New and Convenient Chemoenzymatic Syntheses of (S)-2-Hydroxy-3-octanone, the Major Pheromone Component of Xylotrechus spp., and Its R-Enantiomer

Article abstract of DOI:10.1055/s-0036-1588666

New and efficient chemoenzymatic approaches for the synthesis of both enantiomers of 2-hydroxy-3-octanone in good yields and excellent enantioselectivity are presented. The S-enantiomer is a pheromone component of economically important pests in Japan, India, China, and other Asian countries. The enzymatic approaches involve transesterification of the racemic acyloin with vinyl acetate in the presence of Candida antarctica lipase B (CAL B) in 99% ee of both enantiomers (E = 167-618), or hydrolysis of the acetylated acyloin by double kinetic resolution with CAL B and C. antarctica lipase A (CAL A) in 96-98% ee of either enantiomer (E = 458). CAL A and CAL B induce reverse enantioselectivity.

Full text of DOI:10.1055/s-0036-1588666

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
M. Puigmartí et al.
Paper
Synthesis
New and Convenient Chemoenzymatic Syntheses of (S)-2-Hydroxy-
3-octanone, the Major Pheromone Component of Xylotrechus
spp., and Its R-Enantiomer
Marc Puigmartí
O
O
O
María Pilar Bosch
Josep Coll
CAL B
99% ee
E = 167–618
Angel Guerrero*
OH
OH
OH
OAc
OAc
(S)
(R)
(R)
(S)
(
)
Department of Biological Chemistry and Molecular Modelling,
Institute of Advanced Chemistry of Catalonia (CSIC),
Jordi Girona 18, 08034 Barcelona, Spain
O
O
O
CAL B
angel.guerrero@iqac.csic.es
phosphate buffer
96–98% ee
E = 237
OAc
(
)
Received: 14.10.2016
Accepted after revision: 11.11.2016
Published online: 15.12.2016
ponent of the grape borer Xylotrechus pyrrhoderus Bates
(Coleoptera: Cerambycidae), a major pest of grapevines in
Japan,12 the mulberry pest X. chinensis Chevrolat (Coleop-
tera: Cerambycidae),13 and the coffee white stem borer X.
quadripes Chevrolat (Coleoptera: Cerambycidae), the fore-
most pest of Arabica coffee in India, China, and other asian
countries.14 Chiral nonenzymatic synthesis of (S)-1 and
eventually (R)-1 has been accomplished by Sharpless asym-
metric epoxidation of (±)-1-octen-3-ol,15 a coupling reac-
tion of L-lactic acid and D-alanine, respectively, with amyl-
lithium,12 and treatment of (S)-ethyl lactate with 1-bro-
mopentane.14 Enzymatic synthesis of these compounds has
only been performed by reduction of the 1,2-diketone pre-
cursor either with a keto ester reductase isolated from bak-
er’s yeast,16 with a diacetyl reductase from Bacillus stearo-
thermophilus and the system glucose 6-phosphate/glucose
6-phosphate dehydrogenase,10 or with baker’s yeast in the
presence of an enzyme inhibitor.11 Important drawbacks of
these reductions are the overreduction to the correspond-
ing diols, and the lack of regioselectivity providing two re-
gioisomeric acyloins.9 In this paper we present, for the first
time, new and practical syntheses of both enantiomers (S)-
1 and (R)-1 by chemoenzymatic resolution of the racemic
material by transesterification of the α-hydroxy ketone
with vinyl acetate, as well as by enzymatic hydrolysis of the
corresponding α-acetoxy ketone. Both approaches result in
good yields and excellent enantioselectivity.
DOI: 10.1055/s-0036-1588666; Art ID: ss-2016-z0724-op
Abstract New and efficient chemoenzymatic approaches for the syn-
thesis of both enantiomers of 2-hydroxy-3-octanone in good yields and
excellent enantioselectivity are presented. The S-enantiomer is a pher-
omone component of economically important pests in Japan, India,
China, and other Asian countries. The enzymatic approaches involve
transesterification of the racemic acyloin with vinyl acetate in the pres-
ence of Candida antarctica lipase B (CAL B) in 99% ee of both enantio-
mers (E = 167–618), or hydrolysis of the acetylated acyloin by double
kinetic resolution with CAL B and C. antarctica lipase A (CAL A) in 96–
98% ee of either enantiomer (E = 458). CAL A and CAL B induce reverse
enantioselectivity.
Key words pheromones, biocatalysis, chiral resolution, enzymes, 2-
hydroxy 3-ketones, enantioselectivity
α-Hydroxy ketones are versatile building blocks present
in a variety of chiral bioactive compounds, particularly rele-
vant in the pharmaceutical field, such as inhibitors of amy-
loid-β proteins, farnesyl transferase inhibitors, antifungal
agents, antitumor antibiotics, and antidepressants,1 and
have also been used in natural products synthesis.2 Several
approaches have been reported for the synthesis of these
important chemicals, among them the enantioselective α-
hydroxylation of ketones or enolates,3 the enantioselective
oxidation of racemic benzoins,4 the asymmetric oxidation
of 1,2-diols,5 or via a variety of biocatalytic processes.1,6,7
Most of these latter approaches refer to the synthesis of chi-
ral aryl alkyl and aryl aryl α-hydroxy ketones7 but a few
works report the enzymatic synthesis of nonsymmetric al-
kyl alkyl derivatives,8,9 particularly of 2-hydroxy-3-keto de-
rivatives.10,11
Racemic alcohol (±)-1 was obtained (Scheme 1) in a
similar manner to that described for the synthesis of (S)-2-
hydroxy-3-decanone14 with the following changes: (1) Al-
kylation of lithium 2-(tetrahydropyran-2-yloxy)propanoate
[(±)-4], ethyl lactate [(±)-3] whose hydroxy group has been
protected as the tetrahydropyranyl (THP) ether followed by
lithium hydroxide treatment14 (see Supporting Informa-
tion), with n-pentyllithium was performed with a slight ex-
cess (10%) of the ester to avoid a possible attack of the or-
In an ongoing project of our laboratory, we needed both
enantiomers of 2-hydroxy-3-octanone in enantiomerically
pure form. The S-enantiomer [(S)-1] is a pheromone com-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
M. Puigmartí et al.
Paper
Synthesis
O
OH
CO2Et
)-3
OTHP
1) DHP, p-TsOH/Et2O, 99%
2) LiOH, H2O/EtOH, 99%
C5H11Br, Li, Et2O
79%
CO2Li
)-4
OTHP
(
)-5
(
(
O
O
Ac2O, Et3N, DMAP, CH2Cl2
75%
Amberlite, MeOH
80%
OAc
OH
(
)-2
(
)-1
Scheme 1 Preparation of the racemic compounds (±)-1 and (±)-2
ganolithium reagent at the carbonyl group of product 5,
which we detected as occurring even at a 1:1 ratio of the
reagents. (2) Acid hydrolysis of the THP group of (±)-5 was
conducted with Amberlite® IR120 in MeOH at 30 °C to pre-
vent partial isomerization to the structural isomer 3-hy-
droxy-2-octanone, as previously noticed when this com-
pound and 3-hydroxy-2-hexanone, sex pheromone constit-
uents of the longhorn beetle Anaglyptus subfasciatus,
partially reverted to the isomeric 2-hydroxy 3-ketones at
the GC injection port.17 Racemic (±)-1 was obtained in 80%
isolated yield (47% overall from ethyl lactate). Subsequent
acetylation under standard conditions provided acetate (±)-
2 in 75% isolated yield [35% overall from (±)-3, Scheme 1].
For the kinetic resolution of (±)-1 a number of readily
available lipases, namely Candida antarctica A (CAL A), C.
antarctica B (CAL B), C. rugosa (CRL), Pseudomonas fluo-
rescens (PFL), Burkholderia cepacia (BCL), and porcine pan-
creatic lipase (PPL), were screened. The resolutions were
performed in hexane and with vinyl acetate as the acylating
agent in a thermostated bath under different conditions of
substrate/lipase ratio (from 2:1 to 6:1, and 1:2), tempera-
ture, and time of reaction (Scheme 2, Table 1).
ing chiral acetate 2. In all cases, the corresponding 2-ace-
toxy 3-ketone was the only detectable product and the acy-
loin shift product 3-hydroxy 2-ketone was not detected. Re-
markably, while five of the enzymes produced the R-
enantiomer of the acetate 2 and the S-enantiomer of the re-
maining hydroxy ketone 1, both the immobilized and cross-
linked forms of CAL A induced the reverse enantioselectivi-
ty [i.e., (R)-1 as remaining substrate and (S)-2 as the result-
ing acetate] although in moderate enantioselectivity [40–
80% ee of (R)-1, 71–85% ee of (S)-2; Table 1]. CAL B was the
best resolving enzyme, producing alcohol (S)-1 in 90–99%
ee and acetate (R)-2 in 94–99% ee (entries 1–3); the enan-
tiomeric ratio (E) values were all over 160, being highest at
the lowest reaction time (2.5 h, E >600). This result is in
agreement with the enantiomeric selectivity predicted by
Uppenberg and co-workers,18 who modeled the tetrahedral
intermediate of 1-phenylethyl octanoate within the active
site pocket of the enzyme to predict that only the R-enan-
tiomers of secondary alcohols are suitable for forming suc-
cessful intermediates for catalysis. CAL B has shown out-
standing biocatalytic features, such as excellent enantiose-
lectivity and tolerance for a broad range of substrates,
which has ensured the use of this enzyme in numerous bio-
transformations.19 This enzyme has also been used for the
resolution of pheromone components of many cecidomyiid
midge species, namely compounds with an oxygenated
function at the 2-position of an alkyl or alkenyl chain, with
excellent enantiomeric purity.20 CAL A has received less at-
tention,21,22 which is surprising as it tolerates a broad tem-
The reaction was stopped when ca. 50% conversion was
achieved. The absolute configuration assignment of the al-
cohols was based on the sign of the specific rotation of the
alcohol by comparison with previously reported data.10,15
Lipases CAL A, CAL B, and PFL needed the lowest amount of
enzyme relative to the substrate (substrate/lipase 2:1 to
6:1) to reach a reasonable conversion into the correspond-
O
O
O
lipase, vinyl acetate, hexane
OH
OH
OAc
(
)-1
(S)-1
(R)-2
K2CO3, MeOH
O
OH
(R)-1
Scheme 2 Enzymatic resolution of racemic hydroxy ketone (±)-1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
M. Puigmartí et al.
Paper
Synthesis
Table 1 Lipase-Catalyzed Enzymatic Resolution of Alcohol (±)-1
Entry Conditions
Remaining acyloin 1
Acetylated acyloin 2
Hydrolysis of acyloin 2a
Lipase
Substrate/lipaseb Temp (°C) Time (h) Yield (%)c ee (%)d
Yield (%)c
ee (%)d
Yield (%)c
ee (%)d
Ee
1
2
CAL B (acrylic resin)
CAL B (acrylic resin)
CAL B (acrylic resin)
CAL A (immobilized)
CAL A (immobilized)
CAL A (immobilized)
CAL A (cross-linked)
BCL
2:1
2:1
2:1
6:1
6:1
6:1
5:1
1:2
1:2
1:2
6:1
36.5
36.5
36.5
36.5
30.0
24.0
36.5
36.5
36.5
36.5
36.5
2.5
5
42
36
42
39
34
39
38
73
57
62
48
90 (S)
97 (S)
99 (S)
76 (R)
80 (R)
40 (R)
48 (R)
12 (S)
22 (S)
14 (S)
4 (S)
44
39
44
43
39
40
33
12
12
11
22
99 (R)
96 (R)
94 (R)
82 (S)
79 (S)
85 (S)
71 (S)
63 (R)
78 (R)
68 (R)
5 (R)
–
–
618
229
167
23
21
18
9
–
–
3
8
–
–
4
2
37
35
34
29
–
77 (S)
74 (S)
79 (S)
66 (S)
–
5
4
6
7
7
7
8
72
5
9
PPL
72
72
7
–
–
10
6
10
11
CRL
–
–
PFL
–
–
1
a Data for acyloin (S)-1 after hydrolysis of acetylated acyloin (S)-2.
b Ratio by weight.
c Yields refer to pure isolated products after column chromatographic purification.
d ee values were determined by GC with a chiral stationary phase (Cydex-B) or by 19F NMR analysis of the corresponding Mosher esters.
e Enantiomeric ratio (E) was calculated as reported.26a Alternatively, it can be determined using the program ‘Selectivity’.26b
perature and pH range and is able to maintain its hydrolytic
activity in organic solvents with a minimum of structural
water.21 These two enzymes are not considered closely re-
lated as the A lipase is calcium dependent, in contrast to the
B lipase. In addition, they offer different substrate specifici-
ty, and CAL B does not display interfacial activation towards
p-nitrophenyl acetate and p-nitrophenyl butyrate, a more
typical behavior of an esterase than a lipase.23 It is not sur-
prising, then, that CAL A and CAL B induced opposite enan-
tioselectivity, as has been noticed previously.24 The other
enzymes, BCL, PPL, CRL, and PFL, were poor resolution
agents even after long reaction periods and the use of rela-
tively high amounts of enzyme (Table 1, entries 8–11). The
time course of the reaction showed that immobilized CAL A
(substrate/lipase 6:1) at 36.5 °C was the fastest enzyme to
reach 50% conversion of alcohol (±)-1 into the chiral acetate
(S)-2 (less than 2 h, Figure 1). Lower reaction temperatures
slowed down the rate of the processes, with a maximum
39% conversion reached after reaction for 7 hours. CAL B
steadily achieved, in a straight line, 40% conversion in 1.5
hours, which gradually increased to 50% conversion in 3–7
hours, with remarkably high ee values (94–99%). CRL, BCL,
and PPL afforded <5% conversion after reaction for 7 hours
(Figure 1).
Alternatively, we also explored the possibility to obtain
chiral (R)-1 and (S)-1 by enzymatic hydrolysis of racemic
acetate (±)-2 in aqueous phosphate buffer at room tempera-
ture (ca. 23 °C) (Scheme 3). There are very few reports on
the enzymatic kinetic resolution of acyloin acetates in
which the groups at the α-position to the ester and carbon-
yl are linear alkyl or alkenyl,8,25 and none on 2-acetoxy-3-
keto compounds. In our case, the same lipases were tested,
although in somewhat higher amounts relative to the sub-
strate (substrate/lipase range from 2:1 to 4:1 and 1:2). In
addition, due to the low solubility of the substrate in the
aqueous medium, it was necessary to vortex the dispersion
Figure 1 Time course of the enzymatic resolution of alcohol (±)-1 with several lipases under the conditions listed in Table 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
M. Puigmartí et al.
Paper
Synthesis
O
O
O
lipase, phosphate buffer
OH
OAc
OAc
(S)-2
(R)-1
(
)-2
K2CO3, MeOH
O
OH
(S)-1
Scheme 3 Enzymatic resolution of racemic acetoxy ketone (±)-2
to obtain a reliable medium for the reaction to occur. In a
typical experiment, the racemic acetoxy ketone 2 was treat-
ed with phosphate buffer (pH 7.0) in the absence of a cosol-
vent. The reaction mixture was homogenized by shaking
briefly (15 s) on a vortex until the solution turned cloudy.
Then, it was shaken in a thermostated bath at 90
strokes/min and room temperature (ca. 23 °C), and the
progress of the resolution was followed by GC on a chiral
stationary phase (Cydex-B) until ca. 50% conversion into
the expected chiral alcohol (R)-1 was reached. The mixture
was then extracted with organic solvent, and the crude
product was separated by column chromatography to afford
the unreacted acetoxy ketone (S)-2 and hydroxy ketone (R)-
1. The absolute configuration of the alcohol product was as-
sessed by comparison of its specific rotation with literature
data.10,15 As occurred in the transesterification process, all
enzymes, except CAL A, preferentially hydrolyzed the R-
acetate affording the R-hydroxy ketone, with the S-acetoxy
ketone remaining unreacted. The selectivity of CAL B for the
R-enantiomer again confirmed the validity of the active site
model previously reported (see above).18 This enzyme was,
by far, the best of all enzymes tested and the only one capa-
ble of inducing an enantioselective hydrolysis with an ex-
cellent E value [E = 237, 96% ee of (R)-1, 98% ee of (S)-2; Ta-
ble 2, entry 1].
The other enzymes failed to produce substrate and hy-
drolysis product with worthwhile enantiomeric enrich-
ment, with E values being disappointingly low (Table 2). For
the time course of the reaction, see Figure 2.
In the hydrolysis of acetate (S)-2 with K2CO3 in MeOH,27
we noticed a small but consistent loss of enantioselectivity
(4–6% ee; Table 2, entries 1 and 4–7), probably due to the
enhanced acidity of the α-proton to the carbonyl and ace-
tate groups of (S)-2. Although racemization-free hydrolysis
could be conducted by using 20 mol% scandium triflate in
MeOH–H2O (4:1), as previously described,28 we preferred to
use another enzyme resolution for the hydrolysis to simul-
taneously allow for a possible further improvement in the
global enantioselectivity of the process. Therefore, a double
kinetic resolution with CAL B and CAL A was undertaken
(Scheme 4). A first resolution of the racemic acetate (±)-2
with CAL B under the conditions as given in entry 1 (Table
2) furnished acetate (S)-2 in 44% yield and 98% ee, along
with alcohol (R)-1 in 38% yield and 97% ee (E = 420).
Table 2 Lipase-Catalyzed Hydrolysis of Racemic Acetate (±)-2
Entry
Conditions
Lipase
Resolved acyloin 1
Yield (%)c ee (%)d
Remaining acetoxy ketone 2 Hydrolysis acyloin 2a
Substrate/lipaseb Time (h)
Yield (%)c
ee (%)d
Yield (%)c
ee (%)d
Ee
237
1
2
3
4
5
6
7
CAL B (acrylic resin)
4:1
4:1
2:1
2:1
1:2
2:1
2:1
2
39
37
29
58
21
30
74
96 (R)
26 (S)
26 (S)
30 (R)
22 (R)
58 (R)
8 (R)
41
56
57
27
70
57
16
98 (S)
40 (R)
42 (R)
86 (S)
48 (S)
38 (S)
54 (S)
35
–
92 (S)
–
CAL A (immobilized)
5
2
3
5
2
5
2
CAL A (cross-linked)
7.5
3
–
–
BCL
PPL
CRL
PFL
23
60
49
14
80 (S)
42 (S)
33 (S)
50 (S)
5.5
8
5
a Data for acyloin (S)-1 after hydrolysis of acetylated acyloin (S)-2.
b Ratio by weight.
c Yields refer to pure isolated products after column chromatographic purification.
d ee values were determined by GC with a chiral stationary phase (Cydex-B) or by 19F NMR analysis of the corresponding Mosher esters.
e Enantiomeric ratio (E) was calculated as reported.26a Alternatively, it can be determined using the program ‘Selectivity’.26b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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M. Puigmartí et al.
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Synthesis
Figure 2 Time course of the lipase-catalyzed hydrolysis of acetate (±)-2 under the conditions listed in Table 2
O
O
O
CAL B (4:1), phosphate buffer
OAc
OAc
OH
(
)-2
(R)-1
(38%, 97% ee)
(S)-2
(44%, 98% ee)
CAL A cross-linked (1:1), phosphate buffer
O
O
OH
OAc
(S)-2
(S)-1
(12%, 98% ee)
(69%, 98% ee)
Scheme 4 Double kinetic resolution of acetate (±)-2
Then, new enzymatic hydrolysis of the obtained (S)-2
with cross-linked CAL A in a substrate/lipase 1:1 ratio with
phosphate buffer at 22 °C at the appropriate conversion
(82%) allowed transformation of (S)-2 into the correspond-
ing alcohol (S)-1 in 69% isolated yield and 98% ee with no
racemization, leaving unreacted (S)-2 in 12% yield and 98%
ee (E = 458) (Scheme 4). No further improvement in the ee
was obtained, but the remaining (S)-2 could be epi-
merized29 and recycled to afford a higher isolated yield of
the required enantiomer. In an alternative approach, double
kinetic resolution of alcohol (±)-1 with both forms of CAL A
failed to improve the enantioselectivity of the process.
Thus, a first resolution with immobilized CAL A in a sub-
strate/lipase 10:1 ratio in the presence of vinyl acetate for 3
hours, followed by hydrolysis of the enantioenriched (S)-2
with cross-linked CAL A in a substrate/lipase 2:1 ratio, gave
(R)-1 in 48% yield and only 76% ee and (S)-1 in 46% yield
and 89% ee (not shown).
processes are performed under mild conditions, which
minimize the formation of undesired byproducts, and there
is no isomerization to the isomeric 3-hydroxy 2-ketone. Al-
though the processes have been performed on a small scale
and with a relatively high substrate/lipase ratio, in general
lipase-catalyzed reactions can be easily scaled up and the
substrate/lipase ratio optimized. In addition, while the
maximum yield of the resolution cannot exceed 50%, the
undesired remaining acetoxy ketone could be epimerized
and recycled to optimize the yield of the desired enantio-
mer. Our approach could be extended to other 2-hydroxy 3-
ketones provided that the alkyl side chains of the substrate
have different enough sizes to allow successful recognition
by the active site of the enzyme.
The purity of racemic ethyl lactate, supplied by TCI Europe, was
checked by NMR spectroscopy, chiral GC, and specific rotation mea-
surement prior to use. All lipases were purchased from Sigma Aldrich.
CAL B (Novozyme 435) was an acrylic resin from Candida antarctica
recombinant, expressed in Aspergillus niger (≥5000 U/g, catalogue No.
L4777), CAL A (‘immobilized form’) was immobilized on Immobead
150, recombinant from Aspergillus oryzae (≥500 U/g, catalogue No.
41658), and CAL A (‘cross-linked form’) was the cross-linked enzyme
aggregate (≥1500 U/mL, catalogue No. 743941). The other lipases
In summary, our results provide two new, reliable ap-
proaches for preparing both enantiomers of 2-hydroxy-3-
octanone in excellent enantioselectivity, either by enzy-
matic transesterification of the racemic material with vinyl
acetate using CAL B or by hydrolysis of the acetoxy ketone
with CAL B and CAL A in a double kinetic resolution. The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
M. Puigmartí et al.
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Synthesis
used were Candida rugosa (CRL), type VII (≥700 U/mg solid, catalogue
No. L1754), Amano lipase from Pseudomonas fluorescens (PFL)
(≥20000 U/g, catalogue No. 534730), Amano lipase PS from Burk-
holderia cepacia (BCL) (≥30000 U/g, catalogue No. 534641), and lipase
from porcine pancreas (PPL), lyophilized, type II (100–500 U/mg pro-
tein using olive oil, catalogue No. L3126). These latter enzymes were
not supported. Enzymatic resolution assays were carried out in a Se-
lecta Unitronic 320 OR thermostatic bath shaker at the indicated tem-
perature and 85–90 strokes/min. 1H and 13C NMR spectra were re-
corded on a Varian Mercury 400 spectrometer at 400 MHz and 100
MHz, respectively, in CDCl3 with TMS as internal standard. Chemical
shifts (δ) are given in ppm relative to TMS. 19F NMR spectra were run
at 376 MHz on the Varian Mercury 400 spectrometer with CFCl3 in
CDCl3 as internal standard. IR spectra were recorded on a Nicolet Ava-
tar 360 FT-IR spectrometer. Low-resolution mass spectra (MS) were
obtained in electron impact (EI) mode on a Fisons MD 800 instrument
operating at 70 eV. High-resolution mass spectra (HRMS) were re-
corded in electrospray mode (ESI) on a UPLC Acquity instrument cou-
pled to an LCT Premier XE (Waters) spectrometer. Enantiomeric ex-
cess (ee) of the products was determined by gas chromatography on a
Cydex-B chiral column (25 m × 22 mm i.d. × 0.25 μm film) at 50 °C for
1 min, then 5 °C/min to 200 °C, or from the 19F NMR spectra of the
corresponding Mosher esters with (R)-(–)-α-methoxy-α-(trifluoro-
methyl)phenylacetyl chloride (available from Sigma Aldrich). Both
methods differed by less than 2% of the calculated ee values.
2-Hydroxy-3-octanone [(±)-1]
Compound (±)-5 (10.0 g, 43.8 mmol) was dissolved in anhyd MeOH
(250 mL) and Amberlite® IR120 resin (6 g) was added under N2. The
mixture was stirred at 30 °C for 5 h until no trace of the starting ma-
terial was observed by GC. The resin was removed by filtration
through a Celite pad, and the solvent evaporated under reduced pres-
sure. The wet residue was dissolved in Et2O (100 mL), dried over
Na2SO4, and concentrated under reduced pressure. The resulting
crude was purified by flash chromatography on silica gel (hexane–
Et2O, 95:5) to provide (±)-1 (5.0 g, 80% yield) as a colorless oil; Rf =
0.58 (hexane–Et2O, 2:1).
IR (film): 3454, 2957, 2932, 2862, 1711, 1457, 1368, 1253, 1120,
1052, 1027, 908 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.22 (q, J = 7.1 Hz, 1 H), 2.56–2.29 (m, 2
H), 1.67–1.54 (m, 2 H), 1.36 (d, J = 7.1 Hz, 3 H), 1.35–1.16 (m, 4 H),
0.87 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.91, 72.77, 37.72, 31.60, 23.52,
22.61, 20.07, 14.09.
MS (EI): m/z (%) = 144 (1) [M+], 99 (100), 83 (53), 71 (59), 55 (71), 45
(70), 43 (100).
HRMS (ESI): m/z [M – H]– calcd for C8H15O2: 143.1072; found:
143.1066.
2-Acetoxy-3-octanone [(±)-2]
To a solution of alcohol (±)-1 (2.0 g, 13.9 mmol) and a catalytic
amount of DMAP in anhyd CH2Cl2 (40 mL) were added, under N2, Et3N
(7 mL, 50.2 mmol) and Ac2O (7 mL, 74.1 mmol), and the mixture was
stirred at r.t. for 4 h. The reaction was quenched with sat. NH4Cl solu-
tion (50 mL) and the organic phase was decanted off. The aqueous
layer was extracted with CH2Cl2 (3 × 25 mL) and the combined organic
layers were washed with 0.5 M HCl solution (2 × 50 mL) and brine (50
mL), dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (hex-
ane) to afford acetate (±)-2 (1.9 g, 75% yield) as a colorless oil; Rf = 0.37
(hexane–Et2O, 4:1).
2-(Tetrahydropyran-2-yloxy)-3-octanone [(±)-5]
A small amount (2 mL) of a solution of 1-bromopentane (12 mL, 96.8
mmol) in anhyd Et2O (15 mL) was added to a flask containing small
pieces of clean lithium (1.3 g, 187 mmol) in anhyd Et2O (75 mL) under
argon, and the mixture was stirred for 10 min at r.t. After a cloudy
solution was formed, the remaining bromopentane solution was add-
ed dropwise to the flask, cooled with an ice bath, and stirred at 0 °C
for 1 h. The pentyllithium solution (100 mL, 78.0 mmol) thus pre-
pared was added to a suspension of lithium 2-(tetrahydropyran-2-
yloxy)propanoate [(±)-4; 15 g, 83.2 mmol]14 (see Supporting Informa-
tion) in anhyd Et2O (70 mL) under N2 and cooled in an ice bath. After
the mixture was stirred at r.t. overnight, the reaction was quenched
with sat. NH4Cl solution (100 mL) and the whole was stirred for 15
min. The organic phase was decanted off and the aqueous layer was
further extracted with Et2O (3 × 75 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (hexane–Et2O, 95:5) to provide (±)-5 (14.1 g, 79% yield) as
a colorless oil, as 1:1 mixture of diastereoisomers by GC; Rf = 0.48
(hexane–Et2O, 4:1).
IR (film): 2957, 2934, 2873, 1742, 1727, 1456, 1371, 1231, 1085 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.06 (q, J = 7.1 Hz, 1 H), 2.56–2.30 (m, 2
H), 2.11 (s, 3 H), 1.57 (pent, J = 7.4 Hz, 2 H), 1.37 (d, J = 7.0 Hz, 3 H),
1.34–1.19 (m, 4 H), 0.87 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 208.04, 170.59, 74.84, 38.40, 31.54,
23.06, 22.65, 20.98, 16.38, 14.12.
MS (EI): m/z (%) = 186 (0.1) [M+], 130 (7), 99 (90), 87 (16), 71 (35), 43
(100), 41 (7).
HRMS (ESI): m/z [M – H]– calcd for C10H17O3: 185.1178; found:
185.1171.
IR (film): 2934, 2871, 1717, 1454, 1368, 1123, 1077, 1034, 1022, 979,
874 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.56 (dd, J = 5.2, 2.7 Hz, 1 H), 4.50 (dd,
J = 4.6, 2.9 Hz, 1 H), 4.22 (q, J = 7.0 Hz, 1 H), 4.03 (q, J = 6.8 Hz, 1 H),
3.86–3.70 (m, 2 H), 3.50–3.32 (m, 2 H), 2.65–2.49 (m, 2 H), 2.49–2.32
(m, 2 H), 1.87–1.59 (m, 4 H), 1.58–1.42 (m, 12 H), 1.30 (d, J = 7.1 Hz, 3
H), 1.28–1.16 (m, 8 H), 1.21 (d, J = 6.9 Hz, 3 H), 0.83 (t, J = 7.0 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 212.80, 212.69, 98.62, 98.44, 78.27,
77.68, 63.57, 62.83, 37.95, 37.77, 31.60, 31.02, 30.83, 25.50, 25.42,
23.13, 23.02, 22.65, 22.61, 20.21, 19.60, 18.41, 16.94, 14.09, 14.05.
MS (EI): m/z (%) = 227 (0.1) [M – 1+], 85 (100), 67 (7), 57 (8), 43 (9), 41
(7).
HRMS (ESI): m/z [M – H]– calcd for C13H23O3: 227.1647; found:
227.1640.
Lipase-Catalyzed Enzymatic Resolution of Alcohol (±)-1; General
Procedure
In a 25-mL Erlenmeyer flask, alcohol (±)-1 (120 mg, 0.83 mmol) was
dissolved in hexane (10 mL), and vinyl acetate (770 μL, 8.35 mmol)
and the corresponding amount of lipase were then added. The flask
was tapped with a septum and the mixture was shaken in a thermo-
stated bath at 85 strokes/min at the cited temperature (Table 1). The
progress of the reaction was monitored by chiral GC until ca. 50% con-
version was reached. Then, the reaction mixture was filtered and the
lipase was washed with hexane (10 mL) and Et2O (10 mL). The solvent
was removed under reduced pressure, and the residue was purified by
flash chromatography on silica gel (hexane–Et2O, 4:1) to afford the R-
and S-enantiomers of alcohol 1 and acetate 2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
M. Puigmartí et al.
Paper
Synthesis
Experimental details for Table 1 entries:
Entry 2: immobilized CAL A (25 mg), 5 h; substrate/lipase ratio 4:1.
Compound (S)-1 (28 mg, 37% yield), 26% ee; compound (R)-2 (56 mg,
56% yield), 40% ee.
Entry 1: CAL B (60 mg), 36.5 °C, 2.5 h; substrate/lipase ratio 2:1. Com-
20
pound (S)-1 (50 mg, 42% yield), 90% ee, [α]D +59 (c 0.86, CHCl3);
compound (R)-2 (68 mg, 44% yield), 99% ee, [α]D20 +30 (c 0.96, CHCl3).
Entry 3: cross-linked CAL A (50 mg), 7.5 h; substrate/lipase ratio 2:1.
Compound (S)-1 (22 mg, 29% yield), 26% ee; compound (R)-2 (57 mg,
57% yield), 42% ee.
Entry 2: CAL B (60 mg), 36.5 °C, 5 h; substrate/lipase ratio 2:1. Com-
pound (S)-1 (43 mg, 36% yield), 96.5% ee, [α]D +62 (c 0.70, CHCl3);
compound (R)-2 (60 mg, 39% yield), 96.5% ee, [α]D +28 (c 0.98,
CHCl3).
20
20
Entry 4: BCL (50 mg), 3 h; substrate/lipase ratio 2:1. Compound (R)-1
(45 mg, 58% yield), 30% ee; compound (S)-2 (27 mg, 27% yield), 86%
ee, [α]D20 –25 (c 1.18, CHCl3).
Entry 3: CAL B (60 mg), 36.5 °C, 8 h; substrate/lipase ratio 2:1. Com-
20
pound (S)-1 (52 mg, 42% yield), 99% ee, [α]D +64 (c 1.13, CHCl3);
Entry 5: PPL (200 mg), 5.5 h; substrate/lipase ratio 1:2. Compound
(R)-1 (17 mg, 21% yield), 22% ee; compound (S)-2 (70 mg, 70% yield),
48% ee.
compound (R)-2 (68 mg, 44% yield), 94% ee, [α]D20 +28 (c 1.12, CHCl3).
Entry 4: immobilized CAL A (20 mg), 36.5 °C, 2 h; substrate/lipase ra-
tio 6:1. Compound (R)-1 (47 mg, 39% yield), 76% ee, [α]D20 –54 (c 0.76,
CHCl3); compound (S)-2 (67 mg, 43% yield), 82% ee, [α]D20 –25 (c 0.96,
CHCl3).
Entry 6: CRL (50 mg), 8 h; substrate/lipase ratio 2:1. Compound (R)-1
(23 mg, 30% yield), 58% ee; compound (S)-2 (57 mg, 57% yield), 38%
ee.
Entry 5: immobilized CAL A (20 mg), 30 °C, 4 h; substrate/lipase ratio
Entry 7: PFL (50 mg), 5 h; substrate/lipase ratio 2:1. Compound (R)-1
(57 mg, 74% yield), 8% ee; compound (S)-2 (16 mg, 16% yield), 54% ee.
20
6:1. Compound (R)-1 (41 mg, 34% yield), 80% ee, [α]D –54 (c 0.60,
CHCl3); compound (S)-2 (61 mg, 39% yield), 79% ee, [α]D20 –23 (c 0.86,
CHCl3).
Double Kinetic Resolution Assays; General Procedure
Entry 6: immobilized CAL A (20 mg), 24 °C, 7 h; substrate/lipase ratio
6:1. Compound (R)-1 (60 mg, 39% yield), 40% ee; compound (S)-2 (48
mg, 40% yield), 85% ee, [α]D20 –26 (c 0.95, CHCl3).
The resolutions were performed as described for the single processes,
with the following specific details.
Resolution of (±)-2 (Scheme 4): (±)-2 (402 mg), CAL B (100 mg), 2 h.
20
Entry 7: cross-linked CAL A (25 mg), 36.5 °C, 7 h; substrate/lipase ra-
tio 5:1. Compound (R)-1 (46 mg, 38% yield), 48% ee; compound (S)-2
(51 mg, 33% yield), 71% ee, [α]D20 –21 (c 0.84, CHCl3).
Obtained compound (R)-1 (117 mg, 38% yield), 97% ee, [α]D –63 (c
20
0.93, CHCl3), and compound (S)-2 (175 mg, 44% yield), 98% ee, [α]D
–29 (c 1.60, CHCl3).
Entry 8: BCL (244 mg), 36.5 °C, 72 h; substrate/lipase ratio 1:2. Com-
pound (S)-1 (88 mg, 73% yield), 12% ee; compound (R)-2 (19 mg, 12%
yield), 63% ee.
Double resolution of (S)-2: (S)-2 (150 mg, 98% ee), cross-linked CAL A
(150 mg), 6 h. Obtained compound (S)-1 (80 mg, 69% yield), 98% ee,
20
[α]D +65 (c 1.0, CHCl3), and unreacted (S)-2 (18 mg, 12% yield), 98%
ee, [α]D20 –30 (c 0.98, CHCl3).
Entry 9: PPL (241 mg), 36.5 °C, 72 h; substrate/lipase ratio 1:2. Com-
pound (S)-1 (68 mg, 57% yield), 22% ee; compound (R)-2 (18 mg, 12%
yield), 78% ee, [α]D20 +20 (c 0.88, CHCl3).
Resolution of (±)-1: (±)-1 (400 mg), immobilized CAL A (40 mg), 3 h.
20
Obtained compound (R)-1 (100 mg, 48% yield), 76% ee, [α]D –54 (c
20
0.76, CHCl3), and compound (S)-2 (232 mg, 45% yield), 81% ee, [α]D
Entry 10: CRL (245 mg), 36.5 °C, 72 h; substrate/lipase ratio 1:2. Com-
pound (S)-1 (74 mg, 62% yield), 14% ee; compound (R)-2 (17 mg, 11%
yield), 68% ee.
–25 (c 0.96, CHCl3).
Double resolution of (S)-2: (S)-2 (200 mg, 81% ee), cross-linked CAL A
(100 mg), 5.5 h. Obtained compound (S)-1 (67 mg, 46% yield), 89% ee,
Entry 11: PFL (20 mg), 36.5 °C, 7 h; substrate/lipase ratio 6:1. Com-
pound (S)-1 (57 mg, 48% yield), 4% ee; compound (R)-2 (34 mg, 22%
yield), 5% ee.
20
[α]D +53 (c 1.3, CHCl3), and unreacted (S)-2 (45 mg, 24% yield), 67%
ee, [α]D20 –26 (c 1.1, CHCl3).
Chemical Hydrolysis of Acetate (S)-2
Lipase-Catalyzed Enzymatic Resolution of Acetate (±)-2; General
Procedure
The procedure described by Kiyota and co-workers27 was followed.
Acetate (S)-2 (41 mg, 0.22 mmol) was dissolved in MeOH (3 mL),
K2CO3 (10 mg, 0.07 mmol) was added, and the mixture was stirred at
r.t. for 1 h. Then, water (10 mL) was added and the mixture was ex-
tracted with Et2O (3 × 10 mL). The combined organic layers were
washed with brine (15 mL), dried over Na2SO4, and concentrated un-
der reduced pressure. The crude was purified by chromatography on
silica gel (hexane–Et2O, 95:5) to provide (S)-1 (29 mg, 91% yield).
In a 25-mL Erlenmeyer flask, acetate (±)-2 (100 mg, 0.54 mmol) was
mixed with 0.1 M phosphate buffer pH 7 (10 mL) and the correspond-
ing amount of lipase. The reaction mixture was homogenized by
shaking briefly (15 s) on a vortex until the solution turned cloudy.
Then, it was shaken in a thermostated bath at 90 strokes/min and r.t.,
and the progress of the resolution was followed by chiral GC until ca.
50% conversion into the expected chiral alcohol (R)-1 was reached.
Then, the reaction mixture was extracted with hexane (2 × 10 mL)
and Et2O (2 × 10 mL), and the lipase removed by filtration. The com-
bined organic layers were dried over Na2SO4 and concentrated under
reduced pressure, and the residue was purified by flash chromatogra-
phy on silica gel (hexane–Et2O, 4:1) to give the enantioenriched com-
pounds 1 and 2.
Determination of the ee via the (R)-MTPA Mosher Esters
The procedure described by Ma and co-workers30 was followed. Alco-
hol (S)-1 or (R)-1 (1.5 mg, 0.01 mmol) and a catalytic amount of
DMAP (300 μg) were dissolved in anhyd CH2Cl2 (200 μL) in a glass vial
under argon. Then, anhyd pyridine (2 μL, 0.02 mmol) and (R)-MTPA
chloride (5 μL, 0.02 mmol) were added and the resulting mixture was
stirred at r.t. for 3 h. The solvent was removed under reduced pressure
and the residue was dissolved in Et2O and filtered through a short pad
of silica gel. After evaporation of the solvent, the purified Mosher es-
ters were analyzed by 19F NMR spectroscopy.
Experimental details for Table 2 entries:
Entry 1: CAL B (25 mg), 2 h; substrate/lipase ratio 4:1. Compound (R)-
1 (30 mg, 39% yield), 96% ee, [α]D20 –60 (c 0.32, CHCl3); compound (S)-
2 (41 mg, 41% yield), 98% ee, [α]D20 –29 (c 1.6, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
M. Puigmartí et al.
Paper
Synthesis
19F NMR (376 MHz, CDCl3): δ = –72.03 [(R)-MTPA ester of (S)-1],
–72.30 [(R)-MTPA ester of (R)-1].
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We gratefully acknowledge MINECO for an FPI contract to M.P. and fi-
nancial support (AGL2012-39869-C02-01) with assistance from the
European Regional Development Fund.
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Supporting Information
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Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588666 and contains experimen-
tal details for the intermediates in the synthesis of acyloin (±)-1 and
1
copies of the H and 13C NMR spectra for new compounds and inter-
mediates.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtIo
g
f
rmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H