Synthesis of and NMR studies on the four diastereomeric 1-deoxy-d-ketohexoses

Article abstract of DOI:10.1016/j.tetasy.2007.02.028

The four 1-deoxy-d-ketohexoses-1-deoxy-d-psicose, 1-deoxy-d-fructose, 1-deoxy-d-sorbose and 1-deoxy-d-tagatose-were synthesised by methyl lithium addition to suitably protected and readily available pentonolactones. The 1-deoxy-l-ketohexoses are available

Full text of DOI:10.1016/j.tetasy.2007.02.028

Tetrahedron: Asymmetry 18 (2007) 774–786
Synthesis of and NMR studies on the four diastereomeric
1-deoxy-D-ketohexoses
Nigel A. Jones,a Sarah F. Jenkinson,a Raquel Soengas,a Mette Fanefjord,a
Mark R. Wormald,b Raymond A. Dwek,b Gullapalli P. Kiran,c Rao Devendar,c
Goro Takata,c Kenji Morimoto,c Ken Izumoric and George W. J. Fleeta,*
aChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
bGlycobiology Institute, Department of Biochemistry, Oxford University, South Parks Road, Oxford OX1 3QU, UK
cRare Sugar Research Centre, Kagawa University, 2393 Miki-cho, Kita-gun, Kagawa 761-0795, Japan
Received 18 February 2007; accepted 25 February 2007
Abstract—The four 1-deoxy-D-ketohexoses—1-deoxy-D-psicose, 1-deoxy-D-fructose, 1-deoxy-D-sorbose and 1-deoxy-D-tagatose—were
synthesised by methyl lithium addition to suitably protected and readily available pentonolactones. The 1-deoxy-L-ketohexoses are avail-
able from the enantiomeric lactones. The NMR studies on aqueous solutions of each diastereomer show that the relative amounts of
open chain ketones, a- and b-pyranoses, and a- and b-furanoses vary considerably; at least four different species are identifiable from
each equilibrium.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
For example, 2-deoxy-L-ribose suppresses tumour growth,
showing potential in antitumour therapy.8 Intraperitoneal
administration of L-glucose enhanced memory in mice by
acting peripherally and its effect depended on cholinergic
mechanisms;9 L-glucose has been used in the development
of glycoconjugate vaccines against diseases caused by Shi-
gella sonnei.10 D-Allose is an inhibitor of segmented neutro-
phile production and lowered platelet count without
detrimental clinical effects.11 A combination of D-allose
with a low dose of FK506, a frequently used potent immu-
nosuppressant, significantly increased the rate of six-month
allograft survival with reduced tissue damage. D-Allose was
also reported to possess a protective effect against ischemia
reperfusion.12 D-Tagatose has been found to be an anti-
hyperglycemic agent and therefore useful in the treatment
of diabetes.13 D-Psicose has a significant number of chemo-
therapeutic properties.14
The availability of rare monosaccharides has been trans-
formed by the demand for alternative foods which qualify
as GASF (generally regarded as a safe food).1 Izumoring is
a biotechnological concept, which allows the green produc-
tion of any of the isomeric hexoses.2 Inexpensive chemical
production of D-tagatose by the calcium(II) isomerisation
of D-galactose has led to a drop in price from around
$10,000 to $5 per kilogram.3 A considerable amount of
ingenious effort has been invested in the chemical synthesis
of rare sugars and their potential uses as starting materials
for bioactive compounds,4 but for large scale synthesis a
biotechnological approach is likely to be both more eco-
nomically efficient and environmentally friendly.
D-Tagatose has GASF status and is used as a low calorie
sweetener.5 D-Psicose, readily available from D-fructose
by the action of D-tagatose epimerase,6 shows promise as
a healthy food substitute.7 Rare monosaccharides have
been found to possess interesting biological activity.
Relatively little attention has been paid to the synthesis or
structures of deoxyketoses. While they may have potential
as foods, the main objective of this project is a study of
their ability to interact with a wide variety of biological
receptors and to determine the structure of the free sugars
in solution. If they are of substantial value, it is likely that
they will be prepared on a large scale by biotechnological
*
Corresponding author. E-mail: george.fleet@chem.ox.ac.uk
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.028

N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
775
Izumoring procedures15 by
a
green environmentally
different crystalline forms of 1-deoxy-a-D-tagatopyranose
(Fig. 2) have been isolated.17 However, in solution each
of the diastereomeric ketohexoses exists as an equilibrium
between both anomers of the pyranose and furanose ring
forms as well as the open chain form in varying propor-
tions (Scheme 1). NMR studies on each diastereomer are
presented; the pioneering work of Angyal18 in 1976 on 1-
deoxy-D-fructose, 1-deoxy-L-sorbose and 1-deoxy-L-psi-
cose is extended.
friendly technique; the deoxyketoses reported herein have
been used to confirm the structures and to provide sub-
strates for the initial studies of the interconversions of all
1- and 6-deoxyhexoses by deoxy Izumoring.15
Herein we report efficient short syntheses of each of the
diastereomeric D-ketohexoses by methyl lithium addition
to a suitably protected lactone of an aldonic acid. 1-Deoxy-
D-psicose 1, 1-deoxy-D-fructose 2, 1-deoxy-D-sorbose 3
and 1-deoxy-D-tagatose 4 were prepared from readily
available protected lactones of D-ribonic acid 5, D-
arabinonic acid 6, D-xylonic acid 7 and D-lyxonic acid 8,
respectively. The L-enantiomers of the starting lactones
are also available, giving a formal synthesis of the four
enantiomeric L-ketohexoses.
2.1. Synthesis of 1-deoxy ketohexoses
2.1.1. 1-Deoxy-D-psicose 1. 1-Deoxy-L-psicose has been
synthesised in a multi-step synthesis from L-sorbose;19
two syntheses of 1-deoxy-D-psicose 1 have been reported.20
D-Ribose 9 can be converted to the protected lactone 10 by
oxidation with bromine and subsequent acetonation by an
organic synthesis procedure in a 73% yield;21 lactone 10 is
the equivalent of a protected ribonic acid 5. Treatment of
the resulting lactone 10 with tert-butyldimethylsilyl chlo-
ride (TBDMSCl) and imidazole gave 5-O-silyl protected
11, which with methyl lithium afforded the protected 1-
deoxy-D-psicose 12 in a 96% yield over 2 steps; reaction
of 10 with methyl lithium gave only low yields of the re-
quired lactol 13, so protection of the C5 alcohol is neces-
sary. 5-O-Desilylation of 12 with tetra-n-butylammonium
fluoride (TBAF) in THF to 13, followed by acidic hydroly-
sis, afforded 1-deoxy-D-psicose 1 in 51% yield over 2 steps.
Removal of the 2,3-O-isopropylidene protecting group was
also attempted with an increased reaction temperature and
the use of a different acid (acetic acid) but this led to a com-
plex mixture of products by TLC. It may be that lactols
such as 13, which can give rise to a tertiary carbocation
at the anomeric centre, are more prone than most glyco-
sides to acid catalysed decomposition. 1-Deoxy-D-psicose
1 was obtained in a 36% overall yield from D-ribose
(Scheme 2).
2. Results and discussion
X-ray crystallographic analysis has shown that 1-deoxy-D-
sorbose16 crystallises in the a-pyranose form (Fig. 1); two
Figure 1. Crystal structure of 1-deoxy-a-D-sorbopyranose.
The L-enantiomer of 9 can be readily derived from D-lyxon-
olactone 2822 thus allowing access to 1-deoxy-L-psicose.
Figure 2. Crystal structure of 1-deoxy-a-D-tagatopyranose.
Me
Me
Me
Me
OH
OH
Me
OH
O
O
O
O
OH
O
O
Me
OH
OH
OH
OH
HO
HO
HO
HO
OH
OH
HO
HO
OH
OH
OH
OH
CH2OH
CH2OH
CH2OH
CH2OH
α-pyranose
β-pyranose
1-Deoxy-D-
1-Deoxy-D-
1-Deoxy-D-
1-Deoxy-D-
OH OH
psicose 1
fructose 2
sorbose 3
tagatose 4
Me
HOH2C
OH
O
open chain
CO2H
OH
OH
OH
CH2OH
CO2H
CO2H
OH
CO2H
HO
HO
HO
OH
Me
OH
β-furanose
HOH2C
OH
Me
OH
α-furanose
O
HOH2C
O
OH
OH
CH2OH
HO
OH
CH2OH
OH
CH2OH
HO
HO
D-Ribonic
D-Arabinonic
D-Xylonic
D-Lyxonic
acid 5
acid 6
acid 7
acid 8
Scheme 1.

776
N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
Me
Me
CHO
OH
OH
OH
O
O
O
O
OH
Me
HOH2C
(i)
[Si]OH2C
(ii)
[Si]OH2C
(iii)
O
O
O
(iv)
OH
OH
OH
O
O
(v)
O
O
O
O
O
O
OH
CH2OH
CH2OH
CH2OH
9
10
11
12
13
1
Scheme 2. Reagents and conditions: (i) Ref. 21 (73%); (ii) tert-BuMe2SiCl, imidazole, DMF (98%); (iii) MeLi, THF, ꢀ78 ꢁC (98%); (iv) TBAF, THF
(79%); (v) Dowexꢂ 50WX8-100 ion-exchange resin, water, room temperature (65%).
Me
CHO
OH
Me
O[Si]
OH
Me
OH
O
O
O
O
O
O
O
(iv)
(iii)
HO
(ii)
(i)
(v)
HO
OH
OH
CH2OH
OH
OH
OH
O[Si]
O
O
O
O
O
O
O
O
CH2OH
14
15
[Si] = tert-BuMe2Si
16
17
18
2
(vi)
Scheme 3. Reagents and conditions: (i) Ref. 25 (75%); (ii) tert-BuMe2SiCl, imidazole, DMF (90%); (ii) MeLi, THF, ꢀ78 ꢁC (98%); (iv) TBAF, THF
(69%); (v) CH3COOH, H2O (53%); (vi) Dowexꢂ 50WX8-100 ion-exchange resin, water, room temperature (93%).
2.1.2. 1-Deoxy-D-fructose 2. The synthesis of 2 has
previously been reported.19,23 1-Deoxy-D-fructose was syn-
thesised from D-arabinose 14 as indicated in Scheme 3. The
preparation of 1,5-lactone 15—the equivalent of arabi-
nonic acid 6—as prepared by the procedure reported for
the L-enantiomer; thus treatment of D-arabinose 14 with
dimethoxypropane in DMF, in the presence of catalytic
amounts of p-toluenesulfonic acid, gave the kinetic 3,4-
monoacetonide,24 which on oxidation with bromine affor-
ded lactone 15 in 75% yield.25
able as D-arabinose 14, so that 1-deoxy-L-fructose is also
readily and cheaply available.
2.1.3. 1-Deoxy-D-sorbose 3. The enantiomer 1-deoxy-L-
sorbose is made by the deoxygenation of C-1 in L-sor-
bose,19 and the synthesis of 1-deoxy-D-sorbose has also
been reported.23b
A number of protected derivatives of xylonolactone 19
with a silyl protecting group at C-2 are readily available.
However, the reaction of any of the pertriethyl silyl ether
20, the perTBDMS silyl ether 21, and the 3,5-O-benzyl-
idene silyl ethers 22 and 23 with methyl lithium all gave
very low yields of the addition compounds with either
methyl lithium or methyl magnesium bromide. Accord-
ingly benzyl protecting groups were used in the synthesis
of 1-deoxy-D-sorbose 3 (Scheme 4).
As is in the case of the synthesis of deoxypsicose 1, protec-
tion of the remaining free OH group in 15 was necessary in
order to obtain a good yield on addition of methyl lithium;
only a low yield of 18 could be obtained by reaction of
methyl lithium with 15. Protection of the secondary alcohol
group in 15 with TBDMS chloride gave the fully protected
lactone 16 in 90% yield, which on addition of methyl lith-
ium afforded lactol 17 (98% yield). Removal of the silyl
protecting group from 17 by treatment with TBAF gave
18 in 69% yield. Acid hydrolysis of 18 with aqueous acetic
acid gave deoxy fructose 2 in 53% yield. However, both the
silyl and isopropylidene protecting groups in 17 can be
removed by careful treatment with acidic ion-exchange
resin to give the deprotected target in 93% yield.
D-Xylose 24 can be converted to the tribenzyl furanose 25
in an overall yield of 60% by literature procedures.26 Oxi-
dation of 25 by dimethyl sulfoxide and acetic anhydride
afforded lactone 2627 in 97% yield. The addition of methyl
lithium to lactone 26 gave the protected furanose 2728 (81%
yield) from which the benzyl protecting groups were
removed by palladium catalysed hydrogenolysis to give
1-deoxy-D-sorbose 3 (86%). The overall yield of deoxy-
ketose 3 from D-xylose 24 is 41%.
Thus the overall yield of unprotected 1-deoxy-D-fructose 2
from D-arabinose 14 is 64%. L-Arabinose is equally avail-
HOH2C
[Si]OH2C
O
Et3SiOH2C
Et3SiO
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
HO
O[Si]
OSiEt3
O[Si]
[Si]O
OSiEt3
Ph
Ph
[Si] = tert-BuMe2Si
19
21
22
23
20

N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
777
Me
CHO
OH
O
OH
BnOH2C
BnOH2C
OH
Me
BnOH2C
O
O
O
(iv)
(iii)
(i)
OH
(ii)
O
HO
HO
OH
CH2OH
OBn
OBn
BnO
OBn
BnO
BnO
OH
CH2OH
24
25
26
27
3
Scheme 4. Reagents and conditions: (i) Ref. 26 (60%); (ii) Ac2O, DMSO (97%); (iii) MeLi, THF (81%); (iv) Pd(OH)2, H2, dioxane (86%).
(vi)
Me
Me
COOH
O
O
OH
Me
HOH2C
(i)
[Si]OH2C
(ii)
[Si]OH2C
(iii)
O
O
O
HO
HO
(iv)
HO
HO
O
O
(v)
O
O
O
O
O
O
O
O
OH
CH2OH
OH
OH
CH2OH
CH2OH
8
28
29
30
31
4
Scheme 5. Reagents and conditions: (i) Ref. 31 (60%); (ii) tert-BuMe2SiCl, imidazole, DMF (90%); (iii) MeLi, THF, ꢀ78 ꢁC (97%); (iv) TBAF, THF
(96%); (v) Dowexꢂ 50WX8-100 ion-exchange resin, water, 45 ꢁC (98%); (vi) Dowexꢂ 50WX8-100 ion-exchange resin, water, 45 ꢁC (97%).
2.1.4. 1-Deoxy-D-tagatose 4. The literature procedures for
the synthesis of 1-deoxy-D-tagatose 4 use either starting
materials that are not readily available or involve several
synthetic steps.20b,29 1-Deoxy-D-tagatose 4 can be prepared
from D-lyxonic acid 8, a high yield product of alkaline oxy-
genation of D-galactose30 (Scheme 5).
peaks between the C2 carbon and the H1 and H3 protons.
The keto-form of each compound could be easily identified
by the chemical shift of the C2 carbon. In all cases, the two
pyranose forms could be identified by the C2 to H6/H60
cross-peaks in the HMBC spectra. The furanose forms
could then be identified by elimination, and some also gave
C2 to H5 cross-peaks in the HMBC spectra. The anomer-
icities of the pyranose and furanose forms were identified
by the pattern of NOE peaks from the H1 protons in the
NOESY spectra. For the pyranose forms, the ring confor-
The crude D-lyxonic acid 8 can be converted to isopropyl-
idene lactone 28 in 60% yield.31 5-O-Silylation of the pri-
mary alcohol in 28 gave the fully protected lactone 29,
which with methyl lithium afforded the protected tagato-
pyranose 30 in 89% yield over 2 steps. Initially the silyl
ether in 30 was removed by treatment with TBAF to ketal
31; subsequent acid hydrolysis of 31 gave 1-deoxy-D-taga-
tose 4 in 94% over two steps. However, treatment of 30
with Dowexꢂ 50WX8-100 ion-exchange resin removed
both the silyl and isopropylidene protecting groups, di-
rectly producing 1-deoxy-D-tagatose 4 in 98% yield. The
overall yield of 1-deoxy-D-tagatose 4 from the protected
lyxonolactone 28 is 87%.
3
mations could be determined from the values of the JHH
coupling constants, where available. The relative propor-
tions of each form were determined from the peak integrals
1
in the 1D H NMR spectra. For compounds 1, 2 and 3,
many 13C assignments have been reported18 although some
of these were uncertain and for 3 only three forms were re-
ported. Our assignments are in general agreement with the
previous values and resolve almost all the uncertainties.
1
2/3
The 13C and H chemical shifts and
J
coupling con-
HH
stants, and the proportions of each form, for 1, 2, 3 and
1
2,3-O-Isopropylidene-L-lyxono-1,5-lactone, the enantiomer
of 28, may be prepared on a multi-kilogram scale from D-
ribonolactone 10;22,32 thus 1-deoxy-L-tagatose may also be
prepared efficiently by this procedure.
4, are given in Tables 1–3. The 1D H NMR spectra are
shown in Figure 3.
2.2.1. 1-Deoxy-D-psicose. The 1D 1H NMR spectrum of 1
shows four forms at similar concentrations and one form at
about one third the concentration of the rest, later identi-
fied as the keto-form. All five spin-systems could be identi-
fied in the COSY spectrum, except for the H6 protons of
the keto-form. Complete 1H and 13C assignments of all five
forms could be made, expect for the C6 of the b-furanose
and keto-forms (the peaks are at 63.58 ppm and
63.63 ppm but could not been specifically assigned) and
the H6/H60 of the keto-form. The a-pyranose, b-pyranose
and b-furanose forms could be identified by cross-peaks
from the C2 resonance in the HMBC spectrum. The
NOESY spectrum identified the a-pyranose and a-furanose
forms through strong H1 to H3 and weak H1 to H4 NOEs,
and so the b-pyranose and b-furanose could be identified
2.2. NMR Studies on aqueous solutions of 1-deoxy-D-
ketohexoses
NMR analyses were carried out on 1, 2, 3 and 4 in D2O
solution, pD = 5.0, at a temperature of 30 ꢁC. All four
compounds gave complex spectra with either four (3) or
five (1, 2 and 4) different forms present, corresponding to
the a- and b-anomers of the furanose and pyranose forms,
and the open chain keto-form. In most cases, the H3–H6/
H60 proton spin-systems could be identified in the COSY
spectra and the equivalent carbon shifts determined di-
rectly from the HSQC spectrum. The C1 and C2 carbons
were identified in the HMBC spectra, usually from cross-

778
N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
Me
OH
Me
Me
OH
OH
OH
Me
OH
O
OH
OH
HOH2C
HOH2C
O
O
O
Me
OH
O
HO
HO
OH
HO
HO
HO
OH
OH
OH
CH2OH
1α−pyr
1β−pyr
1-keto
1α−fur
1β−fur
3
by elimination. For the b-pyranose form, the JHH cou-
another at about one tenth the concentration, later identi-
fied as the b-pyranose, and two more at about one twenti-
eth of the concentration, later identified as the a-furanose
and keto-forms. If the b-furanose form is present, it is at
less than one hundredth the concentration of the a-pyra-
nose (the signal-to-noise limit of the spectra). The major
2
pling constants are only consistent with a C5 ring confor-
mation. A C2 conformation would give a trans-di-axial
5
H5–H6 proton pair leading to a very large coupling con-
stant, which is not observed. The a-pyranose form shows
different couplings between H3, H4 and H5, suggesting
that the ring conformation is different to the b-pyranose
form, but the H5 to H6/H60 couplings could not be re-
solved and so the ring conformation could be determined
unambiguously. It is interesting to note that the four pyra-
nose and furanose forms all have similar concentrations
and thus stabilities.
1
form gives a H NMR spectrum that is strongly coupled,
1
with the exception of the H3 peak. The approximate H
chemical shifts of the other resonances could be measured
from the HSQC spectrum, where the overlapping peaks are
pulled apart in the 13C dimension. The large H3 coupling
indicates that H3 and H4 are trans-di-axial. This allows
the ring conformation to be modelled and approximate
1
1
JHH values to be estimated. Accurate H chemical shifts
2.2.2. 1-Deoxy-D-fructose. The 1D H NMR spectrum of
2 shows one major form, later identified as the b-pyranose,
and JHH coupling constants were obtained by simulating
Me
OH
Me
OH
OH
OH
Me
OH
O
HOH2C
HOH2C
O
O
O
Me
O
Me
OH
HO
HO
HO
OH
OH
OH
OH
OH
HO
HO
HO
CH2OH
2α−pyr
2β−pyr
2-keto
2α−fur
2β−fur
1
and four more at about one tenth of the concentration. All
five spin-systems could be identified in the COSY spectrum,
except for the H3 proton of one form, later identified as the
the 1D H NMR spectrum and optimising the parameters
to match the observed spectrum (Fig. 4). The three minor
spin-systems could be identified completely in the COSY
spectrum and complete 1H and 13C assignments made.
The C5 resonance of the b-pyranose is coincident with
the C5 of the dominant a-pyranose and this assignment
was confirmed by an HSQC–TOCSY. The a-pyranose
and b-pyranose forms could be identified by cross-peaks
from the C2 resonance in the HMBC spectrum. The
NOESY spectrum identified the a-pyranose and a-furanose
forms through strong H1 to H3 NOEs, and the b-pyranose
by a strong H1 to H60 NOE. For both the a- and b-pyra-
nose forms, the large 3JHH coupling constants are only con-
sistent with the 5C2 ring conformation, which gives H3, H4
and H5 as all axial. For the b-pyranose, this results in the
C1 methyl group being axial, consistent with the observed
H1 to H60 NOE. The 5C2 conformation places the
C3OH, C4OH and C5OH groups equatorial, and for the
b-anomer putting the methyl group equatorial does not
compensate for placing these three groups axial. However,
the axial methyl group does explain the a:b anomer ratio of
10:1.
1
a-pyranose. Complete H and 13C assignments of all five
forms could be made. The H3 of the a-pyranose could only
be assigned by elimination of all other peaks in the HSQC
spectrum. The a-pyranose, b-pyranose and b-furanose
forms could be identified by cross-peaks from the C2 reso-
nance in the HMBC spectrum. The NOESY spectrum
identified the b-pyranose and b-furanose forms through
strong H1 to H3 NOEs, and so the a-pyranose and a-fura-
nose could be identified by elimination. For the b-pyranose
3
form, the JHH coupling constants are only consistent
2
5
with a C5 ring conformation. A C2 conformation would
give a trans-di-axial H5–H6 proton pair leading to a very
large coupling constant, which is not observed. The
couplings of the a-pyranose could not be resolved and
so the ring conformation could not be determined
unambiguously.
1
2.2.3. 1-Deoxy-D-sorbose. The 1D H NMR spectrum of
3 shows one major form, later identified as the a-pyranose,
Me
Me
OH
OH
O
OH
HOH2C
O
O
O
HO
HO
HO
HO
Me
OH
OH
HO
HO
HO
Me
HO
OH
CH2OH
3α−pyr
3β−pyr
3-keto
3α−fur

N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
779
Me
OH
OH
O
Me
OH
OH
OH
Me
OH
OH
O
O
HOH2C
HOH2C
O
O
HO
HO
Me
OH
HO
HO
Me
OH
HO
HO
HO
OH
CH2OH
4α−pyr
4β−pyr
4-keto
4α−fur
4β−fur
2.2.4. 1-Deoxy-D-tagatose. The 1D 1H NMR spectrum of
4 shows one major form, later identified as the a-pyranose,
another at about one quarter the concentration, later iden-
tified as the b-pyranose, and three more at about one for-
tieth of the concentration. All five spin-systems could be
identified in the COSY spectrum, except for the H5 and
the b-furanose (75.55 ppm in 4 vs 71.7 ppm reported for
D-tagatose), the match between the 1-deoxy-D-tagatose
and D-tagatose pyranose 13C chemical shifts is very accu-
rate. For the a-pyranose form, the 3JHH coupling constants
are only consistent with a 5C2 ring conformation. This
gives a trans-di-axial H5–H60 proton pair leading to a very
large coupling constant, which is observed. The b-pyranose
form shows very different couplings between H4, H5, H6
and H60, only consistent with an equatorial H5 and thus
1
H6/H60 of the keto-form. Complete H and 13C assign-
ments of all five forms could be made, expect for the H5
and H6/H60 of the keto-form. The C5 and C6 of the
keto-form could only be assigned by elimination of all
other peaks in the 1D 13C spectrum. The a-pyranose and
b-pyranose forms could be identified by cross-peaks from
the C2 resonance in the HMBC spectrum. The NOESY
spectrum identified the a-pyranose form through the weak
H1 to H5 NOE, and the b-pyranose form through the weak
H1 to H4 NOE. One of the furanose forms shows a stron-
ger H1 to H3 NOE than the other, suggesting that it is the
b-anomer. The conformation of this was obtained by com-
paring the 13C chemical shifts of the two pyranose forms
versus the reported shifts of the two pyranose forms of
D-tagatose.33 With the exception of the C3 resonance of
2
a C5 ring conformation. Both these conformations place
the C1 methyl groups equatorial. This gives C3OH as axial
and C4OH and C5OH as equatorial for the a-anomer,
whereas for the b-anomer C4OH and C5OH are axial
and C3OH is equatorial. This explains the a:b anomer ratio
of 4:1.
3. Conclusion
Efficient syntheses of the four diastereomeric 1-deoxy-D-
ketohexoses have allowed the investigation of the
Table 1. 13C chemical shifts of 1-deoxy-hexuloses (referenced to acetone at 30.90 ppm)
Percentage
13C chemical shift (ppm)
C1
C2
C3
C4
C5
C6
1-Deoxy-psicose 1
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
21
20
25
27
ꢁ7
24.35
21.88
24.35
24.86
27.04
103.60
106.63
98.67
99.15
213.00
74.89
76.72
70.55
73.87
79.63
71.13
71.92
72.10
65.81
72.90
83.84
83.08
66.74
69.16
70.69
62.09
63.6a
58.89
64.70
63.6a
1-Deoxy-fructose 2
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ7
14
22.39
24.45
18.92
25.23
26.30
105.82
102.17
99.94
98.79
214.17
82.99
80.78
73.52b
72.66
77.52
77.09
75.29
71.57
70.15
71.44
81.91
81.06
67.63
69.86
71.28
61.80
63.27
64.10
63.89
63.48
ꢁ3
69
ꢁ7
1-Deoxy-sorbose 3
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ2.5
<0.8
86
24.42
—
25.12
17.89
26.44
101.80
—
98.37
100.17
213.35
80.09
—
75.67
76.45
78.27
75.99
—
74.34
74.68
71.94
77.84
—
70.29
70.29c
72.95
61.25
—
62.30
64.48
62.90
ꢁ8
ꢁ3.5
1-Deoxy-tagatose 4
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ2
ꢁ2
75
19
ꢁ2
22.49
18.69
24.74
24.35
27.71
105.92
103.16
98.90
99.31
215.24
77.64
75.55
73.56
68.86
77.24
71.94
71.83
71.47
71.56
71.72
79.23
80.01
66.70
69.75
71.21d
60.70
61.62
62.83
61.04
63.17d
Percentages were estimated from peak area in the 1H 1D spectrum.
a The b-furanose-C6 is either 63.58 ppm or 63.63 ppm. The other can be assigned to keto-C6 by elimination in the 1D 13C spectrum.
b Assigned by elimination in the 2D HSQC spectrum.
c Could only be assigned in the 2D HSQC-TOCSY spectrum.
d Assigned by elimination in the 1D 13C spectrum.

780
N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
Table 2. 1H chemical shifts of 1-deoxy-hexuloses (referenced to acetone at 2.220 ppm)
Percentage
1H chemical shift (ppm)
H1
H3
H4
H5
H6
H60
1-Deoxy-psicose 1
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
21
20
25
27
ꢁ7
1.453
1.473
1.376
1.476
2.268
3.856
3.865
3.488
3.627
4.398
4.091
4.349
4.131
4.008
4.085
4.066
3.950
3.824
3.899
3.774
3.714
3.782
3.788
4.025
nd
3.640
3.644
3.600
3.751
nd
1-Deoxy-fructose 2
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ7
14
1.408
1.467
1.357
1.459
2.279
3.963
3.858
3.67a
3.580
4.590
3.914
4.055
3.799
3.804
4.036
4.000
3.825
3.950
3.973
3.766
3.744
3.750
3.826
3.994
3.849
3.666
3.652
3.699
3.625
3.677
ꢁ3
69
ꢁ7
1-Deoxy-sorbose 3
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ2.5
<0.8
86
1.486
—
1.438
1.388
2.288
3.869
—
3.256
3.315
4.424
4.363
—
3.584b
3.491
4.088
4.226
—
3.586b
3.634
3.838
3.755
—
3.663b
3.872
3.752
3.674
—
3.632
3.376
3.65c
ꢁ8
ꢁ3.5
1-Deoxy-tagatose 4
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ2
ꢁ2
75
19
ꢁ2
1.453
1.442
1.429
1.412
2.307
3.984
3.974
3.721
3.729
4.293
4.541
4.3608
3.856
3.958
3.807
4.244
4.122
3.794
3.899
nd
3.771
3.858
3.697
4.120
nd
3.700
3.748
3.593
3.520
nd
Percentages were estimated from peak area in the 1H 1D spectrum.
a Assigned by elimination in the 2D HSQC spectrum.
b H4, H5, H6 and H60 are strongly coupled, assignments are based on simulation of the 1D spectrum.
c Could only be assigned from a partially overlapping peak in the 2D spectra.
possibility of Izumoring technology to be extended to 1-
and 6-deoxyhexoses; biological evaluation of the deoxy-
monosaccharides is currently in progress. The structure
of the free sugars, though a complex mixture of four or five
species, has been elucidated and may help to understand
features about the structures of other novel monosaccha-
rides in aqueous solution and thus their biological activity.
path length of 1 dm. Concentrations are quoted in
g 100 mLꢀ1. Elemental analyses were performed by the
microanalysis service of the Inorganic Chemistry Labora-
tory, Oxford. Infrared spectra were recorded on a
Perkin–Elmer 1750 IR Fourier Transform spectrophoto-
meter using thin films on NaCl plates (thin film). Only
the characteristic peaks are quoted. Low resolution mass
spectra (m/z) were recorded on VG MassLab 20–250,
Micromass BIOQ-II, Micromass Platform 1, Micromass
TofSpec 2E, or Micromass Autospec 500 OAT spectro-
meters and high resolution mass spectra (HRMS m/z) on
a Micromass Autospec 500 OAT spectrometer. The tech-
niques used were electrospray (ESI), chemical ionisation
(CI NH3), or atmospheric pressure chemical ionisation
(APCI). Nuclear magnetic resonance (NMR) spectra were
recorded on Bruker AMX 500 (1H: 500 MHz and 13C:
125.7 MHz) and Bruker DPX 400 and DQX 400 spectro-
meters (1H: 400 MHz and 13C: 100.6 MHz) in the deuter-
ated solvent stated. For spectra recorded in D2O acetone
was used as an internal reference. Residual signals from
other solvents were used as an internal reference. NMR
spectra for 1, 2, 3 and 4 were recorded on a Varian UnityI-
NOVA 500 (1H—500 MHz: 13C—125 MHz) spectrometer,
in D2O, pD = 5.0 0.1, with a probe temperature of
30 ꢁC. Chemical shifts were measured relative to internal
standards (1H—acetone at 2.220 ppm: 13C—acetone at
30.9 ppm). Two-dimensional gradient COSY, HSQC,
HMBC and HSQC–TOCSY spectra were used to aid
4. Experimental
4.1. General experimental
All commercial reagents were used as supplied. Tetra-
hydrofuran and N,N-dimethylformamide were purchased
dry from Aldrich chemical company in sure-seal bottles.
Methanol and pyridine were purchased dry from the Fluka
chemical company in sure-seal bottles over molecular
sieves. All other solvents were used as supplied (Analytical
or HPLC grade), without prior purification. The reactions
were performed under an atmosphere of either nitrogen or
argon, unless stated otherwise. Thin layer chromatography
(TLC) was performed on aluminium sheets coated with 60
F254 silica. Sheets were visualised using a spray of 0.2% w/v
cerium(IV) sulfate and 5% ammonium molybdate in 2 M
sulfuric acid. Flash chromatography was performed on
Sorbsil C60 40/60 silica. Melting points were recorded on
a Kofler hot block and are uncorrected. Optical rotations
were recorded on a Perkin–Elmer 241 polarimeter with a
1
assignment of H and 13C spectra. NOESY spectra were

N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
Table 3. Two and three-bond JHH values of 1-deoxy-hexuloses
781
Percentage
JHH (Hz)
H3–H4
H4–H5
H5–H6
H5–H60
H6–H60
1-Deoxy-psicose 1
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
21
20
25
27
ꢁ7
5.7
4.8
2.9
3.4
3.1
4.2
7.6
2.7
3.4
nd
3.4
nd
nd
1.6
nd
4.6
6.3
nd
2.3
nd
12.4
12.2
nd
12.7
nd
1-Deoxy-fructose 2
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ7
14
6.6a
8.1
nd
10.1
1.5
4.6a
7.3
nd
3.5
9.2
nd
nd
nd
0.9
nd
nd
nd
nd
1.6
nd
nd
nd
nd
12.8
nd
ꢁ3
69
ꢁ7
1-Deoxy-sorbose 3
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ2.5
<0.8
86
6.5
—
9
9.4
2.3
6.6
—
3.8
—
6.2
—
10b
10.3
6.2
12.3
—
11b
11.9
12.0
9b
5b
ꢁ8
9.2
6.3
5.6
3.9
ꢁ3.5
1-Deoxy-tagatose 4
a-Furanose
b-Furanose
a-Pyranose
b-Pyranose
Keto
ꢁ2
ꢁ2
75
19
ꢁ2
5.3
4.5
3.3
3.3
7.1
5.3
4.5
9.6
4.6
nd
nd
nd
5.6
2.0
nd
nd
nd
10.8
2.7
nd
nd
nd
10.8
13.1
nd
Percentages were estimated from peak area in the 1H 1D spectrum.
a H4 appears as a 6.6 Hz/4.6 Hz doublet of doublets, but H3 and H5 cannot be resolved in the 1D 1H spectrum.
b H4, H5, H6 and H60 are strongly coupled, J values are based on simulation of the 1D spectrum.
recorded with a 400 ms mixing time. 1D 1H NMR spectral
simulations were performed using the program gNMR
(Cherwell Scientific Publishing). All chemical shifts (d)
are quoted in ppm and coupling constants (J) in Hz.
found m/z 320.1891 [M+NH4]+, calcd for C14H30O5SiN:
320.1893. Found: C, 55.68, H, 8.65; C14H26O5Si requires
C, 55.60, H, 8.67.
4.2.2. 6-O-tert-Butyldimethylsilyl-1-deoxy-3,4-O-isopropyl-
idene-D-psicofuranose 12. Methyl lithium (1.6 M) in
Et2O (5.0 mL, 7.94 mmol) was added dropwise to a stirred
solution of fully protected lactone 11 (2.18 g, 7.22 mmol)
and THF (20 mL) at ꢀ78 ꢁC. The reaction was stirred at
this temperature for 1.5 h; water (20 mL) was slowly added
and the mixture was allowed to warm to room tempera-
ture. The product was extracted with EtOAc (3 · 30 mL),
dried (MgSO4) and concentrated in vacuo to afford lactol
4.2. 1-Deoxy-D-psicose 1
4.2.1. 5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-D-
ribono-1,4-lactone 11. tert-Butyldimethylsilyl chloride
(8.1 g, 53.8 mmol) was added to a stirred solution of lactone
1021 (5.0 g, 26.9 mmol), imidazole (3.66 g, 53.8 mmol) and
DMF (45 mL) and stirred at room temperature for 16 h.
The reaction mixture was concentrated in vacuo, water
(15 mL) was added and the compound was extracted with
CH2Cl2 (3 · 10 mL), dried (MgSO4) and concentrated in
vacuo. The resulting residue was purified by column chro-
matography (cyclohexane/EtOAc 7:1!4:1) affording com-
pound 11 as a white solid (7.9 g, 98%); mp 70–71 ꢁC [lit.34
12 as a colourless oil (2.25 g, 98%); A/B = 1:5 (from inte-
21
gration of 1H NMR signals); ½aꢂD ¼ ꢀ13:1 (c 0.99, CHCl3)
23
{lit.35 ½aꢂ ¼ ꢀ10:0 (c 1.5, CHCl3)}; mmax (film): 3406 cmꢀ1
(OH); dHD (400 MHz, CDCl3): 0.14 (3H, s, SiCH3), 0.15
(3H, s, SiCH3), 0.94 (9H, s, t-Bu), 1.35 (3H, s, CH3), 1.51
(3H, s, CH3), 1.52 (3H, s, CH3), 3.72 (1H, dd,
J5,6a = 2.1 Hz, J6a,6b = 11.1 Hz, H-6a), 3.76 (1H, dd,
J5,6b = 2.1 Hz, J6a,6b = 11.1 Hz, H-6b), 4.26–4.28 (1H, m,
H-5), 4.45 (1H, d, J3,4 = 5.9 Hz, H-3), 4.80 (1H, dd,
J3,4 = 5.9 Hz, J4,5 = 1.0 Hz, H-4); dC (100 MHz, CDCl3):
ꢀ5.8 (SiCH3), ꢀ5.7 (SiCH3), 18.2 (SiC(CH3)3), 21.2
(CH3), 25.2 (CH3), 25.8 (CH3), 26.6 (t-Bu), 64.9 (C-6),
82.0 (C-4), 85.8 (C-5), 88.0 (C-3), 106.6 (C-1), 112.4
(CMe2); HR CI-MS: found m/z 317.1790 [MꢀH]ꢀ, calcd
for C15H29O5Si: 317.1784. Found: C, 56.60; H, 9.49;
C15H30O5Si requires C, 56.57; H, 9.49.
23
25
mp 69–70 ꢁC]; ½aꢂD ¼ ꢀ49:0 (c 1.16, CHCl3) {lit.34 ½aꢂD
¼
ꢀ46:6 (c 0.80, CHCl3)}; mmax (film): 1775 cmꢀ1 (CO); dH
(400 MHz, CDCl3): 0.06 (3H, s, SiCH3), 0.08 (3H, s,
SiCH3), 0.88 (9H, s, t-Bu), 1.40 (3H, s, CH3), 1.48 (3H, s,
CH3), 3.81 (1H, d, J5a,5b = 11.3 Hz, H-5a), 3.88 (1H, dd,
J4,5b = 1.9 Hz, J5a,5b = 11.3 Hz, H-5b), 4.61–4.63 (1H, m,
H-4), 4.70–4.74 (2H, m, H-2, H-3); dC (100 MHz, CDCl3):
ꢀ5.8 (SiCH3), ꢀ5.6 (SiCH3), 18.2 (SiC(CH3)3), 25.6
(CH3), 25.8 (t-Bu), 26.8 (CH3), 63.0 (C-5), 75.8 (C-2), 78.5
(C-3), 82.3 (C-4), 113.0 (CMe2), 174.2 (C-1); HR CI-MS:

782
N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
Figure 4. (a) Simulated 1D 1H NMR spectrum of the a-pyranose form of
1-deoxy-D-sorbose, 3, used to obtain the peak chemical shifts and JHH
values. (b) Experimental 1H NMR spectrum of 1-deoxy-D-sorbose, 3. The
major component is the a-pyranose form. marks peaks assigned to the
*
minor component spin-systems.
4.3. 1-Deoxy-D-psicose 1
A mixture of compound 13 (2.5 g, 12.3 mmol) and Dowexꢂ
50WX8-100 ion-exchange resin (0.18 g) in water (25 mL)
was stirred for 16 h at room temperature, filtered and
concentrated in vacuo. The resulting residue was purified
by column chromatography (cyclohexane/EtOAc 1:1!
MeOH/EtOAc 1:9) affording 1-deoxy-D-psicose 1 as a
white solid (1.29 g, 65%); mp 99–100 ꢁC [lit.36 mp 97–
21
30
98 ꢁC]; ½aꢂD ¼ þ1:0 (c 0.99, H2O) {lit.20a ½aꢂD ¼ þ1:5 (c
20
5, H2O), lit.36 ½aꢂD ¼ ꢀ0:1 (c 0.88, H2O)}. The NMR of
Figure 3. 1D 1H NMR spectra of (a) 1, (b) 2, (c) 3 and (d) 4, showing the
spin-systems for the a-pyranose, b-pyranose, a-furanose, b-furanose and
keto-forms.
compound 1 is discussed above; HR ESI-MS: found m/z
163.0600 [MꢀH]ꢀ, calcd for C6H11O5: 163.0601.
4.4. 1-Deoxy-D-fructose 2
4.2.3. 1-Deoxy-3,4-O-isopropylidene-D-psicose 13. A 1 M
solution of TBAF in THF (9.0 mL, 9.0 mmol) was added
to a stirred solution of compound 12 (2.2 g, 6.91 mmol)
in THF (20 mL). The reaction was stirred at room temper-
ature for 16 h and then concentrated in vacuo. The result-
ing residue was purified by column chromatography
(cyclohexane/EtOAc 3:1!1:2) affording compound 13 as
a white solid (1.1 g, 79%); A/B = 14:1 (from integration
of H NMR signals); mp 72–74 ꢁC; ½aꢂD ¼ ꢀ15:0 (c 1.11,
CHCl3); mmax (film): 3406 cmꢀ1 (OH); dH (400 MHz,
CDCl3): 1.34 (3H, s, CH3), 1.50 (3H, s, CH3), 1.55 (3H,
s, CH3), 3.75 (2H, m, H-6a, H-6b), 4.29–4.31 (1H, m, H-
5), 4.48 (1H, d, J3,4 = 5.9 Hz, H-3), 4.90 (1H, d,
J3,4 = 5.9 Hz, H-4); dC (100 MHz, CDCl3): 22.3 (CH3),
24.9 (CH3), 26.5 (CH3), 63.7 (C-6), 82.1 (C-4), 86.2 (C-5),
87.0 (C-3), 106.8 (C-1), 112.4 (CMe2); HR CI-MS: found
m/z 203.0911 [MꢀH]ꢀ, calcd for C9H15O5: 203.0919.
Found: C, 52.75; H, 7.89; C9H16O5 requires C, 52.93; H,
7.90.
4.4.1. 2-O-tert-Butyldimethylsilyl-3,4-O-isopropylidene-D-
arabinono-1,5-lactone 16. tert-Butyldimethylsilyl chloride
(8.3 g, 55 mmol) was added to a solution of lactone 15
(9.58 g, 50 mmol) and imidazole (7.70 g, 113 mmol) in
dry DMF (90 mL) and the reaction mixture was stirred
at room temperature for 16 h. The solvent was evaporated
in vacuo and the residue was purified by flash column chro-
matography (cyclohexane/EtOAc 5:1) to afford the fully
21
1
protected lactone 16 as a white solid (13.8 g, 90%); mp
21
86–88 ꢁC; mmax (film): 1757 cmꢀ1 (CO); ½aꢂD ¼ ꢀ87:2 (c
1.0, CHCl3); dH (400 MHz, CDCl3): 0.13 (3H, s, CH3),
0.15 (3H, s, CH3), 0.89 (9H, s, t-Bu), 1.35 (3H, s, CH3),
1.44 (3H, s, CH3), 4.30 (1H, d, J2,3 = 2.9 Hz, H-2), 4.35
(1H, dd, J4,5a = 1.8 Hz, J5a,5b = 12.1 Hz, H-5a), 4.42 (1H,
dd, J2,3= 2.9 Hz, J3,4 = 7.5 Hz, H-3), 4.49 (1H, a-dt,
J = 1.9 Hz, J3,4 = 7.5 Hz, H-4), 4.73 (1H, dd,
J4,5b = 2.0 Hz, J5a,5b = 12.1 Hz, H-5b); dC (100 MHz,
CDCl3): ꢀ5.4 (SiCH3), ꢀ5.2 (SiCH3), 18.0 (SiC(CH3)3),
24.1 (CH3), 25.5 (t-Bu), 26.0 (CH3), 67.4 (C-5), 70.3

N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
783
(C-2), 71.3 (C-4), 76.4 (C-3), 110.4 (CMe2), 168.6 (C-1);
HR ESI-MS: found m/z 303.1623 [M+H]+, calcd for
C14H27O5Si: 303.1622.
HR ESI-MS: found m/z 163.0601 [MꢀH]ꢀ, calcd for
C6H11O5: 163.0607.
Method B: Silyl lactol 17 (2.19 g, 6.9 mmol) and Dowexꢂ
50WX8-100 ion-exchange resin (1.0 g) were suspended in
a solution of water/dioxane (2:1, 18 mL) and stirred for
40 h at room temperature. The reaction mixture was
filtered and partitioned between water (15 mL) and
EtOAc (15 mL). The water layer was washed with
EtOAc (2 · 15 mL) and concentrated in vacuo to afford
1-deoxy-D-fructose as an oil (1.05 g, 93%), which was
identical by 1H NMR to the compound prepared in
method A.
4.4.2. 3-O-tert-Butyldimethylsilyl-1-deoxy-4,5-O-isopropyl-
idene-D-fructose 17. Methyl lithium (1.6 M) in Et2O
(14.5 mL, 23.0 mmol) was added dropwise to a stirred solu-
tion of the fully protected lactone 16 (6.39 g, 21 mmol) at
ꢀ78 ꢁC. The reaction mixture was stirred at ꢀ78 ꢁC for
2 h; the reaction was then quenched by addition of water
(20 mL) and then warmed to room temperature. The water
phase was extracted with EtOAc (3 · 20 mL), the com-
bined organic phases were dried (MgSO4) and concentrated
in vacuo to afford the protected lactol 17 as a white solid
(6.62 g, 98%); mp 94–96 ꢁC; mmax (film): 3404 cmꢀ1 (OH);
4.7. 1-Deoxy-D-sorbose 3
21
½aꢂD ¼ ꢀ61:3 (c 1.0, CHCl3); dH (400 MHz, CDCl3): 0.13
4.7.1. 2,3,5-Tri-O-benzyl-D-xylono-1,4-lactone 26. A mix-
ture of acetic anhydride (8.3 mL) and dimethyl sulfoxide
(5.6 mL) was added to lactol 25 (2.7 g, 6.43 mmol) and stir-
red at room temperature for 24 h. Water (50 mL) was
added and the product extracted with CH2Cl2
(3 · 50 mL), dried (MgSO4) and concentrated in vacuo.
The resulting residue was purified by column chromatogra-
(3H, s, CH3), 0.19 (3H, s, CH3), 0.93 (9H, s, t-Bu), 1.36
(3H, s, CH3), 1.43 (3H, s, CH3), 1.53 (3H, s, CH3), 3.62
(1H, d, J3,4 = 5.8 Hz, H-3), 3.88 (1H, d, J5,6a = 0.7 Hz,
J6a,6b = 13.3 Hz, H6a), 4.11–4.13 (2H, m, H-4, H-6b),
4.19 (1H, ddd, J5,6a = 0.7 Hz, J5,6b = 2.5 Hz, J6a,6b
=
6.1 Hz, H-5); dC (100 MHz, CDCl3): ꢀ5.2 (SiCH3), ꢀ4.2
(SiCH3), 18.0 (SiC(CH3)3), 25.7 (SiC(CH3)3), 25.8 (CH3),
26.8 (CH3) 267.6 (CH3), 60.0 (C-6), 74.6 (C-5), 76.8 (C-
3), 96.4 (C-2), 109.1 (CMe2); HR ESI-MS: found m/z
341.1755 [M+Na]+, calcd for C15H30O5SiNa: 341.1760.
Found: C, 56.50, H, 9.49; C15H30O5Si requires C, 56.57,
H, 9.49.
phy (cyclohexane/EtOAc 8:1!6:1) affording compound 26
20
as a colourless oil (2.62 g, 97%); ½aꢂD ¼ þ89:0 (c 1.0,
CHCl3) {lit.27 [a]D = + 95.6 (c 1.13, CHCl3)}; mmax (film):
1789 cmꢀ1 (CO); dH (400 MHz, CDCl3): 3.72 (1H, dd,
J4,5a = 3.2 Hz, J4a,5b = 10.8 Hz, H-5a), 3.78 (1H, dd,
J4,5b = 2.8 Hz, J5a,5b = 10.8 Hz, H-5b), 4.38 (1H, t,
J2,3 = J3,4 = 7.2 Hz, H-3), 4.52–4.62 (5H, m, H-2, H-4,
3 · OCH2Ph), 4.67 (1H, d, Jgem = 12.0 Hz, OCH2Ph),
4.71 (1H, d, Jgem = 11.6 Hz, OCH2Ph), 5.07 (1H, d,
Jgem = 11.6 Hz, OCH2Ph); dC (100 MHz, CDCl3): 67.1
(C-5), 72.6 (OCH2Ph), 72.7 (OCH2Ph), 73.6 (OCH2Ph),
77.3 (·2), 79.4 (C-2, C-3, C-4), 127.5–128.5 (Ph), 137.1,
137.2, 137.6, (3 · quat. Ph), 173.3 (C-1); HR ESI-MS:
found m/z 436.2113 [M+NH4]+, calcd for C26H26O5N:
436.2118.
4.5. 1-Deoxy-4,5-O-isopropylidene-D-fructose 18
A 1 M solution of TBAF in THF (33.0 mL, 33.0 mmol)
was added to a stirred solution of silyl lactol 17 (8.85 g,
27 mmol) in dry THF (30 mL). After stirring overnight,
the solvent was evaporated in vacuo and the residue was
purified by flash column chromatography (cyclohexane/
EtOAc 1:4) to give ketal 18 as an oil (3.91 g, 69%); mmax
21
(film): 3417 cmꢀ1 (OH); ½aꢂD ¼ ꢀ102:2 (c 1.0, CHCl3);
23
23
½aꢂD ¼ ꢀ137:9 (c 1.04, MeOH), ½aꢂD ¼ þ132 for the L-
enantiomer; dH (400 MHz, CDCl3): 1.37 (3H, s, CH3),
1.51 (3H, s, CH3), 1.54 (3H, s, CH3), 2.79 (1H, br s,
OH), 2.97 (1H, br s, OH), 3.55 (1H, d, J3,4 = 6.8 Hz, H-
3), 3.94 (1H, d, J6a,6b = 13.3 Hz, H-6a), 4.13–4.18 (2H,
4.7.2.
3,4,6-Tri-O-benzyl-1-deoxy-D-sorbofuranose
27.
Methyl lithium (1.6 M) in Et2O (7.4 mL, 11.8 mmol)
was added dropwise to a stirred solution of lactone 26
(4.1 g, 9.80 mmol) and THF (40 mL) at ꢀ78 ꢁC. The reac-
tion was stirred at this temperature for 1.5 h, water (35 mL)
was slowly added and the mixture was allowed to warm to
room temperature. The product was extracted with EtOAc
(3 · 40 mL), dried (MgSO4) and concentrated in vacuo.
The resulting residue was purified by column chromatogra-
phy (cyclohexane/EtOAc 8:1!6:1) affording compound 27
as a colourless oil (3.46 g, 81%); A/B = 3:4 (from integra-
m, H-4, H-6b), 4.22 (1H, ddd, J4,5 = 5.7 Hz, J5,6a
=
0.6 Hz, J5,6b = 2.6 Hz, H-5). dC (100 MHz, CDCl3): 26.3
(CH3), 26.4 (CH3), 28.2 (CH3), 59.9 (C-6), 73.7 (C-5),
74.1 (C-3), 77.1 (C-4), 97.1 (C-2), 109.5 (CMe2); HR ESI-
MS: found m/z 227.0890 [M+Na]+, calcd for C9H16O5Na:
227.0895.
20
1
tion of H NMR signals); ½aꢂ ¼ ꢀ11:0 (c 1.0, CHCl3);
mmax (film): 3492 cmꢀ1 (OH); dDH (400 MHz, CDCl3): 1.50
(3H, s, CH3 B), 1.53 (3H, s, CH3 A), 3.66 (1H, dd,
J5,6a = 5.6 Hz, J6a,6b = 9.6 Hz, H-6a A), 3.71 (1H, dd,
J5,6a = 4.4 Hz, J6a,6b = 9.6 Hz, H-6b A), 3.72–3.78 (3H,
m, H-3 A, H-6a B, H-6b B), 3.91 (1H, d, J3,4 = 2.4 Hz,
H-3 B), 4.03 (1H, dd, J3,4 = 2.0 Hz, J4,5 = 4.4 Hz, H-4
A), 4.07 (1H, dd, J3,4 = 2.4 Hz, J4,5 = 4.8 Hz, H-4 B),
4.34–4.41 (2H, m, H-5 A, H-5 B), 4.46–4.63 (12H, m,
OCH2Ph), 7.25–7.39 (30H, m, Ph); dC (100 MHz, CDCl3):
21.5 (CH3 B), 26.5 (CH3 A), 68.2 (C-6 A), 68.8 (C-6 B),
73.2, 72.4, 72.7, 73.1, 73.4, 73.7 (6 · OCH2Ph), 787.6
4.6. 1-Deoxy-D-fructose 2
Method A: Isopropylidene lactol 18 (0.51 g, 2.50 mmol)
was dissolved in acetic acid/water (2:1, 9 mL), heated to
50 ꢁC and stirred for 16 h. The reaction mixture was con-
centrated in vacuo and the residue was purified by flash
column chromatography (EtOAc/MeOH 9:1) to afford 1-
deoxy-D-fructose 2 as an oil (0.22g, 53%); Rf 0.23
21
(EtOAc/MeOH 9:1); ½aꢂD ¼ ꢀ80:5 (c 1.0, H2O) {lit.37
23
23
½aꢂD ¼ ꢀ82:0 (c 4.4, H2O), lit.38 ½aꢂD ¼ ꢀ81:0 (c 1.5,
H2O)}. The NMR of compound 2 is discussed above;

784
N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
(C-5 A), 78.9 (C-5 B), 81.4 (C-4 B), 82.3 (C-4 A), 85.5
(C-3 A), 86.2 (C-3 B), 102.4 (C-2 A), 106.4 (C-2 B),
127.0–128.6 (Ph), 137.2–138.2 (6 · quat. Ph); HR ESI-
MS: found m/z 457.1984 [M+Na]+, calcd for C27H30O5Na:
457.1985.
J5,6a = 6.4 Hz, J6a,6b = 10.4 Hz, H-6a B). 3.77–3.81 (1H,
m, H-6a A), 3.88–3.94 (1H, m, H-6b A), 3.92 (1H, dd,
J5,6b = 5.2 Hz, J6a,6b = 10.4 Hz, H-6a B), 4.15–4.19 (1H,
m, H-5 B), 4.25 (1H, d, J3,4 = 6.0 Hz, H-3 A), 4.42 (1H,
d, J3,4 = 6.0 Hz, H-3 B), 4.72 (1H, dd, J3,4 = 6.0 Hz,
J4,5 = 3.6 Hz, H-4 A), 4.77 (1H, dd, J3,4 = 6.0 Hz,
J4,5 = 4.0 Hz, H-4 B); dC (100 MHz, CDCl3): ꢀ5.5, ꢀ5.3,
ꢀ5.2 (4 · CH3), 18.4 (SiC(CH3)3A), 18.5 (SiC(CH3)3 B),
21.0 (CH3 A), 22.0 (CH3 A), 22.6 (CH3 B), 24.7 (CH3 A),
24.9 (CH3 B), 25.9 (CH3 B), 25.9 (t-Bu A, t-Bu B), 60.8,
61.4 (C-6 A, C-6 B), 76.8 (C-5 A), 79.7 (C-5 B), 80.6 (C-4
A, C-4 B), 82.2 (C-3 A), 85.4 (C-3 B), 102.2 (C-2 A),
105.1 (C-2 B), 112.4 (CMe2 B), 112.7 (CMe2A); HR ESI-
MS: found m/z 341.1758 [M+Na]+, calcd for C15H30O5Si-
Na: 341.1755.
4.8. 1-Deoxy-D-sorbose 3
A solution of compound 27 (2.1 g, 4.84 mmol) in dioxane
(20 mL) was hydrogenated over 20% Pd(OH)2 on carbon
(210 mg) for 16 h at room temperature. The mixture was
filtered through Celite and concentrated in vacuo to afford
1-deoxy-D-sorbose 3 as a colourless solid (0.69 g, 86%); mp
152–154 ꢁC [lit.19 mp 149–151 ꢁC (for the L-enantiomer)];
20
½aꢂD ¼ þ49:0 (c 1.0, H2O) {lit.19 [a]D = ꢀ51 (c 0.7, H2O)
(for the L-enantiomer)}. The NMR of compound 3 is dis-
cussed above; HR ESI-MS: found m/z 187.0577
[M+Na]+, calcd for C6H12O5Na: 187.0577.
4.9.3. 1-Deoxy-3,4-O-isopropylidene-D-tagatose 31. A 1 M
solution of TBAF in THF (4.95 mL, 4.95 mmol) was added
to a stirred solution of silyl ether 30 (1.15 g, 3.81 mmol) in
THF (10 mL). The reaction was stirred at room tempera-
ture for 1 h, and concentrated in vacuo. The resulting res-
idue was purified by column chromatography
(cyclohexane/EtOAc 2:1!0:1) affording deoxytagatose 31
as a white solid (0.75 g, 96%); A/B = 1:4.4 (from integra-
4.9. 1-Deoxy-D-tagatose 4
4.9.1. 5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-D-
lyxono-1,4-lactone 29. tert-Butyldimethylsilyl chloride
(0.23 g, 1.91 mmol) was added to a stirred solution of lac-
tone 28 (0.3 g, 1.60 mmol), imidazole (0.13 g, 1.91 mmol)
and DMF (3 mL) and stirred at room temperature for
16 h. The reaction mixture was concentrated in vacuo,
water (15 mL) was added and the compound was extracted
with CH2Cl2 (3 · 10 mL), dried (MgSO4) and concentrated
in vacuo. The resulting residue was purified by column
chromatography (cyclohexane/EtOAc 7:1!4:1) affording
1
tion of H NMR signals); mp 119–121 ꢁC [lit.20b mp 123–
25
125 ꢁC]; [a]D = +21 (c 1.0, CHCl3) {lit.20b ½aꢂD ¼ þ16 (c
1.24, CHCl3)}; mmax (film): 3400 cmꢀ1 (OH); dH
(400 MHz, CDCl3): 1.31 (3H, s, CH3 B), 1.37 (3H, s,
CH3 A), 1.41 (3H, s, CH3 A), 1.49 (3H, s, CH3 B), 1.55
(6H, s, CH3 A, CH3 B), 3.76–3.79 (1H, m, H-5 A), 3.89–
3.94 (4H, m, H-6a A, H-6b A, H-6a B, H-6b B), 4.20–
4.24 (1H, m, H-5 B), 4.32 (1H, d, J3,4 = 6.0 Hz, H-3 A),
4.47 (1H, d, J3,4 = 6.0 Hz, H-3 B), 4.78 (1H, dd,
J3,4 = 6.0 Hz, J4,5 = 3.6 Hz, H-4 A), 4.84 (1H, dd,
J3,4 = 6.0 Hz, J4,5 = 4.0 Hz, H-4 B); dC (100 MHz, CDCl3):
22.2, 22.4, 24.6, 25.8, 26.0 (6 · CH3), 61.2 (C-6 A, C-6 B),
76.7 (C-5 A), 78.7 (C-5 B), 80.3 (C-4 A), 81.2 (C-4 B), 82.6
(C-3 A), 85.5 (C-3 B), 102.6 (C-2 A), 105.2 (C-2 B), 112.8
(CMe2B), 113.3 (CMe2A); HR ESI-MS: found m/z
203.0918 [MꢀH]ꢀ, calcd for C9H15O5: 203.0914.
silyl ether 29 as a white solid (0.44 g, 92%); mp 88–90 ꢁC
21
[lit.39 mp 90–91 ꢁC]; ½aꢂD ¼ þ58:0 (c 1.0, CHCl3) {lit.39
23
½aꢂD ¼ þ54:9 (c 1.03, CHCl3)}; mmax (film): 1775 cmꢀ1
(CO); dH (400 MHz, CDCl3): 0.09 (6H, s, 2 · SiCH3),
0.89 (9H, s, t-Bu), 1.38 (3H, s, CH3), 1.45 (3H, s, CH3),
3.93 (1H, dd, J4,5a = 6.4 Hz, J5a,5b = 10.8 Hz, H-5a), 3.97
(1H, dd, J4,5b = 6.0 Hz, J5a,5b = 10.8 Hz, H-5b), 4.49–4.54
(1H, m, H-4), 4.79–4.81 (2H, m, H-2, H-3); dC
(100 MHz, CDCl3): ꢀ5.4 (SiCH3), ꢀ5.4 (SiCH3), 18.3
(SiC(CH3)3), 25.8 (t-Bu), 26.8 (CH3), 26.9 (CH3), 60.9 (C-
5), 75.7, 76.0 (C-2, C-3), 79.4 (C-4), 114.0 (CMe2), 173.8
(C-1); HR ESI-MS: found m/z 325.1440 [M+Na]+, calcd
for C14H26O5SiNa: 325.1442.
4.10. 1-Deoxy-D-tagatose 4
Method A: A mixture of protected compound 31 (1.29 g,
4.05 mmol) and Dowexꢂ 50WX8-100 ion-exchange resin
(0.7 g) in dioxane/water (1:1, 12 mL) was stirred for 8 h
at 45 ꢁC. The mixture was allowed to cool to room temper-
ature, filtered and partitioned between water (40 mL) and
EtOAc (40 mL). The water layer was washed with EtOAc
(2 · 40 mL) and concentrated in vacuo to afford 1-deoxy-
D-tagatose 4 as a white solid (0.65 g, 98%). 1-Deoxy-D-tag-
atose 4 was recrystallised from a mixture of EtOAc and
MeOH to give colourless crystals as two polymorphs;17
4.9.2. 6-O-tert-Butyldimethylsilyl-1-deoxy-3,4-O-isopropyl-
idene-D-tagatofuranose 30. Methyl lithium (1.6 M) in
Et2O (0.8 mL, 1.27 mmol) was added dropwise to a stirred
solution of the protected lactone 29 (0.35 g, 1.16 mmol) in
THF (4 mL) at ꢀ78 ꢁC. The reaction was stirred at this
temperature for 1.5 h, water was slowly added (10 mL)
and the mixture was allowed to warm to room tempera-
ture. The product was extracted with EtOAc (3 · 10 mL),
dried (MgSO4) and concentrated in vacuo to afford the
protected tagatopyranose 30 as a colourless oil (0.36 g,
mp 136–138 ꢁC and 143–145 ꢁC [lit.29a mp 121–123 ꢁC,
22
lit.29b mp 130 ꢁC]; ½aꢂD ¼ ꢀ13 (c 2.0, H2O) {lit.29a
23
1
97%); A/B = 1:5 (from integration of H NMR signals);
½aꢂD ¼ ꢀ14 (c 2.0, H2O)}. The NMR of compound 4 is dis-
20
½aꢂD ¼ þ5:0 (c 1.0, CHCl3); mmax (film): 3403 cmꢀ1 (OH);
cussed above. HR ESI-MS: found m/z 163.0607 [MꢀH]ꢀ,
dH (400 MHz, CDCl3): 0.07 (6H, s, 2 · CH3 A), 0.08 (6H,
s, 2 · CH3 B), 0.89 (9H, s, t-Bu A), 0.90 (9H, s, t-Bu B),
1.31 (3H, s, CH3 A), 1.35 (3H, s, CH3 B), 1.38 (3H, s,
CH3 B), 1.44 (3H, s, CH3 A), 1.51 (3H, s, CH3 A), 1.52
(3H, s, CH3 B), 3.65–3.69 (1H, m, H-5 A), 3.80 (1H, dd,
calcd for C6H11O5: 163.0607.
Method B: A mixture of acetonide silyl ether 30 (0.44 g,
2.15 mmol) and Dowexꢂ 50WX8-100 ion-exchange resin
(0.7 g) in water (5 mL) was stirred for 2.5 h at 45 ꢁC, fil-

N. A. Jones et al. / Tetrahedron: Asymmetry 18 (2007) 774–786
785
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Financial support [to R.S.] provided through the European
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