From α-1,2-Anhydrosugars to C-Glycosides: The Influence of Lewis Acids and Nucleophiles on the Stereochemistry

Article abstract of DOI:10.1081/CAR-120026458

Ring opening of the epoxide function in α-1,2-anhydrosugars with alkynyl zinc and titanium compounds proceeds with retention of configuration to afford α-C-alkynylglycosides in reasonable to good yields, while the use of the corresponding alkynyltrifluoroborates results in the formation α/β mixtures. Vinyl nucleophiles predominantly afford α-products, whereas allyl and allenyl species almost exclusively yield β-C-glycosides.

Full text of DOI:10.1081/CAR-120026458

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From α‐1,2‐Anhydrosugars to C‐Glycosides: The
Influence of Lewis Acids and Nucleophiles on the
Stereochemistry
Michiel A. Leeuwenburgh a , Gijsbert A. van der Marel a , Herman S. Overkleeft a & Prof.
Jacques H. van Boom a
a Leiden Institute of Chemistry , Leiden University , P.O. Box 9502, 2300 RA, Leiden, The
Netherlands
Published online: 23 Feb 2007.
To cite this article: Michiel A. Leeuwenburgh , Gijsbert A. van der Marel , Herman S. Overkleeft & Prof. Jacques H. van Boom
(2003) From α‐1,2‐Anhydrosugars to C‐Glycosides: The Influence of Lewis Acids and Nucleophiles on the Stereochemistry ,
Journal of Carbohydrate Chemistry, 22:7-8, 549-564, DOI: 10.1081/CAR-120026458
To link to this article: http://dx.doi.org/10.1081/CAR-120026458
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 7 & 8, pp. 549–564, 2003
From -1,2-Anhydrosugars to C-Glycosides: The Influence
of Lewis Acids and Nucleophiles on the Stereochemistryy
Michiel A. Leeuwenburgh, Gijsbert A. van der Marel,
*
Herman S. Overkleeft, and Jacques H. van Boom
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
ABSTRACT
Ring opening of the epoxide function in a-1,2-anhydrosugars with alkynyl zinc and
titanium compounds proceeds with retention of configuration to afford a-C-alkynyl-
glycosides in reasonable to good yields, while the use of the corresponding
alkynyltrifluoroborates results in the formation a/b mixtures. Vinyl nucleophiles
predominantly afford a-products, whereas allyl and allenyl species almost exclusively
yield b-C-glycosides.
INTRODUCTION
Carbohydrate analogs in which the anomeric oxygen is replaced by a carbon
substituent have become the subject of intense studies in both synthetic organic
chemistry and biochemistry over the past few decades.[1–3] The interest in these so-
called C-glycosides is based on their occurrence as structural entities in a wide variety
of biologically active compounds, ranging from the pharmacologically interesting class
of C-nucleosides[4,5] to highly complex natural products such as palytoxin[6–8] and
halichondrin B.[9,10] Apart from this, C-oligosaccharides have shown great promise as
yThis paper is dedicated to Professor Ge´rard Descotes on the occasion of his 70th birthday.
*
Correspondence: Prof. J. H. van Boom, Leiden Institute of Chemistry, Leiden University, P.O.
Box 9502, 2300 RA Leiden, The Netherlands; E-mail: boom_j@chem.leidenuniv.nl.
549
DOI: 10.1081/CAR-120026458
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

550
Leeuwenburgh et al.
Table 1. Zn-mediated C-alkynyl glycosidations.
Entry
Epoxide
Alkyne
Methoda
Product
Yield
1
1
2
2
3
1
1
1
1
1
1
1
4
5
6
5
7
7
5
5
6
8
9
A
A
A
A
A
B
A
B
B
B
C
10
11
12
13
14
14
15
15
16
17
18
55%
56%
76%
50%
51%
70%
59%
77%
72%
78%
84%
2
3
4
5
6
7
8
9
10
11
Note: because of the diastereoisomeric mixtures resulting from the introduction of the THP group
(entries 3 and 9), the products were characterized as their acetates, obtained by the sequence of
reactions shown in Scheme 1.
aMethod A: 2 equiv alkyne, in THF at ꢀ50°C, 2 equiv of n-BuLi, 15 min. ꢀ50°C, add 1 equiv
epoxide and 2 equiv ZnCl2, warm up to rt, 2–3 h. Method B: 2 equiv alkyne, in THF at ꢀ50°C, 2
equiv of n-BuLi, stir 15 min. ꢀ50°C, add 2 equiv ZnCl2, stir 5 min. at ꢀ50°C, add 1 equiv epoxide,
warm up to rt, 2–3 h. Method C: sodium acetylide slurry (approx. 2 equiv) in THF at 0°C, add 2
equiv ZnCl2, stir for 5 min, add 1 equiv epoxide, stir at 0°C for 1 h.
potential inhibitors of carbohydrate processing enzymes and metabolically stable mo-
dels for the evaluation of recognition processes in biological systems.[11]
A particularly interesting method for the stereoselective preparation of C-glyco-
sides comprises nucleophilic ring opening of 1,2-anhydrosugars.[12–17] The inherent
liberation of the hydroxyl function on C-2 affords further synthetic possiblities for
elaboration of the ring opened product. In this respect, we[18–20] and others[21–25]
recently demonstrated the efficient conversion of 1,2-anhydrosugars into cis- and trans-
fused cyclic ethers, intermediates in the synthesis of complex marine toxins. We here
present our results on the ring opening of a-1,2-anhydrosugars with a range of alkynyl
and alkenyl nucleophiles. The influence of the nature of the nucleophile on the
stereochemical outcome of the reaction will be discussed.
Scheme 1. Removal of the THP groups and installation of acetates.

Influence of Lewis Acids and Nucleophiles on Stereochemistry
551
Figure 1.
RESULTS AND DISCUSSION
Previous results from our group[26] showed that zinc chloride is a suitable Lewis
acid for the ring opening reaction of 1,2-anhydrosugars with malonate nucleophiles. In
this way, b-C-glycosyl malonates were obtained in good yields. As a first experiment
with alkynyl anions, it was therefore decided to follow an analogous activation
procedure. Thus, zinc chloride (1 M in THF) was added to a mixture of 1-
pentynyllithium and a-1,2-anhydro-3,4,6-tri-O-benzyl-D-glucopyranose (1)[27] in THF at
ꢀ50°C. Warming of the reaction mixture to rt, work-up and purification led to the
isolation of a-pentynyl-C-glucoside 10 as a single isomer in 55% yield (entry 1,
Table 1). Different 1,2-anhydrosugars and alkynyl anions were also subjected to the
same reaction conditions (see entries 2–4). For example, by use of the carbohydrate
derived alkyne 5,[28]C-disaccharide precursors 13 and 15 were obtained (entries 2 and
Table 2. Ti-mediated C-alkynyl glycosidations.
Entry
Alkyne
Product(s)
Yieldb
1
5
6
7
8
9
15 + 19
16 + 19
14 + 19
17
21% (44%)
48% (23%)
28% (16%)
82%
2
3
4
5c
18
16%
aConditions: 1.25 equiv lithioalkyne in THF at ꢀ50°C, 1.25 equiv of ClTi(OiPr)3 (1M in
hexanes) stir for 15 min, add epoxide, slowly warm (1–2 h) to ꢀ20°C.
bYield of 19 in parentheses.
cSodium acetylide (18 wt% slurry in mineral oil/xylenes) was used instead of lithioalkyne.

552
Leeuwenburgh et al.
Figure 2.
4). In addition, the method proved compatible with various protective groups both on
the epoxide (see compounds 2[29] and 3,[30] entries 2 and 4) and on the alkyne (entry 3).
Unfortunately, the yields of the C-glycosidations remained only moderate, owing to the
fact that hydrolysis of the epoxide was often substantial. Based on the assumption that
the reactive species is the zinc alkyne, we reasoned that initial formation of the
organozinc reagent prior to the addition of the epoxide should have a beneficial effect
on the efficiency of the C-glycosidation. Indeed, changing the order of addition of the
reagents (i.e., method B: stir the lithioalkyne with zinc chloride before adding the
epoxide) consistently led to increased yields of the C-glycosides (see entries 6 versus 5
and entries 8 versus 7). By employing this protocol, other nucleophiles gave sat-
isfactory yields when reacted with epoxide 1 (see entries 9 and 10). For the synthesis of
a-ethynyl-C-glucoside 18 (entry 11), a slightly modified procedure was followed.
Commercially available sodium acetylide (18 wt% slurry in xylenes/mineral oil), which
is sparingly soluble in THF at ꢀ50°C, was stirred with zinc chloride at 0°C prior to the
addition of epoxide 1, to give 18 in high yield (84%) (Scheme 1, Figure 1).
As the next research objective, the influence of other Lewis acids on the outcome
of the C-glycosidation was investigated. A report of Seebach et al.[31] demonstrated the
application of the organotitanium complex arising from reaction of phenylethynyl-
lithium with chlorotitanium triisopropoxide in reactions with aldehydes and epoxides.
Accordingly, treatment of a-1,2-anhydroglucose 1 with this reactive species led to a
rewarding yield of a-phenylethynyl-C-glycoside 17 (entry 4, Table 2). The use of other
alkynyltitanium species, however, gave contrasting results. The low yield of 18 (entry
5) may be ascribed to the fact that sodium acetylide is sparingly soluble at the low
temperature required to maintain the stability of the titanoalkyne. In other cases (entries
1–3), isopropoxide instead of alkynyl anion delivery by the titanium complex led to the
isolation of isopropyl a-glucoside 19 as a substantial side product (Figure 2).
Scheme 2. Model for the a-selectivity of Zn- and Ti-mediated C-alkynyl glycosidations.

Influence of Lewis Acids and Nucleophiles on Stereochemistry
553
Table 3. BF3-mediated C-alkynyl glycosidations.
Entry
Alkyne
Product
Yield
a:b ratio
1
2
3
4
5
6
7
8
15
16
14
17
36%
65%
58%
74%
1.2:1
1:1.5
1.7:1
1:2.2
Conditions: 1.5 equiv lithioalkyne in THF at ꢀ78°C, add 1.4 equiv of BF3.OEt2, stir 15 min, add 1
equiv epoxide, stir at ꢀ78°C for 0.5–1 h.
The consistent a-selectivity of both the Zn- and Ti-mediated C-glycosidations led
us to speculate on the mechanism of this reaction. It may be surmised that the
metalloalkyne activates the 1,2-anhydrosugar by complexation of the Lewis acidic
metal atom to the epoxide to give the ion pair A (Scheme 2). Next, intramolecular
delivery of the nucleophile exclusively from the a-face leads to the observed products
B. The selective formation of isopropyl a-glycoside 19 (Table 2) in the case of the
titanium complex probably also takes place via the same pathway. It should be noted
that this mechanism is consistent with the one postulated by Rainier et al.[15–17] for
their explanation of the a-selectivity of C-glycosylations under the influence of
organoaluminium reagents.
The putative mechanism stated above implies that a metalloalkyne complex
containing a negatively charged metal centre would not (or less easily) give rise to
intermediate A, thereby causing a drop in a-selectivity. In this respect, the relatively
stable alkynyl-trifluoroborates[32] (obtained by reaction of alkynyl anions with
BF3 ꢁOEt2) are the reagents of choice to provide more insight into the validity of
this hypothesis. To this end, alkynyl anions also used in the Zn- and Ti-mediated
reactions were treated with BF3.OEt2 (0.9 equiv) at ꢀ78°C, followed by the addition of
epoxide 1 and stirring at the same temperature. As can be seen in Table 3, all the
reactions gave rise to mixtures of a- and b-C-alkynyl glucosides in near equal amounts.
Presumably, the complexation step followed by intramolecular a-directed alkynyl
delivery proposed in Scheme 2 does not occur here. It would seem that in this
case the lithium counterion is responsible for the activation of the epoxide, after
which the oxocarbenium ion is attacked intermolecularly and non-selectively by the
alkynyl nucleophile (Figure 3).
Figure 3.

554
Leeuwenburgh et al.
Table 4. C-vinyl glycosidations.
Reagent
Temperature
Yield
a:b
vinylmagnesium bromide
divinylmagnesium
divinylzinc
0°C
rt
44%
42%
50%
6:1
6:1
1:0
rt
The synthetic potential of vinyl-C-glycosides[18] was an incentive to investigate
whether these compounds could also be obtained by reaction of an appropriate
organometallic reagent with a 1,2-anhydrosugar. To this end, epoxide 1 was treated
with vinylmagnesium bromide and divinylmagnesium (Table 4) in THF at 0°C and rt,
respectively. Notably, these reactions both led to 6:1 mixtures of isomers 20a and 20b
in moderate yields. On the other hand, reaction of 1 with divinylzinc[33] led to the
exclusive formation of the a-vinyl-C-glucoside 20a in 50% yield. These results indicate
that the mechanism stated for the Zn- and Ti-mediated a-C-alkynyl glycosidations
(Scheme 2) is also valid in this case. In contrast, Rainier et al.[23] demonstrated that the
reaction of 1 with vinylmagnesium bromide can be steered exclusively towards the
b-product by lowering the reaction temperature to ꢀ40°C and by using CH2Cl2 as a
solvent. Interestingly, we found that performing the reaction at ꢀ40°C, either in THF or
in CH2Cl2, gave similar product ratios and yields as reported in Table 4 and Figure 4.
Stick[13] and Evans[14] reported that reaction of allylmagnesium bromide with
epoxide 1 exclusively produces the corresponding b-C-allyl glucoside 21b (Scheme 3).
Moreover, b-products were also obtained by reaction of allylstannanes under the
influence of a variety of Lewis acids. However, reactions of epoxide 1 with tri-
allylborane and triallylalane[15] predominantly yield the a-product, supposedly pro-
ceeding via a similar delivery mechanism as depicted in Scheme 2. In order to gain
more insight into the stereochemical outcome of the C-allylation, the reactions of
diallylmagnesium and diallylzinc were explored. Thus, treatment of 1 with an excess of
diallylmagnesiuma in THF at rt led to the formation of the b-isomer alongside a small
amount of 21a, while in the case of diallylzinc, no trace of the a-C-allyl glucoside was
observed and 21b was isolated in 42% yield.
It should be noted that the only difference between the reagents presented in Table
4 and Scheme 3 is only one methylene group. The fact that this causes a complete turn-
around in the stereoselectivity underlines the powerful influence of the nature of the
nucleophile. A possible explanation for the b-selectivity of allyl Grignard reagents has
been proposed by Rainier et al.,[22] involving chelation of the metal center to the
oxygen in the sugar ring and subsequent b-directed intramolecular delivery of the
nucleophile via a six-membered transition state. However, the reason for the difference
in chelation mode of the allylboranes and -alanes on the one hand and the allyl-
magnesium and -zinc species on the other hand remains obscure.
Finally, the reactivity of the allenyl nucleophile was studied. After several attempts
to react metalloallenes with epoxide 1 (i.e., allenylmagnesium bromide and al-
lenyltributylstannaneb with BF3OEt2 or TMSOTf), optimal conditions were found with
[34]
aPrepared according to: Ref.
bPrepared according to: Ref.
.
[35]
.

Influence of Lewis Acids and Nucleophiles on Stereochemistry
555
Figure 4.
the familiar organolithium/zinc chloride system (Scheme 4). Thus, a solution of
allenyllithium, prepared in situ by transmetalation of allenyltributylstannane with n-
butyllithium, was treated consecutively with zinc chloride and epoxide 1 to give b-C-
propargyl glucoside 22 as a single stereoisomer in a yield of 79%. In contrast to the
selectivity of the allyl nucleophile,[22] this cannot be explained by assuming a six
membered cyclic transition state. It is of interest to note that the same compound was
obtained by using propargylmagnesium chloride.[23]
In summary, we have shown that the stereoselectivity of C nucleophilic attack on a
1,2 anhydrosugars is strongly dependent on the nature of both the Lewis acid promotor
and the nucleophile. The chelation control mechanism, postulated earlier for alanes and
boranes,[15–17] also seems to be in accordance with the results from the alkynylzinc and
titanium reactions. Further evidence for this mechanism is provided by comparison of
the results of the Zn and Ti-mediated C-glycosidations with those obtained from the
BF3-mediated reactions. Also, the outcome of the vinyl-C-glycosidations are in
agreement with the proposed intramolecular a-delivery of the nucleophile by the metal
complex, although some discrepancies remain with earlier findings.[15–17,23] In contrast,
the allyl and allenyl nucleophiles described here mainly afford b-C-glycosides. A
general rule regarding the exact factors underlying the stereoselective outcome
for the concerning nucleophiles and Lewis acids is still lacking and will require fur-
ther investigation.
EXPERIMENTAL
General methods and materials. 1H and 13C spectra were recorded on a Jeol
JNM-FX-200 (200 MHz and 50 MHz, respectively). NMR shifts are reported in ppm
(d) relative to tetramethylsilane. Mass spectrometry was performed on a PE/SCIEX
API 165 equipped with an electrospray interface. Solvents used for column
chromatography were of technical grade and distilled before use. Dichloromethane
Scheme 3. C-allyl glycosidations.

556
Leeuwenburgh et al.
Scheme 4. b-C-propargylation.
(Baker, p.a.), 1,2-dichloroethane (DCE, Baker, p.a.), dioxane (Baker, p.a.) and
˚
tetrahydrofuran (THF, Baker, p.a.) were stored over molecular sieves (4 A). Toluene
˚
was refluxed with P2O5 for 2 h, distilled and stored over molecular sieves (4 A).
Anhydrous zinc chloride (Merck) was dissolved in anhydrous THF (1 mL/mmol) and
˚
stored over MS 4 A. Chlorotitanium triisopropoxide (1M in hexanes, Aldrich), Dowex
50 WX 4 (H+ form, Fluka), sodium acetylide (18 wt% slurry in xylenes/mineral oil,
Aldrich), allylmagnesium chloride (2 M in THF, Fluka), vinylmagnesium bromide (1
M in THF, Aldrich), n-butyllithium (n-BuLi, 1.6 M in hexanes, Aldrich) were used as
received. Column chromatography was performed on Baker silica gel (0.063–0.200
mm). TLC analysis was conducted on Merck TLC aluminium sheets silica gel 60
F254, with detection by UV absorption (254 nm) and charring with 20% H2SO4 in
ethanol. Traces of water were removed from the starting compounds by repeated
coevaporation with anhydrous toluene. Drying of organic layers after work-up was
effected by MgSO4. Reactions were run at ambient temperature and on 0.1 to 1 mmol
scale, unless stated otherwise.
General procedure for the Zn-mediated C-alkynyl glycosidations. Method A.
To a cooled (ꢀ50°C) solution of the alkyne (2 equiv relative to the epoxide) in THF (5
mL/mmol) under a nitrogen atmosphere was added n-BuLi (2 equiv, 1.6 M in hexanes).
After stirring for 20 min, a solution of the epoxide in THF (2 mL/mmol) was added,
followed by ZnCl2 (2 equiv, 1 M in THF). The mixture was allowed to warm up to rt
and stirred until TLC analysis (50% EtOAc/light petroleum) showed no more progress
(2–3 h). The reaction mixture was then poured into sat. NH4Cl and extracted with Et2O
(2 ꢂ). The combined organic layers were washed with sat. NH4Cl, dried, filtered and
concentrated. Silica gel chromatography (typically 15–30% EtOAc/light petroleum)
then afforded the pure a-C-alkynyl glycoside. Method B. Largely the same as A, with
the exception that ZnCl2 was stirred for 15 min with the anion at ꢀ50°C before the
epoxide was added.
1-(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)-1-pentyne (10). Colourless syrup
obtained via method A: 0.15 g, 0.28 mmol, 55% based on 0.22 g, 0.50 mmol of
1. 13C NMR (CDCl3): d 138.4, 138.1, 138.0 (3 ꢂ Cq Bn), 128.4–127.7 (CHarom),
91.0, 89.3 (2 ꢂ C C), 83.8, 77.7 (2 ꢂ OCH), 75.2, 75.0 (2 ꢂ CH2 Bn), 73.5 (OCH),
73.4 (CH2 Bn), 71.5, 68.7 (2 ꢂ OCH), 68.6 (C-6), 22.0, 20.8 (2 ꢂ CH2 pentynyl),
13.6 (CH3). MS/ESI: m/z 501.3 [M + H]+. Data of the 2-OAc derivative: 1H NMR

Influence of Lewis Acids and Nucleophiles on Stereochemistry
557
(CDCl3): d 7.38–7.13 (m, 15H, Harom), 4.98 (dt, 1H, H-1, J1,2 = 5.8 Hz, J1,CH2 = 1.7
Hz), 4.87 (dd, 1H, H-2, J2,3 = 9.7 Hz), 4.86–4.49 (m, 6H, 3 ꢂ CH2 Bn), 4.03–3.95
(m, 2H, H-3, H-5), 3.80–3.65 (m, 3H, H-4, 2 ꢂ H-6), 2.21 (dt, 2H, CH2C
,
JCH2,CH2 = 9.2 Hz), 2.01 (s, 3H, CH3 Ac), 1.54 (m, 2H, CH2CH3), 0.99 (t, 3H,
CH3 pentynyl).
(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)trimethylsilylethyne (14). Colourless
syrup. 13C NMR (CDCl3): d 138.9, 138.4, 138.2 (3 ꢂ Cq Bn), 128.7–128.0 (CHarom),
100.2, 95.8 (2 ꢂ C C), 83.7, 77.9 (2 ꢂ OCH), 75.4 (2 ꢂ CH2 Bn), 74.1 (OCH), 73.8
(CH2 Bn), 71.5, 69.3 (2 ꢂ OCH), 68.8 (C-6), 0.3 (CH3 TMS). Data of the 2-OAc
derivative: 1H NMR (CDCl3): d 7.36–7.15 (m, 15H, CHarom), 4.99 (d, 1H, H-1,
J1,2 = 6.0 Hz), 4.86 (dd, 1H, H-2, J2,3 = 9.7 Hz), 4.82–4.49 (m, 6H, 3 ꢂ CH2 Bn),
3.99–3.92 (m, 2H, H-3, H-5), 3.78 (dd, 1H, H-6a, J6a,6b = 11.0 Hz, J6a,5 = 3.6 Hz),
3.72–3.66 (m, 2H, H-4, H-6b), 1.99 (s, 3H, CH3 Ac), 0.18 (s, 9H, 3 ꢂ CH3 TMS). MS/
ESI: m/z 531.3 [M + H]+.
1-(3,4-Di-O-benzyl-6-O-trityl- -D-glucopyranosyl)-3-(tetrahydropyran-2-yloxy)-
1-propyne (12). Colourless syrup. 13C NMR (CDCl3): d 143.5 (Cq Ph), 138.3, 137.5
(2 ꢂ Cq Bn), 128.5–126.6 (CHarom), 96.8, 96.7 (CH THP), 86.0 (Cq Tr), 85.7 (C ),
83.6, (OCH), 80.6 ( C), 77.4 (OCH), 75.2, 74.8 (2 ꢂ CH2 Bn), 73.8, 71.3, 68.3
(4 ꢂ OCH), 68.4 (C-6), 61.7, 61.5 (2 ꢂ OCH2 THP), 54.1 (CH2C ), 29.8, 24.9, 18.6
(3 ꢂ CH2 THP). MS/ESI: m/z 725.3 [M + H]+.
1-(2,6-Di-O-acetyl-3,4-di-O-benzyl- -D-glucopyranosyl)-3-acetoxy-1-propyne
(12a). THP ether 11 (0.74 g, 1.0 mmol) was dissolved in CH2Cl2/MeOH (1/5 mL) and
Dowex H+ (300 mg) was added. The mixture was stirred overnight, after which the resin
was filtered off and the filtrate concentrated. This was dissolved in Ac2O/pyridine (1/2
mL) and stirred for 1 h, and after evaporation of the solvents by repeated coevaporation
with toluene, followed by column chromatography (20–40% EtOAc/light petroleum)
1
triacetate 11a (0.34 g, 0.65 mmol, 65%) was obtained as a colourless syrup. H NMR
(CDCl3): d 7.37–7.25 (m, 10H, Harom), 4.98 (dt, 1H, H-1, J1,2 = 5.9 Hz, J1,CH2 = 1.7 Hz),
4.89 (dd, 1H, H-2, J2,3 = 9.8 Hz), 4.87–4.79 (m, 3H, CH2 Bn, CHH Bn), 4.74 (d, 2H,
CH2C ), 4.57 (d, 1H, CHH Bn), 4.35 (dd, 1H, H-6a, J6a,6b = 12.2 Hz, J6a,5 = 2.4 Hz),
4.28 (dd, 1H, H-6b, J6b,5 = 4.0 Hz), 4.03–3.95 (m, 2H, H-3, H-5), 3.56 (dd, 1H, H-4). 13
C
NMR (CDCl3): d 169.9, 169.4, 169.2 (3 ꢂ C = O), 137.9, 137.1 (2 ꢂ Cq Bn), 128.0–
127.1 (CHarom), 83.6 (C ), 80.7 (OCH), 79.8 ( C), 76.6 (OCH), 74.9, 74.6 (2 ꢂ CH2
Bn), 71.9, 71.5, 65.0 (3 ꢂ OCH), 62.3 (C-6), 51.4 (CH2C ), 20.2, 20.0 (3 ꢂ CH3 Ac).
MS/ESI: m/z 525.2 [M + H]+.
Methyl 7-deoxy-2,3,4-tri-O-benzyl-7-(3,4,6-tri-O-benzyl- -D-glucopyranosyl)- -
D-gluco-hept-6-ynopyranoside (15). 13C NMR (CDCl3): d 138.3–137.5 (Cq Bn),
128.1–127.3 (CHarom), 98.0 (C-1), 86.8 (C ), 83.3, 81.8, 80.5 (3 ꢂ OCH), 79.8 ( C),
78.9, 77.1 (2 ꢂ OCH), 75.5, 75.0, 74.7, 74.6 (4 ꢂ CH2 Bn), 73.7 (OCH), 73.1
(2 ꢂ CH2 Bn), 71.0, 68.2 (2 ꢂ OCH), 68.0 (C-6’), 61.4 (C-5’), 55.5 (OMe). MS/ESI:
1
m/z 891.4 [M + H]+. Data of the 2’-OAc derivative: H NMR (CDCl3): d 7.36–7.10
(m, 30H, Harom), 5.07 (dd, 1H, H-1’, J1’,2’ = 6.0 Hz, J1’,5 = 1.6 Hz), 5.00–4.44 (m, 12H,

558
Leeuwenburgh et al.
6 ꢂ CH2 Bn), 4.92 (dd, 1H, H-2’, J2’,3’ = 9.9 Hz), 4.54 (d, 1H, H-1, J1,2 = 3.0 Hz), 4.43
(dd, 1H, H-5, J5,4 = 9.8 Hz), 3.98 (ddd, 1H, H-5’, J5’,4’ = 9.9 Hz, J5’,6a’ = 3.2 Hz,
J5’,6b’ = 1.2 Hz), 3.90 (t, 1H, H-3’, J3’,4’ = J3’,2’ = 9.4 Hz), 3.89 (t, 1H, H-3,
J3,4 = J3,2 = 9.3 Hz), 3.76–3.61 (m, 3H, 2 ꢂ H-6’, H-4’), 3.55–3.48 (m, 2H, H-2, H-4),
3.42 (s, 3H, OMe), 1.91 (s, 3H, CH3 Ac).
Methyl 7-deoxy-2,3,4-tri-O-benzyl-7-(3,4-di-O-benzyl-6-O-trityl- -D-glucopyra-
nosyl)- -D-gluco-hept-6-ynopyranoside (11). 13C NMR (CDCl3): d 143.5 (Cq Ph),
138.3, 138.2, 137.8, 137.6, 137.5 (5 ꢂ Cq Bn), 128.5–126.6 (CHarom), 98.0 (C-1), 86.6,
85.9 (Cq Tr, C ), 83.5, 81.9, 80.5 (3 ꢂ OCH), 80.3 ( C), 78.9, 77.3 (2 ꢂ OCH),
75.5, 75.0, 74.5 (4 ꢂ CH2 Bn), 73.9 (OCH), 73.1 (CH2 Bn), 70.9, 68.3 (2 ꢂ OCH),
61.8 (C-6’), 61.5 (OCH), 55.4 (OMe). MS/ESI: m/z 1043.5 [M + H]+. Data of the 2’-
1
OAc derivative: H NMR (CDCl3): d 7.48–7.12 (m, 40H, CHarom), 5.17 (dd, 1H, H-1’,
J1’,2’ = 6.0 Hz, J1’,5 = 1.7 Hz), 5.04 (dd, 1H, H-2’, J2’,3’ = 9.4 Hz), 4.98–4.46 (m, 9H,
4 ꢂ CH2 Bn, CHH Bn), 4.52 (d, 1H, H-1, 3.5 Hz), 4.39 (dd, 1H, H-5, J5,4 = 9.9 Hz),
4.31 (d, 1H, CHH Bn), 3.95–3.84 (m, 4H, H-3, H-3’, H-4’, H-5’), 3.59–3.47 (m, 3H,
H-2, H-4, H-6a’), 3.40 (s, 3H, OMe), 3.21 (dd, 1H, H-6b’, J6b’,6a’ = 10.2 Hz, J6b’,5’ = 2.4
Hz), 1.95 (s, 3H, CH3 Ac).
Methyl 7-deoxy-2,3,4-tri-O-benzyl-7-(3,4-di-O-benzyl-6-O-tert-butyldiphenylsi-
lyl- -D-galacto-pyranosyl)- -D-gluco-hept-6-ynopyranoside (13). 13C NMR
(CDCl3): d 138.8–138.1 (Cq Bn), 135.6–127.5 (CHarom), 133.2 (Cq Ph), 98.5 (C-1),
86.0 (C ), 82.3, 81.2, 81.0 (3 ꢂ OCH), 80.7 ( C), 79.2 (OCH), 75.9, 75.4, 74.8
(3 ꢂ CH2 Bn), 74.3 (OCH), 73.6 (CH2 Bn), 73.5 (OCH), 72.1 (CH2 Bn), 68.7, 67.5
(2 ꢂ OCH), 62.2 (C-6’), 61.8 (OCH), 55.9 (OMe), 27.0 (CH3t-Bu), 19.3 (Cqt-Bu). MS/
1
ESI: m/z 1039.5 [M + H]+. Data for the 2’-OAc derivative: H NMR (CDCl3): d 7.65–
7.18 (m, 30H, CHarom), 5.31 (dd, 1H, H-2’, J2’,1’ = 6.0 Hz, J2’,3’ = 10.2 Hz), 5.07 (dd,
1H, H-1’, J1’,5 = 1.5 Hz), 4.95–4.65 (m, 7H, 3 ꢂ CH2, CHH Bn), 4.57 (d, 1H, H-1,
J1,2 = 3.5 Hz), 4.54 (d, 1H, CHH Bn), 4.45 (dd, 1H, H-5, J5,4 = 9.9 Hz), 4.38 (AB, 2H,
CH2 Bn), 4.02–3.96 (m, 2H, H-4’, H-5’), 3.92 (t, 1H, H-3, J3,2 = J3,4 = 9.3 Hz), 3.85–
3.72 (m, 3H, H-3’, 2 ꢂ H-6’), 3.56–3.47 (m, 2H, H-2, H-4), 3.48 (OMe), 1.06 (s, 9H, t-
Bu). MS: m/z 1099 [M + NH4]+, 1104 [M + Na]+, 1120 [M + K]+.
(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)phenylethyne (17). Colourless syrup.
13C NMR (CDCl3): d 138.4, 137.9, 137.7 (3 ꢂ Cq Bn), 131.9 (CH Ph), 128.7–127.6
(CH Bn), 121.8 (Cq Ph), 89.9 (C ), 83.5 (OCH), 83.3 ( C), 77.6 (OCH), 75.2, 75.0
1
(2 ꢂ CH2 Bn), 73.9 (OCH), 73.4 (CH2 Bn), 71.4, 68.9 (2 ꢂ OCH), 68.4 (C-6). H
NMR (CDCl3): d 7.46–7.14 (m, 20H, Harom), 5.04 (d, 1H, H-1, J1,2 = 5.1 Hz), 4.97–
4.49 (m, 6H, 3 ꢂ CH2 Bn), 4.07 (m, 1H, H-5), 3.85–3.65 (m, 5H, H-2, H-3, H-4, H-6).
ESI-MS: m/z 557 [M + Na]+, 573 [M + K]+.
(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)ethyne (18). A cooled (0°C) suspension
of sodium acetylide (16.6 mmol, 5.2 mL 18 wt% slurry in xylenes/mineral oil) in THF
(15 mL) was treated with a solution of anhydrous ZnCl2 (16.6 mL, 1 M in THF).
Almost immediately, the inhomogeneous mixture became more transparent and stirring
was continued for 15 min. Epoxide 1 (8.3 mmol, 3.6 g) was added in THF (15 mL) and

Influence of Lewis Acids and Nucleophiles on Stereochemistry
559
the mixture was warmed up to rt and stirred for 1 h, after which TLC analysis showed
complete conversion of the starting compound. Work-up and column chromatography
in the usual manner gave 18 (3.18 g, 6.9 mmol, 84%) as a colourless oil. 13C NMR
(CDCl3): d 138.0, 137.5, 137.4 (Cq Bn), 127.8–127.2 (CHarom), 83.1 (OCH), 77.6
(C C), 77.0 (OCH), 74.8, 74.4 (CH2 Bn), 73.5 (OCH), 73.0 (CH2 Bn), 70.6 (OCH),
68.0 (C-6), 67.7 (OCH). MS/ESI: m/z 459.2 [M + H]+. Data of the 2-OAc derivative:
1H NMR (CDCl3): d 7.36–7.13 (m, 15H, Harom), 4.98 (dd, 1H, H-1, J1,2 = 5.7 Hz,
J1
= 2.2 Hz), 4.92 (dd, 1H, H-2, J2,3 = 9.6 Hz), 4.87–4.48 (m, 6H, 3 ꢂ CH2 Bn),
CH
4.05–3.96 (m, 2H, H-3, H-5), 3.81–3.65 (m, 3H, H-4, 2 ꢂ H-6), 2.53 (d, 1H, CH),
2.01 (s, 3H, CH3 Ac).
1-(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)-3-(tetrahydropyran-2-yloxy)-1-pro-
pyne (16). 13C NMR (CDCl3): d 138.6, 138.0, 137.8 (Cq Bn), 128.5–127.7 (CHarom),
97.4, 97.1 (2 ꢂ CH THP), 86.5 (C ), 83.9 (OCH), 80.4 ( C), 77.5 (OCH), 75.3, 75.0
(2 ꢂ CH2 Bn), 73.8 (OCH), 73.5 (CH2 Bn), 71.4, 68.6 (2 ꢂ OCH), 68.5 (C-6), 62.2,
62.0 (2 ꢂ OCH2 THP), 54.5, 54.4 (2 ꢂ OCH2C ), 30.3, 25.3, 19.1, 19.0 (4 ꢂ CH2
THP). MS/ESI: m/z 573.3 [M + H]+.
1-(2-O-Acetyl-3,4,6-tri-O-benzyl- -D-glucopyranosyl)-1-propyn-3-ol
(16a). THP-ether 16a (90 mg, 0.13 mmol) was dissolved in Ac2O/pyridine (0.5/1 mL)
and stirred for 1 h. After removal of the solvents by repeated coevaporation with
toluene, the crude acteylated product was redissolved in CH2Cl2/MeOH (0.2/1.5 mL),
treated with Dowex H+ (50 mg) stirred overnight. The resin was then filtered off and
the filtrate concentrated. Column chromatography (50–60% EtOAc/light petroleum)
1
yielded 16a (47 mg, 0.075 mmol, 57%) as a colourless syrup. H NMR (CDCl3): d
7.37–7.13 (m, 15H, Harom), 5.01 (dt, 1H, H-1, J1,2 = 5.9 Hz, J1,CH2C = 1.8 Hz), 4.90
(dd, 1H, H-2, J2,3 = 9.8 Hz), 4.86–4.50 (m, 6H, 3 ꢂ CH2 Bn), 4.31 (d, 2H, CH2C ),
4.00–3.93 (m, 2H, H-3, H-5), 3.78–3.66 (m, 3H, H-4, 2 ꢂ H-6), 2.03 (s, 3H, CH3 Ac).
MS/ESI: m/z 530.2 [M + H]+.
General procedure for the Ti-mediated C-alkynyl glycosidations. To a cooled
(ꢀ50°C) solution of the lithioalkyne (prepared as described in the previous section,
1.25 equiv relative to the epoxide) was added ClTi(O-iPr)3 (1.25 equiv, 1 M in
hexanes). The yellow mixture was stirred at ꢀ50°C for 15 min, after which a solution
of the epoxide in THF (2 mL/mmol) was added. The solution was allowed to slowly
warm to ꢀ20°C (1–2 h). The reaction mixture was poured into aq HCl (1 M) and
extracted with Et2O (2 ꢂ). The combined organic layers were washed with sat.
NaHCO3, dried, filtered and concentrated in vacuo. Column chromatography described
above gave the a-C-alkynyl glycoside and, in some cases, isopropyl glycoside 19.
Isopropyl 3,4,6-tri-O-benzyl- -D-glucopyranoside (19). 13C NMR (CDCl3): d
138.4, 137.7, 137.5 (Cq Bn), 127.8–127.0 (CHarom), 96.5 (C-1), 83.1, 77.4 (2 ꢂ OCH),
74.8, 74.5, 72.9 (3 ꢂ CH2 Bn), 72.4, 70.0, 69.6 (2 ꢂ OCH, CH i-Pr), 68.0 (C-6), 22.8,
21.1 (2 ꢂ CH3i-Pr). MS/ESI: m/z 493.3 [M + H]+, 515.3 [M + Na]+. Data for the 2-
1
OAc derivative: H NMR (CDCl3): d 7.38–7.12 (m, 15H, Harom), 5.15 (d, 1H, H-1,
J1,2 = 3.8 Hz), 4.85–4.47 (m, 7H, 3 ꢂ CH2 Bn, H-2), 4.02 (t, 1H, J = 9.4 Hz, H-3/4),

560
Leeuwenburgh et al.
3.95–3.62 (m, 5H, H-3/4, H-5, 2 ꢂ H-6, CHi-Pr), 2.03 (s, 3H, CH3 Ac), 1.20 (d, 3H,
CH3i-Pr, J = 6.2 Hz), 1.10 (d, 3H, CH3i-Pr).
General procedure for the BF3-mediated C-alkynyl glycosidations. To
a cooled (ꢀ78°C) solution of the lithioalkyne (prepared as described in the previous
section, 1.5 equiv relative to the epoxide) was added BF3.OEt2 (1.4 equiv). The mixture
was stirred at ꢀ78°C for 15 min, after which a solution of the epoxide in THF (2 mL/
mmol) was added. The solution was stirred at ꢀ78°C for 0.5–1 h. The reaction mixture
was poured into sat. NaHCO3 and extracted with Et2O (2 ꢂ). The combined organic
layers were washed with sat. NaHCO3, dried, filtered and concentrated in vacuo.
Column chromatography was effected as described above to give the a- and b-C-
alkynyl glycosides.
(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)trimethylsilylethyne (14 ). Data of the
1
2-OAc derivative: H NMR (CDCl3): d 7.33–7.12 (m, 15H, Harom), 5.15 (t, 1H, H-2,
J2,1 = J2,3 = 9.4 Hz), 4.82–4.48 (m, 6H, 3 ꢂ CH2 Bn), 4.03 (d, 1H, H-1), 3.77–3.56
(m, 4H, H-3, H-4, 2 ꢂ H-6), 3.43 (m, 1H, H-5). MS/ESI: m/z 573.3 [M + H]+.
Methyl 7-deoxy-2,3,4-tri-O-benzyl-7-(3,4,6-tri-O-benzyl- -D-glucopyranosyl)- -
D-gluco-hept-6-ynopyranoside (15 ). Analytical data of 2’-OAc derivative of 15b:
1H NMR (CDCl3): d 7.38–7.13 (m, 30H, Harom), 5.14 (dd, 1H, H-2’, J2’,1’ = 9.7 Hz,
J2’,3’ = 9.3 Hz), 4.93–4.45 (m, 12H, 6 ꢂ CH2 Bn), 4.51 (d, 1H, H-1, J1,2 = 3.5 Hz),
4.36 (bd, 1H, H-5, J5,4 = 9.9 Hz), 4.10 (dd, 1H, H-1’, J1’,5 = 1.4 Hz, J1’,2’ = 10.0 Hz),
3.85 (t, 1H, H-3, J3,4 = J3,2 = 9.3 Hz), 3.73–3.65 (m, 3H, H-4’, H-5’, H-6a’), 3.60 (t,
1H, H-3’), 3.50–3.43 (m, 3H, H-2, H-4, H-6b’), 3.37 (s, 3H, OMe), 1.88 (s, 3H, CH3
Ac). MS/ESI: m/z 933.4 [M + H]+.
(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)phenylethyne (19 ). Spectroscopic da-
ta were identical to those described earlier.[19]
1-(2-O-acetyl-3,4,6-Tri-O-benzyl- -D-glucopyranosyl)-1-propyn-3-ol (16b). 1H
NMR (CDCl3): d 7.32–7.11 (m, 15H, Harom), 5.14 (t, 1H, H-2, J2,1 = J2,3 = 9.5 Hz),
4.83–4.46 (m, 6H, 3 ꢂ CH2 Bn), 4.22 (bs, 2H, CH2C ), 4.07 (dt, 1H, H-1,
J1,CH2C = 1.5 Hz), 3.75–3.58 (m, 4H, H-3, H-4, 2 ꢂ H-6), 3.50–3.44 (m, 1H, H-5).
MS/ESI: m/z 530.2 [M + H]+.
(3,4,6-Tri-O-benzyl- / -D-glucopyranosyl)ethene (20 / ). Method A: To a
chilled (0°C) solution of epoxide 1 (0.29 g, 0.67 mmol) in THF (5 mL) under a
nitrogen atmosphere was added vinylmagnesium bromide (1.0 mmol, 1.0 mL, 1 M in
THF). After 15 min, the reaction mixture was poured into sat. NH4Cl and extracted
with Et2O (2 ꢂ). The combined organic layers were washed with water, dried,
concentrated and the residue purified by column chromatography (0–5% acetone/
toluene) to afford 20a (117 mg, 0.25 mmol, 37%) and 20b (20 mg, 0.043 mmol, 7%).
Spectroscopic data for known acetylated derivatives of compounds 20a[15–17] and
20b[23] were in accordance with those reported. Method B: A divinylmagnesium
solution was prepared according to the known procedure for diallylmagnesium.[34]
Thus, vinylmagnesium bromide (4 mL, 1 M in THF) was treated with dioxane (0.34

Influence of Lewis Acids and Nucleophiles on Stereochemistry
561
mL). The resulting suspension was stirred for 2 h, after which it was centrifuged for 15
min at 1500 rpm. Part of the supernatant (1.0 mL) was added to a solution of epoxide 1
(0.22 g, 0.50 mmol) in THF (2 mL). After stirring for 2 h, the mixture was worked-up
and the product purified in the same manner as described above, giving a 6:1 mixture
of 20a/b (97 mg, 0.21 mmol, 42%). Method C: Divinylzinc was prepared analogous to
a known procedure[33] by treatment of vinylmagnesium bromide (2 mL, 1M in THF)
with ZnCl2 (1 mL, 1M in THF) and stirring for 1 day. Then, dioxane (0.17 mL) was
added and stirring was continued for 0.5 h, after which the suspension was centrifuged
for 15 min at 1500 rpm. Of the supernatant, 1.5 mL was added to a solution of epoxide
1 (0.22 g, 0.50 mmol) in THF (2 mL). After usual work-up and purification, 20a (0.11
g, 0.25 mmol, 50%) was obtained as a single isomer.
3-(3,4,6-Tri-O-benzyl- / -D-glucopyranosyl)-1-propene (21 / ). Method A:
Diallylmagnesium was prepared according to the literature procedure.[34] A solution
of allylmagnesium chloride (2 mL, 2M in THF) was treated with dioxane (0.34 mL)
and the heterogeneous mixture was stirred for 2 h. After centrifugation, 0.5 mL of the
supernatant was added to a solution of epoxide 1 (0.50 mmol) in THF (2 mL). Work-up
and purification proceeded as mentioned for 20, to give 21a (17 mg, 0.036 mmol, 7%)
and 21b (0.18 g, 0.38 mmol, 76%) as colourless syrups. Data of 21b were in full
accord with those reported.[13,14] Data for 21a: 13C NMR (CDCl3): d 138.1, 137.8,
137.6 (3 ꢂ Cq Bn), 134.1 (= CH), 128.6–127.5 (CHarom), 117.3 (= CH2), 79.0, 74.8
(2 ꢂ OCH), 74.2 (CH2 Bn), 74.1 (OCH), 73.3 (CH2 Bn), 72.9 (OCH), 72.1 (CH2 Bn),
68.9 (C-6), 68.3 (OCH), 34.2 (CH2CH =). MS/ESI: m/z 475.2 [M + H]. Data for the 2-
OAc derivative of 21a: 1H NMR (CDCl3): d 7.33–7.15 (m, 15H, Harom), 5.85–5.71 (m,
1H, = CH), 5.30 (bs, = CHH), 5.11–5.03 (m, 2H, = CHH, H-2), 4.85–4.46 (m, 6H,
3 ꢂ CH2 Bn), 4.05 (ddd, 1H, H-1, J1,2 = 7.7 Hz, J1,CH2a = 8.7 Hz, J1,CH2b = 1.9 Hz),
3.87–3.62 (m, 5H, H-3, H-4, H-5, 2 ꢂ H-6), 2.55–2.23 (m, 2H, CH2C =), 2.14 (s, 3H,
CH3 Ac). MS/ESI: m/z 517.3 [M + H]+. Method B: By analogy with the preparation of
divinylzinc,[33] diallylzinc was prepared by adding ZnCl2 (1 mL, 1 M in THF) to
allylmagnesium chloride (1 mL, 2 M in THF). Subsequent further manipulations and
reaction with 1 (0.22 mmol, 0.50 mmol) were executed as described above for
divinylzinc, to give 21b (0.10 g, 0.21 mmol, 42%).
3-(3,4,6-Tri-O-benzyl- -D-glucopyranosyl)-1-propyne (22). To a cooled
(ꢀ78°C) solution of allenyltributylstannane[35] (1.85 mL, 6.0 mmol) in THF (12 mL)
was added n-BuLi (6.0 mmol, 3.75 mL 1.6 M in hexanes). After stirring for 10 min, a
solution of ZnCl2 (6.0 mL 1 M in THF) was added and the mixture was warmed up to
ꢀ40°C over a period of 15 min. After the addition of epoxide 1 (1.30 g, 3.0 mmol),
dissolved in THF (6 mL), the reaction mixture was warmed up to rt and stirred for 45
min. The mixture was poured into sat. NH4Cl and extracted with Et2O (2 ꢂ). The
combined organic layers were washed with sat. NH4Cl, dried and concentrated. Column
chromatography (20–40% EtOAc/light petroleum) yielded 22 (1.12 g, 2.38 mmol,
79%) as a colourless oil. 13C NMR (CDCl3): d 138.1, 137.8, 137.6 (3 ꢂ Cq Bn),
128.1–127.1 (CHarom), 86.0, (OCH), 80.1 (C ), 78.8, 77.7, 76.6 (3 ꢂ OCH), 74.7,
74.3, 72.9 (3 ꢂ CH2 Bn), 72.4 (OCH), 69.8 ( CH), 68.3 (C-6), 21.5 (CH2C ). MS:
m/z 495.2 [M + Na]+. Data for the 2-OAc derivative of 22: 1H NMR (CDCl3): d
7.33–7.15 (m, 15H, Harom), 4.99 (t, 1H, H-2, J2,1 = J2,3 = 9.3 Hz), 4.85–4.52 (m, 6H,

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Leeuwenburgh et al.
3 ꢂ CH2 Bn), 3.80–3.62 (m, 4H), 3.53–3.42 (m, 2H), 2.49–2.45 (m, 2H, CH2C ),
1.99 (t, 1H, CH, J = 2.4 Hz), 1.95 (s, 3H, CH3). MS/ESI: m/z 515.2 [M + H]+.
ACKNOWLEDGMENTS
The authors wish to thank Remy Litjens for recording NMR spectra, Hans van den
Elst for performing mass spectrometry, and the reviewers for helpful suggestions.
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CH2 and RCHO with
Received February 28, 2003
Accepted July 25, 2003