Synthesis of (+)-(1S,2R) and (-)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2004.07.110

(+)-(1S,2R) and (-)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids have been prepared in >97% ee and in 33% and 20% overall yields starting from a single, chiral, bicyclic compound perceived as a chiral uracil equivalent. Construction of the cyclobutane ri

Full text of DOI:10.1016/j.tetlet.2004.07.110

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7095–7097
Synthesis of (+)-(1S,2R) and
(À)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids
Christine Gauzy, Elisabeth Pereira, Sophie Faure and David J. Aitken*
´
´
Laboratoire SEESIB-CNRS, Departement de Chimie, Universite Blaise Pascal, Clermont-Ferrand II,
`
24 Avenue des Landais, 63177 Aubiere cedex, France
Received 8 May 2004; revised 19 July 2004; accepted 24 July 2004
Available online 13 August 2004
Abstract—(+)-(1S,2R) and (À)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids have been prepared in >97% ee and in 33% and 20%
overall yields starting from a single, chiral, bicyclic compound perceived as a chiral uracil equivalent. Construction of the cyclo-
butane ring is achieved via a [2+2] photocycloaddition reaction of this chiral precursor with ethylene.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The incorporation of conformationally constrained b-
amino acids into peptides can dramatically influence
their secondary and tertiary structures and biological
activities.1 In consequence, interest for the synthesis
and study of alicyclic b-amino acids has rapidly in-
creased.2 Most efforts are devoted to cyclohexane,3
cyclopentane4 and cyclopropane5 derivatives. Indeed,
oligopeptide chains containing trans-2-aminocyclohex-
anecarboxylic acid have been shown to adopt 14-helical
structures while those containing trans-2-aminocyclo-
pentanecarboxylic acid prefer 12-helices.3b cis-Cyclopro-
pane derivatives, too, give highly stable helical
conformations in peptides.5c Moreover, some alicyclic
b-amino acid derivatives display antifungal, antibiotic
or analgesic activities.2,6 Despite the clear potential of
cyclobutane b-amino acid building blocks in this con-
text, and some positive indications of their ability to im-
pose secondary structure from preliminary studies,7,8a
there are currently very few means of access to these
compounds.
the first case and alkaloid-mediated opening of the
anhydride in the second. Subsequent transformations
led to the (À)-(1R,2S) antipode in each case. We present
here an alternative strategy allowing rapid access to
both enantiomers using simple and easily accessible
materials.
We previously described the synthesis of racemic 2-
aminocyclobutane-1-carboxylic acid ( )-4.10 The strat-
egy was based on a photochemical reaction of ethylene
(1) with uracil (2) to give the cyclobutane adduct ( )-
3, followed by controlled degradation of the heterocyclic
ring. The target amino acid ( )-4 was obtained with an
overall yield of 52% (Scheme 1).
Our aim was to develop an enantioselective version of
this synthesis. To this end, we decided to introduce a
chiral auxiliary on the uracil ring in order to induce dia-
stereochemical discrimination of cyclobutane adducts.
There was also the possibility for diastereofacial selec-
tion during the photochemical [2+2] reaction,11
although results with ethylene as one of the reaction
components are highly variable.12 We selected to use
Only two enantioselective syntheses of cis-2-aminocyclo-
butane-1-carboxylic acid have been described so far: first
8
9
´
`
by Martın-Vila et al. and then recently by Bolm et al.
Both procedures are based on an enantioselective meso-
cyclobutane-1,2-dicarboxylic acid desymmetrization
strategy, involving enzymatic hydrolysis of a diester in
O
O
H
H
H
CO2H
NH2
hν
NH
O
NH
O
N
H
N
H
H
Keywords: b-Amino acid; Cyclobutane; Stereoselective synthesis; [2+2]
Photocycloaddition reaction.
( ) -
1
4
2
( ) -
3
*
Corresponding author. Tel.: +33 4 73 40 71 84; fax: +33 4 73 40 77
17; e-mail: aitken@chimie.univ-bpclermont.fr
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.110

7096
C. Gauzy et al. / Tetrahedron Letters 45 (2004) 7095–7097
the N1-substituted uracil mimic (R)-5. This bicyclic
compound was easily obtained in enantiomerically pure
form in two steps from commercial (R)-phenylglycinol,
essentially as described by Agami et al. for the S-
enantiomer.13
column chromatography on silica gel, giving both (À)-
6 and (À)-7 in stereochemically pure form in 49% and
31% yield, respectively. Subsequent transformations
were carried out under identical conditions for each pure
compound.
Compound (R)-5 was submitted to [2+2] photocyclo-
addition reaction conditions (Scheme 2). Ethylene (1)
was bubbled through a solution of (R)-5 in acetone at
room temperature, which was irradiated with a 400W
medium-pressure mercury lamp fitted with a Pyrex filter
during 2h. In the event, the desired cyclobutane adduct
was obtained as a mixture of two diastereoisomers. In
conformity with our previous study involving uracil 2
(Scheme 1),10 cyclobutane compounds (À)-6 and (À)-7
each had a cis configuration; a de of 14% was deter-
mined by integration of 1H NMR data obtained on
the crude material. Separation was easily achieved by
Selective opening of the five-membered rings of (À)-6
and (À)-7 was achieved by catalytic hydrogenation in
the presence of palladium on charcoal, as described by
Agami et al. for related heterocyclic structures.13 Single
diastereoisomers (À)-8 and (À)-9 were thus obtained in
effectively quantitative yield.
Next, the a-methylbenzyl group was removed cleanly
and efficiently with refluxing formic acid.14 We thus ob-
tained enantiomers (+)-3 and (À)-3 whose spectroscopic
data were identical with those of our previous sample of
( )-3.10 The two-step transformation of the heterocyclic
ring––involving mild base hydrolysis followed by diazo-
tization with 1equiv of sodium nitrite in acidic med-
ium––followed by purification on ion exchange resin
proceeded in good yield without trace of epimerization
and led to the target b-amino acids (+)-4 and (À)-4 in
zwitterionic form (Scheme 2). NMR spectroscopic
data15 were comparable with those for racemic mate-
rial10 and with those reported by Bolm et al.9 for (À)-4.
O
N
+
N
O
1
Ph
(R)-5
hν, pyrex
acetone, r.t.
The overall yields following this short sequence were
33% and 20% for (+)-4 and (À)-4, respectively, from
(R)-5. Their respective optical rotations were +71 (c
0.88, H2O) and À70 (c 1.03, H2O). We determined an
enantiomeric excess of >97% for each enantiomer (+)-
4 and (À)-4 by HPLC on chiral column.16 Since the ee
31 %
49 %
separation of diastereomers
O
N
O
N
H
H
H
N
N
1
of (R)-5 was 98%, as determined by H NMR with the
O
O
chiral shift reagent Eu(hcf)3, we can conclude that there
was no loss of stereochemical fidelity during the
synthesis.
H
Ph
Ph
(-)-6
(-)-7
H2, Pd-C 10 %
EtOH, r.t.
99 %
100 %
The attribution of the 1R,2S absolute configuration
of the b-amino acid (À)-4 was made by correlation with
O
N
O
N
H
H
8
´
`
the previous observations made by Martın-Vila et al.
and Bolm et al.9 The absolute configuration of (+)-4 is
therefore 1S,2R.
NH
O
NH
O
H
Ph
H
Ph
(-)-9
(-)-8
In summary, we have succeeded in synthesizing both
(+)-(1S,2R) and (À)-(1R,2S)-2-aminocyclobutane-1-
carboxylic acid 4 in five steps from (R)-5. Previous
desymmetrization based stereoselective syntheses started
with derivatives of cis-cyclobutane-1,2-dicarboxylic
acid, which, although commercially available, is rather
expensive. Our synthesis represents a useful complemen-
tary strategy and provides the first described access to
the (+) antipode.17 Millimolar-range quantities of the
title b-amino acids are routinely accessible in this way
and their incorporation into peptides is currently under
study.
HCO2H
reflux
83 %
H
77 %
O
O
H
NH
NH
N
H
(-)-3
O
N
H
(+)-3
O
H
H
1) NaOH, r.t.
2) NaNO2, HCl, r.t.
3) ion exchange resin
83 %
85 %
H
H
H
COOH
NH2
COOH
NH2
Acknowledgements
H
(-)-4
We are grateful to the MENRT for a grant (to C.G.)
and the CNRS for ÔJeune EquipeÕ (AIP) funding. We
also thank undergraduate students E. Rossignol (Cler-
(+)-4
Scheme 2.

C. Gauzy et al. / Tetrahedron Letters 45 (2004) 7095–7097
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2002, 43, 6177–6179.
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