Tandem oxy-Cope/transannular ene reaction of 1,2-divinylcyclohexanols

Article abstract of DOI:10.1021/ol005502w

Graph Presented The syntheses via tandem oxy-Cope/transannular ene reaction of 1,2-divinylcyclohexanols to bi-and tricyclic skeletons are described. This strategy generates a rapid method for the preparation of advanced polycyclic intermediates with high

Full text of DOI:10.1021/ol005502w

ORGANIC
LETTERS
2000
Vol. 2, No. 5
663-665
Tandem Oxy-Cope/Transannular Ene
Reaction of 1,2-Divinylcyclohexanols
Jeffrey M. Warrington, Glenn P. A. Yap,† and Louis Barriault*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada, K1N 6N5
lbarriau@science.uottawa.ca
Received January 2, 2000
ABSTRACT
The syntheses via tandem oxy-Cope/transannular ene reaction of 1,2-divinylcyclohexanols to bi- and tricyclic skeletons are described. This
strategy generates a rapid method for the preparation of advanced polycyclic intermediates with high diastereoselectivity.
Tandem reaction strategies have emerged as powerful
methods for the formation of new carbon-carbon bonds.1
The tandem combination oxy-Cope/transannular ene has been
observed accidentally by Sutherland et al. as an undesired
side reaction of the oxy-Cope rearrangement.2 It was also
reported by Paquette3 and Rajagopalan4 that the transannular
ene reaction byproducts occurred in some cases during the
anionic oxy-Cope rearrangement. Thus, the tandem oxy-
Cope/ene reaction reveals a reliable method to rapidly obtain
polycyclic structures with a tertiary alcohol at the ring
junction. To demonstrate its feasibility, we have investigated
this tandem combination using different 1,2-divinylcyclo-
hexanols.
Scheme 1a
a (a) CH2dC(CH3)MgBr, CuBr-DMS in THF, -30 °C to rt,
88%; (b) (COCl)2, DMSO in CH2Cl2, -78 °C then Et3N, 80%.
using the Swern method6 gave ketone 3 in 80% yield. 1,2-
Divinylcyclohexanols 4 and 5 were obtained as single
diastereoisomers in good yields by treatment of ketone 3 with
vinylmagnesium bromide and isopropenylmagnesium bro-
mide in THF at -78 °C (Scheme 2).
The synthesis started with the epoxide opening5 of
cyclohexene oxide 1 with isopropenylmagnesium bromide
and a catalytic amount of CuBr-DMS in THF to afford
cyclohexanol 2 in 88% yield (Scheme 1). Oxidation of 2
Alkylation of 3 with cyclohexenyllithiums 67 and 88 and
lithiodihydropyran 109 in THF at -78 °C furnished the
corresponding tertiary alcohols 7, 9, and 11 in 50-73%
yields as single trans diastereoisomers. Tertiary alcohol 13
was prepared via [1,2]-migration of the chlorohydrin gener-
ated from commercially available 2-chlorocyclohexanone 12
in 50% yield.10 The 1,2-divinylcyclohexanols were heated
† To whom X-ray inquiries should be addressed.
(1) (a) Ho, T.-L. Tandem Organic reactions; Wiley: New York, 1992.
(b) Ziegler, F. In ComprehensiVe Organic Synthesis, Combining C-C π
bond; Paquette, L. A., Ed.; Pergamon Press: Oxford, 1991; Vol. 5; Chapter
7.3. (c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131.
(2) Chorlton, A. P.; Morris, G. A.; Sutherland, J. K. J. Chem. Soc., Perkin
Trans. 1 1991, 1205.
(3) Paquette, L. A.; Nakatani, S.; Zydowsky, T. M.; Edmondson, S. D.;
Sun, Q.-L.; Skerlj, R. J. Org. Chem. 1999, 64, 3244.
(4) Rajagopalan, K.; Janardhanam, S.; Balakumar, A. J. Org. Chem. 1993,
58, 5482 and references therein.
(5) Linstrumelle, G.; Derguini-Boumechal, F.; Huynh, C. Tetrahedron
Lett. 1979, 20, 1503.
(6) Swern, D.; Mancuso, A. J. Synthesis 1981, 165.
(7) Paquette, L. A.; Pegg, N. A.; Toops, D.; Maynard, G. D.; Rogers, R.
D. J. Am. Chem. Soc. 1990, 112, 277.
(8) Smith, A. B., III.; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J.
Org. Chem. 1982, 47, 1855.
(9) Boeckman, R. K., Jr.; Bruza, K. J. Tetrahedron Lett. 1977, 18, 4187.
10.1021/ol005502w CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/11/2000

Scheme 2
in toluene 5 h in a sealed tube, yielding the corresponding
reaction to furnish tricycle 16 as a single diastereoisomer.
The E olefin geometry of ketone 24 secures the exclusive
formation of the trans ring junction. Moreover, Terada and
Yamamura have demonstrated by computational modeling12
that the transannular ene reaction adopts a chair-like con-
formation at the transition state. An examination of the
transition states B and C reveals pseudo-1,3-diaxial methyl-
methylene interactions in B and a boat-like conformation in
transition state C. Therefore, transition states B and C are
less favored than A and the preferential formation of 16 over
25 is thus readily explained.
cyclic products in 44-86% yields.11 NMR spectroscopy and
X-ray analysis established the stereochemistry of the bi- and
tricyclic compounds.
The high diastereoselectivity observed in the tandem oxy-
Cope/ene reaction can be explained by the proposed mech-
anism shown in Figure 1. At first glance, the thermal oxy-
Cope rearrangement of divinylcyclohexanol 7 affords enol
intermediate 23.
Highly diastereoselective tautomerisation produces, in situ,
ketone intermediate 24, which reacts via transannular ene
However, we isolated unsaturated ketones 17 and 19 as
side products in 34% and 20% yields, respectively. Interest-
ingly, 1,2-divinylcyclohexanol 11 heated at 180 °C gave
exclusively unsaturated ketone 21 in 86% yield. According
(10) Holt, D. A. Tetrahedron Lett. 1981, 22, 2243.
(11) Typical procedure: A solution of 13 (24 mg, 0.12 mmol) in dry
toluene (5 mL) was heated in a pressure tube (previously washed with
aqueous 2-propanol/NaOH solution, water, and acetone) for 5 h at 220 °C.
The tube was cooled to room temperature, and the solution was transferred
and concentrated. The residue was purified by flash chromatography (10%
ether in hexanes) to give 22 as a colorless oil (20 mg, 83%).
(12) Terada, Y.; Yamamura, S. Tetrahedron Lett. 1979, 20, 1623.
Org. Lett., Vol. 2, No. 5, 2000
664

of tricyclic product. This indicates that the acetal moiety may
behave like an electron-withdrawing group and, therefore,
increases the yield of tandem oxy-Cope/ene product.
This strategy offers a simple highly diastereoselective
method for the synthesis polycyclic structures with a tertiary
alcohol at ring junction. Indeed, the synthesis of polycyclic
cores 18 and 22 of rosenonolactone15 and inketone16 has been
achieved in a few steps (Scheme 3). Total synthesis of these
molecules is currently in progress.
Scheme 3
Figure 1. Mechanism and transition state of tandem oxy-Cope/
ene reaction.
Acknowledgment. Financial support from the University
of Ottawa, Natural Sciences and Engineering Research
Council of Canada (undergraduate fellowship to J.M.W.),
and La Cite´ Colle´giale d'Ottawa is gratefully acknowledged.
to preliminary results obtained in our laboratory, the elec-
tronic density on the olefin influences the ratio of oxy-Cope/
ene versus the retroene products. In fact, the retroene pathway
is favored when the olefin is electron rich.13,14 On the basis
of the ratio of tandem versus retroene products depicted in
Scheme 2, the cyclic acetal has an effect on the rate formation
Supporting Information Available: ORTEP view of 15
and X-ray crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL005502W
(13) Barriault, L. Unpublished results.
(14) Recently, Paquette et al. reported that alkoxy substituents on the
olefin have a deceleration rate effect on the anionic oxy-Cope rearrangement.
See: Haeffner, F.; Houk, K. N.; Reddy, R. Y.; Paquette, L. A. J. Am. Chem.
Soc., in press.
(15) Kato, T.; Tsunakawa, M.; Sasaki, N.; Aizawa, H.; Fujita, K.;
Kitahara, Y.; Takahashi, N. Phytochemistry 1977, 16, 45.
(16) Birch, A. J.; Richards, R. W.; Smith, H.; Harris, A.; Whalley, W.
B. Tetrahedron 1959, 7, 241.
Org. Lett., Vol. 2, No. 5, 2000
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