Direct asymmetric vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)-one with aldimine catalyzed by quinine

Article abstract of DOI:10.1021/jo301115t

The direct asymmetric vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)- one with aldimine catalyzed by quinine was first reported, and ?-butenolides have been obtained in excellent yield (up to 98%) and enantioselectivities (up to 95% ee). The synthet

Full text of DOI:10.1021/jo301115t

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Note
Direct Asymmetric Vinylogous Mannich Reaction of 3,4-
dihalofuran-2(5H)-one with Aldimine Catalyzed by Quinine
Yun-Long Guo, Jian-Fei Bai, Lin Peng, Liang-Liang Wang, Li-
Na Jia, Xi-Ya Luo, Fang Tian, Xiao-Ying Xu, and Li-Xin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301115t • Publication Date (Web): 17 Aug 2012
Downloaded from http://pubs.acs.org on August 25, 2012
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Direct Asymmetric Vinylogous Mannich Reaction of 3,4ꢀdihalofuranꢀ2(5H)ꢀone with
Aldimine Catalyzed by Quinine
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YunꢀLong Guo,†,‡ JianꢀFei Bai,†,‡ Lin Peng,† LiangꢀLiang Wang,†,‡ LiꢀNa Jia,†,‡ XiꢀYa Luo,†,‡ Fang Tian,†
XiaoꢀYing Xu,*,† and LiꢀXin Wang*,†
†Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
‡Graduate School of Chinese Academy of Sciences, Beijing, China
E-mail: wlxioc@cioc.ac.cn, xuxy@cioc.ac.cn
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
The direct asymmetric vinylogous Mannich reaction of 3,4ꢀdihalofuranꢀ2(5H)ꢀone with aldimine
catalyzed by quinine was firstly reported and γꢀbutenolides have been obtained in excellent yield (up to
98%) and enantioselectivities (up to 95% ee). The synthetic applications of this protocol are
demonstrated in the preparations of γꢀsubstituted amino butyrolactones and vicinal amino alcohols.
Mannich reaction is an important and effective carbonꢀcarbon bond formation reaction for βꢀamino
functional moieties.1 Particularly, the vinylogous Mannich reaction，a vinyl insertion Mannich reaction,
generates a new CꢀC bond and leads to the formation of δꢀamino α,βꢀunsaturated carbonyl compounds
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which are widely existed in natural compound skeletons.2 The donors of which mainly include acyclic silyl
dienolate,3 2ꢀsilyloxyfurans,4 dicyanoalkylidenes,5 and γꢀbutyrolactams.6 Typically, the utilization of
2ꢀsilyloxyfuran as the nucleophile for vinylogous Mannich reaction catalyzed by transition metal catalysts4aꢀh
and chiral phosphoric acids4iꢀj has been well documented. However, the direct asymmetric vinylogous
Mannich reaction of 2ꢀ(5H)furanone derivatives has not drawn enough attentions until Shibasaki’s group
reported the first direct asymmetric Mannichꢀtype reactions of γꢀbutenolides catalyzed by a chiral
lanthanumpyridine bisoxazolinecomplex.7 To the best of our knowledge, the small molecular catalytic direct
asymmetric Mannich reaction of furanones has not been reported, partially because of the relative lower
activities of furanones. In 2010, Terada8 reported the first asymmetric direct vinylogous aldol reaction of
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3,4ꢀdihalofuranꢀ2(5H)ꢀone
with
aldehydes
catalyzed
by
chiral
guanidines,
in
which
3,4ꢀdihalofuranꢀ2(5H)ꢀone showed extremely high reactivity. Based on those backgrounds, we envisioned
that the asymmetric direct vinylogous Mannich reaction of 3,4ꢀdihalofuranꢀ2(5H)ꢀone with imines may be
realized by an organocatalyst and afforded the chiral 3,4ꢀdihalofuranꢀ2(5H)ꢀone motifs with multifunctional
groups and can be used as versatile building blocks after successive transformations.9
Cinchona alkaloids are widely used chiral organic catalysts for asymmetric synthesis.10 In our previous
work,11 we have successfully applied their derivatives in some asymmetric catalyses. Inspired by those
achievements, we recognized that the tertiary amine group would activate the 3,4ꢀdihalofuranꢀ2(5H)ꢀone and
the hydroxyl group would activate the imine through hydrogen bondings. Thus the synergistic interactions
would ensure high stereoselectivity in this transformation, affording the corresponding optically active
products via a postulated transition state (TS) as shown in Figure 1. As a part of our continuing interests in
asymmetric syntheses,12 herein, we wish to report the first asymmetric direct vinylogous Mannich reaction of
3,4ꢀdihalofuranꢀ2(5H)ꢀone with aldimine catalyzed by quinine.
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Figure 1. Proposed transition state
To devise a model reaction, imine 1a and 3,4ꢀdichlorofuranꢀ2(5H)ꢀone 2a were selected as reactants to
screen the asymmetric reaction conditions and the results were summarized in Table 1. The reaction was
performed smoothly in CH2Cl2 with 20 mol % catalyst 4a at 35 oC and afforded excellent yield and moderate
enantioselectivitiy (91% yield, 41% ee; Table 1, entry 1). While other cinchona alkaloids 4b-4d gave relative
lower yields and enantioselectivities (76%ꢀ85% yield, 6%ꢀ24% ee, Table 1, entries 2ꢀ4). To further improve
the results, a series of bifunctional tertiary amineꢀthiourea catalysts 4e-m were also evaluated, and the
products were obtained in poor ee values (6%ꢀ23% ee, Table 1, entries 5ꢀ13). Based on the screenings of
catalysts, catalyst 4a, with 91% yield, 41% ee and a diastereomeric ratio (dr) of 1.2:1 was selected for further
optimization (Table 1, entry 1).
Scheme 1. catalysts 4a–m investigated.
Table 1. Screenings of catalyst for the vinylogous Mannich reaction of 2a with 1aa
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entry
1
catalyst
4a
yieldb (%)
91
drc (%)
eed (%)
41/40
ꢀ24/ꢀ27
ꢀ6/ꢀ10
19/24
ꢀ9/ꢀ2
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1.2:1
1.2:1
1.5:1
1.2:1
1.3:1
1.2:1
1.2:1
1.3:1
1.7:1
1.9:1
2.9:1
1.3:1
1.2:1
2
4b
4c
85
3
85
4
4d
4e
76
5
77
6
4f
71
7/ꢀ4
7
4g
61
8/ꢀ8
8
4h
4i
74
ꢀ23/ꢀ13
ꢀ23/ꢀ10
ꢀ12/ꢀ8
ꢀ13/ꢀ20
ꢀ13/ꢀ2
ꢀ6/ꢀ9
9
76
10
11
12
13
4j
66
4k
4l
32
73
4m
68
a Reactions were performed with 0.1 mmol of 1a, 0.2 mmol of 2a in 1 mL of dichloromethane at 35 oC for 24h.
b Isolated yield. c Determined by HPLC analysis. d Enantiomeric excess determined by chiral HPLC.
With 20 mol % 4a as the catalyst, solvents, temperature and additives were screened, and the results were
listed in Table 2. Solvents dramatically affected the ee values (Table 2, entries 1ꢀ7). Aprotic solvents, such
as toluene, mesitylene, mꢀxylene and tetrahydrofuran resulted in higher enantioselectivities than protonic
solvent (Table 2, entries 1ꢀ6 vs entry 7). Relative strong polar solvents led to lower ee values (Table 2,
entries 4ꢀ7). In the presence of 3Å MS, mꢀxylene afforded 63% ee (Table 2, entry 10). Lowering the
o
temperature to ꢀ30 C resulted in an increase of enantioselectivity (77% ee, Table 2, entry 14). When 10
mol% of 4a used, the ee value slightly raised to 81% in 95% yield (Table 2, entry 16). The concentration of
the substrates was also screened and 3a was obtained in 85% ee and 85% yield in 2 mL mꢀxylene (Table 2,
entry 19). Based on the above results, 0.1 mmol 1a and 0.2 mmol 2a in 2 mL mꢀxylene with 10 mol %
catalyst 4a at ꢀ30 oC were established as optimal reaction conditions.
Table 2. Screening of optimal reaction conditions for the vinylogous Mannich reaction of 1a with 2aa
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Ts
HN
Cl
O
Ts
Cl
Cl
N
cat. 4a
solvent
Ph
+
Cl
O
O
Ph
6
O
7
1a
2a
8
3a
9
entry
1
solvent
toluene
t
T (oC)
35
yieldb (%)
71
drc (%)
1.2:1
1:1
eed (%)
47
44
44
33
27
11
2
10
11
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13
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24h
24h
24h
24h
24h
24h
24h
24h
24h
24h
69h
52h
71h
76h
71h
71h
71h
2
mesitylene
mꢀxylene
35
75
3
35
67
1.2:1
1.3:1
1.4:1
2.2:1
3:1
4
1,2ꢀdichloroethane
tetrahydrofuran
acetonitrile
methanol
35
71
5
35
76
6
35
73
7
35
91
8e
toluene
35
99
1.2:1
1.8:1
1.3:1
2.2:1
2.3:1
2.4:1
2.0:1
1.9:1
3.2:1
4.9:1
6.0:1
6.5:1
53
54
63
64
68
74
77
82
81
84
84
85
9e
mesitylene
mꢀxylene
35
82
10e
11e
12e
13e
14e
15e, f
16e, g
17e, h
18e, g, i
19e, g, j
35
72
mꢀxylene
0
99
mꢀxylene
ꢀ10
ꢀ20
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
99
mꢀxylene
98
mꢀxylene
99
mꢀxylene
94
mꢀxylene
95
mꢀxylene
71
mꢀxylene
144h
88
mꢀxylene
168h
85
a Reactions were performed with 0.1 mmol of 1a, 0.2 mmol of 2a, 20 mol % 4a in 1 mL solvent. b Isolated yield. c
Determined by HPLC analysis. d Enantiomeric excess of the major diastereoisomer determined by chiral HPLC. e
30 mg 3ÅMS was added. f with 15 mol % 4a. g with 10 mol % 4a. h with 5 mol % 4a. i The reaction was carried
out in 1.5 mL mꢀxylene. j The reaction was carried out in 2.0 mL mꢀxylene.
Under the optimized reaction conditions, the substrate scope of the reaction was further explored to test the
generality of this protocol (Table 3). A series of aldimines derived from aromatic aldehydes bearing
electronꢀwithdrawing and electronꢀdonating groups were selected and gave the adducts in moderate to high
yields (37%ꢀ98%), moderate diastereoselectivities (3:1ꢀ13:1), and excellent ee (up to 95% ee). Aldimines
with orthoꢀsubstitutents afforded slightly higher enantioselectivities than their paraꢀsubstituted counterparts
(Table 3, entries 4ꢀ6 vs 8ꢀ10). When metaꢀchloride substituted aldimine used, no product was detected
(Table 3, entry 13). 4ꢀOMe aromatic aldimine gave moderate yield and the highest enantioselectivity (54%
yield, 95% ee; Table 3, entry 2). The optimized protocol was also expanded to 3,4ꢀdibromofuranꢀ2(5H)ꢀone
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2b, and moderate to good yields and excellent enantioselectivities were obtained (41%ꢀ95% yield, 84%ꢀ94%
ee, Table 3, entries 14ꢀ24).
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Table 3. Direct Catalytic Asymmetric vinylogous Mannich Reactions of Imines 1 and γꢀDihalobutenolides 2a
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entry
1
R1
1
1a
1b
1c
1d
1e
1f
2
3
t
yieldb (%)
85
dr
6.5:1c
4:1c
4:1d
6:1d
7:1d
13:1d
7:1c
5:1d
8:1d
12:1d
10:1d
4:1d
ꢀ
3:1d
6:1c
5:1d
3:1d
7:1d
4:1d
4:1d
4:1d
10:1d
11:1d
4:1d
eee (%)
85
95
80
86
84
86
88
90
91
92
84
85
ꢀ
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
3aa
3ba
3ca
3da
3ea
3fa
7d
2
4ꢀMeOꢀPh
4ꢀMeꢀPh
4ꢀBrꢀPh
4ꢀClꢀPh
4ꢀFꢀPh
7d
54
3
7d
89
4
7d
66
5
7d
81
6
11d
7d
60
7
4ꢀNO2ꢀPh
2ꢀFꢀPh
1g
1h
1i
3ga
3ha
3ia
37
8
10d
8d
86
9
2ꢀClꢀPh
2ꢀBrꢀPh
2ꢀnaphthyl
3ꢀMeꢀPh
3ꢀClꢀPh
Ph
86
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1j
3ja
7d
98
1k
1l
3ka
3la
7d
95
7d
95
1m
1a
1b
1c
1d
1e
1f
3ma
3ab
3bb
3cb
3db
3eb
3fb
3gb
3hb
3ib
7d
nd
11d
13d
11d
10d
10d
10d
8d
80
89
90
86
88
88
94
91
94
93
88
84
4ꢀMeOꢀPh
4ꢀMeꢀPh
4ꢀBrꢀPh
4ꢀClꢀPh
4ꢀFꢀPh
44
55
41
41
51
2ꢀFꢀPh
1g
1h
1i
90
2ꢀClꢀPh
2ꢀBrꢀPh
2ꢀnaphthyl
3ꢀMeꢀPh
7d
90
8d
94
1j
3jb
3kb
11d
11d
95
1k
76
a Reactions performed with 0.1 mmol of 1, 0.2 mmol of 2, 4a (10 mol %), 3Å MS (30 mg) in 2.0 mL mꢀxylene at
ꢀ30 oC for 7ꢀ13 days. b Isolated yield. c Determined by HPLC analysis. d Determined by isolated yield of two
diastereoisomers. e Enantiomeric excess of the major diastereoisomer determined by chiral HPLC.
Vinylogous Mannich products 3, with multiple functional groups and potential chiral centers, may be easily
transformed to γꢀbutyrolactones13 which were the core structure of sapinofuranones.14 Importantly,
γꢀbutyrolactone derivatives could be readily converted to vicinal amino alcohols,15 important pharmaceutical
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skeletons widely exist in protease inhibitors such as ritonavir16a and swainsonine.16b Typically as shown in
Scheme 2, reduction and dehalogation of 3ja afforded the chiral γꢀbutyrolactone 5. After further reduction of
5 with LiBH4 at room temperature, vicinal amino alcohol 6 was obtained in almost unchanged ee value
(Scheme 2). The absolute configuration was determined by an Xꢀray analysis of the single crystal of 6,
which was assigned as (C7R, C8R)(see supporting information).
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Ts
O
Ts
O
Ts
Br HN
Br HN
Br HN
Cl
NiCl2 6H2O, NaBH4
LiBH4
OH
Cl
THF/MeOH (1:1)
(43 %)
rt
OH
(90%)
O
O
6 (91 % ee)
3ja (92 % ee)
5 (91 % ee)
Scheme 2. Preparation of chiral γꢀsubstituted butyrolactone 5 and vicinal amino alcohol 6
In summary, we have developed
a direct vinylogous Mannich reaction of aldimines with
3,4ꢀdihalofuranꢀ2(5H)ꢀone catalyzed by quinine. A series of γꢀbutenolides derivatives were obtained in good
yields (up to 98% yield) and enantioselectivities (up to 95% ee), which were easily transformed to some
chiral pharmaceutical intermediates γꢀbutyrolactones and vicinal amino alcohols.
Experimental Section
General Procedure for Vinylogous Mannich Reaction
Catalyst 4a (10 mol %), 3Å MS (30 mg) and imine 1 (0.1 mmol) were dissolved in 2mL mꢀxylene at ꢀ30 oC
for 0.5h. Substrate 2 (0.2 mmol) was added to the solution and stirred for 7ꢀ13d. The reaction was monitored
by TLC analysis. The reaction mixture was directly subjected to flash column chromatography on silica gel
(petroleum ether/ethyl acetate) to furnish the corresponding products 3.
N-((R)-((S)-3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(phenyl)methyl)-4-methylbenzenesulfonamide (3aa)
o
White solid, mp 148ꢀ149 C; [α]D20=ꢀ85 (c 0.1, CH2Cl2), yield 85 %; 6.5:1 dr, Enantiomeric excess: 85 %,
determined by HPLC (Chiralcel AYꢀH column, hexane/ethanol /TFA= 55/45/0.1%, flow rate 0.7 mL/min,
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UV detection at 220 nm), tR (major) = 14.1 min, tR (minor) = 24.4 min. H NMR (300 MHz, CDCl3) δ 7.51
5
6
7
8
9
(d, J = 8.2 Hz, 2H), 7.24ꢀ7.15 (m,5H), 7.10 (d, J = 8.0 Hz, 2H), 5.54 (d, J = 10.0 Hz, 1H), 5.09 (d, J = 1.6 Hz,
1H), 4.97 (dd, J = 10.0 Hz, 1.5 Hz, 1H), 2.33 (s, 3H); 13C NMR(75 MHz, CDCl3) δ 164.9, 149.8, 143.6,
136.9, 135.9, 129.5, 129.4, 128.9, 128.6, 126.9, 122.8, 84.4, 56.6, 21.4; HRMS (ESI) Calcd. for
C18H15Cl2NNaO4S [M+Na]+: 433.9985; Found: 433.9991; IR (KBr) νmax/cm‐1: 3295, 2923, 1769, 1627, 1337,
1239, 1162, 701.
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N-((R)-((S)-3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(4-methoxyphenyl)methyl)-4-methylbenzenesulfona
mide (3ba) White solid, [α]D20=ꢀ76 (c 0.1, CH2Cl2), yield 54 %; 4:1 dr, Enantiomeric excess: 95 %,
determined by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol = 90/10, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 26.1 min, tR (major) = 39.9 min. 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J
= 8.2 Hz, 2H), 7.11ꢀ7.07 (m, 4H), 6.73 (d, J = 8.7 Hz, 2H), 5.59 (d, J = 9.8 Hz, 1H), 5.08 (d, J = 1.7 Hz, 1H),
4.91 (dd, J = 9.7Hz, 1.3Hz, 1H), 3.75 (s, 3H), 2.33 (s, 3H); 13C MR (75 MHz, CDCl3) δ 165.9, 160.7, 150.8,
149.6, 144.5, 138.0, 130.5, 129.3, 128.0, 124.3, 115.2, 85.5, 57.2, 56.2, 22.4; HRMS (EI) Calcd. for
C19H17NO5SCl2 [M]+: 441.0205; Found: 441.0247; IR (KBr) νmax/cm‐1: 3296, 2936, 1778, 1629, 1334, 1257,
1161, 734.
N-((R)-((S)-3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (3ca)
o
White solid, mp 163ꢀ164 C; [α]D20=ꢀ160 (c 0.2, CH2Cl2), yield 89 %; 4:1 dr, Enantiomeric excess: 80 %,
determined by HPLC (Chiralcel AYꢀH column, hexane/ethanol/TFA = 55/45/0.1%, flow rate 0.7 mL/min,
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UV detection at 220 nm), tR (minor) = 20.5 min, tR (major) = 14.7 min. H NMR (300 MHz, CDCl3) δ 7.51
(d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 7.06ꢀ7.00 (m, 4H), 5.47 (d, J = 9.7 Hz, 1H), 5.08 (d, J = 1.7 Hz,
1H), 4.92 (d, J = 10.0 Hz), 2.34 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.9, 149.8, 143.5,
138.6, 136.9, 132.7, 129.5, 129.4, 127.0, 126.8, 122.7, 84.4, 56.4, 21.4; HRMS (EI) Calcd. for
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C19H17NO4SCl2 [M]+: 425.0255; Found: 425.0246; IR (KBr) νmax/cm‐1: 3316, 2967, 1770, 1622, 1324, 1247,
1160, 706.
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de (3da) White solid, mp 186ꢀ187 C; [α]D20=ꢀ98 (c 0.1, CH2Cl2), yield 66 %; 6:1 dr, Enantiomeric excess:
86 %, determined by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol = 90/10, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 11.0 min, tR (major) = 21.2 min. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J
= 8.5 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.12ꢀ7.03 (m, 4H), 6.82 (d, J = 10.3 Hz, 1H), 5.04 (d, J = 1.1 Hz,
1H), 4.94 (d, J = 10.3 Hz, 1H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.1, 149.7, 143.8, 136.7, 134.6,
131.9, 129.7, 129.5, 128.7, 126.9, 122.7, 84.3, 56.1, 21.4; HRMS (ESI) Calcd. for C18H18BrCl2N2O4S
[M+NH4]+: 506.9542; Found: 506.9539; IR (KBr) νmax/cm‐1: 3316, 2968, 1770, 1621, 1326, 1247, 1163, 722.
N-((R)-(4-chlorophenyl)((S)-3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)methyl)-4-methylbenzenesulfonami
de (3ea) White solid, mp 182ꢀ183 oC; [α]D20=ꢀ105 (c 0.1, CH2Cl2), yield 81 %; 7:1 dr, Enantiomeric excess:
84 %, determined by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol = 80/20, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 10.3 min, tR (major) = 19.8 min. 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J
= 8.2 Hz, 2H), 7.18ꢀ7.07 (m, 6H), 5.87 (d, J = 10.2 Hz, 1H), 5.04 (d, J = 1.4 Hz, 1H)
4.95 (d, J = 10.2 Hz,
1H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.9, 149.6, 143.7, 136.8, 134.6, 134.1, 129.4, 128.9,
128.4, 126.8, 122.8, 84.3, 56.0, 21.3; HRMS (EI) Calcd. for C18H14NO4SCl3 [M]+: 444.9709; Found:
444.9721; IR (KBr) νmax/cm‐1: 3265, 2924, 1760, 1628, 1340, 1243, 1159, 742.
N-((R)-((S)-3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(4-fluorophenyl)methyl)-4-methylbenzenesulfonami
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de (3fa) White solid, mp 138ꢀ139 C; [α]D20=ꢀ84 (c 0.1, CH2Cl2), yield 60 %; 13:1 dr, Enantiomeric excess:
86 %, determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol = 85/15, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 13.0 min, tR (major) = 23.2 min. 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J
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= 8.2 Hz, 2H), 7.19ꢀ7.14(m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.91ꢀ6.86 (m, 2H), 5.87 (d, J = 10.2 Hz, 1H), 5.05
(d, J = 1.6 Hz, 1H), 4.97 ( d, J = 10.2 Hz, 1H), 2.35 (s, 3H); 13 C NMR (75 MHz, DCl3) δ 165.1, 160.9 (JCꢀF
= 247.0 Hz), 149.8, 136.9, 131.7, 129.4, 129.0 (JCꢀF = 8.3 Hz), 128.8, 126.9, 122.7, 115.9 (JCꢀF = 21.6 Hz),
84.5, 56.0, 21.4; HRMS (ESI) Calcd. for C18H14Cl2FNNaO4S [M+Na]+: 451.9897; Found: 451.9902; IR
(KBr) νmax/cm‐1: 3298, 2959, 1766, 1631, 1338, 1230, 1158, 686.
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N-((R)-((S)-3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(4-nitrophenyl)methyl)-4-methylbenzenesulfonamide
(3ga) Light yellow solid, yield 37 %; 7:1 dr, Enantiomeric excess: 88 %, determined by HPLC (Chiralcel
ODꢀH column, hexane/iꢀpropanol = 80/20, flow rate 1 mL/min, UV detection at 220 nm), tR (minor) = 25.4
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min, tR (major) = 58.9 min. H NMR (300 MHz, DMSO) δ 8.95 (d, J = 10.1 Hz, 1H), 8.01 (d, J = 8.5 Hz,
2H), 7.55 (d, J = 8.6 Hz, 1H), 7.47 (m, 2H), 7.13 (m, 1H), 5.60 (d, J = 2.4 Hz, 1H), 5.19 (dd, J = 10.2Hz, 2.1
Hz, 1H), 5.09 (m, 1H), 2.36 (s, 3H); 13C NMR (75 MHz, DMSO) δ 164.4, 147.0, 143.7, 142.6, 141.4, 137.7,
129.2, 126.3, 125.5, 122.8, 84.0, 57.1, 20.8; HRMS (ESI) Calcd. for C18H14Cl2N2NaO6S [M+Na]+: 478.9842;
Found: 478.9837; IR (KBr) νmax/cm‐1: 3404, 2859, 1789, 1635, 1336, 1233, 1159, 756.
N-((3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(2-fluorophenyl)methyl)-4-methylbenzenesulfonamide (3ha)
White solid, mp 150ꢀ151 C; [α]D20=ꢀ96 (c 0.1, CH2Cl2), yield 86 %; 5:1 dr, Enantiomeric excess: 90 %,
o
determined by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol = 85/15, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 13.2 min, tR (major) =14.1 min. 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J =
7.7 Hz, 2H), 7.22ꢀ7.18 (m, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.98ꢀ6.90 (m, 2H), 5.96 (br, 1H), 5.38 (d, J = 10.7
Hz, 1H), 5.04 (d, J = 1.6 Hz, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.0, 157.6 (JCꢀF =244.5 Hz),
149.8, 143.6, 136.7, 130.3 (JCꢀF = 8.3 Hz), 129.4, 128.3, 126.9, 126.4, 124.7, 122.9, 115.6 (JCꢀF = 21.5 Hz),
84.0, 50.3, 21.3; HRMS (ESI) Calcd. for C18H14Cl2FNNaO4S [M+Na]+: 451.9897; Found: 451.9897; IR
(KBr) νmax/cm‐1: 3295, 2925, 1782, 1631, 1343, 1242, 1165, 740.
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N-((2-chlorophenyl)(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)methyl)-4-methylbenzenesulfonamide (3ia)
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White solid, mp 170ꢀ171 C; [α]D20=ꢀ96 (c 0.1, CH2Cl2), yield 86 %; 8:1 dr, Enantiomeric excess: 91 %,
o
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determined by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol = 90/10, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 17.6 min, tR (major) =20.6 min. 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J =
8.3 Hz, 2H), 7.29ꢀ7.28 (m, 1H), 7.21ꢀ7.15 (m, 2H), 7.10ꢀ7.02 (m, 3H), 6.22 (d, J = 10.9 Hz, 1H), 5.62 (d, J =
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11.0 Hz, 1H), 5.06 (d, J = 1.5 Hz, 1H), 2.28 (s, 3H); C NMR (75 MHz, CDCl3) δ 165.4, 150.1, 143.5,
136.7, 133.1, 131.9, 129.5, 129.4, 129.3, 128.3, 127.4, 126.8, 122.5, 83.5, 52.8, 21.3; HRMS (EI) Calcd. for
C18H14NO4SCl3 [M]+: 444.9709; Found: 444.9697; IR (KBr) νmax/cm‐1: 3283, 2948, 1785, 1630, 1243, 1163,
736, 709.
N-((2-bromophenyl)(3,4-dichloro-5-oxo-dihydrofuran-2-yl)methyl)-4-methylbenzenesulfonamide
(3ja)
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White solid, mp 178ꢀ179 C; [α]D20=ꢀ38 (c 0.1, CH2Cl2), yield 98 %; 12:1 dr, Enantiomeric excess: 92 %,
determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 90/10, flow rate 1 mL/min, UV detection at
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220 nm), tR (minor) = 10.5 min, tR (major) =14.7 min. H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.1 Hz,
2H), 7.46ꢀ7.43 (m, 1H), 7.20ꢀ7.18 (m, 1H), 7.10ꢀ7.00 (m, 4H), 6.35 (d, J = 10.9 Hz, 1H), 5.84 (d, J = 11.0
Hz, 1H), 5.07 (d, J = 1.2 Hz, 1H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6, 150.3, 143.3, 136.6,
134.4, 132.6, 129.7, 129.3, 128.6, 128.0, 126.8, 126.4, 122.2, 83.5, 55.2, 21.3; HRMS (EI) Calcd. for
C18H14NO4SCl2Br [M]+: 488.9204; Found: 488.9219; IR (KBr) νmax/cm‐1: 3286, 2946, 1785, 1630, 1348,
1243, 1163, 658.
N-((3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(naphthalene-2-yl)methyl)-4-methylbenzenesulfonamide
o
(3ka) White solid, mp 168ꢀ169 C; [α]D20=ꢀ12 (c 0.1, CH2Cl2), yield 95 %; 10:1 dr, Enantiomeric excess:
84 %, determined by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol= 90/10, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 22.6 min, tR (major) =58.2 min. 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J =
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8.3 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 8.1Hz, 1H), 7.60ꢀ7.50 (m, 2H), 7.42ꢀ7.34 (m, 3H),
7.28ꢀ7.23 (m, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.43 (d, J = 10.5 Hz, 1H), 5.98 (d, J = 10.7 Hz, 1H), 5.14 (s, 1H),
2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.0, 150.0, 143.2, 136.8, 133.6, 130.9, 129.5, 129.3, 129.1,
128.9, 127.1, 126.7, 125.9, 125.3, 125.0, 122.6, 121.0, 84.0, 51.6, 21.2; HRMS (EI) Calcd. for
C22H17NO4SCl2 [M]+: 461.0255; Found: 461.0256; IR (KBr) νmax/cm‐1: 3298, 2920, 1785, 1634, 1339, 1241,
1163, 735.
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N-((3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)(m-tolyl)methyl)-4-methylbenzenesulfonamide
(3la)
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White solid, mp 75ꢀ76 C; [α]D20=ꢀ95 (c 0.1, CH2Cl2), yield 95 %; 4:1 dr, Enantiomeric excess: 85 %,
determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 95/5, flow rate 1 mL/min, UV detection at
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220 nm), tR (minor) = 16.5 min, tR (major) =25.4 min. H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 8.1 Hz,
2H), 7.15ꢀ7.10 (m, 3H), 7.09ꢀ6.99 (m, 2H), 6.88 (s, 1H), 5.50 (brs, 1H), 5.09 (d, J = 1.4Hz, 1H), 4.93 (dd, J
= 10.0 Hz, 1.1 Hz, 1H), 2.35 (s, 3H), 2.22 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.0, 149.9, 143.4, 138.6,
136.9, 135.6, 129.4, 129.3, 128.8, 127.6, 126.9, 123.9, 122.7, 84.5, 56.5, 21.3, 21.1; HRMS (EI) Calcd. for
C19H17NO4SCl2 [M]+: 425.0255; Found: 425.0276; IR (KBr) νmax/cm‐1: 3281, 2923, 1785, 1631, 1339, 1234,
1162, 713.
N-((3,4-dibromo-5-oxo-2,5-dihydrofuran-2-yl)(phenyl)methyl)-4-methylbenzenesulfonamide (3ab) White
solid, mp 116ꢀ117 oC; [α]D20=ꢀ86 (c 0.1, CH2Cl2), yield 80 %; 3:1 dr, Enantiomeric excess: 89 %, determined
by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol= 85/15, flow rate 1 mL/min, UV detection at 220 nm),
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tR (minor) = 14.9 min, tR (major) =19.4 min. H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H),
7.24ꢀ7.11 (m, 5H), 7.08 (d, J = 8.0 Hz, 2H), 5.36 (d, J = 10.1 Hz, 1H), 5.09 (d, J = 1.6 Hz, 1H), 5.02 (dd, J =
10.1 Hz, 1.5Hz, 1H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.7, 145.4, 143.5, 137.1, 136.0, 130.8,
129.4, 128.9, 128.6, 127.0, 116.5, 87.0, 56.9, 21.4; HRMS (ESI) Calcd. for C18H15Br2NNaO4S [M+Na]+:
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521.8981; Found: 521.8993; IR (KBr) νmax/cm‐1: 3293, 2919, 1758, 1605, 1336, 1214, 1161, 702.
N-((3,4-dibromo-5-oxo-2,5-dihydrofuran-2-yl)(4-methoxyphenyl)methyl)-4-methylbenzenesulfonamide
(3bb) White solid, yield 44 %; 6:1 dr, Enantiomeric excess: 90 %, determined by HPLC (Chiralcel AYꢀH
column, hexane/ethanol/TFA= 55/45/0.1%, flow rate 0.6 mL/min, UV detection at 220 nm), tR (minor) =
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22.9 min, tR (major) =47.9 min. H NMR (300 MHz, CDCl3) δ 7.55ꢀ7.50 (m, 4H), 6.91 (d, J =8.6 Hz, 2H),
6.64 (d, J = 8.7 Hz, 2H), 5.09 (d, J = 1.7 Hz, 1H), 4.97ꢀ4.91 (m, 2H), 3.72 (s, 3H), 2.35 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 165.8, 145.5, 143.5, 137.1, 129.5, 128.3, 126.9, 123.4, 116.6, 114.2, 87.1, 58.1, 55.3,
21.4; HRMS (ESI) Calcd. for C19H17Br2NNaO5S [M+Na]+: 551.9086; Found: 551.9090; IR (KBr) νmax/cm‐1:
3294, 2935, 1755, 1607, 1334, 1257, 1159, 733.
N-((R)-((S)-3,4-dibromo-5-oxo-2,5-dihydrofuran-2-yl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (3cb)
White solid, mp 166ꢀ167 C; [α]D20=ꢀ92 (c 0.1, CH2Cl2), yield 55 %; 5:1 dr, Enantiomeric excess: 86 %,
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determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 92/8, flow rate 1 mL/min, UV detection at
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220 nm), tR (minor) = 15.4 min, tR (major) =24.4 min. H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 8.2 Hz,
2H), 7.09ꢀ6.99 (m, 6H), 5.60 (d, J = 10.0 Hz, 1H), 5.06 (d, J = 1.5Hz, 1H), 4.97 (d, J = 10.1 Hz, 1H), 2.33 (s,
3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.9, 145.5, 143.3, 138.4, 137.0, 132.9, 129.4, 129.3,
127.0, 126.8, 116.3, 87.2, 56.7, 21.4, 21.0; HRMS (EI) Calcd. for C19H17NO4SBr2 [M]+: 512.9245; Found:
512.9232; IR (KBr) νmax/cm‐1: 3315, 2960, 1763, 1600, 1323, 1224, 1162, 680.
N-((R)-(4-bromophenyl)(S)-3,4-dibromo-5-oxo-2,5-dihydrofuran-2-yl)methyl)-4-methylbenzenesulfonamid
e (3db) White solid, mp 201ꢀ202 C; [α]D20=ꢀ74 (c 0.1, CH2Cl2), yield 41 %; 3:1 dr, Enantiomeric excess:
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88 %, determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 92/8, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 20.2 min, tR (major) =38.4 min. 1H NMR (300 MHz, CDCl3) δ 7.45(d, J =
8.3 Hz, 2H), 7.33ꢀ7.30 (m, 2H), 7.09ꢀ7.04 (m, 4H), 5.85 (d, J = 10.3 Hz, 1H), 5.03 (d, J = 1.6 Hz, 1H), 4.98
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(dd, J = 10.4 Hz, 1.4Hz, 1H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.9, 145.3, 143.7, 136.8, 134.8,
131.9, 129.4, 128.8, 127.0, 122.7, 116.4, 87.0, 56.5, 21.4; HRMS (ESI) Calcd. for C18H14Br3NNaO4S
[M+Na]+: 599.8086; Found: 599.8096; IR (KBr) νmax/cm‐1: 3279, 2933, 1778, 1609, 1339, 1213, 1160, 723.
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e (3eb) White solid, mp 191ꢀ192 C; [α]D20=ꢀ98 (c 0.1, CH2Cl2), yield 41 %; 7:1 dr, Enantiomeric excess:
88 %, determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 92/8, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 18.6 min, tR (major) =35.7 min. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J =
8.5 Hz, 2H), 7.19ꢀ7.07 (m, 6H), 5.75 (d, J = 10.3 Hz, 1H), 5.03 (d, J = 1.5 Hz, 1H), 5.00 (d, J = 10.4 Hz, 1H),
2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.9, 145.3, 143.7, 136.8, 134.6, 129.4, 129.0, 128.5, 127.0,
126.4, 116.5, 87.0, 56.4, 21.4; HRMS (ESI) Calcd. for C18H14Br2ClNNaO4S [M+Na]+: 555.8591; Found:
555.8588; IR (KBr) νmax/cm‐1: 3296, 2921, 1759, 1602, 1338, 1217, 1158, 739.
N-((R)-((S)-3,4-dibromo-5-oxo-2,5dihydrofuran-2-yl)(4-fluorophenyl)methyl)-4-methylbenzenesulfonamid
o
e (3fb) White solid, mp 151ꢀ152 C; [α]D20=ꢀ85 (c 0.1, CH2Cl2), yield 51 %; 4:1 dr, Enantiomeric excess:
94 %, determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 92/8, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 18.0 min, tR (major) =31.7 min. 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J =
8. 2Hz, 2H), 7.22ꢀ7.17 (m, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.94ꢀ6.88 (m, 2H), 5.73 (d, J = 10.2 Hz, 1H), 5.06
(d, J = 1.6 Hz, 1H), 5.03 (d, J = 10.2 Hz, 1H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.9, 160.9 (JCꢀF
= 246.9 Hz), 145.4, 143.6, 137.0, 131.9 (JCꢀF = 3.3 Hz), 129.4, 129.0 (JCꢀF = 8. 3Hz), 127.0, 116.4, 115.9 (JCꢀF
= 21.6 Hz), 87.2, 56.4, 21.4; HRMS (EI) Calcd. for C18H14NO4FSBr2 [M]+: 516.8994; Found: 516.8965; IR
(KBr) νmax/cm‐1: 3298, 2922, 1754, 1604, 1337, 1229, 1159, 728.
N-((R)-((S)-3,4-dibromo-5-oxo-2,5dihydrofuran-2-yl)(2-fluorophenyl)methyl)-4-methylbenzenesulfonamid
o
e (3gb) White solid, mp 168ꢀ169 C; [α]D20=ꢀ88 (c 0.1, CH2Cl2), yield 90 %; 4:1 dr, Enantiomeric excess:
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91 %, determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 97/3, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 39.2 min, tR (major) =50.2 min. 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J =
8. Hz, 2H), 7.22ꢀ7.16 (m, 2H), 7.08 (d, J = 7.9 Hz, 2H), 7.01ꢀ6.90 (m, 2H), 5.73 (d, J = 10.9 Hz, 1H), 5.41 (d,
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J = 10.9 Hz, 1H), 5.03 (d, J = 1.7 Hz, 1H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6, 157.6 (JCꢀF
=
244.4 Hz), 145.3, 143.6, 136.7, 130.2 (JCꢀF = 8.4 Hz), 129.4, 128.3, 126.9, 124.7, 123.3, 116.4, 115.6 (JCꢀF
=21.6 Hz), 86.6, 50.7, 21.4; HRMS (ESI) Calcd. for C18H14Br2FNNaO4S [M+Na]+: 539.8887; Found:
539.8897; IR (KBr) νmax/cm‐1: 3290, 2946, 1778, 1611, 1348, 1213, 1163, 675.
N-((R)-(2-chlorophenyl)((S)-3,4-dibromo-5-oxo-2,5-dihydrofuran-2-yl)-4-methylbenzenesulfonamide (3hb)
o
White solid, mp 179ꢀ180 C; [α]D20=ꢀ57 (c 0.1, CH2Cl2), yield 90 %; 4:1 dr, Enantiomeric excess: 94 %,
determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 97/3, flow rate 1 mL/min, UV detection at
1
220 nm), tR (minor) = 35.8 min, tR (major) = 49.2 min. H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.0 Hz,
2H), 7.32ꢀ7.28 (m, 1H), 7.22ꢀ7.08 (m, 2H), 7.04ꢀ7.01 (m, 3H), 6.30 (brs, 1H), 5.66 (d, J = 11.5 Hz, 1H), 5.06
(d, J = 1.4 Hz, 1H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.2, 145.8, 143.4, 136.8, 133.3, 131.9,
129.4, 129.3, 128.4, 127.4, 126.9, 126.5, 116.1, 86.1, 53.2, 21.3; HRMS (ESI) Calcd. for C18H18Br2ClN2O4S
[M+NH4]+: 550.9037; Found: 550.9049; IR (KBr) νmax/cm‐1: 3282, 2946, 1778, 1610, 1347, 1213, 1162, 675.
N-((R)-(2-bromophenyl)((S)-3,4-dibromo-5-oxo-2,5-dihydrofuran-2-yl)-4-methylbenzenesulfonamide (3ib)
o
White solid, mp 186ꢀ187 C; [α]D20=ꢀ28 (c 0.1, CH2Cl2), yield 94 %; 10:1 dr, Enantiomeric excess: 93 %,
determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 92/8, flow rate 1 mL/min, UV detection at
1
220 nm), tR (minor) = 15.2 min, tR (major) =21.6 min. H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.2 Hz,
2H), 7.46ꢀ7.43 (m, 1H), 7.11ꢀ7.10 (m, 1H), 7.08ꢀ7.01 (m, 4H), 6.19 (d, J = 11.1 Hz, 1H), 5.64 (d, J = 11.0
Hz, 1H), 5.07 (d, J = 1.3 Hz, 1H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.2, 145.8, 143.4, 136.7,
134.7, 132.7, 129.7, 129.3, 128.6, 128.0, 126.9, 122.4, 116.1, 86.0, 55.6, 21.3; HRMS (EI) Calcd. for
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C18H14NO4SBr3 [M]+: 576.8194; Found: 576.8134; IR (KBr) νmax/cm‐1: 3291, 2945, 1778, 1610, 1347, 1212,
1163, 655.
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N-((R)-((S)-3,4-dibromo-5-oxo-2,5dihydrofuran-2-yl)(naphthalene-2-yl)methyl)-4-methylbenzenesulfonam
ide (3jb) White solid, mp 105ꢀ106 oC; [α]D20=ꢀ28 (c 0.1, CH2Cl2), yield 94 %; 10:1 dr, Enantiomeric excess:
93 %, determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 92/8, flow rate 1 mL/min, UV
detection at 220 nm), tR (minor) = 15.2 min, tR 9major) =21.6 min. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J
= 8.5 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.63ꢀ7.51 (m, 2H), 7.39ꢀ7.36 (m, 3H),
7.30ꢀ7.28 (m, 1H), 6.87 (d, J = 8.0 Hz, 2H), 6.01 (d, J = 10.4 Hz, 1H), 5.86 (d, J = 10.4 Hz, 1H), 5.13 (d. J =
1.2 Hz, 1H), 2.20 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.9, 145.6, 143.2, 136.8, 133.6, 131.1, 129.5,
129.2, 129.1, 128.9, 127.1, 126.7, 125.9, 125.2, 124.8, 121.0, 116.2, 86.4, 51.9, 21.2; HRMS (EI) Calcd. for
C22H17NO4SBr2 [M]+: 548.9245; Found: 548.9240; IR (KBr) νmax/cm‐1: 3278, 3062, 1778, 1610, 1336, 1207,
1160, 666.
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N-((R)-((S)-3,4-dibromo-5-oxo-2,5dihydrofuran-2-yl)(m-tolyl)methyl)-4-methylbenzenesulfonamide (3kb)
o
White solid, mp 83ꢀ84 C; [α]D20=ꢀ88 (c 0.1, CH2Cl2), yield 76 %; 4:1 dr, Enantiomeric excess: 84 %,
determined by HPLC (Chiralcel ODꢀH column, hexane/iꢀpropanol= 85/15, flow rate 1 mL/min, UV
1
detection at 220 nm), tR (minor) = 11.7 min, tR (major) =15.6 min. H NMR (300 MHz, CDCl3) δ 7.52ꢀ7.48
(m, 2H), 7.14ꢀ7.08 (m, 3H), 6.88 (s, 1H), 5.36 (d, J = 9.8 Hz, 1H), 5.07 (d, J = 1.5 Hz, 1H), 4.96 (dd, J =
10.1 Hz, 1.2 Hz, 1H), 2.33 (s, 3H), 2.21 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.8, 145.5, 143.4, 138.6,
137.0, 135.8, 129.4, 129.2, 128.8, 127.6, 127.0, 123.9, 116.3, 87.1, 56.9, 21.4, 21.1; HRMS (EI) Calcd. for
C19H17NO4SBr2 [M]+: 512.9245; Found: 512.9227; IR (KBr) νmax/cm‐1: 3284, 2920, 1766, 1608, 1339, 1215,
1159, 705.
N-((2-bromophenyl)(5-oxotetradrofuran-2-yl)methyl)-4-methylbenzenesulfonamide 5 To a solution of 3ja
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(129 mg, 0.26 mmol, 92% ee) in 1:1 THF/MeOH (2 mL) at 0 °C were added NiCl2ꢁ6H2O (187 mg, 0.79
mmol) and NaBH4 (100 mg, 2.6 mmol). The reaction was quenched with the addition of saturated NH4Cl
until starting material disappeared. The mixture was then filtered, and the filtrate was concentrated, and the
residue was extracted with ethyl acetate several times. The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography
(hexane/EtOAc = 5/1 as eluent) to give 5 (47 mg, 43%) as a white solid. mp 129ꢀ130 oC; [α]D20=ꢀ55 (c 0.1,
CH2Cl2), yield 43 %; Enantiomeric excess: 91 %, determined by HPLC (Chiralcel ODꢀH column,
hexane/ethanol= 92/8, flow rate 1 mL/min, UV detection at 220 nm), tR (minor) = 17.8 min, tR (major) =18.9
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min. H NMR (300 MHz, CDCl3) δ 7.52 ( d, J = 8.1 Hz, 2H), 7.38ꢀ7.35 (m, 1H), 7.18ꢀ7.15 (m, 1H),
7.01ꢀ6.95 (m, 4H), 6.34 (brs, 1H), 5.03 (dd, J= 9.8 Hz, 2.1Hz, 1H), 4.66ꢀ4.62 (m, 1H), 2.57ꢀ2.31 (m, 4H),
2.25 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.2, 143.1, 136.7, 136.2, 132.4, 129.2, 129.0, 128.7, 127.5,
126.8, 122.5, 81.8, 58.8, 28.3, 24.3, 21.3; HRMS (ESI) Calcd. for C18H18BrNNaO4S [M+Na]+: 446.0032;
Found: 446.0040; IR (KBr) νmax/cm‐1: 3234, 2959, 1769, 1337, 1197, 1161, 690.
N-((1R, 2R)-1-(2-bromophenyl)-2,5-dihydroxypentyl)-4-methylbenzenesulfonamide 6 To a solution of 5
o
(31 mg, 0.73 mmol) in dry THF (1 mL) at 0 C was added LiBH4 (33 mg, 1.46 mmol), and the resulting
mixture was stirred at 0 oC until starting material disappeared. Saturated aqueous NH4Cl solution was added
to quench the reaction. The solvent was extracted with ethyl acetate several times. The combined organic
layers
weredried
over
Na2SO4,
filtered,
and
concentrated.
Purification
by
column
chromatography(hexane/EtOAc = 5/1 as eluent) afforded 6 (28 mg, 90%) as a white solid, yield 90 %;
Enantiomeric excess: 91 %, determined by HPLC (Chiralcel ODꢀH column, hexane/ethanol= 90/10, flow
1
rate 1 mL/min, UV detection at 220 nm), tR (major) = 16.8 min, tR (minor) =19.9 min. H NMR (300MHz,
CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.05ꢀ6.93 (m, 4H), 6.26
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(d, J = 8.2 Hz, 1H), 4.80 (dd, J = 8.1 Hz, 3.4 Hz, 1H), 3.74 (d, J = 3.4 Hz, 1H), 3.64 (d, J = 10.3 Hz, 1H),
3.55 (d, J = 10.3 Hz, 1H), 3.15 (brs, 1H), 2.28 (s, 3H), 1.64ꢀ1.58 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
142.9, 137.9, 136.9, 132.5, 129.1, 128.8, 128.6, 127.2, 126.9, 122.8, 73.5, 62.5, 60.2, 31.0, 28.7, 21.3;
HRMS (ESI) Calcd. for C18H23NO4SBr [M+H]+: 428.0531; Found: 428.0534.
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Supporting Information Available: copies of NMR spectra and HPLC analysis spectra of all compounds,
Xꢀray structural data (cif) of compound 6. This material is available free of charge via the Internet at
http://pubs.acs.org.
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