J. Am. Chem. Soc. 2000, 122, 7827-7828
General Approach for the Synthesis of Indole
7827
Alkaloids via the Asymmetric Pictet-Spengler
Reaction: First Enantiospecific Total Synthesis of
(-)-Corynantheidine as Well as the Enantiospecific
Total Synthesis of (-)-Corynantheidol,
(-)-Geissoschizol, and (+)-Geissoschizine
Figure 1. Structure of (-)-corynantheidine, (-)-corynantheidol, (-)-
geissoschizol, and (+)-geissoschizine.
Shu Yu, Otto Mathias Berner, and James M. Cook*
The synthesis of the common intermediate is outlined in
Scheme 1. The benzyl ester of D-tryptophan (5) was prepared on
300 g scale in 96% yield according to a modified literature
procedure.13 Monoalkylation of the Nb-amino moiety with allylic
Department of Chemistry, UniVersity of Wisconsin-Milwaukee
Milwaukee, Wisconsin 53211
ReceiVed May 15, 2000
Corynantheidine 1 was first isolated in 1944 by Janot et al.
from the African plant Pseudocinchona africana,1 and the
structure was determined by the same group.2 A number of partial
and total syntheses of 1 have been reported, all of which resulted
in racemates.3 The related corynantheidol 2 was obtained from
Mitragyna parVifolia (Roxb.) Korth. (Rubiaceae).4a Although
several total syntheses of 2 have been realized,5 only one approach
was enantioselective (up to 86% ee); Meyers and co-workers
completed this route in 1991 in excellent overall yield (16.4%).6
Geissoschizol 3 has been isolated from Hunteria zeylanica Var.
africana,7 and many elegant syntheses have been reported,5b,8 at
least one of which was enantioselective.8a Geissoschizine 4,
historically one of the most important intermediates in the
biosynthesis of monoterpene indole alkaloids,10a has been obtained
from a number of plants.11 Because of the biosynthetic importance
of 4, its structural complexity, and the scarce availability from
natural sources, there have been many important total syntheses
of this natural product.9,10 Among these, those of Winterfeldt,
Overman, and Martin were enantioselective.8a,10
Scheme 1. Preparation of the Common Intermediate 12
bromide 6, a building block prepared earlier by Ensley14a and
employed by Bosch,14b Rawal,8b,15 as well as Kuehne,16 was
achieved in excellent yield, employing 5 and 6 at high concentra-
tion in the presence of a slight excess of the benzyl ester 5. The
stereospecific, enantiospecific construction of the chiral center
at C-112 in 9 was achieved by employing a modification of the
asymmetric Pictet-Spengler reaction.12 When a solution of
aldehyde 817 and 1 equiv of benzyl ester 7 was stirred in methylene
chloride in the presence of TFA, this provided the tetrahydro-â-
carboline 9 in 95% yield with complete trans-transfer of chirality12
from C-3 to C-1. No cis-isomer was detected under these
conditions. In Overman’s elegant synthesis of (+)-geissoschizine,10a
a similar reaction was attempted wherein the Nb-nitrogen atom
in 7 was devoid of the alkyl substituent. In that case, a moderate
(40%) yield was reported with a trans- to cis- ratio of ap-
proximately 1:4. The results (see 9) described herein provide
further evidence of the strong directing and accelerating effect
of the large alkyl group12 on the Nb-nitrogen atom on the
stereoselectivity of the asymmetric Pictet-Spengler reaction.12
This suggests that a bulky substituent on the Nb-nitrogen atom is
the only requirement necessary to achieve 100% diastereoselec-
tivity in the Pictet-Spengler reaction of carbonyl compounds with
tryptophan alkyl esters. With tetrahydro-â-carboline 9 in hand,
the desired R,â-unsaturated ester 12 was readily prepared in good
yield via a series of standard transformations including removal
of one equivalent of thiophenol from 9 followed by an oxidation
(see 10 f 11), sulfoxide elimination sequence (see Scheme 1).17
In this contribution, the first enantiospecific total synthesis of
(-)-corynantheidine (1) as well as an efficient enantiospecific
total synthesis of (-)-corynantheidol (2), (-)-geissoschizol (3),
and (+)-geissoschizine (4) from a common intermediate are
described (Figure 1). The stereochemical integrity of these natural
products was guaranteed via the trans transfer of asymmetry via
a new extension of the asymmetric12 Pictet-Spengler reaction.
(1) Janot, M.-M.; Goutarel, R. C. R. Acad. Sci. 1944, 218, 852.
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Chim. Acta, 1955, 38, 1073.
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Chim. Acta, 1957, 40, 1793.
(5) (a) Imanishi, T.; Inoue, M.; Wada, Y.; Hanaoka, M. Chem. Pharm.
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(10) (a) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989, 111,
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10.1021/ja0016553 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/28/2000