Design of Chiral Bifunctional Dialkyl Sulfide Catalysts for Regio-, Diastereo-, and Enantioselective Bromolactonization

Article abstract of DOI:10.1002/chem.201803703

Although a wide variety of chiral organocatalysts have been developed for asymmetric transformations, effective chiral dialkyl sulfide organocatalysts remain relatively rare and under-developed, despite the potential utility of dialkyl sulfide catalysts. Herein, we report the development of chiral bifunctional dialkyl sulfide catalysts possessing a urea moiety for regio-, diastereo-, and enantioselective bromolactonization. The importance of the bifunctional design of chiral sulfide catalysts was clearly demonstrated in the present work. The roles of both the sulfide and urea moieties of the catalyst were clarified based on the results of experimental and theoretical investigation.

Full text of DOI:10.1002/chem.201803703

A Journal of
Accepted Article
Title: Design of Chiral Bifunctional Dialkyl Sulfide Catalysts for Regio-,
Diastereo-, and Enantioselective Bromolactonization
Authors: Ryuichi Nishiyori, Ayano Tsuchihashi, Ayaka Mochizuki,
Kazuma Kaneko, Masahiro Yamanaka, and Seiji Shirakawa
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201803703
Link to VoR: http://dx.doi.org/10.1002/chem.201803703
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Design of Chiral Bifunctional Dialkyl Sulfide Catalysts for Regio-,
Diastereo-, and Enantioselective Bromolactonization
Ryuichi Nishiyori,[a] Ayano Tsuchihashi,[a] Ayaka Mochizuki,[b] Kazuma Kaneko,[b] Masahiro
Yamanaka,*[b] and Seiji Shirakawa*[a]
Abstract: Although a wide variety of chiral organocatalysts have been
developed for asymmetric transformations, effective chiral dialkyl
sulfide organocatalysts remain relatively rare and under-developed,
despite the potential utility of dialkyl sulfide catalysts. Herein, we
report the development of chiral bifunctional dialkyl sulfide catalysts
possessing a urea moiety for regio-, diastereo-, and enantioselective
bromolactonization. The importance of the bifunctional design of chiral
sulfide catalysts was clearly demonstrated in the present work. The
roles of both the sulfide and urea moieties of the catalyst were clarified
based on the results of experimental and theoretical investigation.
asymmetric bromofunctionalization.[9] Herein, we report the
development of 1,1’-bi-2-naphthol (BINOL)-derived bifunctional
dialkyl sulfide catalysts possessing a urea moiety for highly regio-,
diastereo-, and enantioselective bromolactonization.[10,11]
(a) Chiral dialkyl sulfide-catalyzed epoxidations (Ref. 4)
O
*R
R*
R'
X
O
*R
R*
H
R"
S
S
*
*
R"
R'
base
catalyst
R'
sulfonium ylide
several examples
Asymmetric organocatalysis using well-designed chiral catalysts
is one of the most reliable methods to create important molecules
in
(b) Chiral dialkyl sulfide-catalyzed bromofunctionalizations
Nu
R'
a A variety of chiral
highly stereoselective fashion.[1]
R'
*
*
Br-X
Nu-H
organocatalysts derived from both natural and synthetic scaffolds
have been developed for asymmetric transformations, particularly
over the past two decades. Among these, effective chiral dialkyl
sulfide catalysts have remained relatively rare and under-
developed, despite their potential.[2] Stoichiometric sulfonium
ylide-mediated epoxidation is a well-known method in organic
synthesis.[3] Based on the reaction, several examples of catalytic
asymmetric epoxidation have been developed with chiral sulfide
catalysts that generate sulfonium ylide intermediates (Scheme
1a).[4] Bromosulfonium salt-mediated asymmetric reactions are
another form of chiral sulfide catalysis that seems to be attractive
since bromosulfonium salts are common reagents for bromination
(Scheme 1b).[5] Yeung and co-workers demonstrated the efficient
catalysis of sugar-derived dialkyl sulfides in asymmetric
bromoetherification via desymmetrization of diols.[6] Although this
is an important achievement for chiral dialkyl sulfide-catalyzed
bromofunctionalization, successful results have only been
obtained in the desymmetrization of diols,[7] and a more general
form of sulfide catalysis is highly desired.[8] In this context, we are
interested in the design of new chiral dialkyl sulfide catalysts for
Br
*R
R*
X
*R
R*
or
S
Br
S
R'
*
*
catalyst
Br
Nu
bromosulfonium
salt
limited examples
Desymmetrizations of diols by Yeung (Ref. 6)
OH
OH
O
O
O
OH
O
+
Br N
R
Br
S
Ar
O
NBS
Ar
ArO
OAr
R
catalyst
Scheme 1. Chiral dialkyl sulfide-catalyzed asymmetric reactions.
The design of new chiral dialkyl sulfide catalysts (S)-1 and
a working model of intramolecular bromofunctionalization appear
in Scheme 2. When the sulfide catalyst is mixed with N-
bromosuccinimide (NBS), bromosulfonium succinimide is formed.
The position of the succinimide anion is fixed by the hydrogen-
bonding interactions with a urea moiety of the catalyst. The double
bond of an alkene substrate is then activated by the
[a]
R. Nishiyori, A. Tsuchihashi, Prof. Dr. S. Shirakawa
Department of Environmental Science, Graduate School of
Fisheries and Environmental Sciences,
bromosulfonium moiety to form
a cyclic bromonium ion
intermediate. Simultaneously, an acidic pro-nucleophilic moiety is
activated by the succinimide anion, which serves as a Brønsted
base, to provide a well-organized transition-state (TS). Regio-,
diastereo-, and enantioselective intramolecular cyclization then
occurs to yield the bromofunctionalization product.
Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
E-mail: seijishirakawa@nagasaki-u.ac.jp
Homepage: http://seijishirakawa.wix.com/greenchemistry
A. Mochizuki, K. Kaneko, Prof. Dr. M. Yamanaka
Department of Chemistry and Research Center for Smart
Molecules, Faculty of Science,
[b]
Rikkyo University
3-34-1, Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
E-mail: myamanak@rikkyo.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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R
S
SPr
SR
H
N
H
Br
H
H
N
N
N
Ph
R'
Ar
*
NH
NH
*
O
O
O
Nu
(S)-1a
(S)-1
high regio-, diastereo-,
enantioselectivities
bifunctional catalyst
Ar
NBS
R'
R'
R
S
R
Brønsted
base
S
H-Nu
Br
Nu
H
Br
O
O
NH
NH
NH
N
N
side view
top view
O
O
O
O
NH
Figure 1. X-ray crystal structure of a chiral dialkyl sulfide (S)-1a.
Ar
Ar
Scheme 2. Design and a possible working model of chiral bifunctional dialkyl
sulfides (S)-1.
Asymmetric bromolactonization with alkenes 3 was selected
as a model reaction to examine the catalytic ability of chiral
bifunctional sulfides (S)-1 (Table 1).[14] The bromolactonization of
alkenes 3 has produced 3,4-dihydroisocoumarin products 4 as a
structural motif for important natural products and
pharmaceuticals.[15] A bromo group of 3,4-dihydroisocoumarin
products 4 easily transforms to other functional groups via SN2-
type reactions.[14] Although a highly enantioselective version of
the bromolactonization of alkenes 3 with cinchona alkaloid-
derived amino-thiocarbamate catalysts has already been reported
by Yeung, several drawbacks exist in the catalytic system.[14a]
First, the reaction with 3a was efficiently promoted by a quinidine-
derived catalyst to give (–)-4a (enantiomer of 4a in Table 1).
Surprisingly, however, the quinine-derived version of the catalyst,
which was commonly recognized as a pseudo-enantiomer, did
not promote the bromolactonization. That is to say, the reported
catalytic system could not access product (+)-4a (absolute
configuration of 4a in Table 1). Second, the regioselectivities of
the reactions were moderate, and 5-exo-cyclization products 5
were also produced. Our motivation was to solve these
drawbacks by using bifunctional sulfides (S)-1, and the first issue
was not a problem in our catalytic system since both enantiomers
of BINOL-derived catalyst 1 were readily obtainable.
Target chiral bifunctional sulfides (S)-1 were prepared from
the reported compound (S)-2 (Scheme 3).[12] Following
deprotection of the tert-butoxycarbonyl (Boc) group on the
nitrogen of (S)-2, the resultant primary amino group was treated
with aryl isocyanates to obtain the corresponding aryl urea
compounds. An arylmethyl bromide moiety of the resultant urea
compounds was then treated with thiols to provide the target
sulfide catalysts (S)-1.
Br
Br
O
ArNCO
CF3CO2H
H
H
NHBoc
N
N
THF
RT, 4 h
CH2Cl2
reflux, 12 h
Ar
(S)-2
RSH
K2CO3
SR
H
H
N
N
CH3CN
Ar
55 °C, 3 h
O
(S)-1
Scheme 3. Synthesis of chiral bifunctional dialkyl sulfides (S)-1.
When a solution of substrate 3a and NBS in CH2Cl2 was
stirred at –78 °C for 24 h in the absence of a catalyst, only trace
amounts of product 4a were obtained (entry 1, Table 1). To our
delight, chiral bifunctional sulfide (S)-1a efficiently promoted the
reaction of 3a with NBS to provide product 4a in a high yield with
good enantioselectivity (62% ee; entry 2). Fortunately, 5-exo-
cyclization product 5a was not formed in our catalytic system and
the second issue of the reported method was also solved. Fine-
tunings of sulfide and urea moieties [R and Ar in (S)-1] were
performed (entries 2–8), and the best result was obtained with
catalyst (S)-1b (68% ee; entry 3). Interestingly, phenyl sulfide
catalyst (S)-1e showed a very low level of catalytic activity (entry
6). The reaction conditions were further optimized via the use of
catalyst (S)-1b, and the enantioselectivity was improved to 83%
with complete regio- and diastereoselectivities (entry 9). The
enantiomer of 4a [(–)-4a] could, of course, be obtained in the
reaction using catalyst (R)-1b (entry 10).
The absolute structure of a chiral dialkyl sulfide (S)-1a was
unambiguously confirmed by X-ray diffraction analysis (Figure
1).[13] The positions of sulfide and urea moieties were suitable to
create an effective reaction environment with the substrates, as
shown in Scheme 2.
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Table 1. Catalyst optimization.[a]
Br
(S)-1b
Ph
Ph
(10 mol %)
+
Br-X
OH
O
CH2Cl2
(1.2 equiv)
Br
Br
O
NBS (1.2 equiv)
Ph
–78 °C, 24 h
Ph
O
4a
Ph
(S)-1 (10 mol %)
3a
+
OH
O
5-membered ring
O
CH2Cl2
Br
Br
Br
O
–78 °C, 24 h
Br
N
O
N
O
N
O
O
O
O
S
N
O
O
3a
4a
5a
O
O
O
(single diastereomer) (not formed)
N
Br
(S)-1a: R = Pr, Ar = Ph
(S)-1b: R = Bu, Ar = Ph
NBS
98%, 68% ee
NBP
NBSac
76%, 57% ee
DBH
92%, 63% ee
SR
(S)-1c: R = Pentyl, Ar = Ph
(S)-1d: R = CH2Ph, Ar = Ph
(S)-1e: R = Ph, Ar = Ph
(S)-1f: R = Bu, Ar = 3,5-(CF3)2–C6H3
(S)-1g: R = Bu, Ar = 3,5-(OMe)2–C6H3
91%, 70% ee
(94%, 83% ee)[a] (97%, 82% ee)[a]
H
H
N
N
Ar
6-membered ring
acyclic
O
Br
(S)-1
Br Br
Br
O
N
O
H
Br2
O
N
H
N
N
Entry
Catalyst
none
Yield [%][b]
ee [%][c]
–
Br
Br
Br
O
O
TBCO
20%, 52% ee
1
trace
95
DBI
24%, 55% ee
NBA
86%, 22% ee
66%, ~0% ee
2
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
(S)-1g
(S)-1b
(R)-1b
62
3
98
68
Scheme 4. Effect of brominating reagents. [a] Reactions in parentheses were
performed in CH2Cl2-methylcyclohexane (MeCy) at –95 °C for 48 h.
4
92
66
5
78
38
Control experiments with several catalysts were performed
to establish the importance of the bifunctional design of catalysts
(S)-1 (Table 2). When mono-functional sulfide catalyst (S)-6a was
employed, the reaction of 3a with NBS efficiently proceeded to
give product 4a in a high yield, but with no enantioselectivity (entry
2). A related bifunctional catalyst (S)-6b, that possesses a
hydroxy group was also examined (entry 3). Although
enantioselectivity of the obtained product 4a was moderate (38%
ee), chiral induction was observed. These results suggested that
the bifunctional design of a sulfide catalyst is important for
enantioselective bromofunctionalization. To clarify the role of the
sulfide moiety in the (S)-1, chiral urea catalyst (R)-7 was prepared
and applied to the bromolactonization. As expected, the reaction
was sluggish and product 4a was obtained in only a low yield
(entry 4). These results clearly indicated that the dialkyl sulfide
moiety of the (S)-1 is essential to promote the reaction. A dual
catalyst system employing the (R)-7 and dibutyl sulfide was also
examined. Although the reaction proceeded to give product 4a,
the enantioselectivity was quite low (6% ee; entry 5). The results
appear in Scheme 4 and in Table 2 fully support our proposed
working model of catalysts (S)-1 in Scheme 2.
6
<5
99
–
7
53
8
84
37
9[d]
10[d]
94
83
92
–83
[a] Reaction conditions: 3a (0.10 mmol), NBS (0.12 mmol), catalyst (S)-1 (10
mol %, 0.010 mmol), CH2Cl2 (2.0 mL), –78 °C, 24 h. Regio- and
diastereoselectivities of product 4a were confirmed via 1H NMR analysis of
the crude reaction mixture. [b] Yield of isolated product 4a. [c] Determined
by HPLC analysis on a chiral stationary phase. [d] The reaction was
performed in CH2Cl2-methylcyclohexane (MeCy) (1.0 mL each) at –95 °C for
48 h.
To gain evidence for the proposed role of generated
succinimide anion in Scheme 2, the effects of brominating
reagents were examined with catalyst (S)-1b (Scheme 4). The
enantioselectivities of product 4a significantly depend on the
structure of the brominating reagents. Reactions with brominating
reagents possessing 5-membered ring structures gave product
4a in similar levels of enantioselectivity (57–70% ee). Brominating
reagents with 6-membered ring structures gave slightly lower
enantioselectivities (52–55% ee) than 5-memberd ring structures.
On the other hand, acyclic brominating reagents, such as N-
bromoacetamide (NBA) and bromine, gave product 4a in quite low
enantioselectivities (0–22% ee). These results strongly suggested
that corresponding (imide) anions generated from brominating
reagents were involved in the stereochemistry-determining steps,
as proposed in Scheme 2.
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Table 2. Control experiments.[a]
TSminor is reduced to within 1 kcal/mol in the partially defected TS
models (removing urea or sulfide moiety of (S)-1b, Figure S3 in
Supporting Information). In the control experiments, the
enantioselectivity was significantly decreased with the loss of
either urea or sulfide moiety of (S)-1b (Table 2). Both urea and
Br
catalyst
(10 mol %)
Ph
Ph
+
NBS
OH
O
CH2Cl2
–78 °C, 24 h
(1.2 equiv)
O
O
4a
sulfide moieties of (S)-1b play key roles in the relative energy
3a
[18]
difference between TSmajor and TSminor
.
Whereas TSmajor has
conjugation and a CH–O hydrogen bond between the urea and
naphthyl moieties (Figure 3), the urea moiety is arranged nearly
SBu
SBu
OR
H
N
H
H
H
N
N
N
perpendicular to the naphthyl moiety to lose them in TSminor
.
Ph
Ph
Therefore, the conformational requirements of a urea moiety,
which are needed for keeping the hydrogen-bonding network,
tend to destabilize the catalyst fragment in TSminor. The CH–O
hydrogen bond of the sulfide moiety along with sulfide/bromonium
O
O
(S)-1b
(R)-7
(S)-6a: R = Me
(S)-6b: R = H
interaction stabilizes TSmajor
. These computational results
Entry
Catalyst
(S)-1b
Yield [%][b]
ee [%][c]
clarified the importance of our bifunctional design in connecting
the sulfide and urea units via a chiral scaffold (see, entries 1 and
5 in Table 2).
1
2
3
4
5
98
93
26
<5
64
68
~0
38
–
(S)-6a
(S)-6b
(R)-7
(R)-7 + Bu2S[d]
6
[a] Reaction conditions: 3a (0.10 mmol), NBS (0.12 mmol), catalyst (10
mol %, 0.010 mmol), CH2Cl2 (2.0 mL), –78 °C, 24 h. Regio- and
diastereoselectivities of product 4a were confirmed by 1H NMR analysis of
the crude reaction mixture. [b] Yield of isolated product 4a. [c] Determined
by HPLC analysis on a chiral stationary phase. [d] The reaction was
performed using a dual catalyst system [(R)-7 (10 mol %, 0.010 mmol) +
Bu2S (10 mol %, 0.010 mmol)].
To gain deeper insight into the origin of enantioselectivity,
DFT calculation was conducted.[16] Based on the related
studies,[10c,f,11b,c] the final cyclization step of our working model
(Scheme 2) was investigated as the stereochemistry-determining
step. After screening various cyclization TS models with and
without a succinimide anion (Figure S1 in Supporting Information),
an associative TS model involving monocoordinated succinimide
anion proved to be the most promising model. This is consistent
Figure 2. 3D structures and the relative Gibbs free energies (kcal mol–1) of (a)
TSmajor and (b) TSminor. Bond lengths are in Å.
with
the
experimentally
observed
dependence
of
enantioselectivity on the counter anion of the brominating reagent
(Scheme 4). Using the promising TS model, the origin of the high
level of enantioselectivity was investigated in detail (TSmajor and
TSminor, Figure 2). TSmajor is 4.3 kcal mol–1 (2.6 kcal mol–1 in Gibbs
free energy) more stable than TSminor in qualitatively agreement
with the experimental result. Both TSmajor and TSminor construct
the well-organized structures via a hydrogen-bonding network
around the succinimide anion and the sulfide/bromonium
interaction (Figure 2). Non-covalent interaction (NCI) analysis[17]
clearly revealed the differences in the hydrogen-bonding network
between TSmajor and TSminor (Figure 3). The succinimide anion
coordinated with both urea (e: 1.88 Å) and sulfide (f: 2.51 Å)
moieties in TSmajor, but only with the urea moiety (e: 2.10 Å, f: 2.01
Å) in TSminor. A NH/p interaction exists between a portion of the
NH residue of the urea moiety and naphthyl moiety in TSmajor
(Figure 3). The relative energy difference between TSmajor and
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Figure 3. NCI analysis of (a) TSmajor and (b) TSminor. Gradient surfaces
correspond to s = 0.25 au and a color scale of –0.05 < ρ < 0.05 au (blue, strongly
attractive; green, weakly attractive; red, strongly repulsive).
applications of these bifunctional dialkyl sulfide catalysts to other
asymmetric reactions as well as design of new chiral sulfide
catalysts are currently underway by our group.
With important information of chiral bifunctional sulfide
catalyst (S)-1b in hand, the substrate generality of the asymmetric
Acknowledgements
bromolactonization of
3 was examined (Scheme 5). The
This work was supported by JSPS KAKENHI Grant Numbers
JP16K05780 (for S.S.), JP17KT0011 (for M.Y.), JP18H04660,
(Hybrid Catalysis for M.Y.), and the Cooperative Research
Program of "Network Joint Research Center for Materials and
Devices" (20181268 for S.S.). We are grateful to Dr. Hiroyasu
Sato (Rigaku Corporation) and Dr. Kazunobu Igawa (Kyushu
University) for X-ray crystallographic analysis.
introduction of various substituents on both of the aryl groups in 3
uniformly gave the target products (4a–4l) in high
enantioselectivities (80–90% ee). It should be noted that all the
reactions in Scheme 5 proceeded with complete regio- and
diastereoselectivities.
Br
(S)-1b
(10 mol %)
Ar
Ar
X
Keywords: asymmetric synthesis • lactonizations •
+
NBS
X
OH
O
CH2Cl2-MeCy
–95 °C, 48 h
organocatalysis • sulfides • transition states
(1.2 equiv)
O
3
O
4
perfect regio-, and
diastereoselectivities
[1]
For reviews on organocatalysis, see: a) P. I. Dalko, L. Moisan, Angew.
Chem. Int. Ed. 2001, 40, 3726–3748; Angew. Chem. 2001, 113, 3840–
3864; b) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138–
5175; Angew. Chem. 2004, 116, 5248–5286; c) D. W. C. MacMillan,
Nature 2008, 455, 304–308; d) Comprehensive Enantioselective
Organocatalysis: Catalysts, Reactions, and Applications (Ed.: P. I.
Dalko), Wiley-VCH, Weinheim, 2013.
Ph
Cl
Br
Br
Br
Ph
O
O
O
O
O
O
[2]
[3]
For reviews on chiral sulfide catalysts, see: a) V. K. Aggarwal, Synlett
1998, 329–336; b) V. K. Aggarwal, C. L. Winn, Acc. Chem. Res. 2004,
37, 611–620; c) E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L.
Riches, V. K. Aggarwal, Chem. Rev. 2007, 107, 5841–5883; d) R.
Gómez Arrayás, J. C. Carretero, Chem. Commun. 2011, 47, 2207–2211;
e) J. Luo, X. Liu, X. Zhao, Synlett 2017, 28, 397–401.
4a
4b
4c
94%, 83% ee
89%, 90% ee
54%, 84% ee
F
OMe
Br
Br
Br
Me
O
O
O
a) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353–1364;
b) E. J. Corey, M. Chaykovsky, Org. Synth. 1969, 49, 78–80; c) Y. G.
Gololobov, A. N. Nesmeyanov, V. P. Lysenko, I. E. Boldeskul,
Tetrahedron 1987, 43, 2609–2651; d) L.-X. Dai, X.-L. Hou, Y.-G. Zhou,
Pure Appl. Chem. 1999, 71, 369–376; e) V. K. Aggarwal, J. Richardson,
Chem. Commun. 2003, 2644–2651; f) Y. Tang, S. Ye, X.-L. Sun, Synlett
2005, 2720–2730.
O
O
O
4d
4e
4f
89%, 83% ee
87%, 81% ee[a]
86%, 87% ee
Br
Br
Br
F
Ph
O
O
O
[4]
For examples, see: a) N. Furukawa, Y. Sugihara, H. Fujihara, J. Org.
Chem. 1989, 54, 4222–4224; b) A.-H. Li, L.-X. Dai, X.-L. Hou, Y.-Z.
Huang, F.-W. Li, J. Org. Chem. 1996, 61, 489–493; c) J. Zanardi, C.
Leriverend, D. Aubert, K. Julienne, P. Metzner, J. Org. Chem. 2001, 66,
5620–5623; d) T. Saito, D. Akiba, M. Sakairi, S. Kanazawa, Tetrahedron
Lett. 2001, 42, 57–60; e) C. L. Winn, B. R. Bellenie, J. M. Goodman,
Tetrahedron Lett. 2002, 43, 5427–5430; f) Y. Miyake, A. Oyamada, Y.
Nishibayashi, S. Uemura, Heteroatom Chem. 2002, 13, 270–275; g) M.
Ishizaki, O. Hoshino, Chirality 2003, 15, 300–305; h) M. Davoust, J.-F.
Brière, P.-A. Jaffrès, P. Metzner, J. Org. Chem. 2005, 70, 4166–4169;
see also: i) J. R. Fulton, V. K. Aggarwal, J. de Vicente, Eur. J. Org. Chem.
2005, 1479–1492; j) Q.-Z. Li, X. Zhang, R. Zeng, Q.-S.Dai, Y. Liu, X.-D.
Shen, H.-J. Leng, K.-C. Yang, J.-L. Li, Org. Lett. 2018, 20, 3700–3704.
a) S. A. Snyder, D. S. Treitler, A. P. Brucks, Aldrichimica Acta 2011, 44,
27–40; b) C. Ni, M. Hu, J. Hu, Chem. Rev. 2015, 115, 765–825.
a) Z. Ke, C. K. Tan, F. Chen, Y.-Y. Yeung, J. Am. Chem. Soc. 2014, 136,
5627–5630; b) Z. Ke, C. K. Tan, Y. Liu, K. G. Z. Lee, Y.-Y. Yeung,
Tetrahedron 2016, 72, 2683–2689.
O
O
O
4g
4h
4i
96%, 90% ee[a]
40%, 82% ee
46%, 81% ee
Br
Br
Br
Ph
Ph
Ph
O
O
O
F
F3C
Me
O
O
O
4j
83%, 81% ee
4k
59%, 80% ee
4l
91%, 80% ee
Scheme 5. Substrate scope. [a] The reactions with 3e and 3g were performed
with N-bromophthalimide (NBP) as a brominating reagent in CH2Cl2 at –78 °C
for 48 h.
[5]
[6]
In summary, we have successfully developed chiral
bifunctional dialkyl sulfides that possess a urea moiety, which
functions
bromolactonization. The importance of the bifunctional design of
the catalysts was clearly demonstrated in the asymmetric
bromolactonization, and the roles of both sulfide and urea
moieties on the catalyst were discussed and clarified based on
the results of experimental and theoretical investigation. Further
[7]
[8]
D. Böse, S. E. Denmark, Synlett 2018, 29, 433–439.
as
an
effective
catalyst
for
asymmetric
Other example of chiral sulfide catalysts, see: X. Liu, R. An, X. Zhang, J.
Luo, X. Zhao, Angew. Chem. Int. Ed. 2016, 55, 5846–5850; Angew.
Chem. 2016, 128, 5940–5944.
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Entry for the Table of Contents (Please choose one layout)
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Chiral bifunctional dialkyl sulfide
catalysts possessing a urea moiety
R. Nishiyori, A. Tsuchihashi, A.
Mochizuki, K. Kaneko, M. Yamanaka,*
S. Shirakawa*
Br
O
SBu
H
N
Ar
NBS
Ar
H
were designed for enantioselective
bromolactonization. The roles of both
sulfide and urea moieties on the
catalyst are discussed and clarified
based on the results of both
OH
N
Ph
O
O
O
catalyst
Page No. – Page No.
O
Design of Chiral Bifunctional Dialkyl
Sulfide Catalysts for Regio-,
Diastereo-, and Enantioselective
Bromolactonization
N
N
H
H
experimental
investigation.
and
theoretical
H
S
Br
H
O
N
H
H
O
O
O
H
This article is protected by copyright. All rights reserved.