Synthesis of C-glycosyl β-amino acids by asymmetric Mannich-type three-component reactions

Article abstract of DOI:10.1016/j.tetlet.2004.01.070

C-Galactosyl and C-ribosyl β-amino acids were prepared by one-pot InCl₃-catalyzed Mannich-type three-component condensation (3CC) by combining the corresponding formyl C-glycoside, p-methoxybenzyl amine, and a ketene silyl acetal. In each case

Full text of DOI:10.1016/j.tetlet.2004.01.070

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2381–2384
Synthesis of C-glycosyl b-amino acids by asymmetric Mannich-type
three-component reactions
Alessandro Dondoni,a,* Alessandro Massi,a Simona Sabbatinia and Valerio Bertolasib,
aLaboratorio di Chimica Organica, Dipartimento di Chimica, Universitꢀa di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
bCentro di Strutturistica Diffrattometrica, Dipartimento di Chimica, Universitꢀa di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
Received 12 December 2003; accepted 16 January 2004
Abstract—C-Galactosyl and C-ribosyl b-amino acids were prepared by one-pot InCl3-catalyzed Mannich-type three-component
condensation (3CC) by combining the corresponding formyl C-glycoside, p-methoxybenzyl amine, and a ketene silyl acetal. In each
case the reaction was highly stereoselective and afforded only one single product in good to excellent yields.
Ó 2004 Elsevier Ltd. All rights reserved.
Multicomponent reactions (MCRs) performed either on
a solid phase or in solution1 have emerged as a powerful
tool in combinatorial chemistry for the generation of
small-molecule libraries with the goal of discovering new
leads for drug development and optimization processes
or identifying novel biologically active substances. With
some exceptions,2 most MCRs have been focused on
achieving molecular diversity through functional group
variation of components, whereas stereochemical
aspects have so far played a secondary role. This is quite
surprising in view of the above cited main fields of
application of MCRs because the absolute as well as
the relative configuration of a molecule can profoundly
affect its pharmacological properties and biological
activities.3 Consequently the need of preparing stereo-
diversified libraries by varying the stereochemistry
of compounds having the same constitution has been
stressed by Verdine4 and Tietze5 and their co-workers.
Moreover, the issue regarding the stereochemical
ing natural carbohydrate and glycinyl residues led to
collections of dihydropyrimidine and pyridine glycosides
and amino acids in enantiomerically pure form. In this
context we would like to report below on the asym-
metric version of another classical MCR, namely a
Mannich-type condensation9 that under InCl3-catalysis
as suggested by recent work of Loh and Chen2g com-
bined an anomeric sugar aldehyde, an amine, and a
ketene silyl acetal. This reaction turned out to be highly
stereoselective affording in each case examined a
C-glycosyl b-amino acid as one single stereoisomer in
good yield (60–80%). These sugar amino acids exhibit
two elements of structural diversity in respect to O- and
N-glycosyl a-amino acids, such as the natural glyco-
peptide constituent O-glycosyl serines (threonines) and
N-glycosyl asparagines, and therefore they possess great
potential as useful probes for studies in glycobiology10
and building blocks for the development of artificial C-
glycopeptides.11 The asymmetric synthesis of b-amino
acids12 is a topic of current interest due to their own
pharmacological activities13 and use as a-amino acid
surrogates for the construction of hybrid a- and
b-peptidic materials.14
induction by chiral catalysts in the Passerini reaction has
6
€
been recently addressed by the Domling group, while
reagent-controlled asymmetric Biginelli7 and Han-
tzsch7b;8 cyclocondensations have been investigated over
the last two years in our laboratory. Indeed, the use of
chiral reagents (aldehydes, ketoesters, enamines) carry-
The few existing syntheses of C-glycosyl b-amino acids
have been approached via two multistep routes, both
starting from sugar aldehydes. One route had relied on
the Mannich-type reaction of a-amido glycoalkyl sulf-
ones (prepared from C-glycosyl propionaldehydes) with
Keywords: Multicomponent reaction; Mannich reaction; C-Glycosyl
b-amino acids; Unnatural peptides.
* Corresponding author. Tel.: +39-0532-291176; fax: +39-0532-2911-
67; e-mail addresses: and@dns.unife.it; m38@unife.it
Address correspondence concerning crystallography to this author.
Fax: +39-0532-240709.
the lithium enolate derived from 2-acetylisoborneol;15
a
second route was based on a Michael-type addition of
amines to sugar derived c-alkoxy a,b-unsaturated
esters.16;17 On the other hand, in order to open a rapid
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.070

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A. Dondoni et al. / Tetrahedron Letters 45 (2004) 2381–2384
entry to this scarcely investigated class of artificial sugar
amino acids, we carried out exploratory investigations
of a three-component Mannich-type synthesis by treat-
ment of the b-linked C-galactosyl formaldehyde18
1
(90 mg) with p-methoxybenzyl amine (PMBA, 2)
(1 equiv) and catalytic InCl3 (0.2 equiv) in MeOH at rt,
followed by the addition after 30 min of the third cou-
pling partner (1.5 equiv), the commercially available
ketene silyl acetal 1-methoxy-2-methyl-1-trimethylsilyl-
oxypropene 3a (Scheme 1). After 12 h at rt, the reaction
led to the three-component coupling product C-galac-
tosyl b-amino ester 4a as a single diastereoisomer (by 1H
NMR analysis of the crude reaction mixture) in 80%
isolated yield by column chromatography. The same
high diastereoselectivity and yield were registered in
larger scale reactions starting from 250 up to 800 mg of
the sugar aldehyde 1. While the conservation of the b-
linkage at the sugar anomeric center of 4a was easily
confirmed by estimating the J4;5 value (ꢀ9.0 Hz) in its 1H
NMR spectrum, the absolute stereochemistry of the
newly formed stereocenter carrying the amino group
was assigned as being ÔRÕ by means of 1H NMR studies19
and confirmed by X-ray crystal structure analysis20 of
compound 5 (Fig. 1) derived from 4a by N-acylation,
O- and N-debenzylation, and acetonization. Similar
results were obtained by combining in the same way as
above and in the presence of InCl3 the sugar aldehyde 1,
PMBA 2, and the readily available ketene silyl acetal,
(1-ethoxyvinyloxy)trimethylsilane21 3b (5 equiv) in EtOH
as a solvent. Also this one-pot reaction proceeded with
excellent diastereoselectivity to generate the desired
three-component coupling product 4b exclusively as
judged by 1H NMR analysis of the crude reaction
Figure 1. An ORTEP view of the C-galactosyl b-amino ester 5 dis-
playing the thermal ellipsoids at a 30% probability level.
mixture, although in lower isolated yield (60%). The low
efficiency of the ketene silyl acetal 3b due to the trans-
formation into ethyl trimethylsilyl acetate has been
reported.21a In this case the R-configuration of the
asymmetric carbon of the b-amino acid group was
assigned by analogy with 4a and the assumption that the
two reactions proceeded with the same mechanism.
The effectiveness of this MCR3 approach to other sugar
b-amino acids was demonstrated by the successful
InCl3-catalyzed reactions of the C-ribosyl formalde-
hyde18 6, with PMBA 2 and ketene silyl acetals 3a and
3b (Scheme 2). Each reaction led to a single three-
component coupling product, namely the C-ribosyl
b-amino ester 7a (82%) in one case and the ester 7b
(60%) in the other. The R-configuration of the carbon
bearing the amino group of product 7a was established
1
by H NMR studies19 whereas that of 7b was assigned
by analogy.
1
1
ꢁ
ꢁ
Scheme 1. Reagents and conditions: 1, 2, and InCl3, 4-A MS, R OH,
rt, 30 min, then 3a or 3b, rt, 12 h.
Scheme 2. Reagents and conditions: 6, 2, and InCl3, 4-A MS, R OH,
rt, 30 min, then 3a or 3b, rt, 12 h.

A. Dondoni et al. / Tetrahedron Letters 45 (2004) 2381–2384
2383
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References and notes
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A. Dondoni et al. / Tetrahedron Letters 45 (2004) 2381–2384
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15. Palomo, C.; Oiarbide, M.; Landa, A.; Gonzalez-Rego, M.
with the Cambridge Crystallographic Data Centre as
supplementary publications number CCDC 225844. Cop-
ies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
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17. Only one example of genuine C-glycosyl b-amino acid
should be considered among the compounds reported in
Ref. 15 (see compound 21). For a clarification on this
matter, see Ref. 10.
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19. Following the protocol developed for chiral amines (Seco,
J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry
2001, 12, 2915–2925), compound 4a was transformed into
the corresponding hydroxy-free (R)- and (S)-methoxytri-
fluoromethylacetic amides, which in turn were analyzed by
1H NMR spectroscopy. Configuration assignment of the
carbon bearing the amino group followed the calculation
of suitable DdRS values.
21. (a) Mikami, K.; Matsumoto, S.; Ishida, A.; Takamuku, S.;
Suenobu, T.; Fukuzumi, S. J. Am. Chem. Soc. 1995, 117,
11134–11141; (b) Harada, T.; Egusa, T.; Igarashi, Y.;
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7090.
22. 8: ½aŠ ¼ +31.4 (c 1.5, CHCl3). 1H NMR (CDCl3):
D
d ¼ 7:50–7.25 (m, 20H, 4Ph), 5.42 (d, 1H, JNH;3 ¼ 10:5 Hz,
NH), 5.01 and 4.58 (2d, 2H, J ¼ 12:0 Hz, PhCH2), 4.86
and 4.77 (2d, 2H, J ¼ 10:5 Hz, PhCH2), 4.78 and 4.71 (2d,
2H, J ¼ 11:5 Hz, PhCH2), 4.47 and 4.42 (2d, 2H,
J ¼ 11:8 Hz, PhCH2), 4.26 (d, 1H, H-3), 4.00 (dd, 1H,
J6;7 ¼ 2:8, J7;8 ¼ꢀ 0:5 Hz, H-7), 3.73 (dd, 1H, J4;5 ¼ 9:0,
J5;6 ¼ 9:1 Hz, H-5), 3.61 (dd, 1H, H-6), 3.59 (ddd, 1H,
J8;9a ¼ 6:5, J8:9b ¼ 5:0 Hz, H-8), 3.56 (s, 3H, OCH3), 3.52
(dd, 1H, J6a;6b ¼ 11:5 Hz, H-9a), 3.45 (dd, 1H, H-9b), 3.44
(d, 1H, H-4), 1.42 (s, 9H, t-Bu), 1.22 (s, 6H, 2CH3). 9:
½aŠ ¼ +26.2 (c 0.8, CHCl3). 10: ½aŠ ¼ +2.6 (c 1.2, CHCl3).
D
D
11: ½aŠ ¼ +14.9 (c 0.7, CHCl3).
D
23. (a) Bertozzi, C. R.; Hoeprich, P. D., Jr.; Bednarski, M. D.
J. Org. Chem. 1992, 57, 6092–6094; (b) Fields, G. B.;
Noble, R. L. Int. J. Peptide Protein Res. 1990, 35, 161–214.
20. Complete crystallographic data (excluding structural fac-
tors) for the structure of compound 5 have been deposited