Triacetonide of Glucoheptonic Acid in the Scalable Syntheses of d -Gulose, 6-Deoxy- d -gulose, l -Glucose, 6-Deoxy- l -glucose, and Related Sugars

Article abstract of DOI:10.1021/acs.orglett.6b02041

Ease of separation of petrol-soluble acetonides derived from the triacetonide of methyl glucoheptonate allows scalable syntheses of rare sugars containing the l-gluco or d-gulo structural motif with any oxidation level at the C6 or C1 position of the hexose, usually without chromatography: meso-d-glycero-d-guloheptitol available in two steps is an ideal entry point for the study of the biotechnological production of heptoses.

Full text of DOI:10.1021/acs.orglett.6b02041

Letter
pubs.acs.org/OrgLett
Triacetonide of Glucoheptonic Acid in the Scalable Syntheses of
D‑Gulose, 6‑Deoxy‑D‑gulose, L‑Glucose, 6‑Deoxy‑L‑glucose, and
Related Sugars
Zilei Liu,†,§ Akihide Yoshihara,*,‡ Sarah F. Jenkinson,† Mark R. Wormald,§ Ramon J. Estevez,∥
́
́
George W. J. Fleet,*,† and Ken Izumori‡
†Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, U.K.
‡International Institute of Rare Sugar Research and Education, Kagawa University, Miki, Kagawa 761-0795, Japan
§Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, U.K.
∥Departamento de Química Organ
ica and Centro Singular de Investigacion en Química Bioloxica e Materiais Moleculares,
́ ́ ́
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
S
* Supporting Information
ABSTRACT: Ease of separation of petrol-soluble acetonides
derived from the triacetonide of methyl glucoheptonate allows
scalable syntheses of rare sugars containing the L-gluco or D-
gulo structural motif with any oxidation level at the C6 or C1
position of the hexose, usually without chromatography: meso-
D-glycero-D-guloheptitol available in two steps is an ideal entry
point for the study of the biotechnological production of
heptoses.
odium glucoheptonate 1 >98% pure, prepared from the
and ester groups in 5 by LiAlH4 formed the diol 10 (90%), which
on treatment with acid ion-exchange resin gave L-glucitol 11
(100%) in 77% yield from the triacetonide 2. Alditols are ideal
substrates for biotechnological conversion to rare sugars:
microbial oxidation of L-glucitol 11 gave D-sorbose4 12 in 90%
yield.5 13C and 1H NMR spectra of D-gulose 9 and L-glucitol 11
were identical to those of authentic samples (see Supporting
Information).
Acetonide 2 or 7 can be used for efficient syntheses of 6-deoxy
sugars. Derivatives of 6-deoxy-D-gulose can be efficiently
accessed by initial deoxygenation of the primary alcohol in 7
(Scheme 2). Esterification of 7 with triflic anhydide in the
presence of pyridine, followed by nucleophilic substitution with
sodium iodide in butanone, gave iodide 13 (81% over two steps).
Hydrogenation of 13 in methanol in the presence of palladium
on charcoal and triethylamine gave the crystalline diacetonide 14,
which was deprotected to afford 6-deoxy-D-gulonolactone 156
(100%). Synthesis of the crystalline lactone 15 from the
triacetonide 2 in 61% yield required no chromatography; the
route is far more convenient than procedures from L-rhamnose7
or D-gulonolactone.8
S
Kiliani reaction of sodium cyanide with glucose,1 is one of
the cheapest bulk carbohydrates available. On a 100 g scale, 1
may be converted in a morning to the pure triacetonide methyl
ester 2 by a procedure that involves extraction of the crude
product with cyclohexane as the only purification step (Scheme
1). The value of 2 in the preparation of rare sugars has been
demonstrated by large-scale syntheses of L-glucose 4 and L-
glucuronic acid 6: selective deprotection of the terminal
acetonide in 2, followed by LiAlH4 reduction of 2a, and
periodate cleavage gave aldehyde 3; acid hydrolysis of 3 gave L-
glucose 4 in 80% yield from the triacetonide with purification
only by solvent extraction and crystallization.2 Partial hydrolysis
of 2 and subsequent oxidation with periodate afforded the stable
aldehyde 5, which with trifluoroacetic acid hydrolysis gave L-
glucuronic acid 6, isolated as the crystalline lactone in 78% yield
from 2.2 This paper describes the synthesis of a wide range of rare
sugars via intermediate acetonides derived from 2, all easily
accessible in multigram quantities with any oxidation level at C1
or C6 of the sugar.
For the synthesis of D-gulose 9, treatment of 5 on a multigram
scale with sodium borohydride in methanol at 0 °C gave
completely regioselective reduction of the aldehyde to provide
alcohol 7 (96%); there was no reduction of the ester group
(Scheme 1). Further reduction with DIBAL-H afforded the D-
gulose derivative 8 with C1 and C6 unprotected (86%). One-step
DIBAL-H reduction of 5 directly to 8 did not give a clean
product. Removal of the acetonides in 8 by acid ion-exchange
resin gave D-gulose 93 in quantitative yield (71% from
triacetonide 2). Simultaneous reduction of both the aldehyde
Reduction of ester 14 with DIBAL-H at −78 °C gave the
protected aldehyde 17 (84%) and a small amount of the alcohol
16 (14%), easily separated by flash chromatography. Acid ion-
exchange hydrolysis of the acetonides in 17 formed 6-deoxy-D-
gulose 189 (100%), identical to a sample from L-rhamnose7
Received: July 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02041
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Organic Letters
Letter
Scheme 1. L-Glucose 4, D-Gulose 8, and L-Glucitol 11
not possible to convert 2 to the corresponding iodide 25 by an
analogous protocol used for 7 to 13. Reaction of 20 with mesyl
chloride and triethylamine in DCM gave mesylate 23 (82%); all
attempts at nucleophilic displacement of the primary mesylate in
23 failed: 23 was recovered unchanged on heating overnight with
sodium iodide in acetone at reflux or in DMF at 100 °C;
reduction of 23 with LiAlH4 resulted in nucleophilic attack on
sulfur (rather than carbon) to give 20. Although SN reactions in
carbohydrate chemistry are difficult due to the presence of β-
oxygen substituents,15 iodides are almost always formed in good
yields by displacement of primary mesylates. Additional steric
hindrance to nucleophilic attack may be due to the cis
relationship in the C2−C3 ketal between the ketal at C4−C5
and the leaving group at C1. This would also explain the
instability of triflate 24 because the ketal oxygen at C4 might act
as an internal nucleophile on the leaving group at C1. For the
introduction of an iodide at C1, it is necessary to have the iodide
present during the activation of the leaving group at C1. Appel
reaction16 of alcohol 20 with imidazole/triphenylphosphine/
iodine in a 1:1:1 ratio gave iodide 25 (48%) together with
another acetonide 26 (37%). The structure of 26 was confirmed
by NMR spectra with CDCl3 as solvent: (i) three quaternary
carbon signals (δ = 109.3, 109.7, 109.8 ppm) indicated the
presence of three five-membered-ring ketals; (ii) the peak of free
hydroxyl group (δ = 2.17 ppm) of 26 was a doublet in 1H NMR
Scheme 2. 6-Deoxy-D-gulonolactone 15, 6-Deoxy-D-gulose 18,
and 6-Deoxy-D-gulitol [6-Deoxy-D-glucitol] 19
1
spectrum; (iii) H−1H correlation spectroscopy indicated the
hydroxyl group is correlated with H-3. Formation of 26 was also
observed by leaving 20 in CDCl3 for 3 weeks at room
temperature. 20 and 26 are the only two possible triacetonides
of heptitol 21 with only five-ring ketals. Formation of 26 from 20
is acid-catalyzed. Accordingly, when the Appel reactant ratio of
imidazole/triphenylphosphine/iodine was changed to a 4:1:1
with an excess of base, conversion of alcohol 20 gave iodide 25 in
69% yield on an 11 g scale without the formation of 26.
Hydrogenolysis of iodide 25 with palladium black and
triethylamine gave the methyl triacetonide 27 (80%). However,
no conditions for selective acid hydrolysis of 27 to the diol 29
were found. In contrast, the iodomethyl triacetonide 25 with
aqueous acetic acid gave diol 28 (74%). Hydrogenolysis of 28 in
methanol in the presence of palladium on charcoal and
(overall 56% yield from 2). Acid hydrolysis of 16 gave 6-deoxy-D-
gulitol (1-deoxy-L-glucitol) 19.10
Heptitol11 triacetonide 20 was formed in the reduction of
methyl ester 2 with LiAlH4 (74%) (Scheme 3). Acid ion-
exchange hydrolysis of 20 formed the meso-heptitol 21 (94%).
Microbial oxidation of 21 with Acetobacter suboxydans forms L-
glucoheptulose 22 in 88% yield, as described long ago by
Hudson,12 and provides an ideal entry point for the isomerization
of seven carbon sugars by the biotechnology of Izumori;13 there
is much current interest in the investigation of the synthesis and
biological properties of heptuloses.14
Deoxygenation of the primary alcohol in triacetonide 20 gave
efficient syntheses of 6-deoxy-L-glucose (L-quinovose) deriva-
tives. Triflate ester 24 derived from 20 was unstable, and it was
B
DOI: 10.1021/acs.orglett.6b02041
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Scheme 3. meso-D-Glycero-D-guloheptitol 21, 6-Deoxy-L-glucose [L-Quinovose] 31, and 6-Deoxy-L-glucitol 33
triethylamine afforded the crystalline deoxyheptitol diacetonide
29 (83%). Cleavage of diol 29 with sodium periodate on silica gel
in DCM17 formed aldehyde 30 (93%), which on acid ion-
exchange resin hydrolysis gave deoxyhexose 31 (67%), identical
to a sample produced from L-rhamnose.7 Reduction of aldehyde
30 by sodium borohydride in methanol gave diacetonide 32
(85%), which on removal of the acetonide protecting groups by
acid hydrolysis formed 6-deoxyalditol 33 (100%). 6-Deoxy-L-
glucose 31 and 6-deoxy-L-glucitol 33 were formed in overall
yields of 19 and 24%, respectively, from the heptonate
triacetonide 2 without the need for any chromatography. The
NMR spectra of 6-deoxy-L-glucose were identical to those of
commercially available 6-deoxy-D-glucose.
Heptonic acid lactones with only acetonide protection derived
from Kiliani synthesis on aldoses18 or ketoses19 are well-
established intermediates for the efficient synthesis of highly
functionalized targets.20 This paper underlines the value of
triacetonides21 derived from seven carbon sugars; 2 is a divergent
intermediate for access to rare sugars possessing either a D-gulo
or L-gluco structural motif with any oxidation level at C1 or C6.
This approach, which may be general for heptonates, increases
chemical and biotechnological procedures for easy access to rare
sugars.22 L-Rhamnose, a cheap 6-deoxyhexose, provides an
alternative strategy for the synthesis of many of its diastereomers
and derivatives.7,23 In particular, microbial oxidations of alditols
to ketoses usually give high-yield regioselective reactions to a
pure ketose; 6-deoxyalditols 19 and 33 are useful starting
materials for the biotechnology of Izumori in the synthesis of
deoxyhexoses.24
Experimental procedures and full spectroscopic data
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: yoshihara@ag.kagawa-u.ac.jp.
*E-mail: george.fleet@chem.ox.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Leverhulme Trust (G.W.J.F.)
and Xunta de Galicia (Project GRC2014/040). We are grateful
to Carbosynth for samples of authentic sugars for comparison
purposes.
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