Enantioselective total synthesis of quadrigemine C and psycholeine

Article abstract of DOI:10.1021/ja0267425

The first total syntheses of higher-order members of the polypyrrolidinoindoline alkaloid family are reported. The synthesis of quadrigemine C (1) and psycholeine (3) begins with synthetic meso-chimonanthine (4), which is synthesized from commercially ava

Full text of DOI:10.1021/ja0267425

Published on Web 07/10/2002
Enantioselective Total Synthesis of Quadrigemine C and Psycholeine
Alec D. Lebsack, J. T. Link,1a Larry E. Overman,* and Brian A. Stearns1b
Department of Chemistry, 516 Rowland Hall, UniVersity of California IrVine, California 92697-2025
Received April 30, 2002
Quadrigemine C (1) is representative of the higher-order
members of a remarkable series of Nb-methyltryptamine-derived
plant alkaloids that link together two to eight pyrrolidinoindoline
units.2 First described in 1987 from an extract of Psychotria oleoides
found in New Caledonia,3 quadrigemine C (1) subsequently was
isolated from Psychotria colorata, a plant used by indigenous
peoples of the Amazon for treating pain.4 The relative and absolute
configuration of quadrigemine C (1) was proposed in 1992 by
Se´venet and co-workers, who also identified an isomeric alkaloid,
psycholeine (3), from the same extract.5 The R absolute configu-
ration of the two outer quaternary carbons of 1 is firmly established,6
whereas the configuration of the central hexacyclic unit is less
secure, being formulated on the basis of the similarities of NMR
and circular dichroism measurements of quadrigemine C (1) with
those of the simpler alkaloid hodgkinsine (2).5,6 Quadrigemine C
(1) is reported to exhibit significant antibacterial7 and analgesic
activity4 and, like psycholeine (3), to be a weak antagonist of the
SRIF (somatostatin) receptor.8
Stimulated by the unusual structures and varied biological
activities of higher-order polypyrrolidinoindoline alkaloids,2 we
initiated a program to develop chemistry that would allow various
(R)-Tol-BINAP as ligand, and 1,2,2,6,6-pentamethylpiperidine
members of this polycyclic alkaloid family and their congeners to
be prepared by chemical synthesis.9 Quadrigemine C (1) exemplifies
the two formidable synthetic challenges posed by higher-order
polypyrrolidinoindoline alkaloids: the contiguous stereogenic
quaternary carbons 3a′ and 3a′′ and the stereogenic diaryl quaternary
carbons 3a and 3a′′′. We report herein implementation of the
methods we have developed for dealing with these issues9,10 to
concisely prepare quadrigemine C (1) and psycholeine (3).
As quaternary carbons 3a and 3a′′′ of 1 have the same absolute
configuration, our strategy was to use catalytic asymmetric Heck
cyclizations10 to desymmetrize an advanced meso intermediate and
simultaneously install the two peripheral quaternary stereocenters.11-13
The synthesis began with meso-chimonanthine (4), which was
synthesized from commercially available oxindole and isatin in 13
steps and 35% overall yield (Scheme 1).9c The aniline nitrogens of
4 were protected by premixing 4 with 2.2 equiv of di-tert-butyl
dicarbonate (Boc2O), followed by adding excess sodium bis-
(trimethylsilyl)amide. Using these optimized conditions, dicarbam-
ate 5 was produced in 77% yield. Double ortho-lithiation of 5 with
5 equiv of s-BuLi at -78 °C and subsequent quenching with 10
equiv of 1,2-diiodoethane delivered crystalline diiodide 6 in 88%
yield.14 Exposure of this intermediate to TMSOTf in CH2Cl2 cleaved
the tert-butoxycarbonyl groups to afford diiodide 7 in 97% yield.
Chemoselective double Stille cross coupling of diiodide 7 with
stannane 815 was realized using a catalyst system derived from Pd2-
(dba)3‚CHCl3, tri-2-furylphosphine16 and CuI17 to give meso dibu-
tenanilide 9 in 71% yield.
(PMP) as base.18 The major product formed under these conditions
was the C1-symmetric dioxindole 10, which could be isolated in
62% yield (90% ee) after chromatographic purification. Also formed
in this reaction were minor amounts (14 and 7% yields) of two
meso dioxindole products of unknown relative configuration.19 As
separation of these stereoisomers was difficult, the isomer mixture
was hydrogenated under 100 psi of H2 in 10:1 EtOH-MeOH at
80 °C in the presence of Pd(OH)2 to provide 11 contaminated with
corresponding amounts of two meso stereoisomers. Exposure of
this product to a large excess of sodium in THF-NH3 at -78 °C
for 20 min, followed by addition of solid NH4Cl provided
quadrigemine C (1) in 22% overall yield from 10 after purification
by HPLC. In this final synthetic step, the four protecting groups of
11 are removed, the two oxindole carbonyl groups are reduced,
and the final two rings are formed.20 The optical rotation of synthetic
1, [R]27 -66.5, compares well with that reported for the natural
D
isolate,5 [R]27 -69.0, as do other spectral (1H and 13C NMR,
D
HRMS, and CD) and chromatographic (HPLC and TLC) properties.
Synthetic psycholeine (3), [R]27 -150 (lit.5 [R]27 -150) was
D
D
obtained in 38% yield from synthetic 1 by acid-catalyzed isomer-
ization.5
In summary, the first total synthesis of a higher-order member
of the polypyrrolidinoindoline alkaloid family has been ac-
complished. The synthesis of quadrigemine C (1), which rigorously
confirms its relative and absolute configuration, was executed in
19 linear steps from commercially available starting materials. At
this stage of refinement, the overall yield is 2%. When properly
orchestrated, the chemistry introduced here and in our earlier total
syntheses of meso-, (+)-, and (-)-chimonanthine9 should allow
The pivotal, catalyst-controlled double Heck cyclization of 9 was
accomplished at 80 °C in acetonitrile using Pd(OAc)2 as precatalyst,
* To whom correspondence should be addressed. E-mail: leoverma@uci.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 9008-9009
10.1021/ja0267425 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
(8) Rasolonjanahary, R.; Se´venet, T.; Voegelein, F. G.; Kordon, C. Eur. J.
Pharmacol. 1995, 285, 19-23.
(9) (a) Link, J. T.; Overman, L. E. J. Am. Chem. Soc. 1996, 118, 8166-
8167. (b) Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem.
Soc. 1999, 121, 7702-7703. (c) Overman, L. E.; Larrow, J. F.; Stearns,
B. A.; Vance, J. M. Angew. Chem., Int. Ed. 2000, 39, 213-215.
(10) (a) Ashimori, A. Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477-6487. (b) Ashimori, A.; Bachand, B.; Calter, M.
A.; Govek, S. P.; Overman, L. E. J. Am. Chem. Soc. 1998, 120, 6488-
6499. (c) Oestreich, M.; Dennison, P. R.; Kodanko, J. J.; Overman, L. E.
Angew. Chem., Int. Ed. 2001, 40, 1439-1442.
(11) This approach represents an uncommon variant of two-directional
synthesis.12 In the present case, reagent control is employed to simulta-
neously functionalize both termini.13
many complex polypyrrolidinoindoline alkaloids and their analogues
to be obtained by sterocontrolled chemical synthesis.
Acknowledgment. We thank NIH (HL-25854) for financial
support, Professor Franc¸oise Gue´ritte-Voegelein for a sample of
quadrigemine C, and Mr. Jeremy Kodanko for advice and develop-
ing the synthesis of 8. Fellowship support to J.T.L. (American
Cancer Society), B.A.S. (Bristol-Myers Squibb), and A.D.L.
(Pharmacia) is gratefully acknowledged.
Supporting Information Available: Experimental procedures for
1
the preparation of 1, 3, 5, 6, 7, 8, 9, 10, and 11; copies of H and 13C
(12) For reviews, see: (a) Schreiber, S. L. Chem. Scr. 1987, 27, 563-566. (b)
Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9-17. (c)
Magnuson, S. R. Tetrahedron 1995, 51, 2167-2213.
NMR spectra of these compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) For the first report of this strategy, see: Wang, Z.; Descheˆnes J. Am.
Chem. Soc. 1992, 114, 1090-1091.
References
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(15) Stannane 8 was synthesized in four steps from commercially available
(1) Current addresses: (a) Abbott Laboratories, 100 Abbott Park Road, Abbott
Park, IL 60064-6098. (b) Merck Research Laboratories, 3535 General
Atomics Court, San Diego, CA 92121.
3H-benzooxazol-2-one (see Supporting Information).
(16) Farina, V.; Krishnan, B. J. J. Am. Chem. Soc. 1991, 113, 9585-9595.
(2) Anthoni, U.; Christophersen, C.; Nielsen, P. H. In Alkaloids: Chemical
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(18) The catalyst generated from Pd(OAc)2 and (R)-BINAP was less selective
and provided 10 in lower yield and 65% ee.
(4) Verotta, L.; Pilati, T.; Tatø, M.; Eilsabetsky, E.; Amador, T. A.; Nunes,
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(19) Four dioxindole products are possible, two meso isomers and a pair of
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(20) Sodium (in ethanol) was the reductant employed in the first reported
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P. L.; Pikl, J. J. Am. Chem. Soc. 1935, 57, 539-544.
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