Efficient synthesis of (1R,2S) and (1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester derivatives in enantiomerically pure form

Article abstract of DOI:10.1016/j.tetasy.2008.11.029

A 4-step synthesis of an optically active synthetic intermediate [(1R,2S)-2-(4′-fluorobenzylamino)cyclopentanecarboxylic acid ethyl ester complex with (S)-(+)-mandelic acid; compound 12, >99% de] required for the preparation of a promising HCV NS5B polymerase inhibitor is reported. This process utilizes mandelic acid as a resolving agent, which can be recovered in good yield by a simple extraction. An optimized version of the chemistry described avoids the use of chromatographic purifications making it suitable for large-scale applications. In addition, the straightforward conversion of compound 12 to enantiomerically pure (1R,2S)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is reported. The preparation of the enantiomer of 12 (compound 15) in enantiomerically pure form and the conversion of this entity to (1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz derivatives is also described.

Full text of DOI:10.1016/j.tetasy.2008.11.029

Tetrahedron: Asymmetry 19 (2008) 2796–2803
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of (1R,2S) and (1S,2R)-2-aminocyclopentanecarboxylic
acid ethyl ester derivatives in enantiomerically pure form
*
Peter S. Dragovich , Douglas E. Murphy, Kimkim Dao, Sun Hee Kim, Lian-Sheng Li, Frank Ruebsam,
Zhongxiang Sun, Chinh V. Tran, Alan X. Xiang, Yuefen Zhou
Anadys Pharmaceuticals, 3115 Merryfield Row, San Diego, CA 92121, United States
a r t i c l e i n f o
a b s t r a c t
A 4-step synthesis of an optically active synthetic intermediate [(1R,2S)-2-(40-fluorobenzylamino)cyclop-
entanecarboxylic acid ethyl ester complex with (S)-(+)-mandelic acid; compound 12, >99% de] required
for the preparation of a promising HCV NS5B polymerase inhibitor is reported. This process utilizes man-
delic acid as a resolving agent, which can be recovered in good yield by a simple extraction. An optimized
version of the chemistry described avoids the use of chromatographic purifications making it suitable for
large-scale applications. In addition, the straightforward conversion of compound 12 to enantiomerically
pure (1R,2S)-2-aminocyclopentanecarboxylic acid ethyl ester and the corresponding Boc and Cbz deriv-
atives is reported. The preparation of the enantiomer of 12 (compound 15) in enantiomerically pure form
and the conversion of this entity to (1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester and the cor-
responding Boc and Cbz derivatives is also described.
Article history:
Received 4 October 2008
Accepted 20 November 2008
Available online 23 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
enantiopure 2-aminocyclopentanecarboxylic acid starting material
4 caused us to investigate other methods for the preparation of
During the course of our efforts to develop novel agents for the
treatment of chronic hepatitis C virus (HCV) infection, we identi-
fied a benzothiadiazine-containing inhibitor of the HCV NS5B poly-
merase enzyme that displayed promising in vitro and in vivo
biological properties (1, Scheme 1).1 In order to better characterize
the therapeutic potential of this molecule, we required a reproduc-
ible preparation on a large scale (>20 g) with high enantioselectiv-
ity. Accordingly, we sought to identify an efficient synthesis of at
least one of the optically active (1R,2S)-2-aminocyclopentanecarb-
oxylic acid esters 2a and 2b that could be utilized for the prepara-
intermediates 2a and/or 2b on larger scales.3
Accordingly, we also examined the known transformation of
cyclic anhydride 6 to the corresponding Cbz-protected amino-ester
8 via enantioselective ring opening and subsequent Curtius re-
arangement.4–6 As described in the literature, this chemistry pro-
vided gram quantities of enantiomerically pure 8, (approximately
96% ee) which could be converted to intermediate 2a by Cbz
deprotection and subsequent reductive alkylation with 4-fluoro-
benzaldehyde. However, the relatively high cost of the required
starting material (anhydride 6) induced us to continue our search
for an alternative process for the large-scale preparation of inter-
mediates 2a and/or 2b.
In addition to the enantioselective anhydride opening depicted
in Scheme 2, several other methods are known in the literature for
the synthesis of optically active cis-2-aminocyclopentanecarboxy-
lic acid derivatives.7–9 We considered employing some of these
procedures to prepare enantiomerically pure (1R,2S)-2-aminocy-
clopentanecarboxylic acid esters that could be converted to 2a or
2b via reductive alkylation (cf., Scheme 2). However, we envisioned
that a process employing the resolution of racemic 2a or 2b would
likely represent a more direct and efficient method for the synthe-
sis of these entities. Herein, we report such a preparation of opti-
cally pure amino-ester 2b that involves (1) the convenient
synthesis of the corresponding racemate utilizing inexpensive
starting materials and reagents and (2) the simple and efficient res-
olution of this racemate mediated by mandelic acid.
tion of
1 via coupling to the benzothiadiazine-acid 3 and
subsequent Dieckmann cyclization (Scheme 1).1,2 To enable more
complete biological assessments, we also wished to prepare gram
quantities of the enantiomer corresponding to compound 1 and
therefore also required a practical synthesis that would afford
the (1S,2R)-enantiomer of amino-ester intermediate 2a and/or 2b.
Our initial preparation of optically active 1 involved the conver-
sion of commercially available (1R,2S)-2-aminocyclopentanecarb-
oxylic acid hydrochloride 4 (99% ee) to the corresponding methyl
ester 5 followed by reductive alkylation with 4-fluorobenzalde-
hyde (Scheme 2). This sequence successfully afforded amino-ester
intermediate 2a in hundred-milligram quantities and excellent
enantiomeric purity.2 However, the relatively high cost of the
* Corresponding author. Tel.: +1 858 530 3648; fax: +1 858 527 1540.
E-mail address: pdragovich@anadyspharma.com (P.S. Dragovich).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.029

P. S. Dragovich et al. / Tetrahedron: Asymmetry 19 (2008) 2796–2803
2797
O
O
H
S
N
O
O
O
OH
N
N
S
H
H
H
H
H
S
N
O
O
O
N
S
OR
NH
N
H
O
O
+
HO
N
H
O
1
2
3
F
F
a R = Me
b R = Et
Scheme 1. Retrosynthesis of compound 1.
It was anticipated that the filtrate obtained from the above res-
olution would primarily contain the (1S,2R)-2-(40-fluorobenzyl-
amino)cyclopentanecarboxylic acid ethyl ester salt 13 and that
this material could be utilized to access (1S,2R)-2-aminocyclopen-
tanecarboxylic acid derivatives related to 2b. However, since the
physical properties of 13 did not allow for its simple precipitation
(and presumably recrystallization) from EtOAc, we converted it to
the corresponding diastereomeric (R)-(ꢀ)-mandelic acid salt 15
(the enantiomer of salt 12) prior to exploring the synthesis of
(1S,2R)-2-aminocyclopentanecarboxylic acid ethyl ester deriva-
tives. Accordingly, the above filtrate was washed with aqueous
NaHCO3 solution, after which it was dried and concentrated to give
O
O
H
H
H
OH
HCl
OMe
a
NH2•
NH2 HCl
•
b
H
2a
4
5
ca. $250/g
c, d
O
O
O
H
H
H
OMe
OMe
OH
ref. 4a
ref. 5a
O
crude
(1S,2R)-2-(40-fluorobenzylamino)cyclopentanecarboxylic
NH
H
acid ethyl ester 14 (Scheme 3). The salt of this material complexed
with (R)-(ꢀ)-mandelic acid 15 was then prepared using a proce-
dure similar to that described above for the formation of 12. A sin-
gle recrystallization from EtOAc furnished 15 in 74% yield and
>99% de (determined by analysis of the compound’s 1H NMR spec-
trum; see Section 4).13 We repeated the resolution of 10 on a mul-
ti-gram scale (>10 g) using the procedure described above, and
consistently obtained salts 12 and 15 in good yields and high dia-
stereomeric purities (de >99%). In addition, the (S)-(+)-mandelic
acid liberated during the preparation of 15 could be recovered
from the aqueous washings in nearly quantitative yield by acidifi-
cation and extraction with EtOAc.14
One drawback of the sequence described above with respect to
its application on >50 g scale was the need to chromatographically
separate the cis- and trans-amino-esters 10 and 11 that were
formed during the reduction of 9. Unfortunately, efforts to effect
the resolution of the crude mixture of 10 and 11 using (S)-(+)-man-
delic acid consistently resulted in the co-isolation of minor quanti-
ties (ca. 10%) of both trans-diastereomeric salts corresponding to
12 and 13.15 Therefore we developed an alternative preparation
of cis-amino-ester 10 that provided this entity as a single diaste-
reomer without the use of chromatography.
Thus, 1,2-dipolar cycloaddition of chlorosulfonyl isocyanate to
cyclopentene afforded cis-lactam 16 after reduction of the initially
formed N-chlorosulfonyl lactam (not shown) with sodium sulfite
(Scheme 4).16 Acid-catalyzed ethanolysis of 16 then provided the
hydrochloride salt of racemic cis-2-aminocyclopentanecarboxylic
acid ethyl ester 17,17 which was subsequently transformed into
cis-amino-ester 10 by reductive alkylation with 4-fluorobenzalde-
hyde. Importantly, this alternate synthesis afforded a pure cis-dia-
stereomer 10 in excellent overall yield (87%), and each step in the
preparation could be successfully performed without utilizing sil-
ica gel purifications. As expected, addition of an EtOAc solution
of (S)-(+)-mandelic acid to a room temperature solution of crude
10 prepared as depicted in Scheme 4 afforded salt 12 in good yield.
A single recrystallization of this material from EtOAc furnished
chemically pure 12 in 40% yield and >99% de (determined by anal-
ysis of the compound’s 1H NMR spectrum; see Section 4).13,14 The
desired optically active synthetic intermediate (amino-ester 2b)
O
Cbz
O
6 (cis)
ca. $100/g
7
8
Scheme 2. Initial syntheses of compound 2a. Reagents and conditions: (a)
TMSCHN2, 1:1 C6H6/CH3OH, 0–25 °C, 30 min; (b) 4-fluorobenzaldehyde, Et3N,
NaBH4, CH3OH, 25 °C, 16 h; (c) H2, Pd on C, THF, 25 °C, 3 h; (d) 4-fluorobenzalde-
hyde, NaBH3CN, HOAc, CH3OH, 25 °C, 4 h.
2. Results and discussion
Our synthesis began with the acid-catalyzed condensation of
inexpensive ethyl 2-oxocyclopentanecarboxylate with 4-fluoro-
benzylamine to give enamine 9 (Scheme 3). The crude material
thus obtained was reduced with NaBH(OAc)3 in the presence of
acetic acid to afford the racemic cis-amino-ester 10 along with
minor amounts of the corresponding racemic trans-isomer
11.8g,8h,10 A similar reaction sequence employing (S)-(ꢀ)-1-phen-
ethylamine was previously employed for the large-scale prepara-
tion of (1R,2S)-2-aminocyclohexanecarboxylic acid ethyl ester.11
Compounds 10 and 11 displayed dramatically different affinities
toward silica gel (i.e., TLC retention times) and were easily sepa-
rated by flash chromatography on relatively large scale (ca. 20 g).
The racemic cis-amino-ester 10 obtained in this manner was then
subjected to a chiral resolution employing mandelic acid.12
In this resolution process, an EtOAc solution of (S)-(+)-mandelic
acid was added to a solution of 10 in EtOAc at room temperature
resulting in the selective precipitation of the correspond-
ing (1R,2S)-2-(40-fluorobenzylamino)cyclopentanecarboxylic acid
ethyl ester salt 12 (Scheme 3). This material was isolated by simple
filtration in high diastereomeric purity (95% de). A single recrystal-
lization from EtOAc then provided 12 in 40% isolated yield with a
de of >99% (yield calculated based on the total amount of 10 em-
ployed in the resolution). The diastereomeric purity of 12 was con-
veniently determined by examination of the compound’s 1H NMR
spectrum (see Section 4 for additional details),13 while the absolute
configuration of the amino-ester component of salt 12 was subse-
quently established using the chemistries described below.

2798
P. S. Dragovich et al. / Tetrahedron: Asymmetry 19 (2008) 2796–2803
O
O
O
O
O
a, b
a
OEt
NH
c
OEt
OEt
NH
16 (cis)
NH2 HCl
•
ca. $0.33/g
17 (cis)
ca. $0.83/g
9
F
d
b
f
e
2b
12
10
O
O
Scheme 4. Alternate synthesis of salt 12. Reagents and conditions: (a)
ClSO2N@C@O, neat, ꢀ78 to 23 °C, 18 h; (b) Na2SO3/NaHCO3, 0–23 °C, 45 min, 84%;
(c) SOCl2, EtOH, ꢀ30 to 0 °C, 16 h, 88%; (d) NaOAc, 4-fluorobenzaldehyde, NaBH3CN,
EtOH, 23 °C, 16 h, 99%; (e) (S)-(+)-mandelic acid, EtOAc, 23 °C, 16 h, 40%; (f)
NaHCO3, 76%.
OEt
NH
OEt
+
NH
F
F
coupled with the ease of obtaining 12 and 15, would afford a novel
process for the large-scale preparation of these entities that would
complement existing methodologies.3–9 As depicted in Scheme 5,
palladium-catalyzed hydrogenation of salt 12 at slightly elevated
temperature cleanly afforded the salt of (1R,2S)-2-aminocyclopen-
tanecarboxylic acid ethyl ester complexed with (S)-(+)-mandelic
acid 18. The crude material thus obtained was converted into the
corresponding Cbz and Boc derivatives (19 and 20, respectively)
in good yields (>80% in each case) using standard chemistry.
Similar hydrogenation of salt 15 followed by removal of (R)-(ꢀ)-
mandelic acid via basic extraction afforded crude (1S,2R)-2-amino-
cyclopentanecarboxylic acid ethyl ester 21 in moderate yield (52%;
Scheme 6). This material was subsequently converted to the corre-
sponding hydrochloride salt 2219 and Boc derivative 23 by treat-
ment with HCl and di-tert-butyl dicarbonate, respectively. The
lower isolated yield of crude 21 relative to the yields for com-
pounds 19 and 20 above may result from the higher water solubil-
ity and/or volatility of the former compound. As was noted in the
preparation of 15 above, the (R)-(ꢀ)-mandelic acid liberated during
the synthesis of 21 could be recovered from the aqueous washings
in nearly quantitative yield by acidification and extraction with
EtOAc.
11
10
(trans)
(cis)
c
O
OH
O
H
OEt
•
OH
NH
F
12
+
O
O
OH
O
H
OEt
OH
d
OEt
•
NH
NH
F
F
14
13
O
e
OEt
O
H
HO
NH 19
OH
OEt
Cbz
•
O
NH
b
O
OH
O
H
F
OH
a
OEt
•
15
12
NH2
Scheme 3. Synthesis of salts 12 and 15. Reagents and conditions: (a) 4-fluoro-
benzylamine, HOAc, toluene, 70–145 °C, 3 h; (b) NaBH(OAc)3, 1:1 CH3CN/HOAc, 0–
23 °C, 19 h, 77% (two steps); (c) (S)-(+)-mandelic acid, EtOAc, 23 °C, 19 h, 40% 12;
(d) NaHCO3; (e) (R)-(ꢀ)-mandelic acid, EtOAc, 23 °C, 21 h, 74% (two steps).
18
c
O
required for the preparation of inhibitor 1 was subsequently ob-
tained in good yield from 12 by washing with aqueous NaHCO3
solution and extraction into EtOAc.18
Having identified methods to conveniently prepare multi-gram
quantities of both chiral salts 12 and 15 in high yields and diaste-
reomeric purities, we then examined their conversion into the cor-
responding optically active cis-2-aminocyclopentanecarboxylic
acid ethyl esters and related derivatives. Such a transformation,
OEt
NH 20
Boc
Scheme 5. Debenzylation of salt 12. Reagents and conditions: (a) H2, Pd on C,
MeOH, 50 °C, 18 h; (b) CbzCl, NaHCO3, 1,4-dioxane, 23 °C, 18 h; 88% (two steps); (c)
Boc2O, NaHCO3, 1,4-dioxane, 23 °C, 18 h; 84% (two steps).

P. S. Dragovich et al. / Tetrahedron: Asymmetry 19 (2008) 2796–2803
2799
The specific rotation of 22 measured in EtOH was equal in mag-
nitude but of opposite sign to that reported for (1R,2S)-2-amino-
cyclopentanecarboxylic acid ethyl ester hydrochloride.7e This
result established the absolute configuration of salt 22 as the
(1S,2R)-isomer and thereby allowed the assignment of the absolute
configurations of the other chiral 2-aminocyclopentanecarboxylic
acid derivatives described in this work. Importantly, the specific
rotation data also suggested that a negligible loss of enantiomeric
purity occurred during the transformation of 15 to 22. As expected,
salt 22 could be converted into the corresponding Cbz derivative
24 in good yield using standard chemistry (Scheme 6).
without additional purification. All solutions of reagents, acids,
and bases were aqueous in nature unless otherwise indicated.
Flash chromatography was performed on silica gel using either
self-packed glass columns (Merck Silica Gel 60, 40–63 lM, manual
elution) or commercially available cartridges (Analogix Superflash)
and automated elution systems. Optical rotations were determined
using a Perkin–Elmer model 241 polarimeter. 1H NMR and 13C
NMR spectra were recorded at 400 and 100 MHz, respectively.
Chemical shifts are reported in ppm (d) using internal solvent sig-
nals as references and coupling constants (when given) are re-
ported in Hertz (Hz).
4.1. 2-(40-Fluorobenzylamino)cyclopent-1-enecarboxylic acid
ethyl ester 9
O
OEt
4-Fluorobenzylamine (12.1 g, 97.5 mmol, 1.0 equiv) was added
to a solution of ethyl 2-oxocyclopentanecarboxylate (15.25 g,
97.6 mmol, 1.0 equiv) in toluene (225 mL) at 23 °C. Glacial acetic
acid (6.15 mL, 107 mmol, 1.1 equiv) was then added, producing a
large amount of white solid. The reaction mixture was heated to
70 °C in an oil bath, whereupon most of the solids dissolved. After
stirring for 2 h at 70 °C, a Dean–Stark apparatus and reflux con-
denser were fitted to the reaction flask and approximately 40 mL
of liquid (predominantly toluene) was removed by distillation over
45 min (oil bath temperature = 145 °C). The mixture was allowed
to cool to 23 °C and then used in the next step. A small aliquot of
the crude reaction mixture was concentrated under reduced pres-
sure to give 9 as an orange oil: 1H NMR (CDCl3) d: 1.28 (3H, t,
J = 7.5), 1.79–1.86 (2H, m), 2.51–2.56 (4H, m), 4.15 (2H, q, J = 6.9),
4.34–4.36 (2H, m), 6.98–7.03 (2H, m), 7.19–7.23 (2H, m), 7.73
(1H, br s).
NH 23
Boc
d
O
CO2Et
OEt
•
a, b
c
15
HCl
NH2
NH2
21
22
e
O
OEt
4.2. cis-2-(40-Fluorobenzylamino)cyclopentanecarboxylic acid
ethyl ester 10 and trans-2-(40-fluorobenzylamino)
cyclopentanecarboxylic acid ethyl ester 11
NH
Cbz
24
Scheme 6. Debenzylation of salt 15. Reagents and conditions: (a) H2, Pd on C,
MeOH, 50 °C, 18 h; (b) NaHCO3, 52% (two steps) (c) HCl, 1,4-dioxane; 0–23 °C; 1 h;
66% (three steps from 15); (d) Boc2O, iPr2NEt, DMF, 40 °C, 16 h, 39% (three steps);
(e) CbzCl, Et3N, THF, 0–23 °C; overnight; 91%.
Sodium triacetoxyborohydride (62.1 g, 293 mmol, 3.0 equiv)
was suspended in a 1/1 mixture of glacial acetic acid and CH3CN
(200 mL) at 0 °C. The crude reaction mixture containing 9 prepared
in the previous step was added via cannula over 15 min and the
resulting orange/brown suspension was allowed to warm to
23 °C over 19 h. Then 4.0 M HCl (60 mL) was carefully added and
the mixture was stirred at 23 °C for 20 min. The mixture was trans-
ferred to a large Erlenmeyer flask containing a stir bar and was
cooled to 0 °C. Then NaOH (98 g dissolved in 350 mL H2O; approx.
8.0 M) was added over 20 min with gentle stirring and continued
external cooling (large exotherm noted; melted ice was replen-
ished). After the exotherm subsided, the mixture was transferred
to a separatory funnel and the phases were separated. The aqueous
phase was subsequently extracted with EtOAc (1 ꢁ 300 mL) and
the combined organic layers were washed with half-saturated
NaHCO3 (1 ꢁ 200 mL), dried over Na2SO4, and concentrated under
reduced pressure. Purification of the residue by flash chromatogra-
phy (gradient elution; 15?40% EtOAc in hexanes) gave 10 (19.9 g,
77% over two steps) as a pale yellow oil: Rf = 0.53 (50% EtOAc in
hexanes); 1H NMR (CDCl3) d: 1.27 (3H, t, J = 7.0), 1.55–1.71 (2H,
m), 1.81–1.91 (4H, m), 1.98–2.06 (1H, m), 2.90–2.96 (1H, m),
3.26–3.31 (1H, m), 3.73 (1H, d, J = 13.1), 3.77 (1H, d, J = 13.2),
4.15 (2H, q, J = 7.3), 6.94–7.00 (2H, m), 7.24–7.28 (2H, m); 13C
NMR (CDCl3) d: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2
(d, J = 21.5), 129.6 (d, J = 8.4), 136.5 (d, J = 3.1), 161.9 (d,
J = 243.8), 174.7; Anal. Calcd for C15H20FNO2: C, 67.90; H, 7.60; N,
5.28. Found: C, 67.92; H, 7.88; N, 5.55. The cis-relationship be-
tween the amino and ester moieties present in 10 was established
by a 1D NOE experiment. Continued elution of the silica gel column
with increasing amounts of EtOAc (up to 100% of eluent concentra-
3. Conclusion
In conclusion, we have developed a novel procedure for the
multi-gram preparation of an enantiomerically pure salt [(1R,2S)-
2-(40-fluorobenzylamino)cyclopentanecarboxylic acid ethyl ester
complex with (S)-(+)-mandelic acid; compound 12] which can be
easily converted into a key chiral intermediate 2b required for
the synthesis of a promising HCV NS5B polymerase inhibitor. This
process utilizes mandelic acid as a resolving agent which can be
recovered in good yield by a simple extraction. An optimized ver-
sion of the described chemistry avoids the use of chromatographic
purifications making it suitable for large-scale applications. The 4-
fluorobenzyl substituent present in compound 12 (or the corre-
sponding enantiomer 15) can be easily removed via hydrogenation,
thereby providing access to a variety of optically active cis-2-
aminocyclopentanecarboxylic ethyl ester derivatives. We antici-
pate that the use of this new methodology will facilitate the explo-
ration of novel molecules, which incorporate such entities.20,21
4. Experimental
All reactions were performed in septum-sealed vials or flasks
under a slight positive pressure of dry nitrogen. All commercial re-
agents were used as received from their respective suppliers. All
solvents were purchased from EMD in anhydrous form and used

2800
P. S. Dragovich et al. / Tetrahedron: Asymmetry 19 (2008) 2796–2803
tion) afforded 11 (3.2 g, 12%) as a dark orange oil: Rf = 0.22 (50%
EtOAc in hexanes); 1H NMR (CDCl3) d: 1.26 (3H, t, J = 7.0), 1.40–
1.49 (1H, m), 1.67–1.77 (2H, m), 1.82–1.91 (1H, m), 1.97–2.05
(2H, m), 2.58 (1H, q, J = 7.9), 3.31 (1H, q, J = 7.3), 3.72 (1H, d,
J = 13.2), 3.77 (1H, d, J = 12.5), 4.14 (2H, q, J = 7.0), 6.96–7.01 (2H,
m), 7.24–7.29 (2H, m).
127.5, 128.3, 129.7, 131.2 (d, J = 8.4), 141.6, 162.9 (d, J = 246.9),
174.7, 178.0; Anal. Calcd for C23H28FNO5: C, 66.17; H, 6.76; N,
3.36. Found: C, 66.24; H, 6.99; N, 3.44. Concentration of a small ali-
quot of the filtrate obtained above under reduced pressure afford-
ed 13 (contaminated with ꢃ5% of 12) as a white solid: 1H NMR
(CDCl3) d: 1.26 (3H, t, J = 7.0), 1.56–1.65 (1H, m), 1.74–1.81 (2H,
m), 1.91–2.04 (3H, m), 2.97–3.02 (1H, m), 3.43–3.49 (1H, m),
3.84 (1H, d, J = 13.4), 4.07 (1H, d, J = 13.2), 4.10–4.20 (2H, m),
4.97 (1H, s), 6.82 (2H, br s), 6.89–6.96 (2H, m), 7.19–7.26 (3H,
m), 7.29–7.33 (2H, m), 7.45–7.47 (2H, m).
The diastereomeric purity of 12 was assessed by careful exam-
ination of the compound’s 1H NMR spectrum obtained at 400 MHz
in CDCl3 at 23 °C. These conditions enabled the resolution of the
resonances of 12 and 13 located at 3.86 and 3.84 ppm, respectively
(both doublets; each half of an ‘AB quartet’ spin system; see Fig. 1A
and B). The amount of 13 present in compound 12 prior to recrys-
tallization was estimated to be no more than 2.5% by integration of
these signals. Additional ‘shouldering’ due to 13 was also noted
slightly downfield of the multiplet of 12 centered around
2.96 ppm. Resonances associated with 13 could not be detected
by 1H NMR following a single recrystallization of compound 12
(Fig. 1C).22
4.3. (1R,2S)-2-(40-Fluorobenzylamino)cyclopentanecarboxylic
acid ethyl ester complex with (S)-(+)-mandelic acid 12 and
(1S,2R)-2-(40-fluorobenzylamino)-cyclopentanecarboxylic acid
ethyl ester complex with (S)-(+)-mandelic acid 13
A
solution of (S)-(+)-mandelic acid (11.40 g, 74.9 mmol,
1.0 equiv) in EtOAc (150 mL) was slowly added over 1 min to a
solution of 10 (19.9 g, 74.9 mmol, 1.0 equiv) in EtOAc (200 mL) at
23 °C. The resulting suspension was stirred at 23 °C for 19 h, then
filtered through a medium frit (note: the filtrate was used in the
preparation of compounds 14 and 15 below). The collected white
powder was washed with Et2O (1 ꢁ 40 mL) and air-dried. Recrys-
tallization of this material from EtOAc (ca. 400 mL) afforded 12
(12.4 g, 40%, >99% de) as white needles: mp = 142–143 °C,
½
a 2D3
ꢂ
¼ þ20:1 (c 0.76, CH3OH); 1H NMR (CDCl3) d: 1.26 (3H, t,
J = 7.4), 1.58–1.67 (1H, m), 1.73–1.86 (2H, m), 1.89–2.08 (3H, m),
2.93–2.98 (1H, m), 3.44–3.49 (1H, m), 3.86 (1H, d, J = 13.0), 4.06
(1H, d, J = 12.7), 4.08–4.20 (2H, m), 4.97 (1H, s), 6.77 (2H, br s),
6.89–6.95 (2H, m), 7.18–7.21 (2H, m), 7.25–7.27 (1H, m), 7.29–
7.33 (2H, m), 7.45–7.48 (2H, m); 13C NMR (CDCl3) d: 14.5, 22.0,
28.8, 29.1, 44.8, 50.3, 59.5, 61.7, 74.1, 116.1 (d, J = 21.5), 126.7,
4.4. (1S,2R)-2-(40-Fluorobenzylamino)cyclopentanecarboxylic
acid ethyl ester complex with (R)-(ꢀ)-mandelic acid 15
The filtrate obtained during the preparation of 12 described
above was washed sequentially with saturated NaHCO3 solution
Figure 1. (A) Portion of 400 MHz 1H NMR spectrum (CDCl3, 23 °C) of 12 obtained after initial filtration isolation. Minor resonances associated with 13 are indicated by arrows.
(B) Portion of 400 MHz 1H NMR spectrum (CDCl3, 23 °C) of 13 obtained after concentration of filtrate was obtained during initial isolation of 12. Minor resonances associated
with 12 are indicated by arrows. (C) Portion of 400 MHz 1H NMR spectrum (CDCl3, 23 °C) of 12 obtained after recrystallization.

P. S. Dragovich et al. / Tetrahedron: Asymmetry 19 (2008) 2796–2803
2801
(200 mL) and half-saturated NaHCO3 solution (200 mL). These
aqueous washings were employed in the recovery of (S)-(+)-man-
delic acid as described below. The washed filtrate was then dried
over Na2SO4 and concentrated under reduced pressure to give
crude 14 as a pale yellow oil (10.3 g, 10.3 mmol). This material
was dissolved in EtOAc (100 mL) at 23 °C and a solution of (R)-
(ꢀ)-mandelic acid (5.88 g, 38.6 mmol, 1.0 equiv) in EtOAc (100
mL) was slowly added over 1 min. The resulting suspension was
stirred at 23 °C for 21 h, then was filtered through a medium fritted
funnel. The white powder collected was washed with Et2O
(1 ꢁ 50 mL) and was air-dried. Recrystallization of this material
from EtOAc (ca. 400 mL) afforded 15 (11.9 g, 74%) as white needles:
added over 5 min. The ice bath was removed and the mixture was
stirred for 16 h at 23 °C. The solution was then concentrated under
reduced pressure, after which EtOAc (400 mL) was added to the
thick orange oil thus obtained. The resulting solution was again
concentrated under reduced pressure, and the product began to
precipitate after approximately 50% of the EtOAc had been re-
moved. Hexanes (200 mL) were added at this point and the suspen-
sion was stirred for 10 min at 23 °C. The solids were collected by
filtration, rinsed with ethyl acetate (2 ꢁ 30 mL), and were dried un-
der vacuum to afford 1717 (98 g, 88% yield) as a white powder: 1H
NMR (DMSO-d6) d: 1.21 (3H, t, J = 7.0), 1.52–1.63 (1H, m), 1.72–
1.83 (2H, m), 1.87–2.00 (3H, m), 2.98–3.04 (1H, m), 3.60–3.64
(1H, m), 4.04–4.16 (2H, m), 8.17 (3H, br s).
mp = 142–144 °C; ½a D23
ꢂ
¼ ꢀ19:3 (c 0.54, CH3OH); 1H NMR (CDCl3)
d: 1.26 (3H, t, J = 7.4), 1.58–1.67 (1H, m), 1.73–1.86 (2H, m),
1.89–2.08 (3H, m), 2.93–2.98 (1H, m), 3.44–3.49 (1H, m), 3.86
(1H, d, J = 13.0), 4.06 (1H, d, J = 12.8), 4.08–4.20 (2H, m), 4.97
(1H, s), 6.89–6.95 (4H, m), 7.18–7.21 (2H, m), 7.25–7.27 (1H, m),
7.29–7.33 (2H, m), 7.45–7.48 (2H, m); 13C NMR (CDCl3) d: 14.5,
22.0, 28.8, 29.1, 44.8, 50.3, 59.5, 61.7, 74.2, 116.1 (d, J = 21.5),
126.7, 127.5, 128.3, 129.6, 131.2 (d, J = 8.4), 141.6, 162.9 (d,
J = 246.9), 174.7, 178.0; Anal. Calcd for C23H28FNO5: C, 66.17; H,
6.76; N, 3.36. Found: C, 66.17; H, 6.76; N, 3.43. Signals for the cor-
responding diastereomeric salt (the enantiomer of compound 13)
could not be detected in recrystallized 15 by 1H NMR analysis
using the method described above to assess the diastereomeric
purity of compound 12.22
4.8. cis-2-(40-Fluorobenzylamino)cyclopentanecarboxylic acid
ethyl ester 10 (large-scale preparation)
Sodium acetate (76.3 g, 0.93 mol, 2.0 equiv) was added to a
solution of 17 (90 g, 0.465 mol, 1.0 equiv) in EtOH (875 mL) at 23
°C. After stirring for 10 min at that temperature, 4-fluorobenzalde-
hyde (57.71 g, 0.465 mol, 1.0 equiv) was added, and the resulting
mixture was stirred for 20 min. Sodium cyanoborohydride
(58.4 g, 0.93 mol, 2.0 equiv) was then added portionwise over a
period of 15 min, and the mixture was stirred at 23 °C for 16 h.
The crude reaction mixture was then concentrated under reduced
pressure, and the resulting paste suspended in water (200 mL) and
cooled to 0 °C. Next, HCl (2.0 M, 500 mL, 1 mol) was added, and the
mixture was stirred for 10 min at 0 °C. Additional HCl (6.0 M, 500
mL, 3 mol) was then slowly added at 0 °C over 10 min and the mix-
ture was stirred at that temperature for 30 min. Aqueous NaOH
(6.0 M, 500 mL, 3 mol) was slowly added at 0 °C while stirring,
and the pH of the resulting mixture was subsequently adjusted
to approximately 7.5 by the careful addition of saturated NaHCO3.
After extraction with EtOAc (2 ꢁ 1000 mL), the organic layers were
dried over MgSO4, filtered, and concentrated under reduced pres-
sure to afford 10 (122.8 g, 99% yield) as a pale yellow oil.
4.5. Recovery of (S)-(+)-mandelic acid
The combined aqueous washings described in the preparation
of 14 were acidified to pH 2.0 by the careful addition of 6.0 M
HCl (vigorous gas evolution). They were subsequently extracted
with EtOAc (3 ꢁ 200 mL). The combined EtOAc extracts were dried
over Na2SO4 and concentrated under reduced pressure to afford
(S)-(+)-mandelic acid (6.0 g, 98% of theoretical recovery): Anal.
Calcd for C8H8O3: C, 63.15; H, 5.30. Found: C, 63.12; H, 5.63.
4.6. cis-6-Azabicyclo[3.2.0]heptan-7-one 16
4.9. (1R,2S)-2-(40-Fluorobenzylamino)cyclopentanecarboxylic
acid ethyl ester complex with (S)-(+)-mandelic acid 12 (large-
scale preparation)
Chlorosulfonyl isocyanate (92 g, 0.65 mol, 1.0 equiv) was added
dropwise over 60 min to neat cyclopentene (47 g, 0.69 mol,
1.06 equiv) at ꢀ78 °C (keeping the reaction temperature as close
to ꢀ78 °C as possible). After the addition was complete, the mix-
ture was warmed to room temperature over a period of 60 min
and then stirred at that temperature for 18 h. The reaction mixture
was added dropwise to a stirring suspension of ice water (1700
A
solution of (S)-(+)-mandelic acid (70.29 g, 0.462 mol,
1.0 equiv) in EtOAc (800 mL) was added to a solution of 10
(122.63 g, 0.462 mol, 1.0 equiv) in EtOAc (1000 mL) over 2 min at
23 °C, and the resulting suspension was stirred at that temperature
for 16 h. The solids were collected by vacuum filtration, rinsed with
EtOAc (2 ꢁ 100 mL), and were dried under vacuum for 2 h. Recrys-
tallization from EtOAc (ca. 1500 mL) afforded 12 (76.6 g, 40% yield,
de >99%) as white needles. Anal. Calcd for C23H28FNO5: C, 66.17; H,
6.76; N, 3.36. Found: C, 66.13; H, 6.79; N, 3.44.
mL), Na2SO3 (170 g), and NaHCO3 (510 g) over
a period of
20 min. The mixture was warmed to 23 °C and stirred at that tem-
perature for 20 min, after which CH2Cl2 (500 mL) was added and
stirring was continued for an additional 5 min. The solids were col-
lected by vacuum filtration, rinsed sequentially with water
(2 ꢁ 100 mL) and CH2Cl2 (2 ꢁ 100 mL), and were then discarded.
The organic layer was separated from the filtrate and the aqueous
layer was extracted with CH2Cl2 (3 ꢁ 250 mL). The combined or-
ganic phases were dried over MgSO4, filtered, and were concen-
trated under reduced pressure to afford 16 (64.2 g, 84% yield) as
a pale yellow oil which eventually solidified: 1H NMR (CDCl3) d:
1.30–1.46 (2H, m), 1.69–1.86 (3H, m), 2.01 (1H, dd, J = 13.2, 5.4),
3.45–3.48 (1H, m), 4.02 (1H, t, J = 4.1), 6.03 (1H, br s).
4.10. (1R,2S)-2-(40-Fluorobenzylamino)cyclopentanecarboxylic
acid ethyl ester 2b
Salt 12 (2.0 g, 4.8 mmol) was shaken vigorously for 20 min in a
mixture of saturated NaHCO3 solution (20 mL) and EtOAc (20 mL)
at 23 °C. After separating the phases, the aqueous layer was ex-
tracted with additional EtOAc (10 mL). The combined organic lay-
ers were washed with water (10 mL), brine (15 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure to afford
2b (0.96 g, 76% yield) as a clear oil. 1H NMR (CDCl3) d: 1.26 (3H, t,
J = 7.0), 1.53–1.62 (1H, m), 1.63–1.72 (2H, m), 1.81–1.91 (3H, m),
1.96–2.06 (1H, m), 2.93 (1H, q, J = 7.0), 3.29 (1H, q, J = 7.1), 3.73
(1H, d, J = 13.2), 3.77 (1H, d, J = 13.2), 4.09–4.19 (2H, m), 6.95–
6.99 (2H, m), 7.24–7.28 (2H, m).
4.7. cis-2-Aminocyclopentanecarboxylic acid ethyl ester
hydrochloride 17
Thionyl chloride (50 mL) was added dropwise to EtOH (600 mL)
at ꢀ30 °C over a period of 20 min. The mixture was warmed to 0 °C,
and a solution of 16 (64.2 g, 0.578 mol) in EtOH (150 mL) was then

2802
P. S. Dragovich et al. / Tetrahedron: Asymmetry 19 (2008) 2796–2803
4.11. (1R,2S)-2-Benzyloxycarbonylaminocyclopentanecarb-
oxylic acid ethyl ester 19
afford a thick oil, which was subsequently partitioned between sat-
urated NaHCO3 solution (100 mL) and EtOAc (3 ꢁ 100 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to provide crude
21 as a colorless oil.
This material was dissolved in EtOAc (20 mL) at 0 °C, and HCl
(6.0 mL of a 4.0 M solution in 1,4-dioxane) was added slowly.
The mixture was allowed to warm to 23 °C and was stirred for
1 h. The solvent was removed under reduced pressure to afford
Salt 12 (1.25 g, 2.99 mmol, 1.0 equiv) was dissolved in CH3OH
(30 mL) at 23 °C in a flask equipped with a condenser. Palladium
on carbon (Johnson–Matthey, 5%, ‘wet’, 0.30 g) was then added.
The flask was evacuated and backfilled with hydrogen via a balloon
three times. The mixture was stirred at 50 °C under a hydrogen
atmosphere (balloon) for 18 h, whereupon LCMS analysis showed
completion of the reaction. After cooling to 23 °C, the mixture
was passed through a plug of Celite and the Celite was rinsed with
CH3OH (20 mL). The filtrate was concentrated under reduced pres-
sure to afford a clear oil 18 that was dissolved in 1,4-dioxane (20
mL) at 23 °C. Saturated NaHCO3 solution (20 mL) and benzyl chlo-
roformate (0.59 mL, 3.29 mmol, 1.1 equiv) were then added
sequentially. The mixture was stirred at 23 °C for 18 h, after which
LCMS analysis showed completion of the reaction. The mixture was
then transferred to a separatory funnel and extracted with EtOAc
(3 ꢁ 30 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by flash chromatography (gradient elution; 0?20%
EtOAc in hexanes) afforded 19 (0.77 g, 88%) as a clear oil:
22 (1.82 g, 66%) as a yellow oil19: ½a D23
ꢂ
¼ þ10:4 (c 1.14, EtOH); 1H
NMR (CDCl3) d: 1.29 (3H, t, J = 7.2), 1.68–1.76 (1H, m), 2.01–2.23
(5H, m), 3.00 (1H, m), 3.89 (1H, m), 4.22 (2H, q, J = 7.2), 8.47 (3H,
br s); 13C NMR (CDCl3) d: 14.4, 21.8, 27.7, 30.4, 46.2, 53.5, 61.7,
173.0; Anal. Calcd for C8H16ClNO2 (HCl salt): C, 49.61; H, 8.33; N,
7.23. Found: C, 49.51; H, 7.95; N, 7.25.
4.14. Recovery of (R)-(ꢀ)-mandelic acid
The basic aqueous solution obtained in the above preparation of
21 was acidified to pH 2.0 by careful addition of 6.0 M aqueous HCl
(vigorous gas evolution). The resulting solution was extracted with
EtOAc (3 ꢁ 100 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure to afford (R)-(ꢀ)-mandelic acid (1.94 g, 89% of theoretical
recovery).
Rf = 0.23 (20% EtOAc in hexanes); ½a D23
¼ ꢀ71:9 (c 1.0, CH3OH);
ꢂ
1H NMR (CDCl3) d: 1.23 (3H, t, J = 7.2), 1.59–1.75 (2H, m), 1.78–
1.87 (1H, m), 1.94–2.04 (3H, m), 3.00 (1H, dd, J = 14.8, 6.8), 4.10
(2H, q, J = 7.2), 4.22–4.34 (1H, m), 5.09 (s, 2H), 5.20–5.31 (1H, m),
7.29–7.38 (5H, m); 13C NMR (CDCl3) d: 14.3, 22.3, 27.9, 32.3,
46.8, 54.3, 60.6, 66.6, 127.9, 128.0, 128.4, 136.5, 155.6, 174.0; Anal.
Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 65.93; H,
7.30; N, 4.83.
4.15. (1S,2R)-2-tert-Butoxycarbonylaminocyclopentanecarb-
oxylic acid ethyl ester 23
Salt 15 (3.17 g, 7.59 mmol) was converted to crude amino-ester
21 (0.619 g, 52%) using the procedure described above for the syn-
thesis of 22. Rf = 0.13 (5% CH3OH in CH2Cl2); 1H NMR (CDCl3) d:
1.28 (3H, t, J = 7.4), 1.53–1.63 (1H, m), 1.83–2.09 (3H, m), 2.77–
2.83 (1H, m), 3.62 (1H, br s), 4.17 (2H, q, J = 7.0). This material
was dissolved in DMF (20 mL) at 23 °C after which di-tert-butyl
dicarbonate (1.29 g, 5.90 mmol) and iPr2NEt (1.51 mL, 8.65 mmol)
were added sequentially. The mixture was stirred for 16 h at 40 °C,
then concentrated under reduced pressure. The residue was parti-
tioned between 1.0 M HCl (100 mL) and EtOAc (2 ꢁ 150 mL). The
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. Purification of the residue by flash chro-
matography (gradient elution, 0?15% EtOAc in hexanes) afforded
23 (0.754 g, 75%) as a white solid: mp = 66–67 °C; Rf = 0.43 (25%
4.12. (1R,2S)-2-tert-Butoxycarbonylaminocyclopentanecarb-
oxylic acid ethyl ester 20
Salt 12 (1.10 g, 2.63 mmol, 1.0 equiv) was converted to crude 18
using the procedure described above for the preparation of 19. This
material was dissolved in 1,4-dioxane (20 mL) at 23 °C, and satu-
rated NaHCO3 solution (20 mL) and di-tert-butyl dicarbonate
(1.21 mL, 5.26 mmol, 2.0 equiv) were added sequentially. The mix-
ture was stirred at room temperature for 18 h, after which TLC
analysis showed completion of the reaction. The mixture was then
transferred to a separatory funnel and extracted with EtOAc
(3 ꢁ 30 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by flash chromatography (gradient elution; 0?20%
EtOAc in hexanes) afforded 20 (0.57 g, 84%) as a white solid:
EtOAc in hexanes); ½a D23
ꢂ
¼ þ93:8 (c 1.0, CH3OH); 1H NMR (CDCl3)
d: 1.27 (3H, t, J = 7.0), 1.43 (9H, s), 1.55–1.69 (2H, m), 1.79–1.86
(1H, m), 1.91–2.02 (3H, m), 2.98 (1H, dd, J = 14.8, 8.0), 4.13 (2H,
q, J = 7.1), 4.20–4.28 (1H, m), 4.95 (1H, br s); 13C NMR (CDCl3) d:
14.3, 22.3, 27.8, 28.4, 32.3, 46.9, 53.7, 60.4, 79.0, 155.0, 174.0; Anal.
Calcd for C13H23NO4: C, 60.68; H, 9.01; N, 5.44. Found: C, 60.85; H,
9.12; N, 5.43.
mp = 64–66 °C; Rf = 0.28 (20% EtOAc in hexanes); ½a D23
¼ ꢀ93:9 (c
ꢂ
1.0, CH3OH); 1H NMR (CDCl3) d: 1.28 (3H, t, J = 7.2), 1.44 (9H, s),
1.55–1.71 (2H, m), 1.79–1.86 (1H, m), 1.91–2.02 (3H, m), 2.98
(1H, dd, J = 14.8, 8.0), 4.14 (2H, q, J = 7.2), 4.20–4.28 (1H, m), 4.95
(1H, br s); 13C NMR (CDCl3) d: 14.5, 22.5, 28.0, 28.6, 32.6, 47.1,
54.0, 60.6, 79.3, 155.2, 174.3; Anal. Calcd for C13H23NO4: C,
60.68; H, 9.01; N, 5.44. Found: C, 60.81; H, 8.97; N, 5.51.
4.16. (1S,2R)-2-Benzyloxycarbonylaminocyclopentanecarboxy-
lic acid ethyl ester 24
4.13. (1S,2R)-2-Aminocyclopentanecarboxylic acid ethyl ester
hydrochloride 22
Benzyl chloroformate (0.428 mL, 3.04 mmol) was added to a
solution of salt 22 (0.536 g, 2.77 mmol) and Et3N (0.772 mL,
5.53 mmol) in THF (15 mL) at 0 °C. The resulting mixture was al-
lowed to warm to 23 °C overnight, whereupon LCMS analysis con-
firmed the completion of the reaction. The reaction mixture was
concentrated under reduced pressure and the residue was parti-
tioned between water (15 mL) and EtOAc (3 ꢁ 20 mL). The com-
bined organic layers were washed with brine (15 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
24 (0.736 g, 91%) as a light yellow oil: Rf = 0.61 (40% EtOAc in hex-
Salt 15 (6.0 g, 14.4 mmol) was dissolved in CH3OH (120 mL) at
23 °C in a flask equipped with a condenser. Palladium on carbon
(Johnson–Matthey, 5%, ‘wet’, 1.2 g) was added. The flask was evac-
uated and backfilled with hydrogen via a balloon three times. The
mixture was stirred at 50 °C under a hydrogen atmosphere (bal-
loon) for 18 h, whereupon LCMS analysis showed the reaction to
be complete. After cooling to 23 °C, the mixture was passed
through a plug of Celite, and the Celite was rinsed with CH3OH
(30 mL). The filtrate was concentrated under reduced pressure to
anes); ½a 2D3
ꢂ
¼ þ62:7 (c 1.22, EtOH); 1H NMR (CDCl3) d: 1.23 (3H, t,
J = 7.2), 1.56–1.76 (2H, m), 1.76–1.88 (1H, m), 1.90–2.06 (3H, m),

P. S. Dragovich et al. / Tetrahedron: Asymmetry 19 (2008) 2796–2803
2803
1996, 61, 5557; (i) Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461;
(j) Konosu, T.; Oida, S. Chem. Pharm. Bull. 1993, 41, 1012.
3.00 (1H, dd, J = 14.7, 7.6), 4.10 (2H, q, J = 7.2), 4.22–4.34 (1H, m),
5.09 (2H, s), 5.20–5.31 (1H, m), 7.28–7.40 (5H, m); 13C NMR
(CDCl3): d: 14.4, 22.4, 28.1, 32.5, 46.9, 54.3, 60.7, 66.8, 128.0,
128.1, 128.5, 136.5, 155.7, 174.2; Anal. Calcd for C16H21NO4: C,
65.96; H, 7.27; N, 4.81. Found: C, 65.94; H, 7.32; N, 4.88.
9. For reviews summarizing the preparation and utilization of 2-
aminocycloalkane carboxylic acids, see: (a) Fülöp, F.; Martinek, T. A.; Tóth, G.
K. Chem. Soc. Rev. 2006, 35, 323; (b) Fülöp, F. Chem. Rev. 2001, 101, 2181.
10. Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. J. Org. Chem.
1994, 59, 5328.
ˇ
11. Xu, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron: Asymmetry 1997, 8,
1445; See also: Matsuo, J.-i.; Okano, M.; Takeuchi, K.; Tanaka, H.; Ishibashi, H.
Tetrahedron: Asymmetry 2007, 18, 1906.
Acknowledgments
12. For other recent uses of mandelic acid to resolve benzylic amines, see: (a)
Klingensmith, L. M.; Nadeau, K. A.; Moniz, G. A. Tetrahedron Lett. 2007, 48,
4589; (b) Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmans, W.; Zani, L.; Bolm, C.
J. Org. Chem. 2006, 71, 2320.
The authors thank Drs. David Kucera, Jerry (Lijian) Chen, and
Gregory Haley for many helpful discussions during the course of
this work.
13. No additional attempts were made to more rigorously quantitate the
diastereomeric purity of salts 12 and 15.
References
14. We anticipate that reversing the order in which the mandelic acid enantiomers
are employed in the resolution sequence will allow for the initial isolation of
salt 15 if desired (in lieu of 12).
15. In an independent experiment, the addition of (S)-(+)-mandelic acid to an
EtOAc solution of diastereomerically pure 11 (prepared as described in Scheme
3) resulted in the simultaneous precipitation of both diastereomeric salts
corresponding to 12 and 13. No attempt was made to effect resolution of 11
using other solvents or chiral reagents.
1. Ruebsam, F.; Tran, C. V.; Li, L.-S.; Kim, S. H.; Xiang, A. X.; Zhou, Y.; Blazel, J. K.;
Sun, Z.; Dragovich, P. S.; Zhao, J.; McGuire, H.; Murphy, D. E.; Tran, M. T.;
Stankovic, N.; Ellis, D. A.; Gobbi, A.; Showalter, R. E.; Webber, S. E.; Shah, A. M.;
Tsan, M.; Patel, R.; LeBrun, L. A.; Hou, H. J.; Kamran, R.; Sergeeva, M. V.;
Bartkowski, D. M.; Nolan, T. G.; Norris, D. A.; Kirkovsky, L. Bioorg. Med. Chem.
Lett. 2009, 19, 451.
16. (a) Nativ, E.; Rona, P. Isr. J. Chem. 1972, 10, 55; (b) Parsons, P. J.; Camp, N. P.;
Underhood, J. M.; Harvey, M. D. Tetrahedron 1996, 52, 11637.
2. Tran, C. V.; Ruebsam, F.; Zhou, Y.; Dragovich, P. S.; Xiang, A. X. WO2008/
073982.
17. (a) Zahn, S. K.; Boehmelt, G.; Mantoulidis, A.; Reiser, U.; Treu, M.; Guertler, U.;
Schoop, A.; Solca, F.; Tontsch-Grunt, U.; Brueckner, R.; Reither, C.; Herfurth, L.;
Kraemer, O.; Stadtmueller, H.; Engelhardt, H. US Patent application # 2007/
0032514.; (b) Furrer, H. Chem. Ber. 1972, 105, 2780.
18. We chose not to recover the (S)-(+)-mandelic acid liberated in this step.
However, we anticipate that such a recovery could be accomplished using a
simple process similar to that described in Scheme 3 for the preparation of salt
15.
3. The ephedrine-mediated resolution of racemic Boc-protected cis-2-
aminocyclo-pentanecarboxylic acid has been previously described: Nöteberg,
D.; Brånalt, J.; Kvarnström, I.; Classon, B.; Samuelsson, B.; Nillroth, U.;
Danielson, U. H.; Karlén, A.; Hallberg, A. Tetrahedron 1997, 23, 7975.
However, the cost of racemic cis-2-aminocyclopentanecarboxylic acid (ca.
$70/g) and the utilization of several recrystallizations to achieve high
enantiomeric purity precluded us from employing this method to produce
large quantities of 2a and/or 2b.
19. Analytically pure hydrochloride 22 was obtained as an oil rather than the low-
melting solid described in the literature for the (1R,2S)-isomer.7e This
discrepancy likely results from the solvents employed in the preparation of
22, which differ from those utilized in the earlier report and may retard
crystallization when present in trace amounts. The 1H NMR spectrum of 22
was identical to that reported for (1R,2S)-2-amino-cyclopentanecarboxylic acid
ethyl ester hydrochloride. In addition, the specific rotation of the former
material was of equal magnitude but of opposite sign to that reported for the
latter compound [literature data for (1R,2S)-2-aminocyclopentanecarboxylic
4. (a) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984;
(b) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683.
5. (a) Bolm, C.; Schiffers, I.; Dinter, C. L.; Defrère, L.; Gerlach, A.; Raabe, G. Synthesis
2001, 1719; (b) Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P. R.
Tetrahedron: Asymmetry 2003, 14, 3455.
6. For large-scale applications of the chemistry described in Refs. 4a and 5, see: (a)
Ishii, Y.; Fujimoto, R.; Mikami, M.; Murakami, S.; Miki, Y.; Furukawa, Y. Org.
Process Res. Dev. 2007, 11, 609; (b) Mittendorf, J.; Benet-Buchholz, J.; Fey, P.;
Mohrs, K.-H. Synthesis 2003, 136.
7. For the preparation of optically active cis-2-aminocyclopentanecarboxylic acid
derivatives via enzymatic resolution, see: (a) Forró, E.; Fülöp, F. Chem. Eur. J.
2007, 13, 6397; (b) Forró, E.; Fülöp, F. Org. Lett. 2003, 5, 1209; (c) Theil, F.;
Ballschuh, S. Tetrahedron: Asymmetry 1996, 7, 3565; (d) Csomós, P.; Kanerva, L.
T.; Bernáth, G.; Fülöp, F. Tetrahedron: Asymmetry 1996, 7, 1789; (e) Kanerva, L.
T.; Csomós, P.; Sundholm, O.; Bernáth, G.; Fülöp, F. Tetrahedron: Asymmetry
1996, 7, 1705.
8. For chemical syntheses of cis-2-aminocyclopentanecarboxylic acid and related
derivatives in optically active form, see: (a) Sakai, T.; Doi, H.; Tomioka, T.
Tetrahedron 2006, 62, 8351; (b) Doi, H.; Sakai, T.; Yamada, K.-i.; Tomioka, T.
Chem. Commun. 2004, 1850–1851; (c) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.-
i.; Tomioka, T. J. Am. Chem. Soc. 2003, 125, 2886; (d) Tang, W.; Wu, S.; Zhang, X.
J. Am. Chem. Soc. 2003, 125, 9570; (e) Aggarwal, V. K.; Roseblade, S.; Alexander,
R. Org. Biomol. Chem. 2003, 1, 684; (f) Aggarwal, V. K.; Roseblade, S.; Barrell, J.
K.; Alexander, R. Org. Lett. 2002, 4, 1227; (g) Cimarelli, C.; Palmieri, G.; Volpini,
E. Synth. Commun. 2001, 31, 2943; (h) Cimarelli, C.; Palmieri, G. J. Org. Chem.
acid ethyl ester hydrochloride:7e mp = 68–69.5 °C; ½a 2D0
¼ ꢀ10:4 (c 1.0, EtOH);
ꢂ
1H NMR (400 MHz, CDCl3) d: 1.29 (3H, t, J = 7.1 Hz), 1.65–2.25 (6H, m), 3.02
(1H, dt, J = 8.3, 6.2 Hz), 3.90 (1H, q, J = 5.9 Hz), 4.24 (2H, q, J = 7.1 Hz), 8.50 (3H,
br s)].
20. Optically active trans-2-aminocyclopentanecarboxylic acid esters can be
prepared in good yield by the base-catalyzed isomerization of the
corresponding Boc-protected cis-isomers.8d However, no attempt was made
to use such procedures to isomerize compounds 20 and 23.
21. Preliminary attempts to resolve the cis-isomers of other cyclic b-amino acids
(e.g., 2-aminocyclohexanecarboxylic acid) using the described methodology
were not successful.
22. The use of ‘aged’ CDCl3 in the de-assessments of 12 or 15 often resulted in the
appearance of minor amounts of additional 1H NMR signals. This result is
attributed to the presence of HCl in the CDCl3 that led to the formation of the HCl
salts corresponding to 12 or 15. It is therefore recommend that only relatively
fresh samples of the deuterated NMR solvent be employed for this analysis.