First synthesis of enantiomerically pure (1S,2S)- and (1R,2R)-1,2-diaminocyclobutanecarboxylic acid-ornithine derivative-, from racemic 2-aminocyclobutanone

Article abstract of DOI:10.1016/j.tetasy.2008.07.033

An easy and efficient one-pot reaction from readily available 2-(N-Cbz) aminocyclobutanone selectively gave, by means of an asymmetric Strecker synthesis in the presence of a chiral benzylic amine, the thermodynamic 1,2-diamino nitriles. Basic hydrolysis, cleavage of the benzylic group and acidic hydrolysis of the resulting trans-1,2-diaminocyclobutanecarbonitrile gave, in a four-step sequence from the ketone, (1S,2S)- or (1R,2R)-1,2-diaminocyclobutanecarboxylic acid, ornithine derivatives. The absolute configuration has been established by X-ray analysis of the corresponding trans-diamino amide.

Full text of DOI:10.1016/j.tetasy.2008.07.033

Tetrahedron: Asymmetry 19 (2008) 2063–2067
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First synthesis of enantiomerically pure (1S,2S)- and (1R,2R)-
1,2-diaminocyclobutanecarboxylic acid–ornithine derivative–, from
racemic 2-aminocyclobutanone q
b
Damien Hazelard a, Antoine Fadel a, , Régis Guillot
*
a Laboratoire de Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d’Orsay, Bât. 420, Université Paris-Sud, 91405 Orsay, France
b Institut de Chimie Moléculaire et des Matériaux d’Orsay, Bât. 420, Université Paris-Sud, 91405 Orsay, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy and efficient one-pot reaction from readily available 2-(N-Cbz) aminocyclobutanone selectively
gave, by means of an asymmetric Strecker synthesis in the presence of a chiral benzylic amine, the ther-
modynamic 1,2-diamino nitriles. Basic hydrolysis, cleavage of the benzylic group and acidic hydrolysis of
the resulting trans-1,2-diaminocyclobutanecarbonitrile gave, in a four-step sequence from the ketone,
(1S,2S)- or (1R,2R)-1,2-diaminocyclobutanecarboxylic acid, ornithine derivatives. The absolute configura-
tion has been established by X-ray analysis of the corresponding trans-diamino amide.
Ó 2008 Published by Elsevier Ltd.
Received 10 July 2008
Accepted 30 July 2008
Available online 6 September 2008
1. Introduction
oxylic acids has not received the same amount of attention.11
A
few methods for 2-substituted a-amino acids have been described
Conformationally constrained
a
- and b-amino acids have been
in recent years by means of asymmetric Strecker reactions;12 by
selective Michael-aldol reaction and by [2+2]-cycloaddition13 or
by alkylation of a glycine derivative.14
Conversely, for the synthesis of cyclobutane b-amino acids,
three strategies have been reported: by Curtius rearrangement,15
thermal cycloaddition16 or photochemical [2+2]-cycloaddition.17
We reasoned that compounds bearing both the structural fea-
incorporated into peptide surrogates to be used in structural and
biomechanistic investigations as well as to obtain peptides with
new or improved properties.1,2 This incorporation increases the
stability of these peptides towards chemical and enzymatic degra-
dation. Hence,
for the design and synthesis of new peptide hormones and enzyme
inhibitors.3 Furthermore, alicyclic
-amino acids such as the ste-
a,a-disubstituted a-amino acids are building blocks
a
tures of carbocyclic a-amino acids and of b-amino acids could be
reoisomeric 1-aminocyclopentane-1,3-dicarboxylic acids (ACPD)
have been described as ligands at both the ionotropic and meta-
botropic glutamate receptors.4
of considerable interest in various fields of medicinal chemistry.18
The structural complexity of these molecules, having two vicinal
chiral centres, also represented a challenge for their enantiopure
synthesis. To the best of our knowledge, only a cyclohexane deriv-
On the other hand, b-amino acids, such as the neurotoxin b-N-
methylamino-
L
-alanine (BMAA), are reported to function as modu-
ative of an a,b-diamino acid has recently been prepared by Frahm
lators of the glycine binding site of the NMDA receptor complex.5
In addition, b-peptides, the short oligomers of b-amino acids, can
adopt all types of secondary peptide structures (helix, sheets and
et al.19 Cyclopentane analogues have been synthesized as 1-amino-
2-nitro derivatives,20 whereas the cyclobutane
ornithine analogue21 is still unknown.
a,b-diamino acid–
turns) and are considered as alternatives to
mers since the b-peptide backbone offers greater opportunities
for conformational rigidity than the
-peptides do.6 Consequently,
- and b-ami-
a
-amino acid oligo-
We have previously reported on the asymmetric synthesis of
cyclic analogues of naturally occurring -amino acids from cyclo-
propanone acetals,22 the
-amino-2-alkylcyclobutanecarboxylic
acids 1a12b and serine derivative 1b12c from
-substituted cyclo-
a
a
a
great interest for the synthesis and study of alicyclic
a
a
no acids has rapidly increased,2 in particular for cyclohexane,7
cyclopentane8 and cyclopropane9 derivatives. However, amino
acids from cyclobutane series have been little investigated.10 In
butanones 2, by means of an asymmetric Strecker reaction
(Scheme 1).23
addition, the synthesis of substituted
a-aminocyclobutanecarb-
COOH
NH2
O
R
q
R
Part of this study was previously reported at the Organic Chemistry Symposia at
Palaiseau (SFC, September 2004) and at Chamonix Mont-Blanc (French-Japanese
Symposium, September 2005), France.
2
1a
1b
R = alkyl
R = OH
* Corresponding author. Tel.: +33 1 6915 3239; fax: +33 1 6915 6278.
E-mail address: antfadel@icmo.u-psud.fr (A. Fadel).
Scheme 1.
0957-4166/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2008.07.033

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D. Hazelard et al. / Tetrahedron: Asymmetry 19 (2008) 2063–2067
As part of our ongoing programme in this area, we herein report
bonate at rt for 6 h,27 to afford amides (1S,2S,1S)-9C and
(1R,2R,10S)-9D in good yields (85% and 90%, respectively). However,
treatment of the nitrile 5C with basic hydrogen peroxide (aq H2O2,
KOH)28 in EtOH only gave amide 9C in 20% yield. Furthermore,
acidic hydrolysis with concentrated H2SO4 in CH2Cl2 at 0 °C or rt
led to a degradation of starting nitrile 5C (Scheme 4).
on the preparation of enantiopure 1,2-diaminocyclobutanecarb-
oxylic acid 3 (ornithine analogue, c4Orn)—in four steps—starting
from the racemic 2-aminocyclobutanone 4 and a chiral benzylic
amine as a chiral auxiliary, proceeding via amino nitrile 5 by an
asymmetric Strecker reaction (Scheme 2).
CN
HN
CONH2
HN
H2O2, excess
NH2
HN
CN
O
cat. K2CO3 ,rt
85%
Ph
Ph
Ph
COOH
NHCbz
5C
CbzHN
9C
NH-Cbz
NH2
NH-Cbz
5
3
rac-4
HN
HN
CN
Scheme 2.
H2O2, excess
Ph
Ph
CONH2
cat. K2CO3, rt
90%
2. Results and discussion
NHCbz
9D
NHCbz
5D
The racemic aminocyclobutanone rac-4 was prepared from
bis(trimethylsiloxy)cyclobutene according to Vederas (H2N–Cbz,
Scheme 4.
HCl gas) in 76% yield.24 For the synthesis of the
a-amino nitriles
5A–D, the racemic cyclobutanone rac-4 was subjected to a one-
pot procedure previously developed in our group (Scheme
3).12b,12c,22a The standard one-pot reaction of cyclobutanone rac-4
Hydrogenolysis of pure
a-aminocarboxamide 9C was per-
formed, as we have recently reported,12c with a catalytic amount
of 20% Pd(OH)2 on activated carbon (w/w 30%) in EtOH under
hydrogen (1 atm, 10 h) in the presence of 3 equiv of di-tert-butyl-
carbonate [(Boc)2O],29 to simultaneously furnish, by a double
cleavage and by in situ protection of free amines, the desired car-
bamate 10C in excellent yield. Likewise, amide 9D provided under
the same conditions carbamate 10D in 91% yield (Scheme 5).
The amino amides trans-10C and trans-10D were finally hydro-
lysed with 6 M HCl solution at reflux to furnish quantitatively, the
1,2-diaminocyclobutanecarboxylic acid hydrochlorides (1S,2S)-
3ꢀ2HCl and (1R,2R)-ent-3ꢀ2HCl, respectively (Scheme 5).
with (S)-a-methylbenzylamine 6 (2 equiv) was carried out in
DMSO in the presence of 2 equiv of AcOH, and 1.5 equiv of NaCN
at 50 °C for 3 days. We anticipated that under thermodynamic con-
ditions as we have recently reported,12c the cyclobutanone conden-
sation with the chiral auxiliary (S)-1-phenylethylamine 6 would
give the corresponding iminiums 7 and 8, which by the in situ
addition of sodium cyanide to the C@N bond would predominantly
afford two diastereomers of the four possible
a
-amino nitrile iso-
mers 5A–D (Scheme 3).
O
6
R*
H2N
Ph
R*
N
CONH2
NHBoc
COOH
CONH2
N
+
2 equiv AcOH
50 °C, 36 h
90%
H
H
H2, Pd(OH)2/C
(Boc)2O, EtOH
90%
6 M HCl
NHCbz
N
H
NH2•HCl
NHCbz
reflux
quant.
CbzHN
NaCN
rac-4
7
8
Ph
NHBoc
(—)-10C
NH2 •HCl
(1S,2S)-(—)-3 •2HCl
NHCbz
(—)-9C
COOH
CN
CN
HN
NHBoc
HN
CN
HN
H2, Pd(OH)2/C
(Boc)2O, EtOH
91%
6 M HCl
Ph
CONH2
NHCbz
(—)-9D
Ph
Ph
NH2•HCl
NH2•HCl
(+)-ent-3•2HCl
+
+
+
N
H
reflux
quant.
HN
NHCbz
CONH2
NHBoc
(+)-10D
CN
NHCbz
Ph
Ph
NHCbz
5D (45%)
NHCbz
5A
5B
5C (55%)
Scheme 3. Synthesis of a-amino nitriles 5A–D.
Scheme 5.
Effectively, from cyclobutanone rac-4 under thermodynamic
control, only two major isomers 5C and 5D were isolated in a
55:45 ratio with an excellent yield. The more polar isomer on
TLC is the amino nitrile 5D. However, we are unable to isolate
the kinetic isomers 5A and 5B. Taking into account the 90% yield
and the 55:45 ratio, we can tentatively suppose that the equilib-
rium between the two iminiums 7 and 8 is not favoured,12c even
though this type of iminium equilibrium has previously been re-
ported in similar cyclopentane or cyclohexane systems.25
2.2. Absolute configuration: X-ray crystallography
To determine the absolute configuration of all these molecules,
we found that the amino amide 9D gave suitable crystals. The X-
ray crystallographic analysis showed,30 as depicted in Figure 1, a
(1R,2R,10S)-absolute configuration of 9D. Thus, the corresponding
amino nitrile 5D and the N-Boc amide 10D should be (1R,2R,10S)
and (1R,2R), respectively. Consequently, nucleophilic attack of the
cyanide anion, under thermodynamic conditions, occurred syn to
the N-benzyloxycarbonyl group with an unlike approach to imini-
um 7 and via a thermodynamic–kinetic equilibrium (Scheme 6).
This is in accordance with our very recently reported results, on
the thermodynamic attack of cyanide on an iminium ion of a
benzyloxycyclobutanone analogue.12c The same equilibrium could
occur between amino nitriles 5B and 5C via iminium 8 (Schemes 3
and 6).
2.1. Basic hydrolysis
Subsequently, after straightforward silica gel column separa-
tion, the
a -amino nitriles 5C and 5D were subjected to hydrolysis,
separately26 in DMSO in the presence of an excess of hydrogen per-
oxide (35 wt % in H2O) and a catalytic amount of potassium car-

D. Hazelard et al. / Tetrahedron: Asymmetry 19 (2008) 2063–2067
2065
4.2. General procedure A
To a solution of 2-(N-benzyloxycarbonyl)amino-cyclobutanone
4
24 (2.45 g, 10.0 mmol), in DMSO (18 mL), were added successively
AcOH (1.200 mL, 20.0 mmol), (S)-a-methylbenzylamine 6 (2.60
mL, 20.0 mmol) and NaCN (980 mg, 20.0 mmol). The mixture was
stirred at 50–55 °C for 36 h. It was then diluted with EtOAc
(100 mL), H2O (10 mL) and basified to pH 9 with a saturated soln
of NaHCO3. The mixture was extracted with EtOAc (2 ꢂ 100 mL).
The combined organic layers were washed with water (5 mL),
dried over MgSO4, filtered and then concentrated under vacuum
to give 4.40 g of the crudes amino nitriles as a mixture of two dia-
stereoisomers. Purification by flash chromatography twice on silica
gel (eluent: ether/CH2Cl2/petrol ether: 1:4:4 to 2:4:4) afforded
1.480 g (42.4%) of the less polar amino nitrile 5C, 1.215 g (34.7%)
of the polar amino nitrile 5D and 450 mg (13%) as a mixture.
4.2.1. (1S,2S,10S)-2-(N-Benzyloxycarbonyl)amino-1-(10-phenyl-
ethyl)aminocyclobutanecarbonitrile, 5C
Figure 1. ORTEP plot of X-ray crystal structure of (1R,2R,10S)-9D.
[
a
]
D = ꢁ181 (c 1.00, CHCl3); Rf = 0.42 (EtOAc/petrol ether: 3:7);
IR (neat) m: 3314, 3031, 2217 (C„N), 1712 (NCOO), 1520, 1261;
1H NMR (CDCl3, 250 MHz): d 1.20–1.55 (m, 2H, 2H–C3), 1.41 (d,
J = 6.4 Hz, 3H), 1.77 (dddd, J = 9.4, 10.5, 11.2, 11.2 Hz, 1H–C4),
2.12 (dddd, J = 1.8, 8.5, 8.5, 10.5 Hz, 1H–C4), 2.52 (br s, NH), 4.05
CN
re face
R*
N
R
thermodyn.
kinetic
H
0
(q, J = 6.4 Hz, 1H–C1 ), 4.18 (ddd, J = 8.5, 8.5, 9.4 Hz, 1H–C2), 5.15
CbzHN
CN
(like AB system, J = 12.2, 22.2 Hz, 2Hbenzyl), 5.32 (br d, J = 8.5 Hz,
CN
si face
HN
HNCO), 7.20–7.51 (m, 10H); 13C NMR (CDCl3, 62.9 MHz): d 23.2
7
Ph
0
(t, C3), 24.6 (q, CH3), 28.9 (t, C4), 53.8 (t, C1 ), 56.0 (d, C2), 64.1 (s,
CN
NHCbz
trans-5D
HN
NHCbz
-5A
C1), 67.3 (t, CH2-Ph), 119.9 (C„N), [12 arom. C: 127.6 (4C), 128.2
(1C), 128.3 (4C), 128.5 (1C), 136.0 (1C), 144.1 (1C)], 156.0 (NCOO);
HRMS (EI) m/z: calcd mass for C21H23N3O2: 349.1790. Found:
349.1789.
Ph
cis
Scheme 6. Kinetic–thermodynamic equilibrium.
4.2.2. (1R,2R,10S)-2-(N-Benzyloxycarbonyl)amino-1-(10-phenyl-
ethyl)aminocyclobutanecarbonitrile, 5D
The amides 10D and 10C, presenting the same spectral data but
giving the opposite specific rotation, are enantiomers. Conse-
quently, the absolute configuration of 10C, should be (1S,2S). Fur-
thermore, it should be (1S,2S,10S) for 9C and (1S,2S,10S) for 5C.
[
a
]
D = ꢁ3.2 and [ 365 = ꢁ23.6 (c 1.00, CHCl3); Rf = 0.34 (EtOAc/
a
]
petrol ether: 3:7); IR (neat)
m: 3315, 3063, 2220 (C„N), 1712
(NCO), 1520, 1261; 1H NMR (CDCl3, 360 MHz): d 1.35 (d, J =
6.5 Hz, 3H, CH3), 1.84–2.10 (m, 2H, Hcycle), 2.10–2.53 (m, 3H, 2Hcycle
3. Conclusion
0
and NH), 4.08 (q, J = 6.5 Hz, 1H–C1 ), 4.19 (ddd, J = 9.0, J = 8.6,
J = 7.5 Hz, 1H, H–C2), 5.06 (AB system, JAB = 12.3 Hz, 2H, CH2O),
We have developed an easy and efficient four-step synthesis of
new, enantiopure 1,2-diamino-cyclobutanecarboxylic acids (ꢁ)-3
and (+)-ent-3. Thus starting from readily available racemic 2-N-
Cbz-cyclobutanone, we have demonstrated that the iminium ion
formed from this ketone undergoes an asymmetric Strecker reac-
tion to selectively give thermodynamic aminonitriles 5C and 5D
in excellent yields. Subsequent basic hydrolysis of each nitrile fur-
nished the corresponding amides 9C–D, in good yields. The
hydrogenolysis of the benzyl group of 9C–D required treatment
in the presence of Boc2O to give the N-Boc derivatives 10C–D. Fi-
nally, acidic hydrolysis provided the first optically active 1,2-di-
amino-cyclobutanecarboxylic acids 3 (c4Ornithine derivatives) in
good overall yields.
5.23 (d, J = 7.5 Hz, 1H, Hcarbamate), 7.15–7.45 (m, 10H); 13C NMR
0
(CDCl3, 62.9 MHz): d 23.6 (C3), 23.7 (CH3), 29.8 (C4), 54.3 (C1 ),
55.8 (C2), 63.1 (C1), 67.2 (O–CH2), 119.6 (C„N), [12 arom. C:
126.8 (2C), 127.6 (2C), 128.2 (1C), 128.3 (1C), 128.6 (2C), 128.7
(2C), 136.0 (s), 144.7 (s)], 155.6 (OCON); HRMS (EI) m/z: calcd mass
for C21H23N3O2: 349.1790. Found: 349.1786.
4.3. Amide formation from nitrile: general procedure B
To a solution of amino nitrile 5 (620 mg, 1.776 mmol) in DMSO
(7 mL), were added K2CO3 (200 mg, 1.45 mmol) and an excess
amount of H2O2 (2.8 mL, 31.7 mmol, 35 wt % in water).27 The mix-
ture was stirred at 0 °C for 1 h and at rt for 6 h. Complete elimina-
tion of excess of peroxide was performed by the addition of an
aqueous saturated soln of Na2S2O3 (negative KI test). The resulting
mixture was extracted with EtOAc (3 ꢂ 100 mL). The organic layers
were dried over MgSO4, filtered and then concentrated under vac-
uum, to give after FC (silica gel, 15 g) the desired amide 9.
4. Experimental
4.1. General
The general experimental procedures and the analytical instru-
ments employed have been described in detail in a previous
paper.22b
4.3.1. (1S,2S,10S)-2-(N-Benzyloxycarbonyl)amino-1-(10-phenyl-
ethyl)amino-cyclobutanecarboxamide, 9C
Prepared according to procedure B: From nitrile 5C (700 mg,
2.0 mmol), K2CO3 (220 mg, 1.60 mmol), H2O2 (3.00 mL, 34.0 mmol,
35 wt % in H2O), in DMSO (10 mL). After stirring for 6 h and FC
4.1.1. rac-2-(N-Benzyloxycarbonyl)aminocyclobutanone (4)
rac-2-(N-Benzyloxycarbonyl)aminocyclobutanone 4 was pre-
pared according to Vederas et al.24

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D. Hazelard et al. / Tetrahedron: Asymmetry 19 (2008) 2063–2067
(eluent: EtOAc/CH2Cl2: 20:80?25:75), we isolated 625 mg (85%) of
amide 9C as a white solid.
P212121 (No. 19), Z = 4, with a = 8.712(5), b = 12.110(5), c =
19.141(5) Å, = b =
= 90°, V = 2019.42(15) Å3, d = 1.209 g cmꢁ3
F(000) = 784, k = 0.71069 Å (Mo-K ),
= 0.082 mmꢁ1; 4622 reflec-
tions measured (ꢁ11 6 h 6 11, ꢁ15 6 k 6 15, ꢁ24 6 l 6 24), on a
Bruker X8 diffractometer. The structure was solved and refined
with SHELXL-97.31 Hydrogen atom riding, refinement converged to
a
c
,
[
a
]
D = ꢁ53.0 (c 1.00, CHCl3); mp 36.6 °C; Rf = 0.31 (EtOAc/
a l
CH2Cl2: 10:90); IR (neat)
m
: 3445, 3320, 3031, 1709 (NCOO),
1673 (CON), 1544, 1264; 1H NMR (CDCl3, 360 MHz, 320 K): d
1.35 (d, J = 6.5 Hz, 3H, CH3), 1.40–1.60 (m, 1H, Hcycle), 1.87 (br s,
NH), 1.95–2.05 (m, 1H, Hcycle), 2.05–2.26 (m, 2H, Hcycle), 3.84 (q,
R(gt) = 0.0553 for the 3131 reflections having I > 2r(I), and
0
J = 6.5 Hz, 1H–C1 ), 4.22 (m, 1H, H–C2), 5.13 (br s, 2H, CH2Ph),
wR(gt) = 0.1306, Goodness of Fit S = 1.017, residual electron density:
5.24 (br s, 1H, NHamide), 6.07 (br s, 1H, Hcarbamate), 6.87 (br s,
1Hamide), 7.10–7.38 (m, 10H); 1H NMR (CDCl3, 300 MHz) (two rota-
mers a/b, 73:27): d 1.15:1.33 (d, J = 6.6 Hz, 3H, CH3, a/b), 1.36–1.57
ꢁ0.149 and 0.173 e Åꢁ3
.
4.4. Hydrogenolysis procedure
(m, 1H, Hcycle, a/b), 1.90 (br s, NH, a/b), 1.80–2.32 (m, 3H, Hcycle
,
0
a/b), 3.76:3.82 (q, J = 6.6 Hz, 1H–C1 , b/a), 3.96:4.20 (ddd,
J = 9.7 Hz, J = 9.6 Hz, J = 9.5 Hz, 1 H, H–C2, b/a), [4.98 (d, J =
11.7 Hz, 1H, Hbenzyl, b), 5.16 (d, J = 11.7 Hz, 1H, Hbenzyl, b)], 5.13
(AB system, JAB = 12.3 Hz, br s, 2H, CH2Ph, a), 5.37:5.46 (br s, 1H,
4.4.1. (1S,2S)-1,2-Di-[(N-tert-butyloxycarbonyl)amino]-cyclo-
butanecarboxamide, (ꢁ)-10C
To a solution of amino amide 9C (185 mg, 0.50 mmol) in 7 mL of
EtOH, were added Boc2O (330 mg, 1.50 mmol) and 20% of Pd(OH)2/
C (Pearlman’s catalyst, 100 mg). The mixture was stirred under
1 atm of H2 at room temperature for 18 h (reaction monitored by
TLC). The mixture was degassed under a stream of argon, filtered
NHamide
, b/a), 6.31:6.51 (d, J = 9.6 Hz, 1H, Hcarbamate, a/b),
6.88:6.95 (br s, 1Hamide, b/a), 7.03–7.50 (m, 10H, a/b); 13C NMR
(CDCl3, 62.9 MHz, 320 K): d 23.7 (t, C3), 24.7 (q, CH3), 26.4 (t, C4),
54.7 (d, C1 ), 55.6 (d, C2), 66.7 (t, OCH2), 69.9 (s, C1), [12 arom. C:
through a
2-cm-pad of CeliteÒ, and washed with EtOH
0
126.4 (2C), 127.2 (1C), 128.1 (2C), 128.2 (1C), 128.5 (4C), 136.4
(s), 145.7 (s)], 155.6 (s, COO), 177.3 (s, CON); 13C NMR (CDCl3,
90.56 MHz) (two rotamers a/b, 73:27): d 23.4:22.6 (t, C3, a/b),
(2 ꢂ 10 mL). The combined filtrate and washings were concen-
trated and purified by FC (eluent: MeOH/CH2Cl2: 2:98?4/96).
We isolated 148 mg (90%) of dicarbamate amide 10C as a white
yellow solid.
0
24.6:23.7 (q, CH3, a/b), 26.0:23.4 (t, C4, a/b), 54.9 (C1 ), 56.1 (C2),
66.9:67.0 (OCH2, a/b), 70.3:70.4 (C1, a/b), [12 arom. C: 126.6 (2C),
127.3 (2C), 128.3 (1C), 128.4 (1C), 128.6 (4C), 136.5 (s), 146.1
(s)], 155.9:156.6 (COO, a/b), 177.4 (CON); HRMS (EI) m/z: calcd
mass for C21H25N3O3: 367.1890. Found: 367.1888.
[
a
]
D = ꢁ15 (c 0.25, CHCl3); mp 176 °C; Rf = 0.55 (MeOH/CH2Cl2:
10:90); IR (neat) : 3437, 3332, 3206, 1710 (NCOO), 1669 (CON),
m
1366, 1169; 1H NMR (CDCl3, 250 MHz), (two rotamers a/b): d
1.38:1.41 (s, 18H, a/b), 1.60–1.94 (m, 1Hcycle, a/b), 1.94–2.35 (m,
2Hcycle, a/b), 2.77 (m, like t, 1Hcycle, a/b), 4.09/4.25 (m, 1H–C2, a/
b), 5.85 (br s, 1H–N, a/b), 5.92–6.15 (m, 1H–N, a/b and NH, a),
6.24–6.51 (m, NH, a/b), 7.17 (br s, NH, b); 13C NMR (CDCl3,
62.9 MHz), (two rotamers a/b): d 22.2:23.1 (C3, a/b), 26.6:27.3
(C4, b/a), 28.2:28.3 (C–(CH3)3, b/a), 53.5:53.7 (C2, a/b), 65.1:65.8
(C1, b/a), 79.95:80.3 (C–(CH3)3, a/b), 154.3 (NCOO, a/b), 156.1
(NCOO, a/b), 174.6 (CON, a/b); HRMS (EI) m/z: calcd mass for
4.3.2. (1R,2R,10S)-2-(N-Benzyloxycarbonyl)amino-1-(10-phenyl-
ethyl)aminocyclobutanecarboxamide, 9D
Prepared according to procedure B: From nitrile 5D (620 mg,
1.776 mmol), K2CO3 (200 mg, 1.45 mmol), H2O2 (2.80 mL,
31.7 mmol, 35 wt % in H2O), in DMSO (7 mL). After stirring for
3 h and purification by FC (eluent: CH2Cl2 then EtOAc/CH2Cl2:
20:80), we isolated 585 mg (90%) of amide 9D as colourless crystals
used for X-ray diffraction.
C
15H21N3O5: 352.1848. Found: 352.1848.
[
a
]
D = ꢁ15.4, [
a
]
365 = ꢁ67.6 (c 1, CHCl3); mp 150.2 °C; Rf = 0.31
4.4.2. (1R,2R)-1,2-Di-[(N-tert-butyloxycarbonyl)amino]-cyclo-
butanecarboxamide, 10D
(EtOAc/CH2Cl2: 10:90); IR (neat)
m: 3446, 3322, 3031, 1710
(COO), 1671 (CON), 1502, 1263, 733; 1H NMR (CDCl3, 250 MHz,
320 K): d 1.33 (d, J = 6.7 Hz, 3H), 1.58–1.65 (m, 1Hcycle), 1.83 (s,
NH), 1.92–2.11 (m, 1Hcycle), 2.11–2.32 (m, 2Hcycle), 4.04 (q,
Prepared according to procedure of hydrogenolysis (as for prep-
aration of 10C from amide 9C): From amino amide 9D (295 mg,
0.800 mmol), Boc2O (525 mg, 2.40 mmol), 20% of Pd(OH)2/C
(150 mg) in EtOH (6 mL). After 18 h at room temperature and puri-
fication by FC (eluent: MeOH/CH2Cl2: 2:97?3:96), we isolated
240 mg (91%) of dicarbamate amide (1R,2R)-10D as a white solid.
0
J = 6.7 Hz, H–C1 ), 4.33 (ddd, J = 9.5, 10.2, 10.0 Hz, 1H–C2), 5.09 (s,
2H, 2Hbenzyl), 5.17 (br s, Hamide), 6.11 (d, J = 10.2 Hz, H–NCbz),
7.12 (br s, Hamide), 7.16–7.42 (m, 10H); 1H NMR (CDCl3, 250 MHz)
(two rotamers a/b, 90:10): d 1.31 (d, J = 6.5 Hz, 3H, CH3), 1.62–
1.80 (m, 1Hcycle), 1.86 (s, NH), 1.94–2.44 (m, 3H, Hcycle), 4.04 (q,
[
a
]
]
D = +15, and
[a]365 = +60 (c 0.25, CHCl3); [a]D = +9.6, and
[a
365 = +58 (c 0.40, CHCl3). 1H NMR (CDCl3, 360 MHz), (two rota-
0
J = 6.5 Hz, H–C1 ), 4.33 (ddd, J = 9.7, 10.2, 10.0 Hz, 1H–C2), 5.00–
mers a/b): d 1.42:1.43 (s, 18 H, a/b), 1.60–1.92 (m, 1H–C3, a/b),
1.95–2.33 (m, 2Hcycle, a/b), 2.64–2.85 (m, 1H–C4, a/b), 4.12 (m,
1H–C2, a/b), 5.38 (br s, 1H–N, a/b), 5.48 (br s, 1H–N, a/b),
5.80:5.93 (br s, 1H–N, a/b), 6.33:6.60 (br s, NH, a/b); 13C NMR
(CDCl3, 90.56 MHz), (two rotamers a/b): d 22.2:23.1 (C3, a/b),
26.8:27.5 (C4, b/a), 28.3:28.4 (C–(CH3)3, b/a), 53.6:53.9 (C2, a/b),
65.2:66.0 (C1, b/a), 80.1:80.4 (C–(CH3)3, b/a), 154.4 (NCOO, a/b),
156.2 (NCOO, a/b), 174.9 (CON, a/b). All spectral data are identical
with those reported for its antipode (1S,2S)-10C.
5.22 (br s, AB system, 2H, 2Hbenzyl), 5.54:5.93 (br s, Hamide, a/b),
6.37:6.88 (d, J = 9.7 Hz, H–Ncbz, a/b), 7.26:7.08 (br s, 1H, Hamide
a/b), 7.20–7.50 (m, 10H); 13C NMR (CDCl3, 90.56 MHz) (two rota-
mers a/b, 90:10): d 23.8:23.3 (C3, a/b), 24.3:24.9 (CH3, a/b),
0
27.9:26.4 (C4, a/b), 53.9 (C2), 54.6:55.8 (C1 , a/b), 66.6:66.9 (OCH2,
a/b), 69.5:69.9 (C1, a/b), [12 arom. C: 126.6 (3C), 127.2 (1C),
128.1 (2C), 128.5 (1C), 128.6 (3C), 136.6 (s), 145.8 (s)], 155.6
(COO), 178.0 (CON); 13C NMR (CDCl3, 62.9 MHz, 320 K): d 23.6 (t,
0
C3), 24.1 (q, CH3), 27.7 (t, C4), 53.7 (d, C2), 54.4 (d, C1 ), 66.4 (t,
OCH2), 69.3 (s, C1), [12 arom. C: 126.4 (2C), 127.0 (1C), 127.9
(2C), 128.1 (1C), 128.4 (4C), 136.4 (s), 145.6 (s)], 155.4 (COO),
4.5. (1S,2S)-1,2-Diaminocyclobutanecarboxylic
acidꢀhydrochloride, 3ꢀ2HCl
177.8 (CON); HRMS (EI) m/z: calcd mass for
C21H25N3O3:
367.1890. Found: 367.1889; Anal. Calcd for C21H25N3O3: C, 68.64;
H, 6.86; N, 11.44. Found: C, 68.29; H, 6.51; N, 11.59.
A solution of dicarbamate amide 10C (82 mg, 0.25 mmol) in 6 M
aq HCl (4.0 mL) was heated at reflux for 9 h. After cooling to room
temperature, water (3 mL) was added and the resulting solution
was washed with ether (4 mL). The aqueous layer was concen-
trated to dryness, then the solid residue was washed successively
with EtOAc (2 mL) and ether (2 mL), to give 19 mg (quantitatively)
4.3.2.1. X-ray structure analysis of (ꢁ)-90.30
Crystal data for
(ꢁ)-(1R,2R,10S)-9D: Colourless crystal of 0.13 ꢂ 0.11 ꢂ 0.07 mm.
C21H25N3O3, M = 367.44: orthorhombic system, space group

D. Hazelard et al. / Tetrahedron: Asymmetry 19 (2008) 2063–2067
2067
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[
a]
D = ꢁ4 (c 0.60, H2O); mp 210 °C decomp.; IR (KBr)
m: 3429,
3152, 1735 (COO), 1402, 1246; 1H NMR (D2O, 250 MHz, HOD:
4.80 ppm): d 1.60–3.00 (m, 4Hcycle), 4.46 (m, 1H–C2); 13C NMR
(D2O, 62.86 MHz): d 26.9 (C3), 29.4 (C4), 49.6 (C2), 57.6 (C1),
169.2 (COO); HRMS data were not obtained.
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4.5.1. (1R,2R)-1,2-Diaminocyclobutanecarboxylic
acidꢀhydrochloride, ent-3ꢀ2HCl
Prepared from 10D as noted above: [a]D = +4.8 (c 0.50, H2O); mp
214 °C decomp. 1H NMR (D2O, 360 MHz, HOD: 4.80 ppm): d 1.60–
2.90 (m, 4Hcycle), 4.46 (m, 1H–C2); All spectral data are identical
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