An efficient asymmetric synthesis of Fmoc-L-cyclopentylglycine via diastereoselective alkylation of glycine enolate equivalent

Article abstract of DOI:10.1016/S0040-4039(03)00370-8

Stereoselective alkylation of the enolate derived from benzyl (2R,3S)-(-)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (1) with cyclopentyl iodide afforded anti-α-monosubstituted product, benzyl (2R,3S,5S)-(-)-6-oxo-2,3-diphenyl-5-cyclopentyl-4-morpholineca

Full text of DOI:10.1016/S0040-4039(03)00370-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2683–2685
An efficient asymmetric synthesis of Fmoc-
L
-cyclopentylglycine
via diastereoselective alkylation of glycine enolate equivalent
Satendra Singh* and Michael W. Pennington
BACHEM Bioscience Inc., 3700 Horizon Drive, King of Prussia, PA 19406, USA
Received 17 December 2002; revised 4 February 2003; accepted 6 February 2003
Abstract—Stereoselective alkylation of the enolate derived from benzyl (2R,3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate
(1) with cyclopentyl iodide afforded anti-a-monosubstituted product, benzyl (2R,3S,5S)-(−)-6-oxo-2,3-diphenyl-5-cyclopentyl-4-
morpholinecarboxylate (3) in 60% yield. Catalytic hydrogenolysis over PdCl2 cleaved the auxiliary ring system to give
L
-cyclopentylglycine (4) in 84% yield. Subsequent protection of the a-amino function with Fmoc-OSu gave Fmoc-
L-cyclopentyl-
glycine (5) in high yield. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Fmoc-L-cyclopentylglycine (5) by using benzyl (2R,3S)-
(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (1) as
a template. The reasons behind choosing this chiral
auxiliary were: (1) commercial availability, (2) excellent
optical purity of the final product, (3) high reactivity
towards unactivated electrophiles and (4) scalability.
Nature has afforded us 22 naturally occurring coded
amino acids commonly found in proteins isolated from
eukaryotic and prokaryotic sources. A host of enzymes
are present in nature to extend this repertoire much
further by utilizing post-translational modification.1 A
variety of synthetic means have also been established to
produce a plethora of non-proteinogenic amino acids as
tools to investigate enzymatic mechanisms, extend bio-
logical half-life, establish a specific conformational
determinant or increase potency of therapeutically
interesting peptides.2 Of these, stereoselective homolo-
gation of readily available chiral auxiliaries, such as
cyclic glycine enolate equivalents derived from bis-lac-
tim ethers,3 imidazolidinones,4 and oxazinones5 are par-
2. Results and discussion
As shown in Scheme 1, chiral auxiliary 1 was alkylated
with cyclopentyl iodide in the presence of lithium
bis(trimethylsilyl)amide base. Enolate generation at
−78°C followed by quenching with alkylating agent at
the same temperature did not result in any reaction.
Optimum conditions utilized dissolving
1
and
ticularly
useful.
Besides,
glycylsultam6
and
cyclopentyl iodide in THF/HMPA (10:1) by heating to
ꢀ35°C, generating enolate at −78°C and allowing the
reaction mixture to warm to room temperature over a
period of 2 h. Under these conditions, alkylated
product 3 was obtained in 60% yield.†
pseudoephedrine glycinate hydrate7 are also useful a-
amino acid templates.
Cyclopentylglycine (Cpg) is a competitive inhibitor of
isoleucine uptake in E. coli8 and also has been used in
designing angiotensin II antagonists.9 It has been syn-
thesized via SN2 displacement of bromoglycinate with
an organometallic reagent followed by epimerization.10
Variations in experimental conditions, such as longer
reaction time, increasing the amount of base (>1.5
Syntheses
of
racemic
2-cyclopentenylglycine,11
cyclopentylglycine,8 and 2-cyclopentadieneylglycine12
have also been reported. In this publication, we wish to
report a short and efficient asymmetric synthesis of
† Compound 3: ESI-MS: 456 (C29H30NO4) (M+H)+. 1H NMR (600
MHz, CDCl3): l 7.26–7.07 (13H, m), 6.52 (2H, d, J=6.8 Hz), 6.00
(1H, d, J=3.0 Hz), 5.13 (1H, d, J=3.0 Hz), 4.91 (1H, d, J=12.0
Hz), 4.85 (1H, d, J=12.0 Hz), 3.74 (1H, m), 2.44 (1H, m), 1.90–1.80
(4H, m), 1.65–1.55 (4H, m); mp 216–217°C; [h]2D4 −44.88° (c 0.5,
CH2Cl2). Anal. (recrystallized from EtOAc/hexanes) calcd for
C29H29NO4: C, 76.48; H, 6.37; N, 3.07. Found: C, 76.58, H, 6.29;
N, 3.28.
Keywords: Fmoc-L-cyclopentylglycine; cyclopentylglycine; glycine
enolate equivalent.
* Corresponding author. Tel.: +1-610-239-0300; fax: +1-610-239-0800;
e-mail: ssingh@usbachem.c
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00370-8

2684
S. Singh, M. W. Pennington / Tetrahedron Letters 44 (2003) 2683–2685
Scheme 1.
equiv.) or cyclopentyl iodide (>5 equiv.) and substitut-
ing the solvating agent HMPA with DMPU either did
not result in any improvements or lowered the yield of
the alkylation product 3. Since cyclopentyl iodide is an
unactivated electrophile, raising the reaction tempera-
ture to 40°C was expected to improve the yield of
alkylation product 3. However, reaction at 40°C for 1 h
resulted in the formation of 10–15% of side product 6
(Fig. 1), in addition to alkylation product 3.
tallization of the syrup from MeOH/EtOAc afforded 4
in 84% yield.‡
Protection of the a-amino function of Cpg 4 was
accomplished by treating it with Fmoc-OSu in the
presence of Na2CO3 overnight in dioxane/H2O (1.5:1)
solvent mixture. Fmoc-Cpg-OH (5) was obtained in
quantitative yield after crystallization from EtOAc/
hexane.
It is important to note that no dialkylation product was
formed. Furthermore, only trans-alkylated product (3)
formed and no cis-diastereoisomer (i.e. 2R,3S,5R) was
detected by HPLC. The high diastereoselectivity of the
enolate alkylation can be explained by considering the
expected boat conformation of 2 that disposes the
phenyl ring at C-3 in a pseudoaxial orientation, creat-
ing steric shielding of the same face at C-5 position
from electrophilic attack as shown in Scheme 1.
Thus, an efficient asymmetric synthesis of Fmoc-Cpg-
OH (5) from a commercially available chiral auxiliary
was successfully accomplished on multigram scale. Syn-
thesis was easy to perform, as no chromatographic
purification was required at any step. Furthermore,
excellent optical purity (>99%) and high yield (50%
overall) was obtained.
No purification by column chromatography was neces-
sary. The trans-alkylated product 3 was easily crystal-
lized out as a white solid from EtOAc/hexane in 60% of
isolated yield (>99% de by HPLC) after standard work-
up (cf. syn-alkylated product is usually an oil).10 Addi-
tional evidence of stereoselectivity was apparent from
1H NMR as the methine protons (CH
6 ) at C-2 and C-3
appeared at l 6.00 and 5.13 ppm, respectively (0.87
ppm apart, characteristic of anti-alkylation product; cf.
0.6–0.7 ppm apart for the syn-alkylated product).10
Cleavage of the auxiliary ring system 3 was performed
using H2 and PdCl2 as a catalyst in THF/MeOH (2:1)
solvent mixture at 60 psi for 48–60 h. After removing
the catalyst (pyrophoric), the solvent was removed and
the residue was triturated with ether to afford Cpg 4 in
almost quantitative yield. The contaminating
byproduct, 1,2-diphenylethane was easily removed by
extracting the dilute aqueous HCl solution of 4 with
EtOAc. Removal of aqueous solvent followed by crys-
Figure 1.
‡ Compound 4: ESI-MS: 144 (C7H13NO2) (M+H)+. 1H NMR (600
MHz, DMSO-d6): l 4.74 (1H, m), 2.48 (1H, m), 1.78–1.69 (2H, m),
1.53–1.42 (4H, m), 1.39–1.25 (2H, m); mp 245–247°C (dec.); [h]D24
+12.34° (c 0.5, MeOH); (lit.10, +11.6°, c 0.49, 1N HCl)). Anal.
(recrystallized from MeOH/EtOAc) calcd for C7H13NO2: C, 58.74;
H, 9.09; N, 9.79. Found: C, 58.70, H, 8.85; N, 9.99.

S. Singh, M. W. Pennington / Tetrahedron Letters 44 (2003) 2683–2685
113, 9267–9286.
2685
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