Disaccharide precursors, synthesis

As previously stated, a distinct feature of this rearrangement is the retention of the anomeric information. This advantage is nicely illustrated by the direct synthesis of a carba-disaccharide from a disaccharide [65]. As shown in Scheme 8.35, maltose was first transformed into the thioglycoside 131. Manipulation to the free primary alcohol 132 was achieved using a classical sequence of reactions. At this point, glycosylation of methanol was realized in the presence of NCS to afford 133, and the unsaturated derivative 134 was obtained after iodination and elimination. Triisobutylaluminum induced rearrangement nicely afforded the carba-disaccharide precursor 135 in a yield of 89% as a mixture of two isomers. 

In 1992, the reported preparations of C-disaccharides included the utilization of free radical reactions. Additionally, the use of various polyol cyclizations were discussed. In the application of radical chemistry to the synthesis of C-disaccharides, Bimwala, et al.,35 expanded upon his earlier work illustrated in Scheme 8.9.5. As shown in Scheme 8.10.1, glycosidic radicals were added a,p-unsaturated carbonyl compounds producing yields ranging from 47% to 73%. Furthermore, the illustrated C-disaccharide precursors exhibited diastereomeric ratios of approximately 5.5 1. 

It would, in principle, be possible to convert the polyol 115 into the 6"-deoxy sugar 118, a direct precursor of /3-acarbose. However, we decided that it would be better to reassess the whole synthesis and reasoned that a 1,6-epithio sugar such as 119 would be an ideal pivot for a synthesis of acarbose the amine 81 could easily be introduced at C-4, the sulfur at C-1 allows for activation to produce a glycosyl donor ready for attachment to the disaccharide alcohol 113 and, finally, desulfurization at C-6 leads to the necessary methyl group. 

Scheme 2.2.5.17 Synthesis of disaccharide analogues with variable configuration and tether length from generic dialdehyde precursors by Barbier allylation and tandem a.co-aldolization.

The C-allyl ketoester 69 represents a key precursor for the stereoselective synthesis of the disaccharide analogue 70 in which an ulosonic residue could be installed via the dihydroxylation of the double bond of 69 (equation 98). These glucidic a-ketoacids are involved in biosynthetic pathways of bacteria and constitute important targets for the design of new antibacterial agents. 

In Section III, the syntheses of 2-methoxy-5,6-dihydro-2//-pyrans 2a and 2b are described in racemic and in both enantiomeric forms, and by asymmetric synthesis. Also, the synthesis of l,2 5,6-di-0-isopropylidene-3-0-(2,3,4-trideoxy-a-r.-g/ycero-hex-2-eno-pyranosyl)-a-D-glucofuranose, a precursor of several disaccharides, is presented. 

The synthesis of the disaccharides entailed the preparation of 3,6-dideoxyhexosyl (paratosyl, abequosyl and tyvelosyl) precursors suitable for joining to an appropriately derivatized D-mannose residue ( , 10). In order to couple the synthesized disaccharides to carrier proteins it was necessary to have an aglycone containing a suitable reactive group such as a p-isothiocyanatophenyl group... 

For the synthesis of the D-C portion, two different concepts were followed either by modification of laminaribiose (166) [89] or by a stereospecific P, 1 ->3-glycosylation [20]. Laminaran is isolated from seaweeds or from Poria cocos Wolf, degraded by selective acetolysis, and the lower oligomers separated by preparative HPLC [90]. Following acetylation, the heptaacetyl laminaribiosyl bromide is prepared and transformed into the disaccharide glycal 167 by the classical approach in 93 % yield. The 2-deoxy-2-iodo-a-glycoside is formed by application of the NIS procedure after deprotection and subsequent 4,6-0-benzylidenation, the precursor 168 for the radical formation of the 6,6 -dibromo-6,6 -dideoxy derivative is at hand. This compound may be further reduced to methyl-3-0-(P-D-chinovosyl)-a-D-olivoside (169). 

Mithramycin shows a completely P-linked chain of D-conflgurated saccharides. This requires a totally different approach for the synthesis which is also done by application of the DBE method. The previously obtained disaccharide 180 is P-glycosylated with the monosaccharide precursor 176 to give the trisaccharide 185. After reductive debromination (Bu3SnH), an acid deformylation deblocked the C-3" position which is oxidized with pyridinium dichromate. Nucleophilic attack at the carbonyl group by methyl lithium affords a 1 1.2 mixture of 186 and 187 none of which is the desired compound [93]. Obviously, the methyl branch is formed exclusively in the axial way. 

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