Stereoselective synthesis of cyclobutyl α-aminocyclopropyl carboxylic acid derivatives

Article abstract of DOI:10.1016/S0957-4166(00)00470-5

The highly stereoselective cyclopropanation of chiral cyclobutyl dehydro amino acids, synthesized from (-)-α-pinene or (-)-verbenone, has been achieved by means of a 1,3-dipolar cycloaddition with diazomethane. The proximity of the double bond to the neig

Full text of DOI:10.1016/S0957-4166(00)00470-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4903–4914
Stereoselective synthesis of cyclobutyl a-aminocyclopropyl
carboxylic acid derivatives
A. G. Moglioni,a E. Garc´ıa-Expo´sito,a A. Alvarez-Larena,b V. Branchadell,a
G. Y. Moltrasioc and R. 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
cDepartamento de Qu´ımica Orga´nica, Facultad de Farmacia y Bioqu´ımica, Universidad de Buenos Aires,
1113 Buenos Aires, Argentina
Received 23 October 2000; accepted 21 November 2000
Abstract
The highly stereoselective cyclopropanation of chiral cyclobutyl dehydro amino acids, synthesized from
(−)-a-pinene or (−)-verbenone, has been achieved by means of a 1,3-dipolar cycloaddition with di-
azomethane. The proximity of the double bond to the neighbouring stereogenic center of the cyclobutyl
moiety is crucial to obtain cyclopropanes as single diastereomers whose configuration has been deter-
mined by X-ray structural analysis. DFT theoretical calculations of the more stable conformations allow
us to understand the p-facial diastereoselection as the result of steric hindrance by the gem-dimethyl
substitutuents and the side chain of the cyclobutane-ring. Chiroptical properties of these products have
been studied by ORD and CD techniques and their behavior in CSA-NMR experiments has been
ascertained. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Compounds containing the cyclopropane ring are widespread and, among them, amino acids
and related products from natural or designed origin are prominent.1 Due to the relevant
biological properties of many of these compounds, synthetic methods based mainly on the use
of diazoalkanes, carbenoid species, and phosphorus or sulfur ylides have been developed to
prepare cyclopropane derivatives in a stereoselective manner. In our laboratory, we have utilized
the 1,3-dipolar cycloaddition of diazomethane to chiral dehydro amino acids, followed by
pyrolysis of the resultant pyrazolines, as an efficient procedure for the highly stereoselective
synthesis of protein methanologs,2 non-proteinogenic a- and b-amino acids,2a,3 peptide surro-
gates,3d,4 amino alcohols,5 hydroxy acids,6 and cyclopropane carbocyclic nucleosides.7 The
* Corresponding author. E-mail: rosa.ortuno@uab.es
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00470-5

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stereoselectivity of these processes has also been observed in the reactions between diazomethane
and other olefinic substrates containing electron-withdrawing groups such as ester, nitro or
sulphone.8 The configuration of the new stereogenic centers has been shown to be induced
exclusively by the chirality of the asymmetric carbon in the substrate independently of the Z/E
geometry of the double bond and of the nature and number of their substituents. Thus, the
stereochemical outcome of the cycloadditions was governed by the presence of a dioxolane ring
at the allylic stereogenic center of dehydroamino acids obtained from
D
-glyceraldehyde acet-
onide,8 or by a bulky orthoester group in a serine aldehyde OBO ester.2c A model based on DFT
theoretical calculations has been used to explain and predict the stereoselectivity of this type of
cycloaddition. Thus, we have shown that both steric and orbital effects account for the p-facial
diastereoselection.8
Products containing both the cyclopropane and the cyclobutane moieties are more scarce.
Nevertheless, interesting activity of such compounds have been described in connection with the
study of the NMDA receptors which are potential targets for therapeutic use in a wide range of
neurological processes. In general, the NMDA antagonists possess anticonvulsant, antispastic,
and neuroprotective properties. trans-2,4-Methanoglutamic acid, 1, displays an activity similar
to glutamic acid as a powerful NMDA agonist. On the other hand, amino acids 2 and 3 have
been used to prepare racemic compounds 4 and 5 which have been evaluated as NMDA
antagonists. Amino acid 4 is inactive but compound 5 exhibits strong NMDA antagonism
showing that the configuration of the molecule plays an important role in the biological
activity.9 Therefore, the development of stereoselective synthetic protocols is crucial to synthe-
size new compounds to be tested.
Herein, we describe the stereoselective synthesis of fully protected amino acids 11 and 15, as
well as the synthesis of 10 as a diastereomeric mixture. All these compounds have an a-amino
acid function, directly attached to the cyclopropane ring, and a cyclobutyl unit bearing a
functional group capable of being transformed into a carboxylic acid or suitable for the
incorporation of these molecules into peptide isosteres.
(−)-a-Pinene or (−)-verbenone have been employed as chiral starting materials providing the
cyclobutane moiety and two stereogenic centers. The use of these precursors allowed us to
synthesize dehydro amino acid derivatives 6, 7, and 13 through stereocontrolled Wittig–Horner
condensations with appropriate phosphonates.10

A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
4905
We show herein that the gem-dimethyl substitution is the main control element responsible
for the remarkable stereoselection observed in the cyclopropanation of substrates 7 and 13
which have the double bond attached to the cyclobutane. X-Ray structural analysis led to the
unambiguous configurational assignment of the new stereogenic centers, whereas theoretical
calculations allowed us to understand the stereochemical outcome of the cycloaddition. Chirop-
tical measurements and NMR experiments by using the fully deuterated Pirkle alcohol as a
chiral solvating agent (CSA) have been also carried out.
2. Results and discussion
2.1. Synthesis and stereochemical assignment of amino acids 10, 11, and 15
In a previous paper, we described the syntheses of dehydro amino acids 6 and 13 from
(−)-a-pinene and the synthesis of 7 from (−)-verbenone. It is noteworthy that products 7 and 13
show opposite configurations at C-1% and C-3%.10b These substrates were reacted, in separate
experiments, with excess ethereal diazomethane, at room temperature for 17–20 h, to afford
pyrazolines 8, 9, and 14, respectively, in 80–83% yield (Scheme 1). Photolysis of the pyrazolines
was carried out by irradiation with a 125-W medium-pressure mercury lamp of toluene solutions
of 8, 9, or 14, contained in Pyrex reactors. In such a way, the corresponding cyclopropanes, 10,
11, and 15 resulted in 54–60% yield. NMR analysis showed that 10 was obtained as a mixture
of the two possible diastereomers in about a 1:1 ratio. These isomers could not be separated
either by HPLC or by using other techniques. On the contrary, compounds 11 and 15 were
synthesized in a single isomeric form and they were characterized by their spectroscopic data.
While an analytical sample of compound 15 could be obtained and used for specific rotation
determination and for microanalysis, compound 11 was an unstable product unable to give the
analytical sample. This is due to the high lability of the ketal which is partially removed during
the normal purification process.11 Therefore, compound 11 was submitted to saponification of
the methyl ester and subsequent ketal hydrolysis to afford the keto acid 12. This compound
could be fully characterized and, in addition, afforded crystals suitable for X-ray structural
analysis. Fig. 1 shows the X-ray structure obtained for 12 allowing the (R,R)-configuration to
be assigned to the two stereogenic centers at the cyclopropane ring.12 By analogy, the
(S,S)-configuration was assigned to 15. This stereochemistry is easily rationalized by considering
the conformational bias of substrates 7 and 13, as described in the following section. Otherwise,
it is remarkable that the stereoselectivity is excellent when the double bond is directly linked to
a stereogenic center of the cyclobutane ring and near, therefore, to the gem-dimethyl group. On
the contrary, in 6, the separation of the double bond from the stereogenic carbon by a
methylene unit results in a loss of stereocontrol in the cyclopropanation process.
2.2. Theoretical calculations
We have studied the conformations arising from rotation around the C2ꢀC3 bond (see Fig. 2
for atom numeration) for model molecules 16 and 17. In both structures, the N-Ac protection
has been considered for simplicity, instead of N-Cbz. Thus, structure 17 is analogous to 7.
Moreover, in 16, the side chain has been changed by a hydrogen atom and, therefore, the
cyclobutane has only one stereogenic center. In this way, the steric influence of the second

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A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
Scheme 1.
side chain can be evaluated. In both cases, two energy minima with C4–C3–C2–C1 torsion
angles of about −130° and +170°, respectively, have been obtained. The first conformer, a, is
always more stable than the second one, b. For 17a and 17b we have also considered the
rotation around the dioxolane–cyclobutane bond. Fig. 2 presents the more stable structures, and
Fig. 3 shows the Newman projection for conformers a and b. In the most stable conformer a,
the presence of the gem-dimethyl group orients the attack of diazomethane to the (si,re) face of
the double bond, leading to the production of cyclopropanes with (R,R)-configuration, like
compound 11, or (S,S)-stereochemistry for substrates with the opposite configuration such as
13.

A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
4907
Figure 1. An ORTEP view of the molecular structure of 12. The thermal ellipsoids enclose 50% probability
Figure 2. BPW91 optimized geometries of the two conformers a,b of the model olefins 16 and 17, respectively. t is
the C4–C3–C2–C1 dihedral angle and relative energies are given in kcal mol−1. Methyl hydrogen atoms have been
omitted for clarity

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A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
Figure 3. Newman projections for conformers a and b related to the dehydro amino acids 7, 13, 16, and 17
2.3. Chiroptical determinations and CSA-NMR experiments
The syntheses of compounds 11 and 15 were accomplished starting from commercial
(−)-a-pinene or (−)-verbenone which were used without further treatment. Since the chemical
transformations performed on these precursors were all stereocontrolled, the products obtained
are, presumably, of high enantiomeric purity, diastereomeric purity being assessed by careful 13
and H NMR analysis.
C
1
However, optical rotations for these compounds as well as for derivative 12 were near to zero
when measured at the sodium -line (589 nm). For this reason, ORD and CD experiments were
D
undertaken to secure that the synthesized products are optically active. As a representative
example, Fig. 4 shows the results for compound 12.
The ORD curve (MeOH, 20°C) shows a great variation of a depending on the wavelength of
irradiation. Also, random oscillations were observed at different recording times, the spectrum
shown in Fig. 4(a) being the average of seven scans (see Section 4). A strong decay is observed
between 230–240 nm, the magnitude changes from positive to negative values between 240–350
nm and, finally, becomes zero. The region up to 230–240 nm contains the maximal absorption
in the UV spectrum (Fig. 4(c)) and is negligible in the CD curve (Fig. 4(b)). On the other hand,
CD shows a negative band with a minimum of 200 mdeg at 285 nm. At this wavelength,
[h]285=+435.65 (c 0.07, MeOH).
1
Finally, stereoisomeric purity was ascertained by H NMR by using the (S) enantiomer of
perdeuterio Pirkle alcohol. This CSA has been recently developed in its perdeuterated version
and it has shown its usefulness to resolve mixtures of enantiomers by NMR since the absence
of CSA signals simplifies remarkably the spectra allowing accurate determinations.13 The
induced chemical shifts depending on the CSA concentration are represented in the plots shown
in Fig. 5 for the protons of the methyl ketone group and for the methyl, from gem-dimethyl
substitution, trans to the cyclopropane ring. The determined slopes of 11.6 and 8.8, respectively,
are significant enough to confirm the interaction between the substrate and the CSA. Neverthe-
less, splitting of the signals was not observed in any case. This result is not in contradiction with
the 90% ee previously determined by us for (−)-cis-pinononic acid which derives from (−)-ver-
benone and is the common precursor to 11, 12, and 15.14
3. Concluding remarks
The cyclopropanation of cyclobutyl dehydro amino acids, obtained from (−)-a-pinene or
(−)-verbenone, has been accomplished in a highly stereoselective manner by means of 1,3-dipolar

A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
4909
Figure 4. (a) ORD spectrum (mdeg), (b) CD spectrum (mdeg), and (c) UV absorbance of compound 12 as a 1.9×10−3
M methanol solution in 1.0 cm path-length cell at 20°C
cycloaddition to diazomethane. The cyclobutyl moiety plays the role of a chiral inducer
governing the p-facial diastereoselection whose efficiency depends strongly on the proximity of

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A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
Figure 5. The variation of the chemical shift of the trans-CH3 and CH3CO protons of 12 when perdeuterio (S) Pirkle
alcohol was added (constant volume) at several ratios
the double bond to the cyclobutane. In the most favorable cases, diazomethane attacks
exclusively the face opposite to the gem-dimethyl substituent.
4. Experimental
4.1. General
Commercial (−)-a-pinene (97% ee) and (−)-verbenone (90% ee)14 purchased from Aldrich were
used without further purification. Flash column chromatography was carried out on silica gel
(240–400 mesh). Melting points were determined on a hot stage and are uncorrected. UV spectra
were acquired on a HP-8453 apparatus with software UV–vis ChemStation. ORD and CD data
were acquired on a Jasco J-715 spectropolarimeter with software J-700 for Windows. Both
spectrometers were equipped with a diode-array detector and measurements were made using
methanol solutions contained in 1.0 cm path-length cells. The ORD and CD spectra are the
1
averages of seven scans acquired over a 1 h-period with the base lines subtracted. H NMR and
13C NMR spectra were recorded at 250 and 62.5 MHz, respectively, unless otherwise stated.
CSA-NMR experiments were carried out at constant volume in a Bruker ARX-400 spectrome-
ter. The sample was prepared by dissolving compound 12 (4 mg, 11.2×10−3 mmol) in CDCl3 (0.5
mL). Four portions of CSA (1.6 mg, 5.6×10−3 mmol, 0.5 equiv.) were successively added to the
1
solution. After each addition, a H NMR spectrum was recorded. Dl were determined with
respect to the chemical shifts of the involved protons in the absence of CSA.

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4911
4.2. Computational details
Preliminary geometry optimizations have been done using the semiempirical AM115 method.
The most significant structures have been optimized through density functional calculations
using the gradient-corrected Becke’s16 exchange functional and Perdew–Wang17 correlation
functional (BPW91) with the standard 6-31G(d) basis set.18 All calculations have been done
using the Gaussian-98 program.19
4.3. General procedure for the synthesis of pyrazolines 8, 9, and 14
These compounds were synthesized from amino acids 6, 7, and 13, respectively, which were
previously described. A typical experiment is described for the preparation of pyrazoline 8. An
ethereal solution of excess diazomethane (ca. 10 equiv.) was distilled onto 6 (0.11 g, 0.24 mmol)
in 10 mL of ether. The light-protected resultant solution was stirred at room temperature
overnight, then excess diazomethane was destroyed by addition of CaCl2 and solvent was
removed to afford oily pyrazoline 8 (90 mg, 82% yield) as a 1:1 diastereomeric mixture which
was used in the next step without further purification. Pyrazolines 9 and 14 were prepared and
used in a similar manner.
4.3.1. (3R,4R,1%S,3%R) and (3S,4S,1%S,3%R)-3-N-Benzyloxycarbonylamino-4-[2%,2%-dimethyl-3%-
(2-methyl-1,3-dioxolan-2-yl)cyclobutylmethyl]-3-methoxycarbonyl-1-pyrazoline, 8
IR (film): 3406–3300 (broad, NH), 2955, 2885, 2859, 1732 (CꢁOester), 1500, 1243, 1038 cm−1.
1H NMR (acetone-d6): 0.91 and 0.92 (s, 3H, t-2%CH3), 1.02 and 1.04 (s, 3H, c-2%-CH3), 1.13 (s,
3H, CH3), 1.15–2.10 (complex absorption, 6H, R-CH2-R1/H1%/H4%a/H4%b/H3%), 2.35 (m, 1H, H4),
3.78 and 3.76 (s, 3H, OCH3), 3.70–3.95 (m, 4H, 2×OCH2); 4.50 (dd, 1H, H5a, Jgem=17.6 Hz,
J%=6.6 Hz), 4.85 (dd, J=8.0 Hz, Jgem=17.6 Hz, 1H, H5b), 5.10 (complex absorption, 2H,
CO2CH2Ph), 7.20 (broad s, 1H, NH), 7.35 (complex absorption, 5H). 13C NMR (acetone-d6)
16.83 and 17.13 (t-2%-CH3), 23.54/24.86/25.48/27.69/27.83/30.89/31.07 (4C, c-2%-CH3/RCH2R1/
C4%/CH3), 36.48/37.13/40.89/41.07/41.48/41.92/50.07/50.33/53.30 (5C, C1%/C2%/C3%/C4/OCH3),
63.74/65.51/66.65 (CO2CH2Ph/2×CH2O/OCH2Ph), 84.03 and 84.30 (C5), 101.89 (C3), 109.77
(Cq), 128.15/128.27/128.35/128.82 (5C, Caromatic), 137.32 (1C, Caromatic), 154.68 (CꢁOcarbamate),
168.97 and 169.06 (CꢁOester).
4.3.2. (3S,4S,1%R,3%R)-3-N-Benzyloxycarbonylamino-4-[2%,2%-dimethyl-3%-(2-methyl-
1,3-dioxolan-2-yl)cyclobutyl]-3-methoxycarbonyl-1-pyrazoline, 9
Yield: 85 mg, 80%. IR (film): 3550–3300 (broad, NH), 2956, 1730 (CꢁOester), 1500, 1317, 1041
1
cm−1. H NMR (acetone-d6): 0.87 (s, 3H, t-2%-CH3), 0.99 (s, 3H, c-2%-CH3), 1.11 (s, 3H, CH3),
1.40–2.10 (complex absorption, 4H, H1%/H4%a/H4%b/H3%), 2.42 (m, 1H, H4), 3.84 (s, 3H, OCH3),
3.70–4.00 (m, 4H, 2×OCH2); 4.48 (dd, 1H, H5a, Jgem=17.5 Hz, J%=7.3 Hz), 4.88 (dd, 1H, H5b,
J
gem=17.5 Hz, J=9.5 Hz), 5.01 (d, 1H, Jgem=12.4 Hz, CO2CH2Ph), 5.10 (d, 1H, Jgem=12.4 Hz,
CO2CH2Ph), 6.98 (broad s, 1H, NH), 7.40 (complex absorption, 5H). 13C NMR (acetone-d6):
18.05 (t-2%-CH3), 23.81/24.20/31.71 (3C, c-2%-CH3, C4% and CH3) 40.42/41.11/41.50/49.76 (4C,
C1%/C2%/C3%/C4), 54.17 (OCH3), 64.12/65.84/67.22 (3C, CO2CH2Ph/2×CH2O), 83.70 (C5), 100.19
(C3), 110.09 (Cq), 128.89, 129.19 (5C, Caromatic), 137.48 (1C, Caromatic), 154.47 (CꢁOcarbamate),
169.92 (CꢁOester).

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4.3.3. (3R,4R,1%S,3%R)-3-N-Benzyloxycarbonylamino-4-[3%-(2-benzyloxyethyl)-2%,2%-dimethyl-
cyclobutyl]-3-methoxycarbonyl-1-pyrazoline, 14
Yield: 100 mg, 83%; IR (film): 3406 (broad, NH), 2954, 2929, 2859, 1731 (CꢁOester), 1498,
1
1454, 1266, 1213, 1099, 1027 cm−1. H NMR (acetone-d6): 0.77 (s, 3H, t-2%CH3), 0.93 (s, 3H,
c-2%-CH3), 1.05–2.05 (complex absorption, 6H, RCH2CH2OR1/H1%/H4%a/H4%b/H3%), 2.45 (m, 1H,
H4), 3.36 (t, J1,2=6.6 Hz, 2H, RCH2CH2OR1), 3.83 (s, 3H, OCH3), 4.45 (m, 3H, OCH2Ph/H5a),
4.83 (dd, 1H, H5b, Jgem=17.5 Hz, J=8.8 Hz), 4.98 (d, Jgem=12.1 Hz, 1H, CO2CH2Ph), 5.11 (d,
J
gem=12.1 Hz, 1H, CO2CH2Ph), 6.95 (broad s, 1H, NH), 7.35 (complex absorption, 10H). 13C
NMR (acetone-d6): 17.38 (t-2%-CH3), 28.89/30.74/31.05 (3C, c-2%-CH3/C4%/RCH2CH2OR1),
40.00/40.44/40.69/41.39 (4C, C1%/C2%/C3%/C4), 54.11 (OCH3), 67.19/69.36 (2C, CO2CH2Ph/
RCH2CH2O), 73.19 (OCH2Ph), 83.64 (C5), 100.10 (C3), 128.05/128.19/128.96/129.21 (10C,
Caromatic), 134.73/139.99 (2C, Caromatic), 154.47 (CꢁOcarbamate), 169.99 (CꢁOester).
4.4. General procedure for the photolysis of the pyrazolines: cyclopropanes 10, 11, and 15
Photolysis of 8 is described as a typical instance. A stirred solution of 8 (100 mg, 0.2 mmol)
in anhydrous toluene (30 mL) contained in a Pyrex reactor under an argon atmosphere, cooled
at −78°C, was irradiated with a 125 W medium-pressure mercury lamp for 1.5 h (reaction was
monitored by UV following the disappearance of the band at ꢀ330 nm). Solvent was removed
and the residue was chromatographed (mixtures of ethyl acetate–hexane) to afford cyclopropane
10 as a mixture of diastereomers (50 mg, 58% yield). The single stereoisomers could not be
isolated by the usual chromatographic techniques.
4.4.1. Methyl (1R,2S,1%S,3%R)- and (1S,2R,1%S,3%R)-1-N-benzyloxycarbonylamino-2-[2%,2%-
dimethyl-3%-(2-methyl-1,3-dioxolan-2-yl)cyclobutylmethyl]cyclopropanecarboxylate, 10
1
IR (film): 3330 (broad, NH), 2978, 2885, 1729 (CꢁOester), 1268, 1237, 735 cm−1. H NMR
(CDCl3): 0.97 (s, 3H, t-2%-CH3), 1.07 and 1.08 (s, 3H, c-2%-CH3), 1.20 (s, 3H, CH3), 0.99–2.15
(complex absorption, 9H, RCH2R1/H1%/H4%a/H4%b/H3%/H2/H3a/H3b), 3.65 (s, 3H, OCH3), 3.75–3.95
(4H, m, 2×OCH2); 5.10 (s, 3H, -OCH2Ph and NH), 7.34 (complex absorption, 5H). 13C NMR
(CDCl3): 16.98 and 17.18 (t-2%-CH3), 22.95 and 23.42 (C3), 23.68/24.68/24.89/27.18/28.33/28.42/
31.15 (5C, c-2%-CH3%/C4%/CH3/C2/RCH2R1), 37.62/38.33/40.83/40.89/42.09/49.83/49.91 (4C, C1%/
C2%/C3%/C1), 52.35 (CH3), 63.62/65.41/66.88 (3C, CO2CH2Ph, 2×CH2O), 109.85 (Cq),
128.08/128.44 (5C, Caromatic), 136.29 (1Caromatic), 156.82 (CꢁOcarbamate), 173.43 (CꢁOester). Anal.
calcd for C24H33NO6: C, 66.80; H, 7.71; N 3.25. Found: C, 66.85; H, 7.78; N, 3.50.
4.4.2. (−)-Methyl (1R,2R,1%R,3%R)-1-N-benzyloxycarbonylamino-2-[2%,2%-dimethyl-3%-(2-methyl-
1,3-dioxolan-2-yl)cyclobutyl]cyclopropanecarboxylate, 11
Yield: 50 mg, 60%. This compound was an unstable oil not suitable for [h] determination and
for microanalysis. IR (film): 3445–3353 (broad, NH), 2953, 1721 (CꢁOester), 1455, 1226, 1154
1
cm−1. H NMR (CDCl3): 1.06 (s, 3H, t-2%CH3), 1.10 (s, 3H, c-2%-CH3), 1.19 (s, 3H, CH3), 1.10
(m, 1H, H3a), 1.40–2.15 (complex absorption, 6H, H1%/H4%a/H4%b/H3%/H2/H3b), 3.66 (s, 3H, OCH3),
3.75–3.95 (m, 4H, 2×OCH2); 4.98 (broad s, NH), 5.11 (m, 2H, -OCH2Ph), 7.33 (complex
absorption, 5H). 13C NMR (acetone-d6): 17.71 (t-2%-CH3), 20.21 (C3), 23.18/23.45/27.83/30.89
(4C, c-2%-CH3/C4%/CH3/C2), 38.07/40.30/41.57/50.01 (4C, C1%/C2%/C3%/C1), 51.89 (OCH3), 63.71/
65.45/66.06 (3C, CO2CH2Ph/2×CH2O), 109.85 (Cq), 128.09/128.65 (5C, Caromatic), 137.79
(Caromatic), 156.85 (CꢁOcarbamate), 173.29 (CꢁOester); MS, m/e (%) 418 (M+1, 23.6), 373 (10.5), 356
(24.5), 304 (100), 260 (27.8), 205 (21.4).

A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
4913
4.4.3. Methyl (1S,2S,1%S,3%R)-N-benzyloxycarbonylamino-2-[3%-(2-benzyloxyethyl)-2%,2%-di-
methylcyclobutyl]cyclopropanecarboxylate, 15
Yield: 50 mg, 54%. Oil, [h]285=−164.83 (c 0.09, MeOH). IR (film): 3339 (broad, NH), 2952,
1
2859, 1728 (CꢁOester), 1498, 1454, 1270, 1236, 1197, 1163, 1093, 738, 698 cm−1. H NMR
(CDCl3): 0.92 (s, 3H, t-2%CH3), 1.01 (s, 3H, c-2%-CH3), 0.99–2.10 (complex absorption, 9H,
RCH2CH2OR1/H1%/H4%a/H4%b/H3%/H2/H3a/H3b), 3.35 (t, J1,2=6.6 Hz, 2H, RCH2CH2OR1), 3.66 (s,
3H, OCH3), 4.45 (broad s, 2H, OCH2Ph), 4.97 (broad s, 1H, NH), 5.12 (m, 2H, CO2CH2Ph),
7.32 (complex absorption, 10H). 13C NMR (acetone-d6): 16.86 (t-2%-CH3), 20.21 (C3), 27.65/
30.30, (4C, c-2%-CH3/C4%/RCH2CH2OR1/C2), 37.45/39.42/40.18/40.45 (4C, C1%/C2%/C3%/C1), 51.65
(OCH3), 65.89/68.71 (2C, CO2CH2Ph/RCH2O), 72.45 (OCH2Ph), 127.12/127.26/127.65/128.03/
128.18 (10C, Caromatic), 136.97/138.85 (2C, Caromatic), 156.47 (CꢁOcarbamate), 172.91 (CꢁOester).
Anal. calcd for C28H35NO5: C, 72.23; H, 7.58; N, 3.01. Found: C, 72.35; H, 7.61; N, 3.09.
4.5. (1R,2R,1%R,3%R)-1-N-benzyloxycarbonylamino-2-[3%-acetyl-2%,2%-dimethylcyclobutyl]-
cyclopropanecarboxylic acid, 12
A mixture of ester 11 (150 mg, 0.3 mmol) and 1N aq. NaOH (1.6 mL) in methanol (1.5 mL)
was stirred at room temperature for 20 h. The reaction mixture was extracted with
dichloromethane and the aqueous layer was acidified with 5% HCl and then extracted with
dichloromethane. This last extract was concentrated under vacuum and the residue was poured
into wet acetone (1 mL). Then PPTS (25 mg) was added and the resultant solution was heated
to reflux for 5 h. Solvent was evaporated and the residue was subsequently dissolved in ether
and washed with water. The organic phase was dried (MgSO4) and solvent was removed to
afford keto acid 12 (45 mg, 35% yield) as a solid mp 163–165°C (from ethanol–water), [h]285
=
+435.65 (c 0.07, MeOH). IR (film): 3451 (broad, OH), 3350 (broad, NH), 2959, 1708 (CꢁO),
1
1433, 1258, 1082 cm−1. H NMR (CDCl3, 400 MHz): 0.91 (s, 3H, t-2%CH3), 1.28 (s, 3H,
c-2%-CH3), 2.01 (s, 3H, CH3), 1.12 (1H, m, H3a), 1.60–1.80 (complex absorption, 3H, H4a/b/H3b),
2.05 (2H, m, H1%/H2), 2.78 (1H, m, H3), 5.03 (broad s, 1H, NH), 5.12 (complex absorption, 2H,
OCH2Ph), 7.33 (broad s, 5H). 13C NMR (acetone-d6): 17.18 (t-2%-CH3), 19.41 (C3), 21.03/27.06/
29.47 (4C, c-2%-CH3/C4%/CH3/C2), 37.53/39.56/41.35/43.15 (4C, C1%/C2%/C3%/C1), 53.26 (OCH3),
65.73 (CO2CH2Ph), 127.73/128.29 (5C, Caromatic), 137.38 (Caromatic), 156.64 (CꢁOcarbamate), 173.52
(CꢁOester), 206.14 (CꢁOketone). Anal calcd for C20H25NO5: C, 66.84; H, 7.01; N, 3.90. Found: C,
66.54; H, 7.26; N, 3.83.
Acknowledgements
Authors are grateful to Prof. Albert Virgili and Dr. Anna Mun˜oz, UAB, for their helpful
advice and assistance in the CSA-NMR experiments, as well as for a generous gift of
perdeuterio Pirkle alcohol. A.G.M. thanks the CONICET (Argentina) for a grant. E.G.-E.
thanks the CIRIT (Generalitat de Catalunya) for a predoctoral fellowship. Financial support
from DGESIC (Spain) and from Fundacio´n Antorchas (Argentina) through the projects
PB97-0214 and A-1362211-70, respectively, is gratefully acknowledged.

4914
A. G. Moglioni et al. / Tetrahedron: Asymmetry 11 (2000) 4903–4914
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