A highly stereoselective approach to tetrasubstituted (E)-β-hydroxy silyl enol ethers by addition of aryl-substituted oxiranyl anions to acylsilanes

Article abstract of DOI:10.1016/j.tetlet.2011.02.108

A highly stereoselective approach to tetrasubstituted (E)-β-hydroxy silyl enol ethers is described. The reaction proceeds via a sequential addition/[1,2]-Brook rearrangement/epoxide-opening process of aryl-substituted oxiranyl anions with acylsilanes.

Full text of DOI:10.1016/j.tetlet.2011.02.108

Tetrahedron Letters 52 (2011) 2462–2464
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Tetrahedron Letters
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A highly stereoselective approach to tetrasubstituted (E)-b-hydroxy silyl
enol ethers by addition of aryl-substituted oxiranyl anions to acylsilanes
Cheng Wang a, Zubao Gan a, Ji Lu a, Xia Wu a, Zhenlei Song a,b,
⇑
a Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective approach to tetrasubstituted (E)-b-hydroxy silyl enol ethers is described. The
reaction proceeds via a sequential addition/[1,2]-Brook rearrangement/epoxide-opening process of
aryl-substituted oxiranyl anions with acylsilanes.
Received 15 January 2011
Revised 19 February 2011
Accepted 25 February 2011
Available online 4 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Acylsilane
Oxiranyl anion
Brook rearrangement
Silyl enol ether
Silyl enol ethers1 as important building blocks have shown wide
utilities in a number of synthetic transformations, such as Mukaiy-
ama-aldol reaction,2 cycloaddition,3 sigmatropic rearrangement.4
The traditional method to prepare silyl enol ethers lies on silylation
of thermodynamically or kinetically favorable enolates, which can
be generated through enolization of ketones with bases or the con-
jugate addition of organocopper reagents to enones.5 Although the
strategy has proved to be practical to form di- and trisubstituted
silyl enol ethers in a regio- and stereoselective manner, it is not
applicable to the preparation of geometrically defined acyclic tetra-
substituted one. Given the fact that such species possess great syn-
thetic potentials in the construction of stereogenic quaternary
carbon centers,6 as well as the configuration of double bond is usu-
ally crucial for the high facial selectivity, development of suitable
protocol to achieve the stereoselective accessibility of acyclic tetra-
substituted silyl enol ethers would have great synthetic values.7
Aryl-substituted oxiranyl anion 28 has presented good nucleo-
philities to various electrophiles, such as aldehydes, alkyl halides,
and trialkylsilyl chlorides. To our knowledge, however, no addition
of this species to acylsilanes 19 has been investigated. Additionally,
although preparation of silyl enol ethers from acysilanes have been
reported, there are only limited examples describing the synthesis
of tetrasubstituted ones.10 We envisioned that such addition might
key transformations including a [1,2]-Brook rearrangement11 of
the initially formed lithium alkoxide intermediate 312 and the fol-
lowing epoxide opening of carboanion 4 to relieve ring strain. The
aryl group would be expected to have some key impacts on the
conformation of siloxy carbanion 4, thus providing a reasonable
configurational control during formation of the double bond. Here-
in, we report the realization of this sequential addition/[1,2]-Brook
rearrangement/epoxide-opening process.
Considering the stability of the formed silyl enol ether, acylsi-
lane 1a13 containing triethylsilyl group was examined as a model
initially. Deprotonation of phenyl-substituted epoxide 2a by s-Bu-
Li(1.2 equiv)/TMEDA(2.0 equiv) complex in THF at ꢀ98 °C and the
following addition to 1a afforded the desired silyl enol ether 5a,
despite in moderate 33% yield, as a single E-diastereomer (Table
1, entry 1). Increasing the amount of TMEDA to 6.0 equiv led to
R
O
R1
O
O
O
R1
addition
+
Ar
Et3Si
R2
R
SiEt3
R2
Ar
1
2
3
[1, 2]-Brook rearrangement
initiate an efficient approach to tetrasubstituted b-hydroxy-a-aryl
silyl enol ether 5. As shown in Scheme 1, the process involves two
Et3SiO
R1
R1
Ar
O
epoxide ring opening
then H2O
E
Et3SiO
OH
R2
Ar
R
R1 R2
5
4
⇑
Corresponding author. Tel.: +86 28 85501062.
E-mail address: zhenleisong@scu.edu.cn (Z. Song).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.108

C. Wang et al. / Tetrahedron Letters 52 (2011) 2462–2464
2463
Table 1
Table 2
Screening of reaction conditions
Scope of acylsilanes
Ph
Ph
O
O
base/TMEDA, solvent
T o
t-BuLi/TMEDA, Et2O
-98 o
O
O
Et3SiO
OH
Et3SiO
OH
+
+
Ph
Ph
Ph
SiEt3
R
SiEt3
C
C
Ph
R
5b-5l (E onlyb)
1a
2a
5a (E onlyb)
1b-1l
2a
Entrya
Base (1.2 equiv)
TMEDA
Solvent
T (°C)
Yieldc
Entrya
1
Acylsilane (R)
1b (n-C3H7)
Product
OSiEt3
Ph
Yieldc
1
2
3
4
5
s-BuLi
s-BuLi
s-BuLi
t-BuLi
t-BuLi
2.0 equiv
6.0 equiv
6.0 equiv
6.0 equiv
6.0 equiv
THF
THF
Et2O
Et2O
Et2O
ꢀ98 °C
ꢀ98 °C
ꢀ98 °C
ꢀ98 °C
ꢀ116 °C
33%
42%
64%
74%
22%
5b
5c
52%
50%
50%
76%
72%
66%
71%
66%
60%
72%
78%
OH
OSiEt3
a
Ph
Acylsilane 1a (1.0 equiv), epoxide 2a (1.2 equiv).
The stereoselectivity was determined by 1H NMR spectroscopy and the con-
figuration was determined by NOE experiments of 5a.
2
1c (i-C3H7)
b
OH
c
OSiEt3
Ph
Isolated yield after purification by silica gel column chromatography.
Ph
5d
3
1d (PhMeCH)
1e (p-Cl–C6H4)
1f (p-F–C6H4)
1g (p-Ph–C6H4)
1h (2-Np)
OH
OSiEt3
Ph
the better efficiency (42%, entry 2). Solvent also appeared to play a
key role, as reaction in Et2O gave a much higher yield (64%, entry
3).14 The optimal condition was then obtained when more basic
t-BuLi was used as base (74%, entry 4). Lower temperature than
ꢀ98 °C proved to render the reaction sluggish severely.
5e
4
Cl
F
OH
OSiEt3
Ph
5f
5
With the optimal conditions established, the scope of this ap-
proach was examined. As summarized in Table 2, reaction was
suitable for both unbranched and branched alkyl acylsilanes (Ta-
ble 3, entries 1–3). This success also implies that relief of epox-
OH
OSiEt3
Ph
5g
6
ide ring-strain, to
a
large extent, drives the [1,2]-Brook
Ph
OH
OSiEt3
rearrangement since the Csp2-stabilization of silyloxy carbanion
does not exist in these cases. For various aryl acylsilanes con-
taining either electron-poor or rich phenyl group, reactions were
also applicable to give moderate to good yields (entries 4–9).
The process was tolerant of heterocyclic acysilanes 1k and 1l
as well (entries 10 and 11). The potential deprotonation of het-
erocycle ring by oxiranyl anion appeared not to interfere with
the course.
With acylsilane 1a, reactions of other aryl-substituted epox-
ides were further evaluated under the same condition. As
shown in Table 3, para-chloro and para-methyl phenyl-substi-
tuted epoxides 2b and 2c (Table 3, entries 1 and 2), cis-disub-
Ph
5h
5i
7
OH
OSiEt3
Ph
8
1i (p-OMe–C6H4)
1j (p-Me2N–C6H4)
1k (3-Furyl)
MeO
OH
OSiEt3
Ph
5j
9
Me2N
OH
OSiEt3
Ph
10
11
stituted epoxides 2d and 2e (entries
3 and 4), and even
5k
5l
O
trisubstituted epoxide 2f (entry 5) all presented good reactivity
giving the desired silyl enol ethers in good yields with complete
E-selectivity.
OH
OSiEt3
Ph
1l (2-Thienyl)
Rationalization for the high E/Z selectivity is proposed as
shown in Figure 1. Two potential stereoelectronically required
conformations 4-C1 and 4-C2, in which the P orbital of anionic
carbon is periplanar to the cleaved C–O bond, could be expected
during the epoxide-opening step. Due to the severe eclipsing
S
OH
a
Reaction conditions: acylsilane 1 (1.0 equiv), epoxide 2a (1.2 equiv), t-BuLi
(1.2 equiv), TMEDA (6.0 equiv); 0.12 M in Et2O at ꢀ98 °C.
The stereoselectivity was determined by 1H NMR spectroscopy.
b
c
Isolated yield after purification by silica gel column chromatography.
interactions between aryl and
R groups, conformation 4-C2
leading to Z-isomer 6 appears to be unfavorable. Thus, the reac-
tion is believed to occur through the conformation 4-C1 and
provides the observed (E)-tetrasubstituted silyl enol ether
5
predominantly.15
TS-I suffers a lot from the A1,3 strain (between the Ph at 3-pos-
tion and Me), the competitive A1,2 strain (between the Ph at 2-
postion and Me) in TS-II is essentially negligible for epoxidation
due to the dihedral angle a0 is almost 60°. Thus, TS-II appears to
be energetically more favorable to lead to the complete syn-
selectivity.
In conclusion we have described a sequential addition/1,2-
Brook rearrangement/epoxide-opening process of acylsilanes with
aryl-substituted oxiranyl anions. This route provides a direct and
stereoselective entry to tetrasubstituted b-hydroxy silyl enol
ethers. Further applications of these useful building blocks in or-
ganic synthesis are ongoing in our group.
The stereochemical course of epoxidation of silyl enol ether
5o was further examined with m-CPBA in toluene and satd aq
NaHCO3 as cosolvent. After acidic hydrolysis of the initial formed
epoxide, dihydroxy ketone 7 was obtained in overall 50% yield
and as a single syn-diastereomer.16 Based on Adam’s model of
hydroxyl-directed epoxidation of chiral allylic alcohols,17 we pro-
posed the following explanation for the observed high syn-selec-
tivity.18 Two transition states TS-I and TS-II, in which the
hydroxyl group associates with m-CPBA by hydrogen bonding
and with an estimated dihedral angle
a of 120°, would be ex-
pected to give the different facial selectivities (Scheme 2). While

2464
C. Wang et al. / Tetrahedron Letters 52 (2011) 2462–2464
Table 3
Acknowledgments
Scope of aryl-substituted epoxides
Ar
This research was supported by the National Natural Science
Foundation of China (20802044, 21021001), the National Basic Re-
search Program of China (973 Program, 2010CB833200), and RFDP
(200806101091).
O
O
t-BuLi/TMEDA
Et2O, -98 o
R1
Et3SiO
OH
Ph R1 R2
5m-5q (E onlyb)
Yieldc
+
Ar
Ph
SiEt3
C
R2
1a
2b-2f
Entrya
1
Epoxide
Product
OSiEt3
Supplementary data
O
O
2b
p-Cl-Ph
Ph-p-Cl
Ph
Ph
Ph
58%
54%
78%
74%
5m
Supplementary data (experimental procedures and spectra data
for products) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.02.108.
OH
OSiEt3
2c
p-Me-Ph
Ph-p-Me
2
3
4
5n
OH
References and notes
O
OSiEt3
Ph
2d
2e
Ph
1. (a) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063–2192;
(b) Kobayashi, S.; Manabe, K.; Ishitani, H.; Matsuo, J.-I. Sci. Synth. 2002, 4,
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H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org. Chem.
1980, 45, 1066–1081; (c) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25,
495–498; (d) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991, 113,
9571–9574.
5o
5p
Me
Me
OH
O
OSiEt3
Ph
Ph
Ph
Ph
Ph
Ph
O
Ph
OH
OSiEt3
Me
2f
Ph
5
68%
Ph
5q
Me
OH
Ph
6. (a) Evans, D. A.; Wu, J.; Masse, C. E.; MacMillan, D. W. C. Org. Lett. 2002, 4,
3379–3382; (b) Zhang, Y.-H.; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 15038–15039; (c) Cardinal, D. B.; Guerin, B.; Guindon, Y. J. Org.
Chem. 2005, 70, 776–784; (d) Fujisawa, H.; Takahashi, E.; Mukaiyama, T. Chem.
Eur. J. 2006, 12, 5082–5093; (e) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 2764–2765; (f) Kokubo, M.; Ogawa, C.; Kobayashi, S. Angew. Chem., Int. Ed.
2008, 47, 6909–6911; (g) Mikami, K.; Kawakami, Y.; Akiyama, K.; Aikawa, K. J.
Am. Chem. Soc. 2007, 129, 12950–12951; (h) Clift, M. D.; Taylor, C. N.; Thomson,
R. J. Org. Lett. 2007, 9, 4667–4669.
7. (a) Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1, 2013–2016; (b) Ho, C. Y.;
Ohmiya, H.; Jamison, T. F. Angew. Chem., Int. Ed. 2008, 47, 1893–1895; (c)
Tsubouchi, A.; Enatsu, S.; Kanno, R.; Takeda, T. Angew. Chem., Int. Ed. 2010, 49,
7089–7091.
a
Reaction conditions: acylsilane 1a (1.0 equiv), epoxide 2 (1.2 equiv), t-BuLi
(1.2 equiv), TMEDA (6.0 equiv); 0.12 M in Et2O at ꢀ98 °C.
b
The stereoselectivity was determined by 1H NMR spectroscopy.
Isolated yield after purification by silica gel column chromatography.
c
SiEt3
SiEt3
R
O
-
-
R1
R2
R1
R2
O
R
vs
Ar
Ar
O
O
4-C1 (favorable)
4-C2 (unfavorable)
8. (a) Satoh, T. Chem. Rev. 1996, 96, 3303–3326; (b) Hodgson, D. M.; Gras, E.
Synthesis 2002, 1625–1642.
9. Patrocinio, A. F.; Moran, P. J. S. J. Braz. Chem. Soc. 2001, 12, 7–31.
10. (a) Reich, H. J.; Olson, R. E.; Clark, M. C. J. Am. Chem. Soc. 1980, 102, 1423–1424;
(b) Enda, J.; Kuwajima, I. J. Am. Chem. Soc. 1985, 107, 5495.
Ar
E
HO
R2
R1
Et3SiO
OH
Z
Et3SiO
Ar
R
R1 R2
R
6
11. (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77–84; (b) Moser, W. H. Tetrahedron
2001, 57, 2065–2084.
5
12. Although similar lithium alkoxide intermediate was also proposed in Hartel’s
preparation of b-hydroxy silyl enol ethers, the approach through addition of
Figure 1. Model analysis for the high E/Z-stereoselectivity.
silyllithium reagent to
a,b-epoxyketones does not work for generation of
1. m-CPBA,
toluene/NaHCO3 (aq), rt
tetrasubstituted silyl enol ethers, see: (a) Robertson, B. D.; Hartel, A. M.
Tetrahedron Lett. 2008, 49, 2088–2090; (b) Baker, H. K.; Hartel, A. M.
Tetrahedron Lett. 2009, 50, 4012–4014.
Ph
O
OH
Me
Et3SiO
OH
Ph
2. p-TsOH (cat),
THF, rt
13. Xin, L. H.; David, A. N.; Johnson, J. S. Org. Lett. 2002, 4, 2957–2960.
14. Although both THF and Et2O are ethereal solvents, THF is generally is believed
to be a stronger ligand than Et2O due to its lower steric requirements when
associating with alkyllithium (Lucht, B.L.; Collum, D.B. Acc. Chem. Res. 1999, 32,
1035–1042.). More insightful analysis is still needed to explain how these two
solvents affect our reaction to give quite different reactivities, especially when
6.0 equiv TMEDA is used as a bidentate ligand.
15. Although formation of the corresponding b-silyloxy ketone is possible for Z-
isomer 6 via O to O silyl transfer, no such compounds were observed after
isolation.
16. The relative stereochemistry of syn-7 was assigned by comparison with
literature results: (a) Clerici, A.; Porta, O. Synth. Commun. 1988, 18, 2281–2287;
(b) Clerici, A.; Porta, O. J. Org. Chem. 1989, 54, 3872–3878.
17. Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703–710.
18. The authors thank referees’ helpful suggestions for proposing this mechanism
model.
Ph OH
Ph Me
5o
7 (syn)
50%
anti
Ar
complete syn-selectivity
Et3SiO
Ph
Me
A 1,2
α'
O
O
H
Ph
α
H
O
O
H
α
O
O
H
vs
Et3SiO
H
O
O
Ph
Ph
Me
o
o
A 1,3
α ≈
α' ≈
60
120 ;
Ar
H
TS-I (severe A 1,3 strain)
TS-II (negligible A 1,2 strain)
Scheme 2.