Sialyl Lewis X mimetics

A similar approach was used in the synthesis of the sialyl Lewis X mimetics of type 85 (Scheme 13.22).66 Protein crystallization,67 conformational studies of sLex in solution68 and in bound form to E- and P-selectin69 as well as the study of structure-function relationships70,71 gave information about the functional groups of the sLex-epitope essential for the binding to the selectins. Synthesized mimetics must contain the three essential hydroxyl functions of the fucose. Sialic acid, galactose, and... 

FDP A was employed in a study of pancratistatin analogs to catalyze the formation of the D-threo stereochemistry (Scheme 5.24). When rhamnulose 1-phosphate aldolase (Rha 1-PA) was used the L-threo stereoisomer was obtained with excellent selectivity. Thus these two enzymes allow the stereoselective synthesis of the two threo-stereoisomers [44]. They were also utilised successfully for the synthesis of different diastereoisomers of sialyl Lewis X mimetics as se-lectin inhibitors. Not only the two threo-selective aldolases RAMA and Rha 1-PA, but also the D-erythro-selective Fuc 1-PA was employed. In this way it was possible to synthesise three of the four diastereoisomers enantioselectively (Scheme 5.25). The L-erythro stereochemistry as the only remaining diastereo-isomer was not prepared [45]. This is because the aldolase that might catalyze its formation, TDP A, is not very stereoselective and therefore often yields mixtures of diastereoisomers. 

Scheme 5.25 Aldolase-catalyzed synthesis of three stereoisomers of sialyl Lewis X mimetics.

Scheme 5.50. Synthesis of sialyl Lewis X mimetics using L-threonine aldolase (LTA).

Lin, C-C, ShimazaM, M, Heck, M-P, Aoki, S, Wang, R, Kimura, T, Ritzen, H, Takayama, S, Wu, S-H, Weitz-Schmidt, G, Wong, C-H, Synthesis of sialyl Lewis X mimetics and related structures using the glycosyl phosphite methodology and evaluation of E-selectin inhibition, J. Am. Chem. Soc., 118, 6826-6840, 1996. 

De Vleeschauwer, M, Vaillancourt, M, Goudreau, N, Guindon, Y, Gravel, D, Design and synthesis of a new sialyl Lewis X mimetic how selective are the selectin receptors Bioorg. Med Chem. Lett., 11, 1109-1112, 2001. 

Tsai, C-Y, Huang, X, Wong, C-H, Design and synthesis of cyclic sialyl Lewis X mimetics a remarkable enhancement of inhibition by pre-organizing all essential functional groups. Tetrahedron Lett., 41, 9499-9503, 2000. 

Thioacetal 418 was used by Mootoo to access several C-linked disaccharides [153,154] including the C-hnked analog of a Sialyl Lewis x mimetic [155] (O Scheme 82). 

C.-C. Lin, T. Kimura, S.-H. Wu, G. Weitz-Schmidt, C.-H. Wong. Liposome-like fucopeptides as sialyl Lewis X mimetics. Bioorg. Med. Chem. Lett. 19%, 6,2755-2760. 

P-Hydroxy-amino acids (Figure 10.7) are multifunctional compoimds with valuable interest as intermediates for the synthesis of statine derivatives (106) [166-168], protease inhibitors [169], antivirals [170, 171], peptide mimetics [172], idulonic acid mimetics, for example, 3R,5R-dihydroxy-L-homoproline (111) [173], immimosup-pressive lipid mycestericin d (112) [174], 3,4-dihydroxyprolines (113) [175], (2S,3R)-2-amino-3-hydroxybutyrolactone, precursor of monobactam antibiotics [176], or L-ffereo-3-[4-(me ylthio)phenylserine] precursor of thiamphenicol (114), florfenicol (115) [177], sialyl Lewis x mimetics (117) [178], p-hydroxyomithine (109), a relevant building block for the p-lactamase inhibitor, clavulanic acid, and the antibiotic and anticancer acivicin [179], surveyed in previous reviews [41,57]. 

---