Stereoselective synthesis of (1R,2R)-1-amino-2-hydroxycyclobutanecarboxylic acid-serine derivative-, from racemic or optically active 2-benzyloxycyclobutanone

Article abstract of DOI:10.1016/j.tetasy.2006.05.014

An easy and efficient one-pot reaction from readily available 2-benzyloxycyclobutanone gave, by means of an asymmetric Strecker synthesis, a kinetic or thermodynamic nitrile with good selectivity. After separation, the major trans-amino nitrile underwent basic hydrolysis and hydrogenolysis, followed by acidic hydrolysis, to give optically active (1R,2R)-1-amino-2-hydroxycyclobutanecarboxylic acid, serine derivative. The absolute configuration has been established by X-ray analysis of the corresponding cis-amino nitrile.

Full text of DOI:10.1016/j.tetasy.2006.05.014

Tetrahedron: Asymmetry 17 (2006) 1457–1464
Stereoselective synthesis of (1R,2R)-1-amino-
2-hydroxycyclobutanecarboxylic acid—serine derivative—,
from racemic or optically active 2-benzyloxycyclobutanoneI
Damien Hazelard, Antoine Fadel* and Christian Girard
`
´ ´ ´
Laboratoire de Synthese Organique et Methodologie, UMR 8182, Institut de Chimie Moleculaire et des Materiaux d’Orsay,
ˆ
´
Bat. 420, Universite Paris-Sud, 91405 Orsay, France
Received 12 May 2006; accepted 17 May 2006
Abstract—An easy and efficient one-pot reaction from readily available 2-benzyloxycyclobutanone gave, by means of an asymmetric
Strecker synthesis, a kinetic or thermodynamic nitrile with good selectivity. After separation, the major trans-amino nitrile underwent
basic hydrolysis and hydrogenolysis, followed by acidic hydrolysis, to give optically active (1R,2R)-1-amino-2-hydroxycyclobutanecarb-
oxylic acid, serine derivative. The absolute configuration has been established by X-ray analysis of the corresponding cis-amino nitrile.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Over the course of our work on the asymmetric synthesis of
cyclic analogues of naturally occurring a-amino acids,8 we
have previously published the a-amino-2-alkylcyclobutane-
carboxylic acids 16b prepared from readily available race-
mic a-substituted cyclobutanones 2,6b,9 by means of
asymmetric Strecker reactions (Scheme 1).10
The incorporation of small-ring systems, in particular cyc-
lobutane derivatives, in molecular building-blocks has re-
cently gained much interest.1 However, amino acids from
cyclobutane series have been investigated very little.2
Although, among these amino acids, very few have been de-
tected in natural sources.3 The biological activities of 1-
aminocyclobutanecarboxylic acid derivatives have been well
documented as N-methyl-D-aspartate (NMDA) receptor
agonists or antagonists.4 Despite the development of pepti-
domimetic and pseudopeptides with substituted 1-amino-
cycloalkanecarboxylic acids, which have been the focus
of much research, the synthesis of substituted 1-aminocy-
clobutanecarboxylic acids has not received the same amount
of attention.5 Moreover, a few methods for the synthesis of
2-substituted 1-aminocyclobutanecarboxylic acids have
been described in recent years.6 Serine analogues that incor-
porate the cyclobutane skeleton (c4Ser) have very recently
been synthesised by a selective Michael-aldol reaction, but
in racemic form. However, only a straightforward approach
to the optically active form has been reported, without the
preparation of desired enantiopure amino acid.7
O
R
COOH
NH2
R
2
1
R = alkyl
Scheme 1.
As part of our ongoing programme in this area, we herein
report on the preparation of enantiopure 1-amino-2-
hydroxycyclobutanecarboxylic acid 3 (serine analogue,
c4Ser)—in four steps—starting from the racemic or opti-
cally active cyclobutanones 4 and chiral benzylic amine
as a chiral auxiliary, proceeding via amino nitriles 5 by
an asymmetric Strecker reaction (Scheme 2).
2. Results and discussion
q Part of this study was previously reported at the Organic Chemistry
Symposia at Villers-sur-Mer (GECO 44, September 2003) and at
Palaiseau (SFC, September 2004), France.
The optically active 2-benzyloxycyclobutanone (S)-4 was
prepared in 82% overall yield following our previously
reported work, by protection of hydroxy acetal (S)-6
*
Corresponding author. Tel.: +33 1 6915 7252; fax: +33 1 6915 6278;
e-mail: antfadel@icmo.u-psud.fr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.014

1458
D. Hazelard et al. / Tetrahedron: Asymmetry 17 (2006) 1457–1464
interesting observations. The results of these investigations
are summarised in Table 1.
NH2
HN
O
Ph
COOH
CN
OBn
It can been seen from Table 1 that, from racemic 4 under
kinetic or thermodynamic control, only two major isomers
were isolated in each case with the same ratio (entries 1 and
2). However, from enantiopure (R)-4 under kinetic control,
a major isomer 5A was obtained, and under thermody-
namic conditions the 5D was the major isomer (Table 1, en-
tries 3 and 4). It is interesting to note that the major isomer
5A or 5D was accompanied with two minor isomers (in 6:6
or 2:10 ratio) derived from the other iminium intermediate
10.
OBn
OH
3
5
4
Scheme 2.
obtained with 99% ee by enzymatic transesterification and
subsequent deacetalisation of benzyloxy acetal (S)-7 under
mild acidic conditions (Scheme 3).11 Likewise, (R)-4 was
also obtained with 99% ee.
This minor formation was probably due to the partial rac-
emisation, already known,11 of starting benzyloxycyclobu-
tanone (R)-4 under Strecker conditions, and did not come
from the supposed equilibrium between the two iminiums 9
and 10, even though, this type of iminium equilibrium has
previously been reported in similar cyclopentane or cyclo-
hexane systems.14 Likewise, from cyclobutanone (S)-4, un-
der kinetic conditions (entry 5), the major amino nitrile 5B
was formed, accompanied by the thermodynamic product
5C in a 73:19 ratio, respectively. In addition, these amino
nitriles 5B and 5C were also accompanied with two minor
isomers 5A and 5D derived from the partial racemisation of
starting material (S)-4.
On the other hand, racemic cyclobutanone rac-4 was ob-
tained following the same sequence from readily available
rac-6, in 82% overall yield. However, ketone rac-4, pre-
pared directly from bis-(trimethylsiloxy)cyclobutene
according to Frahm (BnOH, HCl gas), was only obtained
in 38% yield.12
For the synthesis of a-amino nitriles 5A–D, the racemic
cyclobutanone rac-4 was subjected to a one-pot procedure
previously developed in our group8,13 (Scheme 4). We
anticipated that under acidic conditions, the ketone con-
densation with the chiral auxiliary (S)-1-phenylethylamine
8 would give the corresponding iminium mixtures 9 and
10, which by in situ addition of sodium cyanide to the
C@N bond would predominantly afford one diastereoiso-
mer of the four possible a-amino nitrile isomers 5A–D.
By starting from optically active ketone (R)- or (S)-4,
and changing the reaction conditions, we could make some
Thus, by changing the Strecker reaction control, each ami-
no nitrile 5A, 5B, 5C or 5D can be separately obtained as a
major product and isolated on silica gel as a pure
compound.
O
O
H2SO4/silica gel
3/100
O
NaH, THF
O
O
PhCH2Br
CH2Cl2
91%
OBn
OBn
(S )-7
OH
90%
(S)-6
(S )-4
ee > 99%
ee > 99%
ee > 99%
Scheme 3.
O
8
R*
N
H
H2N
2 eq. AcOH
R*
N
H
Ph
+
OBn
rac-4
OBn
OBn
9
10
NaCN
NaCN
CN
CN
HN
HN
HN
Ph
Ph
+
+
+
HN
CN
OBn
5B
CN
Ph
Ph
OBn
5C
OBn
OBn
5D
5A
Scheme 4. Synthesis of a-amino nitriles 5A–D.

D. Hazelard et al. / Tetrahedron: Asymmetry 17 (2006) 1457–1464
1459
Table 1. Asymmetric Strecker reaction from either rac- or enantiopure 2-benzyloxycyclobutanone 4
Entry
Ketone
Conditionsa
Amino nitriles 5
Time
Temperature (ꢁC)
Yield (%)
A
D
B
C
1
2
3
4
5
rac-4
rac-4
(+)-(R)-4
(+)-(R)-4
(ꢀ)-(S)-4
4 h
4 days
4 h
4 days
5 h
20
50
20
50
20
52
54
55
54
55
35
10
75
28
15
40
13
60
2.5
35
10
6
2
72.5
15
40
6
10
19.2
5.8
a One-pot Strecker reactions of ketones 4 were conducted with 2 equiv of (S)-a-phenylethylamine, 2 equiv of NaCN in the presence of 2 equiv of AcOH in
DMSO.
2.1. Basic hydrolysis
HN
NH-Boc
CONH2
H2, Pd(OH)2/C
(Boc)2O, EtOH
Ph
CONH2
OBn
11D
Subsequently, the a-amino nitrile mixtures 5A–D, or each
one, were subjected to hydrolysis in ethanolic potassium
hydroxide solution in the presence of hydrogen peroxide
(35 wt % in H2O) at 0 ꢁC, and then at rt for 2 days,15 to af-
ford the amides (1S,2R)-11A, (1R,2R)-11D, (1R,2S)-11B
and (1S,2S)-11C in 60–75% yields, after easy chromato-
graphic separation (Scheme 5).
OH
12D
92%
CONH2
CONH2
H2, Pd(OH)2/C
(Boc)2O, EtOH
NH-Boc
HN
OBn
11C
Treatment of nitrile 5A with basic hydrogen peroxide
(H2O2, aq NaOH) in the presence of transfer-phase catalyst
Bu4NHSO4 in CH2Cl2,16 gave only the amide 11A in 43%
yield. However, acidic hydrolysis with concentrated
H2SO4 in CH2Cl2 at 0 ꢁC or rt,8a led to a degradation of
starting nitrile 5A.
Ph
OBn
13C
87%
Scheme 6. Catalytic hydrogenolysis of benzyl groups.
CONH2
NH-Boc
Hydrogenolysis of pure a-aminocarboxamide 11D in the
presence of a catalytic amount of 20% Pd(OH)2 on
activated carbon (w/w, 30%) in EtOH or AcOH under
hydrogen (1 atm, 10 h) did not give the expected free
amine, but a degradation product. Nevertheless, the treat-
ment of amide 11D under the same conditions and in the
presence of di-tert-butylcarbonate [(Boc)2O],17 furnished
simultaneously, by a double benzylic cleavage and by
in situ protection of free amine, the desired amine 12D in
excellent yield. Moreover, amide 11C provided under the
same conditions in the presence of Boc2O, amine 13C with-
out deprotection of benzyl group, on oxygen atom, in 87%
yield (Scheme 6).
H , Pd(OH) /C X
2
2
11A
(Boc)2O, EtOH
OX
12A: X = H
13A: X = Bn
Scheme 7.
Amino amide trans-12D was finally hydrolysed with 6 M
HCl at reflux to furnish the target a-amino-2-hydroxycy-
clobutanecarboxylic acid, HCl salt 3DÆHCl in 74% yield,
and with specific rotation given for the first time
[a]D = ꢀ8.8 (c 0.30, H2O) (Scheme 8). Its spectral data were
identical with those reported in the literature,7a while the
specific rotation for the optically active amino acid had
not been previously reported.7b
Conversely, hydrogenolysis of cis-11A or cis-11B under the
1
same conditions as noted above, showed in the H NMR
spectra of the crude products, significant signals similar
to those of amide 12D. Unfortunately, purification of the
crude residues on silica gel did not furnish the desired
12A or 13A, but gave a complete degradation of the prod-
ucts (Scheme 7).
In contrast, the hydrolysis of amino amide 13C under the
same conditions did not give the expected amino acid,
but led to degradation products.
CONH2
HN
CONH2
HN
HN
Ph
CONH2
OBn
11D
75%
Ph
HN
CONH2
Ph
Ph
OBn
11A
67%
OBn
OBn
11B
11C
60%
75%
Scheme 5. Synthesis of amides 11 from corresponding nitriles 5, with H2O2, KOH in EtOH/H2O at rt, for 2 days.

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D. Hazelard et al. / Tetrahedron: Asymmetry 17 (2006) 1457–1464
NH-Boc
CONH2
CN
NH2•HCl
re face
6 M HCl
R*
CO2H
OH
3D•HCl
N
100 ºC, 20 h
thermod.
R
kinetic
H
OH
12D
74%
BnO
si face
CN
CN
HN
CN
9
Scheme 8.
Ph
HN
OBn
5A
Ph
OBn
5D
2.2. Absolute configuration: X-ray crystallography
ZnBr2, cat., DMSO
45 ˚C, 3 days, 98%
To determine the absolute configuration of all these
molecules, we found that the kinetic amino nitrile 5A
gave suitable crystals. The X-ray crystallographic analysis
showed,18 as depicted in Figure 1, a (1R,2R,10S)-absolute
configuration of 5A. The (R)-configuration at the C2 centre
was also in accordance with the previously reported X-ray
crystallographic analysis of the starting 2-benzyloxycyclo-
butanone (R)-(+)-14.11 Consequently, nucleophilic attack
of the cyanide anion, under kinetic conditions, occurred
anti to the benzyloxy group with a like approach to imin-
ium 9. While, under thermodynamic control the syn attack
with an unlike approach occurred to give the amino nitrile
(1S,2R,10S)-5D.
Scheme 9. Kinetic–thermodynamic equilibrium.
account the priority order, the absolute configuration of
amides were (1S,2R,10S) for 11A, (1R,2S,10S) for 11B,
(1S,2S,10S) for 11C and (1R,2R,10S) for 11D. Further-
more, it should be (1R,2R) for 12D, (1S,2S) for 13C and
(1R,2R) for 3D.
Moreover, it is interesting to note that a meticulous study
of the NMR spectra of proton H2 located at C2 centre,
in amino nitriles 5A–D furnished us with this conclusion:
the H2 proton is shielded when it is trans to the nitrile
group, with d = 3.76 ppm for thermodynamic amino nitr-
iles 5C and 5D. The H2 proton is deshielded when the
nitrile group is cis, with d = 4.20–4.25 ppm for kinetic
nitriles 5A and 5B. This characteristic behaviour was also
valid for the amides 11A–D. Thus, H2 protons cis to the
amide groups are deshielded for 11A and 11B (d = 4.20–
4.25 ppm) compared to the shielded H2 protons for 11C
and 11D (d = 3.77–3.85 ppm (Scheme 10).
3. Conclusion
Figure 1. ORTEP plot of X-ray crystal structure of (1R,2R,10S)-5A.
We have developed an easy and efficient four step synthesis
of enantiopure (1R,2R)-(ꢀ)-1-amino-2-hydroxycyclo-
butanecarboxylic acid 3D, starting from readily available
racemic or optically active 2-benzyloxycyclobutanone.11
We have demonstrated that these ketones undergo an
asymmetric Strecker reaction to selectively give one major
kinetic or thermodynamic amino nitrile 5A, 5B or 5C, 5D.
Subsequent basic hydrolysis of each nitrile furnished the
corresponding amide 11A–D, in good yields. The hydro-
genolysis of 11D required treatment in the presence of
Boc2O to give the N-Boc derivative 12D. Finally, acidic
hydrolysis provided, for the first time, the optically active
amino acid 3D (c4Ser derivative) in good yield.
Moreover, it was observed in the X-ray structure of 5A that
the benzyloxy group at C2 occupies an equatorial position,
in accordance with the very recently reported conforma-
tional study.19 The syn 5A adopts only one ring-puckering
conformation characterised by a positive pucker angle
h = +32.4ꢁ. The cyclobutane-ring pucker angle h, defined
as the acute angle between the planes C1–C2–C4 and C2–
C3–C4. The syn compound are stabilised by an intramole-
cular hydrogen bond between the NH of amine and oxygen
˚
of the ether group (NHꢁ ꢁ ꢁO = 2.52 A).
On the other hand, the equilibrium between the kinetic and
thermodynamic compound was confirmed by treating the
pure kinetic 5A with a catalytic amount of ZnBr2 in DMSO
at 45 ꢁC, which exclusively gave 5D within 3 days. The
same equilibrium could occur between amino nitrile 5B
and 5C (Scheme 9).
4. Experimental
4.1. General
The general experimental procedures and the analytical
instruments employed have been described in detail in a
previous paper.8b Enantiomeric excesses were also per-
formed on a GC (Fisons A130) chiral column Cydex B
(SGE) (25 m, 180 ꢁC, 1 bar).
By analogy, the absolute configuration of the kinetic amino
nitrile 5B, derived from benzyloxycyclobutanone (S)-(ꢀ)-4,
should be (1S,2S,10S)-5B, and for the thermodynamic com-
pound must be (1R,2S,10S)-5C. Consequently, taking into

D. Hazelard et al. / Tetrahedron: Asymmetry 17 (2006) 1457–1464
1461
CN
R
HN
CN
R
HN
S
S
Ph
Ph
S
HN
H
S
R
R
CN
S
CN
OBn
HN
OBn
BnO
Ph
3.76
3.76
BnO
H
H
Ph
H
4.20
4.25
(–)-5A
(–)-5B
(–)-5C
(–)-5D
CONH2
S
HN
CONH2
S
HN
R
Ph
R
R
Ph
S
HN
S
R
CONH2
S
CONH2
HN
Ph
BnO
3.77
H
4.25
BnO
Ph
H
3.85
H
OBn
H
OBn
(–)-11D
Scheme 10. d (in italic): chemical shifts in parts per million of H2 protons in cis or trans to nitrile or amide functions.
4.20
(+)-11A
(–)-11B
(+)-11C
4.1.1. (R)- and (S)-2-Benzyloxycyclobutanone 4. (R)- and
(S)-2-Benzyloxycyclobutanone 4 were prepared according
to our reported method.11
75); IR (neat) m: 3340, 3063, 2218 (CN), 1453, 1132, 1099;
1H NMR (CDCl3, 250 MHz) d: 1.20–1.60 (m, 2H, 2Hcycle),
1.63 (br s, NH), 1.38 (d, J = 6.7 Hz, CH3), 1.97–2.16 (m,
1H–C4), 2.17–2.38 (m, 1H–C4), 4.02 (q, J = 6.7 Hz, 1H–
0
4.1.2. rac-2-Benzyloxycyclobutanone 4. rac-2-Benzyloxy-
cyclobutanone 4 was prepared from the readily available
rac-611 by protection (91% yield) with benzyl bromide to
form rac-7 and deacetalisation (91% yield) following the
same sequence applied to prepare optically active
benzyloxycyclobutanone.11
C1 ), 4.21 (dd, J = 8.5, 8.2 Hz, 1H–C2), 4.63 (like AB sys-
tem, J = 12.2 Hz, DmAB = 29.3 Hz, 2Hbenzyl), 7.10–7.65
(m, 10H); 13C NMR (CDCl3, 62.9 MHz) d: 24.8 (C3),
0
25.2 (CH3), 27.3 (C4), 55.2 (C1 ), 56.9 (C1), 72.5 (C2 benzyl),
76.4 (C2), 120.8 (CN), [12 arom. C: 126.9 (2C), 127.2 (1C),
128.2 (2C), 128.3 (3C), 128.7 (2C), 137.0 (s), 145.6 (s)]; ES+
MS m/z: calcd mass for C20H22N2O, [M+Na]+: 329.2.
Found: 329.2. Anal. Calcd for C20H22N2O: C, 78.40; H,
7.24; N, 9.14. Found: C, 78.24; H, 7.45; N, 9.13.
4.2. General procedure A
Preparation of the amino nitriles was carried out according
to our reported methods.6b,8a
4.2.1.1. X-ray structure analysis of (ꢀ)-5A.18 Crystal
data for (ꢀ)-(1R,2R,10S)-5A: Colourless crystal of
0.30 · 0.12 · 0.12 mm. C20H22N2O, M = 306.41: ortho-
rhombic system, space group p21, 21, 21 (No. 19), Z = 4,
To a solution of rac-benzyloxycyclobutanone 4 (1.500 g,
8.52 mmol) in 20 mL of DMSO, were added successively
˚
AcOH (1.0 mL, 2 equiv), (S)-a-methylbenzylamine
8
with a = 5.4044 (2), b = 9.1016 (4), c = 33.7361 (14)ꢀA3,
(2.20 mL, 17 mmol) and 640 mg (13.07 mmol) of NaCN.
The mixture was stirred at room temperature for 4–5 h (ki-
netic conditions) [or stirred and heated at 50 ꢁC for 4–
5 days (thermodynamic conditions)]. It was then concen-
trated under vacuum, diluted with EtOAc (30 mL), H2O
(5 mL) and basified to pH 9 with a saturated solution of
NaHCO3. The mixture was extracted with EtOAc
(3 · 150 mL). The combined organic layers were dried over
MgSO4, filtered and then concentrated under vacuum to
give 3.20 g of the crude amino nitriles as a mixture of four
diastereoisomers. Purification by flash chromatography
(twice, FC) on silica gel (eluent: EtOAc/petrol ether: 10/
90), afforded (under thermodynamic conditions): 130 mg
(5% yield) of 5A, 130 mg (5%) of 5B, 520 mg (20%) of 5C
and 520 mg (20%) of 5D and 210 mg (8%) as a mixture.
a = b = c = 90ꢁ, V = 1659.43 (12) A3, d = 1.226 g cmꢀ1
,
;
˚
F(000) = 656, k = 0.71073 A (Mo-Ka), l = 0.076 mm
4605 reflections measured (ꢀ7 6 h 6 7, ꢀ10 6 k 6 12,
ꢀ41 6 l 6 46) on a Bruker X8 diffractometer. The structure
was solved and refined with SHELXL-97.20 Hydrogen atom
riding, refinement converged to R(gt) = 0.0359 for the
4460 reflections having I = 2r(I), and wR(gt) = 0.0969,
Goodness of Fit S = 1.065, residual electron density:
3
˚
ꢀ0.373 and 0.477 e A .
4.2.2. (1S,2S,10S)-Benzyloxy-1-[(10-phenylethyl)amino]cy-
clobutanecarbonitrile, 5B. Compound 5B can also be pre-
pared under kinetic conditions, from optically active
cyclobutanone (S)-4, as a colourless oil, major product
(40% yield, see Table 1). [a]D = ꢀ78.5 (c 1, CHCl3);
Rf = 0.42 (Et2O/pentane: 25/75); IR (neat) m: 3326, 3062,
1
4.2.1. (1R,2R,10S)-2-Benzyloxy-1-[(10-phenylethyl)amino]-
cyclobutanecarbonitrile, 5A. Compound 5A can also be
prepared under kinetic conditions, from optically active
cyclobutanone (R)-4, as major product (41% yield, see Ta-
ble 1). Crystallisation from ether/pentane furnished colour-
less crystals. The X-ray analysis of these crystals showed a
(1R,2R,10S) configuration.18 [a]D = ꢀ65.8 (c 1, CHCl3); mp
66.7 ꢁC (from ether/pentane); Rf = 0.46 (Et2O/pentane: 25/
2218 (CN), 1494, 1454; H NMR (CDCl3, 250 MHz) d:
1.38 (d, J = 6.7 Hz, CH3), 1.92–2.18 (m, 2H, 1HN and
1H–C3), 2.10–2.50 (m, 3Hcycle), 4.06 (q, J = 6.7 Hz, 1H–
0
C1 ), 4.27 (dd, J = 8.3, 8.0 Hz, 1H–C2), 4.56 (m, sharp,
2Hbenzyl), 7.20–7.50 (m, 10H); 13C NMR (CDCl3,
0
62.9 MHz) d: 24.6 (CH3), 27.2 (C3 and C4), 55.2 (C1 ),
55.6 (s, C1), 72.3 (CH2 benzyl), 76.6 (d, C2), 120.4 (C„N),
[12 arom. C: 126.7 (2C), 127.4 (1C), 128.1 (2C), 128.2

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D. Hazelard et al. / Tetrahedron: Asymmetry 17 (2006) 1457–1464
(1C), 128.4 (2C), 128.6 (2C), 136.8 (s), 144.9 (s)]; ES+ MS
m/z: calcd mass for C20H22N2O + (Na–HCN): 302.2.
Found: 302.1. Anal. Calcd for C20H22N2O: C, 78.40; H,
7.24; N, 9.14. Found: C, 78.51; H, 7.02; N, 9.13.
325 mg (67%) of pure amide 11A, as a colourless oil.
[a]D = +62 (c 1, CHCl3); Rf = 0.49 (MeOH/CH2Cl2: 10/
90); IR (neat) m: 3436, 3325, 3062, 1676 (CON), 1453,
1
1126; H NMR (CDCl3, 250 MHz) d: 1.29 (d, J = 6.7 Hz,
3H, CH3), 1.80–2.00 (m, 2H–C3), 2.05–2.28 (m, 1H–C4),
2.28–2.50 (m, 1H–C4), 3.90 (br s, NH), 4.00 (q, J =
6.7 Hz, 1H–C1), 4.22 (dd, J = 7.2, 7.0 Hz, 1H–C2), 4.45
(d, AB syst. J = 11.6 Hz, 1Hbenzyl), 4.55 (d, AB syst. J =
11.6 Hz, 1Hbenzyl), 6.90 (br d, J = 5.3 Hz, 1Hamide), 7.20–
7.53 (m, 10H), 7.64 (br d, J = 5.3 Hz, 1Hamide); 13C
NMR (CDCl3, 62.9 MHz) d: 15.8 (C3), 24.1 (CH3), 25.1
4.2.3. (1R,2S,10S)-2-Benzyloxy-1-[(10-phenylethyl)amino]-
cyclobutanecarbonitrile, 5C. [a]D = ꢀ101 (c 1, CHCl3);
Rf = 0.6 (EtOAc/petrol ether: 3/7); IR (neat) m: 3315,
3062, 2217 (CN), 1494, 1454, 1122; 1H NMR (CDCl3,
250 MHz) d: 1.01 (ddd, J = 9.7, 9.1, 11.5 Hz, 1H–C3),
1.20 (d, J = 6.7 Hz, CH3), 1.30–1.52 (m, 2H, 1Hcycle and
NH), 1.80–2.10 (m, 2Hcycle), 3.77 (dd, J = 8.0, 8.7 Hz,
0
(C4), 53.8 (C1 ), 65.9 (C1), 71.8 (OCH2), 77.00 (C2), [12
0
1H–C2), 3.90 (q, J = 6.7 Hz, 1H–C1 ), 4.45 (d, AB syst.,
arom. C: 126.0 (2C), 127.0 (1C), 127.7 (3C), 128.2 (2C),
128.4 (2C), 137.1 (s), 146.0 (s)], 179.7 (CON); HRMS
(EI) m/z: calcd mass for C20H24N2O2: 324.1838. Found:
324.1832.
J = 12.0 Hz, 1Hbenzyl), 4.70 (d, AB syst., J = 12.0 Hz,
1Hbenzyl), 7.10–7.50 (m, 10H); 13C NMR (CDCl3,
0
62.9 MHz) d: 24.1 (CH3), 24.7 (C3), 26.4 (C4), 55.6 (C1 ),
63.2 (C1), 72.1 (CH2 benzyl), 78.8 (C2), 119.7 (C„N), [12
arom.: C 127.2 (2C), 127.4 (1C), 128.2 (3C), 128.4 (2C),
128.6 (2C), 137.6 (s), 144.2 (s)]; MS+ ES m/z: 329.2
[M+Na]+; HR ES+ MS m/z: calcd mass for C20H22N2O-
Na, [M+Na]+: 329.1630. Found: 329.1622.
4.3.2. (1R,2S,10S)-2-Benzyloxy-1-[(10-phenylethyl)amino]-
cyclobutanecarboxamide, 11B. According to procedure
B: From 90 mg (0.3 mmol) of nitrile 5B, 230 mg of KOH
(4.1 mmol), 2.2 mL (25 mmol) of H2O2 (35 wt % in water)
and 4 mL of EtOH. After stirring for 22 h and FC, we iso-
lated 60 mg (61%) of pure amide 11B as a colourless oil.
[a]D = ꢀ67 (c 1, CHCl3); Rf = 0.37 (MeOH/CH2Cl2: 5/
95); IR (neat) m: 3442, 3329, 3063, 1676 (CON), 1454,
4.2.4. (1S,2R,10S)-Benzyloxy-1-[(10-phenylethyl)amino]cyc-
lobutanecarbonitrile, 5D. Compound 5D can also be pre-
pared under thermodynamic conditions, from optically
active cyclobutanone (R)-4, as a colourless oil, major prod-
uct (30% yield, see Table 1). [a]D = ꢀ63.1 (c 0.77, CHCl3);
Rf = 0.55 (EtOAc/petrol ether: 30/70); IR (neat) m: 3320,
3063, 2223 (CN), 1495, 1454, 1127; 1H NMR (CDCl3,
250 MHz) d: 1.32 (d, J = 6.7 Hz, 3H, CH3), 1.50 (br s,
NH), 1.67–1.84 (m, 1H–C3), 1.92–2.25 (m, 2Hcycle), 2.36
(ddd, J = 2.2, 10.0, 11.0 Hz, 1H–C4), 3.69 (dd, J = 8.0,
1
1125; H NMR (CDCl3, 250 MHz) d: 1.47 (d, J = 6.6 Hz,
3H), 1.93–2.18 (m, 2Hcycle), 2.18–2.50 (m, 3H, 2Hcycle and
0
NH), 3.89 (q, J = 6.6 Hz, 1H–C1 ), 4.21 (dd, J = 6.6,
6.7 Hz, 1H–C2), 4.43 (d, AB syst. J = 11.5 Hz, 1Hbenzyl),
4.54 (d, AB syst. J = 11.5 Hz, 1Hbenzyl), 5.30 (br d,
J = 4.0 Hz, 1Hamide), 6.80 (br d, J = 4.0 Hz, 1Hamide),
7.15–7.46 (m, 10H); 13C NMR (CDCl3, 62.9 MHz) d:
0
0
8.3 Hz, 1H–C2), 4.00 (q, J = 6.7 Hz, 1H–C1 ), 4.24 (m,
18.3 (C3), 25.5 (C4), 26.0 (CH3), 53.3 (C1 ), 67.1 (C1), 72.1
sharp, AB syst., 2Hbenzyl), 7.10–7.40 (m, 10H); 13C NMR
(OCH2), 77.1 (C2), [12 arom. C: 126.4 (2C), 126.9 (1C),
127.9 (3C), 128.5 (2C), 128.6 (2C), 137.4 (s), 146.3 (s)],
178.3 (CON); HR ES+ MS m/z: calcd mass for
C20H24N2O2Na, [M+Na]+: 347.1735. Found: 347.1736.
(CDCl3, 62.9 MHz) d: 24.2 (CH3), 24.6 (C3), 27.4 (C4),
0
55.7 (C1 ), 62.4 (C1), 71.6 (CH2 benzyl), 78.5 (C2), 119.7
(C„N), [12 arom. C: 126.8 (2C), 127.3 (1C), 127.9 (1C),
128.0 (2C), 128.35 (2C), 128.4 (2C), 137.5 (s), 144.8 (s)];
HR ES+ MS m/z: calcd mass for C20H22N2ONa,
[M+Na]+: 329.1630. Found: 329.1631.
4.3.3. (1S,2S,10S)-2-Benzyloxy-1-[(10-phenylethyl)amino]-
cyclobutanecarboxamide, 11C. According to procedure
B: From 786 mg (2.57 mmol) of nitrile 5C, 1.0 g (17 mmol)
of KOH, 9 mL (102 mmol) of H2O2 (35 wt % in water) and
25 mL of EtOH. After stirring for 2 days and FC, we iso-
lated 625 mg (75%) of pure amide 11C. [a]D = +13.9 (c
1.1, CHCl3); mp 38.4 ꢁC; tR = 206.59 min (Cydex B,
180 ꢁC, 1 bar); Rf = 0.36 (EtOAc/petrol ether: 1/1); IR
4.3. Amide formation from nitrile: general procedure B
To a solution of amino nitrile 5A–D (612 mg, 2 mmol) in
EtOH (20 mL), were added (under argon) at 0 ꢁC succes-
sively KOH (1.57 g, 28 mmol) and an excess amount of
H2O2 (150 mmol, 35 wt % in water). The mixture was stir-
red at 0 ꢁC for 8 h, then at room temperature for 1–2 days.
The complete elimination of excess of peroxide was per-
formed by the addition of an aqueous saturated solution
of Na2S2O3 (KI test). The resulting mixture was concen-
trated, diluted with 5 mL of H2O, then extracted with
EtOAc (3 · 80 mL). The organic layers were dried over
MgSO4, filtered and concentrated under vacuum, to give
after FC (silica gel, 20 g, eluent: MeOH/CH2Cl2: 1/99 to
4/96), the desired amide 11A–D.
1
(neat) m: 3454, 3318, 3062, 1682 (CON), 1454, 1122; H
NMR (CDCl3, 250 MHz) d: 1.15–1.40 (m, 1H–C3), 1.33
(d, J = 6.7 Hz, 3H), 1.85–2.10 (m, 2Hcycle), 2.20 (ddd,
J = 3.5, 8.3, 8.6 Hz, 1H–C3), 2.40 (br s, NH); 3.83 (dd,
J = 8.5, 8.3 Hz, 1H–C2), 3.86 (q, J = 6.7 Hz, 1H–C1),
4.47 (like AB syst. JAB = 12.0 Hz, 2Hbenzyl), 5.86 (br s,
1Hamide), 7.15–7.48 (m, 11H, 10Harom and 1Hamide); 13C
NMR (CDCl3, 62.9 MHz) d: 22.4 (C3), 24.0 (CH3), 24.1
0
(C4), 54.8 (C1 ), 70.2 (C1), 71.3 (OCH2), 80.5 (C2), [12
arom. C: 126.5 (2C), 127.2 (1C), 127.6 (3C), 128.3 (2C),
128.5 (2C), 137.7 (s), 146.1 (s)], 175.6 (CON); HRMS
(EI) m/z: calcd mass for C20H24N2O2: 324.1838. Found:
324.1829.
4.3.1. (1S,2R,10S)-2-Benzyloxy-1-[(10-phenylethyl)amino]-
cyclobutanecarboxamide, 11A. According to procedure
B: From 460 mg (1.5 mmol) of nitrile 5A, 1.12 g (20 mmol)
of KOH and 10.6 mL of H2O2 (35 wt % in H2O) and 20 mL
of EtOH. After stirring at rt for 3 days and FC, we isolated
4.3.4. (1R,2R,10S)-2-Benzyloxy-1-[(10-phenylethyl)amino]-
cyclobutanecarboxamide, 11D. According to procedure

D. Hazelard et al. / Tetrahedron: Asymmetry 17 (2006) 1457–1464
1463
B: From 786 mg (2.57 mmol) of nitrile 5D, 1.0 g (17 mmol)
of KOH, 9 mL (102 mmol) of H2O2 (35 wt % in H2O) and
25 mL of EtOH. After stirring for 2 days and FC, we iso-
lated 625 mg (75%) of amide 11D. [a]D = ꢀ26.6 (c 0.9,
CHCl3); mp 70.1 ꢁC; Rf = 0.28 (EtOAc/petrol ether: 1/1);
IR (neat) m: 3387, 3317, 3062, 1674 (CON), 1454, 1122;
1H NMR (CDCl3, 250 MHz) d: 1.35 (d, J = 6.7 Hz, 3H),
1.48–1.67 (m, 1Hcycle), 1.75–2.40 (m, 2Hcycle), 2.38 (ddd,
J = 9.4, 10.2, 1.0 Hz, 1H–C4), 2.84 (br s, 1H–N), 3.76 (q,
71.3 (CH2 benzyl), 78.0 (C2), 79.8 (C(CH3)3), [6 arom. C:
127.6, 127.7 (2C), 128.2 (2C), 137.5], 154.7 (COO), 174.1
(CONH2); HRMS (EI) m/z: calcd mass for C17H24N2O4:
320.1736. Found: 320.1730.
4.5. (1R,2R)-1-Amino-2-hydroxycyclobutanecarboxylic
acidÆhydrochloride, 3DÆHCl
A solution of 6 M HCl (2 mL) and 23 mg (0.100 mmol) of
amide 12D was heated at reflux for 18 h. After cooling to
room temperature, 5 mL of H2O was added and the result-
ing solution washed with ether (4 mL). The aqueous solu-
tion was concentrated to dryness, then the residue was
washed with EtOAc (1 mL) and with ether (1 mL), to fur-
nish 17 mg (100%) of the (1R,2R)-amino acid 3DÆHCl as a
light yellow solid.
0
J = 6.7 Hz, 1H–C1 ), 3.79 (m, 1H–C2), 4.13 (like AB syst.
J = 11.8 Hz, 2Hbenzyl), 5.37 (br s, 1Hamide), 7.11–7.45 (m,
11H, 10Harom and 1Hamide); 13C NMR (CDCl3,
0
62.9 MHz) d: 24.1 (C3), 24.9 (C4), 25.6 (CH3), 54.8 (C1 ),
69.4 (C1), 70.9 (OCH2), 79.2 (C2), [12 arom. C: 126.7
(3C), 127.5 (3C), 128.1 (4C), 137.4 (s), 145.8 (s)], 176.3
(CON); HRMS (EI) m/z: calcd mass for C20H24N2O2:
324.1838. Found: 324.1840. Anal. Calcd for C20H24N2O2:
C, 74.04; H, 7.46; N, 8.64. Found: C, 73.99; H, 7.45; N,
8.78.
[a]D = ꢀ8.8 (c 0.30, H2O); mp 188.5 ꢁC decomp.; 1H NMR
(D2O, 250 MHz) d: 1.74–2.63 (m, 4Hcycle), 3.99–4.21 (m,
1H–C2); 13C NMR (D2O, 62.9 MHz) d: 26.1 (t, C4), 28.1
(t, C3), 57.9 (s, C1), 60.3 (d, C2), 171.9 (COOH). The spec-
tral data are identical with those reported for the racemic
product.7
4.4. Hydrogenolysis procedure
4.4.1. (1R,2R)-1-(N-tert-Butyloxycarbonyl)amino-2-hydroxy-
cyclobutanecarboxamide, 12D. To a solution of amino
amide 11D (324 mg, 9 mmol) in 15 mL of EtOH, were
added Boc2O (872 mg, 4 mmol) and 20% Pd(OH)2/C
(Pearlman’s catalyst, 200 mg; 60% w/w). The flask was
connected to a hydrogenation apparatus equipped with a
graduated burette containing water that allowed the uptake
of hydrogen to be monitored. TLC control showed that un-
der 1 atm for 27 h, the reaction was complete, then de-
gassed under a stream of argon, filtered through paper
and the collected solid washed with EtOH (2 · 10 mL).
The combined filtrate and washings were concentrated
and purified by FC on silica gel (20 g), eluent (MeOH/
CH2Cl2: 5/95) to give 215 mg (92%) of hydroxyamide
12D as a solid. [a]D = ꢀ35.8 (c 0.5, MeOH); mp 108.2 ꢁC;
Rf = 0.22 (MeOH/CH2Cl2: 10/90); IR (KBr) m: 3474,
Acknowledgement
´
The authors thank Mr. Regis Guillot for running X-ray
analysis.
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´
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