Kinetic Resolution of 1,2-Diols via NHC-Catalyzed Site-Selective Esterification

Article abstract of DOI:10.1021/acs.orglett.8b01029

A kinetic resolution of 1,2-diols bearing both a secondary and a primary alcohol motif through an N-heterocyclic carbene-catalyzed oxidative acylation reaction has been developed. A site- and enantioselective esterification reaction is involved for this process. Both the monoacylated diols obtained and the remaining enantioenriched 1,2-diols are versatile building blocks for the preparation of functional molecules with proven biological activities.

Full text of DOI:10.1021/acs.orglett.8b01029

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Kinetic Resolution of 1,2-Diols via NHC-Catalyzed Site-Selective
Esterification
Bin Liu,†,∥ Jiekuan Yan,†,∥ Ruoyan Huang,† Weihong Wang,† Zhichao Jin,†,§ Giuseppe Zanoni,§
Pengcheng Zheng,† Song Yang,*,† and Yonggui Robin Chi*,†,‡
†Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
‡Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
§Department of Chemistry, University of Pavia, Pavia 27100, Italy
S
* Supporting Information
ABSTRACT: A kinetic resolution of 1,2-diols bearing both a
secondary and a primary alcohol motif through an N-heterocyclic
carbene-catalyzed oxidative acylation reaction has been devel-
oped. A site- and enantioselective esterification reaction is
involved for this process. Both the monoacylated diols obtained
and the remaining enantioenriched 1,2-diols are versatile building
blocks for the preparation of functional molecules with proven
biological activities.
Scheme 2. Access to 1-Arylethane-1,2-diols
hiral 1-arylethane-1,2-diols are versatile building blocks
Cfor the preparation of various pharmaceuticals and natural
products.1 Their derivatives have found tremendous applica-
tions in both medicinal and biological research (Scheme 1). For
example, amino alcohols derived from 1-arylethane-1,2-diols
have been used as drugs for sympathomimetic diseases2 as well
as psychiatric disorders and metabolic problems.3 They have
also been used as hypoglycemic agents4 and β3-adrenergic
receptor agonists5 in biological research. Therefore, the
preparation of chiral 1-arylethane-1,2-diols has attracted much
attention (Scheme 2a).6−9 Nowadays, chiral 1-arylethane-1,2-
diols can be obtained through asymmetric oxidation of
styrenes,6 hydrolysis of epoxides,7 reduction of 1,2-dicarbonyl
compounds,8 and enantioenrichment of racemic 1,2-diols.9
Notably, most of the reported methods have used transition
metals or enzymes as the reaction catalysts. The use of small
organic molecules as catalysts for enantioselective access to 1,2-
diol compounds remains less developed.10
We are interested in developing novel activation modes and
efficient synthetic methods for quick access to functional
molecules using N-heterocyclic carbenes (NHCs or carbenes)
as organic catalysts.11
Scheme 1. Chiral 1-Arylethane-1,2-diol Derivatives
Kinetic resolution is one of the practical methods for
preparing enantioenriched organic compounds from racemic
mixtures.12 A number of kinetic resolution methods via NHC
catalysis have been reported in recent years.13,14 The first
NHC-catalyzed kinetic resolution was reported by Suzuki and
co-workers in 2004.14a In Suzuki’s study, C2-symmetric
imidazolium-derived NHC catalysts were used in the
Received: March 31, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01029
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 3. Scope of Diols
b
c
yield (%) ; er
entry
cat.
solvent
3a
1a′
s
1
2
3
4
A
B
C
D
B
B
B
B
B
B
THF
44; 81:19
47; 89:11
41; 66:34
40; 68:32
48; 86:14
37; 86:14
<5; −
30; 91:9
48; 91:9
37; 93:7
55; 79:21
52; 82:18
53; 66:34
58; 58:42
50; 80:20
59; 65:35
−; −
47; 87:13
44; 87:13
58; 73:27
7.5
15.5
2.6
THF
THF
THF
2.5
d
5
THF
11.2
8.2
d
6
toluene
CH2Cl2
THF
d
7
−
de
,
8
9
22.3
22.3
20.9
de,f
,
THF
THF
df,g
,
10
a
General conditions (unless otherwise specified): 1a (0.20 mmol), 2a
(0.10 mmol), NHC (0.02 mmol), K2CO3 (0.02 mmol), 4 (0.10
b
mmol), 4 Å MS (50 mg), solvent (2.0 mL), 25 °C, 3 h. Isolated yields
of 3a based on 1a after purification via SiO2 column chromatography.
c
Enantiomeric ratios of 3a determined via HPLC on a chiral stationary
d
e
phase. B (0.005 mmol) and K2CO3 (0.005 mmol) were used. At −5
°C for 20 h. Cs2CO3 (0.005 mmol) was used instead of K2CO3 (0.005
mmol). At −10 °C for 20 h.
f
g
enantioselective transesterification reactions of secondary
alcohols. Studer and co-workers reported NHC-catalyzed
oxidative esterification reactions for the kinetic resolution of
secondary alcohols using aldehydes as the acylation reagents.
Recently, Zhao and co-workers successfully realized the kinetic
resolution of tertiary alcohols14e and axially chiral alcohols14f
through NHC-catalyzed asymmetric oxidative acylation reac-
tions. However, to the best of our knowledge, the kinetic
resolution of 1,2-diols bearing both a primary and a secondary
alcohol motif has remained undeveloped. Challenges exist in
the control of both the chemo- and enantioselectivity of the
NHC-catalyzed asymmetric acylation of the two alcohol motifs
presented in the same substrate. Herein we report the kinetic
resolution of secondary alcohols through an NHC-catalyzed
monoesterification of the adjacent primary alcohol motifs
(Scheme 2b). Non-covalent interactions involving the secon-
dary alcohol moiety likely influence both the chemo (regio)-
selective acylation and kinetic resolution processes. Similar
effects of an adjacent hydroxyl group have been observed in
related studies.14f,h,15
Readily available 1-phenylethane-1,2-diol (1a) was chosen as
the model substrate for optimization of the reaction conditions
(Table 1). Substrate 1a could be selectively monoacylated by
benzaldehyde (2) on the primary alcohol site through an NHC-
catalyzed oxidative esterification reaction. The use of 2 equiv of
1a is necessary for efficient chiral resolution since the primary
alcohol motifs in both enantiomers of 1a can be acylated under
these catalytic conditions. Various chiral NHC catalysts were
first evaluated in the formation of the enantioenriched
monoester product 3a (entries 1 to 4). Triazolium-derived
NHC catalysts were found to be efficient for this trans-
formation, and the use of NHC catalyst B, first developed by
a
The reaction conditions were those stated in Table 1, entry 9.
Isolated yields after purification via SiO2 column chromatography are
shown. Er values were determined via HPLC on a chiral stationary
b
c
phase. The reaction was carried out at 25 °C for 2 h. Er of the
recovered (unreacted) diol (see the Supporting Information for
details).
Scheidt and co-workers,16 gave 3a in nearly quantative yield
with moderate enantioselectivity (entry 2). The catalyst loading
could be decreased to 0.005 mmol without seriously
deteriorating the reaction outcome (entry 5). A screen of
reaction solvents did not provide further improvements in the
product yield or er value (entries 6 and 7). The er value of 3a
could be improved to 91:9 when the reaction was carried out at
a lower temperature, although the product yield was decreased
(entry 8). The product 3a could be obtained in excellent yield
with good optical purity when Cs2CO3 was used as the base
(entry 9). Further decreasing the reaction temperature led to a
lower product yield, with a slightly improved er value (entry
10). It is worth noting that the s value calculated using Kagan’s
equation is independent of the conversion (as shown in Table
S5 in the Supporting Information), supporting its relevance in
evaluating the selectivity.
B
DOI: 10.1021/acs.orglett.8b01029
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Gram-Scale Kinetic Resolution of 1a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01029.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: robinchi@ntu.edu.sg.
a
The reaction conditions were those stated in Table 1, entry 9.
Isolated yields after purification via SiO2 column chromatography are
shown. Er values were determined via HPLC on a chiral stationary
phase.
*E-mail: jhzx.msm@gmail.com.
ORCID
Zhichao Jin: 0000-0003-3003-6437
Song Yang: 0000-0003-1301-3030
Yonggui Robin Chi: 0000-0003-0573-257X
Author Contributions
The optimized reaction conditions (as shown in Table 1,
entry 9) were then applied to a range of substituted 1,2-diols to
examine the scope of this kinetic resolution approach (Scheme
3). Both electron-donating and electron-withdrawing groups
could be installed on the benzene ring of diol 1a. Most of the
products were isolated in good to excellent yields with good
optical purities (3b−j), although in several cases an increase in
the reaction temperature was needed in order to obtain an
acceptable product yield (3c, 3d, 3f, 3j, and 3l). The benzene
group on substrate 1a could also be replaced with naphthyl
groups without deterioration of the product yield or er value
(3m and 3n). Various heteroarylethane-1,2-diols could also be
applied in this kinetic resolution process, but the corresponding
monoester products were obtained either in lower yield (3o) or
with a lower er value (3p). It is worth noting that the aromatic
group on 1,2-diol substrate 1 could even be replaced with
various aliphatic groups, as the corresponding linear mono-
esters were obtained in good to excellent yields with moderate
er values under our current reaction conditions (3q−s).
We also carried out this kinetic resolution process on a gram
scale using 1.1 g of 1a and 0.42 g of 2 as the starting materials
under the optimized conditions (Scheme 4). The scaled-up
reaction gave 0.97 g of enantioenriched monoester (R)-3a
(50%, 83:17 er) and 0.50 g of the (S)-enantiomer 1a′ (45%,
84:16 er). A second kinetic resolution of (S)-1a′ with ent-B as
the catalyst under otherwise identical reaction conditions gave
0.40 g of the monoester product (S)-3a′ with an excellent er
value (49%, 97:3 er).
∥B.L. and J.Y. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Natural
Science Foundation of China (21772029 and 21472028); the
National Key Technologies R&D Program (2014BAD23B01);
the “Thousand Talent Plan”; The 10 Talent Plan (Shicengci) of
Guizhou Province; the Guizhou Province Returned Oversea
Student Science and Technology Activity Program, Guizhou
University; the Singapore National Research Foundation
(NRF-NRFI2016-06), the Ministry of Education of Singapore
(MOE2013-T2-2-003, MOE2016-T2-1-032, and RG108/16);
an A*STAR Individual Research Grant (A1783c0008); a
Nanyang Research Award Grant; Nanyang Technological
University; a Regione Lombardia-Cariplo Foundation Grant
(Sottomisura B/2016); and the University of Pavia.
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