Enantioselective total syntheses of communesins A and B

Article abstract of DOI:10.1002/anie.201106205

As easy as A, B: The first total syntheses of (-)-communesins A and B (see picture) were achieved, which featured the formation of their spiro-fused indoline part through an intramolecular oxidative coupling and of their A ring through a cascade reaction.

Full text of DOI:10.1002/anie.201106205

Communications
DOI: 10.1002/anie.201106205
Natural Product Synthesis
Enantioselective Total Syntheses of Communesins A and B**
Zhiwei Zuo and Dawei Ma*
The polycyclic, tryptamine-derived indole alkaloids commu-
nesins A and B (1 and 2, respectively) were first isolated by
Numata and co-workers in 1993 from a marine fungus of the
Penicilliun genus.[1] Their spectroscopically established struc-
tures include two contiguous quaternary centers and two
fused bicyclic aminals. Communesins A and B both demon-
strated potent inhibition of murine lymphocytic leukemia
tumor cell (P-388) proliferation in preliminary studies, with
ED50 values (50% effective doses) of 3.5 and 0.45 mgmLÀ1,
respectively. In the following years, six other members of this
family, namely communesins C–H (3–8) have been isolated
from different marine sources,[2] with most having shown
significant antileukemic and insecticidal activities. The re-
markable biological properties and fascinating structures of
these molecules have stimulated considerable interest in the
synthetic community.[3–8] In the past few years, numerous
elegant methods for assembling their core structures[4] and
three total syntheses of communesin F have been dis-
closed.[5–7]
oxidation-state-equivalent ketal early on in the synthesis.
Obviously, this modification would force us to significantly
alter our synthetic strategy. Herein, we disclose our results.
We envisioned assembling the target molecules through
acylation of amine 9 and a subsequent late-stage, base-
mediated epoxide synthesis (Scheme 1). Amine 9 could then
Scheme 1. Retrosynthetic analysis of communesins A and B.
TBS=tert-butyldimethylsilyl, Ts=toluene-p-sulfonyl.
However, to date, none of the epoxide-containing family
members have been synthesized, likely owing to the sensi-
tivity of communesin F to oxidative conditions. Indeed, we
have previously attempted to convert communesin F and its
synthetic intermediates directly into communesin A, but all
attempts were unsuccessful. We speculated that the problem
is a result of the sensitivity of the aminal nitrogen atoms to
oxidants and therefore decided to mask the epoxide as an
be obtained from lactam 10 through alkylation of the amide
and subsequent reductive amination. We anticipated forming
the hexacyclic intermediate 10 by reductive cyclization of
imine 11, which could be generated through oxidative
coupling of dianion 12 generated from amide 13.[9] Although
a related oxidative coupling reaction had been successfully
applied to form a spiro-fused indoline during our total
synthesis of communesin F,[7] this disconnection remained
daunting. Whereas the coupling in our communesin F syn-
thesis employed a linear amide to form a single six-membered
ring, the coupling in this case would require the formation of a
new [3.2.2] bicyclic system with the amide nitrogen at the
bridgehead, thereby breaking the nitrogen-to-carbonyl con-
jugation. Furthermore, in our communesin F synthesis, we
had depended upon a chiral auxiliary to control the dia-
stereoselectivity of the cyclization; it was not clear if the
azepine substituent would be able to control the stereochem-
istry in this case. This attempt would truly test the flexibility of
our oxidative coupling strategy for assembling spiro-fused
indolines. The requisite amide 13 could be derived from
[*] Z. Zuo, Prof. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: madw@mail.sioc.ac.cn
[**] We are grateful to the National Basic Research Program of China
(973 Program, grant 2010CB833200), Chinese Academy of Sciences,
and the National Natural Science Foundation of China (grant
21132008 & 20921091) for their financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106205.
12008
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12008 –12011

aurantioclavine analogue 14, which in turn could be prepared
from olefin 15 with a Sharpless asymmetric dihydroxylation as
a key step.
Our synthesis started with the preparation of aurantio-
clavine analogue 14 (Scheme 2). Guided by studies on the
total synthesis of aurantioclavine,[10] we employed a Mitsu-
give sulfonamide 21.[13] After cleavage of the silyl ether in 21
with TBAF, the liberated alcohol was exposed to DEAD and
tri-n-butylphosphine to provide a cyclized product,[11] which
was hydrolyzed to deliver azepine 22. Desulfonation of 22
using magnesium and methanol furnished 14 with 92% yield.
Condensation of azepine 14 with 2-(2-nitrophenyl)acetic
acid under the assistance of BOPCl gave rise to amide 13
(Scheme 3). With this intermediate in hand, we investigated
the key oxidative coupling reaction. Initially, we attempted
Scheme 3. Reagents and conditions: a) 2-(2-nitrophenyl)acetic acid,
BOPCl, Et3N, CH2Cl2; b) LiHMDS, then iodine, THF, À788C; c) Raney-
Ni, H2, MeOH; d) KHMDS then MeI; e) 37% HCHO, NaBH(OAc)3.
BOPCl=bis(2-oxo-3-oxazolidinyl)phosphinic chloride, LiHMDS= lith-
ium hexamethyldisilazanide, b.r.s.m.=based on recovered starting
material.
Scheme 2. Reagents and conditions: a) TBSCl, Et3N; b) TsCl, aq
NaOH, nBu4NBr, CH2Cl2; c) 3-methyl-3-hydroxybut-1-ene, Pd(OAc)2,
P(o-Tol)3, nBu4NBr, K2CO3, DMF; d) AD-mix-b, CH3SO2NH2, tBuOH,
H2O, 96% ee; e) SOCl2, Et3N, CH2Cl2, 08C; f) NaN3, nBu4NBr, DMF,
908C; g) p-TsOH, DMP; h) LAH, THF; i) o-NsCl, Et3N, DMAP, CH2Cl2;
j) TBAF, MeOH; k) P(nBu)3, DEAD, THF; l) thioglycolic acid,
LiOH·H2O, DMF; m) Mg, MeOH, sonication. AD-mix-b=
K2OsO2(OH)4, K3Fe(CN)6, hydroquinidine 1,4-phthalazinediyl diether;
DEAD=diethyl azodicarboxylate; DMAP=4-dimethylaminopyridine;
DMP=2,2-dimethoxypropane; LAH=lithium aluminum hydride; o-
NsCl=2-nitrobenzenesulfonic chloride; TBAF=tetrabutylammonium
fluoride.
this reaction under our previous conditions (LiHMDS, THF,
À788C, then I2, À788C to RT), and found that only the
iodination product 23 was produced as a diastereomeric
mixture. However, when iodine was added at room temper-
ature, we isolated the desired spiro-fused, twisted-amide-
containing indoline 11 (73% yield based on 11% recovery of
13) as a single isomer. No further cyclization of 23 occurred,
thus indicating that the formation of 11 did not involve an SN2
reaction. Next, reduction of the nitro group in 11 by Raney-
Ni-catalyzed hydrogenation and the subsequent spontaneous
attack of the resultant amine at the imine moiety afforded
hexacyclic intermediate 10. Selective methylation at N15 to
provide the desired intermediate 24 was achieved by treat-
ment of 10 with KHMDS and iodomethane. Notably, when 10
was subjected to reductive amination with formaldehyde,
dimethylated product 25 was isolated. X-ray structural
analysis of 25 confirmed that the newly created stereocenters
possessed the requisite configuration for synthesizing the
target molecules.[14]
nobu reaction[11] to form the azepine moiety of 14.[10a]
Accordingly, silylation of alcohol 16 and subsequent tosyla-
tion provided 17, which was subjected to a Heck reaction to
afford allyl alcohol 15. Sharpless asymmetric dihydroxyla-
tion[12] of 15 with AD-mix-b worked well, delivering the
desired triol 18 in 94% yield and 96% ee. After treatment of
18 with thionyl chloride to form a cyclic sulfite, regioselective
nucleophilic replacement with sodium azide was carried out
to obtain azide 19. Protection of the diol in 19 with DMP led
to the formation of ketal 20, which was further reduced with
LAH, and treated with 2-nitrobenzenesulfonic chloride to
Angew. Chem. Int. Ed. 2011, 50, 12008 –12011
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12009

Communications
Scheme 4. Possible stereochemical course for conversion of amide 13
into spiro-fused indoline 11.
The stereochemical outcome during the formation of 11
could be rationalized by a proposed transition-state model
(Scheme 4). After treatment of 13 with LiHMDS and
subsequent oxidation with iodine, the diradical transition
state A might form, in which the rigid conformation was
strengthened by the favorable stacking interaction between
the electron-deficient arene and indole moieties, and the
diradical combined from the opposite site of the bulky 1,3-
dioxolane group to give 11 as a single isomer.
After we established the hexacyclic system of commune-
sins A and B, the stage was set for introducing the A ring. In
previous protocols for synthesizing communesin F, allylation
of a pentacyclic intermediate at the C8 position was employed
for obtaining the required two carbon side chain.[6,7] However,
in case of 24, allylation (with KOtBu/allyl iodide) was found
to give an O-allylation product exclusively, which could not be
converted into the desired product through a Claisen
rearrangement as described by the Qin group.[5] To solve
this problem, a number of alkylation reagents and reaction
conditions were screened. We were pleased to find that a
combination of KHMDS and 2-iodoacetonitrile afforded C-
alkylation product 26 with 67% yield. We discovered that the
following reaction sequence could be utilized for highly
efficient A-ring formation: LAH reduction of 26 delivered
lactol 27, and subsequent treatment of 27 with ammonium
acetate and NaBH(OAc)3 produced aminal 28 (in 92% yield
from 26). The transformation of 27 to 28 might have
proceeded through two possible cascade reaction processes
(Scheme 5). The lactol ring of 27 might have first been opened
to yield aldehyde 29, which would have undergone reductive
amination to primary amine 30. Next, the semilactam ring of
30 may have opened to form intermediate 31 (path A;
examples of similar ring openings in reduction of bridged
lactams have been reported[15]), and the intramolecular
condensation of 31 would have afforded imine 32. Finally,
intramolecular attack of the secondary amine onto the imine
moiety would have delivered aminal 28. Alternatively, direct
dehydration of 30 might have afforded bridgehead iminium
ion 33, which would further react with the amine moiety to
furnish 28 (path B).
Scheme 5. Reagents and conditions: a) KHMDS then ICH2CN, THF,
À788C to RT; b) LAH, THF; c) NH4OAc, NaBH(OAc)3, MeOH.
The completion of the syntheses of communesins A and B
is outlined in Scheme 6. Acylation of 28 produced amide 33,
which was deprotected under acidic conditions, reacted with
mesyl chloride, and then treated with potassium carbonate in
methanol to afford communesin A. In a parallel procedure,
condensation of 28 with sorbic acid under the activation of
BOPCl led to the formation of amide 34, which was subjected
to a similar deprotection–mesylation–epoxidation ring-for-
Scheme 6. Reagents and conditions: a) Ac2O, Et3N, DMAP, CH2Cl2;
b) CF3CO2H, H2O; c) MsCl, pyridine, CH2Cl2; d) K2CO3, MeOH;
e) sorbic acid, BOPCl, Et3N, CH2Cl2. Ms=methanesulfonyl.
12010 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12008 –12011

e) J. H. Seo, G. D. Artman III, S. M. Weinreb, J. Org. Chem.
2006, 71, 8891; f) J. H. George, R. M. Adlington, Synlett 2008,
2093; g) J. H. Seo, P. Liu, S. M. Weinreb, J. Org. Chem. 2010, 75,
2667; h) F. J. Robertson, B. D. Kenimer, J. Wu, Tetrahedron 2011,
67, 4327.
mation process as described above to furnish communesin B.
The analytical data of synthetic 1 and 2 are in agreement with
those reported for the natural (À)-communesins A and B,
respectively.
In conclusion, we have achieved the first total syntheses of
communesins A and B with the longest linear sequence for
each of 24 steps from 4-bromotryptophol and overall yields of
approximately 2% and 3%, respectively. The successful
construction of key intermediate 11 by oxidative coupling
further demonstrates the flexibility of our strategy for
assembling spiro-fused indolines. Moreover, our efficient
installation of the A ring in communesins A and B by
reductive lactol amination sets a new precedent in the
synthesis of aminal-embodied natural products. Finally, our
synthetic route opens a new avenue for generating analogues
of communesins with a higher formal oxidation state and will
facilitate the establishment of structure–activity relationships
for these marine alkaloids.
[5] J. Yang, H. Wu, L. Shen, Y. Qin, J. Am. Chem. Soc. 2007, 129,
13794.
[6] P. Liu, J. H. Seo, S. M. Weinreb, Angew. Chem. 2010, 122, 2044;
Angew. Chem. Int. Ed. 2010, 49, 2000.
[7] Z. Zuo, W. Xie, D. Ma, J. Am. Chem. Soc. 2010, 132, 13226.
[8] For synthetic studies toward perophoramidine, a structurally
related alkaloid, see: a) J. R. Fuchs, R. L. Funk, J. Am. Chem.
Soc. 2004, 126, 5068; b) A. Sabahi, A. Novikov, J. D. Rainier,
Angew. Chem. 2006, 118, 4423; Angew. Chem. Int. Ed. 2006, 45,
4317; c) H. Wu, F. Xue, X. Xiao, Y. Qin, J. Am. Chem. Soc. 2010,
132, 14052; d) M. A. Evans, J. R. Sacher, S. M. Weinreb,
Tetrahedron 2009, 65, 6712.
[9] For studies on intermolecular oxidative coupling between
carbonyl compounds and unfunctionalized indoles and pyrroles,
see: a) P. S. Baran, J. M. Richter, J. Am. Chem. Soc. 2004, 126,
7450; b) P. S. Baran, J. M. Richter, J. Am. Chem. Soc. 2005, 127,
15394; c) P. S. Baran, J. M. Richter, D. W. Lin, Angew. Chem.
2005, 117, 615; Angew. Chem. Int. Ed. 2005, 44, 609; d) P. S.
Baran, M. P. DeMartino, Angew. Chem. 2006, 118, 7241; Angew.
Chem. Int. Ed. 2006, 45, 7083; e) J. M. Richter, B. W. Whitefield,
T. J. Maimone, D. W. Lin, M. P. Castroviejo, P. S. Baran, J. Am.
Chem. Soc. 2007, 129, 12875; f) J. M. Richter, Y. Ishihara, T.
Masuda, B. W. Whitefield, T. Llamas, A. Pohjakallio, P. S. Baran,
J. Am. Chem. Soc. 2008, 130, 17938.
[10] a) S. Krishnan, J. T. Bagdanoff, D. C. Ebner, Y. K. Ramtohul,
U. K. Tambar, B. M. Stoltz, J. Am. Chem. Soc. 2008, 130, 13745;
b) K. Brak, J. A. Ellman, Org. Lett. 2010, 12, 2004; c) Z. Xu, W.
Hu, Q. Liu, L. Zhang, Y. Jia, J. Org. Chem. 2010, 75, 7626.
[11] O. Mitsunobu, Synthesis 1981, 1.
[12] a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J.
Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang,
D. Xu, X.-L. Zhang, J. Org. Chem. 1992, 57, 2768; b) H. C. Kolb,
M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94,
2483.
Received: September 1, 2011
Published online: October 14, 2011
À
Keywords: C C coupling · indole alkaloids · indolines ·
natural products · total synthesis
.
[1] A. Numata, C. Takahashi, Y. Ito, T. Takada, K. Kawai, Y. Usami,
E. Matsumura, M. Imachi, T. Ito, T. Hasegawa, Tetrahedron Lett.
1993, 34, 2355.
[2] a) R. Jadulco, R. A. Edrada, R. Ebel, A. Berg, K. Schauman, V.
Wray, K. Steube, P. Proksch, J. Nat. Prod. 2004, 67, 78; b) H.
Hayashi, H. Matsumoto, K. Akiyama, Biosci. Biotechnol.
Biochem. 2004, 68, 753; c) B. Andersen, J. Smedsgaard, J. C.
Frisvad, J. Agric. Food Chem. 2004, 52, 2421; d) P. W. Dalsgaard,
J. W. Blunt, M. H. G. Munro, J. C. Frisvad, C. Christophersen, J.
Nat. Prod. 2005, 68, 258; e) L. J. Wigley, P. G. Mantle, D. A.
Perry, Phytochemistry 2006, 67, 561.
[3] For reviews, see: a) P. Siengalewicz, T. Gaich, J. Mulzer, Angew.
Chem. 2008, 120, 8290; Angew. Chem. Int. Ed. 2008, 47, 8170;
b) Z. Zuo, D. Ma, Isr. J. Chem. 2011, 51, 434; c) D. Zhang, H.
Song, Y. Qin, Acc. Chem. Res. 2011, 44, 447.
[13] T. Fukuyama, C. Jow, M. Cheung, Tetrahedron Lett. 1995, 36,
6373.
[14] CCDC 835717 (25) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[15] a) M. Szostak, L. Yao, J. Aubꢀ, J. Am. Chem. Soc. 2010, 132,
2078; b) C. G. Bashore, I. J. Samardjiev, J. Bordner, J. W. Coe, J.
Am. Chem. Soc. 2003, 125, 3268.
[4] a) J. A. May, R. K. Zeidan, B. M. Stoltz, Tetrahedron Lett. 2003,
44, 1203; b) S. L. Crawley, R. L. Funk, Org. Lett. 2003, 5, 3169;
c) J. Yang, H. Song, X. Xiao, J. Wang, Y. Qin, Org. Lett. 2006, 8,
2187; d) J. A. May, B. M. Stoltz, Tetrahedron 2006, 62, 5262;
Angew. Chem. Int. Ed. 2011, 50, 12008 –12011
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12011