exo-Glycal approaches to C-linked glycosyl amino acid synthesis

Article abstract of DOI:10.1039/a905014k

Two novel routes to C-linked glycosyl amino acids are described; the first involves elaboration of an exo-glycal and subsequent Ramberg-Backlund rearrangement of a sulfone intermediate to give, after functional group manipulation, a protected C-glycosyl serine, while the second uses hydroboration-Suzuki coupling of the same exo-glycal to produce ultimately the corresponding C-glycosyl asparagine analogue.

Full text of DOI:10.1039/a905014k

exo-Glycal approaches to C-linked glycosyl amino acid synthesis
Andrew D. Campbell,a Duncan E. Paterson,a Tony M. Raynhamb and Richard J. K. Taylora*
a Department of Chemistry, University of York, Heslington, York, UK YO10 5DD. E-mail: rjkt1@york.ac.uk
b Roche Discovery Welwyn, Welwyn Garden City, Hertfordshire, UK AL7 3AY
Received (in Cambridge, UK) 22nd June 1999, Accepted 8th July 1999
Two novel routes to C-linked glycosyl amino acids are
described; the first involves elaboration of an exo-glycal and
subsequent Ramberg–Bäcklund rearrangement of a sulfone
intermediate to give, after functional group manipulation, a
protected C-glycosyl serine, while the second uses hydro-
boration–Suzuki coupling of the same exo-glycal to produce
ultimately the corresponding C-glycosyl asparagine ana-
logue.
Diazomethane esterification gave the target C-glycosyl serine
derivative 9 {[a]D 28.2 (c 1.45, CHCl3) [HRMS (FAB+):
Found: 762.3614. C44H53NO9Na requires 762.3618 (0.6 ppm
error)]}.
The second target was the C-glycosyl asparagine analogue 12
depicted in Scheme 3. In principle, this compound could be
made via the methodology outlined in Scheme 2 simply by
using the higher homologue of iodide 46 or of thiol 6. However,
we decided to investigate an alternative approach based on the
Suzuki coupling procedure developed by Johnson and Johns10
but not previously applied to C-glycosyl amino acid synthesis
(Scheme 3). For this route we required vinyl iodide 10 which
has been described but via a rather lengthy route.11 An
improved route to 10 was developed: treatment of the Garner
aldehyde (R)-5‡ with CHI3/CrCl212 produced 10 exclusively as
the E-isomer {[a]D 280.8 (c 1.76, CHCl3); lit.,11 275.3 (c 1.9,
CHCl3)}. Hydroboration of exo-glycal 2 followed by Suzuki
coupling with vinyl iodide 10 gave alkene 11 in moderate yield
but with complete control over ‘anomeric’ configuration and
alkene geometry (J 15.5 Hz). Diimide reduction followed by
treatment with Jones’ reagent and then diazomethane, as before,
Glycopeptides and glycoproteins are of great current interest
from the viewpoints of structure elucidation, molecular recogni-
tion, biological function and chemical synthesis.1 Replacement
of the glycosidic oxygen by carbon gives the corresponding C-
glycoside analogues (glycopeptidomimetics), compounds
which are particularly valuable for biological studies because of
their hydrolytic stability. The recent publications in this area1,2
prompt us to disclose our own results. We have recently
established that the Ramberg–Bäcklund rearrangement of S-
glycoside dioxides provides a versatile route to di-, tri- and
tetra-substituted exo-glycals3 which are themselves useful
intermediates for the preparation of more elaborate C-glyco-
sides.4 Scheme 1 illustrates this methodology with a glucose-
derived sulfone: the Meyers variant5 of the Ramberg–Bäcklund
rearrangement is used to convert the sulfones 1 directly into the
corresponding exo-glycals 2 or 3 without competing 1,2-glycal
formation. We have gone on to apply this methodology to the
synthesis of C-linked disaccharides such as b,b-C-trehalose and
methyl C-gentiobioside.6
We now report the application of this methodology to the
construction of C-linked glycopeptidomimetics. Initial studies
(Scheme 2) were concerned with the synthesis of the C-
glucosyl serine analogue 9. The key starting material, iodide 4,
was readily prepared from exo-glycal 2 by stereoselective
9-BBN hydroboration–oxidation7 followed by iodination.6
Thiol 6 was the required coupling partner. We were surprised to
discover that this useful building block had not been reported
previously but it was easily obtained from the Garner aldehyde
(S)-58 by reduction followed by Mitsunobu displacement using
thioacetic acid and then treatment with sodium methoxide.†
Alkylation of thiol 6 using iodide 4 followed by oxidation of the
resulting sulfide produced sulfone 7 {[a]D 230.1 (c 0.57,
CHCl3) [HRMS (FAB+): Found: 838.3601. C46H57NO10SNa
requires 838.3608 (0.9 ppm error)]}. This sulfone was then
treated under Chan’s tandem halogenation–Ramberg–Bäcklund
conditions5b to produce the E-alkene 8 (J 15.6 Hz) in 37%
unoptimised yield. Alkene reduction was efficiently achieved
using diimide generated in situ and the amino acid was
unmasked using a one-pot hydrolysis–oxidation procedure.9
Scheme 2 Reagents and conditions: i, 9-BBN, then H2O2, NaOH; ii, PPh3,
imidazole, I2, 80% (ref. 6); iii, NaBH4; iv, PPh3, diisopropyl azodicarbox-
ylate, AcSH; v, NaOMe, 38% for 3 steps; vi, K2CO3, MeCN–MeOH,
reflux; vii, MCPBA, Na2HPO4, 66% for 2 steps; viii, CBr2F2, KOH–Al2O3,
ButOH, 60 °C, 37%; ix, TsNHNH2, NaOAc, 85 °C, 82%; x, Jones’ reagent
(1 M), then CH2N2, 60%.
Scheme 1
Chem. Commun., 1999, 1599–1600
1599

linked glycosyl amino acids. We are currently optimising the
above procedures and extending the methodology to more
challenging targets.
We are grateful to the BBSRC and the University of York for
studentships (A. D. C. and D. E. P., respectively). We would
also like to thank Roche Discovery Welwyn for CASE support
(A. D. C.).
Notes and references
† All new compounds were fully characterised spectroscopically and by
HRMS/elemental analysis.
‡ The enantiomeric Garner aldehyde (R)-5 was used in this route because
full data is available for diastereoisomer 12.
1 For a comprehensive review, see C. M. Taylor, Tetrahedron, 1998, 54,
11317.
2 For more recent work in this area, see (a) A. Dondoni, A. Marra and A.
Massi, J. Org. Chem., 1999, 64, 933; (b) R. N. Ben, A. Orellana and P.
Arya, J. Org. Chem., 1998, 63, 4817; D. Urban, T. Skrydstrup and J.-M.
Beau, Chem. Commun., 1998, 955; (c) T. Fuchss and R. R. Schmidt,
Synthesis, 1998, 753; (d) F. Burkhart, M. Hoffmann and H. Kessler,
Angew. Chem., Int. Ed. Engl., 1997, 36, 1191.
3 F. K. Griffin, P. V. Murphy, D. E. Paterson and R. J. K. Taylor,
Tetrahedron Lett., 1998, 39, 8179; see also P. S. Belica and R. W.
Franck, Tetrahedron Lett., 1998, 39, 8225.
4 M.-L. Alcaraz, F. K. Griffin, D. E. Paterson and R. J. K. Taylor,
Tetrahedron Lett., 1998, 39, 8183.
5 (a) C. Y. Meyers, A. M. Malte and W. S. Matthews, J. Am. Chem. Soc.,
1969, 91, 7510; (b) T.-L. Chan, S. Fong, Y. Li, T.-O. Man and C. D.
Poon, Chem. Commun., 1994, 1771.
6 F. K. Griffin, D. E. Paterson and R. J. K. Taylor, Angew. Chem., Int. Ed.,
1999, in the press.
7 T. V. RajanBabu and G. S. Reddy, J. Org. Chem., 1986, 51, 5458.
8 P. Garner and J. M. Park, J. Org. Chem., 1987, 52, 2361; A. D.
Campbell, T. M. Raynham and R. J. K. Taylor, Synthesis, 1998,
1707.
9 A. Dondoni, A. Marra and A. Massi, Tetrahedron, 1998, 54, 2827.
10 C. R. Johnson and B. A. Johns, Synlett, 1997, 1406.
11 G. Reginato, A. Mordini and M. Caracciolo, J. Org. Chem., 1997, 62,
6187.
Scheme 3 Reagents and conditions: i, CHI3, CrCl2, THF, 60%; ii, 9-BBN;
iii, 10, PdCl2(dppf)·CHCl3, aq. K3PO4, DMF, 48%; iv, TsNHNH2, NaOAc,
85 °C, 78%; v, Jones’ reagent (1 M), then CH2N2, 56%.
gave the protected C-glycosyl amino acid 12 in good yield. All
data correlated well with those reported in a previous synthesis
of 12 by Dondoni et al.2a {e.g. [a]D +6.25 (c 0.8, CHCl3); lit.,2a
+6.2 (c 0.7, CHCl3) [HRMS (FAB+): Found: 776.3783.
C45H55NO9Na requires 776.3775 (1.2 ppm error)]} and thus
confirmed the expected7,10 b-selectivity of the hydroboration
step.
In summary, we have devised two new, versatile routes to
glycopeptidomimetics which join together the individual sugar
and amino acid units to produce exclusively b-stereoisomers at
the ‘anomeric’ centre. We have also established that the
Ramberg–Bäcklund rearrangement of S-glycoside dioxides is a
general procedure which can be utilised for the synthesis of exo-
glycals,3 C-linked disaccharides,6 and now in this work, C-
12 K. Takai, K. Nitta and K. Utimoto, J. Am. Chem. Soc., 1986, 108,
7408.
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