L-fucose from vitamin C with only acetonide protection

Article abstract of DOI:10.1021/ol502733x

Addition of human milk oligosaccharides (HMO) to baby foods may protect infants from disease. As many simple HMOs are fucosylated this is likely to increase the demand for l-fucose as a synthetic building block. Any chemical synthesis must be cheap to compete with a biotechnological process. Acetonide is the only protecting group we have used in this new synthesis of l-fucose from vitamin C in 27% overall yield (purification by recrystallization; no chromatography required in the entire sequence).

Full text of DOI:10.1021/ol502733x

Letter
pubs.acs.org/OrgLett
L‑Fucose from Vitamin C with Only Acetonide Protection
†
,‡
§
‡
†
∥
,§
Zilei Liu, Akihide Yoshihara, Mark R. Wormald, Sarah F. Jenkinson, Vicky Gibson, Ken Izumori,*
,
†
and George W. J. Fleet*
†
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
Oxford Glycobiology Institute, University of Oxford, Oxford, OX1 3QU, U.K.
‡
§
Rare Sugar Research Center, Kagawa University, 2393 Ikenobe, Mikicho, Kita-gun, Kagawa 761-0795, Japan
∥Carbosynth Limited, 8, Old Station Business Park, Compton, Berkshire, RG20 6NE, U.K.
*
S Supporting Information
ABSTRACT: Addition of human milk oligosaccharides (HMO) to
baby foods may protect infants from disease. As many simple HMOs
are fucosylated this is likely to increase the demand for L-fucose as a
synthetic building block. Any chemical synthesis must be cheap to
compete with a biotechnological process. Acetonide is the only
protecting group we have used in this new synthesis of L-fucose from
vitamin C in 27% overall yield (purification by recrystallization; no
chromatography required in the entire sequence).
L-Fucose 1 is a monosaccharide that is a common component
of many glycolipids, and N- and O-linked glycans in mammalian
cells; fucosylated glycans have many functions and are often1
regulated during ontogeny and cellular differentiation.
Alterations in the expression of fucosylated oligosaccharides
are found in several pathological processes, including cancer
(95% yield); diastereoselectivity in similar systems has been
14
rationalized by a Felkin−Ahn controlled addition of hydride.
The methyl signals in 6 and 7 allow accurate measurements of
1
the ratio by H NMR. Hydrolysis of the mixture of 6 and 7 by
+
Dowex (50W X8, H ) in methanol/water gave the 1-
deoxyheptitols 8 and 9 in a ratio of 93:7 as shown by both
NMR and HPLC.
Crystallization of the mixture from water/methanol/
acetonitrile gave the deoxyheptitols 8 and 9 in a ratio of 98:2
2
and atherosclerosis. Fucosylated human milk oligosaccharides
3
(
HMO) protect infants from disease and are important in the
4
development and protection of newborn infants. Addition of
HMOs as a baby food supplement would sharply increase the
demand for fucose. There is thus considerable interest in the
biotechnological and chemical synthesis of HMOs; all such
syntheses involve the use of fucose as a starting material. At
present, almost all fucose is produced by acid hydrolysis or
microbial fermentation of sulfated polysaccharides such as
(
81% yield; 74% from the diacetonide 4). The mother liquor
from the crystallization contained 8 and 9 in a ratio of ∼4:3 and
5
6
allowed pure samples of the two heptitols to be isolated by
15
HPLC. The deoxyheptitol 8 was easily crystallized, whereas 9
16
was an oil. Cleavage of the terminal diol in 8 by periodate
would give fucose 1; cleavage of terminal diols is usually more
7
fucoidans. For a chemical synthesis to compete, it is necessary
17
rapid than other diol oxidations. Similar oxidation of 9 would
that the starting material and reagents are cheap and the
process involves minimum purification. This paper describes
the synthesis of fucose from vitamin C 2, a bulk chemical which
18
1
give the C5 epimer of fucose, 6-deoxy-D-altrose. However, H
NMR studies of the direct oxidation of 8 by aqueous periodate
did not indicate formation of any fucose, so protection of the
heptitol 8 was necessary.
8
costs $3−$4 per kg [for 1000 kg].
Palladium-catalyzed hydrogenation of vitamin C 2 formed L-
gulonolactone 3 (99%) which on treatment with acetone and
9
Treatment of 8 with acetone in the presence of p-
toluenesulfonic acid gave the kinetic triacetonide 10 (83%).
Although 10 is also the most stable triacetonide derived from 8,
longer reaction times and alternative reaction conditions gave
small amounts of other acetonides. Accordingly, the reaction
was stopped when other products began to appear; pure
p-toluenesulfonic acid (pTSA) gave the diacetonide 4 in 93%
1
0
11
yield [Scheme 1]. The diacetonide 4 and its enantiomer
12
have been used in several scalable syntheses.
Addition of methyl lithium to lactone 4 afforded the lactols 5
in 96% yield; although 5 can be easily crystallized as the α-
1
3
anomer, the crude residue was used in the next step.
Reduction of 5 by sodium borohydride in methanol afforded a
mixture of the two 1-deoxyheptitols 6 and 7 in a ratio of 93:7
Received: September 16, 2014
Published: October 13, 2014
©
2014 American Chemical Society
5663
dx.doi.org/10.1021/ol502733x | Org. Lett. 2014, 16, 5663−5665

Organic Letters
Letter
Scheme 1. Synthesis of L-Fucose 1
adjusting the oxidation levels at C1 and C6 of derivatives of D-
2
1
galactose, L-galactose, and D-galacturonic acid. Acetonides
have been recognized as the optimum protecting group since
22
the dawn of monosaccharide chemistry. As in an approach to
23
L-glucose, the solubility of the seven carbon sugar triacetonide
1 in cyclohexane is crucial for the success of this multi gram
1
24
synthesis of fucose. The biotechnology of Izumoring allows
the conversion of L-rhamnose, the only cheap deoxyhexose, into
many other 6- and 1-deoxyhexoses; however, the isomer-
ization of rhamnose to fucose is not efficient.
25
Although fucose is the 6-deoxyhexose with a well-established
demand, there is considerable interest in the synthesis of other
deoxyhexoses, particularly as building blocks for their
26
incorporation into oligosaccharides. The strategy of addition
of methyl lithium to sugar lactones gives a 1-deoxy-ketose
which may be stereoselectively reduced to 1,2-syn diols (as in
27
this paper) or under chelation controlled conditions to 1,2-
anti-diols. Elaboration of each epimeric 1-deoxyheptitol
through the triacetonides will generate two 6-deoxyhexoses.
Since some six hexonolactones [the enantiomers of glucono-,
gulono-, and galactono- lactones] are easily available, some 12 of
the 16 6-deoxyhexoses may be accessed by this strategy.
Almost all sugars that are available on industrial scale are
2
8
made by biotechnology; even the Reichstein process
29
involving chemistry for 80 years for the synthesis of vitamin
C 2 has been mostly superseded by a fermentation process
30
developed in China. However, this scalable synthesis of
fucose from vitamin C may be competitive with the present
biotechnological procedures.
ASSOCIATED CONTENT
Supporting Information
■
crystalline 10 was isolated by extraction of the crude residue
with cyclohexane. The residue was subjected to the same
reaction conditions to give 10 in 83% yield. Kinetic hydrolysis
of the terminal acetonide in 10 by acetic acid in aqueous
methanol gave the diol 11 in 81% yield. The most efficient
procedure involved following the reaction by TLC; initially
only 11 was formed. When other products began to appear, the
*
S
Experimental procedures and full spectroscopic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
reaction was quenched with NaHCO (aq, sat). Unreacted
3
triacetonide 10 and the diacetonide 11 were efficiently
recovered by sequential extraction with cyclohexane and ethyl
acetate. Both the triacetonide 10 and the diacetonide 11 are
crystalline materials; no chromatography is necessary at any
stage during the synthesis. Treatment of the diol 11 with
*E-mail: george.fleet@chem.ox.ac.uk.
*E-mail: izumori@ag.kagawa-u.ac.jp.
Notes
The authors declare no competing financial interest.
19
sodium periodate adsorbed on silica gel afforded the aldehyde
2 (80%) from which the acetonides were removed by Dowex
ACKNOWLEDGMENTS
1
■
+
(
50W X8, H ) in water to give a 100% yield of fucose 1 with a
This work was supported by the Leverhulme Trust (G.W.J.F.).
purity, as established by HPLC, of 95.9%. A single
crystallization of fucose from ethanol increased the purity to
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