A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids

Article abstract of DOI:10.1007/s00726-011-0918-y

The synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids has been refined to improve both the efficiency and the simplicity. These improvements provide a shorter and easier access to the racemic cis-cyclobutane β-amino acid core. Derivatization of this material with a chiral non-racemic oxazolidin-2-one allows easy diastereoisomeric separation and presents the advantage of allowing the non-destructive cleavage of the chiral auxiliary either by hydrolysis or by ammonolysis, thus providing an efficacious access to N-protected derivatives of all four stereoisomers of Boc-2-aminocyclobutanecarboxylic acid.

Full text of DOI:10.1007/s00726-011-0918-y

Amino Acids (2011) 41:587–595
DOI 10.1007/s00726-011-0918-y
ORIGINAL ARTICLE
A refined synthesis of enantiomerically pure
2-aminocyclobutanecarboxylic acids
•
Valerie Declerck David J. Aitken
´
Received: 29 January 2011 / Accepted: 12 April 2011 / Published online: 4 May 2011
Ó Springer-Verlag 2011
Abstract The synthesis of enantiomerically pure 2-ami-
nocyclobutanecarboxylic acids has been refined to improve
both the efficiency and the simplicity. These improvements
provide a shorter and easier access to the racemic cis-
cyclobutane b-amino acid core. Derivatization of this
material with a chiral non-racemic oxazolidin-2-one allows
easy diastereoisomeric separation and presents the advan-
tage of allowing the non-destructive cleavage of the chiral
auxiliary either by hydrolysis or by ammonolysis, thus
providing an efficacious access to N-protected derivatives
of all four stereoisomers of Boc-2-aminocyclobutane-
carboxylic acid.
aminocyclohexanecarboxylic acid (trans-ACHC) are
known to adopt a 14-helix conformation (Appella et al.
´
1999a; Hetenyi et al. 2005) while oligomers of trans-
2-aminocyclopentanecarboxylic (trans-ACPC) adopt
a
12-helix conformation (Appella et al. 1997, 1999b); in
contrast, oligomers of cis-2-aminocyclopentanecarboxylic
(cis-ACPC) adopt a strand-like structure (Martinek et al.
2002).
Mixed b-peptides in which ACHC or ACPC has been
combined with other b-amino acids may retain a propensity
´
for regular folding (Pomerantz et al. 2008; Hetenyi et al.
2009b; Dutot et al. 2008; Chakraborty and Diederichsen
2005; Raguse et al. 2002), and some of these materials
display promising biological activities (English et al. 2006;
Karlsson et al. 2006; Imamura et al. 2009). Similarly, a
variety of helical structure types have been demonstrated
for mixed a/b-peptides with heterogeneous backbones in
which ACHC or ACPC has been combined with a-amino
acids (Lee et al. 2009; Horne and Gellman 2008), and an
innovative stereochemical patterning approach to helix
design with such building blocks has been proposed
Keywords 2-Aminocyclobutanecarboxylic acids ꢀ
Photochemical [2 ? 2] cycloaddition ꢀ Chiral resolution ꢀ
Epimerization ꢀ Oxazolidin-2-one
Introduction
There is an increasing demand for synthetic access to
cyclic b-amino acids. Some of these compounds are in
themselves bestowed with biological activity, while others
are considered to be useful tools for the preparation of
peptidomimetics, and for the construction of molecular
´
(Mandity et al. 2009).
Progress in this developing area has inspired studies of
more elaborate bicyclic b-amino acids, in order to widen
´
the range of building blocks for helical manifolds (Mandity
´
et al. 2010; Hetenyi et al. 2009a; Chandrasekhar et al.
¨
architectures exhibiting strong self-organization (Fu¨lop
¨
2001; Fu¨lop et al. 2006; Kuhl et al. 2005; Kiss et al. 2009).
2006). Small ring b-amino acids should make a logical
contribution to the field; the corpus of work is noticeably
less extensive however. One important factor which has to
be confronted is the intrinsic instability of the building
blocks. Indeed, 2-aminocyclopropanecarboxylic acid does
not exist, because the vicinal push–pull substituent system
facilitates rapid and irreversible ring opening (Gnad and
Reiser 2003; Mangelinckx and De Kimpe 2003). Never-
theless, peptides have been made which incorporate
In the area of foldamer science, oligomers of trans-2-
V. Declerck ꢀ D. J. Aitken (&)
`
Laboratoire de Synthese Organique et Methodologie,
ICMMO (UMR 8182-CNRS), Universite Paris-Sud 11,
´
´
15 rue Georges Clemenceau, 91405 Orsay Cedex, France
e-mail: david.aitken@u-psud.fr
URL: http://www.icmo.u-psud.fr/Labos/LSOM
123

588
V. Declerck, D. J. Aitken
Scheme 1 The established
access to enantiopure cis- and
trans-ACBCs
2-aminocyclopropanecarboxylic acids bearing an extra
carboxylic acid function at C1 (Godier-Marc et al. 1997) or
at C3 (D’Elia et al. 2008; Urman et al. 2007; Koglin et al.
2003), and these materials are stable provided the nitrogen
atom remains part of an amide function. Stable helical
conformations were observed in mixed a/b-peptides which
incorporate C3-substituted cis-2-aminocyclopropane-
carboxylic acid residues (De Pol et al. 2004).
cis-ACBC (Aitken et al. 2002), we extended its use to
prepare substituted ACBCs (Gauzy et al. 2006), and also
described an adaptation using a chiral uracil derivative
which provided both cis- and trans-ACBC in enantiome-
rically pure form (Gauzy et al. 2004; Fernandes et al.
2007). Subsequently, using racemic cis-ACBC as the entry
point, a procedure was described which allows access to all
four ACBC stereoisomers (Fernandes et al. 2009)
(Scheme 1). This approach involves a resolution step via
chiral derivatization, and an efficient cis-to-trans epimer-
ization protocol.
Recently, it has emerged that 2-aminocyclobutane-
carboxylic acids (ACBC) also serve as building blocks for
b-peptides with regular structural patterns. Homo-oligo-
mers of cis-ACBC adopt strand-type conformations, sta-
bilized by a succession of localized six-membered ring
hydrogen bonds, and these oligomers undergo self-assem-
While the above-described procedure provides a satis-
factory entry to ACBC stereoisomers, a critical inspection
of the synthesis reveals that it suffers from three drawbacks
which render it less practical for large-scale preparation
(Scheme 1). The first inconvenience is that the preparation
of the key intermediate, racemic Boc-cis-ACBC, ( )-3, is
obtained from the free amino acid form of cis-ACBC,
( )-2, which has an inherent limited stability due to a
push–pull substituent effect which promotes ring opening
(Aitken et al. 2004). The second difficulty is associated
with the low solubility of the intermediate diastereomeric
a-methylbenzylamides, which renders their chromato-
graphic separation fastidious. The third discommodity is
that the chiral auxiliary used for the resolution process,
(R)-a-methylbenzylamine, is destroyed during the trans-
formation to enantiopure amides 4, and thus cannot be
recycled (Scheme 1).
´
bly to furnish nanofibrils or gels (Rua et al. 2007; Torres
et al. 2010). Dipeptides incorporating trans-ACBC appear
to adopt eight-membered hydrogen bond rings (Torres
et al. 2009), while longer oligomers adopt a 12-helix
conformation both in solution and in the solid state (Fer-
nandes et al. 2010).
As a part of a program aimed at the discovery of new
foldamers constructed from four-membered ring b-amino
acids, a rapid and scalable access to enantiomerically pure
cis- and trans-ACBCs was required. Prior to our own
contributions in the area, there were only two stereose-
lective syntheses of this b-amino acid core; taking the lead
from earlier work using racemic material (Kennewell et al.
1982), enantiomerically pure cis-ACBC was prepared by
´ `
the groups of Ortun˜o (Martın-Vila et al. 1998, 2000) and
Bolm (Bolm et al. 2003) via enantioselective desymmet-
rization of
a
meso-1,2-cyclobutanedicarboxylic acid
Results and discussion
derivative. About 10 years ago, we began studies on an
alternative route to the ACBC core, using the [2 ? 2]
photocycloaddition reaction of ethylene with uracil as
the key step for the construction of the 4-membered ring.
After validating the approach for the synthesis of racemic
We began our refinements of the [2 ? 2] cycloaddition
strategy by reconsidering the access to racemic Boc-cis-
ACBC ( )-3 without recourse to the free amino acid 2.
This objective implied the introduction of the Boc
123

A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids
589
Scheme 2 A short access to
racemic Boc-cis-ACBC
protecting group earlier in the sequence, and indeed we felt
that this feature would have the added advantage of facil-
itating the controlled cleavage of the dihydropyrimidinone
moiety. We first studied the introduction of a Boc group at
the N1 position of the photocycloadduct 1, which was
obtained from uracil and ethylene as described previously
(Aitken et al. 2002). The selective protection of 1 proved to
be rather troublesome, because the requisite compound 5
was often accompanied by a significant amount of the bis-
Boc compound 6. The formation of this by-product was
suppressed when cycloadduct 1 was treated with a stoi-
chiometric amount of Boc2O in the presence of 10% of
DMAP using acetonitrile as a solvent, to give 54% of
compound 5 (Scheme 2). An alternative route to compound
5 consisted of employing N1-Boc-uracil 7 in the [2 ? 2]
cycloaddition reaction with ethylene. N1-Boc-uracil 7 was
obtained by regioselective derivatization according to the
procedure developed by Jaime-Figueroa et al. (2001) and
used without purification in the photocycloaddition reac-
tion with ethylene (Scheme 2), using a 400 W mercury
lamp in a reactor fitted with a Pyrex filter, which provides a
280 nm wavelength cutoff. Using this tandem operation,
compound ( )-5 was obtained in 85% yield from uracil.
The Boc group on the N1 position enhances the leaving
group character of this nitrogen center, which was expected
to promote cleavage of the N1–C2 bond. Gratifyingly,
treatment of compound ( )-5 with 3 M aqueous NaOH at
room temperature induced the smooth cleavage of both
N3–C4 and N1–C2 bonds in a single operation to produce
Boc-cis-ACBC ( )-3 in 76% (Scheme 2). By conducting
this reaction at room temperature, the risk of partial base-
mediated epimerization at C1 is avoided. This constitutes
the shortest and the most efficient access to ( )-3 described
to date; the previous synthesis, proceeding via the free
amino acid (Scheme 1), required four steps (49% yield
from uracil).
We next reinvestigated the resolution procedure with the
objective of making it amenable to larger scale preparation.
Our intention was to identify a chiral resolving agent
which, as well as its separation potential, fulfilled two
additional criteria: first, it should not be consumed or
destroyed during the procedure (allowing recycling) and
second, its controlled cleavage should be possible using
conditions which provide either the cis-Boc-amino acid 3
or the cis-Boc-amino amide 4. The reason for requiring
easy access to this latter derivative is its privileged status as
the appropriate precursor for entry to the trans-ACBC
amino acid series as indicated above (Scheme 1) (Fernan-
des et al. 2009).
Chiral oxazolidin-2-ones appeared as good chiral
resolving agent candidates, likely to meet these two
requirements, so we investigated a selection of such com-
pounds. In small-scale reactions (0.1 mmol), a selection of
´
known chiral oxazolidin-2-ones 8–12 (Begis et al. 2009;
¨
Tussetschlager et al. 2007; Ahmed et al. 2002) was prepared
and coupled to ( )-3 via its pentafluorophenyl ester (Moser
et al. 2008) in order to evaluate the feasibility of diaste-
reomeric separation by chromatography (Table 1). The use
of (S)-4-benzyl- or (R)-4-phenyloxazolidin-2-ones (8 and 9,
entries 1 and 2) did not provide any diastereomeric sepa-
ration. The more polar (S)-4-(p-methoxybenzyl)- (10, entry
3) or (S)-4-(p-nitrobenzyl)oxazolidin-2-ones (11, entry 4)
allowed diastereomeric separation, but only with difficulty.
Finally, the use of oxazolidin-2-one 12 derived from
(1R,2S)-norephedrine (entry 5) gave superior results
allowing a clean separation of the two diastereoisomers.
A careful analysis of the reaction mixtures in the above-
screening experiments revealed that a partial endocyclic
123

590
V. Declerck, D. J. Aitken
oxazolidin-2-one 12 provided cleanly a mixture of the two
diastereoisomers 13 and 14. These derivatives were easily
separated by chromatography and isolated in 46 and 44%
yield, respectively (Scheme 3).
Table 1 Screening of oxazolidin-2-ones as resolving agent
The controlled cleavage of the oxazolidin-2-one moiety
was vital to the success of this resolution protocol. While
the removal of the exocyclic acyl component from an
N-acyloxazolidin-2-one by hydrolysis is well documented
(Ager et al. 1996 and references therein), only a few
examples are reported for acyl group removal by ammo-
nolysis (Commerc¸on and Paris 1991; Chibale and Warren
1995; Boger et al. 1998; Zou et al. 2002). In the first
instance, each compound 13 and 14 was treated with lith-
ium hydroperoxide in aqueous THF to produce the two
enantiopure compounds Boc-cis-ACBC (1S,2R)-3 and
(1R,2S)-3 in 95 and 96%, respectively, without epimer-
ization (Scheme 4). The chiral oxazolidin-2-one 12 was
recovered easily at the end of these procedures. In our
quest to prepare the Boc-cis-amino amide derivatives from
the same intermediates 13 and 14, we were pleased to find
that a biphasic mixture of aqueous ammonia and THF
allowed a clean and complete cleavage of the oxazolidin-2-
one auxiliary. An attempt to perform this transformation
using an ammonia solution in ethanol gave a sluggish
reaction, and some unidentified secondary products were
observed. Using the aqueous ammonia–THF procedure, the
cis-amides (1S,2R)-4 and (1R,2S)-4 were obtained in 90
and 91% yield, respectively (Scheme 4). Once again, the
chiral oxazolidin-2-one 12 was recovered efficiently in
these operations. Treatment of these amides with aqueous
NaOH in refluxing MeOH provided access to each of the
enantiomers of Boc-trans-ACBC, (1R,2R)-15 and (1S,2S)-
15, in good yields.
Entry
1
Oxazolidin-2-one
Separation
No
2
3
No
Difficult
4
5
Difficult
Efficient
Scheme 3 Chiral resolution using (1R,2S)-norephedrine derived
oxazolidin-2-one 12
Conclusion
In summary, we have reinvestigated and improved the syn-
thesisof2-aminocyclobutanecarboxylicacids tomakeitmore
suitable for routine larger scale preparations. The problems
associated with the formation of unprotected cis-ACBC as a
synthetic intermediate were circumvented, and the use of
an oxazolidin-2-one as chiral resolving agent provides a
hydrolysis of the oxazolidin-2-one moiety in the products
had occurred. For preparative work, therefore, the coupling
conditions were modified: we decided to activate the acid
as a mixed anhydride using pivaloyl chloride, and intro-
duce the oxazolidin-2-one as its lithium salt. Using these
conditions, the coupling of Boc-cis-amino acid ( )-3 to
Scheme 4 Access to all
stereoisomers of Boc-ACBC
123

A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids
591
welcome combination of clean separation with directed non-
destructive cleavage, to facilitate access to N-protected
derivatives of both cis- and trans-ACBC on gram scale.
which was used directly in the next step without purifica-
tion. A solution of this crude Boc-uracil in acetone (1 L)
was placed in a cylindrical water-cooled reactor, degassed
with an argon stream for 30 min, and then saturated with
ethylene for 30 min. The solution was then irradiated for
4 h with a 400 W medium-pressure mercury lamp fitted
with a Pyrex filter while ethylene was bubbled through.
The solution was then evaporated under reduced pressure.
Flash chromatography of the residue (c-C6H12/EtOAc =
70/30) gave the cycloadduct ( )-5 (6.14 g, 85% over 2
steps) as a white solid.
Experimental
General remarks
All reagents and solvents were of commercial grade and
were used without further purification, except as follows.
Dichloromethane was dried over activated alumina and
THF was distilled from sodium/benzophenone. (4S,5R)-4-
Methyl-5-phenyl-1,3-oxazolidin-2-one was prepared from
(1R,2S)-norephedrine according to a literature procedure
Mp 143°C; Rf 0.16 (c-C6H12/EtOAc); IR (KBr) m 3,383,
3,234, 2,984, 1,785, 1,733, and 1,704 cm-1 1H NMR
;
(360 MHz, CDCl3) d 1.54 (s, 9H), 2.10–2.40 (m, 3H), 2.50
(m, 1H), 3.34 (m, 1H), 4.74 (m, 1H), 7.58 (bs, 1H); 13C
NMR (90 MHz, CDCl3) d 21.5, 28.0, 30.3, 39.5, 49.0,
84.3, 148.7, 150.7, 172.2; HRMS (ESI?) Calcd for
C11H16N2NaO4 [M ? Na]?: 263.1002, found 263.1000;
Anal. Calcd for C11H16N2O4 C, 54.99; H, 6.71; N, 11.66.
Found C, 55.05; H, 6.81; N, 11.74.
(Begis et al. 2009) and had [a]2D4 -168 (c 1.20, CHCl3) {lit.
´
[a]2D0 -170 (c 1.20, CHCl3)}.
Flash chromatography was performed with SDS silica
gel (35–70 lm). Analytical thin-layer chromatography was
performed with 0.25 mm commercial silica gel plates
(EMD, Silica Gel 60F254). TLC plates were visualized by
UV fluorescence at 254 nm and then revealed using a
phosphomolybdic acid solution (10% in EtOH) or a nin-
hydrin solution (0.3% in n-BuOH). Retention factors (Rf)
are given for such analyses. Melting points were obtained
in open capillary tubes and are uncorrected.
cis-(2-t-Butyloxycarbonylamino)cyclobutanecarboxylic
acid [( )-3]
Cycloadduct ( )-5 (6.13 g, 25.5 mmol) was treated with a
0.5 M aqueous NaOH solution (255 mL) for 8 h at room
temperature. The solution was cooled to 0°C and solid
NaOH (25.5 g, 63.8 mmol, 25 eq.) was added portionwise.
The mixture was stirred for 14 h at room temperature, then
was cooled to 0°C and acidified slowly with concentrated
HCl to pH 1. The aqueous phase was extracted with EtOAc
(5 9 75 mL). The organic phase was dried over MgSO4,
filtered and evaporated under reduced pressure to give the
Boc-amino acid ( )-3 (4.15 g, 76%) as a white solid. Mp
170–172°C. The spectral data were identical to those
reported previously (Fernandes et al. 2007).
Optical rotations were measured using a 10 cm quartz
cell. Values for [a]TD were obtained with the D-line of
sodium at the indicated temperature T, using solutions of
concentration (c) in units of g 100 mL-1. Samples for
Fourier-transform infrared spectroscopy (IR) were pre-
pared by the dispersion of the solid in a KBr disc. Maxi-
mum absorbances (m) are given in cm-1
.
Nuclear magnetic resonance (NMR) data were acquired
1
on a spectrometer operating at 360 MHz for H and at
90 MHz for 13C. Chemical shifts (d) are reported in ppm
with respect to tetramethylsilane (d = 0 ppm). Splitting
patterns for H NMR signals are designated as: s (singlet),
1
Chiral derivatization with (4S,5R)-4-methyl-5-
phenyloxazolidin-2-one
d (doublet), t (triplet), q (quartet), quint (quintuplet), broad
singlet (bs) or m (multiplet). High-resolution mass spec-
trometry (HRMS) data were recorded using electrospray
ionization either in positive or negative mode (ESI? or
ESI-).
To a cold (-78°C) solution of Boc-amino acid ( )-3
(2.69 g, 12.5 mmol, 1 equiv.) and Et3N (2.09 mL,
15.0 mmol, 1.2 equiv.) in dry THF (125 mL) was added
dropwise pivaloyl chloride (1.61 mL, 13.1 mmol,
1.05 equiv.). The mixture was stirred for 1 h at 0°C to form
the mixed anhydride, then cooled to -78°C. In a separate
flask, a cold (ca. -40°C) solution of (4S,5R)-4-methyl-5-
phenyloxazolidin-2-one 12 (2.21 g, 12.5 mmol, 1 equiv.) in
THF (60 mL) was treated with n-BuLi (1.6 M solution in
hexanes, 7.81 mL, 12.5 mmol, 1 equiv.) and stirred for
5 min. The resulting solution was added by rapid cannula-
tion to the cooled (-78°C) solution of the mixed anhydride.
Residual metalated oxazolidinone was taken up by rinsing
cis-(1-t-Butyloxycarbonyl)2,4-
diazabicyclo[4.2.0]octane-3,5-dione [( )-5]
To a suspension of uracil (3.36 g, 30 mmol, 1 equiv.) in
acetonitrile (150 mL) was added Boc2O (6.55 g, 30 mmol,
1 equiv.) and DMAP (37 mg, 0.3 mmol, 0.01 equiv.). The
mixture was stirred overnight at room temperature, then the
solvent was removed under reduced pressure to give
the crude Boc-uracil 7 (6.49 g, s = 100%) as a white solid
123

592
V. Declerck, D. J. Aitken
with dry THF (2 9 5 mL), and added to the cooled reaction
mixture; this latter was stirred for 1 h at -78°C. After
warming to 0°C, the mixture was treated with saturated
NaHCO3 (30 mL), and the THF was removed under reduce
pressure. The aqueous phase was extracted with CH2Cl2
(4 9 40 mL). The combined organic phases were washed
successively with saturated NaHCO3 (25 mL) and brine
(25 mL), dried over MgSO4, filtered and evaporated under
reduced pressure. Flash chromatography of the residue
(EtOAc/petroleum ether = 15/85) gave the diastereoiso-
mers 13 (2.15 g, 46%) and 14 (2.04 g, 44%) as white solids.
stirred for 5 h at 0°C then 1 M Na2SO3 (50 mL) and sat-
urated NaHCO3 (50 mL) were added successively. THF
was removed under reduced pressure and the aqueous
residue was washed with CH2Cl2 (4 9 30 mL) to remove
the chiral auxiliary. The aqueous phase was acidified to pH
1 with concentrated HCl and extracted with CH2Cl2
(4 9 40 mL). The combined organic extracts were dried
over MgSO4, filtered and evaporated under reduced pres-
sure to give the Boc-amino acid (1S,2R)-3 (1.02 g, 95%) as
a white solid. Mp 116–118°C; [a]2D6 ?64 (c 0.93, CHCl3);
[a]2D3 ?127 (c 0.92, EtOH). The spectral data were identical
to those reported previously (Fernandes et al. 2007).
(4S,5R)-N-[(1S,2R)-2-(t-Butyloxycarbonylamino)
cyclobutanecarbonyl]-4-methyl-5-phenyl-3-oxazolidin-
2-one (13)
(1R,2S)-(2-t-Butyloxycarbonylamino)
cyclobutanecarboxylic acid [(1R,2S)-3]
Mp 126°C; Rf 0.57 (EtOAc/petroleum ether = 85/15);
[a]2D4 ?59 (c 0.50, CHCl3); IR (KBr) m 3,435, 2,983, 1,784,
To an ice-cold solution of compound 14 (1.81 g, 4.8 mmol,
1 equiv.) in a 1:4 mixture of water and THF (120 mL) was
added a 35% w/w solution of H2O2 (2.5 mL, 29.0 mmol,
6 equiv.). The resulting mixture was stirred for 5 min at
0°C, then a solution of LiOH (231 mg, 9.7 mmol, 2 equiv.)
in water (30 mL) was added. The mixture was stirred for
5 h at 0°C then 1 M Na2SO3 (50 mL) and saturated
NaHCO3 (50 mL) were added successively. THF was
removed under reduced pressure and the aqueous residue
was washed with CH2Cl2 (4 9 30 mL) to remove the chiral
auxiliary. The aqueous phase was acidified to pH 1 with
concentrated HCl and extracted with CH2Cl2 (4 9 40 mL).
The combined organic extracts were dried over MgSO4,
filtered and evaporated under reduced pressure to give the
Boc-amino acid (1R,2S)-3 (993 mg, 96%) as a white solid.
Mp 116–118°C; [a]D26 -64 (c 0.88, CHCl3); [a]2D4 -127
(c 0.89, EtOH). The spectral data were identical to those
reported previously (Fernandes et al. 2007).
1,710, 1,683, 1,504, 1,385, 1,368, and 1,346 cm-1 1H
;
NMR (360 MHz, CDCl3) d 0.92 (d, 3H, J3 = 6.8 Hz), 1.45
(s, 9H), 2.01–2.11 (m, 2H), 2.17 (m, 1H), 2.41 (m, 1H),
4.55 (bs, 2H), 4.72 (quint, 1H, J3 = 6.5 Hz), 5.45 (bs, 1H),
5.64 (d, 1H, J3 = 7.2 Hz), 7.29 (d, 2H, J3 = 7.0 Hz),
7.35–7.45 (m, 3H); 13C NMR (90 MHz, CDCl3) d 14.6,
19.3, 28.4, 28.7, 44.9, 47.7, 55.0, 79.1, 79.3, 125.7, 128.8,
133.5, 152.6, 155.0, 173.1; HRMS (ESI?) Calcd for
C20H26N2NaO5 [M ? Na]?: 397.1734, found 397.1721.
(4S,5R)-N-[(1R,2S)-2-(t-Butyloxycarbonylamino)
cyclobutanecarbonyl]-4-methyl-5-phenyl-3-oxazolidin-
2-one (14)
Mp 102°C; Rf 0.40 (EtOAc/petroleum ether = 85/15); [a]D24
-71 (c 0.50, CHCl3); IR (KBr) m 3,373, 2,974, 1,783, 1,718,
1,677, 1,512, 1,392, 1,365, and 1,346 cm-1 1H NMR
;
(360 MHz, CDCl3) d 0.92 (d, 3H, J3 = 6.6 Hz), 1.41 (s, 9H),
2.00–2.19 (m, 3H), 2.41 (m, 1H), 4.57 (bs, 1H), 4.64 (t, 1H,
J3 = 8.0 Hz), 4.80 (quint, 1H, J3 = 6.8 Hz), 5.37 (bs, 1H),
5.65 (d, 1H, J3 = 7.4 Hz), 7.29 (d, 2H, J3 = 6.9 Hz),
7.34–7.45 (m, 3H); 13C NMR (90 MHz, CDCl3) d 14.8, 18.9,
28.4, 28.3, 45.0, 47.3, 54.7, 78.9, 79.4, 125.7, 128.8, 128.9,
133.5, 152.4, 154.6, 173.5; HRMS (ESI?) Calcd for
C20H26N2NaO5 [M ? Na]?: 397.1734, found 397.1723.
(1S,2R)-(2-t-Butyloxycarbonylamino)
cyclobutanecarboxamide [(1S,2R)-4]
To a solution of compound 13 (2.48 g, 6.6 mmol) in THF
(130 mL) was added aqueous ammonia (25% w/w solu-
tion, 66 mL). The resulting mixture was stirred for 48 h at
room temperature. Solvents were removed under reduced
pressure. Flash chromatography of the residue (EtOAc/
c-C6H12 = 50/50) gave the Boc-amino amide (1S,2R)-4
(1.28 g, 90%) as a white solid. Mp 170°C (dec.); [a]D27
?133 (c 0.51, CHCl3). The spectral data were identical to
those reported previously (Fernandes et al. 2009).
(1S,2R)-(2-t-Butyloxycarbonylamino)
cyclobutanecarboxylic acid [(1S,2R)-3]
To an ice-cold solution of compound 13 (1.87 g, 5.0 mmol,
1 equiv.) in a 1:4 mixture of water and THF (125 mL) was
added a 35% w/w solution of H2O2 (2.6 mL, 30.0 mmol,
6 equiv.). The resulting mixture was stirred for 5 min at
0°C, then a solution of LiOH (240 mg, 10.0 mmol,
2 equiv.) in water (30 mL) was added. The mixture was
(1R,2S)-(2-t-Butyloxycarbonylamino)
cyclobutanecarboxamide [(1R,2S)-4]
To a solution of compound 14 (1.65 g, 4.4 mmol) in THF
(88 mL) was added aqueous ammonia (25% w/w solution,
123

A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids
593
44 mL). The resulting mixture was stirred for 48 h at room
temperature. Solvents were removed under reduced pres-
sure. Flash chromatography of the residue (EtOAc/
c-C6H12 = 50/50) gave the Boc-amino amide (1R,2S)-4
(865 mg, 91%) as a white solid. Mp 170°C (dec.); [a]D27
-133 (c 0.53, CHCl3). The spectral data were identical to
those reported previously (Fernandes et al. 2009).
NaOH (55 mL). The resulting mixture was refluxed for
16 h. Methanol was removed under reduced pressure. The
aqueous residue was diluted with water (55 mL) and
washed with CH2Cl2 (3 9 30 mL). The aqueous phase was
then cooled to 0°C and acidified slowly with concentrated
HCl to pH 1. The aqueous phase was extracted with EtOAc
(4 9 60 mL). The organic phase was dried over MgSO4,
filtered and evaporated under reduced pressure. The crude
Boc-amino acid was dissolved in EtOH and treated with
decolorizing charcoal to give the Boc-amino acid (1S,2S)-
15 (0.74 g, 86%) as a white solid. Mp 104–105°C (dec.);
[a]D24 -11 (c 0.51, CHCl3); [a]2D5 ?23 (c 0.59, EtOH). The
spectral data were identical to those reported previously
(Fernandes et al. 2009).
Recovery of (4S,5R)-4-methyl-5-phenyl-1,3-
oxazolidin-2-one (12)
Washings obtained during the work-up of the hydrolysis of
compound 13 or 14 were dried over MgSO4, filtered and
evaporated under reduced pressure to give oxazolidin-2-
one 12 ([95%) as a white solid. The oxazolidin-2-one was
`
Acknowledgments We thank Magistere-1 (ENS Cachan) under-
purified by
a quick flash chromatography (EtOAc/
graduate student Ms. Charlotte Mocquard for help with some pre-
liminary experiments.
CH2Cl2 = 30/70) before being reused in the coupling
reaction with Boc-amino acid ( )-3.
Conflict of interest None.
Appropriate fractions obtained during the chromato-
graphic purification of Boc-amino amide (1S,2R)-4 or
(1R,2S)-4, prepared by ammonolysis of compound 13 or
14, respectively, were collected and evaporated under
reduce pressure to give the oxazolidin-2-one 12 ([90%) as
a white solid.
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