Addition of TMS-substituted oxiranyl anions to acylsilanes. A highly stereoselective approach to tetrasubstituted (Z)-β-hydroxy-α-TMS silyl enol ethers

Article abstract of DOI:10.1021/ol200116f

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

Full text of DOI:10.1021/ol200116f

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1440–1443
Addition of TMS-Substituted Oxiranyl
Anions to Acylsilanes. A Highly
Stereoselective Approach to
Tetrasubstituted (Z)-β-Hydroxy-r-TMS
Silyl Enol Ethers
Zhenlei Song,*,†,‡,§ Leizhou Kui,† Xianwei Sun,† and Linjie Li†
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal
Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, 610041,
P. R. China, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041,
P. R. China, and Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
zhenleisong@scu.edu.cn
Received January 14, 2011
ABSTRACT
A highly stereoselective approach to novel tetrasubstituted (Z)-β-hydroxy-R-TMS silyl enol ethers is described. The reaction proceeds via a
sequential addition/[1,2]-Brook rearrangement/epoxide-opening process of TMS-substituted oxiranyl anions with acylsilanes.
Silyl enol ethers as important building blocks have
shown wide utility in many synthetic transformations.1
As the configuration of double bonds is crucial for high
facial selectivity, preparation of geometrically defined silyl
enol ethers has been in long-standing demand in organic
synthesis.2 Although good configurational control has
been achieved in the formation of di- and trisubstituted
silyl enol ethers, stereoselective accessibility of the acyclic
tetrasubstituted one, which possesses great potential in the
construction of various stereogenic quaternary carbon
centers,3 still remains quite a challenging task.4
Silyl-substituted oxiranyl anion 2, first introduced by
Eisch and Galle, has presented good nucleophilicity
to various electrophiles.5 However, to our knowledge,
no addition of this species to acylsilanes 16 has been
† Key Laboratory of Drug-Targeting of Education Ministry and Depart-
ment of Medicinal Chemistry, West China School of Pharmacy, Sichuan
University.
(3) (a) Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S.
J. Am. Chem. Soc. 1990, 112, 6679. (b) Morikawa, K.; Park, J.;
Andersson, P. G.; Hashiyama, T.; Sharpless, K. B. J. Am. Chem. Soc.
1993, 115, 8463. (c) Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1,
2013. (d) Cahard, D.; Audouard, C.; Plaquevent, J. C.; Roques, N. Org.
Lett. 2000, 2, 3699. (e) Evans, D. A.; Masse, C. E.; Wu, J. Org. Lett. 2002,
4, 3375. (f) Evans, D. A.; Wu, J.; Masse, C. E.; MacMillan, D. W. C. Org.
Lett. 2002, 4, 3379. (g) Zhang, Y.-H.; Shibatomi, K.; Yamamoto, H.
J. Am. Chem. Soc. 2004, 126, 15038. (h) Cardinal, D. B.; Guerin, B.;
Guindon, Y. J. Org. Chem. 2005, 70, 776. (i) Fujisawa, H.; Takahashi,
E.; Mukaiyama, T. Chem.;Eur. J. 2006, 12, 5082. (j) Corkey, B. K.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764. (k) Kokubo, M.; Ogawa,
C.; Kobayashi, S. Angew. Chem., Int. Ed. 2008, 47, 6909. (l) Mikami, K.;
Kawakami, Y.; Akiyama, K.; Aikawa, K. J. Am. Chem. Soc. 2007, 129,
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4667.
‡ State Key Laboratory of Biotherapy, Sichuan University.
§ Lanzhou University.
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r
10.1021/ol200116f
Published on Web 02/22/2011
2011 American Chemical Society

strain.9 Moreover, despite the fact that the competitive
[1,3]-Brook rearrangement has been used in other systems
as a dominant direct path to vinylsilane,10 formation of the
unstable oxiranyl anion 7 would render path b rather
unfavorable here. On the other hand, for the potential
stereoselectivity in [1,2]-Brook path a, we anticipated the
sterically hindered SiMe3 group might have some key
impacts on the conformation of siloxy carbanion 4, thus
providing reasonable configurational control during for-
mation of the double bond. Herein, we report the realization
of this sequential addition/[1,2]-Brook rearrangement/
epoxide-opening process.
Scheme 1
Table 1. Screening of Reaction Conditions
investigated. Additionally, despite the preparation of silyl
enol ethers from acysilanes having been reported,7 there
are only limited examples describing the synthesis of
tetrasubstituted one. We envisioned that such an addition
might initiate an efficient approach to tetrasubstituted
β-hydroxy-R-TMS silyl enol ethers 6 based on the con-
sideration of the following selectivity issues (Scheme 1).
First, for the potential two Csp3 to O silyl migration paths
of alkoxide intermediate 3, we presumed that the desired
[1,2]-Brook rearrangement8 (path a) should be energeti-
cally more favorable due to the relief of epoxide ring
entrya acylsilane (R3Si)
epoxide
solvent product yieldc
1
2
3
4
5
1a (Et3Si)
1a (Et3Si)
2a (Si = Me3Si) Et2O
6a
6a
6b
6c
6d
18%
63%
42%
23%
50%
2a (Si = Me3Si) pentane
1b (t-BuMe2Si) 2a (Si = Me3Si) pentane
1c (PhMe2Si)
1a (Et3Si)
2a (Si = Me3Si) pentane
2b (Si = Ph3Si) pentane
a Reaction conditions: acylsilane 1 (1.0 equiv), epoxide 2 (2.0 equiv),
t-BuLi (2.0 equiv), TMEDA (2.4 equiv); 0.12 M at -98 °C. b The
stereoselectivity was determined by 1H NMR spectroscopy, and the
configuration was determined by NOE experiments of 6a. c Isolated
yield after purification by silica gel column chromatography.
(4) (a) Ishii, A.; Kojima, J.; Mikami, K. Org. Lett. 1999, 1, 2013. (b)
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Braz. Chem. Soc. 2001, 12, 7. For recent representative studies on
acylsilanes, see:(b) Li, F. Q.; Zhong, S.; Lu, G.; Chan, A. S. C. Adv.
Synth. Catal. 2009, 351, 1955. (c) Tarr, J. C.; Johnson, J. S. Org. Lett.
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To establish feasibility, the reaction of acylsilane 1a11
with epoxide 2a was examined initially. Deprotonation of
2a by t-BuLi/TMEDA complex in Et2O at -98 °C and the
following addition to 1a afforded the desired silyl enol
ether 6a, although in 18% yield, as a single Z-diastereomer
(Table 1, entry 1). To our delight, using nonpolar solvents
such as pentane then led to a much higher yield (63%, entry 2).
The alkoxide intermediate 5 showed good stability even at
room temperature for several hours, and no further 1,3-
Csp2 to O silyl migration occurred.12 The result is consistent
with Takeda’s observation that such silyl migrations are
not active in less polar solvents due to the covalent
character of the Li-O bond.13 Acylsilanes containing the
more hindered t-BuMe2Si and PhMe2Si group proved to
(11) Xin, L. H.; David, A. N.; Johnson, J. S. Org. Lett. 2002, 4, 2957.
(12) Further1,3-Csp2 to O silyl migration of 6a or 6b and the following
alkylation with alkyl halides would potentially generate various tetra-
substituted silyl enol ethers. Investigations on this transformation are
still ongoing. For recent studies on Csp2 to O silyl migration, see: (a)
Moser, W. H.; Endsley, K. E.; Colyer, J. T. Org. Lett. 2000, 2, 718. (b)
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Org. Lett., Vol. 13, No. 6, 2011
1441

bulkiness appears to prohibit further addition partially
with giving 6d in the moderate 50% yield.
Table 2. Scope of Acylsilanes
With the optimal conditions identified, the scope of this
approach was examined. As summarized in Table 2, the reac-
tion is suitable for a wide range of aryl acylsilanes (entries
1-8). Compared to the one bearing an electron-deficient
phenyl group (entry 1 and 2), electron-rich phenyl acylsilanes
appear to undergo the process more efficiently with higher
yields (entries 5-7). Probably, the lower stability of siloxy
carbanion 4 attached to an electron-rich phenyl group might
accelerate the epoxide-opening step and thus make the over-
all process more facile. The steric effects of an aryl ring also
present certain impacts on the efficiency, as reaction of para-
methoxy phenyl acylsilane 1j gave a higher yield (70%, entry
7) than that of ortho-methoxy-substituted one 1k (55%,
entry 8). The process is tolerant of heterocyclic acysilanes
1l and 1m as well (entries 9 and 10). The potential deprotona-
tion of a heterocycle ring by an oxiranyl anion appeared
not to interfere with the course. However, reaction of un-
branched alkyl acylsilane 1n suffered a lot from the depro-
tonation at the R-position of the carbonyl group and led to a
very complex mixture (entry 11). A successful example was
achieved when 1o containing a sterically more hindered
PhMeCH group was employed (50%, entry 12). This success
also implies that relief of epoxide ring strain, to a large extent,
drives the [1,2]-Brook rearrangement since the Csp2-stabiliza-
tion of a silyloxy carbanion does not exist in this case.9b
With acylsilane 1j, multisubstituted epoxides were
further evaluated under the same condition. For cis-dis-
ubstituted epoxide 2c5c bearing an unbranched chain and
2d14 bearing a more bulky isopropyl group, reactions
proceeded quite smoothly to give the desired silyl enol
Table 3. Scope of TMS-Substituted Epoxides
a Reaction conditions: acylsilane 1 (1.0 equiv), epoxide 2a (2.0 equiv),
t-BuLi (2.0 equiv), TMEDA (2.4 equiv); 0.12 M in pentane at -98 °C.
b The stereoselectivity was determined by 1H NMR spectroscopy. c Iso-
lated yield after purification by silica gel column chromatography.
a Reaction conditions: acylsilane 1j (1.0 equiv), epoxide 2c-2e (2.0 equiv),
t-BuLi (2.0 equiv), TMEDA (2.4 equiv); 0.12 M in pentane at -98 °C.
b Deprotonation was performed at -116 °C for 3.0 h. c The stereoselectivity
was determined by 1H NMR spectroscopy. Ar = p-MeOPh. d Isolated yield
after purification by silica gel column chromatography.
be poor substrates in giving 6b and 6c, respectively, in 42%
and 23% yield (entries 3 and 4). Additionally, although the
electron-deficient triphenylsilyl group is expected to make
the oxiranyl anion of 2b more stable than that of 2a, its
ether 6q and 6r, respectively, in 92% and 64% yield (Table 3,
entries 1 and 2). Poor regioselectivity of deprotonation of
1442
Org. Lett., Vol. 13, No. 6, 2011

Scheme 2
Figure 1. Model analysis for the high Z/E-stereoselectivity.
epoxide 2e14 containing a cis-phenyl group was found to
give 6s and 6t as an inseparable mixture and in 50% yield
(entry 3). Additionally, no reaction occurred when trans-
disubstituted epoxide 2f5c was employed. Imaginably, the
formed trans-oxiranyl anion increases the difficulty of its
approach to bulky acylsilane (entry 4).15
Rationalization for the high Z/E selectivity is pro-
posed as follows. The initial addition is expected to
proceed through the favorable transition state 8, in
which the two bulky silyl groups are oriented anti to
each other to avoid the potential steric interaction, and
the two oxygen atoms are also oriented in such a setup to
minimize the dipole moment in the nonpolar solvent
(Figure 1). Thus, alkoxide 3 would be formed diaster-
eoselectively and further transformed via C to O-silyl
migration to siloxy carbanion 4 with retention of the
stereochemistry. Due to the fact that the sp3 hybridized
orbital containing a negative charge is aligned antiper-
iplanar to the cleaved C-O bond, 4 could undergo
smooth epoxide opening to provide the observed (Z)-
silyl enol ether 6 predominantly.16
two transition states TS-I and TS-II involving conflicting
A1,2 strain (between n-C8H17 and SiMe3 groups) and A1,3
strain (between n-C8H17 and aryl groups) would be expected
to give different facial selectivities. In fact, we found that
only the anti-isomer of β-hydroxy ketone 917 containing a
quaternary carbon center was formed in 95% yield. This
result suggests that A1,2 strain in TS-I is much stronger than
A1,3 strain in TS-II; thus TS-II would be more favorable in
leading to the complete anti-selectivity.
In conclusion we have described a sequential ad-
dition/[1,2]-Brook rearrangement/epoxide-opening pro-
cess of TMS-substituted oxiranyl anions with acylsilanes.
This route provides a direct and stereoselective entry to
novel tetrasubsitituted (Z)-β-hydroxy-R-TMS silyl enol
ethers. Further applications of these useful building blocks
are ongoing in our group.
Acknowledgment. This research was supported by the
NSFC (20802044, 21021001), the National Basic Research
Program of China (973 Program, 2010CB833200), and
RFDP (200806101091). The authors also thank Prof.
Richard P Hsung (UW, Madison) for invaluable discussions.
The stereochemical course of the electrophilic addi-
tion of silyl enol ether 6q was further examined with NBS
(Scheme 2). Based on the proposed formation of a
hydrogen bond between the hydroxyl group and NBS,
Supporting Information Available. Experimental proce-
dures and spectra data for products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(14) (a) Burford, C.; Cooke, F.; Roy, G.; Magnus, P. Tetrahedron
1983, 39, 867. (b) Burford, C.; Cooke, F.; Ehlinger, E.; Magnus, P.
J. Am. Chem. Soc. 1977, 99, 4536.
(15) Similar sluggish reactivity was also found in the reaction of
trisubstituted epoxide Me3SiCHOC(CH2)5, in which only the reduced
product of acylsilane 1j was obtained via a proposed successive SET
process.
(17) The stereochemistry of 9 was determined by NOE experiments
of R-bromo enone 10, which was obtained in 79% yield through a
Peterson olefination protocol of 9 with NaH in DMF.
(16) The authors thank referees’ helpful suggestions on proposing
this mechanism. In addition, despite formation of the corresponding β-
silyloxy ketone being possible for the E-isomer via O to O silyl transfer,
no such compounds were observed after isolation.
Org. Lett., Vol. 13, No. 6, 2011
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