Enantioselective synthesis of protected cyanohydrins

Article abstract of DOI:10.1002/1099-0690(200205)2002:9<1516::AID-EJOC1516>3.0.CO;2-C

A straightforward process for the preparation of optically active protected cyanohydrins, important building blocks for the synthesis of drugs and agrochemicals, has been established. Lipase B from Candida Antarctica (CAL-B) catalysed the kinetic resoluti

Full text of DOI:10.1002/1099-0690(200205)2002:9<1516::AID-EJOC1516>3.0.CO;2-C

FULL PAPER
Enantioselective Synthesis of Protected Cyanohydrins
Lars Veum,[a] Marina Kuster,[a] Selvedin Telalovic,[a] Ulf Hanefeld,*[a] and
Thomas Maschmeyer[a]
Keywords: Asymmetric synthesis / Candida antarctica / Cyanohydrins / Natural products / Protecting groups
A straightforward process for the preparation of optically act- addition of vinyl butyrate, or chemically after removal of the
ive protected cyanohydrins, important building blocks for the
synthesis of drugs and agrochemicals, has been established.
Lipase B from Candida Antarctica (CAL-B) catalysed the
kinetic resolution of racemic cyanohydrin acetates under
mild conditions. The resulting labile cyanohydrins were re-
protected either by an enzyme-catalysed route involving the
enzyme from the reaction mixture. This process gave access
to both enantiomers in pure form and in good yields, while
considerably reducing the risks due to HCN. A variety of dif-
ferent protection groups have also been introduced.
(
Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
stable. To avoid this problem, the kinetic resolution should
ideally be coupled with a chemical or enzymatic protection
reaction. This would yield both enantiomers of the cyano-
hydrin, protected as two different, and therefore readily sep-
arable, derivatives.
The TBDMS group and the pivaloyl group were chosen
as protection groups that could be introduced under basic
conditions. Both are known as versatile protecting groups
in cyanohydrin chemistry, and the TBDMS group can be
introduced without significant racemisation.[23] THP ethers
were the obvious choice for a protection group that could
be introduced under acidic conditions.[14]
Cyanohydrins are versatile building blocks in organic
synthesis.[1Ϫ6] They can readily be converted into a wide
range of compounds, such as α-hydroxy acids,[7] α-hydroxy
esters,[8] α-hydroxy ketones,[9] α-hydroxy aldehydes,[10]
and β-hydroxy amines.[11] Indeed, they have been utilised
for the synthesis of, for example, (R)-salbutamol,[12] (R)-
terbutaline[12], (S)-amphetamines (a family of drugs com-
monly referred to as Ecstasy[13]), as well as the Williamson
glycine template.[14] In addition, they are crucial compon-
ents in the synthesis of pyrethroid insecticides.
By using the same enzyme (CAL-B) to protect the (S)-
cyanohydrins directly after kinetic resolution with a suitable
acylating agent in a true one-pot reaction, esters can be
formed under neutral conditions. This procedure should
give access to a wide range of potentially interesting esters.
By the approaches described above, stable, protected and
enantiopure cyanohydrin acetates may be obtained. Since
the racemic cyanohydrin acetates can be prepared by
straightforward treatment of the appropriate aldehyde with
sodium cyanide and acetic anhydride,[24] any risk of releas-
ing HCN is minimised and the remaining cyanide ions can
be destroyed by standard procedures.[25]
Despite the fact that the first enantioselective hydroxy-
nitrile lyase catalysed synthesis of cyanohydrins was de-
scribed as early as 1908,[15] and also their major role in the
‘‘synthon approach’’,[16] they are still not utilised to the ex-
tend that one might expect. We therefore set out to develop
a straightforward, enantioselective process for the synthesis
of protected, and hence stable, cyanohydrins.
The kinetic resolution of cyanohydrin acetates has been
investigated with a range of lipases.[17Ϫ20] Recently, the
readily available Candida antarctica lipase B (CAL-B,
‘‘Novozyme 435’’ or chirazyme L-2, c.-f., C2, Lyo, immo-
bilised on a macroporous acrylic resin) has been used in the
enantioselective deacylation of mandelonitrile acetate
(R,S)-1a to give (R)-mandelonitrile acetate (R)-1a and (S)-
mandelonitrile cyanohydrin (S)-2a.[21] This procedure has Results and Discussion
been optimised for the kinetic resolution of a wide range
of aromatic cyanohydrin acetates, with excellent results.[22]
For kinetic resolution of the racemic cyanohydrin ace-
tates, the conditions described earlier were applied.[22] How-
ever, since the protection reaction had to be performed with
the mixture obtained from the kinetic resolution, these con-
ditions had to be reassessed. For the protection of (S)-2aϪd
as TBDMS ethers, several sets of conditions were explored.
TBDMS triflate in the presence of lutidine[26] gave higher
However, the resulting (S)-cyanohydrins are relatively un-
[a]
Toegepaste Organische Chemie
Universiteit Delft,
& Katalyse, Technische
Julianalaan 136, 2628 BL Delft, The Netherlands
Fax: (internat.) ϩ 31-15/278-4289
E-mail: U.Hanefeld@tnw.tudelft.nl
1516
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0509Ϫ1516 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 1516Ϫ1522

Enantioselective Synthesis of Protected Cyanohydrins
FULL PAPER
yields than when Hünig’s base[27] was employed. TBDMS- and the THP ethers had polarities similar to those of the
Cl in combination with imidazole[23] gave less favourable acetates. Conversions were therefore determined by 1H
results, possibly due to solubility problems of imidazole in NMR. However, these conversions corresponded to the
toluene. Pivaloate was readily introduced as pivaloyl chlor- isolated yields, within the margins of experimental error.
ide in the presence of pyridine and DMAP,[28] and the THP
The results showed that the ee values of (S)-3aϪd and
ethers were also formed with great ease under standard con- (S)-4aϪd were lower than those for (S)-5aϪd. This might
ditions (Scheme 1). Introduction of methoxyisopropyl and be due to the instability of cyanohydrins under basic condi-
benzyl ethers (under acidic[29] and basic[30] conditions) tions (a base being used for the silylation and the ester-
failed, however.
ification), under which they slowly racemise. In contrast to
that of (S)-3aϪd and (S)-4aϪd, the formation of (S)-5aϪd
takes place under acidic reaction conditions. The racemi-
sation was therefore suppressed, and the ee values were
therefore higher. However, when the kinetic resolution was
performed without coupling to a protection reaction[22] the
ee values of (S)-2aϪd were even higher than those of (S)-
3aϪd, (S)-4aϪd, or (S)-5aϪd.
In order to increase the optical purity of the protected
variants of (S)-2aϪd to the level of the unprotected com-
pounds, a different approach was explored. Instead of re-
moving the enzyme and performing the protection chemi-
cally, the acylating agent vinyl butyrate (6) was added to
the reaction mixture (Scheme 2).
Scheme 1. Kinetic resolution of cyanohydrin acetates and protec-
tion of the formed (S)-cyanohydrins
Four cyanohydrin acetates (R,S)-1aϪd were subjected to
kinetic resolution followed by chemical protection of the
newly formed (S)-cyanohydrins (S)-2aϪd. All the desired
products (S)-3aϪd, (S)-4aϪd, and (S)-5aϪd were obtained
in good yields and enantiomeric purities (Table 1,
Scheme 1). Previous work in this group had indicated low
Scheme 2. One-pot synthesis of (S)-7aϪd
Under the same conditions as used for the kinetic resolu-
selectivity for the kinetic resolution of aliphatic cyano- tion, (S)-2aϪd was now acylated in the same pot by the
hydrin acetates, and so this class of compounds was not same enzyme to give the (S)-cyanohydrin butyrates (S)-
included in this work.[32] However, if the kinetic resolution 7aϪd (Table 2). (S)-Cyanohydrin decanoates were prepared
of aliphatic cyanohydrins should be desired, other lipases in the same way with similar results, but with reaction times
has been used with excellent results.[33,34]
of several days.
In order to prevent any enzyme degradation, the protec-
With this truly one-pot procedure, even better ee values
tion reactions were performed after removal of the enzyme could be obtained for the reprotected cyanohydrins (S)-
from the reaction mixture. In the case of the synthesis of the 7aϪd. The separation was, again, a straightforward column
TBDMS and pivaloyl derivatives, straightforward column filtration, giving access to the desired products in good
filtration gave the pure products. This was not the case for yields and with great ease. However, the ee values of (R)-
the THP ethers, since two diastereoisomers were formed 1aϪd obtained from the enzymatic protection were lower
Table 1. Results of the kinetic resolution of cyanohydrin acetates and protection of the formed (S)-cyanohydrins
R
Yield[a] (ee)
(S)-3
Yield (ee)
(R)-1[b]
Yield (ee)
(S)-4
Yield (ee)
(R)-1[a]
Ratio (ee)
(S)-5
Ratio (ee)
(R)-1[d]
Ratio
aldehyde[e]
a
b
c
88 (89)
79 (89)
78 (82)
89 (Ϫ)
93 (96)
90 (97)
96 (Ͼ 99)
94 (87)
99 (83)
81 (88)
76 (78)
71 (81)
98 (98)
90 (97)
85 (Ͼ 99)
89 (90)
96 (93)
84 (93)
86 (90)
86 (84)
100 (93)
100 (92)
99 (Ͼ 99)
100 (91)
4
16
16
14
d
[a] Yields are isolated yields (%). Enantiomeric excess (%) was determined by chiral HPLC. Ratios of 5, 1 and the aldehyde in the reaction
[b]
[c]
[d]
mixture were determined by NMR.
From protection as silyl ether. From protection as pivaloyl ester.
From protection as THP
1517
[e]
ether. Degradation product of cyanohydrin.
Eur. J. Org. Chem. 2002, 1516Ϫ1522

L. Veum, M. Kuster, S. Telalovic, U. Hanefeld, T. Maschmeyer
FULL PAPER
ferently protected cyanohydrins, in excellent yield and op-
tical purities [(R): Ͼ 91% ee; (S): Ͼ 97% ee]. This should
help in further establishing the cyanohydrins as versatile
building blocks in organic synthesis.
Table 2. Results of the kinetic resolution of cyanohydrin acetates
and the enzymatic protection of the formed (S)-cyanohydrins in a
one-pot reaction
R
Yield[a] (ee)[b]
(S)-7
Yield[a] (ee)[b]
(R)-1
Experimental Section
a
b
c
85 (98)
80 (97)
73 (97)
67 (96)
93 (95)
81 (91)
93 (98)
92 (75)
1
General Remarks: H and 13C NMR spectra were recorded with a
d
Varian VXR 400S (400 and 100 MHz, respectively) or a Varian
Unity Inova 300 (300 MHz and 75 MHz, respectively) instrument.
Chemical shifts are expressed in parts per million (δ) relative to
tetramethylsilane. Abbreviations are as follows: s (singlet), d (doub-
let), t (triplet), q (quadruplet), and m (multiplet). Mass spectra were
determined with a VG 70 SE spectrometer working at 70 eV. Op-
tical rotations were obtained with a PerkinϪElmer 241 polarimeter.
Melting points are uncorrected. Column chromatography was car-
ried out with silica gel (0.060Ϫ0.200 mm, pore diameter ca. 6 nm)
and with mixtures of petroleum ether (PE) and ethyl acetate
[a]
[b]
Yields are isolated yields (%).
Enantiomeric excess (%) was
determined by chiral HPLC.
than those observed after the chemical protection. This can
be explained by the presence of propyl acetate formed dur-
ing the kinetic resolution, which can also act as an acylating
agent, (albeit more slowly than 6), to give (S)-1aϪd instead
of (S)-7aϪd. As a consequence, the yields of (S)-7aϪd and
the ee values of (R)-1aϪd would decrease. In addition, any (EtOAc) as solvent. TLC was performed on 0.20 mm silica gel and
developed in a vanillin bath [vanillin (15 g) in ethanol (250 mL) ϩ
concd. H2SO4 (2.5 mL)] in which all products containing a CN
group gave orange spots, except for the THP ethers, which gave
blue spots. Dry toluene and dry n-propanol were purchased from
Aldrich. Racemic cyanohydrin acetates[24] and cyanohydrins[35]
were synthesised according to literature procedures. Immobilised
Lipase B from Candida antarctica (CAL-B, Chirazyme L-2, c.-f.,
C2, Lyo) was a generous gift from Roche Diagnostics Penzberg
(W. Tischer). HPLC analysis: The optical purity was determined
by HPLC using a 4.6 ϫ 250 mm 10 µ Chiracel OD column with a
racemisation of (S)-2aϪd, which would give rise to lower
ee values in the chemical protection reactions, would give
lower yields for the enzyme protections, since (R)-2aϪd is
not a substrate for the enzyme.
Since (R)-1aϪd and (S)-7aϪd can both easily be ra-
cemised[31] and then once more be subjected to the kinetic
resolution, it is possible to obtain either enantiomer in close
to quantitative yields with excellent selectivities.
With this CAL-B-based kinetic resolution and protection
sequence, protected aromatic cyanohydrins become readily Waters 510 pump, and a Waters 486 UV detector. The eluent and
the retention times for the different products are given in Table 4.
available in high optical purity. In the case of aliphatic cy-
anohydrins, CAL-B is significantly less selective.[32] How-
ever, it is well known that Porcine pancreatic lipase and
Candida rugosa lipase show excellent selectivity for these
substrates.[33,34]
The flow was 0.8 mL·minϪ1
.
Table 4. Eluents and retention times for HPLC analysis
Compound
Eluent
tr (R)
tr (S)
To examine the recyclability of CAL-B, the kinetic res-
olution of racemic (R,S)-1c followed by protection as a
THP ether was repeated four times (Table 3). Even in the
fifth run, no loss of activity or selectivity of the enzyme was
observed. This confirms the great versatility of CAL-B for
the enantioselective synthesis of protected cyanohydrins.
hexane/iPrOH
[min]
[min]
(R,S)-1a
(R,S)-1b
(R,S)-1c
(R,S)-1d
(R,S)-3a
(R,S)-3b
(R,S)-3c
(R,S)-4a
(R,S)-4b
(R,S)-4c
(R,S)-4d
(R,S)-5a
(R,S)-5b
(R,S)-5c
(R,S)-5d
(R,S)-7a
(R,S)-7b
(R,S)-7c
(R,S)-7d
98:2
13.87
10.55
10.22
19.40
8.38
9.36
10.78
9.36
14.97
12.43
11.59
10.12
8.16
7.28
8.74
15.49
11.94
12.14
15.28
6.62
90:10
90:10
90:10
99.5:0.5
99.5:0.5
99.75:0.25
99.5:0.5
99.5:0.5
99.5:0.5
90:10
98:2
90:10
90:10
90:10
95:5
95:5
95:5
8.34
Table 3. Recycling experiment
10.19
10.34
16.11
14.51
8.11
10.65
8.73
8.35
12.73
8.45
Cycle
0
1
2
3
4
Ratio[a] (% ee)[b] (R)-1c 98 (99) 96 (99) 98 (97) 98 (98) 98 (98)
Ratio (% ee) (S)-5c
Ratio 4-chlorobenzal-
dehyde 8
86 (90) 86 (90) 88 (93) 90 (93) 91 (93)
16 18 14 12 10
[a] The ratios between 1c, 5c and 8 were determined in the reaction
mixture by 1H NMR (no other products were observed). [b] Enanti-
omeric excess (%) was determined by chiral HPLC.
7.90
10.04
9.11
11.11
10.47
15.96
95:5
18.21
Enzyme Activity Test: Tributyrin (1.47 mL, 5.02 mmol) was added
to 48.5 mL of a 10 m potassium phosphate buffer, pH ϭ 7.0
[10 m of potassium dihydrogen phosphate (100 mL) adjusted to
pH ϭ 7.0 with 10 m of dipotassium hydrogen phosphate (ca.
Conclusion
In summary, we have developed a straightforward, en-
zyme-based method to synthesise either enantiomer of dif- 100 mL)] in a thermostatted vessel at 25 °C, and the mixture was
1518 Eur. J. Org. Chem. 2002, 1516Ϫ1522

Enantioselective Synthesis of Protected Cyanohydrins
FULL PAPER
stirred mechanically. The pH was maintained at 7.0 with an auto-
matic burette, and when the pH had stabilised, immobilised Lipase
B from Candida antarctica CAL-B (9 mg) was added. The con-
sumption of 100 m sodium hydroxide was monitored over 40 min
and plotted against time. The specific activity was calculated from
the base consumption at the linear part of the graph; 1 µmol of
NaOH consumed per min corresponds to 1 unit (1 U) of activity.
The activity was found to be 3.8 KU/g dry carrier.
Compound (S)-3b: Obtained as a pale yellow oil (404 mg, 79%, 89%
ee): [α]2D5 ϭ Ϫ11.6 (c ϭ 1.0, CHCl3) {ref.[23] [α]2D0 ϭ ϩ16 (c ϭ 1.0,
CHCl3) for the (R) enantiomer with Ͼ 99% ee}. 1H NMR
(300 MHz, CDCl3): δ ϭ 0.12 (s, 3 H, CH3Si), 0.20 (s, 3 H, CH3Si),
0.92 [s, 9 H, (CH3)3C], 3.82 (s, 3 H, OCH3), 5.45 (s, 1 H, CHO),
6.92 (m, 2 H, 3,5-H), 7.38 (m, 2 H, 2,6-H). 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ5.1 [(CH3)2Si], 18.2 [SiC(CH3)3], 25.6 [(CH3)3C],
55.4 (OCH3), 63.7 (CHO), 114.3 (C-3,5), 119.5 (CN), 127.7 (C-2,6),
128.7 (C-1), 160.3 (C-4).
General Procedure A. Kinetic Resolution: Immobilised Lipase B
from Candida antarctica CAL-B (368 mg) was dried overnight over
SiO2 in a dessicator and added to a mechanically stirred solution
of 1 (3.68 mmol) in dry toluene (36 mL) under N2, at 25 °C. The
reaction mixture was heated to 60 °C, and n-propanol (0.54 mL,
7.36 mmol) was then added. After stirring for 3 h, the reaction mix-
ture was cooled to 0 °C and transferred through a thin cannula
into a new reaction vessel. The residual immobilised enzyme was
washed with dry toluene (7 mL) to ensure complete transfer. The
liquid phase was then treated according to the following general
procedures.
Compound (R)-1b: Obtained as a pale yellow solid (343 mg, 90%,
97% ee): m.p. 58.2Ϫ58.4 °C. [α]2D5 ϭ Ϫ20.0 (c ϭ 1.0, CHCl3) {ref.[36]
[α]2D0 ϭ ϩ19.0 (c ϭ 1.55, CHCl3) for the (S) enantiomer with 95%
ee}. 1H NMR (400 MHz, CDCl3): δ ϭ 2.13 (s, 3 H, CH3CO), 3.82
(s, 3 H, OCH3), 6.35 (s, 1 H, CHO), 6.94 (m, 2 H, aromatic), 7.44
(m, 2 H, aromatic). 13C NMR (100 MHz, CDCl3): δ ϭ 20.5
(CH3CO), 55.4 (OCH3), 62.6 (CH), 114.6 (C-3,5), 116.4 (CN),
123.9 (C-1), 129.7 (C-2,6), 161.2 (C-4), 169.0 (CϭO).
(S)-(؊)-α-[(tert-Butyldimethylsilyl)oxy]-α-(4-chlorophenyl)aceto-
nitrile [(S)-3c] and (R)-(؊)-Cyano(4-chlorophenyl)methyl Acetate
[(R)-1c]: The title compounds were prepared from racemic (R,S)-
1c according to General Procedure B.
General Procedure B. Protection as TBDMS Ether: Lutidine
(1.46 mL, 12.5 mmol) and TBDMS-Tf (2.11 mL, 9.2 mmol) were
added to the liquid phase of General Procedure A and the mixture
was stirred at ambient temperature under N2 for 3 h. The reaction
was quenched with water (10 mL). The organic phase was washed
with 1  HCl (25 mL) and satd. NaHCO3 (25 mL) and dried with
MgSO4. The solvent was removed under vacuum, and the products
were purified by column chromatography on silica gel; (S)-3aϪd
was eluted with PE/EtOAc (95:5), and (R)-1aϪd with PE/EtOAc
(90:10).
Compound (S)-3c: Obtained as a pale yellow oil (405 mg, 78%, 82%
1
ee): [α]2D5 ϭ Ϫ11.6 (c ϭ 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ ϭ 0.15 (s, 3 H, CH3Si), 0.23 (s, 3 H, CH3Si), 0.94 [s, 9 H,
(CH3)3C], 5.48 (s, 1 H, CHO), 7.4 (m, 4 H, aromatic). 13C NMR
(100 MHz, CDCl3): δ ϭ Ϫ5.2 (CH3Si), Ϫ5.1 (CH3Si), 18.2
[SiC(CH3)3], 25.5 [(CH3)3C], 63.4 (CHO), 118.9 (CN), 127.4 (C-
2,5), 129.2 (C-3,6), 135.1, 135.3 (C-1,4).
Compound (R)-1c: Obtained as a pale yellow oil (370 mg, 96%, Ͼ
99% ee): [α]2D5 ϭ Ϫ10.5 (c ϭ 1.0, CHCl3) {ref.[37] [α]2D5 ϭ ϩ31.5 (c ϭ
1.17, benzene) for the (S) enantiomer with 84% ee}. 1H NMR
(400 MHz, CDCl3): δ ϭ 2.17 (s, 3 H, CH3CO), 6.39 (s, 1 H, CHO),
7.4Ϫ7.5 (m, 4 H, aromatic). 13C NMR (100 MHz, CDCl3): δ ϭ
20.4 (CH3CO), 62.2 (CHO), 115.8 (CN), 129.3, 129.5 (C-2,3,5,6),
130.3 (C-1), 136.6 (C-4), 168.8 (CϭO).
Racemic Cyanohydrins Protected as TBDMS Ethers: Racemic
(R,S)-3aϪd was prepared from racemic (R,S)-2aϪd according to
General Procedure B, with the modification that a solution of the
cyanohydrin (1.84 mmol) in dry toluene (36 mL) and n-propanol
(0.54 mL) was used in place of the filtrate from the kinetic resolu-
tion. The yields were: (R,S)-3a: 71%; (R,S)-3b: 78%; (R,S)-3c: 92%;
(R,S)-3d: 98%. NMR as below.
(S)-(؊)-α-[(tert-Butyldimethylsilyl)oxy]-α-(3-phenoxyphenyl)-
acetonitrile [(S)-3d] and (R)-(؊)-Cyano(3-phenoxyphenyl)methyl
Acetate [(R)-1d]: The title compounds were prepared from racemic
(R,S)-1d according to General Procedure B.
(S)-(؊)-α-[(tert-Butyldimethylsilyl)oxy]-α-(phenyl)acetonitrile
[(S)-3a] and (R)-(؉)-Cyano(phenyl)methyl Acetate [(R)-1a]: The title
compounds were prepared from racemic (R,S)-1a according to
General Procedure B.
Compound (S)-3d: Obtained as a pale yellow oil (555 mg, 89%):
[α]2D5 ϭ Ϫ18.0 (c ϭ 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
0.12 (s, 3 H, CH3Si), 0.21 (s, 3 H, CH3Si), 0.90 [s, 9 H, (CH3)3C],
5.47 (s, 1 H, CHO), 6.98Ϫ7.40 (m, 9 H, aromatic). 13C NMR
Compound (S)-3a: Obtained as a pale yellow oil (399 mg, 88%, 89%
ee): [α]2D5 ϭ Ϫ17.5 (c ϭ 1.0, CHCl3) {ref.[23] [α]2D5 ϭ ϩ17.0 (c ϭ 1.0,
CHCl3) for the (R) enantiomer with ee Ͼ 99%}. 1H NMR
(300 MHz, CDCl3): δ ϭ 0.15 (s, 3 H, CH3Si), 0.23 (s, 3 H, CH3Si),
0.94 [s, 9 H, (CH3)3C], 5.52 (s, 1 H, CHO), 7.36Ϫ7.50 (m, 5 H,
aromatic). 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ5.2 (CH3Si), Ϫ5.1
(CH3Si), 18.2 [SiC(CH3)3], 25.5 [(CH3)3C], 64.0 (CHO), 119.3
(CN), 126.1 (C-2,6), 128.9 (C-3,5), 129.2 (C-4), 136.5 (C-1).
(75 MHz, CDCl3):
δ ϭ Ϫ5.3 (CH3Si), Ϫ5.1 (CH3Si), 18.1
[SiC(CH3)3], 25.5 [(CH3)3C], 63.5 (CHO), 115.8 (C-2Ј), 119.0 (CN),
119.1 (C-4Ј), 119.4 (C-2ЈЈ, 6ЈЈ), 120.3 (C-6Ј), 123.9 (C-4ЈЈ), 129.9
(C-3ЈЈ, 5ЈЈ), 130.3 (C-5Ј), 138.4 (C-1Ј), 156.4 (C-3Ј), 158.1 (C-1ЈЈ).
Compound (R)-1d: Obtained as a pale yellow oil (461 mg, 94%, 87%
ee): [α]2D5 ϭ Ϫ7.1 (c ϭ 1.0, CHCl3) {ref.[36] [α]2D5 ϭ ϩ7.44 (c ϭ 0.75,
CHCl3) for the (S) enantiomer with 99% ee}. 1H NMR (300 MHz,
CDCl3): δ ϭ 2.16 (s, 3 H, CH3CO), 6.36 (s, 1 H, CHO), 7.0Ϫ7.42
(m, 9 H, aromatic). 13C NMR (75 MHz, CDCl3): δ ϭ 20.4
(CH3CO), 62.4 (CHO), 115.9 (CN), 117.7 (C-2Ј), 119.4 (C-2ЈЈ, 6ЈЈ),
120.1 (C-4Ј), 122.1 (C-6Ј), 124.1 (C-4ЈЈ), 130.0 (C-3ЈЈ, 5ЈЈ), 130.6
(C-5Ј), 133.5 (C-1), 156.2 (C-3Ј), 158.2 (C-1ЈЈ), 168.8 (CϭO).
Compound (R)-1a: Obtained as a pale yellow oil (300 mg, 93%, 96%
ee): [α]2D5 ϭ ϩ6.3 (c ϭ 1.0, CHCl3) {ref.[36] [α]2D5 ϭ Ϫ7.2 (c ϭ 2.3,
CHCl3) for the (S) enantiomer with Ͼ 99% ee}. 1H NMR
(300 MHz, CDCl3): δ ϭ 2.14 (s, 3 H, CH3CO), 6.40 (s, 1 H, CHO),
7.20Ϫ7.58 (m, 5 H, aromatic). 13C NMR (75 MHz, CDCl3): δ ϭ
20.5 (CH3CO), 62.9 (CHO), 116.2 (CN), 127.9 (C-2,6), 129.3 (C-
3,5), 130.4 (C-4), 131.8 (C-1), 169.94 (CϭO).
General Procedure C. Protection as Pivaloyl Ester: DMAP (5 mg,
(S)-(؊)-α-[(tert-Butyldimethylsilyl)oxy]-α-(4-methoxyphenyl)aceto- 0.04 mmol), pivaloyl chloride (1.36 mL, 11.04 mmol), and pyridine
nitrile [(S)-3b] and (R)-(؊)-Cyano(4-methoxyphenyl)methyl Acetate (0.71 mL, 8.83 mmol) were added to the filtrate of General Proced-
[(R)-1b]: The title compounds were prepared from racemic (R,S)- ure A, and the mixture was stirred at ambient temperature under
1b according to General Procedure B.
N2 for 14 h. HCl (1 , 25 mL) was added, and the organic phase
Eur. J. Org. Chem. 2002, 1516Ϫ1522
1519

L. Veum, M. Kuster, S. Telalovic, U. Hanefeld, T. Maschmeyer
FULL PAPER
was washed with satd. NaHCO3 (25 mL) and dried with MgSO4.
pounds were prepared from racemic (R,S)-1d according to General
Solvents were removed under vacuum and the crude products were Procedure C.
purified by column chromatography on silica gel (PE/EtOAc,
Compound (S)-4d: Obtained as a pale yellow oil (419 mg, 73%, 81%
90:10).
1
ee): [α]2D5 ϭ ϩ0.2 (c ϭ 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ ϭ 1.23 [s, 9 H, (CH3)3C], 6.35 (s, 1 H, CHO), 7.0Ϫ7.2 (m, 9 H,
aromatic). 13C NMR (100 MHz, CDCl3): δ ϭ 26.8 [(CH3)3C], 38.9
(CCO), 62.3 (CHO), 116.0 (CN), 117.0 (C-2Ј), 119.5 (C-2ЈЈ, 6ЈЈ),
119.9 (C-4Ј), 121.6 (C-6Ј), 124.1 (C-4ЈЈ), 130.0 (C-3ЈЈ, 5ЈЈ), 130.6
(C-5Ј), 133.8 (C-1), 156.2 (C-3Ј), 158.3 (C-1ЈЈ), 176.3 (CϭO).
Racemic Cyanohydrins Protected as Pivaloyl Esters: Racemic (R,S)-
4aϪd was prepared from racemic (R,S)-2aϪd according to General
Procedure C with the modification that a solution of the cyanohyd-
rin (1.84 mmol) in dry toluene (36 mL) and n-propanol (0.54 mL)
was used instead of the filtrate from the kinetic resolution. The
yields were: (R,S)-4a: 76%; (R,S)-4b: 47%; (R,S)-4c: 84%; (R,S)-
4d: 78%.
Compound (R)-1d: Obtained as a pale yellow oil (416 mg, 84%, 90%
ee): [α]2D5 ϭ Ϫ7.2 (c ϭ 1.0, CHCl3). NMR spectroscopic data as
above.
(S)-(؊)-Cyano(phenyl)methyl Pivaloate [(S)-4a] and (R)-(؉)-Cyano-
(phenyl)methyl Acetate [(R)-1a]: The title compounds were pre-
pared from racemic (R,S)-1a according to General Procedure C.
General Procedure D. Protection as THP Ether: pTsOH (5 mg,
0.028 mmol) was added to the filtrate of General Procedure A at 0
°C. DHP (0.75 mL, 8.24 mL) was then added dropwise over a
period of 10 min. The reaction mixture was then stirred under N2
for 2 h at ambient temperature and the reaction quenched with
satd. NaHCO3 (25 mL). The organic phase was dried with MgSO4.
Solvents were removed under vacuum and the crude products were
Compound (S)-4a: Obtained as a pale yellow oil (395 mg, 99%, 83%
1
ee): [α]2D5 ϭ Ϫ5.9 (c ϭ 1.0, CHCl3). H NMR (300 MHz, CDCl3):
δ ϭ 1.24 [s, 9 H, (CH3)3C], 6.41 (s, 1 H, CH-O), 7.41Ϫ7.51 (m, 5
H, aromatic). 13C NMR (75 MHz, CDCl3): δ ϭ 26.9 [(CH3)3C],
38.9 (C-CO), 62.8 (CHO), 116.3 (CN), 127.5 (C-2,6), 129.2 (C-3,5),
130.2 (C-4), 132.1 (C-1), 176.4 (CϭO).
1
analysed by H NMR.
Racemic Cyanohydrins Protected as THP Ethers: Racemic (R,S)-
5aϪd was prepared from racemic (R,S)-2aϪd according to General
Procedure D, with the modification that a solution of the cyanohy-
drin (1.84 mmol) in dry toluene (36 mL) and n-propanol (0.54 mL)
was used in place of the filtrate of the kinetic resolution. The prod-
ucts were purified by column chromatography on silica gel (PE/
EtOAc, 90:10). The yields were: (R,S)-5a: 92%; (R,S)-5b: 96%;
(R,S)-5c: 94%; (R,S)-5d: 92%.
Compound (R)-1a: Obtained as a pale yellow oil (313 mg, 97%, 98%
ee): [α]2D5 ϭ ϩ5.6 (c ϭ 1.0 CHCl3). NMR spectroscopic data as
above.
(S)-(؉)-Cyano(4-methoxyphenyl)methyl Pivaloate [(S)-4b] and (R)-
(؉)-Cyano(4-methoxyphenyl)methyl Acetate [(R)-1b]: The title com-
pounds were prepared from racemic (R,S)-1b according to General
Procedure C.
(2S)-Phenyl[(tetrahydropyran-2-yloxy)]acetonitrile [(S)-5a] and (R)-
(؊)-Cyano(phenyl)methyl Acetate [(R)-1a]: The title compounds
were prepared from racemic (R,S)-1a according to General Proced-
ure D. The ratio of aromatic components in the reaction mixture
was determined by 1H NMR (300 MHz, CDCl3): (S)-5a: 47% (δ ϭ
5.42 and 5.59, CHO); (R)-1a: 51% (δ ϭ 6.40, CHO); benzaldehyde:
2% (δ ϭ 10.03, HCϭO); (S)-5a: 93% ee; (R)-1a: 93% ee.
Characterisation of Racemic (R,S)-5a: 1H NMR (300 MHz,
CDCl3): diastereoisomer A: δ ϭ 1.44Ϫ1.95 (m, 6 H, THP), 3.63
(m, 1 H, OCH2), 4.01 (m, 1 H, OCH2), 4.74 (m, 1 H, OCHO), 5.42
(s, 1 H, CHO), 7.38Ϫ7.56 (m, 5 H, aromatic); diastereoisomer B:
δ ϭ 1.44Ϫ1.95 (m, 6 H, THP), 3.63 (m, 1 H, OCH2), 3.79 (m, 1
H, OCH2), 5.11 (m, 1 H, OCHO), 5.59 (s, 1 H, CHO), 7.38Ϫ7.56
(m, 5 H, aromatic). 13C NMR (75 MHz, CDCl3): diastereoisomer
A: δ ϭ 18.7, 25.1, 29.8 (THP), 62.4 (OCH2), 65.8 (OCHO), 96.8
(CHO), 117.6 (CN), 127.4 (C-2, 6), 129.1 (C-3, 5), 129.8 (C-4),
133.9 (C-1); diastereoisomer B: δ ϭ 18.2, 25.1, 29.8 (THP), 62.0
(OCH2), 66.5 (OCHO), 97.5 (CHO), 118.3 (CN), 127.4 (C-2, 6),
129.0 (C-3, 5), 129.6 (C-4), 133.7 (C-1).
Compound (S)-4b: Obtained as a pale yellow solid (371 mg, 81%,
88% ee): m.p. 40.2Ϫ41.4 °C. [α]2D5 ϭ ϩ0.4 (c ϭ 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.22 [s, 9 H, (CH3)3C], 3.81 (s, 3 H,
CH3O), 6.35 (s, 1 H, CHO), 6.94 (m, 2 H, aromatic), 7.43 (m, 2 H,
aromatic). 13C NMR (75 MHz, CDCl3): δ ϭ 27.0 [(CH3)3C], 39.0
(CCO), 55.5 (OCH3), 62.8 (CHO), 114.7 (C-3,5), 116.7 (CN), 124.3
(C-1), 129.5 (C-2,5), 161.2 (C-4), 176.7 (CϭO). MS: m/z (%) ϭ 247
(43), 163 (14), 146 (100), 135 (33), 57 (64). C14H17NO3 (247.12):
calcd. C 68.00, H 6.93, N 5.66; found C 67.76, H 6.94, N 5.61.
HRMS: calcd. 247.1208; found 247.1209.
Compound (R)-1b: Obtained as a pale yellow solid (340 mg, 90%,
88% ee): [α]2D5 ϭ ϩ13.6 (c ϭ 1.0, CHCl3). NMR spectroscopic data
as above.
(S)-(؉)-Cyano(4-chlorophenyl)methyl Pivaloate [(S)-4c] and (R)-
(؊)-Cyano(4-chlorophenyl)methyl Acetate [(R)-1c]: The title com-
pounds were prepared from racemic (R,S)-1c according to General
Procedure C.
Compound (S)-4c: Obtained as a pale yellow oil (352 mg, 76%, 78%
1
ee): [α]2D5 ϭ ϩ2.8 (c ϭ 1.0, CHCl3). H NMR (400 MHz, CDCl3):
(2S)-(4-Methoxyphenyl)[(tetrahydropyran-2-yloxy)]acetonitrile
[(S)-5b] and (R)-(؊)-Cyano(4-methoxyphenyl)methyl Acetate [(R)-
1b]: The title compounds were prepared from racemic (R,S)-1b ac-
cording to General Procedure D. The ratio of aromatic components
in the reaction mixture was determined by 1H NMR (300 MHz,
CDCl3): (S)-5b: 42% (δ ϭ 5.36 and 5.53, CHO); (R)-1b: 50% (δ ϭ
6.35, CHO); anisaldehyde: 8% (δ ϭ 9.89, HCϭO); (S)-5b: 93% ee;
(R)-1b: 92% ee. The reaction mixture was purified by column chro-
matography (PE/EtOAc, 90:10) to give diastereoisomer A as a pale
yellow oil (218 mg, 48%). 1H NMR (300 MHz, CDCl3): δ ϭ
1.50Ϫ1.85 (m, 6 H, THP), 3.62 (m, 1 H, OCH2), 3.78 (m, 1 H,
OCH2), 3.83 (s, 3 H, MeO), 5.08 (m, 1 H, OCHO), 5.53 (s, 1 H,
CHO), 6.94 (m, 2 H, aromatic), 7.45 (m, 2 H, aromatic). 13C NMR
(75 MHz, CDCl3): δ ϭ 18.7, 25.1, 29.8 (THP), 55.4 (MeO), 62.4
δ ϭ 1.23 [s, 9 H, (CH3)3C], 6.38 (s, 1 H, CHO), 7.44 (m, 4 H,
aromatic). 13C NMR (100 MHz, CDCl3): δ ϭ 26.6 [(CH3)3C], 38.6
(CCO), 62.0 (CHO), 115.8 (CN), 128.8, 129.3 (C-2,3,5,6), 130.5 (C-
1), 136.1 (C-4), 176.0 (CϭO). MS: m/z (%) ϭ 251 (28), 167 (13),
150 (50), 139 (90), 111 (60), 85 (25), 57 (100). C13H14ClNO2
(251.07): calcd. C 62.03, H 5.61, N 5.56; found C 62.44. H 5.76, N
5.41. HRMS: calcd. 251.0713; found 251.0713.
Compound (R)-1c: Obtained as a pale yellow oil (328 mg, 85%, Ͼ
99% ee): [α]2D5 ϭ Ϫ13.9 (c ϭ 1.0, CHCl3). NMR spectroscopic data
as above.
(S)-(؉)-Cyano(3-phenoxyphenyl)methyl Pivaloate (S)-4d and (R)-
(؊)-Cyano(3-phenoxyphenyl)methyl Acetate (R)-1d: The title com-
1520
Eur. J. Org. Chem. 2002, 1516Ϫ1522

Enantioselective Synthesis of Protected Cyanohydrins
FULL PAPER
(OCH2), 65.5 (OCHO), 96.8 (CHO), 114.4 (C-3, 5), 117.8 (CN), aration of the enzyme from the reaction mixture, vinyl butyrate (6)
125.8 (C-1), 129.0 (C-2, 6), 160.6 (C-4). A mixture of diastereo-
(2.8 mL, 18.4 mmol) was added. After stirring at 60 °C overnight,
isomer B together with (R)-1b was also obtained, and was purified the reaction mixture was filtered. HCl (1 , 25 mL) was added to
once more by column chromatography (toluene 100%) to give dia-
the filtrate and the organic phase was washed with satd. NaHCO3
(25 mL) and dried with MgSO4. Solvents were removed under va-
°C. H NMR (300 MHz, CDCl3): δ ϭ 1.50Ϫ1.90 (m, 6 H, THP), cuum and the crude products were purified by column chromatog-
stereoisomer B as a pale yellow solid (164 g, 36%): m.p. 56.2Ϫ56.8
1
3.62 (m, 1 H, OCH2), 4.00 (m, 1 H, OCH2), 5.08 (m, 1 H, OCHO),
5.36 (s, 1 H, CHO), 6.94 (m, 2 H, aromatic), 7.40 (m, 2 H, aro-
matic). 13C NMR (75 MHz, CDCl3): δ ϭ 18.3, 25.2, 29.8 (THP),
55.4 (MeO), 62.0 (OCH2), 66.0 (OCHO), 96.9 (CHO), 114.4 (C-3,
5), 118.5 (CN), 125.9 (C-1), 129.1 (C-2, 6), 160.7 (C-4). MS: m/z
(%) ϭ 247 (9), 205 (8), 163 (29), 146 (100), 107 (12), 85 (86), 55
(27). HRMS calcd. for C14H17NO3: 247.1208; found 247.1216.
raphy on silica gel (PE/EtOAc, 95:5).
Racemic Cyanohydrins Protected as Butyryl Esters: Racemic (R,S)-
7aϪd was prepared from racemic (R,S)-2aϪd according to General
Procedure C, with the modifications that a solution of the cyanohy-
drin (1.84 mmol) in dry toluene (36 mL) and n-propanol (0.54 mL)
was used instead of the filtrate from the kinetic resolution, and
butyryl chloride (11.4 mmol) was used instead of pivaloyl chloride.
The yields were: (R,S)-7a: 62%; (R,S)-7b: 84%; (R,S)-7c: 74%;
(R,S)-7d: 84%.
Compound (R)-1b: Obtained as a pale yellow solid (375 mg, 99%):
[α]2D5 ϭ ϩ17.0 (c ϭ 1.0, CHCl3). NMR spectroscopic data as above.
(2S)-(4-Chlorophenyl)[(tetrahydropyran-2-yloxy)]acetonitrile
[(S)-5c] and (R)-(؊)-Cyano(4-chlorophenyl)methyl Acetate [(R)-1c]:
The title compounds were prepared from racemic (R,S)-1c accord-
ing to General Procedure D. The ratio of aromatic components in
the reaction mixture was determined by 1H NMR (300 MHz,
CDCl3): (S)-5c: 43% (δ ϭ 5.39 and 5.57, CHO); (R)-1c: 49% (δ ϭ
6.38, CHO); 4-chlorobenzaldehyde: 8% (δ ϭ 9.98, HCϭO); (S)-5c:
90% ee; (R)-1c: Ͼ 99% ee. Characterisation of racemic (R,S)-5c:
1H NMR (400 MHz, CDCl3): diastereoisomer A: δ ϭ 1.50Ϫ1.90
(m, 6 H, THP), 3.63 (m, 1 H, OCH2), 4.00 (m, 1 H, OCH2), 4.73
(m, 1 H, OCHO), 5.39 (s, 1 H, CHO), 7.39Ϫ7.49 (m, 4 H, aro-
matic); diastereoisomer B: δ ϭ 1.50Ϫ1.90 (m, 6 H, THP), 3.63 (m,
1 H, OCH2), 3.75 (m, 1 H, OCH2), 5.09 (m, 1 H, OCHO), 5.57 (s,
1 H, CHO), 7.35Ϫ7.49 (m, 4 H, aromatic). 13C NMR (100 MHz,
CDCl3): diastereoisomers A and B: δ ϭ 18.2, 18.7, 25.0, 25.1, 29.7
(2 C) (THP), 62.1, 62.5 (OCH2), 65.1, 65.8 (OCHO), 96.9, 97.6
(CHO), 117.2, 118.0 (CN), 128.8 (2 C), 129.2, 129.3 (C-2,6 or 3,5),
132.2, 132.4 (C-1), 135.7, 135.8 (C-4).
(S)-(؊)-Cyano(phenyl)methyl Butyrate [(S)-7a] and (R)-(؉)-Cyano-
(phenyl)methyl Acetate [(R)-1a]: The title compounds were pre-
pared from racemic (R,S)-1a according to General Procedure E.
Compound (S)-7a was obtained as a pale yellow oil (316 mg, 85%,
98% ee): [α]2D5 ϭ Ϫ7.0 (c ϭ 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ ϭ 0.94 (t, J ϭ 7.5 Hz, 3 H, CH3), 1.70 (tq, 2 H, J ϭ
7.4 Hz, CH2CH3), 2.38 (dt, J ϭ 2.8, 7.5 Hz, 2 H, CH2CO), 6.44 (s,
1 H, CHO), 7.41Ϫ7.58 (m, 5 H, aromatic). 13C NMR (75 MHz,
CDCl3): δ ϭ 13.5 (CH3), 18.2 (CH2CH3), 35.6 (CH2CO), 62.6
(CHO), 116.2 (CN), 127.8 (C-2,6), 129.2 (C-3,5), 130.3 (C-4), 131.9
(C-1), 171.6 (CϭO).
Compound (R)-1a: Obtained as a pale yellow oil (302 mg, 93%, 95%
ee): [α]2D5 ϭ ϩ5.9 (c ϭ 1.0, CHCl3). NMR spectroscopic data as
above.
(S)-(؉)-Cyano(4-methoxyphenyl)methyl Butyrate [(S)-7b] and (R)-
(؉)-Cyano(4-methoxyphenyl)methyl Acetate [(R)-1b]: The title com-
pounds were prepared from racemic (R,S)-1b according to General
Procedure E.
(2S)-(3-Phenoxyphenyl)[(tetrahydropyran-2-yloxy)]acetonitrile
[(S)-5d] and (R)-(؊)-Cyano(3-phenoxyphenyl)methyl Acetate [(R)-
1d]: The title compounds were prepared from racemic (R,S)-1d ac-
cording to General Procedure D. The ratio of aromatic components
in the reaction mixture was determined by 1H NMR (300 MHz,
CDCl3): (S)-5d: 43% (δ ϭ 5.36 and 5.54, CHO); (R)-1d: 50% (δ ϭ
6.36, CHO); 3-phenoxybenzaldehyde: 7% (δ ϭ 9.95, HCϭO); (S)-
5d: 84% ee; (R)-1d: Ͼ 99% ee. Characterisation of racemic (R,S)-
Compound (S)-7b: Obtained as a pale yellow oil (364 mg, 80%, 97%
1
ee): [α]2D5 ϭ ϩ12.0 (c ϭ 1.0, CHCl3). H NMR (300 MHz, CDCl3):
δ ϭ 0.94 (t, 3 H, J ϭ 7.5, CH3), 1.68 (tq, 2 H, J ϭ 7.4, CH2CH3),
2.37 (dt, J ϭ 2.9, 7.5 Hz, 2 H, CH2CO), 3.83 (s, 3 H, CH3O), 6.38
(s, 1 H, CH-O), 6.94 (m, 2 H, aromatic), 7.45 (m, 2 H, aromatic).
13C NMR (100 MHz, CDCl3): δ ϭ 13.5 (CH3), 18.2 (CH2CH3),
35.6 (CH2CO), 55.4 (OCH3), 62.3 (CHO), 114.5 (C-3,5), 116.4
(CN), 124.03 (C-1), 129.6 (C-2,6), 161.1 (C-4), 171.7 (CϭO). MS:
m/z (%) ϭ 233 (26), 163 (32), 146 (100), 135 (77), 77 (37).
C13H15NO3 (233.11): calcd. C 66.94, H6.48, N 6.00; found C 67.22,
H 6.45, N 5.64. HRMS: calcd. 233.1052; found 233.1049.
5d: 1H NMR (300 MHz, CDCl3): diastereoisomer A:
δ ϭ
1.40Ϫ1.90 (m, 6 H, THP), 3.60 (m, 1 H, OCH2), 3.70 (m, 1 H,
OCH2), 5.08 (m, 1 H, OCHO), 5.54 (s, 1 H, CHO), 6.95Ϫ7.36 (m,
9 H, aromatic); diastereoisomer B: δ ϭ 1.40Ϫ1.90 (m, 6 H, THP),
3.60 (m, 1 H, OCH2), 3.95 (m, 1 H, OCH2), 4.72 (m, 1 H, OCHO),
5.36 (s, 1 H, CHO), 6.95Ϫ7.36 (m, 9 H, aromatic). 13C NMR
(75 MHz, CDCl3): diastereoisomer A: δ ϭ 18.5, 25.0, 29.7 (THP),
62.2 (OCH2), 65.3 (OCHO), 96.7 (CHO), 118.1 (CN), 119.2 (C-
2ЈЈ,6ЈЈ), 119.3 (C-2Ј), 121.7 (C-4Ј), 123.8 (C-4ЈЈ), 129.9 (C-3ЈЈ,5ЈЈ),
130.3 (C-5Ј), 135.6 (C-1Ј), 156.4 (C-3Ј), 157.9 (C-1ЈЈ); diastereo-
isomer B: δ ϭ 18.2, 25.1, 29.7 (THP), 62.0 (OCH2), 66.1 (OCHO),
97.7 (CHO), 117.3 (CN), 119.2 (C-2ЈЈ,6ЈЈ), 119.4 (C-2Ј), 121.7 (C-
4Ј), 123.8 (C-4ЈЈ), 129.9 (C-3ЈЈ,5ЈЈ), 130.4 (C-5Ј), 135.9 (C-1Ј), 156.4
(C-3Ј), 158.0 (C-1ЈЈ). MS: diastereoisomer A: m/z (%) ϭ 309 (7),
225 (14), 198 (100), 169 (50), 141 (40), 115 (17), 85 (54). Diastereo-
isomer A: C19H19NO3 (309.14): calcd. C 73.77, H 6.19, N 4.53;
found C 73.54, H 6.26, N 4.32. HRMS: calcd. 309.1365; found
309.1374.
Compound (R)-1b: Obtained as a pale yellow solid (306 mg, 81%,
91% ee): [α]2D5 ϭ Ϫ17.5 (c ϭ 1.0, CHCl3). NMR spectroscopic data
as above.
(S)-(؉)-Cyano(4-chlorophenyl)methyl Butyrate [(S)-7c] and (R)-(؊)-
Cyano(4-chlorophenyl)methyl Acetate [(R)-1c]: The title compounds
were prepared from racemic (R,S)-1c according to General Proced-
ure E.
Compound (S)-7c: Obtained as a pale yellow oil (338 mg, 73%, 97%
1
ee): [α]2D5 ϭ ϩ6.7 (c ϭ 1.0, CHCl3). H NMR (300 MHz, CDCl3):
δ ϭ 0.95 (t, 3 H, J ϭ 7.4, CH3), 1.68 (tq, 2 H, J ϭ 7.4, CH2CH3),
2.39 (dt, J ϭ 3.0, 7.4 Hz, 2 H, CH2CO), 6.41 (s, 1 H, CHO),
7.40Ϫ7.49 (m, 4 H, aromatic). 13C NMR (75 MHz, CDCl3): δ ϭ
13.5 (CH3), 18.2 (CH2CH3), 35.5 (CH2CO), 61.9 (CHO), 115.8
General Procedure E: Enzyme-Catalysed Protection as Butyryl Es-
ter: The kinetic resolution was performed as in General Procedure (CN), 129.2, 129.5 (C-2,6,3,5), 130.5 (C-4), 136.6 (C-1), 171.5 (Cϭ
A, but instead of the cooling of the reaction mixture and the sep-
O). MS: m/z (%) ϭ 237 (16), 167 (45), 150 (76), 139 (26), 71 (100).
Eur. J. Org. Chem. 2002, 1516Ϫ1522
1521

L. Veum, M. Kuster, S. Telalovic, U. Hanefeld, T. Maschmeyer
FULL PAPER
[7]
[8]
[9]
F. Effenberger, J. Eichhorn, J. Roos, Tetrahedron: Asymmetry
1995, 6, 271Ϫ282.
C12H12ClNO2 (237.05): calcd. C 60.64, H 5.09, N 5.89; found C
60.89, H 5.16, N 5.80. HRMS: calcd. 237.0557; found 237.0558.
K. Tanaka, A. Mori, S. Inoue, J. Org. Chem. 1990, 55,
Compound (R)-1c: Obtained as a pale yellow oil (357 mg, 93%, 98%
ee): [α]2D5 ϭ Ϫ9.9 (c ϭ 1.0, CHCl3). NMR spectroscopic data as
above.
181Ϫ185.
L. R. Krepski, K. M. Jensen, S. M. Heilmann, J. K. Ramussen,
Synthesis 1986, 301Ϫ303.
B. R. Matthews, H. Gountzos, W. R. Jackson, K. G. Watson,
Tetrahedron Lett. 1989, 30, 5157Ϫ5158.
R. F. C. Brown, A. C. Donohue, W. R. Jackson, T. D. McCar-
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(S)-(؉)-Cyano(3-phenoxyphenyl)methyl Butyrate [(S)-7d] and (R)-
(؊)-Cyano(3-phenoxyphenyl)methyl Acetate [(R)-1d]: The title com-
pounds were prepared from racemic (R,S)-1d according to general
procedure E.
[12]
[13]
[14]
Compound (S)-7d: Obtained as a pale yellow oil (388 mg, 67%, 96%
1
ee): [α]2D5 ϭ ϩ4.2 (c ϭ 1.0 CHCl3). H-NMR (400 MHz, CDCl3):
δ ϭ 0.95 (t, 3 H, J ϭ 7.4, CH3), 1.68 (tq, 2 H, J ϭ 7.4, CH2CH3),
2.39 (dt, 2 H, 2J ϭ 11.7, 3J ϭ 7.4 Hz, CH2CO), 6.38 (s, 1 H,
CHCN), 7.00Ϫ7.42 (m, 9 H, aromatic). 13C NMR (100 MHz,
CDCl3): δ ϭ 13.5 (CH3), 18.2 (CH2CH3), 35.5 (CH2CO), 62.2
(CHO), 115.9 (CN), 117.5 (C-2Ј), 119.4 (C-2ЈЈ,6ЈЈ), 120.1 (C-4Ј),
122.0 (C-6Ј), 124.1 (C-4ЈЈ), 130.0 (C-3ЈЈ,5ЈЈ), 130.6 (C-5Ј), 133.6 (C-
1Ј), 156.2 (C-3Ј), 158.2 (C-1ЈЈ), 171.5 (CϭO).
[15]
[16]
[17]
[18]
Compound (R)-1d: Obtained as a pale yellow oil (464 mg, 92%, 75%
ee): [α]2D5 ϭ Ϫ5.1 (c ϭ 1.0 CHCl3). NMR spectroscopic data as
above.
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Recycling Experiment: The experiment yielding (S)-5c and (R)-1c
was repeated four times using the same enzyme. The reactions were
performed as described in General Procedure D with the following
modifications. In the four repetitions the enzyme was not dried but
directly used in the next cycle after it had been washed with dry
toluene (7 mL). Toluene, n-propanol and racemic (R,S)-1c were
then added to the enzyme. The ratio of aromatic components in
the reaction mixture was determined by integration of the following
1H NMR signals (300 MHz, CDCl3): (S)-5c (δ ϭ 5.39 and 5.57,
CHO), (R)-1c (δ ϭ 6.38, CHO), 8 (δ ϭ 9.98, HCϭO). Cycle 0: (S)-
5c (49%, ee 99%), (R)-1c (43%, ee 90%), 8 (8%); cycle 1: (S)-5c
(48%, ee 99%), (R)-1c (43%, ee 90%), 8 (9%); cycle 2: (S)-5c (49%,
ee 97%), (R)-1c (44%, ee 93%), 8 (7%); cycle 3: (S)-5c (49%, ee
98%), (R)-1c (45%, ee 93%), 8 (6%); cycle 4: (S)-5c (49%, ee 98%),
(R)-1c (45%, ee 93%), 8 (5%).
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Acknowledgments
L. V. thanks Avantium for financial support, and U. H. thanks the
Royal Netherlands Academy of Arts and Sciences for a fellowship.
The authors gratefully acknowledge Roche Diagnostics Penzberg
(W. Tischer) for the generous gift of the enzyme (CAL-B, Chira-
zyme L-2, c.-f., C2, Lyo).
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