Diastereocontrol in open-chain nucleophilic attack on a double bond adjacent to a stereogenic centre carrying a silyl group

Article abstract of DOI:10.1039/b305882d

The bis[dimethyl(phenyl)silyl]cuprate reagent introduces a silyl group to the β-position of three α,β-unsaturated esters: methyl Z-4-dimethyl(phenyl)silylpent-2-enoate 11, and methyl Z- and E-(1′-dimethylphenylsilylbenzyl)but-2-enoates 14 and 15, diastere

Full text of DOI:10.1039/b305882d

View Article Online / Journal Homepage / Table of Contents for this issue
Diastereocontrol in open-chain nucleophilic attack on a double
bond adjacent to a stereogenic centre carrying a silyl group
Mark S. Betson, Ian Fleming* and Jacqueline V. A. Ouzman
Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: if10000@cam.ac.uk; Fax: ϩ44 (0)1223 336362; Tel: ϩ44 (0)1223 336372
Received 23rd May 2003, Accepted 15th September 2003
First published as an Advance Article on the web 6th October 2003
The bis[dimethyl(phenyl)silyl]cuprate reagent introduces a silyl group to the β-position of three α,β-unsaturated
esters: methyl Z-4-dimethyl(phenyl)silylpent-2-enoate 11, and methyl Z- and E-(1Ј-dimethylphenylsilylbenzyl)but-2-
enoates 14 and 15, diastereoselectively in the unexpected sense, syn to the silyl group in the conformation in which
the hydrogen atom is ‘inside’. The selectivity is low (58 : 42) in the first case 11, where the nucleophilic attack is
adjacent to the stereogenic centre carrying the silyl group, and moderate (72 : 28) for both Z- and E-α,β-unsaturated
esters 14 and 15, where the nucleophilic attack is at the other end of the double bond from the stereogenic centre.
It is conceivable that nucleophilic attack actually takes place in a conformation in which the donor substituent,
the silicon–carbon bond, is out of conjugation with the double bond.
Introduction
Diastereocontrol in electrophilic attack on a C᎐C bond adjacent
᎐
to a stereogenic centre carrying a silyl group is well established
to take place in the sense 1. Evidence comes from such disparate
reactions as the SE2Ј reaction of cationic electrophiles with
allylsilanes,1 the hydroboration of allylsilanes,2 and the alkyl-
ation of enolates derived from β-silyl esters.3 The frequently
high levels of diastereoselectivity are explained by the like-
lihood that steric and electronic effects reinforce each other in
the sense 1, whether the new bond is forming at C-2 or C-3 or
both, but it is not clear whether it is the steric or the electronic
effect that is dominant. The corresponding nucleophilic attack
2 is much less well studied, although it is fairly well known for
attack on a carbonyl group, which takes place in the sense 3.4
Furthermore, although the steric effect ought to be in the same
sense as for electrophilic attack, from below in the general sense
2, there is no agreed way of predicting the electronic effect on
the sense of attack, nor any certainty that it would be the same
at C-2 as at C-3. We are aware of three pieces of work on this
subject. In the first place, Lindeman has shown that nucleo-
philic attack on the intermediate derived from the acetal 4 takes
place predominantly from above (92 : 8), anti to the silyl group,
as drawn, and by way of explanation he suggests the obvious
conformation 5, which is in agreement with a straightforward
steric effect.5 His results have more recently been augmented by
those of Rychnovsky, who used allylsilanes as the nucleophiles.6
Using a more rigid system, described in the first paper of this
series,7 we have shown that a dialkylcuprate adds predomin-
antly (96 : 4) to the enone 6 from above, as drawn, again anti to
the silyl group, and have suggested that the silyl group, held
axially in the cyclohexanone ring, substantially blocks the
lower surface. Finally, in some Ireland–Claisen rearrangements
described in the immediately preceding paper,8 we have again
seen attack anti to the silyl group, whether the electronic bias
was that of nucleophilic attack 7 (98 : 2) or electrophilic attack
8 (86 : 14), where it was notable that the higher of the ratios of
diastereoisomers was in the nucleophilic attack series 7.
The Lindeman and Rychnovsky work was not on an alkene,
and our own work, whether with the rigid cyclic starting
material 6 or possessed of a cyclic transition structure 7, was
not simply on open-chain reactions. We therefore sought an
example of nucleophilic attack on an alkene in the sense 2, one
for open-chain attack at C-2 and another for open-chain attack
at C-3, and report our results for the first time here. In both
cases we have used a silylcuprate addition to an α,β-unsaturated
ester, since the silylcuprate gave us a reaction taking place under
relatively mild conditions, and, at the same time, gave us a
handle with which to prove the relative configuration of some
of the products. We are well aware that with only one type of
reaction, one nucleophile and only two types of substrate, we
cannot be confident that our results, unexpected as they proved
to be, represent a general pattern.
Results and discussion
Our substrates were the α,β-unsaturated esters 11, 14 and 15,
which we prepared by the unexceptional routes shown in
Scheme 1, where the ester 11 was described in the immediately
preceding paper, and the alcohols 12 and 13 were known from
earlier work.9
The conjugate addition reaction with the first substrate 11
gave both possible diastereoisomers 16 and 17 in a disappointing
ratio of 58 : 42 (Scheme 2). We assigned relative configuration
to these compounds from the very different coupling constants
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4017

View Article Online
Scheme 1 Reagents: i, BuLi; ii, ClCO2Me; iii, H2, Pd/BaSO4; iv,
PhMe2SiZnEt2Li; v, MeCHO; vi, MsCl, Et3N; vii, DBU.
Scheme 3 Reagents: i, (PhMe2Si)2CuLiؒLiCN; ii, NH4Cl, H2O.
the conjugate addition took place in the same stereochemical
sense for both isomers—either both were attacked predomin-
antly from the top surface as drawn, or both from the bottom.
This analysis was supported by the result of a treatment with
tetrabutylammonium fluoride (TBAF), which selectively
removed the benzylic silyl group (Scheme 4). A mixture con-
sisting of B, C and D in ratios of 46 : 51 : 3 gave two esters in
essentially quantitative yield in a ratio of 55 : 45, which was the
same whether the reaction was stopped after 5 minutes or left
overnight.
Scheme 2 Reagents: i, (PhMe2Si) 2CuLiؒLiCN; ii, NH4Cl, H2O.
between the protons on C-3 and C-4, 1.1 Hz for the major
product and 6.7 Hz for the minor. A standard molecular model-
ling calculation assessing a Boltzmann distribution of the low-
est-energy conformations suggested that the coupling constant
for the isomer 16 would be 0.6 Hz and for its isomer 17 6.0 Hz.
These are so close to the experimental values, and so different
from each other, that we can be reasonably confident of the
assignment. We chose a cis double bond in the substrate 11 to
minimise any ambiguity about the conformation 37 that will be
the most populated. Insofar as it has any significance, the major
isomer is not the one anyone would have expected, since it
corresponds to attack syn to the silyl group in this conform-
ation. Whatever the explanation, the most important result is
that the degree of diastereoselectivity is low, in contrast to
cuprate additions in the literature, including silylcuprates,
in which the substituents on the stereogenic centre were differ-
entiated either by having an electronegative substituent10,11 or
simply by steric effects.12
Conjugate addition to the second substrates, 14 and 15,
followed by protonation of the intermediate enolates 18 and 19,
can give four diastereoisomeric products 20, 21, 22 and 23
(Scheme 3). All four were detectable, using distinctive signals in
1H-NMR spectra, but they were not all easily separable. Before
we were able to assign the relative configurations to them
shown in Scheme 3, we labelled the four A, B, C and D, in order
of elution on chromatography. The isomers A and D were
separable, free of the other isomers, but the isomers B and C
were only obtained as a mixture.
The conjugate addition to the Z-ester 14 gave the isomers B
and C as the major products. The ratios were much the same
whatever proton source was used to quench the reaction
medium, and averaged over the seven different runs as 7 : 36 : 36
: 21. The conjugate addition to the E-ester 15, on the other
hand, gave the isomers A and D as the major products with
ratios A : B : C : D of 27 : 14 : 13 : 45. It therefore seemed to be
likely that the conjugate addition to the ester 14 was giving
predominantly one enolate 18 or 19, and that conjugate
addition to the ester 15 was giving predominantly the other
enolate. The isomers A and D would then differ from each other
only in the stereocentre adjacent to the methoxycarbonyl group,
and similarly for the isomers B and C. If this is the case, then
Scheme 4 Reagent: i, TBAF
Silyl-to-hydroxy conversion13 of the isomer A using mercuric
acetate in peracetic acid gave a diol 26, which was identical to
the diol prepared by silyl-to-hydroxy conversion from the ester
13. Furthermore, the acetonide 27 derived from this diol had
coupling constants and nuclear Overhauser enhancements (see
Experimental) consistent with the methyl and phenyl groups
being equatorial and the ester group axial as illustrated in
Scheme 5. A similar attempt at silyl-to-hydroxy conversion of
the isomer D using mercuric acetate in peracetic acid did not go
to completion, and we isolated a disiloxane 28, in which both
phenyl groups had been removed from the silicon atoms, but the
oxidation step had not taken place. The triplet (J 12.5 Hz) for
the proton next to the ester group indicated that the ester,
phenyl and methyl groups were all trans and all equatorial. On
the other hand, silyl-to-hydroxy conversion using potassium
bromide in peracetic acid buffered with sodium acetate gave
a known diol 29, which gave a known acetonide 30.14 This
compound also had coupling constants and nuclear Overhauser
enhancements (see Experimental) consistent with the all-
equatorial structure. Thus the isomers A and D differed, as we
had deduced earlier, only in the relative configuration at the
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4018

View Article Online
likely that isomer B had the structure 21 and that isomer C had
the structure 22. This was confirmed when chromatography
on yet another occasion gave us a 14 : 86 mixture of the
isomers B and D, unusually free of the isomer C. Silyl-to-
hydroxy conversion of this mixture failed again to go to
completion, but gave the two cyclic disiloxanes 33 and 28 in
the same ratio.
The configurations of the esters 12 and 13 played an import-
ant part in clinching the assignment of configuration to the
diols 26 and 31, and hence to the esters 20 and 21. To make sure
that we were not being misled by a false assignment to the aldol
products 12 and 13, we confirmed the relative configuration
for the two critical stereogenic centres C-2 and C-3 by the
1
sequence of reactions in Scheme 7. The H-NMR spectra of
the acetonides 35 and 36 showed double quartets for the
methine proton adjacent to the methyl group with coupling
constants of 3.5 and 7 for the former, indicating that the methyl
group was axial, and 9.5 and 7 for the latter, indicating that the
methyl group was equatorial.
Scheme 5 Reagents: i, Hg(OAc)2, AcOOH; ii, Me2C(MeO)2, TsOH,
DMF; iii, KBr, AcOOH, NaOAc.
protonation site, and we can assign to them the structures 20
and 23, respectively.
Silyl-to-hydroxy conversion of an approximately 50 : 50
mixture of the isomers B and C gave in one run only the known
diol 3114 (Scheme 6), which was identical to a sample obtained
by silyl-to-hydroxy conversion of the ester 12. In addition, we
converted the diol from both sources into its acetonide 32,
which is also a known compound14 and which showed coupling
constants and nuclear Overhauser enhancements consistent
with a chair conformation having the phenyl group axial,
confirming that either B or C has the structure 21. On
another occasion, starting with a 29 : 71 mixture of B and C,
an incomplete silyl-to-hydroxy conversion gave two cyclic
disiloxanes 33 and 34 in the same ratio in 52% yield. The minor
product had coupling constants and nuclear Overhauser
enhancements consistent with a conformation 33 having the
phenyl group axial, and the major product had coupling con-
stants consistent with a conformation 34 having the methyl
group axial and the other two groups equatorial. It seemed
Scheme 7 Reagents: i, LiAlH4, Et2O; ii, Me2C(MeO)2, TsOH, DMF.
The remarkable conclusion is that the conjugate addition has
taken place predominantly syn to the silyl group in both the
Z-ester 14 and the E-ester 15, with a syn : anti ratio of 72 : 28
for both isomers. Against all expectation, syn attack is
apparently preferred both adjacent to the stereogenic centre 37
(C-2 in 2), and at the other end of the double bond 38 and 39
(C-3 in 2) (Scheme 8).
Scheme 8
It is known that alkyl cuprates have two steps influencing the
stereochemistry—a reversible coordination step and a copper–
carbon bond-forming step.11 If silylcupration is similar, we
cannot be confident that we know at what stage stereochemistry
is being determined in these reactions. Also, we cannot be
confident in these open-chain systems of the conformation
at the time of reaction—with the Curtin–Hammett principle
making it necessary to know both relative energies and relative
reactivities before predictions can be made. The only comment
that is perhaps worth adding is to recall the “inside alkoxy
effect”,15 which is seen when some electrophilic reagents are
attacking a double bond with an oxygen substituent at an
Scheme 6 Reagents: i, Hg(OAc)2, AcOOH; ii, Me2C(MeO)2, TsOH,
DMF; iii, HBF4, Et2O.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4019

View Article Online
adjacent stereogenic centre—electrophilic attack can be
expected to be faster when the O—C bond is not conjugated to
the double bond. In our case, nucleophilic attack may be faster
when the Si—C bond is not conjugated to the double bond, as
in the drawings 40–42 in the lower part of Scheme 8. To be
consistent with the sense of attack that we see, this looks like an
“outside-silicon effect”, but whether our results here are special
cases or not remains to be seen. A referee pointed out that the
outside silicon in the structures 41 and 42 might even be co-
ordinating to the methoxycarbonyl group, making it a less
unlikely and slightly activated conformation. This type of
coordination between a weak Lewis base and a weak Lewis acid
is detectable in X-ray crystal structures, but there is almost
no evidence for it in solution.16 It must be very weak, and sadly
it cannot be invoked to explain the result illustrated in the
drawing 37.
(OH), 2949 (CH), 1732 (CO), 1249 (SiMe) and 1112 (SiPh);
δH(400 MHz; CDCl3) 7.38–7.28 (5H, m, SiPh), 7.19 (2 H, t,
J 7.6, m-PhH), 7.10 (1 H, t, J 7.3, p-PhH), 6.91 (2 H, d, J 7.7,
o-PhH), 3.83 (1 H, dq, J 5.2 and 6.4, CHOH), 3.44 (3 H, s,
OMe), 3.27 (1 H, dd, J 12.4 and 5.0, CHCO2Me), 2.67 (1 H, d,
J 12.4, PhCH ), 1.2 (3 H, d, J 6.4, MeCH), 0.22 (3H, s, SiMeA-
MeB) and 0.13 (3 H, s, SiMeAMeB); δC(125 MHz, CDCl3)
173.5ϩ, 139.8ϩ, 136.7ϩ, 134.4Ϫ, 129.1Ϫ, 128.7Ϫ, 128.3Ϫ,
127.5Ϫ, 125.3Ϫ, 68.0Ϫ, 51.8Ϫ, 51.4Ϫ, 35.9Ϫ, 17.7Ϫ, Ϫ2.9Ϫ
and Ϫ4.5Ϫ; m/z (ESI) 365 (100%, MNaϩ)(Found MNaϩ,
365.1557, C20H26O3Si requires M ϩ Na, 365.1549), and the
minor isomer 13 (1.1 g, 26%) as a colourless oil: Rf(light petrol-
eum–EtOAc, 9 : 1) 0.05; δH(400 MHz; CDCl3) 7.41–7.26 (5H,
m, SiPh), 7.20 (2H, t, J 6.6, m-PhH), 6.97 (2 H, d, J 7.6, p-PhH),
3.55 (1 H, ddq, J 10.1, 2.6 and 6.5, CHOH), 3.33 (3 H, s, OMe),
2.99 (1 H, d, J 12.6, PhCH ), 2.88 (1 H, dd, J 12.6 and 2.6,
CHCO2Me), 2.50 (1 H, d, J 10.1 OH), 1.02 (3 H, d, J 6.6
MeCH), 0.30 (3 H, s, SiMeAMeB) and 0.04 (3 H, s, SiMeAMeB);
δC(125 MHz, CDCl3) 174.8ϩ, 140.1ϩ, 136.9ϩ, 134.3Ϫ, 129.4Ϫ,
128.8Ϫ, 128.4Ϫ, 127.5Ϫ, 125.3Ϫ, 65.5Ϫ, 51.8Ϫ, 51.2Ϫ, 32.3Ϫ,
21.8Ϫ, Ϫ2.5Ϫ and Ϫ5.2Ϫ; m/z (ESI) 365 (MNaϩ,
100%)(Found MNaϩ, 365.1544).
Experimental
General
Infrared spectra were recorded on a Perkin–Elmer 1600 infra-
red spectrophotometer and wave numbers measured relative to
polystyrene (1603 cmϪ1), using sodium chloride plates or
Methyl (2RS,3SR)-2-[1ЈRS-dimethyl(phenyl)silylbenzyl]-3-
methanesulfonyloxybutanoate
1
sodium chloride solution cells (0.1 mm path length). H- and
13C-NMR spectra were recorded on Bruker NMR spectro-
meters (AM 400, AC 250). Chemical shifts were measured
relative to tetramethylsilane (δ 0.00) or chloroform (δ 7.26) as
internal standards. The coupling constant J is expressed in
Hertz (Hz) and reported as observed. In 13C attached proton
test (APT) spectra, ϩ denotes a signal in the same direction as
the solvent signal. Mass spectra were recorded on AE1 MS89,
Kratos MS50 or HP5988A spectrometers. Flash column
chromatography was carried out using Merck Kieselgel 60
(230–400 mesh ASTM). Thin layer chromatography (TLC)
was performed on glass plates coated to a thickness of 1 mm
with Kieselgel 60 PF254. Tetrahydrofuran (THF) and ether
were freshly distilled from lithium aluminium hydride under
argon. Dichloromethane and toluene were freshly distilled
from calcium hydride under argon. Light petroleum refers to
the fraction boiling between 40 ЊC and 60 ЊC. Other solvents
and reagents where appropriate were purified before use.
Organolithium reagents were titrated using the method of
Gilman.17 Modelling calculations were carried out using the
Macromodel programme (version 5.5),18 applying the Altona
equation.19
The ester 12 (1.99 g, 5.82 mmol), methanesulfonyl chloride
(0.68 cm3, 8.73 mmol) and triethylamine (1.21 cm3, 8.73 mmol)
were stirred in THF (60 cm3) at 0 ЊC for 1.5 h, and then allowed
to warm to room temperature and stirred for 1 h. Water (20
cm3) was added and the mixture was diluted with dichloro-
methane (50 cm3). The aqueous phase was extracted with di-
chloromethane (3 × 30 cm3), and the combined organic extracts
were washed with aqueous citric acid solution (10% w/v, 50
cm3), dried (Na2SO4), filtered and concentrated at reduced pres-
sure to yield the mesylate (2.40 g, 98%) as a crystalline solid;
νmax(solid)/cmϪ1 2954 (CH), 1732 (C᎐O) and 1597 (Ar); δ (400
MHz; CDCl3) 7.36–7.27 (5 H, m, Ar), 7.23–7.19 (2 H, m, Ar),
7.12 (1 H, tt, 7.5 and 1.5, p-ArH ), 6.91 (2 H, m, o-ArH ), 4.76
(1 H, dq, J 6.5 and 5.0, MeCHO), 3.61 (1 H, m, CHCO2Me).
3.40 (3 H, s, CO2Me), 2.88 (3 H, s, OSO2Me), 2.63 (1 H, d,
J 13.0, PhCH ), 1.27 (3 H, d, J 6.5, MeCHO), 0.25 (3 H, s,
SiMeAMeB) and 0.09 (3 H, s, SiMeAMeB); δC(100 MHz; CDCl3)
171.70, 134.30, 132.92, 129.27, 129.19, 128.54, 128.41, 127.64,
127.48, 125.69, 78.60, 51.50, 49.01, 38.45, 35.91, 14.96, Ϫ3.27
and Ϫ5.08; m/z (ESI) 443 (MNaϩ, 70%)(Found MNaϩ,
443.1341. C21H28O5SSi requires M ϩ Naϩ, 443.1324).
᎐
H
Methyl (2RS,3SR)-2-[1ЈRS-dimethyl(phenyl)silylbenzyl]-
3-hydroxybutanoate 12 and methyl (2RS,3RS )-2-[1ЈRS-
dimethyl(phenyl)silylbenzyl]-3-hydroxybutanoate 13
Methyl (2RS,3RS )-2-[1ЈRS-dimethyl(phenyl)silylbenzyl]-3-
methanesulfonyloxybutanoate
This reaction is based on the method of Kilburn,9 but using the
zincate20 rather than the cuprate. Dimethyl(phenyl)silyllithium
(1.2 mol dmϪ3 in THF, 14.3 cm3, 17.2 mmol) was added drop-
wise to diethylzinc (1.0 mol dmϪ3 in hexane, 17.2 cm3, 17.2
mmol) in THF (60 cm3) at 0 ЊC under nitrogen, and the mixture
stirred for 10 min before being cooled to Ϫ78 ЊC. Methyl
cinnamate (2.0 g, 12.3 mmol) in THF (5 cm3) was added drop-
wise and the solution stirred for 10 min, during which time the
solution turned from a dark red to a dark brown colour. Acet-
aldehyde (1.0 cm3, 17.2 mmol) was added and the mixture
stirred at Ϫ78 ЊC for 10 min before being allowed to warm
slowly to room temperature. Water (10 cm3) was cautiously
added, followed by dilute aqueous hydrochloric acid (10 cm3)
and ether (20 cm3). The layers were separated and the aqueous
layer washed with ether (3 × 20 cm3). The organic layers were
combined and washed with water (2 × 20 cm3), brine (20 cm3),
dried (MgSO4) and solvents removed under reduced pressure.
The residue was chromatographed (SiO2, light petroleum–
EtOAc, 8 : 2) to give the major product 129 (2.95 g, 70%);
Rf(light petroleum–EtOAc, 9 : 1) 0.02; νmax(film)/cmϪ1 3434
The ester 13 (350 mg, 1.02 mmol) was similarly converted into
the mesylate (429 mg, 100%) as a colourless oil; νmax(film)/cmϪ1
2954 (CH), 1746 (C᎐O) and 1599 (Ar); δ (400 MHz; CDCl )
᎐
H
3
7.37–7.28 (5 H, m, Ar), 7.25–7.19 (2 H, m, Ar), 7.12 (1 H, tt, 7.5
and 1.5, p-ArH ), 6.91 (2 H, m, o-ArH ), 4.71 (1 H, dq, J 6.5 and
3.0, MeCH ), 3.39 (3 H, s, CO2Me), 3.09 (1 H, dd, J 12.0 and
4.0, CHCO2Me). 2.90 (1 H, d, J 12.0, PhCH ), 2.73 (3 H, s,
OSO2Me), 1.28 (3 H, d, J 6.5, MeCH), 0.23 (3 H, s, SiMeAMeB)
and 0.12 (3 H, s, SiMeAMeB); δC(100 MHz; CDCl3) 171.33,
139.15, 136.32, 134.32, 129.11, 128.76, 128.31, 127.41, 125.62,
77.41, 51.81, 51.37, 38.63, 34.96, 20.06, Ϫ2.74 and Ϫ4.59; m/z
(ESI) 443 (MNaϩ, 100%)(Found MNaϩ, 443.1325. C21H28SiSO5
requires M ϩ Na, 443.1324).
Methyl (Z )-(1ЈRS-dimethylphenylsilylbenzyl)but-2-enoate 14
The mesylate (1.00 g, 2.381 mmol) derived from the alcohol 12
and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 cm3, 6.7 mmol)
were refluxed in hexane (15 cm3) for 3 h and then stirred at room
temperature for 14 h. Water (10 cm3) was added and the organic
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4020

View Article Online
phase was separated, dried (MgSO4), filtered and concentrated
under reduced pressure. Flash column chromatography (SiO2,
hexane) gave the ester 14 (733 mg, 95%) as an oil; Rf(hexane)
Conjugate additions of the silylcuprate reagent to the
ꢀ,ꢁ-unsaturated esters 14 and 15
0.27; νmax(film)/cmϪ1 2950 (CH), 1710 (ester C᎐O) and 1492
Dimethyl(phenyl)silyllithium (0.9 mol dmϪ3, 8.7 cm3, 8.2 mmol)
was added dropwise to a suspension of copper() cyanide (370
mg, 4.1 mmol) in dry THF (20 cm3) at 0 ЊC under nitrogen. The
mixture was stirred for 15 min, and then cooled to Ϫ78 ЊC. The
Z-ester 14 (1.0 g, 3.2 mmol) in dry THF (5 cm3) was added. The
mixture was stirred for a further 1 h at Ϫ78 ЊC, allowed to warm
to Ϫ20 ЊC and kept at that temperature for 1.5 h, and finally
allowed to warm to 0 ЊC and stirred at that temperature for 1 h
before being cooled back to Ϫ78 ЊC. The reaction was then
quenched by the addition of saturated aqueous basic ammo-
nium chloride solution (20 cm3) and allowed to warm to room
temperature. Ether (20 cm3) was added and the layers separ-
ated. The aqueous layer was extracted with ether (2 × 20 cm3)
and the combined organic layers washed with water (2 × 20
cm3), brine (20 cm3), dried (MgSO4) and the solvents removed
under reduced pressure. The residue was chromatographed
(SiO2, light petroleum–EtOAc, 99 : 1) to give the esters (typical
total yield 1.28 g, 88%; average ratios of 7 : 36 : 36 : 21 20 : 21 :
22 : 23) as colourless oils. (Quenching with basic ammonium
chloride solution, methanol, or 2,6-di-tert-butylphenol gave the
esters in similar ratios.) A similar experiment on the E-ester 15
(78 mg, 0.24 mmol) gave the same esters (91 mg, 84%; in ratios
of 27 : 14 : 13 : 45, 20 : 21 : 22 : 22). The esters 20 and 23 were
obtained free enough of the other isomers. The esters 21 and 22
were obtained as a mixture, but the ratios from different runs
were different enough to identify characteristic signals for each.
The following compounds were prepared by this method:
methyl (2SR,3RS)-2-[1Ј(RS)-dimethyl(phenyl)silylbenzyl]-3-
dimethylphenylsilylbutanoate 20: Rf(light petroleum–EtOAc,
᎐
(Ar); δH(400 MHz; CDCl3) 7.43 (2 H, m, m-ArH ), 7.33–7.29
(3 H, m, o- and p-ArH ), 7.17 (2 H, m, m-ArH ), 7. 08 (1 H, tt,
J 7.5 and 2.0, p-ArH ), 7.04 (2 H, m, o-ArH ), 6.87 (1 H, q, J 7.0,
MeCH ), 3.70 (1 H, s, PhCH ), 3.66 (3 H, s, OMe), 1.73 (3 H, d,
J 7.0, MeCH), 0.35 (3 H, s, SiMeAMeB) and 0.31 (3 H, s,
SiMeAMeB); δC(100 MHz; CDCl3) 169.11ϩ, 141.67ϩ, 139.73ϩ,
138.16Ϫ, 134.76ϩ 133.85Ϫ, 128.66Ϫ, 128.31Ϫ, 128.07Ϫ,
127.50Ϫ, 124.66Ϫ, 51.50Ϫ, 36.35Ϫ, 14.47Ϫ, Ϫ2.53Ϫ and
Ϫ2.74Ϫ; m/z (ESI) 347 (MNaϩ, 30%) and 247 (Mϩ Ϫ Ph,
100%)(Found Mϩ, 347.1430. C20H24O2Si requires M ϩ Naϩ,
347.1443).
Methyl (E )-(1ЈRS-dimethylphenylsilylbenzyl)but-2-enoate 15
A similar reaction on the mesylate (351 mg, 0.836 mmol)
derived from the alcohol 13 gave a 1 : 1 mixture of esters 14 and
15 (197 mg, 73%) from which the E-ester could be separated
with difficulty; Rf(hexane) 0.27; δH(400 MHz; CDCl3) 7.37 (2 H,
m, m-ArH ), 7.31–7.28 (3 H, m, o- and p-ArH ), 7.16 (2H, m,
m-ArH ), 7.11 (1H, tt, J 7.5 and 1.5, p-ArH ), 7.03 (2 H, m,
o-ArH ), 5.97 (1 H, dq, J 7.0 and 1.0, MeCH ), 3.66 (1 H, s,
PhCH ), 3.57 (3 H, s, OMe), 1.88 (3 H, dd, J 7.0 and 1.0,
MeCH), 0.32 (3 H, s, SiMeAMeB) and 0.26 (3 H, s, SiMeAMeB);
δC(125 MHz, CDCl3) 169.1ϩ, 141.0ϩ, 137.7ϩ, 135.6Ϫ,
133.9Ϫ, 133.7ϩ, 129.0Ϫ, 128.8Ϫ, 128.3Ϫ, 127.5Ϫ, 125.2Ϫ,
51.2Ϫ, 41.3Ϫ, 15.9Ϫ, Ϫ2.9Ϫ and Ϫ3.4Ϫ.
Methyl (3RS,4RS )-3,4-bisdimethyl(phenyl)silylpentanoate 16
and methyl (3RS,4SR)-3,4-bisdimethyl(phenyl)silylpentanoate
17
95 : 5) 0.40; νmax(KBr)/cmϪ1 2953 (CH), 1733 (C᎐O), 1598
᎐
(aromatic C᎐C), 1427 (CH) and 1249 (SiMe); δ (400 MHz;
᎐
H
CDCl3) 7.42–7.21 (10 H, m, ArH), 7.19 (2 H, t, J 7.4, m-ArH),
7.17 (1 H, t, J 7.7, p-ArH), 6.78 (2 H, d, J 7.5, o-ArH), 3.23
(3 H, s, OMe), 2.97 (1H, dd, J 12.5 and 3.0, CHCO2Me), 2.77
(1 H, d, J 12.5, PhCH ), 1.13 (1H, dq, J 7.5 and 3.0, MeCH ), 0.88
(3H, d, J 7.5, MeCH), 0.33 (3H, s, SiMe), 0.17 (3H, s, SiMe),
0.15 (3H, s, SiMe) and 0.02 (3H, s, SiMe); δC(100 MHz, CDCl3)
175.4ϩ, 140.7ϩ, 139.7ϩ, 137.1ϩ, 134.1Ϫ, 133.8Ϫ, 132.8Ϫ,
128.6Ϫ, 128.2Ϫ, 127.8Ϫ, 127.6Ϫ, 127.2Ϫ, 124.6Ϫ, 50.6Ϫ,
50.4Ϫ, 37.6Ϫ, 22.1Ϫ, 16.3Ϫ, Ϫ1.8Ϫ, Ϫ2.8Ϫ, Ϫ4.8Ϫ and
Ϫ5.0Ϫ; m/z (ESI) 483 (MNaϩ, 23%)(Found Mϩ, 483.2176.
C28H36O2Si2 requires M ϩ Naϩ, 483.2152); for the mixture of
A suspension of copper() cyanide (0.046 g, 0.5 mmol) in dry
THF (1 cm3) was treated with dimethyl(phenyl)silyllithium
(1.1 mol dmϪ3 solution in THF, 0.90 cm3, 1.0 mml) at 0 ЊC
under nitrogen. The mixture was stirred for 30 min and then
cooled to Ϫ78 ЊC. (Z)-Methyl 4-dimethyl(phenyl)silylpent-2-
enoate (11 ؍ 12a in the preceding paper) (0.095 g, 0.38 mmol)
in THF (0.5 cm3) was added and the mixture stirred at Ϫ78 ЊC
for 5 min and then allowed to warm to Ϫ20 ЊC, stirred at that
temperature for 1 h and then cooled to Ϫ78 ЊC. Basic saturated
aqueous ammonium chloride solution (2 cm3) was added and
the mixture allowed to warm to room temperature. Ether
(1 cm3) was added and the layers separated. The aqueous layer
was washed with ether (3 × 2 cm3), the combined organic layers
were washed with water (2 × 2 cm3), brine (3 cm3), dried
(MgSO4) and solvents removed under reduced pressure. The
residue was chromatographed (SiO2, light petroleum–EtOAc,
95 : 5) to give the mixture of esters (0.14 g, 95%, 58 : 42, 16 : 17)
as a colourless oil; Rf(light petroleum–EtOAc, 95 : 5) 0.35; νmax
esters 21 and 22: Rf(light petroleum–EtOAc, 95 : 5) 0.38; νmax
-
(film)/cmϪ1 3069 (CH), 2951 (CH), 1732 (CO), 1598 (PhH),
1494 (PhH), 1249 (SiMe) and 1112 (SiPh); δC(125 MHz,
CDCl3) 175.1ϩ, 174.4ϩ, 142.3ϩ, 140.2ϩ, 138.9ϩ, 138.4ϩ,
138.1ϩ, 134.3Ϫ, 134.1Ϫ, 133.9Ϫ, 133.8Ϫ, 137.1ϩ, 129.2Ϫ,
128.8Ϫ, 128.7Ϫ, 128.3Ϫ, 127.9Ϫ, 127.8Ϫ, 127.6Ϫ, 127.5Ϫ,
127.4Ϫ, 127.3Ϫ, 124.9, 124.8Ϫ, 52.3Ϫ, 50.7Ϫ,47.1Ϫ, 44.1Ϫ,
38.3Ϫ, 36.0Ϫ, 22.3Ϫ, 20.0Ϫ, 16.2Ϫ, 8.3Ϫ, Ϫ1.5Ϫ, Ϫ2.3Ϫ,
Ϫ2.7Ϫ, Ϫ4.5Ϫ, Ϫ4.55Ϫ, Ϫ4.6, Ϫ4.7Ϫ and Ϫ4.8Ϫ; m/z (ESI)
483.2 (100%, Mϩ)(Found MNaϩ 483.2144. C28H36O2Si2
requires MNaϩ 483.2152); methyl (2SR,3SR)-2-[1Ј(RS)-
dimethyl(phenyl)silylbenzyl]-3-dimethylphenylsilylbutanoate 21:
δH(400 MHz; CDCl3) 7.46 (2 H, m, m-ArH ), 7.38 (2 H, m,
o-ArH ), 7.32–7.23 (6 H, m, ArH ), 7.14 (2 H, m, m-ArH ), 7.07
(1 H, m, p-ArH ), 6.73 (2 H, m, o-ArH ), 3.18 (1 H, s, OMe),
3.10 (1 H, dd, J 12.5 and 3.0, CHCO2Me), 2.90 (1 H, d, J 12.5,
PhCH ), 1.11 (1 H, qd, J 7.5 and 2.5, MeCH ), 0.82 (3 H, d,
J 7.5, MeCH), 0.19 (3 H, s, SiMe), 0.16 (3 H, s, SiMe), 0.13
(3 H, s, SiMe) and 0.05 (3 H, s, SiMe); methyl (2RS,3SR)-2-
[(1Ј(RS)-dimethyl(phenyl)silylbenzyl]-3-dimethylphenylsilyl-
butanoate 22: δH(400 MHz; CDCl3) 7.46 (2 H, m, m-ArH ), 7.38
(2 H, m, o-ArH ), 7.32–7.23 (6 H, m, Ar H ), 7.15 (2 H, m,
m-ArH ), 7.06 (1 H, m, p-ArH ), 6.88 (2 H, m, o-ArH ), 3.19
(1 H, s, CHCO2Me), 2.99 (1 H, dd, J 11.0 and 4.0, CHCO2Me),
2.70 (1 H, d, J 11.0, PhCH ), 1.35 (1 H, qd, J 7.5 and 4.0,
(film)/cmϪ1 2952 (CH), 1736 (C᎐O), 1249 (SiMe) and 1111
᎐
(SiPh); δH(400 MHz; CDCl3) (major isomer 16) 7.50–7.39 (2 H,
m, SiPh), 7.37 (3 H, m, SiPh), 3.43 (3 H, s, CO2Me), 2.27 (1 H,
dd, J 15.8 and 10.1, CHAHBCO2Me), 2.17 (1 H, dd, J 15.8 and
4.2, CHAHBCO2Me), 1.77 (1 H, ddd, J 10.1, 4.2 and 1.1, SiCH-
CH2CO2Me), 1.17 (1 H, dq, J 1.0 and 7.5, SiCHMe), 0.82 (3 H,
d, J 7.6, SiCHMe), 0.25 [9 H, s, (SiMeAMeB)2 and SiMeAMeB]
and 0.17 (3 H, s, MeAMeB), and (minor isomer 17, where differ-
ent from the major isomer) 3.47 (3 H, s, CO2Me), 2.34 (2 H, d,
J 6.7, CH2CO2Me), 1.68 (1 H, q, J 6.7, SiCHCH2CO2Me) and
1.0 (3 H, d, J 7.6, SiCHMe); and for the mixture δC(125 MHz,
CDCl3) 174.4ϩ, 174.1ϩ, 139.5ϩ, 139.3ϩ, 133.9Ϫ, 128.8Ϫ,
127.6Ϫ, 51.3Ϫ, 36.3ϩ, 32.1ϩ, 24.6Ϫ, 22.0Ϫ, 21.0Ϫ, 19.1Ϫ,
15.7Ϫ, 11.5Ϫ, Ϫ1.9Ϫ, Ϫ2.7Ϫ, Ϫ3.5Ϫ, Ϫ3.6Ϫ, Ϫ4.1Ϫ and
Ϫ4.5Ϫ; m/z (EI) 384.2 (3%, M), 135.1 (100%, PhMe2Si) and
249.1 (18%, M Ϫ PhMe2Si)(Found Mϩ, 384.1944. C22H32O2Si
requires M, 384.1941).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4021

View Article Online
MeCH ), 0.95 (3 H, d, J 7.5, MeCH), 0.28 (3 H, s, SiMe), 0.25
(3 H, s, SiMe), 0.17 (3 H, s, SiMe) and 0.05 (3 H, s, SiMe);
methyl (2RS,3RS)-2-[(1Ј(RS)-dimethyl(phenyl)silylbenzyl]-3-
dimethylphenylsilylbutanoate 23: Rf(light petroleum–EtOAc,
stirred at room temperature for 14 h. Ether (30 cm3) and sodium
thiosulfate solution (30 cm3) were added. The resulting suspen-
sion was stirred vigorously for 30 min, filtered through Celite
and concentrated under reduced pressure. The residue was
dissolved in ether (30 cm3), washed with sodium bicarbonate
solution (30 cm3), brine (30 cm3), dried (Na2SO4), filtered
and concentrated under reduced pressure. The residue was
chromatographed (SiO2, ether–hexane, 1 : 1 to ether) to give the
products.
Method C. A 29 : 71 mixture of the silanes 21 and 22 (25 mg,
0.05 mmol) and hydrofluoroboric acid (54% w/v Et2O, 0.02 cm3,
0.15 mmol) in dichloromethane (1 cm3) were stirred at 0 ЊC at
room temperature for 10 h. The mixture was diluted with
dichloromethane (10 cm3) and saturated aqueous sodium
hydrogencarbonate solution (20 cm3), and extracted with
dichloromethane (3 × 10 cm3). The combined organic extracts
were dried (MgSO4), filtered and concentrated under reduced
pressure. In an attempt to oxidise the products, they were stirred
with m-chloroperbenzoic acid (28 mg, 0.17 mmol) and triethyl-
amine (0.08 cm3, 0.06 mmol) at room temperature for 2 h, and
worked up in the usual way, but this treatment evidently had
no effect. Chromatography (SiO2; hexane–Et2O, 90 : 10) gave
the mixture of disiloxanes 33 and 34 described below. The
following compounds were prepared by these methods.
95 : 5) 0.36; νmax(film)/cmϪ1 2952 (CH), 1725 (ester C᎐O), 1599
᎐
and 1574 (Ar); δH(400 MHz; CDCl3) 7.48 (2 H, m, m-ArH ),
7.39 (2 H, m, o-ArH ), 7.36–7.28 (6 H, m, ArH ), 7.16 (2 H, m,
m-ArH ), 7.04 (1 H, tt, J 7.5 and 1.0, p-ArH ), 6.99 (2 H, m,
o-ArH ), 3.25 (1 H, dd, J 12.5 and 2.5, CHCO2Me), 3.15 (3 H, s,
OMe), 2.99 (1 H, d, J 12.5, PhCH ), 1.25 (1 H, qd, J 7.5 and 2.5,
MeCH ), 0.72 (3 H, d, J 7.5, MeCH), 0.19 (3 H, s, SiMe), 0.17
(3 H, s, SiMe), 0.12 (3 H, s, SiMe) and 0.01 (3 H, s, SiMe);
δC(100 MHz; CDCl3) 173.94ϩ, 142.45ϩ, 138.41ϩ, 133.93Ϫ,
129.05Ϫ, 128.27Ϫ, 127.97Ϫ, 127.60Ϫ, 124.92Ϫ, 50.48Ϫ,
47.08Ϫ, 36.69Ϫ, 21.48Ϫ, 8.89Ϫ, Ϫ1.57Ϫ, Ϫ4.16Ϫ, Ϫ5.12Ϫ
and Ϫ5.52Ϫ; m/z (ESI) 483 (MNaϩ, 100%)(Found MNaϩ,
483.2168. C28H36O2Si2 requires M ϩ Naϩ, 483.2152).
Methyl (2RS,3RS )-2-benzyl-3-dimethylphenylsilylbutanoate 24
and methyl (2RS,3SR)-2-benzyl-3-dimethylphenylsilylbutanoate
25
Tetrabutylammonium fluoride (1.0 mol dmϪ3 in THF, 0.06 cm3,
0.06 mmol) was added to a mixture of isomers B, C and D (B :
C : D, 46 : 51 : 3, 24 mg, 0.05 mmol) in THF (1 cm3). and the
mixture stirred for 5 min at room temperature. Water (1 cm3)
was added and the layers separated. The aqueous layer was
washed with ether (2 × 1 cm3) and the combined organic layers
washed with water (1 cm3), brine (1 cm3), dried (MgSO4) and
solvents removed under reduced pressure. The residue was
chromatographed (SiO2, light petroleum–EtOAc, 95 : 5) to give
the esters (16 mg, 100%, 55 : 45) as an oil; Rf(light petroleum–
EtOAc, 95 : 5) 0.28; νmax(film)/cmϪ1 3068 (CH), 2952 (CH), 1732
(CO), 1603 (PhH), 1495 (PhH), 1250 (SiMe) and 1112 (SiPh);
δH(400 MHz; CDCl3) 7.58–7.52 (2 H, m, Ar), 7.50–7.45 (2 H,
m, Ar), 7.39–7.32 (6 H, m, Ph), 7.25–7.10 (6 H, m, Ar), 7.02–
6.96 (4 H, m, Ar), 3.45 (3 H, s, OMe), 2.95–2.70 (2 H m,
PhCHAHBCH ), 2.64 (1 H, dd, J 13.0 and 3.1, PhCHAHB)
common to both isomers, and with signals for the major isomer
25, assuming equal yields from the two substrates, at 1.26 (1 H,
quintet, J 7.7, CHSi), 1.03 (3 H, d, J 7.5, CHMe), 0.33 (3 H, s,
SiMeAMeB) and 0.30 (3 H, s, SiMeAMeB), and for the minor
isomer, probably 24, at 3.39 (3 H, s, OMe), 1.45 (1 H, dq, J 7.6
and 5.0, CHSi), 1.08 (3 H, d, J 7.6, CHMe), 0.38 (3 H, s, SiMeA-
MeB) and 0.35 (3 H, s, SiMeAMeB); δC(125 MHz, CDCl3)
175.4ϩ, 175.3ϩ, 140.2ϩ, 139.7ϩ, 138.3ϩ, 137.8ϩ, 134.0Ϫ,
133.8Ϫ, 129.1Ϫ, 129.0Ϫ, 128.8Ϫ, 128.7Ϫ, 128.3Ϫ, 128.2Ϫ,
127.8Ϫ, 127.7Ϫ, 126.1Ϫ, 126.0Ϫ, 50.9Ϫ, 49.2Ϫ, 37.8ϩ, 35.4ϩ,
23.2Ϫ, 22.5Ϫ, 11.8Ϫ, 11.5Ϫ, Ϫ3.7Ϫ, Ϫ3.8Ϫ, Ϫ3.9Ϫ and
Ϫ4.1Ϫ; m/z (EI) 326.2 (8%, Mϩ), 311.1 (22%, M Ϫ Me), 249.1
(33%, M Ϫ Ph) and 235.1 (88%, M Ϫ PhCH2), 135.1 (100%,
PhMe2Si)(Found Mϩ, 326.1698. C20H26O2Si requires M,
326.1702).
Methyl
(2SR,3RS )-2-(1ЈRS-hydroxybenzyl)-3-hydroxy-
butanoate 26. By method A from 20 (6 mg) as an oil (2 mg, 69%)
and from 12 (200 mg, 0.58 mmol) as a solid (117 mg, 89%);
Rf(Et2O) 0.35; νmax(solid)/cmϪ1 3467, 3371 (OH), 1707 (C᎐O),
᎐
1609 (MeO) and 1493 (Ar); δH(400 MHz; CDCl3) 7.41–7.29
(4 H, m, Ar), 7.27 (1 H, tt, J 6.5 and 2.0, p-ArH ), 5.08 (1 H, d,
J 7.5, PhCH ), 3.73 (1 H, qd, J 6.5 and 3.5, MeCHOH), 3.69
(1 H, s, OMe), 2.71 (1 H, dd, J 7.5 and 3.5, CHCO) and 1.18
(3 H, d, J 6.5, MeCHOH); δC(100 MHz; CDCl3) 173.77ϩ,
141.19ϩ, 128.11Ϫ, 127.65Ϫ, 125.73Ϫ, 73.83Ϫ, 66.87Ϫ,
58.43Ϫ, 51.39Ϫ and 21.80Ϫ; m/z (EI) 224 (Mϩ, 40%) and 77
(Ph, 90%)(Found Mϩ, 224.1050. C12H16O4 requires M,
224.1049).
Methyl
(4RS,5SR,6RS )-1,1,3,3,6-pentamethyl-4-phenyl-
[1,2,3]oxadisilinane-5-carboxylate 28. By method A from 23
(190 mg) as a solid (33 mg, 36%), which was a mixture (28 : 29,
58 : 42). Further chromatography gave the disiloxane 28 (12 mg,
9%) as an oil; νmax(film)/cmϪ1 2954 (CH), 1724 (ester C᎐O),
᎐
1600 (Ar), 1431 (CH) and 1250 (SiMe3); δH(400 MHz; CDCl3)
7.20–7.01 (5 H, m, Ar), 3.35 (3 H, s, OMe), 3.07 (1 H, t, J 12.5,
CHCO), 2.50 (1 H, d, J 12.5, PhCH ), 1.17 (1 H, dq, J 12.5 and
7.5, MeCH ), 0.87 (3 H, d, J 7.5, MeCH), 0.20 (3 H, s, SiMe),
0.19 (3 H, s, SiMe), 0.15 (3 H, s, SiMe) and 0.08 (3 H, s, SiMe);
δC(125 MHz; CDCl3) 175.57ϩ, 140.27ϩ, 128.07Ϫ, 127.96Ϫ,
125.02Ϫ, 50.88Ϫ, 49.34Ϫ, 41.95Ϫ, 25.24Ϫ, 13.10Ϫ, Ϫ0.86Ϫ,
Ϫ0.94Ϫ, Ϫ2.35Ϫ and Ϫ3.08Ϫ; m/z (ESI) 345 (M ϩ Naϩ,
100%), 307 (M Ϫ Me, 43%) and 263 (M Ϫ CO2Me,
63%)(Found MNaϩ, 345.1316. C16H26O3Si2 requires M ϩ Na,
345.1318), and the diol 29 (10 mg, 11%).
Silyl-to-hydroxy conversions
Method A. Typically, the substrate (0.5 mmol) and mercury()
acetate (560 mg, 1.75 mmol) were stirred with a solution of
peracetic acid in acetic acid (15%, with 1% H2SO4, 6 cm3) at
room temperature for 16–24 h. Sodium thiosulfate solution (30
cm3) and ether (30 cm3) were added, and the mixture separated.
The organic layer was washed with sodium thiosulfate solution
(10%, 30 cm3), water (2 × 30 cm3) and brine (30 cm3), dried
(Na2SO4) and concentrated under reduced pressure. The residue
was chromatographed (SiO2, hexane to Et2O) to give the
products.
Method B. Typically, the substrate (0.20 mmol), potassium
bromide (29 mg, 0.24 mmol) and anhydrous sodium acetate
(507 mg, 0.61 mmol) were stirred in glacial acetic acid (1 cm3) at
0 ЊC. Peracetic acid (15% solution in acetic acid with 1% H2SO4,
1 cm3, 1.2 mmol) was then added dropwise, and the mixture was
Methyl
(2RS,3RS,)-3-hydroxy-2-(1ЈRS-hydroxybenzyl)-
butanoate 2914. By method B from 23 (93 mg, 0.20 mmol) as a
solid (9 mg, 20%); νmax(solid)/cmϪ13237 (OH) and 1728 (C᎐O);
᎐
δH(400 MHz; CDCl3) 7.35–7.28 (5 H, m, Ar), 5.10 (1 H, d, J 9.0,
PhCH ), 4.34 (1 H, dq, J 8.0 and 6.0, MeCHOH), 3.38 (3 H, s,
OMe), 2.81 (1 H, dd, J 9.0 and 8.5, CHCO) and 1.25 (3 H, d,
J 6.0, MeCHOH); δC(125 MHz; CDCl3) 171.559ϩ, 141.26ϩ,
131.57Ϫ, 128.40Ϫ, 126.55Ϫ, 76.88Ϫ, 70.05Ϫ, 60.64Ϫ, 51.50Ϫ
and 21.81Ϫ; m/z (ESI) 247 (MHϩ, 100%)(Found MNaϩ,
247.0945. C12H16O4 requires M ϩ Na, 247.0946).
Methyl
(2SR,3SR)-3-hydroxy-2-(1ЈRS-hydroxybenzyl)-
butanoate 3114. By method A from a 1 : 1 mixture of 21 and 22
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4022

View Article Online
(40 mg, 0.09 mmol) as an oil (10 mg, 51%), from 13 (100 mg,
0.29 mmol) as an oil (38 mg, 58%) and by method B from 14
(100 mg, 0.29 mmol) as an oil (27 mg, 42%); Rf(Et2O–hexane,
(2SR,3RS )-2-[1ЈRS-Dimethyl(phenyl)silylbenzyl]butane-
1,3-diol
Similarly, the ester 13 (70 mg, 0.21 mmol) gave the diol as an oil
(47 mg, 73%); νmax(film)/cmϪ1 3358 (OH), 2967 (CH) and 1598
(Ar); δH(400 MHz; CDCl3) 7.53 (2 H, m, m-ArH ), 7.36–7.35
(3 H, m, o- and p-ArH ), 7.23 (2 H, t, J 6.0, m-ArH ), 7.11 (1 H,
tt, J 6.0 and 1.0, p-ArCH ), 7.04 (2 H, br d, J 5.5, o-ArCH ), 4.07
(1 H, br dt, J 12.0 and 2.5, CHAHBOH), 3.76 (1 H, ddd, J 12.0,
6.0 and 2.5, CHAHBOH), 3.70 (1 H, m, MeCHOH), 3.02 (1 H,
d, J 12.0, PhCH ), 2.30 (1 H, br d, J 6.0, MeCHOH ), 1.92 (1 H,
br t, J 3.5, CH2OH ), 1.83 (1 H, dq, J 12.0 and 2.5, CHCH2OH),
1.14 (3 H, d, J 6.5, MeCHOH), 0.33 (3 H, s, SiMeAMeB) and
0.09 (3 H, s, SiMeAMeB); δC(100 MHz; CDCl3) 144.14, 140.26
(ArC), 135.39, 130.78, 130.33, 130.03, 129.59, 126.63 (ArCH),
70.53 (MeCHOH), 63.35 (CH2OH), 47.89 (CHCH2OH), 36.57
(PhCH), 23.51 (MeCHOH), 0.00 (SiMeAMeB) and Ϫ2.91
(SiMeAMeB); m/z (ESI) 337 (MNaϩ, 100%)(Found MNaϩ,
337.1604. C19H26O2Si requires M ϩ Na, 337.1600).
1 : 1) 0.1; νmax(film)/cmϪ1 3398 (OH), 2972 (CH), 1717 (C᎐O),
᎐
1495 (Ar), 1438 (CH) and 1050 (CO); δH(400 MHz; CDCl3)
7.44–7.25 (5 H, m, Ar), 5.17 (1 H, dd, J 7.5 and 4.5, PhCH ),
4.20 (1 H, br sextet, J 6.5, MeCHOH), 3.73 (1 H, d, J 7.5,
PhCHOH ), 3.56 (3 H, s, OMe), 2.84 (1 H, dd, J 6.5 and 4.5,
CHCO), 2.72 (1 H, d, J 5.5, MeCHOH ) and 1.27 (3 H, d, J 6.5,
MeCHOH); δC(100 MHz; CDCl3) 173.77ϩ, 141.19ϩ, 128.11Ϫ,
127.65Ϫ, 125.73Ϫ, 73.83Ϫ, 66.87Ϫ, 58.43Ϫ, 51.39Ϫ and
21.80Ϫ; m/z (ESI) 247 (M ϩ Naϩ, 84%)(Found MNaϩ,
247.0948. C12H16O4 requires M ϩ Na, 247.0946).
Methyl
(4SR,5SR,6RS )-1,1,3,3,6-pentamethyl-4-phenyl-
[1,2,3]oxadisilinane-5-carboxylate 33. By method A from a
14 : 86 mixture of 21 and 23 (127 mg, 0.276 mmol) as a solid
(68 mg, 72%) consisting of a 14 : 86 mixture of disiloxane 33;
δH(400 MHz; CDCl3) 7.20–7.01 (5 H, m, Ar), 3.35 (3 H, s,
OMe), 3.07 (1 H, t, J 12.5, CHCO), 2.50 (1 H, d, J 12.5,
PhCH ), 1.17 (1 H, dq, J 12.5 and 7.5, MeCH ), 0.87 (3 H, d,
J 7.5, MeCH), 0.20 (3 H, s, SiMe), 0.19 (3 H, s, SiMe), 0.15
(3H, s, SiMe) and 0.08 (3 H, s, SiMe); δC(125 MHz; CDCl3)
174.29ϩ, 139.78ϩ, 130.06Ϫ, 128.04Ϫ, 125.08Ϫ, 50.95Ϫ,
49.98Ϫ, 38.63Ϫ, 18.19Ϫ, 13.63Ϫ, 0.42Ϫ, Ϫ0.50Ϫ, Ϫ0.61Ϫ and
Ϫ2.23Ϫ; m/z (ESI) 345 (MNaϩ, 100%), 307 (M – Me, 43%)
and 263 (M Ϫ CO2Me, 63%)(Found MNaϩ, 345.1316.
C16H26O3Si2 requires M ϩ Na, 345.1318), and disiloxane 28
with signals (1H-NMR) identifiable from the sample described
above.
Synthesis of acetonides
Typically, the diol (0.12 mmol), 2,2-dimethoxypropane (0.6
cm3) and toluene-p-sulfonic acid (3 mg) in dimethylformamide
(2 cm3) were stirred at room temperature for 14 h. Ether (30
cm3) and water (30 cm3) were added and the layers separated.
The organic phase was washed with water (2 × 30 cm3) and
brine (30 cm3), dried (Na2SO4), and concentrated under
reduced pressure. Chromatography (SiO2, Et2O–hexane, 1 : 3)
gave the acetonides. The following compounds were prepared
by this method.
Methyl (4RS,5SR,6RS )-2,2,4-trimethyl-6-phenyl[1,3]diox-
ane-5-carboxylate 27. From the diol 26 (30 mg, 0.13 mmol) as a
Methyl
(4SR,5RS,6SR)-1,1,3,3,6-pentamethyl-4-phenyl-
[1,2,3]oxadisilinane-5-carboxylate 34. By Method A, from a 35 :
65 mixture of B and C, separated clean from a 35 : 65 mixture
of disiloxanes 33 and 34, as an oil (7 mg, 36%); δH(400 MHz;
CDCl3) 7.21–7.01 (5 H, m, Ar), 3.53 (1 H, dd, J 13.5 and 2.5,
CHCO), 3.45 (3 H, s, OMe), 2.79 (1 H, d, J 13.5, PhCH ), 1.18
(1 H, qd, J 7.5 and 2.5, MeCH ), 1.12 (3 H, d, J 7.5, MeCH),
0.27 (3 H, s, SiMe), 0.19 (3 H, s, SiMe), 0.17 (3 H, s, SiMe) and
Ϫ0.20 (3 H, s, SiMe); δC(125 MHz; CDCl3) 174.61, 149.03,
141.86, 135.96, 129.74, 129.48, 128.28, 127.09, 124.72, 122.05,
51.27, 45.17, 33.73, 22.14, 9.59, Ϫ0.37, Ϫ0.57, Ϫ1.34 and
Ϫ1.60; m/z (ESI) 345 (M ϩ Naϩ, 100%), 307 (M Ϫ Me, 43%)
solid (26 mg, 74%); νmax(solid)/cmϪ1 2991 (CH), 1747 (C᎐O),
᎐
1609 (MeO), 1575, 1493 (Ar) and 1432 (CH); δH(400 MHz;
CDCl3) 7.52–7.24 (5 H, m, ArCH ), 5.15 (1 H, d, J 3.5, PhCH ),
4.35 (1 H, qd, J 6.5 and 3.0, MeCH ), 3.41 (3 H, s, OMe), 2.68
(1 H, t, J 3.5, CHCO), 1.62 (3 H, s, (CMeAMeB), 1.57 (3H, s,
(CMeAMeB) and 1.26 (3 H, d, J 6.5, MeCH); δC(100 MHz;
CDCl ) 168.39 (C᎐O), 134.95 (ArC), 128.72, 128.46, 127.20,
᎐
3
126.59, 124.48 (ArCH), 98.28 (PhCH), 70.40 (MeCH), 64.63
(OMe), 50.02 (CHCO), 28.75 (MeCH), 18.59 (CMeAMeB) and
18.05 (CMeAMeB); m/z (ESI) 287 (MNaϩ, 81%)(Found MNaϩ,
287.1271).
and 263 (M
–
CO2Me, 63%)(Found MNaϩ, 345.1316.
C16H26O3Si2 requires M ϩ Na, 345.1318).
Methyl (4RS,5RS,6RS )-2,2,4-trimethyl-6-phenyl[1,3]diox-
ane-5-carboxylate 3014. From the diol 29 (6 mg, 0.03 mmol) as
an oil (10 mg, 92% yield adjusted for presence of the plasticiser);
νmax(film)/cmϪ1 2924 (CH) and 1739 (C᎐O); δ (400 MHz;
(2SR,3SR)-2-[1ЈRS-Dimethyl(phenyl)silylbenzyl]butane-
1,3-diol
᎐
H
The ester 12 (80 mg, 0.23 mmol) in anhydrous diethyl ether
(2 cm3) was stirred under nitrogen with lithium aluminium
hydride (10 mg, 0.26 mmol) at 0 ЊC for 3 h. Water (2 cm3) and
hydrochloric acid (1 mol dmϪ3, 5 cm3) were added, and the
mixture was partioned between ether (30 cm3) and water
(20 cm3). The organic phase was washed with brine (20 cm3),
dried (Na2SO4) and concentrated under reduced pressure.
Chromatography (SiO2, Et2O–hexane, 1 : 1) gave the diol as an
oil (37 mg, 50%); νmax(film)/cmϪ1 3374 (OH), 2960 (CH) and
1600 (Ar); δH(400 MHz; CDCl3) 7.46 (2 H, m, m-ArH ), 7.34–
7.32 (3 H, m, p- and o-ArH ), 7.23 (2 H, m, m-Ar CH ), 7.10
(1 H, tt, 7.5 and 2.0, p-ArCH ), 7.02 (1 H, m, o-ArCH ), 3.80
(1 H, dd, J 11.0 and 3.5, CHAHBOH), 3.75 (1 H, qd, J 6.5 and
3.0, MeCHOH), 3.57 (1 H, dd, J 11.0 and 9.5, CHAHBOH),
2.60 (1 H, dtd, J 12.5, 9.0 and 3.5, CHCH2OH), 2.07 (1 H, d,
J 12.0, PhCH ), 1.06 (3 H, d, J 6.5, MeCHOH), 0.35 (3 H, s,
SiMeAMeB) and Ϫ0.14 (3 H, s, SiMeAMeB); δC(125 MHz;
CDCl3) 141.93ϩ, 138.59ϩ, 133.63Ϫ, 129.13Ϫ, 128.50Ϫ,
128.25Ϫ, 127.95Ϫ, 125.10Ϫ, 70.25Ϫ, 64.08ϩ, 46.49Ϫ, 35.85Ϫ,
16.42Ϫ, Ϫ1.25Ϫ and Ϫ5.09Ϫ; m/z (ESI) 337 (MNaϩ,
100%)(Found MNaϩ, 377.1613).
CDCl3)1 7.32–7.25 (5 H, m, ArCH ), 5.01 (1 H, d, J 10.5,
PhCH ), 4.26 (1 H, qd, J 10.0 and 6.0, MeCH ), 3.48 (3 H, s,
OMe), 2.42 (1 H, t, J 10.5, CHCO), 1.50 (3 H, s, (CMeAMeB),
1.42 (3 H, s, (CMeAMeB) and 1.19 (3 H, d, J 6.0, MeCH);
δ (125 MHz; CDCl ) 171.78 (C᎐O), 139.57 (ArC), 131.63,
᎐
C
3
128.50, 128.34, 126.63 (ArCH), 99.25 (CMe2), 73.78 (PhCH),
67.21 (MeCH), 56.50 (OMe), 51.56 (CHCO), 29.91 (MeCH),
20.33 (CMeAMeB) and 19.63 (CMeAMeB); m/z (ESI) 287
(MNaϩ, 50%)(Found MNaϩ, 287.1255).
Methyl (4SR,5SR,6RS )-2,2,4-trimethyl-6-phenyl[1,3]diox-
ane-5-carboxylate 3214. From the diol 31 (27 mg, 0.12 mmol,
derived from the monosilylmonoalcohol 12) as an oil (18 mg,
68%), and from the diol 31 (18 mg, 0.080 mmol, derived from
the mixture of disilyl esters 21 and 22) as an oil (21 mg, 99%);
νmax(film)/cmϪ1 2986 (CH), 1732 (C᎐O), 1490 (Ar), 1379 (Me)
᎐
and 1134 (CO); δH(400 MHz; CDCl3) 7.30–7.29 (4 H, m, Ar),
7.22 (1 H, m, p-CH ), 5.13 (1 H, d, J 7.0, PhCH ), 4.37 (1 H, dq,
J 9.0 and 7.0, MeCH ), 3.13 (1 H, s, OMe), 2.89 (1 H, dd, J 9.0
and 7.0, CHCO), 1.55 (3 H, s, (CMeAMeB), 1.41 (3 H, s,
(CMeAMeB) and 1.26 (3 H, d, J 6.0, MeCH); δC(100 MHz;
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4023

View Article Online
CDCl ) 171.70 (C᎐O), 138.44 (ArC), 127.94, 127.43, 125.94
᎐
Acknowledgements
3
(ArCH) 101.51 (Me2C), 69.82 (PhCH), 65.56 (MeCH), 57.60
(OMe), 51.10 (CHCO), 24.51 (CMeAMeB), 24.15, (CMeAMeB)
and 20.80 (MeCH); m/z (ESI) 287 (M ϩ Naϩ, 47%)(Found
MNaϩ, 287.1263. C15H20O4 requires M ϩ Na, 287.1259).
We thank the EPSRC for a maintenance award (MSB) and for
a postdoctoral grant GR/R45802/01 (JVAO). We also thank
Dr J. M. Goodman for the calculations of the coupling
constants for the esters 16 and 17.
(4SR,5SR)-5-[1ЈRS-Dimethyl(phenyl)silylbenzyl]-2,2,4-tri-
methyl[1,3]dioxane 35. From the diol (9 mg, 0.03 mmol) derived
from the alcohol 12 as an oil (8 mg, 79%); νmax(film)/cmϪ1 2989
(CH) and 1596 (Ar); δH(400 MHz; CDCl3) 7.40 (2 H, m,
m-ArH ), 7.33–7.29 (3 H, m, o- and p-ArH ), 7.16 (2 H, m,
m-ArH ), 7.07 (1 H, tt, J 7.5 and 1.5, p-ArH ), 7.02 (2 H, m,
o-ArH ), 4.01(1 H, dq, J 7.0 and 3.5, MeCH ), 3.88 (1 H, dd,
J 12.0 and 4.0, CHAHBO), 3.80 (1 H, dd, J 12.0 and 6.0,
CHAHBO), 3.66 (1 H, d, J 11.5, PhCH ), 2.41 (1 H, ddt, J 11.5,
6.0 and 4.0, MeCHCH ), 1.38 (3 H, s, (CMeAMeB), 1.35 (3 H, s,
(CMeAMeB), 0.83 (3 H, d, J 7.0, MeCH), 0.29 (3 H, s, SiMeA-
MeB) and 0.11 (3 H, s, SiMeAMeB); δC(125 MHz; CDCl3)
143.02ϩ, 138.40ϩ, 133.92Ϫ, 128.85Ϫ, 128.00Ϫ, 127.59Ϫ,
124.61Ϫ, 98.14ϩ, 70.27Ϫ, 63.29ϩ, 39.92Ϫ, 34.27Ϫ, 27.80Ϫ,
24.04Ϫ, 19.09Ϫ, Ϫ1.89Ϫ and Ϫ3.9Ϫ; m/z (ESI) 377 (MNaϩ,
28%)(Found MNaϩ, 377.1905. C22H30O2SiNa requires M ϩ
Na, 377.1913).
References
1 T. Hayashi, M. Konishi, H. Ito and M. Kumada, J. Am. Chem. Soc.,
1982, 104, 4962; T. Hayashi, M. Konishi and M. Kumada, J. Am.
Chem. Soc., 1982, 104, 4963; T. Hayashi, H. Ito and M. Kumada,
Tetrahedron Lett., 1982, 23, 4605; T. Hayashi, M. Konishi and
M. Kumada, J. Chem. Soc., Chem. Commun., 1983, 736; T. Hayashi,
K. Kabeta, T. Yamamoto, K. Tamao and M. Kumada, Tetrahedron
Lett., 1983, 24, 5661; T. Hayashi, Y. Okamoto, K. Kabeta,
T. Hagihara and M. Kumada, J. Org. Chem., 1984, 49, 4224;
T. Hayashi, M. Konishi, Y. Okamoto, K. Kabeta and M. Kumada,
J. Org. Chem., 1986, 51, 3772; T. Hayashi, Y. Matsumoto and Y. Ito,
Organometallics, 1987, 6, 884; G. Wickham and W. Kitching,
Organometallics, 1983, 2, 541; G. Wickham, D. Young and
W. Kitching, Organometallics, 1988, 7, 1187; W. Kitching, K. G.
Penman, B. Laycock and I. Maynard, Tetrahedron, 1988, 44, 3819;
I. Fleming and N. K. Terrett, J. Organomet. Chem., 1984, 264, 99;
M. J. C. Buckle, I. Fleming and S. Gil, Tetrahedron Lett., 1992, 33,
4479.
2 I. Fleming and N. J. Lawrence, J. Chem. Soc., Perkin Trans. 1, 1992,
3309.
3 R. A. N. C. Crump, I. Fleming, J. H. M. Hill, D. Parker, N. L. Reddy
and D. Waterson, J. Chem. Soc., Perkin Trans. 1, 1992, 3277.
4 I. Fleming, D. Hrovat and W. T. Borden, J. Chem. Soc., Perkin Trans.
2, 2001, 331.
(4RS,5SR)-5-[1ЈRS-Dimethyl(phenyl)silylbenzyl]-2,2,4-tri-
methyl[1,3]dioxane 36. From the diol (47 mg, 0.15 mmol)
derived from the alcohol 13 as an oil (50 mg, 94%); νmax(film)/
cmϪ1 2965 (CH) and 1597 (aromatic C᎐C); δ (400 MHz;
᎐
H
CDCl3) 7.45 (2 H, m, m-ArH ), 7.34–7.32 (3 H, m, o- and
p-ArH ), 7.19 (2 H, m, m-ArH ), 7.10 (1 H, tt, J 5.5 and 2.0,
p-ArH ), 7.02 (2 H, m, o-ArH ), 3.93 (1 H, dd, J 11.5 and 5.0,
CHAHBO), 3.60 (1 H, dq, J 9.5 and 6.0, MeCH ), 3.58 (1 H, dd,
J 11.5 and 10.5, CHAHBO), 2.22 (1 H, d, J 7.5, PhCH ), 2.12
(1 H, dddd, J 10.5, 9.5, 7.5 and 5.0, MeCHCH ), 1.29 (3 H, s,
(CMeAMeB), 1.20 (3 H, s, (CMeAMeB), 0.80 (3 H, d, J 6.0,
MeCH), 0.37 (3 H, s, SiMeAMeB) and 0.04 (3 H, s, SiMeAMeB);
δC(100 MHz; CDCl3) 144.56ϩ, 139.81ϩ, 134.89Ϫ, 130.19Ϫ,
129.85Ϫ, 129.32Ϫ, 128.99Ϫ, 126.19Ϫ, 98.76ϩ, 72.72Ϫ,
65.90ϩ, 47.04Ϫ, 38.27Ϫ, 30.45Ϫ, 22.38Ϫ, 20.61Ϫ, 0.00Ϫ and
Ϫ2.58Ϫ; m/z (ESI) 377 (MNaϩ, 76%).
5 R. J. Linderman and T. V. Anklekar, J. Org. Chem., 1992, 57, 5078.
6 J. Cossrow and S. D. Rychnovsky, Org. Lett., 2002, 4, 147.
7 I. Fleming, P. Maiti and S. Chandrashekar, Org. Biomol. Chem.,
2003.
8 M. S. Betson and I. Fleming, Org. Biomol. Chem., 2003.
9 I. Fleming and J. D. Kilburn, J. Chem. Soc., Perkin Trans. 1, 1992,
3295.
10 D. F. Taber, T. E. Christos, M. Rahimizadeh and B. Chen, J. Org.
Chem., 2001, 66, 5911; Y. Yamamoto, S. Nishii and T. Ibuka,
J. Chem. Soc., Chem Commun., 1987, 464; M. T. Reetz and
D. Röhrig, Angew. Chem., Int. Ed. Engl., 1989, 28, 1706; B. Bartels,
J. Clayden, C. G. Martin, A. Nelson, M. G. Russell and S. Warren,
J. Chem. Soc., Perkin Trans. 1, 1999, 1807.
11 E. J. Corey and N. W. Boaz, Tetrahedron Lett., 1985, 26, 6015.
12 Y. Yamamoto, S. Nishii and T. Ibuka, J. Chem. Soc., Chem.
Commun., 1987, 1572; Y. Yamamoto, S. Nishii and T. Ibuka, J. Am.
Chem. Soc., 1988, 110, 617; K. Yamamoto, H. Ogura, J. Jukuta,
H. Inoue, K. Hamada, Y. Sugiyama and S. Yamada, J. Org. Chem.,
1998, 63, 4449.
Nuclear Overhauser enhancements for acetonides 27 and 30
13 I. Fleming, R. Henning, D. C. Parker, H. E. Plaut and P. E. J.
Sanderson, J. Chem. Soc., Perkin Trans. 1, 1995, 317.
14 J.-H. Gu, M. Terada, K. Mikami and T. Nakai, Tetrahedron Lett.,
1992, 33, 1465.
15 K. N. Houk, S. R. Moses, Y.-D. Wu, N. G. Rondan, V. Jäger,
R. Schohe and F. R. Fronczek, J. Am. Chem. Soc., 1984, 106, 3880.
16 For some evidence that the interaction between a carbonyl group
and a fully carbon-substituted silicon atom is weak, see: S. G. Davies
and C. L. Goodfellow, J. Chem. Soc., Perkin Trans. 1, 1990, 393;
C. Mukai, M. Miyakawa, A. Mihira and M. Hanaoka, J. Org.
Chem., 1992, 57, 2034 and for a hint that there may be consequences
from such an interaction in solution, see: N. D. Hone, S. G. Davies,
N. J. Devereux, S. L. Taylor and A. D. Baxter, Tetrahedron Lett.,
1998, 39, 897.
17 M. V. George, D. J. Peterson and H. Gilman, J. Am. Chem. Soc.,
1960, 82, 403.
18 W. C. Still, F. Mohamadi, N. G. J. Richards, W. C. Guida,
R. Liskamp, M. Lipton, C. Canfield, G. Chang and T. Hendrickson,
J. Comp. Chem., 1990, 11, 440.
19 C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona,
Tetrahedron, 1980, 36, 2783.
20 R. A. N. C. Crump, I. Fleming and C. J. Urch, J. Chem. Soc., Perkin
Trans. 1, 1994, 701.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 1 7 – 4 0 2 4
4024