Total synthesis of (±)-communesin F

Article abstract of DOI:10.1021/ja075705g

Total synthesis of the complex polycyclic indole alkaloid (±)-communesin F has been accomplished in 23 reaction steps in about 3% overall yield. The key steps relied on a highly efficient methodology for assembling the pentacyclic substructure 2 with the

Full text of DOI:10.1021/ja075705g

Published on Web 10/23/2007
Total Synthesis of (()-Communesin F
Jun Yang, Haoxing Wu, Liqun Shen, and Yong Qin*
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug Targeting,
West China School of Pharmacy, and State Key Laboratory of Biotherapy, Sichuan UniVersity,
Chengdu 610041, P. R. China
Received July 31, 2007; E-mail: yongqin@scu.edu.cn
Since the isolation of potent cytotoxic communesins A and B
from a marine fungal strain of Penicillium sp. in 1993,1 eight
members (A-H) of this structurally intriguing indole alkaloid
family were consecutively disclosed over the past 5 years2 (Figure
1). Although the polycyclic framework and multiple stereocenters
of communesins have attracted intensive synthetic efforts toward
skeletal construction in recent years,3 the successful synthesis of
members of this indole alkaloid family still remains unresolved.4
In this communication, we describe the first total synthesis of (()-
communesin F.
In view of construction of the multi-ring system (Figure 1), we
envisioned that formation of the F ring could be accomplished by
displacement of the imidate ether group with the second amine
group on the G ring (5 to 6) at a later stage of the synthesis. An
acid-catalyzed cyclization of 4, after introducing an allylic alcohol
side chain at C12a of 3 by a Heck reaction, could readily generate
the azepine ring. Stereoselective R-allylation of the ester functional
group of 2 would lead nicely to set up the C8 quaternary carbon
and would guarantee the subsequent formation of the C, E, F, and
G rings with the correct stereochemical centers. The pentacyclic
substructure 2 with a C7 quaternary carbon could be efficiently
assembled from diazo 1 using a methodology of intramolecular
cyclopropanation, ring opening, and ring closing reactions, the
methodology of which was developed in our group.5
Figure 1. Retrosynthetic analysis of communesin F.
Scheme 1 a
As demonstrated in Scheme 1, the preparation of 3 commenced
with indole 76 and acid 8.5 Condensation of 7 and 8, followed by
two steps of functional transformation from ketone to diazo,
furnished 1. Treatment of 1 with CuOTf led to the formation of a
stable cyclopropane intermediate 9 in an 88% yield as a mixture
of two diastereomeric isomers in a 1.6:1 ratio. Reduction of the
azide group in 9 with PBu3 in aqueous THF resulted in a two-step
cascade reaction of cyclopropane ring collapse and ring closure
with an in situ generated aniline, to give the kinetic product 2 in
an 83% yield as a single diastereoisomer. For stereoselective
generation of the C8 quaternary center by R-allylation for further
construction of the E ring, the nitrogen in 2 had to be protected
first with a methoxycarbonyl group. The N5-protection was easily
completed to afford carbamate 10 in excellent yield when 2 was
treated with methyl chloroformate and DMAP in CHCl3. Interest-
ingly, quantitative conversion of 10 to its epimer 11 was realized
by treatment of 10 with DMAP in CH2Cl2 at room temperature.
We originally thought that epimeric carbamates 10 and 11 might
provide diastereomeric allylation products, but both isomers yielded
the same compound 3 as the sole product with an 84% yield when
10 and 11 were treated with NaH and allyl bromide in dry DMF at
0 °C for 1 h, then at 65 °C for 3 h, respectively. Successful isolation
of the ketene acetal intermediate 12 confirmed that R-allylation of
this type of six-membered lactone proceeded through a stereose-
lective 3,3-rearrangement.7 In such a rearrangement, one face of
the dihydropyran ring was completely shielded by the bromophenyl
group to provide 3 with a secured cis relationship between the C7
a Reagents and conditions: (a) 8, SOCl2, 60 °C, 2 h; (b) 7, Et3N, CH2Cl2,
0 °C, 5 h (95%); (c) TsNHNH2, TsOH, CHCl3, reflux, 5 h (85%); (d) DBU,
CH2Cl2, 12 h (85%); (e) CuOTf, CH2Cl2, rt, 1 h (88%); (f) PBu3, aq. THF,
0 °C, 0.5 h (83%); (g) ClCO2Me, DMAP, CHCl3, rt, 7 h, 93%; (h) DMAP,
CH2Cl2, rt, 6 h, 99%; (i) NaH, allyl bromide, DMF, 0f65 °C, 4 h (84%).
ethylene group and the C8 allylic side chain, verified by a NOEDs
experiment of 3.
Completion of the total synthesis of communesin F from 3 is
depicted in Scheme 2. Oxidative cleavage of the double bond in 3
gave aldehyde 13 in a 95% yield. Conversion of the aldehyde
functionality of 13 into an amine, followed by heating the resulting
amino product with MeONa in MeOH at reflux, furnished the E
ring and left the hydroxyl group of the C7 side chain unprotected
(14). Dess-Martin oxidation, conversion of the resulting aldehyde
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J. AM. CHEM. SOC. 2007, 129, 13794-13795
10.1021/ja075705g CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
communesin F were consistent with that of the natural communesin
F provided by Prof. Hayashi.8 The characterization of two rotamers
and assignments of the isomer geometry were based on careful
NMR studies. The major rotamer with s-cis conformation was found
to have NOEDs among the C9 proton with protons of the C1, C11,
and C2′′ in CDCl3. The minor rotamer with s-trans conformation
was found to have NOEDs between the C17 proton and the C2′′
proton. Interestingly, the conformational distribution has been shown
to be solvent dependent. For example, a 2.6:1 ratio in CDCl3 and
a 5.1:1 ratio in DMSO-d6 were observed, respectively. The
thermodynamic equilibrium between two rotamers was studied to
show that the s-cis rotamer was favorably formed and became
predominant as the temperature increased to over 80 °C in DMSO-
d6. Importantly, protonation of (()-communesin F with 5% of CF3-
CO2H in CDCl3 provided 18 as single isomer, presumably as a
result of the fixed amide bond by formation of an intramolecular
hydrogen bond.
In summary, we have accomplished the total synthesis of (()-
communesin F in 23 reaction steps in about a 3% overall yield.
The key steps relied on a highly efficient methodology for
assembling the pentacyclic substructure, the stereoselective prepara-
tion of the second C8 quaternary carbon by O-allylation and
consecutive 3,3-rearrangement, and the stereoselective acid-
catalyzed cyclization to form the azepine ring. These highly
stereoselective reactions guaranteed the stereochemical results,
allowing the construction of the C, E, F, and G ring systems. Further
synthesis of other promising indole alkaloids of this family is under
investigation and will be disclosed in due course.
a Reagents and conditions: (a) OsO4, aq. acetone; (b) NaIO4, aq. THF
(95% from 3); (c) NH2OH‚HCl, Na2CO3, aq. THF; (d) H2, Raney-Ni,
MeOH, 40 °C, 3 h (87% based on recovered 13); (e) MeONa, MeOH, 70
°C, 12 h (98%); (f) Dess-Martin reagent, CH2Cl2, rt, 5 min; (g)
NH2OH‚HCl, Na2CO3, aq. THF, 10 min; (h) H2, Raney-Ni, MeOH, 50 °C,
1 h; (i) Boc2O, Na2CO3, CH2Cl2 (50% from 17); (j) Pd(OAc)2, P(o-Tol)3,
Et3N, neat 2-methyl-3-butyen-2-ol, microwave, 2 h (68% 4, 21% of 15
recovered); (k) PPTS, CHCl3, rt, 1 h (66% 17, 26% 16); (l) BF4OEt3,
iPrNEt2, CH2Cl2, rt, 2 h (95%); (m) 5% TFA in CH2Cl2, rt, 30 min; (n)
silica gel, CH2Cl2/MeOH 1:1, 50 °C, 12 h (81% from 17); (o) KOH, MeOH/
H2O 10:1, 100 °C, 24 h (65%); (p) NaBH4, AcOH/Ac2O 1:1, 0 °C, 73%;
(q) 5% CF3CO2H in CDCl3.
Acknowledgment. We gratefully acknowledge financial support
from NSFC (20632030 and 20572072) and Ministry of Education
(NCET and RFDP), Prof. Hideo Hayashi of Osaka Prefecture
University for providing the original NMR spectra of the natural
communesin F for comparison with that of the synthetic sample,
and Prof. Wei-Dong Li of Nankai University for variable discus-
sions.
Supporting Information Available: Experimental details and NMR
spectra of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
to an amine, and protection of the amine with Boc provided 15 in
a 50% overall yield. A standard Heck reaction of 15 with neat
2-methyl-3-butyen-2-ol at 100 °C for 10 h in the presence of 0.5
equiv of Pd(OAc)2, 2 equiv of P(o-Tol)3, and Et3N was unsuccess-
ful, and only trace amounts of the desired alcohol 4 were obtained.
Fortunately, when the same reaction was irradiated with a micro-
wave for 2 h, we were able to isolate 4 in a 68% yield and to
recover 15 in a 21% yield (86% yield of 4 based on recovered 15).
As we anticipated, although partial dehydration of 4 was unavoid-
able to give diene 16 in a 26% yield, the stereoselective acid-
catalyzed cyclization of 4 was readily accomplished to form the
desired azepine ring with an acceptable yield (17, 66%) when 4
was treated with PPTS in chloroform at room temperature.
With 17 in hand, our last task for ring system construction was
to convert the amide to a more reactive imidate functionality, which
might allow us to build the F ring upon removal of the Boc
protecting group. In contrast to our anticipation, treatment of 17
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(6) For preparation of intermediate 7, see Supporting Information.
(7) Similar 3,3-rearrangement was also observed in Weinreb’s experiments
of model study; see ref 3c.
(8) The original paper for isolation and characterization of the natural
communesin F reported the major (s-cis) rotamer with NMR data, but
the detectable minor rotamer (s-trans) was ignored by authors; see ref 2e
and personal communication with Prof. H. Hayashi.
i
with freshly made BF4OEt3 and PrNEt2, followed by removal of
the Boc group, was not accompanied by direct attack of the resulting
second amine on the imidate group to form the F ring, instead of
giving the chromatographically unstable imidate 5. To our delight,
without purification, direct treatment of 5 with silica gel at 50 °C
furnished 6a in a 77% yield from 17. Removal of the carbamate
protecting group in 6a with KOH provided 6b in a 65% yield. A
stereoselective reduction of 6b with a large excess of NaBH4 in a
1:1 mixture of AcOH and Ac2O at 0 °C resulted in simultaneous
acetylation of the resulting bisaminal group to afford (()-commu-
nesin F as an inseparable mixture of two amide rotamers in a 73%
yield. The 1H and 13C NMR spectra of the synthetic (()-
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