Tetrahedron Letters 63 (2021) 152718

Contents lists available at ScienceDirect

Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Conversion of a readily available carbohydrate raw material into a rare

L-deoxyhexose

Ya-Han Hsu, Che-Chien Chang ⇑

Department of Chemistry, Fu Jen Catholic University, 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 24205, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: The highly efficient conversion of D-fructose to a L-deoxyhexose is reported. Starting from D-fructose, ben-
Received 24 October 2020 zoyl protection followed by bromination provided an acyclic radical precursor. Using environmentally
Revised 20 November 2020 benign radical conditions (TTMSS/AIBN), a benzoyl-protected 3-deoxy-L-fructose derivative was pro-
Accepted 26 November 2020
duced through a carbonyl translocation process. This unique radical reaction involves the highly efficient
Available online 24 December 2020
translocation of an a-oxy carbonyl group to produce L-deoxysugars from D-sugars. The benzoyl protecting
groups were enzymatically removed by treatment with a lipase (Candida rugosa) to produce the free 3-
Keywords:
deoxy-L-fructose in only four synthetic steps in an overall yield of 40%. The synthesis uses a cheap, readily
L-deoxysugar
Raw material
available carbohydrate raw material as the source and avoids the use of toxic chemicals, such as tin
Rare reagents. This synthetic methodology is concise, providing one of the most efficient methods for prepar-
Conversion ing L-deoxyhexose derivatives from a readily available carbohydrate raw material.
Concise Ó 2020 Elsevier Ltd. All rights reserved.

Introduction reaction at a specific HO group, as shown in Scheme 1. This

L-Deoxysugars are less abundant in nature, compared to their
enantiomers, D-deoxysugars [1]. L-Deoxysugars are biological
important molecules, which are found in many important natural
products [2]. They are subjects of research in a broad range of
fields, ranging from nutritional science to the pharmaceutical
industry [3]. They also serve as carbohydrate building blocks for
the synthesis of antitumor and antiviral agents [4], as well as
L-DNA and L-deoxynucleosides [5]. Because they are available in
limited amounts in nature and are in increasing demand in the
pharmaceutical sciences, several methods for their synthesis have
been explored [6–8]. Although the synthesis of L-deoxysugars from
L-sugars has been reported [6], the use of D-sugars as starting mate-
rials would be more practical [7]. The currently available methods
for preparing L-hexoses mainly rely on isomerization/conversion of
a D-hexose derivative, chain extension of a pentose, or HO group
inversion of another D-hexose [8]. Regarding the synthesis of
L-deoxyhexoses,the conversion of D-hexoses to L-deoxyhexoses is
complicated and requires multi-synthetic steps. It is necessary to
convert all of the stereogenic centers of a D-sugar to an
L-configuration, followed by a highly selective deoxygenation
⇑ Corresponding author.
E-mail address: 080686@mail.fju.edu.tw (C.-C. Chang).
represents a challenging synthetic problem for organic chemists.
One of the important tasks for organic chemists is to develop
practical synthetic methods for converting inexpensive starting
materials into rare, expensive, or important organic molecules
[9]. Further, using raw materials as starting materials, developing
concise synthesis, employing environmentally benign reaction
conditions, and simplifying the purification steps are goals associ-
ated with most organic transformations. Among all raw materials
from nature, carbohydrates are versatile starting materials for
the synthesis of many chiral organic molecules [10]. They also
could serve as chiral building blocks for the synthesis of commer-
cially available pharmaceuticals [11].
To reach this synthetic challenge, a unique radical reaction
involving a carbonyl translocation process [12] was recently devel-
oped in this laboratory, which could allow rare L-deoxysugars to be
prepared from inexpensive D-sugars [13]. To cope with the limita-
tion of this synthetic methodology, an ideal approach would be to
develop a highly efficient method (only a few synthetic steps) for
preparing L-deoxysugars from a raw material. D-fructose, a carbo-
hydrate raw material, is the second cheapest monosaccharide,
found in nature and over 240,000 tons of crystalline D-fructose
are produced annually. The conversion of D-fructose to other
important organic molecules has been widely studied [14]. How-
ever, synthesis of L-deoxysugars from D-fructose was not reported,
except by us [13b], as shown in Scheme 2.

https://doi.org/10.1016/j.tetlet.2020.152718
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Ya-Han Hsu and Che-Chien Chang
Scheme 1. Synthetic strategies for synthesis of L-deoxyhexoses from D-hexoses.
Although we experienced success in developing a carbonyl
translocation reaction to produce an L-deoxyhexose derivative
from D-fructose, the direct deprotection of the benzoyl groups in
the resulting sensitive molecule, which contains a-acidic protons
(Ha) and a b-leaving group (b-OBz), met with failure, as shown in
Scheme 2 [13b]. Elimination reactions occurred which were
accompanied by the generation of an undesired product with an
a,b-unsaturated system. Alternatively, indirect procedures using
dithioacetal protection of the carbonyl group were applied to
eventually afford 3-deoxy-L-fructose. Because the dithioacetal
approach was used, two additional synthetic steps (protection
and deprotection of the carbonyl group) were needed to
hydrolyze the benzoyl groups and produce the desired 3-deoxy-
L-fructose. From synthetic points of view, the benzoyl group
functioned well as the protecting group in the carbonyl
translocation process, but further deprotection remained a
challenge [15].
Results and discussion
Since the benzoyl (Bz) group was still the best protecting group
for this unique radical translocation process [12,13abd], we
decided to continue to use the benzoyl group for protecting hydro-
xyl groups, as shown in Scheme 3. To avoid the use of pyridine and
DCM, benzoyl protection was first carried out in the presence of
NEt3 in THF, but the tetrabenzoyl fructopyranoside 1 was not suc-
cessfully obtained. Mixtures of tetrabenzoyl furanosides appeared
to be generated in these conditions, which is not suitable for fur-
ther bromination reactions. We then examined the use of standard
conditions for achieving benzoyl protection (pyridine and DCM) to
give tetrabenzoyl fructopyranoside 1 in 91% yield [13b].
Bromination reaction proceeded successfully using CBr4 and PPh3
to provide the acyclic precursor 2 in quantitative yield. Pioneered
Scheme 2. Configurations of D-fructose and 3-deoxy-L-fructose and carbonyl translocation process.
2
Tetrahedron Letters 63 (2021) 152718
by Chatgilialoglu, tris(trimethylsilyl)silane (TTMSS) was
successfully used as an alternative radical reagent to avoid the
use of toxic tin reagents [16]. Under these unique radical condi-
tions (TTMSS/AIBN), the a-oxy carbonyl group was successfully
translocated to produce the protected 3-deoxy-L-fructose deriva-
tive 3 in 76% yield, where the C(3) position was deoxygenated,
and the stereochemistry of C(4) and C(5) were inverted [13b].
Conventional procedures to deprotect the benzoyl (Bz) group of
compound 3, such as acidic methanolysis, Cu(OAc)2 assisted
methanolysis [17], hydrazine monohydrate [18], NaOEt, KCN, and
thiophenoxide [19], were all not feasible. (please see the Supple-
mentary Material) We then turned our attention to exploring bio-
logical deprotection methods. Since the use of lipases in the
enzymatic hydrolysis of acetates (OAc) and benzoates (OBz) is well
established in organic synthesis [20], several lipases from different
sources (Aspergillus oryzae, Candida Cyclindracea, Candida rugose,
and Porcine Pancreas), and different benzoyl group acceptors (n-
BuOH, n-hexanol, and n-octanol), and a variety of reaction solvents
(phosphate buffer, DMSO/H2O, THF, tBuOMe, diisopropyl ether,
and toluene) were tested. Eventually, a lipase from Candida rugose
in the presence of n-BuOH and toluene at 37 °C was found to be the
best conditions for accomplishing the whole synthesis and produc-
ing the free sugar form of 3-deoxy-L-fructose (4) in 59% yield.
(please see the Supplementary material) Since the free sugar pro-
duct contains a- and b-forms of furanose and pyranose, compli-
cated 1H/13C spectra were observed, which are identical to
previous work [13b]. We now confirm that D-fructose, a
carbohydrate raw material, could be easily and efficiently
converted into a rare L-deoxyhexose in just four steps in an
overall yield of 39.98%. This example using a carbonyl
translocation process and enzymatic hydrolysis opens a new
synthetic methodology that can be successfully used to prepare
rare, expensive, or important L-deoxysugars from carbohydrate
raw materials.
Conclusions
The highly efficient conversion of D-fructose into rare
3-deoxy-L-fructose was achieved in four synthetic steps. The first
two synthetic steps, benzoyl protection and bromination reaction,
provided an acyclic carbohydrate precursor. The third step, using
environmentally benign radical conditions (TTMSS/AIBN), allowed
Ya-Han Hsu and Che-Chien Chang
Scheme 3. Conversion of D-fructose into 3-deoxy-L-fructose in four steps.
a 3-deoxy-L-fructose derivative to be produced through our unique
carbonyl translocation process, thus representing a highly efficient
approach to the production of L-deoxysugars from D-sugars. The
fourth step, enzymatic deprotection using a lipase, resulted in
the formation of the free sugar, 3-deoxy-L-fructose in an overall
yield of 40%. The synthesis used a readily available carbohydrate
raw material as the starting material and avoided the use of toxic
tin chemicals. To the best of our knowledge, this synthetic method-
ology is sufficiently concise to provide one of the most efficient
methods for preparing L-deoxyhexoses from a simple raw material.
This method could also serve as the standard procedures for fur-
ther applications in the pharmaceutical industry. Meanwhile, with
this methodology in hand, the synthesis of other rare L-deoxysug-
ars using other raw materials is currently being investigated.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgement
We wish to thank the Ministry of Science and Technology, Tai-
wan (grant number: MOST 108-2113-M-030-008) for financial
support. YHH held Department of Chemistry Master Student Fel-
lowships. Tai-Ni Lu is acknowledged for prelimary experiments.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152718.
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