Cinchona Alkaloid Catalyzed Sulfa-Michael Addition Reactions Leading to Enantiopure β-Functionalized Cysteines

Article abstract of DOI:10.1021/acs.joc.5b01660

Sulfa-Michael additions to α,β-unsaturated N-acylated oxazolidin-2-ones and related α,β-unsaturated α-amino acid derivatives have been enantioselectively catalyzed by Cinchona alkaloids functionalized with a hydrogen bond donating group at the C6′ position. The series of Cinchona alkaloids includes known C6′ (thio)urea and sulfonamide derivatives and several novel species with a benzimidazole, squaramide or a benzamide group at the C6′ position. The sulfonamides were especially suited as bifunctional organocatalysts as they gave the products in very good diastereoselectivity and high enantioselectivity. In particular, the C6′ sulfonamides catalyzed the reaction with the α,β-unsaturated α-amino acid derivatives to afford the products in a diastereomeric ratio as good as 93:7, with the major isomer being formed in an ee of up to 99%. The products of the organocatalytic sulfa-Michael addition to α,β-unsaturated α-amino acid derivatives were subsequently converted in high yields to enantiopure β-functionalized cysteines suitable for native chemical ligation.

Full text of DOI:10.1021/acs.joc.5b01660

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Article
Cinchona Alkaloid Catalysed Sulfa-Michael Addition
Reactions Leading to Enantiopure #-Functionalized Cysteines
Arjen C. Breman, Suze E. M. Telderman, Roy P. M. van Santen, Jamie
I. Scott, Jan H. van Maarseveen, Steen Ingemann, and Henk Hiemstra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01660 • Publication Date (Web): 09 Oct 2015
Downloaded from http://pubs.acs.org on October 12, 2015
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Cinchona Alkaloid Catalysed Sulfa-Michael Addition Reactions
Leading to Enantiopure β-Functionalized Cysteines
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Arjen C. Breman, Suze E. M. Telderman, Roy P. M. van Santen, Jamie I. Scott, Jan H. van
Maarseveen, Steen Ingemann, and Henk Hiemstra*
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Van ’t Hoff Institute for Molecular Sciences, Faculty of Science, The University of
Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
h.hiemstra@uva.nl
TABLE OF CONTENTS/GRAPHICAL ABSTRACT
OBn
H
H
N
H
H
H
R'
R'
SR
R'
SH
O
O
RꢀSH
N
O
O
N
N
F3C
N
F3C
N
C6'
Cinchona
catalyst
H2N
CO2Me
H
H
O
O
O
N
O
O
S
enantiopure
ꢀ yields up to 99%
ꢀ dr up to 93:7
ꢀ ee up to 99%
O
catalyst
Me
ABSTRACT: SulfaꢀMichael additions to α,βꢀunsaturated Nꢀacylated oxazolidinꢀ2ꢀones and
related α,βꢀunsaturated αꢀamino acid derivatives have been enantioselectively catalysed by
Cinchona alkaloids functionalized with a hydrogen bond donating group at the C6’ position.
The series of Cinchona alkaloids includes known C6’ (thio)urea and sulfonamide derivatives
and several novel species with a benzimidazole, squaramide or a benzamide group at the C6’
position. The sulfonamides were especially suited as bifunctional organocatalysts as they
gave the products in very good diastereoselectivity and high enantioselectivity. In particular,
the C6’ sulfonamides catalyzed the reaction with the α,βꢀunsaturated αꢀamino acid
derivatives to afford the products in a diastereomeric ratio as good as 93:7 with the major
isomer being formed in an ee of up to 99%. The products of the organocatalytic sulfaꢀ
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Michael addition to α,βꢀunsaturated αꢀamino acid derivatives were subsequently converted in
high yields to enantiopure βꢀfunctionalized cysteines suitable for native chemical ligation.
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Introduction
Catalysis with enantiopure organic molecules (organocatalysis) is widely recognized as
highly valuable in asymmetric synthesis of compounds of pharmaceutical importance.1 This
is manifested in the increasing number of successful studies that have been reported for a
large variety of organic reactions, such as the Henry reaction,2 Michael additions,3 Mannich
reactions,4 MoritaꢀBaylisꢀHillman reactions,5 cycloadditions6 and multiꢀcomponent cascade
reactions.7 In most of the reported studies, the reactions are performed with organocatalysts
derived from a limited number of privileged structures e.g. the natural Cinchona
alkaloids,1a,1g,8 BINOL (1,1'ꢀbiꢀ2ꢀnaphthol)9 and proline.1f,10 In particular, Cinchona alkaloids
have been applied in numerous studies concerned with enantioselective reactions owing to
their availability, the presence of five stereogenic centers and distinct sites that can be
modified with a range of hydrogen bond donating groups. In most studies the hydrogen
bonding moiety is a thiourea,11,12 a urea,13 a squaramide,14 a sulfonamide15 or a guanidine16
group situated at the C9 position. Relatively few studies have been concerned with Cinchona
alkaloid derivatives with a hydrogen bonding group located at one of the sites of the
quinoline moiety. Recently, Palacio and Connon reported that Cinchona alkaloids with a urea
moiety at the C5′ position are efficient catalysts for asymmetric sulfaꢀMichael addition
(SMA)17 to nitroꢀstyrenes.18 Previously we showed that a C6’ thiourea derivative of quinidine
is a highly efficient catalysts for the Henry reaction2 and later Deng and coꢀworkers reported
that a C6’ thiourea with a C9ꢀmethylanthracyl ether group is well suited as a catalyst for
SMA reactions with α,βꢀunsaturated Nꢀacetylated oxazolidinꢀ2ꢀones (Scheme 1).19 More
recently, we reported that the same C6’ thiourea derivative operates as an enantioselective
catalysts in the SMA reaction with Nꢀacylated oxazolidinꢀ2ꢀone derivatives of α,βꢀ
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unsaturated amino acids (Scheme 1) and obtained the products in fair to good
diastereoselectivity with the major diastereomer being obtained in good to high ee. 20
However, we noticed that the C9ꢀmethylanthracyl ether bond is also cleaved during the step
involving demethylation of the methoxygroup at the quinoline moiety thus giving a low
overall yield of this particular Cinchona alkaloid derivative. In other studies we have
introduced a benzyl ether group at the C9 position and observed this to give a robust C6’
thiourea derivative in high yield.2 Unfortunately, in our previous work we noted that the
combination of a C9 benzyl ether and a C6’ thiourea leads to low diastereoselectivity in the
SMA reaction with α,βꢀunsaturated αꢀamino acid derivatives.20
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Scheme 1. SMA reaction with α,βꢀunsaturated Nꢀacetylated oxazolidinꢀ2ꢀones as described by Deng
and coworkers (ref. 19) and with Nꢀacylated oxazolidinꢀ2ꢀone derivatives of α,βꢀunsaturated αꢀamino
acids as described in our earlier work (ref. 20).
In order to optimize the organocatalyzed SMA reactions with unsaturated αꢀamino acid
derivatives we decided to prepare an extended series of C6’ substituted Cinchona bases with
a C9 benzyl ether group. The present series of catalysts includes the known thiourea,2
sulfonamide21 and urea22 derivatives together with novel benzimidazole, squaramide and
benzamide C6’ substituted Cinchona alkaloid derivatives (Scheme 2). The major objectives
of the present study are to i) examine the efficiency of C6’ substituted Cinchona derivatives
as catalyst for the SMA reactions shown in Scheme 1, ii) optimize and broaden the scope of
the SMA reactions with the α,βꢀunsaturated αꢀamino acid derivatives, iii) explore the use of
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benzylic thiols that can be easily removed under mild conditions e.g. Ph2CHSH (DPM),23
thus forming enantiopure βꢀfunctionalized cysteines for applications in peptide chemistry.
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Scheme 2. Cinchona derivatives with a hydrogen bonding group at C6’ and a benzyl ether function at
C9 (Q is the quinidine moiety as shown in 1).
Results and Discussion
Catalyst synthesis: The C6’ urea compound 2 was prepared similarly to the C6’ thiourea 12
by coupling of the C6’ amino derivative 14 (shown in Scheme 3) with commercially
available 1ꢀisocyanatoꢀ3,5ꢀbis(trifluoromethyl)benzene.2 The synthesis of the C6’
benzimidazole derivative 3 was less straightforward, but realized by a BuchwaldꢀHartwig
24
coupling
between 14 and 2ꢀchloroꢀ4,6ꢀbis(trifluoromethyl)ꢀ1Hꢀbenzo[d]imidazole16
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protected with a (trimethylsilyl)ethoxymethyl (SEM) group at one of the nitrogen atoms (15
in Scheme 3).25 The benzimidazole derivative 3 was obtained in 36% overall yield from 15
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.
after removal of the SEM group through treatment with BF3 OEt2 in CH2Cl2.26
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OBn
N
N
CF3
CF3
14
N
SEMCl, NaH,
N
N
NH2
Cl
Cl
3
N
H
DMF, 77%
10:1 regioisomers
CF3
CF3
1) Pd(OAc)2, BINAP,
Cs2CO3, THF, 42%
2) BF3—OEt2, CH2Cl2
85%
SEM
15
Scheme 3. Synthesis of the C6’ guanidine Cinchona derivative.
The novel C6’ squaramide derivative 4 also appeared to be a challenge. First we reacted
amine 14 with dimethyl squarate and obtained the expected product, but the subsequent
coupling with 3,5ꢀbis(trifluoromethyl)aniline proved unsuccessful. The strategy used for the
synthesis of the known C9 squaramide derivative also failed,27 that is, the coupling of 3,5ꢀ
bis(trifluoromethyl)aniline with dimethyl squarate to form 16 in Scheme 4 was facile, but no
reaction occurred between 16 and C6’ amine 14 in neat methanol. Following a recent study
28
by Taylor and coworkers concerning the synthesis of N,Nꢀdiarylsquaramides we then
reacted 16 with 14 in toluene/DMF in the presence of Zn(OTf)2. With 0.2 or 1.0 equiv of
Zn(OTf)2 no reaction occurred, but the addition of 3 equiv of the zinc salt gave the desired
C6’ squaramide 4 in a moderate yield of 36%. The C6’ benzamide 5 and the series of
sulfonamide derivatives 6ꢀ13 were prepared in high yields by the reaction of 14 with the
appropriate sulfonyl chlorides.14,29
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Scheme 4: Synthesis of the C6’ squaramide Cinchona alkaloid derivative.
Catalysts screening: The efficiency of the C6’ derivatives as catalysts was first examined
on the basis of the enantioselectivity in the known SMA reaction between
phenylmethanethiol and the α,βꢀunsaturated Nꢀacetylated oxazolidinꢀ2ꢀone 17 (Table 1). In
line with the results reported by Deng and coworkers the C6’ thiourea 1 gave the product in
68% ee with the major isomer being formed in the R configuration (entry 1, Table 1).19 The
C6’ urea derivative 2 catalyzed the reaction (entry 2) as efficiently as the related thiourea;
that is, both reactions were complete within 6 h. However, the enantioselectivety was not
more than 59 % with 2 as the catalyst and thus somewhat lower than with the thiourea 1
(68% ee). With the C6’ benzimidazole 3 full conversion was obtained within 4 h but the
product was formed in an ee of only 10% (entry 3). Unfortunately, the novel C6’ squaramide
4 did not catalyze the SMA reaction of phenylmethanethiol with 17 (entry 4).30 With the C6’
benzamide 5 the reaction was complete after 16 h yielding the product in poor
enantioselectivity (20% ee, entry 5). In the reactions catalyzed by 1-3 and 5 the major isomer
was consistently formed in the R configuration. However, in the slow reaction catalyzed by
C6’ sulfonamide 6, chiral HPLC analysis in combination with determination of the optical
rotation (see Experimental Section and Supporting Information) revealed that the major
isomer is now formed in the S configuration, that is, an ee of –50% was obtained (entry 6).
Table 1. SMA of phenylmethanethiol onto substrate 17. a
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conversion in %b
ee in %c
68 (R)
59 (R)
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ꢀ
entry
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catalyst
reaction time in h
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–50 (S)
–65 (S)
–84 (S)
–81 (S)
–81 (S)
–85 (S)
–86 (S)
–87 (S)
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a Reaction conditions: 0.2 M in substrate, 3 equiv of BnSH, rt, CHCl3. b Conversion determined by
1HꢀNMR. c Ee determined by chiral HPLC analysis (AD column).
The sulfonamide substituted with a single CF3ꢀgroup at the 4ꢀposition of the phenyl ring 7
(entry 7) gave rise to a somewhat less efficient reaction than catalyst 6 containing two CF3ꢀ
groups (entry 5). The ee was slightly better than with 6 as the catalyst, that is –65%. The C6’
sulfonamide with an unsubstituted phenyl group 8 led to a more efficient reaction than the
catalysts with CF3ꢀ substituents and also to a very good ee of –84% (entry 8). A similar ee (–
81%) was obtained with the 4ꢀmethylꢀsubstituted catalyst 9 (entry 9) and the same result was
obtained with the 2,4,6ꢀtrimethyl substituted C6’ sulfonamide 10 (entry 10). The sulfonamide
with a methoxy at the 4ꢀposition 11 gave –85% ee and full conversion in only 6 hours (entry
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11). With three methoxy groups at the phenyl ring 12 the ee was –86% (entry 12). Finally,
catalyst 13 containing the strongly electron donating dimethylamino group was examined and
observed to yield the product in –87% ee (entry 13).
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Next we explored the reactions of phenylmethanethiol with the α,βꢀunsaturated αꢀamino acid
derivative 19 (Table 2). With the C6’ꢀthiourea 1 (entry 1) the diastereomeric ratio was 64:36
with the major diastereomer being formed in an ee of 93%. The dr is slightly better than the
ratio of 52:48 reported earlier if this reaction is catalyzed by the C9ꢀmethylanthracyl ether
analogue of 1.20 In our previous work,20 we reported the Xꢀray crystal structure of the product
of the addition of 4ꢀmethoxyꢀphenylmethanethiol to 19 as catalyzed by the C6’ꢀthiourea
quinidine with a C9ꢀmethylanthracyl ether group. The Xꢀray analysis revealed that the major
isomer formed in this reaction has the anti stereochemistry with the S configuration at the αꢀ
carbon and the Rꢀconfiguration at the βꢀcarbon atom. Based on this Xꢀray structure in
combination with chiral HPLC and NMR analysis (see Supporting Information), we have
assigned the present products as having the anti or syn stereochemistry as indicated in Table
2.
Table 2. SMA of phenylmethanethiol onto substrate 19.a
reaction time conversion in
entry
catalyst
anti/sync
ee in %d
b
in h
6
%
1
2
3
100
100
100
64:36
29:71
33:67
93/55
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81:19
84:16
67:33
78:22
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61/65
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a Reaction conditions: 0.2 M in substrate, 3 equiv. of BnSH, rt, CH2Cl2. b Conversion as determined by
1HꢀNMR. c Diastereomeric ratios, dr, determined by HꢀNMR. The assignment of the anti and syn
1
configuration is based on our previously work (ref. 20) and the results in the Supporting Information.
dEe determined by chiral HPLC analysis (AD column).
The C6’ urea 2 gave a remarkable result; that is, we observed an inversion of the anti:syn
ratio as compared to the thiourea catalyst 1 (entry 1) and almost complete loss of the
enantioselectivity (entry 2). The benzimidazole species 3 gave a slow reaction (entry 3) and
also a reversal of the anti:syn ratio as compared to the thiourea 1. The squaramide 4 was not
examined for this reaction in view of the results obtained for 17 as substrate.30 With the C6’
benzamide 5 catalyst a slight preference for the syn diastereoisomer was observed and both
diastereoisomers were formed in reasonable ee’s (entry 4). With the C6’ sulfonamide 6 as
catalyst full conversion was obtained only after 160 h (entry 5). Significantly, the major
diastereoisomer was now formed in an ee of 92%. Subsequently, we examined the series of
C6’ sulfonamides 7ꢀ13 as catalysts in order to optimise the SMA reaction with substrate 17.
The presence of a single electron withdrawing CF3 group at the 4ꢀposition (7) led to a very
slow reaction as only 60% conversion was obtained after 160 h (entry 6). In addition, we
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were unable to separate the starting materials from the product of the reaction. Nevertheless,
the diastereoselectivity was improved to 80:20 as compared to ratio of 71:29 obtained with
the 3,5ꢀ(CF3)2 substituted catalyst (6, entry 5).
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With the C6’ sulfonamides, 8 – 13, full conversion occurred within 60 h (Table 2). The
catalyst with an unsubstituted phenyl group in the sulfonamide moiety (8, entry 7) formed the
product in a anti:syn ratio of 81:19. Notably, a very high enantioselectivity of 98% was
obtained for the anti diastereoisomer. The introduction of a methyl group at the 4ꢀposition (9)
caused a further improvement of the diastereoselectivity to 84:16 and with this particular
sulfonamide we obtained the major anti diastereoisomer in an excellent ee of 99% (entry 8).
With the trimethyl substituted catalyst 10 the diastereoselectivity was only 67:33 even though
the anti diastereoisomer was again formed in a very high ee (98%, entry 9). The
diastereoselectivity was moderate, 78:22, if an electron donating methoxy group was
introduced at the 4ꢀposition (11, entry 10) and with the 2,4,6ꢀtrimethoxy substituted catalyst
(12) the diastereoselectivity was reversed to 38:62 (entry 11). The ee of the anti isomer was
slightly lower for the species with three methoxy groups (88%) as compared to the 4ꢀ
methoxy substituted as catalysts (94%). With the sulfonamide containing a dimethylamino
group at the 4ꢀposition (13) we obtained a anti:syn ratio of 81:19 and a high ee (98%) for the
anti diastereoisomer (entry 12).
Scope of the reactions: Based on the results of the catalyst screening we decided to explore
the scope of the SMA reactions. For the reaction with the Nꢀacylated oxazolidinꢀ2ꢀones 17,
21 and 22 we focussed on the C6’ sulfonamide catalyst 13 containing a dimethylamino at the
°
4ꢀposition and performed the reactions at a temperature of –20 C in order to optimize the
ee’s (Table 3).
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Table 3. Substrate and nucleophile scope of the SMA reactions.
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42
43
44
45
46
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48
49
50
51
52
53
54
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reaction product
yield
in %
ee in
entry substrate
R1
R2
R3
time in
h
anti/syna
b
%
1
2
Me
ꢀ
CH2=CHCH
Bn
84
97
97
98
99
99
96
97
90
93
95
97
97c
99
96
96
96
99
ꢀ
91 (S)
93 (S)
92 (S)
85 (S)
92 (S)
91 (S)
92 (S)
94 (R)
99/3
17
17
17
17
21
21
21
22
19
19
19
19
23
23
23
24
24
25
18
26
27
28
29
30
31
32
20
33
34
35
36
37
38
39
Me
ꢀ
84
ꢀ
3
Me
ꢀ
4ꢀMeOBn
Ph2CH
Bn
84
ꢀ
4
Me
ꢀ
84
ꢀ
5
nꢀPr
ꢀ
84
ꢀ
6
nꢀPr
ꢀ
4ꢀMeOBn
Ph2CH
Ph2CH
CH2=CHCH
Bn
84
ꢀ
7
nꢀPr
ꢀ
84
ꢀ
8
Ph
ꢀ
ꢀ
140
24
ꢀ
9
Ph
Ph
73:27
84:16
83:17
93:7
80:20
80:20
90:10
82:18
80:20
10
11
12
13
14
15
16
17
ꢀ
16
99/8
ꢀ
Ph
4ꢀMeOBn
Ph2CH
Bn
16
96/52
>99/33
98/3
ꢀ
Ph
16
ꢀ
4ꢀMeOPh
4ꢀMeOPh
4ꢀMeOPh
Et
16
ꢀ
4ꢀMeOBn
Ph2CH
Bn
16
97/6
ꢀ
16
98/17
97/29
96/26
ꢀ
24
ꢀ
Et
4ꢀMeOBn
24
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18
ꢀ
Et
Ph2CH
16
96
93:7
98/3
24
40
5
6
7
8
a Diastereomeric ratios, dr, determined by 1HꢀNMR. The assignment of the anti and syn configuration
is based on our previously published results (see ref. 20). bEe determined by chiral HPLC analysis
(AD column). c 80% yield and >99.5% ee after recrystallization of the major isomer.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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29
30
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The addition of propꢀ2ꢀeneꢀ1ꢀthiol to 17 yielded the product in a very good ee of 91% and an
excellent yield of 97% (entry 1). With phenylmethanethiol as the nucleophile, performing the
reaction with 17 at –20 °C improved the ee to 93% from 87% at rt (entry 2, Table 3 and entry
1, Table 2) and gave a yield of 97% after 84 h. The addition of 4ꢀmethoxyꢀ
phenylmethanethiol to 17 gave an ee (92%) and a high yield of 98% (entry 3). With the
sterically hindered Ph2CHSH as the nucleophile we obtained an ee of 85% but a very high
yield of 99% after 84 h (entry 4). Excellent results were also obtained for nꢀpropyl substituted
21 even with Ph2CHSH as nucleophile (entries 5ꢀ7). The phenylꢀsubstituted substrate 22
appeared to have a poor solubility in CHCl3 and ꢀ as a result ꢀ the reaction with Ph2CHSH
was performed at low concentration leading to a reaction time of 140 h. Nevertheless, the
product of the reaction was formed in a high yield and also a high ee of 94% (entry 8).
The optimal conditions for the SMA reactions with the α,βꢀunsaturated αꢀamino acid
derivatives 19, 23, and 24 involved the C6’ꢀsulfonamide 9 with a methyl group at the 4ꢀ
position as catalyst, rt and CH2Cl2 as solvent. With propꢀ2ꢀeneꢀ1ꢀthiol as nucleophile, the
diastereoselectivity of the reaction was not more than 73:27 but the ee of the anti isomer was
excellent, 98% (entry 9). The reaction of phenylmethanethiol with 19 gave a diastereomeric
ratio of 84:16 and excellent ee for the anti isomer (entry 10) and similar results were obtained
4ꢀmethoxyphenylmethanethiol as the nucleophile (entry 11). The syn isomer was formed with
a very low enantioselectivity (8 %) in the former reaction (entry 9), while the reaction with
the 4ꢀmethoxyꢀsubstituted thiol gave the syn diastereomer in a moderate ee of 52% (entry
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2
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4
5
6
7
8
9
11). The diastereoselectivity was 93:7 with Ph2CHSH and again an excellent
enantioselectivity (>99%) was obtained for the major isomer (entry 12). After purification the
major isomer was recrystallized as a single enantiomer in 80% yield (see also Experimental
Section).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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In the reaction of the tyrosine derivate 23 with phenylmethanethiol as well as the 4ꢀmethoxy
substituted thiol an 80:20 mixture of diastereoisomers was formed with excellent ee for the
major isomers (entries 13 and 14). Again the best diastereoselectivity was obtained with the
bulky Ph2CHSH thiol, that is 90:10 (entry 15) and also the ee of the major isomer was very
high, 98%. With the ethylꢀsubstituted α,βꢀunsaturated αꢀamino acid 24 the same trend in
stereoselectivity was observed as with the tyrosine derivative 23 (entries 16ꢀ18), in particular,
Ph2CHSH gave the best dr (93:7) and an excellent ee (98%) for the major diastereomer.
β-Thiol-functionalized oxazolidinones and cysteines:
Highly enantioenriched or
enantiopure compounds with a free thiol group could be obtained in a single step from the
products of the SMA with Ph2CHSH. For the product 30 from the reaction with the nꢀPr
substituted Nꢀacylated oxazolidinꢀ2ꢀone 21, the Ph2CHꢀgroup was easily removed at rt with
TFA and triisopropylsilane in CH2Cl2 (Scheme 5).
Scheme 5. Removal of the Ph2CHꢀgroup.
With the purpose of converting the products of the SMA reactions into derivatives suitable
for peptide chemistry we developed the procedure shown in Scheme 6. First, the
trifluoroacetyl group was removed with HCl in methanol at reflux31 and then the amino group
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was Boc protected prior to replacing the oxazolidone group with a methyl ester to form 41
(Scheme 6). Simultaneous removal of the Ph2CHꢀ and the Boc group appeared less facile
than shown in Scheme 5, but could be achieved at an elevated temperature (50 °C) with TFA
9
23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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41
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47
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51
52
53
54
55
56
57
58
59
60
and triisopropylsilane in CH2Cl2 giving 43 in 95% yield without loss of ee. Saponification
of the methyl ester was realized with Tesser’s base32 and gave the βꢀfunctionalized cysteine
42 in 88% yield with no loss in stereochemical integrity.
Scheme 6. Formation of βꢀfunctionalized cysteines (DPM = Ph2CH).
βꢀThiolꢀfunctionalized αꢀamino acids have been applied previously in native chemical
ligation studies.33 For example, Crich and Banerjee applied this strategy with a βꢀthiolꢀ
functionalized phenylalanine for the synthesis of decapeptides.33a Recently, our group
reported an epimerizationꢀfree synthesis of activated aryl ester of small peptides (e.g. 4ꢀ
(methylsulfonyl)phenyl esters) via the Chan–Lam coupling.34 These esters were successfully
applied in native chemical ligation thus avoiding the addition of thiophenol to the reaction
mixture for the in situ generation of a thiol ester as in the more common procedure. Here, we
first coupled compound 42 with a free acid group to the tripeptide, H2NꢀAlaꢀValꢀPheꢀ
CO2Me, with HATU, HOAt and DIPEA giving the tetrapeptide 44 in 73% yield (scheme 7).
Subsequently the Ph2CHꢀ group was removed from the tetrapeptide prior to purification by
preparative HPLC giving a mixture of the thiol and the related disulfide. Subsequently, the
tetrapeptide with a free thiol group was effectively subjected to native chemical ligation with
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a dipeptide containing an activated 4ꢀ(methylsulfonyl)phenyl ester group thus leading to
5
6
hexapeptide 46 (Scheme 7) with a βꢀfunctionalized cysteine incorporated.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Native chemical ligation with a peptide containing a βꢀfunctionalized cysteine.
Conclusion
A extended series of Cinchona organocatalysts with a hydrogen bonding group at C6’ was
prepared and applied in sulfaꢀMichael additions to Nꢀacetylated oxazolidinꢀ2ꢀones and
related α,βꢀunsaturated αꢀamino acid derivatives. In the reactions with the Nꢀacetylated
oxazolidinꢀ2ꢀones the C6’ sulfonamides gave the main enantiomer in the (S)ꢀconfiguration
while, for example, the C6’ꢀ(thio)urea gave rise to the (R)ꢀenantiomer. The C6’ꢀsulfonamides
proved to give the highest ee in the SMA reaction with the α,βꢀunsaturated αꢀamino acid
derivatives, up to 99% for the major anti isomer. The dr was up to 93:7 in the reactions with
the congested nucleophile Ph2CHSH. Facile removal of the Ph2CHꢀ group afforded unnatural
cysteines that could be easily converted into suitable substrates for peptide chemistry.
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Experimental Section
5
6
7
General methods: The 1H NMR and 13C NMR spectra (APT) were recorded (1H 400 MHz,
8
9
13C 100 MHz) at room temperature with CDCl3 as the solvent. Accurate mass measurements
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
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41
42
43
44
45
46
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48
49
50
51
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53
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60
were performed with High Resolution Mass Spectrometry (HRMS) and Fast Atom
Bombardment (FAB) or Electrospray (ESI) as the ionization method. The FAB
measurements were performed with a four sector tandem mass spectrometer, whereas a qTOF
(quadrupole TimeꢀofꢀFlight) instruments was used for the ESI measurements. Low resolution
mass spectra were recorded with a ESI LC Ion Trap instrument. All reactions were carried
out in ovenꢀdried glassware with magnetic stirring. Tetrahydrofuran (THF) was freshly
distilled from Na and benzophenone. Toluene was distilled over CaH2 and stored over 4 Å
mol sieves. DMF was dried over mol sieves. Other solvents were also distilled prior to use.
Synthesis of the unsaturated N-acylated oxazolidinones: The oxazolidinꢀ2ꢀones 17, 21 and
22 were prepared in good yields by reacting the corresponding acid chlorides with the sodium
salt of 1,3ꢀoxazolidinꢀ2ꢀone generated with sodium hydride as described in the literature.35
The α,β–unsaturated α–amino acid derivatives 19, 23 and 24 were synthesized as described in
our earlier work,20 analogous to published procedures.36 This methodology involved reaction
of the amino acids phenylalanine, 4ꢀmethoxyphenylalanine and norvaline, respectively, with
TFAA to give the corresponding pseudoazlactones, followed by bromination and treatment
with excess of the sodium salt of 1,3ꢀoxazolidinꢀ2ꢀone.
General procedure for the synthesis of the pseudoazlactones: A mixture of an amino acid
and TFAA (2.3 equiv) was refluxed for 1 h. After removing the excess reagent the product
was distilled under reduced pressure.
4-(4-Methoxybenzyl)-2-(trifluoromethyl)oxazol-5(2H)-one: According to the general
procedure, 4ꢀmethoxyphenylalanine (5.0 g, 25.6 mmol) was reacted with TFAA (8.3 mL,
58.9 mmol) to afford the title compound (5.7 g, 21.0 mmol, 82%) as a colorless oil after
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8
9
°
distillation under reduced pressure (0.06 mbar, 200 C). IR (neat, cmꢀ1) ν 1808, 1606, 1157,
1018, 702; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, 2H, J = 8.7 Hz), 6.90 (d, 2H, J = 8.7 Hz),
6.10 (m, 1H), 3.99 (s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3, 163.3, 159.0,
130.3, 124.1, 120.0 (q, J = 280.0 Hz), 114.3, 92.8 (q, J = 34.9 Hz), 55.1, 33.5.
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4-Propyl-2-(trifluoromethyl)oxazol-5(2H)-one: According to the general procedure,
norvaline (11.7 g, 100 mmol) was reacted with TFAA (32 mL, 230 mmol) to afford the title
compound (19.0 g, 97.4 mmol, 97%) as a colorless oil after distillation under reduced
1
pressure (0.8 mbar, 81 °C). IR (neat, cmꢀ1) ν 2972, 1802,1648, 1153, 1008, 699; H NMR
(400 MHz, CDCl3) δ 6.13 (m, 1H), 2.70 (t, 2H, J = 5.2 Hz), 1.83 (m, 2H), 1.04 (t, 3H, J = 7.2
Hz); 13C NMR (100 MHz, CDCl3) δ 169.2, 163.8, 120.2 (q, J = 279.8 Hz) 93.1 (q, J = 34.9
Hz), 30.0, 18.6, 13.2; HRMS (FAB) for C7H9F3NO2: calculated [M + H]+: 196.0585, found
[M + H]+: 196.0591.
General procedure for bromination of pseudoazlactones: The pseudoazlactone was
dissolved in 1,2ꢀdichloroethane and cooled to 0 °C and then treated with a small portion of a
solution of bromine (1 equiv) in 1,2ꢀdichloroethane. A small sample was withdrawn and
gently heated until it became colorless and then returned to the flask. This procedure was
repeated until the mixture in the flask became colorless. Next the rest of the bromine solution
was added. The mixture was allowed to warm up to rt and stirred until all the starting
material had disappeared according to TLC. The product was concentrated under reduced
pressure and purified as specified hereafter.
4-(Bromo(4-methoxyphenyl)methyl)-2-(trifluoromethyl)oxazol-5(2H)-one: According the
general procedure, the methoxybenzyl pseudoazlactone (5.2 g, 19.0 mmol) was dissolved in
50 mL 1,2ꢀdichloroethane and reacted with bromine (0.97 mL, 19.0 mmol) in 20 mL 1,2ꢀ
dichloroethane to afford the title compound (5.9 g, 16.7 mmol, 88%) as a greenish oil after
column chromatography (PE/EtOAc 30:1). This product was contaminated with a byproduct,
but this appeared no problem in the next step. IR (neat, cmꢀ1) ν 1808, 1608, 1513, 1257,
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1157; H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 6.94
(m, 2H), 6.27 (q, 0.5H, J = 2.9 Hz), 6.18 (q, 0.5H, J = 3.1 Hz), 6.00 (s, 0.5H), 5.98 (s, 0.5H),
3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 165.5, 163.8, 161.0, 160.7, 130.6, 130.4,
125.5, 120.0 (q, J = 280.0 Hz), 119.9 (q, J = 280.0 Hz), 114.6, 114.5, 92.7 (q, J = 35.4 Hz),
92.7 (q, J = 35.5 Hz), 55.3, 41.4, 40.6.
10
11
12
13
14
15
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17
18
19
20
21
22
23
24
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41
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49
50
51
52
53
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57
58
59
60
4-(1-Bromopropyl)-2-(trifluoromethyl)oxazol-5(2H)-one: According to the general
procedure, the propyl pseudoazlactone (5.85 g, 30 mmol) was dissolved in 60 mL 1,2ꢀ
dichloroethane and reacted with bromine (1.54 mL, 30 mmol) in 20 mL 1,2ꢀdichloroethane to
afford the title compound (7.25 g, 26.7 mmol, 89%) as a colorless oil after distillation under
reduced pressure (0.4 mbar, 110 °C). IR (neat, cmꢀ1) ν 2978, 1806, 1643, 1366, 1305, 1154,
1016, 704; 1H NMR (400 MHz, CDCl3) δ 6.21 (m, 1H), 4.81 (m, 1H), 2.33 (m, 2H), 1.14 (t,
3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 166.4, 116.2, 161.3, 161.2, 120.0, (q, J =
280.1 Hz) 92.4 (q, J = 34.9 Hz), 42.2, 42.0, 27.4, 27.3, 11.9, 11.7.
General procedure for the formation of the sulfa-Michael addition substrates: 1,3ꢀ
Oxazolidinꢀ2ꢀone (2.3 equiv) was dissolved in THF. Sodium hydride (2.2 equiv) was added
in portions and the resulting mixture was stirred for 45 min. Next, a solution of the
bromopseudoazlactone in THF was added dropwise. The resulting mixture was stirred for 30
min and then quenched with saturated NH4Cl. The layers were separated and the water layer
was extracted twice with EtOAc. The organic layers were combined, washed with brine and
dried with MgSO4. The crude was concentrated and purified by column chromatography and
if possible the product was recrystallized to obtain the pure Zꢀisomer.
(Z)-2,2,2-Trifluoro-N-(3-oxo-3-(2-oxooxazolidin-3-yl)-1-phenylprop-1-en-2-yl)-
acetamide (19): According to the general procedure, to a solution of oxazolidinone (5.0 g,
57.4 mmol) in 250 mL THF was added NaH (60% in mineral oil, 1.3 g, 55 mmol), followed
by the brominated pseudoazlactone from phenylalanine36 (8.0 g, 25 mmol) in 50 mL THF.
The reaction gave a mixture of isomers (Z/E 10:1) of compound 19 (5.3 g, 15.5 mmol, 62%)
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as a white solid after column chromatography (PE/EtOAc 2:1). The Zꢀisomer could be
obtained by recrystallization from PE/EtOAc. IR (neat, cmꢀ1) ν 3253, 1617, 1717, 1685,
1529, 1388, 1209, 1184, 1155; Zꢀisomer: mp 139ꢀ141 °C; 1H NMR (400 MHz, CDCl3) δ 8.64
(s, 1H), 7.47ꢀ7.40 (m, 5H), 6.94 (s, 1H), 4.44 (t, 2H, J = 7.6 Hz), 4.05 (t, 2H, J = 7.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 164.5, 155.5 (q, J = 38.0 Hz), 152.9, 132.2, 131.6, 128.8, 129.4,
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1
129.0, 125.6, 115.4 (q, J = 286.0 Hz) 63.0, 42.9; Eꢀisomer: H NMR (400 MHz, CDCl3) δ
8.21 (s, 1H), 7.49ꢀ7.42 (m, 5H), 6.65 (s, 1H), 4.43 (t, 2H, J = 8.0 Hz), 4.07 (t, 2H, J = 8.0
Hz); 13C NMR (100 MHz, CDCl3) δ 162.3, 155.7 (q, J = 38.0 Hz), 151.9, 132.0, 130.1,
129.7, 129.5, 129.1, 125.9, 115.4 (q, J = 286.0 Hz), 62.5, 42.0; HRMS (FAB) for
C14H12F3N2O4: calculated [M + H]+: 329.0749, found [M + H]+: 329.0746; Elemental
analysis for C14H11F3N2O4: calculated: C 51.23%, H 3.38%, F 17.36%, N 8.53% found: C
51.33%, H 3.38%, F 17.22% N 8.48%.
(Z)-2,2,2-Trifluoro-N-(1-(4-methoxyphenyl)-3-oxo-3-(2-oxooxazolidin-3-yl)-prop-1-en-2-
yl)acetamide (23): According to the general procedure, to oxazolidinone (3.1 g, 35.2 mmol)
in 200 ml THF was added sodium hydride (1.35 g, 33.8 mmol, 60% in mineral oil), followed
by the bromo pseudoazlactone (5.4, 15.3 mmol) in 60 ml THF. The reaction gave a mixture
of isomers (Z/E 10:1) as a white solid after column chromatography (PE/EtOAc 2:1). The Zꢀ
isomer 23 (3.7 g, 10.4 mmol, 68%) could be obtained by recrystallization from PE/EtOAc. Zꢀ
isomer: mp 176ꢀ178 °C; IR (neat, cmꢀ1) ν 3248, 1763, 1717, 1678, 1213, 1176, 1157,1034;
1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.45 (d, 2H, J = 9.8 Hz), 7.10 (s, 1H), 6.96 (d,
2H, J = 9.8 Hz), 4.49 (t, 2H, J = 7.9 Hz), 4.12 (t, 2H, J = 7.9 Hz), 3.87 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.9, 161.2, 155.6 (q, J = 38.0 Hz), 134.1, 131.6, 124.7, 123.0, 115.5
(q, J = 286.0 Hz), 114.1, 63.1, 55.4, 43.2; For the Eꢀisomer no good NMR data could be
obtained. HRMS (ESI) for C15H13F3N2O5Na: calculated [M + Na]+: 381.0669, found [M +
Na]+: 381.0656; Elemental analysis for C15H13F3N2O5: calculated: C 50.29%, H 3.66%, F
15.91%, N 7.82% found: C 49.54%, H 3.67%, F 15.61% N 7.61%.
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(Z)-2,2,2-Trifluoro-N-(1-oxo-1-(2-oxooxazolidin-3-yl)pent-2-en-2-yl)-acetamide
(24):
5
6
7
8
According to the general procedure, to a solution of oxazolidinone (1.47 g, 16.9 mmol) in
100 mL THF was added sodium hydride (60% in mineral oil, 387 mg, 16.2 mmol), followed
by the brominated pseudoazlactone from norvaline (2.0 g, 7.3 mmol) in 30 mL THF. The
reaction gave a mixture of isomers (Z/E 2:1) of compound 24 (603 mg, 2.2 mmol, 29%) as
oil. The isomers were purified and separated by column chromatography (PE/Et2O 1:1). IR
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(neat, cmꢀ1) ν 3286, 1766, 1718, 1691, 1532, 1388, 1322, 1192, 1157; Zꢀisomer: H NMR
(400 MHz, CDCl3) δ 8.58 (s, 1H), 6.54 (t, 1H J = 7.6 Hz), 4.51 (t, 2H, J = 8.0 Hz), 4.09 (t,
2H, J = 8.0 Hz), 2.24 (m, 2H), 1.33 (dt, 3H, J = 7.6, 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ
164.3, 155.6 (q, J = 37.8 Hz), 153.8, 142.2, 125.6, 115.5 (q, J = 286.0 Hz), 63.2, 43.2, 21.1,
12.3; Eꢀisomer: 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 5.92 (t, 1H, J = 8.0 Hz), 4.56 (t,
2H, J = 8.0 Hz), 4.13 (t, 2H, J = 8.0 Hz), 2.62 (m, 2H), 1.09 (t, 3H, J = 7.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 162.7, 154.8 (q, J = 38.1 Hz), 152.7, 131.2, 125.9, 115.3 (q, J = 285.6
Hz), 62.8, 42.2, 20.8, 13.2; HRMS (FAB) for C10H12F3N2O4: calculated [M + H]+: 281.0749,
found [M + H]+: 281.0747.
Catalyst syntheses
1-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3-
(3,5-bis(trifluoromethyl)phenyl)urea (2): To a solution of amine 14 (500 mg, 1.25 mmol)2
in 15 mL dry THF was added 3,5ꢀbistrifluoromethylphenyl isocyanate (216 ꢁL, 1.25 mmol)
and the mixture was stirred at rt for 1 h under an inert atmosphere. The THF was removed
and the product purified with flash chromatography (EtOAc/MeOH 95:5) to give urea 13
(752 mg, 1.15 mmol, 93%) as a white powder. Mp 133 °C; [α]D20 = +65.0 (c = 1.0, CH2Cl2);
IR (neat, cm–1) ν 3235, 3089, 2944, 1714, 1560, 1473, 1364, 1176, 1125, 1057, 1027, 952,
851, 833, 728, 701; 1H NMR (500 MHz, CDCl3) δ 10.0 (s, 1H), 9.47 (s, 1H), 8.70 (d, 1H, J =
4.0 Hz), 8.33 (s, 1H), 7.96 (s, 2H), 7.57 (m, 3H), 7.48 (m, 5H), 7.23 (s, 1H), 6.35 (br, 1H),
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5.29 (m, 1H), 5.10 (d, 1H, J = 10.5 Hz), 5.02 (d, 1H, J = 17.5 Hz), 4.92 (d, 1H, J = 10.0 Hz),
4.77 (d, 1H, J = 10.0 Hz), 4.09 (m, 2H), 3.96 (m, 1H), 3.44 (m, 1H), 3.20 (m, 1H), 2.61 (m,
1H), 2.35 (t, 1H, J = 12.0 Hz), 2.00 (s, 1H), 1.93 (m, 1H), 1.84 (m, 1H), 1.20 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 179.3, 153.4, 148.1, 144.4, 141.0, 140.6, 137.0, 136.7, 136.2,
131.4 (q, J = 32.8 Hz), 130.1, 128.8, 128.5, 128.3, 125.1, 124.9, 123.2 (q, J = 271.1 Hz),
122.9, 117.5, 117.3, 114.9, 111.4, 72.4, 60.2, 48.7, 37.4, 27.4, 25.4, 24.4, 23.5, 18.4; HRMS
(FAB) for C35H33F6N4O2: calculated [M + H]+: 655.2508, found [M + H]+: 655.2501.
2-Chloro-4,6-bis(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo-[d]-
imidazole (15): 2ꢀChloroꢀ4,6ꢀbis(trifluoromethyl)ꢀ1Hꢀbenzoꢀ[d]ꢀimidazole (2.0 g, 6.9
mmol)16 was dissolved in 70 mL dry DMF and cooled to –20 °C. SEMCl (1.24 mL, 6.94
mmol) was added dropwise. After 15 min NaH (560 mg, 14 mmol, 60% dispersion in mineral
oil) was added portion wise. The mixture was allowed to warm up to rt and stirred overnight.
The 30 mL water was carefully added together with 45 mL EtOAc. The layers were
separated, the organic phase was washed with 30 mL of water and dried with Na2SO4. The
crude was concentrated and the product was purified with flash chromatography (PE/EtOAc
9:1) yielding protected benzimidazole 15 (2.25 g, 5.4 mmol, 77%) as a colorless liquid,
which solidified upon standing. Mp 44 ºC; IR (neat, cm–1) ν 2956, 2899, 1741, 1636, 1502,
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1440, 1280, 1251, 1160, 1089, 885, 835, 789, 695; H NMR (400 MHz, CDCl3) δ 7.98 (s,
1H), 7.86 (s, 1H), 5.69 (s, 2H), 3.64–3.60 (m, 2H), 0.97–0.93 (m, 2H), 0.01 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 144.8, 140.5, 135.4, 125.8 (q, J = 33.5 Hz), 123.9 (q, J = 270 Hz),
123.0 (q, J = 270 Hz), 121.7 (q, J = 34 Hz), 117.7, 111.7, 73.7, δ 67.2, δ 17.7, –1.81; HRMS
(FAB) for C15H18ClF6N2OSi: calculated [M + H]+: 419.0781, found [M + H]+: 419.0778.
4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)-N-(5,7-bis-(trifluoro-
methyl)-1-((2-(trimethylsilyl)-ethoxy)-methyl)-1H-benzo[d]imidazole-2-yl)-quinolin-6-
amine: Amine 14 (2.31 g, 5.8 mmol)2 was dissolved in 24 mL of dry THF. To the solution
were added protected benzimidazole 15 (2.2 g, 5.3 mmol), Pd(OAc)2 (118 mg, 0.53 mmol),
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rac–BINAP (327 mg, 0.53 mmol), and Cs2CO3 (2.4 g, 7.4 mmol). Prior to heating to reflux,
argon was bubbled through the mixture for 30 min. After 4 h full consumption of the starting
material was observed. The mixture was allowed to cool to rt and filtered over Celite. The
solvents were removed and the residue was purified with flash chromatography
(EtOAc/MeOH 95:5 to 90:10) to give the title compound (1.74 g, 2.23 mmol, 42%) as a
yellow powder. Mp 92–95 °C; [α]D20 = +89.3 (c = 0.7, CH2Cl2); IR (neat, cm–1) ν 3068,
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2950, 2873, 1735, 1599, 1456, 1348, 1286, 1273, 1260, 1161, 1122, 992, 859, 778, 728; H
NMR (400 MHz, CDCl3) δ 8.85 (d, 1H, J = 4.4 Hz), 8.80 (br, 1H), 8.21 (br, 1H), 8.19 (s,
1H), 8.16 (br, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.51 (br, 1H), 7.37–7.28 (m, 5H), 5.95 (m, 1H),
5.61 (s, 2H), 5.29 (m, 1H) 4.93 (m, 2H), 4.49 (m, 2H), 3.71–3.69 (t, 2H, J = 8.4 Hz), 3.28 (br,
1H), 3.20 (br, 1H), 2.89 (m, 2H), 2.72 (m, 1H), 2.24 (m, 1H), 2.06 (m, 1H), 1.82 (br, 1H),
1.62–1.57 (m, 3H), 1.06–1.02 (m, 2H), 0.01 (s, 9H); 13C NMR (100 MHz, CDCl3) 153.3,
148.8, 146.2, 145.5, 142.4, 140.4 138.0, 137.1, 134.5, 131.5, 128.4, 128.0, 127.8, 124.4 (q, J
= 270.0 Hz), 123.7 (q, J = 271.0 Hz), 122.6, 122.2, 121.9, 120.4, 118.7 (q, J = 33.0 Hz),
116.8, 116.8, 114.6, 110.4, 107.9, 72.6, 71.8, 67.2, 60.8, 50.5, 49.8, 40.2, 29.8, 28.2, 26.5,
25.0, 17.7, –1.6; HRMS (FAB) for C41H46F6N5O2Si: calculated [M + H]+: 782.3325, found
[M + H]+: 782.3336.
4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)-N-(5,7-bis-(trifluoro-
methyl)-1H-benzo[d]imidazole-2-yl)quinolin-6-amine (3): Protected 2–aminobenzꢀ
imidazole (1.7 g, 2.2 mmol) was dissolved in 90 mL of dry CH2Cl2. Then BF3·Et2O (2.66
mL, 21.7 mmol) was added dropwise at 0 °C. The mixture was stirred for 2 h under a
nitrogen atmosphere. After removal of the solvent, the product was purified with flash
chromatography (EtOAc/MeOH 9:1) to give 3 (1.2 g, 1.84 mmol, 85%) as a yellow powder.
Mp 95 °C; [α]D20 = +33.0 (c = 0.2, CH2Cl2); IR (neat, cm–1) ν 3065, 2926, 2870, 1575, 1510,
1
1455, 1366, 1335, 1273, 1261, 1165, 1120, 908, 848; H NMR (500 MHz, CDCl3) δ 8.77 (d,
1H, J = 4.0 Hz), 8.43 (br, 2H), 7.93–7.80 (br m, 2H), 7.69 (br, 1H), 4.57 (br, 2H), 7.30 (m,
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5H), 5.91 (m, 1H), 5.70 (br, 1H), 5.08 (d, 1H, J = 10.5 Hz), 5.04 (d, 1H, J = 17.0 Hz), 4.55
(d, 1H, J = 16.5 Hz), 4.43 (d, 1H, J = 16.5 Hz), 3.69 (br, 1H), 3.45 (br, 1H), 3.22 (br, 1H),
3.12 (m, 1H), 2.92 (m, 1H), 2.41 (m, 1H), 2.24 (br, 1H), 1.93 (br, 1H), 1.71 (br, 2H), 1.48 (br,
1H) (NꢀH signal is missing); 13C NMR (125 MHz, CDCl3): 153.1, 148.0, 147.8, 144.6, 144.0,
138.0, 137.0, 130.7, 130.6, 128.7, 128.4, 128.2, 127.7, 127.5, 127.0, 124.8 (q, J = 270.1 Hz),
123.7 (q, J = 270.2 Hz), 123.2, 12.1.0, 120.5, 118.9, 116.1, 115.1, 113.4, 108.0, 71.5, 60.7,
49.6, 49.1, 38.7, 27.5, 24.9, 21.4 (Cꢀ9 carbon is missing; broad and double signals due to
hindered rotation); HRMS (FAB) for C35H32F6N5O: calculated [M + H]+: 652.2511, found
[M + H]+: 652.2507.
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N-[3,5-Bis(trifluoromethyl)phenyl]-N-(9-O-benzylcinchon-6’-yl)squaramide (4): Amine
14 (300 mg, 0.75 mmol) was dissolved in toluene/DMF (5:1, 12 mL) prior to addition of
Zn(OTf)2 (818 mg, 2.25 mmol). The solution was stirred at rt for 10 min and then 3ꢀ(3,5ꢀ
bis(trifluoromethyl)phenylamino)ꢀ4ꢀmethoxycyclobutꢀ3ꢀeneꢀ1,2ꢀdione (16, 280 mg, 0.83
mmol)27 was added. The resulting mixture was stirred for 2 days at 100 °C and cooled to rt.
EtOAc (20 mL) and Na2CO3 (20 mL) were added to the reaction mixture during the cooling
to rt. The water layer was separated and washed with EtOAc (3 x 20 mL). The combined
organic layers were dried over MgSO4 and concentrated. The crude was purified by flash
chromatography (CH2Cl2/MeOH 30/1 to 10/1) giving 4 as yellow crystals (193 mg, 0.27
20
mmol), 36%). Mp 234 °C; [α]D = –92 (c = 0.5, CH2Cl2). IR (neat, cmꢀ1) ν 3325, 3171,
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2962, 1789, 1700, 1610, 1556, 1472, 1372, 1330, 1237, 1169, 1052, 1025. H NMR (400
MHz, DMSOꢀd6) δ 10.50 (s, 1H), 9.96 (s, 1H), 8.89 (d, 1H J = 4.4 Hz), 8.37 (s, 1H), 8.33 (s,
1H), 8.13 (t, 2H, J = 4.5 Hz), 7.84–7.59 (m, 3H), 7.40ꢀ7.35 (m, 5H), 5.95–5.79 (m, 2H),
5.08–4.91 (m, 2H), 4.47 (m, 2H), 3.85 (br, 3H), 3.42 (br, 1H), 2.63 (m, 1H), 2.12 (m, 1H),
1.98–1.78 (m, 3H), 1.23 (s, 2H). 13C NMR (101 MHz, DMSOꢀd6): δ 182.7, 181.7, 166.3,
166.1, 149.2, 145.2, 141.1, 137.4, 136.8, 131.5 (q, J = 33.9 Hz), 131.3, 128.7, 128.4, 128.3,
128.20, 127.4, 126.2, 123.4 (q, J = 271.1 Hz), 122.5, 118.5, 116.4, 115.8, 71.6, 58.9, 48.8,
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26.7 (broad and double signals due to hindered rotation). HRMS (ESI) for C38H33F6N4O3,
calculated [M + H]+: 707.2451, found [M + H]+: 707.2405.
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N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-3,5-
bis(trifluoromethyl)benzamide (5): Amine 14 (200 mg, 0.5 mmol) was dissolved in 10 mL
CH2Cl2. Et3N (74 ꢁL, 0.55 mmol), 3,5–bis–(trifluoromethyl)benzoyl chloride (99 ꢁL, 0.55
mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was
washed with NaHCO3 and brine. The organic layers were combined and dried with Na2SO4
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and then concentrated. The product was purified with flash chromatography (EtOAc/MeOH
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20:1) giving amide 5 (207 mg, 0.33 mmol, 65%) as a white solid. Mp 101–103 °C; [α]D
=
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+33.9 (c = 0.35, CH2Cl2); IR (neat, cm–1) ν 2936, 1626, 1504, 1276, 1127, 794, 753; H
NMR (500 MHz, CDCl3) δ 10.32 (br, 1H), 8.87 (d, 1H, J = 4.5 Hz), 8.65 (s, 2H), 8.57 (s,
1H), 8.18 (m, 2H), 8.03 (s, 1H), 7.56 (d, 1H, J = 2.8 Hz), 7.41–7.30 (m, 5H), 5.96 (m, 1H),
5.79 (br, 1H), 5.06 (m, 2H), 4.61 (d, 1H, J = 11.0 Hz), 4.51 (d, 1H, J =11.0 Hz), 3.69 (br,
1H), 3.42 (br, 2H), 3.16 (m, 1H), 2.92 (m, 1H), 2.44 (br, 1H), 2.36 (br, 1H), 1.93 (s, 1H), 1.77
(br, 1H), 1.68 (br, 1H), 1.29 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 170.3, 163.5, 149.2,
145.9, 143.6, 139.5, 138.7, 137.8, 137.1, 136.9, 132.1 (q, J = 33.9 Hz), 131.3, 131.0 (q, J =
33.9 Hz), 129.4, 128.5, 128.2, 126.0, 125.3, 124.3, 123.6, 123.0 (q, J = 271.5 Hz), 118.5,
116.4, 112.4, 77.3, 71.9, 60.0, 49.3, 48.8, 38.8, 27.8, 25.0, 20.0 (broad signals due to
hindered rotation); HRMS (ESI) for C35H32F6N3O2: calculated [M + H]+: 640.2393, found [M
+ H]+: 640.2365.
General procedure for the synthesis of sulfonamide catalysts: Amine 14 was dissolved in
pyridine (0.2 M), followed by the addition of a sulfonyl chloride (1.2 equiv). The resulting
mixture was stirred at 110 °C for 16 h. The crude was concentrated under reduced pressure
and the product was purified with flash column chromatography. First a column with a
mixture of CH2Cl2/MeOH/Et3N as the eluent was applied. The product was concentrated and
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a second column was performed to remove Et3N using EtOAc/MeOH (10:1) (Et3N formed a
complex with the sulfonamide catalysts) yielding the sulfonamide catalyst.
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N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)-methyl)quinolin-6-yl)-3,5-
bis(trifluoromethyl)benzenesulfonamide (6): According to the general procedure, amine 14
(160 mg, 0.4 mmol) was reacted with 3,5ꢀbisꢀ(trifluoromethyl)benzenesulfonyl chloride (150
mg, 0.48 mmol) in 2 mL of pyridine at 110 °C. The product was purified with column
chromatography using as eluant CH2Cl2/MeOH/Et3N (100:2:1), followed by EtOAc/MeOH
(10:1), yielding sulfonamide 6 (230 mg, 0.34 mmol, 86%) as a yellowish powder. Mp 103–
106 °C; [α]D20 = +66.7 (c = 1.00, MeOH); IR (neat, cm–1) ν 2955, 1624, 1494, 1277, 1239,
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1166, 1125, 1038, 902, 843, 731, 698, 681, 621; 1H NMR (500 MHz, CDCl3) δ 8.73 (br, 2H),
8.43 (s, 2H), 8.08 (d, 1H, J = 4.0 Hz), 7.91 (s, 1H), 7.89 (m, 2H), 7.38 (m, 1H), 7.30 (m, 3H),
7.11 (m, 2H), 5.82 (m, 1H), 5.77 (br, 1H), 5.04 (d, 1H, J = 10.0 Hz), 4.98 (d, 1H, J = 17.5
Hz), 3.90 (br, 2H), 3.61 (br, 2H), 3.40 (br, 3H), 2.60 (br, 1H), 2.38 (br, 1H), 1.99 (m, 1H),
1.90 (br, 1H). 1.64 (br, 1H) 1.21 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 148.3, 146.5,
145.7, 143.5, 140.8, 136.6, 131.8 (q, J = 33.9 Hz), 131.7, 129.0, 128.6, 128.5 128.2, 127.7,
127.1, 126.2, 124.1, 122.9 (q, J = 271.6 Hz), 119.7, 118.0, 117.0, 115.8, 76.4, 70.9, 59.5,
49.8, 48.7, 37.6, 27.5, 23.8, 18.9 (broad signals due to hindered rotation); HRMS (FAB) for
C34H32F6N3O3S: calculated [M + H]+: 676.2069, found [M + H]+: 676.2064.
N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)-methyl)quinolin-6-yl)-4-
(trifluoromethyl)benzenesulfonamide (7): According to the general procedure, amine 14
(400 mg, 1 mmol) was reacted with p–trifluoromethylbenzenesulfonyl chloride (291 mg, 1.2
mmol) in 5 mL of pyridine at 110 °C. The product was purified with column chromatography
using as eluant CH2Cl2/MeOH/Et3N (100:2:1), followed by EtOAc/MeOH (10:1), yielding
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sulfonamide 7 (588 mg, 0.97 mmol, 97%) as a yellowish powder. Mp 122–126 °C; [α]D
=
+91.2 (c = 1.00, CH2Cl2 IR (neat, cm–1) ν 2938, 1623, 1484, 1370, 1323, 1240, 1166, 1128,
1062, 1008, 841, 716, 633; 1H NMR (500 MHz, CDCl3) δ 9.10 (br, 1H), 8.83 (d, 1H, J = 4.0
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Hz), 8.20 (d, 2H, J = 8.0 Hz), 8.16 (s, 1H), 8.12 (m, 1H), 8.03 (m, 1H), 7.71 (d, 2H, J = 8.0
Hz), 7.53 (d, 1H, J = 4.5 Hz), 7.31 (m, 5H), 6.22 (br, 1H), 5.82 (m, 1H), 5.05 (d, 1H, J = 10.0
Hz), 5.02 (d, 1H, J = 17.0 Hz), 4.48 (d, 1H, J =10.5 Hz), 4.41 (d, 1H, J = 10.5 Hz), 4.04 (br,
1H), 3.77 (br, 1H), 3.58 (m, 1H), 3.43 (t, 1H, J = 9.5 Hz), 3.31 (m, 1H), 2.61 (m, 1H), 2.42
(t, 1H, J = 10.5 Hz), 2.00 (s, 1H), 1.95 (m, 1H), 1.71 (m, 1H), 1.21 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 148.9, 147.7, 145.8, 143.9, 141.2, 138.4, 136.6, 136.3, 133.8 (q, J = 32.6
Hz), 131.7, 128.5, 128.5, 128.1, 128.1, 128.0, 127.9, 126.7, 126.1, 125.7, 124.2, 123.3 (q, J =
271.5 Hz), 120.1, 118.4, 112.9, 71.9, 59.8, 49.6, 48.6, 37.1, 27.3, 23.3, 18.6 (broad signals
due to hindered rotation); HRMS (FAB) for C33H33F3N3O3S: calculated [M + H]+: 608.2195,
found [M + H]+: 608.2197.
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N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-
benzenesulfonamide (8): According to the general procedure, amine 14 (200 mg, 0.5 mmol)
was reacted with benzenesulfonyl chloride (115 mg, 0.6 mmol) in 3 mL of pyridine at 110
°C. The product was purified with column chromatography using as eluant
CH2Cl2/MeOH/Et3N (100:1:1), followed by EtOAc/MeOH (10:1), yielding sulfonamide 8
(189 mg, 0.35 mmol, 70%) as a yellowish powder. Mp 98–101 °C; [α]D20 = +66.9 (c = 0.35,
1
MeOH); IR (neat, cm–1) ν 2935, 1518, 1495, 1328, 1164, 1092, 580; H NMR (500 MHz,
CDCl3) δ 8.79 (d, 1H, J = 4.0 Hz), 8.36 (br, 1H), 8.06 (m, 2H), 7.93 (d, 2H, J = 7.5 Hz), 7.81
(br, 1H), 7.48–7.39 (m, 4H), 7.29 (m, 3H), 7.17 (d, 2H, J = 6.0 Hz), 5.89 (m, 1H), 5.34 (br,
1H), 5.01 (s, 1H), 4.99 (d, 1H, J = 9.5 Hz), 4.24 (d, 1H, J = 11.0 Hz), 4.01 (d, 1H, J = 11.0
Hz), 3.32 (m, 1H), 3.13 (m, 1H), 3.00 (m, 2H), 2.82 (m, 1H), 2.31 (m, 1H), 2.09 (m, 1H),
1.80 (s, 1H), 1.59 (m, 1H), 1.45 (m, 1H), 1.26 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 149.1,
146.0, 144.3, 140.6, 138.2, 137.3, 132.3, 131.6, 129.1, 128.9, 128.5, 127.8, 127.4, 126.8,
125.5, 119.4, 115.4, 114.2, 79.4, 71.3, 59.8, 49.7, 49.1, 39.3, 29.7, 28.0, 25.7, 21.7 (broad
signals due to hindered rotation); HRMS (FAB) for C32H34N3O3S: calculated [M + H]+:
540.2321, found [M + H]+: 540.2317.
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N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-4-
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methylbenzenesulfonamide (9): According to the general procedure, amine 14 (400 mg, 0.1
mmol) was reacted with tosyl chloride (268 mg, 1.2 mmol) in 5 mL of pyridine at 110 °C.
The product was purified with column chromatography using as eluant CH2Cl2/MeOH/Et3N
(100:1:1), followed by EtOAc/MeOH (10:1), yielding sulfonamide 9 (484 mg, 0.87 mmol,
87%) as a yellowish powder. Mp 136–140 °C; [α]D20 = +153.6 (c = 1.00, CH2Cl2); IR (neat)
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ν cm–1 3375, 3031, 2931, 2804, 2545, 1622, 1483, 1326, 1159, 1091, 909, 728; 1H NMR (500
MHz, CDCl3) δ 8.80 (d, 1H, J = 4.5 Hz), 8.05 (d, 1H, J = 9.0 Hz), 7.93 (br s, 1H), 7.83 (d,
3H, J = 8.0 Hz), 7.46 (s, 1H), 7.31 (m, 3H), 7.22 (m, 2H), 7.18 (d, 2H, J = 8.0 Hz), 5.92 (m,
1H), 5.57 (m, 2H), 5.02 (d, 1H, J = 2.5 Hz), 5.00 (d, 1H, J = 10.5 Hz), 4.35 (d, 1H, J = 11.0
Hz), 4.27 (d, 1H, J = 11.0 Hz), 3.45 (br, 1H), 3.09 (m, 3H), 2.87 (br, 1H), 2.32 (s, 4H), 2.13
(m, 1H), 1.81 (s, 1H), 1.62 (m, 1H), 1.49 (m, 1H), 1.28 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 148.9, 145.8, 144.1, 143.2, 139.2, 137.3, 137.1, 131.4, 129.9, 129.5, 129.0, 128.4,
127.9, 127.3, 126.6, 126.1, 124.4, 119.6, 115.4, 113.2, 78.6, 71.4, 59.6, 49.6, 49.0, 39.1, 27.9,
25.4, 21.5, 21.4 (broad signals due to hindered rotation); HRMS (FAB) for C33H36N3O3S:
calculated [M + H]+: 554.2477, found [M + H]+: 554.2469.
N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-
2,4,6-trimethylbenzenesulfonamide (10): According to the general procedure, amine 14
(200 mg, 0.5 mmol) was reacted with mesitylsulfonyl chloride (130 mg, 0.6 mmol) in 3 mL
of pyridine at 110 °C. The product was purified with column chromatography by using as
eluant CH2Cl2/MeOH/Et3N (100:1:1), followed by EtOAc/MeOH (10:1), yielding
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sulfonamide 10 (93 mg, 0.16 mmol, 32%) as yellowish solid. Mp 104–108 °C; [α]D
=
+105.2 (c = 1.00, CH2Cl2); IR (neat, cm–1) ν 3030, 2937, 2871, 1623, 1454, 1324, 1153,
1
1056, 958, 832, 736, 654; H NMR (500 MHz, CDCl3) δ 8.79 (d, 1H, J = 4.5 Hz), 8.65 (br,
1H), 8.09 (s, 1H), 8.01 (d, 1H, J = 9.0 Hz), 7.65 (d, 1H, J = 9.0 Hz), 7.49 (br, 1H), 7.35 (m,
5H), 6.90 (s, 2H), 5.85 (m, 1H), 5.02 (d, 1H, J = 10.5 Hz), 4.99 (d, 1H, J = 17.5 Hz), 4.47 (d,
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1H, J = 10.5 Hz), 4.41 (d, 1H, J = 10.5 Hz), 3.72 (br, 1H), 3.31 (br, 2H), 3.05 (br, 1H), 2.76
(m, 7H), 2.45 (br, 1H), 2.23 (m, 4H), 1.89 (s, 1H), 1.76 (br, 1H), 1.63 (m, 1H), 1.26 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 148.6, 145.3, 142.9, 142.2, 139.4, 138.9, 138.0, 137.2, 137.0,
134.3, 132.0, 131.4, 130.9, 128.5, 128.3, 127.8, 127.3, 126.5, 122.4, 118.7, 116.5, 111.5,
71.6, 59.7, 49.7, 48.7, 38.3, 27.7, 24.6, 23.3, 23.2, 20.9 (broad signals due to hindered
rotation); HRMS (FAB) for C35H40N3O3S: calculated [M + H]+: 582.2790, found [M + H]+:
582.2798.
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N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-yl)-4-
methoxybenzenesulfonamide (11): According to the general procedure, amine 14 (100 mg,
0.25 mmol) was reacted with p–methoxybenzenesulfonyl chloride (62 mg, 0.3 mmol) in 1
mL of pyridine at 110 °C. The product was purified with column chromatography using as
eluant CH2Cl2/MeOH/Et3N (100:1:1), followed by EtOAc/MeOH (10:1), yielding
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sulfonamide 11 (114 mg, 0.2 mmol, 80%) as a yellowish powder. Mp 96–99 °C; [α]D
=
+73.8 (c = 1.00, CH2Cl2); IR (neat, cm–1) ν 2936, 1623, 1497, 1455, 1327, 1260, 1157, 1093,
1027, 833, 734; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, 1H, J = 4.5 Hz), 8.05 (d, 1H, J = 9.0
Hz), 8.00 (br, 1H), 7.89 (d, 2H, J = 9.0 Hz), 7.81 (d, 1H, J = 8.0 Hz), 7.71 (br, 1H), 7.44 (br,
1H), 7.29 (m, 3H), 7.20 (m, 2H), 6.85 (d, 2H, J = 9.0 Hz), 5.90 (m, 1H), 5.38 (br, 1H), 5.02
(s, 1H), 4.99 (d, 1H, J = 8.5 Hz), 4.28 (d, 1H, J = 11.5 Hz), 4.11 (d, 1H, J = 11.5 Hz), 3.76 (s,
3H), 3.31 (br, 1H), 3.18 (br, 1H), 3.01 (br, 2H), 2.82 (br, 1H), 2.30 (q, 1H, J = 8.0 Hz), 2.07
(br, 1H), 1.79 (s, 1H), 1.59 (m, 1H), 1.46 (m, 1H), 1.28 (br, 1H); 13C NMR (125 MHz,
CDCl3) δ 162.8, 149.0, 146.0, 144.6, 139.7, 137.4, 137.3, 131.7, 131.5, 129.5, 128.4, 127.8,
127.8, 126.8, 124.8, 119.2, 115.2, 114.1, 113.7, 79.5, 71.3, 59.8, 55.5, 49.8, 49.1, 39.5, 28.0,
25.7, 21.8; HRMS (FAB) for C33H36N3O4S: calculated [M + H]+: 570.2427, found [M + H]+:
570.2429.
N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)-methyl)quinolin-6-yl)-
2,4,6–trimethoxybenzenesulfonamide (12): According to the general procedure, amine 14
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(200 mg, 0.5 mmol) was reacted with 2,4,6–methoxybenzenesulfonyl chloride (160 mg, 0.6
mmol) in 2.5 mL of pyridine at 110 °C. The product was purified with column
chromatography by using as eluant CH2Cl2/MeOH/Et3N (100:1:1), followed by
EtOAc/MeOH (10:1), yielding sulfonamide 12 (296 mg, 0.47 mmol, 78%) as a yellowish
powder. Mp 99–102 °C; [α]D20 = +175.0 (c = 0.32, CH2Cl2); IR (neat, cm–1) ν 2934, 1622,
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1515, 1454, 1344, 1322, 1152, 1122, 1086; H NMR (500 MHz, CDCl3) δ 8.78 (d, 1H, J =
4.0 Hz), 8.02 (d, 1H, J = 9.0 Hz), 7.90 (br, 1H), 7.69 (dd, 1H, J = 9.0, 1.5 Hz), 7.42 (br, 1H),
7.37 (m, 2H), 7.30 (m, 3H), 6.05 (s, 2H), 5.94 (m, 1H), 5.18 (br, 1H), 5.05 (d, 1H, J = 9.0
Hz), 5.03 (s, 1H), 4.35 (d, 1H, J = 11.5 Hz), 4.30 (d, 1H, J = 11.5 Hz), 3.88 (s, 6H), 3.74 (s,
3H), 3.20 (br, 1H), 3.11 (br, 1H), 2.88 (m, 1H), 2.84 (br, 1H), 2.70 (br, 1H), 2.24 (m, 1H),
2.00 (br, 1H), 1.78 (s, 1H), 1.46 (m, 2H), 1.41 (br, 1H) (NH of the sulfonamide is missing);
13C NMR (125 MHz, CDCl3) δ 164.5, 160.6, 148.9, 146.0, 145.5, 140.4, 137.7, 136.4, 131.4,
128.4, 127.9, 127.8, 127.0, 123.4, 119.7, 114.7, 111.8, 108.5, 91.5, 80.0, 71.3, 60.1, 56.7,
55.4, 49.7, 49.0, 39.8, 28.0, 26.3, 22.7 (broad signals due to hindered rotation); HRMS (ESI)
for C35H40N3O6S: calculated [M + H]+: 630.2638, found [M + H]+: 630.2640.
N-(4-((S)-(Benzyloxy)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)-methyl)quinolin-6-yl)-4-
(dimethylamino)-benzenesulfonamide (13): According to the general procedure, amine 14
(400 mg, 1.0 mmol) was reacted with pꢀ(dimethylamino)benzenesulfonyl chloride (263 mg,
1.2 mmol) in 5 mL of pyridine at 110 °C. The product was purified with column
chromatography by using as eluant CH2Cl2/MeOH/Et3N (100:2:1), followed by
EtOAc/MeOH (10:1), yielding sulfonamide 13 (582 mg, 0.8 mmol, 80%) as a yellowish
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powder. Mp 105–107 °C; [α]D = +91.6 (c = 0.57, CH2Cl2); IR (neat, cm–1) ν 2931, 2864,
1594, 1514, 1363, 1314, 1164, 1091, 646; 1H NMR (500 MHz, CDCl3) δ 8.80 (d, 1H, J = 4.5
Hz), 8.04 (d, 1H, J = 9.0 Hz), 7.97 (br, 1H), 7.32 (d, 3H, J = 9.0 Hz), 7.43 (br, 1H), 7.31 (m,
3H), 7.23 (d, 2H, J = 6.5 Hz), 7.10 (br, 1H) 6.53 (d, 2H, J = 9.0 Hz), 5.93 (m, 1H), 5.19 (br,
1H), 5.03 (d, 1H, J = 4.0 Hz), 5.00 (s, 1H), 4.31 (d, 1H, J = 11.5 Hz), 4.16 (d, 1H, J = 11.5
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