A general, two-directional approach to aza-C-(1 → 1)-linked disaccharide mimetics

Article abstract of DOI:10.1039/b417899h

The Upjohn and Donohoe dihydroxylations were exploited in divergent syntheses of aza-C-(1 → 1)-linked disaccharides. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b417899h

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A general, two-directional approach to aza-C-(1 A 1)-linked
disaccharide mimetics
Andrew Kennedy,a Adam Nelson*b and Alexis Perryb
Received (in Cambridge, UK) 29th November 2004, Accepted 20th January 2005
First published as an Advance Article on the web 2nd February 2005
DOI: 10.1039/b417899h
functionalisation was expected to give a range of aza-C-linked
disaccharide mimetics 3.
The Upjohn and Donohoe dihydroxylations were exploited in
divergent syntheses of aza-C-(1 A 1)-linked disaccharides.
Aza-C-linked disaccharides are stable sugar mimetics in which the
oxygen in one of the sugar rings is replaced by a nitrogen atom,
and the inter-ring oxygen by
a methylene group. These
compounds, whose nitrogen atom may be protonated at
physiological pH, can be potent glycosidase inhibitors: the
transition state for glycoside hydrolysis, including the departing
sugar, is effectively mimicked.1 Previously, oxocarbenium ion
cyclisations1c and the samarium Barbier,1d aldol,1e Michael,1f and
Suzuki1g reactions have been used to prepare aza-C-linked
disaccharides from the corresponding monosaccharides.
We envisaged a two-directional approach for the synthesis of
aza-C-linked analogues, 3, of (1 A 1)-linked disaccharides
(Scheme 1). Oxidative ring expansion of the di(2-furyl) amino
alcohol derivatives
1 was expected to give, after further
elaboration, diketones of general structure 2. Stereoselective
Scheme 1
*adamn@chem.leeds.ac.uk
Table 1 Stereoselectivity of the dihydroxylation of the allylic alcohols 4 and 6 under Upjohn and Donohoe’s conditions
Entry
Starting material
R
Conditionsa
anti:synb
Product
Yield (%)
1a
1b
2a
2b
3
4a
4b
H
A
B
A
B
A
A
B
.95:,5
,5:.95
.95:,5
.95:,5
.95:,5
—
anti-5a
syn-5a
anti-5b
anti-5b
anti-5c
—
65
74
OMe
77
4c
4c
6c
allyl
allyl
36d,e
—
c
4a
4b
a
25:75
syn-7c
26d,f
b
A: (i) cat. OsO4, NMO, acetone–H2O; (ii) Ac2O, pyridine; B: (i) OsO4, TMEDA, CH2Cl2, 278 uC; (ii) Ac2O, pyridine. Determined by
analysis of the 500 MHz 1H NMR spectrum of the crude product; configurations determined by analysis of 3J values and NOEs.
Dihydroxylation of the cyclic alkene was slow. ca. 50:50 mixture of side chain epimers. Plus 26% of a side product. Plus 8% yield of
anti-7c.
c
d
e
f
1646 | Chem. Commun., 2005, 1646–1648
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anti product was obtained (entry 2b). The epimeric series of
substrates, 6, fared even less well: 6c reacted sluggishly under
Upjohn conditions, and low syn stereoselectivity was observed
with OsO4?TMEDA.
With scope of the dihydroxylation protocols determined, we
turned to the synthesis of aza-C-(1 A 1)-linked disaccharide
derivatives. At each stage, configurations were determined by
comparison with monocyclic model compounds. The starting
materials were synthesised from the known5 1,3-amino alcohol
derivatives syn- and anti-8. Two-directional6 oxidative ring
expansion and concomitant sulfur oxidation was followed by
acetalisation: the corresponding heterocycles were obtained as
70:30 mixtures of pyran anomers 9b/10b (Scheme 2).
Fig. 1 Stereoselective dihydroxylation of the allylic alcohols 4a–c.
To assess the viability of the approach, we investigated the
dihydroxylation of the allylic alcohols 4 and 6 (Table 1), prepared2
from the corresponding 2-furyl sulfonamide. The Upjohn3 and
Donohoe4 protocols were studied to assess their potential in the
divergent synthesis of stereoisomeric aza-C-linked disaccharide
mimetics 3. With 4a (R 5 H), a high level of complementarity was
observed: dihydroxylation under Upjohn (cat. OsO4, NMO,
acetone–H2O) and Donohoe’s (OsO4, TMEDA, CH2Cl2,
278 uC) conditions gave, after acetylation, the triacetates anti-5a
and syn-5a, respectively, as .95:,5 mixtures of diastereoisomers
(compare entries 1a and 1b). This general pattern of stereo-
selectivity, Fig. 1, has been rationalised elsewhere.3,4
The differential reactivity of the pyran and piperidine rings
allowed one- and two-directional synthetic approaches to be
freely interchanged. Most simply, selective substitution of the
piperidinyl methoxy group was possible with high stereoselectivity,
and gave 9a, 9c and 10c. Furthermore, conformational differences
between the pyran and the N-tosyl piperidine rings could
also be exploited synthetically. Luche reduction7 (A11a, 11c and
12c) was uniformly highly stereoselective, and resulted in different
outcomes (syn and anti) in the two heterocyclic rings (see
Scheme 2).
The introduction of an R substituent had a profound effect on
the complementarity of the Upjohn and the Donohoe methods
(see Fig. 1). Although high (.95:,5) levels of syn selectivity
were still observed using the Upjohn protocol (entries 2a and 3),
efficient direction of OsO4?TMEDA by the hydroxyl group
was precluded: with 4b (R 5 OMe), a very low yield of the
Dihydroxylation of 11a, 11c and 12c, and peracetylation, gave
the protected aza-C-linked disaccharide derivatives 13–16
Scheme 3
Scheme 2 A 70:30 anomeric mixture is denoted by an asterisk (*).
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Andrew Kennedy,a Adam Nelson*b and Alexis Perryb
(Scheme 3); in the cases where yields were disappointing, no
starting materials were recovered. Using the Upjohn protocol,
dihydroxylation occurred anti to the allylic hydroxyl group in
both rings. Unfortunately the remote stereogenic centre in the
side chains of 15 and 16 was not controlled. However, the
outcome of the dihydroxylation of 11a could be controlled
by careful choice of reagent. Indeed, using Donohoe’s
conditions, different stereochemical outcomes were observed in
the two rings (A14): the pseudoaxial methoxy group in the
pyran ring prevented more usual syn-selective dihydroxylation.
In summary, the asymmetric, stereoselective synthesis of aza-C-
(1 A 1)-linked disaccharide derivatives was possible in a
rather divergent manner. The divergency stemmed from (1) the
ability to switch between one- and two-directional modes by
exploiting the differential reactivity of the heterocyclic rings;
and (2) the complementary substrate-controlled stereoselectivity
often possible with the Upjohn and Donohoe dihydroxylation
reagents.
aSynthetic Chemistry, Chemical Development, GlaxoSmithKline,
Gunnels Wood Road, Stevenage, Hertfordshire, UK SG1 2NY
bSchool of Chemistry and the Astbury Centre, University of Leeds,
Leeds, UK LS2 9JT. E-mail: adamn@chem.leeds.ac.uk;
Fax: +44 (0)113 343 6565; Tel: +44 (0)113 343 6502
Notes and references
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X. Cheng, G. Kumaran and D. R. Mootoo, Chem. Commun., 2001, 811;
(d) O. R. Martin, L. Liu and F. Yang, Tetrahedron Lett., 1996, 37, 1991;
(e) A. Baudat and P. Vogel, Tetrahedron Lett., 1996, 37, 483; (f) E. Fre´rot,
C. Marquis and P. Vogel, Tetrahedron Lett., 1996, 37, 2023; (g)
B. A. Johns, Y. T. Pan, A. D. Elbein and C. R. Johnson, J. Am. Chem.
Soc., 1997, 119, 4856.
2 J. C. P. Hopman, E. van den Berg, L. O. Ollero, H. Hiemstra and
W. N. Speckamp, Tetrahedron Lett., 1995, 36, 4315.
3 J. K. Cha, W. J. Christ and Y. Kishi, Tetrahedron, 1984, 40, 2247.
4 T. J. Donohoe, K. Blades, P. R. Moore, M. J. Waring, J. J. G. Winter,
M. Helliwell, N. J. Newcombe and G. Stemp, J. Org. Chem., 2002, 67,
7946.
We thank EPSRC and GlaxoSmithKline for funding and
Jacqueline Colley and James Titchmarsh for HPLC analysis and
purification.
5 A. Kennedy, A. Nelson and A. Perry, Synlett, 2004, 6, 967.
6 C. Poss and S. L. Schreiber, Acc. Chem. Res., 1994, 27, 9.
7 J.-L. Luche, J. Am. Chem. Soc., 1978, 100, 2226.
1648 | Chem. Commun., 2005, 1646–1648
This journal is ß The Royal Society of Chemistry 2005