Asymmetric synthesis of chiral dihydrothiopyrans via an organocatalytic enantioselective formal thio [3 + 3] cycloaddition reaction with binucleophilic bisketone thioethers

Article abstract of DOI:10.1021/ol4027705

An unprecedented organocatalytic highly enantioselective approach to a 3,4-dihydro-2H-thiopyran scaffold with two contiguous stereogenic centers has been implemented through a formal thio [3 + 3] cycloaddition process involving a Michael-aldol condensation cascade sequence. Notably, a new class of binucleophilic bisketone thioethers is designed for the process. Furthermore, the fine-tuning of their reactivity enables the cascade process to proceed with highly regioselectively.

Full text of DOI:10.1021/ol4027705

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Synthesis of Chiral
Dihydrothiopyrans via an Organocatalytic
Enantioselective Formal Thio [3 þ 3]
Cycloaddition Reaction with
Binucleophilic Bisketone Thioethers
Shengzheng Wang, ,† Yongqiang Zhang, ,† Guoqiang Dong,† Shanchao Wu,†
Shiping Zhu,† Zhenyuan Miao,† Jianzhong Yao,† Hao Li,‡ Jian Li,‡ Wannian Zhang,*,†
Chunquan Sheng,*,† and Wei Wang*,‡,§
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical
University, 325 Guohe Road, Shanghai 200433, P. R. China, Department of Chemistry
and Chemical Biology, University of New Mexico, Albuquerque, New Mexico
87131-0001, United States, and School of Pharmacy, East University of Science and
Technology, Shanghai 200237, P. R. China
zhangwnk@hotmail.com; shengcq@hotmail.com; wwang@unm.edu
Received September 24, 2013
ABSTRACT
An unprecedented organocatalytic highly enantioselective approach to a 3,4-dihydro-2H-thiopyran scaffold with two contiguous stereogenic
centers has been implemented through a formal thio [3 þ 3] cycloaddition process involving a Michaelꢀaldol condensation cascade sequence.
Notably, a new class of binucleophilic bisketone thioethers is designed for the process. Furthermore, the fine-tuning of their reactivity enables the
cascade process to proceed with highly regioselectively.
3,4-Dihydro-2H-thiopyrans are widely distributed in a
number of biologically active compounds (Figure 1). They
exhibit interesting pharmacological properties, such as
antipsoriatic (1a),1 antiviral (1b),2 and antiatherosclerosis
(1c).3 Significant workhasbeenperformedon the synthesis
of the frameworks in racemic form.4 The most widely
used strategy employs the thio-DielsꢀAlder reaction with
thioaldehydes, thioketones, or their R,β-unsaturated
equivalent, 1-thiabuta-1,3-dienes.4aꢀc,5,6 In addition, the
asymmetric version of the thio-DielsꢀAlder reactions has
† Second Military Medical University.
‡ University of New Mexico.
§ East University of Science and Technology.
These authors contributed equally to this work.
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r
10.1021/ol4027705
XXXX American Chemical Society

designed binucleophilic bisketone thioethers 2reacting with
enals 3 (Scheme 1).12ꢀ14
In the design of a proposed organocatalyzed formal
[3 þ 3] cyclcoaddition reaction to generate requisite 3,4-
dihydro-2H-thiopyrans, a new class of binucleophilic bis-
ketone thioethers 2 is designed. It is conceived that the
bisketone moiety in 2 renders the two “CH2” acidic to
produce two contingent nucleophilic species for the initial
Michael addition and subsequent aldol-condensation re-
action (Scheme 1). Therefore, they should be nucleophili-
cally active enough to participate in the Michael and
aldolꢀcondensation cascade process. In addition, the dif-
ferentiation of the reactivities of the two similar nucleo-
philic “CH2” moieties presents an important challenge
when R1 and R2 are not the same since this directly affects
the nature of products formed. It is desired that the more
active “CH2” reacts first in the initial Michael reaction
while the less active one engages in the subsequent intra-
molecular aldol-condensation process.
To probe the validity of the proposed organocatalytic
thio [3 þ 3] cycloaddition process, we probed a model reac-
tion by using simple symmetric 2,20-thiobis(1-phenyl-
ethanone) 2a with trans-cinnamaldehyde 3a catalyzed
by diphenylprolinol silyl ether (I) in the initial attempt
(Table 1). To our delight, the reaction proceeded smoothly
to afford the desired 3,4-dihydro-2H-thiopyran 4a in good
yield (69%, entry 1), with excellent enantioselectivity
(ee >99%) and moderate diastereoselectivity (70:30 dr).
This encouraging result proved our working hypothesis.
Moreover, we demonstrated that the newly designed
Figure 1. Representative bioactive molecules containing a 3,4-
dihydro-2H-thiopyran unit.
also been explored using chiral auxiliaries.7 Very recently,
Jørgensen et al. reported the first organocatalytic enantio-
selective thio-DielsꢀAlder reactions, leading to chiral 3,6-
dihydro-2H-thiopyrans.8
While significanteffortshavebeen madeonthesynthesis
of the dihydrothiopyrans using the most popular [4 þ 2]
cycloaddition methods, formal [3 þ 3] cycloaddition reac-
tions offer an alternative approach to creating structurally
different architectures of the 6-membered rings.9,10 In this
context, notably Hsung and co-workers developed a series
of highly useful methods for the synthesis of 6-membered
ring structures.10 Although catalytic enantioselective meth-
ods are appealing, the examples are extremely rare.9bꢀf
Hong, Tang, and Hayashi independently reported efficient
organocatalytic enantioselective [3 þ 3] ring formation of
enantioenriched cyclohexanes,9bꢀd and Hayashi and our
group disclosed approaches to chiral piperidines.9e,f Never-
theless, to the best of our knowledge, organocatalyzed
[3 þ 3] cycloaddition has not been reported for the forma-
tion of chiral dihydrothiopyrans. Toward this end, we wish
to report the first asymmetric construction of 3,4-dihydro-
2H-thiopyran framework with creation of two contiguous
stereogenic centers catalyzed by diphenylprolinol silyl
ethers11 under mild reaction conditions using newly
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Proposed Mechanism for the Designed Formal
[3 þ 3] Cycloaddition Involving a MichaelꢀAldol Condensation
Cascade Sequence
entry cat. add. solvent time yieldb (%)
drc
% eed
1
2
3
4
5
6
7
8
I
CH2Cl2 2 d
CH2Cl2 3.5 d
CH2Cl2 7 d
69
68
52
32
72
50
36
43
41
73
72
<10
50
64
71
76
70:30
75:25
71:29
>99
>99
92
ND
95
>99
>99
>99
>99
97
>99
ND
>99
98
II
III
IV
II
II
II
II
II
II
II
II
II
II
II
II
CH2Cl2 7 d
NDe
A1 CH2Cl2 16 h
92:8
64:36
93:7
84:16
70:30
85:15
90:10
A1 PhMe
A1 EtOEt
A1 CHCl3
30 h
30 h
30 h
9
A1 CH3CN 30 h
A2 CH2Cl2 12 h
A3 CH2Cl2 36 h
A4 CH2Cl2 24 h
A5 CH2Cl2 36 h
A6 CH2Cl2 7 d
A3 CH2Cl2 5 d
A3 CH2Cl2 5 d
10
11
12
13
14
15f
16g
ND
binucleophilic bisketone thioethers could serve as nucleo-
philes in mild organocatalytic reactions. Often used chiral diaryl-
pyrrolidine silyl ether catalysts IIꢀIV were screened next.
Improved diastereoselectivity (75:25 dr) and excellent
enantioselectivity (ee >99%) were also obtained with
catalyst II (entry 2), although a longer reaction time (3.5 d)
was required. In contrast, incomplete conversion and rela-
tively lower ee values were observed for catalysts III and IV,
which bear more bulky side-chain moieties (entries 3 and 4).
It was found that acid additives were beneficial to the
diastereoselectivity (entries 5ꢀ13). With catalyst II in the
presence of 2-fluorobenzoic acid as the additive, 92:8 dr was
achieved (entry 5). Moreover, the reaction time was also
reduced to 16 h. Further optimization of reaction conditions
including screening of solvents and additives (entries 5ꢀ16)
led us to select the protocol consisting of catalyst II in the
presence of AcOH in CH2Cl2 to probe the scope of the
formal [3 þ 3] cycloaddition reaction (entry 11).
76:24
66:34
81:19
81:19
>99
99
a Reaction conditions (unless otherwise specified): solvent (1.5 mL),
2,20-thiobis(1-phenylethanone) 2a (0.11 mmol, 1.0 equiv), cinnamalde-
hyde 3a (0.13 mmol, 1.2 equiv), catalyst (30 mol %), additive (30 mol %),
rt. b Yield of isolated product after column chromatography. c Deter-
mined by 1H NMR analysis. d Determined by HPLC analysis. e Not
determined. f Catalyst (20 mol %), additive (20 mol %). g Catalyst
(20 mol %), additive (50 mol %).
A similar trend was observed with various symmetric
thio-diketones 2 (entries 11ꢀ16). Nevertheless, when the
aromatic ring bore a 2-nitro group in the enal, under the
standard conditions, the desired product 4q was obtained
with excellent stereoselectivities (>20:1 dr and 97% ee),
but the yield was decreased (46%). Further optimization
of reaction conditions with addition of 1,3-bis(3,5-bis-
(trifluoromethyl)phenyl) thiourea as additive, a similar
protocol reported by Xu et al.,15 led to significant improve-
ment of the reaction yield (72%), shortened reaction time
(36 h), and reduced catalyst loading (20 mol %) while
achieving comparable enantio- and diastereoselectivity
(entries 17ꢀ19). The absolute configuration of the adducts
was determined based on the derivative 11 derived from
compound 4g with (2R, 3S) configuration (Figure S1,
Supporting Information).16
Substrate 2a reacting with structurally diverse enals 3
under the optimized conditions was examined (Table 2,
entries 1ꢀ10). It is shown that the protocol serves as the
general procedure for the synthesis of enantioentriched
3,4-dihydro-2H-thiopyrans 4. The desired products were
obtained with good to excellent ee values (84ꢀ99%). It
appears that the substitution pattern and electronic nature
of the substituents on the benzene ring of enals have an
unpredicted manner on the diastereoselectivity. For in-
stance, 4-N,N-dimethyl and 2-NO2 moieties resulted in
excellent diastereoselectivity (95:5 and >20:1 dr, respec-
tively, entries 6 and 7), whereas 4-MeO, 4-Br, 4-NO2,
and 2-MeO offered moderate dr values (entries 2ꢀ5). In
addition to phenyl-substituted enals, fused aromatic and
heterocyclic systems such as furanyl and thienyl (entries
8ꢀ10) were also well tolerated and afforded the products
in good yield (74ꢀ84%) and with excellent ee values
(97ꢀ99%). However, no reaction was observed for the
aliphatic enals (data not shown).
(15) Wang, Y.; Yu, T. Y.; Zhang, H. B.; Luo, Y. C.; Xu, P. F. Angew.
Chem., Int. Ed. 2012, 51, 12339.
(16) The structure of compound 11 derived from molecule 4g was
determined by X-ray crystal analysis. CCDC-958271 contains the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk and see the Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Substrate Scope of the Asymmetric formal [3 þ 3]
Table 3. Substrate Scope of Thiodiketone 2 Involved in the
[3 þ 3] Cycloadditiona
Cycloadditiona
R1, R2, R3
yieldb (%) drc eed (%)
entry pro.
Ar, R
yieldb (%)
drc
% eed
entry pro.
1
2
3
4
5
6
7
8
4a Ph, Ph
4b Ph, 4-CH3OC6H4
72
79
72
66
85
66
63
74
84
75
68
65
61
75
72
80
72
74
70
90:10 >99
1
2
3
4
5
6
5a Ph, tert-butyl, H
5b Ph, isopropyl, H
5c Ph, isobutyl, H
5d Ph, methyl, H
5e 4-BrC6H4, tert-butyl, H
5f 4-BrC6H4, tert-butyl, 4-Br
60
64
66
51
73
66
>20:1
>20:1
>20:1
85:15
>20:1
>20:1
93
97
93
97
90
99
78:22
73:27
74:26
80:20
95:5
>20:1
76:24
76:24
73:27
90:10
73:27
84
96
93
99
95
99
99
97
97
94
95
4c
Ph, 4-BrC6H4
4d Ph, 4-NO2C6H4
4e Ph, 2-CH3OC6H4
4f
Ph, 4-(CH3)2NC6H4
4g Ph, 2-NO2C6H4
4h Ph, 2-naphthyl
a Reactions were performed with 2 (0.11 mmol), 3 (0.13 mmol, 1.2
equiv), catalyst II (30 mol %), and AcOH (30 mol %) in CH2Cl2 (1.5 mL)
at rt for specified time. b Yield of isolated product after column
chromatography. c Determined by 1H NMR analysis. d Determined by
HPLC analysis.
9
4i
4j
Ph, 2-furanyl
Ph, 2-thienyl
10
11
12
13
14
15
16
17e
18e
19e
4k 4-ClC6H4, Ph
4l 4-BrC6H4, Ph
4m 2-FC6H4, Ph
4n 2-ClC6H4, Ph
4o 3-FC6H4, Ph
4p 2-thienyl, Ph
75:25 >99
68:32
72:28
90:10
>20:1
>20:1
>20:1
95
89
91
97
95
86
Scheme 2. Transformation of MichaelꢀAldol Condensation
Adduct 4g to 12 via a Nazarov Reaction
4q 4-CF3C6H4, 2-NO2C6H4
4r
4s
2-FC6H4, 2-NO2C6H4
3-FC6H4, 2-NO2C6H4
a Unless specified, reactions were performed with 2a (0.11 mmol), 3
(0.13 mmol, 1.2 equiv), catalyst II (30 mol %), and AcOH (30 mol %) in
CH2Cl2 (1.5 mL) at rt for 36 h. b Isolated yields. c Determined by 1H
NMRanalysis. d Determined by HPLC analysis. e Catalyst II (20 mol %),
1,3-bis(3,5-bis(trifluoromethyl)phenyl) thiourea (20 mol %) and AcOH
(20 mol %) were added to the solution.
In summary, we have developed an unprecedented
organocatalytic formal [3 þ 3] cycloaddition process to
create a valuable 3,4-dihydro-2H-thiopyran scaffold in
good to high yields (up to 84%) and with good diastereo-
(up to >20:1 dr) and enantioselectivities (up to >99% ee).
Critically, the cascade process relies on newly developed
simple binucleophilic bisketone thioethers. Moreover, the
careful manipulation of the reactivity of binucleophilic
bisketone thioethers enables the cascade process to pro-
ceed highly regioselectively to afford the structurally di-
verse dihydrothiopyrans. Further exploration of the new
reagents in the synthesis and the synthetic elaboration of
the dihydrothiopyran scaffold and the biological proper-
ties of these compounds are currently underway in our
laboratories.
Finally, we turned our attention to the highly challeng-
ing unsymmetrical thiodiketones 2 for the Michaelꢀaldol
condensation cascade reaction with enals. Guided by the
principle of the electronic effect on reactivity, we first
designed and probed an unsymmetrical bisarylketone
thioether, where one aromatic ring possesses a strong
EWG p-NO2. We found that two regioisomers with ca.
3:1 ratio were formed. Then we designed the diketones
bearing respectivearyland alkylgroups, which makes their
nucleophilicity different enough, where aryl ketone is more
active (Table 3). In the initial attempt, we used phenyl and
highly steric tert-butyl diketone (entry 1). To our delight,
the process occurred exclusively regioselectively under the
standard reaction conditions. Furthermore, impressively
high enantio- (93% ee) and diastereoselectivity (>20:1)
were achieved in 60% yield. We also extended the strategy
to less hindered aliphatic ketones: isopropyl (entry 2),
isobutyl (entry 3), and methyl (entry 4). Moreover, there
is a limited impact on the reaction efficiency with the
variation of the aromatic structures in both enals and aryl
ketones (entries 5 and 6).
Acknowledgment. We thank the National Natural Science
Foundation of China (81222044, C.S., and 21372073,
W.W.), the 863 Hi-Tech Program of China (2012AA020302,
C.S.), Shanghai Rising-Star Program (12QH1402600, C.S.),
and Shanghai Municipal Health Bureau (XYQ2011038,
C.S.) for financial support.
The obtained highly functionalized enantioenriched di-
hydrothiopyrans can be readily converted into complex
molecular structures. For example, compound 4g can be
transformedinto anew scaffold12(Scheme2) bearing four
stereogenic centers with good yield (66%) and great stereo-
control (92% ee, 91:9 dr) via a one-step Nazarov reaction.
Supporting Information Available. Experimental de-
tails and analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX