Studies on Instructive Construction of exo-Olefin Terminated Five- and Six-Membered Nitrogen Heterocycles: SmI2-Mediated Intramolecular Cyclization of Haloalkynals

Article abstract of DOI:10.1021/acs.joc.8b01440

Stereoselective construction of exo-olefin terminated pyrrolidine and piperidine frameworks was developed by employing SmI₂-mediated intramolecular radical cyclization of haloalkynaks. The radical cyclization affording 2,3-disubstituted pyrrolidines and piperidines proceeded in a highly stereoselective manner. However, decreasing stereoselectivety was observed in the preparation of 2,4-disubstituted pyrrolidine and 3,4-disubstituted piperidine derivatives in the cyclization.

Full text of DOI:10.1021/acs.joc.8b01440

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Note
Studies on Instructive Construction of exo-Olefin
Terminated 5- and 6-Membered Nitrogen Heterocycles:
SmI2-Mediated Intramolecular Cyclization of Haloalkynals
Kazunori Takahashi, Kei Fukushima, Marina Seto, Azusa
Togashi, Yuichi Arai, Masayoshi Tsubuki, and Toshio Honda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01440 • Publication Date (Web): 25 Jul 2018
Downloaded from http://pubs.acs.org on July 25, 2018
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Studies on Instructive Construction of exo-Olefin Terminated
5- and 6-Membered Nitrogen Heterocycles:
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SmI2-Mediated Intramolecular Cyclization of Haloalkynals
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Kazunori Takahashi*, Kei Fukushima, Marina Seto, Azusa Togashi, Yuichi Arai,
Masayoshi Tsubuki, Toshio Honda
Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo
142-8501, Japan
anti
X
anti
OH
X
Br
OH
(Z)
R
R
CHO
SmI2
n = 1
SmI2
n = 0
(Z)
n
N
R
N
N
X = Br
X = Br, Cl
anti:syn= >95 : 5
Ts
Ts
Ts
anti:syn= 68:32
X = Br, Cl
ABSTRACT： Stereoselective construction of exo-olefin terminated pyrrolidine and piperidine
frameworks was developed by employing SmI2-mediated intramolecular radical cyclization of
haloalkynaks. The radical cyclization affording 2,3-disubstituted pyrrolidines and piperidines
proceeded in a highly stereoselective manner. On the other hand, the decreasing stereoselectivety
was observed in preparation of 2,4-disubstituted pyrrolidine and 3,4-disubstituted piperidine
derivatives in the cyclization.
Naturally occurring alkaloids with a wide range of interesting and important biological
activities, have been recognized as promising lead molecules for the discovery of
potent compounds of therapeutic agents.1,2 Moreover, the structural diversity of these
molecules has attracted extensive attention of many organic chemists, and a great deal of efforts
have been made to develop new and efficient synthetic methodologies for these compounds.
Since pyrrolidine and piperidine nuclei have been identified in a large class of alkaloids with
diverse biological activities, we have been interested in the development of novel synthetic
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strategies for constructing a pyrrolidine skeleton bearing an exo-bromomethylene functionality,
stereoselectively, where 2,3-trans or cis disubstituted pyrrolidines with the desired
stereochemistry were constructed by trivial structural manipulation of the starting materials
(Figure 1).
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tBu
CO2
H
N
N
O
N
iBu
OH
H
HO
MeO
O
N
NH2
NH
O
NHBz
barmumycin
lucentamycin A
MeO H
O
N
Me
CO2
H
H
N
N
H
CO2
O
O
N
H
eleganine A
calophyline A
Figure 1. Structures of pyrrolidine alkaloids.
It has been well-recognized that the exo-halomethylene moiety plays important roles in further
chemical transformations; such as transition metal-catalyzed coupling reaction3 to introduce a
variety of functionalities, stereoselective hydrogenation,4 asymmetric epoxidation5 and so on.
Thus, exploitation of new methods for constructing an exo-haloolefin, stereoselectively, would
be another important research subject in organic synthesis.6
1. Previous work
Br
Br
Br
O
R2
SmI2
HMPA
SmI2
H
CO2
R2
DMPU
CO2
O
R1
N
R1
ref. 9a,b
ref. 9c
N
N
H
Ts
Ts
Ts
2. This work
X
X
Br
OH
(Z)
OH
R
CHO
R
SmI2
SmI2
(Z)
n
R
no HMPA
n = 1
no HMPA
n = 0
N
N
N
Ts
Ts
Ts
X = Br or Cl
Scheme 1. SmI2-Mediated radical cyclization.
SmI2-Mediated intramolecular radical cyclization of alkynes with aldehydes or ketones has
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already been reported to provide the corresponding exo-olefins. However, the stereochemistry of
exo-olefin of the generated heterocyclic or carbocyclic compounds is usually observed as
(E)-form with poor selectivity. Moreover, it is essential to execute this type of cyclization at low
temperature to obtain the products in high diastereoselectivity.7
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Recently, we have reported a stereoselective synthesis of 5-membered carbocyclic and
heterocyclic compounds with an exo-olefin functionality by means of SmI2-mediated
intramolecular cyclization8 of bromoalkynes possessing α,β-unsaturated esters in the same
molecules, where the stereogenic centers of the 2,3-positions and the geometry of the exo-olefin
could be successfully controlled (Scheme 1). As part of our ongoing work with SmI2-mediated
cyclization of alkyne derivatives9 in connection with alkaloid synthesis, we describe herein the
construction of pyrrolidine and piperidine rings with exo-olefin moieties by utilizing an
intramolecular radical cyclization of haloalkynes with aldehydes.
Table 1. Attempted optimization of SmI2-mediated radical cyclization.
Br
Br
Br
DIBAL-H, solvent
Me
OH
–78 °C
CO2
CHO
SmI
2 (5 equiv)
then
proton source
N
N
N
0 °C
Ts
Ts
Ts
1a
2a
3a
entry
solvent
proton source (equiv) 2 steps yield (%)
1a
2a
3a
4
72
70
73
HFIP (5)
MeOH (5)
iPrOH (5)
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
HFIP (10)
tBuOH (10)
MeOH (10)
iPrOH (10)
iPrOH (5)
33
54
69
73
57
5
6
7
8
toluene
9
iPrOH (20)
67
with DIBAL-H/ SmI was two-step synthesis.
a. The reaction of
1a
2
To the aldehyde
in THF solution were added proton source and SmI
.
2a
2
First, preparation of the key bromoalkynal 2a and subsequent formation of a pyrrolidine ring, by
two-step sequence, was investigated as follows (Table 1). Reduction of ester 1a with DIBAL-H at
–78 ºC in CH2Cl2 gave the crude aldehyde, which, however, was found to be unstable in SiO2
chromatographic conditions, and 2a could not be isolated in pure form, unfortunately. Therefore,
the subsequent radical cyclization was conducted without further purification of 2a to obtain 3a
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in reasonably good yield. Moreover, for the work-up of the reduction, we decided to treat the
5
6
i
crude products with alcohol-based proton source, such as HFIP, MeOH, and PrOH, since the
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expected aldehydes appeared to be acid-labile, even by purification with column chromatography
on silica gel.
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Thus, treatment of the reduction products with alcohol-based proton sources, HFIP, MeOH,
and iPrOH, in CH2Cl2, and subsequent SmI2-mediated radical cyclization afforded the desired
pyrrolidine 3a in 72, 70, and 73% yields, respectively, as the sole stereoisomer (entries 1, 2, 3).
Although the above mentioned two-step synthesis of 3a proceeded in fairly good yields, we
thought that DIBAL-H reduction and subsequent radical cyclization can be carried out in a single
pot for increasing the yield of 3a. By screening of a proton source (entries 4-9) in the one-pot
reaction, the use of iPrOH afforded the desired product 3a in 73% yield (entry 7). The
stereochemistry of the alkene moiety in 3a was determined by analysis of its nOe spectrum.
Finally, the best reaction condition for the one-pot reaction sequence was established by
changing the solvent from CH2Cl2 to toluene. As a practical manner, treatment of
chloroalkyne-ester 1b with DIBAL-H (1.3 equiv) in toluene, followed by exposure of the crude
product to SmI2 (5 equiv) in the presence of iPrOH (10 equiv) afforded 3b in 93% yield over 2
steps as the sole product with (Z)-configuration (Table 2). On the other hand, the reaction of
iodoalkyne (1k) under the same reaction conditions as for 1b afforded the cyclization products
(Z-3c) and (E-3c) in 19 and 19% yields, respectively. Moreover, (Z)-selectivity for the resulting
alkene moiety was found to decrease (E:Z= 1:1), remarkably. Due to the low yield and poor
selectivity observed in the reaction of iodoalkyne, the use of bromoalkynes, as starting materials,
was greatly preferable for this type of cyclization.
Table 2. Reduction of ester 1 with DIBAL-H and radical cyclization of 2.
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X
X
DIBAL-H
X
OH
SmI2
5
6
7
8
toluene
R
CO2R'
R
R
CHO
(5 equiv)
–78 °C
0 °C
n N
m
m
n N
Ts
1b- k
n N
m
iPrOH
Ts
Ts
;
3b- k
2b- k
(10 equiv)
n = 1,2
m = 0,1
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anti: syn
Product
X
R
yield (%)
X
OH
3b
93
38a
Cl
R = H
R = H
3c
I
N
Ts
Br
>95:5
>95:5
3d
3e
Br
Br
73
62
R = CH3
R = Bn
OH
R
>95:5
>95:5
3f
Br
Br
77
31
R = CH
2OTBS
N
3g
R = iPr
Ts
Br
OH
R
3h
3i
Br
Br
76b
73b
R = H
R = CH3
68:32
N
Ts
Br
OH
R = H
R = CH3
80b
23b
3j
3k
Br
Br
100:0
N
R
Ts
a. Isolated
in 19% and
in 19% yields, respectively.
-3c
-3c
E
Z
b. MeOH instead of iPrOH was used as a proton source.
The similar reaction for amino acid derivatives 1d–g also gave 2,3-disubstituted pyrrolidines
3d–g in moderate yields (62–77%). However, when this reaction was applied to bromoalkyne 1g,
the yield of the resulting pyrrolidine 3g decreased to only 31%. The observed low yield was due
to the over reduction of 1g with DIBAL-H to the corresponding alcohol, where the radical
cyclization expected for the subsequent 2nd step could not be brought about. It is worthwhile to
note that a similar radical cyclization of 2f with SmI2 in the presence of HMPA resulted in
decreasing of stereoselectivity (anti:syn = 78:22).
Next, we attempted to apply the aforementioned methodology to the preparation of piperidine
derivatives as follows. When iPrOH was used as a proton source under the same reaction
conditions as for the preparation of 3b, the desired cyclization product 3h could not be isolated at
all, but a small amount of aldehyde 2h was recovered. Therefore, the reaction of 1h–k was
carried out using MeOH instead of iPrOH as a proton source. The sequential reduction and
SmI2-mediated radical cyclization of 1h and 1j furnished the corresponding piperidines 3h and 3j
in 76% and 80% yields, respectively. By application of this reaction to 1i possessing a methyl
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group at the α position of the formyl function, the corresponding piperidine 3i was obtained as a
diastereomeric mixture (anti:syn = 68:32) in 73% yield. The observed low selectivity might be
explained by assuming that the 6-exo-dig mode cyclization would proceed sluggishly compared
to 5-exo-dig mode cyclization. On the other hand, the similar reaction for compound 1k having a
methyl group between the tosylamide and formyl groups gave the piperidine derivative 3k,
3-butynyltoluenesulfonamide and 4-bromo-3-butynyltoluenesulfonamide in 23, 7, and 45%
yields, respectively (Scheme 2). Formation of bromobutynyltoluenesulfonamide and
butynyltoluenesulfonamide is assumed that the transition state (B) seems to be preferred over the
weakly chelated transition state (A) in terms of the steric repulsion between sulfonamide group
and methyl group, and hence the C-N bond cleavage may occur prior to ring closing reaction of
the bromoalkyne via ketyl radical.
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Sm
Br
Br
Br
R
H
OH
O
CH3
H
OSm
N
n N
Ts
n N
Ts
n NH
Ts
CH3
CH3
Ts
3k
R = H
R = Br
A
B
(
)
(
)
n = 2
Scheme 2. Plausible reaction mechanism for C-N bond cleavage.
With the aim of increasing yields of cyclization products, an alternative preparation of the
aldehydes via Weinreb amide 4a–e,g was investigated, and the results were summarized in Table
3. Weinreb amide 4g, derived from valine, was first subjected to a one-pot reaction, and the
target compound 3g was obtained in 69% yield. When the reduction of 4g with DIBAL-H was
carried out at 0 °C, the desired pyrrolidine 3g was isolated in 36% yield after the radical
cyclization. The observed low yield was probably due to the presence of a labile bromoalkyne
functional group of 4g under DIBAL-H reduction. The same reaction of chloroalkyne 4a–d
afforded the desired pyrrolidine derivatives 6a–d in moderate yields (42–77%). By changing the
proton source from MeOH to iPrOH for DIBAL-H reduction of 4d, and subsequent radical
cyclization of the crude aldehyde furnished a small amount of the recovered aldehyde 5d and the
cyclized pyrrolidine 6d in 67% yield. When diastereoselective cyclization of 4e having a methyl
group at the propargylic position was attempted under the same reaction conditions, the
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corresponding pyrrolidine 6e was obtained as a diastereoisomeric mixture, in a ratio of anti: syn
5
6
= 50:50, in 72% yield.
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Table 3. Redical cyclization of alkynal via Weinreb amide 4.
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X
X
X
OMe
N
DIBAL-H
(5 equiv)
OH
R2
toluene, 0 °C
O
SmI2
Me
CHO
R2
; MeOH
(30 equiv)
R1
0 °C
R1
N
R2
N
R1
N
Ts
Ts
Ts
-
-
e
e
4a-g
2f, 5a
3f, 6a
anti:syn
Product
X
R
Yield (%)
= H, R2 = iPr
69a
58
42
77
72
R1
R1
R1
R1
R1
>95:5
>95:5
>95:5
>95:5
>95:5
X
3f
Br
Cl
Cl
Cl
Cl
= H, R2 = CH
OH
R2
6a
6b
6c
6d
= H
= Bn 3
,
R2
= H R = iBu
,
2
N
Ts
= H
= iPr
,
R2
Cl
OH
= CH
= H
,
6e
R1
R2
50:50
72
Cl
3
N
Ts
with DIBAL-H was carried out at –78 °C.
a. Reduction of
4f
The plausible reaction mechanism for radical cyclization was shown in Scheme 3. At first,
Ⅱ
treatment of aldehydes with SmI2 would generate the corresponding ketyl radicals, where Sm or
Ⅲ
Sm might be coordinated to both oxygen and halogen atoms of alkynals to restrict the transition
states, and then the radial coupling reaction could proceed to provide 2,3-anti- or
2,3-syn-disubstituted pyrrolidine derivatives (if R is alkyl group). From the examination of
molecular models of conformationally capable of forming cyclic transition states (C–F),
illustrated in Scheme 3, it would be reasonable to deduce that the preferred transition state for
the radical reaction would be the envelope conformer (D) leading to 2,3-anti compound
exclusively, since the steric repulsion between the substituent R and the carbonyl oxygen would
be arisen in the transition states (E) and (F). After forming the 5-membered ring, the protonation
occurred from the convex face of the molecule to give (Z)-alkene. On the other hand, another
possible transition state (C) leading to 2,3-anti compound suffers from unfavorable
1,3-pseudodiaxial interactions between R group and the hydrogen depicted in Scheme 3.
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H
X
TsN
H
X
O
H
anti
O
Sm
Sm
TsN
TsN
Sm
H
R
H
R
(D)
(F)
(C)
H
X
X
TsN
H
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H
H
syn
Sm
R
O
H
O
R
repulsion
(E)
Scheme 3. Plausible reaction mechanism for radical cyclization.
Deuterium-labeling experiment of bromoalkyne 1a was depicted in Scheme 4. DIBAL-H
reduction of 1a, followed by addition of CD3OD gave the crude aldehyde, which on subsequent
treatment with SmI2 afforded pyrrolidine d2-3a. The formation of pyrrolidine d2-3a incorporating
deuterium was confirmed by NMR measurement (76:24 H/D).
Br
Br
DIBAL-H, toluene
OD
D
–78 °C
Me
CO2
then MeOD
(5 equiv)
N
N
SmI2
Ts
Ts
-
0 °C
3a
d2
1a
>24% Deuterium
Scheme 4. Deuterium-labeling experiment.
Further functionalization of pyrrolidine derivative 3a was then attempted by
palladium-catalyzed coupling reaction as shown in Scheme 5. Suzuki-Miyaura coupling reaction
of bromoalkene 3a with phenylboronic acid successfully afforded (Z)-phenylalkene Z-7,
stereosecifically, in 73% yield.3b,10 In addition, Sonogashira coupling reaction of 3a with
phenylacetylene resulted in the formation of enyne 8 in 87% yield.3c,11
Ph
Ph
Br
Ph
OH
OH
OH
PhB(OH)2
Pd(PPh3 4
Pd(PPh3
2Cl2
)
)
, MeOH
N
N
N
Et3N, CuI
60 °C, 24 h
87%
K
2CO3
Ts
Ts
3a
Ts
reflux, 1.25 h
73%
7
8
(Z)-
Scheme 5. Pd-Catalyzed coupling reaction of bromoalkene 3a.
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The comparative experiment was carried out by employing phenylalkyne derivative 1l in order
to prove the importance of bromo or chloro atom in haloalkynes for the observed stereocontrol of
the exo-olefin moiety (Scheme 6). Resultantly, reduction and subsequent cyclization of 1l as
described for the preparation of 3a from 1a gave E- and Z-7 in 56% and 11% yields, respectively
(E:Z =5:1). This result supported that bromo or chloro atom of alkyne obviously contributed to
both the reactivity and stereoselectivity for the radical reaction.
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Ph
1. DIBAL-H, toluene
–78 °C; iPrOH
OH
Ph
Me
CO2
(5 equiv)
2. SmI2
toluene
N
N
0 °C, 67% (2 steps)
(E:Z = 5:1)
Ts
-7
Ts
E
1l
Scheme 6. SmI2-Mediated cyclization of phenylalkyne 1k.
In conclusion, we have developed SmI2-mediated cyclization of haloalkynals leading to 5- and
6-membered heterocycles possessing an exo-haloolefin with (Z)-configuration. Particularly, the
reaction of haloalkynal furnishing 2,3-disubstituted pyrrolidines was proved to proceed with high
diastereoselectivity. The methodology developed here would provide an alternative efficient
route to the construction of pyrrolidine and piperidine skeletons observed in a variety of
naturally occurring nitrogen-heterocycles, and the synthesis of natural products along this line is
under investigation.
EXPERIMENTAL SECTION
General Methods and Materials: Melting points were measured with a Yanaco MP-500P
apparatus and are uncorrected. Optical rotations were measured with JASCO DIP-360 or P-2200.
IR spectra were obtained using a JASCO FT/IR-4100, Shimadzu IRPrestige-21 or PerkinElmer
1
Spectrum Two spectrophotometer. H- and 13C-NMR spectra were obtained on a Bruker AV Ⅲ
400 (1H-NMR: 400 MHz, 13C-NMR: 100 MHz) or JEOL ECA-600 (1H-NMR: 600 MHz,
13C-NMR: 150 MHz) instrument for solutions in CDCl3, and chemical shifts are reported on the δ
1
scale using TMS as an internal standard of 0.00 for H-NMR spectra and CDCl3 as an internal
standard of δ 77.00 for 13C-NMR spectra, respectively. MS spectra were measured with a
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JEOL-600 (EI, CI) or JMS-T100LP (ESI) spectrometer. Elemental analyses were performed on a
Yanaco-MT5.
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General procedure for alkylation of sulfonamide.9a Methyl 3-(4-methyl-N-(prop-2-ynyl)-
phenylsulfonamido)propanoate (1h’). To a solution of N-tosyl-β-alanine methyl ester12 (2.5 g,
9.3 mmol) and propargyl bromide (1.7 g, 14.3 mmol) in CH3CN (39 mL) were added K2CO3 (3.8
g, 27.5 mmol) and nBu4NI (683.0 mg, 1.9 mmol) at ambient temperature. After stirring for 3 h at
70 °C, the reaction mixture was diluted with AcOEt, and filtered through Celite. The volatile
solvent was removed in vacuo. The residue was purified by column chromatography on silica gel
using hexane-AcOEt-CHCl3 (9:2:9, v/v) as eluent to give alkyne 1h’ (2.72 g, 99%) as a colorless
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solid; Mp 45−46 °C; IR ν max 3276, 1737, 1161 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.74 (2H, d,
J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 4.17 (2H, d, J = 2.5 Hz), 3.69 (3H, s), 3.49 (2H, t, J = 7.3
Hz), 2.71 (2H, t, J = 7.3 Hz), 2.43 (3H, s), 2.06 (1H, t, J = 2.5 Hz); 13C-NMR (CDCl3; 100 MHz)
δ 171.6, 143.7, 135.4, 129.5 (2), 127.6 (2), 76.6, 73.8, 51.7, 42.6, 37.5, 33.6, 21.4; HRMS (CI,
magnetic sector) m/z: [M+H]+ Calcd for C14H18NO4S 296.0956; Found 296.0964. Anal. Calcd for
C14H17NO4S: C, 56.93; H, 5.80; N, 4.74. Found: C, 56.87; H, 5.89; N, 4.66.
Methyl
2-methyl-3-(4-methyl-N-(prop-2-ynyl)phenylsulfonamido)propanoate
(1i’).
Alkylation of methyl 2-methyl-3-(4-methylphenylsulfonamido)propanoate12 (619.3 mg, 2.29
mmol) was carried out according to the same procedure as described for 1h’ to give alkyne 1i’
(569.2 mg, 81%) as a colorless solid [eluent: hexane-AcOEt (1:1, v/v)]; Mp 76−78 °C; IR ν max
1
1735, 1350, 1163 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.72 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J =
8.2 Hz), 4.18 (1H, dd, J = 18.6, 2.5 Hz), 4.10 (1H, dd, J = 18.6, 2.5 Hz), 3.69 (3H, s), 3.41 (1H,
dd, J = 14.0, 7.8 Hz), 3.23 (1H, dd, J = 14.0, 6.9 Hz), 2.93-2.84 (1H, m), 2.42 (3H, s), 2.01 (1H, t,
J = 2.5 Hz), 1.21 (3H, d, J = 7.1 Hz); 13C-NMR (CDCl3; 100 MHz) δ 174.9, 143.6, 135.3, 129.4
(2), 127.7 (2), 76.3, 73.9, 51.8, 49.1, 38.8, 37.5, 21.4, 14.9; HRMS (CI, magnetic sector) m/z:
[M+H]+ Calcd for C15H20NO4S 310.1113; Found 310.1133. Anal. Calcd for C15H19NO4S: C,
58.23; H, 6.19; N, 4.53. Found: C, 58.07; H, 6.18; N, 4.44.
(S)-N-Methoxy-N-methyl-2-(4-methyl-N-(prop-2-ynyl)phenylsulfonamido)propanamide
(4a’). Alkylation of (S)-N-methoxy-N-methyl-2-(4-methylphenylsulfonamide)propanamide13
(3.38 g, 11.81 mmol) was carried out according to the same procedure as described for 1h’ to
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give alkyne 4a’ (3.83 g, 92%) as a colorless solid [eluent: hexane-AcOEt-CHCl3 (1:2:2, v/v)];
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Mp 80−82 °C; [α]D = −38.22 (c 0.9, CHCl3); IR ν max 1668, 1343, 1158 cm−1; 1H-NMR
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8
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(CDCl3; 400 MHz) δ 7.78 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 5.03 (1H, q, J = 7.2 Hz),
4.49 (1H, dd, J = 17.2, 2.5 Hz), 4.39 (1H, dd, J = 17.2, 2.5 Hz), 3.76 (3H, s), 3.12 (3H, s), 2.42
(3H, s), 2.17 (1H, t, J = 2.5 Hz), 1.40 (3H, d, J = 7.2 Hz); 13C-NMR (CDCl3; 100 MHz) δ 172.2,
143.5, 136.9, 129.4 (2), 127.4 (2), 80.6, 71.9, 61.5, 50.8, 33.6, 31.8, 21.4, 16.0; HRMS (CI,
magnetic sector) m/z: [M+H]+ Calcd for C15H21N2O4S 325.1222; Found 325.1220. Anal. Calcd
for C15H20N2O4S: C, 55.54; H, 6.21; N, 8.64. Found: C, 55.58; H, 6.27. N, 8.57.
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(S)-N-Methoxy-N-methyl-2-(4-methyl-N-(prop-2-ynyl)phenylsulfonamido)-3-phenylpropan
amide (4b’). Alkylation of (S)-N-methoxy-N-methyl-2-(4-methylphenylsulfonamido)-3-
phenylpropanamide14 (3.11 g, 8.57 mmol) was carried out according to the same procedure as
described for 1h’ to give alkyne 4b’ (2.15 g, 63%) as
a
colorless oil [eluent:
17
hexane-AcOEt-CHCl3 (1:2:2, v/v)]; [α]D = −55.28 (c 1.1, CHCl3); IR ν max 1661, 1338, 1160
1
cm−1; H-NMR (CDCl3; 400 MHz) δ 7.73 (2H, d, J = 8.1 Hz), 7.26-7.23 (5H, m), 7.15-7.13 (2H,
m), 5.21 (1H, dd, J = 9.5, 5.3 Hz), 4.66 (1H, dd, J = 18.8, 2.5 Hz), 4.41 (1H, dd, J = 18.8, 2.5 Hz),
3.37 (3H, s), 3.28 (1H, dd, J = 13.3, 9.5 Hz), 3.00 (3H, s), 2.80 (1H, dd, J = 13.3, 5.3 Hz), 2.42
(3H, s), 2.20 (1H, t, J = 2.5 Hz); 13C-NMR (CDCl3; 100 MHz) δ 170.4, 143.5, 136.9, 136.6, 129.4
(2), 129.3 (2), 128.4 (2), 127.7 (2), 126.7, 80.3, 72.2, 61.3, 55.7, 36.6, 33.7, 31.7, 21.5; HRMS
(CI, magnetic sector) m/z: [M+H]+ Calcd for C21H25N2O4S 401.1535; Found 401.1524.
General procedure for alkylation of sulfonamide: Mitsunobu reaction.15 Methyl
2-(N-(but-3-ynyl)-4-methylphenylsulfonamido)acetate (1j’). To a solution of N-tosylglycine
methyl ester9a (249.5 mg, 1.03 mmol), 3-butyn-1-ol (86.4 mg, 1.23 mmol) and Ph3P (557.9 mg,
2.13 mmol) in THF (4.0 mL) was added DIAD (0.4 mL, 2.03 mmol) at ambient temperature.
After stirring for 5 h at the same temperature, the volatile solvent was removed in vacuo. The
residue was purified by column chromatography on silica gel using hexane-AcOEt-CHCl3
(19:4:19, v/v) as eluent to give alkyne 1j’ (292.9 mg, 97%) as a colorless solid; Mp 65−66 °C; IR
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ν max 3284, 1754, 1341, 1159 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.72 (2H, d, J = 8.2 Hz), 7.31
(2H, d, J = 8.2 Hz), 4.18 (2H, s), 3.64 (3H, s), 3.42 (2H, t, J = 7.2 Hz), 2.51 (2H, dt, J = 7.2, 2.7
Hz), 2.43 (3H, s), 1.98 (1H, t, J = 2.7 Hz); 13C-NMR (CDCl3; 100 MHz) δ 169.3, 143.6, 136.4,
129.6 (2), 127.3 (2), 81.0, 70.4, 52.2, 49.0, 47.3, 21.5, 19.2; HRMS (CI, magnetic sector) m/z:
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[M+H]+ Calcd for C14H18NO4S 296.0956; Found 296.0934. Anal. Calcd for C14H17NO4S: C,
56.93; H, 5.80; N, 4.74. Found: C, 57.06; H, 5.82; N, 4.66.
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(R)-Ethyl 2-(N-(but-3-ynyl)-4-methylphenylsulfonamido)propanoate (1k’). Alkylation of
N-tosyl-L-alanine ethyl ester16 (504.1 mg, 1.86 mmol) was carried out according to the same
procedure as described for 1j’ to give alkyne 1k’ (257.2 mg, 43%) as a colorless oil [eluent:
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hexane-AcOEt (19:1, v/v)]; [α]D = −44.74 (c 1.1, CHCl3); IR ν max 3284, 1739, 1342, 1156
cm−1; H-NMR (CDCl3; 400 MHz) δ 7.71 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 4.62 (1H,
1
q, J = 7.1 Hz), 4.01-3.91 (2H, m), 3.46 (1H, ddd, J = 15.3, 10.4, 5.2 Hz), 3.30 (1H, ddd, J = 15.3,
10.3, 5.8 Hz), 2.72 (1H, dddd, J = 16.5, 10.3, 5.2, 2.7 Hz), 2.53 (1H, dddd, J = 16.5, 10.4, 5.8,
2.7 Hz), 2.42 (3H, s), 2.00 (1H, t, J = 2.7 Hz), 1.44 (3H, d, J = 7.4 Hz), 1.12 (3H, t, J = 7.1 Hz);
13C-NMR (CDCl3; 100 MHz) δ 171.2, 143.5, 136.5, 129.4 (2), 127.3 (2), 81.1, 70.2, 61.3, 55.4,
44.4, 21.5, 21.4, 17.0, 13.9; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C16H22NO4S
324.1269; Found 324.1263.
2-(N-(But-3-yn-2-yl)-4-methylphenylsulfonamido)-N-methoxy-N-methylacetamide
(4e’).
Alkylation of 4-methylphenylsulfonamido-N-methoxy-N-methylacetamide17 (205.40 mg, 0.75
mmol) was carried out according to the same procedure as described for 1j’ to give alkyne 4e’
(163.50 mg, 67%) as a colorless oil [eluent: hexane-AcOEt (1:1, v/v)]; IR ν max 1686, 1340,
1157 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.88 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 4.68
1
(1H, dq, J = 7.1, 2.3 Hz), 4.44 (1H, d, J = 18.0 Hz), 4.11 (1H, d, J = 18.0 Hz), 3.76 (3H, s), 3.22
(3H, s), 2.43 (3H, s), 2.22 (1H, d, J = 2.3 Hz), 1.39 (3H, d, J = 7.1 Hz); 13C-NMR (CDCl3; 100
MHz) δ 169.6, 143.5, 136.3, 129.4 (2), 127.8 (2), 81.2, 73.0, 61.3, 45.8, 44.1, 32.5, 21.6, 21.5;
HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C15H21N2O4S 325.1222; Found 325.1245.
General procedure for bromination of alkynes with NBS and AgNO3.9a Methyl
2-(N-(3-bromoprop-2-ynyl)-4-methylphenylsulfonamido)acetate (1a). To a solution of methyl
2-(4-methyl-N-(prop-2-ynyl)phenylsulfonamido)acetate and N-(prop-2-ynyl)-N-tosylglycine18
(994.7 mg, 3.5 mmol) in acetone (15 mL) were added NBS (950.0 mg, 5.3 mmol) and AgNO3
(136.1 mg, 0.8 mmol) at room temperature under Ar. After stirring for 40 min at the same
temperature, the reaction was quenched with sat. NaHCO3 aqueous solution. The volatile solvent
was removed in vacuo, and the residue was dissolved in AcOEt. The organic layer was washed
with brine, dried over Na2SO4, and removed in vacuo. The residue was purified by column
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chromatography on silica gel using hexane-AcOEt-CHCl3 (9:2:9, v/v) as eluent to give
bromoalkyne 1a (1.24 g, 97%) as a colorless solid; Mp 48−50 °C; IR ν max 1753, 1162 cm−1;
1H-NMR (CDCl3; 400 MHz) δ 7.72 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 4.27 (2H, s),
4.06 (2H, s), 3.71 (3H, s), 2.44 (3H, s); 13C-NMR (CDCl3; 100 MHz) δ 168.8, 144.0, 135.6, 129.6
(2), 127.4 (2), 72.7, 52.4, 47.0, 45.8, 38.6, 21.6; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd
for C13H15BrNO4S 359.9905; Found 359.9893. Anal. Calcd for C13H14BrNO4S: C, 43.35; H,
3.92.; N, 3.89. Found: C, 43.35; H, 3.92; N, 3.81.
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(S)-Ethyl
2-(N-(3-bromoprop-2-ynyl)-4-methylphenylsulfonamido)propanoate
(1d).
Bromination of ethyl (2S)-{N-(prop-2-ynyl)toluenesulfonamido}propanoate9a (2.12 g, 5.9 mmol)
was carried out according to the same procedure as described for 1a to give alkyne 1d (2.66 g,
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99%) as a colorless oil [eluent: hexane-AcOEt-CHCl3 (2:1:2, v/v)]; [α]D = −26.63 (c 1.1,
1
CHCl3); IR ν max 1736, 1348, 1159 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.76 (2H, d, J = 8.3 Hz),
7.30 (2H, d, J = 8.3 Hz), 4.63 (1H, q, J = 7.3 Hz), 4.28 (1H, d, J = 18.7 Hz), 4.14 (1H, d, J = 18.7
Hz), 4.05 (2H, q, J = 7.2 Hz), 2.42 (3H, s), 1.44 (3H, d, J = 7.3 Hz), 1.16 (3H, t, J = 7.2 Hz);
13C-NMR (CDCl3; 100 MHz) δ 170.9, 143.5, 136.7, 129.3 (2), 127.4 (2), 75.2, 61.3, 54.7, 44.2,
34.8, 21.4, 16.0, 13.8; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C15H19BrNO4S
388.0218; Found 388.0208.
(S)-Methyl 2-(N-(3-bromoprop-2-ynyl)-4-methylphenylsulfonamido)-3-phenylpropanoate
(1e). Bromination of methyl (2S)-{N-(prop-2-ynyl)toluenesulfonamido-3- phenyl}propanoate9a
(182.3 mg, 0.49 mmol) was carried out according to the same procedure as described for 1a to
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give bromoalkyne 1e (219.3 mg, 99%) as a colorless oil [eluent: hexane-AcOEt (3:1, v/v)]; [α]D
1
= −41.18 (c 1.0, CHCl3); IR ν max 1740, 1160 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.56 (2H, d, J
= 8.4 Hz), 7.30-7.16 (7H, m), 4.82 (1H, t, J = 7.7 Hz), 4.28 (1H, d, J = 18.7 Hz), 4.22 (1H, d, J =
18.7 Hz), 3.55 (3H, s), 3.30 (1H, dd, J = 14.0, 7.7 Hz), 2.95 (1H, dd, J = 14.0, 7.7 Hz), 2.40 (3H,
s); 13C-NMR (CDCl3; 100 MHz) δ 170.4, 143.5, 136.4, 136.1, 129.1 (2), 129.1 (2), 128.4 (2),
127.5 (2), 126.7, 74.9, 60.5, 52.1, 44.6, 36.2, 34.9, 21.4; HRMS (CI, magnetic sector) m/z:
[M+H]+ Calcd for C20H21BrNO4S 450.0374; Found 450.0380.
(S)-Methyl
2-(N-(3-bromoprop-2-ynyl)-4-methylphenylsulfonamido)-3-
(1f). Bromination of methyl
(tert-butyldimethylsilyloxy)propanoate
(2S)-3-(tert-butyldimethylsilyloxy)-2-{N-(prop-2-ynyl)toluenesulfonamido}propanoate9a (1.0 g,
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2.35 mmol) was carried out according to the same procedure as described for 1a to give
bromoalkyne 1f (1.16 g, 98%) as a colorless solid [eluent: hexane-AcOEt (4:1, v/v)]; Mp
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110−111 °C; [α]D = −0.48 (c 1.1, CHCl3); IR ν max 1753, 1352, 1162 cm−1; H-NMR (CDCl3;
400 MHz) δ 7.74 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 4.66 (1H, dd, J = 5.1, 3.6 Hz),
4.37 (1H, d, J = 18.5 Hz), 4.29 (1H, d, J = 18.5 Hz), 4.07 (1H, dd, J = 10.6, 5.1 Hz), 4.01 (1H, dd,
J = 10.6 , 3.6 Hz), 3.63 (3H, s), 2.42 (3H, s), 0.84 (9H, s), 0.03 (3H, s), 0.01 (3H, s); 13C-NMR
(CDCl3; 100 MHz) δ 169.4, 143.6, 136.8, 129.4 (2), 127.5 (2), 76.2, 62.8, 60.6, 52.2, 43.0, 36.4,
25.5 (3), 21.5, 18.0, −5.8, −6.0; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for
C20H31BrNO5SSi 504.0875; Found 504.0899. Anal. Calcd for C20H30BrNO5SSi: C, 47.61; H,
5.99; N, 2.78. Found: C, 47.53; H, 5.85. N, 2.77.
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Methyl
3-(N-(3-bromoprop-2-ynyl)-4-methylphenylsulfonamido)propanoate
(1h).
Bromination of 1h’ (808.3 mg, 2.74 mmol) was carried out according to the same procedure as
described for 1a to give bromoalkyne 1h (992.0 mg, 97%) as a colorless solid [eluent:
hexane-AcOEt-CHCl3 (9:2:9, v/v)]; Mp 70−72 °C; IR ν max 2216, 1737, 1348, 1161 cm−1;
1H-NMR (CDCl3; 400 MHz) δ 7.73 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 4.17 (2H, s),
3.70 (3H, s), 3.45 (2H, t, J = 7.1 Hz), 2.68 (2H, t, J = 7.1 Hz), 2.44 (3H, s); 13C-NMR (CDCl3;
100 MHz) δ 171.4, 143.7, 134.9, 129.3 (2), 127.4 (2), 72.9, 51.6, 45.0, 42.7, 38.5, 33.5, 21.2;
HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C14H17BrNO4S 374.0061; Found 374.0086.
Anal. Calcd for C14H16BrNO4S: C, 44.93; H, 4.31; N, 3.74. Found: C, 44.65; H, 4.25; N, 3.69.
Methyl 3-(N-(3-bromoprop-2-ynyl)-4-methylphenylsulfonamido)-2-methylpropanoate (1i).
Bromination of 1i’ (298.5 mg, 0.97 mmol) was carried out according to the same procedure as
described for 1a to give bromoalkyne 1i (346.3 mg, 92%) as a colorless oil [eluent:
hexane-AcOEt (2:1, v/v)]; IR ν max 1735, 1350, 1163 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.72
1
(2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 8.3 Hz), 4.19 (1H, d, J = 18.6 Hz), 4.10 (1H, d, J = 18.6 Hz),
3.70 (3H, s), 3.36 (1H, dd, J = 14.1, 8.0 Hz), 3.19 (1H, dd, J = 14.1, 6.8 Hz), 2.91-2.82 (1H, m),
2.43 (3H, s), 1.22 (3H, d, J = 7.1 Hz); 13C-NMR (CDCl3; 100 MHz) δ 174.8, 143.7, 135.0, 129.4
(2), 127.6 (2), 72.8, 51.8, 49.4, 45.1, 38.9, 38.7, 21.4, 14.9; HRMS (CI, magnetic sector) m/z:
[M+H]+ Calcd for C15H19BrNO4S 388.0218; Found 388.0199.
Methyl 2-(N-(4-bromobut-3-ynyl)-4-methylphenylsulfonamido)acetate (1j). Bromination of
1j’ (288.3 mg, 0.98 mmol) was carried out according to the same procedure as described for 1a
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to give bromoalkyne 1j (363.3 mg, 99%) as a colorless solid [eluent: hexane-AcOEt (7:3, v/v)];
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Mp 81−83 °C; IR ν max 1755, 1341, 1158 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.72 (2H, d, J =
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8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 4.15 (2H, s), 3.65 (3H, s), 3.40 (2H, t, J = 7.2 Hz), 2.53 (2H, t,
J = 7.2 Hz), 2.43 (3H, s); 13C-NMR (CDCl3; 100 MHz) δ 169.3, 143.7, 136.4, 129.6 (2), 127.3 (2),
76.9, 52.2, 48.9, 47.1, 40.5, 21.5, 20.4; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for
C14H17BrNO4S 374.0061; Found 374.0080. Anal. Calcd for C14H16BrNO4S: C, 44.93; H, 4.31; N,
3.74. Found: C, 45.21; H, 4.49; N, 3.85.
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(R)-Ethyl
2-(N-(4-bromobut-3-ynyl)-4-methylphenylsulfonamido)propanoate
(1k).
Bromination of 1k’ (247.1 mg, 0.77 mmol) was carried out according to the same procedure as
described for 1a to give bromoalkyne 1k (283.7 mg, 92%) as a colorless oil [eluent:
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hexane-AcOEt (7:3, v/v)]; [α]D = −42.12 (c 1.1, CHCl3); IR ν max 1739, 1343, 1155 cm−1;
1H-NMR (CDCl3; 400 MHz) δ 7.70 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.2 Hz), 4.62 (1H, q, J =
7.3 Hz), 4.01-3.91 (2H, m), 3.45 (1H, ddd, J = 15.2, 10.1, 5.1 Hz), 3.45 (1H, ddd, J = 15.2, 9.9,
6.1 Hz), 2.73 (1H, ddd, J = 16.6, 9.9, 5.1 Hz), 2.57 (1H, ddd, J = 16.6, 10.1, 6.1 Hz), 2.42 (3H, s),
1.43 (3H, d, J = 7.4 Hz), 1.12 (3H, t, J = 7.3 Hz); 13C-NMR (CDCl3; 100 MHz) δ 171.2, 143.6,
136.5, 129.5 (2), 127.3 (2), 77.1, 61.3, 55.5, 44.1, 40.3, 22.5, 21.5, 17.0, 13.9; HRMS (CI,
magnetic sector) m/z: [M+H]+ Calcd for C16H21BrNO4S 402.0374; Found 402.0355.
(S)-2-(N-(3-Bromoprop-2-ynyl)-4-methylphenylsulfonamido)-N-methoxy-N,3-dimethylbuta
namide (4g). Bromination of 4g’ (508.9 mg, 1.44 mmol) was carried out according to the same
procedure as described for 1a to give bromoalkyne 4g (377.0 mg, 61%) as a colorless solid
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[eluent: hexane-AcOEt (7:3, v/v)]; Mp 95−97 °C; [α]D = −25.32 (c 0.9, CHCl3); IR ν max 2967,
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1657, 1336, 1158 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.77 (2H, d, J = 8.3 Hz), 7.28 (2H, d, J =
8.3 Hz), 4.73 (1H, d, J = 19.0 Hz), 4.69 (1H, d, J = 10.8 Hz), 4.28 (1H, d, J = 19.0 Hz), 3.81 (3H,
s), 3.12 (3H, s), 2.42 (3H, s), 2.26-2.16 (1H, m), 0.90 (3H, d, J = 10.8 Hz), 0.89 (3H, d, J = 10.8
Hz); 13C-NMR (CDCl3; 100 MHz) δ 172.1, 143.5, 137.1, 129.3 (2), 127.8 (2), 76.2, 61.5, 59.1,
43.2, 34.4, 31.7, 29.3, 21.6, 20.1, 18.8; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for
C17H24BrN2O4S 431.0639; Found 431.0652. Anal. Calcd for C17H23BrN2O4S: C, 47.34; H, 5.37;
N, 6.49. Found: C, 47.42; H, 5.49. N, 6.49.
General procedure for chlorination of alkyne with NCS and AgOAc.19 Methyl
2-(N-(3-chloroprop-2-ynyl)-4-methylphenylsulfonamido)acetate (1b). To
a
solution of
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N-tosylglycine methyl ester (1.0 g, 3.56 mmol) in acetone (10.0 mL) were added AgOAc (735.1
mg, 4.40 mmol) and NCS (1.71 g, 12.75 mmol) at ambient temperature under Ar. After stirring
for 2.5 h at reflux, the reaction was quenched with sat. NaHCO3 aqueous solution. The volatile
solvent was removed in vacuo, and the residue was dissolved in AcOEt. The organic layer was
washed with brine, dried over Na2SO4, and removed under reduced pressure. The residue was
purified by column chromatography on silica gel using hexane-AcOEt-CHCl3 (4:2:4, v/v) as
eluent to give chloroalkyne (1b) (890.60 mg, 80%) as a colorless oil.; IR ν max 1725, 1353, 1163
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cm−1; H-NMR (CDCl3; 400 MHz) δ 7.72 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 4.25 (2H,
s), 4.07 (2H, s), 3.71 (3H, s), 2.44 (3H, s); 13C-NMR (CDCl3; 100 MHz) δ 168.8, 144.1, 135.7,
129.6 (2), 127.53(2), 64.2, 62.2, 52.4, 47.0, 37.9, 21.6; HRMS (ESI+-TOF) m/z: [M+Na]+ Calcd
for C13H14ClNO4SNa 338.0230; Found 338.0225.
(S)-2-(N-(3-Chloroprop-2-ynyl)-4-methylphenylsulfonamido)-N-methoxy-N-methylpropan
amide (4a). Chlorination of 4a’ (196.80 mg, 0.61 mmol) was carried out according to the same
procedure as described for 1b to give chloroalkyne 4a (162.80 mg, 75%) as a pale yellow oil
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[eluent: hexane-AcOEt-CHCl3 (1:2:2, v/v)]; [α]D = −35.72 (c 1.0, CHCl3); IR ν max 1670, 1159
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cm−1; H-NMR (CDCl3; 400 MHz) δ 7.76 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 5.06 (1H,
q, J = 7.2 Hz), 4.49 (1H, d, J = 18.8 Hz), 4.40 (1H, d, J = 18.8 Hz), 3.78 (3H, s), 3.13 (3H, s),
2.43 (3H, s), 1.34 (3H, d, J = 7.2 Hz); 13C-NMR (CDCl3; 100 MHz) δ 171.9, 143.5, 136.9, 129.3
(2), 127.3 (2), 65.9, 61.7, 61.5, 50.5, 33.9, 31.7, 21.4, 15.8; HRMS (CI, magnetic sector) m/z:
[M+H]+ Calcd for C15H20ClN2O4S 359.0832; Found 359.0841.
(S)-2-(N-(3-Chloroprop-2-ynyl)-4-methylphenylsulfonamido)-N-methoxy-N-methyl-3-phen
ylpropanamide (4b). Chlorination of 4b’ (189.80 mg, 0.47 mmol) was carried out according to
the same procedure as described for 4a to give alkyne (4b) (168.00 mg, 82%) as a pale yellow oil
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[eluent: hexane-AcOEt (6:4, v/v)]; [α]D = −57.14 (c 1.0, CHCl3); IR ν max 1663, 1340, 1161
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cm−1; H-NMR (CDCl3; 400 MHz) δ 7.68 (2H, d, J = 8.1 Hz), 7.26-7.20 (5H, m), 7.15-7.12 (2H,
m), 5.26 (1H, dd, J = 9.5, 5.7 Hz), 4.65 (1H, d, J = 18.8 Hz), 4.41 (1H, d, J = 18.8 Hz), 3.43 (3H,
s), 3.24 (1H, dd, J = 13.2, 9.5 Hz), 3.02 (3H, s), 2.80 (1H, dd, J = 13.2, 5.7 Hz), 2.42 (3H, s);
13C-NMR (CDCl3; 100 MHz) δ 170.2, 143.5, 136.8, 136.4, 129.2 (3), 128.3 (2), 127.5 (2), 126.7,
65.6, 62.1, 61.3, 55.6, 36.3, 33.9, 31.6, 21.4; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for
C21H24ClN2O4S 435.1145; Found 435.1155.
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(S)-2-(N-(3-Chloroprop-2-ynyl)-4-methylphenylsulfonamido)-N-methoxy-N,4-dimethylpent
anamide (4c). Chlorination of (S)-2-(N-(prop-2-ynyl)-4-methylphenylsulfonamido)-N-methoxy-
N,4-dimethyl pentanamide9a (1.09 g, 3.09 mmol) was carried out according to the same procedure
as described for 1b to give chloroalkyne 4c (1.14 g, 95%) as a pale yellow solid [eluent:
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hexane-AcOEt-CHCl3 (3:1:1, v/v)]; Mp 75−76 °C; [α]D = −31.55 (c 0.7, CHCl3); IR ν max 1670,
1347, 1159 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.73 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz),
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4.99-4.95 (1H, m), 4.60 (1H, d, J = 19.1 Hz), 4.41 (1H, d, J = 19.1 Hz), 3.78 (3H, s), 3.08 (3H, s),
2.42 (3H, s), 1.74-1.60 (2H, m), 1.46-1.39 (1H, m), 0.90 (3H, d, J = 6.6 Hz), 0.84 (3H, d, J = 6.5
Hz); 13C-NMR (CDCl3; 100 MHz) δ 172.6, 143.5, 136.3, 129.3 (2), 127.4 (2), 66.0, 61.5, 61.4,
53.1, 38.9, 34.0, 31.9, 24.6, 22.8, 21.5, 21.2; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for
C18H26ClN2O4S 401.1302; Found 401.1287. Anal. Calcd for C18H25ClN2O4S: C, 53.92; H, 6.29;
N, 6.99. Found: C, 53.91; H, 6.31. N, 6.90.
(S)-2-(N-(3-Chloroprop-2-ynyl)-4-methylphenylsulfonamido)-N-methoxy-N,3-dimethylbut
anamide (4d). Chlorination of alkyne 4f’ (103.20 mg, 0.29 mmol) was carried out according to
the same procedure as described for 1b to give chloroalkyne 4d (107.90 mg, 95%) as a colorless
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solid [eluent: hexane-AcOEt-CHCl3 (4:2:4, v/v)]; Mp 74−75 °C; [α]D = −24.16 (c 1.0, CHCl3);
IR ν max 3484, 1337, 1155 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.77 (2H, d, J = 8.3 Hz), 7.28
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(2H, d, J = 8.3 Hz), 4.71 (1H, d, J = 18.9 Hz), 4.69 (1H, d, J = 10.6 Hz), 4.25 (1H, d, J = 18.9
Hz), 3.81 (3H, s), 3.12 (3H, s), 2.42 (3H, s), 2.26-2.16 (1H, m), 0.92 (3H, d, J = 6.6 Hz), 0.89
(3H, d, J = 6.7 Hz); 13C-NMR (CDCl3; 100 MHz) δ 171.9, 143.4, 137.0, 129.1 (2), 127.5 (2), 65.5,
61.4, 61.3, 59.0, 33.5, 31.5, 29.1, 21.4, 19.9, 18.7; HRMS (CI, magnetic sector) m/z: [M+H]+
Calcd for C17H24ClN2O4S 387.1145; Found 387.1158. Anal. Calcd for C17H23ClN2O4S: C, 52.77;
H, 5.99; N, 7.24. Found: C, 52.65; H, 5.95. N, 7.14.
2-(N-(4-Chlorobut-3-yn-2-yl)-4-methylphenylsulfonamido)-N-methoxy-N-methylacetamide
(4e). Chlorination of 4e’ (155.70 mg, 0.48 mmol) was carried out according to the same
procedure as described for 1b to give chloroalkyne 4e (70.60 mg, 41%) as a pale yellow oil
[eluent: hexane-AcOEt-CHCl3 (4:3:3, v/v)]; IR ν max 1687, 1343, 1159 cm−1; H-NMR (CDCl3;
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400 MHz) δ 7.86 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 8.3 Hz), 4.68 (1H, q, J = 7.1 Hz), 4.41 (1H,
d, J = 18.0 Hz), 4.02 (1H, d, J = 18.0 Hz), 3.77 (3H, s), 3.22 (3H, s), 2.43 (3H, s), 1.37 (3H, d, J
= 7.1 Hz); 13C-NMR (CDCl3; 100 MHz) δ 169.5, 143.6, 136.1, 129.4 (2), 127.8 (2), 66.9, 63.1,
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61.3, 46.3, 44.2, 32.5, 21.5, 21.4; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for
C15H20ClN2O4S 359.0832; Found 359.0848.
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General procedure for Iodination of alkynes with NIS and AgNO3.20 Methyl
2-(N-(3-iodoprop-2-ynyl)-4-methylphenylsulfonamido)acetate (1c). To a solution of methyl
2-(4-methyl-N-(prop-2-ynyl)phenylsulfonamido)acetate and N-(prop-2-ynyl)-N-tosylglycine18
(49.9 mg, 0.18 mmol) in acetone (1 mL) were added NIS (60.9 mg, 0.27 mmol) and AgNO3 (6.40
mg, 0.04 mmol) at room temperature under Ar. After stirring for 4 h at the same temperature, the
reaction was quenched with sat. NaHCO3 aqueous solution. The volatile solvent was removed in
vacuo, and the residue was dissolved in AcOEt. The organic layer was washed with brine, dried
over Na2SO4, and removed in vacuo. The residue was purified by column chromatography on
silica gel using hexane-AcOEt (7:3, v/v) as eluent to give iodoalkyne 1c (71.4 mg, 99%) as a
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colorless solid; Mp 112.7−113.1 °C; IR ν max 1750, 1349, 1161 cm−1; H-NMR (CDCl3; 400
MHz) δ 7.71 (2H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 4.39 (2H, s), 4.07 (2H, s), 3.72 (3H, s),
2.44 (3H, s); 13C-NMR (CD3CN; 100 MHz) δ 169.8, 145.4, 136.6, 130.7 (2), 128.4 (2), 87.1, 52.9,
48.5, 40.2, 21.5, 6.30; HRMS (ESI+-TOF) m/z: [M+H]+ Calcd for C13H15INO4S 407.9766; Found
407.9738. Anal. Calcd for C13H14NO4SI: C, 38.34; H, 3.47.; N, 3.44. Found: C, 38.44; H, 3.53; N,
3.41.
General procedure for reduction with DIBAL-H and SmI2-mediated cyclization.
(Z)-4-(Bromomethylene)-1-tosylpyrrolidin-3-ol (3a). To a solution of ester 1a (102.5 mg, 0.28
mmol) in toluene (4.7 mL) was added dropwise DIBAL-H (1.0 M in hexane solution, 0.37 mL) at
−78 °C under Ar. The reaction mixture was stirred for 20 min at −78 °C under Ar. To the reaction
mixture was added iPrOH (0.30 mL, 2.85 mmol) at −78 °C and the whole was stirred for 10 min
at 0 °C. To the reaction mixture was added dropwise SmI2 (0.2 M in THF, 7.0 mL) at 0 °C under
Ar, and the whole was stirred for 10 min at 0 °C, and treated with sat. Rochelle salt aqueous
solution to stir for 1h at ambient temperature. The reaction mixture was filtered through Celite,
and the aqueous layer was extracted with AcOEt. The combined organic layer was washed with
brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using hexane-AcOEt-CHCl3 (9:2:9, v/v) as eluent to give
pyrrolidine 3a (69.0 mg, 73%) as a colorless solid; Mp 132−134 °C; IR ν max 3502, 1343, 1163
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cm−1; H-NMR (CDCl3; 400 MHz) δ 7.71 (2H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 6.23 (1H,
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dd, J = 1.8, 1.8 Hz), 4.81-4.77 (1H, m), 3.93 (1H, dd, J = 13.8, 1.8 Hz), 3.75 (1H, dd, J = 13.8,
1.8 Hz), 3.49 (1H, dd, J = 11.0, 5.8 Hz), 3.35 (1H, dd, J = 11.0, 3.3 Hz), 2.44 (3H, s), 2.31 (1H, d,
J = 4.5 Hz); 13C-NMR (CDCl3; 100 MHz) δ 144.2, 143.0, 131.8, 129.8 (2), 127.9 (2), 103.7, 71.3,
55.5, 51.3, 21.5; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C12H15BrNO3S 331.9955;
Found 331.9962. Anal. Calcd for C12H14BrNO3S: C, 43.38; H, 4.25; N, 4.22. Found: C, 43.18; H,
4.37; N, 4.13.
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(Z)-4-(Chloromethylene)-1-tosylpyrrolidin-3-ol (3b). Reduction of ester 1b (307.7 mg, 0.94
mmol), followed by radical cyclization of the resulting aldehyde was carried out according to the
same procedure as described for 3a to give pyrroldine 3b (259.9 mg, 93%) as a white solid.
[eluent: hexane-AcOEt (6:4, v/v)]; Mp 114.2−115.4 °C; IR ν max 3373, 1340, 1165 cm−1;
1H-NMR (CDCl3; 400 MHz) δ 7.73 (2H, d, J = 8.3 Hz), 7.37 (2H, d, J = 8.3 Hz), 6.14 (1H, dd, J
= 3.8, 1.8 Hz), 4.94-4.88 (1H, m), 3.98 (1H, dd, J = 14.0, 1.8 Hz), 3.83 (1H, dd, J = 14.0, 1.8 Hz),
3.49 (1H, dd, J = 10.9, 5.8 Hz), 3.35 (1H, dd, J = 10.9, 3.1 Hz), 2.47 (3H, s), 2.27 (1H, d, J = 4.6
Hz); 13C-NMR (CDCl3; 100 MHz) δ 144.2, 140.2, 131.8, 129.8 (2), 127.9 (2), 115.3, 69.6, 55.5,
50.2, 21.5; HRMS (ESI+-TOF) m/z: [M+Na]+ Calcd for C12H14ClNO3SNa 310.0281; Found
310.0288.
(Z)-4-(Iodomethylene)-1-tosylpyrrolidin-3-ol (Z-3c). Reduction of ester 1c (199.7 mg, 0.491
mmol), followed by radical cyclization of the resulting aldehyde was carried out according to the
same procedure as described for 3a to give crude [eluent: hexane-AcOEt (7:3, v/v)]. Furthermore,
the mixture was purified by gel permeation chromatography using CHCl3 as eluent to give
pyrrolidine Z-3c (34.9 mg, 19%) as colorless solid and pyrrolidine E-3c (35.3 mg, 19%) as
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colorless oil; Mp 147.5−148.3 °C; IR ν max 3407, 1344, 1163 cm−1; H-NMR (CDCl3; 400 MHz)
δ 7.71 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 6.30 (1H, dd, J = 1.8, 1.7 Hz), 4.63-4.57 (1H,
m), 3.95 (1H, dd, J = 14.2, 1.7 Hz), 3.78 (1H, dd, J = 14.2, 1.8 Hz), 3.47 (1H, dd, J = 11.0, 5.6
Hz), 3.41 (1H, dd, J = 11.0, 3.0 Hz), 2.44 (3H, s), 2.34 (1H, d, J = 5.0 Hz); 13C-NMR (CDCl3;
150 MHz) δ 148.7, 144.2, 132.1, 129.8 (2), 128.0 (2), 75.5, 74.2, 55.4, 52.4, 21.6; HRMS
(ESI+-TOF) m/z: [M+H]+ Calcd for C12H15INO3S 379.9817; Found 379.9789 Anal. Calcd for
C12H14INO3S: C, 38.01; H, 3.72; N, 3.69. Found: C, 38.21; H, 3.79; N, 3.53.
(E)-4-(Iodomethylene)-1-tosylpyrrolidin-3-ol (E-3c). IR ν max 3417, 1343, 1162 cm−1;
1H-NMR (CDCl3; 400 MHz) δ 7.74 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J = 8.1 Hz), 6.49 (1H, dd, J
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= 2.7, 1.7 Hz), 4.60-4.51 (1H, m), 3.83 (1H, dd, J = 15.6, 1.7 Hz), 3.74 (1H, dd, J = 15.6, 2.7 Hz),
3.61 (1H, dd, J = 10.2, 5.9 Hz), 3.23 (1H, dd, J = 10.2, 5.1 Hz), 2.45 (3H, s), 1.96 (1H, d, J = 7.8
Hz); 13C-NMR (CDCl3; 150 MHz) δ 150.5, 144.2, 132.2, 129.9 (2), 127.9 (2), 76.3, 72.6, 56.2,
55.1, 21.6; HRMS (ESI+-TOF) m/z: [M+H]+ Calcd for C12H15INO3S 379.9817; Found 379.9794.
(2R, 3R, Z)-4-(Bromomethylene)-2- methyl-1-tosylpyrrolidin-3-ol (3d). Reduction of ester
1d (517.0 mg, 1.33 mmol), followed by radical cyclization of the corresponding aldehyde was
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carried out according to the same procedure as described for 3a to give pyrrolidine 3d (356.4 mg,
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73%) as a colorless solid [eluent: hexane-AcOEt-CHCl3 (9:2:9, v/v)]; Mp 101−102 °C; [α]D
=
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27.21 (c 1.1, CHCl3); IR ν max 3491, 1339, 1163 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.75 (2H,
d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 6.28-6.27 (1H, m), 4.44 (1H, ddd, J = 3.9, 2.5, 1.7 Hz),
4.03 (1H, dd, J = 14.3, 1.6 Hz), 3.91 (1H, ddd, J = 14.3, 2.5, 1.0 Hz), 3.82 (1H, dq, J = 6.8, 1.7
Hz), 2.42 (3H, s), 1.78 (1H, d, J = 3.9 Hz), 1.28 (3H, d, J = 6.8 Hz); 13C-NMR (CDCl3; 100 MHz)
δ 143.8, 142.6, 134.4, 129.6 (2), 127.7 (2), 104.0, 77.7, 63.7, 50.3, 21.5, 19.6; HRMS (CI,
magnetic sector) m/z: [M+H]+ Calcd for C13H17BrNO3S 346.0112; Found: 346.0132. Anal. Calcd
for C13H16BrNO3S: C, 45.10; H, 4.66; N, 4.05. Found: C, 45.03; H, 4.60. N, 3.96.
(2R, 3R, Z)-2-Benzyl-4-(bromomethylene)-1-tosylpyrrolidin-3-ol (3e). Reduction of ester 1e
(100.0 mg, 0.22 mmol), followed by radical cyclization of the corresponding aldehyde was
carried out according to the same procedure as described for 3a to give pyrrolidine 3e (58.1 mg,
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62%) as a colorless oil [eluent: hexane-AcOEt (7:3, v/v)]; [α]D = 44.49 (c 0.9, CHCl3); IR ν
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max 3484, 1339, 1161, 1094 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.74 (2H, d, J = 8.3 Hz),
7.32-7.21 (7H, m), 6.12 (1H, br s), 4.59 (1H, br s), 4.08 (1H, dd, J = 9.5, 4.3 Hz), 3.93 (1H, dd, J
= 14.2, 2.1 Hz), 3.88 (1H, dd, J = 14.2, 1.6 Hz), 3.07 (1H, dd, J = 13.7, 4.3 Hz), 2.68 (1H, dd, J =
13.7, 9.5 Hz), 2.40 (3H, s), 1.63 (1H, br s); 13C-NMR (CDCl3; 100 MHz) δ 143.8, 142.6, 136.8,
129.7 (2), 129.6 (2), 128.6 (2), 127.7 (2), 126.8, 103.8, 74.7, 69.4, 50.3, 40.5, 21.6; HRMS (CI,
magnetic sector) m/z: [M+H]+ Calcd for C19H21BrNO3S 422.0425; Found 422.0404.
(2R,
3R,
Z)-4-(Bromomethylene)-2-((tert-butyldimethylsilyloxy)methyl)-1-
tosylpyrrolidin-3-ol (3f). Reduction of ester 1f (100.2 mg, 0.20 mmol), followed by radical
cyclization of the resulting aldehyde was carried out according to the same procedure as
described for 3a to give pyrrolidine 3f (73.7 mg, 78%) as a colorless solid [eluent: hexane-AcOEt
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(3:2, v/v)]; Mp 103−104 °C; [α]D = 29.41 (c 0.5, CHCl3); IR ν max 3502, 2954, 1340, 1163,
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1094 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.76 (2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 6.18
(1H, dd, J = 2.3, 1.7 Hz), 4.80 (1H, d, J = 3.4 Hz), 4.03 (1H, dd, J = 14.1, 1.7 Hz), 3.97 (1H, dd,
J = 14.1, 2.3 Hz), 3.86 (2H, m), 3.54 (1H, dt, J = 8.4, 3.4 Hz), 2.42 (3H, s), 1.54 (1H, d, J = 3.4
Hz), 0.87 (9H, s), 0.06 (3H, s), 0.05 (3H, s); 13C-NMR (CDCl3; 100 MHz) δ 143.8, 143.5, 134.5,
129.6 (2), 127.7 (2), 103.0, 74.6, 69.0, 64.5, 51.3, 25.8 (3), 21.6, 18.1, −5.5, −5.6; HRMS (CI,
magnetic sector) m/z: [M+H]+ Calcd for C19H31BrNO4SSi 476.0926; Found 476.0919. Anal.
Calcd for C19H30BrNO4SSi: C, 47.89; H, 6.35; N, 2.94. Found: C, 47.59; H, 6.08. N, 2.90.
(2R, 3R, Z)-4-(Bromomethylene)-2-isopropyl-1-tosylpyrrolidin-3-ol (3g). To a solution of
Weinreb amide 4g (98.0 mg, 0.23 mmol) in toluene (3.9 mL) was added dropwise DIBAL-H (1.0
M in hexane, 0.35 mL) at 0 °C under Ar. After stirring for 20 min at 0 °C under Ar, to the
reaction mixture was added MeOH (0.28 mL, 6.9 mmol) at 0 °C, and the whole was stirred for 10
min at 0 °C. To the reaction mixture was added dropwise SmI2 (0.2 M in THF, 5.8 mL) at 0 °C
under Ar. After stirring for 10 min at 0 °C, the reaction was quenched with sat. Rochelle salt
aqueous solution and stirred for further 1 h at ambient temperature. The reaction mixture was
filtered through Celite, and the aqueous layer was extracted with AcOEt. The combined organic
layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel using hexane-AcOEt (7:3, v/v) as eluent to give
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pyrrolidine 3g (58.0 mg, 69%) as a colorless solid; Mp 128−130 °C; [α]D = 28.25 (c 1.1,
CHCl3); IR ν max 3491, 1339, 1163 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.77 (2H, d, J = 8.3 Hz),
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7.30 (2H, d, J = 8.3 Hz), 6.17 (1H, br s), 4.61 (1H, d, J = 3.3 Hz), 4.01 (1H, dd, J = 15.0, 1.6 Hz),
3.96 (1H, dd, J = 15.0, 1.6 Hz), 3.69 (1H, d, J = 6.2 Hz), 2.41 (3H, s), 1.98-1.86 (1H, m), 1.60
(1H, br s), 1.00 (3H, d, J = 6.9 Hz), 0.90 (3H, d, J = 6.8 Hz); 13C-NMR (CDCl3; 100 MHz) δ
144.3, 143.8, 134.5, 129.6 (2), 128.0 (2), 102.9, 73.9, 73.8, 50.9, 31.6, 21.6, 19.3, 17.9; HRMS
(CI, magnetic sector) m/z: [M+H]+ Calcd for C15H21BrNO3S 374.0425; Found 374.0402. Anal.
Calcd for C15H20BrNO3S: C, 48.13; H, 5.39; N, 3.74. Found: C, 47.93; H, 5.45. N, 3.74.
(Z)-3-(Bromomethylene)-1-tosylpiperidin-4-ol (3h). Reduction of ester 1h (111.3 mg, 0.30
mmol), followed by radical cyclization of the resulting aldehyde was carried out according to the
same procedure as described for 3a to give piperidine 3h (78.1 mg, 76%) as a colorless oil
[eluent: hexane-AcOEt-CHCl3 (9:2:9, v/v)]; IR ν max 3494, 1348, 1332, 1164 cm−1; H-NMR
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(CDCl3; 400 MHz) δ 7.65 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 6.29 (1H, d, J = 1.8 Hz),
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4.91 (1H, br s), 4.10 (1H, dd, J = 12.7, 1.8 Hz), 3.64 (1H, ddd, J = 12.2, 4.6, 2.3 Hz), 3.30 (1H,
dd, J = 12.7, 1.8 Hz), 2.84(1H, dt, J = 12.2, 3.1 Hz), 2.44 (3H, s), 1.94-1.78 (2H, m), 1.60 (1H, br
s); 13C-NMR (CDCl3; 100 MHz) δ 143.8, 138.0, 133.1, 129.7 (2), 127.6 (2), 105.6, 64.1, 48.1,
40.6, 31.5, 21.5; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C13H17BrNO3S 346.0112;
Found 346.0107.
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(4R*, 5R*, Z)-3-(Bromomethylene)-5-methyl-1-tosylpiperidin-4-ol (anti-3i) (Major
product). Reduction of ester 2i (111.3 mg, 0.28 mmol), followed by radical cyclization of the
resulting aldehyde was carried out according to the same procedure as described for 3a to give
piperidine 3i (75.0 mg, 73%, anti:syn = 68:32) as a colorless oil [eluent: hexane-AcOEt (3:2,
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v/v)]; IR ν max 3490, 1347, 1165 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.61 (2H, d, J = 8.3 Hz),
7.31 (2H, d, J = 8.3 Hz), 6.38 (1H, d, J = 1.5 Hz), 4.59 (1H, d, J = 2.8 Hz), 4.00 (1H, dd, J = 12.2,
1.5 Hz), 3.34 (1H, dd, J = 11.5, 1.8 Hz), 3.19 (1H, dd, J = 12.2, 1.6 Hz), 2.89 (1H, dd, J = 11.5,
2.9 Hz), 2.42 (3H, s), 2.09-2.01 (1H, m), 1.94 (1H, br s), 1.00 (3H, d, J = 7.1 Hz); 13C-NMR
(CDCl3; 100 MHz) δ 143.8, 136.6, 133.1, 129.8 (2), 127.6 (2), 107.7, 69.3, 48.2, 46.3, 35.2, 21.6,
14.2; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C14H19BrNO3S 360.0268; Found
360.0258.
(4S*, 5R*, Z)-3-(Bromomethylene)-5-methyl-1-tosylpiperidin-4-ol (syn-3i) (Minor product).
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IR ν max 3507, 1337, 1164, 1095 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.65 (2H, d, J = 8.2 Hz),
7.33 (2H, d, J = 8.2 Hz), 6.28 (1H, d, J = 1.4 Hz), 4.65 (1H, d, J = 2.1 Hz), 4.07 (1H, d, J = 12.6
Hz), 3.48 (1H, dd, J = 11.7, 1.4 Hz), 3.25 (1H, dd, J = 12.6, 1.5 Hz), 2.51 (1H, t, J = 11.7 Hz),
2.44 (3H, s), 1.93-1.84 (1H, m), 1.25 (1H, br s), 1.01 (3H, d, J = 6.9 Hz); 13C-NMR (CDCl3; 100
MHz) δ 143.8, 138.7, 133.3, 129.8 (2), 127.7 (2), 105.6, 68.4, 47.5, 46.4, 35.3, 21.6, 14.3; HRMS
(CI, magnetic sector) m/z: [M+H]+ Calcd for C14H19BrNO3S 360.0268; Found 360.0256.
(Z)-4-(Bromomethylene)-1-tosylpiperidin-3-ol (3j). Reduction of ester 2j (99.9 mg, 0.27
mmol), followed by radical cyclization of the resulting aldehyde was carried out according to the
same procedure as described for 3a to give piperidine 3j (74.1 mg, 80%) as a colorless oil
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[eluent: hexane-AcOEt-CHCl3 (9:2:9, v/v)]; IR ν max 3493, 1335, 1164 cm−1; H-NMR (CDCl3;
400 MHz) δ 7.65 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 6.02 (1H, s), 4.86 (1H, s),
3.98-3.87 (2H, m), 2.80-2.67 (2H, m), 2.66 (1H, br s), 2.43 (3H, s), 2.31-2.24 (2H, m); 13C-NMR
(CDCl3; 100 MHz) δ 143.9, 139.6, 132.8, 129.7 (2), 127.5 (2), 102.7, 65.4, 52.5, 46.9, 30.2, 21.5;
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HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C13H17BrNO3S 346.0112; Found 346.0111.
(2S, 3R, Z)-4-(Bromomethylene)-2-methyl-1-tosylpiperidin-3-ol (3k). Reduction of ester 1k
(101.4 mg, 0.25 mmol), followed by radical cyclization of the resulting aldehyde was carried out
according to the same procedure as described for 3a to give piperidine 3k (21.2 mg, 23%) as a
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colorless oil [eluent: hexane-AcOEt (4:1, v/v)]; [α]D = 35.04 (c 0.4, CHCl3); IR ν max 3500,
1321, 1155 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.74 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz),
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6.19 (1H, d, J = 2.1 Hz), 4.61 (1H, br s), 4.30 (1H, dq, J = 7.0, 2.2 Hz), 3.82 (1H, dddd, J = 12.8,
5.6, 2.1, 1.1 Hz), 2.94 (1H, dt, J = 12.8, 3.2 Hz), 2.64 (1H, dddd, J = 14.5, 12.8, 5.6, 2.1 Hz),
2.55 (1H, br s), 2.42 (3H, s), 2.15 (1H, ddd, J = 14.5, 3.2, 1.1 Hz), 0.90 (3H, d, J = 6.8 Hz);
13C-NMR (CDCl3; 100 MHz) δ 143.5, 138.4, 137.3, 129.7 (2), 127.1 (2), 104.5, 69.9, 55.6, 40.4,
30.3, 21.5, 12.8; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C14H19BrNO3S 360.0268;
Found 360.0298.
(2R, 3R, Z)-4-(Chloromethylene)-2-methyl-1-tosylpyrrolidin-3-ol (6a). To a solution of
amide 4a (160.00 mg, 0.45 mmol) in toluene (7.4 mL) was added dropwise DIBAL-H (1.0M in
hexane, 0.54 mL) at 0 °C under Ar. After stirring for 20 min at 0 °C under Ar, to the reaction
mixture was added MeOH (0.54 mL, 13.38 mmol) at 0 °C, and the whole was stirred for 10 min
at 0 °C. To the reaction mixture was added dropwise SmI2 (0.2M in THF, 11.15 mL) at 0 °C under
Ar. After stirring for 10 min at 0 °C, the reaction was quenched with sat. Rochelle salt aqueous
solution and the resulting mixture were stirred for 1 h at room temperature. The reaction mixture
was filtered through Celite, and the aqueous layer was extracted with AcOEt. The combined
organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel using hexane-AcOEt-CHCl3 (3:1:1, v/v) as
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eluent to give pyrrolidine 6a (78.20 mg, 58%) as a colorless oil; [α]D = 35.97 (c 0.8, CHCl3); IR
ν max 3481, 1338, 1155, 1093 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.74 (2H, d, J = 8.3 Hz), 7.31
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(2H, d, J = 8.3 Hz), 6.16 (1H, br s), 4.51 (1H, br s), 4.04 (1H, d, J = 14.1 Hz), 3.96 (1H, d, J =
14.1 Hz), 3.81 (1H, q, J = 6.8 Hz), 2.42 (3H, s), 1.70 (1H, d, J = 4.0 Hz), 1.26 (3H, d, J = 6.8
Hz); 13C-NMR (CDCl3; 100 MHz) δ 143.7, 139.6, 134.3, 129.6 (2), 127.7 (2), 115.7, 75.6, 63.9,
49.3, 21.5, 19.5; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C13H17ClNO3S 302.0617;
Found 302.0625.
(2R, 3R, Z)-2-Benzyl-4-(chloromethylene)-1-tosylpyrrolidin-3-ol (6b). Reduction of amide
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4b (152.40 mg, 0.35 mmol), followed by radical cyclization of the resulting aldehyde was carried
out according to the same procedure as described for 6a to give pyrrolidine 6b (53.50 mg, 40%)
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as a colorless oil [eluent: hexane-AcOEt-CHCl3 (4:3:3, v/v)]; [α]D = 52.11 (c 0.5, CHCl3); IR ν
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7.32-7.21 (7H, m), 6.01 (1H, br s), 4.67 (1H, d, J = 4.0 Hz), 4.07 (1H, dd, J = 9.4, 4.3 Hz), 4.00
(1H, dd, J = 14.3, 2.3 Hz), 3.93 (1H, dd, J = 14.3, 1.6 Hz), 3.08 (1H, dd, J = 13.7, 4.3 Hz), 2.68
(1H, dd, J = 13.7, 9.4 Hz), 2.41 (3H, s), 1.45 (1H, d, J = 4.0 Hz); 13C-NMR (CDCl3; 100 MHz) δ
143.7, 139.5, 136.7, 134.5, 129.6 (2), 129.5 (2), 128.5 (2), 127.6 (2), 126.7, 115.3, 72.5, 69.4,
49.3, 40.4, 21.5; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C19H21ClNO3S 378.0930;
Found 378.0915.
(2S, 3R, Z)-4-(Chloromethylene)-2-isobutyl-1-tosylpyrrolidin-3-ol (6c). Reduction of amide
4c (52.70 mg, 0.13 mmol), followed by radical cyclization of the resulting aldehyde was carried
out according to the same procedure as described for 6a to give pyrrolidine 6c (34.8 mg, 77%) as
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a colorless solid [eluent: hexane-AcOEt-CHCl3 (3:1:1, v/v)]; Mp 88–89 °C; [α]D = 30.87 (c 1.0,
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CHCl3); IR ν max 1337, 1156, 1093 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.77 (2H, d, J = 8.3 Hz),
7.31 (2H, d, J = 8.3 Hz), 6.13 (1H, br s), 4.56 (1H, d, J = 4.8 Hz), 4.08 (1H, dd, J = 15.1, 2.3 Hz),
3.96 (1H, dd, J = 15.1, 1.7 Hz), 3.92 (1H, t, J = 7.6 Hz), 2.42 (3H, s), 1.79-1.69 (1H, m), 1.66
(1H, d, J = 4.8 Hz), 1.42 (1H, ddd, J = 14.1, 7.6, 7.6 Hz), 1.22 (1H, ddd, J = 14.1, 7.6, 6.9 Hz),
0.96 (3H, d, J = 7.6 Hz), 0.94 (3H, d, J = 6.9 Hz); 13C-NMR (CDCl3; 100 MHz) δ 143.7, 140.5,
134.7, 129.5 (2), 127.8 (2), 115.5, 74.2, 66.8, 48.8, 42.3, 24.8, 22.6, 22.4, 21.5; HRMS (CI,
magnetic sector) m/z: [M+H]+ Calcd for C16H23ClNO3S 344.1087; Found 344.1061. Anal. Calcd
for C16H22ClNO3S: C, 55.89; H, 6.45; N, 4.07. Found: C, 55.86; H, 6.56. N, 4.02.
(2R, 3R, Z)-4-(Chloromethylene)-2-isopropyl-1-tosylpyrrolidin-3-ol (6d). Reduction of
amide 4d (81.7 mg, 0.21 mmol), followed by radical cyclization of the resulting aldehyde was
carried out according to the same procedure as described for 6a to give pyrrolidine 6d (50.0 mg,
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72%) as a colorless solid [eluent: hexane-AcOEt-CHCl3 (2:1:1, v/v)]; Mp 114–115 °C; [α]D
=
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52.90 (c 0.4, CHCl3); IR ν max 3484, 1337, 1155 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.77 (2H,
d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 6.06 (1H, dd, J = 2.4, 1.7 Hz), 4.69 (1H, d, J = 4.2 Hz),
4.07 (1H, dd, J = 14.9, 2.4 Hz), 4.00 (1H, dd, J = 14.9, 1.7 Hz), 3.68 (1H, d, J = 6.2 Hz), 2.42
(3H, s), 1.98-1.86 (1H, m), 1.51 (1H, d, J = 4.0 Hz), 1.01 (3H, d, J = 6.9 Hz), 0.90 (3H, d, J = 6.8
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Hz); 13C-NMR (CDCl3; 100 MHz) δ 143.7, 141.3, 134.4, 129.5 (2), 128.0 (2), 114.6, 74.0, 71.7,
50.0, 31.5, 21.5, 19.3, 17.8; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C15H21ClNO3S
330.0930; Found 330.0937. Anal. Calcd for C15H20ClNO3S: C, 54.62; H, 6.11; N, 4.25. Found: C,
54.52; H, 6.12. N, 4.18.
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(3R*, 5R*, Z)-4-(Chloromethylene)-5-methyl-1-tosyl pyrrolidin-3-ol (anti-6e) and (3S*, 5R*,
Z)-4- (chloromethylene)-5-methyl-1-tosylpyrrolidin-3-ol (syn-6e). Reduction of amide 4e
(66.70 mg, 0.19 mmol), followed by radical cyclization of the resulting aldehyde was carried out
according to the same procedure as described for 6a to give pyrrolidine 6e (40.5 mg, 72%, anti :
syn = 1:1) as a colorless oil [eluent: hexane-AcOEt-CHCl3 (4:3:3, v/v)]; IR ν max 3503, 1341,
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1161 cm−1; H-NMR (CDCl3; 400 MHz) δ 7.76 (1H, d, J = 8.3 Hz), 7.69 (1H, d, J = 8.3 Hz), 7.32
(1H, d, J = 8.3 Hz), 7.31 (1H, d, J = 8.3 Hz), 6.04 (0.5H, dd, J = 2.1, 1.5 Hz), 6.03 (0.5H, dd, J =
1.6, 1.6 Hz), 4.90-4.87 (0.5H, m), 4.72 (0.5H, dddd, J = 6.1, 4.5, 2.9, 1.5 Hz), 4.33-4.27 (0.5H,
m), 4.18 (0.5H, dq, J = 6.5, 1.5 Hz), 3.65 (0.5H, dd, J = 12.6, 5.0 Hz), 3.56 (0.5H, dd, J = 11.7,
2.9 Hz), 3.51 (0.5H, dd, J = 12.6, 2.2 Hz), 3.45 (0.5H, dd, J = 11.7, 6.1 Hz), 2.44 (1.5H, s), 2.43
(1.5H, s), 2.18 (0.5H, d, J = 4.0 Hz), 1.84 (0.5H, d, J = 4.5 Hz), 1.54 (1.5H, d, J = 7.3 Hz), 1.43
(1.5H, d, J = 6.5 Hz); 13C-NMR (CDCl3; 100 MHz) δ 146.8, 146.3, 144.0, 143.8, 134.3, 133.3,
129.8 (2), 129.6 (2), 127.7 (2), 127.6 (2), 115.8, 115.5, 69.5, 68.8, 58.5, 57.1, 55.1, 54.6, 23.8 (2),
21.5, 21.4; HRMS (CI, magnetic sector) m/z: [M+H]+ Calcd for C13H17ClNO3S 302.0617; Found
302.0620.
(Z)-4-Benzylidene-1-tosylpyrrolidin-3-ol (Z-7). To a flask were added bromoalkene 3a (21.6
mg, 65.1 µmol), phenylboronic acid (24.3 mg, 0.199 mmol), K2CO3 (28.1 mg, 0.204 mmol), and
Pd(PPh3)4 (23.4 mg, 20.2 μmol). After the flask was flashed with Ar, MeOH (1 mL) was added to
the reaction mixture at ambient temperature. After stirring for 1.25 h at reflux, the reaction
mixture was diluted with AcOEt, and washed with 1M NaOH aqueous solution. The aqueous
layer was further extracted with AcOEt (×2). The combined organic layer was washed with brine,
and volatile solvent was removed in vacuo. The residue was purified by column chromatography
on silica gel using hexane-AcOEt (7:3, v/v) as eluent to give benzylidene 7 (15.6 mg, 73%) as a
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yellow solid. Mp 125.5–126.1 °C; IR ν max 3497, 1342, 1164 cm−1; H-NMR (CDCl3; 400 MHz)
δ 7.75 (2H, d, J = 8.3 Hz), 7.43 (2H, d, J = 7.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.3
Hz), 7.27 (1H, t, J = 7.3 Hz ), 6.48 (1H, s), 4.73 (1H, dd, J = 7.5, 4.4 Hz), 4.28 (1H, d, J = 14.4
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Hz), 3.76 (1H, d, J = 14.4 Hz) 3.64 (1H, d, J = 10.9 Hz), 3.15 (1H, dd, J = 10.9, 4.4 Hz), 2.44
(3H, s), 2.23 (1H, d, J = 7.5 Hz); 13C-NMR (CDCl3; 100 MHz) δ 144.0, 137.9, 135.4, 132.2,
129.8 (2), 128.6 (2), 128.5 (2), 128.0 (2), 127.9, 127.6, 69.6, 57.4, 51.9, 21.6; HRMS (ESI+-TOF)
m/z: [M+Na]+ Calcd for C18H19NO3SNa 352.0983; Found: 352.0993. Anal. Calcd for
C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.37; H, 5.85; N, 4.13.
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(Z)-4-(3-Phenylprop-2-yn-1-ylidene)-1-tosylpyrrolidin-3-ol (8). To
a
solution of
bromoalkene 3a (30 mg, 0.09 mmol) and phenylacetylene (19.8 μL, 0.181 mmol) in degassed
Et3N (4 mL) were added Pd(PPh3)2Cl2 (14.04 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol) at
ambient temperature under Ar. After stirring for 24 h at 60 °C, the reaction mixture was cooled to
room temperature. The volatile solvent was removed in vacuo, and the residue was treated with
sat. NH4Cl aqueous solution. The mixture was extracted with AcOEt, and the extract was dried
over Na2SO4, and removed to leave a residue, which was purified by column chromatography on
silica gel using hexane-AcOEt-CHCl3 (17:6:17) as eluent to give phenylalkyne 8 (27.9 mg, 87%)
as a pale yellow solid. Mp 159.2–160.8 °C; IR ν max 3450, 1345, 1159 cm−1; H-NMR (CDCl3;
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400 MHz) δ 7.72 (2H, d, J = 8.2 Hz), 7.41-7.39 (2H, m), 7.35 (2H, d, J = 8.0 Hz), 7.33-7.31 (3H,
m), 5.78 (1H, dd, J = 4.0, 2.0 Hz), 4.99-4.96 (1H, m), 4.03 (1H, ddd, J = 15.4, 4.0, 2.0 Hz), 3.93
(1H, dd , J = 15.4, 2.0 Hz), 3.55 (1H, dd, J = 10.4, 6.0 Hz), 3.29 (1H, dd, J = 10.4, 4.0 Hz), 2.52
(1H, d, J = 3.6 Hz), 2.44 (3H, s); 13C-NMR (CDCl3; 100 MHz) δ 151.4, 144.2, 132.2, 131.6 (2),
130.0 (2), 129.0, 128.6 (2), 128.1 (2), 122.4, 106.0, 96.4, 84.1, 70.8, 55.3, 51.4, 21.7; HRMS
(ESI+-TOF) m/z: [M+Na]+ Calcd for C20H19NO3SNa: 376.09833; Found: 376.0983. Anal. Calcd
for C20H19NO3S: C, 67.97; H, 5.42; N, 3.96. Found: C, 67.76; H, 5.52; N, 3.84.
Methyl 2-(4-methyl-N-(3-phenylprop-2-ynyl)phenylsulfonamido)acetate21 (1l). To
a
solution of N-tosylglycine methyl ester9a (599.2 mg, 2.47 mmol), 3-phenyl-2-propyn-1-ol (310.1
mg, 2.35 mmol), and Ph3P (646.1 mg, 2.47 mmol) in THF (11.0 mL) was added DIAD (0.69 mL,
3.52 mmol) at ambient temperature. After stirring for 2 h at the same temperature, the volatile
solvent was removed in vacuo. The residue was purified by column chromatography on silica gel
using hexane-AcOEt-CHCl3 (19:2:19, v/v) as eluent to give alkyne 1l (691 mg, 82%) as a
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colorless solid. Mp 68.4–69.9 °C; H-NMR (CDCl3; 400 MHz) δ 7.77 (2H, d, J = 8.4 Hz),
7.33-7.23 (5H, m), 7.15-7.12 (2H, m), 4.48 (2H, s), 4.16 (2H, s), 3.72 (3H, s), 2.37 (3H, s);
13C-NMR (CDCl3; 100 MHz) δ 168.8, 143.8, 135.8, 131.4 (2), 129.5 (2), 128.5, 128.1 (2), 127.5
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(2), 121.8, 86.0, 81.2, 52.2, 46.9, 38.3, 21.3.
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(E)-4-Benzylidene-1-tosylpyrrolidin-3-ol (E-7). Reduction of ester 8 (99.2 mg, 0.28 mmol),
followed by radical cyclization of the resulting aldehyde was carried out according to the same
procedure as described for 3a to give pyrrolidine Z-7 (9.8 mg, 11%) as a colorless solid [eluent:
hexane-AcOEt (65:35, v/v)] and E-7 (51.5 mg, 56%) as a colorless solid [eluent: hexane-AcOEt
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(65:35, v/v)]; Mp 124.0–124.8 °C; IR ν max 3498, 1341, 1165 cm–1; H-NMR (CDCl3; 400 MHz)
δ 7.74 (2H, d, J = 8.0 Hz), 7.42-7.28 (5H, m), 7.18 (2H, d, J = 7.5 Hz), 6.60 (1H, s), 4.70 (1H, d,
J = 7.0 Hz), 4.24 (1H, d, J = 15.1 Hz), 4.13 (1H, d, J = 15.1 Hz), 3.49 (1H, d, J = 10.2 Hz), 3.19
(1H, d, J = 10.2 Hz), 2.42 (3H, s), 1.89 (1H, d, J = 7.0 Hz); 13C-NMR (CDCl3; 100 MHz) δ 143.9,
138.4, 135.6, 132.6, 129.8 (2), 128.7 (2), 128.4 (2), 127.8, 127.8 (2), 126.0, 73.5, 54.3, 49.5,
21.5; HRMS (ESI+-TOF) m/z: [M+Na]+ Calcd for C18H19NO3SNa 352.0983; Found: 352.0967.
Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.58; H, 5.89; N, 4.20.
ASSOCIATED CONTENT
AUTOHOR INFORMATION
Corresponding Author
E-mail:takakazu@hoshi.ac.jp
ORCID
Kazunori Takahashi: 0000-0001-5418-0586
Notes
The authors declare no competing financial interest.
Supporting Information
Copies of H NMR and 13C NMR spectra for all new compounds. This material is available free
1
of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENTS
The authors thank Prof. M. Ihara and Dr. H. Yokoe is gratefully acknowledged for helpful
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discussions. We also thank Dr. H. Kasai for determination of MS. This work was supported in
part by Grant-in-Aid for Young Scientists (B) (No. 25860013) to K.T. from JSPS.
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