Total synthesis of the polycyclic fungal metabolite (±)-communesin F

Article abstract of DOI:10.1002/anie.200906818

(Chemical Equation Presented) What the Heck: The heptacyclic fungal alkaloid communesin F was the target of a total synthesis featuring a rare example of an intramolecular Heck cyclization of a tetrasubstituted alkene, a reductive cyclization of an N-Boc

Full text of DOI:10.1002/anie.200906818

Communications
DOI: 10.1002/anie.200906818
Total Synthesis
Total Synthesis of the Polycyclic Fungal Metabolite
(ꢀ )-Communesin F**
Peng Liu, Jae Hong Seo, and Steven M. Weinreb*
In 1993, Numata et al. isolated two unique natural products
from a Penicillium mold, which was found growing on the
marine alga Enteromorpha intestinalis.[1] The structures of
these compounds, communesin A (1) and communesin B (5),
were determined by spectroscopic analysis (Scheme 1). Nota-
microfilament disruption. The initial structural assignment of
this metabolite, however, was incorrect, and nomofungin was
in fact found to be communesin B (5). Notably, however,
Hemscheidt and co-workers established the configuration at
C21 of 5, together with the absolute configuration of the
molecule; these structural features were not originally
determined by the Numata group. More recently, several
other structurally modified communesin derivatives have
been isolated,[3,4] including communesin C (6), D (7), E (2), F
(8), G (3), and H (4). Some of these new compounds were
found to have significant biological activity. For example,
communesins D, E, and F are insecticidal, and commune-
sins C and D are moderately active against various leukemia
cell lines.
Several research groups have reported studies on the
synthesis of communesins.[5] In 2007, Qin and co-workers
reported the first successful construction of a communesin in
the form of a total synthesis of racemic communesin F (8).[6]
Herein, we report a new stereoselective synthesis of this
metabolite. Our approach employs a pivotal intramolecular
Heck reaction of a tetrasubstituted olefin to construct the B,
C, E, and F ring system as well as the C7 quaternary center.
The synthesis commenced with the known compound enol
triflate 9[7] (easily prepared from the corresponding commer-
cially available N-benzylpiperidine b-ketoester), which was
coupled with 2-nitrobenzeneboronic acid (10) in a Suzuki–
Miyaura reaction and afforded the arylated product 11
(Scheme 2). Basic hydrolysis of ester 11 gave the acid,
which was transformed into the acid chloride and then
coupled with readily prepared iodo aniline 12 (see Supporting
Information) and yielded amide 13. At this point, the benzyl
group of 13 was replaced by an ethyl carbamate moiety in a
one-pot procedure using ethyl chloroformate, and the result-
ing amide was alkylated to form the N-methyl compound 14.
To our delight, tetrasubstituted alkene 14 underwent a clean
intramolecular Heck reaction,[8] and subsequent b-hydride
elimination afforded tetracyclic enamide 15 (bearing the
quaternary center at C7 of the alkaloid) in high yield. It
should be pointed out that intra-[9a] or intermolecular[9b] Heck
reactions involving tetrasubstituted olefins are uncommon.
To continue the synthesis, the nitro group of 15 was
reduced by catalytic hydrogenation, and the resulting aniline
was protected as the Boc derivative 16 (Scheme 3). It was
then found that lactam 16 can be partially reduced with alane–
dimethylethylamine complex, and subsequent in situ cycliza-
tion to produce the lower aminal 17 having the requisite
configuration at C6 and C7.[10]
Scheme 1. The communesin family of natural products.
ble features of these complex, highly functionalized polycyclic
metabolites are the two contiguous quaternary centers at C7/
8, and the presence of the two aminal moieties. The
communesins were found to have cytotoxic activity against
P-388 lymphoid leukemia cells in vitro. In 2001, Hemscheidt
and co-workers described an alkaloid called nomofungin,
which was isolated from an unidentified fungus growing on
the bark of Ficus microcarpa in Hawaii.[2] This material was
found to have cytotoxic activity against LoVo and KB cells,
which resulted from the ability of the metabolite to cause
[*] P. Liu, J. H. Seo, Prof. Dr. S. M. Weinreb
Department of Chemistry, The Pennsylvania State University
University Park, PA 16802 (USA)
Fax: (+1)814-865-3292
E-mail: smw@chem.psu.edu
[**] We are grateful to the National Institutes of Health (CA-34303) and
the National Science Foundation (CHE-0806807) for the financial
support of this research.
After some exploration, it was decided that the best
approach for installation of the quaternary center at C8 would
be to alkylate the B-ring lactam. To implement this strategy,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906818.
2000
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Scheme 2. a) [Pd(PPh3)4], DME, H2O, Na2CO3, 808C, 10, 98%;
b) LiOH, H2O, MeOH, 508C, 86%; c) SOCl2, reflux; then iPr2NEt,
CH2Cl2, RT, 12, 87%; d) ClCO2Et, CH2Cl2, 08C!RT, 96%; e) NaH,
THF, MeI, 08C!RT, 92%; f) Pd(OAc)2, PPh3, DMA, K2CO3, nBu4NBr,
1508C, 90%. DME=1,2-dimethoxyethane, DMA=N,N-dimethylaceta-
mide, Tf=trifluoromethanesulfonyl, BOM=benzyloxymethyl,
THF=tetrahydrofuran.
enamide 17 was first hydrolyzed to the enamine 18, which
reacted with cyanogen azide generated in situ and afforded N-
cyanoamidine 20.[11] This transformation presumably occurs
through an initial [3+2] dipolar cycloaddition of the enamine
to afford adduct 19, which rearranges spontaneously to afford
20. Basic hydrolysis of this amidine gave the corresponding
lactam, and subsequent acylation led to N-Boc lactam 21 (3:1
mixture of epimers).
The key alkylation step involved treating N-Boc lactam 21
with potassium tert-butoxide and allyl iodide to afford the
desired product 23 in high yield and as a single stereoisomer
at C8. This alkylation proceeds via attack of the iodide on
lactam enolate 22 from the less hindered convex face. To
prepare for construction of the upper aminal system, after
selective removal of the Boc group on the lactam nitrogen
atom of 23 by basic hydrolysis, the allyl group was oxidatively
cleaved and the resulting aldehyde was manipulated by a
straightforward sequence to form mesylate 24.
Scheme 3. a) 5% Pt/C, H2 (40 atm) toluene, RT; b) Boc2O, K2CO3,
THF, H2O, 608C, 87% (2 steps); c) AlH3·Me2NEt, THF, 08C!RT,
74%; d) 1m KOH, EtOH, 948C; e) NCN3, MeCN, RT, 93% (2 steps);
f) 1m KOH, EtOH, 948C, 60%; g) Boc2O, LiHMDS, THF, RT, 95%;
h) KOtBu, THF, allyl iodide, ꢁ788C!RT, 87%; i) 1m KOH, EtOH,
808C, 94%; j) OsO4, NMO, THF, H2O; then NaIO4, RT; k) NaBH4,
EtOH, 08C; l) MsCl, NEt3, CH2Cl2, 08C, 83% (3 steps). Boc=tert-
butoxycarbonyl, HMDS=hexamethyldisilazide, NMO=N-methylmor-
pholine N-oxide, Ms=methanesulfonyl.
The BOM protecting group of 24 was then removed by
catalytic hydrogenolysis, and the resulting benzylic alcohol
was oxidized with Dess–Martin periodinane and afforded
aldehyde 25 (Scheme 4). After conversion of mesylate 25 into
the azide 26 with sodium azide in DMF, we investigated the
conversion of 26 into the a,b-unsaturated ketone 27. Surpris-
ingly, this transformation was not feasible using the Wittig
reaction, but gratifyingly the aldehyde underwent a clean
cross-aldol reaction with acetone using aqueous sodium
hydroxide and produced the desired E-unsaturated ketone
27 in excellent yield. After reinstalling a Boc group on the d-
lactam nitrogen atom of 27, azide reduction using trimethyl-
phosphine in aqueous THF caused an in situ rearrangement
and formed spiro-g-lactam 28.
Scheme 4. a) Pearlman’s catalyst, H2, THF, RT; b) DMP, CH2Cl2, RT,
75% (2 steps); c) NaN3, DMF, 908C, 61%; d) Me2CO, 10% NaOH/
H2O, 608C, 93%; e) Boc2O, LiHMDS, THF, RT, 81%; f) PMe3, THF,
H2O, 708C, 88%. DMP=Dess—Martin periodinane, DMF=N,N-
dimethylformamide.
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To expedite the construction of the remaining B and
In summary, we have achieved a racemic stereoselective
total synthesis of the heptacyclic alkaloid communesin F (8)
in approximately 30 steps from the known compound enol
triflate 9. The key reactions include a novel intramolecular
Heck cyclization of a tetrasubstituted alkene to generate a
tetracycle with a quaternary carbon center, a reductive
cyclization of an N-Boc aniline onto an oxindole moiety to
form the pentacyclic framework containing the lower aminal
group, a stereoselective C allylation of a lactam to introduce
the second quaternary carbon center, and an azide reduction
N-Boc-d-lactam ring opening cascade leading to the upper
aminal functionality. We are currently investigating enantio-
selective methodologies for improving the pivotal Heck
reaction of 14 to produce natural (ꢁ)-communesin F.
G rings of the alkaloid, the unsaturated ketone 28 was first
treated with methyllithium and produced allylic alcohol 29 in
high yield (Scheme 5). The remaining steps of the synthesis
were then carried out based on the work of Qin and co-
workers.[6] Thus, exposure of 29 to PPTS in chloroform at
Received: December 3, 2009
Published online: February 19, 2010
Keywords: alkaloids · Heck reactions · natural products ·
.
nitrogen heterocycles · total synthesis
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Scheme 5. a) MeLi, THF, ꢁ788C, 73%; b) PPTS, CHCl3, RT, 62%;
c) Me3OBF4, iPr2NEt, CH2Cl2, RT, 86%; d) 5% TFA in CH2Cl2, RT, 88%;
e) NaBH4, Ac2O, HOAc; f) 40% TFA in CH2Cl2, RT, 66% (2 steps).
PPTS=pyridinium p-toluenesulfonate, TFA=trifluoroacetic acid.
room temperature led to hexacycle 30 in 62% yield through a
stereoselective allylic substitution reaction to form the G ring
with the requisite configuration at C11. In addition, a small
amount of the diene resulting from dehydration of starting
alcohol 29 was produced. The stereochemical outcome of this
cyclization is undoubtedly due to attack of the NHBoc group
on the isopentenol side chain through the preferred con-
formation shown in 29. This conformation is enforced by
minimization of steric interactions with the A-ring lactam.
To complete the synthesis, g-lactam 30 was treated with
trimethyloxonium tetrafluoroborate in the presence of
Hꢀnigꢁs base to generate imidate 31. The upper Boc protect-
ing group was then selectively removed with TFA (5%) in
methylene chloride, and upon neutralization of the resulting
amine salt, cyclization occurred to form the heptacyclic
amidine 32. Reduction of this amidine with sodium borohy-
dride in acetic acid containing acetic anhydride occurred
stereoselectively from the least congested face, and yielded
the N-acetyl aminal 33. Finally, removal of the Boc protecting
group on the lower aminal functionality with TFA (40%) in
methylene chloride afforded racemic communesin F (8).The
spectroscopic data for the synthetic product 8 correlated
closely with that reported by the Qin group.[6]
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