An asymmetric, chemo-enzymatic synthesis of O-acetylcyanohydrins

Article abstract of DOI:10.1002/ejoc.200600467

A one-pot chemo-enzymatic synthesis of highly enantiomerically enriched O-acetylcyanohydrins has been developed. The bimetallic (salen)titanium complex 1 is used to convert aldehydes into nonracemic (R)-O-acetylcyanohydrins with 61 to 93 % enantiomeric ex

Full text of DOI:10.1002/ejoc.200600467

FULL PAPER
DOI: 10.1002/ejoc.200600467
An Asymmetric, Chemo-Enzymatic Synthesis of O-Acetylcyanohydrins
Yuri N. Belokon,[a] A. John Blacker,[b] Lisa A. Clutterbuck,[c] David Hogg,[b]
Michael North,*[c] and Christopher Reeve[d]
Keywords: Asymmetric catalysis / Biotransformation / Titanium / Schiff bases / Cyanohydrin
A one-pot chemo-enzymatic synthesis of highly enantiomer-
ically enriched O-acetylcyanohydrins has been developed.
The bimetallic (salen)titanium complex 1 is used to convert
aldehydes into nonracemic (R)-O-acetylcyanohydrins with 61
to 93% enantiomeric excess. A lipase enzyme is then used
to hydrolyse the unwanted (S) enantiomer of the product,
high reaction rates and enantioselectivities, two procedures
to allow their sequential use without purification of the O-
acetylcyanohydrin produced by catalyst 1 have been devel-
oped. In the first of these, the reaction with catalyst 1 is car-
ried out in dichloromethane which is then removed and re-
placed with methyl tert-butyl ether prior to addition of the
leaving (R)-O-acetylcyanohydrins with 80 to Ͼ99% enantio- enzyme. In the second procedure, the first reaction is carried
meric excess and in 75 to 96% overall yield. Of ten lipase
enzymes investigated, Candida antarctica lipase-B (CAL-B)
has been shown to be the most suitable and the conditions
for its use have been optimised. Although no single solvent
has been found in which both catalyst 1 and CAL-B gave
out in concentrated dichloromethane solution, and this is
then just diluted with methyl tert-butyl ether prior to addition
of the lipase.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Chiral cyanohydrins are versatile intermediates for the
stereocontrolled synthesis of a wide range of 1,2-difunc-
tional compounds such as α-hydroxy acids,[2] β-amino
alcohols[3] and α-amino acids.[4] As a result, there is cur-
rently considerable interest in the development of new
methods for the synthesis of nonracemic cyanohydrins.[5]
Highly effective catalytic syntheses of cyanohydrins have
been developed using both Lewis acid metal-based catalysts
and enzymes. Metal-based catalysts are capable of inducing
the asymmetric addition of a variety of cyanide sources
(hydrogen cyanide,[6] trimethylsilyl cyanide,[7] potassium cy-
anide,[8] cyanoformates,[9] cyanophosphonates[10] etc.) to al-
dehydes and ketones with good to high enantioselectivity.
Enzymatic approaches have been developed using either
oxynitrilase enzymes[11] to catalyse the asymmetric addition
of hydrogen cyanide to aldehydes, or using lipases to cata-
lyse the asymmetric formation[12] or hydrolysis of cyanohyd-
rin esters.[13]
Introduction
One of the main goals of green chemistry is the develop-
ment of catalysts for organic synthesis which are mutually
compatible and tolerant of any reagents and side products,
thus allowing sequential transformations to be carried out
in one pot without the need to isolate and purify reaction
intermediates.[1] This is often achieved by preparing im-
mobilised versions of catalysts which cannot interact with
one another. However, the immobilisation methodology can
adversely affect both the rate and enantioselectivity of a
catalyst. In this manuscript, we demonstrate the use of an
unmodified, solution-phase synthetic asymmetric catalyst
and a lipase enzyme to achieve two sequential synthetic
transformations, both of which occur enantioselectively.
We have developed bimetallic (salen)titanium complex 1
as a highly effective catalyst for asymmetric cyanohydrin
synthesis.[14,15] Catalyst 1 is compatible with a variety of
cyanide sources including trimethylsilyl cyanide,[16] cyano-
formates,[17] acetyl cyanide[18] and potassium cyanide[19] to
generate a variety of cyanohydrin derivatives derived from
both aldehydes and ketones. An unique feature of complex
1 (along with the related (salen)VV complex[17] and poly-
mer-supported versions of these catalysts[8,20]) is its ability
to catalyse the asymmetric addition of potassium cyanide
to aldehydes in the presence of an anhydride, giving cya-
nohydrin esters with up to 95% enantiomeric excess
[a] A. N. Nesmeyanov Institute of Organo-Element Compounds,
Russian Academy of Sciences,
117813, Moscow, Vavilov 28, Russian Federation
E-mail: yubel@ineos.ac.ru
[b] NPILPharma R+D,
P. O. Box 521, Leeds Rd., Huddersfield, West Yorkshire, HD2
1GA, United Kingdom
E-mail: john.blacker@npilpharma.co.uk
[c] School of Natural Sciences, Bedson building, University of
Newcastle,
Newcastle upon Tyne, NE1 7RU, United Kingdom
E-mail: michael.north@ncl.ac.uk
[d] NPILPharma R+D,
P. O. Box 2, Belasis Avenue, Billingham, Cleveland, TS23 1YN,
United Kingdom
Eur. J. Org. Chem. 2006, 4609–4617
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Yu. N. Belokon, A. J. Blacker, L. A. Clutterbuck, D. Hogg, M. North, C. Reeve
FULL PAPER
(Scheme 1).[17] This chemistry has already been used in an
asymmetric synthesis of α-acetoxy amides,[21] and for the
synthesis of polymer-supported cyanohydrin esters.[22]
However, whilst in the best cases excellent enantioselectivi-
ties are obtained, some substrates give products with ee
Ͻ90%.[17] Because the products of this reaction are esters,
it was attractive to investigate the combined use of catalyst
1 to synthesise chiral O-acetylcyanohydrins, and a suitable
lipase enzyme to hydrolyse the minor enantiomer of the
product back to the corresponding cyanohydrin, which
would decompose back to the starting aldehyde under the
reaction conditions. In this way, the enantiomeric excess of
the O-acetylcyanohydrin would be enhanced without a
major reduction in the chemical yield. Ideally, the two reac-
tions should occur in a one-pot process without any need
to isolate or purify the crude O-acetylcyanohydrin. In this
manuscript, we describe the development of just such a one-
pot, chemo-enzymatic synthesis of O-acetylcyanohydrins.
Results and Discussion
Initially, various lipase enzymes were screened for the hy-
drolysis of racemic O-acetylmandelonitrile [PhCH(OAc)-
CN] 2. Porcine pancreatic lipase, Candida rugosa lipase,
Pseudomonas fluorescens lipase and Pseudomonas cepacia li-
pase, have all previously been used in the synthesis of op-
tically active cyanohydrins,[23–27] but gave poor conversions
and enantioselectivities with substrate 2. Rhizopus nevieus
lipase was also totally unreactive towards compound 2 un-
der the reaction conditions studied. Selected results for
other enzymes are given in Table 1.
Candida antarctica lipase-B (CAL-B) has previously been
used to hydrolyse various O-acetylcyanohydrins, giving
products with high enantiomeric excesses (up to Ͼ99%) in
short reaction times, though at elevated temperature.[28]
This temperature was incompatible with its use in situ with
catalyst 1, which requires ambient or lower temperatures to
obtain high enantioselectivities. Fortunately, a reaction
using this enzyme was found to proceed at room tempera-
ture giving a good conversion and enantioselectivity after
one day (Table 1: Entry 1). By increasing the amount of
enzyme, the reaction time could be reduced to 3 h and (R)-
O-acetylmandelonitrile with 94% enantiomeric excess was
obtained after just over 50% conversion (Table 1: Entries 2
and 3). The enantiomeric excess of the mandelonitrile pro-
duced in these reactions was not determined as this was not
relevant to the ultimate aim of the project and was also
expected to be unreliable due to spontaneous racemisation
of mandelonitrile (vide infra). Changing the nucleophile
from water to propan-2-ol or propan-1-ol so that the enzy-
matic reaction became a transesterification rather than a
hydrolysis,[24] again had a beneficial effect, allowing the
amount of enzyme to be reduced to 100 mg/mmol 2 whilst
maintaining a rapid rate of reaction and a high enantio-
selectivity (Table 1: Entries 4 and 5). The solvent could be
changed to methyl tert-butyl ether without adversely affect-
ing the reaction rate or enantioselectivity (Table 1: Entries 6
and 7), but attempted use of dichloromethane (the optimal
Scheme 1. Synthesis of cyanohydrin esters using catalyst 1.
Table 1. Lipase-catalysed resolution of racemic O-acetylmandelonitrile.
Entry
Lipase [mg/mmol 2]
Solvent
Nucleophile
Time [h]
Conversion [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
CAL-B (83)
CAL-B (167)
CAL-B (500)
CAL-B (100)
CAL-B (100)
CAL-B (100)
CAL-B (100)
CAL-B (100)
ASL (100)
ASL (100)
PSL (100)
PSL (100)
PCL (100)
toluene
toluene
toluene
toluene
water
water
water
19[c]
48
48
51
49
88 (R)
92 (R)
94 (R)
96 (R)
18[c]
3[c]
iPrOH
nPrOH
nPrOH
nPrOH
iPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
6[c]
toluene
4, 20[d]
4, 20[d]
18[c]
15, 45[e]
45, 50[e]
50
21, 83[e] (R)
82, Ͼ99[e] (R)
Ͼ99 (R)
MeOtBu
MeOtBu
CH2Cl2
MeOtBu
MeOtBu
MeOtBu
MeOtBu
MeOtBu
MeOtBu
MeOtBu
141[c]
4, 20[d]
18[c]
48
84 (R)
9
42, 63[e]
53
70, Ͼ99[e] (R)
Ͼ99 (R)
10
11
12
13
14
15
4, 20[d]
18[c]
46, 60[e]
55
85, Ͼ99[e] (R)
Ͼ99 (R)
4, 20[d]
4, 20[d]
18[c]
29, 47[e]
15, 36[e]
34
40, 88[e] (R)
18, 56[e] (S)
51 (S)
CRE (100)
CRE (100)
1
[a] Determined by H NMR spectroscopy with an error of +/– 4%. [b] Determined by chiral GC with an error of +/– 3%. [c] Reaction
was stirred at 20 °C under nitrogen for the specified time. [d] Reaction was shaken at 20 °C under nitrogen and sampled after 4 h and
20 h. [e] first number refers to sample taken after 4 h and the second number to sample taken after 20 h.
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Asymmetric, Chemo-Enzymatic Synthesis of O-Acetylcyanohydrins
FULL PAPER
solvent for catalyst 1) resulted in a significantly lengthened Table 2. Lipase-catalysed resolution of nonracemic O-acetylmande-
lonitrile.[a,b]
reaction time (Table 1: Entry 8).
Alcaligenes sp. lipase (ASL), which has previously been
used to enantioselectively acetylate 3-phenoxymandelo-
nitrile,[29] was found to be highly reactive and enantioselec-
tive for transesterifications carried out in methyl tert-butyl
ether (Table 1: Entries 9 and 10), but was both less reactive
and less enantioselective when toluene or dichloromethane
was used as solvent. Similar results were obtained with
Pseudomonas stutzeri lipase (PSL) (Table 1: Entries 11 and
12), celite-immobilised Pseudomonas cepacia lipase (PCL)
(Table 1: Entry 13) and Candida rugosa esterase (CRE)
(Table 1: Entries 14 and 15), all of which gave the fastest
and most enantioselective reactions in methyl tert-butyl
Entry
Lipase
Time [h]
Conversion [%][c] ee [%][d]
1
2
3
4
5
6
7
8
CAL-B
CAL-B
CAL-B
CAL-B
ASL
ASL
ASL
ASL
ASL
ASL
ASL
PSL
1
2
3.5
5
1
2
3.5
5
3
5
83
88
8
11
3
95
Ͼ99
81
5
8
85
89
10
11
13
31
3
93
95
96
Ͼ99
82
9
6
10
11
12
13
7.5
23.5
1
PSL
2
4
84
ether. However, both the reactivity and enantioselectivity 14
PSL
PSL
PSL
PSL
3.5
5
6
7.5
23.5
6
7
8
9
87
90
91
93
15
decrease in the order PSL Ͼ PCL Ͼ CRE. CRE was how-
16
ever notable as it hydrolysed the opposite enantiomer of the
17
substrate to all of the other enzymes, leaving an excess of
18
PSL
18
Ͼ99
the (S) enantiomer of O-acetylmandelonitrile.
[a] Initial ee of O-acetylmandelonitrile = 77%. [b] All reactions
were carried out at 20 °C in methyl tert-butyl ether using propan-
1-ol as nucleophile and 100 mg of enzyme for every mmol of O-
acetylmandelonitrile. [c] Conversions were determined by 1H NMR
spectroscopy. [d] ee Values were determined by chiral GC.
Enzymatic reactions are often carried out in shaken
rather than stirred reaction vessels so as to avoid physical
damage to the enzyme or its support. Therefore, some of
the reactions described in Table 1 were carried out with
magnetic stirring whilst others were agitated on a shaking
plate. In many cases these reactions were directly compar- and PSL both required reaction times of 23.5 h to achieve
able and demonstrated that the mode of agitation had no the same enantioselectivity (Table 2: Entries 11 and 18).
effect on the rate of reaction or enantioselectivity (compare CAL-B is also intrinsically more enantioselective, as it pro-
the following pairs of Entries in Table 1: 6 and 7; 9 and 10; duces (R)-O-acetylmandelonitrile with Ͼ99% enantiomeric
11 and 12; 14 and 15). This was significant for the eventual excess after hydrolysing just 10% of the substrate whilst
aim of conducting the asymmetric cyanohydrin synthesis ASL has to hydrolyse 31% of the O-acetylmandelonitrile to
and enzymatic hydrolysis in a one-pot process.
achieve the same enantiomeric excess and PSL has to hy-
Because of the above results, three enzymes: CAL-B, drolyse 18% of the substrate. Both of these enzymes are
ASL and PSL were determined to be sufficiently active to clearly capable of hydrolysing both enantiomers of O-ace-
justify further investigation of their reactivity. Whilst CAL- tylmandelonitrile, whereas comparison of the data in
B[24] and ASL[25] have previously been shown to accept cya- Table 2 (Entry 4) with that in Table 1 (Entry 7) indicates
nohydrin substrates, PSL appears not have been previously that under these reaction conditions, CAL-B will not accept
investigated with this class of substrate. These three en- the (R) enantiomer of O-acetylmandelonitrile as a sub-
zymes were therefore employed to enantioselectively hydro- strate. As a result, CAL-B was selected as the only enzyme
lyse a nonracemic sample of O-acetylmandelonitrile which to be used in further studies.
had been prepared using catalyst 1 as previously re-
The nature and number of equivalents of alcohol used in
ported.[17] Because all three enzymes selectively hydrolysed the resolution of racemic O-acetylmandelonitrile was found
the (S) enantiomer of O-acetylmandelonitrile, a sample en- not to have a major influence on the rate or enantio-
riched in the (R) enantiomer was required and this was pre- selectivity of the reaction. Thus, reactions carried out in
pared with 77% enantiomeric excess using the (S,S) enanti- methyl tert-butyl ether in the presence of 1–4 equiv. of pro-
omer of catalyst 1 and was purified by column chromatog- pan-1-ol all gave 51–56% conversion after 22 h and the re-
raphy prior to use in the enzymatic reaction. The enzymatic maining (R)-O-acetylmandelonitrile had an enantiomeric
reactions were carried out using methyl tert-butyl ether as excess of Ͼ99% in each case. However, use of a large excess
solvent and samples were withdrawn at regular intervals to of alcohol did have a small effect in retarding the enzymatic
allow both the progress of the reaction and the enantio- reaction as after 4 h reaction, the conversion decreased
meric excess of the remaining (R)-O-acetylmandelonitrile to from 37% with 1 equiv. of propan-1-ol to 16% with 4 equiv.
be determined. The results are shown in Table 2.
of propan-1-ol. Reactions were carried out using four dif-
This study highlighted two significant factors. The first ferent alcohols (propan-1-ol to hexan-1-ol), and almost
is that reactions catalysed by CAL-B are much faster than identical conversions and enantioselectivities were obtained
those catalysed by either of the other two enzymes (this may in each case. Therefore, use of 1 equiv. of propan-1ol was
reflect the purity of the commercial enzyme preparation selected as the standard conditions for subsequent work.
rather than any intrinsic rate difference) as CAL-B was able
The optimal concentration of O-acetylmandelonitrile
to increase the enantiomeric excess of (R)-O-acetylmande- was next determined by carrying out reactions at racemic
lonitrile to Ͼ99% in just 5 h (Table 2: Entry 4) whilst ASL mandelonitrile concentrations of 0.1–0.2 , and analysing
Eur. J. Org. Chem. 2006, 4609–4617
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Yu. N. Belokon, A. J. Blacker, L. A. Clutterbuck, D. Hogg, M. North, C. Reeve
FULL PAPER
both the conversion and enantioselectivity after 4 h reac- enriched cyanohydrins could be achieved as shown in
tion. A concentration of 0.15  was found to be optimal Scheme 2. Thus, after the initial conversion of aldehydes
(44% conversion and 77% ee), with both lower and higher into (R)-O-acetylcyanohydrins using the (S,S) enantiomer
substrate concentrations giving lower conversions (33% for of catalyst 1 in dichloromethane, the solvent was removed
0.1  and 19% for 0.2 ) and therefore lower apparent in vacuo and without further purification, the O-acetylcya-
enantioselectivities (49% for 0.1  and 23% for 0.2 ). The nohydrin was redissolved in methyl tert-butyl ether or tolu-
substrate to enzyme ratio was also optimised with reactions ene and treated with CAL-B to hydrolyse the small amount
conducted using 50, 100, 125, 150, 175 and 200 mg of en- of the (S) enantiomer of the O-acetylcyanohydrin present.
zyme per mmol of substrate under the standard conditions The highly enantiomerically enriched (R)-O-acetylcyanohy-
developed above. Only at the two highest substrate to en- drin could then be isolated by column chromatography. The
zyme ratios had the reactions not reached completion (50% results obtained for a range of aldehydes are shown in
conversion) after 6 h, and all of the other reactions gave Table 4.
(R)-mandelonitrile with at least 95% enantiomeric excess.
Therefore, use of 125 mg of enzyme per mmol of substrate
was selected as the most effective amount of enzyme.
Under the optimised conditions of: substrate concentra-
tion 0.150 , 125 mg of CAL-B/mmol substrate and
1 equiv. of propan-1-ol in methyl tert-butyl ether at room
temperature, the resolution of a nonracemic (77% ee) sam-
ple of O-acetylmandelonitrile was again investigated. The
enantiomeric excess of both the unreacted O-acetylmande-
lonitrile and the hydrolysed mandelonitrile were determined
by chiral GC, and the results are shown in Table 3. As ex-
pected, the reaction proceeded rapidly under these condi-
tions and after just 5 h all of the (S)-O-acetylmandelonitrile
had been hydrolysed leaving (R)-O-acetylmandelonitrile
with 99% enantiomeric excess. The enantiomeric excess of
Scheme 2. Chemo-enzymatic synthesis of (R)-O-acetylcyanohyd-
rins.
the hydrolysed mandelonitrile was found to decrease as the
As can be seen from Table 4, the presence of cyanide
reaction progressed, presumably due to racemisation by a salts, titanium residues and unreacted acetic anhydride did
cyanide elimination–readdition mechanism.
not inhibit the hydrolytic activity of CAL-B in these reac-
tions. Aromatic aldehydes which had been converted into
(R)-O-acetylcyanohydrins with 70–90% ee by catalyst 1
were enantiomerically enriched to 90–99% ee after treat-
ment with the lipase enzyme. In most cases, the enzymatic
hydrolysis reaction was complete in 5–8 h, with only the
sterically hindered O-acetylcyanohydrin derived from 2-
methylbenzaldehyde requiring a longer reaction time. Two
substrates (the O-acetylcyanohydrins of 3- and 4-methyl-
benzaldehyde) were subjected to enzymatic hydrolysis in
Table 3. CAL-B-catalysed resolution of nonracemic O-acetylmand-
elonitrile.
Time
[h]
ee,
ee,
Conversion
[%]
O-acetylmandelonitrile mandelonitrile
1
2
3.5
5
89 (R)
95 (R)
98 (R)
99 (R)
90 (S)
89 (S)
82 (S)
79 (S)
7
10
12
13
Having determined the optimal conditions for the enzy- toluene rather than methyl tert-butyl ether. Even with this
matic hydrolysis of O-acetylmandelonitrile, the most signifi- nonoptimal solvent, these two substrates still gave (R)-O-
cant limitation in developing a chemo-enzymatic synthesis acetylcyanohydrins with 97–98% ee values, though the reac-
of O-acetylcyanohydrins appeared to be the differing sol- tion times were considerably lengthened compared to those
vent requirements of catalyst 1 and CAL-B. Catalyst 1 is typically needed for reactions carried out in methyl tert-
most active in dichloromethane, whilst the enzyme only butyl ether. This confirmed the general superiority of the
shows high reaction rates in methyl tert-butyl ether and tol- ether solvent for the enzymatic hydrolyses.
uene. Therefore, the use of other solvents for the asymmet-
Heteroaromatic aldehydes which were only moderate
ric synthesis of O-acetylcyanohydrins using catalyst 1 under substrates for catalyst 1 were excellent substrates for CAL-
the conditions shown in Scheme 1 was investigated. How- B and the enantiomeric excess of the corresponding O-ace-
ever, reactions carried out in THF, diethyl ether, 1-butanol, tylcyanohydrins were raised from 61–77% to 88–98% after
2-propanol, toluene or methyl tert-butyl ether were all just 4–6.5 h treatment with the enzyme. Cinnamaldehyde
much slower and less enantioselective than the correspond- was also an excellent substrate for the enzymatic hydrolysis
ing reaction carried out in dichloromethane. Thus it ap- and its (R)-O-acetylcyanohydrin could be isolated with 95%
peared that it would not be possible to find a suitable single ee and in 80% yield. Aliphatic aldehydes are moderate sub-
solvent for both the synthesis and hydrolysis of the cya- strates for catalyst 1, and also gave mixed results in the sub-
nohydrins.
sequent enzymatic hydrolysis. Thus, whilst the O-acetylcya-
Nevertheless, the enzymatic results did indicate that a nohydrin of a primary aldehyde (nonanal) was an excellent
two step asymmetric synthesis of highly enantiomerically substrate for CAL-B, O-acetylcyanohydrins of the second-
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Asymmetric, Chemo-Enzymatic Synthesis of O-Acetylcyanohydrins
Table 4. A two-step, chemo-enzymatic synthesis of O-acetylcyanohydrins.
FULL PAPER
Aldehyde
ee,
ee,
Time
Overall yield
[%]
after (salen)Ti-catalysed synthesis[a] after enzymatic hydrolysis[b]
of enzymatic reaction [h]
PhCHO
84
80
79
87
72
87
81
77
99
97
90
94
90
98
97
98
88
94
95
92
74
68
63
7
8
5
5
27
192
168
6
6.5
4
5
7
23.5
21
23
81
81
74
84
69
61
50
78
72
77
80
66
46
65
60
4-ClC6H4CHO
2-ClC6H4CHO
3-MeOC6H4CHO
2-MeC6H4CHO
3-MeC6H4CHO[c]
4-MeC6H4CHO[c]
2-Furaldehyde
Thiophene-2-carbaldehyde 61
Nicotinaldehyde
PhCH=CHCHO
Me(CH2)7CHO
Me2CHCHO
CyCHO
67
75
77
47
60
63
Me3CCHO
[a] Reaction conditions: aldehyde, potassium cyanide, acetic anhydride (mol ratio = 1:4:4), 1 mol% (S,S)-1, CH2Cl2, tBuOH, H2O,
–40 °C. [b] 125 Mg/mmol CAL-B, 1 equiv. isopropyl alcohol, 0.150 mol/L MeOtBu. [c] Reaction carried out in toluene using isolated and
purified O-acetylcyanohydrin.
Table 5. A one-pot, chemo-enzymatic synthesis of O-acetylcyanohydrins.
Aldehyde
ee,
ee,
Time
Overall conversion
[%]
after (salen)Ti-catalysed synthesis[a]
after enzymatic hydrolysis[b]
of enzymatic reaction [h]
PhCHO
76
89
75
93
64
67
76
97
Ͼ99
89
97
80
90
Ͼ99
95
92
92
26
7
84
94
89
96
90
85
86
83
82
75
4-ClC6H4CHO
2-ClC6H4CHO
3-MeOC6H4CHO
2-MeC6H4CHO
PhCH=CHCHO
2-Furaldehyde
Thiophene-2-carbaldehyde 70
Nicotinaldehyde
Me(CH2)7CHO
22
23
22
23.5
23
8
61
69
7.5
22
[a] Reaction conditions: aldehyde, potassium cyanide, acetic anhydride (mol ratio = 1:4:4), promoted by 1 mol% of (S,S)-1, CH2Cl2,
tBuOH, H2O, stirring at –40 °C. [b] 125 mg/mmol CAL-B, 1 equiv. isopropyl alcohol, 0.15 mol/L MeOtBu added to the CH2Cl2 solution.
ary aldehydes 2-methylpropanal and cyclohexane carboxal- cases, the final enantiomeric excess of the O-acetylcyanohy-
dehyde were much more moderate substrates, requiring ex- drin was comparable for reactions carried out with a change
tended reaction times to show a moderate to marginal in- of solvent (Table 4) or under one-pot conditions (Table 5),
crease in enantiomeric excess. Finally, the O-acetyl- though the latter reactions usually required longer reaction
cyanohydrin of pivaldehyde was not a substrate for CAL-B, times for the enzymatic reactions. The only exception was
clearly indicating that this enzyme can only accommodate the O-acetylcyanohydrin derived from 2-methylbenzalde-
primary and secondary aldehydes within its active hyde, which was obtained with 10% lower enantiomeric ex-
site.
cess in the one-pot process. However, this difference is due
Whilst the above process was effective in synthesising to a change in the enantiomeric excess of the product at
highly enantiomerically enriched cyanohydrins, the need to the end of the titanium-catalysed reaction, rather than any
change the solvent between the two reactions was inconve- difference in the enzymatic reaction. In both cases, CAL-B
nient, especially for large-scale reactions. Therefore, as a fi- raised the enantiomeric excess of the O-acetylcyanohydrin
nal stage of reaction optimisation, it was decided to investi- by 16–18% in 22–27 h.
gate the compatibility of CAL-B to a mixed solvent system
of dichloromethane and methyl tert-butyl ether. This would
allow the asymmetric cyanation reaction to be carried out
in pure dichloromethane followed by the addition of the
Conclusions
enzyme and a fourfold excess of its preferred solvent to
carry out the hydrolysis reaction. Results obtained for this able of enantioselectively hydrolysing O-acetylcyanohydrins.
process are shown in Table 5. From the lipases screened, CAL-B was selected as showing
We have demonstrated that a variety of lipases are cap-
Under these conditions, CAL-B was found to retain its the most promising activity, and the conditions for its use
catalytic activity and ten different aldehydes were converted with a range of O-acetylcyanohydrins have been optimised.
into the corresponding O-acetylcyanohydrins. In most No single solvent could be found in which both catalyst 1
Eur. J. Org. Chem. 2006, 4609–4617
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4613

Yu. N. Belokon, A. J. Blacker, L. A. Clutterbuck, D. Hogg, M. North, C. Reeve
FULL PAPER
N2. The specified amount of a lipase enzyme was then added to the
solution and the reaction mixture was stirred vigorously at room
temperature. At suitable intervals (3–24 h depending on the nature
and concentration of the enzyme), samples were taken from which
the enzyme was removed by filtration and the solvent evaporated
and CAL-B exhibited high activity, but two procedures to
allow the combined use of the synthetic catalyst and en-
zyme were developed. These processes allowed a wide range
of aromatic, heteroaromatic, and aliphatic aldehydes to be
converted into the corresponding O-acetylcyanohydrins
with higher enantiomeric excesses than could be obtained
using catalyst 1 alone and higher yields than could be ob-
tained using an enzyme to resolve the racemic O-acetylcya-
nohydrin. Although this chemistry has been demonstrated
with CAL-B, it is clearly compatible with other lipase en-
zymes, so that in those cases where CAL-B does not give
satisfactory results (e.g. secondary and tertiary aliphatic al-
dehydes), an alterative lipase enzyme could be used.
1
in vacuo. The residue was analysed by H NMR spectroscopy and
chiral GC in order to obtain the conversion and the enantiomeric
excess of the (R)-O-acetylmandelonitrile. After the period of time
specified in Table 1, the whole reaction was worked-up and ana-
lysed in the same way.
General Procedure for the Enzymatic Resolution of Racemic O-Ace-
tylmandelonitrile. Method B: This procedure was used for those re-
actions in Table 1 which were agitated by shaking. To racemic O-
acetylmandelonitrile (80 mg, 0.46 mmol) in a screw-cap vial was
added the specified solvent (4.8 mL), and nPrOH (55 mg, 0.07 mL,
0.91 mmol). The lipase enzyme (46 mg) was then added to the solu-
tion and the reaction mixture was gently agitated on a spiro-mix at
room temperature. After 4 h and 20 h, samples were taken from
which the enzyme was removed by filtration and the solvent re-
moved in vacuo. The residue was analysed by 1H NMR spec-
troscopy and chiral GC in order to obtain the conversion and the
enantiomeric excess of the (R)-O-acetylmandelonitrile.
Experimental Section
Toluene was distilled from sodium prior to use. THF was dried by
distillation from metallic sodium. CAL-B was obtained from
Sigma, other enzymes were obtained from Europa Bioproducts
Ltd. Chromatographic separations were performed with silica gel
60 (230–400 mesh) and thin layer chromatography was performed
on polyester-backed sheets coated with silica gel 60 F254, both sup-
plied by Merck. Chiral gas chromatography was performed on a γ-
CD Butyryl, fused silica capillary column (30 m×0.25 mm) using
hydrogen as the carrier gas.
General Procedure for the Enzymatic Resolution of Nonracemic O-
Acetylmandelonitrile: This procedure was used for the reactions de-
tailed in Table 2 and Table 3. nPrOH (450 mg, 0.58 mL, 7.52 mmol)
was added to nonracemic (R)-O-acetylmandelonitrile[17] (659 mg,
3.76 mmol, ee 77%) in MeOtBu (38 mL) under N2. The lipase en-
zyme (376 mg) was added and the reaction was stirred vigorously
at room temperature. At suitable intervals (1–6 h), samples were
taken from which the enzyme was removed by filtration and the
solvent removed in vacuo. The residue was monitored by 1H NMR
spectroscopy and chiral GC to obtain the conversion and the enan-
tiomeric excess of the (R)-O-acetylmandelonitrile. After the period
of time specified in Table 2 or Table 3, the whole reaction was
worked-up and analysed in the same way.
Optical rotations were recorded with a Perkin–Elmer 343 polarime-
ter in a thermostatted cell of length 1 dm at 20 °C using the sodium
D-line, and a suitable solvent that is reported along with the con-
centration (g/100 mL). Infrared spectra were recorded with a Per-
kin–Elmer FT-IR Paragon 1000 spectrometer, as a thin film be-
tween NaCl plates. The characteristic absorption is reported as
strong (s), medium (m) or weak (w) in cm–1. 1H and 13C NMR
1
spectra were recorded with a Bruker Avance 300 spectrometer. H
and 13C NMR spectra were referenced to TMS and chemical shift
(δ) values, expressed in parts per million (ppm), are reported down-
field of TMS. The multiplicity of signals is reported as singlet (s)
or multiplet (m). Low- and high-resolution mass spectra were re-
corded at the EPSRC national service at the University of Wales,
Swansea. The sample was ionised by electron ionisation (EI), chem-
ical ionisation (CI) or electrospray ionisation (ESI). The major
fragment ions are reported and only the molecular ions are as-
signed.
General Procedure for the Chemo-Enzymatic Synthesis of Enantio-
merically Enriched O-Acetylcyanohydrins. Method A: This method
was used for the reactions detailed in Table 4. tBuOH (0.47 mL,
4.95 mmol), water (0.04 mL, 2.36 mmol) and the aldehyde
(4.7 mmol) were added successively to a stirred solution of potas-
sium cyanide (1.23 g, 18.8 mmol) and (S,S)-1 (57 mg, 0.047 mmol)
in CH2Cl2 (20 mL). The solution was then cooled to –80 °C, and
acetic anhydride (1.8 mL, 18.8 mmol) was added. The yellow solu-
tion was then warmed to –40 °C and was stirred vigorously for
48 h. The reaction mixture was then concentrated in vacuo and
the residue resuspended in MeOtBu (35 mL). CAL-B (0.59 g) and
nPrOH (0.35 mL) were added and the reaction stirred at room tem-
perature for 7 h. At regular intervals, aliquots of the reaction mix-
ture were removed, filtered, and analysed by chiral GC to deter-
mine when the enantiomeric excess of the O-acetylcyanohydrin
stopped increasing. The reaction mixture was then passed through
a pad of silica, eluting with MeOtBu. The eluent was concentrated
in vacuo and the residue was purified by column chromatography
to give the pure O-acetylcyanohydrin as a pale yellow liquid.
Caution: Many of the following experimental procedures involve
the use of potassium cyanide, which is highly toxic and should only
be handled in a well ventilated fume-cupboard and in compliance
with all relevant safety protocols.
General Procedure for the Synthesis of Racemic O-Acetylcyanohyd-
rins: Potassium cyanide (2.5 g, 39.2 mmol), tBuOH (1.0 mL,
10.3 mmol) and water (0.1 mL, 4.4 mmol) were stirred in CH2Cl2
(20 mL) at room temperature. The aldehyde (9.8 mmol) and acetic
anhydride (4.0 g, 39.2 mmol) were added and the reaction moni-
tored by GC until complete. The solid salts were then filtered and
washed with CH2Cl2. The combined organic layers were evaporated
in vacuo and the residual oil used for chiral GC calibration without
further purification.
General Procedure for the Chemo-Enzymatic Synthesis of Enantio-
merically Enriched O-Acetylcyanohydrins. Method B: This method
was used for the reactions detailed in Table 5. tBuOH (0.47 mL,
4.95 mmol), water (0.042 mL, 2.36 mmol) and the aldehyde
(4.71 mmol) were added successively to a stirred solution of potas-
sium cyanide (1.23 g, 18.8 mmol) and (S,S)-1 (57 mg, 0.047 mmol)
in CH2Cl2 (5 mL). The solution was then cooled to –80 °C and
acetic anhydride (1.77 mL, 18.8 mmol) was added. The yellow solu-
General Procedure for the Enzymatic Resolution of Racemic O-ace-
tylmandelonitrile. Method A: This procedure was used for those
reactions in Table 1 which were agitated by stirring. The appropri-
ate nucleophile (11.4 mmol) was added to racemic O-acetylmande-
lonitrile (1.0 g, 5.7 mmol) in the specified solvent (57 mL) under
4614
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Eur. J. Org. Chem. 2006, 4609–4617

Asymmetric, Chemo-Enzymatic Synthesis of O-Acetylcyanohydrins
FULL PAPER
tion was then warmed to –40 °C and was stirred vigorously for
48 h. The reaction mixture was then warmed to room temperature
and MeOtBu (35 mL), CAL-B (0.59 g) and nPrOH (0.35 mL) were
added after which the reaction continued and was worked-up as
for Method A.
(78%). [α]2D2 = –18.8 (c = 1, CHCl3) [ref.[30] [α]2D0 = +24.3 (c = 1.6,
CHCl3) for the (R) enantiomer]. GC conditions: initial temperature
100 °C, hold at initial temperature for 5 min then ramp rate 5 °C
min–1. Retention times: 11.4 min [(R) enantiomer] and 11.7 min
[(S) enantiomer].
(S)-O-Acetyl-2-hydroxy-2-(2-thiophenyl)acetonitrile:[30] Solvent sys-
tem for column chromatography: hexane/ethyl acetate, 7:1. Yield
0.68 g (72%). [α]2D2 –13.4 (c 0.71, CHCl3) [ref.[30] [α]2D0 = +10.4 (c =
0.3, CHCl3) for the (R) enantiomer]. GC conditions: initial tem-
perature 100 °C, hold at initial temperature for 5 min then ramp
rate 5 °C min–1. Retention times: 15.9 min [(R) enantiomer] and
16.1 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-2-(3-pyridinyl)acetonitrile:[35] Solvent sys-
tem for column chromatography: hexane/ethyl acetate, 2:1. Yield
0.63 g (77%). [α]2D0 = +3.8 (c = 1, CHCl3). MS (EI): m/z (%) = 176
(2) [M+], 133 (20), 117 (15), 63 (21), 51 (21), 43 (100). HRMS (ES):
calcd. for C9H9N2O2 [MH+] 177.0569; found 177.0659. GC condi-
tions: initial temperature 100 °C, hold at initial temperature for
5 min then ramp rate 5 °C min–1. Retention times: 18.0 min [(R)
enantiomer] and 18.2 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-4-phenylbut-3-enenitrile:[36] Solvent system
for column chromatography: hexane/ethyl acetate, 7:1. Yield 0.61 g
(80%). [α]2D0 –32.8 (c = 1, CHCl3) [ref.[34] [α]2D2 –22.7 (c = 0.7,
CHCl3) for (R) enantiomer with 69% ee.]. 13C NMR (75 MHz,
CDCl3): δ = 20.9, 61.9, 115.9, 118.7, 127.6, 129.3, 129.8, 134.8,
138.3, 169.3 ppm. GC conditions initial temperature 100 °C, hold
at initial temperature for 5 min then ramp rate 0.5 °Cmin–1. Reten-
tion times: 103.9 min [(R) enantiomer] and 106.5 min [(S) enanti-
omer].
(R)-O-Acetyl-2-hydroxydecanenitrile:[37] Solvent system for column
chromatography: hexane/ethyl acetate, 7:1. Yield 0.49 g (66%).
[α]2D2 = +64.8 (c = 1, CHCl3). 13C NMR (75 MHz, CDCl3): δ =
14.0, 20.3, 22.6, 24.5, 28.7, 29.0, 29.2, 31.7, 32.2, 61.1, 116.9, 169.1.
HRMS (CI): calcd. for C12H25N2O2 (M + NH4+) 229.1911; found
229.1906. GC conditions: initial temperature 120 °C, hold at initial
temperature for 5 min then ramp rate 20 °C min–1. Retention times:
9.2 min [(R) enantiomer] and 9.4 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-3-methylbutanenitrile:[38] Compound de-
composed on attempted silica gel chromatography. Yield before
chromatography 0.45 g (46%). [α]2D2 = +9.1 (c = 1, CHCl3). GC
conditions: initial temperature 100 °C, hold at initial temperature
for 5 min then ramp rate 5 °C min–1. Retention times: 5.4 min [(R)
enantiomer] and 5.6 min [(S) enantiomer].
(R)-O-Acetyl-2-cyclohexyl-2-hydroxyethanenitrile:[30] Solvent sys-
tem for column chromatography: hexane/ethyl acetate, 4:1. Yield
0.61 g (65%). [α]2D2 = +39.5 (c = 1.0, CHCl3). GC conditions: initial
temperature 100 °C, hold at initial temperature for 5 min then ramp
rate 5 °C min–1. Retention times: 14.7 min [(R) enantiomer] and
14.9 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-3,3-dimethylbutanenitrile:[39] Solvent sys-
tem for column chromatography: hexane/ethyl acetate, 4:1. Yield
0.52 g (60%). [α]2D2 = +65.9 (c = 1.0, CHCl3) [ref.[40] [α]2D0 = +106
(c = 5, CHCl3)]. MS (CI): m/z (%) = 156 (28) [MH+], 140 (100),
129 (13). GC conditions: initial temperature 100 °C, hold at initial
temperature for 5 min then ramp rate 5 °C min–1. Retention times:
5.8 min [(R) enantiomer] and 5.9 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-2-phenylacetonitrile:[30] Solvent system for
column chromatography: hexane/ethyl acetate, 7:1. Yield 0.66 g
(81%). [α]2D0 = +8.8 (c = 1, CHCl3) [ref.[28] [α]2D0 = +8.4 (c = 10,
CHCl3) for (R) enantiomer]. GC: initial temperature 120 °C, hold
at initial temperature for 5 min then ramp rate 20 °C min–1. Reten-
tion times: 8.0 min [(R) enantiomer] and 8.3 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-2-(4-chlorophenyl)acetonitrile:[31] Solvent
system for column chromatography: hexane/ethyl acetate, 4:1. Yield
0.60 g (81%). [α]2D0 = –14.1 (c = 1, CHCl3) [ref.[29] [α]2D5 = –13.9 (c
= 1, CHCl3)]. GC: initial temperature 120 °C, hold at initial tem-
perature for 5 min then ramp rate 20 °C min–1. Retention times:
10.5 min (R enantiomer) and 10.8 min (S enantiomer).
(R)-O-Acetyl-2-hydroxy-2-(2-chlorophenyl)acetonitrile:[17] Solvent
system for column chromatography: hexane/ethyl acetate, 4:1. Yield
0.55 g (74%). [α]2D0 = +32.9 (c = 1, CHCl3) [ref.[17] [α]2D5 = +27 (c =
1, CHCl3) for (R) enantiomer with 88% ee]. 13C NMR (75 MHz,
CDCl3): δ = 20.3, 60.7, 115.5, 127.9, 129.8, 130.3, 130.6, 131.9,
133.9, 168.6 ppm. MS (EI): m/z (%) = 209 (8) [M+], 167 (51), 43
(100). HRMS (CI): calcd. for C10H12ClN2O2 (M+NH4+):
227.0582; found 227.0580. GC: initial temperature 100 °C, hold at
initial temperature for 5 min then ramp rate 1 °C min–1. Retention
times: 50.9 min [(R) enantiomer] and 51.2 min [(S) enantiomer].
(R)-O-Acetyl-hydroxy-2-(3-methoxyphenyl)acetonitrile:[32] Solvent
system for column chromatography: hexane/ethyl acetate, 4:1. Yield
0.63 g (84%). [α]2D0 = +4.8 (c = 1, CHCl3) [ref.[30] [α]2D0 –4.8 (c = 2,
CHCl3) for (S) enantiomer]. GC: initial temperature 120 °C, hold
at initial temperature for 5 min then ramp rate 20 °C min–1. Reten-
tion times: 10.9 min [(R) enantiomer] and 11.1 min [(S) enanti-
omer].
(R)-O-Acetyl-2-hydroxy-2-(2-methylphenyl)acetonitrile:[8] Solvent
system for column chromatography: hexane/ethyl acetate, 4:1. Yield
0.38 g (69%). [α]2D2 = +14.7 (c = 1, CHCl3). H NMR (300 MHz,
1
CDCl3): δ = 2.15 (s, 3 H, ArCH3), 2.39 (s, 3 H, COCH3), 6.50 (s,
1 H, CHCN), 7.2–7.6 (m, 4 H, ArCH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.3, 20.9, 61.4, 116.4, 127.2, 128.9, 130.3, 130.9,
131.7, 137.1, 169.3 ppm. IR (film): ν = 3028, 2250, 1755 cm–1. MS
˜
(EI): m/z (%) = 189 (5) [M+], 128 (100), 103 (37), 91 (26). HRMS
(CI): calcd. for C11H15N2O2 (M+NH4+) 207.1128; found 207.1128.
GC conditions: initial temperature 100 °C, hold at initial tempera-
ture for 5 min then ramp rate 5 °C min–1. Retention times: 17.5 min
[(R) enantiomer] and 17.6 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-2-(3-methylphenyl)acetonitrile:[33] Purified
by bulb to bulb distillation at 135 °C (1 Torr). Yield 0.33 g (61%).
1H NMR (300 MHz, CDCl3): δ = 2.18 (s, 3 H, ArCH3), 2.31 (s, 3
H, COCH3), 6.30 (s, 1 H, CHCN), 6.9–7.4 (m, 4 H, ArCH) ppm.
GC conditions: initial temperature 100 °C, hold at initial tempera-
ture for 5 min then ramp rate 3 °C min–1. Retention times:
23.86 min [(R) enantiomer] and 23.93 min [(S) enantiomer].
(R)-O-Acetyl-2-hydroxy-2-(4-methylphenyl)acetonitrile:[34] Purified
by bulb to bulb distillation at 140 °C (1 Torr). Yield 0.27 g (50%).
GC conditions: initial temperature 100 °C, ramp rate 2 °C min–1.
Retention times: 31.1 min (R enantiomer) and 31.5 min (S enanti-
omer).
Acknowledgments
(S)-O-Acetyl-2-hydroxy-2-(2-furanyl)acetonitrile:[30] Solvent system
for column chromatography: hexane/ethyl acetate, 6:1. Yield 0.67 g
The authors thank EPSRC and NPIL, for a studentship (to LAC)
and NPIL for financial support. Mass spectra were recorded by
Eur. J. Org. Chem. 2006, 4609–4617
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Yu. N. Belokon, A. J. Blacker, L. A. Clutterbuck, D. Hogg, M. North, C. Reeve
FULL PAPER
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Asymmetric, Chemo-Enzymatic Synthesis of O-Acetylcyanohydrins
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Received: May 31, 2006
Published Online: August 18, 2006
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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