Organocatalyzed highly diastereo- and enantioselective tandem sulfa-michael-mannich reaction of 2-mercaptoquinoline-3-carbaldimines with maleimides

Article abstract of DOI:10.1002/cctc.201300993

A highly diastereo- and enantioselective organocatalyzed domino sulfa-Michael-Mannich reaction of 2-mercaptoquinoline-3-carbaldimines with maleimides has been developed. This approach provides a convenient and efficient access to multifuntionalized tetracyclic quinoline derivatives with three contiguous stereocenters in high yield with excellent stereoselectivity (up to >99:1 dr and >99 % ee). Four rings, three stereocenters: The asymmetric cascade sulfa-Michael-Mannich reaction of 2-mercapto-quinoline-3-carbaldimines with maleimides catalyzed by a bifunctional tertiary amine-thiourea affords tetracyclic quinoline derivatives with three contiguous stereocenters in high yield with excellent diastereo- (>99:1 dr) and enantioselectivities (90->99 % ee). Copyright

Full text of DOI:10.1002/cctc.201300993

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DOI: 10.1002/cctc.201300993
Organocatalyzed Highly Diastereo- and Enantioselective
Tandem Sulfa-Michael–Mannich Reaction of
2-Mercaptoquinoline-3-carbaldimines with Maleimides
Lulu Wu, Youming Wang, Haibin Song, Liangfu Tang, Zhenghong Zhou,* and Chuchi Tang[a]
A
highly diastereo- and enantioselective organocatalyzed
funtionalized tetracyclic quinoline derivatives with three con-
tiguous stereocenters in high yield with excellent stereoselec-
tivity (up to >99:1 dr and >99% ee).
domino sulfa-Michael–Mannich reaction of 2-mercaptoquino-
line-3-carbaldimines with maleimides has been developed. This
approach provides a convenient and efficient access to multi-
Introduction
Chiral polycyclic quinolines are ubiquitous and important ring
systems found in many bioactive alkaloids and pharmaceuti-
cals.[1] Consequently, the development of efficient synthetic
methodologies, which allow for the rapid construction of intri-
cate polycyclic quinolines scaffold containing multiple stereo-
genic centers, is of considerable significance and remains a pre-
eminent goal in current synthetic chemistry. Compared with
traditional stepwise chemical processes, tandem reactions have
proven to be extremely useful in achieving these goals owing
to their high reaction efficiency, atom economy, and operation-
al simplicity.[2] Recently, we reported an elegant approach to
the highly functionalized dihydro-2H-thiopyrano[2,3-b]quino-
lines with excellent diastereo- and enantioselectivity through
an organocatalyzed cascade Michael–Henry reaction.[3] Subse-
quently, we also uncovered a diarylprolinol silyl ether catalyzed
tandem Michael–aldol reaction of a,b-unsaturated aldehydes
with 2-mercaptoquinoline-3-carbaldehydes to deliver 2H-
thiopyrano[2,3-b]quinoline derivatives.[4] It should be noted
that chiral succinimides, found in numerous biologically inter-
esting natural products and pharmaceuticals, are often used as
pharmacophores in drug discovery.[5,6] The incorporation of
this important pharmacophores into biologically interesting
quinoline architectures is of considerable significance from the
standpoint of the medicinal and organic chemistry. Among the
different methodologies available for the synthesis of syntheti-
cally and biologically interesting chiral a-substituted succini-
mides, the most straightforward one is the asymmetric conju-
gate addition of nucleophile to maleimides, especially using
chiral organocatalysts.[7,8] On the basis of these previous re-
ports and our experience in organocatalysis,[9] we envisioned
achieving easy access to tetracyclic 1,3-dioxo-1,2,3,3a,11,11a-
hexahydropyrrolo[3’,4’:5,6]thiopyrano[2,3-b]quinolines through
an unprecedented tandem sulfa-Michael–Mannich reaction
between 2-mercaptoquinoline-3-carbaldimines and malei-
mides.
Results and Discussion
To explore the proposed catalytic tandem sulfa-Michael–Man-
nich reaction process, a model reaction between 2-mercapto-
quinoline-3-carbaldimine 1a (2,4,6-trimethylphenylsulfonyl was
chosen as the N-protecting group because the introduction of
this group can efficiently improve the solubility of the Mi-
chael–Mannich product in common solvents, which is very im-
portant for the following NMR and HPLC analysis of the prod-
ucts) and N-phenyl maleimide 2a was performed in dichloro-
methane at 208C in the presence of a chiral bifunctional orga-
nocatalyst (Figure 1). Molecular sieves (4 ꢀ) were added as
water scavengers to prevent decomposition of the aldimine.
The results are collected in Table 1.
[a] L. Wu, Y. Wang, Prof. H. Song, Prof. L. Tang, Prof. Z. Zhou, Prof. C. Tang
State Key Laboratory of Elemento-Organic Chemistry
Institute of Elemento-OrganicChemistry
Nankai University
Collaborative Innovation Center of Chemical Science
and Engineering (Tianjin)
Tianjin 300071 (P.R. China)
Fax: (+86)22-23503627
E-mail: z.h.zhou@nankai.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300993.
Figure 1. Catalyst candidates.
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Table 1. Catalyst screening.[a]
Table 2. Optimization of the reaction conditions.[a]
Yield [%][b]
ee [%][c]
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c]
Entry
Solvent
t [h]
1
2
3
4
5
6
I
II
IIIa
IIIb
IVa
IVb
2
3
8
24
4
24
94
93
90
80
93
87
23
ꢀ15
ꢀ83
ꢀ85
87
1
2
3
4
5
6
7
8
9[d]
10[e]
11[f]
12[g]
CH2Cl2
CHCl3
4
10
4
93
90
91
92
80
78
73
95
93
91
79
90
87
84
84
86
40
33
75
16
91
ClCH2CH2Cl
Cl2CHCHCl2
PhCH3
ethyl acetate
Et2O
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
2
10
24
24
5
10
18
48
12
84
[a] All reactions were performed by using 1a (0.2 mmol), 2a (0.4 mmol),
and 4 ꢀ molecular sieve (50 mg) in CH2Cl2 (1.0 mL) at 208C in the pres-
ence of the catalyst (10 mol%). [b] Isolated yield. [c] In all cases, >99:1 dr
was observed. Enantiomeric excesses were determined by HPLC analysis
using a chiral stationary phase.
95
97
>99
CH2Cl2
[a] Unless otherwise specified, all reactions were performed by using 1a
(0.2 mmol), 2a (0.4 mmol), catalyst IVa (0.02 mmol, 10 mol%), and 4 ꢀ
molecular sieve (50 mg) in solvent (1.0 mL) at 208C. [b] Isolated yield.
[c] In all cases, >99:1 dr was observed. Enantiomeric excesses were deter-
mined by HPLC analysis using a chiral stationary phase. [d] Reaction was
performed at 08C. [e] Reaction was conducted at ꢀ208C. [f] Reaction was
run at ꢀ408C. [g] Reaction was performed at ꢀ408C with a 20 mol%
catalyst loading.
Under the catalysis of bifunctional Cinchona alkaloids I and
II, the tandem sulfa-Michael–Mannich reaction took place
smoothly to generate the desired polycyclic quinoline 3aa in
good yields and excellent diastereoselectivities (in all cases,
>99:1 dr was observed), but with unsatisfactory enantioselec-
tivities (Table 1, entries 1 and 2). To further improve the enan-
tioselectivity of this cascade process, we shifted our focus to
some most commonly used tertiary amine–thiourea cata-
lysts,[10] which have been proven to be a good type of hydro-
gen bond donor catalysts and can activate maleimide through
hydrogen bond interaction.[8d,g,i,11] To our delight, amine–thiour-
ea catalysts III and IV exhibited much better chiral induction
ability, but the catalytic efficacy varied greatly depending on
the organocatalyst employed (entries 3–6). Among them, Take-
moto’s catalyst IVa exhibited the most promising results in
terms of ee value and catalytic efficacy (entry 5). This prompted
us to select this catalyst for further optimization of the reaction
conditions (Table 2).
Under the optimized reaction conditions (Table 2, entry 12),
we next examined the scope and limitation of the IVa-promot-
ed tandem sulfa-Michael–Mannich reactions, and the results
are summarized in Table 3. For the aromatic maleimides, it ap-
peared that the position and the electronic property of the
substituents on the aromatic rings have a very limited impact
on the enantioselectivities. The reactions of maleimides with
electron-neutral, -donating and -withdrawing groups with 2-
mercaptoquinoline-3-carbaldimine 1a all proceeded smoothly
to give structurally diverse succinimides 3 with uniformly high
levels of enantioselectivity (entries 1–6, 98–>99% ee). The re-
action was also applicable to less reactive aliphatic maleimides
albeit with a slight decreased ee values (entries 7 and 8, 90%
and 91% ee, respectively). To further expand the scope of this
methodology, we subsequently investigated the tandem Mi-
chael–Mannich reactions with various 2-mercaptoquinoline-3-
carbaldimines and N-phenyl maleimide 2a (entries 9–15). In ad-
dition, the reaction appeared quite general with respect to
other 2-mercaptoquinoline-3-carbaldimines bearing either an
electron-donating or electron-withdrawing substituent in the
quinoline ring. In all cases, the reactions ran efficiently to give
the desired adducts in high yields and with excellent diastereo-
and enantioselectivities.
Solvent evaluation indicated that the reaction medium has
a remarkable influence on the reaction (Table 2, entries 1–8). In
all the examples, although the diastereoselectivity was excel-
lent, the enantioselectivity was highly dependent on the sol-
vent employed. Generally, good ee values were observed by
performing the reaction in chlorohydrocarbons, such as meth-
ylene chloride, chloroform, 1,2-dichloroethane, and 1,1,2,2-tet-
rachloroethane (entries 1–4, 84–87%). The enantioselectivity
was sharply decreased when ethyl acetate, toluene, or acetoni-
trile was used as the solvent. Methylene chloride was the best
solvent giving the highest ee of 87% among all the tested sol-
vents. Moreover, decreasing the reaction temperature had a sig-
nificant positive effect on the enantioselectivity of the reaction
(entries 1, 10–11). Further improvement of the ee value to 97%
could be achieved by lowering the reaction temperature to
ꢀ408C at the expense of reaction time (entry 11). It was grati-
fying that an obvious acceleration of reaction rate and almost
perfect stereocontrol was achieved by adjusting the catalyst
loading from 10 mol% to 20 mol% (entry 12).
To determine the relative and absolute configurations of the
products from the asymmetric tandem Michael–Mannich pro-
cess, a single crystal of compound 3ae was obtained and
the stereoconfiguration was unambiguously assigned as
(3aS,11S,11aS) by X-ray diffraction analysis (Figure 2).[12] The
absolute configurations of other products can therefore be
determined by analogy.
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Conclusions
Table 3. Substrate scope of IVa-catalyzed asymmetric domino Michael–Mannich
reaction between 1 and 2.[a]
In conclusion, we have developed an efficient orga-
nocatalytic tandem sulfa-Michael–Mannich process
for the stereocontrolled synthesis of multifunctional-
ized tetracyclic quinolines. Under the catalysis of
a chiral bifunctional tertiary amine–thiourea catalyst,
a broad range of 2-mercaptoquinoline-3-carbaldi-
mines and maleimides can be tolerated well in this
process, generating the desired tetracyclic quinoline
derivatives with three contiguous stereocenters in
high yields with excellent diastereo- (>99:1 dr) and
enantioselectivities (90–>99% ee).
Entry
3 (R1, R2)
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3aa (H, Ph)
12
12
12
12
12
12
48
48
12
12
12
12
12
12
12
90
93
94
93
95
89
85
93
92
94
90
89
95
87
88
>99
98
99
99
98
99
90
91
98
99
98
97
98
96
90
3ab (H, 4-MeC6H4)
3ac (H, 4-MeOC6H4)
3ad (H, 4-BrC6H4)
3ae (H, 4-ClC6H4)
3af (H, 3-ClC6H4)
3ag (H, Et)
Experimental Section
3ah (H, Bu)
General procedure for the preparation of
2-mercaptoquinoline-3-carbaldimines 1
9
3ba (6-Me, Ph)
3ca (7-Me, Ph)
3da (6-MeO, Ph)
3ea (7-MeO, Ph)
3 fa (6-Et, Ph)
10
11
12
13
14
15
To a solution of 2,4,6-trimethylbenzenesulfonamide and
catalytic amount of 4-methylbenzenesulfonic acid (5%)
in anhydrous toluene was added 2-mercaptoquinoline-3-
carbaldehyde (1 equiv.) in one portion at RT. The result-
ing mixture was heated to reflux for 8 h, the water gen-
erated in the reaction was removed with a Dean–Stark
apparatus. After cooling to RT, aqueous sodium hydro-
gencarbonate was added and the red precipitate was
collected by filtration. The crude product was used di-
3ga (6-Bu, Ph)
3ha (7-Cl, Ph)
[a] All reactions were performed by using 1 (0.2 mmol), 2 (0.4 mmol), catalyst IVa
(0.04 mmol, 20 mol%), and 4 ꢀ molecular sieve (50 mg) and in CH2Cl2 (1.0 mL) at
ꢀ408C. [b] Isolated yield. [c] In all cases, >99:1 dr was observed. Enantiomeric excess-
es were determined by HPLC analysis using a chiral stationary phase.
Figure 3. Proposed mechanism.
rectly without further purification. The structure of carbaldimine
1a was confirmed by NMR and HRMS analysis.
N-(2,4,6-trimethylbenzenesulfonyl)-2-mercaptoquinoline-3-carbaldi-
mine (1a): red solid, 73% yield, m.p. 184–1868C. H NMR (400 MHz,
1
Figure 2. X-ray structure of compound (3aS,11S,11aS)-3ae, most of the hy-
drogen atoms have been omitted for clarity.
[D6]DMSO): d=14.09 (s, 1H), 9.79 (s, 1H), 8.59 (s, 1H), 7.97 (s, 1H),
7.71(s, 1H), 7.61 (s, 1H), 7.35 (s, 1H), 7.08 (s, 2H), 2.58 (s, 6H),
2.25 ppm (s, 3H); 13C NMR (100.6 MHz, [D6]DMSO): d=180.8, 168.1,
143.6, 141.2, 139.6, 138.0, 134.6, 131.9, 131.1, 130.5, 129.9, 125.0,
121.7, 116.3, 22.5, 20.5 ppm; HRMS (ESI) m/z calcd. for
C19H18N2NaO2S2 [M+Na]+: 393.0702; found: 393.0705.
A transition state model that accounts for the stereochemi-
cal outcome is shown in Figure 3. In this model, the acidic pro-
tons of the thiourea moiety activate the maleimide through
hydrogen bond interaction. The tertiary amine functionality of
the catalyst deprotonates and activates the mercapto group to
attack the maleimide from the si-face. This forms an enolate in-
termediate, which is involved in the successively nucleophilic
attack of the carbon of the imine from the si-face to afford the
observed products.
Typical procedure for thiourea–tertiary amine IVa-catalyzed
asymmetric domino sulfa-Michael–Mannich reactions
To a stirred solution of catalyst IVa (20 mol%) in methylene chlo-
ride (1 mL) at ꢀ408C were added 2-mercaptoquinoline-3-carbaldi-
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mines (1.0 equiv., 0.2 mmol) and maleimides (2.0 equiv., 0.4 mmol).
After the reaction was completed (monitored by TLC), the reaction
mixture was concentrated under reduced pressure and the
crude product was purified by column chromatography on
silica gel (200–300 mesh, petroleum ether (PE)/EtOAc=8/1 to
5/1) to afford the desired 1,3-dioxo-1,2,3,3a,11,11a-hexahydro-
pyrrolo[3’,4’:5,6]thiopyrano[2,3-b]quinolines as white solid. The title
compounds were fully characterized by 1 H, 13C NMR spectroscopy,
HRMS and specific rotation data.
2H), 6.75 (br. s, 3H), 4.97 (dd, J=9.6, 4.4 Hz, 1H), 4.40 (d, J=9.2 Hz,
1H), 3.78 (dd, J=9.6, 4.4 Hz, 1H), 2.71 (s, 6H), 2.28 ppm (s, 3H);
13C NMR (100.6 MHz, CDCl3): d=175.0, 173.2, 152.7, 147.8, 143.0,
138.9, 134.3, 133.6, 132.3, 130.8, 129.4, 129.2, 128.5, 128.1, 127.4,
127.3, 126.9, 123.1, 52.7, 45.8, 42.1, 23.0, 20.9 ppm; HRMS (ESI) m/z
calcd. for C29H23BrN3O4S2 [MꢀH]ꢀ: 620.0319; found: 620.0316; HPLC
analysis (Chiralpak OD-H column, hexane/2-propanol/TEA=
60:40:0.1, flow rate=0.8 mLminꢀ1
, wavelength=230 nm): TR =
39.55 (major) and 81.35 min (minor).
(3aS,11S,11aS)-1,3-Dioxo-2-phenyl-11-(2,4,6-trimethylbenzene-sul-
fonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-pyrano-
[2,3-b]quinoline (3aa): White solid, m.p. 188–1908C, 90% yield,
(3aS,11S,11aS)-2-(4-Chlorophenyl)-1,3-dioxo-11-(2,4,6-trimethyl-ben-
zenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3ae): White solid, m.p. 154–1568C, 95%
yield, ½aꢁ2D5 = +75.3 (c=1.0, CH2Cl2), 98% ee. 1H NMR (400 MHz,
CDCl3): d=8.13 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.73 (t, J=8.0 Hz,
2H), 7.55 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.98 (s, 2H),
6.75–81 (m, 3H), 4.97 (dd, J=9.6, 4.4 Hz, 1H), 4.40 (d, J=9.2 Hz,
1H), 3.77 (dd, J=9.6, 4.4 Hz, 1H), 2.71 (s, 6H), 2.29 ppm (s, 3H);
13C NMR (100.6 MHz, CDCl3): d=175.0, 173.3, 152.7, 147.7, 143.0,
138.9, 135.0, 134.3, 133.6, 132.3, 130.8, 129.3, 128.8, 128.5, 128.1,
127.3, 127.1, 126.9, 52.7, 45.8, 42.0, 23.1, 21.0 ppm; HRMS (ESI) m/z
calcd. for C29H23ClN3O4S2 [MꢀH]ꢀ: 576.0824; found: 576.0826; HPLC
analysis (Chiralpak OD-H column, hexane/2-propanol/TEA=
½aꢁ2D5 = +65.0 (c=1.0, CH2Cl2),>99% ee. H NMR (400 MHz, CDCl3):
1
d=8.16 (br. s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.72 (t, J=7.6 Hz, 2H),
7.54 (t, J=7.6 Hz, 1H), 7.26 (br. s, 3H), 6.98 (s, 2H), 6.82 (br. s, 3H),
4.97 (dd, J=9.6, 4.8 Hz, 1H), 4.38 (d, J=9.6 Hz, 1H), 3.76 (dd, J=
9.6, 4.8 Hz, 1H), 2.72 (s, 6H), 2.28 ppm (s, 3H); 13C NMR (100.6 MHz,
CDCl3): d=175.3, 173.6, 152.8, 147.7, 142.9, 138.9, 134.4, 133.6,
132.3, 130.7, 130.4, 129.3, 129.1, 128.5, 128.1, 127.3, 126.9, 125.9,
52.7, 45.7, 42.1, 23.1, 20.9 ppm; HRMS (ESI) m/z calcd. for
C29H24N3O4S2 [MꢀH]ꢀ: 542.1213; found: 542.1217; HPLC analysis
(Chiralpak OD-H column, hexane/2-propanol/triethylamine (TEA)=
60:40:0.1, flow rate=0.8 mLminꢀ1, wavelength=230 nm): reten-
tion time (TR)=28.62 (major) and 57.06 min (minor).
60:40:0.1, flow rate=0.8 mLminꢀ1
, wavelength=230 nm): TR =
36.04 (major) and 71.62 min (minor).
(3aS,11S,11aS)-1,3-Dioxo-2-(4-methylphenyl)-11-(2,4,6-trimethyl-ben-
zenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3ab): White solid, m.p. 166–1688C, 93%
yield, ½aꢁ2D5 = +93.2 (c=1.0, CH2Cl2), 98% ee. 1H NMR (400 MHz,
CDCl3): d=8.15 (br. s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.72 (t, J=
8.0 Hz, 2H), 7.53 (t, J=7.6 Hz, 1H), 7.04 (d, J=7.6 Hz, 2H), 6.98 (s,
2H), 6.87 (d, J=6.4 Hz, 1H), 6.67 (d, J=6.8 Hz, 2H), 4.96 (dd, J=
9.6, 4.8 Hz, 1H), 4.36 (d, J=9.6 Hz, 1H), 3.74 (dd, J=9.6, 4.8 Hz,
1H), 2.72 (s, 6H), 2.28 (s, 3H), 2.24 ppm (s, 3H); 13C NMR
(100.6 MHz, CDCl3): d=175.4, 173.7, 152.9, 147.7, 142.8, 139.3,
138.8, 134.4, 133.6, 132.3, 130.6, 129.7, 129.4, 128.4, 128.1, 127.7,
127.2, 126.9, 125.7, 52.5, 45.6, 42.3, 23.1, 21.0, 20.9 ppm; HRMS
(ESI) m/z calcd. for C30H26N3O4S2 [MꢀH]ꢀ: 556.1370; found:
556.1368; HPLC analysis (Chiralpak OD-H column, hexane/2-propa-
(3aS,11S,11aS)-2-(3-Chlorophenyl)-1,3-dioxo-11-(2,4,6-trimethyl-ben-
zenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3af): White solid, m.p. 193–1958C, 89%
yield, ½aꢁ2D5 = +88.8 (c=1.0, CH2Cl2), 99% ee. 1H NMR (400 MHz,
CDCl3): d=8.14 (br. s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.73 (d, J=
7.6 Hz, 2H), 7.55 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.19 (t, J=7.6 Hz,
1H), 6.98 (s, 2H), 6.91 (s, 1H), 6.76 (br. s, 2H), 4.98 (dd, J=9.6,
4.4 Hz,1H), 4.41 (d, J=9.2 Hz, 1H), 3.78 (dd, J=9.6, 4.4 Hz, 1H),
2.71 (s, 6H), 2.29 ppm (s, 3H); 13C NMR (100.6 MHz, CDCl3): d=
174.9, 173.2, 152.7, 147.8, 143.0, 138.9, 134.7, 134.3, 133.7, 132.4,
132.4, 131.4, 130.8, 130.1, 129.3, 128.5, 128.1, 127.4, 127.0, 126.1,
124.1, 52.6, 45.8, 42.0, 23.1, 21.0 ppm; HRMS (ESI) m/z calcd. for
C29H23ClN3O4S2 [MꢀH]ꢀ: 576.0824; found: 576.0820; HPLC analysis
(Chiralpak OD-H column, hexane/2-propanol/TEA=60:40:0.1, flow
rate=0.8 mLminꢀ1, wavelength=230 nm): TR =24.42 (major) and
50.37 min (minor).
nol/TEA=60:40:0.1, flow rate=0.8 mLminꢀ1
230 nm): TR =28.40 (major) and 48.13 min (minor).
,
wavelength=
(3aS,11S,11aS)-1,3-Dioxo-2-(4-methoxyphenyl)-11-(2,4,6-trimethyl-
benzenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo-
(3aS,11S,11aS)-1,3-Dioxo-2-ethyl-11-(2,4,6-trimethylbenzene-sulfon-
amido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thiopyrano-[2,3-
25
[3’,4’:5,6]thiopyrano[2,3-b]quinoline (3ac): White solid, m.p. 160–
b]quinoline (3ag): White solid, m.p. 168–1708C, 85% yield, ½aꢁD
=
1
1
1628C, 94% yield, ½aꢁD25 = +96.2 (c=1.0, CH2Cl2), 99% ee. H NMR
ꢀ12.0 (c=1.0, CH2Cl2), 90% ee. H NMR (400 MHz, CDCl3): d=8.17
(s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.70 (t, J=
7.6 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 6.97 (s, 2H), 6.89 (d, J=8.4 Hz,
1H), 4.85 (dd, J=9.6, 4.8 Hz, 1H), 4.18 (d, J=9.6 Hz, 1H), 3.53 (dd,
J=10.0, 5.2 Hz, 1H), 3.26 (q, J=6.8 Hz, 2H), 2.71 (s, 6H), 2.28 (s,
3H), 0.67 ppm (t, J=6.8 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): d=
175.9, 174.2, 152.9, 147.6, 142.8, 138.9, 134.4, 133.5, 132.3, 130.5,
129.5, 128.4, 128.0, 127.2, 126.9, 52.5, 45.4, 41.9, 34.3, 23.0, 20.9,
12.5 ppm; HRMS (ESI) m/z calcd. for C25H24N3O4S2 [MꢀH]ꢀ:
494.1213; found: 494.1216; HPLC analysis (Chiralpak OD-H column,
hexane/2-propanol/TEA=85:15:0.1, flow rate=0.8 mLminꢀ1, wave-
length=230 nm): TR =77.22 (minor) and 85.67 min (major).
(400 MHz, CDCl3): d=8.15 (br. s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.72
(t, J=7.6 Hz, 2H), 7.53 (t, J=7.6 Hz, 1H), 6.97 (s, 2H), 6.87 (br. s,
1H), 6.73 (br. s, 4H), 4.95 (dd, J=8.8, 4.0 Hz, 1H), 4.36 (d, J=8.8 Hz,
1H), 3.73 (dd, J=9.2, 4.8 Hz, 1H), 3.69 (s, 3H), 2.71 (s, 6H),
2.28 ppm (s, 3H); 13C NMR (100.6 MHz, CDCl3): d=175.6, 173.8,
159.7, 152.9, 147.7, 142.8, 138.9, 134.4, 133.6, 132.3, 130.6, 129.4,
128.4, 128.1, 127.2, 127.1, 126.9, 122.9, 114.4, 55.4, 52.7, 45.6, 42.0,
23.0, 20.9 ppm; HRMS (ESI) m/z calcd. for C30H26N3O5S2 [MꢀH]ꢀ:
572.1319; found: 572.1313; HPLC analysis (Chiralpak OD-H column,
hexane/2-propanol/TEA=60:40:0.1, flow rate=0.8 mLminꢀ1, wave-
length=230 nm): TR =39.20 (major) and 71.28 min (minor).
(3aS,11S,11aS)-2-(4-Bromophenyl)-1,3-dioxo-11-(2,4,6-trimethylben-
zenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo-
(3aS,11S,11aS)-2-Butyl-1,3-dioxo-11-(2,4,6-trimethylbenzene-sulfon-
amido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thiopyrano-[2,3-
25
[3’,4’:5,6]thiopyrano[2,3-b]quinoline (3ad): White solid, m.p. 164–
b]quinoline (3ah): White solid, m.p. 171–1738C, 93% yield, ½aꢁD
=
1668C, 93% yield, ½aꢁD25 = +67.4 (c=1.0, CH2Cl2), 99% ee. H NMR
ꢀ12.2 (c=1.0, CH2Cl2), 91% ee. H NMR (400 MHz, CDCl3): d=8.20
(br. s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.69 (t,
J=7.6 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 6.98 (s, 2H), 6.91 (d, J=
1
1
(400 MHz, CDCl3): d=8.12 (br. s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.70–
7.75 (m, 3H), 7.55 (t, J=7.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.97 (s,
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9.2 Hz, 1H), 4.85 (dd, J=9.6, 5.2 Hz, 1H), 4.16 (d, J=10.0 Hz, 1H),
3.51 (dd, J=10.0, 5.2 Hz, 1H), 3.24 (t, J=6.8 Hz, 2H), 2.72 (s, 6H),
2.28 (s, 3H), 0.92–1.02 (m, 2H), 0.30–0.35 (m, 2H), 0.20 ppm (t, J=
6.8 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): d=176.2, 174.5, 152.8,
147.7, 142.8, 138.9, 134.4, 133.4, 132.3, 130.5, 129.8, 128.5, 127.9,
127.2, 127.0, 52.5, 45.3, 42.0, 39.1, 28.9, 23.0, 20.9, 19.0, 12.8 ppm;
HRMS (ESI) m/z calcd. for C27H29N3NaO4S2 [M+Na]+: 546.1492;
found: 546.1495; HPLC analysis (Chiralpak OD-H column, hexane/2-
propanol/TEA=85:15:0.1, flow rate=0.8 mLminꢀ1, wavelength=
230 nm): TR =46.97 (major) and 62.78 min (minor).
3H), 4.93 (dd, J=9.2, 4.0 Hz, 1H), 4.36 (d, J=8.8 Hz, 1H), 3.92 (s,
3H), 3.73 (dd, J=8.8, 4.0 Hz, 1H), 2.71 (s, 6H), 2.28 ppm (s, 3H);
13C NMR (100.6 MHz, CDCl3): d=175.4, 173.6, 161.6, 153.0, 149.5,
142.8, 138.9, 134.4, 133.1, 132.3, 130.5, 129.1, 129.0, 126.9, 125.9,
122.1, 120.5, 106.4, 55.6, 52.6, 45.9, 42.1, 23.0, 20.9 ppm; HRMS
(ESI) m/z calcd. for C30H26N3O5S2 [MꢀH]ꢀ: 572.1319; found:
572.1313; HPLC analysis (Chiralpak OD-H column, hexane/2-propa-
nol/TEA=60:40:0.1, flow rate=0.8 mLminꢀ1
230 nm): TR =31.44 (major) and 53.93 min (minor).
,
wavelength=
(3aS,11S,11aS)-1,3-Dioxo-8-ethyl-2-phenyl-11-(2,4,6-trimethyl-benze-
nesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3 fa): White solid, m.p. 160–1628C, 95%
yield, ½aꢁ2D5 = +103.8 (c=1.0, CH2Cl2), 98% ee. 1H NMR (400 MHz,
CDCl3): d=8.08 (br. s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.59 (dd, J=8.8,
1.6 Hz, 1H), 7.48 (s, 1H), 7.25–7.26 (m, 3H), 6.99 (s, 2H), 6.83 (br. s,
3H), 4.97 (dd, J=9.6, 4.4 Hz, 1H), 4.39 (d, J=9.2 Hz, 1H), 3.77 (dd,
J=9.6, 4.8 Hz, 1H), 2.82 (q, J=7.6 Hz, 2H), 2.73 (s, 6H), 2.29 (s, 3H),
1.33 ppm (t, J=7.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): d=175.4,
173.7, 151.6, 146.5, 143.5, 142.8, 138.9, 134.4, 133.1, 132.3, 131.9,
130.4, 129.3, 129.0, 128.2, 127.0, 126.4, 125.9, 125.6„ 52.7, 45.8,
42.1, 28.8, 23.0, 20.9, 15.1 ppm; HRMS (ESI) m/z calcd. for
C31H29N3NaO4S2 [M+Na]+: 594.1492; found: 594.1496; HPLC analy-
sis (Chiralpak OD-H column, hexane/2-propanol/TEA=60:40:0.1,
flow rate=0.8 mLminꢀ1, wavelength=230 nm): TR =21.69 (major)
and 35.74 min (minor).
(3aS,11S,11aS)-1,3-Dioxo-8-methyl-2-phenyl-11-(2,4,6-trimethyl-ben-
zenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3ba): White solid, m.p. 193–1958C, 92%
yield, ½aꢁ2D5 = +82.6 (c=1.0, CH2Cl2), 98% ee. 1H NMR (400 MHz,
CDCl3): d=8.04 (br. s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.55 (dd, J=8.4,
1.2 Hz, 1H), 7.46 (s, 1H), 7.25–7.26 (m, 3H), 6.98 (s, 2H), 6.81 (br. s,
3H), 4.96 (dd, J=9.6, 4.8 Hz, 1H), 4.37 (d, J=9.6 Hz, 1H), 3.76 (dd,
J=9.6, 4.8 Hz, 1H), 2.71 (s, 6H), 2.52 (s, 3H), 2.29 ppm (s, 3H);
13C NMR (100.6 MHz, CDCl3): d=175.3, 173.6, 151.6, 146.3, 142.8,
138.9, 137.4, 134.4, 133.0, 132.9, 132.3, 130.4, 129.3, 129.1, 129.1,
128.1, 127.0, 126.9, 125.9, 52.7, 45.8, 42.1, 23.0, 21.6, 20.9 ppm;
HRMS (ESI) m/z calcd. for C30H26N3O4S2 [MꢀH]ꢀ: 556.1370; found:
556.1369; HPLC analysis (Chiralpak OD-H column, hexane/2-propa-
nol/TEA=60:40:0.1, flow rate=0.8 mLminꢀ1
230 nm): TR =32.48 (major) and 52.90 min (minor).
,
wavelength=
(3aS,11S,11aS)-8-Butyl-1,3-dioxo-2-phenyl-11-(2,4,6-trimethyl-benze-
nesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3ga): White solid, m.p. 149–1518C, 87%
yield, ½aꢁ2D5 = +68.3 (c=1.0, CH2Cl2), 96% ee. 1H NMR (400 MHz,
CDCl3): d=8.09 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.57 (dd, J=8.4,
1.6 Hz, 1H), 7.48 (s, 1H), 7.26–7.28 (m, 3H), 6.99 (s, 2H), 6.82 (br. s,
3H), 4.96 (dd, J=9.6, 4.8 Hz, 1H), 4.36 (d, J=9.6 Hz, 1H), 3.74 (dd,
J=9.6, 4.8 Hz, 1H), 2.78 (t, J=7.6 Hz, 2H), 2.72 (s, 6H), 2.30 (s, 3H),
1.68 (quin, J=7.6 Hz, 2H), 1.39 (sex, J=7.6 Hz, 2H), 0.96 ppm (t,
J=7.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): d=175.3, 173.6, 151.5,
146.5, 142.8, 142.4, 138.9, 134.5, 133.2, 132.3, 130.4, 129.3, 129.1,
128.1, 127.1, 126.3, 126.0, 52.7, 45.7, 42.1, 35.6, 33.2, 23.1, 22.3,
21.0, 13.9 ppm; HRMS (ESI) m/z calcd. for C33H32N3NaO4S2 [M+Na]+:
622.1805; found: 622.1807; HPLC analysis (Chiralpak OD-H column,
hexane/2-propanol/TEA=60:40:0.1, flow rate=0.8 mLminꢀ1, wave-
length=230 nm): TR =21.56 (major) and 33.37 min (minor).
(3aS,11S,11aS)-1,3-Dioxo-7-methyl-2-phenyl-11-(2,4,6-trimethyl-ben-
zenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3ca): White solid, m.p. 151–1538C, 94%
yield, ½aꢁ2D5 = +56.8 (c=1.0, CH2Cl2), 99% ee. 1H NMR (400 MHz,
CDCl3): d=8.09 (s, 1H), 7.79 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.37
(dd, J=8.4, 1.2 Hz, 1H), 7.26–7.28 (m, 3H), 6.98 (s, 2H), 6.82 (br. s,
3H), 4.95 (dd, J=9.6, 4.8 Hz, 1H), 4.35 (d, J=10.0 Hz, 1H), 3.72 (dd,
J=10.0, 4.8 Hz, 1H), 2.71 (s, 6H), 2.54 (s, 3H), 2.29 ppm (s, 3H);
13C NMR (100.6 MHz, CDCl3): d=175.4, 173.6, 152.6, 148.0, 142.8,
141.3, 138.9, 134.4, 133.3, 132.3, 130.4, 129.5, 129.3, 129.1, 127.7,
127.5, 126.4, 125.9, 125.0, 52.7, 45.7, 42.1, 23.1, 21.9, 21.0 ppm;
HRMS (ESI) m/z calcd. for C30H26N3O4S2 [MꢀH]ꢀ: 556.1370; found:
556.1372; HPLC analysis (Chiralpak OD-H column, hexane/2-propa-
nol/TEA=60:40:0.1, flow rate=0.8 mLminꢀ1
230 nm): TR =25.44 (major) and 52.43 min (minor).
,
wavelength=
(3aS,11S,11aS)-1,3-Dioxo-8-methoxy-2-phenyl-11-(2,4,6-trimethyl-
benzenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo-
(3aS,11S,11aS)-7-Chloro-1,3-dioxo-2-phenyl-11-(2,4,6-trimethyl-ben-
zenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo[3’,4’:5,6]thio-
pyrano[2,3-b]quinoline (3ha): White solid, m.p. 150–1528C, 88%
yield, ½aꢁ2D5 = +24.5 (c=1.0, CH2Cl2), 90% ee. 1H NMR (400 MHz,
CDCl3): d=8.15 (br. s, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.66 (d, J=
8.8 Hz, 1H), 7.49 (dd, J=8.4, 1.6 Hz, 1H), 7.26–7.28 (m, 3H), 6.99 (s,
2H), 6.82 (br. s, 3H), 4.93 (dd, J=9.6, 4.8 Hz, 1H), 4.37 (d, J=9.6 Hz,
1H), 3.74 (dd, J=10.0, 4.8 Hz, 1H), 2.71 (s, 6H), 2.30 ppm (s, 3H);
13C NMR (100.6 MHz, CDCl3): d=175.3, 173.4, 154.4, 147.9, 143.0,
138.9, 136.6, 134.4, 133.4, 132.3, 130.3, 129.7, 129.3, 129.2, 128.3,
127.5, 125.9, 125.3, 52.6, 45.5, 42.0, 23.0, 21.0 ppm; HRMS (ESI) m/z
calcd. for C29H23ClN3O4S2 [MꢀH]ꢀ: 576.0824; found: 576.0829; HPLC
analysis (Chiralpak OD-H column, hexane/2-propanol/TEA=
[3’,4’:5,6]thiopyrano[2,3-b]quinoline (3da): White solid, m.p. 194–
1
1968C, 90% yield, ½aꢁ2D5 = +127.5 (c=1.0, CH2Cl2), 98% ee. H NMR
(400 MHz, CDCl3) d 8.13 (br. s, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.36 (dd,
J=9.2, 2.4 Hz, 1H), 7.26 (s, 3H), 7.00 (s, 3H), 6.85 (d, J=7.2 Hz, 1H),
6.78 (s, 2H), 4.93 (dd, J=9.6, 4.8 Hz, 1H), 4.34 (d, J=9.2 Hz, 1H),
3.91 (s, 3H), 3.70 (dd, J=9.6, 4.8 Hz, 1H), 2.73 (s, 6H), 2.30 ppm (s,
3H); 13C NMR (100.6 MHz, CDCl3): d=175.4, 173.7, 158.3, 149.4,
144.0, 142.8, 138.9, 134.5, 132.4, 132.3, 130.4, 129.9, 129.1, 128.3,
125.9, 123.4, 105.5, 55.6, 52.7, 45.7, 42.2, 23.0, 20.9 ppm; HRMS
(ESI) m/z calcd. for C30H26N3O5S2 [MꢀH]ꢀ: 572.1319; found:
572.1318; HPLC analysis (Chiralpak OD-H column, hexane/2-propa-
nol/TEA=60:40:0.1, flow rate=0.8 mLminꢀ1
230 nm): TR =32.65 (major) and 53.89 min (minor).
,
wavelength=
60:40:0.1, flow rate=0.8 mLminꢀ1
, wavelength=230 nm): TR =
27.50 (major) and 45.94 min (minor).
(3aS,11S,11aS)-1,3-Dioxo-7-methoxy-2-phenyl-11-(2,4,6-trimethyl-
benzenesulfonamido)-1,2,3,3a,11,11a-hexahydropyrrolo-
Acknowledgements
[3’,4’:5,6]thiopyrano[2,3-b]quinoline (3ea): White solid, m.p. 218–
2208C, 89% yield, ½aꢁD25 = +1.29 (c=1.0, CH2Cl2), 97% ee. H NMR
1
We are grateful to the National Natural Science Foundation of
China (No. 20972070, 21121002), the National Basic research Pro-
(400 MHz, CDCl3): d=8.04 (br. s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.32
(s, 1H), 7.26 (s, 3H), 7.18 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 6.82 (s,
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 649 – 654 653

CHEMCATCHEM
FULL PAPERS
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2013, 8, 1182; c) E. Gꢅmez-Torres, D. A. Alonso, E. Gomez-Bengoa, C.
Nꢆjera, Eur. J. Org. Chem. 2013, 1434; d) Z.-w. Ma, Y. Wu, B. Sun, H.-l. Du,
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gram of China (973 program 2010CB833300), Program for New
Century Excellent Talents in University (NCET-11-0265) and the
Key laboratory of Elemento-Organic Chemistry for generous
financial support for our programs.
Keywords: enantioselectivity
· mannich bases · Michael
addition · organocatalysis · polycycles
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[12] CCDC 948628 contains the supplementary crystallographic data for this
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Received: November 21, 2013
Revised: December 6, 2013
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Published online on January 8, 2014
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