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.
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Org. Lett., Vol. 9, No. 18, 2007