Simple one-pot regioselective 6-O-phosphorylation of carbohydrates and trehalose desymmetrization

Article abstract of DOI:10.1039/c3cc47180b

Biologically essential carbohydrate 6-phosphates, especially trehalose 6-phosphate, can be synthesized easily in excellent overall yields in 2 steps involving minimum protecting group manipulations. We can cleave the diphenylphosphate group for further synthetic objectives.

Full text of DOI:10.1039/c3cc47180b

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Simple one-pot regioselective 6-O-phosphorylation of
carbohydrates and trehalose desymmetrization†
A. Abragam Joseph,ab Chun-Wei Changa and Cheng-Chung Wang*a
Cite this: Chem. Commun., 2013,
49, 11497
Received 19th September 2013,
Accepted 16th October 2013
DOI: 10.1039/c3cc47180b
www.rsc.org/chemcomm
Biologically essential carbohydrate 6-phosphates, especially trehalose carbohydrates recently developed by us,11 we per-O-trimethyl-
6-phosphate, can be synthesized easily in excellent overall yields in silylated methyl a-D-glucopyranoside (1) in dichloro-methane
2 steps involving minimum protecting group manipulations. We can using HMDS, and directly added pyridine and diphenyl chloro-
cleave the diphenylphosphate group for further synthetic objectives. phosphate (3 equiv.) into the same reaction vessel. After stirring
for another 36 hours, without the need for further protecting
The indispensable roles of carbohydrate 6-phosphates in living group manipulation and protection–deprotection procedures,
systems have long been recognized.1 These essential biomolecules the diphenylphosphate group was successfully placed on the C6
are involved in the metabolism of carbohydrates and the bio- primary hydroxyl group in excellent regioselectivity, affording the
synthesis of numerous saccharides by serving as the precursors per-O-trimethylsilylated methyl a-D-glucoside 6-phosphate deriva-
of carbohydrate metabolisms and interconversions as well as tive 2 in 82%. The fully silylated glucoside intermediate was
the substrates of numerous enzymes.2
recovered in 11% (92% recovered yield of 2). The diphenyl groups
Generally, the chemical phosphorylation of alcohols is achieved of 2 were easily removed under a hydrogenolysis condition using
by reaction with P(V) phosphorylation reagents, such as phosphoryl platinum(IV) oxide as the catalyst in 75% ethanol. Under this
chloride,3 activated phosphotriesters4 or poly phosphoric acid,5 condition the TMS groups were also hydrolyzed to give the methyl
or with the P(III) species followed by oxidation. Though different a-D-glucoside 6-phosphate 3 in a single step in 97% without any
hexokinases readily give sugar 6-phosphates,6 the chemical synthesis cyclization and migration of the phosphate group.12
of these molecules usually requires lengthy synthetic steps.
Generally, the anomerically unprotected sugars are difficult
Phosphorylation of free sugar is low yielding and poor in regio- to deal with due to the anomerization and solubility problems.
selectivity and thus requires extensive purification.7 Despite the However, using this method, for example using free glucose (4) as
primary C6 hydroxyl group is the most reactive one in a sugar, the substrate, without the need for prior anomeric protection, the
the other secondary hydroxyl groups still subsequently react as the phosphate group can still be placed on the C6 in merely a single
solubility of the substrates increases with the phosphorylation step, and gave the O6-phosphorylated glucose 5 in 83% (recovered
level. To solve this problem, a solid-phase methodology has been yield 94%) with the a/b = 6.3/1 (entry 2). Therefore, after simply
developed.8 To produce these molecules more economically the hydrogenolysis, glucose 6-phosphate (6), which is essential for
and efficiently on large scales, a simpler and more reliable carbohydrate metabolism of higher organisms1,13 and the intake
methodology is needed.
and the circulation of aluminum(III) in biological media14 and
Here, we report a simple two-step procedure to efficiently prepare sometimes stimulates the expression of genes,15 can be synthesized
these essential biomolecules. Since the solubility is the key in merely two steps in an overall yield of 94%. This methodology
issue, we proposed that the O6-phosphorylation of carbohydrates can be applied to the synthesis of other monosaccharide
mediated by trimethylsilyl groups can be a solution.9,10 As 6-phosphates, and the results are summarized in Table 1.
described in Table 1, entry 1, by incorporating the TMSOTf- Galactose 6-phosphate (9) (Table 1, entry 3) and biologically
catalyzed 1,1,1,3,3,3-hexamethyldisilazane (HMDS) silylation of important mannose 6-phosphate (12)16 (Table 1, entry 4) and its
anomerically substituted derivative 15 (Table 1, entry 5) can also
a Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
E-mail: wangcc@chem.sinica.edu.tw; Fax: +886-2-2783-1237;
Tel: +886-2-2789-8618
b Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data of new compounds and copies of NMR spectra. See
DOI: 10.1039/c3cc47180b
be prepared by using this universal protocol in two steps via their
O6-phosphorylated products 8 (a/b = 6.2/1), 11 (a only) and 14 in
excellent overall yields directly from their corresponding free
sugars 7, 10 and 13 respectively. 2-Deoxyglycosides are known to
be more unstable, but 2-deoxyglucose 6-phosphate (18) (Table 1,
entry 6) can still be easily synthesized in high overall yield.
c
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Table 1 One-pot regioselective O6 phosphorylation of monosaccharides
Table 2 One-pot regioselective O6-phosphorylation of disaccharides
Entry
Monosaccharide
O6-phosphorylated monosaccharideb
Mono O6-phosphorylated
Entry
Disaccharide
disaccharideb
1
1
2
3
2
3
4
5
4
a
b
H2, PtO2, 75% EtOH(aq.), overnight. In the parentheses are the
recovered yields based on the recovery of the fully silylated disaccharide
intermediates.
6
highly involved in the carbohydrate metabolism of plants,17a,18
can be prepared in two steps in an overall yield of 93% from free
trehalose (19). We believe that the strong electron withdrawing
property of the diphenylphosphate group can be the key to
this excellent regioselectivity; however, the O6 functionalization
attempts of other electron withdrawing groups, such as benzoyl,
p-nitrobenzoyl and carboxybenzyl groups, could not provide similar
a
b
H2, PtO2, 75% EtOH(aq.), overnight. In the parentheses are the
recovered yields based on the recovery of the fully silylated mono-
saccharide intermediates.
With these good results, we extended the scope into selectivity and gave majorly either the non- or the di-functionalized
disaccharides and the results are listed in Table 2. The differ- trehalose derivatives depending on the reaction time. As a matter of
entiation of the two glucose units in trehalose has long been a fact, the phosphorylation of the other primary C6 was difficult
synthetic challenge.9b,17 Surprisingly, the per-O-trimethylsilylation- once compound 20 was formed, and we could barely isolate any
mediated phosphorylation of symmetric trehalose (19) selectively di-phosphorylated product even if we employed more phosphoryl
occurred on one of the two symmetrical C6s, and gave the mono chloride or further extended the reaction time.
O6-phosphorylated 20 in 63% with the recovery of the fully
For lactose (22) and cellobiose (25), as shown in Table 2
silylated trehalose intermediate in 32% (93% recovered yield of 20) (entries 8 and 9), the phosphorylation took place regioselectively
(Table 2, entry 1). Similarly, after the hydrogenolysis and the hydro- on the O6 of the non-reducing sugar unit and gave their corre-
lysis in a single step, biologically important trehalose 6-phosphate, sponding O60 mono-phosphorylated product 23 and 26 in 44%
c
11498 Chem. Commun., 2013, 49, 11497--11499
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The synthesis of other natural products containing an unsymme-
trical trehalose core, such as trehalose monomycolate, trehalose
tetraester and SL-1, using this methodology is currently underway
in our laboratory.
This work was supported by the National Science Council of
Taiwan (NSC 101-2113-M-001-011-MY2) and Academia Sinica.
Notes and references
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Scheme 1 Desymmetrization of trehalose.
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and 49% (recovered yield 86% and 96%) respectively. Hence,
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