a â-turn conformation when incorporated in selected oligo-
peptide sequences. A closer inspection of SAA 1 reveals
structural similarity to a Gly-Ser/Thr dipeptide,5 with the
functionalized tetrahydropyran core stemming from the
original carbohydrate resembling, in part, the serine/threonine
side chains. Several examples of SAAs, in which the furan/
pyran core is modified to contain functionalities resembling
amino acid side chains other than Ser/Thr, have been reported
in recent years.2
tert-butanesulfinyl amide (Ellman’s reagent)8 in the presence
of anhydrous CuSO4 in DCM9 (70%, Scheme 1) provided
Scheme 1. Synthesis of Sugar Amino Acids 7 and 9a
However, the reported dipeptide isosters, as exemplified
by 1, normally contain a primary amine functionality that is
employed for incorporation in oligopeptide sequences. In
other words, the reported SAA-based dipeptide isosters
almost without exception display glycine-like properties. Any
synthetic sequence enabling the construction of SAAs that
are alkylated at the δ-position, as in 2 (Figure 1), will result
a Reagents and conditions: (i) (R)-tert-butylsulfinamide, anhy-
drous CuSO4, DCM, rt, 24 h, 70%. (ii) PhMgBr, PhCH3, -78 °C,
3 h. (iii) HCl/MeOH, rt, 30 min. (iv) (a) Boc2O, DiPEA, DCM, rt,
4 h, 73%; (b) H2, Pd/C, MeOH, acetone, rt, 12 h, 86%; (c) 95%
TFA/H2O, rt, 2 h, quantitative. (v) Fmoc-OSu, DiPEA, DCM, 1,4-
dioxane, rt, 1 h. (vi) (a) ZnCl2, AcOH, Ac2O, rt, 12 h; (b) HCl/
MeOH, rt, 6 h; (c) TEMPO, BAIB, DCM/H2O, rt, 12 h.
Figure 1. Structures of known δ-SAA 1, a Gly-Ser/Thr mimic,
and the here reported alkylated δ-SAA 2.
in the preparation of dipeptide isosters other than those
including glycine. With this aim in mind, we set out to
develop a suitable route to the synthesis of δ-substituted
SAAs, the initial results of which are presented here.6
carbohydrate-derived sulfinimine 4. Treatment of 4 with
PhMgCl led to the formation of sulfinamide 5 in high
diastereoisomeric excess (>95%, de), as judged by NMR
analysis of the crude product.
The key step in our synthetic strategy entails the introduc-
tion of alkyl/aryl functionality via diastereoselective addition
on a carbohydrate-derived sulfinimine. The applicability of
the new SAA derivatives in a standard peptide synthesis
protocol is demonstrated by the use of one of these, the
conformationally restricted protected D-Ala-Ser/Thr mimic
SAA 11, for the construction of cyclic tetramer 19.
To determine the stereochemical outcome of the alkylation
reaction, compound 5 was desulfinylated under the influence
of HCl in MeOH to give HCl salt 6, which was subsequently
transformed to the corresponding t-butoxycarbonylate (Boc2O,
DiPEA, DCM). Ensuing Pd/C hydrogenolysis of the benzyl
ethers followed by acid-mediated removal of the Boc
protective group (95% TFA in H2O) afforded known TFA-
salt 7.10 All analytical and spectroscopic data of 7 were
consistent with those reported in the literature. The Re-site
addition of the Grignard reagent to sulfinimine 3 suggests
the involvement in chelation of an oxygen of the sugar
moiety with the magnesium reagent, besides chelation of the
oxygen of the sulfinyl functionality.11
Our synthetic strategy is exemplified by the synthesis of
SAA 9. Condensation of the known formyl tetra-O-benzyl-
â-D-C-glucopyranoside 37 with commercially available (R)-
(3) Smith, A. B., III; Sasho, S.; Barwis, B. A.; Sprengeler, P.; Barbosa,
J.; Hirschmann, R.; Cooperman, B. S. Bioorg. Med. Chem. Lett. 1998, 8,
3133-3136.
(4) Graf von Roedern, E.; Lohof, E.; Hessler, G.; Hoffmann, M.; Kessler,
H. J. Am. Chem. Soc. 1996, 118, 10156-10167.
In continuation of the synthesis of SAA 9, HCl salt 6 was
protected as the Fmoc derivative (Fmoc-OSu, DiPEA, DCM/
(5) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1994,
33, 687-689.
(6) For related work from our laboratory, see: (a) van Well, R. M.;
Overkleeft, H. S.; Overhand, M.; Vang Carstenen, E.; van der Marel, G.
A.; van Boom, J. H. Tetrahedron Lett. 2000, 41, 9331-9335. (b) van Well,
R. M.; Marinelli, L.; Altona, C.; Erkelens, K.; Siegal, G.; van Raaij, M.;
Llamas-Saiz, A. L.; Kessler, H.; Novellino, E.; Lavecchia, A.; van Boom,
J. H.; Overhand, M. J. Am. Chem. Soc. 2003, 125, 10822-10829. (c)
Grotenbreg, G. M.; Timmer, M. S. M.; Llamas-Saiz, A. L.; Verdoes, M.;
van der Marel, G. A.; van Raaij, M. J.; Overkleeft, H. S.; Overhand, M. J.
Am. Chem. Soc. 2004, 126, 3444-3446. (d) El Oualid, F.; Bruining, L.;
Leroy, I. M.; Cohen, L. H.; van Boom, J. H.; van der Marel, G. A.;
Overkleeft, H. S.; Overhand, M. HelV. Chim. Acta 2002, 85, 3455-3472.
(e) El Oualid, F.; Burm, B. E. A.; Leroy, I. M.; Cohen, L. H.; van Boom,
J. H.; van den Elst, H.; Overkleeft, H. S.; van der Marel, G. A.; Overhand,
M. J. Med. Chem. 2004, 47, 3920-3923.
(7) (a) For synthesis of formyl tetra-O-benzyl-â-D-C-glucopyranoside
see: Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. Tetrahedron Lett.
1992, 33, 737-740. (b) Dondoni, A.; Scherrmann, M.-C. J. Org. Chem.
1994, 59, 6404-6412. (c) Sa´nchez, M. E.; Michelet, V.; Besnier, I.; Geneˆt,
J. P. Synlett 1994, 705-708. (d) Dondoni, A.; Marra, A. Tetrahedron Lett.
2003, 44, 13-16.
(8) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913-9914.
(9) Use of a stronger Lewis acid such as Ti(O-iPr)4 resulted in a lower
yield (50%).
(10) Schmidt, R. R.; Dietrich, H. Angew. Chem., Int. Ed. Engl. 1991,
30, 1328-1329.
(11) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39-46.
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