Our retro-synthetic analysis, Scheme 1, would require a
facile method for the synthesis of perhydroindole 7. We
envisioned that coupling of an aryl organometallic species
nolone and perhydrobenzazepinone skeletons are the core
structures of several important classes of natural products,
including the Aspidosperma and Stemona alkaloids.12
Having developed a reliable procedure for synthesis of
perhydroindolone unit 14a, we turned our attention to the
total synthesis of (-)-brunsvigine. Required chiral enone 15
was obtained from (-)-quinic acid in five steps using
published procedures.13 Chiral enone 15 was then smoothly
transformed into R-iodo enone 16 using Johnson’s method.14
Luche reduction15 of iodo enone 16 in methanol at 0 °C
afforded a mixture of epimeric allylic alcohols 17 and 18 in
a ratio of 71:29 with 92% combined yield, Scheme 3.
Scheme 1
Scheme 3
with perhydroindole 7 followed by a Pictet-Spengler cy-
clization would provide the core structure of brunsvigine and
related natural products 2-6. Compound 7 could be prepared
from iodo allylic alcohol 9 and a glycine unit 10 via
Mitsunobu coupling (9 + 10 f 8) followed by anionic
cyclization (8 f 7).
We began our investigation with the development of an
efficient synthesis of perhydroindolone skeleton 14 (Scheme
2). Allylic alcohol 1110 was first converted into the required
Scheme 2
R-Isomer 17 was separated and converted into the required
â-allylic alcohol 18 using Mitsunobu’s procedure.11b Com-
pound 18 was then reacted with compound 12a under
Mitsunobu’s conditions to give 19 in 92% yield. When
treated with n-BuLi under standard conditions, compound
19 underwent anionic cyclization to give enone 20 in 73%
yield. Sodium borohydride reduction of chiral enone 20 under
Luche conditions15 afforded a single diastereomer, which was
then converted into the corresponding pivaloate ester 21,
Scheme 4.
Weinreb amide intermediate 13a using a Mitsunobu proto-
col.11 Treatment of 13a with n-BuLi affected metalation and
anionic cyclization to give perhydroindolone 14a in 74%
overall yield. Similarly, compound 11 was reacted with
compounds 12b and 12c to afford compounds 13b and 13c.
Metalation of 13b and 13c followed by anionic cyclization
gave perhydroquinolone 14b and perhydrobenzazepinone 14c
in 80% and 75% yields, respectively. These perhydroqui-
The stereochemistry of 21 was confirmed through single-
crystal X-ray analysis.16 CuI-promoted SN2 displacement of
(12) (a) Go¨tz, M.; Strunz, G. M. In Alkaloids: MTP International ReView
of Science; Wiesnor, K., Ed.; Series 1; Butterworths: London, 1973; Vol.
IX, p 143. (b) Hesse, M. In Alkaloid Chemistry; Wiley: New York, 1981;
pp 41, 42, 176. (c) Ye, Y.; Qin, G.-W.; Xu, R.-S. Phytochemistry 1994,
37, 1201. (d) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org.
Chem. 1998, 63, 5587.
(13) (a) Elliott, J. D.; Hetmanski, M.; Stoodley, R. J. J. Chem. Soc.,
Perkin Trans. 1 1981, 1782. (b) Rohloff, J. C.; Kent, K. M.; Postich, M. J.;
Becker, M. W.; Chapman, H. H.; Kelley, D. E.; Lew, W.; Louie, M. S.;
McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org.
Chem. 1998, 63, 4545.
(9) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions; CRC
Press: Boca Raton, FL, 1994; Chapter 4, p 169.
(10) Compound 11 was obtained via Luche reduction (see ref 15) of
2-iodocyclohex-2-en-1-one, which was prepared via iodination of cyclohex-
2-en-1-one according to Johnson’s method (see ref 14).
(11) (a) Mitsunobu, O.; Jenkins, I. D.; in Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 8,
p 5379. (b) Mitsunobu, O. Synthesis 1981, 1. (c) Uesaka, N.; Saitoh, F.;
Mori, M.; Shibasaki, M.; Okamura, K.; Date, T. J. Org. Chem. 1994, 59,
5633.
(14) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
(15) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(16) X-ray data of compound 21 will be presented in a full paper.
2178
Org. Lett., Vol. 3, No. 14, 2001