Allylic Lithium Oxyanionic Directed and Facilitated Simmons-Smith Cyclopropanation: Stereoselective Synthesis of (±)-cis-Sabinene Hydrate and a Novel Ring Expansion

Article abstract of DOI:10.1021/ol016086y

(matrix presented) The lithium salts of acid-sensitive allyl alcohols, which themselves decompose during Simmons-Smith cyclopropanation, undergo smooth cyclopropanation in the usual stereocontrolled manner. This concept is applied to the most efficient synthesis of (±)-cis-sabinene hydrate and to the cyclopropanation of the anion of a nonisolable allyl alcohol resulting upon workup in a ring-expanded enone. The cyclopropanations are also faster for the lithium salts than for the allyl alcohols themselves.

Full text of DOI:10.1021/ol016086y

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2121-2123
Allylic Lithium Oxyanionic Directed and
Facilitated Simmons−Smith
Cyclopropanation: Stereoselective
Synthesis of (±)-cis-Sabinene Hydrate
and a Novel Ring Expansion
Dai Cheng, Thanapong Kreethadumrongdat, and Theodore Cohen*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
cohen@pitt.edu
Received May 9, 2001
ABSTRACT
The lithium salts of acid-sensitive allyl alcohols, which themselves decompose during Simmons−Smith cyclopropanation, undergo smooth
cyclopropanation in the usual stereocontrolled manner. This concept is applied to the most efficient synthesis of (±)-cis-sabinene hydrate and
to the cyclopropanation of the anion of a nonisolable allyl alcohol resulting upon workup in a ring-expanded enone. The cyclopropanations
are also faster for the lithium salts than for the allyl alcohols themselves.
The Simmons-Smith1 reaction and its variants are probably
the most widely used methods of formation of cyclopropanes,
compounds of enormous importance as reactive substrates
for further transformations.2 In addition, many are very
important in their own right, especially because they are often
biologically active.3 A major advance in this field was
afforded by the discovery that allylic and homoallylic
hydroxyl groups accelerate and exert great stereochemical
control over Simmons-Smith cyclopropanations of alkenes.4
Recently, a great deal of use has been made of this
phenomenon in the induction of enantioselectivity in the
reaction.1b,5
Some allylic alcohols, however, are acid-sensitive and are
destroyed by the Simmons-Smith conditions.6 There is little
doubt that this is the reason for the reported failure in the
(4) (a) Winstein, S.; Sonnenberg, J.; DeVries, L. J. Am. Chem. Soc. 1959,
81, 6523-6524. Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem.
Soc. 1969, 91, 6892-6894 and references therein. (b) Dauben, W. G.;
Berezin, G. H. J. Am. Chem. Soc. 1963, 85, 468-472. (c) For an excellent
review including directed Simmons-Smith cyclopropanations, see: Ho-
veyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(5) Charette, A. B.; Marcoux, J.-F. Synlett 1995, 1197-1207. Charette,
A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120,
11943-11952 and citations therein. Denmark, S. E.; Christenson, B. L.;
O’Conner, S. P.; Murase, N. Pure Appl. Chem. 1996, 68, 23-27.
(6) Some examples: Kelly, D. P.; Leslie, D. R.; Smith, B. D. J. Am.
Chem. Soc. 1984, 106, 687-694. Nash, G.; Waring, A. J. J. Chem. Res.,
Miniprint 1988, 1811-1823. Bessmertnykh, A. G.; Bubnov, Y. N.;
Voevodskaya, T. I.; Donskaya, N. A.; Zykov, A. Y. Zh. Org. Khim. 1991,
26, 2348-2355. Tori, M.; Hamaguchi, T.; Aoki, M.; Sono, M.; Asakawa,
Y. Can. J. Chem. 1997, 75, 634-640.
(1) (a) Reviews: Simmons, H. E.; Cairns T. L.; Vladuchick, S. A.;
Hoiness, C. M. Org. React. (N. Y.) 1973, 20, 1-131. Furukawa, J.;
Kawabata, N. AdV. Organomet. Chem. 1974, 12, 83-134. Motherwell, W.
B.; Nutley, C. J. Contemp. Org. Synth. 1994, 1, 219-41. Subramanian, L.
R.; Zeller, K.-P. In Methods of Organic Chemistry (Houben-Weyl); Meijere,
A., Ed.; Georg Thieme Verlag: Stuttgart, 1997; Vol. E17a, pp 256-308.
Charette, A. B. In Organozinc Reagents. A Practical Approach; Knochel,
P., Jones, P., Eds.; Oxford University Press: Oxford, 1999; pp 263-283.
(b) For a discussion of various methods of producing zinc carbenoids and
their structures, see: Denmark, S. E.; Edwards, J. P.; Wilson, S. R. J. Am.
Chem. Soc. 1992, 114, 2592-2602.
(2) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.;
Hudlicky, T. Chem. ReV. 1989, 89, 165-198.
(3) Salau¨n, J. In Small Ring Compounds in Organic Synthesis (VI);
Meijere, A., Ed.; Springer: Berlin, 2000; pp 1-64.
10.1021/ol016086y CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/17/2001

attempt to cyclopropanate the allyl alcohol 3 to (()-cis-
sabinene hydrate 4 (Scheme 1).7 The tertiary alcohol 3 was
Scheme 2
Scheme 1
ment with ice11) was subjected to the Simmons-Smith
reaction. The product 712 was immediately subjected to a
catalytic amount of HCl, leading to the ring expansion13
product 8. Thus, in this case the conventional allylic hydroxy-
directed cyclopropanation is unavailable and the lithium
oxyanionic version is a considerable advance.
reported to be “extremely unstable” and “when subjected to
a Simmons-Smith reaction, decomposed rapidly and no
bicyclic product could be isolated.”7 The allylic carbocation
derived by acid-induced dehydroxylation of 3 would be
exceptionally stable in view of the tertiary nature of both of
its termini. Since we required a sample of 4 for comparison
with one that we had synthesized as a demonstration of the
use of a new synthetic procedure based on the lithium-ene
cyclization,8 we sought to surmount this obstacle.
Since it is well established, as indicated above, that allylic
hydroxyl groups facilitate Simmons-Smith cyclopropana-
tions via complexation of the organozinc intermediate with
the hydroxyl group, it seemed possible that the lithium
oxyanionic group could be even more activating. Two tests
of this concept were applied. In the first, we attempted to
cyclopropanate the conjugate base of 9, which had been
reported14 to be unreactive toward 1.1 equiv of Simmons-
Smith reagent. Indeed, the inseparable mixture of product
and unreacted starting material contained 44% of the
cyclopropane (NMR, Scheme 3). In the second test, a large
We now present an operationally extremely simple and
apparently general solution to the instability of certain
alcohols under Simmons-Smith cyclopropanation condi-
tions. The procedure is illustrated with the most efficient
synthesis of (()-cis-sabinene hydrate 4 (Scheme 1). The
ketone 17 is treated with methyllithium in dry ether at -78
°C. After the reaction mixture is warmed to 0 °C, the
resulting lithium alkoxide 2 is subjected directly to the
Simmons-Smith conditions9 to provide the racemic natural
product in 64% yield.10 Thus, not only is the reaction
successful in the presence of the allylic oxyanionic group,
but even had the conversion of 3 to 4 been successful, the
route from 1 is shorter than that which would proceed
through 3.
Scheme 3
excess of an equimolar amount of the of the allyl methyl
ether 11 (R ) CH3)15 and the corresponding allylic lithium
The lithium oxyanion mediated procedure also allows one
to cyclopropanate allylic alcohols that cannot be isolated.
This is demonstrated by the alkylative ring expansion shown
in Scheme 2. The butyllithium adduct 6, the corresponding
alcohol of which is expected to be too unstable to isolate
(rearranging to a 3-substituted cyclohexen-2-one upon treat-
Scheme 4
(7) Fanta, W. I.; Erman, W. F. J. Org. Chem. 1968, 33, 1656-1659.
(8) Cheng, D.; Knox, K. R.; Cohen, T. J. Am. Chem. Soc. 2000, 122,
412-413.
oxyanion 11 (R ) Li) was subjected to the standard
(9) In the experiments described in this paper, the zinc-copper couple
is prepared freshly according to Shank, R. S.; Shechter, H. J. Org. Chem.
1959, 24, 1825-1826. The following general cyclopropanation procedure
is based on that of Dauben.4b MeLi (0.80 mL, 1.40 M in ether, 1.12 mmol)
was added under argon to a solution of enone 1 (1.0 mmol) dissolved in
ether (5 mL) at -78 °C, and the reaction mixture was warmed to 0 °C
before it was cannulated into a suspension of Zn-Cu couple(180 mg, 2.75
mmol), I2 (1 mg), and CH2I2 (576 mg, 2.15 mmol) in ether (20 mL). The
reaction mixture was heated at reflux for 2 h. It was then diluted with ether
(3 × 25 mL), and the organic phase was decanted. The latter was washed
with 5% K2CO3 (2 × 30 mL), brine (50 mL), and water (50 mL) and dried
(K2CO3). The solvent was removed to give an oily residue that was subjected
to column chromatography to give 99 mg (0.64 mmol, 64% yield) of the
cyclopropanation product 4.
cyclopropanation conditions.9 The cyclopropanation products
(11) Woods, G. F.; Griswold, P. H., Jr.; Armbrecht, B. H.; Blumenthal,
D. I.; Plapinger, R. J. Am. Chem. Soc. 1950, 72, 1645-1648.
(12) Bicyclic 7 can be isolated by careful column chromatography with
1
1% NEt3 in the eluent (hexanes/ethyl acetate 4:1). A reasonable H NMR
spectrum was obtained, but it was not further characterized because of its
instability. The 45% yield of 8 was obtained by treating the crude 7 with
a catalytic amount of HCl.
(13) Wenkert, E.; Buckwalter, B. L.; Sathe, S. S. Synth. Commun. 1973,
3, 261-264.
(14) Morikawa, T.; Sasaki, H.; Mori, K.; Shiro, M.; Taguchi, T. Chem.
Pharm. Bull. 1992, 40, 3189-3193.
(10) For previous syntheses of (()-cis-sabinene hydrate 4, see refs 7
and 8 and Gaoni, Y. Tetrahedron 1972, 28, 5525-5531.
(15) Shono, T.; Ikeda, A. J. Am. Chem. Soc. 1972, 94, 7892-7898.
Damico, R. J. Org. Chem. 1968, 33, 1550-1556.
2122
Org. Lett., Vol. 3, No. 13, 2001

12 (R ) CH3)16 and 12 (R ) H)17 were separated, and the
relative quantities were analyzed by gas-phase chromatog-
raphy-mass spectrometry.18 The ratio of 12 (R ) H) to 12
(R ) CH3) was found to be 4.75 ( 0.15. Chan and
Rickborn19 had previously reported that the ratio of rates of
cyclopropanation of 11 (R ) H) to 11 (R ) CH3) is 2 ( 0.2
Thus, converting the allylic alcohol group into its conjugate
base increases the rate of cyclopropanation by a factor of
2.4. Both experiments show that the use of an allylic
oxyanionic group facilitates the Simmons-Smith procedure
much as such a group facilitates metallo-ene cyclizations as
recently reported from this laboratory.8,20
sensitive allyl alcohols that are unstable to the Simmons-
Smith conditions are readily cyclopropanated, and if the
alcohol is produced by addition of an organolithium to a
carbonyl group, it is not necessary to isolate the alcohol itself.
Finally, cyclopropanation of the lithium salt is more facile
than that of the corresponding alcohol. It is probably prudent
to use the lithium salt rather than the alcohol in the first
attempt provided that it can be generated without destruction
of other functional groups.
Acknowledgment. We thank the National Science Foun-
dation for support of this work, Dr. Fu-Tyan Lin for help in
NMR spectroscopy, Dr. Kasi Somayajula for help with the
mass spectra, and MDL Information Systems and DuPont
Pharmaceuticals for generous software and database support.
We also thank Professor Andre´ Charette and particularly
Andre´ Beauchemin, of his research group, for providing
important references.
In summary, the use of the lithium salts of allylic alcohols
rather than the alcohols themselves can have two major
advantages in classical allylic hydroxyl-directed Simmons-
Smith cyclopropanations.21 Nonisolable allyl alcohols or acid-
(16) Daino, Y.; Hagiwara, S.; Hakushi, T. J. Chem. Soc., Perkin Trans.
2 1989, 275-282.
(17) Molander, G. A.; Harring, L. S. J. Org. Chem. 1989, 54, 3525-
3532. Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974-6981.
(18) It was determined using a mixture of the two products of known
compostion that the ratio of the two products as determined by integration
of the peaks in GC-MS was identical to that determined by integration of
OL016086Y
(21) The lithium salt of a cyclopent-2-ene-1-ol was reported by Corey
and Virgil to be cyclopropanated under Simmons-Smith conditions, and
their procedure was then used by Saxton et al. in a very similar system.
However, there was no indication as to why the lithium salt was used. Corey,
E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 6429-6431. Guile, S. D.;
Saxton, J. E.; Thornton-Pett, M. J. Chem. Soc., Perkin Trans. 1 1992, 1763-
1767.
1
appropriate peaks in the H NMR spectrum of the same mixture.
(19) Chan, J. H.-H.; Rickborn, B. J. Am. Chem. Soc. 1968, 90, 6406-
6411.
(20) Cheng, D.; Zhu, S.; Yu, Z.; Cohen, T. J. Am. Chem. Soc., 2001,
123, 30-34.
Org. Lett., Vol. 3, No. 13, 2001
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