Diastereoselective intramolecular ester transfer reaction of N-alkenylcarbamate derivatives mediated by zirconocene-butene complex: Preparation of α,γ-disubstituted γ-aminobutyric acid (GABA) derivatives and 2,4-disubstituted pyrrolidine derivatives

Article abstract of DOI:10.1055/s-2005-870027

Zirconium-mediated diastereoselective alkene-carbonyl coupling reactions of N-alkenylcarbamate derivatives are reported. The present alkene-carbonyl coupling reactions using chiral tertbutyl 3-butenylcarbamates having a substituent at the homoallylic posi

Full text of DOI:10.1055/s-2005-870027

2046
SPECIAL TOPIC
Diastereoselective Intramolecular Ester Transfer Reaction of N-Alkenylcar-
bamate Derivatives Mediated by Zirconocene–Butene Complex: Preparation
of a,g-Disubstituted g-Aminobutyric Acid (GABA) Derivatives and 2,4-Di-
substituted Pyrrolidine Derivatives
D
iastereoselective
a
Intramolec
s
ular
E
ster
u
T
ransfer Re
s
actionof
N
h
-Alkenylcar
i
bamate
D
eriv
T
atives akigawa,a Hisanaka Ito,b Katsunori Omodera,a Minoru Koura,a Yasuyuki Kai,a Emi Yoshida,a
Takeo Taguchi*a
a
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(426)763257; E-mail: taguchi@ps.toyaku.ac.jp
School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b
Received 14 February 2005
high oxophilic nature of zirconium, intramolecular cou-
Abstract: Zirconium-mediated diastereoselective alkene-carbonyl
pling reaction of carbonyl group with alkene and alkyne is
coupling reactions of N-alkenylcarbamate derivatives are reported.
The present alkene-carbonyl coupling reactions using chiral tert-
very uncommon,10 while intermolecular coupling reac-
tions of carbonyl compound with zirconacyclopropane
butyl 3-butenylcarbamates having a substituent at the homoallylic
position proceeded in a highly diastereoselective manner to give formed through ligand exchange of zirconocene–butene
a-methyl-g-substituted g-aminobutyric acid (GABA) derivatives.
Iodination of the intermediary zirconium species gave the a-iodo-
methylated g-aminobutyrates, which were, in turn, converted to the
5-substituted pyrrolidine-3-carboxylate having cis stereochemistry.
complex with alkene leading to the formation of oxazir-
conacyclopentane derivative have been well document-
ed.1
We have recently demonstrated successful examples of
zirconium mediated intramolecular alkene-carbonyl cou-
pling reaction of tert-butyl N-alkenyl-N-sulfonylcarba-
mate derivatives to give ester group transferred product
(Scheme 1).11,12 We have also clarified the reaction path-
way on the basis of the observed stereospecificities in the
iodination reactions of the reaction intermediates formed
from both E- and Z-isomer of 3-akenylcarbamate deriva-
tives.11 As shown in Scheme 1 the reaction pathway can
be simply illustrated using 3-butenylcarbamate derivative
1a. The ligand exchange reaction of zirconocene equiva-
lent ‘Cp2Zr’ with carbon–carbon double bond in the sub-
strate 1a gave zirconacyclopropane intermediate A and
then it coupled with carbonyl moiety intramolecularly to
form a bicyclo[3.3.0]octane intermediate B. The bicyclic
intermediate B converted to the cyclopropane intermedi-
Key words: zirconium, cyclization, pyrrolidines, amino acids
Low valent zirconium-mediated intramolecular coupling
reactions of unsaturated functional groups have been de-
veloped as useful means for the construction of cyclic
compounds.1 In particular, extensive advances in this area
have been accomplished since Negishi and Takahashi re-
ported the convenient generation of zirconocene–butene
complex (‘Cp2Zr’, Negishi reagent) from Cp2ZrBu2 by
simply mixing Cp2ZrCl2 and two molar equivalent of n-
butyllithium.2 In addition to intramolecular coupling reac-
tions of diene,3 diyne4 and enyne5 with ‘Cp2Zr’, carbon–
nitrogen multiple bonds such as those in imine,6 hydra-
zone,7 isocyanate8 and nitrile9 can participate in the cou-
pling reactions with alkene and alkyne. However, due to
Ts
O
ZrCp2
N
ZrCp2
O
Ot-Bu
H3O+
"Cp2Zr"
Ot-Bu
TsNH
O
O
ZrCp2
O
Ot-Bu
N
N
Ot-Bu
N
Ts
Ts
Ts
1a
Ot-Bu
2a (95%)
A
B
C
I2
CO2t-Bu
O
I
TsNH
K2CO3
Ot-Bu
N
Ts
3a 88%)
4a (97%)
Scheme 1 Possible reaction pathway for intramolecular ester transfer reaction
SYNTHESIS 2005, No. 12, pp 2046–2054
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.07.2005
DOI: 10.1055/s-2005-870027; Art ID: C03505SS
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Diastereoselective Intramolecular Ester Transfer Reaction of N-Alkenylcarbamates
2047
R
O
O
1) LiAlH4
2) MsCl, Et3N
1) "Cp2Zr"
2) H3O+
TsNH
N
Ot-Bu
Ot-Bu
R
N
3) NaH
Ts
R
Ts
5
1
2
CO2t-Bu
O
I
1) "Cp2Zr"
2) I2
TsNH
R
K2CO3
Ot-Bu
R
N
Ts
4
3
R = Me, n-Pr, PhCH2CH2, BnOCH2CH2, TBSOCH2CH2, PhOCH2
Scheme 2 Diastereoselective alkene-carbonyl coupling reaction
ate C through the facile cleavage of bridgehead carbon– The degree of diastereoselection was found to be depen-
nitrogen bond by attacking the nucleophilic carbon center dent on the steric size of the substituent at the homoallylic
bearing zirconium atom. Finally, addition of water gave position. For example, the substrate 1b having the steri-
a-methyl g-aminobutyric acid (GABA) derivative 2a and cally smallest methyl group provided the ester transfer
treatment with iodine gave the a-iodomethyl derivative product 2b in 93% yield, but with low selectivity (a 3:2
3a, which was easily converted to pyrrolidine-3-carboxyl- mixture of diastereomers, entry 1). When the substituent
ate 4a by treating with K2CO3 (Scheme 1).
was changed to n-propyl group (substrate 1c), a remark-
able increase in diastereoselectivity was observed to ob-
tain g-propyl GABA derivative 2c in 85% yield with an
isomer ratio of 8:1 (entry 2). Under the similar reaction
conditions, good yields (74–91%) and slightly higher se-
lectivities (dr 9:1–14:1) of the ester transfer products 2d–
2g were observed with the substrates having b-phenyleth-
yl, b-benzyloxyethyl, b-tert-butyldimethylsilyloxyethyl
and phenoxymethyl group (entries 3–6). In these exam-
ples, the relative stereochemistry of the major product was
assigned as 2,5-anti based on the structure determination
of the pyrrolidine derivatives 4 obtained from the iodina-
tion products 3 (vide infra).
Further study was made to develop diastereoselective es-
ter transfer reaction using various 3-alkenyl(tosyl)car-
bamate derivatives having a chiral center at the
homoallylic or the allylic position in the N-akenyl moiety.
In the case of the substrates 1 having alkyl substituent at
the homoallylic position, ‘Cp2Zr’ mediated alkene-carbo-
nyl coupling reaction proceeded in a highly diastereose-
lective manner to give the a,g-disubstituted GABA
derivatives 2 or 5-substituted pyrrolidine-3-carboxylate
derivatives 4 through iodination of the reaction intermedi-
ate followed by intramolecular substitution reaction of the
iodide 3 (Scheme 2). Details are described in this paper.
It should be noted that not only the steric requirement of
the substituent at the homoallylic position as shown
above, but also sterically bulky tert-butyl ester moiety is
crucial to achieve high asymmetric induction. This is be-
cause the reaction of the corresponding benzyl ester hav-
ing propyl and benzyloxyethyl substituent (1i and 1j) with
‘Cp2Zr’ under the similar reaction conditions (THF, 0 °C–
r.t.) proceeded in completely nonstereoselective manner
to give the ester transfer product 2i and 2j as an equal
amount mixture of the diastereomers (Scheme 3).
Reaction of tert-butyl 3-butenyl(tosyl)carbamates 1b–1g
having various substituent at the homoallylic position
with ‘Cp2Zr’ in situ generated from Cp2ZrCl2 and BuLi in
THF proceeded at room temperature to give g-substituted
a-methyl GABA derivatives 2b–2g in good yields. Re-
sults are summarized in Table 1.
R
O
O
1) "Cp2Zr"
2) H3O+
TsNH
N
OBn
OBn
Ts
R
Next, we examined the present ester transfer reaction with
tert-butyl 3-butenyl(tosyl)carbamates having n-propyl,
benzyloxyethyl and phenyl substituent at the allylic posi-
tion (Scheme 4). Reaction of n-propyl and benzyloxyeth-
yl derivatives (1k and 1m) with Cp2ZrBu2 in THF at room
temperature proceeded smoothly to give b-substituted a-
methyl GABA derivative 2k and 2m in 62% and 67%
yields, respectively, but in both cases any appreciable
chiral induction was not observed giving rise to an almost
1:1 mixture of the diastereomers. With phenyl substituted
substrate 1n, while reaction in THF resulted in a complex
mixture, in Et2O or toluene as the solvent alkene-carbonyl
coupling reaction proceeded to give the ester transfer
product 2n in a reasonable yield (70% in Et2O and 46% in
toluene) with a moderate selectivity (dr 3:1 in both sol-
vent) and 2,3-syn isomer was a major product (Scheme 4).
1i R = n-Pr
1j R = BnOCH2CH2
2i (78%, dr 1:1)
2j (29%, dr 1:1)
Scheme 3 Reaction of benzyl alkenylcarbamate derivatives with
‘Cp2Zr’
R
R
R
O
"Cp2Zr"
ZrCp2 H3O+
O
O
TsNH
Ot-Bu
N
Ot-Bu
N
Ot-Bu
Ts
Ts
R = n-Pr
R = BnOCH2CH2
R = Ph
1k
1m
1n
(62%, dr 1:1)
(67%, dr 1:1)
(70%, syn/anri = 3:1)
2k
2m
2n
Scheme 4 Reaction of 2-substituted 3-butenylcarbamete deriva-
tives with ‘Cp2Zr’.
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York

2048
Y. Takigawa et al.
SPECIAL TOPIC
Table 1 Reaction of 1-Substituted tert-Butyl 3-Alkenyl(tosyl)carbamates with ‘Cp2Zr’
ZrCp2
O
"Cp2Zr"
THF, r.t.
H3O+
ZrCp2
O
Ot-Bu
O
O
TsNH
Ot-Bu
R
N
R
N
Ot-Bu
R
R
N
Ot-Bu
Ts
Ts
Ts
1
2
Entry
1
Substrate
Producta
Yield (%)b
93
drc
O
O
3:2
TsNH
Ot-Bu
Ot-Bu
N
Ot-Bu
Ot-Bu
Ts
1b
2b
2
3
4
5
6
85
82
91
85
74
8:1
10:1
13:1
9:1
O
O
O
TsNH
N
Ts
1c
2c
Ph
O
O
TsNH
Ph
Ot-Bu
N
Ot-Bu
Ot-Bu
Ts
1d
2d
O
BnO
TsNH
BnO
2e
Ot-Bu
N
Ts
1e
O
TBSO
O
TsNH
TBSO
2f
Ot-Bu
N
Ot-Bu
Ts
1f
14:1
PhO
O
O
TsNH
Ot-Bu
N
Ot-Bu
Ts
PhO
1g
2g
a Major isomer is shown.
b Isolated yield.
c Diastereomer ratio (dr) was determined by 1H NMR of the crude mixture.
Thus, chiral induction in the zirconium mediated alkene- substitution by tosylamide group. Thus, g-propyl-a-meth-
carbonyl coupling reaction with the substrate having a yl GABA derivative 2c obtained as majorly anti mixture
chiral center at the allylic position in N-3-butenyl moiety (anti/syn = 8:1) provided the 2-propyl-4-methylpyrroli-
was very low as compared with the substrates having a dine 5c in the same isomeric ratio (trans/cis = 8:1) as
chiral center at the homoallylic position. Related to our shown in Scheme 5.
present reactions, in the low-valent titanium mediated in-
tramolecular nucleophilic acyl substitution (INAS) reac-
O
1) LiAlH4
2) MsCl, Et3N
3) NaH
TsHN
tion of alkene with a carbonate moiety, it was reported
that the reaction proceeded in non-diastereoselective
manner with 3-butenyl carbonate derivative having a
chiral center at either homoallylic or allylic position.13
Ot-Bu
N
Ts
2c
(anti/syn = 8:1)
5c
Since the ester transfer reaction of 1-substituted 3-bute-
nylcarbamate derivative (chiral center at the homoallylic
position) proceeded in a highly diastereoselective manner,
we applied the present reaction to either trans-selective or
cis-selective preparation of 2,4-disubstituted pyrrolidine
derivatives. The trans-selective synthesis involves reduc-
tion of the ester group of the alkene-carbonyl coupling
product 2 to hydroxyl group followed by intramolecular
(50%, trans/cis = 8:1)
Scheme 5 Conversion of GABA derivative to 2,4-disubstituted pyr-
rolidine
The cis-selective synthesis could be achieved through the
iodination reaction of the zirconium-containing reaction
intermediate. The results are summarized in Table 2.
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York

SPECIAL TOPIC
Diastereoselective Intramolecular Ester Transfer Reaction of N-Alkenylcarbamates
2049
Table 2 Diastereoselective Synthesis of 5-Substituted Pyrrolidine-3-carboxylate 4
O
I
COOt-Bu
R
O
1) "Cp2Zr"
2) I2
TsNH
K2CO3
Ot-Bu
N
Ot-Bu
R
N
R
Ts
Ts
1
3
4
Entry
1
Substrate
Product 3a
Yield (%)b
–
Product 4a
Yield (%)b
48
Cis/transc
1b
COOt-Bu
2:1
O
TsNH
Ot-Bu
Ot-Bu
N
Ts
I
4b
4c
3b
2
3
4
1c
74
64
78
80
96
78
13:1
O
COOt-Bu
TsNH
3c
3d
N
Ts
I
3c
1d
1e
1f
20:1
COOt-Bu
O
TsNH
Ph
Ot-Bu
N
Ts
I
Ph
3d
4d
12:1
COOt-Bu
COOt-Bu
O
TsNH
BnO
Ot-Bu
3e
N
Ts
I
BnO
3e
4e
5
6
72
54
78
92
12:1
O
TsNH
TBSO
Ot-Bu
N
Ts
I
TBSO
3f
4f
1g
>90:<1
COOt-Bu
O
I
TsNH
Ot-Bu
N
Ts
PhO
PhO
3g
4g
a Major isomer is shown.
b Isolated yield.
c Ratio was determined by 1H NMR.
After the reaction of 3-butenylcarbamate 1c–1g with tuted pyrrolidines 4b–4g was determined by NOE corre-
Cp2ZrBu2 was completed (THF, r.t., 2–4 h), the reaction lations obtained by 2D-NOESY measurements. A large
mixture was quenched by the addition of iodine (4 equiv) chemical shift difference of the methine proton at 3-posi-
at –20 °C to give the corresponding a-iodomethyl GABA tion (a position to the carboxyl group) between the major
derivative 3c–3g, which were roughly purified by passing cis isomer and the minor trans isomer is noted, for e.g.
through a short silica gel column. Conversion of the io- 2.74 ppm for cis-4e while much lower field, 3.02 ppm, for
dide thus obtained to the pyrrolidine derivative 4c–4g trans-4e. Based on the structure of the pyrrolidine deriva-
could be easily achieved by treating with K2CO3 at room tives 4, the relative stereochemistry of ester transferred
temperature in aqueous THF solution. The overall yields products 2 was confirmed.
of 5-substituted pyrrolidine-3-carboxylates 4c–4g were
about 50–60% and the cis/trans selectivities were from
12:1 to >90:<1, which were somewhat higher than those
observed for the products 2c–2g obtained by hydrolytic
workup (entries 2–6). In the case of 1-methyl-3-butenyl-
carbamate 1b, the fairly labile iodide 3b was used in the
next K2CO3 treatment without purification by silica gel
column and pyrrolidine-3-carboxylate 4b was obtained in
As shown in Scheme 6, iodination of the zirconium-con-
taining reaction intermediate derived from 2-phenyl sub-
stituted substrate 1n followed by K2CO3 treatment gave 4-
phenylpyrrolidine-3-carboxylate 4n in 68% yield with
preferential formation of cis-isomer (cis/trans = 2:1). This
moderate stereoselectivity was already observed in the
formation of the GABA derivative 2n as shown in
Scheme 4.
48% yield (entry 1). The stereochemistry of the disubsti-
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York

2050
Y. Takigawa et al.
SPECIAL TOPIC
17.1 Hz, 1 H), 5.02 (d, J = 10.2 Hz, 1 H), 4.48 (tt, J = 8.6, 6.4 Hz, 1
H), 2.67 (dt, J = 13.8, 7.7 Hz, 1 H), 2.48 (dt, J = 14.0, 6.9 Hz, 1 H),
2.42 (s, 3 H), 1.97–1.87 (m, 1 H), 1.73–1.62 (m, 1 H), 1.41–1.30 (m,
2 H), 1.36 (s, 9 H), 0.93 (t, J = 7.4 Hz, 3 H).
13C NMR (100.6 Hz, CDCl3): d = 150.8, 143.8, 137.7, 135.5, 128.9,
128.4, 117.5, 83.9, 59.4, 38.3, 35.5, 28.0, 21.6, 20.2, 14.0.
1) "Cp2Zr"
2) I2
3) K2CO3
O
Ph
O
Ot-Bu
N
Ot-Bu
Ts
Ph
N
Ts
1n
4n (68%)
(cis/trans = 2:1)
MS: m/z = 390 [M + Na]+.
Scheme 6 Synthesis of 4-phenylpyrrolidine-3-carboxylate 4n
Anal. Calcd for C19H29NO4S: C, 62.10; H, 7.95; N, 3.81. Found: C,
62.38; H, 7.89; N, 3.76.
From the results shown in Scheme 5 and in Table 2, the
present diastereoselective intramolecular ester transfer re-
action of 1-substituted 3-butenylcarbamate derivatives
with ‘Cp2Zr’ provides an efficient mean for the prepara-
tion of 2,4-disubstituted pyrrolidine derivatives.
tert-Butyl (4-Methylphenyl)sulfonyl[1-(2-phenylethyl)-3-bu-
tenyl]carbamate (1d)
Colorless oil.
IR (neat): 1726, 1356, 1152 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.82 (d, J = 8.3 Hz, 2 H), 7.27–
7.25 (m, 4 H), 7.22–7.15 (m, 3 H), 5.77 (ddt, J = 17.1, 10.0, 7.0 Hz,
1 H), 5.08 (d, J = 17.1 Hz, 1 H), 5.03 (d, J = 10.0 Hz, 1 H), 4.61–
4.53 (m, 1 H), 2.77–2.62 (m, 1 H), 2.67 (t, J = 8.4 Hz, 2 H), 2.55 (dt,
J = 14.0, 7.0 Hz, 1 H), 2.43 (s, 3 H), 2.32–2.20 (m, 1 H), 2.10–2.00
(m, 1 H), 1.39 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): d = 150.8, 143.9, 141.7, 137.6,
135.2, 129.0, 128.4, 128.3, 125.9, 117.8, 84.1, 59.3, 38.3, 35.3,
33.4, 28.0, 21.6.
All reactions were carried out under an Ar atmosphere. Toluene (an-
hyd), THF (anhyd, no stabilizer) and zirconocene dichloride are
available commercially. 1H and 13C NMR spectra were measured on
a Bruker DPX-400 NMR spectrometer in CDCl3 and the chemical
1
shifts are given in ppm using CHCl3 (7.26 ppm) in CDCl3 for H
NMR and CDCl3 (77.01 ppm) for 13C NMR as an internal standard,
respectively. Mass spectra and HRMS were recorded by EI tech-
nique. Melting points were obtained on a Yanagimoto MP-J3 appa-
ratus, and reported values are uncorrected. IR spectra were recorded
on a JASCO FT/IR-620 spectrometer. Column chromatography
was performed on silica gel (70–230 mesh). Medium-pressure liq-
uid chromatography (MPLC) was performed on a 30 cm (2.2 cm
i.d.) prepacked column (silica gel, 50 mm) with a UV or RI detector.
Elemental analyses were performed on a Perkin-Elmer 240B.
EI–MS: m/z = 430 [M+ + 1], 373 [M+ + 1 – t-Bu]
Anal. Calcd for C24H31NO4S: C, 67.10; H, 7.27; N, 3.26. Found: C,
67.23; H, 7.31; N, 3.31.
tert-Butyl 1-[2-(Benzyloxy)ethyl]-3-butenyl[(4-methylphe-
nyl)sulfonyl]carbamate (1e)
Preparation of the Carbamate Derivative; General Procedure
To a THF solution of tert-butyl or benzyl (4-methylphenyl)sulfo-
nylcarbamate (1.4 equiv) was added a toluene solution of triphe-
nylphosphine (2.8 equiv), diethyl azodicarboxylate (2.3 equiv) and
the appropriate allylic alcohol (1 equiv), for example 1-pentene-4-
ol for the preparation of 1-methyl-3-butenylcarbamate derivative
2b. The reaction mixture was stirred for 3–6 h at r.t. The residue ob-
tained by evaporation of the reaction mixture under reduced pres-
sure was purified by silica gel column chromatography eluted by a
mixture of hexane and EtOAc to give the 3-butenylcarbamate deriv-
ative 1b–1n.
Colorless oil.
IR (neat): 1726, 1358, 1153 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.84 (d, J = 8.3 Hz, 2 H), 7.38–
7.26 (m, 5 H), 7.24 (d, J = 8.3 Hz, 2 H), 5.78 (ddt, J = 17.2, 9.9, 7.2
Hz, 1 H), 5.09 (d, J = 17.1 Hz, 1 H), 5.04 (d, J = 10.1 Hz, 1 H), 4.73
(tt, J = 8.4, 6.3 Hz, 1 H), 4.55 (d, J = 11.8 Hz, 1 H), 4.46 (d, J = 11.8
Hz, 1 H), 3.53 (t, J = 6.2 Hz, 2 H), 2.72 (dt, J = 13.9, 7.6 Hz, 1 H),
2.51 (dt, J = 14.0, 6.8 Hz, 1 H), 2.42 (s, 3 H), 2.26 (ddt, J = 14.4,
8.6, 5.8 Hz, 1 H), 2.05 (dtd, J = 14.3, 6.7, 6.4 Hz, 1 H), 1.36 (s, 9 H).
13C NMR (100.6 Hz, CDCl3): d = 150.8, 143.8, 138.4, 137.7, 135.3,
128.9, 128.4, 128.3, 127.7, 127.5, 117.7, 84.0, 73.0, 67.4, 56.4,
38.4, 33.5, 28.0, 21.6.
tert-Butyl 1-Methyl-3-butenyl[(4-methylphenyl)sulfonyl]car-
bamate (1b)
Mp 60–61 °C.
MS: m/z = 482 [M + Na]+.
IR (KBr): 1718, 1356, 1155 cm–1.
Anal. Calcd for C25H33NO5S: C, 65.33; H, 7.24; N, 3.05. Found: C,
65.09; H, 7.07; N, 3.32.
1H NMR (400 MHz, CDCl3): d = 7.79 (d, J = 8.4 Hz, 2 H), 7.28 (d,
J = 8.0 Hz, 2 H), 5.74 (ddt, J = 17.2, 10.0, 7.2 Hz, 1 H), 5.08 (d, J =
17.1 Hz, 1 H), 5.03 (d, J = 10.2 Hz, 1 H), 4.99 (tq, J = 7.6, 7.0 Hz,
1 H), 2.72 (dt, J = 14.0, 7.6 Hz, 1 H), 2.47 (dt, J = 14.0, 7.0 Hz, 1
H), 2.43 (s, 3 H), 1.46 (d, J = 6.8 Hz, 3 H), 1.31 (s, 9 H).
13C NMR (100.6 Hz, CDCl3): d = 150.6, 143.7, 138.0, 135.3, 129.1,
127.8, 117.6, 83.9, 54.9, 39.4, 27.9, 21.5, 19.4.
tert-Butyl 1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-buten-
yl[(4-methylphenyl)sulfonyl]carbamate (1f)
Colorless oil.
IR (neat): 1728, 1360, 1155 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.85 (d, J = 8.3 Hz, 2 H), 7.26 (d,
J = 8.1 Hz, 2 H), 5.78 (ddt, J = 17.2, 9.8, 7.2 Hz, 1 H), 5.09 (d, J =
17.1 Hz, 1 H), 5.05 (d, J = 10.1 Hz, 1 H), 4.68 (tt, J = 8.0, 6.6 Hz, 1
H), 3.64 (t, J = 6.5 Hz, 1 H), 2.71 (dt, J = 14.0, 8.2 Hz, 1 H), 2.52
(dt, J = 14.0, 6.9 Hz, 2 H), 2.43 (s, 3 H), 2.13 (ddt, J = 14.0, 7.7, 6.8
Hz, 1 H), 1.97(dtd, J = 13.9, 6.7, 6.6 Hz, 1 H), 1.36 (s, 9 H), 0.91 (s,
9 H), 0.07 (s, 3 H), 0.07 (s, 3 H).
EI–MS: m/z = 340 [M+ + 1].
Anal. Calcd for C17H25NO4S: C, 60.15; H, 7.42; N, 4.13. Found: C,
60.35; H, 7.41; N, 4.06.
tert-Butyl (4-Methylphenyl)sulfonyl(1-propyl-3-butenyl)car-
bamate (1c)
Mp 50–51 °C.
IR (KBr): 1718, 1344, 1151 cm–1.
13C NMR (100.6 Hz, CDCl3): d = 150.8, 143.7, 137.9, 135.3, 128.9,
128.3, 117.6, 83.9, 60.4, 56.1, 38.2, 36.6, 28.0, 25.9, 21.6, 18.3,
–5.3, –5.3.
1H NMR (400 MHz, CDCl3): d = 7.81 (d, J = 8.4 Hz, 2 H), 7.27 (d,
J = 8.1 Hz, 2 H), 5.77 (ddt, J = 17.4, 9.9, 7.2 Hz, 1 H), 5.07 (d, J =
EI–MS: m/z = 506 [M + Na]+.
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York

SPECIAL TOPIC
Diastereoselective Intramolecular Ester Transfer Reaction of N-Alkenylcarbamates
2051
Anal. Calcd for C24H41NO5SSi: C, 59.59; H, 8.54; N, 2.90. Found:
C, 59.79; H, 8.37; N, 3.17.
Anal. Calcd for C17H27NO4S: C, 59.80; H, 7.97; N, 4.10. Found: C,
59.81; H, 7.72; N, 4.10.
tert-Butyl (4-Methylphenyl)sulfonyl(1-phenoxy-3-butenyl)car-
bamate (1g)
tert-Butyl 2-Methyl-4-{[(4-methylphenyl)sulfonyl]amino}hep-
tanoate (2c)
Mp 55–56 °C.
Mp 65–66 °C.
IR (KBr): 1718, 1356, 1155 cm–1.
IR (KBr): 3282, 1722, 1157 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.92 (d, J = 8.3 Hz, 2 H), 7.30–
7.25 (m, 4 H), 6.95 (t, J = 7.3 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 2 H),
5.87 (ddt, J = 17.2, 9.5, 7.2 Hz, 1 H), 5.20–5.12 (m, 2 H), 4.99 (tdd,
J = 8.7, 6.7, 5.5 Hz, 1 H), 4.47 (t, J = 9.2 Hz, 1 H), 4.14 (dd, J = 9.7,
5.5 Hz, 1 H), 2.80 (dt, J = 14.0, 7.6 Hz, 1 H), 2.65 (dt, J = 14.1, 6.9
Hz, 1 H), 2.43 (s, 3 H), 1.31 (s, 9 H).
13C NMR (100.6 Hz, CDCl3): d = 158.4, 150.6, 143.8, 137.8, 134.1,
129.5, 128.9, 128.4, 121.0, 118.4, 114.6, 84.4, 67.6, 57.7, 35.4,
27.9, 21.6.
1H NMR (400 MHz, CDCl3; major isomer): d = 7.73 (d, J = 8.3 Hz,
2 H), 7.28 (d, J = 8.1 Hz, 2 H), 4.45 (d, J = 8.7 Hz, 1 H), 3.33–3.24
(m, 1 H), 2.50–3.43 (m, 1 H), 2.42 (s, 3 H), 1.78 (ddd, J = 14.1, 9.4,
4.8 Hz, 1 H), 1.43 (s, 9 H), 1.41–1.08 (m, 5 H), 1.04 (d, J = 7.1 Hz,
3 H), 0.75 (t, J = 7.1 Hz, 3 H).
13C NMR (100.6 Hz, CDCl3): d = 175.7, 143.1, 138.4, 129.6, 127.0,
80.3, 52.5, 39.0, 37.6, 36.8, 28.0, 21.5, 18.4, 18.1, 13.8.
MS: m/z = 392 [M + Na]+.
Anal. Calcd for C19H31NO4S: C, 61.76; H, 8.46; N, 3.79. Found: C,
61.71; H, 8.38; N, 3.79.
EI–MS: m/z = 431 [M+].
Anal. Calcd for C23H29NO5S: C, 64.01; H, 6.77; N, 3.25. Found: C,
63.93; H, 6.76; N, 3.19.
tert-Butyl 2-Methyl-4-{[(4-methylphenyl)sulfonyl]amino}-6-
phenylhexanoate (2d)
syn-2d
Colorless oil.
tert-Butyl (4-Methylphenyl)sulfonyl(2-phenyl-3-butenyl)car-
bamate (1n)
Colorless oil.
IR (neat): 1730, 1361, 1156 cm–1.
IR (neat): 3277, 1725, 1159 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.70 (d, J = 8.3 Hz, 2 H), 7.29–
7.13 (m, 5 H), 6.98 (d, J = 8.3 Hz, 2 H), 4.40 (d, J = 8.6 Hz, 1 H),
3.36–3.27 (m, 1 H), 2.48 (t, J = 8.1 Hz, 1 H), 2.43 (s, 3 H), 2.33
(quint, J = 6.9 Hz, 1 H), 1.85–1.55 (m, 3 H), 1.50–1.41 (m, 1 H),
1.43 (s, 9 H), 1.01 (d, J = 6.9 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 175.9, 143.3, 141.1, 138.3,
130.0, 128.4, 128.3, 127.1, 126.0, 80.5, 52.1, 38.3, 37.1, 37.0, 31.5,
28.0, 21.5, 17.3.
1H NMR (400 MHz, CDCl3): d = 7.59 (d, J = 8.3 Hz, 2 H), 7.31–
7.10 (m, 7 H), 6.05 (ddd, J = 16.9, 10.2, 8.3 Hz, 1 H), 5.11 (d, J =
16.9 Hz, 1 H), 5.10 (d, J = 10.2 Hz, 1 H), 4.10 (dd, J = 14.2, 8.5 Hz,
1 H), 4.04 (dd, J = 14.2, 7.4 Hz, 1 H), 3.83 (ddd, J = 8.5, 8.3, 7.4 Hz,
1 H), 2.36 (s, 3 H), 1.24 (s, 9 H). 13C NMR (100.6 MHz, CDCl3):
d = 151.0, 144.0, 141.1, 138.3, 137.6, 129.1, 128.7, 128.1, 128.0,
127.0, 117.1, 84.1, 51.4, 50.4, 27.8, 21.6.
EI–MS: m/z = 401 [M+], 300 [M+ – CO2t-Bu].
HRMS m/z (M+ + 1 – t-Bu] calcd for C18H18NO4S: 345.1035; found:
EI–MS: m/z = 432 [M+ + 1], 375 [M+ + 1 – t-Bu), 358 [M+ – CO2 –
t-Bu].
345.1049.
HRMS: m/z [M+ – t-Bu] calcd for C20H24NO4S: 375.1504; found:
375.1517.
Zirconocene–butene Complex Mediated Reaction of Carbam-
ate Derivatives; General Procedure
anti-2d
To a solution of Cp2ZrCl2 (1.2 equiv) in THF was added n-BuLi
(1.56 M hexane solution, 2.4 equiv) at –78 °C and the mixture was
stirred for 1 h at the same temperature. To this solution was added
the carbamate 1 (1 equiv) and the mixture was stirred at r.t. for 2–6
h. The reaction mixture was extracted with Et2O after addition of 1
N HCl. The organic extracts were washed with NaHCO3 solution,
brine and dried over MgSO4. Purification of the residue obtained by
evaporation of the solvent, by silica gel column chromatography
(hexane–EtOAc as eluent) gave the product 2 as shown in Table 1
and Schemes 3 and 4.
Mp 68–71 °C.
IR (KBr): 3251, 1325, 1152 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.74 (d, J = 8.2 Hz, 2 H), 7.32–
7.15 (m, 5 H), 7.02 (d, J = 7.1 Hz, 2 H), 4.87 (d, J = 8.7 Hz, 1 H),
3.42–3.30 (m, 1 H), 2.59–2.42 (m, 3 H), 2.43 (s, 3 H), 1.87 (ddd,
J = 14.0, 9.3, 4.8 Hz, 1 H), 1.78–1.52 (m, 2 H), 1.45 (s, 9 H), 1.34
(ddd, J = 14.0, 8.7, 4.8 Hz, 1 H), 1.05 (d, J = 7.2 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 175.6, 143.1, 141.3, 138.3,
129.6, 128.3, 128.3, 127.0, 125.8, 80.4, 52.5, 38.9, 37.1, 36.8, 31.5,
28.0, 21.5, 18.0.
tert-Butyl 2-Methyl-4-{[(4-methylphenyl)sulfonyl]amino}pen-
tanoate (2b)
EI–MS: m/z = 432 [M+ + 1], 375 [M+ + 1 – t-Bu].
IR (KBr): 3280, 1724, 1151 cm–1.
Anal. Calcd for C22H33NO4S: C, 66.79; H, 7.71; N, 3.25. Found: C,
66.90; H, 7.65; N, 3.31.
1H NMR (400 MHz, CDCl3; 3:2 mixture of diastereomers): d =
7.76–7.73 (m, 2 H), 7.30–7.26 (m, 2 H), 4.39 (d, J = 8.3 Hz, 0.6 H),
4.35 (d, J = 8.5 Hz, 0.4 H), 3.44–3.30 (m, 1 H), 2.52–2.44 (m, 0.6
H), 2.47 (s, 3 H), 2.34 (sextet, J = 7.0 Hz, 0.4 H), 1.83–1.70 (m, 1
H), 1.44 (s, 5.4 H), 1.43 (s, 3.6 H), 1.37–1.25 (m, 1 H), 1.07–0.98
(m, 6 H).
13C NMR (100.6 Hz, CDCl3; 3:2 mixture of diastereomers): d =
176.2, 176.1, 143.5, 138.7, 130.0, 127.4, 80.8, 49.0, 48.8, 41.5,
41.4, 37.7, 37.3, 28.4, 22.2, 21.9, 18.3, 17.6.
tert-Butyl 6-(Benzyloxy)-2-methyl-4-{[(4-methylphenyl)sulfo-
nyl]amino}hexanoate (2e)
Colorless oil.
IR (neat): 3251, 1720, 1161 cm–1.
1H NMR (400 MHz, CDCl3; major isomer): d = 7.70 (d, J = 8.2 Hz,
2 H), 7.38–7.24 (m, 7 H), 5.37 (d, J = 8.2 Hz, 1 H), 4.57 (s, 2 H),
3.55–3.42 (m, 2 H), 3.35 (quin, J = 4.7 Hz, 1 H), 2.58–2.49 (m, 1
H), 2.41 (s, 3 H), 1.98 (ddd, J = 14.0, 9.2, 4.8 Hz, 1 H), 1.65–1.59
(m, 1 H), 1.55–1.33 (m, 2 H), 1.44 (s, 9 H), 1.07 (d, J = 7.2 Hz, 3 H).
MS: m/z = 364 [M + Na]+.
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York

2052
Y. Takigawa et al.
SPECIAL TOPIC
13C NMR (100.6 Hz, CDCl3): d = 175.7, 142.9, 138.3, 137.8, 129.5,
128.4, 127.7, 127.5, 127.0, 80.1, 73.1, 66.8, 51.1, 38.5, 36.9, 33.6,
27.9, 21.4, 18.1.
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 8.3 Hz, 2 H), 7.29–
7.21 (m, 5 H), 7.04–7.01 (m, 2 H), 4.19 (dd, J = 7.9, 4.6 Hz, 1 H),
3.39 (ddd, J = 12.7, 8.0, 4.8 Hz, 1 H), 3.08 (ddd, J = 12.7, 9.4, 4.6
Hz, 1 H), 2.86 (ddd, J = 9.4, 9.2, 4.8 Hz, 1 H), 2.62 (dq, J = 9.2, 6.9
Hz, 1 H), 2.16 (s, 3 H), 1.15 (t, J = 6.9 Hz, 3 H), 1.14 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): d = 173.7, 143.5, 139.3, 136.9,
129.7, 128.7, 128.4, 127.5, 127.1, 80.4, 48.4, 45.4, 43.9, 27.6, 21.5,
15.3.
MS: m/z = 484 [M + Na]+.
Anal. Calcd for C25H35NO5S: C, 65.05; H, 7.64; N, 3.03. Found: C,
64.78; H, 7.59; N, 3.14.
tert-Butyl 6-{[tert-Butyl(dimethyl)silyl]oxy}-2-methyl-4-{[(4-
methylphenyl)sulfonyl]amino}hexanoate (2f)
Colorless oil.
IR (neat): 3263, 1728, 1155 cm–1.
EI–MS: m/z = 404 [M+ + 1], 347 [M+ + 1 – t-Bu].
Anal. Calcd for C22H29NO4S: C, 65.48; H, 7.24; N, 3.47. Found: C,
65.22; H, 7.33; N, 3.27.
1H NMR (400 MHz, CDCl3; major isomer): d = 7.72 (d, J = 8.3 Hz,
2 H), 7.27 (d, J = 8.4 Hz, 2 H), 5.62 (d, J = 7.9 Hz, 1 H), 3.73–3.68
(m, 1 H), 3.53–3.39 (m, 2 H), 2.60–2.52 (m, 1 H), 2.41 (s, 3 H), 1.77
(ddd, J = 14.0, 9.0, 5.0 Hz, 1 H), 1.55–1.36 (m, 3 H), 1.45 (s, 9 H),
1.10 (d, J = 7.2 Hz, 3 H), 0.90 (s, 9 H), 0.04 (s, 6 H).
13C NMR (100.6 Hz, CDCl3): d = 175.8, 142.9, 138.4, 129.5, 127.1,
80.2, 60.1, 51.5, 38.4, 36.9, 35.3, 28.0, 25.9, 21.5, 18.2, 18.1, –5.2,
–5.6.
Iodination of the Reaction Intermediate Followed by K2CO3
Treatment Leading to Pyrrolidine Carboxylate 4; General Pro-
cedure
After the reaction of the carbamate 1 (1 equiv) with Cp2ZrBu2 was
completed as described above, to the reaction mixture was added a
THF solution of iodine (4 equiv) at –20 °C and then the whole was
stirred for 1 h at the same temperature. After addition of 1 N HCl,
the reaction mixture was extracted with Et2O and the organic ex-
tracts were washed with NaHCO3 solution, brine and dried over
MgSO4. Purification by silica gel column chromatography eluted by
a mixture hexane and EtOAc gave a-iodomethyl GABA derivatives
3. A mixture of the iodide in THF and 1 M K2CO3 solution (10
equiv) was stirred at r.t. for 1 h. The reaction mixture was extracted
with Et2O after addition of water and then the organic extract was
purified by silica gel chromatography (a mixture of hexane and
EtOAc) to give 5-alkyl pyrrolidine-3-carboxlates 4b–4g from 1b–
1g and 4-phenyl pyrrolidine-3-carboxlate 4n from the 1n.
MS: m/z = 508 [M + Na]+.
Anal. Calcd for C24H43NO5SSi: C, 59.34; H, 8.92; N, 2.88. Found:
C, 59.35; H, 8.76; N, 2.91.
tert-Butyl 2-Methyl-4-{[(4-methylphenyl)sulfonyl]amino}-4-
phenoxybutanoate (2g)
Colorless oil.
IR (neat): 3263, 1724, 1164 cm–1.
1H NMR (400 MHz, CDCl3; major isomer): d = 7.71 (d, J = 8.3 Hz,
2 H), 7.25–7.20 (m, 4 H), 6.94 (d, J = 7.3 Hz, 1 H), 6.69 (d, J = 8.6
Hz, 2 H), 5.08 (d, J = 8.3 Hz, 1 H), 3.87–3.74 (m, 1 H), 3.70–3.63
(m, 2 H), 2.64–2.56 (m, 1 H), 2.83 (s, 3 H), 1.90 (ddd, J = 14.2, 10.0,
4.0 Hz, 1 H), 1.67–1.52 (m, 1 H), 1.45 (s, 9 H), 1.11 (d, J = 7.2 Hz,
3 H).
13C NMR (100.6 Hz, CDCl3): d = 175.7, 158.2, 143.3, 138.0, 129.7,
129.4, 127.0, 121.2, 114.4, 80.5, 69.1, 51.7, 36.6, 36.3, 28.0, 21.5,
18.2.
tert-Butyl 5-Methyl-1-[(4-methylphenyl)sulfonyl]-3-pyrroli-
dinecarboxylate (4b)
Colorless oil.
IR (neat): 1728, 1346, 1155 cm–1.
1H NMR (400 MHz, CDCl3; 2:1 mixture of stereoisomers): d =
7.73–7.71 (m, 2 H), 7.33–7.30 (m, 2 H), 3.82–3.65 (m, 1.33 H), 3.62
(dd, J = 16.4, 8.0 Hz, 0.67 H), 3.53 (dd, J = 11.4, 8.7 Hz, 0.67 H),
3.22 (t, J = 9.5 Hz, 0.33 H), 3.09–3.00 (m, 0.33 H), 2.50–2.43 (m,
0.67 H), 2.43 (s, 2 H), 2.43 (s, 0.99 H), 2.18–2.09 (m, 0.67 H), 1.89–
1.70 (m, 1 .33 H), 1.41 (s, 6 H), 1.37 (s, 3 H), 1.36 (d, J = 6.2 Hz, 2
H), 1.31 (d, J = 6.4 Hz, 1 H).
13C NMR (100.6 Hz, CDCl3; 2:1 mixture of stereoisomers): d =
171.4, 171.2, 143.4, 143.4, 135.2, 134.3, 129.7, 129.6, 127.5, 127.4,
81.3, 81.3, 56.3, 55.7, 50.8, 50.6, 43.1, 42.4, 37.4, 36.3, 27.9, 22.7,
22.3, 21.5.
MS: m/z = 456 [M + Na]+.
Anal. Calcd for C23H31NO5S: C, 63.72; H, 7.21; N, 3.23. Found: C,
63.56; H, 7.15; N, 3.26.
tert-Butyl 2-Methyl-4-{[(4-methylphenyl)sulfonyl]amino}-3-
phenylbutanoate (2n)
syn-2n
Mp 122–126 °C.
MS: m/z = 340 [M + H]+.
IR (KBr): 3303, 1719, 1159 cm–1.
Anal. Calcd for C17H25NO4S: C, 60.15; H, 7.42; N, 4.13. Found: C,
60.24; H, 7.39; N, 4.19.
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 8.3 Hz, 2 H), 7.32–
7.24 (m, 5 H), 7.04–7.00 (m, 2 H), 4.22–4.19 (m, 1 H), 3.36 (ddd,
J = 12.8, 8.5, 4.7 Hz, 1 H), 3.09 (ddd, J = 12.8, 9.7, 3.7 Hz, 1 H),
2.88 (ddd, J = 10.1, 9.7, 8.5 Hz, 1 H), 2.50 (dq, J = 10.1, 7.0 Hz, 1
H), 2.45 (s, 3 H), 1.48 (s, 9 H), 0.86 (t, J = 7.0 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 174.7, 143.3, 138.8, 136.9,
130.0, 129.0, 183.3, 127.5, 127.1, 81.0, 48.5, 46.7, 44.3, 28.0, 21.5,
16.0.
tert-Butyl 1-[(4-Methylphenyl)sulfonyl]-5-propyl-3-pyrroli-
dinecarboxylate (4c)
trans-4c
Mp 49–50 °C.
IR (KBr): 1728, 1348, 1159 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.72 (d, J = 8.3 Hz, 2 H), 7.28 (d,
J = 8.0 Hz, 2 H), 3.70–3.62 (m, 2 H), 3.25 (t, J = 9.7 Hz, 1 H), 3.05–
2.96 (m, 1 H), 2.43 (s, 3 H), 1.86–1.74 (m, 2 H), 1.69–1.60 (m, 2 H),
1.48–1.39 (m, 2 H), 1.37 (s, 9 H), 0.94 (t, J = 7.2 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 171.4, 143.4, 134.5, 129.7,
127.6, 81.3, 60.1, 50.5, 42.7, 38.2, 33.6, 27.9, 21.5, 19.3, 13.9.
EI–MS: m/z = 330 [M+ – Ot-Bu], 191 [M+ – t-Bu – Ts].
Anal. Calcd for C22H29NO4S: C, 65.48; H, 7.24; N, 3.47. Found: C,
65.43; H, 7.30; N, 3.30.
anti-2n
Mp 136–139 °C.
MS: m/z = 390 [M + Na]+.
IR (KBr): 3281, 1710, 1153 cm–1.
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York

SPECIAL TOPIC
Diastereoselective Intramolecular Ester Transfer Reaction of N-Alkenylcarbamates
2053
HRMS m/z [M + Na]+ calcd for C19H29INO4S: 390.1715; found:
390.1692.
13C NMR (100.6 MHz, CDCl3): d = 171.3, 143.6, 138.5, 135.0,
129.8, 128.3, 127.7, 127.5, 127.5, 80.3, 72.9, 67.3, 58.3, 50.5, 43.3,
36.0, 35.1, 27.9, 21.5.
cis-4c
Mp 98–99 °C.
MS: m/z = 482 [M + Na]+.
Anal. Calcd for C25H33NO5S: C, 65.33; H, 7.24; N, 3.05. Found: C,
65.51; H, 7.26; N, 3.07.
IR (KBr): 1714, 1338, 1159 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.71 (d, J = 8.3 Hz, 2 H), 7.31 (d,
J = 8.0 Hz, 2 H), 3.69–3.62 (m, 2 H), 3.44 (dd, J = 11.8, 9.2 Hz, 1
H), 2.43–2.34 (m, 1 H), 2.41 (s, 3 H), 2.03 (dt, J = 12.9, 7.7 Hz, 1
H), 1.92–1.83 (m, 1 H), 1.77 (ddd, J = 12.9, 9.1, 7.0 Hz, 1 H), 1.52–
1.43 (m, 1 H), 1.40 (s, 9 H), 1.38–1.24 (m, 2 H), 0.92 (t, J = 7.3 Hz,
3 H).
13C NMR (100.6 MHz, CDCl3): d = 171.4, 143.4, 135.5, 129.8,
127.4, 81.3, 60.4, 50.5, 43.4, 38.3, 34.7, 27.9, 21.5, 19.1, 13.9.
MS: m/z = 390 [M + Na]+.
trans-4e
Colorless oil.
IR (neat): 1728, 1346, 1159 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.71 (d, J = 8.3 Hz, 2 H), 7.36–
7.27 (m, 7 H), 4.57 (d, J = 11.7 Hz, 1 H), 4.47 (d, J = 11.7 Hz, 1 H),
3.89–3.83 (m, 2 H), 3.66 (dd, J = 10.1, 8.0 Hz, 1 H), 3.62–3.60 (m,
1 H), 3.26 (t, J = 9.8 Hz, 1 H), 3.06–2.97 (m, 1 H), 2.41 (s, 3 H),
2.17–2.09 (m, 1 H), 1.91 (dd, J = 12.6, 6.9 Hz, 1 H), 1.78–1.70 (m,
1 H), 1.67–1.59 (m, 1 H), 1.36 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): d = 171.3, 143.5, 138.4, 134.1,
129.7, 128.4, 12.7, 127.7, 127.6, 81.3, 72.9, 67.3, 58.1, 50.6, 42.6,
35.9, 34.2, 27.9, 21.5.
Anal. Calcd for C19H29NO4S: C, 62.10; H, 7.95; N, 3.81. Found: C,
62.18; H, 7.90; N, 3.81.
tert-Butyl 1-[(4-Methylphenyl)sulfonyl]-5-(2-phenylethyl)-3-
pyrrolidinecarboxylate (4d)
trans-4d
Colorless oil.
IR (neat): 1728, 1346, 1157 cm–1.
MS: m/z = 482 [M + Na]+.
HRMS m/z [M + Na]+ calcd for C25H33INO5S: 3482.1977; found:
482.1967.
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J = 8.2 Hz, 2 H), 7.34–
7.17 (m, 7 H), 3.61 (dd, J = 9.9, 7.9 Hz, 1 H), 3.59–3.52 (m, 1 H),
3.25 (t, J = 9.8 Hz, 1 H), 3.00–2.91 (m, 1 H), 2.66 (ddd, J = 14.2,
9.7, 7.9 Hz, 1 H), 2.55 (ddd, J = 14.2, 9.4, 7.3 Hz, 1 H), 2.41 (m, 3
H), 2.18–2.08 (m, 1 H), 1.88 (m, 3 H), 1.36 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): d = 171.3, 143.4, 141.2, 134.0,
129.6, 128.5, 128.4, 127.7, 126.0, 81.4, 59.4, 50.8, 42.6, 37.3, 33.6,
32.3, 27.9, 21.5.
tert-Butyl 5-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-1-
[(4-methylphenyl)sulfonyl]-3-pyrrolidinecarboxylate (4f)
Mp 98–99 °C.
IR (KBr): 1724, 1348, 1161 cm–1.
1H NMR (400 MHz, CDCl3; major isomer): d = 7.72 (d, J = 8.2 Hz,
2 H), 7.31 (d, J = 8.1 Hz, 2 H), 3.79–3.64 (m, 4 H), 3.48 (dd, J =
11.9, 9.2 Hz, 1 H), 2.43 (s, 3 H), 2.41–2.32 (m, 2 H), 2.29–2.21 (m,
1 H), 1.87 (ddd, J = 13.0, 9.5, 7.4 Hz, 1 H), 1.68 (ddt, J = 14.0, 8.8,
5.3 Hz, 1 H), 1.40 (s, 9 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H).
EI–MS: m/z = 429 [M+], 373 [M+ + 1 – t-Bu).
HRMS: m/z [M+] calcd for C24H31NO4S: 429.1940; found:
429.1956.
13C NMR (100.6 MHz, CDCl3): d = 171.3, 143.5, 135.0, 129.8,
127.5, 91.3, 60.2, 58.5, 50.6, 43.3, 38.9, 35.2, 27.9, 25.9, 21.5, 18.1,
–5.4, –5.5.
cis-4d
Colorless oil.
MS: m/z = 506 [M + Na]+.
Anal. Calcd for C24H41NO5SSi: C, 59.59; H, 8.54; N, 2.90. Found:
C, 59.66; H, 8.35; N, 2.97.
IR (neat): 1726, 1347, 1159 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J = 8.2 Hz, 2 H), 7.33–
7.24 (m, 4 H), 7.24–7.17 (m, 3 H), 3.69 (dd, J = 11.9, 8.0 Hz, 1 H),
3.61 (qd, J = 7.8, 4.7 Hz, 1 H), 3.49 (dd, J = 11.9, 9.2 Hz, 1 H), 2.75
(ddd, J = 14.1, 9.6, 4.7 Hz, 1 H), 2.60 (ddd, J = 14.1, 9.4, 7.4 Hz, 1
H), 2.42 (m, 3 H), 2.42–2.24 (m, 2 H), 2.08 (dt, J = 12.8, 7.7 Hz, 1
H), 1.90–1.78 (m, 2 H), 1.41 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): d = 171.2, 143.5, 141.3, 135.0,
130.0, 128.5, 128.4, 127.4, 125.9, 81.4, 59.8, 50.8, 43.3, 37.4, 34.7,
32.0, 28.0, 21.5.
tert-Butyl 1-[(4-Methylphenyl)sulfonyl]-5-phenoxymethyl-3-
pyrrolidinecarboxylate (4g)
Mp 111–112 °C.
IR (KBr): 1724, 1346, 1157 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.74 (d, J = 8.2 Hz, 2 H), 7.31–
7.25 (m, 5 H), 6.89 (d, J = 8.10 Hz, 2 H), 4.36 (dd, J = 9.0, 3.6 Hz,
1 H), 4.04–3.98 (m, 1 H), 3.94 (t, J = 8.6 Hz, 1 H), 3.66 (dd, J = 11.4,
7.8 Hz, 1 H), 3.60 (dd, J = 11.4, 8.3 Hz, 1 H), 2.52 (quint., J = 8.2
Hz, 1 H), 2.42 (s, 3 H), 2.21 (dd, J = 8.2, 7.2 Hz, 2 H), 1.39 (s, 9 H).
EI–MS: m/z = 429 [M+], 372 [M+ – t-Bu].
Anal. Calcd for C24H31NO4S: C, 67.10; H, 7.27; N, 3.26. Found: C,
66.78; H, 7.10; N, 3.22.
13C NMR (100.6 MHz, CDCl3): d = 171.0, 158.4, 143.8, 134.7,
129.9, 129.4, 127.5, 121.0, 114.6, 81.5, 70.1, 58.5, 51.0, 43.4, 32.7,
27.9, 21.5.
tert-Butyl 5-[2-(Benzyloxy)ethyl]-1-[(4-methylphenyl)sulfonyl]-
3-pyrrolidinecarboxylate (4e)
cis-4e
MS: m/z = 454 [M + Na]+.
Anal. Calcd for C23H29NO5S: C, 64.01; H, 6.77; N, 3.25. Found: C,
63.90; H, 6.70; N, 3.17.
Colorless oil.
IR (neat): 1726, 1348, 1159 cm–1.
tert-Butyl 1-[(4-Methylphenyl)sulfonyl]-4-phenyl-3-pyrroli-
dinecarboxylate (4n)
trans-4n
Mp 91–94 °C.
1H NMR (400 MHz, CDCl3): d = 7.71 (d, J = 8.3 Hz, 2 H), 7.34–
7.28 (m, 7 H), 4.56 (d, J = 11.7 Hz, 1 H), 4.46 (d, J = 11.7 Hz, 1 H),
3.87–3.80 (m, 1 H), 3.68 (dd, J = 12.0, 8.0 Hz, 1 H), 3.65–3.55 (m,
2 H), 3.48 (dd, J = 12.0, 9.0 Hz, 1 H), 2.41 (s, 3 H), 2.39–2.23 (m,
2 H), 2.08–2.02 (m, 1 H), 1.89–1.74 (m, 2 H), 1.40 (s, 9 H).
IR (KBr): 1732, 1317, 1154 cm–1.
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York

2054
Y. Takigawa et al.
SPECIAL TOPIC
1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 8.1 Hz, 2 H), 7.38 (d,
J = 8.1 Hz, 2 H), 7.33–7.21 (m, 3 H), 7.17–7.12 (m, 2 H), 3.78 (dd,
J = 10.0, 8.7 Hz, 1 H), 3.72 (dd, J = 9.6, 7.7 Hz, 1 H), 3.48 (dd, J =
10.0, 9.0 Hz, 1 H), 3.42 (q, J = 9.0 Hz, 1 H), 3.34 (t, J = 9.6 Hz, 1
H), 2.98 (q, J = 8.8 Hz, 1 H), 2.48 (s, 3 H), 1.29 (s, 9 H).
MS: m/z = 304 [M + Na]+.
Anal. Calcd for C15H23NO2S: C, 64.02; H, 8.24; N, 4.98. Found: C,
64.12; H, 8.17; N, 4.90.
13C NMR (100.6 MHz, CDCl3): d = 170.4, 143.7, 139.0, 133.5,
129.8, 128.7, 127.6, 127.3, 127.3, 81.5, 54.3, 51.2, 50.4, 47.6, 27.8,
21.5.
EI–MS: m/z 402 [M+ + 1].
HRMS: m/z [M+ – t-Bu] calcd for C18H18NO4S: 344.0957; found:
References
(1) (a) Negishi, E. In Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 1163. (b) Negishi, E. Acc. Chem. Res. 1987, 20, 65.
(2) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron
Lett. 1986, 27, 2829.
344.0957.
(3) (a) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E.
Tetrahedron Lett. 1989, 30, 5105. (b) Nugent, W. A.;Taber,
D. F. J. Am. Chem. Soc. 1989, 111, 6435. (c) Mori, M.;
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(d) Saitoh, F.; Mori, M.; Okamura, K.; Date, T. Tetrahedron
1995, 51, 4439. (e) Negishi, E.; Maye, J. P.; Choueiry, D.
Tetrahedron 1995, 51, 4447. (f) Taber, D. F.; Louey, J. P.
Tetrahedron 1995, 51, 4495. (g) Mori, M.; Kuroda, S.;
Zhang, C.-S.; Sato, Y. J. Org. Chem. 1997, 62, 3263.
(4) (a) Nugent, W. A.; Thorn, D. L.; Harlow, R. L. J. Am. Chem.
Soc. 1987, 109, 2788. (b) Fagan, P. J.; Nugent, W. A. J. Am.
Chem. Soc. 1988, 110, 2310.
cis-4n
Mp 106–110 °C.
IR (KBr): 1714, 1341, 1162 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.78 (d, J = 8.1 Hz, 2 H), 7.35 (d,
J = 8.1 Hz, 2 H), 7.22–7.17 (m, 3 H), 7.05–6.98 (m, 2 H), 3.79–3.72
(m, 1 H), 3.68 (dd, J = 10.5, 8.3 Hz, 1 H), 3.65–3.53 (m. 3 H), 3.24
(q, J = 7.9 Hz, 1 H), 2.46 (s, 3 H), 1.02 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): d = 169.4, 143.6, 138.6, 133.8,
129.8, 128.3, 127.9, 127.7, 127.2, 81.3, 53.0, 48.9, 48.9, 45.9, 27.5,
21.5.
(5) (a) Negishi, E.; Swanson, D. R.; Cederbaum, F. E.;
Takahashi, T. Tetrahedron Lett. 1987, 28, 917.
EI–MS: m/z = 401 [M+].
HRMS: m/z (M+ – t-Bu] calcd for C18H18NO4S: 344.0957; found:
344.0963.
(b) RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P.
J. J. Am. Chem. Soc. 1988, 110, 7128. (c) Lund, E. C.;
Livinghouse, T. J. Org. Chem. 1989, 54, 4487. (d) Mori,
M.; Uesaka, N.; Shibasaki, M. J. Chem. Soc., Chem.
Commun. 1990, 1222. (e) Wender, P. A.; McDonald, F. E. J.
Am. Chem. Soc. 1990, 112, 4956. (f) Pagenkopf, B. L.;
Lund, E. C.; Livinghouse, T. Tetrahedron 1995, 51, 4421.
(g) Negishi, E.; Ma, S.; Sugihara, T.; Noda, Y. J. Org. Chem.
1997, 62, 1922.
4-Methyl-1-[(4-methylphenyl)sulfonyl]-2-propylpyrrolidine
(5c)
After a mixture of 2c (149 mg, 0.4 mmol) and LiAlH4 (22.8 mg, 0.6
mmol) in Et2O (6 mL) was stirred at 0 °C for 1 h, to the mixture was
added 1 N HCl and then the mixture was extracted with Et2O. The
organic layer was washed with brine, dried over MgSO4, concen-
trated in vacuo, and then passed through short silica gel column
(hexane–EtOAc, 2:1) to give the corresponding alcohol as a color-
less oil (quantitative yield).
(6) (a) Makabe, M.; Sato, Y.; Mori, M. J. Org. Chem. 2004, 69,
6238. (b) Makabe, M.; Sato, Y.; Mori, M. Synthesis 2004,
1369.
(7) Jensen, M.; Livinghouse, T. J. Am. Chem. Soc. 1989, 111,
4495.
IR (neat): 3502 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.75 (d, J = 8.3 Hz, 2 H), 7.28 (d,
J = 8.1 Hz, 2 H), 3.42 (dd, J = 10.5, 5.5 Hz, 1 H), 3.37–3.29 (m, 2
H), 2.41 (s, 3 H), 1.78–1.70 (m, 1 H), 1.48–1.42 (m, 1 H), 1.37–1.05
(m, 5 H), 0.81 (d, J = 6.9 Hz, 3 H), 0.74 (t, J = 7.1 Hz, 3 H).
(8) Takahashi, T.; Tsai, F. Y.; Li, Y.; Nakajima, K.
Organometallics 2001, 20, 595.
(9) (a) Mori, M.; Uesaka, N.; Shibasaki, M. J. Chem. Soc.,
Chem. Commun. 1989, 776. (b) Takahashi, T.; Kageyama,
M.; Denisov, V.; Hara, R.; Negishi, E. Tetrahedron Lett.
1993, 34, 687. (c) Hara, R.; Xi, Z.; Kotora, M.; Xi, C.;
Thakahashi, T. Chem. Lett. 1996, 1003. (d) Takahashi, T.;
Xi, C.; Kageyama, M.; Fischer, R.; Nakajima, K.; Negishi,
E. J. Org. Chem. 1998, 63, 6802.
(10) For titanium-mediated intramolecular ene-carbonyl
coupling reaction, see: (a) Hewlett, D. F.; Whitby, R. J. J.
Chem. Soc., Chem. Commun. 1990, 1684. For reviews, see:
(b) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000,
100, 2789. (c) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev.
2000, 100, 2835. (d) Kablaoui, N. M.; Buchwald, S. L. J.
Am. Chem. Soc. 1995, 117, 6785. (e) Kablaoui, N. M.;
Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
4424. (f) Lee, J.; Kim, Y. G.; Bae, J. G.; Cha, J. K. J. Org.
Chem. 1996, 61, 4878. (g) Okamoto, S.; Kasatkin, A.;
Zubaidha, P. K.; Sato, F. J. Am. Chem. Soc. 1996, 118, 2208.
(11) Ito, H.; Omodera, K.; Takigawa, Y.; Taguchi, T. Org. Lett.
2002, 4, 1499.
MS: m/z = 300 [M + Na]+.
A mixture of the above alcohol (121 mg, 0.4 mmol), MsCl (0.05
mL, 0.6 mmol) and Et3N (0.11 mL, 0.8 mmol) in CH2Cl2 (4 mL)
was stirred for 1 h and then extracted with Et2O after addition of 1
N HCl. The organic layer was washed with brine, dried over MgSO4
and concentrated in vacuo to leave the residue. A THF solution of
the residue was added to NaH (120 mg, 3.0 mmol) in THF at 0 °C
and the mixture was stirred for 12 h at r.t. Addition of 1 N HCl, ex-
traction with Et2O and purification by silica gel column (hexane–
EtOAc, 7:1) gave the pyrrolidine 5c (56 mg, 50% yield) as colorless
solid (trans/cis = 8:1).
IR (KBr): 1338, 1153 cm–1.
1H NMR (400 MHz, CDCl3; major isomer): d = 7.71 (d, J = 8.2 Hz,
2 H), 7.31 (d, J = 8.2 Hz, 2 H), 3.63–3.56 (m, 1 H), 3.51 (dd, J = 9.3,
6.9 Hz, 1 H), 2.58 (t, J = 9.4 Hz, 1 H), 2.43 (s, 3 H), 2.34–2.25 (m,
1 H), 1.86–1.77 (m, 1 H), 1.70–1.65 (m, 1 H), 1.50–1.40 (m, 1 H),
1.31 (sext, J = 7.5 Hz, 2 H), 1.15–1.07 (m, 1 H), 0.93 (d, J = 7.2 Hz,
3 H), 0.83 (t, J = 6.6 Hz, 3 H).
(12) Takigawa, Y.; Ito, H.; Omodera, K.; Ito, M.; Taguchi, T.
Tetrahedron 2004, 60, 1385.
(13) Okamoto, S.; Kasatkin, A.; Zubaidha, P. K.; Sato, F. J. Am.
13C NMR (100.6 Hz, CDCl3): d = 143.1, 134.5, 129.5, 127.6, 50.5,
55.6, 38.8, 38.5, 31.6, 21.5, 19.5, 17.1, 14.0.
Chem. Soc. 1996, 118, 2208.
Synthesis 2005, No. 12, 2046–2054 © Thieme Stuttgart · New York