Total synthesis of (+)-condylocarpine, (+)-isocondylocarpine, and (+)-tubotaiwine

Article abstract of DOI:10.1021/ol102709s

The first enantioselective total syntheses of indole alkaloids of the condylocarpine type are reported. (+)-Condylocarpine, (+)-isocondylocarpine, and (+)-tubotaiwine were prepared in high enantiomeric purity (er > 99:1) from (1S,5R)-hexahydro-1,5-methano-1H-azocino[4,3-b]indole-12-one 7b by way of five or six isolated intermediates.

Full text of DOI:10.1021/ol102709s

ORGANIC
LETTERS
2011
Vol. 13, No. 1
138-141
Total Synthesis of (+)-Condylocarpine,
(+)-Isocondylocarpine, and
(+)-Tubotaiwine
Connor L. Martin, Seiichi Nakamura,† Ralf Otte,‡ and Larry E. Overman*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
California 92697-2025
leoVerma@uci.edu
Received November 9, 2010
ABSTRACT
The first enantioselective total syntheses of indole alkaloids of the condylocarpine type are reported. (+)-Condylocarpine, (+)-isocondylocarpine,
and (+)-tubotaiwine were prepared in high enantiomeric purity (er > 99:1) from (1S,5R)-hexahydro-1,5-methano-1H-azocino[4,3-b]indole-12-one
7b by way of five or six isolated intermediates.
The hexahydro-1,5-methano-1H-azocino[4,3-b]indole ring
system 1 is a major fragment of Strychnos alkaloids of the
strychnan and aspidopermatan types (e.g., 2-4, Figure 1)
and the ring system of indole alkaloids of the uleine group
(e.g., 5, Figure 1).1 During our recent total synthesis of the
structurally unique indole alkaloid (-)-actinophyllic acid, we
developed a concise synthesis of the hexahydro-1,5-methano-
1H-azocino[4,3-b]indole ring system.2,3 A central step in this
synthesis is an iron(III)-promoted intramolecular oxidative
coupling of malonate and ketone enolates generated from
indole piperidones 6 to deliver hexahydro-1,5-methano-1H-
azocino[4,3-b]indole-12-ones 7 (eq 1). Ketone (1S,5R)-7b
was prepared in enantioenriched form (er ) 95:5) in 26%
overall yield from 4-(tert-butoxycarbonylamino)butyric acid
by way of six isolated intermediates.2,4 Herein we report the
use of tetracyclic intermediate (1S,5R)-7b for the enantiose-
lective synthesis of three representative members of the
condylocarpine subtype of the aspidospermatan group of
alkaloids.5,6
Transformation of hexahydro-1,5-methano-1H-azocino[4,3-
b]indole-12-ones 7 to the condylocarpine skeleton requires
introduction of a two-carbon unit at C12, installation of a
two-carbon bridge between C11b and N2, and dealkoxycar-
bonylation of the malonate unit. Our early exploratory
investigations were carried out in the racemic series and
focused on elaboration of C12 and N2. Several observations
made during these studies provided essential insight into the
chemical reactivity of the hexahydro-1,5-methano-1H-azo-
cino[4,3-b]indole ring system (Scheme 1). Wittig reaction
† Current address: Graduate School of Pharmaceutical Sciences, Nagoya
City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603,
Japan.
‡ Current address: The Boston Consulting Group GmbH, Chilehaus A,
Fischertwiete 2, 20095 Hamburg, Germany.
(1) (a) The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York,
1996; Vol. 48, Chapter 4. (b) Alvarez, M.; Joule, J. A. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 2001; Vol. 57, Chap-
ter 4.
10.1021/ol102709s  2011 American Chemical Society
Published on Web 12/06/2010

Scheme 1
.
Facile Gramine-Type Fragmentation of
12-Ethylidene and 12-Oxo
Hexahydro-1,5-methano-1H-azocino[4,3-b]indoles and
Contrasting Acid Stability of Structurally Related Indole
Derivative 12
Figure 1. 1,5-Methanoazocino[4,3-b]indole ring system and some
representative alkaloids that possess this fragment.
of ketone (()-7a with ethylidenetriphenylphosphorane de-
livered ethylidene derivative (()-8 as a single stereoisomer
in 73% yield, with the Z configuration of the double bond
1
being readily secured by H NMR NOE analysis. To our
surprise, this product was extremely acid sensitive. For
example, (()-8 rearranged to hexahydro-6H-pyrido[4,3-
b]carbazole isomer (()-9 when stored in CDCl3 for several
days, or within 2 h at room temperature in the presence of
10 mol % of DCl (0.004 M). Related instability was observed
with hexahydro-1,5-methano-1H-azocino[4,3-b]indole-12-
one (()-7b, which when exposed in CDCl3 to 0.15 M DCl
for 2 h gave dihydropyrrolo[3,2-b]carbazole 10 in 55%
yield.7 Under stronger acidic conditions (neat TFA), ketone
(()-7b yielded 3-hydroxycarbazole-1-carboxylic acid 11 as
the major product within 4 h at room temperature. In marked
contrast, structurally related hexahydro-1,5-methano-1H-
(2) (a) Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc.
2008, 130, 7568–7569. (b) Martin, C. L.; Overman, L. E.; Rohde, J. M.
J. Am. Chem. Soc. 2010, 132, 4894–4906.
(3) For representative examples of syntheses of the hexahydro-1,5-
methano-1H-azocino[4,3-b]indole ring system, see: (a) Jackson, A.; Joule,
J. A. Chem. Commun. 1967, 459–460. Full paper: Jackson, A.; Wilson,
N. D. V.; Gaskell, A. J.; Joule, J. A. J. Chem. Soc. C 1969, 19, 2738–2747.
(b) Bu¨chi, G.; Gould, S. J.; Na¨f, F. J. Am. Chem. Soc. 1971, 93, 2492–
2501. (c) Grierson, D. S.; Harris, M.; Husson, H.-P. Tetrahedron 1983, 39,
3683–3694. (d) Magnus, P.; Sear, N. L.; Kim, C. S.; Vicker, N. J. Org.
Chem. 1992, 57, 70–78. (e) Gra`cia, J.; Casamitjana, N.; Bonjoch, J.; Bosch,
J. J. Org. Chem. 1994, 59, 3939–3951. (f) Micouin, L.; Diez, A.; Castells,
J.; Lo´pez, D.; Rubiralta, M.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett.
1995, 36, 1693–1696. (g) Blechert, S.; Knier, R.; Schroers, H.; Wirth, T.
Synthesis 1995, 592–604. (h) Saito, M.; Kawamura, M.; Hiroya, K.;
Ogasawara, K. Chem. Commun. 1997, 765–766. (i) Amat, M.; Hadida, S.;
Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158–3175. (j) Ergu¨n,
Y.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2002, 39, 315–317. (k) Jiricek,
J.; Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534–3538. (l) Ishikura, M.;
Takahashi, N.; Takahashi, H.; Yanada, K. Heterocycles 2005, 66, 45–50.
(m) Uludag, N.; Ho¨kelek, T.; Patir, S. J. Heterocycl. Chem. 2006, 43, 585–
591. (n) Bennasar, M.-L.; Roca, T.; Garc´ıa-D´ıaz, D. J. Org. Chem. 2008,
73, 9033–9039.
azocino[4,3-b]indole diester (()-12 does not undergo skeletal
rearrangement when exposed to TFA at 0 or 23 °C (Scheme
1).2,8
(6) For total syntheses of (()-condylocarpine, see: (a) Harley-Mason,
J. Pure Appl. Chem. 1975, 41, 167–174. (b) Kuehne, M. E.; Brook, C. S.;
Frasier, D. A.; Xu, F. J. Org. Chem. 1995, 60, 1864–1867. For studies on
the synthesis of condylocarpine, see: (c) Lounasmaa, M.; Somersalo, P.
Tetrahedron 1986, 42, 1501–1509. For total syntheses of (()-tubotaiwine,
see: (d) Dadson, B. A.; Harley-Mason, J. J. Chem. Soc. D 1969, 665b. (e)
Kuehne, M. E.; Frasier, D. A.; Spitzer, T. D. J. Org. Chem. 1991, 56, 2696–
2700. (f) Gracia, J.; Bonjoch, J.; Casamitjana, N.; Amat, M.; Bosch, J.
J. Chem. Soc., Chem. Commun. 1991, 614–615. (g) Gracia, J.; Casamitjana,
N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994, 59, 3939–3951. (h) Amat,
M.; Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158–
3175. For studies on the synthesis of tubotaiwine, see: (i) Legseir, B.; Henin,
J.; Massiot, G.; Vercauteren, J. Tetrahedron Lett. 1987, 28, 3573–3576. (j)
Lavilla, R.; Gotsens, T.; Rodriguez, S.; Bosch, J. Tetrahedron 1992, 48,
6445–6454.
(4) Ketones 7a and 7b are available in racemic form in four steps from
dimethyl or di-tert-butyl malonate in 24% and 33% overall yield, respec-
tively.2
(5) For review of this group of alkaloids, see: (a) Lounasmaa, M.;
Somersalo, P. The Condylocarpine Group of Indole Alkaloids. In Progress
in the Chemistry of Natural Products; Herz, W., Grisebach, H., Kirby, G. W.,
Tamm, Ch., Eds.; Springer-Verlag/Wien: New York, 1986; Vol. 50, pp
27-56. For the recent isolation of isocondylocarpine, see: (b) Wu, Y.;
Kitajima, M.; Kogure, N.; Wang, Y.; Zhang, R.; Takayama, H. J. Nat. Med.
2009, 63, 283–289.
Org. Lett., Vol. 13, No. 1, 2011
139

Scheme 2
.
Fragmentation of Ethylidene- and Keto-Bridged
Scheme 3. Total Syntheses of (+)-Condylocarpine,
Hexahydro-1,5-methano-1H-azocino[4,3-b]indole Intermediates
(+)-Isocondylocarpine, and (+)-Tubotaiwine
Gramine-type fragmentations of hexahydro-1,5-methano-
1H-azocino[4,3-b]indoles to carbazoles and pyridinocarba-
zoles are well-known.9 However, not previously recognized
is the notable accelerating effect of a keto or alkylidene
substituent at C12 on this fragmentation. The formation of
products (()-9 and 10 from respectively ethylidene and keto
precursors (()-8 and (()-7b suggests that the initial step is
cleavage of the C1-N bond to generate delocalized iminium
ion intermediate 16 (Scheme 2). In the ethylidene series,
cyclization of the pendant side chain of 16 delivers (()-9 as
a single stereoisomer.10 In the oxo series, dehydrative
cyclization of the ꢀ-(tert-butoxycarbonylamino)ethyl side
chain of 16 and loss of isobutylene and CO2 leads to
dihydropyrrolocarbazole ester 10.11 The facile fragmentations
in the keto and ethylidene series to generate intermediate
(7) Precursor (()-7b was recovered in 25% yield.
(8) In our earlier total synthesis of actinophyllic acid, products (()-13
and (()-14 were not purified, but directly employed in aza-Cope-Mannich
transformations.2 1H NMR analysis of these crude intermediates showed
no significant impurities, which we indicate in Scheme 1 as a crude yield
of >90%.
16 undoubtedly reflect activation of the C1sNBoc bond as
a result of its excellent overlap with the exocyclic π-bond.12
With a better understanding of the potential gramine-type
fragmentation of hexahydro-1,5-methano-1H-azocino[4,3-
b]indole-12-ones and their alkylidene derivatives, a success-
ful synthetic sequence was developed in which the pyrroli-
dine ring of the condylocarpine skeleton was constructed
using intermediates in which C12 is an sp3 carbon (Scheme
3). The syntheses began with stereoselective reduction of
(1S,5R)-ketone 7b (er ) 95:5)2 with sodium borohydride.13
After quenching the reduction with TFA, the reaction mixture
(9) To our knowledge, the first unambiguous example of such fragmen-
tation promoted by acid was described by Husson: Besselie`vre, R.; Husson,
H.-P. Tetrahedron 1983, 37 (Supplement 1), 241–246.
(10) The stereoisomer having a cis relationship of the angular hydrogen
and the methyl substituent would be both the expected kinetic product of
cyclization of (E)-ethylidene intermediate 16 and the thermodynamic product
of reversible gramine-type fragmentation of product (()-9; an axial
orientation of the Me substituent minimizes destabilizing A1,3 interactions
with the Boc substituent.
(11) (a) Gramine-type cleavage is likely the first step in the keto series
also, because exposure of i to 0.15 M DCl in CDCl3 at room temperature
for 2 h yielded a mixture of i (48%) and ii (36%). (b) In neat TFA,
decarboxylative aromatization of 16 (X ) O, R ) t-Bu) apparently occurs
rapidly leading to the eventual formation of carbazole acid 11.
(12) For a concise discussion of the effect of adjacent C-C and C-O
π-bonds on nucleophilic substitution reactions, see: Anslyn, E. V.; Dough-
erty, D. A. Modern Physical Organic Chemistry; University Science:
Sausalito, CA, 2006; pp 653-655.
(13) The ꢀ-tert-butoxycarbonyl group sterically shields the Si face of
the ketone carbonyl group,2 resulting in hydride addition from the Re
face.
140
Org. Lett., Vol. 13, No. 1, 2011

was concentrated and the crude residue was dissolved in a
4:1 mixture of TFA and water to promote cleavage of the
Boc and tert-butyl esters, and decarboxylation to yield the
corresponding amino acid. Removal of TFA and water in
vacuo, followed by dissolution of the residue in a 0.5 M
solution of hydrochloric acid in methanol and heating at 50
°C delivered amino ester 17, a 2:1 mixture of ester epimers,
in 86% overall yield from 7b. Reductive alkylation of this
crude amine with 2,2-bis(ethylthio)acetaldehyde14 furnished
tertiary amine 18 in 70% yield. Exposure of 18 to a
suspension of dimethyl(methylthio)sulfonium tetrafluorobo-
rate (DMTSF)15 and 4 Å molecular sieves in dichlo-
romethane at room temperature delivered pentacyclic alcohol
19 as a single stereoisomer in 75% yield.16-18 It was essential
that this ring construction be carried out after dealkoxycar-
bonylation, as earlier extensive attempts to cyclize malonate
precursors under various conditions were unsuccessful.
Enantiomerically pure 19 (er >99:1) was obtained in 91%
yield after separation of the highly crystalline racemate.
In three additional steps, pentacyclic intermediate 19 was
converted to (+)-condylocarpine (2a) and (+)-isocondylo-
carpine (2b). The thioether group of 19 was cleaved with Raney
nickel in THF at 50 °C to deliver the desulfurized product in
75% yield.19 After extensively screening conditions for oxida-
tion of the secondary alcohol of this product, Albright-Goldman
oxidation20 was identified as optimal for accomplishing this
transformation, giving 20 in 72% yield for the 2 steps.21
Reaction of pentacyclic ketone 20 with ethyltriphenylphospho-
nium ylide in a mixture of THF and toluene at room temperature
delivered a 1:1 mixture of enantiopure (+)-condylocarpine (2a)
and (+)-isocondylocarpine (2b) in 77% combined yield. Pure
samples of these interconvertible stereoisomers22 were obtained
by preparative HPLC: (+)-condylocarpine (2a), [R]D +854 (c
0.39, CHCl3), and (+)-isocondylocarpine (2b), [R]D +798 (c
0.15, CHCl3). Catalytic hydrogenation23 of the initially produced
mixture of 2a and 2b delivered (+)-tubotaiwine (21), [R]D +584
(c 0.91, CHCl3), in 91% yield.24-26
In summary, the first enantioselective total syntheses of indole
alkaloids of the condylocarpine type have been accomplished.
One important outcome of this study was the discovery that
hexahydro-1,5-methano-1H-azocino[4,3-b]indoles having a car-
bonyl or alkylidene group as the one carbon bridge undergo
facile gramine-type fragmentation in the presence of even dilute
acids. This lability necessitated that the C12 carbonyl group of
precursor 7b be masked by reduction during formation of the
pyrrolidine ring. As a result, a synthetic sequence proceeding
via five isolated intermediates was required for the elaboration
of (1S,5R)-hexahydro-1,5-methano-1H-azocino[4,3-b]indole 7b
to enantiopure (+)-condylocarpine (2a) and (+)-isocondylo-
carpine (2b).
Acknowledgment. This research was supported by the NIH
Neurological Disorders & Stroke Institute (NS-12389) and the
National Institute of General Medical Sciences (GM-098601).
Fellowship assistance for C.L.M. (UC Irvine Chancellor’s
Fellowship, Bristol-Myers Squibb Graduate Fellowship, and
ACS Division of Organic Chemistry Fellowship sponsored by
Amgen) and R.O. (Feodor Lynen Fellowship of the Alexander
von Humboldt Foundation) is gratefully acknowledged. We
thank Dr. Jason M. Rohde, Ironwood Pharmaceuticals, Inc., 301
Binney Street, Cambridge, MA 02142, for preliminary studies,
and Dr. Joe Ziller, School of Physical Sciences, UC Irvine, for
X-ray analyses. NMR, mass spectra, and X-ray analyses were
obtained at UC Irvine using instrumentation acquired with the
assistance of NSF and NIH Shared Instrumentation programs.
(14) Bates, G. S.; Ramaswamy, S. Can. J. Chem. 1983, 61, 2466–2475.
(15) Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529–
6530.
(16) The relative configuration of 19, and that of the secondary alcohol
in precursors 17 and 18, was secured on the basis of X-ray crystallographic
analysis of silyl ether derivative (()-iii, which was prepared in an analogous
fashion to 19. Crystallographic data for (()-iii were deposited at the
Cambridge Crystallographic Data Centre: CCDC 799190.
Supporting Information Available: Experimental details
and copies of 1H and 13C NMR spectra of new compounds;
CIF files for compounds (()-20 and (()-iii. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) The use of 5-exo thionium ion cyclizations to form this ring of
indole alkaloids is a well-established tactic in indole alkaloid synthesis,
see: (a) Gallagher, T.; Magnus, P.; Huffman, J. C. J. Am. Chem. Soc. 1983,
105, 4750–4757. (b) Amat, M.; Linares, A.; Bosch, J. J. Org. Chem. 1990,
55, 6299–1312. (c) Amat, M.; Bosch, J. J. Org. Chem. 1992, 57, 5792–
5796
.
OL102709S
(18) Methyl thioether (()-iv was isolated with 19 as an inseparable
contaminant (diagnostic 1H NMR singlet corresponding to the methyl
thioether group at 1.81 ppm and LRMS analysis). This inconsequential side
product likely arose by hydrolysis of DMTSF by adventitious water to give
methanethiol, which underwent thiol exchange by way of the reactive
thionium ion prior to cyclization.
(21) Crystallographic data for a racemic sample of intermediate 20
were deposited at the Cambridge Crystallographic Data Centre: CCDC
799189.
(22) Condylocarpine (2a) and isocondylocarpine (2b) equilibrate to a
2:1 mixture of 2a:2b when heated for 4 h at reflux in toluene or when
exposed for 24 h at room temperature to acetic acid in chloroform.6b
(23) Schumann, D.; Schmid, H. HelV. Chim. Acta 1963, 46, 1996–2003.
(24) A range of optical rotations at the sodium D line has been reported
for natural samples of condylocarpine (+501 to +90125 in CHCl3) and
tubotaiwine (+417 to +62826 in CHCl3); citation to the highest reported
rotation is provided here, and a complete summary is provided in the
Supporting Information. Natural isocondylocarpine is reported to show [R]D
+537 (c 0.1, CHCl3).5b
(19) It was advantageous to use THF as the solvent instead of methanol
or ethanol, as byproducts arising from reduction of the vinylogous carbamate
were suppressed in THF.
(20) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1965, 87, 4214–
4216.
(25) Stauffacher, D. HelV. Chim. Acta 1961, 44, 2006–2015
(26) Pinar, M.; Renner, U.; Hesse, M.; Schmid, H. HelV. Chim. Acta
1972, 55, 2972–2974
.
.
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