Asymmetric synthesis of polymer-supported cyanohydrin acetates

Article abstract of DOI:10.1016/j.tetlet.2005.04.109

A bimetallic titanium(salen) complex has been used to catalyze the asymmetric addition of potassium cyanide to aldehydes attached to Wang resin giving polymer supported cyanohydrin propionates with up to 91% enantiomeric excesses.

Full text of DOI:10.1016/j.tetlet.2005.04.109

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4483–4486
Asymmetric synthesis of polymer-supported cyanohydrin acetates
Yuri N. BelokonÕ,a Paola Cartab and Michael Northb,c,
*
aA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 119991, Moscow,
Vavilov 28, Russian Federation
bDepartment of Chemistry, KingÕs College London, Strand, London WC2R 2LS, UK
cSchool of Natural Sciences, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK
Received 1 April 2005;accepted 20 April 2005
Available online 17 May 2005
Abstract—A bimetallic titanium(salen) complex has been used to catalyze the asymmetric addition of potassium cyanide to alde-
hydes attached to Wang resin giving polymer supported cyanohydrin propionates with up to 91% enantiomeric excesses.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Over the last eight years, we have developed bimetallic
titanium(salen) complex 1 as a highly enantioselective
OCOR'
CN
O
OSiMe3
CN
and remarkably versatile catalyst for the asymmetric
addition of various cyanide sources to aldehydes1 and
ketones.2 Catalyst 1 will induce the asymmetric addition
of trimethylsilyl cyanide,3 potassium cyanide/an anhy-
dride4 and ethyl cyanoformate4c,5 to aldehydes, provid-
ing access to non-racemic cyanohydrin trimethylsilyl
ethers, cyanohydrin esters and cyanohydrin ethyl car-
bonates as shown in Scheme 1. The best substrates for
catalyst 1 are electron rich aromatic aldehydes, which
typically give cyanohydrin derivatives with 90–99%
enantiomeric excess.
a
b
R
H
R
R
c
OCO2Et
R
CN
tBu
tBu
tBu
tBu
N
N
O
O
N
N
O
O
O
Ti
Ti
In view of the significant potential of catalyst 1, there
has recently been interest in the synthesis and use of
polymeric or polymer supported analogues of this cata-
lyst.6 Zheng and co-workers have used a linear poly-
meric version of catalyst 1 to catalyze the asymmetric
addition of trimethylsilyl cyanide to aldehydes,7 and a
cross-linked polymeric version of catalyst 1 to catalyze
the asymmetric addition of potassium cyanide and acetic
anhydride to aldehydes.8 The related vanadium(V)salen
complex 2, which we also developed2b,4b,9 and showed to
be even more enantioselective than complex 1 has also
been immobilized on silica,10,11 single walled carbon
nanotubes,11,12 or attached to an ionic liquid.11,13 A lin-
ear polymeric version of this catalyst has also been pre-
pared.8 Whilst the use of a polymer supported catalyst is
O
tBu
tBu
tBu
tBu
1
O
V
N
N
tBu
tBu
O
H
O
H
O
tBu
tBu
EtOSO3
2
Keywords: Cyanohydrin;Catalysis;Asymmetric;Polymer.
*
Scheme 1. Reagents: (a) KCN/(R0CO)2O/1 (1 mol %);(b) Me 3SiCN/
1 or 2 (0.1 mol %);(c) EtOCOCN/ 1 (5 mol %).
Corresponding author. Tel.: +44 191 2227128;fax: +44 870
1313783;e-mail: michael.north@ncl.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.109

4484
Y. N. BelokonÕ et al. / Tetrahedron Letters 46 (2005) 4483–4486
attractive, the methodology does suffer from a number
of disadvantages including: the catalysts are less readily
prepared than the soluble version of the catalyst;the
polymer supported catalysts are often less enantioselec-
tive than their soluble analogues;and the chiral cyano-
hydrin derivative still requires purification to remove
the other reagents and any metal that may have leached
from the polymer supported catalyst. In view of these
limitations, we have investigated the opposite approach
that of attaching the aldehyde substrate to an insoluble
polymeric support, and converting it into a polymer
supported cyanohydrin ester using catalyst 1. In this
communication we report the results of this study.14
Br
+
CO2H
OHC
a
O
3
O
CHO
O
O
O
O
4
b
Of the various cyanohydrin derivatives that can be pre-
pared using catalyst 1, the cyanohydrin esters were felt
to be the most attractive due to the hydrolytic stability
of the products, the relatively small amount of catalyst
(1 mol %) required, and the potential for subsequent
chemoselective transformations of the functional
groups.15 However, even using a simple aldehyde, the
synthesis of cyanohydrin acetates using catalyst 1 is a
heterogeneous process, which is carried out in dichloro-
methane in the presence of solid potassium cyanide and
both tert-butanol and water additives.4 Hence, at the
start of this work it was far from clear that this process
could be applied to polymer supported aldehydes as this
would effectively be a three-phase system involving two
solid reagents and a solvent system in which neither of
them was soluble.
OCOEt
CN
O
O
O
O
5
Scheme 2. Reagents: (a) CsCO3 (5 equiv)/KI (1 equiv)/DMF/80 ꢁC
then repeat coupling;(b) KCN (8 equiv)/(EtCO) 2O (8 equiv)/1
t
(2 mol %) BuOH (2 equiv)/H2O (1 equiv)/0 ꢁC/12 h.
OCOEt
CN
As an initial system, we selected 1% cross-linked Wang
resin16 as the polymeric support and commercially avail-
able aldehyde 3 as the substrate. This system had the
advantage that products could be readily cleaved from
the polymeric support by acidolysis without any danger
of racemization. Attachment of aldehyde 3 to Wang re-
sin occurred smoothly under standard conditions
(Scheme 2) to give polymer supported aldehyde 4. This
reaction (and subsequent transformations) could be
O
O
O
O
5
a
1
OCOEt
followed by both single bead magic angle spinning H
and 13C NMR spectroscopy and diffuse reflectance FTIR
spectroscopy.
CN
O
When aldehyde 4 was reacted with potassium cyanide/
propionic anhydride under the standard conditions
(ꢀ90 to ꢀ40 ꢁC, dichloromethane solvent with water
and tert-butanol additives), no reaction occurred after
48 h, even using double the amount of catalyst
(2 mol %) and reagents (up to 8 equiv of potassium cya-
nide and propionic anhydride). However, when this
reaction was carried out at 0 ꢁC, then polymer sup-
ported cyanohydrin propionate 5 was formed after just
24 h. After this time, no unreacted aldehyde 4 could be
6
b
HO2C
OCOEt
CN
O
MeO2C
7
Scheme 3. Reagents: (a) CF3CO2H;(b) Me 3SiCHN2/MeOH.
1
detected by H or 13C NMR spectroscopy and peaks
corresponding to the cyanohydrin-CH (1H NMR
6 ppm and 13C NMR 65 ppm) and propionate groups
of compound 5 were apparent in the spectra.
methyl ester 7 (Scheme 3). For comparison, racemic
and non-racemic samples of ester 7 were also prepared
by a solution phase synthesis. Thus, acid 3 was first
esterified with trimethylsilyldiazomethane and then trea-
ted with potassium cyanide and propionic anhydride in
the absence of catalyst 1 to give racemic-7, or in the
To determine the enantiomeric excess of compound 5, a
sample of the resin was treated with trifluoroacetic acid
to give acid 6, which was subsequently esterified by
treatment with trimethylsilyldiazomethane17 to give
presence of catalyst
1 (1 mol %) under standard

Y. N. BelokonÕ et al. / Tetrahedron Letters 46 (2005) 4483–4486
4485
Table 1. Enantiomeric excessesa of cyanohydrin propionates obtained
from aldehydes through solution and polymer supported syntheses
conditions to give a non-racemic sample of compound 7.
The enantiomeric excess of compound 7 could be deter-
mined by chiral GC, using the racemic sample to deter-
mine the retention times of the two enantiomers. The
sample of ester 7 prepared under standard solution
phase conditions was found to have an enantiomeric
excess of 81%, whilst the sample prepared on the poly-
meric support had an enantiomeric excess of 54%.
Although the sample of compound 7 prepared via a
polymer supported synthesis had a lower enantiomeric
excess than that prepared by a solution state synthesis,
this result did demonstrate that polymer supported
asymmetric cyanohydrin propionate synthesis using cat-
alyst 1 was feasible.
Cyanohydrin propionate ee (solution) ee (polymer supported)
7
81
91
11
12
13
ndb
94
ndb
75
80
50
a All enantiomeric excesses were determined by chiral GC using a c-
butyryl cyclodextrin fused silica capillary column (30 m · 0.25 mm)
using hydrogen as the carrier gas (flow rate 2.3 ml/min).
b The enantiomeric excess could not be determined as no separation
could be obtained on the chiral GC column.
fied to give the corresponding methyl esters 11–13. In
each case, racemic and non-racemic samples of the
methyl esters were also prepared by a solution phase
synthesis analogous to Scheme 3.
By increasing the amount of catalyst 1 from 2 to
5 mol %, the polymer supported reaction shown in
Scheme 2 was complete in 12 h18 and gave cyanohydrin
ester 5 with 91% enantiomeric excess (determined by chi-
ral GC after conversion to compound 7). Under these
conditions, the polymer supported reaction was more
enantioselective than the solution phase synthesis,
though the reaction conditions were very different. In
particular, the polymer supported synthesis required
more catalyst, but was also conducted at a higher tem-
perature than the solution phase synthesis.
Table 1 details the enantiomeric excesses observed for
the various cyanohydrin esters. In the case of cyanohy-
drin 11, it was not possible to separate the enantiomers
by chiral GC. Cyanohydrin propionates 12 and 13 could
be prepared in non-racemic form by the polymer sup-
ported synthesis, though the enantiomeric excesses were
lower than those obtained by a solution phase synthesis
under standard conditions. However, the reaction con-
ditions for the polymer supported syntheses have not
been optimized for each substrate.
To demonstrate the utility of this process, three other
aldehydes19 8–10 were attached to Wang resin and con-
verted into cyanohydrin propionates under the opti-
mized conditions (Scheme 4). Aldehydes 8–10 were
prepared from the commercially available formyl-phe-
nols by O-alkylation with methyl bromoacetate followed
by hydrolysis of the methyl ester using sodium hydrox-
ide. Samples of each polymer supported cyanohydrin
propionate were then cleaved from the resin and esteri-
In summary, we have shown for the first time that cata-
lyst 1 can be used to convert polymer supported alde-
hydes into non-racemic cyanohydrins. Ongoing work
is concerned with the subsequent transformations of
the polymer supported cyanohydrins, and the synthesis
of combinatorial libraries using this methodology.
CO2H
CO2Me
OCOEt
CN
Acknowledgements
O
O
The authors thank the EPSRC for a studentship (to
P.C.) and the EPSRC mass spectrometry service at the
University of Wales, Swansea for recording low and
high resolution mass spectra.
CHO
8
11
CO2Me
CO2H
References and notes
O
O
1. For recent reviews of this work and other catalysts for
asymmetric cyanohydrin synthesis see: (a) North, M.
Tetrahedron: Asymmetry 2003, 14, 147;(b) Brunel, J. M.;
Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752;(c)
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OCOEt
CHO
CN
12
9
CO2Me
CO2H
O
O
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CHO
NC
OCOEt
13
10
Scheme 4.

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Y. N. BelokonÕ et al. / Tetrahedron Letters 46 (2005) 4483–4486
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(26 mmol), water (12.5 mmol), resin 4 (12.5 mmol) and
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Tetra-