Enantioselective synthetic approaches to cyclopropane and cyclobutane β-amino acids: Synthesis and structural study of a conformationally constrained β-dipeptide

Article abstract of DOI:10.1016/S0957-4166(00)00297-4

Synthetic approaches to carbocyclic compounds, namely cyclopropane and cyclobutane β-amino acids, are presented. One of them is based on enzymatic desymmetrization of meso diesters, leading to the enantioselective production of cis-hemiesters, which afforded β-amino acids through Curtius rearrangements. The enantiomeric excess for the cyclobutane derivatives was 91% whereas the cyclopropanes were obtained in 63% ee. According to another strategy, an enantiomerically pure cyclopropane trans-β-amino acid, bearing a quaternary center, has been synthesized from a homochiral precursor easily available from D-glyceraldehyde. The preparation and structural investigation of the first synthesized cyclobutane containing dipeptide is also described. A hairpin-like conformation of this molecule in the solid state has been demonstrated by X-ray structural analysis, showing crystal packing induced by the presence of the rigid cyclobutane moiety and the formation of intermolecular hydrogen bonds. NMR experiments confirmed that these molecules also tend to produce aggregates in solution. On the contrary, theoretical calculations suggest that intramolecular interactions are important in the gas phase, as expected. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00297-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3569–3584
Enantioselective synthetic approaches to cyclopropane and
cyclobutane b-amino acids: synthesis and structural study of
a conformationally constrained b-dipeptide
Marta Mart´ın-Vila`,a Elena Muray,a Gemma P. Aguado,a Angel Alvarez-Larena,b
Vicenc¸ Branchadell,a Cristina Minguillo´n,c Ernest Giraltd and Rosa M. Ortun˜oa,*
aDepartament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
bUnitat de Cristal.lografia, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
cLaboratori de Qu´ımica Farmace`utica, Facultat de Farma`cia, Universitat de Barcelona, 08028 Barcelona, Spain
dDepartament de Qu´ımica Orga`nica, Universitat de Barcelona, 08028 Barcelona, Spain
Received 21 July 2000; accepted 28 July 2000
Abstract
Synthetic approaches to carbocyclic compounds, namely cyclopropane and cyclobutane b-amino acids,
are presented. One of them is based on enzymatic desymmetrization of meso diesters, leading to the
enantioselective production of cis-hemiesters, which afforded b-amino acids through Curtius rearrange-
ments. The enantiomeric excess for the cyclobutane derivatives was 91% whereas the cyclopropanes were
obtained in 63% ee. According to another strategy, an enantiomerically pure cyclopropane trans-b-amino
acid, bearing a quaternary center, has been synthesized from a homochiral precursor easily available from
D
-glyceraldehyde. The preparation and structural investigation of the first synthesized cyclobutane
containing dipeptide is also described. A hairpin-like conformation of this molecule in the solid state has
been demonstrated by X-ray structural analysis, showing crystal packing induced by the presence of the
rigid cyclobutane moiety and the formation of intermolecular hydrogen bonds. NMR experiments
confirmed that these molecules also tend to produce aggregates in solution. On the contrary, theoretical
calculations suggest that intramolecular interactions are important in the gas phase, as expected. © 2000
Elsevier Science Ltd. All rights reserved.
1. Introduction
b-Amino acids are a widespread class of non-proteinogenic amino acids found in nature in
free form or as a part of peptidic products with antibiotic, antifungal, cytotoxic and other
pharmacological properties. Among the non-peptidic compounds, b-lactams are prominent and
* Corresponding author.
E-mails: angel@salduba.uab.es; minguill@farmacia.far.ub.es; giralt@admin.qo.ub.es; rosa.ortuno@uab.es
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00297-4

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include antibiotics and other medicinal agents. b-Amino acids are also key structural compo-
nents of important products such as the potent enzyme inhibitors statins and the anticancer
agent taxol (Paclitaxel®).1
These amino acids have recently been the object of a renewed interest since the pioneer works
of Seebach2 and Gellman3 showing that polymers composed of b-amino acids, i.e. b-peptides,
can fold into a stable helical secondary structure analogous to the a-helix in proteins.4 Thus, in
the last 4 years, it has been shown that cyclic as well as acyclic peptides composed of b-amino
acid residues adopt turn, helical, and sheet-like conformations.5 Theoretical studies of b-peptide
models have also been reported.6 Moreover, some peptides consisting of b-amino acids display
interesting biological properties, such as high stability against degradation by proteases,2,7
conferring on them a great potential as drug candidates.8
Consequently, the excitement about the promising biological and pharmacokinetic properties
of b-peptides has stimulated a strong synthetic activity in the field of the corresponding building
blocks, i.e. the b-amino acids.9
Conformationally constrained a- and b-amino acids have been incorporated into peptide
surrogates to be used in structural and biomechanistic investigations as well as to obtain
peptides with new or improved properties.10 With this purpose in mind, in contrast to a-amino
acids, the use of carbocyclic b-amino acids is very limited and there are only a few examples on
the incorporation of cyclopropane,11 cyclopentane4b or cyclohexane3 residues in peptidic chains
and, as far as we know, there are no examples of cyclobutane containing b-peptides. Further-
more, among the large number of general synthetic methods used to prepare b-amino acids,12
2-aminocyclopropane-11,13a and 2-aminocyclobutane-1-carboxylic acids13b have been synthesized
only in racemic form.
As part of our research program on the synthesis and structural investigation of carbocyclic
amino acids and related peptidomimetics,14 we envisaged the synthesis of cyclopropane and
cyclobutane b-amino acids15 as well as their incorporation into new b-oligomers to be studied
from structural and biological points of view.
In this paper, we report two synthetic approaches to such amino acids. The first one is based
on enzymatic desymmetrization of carbocyclic meso diesters and affords cis-derivatives. The use
of a chiral precursor in the synthesis of a cyclopropane b-amino acid with trans stereochemistry
is also described. The enantio- and diastereomeric purity of the synthesized products has been
determined by NMR and by HPLC using non-commercial chiral stationary phases. These amino
acids are conveniently protected for their latter incorporation into peptidic chains. As an
illustrative example, we describe herein the synthesis and the structural determination, using
NMR and CD spectroscopies and by X-ray crystallography, of the first cyclobutane containing
b-peptide which results from the coupling between (1R,2S)-2-(N-Cbz-amino)cyclobutane-1-car-
boxylic acid with b-Ala-OMe. Results of theoretical calculations simulating its structural
features in the gas phase are also reported.
2. Results and discussion
2.1. Synthesis of cyclopropane or cyclobutane amino acids and dipeptide 16
The enzymatic synthesis of chiral building blocks from prochiral substrates has been applied
to the production of enantiopure bioactive molecules,16 and hydrolytic enzymes, such as pig

M. Mart´ın-Vila` et al. / Tetrahedron: Asymmetry 11 (2000) 3569–3584
3571
leaver esterase (PLE), play a prominent role in such biotransformations. Jones et al.17 described
the enantioselective hydrolysis of cyclopropane or cyclobutane meso diesters to afford the
corresponding hemiesters in high ee. We have used these compounds as the synthetic precursors
to carbocyclic b-amino acids via Curtius rearrangements. Alternatively, we have also prepared
cyclopropane derivatives from optically active starting materials, obtained from
hyde as a source of chirality.
D-glyceralde-
2.1.1. Synthesis of 2-amino-(1R,2S)-cyclopropane- and 2-amino-(1R,2S)-cyclobutane-1-
carboxylic acid derivatives (−)-7a and (−)-7b through a chemoenzymatic approach
The synthetic sequences leading to compounds (−)-7a and (−)-7b are depicted in Scheme 1.
Maleic anhydride derivatives 1a and 1b were the precursors providing cyclopropane and
cyclobutane meso diesters 4a and 4b, respectively, through Fisher esterification. Compound 1a
is commercially available but 1b is not. This product could be prepared, according to the
literature, by photochemical [2+2] cycloaddition of ethylene to maleic anhydride,18 but the
reaction was very slow and afforded 1b in modest yield (35–40%) after several days. Commercial
cyclobutane-1,2-dicarboxylic diacid 3 is quite expensive but it is a more convenient starting
material which provided diester 4b quantitatively upon reaction with diazomethane.
Scheme 1.
Dimethyl diesters 4a,b were hydrolyzed chemoselectively by PLE to afford hemiesters 5a,b in
91% yield and >97% ee.17 The next synthetic steps involve the degradative conversion of the
carboxyl into an amino group via an intermediate acyl azide. Thus, hemiester 5a was reacted
with ethyl chloroformate in the presence of triethylamine followed by reaction with sodium

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M. Mart´ın-Vila` et al. / Tetrahedron: Asymmetry 11 (2000) 3569–3584
azide to produce 6a. In a parallel way, hemiester 5b was converted into 6b. Curtius rearrange-
ment of these compounds was carried out by heating respective toluene solutions of 6a and 6b
in the presence of benzyl alcohol in order to produce the corresponding N-Cbz protected
amines. Temperature was crucial in order to obtain carbamate (−)-7a in good ee. When a
solution containing the cyclobutane derivative 6b was heated to reflux for 16 h, (−)-7b was
produced in 91% ee, as determined by HPLC (vide infra). However, heating of 6a under similar
conditions afforded 7a as a racemate. In contrast, compound (−)-7a was obtained in 63% ee
when a toluene solution of 6a and benzyl alcohol was heated at 50°C for 3 h. The observed
racemization can be attributed to the labile proton at C1 and to the presence of an electron-
withdrawing group and an electron-donor function in the cyclopropane 1,2-relative positions.
This capto-dative system shows the ability to isomerize through open-chain species produced
under a variety of conditions.19 These features also account for the isomerization observed
during the Curtius rearrangement of related molecules.20 On the other hand, diastereomerical
1
homogeneity of compounds (−)-7a and (−)-7b was assessed by H and 13C NMR, since only one
set of signals was observed in each case.
Racemic 7a,b were prepared from racemic 2a,b following the same transformations as those
described above for the optically active products, and were used as the reference standards in
HPLC ee measurements. Hemiesters 2a,b resulted, in turn, from the reaction of 1a,b with
methanol.
Although chemical overall yields for (−)-7a and (−)-7b were very satisfactory (89 and 57%
from 1a and 1b, respectively), the modest enantiomeric excess accomplished for the cyclo-
propane derivative (−)-7a prompted us to explore another synthetic route leading to cyclo-
propane b-amino acids.
2.1.2. Synthesis of ethyl (1R,2R)-2-N-(benzyloxycarbonylamino)-2-methyl-1-cyclopropane
carboxylate, 12, from a chiral precursor
Unsaturated ester 8 (Scheme 2) is easily prepared from
D
-glyceraldehyde by Wittig–Horner
condensation with a suitable phosphonate.21 In a recent report,22 we described the highly
stereoselective cyclopropanation (85% de) of 8 by means of the 1,3-dipolar cycloaddition of
diazomethane and photolysis of the produced pyrazoline. Subsequent hydrolysis of the ace-
tonide afforded the cyclopropane derivative 9 in 60% overall yield for the three steps. Diol was
Scheme 2.

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3573
oxidatively cleaved by RuO2 affording carboxylic acid 10. Curtius rearrangement of acyl azide
11, promoted by heating a mixture of this compound and benzyl alcohol in toluene to reflux for
1.5 h, afforded compound 12 in 53% yield from diol 9 and in enantiomerically pure form as
deduced from the HPLC analysis described below. In this case, the presence of the quaternary
center at C1 must prevent isomerization of these molecules.
2.1.3. Selective functional group manipulations in 7b: syntheses of free amino acid 15 and
dipeptide 16
The orthogonal protecting groups in (−)-7b are convenient for the selective deprotection of the
carboxylic acid or the amine function in order to provide derivatives suitable for their
incorporation into peptides (Scheme 3).
Scheme 3.
Thus, benzyl carbamate was removed through Pd/C catalyzed hydrogenation of (−)-7b
affording amino ester 13 in 84% yield. Alternatively, methyl ester in (−)-7b was hydrolyzed by
treatment with potassium carbonate in a 3:1 methanol/water mixture at room temperature for
4 h, furnishing compound 14. A long reaction time and the use of strong bases was precluded
in order to prevent cis–trans epimerization. The cis-configuration of 14 was assured by NOE
experiments.15 The amine protection was removed by hydrogenation, as above, to give the free
amino acid 15, as a very hygroscopic solid, in 40% overall yield from diacid 3.
Acid 14 was condensed with b-Ala-OMe hydrochloride by using excess 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide as a dehydratating agent and 1 equivalent of 1-hydroxyben-
zotriazole (HOBT) as a catalyst, in the presence of TEA to liberate the amine, in anhydrous
DMF at room temperature for 20 h. In this way, fully protected dipeptide 16 was obtained as
a crystalline solid in 86% yield.

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2.2. HPLC determinations
Several chiral stationary phases based on immobilized polysaccharide derivatives23 were tested
in order to develop an analytical method to asses the enantiomeric content of 7a,b and 12. The
low wavelength of maximal absorption (210 nm) and the low absorptivity of these compounds
prevented the use of solvents other than heptane and 2-propanol, mixtures of which were used
as the mobile phase. Refractive index detection was not possible because of the low response of
the sample.
Compound ( )-7b was the first to be analyzed and several conditions were tried (Table 1). A
slight splitting of peaks was observed when using columns based on amylose 3,5-
dimethylphenylcarbamate or chitosan 3,5-dichlorophenylcarbamate. Cellulose 3,5-dimethyl-
phenylcarbamate and amylose 4-chlorophenylcarbamate were unable to distinguish between
the two enantiomers of ( )-7b. Resolved peaks were obtained with cellulose 3,5-dichloro-
phenylcarbamate, chitosan 3,5-dimethylphenylcarbamate and amylose 3,5-dichlorophenylcarba-
mate. However, completely resolved peaks were only obtained with the latter two phases
when using a 95:5 heptane/2-propanol mixture as the eluent. When (−)-7b was chromatographed
on both columns, an enantiomeric excess of 91% was determined.
Table 1
HPLC data for compounds 7a, 7b, and 12 on chiral stationary phases (CSP)a,b
Compound Chiral selector in the CSP
k%
1
h
Rs
Mobile phase heptane/2-PrOH
7b
7b
7b
7b
7b
7b
7b
7a
7a
7a
7a
12
12
Cellulose 3,5-dimethylphenylcarbamate
2.50
1.85
2.34
2.86
2.23
1.90
5.33
8.91
4.75
20.57
28.23
7.00
8.30
1.00
1.08
1.00
1.17
95:5
95:5
90:10
95:5
Amylose 3,5-dimethylphenylcarbamate
Amylose 4-chlorophenylcarbamate
Chitosan 3,5-dichlorophenylcarbamate
Cellulose 3,5-dichlorophenylcarbamate
Chitosan 3,5-dimethylphenylcarbamate
Amylose 3,5-dichlorophenylcarbamate
Amylose 4-chlorophenylcarbamate
Chitosan 3,5-dimethylphenylcarbamate
Cellulose 3,5-dichlorophenylcarbamate
Amylose 3,5-dichlorophenylcarbamate
Chitosan 3,5-dimethylphenylcarbamate
Amylose 3,5-dichlorophenylcarbamate
1.32 1.29 90:10
2.17 3.07 95:5
1.47 2.55 95:5
1.08
1.09
1.21 1.08 98:2
1.24 1.55 98:2
95:5
95:5
95:5
95:5
a See Section 4 for a definition of the chromatographic parameters k% , h and Rs.
1
b All chromatographic runs were performed on 15×0.46 cm ID columns. Flow: 1 mL/min. UV detection: 7a, 208
nm; 7b, 254 nm; 12, 211 nm.
Similarly, even if several chiral selectors showed a certain enantioselectivity for the two
enantiomers of ( )-7a, this compound was only fully resolved when the column containing
amylose 3,5-dichlorophenyl carbamate was employed. Using the chromatographic conditions
determined for the racemic mixture, an enantiomeric excess of 63% was determined for (−)-7a.
In contrast, only one peak was observed when 12 was chromatographed on both amylose
3,5-dichlorophenyl carbamate- and chitosan 3,5-dimethylphenylcarbamate-based columns elut-
ing with 95:5 heptane/2-propanol, suggesting the presence of only one enantiomer. Polarimetric
detection confirmed this hypothesis.

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3575
2.3. Structure analysis
Several experiments were carried out to investigate the secondary stucture of 16 both in
solution and in the solid state. Circular dichroism shows a negative band, at 222 nm, of difficult
interpretation. Otherwise, in order to evidence hydrogen bonds in solution, the NMR chemical
shift of the NH protons was investigated at different concentrations in CD2Cl2 or in CD2Cl2
after the addition of small amounts of DMSO. The fact that lNH was shown to be dilution
dependent, at low sample concentration, suggests a strong tendency to produce molecular
aggregates whereas the non-dependence of the DMSO concentration agrees with the presence of
strong hydrogen bonds.
A single crystal X-ray diffraction study revealed the molecular features and the intermolecular
interactions present in the solid state. Some selected data are collected in Table 2 (see Fig. 1 for
Table 2
,
Selected distances (A) and angles (°) with e.s.d. values in parentheses for 16
Bond lengths
N1ꢀC4
C5ꢀN1
C5ꢀO3
1.440(5)
1.340(5)
1.232(5)
1.506(5)
1.536(5)
1.554(5)
1.426(4)
C9ꢀC8
1.525(6)
1.528(6)
1.342(5)
1.216(5)
1.342(5)
1.448(5)
C8ꢀC7
N2ꢀC10
C10ꢀO4
C10ꢀO5
O5ꢀC11
C6ꢀC5
C6ꢀC7
C6ꢀC9
C9ꢀN2
Bond angles
C4ꢀN1ꢀH1
C5ꢀN1ꢀC4
C5ꢀN1ꢀH1
O3ꢀC5ꢀN1
O3ꢀC5ꢀC6
N1ꢀC5ꢀC6
C5ꢀC6ꢀC7
C5ꢀC6ꢀC9
C7ꢀC6ꢀC9
C8ꢀC7ꢀC6
C9ꢀC8ꢀC7
121(4)
121.9(4)
117(4)
N2ꢀC9ꢀC8
N2ꢀC9ꢀC6
C8ꢀC9ꢀC6
C9ꢀN2ꢀH2
C10ꢀN2ꢀH2
C10ꢀN2ꢀC9
O4ꢀC10ꢀN2
O4ꢀC10ꢀO5
N2ꢀC10ꢀO5
C10ꢀO5ꢀC11
117.2(3)
120.2(3)
89.4(3)
120(3)
115(3)
121.9(4)
124.2(4)
123.5(4)
112.3(4)
115.7(3)
122.2(4)
123.0(4)
114.7(4)
114.8(4)
110.4(3)
87.3(3)
89.9(3)
88.7(3)
Torsion angles
C6ꢀC5ꢀN1ꢀC4
O3ꢀC5ꢀN1ꢀC4
C9ꢀN2ꢀC10ꢀO4
C9ꢀN2ꢀC10ꢀO5
O5ꢀC11ꢀC12ꢀC17
−179.2(4)
−2.5(6)
−11.4(7)
169.8(3)
72.2(5)
C9ꢀC6ꢀC7ꢀC8
C7ꢀC6ꢀC9ꢀC8
C6ꢀC9ꢀC8ꢀC7
C9ꢀC8ꢀC7ꢀC6
C5ꢀC6ꢀC9ꢀN2
16.2(3)
−16.2(3)
16.3(3)
−16.5(3)
−22.2(5)
Hydrogen bonds
N1ꢀH1
N1···O3i
2.993(5)
N2···O4ii
2.849(5)
H1···O3i
2.20(6)
N1ꢀH1···O3i
165(6)
0.82(6)
N2ꢀH2
0.90(6)
H2···O4ii
1.97(6)
N2ꢀH2···O4ii
168(5)
i x, y+1, z.
ii x, y−1, z.

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M. Mart´ın-Vila` et al. / Tetrahedron: Asymmetry 11 (2000) 3569–3584
atom numeration). Both the carbamate and amide groups are planar with a null pyramidaliza-
tion of nitrogen atoms. Cyclobutane is twisted and, therefore, its substituents are not synperipla-
nar but are almost synclinal. On the whole, the molecule shows a hairpin-like conformation as
can be observed in Fig. 1. In the crystal structure, molecules are linked by intermolecular
hydrogen bonds forming infinite chains parallel to crystallographic vector b, as shown in Fig. 2.
Two NꢀH···O hydrogen bonds are present between every pair of neighboring molecules in the
chain.
Figure 1. Structure of dipeptide 16 as determined by X-ray structural analysis. Inset: Projection view of the
cyclobutane ring showing the almost synclinal disposition of the two chains
In contrast, intramolecular interactions are important in the gas phase, as suggested by
theoretical calculations on several structures of 16.24–28 In the first calculation, the X-ray
structure has been taken as the starting point and it is similar to the final geometry, the main
difference being the presence of an intramolecular hydrogen bond involving N1ꢀH and O4 with
,
an H···O bond length of 2.30 A. An exploration of the potential energy surface using the
semiempirical PM3 method29 leads to different alternative conformations. Those having the
lowest energies have been reoptimized at the BPW91 level of calculation. The structure
presented in Fig. 3 is the most stable one obtained by this procedure. It is 1.7 kcal mol−1 lower
in energy than the former structure and presents an intramolecular N2ꢀH···O hydrogen bond.

M. Mart´ın-Vila` et al. / Tetrahedron: Asymmetry 11 (2000) 3569–3584
3577
Figure 2. Crystal packing for dipeptide 16 showing the intermolecular hydrogen bonds
Figure 3. Optimized (BPW91) structure of dipeptide 16 showing an intramolecular hydrogen bond
3. Concluding remarks
Optically active carbocyclic b-amino acids have been synthesized in high ee and good yields.
A cyclobutane derivative has been incorporated for the first time into a b-dipeptide, which
shows a hairpin-like conformation in the solid state. This secondary structure is determined both
by the rigid cyclobutane moiety and by the presence of intermolecular hydrogen bonds in the
crystal packing. The strong tendency of these molecules to form aggregates also in solution has
been confirmed by NMR. Otherwise, theoretical calculations show the presence of intramolecu-
lar hydrogen bonds in the gas phase.

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4. Experimental
4.1. General
Flash column chromatography was carried out on silica gel (240–400 mesh) unless otherwise
stated. Baker-silica® (40 mm) was used for the chromatography of acid-sensitive products.
Melting points were determined on a hot stage and are uncorrected. Distillation of small
amounts of material was effected in a bulb-to-bulb distillation apparatus, with oven tempera-
1
tures (ot) being reported. H and 13C NMR spectra were recorded at 250 and 62.5 MHz,
respectively.
4.2. HPLC determinations
Columns of 150×4.6 mm were used. The chiral stationary phases are listed in Table 1.
Heptane/2-propanol mixtures were used as the mobile phase. Flow rate: 1 mL/min; UV
detection: 210 nm. Chromatographic parameters are defined as follows. Selectivity factor,
h=t2−t0/t1−t0, where ti is the retention time for each enantiomer and t0 the dead time of the
column. Resolution factor, Rs, calculated as Rs=2(t2−t1)/w2+w1, where wi is the peak width at the
baseline. An Rs value over 1.5 implies the complete resolution of peaks. Capacity factor for the
first eluted enantiomer, k%=t1−t0/t0.
1
4.3. Crystal structure analysis of 16
Data: C17H22N2O5, Mr=334.37, colorless prism, crystallized from ethyl acetate, crystal size
3
,
,
,
,
0.58×0.11×0.04, a=12.368(3) A, b=4.930(1) A, c=14.734(3) A, i=96.50(2)°, V=892.6(3) A ,
T=293 K, monoclinic, space group P21 (No. 4), Z=2, Dc=1.244 g cm−3, v=0.92 cm−1,
,
Enraf–Nonius CAD4 diffractometer, graphite monochromated Mo Ka (u=0.71069 A), data
collected range 2°<2q<50°, ꢀ–2q scan. The structure was resolved by direct methods30 and
refined by full matrix least squares31 on F2 for all reflections, 1766 unique reflections, 1007
observed [I>2|(I)], number of variables 223, non-hydrogen atoms were refined anisotropically,
H atoms bonded to carbon atoms were placed in calculated positions with isotropic displace-
ment parameters fixed at 1.5 (methyl H) or 1.2 times (the rest) Ueq of the corresponding carbon
atoms, R(F)=0.046 for the observed reflections, Rw(F2)=0.118 for all data, max. shift/error
−3
,
0.001, and residual zmax 0.176 e A .
4.4. Reaction of 1a,b with methanol: diesters 4a,b and racemic hemiesters 2a,b
Typical experiments were run as follows.
4.4.1. Acid-catalyzed reaction
A mixture of compound 1b (200 mg, 1.6 mmol), concentrated H2SO4 (two drops) and
anhydrous methanol (10 mL) was heated to reflux for 2 h. Then methanol was removed at
reduced pressure, the residue was dissolved in water and the resulting solution was extracted
with dichloromethane. The combined extracts were dried over MgSO4 and the solvent was
removed to afford dimethyl cis-cyclobutane-1,2-dicarboxylate, 4b (240 mg, 87% yield), as an oil.
In a similar manner, dimethyl cis-cyclopropane-1,2-dicarboxylate, 4a, was prepared from 1a.

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3579
1
Spectroscopic data for these compounds (IR, H and 13C NMR) are in good agreement with
those described in Ref. 15 for the same products.
4.4.2. Uncatalyzed reaction
A solution of anhydride 1b (200 mg, 1.6 mmol) in anhydrous methanol was heated to reflux
for 7 h. The solvent was removed affording methyl hydrogen cis-cyclobutane-1,2-dicarboxylate,
2b (253 mg), quantitatively. Methyl hydrogen cis-cyclopropane-1,2-dicarboxylate, 2a, was
prepared from 1a following the same protocol. Spectroscopic data for 2a,b agree with those data
reported for optically pure compounds in this work and in Ref. 17.
4.5. Synthesis of diester 4b through reaction of diacid 3 with diazomethane
An ethereal solution of excess diazomethane was distilled onto 3 (500 mg, 3.5 mmol) in 10 mL
of ether, at 0°C, and the resultant solution was stirred at 0°C for 20 min. Excess diazomethane
was destroyed by the addition of CaCl2, and the solvent was removed to give 4b (600 mg)
quantitatively.
4.6. PLE-catalyzed hydrolyses of diesters 5a,b: hemiesters (−)-5a and (−)-5b
These compounds were prepared according to the procedure described by Jones et al.17
Methyl hydrogen (−)-(1R,2S)-cyclopropane-1,2-dicarboxylate, 5a: yield, 577 mg (91%); crystals,
mp 78–81°C (from EtOAc); [h]D −11.2 (c 1.2, MeOH), −23.5 (c 1.1, CHCl3) (lit17 mp 81–83°C
(solvent not mentioned); [h]D −13.4 (c 0.97, CHCl3)). Methyl hydrogen (−)-(1R,2S)-cyclobutane-
1,2-dicarboxylate, 5b: yield, 500 mg (90%); oil, [h]D −3.6 (c 2.4, CHCl3) (lit17 [h]D −3.0 (c 2.1,
CHCl3)). The spectroscopic data for these products are in good agreement with those described
in Ref. 17.
4.7. Synthesis of protected amino acids (−)-7a and (−)-7b through acyl azides 6a and 6b
4.7.1. Synthesis of the acyl azides
A typical experiment is described for the preparation of 6a. Ethyl chloroformate (200 mL, 2.4
mmol) was added to an ice-cold solution of hemiester (−)-5a (230 mg, 1.6 mmol) and freshly
distilled TEA (0.3 mL, 2.1 mmol) in dry acetone (10 mL). After stirring at 0°C for 2 h, sodium
azide (167 mg, 2.6 mmol) in 5 mL of water was added, and the mixture was stirred at room
temperature for 1.5 h. The reaction mixture was extracted with ether and the combined organic
extracts were dried over MgSO4. The solvents were removed under reduced pressure to afford
a yellowish oil identified by the spectroscopic data as methyl 2-azidocarbonyl-(1R,2S)-cyclo-
propane-1-carboxylate, 6a (257 mg, 95% yield); IR (film) 2130, 1736, 1170, 1110 cm−1; 250 MHz
1H NMR (acetone-d6) 1.35 (m, 1H), 1.54 (m, 1H), 2.24 (m, 2H), 3.63 (s, 3H); 62.5 MHz 13C
NMR (acetone-d6) 12.21, 22.68, 23.27, 51.50, 169.34, 176.34.
In a similar manner, methyl 2-azidocarbonyl-(1R,2S)-cyclobutane-1-carboxylate, 6b, was
1
prepared. Yield, 692 mg (90%); oil; IR (film) 2137, 1736, 1173, 1110 cm−1; 250 MHz H NMR
(acetone-d6) 2.16 (m, 4H), 3.38 (m, 2H), 3.59 (s, 3H); 62.5 MHz 13C NMR (acetone-d6) 23.11
(2C), 42.35, 44.07, 52.66, 175.34, 182.08.

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4.7.2. Curtius rearrangement
4.7.2.1. Synthesis of methyl 2-benzyloxycarbonylamino-(1R,2S)-cyclopropane-1-carboxylate, (−)-
7a. A solution of azide 6a (150 mg, 0.9 mmol) and benzyl alcohol (0.2 mL, 1.9 mmol) was
heated at 50°C for 3 h. The solvent was evaporated at reduced pressure and the residue was
chromatographed on Baker-silica® (dichloromethane). The solvent was removed to afford (−)-7a
(140 mg, 89% yield) in 63% ee, as determined by HPLC by using chitosan 3,5-dimethylphenyl-
carbamate as the chiral stationary phase and 95:5 heptane/2-propanol as eluent. Crystals,
74–77°C (from EtOAc–hexane); [h]D −91 (c 1.1, MeOH); IR (film) 3412, 1710, 1687, 1110 cm−1;
1
250 MHz H NMR (CDCl3) 1.13–1.33 (m, 2H), 1.90 (m, 1H), 3.34 (m, 1H), 3.66 (s, 3H), 5.09
(s, 2H), 5.50 (broad s, 1H), 7.33 (m, 5H); 62.5 MHz 13C NMR (CDCl3) 14.56, 19.21, 32.09,
52.44, 67.29, 128.56, 128.94, 136.91, 157.05, 172.93. Anal. calcd for C13H15NO4: C, 62.64; H,
6.07; N, 5.62. Found: C, 62.59; H, 5.91; N, 5.71.
4.7.2.2. Synthesis of methyl 2-benzyloxycarbonylamino-(1R,2S)-cyclobutane-1-carboxylate, (−)-
7b. A solution of azide 6b (300 mg, 1.6 mmol) and benzyl alcohol (0.4 mL, 3.6 mmol) in toluene
(8 mL) was heated to reflux for 16 h. The solvent was evaporated at reduced pressure and the
residue was chromatographed on Baker-silica® (dichloromethane). The solvent was removed to
afford (−)-7b (320 mg, 70% yield) in 91% ee, as determined by HPLC by using chitosan
3,5-dimethylphenylcarbamate or amilose 3,5-dichlorophenylcarbamate as chiral stationary
phases and 95:5 heptane/2-propanol as eluent. Dense oil, ot 155°C (0.05 torr); [h]D −83 (c 2.05,
1
CHCl3); IR (film) 3355, 1723, 1687, 1110 cm−1; 250 MHz H NMR (CDCl3) 1.97 (m, 2H), 2.31
(m, 2H), 3.35 (m, 1H), 3.63 (s, 3H), 4.52 (m, 1H), 5.06 (s, 2H), 5.65 (broad s, 1H), 7.32 (m, 5H);
62.5 MHz 13C NMR (CDCl3) 19.12, 30.10, 45.53, 46.56, 52.18, 67.15, 128.58, 128.97, 136.97,
155.79, 175.53. Anal. calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 64.04; H, 6.30;
N, 5.31.
4.8. Ethyl 2-carboxy-1-methyl-(1R,2R)-cyclopropane-1-carboxylate, 10
A mixture of diol 9 (300 mg, 1.6 mmol), prepared according to Ref. 20, RuO2·xH2O (80 mg)
and NaIO4 (1.7 g, 8.0 mmol) in 2:2:3 CCl4/CH3CN/H2O (14 mL) was stirred at room
temperature for 1 h. Ether (2 mL) was added and the layers were separated. The aqueous layer
was extracted with ether and the combined organic phases were dried over MgSO4. The solvents
were removed at reduced pressure and the residue was filtered through Celite® in vacuo, to
afford a brownish oil (220 mg, 80% yield) that was impossible to purify using the usual
chromatographic techniques and unsuitable for [h]D determination and for microanalysis. IR
1
(film) 3600–2600 (broad), 1729, 1708 cm−1; 250 MHz H NMR (CDCl3) 1.22 (t, J=7.3, 3H),
1.30 (dd, J=6.6, J=4.4, 1H), 1.41 (s, 3H), 1.59 (dd, J=8.8, J%=4.4, 1H), 2.30 (dd, J=8.8,
J%=6.6, 1H), 4.11 (q, J=7.3, 2H); 62.5 MHz 13C NMR (CDCl3) 13.00, 14.06, 21.47, 27.42,
28.12, 61.41, 173.17, 176.70.
4.9. Synthesis of ethyl 2-benzyloxycarbonylamino-1-methyl-(1R,2R)-cyclopropane-1-
carboxylate, 12, through acyl azide 11
Ethyl chloroformate (170 mL, 1.8 mmol) was added to an ice-cold solution of acid 10 (210 mg,
1.2 mmol) and freshly distilled TEA (220 mL, 1.6 mmol) in dry acetone (8 mL). The mixture was

M. Mart´ın-Vila` et al. / Tetrahedron: Asymmetry 11 (2000) 3569–3584
3581
stirred at 0°C for 1 h, then a solution of NaN3 (133 mg, 2.0 mmol) in 3 mL of water was added
and the resultant solution was stirred at room temperature for 2 h. Water (7 mL) was added and
the reaction mixture was extracted with ether. The combined organic phases were dried over
MgSO4 and the solvents were removed affording an oil which was identified as ethyl 2-azidocar-
bonyl-1-methyl-(1R,2R)-cyclopropane-1-carboxylate, 11, by its spectroscopic data. IR (film)
1
2137, 1729, 1708, 1279 cm−1; 250 MHz H NMR (CDCl3) 1.22 (t, J=7.3, 3H), 1.35 (dd, J=6.6,
J%=4.4, 1H), 1.36 (s, 3H), 1.61 (dd, J=8.8, J%=4.4, 1H), 2.28 (dd, J%=8.8, J%=6.6, 1H), 4.12
(q, J=7.3, 2H); 62.5 MHz 13C NMR (CDCl3) 15.49, 14.09, 24.58, 32.54, 32.73, 64.31, 175.26,
179.75.
A solution of compound 11 (250 mg, 1.2 mmol) and benzyl alcohol (300 mL, 2.8 mmol) in
toluene (5 mL) was heated to reflux for 1.5 h. The solvent was removed at reduced pressure and
the residue was chromatographed on silica gel (5:1 hexane/ethyl acetate). Traces of benzyl
alcohol were removed by crystallization to afford 243 mg of pure 12 (70% yield). Crystals, mp
101–103°C (from EtOAc–pentane); [h]D +27.9 (c 0.70, CHCl3); IR (KBr) 3325, 1715, 1687 cm−1;
1
250 MHz H NMR (CDCl3) 0.70 (m, 1H), 1.21 (t, J=7.0, 3H), 1.25 (s, 3H), 1.59 (m, 1H), 3.18
(m, 1H), 4.09 (q, J=6.6, 2H), 5.03 (s, NH), 5.10 (s, 2H), 7.32 (s, 5H); 62.5 MHz 13C NMR
(CDCl3) 13.06, 14.09, 21.65, 36.24, 60.76, 66.94, 128.14, 128.47, 136.17, 156.73, 173.88. Anal.
calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 65.03, H, 6.82; N, 4.86.
4.10. Methyl 2-amino-(1R,2S)-cyclobutane-1-carboxylate, 13
A stirred mixture of (−)-7b (140 mg, 0.5 mmol) and 10% Pd/C (14 mg) in methanol (10 mL)
was hydrogenated overnight under 2 atmospheres of pressure. The catalyst was removed by
filtration through Celite® and the solvent was evaporated to afford amine 13 (61 mg, 84% yield)
as a hygroscopic solid unsuitable for microanalysis; mp 77–80°C (from EtOH); [h]D −19 (c 1.4,
1
MeOH); IR (film) 2951, 1734, 1104 cm−1; 250 MHz H NMR (methanol-d4) 1.65 (m, 4H), 2.42
(m, 1H), 3.01 (m, 1H), 3.66 (s, 3H), 4.79 (broad s, 3H); 62.5 MHz 13C NMR (methanol-d4)
24.63, 28.37, 36.39, 50.52, 55.63, 180.13.
4.11. 2-Benzyloxycarbonylamino-(1R,2S)-cyclobutane-1-carboxylic acid, 14
Ester (−)-7b (130 mg, 0.5 mmol) was added to a solution of K2CO3 (340 mg, 2.5 mmol) in a
3:1 methanol/water mixture and the solution was stirred at room temperature for 6 h. Methanol
was evaporated under reduced pressure and the resultant aqueous solution was washed with
ether and 5% HCl was added until the pH reached 2. The acid aqueous solution was extracted
with ether and the combined organic extracts were dried over MgSO4. The solvent was
evaporated to afford acid 14 (102 mg, 86% yield) as a pasty solid unsuitable for microanalysis;
1
[h]D −98 (c 1.1, MeOH); IR (film) 3433, 3353, 1711, 1687, 1433, 1155 cm−1; 250 MHz H NMR
(acetone-d6) 2.11 (m, 2H), 2.36 (m, 2H), 3.22 (broad s, 1H), 3.42 (m, 1H), 4.56 (m, 1H), 5.10 (s,
2H), 6.57 (broad s, 1H), 7.41 (m, 5H); 62.5 MHz 13C NMR (acetone-d6) 17.92, 28.36, 44.9,
46.48, 67.74, 127.58, 128.19, 137.06, 155.24, 174.58.
4.12. 2-Amino-(1R,2S)-cyclobutane-1-carboxylic acid, 15
A stirred mixture of 14 (140 mg, 0.6 mmol) and 10% Pd/C (15 mg) in methanol (10 mL) was
hydrogenated overnight under 2 atmospheres of pressure. The catalyst was removed by filtration

3582
M. Mart´ın-Vila` et al. / Tetrahedron: Asymmetry 11 (2000) 3569–3584
through Celite®, the solvent was evaporated and the residue was washed with methanol to give
amino acid 15 (60 mg, 85% yield) as a highly hygroscopic solid unsuitable for microanalysis; mp
130°C (dec) (from MeOH−H2O); [h]D −9 (c 1.5, H2O); IR (KBr) 3414, 3390, 1714 cm−1; 250
1
MHz H NMR (D2O) 1.59 (m, 4H), 2.20 (m, 1H), 2.98 (m, 1H), 4.79 (broad s, 3H); 62.5 MHz
13C NMR (D2O) 23.31, 23.40, 36.95, 48.28, 182.86.
4.13. 2-Benzyloxycarbonylamino-(1R,2S)-cyclobutane-1-carboxylic acid N-methoxycarbonyl-
ethyl amide, 16
To a solution of acid 14 (120 mg, 0.5 mmol) in dry DMF (3 mL) under a nitrogen atmosphere,
freshly distilled TEA (70 mL, 0.5 mmol), methyl b-alaninate hydrochloride (100 mg, 0.7 mmol),
and 1-hydroxybenzotriazole (32 mg, 0.2 mmol) were added successively. The mixture was stirred
until all reagents were dissolved and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (276 mg, 1.5 mmol) was added. The light-protected resultant solution was stirred at room
temperature for 20 h, ethyl acetate (10 mL) was added and then the solution was washed with
saturated aqueous NaHCO3. The organic phase was dried over MgSO4, the solvents were removed
at reduced pressure and the residue was chromatographed on Baker-silica® (1:1 dichloromethane/
EtOAc) to afford dipeptide 16 (142 mg, 86% yield) as a solid. Crystals, mp 91–93°C (from EtOAc);
1
[h]D −67 (c 2.9, MeOH); IR (KBr) 3304, 1738, 1687, 1643 cm−1; 400 MHz H NMR (acetone-d6)
1.94 (m, 2H, H7), 2.25 (m, 2H, H8), 2.46 (m, 2H, H3), 3.24 (m, 1H, H6), 3.41 (m, 2H, H4), 3.60
(s, 3H, H1), 4.39 (m, 1H, H9), 5.03 (s, 2H, H11), 6.53 (broad s, 1H, N2ꢀH), 7.09 (broad s, 1H,
N1ꢀH), 7.30 (m, 5H, Ph); 100 MHz 13C NMR (acetone-d6) 18.68 (C7), 29.03 (C8), 34.80 (C3), 36.12
(C4), 47.18 (C6), 48.32 (C9), 52.15 (C1), 67.44 (C11), 128.88 (C13/C14/C15), 128.99 (C13/C14/C15),
129.44 (C13/C14/C15), 138.17 (C12), 157.70 (C10), 173.73 (C5), 174.73 (C2). Anal. calcd for
C17H22N2O5: C, 61.07; H, 6.63; N, 8.38. Found: C, 61.08; H, 6.52; N, 8.34.
5. Supporting information
A complete list of crystallographic data for dipeptide 16 is available on request from the Director
of the Cambridge Crystallographic Data Centre. Any request should be accompanied by a full
literature citation of this paper.
Acknowledgements
G.P.A., E.M. and M.M.-V. thank the Ministerio de Educacio´n for respective predoctoral
fellowships. Financial support from DGESIC through the project PB97-0214 is gratefully
acknowledged.
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