Masked constrained cysteines: Diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

Article abstract of DOI:10.1016/S0957-4166(01)00466-9

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (-)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.

Full text of DOI:10.1016/S0957-4166(01)00466-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2663–2669
Masked constrained cysteines: diastereoselective and
enantioselective synthesis of
1-amino-2-mercaptocyclopropanecarboxylic acid derivatives
Francesca Clerici,a Maria Luisa Gelmi,a,* Donato Pocara and Tullio Pilatib
aIstituto di Chimica Organica,
Facolta` di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi Etero e Carbociclici,
Universita` di Milan, Via Venezian 21, I-20133 Milan, Italy
bCNR Centro Studio delle Relazioni tra Struttura e Reattivita` Chimica, via Golgi 19, I Milan, Italy
Received 7 September 2001; accepted 22 October 2001
Abstract—A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid
derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Com-
pounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were
transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large
class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and
subsequent alkylation reactions. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Clearly, diastereoselective and, most of all, enantiose-
lective syntheses are of general interest and our research
toward the syntheses of constrained cysteine derivatives
8,9 are proceeding in this direction. We now report the
diastereoselective and enantioselective synthesis of
(1R,2R)- and (1S,2S)-1-benzoylamino-2-tritylsulfanyl-
cyclopropanecarboxylic acid derivatives, which, as
underlined before, are interesting key starting materials.
For their preparation, new chiral aminoacrylate deriva-
tives 3 were prepared.
Recently,1 we reported the synthesis of a series of
1-amino-2-mercaptocyclopropanecarboxylic acid de-
rivatives having different substituents on the sulfur. We
found that the compound substituted at sulfur with a
trityl group could be used as the key starting material
for the preparation of a large number of the above
compounds in which an alkyl group is present.
In addition to their biological interest as single
molecules,2 new classes of cyclopropylamino acid
derivatives are worth synthetic effort due to the possi-
bility of using them in the synthesis of special peptides.3
The choice of cyclopropylamino acid derivatives is very
interesting owing to the possibility of making the pep-
tide skeleton stiff because of hindered rotation around
the CaꢀCb bond by the cyclopropyl ring. Furthermore,
when a b-substituent is present on the cyclopropyl ring,
the possibility of choosing the cis (b-substituent to
respect nitrogen atom) or trans stereoisomer allows the
evaluation of the substituent effect on the interaction
between the drug and the receptor site.
2. Results and discussion
The new chiral aminoacrylates 3a,b were obtained in
66–84%
yield
when
2-phenyl-4-(tritylsulfanyl-
methylene)-5(4H)-oxazolone 1 was reacted with (−)- or
(+)-menthol 2a,b, respectively, in a benzene solution
and in the presence of bis-(dibutylchlorotin)oxide as
catalyst5 (Scheme 1). The use of this catalyst is essential
for product formation because nucleophiles can react
both at the carbonyl group and at the double bond
when the starting oxazolone is functionalized at the
double bond with an heteroatom. When 1 was reacted
with the menthol under the classical basic or acidic
conditions, the reaction was not successful and a mix-
* Corresponding author. Tel.: +39-2-70630348; fax: +39-2-70638473;
e-mail: marialuisa.gelmi@unimi.it
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00466-9

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F. Clerici et al. / Tetrahedron: Asymmetry 12 (2001) 2663–2669
ture of compounds or the starting oxazolone was
obtained.
The structure of the enantiomeric acrylates 3 was deter-
mined by analytical and spectroscopic data. The 1H
NMR spectrum is characterized by a singlet at 7.93 l
(NH) and at 7.03 l associated with the olefinic proton.
The NOESY experiment evidenced the spatial proxim-
ity between the H-3 and the menthyl protons, thus
assuring the Z stereochemistry of the double bond.
Compound 3a was reacted in dichloromethane at room
temperature with an excess of diazomethane. Two
diastereoisomeric pyrazoline derivatives 4a and 5a were
1
detected by H NMR and HPLC in a 1:1.8 ratio and
were separated by column chromatography. During
this process partial isomerization of the D1-pyrazolines
4a,5a to D2-pyrazolines 6a,7a was observed. The overall
reaction yield was good (93%) and the D1/D2-pyrazoline
ratio is about 5.2:1 (Scheme 2).
Under the above reaction conditions, the diastereoiso-
meric pyrazoline derivatives 4b and 5b were obtained
Scheme 1.
Scheme 2.

F. Clerici et al. / Tetrahedron: Asymmetry 12 (2001) 2663–2669
2665
(2:1) when starting from the acrylate 3b. These com-
pounds also partially isomerized to the D2-pyrazolines
6b,7b during chromatography on silica gel, and com-
pounds 4–7b were obtained in 88% (D1/D2=5.7:1) over-
all yield (Scheme 2). The D1-pyrazolines 4a,5b, with
respect to compounds 5a,4b, isomerize slowly to the
corresponding D2-isomers.
Pyrazolines 4a and 5b showed identical 1H and 13C
NMR spectra. Furthermore, they are characterized by
the same absolute value of specific rotation (4a: +125.4;
5b: −125.4). On the basis of these results, we can
conclude that 4a and 5b are enantiomers. On the same
basis, the enantiomeric relationship between 5a and 4b
was established ([h]D=−202, +202 for 5a and 4b,
respectively).
Figure 1.
values observed in the ABX system confirms the
assigned regiochemistry.
These results are in agreement with the literature2a,4
data concerning the diazomethane addition reaction to
a-aminoacrylate derivatives. In fact, it has been
reported that the dipolar cycloaddition reaction usually
occurs under charge control giving a single regioisomer
for which the relationship between the two substituents
is maintained. In our case, the asymmetric induction of
the menthyl group is better in respect to other auxiliary
alcohols used for the esterification of aminoacrylate
derivatives.4b
1
The H NMR spectra of enantiomeric compounds 4a
and 5b showed the presence of a singlet at 8.35 l (NH),
a multiplet at 4.76–4.70 associated to the CHO of
menthyl group. An ABX system is present and the
chemical shift values at low fields (l=4.62, 3.97, 3.05;
J=18.9, 9.4, 6.8 Hz) are in good agreement with the
values expected for a pyrazoline structure.
The structure of the D2-pyrazolines 6b,7a was assigned
on the basis of their identical H NMR spectra, which
1
Analogous results were observed for the couple of
enantiomers 5a and 4b having 1H NMR spectra charac-
terized by a singlet at 8.22 l (NH), a multiplet at
4.65–4.54 l (CHO) and an ABX system at l=4.65,
4.07, 3.10 (J=19.0, 9.4, 6.2 Hz).
are characterized by the presence of signals associated
with the amidic proton (l=7.94), and with the NH
proton of the D2-pyrazolinyl ring (l=7.12) and by an
AX system (l=6.29, 3.99, J=1.4 Hz) associated with
H-3 and H-4. Analogous data were observed for enan-
tiomers 6a, 7b (l=8.05, NH; l=6.58, NH; l=6.14,
4.09, J=1.5 Hz, AX system).
Through a NOESY experiment on the pyrazoline
derivative 4a, positive Overhauser effects between H-4
(l=3.05) and H-5 (l=3.97) and between the latter and
H-5% (l=4.62) were observed. Analogously, in the case
of the diastereoisomeric compound 5a, spatial proxim-
ity was observed between H-4 (l=3.10) and H-5 (l=
4.07) and between the latter and H-5% (l=4.65). In both
diastereoisomeric compounds 4a and 5a the Overhauser
effect was not detected between H-4 and the proton
linked to the nitrogen atom (Fig. 1).
The transformation of pyrazoline derivatives 4 and 5
into the corresponding cyclopropane amino acid
derivatives was not possible in solution. In fact, these
compounds are stable from room temperature to
150°C. Instead, when melted at 150°C for 10 min, they
were readily transformed into cyclopropane derivatives.
Starting from pure 4a, cyclopropane 8a was isolated in
70% yield in diastereomerically pure form, as confirmed
1
These data confirm the assigned configuration which is
the same of the starting olefin 3. Furthermore, the J
by H NMR and HPLC. An acrylate derivative 10a, as
secondary product (17%), was also isolated. The same
Scheme 3.

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F. Clerici et al. / Tetrahedron: Asymmetry 12 (2001) 2663–2669
behavior was observed when starting from 5a, 4b and
5b. Cyclopropane derivatives 9a (82%), 8b (64%) and 9b
(72%) were obtained, respectively, as well as the acryl-
ate derivative 10a (13%) in the first case and its enan-
tiomer 10b (10–16%) in the other (Scheme 3).
the trityl and benzoylamino groups as in the starting
pyrazoline 4a. Accordingly, the S and R configuration
at C-3 and C-4 was assigned.
On the basis of the above analytical and spectroscopic
data, it was concluded that the contraction of the
pyrazoline ring into the cyclopropane is sterically con-
trolled and retention of configuration exists at C-a of
the amino acid derivatives. As a consequence of this
observation and on the basis of the experimental results
illustrated below (hydrolysis of compound 9a), the S,S
configuration was assigned to the stereoisomer 9a. Any
attempt to prepare suitable crystals for X-ray analysis
of this compound failed.
The structure of the enantiomers 8a/9b as well as the
enantiomers 8b/9a was demonstrated by spectroscopic
1
data. In the H NMR spectrum of compounds 8a/9b, a
singlet at 5.42 l (amidic proton) and a multiplet at
4.64–4.58 l (CHO) are present. The l values of the
ABX system (l=2.66, 2.21, 1.24; J=10.2, 7.4, 6.3 Hz)
are in agreement with the values reported for similar
cyclopropane compounds.1 Analogous results were
observed for the couple 8b/9a. Signals at 5.09 l (NH),
4.61–4.48 l (CHO) and l=2.73, 2.26, 1.25 (ABX sys-
tem, J=10.1, 7.5, 6.3 Hz) were observed.
The formation of by-products 10a,b can be explained as
an insertion olefin reaction typical for pyrazoline ring
decomposition (Scheme 4).
NOESY experiments were carried out on both 8a and
9a. A positive Overhauser effect was observed in com-
pound 8a between H-2 (l=2.66) and H-3 (l=2.21). In
contrast, the spatial proximity between H-2 and NH
was absent, thus confirming the assigned configuration.
The NOESY experiment on compound 9a revealed
spatial proximity for the latter mentioned protons also.
As a consequence of breaking the bond between the
pyrazoline nitrogen and the quaternary carbon, an
intermediate A is formed, which rearranges to the
acrylate derivatives 10 with formation of the double
bond and transposition of the S-trityl group to C-4 on
nitrogen elimination. The structure of compounds 10
1
was confirmed by spectroscopic data. In the H NMR
spectrum a doublet at l=3.12 and a triplet at l=6.82
associated with H-4 and H-3, respectively (J=7.7 Hz),
are present. A Hetcor reverse experiment allowed asso-
ciation of these protons to the corresponding carbons,
which values were in agreement with the proposed
structure (C-3: l=132.4; C-4: l=31.0). Finally, a
NOESY experiment allowed confirmation of the Z
geometry of the double bond because spatial proximity
was demonstrated between H-3 and the protons of the
menthyl group.
As demonstrated by X ray analysis of compound 8a
(Fig. 2), the absolute configuration of the two stereo-
centers is R confirming the cis relationship between
The behavior of the D1-pyrazolines was also tested
under ultraviolet light. The reaction was carried out
both in a dichloromethane solution and in acetone
starting from the pyrazoline 4a using a HPK-Philips
125 W high pressure Hg lamp. The reactions were
1
monitored by H NMR and by HPLC. After 3 h the
reaction was complete and the above analyses revealed
the formation of the cyclopropane derivative 8a and of
the acrylate 10a in a 1.5:1 ratio, when using CH2Cl2
and 1:1 ratio when using acetone. However, this proce-
dure was not considered convenient for the preparation
of compounds 8 and 9 considering the increase in the
amount of unwanted compound 10.
Figure 2. Projection of 8a with the crystallographic number-
ing scheme. Ellipsoids at 50% probability level. For clarity H
atoms of phenyl, CH2 and CH3 groups are omitted.
The hydrolysis of the ester function in compound 9a
was carried out in methanol in the presence of sodium
Scheme 4.

F. Clerici et al. / Tetrahedron: Asymmetry 12 (2001) 2663–2669
2667
hydroxide. The reaction gave the chiral acid 12, which
q=28.24°, 7752 independent, Rave=0.0229, 4771 with
Io>2|(Io). Data collection, reduction and cell determi-
nation were carried on by SMART and SAINT;6 no
absorption correction was applied. The structure was
solved by SIR927 and refined by SHELX97;8 non-H
atom were anisotropic, H atoms of methyl groups were
fixed in calculated positions; 543 parameters refined,
R1=0.0398 for Io>2|(Io) and 0.0679 for all data. Quite
unusually, the amino H atom does not show any rele-
vant intermolecular interaction, being screened off by
two phenyl rings.
1
was characterized by the same H NMR of the racemic
acid obtained when the known spiro compound 111 was
hydrolyzed in THF and in the presence of NaOH
(Scheme 5). This result confirms indirectly the cis rela-
tionship between nitrogen and sulfur atoms, and the
absolute configuration S was assigned at the two stereo-
centers in compound 9a.
The crystal structures have been deposited at the Cam-
bridge Crystallographic Data Centre and allocated the
deposition number 169988.
3.2. General procedure for the preparation of acrylates
3
Operating under nitrogen, compound 1 (805 mg, 1.8
mmol), menthol 2 (218 mg, 1.8 mmol) and (Et2SnCl)2O
(1.1 h, 1.98 mmol) were dissolved in anhydrous benzene
(20 mL). The mixture was heated at reflux for 48 h after
which time the solvent was evaporated. The crude
reaction mixture was crystallized giving pure compound
3. In the case of 3b a further crop was obtained by
mother liquor purification by flash column chromatog-
raphy (cyclohexane/AcOEt, 8:1; 3.5×10 cm, 20 mL/
min).
Scheme 5.
On the basis of the above results, we conclude that the
new chiral synthons 3 are useful key starting materials
for the preparation of amino acid derivatives 8/9 with
diastereoselective and enantioselective control. Even
though the ratio between the two pyrazolines 4/5 was
not very high (about 1:2), the complementary distribu-
tion of the latter compounds, when starting from 3a
(4a/5a, 1:1.8) or 3b (4b/5b, 2:1), the good yields and the
easy separation of the diastereoisomers and, most of
all, the possibility of transforming the pyrazolines 4/5
into the cyclopropane derivatives 8/9 in a stereocon-
trolled way, make this synthetic procedure satisfying.
3.2.1. (−)-Menthyl 2-benzoylamino-3-tritylsulfanylacryl-
ate (3a). Yield: 78%. [h]2D5=−88.6 (c 5.2×10−3, CHCl3).
3.2.2. (+)-Menthyl 2-benzoylamino-3- tritylsulfanylacryl-
ate (3b). Yield: 66%. [h]2D5=+88.6 (c 5.4×10−3, CHCl3).
3a,b: Mp 198°C (CH2Cl2/iPr2O). IR wmax 3315, 1700,
1
1650 cm−1; H NMR l 0.64–2.00 (m, 18H), 4.50–4.65
(m, 1H), 7.03 (s, 1H), 7.28–7.90 (m, 20H), 7.93 (s, 1H,
exch.); 13C NMR l 16.7–47.4, 70.3, 76.1, 121.2, 127.6–
144.6, 163.3, 164.8; anal. calcd: C, 77.58; H, 6.84; N,
2.32. Found: C, 77.50; H, 6.80; N, 2.28.
3. Experimental
Melting points were determined using an Electrother-
1
mal 9100 apparatus. H and 13C NMR spectra were
3.3. General procedure for the cycloaddition reaction
recorded in CDCl3 as the solvent with Bruker Avance
300 and Varian Gemini 200 instruments. Coupling con-
stants values (J) are given in hertz. HPLC using Hiper-
sil column (250×4.6 mm; CH2Cl2/AcOEt, 100: 2.5;
T=30°C; flow=1 mL/min, u=254). Ethanol-free
CH2Cl2 was used in all experiments. Oxazolone 1 and
spirooxazolone 11 are known compounds.1
The acrylate 3 (549 mg, 0.9 mmol) was dissolved in
anhydrous CH2Cl2 (10 mL). An ethereal solution of
diazomethane (15 mL, 0.25 M) was added at room
1
temperature over a period of 70 h. The H NMR and
HPLC analyses revealed the presence of a mixture of
compounds 4/5. Starting from 3a, the pyrazolines 4a
and 5a were detected in 1:1.8 ratio; starting from 3b,
the pyrazolines 4b and 5b were detected in 2:1 ratio.
The solvent was eliminated and the crude reaction
mixture was chromatographed by flash column chro-
matography (cyclohexane/AcOEt, 5:1; 2×20 cm, 10 mL/
min) giving four fractions containing, respectively, 4a
(170 mg, 28%), 5a (304 mg, 50%), 6a (29 mg, 5%) and
7a (58 mg, 10%) in 93% total yield, when starting from
3a. Pyrazolines 5b (152 mg, 25%), 4b (304 mg, 50%), 7b
(23 mg, 4%) and 6b (52 mg, 9%) where isolated in 88%
total yield, when starting from 3b.
3.1. X-Ray crystallographic analysis data for compound
8a
X-Ray data were collected on a Bruker SMART-CCD
area-detector diffractometer using graphite monochro-
,
mated Mo-Ka radiation (u=0.71073 A). Crystal data:
C40H43NO3S, M=617.81, monoclinic, P21, room tem-
,
perature, a=9.7905(11), b=9.1636(12), c=19.901(2) A,
i=102.453(2), V=1743.4(3) A , Z=2, Dx=1.177 Mg
3
,
m−3, v=0.130 mm−1, 15523 measured reflections below

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F. Clerici et al. / Tetrahedron: Asymmetry 12 (2001) 2663–2669
3.3.1. (−)-Menthyl (3S,4R)-3-benzoylamino-4-tritylsul-
fanyl-4,5-dihydro-3H-pyrazole-3-carboxylate 4a. [h]2D5=
+125.4 (c 5.03×10−3, CHCl3).
9b/10b, 6:1). The residue was crystallized affording pure
8 or 9. The mother liquors were chromatographed by
flash column chromatography (cyclohexane/AcOEt,
10:1; 1×10 cm, 6 mL/min) giving two fractions: the first
containing acrylate 10, the second compound 8 or 9.
3.3.2. (+)-Menthyl (3R,4S)-3-benzoylamino-4-tritylsul-
fanyl-4,5-dihydro-3H-pyrazole-3-carboxylate 5b. [h]2D5=
−125.4 (c 2.1×10−3, CHCl3).
3.4.1. (−)-Menthyl (1R,2R)-1-benzoylamino-2-tritylsul-
fanyl-cyclopropylcarboxylate 8a. [h]2D5=+152 (c 2.8×
10−3, CHCl3).
1
4a/5b: Oil. IR wmax 3400, 1731, 1670 cm−1; H NMR l
0.64–1.70 (m, 18H), 3.05, 3.97, 4.62 (ABX system,
J=18.9, 9.4, 6.8, 3H), 4.70–4.76 (m, 1H), 7.20–7.99 (m,
20H), 8.35 (s, 1H, exch.); 13C NMR l 14.5–47.3, 42.5,
68.6, 78.3, 88.1, 100.8, 127.3–144.8, 167.0, 168.0; anal.
calcd: C, 74.39; H, 6.71; N, 6.51. Found: C, 74.20; H,
6.63; N, 6.38.
3.4.2. (+)-Menthyl (1S,2S)-1-benzoylamino-2-tritylsul-
fanyl-cyclopropylcarboxylate 9b. [h]2D5=−152 (c 3.0×
10−3, CHCl3).
8a/9b: Mp 179°C (CH2Cl2/iPr2O). IR wmax 3400, 1740,
1
1670 cm−1; H NMR l 0.68–1.81 (m, 18H), 1.24, 2.21,
3.3.3. (−)-Menthyl (3R,4S)-3-benzoylamino-4-tritylsul-
fanyl-4,5-dihydro-3H-pyrazole-3-carboxylate 5a. [h]2D5=
−202 (c 4.8×10−3, CHCl3).
2.66, (ABX system, J 10.2, 7.4, 6.3, 3H), 4.58–4.64 (m,
1H), 5.42 (s, 1H, exch.), 7.24–7.51 (m, 20H); 13C NMR
l 16.3–47.0, 22.6, 29.9, 39.5, 66.9, 75.5, 127.2–144.4,
168.2, 169.5; anal. calcd: C, 77.76; H, 7.01; N, 2.27.
Found: C, 77.40; H, 7.13; N, 2.32.
3.3.4. (+)-Menthyl (3S,4R)-3-benzoylamino-4-tritylsul-
fanyl-4,5-dihydro-3H-pyrazole-3-carboxylate 4b. [h]2D5=
+202 (c 3.0×10−3, CHCl3).
3.4.3. (−)-Menthyl (1S,2S)-1-benzoylamino-2-tritylsul-
fanyl-cyclopropylcarboxylate 9a. [h]2D5=−235 (c 2.8×
10−3, CHCl3).
5a/4b: Mp 112°C (CH2Cl2/iPr2O). IR wmax 3400, 1730,
1
1670 cm−1; H NMR l 0.34–1.67 (m, 18H), 3.10, 4.07,
4.65 (ABX system, J=19.0, 9.4, 6.2, 3H), 4.54–4.65 (m,
1H), 7.20–7.97 (m, 20H), 8.22 (s, 1H, exch.); 13C NMR
l 15.9–46.7, 42.6, 68.2, 79.0, 88.5, 101.2, 127.4–144.7,
167.0, 167.9; anal. calcd: C, 74.39; H, 6.71; N, 6.51.
Found: C, 74.31; H, 6.65; N, 6.40.
3.4.4. (+)-Menthyl (1R,2R)-1-benzoylamino-2-tritylsul-
fanyl-cyclopropylcarboxylate 8b. [h]2D5=+235 (c 3.0×
10−3, CHCl3).
9a/8b: Mp 205°C (CH2Cl2/iPr2O). IR wmax 3400, 1735,
1
1670 cm−1; H NMR l 0.55–1.63 (m, 18H), 1.25, 2.26,
3.3.5. Menthyl (3S*,4R*)-3-benzoylamino-4-tritylsul-
fanyl-3,4-dihydro-2H-pyrazole-3-carboxylate 6a,7b. IR
2.73, (ABX system, J 10.1, 7.5, 6.3, 3H), 4.48–4.61 (m,
1H), 5.09 (s, 1H, exch.), 7.21–7.55 (m, 20H); 13C NMR
l 15.6–46.9, 22.4, 29.7, 39.6, 66.8, 75.6, 127.2–144.2,
168.2, 169.2; anal. calcd: C, 77.76; H, 7.01; N, 2.27.
Found: C, 77.45; H, 6.90; N, 2.24.
1
wmax 3380, 3360, 1730, 1660 cm−1; H NMR l 0.58–1.87
(m, 18H), 4.09, 6.14 (AX system, J 1.4, 2H), 4.59–4.68
(m, 1H), 6.58 (s, 1H, exch.), 7.26–7.67 (m, 20H), 8.05 (s,
1H, exch.).
3.4.5. Menthyl 2-benzoylamino-4-tritylsulfanylbut-2-
1
3.3.6. (−)-Menthyl (3R,4S)-3-benzoylamino-4-tritylsul-
fanyl-4,5-dihydro-3H-pyrazole-3-carboxylate 7a. [h]2D5=
−69 (c 5.1×10−3, CHCl3).
enoate 10a,b. Oil. IR wmax 3400, 1735, 1670 cm−1; H
NMR l 1.03–2.04 (m, 18H), 3.11, 6.27 (AX2 system, J
7.7, 2H), 7.04–7.59 (m, 20H) 7.79 (s, 1H, exch.); 13C
NMR l 16.7–47.5, 31.0, 67.7, 76.3, 126.2, 127.4–144.9,
132.4, 164.3, 165.8; anal. calcd: C, 77.76; H, 7.01; N,
2.27. Found: C, 77.50; H, 7.12; N, 2.11.
3.3.7. (+)-Menthyl (3S,4R)-3-benzoylamino-4-tritylsul-
fanyl-4,5-dihydro-3H-pyrazole-3-carboxylate 6b. [h]2D5=
+69 (c 5.0×10−3, CHCl3).
3.5. General procedure for the synthesis of 1-benzoyl-
amino-2-tritylsulfanyl-cyclopropylcarboxylic acid 12
7a/6b: Mp 172°C (CH2Cl2/iPr2O). IR wmax 3380, 3360,
1
1730, 1660 cm−1; H NMR l 0.58–1.87 (m, 18H), 3.99,
6.29 (AX system, J=1.4, 2H), 4.59–4.68 (m, 1H), 7.12
(s, 1H, exch.), 7.26–7.67 (m, 20H), 7.94 (s, 1H, exch.);
13C NMR l 15.9–47.3, 57.7, 69.8, 77.2, 77.5, 127.6–
133.1, 141.5, 144.5, 167.7, 170.1; anal. calcd: C, 74.39;
H, 6.71; N, 6.51. Found: C, 74.25; H, 6.60; N, 6.38.
Ester 9a (64 mg, 0.104 mmol) or spirooxazolone (Z)-11
(47.6 mg, 0.55 mmol) was suspended in MeOH (1 mL).
A solution of KOH in MeOH (1 mL, 0.31 M) and H2O
(0.1 mL) were added and the mixture was heated at
90°C for 72 h. The solvent was evaporated and the
crude reaction mixture was taken up with H2O (3 mL)
and washed with AcOEt (3 mL). The water was aci-
dified with HCl (1 mL, 10%) and extracted with CH2Cl2
(3×3 mL). After drying with Na2SO4 the solvent was
evaporated and the crude mixture was recrystallized.
Pure acid 12 was obtained when starting from 9a (22
mg, 44%) or 11 (38.7 mg, 78%). Mp 216°C (CH2Cl2/
Et2O); IR wmax 3380, 1720, 1640 cm−1; 1H NMR l
1.03–2.04 (m, 18H), 1.23, 2.24, 2.78 (ABX system, J
3.4. General procedure for the synthesis of cyclopropyl-
amino acids 8/9
The pyrazoline derivative 4 or 5 (98 mg, 0.15 mmol)
1
was melted at 150°C for 10 min. The H NMR and
HPLC analyses revealed the presence of a mixture of
cyclopropane derivative 8 or 9 and the acrylate 10 (4a:
8a/10a, 4.5:1; 5a: 9a/10a, 6.5:1; 4b: 8b/10b, 4.5:1; 5b:

F. Clerici et al. / Tetrahedron: Asymmetry 12 (2001) 2663–2669
2669
10.0, 7.5, 6.2, 3H), 5.35 (s, 1H, exch.), 7.22–7.57 (m,
20H); anal. calcd: C, 75.13; H, 5.25; N, 2.92. Found: C,
75.00; H, 5.36; N, 2.78.
Ho, K.-K.; Pal, B. J. Am. Chem. Soc. 1995, 117, 3808–
3819; (e) Jimertez, A. I.; Cativiela, C.; Aubry, A.; Mar-
raud, M. J. Am. Chem. Soc. 1998, 120, 9452–9459; (f)
Pellicciari, R.; Marinozzi, M.; Costantino, M.; Natalini,
B.; Moroni, F.; Pellegrini, G. D. J. Med. Chem. 1999, 42,
2716–2720; (g) Llinas-Brunet, M.; Bailey, M. D.;
Cameron, D.; Ghiro, E.; Goudreau, N.; Poupart, M.-A.;
Rancourt, J.; Tsantrizos, Y. S. PTC Int. Appl. WO 00
09,558. Chem. Abstr. 2000, 132, 175808.
Acknowledgements
We thank MURST for financial supports.
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