One pot conversion of ketoses into sugar β-peptides via a ritter reaction

Article abstract of DOI:10.1055/s-2001-16797

α-D-Galacto-2-deoxy-oct-3-ulopyranosonic acids can be converted into unnatural glycopeptides via a one pot intramolecular Ritter reaction. Initially, the ketopyranoside reacts under Lewis acid catalyzed conditions with a nitrile (aromatic or aliphatic) to

Full text of DOI:10.1055/s-2001-16797

1434
LETTER
One Pot Conversion of Ketoses into Sugar -Peptides via a Ritter Reaction
Frank Schweizer,a Anders Lohse,b Albin Otter,a Ole Hindsgaul*a
aDepartment of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
bOn leave from the Department of Chemistry, University of Aarhus, DK-8000 Aarhus C., Denmark
Fax +45-780-492-7705
Received 7 May 2001
age. The synthesis (Scheme) started from the readily
Abstract: -D-Galacto-2-deoxy-oct-3-ulopyranosonic acids can be
available lactone 3.8 Reaction of tert-butylacetate enolate
with lactone 3 at –78 °C led to ketose 4 in 84% yield. Ad-
dition of a second enolate was not observed. Compound 4
converted into unnatural glycopeptides via a one pot intramolecular
Ritter reaction. Initially, the ketopyranoside reacts under Lewis acid
catalyzed conditions with a nitrile (aromatic or aliphatic) to form a
glycosylimino anhydride intermediate which can be isolated. Expo- exists entirely in the pyranose form (CDCl3, room temper-
ature, 360 MHz NMR).9 Removal of the tert-butyl group
and treatment of the ketose 5 with trimethylsilyl-trifluo-
sure of this intermediate to simple primary amines or amino acids
produces novel sugar- -peptides. Three different nitriles and three
different amines have been used to generate 6 sugar -peptides to
romethanesulfonate and benzonitrile (PhCN) in dichlo-
demonstrate the generality of this reaction.
romethane (CH2Cl2) gave the spiro dihydrooxazinone 710
(92%) after 10 minutes. The formation of 7 can be ex-
plained by irreversible intramolecular trapping of the ini-
Key words: carbohydrates, combinatorial chemistry, glycopep-
tides, glycosylamides
tially formed nitrilium ion 6 by the free carboxylic acid
and represents a modified Ritter reaction.11 To our knowl-
Molecular recognition of carbohydrates by proteins plays
an important role in many cellular processes and underlies
a significant pharmaceutical potential.1 Due to the low af-
finity of monovalent protein-carbohydrate interactions,
novel glycomimetics with enhanced binding affinities are
high in demand for the drug discovery process. In addi-
tion, carbohydrate-based scaffolds2 and sugar-amino acid
hybrids3 have been used to mimick peptidesand also have
been shown to influence the pharmacokinetic and dynam-
ic properties of pharmaceutically active compounds.4
α,α-Disubstituted pyran amides 1 projecting functional
groups in both α- and β-directions (Figure 1), appeared to
us to be useful molecular probes to study carbohydrate
protein recognition because of two reasons. First of all,
many carbohydrate-binding proteins (with the exception
of glycosidases) recognize monosaccharidic α- or β-gly-
cosides equally5 and secondly, carbohydrate-protein rec-
ognition may be dominated through amide bonds present
in the sugar.6 Ideally, the synthesis of compounds such as
1 should be general, allowing the implementation of com-
binatorial synthesis7 for library preparation.
edge, this is the first reported Ritter reaction on sugar ke-
toses with intramolecular carboxylic acid delivery,
although an intermolecular version on sugar aldoses has
been described.12 The cyclic imino anhydride 7 was stable
to the work-up conditions (aqueous sodium bicarbonate)
and purification (flash-chromatography on silica gel).
However, when 7 was treated with cycloheptylamine, the
diamide 8 (containing a sugar β-amino acid core) was iso-
lated in 90% yield as the only product.13 The stereochem-
istry of 8 was unambiguously established by NMR
spectroscopy. The two amide protons (Figure 2) were eas-
ily distinguished as a singlet and a doublet (J = 7.4 Hz).
The former was subjected to a one-dimensional TROESY
experiment,14,15 whereby the resonance was excited by a
240 ms selective e-burp1 pulse.16 Inter-proton effects
were observed both to H-5 and H-7 (2.5% and 0.5% NOE,
respectively measured relative to the amide resonance in-
tegral, Figure 2). The observation of these ROEs is only
compatible with an axial orientation of the anomeric
amide group.
Once the stereochemistry of the sugar-β-peptide 8 was de-
duced, we focused on a one-pot conversion of the ketose
4 to the diamide 8. Removal of the tert-butyl group in 4
with trifluoroacetic acid generated 5 in situ. After solvent
In this paper we report a stereoselective synthesis of a se-
ries of anomerically branched galactosyl amides having
the general structure 2, which contains a β-peptidic link-
Figure 1 General structures of α,α-disubstituted pyrans as molecular probes for carbohydrate binding proteins. R’and R" in 1 represent side
chains which may enhance the binding affinity with a protein at the periphery of the sugar binding site. Structure 2 represents a novel functio-
nalized β-peptidic scaffold. Compound 15 is a highly hindered amine which is resistant to acylation.
Synlett 2001, No. 9, 1434–1436 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
One Pot Conversion of Ketoses into Sugar -Peptides via a Ritter Reaction
1435
Scheme a) LiCH2COOtBu (4 eq.), THF, 78°C→rt, 1h, 84%; b) TFA/CH2Cl2 (1:1), O °C→rt, 1.5 h, quant.; c) TMSOTf (3.5 eq.), PhCN (10
eq.), CH2Cl2, O °C, 10 min, 92%; d) C7H13NH2 (10 eq.), CH2Cl2, 90%; e) TFA/CH2Cl2 (1:1), O °C→rt, 1.5h, codistillation with toluene, then
TMSOTf (3.5 eq.), R1CN (10 eq.), CH2Cl2, O °C, 1.5 h, then R2NH2 (10 eq.), CH2Cl2, rt, 1.5 h, 60-70%; f) 12, C/Pd(OH)2, H2, MeOH, quant.
methylester, benzylamine, and cycloheptylamine. In all
cases, we obtained the desired β-peptidic sugar diamides
10–14 as single stereoisomers in 60–70% overall isolated
yield (see NMR data in Table).20 The new stereochemistry
in each of 10–14 was verified as described for 8, using the
1D-TROESY NMR technique. Hydrogenolysis of 12 led
to 9 in quantitative yield, an example of a deprotected sug-
ar β-peptide.
The present “Ritter”-based method is very effective for
Figure 2 Conformationally relevant ROE interactions observed
generating glycosylamides which are not acessible by
acylation of glycosylamines. For example, attempts to
acylate the amine 15.17 prepared from the corresponding
anomeric azide by hydrogenation using activated amino
acid esters failed.18 The commercial availability of large
numbers of nitriles and amines suggests that the one-pot
reaction presented here should be attractive for the prepa-
ration of β-peptidic sugar diamide libraries. Furthermore,
the highly functionalized α,α-disubstituted pyran scaffold
2 with its rigid β-sugar amino acid core might also find
use in peptide mimetic2,3 and β-peptide synthesis.19
for 8.
removal, 5 was treated with trimethylsilyl-trifluo-
romethanesulfonate and PhCN in CH2Cl2 for 2 h at 0 °C
followed by quenching the reaction mixture with excess
cycloheptylamine which produced 8 directly in an overall
yield of 71%. In order to demonstrate the generality of the
reaction we then treated the ketose 5 with two other ni-
triles, acetonitrile and phenylacetonitrile, and quenched
the reaction with three different amines, namely glycine
Synlett 2001, No. 9, 1434–1436 ISSN 0936-5214 © Thieme Stuttgart · New York

1436
F. Schweizer et al.
LETTER
1
Table Characteristic H NMR- (360 MHz, CDCl3, rt, TMS) and high resolution
MS-data (HRMS) for the compounds 8,10-14.
80.5, 80.5, 74.8, 71.0 (C-4, C-5, C-6, C-7), 38.3 (C-2). IR
References and Notes
(CH2Cl2): 1798, 1674, 1199, 1099 cm-1. HRMS (ES,
(1) Varki, A. Glycobiology 1993, 3, 97.
[M+Na]+) calc. 706.27807, found 706.27842.
(2) a) Hirschmann, R.; Nicolaou, K.C.; Pietranico, S.; Leahy,
E.M.; Salvino, J.; Arison, B.; Cichy, M.A.; Spoors, P.G.;
Shakespeare, F.W.C.; Sprengeler, P.A. et al. J. Am. Chem.
Soc. 1993, 115, 12550 b) Hirschmann, R.; Hynes, J.J.; Cichy-
Knight, M.A.; van Rijn, R.D.; Sprengeler, P.A.; Spoors, P.G.;
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al. J. Med. Chem. 1998, 41, 1382
(3) a) Graf von Roedern, E.; Kessler, H. Angew. Chem. Int. Ed.
Engl. 1994, 33, 670 b) Graf von Roedern, E.; Lohof, E.;
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E.; Mang, C.; Burkhart, F.; Dechantsreiter, M.A.; Haubner,
R.; Wester, H-J. Schwaiger, M.; Hölzemann, G.; Goodman,
S.L.; Kessler, H. Angew. Chem. Int. Ed. 2000, 39, 2761.
(5) Goldstein, I.J.; Poretz, R.D. In The Lectins; Liener, I.E.;
Sharon, N.; Goldstein, I.J., Eds.; Academic Press: London
1986; p 35.
(6) Liang, R.; Yan. L.; Loebach, J.; Ge, M.; Uozumi, Y.;
Sekanina, K.; Horan, N.; Gildersleeve, J.; Thompson, C.;
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(11) a) Ritter, J.J.; Minieri, P.P. J. Am. Chem. Soc. 1948, 70, 4045
b) Krimen, L.J.; Cota, D.J. Org. React. 1969, 17, 213.
(12) Ratcliffe, A.J.; Konradsson, P.; Fraser-Reid, B. J. Am. Chem.
Soc. 1990, 112, 5665.
(13) Dihydrooxazinones have been previously observed and were
used to synthesize -peptides: a) Podlech, J.; Seebach, D.
Angew. Chem. Int. Ed. Engl. 1995, 34, 471 b) Drey, C.N.C.;
Mietwa, E. J. Chem. Soc. Perkin Trans., 1 1982, 1587.
(14) Bothner-By, A.A.; Stephens, R.L.; Lee, J.; Warren, C.D.;
Jeanloz, R.W. J. Am. Chem. Soc. 1984, 106, 811.
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(16) Geen, H.; Freeman, R. J. Magn. Reson. 1991, 93, 93-141.
(17) Characteristic data for compound 15: 1H NMR (360 MHz,
CDCl3, r.t., TMS): = 3.96 (dd, 3J(H6,H7) = 1.2 Hz,
3J(H5,H6) = 2.8 Hz, 1H, H-6), 3.83 (d,3J(H4,H5) = 9.8 Hz, 1H,
H-4), 2.1-2.0 (s, br., 2H, NH2).
(18) Attempted acylation of the amine 15 was performed with 3
equiv of a 1:1 mixture containing 1-hydroxybenzotriazole and
Fmoc-L-Ala-OPfp in a 1:1 mixture of DMF and CH2Cl2 over
a period of 48 hours. No product formation was observed and
the ketose 16 was isolated after aqueous work up and
chromatography.
(19) Koert, U. Angew. Chem. Int. Ed. Engl. 1997, 36, 1836.
(20) Typical procedure for the one pot synthesis of a sugar
-
(7) Terrett, N.K.; Gardner, M.; Gordon, D.W.; Kobylecki, R.J.;
Steele, J. Tetrahedron 1995, 51, 8135.
peptide: Ketol 5 (0.1 mmol) was dissolved in 1:1 mixture
containing trifluoroacetic acid and dichloromethane (4 mL) at
0 C for 90 min. The solvent was removed under reduced
pressure and codistilled with toluene (2 10 mL) to dryness.
The oily residue was redissolved in dichloromethane (2 mLl)
trimethylsilyl trifluoromethanesulfonate (0.35 mmol) and
nitrile (1 mmol) were added at 0 C. After 90 min. the amine
component (1 mmol) was added and the reaction was stirred
for an additional 90 min at 0 C. Aqueous work up with sodium
bicarbonate followed by chromatographic purification
afforded the sugar -peptide in 60-70% yield.
(8) Overkleeft, H.S.; van Wiltenburg, J.; Pandit, U.K.
Tetrahedron 1994, 50, 4215.
(9) Characteristic data for compound 4: 1H NMR (360 MHz,
CDCl3, r.t., TMS): = 5.43 (s, br., 1H, OH), 4.00 (dd,
3J(H6,H7) = 1.2 Hz, 3J(H5,H6) = 2.8 Hz, 1H, H-6), 3.75 (d,
3J(H4,H5) = 9.8 Hz, 1H, H-4).
(10) Characteristic data for compound 7: 1H NMR (360 MHz,
CDCl3, r.t., TMS): = 4.67 (ddd, 3J(H6,H7) ~ 1 Hz,
3J(H7,H8a) = 7.9 Hz, 3J(H7,H8b) = 5.5 Hz, 1H, H-7), 4.12 (dd,
3J(H5,H6) = 2.4 Hz, 1H, H-6), 4.06 (dd, 3J(H4,H5) = 9.9 Hz,
1H, H-5), 4.02 (d, 1H, H-4), 3.65 (dd, 2J(H8a,H8b) = 9.1 Hz,
1H, H-8a), 3.56 (dd, 1H, H-8b), 2.89 (d, 2J(H2a,H2b) = 16.3 Hz,
1H, H-2a), 2.73 (d, 1H, H-2b). 13C NMR (75 MHz, CDCl3,
25 C, TMS): = 164.9 (C=O), 152.3 (C=N), 88.9 (C-3),
Article Identifier:
1437-2096,E;2001,0,09,1434,1436,ftx,en;S03001ST.pdf
Synlett 2001, No. 9, 1434–1436 ISSN 0936-5214 © Thieme Stuttgart · New York