A short, protecting group-free total synthesis of bruceollines D, E, and J

Article abstract of DOI:10.1021/ol402042f

A short, protecting group-free total synthesis of bruceollines D, E, and J has been achieved. The enantioselective reduction of bruceolline E with β-chlorodiisopinocampheylborane delivers both the natural and unnatural enantiomers of bruceolline J in excellent yields and enantioselectivities. Reduction with baker's yeast and sucrose was shown to provide the unnatural enantiomer of bruceolline J in 98% ee.

Full text of DOI:10.1021/ol402042f

ORGANIC
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A Short, Protecting Group-Free Total
Synthesis of Bruceollines D, E, and J
Justin M. Lopchuk,† Ilene L. Green,‡ Jeanese C. Badenock,‡ and Gordon W. Gribble*,†
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755,
United States, and Department of Biological and Chemical Sciences,
University of the West Indies, Cave Hill, Barbados
gordon.w.gribble@dartmouth.edu
Received July 19, 2013
ABSTRACT
A short, protecting group-free total synthesis of bruceollines D, E, and J has been achieved. The enantioselective reduction of bruceolline E with
β-chlorodiisopinocampheylborane delivers both the natural and unnatural enantiomers of bruceolline J in excellent yields and enantioselectivities.
Reduction with baker’s yeast and sucrose was shown to provide the unnatural enantiomer of bruceolline J in 98% ee.
The bruceolline family of natural products is comprised
of various structurally related cyclopent[b]indole and cathan-
6-one alkaloids which have been isolated from the root wood
of Brucea mollis Wall. var. tonkinensis Lecomte (Figure 1).1
Brucea mollis and B. javanica are native to southwestern
China and traditionally used for the treatment of various
parasitic diseases including malaria.2 Despite the potential
medicinal utility, both the biological evaluation and synthetic
investigations have been limited.3
As a part of our longstanding interest in the synthesis
of fused indoles and cyclopent[b]indole natural products,4
we were intrigued by the possibility of developing a short
† Department of Chemistry, Dartmouth College.
‡ Department of Biological and Chemical Sciences, University of the
West Indies.
(1) (a) For a review of natural products isolated from Brucea plants,
see: Liu, J.-H.; Jin, H.-Z.; Zhang, W.-D.; Yan, S.-K.; Shen, Y.-H. Chem.
Biodiversity 2009, 6, 57–70. (b) For the isolation of bruceollines A and B,
see: Ouyang, Y.; Koike, K.; Ohmoto, T. Phytochemistry 1994, 36, 1543–
1546. (c) For the isolation of bruceollines C and G, see: Ouyang, Y.;
Mitsunaga, K.; Koike, K.; Ohmoto, T. Phytochemistry 1995, 39, 911–
913. (d) For the isolation of bruceollines DꢀF, see: Ouyang, Y.; Koike,
K.; Ohmoto, T. Phytochemistry 1994, 37, 575–578. (e) For the isolation
of bruceollines HꢀN, see: Chen, H.; Bai, J.; Fang, Z.-F.; Yu, S.-S.; Ma,
Figure 1. Bruceolline natural products.
S.-G.; Xu, S.; Li, Y.; Qu, J.; Ren, J.-H.; Li, L.; Si, Y.-K.; Chen, X.-G.
J. Nat. Prod. 2011, 74, 2438–2445.
(2) (a) Guo, Z.; Vangapandu, S.; Sindelar, R. W.; Walker, L. A.;
Sindelar, R. D. Curr. Med. Chem. 2005, 12, 173–190. (b) Muhammad, I.;
Samoylenko, V. Expert Opin. Drug Discovery 2007, 2, 1065–1084.
(3) For the only synthesis of bruceolline E to date, see: Jordan, J. A.;
Gribble, G. W.; Badenock, J. C. Tetrahedron Lett. 2011, 52, 6772–6774.
(4) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417–1432.
synthesis that could allow successive access to bruceollines
D (5), E(6), andJ(9) without the need for protecting groups.
Our initial attempt toconstructbruceolline D (5) utilized
phenylhydrazine and dione 12 through Fischer indolization
r
10.1021/ol402042f
XXXX American Chemical Society

of bruceolline E (6) wasinvestigatedwhich involved Fischer
or palladium-catalyzed cyclization to indole 13 and sub-
sequent DDQ oxidation to indolone 14. Unfortunately,
attempts to convert the indolone directly to bruceolline E
(6) via selenium dioxide oxidation without protection of the
indole NH were unsuccessful, typically returning unreacted
starting material.11 Protection of 14 at this stage would
intercept the route used in the only previous synthesis
of bruceolline E (6).3 With bruceolline E (6) in hand, we
turned our focus to the selective monoreduction of the
dione moiety to furnish racemic bruceolline J (9). As
expected, the ketone was reduced rapidly and selectively
in the presence of the vinylogous amide with none of
the possible bis-reduction product detected (Scheme 3).
A variety of reductants worked well including sodium
borohydride, borane-dimethyl sulfide, and catecholborane.
The structure was confirmed by X-ray crystallography.12
Scheme 1. Synthesis of Bruceolline D
chemistry even though a report by Dashkevich5 indicated
yields may be low due to both thermal instability and acid
sensitivity of the target compound. Indeed, despite screen-
ing numerous conditions (including recently reported cy-
clizations in low melting mixtures) we were never able to
achieve yields above 35%.6 In addition to problems with
the stability of the product, formation of the unproductive
bis-hydrazone tended to be more competitive than initially
suspected.7 We turned instead to palladium-catalyzed cy-
clization conditions reported by Nazare and co-workers.
8
ꢀ
Scheme 3. Synthesis of rac-Bruceolline J
To our delight, the cyclization of o-chloroaniline with dione
12 proceeded smoothly to provide bruceolline D (5) in 88%
yield (Scheme 1). The structure was confirmed by X-ray
crystallography.9
Scheme 2. Synthesis of Bruceolline E
With the first total synthesis of racemic bruceolline J (9)
complete, we turned our attention to effecting an enantio-
selective reduction and obtaining both the natural and
unnatural enantiomers. Initial testing with the venerable
CBS reduction was disappointing. Both catalytic and
stoichiometric versions of the reaction gave poor enan-
tioenrichment due to the overly competitive background
reduction (Table 1, entries 1ꢀ3).13 Although the CBSꢀ
catecholborane system has been shown to promote enantio-
selective reductions at low temperatures, only a trace of pro-
duct was observed after 12 h at ꢀ78 °C (Table 1, entry 4).14
As foreshadowed by a literature precedent of related sub-
strates, the dione proved to be too hindered for Alpine
Borane to furnish any of the desired product, even after
10 days at room temperature.15
β-Chlorodiisopinocampheylborane16 (DIPCl) delivered
the most promising result from the initial screen (Table 1,
Oxidation of bruceolline D (5) to bruceolline E (6)
proved straightforward by treatment of 5 with DDQ in
aqueous acetonitrile (Scheme 2).10 An alternative synthesis
(11) Gribble, G. W.; Barden, T. C.; Johnson, D. A. Tetrahedron 1988,
44, 3195–3202.
(5) Dashkevich, S. N. Chem. Heterocycl. Cmpds. 1978, 14, 109.
(6) Conditions tested included HCl, H2SO4, polyphosphoric acid
(PPA), and buffered phosphoric acid. For the unsuccessful low melting
mixture Fischer indolization conditions, see: Gore, S.; Baskaran, S.;
(12) Lopchuk, J. M.; Gribble, G. W.; Jasinski, J. P. Acta Crystallogr.
2013, E69, o1351–o1352.
(13) (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen,
K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993,
58, 2880–2888 and references therein. (b) Corey, E. J.; Helal, C. J.
Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
(14) (a) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30, 6275–
6278. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611–614.
(c) West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R. R.; Sarpong, R. J. Am.
Chem. Soc. 2009, 131, 11187–11194.
(15) Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984,
106, 1531–1533. Although reductions with Alpine Borane are known to
run more efficiently neat or at high concentrations, the poor solubility of
6 required lower concentrations than desired.
€
Konig, B. Org. Lett. 2012, 14, 4568–4571.
(7) Interestingly, both high dilutions and changing solvents failed to
significantly alter the distribution of hydrazone formation. The low
melting mixtures (ref 6) favored the monohydrazone more than any
other tested condition; however, the cyclization itself did not proceed.
(8) Nazare, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W.
Angew. Chem., Int. Ed. 2004, 43, 4526–4528.
(9) Lopchuk, J. M.; Gribble, G. W.; Jasinski, J. P. Acta Crystallogr.
2013, E69, o1043.
(10) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213–1216.
B
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Table 1. Enantioselective Reduction of Bruceolline E to Bruceolline J
a Enantiomeric excess (ee) was determined by HPLC (Chiralpak OD-H, 85% hexanes: 15% isopropanol). b nd = not determined. c Based on
recovered starting material (brsm).
entry 7) and, after optimization, gave natural (þ)-9 in
an excellent 94% yield and 98% ee. Assignment of the
absolute stereochemistry was done by comparison of
the CD spectrum of the synthetic material to that of the
natural product.1e,17 Similar results were obtained for the
unnatural enantiomer. The reduction of bruceolline E (6)
was also investigated by subjecting 6 to baker’s yeast
suspended in a solution of sucrose and water.18 After
14 days (ꢀ)-9, the unnatural enantiomer, was obtained in
63% yield (91% brsm) and 98% ee.
In conclusion, we have developed a short, protecting
group-free total synthesis of bruceollines D, E, and J. Both
the natural and unnatural enantiomers of bruceolline J
have been synthesized for the first time in excellent yields
and enantioselectivities (94%, 98% ee and 93%, 98% ee,
respectively). The concise nature of the synthetic route
should allow for substantial analog development and
biological testing in the future.
Acknowledgment. J.M.L. acknowledges support from
a Department of Education GAANN fellowship. G.W.G.
acknowledges support by the Donors of the Petroleum
Research Fund (PRF), administered by the American
Chemical Society, and by Wyeth.
(16) (a) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V.
J. Org. Chem. 1986, 51, 3396–3398. (b) Brown, H. C.; Chandrasekharan,
J.; Ramachandran, P. V. J. Am. Chem. Soc. 1988, 110, 1539–1546. (c)
Brown, H. C.; Ramachandran, P. V. Pure Appl. Chem. 1994, 66, 201–
212. (d) Ramachandran, P. V.; Pitre, S.; Brown, H. C. J. Org. Chem.
2002, 67, 5315–5319.
(17) The absolute stereochemistry of the natural product (9) was
assigned by comparison of a DFT-calculated CD spectra to the experi-
mentally generated CD spectra (ref 1e). The CD spectrum of syntheti-
cally prepared (þ)-9 matched that found from the natural product.
(18) (a) Chenevert, R.; Thiboutot, S. Chem. Lett. 1988, 1191–1192.
(b) Inoue, T.; Hosomi, K.; Araki, M.; Nishide, K.; Node, M. Tetrahedron:
Asymmetry 1995, 6, 31–34.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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