Total synthesis of (±)-psychotrimine

Article abstract of DOI:10.1021/ja8042307

A new process for the union of anilines with tryptamine derivatives has been developed, furnishing C-3 quaternized pyrroloindoline architectures. This chemoselective coupling of a tryptamine with 1.2 equiv of 2-iodoaniline proceeds efficiently on a gram-scale using only the simple reagents N-iodosuccinimide and triethylamine. Using this new reaction, the complex natural product psychotrimine has been fashioned with a rare level of efficiency and practicality. From a readily available bromotryptamine, only four steps (41-45% overall isolated yield) are necessary to procure gram quantities of the natural product. Functional group manipulations, protecting group chemistry, and unnecessary redox fluctuations have been minimized. Copyright

Full text of DOI:10.1021/ja8042307

Published on Web 07/26/2008
Total Synthesis of (()-Psychotrimine
Timothy Newhouse and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
Received June 4, 2008; E-mail: pbaran@scripps.edu
Polymeric indole alkaloids have been a subject of intense
synthetic investigation for the past 50 years, and progress in this
1
area continues unabated. In particular, oxidative (radical) dimer-
ization of indole derivatives has provided a relatively simple solution
to several classes of natural products, and it is believed that Nature
uses a similar strategy.
2
Psychotrimine (1) is a recently isolated alkaloid whose biosyn-
thesis also appears to involve a tryptophan dimerization reaction.
However, in this case, a rare example of N1-C3 (indole numbering
system) tryptophan linkage is observed in contrast to the more
common carbon-carbon linkages. The inherent preference of
indoles to oxidatively dimerize at carbon, instead of at nitrogen,
3
makes the construction of this bond uniquely challenging. Unsur-
prisingly, there are currently no known methodologies to directly
construct this type of C-N bond. Herein, we report the invention
of such a method and demonstrate its power with an exceptionally
concise synthesis of 1 that proceeds on a gram-scale with minimal
use of protection chemistry and redox manipulations.
The simplest route to 1 would involve the merger of a dimeric
tryptamine such as 2 with the hypothetical tryptamine cation 3
Figure 1. (A) Retrosynthetic analysis of 1 suggests the need to invent a
direct coupling of indoles with anilines. (B) Potential products formed in
the union of o-iodoaniline and a tryptamine derivative.
(
Figure 1A). Since no such method for this construction existed,
considerable efforts were devoted to inventing one. The direct union
of prefunctionalized and activated tryptamine and indole subunits
4
proved unsuccessful despite extensive experimentation. Attention
Table 1. Invention and Optimization of a Direct Indole-Aniline
Coupling
was turned to o-iodoaniline (4) as a potential surrogate for 3 (see
Figure 1B). In principle, an activated (oxidized) form of 4 could
react with a tryptamine derivative to furnish the desired N-C
coupled product A. Unfortunately, products B-F are seemingly
more likely to form if the tryptamine were to react with the oxidant
or if the activated form of 4 were to act as an oxidant rather than
5
6
7
3a,c,d,f
an N-electrophile. For instance, products such as B, C, D, E,
3
b,e,g,h
and F
are all known pathways during the oxidation of
tryptamines, whereas A is not.
The proposed coupling reaction was explored using 4 and
tryptophan derivative 5 (Table 1) with a variety of oxidants. Selected
results are summarized in Table 1. Most oxidants (entries 1-3)
led to complex mixtures from which the desired adduct 6 could be
8
9
isolated. The use of Koser’s reagent (entry 4), while slightly
cleaner, required a lengthy purification, was not scalable, and
required a 3-fold excess of 4. Notably, simple halogenating agents
such as NCS and NBS (entries 5 and 6) delivered 6 as the major
diastereomer using only 1.2 equiv of 4. The key finding in
rendering the reaction robust and scalable was using NIS (entry 7)
to afford the C3 aminated product in 45% isolated yield along with
a
b
c
dr ) 3:1. dr ) 10:1. dr ) 13:1 (major diastereomer is 6 in all
d
entries). ∼40% recovered 5.
1
0
last) led to only trace formation of the desired product. The observed
diastereoselectivity for the kinetically favored exo diastereomer is
consistent with the indole 2,3-π bond reacting with aniline nitrogen,
∼
40% recovered 5.
12
as has been observed with other electrophiles. In line with these
While an unambiguous mechanistic picture requires more
observations, the initially formed N-haloaniline is primed for
nucleophilic attack by the tryptamine C-3 position, giving rise to a
transient indolenine species, which after irreversible ring closure
affords the desired product.
With an effective method for forging the hallmark feature of 1
in hand, its total synthesis was pursued. Beginning with the
extensive studies, order of addition experiments strongly suggest
1
1
initial aniline halogenation. Although the optimal procedure
required addition of the oxidant to a mixture of the tryptamine and
the aniline, significant product was obtained by preforming the
N-haloaniline, whereas the inverse experiment (addition of aniline
1
0886 9 J. AM. CHEM. SOC. 2008, 130, 10886–10887
10.1021/ja8042307 CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
a
Scheme 1. Short Gram-Scale Total Synthesis of (()-Psychotrimine (1)
a
Reagents and conditions: (a) o-iodoaniline (1.2 equiv), N-iodosuccinimide (3.0 equiv), Et3N (1.2 equiv), MeCN, -45 f 23 °C, 1 h, 61-67%; (b)
Pd(OAc)2 (0.21 equiv), Na2CO3 (2.6 equiv), LiCl (0.90 equiv), 10 (2.7 equiv), DMF, 102 °C, 20 min, 85%; (c) CuI (0.32 equiv), (()-trans-N,N′-dimethyl-
1
,2-cyclohexanediamine (0.60 equiv), K2CO3 (7.0 equiv), Nb-(methoxycarbonyl)tryptamine (3.0 equiv), 1,4-dioxane, 101 °C, 9 h, 89%; (d) sodium bis(2-
methoxyethoxy)aluminum hydride (22 equiv), toluene, 110 °C, 30 min, 89%.
methylcarbamate of 7-bromotryptamine (7; available by simple
carbamoylation of the commercial amine in quantitative yield),
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1
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9
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Acknowledgment. Financial support for this work was provided
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Supporting Information Available: This material is available free
of charge via the Internet at http://pubs.acs.org.
JA8042307
J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008 10887