A short synthesis of the cis-cyclobutane β-aminoacid skeleton using a [2+2] cycloaddition strategy

Article abstract of DOI:10.1016/S0040-4039(02)01276-5

A short synthesis of (±)-cis-2-amino-1-cyclobutanecarboxylic acid is described with an overall yield of 52%. The key step is the photochemical [2+2] cycloaddition reaction between ethylene and uracil.

Full text of DOI:10.1016/S0040-4039(02)01276-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6177–6179
A short synthesis of the cis-cyclobutane b-aminoacid skeleton
using a [2+2] cycloaddition strategy
David J. Aitken,* Christine Gauzy and Elisabeth Pereira
Laboratoire SEESIB-CNRS, De´partement de Chimie, Universite´ Blaise Pascal, Clermont-Ferrand II, 24 Avenue des Landais,
63177 Aubie`re cedex, France
Received 7 June 2002; accepted 28 June 2002
Abstract—A short synthesis of ( )-cis-2-amino-1-cyclobutanecarboxylic acid is described with an overall yield of 52%. The key
step is the photochemical [2+2] cycloaddition reaction between ethylene and uracil. © 2002 Elsevier Science Ltd. All rights
reserved.
b-Aminoacids and peptide structures which incorporate
them are of considerable interest due to their unusual
structures1,2 and biological activities,2 and there has
been a corresponding interest in methods of synthesis
of such compounds.3 Conformationally constrained ali-
cyclic b-aminoacids and b-peptides are of particular
interest, and intensive studies have been carried out on
cyclohexane,4 cyclopentane,2c,4a,5 cyclopropane6 and
other alicyclic derivatives.7 In contrast, almost no work
has been done on cyclobutane compounds.
two olefins should supply both the amine and the acid
functions. A cheap and readily available equivalent of
such an olefin is uracil 2; indeed, photochemical [2+2]
cycloaddition reactions are known to provoke dimer-
ization of pyrimidinedione-type DNA bases,11 and sev-
eral examples of cycloaddition reactions between uracil
derivatives and alkenes have been described.12 In this
communication, we report the first application of this
new approach for the preparation of the cyclobutane
b-aminoacid system, in the short, efficient synthesis of
cis-1 (Scheme 1).
Only two strategies have been reported for entry to the
cyclobutane b-aminoacid skeleton. Kennewell et al.
described the synthesis of racemic cis- and trans-2-
amino-1-cyclobutanecarboxylic acid 1 from the corre-
sponding cyclobutane-1,2-dicarboxylic acids by a series
of selective transformations after chemical desym-
metrization.8 Recently, Ortun˜o’s group adapted this
strategy for the first enantioselective synthesis of the
cis-(1R,2S) antipode of 1 using an esterase to carry out
the enantioselective partial hydrolysis of the meso-
diester.9 In earlier work, Brannock et al.10 synthesized a
series of N,N-disubstituted cyclobutane b-aminoesters
or nitriles by thermal cycloaddition between N,N-di-
substituted enamines and acrylic esters or nitriles. These
reactions worked well with highly substituted reagents,
but had no apparent control of stereoselectivity.
Ethylene was bubbled through a solution of uracil 2 in
acetone–water (1:1) at room temperature which was
irradiated with a 400 W medium-pressure mercury lamp
fitted with a Pyrex filter. The expected cyclobutane
We were interested in the [2+2] strategy, but prefered a
disconnection in the alternative sense, so that one of the
* Corresponding author. Tel.: 33-4-73-40-74-81; fax: 33-4-73-40-77-
17;
e-mail:
aitken@chisg1.univ-bpclermont.fr;
pereira@
Scheme 1.
chisg1.univ-bpclermont.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01276-5

6178
D. J. Aitken et al. / Tetrahedron Letters 43 (2002) 6177–6179
ment for chromatographic separations at any stage)
illustrates a useful strategy which should be of a general
character. Development of the method for access to
ring-substituted cyclobutane b-aminoacids (through use
of other uracils and/or olefins) and its adaptation for
enantioselective synthesis are currently in progress.
compound 3 was formed, accompanied by ethylene
oligomers and small amounts of uracil photodimers,13
and was isolated in 75% yield after washing with cyclo-
hexane, then acetone, then rapid filtration through sil-
ica gel.14 The second step consisted of the hydrolysis of
the heterocyclic moiety of 3 by treatment with 0.5 M
aqueous NaOH at room temperature.15 After neutral-
ization with H+ cation exchange resin, the correspond-
ing N-carbamoyl-b-aminoacid 4 was isolated directly as
a single stereoisomer in 82% yield.16
Acknowledgements
Hydrolysis of a urea function generally calls for the use
of strongly basic conditions, which was of some con-
cern here, since Ortun˜o observed that derivatives of
cis-1 are prone to epimerization. In the event, the
action of nitrous acid17—recently used by Azerad18 in
similar circumstances for decarbamoylation of epimer-
ization-sensitive arylglycines—permitted the smooth
transformation of 4 into the required target molecule
cis-1 which was isolated in zwitterionic form in 85%
yield after passage through cation exchange resin.19
We are grateful to P. Lemoine and B. Viossat, Univer-
site´ Rene´ Descartes, Paris 5, for the X-ray crystallo-
graphic study, and we thank the MENRT for a grant
(to C.G.) and the CNRS for ‘Jeune Equipe’ (AIP)
funding.
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Figure 1. X-Ray crystallographic structure of derivative 5.

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