Galactosylamines

Stereoselective Strecker reactions with galactosylamine 1 can also be achieved with sodium cyanide and acetic acid in 2-propanol. The reactions, however, proceed slowly and with a lower stereoselectivity, giving diastereomeric ratios of the products between 3 1 and 7 1. The scope of the method can be extended to other glycosylamines, e.g., 2,3,4-tri-O-pivaloyl-a-D-arabinosyl-amine which allows the stereoselective synthesis of (A )-amino nitriles61,62. 

Interestingly, the diastereofacial selectivity can be reversed in the Strecker reaction of aldimines derived from galactosylamine 1 by simply changing the solvent. When the reaction of trimethylsilyl cyanide with the Schiff bases 2 catalyzed by zinc chloride, is carried out in chloroform instead of 2-propanol, there is a preferred formation of the (.S)-amino nitrile diastereomers63. 

The diastereodifferentiating effect of the galactosylamine template in these Strecker reactions is rationalized in terms of a preferred conformation 5 of the Schiff bases which is stabilized by a (7i-double bond into the carbohydrate ring. This conformation is supported by a strong NOE in the H-NMR spectrum between the anomeric and the iminc proton. 

Fig. 22. Potent pentavalent D-galactosylamine inhibitors used by Fan s group for the cholera toxin B...

S)-fl-Amino acids.1 The Mannich reaction of the Schiff base 1, prepared from 2,3,4,6-tetra-O-pivaloyl-fl-D-galactosylamine, reacts with the silyl ketene acetal 2 in... 

The Ugi reaction produces a-amino acid amides from four components (isonitrile, carboxylic acid, aldehyde, and amine) in a one-pot reaction. With glycosylamines and ZnCl2 as promoting Lewis acid, a-amino acid amides are obtained [13,45] with excellent stereoselectivity in these reactions. For example, the galactosylamine 2 gave Ugi product 30 with formic acid as carboxylic component and various aldehydes and isonitriles in high yields and a diastereoselectivity of 19 1 in favor of the D-amino acid amides 30 (Scheme 20). 

Table 4.3 Diastereoselective Ugi synthesis of D-amino acid amides with galactosylamine 2...

D-Arabinosylamine 10 is more reactive and shows even higher asymmetric induction than D-galactosylamine 2 in this case [19b]. A variation of this method was reported by Ugi et al., who used 2-acetamidoglucosyl imine derivatives for the synthesis of (/ )-amino acid derivatives [46]. 

Decahydroquinolines are another important class of alkaloids isolated from the skin of tropical frogs. Frogs of the family Dendrobates pumilio produce highly toxic alkaloids, the pumiliotoxins [58]. Pumiliotoxin C, one of the prominent members of this class of compounds, has a ds-annulated decahydroquinoline structure, whereas toxins of the related family of Dendrobates histrionicus have fraras-annulated decahydroquinoline structures [49]. These decahydroquinoline systems can be synthesized from the galactosylamine auxiliary 2 in a 12-step pathway(see Scheme 33) [59]. 

In Ugi s four-component condensation, imine formation from an aldehyde 1 and an amine 2 is likewise the initiating step [5, 6] a carboxylic acid 9 and an isonitrile 10 are the other reaction components, which finally yield the bisamide 11. Both for this reaction and the Strecker synthesis, the galactosylamine 12 is particularly suitable for carrying out a stereoselective reaction (synthesis of 13) [4d-e, 5f. With an aminoglucopyranose as a chiral auxiliary, the stereoselectivity of the reaction can be further increased [5b]. Amino acids as condensation components yield particularly impressive results. For instance, the imino-... 

Carbohydrate moieties have also been used as chiral auxiliaries in the addition of dialkyl phosphites to the C = N bond. Thus, 0-pivaloylated iV-benzylidene-/ -D-galactosylamine reacts with diethyl phosphite to give four diastereomeric esters (the a and (i forms not shown), in which those with the S configuration at the newly created stereogenic center prevail69. 

These kinetic studies have been extended by Isbell and Fru sh to the D-galactosylamines, where similar results were obtained. It is likely that similar mechanisms operate during the mutarotation and hydrolysis of other compounds of this type. Isbell s work largely follows the earlier kinetic work carried out on the general acid-catalyzed condensations of nitrogen bases and carbonyl compounds, the original references to which are given by Hammett. ... 

Deacetylatioii of the esters, which proceeds normally, has been siu cess-fully carried out with ammonia, sodium methoxide, or barium methoxide in methanol. In this way, for example, iV-p-tolyl-/8-D-glucosylamine 2,3,4,()-tetraacetate is converted into iV -p-tolyl-/8-D-gluoosylamine, and iV-acetyl-/8-D-galactosylamine tetraacetate into iV-acetyl-/8-D-galactosyl-amine. ... 

Imines derived from optically active amines have also been used in asymmetric Staudinger syntheses of p-lactams. Georg et al. [32] employed O-acetylated galactosylamine as the chiral auxiliary for the synthesis of P-lactams. The reaction between imines 41 and aryloxyacetyl chlorides 42 in the presence of Et3N afforded c/ -configurated A -galactosyl-P-lactams 43 in diastereomeric ratios not exceeding 66 34 (Scheme 10.11). 

The methodology outlined in Scheme 10.50 has also been adopted to a corresponding stereoselective solid-phase approach to a-amino acids using the galactosylamine 160 immobilized on a polystyrene-based resin, enabling the combinatorial synthesis of stereoisomerically pure compounds (Figure 10.15) [123]. 

FIGURE 10.15 Polymer-linked galactosylamine for stereoselective combinatorial synthesis (Ref [123]). 

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