J. Xu, L. Hu / Tetrahedron Letters 60 (2019) 868–871
869
Ramström and coworkers had previously studied the synthesis
of 1,3-Oxathiolan-5-one via lipase-catalyzed lactonization of tran-
sient hemiacetal intermediates [12,13]. However, enzyme-medi-
ated formation of asymmetric
was still unexplored. To verify lipase reactivity on formation of
-butyrolactone, lipases from Burkholderia (formerly Pseudomonas)
c-butyrolactones through DCKR
c
cepacia (PS-IM), Candida antarctica (CALB), Pseudomonas fluorescens
(PFL) and Candida rugosa (CRL) were tested in a reaction using alde-
hyde 1 and 1-butanethiol 2 as starting materials (Table 1). Among
the enzymes tested, no product was detected with PFL and CRL. PS-
IM gave moderate conversion and low product enantiomeric
excess. CALB led to the best conversion and stereoselectivity, and
therefore was used for the following studies.
In organic solvents, lipase is utilized for the kinetic resolution of
substrates bearing secondary hydroxyl groups through acylation
reactions. In most cases, mono reaction site was presented in the
substrate, meaning only one type of product could be predicted.
To further challenge the regioselectivity of lipase, aldehyde 1 and
methyl 2-sulfanylacetate 5 were used to generate dynamic inter-
mediate 6 (Scheme 1), where the hydroxyl group could react with
two reaction sites, leading to the possible formation of both 1,3-
Scheme 1. Solvent-dependent effect in lipase-catalyzed five-membered lactone
formation through DCKR.
Table 2
DCKR with different bases.a
Oxathiolan-5-one and
c-butyrolactone products. Toluene and
tert-butyl methyl ether (TBME), two commonly used solvents in
enzyme-mediated DCKR protocols [40,41], were initially tested
for the designed reaction. It turned out that 1,3-Oxathiolan-5-one
7 was obtained with much higher conversion than
c-butyrolactone
Entry
1
Base
Et3N
Solvent
Ratio 7:8
Conversion [%]
ee [%]b
8 in both solvents, and toluene gave a faster reaction rate. Interest-
ingly, when THF was applied to the same reaction conditions, a
Toluene
THF
14:1
1:6
79 (7)
72 (8)
76 (7)
71 (8)
reversed product selectivity was recorded as
c-butyrolactone 8
2
3
4
NaHCO3
TMG
Toluene
THF
15:1
1:8
76 (7)
68 (8)
79 (7)
88 (8)
became the major product. This solvent-dependent effect was pos-
sibly due to the conformational change of the enzyme in solvents
of different polarities: in non-polar toluene and TBME, enzyme
active site accommodates the structure of compound 7 better than
that of compound 8; while in more polar THF, changed enzyme
pocket selects the substrates in an opposite way.
With the controlled regioselectivity in hand, other reaction
parameters were subsequently evaluated (Table 2). Base catalyst
not only could accelerate reversibility of the reaction but also dis-
placed equilibrium toward the hemithioacetals to improve the
overall outcome of enzyme transformation. Therefore, effects of
base on the conversion and selectivity were investigated. Four
bases, including Et3N, NaHCO3, 1,1,3,3-tetramethylguanidine
Toluene
THF
10:1
1:5
43 (7)
26 (8)
62 (7)
49 (8)
Morpholine
Toluene
THF
11:1
1:8
47 (7)
21 (8)
54 (7)
67 (8)
The bold values indicates the product ratio between compound 7 and 8.
Reaction conditions: 1a (0.1 mmol),
preparation (20 mg), 4 Å molecular sieves (200 mg), toluene/THF (0.5 mL), 0 °C for
a
5 (0.3 mmol), base (0.1 mmol), lipase
4 days.
b
Determined by HPLC analysis using Chiralpak OJ chiral column.
(TMG) and morpholine, were tested (Table 2). NaHCO3 led to the
best ee and product selectivity but slightly lower conversion com-
pared to those of Et3N in both toluene and THF. Considerably lower
conversion and ees were recorded with TMG and morpholine.
Among these, NaHCO3 (pKa = 10.3) and Et3N (pKa = 10.8) shared
similar basicity, which proved suitable for the current system. On
the other hand, TMG (pKa = 13.0) was probably too strong and mor-
pholine (pKa = 8.4) was too weak as base for this DCKR. Thus,
NaHCO3 was chosen as base for the further optimization due to
its fine catalytic efficiency.
Table 1
DCKR with different lipases.a
Temperature effect, another important parameter that regulates
the DCKR outcome, was subsequently addressed (Table 3). As the
reaction temperature decreased from 40 °C to À18 °C, increased
product differentiation and stereoselectivity at the cost of lower
conversion were observed. Those phenomena are very likely due
to the transition of a more loss enzyme catalytic structure to a
more rigid one, resulting in a better fitting of the optimal substrate
and its corresponding enantiomer. The best ees of compound 7 and
8 at À18 °C were up to 96% and 99%, respectively. Although with
expected slower reaction rate, reasonable conversion could still
be obtained with prolonged reaction time at À18 °C.
Entry
Enzyme
Conversion [%]
ee [%]b
1
2
3
4
CALB
PS-IM
PFL
71
43
–
92
42
–
CRL
–
–
In classic kinetic resolution, lipase had been reported to cat-
alyze the formation of both five- and six-membered lactones in
organic solvent [11]. After obtaining the optimal reaction condi-
tions, different starting materials were applied to expand the scope
a
Reaction conditions: 1a (0.1 mmol),
preparation (20 mg), 4 Å molecular sieves (200 mg), toluene (0.5 mL), 0 °C for
4 days.
2 (0.3 mmol), Et3N (0.1 mmol), lipase
b
Determined by HPLC analysis using Chiralpak OJ chiral column.
Xu, Jintao
