Synthesis of vinyl glycosides and carbohydrate vinyl ethers from mixed acetals: A hetero-Diels-Alder approach to deoxygenated disaccharides

Article abstract of DOI:10.1016/j.tetasy.2004.11.033

A new method for the synthesis of vinyl glycosides and carbohydrate vinyl ethers is described. Mixed acetal glycosides and other types of carbohydrate mixed acetals are treated with TMS-triflate and an amine base, conditions developed by Gassman for the synthesis of enol ethers from acetals. The elimination proceeds regioselectively in most cases but also gives silyl ethers as side products in others. The hetero-Diels-Alder reactions of carbohydrate 3-O- and 6-O-vinyl ethers with ethyl (E)-ethoxymethylenepyruvate were carried out as part of a model study for the synthesis of deoxygenated disaccharides of antibiotics.

Full text of DOI:10.1016/j.tetasy.2004.11.033

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 273–282
Synthesis of vinyl glycosides and carbohydrate vinyl ethers from
mixed acetals: a hetero-Diels–Alder approach to deoxygenated
disaccharides
Kevin D. Hughes, Tuan-Linh N. Nguyen, Damian Dyckman, Doreen Dulay,
Walter J. Boyko and Robert M. Giuliano*
Department of Chemistry, Villanova University, Villanova, PA 19085, USA
Received 1 November 2004; accepted 17 November 2004
Available online 8 January 2005
Abstract—A new method for the synthesis of vinyl glycosides and carbohydrate vinyl ethers is described. Mixed acetal glycosides
and other types of carbohydrate mixed acetals are treated with TMS-triflate and an amine base, conditions developed by Gassman
for the synthesis of enol ethers from acetals. The elimination proceeds regioselectively in most cases but also gives silyl ethers as side
products in others. The hetero-Diels–Alder reactions of carbohydrate 3-O- and 6-O-vinyl ethers with ethyl (E)-ethoxymethylene-
pyruvate were carried out as part of a model study for the synthesis of deoxygenated disaccharides of antibiotics.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
CH2OR
Ph
O
O
O
RO
RO
O
Carbohydrates in which the anomeric hydroxyl group is
derivatized as a vinyl ether (vinyl glycosides) have
numerous applications in carbohydrate chemistry. Vinyl
glycosides have been used as substrates in cycloaddition
reactions, both as chiral auxiliaries in inverse-electron-
demand cycloadditions to give homochiral tetralins,1
and as precursors to enantiomerically pure cyclobuta-
nols.2 Vinyl glycosides that are unsaturated at C2–C3
undergo thermal Claisen rearrangement to give C-3
branched glycal derivatives.3 Isopropenyl4 and butenyl5
glycosides have been used extensively as glycosyl donors
in oligosaccharide synthesis. Structurally related carbo-
hydrate vinyl ethers, in which the vinyl group is attached
to nonanomeric hydroxyl groups, have been utilized in
the synthesis of cyclooctanoic mimetics of carbohy-
drates,6 as precursors to C-glycosides,7 and as intermedi-
ates in the synthesis of b-mannosides by intramolecular
tethering and delivery.8 In studies of carbohydrate
processing enzymes, vinyl glycosides and mixed acetal
glycosides have been investigated as substrates for
glycosidases.9 Structures of vinyl glycosides and a carbo-
hydrate vinyl ether are illustrated in Figure 1.
RO
RO
O
OCH3
O
R
3-O-vinyl ether
vinyl glycosides
Figure 1. Vinyl glycosides and carbohydrates vinyl ethers.
These applications demonstrate the potential of vinyl
glycosides and related carbohydrate vinyl ethers in syn-
thetic carbohydrate chemistry; however, there are draw-
backs associated with their preparation. The synthesis of
these compounds is usually carried out with mercury
reagents. Most other methods involve several steps
and proceed in low overall yield. Vinyl glycosides are
most often synthesized by transvinylation with mercuric
acetate10 or from glycosyl halides by nucleophilic dis-
placement with bis(acylmethyl)mercury reagents.11
Elimination reactions of 2-(phenylselenyl)ethyl glyco-
sides12 and 2-(trimethylammonium)ethyl glycosides,10
and photolysis of 4-oxopentyl glycosides by Norrish
type II reactions also give vinyl glycosides.13 Palla-
dium-catalyzed vinylation of protected monosaccha-
rides has recently been reported,14 and Tebbe
methylenation has been used to prepared both vinyl
glycosides and vinylated sugar derivatives involving a
*
Corresponding author. Tel.: +1 610 519 5433; fax: +1 610 519 7167;
e-mail: robert.giuliano@villanova.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.033

274
K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
nonanomeric hydroxyl group.4,7 In earlier studies, the
addition of acetylene at high pressure was used to pre-
pared vinyl ethers of carbohydrates for use in polymer
synthesis.15
nearly equal amounts, with no attempt at separation
being made. However, extensive NMR assignments
could be carried out on the mixture. For mixed acetal
1, the ratio of a to b anomer was 9:1, while only traces
of b anomer were observed for 3. The elimination step
could be carried out without any further purification
of the mixed acetals; however, longer reaction times,
up to two days in some cases, were required. Purification
of the mixed acetals could be carried out by column
chromatography on Florisil because the acid-sensitivity
of these compounds precludes the use of silica gel. Treat-
ment of the mixed acetal glycosides with TMS-triflate
and triethylamine gave the desired vinylated products
in acceptable yields, with the exception of the 6-O-vinyl
ether. The main cause for reduction in yield of the viny-
lated product in the elimination step is the competing
formation of silyl ether (Scheme 1). Complexation of
the trimethylsilyl cation with the anomeric oxygen gives
intermediate A, in which the O1 (pyranose)–CH bond is
activated for cleavage, and results in formation of silyl
ether 9. Silyl ether 9 was isolated along with vinyl glyco-
sides 2 and 4. Complexation of the trimethylsilyl cation
with the ethoxy group oxygen gives intermediate B and
produces the desired vinyl glycosides. Competition
between these two pathways ultimately determines the
regioselectivity of the elimination step, and previous
studies reveal some interesting characteristics of this
type of process.
TMS triflate
OCH3
OCH3
ð1Þ
(iPr)2NEt
OCH3
CH2Cl2
Our research on the synthesis of carbohydrate compo-
nents of antibiotics required a flexible, efficient route
to carbohydrate vinyl ethers, as part of a program aimed
at oligosaccharides that contain highly deoxygenated
sugars. In preliminary studies, we have demonstrated
that a new route to vinyl glycosides and carbohydrate
vinyl ethers can be developed based upon a synthesis
of vinyl ethers from symmetrical acetals, first reported
by Gassman in 1994.16 In this reaction, acetals are trea-
ted with trimethylsilyltrifluoromethane sulfonate and
DIPEA (Eq. 1). Dujardin et al. reported the preparation
of vinyl ethers derived from chiral secondary alcohols
such as menthol using a similar method, with triethyl-
amine as the base.17 The application of three methods
to the synthesis of vinyl glycosides requires the prepara-
tion of mixed acetal glycosides, which are readily acces-
sible by the treatment of monosaccharides with simple
vinyl ethers in the presence of an acid catalyst.18 The
resulting mixed acetals are then subjected to the elimina-
tion reaction. In preliminary studies, we found that the
mixed acetal glycoside derived from 2,3,4,6-tetra-O-ben-
zyl-D-glucopyranoside and ethyl vinyl ether underwent
facile elimination in the presence of trimethylsilyltrifluo-
romethanesulfonate and triethylamine to give vinyl a-D-
glucopyranoside 2 in 68% yield after purification by
flash chromatography (Eq. 2).19 Products resulting from
ring-opening or glycals derived from elimination of the
anomeric substituent were not observed. Herein, we de-
scribe the preparation of a number of vinyl glycosides
and carbohydrate vinyl ethers using this method. Two
examples of the use of carbohydrate vinyl ethers in
hetero-Diels–Alder reactions are also described.
OCH3
OCH3
TMS triflate
OCH3
OCH3
(iPr)2NEt
CH2Cl2
CH3
CH3
major
CH3
minor
ð3Þ
The results Gassman obtained with acetals derived from
cyclic ketones revealed a preference for the formation of
the less-substituted alkene from unsymmetrical sub-
CH2OBn
CH2OBn
CH2OBn
TMSOTf
O
ethyl vinyl
ether, PPTS
O
O
BnO
BnO
BnO
BnO
BnO
CH2Cl2
BnO
BnO
BnO
BnO
ð2Þ
OH
NEt3
CH2Cl2
O
Me
OEt
O
2
1
Vinyl glycosides and carbohydrate vinyl ethers that were
prepared herein are shown in Table 1. Monosaccharides
were treated with ethyl vinyl ether (entries 1, 3, and 4) or
2-methoxypropene (entry 2) in the presence of PPTS to
give mixed acetals. Reactions were straightforward and
conversions were usually complete within 2 h, with no
side products observed. In reactions involving ethyl
vinyl ether, a mixture of diastereomers is produced in
strates (Eq. 3), and it was proposed that this occurs in
the elimination step by abstraction of the less hindered
proton by the hindered base. The ratio of the major
and minor products (88:12) does not correspond to the
expected thermodynamic ratio (63:37) for the dimethyl
acetal derived from 2-methylcyclohexanone, as the
authors noted, yet the reaction was thought to proceed
from an initial and reversible complexation of the silyl-

K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
Table 1. Synthesis of vinyl glycosides and carbohydrate vinyl ethers
275
Entry
Substrate
Mixed acetal
Vinylated product
CH2OBn
CH2OBn
CH2OBn
O
O
BnO
BnO
BnO
O
1
BnO
BnO
BnO
BnO
O
BnO
BnO
OH
OH
Me
OEt
O
2
(68%)
1 (93%)
CH2OBn
O
CH2OBn
O
BnO
BnO
BnO
BnO
CH2OBn
O
BnO
BnO
BnO
2
BnO
Me
O
Me
O
BnO
OMe
4 (56%)
3 (quant)
Me
OEt
OH
O
O
O
O
O
Me
BnO
BnO
BnO
BnO
BnO
BnO
3
BnO
BnO
BnO
OMe
OMe
OMe
O
5 (99%)
6 (21%)
Ph
O
O
Ph
O
O
O
Ph
O
O
O
Me
O
4
OMe
O
OMe
OH
OMe
OEt
8 (56%)
7 (92%)
CH2OR
CH2OR
CH2OR
O
O
O
SiMe3
OEt
RO
RO
RO
RO
RO
RO
RO
RO
RO
OEt
O
O
OEt
O
Me3Si
B
A
1
CH2OR
CH2OR
O
O
RO
RO
RO
RO
RO
RO
OSiMe3
O
9
2
Scheme 1. Regioselectivity of vinyl glycoside formation.
ating reagent. Loss of a proton from the sterically less
hindered site seems to provide the basis for selectivity
according to these authors. The importance of steric fac-
tors in the elimination was further demonstrated in the
study of Dujardin, in which different bases influenced
the regioselectivity of the elimination from mixed acetals
of menthol and other alcohols.17 As applied to carbohy-
drate substrates in this study, the Gassman procedure
gave acceptable yields of vinyl glycosides with minimal
formation of silyl ether in entries 1 and 4 in Table 1.
We had only modest success in obtaining less silyl ether
in one case by using diisopropylethylamine instead of
triethylamine (entry 2). A more extensive survey of reac-
tion conditions needs to be conducted to optimize the
elimination step for vinyl glycoside and carbohydrate
vinyl ether synthesis. The silyl ethers were separated
from the vinylated products by flash chromatography.
We were unable to synthesize vinyl glycosides or ethers
containing ester protecting groups by the Gassman
method. Side reactions occurred in the case of acetylated
sugars during the elimination step, and benzoylated sug-
ars reacted very slowly. However, vinyl 2,3,4,6-tetra-O-
acetyl-a-D-glucopyranoside 10 could be obtained in high

276
K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
yield from the corresponding tetra-O-benzyl ether by
reductive debenzylation followed by acetylation (Eq.
4).20
oxymethylenepyruvate because of it had been shown
previously to undergo cycloadditions with vinyl ethers,
as a route to deoxy sugars23 and the lactone moiety
of compactin.26,27 Synthesis of a disaccharide by this
approach requires that the carbohydrate vinyl ether
CH2OBn
O
CH2OAc
O
1. NH3, Na, -45 oC
2. Ac2O, pyr
BnO
BnO
AcO
AcO
undergo cycloaddition efficiently with
a suitable
BnO
AcO
heterodiene, with functionality that can be further
elaborated to the deoxy sugar. Because two new stereo-
genic centers are formed in this reaction, there are
four possible products, assuming a unique regiochem-
istry for the cycloaddition step. When 8 was treated
with ethyl (E)-ethoxymethylenepyruvate in the pres-
ence of a catalyst, a 64% yield of two cycloadducts
was obtained (Scheme 2). The products were formed
in equal amounts. Structures for these were assigned
as 11 and 12 based on extensive NMR analysis,
including 2D and NOE difference spectroscopy. Irradi-
ation of the anomeric proton on the unsaturated ring
resulted in a 7% enhancement of the C-3 proton on
this ring. The other product was assumed to have
the opposite configuration at these two newly formed
stereogenic centers. The resulting stereochemistry in
both cycloadducts is consistent with literature prece-
dent and results from endo-addition from the two
heterodienophile faces.23 Similarly, cycloaddition of
6-O-vinyl ether 6 with the same heterodiene gave
cycloadducts 13 and 14 in 53% yield, which were also
assigned as the endo-adducts. The functionality present
in these cycloadducts, while amenable to conversion to
a disaccharide, is not well suited for the synthesis of
disaccharides of antibiotics that contain rhodinose or
amicetose, because of the additional transformations
that would be required. A number of steps would be
required to modify the ester group in the heterodiene,
and the ethoxy group would be difficult to work with.
It should be possible; however, to carry out the
cycloaddition step with other heterodienes as well as
with different carbohydrate substrates that would
more closely resemble the final sugar residues in the
antibiotics. Further studies of the cycloaddition of
carbohydrate vinyl ethers with heterodienes are in
progress.
O
O
2
10
ð4Þ
The synthesis of styryl glycosides by this method was
problematic for different reasons. Condensation of tet-
ra-O-benzyl-D-glucopyranose with a-methoxystyrene
gave good yields of the mixed acetal glycoside; however,
the elimination step produced a complex mixture of
products, perhaps due to the possibility of rearrange-
ment of the styryl glycosides to carbon-linked glyco-
sides. This rearrangement has been demonstrated for
THP-substituted styryl ethers (Eq. 5).21
R
O
O
R
Ph
Ph
CH2
Lewis acid
O
O
ð5Þ
Aside from the use of vinyl glycosides as chiral auxilia-
ries in the Bradsher reaction and the cyclobutane syn-
thesis, there have been few examples of the use of
vinyl glycosides or other carbohydrate vinyl ethers in
cycloaddition reactions, with the exception of glycals.22
Dujardin et al. have described the asymmetric synthesis
of monosaccharides by cycloaddition of unsaturated
carbonyl compounds with chiral vinyl ethers derived
from noncarbohydrates.23 Earlier work by Catelani
showed that deoxygenated monosaccharides such as
amicetose can be synthesized in racemic form by the
hetero-Diels–Alder reaction of methyl vinyl ketone
and isobutyl vinyl ether, followed by hydroboration–
oxidation (Eq. 6).24
O
OiBu
.
H3C
O
OiBu
H3C
HO
O
OiBu
1. BH3 Me2S
ð6Þ
2. H2O2
isobutyl amicetosides
During the course of our studies of the synthesis of
carbohydrate components of antibiotics, it occurred
to us that highly deoxygenated sugars25 such as amice-
tose or rhodinose could be constructed onto sugar
templates by a hetero-Diels–Alder reaction of a carbo-
hydrate vinyl ether with an unsaturated carbonyl com-
pound. The resulting cycloadducts can then be
transformed into oligosaccharide components of anti-
biotics. Among possible hetero-dienes to explore the
feasibility of this approach, we chose ethyl (E)-eth-
2. Experimental
2.1. General methods
1H NMR spectra were recorded at 300 MHz with TMS
as an internal reference in CDCl3, and 13C NMR spectra
were recorded at 75 MHz and referenced with CDCl3,
unless otherwise noted. Melting points were determined
in an open capillary tube with a Thomas Hoover appa-
ratus and are uncorrected. TLC analyses were con-

K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
277
Ph
Ph
O
O
O
O
EtO2C
O
pet. ether/toluene
Eu(fod)3, 100 oC
(64%)
O
O
O
OCH3
OCH3
O
O
EtO2C
OEt
8
11
OEt
Ph
O
O
O
O
OCH3
O
EtO2C
12
OEt
Scheme 2. Hetero-Diels–Alder approach to 3-O-linked deoxy disaccharides.
ducted on aluminum-backed silica gel Kieselgel 60 F254
plates and visualized by UV254 nm or with ammonium
molybdate–ceric sulfate reagent. Flash chromatogra-
phy28 was carried out with ÔBakerÕ silica gel. Optical
rotations were recorded on a Perkin–Elmer 241 polari-
meter as [a]D values at 23 ꢁC. Elemental analyses were
carried out at Robertson Microlit Laboratories. High
resolution mass spectra were measured at the University
of Pennsylvania Mass Spectrometry Laboratory, using
electrospray ionization.
(ABq, 2H, J 10.9, PhCH2), 4.54 (ABq, 2H, J 12.2,
PhCH2), 4.03 (dd, J3,4 9.0, H-3), 3.83 (dddd, 1H, J1,5
0
0.6, J5,4 10.0, J5,6 3.4, J5,6 1.9, H-5), 3.73 (dq, 1H, J
9.3, 7.1, OCH2CH3), 3.73 (dq, 1H, H-60), 3.65 (dd,
0
1H, J4,3 9.0, H-4), 3.61 (dd, 1H, J6,6 10.6, H-6), 3.60
(dd 1H, J2,3 9.7, H-2), 3.50 (dq, 1H, OCH2CH3), 1.37
(d, 3H, OCHCH3), 1.17 (t, 3H, OCH2CH3); 13C NMR
(major isomer) d 138.8–137.8, 128.3–127.7, 98.3, 94.0,
82.0, 79.6, 77.8, 75.5, 75.0, 73.4, 73.1, 70.6, 68.5, 60.8,
20.8, 15.1; 1H NMR (minor isomer) d 7.36–7.12 (m,
20H, Ph–H), 5.17 (d, 1H, J1,2 3.7, H-1), 4.91 (ABq,
2H, J 10.9, PhCH2), 4.84 (q, 1H, J 5.3, OCHCH3),
4.72 (ABq, 2H, J 11.8, PhCH2), 4.83 (ABq, 2H, J
10.9, PhCH2), 4.53 (ABq, 2H, J 12.2, PhCH2), 4.02
(dd, J3,4 9.0, H-3), 3.96 (dddd, 1H, J1,5 0.5, J5,4 10.0,
2.2. General procedure of the preparation of mixed acetals
Ethyl vinyl ether (5 M equiv) and PPTS (10 mg/mmol of
carbohydrate substrate) were added to a solution the
starting carbohydrate in dry dichloromethane (10 mL/
mol) and the mixture was stirred at room temperature
for 1–2 h. Progress of the reaction was monitored by
TLC using 20% ethyl acetate/hexanes; the mixed acetals
had much higher Rf values than the starting carbohy-
drates (see below). Solid NaHCO3 (1 g) was added and
after stirring 10 min, the mixture was filtered, dried
(MgSO4), and concentrated to an oil containing a mix-
ture of two diastereomeric mixed acetals. The product
was used directly for preparation of the vinyl glycosides
and carbohydrate vinyl ethers; however, by flash chro-
matography over Florisil gave analytically pure
products.
0
J5,6 3.6, J5,6 2.2, H-5), 3.86 (dq, 1H, J 9.3, 7.1,
OCH2CH3), 3.74 (dq, 1H, H-60), 3.67 (dd, 1H, J4,3 9.0,
0
H-4), 3.60 (dd, 1H, J6,6 10.6, H-6), 3.57 (dd 1H, J2,3
9.7, H-2), 3.43 (dq, 1H, OCH2CH3), 1.38 (d,
3H, OCHCH3), 1.13 (t, 3H, OCH2CH3); 13C NMR
(major isomer) d 138.8–137.8, 128.3–127.7, 99.9, 92.4,
82.0, 79.9, 77.8, 75.5, 74.8, 73.4, 73.1, 70.6, 68.6, 62.8,
20.9, 14.9. Anal. Calcd for C38H44O7: C, 74.48; H,
7.24. Found: C, 74.69; H, 7.19.
2.4. 1-Methoxy-1-methylethyl 2,3,4,6-tetra-O-benzyl-a-
D-glucopyranoside 3
To a solution of 2,3,4,6-tetra-O-benzyl-a-D-glucopyra-
nose (0.54 g, 1 mmol) in anhydrous dichloromethane
(20 mL) was added pyridinium p-toluenesulfonate
(10 mg) and 2-methoxypropene (0.5 mL, 5 equiv) and
the mixture was stirred at room temperature for 2 h.
Solid sodium carbonate was added and after stirring
briefly, the mixture was filtered and the filtrate concen-
trated to an oil, which was dried under vacuum
(0.635 g, quantitative): [a]D = +60 (c 1.1, chloroform),
1H NMR d 7.35–7.11 (m, 20H, Ph–H), 5.36 (d, 1H,
J1,2 3.5, H-1), 4.92 (ABq, 2H, J 10.9, PhCH2), 4.72
(ABq, 2H, J 11.6, PhCH2), 4.65 (ABq, 2H, J 10.6,
2.3. 1-Ethoxyethyl 2,3,4,6-tetra-O-benzyl-a-D-glucopyr-
anoside 1
From 1.5 g (2.77 mmol) of 2,3,4,6-tetra-O-benzyl-a-D-
glucopyranose there was obtained 1.58 g (93%) of mixed
acetal glycoside 1 as an inseparable mixture of diastereo-
mers: Rf 0.44 (20% ethyl acetate/hexanes), [a]D = +29.2
1
(c 0.61, chloroform), H NMR29 (major isomer) d
7.36–7.12 (m, 20H, Ph–H), 5.17 (d, 1H, J1,2 3.7, H-1),
4.91 (ABq, 2H, J 10.9, PhCH2), 4.90 (q, 1H, J 5.3,
OCHCH3), 4.73 (ABq, 2H, J 11.8, PhCH2), 4.66

278
K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
PhCH2), 4.55 (ABq, 2H, J 12.2, PhCH2), 4.04 (dd, J3,4
0
9.0, H-3), 3.92 (ddd, 1H, J5,4 10.0, J5,6 3.6, J5,6 2.0, H-
1), 4.29 (m, 2H, H-5, H-6), 4.15 (q, 1H, J3,4 2.5, H-3),
3.69 (t, 1H, J6,6 12.1, H-60), 3.79 (dq, 1H, J 9.4,
0
0
5), 3.75 (dd, 1H, J6,6 10.5, H-6), 3.68 (dd, 1H, J4,3
OCH2CH3), 3.62 (dd, 1H, J4,5 9.3, H-4), 3.57 (dq, 1H,
OCH2CH3), 3.36 (s, 3H, OCH3), 2.16 (ddd, 1H, J2eq,3
2.8, H-2eq), 1.91 (ddd, 1H, J2ax,3 3.4, H-2ax), 1.32 (d,
1H, OCHCH3), 1.11 (t, 3H, OCH2CH3); 13C NMR
(minor isomer) d 137.8, 128.9, 128.0, 126.1, 101.8,
98.1, 97.9, 79.2, 69.6, 66.0, 60.0, 58.1, 55.3, 34.2, 19.9,
15.1. Anal. Calcd for C18H26O6: C, 63.89; H, 7.74.
Found: C, 63.55; H, 7.53.
10.0, H-4), 3.60 (dd, 1H, H-60), 3.58 (dd 1H, J2,3 9.8,
H-2), 3.28 (s, 3H, OCH3), 1.43 (s, 3H, CH3), 1.38 (s,
3H, CH3); 13C NMR d 138.9–137.3 (4C), 128.4–127.4
(20C), 101.1 (CMe2), 89.8 (C-1), 82.0 (C-3), 80.1 (C-2),
78.0 (C-4), 75.4 (PhCH2), 75.0 (PhCH2), 73.4 (PhCH2),
73.3 (PhCH2), 70.2 (C-5), 68.7 (C-6), 49.3 (OCH3),
26.4 (CH3), 24.6 (CH3). HRMS (ES+) Anal. Calcd for
C38H44O7Na [M+Na]: 635.3009. Found: 635.2985.
2.7. Vinyl 2,3,4,6-tetra-O-benzyl-a-D-glucopyranoside 2
2.5. Methyl 2,3,4-tri-O-benzyl-6-O-(1-ethoxyethyl)-a-D-
glucopyranoside 5
To a solution of acetal 1 (1.75 g, 2.86 mmol) in anhy-
drous dichloromethane (10 mL) at 0 ꢁC under nitrogen
was added freshly distilled triethylamine (0.3 g,
2.97 mmol) followed by trimethylsilyltrifluoromethane-
sulfonate (0.689 g, 2.92 mmol) over a 5 min period.
After 1 h, 1.0 M NaOH (4 mL) was added followed by
diethyl ether (15 mL). The organic phase was separated,
dried (MgSO4) and concentrated to an oil (1.74 g),
which was purified by flash chromatography on silica
gel using 20% ethyl acetate/hexanes to give vinyl glyco-
side 2; yield, 0.83 g (51%). In a different run, 1.25 g
(2.04 mmol) of mixed acetal was treated with 1.5 equiv
of triethylamine and 1.3 equiv of TMS-triflate overnight
at room temperature, to give 388 mg (68%) of vinyl gly-
coside after purification by flash chromatography: Rf
From 0.271 g (0.585 mmol) of methyl 2,3,4-tri-O-benz-
yl-a-D-glucopyranoside30 there was obtained 0.311 g
(99%) of mixed acetal 5 as a mixture of inseparable dia-
stereomers: Rf 0.30 (20% ethyl acetate/hexanes),
[a]D = +44 (c 1.0, chloroform), 1H NMR (major isomer)
d 7.37–7.28 (m, 15H, Ph–H), 4.86 (ABq, 2H, J 10.8,
PhCH2), 4.78 (ABq, 2H, J 11.0, PhCH2), 4.73 (ABq,
2H, J 12.3, PhCH2), 4.72 (q, 1H, J 5.4, OCHCH3),
4.62 (d, 1H, J1,2 3.5, H-1), 4.00 (dd, 1H, J 9.8, 8.8,
0
0
H-3), 3.79 (dd, 1H, J6,6 10.8, J5,6 1.6, H-6), 3.725 (m,
1H, H-5), 3.64 (dq, 1H, J 9.5, 7.1 OCH2CH3),
3.60 (dd, 1H, J6,6 10.6, H-60), 3.54 (m, 1H, H-4),
0
3.54 (m, 1H, H-2), 3.44 (dq, 1H, OCH2CH3), 3.37 (3,
3H, OCH3), 1.29 (d, 1H, OCHCH3), 1.16 (t, 3H,
0.25 (20% ethyl acetate/hexanes), [a]D = +30.2 (c 0.7,
21
1
OCH2CH3); H NMR (minor isomer) d 7.37–7.28 (m,
chloroform), lit.10 ½aŠ ¼ þ30:9 (c 1.12, chloroform);
D
15H, Ph–H), 4.90 (ABq, 2H, J 10.8, PhCH2), 4.75
(ABq, 2H, J 11.0, PhCH2), 4.73 (ABq, 2H, J 12.3,
PhCH2), 4.66 (q, 1H, J 5.4, OCHCH3), 4.62 (d, 1H,
J1,2 3.5, H-1), 4.00 (dd, 1H, J 9.8, 8.8, H-3), 3.80 (dd,
1H NMR (major isomer) d 7.37–7.10 (m, 20H, Ph–H),
6.36 (dd, 1H, J 14.2, 6.5, vinyl), 5.07 (d, 1H, J1,2 3.5,
H-1), 4.92 (ABq, 2H, J 10.8, PhCH2), 4.72 (ABq, 2H,
J 12.2, PhCH2), 4.65 (ABq, 2H, J 10.9, PhCH2), 4.62
(dd, 1H, J 1.7, 14.2, vinyl), 4.51 (ABq, 2H, J 12.0,
PhCH2), 4.21 (dd, 1H, vinyl), 4.05 (dd, 1H, J3,2 9.6,
J3,4 8.3, H-3), 3.73 (m, 3H, H-5, H-6), 3.61 (dd, 1H,
H-2), 3.59 (m, 1H, H-60); 13C NMR d 138.6–137.7,
128.3–127.4, 148.4 (vinyl), 96.1 (C-1), 92.4 (vinyl), 81.8
(C-3), 79.2 (C-2), 77.2 (C-4), 75.6 (PhCH2), 74.9
(PhCH2), 73.3 (PhCH2), 73.2 (PhCH2), 70.1 (C-5), 68.0
(C-6). Anal. Calcd for C37H40O5: C, 76.30; H, 6.76.
Found: C, 76.45; H, 6.59.
0
0
1H, J6,6 10.6, J5,6 3.6, H-6), 3.725 (m, 1H, H-5), 3.60
0
(dd, 1H, J6,6 10.6, H-60), 3.57 (dq, 1H, J 9.3, 7.1
OCH2CH3), 3.54 (m, 1H, H-4), 3.54 (m, 1H, H-2),
3.46 (dq, 1H, OCH2CH3), 3.38 (3, 3H, OCH3), 1.29
(d, 1H, OCHCH3), 1.15 (t, 3H, OCH2CH3). Anal. Calcd
for C31H38O7: C, 71.24; H, 7.33. Found: C, 71.27; H,
7.46.
2.6. Methyl 4,6-O-benzylidene-3-O-(1-ethoxyethyl)-2-
deoxy-a-D-ribo-hexopyranoside 7
2.8. Methyl 2,3,4-tri-O-benzyl-6-O-vinyl-a-D-glucopyr-
anoside 6
From 1.29 g (4.84 mmol) of methyl 4,6-O-benzylidene-2-
deoxy-a-D-ribo-hexopyranoside31 there was obtained
1.51 g (92%) of mixed acetal 7 as a mixture of insepara-
ble diastereomers: Rf 0.16 (20% ethyl acetate/hexanes),
To a solution of acetal 5 (0.58 g, 1.08 mmol) in anhy-
drous dichloromethane (3.5 mL) at 0 ꢁC was added
freshly distilled triethylamine (0.12 g, 1.19 mmol)
followed by trimethylsilyltrifluoromethanesulfonate
1
[a]D = +201 (c 1.0, chloroform), H NMR (major iso-
mer) d 7.49–7.39 (m, 5H, Ph–H), 5.54 (s, 1H, PhCH),
4.89 (q, 1H, J 5.3, OCHCH3), 4.70 (dd, 1H, J1,2eq 0.7,
J1,2ax 4.5, H-1), 4.29 (m, 2H, H-5, H-6), 4.18 (1H, J3,4
(0.269 g, 1.14 mmol) over
a 5 min period. After
40 min, 1.0 M NaOH (4 mL) was added followed by
diethyl ether (25 mL). The organic phase was separated,
dried (MgSO4), and concentrated to an oil (0.431 g),
which was purified by flash chromatography on silica
gel using 20% ethyl acetate/hexanes to give analytically
pure vinyl ether 6; yield, 0.112 g (21%): Rf 0.48 (20%
ethyl acetate/hexanes), [a]D = +16.7 (c 1.0, chloroform),
1H NMR (major isomer) d 7.38–7.24 (m, 15H, Ph–H),
6.48 (dd, 1H, vinyl), 4.92 (ABq, 2H, J 10.9, PhCH2),
4.72 (ABq, 2H, J 11.6, PhCH2), 4.65 (ABq, 2H, J
10.6, PhCH2), 4.60 (d, 1H, J1,2 3.6, H-1), 4.18 (dd, 1H,
2.5, H-3), 3.69 (t, 1H, J6,6 12.0, H-60), 3.69 (dq, 1H, J
0
9.0, 7.1 OCH2CH3), 3.63 (dd, 1H, J4,5 9.3, H-4), 3.44
(dq, 1H, OCH2CH3), 3.37 (s, 3H, OCH3), 2.16 (ddd,
1H, J2eq,3 2.7, H-2eq), 2.02 (ddd, 1H, J2ax,3 3.9, H-
2ax), 1.37 (d, 1H, OCHCH3), 1.12 (t, 3H, OCH2CH3);
13C NMR (major isomer) d 137.7, 128.9, 128.1, 126.1,
101.9, 101.1, 97.8, 79.8, 69.5, 68.9, 60.2, 57.9, 55.3,
1
35.4, 20.7, 15.2; H NMR (minor isomer) d 7.49–7.39
(m, 5H, Ph–H), 5.56 (s, 1H, PhCH), 4.92 (q, 1H, J
5.4, OCHCH3), 4.70 (dd, 1H, J1,2eq 0.8, J1,2ax 4.6, H-

K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
279
vinyl), 4.02 (dd, 1H, vinyl), 4.00 (dd, 1H, J3,2 9.6, J3,4
9.4, H-3), 3.90–3.78 (m, 3H, H-5, H-6, H-60), 3.59 (dd,
1H, J4,5 9.0, H-4), 3.55 (dd, 1H, H-2), 3.37 (s, 3H,
OCH3); 13C NMR d 138.7–138.1 (3C), 128.4–127.5
(15C, Ph), 151.5 (vinyl), 98.2 (C-1), 87.0 (vinyl), 82.0
(C-3), 79.8 (C-2), 77.4 (C-4), 75.7 (PhCH2), 75.1
(PhCH2), 73.4 (PhCH2), 69.0 (C-5), 66.3 (C-6), 55.2
(OCH3). Anal. Calcd for C30H34O6: C, 73.45; H, 6.99.
Found: C, 73.27, 7.12.
OCH3), 2.31 (ddd, 1H, J2e,3 2.8, J2e,2a 15.1, H-2e), 1.98
(ddd, 1H, J2a,3 3.7, H-2a); 13C NMR d 152.7, 137.5,
129.0, 128.2, 126.3, 103.1, 97.6, 88.4, 78.9, 71.4, 69.4,
58.0, 55.3, 33.5. Anal. Calcd for C16H20O5: C, 65.74;
H, 6.90. Found: C, 65.43, 6.88.
2.11. Vinyl 2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside 10
Freshly cut sodium (212 mg, 9.22 mmol) was added in
small pieces to liquid ammonia (15 mL) at ꢀ43 ꢁC (ace-
tonitrile–dry ice bath). Approximately one-half of the
sodium was added to produce a blue color, followed
by a solution of vinyl 2,3,4,6-tetra-O-benzyl-a-D-gluco-
2.9. Isopropenyl 2,3,4,6-tetra-O-benzyl-a-D-glucopyrano-
side 4
To a solution of 1-methoxy-1-methylethyl 2,3,4,6-tetra-
O-benzyl-a-D-glucopyranoside 3 (0.61 g, 0.97 mmol) in
anhydrous dichloromethane (3 mL) was added triethyl-
amine (0.216 mL, 1.6 equiv) and, at 0 ꢁC, trimeth-
ylsilyltrifluorormethanesulfonate (0.297 g, 1.3 equiv)
under nitrogen and the mixture was stirred overnight
at room temperature. TLC (30% ethyl acetate/hexane)
showed the presence of starting material so additional
triethylamine (54 lL) and TMS-triflate (0.31 lL) were
added and the reaction was again stirred at rt overnight.
Aqueous sodium hydroxide solution (1 mL of 1.0) was
added followed by diethyl ether (50 mL). The mixture
was shaken and the organic phase separated, dried
(Na2SO4), and concentrated to a residue, which was
purified by flash chromatography using 20% ethyl ace-
tate/hexanes to give 0.318 g (56%) of isopropenyl glyco-
side 4 as a syrup: Rf 0.53 (20% ethyl acetate/hexanes).
pyranoside 2 (300 mg, 0.53 mmol) in dry THF
(1.5 mL), and then the remaining sodium was added.
The mixture was stirred at ꢀ43 ꢁC for 6 h. Solid ammo-
nium chloride was added and the mixture was allowed
to warm to room temperature. Remaining ammonia
was allowed to evaporate using a stream of argon, and
then dry pyridine (93 mL) was added followed by acetic
anhydride (1.0 mL) and the mixture was stirred over-
night at room temperature. The reaction was diluted
with dichloromethane (20 mL) and then washed with
satd aq NaHCO3. The organic phase was washed with
water, satd aq NaCl, dried (Na2SO4), and concentrated
to an oil that was purified by flash chromatography on a
Table 2. 1H data for hetero-Diels–Alder adduct 11
6
1
The H NMR spectrum matched that reported4 except
Ph
O
O
for one of the vinyl resonances, which the authors re-
O
4
2
5
1
ported and 4.24 and we assigned at 4.04: H NMR d
1
O
3
7.37–7.10 (m, 5H, Ph–H), 5.32 (d, 1H, J1,2 3.6, H-1),
4.92 (ABq, 2H, J 10.6, PhCH2), 4.70 (ABq, 2H, J
12.0, PhCH2), 4.65 (ABq, 2H, J 10.6, PhCH2), 4.53
(ABq, 2H, J 12.2, PhCH2), 4.29 (dd, 1H, J 1.6, vinyl),
4.04 (dq, 1H, J 1.6, 1.0 vinyl), 4.03 (dd, 1H, J3,2 9.6,
J3,4 8.7, H-3), 3.79–3.72 (m, 3H, H-4, H-5, H-6), 3.63
(dd, 1H, H-2), 3.59 (m, 1H, H-60), 1.86 (d, 3H, J 1.0,
CH3).
O
O
OCH3
A
1
CH3CH2O
H
B
4
2
3
H
OCH2CH3
1H A-ring
d (ppm)
1H B-ring
d (ppm)
1
2ax
4.69d
1
2
20
3
4
5.35dd
2.05ddd
2.32ddd
4.40q
2.34dddd
2.06dt
4.13dt
2.10. Methyl 4,6-O-benzylidene-2-deoxy-3-O-vinyl-a-D-
ribo-hexopyranoside 8
2eq
3
4
3.68dd
4.30m
4.30m
3.71t
6.04dd
4.24, 4.92 cm
1.28t
To a solution of acetal 7 (0.824 g, 2.43 mmol) in anhy-
drous dichloromethane (11 mL) at 0 ꢁC was added
freshly distilled triethylamine (0.258 g, 2.55 mmol)
followed by trimethylsilyltrifluoromethanesulfonate
(0.591 g, 2.5 mmol) over a 5 min period. After 40 min,
1.0 M NaOH (4 mL) was added followed by diethyl
ether (25 mL). The organic phase was separated, dried
(MgSO4) and concentrated to an oil (0.617 g), which
was purified by flash chromatography on silica gel using
20% ethyl acetate/hexanes to give solid 3-O-vinyl ether;
yield, 0.396 g (56%): Rf 0.25 (20% ethyl acetate/hexanes),
5
CH3CH2O2C
CH3CH2O2C
CH3CH2O
6
60
3.55, 3.49 cm
1.21t
OCH3
PhCH
Ph–H
3.34s
5.56s
CH3CH2O
o 7.45m;
m,p 7.38–7.35m
J
Hz
4.5
0.6
15.2
4.0
2.9
2.9
J
Hz
2.5
7.9
13.3
6.8
1.2
7.9
10.8
7.2
8.9
7.0
3.0
1, 2ax
1, 2eq
2ax, 2eq
2ax, 3
2eq, 3
3, 4
1, 2
1, 20
2, 20
2, 3
20, 4
20, 3
1
[a]D = +104.2 (c 1.0, chloroform), H NMR (major iso-
mer) d 7.43–7.33 (m, 5H, Ph–H), 6.41 (dd, 1H, J 14.1,
6.6, vinyl), 5.56 (s, 1H, PhCH), 4.72 (d, 1H, J1,2a 4.6,
J1,2e 0.7, H-1), 4.38 (dd, 1H, vinyl), 4.33 (m, 1H, J5,6
3, 1 (B-ring) Not measured
CH3CH2O2C
CH3CH2O2C
CH3CH2O
CH3CH2O
3, 4
4, 5
5, 6
5, 60
6, 60
9.1
Not measured
12.0
12.0
0
5.4, J5,6 12.2, H-5), 4.31 (m, 1H, J3,4 2.9, H-3), 4.30
0
(dd, 1H, J6,6 12.2, H-6), 4.04 (dd, 1H, vinyl), 3.71 (t,
1H, H-60), 3.70 (dd, 1H, J4,5 9.5, H-4), 3.38 (s, 3H,

280
K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
OEt
EtO2C
O
O
O
O
EtO2C
O
pet. ether/toluene
O
BnO
BnO
BnO
BnO
BnO
Eu(fod)3, 100 oC
(53%)
OCH3
BnO
OCH3
OEt
6
13
OEt
O
EtO2C
O
O
BnO
14
BnO
BnO
OCH3
Scheme 3. Hetero-Diels–Alder approach to 6-O-linked deoxy disaccharides.
Table 3. 1H NMR data for hetero-Diels–Alder adduct 12
solid tetraacetate 10: mp 103–105 ꢁC lit.9a mp 105 ꢁC;
21
[a]D = +129.8 (c 0.5, chloroform), lit.9a ½aŠ ¼ þ135:4
6
D
Ph
O
O
O
4
2
5
1
O
3
Table 4. 1H NMR data for hetero-Diels–Alder adduct 13
O
O
OCH3
A
1
OCH2CH3
CH3CH2O
H
B
3
4
2
2
1
4
B
3
H
OCH2CH3
CH3CH2O2C
O
1H A-ring
d (ppm)
1H B-ring
d (ppm)
O
6
4
1
2ax
4.66d
1
2
5.47dd
2.24m
5
O
BnO
BnO
1.99ddd
2.14ddd
4.40q
2
2eq
3
20
1.86ddd
4.29m
1
3
3
OBn
4
3.66dd
4.29m
4.29m
3.71t
4
6.18dd
4.26–4.22m
1.30t
OCH3
A
5
CH3CH2O2C
CH3CH2O2C
CH3CH2O
1H A-ring d (ppm)
1H B-ring
d (ppm)
6
60
3.59–3.54m
1.20t
1
4.58d
3.5
1
4.96dd
2.04m
4.04dd
6.12dd
OCH3
PhCH
Ph–H
3.32s
5.56 s
CH3CH2O
2
2, 20
3
3.99t
3.5
3
4
o 7.45m;
m,p 7.38–7.33m
4
5
3.78m
4.14dd
3.67dd
3.36s
CH3CH2O2C 4.21, q
CH3CH2O2C 1.27t
J
Hz
4.3
J
Hz
4.3
2.6
13.1
5.9
1.2
8.6
10.8
7.1
9.1
7.0
2.9
6
60
1, 2ax
1, 2eq
2ax, 2eq
2ax, 3
2eq, 3
3, 4
1, 2
1, 20
2, 20
2, 3
CH3CH2O
CH3CH2O
3.52m
1.18t
0.9
15.1
OCH3
PhCH2
Ph–H
4.90, 4.73, 4.72, ABq
7.36–7.28
3.8
3.0
2, 4
20, 3
2.8
0.5
J
Hz
3.4
J
Hz
3.3
6.2
6.6
3, 1(B-ring)
4, 5
5, 6
5, 60
6, 60
CH3CH2O2C
CH3CH2O2C
CH3CH2O
CH3CH2O
3, 4
1, 2
2, 3
3, 4
1, 2
1, 20
9.0
Not measured
Not measured
Not measured
12.1
12.1
2, 3, 20, 3
CH3CH2O2C Not measured
CH3CH2O2C 7.1
4, 5
5, 6
5, 60
6, 60
10.0
1.8
CH3CH2O
CH3CH2O
3, 4
Not measured
5.2
10.8
6.9
3.3
30 mm · 20 cm column of silica gel using 20% ethyl acet-
ate/hexane. There was obtained 205 mg (quantitative) of

K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
281
(c 1, chloroform); Rf 0.34 (20% ethyl acetate/hexanes);
ylenepyruvate26 (39.2 mg, 0.228 mmol), and Eu(fod)3
(15 mg, 0.014 mmol) in 900 lL petroleum ether/100 lL
toluene was heated in a thick-walled reaction tube fitted
with a Teflon screw cap under nitrogen at 100 ꢁC for 3
days. TLC (1:1 ethyl acetate/hexanes) showed complete
consumption of starting materials. The sample was
diluted with toluene (2 mL) and concentrated to an oil
(0.140 g). Flash chromatography afforded cycloadducts
13 and 14 with Rf 0.50 and Rf 0.62 (1:1 ethyl acetate/hex-
anes); combined yield, 80.1 mg (53%). Rechromatogra-
phy of the cycloadduct mixture gave enriched fractions
1
the H NMR spectrum of 9 matched that reported.9a
2.12. Methyl 4,6-O-benzylidene-2-deoxy-3-O-(ethyl 2,4-
dideoxy-3-O-ethyl-a-D/L-glycero-hex-4-enopyranosyluro-
nate)-a-D-ribo-hexopyranoside 11 and 12
A mixture of methyl 4,6-O-benzylidene-2-deoxy-3-O-
vinyl-a-D-ribo-hexopyranoside 8 (150 mg, 0.5 mmol),
ethyl (E)-ethoxymethylenepyruvate26 (91 mg, 0.53
mmol), and Eu(fod)3 (20 mg, 0.019 mmol) in 900 lL
petroleum ether/100 lL toluene was heated in a thick-
walled reaction tube fitted with a Teflon screw cap under
nitrogen at 100 ꢁC for 2 days. TLC (30% ethyl acetate/
hexanes) showed complete consumption of starting
materials. The sample was diluted with toluene (2 mL)
and concentrated to an oil. Flash chromatography af-
forded cycloadducts 11 (74 mg) and 12 (79 mg) with Rf
0.28 and Rf10.41 (30% ethyl acetate/hexanes); combined
yield, 64%. H NMR data are shown in Tables 2 and 3.
HRMS (ES+) Anal. Calcd for C24H32O9Na [M+Na]:
487.1944. Found: 487.1939 (Scheme 3).
1
for NMR analysis. H NMR data are shown in Tables
4 and 5. HRMS (ES+) Anal. Calcd for C38H46O10Na
[M+Na]: 685.2989. Found: 685.2993.
Acknowledgements
The authors thank the Petroleum Research Fund,
administered by the American Chemical Society, and
Villanova University for financial support of this work.
2.13. Methyl 2,3,4-tri-O-benzyl-6-O-(ethyl 2,4-dideoxy-3-
O-ethyl-a-D/L-glycero-hex-4-enopyranosyluronate)-a-D-
glucopyranoside 13 and 14
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4
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¨
B
CH3CH2O2C
O
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6
4
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5
O
BnO
BnO
2
1
3
OBn
OCH3
A
1H A-ring d (ppm)
1H B-ring
d (ppm)
1
4.60d
3.5dd
1
5.27dd
2.14m
4.21dd
6.18d
2
2, 20
3
3.96t
3.67t
3
4
12. Rollin, P.; Verez Bencomo, V.; Sinay, P. Synthesis 1984,
134–135.
¨
4
5
3.77–3.70m
3.77–3.70m
3.77–3.70m
3.36s
CH3CH2O2C 4.13, 4.11q
CH3CH2O2C 1.20t
13. Cottier, L.; Remy, G.; Descotes, G. Synthesis 1979, 711–
712.
14. Handerson, S.; Schlaf, M. Org.Lett. 2002, 4, 407–409.
15. Reinhart, K. L., Jr.; Beck, J. R.; Borders, D. B.; Kinstle,
6
60
CH3CH2O
CH3CH2O
3.53q
1.19t
OCH3
PhCH2
Ph–H
J
4.89, 4.74, 4.73, ABq
7.37–7.25m
T. H.; Krauss, D. J.Am.Chem.Soc
.
16. Gassman, P.; Burns, S. J.; Pfister, K. B. J.Org.Chem.
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Chim.Ital. 1983, 113, 453–455.
Hz
3.6
9.8
8.5
J
Hz
5.0
1, 2
2, 3
3, 4
1, 2
1, 20
2, 3, 20,3
3.4
Not measured
CH3CH2O2C 10.8
CH3CH2O2C 7.1
4, 5
5, 6
5, 60
6, 60
8.5
Not measured
Not measured
Not measured
CH3CH2O
CH3CH2O
3, 4
Not measured
6.9
3.8

282
K.D.Hughes et al./ Tetrahedron: Asymmetry 16 (2005) 273–282
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