Enantioselective synthesis of 2-substituted cyclobutanones

Article abstract of DOI:10.1021/ol005820v

(equation presented) An enantioselective synthesis of 2-substituted cyclobutanones has been achieved by sequential application of the titanium-mediated cyclopropanation of α-hydroxy esters and the pinacol-type rearrangement of the resulting α-hydroxycyclo

Full text of DOI:10.1021/ol005820v

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1337-1339
Enantioselective Synthesis of
2-Substituted Cyclobutanones
Sung Yun Cho and Jin Kun Cha*
Department of Chemistry, UniVersity of Alabama, Tuscaloosa, Alabama 35487
cha@jkc.ch.ua.edu
Received March 15, 2000
ABSTRACT
An enantioselective synthesis of 2-substituted cyclobutanones has been achieved by sequential application of the titanium-mediated
cyclopropanation of r-hydroxy esters and the pinacol-type rearrangement of the resulting r-hydroxycyclopropylcarbinols.
Cyclopropanes and cyclobutanes offer considerable utility
as useful building blocks in organic synthesis.1 Their unique
reactivity associated with the strain release upon cleavage
of these small rings has found many elegant applications in
the development of new annulation methods for five-
membered, six-membered, and medium-sized rings. The
synthetic utility of these strained molecules is enhanced by
the presence of a carbonyl group. For example, cyclo-
butanones, in particular, 2-alkenylcyclobutanones, have been
utilized in some imaginative ring expansion reactions.1d,2
Although several methods for preparing cyclobutanones and
cyclobutanes are available, their enantioselective syntheses
have received relatively little attention.2,3 A paucity of general
procedures for preparing enantiomerically pure cyclobutane
derivatives remains in striking contrast with recent impressive
advances in asymmetric cyclopropanation. Herein we report
an enantioselective synthesis of 2-substituted cyclobutanones
by facile rearrangement of R-hydroxycyclopropylcarbinols.
Among the known methods for preparing cyclobutanones
(which can also be extended to the synthesis of 2-alkenyl-
cyclobutanones),4 a commonly used approach utilizes the
heteroatom-substituted cyclopropylcarbinyl-cyclobutyl ring
expansion, 2 f 3 (eq 1), where the heteroatom substituent
(1) For general reviews, see: (a) Battiste, M. A.; Coxon, J. M. In The
Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: Chichester,
1987; Chapter 6. (b) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.;
Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165. (c) Trost, B. M. Top.
Curr. Chem. 1986, 133, 3. (d) Wong, H. N. C.; Lau, K.-L.; Tam, K.-F..
Top. Curr. Chem. 1986, 133, 83. (e) Salau¨n, J. R. In Small Ring Compounds
in Organic Synthesis III; de Meijere, A., Ed.; Springer-Verlag: Berlin, 1988;
pp 1-71.
(2) For an excellent review, see: Bellus, D.; Ernst, B. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 797.
(3) Recently Krief and co-workers reported the pinacol rearrangement
of R-hydroxycyclopropylcarbinols: (a) Krief, A.; Ronvaux, A.; Tuch, A.
Tetrahedron 1998, 54, 6903. See also: (b) Miyata, J.; Nemoto, H.; Ihara,
M. J. Org. Chem. 2000, 65, 504. Fukumoto and co-workers also developed
an asymmetric variant of Trost’s rearrangement of oxaspiropentanes to
cyclobutanones by means of the Sharpless asymmetric epoxidation of
cyclopropylidene alcohols: (c) Nemoto, H.; Fukumoto, K. Synlett 1997,
863 and references therein. For other related studies, see: (d) Hiroi, H.;
Nakamura, H.; Anzai, T. J. Am. Chem. Soc. 1987, 109, 1249. (e) Salaun,
J.; Karkour, B.; Ollivier, J. Tetrahedron 1989, 45, 3151. (f) Ollivier, J.;
Legros, J.-Y.; Fiaud, J.-C.; de Meijere, A.; Salau¨n, J. Tetrahedron Lett.
1990, 31, 4135.
X of 2 not only facilitates the rearrangement but also affords
the ketone functionality of 3 upon hydrolysis. The requisite
starting materials 2 are obtained by addition of a suitable
cyclopropyllithium reagent 1 to carbonyl compounds (in-
cluding enones and enals). An alternative route (eq 2)
involving R-hydroxycyclopropylcarbinols 5 (i.e., X ) OH
in 2), which should be easily prepared by the Kulinkovich
10.1021/ol005820v CCC: $19.00 © 2000 American Chemical Society
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cyclopropanation5,6 of R-hydroxy esters 4, would lend itself
to an enantioselective synthesis of 2-substituted cyclo-
butanones 6, since enantiomerically pure 4 are readily
available by standard methods. Preferential migration of a
single diastereotopic C-C bond of cyclopropanol 5, along
with inversion of configuration at the stereocenter, is
obligatory to achieve high enantioselectivity.3a,b
Table 1
Sharpless asymmetric dihydroxylation of acrylates pro-
vides easy access to the starting R-hydroxy esters.7 Thus,
the known diol 7 (77-80% ee) was subjected to selective
silylation of the primary alcohol to afford 4a in 73% yield
(Scheme 1). The Kulinkovich cyclopropanation of 4a with
Scheme 1
the ethyl Grignard reagent afforded directly the requisite
substrate 5a, albeit in moderate (62%) yield. Although a
higher overall yield can be obtained by protection of the free
hydroxyl group prior to the Kulinkovich cyclopropanation,
the direct conversion of 4a to 5a was chosen for convenience
in the present work. Treatment of 5a with mesyl chloride in
pyridine resulted in facile pinacol rearrangement to afford
6a, [R]25D ) -19.3° (c 0.4, CH2Cl2), in 58% (unoptimized)
yield (Table 1). Since the optical rotation of 6a is known,8
-16.2° (c 1.0, CH2Cl2); lit.8b [R]25 ) -22.5 to -24.1° (c
D
2.0, CHCl3)} allowed us to ascertain that the key rearrange-
ment of 5a f 6a takes place with a high (>90%) level of
chirality transfer. The (S) configuration of cyclobutanone 6a
can be rationalized by the antiperiplanar requirement in the
preferred transition state arising from conformer A. As shown
in the Newman projection, the alternate transition state from
conformer B suffers from nonbonded interactions between
the cyclopropyl ring protons and the substituent CH2-
OTBDPS.9
a comparison of the optical rotation values {lit.8a [R]25
)
D
(4) See, inter alia: 1. addition of vinylketenes to olefins: (a) Danheiser,
R. L.; Martinez-Davila, C.; Sard, H. Tetrahedron 1981, 37, 3943. (b)
Jackson, D. A.; Rey, M.; Dreiding, A. S. HelV. Chim. Acta 1983, 66, 2330.
2. epoxidation of alkylidenecyclopropanes: (c) Salaun, J. R.; Champion,
J.; Conia, J. M. Organic Syntheses; Wiley: New York, 1988; Collect. Vol.
VI, p 320. (d) Cohen, T.; McCullough, D. W. Tetrahedron Lett. 1988, 29,
27. 3. R-arylthio- or alkoxycyclopropylcarbinol-to-cyclobutanone rearrange-
ment: (e) Trost, B. M.; Keeley, D. E.; Bogdanowicz, M. J. J. Am. Chem.
Soc. 1973, 95, 3068. (f) Trost, B. M.; Keeley, D. E.; Arndt, H. C.;
Bogdanowicz, M. J. J. Am. Chem. Soc. 1977, 99, 3088. (g) Cohen, T.; Matz,
J. R. Tetrahedron Lett. 1981, 22, 2455. (h) Wenkert, E.; Arrhenius, T. S.
J. Am. Chem. Soc. 1983, 105, 2030. (i) Krumpolc, M.; Rocek, J. Organic
Syntheses; Wiley: New York, 1990; Collect. Vol. VII, p 114 and references
therein.
To facilitate analysis of the degree of chirality transfer in
the rearrangement process, R-hydroxycyclopropylcarbinols
5 bearing an adjacent stereocenter were next examined, where
the diastereoselectivity of the cyclobutanone formation can
1
be easily determined by the H NMR analysis. Following
the identical reaction sequence, 4b and 5b were prepared
uneventfully starting from ethyl trans-crotonate.10 Ring
expansion of 5b by the action of MsCl gave, as a single
(5) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pri-
tytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244. (b) Kulinkovich, O. G.;
Sviridov, S. V.; Vasilevskii, D. A.; Savchenko, A. I.; Pritytskaya, T. S. Zh.
Org. Khim. 1991, 27, 294. (c) Kulinkovich, O. G.; Sorokin, V. L.; Kel’in,
A. V. Zh. Org. Khim. 1993, 29, 66.
(6) (a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc.
1996, 118, 291. (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 4198.
(7) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768. (b) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
(8) (a) Narasaka, K.; Kusama, H.; Hayashi, Y. Bull. Chem. Soc. Jpn.
1991, 64, 1471. (b) Sato, M.; Ohuchi, H.; Abe, Y.; Kaneko, C. Tetrahe-
dron: Asymmetry 1992, 3, 313.
(9) The origin of the high stereoselectivity is reminiscent of Julia’s
stereoselective synthesis of trisubstituted olefins by acid-promoted re-
arrangement of cyclopropylcarbinols: Julia, M.; Julia, S.; Tchen, S.-Y. Bull.
Soc. Chim. Fr. 1961, 1849.
1338
Org. Lett., Vol. 2, No. 9, 2000

isomer, cyclobutanone 6b (57% yield), the stereochemistry
of which was assigned by analogy to that of 5a f 6a.
Treatment of 5b with Martin sulfurane also afforded 6b in
77% yield.11 In both of the ring expansion reactions effected
by MsCl and Martin sulfurane, the observed stereochemical
outcome is congruent with the concerted rearrangement as
generalized in transition state A but precludes the interme-
diacy of the corresponding oxaspiropentane. Ring expansion
of the related oxaspiropentanes was shown by Fukumoto3c,12
to proceed with inversion of configuration at the migrating
terminus: the rearrangement of the oxaspiropentane derived
from 5a would thus lead to the enantiomer of 6a.
Scheme 2
As shown in additional examples in Table 1, the ring
expansion reactions of R-hydroxycyclopropylcarbinols 5c-f
were also found to take place with excellent selectivity.
Particularly noteworthy is a convenient preparation of
synthetically useful 2-alkenylcyclobutanone 6f, which relies
on the successful cyclopropanation of allylic alcohol 4f
without complication due to formation of an allylic titanium
intermediate.13
Preparation of trisubstituted cyclopropanols by treatment
of 4e with hexylmagnesium chloride in place of ethyl-
magnesium bromide under otherwise identical Kulinkovich
cyclopropanation conditions [i.e., in the presence of ClTi-
(O-i-Pr)3] surprisingly afforded all four possible diastereo-
mers 8 (57%) as a 1:0.7:0.3:0.25 mixture (Scheme 2).14
Difficulties in separating the individual isomers have so far
precluded a detailed investigation of the subsequent pinacol
rearrangement of 8a-d. However, cursory examination with
a diastereomeric mixture of 8 revealed that steric effects in
the transition state outweigh the migratory aptitude of the
two alkyl substituents, leading to 2,3-disubstituted or 2,4-
disubstituted cyclobutanones. It is presumed that ring expan-
sion of two diastereomers 8a,d will occur with the indicated
stereochemistry given in Scheme 2.15
In summary, sequential application of the titanium-
mediated cyclopropanation of readily available R-hydroxy
esters and the pinacol-type rearrangement of the resulting
R-hydroxycyclopropylcarbinols provides convenient access
to enantiomerically pure 2-substituted cyclobutanones.16,17
The latter ring expansion reaction was found to proceed with
an excellent degree of stereoselectivity.
(10) Silylation of the diols derived from osmylation of â-alkyl acrylates
was found to proceed with regioselective protection of the â-alcohol: Ha,
J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012.
(11) Martin, J. C.; Franz, J. A.; Arhart, R. J. J. Am. Chem. Soc. 1974,
96, 4604.
(12) Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org.
Chem. 1992, 57, 1707.
Acknowledgment. We thank the National Science Foun-
dation (CHE98-13975) for financial support. We also thank
a referee for bringing to our attention ref 3a.
(13) Under the Kulinkovich reaction conditions, allylic alcohols and
ethers could give the corresponding allylic titanium reagents. The successful
formation of 5f is a consequence of unfavorable exchange between the
parent, the unsubstituted titanacyclopropane, and the trisubstituted olefin
of 4f, which in turn reflects the greater stability of the former presumed
intermediate. For related work, see: (a) refs 6a,b. (b) Kasatkin, A.;
Nakagawa, T.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1995, 117, 3881.
(c) Teng, X.; Takayama, Y.; Okamoto, S.; Sato, F. J. Am. Chem. Soc. 1999,
121, 11916.
(14) The Kulinkovich cyclopropanation reactions of carboxylic esters
bearing R-oxy or â-oxy substituents have been found to afford a diastereo-
meric mixture of cis- and trans-1,2-disubstituted cyclopropanols, in sharp
contrast to the otherwise exceptional (>30:1) diastereoselectivity for the
cis isomers: Lee, C.-W.; Cho, S. Y.; Cha, J. K. Unpublished results.
(15) In fact, Trost reported migration of the less substituted carbon in
the pinacol rearrangement of 1-phenylthiocyclopropanes closely related to
8a, although a different rationalization was advanced: Trost, B. M.;
Ornstein, P. L. J. Org. Chem. 1983, 48, 1131.
OL005820V
(16) Representative procedure for the preparation of 6a: To a solution
of 5a (39 mg, 0.1 mmol) in pyridine (1 mL) was added dropwise at room
temperature mesyl chloride (0.085 mL, 1 mmol). The reaction mixture was
stirred for 1 h, poured to ice water, and extracted three times with ether.
The combined extracts were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. Purification by column chromatog-
raphy (silica gel) afforded 21.4 mg (58%) of 6a as a colorless oil.
(17) Swern oxidation of 5 affords 2-alkyl-2-hydroxycyclobutanones, as
a consequence of the R-ketol rearrangement. For example, a 2:1 diastereo-
meric mixture of R-hydroxycyclobutanones was obtained by Swern oxida-
tion of 5b.
Org. Lett., Vol. 2, No. 9, 2000
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