An Efficient Procedure for Preparation of C- and N-Protected 1-Aminocyclobutane Carboxylic Acid

Article abstract of DOI:10.1081/SCC-120027708

An efficient method for the synthesis of differentially protected 1-aminocyclobutane carboxylic acid is described. Synthetically useful intermediates 7 and 8 were prepared from ethyl 1-bromocyclobutane-carboxylate in excellent yields (95% and 69%, respectively).

Full text of DOI:10.1081/SCC-120027708

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An Efficient Procedure for Preparation of C‐ and
N‐Protected 1‐Aminocyclobutane Carboxylic Acid
a
a
June J. Kim & Michael R. Wood
a
Department of Medicinal Chemistry , Merck Research Laboratories , P.O. Box 4, West
Point, Pennsylvania, 19486, USA
Published online: 16 Aug 2006.
To cite this article: June J. Kim & Michael R. Wood (2004) An Efficient Procedure for Preparation of C‐ and N‐Protected
1‐Aminocyclobutane Carboxylic Acid, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:4, 607-613, DOI: 10.1081/SCC-120027708
To link to this article: http://dx.doi.org/10.1081/SCC-120027708
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SYNTHETIC COMMUNICATIONS
Vol. 34, No. 4, pp. 607–613, 2004
An Efficient Procedure for Preparation of
C- and N-Protected 1-Aminocyclobutane
Carboxylic Acid
*
June J. Kim and Michael R. Wood
Department of Medicinal Chemistry, Merck Research Laboratories,
West Point, Pennsylvania, USA
ABSTRACT
An efficient method for the synthesis of differentially protected
1-aminocyclobutane carboxylic acid is described. Synthetically useful
intermediates 7 and 8 were prepared from ethyl 1-bromocyclobutane-
carboxylate in excellent yields (95% and 69%, respectively).
Key Words: 1-Aminocyclobutane carboxylic acid; Ethyl 1-bromocyclo-
butane carboxylate; Tertiary a-bromo esters.
1-Aminocyclobutane carboxylic acid is an amino acid that is attracting
increasing interest due to its inherent biological activity and utility as a
*
Correspondence: June J. Kim, Department of Medicinal Chemistry, Merck Research
Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA; E-mail:
jeeyoon_kim@merck.com.
6
07
DOI: 10.1081/SCC-120027708
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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6
08
Kim and Wood
substitute for natural amino acids. As a monomer, this a-amino acid and
several of its derivatives are known antagonists at excitatory amino acid
[1–4]
receptors, particularly NMDA receptors in the central nervous system.
Incorporated into peptides, 1-aminocyclobutane carboxylic acid can induce
unique conformational restrictions, thereby modulating their physical
properties, biological activities, and bioavailabilities. For example, this a-
amino acid has been used in studies examining the role of 1-aminocycloalkane
[5]
carboxylic acids in a series of L-aspartyl dipeptide sweeteners, as well as in
studies of conformational properties of peptides.
[6]
In support of a medicinal chemistry program, we required ready access to
the 1-aminocycloalkane amino acid series: c-propane, c-butane, c-pentane,
and c-hexane. While the 3-, 5-, and 6-membered ring amino acids are reliably
obtained at reasonable cost from commercial sources, 1-aminocyclobutane
carboxylic acid 4 and its protected derivatives 7 and 8 are not only expensive
($1700–$4200/g), but are also difficult to obtain. Due to these limitations, we
found it necessary to prepare both the C- and N-protected forms of
1
-aminocyclobutane carboxylic acid (7 and 8).
Several methods to prepare the 1-aminocyclobutane carboxylic acid
[
1,3,7–10]
scaffold have been reported.
include the Strecker synthesis, starting from cyclobutanone 1, and the
The most common approaches to 3
[1,7]
Bucherer-Bergs reaction of 1 via hydantoin 2 (Sch. 1).
However, these
methods suffer from low overall yields or involve time-consuming steps.
Woodard reported the synthesis of amino acid 4 beginning with N-
[8]
formylglycine ethyl ester (Sch. 2), but again in low overall yield (,30%).
Hence, an alternative methodology for the preparation of these useful
intermediates was explored. Herein we report an operationally simple and
highly efficient procedure for the synthesis of 1-aminocyclobutane carboxylic
acid in conveniently protected forms.
Ethyl 1-bromocyclobutane carboxylate 5 serves as the commercially
available starting material (Sch. 3). Addition of this bromide to a suspension
Scheme 1.

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C- and N-Protected 1-Aminocyclobutane Carboxylic Acid
609
Scheme 2.
of sodium azide in DMSO, followed by warming to 408C for 7 hours, afforded
the desired azide adduct 6 in nearly quantitative yield. Although this reaction
can be performed at ambient temperature, the reaction typically stalls at
ꢀ
75% conversion after 24 hours. The presence of unreacted bromide 5,
however, does not affect subsequent steps (vida infra). Concern over the
potential volatility of 6 dictated that a low-boiling solvent (diethyl ether) be
used to extract the desired azide from an aqueous/DMSO mixture during
work-up. Hydrogenation of the crude azide 6 in methanol with 10% Pd/C
gave the corresponding amine, which was converted to the HCl salt 7 to
facilitate isolation and handling of this low molecular weight compound. In
this manner, the ethyl ester of 1-aminocyclobutane carboxylic acid (7) was
obtained in two simple steps without purification in 95% overall yield. In
practice, even if the initial azide displacement reaction does not proceed to
completion, residual 5 is reduced to ethyl cyclobutane carboxylate upon
hydrogenation, which evaporates during solvent removal. The Boc-protected
amino acid 8 was obtained by reacting 7 with di-tert-butyl dicarbonate
followed by conventional saponification.
Secondary a-bromo esters have been converted to the corresponding
[
11–13]
azides en route to preparing a-amino acids.
esters have been reported in mechanistic studies to react through S 2
Although tertiary a-bromo
N
[14,15]
displacement when treated with metal azides,
the product azides were
never elaborated to quaternary a-amino acids. To our knowledge, this is the
first reported conversion of a quaternary a-bromo ester into the corresponding
amino acid via the azide. Since tertiary a-bromo esters can be accessed by
[
16,17]
bromination of the corresponding esters by known methods,
methodology reported in this paper should be applicable to the synthesis of a
the
wide range of quaternary a-amino acids.
Scheme 3.

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Kim and Wood
In conclusion, we have described a highly efficient procedure for the
synthesis of both protected forms of 1-aminocyclobutane carboxylic acid. The
operational simplicity, excellent yields, and cost effectiveness of this synthesis
make this procedure very attractive.
EXPERIMENTAL
1
13
H (400 MHz) and C (100 MHz) NMR spectra were recorded on a
Varian VXR 400 spectrometer. The chemical shifts are reported in d (ppm)
1
using the d 0.00 signal of Me Si ( H) and the d 49.15 signal of MeOH-d ( C)
13
4
4
as internal standards. High-resolution MS data were obtained on a Bruker
Daltonics FTICR/MS. HPLC data were obtained on a Waters 2695 LC using a
3
eluted over 4 minutes to record retention times.
mm  5 cm YMCPRO C-18 column and a 14–100% CH CN/H O gradient
3
2
Ethyl 1-azidocyclobutanecarboxylate (6). To a suspension of sodium
azide (3.14 g, 48.3 mmol) in anhydrous DMSO (50 mL) was added ethyl 1-
bromocyclobutanecarboxylate 5 (5.00 g, 24.2 mmol) dropwise under nitrogen.
A modest temperature rise was observed. The reaction vessel was sealed and
heated at 408C for 7 hours. Upon cooling to room temperature, the reaction
solution was partitioned between water (700 mL) and diethyl ether (200 mL).
The organic layer was washed with half brine three times and then with
saturated brine. The solution was dried over sodium sulfate, filtered, and
1
carefully concentrated in vacuo to obtain an oil (4.00 g, 98% yield). H NMR
(
(
CDCl ): d 1.34 (t, J ¼ 7.2 Hz, 3H), 2.11–1.94 (m, 2H), 2.27 (m, 2H), 2.61
3
m, 2H), 4.27 (q, J ¼ 7.2 Hz, 2H). HPLC: t ¼ 2.34 min.
Ethyl 1-aminocyclobutanecarboxylate hydrochloride (7). A solution
of 6 (4.00 g, 23.6 mmol) in MeOH (150 mL) was purged with nitrogen prior to
the addition of 10% Pd/C catalyst (840 mg). The mixture was again purged
with nitrogen and then purged with hydrogen from a balloon. The mixture was
stirred under hydrogen for 3 hours. Upon completion, the reaction mixture was
filtered through a pad of celite. The filtrate was acidified by addition of HCl in
ether (4M) and then concentrated in vacuo to provide an oil (4.14 g, 97%
a 1
yield) that crystallized over time. H NMR (CDCl ): d 1.36 (t, J ¼ 7.2 Hz,
3
3
9
H), 2.18 (m, 1H), 2.34 (m, 1H), 2.81–2.64 (m, 4H), 4.32 (q, J ¼ 7.2 Hz, 2H),
3
1
.21 (bs, 3H). C NMR (CD OD): d 14.5, 15.5, 30.9, 58.6, 63.9, 172.0.
3
a
Although methanol is the preferred solvent, some trans-esterification to the methyl
ester can occur at this stage (ꢀ5–10%). However, performing the hydrogenation in
ethanol provides 7 free of methyl ester.

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C- and N-Protected 1-Aminocyclobutane Carboxylic Acid
611
HRMS (ES): calc’d for C H NO : 144.1019, found: 144.1025. HPLC:
7
14
2
t ¼ 0.52 min.
Ethyl 1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylate. To a
solution of 7 (1.53 g, 8.52 mmol) and di-tert-butyl dicarbonate (1.86 g,
8
.52 mmol) in DMF (16 mL) was added triethylamine (1.03 g, 10.2 mmol)
dropwise. After 2 hours, the reaction mixture was partitioned between water
160 mL) and diethyl ether (160 mL). The organic layer was washed with
(
saturated copper sulfate, half brine, and saturated brine. The organic layer was
then dried over sodium sulfate, filtered, and concentrated. The residue was
purified by silica gel chromatography to give the title compound (1.67 g, 81%
1
yield) as a clear oil. H NMR (CD OD): d 1.26 (t, J ¼ 6.8 Hz, 3H), 1.42 (s,
3
1
3
9
H), 1.99 (m, 2H), 2.17 (m, 2H), 2.56 (m, 2H), 4.17 (q, J ¼ 6.8 Hz, 2H). C
NMR (CD OD): d 14.7, 16.3, 28.9, 32.2, 59.6, 62.2, 80.3, 157.3, 175.7. HRMS
3
(
ES): calc’d for C H NO Na: 266.1363, found: 266.1377. HPLC:
12 21 4
t ¼ 2.21 min.
1-[(tert-Butoxycarbonyl)amino]cyclobutanecarboxylic acid (8). Into a
solution of ethyl 1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylate
1.67 g, 6.85 mmol) in THF (50 mL) was added 1N NaOH (10.3 mL). The
(
reaction vessel was sealed and heated at 408C overnight. Solvent was removed
in vacuo. The residual aqueous layer was diluted with water and extracted
three times with diethyl ether. The aqueous layer was then neutralized by
addition of 1N HCl (10.3 mL) and saturated with sodium chloride. The
product in the aqueous phase was extracted with ethyl acetate three times. The
combined ethyl acetate extracts were dried over sodium sulfate, filtered, and
1
concentrated to provide 8 (1.35 g, 91% yield) as a white solid. H NMR
1
CD OD): d 1.42 (s, 9H), 2.00 (m, 2H), 2.20 (m, 2H), 2.57 (m, 2H). C NMR
CD OD): d 16.3, 28.9, 32.3, 59.4, 80.4, 157.4, 177.7. HRMS (ES): calc’d for
3
3
(
(
3
C H NO : 216.1230, found: 216.1245. HPLC: t ¼ 1.54 min.
1
0
18
4
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Received in the USA August 7, 2003

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