Enantioselective Bromo-oxycyclization of Silanol

Article abstract of DOI:10.1021/acs.orglett.5b03303

Relying on the nucleophilicity of silanol for building up silicon-incorporated scaffold with an enantiopure tetrasubstituted carbon center remains elusive. In this report, asymmetric bromo-oxycyclization of olefinic silanol by using chiral anionic phase-transfer catalyst is described. This protocol provided a facile entry to a wide arrangement of enantiopure benzoxasilole in moderate to excellent enantioselectivities depending on the unique reactivity of bromine/N-benzyl-DABCO complex.

Full text of DOI:10.1021/acs.orglett.5b03303

Letter
pubs.acs.org/OrgLett
Enantioselective Bromo-oxycyclization of Silanol
Zilei Xia,†,‡ Jiadong Hu,†,‡ Zhigao Shen,‡ Xiaolong Wan,§ Qizheng Yao,‡ Yisheng Lai,‡ Jin-Ming Gao,†
and Weiqing Xie*,†,§
†Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, 22 Xinong Road,
Yangling 712100, Shaanxi, China
‡State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing
210009, China
§State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Relying on the nucleophilicity of silanol for building up
silicon-incorporated scaffold with an enantiopure tetrasubstituted carbon
center remains elusive. In this report, asymmetric bromo-oxycyclization of
olefinic silanol by using chiral anionic phase-transfer catalyst is described.
This protocol provided a facile entry to a wide arrangement of enantiopure
benzoxasilole in moderate to excellent enantioselectivities depending on
the unique reactivity of bromine/N-benzyl-DABCO complex.
rganosilicon has undoubtedly occupied a unique position
Oin organic chemistry, as shown by its wide applications in
synthetic chemistry,1a,b material chemistry,1c,d and pharmaceut-
ical chemistry.1e Therefore, an enormous endeavor has been
dedicated to the incorporation of silicon into an organic
scaffold, particularly into the enantiopure molecules, as the
resulting organosilicon could be employed to construct
diversely valuable chemical bonds (e.g., C−C, C−O, C−X
bonds).2 In this regard, although silanol is easily accessible and
widely employed in synthetic chemistry (e.g., for the synthesis
of siloxane,1c cross-coupling2d), harnessing the nucleophilicity
of silanol for organic transformations is not well investigated,
presumably due to its instability (easy to dehydrate to form
siloxanes) and weak nucleophilicity of hydroxyl.3 In this
account, catalytic asymmetric reactions by directly taking
advantage of silanol as oxygen source are scarce.4 Only iridium-
and palladium-catalyzed asymmetric allylic etherification of
silanol has been reported by Hartwig and Xu respectively
(Figure 1).4a,b However, silanol is only used as a water
Figure 1. Enantioselective reactions directly relying on the
nucleophilicity of silanol.
surrogate in those reactions, and the synthetic potential of
silicon could not be fully utilized for constructing other chiral
powerful strategy for construction of other functionalized chiral
heterocycles.6g−l Despite the significant progress in asymmetric
halo-oxycyclization reactions, synthetic applications of those
enantiopure halogenated products are mainly limited to the
derivatization of halogen. Therefore, incorporation of other
orthogonally versatile functionality (e.g., Si, B) via asymmetric
halogenation reaction is still highly desirable. In continuation of
our work on asymmetric halogenation reactions,7 herein we
report our preliminary results on the first enantioselective
scaffolds in subsequent transformations. To this end,
construction of an asymmetric tetrasubstituted carbon center
directly based on the nucleophilicity of silanol represents a big
challenge in the chemistry of silanol, which to the best of our
knowledge has not been described to date.
Recently, asymmetric electrophilic halo-functionalization of
unsaturated C−C bonds has witnessed great advances.5,6 In this
context, asymmetric halo-oxycyclization of olefinic alcohol has
been extensively studied for giving easy access to enantiopure
halogenated tetrahydrofuran and tetrahydropyran (Figure 1).6
Furthermore, by employing tethered nucleophiles other than
alcohol, asymmetric halo-oxycyclization has also emerged as
Received: November 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03303
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Organic Letters
Letter
bromo-oxycyclization of olefinic silanol,3b which enables access
to chiral benzoxasilole in moderate to excellent enantioselectiv-
ities.
The reaction condition optimization commenced with
asymmetric bromocyclization of silanol 1a using chiral anionic
phase-transfer catalyst,8 and selected results are listed in Table
1. Encouragingly, benzoxasilole 2a was initially obtained in 82%
other than toluene (entries 5−7). Among bases tested for this
reaction, K2CO3 gave the best outcome, leading to 2a in 95.5%
ee (entries 8−10). Furthermore, reducing the temperature was
detrimental to the reaction (entry 11). Two phenyls on silicon
were indispensible for this reaction, as putting other
substituents (e.g., Me, i-Pr) on silicon only led to the
corresponding benzoxasiloles in moderate enantioselectivities
(2ab, 2ac, entries 12 and 13).
With optimal reaction conditions being set up, we turned our
attention to examine the substrate scope of this reaction.
Electron-donating or electron-withdrawing groups on phenyl
have little impact on this reaction, leading to the corresponding
benzoxasilole in excellent enantioselectivities (Figure 2, 92−
Table 1. Screening of Reaction Conditions for
Enantioselective Bromo-Cycloetherification of Olefinic
a
Silanol 1a
b
c
time
(h)
yield
ee
entry cat. Br+
base
solvent
(%)
(%)
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
B1
B2
B3
B4
B1
B1
B1
B1
B1
B1
B1
B1
B1
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
K2CO3
toluene
toluene
toluene
toluene
hexane
bezene
Et2O
6
12
12
12
20
4
81
64
40
0
92
81
75
NR
93
53
61
66
81
87
77
80
91
89
d
91
5
91
toluene
toluene
toluene
toluene
toluene
toluene
4
95
4
95.5
94
d
e
f
10
11
12
13
K3PO4
4
K2CO3
20
4
94
K2CO3
72
g
K2CO3
4
68
a
The reaction was carried out by addition of silanol 1a (0.1 mmol) in
toluene (1 mL) to a mixture of catalyst (0.01 mmol), brominating
reagent (0.13 mmol), and base (0.40 mmol) in toluene (1 mL) at 0
b
c
°C. Isolated yield. Determined by HPLC on a Chiralpak AD-H
d
e
column. The reaction was carried out at rt. The reaction was
conducted at −20 °C. Silanol 1ab as substrate. Silanol 1ac as
substrate.
f
g
Figure 2. Substrate scope of enantioselective bromo-cycloetherifica-
tion of olefinic silanols. Key: (a) The reaction was carried out by
addition of silanol (0.1 mmol) in toluene (1 mL) to a mixture of 8H-
R-TRIP (0.01 mmol), B1 (0.13 mmol), and K2CO3 (0.40 mmol) in
toluene (1 mL) at 0 °C.
yield and 92% ee under our previous optimal conditions for
asymmetric bromocyclization of tryptamine7a (entry 1).
Subsequent evaluation of different bromine/N-benzyl-
DABCO complexes showed that enantioselectivity of this
reaction greatly depended on the counteranion of those
complexes. B1 with chloride as counteranion was superior to
other bromine complexes in terms of yield and enantiose-
lectivity (entries 2 and 3). To our surprise, bromonium salt
B48d was ineffective for this reaction even after the reaction
time was extended (entry 4). This could be ascribed to the
reduced reactivity of bromine by double complexation with N-
benzyl-DABCO. Next, a survey of different chiral phosphoric
acids revealed that 8H-R-TRIP L1 was the catalyst of choice
(see the Supporting Information). Solvent screening showed
that inferior results were produced using nonpolar solvents
97% ee, 2a−g). However, presumably due to steric repulsion,
introducing substituents adjacent to silicon dramatically
reduced enantioselectivity of this reaction, leading to 2h and
2i only in 75% ee and 84% ee, respectively. On the other hand,
substituents on olefin have complicated effect on enantiose-
lectivities. Replacement of the olefinic methyl with other alkyl
groups (e.g., Et, i-Pr) resulted in decreased enantioselectivities
(87% for 2j and 59% ee for 2k). Only 6-endo-bromo-
oxycylization was detected when this methyl group was
removed from the substrate, delivering benzoxasiline 2′l9 and
2′m in moderate enantioselectivities. Substituents on the
B
DOI: 10.1021/acs.orglett.5b03303
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
terminal olefin were also tolerated, while enantioselectivities
depended on the configuration of alkene. As shown in Figure 2,
lower enantioselectivities were obtained when the more bulky
group was present on E-olefins (93% ee for 2n to 86% ee for
2p), while a reverse trend was observed for Z-olefins (69%ee
for 2q to 98.5% ee for 2s). Finally, even tetrasubstituted olefin
could be smoothly transferred to benzoxasilole 2t in 91% ee.
To display the synthetic application of the resulting chiral
benzoxasilole, synthesis of 2a on a 4 mmol scale was first
implemented to afford benzosilole in comparable enantiose-
lectivity (Scheme 1). Its subsequent transformations by taking
Scheme 2. Selective Transmetalation of Phenyl on Silicon
Scheme 1. Synthetic Transformations of Benzoxasilole 2a
catalyst. Structurally diverse benzosiloles were obtained in
moderate to excellent enantioselectivities, which mainly
depended on the substituents and configuration of alkene.
Selective transfer of the phenyl of silane derived from chiral
benzoxasilole was enabled by copper-catalyzed oxidative
dimerization, albeit with no diastereoselectivity on the silicon
stereogenic center.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03303.
advantage of bromine and silicon were tested, respectively.
Halogen as a handle for introduction of other functionality was
routinely achieved by substituting of bromide with azide and
cyanide, respectively, affording the corresponding benzosiloles
3a and 3b in high enantiopurities. For transformation of silicon,
Tamao−Fleming oxidation of 2a smoothly furnished phenol 4
with retention of bromine. Protonation of silicon concurrently
with displacement of bromine with H2O could be readily
realized by heating 2a in NaOH/EtOH, affording the known
diol 5, which established absolute configuration of 2a to be S.10
Although benzoxasilole has emerged as an efficient transfer
reagent for reactive organometallic reagents for cross-coupling
reactions,11 diastereoselective transmetalation of substituents
on silicon for construction of stereogenic silicon is not well
explored.12 To this end, synthesis of 2o on a 2.5 mmol scale
enabled us to obtain a good crystal of 2o for X-ray analysis,
which confirmed its absolute configuration (Scheme 2).13
Removal of bromine with AIBN/Bu3SnH followed by ring
opening of benzoxasilole with methyllithium generated silane 7
in excellent yields. Selective transfer of one phenyl of 7 proved
to be challenging owing to the competitive transfer of methyl
under previous cross-coupling conditions11c,d (see the Support-
ing Information). After extensive optimization (see the
Supporting Information), transfer of methyl could be totally
suppressed using CuI-catalyzed oxidative homodimerization of
silane 7.14 Disappointingly, only poor diastereoselectivities
resulted, and initial attempts employing achiral or chiral ligands
proved to be fruitless (see the Supporting Information).
Experimental procedures, spectral data, and copies of all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xiewqsioc@aliyun.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21372239,
21202187) and the Scientific Research Foundation of North-
west A&F University (Grant No. Z111021501).
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DOI: 10.1021/acs.orglett.5b03303
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D
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Org. Lett. XXXX, XXX, XXX−XXX