Copper-catalyzed diastereoselective arylation of tryptophan derivatives: Total synthesis of (+)-naseseazines A and B

Article abstract of DOI:10.1021/ja4023557

A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site-and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B.

Full text of DOI:10.1021/ja4023557

Communication
pubs.acs.org/JACS
Copper-Catalyzed Diastereoselective Arylation of Tryptophan
Derivatives: Total Synthesis of (+)-Naseseazines A and B
Madeleine E. Kieffer,† Kangway V. Chuang,† and Sarah E. Reisman*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: A copper-catalyzed arylation of tryptophan
derivatives is reported. The reaction proceeds with high
site- and diastereoselectivity to provide aryl pyrroloindo-
line products in one step from simple starting materials.
The utility of this transformation is highlighted in the five-
step syntheses of the natural products (+)-naseseazine A
and B.
he pyrroloindoline is a common structural motif that
Tunites several biosynthetically distinct families of alkaloids
(Figure 1).1 The prevalence of this indole-derived heterocyclic
framework continues to inspire the development of new
reactions for its construction,2 and these efforts have delivered
increasingly efficient total syntheses of biologically active
natural products.3 Specifically, the development of tandem
C3-functionalization/cyclization reactions of tryptamine and
tryptophan derivatives has proven to be a particularly fruitful
line of research. Such methods include a variety of oxidative
cyclization reactions4 as well as recently discovered organo-
catalyzed5 and transition-metal-catalyzed6 C−C bond-forming
processes.
Despite the advances described above, the direct preparation
of aryl-substituted pyrroloindolines has until recently remained
a challenge.7 In 2011, Movassaghi and co-workers reported a
Friedel−Crafts-type arylation of 3-bromocyclotryptophans that
provides access to aryl pyrroloindolines in two steps from the
corresponding tryptophan derivatives (Figure 2a).8 In an effort
to streamline this overall transformation further, we sub-
sequently developed a one-step synthesis of aryl pyrroloindo-
lines via Cu-catalyzed arylation of N-tosyltryptamines (Figure
Figure 2. Strategies for the formation of aryl pyrroloindolines.
2b).9 Concomitant with our studies, Zhu and MacMillan
reported a catalytic asymmetric arylation of indole-3-carbox-
amides to generate arylated 2-oxopyrroloindolines in high
yields and ee’s (Figure 2c).10 Although the latter two
methodologies provide direct access to aryl pyrroloindolines
from simple starting materials, in neither case do the products
obtained contain an appropriate carboxylate functionality for
Received: March 6, 2013
Published: March 29, 2013
Figure 1. Pyrroloindoline alkaloids.
© 2013 American Chemical Society
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a
Table 1. Optimization Studies
Table 2. Substrate Scope of Pyrroloindoline Formation
a
a
a
entry
ligand
[Ph2I]X
C3:C2
dr
yield (%)
b
1
2
−
−
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]PF6
[Ph2I]BF4
[Ph2I]AsF6
[Ph2I]OTf
−
1:1
−
3:1
0
22
15
<5
20
38
26
24
70
15
35
76
3
L1
L2
L3
L4
L5
L6
L7
L8
L9
L7
L7
L7
1:1
3:1
4
1:2
2:1
5
6:1
10:1
12:1
5:1
6
12:1
2:1
7
8
1:1
4:1
9
>20:1
1:1
>20:1
4:1
10
11
12
13
14
2:1
20:1
>20:1
>20:1
>20:1
>20:1
>20:1
81
c
>20:1
83 (85 )
a
1
Yield of major diastereomer as determined by H NMR analysis of
b
c
the crude reaction mixture. No (CuOTf)2·PhMe was used. Isolated
yield.
direct elaboration to diketopiperazine-containing natural
products such as 1−3 (Figure 1).11,12
a
Given our interest in the synthesis of such compounds, we
sought to develop a complementary diastereoselective arylation
of tryptophan derivatives (Figure 2d). We hypothesized that
reductive elimination from a CuIII−aryl complex involving
bidentate substrate coordination (e.g., 6) could permit
transmission of the stereochemical information from the
tryptophan α-carbon to the newly formed quaternary center.
Here we report the successful execution of this synthetic plan,
which enabled a concise diastereoselective synthesis of the
pyrroloindoline alkaloids (+)-naseseazines A and B.
Reactions were conducted on a 0.3 mmol scale using symmetric
[Ar2I]OTf, unless otherwise noted. Isolated yields are reported.
b
c
Ligand L6 (40 mol %) was used with [Ph2I]PF6. Nonsymmetric
[Ar(p-xylyl)I]OTf was used.
Scheme 1. Arylation of Tryptophan Carboxamide 7
We began our studies by investigating the Cu-catalyzed
arylation of cyclo-(Trp-Phe) (4a), which is readily accessible by
cyclocondensation of the corresponding amino acids.13
Exposure of 4a to 10 mol % (CuOTf)2·PhMe and 1.1 equiv
of diphenyliodonium hexafluorophosphate ([Ph2I]PF6) in
CH2Cl2 furnished pyrroloindoline 5a in low yield as a mixture
of diastereomers (Table 1, entry 2). Under these conditions, 5a
was formed in an equimolar ratio with the corresponding C2-
arylated product (not shown). A control experiment confirmed
that no reaction occurs in the absence of copper (entry 1).
In an effort to improve both the C3:C2 arylation ratio and
the diastereoselectivity, a survey of several achiral bidentate
ligands was conducted. We were pleased to find that use of
readily available bis(mesityl)-α-diimine ligand L714 MesDABMe)
(
delivers 5a in 70% yield with high C3:C2 selectivity and an
excellent level of diastereocontrol (Table 1, entry 9).
Comparison of a series of α-diimine ligands revealed that the
aryl substitution pattern exerts a significant effect on both the
yield and the C3:C2 selectivity (entries 7−9). The yield of the
reaction was further improved by using diphenyliodonium
triflate ([Ph2I]OTf) (entry 14). Under our optimal conditions,
5a was isolated in 85% yield as a single diastereomer.
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Scheme 2. Concise Total Syntheses of (+)-Naseseazines A and B
Interestingly, use of either enantiomer of the chiral bisoxazoline
ligand previously employed by Zhu and MacMillan for
enantioselective pyrroloindoline formation10 (L8 or L9) gave
poor yields and low C3:C2 arylation ratio (entries 10 and 11).
As might be expected, clear matching and mismatching
between the diketopiperazine substrate and the chiral ligand
was observed, with L9 providing higher dr and C3 selectivity.
A variety of arylated pyrroloindolines can be prepared in one
step from the corresponding diketopiperazines (Table 2). The
diketopiperazines derived from either L- or D-alanine react to
deliver diastereomeric pyrroloindolines 5b and 5c, respectively,
which possess the same configuration at the newly formed
quaternary center. This observation indicates that the chirality
at the tryptophan-derived stereogenic center is the dominant
stereocontrolling factor. The relatively modest yields of 5b and
5c reflect the poor solubility and lower reaction rates for these
substrates; in both cases, high site- and diastereoselectivity were
still observed. In contrast, the diketopiperazine cyclo-(Pro-Trp)
(4f) proved to be a challenging substrate, providing 5f in low
yield as a result of poor C3:C2 selectivity under our standard
conditions. We hypothesized that the increased rigidity of the
bicyclic diketopiperazine may result in destabilizing non-
bonding interactions with the CuI(L7)OTf catalyst. A screen
of α-diimine ligands possessing less steric encumbrance at the
ortho positions revealed that the use of CuI(L6)OTf in
conjunction with [Ph2I]PF6 restores the C3:C2 selectivity and
delivers pyrroloindoline 5f in 71% yield.
The scope of the aryl coupling partner was also investigated.
Whereas symmetric diaryliodonium salts reacted smoothly
under the reaction conditions (Table 2, products 5g−j), the use
of iodonium salts containing the more hindered mesityl
substituent as a nontransferable group15 exhibited lower
reaction rates and diminished C3:C2 selectivity under the
standard conditions. Fortunately, mitigating the steric demand
of these nonsymmetric iodonium salts by using a p-xylyl
substituent as a nontransferable group restored both the
reaction rate and site selectivity.16 Thus, with either symmetric
or p-xylyl-substituted nonsymmetric iodonium salts, a variety of
arenes bearing either electron-donating or -withdrawing
substituents at the para or meta positions could be coupled,
providing the pyrroloindolines in moderate to excellent yields
as single diastereomers. Unfortunately, ortho-substituted arenes
are not transferred efficiently and represent one limitation of
the existing methodology.
Although our initial studies focused on the arylation of
tryptophan-derived diketopiperazines, we wondered whether
the simple tryptophan carboxamide 7 would be a suitable
substrate. We were pleased to find that subjecting 7 to our
optimized reaction conditions afforded arylated pyrroloindoline
8 in 81% yield as a single diastereomer (Scheme 1). However,
upon careful analysis by a variety of NMR spectroscopic
methods, we determined that 8 possesses the opposite
configuration at the newly formed quaternary center relative
to the diketopiperazine-containing products in Table 2. At this
time, the origin of this stereodivergent reactivity remains
unclear. Nonetheless, this finding presents the exciting
opportunity to generate either enantiomeric series of
pyrroloindoline products from naturally occurring L-trypto-
phan.
To highlight the utility and efficiency of this direct arylation
methodology for the synthesis of pyrroloindoline natural
products, we sought to complete a total synthesis of the
bisindole alkaloids naseseazine A (3a) and B (3b) (Scheme 2).
To this end, diaryliodonium salt 9 containing a protected o-
bromoaniline was efficiently prepared on a gram scale from 2-
bromo-5-iodoaniline in 70% overall yield. Addition of 9 and
diketopiperazine 4f and to a prestirred solution of
(CuOTf)2·PhMe (10 mol %) and L6 (40 mol %) in CH2Cl2
(the conditions previously developed for the arylation of 4f)
delivered the desired pyrroloindoline 11 in 62% yield. This
direct and efficient procedure is easily performed on large scale
and provides the desired pyrroloindoline with excellent levels of
diastereocontrol. Although reactions conducted with the
corresponding p-xylyl iodonium salt provided higher con-
versions of 4f, the yields of 11 were lower because of
competitive transfer of the p-xylyl group. The coupling of 9 and
cyclo-(Ala-Trp) (4b) under the same conditions provided the
related pyrroloindoline 12 in 59% yield.
To complete the syntheses of 3a and 3b, diketopiperazine-
containing alkyne 10 was prepared in four steps from
commercially available N-Boc-β-iodoalanine methyl ester.
Following cleavage of the trifluoroacetamide group in 11,
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Hernandez, G.; Mendoza, R.; Larionov, O. V. Chem.Eur. J. 2012,
18, 16612.
coupling with alkyne 10 by a modified Larock indolization
procedure17,18 provided 3b in 51% yield upon acidic workup.
Elaboration of 12 by the same sequence delivered 3a in 56%
yield. Through the Cu-catalyzed arylation chemistry developed
herein, these complex polycyclic alkaloids are available in five
steps (longest linear sequence) from commercially available
starting materials.
In conclusion, a Cu-catalyzed site- and diastereoselective
arylation of tryptophan derivatives has been developed. This
reaction provides direct access to aryl pyrroloindolines under
mild conditions with good functional group tolerance. Using
this transformation to assemble the pyrroloindoline core
enables the concise, stereoselective syntheses of the bisindole
alkaloids (+)-naseseazines A and B in overall yields of 25 and
19%, respectively. The further development and application of
this transformation in natural product synthesis is the subject of
ongoing research in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, compound characterization
1
data, and H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
reisman@caltech.edu
■
Author Contributions
(10) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134,
10815.
†M.E.K. and K.V.C. contributed equally.
(11) Isolation papers: (a) Gliocladine: Dong, J.-Y.; He, H.-P.; Shen,
Y.-M.; Zhang, K.-Q. J. Nat. Prod. 2005, 68, 1510. (b) Asperazine:
Varoglu, M.; Corbett, T. H.; Valeriote, F. A.; Crews, P. J. Org. Chem.
1997, 62, 7078. (c) Naseseazines A and B: Raju, R.; Piggott, A. M.;
Conte, M.; Aalbersberg, W. G. L.; Feussner, K.; Capon, R. J. Org. Lett.
2009, 11, 3862. The relative stereochemistry was subsequently
reassigned by Kim and Movassaghi.8a
(12) Completed total syntheses: (a) Gliocladine C: DeLorbe, J. E.;
Jabri, S. Y.; Mennen, S. M.; Overman, L. E.; Zhang, F.-L. J. Am. Chem.
Soc. 2012, 133, 6549. (b) Asperazine: Govek, S. P.; Overman, L. E. J.
Am. Chem. Soc. 2001, 123, 9468. (c) Naseseazines: Reference 8a.
(13) Prepared by a two-step procedure adapted from ref 8a.
(14) (a) Zhong, H. A.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc.
2002, 124, 1378. (b) Winston, M. S.; Oblad, P. F.; Labinger, J. A.;
Bercaw, J. E. Angew. Chem., Int. Ed. 2012, 51, 9822.
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Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (c) Deprez, N.;
Sanford, M. Inorg. Chem. 2007, 46, 1924. (d) Phipps, R. J.; Grimster,
N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
(16) One-pot preparation of diaryliodonium salts: (a) Bielawski, M.;
Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610. (b) Bielawski,
M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602.
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(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech
Center for Catalysis and Chemical Synthesis for access to
analytical equipment and Dr. Matthew Winston for samples of
L6. We also thank Sigma-Aldrich for a kind donation of
chemicals. Fellowship support was provided by the National
Science Foundation (Graduate Research Fellowships to M.E.K.
and K.V.C., Grant DGE-1144469). S.E.R. is a fellow of the
Alfred P. Sloan Foundation and a Camille Dreyfus Teacher-
Scholar. Financial support from the California Institute of
Technology, Amgen, DuPont, and the NIH (NIGMS
RGM097582A) is gratefully acknowledged.
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