An efficient method for synthesising unsymmetrical silaketals: Substrates for ring-closing, including macrocycle-closing, metathesis

Article abstract of DOI:10.1039/b804769n

Diisopropylsilyl ethers were activated with N-bromosuccinimide, and reacted with a fluorous-tagged alcohol, to yield tethered substrates for ring-closing metathesis reactions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b804769n

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An efficient method for synthesising unsymmetrical silaketals: substrates for
ring-closing, including macrocycle-closing, metathesis†
Christopher Cordier,a,b Daniel Morton,a,b Stuart Leach,a,b Thomas Woodhall,a,b Catherine O’Leary-Steele,a,b
Stuart Warrinera,b and Adam Nelson*a,b
Received 19th March 2008, Accepted 20th March 2008
First published as an Advance Article on the web 10th April 2008
DOI: 10.1039/b804769n
Diisopropylsilyl ethers were activated with N-bromosuc-
cinimide, and reacted with a fluorous-tagged alcohol, to yield
tethered substrates for ring-closing metathesis reactions.
A number of methods2,4,5 have been developed for the selec-
tive synthesis of the required unsymmetrical silaketals. Usually,
one of the alcohols is reacted with an excess of a volatile
dichlorosilane.2a–b,4 Alternatively, reaction of the anion of one of
the alcohols with a dichlorosilane can give the monosubstituted
reagent needed to prepare selectively the unsymmetrical product.2c
In this communication, we describe an improved efficient and
selective method for preparing unsymmetrical silaketal substrates
for ring-closing (including macrocycle-closing) metathesis reac-
tions.
We required an efficient method for the formation of unsymmet-
rical silaketals from the fluorous-tagged alcohol6 6 (Scheme 2). The
key design features of the fluorous-tagged linker 6 are summarised
in Scheme 3. A fluorous tag was incorporated to facilitate the
purification by fluorous-solid phase extraction7 (F-SPE) of the
required silaketals 7 from excess reagents used. The linker 6 was
designed6 such that metathesis of the unsymmetrical silaketals (e.g.
7d) would release the required cyclic products (e.g. 9) from the
fluorous tag, thus facilitating purification by F-SPE. Subsequent
cyclisation of 10 (→ 11) would then regenerate the catalytically
active methylene complex.8
The use of temporary tethers between reactants is an extremely
valuable approach in synthetic organic chemistry.1 The approach
can promote selective reaction between the tethered components,
often under much milder conditions than the corresponding inter-
molecular process. Furthermore, reactions between the tethered
components often proceed with stereoselectivities that comple-
ment, or improve on, those observed in intermolecular reactions.
Silicon tethers can control the cross-metathesis of pairs of allylic
or homoallylic alcohols (e.g. 1 and 2, Scheme 1). After tethering
of the reactants (e.g. → 3), a ring-closing metathesis reaction gives
a cyclic silaketal; silaketal cleavage (e.g. 4 → 5) then yields the Z
isomer of net cross-metathesis of the components. The approach
has been used in target2 and library3 synthesis, for example in
the synthesis of attenol A,2a mucocin,2b and the epothilones.2c
Furthermore, tethering metathesis reactions can lead to long-
range diastereoselection.4
Scheme 2 Synthesis of fluorous-tagged unsymmetrical silaketals 7a–l.
See Fig. 1 for definitions of the R groups.
To start with, we investigated Malacria’s method for the forma-
tion and activation of diisopropylsilyl ethers (entry 1, Table 1).9
Hence the alcohol 12 was silylated, activated with NBS, and the
resulting bromosilane reacted with the fluorous-tagged alcohol 6.
Unfortunately, only a trace of the required silaketal was isolated,
and the fluorous-tagged alcohol was recovered in >98% yield.
We therefore re-investigated the activation of the racemic
diisopropylsilyl ether rac-13d with NBS. NBS was added to a
sample of the silyl ether 13d in CDCl3, and the reaction was
monitored by 500 MHz 1H NMR spectroscopy (see Fig. 2). Within
15 min, the silyl ether 13d had been consumed, and had been
converted cleanly into the corresponding bromosilane.
Scheme 1 Net Z-selective cross-metathesis of an allylic and a homoallylic
alcohol.
aSchool of Chemistry, University of Leeds, Leeds, UK, LS2 9JT.
E-mail: a.s.nelson@leeds.ac.uk; Fax: +44 (0)113 343 6565; Tel: +44
(0)113 343 6502
bAstbury Centre for Structural Molecular Biology, University of Leeds,
Leeds, UK LS2 9JT
† Electronic supplementary information (ESI) available: Full experimental
details and copies of NMR spectra for key compounds. See DOI:
10.1039/b804769n
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Table 1 Synthesis of fluorous-tagged silaketals 7a–l (Scheme 2)
Entry
Substrate
Methoda
Product
Yield (and purity) after F-SPE only (%)b
Yield of purified product (%)c
1
12d
A
B
B
C
C
C
C
C
D
C
C
C
C
C
C
ent-7g
7a
rac-7d
7a
7b
7c
rac-7d
7e
rac-7f
7g
rac-7h
rac-7i
rac-7j
rac-7k
7l
—
Tracee
—
56
—
—
—
56
—
—
—
54
59
32
64
—
2a
2b
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
13a
98 (65)f
—
rac-13d
13a
13b
13c
rac-13d
13e
rac-13f
13g
rac-13h
rac-13i
rac-13j
rac-13k
13l
94 (98)
>98 (98)
>98 (98)
—
55 (93)
>98 (76)
96 (85)
—
93 (67)
—
—
95 (>85g)
a Methods: A: (i) 12 (0.5 M), iPr2HSiCl (1 eq.), Et3N (1.1 eq.), DMAP (0.1 eq.), CH2Cl2, 0 ◦C → rt; (ii) NBS (1 eq.); (iii) 6 (1 eq.), Et3N (1.1 eq.), DMAP
(0.1 eq.), CH2Cl2, 0 ◦C → rt; B: (i) 13 (3.5 eq., 0.2 M), NBS (3 eq.), CH2Cl2, 0 ◦C → rt, 15 min; (ii) add to 6 (1 eq., 40 mM), Et3N (15 eq.), DMAP
(10 mol%), CH2Cl2, 0 ◦C → rt; (iii) F-SPE; C: (i) 13 (3.5 eq., 0.2 M), NBS (3 eq.), CH2Cl2, 0 ◦C → rt, 15 min; (ii) inverse addition of 6 (1 eq., 0.25 M),
DMAP (50 mol%), Et3N, 0 ◦C → rt; (iii) F-SPE; D: (i) 13 (5.5 eq., 0.2 M), NBS (5 eq.), CH2Cl2, 0 ◦C → rt; (ii) inverse addition of 6 (1 eq., 0.25 M),
DMAP (50 mol%), Et3N, 0 ◦C → rt; (iii) F-SPE. b Yield of product after F-SPE; the purity, determined by analytical HPLC, is given in parentheses.
c Yield of product after purification on FlorisilꢀR . d An alcohol was used as the substrate; method A involves the synthesis of the diisopropylsilyl ether
in situ. e The fluorous-tagged alcohol 6 was recovered in >98% yield. f In the absence of DMAP, an 86% yield of material with 56% purity was obtained.
g Determined by 500 MHz 1H NMR spectroscopy.
Scheme 3 Design of the fluorous-tagged linker 6 illustrated for the
proposed synthesis of the cyclic silaketal 9.
With a method for the activation of a diisopropylsilyl ether in
hand, we investigated the formation of unsymmetrical silaketals
from the silyl ethers 13a and 13d (entries 2a–b, Table 1). The
silyl ethers (3.5 eq., 0.2 M in CH2Cl2) were treated with NBS
(3 eq.) and, after 15 min, were added to a solution of the fluorous-
tagged alcohol 6 (1 eq., 40 mM) and DMAP (10 mol%) in CH2Cl2.
Unfortunately, neither of the reactions proceeded to completion:
in each case, following F-SPE, both the fluorous-tagged alcohol
6 and the required silaketal 7 were found in the fluorous fraction.
Although the silaketals could be purified by filtration through a
R
short pad of Florisilꢀ, the method was not sufficiently efficient for
Fig. 1 Substrates, including the diisopropylsilyl ethers HiPr2SiOR (13),
application in parallel synthesis.
used in this study.
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complete by TLC. Work-up involved treatment with P(CH2OH)3,
Et3N and silica, filtration through Celite,10 and evaporation. The
products of the metathesis reactions described in Table 2 are shown
in Fig. 3.
Treatment of the silaketal 7d with the catalyst 8 triggered
the release of the stable cyclic silaketal 9 from the fluorous
tag (entry 1, Table 2). In the case of 7h, however, both the
expected silaketal 16 and the corresponding diol 15 were obtained
after chromatography (entry 3a). In later experiments, therefore,
the crude cyclic silaketals were treated with HF·pyridine before
purification. Using this protocol, the silaketals 7f, 7h and 7l yielded
the diols 14, 15 and 18 (entries 2, 3b and 5).
Fig. 2 Activation of the diisopropylsilyl ether rac-13d. 500 MHz 1H NMR
spectra of the silyl ether 13d in CDCl3 (a) before treatment with NBS (SiH:
d = 4.2 ppm); and (b) 15 min after treatment with NBS.
We increased the efficiency of the transformation by developing
a protocol in which the concentration of the fluorous-tagged
alcohol 6 was higher (entries 3a–l, Table 1). The diisopropylsilyl
ethers 13a–l were prepared by silylation of the corresponding
alcohols, and were used without further purification. The modified
procedure involved inverse addition of a solution of the fluorous-
tagged alcohol 6 and DMAP in triethylamine to a solution of the
activated silyl ether in CH2Cl2. Following evaporation, addition of
pentane and filtration, the crude reaction mixtures were dissolved
in DMF, purified by F-SPE, and the fluorous fractions analysed,
usually by HPLC. In some cases, the unsymmetrical silaketal
R
products 7 were purified by filtration through a Florisilꢀ pad.
The reactions of the silyl ethers 13a–c, derived from unhin-
dered primary alcohols, were highly efficient: the unsymmetrical
silaketals 7a–c were obtained in high yield (entries 3a–c, Table 1).
With the silyl ethers 13d–g, derived from secondary alcohols, good
yields of the corresponding silaketals 7d–g were obtained (entries
3d–f). We investigated more hindered bridged (13h–j) and cyclic
substrates (13k–l) (entries 3h–l). Even when the reaction was not
highly efficient, reasonable yields of the required silaketals were
Fig. 3 Products of the ring-closing metathesis reactions.
For the substrates 7d, 7f, 7h and 7l, the initial metathesis
product was a seven- to nine-membered cyclic silaketal. Similar
ring-closing metatheses are well known.2–4 However, in the case of
the silaketal 7j, the outcome of the metathesis reaction was remark-
able: the diol 17 was isolated as a 55 : 45 E : Z mixture (entry 4).
The fate of 7j is consistent with the macrocycle-closing metathesis
reaction (→ 20) which is described in Scheme 4. Cyclisation of
19 to form a six-membered ring was not observed: presumably
six-membered ring formation is reversible, and macrocyclisation
(19 → 20) allows more efficient release from the fluorous
tag.
R
obtained after filtration through a Florisilꢀ pad.
The chemoselectivity of our method for the activation of
diisopropylsilyl ethers is remarkable. The silyl ethers 13a–l contain
a range of functional groups that may react with NBS: alkenes,
including strained substrates (13h–i); electron-rich aromatic rings
(13d) and an alkyne (13a). We never observed any brominated
products.
The ring-closing metatheses of five unsymmetrical fluorous-
tagged silaketals (7d, 7f, 7h, 7j and 7l) were investigated (Table 2).
The silaketals 7 were treated with 3 mol% portions of Grubbs’
first generation catalyst (8) until the reactions were judged to be
In summary, we have developed an efficient method for the form-
ation of unsymmetrical silaketals, which we applied in the synthesis
of the fluorous-tagged metathesis substrates 7a–l. The method is
Table 2 Ring-closing metathesis reactions of fluorous-tagged silaketals 7
Entry
Substrate
Methoda
Catalystb (mol%)
Time/days
Product (yieldc)
1
2
3a
3b
4
7d
7f
7h
7h
7j
A
B
A
B
B
B
8 (3 × 3)
8 (5 × 3)
8 (4 × 3)
8 (4 × 3)
8 (2 × 3)
8 (8 × 3)
0.3
7
1.1
1
0.3
13
9 (71%)
14 (19%)
15 (8%), 16 (23%)d
15 (21%)d
17 (35%)d,e
18 (21%)
5
7l
a Methods: A: (i) 7 (1 mM), CH2Cl2, 45 ◦C; (ii) P(CH2OH)3 then Et3N; (iii) F-SPE; B: (i) 7 (1 mM), CH2Cl2, 45 ◦C; (ii) P(CH2OH)3 then Et3N;
(iii) F-SPE; (iv) HF·pyridine then Me3SiOMe. b The catalyst was added at regular intervals in 3 mol% portions. c Yield of products (see Fig. 3) purified
by column chromatography. d The product was purified by preparative HPLC. e 55 : 45 E : Z isomers mixture.
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Acknowledgements
We thank the Wellcome Trust, EPSRC, the University of Leeds and
GSK for funding, James Titchmarsh for HPLC analyses, Simon
Barrett for NMR analysis, and Dr Gordon McKiernan for helpful
discussions.
Notes and references
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Scheme 4 Macrocycle-closing metathesis of the silaketal 7j.
remarkably chemoselective, and can be used to prepare silaketals
with alkenyl and electron-rich aromatic substituents. We also
observed a macrocycle-closing metathesis reaction that proceeded
via a 13-membered cyclic silaketal. Through the use of a temporary
silicon connection, therefore, it was possible to effect the net
cross-metathesis of an unsaturated alcohol in which the reacting
alkene was rather remote from the tether. Similar macrocycle-
closing metathesis reactions may be useful in the synthesis of
other compounds in which an alkene is remote from a potential
tethering point.
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