Polyene cyclization promoted by the cross-conjugated α-carbalkoxy cyclohexenone system. An unusual 1,2-hydride shift under lewis acid catalysis

Article abstract of DOI:10.1021/ol802878t

Polyene cyclization of the titled compounds under catalysis with AICI ₃/SnCI₄ gave rise to the corresponding polycycllc products, many of which were structurally highly unexpected, and thus, Individual X-ray analysis was required to

Full text of DOI:10.1021/ol802878t

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1673-1675
Polyene Cyclization Promoted by the
Cross-Conjugated r-Carbalkoxy
Cyclohexenone System. An Unusual
1,2-Hydride Shift under Lewis Acid
Catalysis
Min-Tsang Hsieh,† Ho-Hsuan Chou,‡ Hsing-Jang Liu,‡ Huang-Min Wu,‡
Tai Wei Ly,§ Yen-Ku Wu,‡ and Kak-Shan Shia*,†
DiVision of Biotechnology and Pharmaceutical Research, National Health Research
Institutes, Miaoli County 350, Taiwan, R.O.C., Department of Chemistry, National
Tsing Hua UniVersity, Hsinchu, Taiwan 30013, R.O.C., and Axikin Pharmaceuticals,
Inc., 10835 Road to the Cure, Suite 250, San Diego, California 92121
ksshia@nhri.org.tw
Received December 15, 2008
ABSTRACT
Polyene cyclization of the titled compounds under catalysis with AlCl3/SnCl4 gave rise to the corresponding polycyclic products, many of
which were structurally highly unexpected, and thus, individual X-ray analysis was required to finalize the structural identification. Mechanistically,
an unusual 1,2-hydride shift is proposed to elucidate the product formation.
The polyene cyclization process, commonly recognized as
a highly biosynthesis-mimicking paradigm, has been widely
applied to facilitate the assembly of multiple ring systems
in organic synthesis. As documented, functionalities serving
as effective initiators for the polyene cyclization process
included epoxide,1 acetal,2 allylic alcohol,3 and R, ꢀ-unsatur-
ated carbonyl groups (aldehyde or ketone).4 During the past
decade, intramolecular polyene cyclization focusing on the
cross conjugated R-carbalkoxy enone systems has been
extensively studied in Liu’s laboratories to have facile access
to various structurally complex polycylic frameworks.5 Along
this line, it was recently reported that enones 1 and 2 could
undergo effective intramolecular cyclization under Lewis acid
catalysis to give rise to structurally unusual products.5g The
corresponding positional analogues 3 and 4, each possessing
a terminal olefinic linker at the ꢀ′-position, were then
prepared.
† National Health Research Institutes.
‡ National Tsing Hua University.
§ Axikin Pharmaceuticals, Inc.
(1) (a) van Tamelen, E. E. Acc. Chem. Res. 1975, 8, 152. (b) Goldsmith,
D. J.; Philips, F. J. Am. Chem. Soc. 1969, 91, 5862. (c) van Tamelen, E. E.;
Freed, J. H. J. Am. Chem. Soc. 1970, 92, 7206.
(2) Johnson, W. S. Bioorg. Chem. 1976, 5, 51.
(3) van der Gen, A.; Weidhaup, K.; Swoboda, J. J.; Dunathan, H.;
Johnson, W. S. J. Am. Chem. Soc. 1973, 95, 2656.
Compounds thus obtained were treated with an appropriate
Lewis acid under standard reaction conditions to effect
polyene cyclization as indicated in the preceding work.5g
Most of the cyclization products failed to be elucidated by
10.1021/ol802878t CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society

general spectral data, and X-ray crystallographic analyses
were required to finalize the structural identification. Details
of this investigation will be described as follows.
nonane 7a. To further investigate the mechanistic aspects,
compound 3 under treatment with both AlCl3 and TMSCl
(Scheme 3), an enolate-trapping agent, was also carried out
Enone ester 3 was readily prepared from commercially
available 4,4-dimethyl-2-cyclohexen-1-one through a three-
step sequence as illustrated in Scheme 1. Hosomi-Sakurai
Scheme 3
Scheme 1
at the same reaction conditions. As a result, only a ca. 1:1
mixture of epimeric chlorides 7b was formed in 72% yield,
implying that the ensuing enolate might play a critical role
in promoting the 1,2-hydride shift; however, exactly what
driving force triggers the proposed 1,2-hydride shift is still
not fully understood and thus more evidence is required
before any conclusions can be derived.7
Similar product outcomes were also observed with enone
ester 1 upon treatment with SnCl4. As illustrated in Scheme
4, the resulting tricyclo[3.3.1.0]nonane 8a and chloride 8b
addition of allyltrimethylsilane to 4,4-dimethyl-2-cyclohexen-
1-one in the presence of TiCl4 at -78 °C afforded compound
5 in 81% yield. Subsequent treatment of 5 with dimethyl
carbonate using NaH as a base gave rise to keto ester 6 (80%)
as an inseparable mixture of keto and enol isomers, which
in turn were oxidized by DDQ to provide the desired 3 in
52% yield. The carbomethoxylation occurred in a highly
regioselective manner, which was somewhat unexpected, and
thus accelerated the entire synthetic process. With enone ester
3 in hand, the intramolecular polyene cyclization was then
explored. Upon treatment with aluminum trichloride
(2 equiv) at ambient temperature, a separable mixture of
products 7a and 7b was obtained in a 1.1:1 ratio in 78%
yield. The structure of 7a was determined unambiguously
by X-ray analysis,6 and a pair of inseparable diastereomers
7b were tentatively assigned based on the previously
structurally closely related compounds.5a-c A plausible
mechanistic rationale is proposed in Scheme 2.
Scheme 4
Scheme 2
were obtained in 22% and 40% yield, respectively. The
structure of 8a was unambiguously determined by an X-ray
analysis.8 However, the stereochemistry of chloride 8b was
ascertained via its corresponding acetate 9 by NOE experi-
(4) (a) Majetich, G.; Khetani, V. Tetrahedron Lett. 1990, 31, 2243. (b)
Snider, B. B.; Rodini, D. J.; van Straten, J. J. Am. Chem. Soc. 1980, 102,
5873. (c) Marshall, J. M.; Wuts, P. G. A. J. Org. Chem. 1977, 42, 1794.
(d) Dastur, K. P. J. Am. Chem. Soc. 1974, 96, 2605. (e) Naegeli, P.
Tetrahedron Lett. 1978, 2127. (f) Schinzer, D.; Ringe, K. Synlett 1994,
463.
(5) (a) Liu, H. J.; Sun, D.; Shia, K. S. Tetrahedron Lett. 1996, 37, 8073.
(b) Liu, H. J.; Sun, D.; Shia, K. S. J. Chin. Chem. Soc. 1999, 46, 453. (c)
Liu, H. J.; Sun, D.; Roa-Gutierrez, F.; Shia, K. S. Lett. Org. Chem. 2005,
2, 364. (d) Liu, H. J.; Sun, D. Heterocycles 2000, 52, 1251. (e) Liu, H. J.;
Tran, D. D. P. Tetrahedron Lett. 1999, 40, 3827. (f) Chin, C. L.; Tran,
D. D. P.; Shia, K. S.; Liu, H. J. Synlett 2005, 417. (g) Chou, H. H.; Wu,
H. M.; Wu, J. D.; Ly, T. W.; Jan, N. W.; Shia, K. S.; Liu, H. J. Org. Lett.
2008, 1, 121.
Following an ensuing aluminoxy complex, we envisaged
that a tandem migration process including a 1,2-hydride shift
took place, resulting in the formation of the tricyclo[3.3.1.0]-
1674
Org. Lett., Vol. 11, No. 8, 2009

ments.9 The product formation of 1 was found to be catalyst
dependent as compared to the preceding work wherein
compound 1 was catalyzed with AlCl3, affording a single
product with the bicyclo[3.3.1]nonane skeleton instead.5g
The preparation of enone ester 4 was fulfilled following a
similar synthetic sequence as described for 3 with the
exception that the Hosomi-Sakurai addition was replaced
with a regular 1,4-conjugate addition with 3-butenylmagne-
sium bromide in the presence of copper(I) iodide. Similarly,
when 4 was treated with AlCl3 (2 equiv) for 6 h at ambient
temperature (Scheme 5), the polyene cyclization process
direct the pathway A for 10 rather than pathway B for 11,
appearing more preferred in terms of the spatial distance
between R anion and the ensuing carbocation, remains
unclear and is worth further studies. Indeed, the 1,2-hydride
shift proposed for the above systems is somewhat unusual
as compared to those described in many historical cases,
where they are limited to substrates containing a C(sp3)-H
bond adjacent to an oxygen atom11 or a tertiary benzylic
C(sp3)--H bond12 as a hydride donor so that the ensuing
carbocation could be stabilized by electron delocalization;
this carbocation-stabilizing ability is believed to serve, in
part, as the essential driving force to facilitate the 1,2-hydride
shift in these systems.
Scheme 5
In conclusion, under catalysis with an appropriate Lewis
acid, the R-activated cross-conjugated cyclohexenone systems
might undergo polyene cyclization in an enzyme-mimicking
way to afford various carbon skeletons which are difficult
to access by other existing methods. In addition, the product
formation was found to be catalyst-dependent, thus making
the titled systems not only useful in organic synthesis but
also challenging in mechanistic aspects.
Acknowledgment. We are grateful to the National Health
Research Institutes and National Science Council of the
Republic of China for financial support.
occurred smoothly to afford tricyclo[4.3.1.0]decane 10
exclusively in ca. 68% yield, the structure of which was
characterized spectroscopically and further substantiated by
X-ray crystallographic studies.10 Our proposed mechanism
for the formation of 10 proceeds from the cationic intermedi-
ate upon cyclization of the terminal olefin to the activated
enone unit followed by a series of tandem rearrangements
involving 1,2-hydride migration and the through-space ring
closure. However, as depicted in Scheme 6, what factors
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for all new com-
pounds described in this paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802878T
(6) CCDC 261323 (7a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html or deposite@ccdc.cam.ac.uk.
(7) All the 1,2-hydride shifts represented in the paper are presumably
reversible.
(8) CCDC 261322 (8a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html or deposite@ccdc.cam.ac.uk.
Scheme 6
(9) Although 8b was obtained as a single diastereomer in an enol form
as indicated by its 1H NMR spectrum, to rule out any undesired signals
from other potential isomers, the labile stereogenic center linked to the
carbonyl was destroyed by acetylation to give acetate 9 prior to performing
NOE experiments.
(10) CCDC 701542 (10) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html or deposite@ccdc.cam.ac.uk.
(11) (a) Donohoe, T. J.; Williams, O.; Churchill, G. H. Angew. Chem.,
Int. Ed. 2008, 47, 2869. (b) Kimishima, A.; Nakata, T. Tetrahedron Lett.
2008, 49, 6563. (c) Robins, M. J.; Nowak, I.; Wnuk, S. F.; Hansske, F.;
Madej, D. J. Org. Chem. 2007, 72, 8216. (d) Selvakumar, S.; Baktharaman,
S.; Singh, V. K. J. Org. Chem. 2007, 72, 10141. (e) Treiber, A. J. Org.
Chem. 2002, 67, 7261.
(12) Mladenova, G.; Chen, L.; Rodriquez, C. F.; Siu, K. W. M.; Johnston,
L. J.; Hopkinson, A. C.; Lee-Ruff, E. J. Org. Chem. 2001, 66, 1109.
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