Asymmetric total synthesis of enantiopure (-)-methyl jasmonate via catalytic asymmetric intramolecular cyclopropanation of α-diazo-β-keto sulfone

Article abstract of DOI:10.1016/j.tet.2006.06.022

A new asymmetric total synthesis of enantiopure (-)-methyl jasmonate is described. This synthesis was accomplished starting from the new enantiopure building block prepared via the catalytic asymmetric intramolecular cyclopropanation (IMCP) of the α-diazo-β-keto 1-naphthyl sulfone, which was devised to give good selectivity both in the IMCP reaction and in the C-alkynylation of the intermediate required for the total synthesis of enantiopure (-)-methyl jasmonate.

Full text of DOI:10.1016/j.tet.2006.06.022

Tetrahedron 62 (2006) 8054–8063
Asymmetric total synthesis of enantiopure (L)-methyl jasmonate
via catalytic asymmetric intramolecular cyclopropanation
of a-diazo-b-keto sulfone
*
Hiroyuki Takeda, Hideaki Watanabe and Masahisa Nakada
Department of Chemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received 8 May 2006; revised 6 June 2006; accepted 7 June 2006
Available online 30 June 2006
Abstract—A new asymmetric total synthesis of enantiopure (ꢀ)-methyl jasmonate is described. This synthesis was accomplished starting
from the new enantiopure building block prepared via the catalytic asymmetric intramolecular cyclopropanation (IMCP) of the a-diazo-b-
keto 1-naphthyl sulfone, which was devised to give good selectivity both in the IMCP reaction and in the C-alkynylation of the intermediate
required for the total synthesis of enantiopure (ꢀ)-methyl jasmonate.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
(ꢀ)-Methyl jasmonate1 is a key natural product occurring in
Jasminium grandiflorum L. and in the blossoms of many
flowers, and is used widely in the formulation of many per-
fumes. Although its structure is not complicated, key bio-
logical roles for (ꢀ)-methyl jasmonate have been noted2
including roles in gene expression,3 odor production,4 and
growth inhibition.5 (ꢀ)-Methyl jasmonate possesses two
stereogenic centers on a cyclopentanone ring substituted
by a cis-2-pentenyl group and a methoxycarbonylmethyl
group at its a- and b-positions of the carbonyl group, respec-
tively. Its biological activities and structural features have
motivated numerous attempts for total synthesis.6 The asym-
metric synthesis of enantiopure (ꢀ)-methyl jasmonate via
enantioselective reaction has been limited6 because an enan-
tiopure cyclopentanone derivative suitable for the starting
material is not commercially available, indicating one of
the synthetic problems in the asymmetric total synthesis of
this compound.
As outlined in Scheme 1, we expected that hydrogenation of
the alkyne 1 with Lindlar’s catalyst, following hydrolysis of
the nitrile, and methylation of the resulting carboxylic acid
would afford (ꢀ)-methyl jasmonate. The alkyne 1 could be
produced as a mixture of diastereomers at the stereogenic
center adjacent to the carbonyl group because it would be
converged to the thermodynamically more stable trans-
2,3-disubstituted isomer during the hydrolysis of the nitrile
group under basic conditions. Alkyne 1 was difficult to
obtain by direct alkynylation of the corresponding cyclopen-
tanone derivative because the alkynylation would proceed at
COOMe
CN
O
O
1
(–)-methyl jasmonate
CN
CN
We report herein an asymmetric total synthesis of enantio-
pure (ꢀ)-methyl jasmonate starting from a new enantiopure
chiral building block prepared via the originally developed
catalytic asymmetric intramolecular cyclopropanation
(IMCP) reaction of the a-diazo-b-keto sulfone.
SO2Ar
SO2Ar
O
O
2
3
N2
SO2Ar
SO2Ar
O
O
Keywords: Catalytic asymmetric synthesis; Chiral building blocks; Intra-
molecular cyclopropanation; Total synthesis.
4
5
* Corresponding author. Tel./fax: +813 5286 3240; e-mail: mnakada@
waseda.jp
Scheme 1. Retrosynthetic analysis of (ꢀ)-methyl jasmonate.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.022

H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
8055
the less hindered a-position of the carbonyl group. Rather
alkynylation of b-keto sulfone 3 was expected to produce
2 regioselectively because the aryl sulfonyl group stabilizes
the anion generated at its a-position. Although O-alkynyla-
tion of 3 was also expected to occur as a side reaction, the
O-alkynylated product would be hydrolyzed to regenerate
3 under acidic conditions. Since the bicyclo[3.1.0]hexan-2-
one derivative 4 reacts with soft nucleophiles (such as
sodium thiophenoxide)7,8 to open the cyclopropane ring,
and reaction of a cyanide ion with the cyclopropane deriva-
tive possessing an ester group in place of the sulfonyl group
in 4 has been reported,6bb reaction of a cyanide ion with 4
was expected to afford b-keto sulfone 3. Consequently, the
bicyclo[3.1.0]hexan-2-one derivative 4 was envisioned to
be a key intermediate for the asymmetric total synthesis of
(ꢀ)-methyl jasmonate.
produced b-keto sulfone 1311 in 93% yield. Since the alkyl-
ation reaction of b-keto phenyl sulfone under basic condi-
tions was known to afford the C-alkylated product
exclusively,12 propargylation of 13 was studied as the model
reaction for the conversion of 3 to 2 (Scheme 1) toward the
total synthesis of (ꢀ)-methyl jasmonate.
CN
NaCN, DMSO
80 °C, 5 h
SO2Ar
S
O2
O
O
4 (Ar = Mes)
13 93%
Scheme 3. Reaction of 4 (Ar¼Mes) with sodium cyanide.
The propargylation of 13 afforded the O-propargylated prod-
uct, designated as 14o, as the major product under various
conditions (Table 1), while the best yield of the C-propargy-
lated product, 14c, was 27% (entry 2). We examined alkyl-
ation of 13 with less bulky methyl iodide (Table 2), too;
however, all the reactions under several conditions afforded
the O-methylated product 15o as the major product.
The asymmetric synthesis of natural products starting from
the bicyclo[3.1.0]hexan-2-one derivatives prepared by the
IMCP reaction of a-diazo-b-keto ester has been reported,7,9
however, the reported preparation has been limited to the
diastereoselective cyclopropanation reaction by use of a
chiral auxiliary.9
We have studied the asymmetric catalysis of the IMCP reac-
tion of a-diazo-b-keto ester, but found it to be difficult.10a
Hence, we have developed the catalytic asymmetric IMCP
reactions of a-diazo-b-keto sulfones 7, 9, and 10 (Scheme
2) by use of ligand 6 to afford the corresponding cyclopro-
panes 8, 11, and 12 with 93–98% ee, respectively.10 Since
cyclopropanes thus prepared from a-diazo-b-keto sulfones
are highly crystalline and easily purified by recrystallization
as enantiomerically pure compounds, this catalytic asym-
metric IMCP reaction is useful for preparing new enantio-
pure chiral building blocks toward natural products’
syntheses. Our recent reports regarding the asymmetric total
synthesis of enantiopure (ꢀ)-malyngolide8a and the first
Table 1. Propargylation of 13
propargyl
CN
CN
CN
bromide
(3.0 equiv)
+
SO2Mes
SO2Mes
SO2Mes
NaI
(3.0 equiv)
base
O
O
O
(1.5 equiv)
solvent
13
14c
14o
Entry Base
Solvent Temperature (ꢁC) Time (h) Yield (%)a
14cb 14o
1
2
3
4
5
6
7
K2CO3 Acetone Reflux
K2CO3 DMF rt
K2CO3 DMSO rt
K2CO3 CH3CN rt
8
2
2
10
27
23
16
7
81
63
68
82
92
80
70
8b
asymmetric total synthesis of (ꢀ)-allocyathin B2 via the
catalytic asymmetric IMCP reaction prove its wide applica-
bility.
4
NaH
TBAF
Cs2CO3 DMF
THF
THF
0/rt
Reflux
rt
36
12
2
16
22
R1
N
R1
N
6a: R1=Me, R2=Bn
6b: R1=Me, R2=i-Pr
6c: R1=Me, R2=t-Bu
6d: R1=Et, R2=i-Pr
6e: R1=Bn, R2=i-Pr
The relative stereochemistry was determined by NOESY.
Isolated yields.
A single isomer.
a
O
O
b
R2
R2
Table 2. Methylation of 13
R5
R5
N2
R3
R4
SO2Mes
MeI
(3.0 equiv)
base
CN
CN
CuOTf (10 mol %)
ligand 6e (15 mol %)
93-98% ee
CN
SO2Mes
OMe
15o
R3
SO2Mes
+
R4
O
SO2Mes
SO2Mes
(1.5 equiv)
solvent
O
8
O
O
7
13
15c
CuOTf (10 mol %)
n
n
O
H
H
O
Entry Base
Solvent Temperature (ꢁC) Time (h) Yield (%)a
ligand 6b or 6e (15 mol %)
N2
MesO2S
9 (n=1): 10 (n=2)
15cb 15o
MesO2S
n=1, 6e: 96% ee
n=2, 6b: 97% ee
11 (n=1): 12 (n=2)
1
2
3
4
5
K2CO3 Acetone Reflux
K2CO3 CH3CN Reflux
K2CO3 DMF
NaH DMF
TBAF DMF
5
12
5
3
3
5
27
38
15
12
92
71
60
78
81
Scheme 2. Asymmetric catalysis of a-diazo-b-keto sulfones 7, 9, and 10.
rt
rt
rt
Initial synthetic studies on (ꢀ)-methyl jasmonate began
with the previously reported enantiopure cyclopropane 4
(Ar¼Mes) (Scheme 3).10 Reaction of cyclopropane 4
(Ar¼Mes) with sodium cyanide in DMSO at 80 ꢁC smoothly
The relative stereochemistry was determined by NOESY.
Isolated yields.
A single isomer.
a
b

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H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
Table 3. Enantioselective IMCP reaction of a-diazo-b-keto sulfone 5
The preferred formation of the O-alkylated products in the
reaction of 13 could be attributed to the bulky mesityl group.
The b-keto sulfone possessing a less bulky phenyl group in
place of the mesityl group was expected to increase the ratio
of C-alkylated product, however, the cyclopropane 4
(Ar¼Ph) was generated with a relatively low ee (75%
ee10a), not useful for the asymmetric synthesis of natural
products. Consequently, we decided to find other a-diazo-
b-keto sulfones, which afforded the products with high ee
by the catalytic asymmetric IMCP reaction.
CuOTf
N2
(10 mol %)
SO2Ar
SO2Ar
ligand
(15 mol %)
50 °C
O
O
5
4
Entry
Ligand
Ara
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6a
6b
6c
6d
6e
Np
Np
Np
Np
Np
Xy
Xy
Xy
Xy
Xy
4
3
14
5
2
4
2
12
5
91
95
59
93
82
75
83
89
99
97
71 (1R)
72 (1R)
45 (1R)
83 (1R)
79 (1R)
72 (1R)
62 (1R)
37 (1R)
74 (1R)
81 (1R)
The enantioselectivity in the catalytic asymmetric IMCP
reaction of 7 (R3¼R4¼R5¼H) was higher than that of the
corresponding phenyl sulfone.10a This result suggested that
the ortho methyl groups of 2,4,6-trimethylphenyl sulfone
in 7 played a crucial role for the high enantioselectivity.
Consequently, we examined the catalytic asymmetric IMCP
reactions of a-diazo-b-keto sulfones 5 (Ar¼Np, Xy) because
a 1-naphthyl group and a 2,4-dimethylphenyl group are
smaller than the mesityl group but retain sufficient bulkiness
to give good selectivity both in the IMCP reaction and in the
C-alkylation of the intermediates corresponding to 13. In
addition, commercial availability of the starting materials
for the preparation of methyl 1-naphthyl sulfone13 and 2,4-
dimethylphenyl methyl sulfone14 was also the point in
employing these aryl groups.
5
a
Np¼1-naphthyl; Xy¼2,4-dimethylphenyl.
b
c
Isolated yields.
Enantiomeric excess (ee) determined by HPLC. For HPLC conditions,
see Section 4.
(Ar¼Np, Xy)11 in 95% and 60% yields, respectively. Desul-
fonylation of 3 (Ar¼Np, Xy) and 13 with SmI2 in the pres-
ence of methanol successfully afforded 16 in 48%, 51%, and
59% yields, respectively. Their specific rotations had a minus
sign, elucidating that 4 possesses 1R configuration because
the absolute configuration of 13, which was derived from 4
(Ar¼Mes),10a is known. These results indicate that enantio-
selectivity of the IMCP reaction of 5 (Ar¼Np, Xy) with
ligand 6e is well explained by our previously reported
model,10a which had been proposed to explain the enantio-
selectivity of the IMCP reaction of 7 (R3¼R4¼R5¼H).
a-Diazo-b-keto sulfones 5 (Ar¼Np, Xy) were successfully
prepared according to the previously reported procedure
for 710a (Scheme 4). Dianions of either methyl 1-naphthyl
sulfone or 2,4-dimethylphenyl methyl sulfone were reacted
with ethyl 4-pentenoate to produce the corresponding
b-keto sulfones, which were converted to a-diazo-b-keto
sulfones 5 (Ar¼Np, Xy), respectively.15
CN
NaCN
N2
1) n-BuLi (2.0 equiv)
SO2Ar
CH3SO2Ar
SO2Ar
DMSO
80 °C
5 h
THF, 0 °C
SO2Ar
O
Ar = Np (1-naphthyl)
O
3
Ar = Np 95%
Xy 60%
then,
4
Xy (2,4-dimethylphenyl)
O
ethyl 4-pentenoate
5
2) TsN3, TEA
Ar = Np 77% (2 steps)
Xy 67% (2 steps)
CH3CN, rt
-78 °C
5 min
SmI2, THF
methanol
Scheme 4. Preparation of 5.
CN
CN
The relationships between the ligand and the enantioselec-
tivity in the IMCP reaction of 5 (Ar¼Np) differed from those
of 7, which were reported previously.10a As indicated in
Table 3, ligand 6e, which had endowed the highest ee
in the IMCP reaction of 7 (Scheme 2), was not so effective
in the IMCP reaction of 5 (Ar¼Np), affording 4 with 79% ee
(entry 5). The best result (83% ee) was obtained with ligand
6d in the case of 5 (Ar¼Np). On the other hand, the IMCP
reaction of 5 (Ar¼Xy) showed the same trend in the rela-
tionships between the ligand and the enantioselectivity as
that of 7 because ligand 6e gave the best result (81% ee).
SmI2, THF
methanol
SO2Mes
-78 °C
5 min
O
O
16
13
Ar = Np 48%
Xy 51%
Mes 59%
Scheme 5. Conversion of 4 to 16 and 13 to 16.
Since the catalytic asymmetric IMCP reactions of a-diazo-
b-keto sulfone 5 (Ar¼Np, Xy) afforded the products with
high ee, which were isolated in enantiopure form by recrys-
tallization, we next examined the propargylation of 3
(Ar¼Np, Xy). Among various solvents examined, polar
aprotic solvents were effective for the C-propargylation in
both substrates 3 (Ar¼Np, Xy) (Table 4). DMF and
DMSO gave comparable yields in the reactions of both sub-
strates 3 (Ar¼Np, Xy) (entries 2 and 3, 9 and 10), but the
ratio of 17c/17o was slightly higher when the solvent was
DMF. In DMF, the use of potassium carbonate as the base
Since 4 (Ar¼Np, Xy) and their crystalline derivatives were
unsuitable for X-ray crystallographic analysis, we converted
4 (Ar¼Np, Xy) to 16 to determine their absolute configura-
tion by comparing their sign of the specific rotations with
that of 16, which was derived from the known 4
(Ar¼Mes)10a via 13 (Scheme 5). As shown in Scheme 5, re-
actions of 4 (Ar¼Np, Xy) with sodium cyanide in DMSO at
80 ꢁC for 5 h opened the cyclopropane ring to generate 3

H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
8057
Table 4. Propargylation of 3 (Ar¼Np, Xy)
CN
CN
CN
1-bromo-2-pentyne
propargyl
NaI, K2CO3
DMF, rt, 5 h
SO2Np
bromide
CN
+
CN
(3.0 equiv)
NaI
CN
SO2Np
SO2Ar
O
O
O
(3.0 equiv)
+
SO2Ar
SO2Ar
PPTS (cat.)
5% H2O/MeOH
rt, 12 h
SO2Ar
base
3 (Ar = Np)
18o 36%
18c 59%
dr = 6 : 1
O
O
O
(1.5 equiv)
solvent
17o
Yield (%)a
98%
17c
3 (Ar = Np, Xy)
CN
H2
SmI2
Lindlar's
Entry Ar Base
Solvent Temperature Time
(ꢁC)
THF/MeOH
catalyst
(h)
17cb
17o
18c
-78 °C, 5 min
MeOH
rt, 3 h
1
Np K2CO3 Acetone Reflux
10
2
2
3
12
10
2.5 72
5
2
2
3
15
80
21
26
41
81
40
24
72
52
58
67
81
64
54
O
100%
dr = 4 : 1
19
2
3
Np K2CO3 DMF
Np K2CO3 DMSO
rt
rt
75
72
58
11
55
CN
1) KOH
4
Np K2CO3 CH3CN rt
ethylene glycol
80 °C, 12 h
5
6
7
Np NaH
Np TBAF
Np Cs2CO3 DMF
THF
THF
0/rt
Reflux
rt
(–)-methyl jasmonate
2) MeI, K2CO3
acetone
88% (2 steps)
O
20
reflux, 5 h
8
Xy K2CO3 Acetone Reflux
21
44
41
31
15
27
40
90%
9
Xy K2CO3 DMF
Xy K2CO3 DMSO
Xy K2CO3 CH3CN rt
rt
rt
10
11
12
13
14
Scheme 6. Total synthesis of (ꢀ)-methyl jasmonate.
Xy NaH
Xy TBAF
THF
THF
0/rt
Reflux
rt
24
6
2
of the synthetic methyl jasmonate ([a]2D3) showed ꢀ90.2
(c 1.03, MeOH) (lit.1a [a]D23 ꢀ90.3 (c 1.03, MeOH)), reveal-
ing that (ꢀ)-methyl jasmonate has been synthesized.
Xy Cs2CO3 DMF
a
Isolated yields.
A mixture of diastereomers; dr¼11/1 for entries 1–7; dr¼7/1 for entries
b
8–14.16
3. Conclusion
gave a higher ratio of 17c/17o than did cesium carbonate
(entries 2 and 7, 9 and 14). A crucial factor in the ratio of
17c/17o was attributed to the nature of the aryl sulfonyl
group. Thus, Table 4 clearly shows that the ratio of 17c/
17o in the reaction is improved if the naphthyl substituent
of 5 is used rather than the 2,4-dimethylphenyl substituent.
Consequently, although both versions of 5 (Ar¼Np, Xy)
showed comparable enantioselectivities in the IMCP reac-
tion, 3 (Ar¼Np) was adopted for the synthesis of (ꢀ)-methyl
jasmonate.
In summary, we found that catalytic asymmetric IMCP reac-
tions of the 1-naphthyl sulfone 5 (Ar¼Np) and 2,4-dimethyl-
phenyl sulfone 5 (Ar¼Xy) produced new cyclopropanes 4
(Ar¼Np, Xy) in 83% and 81% ee, respectively, and 4
(Ar¼Np) was successfully purified by recrystallization in
optically pure form. Reaction of 4 (Ar¼Np) with sodium
cyanide gave 3 (Ar¼Np), which was alkylated with 1-bromo-
2-pentyne to produce C-alkylated product 18c as the major
product. O-Alkylated product 18o was hydrolyzed under
acidic conditions to regenerate 3 (Ar¼Np), and C-alkylated
product 18c was successfully converted to enantiopure
(ꢀ)-methyl jasmonate. Optically pure new chiral building
blocks 4 (Ar¼Np, Xy) developed in this study would be use-
ful for the asymmetric total synthesis of enantiopure natural
products, especially those containing a 2,3-disubstituted
cyclopentanone ring in their molecules.
The reaction of 3 (Ar¼Np) with 1-bromo-2-pentyne under
the same conditions as those employed in entry 2 of Table
4 afforded C-alkylated product 18c as a mixture of diastereo-
mers (6/1)16 in 59% yield and O-alkylated product 18o in
36% yield (Scheme 6). The C- and O-alkylated products
were separated by flash chromatography, and 18o was suc-
cessfully hydrolyzed under acidic conditions to regenerate
3 (Ar¼Np) in 98% yield.
4. Experimental
4.1. General procedures
Desulfonylation of 18c was successfully carried out by SmI2
in 100% yield, but affording 19 as a mixture of diastereo-
mers (dr¼4/1).16 This mixture was used for the next step
without separation because the hydrolysis of nitrile 20 was
anticipated to proceed with epimerization at its C-2 position.
Hydrogenation of 19 with Lindlar’s catalyst gave cis-alkene
20 in 90% yield, and successive treatment of 20 with KOH in
ethylene glycol produced the corresponding carboxylic acid
with concomitant epimerization at its C-2 position to afford
the carboxylic acid expectedly as the single product. Finally,
methylation of the obtained carboxylic acid with methyl io-
dide furnished methyl jasmonate (88%, two steps). Synthetic
methyl jasmonate proved to be identical in all respects to the
reported spectral data (1H NMR, IR, MS, and 13C NMR;
>99% de16)1a of methyl jasmonate. The specific rotation
1H and 13C NMR spectra were recorded on a JEOL AL-400
1
spectrometer. H and 13C chemical shifts are reported in
parts per million downfield from tetramethylsilane (TMS,
d scale) with the solvent resonances as internal standards.
The following abbreviations were used to explain the multi-
plicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multi-
plet; band, several overlapping signals; br, broad. IR spectra
were recorded on a JASCO FT/IR-8300. Melting points (mp)
are uncorrected, recorded on a Yamato capillary melting
point apparatus equipped with a digital thermometer. Optical
rotations were measured using a 2 mL cell with a 1 dm
path length on a JASCO DIP-1000. Chiral HPLC analysis

8058
H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
was performed on JASCO PU-980 and UV-970. Mass spec-
trometric analyses and elemental analyses were provided at
the Materials Characterization Central Laboratory, Waseda
University. All reactions were carried out under an argon at-
mosphere with dry, freshly distilled solvents under anhy-
drous conditions, unless otherwise noted. All reactions
were monitored by thin-layer chromatography carried out
on 0.25 mm E. Merck silica gel plates (60F-254) using UV
light as visualizing agent and phosphomolybdic acid and
heat as developing agents. E. Merck silica gel (60, particle
size 0.040–0.063 mm) was used for flash column chromato-
graphy. Preparative thin-layer chromatography (PTLC) sep-
arations were carried out on self-made 0.3 mm E. Merck
silica gel plates (60F-254). THF was distilled from sodium/
benzophenone ketyl, and methylene chloride (CH2Cl2),
benzene were distilled from calcium hydride. Toluene was
distilled from sodium. Acetonitrile was distilled from
CaH2 under reduced pressure. (CuOTf)2C6H6 and all other
reagents were purchased from Aldrich, TCI, or Kanto
Chemical Co. Ltd.
Compound 14c: mp¼112–113 ꢁC (CH2Cl2/hexane); [a]2D5
+67.4 (c 1.25, CHCl3); IR (KBr) nmax: 2260, 2132, 1666,
854, 734 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼7.02
(s, 2H), 3.75–3.58 (m, 1H), 3.06 (dd, J¼4.3, 16.8 Hz, 1H),
2.97 (dd, J¼11.5, 16.8 Hz, 1H), 2.87 (dd, J¼2.7, 16.0 Hz,
1H), 2.80–2.25 (m, 13H, including d¼2.33, s, 3H), 2.06
(dd, J¼2.7, 2.7 Hz, 1H), 2.01–1.80 (m, 1H); 13C NMR
(100 MHz, CDCl3): d¼206.8, 144.9, 133.1, 127.2, 117.5,
76.7, 75.9, 73.4, 39.0, 36.7, 26.0, 23.9, 21.1, 19.2, 18.7;
HRMS (FAB): m/z calcd for C19H21NO3S+H 344.1320,
found 344.1389.
Compound 14o: mp¼94–96 ꢁC (CH2Cl2/hexane); [a]2D4
ꢀ42.8 (c 1.40, CHCl3); IR (KBr) nmax: 2252, 854,
1
734 cmꢀ1; H NMR (400 MHz, CDCl3): d¼6.91 (s, 2H),
4.42 (dd, J¼2.4, 16.3 Hz, 1H), 4.37 (dd, J¼2.4, 16.3 Hz,
1H), 3.50–3.32 (m, 1H), 3.00–2.85 (m, 2H), 2.75–2.57 (m,
8H, including d¼2.62, s, 6H), 2.47 (dd, J¼2.4, 2.4 Hz, 1H),
2.38–2.25 (m, 4H, including d¼2.30, s, 3H), 1.94 (dddd,
J¼3.2, 7.8, 9.0, 10.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d¼163.9, 142.6, 140.1, 135.1, 131.7, 118.3, 117.5,
76.6, 57.9, 39.9, 28.9, 25.7, 23.4, 22.5, 20.9; HRMS (FAB):
m/z calcd for C19H21NO3S+H 344.1320, found 344.1307.
4.1.1. (1R,2R)-[3-Oxo-2-(2,4,6-trimethylphenylsulfonyl)-
cyclopentyl]acetonitrile (13). To a solution of 4 (Ar¼
Mes)10a (1.00 g, 3.59 mmol) in DMSO (30 mL) was added
sodium cyanide (194.0 mg, 3.95 mmol) and the reaction
mixture was stirred at 80 ꢁC for 5 h. After the starting mate-
rial disappeared, the reaction mixture was quenched with
saturated aqueous NaHCO3 solution (30 mL) and extracted
with ethyl acetate (30 mLꢂ2). The combined organic layer
was washed with brine (30 mL), dried over Na2SO4, and
evaporated. The residue was purified by flash chromato-
graphy (hexane/ethyl acetate¼4/1) to afford 13 (1.02 g,
93%) as a white solid.
4.1.3. (1R,2S)-[2-Methyl-3-oxo-2-(2,4,6-trimethylphenyl-
sulfonyl)cyclopentyl]acetonitrile (15c) and (R)-[3-meth-
oxy-2-(2,4,6-trimethylphenylsulfonyl)-2-cyclopentenyl]-
acetonitrile (15o). To a solution of 13 (1.00 g, 3.27 mmol) in
DMF (30 mL) were added potassium carbonate (452.0 mg,
4.91 mmol) and methyl iodide (0.61 mL, 9.81 mmol) suc-
cessively, and the reaction mixture was stirred at room tem-
perature for 5 h. The reaction mixture was quenched with
saturated aqueous NH4Cl solution (30 mL) and extracted
with ether (30 mLꢂ2). The combined organic layer was
washed with brine (5 mL), dried over Na2SO4, and evapo-
rated. The residue was purified by flash chromatography
(hexane/ethyl acetate¼4/1) to afford 15c (397 mg, 38%,
a single isomer) and 15o (626 mg, 60%) as white solids.
Mp¼117–118 ꢁC (CH2Cl2/hexane); [a]2D4 ꢀ78.2 (c 1.00,
CHCl3); IR (KBr) nmax: 2247, 1654, 1449, 1143, 932,
1
741 cmꢀ1; H NMR (400 MHz, CDCl3): d¼7.01 (s, 2H),
3.73 (d, J¼9.8 Hz, 1H), 3.34–3.24 (m, 1H), 3.08 (dd,
J¼5.9, 17.1 Hz, 1H), 2.84 (dd, J¼3.9, 17.1 Hz, 1H), 2.60
(s, 6H), 2.56–2.36 (m, 3H), 2.33 (s, 3H), 1.82 (dddd,
J¼1.7, 7.8, 9.3, 9.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d¼204.4, 144.3, 140.5, 132.4, 131.7, 116.9, 71.3,
38.9, 33.8, 25.9, 22.9, 22.5, 21.2; HRMS (FAB): m/z calcd
for C16H19NO3S+H 306.1164, found 306.1169. Anal. Calcd
for C16H19NO3S: C, 62.93; H, 6.27; N, 4.59; S, 10.50.
Found: C, 62.89; H, 6.24; N, 4.61; S, 10.53.
Compound 15c: mp¼108–109 ꢁC (CH2Cl2/hexane); [a]2D6
ꢀ60.6 (c 1.01, CHCl3); IR (KBr) nmax: 2240, 1657, 1452,
1
1126, 857, 719 cmꢀ1; H NMR (400 MHz, CDCl3): d¼
6.94 (s, 2H), 3.65–3.40 (m, 1H), 2.88 (dd, J¼4.6, 16.8 Hz,
1H), 2.70–2.05 (m, 9H, including d¼2.53, s, 3H; d¼2.51,
s, 3H), 2.26 (s, 3H), 1.75–1.45 (m, 2H), 1.26 (s, 3H); 13C
NMR (100 MHz, CDCl3): d¼208.3, 144.4, 132.9, 128.1,
117.7, 75.0, 38.5, 36.5, 24.7, 23.9, 21.0, 19.7, 13.5; HRMS
(FAB): m/z calcd for C17H21NO3S+H 320.1320, found
320.1343.
4.1.2. (1R,2S)-[3-Oxo-2-(2-propynyl)-2-(2,4,6-trimethyl-
phenylsulfonyl)cyclopentyl]acetonitrile (14c) and
(R)-[3-(2-propynyloxy)-2-(2,4,6-trimethylphenylsul-
fonyl)-2-cyclopentenyl]acetonitrile (14o). To a solution of
13 (41.5 mg, 0.137 mmol) in DMF (2 mL) were added
potassium carbonate (28.4 mg, 0.205 mmol), sodium iodide
(61.6 mg, 0.411 mmol), and propargyl bromide (0.031 mL,
0.411 mmol) successively, and the reaction mixture was
stirred at room temperature for 2 h. The reaction mixture
was quenched with saturated aqueous NH4Cl solution
(3 mL) and extracted with ether (5 mLꢂ2). The combined
organic layer was washed with brine (5 mL), dried over
Na2SO4, and evaporated. The residue was purified by flash
chromatography (hexane/ethyl acetate¼4/1) to afford 14c
(12.7 mg, 27%, a single isomer) and 14o (29.6 mg, 63%)
as white solids.
Compound 15o: mp¼139–140 ꢁC (CH2Cl2/hexane); [a]2D6
ꢀ34.5 (c 1.00, CHCl3); IR (KBr) nmax: 2241, 1445, 1136,
1
877, 723 cmꢀ1; H NMR (400 MHz, CDCl3): d¼6.91 (s,
2H), 3.63 (s, 3H), 3.42–3.32 (m, 1H), 2.89 (dd, J¼3.7,
16.8 Hz, 2H), 2.75–2.50 (m, 8H, including d¼2.60, s, 6H),
2.45–2.20 (m, 4H, including d¼2.30, s, 3H), 2.00–1.85 (m,
1H); 13C NMR (100 MHz, CDCl3): d¼166.6, 142.5, 140.0,
135.4, 131.7, 118.5, 114.7, 57.9, 40.2, 28.8, 25.6, 23.5,
22.4, 20.9; HRMS (FAB): m/z calcd for C17H21NO3S+H
320.1320, found 320.1335.
4.1.4. 1-(1-Naphthalenesulfonyl)-5-hexen-2-one. To a
solution of methyl 1-naphthyl sulfone (347.0 mg,

H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
8059
1.68 mmol) in THF (10 mL) was added n-butyllithium in
hexane (2.12 mL, 3.36 mmol) at 0 ꢁC and the reaction
mixture was stirred at 0 ꢁC for 15 min. Then to the reaction
mixture was added ethyl 4-pentenoate (227 mg, 1.77 mmol)
at 0 ꢁC, and the stirring was continued for 30 min. The reac-
tion mixture was quenched with saturated aqueous NH4Cl
solution (30 mL) and extracted with ether (5 mLꢂ2). The
combined organic layer was washed with brine (5 mL), dried
over Na2SO4, and evaporated. The residue was purified by
flash chromatography (hexane/ethyl acetate¼6/1) to afford
1-(1-naphthalenesulfonyl)-5-hexen-2-one (461 mg, 95%)
as a white solid.
18.2 mmol) was added to the reaction mixture at the same
temperature. After 1 h, the reaction mixture was quenched
with saturated aqueous NH4Cl solution (60 mL) and ex-
tracted with ether (10 mLꢂ2). The combined organic layer
was washed with brine (5 mL), dried over Na2SO4, and evap-
orated. The residue was purified by flash chromatography
(hexane/ethyl acetate¼4/1) to afford 1-(2,4-dimethylphenyl-
sulfonyl)-5-hexen-2-one (3.56 g, 80%) as a white solid.
Mp¼33–34 ꢁC (CH2Cl2/hexane); IR (KBr) nmax: 1684, 1462,
1
884, 770 cmꢀ1; H NMR (400 MHz, CDCl3): d¼7.79 (d,
J¼8.5 Hz, 1H), 7.15 (d, J¼8.5 Hz, 1H), 7.14 (s, 1H), 5.74
(ddt, J¼10.5, 17.1, 6.6 Hz, 1H), 5.02 (dd, J¼1.5, 17.1 Hz,
1H), 4.97 (dd, J¼1.5, 10.5 Hz, 1H), 4.16 (s, 2H), 2.80 (t,
J¼7.1 Hz, 2H), 2.63 (s, 3H), 2.37 (s, 3H), 2.28 (dt, J¼6.6,
7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): d¼197.2,
145.0, 137.7, 136.0, 133.8, 133.4, 130.1, 127.1, 115.5,
66.2, 43.3, 27.0, 21.3, 20.2; HRMS (FAB): m/z calcd for
C14H18O3S+H 267.1055, found 267.1057.
Mp¼37.5–37.6 ꢁC (CH2Cl2/hexane); IR (KBr) nmax: 1660,
1
1507, 1316, 1157, 1127, 768 cmꢀ1; H NMR (400 MHz,
CDCl3): d¼8.62 (d, J¼8.7 Hz, 1H), 8.20 (d, J¼7.3 Hz,
1H), 8.10 (d, J¼8.3 Hz, 1H), 7.93 (d, J¼8.3 Hz, 1H), 7.66
(dd, J¼8.7, 8.3 Hz, 1H), 7.58 (dd, J¼7.3, 8.3 Hz, 1H), 7.54
(dd, J¼8.3, 8.3 Hz, 1H), 5.67 (ddt, J¼10.4, 17.0, 6.6 Hz,
1H), 4.94 (dd, J¼1.5, 17.0 Hz, 1H), 4.91 (dd, J¼1.5,
10.4 Hz, 1H), 4.26 (s, 2H), 2.75 (t, J¼7.1 Hz, 2H), 2.32 (dt,
J¼6.6, 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d¼196.9, 136.0, 135.8, 134.1, 133.7, 131.0, 129.4, 129.0,
128.5, 127.1, 124.3, 123.5, 115.7, 66.4, 43.7, 27.2; HRMS
(FAB): m/z calcd for C16H16O3S+H 289.0898, found
289.0901. Anal. Calcd for C16H16O3S: C, 66.64; H, 5.59;
S, 11.12. Found: C, 66.71; H, 5.65; S, 11.36.
4.1.7. 1-Diazo-1-(2,4-dimethylphenylsulfonyl)-5-hexen-
2-one (5 (Ar¼Xy)). To a solution of 1-(2,4-dimethylphenyl-
sulfonyl)-5-hexen-2-one (3.56 g, 13.4 mmol) in CH3CN
(150 mL) was added triethylamine (4.47 mL, 32.1 mmol)
at 0 ꢁC, and then a solution of p-toluenesulfonyl azide
(3.16 g, 16.0 mmol) in CH3CN (15 mLꢂ2) was added via
a canula. The reaction mixture was stirred at room tempera-
ture for 8 h. The light yellow reaction mixture was concen-
trated under reduced pressure and diluted with ether
(300 mL). To the ether solution was added 1 M KOH aque-
ous solution (50 mL), and the separated aqueous layer was
extracted with ether (20 mLꢂ2). The combined organic
layer was washed with brine (10 mL), dried over Na2SO4,
and evaporated. The residue was purified by flash chromato-
graphy (hexane/ethyl acetate¼15/1) to afford 5 (Ar¼Xy)
(3.27 g, 84%) as a yellow-green solid.
4.1.5. 1-Diazo-1-(1-naphthalenesulfonyl)-5-hexen-2-one
(5 (Ar¼Np)). To a solution of 1-(1-naphthalenesulfonyl)-
5-hexen-2-one (417.0 mg, 1.44 mmol) in CH3CN (10 mL)
was added triethylamine (0.482 mL, 3.47 mmol) at 0 ꢁC,
and then a solution of p-toluenesulfonyl azide (456.0 mg,
2.31 mmol) in CH3CN (1.5 mLꢂ2) via a canula. The reac-
tion mixture was stirred at room temperature for 6 h. The
light yellow reaction mixture was concentrated under re-
duced pressure and diluted with ether (100 mL). To the ether
solution was added 1 M KOH aqueous solution (10 mL), and
the separated aqueous solution was extracted with ether
(10 mLꢂ2). The combined organic layer was washed with
brine (10 mL), dried over Na2SO4, and evaporated. The resi-
due was purified by flash chromatography (hexane/ethyl
acetate¼15/1) to afford 5 (Ar¼Np) (366.0 mg, 81%) as a
yellow-green solid.
Mp¼78–79 ꢁC; IR (KBr) nmax: 2139, 1653, 1330, 923, 831,
749 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼8.00 (d,
J¼8.5 Hz, 1H), 7.21 (d, J¼8.5 Hz, 1H), 7.18 (s, 1H), 5.67
(ddt, J¼10.0, 17.2, 6.9 Hz, 1H), 4.94 (dd, J¼1.5, 17.2 Hz,
1H), 4.89 (dd, J¼1.5, 10.0 Hz, 1H), 2.56 (s, 3H), 2.55 (t,
J¼7.9 Hz, 2H), 2.41 (s, 3H), 2.24 (dt, J¼6.9, 7.9 Hz, 2H);
13C NMR (100 MHz, CDCl3): d¼188.1, 145.3, 137.2,
136.6, 136.0, 133.7, 130.3, 127.3, 115.6, 38.0, 27.4, 21.3,
19.9; HRMS (FAB): m/z calcd for C14H16N2O3S+H
293.0960, found 293.0986.
Mp¼84–86 ꢁC; IR (KBr) nmax: 1666, 1334, 1127, 768 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼8.36 (d, J¼7.6 Hz, 1H),
8.35 (d, J¼7.6 Hz, 1H), 8.09 (d, J¼8.3 Hz, 1H), 7.93 (d,
J¼8.1 Hz, 1H), 7.67 (dd, J¼7.6, 8.1 Hz, 1H), 7.59 (dd, J¼
7.6, 8.1 Hz, 1H), 7.57 (dd, J¼8.1, 8.3 Hz, 1H), 5.47 (ddt,
J¼11.2, 15.6, 6.6 Hz, 1H), 4.78 (dd, J¼1.3, 11.2 Hz, 1H),
4.76 (dd, J¼1.3, 15.6 Hz, 1H), 2.48 (t, J¼7.3 Hz, 2H), 2.11
(dt, J¼6.6, 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d¼187.6, 136.2, 135.8, 135.7, 134.3, 131.3, 129.1, 127.6,
127.2, 124.1, 123.2, 115.6, 38.1, 27.4; HRMS (FAB): m/z
calcd for C16H14N2O3S+H 315.0803, found 315.0808.
4.1.8. (1R,5R)-1-(1-Naphthalenesulfonyl)bicyclo[3.1.0]-
A
hexan-2-one (4 (Ar¼Np)).
toluene azeotroped
(CuOTf)2$C6H6 (50.0 mg, 0.110 mmol, 10 mol % as CuOTf
(90% purity)) was placed in a dried flask (100 mL) under Ar
atmosphere. To this flask was added a solution of toluene
azeotroped ligand 6d (98.0 mg, 0.331 mmol, 15 mol %) in
toluene (5 mLꢂ3) via a canula. The mixture was stirred at
room temperature for 0.5 h and then to the light blue solution
was added a solution of toluene azeotroped 5 (Ar¼Np)
(624.0 mg, 1.99 mmol) in toluene (5 mLꢂ3) via a canula.
The reaction mixture was stirred at 50 ꢁC for 5 h, quenched
with aqueous NH4OH solution (10 mL), and the separated
aqueous layer was extracted with ether (10 mL). The aque-
ous layer was further extracted with CH2Cl2 (5 mLꢂ2).
The combined organic layer was washed with brine
4.1.6. 1-(2,4-Dimethylphenylsulfonyl)-5-hexen-2-one. To
a solution of 2,4-dimethylphenyl methyl sulfone (3.05 g,
16.6 mmol) in THF (160 mL) was added n-butyllithium
(21.5 mL, 33.1 mmol) at 0 ꢁC, and the reaction mixture
was stirred at room temperature for 2 h. After cooling the
reaction mixture to 0 ꢁC again, ethyl 4-pentenoate (2.34 g,

8060
H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
(10 mL), dried over Na2SO4, and evaporated. The residue
was purified by flash chromatography (hexane/ethyl
acetate¼6/1) to afford 4 (Ar¼Np) (528.0 mg, 93%, 83% ee)
as a white solid.
(Ar¼Np) (1.36 g, 4.76 mmol) in DMSO (40 mL) was added
sodium cyanide (257.0 mg, 5.24 mmol) and the reaction
mixture was stirred at 80 ꢁC for 5 h. After the starting mate-
rial disappeared, the reaction mixture was quenched with
saturated aqueous NaHCO3 solution (40 mL), and extracted
with ethyl acetate (40 mLꢂ2). The combined organic layer
was washed with brine (8 mL), dried over Na2SO4, and
evaporated. The residue was purified by flash chromato-
graphy (hexane/ethyl acetate¼4/1) to afford 3 (Ar¼Np)
(1.41 g, 95%) as a white solid.
Enantiomeric excess (ee) was determined by HPLC
(254 nm); DAICEL CHIRALCEL OD-H (0.46 cm vꢂ
25 cm; hexane/2-propanol¼4/1; flow rate¼5 mL minꢀ1);
retention time: 42 min for 4 (Ar¼Np), 38 min for ent-4
(Ar¼Np).
Mp¼111–112 ꢁC (CH2Cl2/hexane); [a]2D3 ꢀ60.3 (c 1.00,
Mp¼137–138 ꢁC (CH2Cl2/hexane); [a]2D3 +20.0 (c 1.00,
1
CHCl3, >99% ee); IR (KBr) nmax: 1737, 1302, 1124,
;
CHCl3); IR (KBr) nmax: 1737, 1302, 1124, 763 cmꢀ1; H
763 cmꢀ1
1H NMR (400 MHz, CDCl3): d¼8.75 (d,
NMR (400 MHz, CDCl3): d¼8.62 (d, J¼8.6 Hz, 1H), 8.27
(d, J¼7.3 Hz, 1H), 8.25 (d, J¼7.3 Hz, 1H), 8.01 (d,
J¼8.3 Hz, 1H), 7.80–7.58 (m, 3H), 3.92 (d, J¼9.8 Hz,
1H), 3.50–3.32 (m, 1H), 3.08 (dd, J¼4.9, 17.1 Hz, 1H),
2.88 (dd, J¼3.9, 17.1 Hz, 1H), 2.60–2.30 (m, 3H), 1.90–
1.72 (m, 1H); 13C NMR (100 MHz, CDCl3): d¼202.4,
136.2, 134.2, 134.1, 132.4, 131.8, 129.3, 127.2, 124.3,
123.0, 116.7, 70.9, 38.6, 34.4, 25.7, 22.5, 21.9; HRMS
(FAB): m/z calcd for C17H15NO3S+H 314.0851, found
314.0857.
J¼8.8 Hz, 1H), 8.51 (d, J¼7.5 Hz, 1H), 8.12 (d, J¼8.1 Hz,
1H), 7.93 (d, J¼8.1 Hz, 1H), 7.67–7.55 (m, 3H), 3.15–
3.10 (m, 1H), 2.47 (dd, J¼3.9, 17.1 Hz, 1H), 2.18–1.94
(m, 4H), 1.58 (dd, J¼5.6, 5.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d¼202.9, 135.2, 132.8, 129.6, 129.1,
128.1, 126.6, 126.4, 124.4, 124.3, 53.5, 33.5, 31.3, 20.2,
20.0; HRMS (FAB): m/z calcd for C16H14O3S+H
287.0742, found 287.0773. Anal. Calcd for C16H14NO3S:
C, 67.11; H, 4.93; S, 11.20. Found: C, 66.13;H, 4.88;S, 11.87.
4.1.9. (1R,5R)-1-(2,4-Dimethylphenylsulfonyl)bicy-
clo[3.1.0]hexan-2-one (4 (Ar¼Xy)). A toluene azeotroped
(CuOTf)2$C6H6 (6.0 mg, 0.0132 mmol, 10 mol % as CuOTf
(90% purity)) was placed in a dried flask (20 mL) under Ar
atmosphere and to this flask was added a solution of toluene
azeotroped ligand 6e (17.0 mg, 0.397 mmol, 15 mol %) in
toluene (2 mLꢂ2) via a canula. The mixture was stirred at
50 ꢁC for 5 h and then to the blue-green solution was added
a solution of toluene azeotroped 5 (Ar¼Xy) (77.0 mg,
0.264 mmol) in toluene (2 mLꢂ2) via a canula. The reaction
mixture was stirred at 50 ꢁC for 5 h, quenched with a mixture
of saturated aqueous NH4Cl solution (2 mL) and aqueous
NH4OH solution (10 mL), and the separated aqueous layer
was extracted with ether (10 mL). The aqueous layer was
further extracted with CH2Cl2 (5 mLꢂ2). The combined
organic layer was washed with brine (10 mL), dried over
Na2SO4, and evaporated. The residue was purified by
flash chromatography (hexane/ethyl acetate¼3/1) to afford
(1R,5R)-1-(2,4-dimethylphenylsulfonyl)bicyclo[3.1.0]hexan-
2-one 4 (Ar¼Xy) (98.0 mg, 97%, 81% ee) as a white solid.
4.1.11. (1R,2R)-[2-(2,4-Dimethylphenylsulfonyl)-3-oxo-
cyclopentyl]acetonitrile (3 (Ar¼Xy)). To a solution of 4
(Ar¼Xy) (1.12 g, 4.24 mmol) in DMSO (40 mL) was added
sodium cyanide (229.0 mg, 4.66 mmol) and the reaction
mixture was stirred at 80 ꢁC for 5 h. After the starting mate-
rial disappeared, the reaction mixture was quenched with
saturated aqueous NaHCO3 solution (40 mL) and extracted
with ethyl acetate (40 mLꢂ2). The combined organic layer
was washed with brine (6 mL), dried over Na2SO4, and
evaporated. The residue was purified by flash chromato-
graphy (hexane/ethyl acetate¼2/1) to afford 3 (Ar¼Xy)
(740.0 mg, 60%) as a white solid.
Mp¼89–90 ꢁC (CH2Cl2/hexane); [a]2D3 ꢀ23.5 (c 1.14,
CHCl3); IR (KBr) nmax: 1758, 1407, 827, 742, 607 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼7.79 (d, J¼8.1 Hz, 1H),
7.18 (d, J¼8.1 Hz, 1H), 7.13 (s, 1H), 3.69 (d, J¼9.8 Hz,
1H), 3.40–3.18 (m, 1H), 2.97 (dd, J¼3.7, 17.1 Hz, 1H),
2.81 (dd, J¼1.2, 17.1 Hz, 1H), 2.62 (s, 3H), 3.02–2.30 (m,
6H, including d¼2.41, s, 3H), 1.85–1.75 (m, 1H); 13C
NMR (100 MHz, CDCl3): d¼203.9, 145.5, 138.2, 133.5,
132.7, 131.4, 127.2, 116.8, 70.8, 38.6, 34.1, 25.6, 22.2,
21.4, 20.3; HRMS (FAB): m/z calcd for C15H17NO3S+H
292.1007, found 292.1009.
Enantiomericexcess(ee)wasdeterminedbyHPLC(254 nm);
DAICEL CHIRALPAK AS-H (0.46 cm vꢂ25 cm; hexane/
2-propanol¼4/1; flow rate¼5 mL minꢀ1); retention time:
89 min for 4 (Ar¼Xy), 86 min for ent-4 (Ar¼Xy).
4.1.12. (R)-(3-Oxocyclopentyl)acetonitrile (16). To a SmI2
solution in THF, which was prepared from samarium
(1.33 g, 8.87 mmol) and 1,2-diiodoethane (1.24 g,
4.43 mmol) in THF (10 mL), was added methanol (1 mL),
and the solution was cooled to ꢀ78 ꢁC. To this cooled
Mp¼98–99 ꢁC (CH2Cl2/hexane); [a]2D7 ꢀ48.5 (c 1.00,
CHCl3, >99% ee); IR (KBr) nmax: 1686, 1035, 967,
;
810 cmꢀ1
1H NMR (400 MHz, CDCl3): d¼7.88 (d,
J¼8.1 Hz, 1H), 7.09 (d, J¼8.1 Hz, 1H), 7.03 (s, 1H),
2.96–2.90 (m, 1H), 2.58 (s, 3H), 2.34–2.23 (m, 4H, including
d¼2.30, s, 3H), 2.21–2.09 (m, 3H), 2.02–1.90 (m, 1H), 1.52
(dd, J¼5.5, 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d¼203.4, 144.3, 138.1, 133.2, 131.5, 126.9, 53.5, 33.6,
30.7, 21.4, 20.8, 20.4, 20.2; HRMS (FAB): m/z calcd for
C14H16O3S+H 265.0898, found 265.0890.
solution was added
a solution of 13 (536.0 mg,
1.77 mmol) in THF (3 mL) via a canula, and the reaction
mixture was stirred at the same temperature for 5 min. The
reaction was quenched by introducing air into the solution,
and to the resultant solution was added saturated aqueous
NH4Cl solution (10 mL) and extracted with ether
(4 mLꢂ2). The combined organic layer was washed
with brine (6 mL), dried over Na2SO4, and evaporated.
The residue was purified by flash chromatography
4.1.10. (1R,2R)-[2-(1-Naphthalenesulfonyl)-3-oxocyclo-
pentyl]acetonitrile (3 (Ar¼Np)). To a solution of 4

H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
8061
(hexane/ethyl acetate¼2/1) to afford 16 (135.0 mg, 59%) as
HRMS (FAB): m/z calcd for C20H17NO3S+H 352.1007,
found 352.1008.
a colorless oil.
[a]2D2 ꢀ70.1 (c 1.20, CHCl3); IR (neat) nmax: 1744, 1462,
(m, 7H), 1.98–1.92 (m, 1H), 1.73–1.66 (m, 1H); 13C NMR
(100 MHz, CDCl3): d¼215.9, 117.6, 43.4, 37.9, 33.1, 28.3,
22.2; HRMS (FAB): m/z calcd for C7H9NO+Na 146.0582,
found 146.0582.
4.1.14. (1R,2RS)-[2-(2,4-Dimethylphenylsulfonyl)-3-oxo-
2-(2-propynyl)cyclopentyl]acetonitrile (17c (Ar¼Xy))
and (R)-[2-(2,4-dimethylphenylsulfonyl)-3-(2-propynyl-
oxy)-2-cyclopentenyl]acetonitrile (17o (Ar¼Xy)). To a
solution of 3 (Ar¼Xy) (200.0 mg, 0.686 mmol) in DMF
(6 mL) were added potassium carbonate (142.0 mg,
1.02 mmol), sodium iodide (307.0 mg, 2.05 mmol), and
propargyl bromide (0.182 mL, 2.05 mmol) successively,
and the reaction mixture was stirred at room temperature
for 2 h. The reaction mixture was quenched with saturated
aqueous NH4Cl solution (10 mL) and extracted with ether
(5 mLꢂ2). The combined organic layer was washed with
brine (1 mL), dried over Na2SO4, and evaporated. The resi-
due was purified by flash chromatography (hexane/ethyl
acetate¼4/1) to afford 17c (Ar¼Xy) (95.0 mg, 44%, a mix-
ture of diastereomers, dr¼7/1) as a white solid and 17o
(Ar¼Xy) (112.0 mg, 52%) as a yellow oil.
1164 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d¼2.56–2.10
According to the above procedure, 16 was also obtained
from 3 (Ar¼Np, Xy) in 48% and 51% yields, respectively.
[a]2D2 ꢀ70.1 (c 1.20, CHCl3) (from 3 (Ar¼Np)).
[a]2D3 ꢀ70.0 (c 1.20, CHCl3) (from 3 (Ar¼Xy)).
4.1.13. (1R,2RS)-[2-(1-Naphthalenesulfonyl)-3-oxo-2-(2-
propynyl)cyclopentyl]acetonitrile (17c (Ar¼Np)) and
(R)-[2-(1-naphthalenesulfonyl)-3-(2-propynyloxy)-2-cy-
clopentenyl]acetonitrile (17o (Ar¼Np)). To a solution of
3 (Ar¼Np) (200.0 mg, 0.638 mmol) in DMF (6 mL) were
added potassium carbonate (132.0 mg, 0.957 mmol), so-
dium iodide (286.0 mg, 1.91 mmol), and propargyl bromide
(0.170 mL, 1.91 mmol) successively, and the reaction mix-
ture was stirred at room temperature for 2 h. The reaction
mixture was quenched with saturated aqueous NH4Cl solu-
tion (10 mL) and extracted with ether (5 mLꢂ2). The com-
bined organic layer was washed with brine (1 mL), dried
over Na2SO4, and evaporated. The residue was purified by
flash chromatography (hexane/ethyl acetate¼4/1) to afford
17c (Ar¼Np) (161.0 mg, 75%, a mixture of diastereomers,
dr¼11/1) as a white solid and 17o (Ar¼Np) as a yellow oil
(45.0 mg, 21%).
Compound 17c (Ar¼Xy): IR (KBr) nmax: 2263, 1661, 822,
767 cmꢀ1 1H NMR (400 MHz, CDCl3): major product:
;
d¼7.63 (d, J¼8.0 Hz, 1H), 7.17 (d, J¼8.0 Hz, 1H), 7.13
(s, 1H), 3.66–3.52 (m, 1H), 3.10–2.75 (m, 3H, including
d¼2.83, dd, J¼2.7, 16.5 Hz, 1H), 2.64–2.45 (m, 8H, includ-
ing d¼2.50, s, 3H), 2.41 (s, 3H), 2.10–1.90 (m, 1H); minor
product: d¼7.56 (d, J¼8.3 Hz, 1H), 7.16 (d, J¼8.3 Hz,
1H), 7.13 (s, 1H), 3.66–3.52 (m, 1H), 3.10–2.75 (m, 3H, in-
cluding d¼2.76, dd, J¼2.4, 16.5 Hz, 1H), 2.66–2.45 (m, 8H,
including d¼2.53, s, 3H), 2.41 (s, 3H), 2.10–1.90 (m, 1H);
HRMS (FAB): m/z calcd for C18H19NO3S+H 330.1164,
found 330.1177.
Compound 17o (Ar¼Xy): [a]2D3 ꢀ9.82 (c 1.15, CHCl3); IR
Compound 17c (Ar¼Np): IR (KBr) nmax: 2250, 1681, 809,
(neat) nmax: 2240, 854, 740 cmꢀ1 1H NMR (400 MHz,
;
771 cmꢀ1
;
1H NMR (400 MHz, CDCl3): major product:
CDCl3): d¼7.89 (d, J¼8.0 Hz, 1H), 7.12 (d, J¼8.0 Hz,
1H), 7.08 (s, 1H), 4.53 (dd, J¼2.4, 16.0 Hz, 1H), 4.48 (dd,
J¼2.4, 16.0 Hz, 1H), 3.30–3.20 (m, 1H), 3.02–2.85 (m,
1H), 2.80 (dd, J¼3.7, 14.6 Hz, 2H), 2.72 (dddd, J¼3.7,
3.7, 7.1, 10.0 Hz, 1H), 2.67–2.55 (m, 4H, including
d¼2.58, s, 3H), 2.52 (dd, J¼2.4, 2.4 Hz, 1H), 2.37 (s, 3H),
1.90 (dddd, J¼3.7, 7.8, 9.0, 10.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d¼165.8, 143.8, 137.9, 136.5, 133.0,
129.5, 126.6, 118.2, 114.4, 76.8 (6), 76.8 (2), 58.0, 39.8,
29.0, 25.6, 23.3, 21.2, 19.9; HRMS (FAB): m/z calcd for
C18H19NO3S+H 330.1164, found 330.1171.
d¼8.78 (d, J¼8.5 Hz, 1H), 8.22 (d, J¼7.8 Hz, 1H), 8.14 (d,
J¼7.6 Hz, 1H), 7.96 (d, J¼7.8 Hz, 1H), 7.69 (dd, J¼7.6,
8.5 Hz, 1H), 7.62 (dd, J¼7.8, 8.5 Hz, 1H), 7.59 (dd, J¼7.8,
8.5 Hz, 1H), 3.70–3.58 (m, 1H), 3.10–2.90 (m, 2H), 2.83
(dd, J¼1.5, 16.3 Hz, 1H), 2.69 (dd, J¼1.5, 16.3 Hz, 1H),
2.60–2.40 (m, 3H), 2.10–1.90 (m, 2H); minor product:
d¼8.78 (d, J¼8.5 Hz, 1H), 8.22 (d, J¼7.8 Hz, 1H), 8.14 (d,
J¼7.6 Hz, 1H), 8.00 (d, J¼7.8 Hz, 1H), 7.69 (dd, J¼7.6,
8.5 Hz, 1H), 7.62 (dd, J¼7.8, 8.5 Hz, 1H), 7.59 (dd, J¼7.8,
8.5 Hz, 1H), 3.70–3.58 (m, 1H), 3.10–2.90 (m, 2H), 2.83
(dd, J¼1.5, 16.3 Hz, 1H), 2.69 (dd, J¼1.5, 16.3 Hz, 1H),
2.60–2.40 (m, 3H), 2.10–1.90 (m, 2H); HRMS (FAB): m/z
calcd for C20H17NO3S+H 352.1007, found 352.0970.
4.1.15. (1R,2RS)-[2-(1-Naphthalenesulfonyl)-3-oxo-2-(2-
pentynyl)cyclopentyl]acetonitrile (18c) and (R)-[2-(1-
naphthalenesulfonyl)-3-(2-pentynyloxy)-2-cyclopentenyl]-
acetonitrile (18o). To a solution of 3 (Ar¼Np) (564.0 mg,
1.80 mmol) in DMF (20 mL) were added potassium car-
bonate (373.0 mg, 2.70 mmol), sodium iodide (809.0 mg,
Compound 17o (Ar¼Np): [a]2D7 +10.1 (c 1.30, CHCl3); IR
(neat) nmax: 2248, 866, 736 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d¼8.69 (d, J¼8.5 Hz, 1H), 8.34 (d, J¼7.3 Hz,
1H), 8.09 (d, J¼8.0 Hz, 1H), 7.94 (d, J¼8.0 Hz, 1H), 7.67
(dd, J¼8.0, 8.5 Hz, 1H), 7.62 (dd, J¼7.3, 7.8 Hz, 1H),
7.59 (dd, J¼7.8, 8.0 Hz, 1H), 4.52 (dd, J¼2.2, 16.3 Hz,
1H), 4.46 (dd, J¼2.2, 16.3 Hz, 1H), 3.32–3.22 (m, 1H),
2.93 (dd, J¼3.7, 16.8 Hz, 2H), 2.75–2.62 (m, 2H), 2.43
(dd, J¼2.2, 2.2 Hz, 1H), 2.29–2.18 (m, 1H), 1.94–1.82 (m,
1H); 13C NMR (100 MHz, CDCl3): d¼166.6, 136.3, 134.5,
134.0, 129.7, 128.9, 128.8, 128.1, 126.7, 124.3, 124.1,
118.2, 114.3, 76.8, 76.6, 58.1, 39.9, 29.0, 25.5, 23.4;
5.40 mmol),
and
1-bromo-2-pentyne
(0.533 mL,
5.40 mmol) successively, and the reaction mixture was
stirred at room temperature for 5 h. The reaction mixture
was quenched with saturated aqueous NH4Cl solution
(30 mL) and extracted with ether (30 mLꢂ2). The combined
organic layer was washed with brine (5 mL), dried
over Na2SO4, and evaporated. The residue was purified
by flash chromatography (hexane/ethyl acetate¼6/1) to
afford 18c (399.0 mg, 59%, a mixture of diastereomers,

8062
H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
dr¼6/1) as a white solid and 18o (243.0 mg, 36%) as a yellow
brine (5 mL), dried over Na2SO4, and evaporated. The resi-
due was purified by flash chromatography (hexane/ethyl
acetate¼4/1) to afford 19 (101.0 mg, 100%, a mixture of
diastereomers, dr¼4/1) as a colorless oil.
oil.
Compound 18c: IR (KBr) nmax: 2921, 1662, 1508, 1309,
1
1123, 808, 770 cmꢀ1; H NMR (400 MHz, CDCl3): major
1
product: d¼8.79 (d, J¼8.8 Hz, 1H), 8.20 (d, J¼8.1 Hz,
1H), 8.13 (d, J¼7.6 Hz, 1H), 7.95 (d, J¼7.8 Hz, 1H), 7.66
(dd, J¼7.6, 8.8 Hz, 1H), 7.62 (dd, J¼7.6, 8.1 Hz, 1H),
7.60 (dd, J¼7.6, 7.8 Hz, 1H), 3.67–3.56 (m, 1H), 3.08–
2.85 (m, 2H), 2.81 (dd, J¼2.4, 16.1 Hz, 1H), 2.65 (dd,
J¼2.2, 16.1 Hz, 1H), 2.58–2.40 (m, 3H), 2.10–1.70 (m,
3H), 1.01 (t, J¼7.3 Hz, 3H); minor product: d¼8.79 (d,
J¼8.8 Hz, 1H), 8.20 (d, J¼8.1 Hz, 1H), 8.13 (d, J¼7.6 Hz,
1H), 8.00 (d, J¼7.8 Hz, 1H), 7.66 (dd, J¼7.6, 8.8 Hz, 1H),
7.62 (dd, J¼7.6, 8.1 Hz, 1H), 7.60 (dd, J¼7.6, 7.8 Hz,
1H), 3.67–3.56 (m, 1H), 3.08–2.85 (m, 2H), 2.81 (dd,
J¼2.4, 16.1 Hz, 1H), 2.65 (dd, J¼2.2, 16.1 Hz, 1H), 2.58–
2.40 (m, 3H), 2.10–1.70 (m, 3H), 1.00 (t, J¼7.3 Hz, 3H);
HRMS (FAB): m/z calcd for C22H21NO3S+H 380.1320,
found 380.1316.
IR (neat) nmax: 1748, 1560, 1462, 1324, 1154 cmꢀ1; H
NMR (400 MHz, CDCl3): major product: d¼2.83 (dd,
J¼4.4, 17.1 Hz, 1H), 2.70 (dd, J¼6.8, 17.1 Hz, 1H), 2.61
(ddt, J¼4.4, 17.1, 2.4 Hz, 1H), 2.57–1.99 (m, 8H), 1.78–
1.68 (m, 1H), 1.09 (t, J¼7.6 Hz, 3H); minor product: d¼
2.83 (dd, J¼4.4, 17.1 Hz, 1H), 2.66 (dd, J¼7.1, 17.1 Hz,
1H), 2.61 (ddt, J¼4.4, 17.1, 2.4 Hz, 1H), 2.57–1.99 (m,
8H), 1.78–1.68 (m, 1H), 1.10 (t, J¼7.6 Hz, 3H); HRMS
(FAB): m/z calcd for C12H15NO+H 190.1232, found
190.1236.
4.1.18. (1R,2RS,Z)-[3-Oxo-2-(2-pentenyl)cyclopentyl]-
acetonitrile (20). A mixture of 19 (57.0 mg, 0.301 mmol,
a mixture of diastereomers) and a catalytic amount of
Lindlar’s catalyst in MeOH (3 mL) was stirred under an
atmosphere of hydrogen. After 3 h, the mixture was filtered
through Celite, and the residue was washed with ether. The
combined filtrate was concentrated under reduced pressure,
and the resulting oil was purified by flash chromatography
(hexane/ethyl acetate¼4/1) to afford 20 (52.0 mg, 90%, a
mixture of diastereomers at the C-2 position) as a colorless oil.
Compound 18o: [a]D26 ꢀ17.6 (c 1.00, CHCl3); IR (neat) nmax
:
2934, 1507, 1349, 1122, 1021, 928, 776 cmꢀ1; H NMR
(400 MHz, CDCl3): d¼8.73 (d, J¼8.3 Hz, 1H), 8.33 (d,
J¼7.3 Hz, 1H), 8.07 (d, J¼8.3 Hz, 1H), 7.91 (d, J¼7.9 Hz,
1H), 7.65 (dd, J¼7.3, 8.6 Hz, 1H), 7.57 (dd, J¼8.3,
8.6 Hz, 1H), 7.55 (dd, J¼7.9, 8.3 Hz, 1H), 4.48 (dt,
J¼15.6, 2.0 Hz, 1H), 4.43 (dt, J¼15.6, 2.1 Hz, 1H), 3.70–
3.20 (m, 1H), 2.95–2.80 (m, 2H, including d¼2.82, dd,
J¼3.7, 16.1 Hz, 1H), 2.75–2.60 (m, 2H), 2.30–2.20 (m,
3H), 1.95–1.80 (m, 1H), 1.02 (t, J¼7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d¼167.5, 136.7, 134.5, 134.1, 129.8,
129.0, 128.9, 128.1, 126.7, 124.6, 124.2, 118.4, 113.6,
91.0, 72.7, 59.1, 40.0, 29.2, 25.7, 23.5, 13.3, 12.3; HRMS
(FAB): m/z calcd for C22H21NO3S+H 380.1320, found
380.1346.
1
1
IR (neat) nmax: 1742, 1652, 1464, 1288, 1154 cmꢀ1; H
NMR (400 MHz, CDCl3): major product: d¼5.60–5.47 (m,
1H), 5.31–5.21 (m, 1H), 2.70 (dd, J¼4.4, 17.1 Hz, 1H),
2.51–1.97 (m, 10H), 1.75–1.61 (m, 1H), 0.96 (t, J¼7.6 Hz,
3H); minor product: d¼5.60–5.47 (m, 1H), 5.31–5.21 (m,
1H), 2.66 (dd, J¼4.4, 17.1 Hz, 1H), 2.51–1.97 (m, 10H),
1.75–1.61 (m, 1H), 0.97 (t, J¼7.5 Hz, 3H); HRMS (FAB):
m/z calcd for C12H17NO+H 192.1388, found 192.1397.
4.1.19. (L)-Methyl jasmonate. To a solution of 20
(30.0 mg, 0.157 mmol, a mixture of diastereomers at C-2 po-
sition) in ethylene glycol (2 mL) was added KOH (35.0 mg,
0.627 mmol), and the mixture was stirred at 80 ꢁC for 12 h.
After cooling to room temperature, the reaction mixture
was quenched with water (2 mL) and extracted with
CH2Cl2 (2 mLꢂ3). The aqueous layer was acidified with
2 M HCl (1 mL) and was extracted with CH2Cl2
(2 mLꢂ3). The combined organic layer was washed with
brine (1 mL), dried over Na2SO4, and evaporated. The resi-
due was dissolved in acetone (3 mL), and to this solution
were added potassium carbonate (32.0 mg, 0.235 mmol)
and methyl iodide (0.029 mL, 0.471 mmol). The reaction
mixture was refluxed for 5 h. After cooling to room temper-
ature, the reaction mixture was quenched with saturated
aqueous NH4Cl solution (2 mL) and extracted with ether
(3 mLꢂ2). The combined organic layer was washed with
brine (1 mL), dried over Na2SO4, and evaporated. The resi-
due was purified by flash chromatography (hexane/ethyl
acetate¼4/1) to afford (ꢀ)-methyl jasmonate (35.0 mg,
88%, two steps) as a colorless oil.
4.1.16. (1R,2R)-[2-(1-Naphthalenesulfonyl)-3-oxocyclo-
pentyl]acetonitrile (3 (Ar¼Np)). To a solution of 18o
(100.0 mg, 0.264 mmol) in 5% H2O/MeOH (methanol
including 5% H2O, 3.0 mL) was added PPTS (10.0 mg,
0.026 mmol) and the reaction mixture was stirred at room
temperature for 12 h. The reaction mixture was quenched
with saturated aqueous NH4Cl solution (5 mL) and extracted
with ether (5 mLꢂ2). The combined organic layer was
washed with brine (5 mL), dried over Na2SO4, and evapo-
rated. The residue was purified by flash chromatography
(hexane/ethyl acetate¼4/1) to afford 3 (Ar¼Np) (81.0 mg,
98%) as a white solid.
4.1.17. (1R,2RS)-[3-Oxo-2-(2-pentynyl)cyclopentyl]-
acetonitrile (19). To a suspension of samarium chip
(402.0 mg, 2.68 mmol) in THF (3.0 mL) was added a
solution of 1,2-diiodoethane (377 mg, 1.34 mmol) in THF
(2 mL) via a canula at room temperature, and the reaction
mixture was stirred at this temperature for 2 h. To the
resultant SmI2 solution in THF was added methanol
(0.4 mL) at ꢀ78 ꢁC, and then a solution of 18c (203.0 mg,
0.535 mmol) in THF (2 mL). The reaction mixture was
stirred at this temperature for 5 min. After air was bubbled
into the solution, the reaction was quenched with saturated
aqueous NH4Cl solution (5 mL) and extracted with ether
(5 mLꢂ2). The combined organic layer was washed with
[a]2D3 ꢀ90.2 (c 1.03, MeOH); IR (neat) nmax: 1738, 1438,
1
1198, 1164 cmꢀ1; H NMR (400 MHz, CDCl3): d¼5.48–
5.41 (m, 1H), 5.29–5.22 (m, 1H), 3.69 (s, 3H), 2.74–2.67
(m, 1H), 2.42–2.01 (m, 9H), 1.89–1.87 (m, 1H), 1.51–1.43
(m, 1H), 0.95 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,

H. Takeda et al. / Tetrahedron 62 (2006) 8054–8063
8063
J. Org. Chem. 1982, 47, 4254–4255; (w) Kita, Y.; Segawa, J.;
Haruta, J.; Yasuda, H.; Tamura, Y. J. Chem. Soc., Perkin
Trans. 1 1982, 1099–2104; (x) Stevens, R. V.; Hrib, N.
Tetrahedron Lett. 1981, 22, 4791–4794; (y) Matsuda, I.;
Murata, S.; Izumi, Y. J. Org. Chem. 1980, 45, 237–240; (z)
Naoshima, Y.; Nishimoto, K.; Wakabayashi, S.; Hayashi, S.
Agric. Biol. Chem. 1980, 44, 687–688; (aa) Naef, F.;
Decorzant, R. Helv. Chim. Acta 1978, 61, 2524–2529; (bb)
Kondo, K.; Takahatake, Y.; Sugimoto, K.; Tunemoto, D.
Tetrahedron Lett. 1978, 10, 907–910; (cc) Torii, S.; Tanaka,
H.; Kobayasi, Y. J. Org. Chem. 1977, 42, 3473–3477; (dd)
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CDCl3): d¼219.0, 172.6, 134.1, 124.9, 54.1, 51.6, 38.8,
38.1, 37.8, 27.2, 25.6, 20.6, 14.1; HRMS (FAB): m/z calcd
for C13H20O3+H 225.1491, found 225.1465.
Acknowledgements
We thank the Material Characterization Central Laboratory,
Waseda University, for technical support of the X-ray crys-
tallographic analysis. This work was financially supported
in part by a Waseda University Grant for Special Research
Projects and a Grant-in-Aid for Scientific Research on Prior-
ity Areas (Creation of Biologically Functional Molecules
(No. 17035082)) from The Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. We are
also indebted to 21COE ‘Practical Nano-Chemistry’.
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16. The ratio was determined by 1H NMR.