Minor enantiomer recycling: Application to enantioselective syntheses of beta blockers

Article abstract of DOI:10.1002/chem.201303890

Continuous recycling of the minor product enantiomer obtained from the acetylcyanation of prochiral aldehydes provided access to highly enantiomerically enriched products. Cyanohydrin derivatives, which under normal conditions are obtained with modest or poor enantiomeric ratios, were formed with high enantiomeric purity by using a reinforcing combination of a chiral Lewis acid catalyst and a biocatalyst. The primarily obtained products were transformed into β-adrenergic antagonists (S)-propanolol, (R)-dichloroisoproterenol, and (R)-pronethalol by means of a two-step procedure.

Full text of DOI:10.1002/chem.201303890

DOI: 10.1002/chem.201303890
Full Paper
&
Enantioselectivity
Minor Enantiomer Recycling: Application to Enantioselective
Syntheses of Beta Blockers
Ye-Qian Wen, Robin Hertzberg, Inanllely Gonzalez, and Christina Moberg*[a]
Abstract: Continuous recycling of the minor product enan-
tiomer obtained from the acetylcyanation of prochiral alde-
hydes provided access to highly enantiomerically enriched
products. Cyanohydrin derivatives, which under normal con-
ditions are obtained with modest or poor enantiomeric
ratios, were formed with high enantiomeric purity by using
a reinforcing combination of a chiral Lewis acid catalyst and
a biocatalyst. The primarily obtained products were trans-
formed into b-adrenergic antagonists (S)-propanolol, (R)-di-
chloroisoproterenol, and (R)-pronethalol by means of a two-
step procedure.
Introduction
Enantioenriched vicinal amino alcohols are conveniently acces-
sible by cyanation of prochiral aldehydes and subsequent re-
duction of the nitrile function.[1] A variety of chiral catalysts,
which comprise metal complexes as well as biocatalysts, are
available for the enantioselective cyanide addition, most com-
monly by using trimethylsilyl cyanide and ethyl or methyl cya-
noformate as a source of cyanide ion. We,[2] as well as Sansano
and co-workers,[3] found that acyl cyanides are attractive alter-
natives that provide stable, highly versatile enantioenriched O-
acylated cyanohydrins in a simple addition process without
the accompanying formation of by-products. High enantiose-
lectivities are observed in reactions with a broad range of sub-
strates. In cases in which O-acetylated cyanohydrins are ob-
tained with insufficient enantiopurity, subsequent treatment of
the primarily obtained product with a suitable biocatalyst ca-
pable of selective hydrolysis of the minor enantiomer might
lead to a single-product isomer.[4]
Scheme 1. a) Enantioselective reaction of a prochiral substrate (A) to yield
minor (S) and major (R) enantiomers followed by kinetic resolution (KR)
transforming S to C, where C is a chiral or achiral compound obtained from
S, the minor enantiomer, with a selectivity factor E. b) Minor enantiomer
recycling (MER) using a sacrificial reagent (X). c) Dynamic kinetic resolution
(DKR).
kinetic resolution (DKR), a reinforcing effect of the two cata-
lysts is achieved, thereby resulting in an enantioselectivity that
is higher than that of any of the individual processes. Thus, as-
suming that E1 and E2 are the selectivities for the product-
forming and the reverse processes, respectively, the maximum
enantiomeric excess (ee) is equal to (E1E2À1)/(E1E2+1), whereas
that for a dynamic kinetic resolution (Scheme 1c) relies on the
selectivity of a single catalyst (E) and is equal to (EÀ1)/(E+1). In
both types of processes the enantioselectivities are thus limit-
ed, but in the cyclic process an enantiopure product might be
obtained if the kinetic resolution is allowed to continue after
addition of the sacrificial reagent has ceased.
Although an enantioselective reaction coupled to a kinetic
resolution (KR) might result in an enantiopure product
(Scheme 1a), the gain in selectivity obtained in the second
step is necessarily accompanied by a decrease in yield.[5] To cir-
cumvent this drawback, we developed a recycling process
whereby the minor, undesired, enantiomer is continuously
transferred to starting material with the aid of a biocatalyst.[6]
A cyclic procedure is maintained by continuous addition of
a sacrificial reagent (Scheme 1b). This minor enantiomer recy-
cling (MER) methodology thus constitutes a combination of an
enantioselective forward reaction and a kinetic resolution of
the product of the forward reaction. In contrast to a dynamic
We decided to evaluate the process for the synthesis of the
b-adrenergic antagonists (S)-propanolol (1a),[7] (R)-dichloroiso-
proterenol (1b),[8] and (R)-pronethalol (1c) (Figure 1).[7] Several
enantioselective methods for the preparation of propanolol,
which is active in its S form,[9,10] have been reported. In addi-
tion to routes based on separation of the enantiomers[11] and
use of the chiral pool[12] or readily available enantiopure start-
ing materials,[13] biocatalytic methods have been used for ki-
netic resolution of either propanolol derivatives or smaller
[a] Dr. Y.-Q. Wen, R. Hertzberg, I. Gonzalez, Prof. C. Moberg
KTH Royal Institute of Technology, Department of Chemistry
Organic Chemistry, 10044 Stockholm (Sweden)
E-mail: kimo@kth.se
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303890.
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enzymatic kinetic resolution of the racemic compound,[27]
whereas the corresponding trimethylsilyl (TMS) ether was ob-
tained with 78% ee in connection to mechanistic studies.[28]
Our results from an exploration of a route for the synthesis
of these b blockers based on acylcyanation of prochiral alde-
hydes 2a–c by employing the two-catalyst minor enantiomer
recycling procedure are reported here.
Figure 1. b-Blockers (S)-propanolol (1a), (R)-dichloroisoproterenol (1b), and
(R)-pronethalol (1c).
building blocks that serve as precursors to the final com-
pound.[14,15] Although kinetic resolutions might give access to
enantiopure products, yields are limited to a maximum of 50%
and are often considerably lower owing to insufficient selectivi-
ty of the biocatalyst, a circumstance that severely limits the
usefulness of these processes. Thus, Pseudomonas cepacia
lipase (PSL)-catalyzed acetylation of a cyanohydrin precursor of
propanolol provided (S)-cyanohydrin with 96% ee after 56%
conversion.[16] A higher yield (71%) was obtained from dynam-
ic kinetic resolution of the azido alcohol precursor, but the ee
was merely 86%.[17]
Results and Discussion
Synthesis of (S)-propanolol (1a)
(1-Naphthyloxy)acetaldehyde (2a), the aldehyde required for
the acetylcyanation, was prepared by means of a previously
described procedure, that is, by reaction of 1-naphthol with a-
bromoacetaldehyde diethyl acetal followed by hydrolysis.[29]
First, conventional methods for the cyanation of 2a were at-
tempted. The aldehyde was therefore treated with acetyl cya-
nide (3) in the presence of (S,S)-[{4,6-bis(tert-butyl)salen}Ti(m-
O)]2 (4) and triethylamine at À308C in CH2Cl2 (Scheme 3). From
A variety of metal-catalyzed synthetic procedures have also
been reported. Several routes based on the nucleophilic ring-
opening of (2S)-3-(1-naphthyloxy)-1,2-epoxypropane, accessible
by means of Sharpless epoxidation,[18] dihydroxylation,[19] l-pro-
line-catalyzed a-aminoxylation,[20] and kinetic resolution,[21]
have been explored (Scheme 2, route I). A route that comprises
Scheme 2. Retrosynthetic analysis for b-adrenergic antagonists.
a nitroaldol condensation as the key step allowed the product
to be isolated in a reasonable overall yield with up to 97% ee
(Scheme 2, route II).[22] Hydrolytic kinetic resolution of racemic
epoxypropylamine[23] (Scheme 2, route III) and nucleophilic
attack of 1-naphthol on C3-symmetric (2S,2’S,2’’S)-tris(2,3-
epoxypropyl)isocyanurate are additional examples.[24] To our
surprise, we have not been able to find any reports on pro-
cesses that incorporate enantioselective cyanation of prochiral
2-(1-naphthyloxy)propanal (Scheme 2, route IV).
Scheme 3. a) Acetylcyanation and b) silylcyanation of 2a.
this reaction the desired acylated cyanohydrin 5a was isolated
in 69% yield, although with low enantiomeric purity of
15% ee. Treatment of 2a with trimethylsilyl cyanide in the
presence of the same titanium complex[30] also proceeded with
low selectivity to give the product with 35% ee, as determined
after transformation to the O-acetylated cyanohydrin.[31] It
should also be noted that (R)-hydroxynitrilase-catalyzed HCN
addition to 2a has been reported to result in a racemic prod-
uct.[32] These poor results called for an improved procedure.
Biocatalysts capable of selective hydrolysis of the R enantio-
mer of a racemic mixture of the acetylated cyanohydrin 5a[33]
as well as of acetylation of the racemic cyanohydrin[16] are
known. We therefore anticipated that a cyclic process that in-
volves in situ hydrolysis of this undesired enantiomer should
lead to higher selectivity than that observed in the reactions
shown in Scheme 3, and at the same time to a yield higher
than the theoretically maximum 50% obtained by kinetic reso-
lution. By subjecting rac-5a, which was obtained from alde-
Although cyanation of 2-naphthylaldehyde, employing tri-
methylsilyl cyanide as well as cyanoformates, results in prod-
ucts with high enantiomeric excess,[25] highly enantioenriched
(R)-pronethalol (1c) has, as far as we are aware, only been pre-
pared by enantioselective reduction of 1-(2-naphthyl)etha-
nones with a leaving group in the 2-position, followed by sub-
stitution with isopropylamine.[26] The same methodology has
also been used for the preparation of (R)-dichloroisoproterenol
(1b).[26] A synthetic procedure that involves the cyanation of
3,4-dichlorobenzaldehyde might seem less attractive since the
acetylated cyanohydrin from 3,4-dichlorobenzaldehyde has
previously been prepared in merely 40% yield and 93% ee by
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hyde 2a by reaction with acetyl cyanide in the presence of
triethylamine, to different biocatalysts in toluene/aqueous
phosphate buffer pH 8, we found that Candida antarctica
lipase B (CALB) catalyzed the hydrolysis with high preference
for the R enantiomer (Scheme 4; also see the Supporting Infor-
amount of enzyme accelerated the hydrolytic reaction and led
to an enantiopure product (Table 1, entry 4), but at the same
time it led to a further decrease in yield as a result of the re-
verse process being favored. A successive increase in the
amount of titanium complex resulted in gradually improved
yields, albeit at some expense to the enantiomeric excess
(Table 1, entries 5 and 6).
Since the reactions were run in a two-phase system in which
the metal-catalyzed reaction occurs in the organic phase and
that catalyzed by the enzyme in the aqueous phase, we were
concerned that the rate of stirring might influence the results.
To test the reproducibility, the reaction was repeated seven
times using the conditions described in Table 1, entry 6, but
with different stir rates. Yields varied between 55 and 67%,
a variation that seemed to be independent of stir rate. Howev-
er, higher enantiomeric excesses of 96–98% were observed in
reactions with fast stirring than in reactions with slow stirring,
most probably as a consequence of more efficient phase trans-
fer and therefore more efficient hydrolysis in the former case.
The progress of the reaction was also followed over time. As
expected, gradual increases in both yield and ee were ob-
served with time. In one case, the ee was 96% and the yield
58% at steady state. When the reaction mixture was allowed
to stir after terminated addition of acetyl cyanide, the ee in-
creased to 99.7%, an increase that was necessarily accompa-
nied by a corresponding decrease in yield.
Scheme 4. Hydrolysis of rac-5 catalyzed by Candida antarctica lipase B.
mation). In this two-phase system, the product-forming step
was found to be unselective, but with the high selectivity ob-
served for the hydrolysis, the cyclic process was expected to
lead to preferential formation of the S enantiomer.
First our standard conditions for minor enantiomer recy-
cling[4d,34]—room temperature, 5 mol% titanium complex 4,
CALB (20 mg), and 25 h addition time of acetyl cyanide (3;
3 equiv)—were attempted. This led to unsatisfactory results:
44% yield and 41% ee (Table 1, entry 1). The low enantioselec-
Table 1. Formation of (S)-propanolol precursor (S)-5a by minor enantio-
mer recycling.[a]
Although high ee was observed, we were concerned about
the yields. We suspected that the moderate yields might be
due to decomposition of the labile aldehyde. This was indeed
found to be the case: treatment of 2a under the reaction con-
ditions (toluene/4/buffer/CALB, 24 h) allowed only approxi-
mately 50% of the aldehyde to be recovered.
On the basis of the results from this initial screening, the re-
action conditions used in entry 6 of Table 1 were selected for
a reaction run on a preparative scale. After purification by
column chromatography, the desired compound (S)-5a was
isolated in 59% yield and with 97.6% ee.
Entry
T [8C] t[b] [h] 4 [mol%] CALB [mg] Yield [%][c] ee [%][d]
1
2
3
4
5
6
20
40
40
40
40
40
25[e]
25[e]
50[f]
50[f]
50[f]
50[f]
5
5
5
5
7.5
10
20
20
20
40
20
20
44
50
35
11
34
61
41
77
98
100
95
96
With the enantioenriched compound (S)-5a in hand, b-adre-
nergic antagonist (S)-propanolol was successfully synthesized
in two steps, which consisted of the reduction of the ester and
nitrile functions by using lithium aluminum hydride (LAH) to
yield (S)-6a, followed by reductive amination with acetone and
sodium borohydride (Scheme 5).[33] Starting from (S)-5a with
[a] Conditions: 0.24 mmol aldehyde 2a in 1 mL toluene/1 mL phosphate
buffer, pH 8. [b] Time for addition of 3. [c] Determined by GC by using un-
decane as internal standard. [d] Determined by chiral GC. [e] Acetyl cya-
nide was diluted with toluene to a total volume of 250 mL. [f] Acetyl cya-
nide was diluted with toluene to a total volume of 350 mL.
tivity suggests that steady state had not been reached. To in-
crease the rate of the catalytic processes, the temperature was
increased to 408C while other conditions were kept constant.
This resulted in both a higher yield and higher ee (Table 1,
entry 2). That higher ee is observed at higher temperature is
counterintuitive, but it is characteristic of the process, since
the ee is steadily increasing as the reaction proceeds. A longer
reaction time, with the addition of acetyl cyanide over 50 h, re-
sulted in a further increase in the ee (98%; Table 1, entry 3) but
in an unacceptable yield of 35%. As expected, a higher
Scheme 5. Preparation of (S)-propanolol (1a) from (S)-5a.
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97.6% ee, (S)-propranolol was obtained in 56% yield (over two
steps) and with 96.9% ee. Optical rotation showed that the
product had S absolute configuration.
stir to increase the ee of the product. The acylated cyanohydrin
5c was then isolated in 82% yield and 97.6% ee. This should
be compared to lipase-catalyzed dynamic kinetic resolution,
which has been reported to give the same acetylated cyanohy-
drin in 88% yield and with only 85% ee.[35] Subsequent LAH re-
duction and reductive amination gave the target compound
(R)-1c in 41% yield and with 96.0% ee. The absolute configura-
tion was shown to be R by comparison of the HPLC elution
order to that published.[26b]
Synthesis of (R)-dichloroisoproterenol (1b)
We assumed that our minor enantiomer recycling procedure
would provide the cyanoacylated product from aldehyde 2b
with higher enantiopurity than previously observed.[27,28] In an
initial experiment, continuous addition of acetyl cyanide to
3,4-dichlorobenzaldehyde (2b), titanium complex 4, and CALB
in toluene/buffer pH 7 over 50 h at 408C resulted in a continu-
ous increase in the yield of 5b. The enantiomeric excess in-
creased during the first approximately 30 h to 94%, after
which time a decrease in enantiomeric purity was observed.
We suspected that this decrease could be a result of enzyme
inhibition and, as a consequence, to slower enzymatic hydroly-
sis, in turn leading to an imbalance between the forward and
reverse processes. A successive decrease in the rate of addition
of acetyl cyanide indeed helped to maintain the high ee (see
also the Supporting Information). A more convenient proce-
dure for the preparation of 5b consisted of the addition of
acetyl cyanide over 8 h at 408C. Under these conditions, the
acetylated cyanohydrin (R)-5b was formed with only 70% ee.
However, the addition of additional CALB gave the product in
54% isolated yield and with 96.0% ee. Subsequent LAH reduc-
tion and reductive amination according to the procedure used
for the preparation of (S)-propanolol resulted in considerable
erosion of the enantiomeric purity (58% ee of (R)-1b prepared
in this way). In contrast, hydrolysis under acidic conditions (p-
toluenesulfonic acid) followed by BH3 reduction and reductive
amination using NaBH4/acetone gave the target compound in
60% yield (over three steps) and with 98.6% ee (Scheme 6).
The absolute configuration was shown to be R by comparison
of the HPLC elution order to that published.[26b]
Conclusion
Aldehydes 2a–c were transformed to acetylated cyanohydrins,
which were subsequently used for the preparation of b-adre-
nergic antagonists (S)-propanolol, (R)-dichloroisoproterenol,
and (R)-pronethalol. Although direct cyanation of 2a and 2b
proceeded with low enantioselectivity, a cyclic process that
comprised a combination of a Lewis acid catalyst and a biocata-
lyst provided highly enantioenriched products in good yields.
The yields of compounds 5a and 5b were moderate, but that
of 5a was considerably higher than the yield obtained by ki-
netic resolution of the corresponding alcohol. The final prod-
ucts derived from aldehydes 2a and 2c were obtained without
erosion of the ee by LAH reduction followed by reductive elim-
ination, whereas an alternative procedure that consisted of
acid-catalyzed hydrolysis, BH3 reduction, and reductive amina-
tion was required to obtain (R)-dichloroisoproterenol with high
enantiomeric excess. The enantioselective synthesis of these
pharmaceuticals is another example of the usefulness of the
minor enantiomer recycling procedure for the preparation of
compounds that are obtained with poor enantioselectivity
using conventional methods.
Experimental Section
General
Synthesis of (R)-pronethalol (1c)
1H (500 MHz) and 13C (125 MHz) NMR spectra were recorded using
a Bruker Avance DMX 500 instrument in CDCl3. Chemical shifts (d)
[ppm] are reported with reference to residual CHCl3 in the solvent.
Enantiomeric excess (ee) values were determined by gas chroma-
tography using an Agilent Technol-
The same synthetic sequence was applied to 2-naphthylalde-
hyde (2c), with acetyl cyanide added over 50 h at 408C. After
the addition was completed, the reaction mixture was left to
ogies
6850
Chromatograph
equipped with a column (30 mꢁ
0.250 mmꢁ0.25 mm) that con-
tained Cyclosil-B as the stationary
phase. HPLC analyses were con-
ducted using a Shimadzu SIL-20A
instrument with a UV detector and
chiral column (Daicel Chiralpak IC,
0.46 cmꢁ25 cm, and Daicel Chiral-
cel ODH, 0.46 cmꢁ25 cm). Optical
rotation was measured using
a Perkin–Elmer 341LC instrument.
Acetyl cyanide,[36] (S,S)-[{4,6-bis(tert-
butyl)salen}Ti(m-O)]2,[37] and (1-
naphthyloxy)acetaldehyde[29] were
prepared according to literature
procedures. 3,4-Dichlorobenzalde-
Scheme 6. Synthesis of (R)-dichloroisoproterenol and (R)-pronethalol (1c).
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hyde and 2-naphthaldehyde were commercial products, which 58CminÀ1 to 2008C, hold for 35 min, 208CminÀ1 to 2208C, hold
were purified by recrystallization from EtOH/H2O and EtOH, respec- 5 min): tR (major)=63.7 min, tR (minor)=64.8 min. 1H NMR
tively, before use. All other reagents were commercially available (500 MHz, CDCl3): d=8.2 (split d, 1H), 7.82 (split d, 1H), 7.51–7.53
and were used without further purification. Immobilized (acrylic (m, 3H), 7.38 (t, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.91 (t, J=
resin, >5000 UgÀ1) Candida antarctica lipase B (CALB, expressed in 5.3 Hz, 1H), 4.50 (d, J=5.3 Hz, 2H), 2.20 ppm (s, 3H); 13C NMR
Aspergillus niger) was purchased from Sigma Aldrich (product (125 MHz, CDCl3): d=168.9, 153.3, 134.6, 127.5, 126.9, 125.9, 125.5,
number L4777, EC number 3.1.1.3). Dry solvents were taken from 125.4, 122.0, 121.7, 114.9, 105.3, 66.8, 59.9, 20.4 ppm.
a Glass Contour solvent dispensing system.
(S)-1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-ol
General procedure for preparation of racemic acetylated
cyanohydrins
((S)-1a)
Compound (S)-5a (0.76 g, 3.0 mmol, 97.6% ee) in Et2O (20 mL) was
added slowly to a suspension of LAH (0.34 g, 9.0 mmol) in anhy-
drous Et2O (30 mL) at 08C under an N2 atmosphere.[38] The mixture
was heated at reflux for 5 h before H2O was added to destroy
excess amounts of LAH. The solid was removed by filtration and
washed with Et2O. The combined organic phases were washed
with brine and dried over MgSO4. Removal of the solvent under re-
duced pressure provided a pale white solid (0.53 g; crude yield:
82%[39]), which was dissolved in absolute ethanol (5 mL), then ace-
tone (0.27 mL, 3.68 mmol) was added dropwise, followed by NaBH4
(0.19 g, 4.90 mmol).[11a] The mixture was stirred overnight, then H2O
was added and the pH was adjusted to 8 by the addition of 1m
HCl. After removal of the solvents, a white solid was obtained,
which was partly dissolved in ethyl acetate and methanol (9:1,
50 mL). The remaining solid was removed by filtration, then the fil-
trate was concentrated and purified by column chromatography
with dichloromethane/methanol (5:1) as eluent to give (S)-1a as
a white solid (0.43 g, 68% yield) with 96.9% ee.[15b] HPLC condi-
tions: Daicel Chiralcel OD-H column, detection at 254 nm, hexanes/
Triethylamine (0.1 equiv) was added dropwise to acetyl cyanide (3,
1.2 equiv) and the appropriate aldehyde in CH2Cl2. The solution
was stirred at room temperature overnight before the solvent was
removed. The crude product was purified by column chroma-
tography.
General procedure for enzymatic hydrolysis of O-acetylated
cyanohydrin
Undecane (10 mL) as internal standard was added to the O-acetylat-
ed cyanohydrin (0.078 mmol) in toluene (1 mL) contained in a vial
with 80 mm height and 13 mm diameter equipped with a stir bar.
The biocatalyst (10 mg) was then added, followed by aqueous
phosphate buffer (1 mL, pH 7 or 8), which was prepared from
KH2PO4 and NaOH (1 and 2m for pH 7 and pH 8 buffers, respective-
ly). The reaction was monitored by GC. For this purpose, aliquots
were taken from the upper organic phase of the two-phase
system; the stirring was maintained at a rate that kept the two
phases separated. The samples were filtered through a plug of
silica, which was rinsed with diethyl ether, and the solution inject-
ed into the GC.
isopropanol/Et2NH=90:10:0.1, rate=0.5 mLminÀ1
, tR (minor)=
22.7 min, tR (major)=46.6 min. [a]D20 =À9.9 (c=0.82, EtOH)
[Ref. [15b]: [a]D20 =À8.83 (c=1, EtOH, 95% ee)]; 1H NMR (500 MHz,
CDCl3): d=8.26 (split d, 1H), 7.80 (split d, 1H), 7.43–7.50 (m, 3H),
7.35 (t, J=7.9 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 4.30 (ddt, J=8.4, 3.5,
5.3 Hz, 1H), 4.20 (A part of ABX, J(A,B)=9.4 Hz, J(A,X)=5.3 Hz, 1H),
4.12 (B part of ABX, J(A,B)=9.4 Hz, J(B,X)=5.3 Hz, 1H), 3.81 (brs,
2H), 3.07 (A part of ABX, J(A,B)=12.2 Hz, J(A,X)=3.5 Hz, 1H), 2.96
(hept, J=6.2 Hz, 1H), 2.92 (B part of ABX, J(A,B)=12.2 Hz, J(B,X)=
8.4 Hz, 1H), 1.18 (d, J=6.2 Hz, 3H), 1.17 ppm (d, J=6.2 Hz, 3H);
13C NMR (125 MHz, CDCl3): d=153.8, 134.4, 127.5, 126.5, 125.8,
125.5, 125.3, 121.8, 120.9, 104.9, 69.7, 65.9, 51.6, 48.3, 19.1,
19.0 ppm.
General procedure for the minor enantiomer recycling
Titanium complex 4 (5–10 mol%) and undecane (10 mL) as internal
standard were added to the aldehyde (0.24 mmol) in toluene
(1 mL) contained in a vial with the dimensions described above
and equipped with a stir bar, followed by CALB, then aqueous
phosphate buffer solution (1 mL, pH 7 or 8), and the mixture was
stirred at the indicated temperature. Acetyl cyanide (51 mL,
0.72 mmol) in toluene was added into the organic phase over the
indicated time using a syringe pump. Aliquots of the reaction mix-
ture were taken and analyzed as described above.
(R)-1-Cyano-2-(3,4-dichlorophenyl)methyl acetate ((R)-5b):
Preparative scale
(S)-1-Cyano-2-(naphthalen-1-yloxy)ethyl acetate ((S)-5a):
3,4-Dichlorobenzaldehyde (2c; 420 mg, 2.4 mmol) and titanium
complex 4 (146 mg, 0.12 mmol) were dissolved in toluene (10 mL)
Preparative scale
(1-Naphthyloxy)acetaldehyde (2a; 223 mg, 1.2 mmol) and titanium in a 50 mL round-bottomed flask, and then CALB (200 mg) and
complex 4 (146 mg, 0.12 mmol) were dissolved in toluene (5 mL) phosphate buffer pH 7 (10 mL) were added. The mixture was
in a 25 mL round-bottomed flask, and then CALB (100 mg) and stirred using a magnetic stir bar at 408C while acetyl cyanide (3;
phosphate buffer pH 8 (5 mL) were added. The mixture was stirred 510 mL, 7.2 mmol) dissolved in toluene (1 mL total volume) was
using a magnetic stir bar at 408C while acetyl cyanide (3; 255 mL, added into the organic phase over 8 h using a syringe pump. After
3.6 mmol) dissolved in toluene (1.75 mL total volume) was added the addition was finished, another 200 mg of CALB was added. The
into the organic phase over 50 h using a syringe pump. After the mixture was allowed to stir for another 2 h, then the two phases
addition was complete, the two phases were separated, and the were separated, and the aqueous phase was extracted with diethyl
aqueous phase was extracted with diethyl ether (2ꢁ30 mL). The ether (2ꢁ60 mL). The combined organic phases were washed with
combined organic phases were washed with brine (1ꢁ60 mL) and brine (1ꢁ100 mL) and dried over MgSO4. After the solvent was
dried over MgSO4. After the solvent was evaporated, the residue evaporated, the residue was purified by column chromatography
was purified by column chromatography using hexanes/CH2Cl2 using hexanes/ethyl acetate (10:1) as eluent to give (R)-5b as
(1:2) as eluent to give (S)-5a as an orange oil (180 mg, 59% yield). a yellow oil (314 mg, 54% yield). The ee was determined to be
The ee was determined to be 97.6% by chiral GC analysis (flow 96.0% by chiral GC analysis (flow 1 mLminÀ1, 608C for 10 min,
1 mLminÀ1, 608C for 10 min, 108CminÀ1 to 1008C, hold for 5 min, 108CminÀ1 to 1008C, 28CminÀ1 to 2108C): tR (major)=56.0 min, tR
Chem. Eur. J. 2014, 20, 3806 – 3812
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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1
(minor)=58.1 min. H NMR (500 MHz, CDCl3): d=7.62 (d, J=2.0 Hz,
65.7 min, tR (minor)=66.6 min. 1H NMR (500 MHz, CDCl3): d=8.03
(s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.87–7.91 (m, 2H), 7.55–7.60 (m,
3H), 6.59 ppm (s, 1H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl3): d=
169.1, 134.0, 133.0, 129.6, 129.1, 128.5, 128.2, 128.0, 127.7, 127.3,
124.4, 116.3, 63.2, 20.7 ppm.
1H), 7.54 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 2.0 Hz, 1H), 6.36 (s,
1H), 2.19 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=168.7, 135.0,
133.7, 131.7, 131.3, 129.8, 127.1, 115.4, 61.6, 20.4 ppm.
(R)-2-(3,4-Dichlorophenyl)-2-hydroxyacetonitrile
(R)-2-(Isopropylamino)-1-(naphthalen-2-yl)ethanol ((R)-1c)
Compound (R)-5c (192 mg, 0.85 mmol, 97.6% ee) dissolved in THF
p-TsOH·H2O (136 mg, 0.71 mmol) was added to a solution of (R)-5b
(173 mg, 0.71 mmol) in ethanol (10 mL). The remaining solution
was stirred for 3 days at room temperature before the solvent was
removed.[28] The residue was purified by column chromatography
with hexanes/EtOAc 5:1 as eluent to give the free cyanohydrin
(130 mg, 91% yield). 1H NMR (500 MHz, CDCl3): d=7.65 (d, J=
1.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.38 (dd, J=8.3, 1.8 Hz, 1H),
5.54 (d, J=6.8 Hz, 1H), 2.92 ppm (d, J=6.8 Hz, 1H).
(2 mL) was added slowly to
a suspension of LAH (100 mg,
2.6 mmol) in THF (3 mL) at 08C under an N2 atmosphere. The mix-
ture was heated to reflux for 2 h and left to stir overnight at room
temperature. H2O (0.7 mL) was added to quench the reaction, then
15% NaOH (0.35 mL) was added. The mixture was diluted with
THF, dried over MgSO4, then filtered and evaporated under
vacuum to provide a white solid (149 mg). The white solid was dis-
solved in EtOH (3 mL), and acetone (87 mL, 1.2 mmol) was added
followed by NaBH4 (61 mg, 1.6 mmol) after 0.5 h. The mixture was
stirred for 1 h at room temperature before the reaction was
quenched by the addition of 1m HCl (1 mL), then the pH was ad-
justed to 8 with 15% NaOH. After removal of the solvents, a white
solid was obtained, which was partly dissolved in ethyl acetate and
methanol (9:1, 50 mL). The remaining solid was removed by filtra-
tion, then the filtrate was concentrated and purified by column
chromatography (EtOAc/MeOH/Et3N 200:10:1) to provide (R)-1c as
a white solid (80 mg, 41% yield based on (R)-5c, 96.0% ee). HPLC
conditions: Chiralpak IC column, detection at 280 nm, hexanes/iso-
(R)-1-(3,4-Dichlorophenyl)-2-(isopropylamino)ethanol
((R)-1b)
BH3·THF (1.92 mL of 1m THF solution, 1.92 mmol) was added
slowly to a solution of the above cyanohydrin (130 mg, 0.64 mmol)
in THF (4 mL) at 08C. The remaining solution was heated to reflux
for 2 h, then left overnight at room temperature. The reaction was
quenched by the addition of methanol (0.5 mL); 15% NaOH was
used to adjust the pH to 8. The mixture was diluted with THF,
dried over MgSO4 and filtered, and the solvent evaporated under
vacuum to provide a white solid (180 mg). The solid was dissolved
in EtOH (4 mL) and acetone (125 mL, 1.7 mmol) was added followed
by NaBH4 (87 mg, 2.3 mmol) after 0.5 h. The mixture was stirred for
1 h at room temperature before quenching the reaction with 1m
HCl (1 mL). The pH was adjusted to 8 with 15% NaOH. After re-
moval of the solvents, a white solid was obtained, which was
partly dissolved in ethyl acetate and methanol (9:1, 50 mL). The re-
maining solid was removed by filtration, the filtrate was concen-
trated and purified by column chromatography (EtOAc/MeOH/Et3N
100:10:1) to provide (R)-1b as a white solid (105 mg, 66% yield,
98.6% ee). HPLC conditions: Chiralpak IC column, detection at
propanol/Et2NH=94.9:5:0.1, rate=0.7 mLminÀ1
,
tR (major)=
1
14.7 min, tR (minor)=23.4 min. H NMR (500 MHz, CDCl3): d=7.82–
7.87 (m, 4H), 7.45–7.50 (m, 3H), 5.00 (dd, J=9.1, 3.1 Hz, 1H), 3.10
(A part of ABX, J(A,B)=12.2 Hz, J(A,X)=3.4 Hz, 1H), 2.99 (hept, J=
6.1 Hz, 1H), 2.83 (B part of ABX, J(A,B)=12.2 Hz, J(B,X)=9.2 Hz,
1H), 2.53 (brs, 2H), 1.19 (d, J=6.1 Hz, 3H), 1.18 ppm (d, J=6.1 Hz,
3H); 13C NMR (125 MHz, CDCl3): d=140.1, 133.3, 133.0, 128.1,
128.0, 127.7, 126.1, 125.8, 124.5, 124.0, 71.9, 54.4, 48.9, 23.1,
22.9 ppm.
280 nm,
hexanes/isopropanol/Et2NH=98.4:1.5:0.1,
rate=
0.7 mLminÀ1, tR (major)=11.6 min, tR (minor)=16.4 min. 1H NMR
(500 MHz, CDCl3): d=7.49 (d, J=1.4 Hz, 1H), 7.41 (d, J=8.2 Hz,
1H), 7.20 (dd, J=8.2, 1.4 Hz, 1H), 4.64 (dd, J=9.0, 3.4 Hz, 1H), 2.96
(A part of ABX, J(A,B)=12.2 Hz, J(A,B)=3.6 Hz, 1H), 2.87 (hept, J=
6.2 Hz, 1H), 2.59 (B part of ABX, J(A,B)=12.2 Hz, J(B,X)=9.0 Hz,
1H), 2.62 (brs, 2H), 1.12 (d, J=6.2 Hz, 3H), 1.11 ppm (d, J=6.2 Hz,
3H); 13C NMR (125 MHz, CDCl3): d=142.8, 132.5, 131.4, 130.4,
127.8, 125.2, 70.0, 53.8, 49.3, 22.1, 22.0 ppm.
Acknowledgements
We thank Dr. Khalid Widyan of Tafila Technical University, Tafila,
Jordan, for valuable discussions. This work was supported by
the Wennergren Foundation for Scientific Research and by the
Swedish Research Council (grant no. 621-2012-3391). I.G. was
supported by a scholarship from the Louis Stroke Alliance for
Minority Participation.
(R)-Cyano(naphthalen-2-yl)methyl acetate ((R)-5c):
Preparative scale
Keywords: aldehydes
·
beta blockers
·
biocatalysis
·
enantioselectivity · Lewis acids
2-Naphthaldehyde (2c; 375 mg, 2.40 mmol) and titanium complex
4 (147 mg, 0.121 mmol) were dissolved in toluene (10 mL) in
a 50 mL round-bottomed flask, then CALB (200 mg) and phosphate
buffer pH 7 (10 mL) were added. The mixture was stirred using
a stir bar at 408C while acetyl cyanide (3; 510 mL, 7.19 mmol) dis-
solved in toluene (2.5 mL total volume) was added into the organic
phase during 50 h. After the addition was completed, the mixture
was allowed to stir for another 5 h 40 min. The phases were sepa-
rated, the aqueous phase was extracted with diethyl ether, the
combined organic phases were dried over MgSO4, and the solvents
were evaporated. The crude product was purified by column chro-
matography (petroleum ether/EtOAc 9:1 to 4:1) to give (R)-5c
(442 mg, 82%, 97.6% ee) as a yellow oil. GC (flow 1 mLminÀ1, 608C
for 10 min, 108CminÀ1 to 1008C, 28CminÀ1 to 2108C): tR (major)=
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Published online on February 26, 2014
Chem. Eur. J. 2014, 20, 3806 – 3812
www.chemeurj.org
3812
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim