On the stereochemistry of anion-accelerated [1,3]-sigmatropic rearrangement of 2-vinylcyclobutanols

Article abstract of DOI:10.1016/S0040-4039(01)01929-3

Stereochemical studies on the oxyanion-accelerated [1,3]-sigmatropic rearrangement reactions of nonracemic cis- and trans-2-(1-cyclohexenyl)cyclobutanols are described. Epimerization of cis-2-(1-cyclohexenyl)cyclobutanol to the trans-isomer at -20°C was f

Full text of DOI:10.1016/S0040-4039(01)01929-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8769–8772
On the stereochemistry of anion-accelerated [1,3]-sigmatropic
rearrangement of 2-vinylcyclobutanols
Se-Ho Kim, Sung Yun Cho and Jin Kun Cha*
Department of Chemistry, University of Alabama, Tuscaloosa, AL 35487, USA
Received 28 August 2001; accepted 10 October 2001
Abstract—Stereochemical studies on the oxyanion-accelerated [1,3]-sigmatropic rearrangement reactions of nonracemic cis- and
trans-2-(1-cyclohexenyl)cyclobutanols are described. Epimerization of cis-2-(1-cyclohexenyl)cyclobutanol to the trans-isomer at
−20°C was found to proceed with predominant retention of configuration, the degree of which was enhanced by an increasing
amount of 18-crown-6. © 2001 Elsevier Science Ltd. All rights reserved.
Sigmatropic rearrangements have found frequent use in
the stereocontrolled synthesis of organic compounds.
When judiciously placed, an anionic substituent pro-
vides an enormous rate of acceleration.1 Since the first
example was reported for an oxy-Cope rearrangement,2
the utility and generality of anion-accelerated sigmat-
ropic rearrangements have been amply demonstrated in
natural product synthesis. As shown in Eq. (1),3e,f the
Danheiser and Cohen groups have elegantly shown that
the diastereochemical course of an oxyanion-acceler-
ated [1,3]-sigmatropic rearrangement of a 2-vinylcy-
clobutanol to the corresponding cyclohexenol product
is influenced by the presence or absence of a complex-
ing agent for the metal counterion (e.g. K+).3b,e,f,4 Little
was known, however, about what level, if any, of
enantioselectivity would be observed for the non-con-
certed rearrangement of a nonracemic 2-vinylcyclobu-
tanol. We describe herein stereochemical studies on the
oxyanion-accelerated [1,3]-sigmatropic rearrangement
reactions of nonracemic cis- and trans-2-(1-cyclohex-
enyl)cyclobutanols (1 and 2).5
The requisite, nonracemic alcohols 1 and 2 were conve-
niently prepared via the corresponding cyclobutanone 7
which was produced by the titanium-mediated cyclo-
propanation of a-hydroxy ester 5a or 5b and the subse-
quent pinacol-type rearrangement of the resulting
cyclopropanol 6 (Scheme 1).6,7 The latter ring expan-
sion reaction, which was achieved by the action of
methanesulfonyl chloride (in pyridine) or sequential
treatment with sulfuryl chloride–imidazole and
Florisil,6,8 was previously shown to provide 7 with an
excellent degree of enantioselectivity. Reduction of this
ketone with NaBH4 afforded an easily separable 1:1.8
mixture of (+)-1 and (−)-2 in 98% yield. Since both
alcohols were desired for stereochemical studies of their
rearrangements, no attempt was made to improve the
diastereoselectivity of reduction.
When (−)-trans-2-(1-cyclohexenyl)cyclobutanol [(−)-2],
[h]D=−23.9 (c 1.1, CH2Cl2), was treated with KH at
−25°C for 15–30 min in the presence of 1 equiv. of
18-crown-6 in THF, a facile oxyanion-accelerated rear-
(1)
* Corresponding author. E-mail: jcha@bama.ua.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01929-3

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S.-H. Kim et al. / Tetrahedron Letters 42 (2001) 8769–8772
Scheme 1.
rangement took place to give a ]15:1 mixture of trans-
and cis-octalinols 8 and 9 in 95% yield (Scheme 2).9
The rearrangement of the cis isomer (+)-1, [h]D= +32.3
(c 1.1, CH2Cl2), afforded 8 (as the virtually sole iso-
mer), along with varying amounts of the epimerized
cyclobutanol which proved to be non-racemic.10 The
yield and enantiomeric purity of the epimerization
product (−)-2 depended upon the reaction time and
other variables (vide infra).
quenched in 20–40 min when most of the starting
alcohol had disappeared.11 The products were then
analyzed by the 1H NMR and/or GC/MS methods,
where material balance was excellent in all cases.
Epimerization took place with retention of configura-
tion. Remarkably, the degree of enantioselectivity was
controlled primarily by the amounts of 18-crown-6:
whereas the trans/cis diastereoselectivity for formation
of 8 was independent of (catalytic or stoichiometric)
quantities of 18-crown-6,3f the enantioselectivity of
epimerization [i.e. (+)-1“(−)-2] was enhanced by an
increasing amount of this complexing agent. For exam-
ple, when 1 equiv. (entry 2) and 2.6 equiv. (entry 5) of
18-crown-6 were employed, 2 was obtained in 54 and
90% ee, respectively. This striking influence of quanti-
ties of 18-crown-6 on the level of enantioselectivity
seemed at first counter-intuitive: epimerization, which
primarily involves the different orientation of the alde-
hyde with respect to the allylic anion, takes place faster
than racemization of an allylic anion/aldehyde interme-
diate (Table 1 where M depicts a pair of electrons; the
complexing agent and the solvent are omitted for clar-
ity). The difference in the relative rates of these two
competing processes apparently becomes larger with an
increasing amount of 18-crown-6, presumably because
of greater dissociation of the potassium ion and hence
higher reactivity of the resulting allylic anion intermedi-
ate. Subsequent rotation of the bond between the cyclo-
hexenyl ring and the side chain, which is required for
the ring closure to the trans-octalinol product, leads to
Not surprisingly, the rearrangement products 8 and 9
were shown to be racemic, i.e. identical to ( )-4 and
( )-3, respectively, on the basis of NMR studies of the
corresponding acetates (Ac2O, pyridine) with a chiral
shift reagent [Eu(hfc)3]. The thermal [1,3]-sigmatropic
rearrangement reactions were also investigated: individ-
ual treatment of (+)-1 and (−)-2 with KH in refluxing
THF for 2 h afforded a ꢀ1.7:1 mixture of ( )-3 and
( )-4 in 74% yield in each case.
Gadwood and Cohen had previously observed facile
epimerization of cis-vinylcyclobutanols to the trans-iso-
mers at low temperatures (Eq. (1)).3d,e With nonracemic
1, the key reaction parameters were systematically eval-
uated to probe the retention of configuration in this
cis“trans isomerization reaction at −25 to −20°C
(Table 1). Use of 18-crown-6 was known to accelerate
both the epimerization and ring expansion reactions.
To ensure reliable reproducibility, an excess (ca. 10
equiv.) of KH was employed. The reaction mixture was
Scheme 2.

S.-H. Kim et al. / Tetrahedron Letters 42 (2001) 8769–8772
8771
Table 1.
Entry
KH (equiv.)
18-Crown-6 (equiv.)
Product ratiob (2:8:1)
ee of 2c (%)
1
2
3
4
11
11
9.2
10
11
10
0.5
1.0
1.3
1.5
2.6
2.7
2.4:1:0.4
2.3:1:0.1
2.5:1:0.2
2.5:1:0.1
2.17:1:0.02
2.74:1:0.21
33
54
72
84
90
83a
5
6a
a Reaction conditions: THF (0.02 M), except for entry 6 (0.01 M), −25 to −20°C, 20 to 40 min.
b Determined by the 1H NMR spectra (for entries 1–4) or GC (for entries 5 and 6).
c Determined by comparison of optical rotation and/or NMR studies with Eu(hfc)3.
racemization.12 Finally, the alkoxide of the epimerized
alcohol 2 is not believed to be an obligatory intermedi-
ate for 1“8, at least at −25 to −20°C, but is directly
involved in epimerization and also ring closure.
3. For recent examples, see: (a) Wilson, S. R.; Mao, D. T. J.
Chem. Soc., Chem. Commun. 1978, 479; (b) Danheiser, R.
L.; Martinez-Davila, C.; Sard, H. Tetrahedron 1981, 37,
3943; (c) Zoeckler, M. T.; Carpenter, B. K. J. Am. Chem.
Soc. 1981, 103, 7661; (d) Gadwood, R. C.; Lett. R. M. J.
Org. Chem. 1982, 47, 2268; (e) Cohen, T.; Bhupathy, M.;
Matz, J. R. J. Am. Chem. Soc. 1983, 105, 520; (f)
Bhupathy, M.; Cohen, T. J. Am. Chem. Soc. 1983, 105,
6978; Cf. (g) Cohen, T.; Yu, L.-C.; Daniewski, W. M. J.
Org. Chem. 1985, 50, 4596.
4. For a detailed mechanistic study of the 1,3-sigmatropic
shift of vinylcyclobutanol alkoxides, see: Harris, N. J.;
Gajewski, J. J. J. Am. Chem. Soc. 1994, 116, 6121.
5. A chiral ketal was employed to probe the mechanism for
the lithium alkoxide-induced [1,3]-rearrangement of a
vinyl benzocyclobutene: Spangler, L. A.; Swenton, J. S. J.
Org. Chem. 1984, 49, 1800.
In summary, both thermal and potassium alkoxide-
accelerated [1,3]-sigmatropic rearrangements of non-
racemic 2-(1-cyclohexenyl)cyclobutanols were found to
take place with complete loss of chirality, that confir-
med the accepted mechanism involving the non-con-
certed, fragmentation–rearragement pathway.3,4 On the
other hand, the new finding that facile epimerization of
(+)-1 to (−)-2 at −20°C took place with predominant
retention of enantiomeric purity should be of mechanis-
tic and preparative interest.13
6. Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337.
7. For an enantioselective preparation of 5b by enzymatic
kinetic resolution, see: Vankar, P. S.; Bhattacharya, I.;
Vankar, Y. D. Tetrahedron: Asymmetry 1996, 7, 1683.
We have found that the use of Candida rugosa was
superior to that of PLAP, affording the alcohol 5b,
[h]D=−84.7 (c 1.15, CHCl3), in an excellent level of
enantioselectivity and in the opposite sense.
8. Nemoto, H.; Fukumoto, K. Synlett 1997, 863.
9. The cis/trans nomenclature for octalinols refers to the
relative stereochemistry of the two methine hydrogens.
10. (a) After 4 h at −20°C, the anion-assisted rearrangement
of (+)-1 gave a 20:1 mixture of 8 and 2 in 96% yield. (b)
The rearrangement of (+)-1 was slower than that of (−)-2
under the reaction conditions employed, suggesting that
ring opening of 1 was the slowest step.
Acknowledgements
We thank the National Science Foundation (CHE98-
13975) for financial support.
References
1. For excellent reviews, see: (a) Bronson, J. J.; Danheiser,
R. L. In Comprehensive Organic Syntheses; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp.
999–1035; (b) Wilson, S. R. Org. React. 1993, 43, 93.
2. Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97,
4765.

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S.-H. Kim et al. / Tetrahedron Letters 42 (2001) 8769–8772
11. There was no appreciable change in enantiomeric purity
of recovered 1.
12. For each of the species drawn in Table 1, there are two
possible geometrical isomers. The second one (not
shown) cannot possibly undergo ring closure, but may
as well be responsible for some of epimerization noted.
13. Although speculative at this point, the anionic oxy-
Cope rearrangement of non-racemic trans-dialkenylcy-
clobutanols,3c which would be readily available from
addition of
a suitable alkenyllithium to 7, might
provide enantiomerically pure substituted 4-cyclo-
octenones by way of the initial isomerization of the
trans-“cis-dialkenylcyclobutanols free from racemiza-
tion.