X-ray crystal structure determinations of galactosylacetylene building blocks

Article abstract of DOI:10.1080/07328303.2011.554935

We report the crystal structures of two galactosylacetylenes: 3,7-anhydro-4,5,6,8-tetra-O-benzyl-1,1,2,2-tetradehydro-1,2-dideoxy-1-C- (trimethylsilyl)-D-glycero-L-mann ooctitol (7) and 3,7-anhydro-4,5,6,8-tetra-O- benzyl-1,1,2,2-tetradehydro-1,2-D-glycero-L-mannooctitol (8). A short overview of the synthetic chemistry used to obtain these targets is mentioned. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/07328303.2011.554935

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X-Ray Crystal Structure Determinations
of Galactosylacetylene Building Blocks
David J. Leaver a , Andrew B. Hughes a , Anastasios Polyzos b c
Jonathan M. White d
&
a Department of Chemistry, La Trobe University, Melbourne, Victoria,
3086, Australia
b CSIRO Materials Science and Engineering, Clayton South, Victoria,
3169, Australia
c Department of Chemistry, University of Cambridge, Cambridge,
CB2 1EW, United Kingdom
d Bio21 Institute, School of Chemistry, University of Melbourne,
Parkville, Victoria, 3010, Australia
Published online: 15 Mar 2011.
To cite this article: David J. Leaver , Andrew B. Hughes , Anastasios Polyzos & Jonathan M. White
(2010): X-Ray Crystal Structure Determinations of Galactosylacetylene Building Blocks, Journal of
Carbohydrate Chemistry, 29:8-9, 379-385
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Journal of Carbohydrate Chemistry, 29:379–385, 2010
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C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2011.554935
X-Ray Crystal Structure
Determinations of
Galactosylacetylene
Building Blocks
David J. Leaver,1 Andrew B. Hughes,1 Anastasios Polyzos,2
and Jonathan M. White3
1Department of Chemistry, La Trobe University, Melbourne, Victoria 3086, Australia
2CSIRO Materials Science and Engineering, Clayton South, Victoria 3169, Australia;
and Department of Chemistry, University of Cambridge, Cambridge CB2 1EW,
United Kingdom
3Bio21 Institute, School of Chemistry, University of Melbourne, Parkville,
Victoria 3010, Australia
We report the crystal structures of two galactosylacetylenes: 3,7-anhydro-4,5,6,8-
tetra-O-benzyl-1,1,2,2-tetradehydro-1,2-dideoxy-1-C-(trimethylsilyl)-D-glycero-L-mann
ooctitol (7) and 3,7-anhydro-4,5,6,8-tetra-O-benzyl-1,1,2,2-tetradehydro-1,2-D-glycero-
L-mannooctitol (8). A short overview of the synthetic chemistry used to obtain these
targets is mentioned.
Keywords X-ray crystal structure; Galactosylacetylene; Structure; Synthesis
INTRODUCTION
Glycosylacetylene building blocks have been appearing in the literature[1,2] and
are proving to be valuable building blocks in carbohydrate chemistry. Galacto-
sylacetylenes are an important member of this group and have been used in the
ever expanding area of 1,3-dipolar cycloaddition of terminal azides and alkynes
(Huisgen reactions), which are a subset of “click” chemistry.[3–6] “Click” chem-
istry of azides and alkynes has been heavily utilized due to its robust nature
in facilitating aqueous or oxygenated conditions, uncomplicated operation and
workup, and high-yielding transformations.[7,8] The glycosylacetylenes, includ-
ing the galactosylacetylenes, have also been used in C-glycosylamino acid and
Received August 27, 2010; accepted January 11, 2011.
Address correspondence to Andrew B. Hughes, Department of Chemistry, La Trobe Uni-
versity, Melbourne, Victoria 3086, Australia. E-mail: a.hughes@latrobe.edu.au
379

D.J. Leaver et al.
380
glycopeptide synthesis.[5,6,9–13] Due to 7 and 8 being widely used as building
blocks for C-glycosylamino acids, glycopeptides, and other carbohydrate-based
structures, it is important to confirm the anomeric configurations.
RESULTS AND DISCUSSION
The synthesis of compounds 7 and 8 is shown in Scheme 1. Key to the synthe-
sis of the anomer-substituted galactosylacetylene 8 was the alkynyl addition
to the lactone intermediate 5. Accordingly, the synthesis of D-galactonolactone
5 was readily achieved by oxidation of the methyl 2,3,4,6-tetra-O-benzyl-D-
galactoside 3 via the methyl-D-galactopyranoside 2.[14–16]
Scheme 1: Synthesis of galactosylacetylenes 7 and 8.
Reagents and conditions: (i) Amberlite IR 120, 115◦C, MeOH, 92% (lit.[17]
78%); (ii) BnBr, NaH, Bu4NI, DMF, 84% (lit.[14] 82%); (iii) AcOH (80%), 1M
H2SO4, 145◦C, 70% (lit.[14] 62%); (iv) Ac2O, DMSO, 88% (lit.[16] 90%); (v) Li-
TMS acetylene, CeCl3, THF, 80% (lit.[9] 91%); (vi) Et3SiH, BF3·OEt2, CH3CN-
CH2Cl2, 73% (lit.[9] 71%); (vii) NaOH, MeOH-CH2Cl2, 90% (lit.[9] 99%).
Deprotection of the methyl acetal 3 to the hemiacetal 4 was carried out
with 80% AcOH and 1M H2SO4 at reflux.[14] The oxidation method used
for the tetraacetate analogue of galactonolactone 5 was used successfully
for the oxidation of compound 4 to 5.[15,16] We noted, however, that insuffi-
ciently pure methyl α/β-D-galactoside gave unwanted 2,3,4,6-tetra-O-benzyl-
D-galactonofurano-δ-lactone, which was evidenced by the 13C NMR analysis,
where the furano carbonyl peak was deshielded by δ 2.2 ppm relative to the
corresponding pyrano carbonyl signal.[16,18–21]

Galactosylacetylene Building Blocks
381
Alkyne addition to the galactolactone 5 was mediated by lithiated
trimethylsilyl (TMS)-acetylene in the presence of CeCl3 affording the hemiac-
etal 6 in 80% yield.[9] Treatment of 6 with a Lewis acid promoted the formation
of the oxonium ion, which was stereoselectively intercepted by triethylsi-
lane to afford the protected alkynylgalactose 7 in good yield.[9] The struc-
ture of this compound was verified by X-ray crystallography (Fig. 1), which
showed that the product is in the beta configuration and is the pyranose iso-
mer. 3,7-Anhydro-4,5,6,8-tetra-O-benzyl-1,1,2,2-tetradehydro-1,2-D-glycero-L-
mannooctitol 8 was also successfully crystallized and analyzed by X-ray
crystallography (Fig. 2), which again confirmed the beta configuration of the
alkyne and the pyranose form.
We noted that 7 was successfully crystallized, while previous workers re-
ported this compound as an oil.[9]
Both compounds 7 and 8 crystallized in the monoclinic space group P21,
compound 7 having two independent molecules in the asymmetric unit. The
two molecules differed slightly with respect to the conformations of the 2- and
Figure 1: Thermal ellipsoid plot for compound 7, molecule 1. Ellipsoids are at the 20%
probability level.

D.J. Leaver et al.
382
Figure 2: Thermal ellipsoid plot for compound 8. Ellipsoids are at the 20% probability level.
3-O-benzyl substituents; however, the bond distances and angles for the two
molecules were not significantly different from one another. Selected bond dis-
tances and angles for the pyranose rings of 7 and 8 and of the anomeric alkyne
substituents are presented in Table 1.
Table 1: Selected bond distances (Å) and angles (◦) for compounds 7 (both
molecules), 8, 9, and 10
7(M1)
7(M2)
8
9
10
C1-C2
1.547(3)
1.471(4)
1.507(4)
1.528(3)
1.518(4)
1.432(3)
1.433(3)
1.421(3)
1.426(3)
1.426(3)
1.544(3)
1.476(4)
1.517(4)
1.525(4)
1.522(3)
1.431(3)
1.431(3)
1.419(3)
1.433(3)
1.422(3)
1.540(4)
1.462(4)
1.517(4)
1.538(4)
1.520(4)
1.427(3)
1.433(3)
1.434(3)
1.430(3)
1.418(3)
1.528
1.475
1.513
1.534
1.543
1.434
1.416
1.421
1.419
1.422
1.544
1.484
1.521
1.545
1.528
1.441
1.425
1.427
1.410
C1-C7
C2-C3
C3-C4
C4-C5
C5-O1
O1-C1
C2-O2
C3-O3
C4-O4
O1-C1-C2
C1-C2-C3
C2-C3-C4
C3-C4-C5
C4-C5-O1
C5-O1-C1
O1-C1-C7
110.8(2)
111.6(2)
110.7(2)
110.3
110.3
107.5(2)
109.7(2)
108.0(2)
110.8(2)
111.5(2)
108.6(2)
109.1(2)
110.9(2)
107.6(2)
113.6(2)
112.4(2)
107.5(2)
109.8(2)
111.2(2)
107.5(2)
110.1(2)
110.6(2)
107.5(2)
110.7
110.1
110.2
108.9
114.0
112.0
111.7
109.2
109.5
109.0
113.2
113.2

Galactosylacetylene Building Blocks
383
Both alkynes 7 and 8 have the β-configuration and the C1 C7 bond dis-
tances are not significantly different from one another. It is of interest to com-
pare these structures with other anomeric alkynes, particularly those with
the α-configuration, as these may reveal structural effects arising from the
anomeric effect. A survey of the Cambridge Crystallographic database[22] gave
the structures 9 and 10, which were deemed accurate enough and suitable for
comparison.[23] The C1-C7 bond distance in compound 9, which is an anomeric
alkyne having the α-configuration, is not significantly different from either 7
or 8; however, the C C bond distance in the anomeric alkyne 10 is lengthened
slightly compared to the nonanomeric alkyne at the 4-position in the same
structure, suggesting that the nO-σ∗
interaction is lengthening this bond.
CC
Comparison with a larger range of structures needs to be made before any
conclusions can be made as to whether there are any significant structural
differences between α- and β-anomeric alkynes.
CONCLUSION
We have successfully solved the X-ray crystal structures of 3,7-anhydro-
4,5,6,8-tetra-O-benzyl-1,1,2,2-tetradehydro-1,2-dideoxy-1-C-(trimethylsilyl)-D-
glycero-L-mannooctitol 7 (Fig. 1) and 3,7-anhydro-4,5,6,8-tetra-O-benzyl-1,1,
2,2-tetradehydro-1,2-D-glycero-L-mannooctitol 8 (Fig. 2), which were success-
fully synthesized via Scheme 1. These novel XRD crystal structures clearly
confirmed the relative configuration of 7 and 8. Compounds such as 8 are
proving to be useful building blocks in carbohydrate synthesis.
EXPERIMENTAL
Crystallography
Intensity data for compound 8 was collected with an Oxford Diffrac-
tion Sapphire CCD diffractometer using Cu-Ka radiation (graphite crys-
tal monochromator ꢁ = 1.54184); intensity data for 7 was collected with a
Bruker SMART Apex CCD detector using Mo-Ka radiation (graphite crys-
tal monochromator ꢁ = 0.71073). The temperature during data collection was
maintained at 130.0(1) K.

D.J. Leaver et al.
384
Crystal data for 7
The crystals obtained for
7
were recrystallized from hexane-
dichloromethane, mp 78–80◦C. C39H44O5Si, M = 620.83, T = 130.0(2) K,
˚
˚
ꢁ = 0.71073 A, Monoclinic, space group P21 a = 18.607(1), b = 7.5190(5), c
ꢀR
◦
3
−3
˚
= 25.337(2) A,
= 99.639(1) . V 3494.8(4) A , Z = 4, Dc = 1.180 mg M
ꢂ(Mo-Kꢃ) 0.109 mm−1, F(000) = 1328, crystal size 0.5 × 0.45 × 0.40 mm. 18212
reflections measured, 9143 independent reflections (Rint = 0.0335); the final R
was 0.042, [I > 2ꢂ(I)] and wR(F2) was 0.0987 (all data).
Crystal data for 8
The crystals obtained for
8
were recrystallized from hexane-
dichloromethane, mp 81–83◦C (lit.[11] 79–80◦C (pentane)). C36H36O5, M =
˚
548.65, T = 130.0(2) K, ꢁ = 1.54184 A, Monoclinic, space group P21 a =
ꢀR
◦
3
˚
˚
11.2772(3), b = 8.4295(2), c = 16.5947(2) A, = 109.206(2) . V 1489.71(6) A ,
Z = 2, Dc = 1.223 mg M−3 ꢂ(Mo-Kꢃ) 0.642 mm−1, F(000) = 584, crystal size 0.5
× 0.45 × 0.40 mm. 5898 reflections measured, 4399 independent reflections
(Rint = 0.0351); the final R was 0.045, [I > 2ꢂ(I)] and wR(F2) was 0.0984 (all
data).
ACKNOWLEDGMENTS
DL acknowledges the Australian government for the provision of an Australian
Postgraduate Award (APA) and La Trobe University/CSIRO for the La Trobe
University/CSIRO Aurora PhD top-up scholarship.
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