Total synthesis and absolute stereochemical assignment of (-)-communesin F

Article abstract of DOI:10.1021/ja106739g

A concise asymmetric total synthesis of (-)-communesin F (～6% overall yield in the longest linear sequence of 19 steps) is described. It features an unprecedented intramolecular oxidative coupling strategy for the elaboration of the requisite spiro-fused indoline moiety. Other notable elements are the use of TBS-protected (S)-phenylglycinol as a chiral auxiliary to induce the asymmetric formation of the spiro-fused indoline part, the mesylate-mediated formation of its G ring, and the introduction of the A ring at the final stage via intramolecular Staudinger reaction. This intramolecular Staudinger reaction proceeded smoothly at 80 °C, providing an additional example illustrating that twisted amides are more reactive than simple amides. Along with the total synthesis, we were able to assign the absolute configuration of natural communesin F as 6R,7R,8R,9S,11R.

Full text of DOI:10.1021/ja106739g

Published on Web 09/02/2010
Total Synthesis and Absolute Stereochemical Assignment of
(-)-Communesin F
Zhiwei Zuo, Weiqing Xie, and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received August 9, 2010; E-mail: madw@mail.sioc.ac.cn
Abstract: A concise asymmetric total synthesis of (-)-commu-
nesin F (∼6% overall yield in the longest linear sequence of 19
steps) is described. It features an unprecedented intramolecular
oxidative coupling strategy for the elaboration of the requisite
spiro-fused indoline moiety. Other notable elements are the use
of TBS-protected (S)-phenylglycinol as a chiral auxiliary to induce
the asymmetric formation of the spiro-fused indoline part, the
mesylate-mediated formation of its G ring, and the introduction
of the A ring at the final stage via intramolecular Staudinger
reaction. This intramolecular Staudinger reaction proceeded
smoothly at 80 °C, providing an additional example illustrating
that twisted amides are more reactive than simple amides. Along
with the total synthesis, we were able to assign the absolute
configuration of natural communesin F as 6R,7R,8R,9S,11R.
The indole alkaloid communesin F (1, Figure 1) belongs to a
growing family of natural products isolated from a marine fungal
strain of Penicillium species that now contains eight members
(communesins A-H).1,2 Preliminary biological evaluation has
revealed that these alkaloids possess significant cytotoxicity and
insecticidal activity.1 Their interesting biological activities and
unique structures have attracted considerable attention from syn-
thetic chemists worldwide.2-5 This campaign has afforded several
Figure 1. Retrosynthetic analysis of (-)-communesin F.
elegant protocols for assembling the core structure of these indole
alkaloids.3 However, only two completed total syntheses have been
With this idea in mind, we conducted a model reaction by
disclosed,4,5 implying that there are some challenges in the total
syntheses of these natural products. Herein we report the first
asymmetric total synthesis of (-)-communesin F, which allows the
establishment of the absolute configuration of these natural products.
As depicted in Figure 1, we expected that the target molecule 1
could be synthesized from diol 2 via formation of the G and A
rings. The diol 2 could be obtained from pentacyclic compound 3
via two carbon-chain elongation reactions. Since a nucleophilic
cyclization of indoline 4 could deliver the amide 3, we planned to
assemble the requisite spiro-fused indoline 4 through an intramo-
lecular oxidative coupling reaction of dianion 5 generated from
3-substituted indole 6.
treatment of 7a (X ) H) with LiHMDS (Scheme 1). To our delight,
after the resultant dianion was trapped with iodine, the desired
indoline 8a was isolated in 38% yield. We next checked Boc-
protected aniline 7b and were disappointed by our inability to find
any cyclization products. Further evaluation indicated that nitro-
containing amide 7c is a suitable substrate, as spiro-fused indoline
8c could be obtained in 83% yield as a diastereomeric mixture with
a ratio of 2:1. These differences in reactivity indicated that the pKa
values of the activated methylene units might have a crucial
influence on the oxidative coupling step.
Scheme 1
During the past few years, Baran and co-workers6 have dem-
onstrated that the direct intermolecular coupling of some carbonyl
compounds with unfunctionalized indoles and pyrroles can be
accomplished by deprotonation and subsequent oxidation. Inspired
by these achievements, we decided to explore the possibility of
constructing spiro-fused indolines via an intramolecular oxidative
coupling of 3-substituted indoles bearing an activated methylene
moiety. If this transformation were to succeed, we would have a
powerful approach for accessing a number of indole alkaloids that
contain spiro-fused indoline core structures.
On the basis of the success of the model reactions, we started
our total synthesis of communesin F. As shown in Scheme 2,
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13226 J. AM. CHEM. SOC. 2010, 132, 13226–13228
10.1021/ja106739g  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3a
oxidation of 4-bromotryptophol (9) followed by reductive amination
with TBS-protected (S)-phenylglycinol afforded secondary amine
10, which was condensed with 2-(2-nitrophenyl)acetic acid with
the assistance of BOPCl to provide the desired amide 6. As we
expected, oxidative coupling of 6 proceeded well under the
established reaction conditions, delivering spiro-fused indoline 4
as a diastereomeric mixture. After reduction of the nitro group in
4 with iron powder and ammonium chloride, the resultant amine
attacked the imine part spontaneously to afford a pentacyclic
intermediate, which was subjected to selective methylation to afford
aminal 11a in 50% overall yield together with its diastereomer 11b
in 16% yield. This result indicated that the chiral auxiliary part
could lead to reasonable asymmetric induction in the oxidative
coupling step.
Scheme 2a
a Conditions: (a) KHMDS, (Boc)2O, THF, 0 °C; (b) KOtBu, allyl iodide,
ether, rt; (c) TBAF, THF; (d) LiOH ·H2O, DMSO, 100 °C; (e) HCl, THF,
60 °C; (f) NaIO4, K2OSO4(H2O)2, NMO, THF, H2O; (g) NaBH4, MeOH;
(h) Pd(OAc)2, P(o-Tol)3, PMP, nBu4NBr, 3:2 2-methyl-3-buten-2-ol/DMF,
microwave, 140 °C, 20 min; (i) MsCl, Et3N, CH2Cl2, 0 °C; (j) NaN3,
nBu4NBr, DMF, 90 °C; (k) P(nBu)3, toluene, 80 °C; (l) NaBH4, HOAc,
Ac2O; (m) CF3CO2H, CH2Cl2.
a Conditions: (a) IBX, DMSO; (b) (S)-O-TBS-phenylglycinol, NaB-
H(OAc)3; (c) 2-(2-nitrophenyl)acetic acid, BOPCl, Et3N, CH2Cl2, 0 °C to
rt; (d) LiHMDS, THF, -78 °C followed by iodine, -78 °C to rt; (e) Fe,
NH4Cl, tBuOH, H2O, reflux; (f) KOtBu, MeI, THF, 0 °C.
out. To our surprise, treatment of 2 with mesyl chloride and
triethylamine not only resulted in the mesylation but also formation
of the G ring, thereby providing hexacyclic mesylate 15 in 63%
yield. This mesylate was treated with sodium azide in DMF at 90
°C to give azide 16. We then shifted our attention to the formation
of the amidine moiety via an intramolecular Staudinger reaction.
A literature survey indicated that intramolecular Staudinger reactions
of simple amides require rather high reaction temperatures to afford
the cyclic amidines in moderate yields,9 although activated amides
proceed smoothly in similar transformations.10 Indeed, Funk and
Fuchs11a were unsuccessful in using this method to construct the
amidine unit of perophoramidine, a natural product structurally
related to the communesins. This problem forced them to reach
the goal by transforming the lactam into the more reactive imidate
with Meerwein’s reagent.11 We envisioned that the intermediate
16 is a twisted amide in which the carbonyl group should become
more reactive because of the loss of conjugation between the amide
nitrogen and the CdO π bond,12 and we thought that this character
might offer us an opportunity to obtain the desired cyclic amidine
under mild conditions. Gratifyingly, exposure of 16 to tri-n-butylphos-
phine in toluene at 80 °C delivered amidine 17 in 82% yield (53%
overall yield from 2 to 17 was obtained when purification of 15 and
17 was omitted). Finally, reduction of 17 with NaBH4 followed by
cleavage of the Boc group with TFA furnished the target molecule 1.
The sign of rotation for our synthetic 1 ([R]2D4.5 ) -249.5 (c 0.30,
CHCl3)) was consistent with that reported for natural communesin F
([R]2D0 ) -264 (c 0.34, CHCl3)). Therefore, we could conclude that
the absolute configuration of natural communesin F is identical to that
of communesins A and B.
Protection of 11a with (Boc)2O produced 3 (Scheme 3), which
was subjected to allylation (KOtBu then allyl iodide) and subsequent
desilylation with TBAF to deliver alcohol 12 as a single isomer. A
similar stereochemical outcome in the allylation step was observed
in Weinreb’s synthesis of communesin F.5 X-ray structural analysis
of 12 revealed that this heterocycle has a 6S,7R,8R configuration
(see the Supporting Information for detailed studies), which would
allow us to establish the absolute configuration of natural commu-
nesin F. Next, removal of the chiral auxiliary in 12 was successively
conducted using Ennis’ elimination/hydrolysis method7 to give amide
13. Oxidative cleavage of the C-C double bond in 13 with NaIO4/
K2OSO4(H2O)2 followed by reduction with NaBH4 afforded alcohol
14 in 95% yield. Aryl bromide 14 was coupled with 2-methyl-3-buten-
2-ol under modified Heck reaction conditions to afford the desired
diol 2 (80% yield based on 17% recovery of 14).4,8
With allyl alcohol 2 in hand, we continued our synthesis by
formation of the G and A rings of communesin F. In their previous
reports, both Qin4 and Weinreb5 chose to construct the B ring at
the final stage. This strategy would have required opening of the
existing B ring and subsequent operations, which would have
decreased the synthetic efficiency considerably. We thought that it
would be possible to synthesize the target molecule more efficiently
if formation of the A ring could be achieved at the final stage.
Accordingly, conversion of 2 to the corresponding azide was carried
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C O M M U N I C A T I O N S
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In conclusion, we have accomplished the first total synthesis of
(-)-communesin F in 19 steps (longest linear sequence from
4-bromotryptophol) in ∼6% overall yield. Along with the total
synthesis, the absolute configuration of this natural product was
established, which will be helpful in solving the remaining
stereochemical questions for the other communesins as well as
perophoramidine. Our approach for efficiently constructing the G
and A rings will be of benefit for the assembly of the other members
of the communesin family, while our spiro-fused indoline formation
via an intramolecular oxidative coupling will stimulate further
applications in the syntheses of related indole alkaloids. Investiga-
tions in this direction are being actively pursued in our laboratory,
and the results will be disclosed in due course.
(2) For a brief review, see: Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew.
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Acknowledgment. The authors are grateful to the National
BasicResearchProgramofChina(973Program,Grant2010CB833200),
the Chinese Academy of Sciences, and the National Natural Science
Foundation of China (Grants 20632050 and 20921091) for their
financial support.
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Supporting Information Available: Experimental and spectral data
for all new compounds and crystallographic data (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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