Prunus armeniaca hydroxynitrile lyase (ParsHNL)-catalyzed asymmetric synthesis of cyanohydrins from sterically demanding aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2009.05.022

Herein we report the biocatalytic asymmetric synthesis of cyanohydrins by using a new (R)-HNL from Prunus armeniaca. Several sterically demanding aromatic aldehydes which have never been used as substrates for any known HNLs are employed for the new (R)-H

Full text of DOI:10.1016/j.tetasy.2009.05.022

Tetrahedron: Asymmetry 20 (2009) 1526–1530
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Prunus armeniaca hydroxynitrile lyase (ParsHNL)-catalyzed asymmetric
synthesis of cyanohydrins from sterically demanding aromatic aldehydes
*
Rajib Bhunya, Tridib Mahapatra, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the biocatalytic asymmetric synthesis of cyanohydrins by using a new (R)-HNL from
Prunus armeniaca. Several sterically demanding aromatic aldehydes which have never been used as sub-
strates for any known HNLs are employed for the new (R)-HNL from P. armeniaca. The cyanohydrins syn-
thesized are obtained in good chemical yield with excellent enantioselectivities.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 11 May 2009
Accepted 20 May 2009
Available online 24 June 2009
1. Introduction
selective towards aliphatic or aromatic substrates.3 In a true sense
of chemical reactivity HNL from almond (Prunus amygdalus), Japa-
Hydroxynitrile lyases (HNLs) are one of the key enzymes in cya-
nogenic plants, catalyzing the final step in the biodegradation
pathway of cyanogenic glycosides releasing HCN and the corre-
sponding carbonyl components.1 There exist four different types
of HNL (EC. No. 4.1.2.10; 4.1.2.11; 4.1.2.37 and 4.1.2.39), among
them mandelonitrile lyase (4.1.2.10) is only (R)-selective [i.e., it ac-
cepts (R)-mandelonitrile as its natural substrate] whereas rest are
(S)-selective. (R)-Selective hydroxynitrile lyases found from differ-
ent plant species are quiet similar in their enzymatic properties
(molecular weight distribution, sequence homology and reactive
properties).2 Enantiomerically pure cyanohydrins have attracted
the attention of organic chemists, as well as enzymologists, due
to their potential as chiral building blocks and interesting biologi-
cal properties. Enantiopure cyanohydrins serve as intermediates
for several industrially useful chemicals; the use of chiral cyanohy-
drins as building blocks for the production of important chemicals
is likely to continue growing, as it avoids problems associated with
the resolution of or asymmetric synthesis of certain products.3 One
of the most promising and interesting ways to enantiomerically
pure cyanohydrins is the HNL-catalyzed addition of a cyanide
source to the respective carbonyl compounds.4 HNLs are now
widely used as efficient biocatalysts for the asymmetric synthesis
of various cyanohydrins. The resulting cyanohydrins are versatile
intermediates for a broad variety of chiral synthons. The reaction
is important from an organic chemists point of view, as it allows
the synthesis of enantiomerically pure compounds from pro-stere-
ogenic substrates in quantitative yield.
nese apricot (Prunus mume) shows excellent substrate (saturated
aliphatic aldehydes, unsaturated aliphatic aldehydes, aromatic
aldehydes, heteroaromatic aldehydes, methyl ketones and cyclic
ketones) tolerance over other species for the asymmetric synthesis
of the corresponding cyanohydrins.5 Herein we report our findings
on the biocatalytic cyanohydrin formation by a new (R)-HNL, Pars-
HNL (P. armeniaca, white apricot, shakarpara cultivar) from polycy-
clic aromatic aldehydes and aromatic aldehydes with bulky
substitution.
2. Results and discussion
Recently we found a new (R)-HNL from white apricot (shakar-
para cultivar, found in the himalayan region of Nepal and India;
P. armeniaca). The new enzyme (ParsHNL) exhibits excellent
enantioselectivity for the preparation of several cyanohydrins from
aliphatic and aromatic carbonyl compounds.6 Recently we have
synthesized several d,e-unsaturated cyanohydrins by using Pars-
HNL from the corresponding
c,d-unsaturated aldehydes with excel-
lent enantioselection.7 At this point we thought that it would be
appropriate to use the new enzyme ParsHNL for the asymmetric
biocatalytic synthesis of several cyanohydrins from various alde-
hydes, which have been never tested as HNL substrates with all
the known HNLs existing in the literature. We chose different poly-
cyclic aromatic aldehydes and substituted aromatic aldehydes for
the substrate of ParsHNL-catalyzed cyanohydrin formation
(Scheme 1).
In general it has been observed that HNL from Rosaceae species
(almond, plum, cherry and peach) exhibits broad levels of sub-
strate acceptance (aliphatic, aromatic), whereas HNL from cassava
(Manihot esculenta) and rubber tree (Hevia brasilinesis) are only
We generally applied vigorously stirred biphasic reaction media
(diisopropyl ether/aq Na-citrate buffer, pH 4.0) to the biocatalytic
cyanation reaction for substrates 1–11, freshly generated HCN
was used as the cyanating source. When 4-biphenyl carboxalde-
hyde (Substrate 1) was used as a substrate for ParsHNL-catalyzed
hydrocyanation reaction, the respective cyanohydrin was obtained
with excellent selectivity (yield: 78% and ee: 96%). On the other
* Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.022

R. Bhunya et al. / Tetrahedron: Asymmetry 20 (2009) 1526–1530
1527
CHO
CHO
CHO
CHO
CHO
MeO
3
2
OMe
5
4
CHO
CHO
CHO
CHO
1
H
N
O
N
HO
O
N
6
CHO
N
N
CHO
N
11
7
8
9
CN
10
Scheme 1. Potential ParsHNL substrates for asymmetric cyanohydrin formation.
hand, when a structurally similar 2-biphenyl carboxaldehyde (Sub-
strate 2) was subjected to ParsHNL-catalyzed hydrocyanation, the
respective cyanohydrin was obtained with low enantioselection
(ee: 32%). A similar trend with ortho-substituted aromatic alde-
hydes has already been pointed out and it was observed that, the
presence of substituents at the ortho-position (irrespective of their
electronic nature) always lead to sluggish reactions (poor ee) com-
pared to meta- and para-substituents.5a Next we attempted Pars-
HNL-catalyzed hydrocyanation reaction of two polycyclic
aromatic aldehydes 3 and 4. HNL-catalyzed hydrocyanation (PaH-
NL, P. amygdalus, almond seed) of aromatic polycyclic aldehydes,
for example, 1-naphthaldehyde and 2-naphthaldehyde were re-
ported earlier by Cruz Silva et al.,8 with excellent stereoselectivity
was observed for the synthesized cyanohydrins. When we have at-
tempted ParsHNL-catalyzed cyanohydrin formation of 6-methoxy-
2-naphthaldehyde (Substrate 3) and 4-methoxy-1-naphthalde-
hyde (Substrate 4), the respective cyanohydrins were obtained
with excellent enantioselectivities (Table 1) and good chemical
yields. This was not true in the case of 9-anthracenecarboxalde-
hyde (Substrate 5). When substrate 5 is subjected to the Pars-
HNL-catalyzed hydrocyanation reaction, the cyanohydrin is
obtained in good chemical yield, but the cyanohydrin is racemic.
It is obvious that the enzyme plays a small role in the outcome
of this reaction product; chemical cyanation prevails over a bio-
catalytic reaction and the cyanohydrin obtained is purely racemic
in nature. When we attempted a biocatalytic hydrocyanation reac-
tion of 9-anthracene carboxaldehyde with PaHNL, the respective
cyanohydrin was also obtained as a racemic mixture. Hence we
can conclude that (R)-HNL from prunus species in its active site
can accommodate polycyclic aromatic aldehydes having two fused
aromatic rings only, extra substituents in those aromatic rings are
also well accepted by the enzymes (Substrates 3 and 4).
Next we attempted ParsHNL-catalyzed hydrocyanation of alde-
hydes 6–10, where the aromatic aldehyde is substituted either at
the meta or para position by a bulky phenyl, pyridyl, pyrimidinyl
and related groups. Substrates 6 and 7 can be considered as para
substituted benzaldehyde mimic, where a pyridyl group is present
at the para position. It is known that pyridine-2-carboxaldehyde
and pyridine-4-carboxaldehyde are not good substrates for (R)-
HNL isolated from prunus species. As these aldehydes are highly
activated, the corresponding competing chemical cyanation reac-
tion causes lowering of the enantioselection for the cyanohydrins
synthesized.5 However for substrates 6 and 7 the aldehyde func-
tionality and the pyridine nucleus are not part of the same aro-
matic ring, both the substrates provide excellent enantioselection
for the respective cyanohydrins. For substrate 8, a pyrimidinyl ring
is introduced at the para-position of the benzaldehyde. The respec-
tive cyanohydrin from compound 8 is obtained with good chemical
yield (78%) and with 94% enantioselection. In substrate 9, the benz-
aldehyde is substituted by a piperazinyl group at the meta position.
Compound 9 yields the respective cyanohydrin in 72% yield with
96% enantioselection after biocatalytic hydrocyanation with pars-
HNL. For compounds 10 and 11, the benzaldehyde is substituted
at the para and meta position by phenoxy groups and both the sub-
strates provide excellent results in terms of chemical yield and
enantioselection for their respective cyanohydrins. Substrate 11,
3-phenoxybenzaldehyde, was used as a substrate for the first time
with this type of HNL from prunus species, for example, ParsHNL
which yields the respective cyanohydrin in 82% yield and with
99% enantioselection. The cyanohydrin obtained from 3-phenoxy-
benzaldehyde served as an advanced intermediate for synthetic
pyrethroids such as cypermethrin and deltamethrin.
Table 1
ParsHNL-catalyzed hydrocyanation of several aldehydes
Aldehydes
Reaction time (h)
Yield (%)
Eea (%)
1
2
3
4
5
6
7
8
9
8
8
7
8
10
8
10
12
9
8
6
72
68
70
68
78
74
74
78
72
80
82
96
32
97
94
0
98
96
94
96
96
99b
The enantioselectivity of all the cyanohydrins are determined
by chiral HPLC measurement of their respective-OTBS (tert-butyl-
dimethyl silyl; di-OTBS ether in the case of 6 and 9, Scheme 2)
ethers.
10
11
3. Conclusion
a
Ee was determined by chiral HPLC (CHIRALCEL-OJ H; hexane: 2-PrOH; flow rate
0.5–1 ml/min) measurement of the -OTBS ethers of the cyanohydrins.
This cyanohydrin itself is well resolved using HPLC under the experimental
condition.
In conclusion the present study demonstrates that ParsHNL is
capable of catalyzing a biocatalytic hydrocyanation reaction of var-
ious structurally unique aromatic aldehydes with HCN. Although
b

1528
R. Bhunya et al. / Tetrahedron: Asymmetry 20 (2009) 1526–1530
OTBS
CN
OH
CHO
ParsHNL
TBS-Cl
CN
Im, DCM
HCN, DIPE
X
X
X
1-10b
Chiral HPLC measurement
1-11
1-11a
Scheme 2. Enzymatic hydrocyanation reaction and derivatization of the cyanohydrins.
the enzyme is relatively new, it exhibits excellent substrate accep-
tance in terms of chemical yield and enantioselection for the syn-
thesized cyanohydrins. Many of the substrates, which act as very
good HNL substrates, are reported for the first time in this article.
Further studies on the synthetic potential of the new enzyme sys-
tem ParsHNL are currently in progress in our laboratory.
4.0), followed by the addition of 100
100 L of 1.0 M NaCN solution (total reaction volume 1 mL), and
the reaction mixture was incubated in a rotary shaker. After
5 min, the 100 L of the reaction mixture was taken out and ex-
tracted with 900 L hexane/2-propanol (9:1), the organic layer
was analyzed with chiral HPLC for the formation of (R)-mandelo-
nitrile. A blank reaction was also performed without enzyme, and
the amount of mandelonitrile obtained was deducted from the bio-
catalyzed reaction product. One unit of the enzyme is defined as
the amount of the enzyme that produces 1 mmol of (R)-mandelo-
nitrile under the reaction conditions in 1 min. The protein content
in all the HNL was measured by the Bradford method using Bio-Rad
protein assay kit using BSA as the standard.
lL of enzyme solution and
l
l
l
4. Experimental
4.1. General
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. Ripened
white apricot (shakarpara, P. armeniaca) was obtained from local
fruit market in Shimla (Himachal Pradesh, India) in the month of
June, 2008 and was stored at 4 °C. All aldehydes used in the exper-
iment are freshly distilled or washed with aq NaHCO3 solution to
minimize the amount of free acid, which is supposed to inhibit
HNL activity. Mandelonitrile and acetone cyanohydrins were
freshly distilled prior to use. Reactions were monitored by TLC, car-
ried out on 0.25 mm silica gel plates (Merck) with UV light, etha-
nolic anisaldehyde and phosphomolybdic acid/heat as developing
agents. Silica gel 100–200 mesh was used for column chromatog-
raphy. Yields refer to chromatographically and spectroscopically
homogeneous materials unless otherwise stated. NMR spectra
were recorded on 400 MHz spectrometer at 25 °C in CDCl3 using
TMS as the internal standard. Chemical shifts are shown in d. 13C
NMR spectra were recorded with a complete proton decoupling
environment. The chemical shift value is listed as dH and dC for
1H and 13C, respectively. Chiral HPLC was performed using chiral
OJ-H column (0.46 Â 25 cm, Daicel industries) with Shimadzu
Prominence 20AT and UV–vis detector (254 nm). Eluting solvent
used was different ratios of hexane and 2-propanol.
4.4. Preparation of racemic cyanohydrin-TBDMS ethers for
HPLC standard
Normally, an aqueous solution of NaCN (3–5 equiv) in water is
added to a solution of the carbonyl compounds (1 equiv) in acetic
acid. After completion of reaction (as indicated by TLC), the reac-
tion mixture was neutralized with an aq NaHCO3 solution. Then
it was extracted with ether and dried (anhydrous Na2SO4). Evapo-
ration and purification by column chromatography on silica affor-
ded the cyanohydrins in good yield. Racemic cyanohydrins
obtained by this method are taken in dry DCM (dichloromethane)
followed by the addition of imidazole (3 equiv) and TBDMS-Cl
(3 equiv). The reaction mixture was stirred overnight at room tem-
perature. After completion of the reaction (indicated by TLC) it was
evaporated and purified by chromatography to yield the cyanohy-
drin-TBDMS ethers which were fully characterized by NMR spec-
troscopy and used for HPLC standard.
4.5. General procedure for synthesis of cyanohydrins by ParHNL
To a solution of aromatic aldehydes 1–10 in DIPE, a solution of
ParsHNL (300 IU/mmol of aldehyde, DIPE/enzyme; 1:1 v/v) was
added and the resulting mixture was stirred vigorously until an
emulsion was formed. The pH of the enzyme solution was previ-
ously adjusted to 4.0 with 10% citric acid solution. Freshly pre-
pared HCN in DIPE (2 equiv) was added to it, and the
temperature of the solution was maintained at 10 °C. After com-
pletion of the reaction it was extracted thoroughly with ether
several times and the organic layer was dried (Na2SO4). Evapora-
tion of the solvent yielded the crude cyanohydrins which were
purified by chromatography.
4.2. Enzyme extraction from P. armeniaca (shakarpara apricot)
Ripened fruits were taken and the fleshy cover was removed to
obtain the seeds. The upper layers of the seeds were cracked with
hammer to give the soft kernels inside. Those kernels were col-
lected and homogenized in a homogenizer at 4 °C, with aq potas-
sium phosphate buffer (10 mM, pH 6.0), to give
a milky
suspension. The suspension was filtered through four layers of
cheese cloth to remove the insoluble part. After this it was centri-
fuged (18,800g, 30 min), removal of the residue gives a crude prep-
aration of HNL. The crude preparation was fractionated with
(NH4)2SO4. Proteins precipitating with 30% saturation were col-
lected by centrifugation (18,800g, 20 min), dissolved in the mini-
mum volume of phosphate buffer and dialyzed against the same
buffer with three changes. After this the dialyzed solution was cen-
trifuged and the supernatant was stored at 4 °C and assayed for
HNL activity.
4.6. Preparation of HCN in DIPE
A first, NaCN (10 g) and citric acid (0.1 g) were dissolved in
water (100 mL). The solution was cooled in an ice/water bath
and extracted with DIPE (50 mL), while acidifying with 33% HCl
until pH 5.5. The water layer, which contained a suspension of
NaCl, was extracted twice with DIPE (25 mL). The combined DIPE
layers were stored in a dark bottle. The above procedure must be
performed in a well-ventilated fume hood with proper glass ware
and safety precautions.
4.3. ParsHNL assay
In a typical assay reaction, 1.0 M of benzaldehyde solution (in
DMSO, 40 lL) was dissolved in 400 mM citrate buffer (760 lL, pH

R. Bhunya et al. / Tetrahedron: Asymmetry 20 (2009) 1526–1530
1529
4.7. (R)-Biphenyl-4-yl-(tert-butyl-dimethyl-silanyloxy)-
acetonitrile 1b
flow rate = 0.5 mL/min) tR = 9.08 min (major, R), tR = 10.07 min
(minor, S).
dH: 0.18 (s, 3H), 0.26 (s, 3H), 0.91 (s, 9H), 5.57 (s, 1H, CH–CN),
7.2–7.6 (m, 9H, Ar-H). dC: À5.0, À5.1, 18.24, 25.6, 63.87, 119.27,
126.6, 127.19, 127.67, 127.74, 128.9, 135.46, 140.3, 142.3. Elemen-
tal Anal. Calcd for C20H25NOSi: C, 74.25; H, 7.79; N, 4.33. Found: C,
74.20; H, 7.83; N, 4.35. HPLC (Daicel Chiralcel OJ-H, hexane/i-
PrOH = 19/1, flow rate = 0.8 mL/min) tR = 10.56 min (major, R),
tR = 11.8 min (minor, assumed S).
4.13. (R)-(tert-Butyl-dimethyl-silanyloxy)-(4-pyridin-4-yl-
phenyl)-acetonitrile 7b
dH: 0.18 (s, 3H), 0.25 (s, 3H), 0.95 (s, 9H), 5.58 (s, 1H, CH–CN), 7.5
(d, J = 5.6 Hz, 2H, Ar-H), 7.59 (d, J = 8.0 Hz, 2H, Ar-H), 7.68 (d,
J = 8.0 Hz, 2H, Ar-H), 8.67 (d, J = 5.2 Hz, 2H, Ar-H). dC: À5.22, À5.09,
18.14, 25.48, 63.55, 118.96, 121.59, 126.78, 127.54, 137.28, 139.08,
147.38, 150.26. Elemental Anal. Calcd for C19H24N2OSi: C, 70.33; H,
7.45; N, 8.63. Found: C, 70.39; H, 7.43; N, 8.71. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 49/1, flow rate = 0.8 mL/min) tR = 25.8 min
(major, R), tR = 27.44 min (minor, S).
4.8. (R)-Biphenyl-2-yl-(tert-butyl-dimethyl-silanyloxy)-
acetonitrile 2b
dH: À0.11 (s, 3H), 0.014 (s, 3H), 0.83 (s, 9H), 5.45 (s, 1H, CH–CN),
7.2–7.35 (m, 3H, Ar-H), 7.4–7.55 (m, 5H, Ar-H), 7.7 (d, J = 6.0 Hz,
1H, Ar-H). dC: À5.42, À5.37, 17.96, 25.4, 61.14, 119.71, 127.66,
127.87, 128.29, 128.52, 129.07, 129.13, 129.95, 134.5, 139.19,
140.5. Elemental Anal. Calcd for C20H25NOSi: C, 74.25; H, 7.79; N,
4.33. Found: C, 74.26; H, 7.85; N, 4.32. HPLC (Daicel Chiralcel OJ-
H, hexane/i-PrOH = 99/1, flow rate = 0.5 mL/min) tR = 8.02 min
(major, R), tR = 8.79 min (minor, S).
4.14. (R)-(tert-Butyl-dimethyl-silanyloxy)-(4-pyrimidin-5-yl-
phenyl)-acetonitrile 8b
dH: 0.19 (s, 3H), 0.26 (s, 3H), 0.96 (s, 9H), 5.58 (s, 1H, CH–CN),
7.64 (s, 4H, Ar-H), 8.96 (s, 2H, Ar-H), 9.23 (s, 1H, Ar-H). dC: À5.24,
À5.09, 18.14, 25.47, 63.48, 118.86, 127.08, 127.53, 133.49,
135.21, 137.35, 154.88, 157.75. Elemental Anal. Calcd for
C18H23N3OSi: C, 66.42; H, 7.12; N, 12.91. Found: C, 66.39; H,
7.13; N, 12.79. HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1,
flow rate = 0.8 mL/min) tR = 28.97 min (major, R), tR = 32.18 min
(minor, S).
4.9. (R)-(tert-Butyl-dimethyl-silanyloxy)-(6-methoxy-
naphthalen-2-yl)-acetonitrile 3b
dH: 0.14 (s, 3H), 0.23 (s, 3H), 1.0 (s, 9H), 3.94 (s, 3H), 5.64 (s, 1H,
CH–CN), 7.1–7.3 (m, 2H, Ar-H), 7.5 (m, 1H, Ar-H), 7.6-7.8 (m, 3H,
Ar-H). dC: À4.23, À4.16, 19.06, 26.42, 56.2, 65.14, 106.65, 120.22,
120.42, 124.99, 126.24, 128.67, 129.26, 130.56, 132.43, 135.75,
159.31. Elemental Anal. Calcd for C19H25NO2Si: C, 69.68; H, 7.69;
N, 4.28. Found: C, 69.74; H, 7.65; N, 4.22. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 19/1, flow rate = 0.8 mL/min) tR = 9.58 min
(major, R), tR = 10.24 min (minor, S).
4.15. (R)-(tert-Butyl-dimethyl-silanyloxy)-{3-[4-(1,1,2,2-
tetramethyl-propylsilanyl)-piperazin-1-yl]-phenyl}-acetonitrile
dH: 0.1–0.2 (s, 12H), 0.92 (s, 9H), 0.96 (s, 9H), 2.82 (s, 4H), 3.58
(s, 4H), 5.56 (s, 1H, CH–CN), 6.5–7.1 (m, 4H, Ar-H). dC: À5.32, À5.21,
À5.14, À5.06, 18.68, 18.82, 25.36, 25.77, 48.67, 59.85, 63.75, 114.6,
116.26, 118.83, 119.32, 127.32, 132.45, 142.62. Elemental Anal.
Calcd for C24H43N3OSi2: C, 64.66; H, 9.72; N, 9.43. Found: C,
64.64; H, 9.83; N, 9.49. HPLC (Daicel Chiralcel OJ-H, hexane/i-
PrOH = 9/1, flow rate = 1 mL/min) tR = 30.12 min (major, R),
tR = 36.48 min (minor, S).
4.10. (R)-(tert-Butyl-dimethyl-silanyloxy)-(4-methoxy-
naphthalen-2-yl)-acetonitrile 4b
dH: 0.1 (s, 3H), 0.15 (s, 3H), 0.9 (s, 9H), 4.02 (s, 3H), 5.95 (s, 1H,
CH–CN), 6.8 (d, J = 8.0 Hz, 1H, Ar-H), 7.5–7.6 (m, 3H, Ar-H), 8.1–8.4
(m, 2H, Ar-H). dC: À5.01, À4.97, 18.19, 25.55, 55.63, 63.27, 102.63,
119.43, 122.89, 123.23, 123.78, 124.22, 125.66, 126.07, 127.42,
130.96, 156.92. Elemental Anal. Calcd for C19H25NO2Si: C, 69.68;
H, 7.69; N, 4.28. Found: C, 69.69; H, 7.63; N, 4.21. HPLC (Daicel Chi-
ralcel OJ-H, hexane/i-PrOH = 19/1, flow rate = 0.8 mL/min)
tR = 10.5 min (major, R), tR = 11.68 min (minor, S).
4.16. (R)-4-{4-[(tert-Butyl-dimethyl-silanyloxy)-cyano-
methyl]-phenoxy}-benzonitrile 10b
dH: 0.17 (s, 3H), 0.25 (s, 3H, 0.98 (s, 9H), 5.52 (s, 1H, CH–CN), 7.02
(d, J = 8.8 Hz, 2H, Ar-H), 7.1 (d, J = 8.8 Hz, 2H, Ar-H), 7.5 (d, J = 8.8 Hz,
2H, Ar-H), 7.62 (d, J = 8.8 Hz, 2H, Ar-H). dC: À5.15, À5.03, 18.19,
25.55, 63.44, 106.56, 118.42, 119.08, 120.53, 128.14, 133.23,
134.27, 155.79, 160.99. Elemental Anal. Calcd for C21H24N2O2Si: C,
69.20; H, 6.64; N, 7.68. Found: C, 69.29; H, 6.67; N, 7.78. HPLC (Daicel
Chiralcel OJ-H, hexane/i-PrOH = 49/1, flow rate = 1 mL/min)
tR = 25.16 min (major, R), tR = 27.79 min (minor, S).
4.11. Anthracen-9-yl-(tert-butyl-dimethyl-silanyloxy)-
acetonitrile 5b
Spectroscopic data are in agreement as reported in the
literature.7
4.17. (R)-2-Hydroxy-2-(3-phenoxy-phenyl)-acetonitrile
Elemental Anal. Calcd for C22H25NOSi: C, 76.03; H, 7.25; N, 4.03.
Found: C, 76.09; H, 7.23; N, 4.11.
dH: 7.38 (m, 3H, Ar-H), 7.2 (m, 1H, Ar-H), 7.16 (m, 2H, Ar-H), 7.0
(m, 3H, Ar-H), 5.48 (s, 1H, CH–CN). dC: 158.0, 156.3, 137.0, 130.5,
129.9, 123.9, 120.9, 119.6, 119.2, 118.6, 116.7, 62.9. Elemental
Anal. Calcd for C14H11NO2: C, 74.65; H, 4.92; N, 6.22. Found: C,
74.56; H, 4.87; N, 6.28. HPLC (Daicel Chiralcel OJ-H, hexane/i-
PrOH = 9/1, flow rate = 1 mL/min) tR = 25.4 min (major, R),
tR = 33.0 min (minor, S).
4.12. 4.11.(R)-(tert-Butyl-dimethyl-silanyloxy)-{4-[6-(tert-
butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-phenyl}-
acetonitrile 6b
dH: 0.15 (s, 12H), 0.92 (s, 9H), 0.99 (s, 9H), 4.91 (s, 2H), 5.56 (s,
1H, CH–CN), 7.5–7.6 (m, 4H, Ar-H), 7.7 (t, J = 8.0 Hz, 1H, Ar-H), 8.0
(d, J = 8.0 Hz, 2H, Ar-H). dC: À5.30, À5.24, À5.12, À5.03, 18.21,
18.42, 25.56, 25.97, 63.88, 66.32, 118.77, 119.16, 126.55, 127.55,
136.9, 137.43, 140.59, 155.45, 161.63. Elemental Anal. Calcd for
C26H40N2O2Si2: C, 66.62; H, 8.60; N, 5.98. Found: C, 66.69; H,
8.63; N, 5.91. HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 49/1,
Acknowledgements
We are thankful to IFS, Sweden (Grant agreement no: F/4192-1)
for financial assistance. Two of the authors (TM and RB) are thank-
ful to CSIR, India for research fellowships.

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R. Bhunya et al. / Tetrahedron: Asymmetry 20 (2009) 1526–1530
4. There are few recent references on HNL catalyzed cyanohydrin synthesis and
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