Hydroxy-directed, fluoride-catalyzed epoxide hydrosilylation for the synthesis of 1,4-diols

Article abstract of DOI:10.1002/anie.201501729

Abstract A novel highly regioselective, fluoride-catalyzed hydrosilylation of β-hydroxy epoxides has been developed. The reaction is modular and applicable to the synthesis of a broad range of 1,4-diols. Fluoride is crucial for two reasons: First, it promotes the formation of a silyl ether (which contains a Si-H bond) and, second, it enables ring opening by an intramolecular S_N2 reaction through activation of the silane. The reaction can be performed under air. A modular, convergent, and stereoselective synthesis of 1,4-diols by epoxide hydrosilylation has been developed (see scheme). The reaction occurs under fluoride catalysis, is high yielding, highly regioselective, and can be carried out on a large scale.

Full text of DOI:10.1002/anie.201501729

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501729
German Edition: DOI: 10.1002/ange.201501729
Synthetic Methods
Hydroxy-Directed, Fluoride-Catalyzed Epoxide Hydrosilylation for the
Synthesis of 1,4-Diols**
Yong-Qiang Zhang, Nico Funken, Peter Winterscheid, and Andreas Gansꢀuer*
Dedicated to Prof. Reinhard Brꢁckner on the occasion of his 60th birthday
Abstract: A novel highly regioselective, fluoride-catalyzed
hydrosilylation of b-hydroxy epoxides has been developed.
The reaction is modular and applicable to the synthesis of
a broad range of 1,4-diols. Fluoride is crucial for two reasons:
First, it promotes the formation of a silyl ether (which contains
a Si-H bond) and, second, it enables ring opening by an
intramolecular SN2 reaction through activation of the silane.
The reaction can be performed under air.
Table 1: Initial optimization of the silane reduction.
Substrate Silane
TBAF [mol%] Conversion [%] Yield [%][a,b]
1a
1a
1a
1a
1a
PhSiH3
Ph2SiH2
PhSiH3
PhSiH3
PhSiH3
–
–
10
20
20
0
0
84
100
100
2a, 0
2a, 0
2a, 71
2a, 82
2a, 94[c]
91[d]
2a, 78
2a, 0
2a, 0
2b, 0
2c, 0
1,4-Diol units are important structural motifs in many
natural products and biologically active substances, such as
amphotericin B,[1] pladienolide B,[2] the feigresolides,[3] and
the schulzeines.[4] Therefore, a number of methods have been
devised for the synthesis of 1,4-diols.[5] The highest stereose-
lectivities were obtained for the rearrangement of 1,2-
disubstituted cyclobutenes to anti-1,4-diols,[6] the synthesis
of syn-(E)-1,4-diol-2-enes using allyl boronates,[7] and the
preparation of syn- and anti-(E)-1,4-diol-2-enes by a Cu-
catalyzed boration of an allylic epoxide.[8]
Here, we report a complementary synthetic approach to
1,4-diols that is based on an unprecedented highly regiose-
lective and hydroxy-directed silane reduction of b-hydroxy
epoxides. Thermodynamically, epoxide opening through
silane reduction is an attractive reaction because ring strain
1a
1a
1a
1b
1c
Ph2SiH2
(EtO)3SiH 20
PMHS
PhSiH3
PhSiH3
20
100
<5
<5
<5
<5
20
20
20
[a] Reaction conditions: substrate 0.5 mmol in THF (2.0 mL), TBAF
added as a 1.0m solution in THF, room temperature, 16 h. [b] Yield of
isolated product. [c] Reaction carried out on a 14.8 mmol scale with
enantiomerically pure substrate. [d] Reaction carried out on a 10 mmol
scale in an open flask under air.
À
À
is released and strong C H and Si O bonds are formed.
However, such reactions have remained virtually unex-
plored.[9] To the best of our knowledge, the only catalytic
reduction of epoxides involving silanes as terminal reductants
is a titanocene(III)-catalyzed process.[10,11] It features epox-
ide-derived radicals and titanocene(III) hydrides as key
intermediates.
Gratifyingly, the addition of tetrabutylammonium fluoride
(TBAF) induced a dramatic change. The reaction proceeds to
completion in 16 h with 20 mol% TBAF, and the desired 1,4-
diols can be obtained in good yield. No 1,3-diol could be
detected or isolated. PhSiH3 is superior to Ph2SiH2 in terms of
product purification. Other silanes, such as polymethylhydro-
siloxane (PMHS) or triethoxysilane [(EtO)3SiH] gave very
low conversion into products (< 5%). Even higher yields
were obtained (94%) when the reaction was carried out on
a gram scale (3.6 g of enantiomerically pure 1a, 14.8 mmol).
Furthermore, the reaction has also been performed under air
(2.2 g of racemic 1a, 10.0 mmol) in an open flask with an
almost identical yield (91%).
Our initial investigations on the synthesis of 1,4-diols are
summarized in Table 1. It is clear that PhSiH3 and Ph2SiH2
alone are not appropriate reagents for opening epoxide 1a.
Therefore, activation of the silane by a catalyst is necessary.
Fluoride salts are attractive in this respect because they have
been shown to induce the reduction of ketones by silanes.[12]
The addition of TBAF to the solution of 1a and PhSiH3 or
Ph2SiH2 results in a violent evolution of gas. This is not the
case with the O-methylated and O-benzylated 1b and 1c or
without TBAF. This finding suggests that the formation of
a silyl ether is mandatory for epoxide opening.
Based on these results, a plausible mechanism for the
fluoride-catalyzed hydroxy-directed epoxide opening was
developed (Scheme 1). Silylation of 1a with PhSiH3 in the
presence of TBAF gives the silyl ether A,[13] along with
evolution of H2. Ensuing binding of fluoride leads to the
formation of a pentavalent Si species B, which subsequently
[*] Dr. Y.-Q. Zhang, N. Funken, P. Winterscheid, Prof. Dr. A. Gansꢀuer
Kekulꢁ-Institut fꢂr Organische Chemie und Biochemie
Universitꢀt Bonn
Gerhard Domagk Strasse 1, 53121 Bonn (Germany)
E-mail: andreas.gansaeuer@uni-bonn.de
[**] We gratefully acknowledge support by the Alexander von Humboldt-
Stiftung (research fellowship for Y.-Q.Z.) and the DFG (SFB 813
“Chemistry at Spin Centers”).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501729.
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detected or isolated. The opening of the
monosubstituted epoxide 15 occurs with com-
plete regioselectivity at the more hindered
position, in agreement with our mechanistic
proposal. Furthermore, sensitive functional
groups, such as acetals of aldehydes and
ketones, are readily tolerated (19, 21). The
hydrosilylation of 17 with PhSiD3 affords the
1,4-diol 18D stereospecifically, with a deute-
rium incorporation of > 98% (entry 7). The
configuration was tentatively assigned by
assuming an intramolecular ring opening. An
additional stereocenter, as in 23, is readily
tolerated.
Scheme 1. Tentative mechanism of the fluoride-catalyzed epoxide opening.
Table 2: Regioselectivity of the epoxide opening of phenyl-substituted
substrates.
Entry Substrate
Products
Ratio Yield
5/6 [%]
1
2
76:24 74[a]
95:5 72[b]
Scheme 2. Reduction of 1a with hydride reagents (at À788C less than
5% conversion to products was observed).
undergoes the pivotal intramolecular hydride transfer that
opens the epoxide. The catalytic cycle is closed by formation
of D and release of fluoride. The 1,4-diol 2a is generated
through hydrolytic work-up.
3
4
96:4 68[a]
The high regioselectivity of the ring opening is a unique
feature of our system. Mixtures of 1,3- and 1,4-diols were
obtained with classic hydride reductants (Scheme 2).[14] Fur-
ther examples addressing the stereochemical issues of the
intramolecular SN2 reaction are summarized in Table 2.
Phenyl substitution was chosen to probe the importance
of the six-membered transition state for epoxide opening.
Nucleophilic substitution at a benzylic center usually results
in a substantial acceleration compared to alkyl-substituted
substrates.
96:4 82[a]
[a] Reaction conditions: substrate 0.5 mmol in THF (2.0 mL), PhSiH3
(2.0 mmol), TBAF added as a 1.0m solution in THF (0.1 mmol), room
temperature, 16 h. [b] TBAF (0.125 mmol) used, reflux, 24 h.
In our case, however, benzylic ring opening to the 1,3-diol
requires a seven-membered transition state. The 1,4-diols
were still formed with excellent regioselectivity (95:5 or 96:4)
from all the cis-b-hydroxy epoxides (Table 2, entries 2, 3, and
4). However, the regioselectivity of the ring opening of the
trans-epoxide (entry 1) was significantly lower (76:24), thus
indicating a substantial competition of ring opening via
a seven-membered transition state.
Some representative examples of the novel 1,4-diol
synthesis are summarized in Table 3. The examples show
that our method can be employed for the synthesis of 1,4-diols
with a wide range of substitution patterns, including syn- and
anti-1,4-diols. 1,4-Diols containing primary and tertiary alco-
hols can be readily prepared. Notably, ring opening was
regiospecific in all the cases examined: only 1,4-diols were
Scheme 3. Modular approach to syn-b-hydroxy epoxides.
The syn- and anti-b-hydroxy cis-epoxides can be prepared
in a convergent and highly modular manner (Scheme 3). The
[VO(acac)2]-catalyzed epoxidation of (Z)-homoallylic alco-
hols provides the syn-epoxides with high diastereoselectivi-
ty.[15a] The anti-epoxides can be obtained from these com-
pounds through Mitsunobu inversion.[16]
The homoallylic alcohols are easily synthesized by the
addition of alkynes to epoxides and a chemoselective and Z-
2
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Table 3: Epoxide opening for the synthesis of 1,4-diols.
diols is accessible from syn- and anti-b-hydroxy cis-epoxides
by our novel method.
The 1,4-diol 28 was also obtained as the sole product from
the n-alkyl-substituted trans-epoxide 27. This suggests that
alkyl-substituted trans-substituted b-hydroxy epoxides are
also interesting substrates for the synthesis of 1,4-diols.
However, since the [VO(acac)2]-catalyzed epoxidation of
secondary (E)-homoallylic alcohols proceeds with very low
diastereoselectivity,[15a] the necessary substrates for the 1,4-
diol synthesis cannot be easily prepared.
Entry Substrate
Product
Yield
[%]
1
81,[a] 83[a,d]
In conclusion, we have developed an unprecedented
fluoride-catalyzed, hydroxy-directed hydrosilylation of b-
hydroxy epoxides. The intramolecular ring opening through
hydride transfer occurs with very high regioselectivity and,
therefore, 1,4-diols are obtained exclusively or with very high
selectivity. The reaction can be performed on a gram scale in
an open flask under air without a significant effect on the
yield. Since the hydrosilylation tolerates a wide range of
functionality and the substrates can be prepared in a con-
vergent and modular manner, our novel method is broad in
scope and will be useful for the synthesis of diol and polyol
targets.
2
3
4
72[b]
91[b]
63[b]
5
6
78[a]
81[b]
Experimental Section
1a (2.24 g, 10 mmol, 1.0 equiv) as a 94:6 mixture of syn and anti
isomers, THF (20 mL), and PhSiH3 (4.9 mL, 40 mmol, 4.0 equiv) were
added to a 50 mL round bottom flask under air. TBAF (2.0 mL, 1.0m
in THF, 0.2 equiv) was then added dropwise over 40 min. During that
time, gas was evolved. The resulting mixture was stirred at room
temperature for 16 h and then diluted with THF (20 mL). Subse-
quently, NaOH solution (2.0m in H2O, 10 mL) was added dropwise
over 10 min. After stirring the mixture for 3 h at room temperature, it
was diluted with H2O (10 mL), and extracted with ethyl acetate (3 ꢀ
20 mL). The combined organic solutions were washed with brine,
dried over MgSO4, and the solvent was removed under reduced
pressure. Chromatography (SiO2, cyclohexane/ethyl acetate 60:40)
gave 2.04 g (9.1 mmol, 91%) of 2a as a 94:6 mixture of the anti and
syn isomers.
7
8
72[b,c]
81[a]
9
94[a]
Keywords: 1,4-diols · epoxide opening · fluoride catalysis ·
hydrosilylation · regioselectivity
10
70[b]
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Received: February 23, 2015
Revised: March 16, 2015
Published online: && &&, &&&&
4
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
Y.-Q. Zhang, N. Funken, P. Winterscheid,
A. Gansꢁuer*
&&&& — &&&&
Hydroxy-Directed, Fluoride-Catalyzed
Epoxide Hydrosilylation for the Synthesis
of 1,4-Diols
A modular, convergent, and stereoselec-
tive synthesis of 1,4-diols by epoxide
hydrosilylation has been developed (see
scheme). The reaction occurs under
fluoride catalysis, is high yielding, highly
regioselective, and can be carried out on
a large scale.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!