General, stereoselective synthesis of ethylene isosteres of α- and β- glycosylasparagines

Article abstract of DOI:10.1016/S0040-4039(00)00403-2

The coupling of α- or β-D-linked lithium C-glycosyl acetylides with N- Boc D-serinal acetonide followed by the reduction of the triple bond, deoxygenation, and oxidative cleavage of the oxazolidine ring afforded α- and β-anomer pairs of C-glycosyl α-aminopentanoic acids (gluco, manno, galacto, and 2-acetamido-galacto). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00403-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3483–3486
General, stereoselective synthesis of ethylene isosteres of
α- and β-glycosylasparagines
Alessandro Dondoni,∗ Giandomenico Mariotti and Alberto Marra
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy
Received 1 February 2000; accepted 7 March 2000
Abstract
The coupling of α- or β-D-linked lithium C-glycosyl acetylides with N-Boc D-serinal acetonide followed by
the reduction of the triple bond, deoxygenation, and oxidative cleavage of the oxazolidine ring afforded α- and
β-anomer pairs of C-glycosyl α-aminopentanoic acids (gluco, manno, galacto, and 2-acetamido-galacto). © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: amino acids; C-glycosides; glycopeptide mimetics; C-glycosylasparagines; sugar acetylenes.
As potential precursors to glycopeptide mimetics,1 C-glycosyl amino acids in which the glycinyl
moiety is linked to the anomeric carbon of the sugar through an all carbon tether, constitute the target
of recent synthetic efforts.2 While natural glycopeptides contain O-glycosylserine, O-glycosylthreonine
and N-glycosylasparagine units, the incorporation of C-glycosyl amino acids in the peptide backbone is
expected to induce higher stability toward both chemical and enzymatic deglycosylation with consequen-
tial interesting biological properties. Moreover, such a simple yet substantial chemical modification may
provide very useful information in studies directed at understanding the specific role of the carbohydrate
moieties of glycopeptides in their properties and activities.3 However, there is still a great need for new
synthetic methods endowed with a good level of generality and allowing entry to either α- or β-linked
isomers. We would like to report here a sugar acetylene approach to N-Boc C-glycosyl α-aminopentanoic
acids 1, i.e. isosteric mimetics of N-glycosylasparagines 2 in which the amide group has been replaced
by an ethylene group. The scope of the method is documented by the preparation of the α- and β-anomer
pairs of four D-pyranosides (gluco, manno, galacto, and 2-acetamido-galacto) (Table 1).
∗
Corresponding author. Tel: +39-0532291176; fax +39-0532291167; e-mail: adn@dns.unife.it (A. Dondoni)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00403-2
tetl 16683

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Table 1
Starting sugar acetylenes 3 and final C-glycosyl α-amino acids 1 prepared

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While sugar acetylenes are receiving increasing attention as building blocks in carbohydrate
chemistry,4 the reaction of their metalated derivatives with aldehydes has not been reported so far. Thus,
we were delighted to observe that the model reaction generated by addition of the lithium acetylide
derivative5 β-3a of the tetra-O-benzyl-C-glucopyranoside to the protected D-serinal 4 proceeded readily
at low temperature to give the propargylic alcohol β-5a in good isolated chemical yield (Scheme 1).9
1
This compound appeared to be a single diastereomer as judged by H NMR analysis, very likely with
(S) configuration at the newly formed stereocenter (anti adduct).12 Suitable and high yielding reactions
were employed for the elaboration of the side chain of the C-glucoside β-5a. First, the triple bond
was reduced by the use of diimide generated in situ from (p-toluenesulfonyl)hydrazine and sodium
acetate. The saturated alcohol β-6a was deoxygenated by the standard Barton–McCombie method and
the oxazolidine ring was cleaved and oxidized in one pot by use of the Jones reagent as described in
recent work conducted in this laboratory.2a The resulting C-glucosyl α-aminopentanoic acid β-1a was
isolated in 61% overall yield from the adduct β-5a and was characterized as its methyl ester.9 This
product showed consistent NMR and optical rotation data with that of the product prepared by us by a
previous route.2a An identical reaction scheme was followed for the preparation9 of the anomer α-1a as
well as the C-mannosyl pair α-1b and β-1b and the C-galactosyl pair α-1c and β-1c starting from the
corresponding O-benzylated sugar acetylenes5 (Table 1). The yields of isolated intermediates and final
products were comparable to those registered in Scheme 1.
Scheme 1. Synthesis of the glucosylasparagine isostere β-Glc(CH2)2-Asn β-1a. Reagents and conditions: (a) TsNHNH2,
AcONa, DME–H2O, 80°C, 5 h; (b) 1,10-thiocarbonyldiimidazole, DMAP, THF, reflux, 4 h; Bu3SnH, AIBN, toluene, 85°C,
2 h; (c) 1 M Jones reagent, acetone, 0°C to rt, 3 h
The C-GalNAc derivatives β-1d and α-1d were obtained9 in a similar way, and in comparable yields
to those above, starting from the dilithio derivative of the corresponding 2-acetamido sugar acetylenes5
β-3d and α-3d. The synthesis of the α-linked isomer α-1d is presented in Scheme 2. It is worth noting
that an alternative synthetic approach to this compound by the use of the lithium acetylide derivative of
the azidosugar was hampered by the very low yields (5%) of the coupling reaction with the aldehyde
4. Instead, unstable products, very likely cycloadducts of the azido group to the ethynyl moiety, were
observed which decomposed during the workup of the reaction mixture. Reactions of the azido group
with adjacent unsaturated centres linked to the anomeric carbon of sugars have been reported.13
In summary, centered on the coupling of two chiral building blocks, i.e. sugar acetylenes and a
protected α-amino aldehyde, a new route has been paved to C-glycosyl amino acids that are ethylene
isosteres of N-glycosylasparagines. The method appears to be suitable for the preparation of α- and β-D-
linked anomers of various sugars including 2-deoxy-2-acetamido derivatives that are of special biological
relevance. The method exploits the stereochemistry already in place at the anomeric carbon of sugar
acetylenes that provide part of the carbon tether while the oxazolidine ring of the aldehyde 4 serves

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Scheme 2. Synthesis of the 2-acetamido-galactosylasparagine isostere α-GalNAc(CH2)2-Asn α-1d. Reagents and conditions
as in Scheme 1
as the protected and configurationally stable glycinyl moiety.2a Finally, the O-benzylated compounds
α-1c and α-1d were transformed into the corresponding O-acetylated derivatives α-1c0 and α-1d0 by
debenzylation (H2, Pd(OH)2, rt, 2 h) and acetylation (Ac2O, Py, rt, 4 h). This simple yet important
transformation demonstrated that the products of this synthetic approach are orthogonally protected and
therefore can be easily converted into suitable building blocks for the incorporation within large peptide
frameworks.
Acknowledgements
Generous financial support from MURST, COFIN-98 (Italy), is gratefully acknowledged.
References
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5. β-D-Linked glucosyl, mannosyl, and galactosyl acetylenes β-3a–c were prepared from the corresponding lactones as
described.4a In a similar way the 2-acetamido-galactosyl derivative β-3d was prepared from the known6 2-azido-3,4,6-tri-
O-benzyl-2-deoxy-D-galactonolactone followed by the reduction of the azido group (Ph3P, H2O, rt, 16 h) and N-acetylation
(Ac2O, rt, 2 h). The α-isomers α-3a–d were prepared by C-glycosidation (alkynylation) of the corresponding sugar acetates
using7 nBu3SnC^CSiMe3 in the presence of trimethylsilyl triflate (TMSOTf) in CH2Cl2. The use of this mixed Sn–Si bis-
metalated acetylene for the alkynylation of sugars has been recommended by others.8
6. Dondoni, A.; Scherrmann, M.-C. J. Org. Chem. 1994, 59, 6404–6412.
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8. Nishika, T.; Ishikawa, M.; Isobe, M. Synlett 1999, 123–125.
9. Physical data of C-glycosides. Optical rotation were measured at 20±2°C in CHCl3 (λ=589 nm). Compound β-3a: m.p.
66–67°C (pentane); [α]=+17.3 (c 2.0); lit.10 m.p. 58°C; [α]=+17.4 (c 1.6). Compound α-3a: [α]=+35.8 (c 1.5); lit.11
[α]=+46.7 (c 1.7). Compound β-3b: m.p. 94–96°C (pentane); [α]=−31.8 (c 1.1); lit.4a [α]=−29.1 (c 0.5). Compound α-
3b: [α]=+23.1 (c 1.0); lit.4a [α]=+23.5 (c 0.9). Compound β-3c: m.p. 79–80°C (pentane); [α]=+9.9 (c 0.9); lit.4a [α]=+5.9

3487
(c 0.8). Compound α-3c: [α]=+31.1 (c 1.7). Compound β-3d: m.p. 174–176°C (AcOEt–cyclohexane); [α]=+36.1 (c
0.9). Compound α-3d: m.p. 143–145°C (cyclohexane); [α]=+95.9 (c 0.9). Compound β-1a Me-ester: [α]=+6.2 (c 0.7).
Compound α-1a Me-ester: m.p. 79–81°C (pentane); [α]=+36.5 (c 1.5). Compound α-1b Me-ester: [α]=+22.6 (c 0.8).
Compound β-1b Me-ester: [α]=+5.5 (c 0.6). Compound α-1c Me-ester: [α]=+26.5 (c 0.6). Compound β-1c Me-ester:
[α]=+6.4 (c 0.5). Compound α-1c0 Me-ester: [α]=+60.0 (c 0.6). Compound β-1d Me-ester: [α]=+27.0 (c 0.6). Compound
α-1d Me-ester: [α]=+23.3 (c 1.2). Compound α-1d0 Me-ester: [α]=+46.3 (c 0.5).
10. Alzeer, J.; Vasella, A. Helv. Chim. Acta 1995, 78, 177–193.
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documented. For relevant recent references and an improved synthesis of these α-amino aldehydes, see: (a) Dondoni,
A.; Perrone, D. Synthesis 1997, 527–529. (b) Org. Synthesis 1999, 77, in press.
13. (a) Bertozzi, C. R.; Bednarski, M. D. Tetrahedron Lett. 1992, 33, 3109–3112. (b) Dondoni, A.; Scherrmann, M.-C.; Marra,
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