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a 2,3-dihydroxy-1,1-dimethylpropyl unit were isolated
from the basidiomycete Asporpium caryae.2 Another
class of the N-reverse prenylated indole is the tryp-
tophan derivatives 4 and 5, and the latter has a 2,3-
epoxy-1,1-dimethylpropyl unit on the indole nitrogen.
These tryptophan derivatives are found in the cyclic
peptides, rufomycins (illamycins), and some of these
peptides have shown useful antibiotic properties.3
Moreover, the novel tryptophan derivative 6 has
emerged as the anti-inflammatory cyclic peptide,
cyclomarin A (7),4 which was isolated from the
marine bacterium Streptomyces sp. by Fenical et al.
Cyclomarin A (7) is currently undergoing preclinical
trials as an anti-inflammatory and an antiviral agent
by Phytera, Inc.4b In spite of their structural novelties
and attractive biological activities, synthetic studies of
the N-reverse prenylated indole and its related com-
pounds have not been reported to date. As a part of
our program for the total synthesis of cyclomarin A
(7), we now wish to report the efficient synthesis of
the N-reverse prenylated indole and its application to
the synthesis of the antifungal indole alkaloids 2, 3
and N-reverse prenylated tryptophan 4.
verse prenylated indole (12) to the antifungal indole
alkaloids 2 and 3. The C-3 bromination of the indole
ring with NBS in DMF gave the bromide 13 in 96%
yield. Lithiation of the resulting bromide 13 with
t-BuLi followed by methoxycarbonylation afforded
the natural indole alkaloid 2 in 89% yield. Interest-
ingly, no C-2 carbonylation of the indole ring was
observed in this reaction, though some 3-lithioindoles
are known to be prone to the 32 migration of
lithium.8 We speculated that the steric hindrance at
the C-2 position of the indole ring by the N-reverse
prenyl group would cause the selective C-3 car-
bonylation.
We next investigated the conversion of 2 to the other
indole alkaloid
3
by the Sharpless asymmetric
dihydroxylation9 of the 1,1-dimethyl-2-propenyl
group. Oxidation of 2 by the standard procedure with
commercially available AD-mix-b (0.2% osmium, 1%
(DHQD)2-PHAL ligand) proceeded very slowly, but
an acceptable rate (24 h at 4°C) was obtained by
fortifying the AD-mix-b with up to 10% osmium and
10% ligand. After the work-up, we isolated more than
a 90% yield of the diol (R)-3, but the enantiomeric
excess was revealed to be only 30%.10 After screening
of the Sharpless’ AD ligands as shown in Table 1,
oxidation of 2 with (DHQD)2-PYR produced (R)-3
with an improved ee of 89%, and its absolute stereo-
chemistry was assigned to be (R) in comparison with
the optical rotation. The alkaloid (S)-3, having the
natural configuration, was also obtained with 69% ee
using the pseudoenantiomeric (DHQ)2-PYR, with the
usual decrease in the ee values upon changing from
DHQD to DHQ.
To construct the N-reverse prenylated indole 12, we
first attempted the N-propargylation of the indole fol-
lowed by partial hydrogenation of the resulting termi-
nal alkyne, the method of which was applied to the
synthesis of the N-reverse prenylated valine for the
total synthesis of muscoride A independently devel-
oped by Wipf and Pattenden.5 However, the direct
N-propargylation of the indole did not proceed at all
under the various conditions due to the low nucleo-
philicity of the indole nitrogen. Accordingly, we
used indoline (8) as a precursor of the indole. Treat-
ment of the indoline (8) with 3-acetoxy-3-methylbut-1-
yne in the presence of copper(I) chloride6 provided
the N-propargyl indoline (10) in 90% yield, as shown
in Scheme 1. The terminal alkyne 10 was partially
hydrogenated using Lindlar’s catalyst to form the
alkene 11 in 91% yield, which was oxidized to the
indole using MnO2 (CMD; chemical manganese diox-
ide)7 to afford the N-reverse prenylated indole (12) in
86% yield. Next, we tried to convert the N-re-
N-Reverse prenylated tryptophan was also synthesized
as shown in Scheme 2. After methyl esterification of
14, the reduction of the indole ring with
(CF3CO2)2BH·THF11 afforded the indoline 15 in 96%
yield. In a manner similar to our strategy, propargy-
lation with 9 followed by CMD oxidation gave the
indole 16 in good yield. Finally, partial reduction of
the terminal alkyne provided the N-reverse prenylated
tryptophan 17 as its protected form.
OAc
9
H
b
c
N
N
a
N
H
8
11
10
H
Br
CO2Me
e, f
d
N
N
N
12
13
2
Scheme 1. (a) CuCl, i-Pr2NEt, 9, THF, 50°C, 90%; (b) H2 (1 atm), Lindlar’s catalyst, MeOH, rt, 91%; (c) MnO2(CMD), toluene,
rt, 86%; (d) NBS, DMF, 96%; (e) t-BuLi, THF, −78 to 0°C; (f) ClCO2Me, −78 to 0°C, 89%.
Sugiyama, Hideyuki
