Aza-Diels - Alder reaction of methyl 2-[(R)-1-phenylethyl]iminoethanoate with cyclopentadiene using practical and environmentally friendly biphasic solvent system

Article abstract of DOI:10.1021/op049828m

Aza-Diels - Alder reaction between 2-[(R)-1-phenylethyl]imino-ethanoate (1) and cyclopentadiene using the biphasic solvent system (TMSCl-CH ₃OH/toluene) gave (1S,3S,4R)-2-[(R)-1-phenylethyl]-2-aza-bicyclo[2.2. 1]hept-5-ene-3-carboxylates (3a) i

Full text of DOI:10.1021/op049828m

Organic Process Research & Development 2005, 9, 105−109
Technical Notes
Aza-Diels-Alder Reaction of Methyl 2-[(R)-1-Phenylethyl]iminoethanoate with
Cyclopentadiene Using Practical and Environmentally Friendly Biphasic Solvent
System
Norio Hashimoto,*,†,‡ Hironobu Yasuda,† Masaru Hayashi,† and Yoo Tanabe‡
Chemical DeVelopment Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku,
Osaka 532-8514, Japan, and School of Science, Kwansei Gakuin UniVersity, 2-1, Gakuen, Sanda,
Hyogo 669-1337, Japan
Abstract:
To overcome these problems, we investigated a new
protocol from the standpoint of process chemistry. Here, we
disclose a practical method for the preparation of methyl
analogue 3a using the aza-DA reaction in the biphasic solvent
system, TMSCl-CH3OH/toluene. Utilizing the present
method, 3a was successfully obtained as highly pure crystal-
line solid for the first time,11 using neither column chroma-
tography nor any fluorinated chemicals.
Aza-Diels-Alder reaction between 2-[(R)-1-phenylethyl]imino-
ethanoate (1) and cyclopentadiene using the biphasic solvent
system (TMSCl-CH3OH/toluene) gave (1S,3S,4R)-2-[(R)-1-
phenylethyl]-2-aza-bicyclo[2.2.1]hept-5-ene-3-carboxylates (3a)
in 32% isolated yield. The present method is advantageous for
the large-scale synthesis, because (i) the reported methods
required harmful and expensive fluorinated chemicals, (ii)
methyl analogue 3a was practically isolated as a crystalline solid,
and (iii) the reaction was conducted with very little observable
exotherm. In addition, the absolute configurations of the other
three diastereomers 2, 4, and 5 were unambiguously deter-
mined.
Results and Discussion
First, we reexamined the aza-DA reaction of methyl
2-[(R)-1-phenylethyl]iminoethanoate (1a) with cyclopenta-
diene, following the reported conditions (CF3CO2H-CF3-
CH2OH monophasic system).10 Imine 1a was readily pre-
pared from available (R)-1-phenylethylamine12 and methyl
2-hydroxy-2-methoxyacetate.13 Reverse-phase HPLC analysis
of the crude product showed four main peaks (Chart 1).14
LC-MASS/MASS analysis for each peak revealed that all
four products have the same M+ data (MW ) 257) with
very similar degradation patterns. This result indicates that
these four products correspond to methyl ester diastereomers
2a, 3a, 4a, and 5a, in order of elution from the HPLC as an
end result.
Introduction
Recently, a class of bicyclic proline analogue, (1S,3S,4R)-
2-[(R)-1-phenylethyl]-2-aza-bicyclo[2.2.1]hept-5-ene-3-car-
boxylates (3) have attracted considerable attention due to
the application not only for biologically active peptides1,2
but also for chiral catalysts.3-5 In general, bicyclic compound
3 can be obtained as the major adduct by the diastereose-
lective [4 + 2]-type aza-Diels-Alder (aza-DA) reaction
between 2-[(R)-1-phenylethyl]iminoethanoate (1) and cyclo-
pentadiene, along with three other diastereomers 2, 4, and 5
(Scheme 1).6
The isolation of the desired diasteromer 3, however,
requires tedious procedures for industrial-scale production
and the use of silica gel column chromatography and
fluorinated chemicals such as CF3CO2H, BF3‚OEt2 reagents,
and CF3CH2OH solvent.6-10
The absolute configuration of diastereomer 5a, which
eluted first from the silica gel column chromatography
(normal phase), was deduced to be endo-[1S,3R,4R] (Scheme
(7) Tararov, V. I.; Kadyrov, R.; Kadyrova, Z.; Dubrovina, N.; Bo¨rner, A.
Tetrahedron: Asymmetry 2002, 13, 25. (Tararov et al. succeeded in the
conversion of crude 3b to ethyl (1R,3S,4S)-2-[(R)-1-phenylethyl]-2-
azabicyclo[2.2.1]heptane-3-carboxylate hydrochloride as crystals in 32%
overall yields.
(8) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707.
(9) Balley, P. D.; Brown, G. R.; Korber, F.; Reed, A.; Wilson, R. D.
Tetrahedron: Asymmetry 1991, 2, 1263.
* To whom correspondence should be addressed. E-mail: norio_hasimoto@
po.fujisawa.co.jp. Telephone: 81-6-6390-1183. Fax: 81-6-6304-4419.
† Fujisawa Pharmaceutical Co. Ltd.
(10) Bailey, P. D.; McDonald, I. M.; Rosair, G. M.; Taylor, D. Chem. Commun.
2000, 2451.
‡ Kwansei Gakuin University.
(1) Limburg, D. C.; Thomas, B. E.; Li, J.; Fuller, M.; Spicer, D.; Chen, Y.;
Guo, H.; Steiner, J. P.; Hamilton, G. S.; Wu, Y. Bioorg. Med. Chem. Lett.
2003, 13, 3867.
(2) Mellor, J. M.; Richards, N. G. J.; Sargood, K. J.; Anderson, D. W.;
Chamberlin, S. G.; Davies, D. E. Tetrahedron Lett. 1995, 36, 6765.
(3) Pinho, P.; Guijarro, D.; Andersson, P. G. Tetrahedron 1998, 54, 7897.
(4) So¨dergren, M. J.; Andersson, P. G. Tetrahedron Lett. 1996, 37, 7577.
(5) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998, 63, 2530.
(6) Stella, L.; Abraham, H.; Feneau-dupont, J.; Tinant, B.; Declercq, J. P.
Tetrahedron Lett. 1990, 31, 2603.
(11) Stella et al. reported in ref 6 that neither 3a nor its enantiomer could be
obtained in crystalline form.
(12) Juaristi, E.; Leo´n-Romo, J.; Reyes, A.; Escalante, J. Tetrahedron: Asym-
metry 1999, 10, 2441.
(13) Ethyl form 1b was prepared according to the method of ref 7. See
Experimental Section for 1a.
(14) HPLC analytical conditions: YMC-Pack ODS-Am (YMC Co., Ltd.)
(particle size: 5 µm, diameter: 4.6 mm, length: 150 mm), column
temperature: 40 °C, mobile phase: 60% aqueous acetonitrile (Na2-
HPO4‚12H2O, KH2PO4, 0.5 g/L each), wavelength: 235 nm.
10.1021/op049828m CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/13/2004
Vol. 9, No. 1, 2005 / Organic Process Research & Development
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105

Scheme 1
Chart 1
indicate that the absolute configuration of diastereomer 5a
should be revised as either endo-[1S,3R,4R] or exo-
[1R,3R,4S] at this stage.
1H NMR chemical shifts of methyl esters endo-2a and
exo-3a were 3.43 and 3.35 ppm, respectively; the upper field
value of exo-3a is supposed due to the shield effect of the
benzene ring. Those of 4a and 5a were 3.68 and 3.78 ppm,
respectively. By close analogy, based on the shield effect,
the configurations of 4a and 5a were finally determined as
exo-[1R,3R,4S] and endo-[1S,3R,4R], respectively.
Taking into account this information, we started to
investigate the reaction conditions without fluorinated re-
agents and/or CF3CH2OH as the solvent. Table 1 lists these
results. The most common acid, HCl, which was con-
veniently and quantitatively generated by reaction of TMSCl
with CH3OH, was selected instead of the reported method
that used CF3CO2H (entries 1, 2). However, the reaction did
not proceed to completion and only a moderate conversion
was observed (entry 3). We speculated that cyclopentadiene
was poorly soluble in CH3OH leading to the observed white
suspension due to its low solubility. To dissolve the problem,
toluene was added to the system as a cosolvent (entries 4,
5). As we expected, the reaction proceeded smoothly
compared with the reported methods.9-10 It should be noted
that undesirable suspension disappeared and the system
became a homogeneous biphasic solvent system with cy-
clopentadiene soluble in toluene, and the imine, 1a, dissolved
in CH3OH as its hydrochloride salt. The major impurity was
endo-5a in the CF3CO2H-CF3CH2OH system (entry 1),
while in the present system (entry 4) the major impurity is
endo-2a. Lowering the temperature decreased the amount
of 2a (entry 5).
1), although Stella et al. reported that of 5a was endo-
[1R,3S,4S]6 based on the 1H NMR chemical shift of methyl
ester moiety (3.78 ppm, the highest value among four
diastereomers). The absolute configuration of diastereomers
were assigned as follows.
Hydrogenation/hydrogenolysis of 5a using H2-Pd/C
catalyst by the reported method15 resulted in the formation
of (2R)-cyclopentyl glycine methyl ester (7a) ([R]25D -24.9
(c 1, CHCl3)), wherein the chiralty of the 3-position of 5a
was retained. On the other hand, major diasteromer 3a,
known as exo-[1S,3S,4R],6,16 was similarly converted into
the antipodal ester 6a ([R]25 +22.7 (c 1, CHCl3)). In
D
addition, minor diastereomer 2a, which could also be
separated by silica gel column chromatography, was trans-
formed into 6a ([R]25 +21.4 (c 1, CHCl3)) by a similar
D
method. The absolute configuration of 2a was inevitably
endo-[1R,3S,4S]. These experimental results apparently
(15) Alonso, D. A.; Bertilsson, S. K.; Johnsson, S. Y.; Nordin, S. J. M.;
So¨dergren, M. J.; Andersson, P. G. J. Org. Chem. 1999, 64, 2276.
(16) Waldmann, H.; Braun, M. Liebigs Ann. Chem. 1991, 1045.
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Table 1. Aza-Diels-Alder reaction utilizing biphasic systema
solvent (vol)
solvent (vol)
acid
reaction temp (°C)/
%b conversion of 3
isolated
entry
imine
1a
(equiv)
time (h)
(diastereomer ratio 2:3:4:5)
yield (%)c
de (%)b
99.3
1
2
3
4
5
6
7
8
CF3CH2OH (6)
tolueme (1)
DMF (4)
H2O (0.01 equiv)
MeOH (10)
CF3CO2H
(1.0)
CF3CO2H
(1.0)
TMSCl
(2.0)
-15 to -10/
54.7 (5:78:4:13)
33.0 (s.m. remained)
46.0 (7:82:5:6)
21.5
0.25
23 to 25/
26
1a
1a
2 to 5/
4
2 to 3/
19
-15 to 3/
3
2 to 3/
3
-13 to 5/
2
1a
toluene (4)
MeOH (1)
toluene (4)
MeOH (1)
toluene (4)
EtOH (1)
TMSCl
59.8 (16:74:5:5)
62.4 (11:79:6:4)
71.0 (5:80:10:5)
61.8 (8:76:12:4)
59.4 (7:77:9:7)
36.1
36.5
64.7f
94.6 (98.3)e
97.8
(2.0)d
1a
TMSCl
(2.0)
TMSCl
(2.0)
TMSCl
(2.0)
TMSCl
(2.0)
1b
1a
toluene (4)
iPrOH (1)
1a
toluene (4)
CF3CH2OH (1)
-11 to 5/
2.5
a Cyclopentadiene (1.5 equiv) was used in all entries. b Conversion based on 1 and diastereomeric excess were determined by the HPLC analysis mentioned in the
text. c Product 3a could be crystallized in n-heptane at 0 °C, followed by filtration at -15 °C after stirring for 1 h. d TMSCl (1.0 equiv) gave an unsatisfactory
conversion. e One more recrystallization with n-heptane gave a higher purified product. f Purified by silica gel column chromatography.
Table 2. Stereoselectivity of aza-DA reaction using
cosolvents
to the corresponding covalent form should be sufficiently
retarded.6
One more notable aspect lies in the fact that the present
aza-DA reaction displayed only a small exotherm compared
to the CF3CO2H-CF3CH2OH system (ca. 60 kJ/mol of
cyclopentadiene). Actually, auto-MATE17 indicated a small
heat release value of 4.4 kJ during the addition of 1 mol of
cyclopentadiene. Thus, cyclopentadiene could be added in
one portion into the biphasic solvent system, which is
regarded as a safe and desirable process. Finally, we
successfully scaled up the present procedure for the large-
scale production of 3a (103 kg) in 32% isolated yield. As
the reaction displayed only a mild exotherm, it was easily
controlled using -15 °C brine in a 4000-L glass-lined
reactor.
cosolvent
exo/endo
3S/3R
MeOH
5.7
9.0
7.3
6.0
9.0
5.7
5.3
5.3
EtOH
iPrOH
CF3CH2OH
In the case of using ethyl analogue 1b, the conversion
yield increased compared with that using 1a (entry 6), but
unfortunately, the desired major product 3b, which was
purified by silica gel column chromatography, did not
solidify. Diastereomer 2b was isolated in 7% yield as a major
1
impurity, and the H NMR analysis coincided with the
reported data9 of the endo form. To determine the absolute
configuration, 2b was converted into (2S)-cyclopentyl glycine
ethyl ester (6b) in a manner similar to the case of the methyl
Conclusions
We have established the practical and environmentally
friendly aza-DA reaction between methyl 2-[(R)-1-phenyl-
ethyl]iminoethanoate (1a) and cyclopentadiene using a
biphasic solvent system (TMSCl-CH3OH/toluene), which
not only avoided expensive and pollutive fluorinated chemi-
cals but also produced methyl (1S,3S,4R)-2-[(R)-1-phenyl-
ethyl]-2-aza-bicyclo[2.2.1]hept-5-ene-3-carboxylate (3a) as
a high quality crystalline solid. In addition, the absolute
configurations of all four diastereomers 2, 3, 4, and 5 were
unambiguously determined by using LC-MASS/MASS, 1H
NMR analyses, and a valid derivatization to cyclopentyl-
glycine derivatives.
form 6a. The optical rotation of 6b was [R]25 +15.3 (c 1,
D
CHCl3), which surpassed the reported data ([R]25D +10.2 (c
1, CHCl3))15 derived from exo-3b. Thus, the absolute
configuration of 2b was unambiguously determined to be
i
endo-[1R,3S,4S]. The use of PrOH or CF3CH2OH as
cosolvent did not show promising results (entries 7, 8).
Table 2 summarizes the relationship between solvents and
exo/endo, 3S/3R (si/re-face) selectivities. No apparent cor-
relation of solvents with exo/endo ratios was observed. In
contrast, as the bulk of alcohols (ROH) increased, 3S/3R
ratios considerably decreased. This tendency would be
explained by the following plausible mechanism (Scheme
2). As Balley et al. pointed out,9 chiral imine 1a chelates
with an alcohol through two hydrogen bonds to give the
activated seven-membered ring intermediate 8. Sterically
unhindered CH3OH avoids the repulsion against (R)-1-
phenylethyl group, and cyclopentadiene predominantly ap-
proaches from the si-face of 8. Regarding the counterion,
chloride forms a tighter ion pair than trifluoroacetate8 so that
the undesirable reverse reaction from ionic intermediate 8
Experimental Section
All reagents and solvents were commercially available.
1H NMR spectra were recorded with a Bruker AC200P(200
MHz) spectrometer using tetramethylsilane as an internal
standard. HPLC analysis was performed with a Shimadzu
10A. Melting points were determined in open capillary tubes
(17) auto-MATE is a product of Hazard Evaluation Laboratory Limited.
Vol. 9, No. 1, 2005 / Organic Process Research & Development
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107

Scheme 2
and were uncorrected. Mass, LC-MASS/MASS, and optical
analyses were carried out by Analytical Science Laboratories,
Inc.
n-heptane:ethyl acetate ) 3:1 to 1:1) to give 2a and 5a each
as a pale-yellow oil.
Methyl (1R,3S,4S)-2-[(R)-1-phenylethyl]-2-aza-bicyclo-
[2.2.1]hept-5-ene-3-carboxylate (2a): 1H NMR (CDCl3) δ
(ppm): 1.48 (3H, d, J ) 6.5 Hz), 1.40-1.67 (2H, m), 3.20-
3.30 (1H, m), 3.30-3.36 (1H, m), 3.43 (3H, s), 3.60-3.70
(1H, q, J ) 7.0 Hz), 4.02-4.10 (1H, m), 6.04-6.12 (1H,
m), 6.54-6.62 (1H, m), 7.18-7.40 (5H, m). MASS (e/z):
258 (M + H+).
Methyl (1S,3R,4R)-2-[(R)-1-phenylethyl]-2-aza-bicyclo-
[2.2.1]hept-5-ene-3-carboxylate (5a): 1H NMR (CDCl3) δ
(ppm): 1.22 (3H, d, J ) 6.5 Hz), 1.61 (1H, s), 1.89 (1H, d,
J ) 8.5 Hz), 2.49 (1H, s), 3.03 (1H, q, J ) 6.5 Hz), 3.05-
3.12 (1H, m), 3.50-3.56 (1H, m), 3.78 (3H, s), 6.00-6.06
(1H, m), 6.38-6.44 (1H, m), 7.20-7.40 (5H, m). MASS
(e/z): 258 (M + H+).
Methyl 2-[(R)-1-phenylethyl]iminoethanoate (1a). To
a 2000-L glass-lined reactor were added toluene (653 kg)
and methyl 2-hydroxy-2-methoxyacetate (164 kg, 1365 mol).
To the mixture was added dropwise (R)-1-phenylethylamine
(150 kg, 1241 mol) at -5-0 °C, followed by stirring for 1
h at room temperature. The reaction solution was washed
with water (750 L), and the aqueous layer was re-extracted
with toluene (392 kg). The combined organic layer was
washed with 20% (w/v) aqueous NaCl (450 L), followed by
concentration under reduced pressure to give 1a quantita-
1
tively. H NMR (CDCl3) δ (ppm): 1.63 (3H, d, J ) 7.0
Hz), 3.87 (3H, S), 4.61 (1H, q, J ) 6.5 Hz), 7.20-7.40 (5H,
m), 7.74 (1H, s). MASS (e/z): 192 (M + H+). Compound
1a was stable for at least 2 weeks in the refrigerator.
Methyl (1S,3S,4R)-2-[(R)-1-Phenylethyl]-2-aza-bicyclo-
[2.2.1]hept-5-ene-3-carboxylate (3a). To a sufficiently
stirred imine 1a (237 kg, 1241 mol) in toluene (815 kg) and
methanol (206 kg) in a 4000-L glass-lined reactor was added
TMSCl (270 kg, 2486 mol) dropwise at 0-5 °C for 2 h.
Then, freshly distilled cyclopentadiene (123 kg, 1861 mol)
was added dropwise at -10 to -5 °C for 1 h, followed by
stirring for an additional 1 h and at 0-5 °C for 1 h.
The lower layer containing 3a as its hydrochloride salt
was separated, and the top layer was back extracted with
9% aqueous HCl. Combined aqueous CH3OH solution was
neutralized to pH 8-9 with 25% aqueous H4NOH solution,
followed by extraction with n-heptane (1068 kg). Evaporation
under reduced pressure gave a concentrated solution (610
kg), which was stirred over 1 h at 0-5 °C and an additional
1 h at -5 to -10 °C for the crystallization. Filtration and
drying gave 3a as a white solid (103.4 kg, 32.4% yield):
mp ) 47-48 °C; the 1H NMR spectrum was identical with
the reported data.6 1H NMR (CDCl3) δ (ppm): 1.42 (3H, d,
J ) 6.5 Hz), 1.63 (1H, broad s), 2.10 (1H, d, J ) 8.5 Hz),
2.22 (1H, s), 2.91 (1H, broad s), 3.04 (1H, q, J ) 6.5 Hz),
3.36 (3H, s), 4.32 (1H, broad s), 6.22-6.30 (1H, m), 6.40-
6.46 (1H, m), 7.16-7.30 (5H, m). MASS (e/z): 258 (M +
H+).
Methyl (1R,3R,4S)-2-[(R)-1-Phenylethyl]-2-aza-bicyclo-
[2.2.1]hept-5-ene-3-carboxylate (4a). Compound 4a could
not be sufficiently purified due to the nearly identical Rf
values of 4a and 3a; therefore, 4a was identified as a mixture
1
with 3a. H NMR (CDCl3) δ (ppm): 1.33 (3H, d, J ) 6.6
Hz), 1.72-1.75 (1H, m), 1.78 (1H, s), 3.42-3.46 (1H, m),
3.48-3.56 (3H, m), 3.68 (3H, s), 6.08-6.10 (1H, m), 6.38-
6.40 (1H, m), 7.15-7.40 (5H, m).
(2S)-Cyclopentyl Glycine Methyl Ester (6a). To com-
pound 3a (1.0 g, 3.89 mmol) in CH3OH (50 mL) and CH3-
CO2H (0.10 g, 38.9 mmol) was added 10% Pd-C (50% wet)
(0.10 g) at room temperature. Equipped with hydrogen
balloon, the suspension was stirred overnight at the same
temperature. Then, the mixture was filtered, washed with
CH3OH, and concentrated under reduced pressure. The
residual oil was purified with column chromatography
(SiO2: 15 g, ethyl acetate:n-heptane (1:1) as elution) to give
6a as a pale-yellow oil ([R]25 +22.7 (c 1, CHCl3), 0.39 g,
D
63.8% yields). 1H NMR (CDCl3) δ (ppm): 1.25-1.82 (10H,
m), 2.02-2.18 (1H, m), 3.33 (1H, d, J ) 7.0 Hz), 3.72 (3H,
s). MASS (e/z): 158 (M + H+). In the same manner, 6a
([R]25D +21.4 (c 1, CHCl3)) was obtained from 2a in similar
yields.
(2R)-Cyclopentyl Glycine Methyl Ester (7a). Compound
5a was converted into 7a ([R]25D -24.9 (c 1, CHCl3)) in the
1
same way as that described above. The H NMR spectrum
An aliquot sample of mother liquid was concentrated
under reduced pressure to give orange oil (5 g), which was
purified by column chromatography (SiO2:160 g, elution:
was identical with 6a completely.
Ethyl (1S,3S,4R)-2-[(R)-1-Phenylethyl]-2-aza-bicyclo-
[2.2.1]hept-5-ene-3-carboxylate (3b). Imine 1b (5.66 g, 27.6
108
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mmol) readily prepared by the condensation of ethyl gly-
oxylate and (R)-phenylethylamine was used instead of 1a
under the same conditions as those for3a. The residual oil
after workup was purified by column chromatography
(SiO2: 200 g, elution: n-heptane:ethyl acetate ) 3:1 to 1:1)
to give 3b and 2b as a colorless oil in 64.7% and 7.4% yields,
conditions as those for6a. 1H NMR (CDCl3) δ (ppm): 1.28
(3H, t, J ) 7.0 Hz), 1.30-1.82 (10H, m), 2.00-2.20 (1H,
m), 3.30 (1H, d, J ) 7.0 Hz), 4.18 (2H, q, J ) 7.0 Hz).
MASS (e/z): 172 (M + H+). The optical purity of 6b was
also checked by the chiral HPLC analysis (CHIRALPAK
AD-RH, Daisel Chemical Industries, Ltd. Elution: 30%
aqueous acetonitrile, wave length: 235 nm) to give 99.5%
ee.
1
respectively. H NMR (CDCl3) δ (ppm): 0.95 (3H, t, J )
7.5 Hz), 1.41 (4H, d, J ) 6.5 Hz), 2.12 (1H, d, J ) 8.0 Hz),
2.20 (1H, s), 2.90 (1H, broad s), 3.03 (1H, q, 6.5 Hz), 3.81
(2H, q, J ) 7.5 Hz), 4.30 (1H, broad s), 6.25-6.29 (1H,
m), 6.40-6.45 (1H, m), 7.13-7.42 (5H, m). MASS (e/z):
272 (M + H+).
Ethyl (1R,3S,4S)-2-[(R)-1-phenylethyl]-2-aza-bicyclo-
[2.2.1]hept-5-ene-3-carboxylate (2b): 1H NMR (CDCl3) δ
(ppm): 1.04 (3H, t, J ) 7.0 Hz), 1.48 (3H, d, J ) 6.5 Hz),
1.50 (1H, d, J ) 8.5 Hz), 1.65 (1H, d, J ) 8.5 Hz), 3.24
(1H, broad s), 3.31 (1H, d, J ) 3.0 Hz), 3.65 (1H, q, J )
6.5 Hz), 3.90 (2H, q, J ) 7.0 Hz), 4.06 (1H, broad s), 6.02-
6.10 (1H, m), 6.56-6.62 (1H, m), 7.16-7.40 (5H, m).
MASS (e/z): 272 (M + H+).
Acknowledgment
N.H. thanks Fujisawa Pharmaceutical Company for
financial support, and we are also grateful to Mr. Toshio
Azuma in Analytical Research Laboratories for the analysis
of LC-MASS/MASS and Mr. Hiroki Takeuchi in Chemical
Development Laboratories for his measurement techniques
of reaction heat. Last, we are very grateful to KURARAY
CO., Ltd. for the large-scale production of 3a and their
cooperative studies for scale-up.
(2S)-Cyclopentyl Glycine Ethyl Ester (6b). Compound
Received for review September 15, 2004.
OP049828M
2b was converted into 6b ([R]25 +15.3 (c 1, CHCl3), 0.39
D
g, 63.8% yields) as a pale-yellow oil under the same
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