Catalytic asymmetric bromoetherification and desymmetrization of olefinic 1,3-diols with C2-symmetric sulfides

Article abstract of DOI:10.1021/ja5029155

An enantioselective and highly diastereoselective bromoetherification and desymmetrization of olefinic 1,3-diols has been developed using a C ₂-symmetric cyclic sulfide catalyst. This methodology has been successfully applied to the synthesis of the key intermediate of an orally active antifungal drug posaconazole (Noxafil).

Full text of DOI:10.1021/ja5029155

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Bromoetherification and Desymmetrization of
Olefinic 1,3-Diols with C2‑Symmetric Sulfides
Zhihai Ke,† Chong Kiat Tan,† Feng Chen, and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
S
* Supporting Information
Scheme 1. Asymmetric Bromoetherification and
Desymmetrization of Diols
ABSTRACT: An enantioselective and highly diastereose-
lective bromoetherification and desymmetrization of
olefinic 1,3-diols has been developed using a C2-symmetric
cyclic sulfide catalyst. This methodology has been
successfully applied to the synthesis of the key
intermediate of an orally active antifungal drug posacona-
zole (Noxafil).
he asymmetric halofunctionalization of olefins is a field with
1
Trenewed interest. After remarkable endeavors by pio-
neers,2,3 torrents of novel solutions to this problem have
emerged in recent years. A number of catalytic halolactonization
reactions have been reported. In contrast, suitable methods for
haloetherification4 remain elusive.1,5
Among the efforts devoted to halo-O-cyclization of olefins, the
involvement of desymmetrization is a tempting element as it can
convert remote, prostereogenic centers to stereogenic centers,
although such examples are not that common. Several elegant
examples including the use of diolefinic carbonyl,6a−e diolefinic
carboxylic acid,6f,g and dialkynyl carboxylic acid5h substrates in
the asymmetric halogenation−desymmetrization process have
been documented. Nonetheless, the desymmetrization of
dinucleophile olefinic substrates is rare. Recently, cyclization of
oct-4-ene-1,8-diol using chiral BINOL-derived phosphoric acid
catalyst has been reported.6i
Herein we disclose the asymmetric bromoetherification and
desymmetrization of trisubstituted alkenoic 1,3-diols using a
monofunctional C2-symmetric cyclic sulfide as the catalyst
(Scheme 1). It is noteworthy that monofunctional dialkyl
sulfides have been reported to be useful in promoting the
halogenation process. However, the asymmetric catalytic variant
remains unknown.7,8 This report represents the first case of
monofunctional Lewis basic sulfide-catalyzed enantioselective
bromocyclization reaction. Our methodology is also the catalytic
version (using substoichiometric amount of catalyst) of asymmetric
desymmetrization of olefinic 1,3-diols, which is an important
transformation.9 The resulting substituted tetrahydrofuran
products contain up to three new stereogenic centers, of which
two are tetrasubstituted carbons. These compounds resemble the
core of the broad-spectrum, orally active azole antifungals
posaconazole (Noxafil)10 and Sch 51048.11
lysts.13 Initial experiments began with alkenoic diol 1a. NBS was
used as the brominating agent, and the reaction was conducted in
CH2Cl2 at −78 °C. Without catalyst and additive, 2a was
obtained in 57% yield and 84:16 dr after 2 days (Table 1, entry 1).
With bases such as K2CO3 or triethylamine, which are known to
be effective in promoting halocyclization reactions, low
diastereoselectivity of 2a was obtained (entries 2, 3). No desired
product was observed when cyclic selenide catalyst 3a was used
(entry 6). Interestingly, 29% yield of 2a was isolated with high
diastereoselectivity and moderate enantioselectivity when 1
equiv of MsOH was added as an additive (entry 6 vs 7).14 An
improved er of 83:17 was observed when cyclic selenide 3b was
used (entry 8).
To try to boost the diastereoselectivity and enantioselectivity,
we continued to search for different catalysts.15 Cyclic sulfide
catalyst 4a, an analogue of cyclic selenide 3, showed improved
diastereoselectivity without sacrificing reaction yield (Table 1,
entry 9). Reaction yields were reduced when p-tolyl catalyst 4b
and p-isopropylphenyl catalyst 4c were used (entries 10, 11).
Surprisingly, the best result was obtained with the bulkier tert-
butyl substituted catalyst 4d, and 80% yield of the desired
product was isolated with dr 92:8 and enantioselectivity
85.5:14.5 (entry 13). Although MsOH itself could promote the
reaction (entry 4), addition of 4d (10 mol %) further accelerated
the reaction and improved the dr (entry 4 vs 12). Similar to the
reaction with cyclic selenide catalysts 3, MsOH was necessary in
The inspiration for this work came from our recent success
with the asymmetric bromoaminocyclization of trisubstituted
olefinic amides with C2-symmetric cyclic selenide catalysts.12 The
success with cyclic selenide catalyst is a departure from our recent
development on the bifunctional amino-thiocarbamate cata-
Received: March 22, 2014
Published: April 3, 2014
© 2014 American Chemical Society
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Communication
With the groundwork established, trisubstituted olefinic
substrates were then subjected to the study. After a brief
screening, mixed solvent systems were found to be superior
reaction media which offered better er and dr.16 As shown in
Table 3, the diastereoselectivities obtained with catalyst 4d were
Table 1. Asymmetric Bromoetherification and
Desymmetrization of Alkenoic Diols
a
Table 3. Asymmetric Bromoetherification and
Desymmetrization of Trisubstituted Alkenoic Diols
a
b
c
entry
catalyst
yield (%)
dr
er
b
c
entry
diol, R1, R2
5, Ph, Et
yield (%)
dr
er
d
1
57
51
53
35
72
trace
29
99
73
55
59
81
80
61
84:16
64:36
68:32
88:12
88:12
1
2
99
99
95
99
99
98
96
92
91
99
94
96
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
92:8
90.5:9.5
96.5:3.5
55:45
96:4
d
d
f
,
e
e
2
3
4
5
6
7
8
9
K2CO3
Et3N
7a, Ph, Ph
,
3
7b, 2-Me-C6H4, Ph
7c, 4-Et-C6H4, Ph
7d, 3,5-Me2-C6H3, Ph
7e, 3-MeO-C6H4, Ph
7f, 4-Ph-C6H4, Ph
7g, 4-F-C6H4, Ph
7h, 4-CF3O-C6H4, Ph
7i, 4-iPr-C6H4, Ph
7a, Ph, Ph
4
5
95:5
d,
g
3a
3a
3b
4a
4b
4c
4d
4d
4d
6
86:14
73:27
97.5:2.5
67:33
97:3
g
92:8
88:12
93:7
93:7
92:8
92:8
92:8
86:14
65.5:34.5
83:17
7
8
>99:1
95:5
82.5:17.5
82:18
9
g
g
f
10
11
12
13
14
10
>99:1
>99:1
>99:1
82:18
d
11
e
96:4
85.5:14.5
85.5:14.5
52:48
12
7a, Ph, Ph
96:4
a
d,g
Reactions were carried out with alkenoic diol 5 or 7 (0.05 mmol),
catalyst 4d (0.0025 mmol), methanesulfonic acid (0.05 mmol), and
a
Reactions were carried out with alkenoic diol 1a (0.05 mmol),
NBS (0.06 mmol) in CH2Cl2/ClCH2CH2Cl (0.75/0.75 mL) in the
catalyst (0.005 mmol), methanesulfonic acid (0.05 mmol), and NBS
b
c
d
absence of light. Isolated yield. Determined by 1H NMR. 1.0 mmol
b
(0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. Isolated
e
scale. 2.0 mmol scale.
c
d
e
yield. Determined by 1H NMR. Reaction without MsOH. 0.05
f
g
mmol of catalyst was used. Reaction was quenched at 12 h. Starting
material was consumed, and significant amount of inseparable side
products was observed.
generally in excess of 99:1. For the relatively lower dr entries,
only a pair of diastereomeric isomers were identified in these
reactions, suggesting that the bromonium ring opening was
highly regio- and stereoselective. The enantioselectivities were
also good in which bromoether 6 was obtained with 90.5:9.5 er
and 8a with 96.5:3.5 er (Table 3, entries 1, 2).
obtaining high dr and er (entry 14) (vide infra). Thus, 4d was
selected in the later studies. Other acids were also examined, and
MsOH was found to be superior.16
Next, we focused on asymmetric cyclization of the
trisubstituted olefinic diol 5 and examined the catalyst loading.
Substituted tetrahydrofuran 6, which contains three stereogenic
centers, was obtained in excellent dr and yield, and good er when
using 10 mol % of catalyst 4d (Table 2, entry 1). Similar dr and er
were observed when 5 mol % of 4d was used (entry 2). Notably,
only a slight er erosion was detected when the catalyst loading
was reduced to 2 mol % (entry 3).
The substituent effect on the trisubstituted alkenoic diol 7 was
then studied (Table 3). Generally, higher enantioselectivities
were obtained for substrates with alkyl-substituted aryl groups in
the R1 position (Table 3, entries 4, 5, 10). Other substrates with
3-methoxyphenyl and 4-biphenyl substitutions also returned
with good er (entries 6, 7). The substrate containing 4-
fluorophenyl substituent was also able to achieve a high
enantioselectivity of 97.5:2.5 er (entry 8), whereas the other
electron withdrawing substrates with 4-trifluoromethoxy phenyl
(7h) recorded much diminished enantioselectivity (entry 9).
Ortho substitution was found to affect the enantioselectivity
adversely (entry 3).17 The reaction was also readily scalable
(entries 11, 12). The absolute configuration of 8 was assigned
based on an X-ray crystallographic study on the 3,5-
dinitrobenzoyl ester derivative of 8a.16
Also it was found that substrates 9 and 11 with an additional
benzyl substituent at the C(2) position are also amenable to this
protocol and yielded products that contain two tetrasubstituted
carbon stereogenic centers (Table 4). For the cyclization of diols
9, the enantioselectivity was not significantly affected by the R1
substituent. Good enantioselectivities were recorded for
electron-rich (Table 4, entries 1−3) and electron-deficient
(entries 4−6) olefinic substrates. Cyclization of trisubstituted
diols 11 catalyzed by 4d could also afford the desired substituted
Table 2. Effect of Catalyst Loading on the Asymmetric
a
Bromoetherification and Desymmetrization of 5
a
b
c
entry
4d (mol %)
yield (%)
dr
er
1
2
3
10
5
88
97
92
>99:1
>99:1
94:6
90:10
90:10
2
86.5:13.5
a
Reactions were carried out with alkenoic diol 5 (0.05 mmol), catalyst
4d, methanesulfonic acid (0.05 mmol), and NBS (0.06 mmol) in
b
c
CH2Cl2 (1.5 mL) in the absence of light. Isolated yield. Determined
by H NMR.
1
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Journal of the American Chemical Society
Communication
our protocol, enantiopure 2b that is the synthetic equivalent
intermediate of 18 could readily be furnished.19
Table 4. Asymmetric Bromoetherification and
Desymmetrization of 9, 11, 13, and 15
a
Regarding the reaction mechanism, we believe that the chiral
cyclic sulfide catalyst 4 may activate NBS to give active species 4-
Br through a Lewis base activated Lewis acid mechanism.20 4-Br
might then deliver the Br asymmetrically to the olefin to give A
(Scheme 3).7,8,12 For MsOH, we speculate that its role is to
Scheme 3. A Plausible Mechanism of the Asymmetric
Bromocyclization−Desymmetrization Process
facilitate the formation of the cyclic sulfide−Br complex 4-Br
through the protonation of the succinimide and enhance the
turnover as described in Denmark’s proposal.21 However, the
overall mechanism and the role of MsOH remain unclear and are
subjected to further investigation.22
In summary, we have developed a facile, efficient, and highly
enantio- and diastereoselective bromocyclization−desymmetri-
zation of olefinic 1,3-diols using a cyclic sulfide catalyst. The
process allows for the construction of substituted THFs with up
to three stereogenic centers with two tetrasubstituted carbons.
This methodology is applicable to the synthesis of a key
intermediate of the orally active antifungal drug posaconazole
(Noxafil).
a
Reactions were carried out with alkenoic diol (0.05 mmol), catalyst
4d (0.0025 mmol), methanesulfonic acid (0.05 mmol), and NBS (0.06
b
mmol) in CH2Cl2 (1.5 mL) in the absence of light. Isolated yield.
c
d
1
Determined by H NMR. 1.0 mmol scale.
tetrahydrofurans 12 in excellent yields and enantioselectivities.
Results from Table 4 suggest that the enantioselectivity was not
significantly affected by the electronic nature of the substituents
(Table 4, entries 7−11). High er was also obtained for substrate
13 (R1 = Ph, R2 = Et). Similar to the cyclization of 5 and 7,
excellent diastereoselectivities were obtained in the asymmetric
bromocyclization−desymmetrization of 9 and 11. Cyclization of
15, a substrate with methyl in place of benzyl group in 9a, also
gave the desired product 16 in 73% yield and 91:9 er (entry 14).
An X-ray study on a single crystal of 12c confirmed the absolute
configuration.16
ASSOCIATED CONTENT
* Supporting Information
Experimental detail, CIF files, and spectroscopic and analytical
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
This type of reaction is applicable in the synthesis of useful
drug molecules. As indicated in Scheme 2, our cyclized product 2
resembles the core structure of the highly active antifungal drug
candidates posaconazole (Noxafil) and Sch 51048. A reported
efficient synthetic route involves the enzymatic desymmetriza-
tion of diol 1b by selectively acetylating one of the hydroxyl
groups. Subsequent iodoetherification of 17 afforded 18.18 With
AUTHOR INFORMATION
Corresponding Author
chmyyy@nus.edu.sg
■
Author Contributions
†Z.K. and C.K.T. gave equal contributions to this work.
Notes
The authors declare no competing financial interest.
Scheme 2. Single Step Asymmetric Bromoetherification and
Desymmetrization Leading to Intermediate of Posaconazaole
and Sch 51048
ACKNOWLEDGMENTS
■
We thank the National University of Singapore (Grant No. 143-
000-509-112), GSK-EDB (Grant No. 143-000-564-592),
ASTAR-Public Sector Funding (Grant No. 143-000-536-305),
and NEA-ETRP (Grant No. 143-000-547-490) for financial
support. We acknowledge the receipt of President’s Graduate
Fellowship (to C.K.T.). Special thanks to Prof. Scott E. Denmark
(University of Illinois) for the valuable discussion.
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Figure S3.
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