Total synthesis of (+)-gliocladin C enabled by visible-light photoredox catalysis

Article abstract of DOI:10.1002/anie.201103145

Lighting the way: In a 10-step total synthesis of the title compound, visible-light photoredox catalysis enabled the construction of the key bond by facilitating the direct coupling of a pyrroloindoline-derived radical with a substituted indole (see schem

Full text of DOI:10.1002/anie.201103145

DOI: 10.1002/anie.201103145
Total Synthesis
Total Synthesis of (+)-Gliocladin C Enabled by Visible-Light
Photoredox Catalysis**
Laura Furst, Jagan M. R. Narayanam, and Corey R. J. Stephenson*
Hexahydropyrroloindoline alkaloids are a large class of
natural products that are formally derived from two mole-
cules of tryptophan.[1] A subset of this class, the C3–C3’ indole
alkaloids, contain the 3a-(3-indolyl)-hexahydropyrrolo-[2,3-
b]indole skeleton and include compounds such as gliocla-
din C,[2] gliocladine C,[3] leptosin D,[4] and the bionectins[5]
(Figure 1). Aside from their interesting structural features,
also been achieved by Overman and Govek (C3–C7’),[10]
Baran and co-workers,[11a,c] and Rainier and Espejo (C3–
N1’).[11b] However, the total syntheses of gliocladin C by
Overman and co-workers, starting from isatin in 2007[12a] and
the subsequent second generation synthesis in 2011,[12b]
remain the only completed nondimeric C3–C3’ bisindole
alkaloid syntheses. Moreover, the strategy by Overman and
co-workers illustrated the importance of gliocladin C as a key
intermediate for the preparation of other C3–C3’ bisindole
alkaloids. For example, bis-Boc-protected 1 can be effectively
converted into gliocladine C (2) in six steps. Two additional
reports by Crich et al.,[13] and Somei and co-workers[14] were
aimed at the synthesis of the core.[15,16] Herein, we report the
total synthesis of gliocladin C (10 steps total) which was
enabled by a highly efficient radical coupling reaction that is
mediated
by
visible-light
photoredox
catalysis
(Scheme 1).[17–24]
Figure 1. Representative examples of cytotoxic and antibiotic C3–C3’
bisindole alkaloids.[6]
they exhibit a broad range of potent biological activities. For
example, gliocladin C[2] and leptosin D[4] are cytotoxic against
P-388 lymphocytic leukemia cell lines with ED50 values of
240 ngmLꢀ1 and 86 ngmLꢀ1, respectively, while bionectins A
and B[5] exhibit antibacterial activity against MRSA (methi-
cillin-resistant S. aureus) and QRSA (quinolone-resistant
S. aureus) with MIC = 10–30 mm mLꢀ1.
The structural complexity and high biological activities of
hexahydropyrroloindoline alkaloids,[7] have gained the atten-
tion of several research groups, thus resulting in total
syntheses of natural products that incorporate C3–C3’ pyrro-
loindoline dimers,[8,9] including work by the research groups
of Hino,[9a] Danishefsky,[9b] Overman,[9c] Movassaghi,[9d–g]
de Lera,[9h,i] Sodeoka,[9j] and Baran.[9k] Elegant approaches to
the synthesis of C3–C7’ and C3–N1’ bisindole alkaloids have
Scheme 1. Retrosynthesis of gliocladin C (1; top) and visible-light-
ꢀ
mediated C C bond formation (bottom).
During our studies into the visible-light-mediated syn-
thesis of indole alkaloid natural products using the photo-
redox catalyst tris(bipyridyl)ruthenium(II) chloride ([Ru-
(bpy)3Cl2])[25] we serendipitously discovered an efficient
[*] L. Furst, Dr. J. M. R. Narayanam, Prof. C. R. J. Stephenson
Department of Chemistry, Boston University
Boston, MA 02215 (USA)
ꢀ
method for the reductive dehalogenation of activated C X
bonds.[20a,26] In the process, we were able to effectively access
the tertiary benzylic radical 7 (Scheme 1) from bromopyrro-
loindolines 6 en route to the corresponding reduced com-
pounds. By utilizing the method developed within our group,
we envisioned that the trapping of 7 with an indole derivative
would provide a direct approach to C3–C3’ bisindoles 8, and
thus efficient access to an entire class of natural products.
The key step in our synthetic strategy was evaluated by
exposing simple bromopyrrolindoline 9,[11b] which is derived
E-mail: crjsteph@bu.edu
Homepage: http://people.bu.edu/crjsteph/
[**] Financial support for this research from the NIH-NIGMS (R01-
GM096129), Boston University, and Boehringer Ingelheim is
gratefully acknowledged. C.R.J.S. is a fellow of the Alfred P. Sloan
Foundation. L.F. thanks the Novartis Institutes for BioMedical
Research for a graduate fellowship. NMR (CHE-0619339) and MS
(CHE-0443618) facilities at BU are supported by the NSF.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103145.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9655

Communications
from tryptamine in two steps on a large scale, to N-
methylindole (10) under typical reductive quenching reaction
conditions for photoredox catalysis (Scheme 2). As
Scheme 3. a) CbzCl, NaOH, Bu4NHSO4, CH2Cl2, 12 h; b) NBS, PPTS,
CH2Cl2, 238C, 12 h, 91% (two steps); c) MeNH2, THF, 238C, 3 d,
87%; d) [Ru(bpy)3Cl2] (1.0 mol%), Bu3N (2 equiv), 15 (5 equiv), DMF,
blue LEDs, 12 h, 82%; e) [Rh(Ph3P)3Cl] (1 equiv), xylenes, 1408C, 12 h,
86% or [Rh(CO)(Ph3P)2Cl] (20 mol%), dppp (44 mol%), DPPA
(2 equiv), xylenes, 1408C, 85%; f) CbzCl, NaOH, Bu4NHSO4, CH2Cl2,
12 h, 98%; g) TMSI, CH3CN, 08C, 1 h, 91%. Cbz=benzyloxycarbonyl;
DMF=N,N’-dimethylformamide; DPPA=diphenylphosphoryl azide;
dppp=1,3-bis(diphenylphosphino)propane; LED=light-emitting
diode; NBS=N-bromosuccinimide; PPTS=pyridinium p-toluenesulfo-
nate; THF=tetrahydrofuran; TMS=trimethylsilyl.
Scheme 2. Visible-light-mediated coupling of bromopyrroloindoline 9
with indoles enables selective access to both C2’- and C3’-substituted
bisindoles. Boc=tert-butyloxycarbonyl.
expected[27] only the C3–C2’ coupled product 11 was
observed, with no detectable traces of products containing
the desired C3–C3’ connectivity. However, by effectively
blocking the indole C2’-position with a carboxylate group, we
were able to direct the reactivity towards the preferred indole
C3’-position. Indeed, coupling with methyl indole-2-carbox-
ylate (12) led to 58% yield of the desired C3–C3’ coupling
product 13 (Scheme 2). The visible-light-mediated coupling of
indoles with bromopyrroloindolines now selectively enables
the synthetic access to both the unnatural C3–C2’ and the
natural C3–C3’ connectivity, depending on the indole sub-
stitution pattern.
steps. Methylamidation of 18 with aqueous MeNH2 in THF
resulted in the formation of the corresponding methylamide
19 in 87% yield. Bromopyrroloindoline 19 was then subjected
to the key indole coupling reaction using the previously
optimized reaction conditions. Treatment of a mixture of
amide 19 and aldehyde 15 (5.0 equiv)[30] with Et3N (2.0 equiv)
in the presence of 1 mol% of [Ru(bpy)3Cl2] in DMF under
blue-light[31,32] irradiation, successfully provided the desired
coupling product 20 in 82% yield. During further optimiza-
tion studies, we found that the use of an amine with a lower
vapor pressure instead of Et3N proved beneficial to the
reaction conversion and the yield of the isolated product.[33]
As a result, the use of nBu3N as the stoichiometric reducing
agent resulted in the complete conversion of the starting
material on a preparative scale (3.8 mmol) and provided 20 in
82% yield.
Further model studies towards the total synthesis of
gliocladin C were conducted with Boc-l-tryptophan-derived
bromopyrroloindoline 14 [Eq. (1)]. We identified indole-2-
With a scalable and highly efficient synthetic route to the
core structure established, catalytic decarbonylation of the
aldehyde at the C2’-position of the indole was explored.
Initial attempts using [Rh(Ph3P)3Cl] (20 mol%) and DPPA
(2.0 equiv)[34] provided 21 in an unsatisfactory yield of 60%.
Hence, we opted to complete the synthesis using a stoichio-
metric decarbonylation reaction by heating compound 20 in
xylenes (1408C) in the presence of [Rh(Ph3P)3Cl] to achieve
the desired decarbonylation in 86% yield. Subsequent re-
evaluation of the catalytic decarbonylation conditions led to
improved results using 20 mol% of [Rh(CO)(Ph3P)3Cl],
dppp[35] (44 mol%), and DPPA (2.0 equiv) in xylenes at
1408C, and provided 21 in 85% yield.
carboxaldehyde (15) as the best coupling partner and the
desired product 16 was obtained in 72% yield with only
1 mol% of [Ru(bpy)3Cl2] on up to a 2 g scale.[28] This strategy
not only employs mild reaction conditions and low catalyst
loading, but also provides rapid access to the C3–C3’ bisindole
alkaloid core structure in high yield on a large scale.
After securing a rapid and scalable route to the core
structure of the C3–C3’ bisindole alkaloid framework, we
initiated our synthesis of 1 by using an orthogonal nitrogen
protection of Boc-d-tryptophan methyl ester (17) with CbzCl
(Scheme 3). Bromocyclization using NBS and PPTS[29]
yielded bromopyrroloindoline 18 in 91% yield over the two
At this stage, two challenges remained to complete an
efficient synthesis of gliocladin C: 1) the formation of the
triketopiperazine moiety and 2) the introduction of the a,b-
unsaturated imide. Several attempts to complete the syn-
thesis, first by conversion of 21 into bis-Cbz-protected
dihydrogliocladin C [23; N-acylation with ClCOCO2Et/Et3N
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Angew. Chem. Int. Ed. 2011, 50, 9655 –9659

then cyclization using hexamethyldisilazane (HMDS),
1408C,[36] 56% yield over the two steps; Eq. (2)] followed
by dehydrogenation to introduce the a,b-unsaturated imide
238C) provided gliocladin C (1) in 80% yield. Spectroscopic
and optical rotation data for synthetic 1 were in agreement
with the data reported for the natural sample.[39]
In summary, gliocladin C (1) was synthesized in 10 steps
from commercially available Boc-d-tryptophan methyl ester
in 30% overall yield. This study highlights photoredox
catalysis not only as a viable method in the context of this
particular synthesis, but also as a general, mild, and robust
means to potentially access a wide variety of complex
molecules. With the route to gliocladin C by photoredox
catalysis established, we anticipate using imine 25 as a
common intermediate for the preparation of other members
of this important class of indole alkaloids by using the imine
annulation sequence outlined in Scheme 4.
(e.g. LiHMDS/NBS, DDQ) failed to provide 24 in an
acceptable yield. Under unoptimized reaction conditions,
treatment of 23 with Pd/C (20 mol%, toluene, reflux, 3 days)
provided 24 in < 50% yield. We reasoned that the orientation
of the methine hydrogen at C11a inside the concave face of
the ring prevented efficient conversion into 24. Attempts to
epimerize C11a resulted only in the ring opening of the
triketopiperazine.
Inspired by the historical approach by Woodward and
Ling to unnatural cyclic amino acids by using the acylation/
elimination of cyclic oxime ethers,[37] we chose to pursue a
one-pot N-acyliminium ion promoted enamine formation/
intramolecular amidation to introduce the triketopiperazine
and the a,b-unsaturated imide in a single transformation
(Scheme 4; 25!24).[38] Accordingly, the oxidation of the
Received: May 7, 2011
Published online: July 12, 2011
Keywords: alkaloids · homogeneous catalysis ·
.
natural products · photoredox · total synthesis
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Angew. Chem. Int. Ed. 2011, 50, 9655 –9659
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www.angewandte.org
9657

Communications
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[32] The reaction temperature does not exceed 308C upon irradiation
with blue LEDs.
[33] We observed that the headspace volume of the reaction flask
correlated inversely with the reaction conversion when using
Et3N as the reductive quencher (stoichiometric reducing agent),
wherein lower conversion was observed when there was a larger
headspace volume. We hypothesized that the reductive quencher
(Et3N) was partitioning into the headspace of the reaction flask,
thereby impeding the catalytic cycle. Switching to a trialkyl-
amine with a lower vapor pressure, eg. nBu3N (0.3 mm Hg,
208C) compared with Et3N (51.8 mm Hg, 208C) recovered the
reactivity observed on a smaller scale.
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[35] M. D. Meyer, L. I. Kruse, J. Org. Chem. 1984, 49, 3195.
[36] These reaction conditions were used by Overman and Shin for a
related compound in the 2007 synthesis of 1 (see Ref. [12a]).
[37] V. J. Ling, R. B. Woodward, J. Org. Chem. 1979, 44, 2487.
[38] Alternative mechanisms are also possible, such as initial imide
formation with the subsequent attack of the imine. However,
based on observations made on similar systems, both in our
9658 www.angewandte.org
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Angew. Chem. Int. Ed. 2011, 50, 9655 –9659

studies and in the literature (e.g. Ref. [12a]), we believe imine
acylation precedes imidation.
and Shin in 2007[12a] ([a]D = + 116.4 degcm3 gꢀ1 dmꢀ1 (c = 0.02 g/
100mL, CHCl3)). In their most recent synthesis,[12b] Overman
and co-workers observed poor solubility of crystalline gliocla-
din C in chloroform ([a]D = + 113 degcm3 gꢀ1 dmꢀ1 (c = 0.0093 g/
100mL, CHCl3)) and optical rotation data was also reported in
[39] The measured optical rotation for synthetic 1 in two solvents
([a]D = + 128 degcm3 gꢀ1 dmꢀ1 (c = 0.04 g/100mL, CHCl3); + 125
(c = 0.2 g/100mL, C5H5N)) correlates well to the reported data
for the natural product ([a]D = + 131.4 degcm3 gꢀ1 dmꢀ1 (c =
0.07 g/100mL, CHCl3))[2] as well as to that reported by Overman
pyridine
([a]D = + 127 degcm3 gꢀ1 dmꢀ1
(c = 0.23 g/100mL,
C5H5N)).
Angew. Chem. Int. Ed. 2011, 50, 9655 –9659
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9659