Enantioenriched ω-bromocyanohydrin derivatives. Improved selectivity by combination of two chiral catalysts

Article abstract of DOI:10.1016/j.tet.2012.05.090

Highly enantioenriched (R)-4-bromo-1-cyanobutyl acetate and (R)-5-bromo-1-cyanopentyl acetate were prepared by acetylcyanation of 4-bromobutanal and 5-bromopentanal, respectively, catalyzed by (S,S)-[(4,6-bis(t-butyl)salen)Ti(μ-O)]₂ and triethylamine followed by enzymatic hydrolysis of the minor enantiomer. A cyclic procedure employing the same two chiral catalysts provided inferior results due to a slowly reached steady state and, in reactions with the former substrate, to ring-closure of the free cyanohydrin formed as an intermediate in the reaction. Hydrolysis of the acylated cyanohydrins followed by AgClO₄-promoted cyclization provided (R)-2-cyanotetrahydrofuran and (R)-2-cyanotetrahydropyran in essentially enantiopure form.

Full text of DOI:10.1016/j.tet.2012.05.090

Tetrahedron 68 (2012) 7680e7684
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioenriched
u
-bromocyanohydrin derivatives. Improved selectivity by
combination of two chiral catalysts
y
*
Robin Hertzberg, Khalid Widyan , Berenice Heid, Christina Moberg
KTH Royal Institute of Technology, School of Chemical Science and Engineering, Department of Chemistry, Organic Chemistry, SE 100 44 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly enantioenriched (R)-4-bromo-1-cyanobutyl acetate and (R)-5-bromo-1-cyanopentyl acetate were
Received 27 February 2012
Received in revised form 4 May 2012
Accepted 22 May 2012
prepared by acetylcyanation of 4-bromobutanal and 5-bromopentanal, respectively, catalyzed by
(S,S)-[(4,6-bis(t-butyl)salen)Ti(m-O)]2 and triethylamine followed by enzymatic hydrolysis of the minor
enantiomer. A cyclic procedure employing the same two chiral catalysts provided inferior results due to
a slowly reached steady state and, in reactions with the former substrate, to ring-closure of the free
cyanohydrin formed as an intermediate in the reaction. Hydrolysis of the acylated cyanohydrins followed
by AgClO4-promoted cyclization provided (R)-2-cyanotetrahydrofuran and (R)-2-cyanotetrahydropyran
in essentially enantiopure form.
Available online 28 May 2012
Keywords:
Acetylcyanation
2-Cyanotetrahydrofuran
2-Cyanotetrahydropyran
Enzymatic hydrolysis
Kinetic resolution
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
was observed in the hydrocyanation of 5-bromopentanal by the use
of crude preparations from the leaves of food plants and HCN.9 By
Chiral enantioenriched cyanohydrins derived from
u
-bro-
an alternative procedure, 2-cyanotetrahydrofuran with 86.8% ee
was prepared from tetrahydrofurfurylamine subsequent to its reso-
lution using tartaric acid.10
Since the enantiopurity of the final products is normally limited
by the selectivity of the initial process, methods providing the cy-
anohydrins with higher purity are desirable, in particular for the
preparation of biologically active compounds.
moalkanals serve as versatile starting materials for a variety of
nonracemic heterocyclic compounds. Cyclization of the cyanohy-
drins obtained from 4-bromobutanal and 5-bromopentanal leads
directly to 2-cyanotetrahydrofuran and 2-cyanotetrahydropyran.1
The former compound in enantioenriched form has been used for
the preparation of tertahydrofuranyl ketones2 as well as atropiso-
meric bipyridine derivatives via cobalt-catalyzed [2þ2þ2]-cyclo-
trimerization of the nitrile and a tetraalkyne,3 and the racemic
compound has been transformed to bicyclic ethers.4 Chiral tetra-
hydrofurans are also present as structural elements in a variety of
natural products and are therefore currently attractive synthetic
targets.5 From the initially obtained cyanohydrins, a variety of pi-
peridine N,N0-dioxide derivatives6 and azacycloalkanols have also
been prepared via other types of synthetic transformations.7
The required enantioenriched cyanohydrins are usually
obtained by oxynitrilase catalyzed addition of HCN to the appro-
priate aldehyde.8 By employing (R)-oxynitrilase from almonds and
ketone cyanohydrins as sources of HCN, the desired products were
obtained with 91e92% ee1 Similar enantioselectivity of 90e94% ee
The combination of two chiral catalysts can lead to higher
enantioselectivity than that observed using a single catalyst. Most
commonly consecutive catalytic processes have been performed
where an enantioselective reaction is followed by a kinetic reso-
lution, in which the minor enantiomer is transformed to some
compound, which easily can be separated from the product
(Fig. 1a).11,12 We have recently described an alternative cyclic pro-
cedure where the minor enantiomer is recycled by transformation
back to the prochiral starting material by use of a second chiral
catalyst (Fig. 1b).13 In the first type of process, the enantiopurity of
the desired product increases steadily over time, at the same time
as the yield decreases; enantiopure products can thus be obtained,
but yields may be low. The advantage of the cyclic procedure is that
higher yields can be obtained. The selectivity does not exceed
E1ꢀE2, where E1 and E2 are the selectivities of the forward and
reverse reactions, respectively, but is higher than that of the
individual steps.14 By using a combination of a chiral Lewis acid
catalyst and a biocatalyst, O-acetylmandelonitrile, for example,
has been obtained with higher enantioselectivity via the cyclic
* Corresponding author. Tel.: þ46 8 790 9036; fax: þ46 8 791 2333; e-mail
address: kimo@kth.se (C. Moberg).
y
Present address: Department of chemistry, Tafila Technical University,
Tafila-Jordan.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.090

R. Hertzberg et al. / Tetrahedron 68 (2012) 7680e7684
7681
At lower pH slightly lower selectivites were observed (E¼99 for 4a).
Hydrolyses of rac-4a as well as rac-4b catalyzed by Candida Rugosa
lipase (CRL) and Candida antarctica lipase A (CALA) were less se-
lective, the former preferentially hydrolyzing the (R)-enantiomer.
Treatment of enantioenriched 4a with 81% ee (obtained as de-
scribed above, whereafter the crude product mixture was filtered
through silica using diethyl ether as eluent) with CALB/buffer pH 8 at
room temperature resulted after an additional 5 h in 86% (from 1a)
of (R)-4a with >99% ee (Scheme 2). The same treatment of 4b with
80% ee resulted after 24h in (R)-4b in 88% yield (from 1b) and 99% ee.
A
A
S
+
R
P
+
R
(a)
(b)
minor major
X
S
+
R
minor major
Y
Fig. 1. (a) Enantioselective reaction followed by kinetic resolution; (b) Enantioselective
reaction combined with recycling of the minor enantiomer to starting material. A
unidirectional cycle is achieved by continuous addition of a reagent X and formation of
a compound Y.
procedure than by any other method, and at the same time in close
to quantitative yield.13a
Due to the different yield/selectivity profiles of the two pro-
cesses, either a consecutive or a cyclic process may be the optimal
choice in a particular case. This is illustrated here by acetylcyana-
tions of 4-bromobutanal and 5-bromopentanal.
2. Results and discussion
2.1. Sequential reactions
The addition of acyl cyanides to prochiral aldehydes proceeds
readily in the presence of a dual Lewis acid/Lewis base catalytic
system consisting of a chiral titanium-salen dimer and a tertiary
amine to provide high yields of enantioenriched O-acylated cya-
nohydrins.15 Treatment of 4-bromobutanal16 (1a) and 5-
Scheme 2. Enzymatic hydrolysis of enantioenriched 4.
bromopentanal17 (1b) with acetyl cyanide (2) in the presence of
2.2. Minor enantiomer recycling
18
(S,S)-[(4,6-bis(t-butyl)salen)Ti(
m
-O)]2 (3) and triethylamine at
ꢁ20 ꢂC in dichloromethane gave, however, unsatisfactory results:
96% of (R)-4a with 81% ee and 98% of (R)-4b with 80% ee (Scheme
1). At ꢁ40 ꢂC somewhat higher selectivities were observed, but the
reactions were slow and the yields were too low to be acceptable.
The results obtained from the sequential processes were com-
pared to those from minor enantiomer recycling employing tita-
nium catalyst 3 for the forward reaction and CALB for selective
hydrolysis of the minor (S)-enantiomer using a two-phase system
consisting of toluene and aqueous buffer. In order to verify whether
the acetylcyanation of 1a and 1b was compatible with conditions
used for the recycling process, the Ti-catalyzed reactions were first
run in toluene/aqueous buffer pH 8 at room temperature. Although
the presence of base is required for the reactions to work at ꢁ20 ꢂC,
at higher temperatures the reactions proceed readily in the absence
of base. Reaction of 1a under these conditions afforded (R)-4a in
75% yield with 42% ee after 24 h. Cyclization to yield 6a with 40% ee
was observed (13% yield by 1H NMR spectroscopy after isolation of
the product mixture); this product was not obtained when the
reaction was run in dichloromethane in the absence of aqueous
phase. It is assumed that the two products are formed via an in-
termediate titanium(IV) complex (Scheme 3). Under the same
conditions (R)-4b was formed from 1b in 78% yield and 22% ee, and
at 40 ꢂC in the same yield but merely 11% ee.
Scheme 1. Acetylcyanation of 4-bromobutanal and 5-bromopentanal catalyzed by Ti
complex 3 and triethylamine.
It is known that Candida antarctica lipase B (CALB) hydrolyses
a variety of cyanohydrin esters with high selectivity,19,20 and we
therefore decided to treat the products obtained from the ace-
tylcyanations with this enzyme in toluene/aqueous buffer pH 6e8.
We were pleased to find that the (S)-enantiomers of the present
acylated cyanohydrins were hydrolyzed with equally high selectiv-
ity at pH 8 (E>100), although with different rates, (S)-4a undergoing
hydrolysis considerably faster than (S)-4b (see Supplementary data).
Scheme 3. Formation of (R)-4a and (R)-6a via proposed common intermediate.

7682
R. Hertzberg et al. / Tetrahedron 68 (2012) 7680e7684
For the cyclic process, a two-phase system consisting of 1a, ti-
and 28% yields from reactions that had been left to stir for 15 h after
complete addition of acetyl cyanide at room temperature and 40 ꢂC,
respectively (reactions entries 5 and 6); in the latter reaction ra-
cemic 6a was obtained, whereas in the room temperature process,
(S)-6a (i.e., with absolute configuration opposite to that formed in
the two-phase forward reaction) with 33% ee was obtained. These
results demonstrate that (R)-6a is formed along with (R)-4a in the
forward reaction, whereas in the reverse process, which comprises
the hydrolysis of (S)-4a, the opposite enantiomer is formed.
When aldehyde 1b was subjected to the same procedure, (R)-4b
was obtained in higher yield than (R)-4a under the same conditions
(compare entries 7 and 8 with entries 3 and 4), but steady state was
not reached within a reasonable time, resulting in low enantiose-
lectivities (entries 7 and 8). By leaving the reaction mixture to stir
for an additional 15 h after complete addition of acetyl cyanide,
highly enantioenriched product (>99% ee) was obtained, but the
yield, 67% (entry 8), was lower than that obtained from the se-
quential process (88%).
tanium complex 3, and CALB in toluene/aqueous buffer was pre-
pared. Acetyl cyanide was added to the organic phase at room
temperature over 25 h, resulting in an increase in both yield and ee
over time (Scheme 4).
In contrast to the present results, the recycling process13a,21 has
proven to afford superior results than the sequential processes for
other aldehydes.21,22 The major reason for the low yields observed
in the cyclic process in the present case are, for 1a, the tendency of
the cyanohydrin to cyclize to 6a, and for 1b its comparably slow
enzymatic hydrolysis.
2.3. Opposite enantiomer
Reaction of 1a with acetyl cyanide in the presence of (R,R)-[(4,6-
bis(t-butyl)salen)Ti(
m
-O)]2 and triethylamine at ꢁ20 ꢂC afforded (S)-
4a in quantitative yield with 78% ee. Addition of pH 8 buffer and CRL
resulted in slow hydrolysis with only a slight preference for the (R)-
enantiomer. After 125 h, 87% of (S)-4a with 91% ee was obtained.
Scheme 4. Minor enantiomer recycling.
In the reaction of 1a, extensive cyclization to 6a occurred at pH
8, and yields of the desired product were therefore low (Table 1,
entries 1 and 2). As a consequence, fewer cycles were needed to
reach steady state, resulting at 40 ꢂC in high ee (entry 2). At lower
pH, the yields of acylated cyanohydrin were higher (compare en-
tries 1, 3, and 5), but it took a long time to reach steady state. After
complete addition of acetyl cyanide at pH 7 the yield was however
still only 57% of a product with 87% ee (entry 3). By allowing the
reaction mixture to stir for an additional 13 h after complete ad-
dition of acetyl cyanide, enantiomerically pure product was
obtained, but in a yield of merely 50% (entry 3). The same reactions
at 40 ꢂC resulted after complete addition in higher ee, 99 and 90% at
pH 7 and 6, respectively, but in low yields (entries 4 and 6). Cyclized
product 6a was formed in all reactions, and as expected in higher
amounts at the higher temperature. At pH 6, 6a was obtained in 17
2.4. Hydrolysis and cyclization
Since the sequential procedure proved advantageous for the
prepraration of (R)-4a and (R)-4b, this procedure was used for
preparative scale (2.4 mmol) syntheses. After chromatographic
purification, 71% of 4a with >99% ee and 61% of 4b with 99.6% ee
were isolated. The compounds were hydrolyzed (p-toluenesulfonic
acid, ethanol)23 to afford the free cyanohydrins in 93 and 84%
yields, respectively (Scheme 5). The (R)-absolute configurations
were confirmed by comparison of the optical rotations with those
of the known compounds.1 Cyclization using AgClO41 gave (R)-6a in
57% yield with 98% ee, whereas tetrahydropyran (R)-6b was
obtained in 41% yield with 99.6% ee.
Table 1
Minor enantiomer recycling
Entry
Aldehyde
pH
Temp (ꢂC)
Yield (%) of 4
ee (%) of 4
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
8
8
7
7
6
6
7
7
rt
40
rt
40
rt
40
rt
46
26
57
21
70
42
84
78
82
100
87a
99
82b
90c
61
40
86d
Acetyl cyanide (3 equiv) was added over 24e25 h to the aldehyde in toluene/aq
Scheme 5. Hydrolysis and cyclization of (R)-4.
buffer.
a
Continued stirring for 13 h gave 50% of (R)-4a with 100% ee.
Continued stirring for 15 h gave 62% of (R)-4a with 99% ee, 17% 6a with ꢁ33% ee,
b
3. Conclusion
and 10% 5a.
c
Continued stirring for 15 h gave 34% of (R)-4a with 100% ee, 28% racemic 6a and
Good yields of highly enantioenriched (ꢃ99% ee) acetylated cya-
3% of 5a.
d
Continued stirring for 15 h gave 67% of (R)-4b with >99% ee.
nohydrins were obtained by sequential dual Lewis acid-Lewis base

R. Hertzberg et al. / Tetrahedron 68 (2012) 7680e7684
7683
catalyzed acetylcyanation of prochiral 4-bromobutanal and 5-
bromopentanal using acetyl cyanide and enzyme catalyzed hydro-
lysis of the minor, undesired enantiomer. Hydrolysis of the acetylated
cyanohydrins followed by cyclization to (R)-2-cyanotetrahydrofuran
and (R)-2-cyanotetrahydropyran, respectively, occurred with minor
or no loss in ee.
and Et3N (34 mL, 0.24 mmol) were dissolved in dry CH2Cl2 (10 mL).
The mixture was cooled to ꢁ78 ꢂC under nitrogen and stirred for
15 min before AcCN (511 mL, 7.21 mmol) was added. The solutionwas
stirred at ꢁ20 ꢂC for 16 h, then allowed to reach room temperature
and filtered through a short pad of silica and eluted with Et2O. The
solvents were evaporated in vacuo, the residue was dissolved in
toluene (10 mL), and CALB (200 mg) and 1 M phosphate buffer pH 8
(10 mL) were added. The two-phase mixture was stirred at room
temperature. After 22.5 h the phases were separated, the aqueous
phase extracted with Et2O, the combined organic phases dried over
MgSO4, and the solvents evaporated in vacuo. The crude product
was purified by flash chromatography (hexanes/EtOAc 9:1, Rf¼0.26)
to give (R)-4b (342 mg,1.46 mmol, 61%, 99.6% ee) as a pale yellow oil.
4. Experimental section
4.1. General
CH2Cl2 was dried using a Glass Contour solvent dispensing
system. Aldehydes 1a,16 and 1b,17 and (S,S)-, and (R,R)-[(4,6-bis(t-
butyl)salen)Ti(
m
-O)]2 were prepared following literature pro-
½ ꢄ
a 2D3
1459, 1373, 1215, 1050 cmꢁ1; 1H NMR (500 MHz, CDCl3):
J¼6.6 Hz, 1H), 3.42 (t, J¼6.6 Hz, 2H), 2.15 (s, 3H), 1.91e1.97 (m, 4H),
þ55.1 (c 1.0, CHCl3); IR (film): nmax 2964, 2950, 2877,1750,1461,
18
cedures. rac-4a and rac-4b were prepared in the same way as
analogous compounds.21 Immobilized (acrylic resin, ꢃ10,000 U/g)
Candida antarctica lipase B, immobilized (Immobead 150) Candida
antarctica lipase A, and Candida rugosa lipase (CRL) were purchased
from SigmaeAldrich. 1H NMR spectra were recorded at 500 MHz
and 13C NMR spectra at 125 MHz. The 1H and 13C chemical shifts are
reported relative to CHCl3. Optical rotations were measured with
a Rudolph Research Analytical Autopol IV polarimeter, HRMS on
a Bruker Daltonik GmbH micrOTOF and IR spectra on a Mettler
Toledo ReactIR iC10. Yields and enantiomeric excesses were de-
termined with a GC-FID equipped with a chiral column (CYCLOSIL-
d¼5.34 (t,
1.65e1.71 (m, 2H); 13C NMR (500 MHz, CDCl3):
d
¼169.2, 116.8, 60.9,
32.7, 31.8, 31.6, 23.4, 20.5; HRMS (ESI): (MþNa)þ, found 255.9937.
C8H12BrNNaO2 requires 255.9944.
4.1.4. (R)-5-Bromo-1-cyanopentyl acetate (4b) (analytical scale). 5-
Bromopentanal (40.1 mg, 0.243 mmol), (S,S)-[(salen)Ti(m-O)]2
(14.7 mg, 0.0121 mmol), and Et3N (3.4 mL, 0.024 mmol) were dis-
solved in dry CH2Cl2 (1 mL). The solution was cooled to ꢁ20 ꢂC and
stirred for 15 min before AcCN (34
mL, 0.45 mmol) was added.
B, 30 mꢀ0.25 mmꢀ0.25
m
m) using n-undecane as internal stan-
Stirring at ꢁ20 ꢂC was continued for 43 h. The solution was filtered
through a short pad of silica, and eluted with Et2O. The solvents
were evaporated in vacuo, the residue was dissolved in toluene
(1 mL), and CALB (20 mg) and 1 M phosphate buffer pH 8 (1 mL)
were added. The two-phase mixture was stirred at room temper-
ature while the reaction was monitored by chiral GC using unde-
dard. Samples were taken from the organic phase, filtered through
a short silica plug and eluted with Et2O directly into the GC-vial.
4.1.1. (R)-4-Bromo-1-cyanobutyl acetate (4a). 4-Bromobutanal
(363 mg, 2.40 mmol), (S,S)-[(salen)Ti(m-O)]2 (146 mg, 0.120 mmol)
and Et3N (34
m
L, 0.24 mmol) were dissolved in dry CH2Cl2 (10 mL).
cane (10
mL, 0.0473 mmol) as internal standard. After 24 h of
The solution was cooled to ꢁ20 ꢂC under nitrogen and stirred for
stirring, 88% yield of (R)-4b with 99% ee was observed.
15 min before AcCN (340 mL, 4.80 mmol) was added. After a total of
16 h of stirring at ꢁ20 ꢂC, the mixture was filtered through a short
pad of silica and eluted with Et2O. The solvents were evaporated in
vacuo, the residue was dissolved in toluene (10 mL), and CALB
(200 mg) and 1 M phosphate buffer pH 8 (10 mL) were added. The
two-phase mixture was stirred at room temperature. After 5.5 h, the
phases were separated, the aqueous phase extracted with Et2O, the
combined organic phases dried over MgSO4, and the solvents
evaporated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 9:1, Rf¼0.24) to give (R)-4a
4.1.5. (R)-4-Bromo-1-cyanobutyl
alcohol
(5a).1 p-TsOH$H2O
(239 mg, 1.26 mmol) was added to compound (R)-4a (230 mg,
1.05 mmol, >99% ee) in EtOH (5 mL), and the resulting solution was
stirred at room temperature. After 44.5 h of stirring the solvent was
evaporated in vacuo. The crude product was purified by flash
chromatography (hexanes/EtOAc 4:1, Rf¼0.20) to give (R)-5a
(174 mg, 0.977 mmol, 93%) as a pale yellow oil. ½a D22
ꢄ þ19.6 (c 1.0,
CHCl3); lit.:1 þ16.1 (c 1.0, CHCl3, 92% ee); 1H NMR (500 MHz, CDCl3):
d
¼4.57 (q, J¼6.1 Hz, 1H), 3.48 (t, J¼6.2 Hz, 2H), 2.37 (bs, 1H),
(374 mg,1.70 mmol, 71%, >99% ee) as a pale yellow oil. ½a D22
ꢄ
þ64.8 (c
2.08e2.16 (m, 2H), 2.02e2.07 (m, 2H); 13C NMR (500 MHz, CDCl3):
¼119.4, 60.7, 33.8, 32.4, 27.7.
1.0, CHCl3); IR (film): nmax 2972, 2966, 2901, 2877, 1754, 1442, 1375,
d
1222, 1041 cmꢁ1; 1H NMR (500 MHz, CDCl3):
3.45e3.48 (m, 2H), 2.16 (s, 3H), 2.06e2.13 (m, 4H); 13C NMR
d
¼5.37e5.40 (m, 1H),
4.1.6. (R)-5-Bromo-1-cyanopentyl
alcohol
(5b).6a p-TsOH$H2O
(500 MHz, CDCl3):
d
¼169.1, 116.6, 60.4, 31.8, 31.1, 27.7, 20.5; HRMS
(309 mg, 1.62 mmol) was added to compound (R)-4b (315 mg,
1.35 mmol, 99.6% ee) in EtOH (6 mL), and the solution was stirred at
roomtemperature. After 44.5 h ofstirringthesolvent wasevaporated
in vacuo. The crude product was purified by flash chromatography
(hexanes/EtOAc 4:1, Rf¼0.26) to give (R)-5b (218 mg,1.14 mmol, 84%)
(ESI): (MþNa)þ, found 241.9784. C7H10BrNNaO2 requires 241.9787.
4.1.2. (R)-4-Bromo-1-cyanobutyl acetate (4a) (analytical scale). 4-
Bromobutanal (36.2 mg, 0.240 mmol), (S,S)-[(salen)Ti(
(14.6 mg, 0.0120 mmol) and Et3N (3.4 L, 0.024 mmol) were dis-
m-O)]2
m
as a colorless oil. ½a D23
ꢄ
þ14.1 (c 1.0, CHCl3); lit.:1 þ10.7 (c 1.0, CHCl3, 91%
solved in dry CH2Cl2 (1 mL) under nitrogen. The solution was cooled
ee); 1H NMR (500 MHz, CDCl3):
d
¼4.52 (q, J¼6.4 Hz, 1H), 3.43 (t,
to ꢁ78 ꢂC and stirred for 15 min before AcCN (51
mL, 0.72 mmol) was
J¼6.6 Hz, 2H), 2.29 (d, J¼6.1 Hz,1H),1.87e1.97 (m, 4H),1.65e1.73 (m,
added. The solution was stirred at ꢁ20 ꢂC for 44 h, then allowed to
reach room temperature, filtered through a short pad of silica and
eluted with Et2O. The solvents were evaporated in vacuo, the residue
was dissolved in toluene (1 mL), and CALB (20 mg) and 1 M phos-
phate buffer pH 8 (1 mL) were added. The two-phase mixture was
stirred at room temperature while the reaction was monitored by
2H); 13C NMR (500 MHz, CDCl3):
d
¼119.6, 61.3, 34.5, 33.0, 32.0, 23.4.
4.1.7. (R)-Tetrahydrofuran-2-carbonitrile (6a).24 AgClO4 (175 mg,
0.844 mmol) was added to compound (R)-5a (136 mg, 0.766 mmol)
in dry CH2Cl2 (5 mL). The mixture was stirred at room temperature
for 1 h. Brine was added, the phases were separated, and the
aqueous phase was extracted with CH2Cl2. The combined organic
phases were dried over MgSO4 and the solvents evaporated in
vacuo. The crude product was purified by flash chromatography
(petroleum ether/Et2O 4:1, Rf¼0.44) to give (R)-6a with <5% im-
purities (42.7 mg, 0.440 mmol, 57%, 98% ee) as a colorless oil.
chiral GC using undecane (10 mL, 0.0473 mmol) as internal standard.
After 5 h of stirring, 86% yield of (R)-4a with>99% ee was observed.
4.1.3. (R)-5-Bromo-1-cyanopentyl acetate (4b). 5-Bromopentanal
(397 mg, 2.40 mmol), (S,S)-[(salen)Ti(m-O)]2 (147 mg, 0.121 mmol),

7684
R. Hertzberg et al. / Tetrahedron 68 (2012) 7680e7684
½
a 2D2
ꢄ
ꢁ34.2 (c 1.0, CHCl3); lit.:1 ꢁ26.1 (c 0.85, CHCl3, 92% ee); 1H NMR
Supplementary data
(500 MHz, CDCl3):
d
¼4.71 (dd, J¼7.1, 4.6 Hz, 1H), 3.92e4.02 (m, 2H),
2.21e2.31 (m, 2H), 2.09e2.19 (m, 1H), 1.97e2.05 (m, 1H); 13C NMR
(500 MHz, CDCl3):
¼119.5, 69.2, 66.4, 31.8, 25.0.
Procedure for the preparation of (S)-4a. Experimental curves for
enzymatic hydrolyses of rac-4a and rac-4b, copies of 1H and 13C
NMR spectra of compounds 4a, 4b, 5a, 5b, 6a, and 6b, and gas
chromatograms of racemic and enantiomerically enriched com-
pounds. Supplementary data related to this article can be found
online at doi:10.1016/j.tet.2012.05.090.
d
4.1.8. (R)-Tetrahydro-2H-pyran-2-carbonitrile
(6b).25 AgClO4
(252 mg, 1.22 mmol) was added to compound (R)-5b (195 mg,
1.02 mmol) in dry CH2Cl2 (7 mL). The mixture was stirred at room
temperature for 1.75 h. Brine was added, the phases were sepa-
rated, and the aqueous phase was extracted with CH2Cl2. The
combined organic phases were dried over MgSO4 and the solvents
evaporated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/Et2O 9:1, Rf¼0.41) to give (R)-6b
References and notes
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(c 1.0, CHCl3); lit.:1 ꢁ32.9 (c 0.77, CHCl3, 91% ee); 1H NMR (500 MHz,
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d¼4.63 (t, J¼4.3 Hz, 1H), 3.89 (m, 1H), 3.77 (dt, J¼11.8,
ꢁ
Adv. Synth. Catal. 2008, 350, 1449e1456; (b) Kadlcíkova, A.; Hrdina, R.;
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13C NMR (500 MHz, CDCl3):
¼118.0, 66.3, 65.3, 29.4, 25.2, 20.3.
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diluted to a total volume of 250
25 h using a syringe pump. The reaction was monitored by chiral GC
using undecane (10 L, 0.0473 mmol) as internal standard.
mL with toluene) was added over
m
4.4. General procedure for the enzymatic hydrolysis
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Financial support from the Swedish Research Council and from
The Wenner-Gren Center Foundation for Scientific Research is
gratefully acknowledged. We thank Dr. Linda Fransson for fruitful
discussions and Carin Larsson for kind help with HRMS analyses.
We are grateful to the Department of Organic Chemistry at Stock-
holm University for being able to use their polarimeter.
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