
Acylation with chloroacetyl chloride and Et3N provided
chloroacetamide 5 in 95% yield. A Finklestein reaction
(8) Bonjoch, J.; Sole, D.; Garcia-Rubio, S.; Bosch, J. J. Am. Chem. Soc.
1997, 119, 7230, and references therein.
(9) Trost, B. M. Science 1991, 254, 1471, and references therein.
(10) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40, and references therein.
(11) Ungemach, F.; Cook, J. M. Heterocycles 1978, 9, 1089.
(12) For previous approaches to 3,3-spiroindolenines, see: (a) van
Tamelen, E. E.; Webber, J.; Schiemenz, G. P.; Barker, W. Bioorg. Chem.
1976, 5, 283. (b) King, F. D. J. Heterocycl. Chem. 2007, 44, 1459. (c)
Stevens, C. V.; Van Meenen, E.; Eeckhout, Y.; Vanderhoydonck, B.;
Hooghe, W. Chem. Commun. 2005, 38, 4827.
(13) (a) Forns, P.; Diez, A.; Rubiralta, M. J. Org. Chem. 1996, 61, 7882.
(b) Rubiralta, M.; Diez, A.; Bosch, J.; Solans, X. J. Org. Chem. 1989, 54,
enoate functionality.24 Phosphine-free Hoveyda-Grubbs II
catalyst (HG-II)25 proved effective for this transformation,
affording enoate 9 in 90% yield (dr ) 12:1 by LC-MS).
5591
(14) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki,
M. J. Am. Chem. Soc. 2002, 124, 14546
(15) Amat, M.; Linares, A.; Bosch, J. J. Org. Chem. 1990, 55, 6299
.
.
.
2086
Org. Lett., Vol. 11, No. 10, 2009

Gratifyingly, the key spirocyclization also proceeded well
with bromoacetamide 9, accessing spiroindolenine 10 in 95%
yield (dr ) 13:1).
With spiroindolenine 10 in hand, we screened a variety
of conditions to effect either the intramolecular aza-Morita
or IABH reaction. We observed no reaction of 10 with Bu3P,
Et3N, i-Pr2NEt, DMAP, or DABCO regardless of solvent
used (e.g., CH2Cl2, THF, PhMe). However, treatment of 10
with 2 equiv of 1,8-diazabicycloundec-7-ene (DBU) in
toluene at room temperature for 12 h cleanly afforded ABCE
tetracycle 11 in 90% yield (Scheme 3). The use of less DBU
Scheme 3
.
Novel Intramolecular aza-Baylis-Hillman Reaction
To Close the E-Ring
Figure 2. ORTEP of ABCE tetracycle 11.
Our laboratory has had a longstanding interest in maxi-
mizing synthetic efficiency in the context of natural product
total synthesis either by deliberately avoiding protecting
groups27,28 or sequencing reactions in a one-pot (tandem)
manner to rapidly access useful building blocks.29,30 By not
isolating spiroindolenine 10, a sequential one-pot version
(i.e., 9 f 11) could be achieved, thus streamlining the
synthesis. In the event, treatment of bromoacetamide 9 with
AgOTf and DTBMP in toluene at room temperature for 1.5 h
followed by the addition of DBU and additional stirring (12
h) afforded 11 in 70% yield after flash silica gel chroma-
tography (Scheme 4).
translated into longer reaction times. Performing the reaction
in THF gave 11 in slightly lower yield (83%).
As the more traditional Baylis-Hillman bases did not
effect the cyclization irrespective of loading (0.1-2.0 equiv),
an alternative mechanistic hypotheses emerged, namely,
γ-deprotonation of the enoate by DBU, cyclization, and olefin
isomerization.26 To test this hypothesis, we carried out the
same reaction with PhMe that had been saturated with D2O.
If the DBU-promoted deprotonation and attendant cycliza-
tion/isomerization sequence was operative, a fraction of
deuterium incorporation at C14 (see Scheme 3) should be
Scheme 4. Sequential One-Pot Synthesis of 11
1
observed in the H NMR spectrum of 11. In the event,
however, we found no such evidence of this taking place.
While this experiment does not invalidate the alternate
mechanistic hypothesis, it does strengthen the IABH argu-
ment.
Recrystallization of tetracycle 11 from EtOAc afforded
material suitable for single crystal X-ray analysis. The
ORTEP representation of 11 is shown in Figure 2, confirming
the structural assignment of the ABCE Strychnos tetracycle.
(16) Gallagher, T.; Magnus, P.; Huffman, J. C. J. Am. Chem. Soc. 1983,
105, 4750.
(17) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem.
Soc. 2002, 124, 4628.
(18) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642.
(19) For similar strong base-mediated cyclizations of substrates bearing
an indole moiety see: Heureux, N.; Wouters, J.; Marko, I. E. Org. Lett.
2005, 7, 5245, and references therein.
In summary, we have developed a concise and efficient
route to the ABCE tetracyclic scaffold 11 of Strychnos
(20) (a) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030. (b) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685.
(21) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127,
3680, and references therein.
(24) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42,
1900. (b) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360.
(22) For a comprehensive review, see: Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811.
(25) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(23) For a related Lewis acid assisted, Me2S-mediated cyclization of an
enal onto an N-acyliminium ion, see: Myers, E. L.; de Vries, J. G.; Aggarwal,
V. K. Angew. Chem., Int. Ed. 2007, 46, 1893.
(26) We thank the reviewers for bringing this alternative mechanistic
hypothesis to our attention.
(27) Velvadapu, V.; Andrade, R. B. Carbohydr. Res. 2008, 343, 145.
Org. Lett., Vol. 11, No. 10, 2009
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alkaloids (five steps from commercially available aldehyde
3, 53% overall yield). The route features a novel sequential
one-pot spirocyclization/intramolecular aza-Baylis-Hillman
reaction that proceeds in 70% overall yield. We are currently
investigating the mechanism of the E-ring cyclization and
applying our method to the total syntheses of various
Strychnos alkaloids, in addition to developing an asymmetric
variant thereof. Those results will be reported in due course.
acknowledged. We thank Dr. Charles DeBrosse, Director of
the NMR Facilities at Temple Chemistry, for kind assistance
with NMR experiments. We thank Prof. Chris Schafmeister
(Temple University) for access to LC-MS instrumentation.
We kindly thank Prof. David Dalton (Temple University)
for carefully reading our manuscript. We thank Dr. Patrick
Carroll for the X-ray analysis. Finally, we thank Materia for
generous catalyst support (Hoveyda-Grubbs II).
Supporting Information Available: Experimental pro-
cedures, characterization of compounds 4-7 and 8-11
(including 1H and 13C NMR spectra). Crystallograpic details
for 11 in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support of this work by the
Department of Chemistry at Temple University is gratefully
(28) Sirasani, G.; Paul, T.; Andrade, R. B. J. Org. Chem. 2008, 73, 6386.
(29) Paul, T.; Andrade, R. B. Tetrahedron Lett. 2007, 48, 5367, and
references therein.
(30) Paul, T.; Sirasani, G.; Andrade, R. B. Tetrahedron Lett. 2008, 49,
3363.
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