A Mild and General Larock Indolization Protocol for the Preparation of Unnatural Tryptophans

Article abstract of DOI:10.1021/acs.orglett.6b02477

A mild and general protocol for the Pd(0)-catalyzed heteroannulation of o-bromoanilines and alkynes is described. Application of a Pd(0)/P(^tBu)₃ catalyst system enables the efficient coupling of o-bromoanilines at 60 °C, mitigating deleterious side reactions and enabling access to a broad range of useful unnatural tryptophans. The utility of this new protocol is demonstrated in the highly convergent total synthesis of the bisindole natural product (-)-aspergilazine A.

Full text of DOI:10.1021/acs.orglett.6b02477

Letter
pubs.acs.org/OrgLett
A Mild and General Larock Indolization Protocol for the Preparation
of Unnatural Tryptophans
Kangway V. Chuang, Madeleine E. Kieffer, and Sarah E. Reisman*
The Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology Pasadena, California 91125, United States
*
S Supporting Information
ABSTRACT: A mild and general protocol for the Pd(0)-
catalyzed heteroannulation of o-bromoanilines and alkynes is
t
described. Application of a Pd(0)/P( Bu) catalyst system
3
enables the efficient coupling of o-bromoanilines at 60 °C,
mitigating deleterious side reactions and enabling access to a
broad range of useful unnatural tryptophans. The utility of this
new protocol is demonstrated in the highly convergent total
synthesis of the bisindole natural product (−)-aspergilazine A.
he development of new methods to prepare unnatural
T
tryptophan derivatives is an important endeavor with
interdisciplinary applications. In the context of natural product
synthesis, a large number of alkaloids contain tryptophan
subunits embedded explicitly or implicitly within their
1
structures; in chemical biology, functionalized tryptophan
derivatives have emerged as important molecules for studying
2
protein function and dynamics. Although subtle perturbations
to this core amino acid may seem trivial, the preparation of the
requisite tryptophan building block often constitutes a
substantial synthetic undertaking. The Pd-catalyzed hetero-
annulation reaction between o-bromoanilines and serine-derived
alkynes represents a convergent approach to unnatural
tryptophan derivatives, yet its versatility has thus far been limited
due to challenges of reactivity and functional group tolerance.
Herein, we describe the development and application of a Pd-
catalyzed synthesis of structurally complex and synthetically
useful tryptophan derivatives from widely available o-bromoani-
lines. Using this method, a concise synthesis of the bisindole
alkaloid (−)-aspergilazine A is reported.
Figure 1. Larock indole synthesis.
substrates containing peptide functionality and o-bromoanilines,
reveal significant limitations in the state of the art. For example,
Baran’s elegant synthesis of (+)-kapakahine B necessitated
prolonged reaction times (24 h) and increased catalyst loadings
The Pd(0)-catalyzed heteroannulation of disubstituted
3
alkynes with o-haloanilines, commonly known as the Larock
indole synthesis, is a powerful method for the preparation of 2,3-
5c
4
−6
(
20 mol %) under Larock’s standard conditions (Scheme 1A).
disubstituted indoles.
Larock’s original conditions, which
Similarly, Boger’s landmark synthesis of the chloropeptins, which
employed an intramolecular Larock macrocyclization of an aryl
bromide, required excess [Pd] and dtbpf (1.1 and 1.3 equiv,
employ a “ligandless” Pd catalyst in conjunction with an
inorganic base and chloride salt additive, were developed for o-
7
iodoanilines and remain the most widely utilized (Figure 1A). In
6a
respectively) to effect high yields (Scheme 1B).
2004, Senanayake and co-workers expanded the scope of this
We also encountered challenges during our efforts to
implement a late-stage indole annulation for the total syntheses
of the C3-arylpyrroloindolines (+)-naseseazines A and B
transformation to include o-chloro- and o-bromoanilines by
employing a bidentate phosphine ligand, 1,1′-bis-di-tert-
butylphosphinoferrocene (dtbpf), at elevated temperatures
(
Scheme 1C). Specifically, poor catalyst turnover and low yields
(
110−130 °C), providing simple indoles in good yield and
8
high regioselectivity (not shown).
Despite these advances, efforts to employ the Larock indole
Received: August 18, 2016
synthesis in complex settings, particularly using alkynyl
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02477
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Challenging Larock Indolizations in Natural
Product Synthesis
Although this elementary step could be enabled by the use of an
12
electron-donating phosphine ligand, it was recognized that
such ligands might slow the rate of subsequent alkyne insertion.
We reasoned that sterically demanding phosphines, which have
1
3
been demonstrated to favor Pd−monophosphine complexes,
could serve to balance these opposing effects by providing a
vacant coordination site to facilitate alkyne insertion.
Our studies commenced with the coupling between o-
14
bromoaniline (1a) and alkyne 2 to afford tryptophan 3a.
Treatment of a mixture of 1a and 2 with 5 mol % of Pd(OAc)
2
3
and Na CO at 100 °C, Larock’s original conditions, provided
2
3
3a in 27% yield (Table 1, entry 1). A survey of conditions
Table 1. Optimization Studies
temp
b
entry
[Pd cat.]
ligand
PPh3
base
(°C)
yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Na CO3
2
100
100
100
100
100
100
100
60
27
17
8
Na CO3
2
DavePhos
PCy3
Na CO3
2
Na CO3
2
<5
<5
70
78
85
85
dtbpf
Na CO3
2
Pd[P(o-tol) ]
Na CO3
2
3
2
t
Pd[P( Bu) ]
Na CO3
2
3
2
2
2
2
t
Pd[P( Bu) ]
Na CO3
2
3
t
9
Pd[P( Bu) ]
Cy NMe
2
60
3
e
t
d
10
1
Pd[P( Bu) ]
Cy NMe
2
60
84 (87)
3
c
,
e
t
1
Pd (dba)3
2
P( Bu)3
Cy NMe
2
60
83
a
Reactions conducted on 0.1 mmol scale with 2.0 equiv of alkyne 2
b
1
and 2.5 equiv of base in DMF (0.5 mL). Yield determined by H
NMR analysis of the crude reaction mixture relative to an internal
c
d
standard. 1:1 [Pd]/ligand used. Isolated yield on 0.3 mmol scale.
e
Reaction performed in 1,4-dioxane.
previously reported in the literature to promote Larock
indolizations, including the addition of 11 mol % of PPh3,
were obtained using substoichiometric [Pd], while the use of
higher catalyst loadings or higher temperatures resulted in
hydrodehalogenation, epimerization of the diketopiperazine,
poor regioselectivity, and low mass recovery. Following
extensive experimentation, we determined that use of 25 mol
PCy , DavePhos, or dtbpf (the optimal ligand in Senanayake’s
3
8
report), suppressed the reaction (entries 2−5). The preformed
9
complex Pd[P(o-tol) ] , our most successful catalyst in the
3
2
9
synthesis of the naseseazines, delivered 3a in 70% yield.
%
of Pd[P(o-tol) ] in conjunction with Na CO provided the
Increasing the steric demand of the ligand through the use of
3
2
2
3
t
13
product in 56% isolated yield. Although only two turnovers of
Pd] were achieved, this report represents the first Larock indole
synthesis using an o-bromoaniline with substoichiometric Pd in
Pd[P( Bu) ] further increased the yield (Table 1, entry 7).
3 2
[
Pleasingly, lowering the temperature to 60 °C enabled a clean
reaction and provided the product in 85% yield (entry 8). Use of
10
the context of a complex polypeptide substrate.
Given our general interest in the synthesis of indole
the soluble organic base Cy NMe in 1,4-dioxane furnished 3a
2
with comparable efficiency (entries 9 and 10). Generation of the
catalyst from a 1:1 [Pd]/ligand ratio was also feasible and
improved the initial rate of the reaction (entry 11). To the best of
our knowledge, this reaction represents the lowest temperature
Larock indolization of any o-haloaniline reported to date.
As shown in Figure 2, the reaction exhibits excellent scope:
both electron-rich (3b−d) and electron-deficient (3e−l) o-
bromoanilines react efficiently to provide an array of unnatural
tryptophan derivatives. Substitution is readily tolerated at all
positions of the aniline substrate, including at nitrogen, although
the preparation of 4-substituted indoles requires slightly elevated
temperatures to achieve acceptable reaction rates (3c and 3i).
1
1
alkaloids, we sought to develop a mild and reliable Pd-
catalyzed synthesis of tryptophan derivatives that addresses the
challenges outlined above. Specifically, we hoped to identify
conditions that would (1) enable the general use of widely
available o-bromoanilines, (2) proceed with synthetically useful
catalyst loadings, and (3) deliver tryptophan products at lower
temperatures in order to mitigate deleterious side reactivity.
In assessing the existing limitations of the Larock indole
synthesis, we hypothesized that the poor reactivity of o-
bromoanilines under the originally disclosed ligandless con-
ditions was likely due to slow rates of oxidative addition.
B
DOI: 10.1021/acs.orglett.6b02477
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Organic Letters
Letter
extended to o-bromophenol to provide direct access to a
substituted benzofuran derivative (3u). Importantly, chiral SFC
analysis of the products verifies that this reaction proceeds
without racemization, providing all products in enantiopure
16
form. The 2-triethylsilyl group is easily removed using aqueous
acid or fluoride sources or, alternatively, can serve as a useful
17
functional handle for a variety of transformations.
To investigate the scope of the alkyne, several dipeptide-and
diketopiperazine-based substrates were prepared and subjected
to the reaction conditions (Figure 3). In all cases, the products
are obtained in good yields and with no observed epimerization
of the α-stereocenters.
Figure 3. Substrate scope of the alkyne. Reactions were conducted with
1
(1.0 equiv), 4 (2.0 equiv), and Cy NMe (2.5 equiv) in 1,4-dioxane (0.2
2
M) at 60 °C; isolated yields of 5 are reported. For compound 5e, the
reaction was performed at 80 °C.
The synthetic studies described above utilize 5 mol % of
catalyst for ease of operation; however, individual couplings can
be conducted on preparatively useful scales with lower catalyst
loadings. For example, the coupling between 2-amino-3-
bromopyridine (1n) and alkyne 2 was carried out on 5 mmol
t
scale using 2.5 mol % of Pd[P( Bu) ] and 1.5 equiv of alkyne,
3
2
which upon desilylation with 1 M TBAF in THF provided 1.28 g
1
8
(
80% yield) of 7-azatryptophan (Figure 2, 3o).
To further highlight the utility of this protocol, we sought to
complete a total synthesis of the dimeric diketopiperazine natural
Figure 2. Substrate scope of the o-bromoaniline. Reactions were
19,20
product (−)-aspergilazine A (10),
which is characterized by
conducted with 1 (1.0 equiv), 2 (2.0 equiv), and Cy NMe (2.5 equiv) in
2
its novel C6-to-N1 bisindole linkage (Scheme 2). We envisioned
that 10 would be ideally suited for a sequential indolization
strategy that would allow assembly of the natural product in a
direct and convergent manner. To this end, the requisite
dibromide (8) was prepared via Buchwald−Hartwig coupling of
1
,4-dioxane (0.2 M) at 60 °C; the isolated yields of 3 are reported. For
compounds 3c and 3i, the reaction was performed at 80 °C. For
compounds 3h, 3s, and 3u, desilylation with 1 M TBAF or 1 N HCl in
MeOH was performed prior to chromatography. The synthesis of 3o
t
was conducted on 5.0 mmol scale with 2.5 mol % of Pd[P( Bu) ] and
3
2
21
1
.5 equiv of 2 and then desilylated with 1.0 M TBAF.
1
-bromo-2-iodobenzene (6) with diamine 7. Subjection of a
t
mixture of dibromide 8 and alkyne 9 to 10 mol % of Pd[P( Bu) ]
3
2
Halogenated substrates react with excellent chemoselectivity
and 2.5 equiv of Cy NMe in 1,4-dioxane at 80 °C furnished
2
for the aryl bromide over the aryl chloride; a variety of useful
chlorinated (3f,g,i) and fluorinated (3e,j) tryptophans are readily
prepared. Lewis-basic heterocycles also perform well under these
conditions (3n,o). It is noteworthy that tryptophan 3o, prepared
here in two steps from commercially available materials, has
recently been reported as a new fluorescent probe with useful
bis(triethylsilyl)-(−)-aspergilazine A in 62% isolated yield,
representing an average reaction efficiency of 79% per
indolization. Subsequent HCl-mediated desilylation cleanly
provided the natural product. Importantly, the success of this
strategy hinges largely on the ability of this new protocol to
enable the coupling of 2-bromoanilines; the preparation of the
diiodinated analogue of diarylamine 8 via C−N bond formation
15
photophysical properties. Finally, these conditions can be
C
DOI: 10.1021/acs.orglett.6b02477
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Organic Letters
Letter
Scheme 2. Total Synthesis of (−)-Aspergilazine A
REFERENCES
■
(
1) For representative reviews, see: (a) Veale, C. G. L.; Davies-
Coleman, M. T. Alkaloids: Chemistry and Biology 2014, 73, 1−64. (b) Li,
S.-M. Nat. Prod. Rep. 2010, 27, 57−58.
(
2) For the use of tryptophan derivatives as biological probes, see:
(
a) Royer, C. A. Chem. Rev. 2006, 106, 1769. (b) Lepthien, S.; Hoesl, M.
G.; Merkel, L.; Budisa, N. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 16095.
c) Zhong, W.; Gallivan, J. P.; Zhang, Y.; Li, L.; Lester, H. A.; Dougherty,
D. A. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 12088.
3) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(
(
(
(
b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652.
c) Chen, Y.; Markina, N. A.; Yao, T.; Larock, R. C. Org. Synth. 2011, 88,
3
(
2
77.
4) (a) Ma, C.; Yu, S.; He, X.; Liu, X.; Cook, J. M. Tetrahedron Lett.
000, 41, 2781. (b) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.;
Cook, J. M. J. Org. Chem. 2001, 66, 4525. (c) Liu, X.; Deschamp, J. R.;
Cook, J. M. Org. Lett. 2002, 4, 3339.
(
5) (a) Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10886.
b) Newhouse, T.; Lewis, C. A.; Baran, P. S. J. Am. Chem. Soc. 2009, 131,
360. (c) Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am.
(
6
Chem. Soc. 2010, 132, 7119. (d) Foo, K.; Newhouse, T.; Mori, I.;
Takayama, H.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 2716.
(6) (a) Garfunkle, J.; Kimball, F. S.; Trzupek, J. D.; Takizawa, S.;
Shimamura, H.; Tomishima, M.; Boger, D. L. J. Am. Chem. Soc. 2009,
is a considerably more challenging synthetic undertaking. This
highly convergent synthesis proceeds in an overall yield of 21%
from commercially available starting materials and underscores
the utility of this methodology in the direct preparation of
complex molecular scaffolds.
1
31, 16036. (b) Shimamura, H.; Breazzano, S. P.; Garfunkle, J.; Kimball,
F. S.; Trzupek, J. D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 7776.
(
(
c) Breazzano, S. P.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 18495.
d) Breazzano, S. P.; Poudel, Y. B.; Boger, D. L. J. Am. Chem. Soc. 2013,
In summary, we have developed a mild and general protocol
for the Pd-catalyzed synthesis of functionalized tryptophan
derivatives. The reaction proceeds with low catalyst loadings,
displays excellent substrate scope, and is readily scalable to
provide gram quantities of synthetically useful unnatural
tryptophans. Furthermore, the synthetic utility of this trans-
formation has been demonstrated in the concise synthesis of the
natural product (−)-aspergilazine A.
1
(
(
35, 1600.
7) For recent reports utilizing Larock’s original conditions, see:
a) Shan, D.; Gao, Y.; Jia, Y. Angew. Chem., Int. Ed. 2013, 52, 4902.
(b) Danner, P.; Morkunas, M.; Maier, M. E. Org. Lett. 2013, 15, 2474.
(c) Tao, P.; Liang, J.; Jia, Y. Eur. J. Org. Chem. 2014, 2014, 5735.
(d) Miyamoto, H.; Hirano, T.; Okawa, Y.; Nakazaki, A.; Kobayashi, S.
Tetrahedron 2013, 69, 9481.
(
8) (a) Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina,
V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129. (b) Liu, J.; Shen, M.;
Zhang, Y.; Li, G.; Khodabocus, A.; Rodriguez, S.; Qu, B.; Farina, V.;
Senanayake, C.; Lu, B. Z. Org. Lett. 2006, 8, 3573.
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
9) Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. J. Am. Chem. Soc. 2013,
135, 5557.
10) For elegant syntheses in complex systems using o-iodoanilines,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02477.
(
see ref 5a−d. For examples using stoichiometric [Pd] o-bromoanilines,
see ref 6a−c.
(
Experimental data, characterization information, and
spectra (PDF)
11) Wang, H.; Reisman, S. E. Angew. Chem., Int. Ed. 2014, 53, 6206.
12) Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to
(
AUTHOR INFORMATION
Corresponding Author
Catalysis; University Science Books: Sausalito, CA, 2010.
13) (a) Littke, A.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
b) Littke, A.; Fu, G. C. J. Org. Chem. 1999, 64, 10. (c) Littke, A.; Fu, G.
C. Angew. Chem., Int. Ed. 1999, 38, 2411. (d) Littke, A. F.; Dai, C.; Fu, G.
C. J. Am. Chem. Soc. 2000, 122, 4020. (e) Littke, A.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 6989. (f) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 6343. (g) Littke, A. F.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 4176.
(14) Readily prepared on decagram scale following the protocol of
Baran and co-workers; see ref 5b.
(15) For an eight-step synthesis of the analogous o-nitrobenzyl
carbamate protected compound, see: Talukder, P.; Chen, S.; Arce, P. M.;
Hecht, S. M. Org. Lett. 2014, 16, 556.
■
*
(
(
E-mail: reisman@caltech.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Scott Virgil of Caltech for helpful discussions, the
Caltech Center for Catalysis and Chemical Synthesis for access
to screening facilities and analytical equipment, and Sigma−
Aldrich for a kind donation of chemicals. We gratefully
acknowledge Jordan Beck and Lauren Chapman of Caltech for
their assistance in the preparation of this manuscript. Fellowship
support was provided by the National Science Foundation
(
(
16) See the Supporting Information for additional details.
17) Toutov, A. A.; Liu, W.-B.; Betz, K. N.; Fedorov, A.; Stoltz, B. M.;
Grubbs, R. H. Nature 2015, 518, 80.
(
(
18) The previously reported yield was 63%; see ref 8a.
19) Cai, S.; Kong, X.; Wang, W.; Zhou, H.; Zhu, T.; Li, D.; Gu, Q.
(
Graduate Research Fellowship to M.E.K. and K.V.C., Grant No.
DGE-1144469). S.E.R. is an American Cancer Society Research
Scholar and a Heritage Medical Research Foundation inves-
tigator. Financial support from the NIH (NIGMS
RGM097582A) and the donors of the ACS Petroleum Research
Foundation is gratefully acknowledged.
Tetrahedron Lett. 2012, 53, 2615.
(20) For a recent total synthesis of (−)-aspergilazine A, see: Boyd, E.
M.; Sperry, J. Org. Lett. 2014, 16, 5056.
(21) Garcia-Fortanet, J.; Kessler, F.; Buchwald, S. L. J. Am. Chem. Soc.
2
009, 131, 6676.
D
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Org. Lett. XXXX, XXX, XXX−XXX