Cinchona alkaloid/sulfinyl chloride combinations: Enantioselective sulfinylating agents of alcohols

Article abstract of DOI:10.1021/ja0430189

We report a novel approach to asymmetric sulfinylation reactions based on a cinchona alkaloid/sulfinyl chloride combination that acts as the first asymmetric sulfinylating agents of achiral alcohols. Both enantiomers of arenesulfinates are obtained with u

Full text of DOI:10.1021/ja0430189

Published on Web 01/15/2005
Cinchona Alkaloid/Sulfinyl Chloride Combinations: Enantioselective
Sulfinylating Agents of Alcohols
Norio Shibata,* Mitsuharu Matsunaga, Masaya Nakagawa, Takeo Fukuzumi, Shuichi Nakamura, and
Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso,
Showa-ku, Nagoya 466-8555, Japan
Received November 19, 2004; E-mail: nozshiba@nitech.ac.jp; toru@nitech.ac.jp
Chiral sulfinates play an important role in organic chemistry as
key precursors in many chiral sulfoxides that are useful building
blocks for biologically active molecules and natural products.1
Despite the development of many synthetic strategies to access
chiral sulfinates in the last two decades,2 the most industrially viable
procedure is still the one based on the resolution of diastereomeric
Figure 1. Structures of QDA, HQA, and arenesulfinyl chloride 1.
sulfinates prepared from sulfinyl halides and chiral alcohols such
as menthol and diacetone-D-glucose.2a-c On the other hand, the
enantioselective sulfinylation reaction of achiral alcohols with
Table 1. Asymmetric Sulfinylation of t-BuOH by a Cinchona
Alkaloid/p-Toluenesulfinyl Chloride Combinationa
racemic sulfinyl chlorides is particularly attractive.3 The initial report
by Mikolajczyk and Drabowicz for the enantioselective sulfinylation
reaction of alcohols with p-toluenesulfinyl chloride using chiral
amines revealed limitations in enantioselectivities of the sulfinates.3a-c
Very recently, Ellman and co-workers have reported the first
catalytic enantioselective preparation of 1,1-dimethylethanesulfinate
with up to 81% ee using chiral peptides,3d although its synthetic
utility is somewhat limited by the lack of a route to chiral
arenesulfinates which are the most useful precursors in the synthesis
of chiral sulfoxides.1 We now report a novel approach to the
asymmetric sulfinylation reaction based on a cinchona alkaloid/
sulfinyl chloride combination that acts as the first asymmetric
sulfinylating agents of achiral alcohols (Figure 1). Both enantiomers
of arenesulfinates are obtained with up to 99% ee.
We recently reported a new approach to enantioselective
fluorination based on a cinchona alkaloid/Selectfluor combination.
The enantioselective fluorination reaction is mediated by N-
fluoroammonium salts generated in situ via transfer fluorination
of cinchona alkaloids by Selectfluor.4 We envisioned that chiral
sulfinylating agents, N-sulfinylammonium salts, might be generated
in situ via a cinchona alkaloid/sulfinyl chloride combination by
transfer sulfinylation. Since p-toluenesulfinates are the most widely
used precursors for building up chiral sulfoxides,1 we chose tert-
butyl p-toluenesulfinate (2a) as the initial synthetic target of this
study. Treatment of tert-butyl alcohol (t-BuOH) with the combina-
tion prepared in situ from QDA and p-toluenesulfinyl chloride (1a)
in MeCN/CH2Cl2 (3/4) for 1 h at -78 °C furnished product 2a in
51% yield with 58% ee (Table 1, run 1). The preliminary result
encouraged us to investigate other systems in an attempt to improve
enantioselectivity.
cinchona
alkaloidb
run
solvent
yield (%)
ee (%)c
confignd
1
2
3
4
5
6
QDA
HQDA
QDB
QDA
HQDA
QDB
QDA
QDA
HQDA
QDP
QDN
CDA
CNA
HQA
HQA
HQA
QDA
QDA
QDA
QDA
MeCN/CH2Cl2
MeCN/CH2Cl2
MeCN/CH2Cl2
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN/CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
51
82
89
74
75
90
92
70
84
85
83
81
61
93
93
58
S
R
S
S
S
S
S
S
S
18
54
24
22
35
87
95
60
80
59
43
3
81
96
93 (99)k
47
50
86
86
7
8d
9
10
11
12
13
14
15e
16e,f
17g
18h
19i
20j
S
S
R
R
R
R
R
nd
nd
S
93 (63)k
85
90
88
89
CH2Cl2
S
a The combination was prepared from 1.3 equiv of 1a and 1.4 equiv of
cinchona alkaloid in the solvent at -78 °C for 30 min. b Legend: QDA,
quinidine acetate; HQDA, hydroquinidine acetate; QDB, quinidine benzoate;
QDP, quinidine pivaloate; QDN, quinidine naphthyl ether; CDA, cinchoni-
dine acetate; CNA, cinchonine acetate. c Determined by HPLC analysis.
d The absolute configuration of 2 was assigned by the stereospecific
conversion to methyl p-tolyl sulfoxide or p-toluenesulfinamide. See the
Supporting Information. e The reaction was performed at -90 °C for 4 h.
f 1-Adamantanol was used instead of t-BuOH to furnish 1-adamantyl
p-toluenesulfinate (4a). g Cyclohexanol was used instead of t-BuOH to
furnish cyclohexyl p-toluenesulfinate (4b). h 9-Fluorenol was used instead
of t-BuOH to furnish 9-fluorenyl p-toluenesulfinate (4c). i A large excess
amount of the combination (11 equiv of 1a and 12 equiv of QDA) was
used. j The reaction was carried out using recovered QDA. k Results in
parentheses were obtained after recrystallization from hexane.
After screening several cinchona alkaloids as a chiral source,
we found that a QDA/1a combination in CH2Cl2 at -78 °C effected
the enantioselective sulfinylation of t-BuOH to furnish (S)-2a with
87% ee (Table 1, run 7). Quinidine pivaloate (QDP) was also found
to afford high enantioselectivity (80% ee, run 10). Excellent
enantioselectivity could be achieved with a QDA/1a combination
when the reaction was performed at -90 °C in CH2Cl2 (95% ee,
run 8). Importantly, both enantiomers of the sulfinates 2a can be
accessed in excellent yield and enantioselectivity by using either
of the pseudoenantiomeric quinine or quinidine derivatives. For
example, when t-BuOH was treated with a hydroquinine acetate
(HQA)/1a combination, the highly enantiopure product was ob-
tained with reversal of facial selectivity (runs 14 and 15, (R)-2a
with 81-96% ee). Asymmetric sulfinylation of other alcohols was
9
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J. AM. CHEM. SOC. 2005, 127, 1374-1375
10.1021/ja0430189 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Sulfinylation of t-BuOH by a Combination of
Various Arenesulfinyl Chlorides (1b-f) with HQA or QDA
cinchona
alkaloid
yield
(%)
ee
entry
Ar
2
(%)b
Figure 2. Proposed structures for the QDA/1a combination and the dynamic
kinetic resolution pathway to (S)-2a.
1a
2
Ph
HQA
QDA
HQA
QDA
HQA
QDA
HQA
QDA
HQA
QDA
(R)-2b
(S)-2b
(+)-2c
(-)-2c
(+)-2d
(-)-2d
(+)-2e
(-)-2e
(+)-2f
(-)-2f
88
93
73
78
74
70
74
78
72
68
83
88
84
88
96
99
94
93
92
92
3c
4a
5a
6a
7a
8
4-chlorophenyl
with 1a to stop the sulfinylation before completion gave 2a with
an enantioselectivity similar to that under the usual conditions (runs
7 and 19). The significantly high enantioselectivity observed in our
case could be explained by dynamic kinetic resolution,6 in which
the enantioselectivity depends on the rate of the alcohol with the
diastereomeric sulfinylammonium salts through rapid epimerization
on the sulfinyl stereocenter of the N-arenesulfinylammonium salt.
The proposed mechanism is shown in Figure 2, assuming that an
alcohol approaches from the direction opposite the sulfur-nitrogen
bond.
4-methoxyphenyl
4-methoxy-3-methylphenyl
2,4,6-trimethylphenyl
9a
10a
a The reaction was performed at -90 °C. b Determined by HPLC
analysis. c MeCN/CH2Cl2 (3/4) was used as a solvent.
also examined using the QDA/1a combination. While 1-adaman-
tanol was sulfinylated by the combination to give 1-adamantyl
p-toluenesulfinate (4a) with very high ee, asymmetric sulfinylation
of cyclohexanol and 9-fluorenol slightly lowered the enantioselec-
tivity (runs 16-18, 47-93% ee). Importantly, the optically pure
adamantyl sulfinate 4a was obtainable in a 63% overall yield from
1-adamantanol after single recrystallization from hexane (run 16
in parentheses). To examine the possibility of reusing the alkaloids,
we repeated the sulfinylation of t-BuOH using QDA recovered from
the first reaction mixture by acid-base extraction/short-column
chromatography (QDA was recovered in 80-90% yield). Formation
of (S)-2a having 86% ee demonstrates that recycling of QDA causes
no erosion in enantioselectivity of the combination (runs 7 and 20).
Having identified an asymmetric process, its scope was inves-
tigated with the aim of producing a general enantioselective
sulfinylation reaction. Table 2 shows the range of arenesulfinates
2b-f that can be formed by this method. t-BuOH reacts with a
combination of a variety of racemic arenesulfinyl chlorides5 1b-f
with HQA to form tert-butyl arenesulfinates 2b-f in good yield
and with high ee (up to 96% ee). The opposite enantiomer is also
accessible by using the QDA-derived combinations (up to 99% ee).
It should be noted that the cinchona alkaloid derivative and sulfinyl
chloride must be mixed prior to the addition of substrates to achieve
enantioselective sulfinylation. For example, after a mixture of
t-BuOH and QDA was stirred in CH2Cl2 at -78 °C for 30 min,
addition of 1a gave racemic 2a. This result gives useful information
on the reaction mechanism of this new sulfinylation procedure, since
the involvement of an alkaloid-alcohol complex in stereochemical
control seems to be ruled out. This has certain implications
regarding the N-arenesulfinylammonium salt, which must be taken
into account. Although the N-sulfinylammonium salt has not been
isolated yet, 1H NMR tentatively ascertained the structure. The 600
In summary, we have developed a highly enantioselective
preparation of chiral sulfinates based on the cinchona alkaloid/
sulfinyl chloride combination. Importantly, our process can have
access to both enantiomers of sulfinates depending on the cinchona
alkaloids via a dynamic kinetic resolution pathway in the sulfin-
ylation reaction. This new sulfinylation system will complement
or even substitute the most commonly used preparative method for
chiral sulfoxides through diastereomeric sulfinates.
Supporting Information Available: Text giving experimental
procedures, determination of the absolute stereochemistry of 2, and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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1
MHz H NMR spectrum of QDA in CDCl3 at room temperature
showed characteristic peaks at 2.72-2.95 ppm (4H, m) and 3.25
ppm (1H, dd, J ) 7.2, 8.8 Hz), whereas the spectrum of the QDA/1
combination (QDA:1 ) 1:1) displayed corresponding signals at
3.50-3.70 ppm (4H, m) and 3.30 ppm (1H, br q, J ) 8.5 Hz).
These signals could be assigned to R-protons of tertiary or
quaternary nitrogen, and the low-field shifts observed are attribut-
able to the cationic character of the ammonium salt. The enantio-
selectivity increased at lower reaction temperature (runs 7 and 8,
Table 1) and the reaction with much fewer equivalents of t-BuOH
JA0430189
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J. AM. CHEM. SOC. VOL. 127, NO. 5, 2005 1375