Chemoenzymatic approaches to the montanine alkaloids: A total synthesis of (+)-brunsvigine

Article abstract of DOI:10.1021/ol071344y

The readily available and enzymatically derived cis-1,2-dihydrocatechols 3a and 3b have been elaborated over 17 steps, including a novel radical addition/elimination sequence, into the enantiomer, (+)-1, of the montanine alkaloid brunsvigine [(-)-1].

Full text of DOI:10.1021/ol071344y

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3503-3506
Chemoenzymatic Approaches to the
Montanine Alkaloids: A Total Synthesis
of (+)-Brunsvigine
Martin G. Banwell,* Okanya J. Kokas, and Anthony C. Willis
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received June 7, 2007
ABSTRACT
The readily available and enzymatically derived cis-1,2-dihydrocatechols 3a and 3b have been elaborated over 17 steps, including a novel
radical addition/elimination sequence, into the enantiomer, ( )-1, of the montanine alkaloid brunsvigine [( )-1].
+
−
(-)-Brunsvigine [(-)-1]1-3 is a representative member of a
relatively small group of natural products known as the
montanine alkaloids which incorporate the 5,11-methano-
morphanthridine framework and bear hydroxy or methoxy
groups in varying configurations at C-2 and C-3.4 The
isolation of (+)-montabuphine,5 assigned structure 2, from
the Amaryllidaceae species Boophane flaVa found in South-
ern Africa suggests that both enantiomeric forms of the
framework can be encountered within this class of natural
product. Little is known about the biological properties of
such compounds,4,6 although their structural similarity to
other pharmacologically active Amaryllidaceae alkaloids
suggests they deserve attention in this regard.
Two distinct end-games have been employed in the limited
number of total syntheses of the montanine alkaloids reported
(1) Dry, L. J.; Poynton, M.; Thompson, M. E.; Warren, F. L. J. Chem.
Soc. 1958, 4701.
(2) Inubushi, Y.; Fales, H. M.; Warnhoff, E. W.; Wildman, W. C. J.
Org. Chem. 1960, 25, 2153.
(3) Clark, R. C.; Warren, F. L.; Pachler, K. G. R. Tetrahedron 1975, 31,
1855.
thus far. The first of these, as highlighted in Overman’s 1992
synthesis of (()-pancracine,7 involves subjecting an ap-
propriately configured 3-arylated perhydroindole to the
Pictet-Spengler reaction. Pearson has exploited this same
approach in the preparation of (+)-coccinine,8 as has Sha in
a synthesis of (-)-brunsvigine.9 The second type of end-
(4) For reviews dealing with this class of alkaloid, see: (a) Martin, S.
F. In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego, 1987;
Vol. 30, p 251. (b) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 1998; Vol. 51, p 323. (c) Lewis, J. R. Nat.
Prod. Rep. 2000, 17, 57 and previous reviews in the series.
(5) Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.; Mathee, S.
Phytochemistry 1995, 40, 307.
10.1021/ol071344y CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/02/2007

game relies on the assembly of the morphanthridine skeleton
incorporating a hydroxymethyl group at C-11 and installation
of the 5,11-methano bridge by activation of the hydroxyl
moiety, then displacement of the activated unit by N-5.
Hoshino first deployed this approach in syntheses of (()-
montanine, (()-coccinine, (()-O-acetylmontanine, (()-pan-
cracine, and (()-brunsvigine.10 Subsequently, Weinreb ap-
plied this strategy in enantioselective total syntheses of (-)-
montanine, (-)-coccinine, and (-)-pancracine.11 Several
formal total syntheses of various members of the montanine
alkaloid class have also been described,12 and all but two12a,d
rely on one or other of the two end-games just described.
Herein we outline a chemoenzymatic synthesis of the
enantiomer, (+)-1, of (-)-brunsvigine [(-)-1] that starts from
the monochiral 3-halo-cis-1,2-dihydrocatechols 3a and 3b,
each of which can be obtained in multigram quantities
through the whole-cell biotransformation of the correspond-
ing halobenzene.13 The strategy used involves the late-stage
application of the Pictet-Spengler reaction and a novel
radical addition/elimination process14 that permits the ready
Scheme 1
and completely regiocontrolled introduction of the ∆1,11a
-
alkene associated with all of the title alkaloids.
The early stages (Scheme 1) of the total synthesis of (+)-
brunsvigine involved assembly of the precursor to the E-ring
and began with the p-methoxyphenyl or PMP-based acetal
derivatives 4,15 of compounds 3a and 3b. These acetals were
subjected to a regio- and diastereo-selective cis-dihydroxy-
lation under the UpJohn conditions,16 and the resulting diols
5a (65% from 3a) and 5b (66%) converted, under standard
conditions involving MOM-Cl and sodium hydride, into the
corresponding bis-MOM ethers 6a (91%) and 6b (88%),
respectively. Reductive cleavage of the acetal moiety within
these last compounds was effected regioselectively using
DIBAL-H,15 affording the p-methoxylbenzyl or PMB-ethers
7a (64%) and 7b (60%), respectively. Conversion of these
alcohols into the corresponding iodides, 8a (81%) and 8b
(66%), could be achieved using triiodoimidazole in the
presence of imidazole and triphenylphosphine,17 although in
each of these reactions leading to such products they were
accompanied by the hydroquinone derivative 9 (2.5-6%).
The structures of compounds 8a and 9b follow from single-
crystal X-ray analyses.18 Reductive deiodination of dihalides
8a and 8b was achieved using tri-n-butyltin hydride and
without any complications arising from competitive removal
of the halogens attached to the associated alkene. The ensuing
PMB-ethers 10a (85%) and 10b (84%) were each subjected
to cleavage with DDQ, and the alcohols 11a (96%) and 11b
(98%) so formed engaged in Mitsunobu reactions using
diphenylphosphoryl azide (DPPA)19 as the nucleophile. The
ensuing azides 12a (93%) and 12b (75%) thus formed were
then each subjected to a Staudinger reaction using tri-
phenylphosphine in aqueous THF, and the resulting primary
amines 13a (87%) and 13b (98%) engaged in reductive
amination reactions using p-methoxybenzaldehyde then
sodium cyanoborohydride to give the corresponding second-
ary amines 14a (90%) and 14b (56%).
(6) Very recently (-)-montanine has been shown to display anxiolytic,
antidepressant and anticonvulsant-type effects in mice: Schu¨rmann da Silav,
A. F.; de Andrade, J. P.; Bevilaqua, L. R. M.; da Souza, M. M.; Izquierdo,
I.; Henriques, A. T.; Zuanazzi, J. A. S. Pharmacol., Biochem. BehaV. 2006,
85, 148.
(7) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005.
(8) Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724.
(9) Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.
(10) Ishizaki, M.; Hoshino, O.; Iitaka, Y. J. Org. Chem. 1992, 57, 7285.
(11) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5773.
(12) (a) Ishizaki, M.; Kurihara, K.-I.; Tanazawa, E.; Hoshino, O. J. Chem.
Soc., Perkin Trans. 1 1993, 101. (b) Ikeda, M.; Hamada, M.; Yamashita,
T.; Matsui, K.; Sato, T.; Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1999,
1949. (c) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Kemmler, M. J.
Chem. Soc., Perkin Trans. 1 2001, 1345. (d) Pandey, G.; Banerjee, P.;
Kumar, R.; Puranik, V. G. Org. Lett. 2005, 7, 3713.
(13) For reviews on methods for generating cis-1,2-dihydrocatechols by
microbial dihydroxylation of the corresponding aromatics, as well as the
synthetic applications of these metabolites, see: (a) Hudlicky, T.; Gonzalez,
D.; Gibson, D. T. Aldrichimica Acta 1999, 32, 35. (b) Banwell, M. G.;
Edwards, A. J.; Harfoot, G. J.; Jolliffe, K. A.; McLeod, M. D.; McRae, K.
J.; Stewart, S. G.; Vo¨gtle, M. Pure Appl. Chem. 2003, 75, 223. (c) Johnson,
R. A. Org. React. 2004, 63, 117.
The assembly of the precursor to the AB-ring substructure
of (+)-brunsvigine is shown in the early parts of Scheme 2
and used protocols defined by Ikeda et al.12b Thus, 1,2-
methylenedioxybenzene was treated with ethyl R-chloro-R-
(14) Stanislawski, P. C.; Willis, A. C.; Banwell, M. G. Org. Lett. 2006,
8, 2143.
(17) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866.
(15) Compound 4b has been described previously: Banwell, M. G.;
McRae, K. J.; Willis, A. C. J. Chem. Soc., Perkin Trans. 1 2001, 2194.
(16) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(18) Details of X-ray analyses carried out as part of this study are
provided in the Supporting Information.
(19) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977.
3504
Org. Lett., Vol. 9, No. 18, 2007

Scheme 2
thiophenylacetate in the presence of TiCl4 to give, after
residue within substrate 22 into the acid-stable cyclic
carbonate but also effected cleavage of the PMB-protected
amine to form the corresponding carbamoyl chloride 23
which was immediately treated with aqueous dioxane in the
presence of traces of HCl to give the cyclic secondary amine
24 (42% from 22). Treatment of the last compound with
paraformaldehyde in aqueous formic acid at 80 °C effected
the pivotal Pictet-Spengler reaction to generate compound
25 (65%) embodying the full pentacyclic framework of target
(+)-brunsvigine. Finally, subjection of carbonate 25 to
reaction with KOH in methanol at 18 °C afforded compound
(+)-1 [mp 130-140 °C (sesquihydratesrecrystallized from
wet acetone); lit.1 mp 140-150 °C (for sesquihydrate of the
enantiomer)] in 87% yield. The spectral data derived from
this material were in full accord with the assigned structure,
but final confirmation of this followed from a single-crystal
X-ray analysis.18 The specific rotation of (+)-brunsvigine
{[R]D +75.9 (c 0.1, ethanol)} was of similar magnitude but
opposite sign to that reported21 for its enantiomer {[R]D
-76.3 (c 1, ethanol)}.
saponification of the product ester with NaOH, the R-arylated
acetic acid 17 (99%). EDCI-promoted coupling of this
compound with either amine 14a or 14b gave the corre-
sponding amides 18a (86%) and 18b (74%), each of which
was obtained as a ca. 1:1 mixture of diastereoisomers. In a
pivotal step of the synthesis, compounds 18a and 18b were
each subjected to reaction with mixtures of hexa-n-butylditin,
tri-n-butyltin hydride, and AIBN so as to generate, via
homolytic cleavage of the thiophenyl unit, a benzylic radical
that engages in a 5-exo-trig cyclization/halide radical elimi-
nation reaction sequence,14 thus forming the D-ring of target
(+)-1. This sequence led to a mixture of the 3-arylhexahy-
drooxindole 19 (0% from 18a and 7% from 18b) and the
required epimer 20 (29% from 18a and 60% from 18b)
together with varying quantities of those compounds arising
from reductive cleavage of the thiophenyl and/or halogen
residue within the starting materials. The lactam carbonyl
within product 20 was removed using in situ generated AlH3
and the hexahydroindole 21 thus obtained in 94% yield.
Because the looming Pictet-Spengler reaction requires the
presence of acid-stable hydroxyl protecting groups, the
MOM-ether residues within compound 21 were removed
using aqueous HCl in methanol and the ensuing diol 22
(73%) subjected to reaction with triphosgene.20 Use of this
reagent not only resulted in the conversion of the cis-diol
Given the availability of the enantiomeric forms of starting
materials 3a and 3b,13 the work detailed above will also
(20) Banwell, M. G.; Coster, M. J.; Harvey, M. J.; Moraes, J. J. Org.
Chem. 2003, 68, 613.
(21) Pancricine. Dictionary of Natural Products; Buckingham, J., Ed.;
Chapman & Hall: London, U.K., 1994; Vol. 4, p 4432, entry P-00106.
Org. Lett., Vol. 9, No. 18, 2007
3505

provide access to (-)-brunsvigine. Moreover, it seems
reasonable to suggest that rather straightforward modifica-
tions to the reaction sequences defined above should permit
the efficient preparation of many other members of the
montanine alkaloid class. Work directed to such ends is now
underway in these laboratories, and results will be reported
in due course.
Supporting Information Available: Preparation and
characterization of selected compounds; atomic displacement
ellipsoid plots together with certain other materials derived
from the single-crystal X-ray analyses of compounds 8a, 9b,
and (+)-1 (CCDC numbers 632321, 632322, and 641134,
respectively); and 1H or 13C NMR spectra of compounds 11a,
11b, 14a, 14b, 20, 25, and (+)-1. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for generous
financial support.
OL071344Y
3506
Org. Lett., Vol. 9, No. 18, 2007