First synthesis of (1S,2S)- and (1R,2R)-1-amino-2-isopropylcyclobutanecarboxylic acids by asymmetric Strecker reaction from 2-substituted cyclobutanones

Article abstract of DOI:10.1016/S0957-4166(03)00073-9

An efficient and easy one-pot reaction from readily available racemic 2-substituted cyclobutanones gave, by means of asymmetric Strecker synthesis in the presence of an amine chiral auxiliary, two major aminonitriles with excellent diastereoselectivity. After separation, the major cis-aminonitriles were hydrolysed and hydrogenolysed to lead for the first time to pure non-racemic (+)-1-amino-2-isopropylcyclobutanecarboxylic acid (ACBC) and its antipode.

Full text of DOI:10.1016/S0957-4166(03)00073-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1063–1072
First synthesis of (1S,2S)- and
(1R,2R)-1-amino-2-isopropylcyclobutanecarboxylic acids by
asymmetric Strecker reaction from 2-substituted cyclobutanonesꢀ
Molika Truong, Fre´de´ric Lecornue´ and Antoine Fadel*
Laboratoire des Carbocycles (Associe´ au CNRS), Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay, Baˆt. 420,
Universite´ Paris-Sud, 91405 Orsay, France
Received 6 December 2002; accepted 14 January 2003
Abstract—An efficient and easy one-pot reaction from readily available racemic 2-substituted cyclobutanones gave, by means of
asymmetric Strecker synthesis in the presence of an amine chiral auxiliary, two major aminonitriles with excellent diastereoselec-
tivity. After separation, the major cis-aminonitriles were hydrolysed and hydrogenolysed to lead for the first time to pure
non-racemic (+)-1-amino-2-isopropylcyclobutanecarboxylic acid (ACBC) and its antipode. © 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
transaminases.4b Methods for the synthesis of enantio-
pure ACBCs have not received the same attention as
those for the preparation of ACPCs and as far as we
are aware, only a few methods for the synthesis of
optically active 1-amino-2-alkylcyclobutanecarboxylic
acids have been described by recrystallisation with tar-
taric acid.5–7 In the course of our work on asymmetric
syntheses of cyclic analogues of naturally occuring a-
amino acids we have previously published the amino-
cyclopropanecarboxylic acids methanovalines I,8 allo-
norcoronamic acids II, and allo-coronamic acids III,9
by means of asymmetric Strecker reactions (Scheme
1).10,11
In the last few years, a variety of interesting biological
properties of a-amino acids have been described. 1-
Aminocyclopropanecarboxylic
aminocyclobutanecarboxylic
acid
acid
(ACPC),
(ACBC),
1-
and
1-aminocyclopentanecarboxylic acid (ACPentC) are
known to be partial agonists at the strychnine insensi-
tive glycine binding site of the NMDA receptor com-
plex.1 Recently, it was shown that ACPC acts
concurrently as a glycine site partial agonist and as a
glutamate site antagonist,2 thus protecting against neu-
ral cell death and exhibiting antipsychotic-like effects in
animal models.3 Moreover, a-tetrasubstituted a-amino
acids such as ACPC are also able to function as enzyme
inhibitors by covalently binding to pyridoxal phos-
phate-dependent enzymes such as decarboxylases4a and
Herein, we report on the preparation of homochiral
1-amino-2-substituted cyclobutanecarboxylic acids 1—
in four steps—starting from the racemic cyclobu-
Scheme 1.
ꢀ Part of this study was previously reported at the Organic Chemistry Symposium at Palaiseau (SFC, Sept., 2001), France.
* Corresponding author. Fax: +33-(1)-691-56278; e-mail: antfadel@icmo.u-psud.fr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00073-9

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M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
tanones 3 and chiral benzylic amine as a chiral auxil-
iary, proceeding via the amino nitriles 2 by asymmetric
Strecker reaction (Scheme 2).
ing iminium mixtures 7.a–c (each as a mixture of the
(E/Z,aS,2S) and (E/Z,aS,2R) stereoisomers), which by
in situ addition of sodium cyanide to the CꢀN bond
would predominantly afford one diastereomer of the
four possible a-aminonitrile isomers 2.a–c.
2. Results and discussion
By changing the solvent, the amine and the R group of
the ketones, we could make some interesting observa-
tions. Our results of these investigations are sum-
marised in Table 1. It shows that, from the
cyclobutanone 3a the use of DMSO solvent,14 increases
the rate reaction (entries 1 and 2). Whereas, from the
2-alkyl- or 2-arylcyclobutanones 3b, there are a slight
difference (entries 3–8). However in all cases, only a
slight difference in the major cis configurated a-
aminonitriles 2A and 2C ratio was observed, 51–56 and
42–44, respectively. Thus the selective synthesis of only
a single a-aminonitriles failed. The trans configured
a-aminonitriles 2B and 2D were the minor products
only obtained in negligible amounts <1–2.5%.
2.1. a-Aminonitrile synthesis
The racemic starting 2-substituted cyclobutanones 3a–c,
were prepared from cyclopropyl aldehyde 4, by a
modified ring enlargement according to our previously
reported method.12 Thus, aldehyde 4 underwent, in a
‘one-pot’ reaction, addition of alkyllithium or Grignard
reagent, followed by acidic hydrolysis, to give by ring
enlargement13 of the intermediate 5, the desired ketone
3b–c with good yields (Scheme 3); 3a is available
commercially.
For the synthesis of the a-aminonitriles 2a–c, the alkyl-
ated ketones ( )-3a–c were subjected to a one-pot pro-
cedure previously developed in our group8,9 (Scheme
4). We anticipated that, under acidic conditions, the
ketone condensations with the chiral auxiliary (S)-1-
phenylethylamine or derivatives 6 give the correspond-
Heating a mixture of nitriles 2A.b/2C.b (3/7) for 24 h in
iPrOH in the presence of TFA does not change their
stereochemical composition. Furthermore, the amount
of A increases by changing the R-substituent from 51%
Scheme 2.
Scheme 3. Synthesis of racemic cyclobutanones 3a–c.
Scheme 4. Synthesis of a-amino acids 1a–c.

M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
1065
Table 1. Preparation of amino nitriles 2A–D from racemic 2-substituted cyclobutanones 3a–c
Entry
Amine 6
Ketone 3
Solvent
Time
Yield (%)
2 Diastereomers ratioa
Y
R
A
B
C
D
cis/trans
1
2
3
4
5
6
7
8
H
H
H
H
OH
OMe
H
a H
a H
DMSO
MeOH
DMSO
MeOH
DMSO
DMSO
DMSO
MeOH
6 h
57
55
54
43
42.5
44.5
46
2.a
2.a
2.b
2.b
2.b%
2.b¦
2.c
100
100
51
52
54
53
56
54
–
–
–
–
–
–
–
–
3 days
4 days
4 days
4 days
4 days
4 days
4 days
b Ph
b Ph
b Ph
b Ph
c iPr
c iPr
B2.5
2.5
B2
B2
1
45
44
43
44
42
44
B1.5
B1.5
B1
B1
B1
B1
96/4
96/4
97/3
97/3
98/2
98/2
H
42
2.c
B1
All reactions of racemic acetal 4 were carried out in the presence of 1.5 equiv. of amine, 1.5 equiv. of NaCN and 3 equiv. of AcOH in DMSO
at 55°C.
a Diastereoisomeric ratios were measured by GC analysis using a chiral column.
for 2A.b (R=Ph) to 56% for 2A.c (R=isopropyl). In
parallel, the amount of the second cis nitrile C
decreases slightly from 45% to 42% under these condi-
tions. These major cis nitriles 2A.a–c/2C.a–c are readily
separated from the minor trans isomers by chromatog-
raphy on silica gel. But infortunately isolation of pure
Hydrogenolysis of pure a-aminocarboxamides 8A.a–c
and 8C.c, separately in the presence of a catalytic
amount of 20% Pd(OH)2 on activated carbon (w/w,
20%) in AcOH under hydrogen (1 atm, 10 h) gives after
flash chromatography the free amino amides 9a, 9A.c
and 9C.c in 84, 98 and 98% yields, respectively. These
latters were finally hydrolysed with 6N HCl at reflux
followed by the addition of propylene oxide in ethanol,
to furnish the target a-amino acid 1.a, and for the first
time optically active 1A.c and 1C.c with 90–94% yields
(Scheme 5).
2A.a–c
from
2C.a–c
required
exhaustive
chromatography.
2.2. Acidic hydrolysis
2.3. Absolute configuration
Subsequently, the a-aminonitriles mixtures 2A.a,c/
2C.a,c or each one were subjected to hydrolysis in the
concentrated sulfuric acid in methylene chloride at 0°C
to rt for 10 h, to afford the amides (1S,2S)-8A.a–c and
(1R,2R)-8C.c in 70–90% yields after easy chromato-
graphic separation.
Following Mosher derivatization15 the resulting (R)-
and (S)-methoxy-a-trifluoromethylphenylacetic acid
amides (MTPA) of 9A.c showed positive chemical shift
differences (Dl=lS−lR) for the 2-H1 and Hisopropyl
protons located on the right side of the MTPA plane
Scheme 5. Synthesis of amino acids via free amino amides.

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M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
and negative values for the 4-H2 and 3-H2 protons
located on the left side of the cyclobutane. The protons
3-H3 and CH3 protons were found to reside virtually in
the plane of the MTPA moiety, thus their l values were
nearly equal (Dl:0 ppm). The optimized structure
obtained by molecular mechanics (MM2) calculations
on the (S)-MTPA amide of (1S,2S)-9A.c was wholly
consistent with these results (Fig. 1).
In all cases the 1,2-induction mechanism is favorable,
and the cyanide addition occurs anti to the bulky group
with an unlike approach to the iminium intermediates.
For example, in the (E,aS,2S)- and (Z,aS,2S)-iminiums
the isopropyl group hampers the nucleophilic si-face
attack, thus leading to a high re-face selectivity of
(A:B:56:1). While for the (E,aS,2R)- and (Z,aS,2R)-
iminiums the re-face is completely blocked by both
isopropyl group and the phenyl group of amine, in
addition, in (Z,aS,2R)-iminium the si-face is partially
favored, thus leading to high si-face selectivity of
(C:D=42:1) (Fig. 2). In some cases, we cannot exclude
C-2 epimerisation under the applied reaction conditions
of the iminium intermediate, which occurs most likely
via a carbanion intermediate.
In addition, the (S)-configuration at C-1 was also
assigned by means of Kelly’s empirical method16 as
follows. For (R)-MTPA (u) and (S)-MTPA amide (l)
of 9A.c, the l values (1H NMR) for their methoxy
groups appears at 3.47 and 3.43 ppm, respectively
taking into account that the isopropyl group shield the
methoxy group in the l-diastereoisomer, but not in the
u-diastereoisomer. Consequently the DlOMe=u−l=
+0.04 indicating an (S)-configuration at C-1.
3. Conclusion
Moreover, we assume that the configuration in the
present case (major nitrile) is cis and consequently the
absolute configuration at C-2 must be (S). Unfortu-
nately, we were unable to confirm these conclusion by
X-ray crystallographic analyses since the compounds
could not be obtained in crystalline form.
We have developed an easy and efficient four-step
synthesis of new enantiopure (+)-(1S,2S)-1-amino-2-
isopropylcyclobutanecarboxylic acid (+)-1A.c and its
antipode (−)-1C.c starting from readily available
1
Figure 1. Dl=(lS−lR) for (S)- and (R)-MTPA amides of 9A.c by H NMR spectroscopy at 250 MHz.
Figure 2. Proposed nucleophilic attack to Z and E iminiums 7.c.

M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
1067
racemic a-alkylcyclobutanones, prepared from cyclo-
propylcarboxaldehyde.10 These acids were obtained
from separable major cis-amino nitriles 2A and 2C
which were prepared by asymmetric Strecker reaction
with excellent selectivity (dr>97:3). This approach
should constitute an efficient method for the synthesis
of a wide variety of aminocyclobutanecarboxylic acids.
Efforts to obtain one major cis-amino nitrile are cur-
rently in progress in our laboratory.
MeOH or DMSO (4 mL) was added successively (S)-a-
phenylethylamine (525 mL, 500 mg, 4.5 mmol), AcOH
(540 mL, 9 mmol) and finally NaCN (220 mg, 4.5
mmol). The reaction mixture was stirred and heated at
55–60°C for 3–4 days. Monitored by TLC, the reaction
mixture was concentrated, then eluted with EtOAc (100
mL) and neutralised with NaHCO3 solution to pH 8.
After extraction with EtOAc (2×50 mL) the combined
organic layer was dried, filtered, then concentrated. The
residue was purified by FC to give two major and two
minor diastereoisomers 2.a–c with acceptable yields.
4. Experimental
The general experimental procedures and the analytical
instruments employed have been described in detail in a
previous paper.17 Enantiomeric excess were also per-
formed on a GC (Fisons 9130) chiral column Cydex B
(SGE) (25 m, 155°C, 1 bar).
4.3.1. (1%S)-1-[(1%-Methylbenzyl)amino]cyclobutanecar-
bonitrile, 2.a. Following procedure A: From cyclobu-
tanone 3a (210 mg, 3 mmol), DMSO (4 mL), (S)-a-
phenylethylamine (525 mL, 500 mg, 4.5 mmol), AcOH
(9 mmol) and NaCN (220 mg) heated at 55°C for 6 h,
we isolated after FC (EtOAc/petrol ether: 5“25%), 343
mg (57%) of pure aminonitrile 2.a. [h]2D0=−126 (c 1,
CHCl3); Rf=0.4 (AcOEt/petrol ether: 2/8); IR (neat): w
3420 and 3300 cm−1 (NH), 2210 (CN); 1H NMR
(CDCl3): l 1.40 (d, J=6.5 Hz, 3H), 1.56–1.82 (m, 1H
and NH), 1.80–2.15 (m, 3H), 2.15–2.35 (m, 1H), 2.48–
2.62 (m, 1H), 4.07 (q, J=6.5 Hz, 1H), 7.20–7.50 (m,
5H); 13C NMR (CDCl3): l 15.4 (t, C3), 24.1 (q), 34.3 (t,
C4), 34.9 (t, C2), 54.0 (s, C1), 55.8 (d), 122.4 (s, CN) [6
arom. C: 127.0, (2C), 127.3, 128.3 (2C), 144.4]; MS (70
ev) m/z (%): 174 (1) (M+−CN), 106 (20), 105 (100), 104
(10), 79 (13), 77 (16); ES+MS m/z: 223.1 [M+Na]+.
4.1. ( )-2-Phenylcyclobutanone, 3b
To a cold solution (−78°C) of 1-(methoxyethoxy-
12
methoxy)cyclopropanecarboxaldehyde 4
(2.61 g, 15
mmol) in THF (15 mL) was added dropwise a solution
of phenyllithium (1.5 M, 12 mL, 18 mmol). After
stirring at −78°C for 1 h, concentrated H2SO4 (3 mL)
was slowly added. The reaction mixture was stirred at
−78°C for 1 h and allowed to warm to rt (1 h).
Recooled to 0°C, the acidic medium was neutralised
very slowly by Na2SO3 (solid). After adding water (20
mL) the mixture was extracted with ether (3×100 mL),
and the combined organic layers, dried, filtered then
concentrated under partial vacuum (bath <35°C). The
residue purified by FC (eluent, CH2Cl2/petrol ether:
1/1) gave 1.095 g (50%) of pure 2-phenylcyclobutanone
3b.
4.3.2.
(1S*,2S*,1%S)-1-[(1%-Methylbenzyl)amino]-2-
phenylcyclobutanecarbonitrile, (1S,2S,1%S)-2A.b and
(1R,2R,1%S)-2C.b. Following procedure A: From
phenylcyclobutanone 3b (438 mg), DMSO (4 mL), (S)-
a-phenylethylamine 6a (525 mL), AcOH (540 mL) and
NaCN (220 mg) heated at 55°C for 4 days, were
obtained 1.5 g of crude nitriles as a mixture of four
diastereoisomers in 51:45:2.5:1.5 ratio (determined by
chiral GC). Purified twice by FC (eluent, Et2O/pentane:
25/75) gave 228 mg (27.5%) of nitrile 2A.b, 200 mg
(24.3%) of nitrile 2C.b, 11 mg (1.3%) and 7 mg (0.8%)
of nitriles 2B.b or 2D.b.
1H NMR (CDCl3): l 2.15–2.42 (m, 1H), 2.41–2.69 (m,
1H), 2.95–3.16 (m, 1H), 3.16–3.40 (m, 1H), 4.44–4.65
(m, 1H-C2), 7.12–7.46 (m, 5H); 13C NMR (CDCl3): l
17.4 (C3), 44.6 (C4), 64.3 (C2) [6 arom. C: 126.7, 126.8
(2C), 128.4 (2C), 136.3], 207.7 (C1). All spectra are
13a
identical with those of lit.
4.2. ( )-2-Isopropylcyclobutanone, 3c
Following the procedure described above: From car-
boxaldehyde 4 (2.61 g, 15 mmol), THF (15 mL), iPr-
MgCl 1 M solution (18 mL), then concentrated H2SO4,
gave after FC (eluent, CH2Cl2/pentane: 70/30) 1.353 g
(82%) of pure 2-iso-propylcyclobutanone 3c.18 IR
4.3.2.1. Data for (1S,2S,1%S)-2A.b major cis isomer.
[h]2D0=−155, [h]365=−528 (c 1, CHCl3); mp 108.5°C;
tR=29.75 min (Cydex B, 160°C, 1 bar); Rf=0.44 (ether/
pentane: 25/75); IR (neat): w 3330 and 3300 cm−1 (NH),
1
2220 (CN); H NMR (CDCl3): l 1.40 (d, J=6.6 Hz,
1
(neat): w 1778 (CO) cm−1; H NMR (CDCl3): l 0.91 (d,
3H), 1.50–1.75 (m, 2H), 1.87 (br s, NH), 1.90–2.13 (m,
1H), 2.13–2.40 (m, 1H), 3.55 (dd, J=11.0 Hz, J=9.0
Hz, 1H-C2), 4.07 (q, J=6.6 Hz, 1H), 7.15–7.56 (m,
10H); 13C NMR (CDCl3): l 20.7 (C3), 24.5 (q, C-C1%),
32.6 (C4), 51.0 (C2), 55.7 (C1%), 62.8 (C1), 120.35 (CN)
[12 arom. C: 127.4, (2C), 127.5 (s, 1C), 127.6 (2C),
127.7 (s), 128.3 (2C), 128.5 (2C), 137.9 (s), 144.3 (s)];
MS (70 ev) m/z (%): no peak parent, 250 (1) (M+−CN),
105 (100), 124 (25), 79 (18), 77 (24); HRMS m/z:
276.1613 (calcd for C19H20N2: 276.1626). Anal. calcd
for C19H20N2: C, 82.57; H, 7.29; N, 10.14. Found: C,
82.19; H, 7.41; N, 9.94%.
J=6.4 Hz, 3H), 1.01 (d, J=6.4 Hz, 3H), 1.62–1.84 (m,
1H), 1.90 (dq, J=6.4 Hz, J=7.3 Hz, 1H, CH-(Me)2),
1.99–2.20 (m, 1H), 2.75–2.97 (m, 2H-C4), 2.97–3.18 (m,
1H-C2); 13C NMR (CDCl3): l 14.6 (C3), 19.9 (CH3),
20.3 (CH3), 28.9 (CHisopropyl), 44.2 (C4), 67.4 (C2), 212.1
(C1).
4.3. General procedure A: aminonitriles formation by
modified Strecker reaction
To a solution of alkylcyclobutanone 3.a–c (3 mmol), in

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M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
4.3.2.2. Data for (1R,2R,1%S)-2C.b major cis isomer.
J=8.1 Hz, 1H), 6.93–7.05 (m, 2H), 7.17–7.47 (m, 8H);
13C NMR (CDCl3): l 20.5 (C3), 31.8 (C4), 51.0 (C2),
61.3 (C1%), 61.9 (C1), 66.5 (CH2-O), 120.2 (CN) [12
arom. C: 127.5, (3C), 127.6 (3C), 128.2 (2C), 128.6
(2C), 137.9, 140.2].
[h]2D0=−85.5 (c 1, CHCl3); Rf=0.40 (ether/pentane: 25/
75); IR (neat): w 3420 and 3300 cm−1 (NH), 2220 (CN);
1H NMR (CDCl3): l 1.38 (d, J=6.7 Hz, 3H), 1.68–2.00
(br s, NH), 2.10–2.50 (m, 3H), 2.50–2.68 (m, 1H),
3.48–3.52 (m, 1H), 4.05 (q, J=6.7 Hz, 1H), 7.00–7.60
(m, 10H); 13C NMR (CDCl3): l 20.9 (C3), 24.1, 33.5
(C4), 50.7 (C2), 55.7 (C1%), 62.0 (C1), 120.1 (CN) [12
arom. C: 126.7, (2C), 127.4, 127.6 (2C), 128.3 (2C),
128.5 (2C), 137.1 (s), 145.1 (s)]; MS (70 ev) m/z (%): no
peak parent, 250 (1) (M+−CN), 105 (100), 124 (24), 79
(19), 77 (25); HRMS m/z: 276.1615 (calcd for
C19H20N2: 276.1626).
4.3.3.3. Data for (1R,2S,1%R)-2B.b% (or (1S,2R,1%R)-
2D.b%) minor isomer. Rf=0.51 (EtOAc/petrol ether: 3/7);
1H NMR (CDCl3): l 1.20-1.42 (m, 1H), 1.42–1.98 (m,
3H, 1Hcycle, NH and OH), 1.98–2.22 (m, 1Hcycle), 2.43–
2.70 (m, 1Hcycle), 3.37 (dd, JAB=11.0 Hz, J=8.7 Hz,
1H-C2%), 3.64 (dd, JAB=11.0 Hz, J=4.3 Hz, 1H-C2%),
3.95 (dd, J=8.7 Hz, J=4.5 Hz, H-C1%), 3.97-4.10 (m,
1H, C2), 7.18–7.70 (m, 10H).
4.3.2.3. Data for (1R,2S,1%S)-2B.b (or (1S,2R,1%S)-
1
2D.b) minor isomer. Rf=0.62 (ether/pentane: 25/75); H
NMR (CDCl3): l 1.04 (d, J=6.7 Hz, 3H), 1.20–1.60
(m, 3H, 2Hcycle and NH), 1.90–2.10 (m, 1Hcycle), 2.14–
2.41 (m, 1Hcycle), 3.70 (q, J=6.7 Hz, 1H), 3.99 (dd,
J=8.5 Hz, J=10.7 Hz, 1H-C2), 7.10–7.64 (m, 10H).
4.3.4.
(1S*,2S*,1%R)-1-[(1%-Methoxymethylbenzyl)-
(1S,2S,1%R)-
amino]-2-phenylcyclobutanecarbonitrile:
2A.b% and (1R,2R,1%R)-2C.b%. Following procedure A:
From 2-phenylcyclobutanone 3b (219 mg, 1.5 mmol),
DMSO (3 mL), (R)-a-methoxymethylbenzylamine 6b%
(616 mg, 3 mmol), AcOH (240 mL) and NaCN (150 mg)
heated at 55–60°C for 4 days, we obtained after flash
chromatography (twice, eluent, ether/pentane: 10“
15%) 106 mg (23%) of major nitrile 2A.b%, 86 mg
(18.7%) of major nitrile 2C.b%, and 11 mg (2.5%) of a
mixture of nitriles: (1R,2S,1%R)-2B.b% and (1S,2R,1%R)-
2D.b¦.
4.3.2.4. Data for (1S,2R,1%S)-2D.b (or (1R,2S,1%S)-
1
2B.b) minor isomer. Rf=0.56 (ether/pentane: 25/75); H
NMR (CDCl3): l 1.15 (d, J=6.7 Hz, 3H), 1.25–1.70
(m, 3H, 2Hcycle and NH), 2.05–2.29 (m, 1Hcycle), 2.30–
2.60 (m, 1Hcycle), 3.73 (q, J=6.7 Hz, 1H), 3.95–4.12 (m,
1H-C2), 6.95–7.60 (m, 10H).
4.3.3.
(1S*,2S*,1%R)-1-[(1%-Hydroxymethylbenzyl)-
(1S,2S,1%S)-
amino]-2-phenylcyclobutanecarbonitrile:
4.3.4.1. Data for (1S,2S,1%R)-2A.b¦ major cis isomer.
[h]2D0=−124.1 (c 1, CHCl3); mp 114.4°C; Rf=0.38
(Et2O/pentane: 25/75); IR (neat): w 3290 cm−1 (NH),
2A.b% and (1R,2R,1%S)-2C.b%. Following procedure A:
From 2-phenylcyclobutanone 3b (292 mg), DMSO (4
mL), (R)-a-hydroxymethylbenzylamine 6b% (548 mg),
AcOH (360 mL) and NaCN (196 mg) heated at 55–60°C
for 4 days, were obtained after flash chromatography
(twice, eluent, EtOAc/petrol ether: 25“75%) 134 mg
(23%) of major nitrile 2A.b%, 107 mg (18.3%) of major
2C.b%, and 7 mg (1.3%) of a mixture of nitriles 2B.b% and
2D.b%.
1
2230 (CN); H NMR (CDCl3): l 1.58–1.73 (m, 2Hcycle),
1.95–2.15 (m, 1Hcycle), 2.15–2.40 (m, 1Hcycle), 2.70 (br s,
NH), 3.38 (s, 3H, CH3-O), 3.41 (dd, JAB=9.7 Hz,
J=3.8 Hz, 1H-C2%), 3.55 (dd, JAB=9.7 Hz, J=9.7 Hz,
1H-C2%), 3.63 (dd, J=8.7 Hz, J=11.3 Hz, 1H-C2), 4.18
(dd, J=3.8 Hz, J=9.7 Hz, 1H, CH-N), 7.20–7.55 (m,
10H); 13C NMR (CDCl3): l 20.8 (C3), 32.5 (C4), 50.6
(C2), 58.4 (C1%), 59.4 (CH3-O), 62.6 (C1), 76.4 (CH2-O),
120.1 (CꢁN) [12 arom. C: 127.5, (2C), 127.6, 128.1,
128.3 (4C), 128.5 (2C), 138.0, 139.4]; MS (70 ev) m/z
(%): no peak parent, 280 (1.2) (M+−CN), 157 (44), 135
(93), 105 (34), 104 (40), 103 (100), 91 (85), 77 (44);
ES+MS m/z: 329.0 [M+Na]+; HR ES+MS m/z:
329.1634 (calcd mass for C20H22NaN2O: 329.1630).
4.3.3.1. Data for (1S,2S,1%R)-2A.b% major cis isomer.
[h]2D0=−127.3 (c 1, CHCl3); mp 77.7°C; Rf=0.32
(EtOAc/petrol ether: 3/7); IR (neat): w 3445 and 3313
1
cm−1 (OH and NH), 2222 (CN); H NMR (CDCl3): l
1.63–1.87 (m, 2Hcycle), 1.98–2.17 (m, 1Hcycle), 2.17–2.40
(m, 1Hcycle), 2.30–2.70 (br s, 2H, NH and OH), 3.54–
3.80 (m, 3H, CH2-O, and 1Hcycle), 4.05 (dd, J=9.0 Hz,
J=4.5 Hz, 1H, CH-N), 7.20–7.57 (m, 10H); 13C NMR
(CDCl3): l 20.6 (C3), 32.7 (C4), 50.8 (C2), 62.1 (C1%),
62.6 (C1), 66.6 (CH2-O), 120.2 (CN) [12 arom. C: 127.5,
(2C), 127.7, 128.0 (2C), 128.1, 128.45 (2C), 128.5 (2C),
137.9, 139.6]; MS (70 ev) m/z (%): no peak parent, 266
(1) (M+−CN), 237 (32), 161 (91), 120 (50), 118 (80), 117
(35), 104 (67), 103 (69), 91 (100), 92 (56), 90 (32);
ES+MS m/z: 315.0 [M+Na]+; HR ES+MS m/z:
315.1471 (calcd mass for C19H20NaN2O: 315.1473).
4.3.4.2. Data for (1R,2R,1%R)-2C.b¦ major cis isomer.
[h]D=−90 (c 0.40, CHCl3); Rf=0.30 (Et2O/pentane:
1
25/75); IR (neat): w 3325 cm−1 (NH), 2230 (CN); H
NMR (CDCl3): l 2.15–2.43 (m, 3Hcycle), 2.43–2.65 (m,
1Hcycle), 2.72 (br s, 1H, NH), 3.39 (s, 3H, CH3-O),
3.30–3.60 (m, 3H, CH2-O and 1H-C2), 4.05 (dd, J=5.9
Hz, J=7.4 Hz, 1H, CH-N), 6.83–6.98 (m, 2H), 7.14–
7.26 (m, 3H), 7.26–7.54 (m, 5H); 13C NMR (CDCl3): l
20.7 (C3), 32.0 (C4), 50.6 (C2), 58.6 (CH3-O), 59.0 (C1%),
62.0 (C1), 76.8 (CH2-O), 120.3 (CꢁN) [12 arom. C:
127.2, 127.6 (2C), 127.8 (3C), 128.1 (2C), 128.5 (2C),
138.2, 140.5]; MS (70 ev) m/z (%): no peak parent, 279
(1.6) (M+−HCN), 157 (38), 135 (50), 106 (35), 105 (35),
104 (43), 103 (76), 91 (100), 77 (45); ES+MS m/z: 329.0
[M+Na]+.
4.3.3.2. Data for (1R,2R,1%R)-2C.b% major cis isomer.
[h]2D0=−96.4 (c 1.27, CHCl3); Rf=0.22 (EtOAc/petrol
ether: 3/7); IR (neat): w 3435 and 3315 cm−1 (OH and
1
NH), 2230 (CN); H NMR (CDCl3): l 2.16–2.43 (m,
5H, 3Hcycle and NH, OH), 2.44–2.68 (m, 1Hcycle), 3.43–
3.61 (m, 2H), 3.61–3.78 (m, 1H), 3.93 (dd, J=4.5 Hz,

M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
1069
4.3.4.3. Data for (1R,2S,1%R)-2B.b¦ and (1S,2R,1%R)-
2D.b¦) minor trans isomers. (Data obtained from mix-
onto crushed ice (10 g), and was slowly basified with
concentrated ammonia. The mixture extracted with
EtOAc (4×50 mL), dried over MgSO4 then concen-
trated to give, after flash chromatography (silica gel, 30
g, eluent, EtOAc/petrol ether), the title amide 8A.a–c4.
1
ture): H NMR (CDCl3): l 1.15–1.70 (m, 1H, B/D),
1.71–1.94 (m, 2H, D), 1.94–2.21 (m, 2H, B), 2.44–2.72
(m, 1H, B/D), 3.23 (s, 3H, B), 3.34 (s, 3H, D), 3.20–3.60
(m, 2H, B/D), 4.04 (dd, J=10.0 Hz, J=8.0 Hz, 1H-C2,
B), 4.13 (dd, J=4.8 Hz, J=8.8 Hz, 1H, 1H-C1%, B),
4.05–4.30 (m, 2H, H-C2 and H-C1%, D), 7.20–7.60 (10H,
B/D).
4.4.1. (1%S)-1-[(1%-Methylbenzyl)amino]cyclobutanecar-
boxamide, 8A.a-c. According to general procedure B:
From nitrile 2.a (220 mg, 1.1 mmol), concentrated
H2SO4 (1.5 mL), and stirring at rt for 4 h gave after FC
(eluent, EtOAc/petrol ether: 4/6“6/4) 216 mg (90%) of
pure amide 8A.a. [h]2D0=−16.0 [h]365=65.8 (c 1, CHCl3);
Rf=0.45 (EtOAc); IR (neat): w 3420 and 3300 cm−1
(NH), 1670 (CON); 1H NMR (CDCl3): l 1.34 (d,
J=6.7 Hz, 3H), 1.60–2.10 (m, 4Hcycle and NH), 2.35–
2.67 (m, 2Hcycle), 3.82 (q, J=6.7 Hz, 1H), 5.29 (br s,
1Hamide), 6.80 (br s, 1Hamide), 7.12–7.45 (m, 5H); 13C
NMR (CDCl3): l 14.5 (C3), 24.2 (C-C1%), 30.2 (C4), 34.1
(C2), 54.5 (C1%), 63.0 (C1) [6 arom. C: 126.3 (2C), 126.9,
128.3 (2C), 146.0], 179.4 (CON); MS (70 ev) m/z (%):
218 (0.5) (M+), 190 (28), 174 (18), 105 (100), 104 (21),
70 (32); HRMS m/z: 218.1412 (calcd for C13H18N2O:
218.1419)
4.3.5. (1S*,2S*,1%S)-1-[(1%-Methylbenzyl)amino]-2-iso-
propylcyclobutanecarbonitrile: (1S,2S,1%S)-2A.c and
(1R,2R,1%S)-2C.c. According to procedure A: From
2-isopropylcyclobutanone 3c (336 mg, 3 mmol), DMSO
(6 mL), (S)-a-phenylethylamine 6a (700 mL, 6 mmol),
AcOH (540 mL, 9 mmol) and NaCN (300 mg, 6 mmol).
After heating 55–60°C for 4 days and flash chromatog-
raphy (twice, eluent, ether/CH2Cl2, 3/7) we isolated 1.87
mg (56%) of major nitrile cis-2A.c, 140 mg (52%) of
major nitrile cis-2C.c, and 6.5 mg (2%) of a mixture of
nitriles 2B.c and 2D.c. The separation of these two
major products is better after transformation into their
amides 8A.c and 8C.c.
4.3.5.1. Data for (1S,2S,1%R)-2A.c major cis isomer.
[h]2D0=−100 (c 1, CHCl3); mp 66.2°C; Rf=0.63 (MeOH/
pentane: 2/98); IR (neat): w 3330 cm−1 (NH), 2215
4.4.2. (1S,2S,1%S)-1-[(1%-Methylbenzyl)amino]-2-phenyl-
cyclobutanecarboxamide, 8A.b. According to procedure
B: From nitrile 2A.b (120 mg, 0.43 mmol), CH2Cl2 (4
mL), concentrated H2SO4 (1 mL) reacted for 8 h at rt,
we isolated after FC (eluent, EtOAc/petrol ether: 3/7)
88 mg (70%) of pure amide 8A.b. [h]2D0=+29.0 (c 1,
CHCl3); mp 175.0°C; Rf=0.20 (EtOAc/petrol ether:
3/7); IR (neat): w 3500, 3380 and 3280 cm−1 (NH), 1670
1
(CN); H NMR (CDCl3): l 0.82 (d, J=6.0 Hz, 3H),
1.00 (d, J=6.0 Hz, 3H), 1.21–1.57 (m, 3H), 1.41 (d,
J=6.8 Hz, 3H, CH3-C1), 1.65–2.02 (m, 3H and NH),
4.13 (q, J=6.8 Hz, 1H-C1%), 7.21–7.44 (m, 5H); 13C
NMR (CDCl3): l 19.1 (C3), 20.5 (CH3,isopropyl), 21.2
(CH3,isopropyl), 24.7 (CH3-C1%), 31.9 (CH-C2), 31.95 (C4),
53.1 (C1%), 55.6 (C2), 59.5 (C1), 121.1 (CN) [6 arom. C:
127.3 (3C), 128.2 (2C), 144.4]; MS (70 ev) m/z (%): 242
(0.4) (M+), 199 (14), 106 (11), 105 (100), 79 (11), 77
(15); HRMS m/z: 242.1784 (calcd for C16H22N2:
242.1783).
1
(CON); H NMR (CDCl3): l 1.32 (d, J=6.7 Hz, 3H),
1.40–1.68 (m, 1Hcycle), 1.75–2.20 (m, 2H, 1Hcycle and
NH), 2.26–2.57 (m, 2H), 3.38 (dd, J=9.4 Hz, J=9.5
Hz, 1H), 3.88 (q, J=6.7 Hz, 1H, CH-CH3), 4.93 (br s,
1Hamide), 6.55 (br s, 1Hamide), 7.10–7.45 (m, 10H); 13C
NMR (CDCl3): l 19.4 (d, C4), 24.0 (CH3-C1%), 27.5 (t,
C5), 54.3 (C1%), 55.1 (C2), 70.4 (C1) [12 arom. C: 126.5
(2C), 126.9, 127.3, 127.8 (2C), 128.1 (2C), 128.6 (2C),
138.7, 146.4], 175.5 (CON); ES+MS m/z: 295.1 [M+H]+;
HR ES+MS m/z: 317.1630 (calcd mass for
C19H22NaN2O: 317.1630).
4.3.5.2. Data for (1R,2R,1%R)-2C.c major cis isomer.
[h]2D0=−60.3 (c 1, CHCl3); Rf=0.57 (MeOH/pentane:
1
2/98); tR=14.88 min (Cydex B, 155°C/1 bar); H NMR
(CDCl3): l 0.79 (d, J=6.0 Hz, 3H), 0.90 (d, J=6.0 Hz,
3H), 1.36 (d, J=6.7 Hz, CH3-C1%), 1.58–1.81 (m, 1H
and NH), 1.82–2.23 (m, 4H), 2.45 (dd, J=9.5 Hz,
J=7.9 Hz, 1H–C2), 4.15 (q, J=6.7 Hz, 1H-C1%), 7.21–
7.48 (m, 5H); 13C NMR (CDCl3): l 19.1 (C3), 20.4
(CH3,isopropyl), 21.0 (CH3,isopropyl), 23.5 (CH3-C1), 31.2
(CH-C2), 33.5 (C4), 53.1 (C1%), 55.6 (C2), 58.6 (C1),
120.5 (CN) [6 arom. C: 126.6 (2C), 127.4, 128.5 (2C),
145.0]; MS (70 ev) m/z (%): 242 (0.5) (M+), 199 (11),
106 (11), 105 (100), 77 (14);); HRMS m/z: 242.1784
(calcd for C16H22N2: 242.1783).
4.4.3.
(1S,2S,1%S)-1-[(1%-Methylbenzyl)amino]-2-iso-
propylcyclobutanecarboxamide, 8A.c. According to gen-
eral procedure B: From nitrile 2A.c (122 mg, 0.5
mmol), CH2Cl2 (4 mL), H2SO4 (1.5 mL) stirring at rt
for 8 h, we isolated after FC (eluent, EtOAc/CH2Cl2:
5“20%), 110 mg (85%) of pure amide 8A.c.
[h]2D0=+29.5 (c 0.85, CHCl3); Rf=0.58 (EtOAc/CH2Cl2:
3/7); tR=62.63 min (Cydex B, 155°C/1 bar); IR (neat):
1
w 3445 and 3322 cm−1 (NH), 1676 (CON); H NMR
4.4. General procedure B of amide formation from
nitrile
(CDCl3): l 0.72 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.3 Hz,
3H), 1.27 (d, J=6.7 Hz, CH3-C1%), 1.47–1.97 (m, 5Hcycle
and NH), 2.18–2.35 (m, 1Hcycle), 3.90 (q, J=6.7 Hz,
1H-C1%), 5.70 (br s, 1Hamide), 7.10–7.37 (m, 5H), 7.42 (br
s, 1Hamide); 13C NMR (CDCl3): l 19.4 (C3), 20.6
(CH3,isopropyl), 22.4 (CH3,isopropyl), 24.0 (CH3-C1%), 26.4
(CH-C2), 30.0 (C4), 54.9 (C1%), 57.7 (C2), 67.3 (C1) [6
arom. C: 126.3 (2C), 127.1, 128.5 (2C), 146.6], 178.1
(CON); MS (70 ev) m/z (%): 260 (1) (M+), 190 (61), 175
A solution of nitrile 2A.a–c or 2C.a–c (3 mmol), in
CH2Cl2 (12 mL) was cooled to 0°C and concentrated
sulphuric acid (5 mL) was added very slowly with
efficient stirring. The reaction mixture was allowed to
warm to rt and stirred for 5 h. The aqueous layer was
separated, washed with CH2Cl2 (2 mL), then poured

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M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
1
(17), 145 (30), 105 (100), 77 (15); HRMS m/z: 260.1885
and 3294 cm−1 (NH), 1668 (CON); H NMR (CDCl3):
(calcd for C16H24N2O: 260.1888).
l 0.77 (d, J=6.2 Hz, 3H), 0.90 (d, J=6.2 Hz, 3H),
1.53–2.05 (m, 5H and NH2), 2.40–2.70 (m, 1H), 5.56 (br
s, 1Hamide), 7.24 (br s, 1Hamide); 13C NMR (CDCl3): l
19.7 (CH3,isopropyl), 20.0 (C3), 21.1 (CH3,isopropyl), 30.0
(CHisopropyl), 33.8 (C4), 58.2 (C2), 62.3 (C1), 178.0
(CON);); MS (70 ev) m/z (%): 157 (1.8) [M++1], 156 (5)
[M+], 111 (11), 96 (10), 86 (100), 83 (16); ES+MS m/z:
157.1 [M+H]+; HR ES+MS m/z: 179.1158 (calcd mass
for C8H16NaN2O: 179.1160).
4.4.4.
(1R,2R,1%S)-1-[(1%-Methylbenzyl)amino]-2-iso-
propylcyclobutanecarboxamide, 8C.c. According to gen-
eral procedure B: From amino nitrile 2C.c (120 mg, 0.5
mmol), H2SO4 (1 mL), CH2Cl2, (4 mL) stirring at rt for
8 h, we isolated after FC (eluent, EtOAc/CH2Cl2: 5“
20%), 111 mg (85%) of pure amide 8C.c. [h]2D0=−119.5
(c 0.9, CHCl3); Rf=0.64 (EtOAc/CH2Cl2: 3/7); tR=
55.77 min (Cydex B, 155°C/1 bar); IR (neat): w 3445
and 3322 cm−1 (NH), 1676 (CON); H NMR (CDCl3):
4.5.3. (1R,2R)-1-Amino-2-isopropylcyclobutanecarbox-
amide, 9C.c. According to procedure C: Amide 8C.c
(104 mg, 0.40 mmol), AcOH/EtOH (2 mL/2 mL), 20%
Pd(OH)2/C (70 mg) stirring at rt for 4 h, gave after FC
(eluent, MeOH/EtOAc: 1/9), 59 mg (:95%) of pure
free amino amide 9C.c. [h]2D0=−39.5 (c 0.7, CHCl3); mp
44.9°C; Rf=0.20 (MeOH/EtOAc: 1/9); IR (neat): w
3445 and 3294 cm−1 (NH), 1668 (CON); 1H NMR
(CDCl3): l 0.77 (d, J=6.2 Hz, 3H), 0.90 (d, J=6.2 Hz,
3H), 1.56–2.10 (m, 5H and NH2), 2.42–2.65 (m, 1H),
5.56 (br s, 1Hamide), 7.24 (br s, 1Hamide); 13C NMR
1
l 0.75 (d, J=6.2 Hz, 3H), 0.91 (d, J=6.2 Hz, 3H), 1.41
(d, J=6.6 Hz, CH3-C1%), 1.48–2.00 (m, 5Hcycle and NH),
2.51–2.68 (m, 1Hcycle), 3.77 (q, J=6.6 Hz, 1H-C1%), 5.10
(br s, 1Hamide), 6.60 (br s, 1Hamide), 7.15–7.38 (m, 5H);
13C NMR (CDCl3): l 19.5 (C3), 20.4 (CH3,isopropyl), 22.2
(CH3,isopropyl), 26.2 (CH3-C1%), 28.3 (CH-C2), 29.9 (C4),
54.2 (C1%), 57.5 (C2), 67.9 (C1) [6 arom. C: 126.3 (2C),
126.8, 128.4 (2C), 146.3], 176.7 (CON); MS (70 ev) m/z
(%): 232 (2) (M+−28), 190 (55), 175 (19), 145 (32), 105
(100), 77 (18); HRMS m/z: 260.1885 (calcd for
C16H24N2O: 260.1888).
(CDCl3):
l
19.7 (CH3,isopropyl), 20.0 (C3), 21.1
(CH3,isopropyl), 30.0 (CHisopropyl), 33.8 (C4), 58.2 (C2),
62.3 (C1), 178.0 (CON);); MS (70 ev) m/z (%): 157 (1.5)
[M++1], 156 (5) [M+], 111 (12), 96 (10), 86 (100), 83
(17); HRMS m/z: 179.1159 (calcd for C8H16NaN2O:
179.1160).
4.5. Procedure C: hydrogenolysis of benzylic amine
Amino amide adduct 8.a–c (1.00 mmol) obtained as
described above, was dissolved in a mixture of AcOH/
EtOH (3 mL/3 mL), and 20% Pd(OH)2/C (Pearlman’s
catalyst, 120 mg) was added. The flask was connected
to a hydrogenation apparatus equipped with a gradu-
ated burette containing water that allowed the uptake
of hydrogen to be monitored. TLC control showed that
under 1 atm H2 at rt the reaction was complete within
3 h. The mixture was then degassed under a stream of
argon, filtered through Celite, and the collected solid
was washed with EtOH (3×10 mL). The combined
filtrate and washings were concentrated and the residue
was subjected to FC (eluent, MeOH/CH2Cl2: 5“20%)
to afford pure free amino amides 9.a–c.
4.6. General procedure D: aminocarboxylic acid
formation
A mixture of amide 9X.a–c (0.50 mmol) and 6N HCl (4
mL) was heated to gentle reflux. The reaction was
complete within 20 h as shown by TLC. The solution
reaction was cooled to rt, and extracted with ether (5
mL) to remove coloured ether soluble material. The
hydrochloric acid was evaporated to dryness under
reduced pressure to give amino acids 1.(a–c)·HCl as a
white solid. Recrystallisation from MeOH–ether fur-
nished pure crystalline amino acid·hydrochloride with
excellent yield.
4.5.1. 1-Aminocyclobutanecarboxamide, 9.a. According
to procedure C: From amide 8.a (166 mg, 0.76 mmol),
(AcOH/EtOH: 2 mL/2 mL), and 20% Pd(OH)2/C (80
mg) stirring at rt for 3 h, gave after FC, 73 mg (84%) of
pure amino amide 9.a. Rf=0.18 (MeOH/CH2Cl2: 1/4);
tR=3.73 min (Cydex B, 140°C/1 bar); mp 81.9°C; IR
To the amino acid salt were added EtOH (2 mL) and
propylene oxide (1 mL). The mixture was stirred at rt
for 5 h. After complete precipitation the organic sol-
vents were removed under reduced pressure to furnish a
solid residue. The latter was dissolved in distilled water
then filtered through cotton, to give a clean solution,
which was concentrated under reduced pressure leading
to pure amino acids 1.(a–c) with excellent yield.
(neat): w 3420 and 3340 cm−1 (NH), 1680 (CON); H
1
NMR (CDCl3): l 1.75 (s, 2H, NH2), 1.70–2.10 (m, 4H),
2.60–2.78 (m, 2H), 5.76 (br s, 1Hamide), 7.07 (br s,
1Hamide); 13C NMR (CDCl3): l 13.9 (C3), 34.8 (C2 and
C4), 58.7 (C1), 179.5 (CON); MS (70 ev) m/z (%): 114
(0.5) (M+), 86 (44), 70 (21), 42 (100), 41 (21); HRMS
m/z: 114.0797 (calcd for C5H10N2O: 114.0793).
4.6.1. 1-Aminocyclobutanecarboxylic acid hydrochloride
salt, 1a·HCl. Following procedure D: Amino amide 9a
(57 mg, 0.50 mmol), 6N HCl (4 mL), 20 h at reflux,
gave after recrystallisation 71 mg (90%) as a white solid
of pure 1a·HCl. Mp 225–226°C (dec.); IR (KBr): w 3411
4.5.2. (1S,2S)-1-Amino-2-isopropylcyclobutanecarbox-
amide, 9A.c. According to procedure C: Amino amide
8A.c (130 mg, 0.50 mmol), AcOH/EtOH (2 mL/2 mL),
20% Pd(OH)2/C (80 mg) stirring at rt for 4 h, gave after
FC (eluent, MeOH/EtOAc: 5“10%) 76.5 mg (98%) of
pure free amino amide 9A.c. [h]2D0=+41 (c 0.68,
CHCl3); mp 45.0°C; Rf=0.20 (MeOH/EtOAc: 1/9);
tR=6.47 min (Cydex B, 140°C/1 bar); IR (neat): w 3445
1
cm−1 3024, 1729 (COO), 1592; H NMR (D2O, HOD,
4.6 ppm): l 1.99 (s, 4H, NH3 and Hacid), 1.80–2.00 (m,
2H), 2.11–2.30 (m, 2H), 2.33–2.56 (m, 2H); lit.19 for
acid 1a: mp 295–296 °C (dec.); 1H NMR (D2O): l
1.86–1.97 (m, 2H), 2.07–2.17 (m, 2H), 2.32–2.42 (m,
2H); 13C NMR (D2O): l 15.58, 30.96, 60.32, 178.61.

M. Truong et al. / Tetrahedron: Asymmetry 14 (2003) 1063–1072
1071
4.6.2.
(1S,2S)-1-Amino-2-isopropylcyclobutanecar-
(d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H), 1.26 (br s,
NH), 1.62–1.90 (m, 1Hisopropyl), 1.65–1.90 (m, 1Hcycle),
2.13 (m, 1Hcycle), 2.42–2.69 (m, 1H-C2), 2.45–2.69 (m,
2Hcycle), 3.47 (d, J=1.6 Hz, 3H, OMe), 5.80 (br s,
1Hamide), 5.90 (br s, 1Hamide), 7.35–7.67 (m, 5H); 13C
NMR (CDCl3): l 19.2 (C3), 20.9 (CH3,isopropyl), 21.2
(CH3,isopropyl), 28.0 (CH-C2), 30.1 (C4), 52.1 (C2), 55.1
(OCH3), 62.8 (C1), 83.9 (d, J=26.2 Hz, C2%), 123.7 (d,
J=289.7 Hz, CF3) [6 arom. C: 127.5 (2C), 128.7 (2C),
129.6, 132.3], 165.8 (C1%), 173.6 (CONH2).
boxylic acid, 1A.c. Following procedure D: Amino
amide (1S,2S)-9A.c (31.2 mg, 0.20 mmol), 6N HCl (3
mL), 20 h at reflux, gave 36.4 mg (94%) as a white solid
of pure (1S,2S)-1A.c·HCl.
4.6.2.1. Data for (1S,2S)-1A.c·HCl. [h]2D0=+42 (c
0.75, H2O); Rf=0.52 (MeOH); mp 197–199°C (dec.);
IR (KBr): w 3401 cm−1 1720 (COO), 1592, 1496, 1404;
1H NMR (D2O, HOD: 4.63 ppm): l 0.58 (d, J=6.8 Hz,
3H), 0.62 (d, J=6.8 Hz, 3H), 1.39–1.60 (m, 1H,
CHisopropyl), 1.60–1.80 (m, 1Hcycle), 1.80–2.07 (m,
2Hcycle), 2.07–2.37 (m, 2Hcycle); 13C NMR (D2O, with
4.7.2.
(1S,2S,2%S)-2-Isopropyl-1-(3%,3%,3%-trifluoro-2%-
(S)-
phenylpropionylamino)cyclobutanecarboxamide
MTPA-9A.c, the (S)-MTPA-amide of (1S,2S)-9A.c.
Following the procedure described above: From
(1S,2S)-9A.c (6 mg, 0.040 mmol), (R)-(−)-Mosher’s
acid chloride (7.5 mL, 0.040 mmol), and propylene
oxide (14 mL, 0.200 mmol), 5 equiv.). After evaporation
of the solvent and subsequent FC (EtOAc/pentane: 8/2)
of the residue, the amide (S)-MTPA-9A.c (13 mg, 93%)
was obtained. [h]2D0=−47 (c 0.4, CHCl3); 1H NMR
(CDCl3): l 0.80 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.6 Hz,
3H), 1.26 (br s, NH), 1.79 (m, 1H-C3), 1.82 (m, CH-
C2), 2.07 (m, 1H-C3), 2.24 (m, 1H-C4), 2.41 (m, 1H-C4),
2.67 (ddd, J=2.5 Hz, J=9.4 Hz, J=11.6 Hz, 1H-C2),
3.43 (d, J=1.5 Hz, OCH3), 5.89 (br s, 1Hamide), 6.06 (br
s, 1Hamide), 7.32–7.67 (m, 5H); 13C NMR (CDCl3): l
19.2 (C3), 21.0 (CH3,isopropyl), 21.4 (CH3,isopropyl), 28.6
(CH-C2), 29.9 (C4), 52.5 (C2), 55.1 (OCH3), 62.7 (C1),
83.9 (d, J=26.2 Hz, C2%), 123.9 (d, J=290.2 Hz, CF3)
[6 arom. C: 127.6 (2C), 128.7 (2C), 129.6, 131.9], 165.6
(C1%), 173.6 (CONH2).
CDCl3 as internal reference):
(CH3,isopropyl), 20.5 (CH3,isopropyl), 26.2 (CHisopropyl), 29.9
(C4), 51.6 (C2), 61.0 (C1), 173.5 (COO).
l 18.5 (C3), 19.6
4.6.2.2. Data for (1S,2S)-1A.c. [h]2D0=+51.2 (c 0.51,
H2O); mp 199–202°C (dec.); IR (KBr): w 3390 cm−1
1
1727 (COO), 1453, 1399; H NMR (D2O, with HOD:
4.63 ppm): l 0.54 (d, J=6.5 Hz, 3H), 0.60 (d, J=6.5
Hz, 3H), 1.36–1.55 (m, 1H, CHisopropyl), 1.55–1.73 (m,
1Hcycle), 1.73–1.96 (m, 2Hcycle), 2.02 (dd, J=9.3 Hz,
J=9.3 Hz, 1Hcycle),), 2.15 (dd, J=9.3 Hz, J=8.7 Hz,
1Hcycle); 13C NMR (D2O, with CDCl3 as internal refer-
ence):
l
18.5 (C3), 19.9 (CH3,isopropyl), 20.7
(CH3,isopropyl), 26.2 (CHisopropyl), 30.1 (C4), 51.6 (C2),
62.3 (C1), 175.4 (COO); ES+MS m/z: 158.1 [M+H]+;
HR ES+MS m/z: calcd for C8H16NO2 [M+H+]:
158.1181. Found 158.1182.
4.6.3.
(1R,2R)-1-Amino-2-isopropylcyclobutanecar-
boxylic acid, 1C.c. Following procedure D: amino
amide (1R,2R)-9C.c (22 mg, 0.141 mmol), 6N HCl (3
mL), 22 h at reflux, gave 27 mg (98%) as a white solid
of pure (1R,2R)-1C.c·HCl.
References
1. (a) Hood, W. F.; Sun, E. T.; Compton, R. P.; Monahan,
J. B Eur. J. Pharmacol. 1989, 161, 281–282; (b) Watson,
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Danysz, W. J. Neural. Transm. 1999, 105, 1189–1204 and
references cited therein.
4.6.3.1. Data for (1R,2R)-1C.c·HCl. [h]2D0=−43 (c
0.65, H2O), [h]2D0=−44 (c 0.64, MeOH). All spectral
data are identical with those of the enantiomer (1S,2S).
4.6.3.2. Data for (1R,2R)-1C.c. [h]2D0=−51.7 (c 0.51,
H2O). All spectral data are identical with those of the
(1S,2S)-enantiomer.
4. (a) Malashkevich, V. N.; Strop, P.; Keller, J. W.; Janso-
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4.7. General procedure for the preparation of Mosher
amides of amino amide 9A.c
4.7.1.
(1S,2S,2%R)-2-Isopropyl-1-(3%,3%,3%-trifluoro-2%-
methoxy - 2% - phenylpropionylamino)cyclobutanecar-
boxamide [(R)-MTPA-9A.c] (R)-MTPA-amide of
(1S,2S)-9A.c. To a stirred suspension of 9A.c (6 mg,
0.040 mmol) in THF (1 mL) was added (S)-(+)-Mosh-
er’s acid chloride (7.5 mL, 0.040 mmol, 1 equiv.) and
propylene oxide (14 mL, 0.200 mmol, 5 equiv.). The
resulting mixture was heated to reflux for 4 h (T:
80°C), allowed to cool to room tempearture, and the
solvents were completely evaporated. FC (EtOAc/pen-
tane: 8/2) of the residue afforded 13 mg (:93%) of the
pure (R)-MTPA amide of 9A.c [(R)-MTPA-9A.c].
[h]2D0=+70.5 (c 0.6, CHCl3); mp 136.1°C; Rf=0.82
(MeOH/EtOAc: 1/9); IR (neat): w 3620–3352 cm−1
(NH), 1670 and 1600 (CON); 1H NMR (CDCl3): l 0.80

1072
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