Exocyclic vinyl ethers of ketofuranosides

Article abstract of DOI:10.1016/j.tet.2007.12.049

Exocyclic vinyl ether derivatives of sugars are found in biosynthetic pathways and may serve as useful synthetic intermediates. The ketose subfamily of sugars is the least characterized in this field. Thus, the synthesis of exocyclic vinyl ether derivativ

Full text of DOI:10.1016/j.tet.2007.12.049

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2080e2089
www.elsevier.com/locate/tet
Exocyclic vinyl ethers of ketofuranosides
*
Yosi Bechor, Amnon Albeck
The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel
Received 12 March 2007; received in revised form 27 November 2007; accepted 20 December 2007
Available online 24 December 2007
Abstract
Exocyclic vinyl ether derivatives of sugars are found in biosynthetic pathways and may serve as useful synthetic intermediates. The ketose
subfamily of sugars is the least characterized in this field. Thus, the synthesis of exocyclic vinyl ether derivatives of ketohexoses via b-elimi-
nation was studied with respect to the nature of the 6-O leaving group and the protection of the 4-hydroxy group. We applied this study to pro-
tected L-sorbofuranoside and D-tagatofuranoside sugar derivatives in which the 4-hydroxy group and the 6-O-leaving group are in the syn
configuration. Some reactions involving deprotection and reductive rearrangement of the tagatose-derived vinyl ether product were also studied.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: b-Elimination; Enol ether; Ketose; Sugar derivatives
1. Introduction
neplanocin A and aristeromycin biosyntheses may involve
a common exocyclic vinyl derivative of fructose-6-phosphate
(Scheme 1), in analogy with DHQ biosynthesis.3
Exocyclic vinyl ether derivatives of sugars are found as in-
termediates in various metabolic pathways, such as the hydro-
lysis of S-adenosylhomocysteine by the enzyme SAHC
hydrolase,1 the 2-deoxy-scyllo-inosose synthase catalytic reac-
tion,2 and the formation of dehydroquinate in the shikimic
pathway3 (Fig 1). They also serve as intermediates in the
synthesis of enzyme inhibitors and biologically related com-
pounds4 or as monomers for polymerization.5 It was demon-
strated that a compound of this family could undergo
biomimetic rearrangement to the corresponding carbocyclic
derivative.6 Most of the available data refer to aldohexopyra-
nose and aldopentofuranose derivatives, whereas only a few
examples of ketofuranose derivatives have been described.
Among the latter is the natural antibiotic angustmycin A
(Fig. 1D).7 Labeling studies suggested that the biosynthesis
of the carbocyclic moiety of the natural products neplanocin
A and aristeromycin involves a key intramolecular aldol con-
densation,8 in analogy with the cyclization of glucose-6-phos-
phate to myo-inositol-1-phosphate.9 We hypothesize that
The synthesis of such vinyl fructofuranoid derivatives pro-
ceeds either by b-elimination of the corresponding 6-tosyl- or
6-deoxy-6-halo protected furanoside10 or by reductive elimi-
nation of 6-O-acyl-5-halo-fructofuranoside.6 As part of our
studies on ‘locked’ fructofuranosides,11 we further explored
the b-elimination reaction, with respect to the leaving group
and the 4-O protecting group. We demonstrate successful
preparation of exocyclic vinyl ether ketofuranoside derivatives
and present some unexpected reactions of these products.
2. Results and discussion
2.1. Synthesis
The strategy we used relied on locking a ketohexose sugar
in its furanose form, proper protection of the sugar hydroxy
groups, and activation of the primary C-6 hydroxy group as
a good leaving group (Scheme 2).
Our first target was the commercially available 2,3-O-isopro-
pylidene-L-sorbofuranose 1 (Scheme 3), previously studied by
Hough and Otter.10 They demonstrated that 4-O-acetyl-1-O-
benzoyl-6-deoxy-6-iodo-2,3-O-isopropylidene-L-sorbofuranose
* Corresponding author. Tel.: þ972 3 5318862; fax: þ972 3 7384053.
E-mail address: albecka@mail.biu.ac.il (A. Albeck).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.049

Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
2081
A
-O2C
Ad
OH
H
+
S
NH3
Ad
OH
Ad
OH
O
O
O
HO
HO
O
HO
SAHC
adenosine
B
-2O3PO
HO
O
O
O
O
O
HO
HO
HO
HO
OH
OH
OH
O
OH
OH
HO
HO
OH
OH
OH
OH
glucose-6-phosphate
2-deoxy-scyllo-inosose
C
H
H
HO
HO
-O2C
O
HO
-O2C
HO
-O2C
H
O
-O2C
OH
O
O
O
=
OPO3
O
OH
DHQ
OH
OH
H
D
Ad
OH
O
OH
HO
angustmycin A
Figure 1. Biological reactions involving exocyclic vinyl ether sugar derivatives. (A) The catalytic activity of SAHC hydrolase. (B) The catalytic activity of
2-deoxy-scyllo-inosose synthase. (C) The catalytic activity of DHQ synthase. (D) The angustmycin A antibiotic.
canbetransformedtothecorrespondingvinyletheringoodyield.
= O3PO
= O3PO
O
OH
OH
OH
O
OH
OH
OH
O
OH
OH
OH
H
On the other hand, 5-deoxy-5-iodo-1,2-O-isopropylidene-a-
D-xylofuranose, in which the unprotected 4-hydroxy group is
syn tothe5-iodo leavinggroup, undergoes anintramolecularsub-
stitution reaction to form the corresponding oxetane. Thus, we
studied the fate of the 6-activated-4-unprotected derivatives2 un-
der basic conditions. Three activating groups were tested, triflate,
iodo, and mesyl, with pKa values of the conjugated acids of ꢀ13,
ꢀ10, and ꢀ2, respectively. All three compounds yielded the
oxetane product 3, with no traces of the b-elimination products
(Scheme 3).
H
O
O
HO
fructose-6-phosphate
H
O
O
OH
OH
OH
OH
OH
OH
O
O
HO
OH
HO
HO
OH
neplanocin A
?
O
OH
HO
OH
OH
?
OH
HO
HO
aristeromycin
Scheme 1. Suggested biosynthetic pathway for the carbocyclic moiety of
neplanocin A and aristeromycin. This pathway involves an exocyclic vinyl
furanose intermediate.
Next, we examined various protecting groups for the 4-hy-
droxy group. 1,6-Dideoxy-1,6-diiodo-2,3-O-isopropylidene-L-
sorbofuranose was prepared via a one-pot two-step procedure
in quantitative yield. It was then subjected to several protect-
ing protocols and subsequent b-elimination reaction (Scheme
4). An attempt to protect the 4-hydroxy group with the bulky
tert-butyl dimethyl silyl group failed, probably due to steric
hindrance. On the other hand, the smaller trimethyl silyl pro-
tecting group was efficiently introduced at the 4-hydroxy posi-
tion. Unfortunately, this protecting group was not stable under
the basic elimination conditions, yielding the unprotected
starting material 2b. Protection with either THP or benzoyl
protecting groups was also efficient, yielding 4b (as a nearly
1:1 diastereomeric mixture) and 4c, respectively. Elimination
from either of these compounds proceeded in a moderate
yield, providing the desired exocyclic vinyl ethers 5b (as
nearly 1:1 mixture of two diastereomers) and 5c (Scheme 4).
Of special interest is our attempt to protect the 4-hydroxy
group by methylation (4d). To our surprise, treatment of the
PG-O
O
PG-O
O
OH
H
O-PG
O-PG
O-PG
O-PG
OH
OH
O
LG-O
HO
O-PG
O-PG
OH
Scheme 2. Retrosynthetic analysis of the vinyl ether derivatives of
ketohexoses.
O
O
O
O
O
O
base
O
O
O
X
X
OH
HO
OH
OH
OH
O
3
1
2a X = OTf base = DBU
b
I
OMs
AgF
t-BuO-K+
c
Scheme 3. Oxetane formation from the unprotected 4-hydroxy, 6-activated
L-sorbofuranoside.

2082
Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
O
O
DBN, NH3
MeOH
O
2b
I
I
I
OTMS
Li2S, TMSCl
86%
4a
O
O
O
O
O
O
AgF, Py
58%
O
O
I
I
I
I
DHP, PPTS
71%
OTHP
OTHP
5b
O
4b
1. Tf2O, Py
O
O
1
I
I
2. NaI
100%
O
O
O
O
O
O
Bz2O, TEA
DMAP 85%
AgF, Py
34%
OH
2b
I
OBz
OBz
4c
5c
BF4O(Me)3
proton sponge
30%
O
O
O
O
AgF, Py
OH
I
I
O
OMe
4d
3
Scheme 4. Synthesis of exocyclic vinyl ether derivatives of L-sorbofuranoside. Effect of the 4-hydroxy protecting group.
methyl-protected 4d with AgF did not produce the desired
elimination product but rather the oxetane 3, probably via an
oxonium intermediate. Thus, protection of the hydroxy group
as an ether does not prevent oxetane formation when the
hydroxy and the leaving group are in syn configuration.
Our next target was the ketohexose D-tagatose (Scheme 5).
It too was expected to have a syn configuration between the 4-
hydroxy and the leaving groups, necessitating protection of the
former. Ketohexoses are more stable in aqueous solution in
their pyranose form, rather than in the furanose form,12 but
the equilibrium shifts toward the furanose form in less polar
solvents.12a Thus, the outcome of tagatose protection in terms
of configuration and anomeric composition is not straightfor-
ward. Only the furanose form will have a free 6-hydroxymethyl
group available for activation and elimination to the exocy-
clic enol ether.
Put into practice, D-tagatose was protected as the 1,2:3,4-di-
acetonide, yielding a single isomer in 80% yield. This reaction
was very sensitive to the conditions, being optimal in toluenee
CH2Cl2, 4:5, at 60e65 ꢁC for 18 h with 3.8 equiv of dime-
thoxypropane (DMP) and a catalytic amount of p-TsOH.
Deviation from the optimal temperature or extension of the re-
action time led to significant reduction in the reaction yield.
The identification of the single isomer product was not trivial.
In principle, it could be any of the four possible isomers, a- and
b-furanose, and a- and b-pyranose (6a and 6b, Scheme 5).
Therefore, the product of unknown configuration was further tri-
flated, providing a single isomer that was fully characterized by
NMR (including 2D COSY, NOESY, and HMQC). The hydroxy
to triflate transformation was accompanied by a shift of two
geminal methylene protons from d w3.8 to w4.7 ppm in the
1H NMR spectrum and a shift of the corresponding methylene
carbon from d 68 to 76 ppm in the 13C NMR spectrum. This con-
firmed triflation of the 6-hydroxy group of the furanoside form
6a. NOESY data established a configuration of both the free hy-
droxy furanoside 6a and its triflate product 7a (Fig. 2). Thus, this
reaction provided both the desired furanose configuration, re-
quired for the b-elimination reaction, and the protection of the
4-hydroxy group, to prevent the competing oxetane formation.
Having established the furanose configuration for the D-
tagatose diacetonide 6a and its 6-triflate 7a, we studied the
O
O
OH
HO
OH
HO
OH
OH
OH
HO
D - tagatofuranose
HO
OH
D - tagatopyranose
DMP, p-TsOH
toluene:CH2Cl2
65 °C, 18h, 80%
O
O
O
O
HO
HO
O
O
O
O
O
O
4.61
H
3.87
6b
6a
H
3.83
4.76
76
OH
H
OTf
H
H3C
1.36
H3C
68
H
H
O
O
4.20
H
Tf2O, Py
CH2Cl2
rt, 1h, 92%
O
O
4.28
H
O
O
H3C
1.24
H3C
1.30
H
H
4.01
4.07
4.84
4.78
O
H
O
H
H
H
O
4.00
4.25
O
O
O
4.56
4.63
O
O
TfO
TfO
O
CH3
1.42
CH3
O
H3C
1.33
H3C
O
O
O
O
7b
7a
Figure 2. NOESY correlation support for the structural determination of the di-
acetonide furanosides 6a and 7a. Solid and dashed lines represent medium and
weak correlations, respectively. The strong geminal correlations are not marked.
Scheme 5. Structure of the 1,2:3,4-diisopropylidene-D-tagatofuranoside versus
D-tagatopyranoside.

Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
2083
O
O
O
1. Tf2O, Py, rt, 1.5h
DMP, p-TsOH
HO
OH
HO
OH
OH
O
2. NaI, acetone, rt, 15h
92%
65 °C, 15h
80%
HO
O
O
6a
D - tagatofuranose
O
O
O
O
AgF, rt, 7 days
40%
I
O
O
O
O
O
O
8
9
Scheme 6. Synthesis of the exocyclic vinyl ether derivative of D-tagatofuranoside.
b-elimination reaction. Attempts to eliminate the triflate under
various basic conditions (2e10 equiv of DBU, rt to 85ꢁC, 15e
72 h) did not provide the desired exocyclic vinyl ether 9. Direct
iodination of 6a (PPh3, I2, imidazole) yielded mainly starting
material, with only 2% traces of the desired iodide 8. Therefore,
the diacetonide 6a was quantitatively iodinated via the one-pot
two-step procedure mentioned above. Treatment of iodide 8
with AgF finally afforded the desired vinyl ether 9 in moderate
yield (Scheme 6).
derivatives,11 is their transformation to carbocyclic sugar ana-
logs. We anticipated that deprotection of the diacetonide vinyl
ether 9 might lead to rearrangement to the corresponding
cyclopentanone 10 (Scheme 7A). This assumption was based
on the analogous spontaneous rearrangement of a vinyl pyra-
nose derivative to the corresponding cyclohexanone, as
a model reaction for the final step of the complex reaction cata-
lyzed by the enzyme DHQ synthase.6 Thus, diacetonide 9
was treated with acidic Dowex-50 in a watereacetone mix-
ture. To our surprise, the only product, obtained in quantitative
yield, was the nine-membered ring dimer 11 (Scheme 7B).13
The same product was efficiently obtained even at high dilu-
tion. We assigned structure 11 to the dimer (with a central
9-membered ring) rather than a central 6-, 8-, or 10-membered
2.2. Reactions
One possible application of the exocyclic vinyl ether deriva-
tives, related to our studies on ‘locked’ fructofuranose
A
O
O
O
OH
O
OH
Dowex-50
water-acetone
O
OH
HO OH
10
OH
OH
O
O
HO
9
B
OH
O
O O
O
O
OH
HO
HO
HO
HO
HO
OH
OH
OH
OH
Dowex-50
water-acetone
O
O
O
O
O
O
OH
9
OH
OH
11
C
OH
HO
OH
O
HO
OH
OH
HO
HO
OH
OH
O
O
O
O
HO
O
HO
OH
HO
HO
HO
HO
O
O
HO
HO
HO
HO
OH
OH
OH
O
O
O
OH
O
OH
OH
O
OH
O
OH
HO
HO
O
O
O
HO
HO
OH
OH
OH
OH
HO
HO
OH
O
HO
OH
Scheme 7. Dimerization of the deprotected exocyclic vinyl ether derivative of D-tagatofuranose. (A) The anticipated rearrangement reaction. (B) The nine-
membered ring product of the dimerization. (C) Other possible dimerization reactions, which were rejected based on NMR analysis.

2084
Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
ring structure (Scheme 7C). This assignment was based on the
1
analysis of the dimer’s H NMR spectrum: each of the mono-
with two reductions yielded the seven-membered cyclic ether
14 (Scheme 8C). The relative stereochemistry of 14 at C2 and
C5 was assigned unequivocally, based on excellent agreement
between measured and calculated15 1H NMR coupling con-
stants. The C2eC3, C3eC4, and C4eC5 calculated (and mea-
sured) 3JHH values for 14 at the conformation corresponding to
its global minimum energy were 9.6 (9.5), 7.9 (7), and 2.6
(3) Hz, respectively. The opposite configuration at C2 and
C5 was calculated to exhibit C2eC3 and C4eC5 coupling
constants of about 4.6 and 11.2 Hz, respectively. We suggest
a mechanism in which the TIBAL Lewis acid interacts with
one of the acetonide oxygens, rather than with the ‘classic’
enol oxygen (Scheme 8C). Another ring expansion reaction
was previously observed with C-vinyl glycosides.14a
A few such rearrangement reactions were previously
described, mainly for exo vinyl ethers derived from aldopyra-
nosides and also for some aldofuranoside derivatives.14c The
present study presents the first rearrangement of an exo vinyl
ether ketofuranoside. It is possible that, whereas the previous
studies involve intramolecular aldol condensation on an alde-
hyde moiety, which is energetically favorable, the present
study addresses a corresponding much less favored condensa-
tion on a ketone moiety, allowing other side reactions to occur.
It is interesting to compare the above rearrangement reactions
to similar reactions on other five-membered ring systems. An
exocyclic g-enollactone, derived from ribonic acid g-lactone,
was reduced to a relatively stable g-enollactol, which spontane-
ously isomerized to the corresponding b-hydroxyketone (via
ring opening and intramolecular aldol condensation).16 This
isomerization of a g-enollactol is very similar to that reported
mers in the dimer had a discrete set of resonances in the spec-
trum, indicating an asymmetric structure. The spectrum
exhibited two sets of methylene protons: one pair of protons
resonated at d 3.83 and 3.86 ppm, while the other at d 3.71
and 4.15 ppm. The fact that one pair of protons resonated at
two very close frequencies (Dd¼0.03 ppm) while the other
pair was split (Dd¼0.44 ppm) may indicate that one methylene
is part of a ring and the other is not. This distinction supports
only the 9-membered ring dimer structure, but not the 6, 8-,
and 10-membered ring alternatives.
Another approach we examined was the glycoside-to-car-
bocycle reductive rearrangement, promoted by triisobutylalu-
minum (TIBAL).14 It was applied in some rearrangements of
vinyl glucopyranosides to cyclohexane derivatives,4b,14a but
not to vinyl furanosides. Unfortunately, treatment of 9 with
2.6 equiv TIBAL in toluene at rt for 2.5 h afforded mainly
tar, from which the desired cyclopentanol diacetonide 12
was isolated, though at a low 7% yield. The structure was fully
characterized by 2D NMR, demonstrating that the 1,2-aceto-
nide retained its configuration and that the hydride transfer
occurred from the less hindered a face (Scheme 8A).
This reaction was very sensitive to the conditions, yielding
some unexpected products. When 9 was treated with 5 equiv
of TIBAL for 15 h, a second reduction of the 1,2-acetonide
protecting group afforded the isopropyl ether 13 in similar
low yield (Scheme 8B). Under a different set of conditions,
in which 4 equiv of TIBAL was added at ꢀ78 ꢁC and then
kept at rt for 12 h, a ring expansion/rearrangement reaction
A
O
HO
O
O
2.6 eq TIBAL
rt, 2.5h
O
O
O
O
O
O
9
12
B
i
i
AlBu3
AlBu3
HO
O
HO
O
O
HO
OH
H-
5 eq TIBAL
rt, 15h
O
O
O
9
12
O
O
O
O
O
13
C
i
i
AlBu3
AlBu3
O
O
O
O
4 eq TIBAL
-78 °C --> rt, 12h
O
O
9
O
O
O
O
i
AlBu3
O
O
O
O
O
OH
OH
O
H-
H-
O
HO
O
O
O
O
O
14
Scheme 8. (A) TIBAL promoted rearrangement, (B) protecting group reduction, and (C) ring expansion of 1,2:3,4-diisopropylidene-D-tagatofuranoside exocyclic
vinyl ether derivative 9.

Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
2085
for the d-enollactol in the model reaction of the last step cata-
4.2. 2,3-O-Isopropylidene-1,6-di(O-triflate)-L-a-sorbo-
furanose (2a)
lyzed by DHQ synthase.6 The lactol led to a single desired
rearrangement product. In our case on the other hand, the
presence of five different oxygen atoms, involved in three ketal
functional groups, may lead to many competing and tandem
reactions, providing only a small amount of the desired product.
Another analogous reaction is the palladium(0)-catalyzed
isomerization of 5-vinyl-2-alkylidenetetrahydrofurans to the
corresponding cyclopentanones.17 The main limitation of this
reaction is its requirement of a substituting vinyl group, in addi-
tion to the rearranging exocyclic enol functionality, to serve as
a ligand to the palladium complex. Thus, despite its efficiency,
this reaction could not be applied to our sugar derivatives.
To a solution of 2,3-O-isopropylidene-L-a-sorbofuranose
(1.0 g, 4.54 mmol) in dry CH2Cl2 (25 ml) and dry pyridine
(1 ml, 2.5 equiv) was added Tf2O (2 ml, 11.4 mmol) at 0 ꢁC.
The mixture was stirred under Ar at rt. After 1 h, the reaction
was quenched by the addition of saturated aqueous NaHCO3
(25 ml). The mixture was partitioned between water and
EtOAc. The organic layer was washed with 1 M HCl and
brine, dried over MgSO4, filtered, and evaporated to give
pure 2a (2.20 g, 4.54 mmol, 100%) as a white solid, mp
1
72e74 ꢁC. H NMR d 1.39 (s, 3H, CH3), 1.55 (s, 3H, CH3),
4.56 (d, 1H, J¼11 Hz, CH2-1), 4.52 (br s, 1H, CH-3), 4.45
(d, 1H, J¼2.5 Hz, CH-4), 4.63 (d, 1H, J¼11 Hz, CH2-1),
4.63e4.65 (m, 1H, CH-5), 4.64 (dd, 1H, J¼10, 6.5 Hz,
CH2-6), 4.74 (dd, 1H, J¼10, 4.5 Hz, CH2-6); 13C NMR
d 26.10 (CH3), 27.36 (CH3), 72.00 (C-1), 73.00 (C-6), 74.50
(C-4), 85.00 (C-3), 104.00 (C(CH3)2), 105.00 (C-2); MS
(DCI) m/z 484 (Mþ, 40); HRMS (m/z) calcd for
C11H15O10S2F6 (MHþ): 485.0013, found: 485.0031.
3. Conclusions
Exocyclic vinyl ether derivatives of sugars are of interest
due to their involvement in metabolic processes, and their po-
tential as synthetic intermediates. The least studied of these
compounds are the ketose derivatives. Hough and Otter
studied their preparation via b-elimination reaction of the cor-
responding 6-iodo derivatives. Here, we extended these stud-
ies, concentrating on ketohexoses in which the leaving group
and the 4-hydroxy group are in syn configuration. This specific
configuration may result in an intramolecular substitution
reaction to form an oxetane ring. Therefore, we examined
the effect of the nature of the leaving group and the effect
of various protecting groups. The most successful procedure
involves the preparation of a 6-iodo activating group through
an efficient one-pot two-step reaction and AgF-promoted
b-elimination with a properly protected 4-hydroxy group.
We further examined some interesting reactions involving
deprotection and reductive rearrangement of the exocyclic vi-
nyl ether products. These reactions led to unexpected dimeri-
zation, excess reduction, and ring expansion to an oxepane
skeleton. Optimization of these reactions may provide an entry
to useful synthetic structures.
4.3. 1,6-Dideoxy-1,6-diiodo-2,3-O-isopropylidene-L-a-
sorbofuranose (2b)
To a solution of 2,3-O-isopropylidene-L-a-sorbofuranose
(0.64 g, 2.9 mmol) in dry CH2Cl2 (16 ml) and dry pyridine
(0.5 ml, 2.1 equiv), was added Tf2O (1.0 ml, 6.1 mmol) at
0 ꢁC under Ar to provide a frozen light pink solution. The
cooling bath was removed, and the mixture was allowed to
melt and then to stir for 1.5 h. The reaction was quenched
by saturated aqueous solution of NaHCO3 (9 ml). The mixture
was then partitioned between water and EtOAc and the or-
ganic layer was washed with 0.1 M HCl and brine, dried
over MgSO4, filtered, and evaporated to give a red oil, which
was dissolved in dry acetone (17 ml). NaI (1.74 g, 11.6 mmol)
was then added and the mixture was stirred over night in dark.
The mixture was then partitioned between saturated aqueous
Na2S2O3$5H2O and EtOAc. The aqueous layer was washed
with EtOAc (ꢂ2), and the combined organic layer was washed
with brine, dried over MgSO4, filtered, and evaporated to give
pure 2b (1.276 g, 2.9 mmol, 100%) as a white solid, mp 107e
110 ꢁC. 1H NMR d 1.43 (s, 3H, CH3), 1.52 (s, 3H, CH3), 3.25
(t, 1H, J¼9 Hz, CH2-6), 3.30 (dd, 1H, J¼9, 6 Hz, CH2-6), 3.50
(d, 1H, J¼11 Hz, CH2-1), 3.58 (d, 1H, J¼11 Hz, CH2-1), 4.43
(d, 1H, J¼3 Hz, CH-4), 4.53 (ddd, 1H, J¼9, 6, 3 Hz, CH-5),
4.55 (s, 1H, CH-3); 13C NMR d ꢀ1.10 (C-6), 7.40 (C-1),
26.54 (CH3), 27.59 (CH3), 75.10 (C-4), 82.36 (C-5), 86.26
(C-3), 112.56 (C-2), 113.10 (C(CH3)2) MS (DCI) m/z 440
(Mþ, 34.8), 424 (100); HRMS (m/z) calcd for C9H14O4I2
(Mþ): 439.8982, found: 439.8967.
4. Experimental
4.1. General
˚
Dry solvents were prepared by treatment with 4 A molecu-
lar sieves or by distillation over sodium. 1H NMR spectra were
recorded at 200, 300, or 600 MHz in CDCl3, unless otherwise
specified. Chemical shifts are expressed in parts per million,
relative to TMS as an internal standard. Spectra in D2O
1
were calibrated by the HOD peak (d 4.80, H NMR) or by
the peak of a small amount of added MeOH (d 49.50, 13C
NMR). 13C NMR spectral (at 50, 75, or 150 MHz) assign-
ments were supported by DEPT, HMQC, and HMBC experi-
ments. TLC was performed on E. Merck 0.2 mm pre-coated
silica gel F-254 plates, and viewed by UV light and vanillin.18
Chromatography refers to flash column chromatography,19
carried out on silica gel 60 (230e400 mesh ASTM, E. Merck
4.4. 2,3-O-Isopropylidene-1,6-di(O-mesyl)-L-a-sorbo-
furanose (2c)
or Riedel-de Haen). Manipulated sugar derivatives were
¨
named according to the parent carbohydrate structure.
To a solution of 2,3-O-isopropylidene-L-a-sorbofuranose
(0.5 g, 2.30 mmol) in dry CH2Cl2 (3 ml) and dry pyridine

2086
Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
(0.4 ml, 4.60 mmol), was added mesyl chloride (0.3 ml,
4.60 mmol) at 0 ꢁC under Ar. The mixture was stirred at
0 ꢁC for 5 h, and was then partitioned between ice-cold water
and EtOAc. The organic phase was washed with 0.1 M HCl,
saturated aqueous NaHCO3, and brine, dried over MgSO4, fil-
tered, and evaporated to give pure 2c (415 mg, 1.1 mmol,
HRMS (m/z) calcd for C12H22O4I2Si (Mþ): 511.9377, found:
511.9368.
4.7. 1,6-Dideoxy-1,6-diiodo-2,3-O-isopropylidene-4-O-
tetrahydropyranyl-L-a-sorbofuranose (4b)
1
46%) as a white solid, mp 82e85 ꢁC. H NMR d 1.39 (s,
To a solution of 2b (1.46 g, 3.31 mmol) and PPTS
(19.6 mg) in dry CH2Cl2 (35 ml) was added DHP (6 ml,
70 mmol) under Ar at rt. The mixture was stirred at rt for 11
days. The mixture was then partitioned between water and
EtOAc, and the aqueous layer was washed with EtOAc
(ꢂ2). The combined organic layer was washed with brine,
dried over MgSO4, filtered, and evaporated to give the crude
product as a yellow oil. Chromatography (EtOAcehexane,
1:9) gave nearly 1:1 mixture of two isomers of 4b as a clear
3H, CH3), 1.54 (s, 3H, CH3), 3.08 (s, 6H, SO2CH3ꢂ2), 4.34
(d, 1H, J¼0.5 Hz, CH-4), 4.35 (d, 1H, J¼11.5 Hz, CH2-1),
4.39 (dd, 1H, J¼11, 6.5 Hz, CH2-6), 4.46 (d, 1H,
J¼11.5 Hz, CH2-1), 4.51 (dd, 1H, J¼11, 5.5 Hz, CH2-6),
4.54 (ddd, 1H, J¼6.5, 5.5, 0.5 Hz, CH-5), 4.55 (s, 1H, CH-
3); 13C NMR d 26.21 (CH3), 27.25 (CH3), 37.56 (SO2CH3),
37.99 (SO2CH3), 66.46 (C-6), 68.09 (C-1), 74.60 (C-4),
77.44 (C-5), 85.43 (C-3), 111.67 (C(CH3)2), 113.30 (C-2);
MS (DCI, CH4) m/z 377 (MHþ, 6.9), 205 (100); HRMS (m/z)
calcd for C11H21O10S2 (MHþ): 377.0576, found: 377.0573.
1
oil (2.36 mmol, 71%). H NMR d 1.44 (s, 3H, CH3), 1.46 (s,
3H, CH3), 1.51 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.51e1.67
(m, 12H, 2ꢂCH2-30e40e50), 3.19 (dd, 1H, J¼10.2, 9.0 Hz,
CH2-6), 3.21 (dd, 1H, J¼10.2, 9.0 Hz, CH2-6), 3.27 (dd, 1H,
J¼9.0, 5.1 Hz, CH2-6), 3.35 (dd, 1H, J¼10.5, 5.7 Hz, CH2-
6), 3.455 (d, 1H, J¼10.8 Hz, CH2-1), 3.457 (d, 1H,
J¼11.4 Hz, CH2-1), 3.51 (d, 1H, J¼11.4 Hz, CH2-1), 3.57
(d, 1H, J¼10.8 Hz, CH2-1), 3.54e3.65 (m, 2H, CH2-60),
3.87e4.0 (m, 2H, CH2-60), 4.29 (d, 1H, J¼3 Hz, CH-4),
4.63 (ddd, 1H, J¼10.2, 5.1, 3.0 Hz, CH-5), 4.69 (ddd, 1H,
J¼9.0, 5.7, 2.4 Hz, CH-5), 4.72 (s, 1H, CH-3), 4.74e4.76
(m, 2H, 2ꢂCH-20), 4.81 (s, 1H, CH-3), 5.36 (d, 1H, J¼3 Hz,
CH-4); 13C NMR d ꢀ4.61 (C-1), ꢀ0.53 (C-1), 4.76 (C-6),
6.94 (C-6), 19.72 (C-40), 25.21 (C-40), 26.54 (C-50), 26.65
(C-50), 26.71 (CH3), 27.48 (CH3), 27.58 (CH3), 27.68 (CH3),
29.66 (C-30), 30.52 (C-30), 62.71 (C-60), 63.33 (C-60), 80.97
(C-4), 81.67 (C-4), 82.54 (C-5), 84.37 (C-5), 84.71 (C-3),
87.49 (C-3), 95.87 (C-20), 102.45 (C-20), 112.62 (C-2),
112.84 (C-2), 113.17 (C(CH3)2), 113.84 (C(CH3)2); MS
(DCI, CH4) m/z 524 (Mþ, 50) 269 (100); HRMS (m/z) calcd
for C14H22O5I2 (Mþ): 523.9557, found: 523.9556.
4.5. 4,6-Anhydro-2,3-O-isopropylidene-L-a-sorbo-
furanose (3)
To a solution of 2a (0.34 g, 0.70 mmol) in dry THF (22 ml)
was added DBU (0.3 ml, 2.0 mmol). The mixture was stirred
under Ar at rt for 72 h. The mixture was partitioned between
water and EtOAc. The organic phase was dried over MgSO4,
filtered, and evaporated to dryness. Chromatography (ethere
1
hexane, 2:1) gave 3 as a clear oil. H NMR d 1.42 (s, 3H,
CH3), 1.44 (s, 3H, CH3), 3.90 (d, 1H, J¼12 Hz, CH2-1),
4.00 (d, 1H, J¼12 Hz, CH2-1), 4.18 (dd, 1H, J¼8, 2 Hz,
CH2-6), 4.72 (s, 1H, CH-3), 4.79 (dd, 1H, J¼8, 4 Hz,
CH2-6), 5.14 (td, 1H, J¼4, 2 Hz, CH-5), 5.26 (d, 1H,
J¼4 Hz, CH-4); 13C NMR d 27.33 (CH3), 27.89 (CH3),
73.88 (C-1), 78.50 (C-6), 78.93 (C-5), 84.04 (C-3), 88.25
(C-4), 113.63 (C(CH3)2), 118.51 (C-2); MS (DCI, CH4) m/z
203 (MHþ, 9), 187 (100); HRMS (m/z) calcd for C9H15O5
(MHþ): 203.0919, found: 203.0915.
4.8. 1,6-Dideoxy-1,6-diiodo-2,3-O-isopropylidene-4-O-
4.6. 1,6-Dideoxy-1,6-diiodo-2,3-O-isopropylidene-4-O-
benzoyl-L-a-sorbofuranose (4c)
trimethylsilyl-L-a-sorbofuranose (4a)
To a solution of 2b (1.34 g, 3.04 mmol), triethylamine
(1.3 ml, 9.1 mmol), and DMAP (37 mg, 0.3 mmol) in dry
THF (30 ml) was added benzoic anhydride (1.04 g,
4.6 mmol) under Ar at rt. The mixture was stirred overnight,
and was then partitioned between water and EtOAc. The aque-
ous layer was washed with EtOAc (ꢂ2), and the combined or-
ganic layer was washed with brine, dried over MgSO4, filtered,
and evaporated to give the crude product as a brown oil. Chro-
matography (EtOAcehexane, 1:3) gave 4c as a yellow oil
To a vigorously stirred suspension of Li2S (1.52 mmol) in
dry acetonitrile (2 ml) was added TMSCl (3.13 mmol) at rt un-
der Ar followed by a solution of 2b (0.46 g, 1.05 mmol) in dry
acetonitrile (5 ml). The mixture was stirred at rt, over night.
The mixture was then partitioned between water and EtOAc,
and the aqueous layer was washed with EtOAc (ꢂ2). The
combined organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated to give pure 4a as a clear
oil (0.90 mmol, 86%). 1H NMR d 0.23 (s, 9H, Si(CH3)3),
1.45 (s, 3H, CH3), 1.51 (s, 3H, CH3), 3.19e3.22 (m, 2H,
CH2-6), 3.42 (d, 1H, J¼11 Hz, CH2-1), 3.56 (d, 1H,
J¼11 Hz, CH2-1), 4.37 (d, 1H, J¼3 Hz, CH-4), 4.42 (br s,
1H, CH-3), 4.58 (ddd, 1H, J¼7, 6, 3 Hz, CH-5); 13C NMR
d ꢀ0.33 (C-6), 0.18 (Si(CH3)3), 6.74 (C-1), 26.73 (CH3),
27.74 (CH3), 74.77 (C-4), 83.48 (C-3), 85.74 (C-5), 112.79
(C-2), 113.25 (C(CH3)2); MS (DCI, CH4) m/z 512 (Mþ, 22);
1
(2.60 mmol, 85%). H NMR d 1.44 (s, 3H, CH3), 1.58 (s,
3H, CH3), 3.32 (t, 1H, J¼9 Hz, CH2-6), 3.37 (dd, 1H, J¼9,
6 Hz, CH2-6), 3.52 (s, 2H, CH2-1), 4.69 (s, 1H, CH-3), 4.77
(ddd, 1H, J¼9, 6, 3.5 Hz, CH-5), 5.60 (d, 1H, J¼3.5 Hz,
CH-4), 7.45e7.56 (m, 2H, C6H5), 7.60e7.71 (m, 1H, C6H5),
8.03e8.07 (m, 2H, C6H5); 13C NMR (CDCl3) d ꢀ2.47 (C-
1), 6.27 (C-6), 26.64 (CH3), 27.62 (CH3), 77.03 (C-3), 81.22
(C-4), 84.95 (C-5), 112.90 (C-2), 113.00 (C(CH3)2), 128.74

Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
2087
(C6H5), 128.88 (C6H5), 129.78 (C6H5), 130.59 (C6H5), 133.77
(C6H5), 134.53 (C6H5), 165.04 (CO2); HRMS (m/z) calcd for
C16H19O5I2 (MHþ): 544.9322, found: 544.9341.
at rt in dark for a week to form a black solution. The mixture
was then filtered and the filtrate was partitioned between 1 M
HCl and EtOAc. The organic layer was washed with water and
brine, dried over MgSO4, filtered, and evaporated to give 5c as
1
4.9. 1,6-Dideoxy-1,6-diiodo-2,3-O-isopropylidene-4-O-
a brown oil (0.20 mmol, 34%). H NMR d 1.54 (s, 3H, CH3),
methyl-L-a-sorbofuranose (4d)
1.540 (s, 3H, CH3), 3.57 (d, 1H, J¼11 Hz, CH2-1), 3.74
(d, 1H, J¼11 Hz, CH2-1), 4.49 (d, 1H, J¼2 Hz, CH2-6), 4.66
(dd, 1H, J¼2, 0.5 Hz, CH2-6), 4.79 (s, 1H, CH-3), 5.81 (d,
1H, J¼0.5 Hz, CH-4), 7.42e7.52 (m, 2H, C6H5), 7.57e7.65
(m, 1H, C6H5), 8.00e8.07 (m, 2H, C6H5); 13C NMR d 4.01
(C-1), 26.92 (CH3), 27.89 (CH3), 76.03 (C-4), 84.46 (C-3),
90.25 (C-6), 114.11 (C-2), 114.11 (C(CH3)2), 128.56 (C6H5),
129.73 (C6H5), 133.54 (C6H5), 158.33 (C-5), 164.97 (COO);
MS (DCI, CH4) m/z 417 (MHþ, 32); HRMS (m/z) calcd for
C16H18O5I (MHþ): 417.0199, found: 417.0206.
˚
To a mixture of 2b (0.72 g, 1.64 mmol), 4 A molecular sieves
(0.8 g), and proton sponge (0.88 g, 4.1 mmol) in dry CH2Cl2
(20 ml) was added BF4(OMe)3 (0.97 g, 6.56 mmol).20 The mix-
ture was stirred at 40 ꢁC overnight. Filtration and evaporation
gave the crude product as a yellow solid. Chromatography
(EtOAcehexane, 1:4) gave 4d as a clear oil (0.49 mmol,
1
30%). H NMR d 1.45 (s, 3H, CH3), 1.52 (s, 3H, CH3), 3.23
(dd, 1H, J¼8.7, 5.4 Hz, CH2-6), 3.28 (t, 1H, J¼9.5 Hz,
CH2-6), 3.41 (d, 1H, J¼10.8 Hz, CH2-1), 3.47 (s, 3H, OCH3),
3.52 (d, 1H, J¼10.8 Hz, CH2-1), 3.92 (d, 1H, J¼3.3 Hz,
CH-4), 4.59 (ddd, 1H, J¼9.6, 5.4, 3.3 Hz, CH-5), 4.60 (br s,
1H, CH-3); 13C NMR d ꢀ0.87 (C-6), 6.78 (C-1), 26.72 (CH3),
27.76 (CH3), 58.65 (OCH3), 82.52 (C-4), 82.79 (C-5), 83.27
(C-3), 112.79 (C-2), 113.35 (C(CH3)2); MS (DCI, CH4) m/z
454(Mþ, 75); HRMS (m/z) calcd for C10H16O4I2 (Mþ):
453.9138, found: 453.9102.
4.12. 1,2:3,4-O-Diisopropylidene-D-a-tagatose (6a)
A suspension of D-tagatose (0.8 g, 4.44 mmol) and
p-TsOH$H2O (20 mg) in dry toluene (16 ml) and dry CH2Cl2
(20 ml) was heated to reflux (60e65 ꢁC). 2,2-Dimethoxypro-
pane (2.1 ml, 16.9 mmol) was then added and the mixture
was refluxed for 18 h to give a clear yellow solution. The mix-
ture was partitioned between water and EtOAc. The aqueous
layer was washed with EtOAc (ꢂ2), and the combined organic
phase was washed with brine, dried over MgSO4, filtered, and
4.10. 1-Deoxy-1-iodo-2,3-O-isopropylidene-4-O-tetrahydro-
pyranyl-5,6-anhydro-L-a-sorbofuranose (5b)
1
evaporated to give 6a as a yellow oil (3.47 mmol, 78%). H
To a solution of 4b (0.66 g, 1.25 mmol) in dry pyridine
(50 ml) was added AgF (18.13 mmol). The mixture was stirred
at rt in dark for a week to form a black solution. The mixture
was filtered and the filtrate was partitioned between 1 M HCl
and EtOAc. The organic layer was washed with water and
brine, dried over MgSO4, filtered, and evaporated to give
nearly 1:1 mixture of two isomers of 5b as a brown oil
NMR d 1.24 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 1.40 (s, 3H, CH3), 3.82 (dd, 1H, J¼12, 5 Hz, CH2-6),
3.87 (dd, 1H, J¼12, 5 Hz, CH2-6), 3.99 (td, 1H, J¼5, 4 Hz,
CH-5), 4.01 (d, 1H, J¼10 Hz, CH2-1), 4.20 (d, 1H,
J¼10 Hz, CH2-1), 4.56 (d, 1H, J¼6 Hz, CH-3), 4.78 (dd,
1H, J¼6, 4 Hz, CH-4); 13C NMR d 23.64 (CH3), 24.91
(CH3), 25.42 (CH3), 25.42 (CH3), 59.30 (C-1), 68.18 (C-6),
78.80 (C-5), 80.52 (C-4), 85.37 (C-3), 110.70 (C(CH3)2),
110.75 (C(CH3)2), 111.90 (C-2); MS (DCI, CH4) m/z 261
(MHþ, 9), 203 (75), 245 (100); HRMS (m/z) calcd for
C12H21O6 (MHþ): 261.1338, found: 261.1301.
1
(0.73 mmol, 58%). H NMR d 1.48 (s, 2ꢂ3H, 2ꢂCH3), 1.49
(s, 3H, CH3), 1.50 (s, 3H, CH3), 1.57e1.93 (m, 12H,
2ꢂCH2-30e40e50), 3.48 (d, 1H, J¼11 Hz, CH2-1), 3.50 (d,
1H, J¼11 Hz, CH2-1), 3.52e3.60 (m, 2H, CH2-60), 3.65 (d,
1H, J¼11 Hz, CH2-1), 3.68 (d, 1H, J¼11 Hz, CH2-1), 3.80e
3.92 (m, 2H, CH2-60), 4.21 (d, 1H, J¼2 Hz, CH-4), 4.27 (d,
1H, J¼2 Hz, CH-4), 4.57e4.58 (m, 4H, 2ꢂCH2-6), 4.61 (s,
1H, CH-3), 4.65 (s, 1H, CH-3), 4.83e4.84 (m, 1H, CH-20),
4.89e4.91 (m, 1H, CH-20); 13C NMR d 4.70 (C-1), 5.02 (C-
1), 18.81 (C-40), 19.00 (C-40), 25.01 (C-50), 25.29 (C-50),
26.86 (CH3), 26.90 (CH3), 27.09 (CH3), 27.88 (CH3), 30.12
(C-30), 30.43 (C-30), 62.01 (C-60), 62.20 (C-60), 77.00 (C-4),
78.36 (C-4), 83.82 (C-3), 84.52 (C-3), 88.16 (C-6), 89.17
(C-6), 94.99 (C-20), 97.44 (C-20), 114.14 (C-2), 114.25 (C-
2), 114.48 (C(CH3)2), 114.48 (C(CH3)2), 158.27 (C-5),
158.71 (C-5); MS (DCI, CH4) m/z 297 (MHþ, 5); HRMS
(m/z) calcd for C14H22O5I (MHþ): 397.0512, found: 397.0490.
4.13. 1,2:3,4-O-Diisopropylidene-6-O-triflate-D-tagatose (7a)
To a solution of 6a (0.62 g, 2.40 mmol) and dry pyridine
(0.3 ml, 3.6 mmol) in dry CH2Cl2 (23 ml) was added Tf2O
(0.6 ml, 3.6 mmol) at 0 ꢁC under Ar. The cool bath was re-
moved and the mixture was allowed to stir for 1 h. The reac-
tion mixture was quenched by saturated aqueous NaHCO3
(13 ml). The mixture was then partitioned between water
and CH2Cl2. The organic layer was washed with 0.1 M HCl,
water, and brine. The organic phase was dried over MgSO4,
filtered, and evaporated to give pure 7a as a yellow oil
1
(2.2 mmol, 92%). H NMR d 1.23 (s, 3H, CH3), 1.33 (s, 3H,
CH3), 1.34 (s, 3H, CH3), 1.39 (s, 3H, CH3), 4.07 (d, 1H,
J¼10 Hz, CH2-1), 4.28 (d, 1H, J¼10 Hz, CH2-1), 4.25 (dt,
1H, J¼7, 4 Hz, CH-5), 4.61 (dd, 1H, J¼11, 7 Hz, CH2-6),
4.63 (d, 1H, J¼6 Hz, CH-3), 4.76 (dd, 1H, J¼11, 4 Hz,
CH2-6), 4.84 (dd, 1H, J¼6, 4 Hz, CH-4); 13C NMR d 25.94
(CH3), 25.98 (CH3), 26.24 (CH3), 26.56 (CH3), 69.30 (C-1),
4.11. 1-Deoxy-1-iodo-2,3-O-isopropylidene-4-O-benzoyl-5,6-
anhydro-L-a-sorbofuranose (5c)
To a solution of 4c (0.32 g, 0.58 mmol) in dry pyridine
(50 ml) was added AgF (8.7 mmol). The mixture was stirred

2088
Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
74.22 (C-6), 76.34 (C-5), 79.70 (C-4), 85.13 (C-3), 112.30
(C(CH3)2), 112.35 (C(CH3)2), 113.61 (C-2), 118.73 (q,
J¼160 Hz, CF3); HRMS (m/z) calcd for C13H20O8F3S
(MHþ): 393.0518, found: 393.0586.
1.58 (s, 3H, CH3-6), 3.71 (d, 1H, J¼12.5 Hz, CH2-1), 3.83
(d, 1H, J¼12.5 Hz, CH2-10), 3.85 (d, 1H, J¼3.5 Hz, CH-4),
3.86 (d, 1H, J¼12.5 Hz, CH2-10), 4.07 (d, 1H, J¼5.2 Hz,
CH-40), 4.15 (d, 1H, J¼12.5 Hz, CH2-1), 4.41 (d, 1H,
J¼3.5 Hz, CH-3), 4.60 (d, 1H, J¼5.2 Hz, CH-30); 13C NMR
(D2O) d 22.47 (CH3-6), 24.25 (CH3-60), 60.98 (C-10), 63.30
(C-1), 72.70 (C-4), 76.06 (C-40), 76.91 (C-3), 80.06 (C-30),
98.52 (C-50), 106.83 (C-2), 108.86 (C-5), 111.51 (C-20); MS
(DCI, CH4) m/z 289 (MHþꢀ2H2O, 100); HRMS (m/z) calcd
for C12H17O8 (MHþꢀ2H2O): 289.0923, found: 289.0956.
4.14. 6-Deoxy-6-iodo-1,2:3,4-O-diisopropylidene-D-tagatose
(8)
To a solution of crude 7a (0.15 g, 0.4 mmol) in dry acetone
(2 ml) was added NaI (0.8 mmol, 0.8 mmol). The mixture was
stirred at rt, over night. The mixture was then partitioned be-
tween water and EtOAc. The aqueous layer was washed with
EtOAc (ꢂ2), and the combined organic layer was washed
with saturated aqueous Na2S2O3$5H2O and brine, dried over
MgSO4, filtered, and evaporated to give the crude product as
an orange oil. Chromatography (EtOAcehexane, 1:9) gave 8
4.17. 1-Hydroxymethyl-1,10:2,3-O-diisopropylidene-cyclo-
pentane-1,2,3,4-tetraol (12)
To a solution of 9 (0.57 g, 2.35 mmol) in dry toluene (6 ml)
was added TIBAL (6 ml of a 1 M solution in toluene, 6 mmol)
at 0 ꢁC under Ar. The cooling bath was removed and the mixture
was allowed to stir for 2 h. Water was added dropwise at 0 ꢁC to
form a yellow suspension. The mixturewas then filtered through
Celite and partitioned between water and EtOAc. The aqueous
layer was washed with EtOAc (ꢂ2) and the combined organic
layer was washed with brine, dried over MgSO4, filtered, and
evaporated to give the crude product as a brown oil. Chromato-
graphy (EtOAcehexane, 1:9) gave 12 as a clear oil (0.16 mmol,
7%). 1H NMR d 1.31 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.41 (s, 3H,
CH3), 1.46 (s, 3H, CH3), 1.54 (dd, 1H, J¼13, 10.5 Hz, CH2-5),
2.32 (dd, 1H, J¼13, 6.5 Hz, CH2-5), 4.02 (d, 1H, J¼9.5 Hz,
CH2-10), 4.25 (d, 1H, J¼9.5 Hz, CH2-10), 4.24e4.31 (m, 1H,
CH-4), 4.34 (dd, 1H, J¼5.5, 1.5 Hz, CH-2), 4.57 (t, 1H,
J¼5.5 Hz, CH-3); 13C NMR (CDCl3) d 26.07 (CH3), 26.12
(CH3), 26.33 (CH3), 26.55 (CH3), 37.81 (C-5), 69.27 (C-10),
70.93 (C-4), 78.71 (C-3), 82.86 (C-2), 111.31 (C-1), 111.67
(C(CH3)2), 112.64 (C(CH3)2); HRMS (m/z) calcd for
C12H21O5 (MHþ): 245.1389, found: 245.1381.
1
as a yellow oil (0.35 mmol, 88%). H NMR d 1.33 (s, 3H,
CH3), 1.40 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.48 (s, 3H, CH3),
3.25 (dd, 1H, J¼9.5, 6 Hz, CH2-6), 3.33 (dd, 1H, J¼9.5, 8 Hz,
CH2-6), 4.03 (d, 1H, J¼9.5 Hz, CH2-1), 4.20 (ddd, 1H, J¼8,
6, 3.5 Hz, CH-5), 4.25 (d, 1H, J¼9.5 Hz, CH2-1), 4.64 (d, 1H,
J¼6 Hz, CH-3), 4.83 (dd, 1H, J¼6, 3.5 Hz, CH-4); 13C NMR
d ꢀ0.1 (C-6), 25.01 (CH3), 26.05 (CH3), 26.43 (2ꢂCH3),
69.36 (C-1), 79.75 (C-5), 79.80 (C-3), 85.44 (C-4), 111.87
(2ꢂCq), 112.93 (Cq); MS (CI, i-Bu) m/z 371 (MHþ, 15), 312
(100); HRMS (m/z) calcd for C12H19O5I (Mþ):370.0277, found:
370.0286.
4.15. 1,2:3,4-O-Diisopropylidene-5,6-anhydro-D-tagatose (9)
To a solution of 8 (0.81 g, 2.2 mmol) in dry pyridine (20 ml)
and dry CH2Cl2 (13 ml) was added AgF (4.2 g, 33 mmol) at rt in
the dark. The mixture was stirred at rt, in the dark for a week to
form a black solution. The mixture was filtered, and the filtrate
was partitioned between 1 M HCl and EtOAc. The organic layer
was washed with water and brine, dried over MgSO4, filtered,
and evaporated to give the crude product as a dark brown oil.
Chromatography (EtOAcehexane, 0.5:9.5) gave 9 as a light yel-
low oily-solid (0.88 mmol, 40%). 1H NMR d 1.36 (s, 3H, CH3),
1.42 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.51 (s, 3H, CH3), 4.16 (d,
1H, J¼10 Hz, CH2-1), 4.362 (d, 1H, J¼10 Hz, CH2-1), 4.364
(dd, 1H, J¼2, 1 Hz, CH2-6), 4.56 (d, 1H, J¼5.5 Hz, CH-3),
4.58 (ddd, 1H, J¼2, 1, 0.5 Hz, CH-6), 5.12 (dt, 1H, J¼5.5,
1 Hz, CH-4); 13C NMR d 25.95 (CH3), 26.30 (CH3), 26.44
(CH3), 26.84 (CH3), 69.80 (C-1), 79.47 (C-4), 83.03 (C-3),
88.35 (C-6), 112.67 (C(CH3)2), 112.95 (C(CH3)2), 113.53
(C-2), 160.00 (C-5); MS (CI, i-Bu) m/z 243 (MHþ, 100); HRMS
(m/z) calcd for C12H18O5 (Mþ): 242.1154, found: 242.1171.
4.18. 4-Hydroxymethyl-4-isopropoxy-2,3-O-isopropylidene-
cyclopentane-1,2,3,-triol (13)
To a solution of 9 (0.2 g, 0.83 mmol) in dry toluene (4 ml)
was added TIBAL (4 ml of a 1 M solution in toluene, 4 mmol)
at 0 ꢁC under Ar. The cooling bath was removed and the mix-
ture was allowed to stir at rt over night. Water was added drop-
wise at 0 ꢁC to form a yellow suspension. The mixture was
then filtered through Celite and partitioned between water
and EtOAc. The aqueous layer was washed with EtOAc
(ꢂ2) and the combined organic layer was washed with brine,
dried over MgSO4, filtered, and evaporated to give the crude
product as a brown oil. Chromatography (EtOAcehexane,
1:9) gave 13 as a clear oil (0.03 mmol, 4%). 1H NMR
d 1.166 (d, 3H, J¼6.5 Hz, CHCH3), 1.169 (d, 3H, J¼6.5 Hz,
CHCH3), 1.35 (s, 3H, CH3), 1.47 (s, 3H, CH3), 1.52 (dd,
1H, J¼12.5, 10.5 Hz, CH2-5), 1.97 (dd, 1H, J¼12.5, 5.5 Hz,
CH2-5), 3.34 (d, 1H, J¼9 Hz, CH2OH), 3.60 (d, 1H,
J¼9 Hz, CH2OH), 3.62 (sext, 1H, J¼6.5 Hz, CH(CH3)2),
4.26 (dd, 1H, J¼5.5, 1.5 Hz, CH-3), 4.34 (dt, 1H, J¼10.5,
5.5 Hz, CH-1), 4.62 (t, 1H, J¼5.5 Hz, CH-2); 13C NMR
d 22.05 (CHCH3), 24.31 (CHCH3), 26.12 (CH3), 30.83 (C-5),
4.16. 6-Deoxytagatoso[2,5-b]-6-deoxytagatose (11)
To a solution of 9 (42 mg, 0.17 mmol) in water (2.5 ml) and
acetone (2.5 ml) was added Dowex-50WX8-100 (0.5 g). The
mixture was refluxed for 3.5 h, and was then filtered and evap-
orated to give the crude product as an orange oil. Chromatog-
raphy (EtOAcehexane, 1:1) gave 11 as a light yellow oil
1
(0.17 mmol, 100%). H NMR (D2O) d 1.49 (s, 3H, CH3-60),

Y. Bechor, A. Albeck / Tetrahedron 64 (2008) 2080e2089
2089
3. (a) Bender, S. L.; Widlanski, T.; Knowles, J. R. Biochemistry 1989, 28,
7560e7572; (b) Widlanski, T.; Bender, S. L.; Knowles, J. R. Biochemistry
1989, 28, 7572e7582.
39.98 (CH3), 69.49 (CH(CH3)2), 70.75 (CH2OH), 72.46 (C-3),
78.34 (C-4), 78.82 (C-1), 84.22 (C-2). HRMS (m/z) calcd for
C12H23O5 (MHþ): 247.1546, found: 247.1560.
4. (a) Neogi, A.; Majhi, T. P.; Ghoshal, N.; Chattopadhyay, P. Tetrahedron
2005, 61, 9368e9374; (b) Boyer, S. H.; Ugarkar, B. G.; Solbach, J.;
Kopcho, J.; Matelich, M. C.; Ollis, K.; Gomez-Galeno, J. E.; Mendonca,
R.; Tsuchiya, M.; Nagahisa, A.; Nakane, M.; Wiesner, J. B.; Erion, M. D.
J. Med. Chem. 2005, 48, 6430e6441; (c) Deleuze, A.; Menozzi, C.;
4.19. 2-Hydroxymethyl-3,4-O-isopropylidene-7,7-dimethyl-
oxepane-3,4,5-triol (14)
Sollogoub, M.; Sinay, P. Angew. Chem., Int. Ed. 2004, 43, 6680e6683;
¨
To a mixture of 9 (0.43 g, 1.40 mmol) in dry toluene (14 ml)
was added TIBAL (5.6 ml of a 1 M solution in toluene,
5.6 mmol) at ꢀ78 ꢁC under Ar. The cooling bath was removed
and the mixture was allowed to stir at rt over night. Saturated
aqueous NaHCO3 (20 ml) was added at 0 ꢁC to form a yellow
suspension. The mixture was then filtered through Celite and
partitioned between water and EtOAc. The aqueous layer was
washed with EtOAc (ꢂ2) and the combined organic layer was
washed with brine, dried over MgSO4, filtered, and evaporated
to give the crude product as a yellow oil. Chromatography
(EtOAcehexane, 1:5) gave 14 as a clear oil (0.08 mmol, 6%).
1H NMR d 1.24 (s, 3H, (C-7)eCH3), 1.25 (s, 3H, (C-7)e
CH3), 1.42 (s, 3H, CH3), 1.55 (s, 3H, CH3), 1.92 (dd, 1H,
J¼15, 9 Hz, CH2-6), 1.99 (dd, 1H, J¼15, 7 Hz, CH2-6), 3.37
(dd, 1H, J¼13, 9 Hz, CH2OH), 3.95 (dd, 1H, J¼13, 6 Hz,
CH2OH), 4.08 (ddd, 1H, J¼9, 7, 3 Hz, CH-5), 4.27 (dd, 1H,
J¼9.5, 7 Hz, CH-3), 4.51 (td, 1H, J¼9.5, 6 Hz, CH-2), 4.57
(dd, 1H, J¼7, 3 Hz, CH-4); 13C NMR d 24.46 (CH3), 26.26
((C-7)eCH3), 26.85 (CH3), 27.96 ((C-7)eCH3), 43.20 (C-6),
63.82 (CH2OH), 68.02 (C-5), 69.64 (C-2), 74.19 (C-7), 77.90
(C-4), 80.29 (C-3), 107.64 (C(CH3)2); MS (DCI, CH4) m/z
247 (MHþ, 42), 189 (66); HRMS (m/z) calcd for C12H23O5
(MHþ): 247.1545, found: 147.1554.
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Acknowledgements
We thank Hugo Gottlieb for his help with the NMR
assignments.
14. (a) Sollogoub, M.; Mallet, J.-M.; Sinay, P. Angew. Chem. Int. Ed. 2000,
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Supplementary data
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2779e2831.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.12.049.
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