Benzyne arylation of oxathiane glycosyl donors

Article abstract of DOI:10.3762/bjoc.6.19

The arylation of bicyclic oxathiane glycosyl donors has been achieved using benzyne generated in situ from 1-aminobenzotriazole (1-ABT) and lead tetraacetate. Following sulfur arylation, glycosylation of acetate ions proceeded with high levels of stereoselectivity to afford a-glycosyl acetates in a 'one-pot' reaction, even in the presence of alternative acceptor alcohols.

Full text of DOI:10.3762/bjoc.6.19

Benzyne arylation of oxathiane glycosyl donors
Martin A. Fascione and W. Bruce Turnbull*
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 19.
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
doi:10.3762/bjoc.6.19
Email:
Received: 27 November 2009
Accepted: 11 February 2010
Published: 22 February 2010
W. Bruce Turnbull* - w.b.turnbull@leeds.ac.uk
* Corresponding author
Guest Editor: T. K. Lindhorst
Keywords:
benzyne; 1,2-cis-glycosides; glycosyl acetates; oxathiane glycosyl
donors; stereoselective glycosylations
© 2010 Fascione and Turnbull; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The arylation of bicyclic oxathiane glycosyl donors has been achieved using benzyne generated in situ from 1-aminobenzotriazole
(1-ABT) and lead tetraacetate. Following sulfur arylation, glycosylation of acetate ions proceeded with high levels of stereose-
lectivity to afford α-glycosyl acetates in a ‘one-pot’ reaction, even in the presence of alternative acceptor alcohols.
Introduction
Carbohydrates play important roles in many biological tached to O-2 of an imidate glycosyl donor 1 (Scheme 1a). Low
processes including tumour metastasis [1,2], bacterial and viral temperature 1H NMR spectroscopy studies confirmed the for-
recognition [3-5], and the immunological response [6-8]. In mation of a quasi-stable trans-decalin intermediate 2, which
order to obtain pure samples of oligosaccharides for biological was able to cause glycosylation to take place from the α-face of
studies, carbohydrate chemists must overcome the myriad chal- the glycosyl donor. We sought to improve this strategy and
lenges presented by their complex synthesis. The most recently reported a novel class of bicyclic oxathiane ketal
important challenge is control over the stereoselectivity of reac- donors 5 containing an inbuilt α-directing group (Scheme 1b)
tions at the anomeric centre; in particular for the stereoselective [13]. The principal objective of our approach was to develop a
synthesis of 1,2-cis-glycosides [9]. This area has been the thioglycoside donor that could mimic the key trans-decalin
subject of much fervent study in the last two decades, and has intermediate 2 by using the sulfur-containing auxiliary as both
led to many significant developments [10,11]. However, despite the anomeric leaving group and α-directing participating group.
these advances, modern synthetic carbohydrate chemistry has An efficient synthesis of the key bicyclic intermediate was
still to provide a general method for the efficient synthesis of achieved starting from a simple thioglycoside 4 where the
1,2-cis-α-glycosidic linkages.
essential β-sulfur linkage was already installed, followed by a
regio and stereoselective cyclisation onto the O-2 position to
In 2005 Boons and co-workers reported an elegant chiral auxil- afford oxathiane glycosyl donor framework 5. The oxathiane
iary-based glycosylation protocol for the synthesis of 1,2-cis-α- ketal donor 5 is then already pre-organised to give a 1,2-cis
glycosides [12]. Completely stereoselective glycosylation was directing group upon activation, and afford 1,2-cis-glycosides 7
achieved when a thiophenyl-containing chiral auxiliary was at- on alcohol addition.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 19.
Scheme 1: a) Boons’ chiral auxiliary-based approach to α-stereoselective glycosylations. b) Modified strategy for stereoselective glycosylations using
oxathiane ketal glycosyl donors 5.
Following the synthesis of the oxathiane ketal glycosyl donors the reaction of 1-ABT (8) with lead tetraacetate, benzyne (9)
5, activation of the β-thioglycoside linkage was necessary to formation is believed to occur via degradation of either an
form the key trans-decalin sulfonium ion 6, and turn the N-nitrene intermediate 10 or an N-acetate substituted interme-
α-directing participating group into an anomeric leaving group diate 11 the driving force for which is the release of di-nitrogen
reactive enough to partake in glycosylations. Thioglycosides are [29].
widely used as glycosyl donors [14,15], and many different
reagents are available for their activaton including N-iodosuc- The synthesis of oxathiane ketal 13 was achieved in two steps
cinimide (NIS)/TMSOTf [16], dimethyl(methylthio)sulfonium from thioglycoside 12 as previously reported, followed by
trifluoromethanesulfonate (DMTST) [17,18], PhSeOTf [19], protection to afford the acetylated oxathiane ketal 14 or the
MeS-SMe/Tf2O [20], and MeOTf [21-23]. However, in order to benzylated oxathiane ketal 15 (Scheme 3) [13]. Ketal 13 was
recreate the reactive sulfonium ion used by Boons, it would be also reduced to the novel oxathiane ether 16 in 89% yield, and
necessary to activate the anomeric sulfur with a phenyl group.
Herein we describe our synthetic endeavours to achieve this
goal and the first use of benzyne as an activating agent for
thioglycosides [24].
Results and Discussion
The method chosen for in situ benzyne (9) generation was the
reaction of 1-aminobenzotriazole (1-ABT) (8) with lead
tetraacetate by the procedure pioneered by Rees and co-workers
(Scheme 2) [25-28]. The low reaction temperature was expected
to be compatible with stereoselective glycosylation. Following
Scheme 2: Benzyne generation from 1-ABT.
Scheme 3: Oxathiane donor synthesis.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 19.
Scheme 4: Arylation/acetate glycosylation of oxathiane glycosyl donors.
protected to afford acetylated oxathiane ether 17 and benzylated Presumably, the mechanism proceeds via sulfur arylation with
oxathiane ether 18 in yields of 72% and 83%, respectively.
benzyne to afford putative phenyl sulfonium ion 20, followed
by glycosylation of the acetate anion. The very high α-stereose-
With the oxathiane ketal and ether donors in hand, initial lectivity (α:β > 98:2) of the reaction was in line with selectiv-
studies focussed on benzyne arylation in the absence of any ities previously observed for intermediate oxathiane sulfonium
alcohol acceptor. Unexpectedly, when activated under the reac- ions [13]. When the reaction was repeated in the absence of
tion conditions, acetylated oxathiane ketal 14 afforded α-glyco- 1-ABT, the starting material was unchanged, thus precluding
syl acetate 19 stereoselectively in 82% yield (Scheme 4a). the possibility of initial sulfur activation by lead tetraacetate.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 19.
Arylation of benzylated oxathiane ketal 15 under identical tetraacetate as the oxidising agent. Further studies using the
conditions also afforded α-glycosyl acetate 21 as the sole crude more reactive Zefirov’s reagent (µ-oxobis[(trifluoromethanesul-
product as evidenced by 1H NMR spectroscopy (Scheme 4b). fonato)(phenyl)iodine]) [36,37] were also undertaken. Prelim-
However, only α-hemiacetal 22 was isolated in 70% yield inary results were promising yielding simple α-glycosides and a
following purification by flash silica chromatography [30]. full study will be reported in due course. Unfortunately,
Cleavage of the acyclic O-2 ketal on glycosyl acetate 21, attempted extension of the arylation/acetate glycosylation meth-
followed by acetyl transfer from O-1 to O-2 could account for odology to conventional thiophenyl glycosyl donors was disap-
this transformation [31].
pointing, as experiments either did not proceed to completion,
or were hampered by oxidation of the thiophenyl group in the
Arylation/acetate glycosylation using oxathiane ether donor 17 presence of lead tetraacetate [38].
also occurred readily to give the α-glycosyl acetate 23 in 62%
yield with complete anomeric control (Scheme 4c). It is of Conclusion
interest to note that glycosyl acetate 23 has been reported previ- In conclusion, it has been demonstrated that benzyne arylation
ously by Boons and co-workers as an advanced intermediate in of novel oxathiane glycosyl donors can be achieved using a
their synthesis of trichloroacetimidate donor 24 bearing a 2-O- combination of 1-ABT and lead tetraacetate. Following aryl-
(1S)-phenyl-2-(phenylsulfanyl)ethyl group (Scheme 4c) [12]. ation, glycosylation with an acetate anion takes place with a
Although the benzyne arylation method does not allow us to high degree of stereoselectivity to afford 1,2-cis-α-acetates.
access α-glycosides directly, it could be beneficial as an alterna-
tive route to glycosyl donors bearing the Boons’ participating
Supporting Information
group. This strategy has the advantage of utilising the inherent
chirality of the sugar to determine the stereochemistry of the
Supporting Information File 1 features full experimental
key benzylic centre in the chiral auxiliary, and also facilitates
data for the synthesis of compounds 16–19, 22, 23 and 25.
regioselective attachment of the auxiliary group to O-2.
Supporting Information File 1
Experimental data for the synthesis of compounds 16–19,
22, 23 and 25.
The benzylated oxathiane ether 18 also afforded a glycosyl
acetate 25 in 57% yield but on this occasion as a 96:4 (α:β) mix-
ture of anomers (Scheme 4d). This slight drop in stereose-
lectivity is consistent with the increased reactivity of benzylated
relative to acetylated thioglycoside donors [13,32], commonly
attributed to greater stabilisation of the developing positive
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-19-S1.pdf]
charge on an oxacarbenium intermediate 27 on the reaction Acknowledgements
pathway. Overall, reactions using the oxathiane ether donors The authors would like to thank The Royal Society, the EPSRC
proceeded more rapidly than those with the oxathiane ketal and the University of Leeds for funding. MAF is the recipient of
donors, indicating that the methoxy substituent moderates the a Henry Ellison Scholarship, and WBT is a Royal Society
reactivity of the glycosyl donors.
University Research Fellow.
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