Polyene cyclizations to indole diterpenes. The first synthesis of (+)-emindole SA using a biomimetic approach

Article abstract of DOI:10.1016/S0040-4039(00)01528-8

A biomimetic synthesis of the indole diterpene emindole SA (5) has been achieved via Lewis acid promoted polyene cyclization. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01528-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9419–9423
Polyene cyclizations to indole diterpenes. The first synthesis
of (+)-emindole SA using a biomimetic approach†
Jon D. Rainier‡ and Amos B. Smith III*
Department of Chemistry, The University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Received 31 August 2000; accepted 11 September 2000
Abstract
A biomimetic synthesis of the indole diterpene emindole SA (5) has been achieved via Lewis acid
promoted polyene cyclization. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: indole alkaloids; acid-promoted polyene cyclization; biomimetic synthesis.
Paspaline (1) and paspalicine (2), the first members of the family of fungal indole diterpenes,
were isolated in 1966 by Fehr and Acklin in the Arigoni laboratories from the ergot fungus
Claviceps paspali.1 Subsequently, other indole diterpene fungal metabolites having a similar
framework were also isolated [cf. paspalinine (3)2 and penitrem A (4)3] and shown to possess
significant tremorgenic activity.
H
O
H
O
OH
OH
N
H
N
H
N
H
H
O
H
O
OH
H
H
1 Paspaline
Claviceps paspali
4 Penitrem A
H
H
OH
6 Emindole DA
Penicillum cyclopium
Emericella desortorum
O
N
H
N
N
R
H
H
H
H
H
O
OH
O
5 Emindole SA
7 Emindole DB
O
2 R = H: Paspalicine
H
Emericella striata
Emericella desortorum
3 R = OH: Paspalinine
Claviceps paspali
* Corresponding author.
†
This article is dedicated to Professor Harry H. Wasserman, colleague and friend, on the occasion of his 80th
birthday.
‡ Present address: Department of Chemistry, The University of Arizona, Tucson, AZ 85721, USA.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01528-8

9420
In 1977 Arigoni and coworkers, exploiting 13C labeled intermediates, reported that paspaline
(1), the common biosynthetic precursor of these metabolites, is formed via condensation of
tryptophan and geranylgeranylpyrophosphate.4 Presumably, subsequent dealkylation of the
amino acid side chain and selective epoxidation of the internal olefin provides the polyene
cyclization precursor 8. Transformation of 8 into the paspaline precursor 11 in turn comprises
an intriguing process not only involving a polyene cyclization to 9 but also skeletal rearrange-
ment to 10 (Scheme 1).
HN
N
HN
O
H
OH
OH
10
8
9
N
N
H
H
H
OH
O
OH
H
H
11
Paspaline (1)
Scheme 1.
It also appears that fungi are capable of inducing a more conventional polyene cyclization of
8. After isolating the emindoles SA,5 DA,6 and DB7 in the late 1980s, Kawai and coworkers
proposed that these indole diterpenes also arise from 8 but via tertiary carbocation 12 instead
of the secondary cation 9 (Scheme 2).5
H
8
N
N
H
H
H
H
OH
OH
Emindole SA (5)
12
Scheme 2.
Our long standing interest in the chemical synthesis of indole terpenes8–10 led us to consider
a biomimetic approach to these targets. The development of a polyene cyclization approach to
both the emindoles and to paspaline would clearly demonstrate the viability of the proposed
biosyntheses. In addition, it seemed reasonable that a polyene cyclization of an appropriately
functionalized indole diterpene might lead to an efficient entry into this class of natural
products.11 Herein we report our initial experiments in this area, including the first total
synthesis of (+)-emindole SA (5).

9421
Synthesis of the requisite polyene cyclization precursor (−)-18 from geraniol is illustrated in
Schemes 3 and 4. Noteworthy in the generation of (−)-18 is the efficient utilization of two
molecules of geraniol, the introduction of an epoxide at an internal olefin, and the selective
removal of the allylic sulphone in the presence of the epoxide.
Sulphone 1312 (Scheme 3) is available in four steps from geranyl acetate. Hydrolysis of the
acetate, conversion of the resulting allylic alcohol to the corresponding allylic bromide,13 and
displacement of the bromide with indole magnesium bromide14 afforded 14. Protection of the
indole nitrogen as the corresponding sulphonamide15 then provided indole 15 in 34% overall
yield for the four steps.
SO2Ph
SO2Ph
1. Na2CO3, MeOH, 80%
2. NBS, DMS, CH2Cl2, -20°C
3. indole, EtMgBr, PhH, rt
60% (2 steps)
OAc
N
R
13
14: R = H
PhSO2Cl, 50% KOH (aq)
Bu4NHSO4, PhH, rt
72%
15: R = SO2Ph
Scheme 3.
The anionic coupling of 15 with iodo epoxide (−)-16 (available in three steps from geraniol)16
afforded a 1:1 mixture of sulphone diastereomers 17 in 83% yield (Scheme 4). The use of DMEU
R
LDA (4eq),
DMEU (10eq),
THF, -78°C;
O
15
I
O
N
(-)-16
SO2Ph
(83%)
1. EtNH2: Et2O (3:1)
17: R = SO2Ph
(-)-18: R = H
Li, -78°C; MeOH
(63%)
2. PhSO2Cl, KOH
Bu4NHSO4
(95%)
Scheme 4.

9422
in this coupling proved essential, as the absence led to a dramatic reduction in yield (15% yield).
Reductive removal17 of both the indole and allylic phenyl sulphone groups in the presence of the
epoxide provided the polyene cyclization precursor (−)-18 in 60% yield, after reprotection of the
indole. When the reduction was carried out in the absence of ether (i.e. neat EtNH2) or at
temperatures higher than −78°C, competitive reduction of the epoxide occurred.
With ready access to polyene (−)-18, we investigated a wide variety of acidic conditions to
effect cyclization. Our best results were achieved with stoichiometric quantities of BF3·Et2O at
−40°C in CH2Cl2. These conditions led to a modest 20% yield of inseparable bicyclic material.18
Upon removal of the phenyl sulphonyl protecting group, the mixture could be separated to
provide emindole SA (5) in 8% yield for the two steps.19 Importantly, an additional 50% of the
bicyclic material consisted of two isomeric compounds (ca. 1:1), which have tentatively been
assigned as the endocyclic alkene isomers (Scheme 5).
1. BF3•Et2O, CH2Cl2
-40°C
20%
+ olefin isomers
(-)-18
2. Et2NH, Li
75%
N
H
H
H
OH
Emindole SA (5)
Scheme 5.
In summary, this study indicates that polyene cyclizations can be used to access indole
diterpenes, although at present the yield is modest. Further studies on this biomimetic process
including investigations of cyclizations leading to paspaline and emindole DA, and efforts to
improve the yield of polycyclic material are ongoing in our laboratory.
Acknowledgements
Financial support by the National Institutes of Health (Institute of General Medical Sciences)
through grant GM-29028 is acknowledged. J.D.R. gratefully acknowledges the National Insti-
tutes of Health (National Cancer Institute) for a postdoctoral fellowship. In addition, we thank
Professor Ken-ichi Kawai (Hoshi University) for graciously providing an authentic sample of
(+)-emindole SA.
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9423
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1
19. Synthetic (+)-emindole SA (5) was identical [TLC, H and 13C NMR, UV, IR, and mass spectral analyses, and
optical rotation [h]2D0 +30.2 (c 0.14, CH3OH); lit.2 [h]D20 +32.0 (c 1.0, CH3OH)] with an authentic sample
generously provided by Professor Kawai (Hoshi University).
.