Expedient preparation of all isomers of 2-aminocyclobutanecarboxylic acid in enantiomerically pure form

Article abstract of DOI:10.1021/jo900175p

A short, convenient, gram scale protocol has been established to allow facile access to all four stereoisomers of 2-ami-nocyclobutanecarboxylic acid, each in enantiomerically pure form (ee >99%). Starting from the readily available cis racemate, the proce

Full text of DOI:10.1021/jo900175p

active materials.4 Given this interest, a convenient access to the
enantiomerically pure parent amino acids is of major importance.
Expedient Preparation of All Isomers of
2-Aminocyclobutanecarboxylic Acid in
Enantiomerically Pure Form
While many elegant approaches have been described for the
asymmetric synthesis of ꢀ-amino acids,5 only a few of these
are applicable for the preparation of cyclic compounds.6 The
synthesis of enantiomerically pure cis-cyclobutane ꢀ-amino acid
was described by each of the groups of Ortun˜o7 and Bolm,8
using an approach based on the enantioselective desymmetri-
zation of a derivative of meso-1,2-cyclobutanedicarboxylic acid.9
Recently, we described an alternative approach based on the
[2+2] photocycloaddition reaction of ethene with a nonracemic
uracil derivative, which furnished both enantiomers of the cis
compound.10 A protocol for the transformation of each cis
enantiomer into its corresponding trans isomer was also
described.10a To date, this is the only published preparation of
the trans compounds in enantiomerically pure form. However,
due to the likely increase in demand for these materials for the
above-stated reasons, we sought a more practical access to the
title compound in its various stereochemical forms.
Carlos Fernandes,† Elisabeth Pereira,† Sophie Faure,† and
David J. Aitken*,‡
Laboratoire SEESIB (UMR 6504-CNRS), De´partement de
Chimie, UniVersite´ Blaise Pascal-Clermont-Ferrand 2,
24 AVenue des Landais, 63177 Aubie`re cedex, France, and
Laboratoire de Synthe`se Organique et Me´thodologie,
ICMMO (UMR 8182-CNRS), UniVersite´ Paris-Sud 11,
15 rue Georges Clemenceau, 91405 Orsay cedex, France
daVid.aitken@u-psud.fr
ReceiVed January 27, 2009
To this end, racemic cis-2-aminocyclobutanecarboxylic acid,
(()-cis-1, was considered a good entry point. Multigram
quantities of this compound are readily available via a short
photochemical route11 or through conventional transformations
of meso-cyclobutane-1,2-dicarboxylic acid derivatives.7,8,12
The first objective was to optimize the cis-to-trans isomer-
ization procedure. This was a considerably more delicate
operation than the corresponding transformation for the cyclo-
pentane and cyclohexane congeners, generally done with
carboxylic ester derivatives.13 Indeed, basic treatment of an
N-Boc methyl ester derivative of (()-cis-1 was previously
shown to give 60% yield of the trans isomer at best;10a
furthermore, the process is capricious and loss of material is a
A short, convenient, gram scale protocol has been established
to allow facile access to all four stereoisomers of 2-ami-
nocyclobutanecarboxylic acid, each in enantiomerically pure
form (ee >99%). Starting from the readily available cis
racemate, the procedure combines efficient R-phenylethy-
lamine derivative resolution and controlled cis-to-trans
epimerization procedures, and proceeds with invariably high
yields.
(4) Recent patents: (a) Zenkoh, T.; Nozawa, E.; Matsuura, K.; Seo, R. Chem.
Abstr. 2008, 149, 471824. (b) Barchuk, W. T.; Dunford, P. J.; Edwards, J. P.;
Fourie, A. M.; Karlsson, L.; Quan, J. M. Chem. Abstr. 2008, 149, 268051. (c)
Zahn, S. K.; Bister, B.; Boehmelt, G.; Guertler, U.; Mantoulidis, A.; Reiser, U.;
Schoop, A.; Solca, F.; Tontsch-Grunt, U.; Treu, M. Chem. Abstr. 2008, 148,
11249.
(5) (a) EnantioselectiVe Synthesis of ꢀ-Amino Acids, 2nd ed.; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b) Liu, M.;
Sibi, M. P. Tetrahedron 2002, 58, 7991–8035.
(6) For reviews which include particular mention of cyclobutane ꢀ-amino
acids, see: (a) Ortun˜o, R. M.; Moglioni, A. G.; Moltrasio, G. Y. Curr. Org.
Chem. 2005, 9, 237–259. (b) Ortun˜o, R. M. In EnantioselectiVe Synthesis of
ꢀ-Amino Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2005; Chapter 5, pp 117-137. (c) Avotins, F. M. Russ.
Chem. ReV. 1993, 62, 897–906.
(7) (a) Mart´ın-Vila`, M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.;
Branchadell, V.; Minguillo´n, C.; Giralt, E.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 2000, 11, 3569–3584. (b) Mart´ın-Vila`, M.; Minguillo´n, C.; Ortun˜o,
R. M. Tetrahedron: Asymmetry 1998, 9, 4291–4294.
There is considerable interest in alicyclic ꢀ-amino acids as
intermediates in synthetic chemistry, as structural features in
biologically active compounds, and as valuable components for
the design and synthesis of molecular architectures bestowed
with local or long-ranging self-organizational ability.1 Recently,
cyclobutane ꢀ-amino acids have begun to show a potential that
is comparable with that of their 5- and 6-membered congeners.
A strong tendency for regular structuring in peptides containing
this moiety has been demonstrated,2 and very recently a
cyclobutane ꢀ-tetrapeptide self-assembled to produce nanosized
fibrils.3 Furthermore, patent literature suggests that cyclobutane
ꢀ-amino acid building blocks are increasingly a part of the
molecular inventory for the construction of new biologically
(8) Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P. R. Tetrahedron:
Asymmetry 2003, 14, 3455–3467.
(9) For a recent review on the desymmetrization of cyclic meso-anhydrides,
see: Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. ReV. 2007, 107, 5683–5712.
(10) (a) Fernandes, C.; Gauzy, C.; Yang, Y.; Pereira, E.; Faure, S.; Aitken,
D. J. Synthesis 2007, 2222–2232. (b) Gauzy, C.; Pereira, E.; Faure, S.; Aitken,
D. J. Tetrahedron Lett. 2004, 45, 7095–7097.
(11) (a) Aitken, D. J.; Gauzy, C.; Pereira, E. Tetrahedron Lett. 2002, 43,
6177–6179. (b) Gauzy, C.; Saby, B.; Pereira, E.; Faure, S.; Aitken, D. J. Synlett
2006, 1394–1398.
† Universite´ Blaise Pascal-Clermont-Ferrand 2.
‡ Universite´ Paris-Sud 11.
(1) Reviews: (a) Fu¨lo¨p, F. Chem. ReV. 2001, 101, 2181–2204. (b) Kuhl, A.;
Hahn, M. G.; Dumic´, M.; Mittendorf, J. Amino Acids 2005, 29, 89–100. (c)
Fu¨lo¨p, F.; Martinek, T. A.; To´th, G. Chem. Soc. ReV. 2006, 35, 323–334.
(2) (a) Izquierdo, S.; Ru´a, F.; Sbai, A.; Parella, T.; Alvarez-Larena, A.;
Branchadell, V.; Ortun˜o, R. M. J. Org. Chem. 2005, 70, 7963–7971. (b) Izquierdo,
S.; Kogan, M. J.; Parella, T.; Moglioni, A. G.; Branchadell, V.; Giralt, E.; Ortun˜o,
R. M. J. Org. Chem. 2004, 69, 5093–5099.
´
´
(12) Kennewell, P. D.; Matharu, S. S.; Taylor, J. B.; Westwood, R.; Sammes,
P. G. J. Chem. Soc., Perkin Trans. 1 1982, 2563–2570.
(3) Ru´a, F.; Boussert, S.; Parella, T.; D´ıez-Pe´rez, I.; Branchadell, V.; Giralt,
E.; Ortun˜o, R. M. Org. Lett. 2007, 9, 3643–3645.
(13) Davies, S. G.; Ichihara, O.; Lenoir, I.; Walters, I. A. S. J. Chem. Soc.,
Perkin Trans. 1 1994, 1411–1414.
10.1021/jo900175p CCC: $40.75
Published on Web 03/16/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3217–3220 3217

SCHEME 1. Epimerization Protocol for Racemic Amino
Acid 1
SCHEME 2. Resolution Protocols Leading to
Enantiomerically Pure Amino Acids 1
TABLE 1. Qualitative Evaluation of the Transformation of
Racemic cis-3 under Basic Conditionsa
reflux
entry
NaOH solution (molar equiv)
rt, 4 h
4 h
18 h
1
2
3
0.04 M (2 equiv)
0.2 M (10 equiv)
1.5 M (90 equiv)
cis-3
cis-3
cis-3
cis-3
trans-3
trans-2
trans-3
trans-2
trans-2
a Reactions were conducted with use of racemic material in aqueous
methanol solution on a 0.2 mmol scale. For each entry, the sample was
subjected successively to the conditions indicated in the three columns.
The evolution of the reaction was examined at the end of each reaction
period (by 1H NMR); the major constituent (>80%) of the mixture is
reported.
basic medium, the entirely chemoselective alkaline hydrolysis
of a primary carboxamide in the presence of a tert-butyl
carbamate is noteworthy, since this operation is not often
encountered in the literature.15 Furthermore, no trace of (()-
cis-2 was detected at any time, and it was verified in a separate
control reaction that (()-cis-2 is completely stable in the basic
reaction conditions. This implies the specific sequence of events
presented in Scheme 1: compound (()-cis-3 reacts with NaOH
by epimerizing to provide (()-trans-3; this process may or may
not be reversible, but only the latter isomer undergoes carboxa-
mide hydrolysis to provide a carboxylate product. With this
completely selective tandem operation secured, TFA-mediated
N-Boc group cleavage of (()-trans-2 completed access to (()-
trans-1 (Scheme 1). Overall, the transformation of cis-1 to
trans-1 is remarkably efficient (84% overall yield).
We next sought to combine this operation with a practical
resolution procedure to access all stereoisomers of the target
amino acid. R-Phenylethylamine and some derivatives are
commercially available and have an established portfolio as
chiral reagents for the preparation of enantiomerically pure
compounds.16 One of the advantages of using these chiral agents
is that their “easy-on-easy-off” resolution protocols can be
combined with a net structural transformation. We felt that this
class of reagent should be able to provide resolved cis-3 from
(()-cis-2 in only two steps, and indeed two complementary
procedures were established to this end (Scheme 2).
frequent problem, doubtless due to the push-pull ring opening
propensity of the system.2a,14 We reasoned that an alternative
carboxylic acid derivative might be better suited for this
operation for the cyclobutane skeleton, and after some unpro-
ductive experimentation with urea derivatives we focused on a
primary carboxamide function.
Racemic N-Boc-amino carboxamide derivative (()-cis-3 was
prepared easily from (()-cis-1 in two steps in 95% yield
(Scheme 1). From the preliminary studies on the behavior of
this material in the presence of NaOH in aqueous methanol, it
soon became apparent that more than one process was operating.
Various reaction conditions were investigated and the evolution
of each reaction mixture was followed by NMR analysis of a
small sample; the qualitative results of these analyses are
summarized in Table 1.
The reaction of starting material (()-cis-3 produced first the
epimer (()-trans-3, which was in turn transformed into the
N-Boc-amino acid (()-trans-2 (as its sodium salt until final acid
workup). Base strength and reaction temperature determined the
rapidity of this tandem process. The intermediate (()-trans-3
was isolated and characterized in one preparative run, while
the two-step transformation of (()-cis-3 was optimized for
preparative purposes by refluxing in 1.5 M NaOH (in aqueous
MeOH) for 12 h, which provided (()-trans-2 in quantitative
yield. This highly gratifying result warrants further comment.
First, while an N-Boc group is generally reputed to be stable in
(15) For a precedent, see: Onoprienko, V. V.; Yelin, E. A.; Miroshnikov,
A. I. Russ. J. Bioorg. Chem. 2000, 26, 361–368.
(16) (a) Juaristi, E.; Escalante, J.; Leo´n-Romo, J. L.; Reyes, A. Tetrahedron:
Asymmetry 1998, 9, 715–740. (b) Juaristi, E.; Leo´n-Romo, J. L.; Reyes, A.;
Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441–2495.
(14) Aitken, D. J.; Gauzy, C.; Pereira, E. Tetrahedron Lett. 2004, 45, 2359–
2361.
3218 J. Org. Chem. Vol. 74, No. 8, 2009

The organic layer was dried with MgSO4, filtered, and evaporated.
Flash chromatography (EtOAc/cyclohexane 15:85) of the residue
furnished 4a (1.26 g, 43%) and 4b (1.23 g, 42%).
Condensation of (()-cis-2 with commercial (R)-R-phenyl-
ethylamine gave a mixture of diastereoisomers 4a and 4b which
were completely separated by column chromatography. The
isolated yield of each pure stereoisomer was reproducibly above
40%. Each was then treated with sodium in liquid ammonia to
cleave the N-benzylic bond and furnish enantiomerically pure
cis-3 efficiently. As an alternative that avoids the Na/NH3
procedure, diastereomeric amides 5a and 5b were prepared with
(R)-R-(p-methoxyphenyl)ethylamine and were separated chro-
matographically, again with good isolated material recovery
(above 40% for each isomer). Conversion of each compound
into the corresponding cis-3 enantiomer was achieved by using
ceric ammonium nitrate. All of the above procedures can be
reproduced on quantities up to gram scale.17
Each pure enantiomer of cis-3 was easily transformed into
either the cis or trans isomer of 1 (Scheme 2). For the trans
isomers, the procedures which had been established above for
racemic materials were reproduced successfully. In practice,
stock samples of each enantiomer of the intermediate trans-2
are prepared on several-hundred milligram scale, since this
compound is completely stable. The final N-deprotection step
is best performed only on such quantities of amino acid as are
required, since this material is visibly less stable over time.
For direct access to enantiomerically pure cis-1, we found
after some experimentation that commercial nitrosylsulfonic acid
solution18 was a very convenient reagent for the one-pot
combined cleavage of the N-Boc group and controlled diazo-
tization of the carboxamide of cis-3 (Scheme 2). This operation
was complete within 2 h at ambient temperature, with no
significant over-reaction (diazotization of the amine) and no trace
of epimerization. Thus each enantiomer of cis-3 can be
converted smoothly into the corresponding cis-1 enantiomer in
a single, high-yielding reaction (>90%).
Carboxamides 5a and 5b. To a solution of (()-cis-2 (2.50 g,
11.6 mmol) in dry CH2Cl2 (210 mL) at 0 °C under argon were
added 1-hydroxybenzotriazole monohydrate (2.19 g, 16.2 mmol)
and (R)-R-(p-methoxyphenyl)ethylamine (1.86 g, 12.7 mmol). After
10 min, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (3.33 g, 17.4 mmol) was added and the cooling bath was
removed; the mixture was stirred at rt for 12 h, then washed with
5% citric acid solution (210 mL) then saturated NaHCO3 solution
(210 mL). The organic layer was dried with MgSO4, filtrated, and
evaporated. Flash chromatography (EtOAc/cyclohexane 15:85) of
the residue furnished 5a (1.70 g, 42%) and 5b (1.66 g, 41%).
(+)-(1S,2R)-2-(tert-Butyloxycarbonylamino)cyclobutanecar-
boxamide, (+)-(1S,2R)-3. Method A: Sodium (0.50 g, 21.7 mmol)
was added under a stream of argon to liquid ammonia (50 mL) at
-40 °C. A solution of amide 4a (1.00 g, 3.14 mmol) in THF (30
mL) was added, and the mixture was stirred at -40 °C for 1 h
then quenched by addition of solid NH4Cl (1.76 g, 32.9 mmol)
and allowed to warm to rt as the ammonia evaporated. Water (30
mL) was added to the residual solution, then 1 M HCl was added
slowly until pH 7. The mixture was extracted with CH2Cl2 (3 ×
45 mL), and combined organic extracts were dried with anhydrous
MgSO4, filtered, and evaporated. Flash chromatography (EtOAc/
cyclohexane 50:50) provided the title compound as a white powder
(0.54 g, 80%).
Method B: A solution of amide 5a (0.75 g, 2.15 mmol) and CAN
(5.86 g, 10.7 mmol) in acetonitrile (75 mL) and water (20 mL) was
stirred at rt until TLC analysis showed no remaining starting material
(approximately 1 h). The mixture was diluted with water (20 mL) and
extracted with EtOAc (3 × 20 mL). The combined extracts were
washed successively with saturated NaHCO3 solution (6 mL) and water
(10 mL), dried with MgSO4, then evaporated to give crude product.
Flash chromatography (EtOAc/cyclohexane 50:50) provided the title
compound as a white powder (0.30 g, 65%).
(-)-(1R,2S)-2-(tert-Butyloxycarbonylamino)cyclobutanecar-
boxamide, (-)-(1R,2S)-3. Method A: Sodium (0.33 g, 14.3 mmol)
was added under a stream of argon to liquid ammonia (35 mL) at
-40 °C. A solution of amide 4b (0.67 g, 2.10 mmol) in THF (23
mL) was added, and the mixture was stirred at -40 °C for 1 h
then quenched by addition of solid NH4Cl (1.17 g, 21.9 mmol)
and allowed to warm to rt as the ammonia evaporated. Water (20
mL) was added to the residual solution, then 1 M HCl was added
slowly until pH 7. The mixture was extracted with CH2Cl2 (3 ×
30 mL), and combined organic extracts were dried with anhydrous
MgSO4, filtered, and evaporated. Flash chromatography (EtOAc/
cyclohexane 50:50) provided the title compound as a white powder
(0.38 g, 85%).
Method B: A solution of amide 5b (0.48 g, 1.38 mmol) and
CAN (3.84 g, 7.00 mmol) in acetonitrile (60 mL) and water (15
mL) was stirred at rt until TLC analysis showed no remaining
starting material (approximately 1 h). The mixture was diluted with
water (15 mL) and extracted with EtOAc (3 × 15 mL). The extracts
were washed successively with saturated NaHCO3 solution (3 mL)
and water (5 mL), dried with MgSO4, then evaporated to give crude
product. Flash chromatography (EtOAc/cyclohexane 50:50) pro-
vided the title compound as a white powder (0.12 g, 41%).
(+)-(1R,2R)-2-(tert-Butyloxycarbonylamino)cyclobutanecar-
boxylic Acid, (+)-(1R,2R)-2. A solution of (+)-(1S,2R)-3 (0.46 g,
2.15 mmol) in MeOH (90 mL) was treated with 6.25 M aqueous
NaOH solution (30 mL) and the mixture was heated at reflux for
12 h. The methanol was then removed by careful evaporation under
reduced pressure and the residual aqueous phase was washed with
EtOAc (3 × 40 mL). The aqueous phase was then cooled at -5
°C, while concd HCl was added slowly until pH 2. The aqueous
phase was then extracted with EtOAc (3 × 80 mL) and the
combined organic extracts were dried with MgSO4 and concentrated
under vacuum. Flash chromatography (EtOAc/HOAc 99.7:0.3)
In conclusion, we have established a short and efficient
protocol, combining resolution and controlled epimerization, to
provide access to all the stereoisomers of the title cyclobutane
amino acid from a single parent racemate. This approach
highlights the use of a carboxamide rather than an ester function
for the epimerization step, and has several advantages over the
only other previous route to the trans isomers of the target amino
acid in enantiomerically pure form. Although we have applied
the process to obtain hundred-milligram quantities of intermedi-
ates (sufficient for our requirements), the procedures appear
amenable to larger scale preparations. By extension, they should
also have useful applications in the configuration control and
functional group manipulation of other ꢀ-amino acid derivatives.
Experimental Section
Carboxamides 4a and 4b. To a solution of (()-cis-2 (1.98 g,
9.20 mmol) in dry CH2Cl2 (170 mL) at 0 °C under argon were
added 1-hydroxybenzotriazole monohydrate (1.96 g, 12.8 mmol)
and (R)-R-phenylethylamine (1.22 g, 10.1 mmol). After 10 min,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.63
g, 13.7 mmol) was added and the cooling bath was removed; the
mixture was stirred at rt for 12 h, then washed with 5% citric acid
solution (170 mL) then with saturated NaHCO3 solution (170 mL).
(17) The possibility of epimerization of 4 or 5 to give trans-isomers was
considered. In a series of tests, however, 4a/4b mixtures were recovered
completely unreacted from basic aqueous conditions, or extensively degraded
when treated with t-BuOK/THF at reflux. For a related use of these latter
conditions, see: Priego, J.; Flores, P.; Ortiz-Nava, C.; Escalante, J. Tetrahedron:
Asymmetry 2004, 15, 3545–3549.
(18) Wade, L. G.; Silvey, W. B. Org. Prep. Proced. Int. 1982, 14, 357–359.
J. Org. Chem. Vol. 74, No. 8, 2009 3219

provided the title compound as a white powder (0.46 g, 100%).
(1.2 g). After warming to rt, the solution was applied to an ion
exchange column; elution provided the title compound as a white
[R]27 +44 (c 0.50, CHCl3). Other physical and spectral data for
D
this compound were identical with those reported previously.10a
(-)-(1S,2S)-2-(tert-Butyloxycarbonylamino)cyclobutanecar-
boxylic Acid, (-)-(1S,2S)-2. A solution of (-)-(1R,2S)-3 (0.10 g,
0.47 mmol) in MeOH (20 mL) was treated with 6.25 M aqueous
NaOH (7 mL) and the mixture was heated at reflux for 12 h. The
methanol was then removed by careful evaporation under reduced
pressure and the residual aqueous phase was washed with EtOAc
(3 × 20 mL). The aqueous phase was then cooled at -5 °C, while
concd HCl was added slowly until pH 2. The aqueous phase was
then extracted with EtOAc (3 × 40 mL) and the combined organic
extracts were dried with MgSO4 and concentrated under vacuum.
Flash chromatography (EtOAc/HOAc 99.7:0.3) provided the title
compound as a white powder (0.10 g, 100%). [R]27D -44 (c 0.50,
CHCl3). Other physical and spectral data for this compound were
identical with those reported previously.10a
powder (24.5 mg, 91%). [R]27 -70 (c 0.55, H2O). Chiral HPLC
D
analysis: >99% ee. Other physical and spectral data for this
compound were identical with those reported previously.2a,8,10a
(-)-(1R,2R)-2-Aminocyclobutanecarboxylic Acid, (-)-(1R,2R)-
1. TFA (0.42 mL) was added dropwise to a solution of (+)-
(1R,2R)-2 (40 mg, 0.19 mmol) in dry CH2Cl2 (1.2 mL) at rt. The
mixture was stirred for 30 min then evaporated under vacuum to
leave a brown residue. This material was taken up in water and
purified on an ion exchange column to provide the title compound
as a white solid (18 mg, 84%). [R]27 -99 (c 0.55, H2O). Chiral
D
HPLC analysis: >99% ee. Other physical and spectral data for this
compound were identical with those reported previously.10a
(+)-(1S,2S)-2-Aminocyclobutanecarboxylic Acid, (+)-(1S,2S)-
1. TFA (0.40 mL) was added dropwise to a solution of (-)-
(1S,2S)-2 (37 mg, 0.17 mmol) in dry CH2Cl2 (1.0 mL) at rt. The
mixture was stirred for 30 min then evaporated under vacuum to
leave a brown residue. This material was taken up in water and
purified on an ion exchange column to provide the title compound
(+)-(1S,2R)-2-Aminocyclobutanecarboxylic Acid, (+)-(1S,2R)-
1. Commercial nitrosylsulfuric acid (40% solution in concd H2SO4;
0.45 mL) was added cautiously to water (0.18 mL) that was chilled
in an ice bath. Solid amide (+)-(1S,2R)-3 (50 mg, 0.23 mmol) was
added, and the mixture was allowed to warm to rt over 2 h while
being stirred. The reaction mixture was poured over crushed ice
(1.2 g). After warming to rt, the solution was applied to an ion
exchange column; elution provided the title compound as a white
as a white solid (17 mg, 86%). [R]27 +99 (c 0.45, H2O). Chiral
D
HPLC analysis: >99% ee. Other physical and spectral data for this
compound were identical with those reported previously.10a
Acknowledgment. This work was supported by a research
grant (to C.F.) from the French Ministry of Research.
powder (25 mg, 93%). [R]27 +70 (c 0.50, H2O). Chiral HPLC
D
analysis: >99% ee. Other physical and spectral data for this
compound were identical with those reported previously.2a,10a
(-)-(1R,2S)-2-Aminocyclobutanecarboxylic Acid, (-)-(1R,2S)-
1. Commercial nitrosylsulfuric acid (40% solution in concd H2SO4;
0.45 mL) was added cautiously to water (0.18 mL) that was chilled
in an ice bath. Solid amide (-)-(1R,2S)-3 (50 mg, 0.23 mmol) was
added, and the mixture was allowed to warm to rt over 2 h while
being stirred. The reaction mixture was poured over crushed ice
Supporting Information Available: Full experimental pro-
cedures, characterization, and copies of NMR spectra of all
compounds and copies of chiral hplc chromatograms of each
stereoisomer of the title compound. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO900175P
3220 J. Org. Chem. Vol. 74, No. 8, 2009