Facile Synthesis of Enantiopure Sugar Alcohols: Asymmetric Hydrogenation and Dynamic Kinetic Resolution Combined

Article abstract of DOI:10.1002/anie.202006661

An unprecedented Ir/f-amphox-catalyzed asymmetric hydrogenation of racemic 2,3-syn-dihydroxy-1,4-diones is presented involving dynamic kinetic resolution, which produces (1R,2R,3R,4R)-tetraols. This protocol constitutes an efficient and straightforward approach to accessing sugar alcohols bearing four contiguous stereocenters. The strategy exhibits various advantages over existing methods, including excellent yields (up to 98 %), exceptional stereoselectivities (up to 99:1 dr, 99.9 % ee), operational simplicity and substrate generality. Moreover, the nature of the reaction was revealed as a stepwise transformation by in situ Fourier-transform infrared spectroscopy and isolation of intermediates.

Full text of DOI:10.1002/anie.202006661

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Accepted Article
Title: Facile Synthesis of Enantiopure Sugar Alcohols Enabled by
Asymmetric Hydrogenation via Dynamic Kinetic Resolution
Authors: Jiang Wang, Pan-Lin Shao, Xin Lin, Baode Ma, Jialin Wen,
and Xumu Zhang
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Facile Synthesis of Enantiopure Sugar Alcohols Enabled by
Asymmetric Hydrogenation via Dynamic Kinetic Resolution
Jiang Wang,[a],[c] Pan-Lin Shao,*[b],[c] Xin Lin,[b] Baode Ma,[b],[c] Jialin Wen,[c],[d] and Xumu Zhang*[c]
Dedicated to Professor Henry N. C. Wong on the occasion of his 70th birthday
Abstract: Presented herein is an unprecedented Ir/f-amphox-
catalyzed asymmetric hydrogenation of racemic 2,3-syn-dihydroxy-
1,4-diones via dynamic kinetic resolution to produce (1R,2R,3R,4R)-
tetraols. This protocol constitutes an efficient and straightforward
approach to accessing sugar alcohols bearing four contiguous
stereocenters. The strategy exhibits various advantages over existing
methods, including excellent yields (up to 98%), exceptional
stereoselectivities (up to 99:1 dr, 99.9% ee), operational simplicity and
substrate generality. Moreover, the nature of the reaction was
revealed as a stepwise transformation by in situ FTIR spectroscopy
and isolation of intermediates.
relationships necessary for pharmaceutical design.5 Herein, we
report our achievement on the synthesis of 1,2,3,4-tetraols.
1,2,3,4-tetraols (C4 sugar alcohol), with four contiguous
stereogenic oxidized carbons, have been considered “privileged
scaffolds”, are commonly found in pharmaceuticals,
agrochemicals, commodity chemicals and organic materials.
Traditional synthesis to assemble 1,2,3,4-tetraol frameworks is
dominated by the iterative Sharpless dihydroxylation of
conjugated dienes,6 sequential dihydroxylation of 1,2-dioxines
and reduction,7 deoxygenation of carbohydrates8, metabolic
activation,9 and nucleophilic addition or reduction of 1,4-diketones
derived from tartaric acid (Scheme 1).10 Nevertheless, these
methods are often painstaking, laborious, and time-consuming
multistep processes, making the preparations typically inefficient
and uneconomical.
Carbohydrates or sugars constitute
a broad range of
polyhydroxylated organic compounds which are abundant in
nature and implicated in a number of biological processes.1 Up
until recently, sugars were essentially only obtained from natural
sources, such densely oxidized scaffolds remain valuable for
applications in many disciplines such as medicinal chemistry,
material science or synthetic chemistry.2 As such, sugar alcohols,
with the potential to act as sugar mimics and oxygen-
functionalized chiral synthons,3 are becoming increasingly
popular as investigation targets for creating drugs and functional
materials.4 The development of straightforward synthetic methods
to construct such moieties is significantly rewarding.
Generally, sugar alcohols possess several relevant points of
diversity: stereogenic diversity (configuration of hydroxyl groups),
substituent diversity, and length diversity of the hydroxyl chain.
However, the polyhydroxylated structure always presents poor
solubility in organic solvents, thermal instability, and limited scope
for functionalization. Thus, sugar alcohols are relatively
inaccessible, prohibiting their use in further synthesis, and
denying the comprehensive assessment of structure activity
[a]
[b]
J. Wang
School of Chemical Biology and Biotechnology, Peking University
Shenzhen Graduate School, University Town, Nanshan District,
Shenzhen, 518055, China.
X. Lin, Prof. Dr. P.-L. Shao and Prof. Dr. B. Ma
College of Innovation and Entrepreneurship, Southern University
of Science and Technology, 1088 Xueyuan Road, Shenzhen,
518055, China.
Scheme 1. Representative strategies for 1,2,3,4-tetraol synthesis.
E-mail: shaopl@sustech.edu.cn.
J. Wang, Prof. Dr. P.-L. Shao, Prof. Dr. B. Ma, Prof. Dr. J. Wen
and Prof. Dr. X. Zhang
Guangdong Provincial Key Laboratory of Catalysis, Department of
Chemistry, Southern University of Science and Technology, 1088
Xueyuan Road, Shenzhen, 518055, China.
E-mail: zhangxm@sustech.edu.cn.
We sought to develop catalytic methods to construct 1,2,3,4-
tetraols from non-carbohydrate starting materials, employing
asymmetric hydrogenation, particularly via dynamic kinetic
resolution (DKR) manner (Scheme 2). Over the past three
decades, asymmetric hydrogenation has undergone tremendous
development, evolving from pioneering examples into robust tools
for modern organic synthesis.11 These methods lay solid
foundations in the context of asymmetric hydrogenation of
prochiral (functional) ketones. Moreover, various stereoselective
hydrogenation of racemic α-substituted (alkyl, aryl, amino, amido
et al.) ketones were accomplished with DKR processes in the past
few years, and the corresponding (functional) alcohols were
[c]
[d]
Prof. Dr. J. Wen
Academy for Advanced Interdisciplinary Studies, Southern
University of Science and Technology, 1088 Xueyuan Road,
Shenzhen, 518055, China.
Supporting information and the ORCID identification number(s) for
the author(s) for this article can be found under
http://www.angewandte.org
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10.1002/anie.202006661
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efficiently produced.12 However, to the best of our knowledge, the
asymmetric hydrogenation of α-hydroxyketones via DKR, and
specifically, the synthesis of polyols have been systematically
neglected. Hereby, we envisioned that a facile synthetic route to
1,2,3,4-tetraols from cheap building blocks such as
acetophenones might be realized with asymmetric hydrogenation
and the strategy of DKR.
amphox as ligand, we did obtain the product enriched in the
opposite enantiomer in full conversion though with moderate
enantioselectivity (entry 8). Several bases were screened to
evaluate their ability to promote the hydrogenation (entries 9-14),
however the level of efficiency and selectivities were far from
satisfactory. Lowering the H2 pressure (30 atm) led to a dramatic
negative impact on the conversion (entry 12).
Table 1. Screening of reaction conditions.[a]
Scheme 2. Our strategy for 1,2,3,4-tetraol synthesis.
Entry
1
Solvent
MeOH
EtOH
iPrOH
DCM
EA
Base
Conversion (%)[b]
ee (%)[c]
79
For an asymmetric hydrogenation strategy to reach its full
potential, the transformation with high levels of chemo-, regio- and
stereo-selectivities must be identified and developed. As a
benchmark for testing our strategy, we hypothesized that if the
enantioselective hydrogenation of racemic 2,3-syn-dihydroxy-1,4-
diones (±)-113 via DKR could be performed, chiral 1,2,3,4-tetraols
(3) with four contiguous stereocenters would be obtained with
high stereochemical purity in a single reaction (Scheme 3). Taken
symmetry into consideration, the absolute configuration of C1
should be kept the same with C4, and similarly, the absolute
configuration of C2 should be the same with C3. Therefore, no
meso-isomers 3-3 and 3-4 should be generate. In fact, the
rationale was consistent with our experimental results.
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
72
77
83
70
85
87
>99
>99
13
64
78
73
<5
22
70
2
87
3
99.4
>99.9
91
4
5
6
Toluene
THF
86
7
>99.9
-57
8[d]
9
THF
THF
71
10
11
12
13
14
15[e]
THF
99
THF
NaOH
79
THF
KOH
99
THF
tBuONa
tBuOK
--
THF
88
THF
Cs2CO3
>99.9
[a] Reaction conditions: (±)-1a (0.20 mmol), [Ir(COD)Cl]2 (0.0005 mmol), (RC,
RC, SFC)-f-amphox (0.0011 mmol), Cs2CO3 (0.01 mmol ), solvent (2 mL), H2 (60
atm), RT, 24 h. [b] Determined by 1H NMR analysis. [c] Determined by HPLC
analysis, and racemic samples for the standard of chiral HPLC spectra were
prepared using the mixture of 0.25 mol % (RC, RC, SFC)-f-amphox and 0.25
mol % (SC, SC, RFC)-f-amphox as ligands. [d] (RC, SC, RFC)-f-amphox (0.0011
mmol) instead of (RC, RC, SFC)-f-amphox. [e] H2 pressure = 30 atm.
Scheme 3. Concept of catalytic asymmetric hydrogenation of 2,3-syn-
dihydroxy-1,4-diones.
Our recent effort has accumulated in the use of Ir/f-amphox-
catalyzed asymmetric hydrogenation system to synthesize
secondary (functionalized) alcohols.14 We were drawn to this
particular catalyst, due to its inherent advantages and the major
contributions it has already made with superb activities and
excellent enantioselectivities (up to 1,000,000 TON). As shown in
Table 1, our study commenced with assaying the asymmetric
hydrogenation and investigation the feasibility of DKR using the
racemic syn-2,3-dihydroxy-1,4-diphenyl-1,4-butanedione (±)-1a
(CCDC 2006347, see SI for details)15 as the model substrate, and
Ir/(Rc, Rc, SFC)-f-amphox as the catalyst. A survey of solvents
identified THF as the most suitable media (entries 1-7), affording
predominantly the desired 1,2,3,4-tetraol 3a with excellent
enantioselectivity (>99.9% ee) and diastereoselectivity (>99:1 dr)
in quantative yield (entry 7). Interestingly, using (Rc, Sc, RFC)-f-
We identified the following protocol as optimal: hydrogenation
of (±)-1a with Ir/(Rc, Rc, SFC)-f-amphox (0.5 mol%) in the
presence of H2 (60 atm) and Cs2CO3 (5 mol%) in THF at room
temperature for 24 h. The relative and absolute configurations of
3a were determined to be “anti−syn−anti” and (1R,2R,3R,4R) by
single crystal X-ray crystallographic analysis (CCDC 1996169,
see SI for details).15 The configurations of other 1,2,3,4-tetraols 3
and 4 in Table 2 were assigned by analogy.
Under the optimal conditions, the effect of substitution of 2,3-
syn-dihydroxy-1,4-diones (±)-1 on the reactivity and
stereoselectivity was investigated (Table 2). Gratifyingly, with
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respect to the substrates bearing symmetrical substituents (±)-1
(R1 = R2) or unsymmetrical substituents (±)-2 (R1 ≠ R2), Ir/(Rc, Rc,
SFC)-f-amphox system could act as the highly efficient catalyst in
the asymmetric hydrogenation via DKR sequence, furnishing the
anti−syn−anti-tetraols 3 or 4 in uniformly almost quantitative
yields with exclusive enantioselectivities, respectively. Different
substitution patterns on the aryl ring (para, meta and ortho) were
all well tolerated, and the electronic properties of these
substituents does not show notable influence. Moreover and
notably, in almost all cases perfect diastereoselectivities were
obtained for the 1,2,3,4-tetraols (>99:1 dr) except 3f (1.3:1 dr) and
3k (9:1 dr), which bear F atom at the para or ortho position of the
phenyl groups, respectively. To our delight, when the R2 group of
3i was an aliphatic substituent (Me), the reaction also showed
Table 2. Substrate scope.[a]
perfect enantioselectivity (>99.9% ee) and diastereoselectivity
(>99:1 dr). Such
a facile transformation with excellent
stereocontrol represents an important and straightforward
approach, which would constitute significant interests, not only
because chiral 1,2,3,4-tetraols are a privileged substructure in
various bioactive molecules, but also because it could rapidly
increase molecular diversity and complexity, thereby facilitating
streamlined synthesis of polyhydroxylated organic compounds.
Of particular note, the method can be readily scaled up to a
preparative scale (10 g) without erosion of the yield and
enantioselectivity. Moreover and interestingly, the product can be
obtained by simply filtering the precipitates formed from the
reaction. So the scaling up was straightforward and demonstrated
the practicability of this methodology.
[a] Unless otherwise indicated, the reactions were carried out with (±)-1 or (±)-2 (0.20 mmol), [Ir(COD)Cl]2 (0.0005 mmol), (RC, RC, SFC)-f-amphox (0.0011 mmol),
Cs2CO3 (0.01 mmol ), THF (2 mL), H2 (60 atm), RT, 24 h; [b] Determined after chromatographic purification; [c] Determined by HPLC analysis; [d] Determined by
1H NMR analysis of crude reaction mixture.
In an effort to better understand the mechanism of the system,
the kinetics of the reaction were monitored by in situ FTIR
spectroscopy. The intensity of carbonyl peak at ~1695 cm-1
decaded over the course of reaction time. It suggested neither a
first order or a zeroth order kinetics and a noticeable change of
slope was found when the curve droped to half (marked with red
dotted line). We made the assumption that the reaction from (±)-
1a to 3a is stepwise since the intensity of carbonyl is in
proportional to the number of carbonyls. The formation of mono-
reduced species 5 was supposed to be much faster than the
further hydrogenation to double-reduced tetraol 3a (k1 > k2). The
stimulated concentration of species in the reaction mixture was
depicted in Scheme 4 (see SI for details).
Actually, we have experimentally revealed the nature of this
stepwise transformation from (±)-1a to 3a. As shown in Scheme
5a, when the reaction was quenched at 30 min, the mono-reduced
product triol 5 was isolated in 27% yield with 4:1 dr16 and >99.9%
ee (major), and the double-reduced product tetraol 3a was trace.
Meanwhile, the kinetic resolution of (±)-1a was also observed.
When the reaction was quenched at 1 h (Scheme 5b), the triol 5
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In addition, the isolated mono-reduced product triol 5 could be
further hydrogenated. However, using BH3•THF as reducing
reagent, the reaction gave a complicated mixture, which might be
attributed to the formation of several isomers. To our delight,
using Ir/(Rc, Rc, SFC)-f-amphox as the catalyst, the reaction could
afford the desired 1,2,3,4-tetraol 3a in 98% yield with >99:1 dr
and >99.9% ee by asymmetric hydrogenation via DKR (Scheme
6a). Furthermore, the recovered optically active diol (-)-1a (53.6%
ee or 99.9% ee) could be hydrogenated as expected under the
optimal conditions, both furnishing 3a in 98% yield with >99:1 dr
and >99.9% ee (Scheme 6b).
Scheme 4. React kinetics obtained with FTIR demonstrating a stepwise
pathway. An approximation was made that the intensity of carbonyl peak is in
proportational to the numbers of carbonyls, regardless of different species.
was isolated in 30% yield with 4:1 dr16 and >99.9% ee (major),
and tetraol 3a was isolated in 62% yield with >99:1 dr and >99.9%
ee. Only a trace amount of 1a was detected.
More interestingly, 67% of the diol with 53.6% ee was
recovered after 30 min (Scheme 5a). This means that the
enantiomeric ratio ((-)-1a : (+)-1a) is 76.8 : 23.2. This suggest that
initially only (+)-1a is converted and the racemization of (-)-1a
starts once (+)-1a have been largely consumed (see SI for details).
The hydrogenation only occurs, highly selectively, on the carbonyl
flanked by the carbon atom with the correct configuration. The
absolute configuration of (-)-1a was unambiguously determined to
be (2R,3R) by single crystal X-ray crystallographic analysis after
recrystallization experiment (CCDC 1996168, see SI for details).15
Scheme 6. Hydrogenation of optically active triol 5 and diol (-)-1a.
In this report, we have introduced a facile, practical and
straightforward synthetic method for the construction of sugar
alcohol 1,2,3,4-tetraols using Ir/f-amphox-catalyzed asymmetric
hydrogenation of 2,3-syn-dihydroxy-1,4-diones via dynamic
kinetic resolution. A variety of optically enriched sugar alcohols
bearing four contiguous stereocenters were obtained from non-
carbohydrate starting materials. The strategy exhibits various
advantages over existing methods, including excellent yields (up
to 98%), exceptional stereoselectivities (up to 99:1 dr, 99.9% ee),
operational simplicity and substrate generality. Moreover, the
nature of the reaction was revealed as a stepwise transformation
by in situ FTIR spectroscopy and isolation of intermediates.
Acknowledgements
This project was financially supported by the Science, Technology
and
Innovation
Commission
of
Shenzhen
(JCYJ20190809160211372, KQTD20150717103157174), the
National Natural Science Foundation of China (21991113),
Shenzhen Clean Energy Research Institute (No. CERI-KY-2019-
003), Guangdong Provincial Key Laboratory of Catalysis
(2020B121201002). We sincerely thank Dr. Xiao-Yong Chang
(SUSTech) for the X-ray crystallographic analysis.
Scheme 5. Isolation of intermediate.
Keywords: Asymmetric Hydrogenation • 1,2,3,4-Tetraols •
Sugar Alcohol• Dynamic Kinetic Resolution
The racemization/epimerization of (-)-1a (99.9% ee, after
recrystalization) was observed in the presence of Cs2CO3 (5
mol%) (see SI for details). Strikingly, during the first 30 minutes,
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[16] The absolute configurations of C3 and C4 of triol 5 should be kept the
same with the C1 and C2 of 1,2,3,4-tetraol 3a. The diastereomers are
anti-anti-5 and anti-syn-5. The dr of compound 5 is the molar ratio of the
two diastereomers (major : minor), and the dr value was determined by
1H NMR analysis of crude reaction mixture. Because the two
diastereomers are easy to epimerize at C2 stereocenter, the dr value
(4:1) does not mean the real diastereoselectivity, only reflects the molar
ratio of the diastereomers at the time of NMR data acquisition.
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10.1002/anie.202006661
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
J. Wang, P.-L. Shao,* X. Lin, B. Ma, J.
Wen, X. Zhang*
Page No. – Page No.
Facile Synthesis of Enantiopure
Sugar Alcohols Enabled by
Asymmetric Hydrogenation via
Dynamic Kinetic Resolution
Presented herein is an Ir/f-amphox-catalyzed asymmetric hydrogenation of racemic
2,3-syn-dihydroxy-1,4-diones via dynamic kinetic resolution to produce 1,2,3,4-
tetraols. This protocol constitutes an efficient and straightforward approach to
accessing chiral sugar alcohols. The nature of the reaction was revealed as a
stepwise transformation by in situ FTIR spectroscopy and isolation of intermediates.
This article is protected by copyright. All rights reserved.