Stereoselective synthesis of C-glycosides via Tebbe methylenation and Claisen rearrangement

Article abstract of DOI:10.1016/S0040-4039(00)01303-4

A variety of β-C-glycosides may be readily accessed in a stereoselective fashion from 3-OH glycal esters, via the use of Tebbe methylenation and subsequent thermal Claisen rearrangement. The use of carbohydrate ester substrates allows the formation of β(1

Full text of DOI:10.1016/S0040-4039(00)01303-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7589–7593
Stereoselective synthesis of C-glycosides via Tebbe
methylenation and Claisen rearrangement
H. Yasmin Godage and Antony J. Fairbanks*
Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QY, UK
Received 7 July 2000; accepted 28 July 2000
Abstract
A variety of b-C-glycosides may be readily accessed in a stereoselective fashion from 3-OH glycal esters,
via the use of Tebbe methylenation and subsequent thermal Claisen rearrangement. The use of carbohy-
drate ester substrates allows the formation of b(1“6) linked C-disaccharides. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: C-glycosides; carbohydrates; glycals; Tebbe reagent; Claisen rearrangement.
The combination of the natural occurrence of C-glycosides,1 be it either discretely or as
fragments of larger biologically active natural products, together with the idea that such
materials may possess potential therapeutic benefits by acting as carbohydrate mimetics,2 has
provoked a large amount of interest from the synthetic community.3
The development of high throughput screening processes has provided much of the impetus
for the development of combinatorial and parallel synthetic techniques in the pharmaceutical
industry. Due to the well-established importance of carbohydrates in a plethora of biological
processes4 it would therefore seem a logical progression to develop parallel synthetic routes to
glycomimetics, and in particular C-glycosides, for biological screening purposes.
When considering the development of a new parallel synthetic approach to C-glycosides, two
important factors should be considered. The first of these is the stereochemical outcome of the
C-glycosylation reaction, which must be at least highly stereoselective, if not stereospecific, and
the second is the potential generality of the overall reaction sequence. In order to address the
former consideration it seemed that one can profitably use a thermal sigmatropic rearrangement
for the construction of the new carbonꢀcarbon bond at the anomeric centre with complete
control of stereochemistry. In addition, rather than choosing to adopt the classic Claisen–Ire-
land approach,5 it was envisaged that a tandem process involving Tebbe methylenation6 of a
* Corresponding author. Tel: +441865275647; fax +441865275674; e-mail: antony.fairbanks@chem.ox.ac.uk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01303-4

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glycal ester could be followed by thermal sigmatropic rearrangement, and thereby allow
stereoselective access to C-glycosides (Fig. 1).7
Fig. 1.
Since any carboxylic acid could in theory be used for the esterification step, then this sequence
would provide a straightforward parallel synthetic route to a wide range of C-glycosides.
Such a strategy initially requires access to selectively protected glycals in which the 3-hydroxyl
group is free for esterification. To this end the known silyl protected glucose-derived glycal 18
was synthesised from glucose b-pentaacetate in four steps following literature procedures (72%
overall yield). The corresponding 4,6-benzylidene protected glycal 2 was also synthesised as a
starting material, this time by a more protracted literature procedure.9
Esterification of 1 with either benzoic, octanoic, Boc-protected 4-amino butyric, or palmitic
acids was achieved by treatment of the glycal with the corresponding carboxylic acid and DCC,
with catalytic DMAP, yielding esters 3a–d in excellent yields. The two step sequence of Tebbe
methylenation and Claisen rearrangement was then undertaken. Tebbe reaction proceeded
smoothly to yield the corresponding enol ethers 4a–d. Thermal rearrangement of enol ethers
4a–d, which occurred upon heating to 180°C in either benzonitrile or tributylamine,10 then
produced the corresponding b-C-glycosides 5a–d11 in good to excellent yield (Scheme 1, reaction
yields quoted over two steps of methylenation and rearrangement). The success of the Tebbe
methylenation and subsequent rearrangement of the Boc-protected amino ester 4c is notable,
since this indicates that Boc-protected amino acids may be suitable substrates for this reaction
sequence, thereby allowing access to C-glycosyl amino acids, which have recently become the
objects of synthetic interest.12
Scheme 1. (i) RCO2H, DCC, DMAP, CH2Cl2, rt; (ii) Tebbe, THF, pyridine, −40°C; (iii) 180°C, PhCN or Bu3N

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A similar sequence of reactions was undertaken for the benzylidene protected glycal 2. In this
casethebenzoate6aandacetate6bwereaccessedbytheuseofbenzoylchlorideandaceticanhydride,
respectively (94 and 96% yields). Tebbe methylenation again yielded the intermediate enol ethers
7a and 7b. Thermal rearrangement proceeded rapidly upon heating to 180°C in tributylamine to
yield the b-C-glycosides 9a and 9b (71 and 80% yields over two steps, Scheme 2).
Scheme 2. (i) BzCl, DMAP, pyridine, 0°C; (ii) Ac2O, pyridine, rt; (iii) Tebbe, THF, pyridine, −40°C; (iv) 180°C, Bu3N
An appealing feature of this C-glycosylation strategy is, as previously mentioned, the potential
range of carboxylic acids which may be used for the esterification reaction. In order to exemplify
the flexibility of this approach the synthesis of a b-C-disaccharide was undertaken. Thus, the known
galacturonic acid 9,13 which was obtained in high yield by ruthenium-mediated14 oxidation of
diacetone galactose 10, was coupled with glycal 1 to yield the ester 11. Tebbe methylenation of
11 was found to be much more sluggish than the previous examples, but by the use of an extended
reaction time (24 h) a satisfactory yield of the desired enol ether 12 was obtained (72% yield based
on recovered starting material; it should be noted that the reaction could not be driven to
completion). Claisen rearrangement of enol ether 12 occurred rapidly at 180°C, in this instance
to yield the desired b-C-disaccharide 1315 in a satisfactory 56% yield (Scheme 3).
Scheme 3. (i) RuCl3, NaIO4, CHCl3, MeCN, H2O, 82%; (ii) 1, DCC, DMAP, CH2Cl2, 91%; (iii) Tebbe, THF,
pyridine, −40°C to rt, 72%; (iv) 180°C, PhCN, 56%

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In summary it is clear that the combined use of Tebbe methylenation and thermal Claisen
rearrangement provides a powerful and potentially general route to stereodefined C-glycosides.
By the use of uronic acids as coupling partners such methodology may be applied to the
synthesis of 1“6 linked C-disaccharides. The use of suitably protected amino acids will also
allow access to C-glycosyl amino acids, which are the required building blocks for the synthesis
of C-glycopeptides. It should be noted that the use of the corresponding allose-derived glycals
will allow access to the corresponding a-C-glycosides and that in addition simple iteration of the
process using uronic acid substrates will allow access to 1“6 linked C-oligosaccharides. Further
investigations in this area are currently in progress and will be reported in due course.
Acknowledgements
We gratefully acknowledge financial support from the EPSRC (Project Studentship to
H.Y.G.) and the use of the EPSRC Mass Spectrometry Service (Swansea, UK) and the
Chemical Database Service (CDS) at Daresbury, UK.
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.