A convenient access to the 1,5-anhydro forms of d-tagatose, l-rhamnulose and d-xylulose via 2-hydroxyglycal esters

Article abstract of DOI:10.1016/j.tetasy.2009.03.016

Zemplen methanolysis or a three-step protocol comprising hydroxylaminolysis, de-O-acetylation and deoximination smoothly and efficiently convert the benzoylated 2-hydroxy-d-glycals of d-galactose, l-rhamnose and d-xylose into their configurationally relat

Full text of DOI:10.1016/j.tetasy.2009.03.016

Tetrahedron: Asymmetry 20 (2009) 952–960
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A convenient access to the 1,5-anhydro forms of D-tagatose, L-rhamnulose
and D-xylulose via 2-hydroxyglycal esters q
*
Pan Jarglis, Volker Göckel, Frieder W. Lichtenthaler
Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, D-64287 Darmstadt, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Zemplén methanolysis or a three-step protocol comprising hydroxylaminolysis, de-O-acetylation and
Received 26 February 2009
Accepted 18 March 2009
Available online 22 April 2009
deoximination smoothly and efficiently convert the benzoylated 2-hydroxy-
rhamnose and -xylose into their configurationally related 1,5-anhydro-ketoses, thereby providing con-
venient access to the 1,5-anhydro forms of -tagatose, -rhamnulose and -xylulose. Invariably obtained
as amorphous solids, they are best characterized through their highly crystalline oximes.
Ó 2009 Elsevier Ltd. All rights reserved.
D-glycals of D-galactose, L-
D
D
L
D
Special edition of Tetrahedron: Asymmetry
in honour of Professor George Fleet’s 65th
birthday
1. Introduction
5 into the E-oxime 6 (82%), readily deprotectable by Zemplén
methanolysis to 7 (Scheme 1), both oximes feature useful proper-
ties such as high crystallinity and ease of isolation. Their deoxima-
Potential applications of 1,5-anhydro-D-fructose 1 as a powerful
antioxidant,2,3 an antimicrobial agent,2,3 a food additive3 or a phar-
maceutical4 have generated the elaboration of a series of chemical
tion with acetaldehyde/HCl either afforded 1,5-anhydro-
D-tagatose
2 or its triacetate 8 in excellent yields, yet as revealed by 1H and 13
C
and enzymatic syntheses, the most convenient being the
glucan lyase-induced degradation of starch,5 and the Zemplén
methanolysis of tetra-O-acetyl-2-hydroxy-
-glucal.1 Of other 1,5-
anhydro-ketoses, which are likely to have similar application pro-
files, only 1,5-anhydro- -tagatose 2 has become known, either
through a laborious seven-step chemical procedure starting from
-galactose,6 or by bacterial oxidation of 1,5-anhydro- -galactitol,7
whose acquisition from -galactose requires four steps.
Relying on the methodology developed for the obtention of 1,5-
anhydro-
-fructose,1 we here describe convenient procedures for
the conversion of -galactose, -rhamnose and -xylose into the
-tagatose 2, -rhamnulose 3 and
a
-1,4-
NMR data, both accumulated as mixtures of the keto and 2,2-dihy-
droxy (hydrate) forms in ratios varying between 5:2 and 2:1 in fa-
vour of the monohydrates. This tendency towards elaboration of
the monohydrate forms—in the case of 2 ꢀ 2ꢀH2O already previ-
ously observed by Freimund and Köpper7—is in distinct contrast
D
D
to that of the 4-epimeric 1,5-anhydro-
responding ulose triacetate, analogously prepared by hydroxylam-
inolysis of the 2-hydroxy- -glucal ester and subsequent
deoximation, was obtained in crystalline form (89%) as the unhy-
drated ketose,1 whilst 1,5-anhydro-
-fructose 1 fully adopts the
2,2-dihydroxy (hydrate) form in aqueous solution.
D-fructo compounds: the cor-
D
D
D
D
D
D
D
L
D
1,5-anhydro derivatives of
D
L
D-
OH
O
OH
O
xylulose 4, respectively.
HO
OH
OH
HO
2. Results and discussion
O
O
1
2
2.1. 1,5-Anhydro-D-tagatose
(D-tagato)
(D-fructo)
The methodology recently advanced for the straightforward lib-
eration of 1,5-anhydro- -fructose from 2-hydroxy-
-glucal esters,1
(direct Zemplén methanolysis or a three-step protocol involving
enol ester hydroxylaminolysis, de-O-acylation and deoximation)
HO
D
D
O
O
OH
Me
OH
HO
O
O
could readily be applied to the D-galacto analogue 5 with only min-
or experimental adaptations: Exposure to hydroxylamine hydro-
chloride in pyridine at ambient temperature smoothly converted
3
4
(L-rhamnulo)
(D-xylulo)
In the acetylated ulose 8, b-elimination of acetic acid is facili-
tated by the trans-diaxial disposition of H-3 and 4-OAc; thus con-
version to the enolone ester 11 already occurred on longer contact
q
Part 43 of the series ’Sugar-Derived Building Blocks’; for Part 42, see Ref. 1.
* Corresponding author. Tel.: +49 6151 162376.
E-mail address: lichtenthaler@chemie.tu-darmstadt.de (F.W. Lichtenthaler).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.016

P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
953
OAc
OAc
O
AcO
AcO
OR
O
AcO
AcO
AcO
AcO
RO
RO
OH
OAc
O
H2O
O
c
a
(6)
N
OH
O
OH
H2O
OAc
8
6 R = Ac
7 R = H
5
8
b
g
e
(7)
f
EtSH
d
OH
OR
OAc
HO
HO
OH
O
RO
RO
HO
HO
SEt
O
OH
O
O
H2O
h
(10)
OH
H2O
SEt
O
AcO
O
9 R = Ac
10 R = H
2
2
11
i
Scheme 1. Reactions and conditions: (a) NH2OHꢀHCl/pyridine, 15 h, rt, 82%; (b) NaOMe/MeOH, 20 min, rt, 78%; (c) acetaldehyde/HCl in MeCN, 6 h, rt, 95%; (d) NaOMe/MeOH,
2 h at ꢁ15 °C?rt, 84%; (e) acetaldehyde/HCl in MeCN, 5 h, rt, 83%; (f) EtSH (BF3, 15 min, rt, 61%; (g) NaOAc/acetone, 1 h, rt, 91%; (h) CdCO3/HgCl2 in water, 30 min, rt, 69%; (i)
NaOMe/MeOH, 3 h, 0 °C, 87%.
with silica gel or, for preparative purposes, by briefly stirring with
sodium acetate in acetone. Mercaptalization was readily effected
by exposure to ethanethiol/HCl to provide 9, which could also be
The well-crystallizing dibenzoate of 1,5-anhydro-
15 could be procured in either one of two ways: through hydrox-
ylaminolysis of the -rhamnal ester 12 and subsequent transoxi-
L-rhamnulose
L
converted into 1,5-anhydro-
to 10 and subsequent desulfurization. By far the most simple gen-
eration of 1,5-anhydro- -tagatose, however, proved to be the di-
rect Zemplén methanolysis of the 2-acetoxygalactal triacetate 5
which, when performed at low temperature, proceeded without
b-elimination, obviously due to the formation of the monomethan-
olate 8ꢀMeOH as the first intermediate rather than the ketose 8
which under the slightly basic Zemplén conditions would readily
undergo b-elimination to enolone 11.
D
-tagatose 2 by Zemplén methanolysis
mation of the oxime 14?15, or, alternatively, by tributyltin
hydride-promoted debromination of the rhamnosulosyl bromide
13. Not unexpectedly, b-elimination of benzoic acid in 15 was
readily induced either by brief heating in pyridine or by stirring
with sodium acetate in acetone to provide the single-stereogen-
ic-centre dihydropyranone 16, a versatile enantiopure six-carbon
building block (Scheme 2).
D
Exposure of dihydropyranone 16 to Zemplén methanolysis did
not liberate the respective 2,3-diketone (or enol forms thereof),
but gave the 2-dimethyl acetal 17 in a uniform reaction, conceiv-
ably proceeding through addition of methoxide onto the car-
bonyl group and subsequent 4-O-?5-O-benzoyl migration (to
the methyl acylal 18) and replacement of the benzoyloxy group
by OMe (18?17). Such a course receives some credence by the
detection of 19 by 1H NMR and TLC on brief methanolysis, and
by the obtention of benzoyl-allomaltol 22 on the attempt to ano-
merically refunctionalize dihydropyranone 16 by photobromina-
tion with NBS (Scheme 3). As observed for the 6-
benzoyloxymethyl analogue of 16,9 the bromine radical either
enters the anomeric position next to the carbonyl group (?20)
or the one vinologous thereto (?21), each being capable of elab-
2.2. 1,5-Anhydro-L-rhamnulose
Being readily accessible in a four-step, large scale-adaptable
protocol from -rhamnal dibenzo-
-rhamnose,8 the 2-benzoyloxy-
L
L
ate 12 was similarly subjected to Zemplén methanolysis which
proved to be somewhat capricious due to its low solubility in
methanol and, hence, comparatively long contact to the basic con-
ditions (NaOMe/MeOH). However, when working at low tempera-
ture (ꢁ10?0 °C) in high dilution and short-reaction times (3–
5 min), the parent sugar, 1,5-anhydro-D-rhamnulose 3 could be re-
leased without appreciable formation (TLC) of side products; it was
characterized as an amorphous solid, which in aqueous solution
adopted the 2,2-dihydroxylated (monohydrate) form 3ꢀH2O.
orating the
c
-pyrone system via benzoyl group shifts10 (arrows
in 20 and 21, respectively).
BzO
O
H2O
4 steps [8]
46%
Me
HO
Me
HO
O
O
a
L-Rhamnose
Me
OH
HO
HO
O
OR
OH
BzO
3
H2O
3
12
b
c
Br
O
Me
BzO
Me
Me
BzO
O
O
O
d
g
f
Me
BzO
OMe
(15)
BzO
O
BzO
X
O
OMe
O
13
14 X = NOH
15 X = O
17
16
e
Scheme 2. Reactions and conditions: (a) NaOMe/MeOH, ꢁ10?0 °C, 84%; (b) NBS/MeOH in CH2Cl2, 30 min, rt, 75%;8 (c) NH2OH/pyridine in EtOH, 5 d, rt, 86%; (d) Bu3SnH/AIBN
in toluene, 5 h, 90 °C, 71%; (e) acetaldehyde/HCl in MeCN, 15 h, rt, 82%; (f) pyridine in CHCl3, 5 min reflux, 87%; (g) NaOMe/MeOH, 5 min, rt, 68%.

954
P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
O
Ph
OMe
H
O
OBz
O
RO
MeO
O
O
NaOMe
MeOH
MeO
O
Me
O
Me
O
Me
19 R = Bz
18
16
17 R = Me
NBS
hν
O
O
Ph
Ph
O
O
O
O
O
BzO
or
Br
Me
H
H
O
Br
O
O
Me
H
Me
20
21
22
Scheme 3.
2.3. 1,5-Anhydro-
D
-xylulose
With respect to the conformations adopted by 1,5-anhydro-D-
xylulose 4 and its derivatives 25–30, 1H NMR data—most notably
their J3,4 and J4,5 values—reveal the uloses 4 and 28, respectively,
and their monohydrates to be in the 4C1 conformation, whilst the
couplings of the oximes 25–27 based on J3,4 and J4,5 values of
2.5–4 Hz are best interpreted by their adoption of the 0S2 boat-
Application of the methodology developed for hydroxylaminol-
ysis and Zemplén deacylation to the 2-hydroxy- -xylal esters 23
D
and 24 proceeded in a straightforward manner providing the E-oxi-
mes 25–27, the ulose dibenzoate 28, as well as the respective diet-
hyldithio acetals 29 and 30, in crystalline form each and in
satisfactory yields. The only peculiarity observed was that the form
in which the ulose dibenzoate 28 accumulated on deoximation of
26 with acetaldehyde depended on the workup procedure: the ke-
tose as such or its 2,2-diol (hydrate form), was separately isolable,
and characterized by their distinctly different 1H and 13C NMR
data, the former showing its C-2 resonance at 199.4, the hydrate
at 91.7 ppm (Scheme 4).
twist or skew conformation.
OH
O
O
BzO
BzO
RO
RO
OH
O
28
5
H2O (R = H)
28 H2O (R = Bz)
OR
H4
Liberation of the unprotected 1,5-anhydro-D-xylulose 4 could
be effected from the oxime 27 by transoximation, from the dithio-
acetal 30 by desulfurization and, preparatively most straightfor-
25 R = Ac
26 R = Bz
27 R = H
O
H3
RO
NOH
ward, by Zemplén methanolysis of the 2-acetoxy-
D-xylal
diacetate 23. The resulting 1,5-anhydro- -pentulose was charac-
D
terized by NMR to be the monohydrate in aqueous solution, whilst
in DMSO-d6 or in pyridine-d5, spectra turned out to be unusually
complex indicating the presence of dimeric forms.
3. Conclusion
Simple protocols based on direct Zemplén methanolysis or on a
three-step hydroxylaminolysis/deacylation/deoximation sequence
O
O
O
have been elaborated to convert 2-hydroxyglycal esters of
actose, -rhamnose and -xylose into their configurationally re-
lated 1,5-anhydro-ketoses. The convenient access thereby
provided to -tagatose, -rhamnulose and -xylulose in their 1,5-
D-gal-
a
b
OR
OR
OBz
L
D
(26)
RO
RO
BzO
OR
N OH
O
28
D
L
D
23 R = Ac
24 R = Bz
25 R = Ac
26 R = Bz
27 R = H
anhydro forms now renders them available for evaluation of their
application profiles, most notably of their potential antioxidant
properties. Moreover, the methodologies developed for their acqui-
sition are apt to be applicable to any other 2-hydroxyglycal ester,
c
f
g
(24)
d
e
(27)
such as, for example, to the peracetates of 2-hydroxy-
D–D-gulal
32,11 2-hydroxy- -allal 3311,12 and 2-hydroxy-cellobial 34,13 inas-
D
O
O
O
OR EtS
OH
h
much as their enol ester hydroxylaminolysis smoothly provides
the respective E-oximes 35–37 in crystalline form each. Thus, the
low temperature Zemplén de-O-acetylations elaborated should
similarly proceed in a straightforward manner furnishing, for
HO
RO
O
O
BzO
EtS
29 R = Bz
4
31
i
30 R = H
example, 1,5-anhydro-D-sorbose from 32 and its D-psico analogue
Scheme 4. Reactions and conditions: (a) NH2OHꢀHCl in THF/acetate buffer pH 4.5,
20 h, rt or in pyridine 10 d, rt, 79% 25, 75% 26; (b) acetaldehyde/2 M HCl in MeCN,
18 h, rt, 92%; (c) NaOMe/MeOH, 1 h, rt, 63%; (d) NaOMe/MeOH, 2 h, ꢁ15 °C?rt, then
H+, 69%; (e) acetaldehyde/2 M HCl in MeCN, 5 h, rt, 78%; (f) EtSH/BF3 in CHCl3,
5 min, rt, 88%; (g) pyridine in CHCl3, reflux, 10 min, 82%; (h) CdCO3/HgCl2 in water,
30 min, rt, 75%; (i) NaOMe/MeOH, 3 h, rt, 95%.
from 33. In similar fashion, the readily accessible disaccharide-de-
rived 2-hydroxyglycal esters 3413 and their benzoylated maltal,
cellobial and lactal analogues14 are to generate the underlying 4-
O-glycosylated 1,5-anhydro-D-fructoses, should there be need for
their availability.

P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
955
the axially-oriented protons H-1 and H-3 show minimally changed
chemical shifts (cf. Table 1), whereas the equatorial H-1 exhibits a
distinct downward shift of 0.6 ppm when going from ulose to
oxime. This clearly indicates that the oxime hydroxyl group is
pointing towards the anomeric carbon rather than C-3, hence
establishing the E-configuration for oximes 40–45.
OAc
O
OAc
O
OAc
O
AcO
OAc
OAc
O
O
OAc
AcO
AcO
OAc
OAc
OAc
AcO
34
AcO
32
33
OAc
OR
O
RO
H1e
H1a
1
R = H
OAc
RO
38 R = Ac
39 R = Bz
OAc
O
OAc
O
O
O
H3
OR
AcO
OAc
OAc
O
R
H
R’
H
Ac
Bz
βAc4Glc
βBz4Glc
αBz4Glc
βBz4Gal
O
N
OH
AcO
AcO
40
41
42
37
43
44
45
OAc
N
OH
N OH
AcO
Ac
Bz
Ac
Bz
Bz
Bz
O
37
R'O
RO
35
(D-sorbo)
36
(D-psico)
H1e
OH
H1a
AcO
OAc
N
H3
4. On the E-geometry of 1,5-anhydroketose oximes
Oximes of pyranoid 2-ketosugars, that is, -glycosiduloses of
type I, invariably assume the Z geometry with the oxime hydroxyl
pointing in the direction of the anomeric centre, proof being de-
rived from the significant deshielding of the equatorially oriented
H-1 by the oxime hydroxyl which finds expression in an downfield
shift of 0.9–1 ppm when going from the parent ketose to its
oxime.15 The Z assignments were in fact corroborated by several
X-ray structures.16
In the D-tagato and L-rhamnulo cases the respective downfield
shifts for H-1e from ketose to oxime are even higher (0.8 ppm),
which can only be rationalized by the E-geometry of the oximes.
In the D-xylulo case 28 (Table 1, X = O) and 26 (X = NOH) there is
a downfield shift of both, H-1e (0.23) and H-1a (0.27 ppm)—obvi-
ously due adaption of the 0S2 boat-twist conformation of the pyra-
noid ring, wherein the oxime hydroxyl exerts its deshielding
equally on either of the anomeric hydrogens.
a
-D
The E-geometry of 1,5-anhydroketoximes can similarly be de-
rived from the 13C chemical shifts of the carbons vicinal to the car-
bonyl respectively, oximinocarbonyl group. As documented by vast
literature data,17,18 the 13C resonances of the carbonyl and both
vicinal carbons shift upfield on oxime formation, with the effect
for the carbon on the same side as the N–OH group being greater
than that for the other. In the case of 3-methyl cyclohexanone
and its oxime these upfield shifts are 15.8 ppm for the oxime-OH
deshielded carbon, yet still 9.6 ppm for the other (Fig. 1).
OAc
O
X
AcO
AcO
RO
RO
O
H1e
OH
H1e
OH
N
N
X
H
II
I
X = OAlkyl, OAc, Cl
X = H, CH3, CH2OR
R = H, Ac, Bz
OH
O
N
Compounds differing from I only by the absence of an anomeric
substituent, that is, 1,5-anhydroketoximes of type II, would simi-
larly be anticipated to generally adopt the E-oxime geometry. This
conjecture could readily be verified by comparison of 1H and 13C
NMR data of the oximes and their parent 2-oxo analogues. As
41.5
25.7
41.5
31.9
1
1
6
6
2
2
Figure 1. 13C chemical shifts (ppm) of cyclohexanone versus those of its oxime.17
The upfield shift for C-2 from ketone to oxime is significantly larger (15.8) than for
C-6 (9.6 ppm).
clearly evident from the juxtaposition of the D-fructo-configured
oximes 37 and 40–45 to their 2-ulose counterparts 38 and 39,
Table 1
1H NMR data for H-1 and the anomeric hydrogens of 1,5-anhydroketoses and acylated derivatives in comparison to those of their E-oximes
Configuration
1,5-Anhydroketoses
X = O
1,5-Anhydroketose E-oximes
X = N–OH
Ref.
H-1e
H-1a
H-3
Solvent
H-1e
H-1a
H-3
Solvent
D
-Fructo
1a
38
39
40
41
42
37
43
44
45
5.03
4.88
5.17
4.91
4.96
4.90
4.91
3.89
4.04
4.22
4.25
5.54
6.02
6.80
6.13
6.12
5.89
D2O
DMSO-d6
CDCl3
DMSO-d6
CDCl3
CDCl3
1
1
4.25
4.57
4.09
4.33
5.41
6.19
CDCl3
DMSO-d6
1
b
4.03
c
14
14
14
b
c
c
CDCl3
D-Tagato
2
8
4.04
4.38
3.92
4.09
4.45
5.88
D2O
DMSO-d6
7
6
4.85
5.01
3.68
3.94
4.23
5.76
DMSO-d6
DMSO-d6
b
b
L
-Rhamnulo
15
4a
4.33
4.16
5.86
CDCl3
14
5.12
4.00
5.94
CDCl3
b
b
b
D
-Xylulo
27
25
26
4.48
4.52
4.67
4.04
4.28
4.48
3.90
5.36
5.86
DMSO-d6
CDCl3
CDCl3
28
4.44
4.21
6.13
Me2CO-d6
a
1,5-Anhydro-
Data from this paper.
Signal not resolved from glycosyl protons.
D
-fructose 1 and its D-xylulo analogue 4 adopt in water (D2O) the 2,2-dihydroxy(hydrate) form, and hence are not suited for comparison.
b
c

956
P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
Table 2
13C NMR data (ppm) for C-1 through C-3 of 1,5-anhydro-ketoses and acylated derivatives compared to those of their E-oximes
Configuration
1,5-Anhydroketoses
C-2
1,5-Anhydroketoximes
C-2
Compd.
C-1
C-3
Solvent
Compd.
C-1
C-3
Solvent
D-Fructo
D-Fructo
D-Fructo
D-Tagato
D-xylulo
1a
38
39
2
–
–
–
40
41
42
7
61.5
62.9
62.5
59.4
61.7
156.1
150.6
151.3
153.7
151.4
72.6
69.7
71.7
69.5
69.8
D2O
DMSO-d6
CDCl3
DMSO-d6
CDCl3
72.5
72.5
72.5
67.5
196.9
197.9
210.1
199.4
76.9
77.5
76.1
77.3
CDCl3
DMSO-d6
D2O
28
Me2CO-d6
26
a
1,5-Anhydro-D-fructose 1 forms dimers in the solid state and the hydrate in water, hence is unsuited for comparison.
Analogous shift differences are observed for the 13C resonances
of the four ketose/oxime examples listed in Table 2: in the -fructo
and -tagato configured compounds upfield shifts of 10–13 ppm
for the vicinal carbon deshielded by the oxime hydroxyl, and 6–
7 ppm only for the other, thus equally proving the E-geometry of
showing complete conversion within 20 min with the exclusive
formation of 7 (Rf = 0.5 in nPrOH/water 7:3). The solution was di-
luted with 200 mL of MeOH and neutralised by stirring with Dow-
ex 50 WX8, H+ form for 10 min. The suspension was filtered and
the resin was washed with methanol. Filtrate and washings were
evaporated to a volume of about 50 mL whereupon crystallization
occurred. The precipitate was redissolved by warming to allow
smooth crystallization: 3.05 g (78%) of 7 as fine needles of mp
D
D
the 1,5-anhydroketoximes. In the D-xylulose case though this up-
field shift difference between ketose and ketoxime is nearly equal-
ized—understandably, as the 0S2 skew-boat conformation of the
pyranoid ring levels the deshielding effects.
172–173 °C; ½a 2D0
ꢃ
¼ ꢁ12:8 (c 1, MeOH), ½a D22
¼ ꢁ5:0 (c 1, H2O);
ꢃ
lit.6: mp 176–179 °C;
½
aꢃD
¼ ꢁ9:2 (c 0.5, MeOH). 1H NMR
(300 MHz, DMSO-d6) after two reevaporations from D2O to elimi-
nate H, OH couplings: d 3.47 (3H-m, 5-H, 6-H2), 3.68 (1H-d, 1-
Ha), 3.82 (dd, 1H, 4-H), 4.23 (dd, 1H, 3-H), 4.85 (1H, H-1e), 10.83
(1H-s, NOH), J1,1 = 13.9, J3,4 = 3.3, J4,5 = 0.5 Hz. 13C NMR (25.2 MHz,
DMSO-d6): d 59.4 (C-1), 60.4 (C-6), 69.5 and 69.9 (C-3 and C-4),
78.3 (C-5), 153.7 (C-2). MS (FD): m/e = 177 (M+). Anal. Calcd for
C6H11NO5 (177.16): C, 40.68; H, 6.26; N, 7.91. Found: C, 40.43; H,
6.19; N, 7.80.
5. Experimental
5.1. General
Melting points were determined with a Bock hot-stage micro-
scope and are uncorrected. Optical rotations were measured on a
Perkin–Elmer 241 polarimeter at 20 °C using a cell of 1 dm path
length; concentration (c) in g/100 mL and solvent are given in paren-
theses. 1H and 13C NMR spectra were recorded on a Bruker ARX-300
spectrometer in CDCl3. Mass spectra were acquired on Varian MAT
311 spectrometer. Microanalyses were determined on a Perkin–El-
mer 240 elemental analyzer. Analytical thin layer chromatography
(TLC) was performed on precoated Merck plastic sheets (0.2 mm Sil-
ica Gel60 F254)with detectionby UV light(254 nm) andeither spray-
ing with H2SO4 (50%) or by dipping into sulphuric acid/anisaldehyde
reagent [containing anisaldehyde (1 mL), concd H2SO4 (9 mL) HOAc
(10 mL) and MeOH (85 mL)] followed by heating at 110 °C for
10 min. Column and flash chromatography was carried out on Fluka
Silica Gel 60 (70–230 mesh) using the specified eluents.
5.4. 3,4,6-Tri-O-acetyl-1,5-anhydro-D-tagatose 8
Stirring of 7 in acetonitrile solution (4.60 g, 15.2 mmol, in
50 mL) with acetaldehyde (3.0 mL) and 1 M HCl (15 mL) for 6 h
at ambient temperature followed by dilution with water
(250 mL), extraction with EtOAc (3 ꢂ 100 mL) and removal of the
solvent from the organic layer gave a glassy syrup (4.5 g, 95%),
which on the basis of 1H NMR data in DMSO-d6 comprised a 2:3
mixture of the keto form 8 and its monohydrate which due to its
propensity for elimination of acetic acid to the enolone 11 in con-
tact with silica gel was not attempted to separate. 1H NMR
(300 MHz, DMSO-d6), keto form: d 2.03, 2.06 (3H and 6H-s, 3
AcCH3), 4.05 and 4.08 (two 1H-m, A and B part of an ABX system,
6-H2), 4.09 and 4.38 (two 1H-d, 1-H2), 4.54 (1H-m, X part of an ABX
system, 5-H), 5.67 (dd, 1H, 4-H), 5.88 (1H-d, 3-H), J1,1 = 14.5,
J3,4 = 4.0, J4,5 = 0.9 Hz; monohydrate: 4.99 (1H-d, 3-H), 5.23 (dd,
1H, 4-H), 7.39 and 7.60 (two 1H-s, 2 OH, exchangeable with D2O,
J3,4 = 5.3, J4,5 = 5.8 Hz.
5.2. 3,4,6-Tri-O-acetyl-1,5-anhydro-D-tagatose E-oxime 6
To a solution of hydroxylamine hydrochloride (7.4 g) in pyridine
(50 mL) was added 10.0 g (30.3 mmol) of 2-acetoxy- -galactal triac-
D
etate 519,20 and the mixture was stirred at ambient temperature for
15 h, followed by pouring into water (350 mL). Extraction with
CHCl3 (5 ꢂ 100 mL) and consecutive washing of the combined ex-
tracts with 2 N H2SO4 (3 ꢂ 100 mL), water (100 mL), satd NaHCO3
solution (100 mL) and water (50 mL), drying (Na2SO4) and evapora-
tion to dryness in vacuo left a solid residue which was recrystallized
from EtOH: 7.51 g (82%) of 6 as well-formed prisms of mp 154–
5.5. 1,5-Anhydro-D-tagatose 2
156°C; ½a 2D3
ꢃ
¼ ꢁ44:3 (c 0.5, CHCl3). 1H NMR (300 MHz, DMSO-d6):
5.5.1. Deoximation of oxime 7
Acetaldehyde (1.7 mL, 30 mmol) and 1 M HCl (15 mL) were
added to a suspension of 7 (1.43 g, 8 mmol) in acetonitrile
(50 mL) and the mixture was stirred for 5 h at ambient tempera-
ture. The resulting clear solution was diluted with water (15 mL)
and neutralised by stirring with an acidic resin (Amberlite IR 120
H+ form) and the filtrate was evaporated to dryness in vacuo. The
d 2.01, 2.03, 2.08 (three 3H-s, 3 AcCH3), 3.94 (1H-d, 1-Ha), 3.98
(2H-m, 6-H2), 4.18 (1H-dd, 5-H), 5.01 (1H-d, 1-He), 5.39 (1H-d, 4-
H), 5.76 (1H-d, 3-H), 11.32 (1H-s, NOH), J1,1 = 14.5, J3,4 = 3.7,
J4,5 = 0 Hz. 13C NMR (75.5 MHz, DMSO-d6): d 20.2, 20.38, 20.42 (3
AcCH3), 60.3 (C-1), 62.1 (C-6), 68.2 and 68.9 (C-3, C-4), 73.5 (C-5),
147.6 (C-2), 168.9, 169.9, 170.0 (3 AcCO). Anal. Calcd for C12H17NO8
(303.26): C, 47.52; H, 5.65; N, 4.62. Found: C, 47.58; H, 5.57; N, 4.53.
syrupy residue was then eluted from
a silica gel column
(3 ꢂ 45 cm) with n-propanol/water (7:3), to give upon evaporation
of the product-carrying eluates in vacuo, finally at 0.01 mm, 1.08 g
(83%) of 2 as an amorphous solid of Rf = 0.5 in 7:3 n-PrOH/water
5.3. 1,5-Anhydro-D-tagatose E-oxime 7
(extended spot); ½a D21
ꢃ
¼ ꢁ7:9 (c 0.9, H2O); lit.6: ½a D
ꢃ ¼ ꢁ6:8 (c 1.1,
Fifty millilitres of a 1 M NaOMe/MeOH solution were cooled to
0 °C with stirring and oxime 6 (3.03 g, 10 mmol) was added, TLC
MeOH); MS (FD): m/e = 162 [M+], 163 (M+1), 180 (M+H2O). Anal.

P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
957
Calcd for C6H10O5 (162.14): C, 44.44; H, 6.22. Found: C, 44.29 H,
6.17.
5.7. 1,5-Anhydro-D-tagatose diethyldithioacetal 10
NMR data in D2O indicate an approximate 3:2 equilibrium be-
tween ketose and monohydrate form, as previously observed by
Freimund and Köpper7 for a product prepared by enzymatic oxida-
A solution of 1.54 g (4.1 mmol) of triacetate 9 in 40 mL of 0.1 M
methanolic sodium methoxide was stirred at 0 °C for 3 h and sub-
sequently neutralised by stirring with Dowex WXl (H+ form). Fil-
tration and evaporation of the filtrate in vacuo afforded a syrup,
which was chromatographed on silica gel (2 ꢂ 30 cm column) by
elution with 2:1 toluene/EtOAc to result in 910 mg (87%) of 10 as
tion of 1,5-anhydro-D
-galactitol. 1H NMR (500 MHz, D2O), keto
form: 3.58 (2H-m, 6-H2), 3.92 (2H-m, H-1a, H-5), 4.04 (1H-d, H-
1e) 4.20 (1H-dd, H-4), 4.45 (1H-d, H-3); J1,1 = 14.8; J3,4 = 3.9,
J4,5 = 0.9 Hz; hydrate: 3.23 (1H-d, H-1a), 3.43 (1H-m, H-5), 3.50
and 3.55 (AB part of an ABX system, 6-H2), 3.54 (1H-d, H-3), 3.59
(1H-d, H-1e), 3.76 (1H-dd, H-4); J1,1 = 12.0, J3,4 = 3.8; J4,5 = 1.0. 13C
NMR (75.2 MHz, D2O). d 210.1 (C-2, ketose), 92.5 (C-2, hydrate),
79.9/78.6 (C-5), 76.1/72.1 (C-3), 72.5/72.6 (C-1), 71.7/69.5 (C-4),
61.5/61.3 (C-6).
a colourless syrup of ½a D20
¼ ꢁ57 (c 1.1, MeOH); Rf = 0.43 in n-buta-
ꢃ
none satd with water. 13C NMR (25.2 MHz, D2O): d 61.9 (C-6), 62.4
(C-2), 67.4 (C-4), 72.9 (C-1), 74.6 and 81.5 (C-3 and C-5). MS (FD):
m/e = 268 (M+), 269 (M+ + 1). Anal. Calcd for C10H20O4S2 (268.4): C,
44.75; H, 7.51. Found: C, 44.70; H, 7.62.
5.8. (6S)-4-Acetoxy-6-acetoxymethyl-2H-pyran-3(6H)-one 11
5.5.2. De-O-acetylation of 2-acetoxy-D-galactal triacetate 5
A solution of 519,20 (2.0 g, 6 mmol) in dry MeOH (100 mL) was
cooled to about ꢁ15 °C (salt–ice mixture) followed by the addition
of 5 mL of 1 M NaOMe/MeOH solution and stirring of the mixture
for 2 h at ꢁ15 °C, whereafter the solution was allowed to warm
to 0 °C (ꢄ1 h). Neutralization was then effected by stirring with
Amberlite IR 120, H+ form (10 min). Filtration and evaporation to
A 1.0 g portion of 8 and freshly molten NaOAc (2.0 g) were stir-
red in 50 mL of dry acetone for 1 h at room temperature. Filtration
and evaporation of the filtrate in vacuo, and purification of the
resulting syrup on silica gel column (2 ꢂ 30 cm) by fast elution
with 3:1 n-hexane/EtOAc afforded 1.03 g (91%) of enolone 11 as
a
colourless syrup;
½
a 2D0
ꢃ
¼ ꢁ42:7 (c 1.2, CHCl3); lit.7,21
:
dryness in vacuo gave
a
slightly yellowish, syrupy residue
½
a 2D0
ꢃ
¼ ꢁ17:7 (c 0.34, CH2Cl2);1
½
aꢃD
¼ ꢁ43:7 (c 1.7, CHCl3).17 1H
(910 mg) which was eluted from a Sephadex LH 20 column
(2 ꢂ 30 cm) with water. Collecting the product-carrying eluates
and removal of the solvent in vacuo, finally at 0.05 Torr, gave
820 mg (84%) of 2 as an amorphous solid, identical with the prod-
uct described under 5.5.1.
and 13C NMR data corresponded with those reported.7,21
5.9. 1,5-Anhydro-
fructose) 3
L-rhamnulose (1,5-anhydro-6-deoxy-L-
Five mmol (2.29 g) of 128 was dissolved in 150 mL of anhy-
drous MeOH with slight warming, then cooled to ꢁ5 °C with vig-
orous stirring followed by the addition of 5 mL of 1 M NaOMe/
MeOH solution. The mixture was allowed to warm to 0?+5 °C
any precipitate occurring being dissolved within 10 min. After
about 20 min (TLC monitoring with n-PrOH/water 9:1 or 7:3, Rf
of product 0.65 and 0.72, respectively), the reaction was
quenched by stirring with methanol-washed Amberlite IR 120
(H+ form). Filtration and evaporation of the filtrate to dryness
in vacuo left a syrup which was dissolved in water and eluted
from a Sephadex LH 20 column (2 ꢂ 30 cm) with water. Evapora-
tion of the product-carrying eluates in vacuo, finally at 0.1 Torr,
5.5.3. Demercaptalization of dithioacetal 10
To a solution of 1.0 g (2.7 mmol) of 10 in 20 mL of water were
added CdCO3 (1.8 g, 10 mmol) and HgCl2 (1.4 g, 5 mmol), and the
mixture was stirred for 30 min at ambient temperature. The insol-
uble materials are subsequently removed by filtration through a
layer of silica gel. The filtrate was then saturated with H2S, and
after another filtration with suction through silica gel the filtrate
was neutralised with a weakly basic ion exchange resin (Lewatit
MP 7080). Removal of the resin and concentration to dryness in va-
cuo left a viscous syrup which was purified by elution from a
Sephadex LH 20 column (2 ꢂ 30 cm) with water. Removal of the
solvent in vacuo from the product-carrying eluates and drying of
the residue at 0.1 Torr gave 425 mg (69%) of a colourless foam,
identical (TLC, NMR) with the product described under 5.5.1.
gave 405 mg (69%) of
3
as an amorphous solid. 1H NMR
(500 MHz, D2O): d 1.20 (3H-d, CH3), 3.16 (1H-t, H-4), 3.34 (1H-
ddd, H-5), 3.37 (1H-d, H-1a), 3.44 (1H-d, H-3), 3.63 (1H-d, H-
1e); J1,1 = 12.3, J3,4 = J4,5 = 9.3, J5,6 = 6.2 Hz. 13C NMR (125.7 MHz,
D2O): d 17.4 (C-6), 72.3 (C-1), 74.6 (C-4), 77.0 and 77.1 (C-3
and C-5), 93.2 (C-2): Anal. Calcd for C6H10O4 (146.14): C,
49.31; H, 6.90. Found: C, 49.24; H, 6.96.
5.6. 3,4,6-Tri-O-acetyl-1,5-anhydro-D-tagatose
diethyldithioacetal 9
Ethanediol (3.7 mL, 50 mmol) and BF3-etherate solution (10 mL)
were added to a solution of 1.9 g (ꢄ10 mmol) of anhydrotagatose
triacetate 8 (mixture of ulose and hydrate as obtained under 5.4)
in CHCl3 (30 mL). After 15 min of stirring at ambient temperature,
the solution was diluted with 50 mL of CHCl3, neutralised by wash-
ing with 2 M NaOH and water (3 ꢂ 30 mL), dried (Na2SO4) and
evaporated to dryness in vacuo. The resulting syrup, 2.23 g (61%)
of 9, was chromatographically uniform (Rf = 0.59 in toluene/ace-
tone 2:1) and was used for the deacetylation (cf. below).
5.10. 3,4-Di-O-benzoyl-1,5-anhydro-
L-rhamnulose E-oxime 14
2-Benzoyloxy-
L
-rhamnal dibenzoate 128 (9.20 g, 20 mmol)
was added to a solution of NH3ꢀHCl (3.5 g, 50 mmol) in 1:1 pyr-
idine/EtOH (100 mL) and the mixture was kept at ambient tem-
perature for one week and subsequently taken to dryness in
vacuo. The residue was dissolved in CH2Cl2 (100 mL) and succes-
sively washed with 2 M HCl (20 mL) and satd NaHCO3 solution
(2 ꢂ 20 mL), dried (Na2SO4), followed by removal of the solvent
in vacuo and crystallization of the residue by trituration with
EtOH: 6.35 g (86%) of 14 as colourless needles; mp 159–160 °C,
The analytical sample was purified by elution from silica gel
with 40:1 CH2Cl2/EtOAc: syrup of ½a D23
ꢃ
¼ þ15:7 (c 1, CHCl3). 1H
NMR (300 MHz, DMSO-d6): d 1.14 and 1.16 (two 3H-t, 2 EtS-
CH3), 2.00 and 2.05 (6H- and 3H-s, 3 AcCH3), 2.65 (4H-m, 2 EtSCH2),
3.74 and 3.99 (two 1H-d, 1-H2), 3.99 (1H-m, 5-H), 4.17 (2H-m, 6-
H2), 5.25 (1H-dd, 4-H), 5.31 (1H-d, 3-H), J1,1 = 12.5, J3,4 = 3.7,
J4,5 = 3.2 Hz. 13C NMR (25.2 MHz, CDCl3): d 60.3 (C-2), 61.2 (C-6),
66.6 (C-4), 70.3 (C-1), 73.9 and 74.6 (C-3 and C-5). Anal. Calcd for
C16H26O7S2 (394.5): C, 48.71; H, 6.64. Found: C, 48.70; H, 6.72.
½
a 2D1
ꢃ
¼ þ123 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): d 1.35
(3H-d, CH3), 3.75 (1H-m, 5-H), 4.00 and 5.12 (two 1H-d, 1-H2),
5.36 (1H-t, 4-H), 5.94 (1H-d, 3-H), 7.4–8.0 (10H-m, 2 C6H5),
8.44 (1H-s, NOH); J1,1 = 16.0, J3,4 = J4,5 = 8.0, J5,6 = 5.9 Hz. Anal.
Calcd for C20H19NO6 (369.36): C, 65.03; H, 5.19; N, 3.79. Found:
C, 64.91; H, 5.10; N, 3.71.

958
P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
5.11. 3,4-Di-O-benzoyl-1,5-anhydro-L-rhamnulose 15
5.14. 5-Benzoyloxy-2-methyl-4H-pyran-4-one (O-benzoyl-
allomaltol) 22
5.11.1. Deoximation of oxime 14
Stirring of 14 (3.69 g, 10 mmol) in acetonitrile solution
(50 mL) with acetaldehyde (2.3 mL, 40 mmol) and 2 M HCl
(5 mL, 10 mmol) was done overnight at ambient temperature
followed by dilution with water (200 mL) and extraction with
EtOAc (3 ꢂ 100 mL). Removal of the solvent from the extracts
gave a syrup which crystallized from ether: 2.80 g (79%) of 15
N-Bromosuccinimide (360 mg, 2.5 mmol) and BaCO3 (0.5 g)
were added to a solution of enolone 16 (465 mg, 2 mmol) in
EtOH-free CCl4 (40 mL), and the mixture was irradiated with a
450 W IR lamp with vigorous stirring for 20 min, whereafter TLC
in 19:1 CH2Cl2/EtOAc revealed the absence of educt in favour of
several products. The major one, 22, was isolated by filtration,
evaporation of the filtrate to dryness and solution of the residue
from a silica gel column (2 ꢂ 20 cm) with 19:1 CH2Cl2/EtOAc and
crystallization from diisopropyl ether: 205 mg (44%) of 22 as nee-
dles of mp 128–129 °C. The product was identical (mixed mp, 1H
NMR) with an authentic sample.22
as colourless needles of mp 123–124 °C, ½a D21
¼ þ109:9 (c 1.1,
ꢃ
CHCl3). 1H NMR (300 MHz, CDCl3): d 1.41 (3H-d, CH3), 4.11
(1H-m, 5-H), 4.16 and 4.33 (two 1H-d, 1-H2), 5.56 (1H-t, 4-H),
5.86 (1H-d, 3-H), 7.4 and 8.0 (two m,
2 C6H5); J1,1 = 15.8,
J3,4 = J4,5 = 7.9 Hz. Anal. Calcd for C20H18O6 (354.34): C, 67.79; H,
4.90. Found: C, 67.69; H, 4.93.
5.15. 3,4-Di-O-acetyl-1,5-anhydro-D-threo-pent-2-ulose E-
oxime 25
5.11.2. Reductive debromination of ulosyl bromide 13
To a solution of 138 (1.1 g, 2 mmol) in toluene (50 mL) were
added azoisobutyronitrile (50 mg, 0.3 mmol) and tributyltin hy-
dride (880 mg, 3 mmol) and the mixture was heated for 5 h at
90 °C, followed by cooling and washing with 10% aqueous KF
solution (3 ꢂ 20 mL) and water. Drying (MgSO4) and removal
of the solvent in vacuo left an oily residue, uniform by TLC,
which was freed from tin compounds by rapid chromatography
on a silica gel column (2 ꢂ 20 cm) with 2:1 ether/n-pentane
applying pressure to effect this operation within 10 min. The
syrup remaining after evaporation of the eluate containing 15
crystallized on trituration with CH2Cl2/n-hexane to afford
505 mg (71%), identical with the product described under
5.11.1.
A mixture of 2,3,4-tri-O-acetyl-1,5-anhydro-D–D-threo-pent-1-
enitol 2320 (1.03 g, 4 mmol), hydroxylamine hydrochloride (1.0 g),
tetrahydrofuran (10 mL) and acetate buffer (pH 4.5) was stirred for
20 h at ambient temperature, followed by gradual neutralization
with satd NaHCO3 solution and extractions with CHCl3
(3 ꢂ 20 mL). The CHCl3 extracts were washed with water, dried
(Na2SO4) and taken to dryness in vacuo. The syrupy residue crystal-
lized on trituration with EtOH: 730 mg (79%) of 25 as needles of mp
103–104 °C; ½a 2D2
ꢃ
¼ ꢁ58:3 (c 0.3, CHCl3). 1H NMR (300 MHz, CDCl3):
d 2.06 and 2.08 (two 3H-s, 2 Ac CH3), 3.92 (1H-dd, 5-Hax), 4.28 and
4.52 (two 14.1 Hz-d, 1H each, 1-H2), 4.66 (1H-dd, 5-Heq), 4.90
(1H-sx, 4-H), 5.36 (1H-d, 3-H), 11.48 (1H-s, NOH), J1,1 = 14.1,
J3,4 = 5.0, J4,5 = 3.1 and 5.0, J5,5 = 12.2 Hz. Anal. Calcd for C9H13NO6
(231.20): C, 46.75; H, 5.67; N, 6.06. Found: C, 46.70; H, 5.59; N, 6.09.
Longer contact of crude 15 with silica gel, for example, several
hours on column purification, induced b-elimination of benzoic
acid to the dihydropyran one 17; it may be isolated in yields over
80% by slow elution of a silica gel column (3 ꢂ 30 cm) with 2:1
ether/n-pentane.
5.16. 3,4-Di-O-benzoyl-1,5-anhydro-D-threo-pent-2-ulose E-
oxime 26
Hydroxylamine hydrochloride (10.0 g, 1.4 mmol) was added to a
solution of 2,3,4-tri-O-benzoyl-1,5-anhydro- -threo-pent-1-enitol
5.12. (6S)-4-Benzoyloxy-6-methyl-2H-pyran-3(6H)-one 16
D
2420 (10.0 g, 22.5 mmol) in pyridine (60 mL) and the mixture was
stirred for 1 h and then stood for 5 d at ambient temperature, fol-
lowed by stirring into water (1.5 mL). The precipitate formed was fil-
tered off, washed with water, dried (Na2SO4) and recrystallized from
CHCl3/EtOH to give 9.4 g (75%) of colourless needles of mp 194–
196 °C, which consisted of a 10:1 mixture (1H NMR) of the E-oxime
26 (Rf = 0.56 in 10:1 CH2Cl2/EtOAc) and the respective Z-isomer
(Rf = 0.49).
Pyridine (0.3 mL) was added to a solution of 15 (1.42 g, 4 mmol)
in CHCl3 (10 mL) and the mixture was heated for 5 min, followed
by evaporation to dryness in vacuo. Crystallization of the residue
from MeOH afforded 810 g (87%) of 16 as colourless needles; mp
116 °C; ½a 2D1
ꢃ
¼ ꢁ10:5 (c 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): d
1.49 (3H-d, CH3), 4.26 and 4.42 (two 1H-d, 2-H2), 4.76 (1H-ddt,
6-H), 6.72 (1H-d, 5-H), 7.4-8.2 (5H-m, C6H5); J2,6 = J5,6 = 1.9,
J6;CH ¼ 6:9 Hz. Anal. Calcd for C13H12O4 (232.23): C, 67.23; H,
3
A 500 mg sample was subjected to elution from a silica gel col-
umn (2 ꢂ 20 cm) with CH2Cl2/EtOAc30:1, the firstfractions contain-
5.21. Found: C, 67.26; H, 5.15.
ing 220 mg of the pure E-isomer; mp 198–199 °C; ½a D23
¼ ꢁ111 (c
ꢃ
0.6, CHCl3). 1H NMR (500 MHz, CDCl3): d 3.89 and 4.13 (two 1H-dd,
5.13. (2S)-5,5-Dimethoxy-2-methyl-tetrahydropyran-4-one 17
5-H2), 4.48 and 4.67 (two 1H-d, 1-H2), 5.37 (1H-ddd, 4-H), 5.86
(1H-d, 3-H), J1,1 = 15.1, J3,4 = 5.6, J4,5 = 3.4 and 4.5, J5,5 = 12.7 Hz. 13
C
Two millilitres of a 1 M NaOMe/MeOH solution were stirred
into a suspension of enolone 16 (465 mg, 2 mmol) in dry MeOH
(10 mL) and the mixture was neutralised after 5 min by addition
of Amberlite IR (H+ form). Filtration and evaporation of the filtrate
to dryness gave a colourless oil, which can be purified by chroma-
tography (2.5 ꢂ 25 cm silica gel column, elution with CCl4/EtOAc
2:1) or distillation at 65 °C/0.3 Torr: 235 mg (68%) of 17;
NMR (125.7 MHz, CDCl3): d 61.7 (C-1), 67.4 (C-5), 69.8 (C-3), 71.0
(C-4), 151,4 ((C-2). Anal. Calcd for C19H17NO6 (355.33): C, 64.22; H,
4.82; N, 3.94. Found: C, 64.08; H, 4.75; N, 3.84.
The further fractions consisted of E/Z-mixtures in various ratios,
which were not further separated. 1H NMR (500 MHz, CDCl3 for Z-
form): d 4.10 (2H-m, 5-H2), 4.28 and 4.37 (two 13.0 Hz-d, 1H each,
½
a 2D0
ꢃ
¼ ꢁ þ 154:6 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3): d
1-H2), 5.27 (1H-ddd, 4-H), 6.50 (d, 1H, 3-H), J1,1 = 13.0, J3,4
=
1.33 (3H-d, CH3), 2.43 and 2.71 (two 1H-d, 3-H2), 3.29 and 3.39
J4,5 = 1.3-1.4 Hz; most distinct difference between the E/Z-isomers
is the chemical shift for H-3: 5.86 (E) vs. 6.50 ppm for the Z-form.
(two 3H-s, 2 OCH3), 3.76 (1H-ddq, 2-H), 3.38 and 4.24 (two 1H-d,
6-H2); J2,3 = 2.5 and 11.0, J
¼ 6:1, J3,3 = 13.3, J6,6 = 12.4 Hz. 13C
2;CH3
NMR (75.5 MHz, CDCl3): d 21.5 (CH3), 41.4 (C-3), 49.9 (OCH3),
71.0 (C-6), 75.6 (C-2), 98.3 (C-5), 202.7 C-4. MS (FD, 5 mA): m/
e = 174 (M+). Anal. Calcd for C8H14O4 (174.18): C, 55.17; H, 8.10.
Found: C, 54.98; H, 8.03.
5.17. 1,5-Anhydro-D-threo-pent-2-ulose E-oxime 27
Oxime 26 (3.55 g, 10 mmol, in the form of its 10:1 E/Z-mixture
obtained above) was dissolved in 50 mL cooled (0 °C) 1 M NaOMe/

P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
959
MeOH solution and stirred for 1 h. Subsequent neutralization with
Dowex 50 WX8 (H+ form) filtration and evaporation to dryness in
vacuo left a syrup which was dissolved in water (30 mL) and
washed with ether to remove methyl benzoate. The syrup remain-
ing after evaporation of the aqueous phase to dryness in vacuo
crystallized from water/i-propanol. Recrystallization from the
same solvents afforded 0.93 g (63%) of 27 as fine prisms of mp
(1H-d, 3-H), 3.60 and 3.94 (two 1H-dd, 5-H2), J1,1 = 12.4, J3,4 = 8.7,
J4,5 = 7.9 and 4.7 Hz. 13C NMR (75.5 MHz, D2O): d 66.9 (C-1), 70.2
(C-4), 71.9 (C-3), 78.2 (C-5), 92.5 (C-2). Anal. Calcd for C5H8O4
(132.11): C, 45.45; H, 6.10. Found: C, 45.34; H, 6.00.
5.19.2. De-O-acetylation of 2-acetoxy-D-xylal diacetate 23
A methanolic solution of 2316 (1.29 g, 5 mmol, in 80 mL) was
cooled to ꢁ15 °C (ice–salt mixture), and upon dropwise addition of
1 M NaOMe/MeOH (5 mL) the mixture was allowed to come to
0 °C within about 1 h (TLC monitoring with n-PrOH/water 7:3). Sub-
sequent quenching by stirring methanol-washed Amberlite IR 120
(H+ form) into the still cold solution. Filtration, evaporation of the fil-
trate in vacuo, elution of the residue from an LH 20 Sephadex column
(2 ꢂ 25 cm) with water, evaporation of the product-carrying eluates
and drying, finally at 0.1 Torr, gave 440 mg (67%) of 4 as a foam, iden-
tical with respect to 1H and 13C NMR data with the product described
above.
129.5–130.5 °C; ½a D20
ꢃ
¼ þ14:8 (c 1, H2O). 1NMR (300 MHz, DMSO-
d6): d 3.45 and 3.76 (two 1H-dd, AB part of ABX system, 5-H2),
3.54 (1H-m, X part, 4-H), 3.90 (1H-dd, 3-H), 4.04 and 4.48 (two
1H-d, 1-H2), 5.01 and 5.32 (two 1H-d, 2 OH), 10.83 (1H-s, NOH);
J1,1 = 13.8, J3,4 = 4.2, J4,5 = 2.2 and 3.6, J5,5 = 11.6 Hz. 13C NMR
(75.47 MHz, DMSO-d6): d 58.8 (C-1), 67.3 (C-5), 69.8 (C-3), 70.1
(C-4), 153.5 (C-2). Anal. Calcd for C5H9 NO4 (147.13): C, 40.81; H,
6.17; N, 9.52. Found: C, 40.72; H, 6.12; N, 9.40.
5.18. 3,4-Di-O-benzoyl-1,5-anhydro-D-pentulose 28
Desulfurization of dithioacetal by stirring an aqueous solution
with CdCO3/HgCl2 as described for 10?2 and analogous workup
similarly gave 4 in 75% yield.
5.18.1. Monohydrate
Pentulose oxime 26 (10.0 g, 30 mmol), in the form of its 10:1 E/Z-
mixture as obtained above, was stirred with a mixture of acetonitrile
(250 mL), 2 M HCl (18 mL) and acetaldehyde (10 mL) at ambient
temperature for 18 h and subsequently poured into water (1 L) with
vigorous stirring. The resulting precipitate was filtered, washed with
water and dried (CaCl2). Dissolution in the minimum amount of
methanol and trituration with 2:1 cyclohexane/ether resulted in
crystallization: 9.3 g (92%) of 28-monohydrate; mp 89–90 °C,
5.20. 3,4-Di-O-benzoyl-1,5-anhydro-D-threo-pentulose
diethyldithioacetal 29
Ethanthiol (7.0 mL) and BF3 etherate (5 mL) were added to a sus-
pension of ulose monohydrate 28ꢀH2O (3.2 g, 8.9 mmol) in CHCl3
(30 mL). The mixture was stirred for 5 min followed by dilution with
CHCl3 (100 mL)and consecutivewashings with 2 M NaOHand water
(3 ꢂ 30 mL). Drying (Na2SO4) and evaporation in vacuo left a syrup
which was purified by elution from silica gel (3 ꢂ 30 cm column)
with 20:1 cyclohexane/EtOAc. Removal of the solvents from the
product-carrying fractions (Rf = 0.57 in 2:1 cyclohexane/EtOAc)
½
a 2D0
ꢃ
¼ ꢁ131 (c 0.6, CHCl3). 1NMR (300 MHz, DMSO-d6): d 3.47 and
3.66 (two 11.5 Hz-d, 1H each, 1-H2), 3.54 and 4.06 (two 1H-ddd, 5-
H2), 5.23 (1H-ddd, 4-H), 5.38 (d, 1H, 3-H), 6.20 and 6.28 (two 1H-s,
2 OH, exchangeable with D2O), 7.4-8.1 (10H-m, 2 C6H5); J1,1 = 11.5,
J3,4 = 9.3, J4,5 = 5.0 and 9.7, J5,5 = 11.0 Hz. 13C NMR (75.5 MHz,
DMSO-d6): d 66.7 (C-1), 70.1 (C-4), 78.5 (C-5), 75.9 (C-3), 91.7 (C-
2). Anal. Calcd for C19H16O6ꢀH2O (358.33): C, 63.68; H, 5.06. Found:
C, 63.54; H, 4.95.
afforded 3.5 g (88%) of 29 as a colourless syrup; ½a D20
¼ ꢁ121:4 (c
ꢃ
0.8, CHCl3). 1NMR (300 MHz, DMSO-d6): d 1.10 and 1.24 (two 3H-t,
SEt-CH3), 2.70 (4H-m, SEt-CH2), 3.72 and 4.21 (two 1H-dd, 5-H2),
3.90 and 4.07 (two 1H-d, 1-H2), 5.69 (1H-ddd, 4-H), 5.80 (1H-d, 3-
H); J1,1 = 12.6, J3,4 = 9.5, J4,5 = 5.5 and 9.5 Hz, J5,5 = 10.5 Hz. 13C NMR
(75.47 MHz, DMSO-d6): d 14.1 and 14.2 (2 SEt-CH3), 22.4 and 22.5
(2 SEt-CH2), 62.1 (C-2), 67.2 (C-5), 69.1 (C-4), 72.1 (C-1), 76.0 (C-3).
Anal. Calcd for C23H26O5S2 (446.6): C, 61.86; H, 5.87. Found: C,
61.76; H, 5.91.
5.18.2. Keto-form
The reaction mixture resulting from a deoximation as described
above (after stirring for 18 h), was subjected to a different workup,
by elution with water (500 mL), extraction with EtOAc
(3 ꢂ 200 mL), washing of the combined extracts with water, drying
(Na2SO4) and removal of the solvent in vacuo. The resulting syrup
crystallized CH2Cl2/n-hexane or CCl4: 8.1 g (75%) of 28 as an amor-
5.21. 1,5-Anhydro-D-threo-pentulose diethyldithioacetal 30
phous product of mp 93–95 °C and ½a D20
¼ ꢁ117 (c 0.6, CHCl3),
ꢃ
To a cooled (0 °C) 0.1 M NaOMe/MeOH solution (100 mL) was
added 5.5 g (12.3 mmol) of dibenzoate 29 and the mixture was stir-
red for 3 h at this temperature followed by neutralization with an
acidic resin (Dowex 50, H+ form). Filtration and evaporation in vacuo
left a syrup which was dissolved in water (50 mL). Washing with
ether (2 ꢂ 5 mL), evaporation to dryness and purification of the syr-
upy residue by elution from silica gel (2.5 ꢂ 30 cm) with 20:1
CH2Cl2/EtOAc gave 2.8 g (95%) of a uniform (TLC) amorphous prod-
uct, which upon freeze drying of an aqueous solution crystallized;
which appeared (NMR) to contain only small amounts of the
monohydrate. 1H NMR (300 MHz, acetone-D6): d 4.16 (1H-dd, 5-
Ha), 4.21 and 4.44 (two 1H-d, 1-H2), 4.46 (1H-ddd, 5-He), 5.73
(1H-ddd, 4-H), 6.13 (1H-d, 3-H); J1,1 = 15.0, J1,5 = 1.1, J3,4 = 9.0,
J4,5 = 8.0 and 5.1, J5,5 = 12 Hz. 13C NMR (75.5 MHz, DMSO-d6): d
67.5 (C-1), 71.6 (C-4), 73.4 (C-5), 77.3 (C-3), 199.4 (C-2). Anal. Calcd
for C19H16O6 (340.32): C, 67.05; H, 4.75. Found: C, 66.85; H, 4.80.
mp 51–52 °C;
½
a 2D0
ꢃ
¼ ꢁ79:3 (c 1.1, MeOH). 1NMR (300 MHz,
5.19. 1,5-Anhydro-D-xylulose (1,5-anhydro-D-threo-pentulose) 4
DMSO-d6): d 1.13 and 1.14 (two 3H-t, SEt, CH3), 2.72 (4H-m, SEt-
CH2), 3.02 (1H-m, 4-H), 3.41 (1H-dd, 3-H), 3.46 and 3.76 (two 1H-
d, 1-H2), 3.80 (2H-m, 4-H, 5-H), 5.01 and 5.40 (two 1H-d, 2 OH);
J1,1 = 12.2, J3,4 = 8.1. 13C NMR (75.47 MHz, DMSO-d6): d 14.2 and
14.4 (2 SEt-CH3), 21.8 and 22.6 (2 SEtCH2), 64.1 (C-2), 67.7 (C-4),
71.1 (C-5), 73.3 (C-1), 79.8 (C-3). Anal. Calcd for C9H18O3S2 (238.4):
C, 45.35; H, 7.61. Found: 45.18; H, 7.65.
5.19.1. Deoximation of oxime 27
Acetaldehyde (0.56 mL, 10 mmol) and 1 M HCl (5 mL) were
added to a suspension of oxime 27 (440 mg, 3 mmol) in acetoni-
trile (15 mL) and the mixture was stirred for 5 h at ambient tem-
perature. The resulting clear solution was diluted with water
(5 mL) and neutralised by stirring with an acidic resin (Amberlite
IR 120 H+ form) and the filtrate was evaporated to dryness in va-
cuo. The syrupy residue was then eluted from a silica gel column
(2 ꢂ 15 cm) with 7:3 n-propanol/water, to give upon evaporation
of the product-carrying eluates in vacuo, finally at 0.01 mm,
265 mg (67%) of 4 as a fluffy solid. 1H NMR (300 MHz, D2O, 2 h after
solution): d 3.38 and 3.69 (two 1H-d, 1-H2), 3.40 (1H-t, 4-H), 3.54
5.22. 4-Benzoyloxy-2H-pyran-3(6H)-one 31
A few drops of pyridine were added to a solution of 680 mg
(2 mmol) of ulose dibenzoate 29 in CHCl3 (10 mL) and the mixture
was heated at reflux for 10 min. Evaporation to dryness and recrys-

960
P. Jarglis et al. / Tetrahedron: Asymmetry 20 (2009) 952–960
tallization of the residue from methanol gave 560 mg (82%) of 31
as colourless needles; mp 111–112 °C. 1H NMR (300 MHz, CDCl3):
d 4.32 (2H-s, 2-H2, 4.61 (2H-d, 6-H2), 4.61 (1H-t, 5-H); J5,6 = 4.0 Hz.
MS (FD): m/e = 218 (M+). Anal. Calcd for C12H10O4 (218.2): C, 66.05;
H, 4.62. Found: C, 66.01; H, 4.54.
5.25. 3,6-Di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-b-
D-
glucopyranosyl)-1,5-anhydro- -fructose E-oxime 37
D
To a solution of NH2OH.HCl (620 mg, 1 mmol) in pyridine
(10 mL) was added 620 mg (1 mmol) of 2-acetoxy-cellobial hexa-
acetate 3413 and the mixture was stirred at ambient temperature
for 7 h, subsequently diluted with water (10 mL) and extracted
with CHCl3 (3 ꢂ 10 mL). The combined CHCl3 extracts were
washed with water, dried (Na2SO4) and taken to dryness in vacuo.
The syrupy residue crystallized on trituration with ethanol:
5.23. 3,4-6-Tri-O-acetyl-1,5-anhydro-D-sorbose E-oxime 35
A solution of hydroxylamine hydrochloride (2.50 g) and of syr-
upy 2-acetoxy-
-gulal triacetate 3211 (3.90 g, 11.8 mmol) in 30 mL
D
of 1:1 pyridine/EtOH was made to stand for 6 h at ambient tem-
perature and then stirred into water (300 mL) followed by extrac-
tion with CHCl3 (3 ꢂ 50 mL) and consecutive washings of the
combined extracts with 2 N HCl (3 ꢂ 50 mL), water (50 mL) satd
NaHCl3 solution (50 mL) and water (50 mL). Drying (Na2SO4)
and evaporation to dryness in vacuo left 3.40 g (95%) of a solid
residue which by 1H NMR proved to be a 4:1 mixture of E and Z
isomers.
430 mg (87%) of 37; mp 125–127 °C; ½a D21
¼ ꢁ22:3 (c 0.3, CHCl3);
ꢃ
Rf = 0.31 (benzene/EtOAc 10:1). 1H NMR (300 MHz, DMSO-d6):
d = 1.99, 2.01 and 2.03 (3s, 18H, 6 Ac-CH3), 4.03 (15.1 Hz-d, 1H,
1-Ha), 4.03–4.30 (5H-m, 5-H, 6-H2, 60-H2), 4.91 (15.1 Hz-d, 1-He),
5.0-5.7 (5H-m, 4-H, 10-H through 40-H), 6.80 (1H-d, 3-H), 11.4
(14-s, NOH). Anal. Calcd for C24H33NO16 (494.51): C, 58.29; H,
6.52; N, 2.83. Found: C, 58.17; H, 6.48; N, 2.74.
Chromatography on a silica gel column (3 ꢂ 40 cm, elution with
10:1 CH2Cl2/EtOAc) and processing of the first product-carrying
fraction gave a syrup upon evaporation in vacuo which gradually
crystallized on drying at 0.01 Torr overnight: 2.85 g (80%) of E-
Acknowledgements
Our thanks are due to Priv.Doz. Dr. Reinhard Meusinger for lu-
cid discussions on NMR topics and to the Deutsche Forschungs-
gemeinschaft for support of this research.
oxime 35; mp 118–120 °C; ½a D20
ꢃ
¼ ꢁ15:1 (c 0.6, CHCl3). 1H NMR
(300 MHz, DMSO-d6): d 2.03, 2.09 and 2.10 (three 3H-s, 3 Ac-
CH3), 3.96 (1H-m, 5-H), 4.11 (2H-m, 6-H2), 4.01 and 4.95 (two
13.1 Hz-d, 1H each, 1-H2), 5.00 (1H-dd, 4-H), 5.23 (1H-d, 3-H),
11.63 (1H-s, NOH): J1,1 = 13.1, J3,4 = 3.2 Hz. 13C NMR (75.47 MHz,
DMSO-d6): d 59.1 (C-1), 62.6 (C-6), 67.9 and 68.6 (C-3 and C-4),
71.8 (C-5), 148.0 (C-2). MS (FD): m/e = 304 (M+1), 303 (M+). Anal.
Calcd for C12H17NO8 (303.26): C, 47.52; H, 5.65; N, 4.62. Found:
C, 47.60; H, 5.60; N, 4.45.
The fractions eluted next contained the E/Z isomers in varying
compositions as evidenced by 1H NMR, the Z-oxime being clearly
differentiated by shifts of H-3 from 5.23 (E-form) to 6.03 and one
of the H-1 protons from 4.95?4.37 ppm.
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-allal triacetate 3311,12 was stirred for 6 h at ambient temper-
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ature and subsequently poured into water (300 mL). Extraction
with CHCl3 (3 ꢂ 50 mL), and consecutive washings of the combined
extracts with 2 M HCl, water, satd NaHCO3 solution and again
water, drying (Na2SO4) and removal of the solvent in vacuo left
3.0 g of a crystalline product, which was recrystallized from EtOH:
2.48 g (82%) of 36; mp 129–131 °C; ½a D20
¼ þ27:2 (c 0.84, CHCl3).
ꢃ
1H NMR (300 MHz, DMSO-d6): d 1.98, 2.01 and 2.10 (three H-s, 3
Ac-CH3), 4.00 (1H-m, H-5), 4.02 (1H-d, H-1a), 4.17 (2H-m, 6-H2),
4.84 (1H-dd, 4-H), 4.91 (1H-d, H-1e), 5.71 (1H-d, H-3), 11.62
(1H-s, NOH); J1,1 = 14.5, J3,4 = 3.5, J4,5 = 8.9 Hz. 13C NMR
(75.47 MHz, DMSO-d6): d 20.3, 20.4, 20.5 (3 Ac-CH3), 59.6 (C-1),
62.7 (C-6), 68.1 and 68.6 (C-3, C-4), 72.7 (C-5), 149.2 (C-2). MS
(FD): m/e = 304 (M+1), 303 (M+). Anal. Calcd for C12H17NO8
(303.26): C, 47.52; H, 5.65; N, 4.62. Found: C, 47.30; H, 5.55; N,
4.53.
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