Enantioselective Construction of Sulfur-Containing Tetrasubstituted Stereocenters via Asymmetric Functionalizations of α-Sulfanyl Cyclic Ketones

Article abstract of DOI:10.1002/adsc.202000520

Asymmetric functionalizations of α-sulfanyl cyclic ketones were realized via chiral phosphoric acid catalyzed enantioselective addition reactions with aldimines, azodicarboxylates and allenamides. A series of chiral organosulfur compounds possessing sulfur-containing tetrasubstituted stereocenters were accessed via these methods, with excellent regioselectivities and high stereoselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.202000520

Title: Enantioselective Construction of Sulfur-Containing
Tetrasubstituted Stereocenters via Asymmetric Functionalizations
of α-Sulfanyl Cyclic Ketones
Authors: Xueqian Ye, Yongkai Pan, Yunrong Chen, and Xiaoyu Yang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000520
Link to VoR: https://doi.org/10.1002/adsc.202000520

10.1002/adsc.202000520
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Construction of Sulfur-Containing
Tetrasubstituted Stereocenters via Asymmetric
Functionalizations of α-Sulfanyl Cyclic Ketones
Xueqian Yea,b, Yongkai Pana, Yunrong Chena, and Xiaoyu Yang a*
a
School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
E-mail: yangxy1@shanghaitech.edu.cn
University of Chinese Academy of Sciences, Beijing 100049, China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
one. Shibasaki and co-workers reported the chiral
Abstract. Asymmetric functionalizations of α-sulfanyl
cyclic ketones were realized via chiral phosphoric acid Ag(I) catalyzed enantioselective aldol[7] and
Mannich-type reactions[8] of α-sulfanyl lactones
catalyzed enantioselective addition reactions with
aldimines, azodicarboxylates and allenamides. A series of
chiral organosulfur compounds possessing sulfur-
containing tetrasubstituted stereocenters were accessed via
these methods, with excellent regioselectivities and high
stereoselectivities.
(Figure 1, a). Zhou group and others developed a
series asymmetric catalytic reactions of 3-
thioxindoles, including asymmetric aminations with
azodicarboxylates[9],
Michael
additions
with
nitrolefines[10] and enals[11] and electrophilic
sulfenylations[12] (Figure 1, b). In addition, Secci and
co-workers disclosed the asymmetric Michael
additions of 2-arylthio substituted cyclobutanones
with nitrolefines by chiral amine-thiourea catalyst;
however, expanding the scope to five and six
membered cyclic ketones led to the generation of
products in moderate yields[13] (Figure 1, c).
Keywords: asymmetric catalysis; organic catalysis; α-
sulfanyl cyclic ketones; Mannich-type reaction;
azodicarboxylates; allenamides
Organosulfur compounds are widely present in a
series of bioactive natural products and
pharmaceuticals[1]. Accordingly, the catalytic
enantioselective synthesis of optically active
organosulfur compounds has received considerable
research interest[2]. However, the asymmetric
synthesis of sulfur-containing tetrasubstituted
stereocenters is still a challenging task, due to the
relatively low reactivities and difficulties in
stereoselectivity control.[3] In spite of these
challenges, a number of elegant asymmetric methods
have
been
developed
for
enantioselective
construction of sulfur-containing tetrasubstituted
stereocenters recently, using the strategies of
asymmetric addition of sulfur-based nucleophiles[4],
asymmetric
electrophilic
sulfenylation[5]
and
asymmetric functionalization of sulfur-containing
substrates[6]. Although the enantioselective C-S bond
formation provided a straightforward method for
asymmetric synthesis of chiral organosulfur
compounds, the alternative strategy based on
asymmetric functionalizations of sulfur-containing
substrates has also proved to be fruitful, because of
the more extensive reaction types. Among various
reactions developed via this strategy, the asymmetric
functionalizations of α-sulfanyl substituted cyclic
carbonyl compounds represent as the most versatile
1
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10.1002/adsc.202000520
Advanced Synthesis & Catalysis
Figure 1. Enantioselective construction of sulfur-
containing tetrasubstituted stereocenters via asymmetric
functionalizations of α-sulfanyl carbonyl compounds.
The chiral phosphoric acid[14] (CPA) catalyzed
asymmetric functionalizations of α-substituted cyclic
ketones have become a versatile strategy for
construction of quaternary stereocenters on cyclic
ketones, which were independently developed by
List[15] and Toste[16] group. Recently, we reported the
asymmetric Mannich-type reactions of α-azido cyclic
ketones under CPA catalysis, generating chiral azides
possessing α-quaternary stereocenters[17]. With our
continuous interest on developing asymmetric
reactions for construction of chiral quaternary
stereocenters[18], herein we report a general protocol
for enantioselective construction of sulfur-containing
tetrasubstituted stereocenters via asymmetric
functionalizations of α-sulfanyl cyclic ketones,
Yield
Ee
Entry
Cat.
Sol.
Drc
(%)b
16
21
31
52
45
68
54
78
44
42
29
25
82
(%)d
1
2
3
4
5
6
7
8
9
10
11
12e
13f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Tol
CHCl3
THF
DCM
DCM
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
54
94
49
94
95
99
98
97
98
94
95
88
99
A1
A2
A3
A4
A5
A6
A7
A8
A6
A6
A6
A6
A6
including asymmetric Mannich-type reactions[19]
,
20]
aminations with azodicarboxylates[16a,
and
additions with allenamides[16b, 21] (Figure 1, d).
We commenced our study by choosing racemic α-
sulfanyl substituted cyclohexanone 1a and aldimine
2a as substrates under the catalysis of CPA catalysts
(Table 1). The reaction between these two substrates
under the catalysis of cat A1 (10 mol%) in DCM (1.0
o
M) at 40 C in the presence of 4 Å molecular sieves
provided the desired Mannich-type product 3a with
excellent diastereomeric ratio (dr) and moderate
enantiomeric excess (ee), albeit in low yield (Table 1,
entry 1). Next, a series of BINOL-derived CPA
catalysts were screened in this reaction (entries 2-7),
and encouragingly the TRIP catalyst (cat A6)
provided the optimal results, generating 3a in 68%
yield with 99% ee (entry 6). Switching the chiral
scaffold of catalyst to H8-BINOL-type led to
improved yield, but with decreased ee (entry 8). A
range of solvents were also examined in this reaction,
which indicated DCM was still the optimal one
(entries 9-11). The role of molecular sieve was also
investigated (entries 12-13). Interestingly, in the
absence of 4 Å MS, the yield of this reaction
diminished to 25%; while switching 4 Å MS to acid-
wash molecular sieves (AW-300 MS) gave an
improved yield of 82% with retained stereoselectivity
(entry 13).
a)
Reactions were performed with 1a (0.1 mmol), 2a (0.2
mmol), CPA catalysts (0.01 mmol) in solvents (0.1 mL)
with 4 Å MS (150 mg) at 40 oC for 16 h. b) Isolated yield. c)
Dr value was determined by crude H NMR analysis. d) Ee
1
value was determined by HPLC analysis on a chiral
stationary phase. e) Without 4 Å MS. f) With AW-300 MS.
Having the optimized reaction conditions
established, the scope of this reaction was studied
with CPA catalyst (R)-A6 (Scheme 1). A series of
para- and meta-substituted benzaldimins (with
various electron-donating, electron-withdrawing and
electron-neutral substitutions) were well tolerated
under the optimal conditions, generating the
Mannich-type
products
with
excellent
diastereoselectivities and enantioselectivities (3b-3f).
The absolute configurations of these products were
assigned by analogy to product 3b, whose structure
Table 1. Optimizations of reaction conditions.a
was
unambiguously
confirmed
by
X-ray
crystallography[22]. The sterically demanding ortho-
substituted benzaldimins was also compatible under
the standard conditions (3k). 2-Naphthyl group (3l)
and heteroaryl groups, like 2-furanyl group (3m) and
3-thienyl group (3n), were also amenable variants.
Switching the N-Boc aldimine to N-Cbz aldimine led
to the formation of product with high
enantioselectivity as well, albeit in moderate yield
(3o). Next, the scope for cyclic ketones was
investigated.
Using
α-sulfanyl
substituted
cyclopentanone (3p) and other six-membered cyclic
ketones (3r and 3s) as substrates afforded the
Mannich-type products with good yields and high
2
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10.1002/adsc.202000520
Advanced Synthesis & Catalysis
stereoselectivities under the optimal conditions.
cyclic ketones through dual H-bonding interactions
(Scheme 2). Under the guidance of CPA (R)-A6, the
Re-face the enol intermediate attacks the Si-face of
imine through this transition state to give the (R,R)-
addition product 3, as was observed.
Additionally,
the
α-sulfanyl
substituted
cyclobutanone could produce the product with high
stereoselectivity as well, albeit in low yield (3q).
Finally, the scope for the sulfanyl groups was also
examined; switching the arylsulfanyl group to
methylsulfanyl (3t) and benzylsulfanyl group (3u)
was well tolerated, giving access to Mannich-type
products with comparable results.
Scheme 2. Postulated transition state that accounts
for the observed stereoselectivity.
Scheme 1. Substrate scope for direct Mannich-type
reactions of α-sulfanyl cyclic ketones with
aldimines.a
To extend the applicability of this strategy for
asymmetric construction of sulfur-containing
tetrasubstituted stereocenters, the asymmetric
functionalization of α-sulfanyl cyclic ketones with
other electrophiles was investigated. Satisfyingly, the
asymmetric amination of 1a with di-tert-butyl
azodicarboxylate 4a under the catalysis of (S)-A7
catalyst provided the S,N-acetal 5a in 64% yield with
91% ee[23], which was an important motif in
biologically active small molecules[24] (Scheme 3).
Switching
the
cyclohexanone
scaffold
to
cyclopentanone (5b) and other six-membered cyclic
ketone (5c) were well compatible with the optimal
conditions, generating S,N-acetal products with high
enantioselectivities. The scope for azodicarboxylates
was also studied; however, using dibenzyl and
diisopropyl azodicarboxylates as amination reagent
under the standard conditions gave products with
diminished enantioselectivities (5d and 5e).
Switching the aryl sulfanyl substitution of benzyl
sulfanyl group was also investigated, however, which
led to the generation of product in both diminished
yield and ee (5f).
aReactions were performed with 1 (0.1 mmol), 2 (0.2
mmol), CPA catalysts (R)-A6 (0.01 mmol) in DCM (0.1
o
mL) with AW-300 MS (150 mg) at 40 C for 16 h. Yields
were isolated yield. The dr values were >20:1 as
determined by 1H NMR analysis. Ee values were
determined by HPLC analysis on a chiral stationary phase.
Ar = 4-methylphenyl.
To account for the observed stereochemical
outcome of these reactions, we propose that the CPA
catalyst acts as a bifunctional catalyst to activate both
the imine substrates and the enol form of α-sulfanyl
3
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10.1002/adsc.202000520
Advanced Synthesis & Catalysis
a)
Scheme 3. Substrate scope for asymmetric
aminations of α-sulfanyl cyclic ketones with
azodicarboxylate.a
Reactions were performed with 1 (0.1 mmol), 6 (0.2
mmol), CPA catalysts (R)-A9 (0.01 mmol) in DCM (0.1
mL) with AW-300 MS (150 mg) at 40 C for 16 h. Yields
o
were isolated yield. Ee values were determined by HPLC
analysis on a chiral stationary phase.
To demonstrate the practicability of these methods,
a large-scale reaction between 1a (1.0 mmol) and 2a
was performed with the standard conditions, which
provided the product 3a in high yield with excellent
stereoselectivity, without exception (Scheme 5, a).
The derivatizations of the chiral products were also
carried out to showcase the potential applications of
these methods. Stereoselective reduction of the
ketone motif in 3a with DIBAL-H at -78 oC gave the
alcohol 8a in 99% yield with 7:1 dr and retained ee
(Scheme 5, b). Facile hydrolysis of enamide motif in
7a in the presence of TFA generated the 5-keto
aldehyde 9a without erosion of optical purity, which
would be a valuable building block for further
transformations (Scheme 5, c).
aReactions were performed with 1 (0.1 mmol), 4 (0.2
mmol), CPA catalysts (S)-A7 (0.01 mmol) in DCM (0.1
mL) with AW-300 MS (150 mg) at 40 C for 16 h. Yields
were isolated yield. Ee values were determined by HPLC
analysis on a chiral stationary phase. Ar = 4-methylphenyl.
o
Scheme 5. Large-scale reaction and derivatizations of
the chiral products.
The chiral phosphoric acid catalyzed asymmetric
additions of α-sulfanyl cyclic ketones with
allenamides for the construction of sulfur-containing
tetrasubstituted stereocenters was also studied
(Scheme 4). Encouragingly, in the presence of C8-
TRIP catalyst (R)-A9 (10 mol%), the reaction
between 1a and allenamide 6 proceeded smoothly to
give the addition product 7a in 87% yield with 91%
ee[25]. The scope of this reaction was investigated,
which indicated that the α-sulfanyl cyclopentanone
and other six-membered cyclic ketones were well
tolerated under these conditions, giving products with
high yields and enantioselectivities (7b and 7c). The
scope for sulfanyl substituents were also examined;
switching the arylsulfanyl group to alkylsulfanyl
groups were amenable to the standard conditions,
generating products with high enantioselectivities as
well (7d and 7e).
Scheme 4. Substrate scope for asymmetric addition
reactions of α-sulfanyl cyclic ketones with
allenamides.
In conclusion, we disclose the asymmetric
functionalizations of α-sulfanyl cyclic ketones
enabled by chiral phosphoric acid catalysis, which
generated a series of chiral cyclic ketone derivatives
possessing a sulfur-containing chiral tetrasubstituted
stereocenter. A range of aldimines, azodicarboxylates
and allenamides were well compatible in these
reactions, as well as various cyclic ketones and
sulfanyl groups. The facile and diverse
transformations of the chiral products demonstrate
the utilities of these methods in asymmetric synthesis
of optically active organosulfur compounds.
Experimental Section
4
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10.1002/adsc.202000520
Advanced Synthesis & Catalysis
To a 4 ml reaction tube was added α-sulfanyl cyclic ketone
1 (0.10 mmol), aldimine 2 (0.20 mmol), (R)-cat A6 (0.01
mmol) and AW-300 MS (150 mg). Subsequently, DCM
(0.1 ml) was added to dissolve the reagents, and the
reaction mixture was warmed to 40 ºC under N2
atmosphere. After stirring at 40 ºC for 16 h, the reaction
mixture was cooled to room temperature and directly
purified by flash column chromatography to afford the
desired product 3.
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Acknowledgements
We gratefully acknowledge NSFC (Grant No. 21901162) and
ShanghaiTech University start-up funding for financial support.
The authors thank the support from Analytical Instrumentation
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Advanced Synthesis & Catalysis
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2019, 21, 330-334; c) S. Biswas, H. Kim, K. Le Anh
[25] The absolute structures of products 7 were assigned
via analogy to products in ref 16b.
6
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10.1002/adsc.202000520
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Construction of Sulfur-Containing
Tetrasubstituted Stereocenters via Asymmetric
Functionalizations of α-Sulfanyl Cyclic Ketones
Adv. Synth. Catal. Year, Volume, Page – Page
Xueqian Yea,b, Yongkai Pana, Yunrong Chena and
Xiaoyu Yang a*
7
This article is protected by copyright. All rights reserved.