Studies directed toward the synthesis of hamigeran B: A catalytic oxidative cyclization

Article abstract of DOI:10.1021/ol102478h

An approach to the synthesis of hamigeran B is described. Key steps include a Tius - Nazarov cyclization and a palladium-catalyzed oxidative cyclization of an -hydroxyenone.

Full text of DOI:10.1021/ol102478h

ORGANIC
LETTERS
2
010
Vol. 12, No. 24
668-5670
Studies Directed toward the Synthesis
of Hamigeran B: A Catalytic Oxidative
Cyclization
5
Zhengxin Cai and Michael Harmata*
Department of Chemistry, UniVersity of MissourisColumbia, Columbia,
Missouri 65211, United States
harmatam@missouri.edu
Received October 13, 2010
ABSTRACT
An approach to the synthesis of hamigeran B is described. Key steps include a Tius-Nazarov cyclization and a palladium-catalyzed oxidative
cyclization of an r-hydroxyenone.
We recently reported the electrocyclization of a series of
1
cyclopentadienones under relatively mild conditions. For
example, treatment of 1 with triethylamine (TEA) in trif-
luoroethanol (TFE) afforded 4 through the intermediacy of
Scheme 1. Electrocyclization of a Cyclopentadienone
2
and 3 (Scheme 1). Compound 4 possesses the carbocyclic
2
skeleton of the antiviral agent hamigeran B (5), whose
activity against the polio and herpes viruses, coupled with
low cytotoxicity, has made it an attractive target for
3
synthesis.
A precursor for 5 that would use the methodology
exemplified in Scheme 1 would contain a methyl group as
shown in compound 6. Unfortunately, treatment of 6 with
base under our standard conditions resulted only in the
4
isolation of 7 in low yield (Scheme 2). Rather than abandon
(
1) Harmata, M.; Zheng, P.; Schreiner, P. R.; Navarro-Vazquez, A.
Angew. Chem., Int. Ed. 2006, 45, 1966. (b) Harmata, M.; Zheng, P.;
Schreiner, P. R.; Navarro-Vazquez, A. Tetrahedron Lett. 2007, 48, 5919.
the target, we realized that precursors similar to those we
would use for the cyclopentadienone electrocyclization could
also be used for other carbon-carbon bond forming pro-
(
2) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R.
J. Nat. Prod. 2000, 63, 79.
10.1021/ol102478h  2010 American Chemical Society
Published on Web 11/16/2010

Scheme 3. Synthesis of Compound 14
cesses that could lead to the synthesis of hamigeran B and
various congeners. We describe herein our progress toward
that goal.
Scheme 2
Our original plan called for the synthesis of 14, whose
enolic hydroxy group would be activated in some way to
allow elimination, but we realized that enol could also
function as a nucleophile, as will be seen. The synthesis of
5
1
4 is shown in Scheme 3. The readily available ester 8 was
reduced with DIBAL and oxidized to the corresponding
aldehyde with excess MnO in excellent overall yield. A
Stille coupling with tributylvinyl stannane gave 10, which
2
center bearing the isopropyl group will be destroyed, for this
could also be prepared by a Suzuki coupling with the pinacol
particular purpose the relative stereorelationships in 14 are
not of importance.
6
12
boronate ester of vinyl boronic acid in high yield. The
7
reaction of 10 with the dithiane organolithium 11 led to
We did, in fact, prepare the triflate of 14 and treat it with
various bases to attempt cyclopentadienone formation, but
none of these experiments were productive. However, we
the ketol 12 after hydrolysis in 56% yield. Oxidation of this
8
compound with IBX afforded the dione 13, which was
9
13
cyclized according to the Tius protocol by treatment with
were inspired by a paper by Widenhoefer concerning the
LiTMP from -78 °C to room temperature affording 14 in
intramolecular oxidative cyclization of simple alkenes with
ꢀ-diketones. We thus treated 14 under the Wacker reaction
conditions associated with this process and were pleased to
find that cyclization occurred smoothly to afford 17 in high
yield. The process presumably took place via nucleophilic
attack of the enol of 14 on the styryl double bond, which
had been activated by Pd(II) as in the case of 15. Palladium
hydride elimination from 16 then afforded 17. Regeneration
of Pd(II) took place by the typical Cu(I) to Cu(II) cycle
illustrated in Scheme 4. It is noteworthy that the use of
R-hydroxyenones as nucleophiles is rather rare, and we
venture to anticipate that many other opportunities to discover
10
5
9% yield. The relative stereochemistry of 14 was assigned
on the basis of the anticipated stereochemistry of the
intermediate enolate and the selection rules for electrocyl-
ization, which call for a conrotatory ring closure in Nazarov
1
1
and related cyclizations. However, since the stereogenic
(
3) For a review of the area, see: (a) Clive, D. L. J.; Wang, J. Org.
Prep. Proced. Int. 2005, 37, 1. For relevant work appearing after the review,
see: (b) Miesch, L.; Welsch, T.; Rietsch, V.; Miesch, M. Chem.sEur. J.
2
009, 15, 4394. (c) Taber, D. F.; Tian, W. J. Org. Chem. 2008, 73, 7560.
(
d) Arnaiz, E.; Blanco-Urgoiti, J.; Abdi, D.; Dominguez, G.; Castells, J. P.
J. Organomet. Chem. 2008, 693, 2431. (e) Trost, B. M.; Pissot-Soldermann,
C.; Chen, I. Chem.sEur. J. 2005, 11, 951. (f) Sperry, J. B.; Wright, D. L.
Tetrahedron Lett. 2005, 46, 411.
1
4
their synthetic utility exist.
(
4) Zheng, P.; Harmata, M. Unpublished results from these labora-
tories.
Compound 17 was actually obtained as a mixture of the
dione containing varying amounts of the enol 18, and
isomerization with triethylamine in the presence of some
silica gel to give 18 proved relatively facile (Scheme 5).
(
(
(
5) Harmata, M.; Hong, X. Org. Lett. 2004, 6, 2201.
6) See Supporting Information.
7) Kayser, M. M.; Zhao, H.; Chen, G.; Feicht, A. ARKIVOC (Gaines-
Ville, FL, U.S.) 2002, 12, 47.
(
(
8) Moore, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
9) (a) Batson, W. A.; Sethumadhavan, D.; Tius, M. A. Org. Lett. 2005,
7
2
, 2771. (b) Uhrich, E. A.; Batson, W. A.; Tius, M. A. Synthesis 2006, 13,
(12) It is worth noting that a slight light broadening in the proton NMR
of 14 suggested hindered rotation, presumably about the bond between the
cyclopentyl and arene rings. This phenomenon has yet to be studied.
(13) (a) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003,
125, 648. (b) Liu, C.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem.sEur.
J. 2004, 10, 6343.
139.
(
10) When the reaction was conducted with LiHMDS, the yield was
only 44%.
(
11) (a) Nakanishi, W.; West, F. G. Curr. Opin. Drug DiscoVery DeV.
2
009, 12, 732. (b) Tius, M. A. Eur. J. Org. Chem. 2005, 2193. (c) Pellissier,
H. Tetrahedron 2005, 61, 6479. (d) Frontier, A. J.; Collison, C. Tetrahedron
(14) Trost, B. M.; Dong, G.; Wance, J. A. Chem.sEur. J. 2010, 16,
6265.
2
005, 61, 7577.
Org. Lett., Vol. 12, No. 24, 2010
5669

Scheme 4. Oxidative Cyclization of 14
convinced us of the structures of our intermediates, it was
gratifying to find that 21 was a crystalline solid and its
structure was confirmed by X-ray analysis.
Scheme 5. Preparation of an Advanced Intermediate
In summary, we have prepared a highly functionalized
intermediate toward the synthesis of hamigeran B using a
Tius-Nazarov cyclization and an oxidative cyclization in
which the enol form of an R-diketone served as the
nucleophilic agent. Efforts to convert this intermediate (21)
to hamigeran B are in progress and further study of the
chemistry of R-hydroxyenones is in progress, and results will
be reported in due course.
Acknowledgment. This work was supported by a grant
from the National Science Foundation to whom we are
grateful. We thank Dr. Charles L. Barnes (Missouris
Columbia) for acquisition of X-ray data.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds and
X-ray crystallographic data of compound 21 in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Functionalization of 18 as a triflate and palladium-catalyzed
reduction gave 20 in very good overall yield. The dihy-
droxylation of 20 was conducted under standard conditions
and afforded 21 in moderate yield. Although NMR data
OL102478H
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Org. Lett., Vol. 12, No. 24, 2010