A concise approach to the synthesis of all twelve 5-deoxyhexoses: d-tagatose-3-epimerase-a reagent that is both specific and general

Article abstract of DOI:10.1016/j.tetlet.2009.03.061

2-Deoxy-d-glucitol and 2-deoxy-d-allitol, both prepared as crystalline polyols from d-erythronolactone, are oxidized by Gluconobacter thailandicus NBRC 3254 to 5-deoxy-d-threo-hexulose [5-deoxy-d-fructose = 5-deoxy-l-sorbose] and 5-deoxy-d-erythro-hexulose [5-deoxy-l-psicose = 5-deoxy-d-tagatose], respectively. d-Tagatose-3-epimerase (DTE) equilibrates 5-deoxy-d-fructose to 5-deoxy-d-psicose and 5-deoxy-l-psicose to 5-deoxy-l-fructose, providing substrates for the preparation of all eight d- and l-5-deoxy aldohexoses by aldose isomerases. This combination of chemical and biotechnological methods allows a concise approach to the synthesis of all twelve 5-deoxy hexoses and further demonstrates the range of deoxy sugar substrates on which DTE is active. NMR studies show that 5-deoxy-d-fructose exists solely as the β-pyranose form whereas both pyranoses of 5-deoxy-d-fructose [α:β. 22:78] are observed. [For the sake of clarity, all ketoses in this Letter are shown in blue, alditols in red and aldoses in purple.].

Full text of DOI:10.1016/j.tetlet.2009.03.061

Tetrahedron Letters 50 (2009) 3559–3563
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Tetrahedron Letters
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A concise approach to the synthesis of all twelve 5-deoxyhexoses:
D-tagatose-3-epimerase—a reagent that is both specific and general
Devendar Rao a, Daniel Best b, Akihide Yoshihara a, Pushpakiran Gullapalli a, Kenji Morimoto a,
b,
Mark R. Wormald c, Francis X. Wilson d, Ken Izumori a, , George W. J. Fleet
*
*
a Rare Sugar Research Center, Faculty of Agriculture, Kagawa University, 2393 Ikenobe, Mik-choi, Kita-gun, Kagawa 761-0795, Japan
b Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
c Glycobiology Institute, Department of Biochemistry, Oxford University, South Parks Road, Oxford OX1 3QU, UK
d Summit PLC, 91, Milton Park, Abingdon, Oxon OX14 4RY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Deoxy-
are oxidized by Gluconobacter thailandicus NBRC 3254 to 5-deoxy-
tose = 5-deoxy- -sorbose] and 5-deoxy- -erythro-hexulose [5-deoxy-
respectively. -Tagatose-3-epimerase (DTE) equilibrates 5-deoxy- -fructose to 5-deoxy-
5-deoxy- -psicose to 5-deoxy- -fructose, providing substrates for the preparation of all eight
D
-glucitol and 2-deoxy-
D
-allitol, both prepared as crystalline polyols from
-threo-hexulose [5-deoxy-
-psicose = 5-deoxy- -tagatose],
-psicose and
- and L-
D
-erythronolactone,
Received 13 January 2009
Revised 15 February 2009
Accepted 6 March 2009
Available online 14 March 2009
D
D-fruc-
L
D
L
D
D
D
D
L
L
D
5-deoxy aldohexoses by aldose isomerases. This combination of chemical and biotechnological methods
allows a concise approach to the synthesis of all twelve 5-deoxy hexoses and further demonstrates the
range of deoxy sugar substrates on which DTE is active. NMR studies show that 5-deoxy-
D-fructose exists
solely as the b-pyranose form whereas both pyranoses of 5-deoxy- -fructose [ :b. 22:78] are observed.
D
a
[For the sake of clarity, all ketoses in this Letter are shown in blue, alditols in red and aldoses in purple]
Ó 2009 Elsevier Ltd. All rights reserved.
Carbohydrates are involved in a wide variety of biological
processes at a cellular level.1 Because rare and synthetic monosac-
charides [including deoxysugars] possess considerable chemother-
apeutic potential,2 there is considerable effort directed towards the
chemical synthesis of mostly protected derivatives.3 An alternative
more environmentally friendly approach is by the application of
enzymes to organic synthesis4 including directed evolution and
the discovery of new enzymes.5 In particular, the concept of Izu-
moring6 allows the preparation, in significant quantities, of all 24
hexoses via isomerization reactions from common to rare sugars
with no need for any protection; this depends on a range of
microorganisms which interconvert polyols and ketoses,7 aldose
This Letter shows that 5-deoxyketohexoses 2 and 3 are sub-
strates for DTE (Scheme 1). 2-Deoxy- -glucitol 1 and 2-deoxy-
allitol 4 are specifically oxidized by Gluconobacter thailandicus
NBRC 3254 at C-5 to form 5-deoxy- -fructose 2D and 5-deoxy-
psicose 3L; DTE equilibrates 3L with 2L, and 2D with 3D— allowing
the easy formation of all the 5-deoxy-hexuloses. Both the deoxy
D
D-
D
L-
alditols 1 and 4 may be synthesized from
The acetonide of -erythronolactone 5 is readily available from
the oxygenation of an alkaline solution of
-arabinose13 or by
D-erythronolactone.
D
D
hydrogen peroxide oxidation of erythrobic acid,14 followed by ace-
tonation (Scheme 2). Although samarium diodide-15 and cobalt-
mediated16 Reformatsky reactions on aldonolactones have been
reported, addition of lithium tert-butyl acetate [generated by treat-
ment of tert-butyl acetate with LDA in THF at ꢀ78 °C] to the aceto-
isomerases which equilibrate ketoses and aldoses, and
D-taga-
tose-3-epimerase (DTE) which equilibrates C-3 in each of the four
pairs of ketoses.8 DTE is a highly promiscuous enzyme which
accepts a very wide range of substrates, including C-branched sug-
ars. For example, DTE equilibrates both enantiomers of 4-C-methyl
ribulose with both enantiomers of 4-C-methyl xylulose,9 and also
isomerizes 5-C-methyl ketoses to their C-3 epimers.10 The isomer-
nide 5 afforded the lactol 6, mp 23–25 °C, ½a D18
ꢀ63.7 (c 0.91,
ꢁ
CHCl3) in an excellent yield of 90% on a multi-gram scale. Reduc-
tion of 6 by sodium borohydride in methanol gave unselective
reduction in a combined yield of 97% to afford the epimeric deoxy
glucono- 7 (51%) and allono- 8 (46%) esters. The hydroxyesters 7
ization of
L
-rhamnose to 1-deoxy-
L
-fructose11 and of fucose to
and
8
were separable by chromatography; the relative
deoxytagatose12 indicates the technology may be extended to
configuration of the gluconic ester 7 was unequivocally established
by X-ray crystallographic analysis.17 Treatment of the deoxy allon-
o-tert-butyl ester 8 with trifluoroacetic acid facilitated deprotec-
tion of both the tert-butyl ester and isopropylidene protecting
groups and subsequent cyclization to the crystalline deoxy
deoxy sugars.
* Corresponding authors.
E-mail addresses: izumori@ag.kagawau.ac.jp (K. Izumori), george.fleet@chem.
ox.ac.uk (G.W.J. Fleet).
allono-lactone 10 mp 66–68 °C, ½a D25
ꢁ
ꢀ38.1 (c, 1.49 EtOH) [lit.18
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.061

3560
D. Rao et al. / Tetrahedron Letters 50 (2009) 3559–3563
OH OH
OH
OH OH
OH
(ii)
CH2OH
CH2OH
CH2OH
CH2OH
(i)
HOH2C
HOH2C
HOH2C
HOH2C
OH OH
OH
O
OH O
5-deoxy-D-mannitol
2D 5-deoxy-D-fructose
3D 5-deoxy-D-psicose
2-deoxy-D-allitol
O
O
4
1
HO
OH
180o
180o
D-erythronolactone
OH OH
OH
OH
OH
(ii)
CH2OH
CH2OH
CH2OH
CH2OH
(i)
-tagatose-3-epimerase (DTE).
OH OH
HOH2C
HOH2C
HOH2C
HOH2C
OH
OH
O
OH O
OH OH
2-deoxy-D-glucitol
2L 5-deoxy-L-fructose
3L 5-deoxy-L-psicose
5-deoxy-L-allitol
Scheme 1. (i) Gluconobacter thailandicus NBRC 3254 (ii)
D
OH
O
O
CH2OH
HO
HOH2C
(iv)
(iii)
HOH2C
OH O
CH2OH
HOH2C
O
O
HOH2C
OH OH
O
O
O
O
OH
O
HO
7
5
9
2-deoxy-D-glucitol
1
5-deoxy-D-mannitol
(i)
(ii)
HO
HOH2C
O
OH
OH
(iii)
O
HOH2C
O
OH
O
OH OH
CH2OH
O
(iv)
O
CH2OH
OtBu
HOH2C
O
HOH2C
OH OH
O
O
O
HO
OH
5-deoxy-L-allitol
8
6
10
2-deoxy-D-allitol
4
Scheme 2. Reagent and conditions: (i) MeCO2tBu, LDA, ꢀ78 °C, 90%; (ii) NaBH4, MeOH; (iii) CF3CO2H, H2O, dioxane, 1:6:3; (iv) NaBH4, tert-BuOH, MeOH.
D
-psicose;25 likewise, 2-deoxy-
-allitol] gave pure 5-deoxy-
D-allitol 4 [equivalent to 5-deoxy-
71–73 °C, [
lactone 10 in tert-butanol by sodium borohydride with addition
of methanol gave 2-deoxy-
-allitol 419 in 78% yield; the mixed sol-
a
]
ꢀ42 (EtOH)] in quantitative yield. Reduction of the
D
L
L
-psicose 3L (80%), as an oil, ½a D20
ꢁ
+19.2 (c 1.0, H2O). The oxidation of 2-deoxy-D-glucitol 1 to
D
5-deoxy-D-fructose 2D by Gluconobacter oxydans has been previ-
vent-sodium borohydride method gave much cleaner products in
higher yields than other hydride reductions.20 Similarly, treatment
of 7 with trifluoroacetic acid gave the deoxy gluconolactone 9, mp
ously reported.24
DTE epimerizes the C-3 position of many ketoses and, in par-
92–94 °C, ½a 2D5
ꢁ
+70.4 (c 0.49, H2O) [lit.21 95–96 °C, ½a D25
ꢁ
+73 (c, 0.5
ticular, equilibrates
-psicose.26 Equilibration of 5-deoxy-
psicose 3D was carried out under similar conditions. A solution
of 5-deoxy- -fructose 2D (final concentration: 10% w/v) and
manganese(II) chloride (final concentration: 1 mM) in 30 mL of
50 mM Tris–HCl buffer (pH 7.5), was shaken at 42 °C in
D
-fructose with
D
-psicose and
L-fructose with
L
D
-fructose 2D to 5-deoxy-
D-
H2O)], which was then reduced to give the deoxy glucitol 1 in
70% yield.22
D
Gluconobacter strains attack polyols and sugar alcohols accord-
ing to the Bertrand and Hudson rule23 which states that polyols
with a syn-arrangement of two secondary hydroxyl groups in
a
100 mL Erlenmeyer flask containing 2 g of immobilized DTE
(200 U) prepared as described previously.6c,26 Ketoses 2D and
3D reached an equilibrium state after 8 h with a ratio of 80%
substrate and 20% product. The accumulation of product was
analyzed by HPLC. The reaction mixture was concentrated and
applied to a column of Dowex 50W-X2 (Ca2+ form). The column
was eluted with deionized water and 3 mL fractions were col-
D
-configuration to the adjacent primary alcohol group (D-erythro
configuration) are oxidized regioselectively to the corresponding
ketoses. The size and structure of the remaining part of the polyol
molecule have little or no effect on the oxidation capability of
Gluconobacter. Thus, polyols with different carbon chain lengths
ranging from glycerol to heptitols and octitols, and chemically
modified pentitols and hexitols are oxidized to the corresponding
lected. The fractions containing only 5-deoxy-D-psicose 3D were
ketoses. G. thailandicus NBRC 3254 oxidizes
C-5 to give -fructose and -sorbose, respectively; the efficient syn-
D-glucitol at C-2 and
pooled and concentrated under vacuum at 39 °C to give pure
D
L
5-deoxy-
D
-psicose (0.45 g, 15%), as an oil, ½a D20
ꢀ18.5 (c 1.0,
ꢁ
thesis of 4-C-methyl ketopentoses and 5-C-methyl ketohexoses
from the corresponding alditols has been described.9,10 Under sim-
H2O). The epimerization of 5-deoxy-L-psciose 3L with 5-deoxy-
L-fructose 2L was carried out under similar conditions to attain
ilar conditions [Scheme 3], 2-deoxy-
5-deoxy- -mannitol by a 180° rotation] was oxidized by G. thai-
D-glucitol 1 (10 g) [related to
an equilibrium state after 6 h with ratios of 20% substrate 3L
D
and 80% product 2L. Pure 5-deoxy-
L
-fructose (0.2 g, 50%), was
landicus NBRC 3254 to afford crystalline 5-deoxy-D-fructose 2D
isolated as an oil, ½a D20
ꢁ
+59.5 (c 1.0, H2O). Thus DTE is active on
(8 g, 80%), mp 101–103 °C, ½a D20
ꢁ
ꢀ58.3 (c 1.0, H2O) [lit.24 mp 109–
111 °C, ½a 2D0
ꢀ67.3 (c 0.7, H2O)]. G. thailandicus NBRC 3254 also
ꢁ
all the 5-deoxyketohexoses. The purity of the deoxyketoses was
established by HPLC.
oxidizes allitol to L-psicose with no oxidation to the enantiomer

D. Rao et al. / Tetrahedron Letters 50 (2009) 3559–3563
3561
OH
OH
CHO
CHO
HOH2C
HOH2C
OH OH
OH OH
OH
OH
(iii)
CH2OH
CH2OH
5-deoxy-D-allose
5-deoxy-D-glucose
HOH2C
(iii)
HOH2C
OH
O
OH
O
(ii)
OH
OH
5-deoxy-D-fructose
(i)
CHO
2D
CHO
5-deoxy-D-psicose
3D
HOH2C
HOH2C
OH OH
OH OH
5-deoxy-D-altrose
5-deoxy-D-mannose
OH OH
CH2OH
OH OH
CH2OH
HOH2C
HOH2C
OH
OH
OH
1
2-deoxy-D-glucitol
2-deoxy-D-allitol
(i)
4
CHO
OH
HOH2C
CHO
OH OH
HOH2C
OH OH
5-deoxy-L-allose
OH
OH
5-deoxy-L-glucose
CH2OH
(iii)
CH2OH
(iii)
HOH2C
HOH2C
OH
OH
O
OH
O
CHO
OH
HOH2C
(ii)
CHO
OH OH
3L
5-deoxy-L-fructose
2L
HOH2C
5-deoxy-L-psicose
OH OH
5-deoxy-L-altrose
5-deoxy-L-mannose
Scheme 3. (i) G. thailandicus NBRC 3254, H2O; (ii) DTE, H2O, ratio of 68:32; (iii) aldose isomerases.
OH
H
H
OH
H
H
OH
OH
O
H
H
O
O
H
H
H
H
H
H
H
H
H
H
OH
H
OH
OH
OH
OH
O
O
H
H
OH
H
2Dβ 5-deoxy-β-D-
fructopyranose
3Dβ 5-deoxy-β-D-
psicopyranose
3Dα 5-deoxy-α-D-
psicopyranose
Figure 1. Pyranose forms of 5-deoxy-D-fructose 2 and of 5-deoxy-D-psicose 3.
The solution structures of both 2 and 3 were established by
500 ms NOESY, there is no evidence of NOEs from H1/H10 to any
other protons, although the severe overlap between H1 and H60
makes this difficult to assess. From the absence of NOEs from H1,
it is most likely to be the b-anomer 2Db. This is fully consistent
with the previous NMR studies of 2D.27
2/3
NMR analysis (Fig. 1). The 13C and 1H chemical shifts and
J
HH
coupling constants, and the proportions of each form, for 2D and
3D are given in Tables 1–3. The 1D 1H NMR spectra are shown in
Figure 2.
For 5-deoxy-
D
-fructose 2D, there is only one major spin-system
For 5-deoxy-D-psicose 3D, there are two components, with rel-
3
observed at ꢂ90% (Fig. 1). The large and small JHH couplings ob-
ative intensities 0.78:0.22. There are several other minor compo-
nents at less than 4%. The two major components are consistent
with the two pyranose anomers of 5-deoxy-psicose. In the major
served for H6/H60 are only consistent with a pyranose ring struc-
3
ture of fixed geometry. From the large JHH couplings, H3, H4, H50
3
and H6 are all axial, hence H5 and H60 are both equatorial. This
confirms the relative stereochemistry at C3 and C4 and is consis-
isomer, the large JHH couplings indicate that H4, H5 and H6 are
all axial, whilst H3, H50 and H60 must be equatorial. This is in agree-
tent with the 2C5 ring conformation of 5-deoxy-
D
-fructose. From
ment with the 2C5 ring conformation of 5-deoxy-
D-psicose. In the
minor isomer, both H5 and H6 must be axial, with H4, H50 and
H60 being equatorial. There is a very weak H3/H5 NOE at 300 ms
mixing time, which suggests that H3 is also axial. This is consistent
Table 1
with the 5C2 ring conformation of 5-deoxy-
D-psicose. There are no
13C chemical shifts of 5-deoxy-D-ketoses (referenced to acetone at 30.90 ppm)
significant NOEs from either H1/H10 for either anomer, suggesting
%age
13C chemical shift (ppm)
that C1 is equatorial in both, that is, the major isomer is b and the
C1
C2
C3
C4
C5
C6
minor isomer is
In summary, this Letter describes efficient syntheses of both the
deoxy alditols 1 and 4 from -erythronolactone. Although the
a.
5-Deoxy-
D
-fructose 2D
b-Pyranose
5-Deoxy- -psicose 3D
-Pyranose
b-Pyranose
100
64.39
98.83
72.93
68.97
33.45
59.39
D
D
isomerization of the ketoses to all the corresponding aldoses [in
purple in Scheme 3] by aldose isomerases has yet to be confirmed,
this work indicates that the technique of Izumoring may be applied
to provide deoxy hexoses in amounts sufficient for exploitation of
a
22
78
63.97
65.05
99.11
98.83
67.09
68.89
68.70
66.11
31.34
27.80
55.92
59.82
%ages were estimated from peak area in the 1H 1D spectrum.

3562
D. Rao et al. / Tetrahedron Letters 50 (2009) 3559–3563
Table 2
1H chemical shifts of 5-deoxy-D-ketoses (referenced to acetone at 2.220 ppm)
%age
1H chemical shift (ppm)
H1
H10
H3
H4
H5
H50
H6
H60
5-Deoxy-
b-Pyranose
5-Deoxy- -psicose 3D
-Pyranose
b-Pyranose
D-fructose 2D
100
3.698
3.481
3.436
3.903
1.976
1.646
3.886
3.705
D
a
22
78
3.689
3.705
3.412
3.485
3.703
3.760
4.200
4.102
1.949
1.840
1.849
1.676
4.066
3.905
3.639
3.741
%ages were estimated from peak area in the 1H 1D spectrum. Values in italics were determined from simulation of the 1D 1H spectrum and traces through the gHSCQ
spectrum.
Table 3
Two and three-bond JHH values of 5-deoxy-D-ketoses
%age
JHH (Hz)
H5–H6
H1–H10
H3–H4
9.7
H4–H5
5.2
H4–H50
H5–H50
H5–H60
H50–H6
H50–H60
5.3
H6–H60
5-Deoxy-
b-Pyranose
5-Deoxy- -psicose 3D
-Pyranose
b-Pyranose
D
-fructose 2D
100
ꢀ11.7
11.5
ꢀ13.2
2.0
2.0
13.0
ꢀ12.0
D
a
22
78
ꢀ11.8
ꢀ11.8
3.2
3.2
3.1
11.9
3.2
4.7
ꢀ13.2
ꢀ13.0
12.1
11.9
5.8
5.3
2.7
2.7
2.1
1.5
ꢀ12.2
ꢀ12.7
%ages were estimated from peak area in the 1H 1D spectrum. Values in italics determined from simulation of the 1D 1H spectrum and traces through the gHSCQ spectrum.
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3.6
3.2
2.8
2.4
2.0
1.6
Chemical Shift (ppm)
Figure 2. 1D 1H NMR spectra of (a) 5-deoxy-
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Bioeng. 2008, 106, 473–480.
their biological and chemical properties; the isomerization of some
5-deoxyaldoses with glucose isomerase has been reported.28 This
Letter further illustrates the synergistic potential of the combina-
tion of chemistry with biotechnology in providing access to novel
monosaccharides and rare sugars with a minimum use of protect-
ing groups, and further extends the range of substrates recognized
by DTE.
7. (a) Rahman, A. K.; Tokunaga, H.; Yoshida, K.; Izumori, K. J. Ferment. Bioeng.
1991, 72, 488–490; (b) Muniruzzaman, S.; Tokunaga, H.; Izumori, K. J. Ferment.
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Acknowledgements
8. (a) Yoshida, H.; Yamada, M.; Nishitani, T.; Takada, G.; Izumori, K.; Karnitori, S. J.
Mol. Biol. 2007, 374, 443–453; (b) Ishida, Y.; Kamiya, T.; Izumori, K. J. Ferment.
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9. Rao, D.; Yoshihara, A.; Gullapalli, P.; Morimoto, K.; Takata, G.; da Cruz, F. P.;
Jenkinson, S. F.; Wormald, M. R.; Dwek, R. A.; Fleet, G. W. J.; Izumori, K.
Tetrahedron Lett. 2008, 49, 3316–3321.
This work was supported in part by the Program for Promotion
of Basic Research Activities for Innovative Biosciences (PROBRAIN)
and by Summit PLC.
10. Jones, N. A.; Rao, D.; Yoshihara, A.; Gullapalli, P.; Morimoto, K.; Takata, G.;
Hunter, S. J.; Wormald, M. R.; Dwek, R. A.; Izumori, K.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2008, 19, 1904–1918.
References and notes
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19. Selected data for 2-deoxy- -allitol 4: mp 82–84 °C [lit.29 84–85 °C]; ½a D25
ꢁ
ꢀ17.8
(c 1.62, MeOH) [lit.29
½
a 2D6
ꢁ
Dꢀ20.4 (c 1.6, MeOH)]; dH (CD3OD, 400 MHz): 1.69
(1H, ddt, H2a, Jgem 14.1, J2a,1 5.6, J2a,3 9.3), 1.91 (1H, ddt, H2b, Jgem 14.1, J2b,1 7.0,
J2b,3 2.8), 3.50 (1H, dd, H4, J4,3 5.8, J4,5 6.8), 3.59-3.80 (5H, m, H1, H5, H6), 3.87
(1H, ddd, H3, J3,2a 9.3, J3,2b 2.8, J3,4 5.8). dC (CD3OD, 100 MHz): 35.6 (C2), 60.2
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D
-glucitol 1: mp 100–102 °C [lit.30 103.5–105 °C];
½
a 2D5
ꢁ
+17.2 (c 1.02, H2O) [lit.30
½
a 2D0
ꢁ
+17.5 (c 1, H2O)]; dH (CD3OD, 400 MHz):
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1.64–1.72 (1H, m, H2a), 1.78–1.86 (1H, m, H2b), 3.32 (1H, dd, H4, J4,3 1.8, J4,5
8.1), 3.58 (1H, dd, H6a, Jgem 11.0, J6a,5 5.9), 3.63–3.78 (3H, m, H1, H5), 3.76 (1H,