Total synthesis guided structure elucidation of (+)-psychotetramine

Article abstract of DOI:10.1002/anie.201008048

Solving the puzzles: Total synthesis played a key role in the elucidation of the stereochemistry and verification of the constitution of the complex polymeric natural product psychotetramine. The route features three powerful assembly processes that enabl

Full text of DOI:10.1002/anie.201008048

Communications
DOI: 10.1002/anie.201008048
Natural Product Synthesis
Total Synthesis Guided Structure Elucidation of
(+)-Psychotetramine**
Klement Foo, Timothy Newhouse, Ikue Mori, Hiromitsu Takayama, and Phil S. Baran*
Polymeric tryptamine-based alkaloids belong to a structurally
and biologically fascinating class of natural products.[1]
Whereas the vast majority of such molecules are linked
ꢀ
through C C bonds, a small subset are linked from the C3 of
one indole nucleus to the N1 of another. Psychotetramine (1,
Scheme 1A) represents the curious case of a tryptamine
ꢀ
tetramer containing both types of connectivity: a C3 C3
ꢀ
linked dimer bonded to a C3 N1 dimer through an unusual
ꢀ
C7 N1 linkage. This interesting alkaloid was isolated in
2004,[2] but due to the limited quantity from nature and its
complicated NMR spectra, a final chemical structure includ-
ing stereochemistry was not determined. Here, a joint venture
between our groups (H.T. and P.S.B.) is described, leading to
the total synthesis and final structure elucidation of 1. The
pursuit of this complex natural product also led to an efficient
enantioselective synthesis of the related alkaloid (+)-psycho-
trimine, an improved procedure for direct-indole aniline
coupling, and one of the most complex and demanding
contexts for a Buchwald-Hartwig amination.
Psychotetramine (1) was isolated from a rubiaceous plant,
Psychotria rostrata, and exhibited ½aꢁ2D5 = + 82 (c = 0.2,
CHCl3). The molecular formula (C44H50N8), obtained by
high-resolution FABMS analysis as well as the 13C NMR
spectrum (see Supporting Information), revealed 26 aromatic
carbons and 18 sp3 carbons, including three aminoacetal
carbons, indicated that 1 composed of four tryptamine-related
moieties containing one indole and three indoline chromo-
phores. Detailed analyses of MS fragment pattern (Support-
ing Information) and 2D-NMR data indicated the presence of
ꢀ
ꢀ
a chimonanthine unit, joined together by a N1 C7 and a C3
N1 linkage, respectively. This type of linkage at the chimo-
nanthine aniline nitrogen is the first reported of hitherto
known polymeric tryptamine-related alkaloids.[1] A final
chemical structure including relative and absolute stereo-
chemistry could not be determined by spectroscopic means.
Scheme 1. Modular retrosynthetic analysis for rapid structure elucida-
tion.
[*] K. Foo, T. Newhouse, Prof. P. S. Baran
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
Psychotetramine (1) is a challenging target, especially
without configurational assignment of its six stereogenic
centers and the practical demands of molecules with high
nitrogen content. Since the three pyrrolidine subunits of 1
must be cis-fused, there are eight possible stereoisomers (four
pairs of enantiomers). The stereochemical determination and
constitutional assignment of 1 was systematically accom-
plished through four “rounds” of total synthesis as graphically
summarized in Scheme 1B.
E-mail: pbaran@scripps.edu
I. Mori, Prof. H. Takayama
Graduate School of Pharmaceutical Sciences
Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
[**] Prof. Stephen L. Buchwald is gratefully acknowledged for advice and
generous samples of ligands. Funding for this work was provided by
Bristol-Myers Squibb, the NIH/NCI (CA134785) and A*STAR for a
predoctoral fellowship to K.F.
In order to systematically elucidate the structure of 1, a
modular retrosynthetic plan was devised (Scheme 1A). The
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008048.
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ꢀ
Table 1: Optimization table for indole–aniline coupling.
C7 N1 linkage was ruptured leading to two fragments of
equal size and complexity (2 and 3). The union of fragments 2
and 3 was anticipated to test the limits of the Buchwald–
Hartwig amination.[3] Fragment 2, a chimonanthine deriva-
tive, could be fashioned rapidly as a mixture of isomers using
Takayamaꢀs procedure for dimerization[4] or controllably in
Movassaghiꢀs elegant stepwise procedure.[1q] Fragment 3, an
intermediate in the total synthesis of psychotrimine,[5] could
be made in both racemic and enantiopure fashion by using the
direct indole-aniline coupling of o-iodoaniline to 5, followed
by Larock annulation on adduct 4.
In round 1, two diastereomers (6 and 7) were synthesized
using a meso-chimonanthine fragment (in blue) and a racemic
truncated psychotrimine fragment 3 (in green and black).
However, neither of these structures matched the spectral
data of psychotetramine (1). In round 2, the racemic d,l-
chimonanthine series was coupled to the racemic truncated
psychotrimine portion 3 to deliver diastereomers (9 and 10),
one of which matched the spectral data of psychotetramine.
Up until this point, the Takayama procedure for dimerization
was employed since his rapid procedure allowed us to draw
some conclusions quickly. In round 3, reasoning that the
chimonanthine portion would correspond to the naturally
occurring l-series, diastereomers 11 and 1 were synthesized
by using Movassaghiꢀs procedure to procure fragment 12.
Gratifyingly, one of those diastereomers matched psychote-
tramine (1), and thus, the final round involved the truncated
psychotrimine fragments being synthesized in an enantiopure
fashion leading to the finding that the structure of psychote-
tramine corresponds to 1 (see box, Scheme 1B). Notably, the
top portion of 1 has the same absolute configuration as that of
psychotrimine (23) as determined by Takayama et al. in their
enantiospecific synthesis.[5c] Albeit speculative, this may
suggest similar biosynthetic pathways of the two natural
products.
The total synthesis of (+)-1 is illustrated in Scheme 2 and
is representative (in terms of overall approach) of the
syntheses of those preceding it (rounds 1–3, Scheme 1B).
Beginning with 7-bromo-d-tryptophan derivative ((ꢀ)-13, see
Supporting Information for preparation), direct indole–ani-
line coupling with o-iodoaniline would furnish the required
adduct (+)-14. However, previously reported conditions[5a,d]
on (ꢀ)-13 (see Table 1, entries 1–5) failed to give adduct (+)-
14 in reasonable yield. Drawing inspiration from our mech-
anistic studies and previous reports on electrophilic vicinal
difunctionalizations of tryptamines,[6] it was found that
Brønsted acids effectively promoted the reaction, affording
(+)-14, even at temperatures as low as ꢀ358C with greater
than 20:1 d.r. (entries 6–11). This contrasted with previously
reported conditions[5a,d] wherein reasonable conversions did
not proceed until above 08C (entries 4 and 5). The best result
was obtained with the use of PPTS as an additive, delivering
(+)-14 in 66% yield (entry 6). Interestingly, these newly
developed conditions also improved the yield on the non-
brominated analog 25 (entries 12 and 13), brominated and
non-brominated Boc-Trp-OMe products 26 and 27
(entries 14–18), as well as the previously reported brominated
tryptamine derivative product 28 (entries 19–21). The versa-
tility of this new indole-aniline coupling procedure is further
[a]
Product
No. Conditions
%
14
X=Br
Y=NCO2Me
Z=CO2Me
1
2
3
4
5
NIS (1.5 equiv), ꢀ45 to ꢀ358C
0
0
0
NIS (1.1 equiv), EtNO2, ꢀ788C
Koser’s reagent (3.0 equiv), 08C
NIS (3.5 equiv), Et3N (1.2 equiv), 0 to 238C 32[b]
NIS (1.5 equiv), MeOH:MeCN (1:20), ꢀ45 33[b]
to 38C
6
7
8
9
NIS (1.6 equiv), PPTS (1.0 equiv), ꢀ45 to
66
ꢀ358C
NIS (1.6 equiv), (ꢂ)-CSA (1.0 equiv), ꢀ45 46
to ꢀ358C
NIS (1.6 equiv), TsOH (1.0 equiv), ꢀ45 to 30
ꢀ358C
NIS (1.6 equiv), TFA (1.0 equiv), ꢀ45 to
ꢀ358C
23
10 NIS (1.6 equiv), Sc(OTf)3 (1.0 equiv), ꢀ45 58
to ꢀ358C
11 NIS (1.6 equiv), AcOH (1.0 equiv), ꢀ45 to 23
ꢀ358C
25, X=H
Y=NCO2Me
12 NIS (1.5 equiv), MeOH:MeCN (1:20),
68
ꢀ458C
Z=CO2Me 13 NIS (1.6 equiv), PPTS (1.0 equiv), ꢀ45 to
ꢀ358C
75
26, X=Br
Y=NBoc
Z=CO2Me
14 NIS (3.5 equiv), Et3N (1.2 equiv), 0 to 238C 24[b]
15 NIS (1.5 equiv), MeOH:MeCN (1:20),
22[c]
ꢀ458C
16 NIS (1.6 equiv), PPTS (1.0 equiv), ꢀ45 to
ꢀ358C
64
27, X=H
Y=NBoc
17 NIS (1.5 equiv), MeOH:MeCN (1:20),
79[d]
ꢀ458C
Z=CO2Me 18 NIS (1.6 equiv), PPTS (1.0 equiv), ꢀ45 to
94
ꢀ358C
28
X=Br
19 NIS (3.5 equiv), Et3N (1.2 equiv), ꢀ45 to
ꢀ358C
24
Y=NCO2Me 20 NIS (3.5 equiv), Et3N (1.2 equiv), ꢀ45 to
61–
67[d]
70
Z=H
238C
21 NIS (1.6 equiv), PPTS (1.0 equiv), ꢀ45 to
ꢀ358C
29, X=H
Y=O, Z=H
22 NIS (1.6 equiv), PPTS (1.0 equiv), ꢀ45 to
ꢀ358C
56
[a] Yield of isolated products. [b] No conversion was observed until
warmed above 08C. [c] A d.r. of 1.2:1 was observed. [d] Best yields
previously reported. All reactions were run on at least 20 mg scale and in
MeCN as solvent, unless otherwise stated. A d.r. of >20:1 was observed
unless otherwise stated. Either enantiomer of 13 was used in the
optimization study to obtain 14. NIS=N-iodosuccinimide, PPTS=pyr-
idinium p-toluenesulfonate, CSA=camphorsulfonic acid.
exemplified by the successful transformation of tryptophol to
give compound 29 in 56% yield.
Subsequent Larock annulation[7] of (+)-14 led to trypt-
amine-tryptophan dimer (+)-16 in 46% yield. Following
saponification with aqueous KOH and Barton decarboxyla-
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Communications
Scheme 2. Total synthesis of (+)-psychotetramine (1) and (+)-psychotrimine (23). Reagents and conditions: a) PPTS (1.0 equiv), o-iodoaniline
(1.2 equiv), NIS (1.6 equiv), MeCN, ꢀ458C to ꢀ358C, 66%; b) Pd(OAc)2 (0.21 equiv), LiCl (0.9 equiv), 15 (2.7 equiv), Na2CO3 (2.6 equiv), DMF,
1028C, 1 h, 46%; c) 5n aq KOH, THF/MeOH (1:2), 238C, 1 h; d) THF/MeCN (2:1), iBuOCOCl (1.2 equiv), NMM (1.0 equiv), 08C then 238C,
15 min, then 08C, 18 (1.2 equiv), Et3N (1.0 equiv), 15 min, then tBuSH (10 equiv), hn, 10 min, 238C, 72% from 16; e) CuI (0.32 equiv), K2CO3
(7.0 equiv), 20 (0.60 equiv), 21 (3.0 equiv), 1,4-dioxane, 1018C, 9 h, 89%; f) Red-Al (16 equiv), toluene, 1108C, 5 min, 89%; g) [Pd2(dba)3]
(5 mol% based on 19), RuPhos (20 mol% based on 19), NaOtBu (2.7 equiv), 12 (0.38 equiv), PhMe, 1008C, 5 h, 41% from 12; h) AlH3
(26 equiv), THF, 608C, 5 min, 68%. MeCN=acetonitrile, DMF=N,N-dimethylformamide, THF=tetrahydrofuran, NMM=N-methylmorpholine.
tion,[8] enantiopure (+)-19 was in hand without any sign of
debromination under the optimized conditions in 72% yield
over two steps. The key subunit coupling of the truncated
psychotrimine portion (+)-19 with chimonanthine derivative
(+)-12[1q] was accomplished via an unusually complex Buch-
wald–Hartwig amination.[3] It is noteworthy that amination
between two sterically congested coupling partners, in this
case between an indoline nitrogen (of chimonanthine (+)-12)
and an ortho substituted aryl halide (+)-19, in the presence of
a total of four N-Hꢀs, is a challenging task that required
significant optimization; a selected listing of parameters that
were screened is shown in Table 2.
solvent all proved to be less effective. The water-mediated
catalyst preactivation protocol[10b] was also unsuccessful.
Initially, it was hypothesized that the yield of the reaction
was hampered by rapid debromination of the truncated
psychotrimine fragment (+)-19. Means to reduce debromi-
nation, such as the slow addition of the [Pd2(dba)3], were
unsuccessful. Using a large excess of the chimonanthine-
derived fragment (+)-12 also failed to improve the yield of
the reaction. Gratifyingly, the yield of the reaction improved
to 41% using an excess (2.6 equiv, 47% of which is
recoverable) of (+)-19 rather than the chimonanthine frag-
ment (+)-12.
Thus, it was found that RuPhos[3c] provided the best results
The total synthesis was completed using alane[11] to
reductively convert the methylcarbamate groups into the
methyl groups expressed in the natural product (+)-1. With a
scalable route to enantiopure (+)-19 in hand, an enantiose-
lective total synthesis of psychotrimine (23) was also pursued.
as compared to that of other Buchwald ligands known to form
[9]
ꢀ
C N bonds such as XPhos and SPhos. Buchwaldꢀs recent
modified procedure[10a] using LHMDS and the use of weaker
bases[3f] such as Cs2CO3 and K2CO3 in tBuOH or toluene as
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Table 2: Optimization table for Buchwald–Hartwig amination of 19.
[1] Vinblastine: a) H. Ishikawa, D. A. Colby, S. Seto, P. Va, A. Tam,
H. Kakei, T. J. Rayl, I. Hwang, D. L. Boger, J. Am. Chem. Soc.
2009, 131, 4904; b) S. Yokoshima, T. Ueda, S. Kobayashi, A.
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Langlois, Y. Langlois, P. Potier, J. Am. Chem. Soc. 1979, 101,
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McHugh, C. A. Boulet, Heterocycles 1988, 27, 1845; e) M. E.
Kuehne, P. A. Matson, W. G. Bornmann, J. Org. Chem. 1991, 56,
513; f) P. Magnus, J. S. Mendoza, A. Stamford, M. Ladlow, P.
Willis, J. Am. Chem. Soc. 1992, 114, 10232. Asperazine: g) S. P.
Govek, L. E. Overman, J. Am. Chem. Soc. 2001, 123, 9468;
h) S. P. Govek, L. E. Overman, Tetrahedron 2007, 63, 8499.
Quadrigemine C: i) A. D. Lebsack, T. J. Link, L. E. Overman,
B. A. Stearns, J. Am. Chem. Soc. 2002, 124, 9008. Himastatin:
j) T. M. Kamenecka, S. J. Danishefsky, Angew. Chem. 1998, 110,
3164; Angew. Chem. Int. Ed. 1998, 37, 2993; k) T. M. Kame-
necka, S. J. Danishefsky, Angew. Chem. 1998, 110, 3166; Angew.
Chem. Int. Ed. 1998, 37, 2995; l) T. M. Kamenecka, S. J.
Danishefsky, Chem. Eur. J. 2001, 7, 41. Perophoramidine:
m) J. R. Fuchs, R. L. Funk, J. Am. Chem. Soc. 2004, 126, 5068.
Chimonanthine: n) J. B. Hendrickson, R. Gꢁschke, R. Rees,
Tetrahedron 1964, 20, 565; o) A. I. Scott, F. McCapra, E. S. Hall,
J. Am. Chem. Soc. 1964, 86, 302; p) J. T. Link, L. E. Overman, J.
Am. Chem. Soc. 1996, 118, 8166; q) M. Movassaghi, M. A.
Schmidt, Angew. Chem. 2007, 119, 3799; Angew. Chem. Int. Ed.
2007, 46, 3725. Haplophytine: r) H. Ueda, H. Satoh, K.
Matsumoto, K. Sugimoto, T. Fukuyama, H. Tokuyama, Angew.
Chem. 2009, 121, 7736; Angew. Chem. Int. Ed. 2009, 48, 7600;
s) K. C. Nicolaou, S. M. Dalby, S. Li, T. Suzuki, D. Y. K. Chen,
Angew. Chem. 2009, 121, 7752; Angew. Chem. Int. Ed. 2009, 48,
7616. Communesin F: t) J. Yang, H. Wu, L. Shen, Y. Qin, J. Am.
Chem. Soc. 2007, 129, 13794.
Entry
Ligand
Base (equiv)
12/19 (equiv)
Yield[a]
1[b]
2
RuPhos
SPhos
XPhos
NaOtBu (2.5)
NaOtBu (2.5)
NaOtBu (2.5)
LHMDS (3.0)
K2CO3 (5.0)
NaOtBu (2.5)
NaOtBu (2.5)
NaOtBu (4.0)
NaOtBu (4.0)[f]
NaOtBu (3.0)[f]
NaOtBu (2.7)[f]
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
3.0:1
1:3.0
1:2.0
1:2.6
30
<30
<20
trace
<15
trace
10–16
10
3
4[c]
5
RuPhos
RuPhos
P(tBu)3·HBF4
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
6[d]
7[e]
8[e]
9[e]
10[e]
11[e]
32[g]
17[g]
41[g]
[a] Yield of isolated products. [b] Slow addition of [Pd2(dba)3] has no
effect on yield. [c] Reaction was performed at 658C in THF.[10a] [d] Pd-
(OAc)2 (5 mol%) was used with ligand (6 mol%). [e] Reaction was
performed on at least 10 mg scale of 19. [f] Base equivalents based on
12. [g] Yield based on 12. All reactions were run with 5 mg of 19 unless
otherwise stated. Reactions were monitored with LC-MS for a maximum
of 12 h. Other solvents (tBuOH, 1,4-dioxane), temperature, and amount
of base (molar sum of 12 + 19) were screened.
Thus, copper-mediated amination of (+)-19 with the known
tryptamine derivative 21, followed by reduction of the
methylcarbamate groups using Red-Al furnished psychotri-
mine (+)-23 rapidly, ½aꢁ2D0 = + 193 (c = 1.0, CHCl3) (natural
½aꢁD18 = + 179 (c = 0.2, CHCl3).[5c] This represents the shortest
and highest yielding route to enantiopure psychotrimine (23)
(9 steps, 7% overall from 7-bromoindole).
[2] The absolute configuration of psychotetramine is not known,
see: I. Mori, M.S. Thesis, Chiba University, Japan, 2004.
[3] a) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534; b) M. D.
Charles, P. Schultz, S. L. Buchwald, Org. Lett. 2005, 7, 3965;
c) J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc. 2004, 126,
13028; d) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald,
Acc. Chem. Res. 1998, 31, 805; e) J. F. Hartwig, Acc. Chem. Res.
1998, 31, 852; f) J. P. Wolfe, S. L. Buchwald, Tetrahedron Lett.
1997, 38, 6359.
Synthetic psychotetramine (1) was spectroscopically sim-
ilar to the spectra recorded in 2004 for nat-1 but it was not
1
identical. Although the H NMR spectrum is a nearly exact
match to that reported by Takayama et al., the 13C NMR
spectrum had several small differences (mainly in the N-Me
1
region). It was found that the H NMR spectrum displayed
small differences as a function of concentration and solvent
batch. The structure was finally secured and confirmed to be
identical to nat-1 upon repurification of the last remaining
sample of nat-1 followed by both co-HPLC and NMR with a
synthetic sample.
In conclusion we have reported a solution to the
stereochemical puzzle posed by psychotetramine (1) and the
shortest and most efficient route thus far to access enantio-
pure psychotrimine (23). Along the way, a new general
protocol was invented for the direct aniline–indole coupling
that utilizes PPTS as a crucial additive. Overall, the described
total synthesis showcases the utility of a modular approach to
the synthesis of chimonanthine–psychotrimine hybrids
through three powerfully simplifying assembly events: homo-
dimerization of tryptophan,[1q,4] heterocoupling of tryptophan
with o-iodoaniline,[5a,d] and Buchwald–Hartwig amination.[3]
[4] H. Ishikawa, H. Takayama, N. Aimi, Tetrahedron Lett. 2002, 43,
5637.
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Received: December 20, 2010
Revised: January 17, 2011
Published online: February 17, 2011
[11] Alane was found to be far superior to Red-Al in terms of ease of
purification, conversion, and yield.
Keywords: natural products · structure elucidation ·
total synthesis
.
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