Synthesis of 2-methyl- and 2-methylenecyclobutane amino acids

Article abstract of DOI:10.1016/j.tet.2005.02.039

An efficient and easy formal [2+2] cycloaddition (Michael-Dieckmann-type reaction) on methyl 2-acetamidoacrylate with ketene diethyl acetal gave the cyclobutane core. Two kinds of 2-substituted cyclobutane amino acids have been obtained from this compound

Full text of DOI:10.1016/j.tet.2005.02.039

Tetrahedron 61 (2005) 4165–4172
Synthesis of 2-methyl- and 2-methylenecyclobutane amino acids
* *
´
Alberto Avenoza, Jesus H. Busto, Jesus M. Peregrina and Marta Perez-Fernandez
´
´
´
´ ´ ´
Departamento de Quımica, Universidad de La Rioja, Grupo de Sıntesis Quımica de La Rioja, U.A.-C.S.I.C., E-26006 Logron˜o, Spain
Received 13 October 2004; revised 29 October 2004; accepted 8 November 2004
Abstract—An efficient and easy formal [2C2] cycloaddition (Michael–Dieckmann-type reaction) on methyl 2-acetamidoacrylate with
ketene diethyl acetal gave the cyclobutane core. Two kinds of 2-substituted cyclobutane amino acids have been obtained from this compound
by means of stereocontrolled interconversion of functional groups: 1-amino-2-methylcyclobutane-1-carboxylic acids (2,4-methanovalines)
and 1-amino-2-methylenecyclobutane-1-carboxylic acid. The latter amino acid can be regarded as a restricted a-methyl-a-vinylglycine.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
1-Aminocycloalkane-1-carboxylic acids,1 especially those
with three-, five-, or six-membered rings, have attracted
considerable attention, mainly due to the conformational
restriction produced when they are incorporated into
peptides.2 Despite this interest, 1-aminocyclobutane-1-
carboxylic acids received very little attention until 1980.3
Since then, a number of naturally occurring cyclobutane
amino acids were discovered and several derivatives were
found to be potent neurotransmitters.4 Synthetic efforts have
since been extended to a whole range of cyclobutane amino
acids of potential biological interest.5
Figure 1. The all four stereoisomers of 2,4-methanovalines 1.
As part of our research programme on the synthesis of cyclic
amino acids,8 we recently described the synthesis of the
serine analogue derivative 2, which incorporates the
cyclobutane skeleton (c4Ser).8h The key step in this
synthesis involves a reaction of methyl 2-acetamidoacrylate
5 with ketene diethyl acetal 6 in a formal [2C2]
cycloaddition (Scheme 1).
Nevertheless, the synthesis of 2-substituted cyclobutane
amino acids has not received the same attention as the
preparation of other substituted cyclobutane a-amino acids5
and, to the best of our knowledge, only a few methods for
the synthesis of 1-amino-2-alkylcyclobutane-1-carboxylic
acids have been described.6 In particular, (1S*,2S*)-1-
amino-2-methylcyclobutane-1-carboxylic acid (1) (2,4-
methanovaline) was first synthesized by Gaoni in 1995
by the azidation of methyl 2-methyl-3-(phenylsulfonyl)bi-
cyclo[1.1.0]butane-1-carboxylate, followed by hydrogen-
ation, desulfonylation and hydrolysis.5c Later, Frahm and
co-workers7 obtained the four stereoisomers in enantiopure
form by an asymmetric Strecker synthesis starting from
racemic 2-methylcyclobutanone and (R)-phenylethylamine
as a chiral auxiliary, which gave poor diastereoselectivity,
followed by separation by column chromatography (Fig. 1).
Keywords: Amino acid; Cyclobutane; Hydrogenation; Valine.
*
Corresponding authors. Tel./fax: C34 941 299655;
e-mail addresses: alberto.avenoza@dq.unirioja.es;
jesusmanuel.peregrina@dq.unirioja.es
Scheme 1. Retrosynthesis of a c4Ser derivative from methyl 2-acetamido-
acrylate 5 by a [2C2] cycloaddition.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.039

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A. Avenoza et al. / Tetrahedron 61 (2005) 4165–4172
In this way, the cyclobutane skeleton was obtained by a
tandem Michael–Dieckmann-type process that gave com-
pound 4, which was then transformed into the intermediate 3
(Scheme 1).
was achieved with 3.0 equiv of this base, which afforded
alkene 8 in 86% yield (Scheme 3).
The structure of compound 8 was confirmed by X-ray
analysis† of monocrystals and is shown in the ORTEP
representation Figure 2.
This pathway opens the door to important 2-substituted
cyclobutane amino acids. In an effort to exemplify this
feature, we decided to explore the reactivity of intermediate
3 as a building block in stereocontrolled organic synthesis in
order to obtain both stereoisomers of 2,4-methanovaline 1
as well as 2-methylenecyclobutane amino acid 7 in racemic
forms (Scheme 2).
Scheme 2. Retrosynthesis of 2-substituted cyclobutane amino acids from
intermediate 3.
b,g-Unsaturated amino acid derivatives have received a
great deal of attention because they are important enzyme
inhibitors.9 For example, a-vinyl amino acids are known to
inhibit pyridoxal phosphate-dependent enzymes and, in
particular, amino acid decarboxylases.10 Given this back-
ground, the interesting amino acid 7 can be regarded as a
particularly restricted analogue of a-vinylalanine.11 More-
over, it has only been synthesized on one occasion and
this involved isomerization of a spiranic amino acid
derivative.12
Figure 2. ORTEP representation of compound 8.
Subsequent cleavage of the silyl group in compound 8 with
tetrabutylammonium fluoride (TBAF) in THF at room
temperature gave the corresponding primary alcohol 9 in
excellent yield. This compound was subjected to oxidation
in the presence of Jones reagent14 to give the carboxylic acid
derivative 10. The required amino acid 7 was obtained as the
hydrochloride salt by acid hydrolysis of 10 using 3 N HCl
at reflux. In order to purify carboxylic acid derivative 10,
an aliquot was converted into the corresponding methyl
ester by addition of diazomethane in ethyl ether at room
temperature. Acid hydrolysis of compound 11 gave amino
acid 7 as the hydrochloride salt with a similar yield
(Scheme 3).
2. Results and discussion
2.1. Synthesis of 2-methylenecyclobutane amino acid 7
Racemic 2-methylenecyclobutane amino acid 7 was
obtained as the hydrochloride salt in 22% overall yield
from a four-step synthesis starting from intermediate 3
(Scheme 3). The initial step involved Wittig methylena-
tion13 of 3 and was carried out under salt-free Wittig
conditions using methyltriphenylphosphonium bromide
(Ph3PMeCBrK) with several bases tested. The use of
2.0 equiv of potassium bis(trimethylsilyl)amide (KHMDS)
at K78 8C gave 67% yield of alkene 8 but the best result
2.2. Synthesis of racemic 2-methylcyclobutane amino
acids (1S*,2S*)-1
Starting from compound 8, which in turn comes from the
intermediate 3, we envisioned a synthetic route to the
† The monocrystals were obtained by slowly adding octane to a solution of
compound 8 in dichloromethane to form an interface. The crystal grew at
the border of the two solvents. Crystal data: C48H62N2O4Si2, MwZ
787.18, colourless prism of 0.50!0.42!0.20 mm3, TZ223(2) K,
˚
˚
triclinic, space group P-1, ZZ2, aZ9.6181(4) A, bZ14.6066(6) A,
˚
cZ16.5421(8) A, aZ79.3829(17), bZ82.0665(17), gZ90.0352(13),
VZ2261.51(17) A , dcalcZ1.156 g cmK3, F(000)Z848, lZ0.71073 A
(Mo Ka), mZ0.12 mmK1, Nonius kappa CCD diffractometer, q range
1.26–28.008, 28,939 collected reflections, 10,432 unique (RintZ0.1694),
full-matrix least-squares (SHELXL97),15 R1Z0.1156, wR2Z0.2618,
(R1Z0.2373, wR2Z0.3537 all data), goodness of fitZ1.601, residual
3
˚
˚
electron density between 0.870 and K1.034 e AK3. Hydrogen atoms
˚
Scheme 3. Reagents and conditions: (i) KHMDS (3.0 equiv), Ph3PMeCBrK
THF, rt, 5 h, 86%; (ii) TBAF, THF, rt, 1 h, 91%; (iii) Jones reagent,
acetone, 0 8C, 4 h, 64%; (iv) CH2N2, ethyl ether, rt, 30 min, 85%; (v) 3 N
HCl, reflux, 3 h, 51%.
,
were located from mixed methods. Further details on the crystal structure
are available on request from Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, UK on quoting the depository number
239349.

A. Avenoza et al. / Tetrahedron 61 (2005) 4165–4172
4167
alcohol (1S*,2S*)-13, which was treated with Jones reagent
to give the carboxylic acid (1S*,2S*)-14. Acid hydrolysis of
this compound furnished the racemic 2,4-methanovaline
(1S*,2S*)-1, as its hydrochoride salt, in which the
carboxylic acid group and methyl substituent are in a cis
disposition. This stereochemistry was confirmed by ROE
experiments on compound (1S*,2S*)-13 (see Section 2.4).
2.3. Synthesis of racemic 2-methylcyclobutane amino
acids (1S*,2R*)-1
Racemic 2,4-methanovaline (1S*,2R*)-1 was obtained
following the same strategy as described above for 2,4-
methanovaline (1S*,2S*)-1, but starting from compound 9,
which was obtained by desilylation of compound 8
(Scheme 5). The structure of the new starting compound 9
was determined by X-ray analysis‡ in the same way as for
compound 8 (Fig. 3).
Scheme 4. Reagents and conditions: (i) H2, Pd–C, CH2Cl2, rt, 17 h, 96%;
(ii) TBAF, THF, rt, 1 h, 76%; (iii) Jones reagent, acetone, 0 8C, 2 h, 73%;
(iv) 3 N HCl, reflux, 6 h, 90%.
2-methylcyclobutane amino acid (1S*,2S*)-1. The reaction
sequence on compound 8 starts with a selective hydrogen-
ation followed by deprotection by removing the silyl group,
oxidation and hydrolysis (Scheme 4).
Hydrogenation of the exocyclic double bond in compound 8
using palladium–carbon as a catalyst was studied in two
solvents. Ethyl acetate gave an excellent yield (97%) of the
mixture of hydrogenation products (1S*,2S*)-12 and
(1S*,2R*)-12 and a stereoselectivity of 89:11 in favour of
(1S*,2S*)-12. Fortunately, dichloromethane gave a similar
yield (96%) but the stereoselectivity was increased to 93:7.
Once separated by column chromatography, (1S*,2S*)-12
was desilylated by the action of TBAF to give primary
Figure 3. ORTEP structure of compound 9.
Hydrogenation of the double bond in compound 9 was
investigated under several sets of conditions. Initially,
the homogeneous hydrogenation was attempted with
(Ph3P)3RhCl and after 24 h at 55 8C only a 16% of
hydrogenation products (1S*,2S*)-13 and (1S*,2R*)-13
was obtained without selectivity. Therefore, the hetero-
geneous hydrogenation was assayed using palladium–
carbon in three different solvents; methanol, ethyl acetate
and dichloromethane. In all cases the yield was excellent
(98, 96 and 95%, respectively) and the stereoselectivity of
hydrogenated products (1S*,2S*)-13 and (1S*,2R*)-13 was
as follows, 45:55, 38:62 and 37:63, respectively, always in
favour of (1S*,2R*)-13. The change in the catalyst for
the hydrogenation only led to a slight increase in the
‡ Crystal data: C8H13NO2, MwZ155.19, colourless prism of 0.50!0.37!
0.25 mm3, TZ223(2) K, monoclinic, space group P 21/c, ZZ4, aZ
˚
˚
˚
8.5399(3) A, bZ10.0205(4) A, cZ10.3072(4) A, aZ90, bZ104.454(2),
gZ90, VZ854.11(6) A , dcalcZ1.207 g cmK3, F(000)Z336, lZ
3
˚
0.71073 A (Mo Ka), mZ0.087 mmK1, Nonius kappa CCD diffract-
˚
ometer, q range 2.03–27.888, 6840 collected reflections, 2009 unique
(RintZ0.0755), full-matrix least-squares (SHELXL97),15 R1Z0.0687,
wR2Z0.2038, (R1Z0.0812, wR2Z0.2174 all data), goodness of fitZ
K3
˚
1.068, residual electron density between 0.425 and K0.352 e A
.
Hydrogen atoms were located from mixed methods. Further details on the
crystal structure are available on request from Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, UK on quoting the
depository number 239348.
Scheme 5. Reagents and conditions: (i) H2, Pd(OH)2–C, CH2Cl2, rt, 17 h;
(ii) TBDPSCl, imidazole, DMF, 50 8C, 17 h; (iii) column chromatography:
hexane/ethyl acetate 65:35; 32% from 9; (iv) TBAF, THF, rt, 1 h, 95%;
(v) Jones reagent, acetone, 0 8C, 2 h, 63%; (vi) 3 N HCl, reflux, 6 h, 70%.

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A. Avenoza et al. / Tetrahedron 61 (2005) 4165–4172
stereoselectivity; indeed, when the hydrogenation was
carried out in the presence of palladium hydroxide
supported on carbon and using dichloromethane as solvent,
the stereoselectivity was 34:66 with a yield of 95%. This
mixture of products could not be separated by column
chromatography, so it was transformed into the correspond-
ing silylated derivatives (1S*,2S*)-12 and (1S*,2R*)-12
with tert-butyldiphenylsilyl chloride (TBDPSCl). Once
separated, (1S*,2R*)-12 was desilylated to give pure
(1S*,2R*)-13, which was oxidized to carboxylic acid
(1S*,2R*)-14 and hydrolysed to give the desired racemic
2,4-methanovaline (1S*,2R*)-1 as its hydrochloride salt
(Scheme 5).
2.4. Stereochemical outcome of the hydrogenation
Figure 5. PES scans with PM3 method on compound 8.
The stereochemistry of the minor product (1S*,2S*)-13
obtained in the heterogeneous hydrogenation reaction of
compound 9 was assigned on the basis of selective gradient-
enhanced 1D ROESY experiments.16 Therefore, once the
signals of the 1H NMR spectra of this compound were
assigned by COSY and HSQC experiments, the signal at
6.30 ppm, corresponding to the NH proton, was presaturated
using a mixing time of 500 ms. As a consequence, a ROE
enhancement of 2% was observed in the signal at 2.53 ppm,
corresponding to proton H-2, indicating that the NHAc
group is in a cis disposition with respect to the H-2 proton
attached to C-2 of the cyclobutane ring. When the same
experiment was performed on the major product (1S*,2R*)-
13, a ROE enhancement was not observed on proton H-2
(Fig. 4).
The lowest energy structure found in these preliminary
calculations was fully optimised and characterised by a
frequency calculation that took into account the solvent
effects using the Onsager SCRF method18 implemented in
Gaussian 98. A dielectric constant of 8.93 (dichloro-
methane) was used in order to be consistent with the
experimental conditions. The calculations were carried out
at the B3LYP/6-31G(d) level19 with the Gaussian 98
package20 (Fig. 6).
Figure 4. Selective 1D ROESY on compound (1S*,2S*)-13.
Figure 6. Optimized structure at B3LYP/6-31G(d) level considering solvent
effects (Onsager) for compound 8.
A number of calculations were performed in an effort to
explain the stereochemical outcome obtained in the
hydrogenation of compound 8. First, and in order to obtain
the conformational preferences of compound 8, the initial
geometry extracted from the X-ray structure of this
compound was optimised by the semi-empirical PM3
method17 with the CS MOPAC Pro 8.0 program based on
MOPAC 2000, as implemented in Chem3D Ultra 8.0
software. Once other variables had been properly evaluated,
the relaxed potential-energy surface (PES) scan was
performed by varying the CH2–O–Si–C(CH3)3 dihedral
angle with step-sizes of 58 (Fig. 5). The global minimum
was located at 2908.
The geometry obtained from the calculations that con-
sidered the solvent effects was very similar to that obtained
from the solid state. In order to confirm this feature
a gradient-enhanced 2D NOESY experiment,21 using a
mixing time of 500 ms, was performed on compound 8 and
a small NOE enhancement between vinylic protons and the
protons of the tert-butyl group was observed. Therefore, it
can be concluded that the conformation obtained in both the
calculation and the solid state also exists in solution (Fig. 6).
In this situation the tert-butyl group probably shields the re

A. Avenoza et al. / Tetrahedron 61 (2005) 4165–4172
4169
face of the double bond of compound 8 in such a way that
the olefinic bond is forced to coordinate to the catalyst
surface by the Si face. Consequently, the addition of
hydrogen occurs at this face to give a remarkably
stereochemically controlled hydrogenated product
(1S*,2S*)-12 (Fig. 6). In contrast, when the hydrogenation
is carried out on olefin 9, we believe that the opposite
selectivity obtained is due to the presence of a coordinating
function, that is, the primary alcohol, in the olefinic
molecule. This group anchors itself on the catalyst surface
and forces the addition of hydrogen to its own side of
the molecule (Re face). There are numerous examples in
the literature of such an anchoring effect.22
(20 mL) at 25 8C and KHMDS (0.5 M in toluene, 7.6 mL,
3.80 mmol) was added. The resulting yellow suspension
was stirred at 25 8C for 1 h, then cooled to K78 8C and a
solution of ketone 3 (500 mg, 1.27 mmol) in THF (10 mL)
was added dropwise. The cooling bath was removed and the
mixture allowed to reach 25 8C over 5 h. The reaction was
quenched with MeOH (2 mL) and the resulting mixture
was poured into a saturated solution of potassium sodium
tartrate and H2O (1:1, v/v, 30 mL). Extraction with ethyl
ether (2!15 mL), drying and evaporation of the solvent
gave a pale yellow syrup, which was purified by column
chromatography (hexane/ethyl acetate, 7:3) to give 8
1
(430 mg, 86%) as a white solid. Mp 114–116 8C. H NMR
(CDCl3): d 1.08 [s, 9H, C(CH3)3], 1.92 (s, 3H, CH3CO),
1.97–2.08 (m, 1H, CH2C–N), 2.40–2.72 (m, 3H, CH2C–N,
CH2C]CH2), 3.76 (d, 1H, JZ9.9 Hz, CH2O), 3.87 (d, 1H,
JZ10.2 Hz, CH2O), 4.91 (s, 1H, C]CH2), 5.05 (s, 1H,
C]CH2), 5.88 (br s, 1H, NH), 7.36–7.47 (m, 6H, Arom.),
7.64–7.68 (m, 4H, Arom.); 13C NMR (CDCl3): d 19.3
[C(CH3)3], 23.9 (CH3CO), 25.7 (CH2C–N), 26.8 [C(CH3)3],
27.0 (CH2C]CH2), 63.1 (CCH2O), 66.7 (CCH2O), 106.5
(C]CH2), 127.8, 129.7 (Arom.), 133.2 (C]CH2), 135.6,
151.1 (Arom.), 169.2 (CONH); ESIC (m/z)Z393.9. Anal.
Calcd for C24H31NO2Si: C, 73.24; H, 7.94; N, 3.56. Found:
C, 73.54; H, 7.90; N, 3.50.
3. Conclusions
In summary, we have developed a new stereoselective
synthetic route for 2-substituted cyclobutane-a-amino acids
from the cycloadduct obtained in the formal [2C2]
cycloaddition of methyl 2-acetamidoacrylate and ketene
diethyl acetal. Two kinds of a-amino acid could be
synthesised, 2-alkyl- and 2-alkylidenecyclobutane-a-
amino acids. As an example of the first type, both
stereoisomers of the well-known 2,4-methanovaline were
obtained in racemic form by stereocontrolled reactions on
the aforementioned cyclobutane derivative. The key step
is the hydrogenation of an exocyclic double bond. This
reaction is controlled by the functional groups attached to
the cyclobutane skeleton. The second type of amino acid
was exemplified by the synthesis of 1-amino-2-methylene-
cyclobutane-1-carboxylic acid, which can be considered
as a conformationally restricted analogue of an important
b,g-unsaturated a-amino acid (a-vinylalanine).
4.1.2. N-[1-(Hydroxymethyl)-2-methylenecyclobutyl]-
acetamide 9. TBAF (1.53 mL, 1 M in THF) was added to
a solution of compound 8 (500 mg, 1.53 mmol) in dry THF
(15 mL) at 25 8C under an inert atmosphere and the mixture
was stirred for 1 h. Saturated aqueous NH4Cl (10 mL) was
added and the organic material was extracted with CHCl3/
iPrOH (4:1) (2!20 mL). The organic layers were dried,
filtered and concentrated. The residue was purified by silica
gel column chromatography, eluting with hexane/ethyl
acetate (5:95), to give 180 mg (91%) of 9 as a white solid.
4. Experimental
1
Mp 85–87 8C. H NMR (CDCl3): d 1.97 (s, 3H, CH3CO),
2.17–2.24 (m, 1H, CH2C–N), 2.30–2.39 (m, 1H, CH2C–N),
2.54–2.63 (m, 2H, CH2C]CH2), 3.65–3.77 (m, 2H, CH2O),
4.86 (s, 1H, C]CH2), 4.99 (s, 1H, C]CH2), 6.44 (br s, 1H,
NH); 13C NMR (CDCl3): d 23.5 (CH2C]CH2), 25.8
(CH3CO), 28.1 (CH2C–N), 64.7 (CCH2O), 67.0 (CCH2O),
106.6 (C]CH2), 151.1 (C]CH2), 171.2 (CONH); ESIC
(m/z)Z156.1. Anal. Calcd for C8H13NO2: C, 61.91; H, 8.44;
N, 9.03. Found: C, 61.97; H, 8.47; N, 9.07.
4.1. General procedures
Solvents were purified according to standard procedures.
Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using Silica
gel 60 (230–400 mesh). H and 13C NMR spectra were
1
recorded on a Bruker ARX-300 spectrometer using CDCl3
with TMS as the internal standard or using CD3OD or D2O
with TMS as the external standard with a coaxial microtube
(chemical shifts are reported in ppm on the d scale, coupling
constants in Hz). The assignment of all separate signals in
4.1.3. 1-Acetamido-2-methylenecyclobutane-1-carb-
oxylic acid 10. To a solution of compound 9 (120 mg,
0.77 mmol) in acetone (15 mL) at 0 8C was added a 2.0-fold
excess of Jones reagent (0.77 mL, 2 M in water) dropwise
over 5 min. The mixture was stirred at 0 8C for 4 h. The
1
the H NMR spectra was made on the basis of coupling
constants, proton–proton COSY experiments and proton–
carbon HETCOR experiments on a Bruker AVANCE 400
spectrometer. This spectrometer was also used for the
selective gradient-enhanced 1D ROESY and 2D NOESY
experiments described in the text. Melting points were
determined on a Bu¨chi SMP-20 melting point apparatus and
are uncorrected. Microanalyses were carried out on a CE
Instruments EA-1110 analyser and are in good agreement
with the calculated values.
i
excess Jones reagent was destroyed with PrOH. The
mixture was then diluted with water (10 mL) and extracted
with CHCl3/iPrOH (4:1) (3!15 mL). The combined
organic extracts were dried with anhydrous Na2SO4 and
concentrated in vacuo to give 77 mg (64%) of compound 10
as a white solid. This compound was used in the next step
1
without further purification. Mp O200 8C (decomp.). H
NMR (CD3OD): d 1.96 (s, 3H, CH3CO), 2.04–2.13 (m, 1H),
2.67–2.79 (m, 2H), 2.86–2.95 (m, 1H), 5.00 (s, 1H,
C]CH2), 5.23 (s, 1H, C]CH2); 13C NMR (CD3OD): d
21.5, 26.4, 28.7, 64.4 (CCOO), 109.9 (C]CH2), 147.0
4.1.1. N-[1-(tert-Butyldiphenylsilyloxymethyl)-2-methyl-
enecyclobutyl]acetamide 8. Methyltriphenylphosphonium
bromide (1.36 g, 3.80 mmol) was suspended in THF

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A. Avenoza et al. / Tetrahedron 61 (2005) 4165–4172
(C]CH2), 173.9, 175.0 (COO, CONH); ESIC (m/z)Z
170.1.
4.1.7. (1S*,2S*)-N-[1-(Hydroxymethyl)-2-methylcyclo-
butyl]acetamide (1S*,2S*)-13. TBAF (0.52 mL, 1 M in
THF) was added to a solution of (1S*,2S*)-12 (170 mg,
0.43 mmol) in dry THF (15 mL) at 20 8C under an inert
atmosphere and the mixture was stirred for 1 h. Saturated
aqueous NH4Cl (10 mL) was added and the organic material
was extracted with CHCl3/iPrOH (4:1) (2!15 mL). The
combined organic layers were dried, filtered and concen-
trated. The residue was purified by silica gel column
chromatography, eluting with hexane/ethyl acetate (5:95),
to give 52 mg (76%) of (1S*,2S*)-13 as a white solid. Mp
4.1.4. 1-Acetamido-2-methylenecyclobutane-1-carb-
oxylic acid methyl ester 11. Compound 10 was purified
by transforming the carboxylic acid group into the
corresponding methyl ester by addition of an excess of an
ethereal solution of diazomethane to a solution of the
carboxylic acid 10 (12 mg, 0.07 mmol) in ethyl ether
(3 mL). The mixture was stirred for 10 min, then anhydrous
CaCl2 was added and the solution was filtered, the solvent
evaporated and the residue purified by silica gel column
chromatography, eluting with hexane/ethyl acetate (3:7), to
1
112–113 8C. H NMR (CDCl3): d 1.08 (d, 3H, JZ7.0 Hz,
CH3CH), 1.40–1.53 (m, 1H, CH2CH), 1.87–2.10 (m, 5H,
CH3CO, CH2CH, CH2C), 2.21–2.29 (m, 1H, CH2C), 2.46–
2.54 (m, 1H, CH3CH), 3.77–3.88 (m, 2H, CH2O), 4.38 (br s,
1H, OH), 6.22 (br s, 1H, NH); 13C NMR (CDCl3): d 15.0
(CH3CH), 23.1 (CH2CH), 23.6 (CH3CO), 28.4 (CH2C), 39.8
(CH3CH), 60.4 (CH2C), 65.0 (CH2O), 171.5 (CONH);
ESIC (m/z)Z158.3. Anal. Calcd for C8H15NO2: C, 61.12;
H, 9.62; N, 8.91. Found: C, 61.22; H, 9.56; N, 8.88.
1
give 9 mg (85%) of methyl ester 11 as a colourless oil. H
NMR (CDCl3): d 2.00 (s, 3H, CH3CO), 2.27–2.37 (m, 1H,
CH2CCOO), 2.72–2.79 (m, 2H, CH2C]CH2), 2.85–2.91
(m, 1H, CH2CCOO), 3.75 (COOCH3), 4.96 (s, 1H,
C]CH2), 5.09 (s, 1H, C]CH2), 6.38 (br s, 1H, NH); 13C
NMR (CDCl3): d 23.0 (CH3CO), 26.3 (CH2C]CH2), 28.8
(CH2CCOO), 52.8 (COOCH3), 64.4 (CCOO), 108.4
(C]CH2), 148.2 (C]CH2), 169.4, 171.3 (COO, CONH);
ESIC (m/z)Z184.0. Anal. Calcd for C9H13NO3: C, 59.00;
H, 7.15; N, 7.65. Found: C, 58.91; H, 7.22; N, 7.58.
4.1.8. (1S*,2S*)-1-Acetamido-2-methylcyclobutane-1-
carboxylic acid (1S*,2S*)-14. To a solution of (1S*,2S*)-
13 (49 mg, 0.32 mmol) in acetone (10 mL) at 0 8C was
added a 1.5-fold excess of Jones reagent (0.23 mL, 2 M in
water) dropwise over 5 min. The mixture was stirred at
20 8C for 2 h. The excess Jones reagent was destroyed with
iPrOH. The mixture was then diluted with water (10 mL)
and extracted with CHCl3/iPrOH (4:1) (3!15 mL). The
combined organic extracts were dried with anhydrous
Na2SO4 and concentrated in vacuo to give 40 mg (73%)
of (1S*,2S*)-14 as a white solid. This compound was used
in the next step without further purification. Mp O200 8C
4.1.5. 1-Amino-2-methylenecyclobutane-1-carboxylic
acid hydrochloride salt 7$HCl. The white solid corre-
sponding to carboxylic acid 10 (77 mg, 0.46 mmol) was
dissolved in aqueous 3 N HCl (5 mL) and heated at 100 8C
for 3 h. The solution was concentrated to give a residue,
which was eluted through a C18 reverse-phase Sep-pak
cartridge to give, after removal of the water, 39 mg of a
white solid; yield: 51%. Mp O200 8C (decomp.). 1H NMR
(D2O): d 2.31–2.41 (m, 1H), 2.66–2.75 (m, 2H), 2.84–2.92
(m, 1H), 5.21–5.24 (m, 1H, C]CH2), 5.27–5.29 (m, 1H,
C]CH2); 13C NMR (D2O): d 25.1 (CH2C]CH2), 27.5
(CH2CCOO), 63.5 (CCOO), 113.1 (C]CH2), 144.8
(C]CH2), 173.1 (COO). Anal. Calcd for C6H10ClNO2: C,
44.05; H, 6.16; N, 8.56. Found: C, 44.18; H, 6.20; N, 8.61.
1
(decomp.). H NMR (CD3OD): d 1.03 (d, 3H, JZ5.4 Hz,
CH3CH), 1.63–1.75 (m, 1H, CH2CH), 1.87–2.07 (m, 5H,
CH3CO, CH2CH, CH2C), 2.61–2.82 (m, 2H, CH2C,
CH3CH); 13C NMR (CD3OD): d 16.9 (CH3CH), 22.5
(CH3CO), 24.6 (CH2CH), 30.6 (CH2C), 39.7 (CH3CH), 64.0
(CH2C), 172.9, 175.9 (COO, CONH); ESIC (m/z)Z172.2.
4.1.9. (1S*,2S*)-1-Amino-2-methylcyclobutane-1-carb-
oxylic acid hydrochloride salt (1S*,2S*)-1$HCl. The
white solid corresponding to carboxylic acid (1S*,2S*)-14
(20 mg, 0.12 mmol) was dissolved in aqueous 3 N HCl
(3 mL) and heated at 100 8C for 6 h. The solution was
concentrated to give 18 mg of a white solid; yield: 90%. Mp
O200 8C (decomp.). Spectral data in CD3OD agree with
those published in the literature7 for the corresponding
enantiopure forms; the spectral data in D2O are given below.
1H NMR (D2O): d 1.04 (d, 3H, JZ6.3 Hz, CH3CH), 1.75–
1.87 (m, 1H, CH2CH), 2.04–2.27 (m, 2H, CH2CH, CH2C),
4.1.6.
(1S*,2S*)-N-[1-(tert-Butyldiphenylsilyloxy-
methyl)-2-methylcyclobutyl]acetamide (1S*,2S*)-12. A
solution of olefin 8 (200 mg, 0.51 mmol) in dichloro-
methane (40 mL) was hydrogenated at 20 8C for 15 h with
10% palladium–carbon (40 mg) as a catalyst. Removal of
the catalyst and the solvent gave a white solid corresponding
to a mixture of compounds (1S*,2S*)-12 and (1S*,2R*)-12
in a ratio of 93:7 in favour of (1S*,2S*)-12 and in 96% yield.
The major compound was purified by column chroma-
tography (hexane/ethyl acetate, 65:35) to give (1S*,2S*)-12
1
(179 mg, 89%) as a white solid. Mp 116–117 8C. H NMR
2.49–2.56 (m, 1H, CH2C), 2.81–2.88 (m, 1H, CH3CH); 13
C
(CDCl3): d 1.05–1.08 [m, 12H, CH3CH, C(CH3)3], 1.25–
1.38 (m, 1H, CH2CH), 1.86 (s, 3H, CH3CO), 1.91–2.04 (m,
2H, CH2CH, CH2C), 2.19–2.29 (m, 1H, CH2C), 2.74–2.87
(m, 1H, CH3CH), 3.82 (d, 1H, JZ10.2 Hz, CH2O), 3.95 (d,
1H, JZ10.2 Hz, CH2O), 5.69 (br s, 1H, NH), 7.37–7.47 (m,
6H, Arom.), 7.66–7.86 (m, 4H, Arom.); 13C NMR (CDCl3):
d 15.6 (CH3CH), 19.4 [C(CH3)3], 23.0 (CH2CH), 24.0
(CH3CO), 26.9 [C(CH3)3], 27.1 (CH2C), 37.9 (CH3CH),
59.8 (CH2C), 64.0 (CH2O), 127.8, 129.8, 133.5, 135.6
(Arom.), 169.3 (CONH); ESIC (m/z)Z396.4. Anal. Calcd
for C24H33NO2Si: C, 72.86; H, 8.41; N, 3.54. Found: C,
72.94; H, 8.48; N, 3.58.
NMR (D2O): d 15.9 (CH3CH), 23.5 (CH2CH), 27.2 (CH2C),
39.4 (CH3CH), 62.5 (CH2C), 173.7 (COO). Anal. Calcd for
C6H12ClNO2: C, 43.51; H, 7.30; N, 8.46. Found: C, 43.43;
H, 7.37; N, 8.51.
4.1.10. (1S*,2R*)-N-[1-(tert-Butyldiphenylsilyloxy-
methyl)-2-methylcyclobutyl]acetamide (1S*,2R*)-12. A
solution of olefin 9 (120 mg, 0.78 mmol) in dichloro-
methane (60 mL) was hydrogenated at 20 8C for 17 h with
10% palladium hydroxide–carbon (12 mg) as a catalyst.
Removal of the catalyst and the solvent gave a white solid

A. Avenoza et al. / Tetrahedron 61 (2005) 4165–4172
4171
corresponding to a mixture of compounds (1S*,2S*)-13 and
(1S*,2R*)-13 in a 35:65 ratio in favour of (1S*,2R*)-13 and
in 95% yield. This mixture could not be separated by
column chromatography and therefore the compounds were
transformed into the corresponding silylated derivatives. To
a solution of the mixture of (1S*,2S*)-13 and (1S*,2R*)-13
(90 mg, 0.57 mmol) in DMF (5 mL) were added imidazole
(117 mg, 1.70 mmol) and TBDPSCl (0.43 mL, 1.80 mmol)
and the mixture was stirred at 50 8C for 17 h. The solvent
was evaporated under reduced pressure and 5% aqueous
NaHCO3 (10 mL) and ethyl acetate (15 mL) were added.
The organic layer was separated and the aqueous layer was
washed with ethyl acetate (3!10 mL). The combined
organic layers were dried, filtered and the solvent
evaporated. The residue was purified by silica gel column
chromatography, eluting with hexane/ethyl acetate (65:35),
to give 50 mg of (1S*,2R*)-12 (32% from 9) as a white
used in the next step without further purification. Mp O
200 8C (decomp.). H NMR (CD3OD): d 1.03 (d, 3H, JZ
1
7.2 Hz, CH3CH), 1.44–1.54 (m, 1H, CH2CH), 1.97 (s, 3H,
CH3CO), 2.12–2.31 (m, 3H, CH2CH, CH2C), 3.04–3.11 (m,
1H, CH3CH); 13C NMR (CD3OD): d 16.3 (CH3CH), 22.2
(CH3CO), 24.4 (CH2CH), 29.9 (CH2C), 37.0 (CH3CH), 61.8
(CH2C), 173.5, 177.4 (COO, CONH); ESIC (m/z)Z172.2.
4.1.13. (1S*,2R*)-1-Amino-2-methylcyclobutane-1-carb-
oxylic acid hydrochloride salt (1S*,2R*)-1$HCl. The
white solid corresponding to carboxylic acid (1S*,2R*)-14
(10 mg, 0.06 mmol) was dissolved in aqueous 3 N HCl
(2 mL) and heated at 100 8C for 6 h. The solution was
concentrated to give 7 mg of a white solid; yield: 70%. Mp
O200 8C (decomp.). Spectral data in CD3OD agree with
those published in the literature7 for the corresponding
enantiopure forms; the spectral data in D2O are given below.
1H NMR (D2O): d 1.14 (d, 3H, JZ7.5 Hz, CH3CH), 1.75–
1.88 (m, 1H, CH2CH), 2.17–2.35 (m, 2H, CH2CH, CH2C),
1
solid. Mp 146–147 8C. H NMR (CDCl3): d 1.07–1.12 [m,
12H, CH3CH, C(CH3)3], 1.43–1.51 (m, 1H, CH2CH), 1.86–
1.99 (m, 4H, CH2CH, CH3CO), 2.09–2.13 (m, 1H, CH2C),
2.19–2.29 (m, 1H, CH2C), 2.40–2.44 (m, 1H, CH3CH), 3.87
(d, 1H, JZ10.0 Hz, CH2O), 3.97 (d, 1H, JZ10.0 Hz,
CH2O), 5.50 (br s, 1H, NH), 7.36–7.45 (m, 6H, Arom.),
7.63–7.74 (m, 4H, Arom.); 13C NMR (CDCl3): d 15.8
(CH3CH), 19.4 [C(CH3)3], 23.6 (CH2CH), 23.8 (CH3CO),
26.6 (CH2C), 26.9 [C(CH3)3], 34.8 (CH3CH), 59.8 (CH2C),
67.0 (CH2O), 127.7, 129.6, 129.7, 133.7, 133.8, 134.8,
135.6, 135.7 (Arom.), 169.5 (CONH); ESIC (m/z)Z396.4.
Anal. Calcd for C24H33NO2Si: C, 72.86; H, 8.41; N, 3.54.
Found: C, 72.92; H, 8.45; N, 3.61.
2.61–2.71 (m, 1H, CH2C), 3.03–3.15 (m, 1H, CH3CH); 13
C
NMR (D2O): d 15.4 (CH3CH), 24.1 (CH2CH), 27.9 (CH2C),
37.0 (CH3CH), 62.3 (CH2C), 175.2 (COO). Anal. Calcd for
C6H12ClNO2: C, 43.51; H, 7.30; N, 8.46. Found: C, 43.41;
H, 7.41; N, 8.53.
Acknowledgements
´
We thank the Ministerio de Ciencia y Tecnologıa (project
PPQ2001-1305), and the Universidad de La Rioja (project
API-03/04) for financial support. M. P. thanks the
Comunidad Autonoma de La Rioja for a doctoral
fellowship.
4.1.11. (1S*,2R*)-N-[1-(Hydroxymethyl)-2-methylcyclo-
butyl]acetamide (1S*,2R*)-13. TBAF (0.15 mL, 1 M in
THF) was added to a solution of (1S*,2R*)-12 (50 mg,
0.13 mmol) in dry THF (10 mL) at 20 8C under an inert
atmosphere and the mixture was stirred for 1 h. Saturated
aqueous NH4Cl (5 mL) was added and the organic material
was extracted with CHCl3/iPrOH (4:1) (2!10 mL). The
organic layers were dried, filtered and concentrated. The
residue was purified by silica gel column chromatography,
eluting with hexane/ethyl acetate (5:95), to give 20 mg
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