Practical method for the synthesis of (R)-homopipecolinic acid and (R)-homoproline esters from ω-chloroalkanoic acids and available chiral amines

Article abstract of DOI:10.1016/j.tet.2005.12.014

A practical synthesis of (R)-homopipecolinic acid methyl ester 1 and (R)-homoproline methyl ester 2 was performed utilizing (i) a direct intramolecular cyclization of ω-chloro-β-enamino esters 11 and 12, which were prepared from available (S)-1-phenylethy

Full text of DOI:10.1016/j.tet.2005.12.014

Tetrahedron 62 (2006) 2214–2223
Practical method for the synthesis of (R)-homopipecolinic acid
and (R)-homoproline esters from u-chloroalkanoic acids
and available chiral amines
b
b
b,
Norio Hashimoto,a,b, Takashi Funatomi, Tomonori Misaki and Yoo Tanabe
*
*
aProcess Chemistry Labs, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka, 532-8514, Japan
bSchool of Science, Kwansei Gakuin University, 2-1, Gakuen, Sanda, Hyogo 669-1337, Japan
Received 28 October 2005; accepted 7 December 2005
Available online 27 December 2005
Abstract—A practical synthesis of (R)-homopipecolinic acid methyl ester 1 and (R)-homoproline methyl ester 2 was performed utilizing
(i) a direct intramolecular cyclization of u-chloro-b-enamino esters 11 and 12, which were prepared from available (S)-1-phenylethylamine
or (S)-1-(1-naphthyl)ethylamine and u-chloro-b-keto esters 5 and 10, respectively and (ii) a highly diastereoselective NaBH4 reduction
followed by hydrogenolysis. The present method is a short-step process using inexpensive and readily available substrates and reagents with
fewer wasted materials.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
u-oxo-2-alkynoates.4f Due to the multi-steps and/or
expensive starting materials and reagents, there remains a
need for an easier, more practical, and less expensive
method.
Considerable attention has been focused on chiral piperidine
and pyrrolidine derivatives, especially as key synthetic
precursors of a variety of biologically active alkaloids.
Among them, methyl (R)-(2-piperidino)acetate [(R)-homo-
pipecolinic acid methyl ester] (1) and methyl (R)-(2-
pyrrolidino)acetate [(R)-homoproline methyl ester] (2) are
two attractive chiral building blocks for the synthesis of
natural alkaloids1 and useful pharmaceuticals.2 There are
several methods to synthesize these compounds;3 the
Lhommet’s protocol4 and the Michael type addition of
chiral amines to a,b-unsaturated esters, followed by
cyclizations utilizing either alkylation5 or ring-closing
metathesis.6
O
O
N
OMe
N
OMe
H
H
2
1
As outlined in Scheme 1, we disclose a new practical
synthetic method of 1 and 2, which involves (i) the
preparation of b-keto esters; (ii) b-enamino ester formation
using available chiral benzylamines; (iii) regioselective
cyclization; (iv) highly diastereoselective NaBH4 reduction
and (v) hydrogenolysis.
Lhommet and co-workers extensively investigated the
synthesis of various chiral cyclic b-amino acid esters,
which serve as key intermediates for the synthesis of
alkaloids.4 Their study began with the utilization of the
Eschenmoser sulfide contraction,7 which requires the
tedious removal of undesirable sulfur-containing
by-products, for the next Pd-catalyzed hydrogenation
step.4a–d,8 To resolve these problems, they developed
three efficient alternative synthetic methods that utilize
u-chloro-2-alkynoates,4e u-chloro-b-keto esters, and
2. Results and discussion
The preparation of u-chloro-b-keto ester precursors 5 and
10 is illustrated in Scheme 2. C-Acylation of Meldram’s
acid with 5-chloropentanoic acid (3) was performed using
a condensation reagent, 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC$HCl), to give
product 4 in 95% yield. Methanolysis of 4 gave methyl
7-chloro-3-oxoheptanoate (5) quantitatively, which was
used for the next step without any purification procedure
such as distillation or column chromatography. On the other
hand, a similar reaction using 4-chlorobutanoic acid (6) did
Keywords: Chiral amines; Intramolecular cyclization; Keto esters;
Diastereoselective reduction.
Corresponding authors. Tel.: C816 6390 1183; fax: C81 6 6304 4419;
e-mail: norio.hashimoto@jp.astellas.com
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.014

N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
2215
Ar
O
O
(i)
(ii)
Me
NH
O
Cl
CO2H
Cl
OMe
Cl
n
n
OMe
n
n = 1, 2
O
O
(iii)
(iv)
(v)
n
n
1 and 2
N
OMe
N
OMe
Ar
Me
Ar
Me
Scheme 1.
O
O
O
O
O
MeOH
O
O
Meldram's acid
CO2H
Cl
Cl
OMe
Cl
EDC HCl –Et3N
3
5
4
quant.
95%
O
O
O
O
Meldram's acid
O
O
O
O
Cl
Cl
CO2H
EDC HCl –Et3N
O
O
O
O
O
O
O
6
8
7
40%
CH3OAc
O
O
Cl
COCl
Cl
OMe
TiCl4 – Et3N –
N
NMe
9
10
82%
Scheme 2.
not result in the formation of the desired product 8, but
rather in the side formation of dimerized product 7 mainly
under the identical conditions. We attribute this unexpected
result to the fact that intermediate 8 is very labile due to the
high reactivity of the 4-(g-)chloro atom (neighboring group
participation).9 To solve the problem, we utilized Ti-
Crossed Claisen condensation of acid chloride 9 with
methyl acetate, which successfully afforded the desired
b-keto ester 10 in good yield.10
conditions (Scheme 3). Note that, due to the instability of
11a and 11b against SiO2 column chromatographic
purification, one-pot procedure for the subsequent cycliza-
tion leading to 16a and 16b, respectively, should be desired
(see Section 3).
A similar reaction between 10 and (S)-1-phenylethylamine
gave the desired b-enamino ester 12a and cyclized-
homoproline ester 13a; however, both resulted in poor
yields, with considerable amounts of undesirable b-keto
amides 14 and 15 (Table 1, entry 1). A longer reaction
period did not improve the total yield of 12a and 13a, and
increased the formation of 15 (entry 2), probably because
the reactivity of the ketone function of 10 paralleled that of
the ester. To solve this problem, we applied the TiCl4-
catalyzed method for b-enamino ester formation:12 the side
According to the reported method,11 the condensation of 5
with readily available chiral amines, (S)-1-phenylethyl-
amine and (S)-1-(1-naphthyl)ethylamine, smoothly pro-
ceeded to give the corresponding b-enamino esters 11a
(64%) and 11b (69%), respectively, using the p-TsOH$H2O
catalyst (0.05 equiv) in toluene under convenient azeotropic
Ar
Ar
O
O
Me
NH2
Me
NH
O
Cl
OMe
Cl
OMe
- H2O
reflux / toluene
5
11a : Ar = Ph
11b : Ar = α-Naphthyl
Scheme 3.

2216
N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
Table 1.
O
O
cat. (0.05 equiv.)
/ Benzene, reflux
Ar
Cl
+
OMe
Me
NH2
O
10
O
Me
Ph
Ar
O
O
Me
OMe
N
Cl
+
Me
NH
O
+
+
N
N
Ph
N
H
Cl
H
OMe
Ar
Me
Ph
Me
15
12a : Ar = Ph
12b : Ar = α-Naphthyl
13a
13b
14
Entry
Cat.
Time (h)
Yield (%)a
14
Ar
12a
13a
15
Recovery of
10
Me
(equiv)
NH2
1b
2b
3
4
5
TsOH$H2O
1.5
1
4
4
4
4
4
6
6
6
28
20
50
61
73
68
78
94
6
16
8
15
15
14
19
4
18
11
6
44
42
8
35
24
12
18
Trace
Trace
Trace
TiCl4
1.2
1.4
1.5
1.5
Trace
Trace
Trace
Trace
Trace
Trace
—
Trace
Trace
Trace
Trace
Trace
Trace
—
6
7
SnCl4
TiCl4
8c
9c,d
96 (12b)
3 (13b)
a Determined by 1H NMR.
b Toluene was used as a solvent and refluxed with removal of H O using Dean–Starks apparatus.
2
c Cyclohexane was used as a solvent.
d (S)-1-(1-Naphthyl)ethylamine was used instead of (S)-1-phenylethylamine.
formation of 14 and 15 was completely suppressed (entries
3–5). The use of SnCl4 was somewhat inferior to that of
TiCl4 (entry 6). Under optimized conditions, the desired
enamine 12a (or its analog, 12b) together with homoproline
13a (or 13b) resulted in a total 97% (or 99%) yield (entries 8
and 9).
sufficiently strong enough to eventually deprotonate
amine hydrogen via the N-alkylation pathway. Wang and
co-workers described another notable N-cyclization, which
seems to be a back-to front mode of the present reaction;
that is, N-alkylation occurs first, followed by enamine
formation.3f
Next, we investigated the cyclization reaction of b-enamino
ester 11a and 11b into homopipecolinic acid esters 16a and
16b, respectively, using tBuOK as a base (Table 2). The use
of tBuOK alone resulted in slow conversion of the reaction
with poor yield of 16a (entry 1). To facilitate the reaction,
0.1 equiv of Bu4NI was used as a co-catalyst and remarkable
effects were observed; a shorter reaction time (1 h) and
higher yield (55%) (entry 2). An increase in the number of
Bu4NI equivalents (0.2 and 0.4 equiv) did not affect the
reaction yield, but rather the reaction became sluggish; that
is, the purity of 16a decreased (entries 3 and 4). The
naphthyl analog 16b also underwent the reaction smoothly
(entry 5). Note that homoproline esters 13a and 13b were
synthesized in better yield than 16a and 16b (entries 6
and 7), probably because of the advantageous five-
membered ring formation.
Next, we discuss diastereoselective reduction of
N-protected homopipecolinic acid esters 16a, 16b, and
homoproline esters 13a, and 13b, followed by deprotec-
tion, leading to (R)-homoproline methyl esters 2 and (R)-
homopipecolinic acid methyl esters 1. Catalytic hydrogen-
ation of N-protected homoproline esters using the PtO2
catalyst was previously reported.4a,f The MeCH(Cl)OCOCl
mediated deprotection method is also documented.5 We
examined the reduction using readily available NaBH4 of
16a, 16b, 13a, and 13b, which proceeded smoothly to give
the desired products 17a, 17b, 18a, and 18b, respectively,
with high stereoselectivity (Table 3). Compared with
reported methods (entries 1–3),14 NaBH4 reduction in
DME–AcOH mixed solvent gave almost similar results
(entry 4). Compound 17b (84% de) was isolated by its HCl
salt, which was purified by recrystallization in 2-propanol
to give pure product 17b (98% de) in 56% total isolated
yield. Note that naphthyl analogs 17b and 18b were
obtained in good yield with excellent de (entries 6 and 8).
This result would be a promising method to avoid column
chromatographic purification from starting substrates 3
and 6.
The reaction between 5 and (S)-1-phenylethylamine using
two different reagents (Na2SO4–Na2HPO4–cat. I2 and
13
Na2CO3–cat. Bu4NI) resulted in competitive C-cyclization
to give mainly compound 16a0,4f a regioisomer of 16a. The
mechanism underlying the successful result of the desired
t
regioselectivity using BuOK–cat. Bu4NI is not clear at
present. We assume that the reported reaction proceeds via
A proposed mechanism for the present stereoselective
reduction, exemplified by naphthyl b-enamino ester 16b,
t
the enamine C-alkylation pathway, whereas BuOK is

N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
2217
Table 2. Intramolecular cyclization of b-enamino esters 11a, 11b, 12a, and 12b
Ar
CO2Me
NH
O
tBuOK (1.5 equiv) – cat. Bu4NI
Me
NH
O
N
OMe
Cl
OMe
H
Me
Ar
Me
Ph
/ DME, reflux
11a : Ar = Ph
16a
16b
16a'
11b : Ar = α-Naphthyl
Ar
O
Me
NH
O
Cl
N
OMe
OMe
Ar
Me
13a
13b
12a : Ar = Ph
12b : Ar = α-Naphthyl
Entry
b-Enamino ester
Bu4NI (equiv)
Time (h)
Product
Purity (%)a
Yield (%)b
1
2
3
4
5
6
7
11a
11a
11a
11a
11b
12a
12b
None
0.1
0.2
0.4
0.1
4
1
1
1
1
1
1
16a
16a
16a
16a
16b
13a
13b
—
97
89
86
—
—
—
27
55c
56c
55c
68
0.1
0.1
84
89
a Quantitative HPLC analysis: Column (YMC ODS-AM302; 5 mm, 4.6 mm!150 mm), mobil phase (H2O/CH3CNZ30:70).
b Isolated yield.
c Calculated yield based on the purity of both starting material and product.
a
Table 3. Diastereoselective reduction of cyclized enamines 13 and 16 using NaBH4
O
O
NaBH4
N
OMe
N
OMe
DME
AcOH
Ar
Me
Ar
Me
16a : Ar = Ph
17a
17b
16b : Ar = α-Naphthyl
O
O
N
OMe
N
OMe
Ar
Me
Ar
Me
13a : Ar = Ph
18a
18b
13b : Ar = α-Naphthyl
Entry
Enamine
Reaction condition
Solvent
Product de (%)b
Yield (%)c
1
2
3
4
5
6
7
8
16a
16a
16a
16a
16a
16b
13a
13b
H2 (balloon), PtO2 (0.2W) rt, 18 h
NaBH(OAc)3 (100 mol%) rt, 18 h
NaBH(OAc)3 (100 mol%) rt, 7 h
NaBH4 (100 mol%) rt, 2 h
NaBH4 (400 mol%) rt, 3 h
NaBH4 (100 mol%) rt, 2 h
DME
DME
DME
DME–AcOH (4/1)
MeOH
DME–AcOH (4/1)
DME–AcOH (4/1)
DME–AcOH (4/1)
17a 86
17a 84
17a 80
17a 84
17a 62
17b 94
18a 62
18b 92
77d
72
80e
68
69
88
79
89
NaBH4 (100 mol%) rt, 2 h
NaBH4 (100 mol%) rt, 2 h
a The reaction conversion and diastereomeric excess were checked by either HPLC analysis: Column (YMC ODS-AM302; 5 mm, 4.6 mm!150 mm), mobil
phase (H2O/CH3CNZ70:30) or 1H NMR integration for 18a.
b de was checked before a chromatographic purification.
c Calculated yield based on the product purity.
d The reaction did not complete after 18 h.
e Conversion of HPLC analysis.

2218
N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
Scheme 4.
is as follows (Scheme 4). Ester 16b has a preferential
conformation of 16b-A rather than 16b-B or 16b-C;
Computer-assisted conformation analysis supports this
assumption [MM2 force field, Chem3D 5.0 Windows,
CambridgeSoft Corporation (Cambridge Scientific
Computing, Inc.), Cambridge, Massachusetts, USA].
Initially, the reaction of 16b-A with NaBH(OAc)3,
generated by NaBH4 and AcOH, produces (Z)-b-iminium
borate 19a, which was in turn transformed into b-amino
boron-enolate 20 by the intramolecular reduction; bulky
naphthyl group hangs over the Re face of 19a and hydride
transfer occurs from less hindered Si face. Final hydrolysis
of 20 affords the desired b-amino ester 17b.
Final stage of the present syntheses, that is, deprotection of
17a and 17b was performed by catalytic hydrogenation
using H2–10% Pd–C to give (R)-homopipecolinic acid
methyl ester 1 in good yield in contrast to the reported
description (Scheme 5).5 The analytical data of 1 was
identical with that of the authentic sample12 with high
optical purity (98% ee). (R)-homoproline methyl ester (2)
was obtained in a similar manner (91% ee).
O
O
N
OMe
N
OMe
H
Ar
Me
1
17a : Ar = Ph
91%
72%
17b : Ar = α-Naphthyl
O
OMe
Me
O
N
N
OMe
H
Ar
2
18a : Ar = Ph
91%
90%
18b : Ar = α-Naphthyl
Scheme 5.

N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
2219
In conclusion, we performed an efficient practical method
for the synthesis of two useful chiral building brocks, (R)-
homopipecolinic acid methyl ester 1 and (R)-homoproline
methyl ester 2.
3.1.3. Methyl 6-chloro-3-oxohexanoate (10).3a,4f 4-Chloro-
butanoyl chloride (9; 5.07 g, 30 mmol) was added to a
stirred solution of AcOMe (3.56 g, 48 mmol) and N-methy-
limidazole (2.96 g, 36 mmol) in toluene (90 mL) at 0–5 8C
under an Ar atmosphere, followed by being stirred at the
same temperature for 10 min. TiCl4 (18.78 g, 99 mmol) and
N,N-diisopropylethylamine (13.96 g, 108 mmol) were suc-
cessively added to the mixture at 0–5 8C, which was stirred
at same temperature for 30 min. Water was added to the
mixture, which was extracted three times with ether. The
combined organic phase was washed with water, brine,
dried (Na2SO4), and concentrated to give crude oil (6.00 g).
Purification by silica gel column chromatography (hexane/
AcOEtZ20:1) gave the desired product 10 (4.39 g, 82%).
3. Experimental
3.1. General
All reagents and solvents were commercially available.
Flash column chromatography was performed with silica
gel Merck 60 (230–400 mesh ASTM). H NMR spectra
1
were recorded on a Bruker AC200P (200 MHz), or a on a
JEOL DELTA 300 spectrometer, operating at 300 MHz
1
Yellowish oil; H NMR (CDCl3, 300 MHz) d: 2.08 (quin,
1
for H NMR and 75 MHz for 13C NMR. Melting points
2H, JZ6.5 Hz), 2.76 (t, 2H, JZ6.9 Hz), 3.48 (s, 2H), 3.59
(t, 2H, JZ6.5 Hz), 3.75 (s, 3H); 13C NMR (CDCl3,
75 MHz) d: 25.85, 39.43, 43.90, 48.82, 52.16, 167.27,
201.46; IR (neat) 2957, 1748, 1719, 1439, 1408, 1325,
1265 cmK1; HRMS (ESI) calcd for C7H11ClO3 (MCNaC)
201.0294, found 201.0300.
were determined on a hot stage microscope apparatus
(Yanagimoto) and were uncorrected. NMR spectra were
recorded Chemical shifts (d ppm) in CDCl3 were reported
1
downfield from TMS (Z0) for H NMR. For 13C NMR,
chemical shifts were reported in the scale relative to CDCl3
(77.00 ppm) as an internal reference. IR Spectra were
recorded on a JASCO FT/IR-5300 spectrophotometer.
Optical rotations were measured on a JASCO DIP-370 (D
589 nm). Mass spectra were measured on a JEOL JMS-
T100LC spectrometer. HPLC analyses were performed
using a Shimadzu 10A apparatus.
3.1.4. Methyl 3-[1(S)-phenylethylamino]-7-chlorohept-2-
enoate (11a). Methyl 7-chloro-3-oxoheptanoate (5; 96 mg,
0.50 mmol) was added to a stirred solution of (S)-
phenylethylamine (91 mg, 0.75 mmol) and p-TsOH$H2O
(5 mg, 0.03 mmol) in toluene (1.5 mL). After reflux for 1 h
using Dean–Stark apparatus with continual removal of
water, water was added to the mixture, which was extracted
three times with ether. The combined organic phase was
washed with water, brine, dried (Na2SO4), and concentrated
to give crude oil (w100% 1H NMR conversion yield),
which was purified by silica gel column chromatography
(hexane/AcOEtZ10:1) gave the desired product 11a
(95 mg, 64%). Because 11a was somewhat labile to silica
gel column chromatography, the isolated yield decreased.
One-pot reaction improved the yield (See the preparation
of 16a).
3.1.1. 2,2-Dimethyl-5-(5-chloropentanoyl)-1,3-dioxane-
4,6-dione (4). Meldram’s acid (10.0 g, 69 mmol) was
added to a stirred solution of 5-chlorohexanoic acid (1b,
9.5 g, 69 mmol), 4-dimethylaminopyridine (2.1 g,
17 mmol), Et3N (14.0 g, 139 mmol), and EDC hydro-
chloride (14.6 g, 76 mmol) in CH2Cl2 (200 mL) at 0–5 8C.
After stirring at 20–25 8C for 24 h, the mixture was
concentrated, and extracted with AcOEt (200 mL). The
organic phase was washed with 1 M HCl (200 mL), water,
brine, dried (MgSO4), and concentrated to give the desired
product 4 (17.4 g, 95%).
Yellowish oil; [a]D27 C403.9 (c 1.85, CHCl3); H NMR
1
Viscid yellowish oil. Leaving the oil at room temperature it
solidified; mp 40–41 8C; H NMR (CDCl3, 300 MHz) d:
1
(CDCl3, 300 MHz) d: 1.41–1.51 (1H, m), 1.53 (3H, d, JZ
7.2 Hz), 1.56–1.86 (3H, m), 1.87–2.05 (1H, m), 2.10–2.22
(1H, m), 3.42 (2H, t, JZ6.2 Hz), 3.67 (3H, s), 4.50 (1H, s),
4.64 (1H, quin, JZ7.2 Hz), 7.20–7.38 (4H, m), 8.95–9.07
(1H, m); 13C NMR (CDCl3, 75 MHz) d: 25.10, 31.43, 31.78,
44.34, 50.04, 52.47, 82.20, 125.34, 127.14, 128.80, 145.03,
164.58, 171.10; IR (neat) 3279, 2948, 1655, 1607,
1258 cmK1; HRMS (ESI) calcd for C16H22ClNO2 (MC
NaC) 318.1237, found 318.1232.
1.74 (s, 6H), 1.85–1.95 (m, 4H), 3.08–3.16 (m, 2H), 3.52–
3.64 (m, 2H), 15.35 (m, 1H); 13C NMR (CDCl3, 75 MHz) d:
23.16, 26.77, 31.90, 34.77, 44.23, 91.40, 104.90, 197.08;
HRMS (ESI) calcd for C11H15ClO5 (MKHC) 261.0530,
found 261.0529. Anal. Calcd for C11H15ClO5: C, 50.29; H,
5.76. Found: C, 49.9; H, 5.5.
3.1.2. 2,7-Bis(4,4-dimethyl-3,5-dioxo-2,6-dionecyclo-
hexylidene)[1,6]dioxetane (7). Following the procedure
for the preparation of 4, the reaction of 6 (5.0 g, 40 mmol)
gave not the desired product but dimeric compound 3b
(3.45 g, 40%) as a main product.
3.1.5. Methyl 3-[1(S)-naphthylethylamino]-7-chloro-
hept-2-enoate (11b). Following the procedure for the
preparation of 11a, the reaction using 5 (96 mg,
0.50 mmol) and (S)-naphthylethylamine (128 mg,
0.75 mmol), gave the desired product 11b (120 mg, 69%).
Colorless solid; mp 145–148 8C; 1H NMR (CDCl3,
300 MHz) d: 1.71 (s, 12H), 2.18–2.34 (m, 4H), 3.53 (t,
4H, JZ7.9 Hz), 4.78 (t, 4H, JZ7.6 Hz); 13C NMR (CDCl3,
75 MHz) d: 21.80, 26.88, 36.16, 77.42, 91.57, 103.22,
159.83, 162.95, 190.35; IR (KBr) 3430, 2986, 1741, 1707,
1537, 1304, 1209 cmK1; HRMS (ESI) calcd for C20H24O10
(MCNaC) 447.1267, found 447.1270. Anal. Calcd for
C20H24O10: C, 56.60; H, 5.70. Found: C, 56.8; H, 5.9.
1
(w100% H NMR conversion yield). 11b was somewhat
labile to silica gel column chromatography.
1
Yellowish oil; [a]D24 C443.0 (c 1.74, CHCl3); H NMR
(CDCl3, 300 MHz) d: 1.40–1.62 (4H, m), 1.66 (3H, d, JZ
7.2 Hz), 1.82–1.95 (1H, m), 2.00–2.13 (1H, m), 3.30 (2H, t,
JZ6.2 Hz), 3.72 (3H, s), 4.55 (1H, s), 5.45 (1H, quin, JZ

2220
N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
7.2 Hz), 7.42–7.62 (4H, m), 7.72–7.80 (1H, m), 7.87–7.93
(1H, m), 8.00–8.06 (1H, m), 9.17–9.25 (1H, m); 13C NMR
(CDCl3, 75 MHz) d: 24.12, 25.06, 31.41, 31.71, 44.26,
48.54, 50.09, 82.61, 121.81, 122.41, 125.64, 125.85, 126.38,
127.61, 129.15, 129.73, 133.78, 140.80, 164.60, 171.20; IR
(neat) 3283, 2948, 1653, 1605, 1262 cmK1; HRMS (ESI)
calcd for C20H24ClNO2 (MCNaC) 368.1393, found
368.1397.
(Na2SO4), and concentrated to give crude oil [1H NMR
conversion yields; 12a (20%), 13a (16%), 14 (11%), 15
(44%)]. The mixture was purified by silica gel column
chromatography (hexane/AcOEtZ1:1) to give the products
12a (28 mg, 10%), 13a (29 mg, 12%), 14 (27 mg, 10%), 15
(117 mg, 35%).
3.1.9. 6-Chloro-3-oxo-N-[1(S)-phenylethyl]hexanamide
(14). Yellowish oil; [a]2D6 K64.7 (c 0.42, CHCl3); 1H
NMR (CDCl3, 300 MHz) d: 1.50 (3H, d, JZ7.2 Hz), 4.67
(2H, quin, JZ6.2 Hz), 2.71–7.77 (2H, m), 3.42–3.44 (1H,
m), 3.56 (2H, t, JZ6.2 Hz), 5.12 (1H, quin, JZ6.2 Hz),
7.20–7.39 (1H, m); 13C NMR (CDCl3, 75 MHz) d: 15.26,
22.04, 25.87, 40.48, 43.94, 49.04, 49.18, 65.83, 126.05,
127.38, 128.70, 142.93, 164.31, 205.67; IR (KBr) 3283,
3.1.6. Methyl 3-[1(S)-phenylethylamino]-6-chlorohex-2-
enoate (12a) (Table 1, entry 8). TiCl4 (3 mL, 0.03 mmol)
was added to a stirred solution of 10 (89 mg, 0.5 mmol) and
(S)-phenylethylamine (81 mg, 0.75 mmol) in cyclohexane
(2.0 mL) at 20–25 8C. The reaction mixture was refluxed for
6 h. Water was added to the mixture, which was extracted
three times with ether. The combined organic phase was
washed with water, brine, dried (Na2SO4), and concentrated
3061, 2973, 2928, 1721, 1495, 1547 cmK1
.
1
to give crude oil (94% H NMR conversion yield), which
3.1.10. 1-(1(S)-Phenylethyl)-2-[(1(S)-phenylethylamino-
carbonyl)methylidene]pyrrolidine (15). Yellowish oil;
[a]2D6 K176.4 (c 1.29, CHCl3); 1H NMR (CDCl3,
300 MHz) d: 1.46 (d, 3H, JZ6.2 Hz), 1.52 (d, 3H, JZ
7.0 Hz), 1.76–1.99 (m, 2H), 3.00–3.44 (m, 4H), 4.49 (s, 1H),
4.77 (br s, 1H), 5.13 (br s, 2H), 7.16–7.38 (m, 10H); 13C
NMR (CDCl3, 75 MHz) d: 15.16, 16.84, 21.22, 22.39,
32.29, 46.58, 47.99, 52.64, 65.72, 81.01, 126.12, 126.41,
126.66, 127.15, 128.32, 128.47, 140.81, 144.76, 161.84; IR
(neat) 3293, 2975, 1638, 1580, 1213, 1177 cmK1; HRMS
(ESI) calcd for C22H26N2O (MCNaC) 357.1943, found
357.1939.
was purified by silica gel column chromatography (hexane/
AcOEtZ10:1) to give the desired product 12a (104 mg,
74%). Compound 12a was somewhat labile to silica gel
column chromatography.
1
Yellowish oil; [a]D26 C299.9 (c 1.57, CHCl3); H NMR
(CDCl3, 300 MHz) d: 1.53 (3H, d, JZ7.2 Hz), 1.73–1.98
(2H, m), 2.03–2.20 (1H, m), 2.26–2.41 (1H, m), 3.37–3.57
(2H, m), 3.67 (3H, s), 4.51 (1H, s), 4.67 (1H, quin, JZ
7.2 Hz), 7.19–7.39 (5H, m), 8.96–9.08 (1H, m); 13C NMR
(CDCl3, 75 MHz) d: 25.07, 29.37, 30.80, 44.00, 50.06,
52.47, 82.51, 125.36, 127.16, 128.80, 144.88, 163.66,
171.02.
3.1.11. 1-[(1S)-Phenylethyl]-2-[(methoxycarbonyl)-
methylidene]piperidine (16a).4a,15 (one-pot reaction
from 1,3-dioxane-4,6-dione 4) 1,3-Dioxane-4,6-dione 4
(3.00 g, 11 mmol) was added to a stirred solution of MeOH
(30 mL) and the mixture was refluxed for 2 h. After cool
down to room temperature the mixture was concentrated to
give methyl 7-chloro-3-oxoheptanoate (5). To the residual
oil of was added toluene (45 mL), (S)-phenylethylamine
(1.66 g, 14 mmol), and p-TsOH$H2O (0.13 g, 0.68 mmol).
After reflux for 1 h using Dean–Stark trap with continual
removal of water, the mixture was concentrated to give
3.1.7. Methyl 3-[1(S)-naphthylethylamino]-6-chlorohex-
2-enoate (12b) (Table 1, entry 9). Following the procedure
for the preparation of 12a, the reaction using 10a (89 mg,
0.5 mmol) and (S)-naphthylethylamine (128 mg,
1
0.75 mmol), gave the desired product 12b (96% H NMR
conversion yield) (130 mg, 78%). Compound 12b was
somewhat labile to silica gel column chromatography.
Yellowish oil; [a]D24 C325.4 (c 1.74, CHCl3); H NMR
1
t
(CDCl3, 300 MHz) d: 1.65 (3H, d, JZ6.9 Hz), 1.68–1.94
(2H, m), 1.96–2.08 (1H, m), 2.19–2.32 (1H, m), 3.23–3.34
(1H, m), 3.36–3.48 (1H, m), 3.71 (3H, s), 4.58 (1H, s), 5.48
(1H, quin, JZ6.9 Hz), 7.40–7.59 (4H, m), 7.71–7.79 (1H,
m), 7.85–7.91 (1H, m), 7.94–8.07 (1H, m), 9.09–9.31 (1H,
m); 13C NMR (CDCl3, 75 MHz) d: 24.07, 29.19, 30.74,
43.73, 48.55, 50.07, 82.89, 121.89, 122.26, 125.60, 125.74,
126.29, 127.59, 129.05, 129.64, 133.73, 140.63, 163.66,
product 11a, to which was added DME (45 mL), BuOK
(1.92 g, 17 mmol), and Bu4NI (0.42 g, 1.1 mmol). After
reflux for 1 h, the mixture was concentrated and dissolved
with AcOEt (100 mL), which was extracted with 0.2 M HCl
(15 mL!3). Separated combined aqueous phase was
adjusted to pH 8–9 using Na2CO3, and then re-extracted
with AcOEt (25 mL!2). Combined separated organic
phase was washed with water, brine, dried (Na2SO4), and
concentrated to give the desired product 16a (1.68 g, 57%).
171.07; IR (neat) 3281, 2948, 1653, 1607, 1262 cmK1
;
HRMS (ESI) calcd for C19H22ClNO2 (MCNaC) 354.1237,
found 354.1233.
Yellowish orange solid; mp 50–52 8C; [a]2D5 K126.0 (c
1
0.88, CH2Cl2); {lit.,4e [a]D20 K121 (c 1.10, CH2Cl2)}; H
NMR (CDCl3, 200 MHz) d: 1.53 (d, 3H, JZ6.9 Hz), 1.54–
1.74 (m, 4H), 2.75–2.90 (m, 1H), 2.90–3.06 (m, 1H), 3.10–
3.30 (m, 2H), 3.61 (s, 3H), 4.87 (s, 1H), 5.13 (q, 1H, JZ
6.9 Hz), 7.20–7.40 (m, 5H); Mass (TIC, m/z): 282 (MCNa);
13C NMR (CDCl3, 50 MHz) d: 15.2, 19.3, 23.0, 26.3, 41.9,
49.9, 55.2, 81.4, 126.9, 127.4, 128.6, 140.4, 164.0, 169.8; IR
3.1.8. p-TsOH$H2O catalyzed reaction of methyl
6-chloro-3-oxohexanoate (10) with (S)-phenylethylamine
(Table 1, entry 2). Methyl 6-chloro-3-oxohexanoate 10
(179 mg, 1.0 mmol,) was added to a stirred solution of (S)-
phenylethylamine (182 mg, 1.5 mmol) and p-TsOH$H2O
(10 mg, 0.05 mmol) in toluene (3 mL) at room temperature.
After reflux for 4 h using Dean–Stark apparatus with
continual removal of water, water was added to the mixture,
which was extracted three times with ether. The combined
organic phase was washed with water, brine, dried
(KBr) 2949, 2868, 1684, 1589, 1142 cmK1
.
3.1.12. 1-[(1S)-Naphthylethyl]-2-[(methoxycarbonyl)-
methylidene]piperidine (16b). Following the procedure

N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
2221
for the preparation of 16a, use of (S)-naphthylethylamine
(445 mg, 2.6 mmol) and 4 (545 mg, 2.0 mmol) gave the
desired product 16b (418 mg, 68%).
C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.1;
H, 6.9; N, 4.6.
3.1.15. Methyl[(1S)-phenylethyl]-2(R)-piperidylacetate
(17a).4g NaBH4 (29 mg, 0.77 mmol) was added to a stirred
solution of 16a (200 mg, 0.77 mmol) in DME (8 mL) and
CH3CO2H (2 mL) at 10–15 8C. After stirring at 20–25 8C
for 2 h, the mixture was concentrated and then 10% NaOH
aqueous solution (20 mL) was added to the mixture, which
was extracted with AcOEt (15 mL!2). Combined separ-
ated organic phase was washed with water, brine, dried
(Na2SO4), and concentrated to give crude oil (248 mg).
Purification by silica gel column chromatography (hexane/
AcOEtZ5:1) gave the desired product 17a (137 mg, 68,
84% de).
Pale yellow solid; mp 146–148 8C; [a]2D5 K153.3 (c 1.58,
CHCl3); 1H NMR (CDCl3, 200 MHz) d: 1.20–1.60 (m, 4H),
1.65 (d, 3H, JZ6.8 Hz), 2.35–2.50 (m, 1H), 2.80–2.98 (m,
1H), 3.22 (t, 2H, JZ6.4 Hz), 3.69 (s, 3H), 5.12 (s, 1H), 5.61
(q, 1H, JZ6.8 Hz), 7.42–7.60 (m, 4H), 7.62–7.74 (m, 1H),
7.78–7.94 (m, 2H); 13C NMR (CDCl3, 50 MHz) d: 13.7,
18.9, 22.9, 26.3, 41.5, 50.0, 52.6, 80.9, 123.6, 124.7, 124.8,
126.0, 126.9, 128.7, 128.9, 131.9, 133.7, 135.5, 162.9,
169.9. Mass (TIC, m/z): 332 (MCNa). Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.3; H,
7.2; N, 4.3.
3.1.13. 1-[(1S)-Phenylethyl]-2-[(methoxycarbonyl)-
methylidene]pyrrolidine (13a).4a,15 TiCl4 (65 mg,
0.25 mmol) was added to a stirred solution of b-keto ester
10 (894 mg, 5.00 mmol) and (S)-phenylethylamine
(916 mg, 7.50 mmol) in cyclohexane (20 mL) at 20–25 8C.
The reaction mixture was refluxed for 6 h. After cool down
to room temperature, water was added to the mixture, which
was extracted three times with ether. The combined organic
phase was washed with water, brine, dried (Na2SO4), and
concentrated to give product sufficiently pure b-enamine
The de was checked by HPLC analysis [UV (wave length,
230 nm), Mobil phase (H2O/CH3CNZ70:30), Column
(YMC ODS-AM302; 5 mm, 4.6 mm!150 mm), Column
temperature (40 8C), Flow rate (1 mL/min)]. The retention
times of (1S,2S)-isomer and (1S,2R)-isomer were 7.2 and
9.8 min, respectively. Further purification using column
chromatography gave pure (1S,2R)- and (1S,2S)-isomers.
(1S,2R)-Isomer: [a]2D4 K35.3 (c 1.84, CHCl3); colorless oil;
1H NMR (CDCl3, 200 MHz) d: 1.29 (d, 3H, JZ6.7 Hz),
1.35–1.68 (m, 5H), 1.68–1.88 (m, 1H), 2.14–2.40 (m, 2H),
2.50–2.60 (m, 2H), 3.42–3.55 (m, 1H), 3.68 (s, 3H), 3.70 (q,
1H, JZ6.7 Hz), 7.18–7.40 (m, 5H); IR (neat) 3050, 2971,
t
12a, to which was added DME (20 mL), BuOK (841 mg,
7.50 mmol), and Bu4NI (185 mg, 0.50 mmol). After reflux
for 1 h, the reaction mixture was concentrated and dissolved
with AcOEt (20 mL) and then extracted with 0.2 M HCl
(15 mL!3). Combined separated aqueous phase was
adjusted to pH 8–9 using Na2CO3, and then re-extracted
with AcOEt (25 mL!2). Combined separated organic
phase was washed with water, brine, dried (Na2SO4), and
concentrated to give the desired product 13a (1.06 g, 86%).
2876, 1736 cmK1 13C NMR (CDCl3, 75 MHz) d: 17.86,
;
20.77, 25.57, 29.96, 31.93, 44.92, 51.53, 52.34, 59.26,
126.49, 127.25, 128.11, 146.11, 173.60; IR (neat) 3407,
2934, 1736, 1443, 1161 cmK1; Mass (TIC, m/z): 262 (MC
1). (1S,2S)-Isomer: 1H NMR (CDCl3, 200 MHz) d: 1.33 (d,
3H, JZ6.7 Hz), 1.38–1.74 (m, 6H), 2.39–2.75 (m, 4H),
3.10–3.26 (m, 1H), 3.60 (s, 3H), 3.82 (q, 1H, JZ6.7 Hz),
7.18–7.37 (m, 5H). Mass (TIC, m/z): 262 (MC1).
Yellowish orange solid; mp 68–70 8C; [a]2D5 K251.1 (c
0.94, EtOH); {lit.,4e [a]2D0 K256 (c 1.10, EtOH)}; 1H NMR
(CDCl3, 300 MHz) d: 1.55 (d, 3H, JZ6.9 Hz), 1.75–2.02
(m, 2H), 3.05–3.23 (m, 2H), 3.23–3.40 (m, 2H), 3.61 (s,
3H), 4.68 (s, 1H), 4.87 (q, 1H, JZ6.9 Hz), 7.19–7.38 (m,
5H); 13C NMR (CDCl3, 75 MHz) d: 16.73, 20.84, 32.77,
47.13, 49.91, 52.87, 77.82, 126.51, 127.40, 128.57, 140.31,
164.90, 169.91; IR (KBr) 2949, 2868, 1684, 1589,
3.1.16. Methyl[(1S)-naphthylethyl]-2(R)-piperidylacetate
(17b). Following the procedure for the preparation of 17a,
the reaction using 16b (160 mg, 0.517 mmol) gave the
desired product 17b (142 mg, 88, 94% de). The retention
times of (1S,2S)- and (1S,2R)-isomers, using HPLC analysis
described above, were 11.7 and 13.3 min, respectively.
Further purification using column chromatography gave a
pure (1S,2R)-isomer.
1142 cmK1
.
3.1.14. 1-[(1S)-Naphthylethyl]-2-[(methoxycarbonyl)-
methylidene]pyrrolidine (13b). Following the procedure
for the preparation of 13a, the reaction using 10 (0.72 g,
4.0 mmol) and (S)-naphthylethylamine (1.30 g, 6.0 mmol)
gave the desired product 13b (1.32 g, 89%).
Colorless oil; [a]D27 K83.2 (c 1.54, CHCl3); 1H NMR
(CDCl3, 200 MHz) d: 1.26–1.40 (m, 1H); 1.46 (d, 3H, JZ
6.6 Hz); 1.61–1.70 (m, 6H); 2.18–2.33 (m, 1H); 2.33–2.48
(m, 1H); 2.60–2.86 (m, 2H); 3.60–3.77 (m, 1H); 3.70 (s,
3H); 4.42 (q, 1H, JZ6.6 Hz); 7.38–7.55 (m, 3H); 7.60–7.90
(m, 3H); 8.40–8.54 (m, 1H); 13C NMR (CDCl3, 75 MHz) d:
18.18, 20.21, 25.62, 29.63, 30.51, 45.07, 51.53, 52.12,
56.90, 123.94, 124.53, 125.14, 125.24, 125.41, 127.10,
128.64, 131.57, 134.00, 141.36, 173.69; IR (KBr) 2934,
1736, 1437, 1161 cmK1; HRMS (ESI) calcd for C20H25NO2
(MCHC) 312.1964, found 312.1696.
Yellowish orange solid; mp 123–125 8C; [a]2D5 K197.3 (c
1.82, CHCl3); 1H NMR (CDCl3, 300 MHz) d: 1.66 (d,
3H, JZ6.9 Hz), 1.72–1.90 (m, 2H), 2.48–2.59 (m, 1H),
3.06–3.33 (m, 3H), 3.69 (s, 3H), 4.94 (s, 1H), 5.44 (q, 1H,
JZ6.9 Hz), 7.42–7.55 (m, 4H), 7.66–7.74 (m, 1H),
7.79–7.91 (m, 2H); 13C NMR (CDCl3, 75 MHz) d: 14.26,
20.76, 32.87, 47.13, 49.58, 50.06, 77.36, 123.01, 123.68,
124.99, 125.99, 126.96, 128.76, 131.67, 133.64, 135.28,
164.17, 170.12; IR (KBr) 2973, 2940, 1678, 1582,
1140 cmK1; HRMS (ESI) calcd for C19H21NO2 (MC
NaC) 318.1470, found 318.1472. Anal. Calcd for
3.1.17. Methyl 1-[(1S)-phenylethyl]-(2R)-pyrrolidyl-
acetate (18a). Following the procedure for the preparation
of 17a, the reaction using 13a (245 mg, 1.0 mmol) gave the
desired product 18a (195 mg, 79% yield, 62% de).

2222
N. Hashimoto et al. / Tetrahedron 62 (2006) 2214–2223
Yellowish oil (diastreomixtures); 1H NMR (CDCl3,
300 MHz) d: 1.38 (d, 2.43H, JZ6.5 Hz), 1.43 (d, 0.57H,
JZ6.9 Hz), 1.50–2.03 (m, 5H), 2.06–2.86 (m, 4H),
3.08–3.02 (m, 0.19H), 3.23–3.38 (m, 0.81H), 3.60 (s,
2.43H), 3.65 (m, 0.19H), 3.67–3.80 (m, 1H), 7.18–7.40 (m,
3H); 13C NMR (CDCl3, 75 MHz) d: 14.03, 18.03, 20.82,
22.08, 22.70, 30.71, 39.08, 40.00, 49.50, 50.00, 51.11,
56.64, 57.84, 60.17, 60.38, 60.63, 126.70, 127.39, 127.58,
127.96, 128.04, 142.97, 144.92, 170.87, 172.76; IR (neat)
3028, 2971, 2876, 1738 cmK1; HRMS (ESI) calcd for
C15H21NO2 (MCHC) 248.1651, found 248.1648. The
retention times of (1S,2S)- and (1S,2R)-isomers, using
HPLC analysis described above, were same 4.83 min.
Further purification using column chromatography gave a
pure (1S,2R)-isomer; [a]2D5 K10.2 (c 0.97, CHCl3).
1.00, MeOH); {lit.,3g [a]D26 C3.9 (c 0.64, CHCl3), the
antipodal (S) isomer}, 1H NMR (CDCl3, 200 MHz) d: 1.05–
1.85 (m, 6H), 1.95–2.08 (br s, 1H), 2.30–2.42 (m, 2H), 2.58–
2.76 (m, 1H), 2.80–3.10 (m, 2H), 3.68 (s, 3H); Mass (TIC,
m/z): 158 (MC1).
3.1.20. Methyl (R)-(2-pyrrolidino)acetate [(R)-homo-
proline methyl ester] (2).17 Compound 18a (247 mg,
1 mmol, 62% de) was added to a stirred suspension of
10% Pd–C (50% wet, 108 mg) in MeOH (3 mL) at 20–25 8C
with a H2 balloon. After stirring for 14 h, the reaction
mixture was filtered through a plug Celitew, and concen-
trated to give crude oil (154 mg). Purification by Florisilw
column chromatography (hexane to MeOH/Et3NZ10:1) to
give the desired product 2 (130 mg, 91, 62% ee). The
enantioselectivity was checked by the chiral derivatization
and HPLC analysis described above. Yellowish oil; [a]D25
K4.3 (c 1.01, CHCl3); {lit.,18 [a]D C7.0 (c 2.6, CHCl3), the
antipodal (S) isomer}.
3.1.18. Methyl 1-[(1S)-Naphthylethyl]-2(R)-pyrrolidyl-
acetate (18b). Following the procedure for the preparation
of 18a, the reaction using 13b (295 mg, 1.0 mmol) gave the
desired product 18b (260 mg, 89% yield, 92% de). The
retention times of (1S,2S)- and (1S,2R)-isomers, using
HPLC analysis described above, were 13.3 and 11.7 min,
respectively. Further purification using column chromatog-
raphy gave a pure (1S,2R)-isomer.
Following the procedure for the preparation of 2, the
reaction using 18b (297 mg, 1 mmol, 92% de) gave 2
(128 mg, 90, 91% ee), [a]2D5 K6.3 (c 1.85, CHCl3).
1
Yellowish oil; H NMR (CDCl3, 300 MHz) d: 1.27–1.42
Colorless oil; [a]D24 K7.6 (c 1.17, CHCl3); 1H NMR (CDCl3,
300 MHz) d: 1.51 (d, 3H, JZ6.9 Hz), 1.53–1.62 (m, 1H),
1.63–1.75 (m, 2H), 1.90–2.08 (m, 1H), 2.20 (dd, 1H, JZ
(m, 1H), 1.64–1.85 (m, 2H), 1.87–2.01 (m, 1H), 2.43 (dd,
1H, JZ7.9 Hz, JgemZ15.5 Hz), 2.50 (dd, 1H, JZ5.50 Hz,
JgemZ15.5 Hz), 2.83–2.94 (m, 1H), 2.95–3.05 (m, 1H),
3.36–3.48 (m, 1H), 3.68 (s, 3H); 13C NMR (CDCl3,
75 MHz) d: 24.88, 31.11, 40.52, 46.18, 51.42, 54.84,
9.6 Hz, JgemZ14.5 Hz), 2.52 (dd, 1H, JZ4.1 Hz, Jgem
Z
14.5 Hz), 2.56–2.68 (m, 1H), 3.33–3.45 (m, 1H), 3.58 (s,
3H), 4.53 (q, 1H, JZ6.9 Hz), 7.37–7.52 (m, 3H), 7.53–7.60
(m, 1H), 7.69–7.76 (m, 1H), 7.79–7.88 (m, 1H), 8.37–8.45
(m, 1H); 13C NMR (CDCl3, 75 MHz) d: 17.15, 22.35, 30.90,
38.32, 49.03, 51.26, 56.27, 58.15, 124.10, 124.54, 125.15,
125.21, 125.36, 127.39, 128.59, 131.48, 133.91, 140.64,
172.95; IR (neat) 3050, 2971, 2876, 1736 cmK1; HRMS
(ESI) calcd for C19H23NO2 (MCHC) 298.1807, found
298.1805.
172.80; IR (neat) 3401, 2957, 1736, 1620, 1418 cmK1
.
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘17035087’ and
Exploratory Research ‘17655045’ from the Ministry of
Education, Culture, Sports, Science and Technology
(MEXT).
3.1.19. Methyl(R)-(2-piperidino)acetate[(R)-homopipe-
colinic acid methyl ester] (1).3d,g Compound 17a
(233 mg, 0.892 mmol, O99% de) was added to a stirred
suspension of 10% Pd–C (50% wet, 47 mg) in DME
(15 mL) at 20–25 8C with a H2 balloon. After stirring for
17 h, the reaction mixture was filtered through a plug
Celitew, and concentrated to give the desired product 1
(127 mg, 91% yield, 98% ee).
References and notes
1. For representative reports: (a) Morley, C.; Knight, D. W.;
Share, A. C. J. Chem. Soc., Perkin Trans. 1 1994, 2903. (b)
Harrison, J. R.; O’Brien, P.; Porter, D. W.; Smith, N. M.
J. Chem. Soc., Perkin Trans. 1 1999, 3623. (c) Hermet, J. R.;
McGrath, M. J.; O’Brien, P.; Porter, D. W.; Gilday, J. Chem.
Commun. 2004, 1830.
In the case of this method using 17b (307 mg, 0.98 mmol,
99% de), an additional work-up process was necessary for
the isolation of 1. After concentration, 0.2 M aqueous HCl
was added to a residual oil, which was washed with AcOEt
to eliminate 1-ethylnaphthalene. Successive neutralization
of the aqueous phase with Na2CO3, which was reextracted
with AcOEt, followed by the concentration of the organic
phase to give the desired product 1 (111 mg, 72% yield,
98% ee). The enantioselectivity was checked by the chiral
derivatization to N-R-(C)-1-phenylethylcarbamate of 1
using N-succinimidyl R-(C)-1-phenylethyl carbamate16
and HPLC analysis [UV (wave length; 220 nm), Mobile
phase (pH 6.5 phosphoric acid buffer/CH3CNZ70:30),
Column (ULTRON VX-ODS; 5 mm, 4.6 mm!150 mm),
Column temperature (25 8C)]. Colorless oil; [a]2D4 K16.5 (c
2. For an example, a fragment of adenosine A2 antagonist
FR139352; (a) Shiokawa, Y.; Akahane, A.; Katayama, H.;
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