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Title: Studies in the synthesis of sinefungin
Author: Flinn, Anthony
ISNI:       0000 0001 3470 6579
Awarding Body: Heriot-Watt University
Current Institution: Heriot-Watt University
Date of Award: 1985
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The history of the nucleoside antibiotic 9-[6',9'(5)- bis am ino-5', 6',7',8',9 '-pen tadeoxy- e-Q- ribodecafu ranosyl uronate]adenine (sinefungin: 1) and its biological effects, structural analogues of S-adenosylmethionine (6) and ~- adenosylhomocysteine (8) and the nitro aldol reaction are reviewed. A total synthesis of sinefungin (1) and its 6'epimer (153) is described in a total of 19 steps by a convergent synthetic route. Benzhydryl-N-tert-butyloxycarbonyl-S-nitro-Lnorvaline (94) was synthesised in two ways. Alkylation of 2-(y-bromo-_!2-propoxy)-tetrahydropyran (64) with the sodium salt of diethylacetamidomalonate (55) followed by acidic treatment gave 5-hydroxy-DL-norvaline (54). The amino acid (54) was also synthesised from 3-chloropropan-I-ol (58) in four steps and from 2,3 dihydrofuran (71) in one step. Conversion of the o-hydroxyl group of (54) to a nitro group followed by an enantiomeric resolution (five steps overall)gave 6 -nitro-L-norvaline (24) and N-acetyl-8-nitro-0- norvaline (85). The latter compound (85) was recycled. Protection of (24) gave (94), which was also synthesised in four steps from L-homoserine (98), via O-benzhydryl-N-BOC- -L-homoserine-y-aldehyde (104). Model reactions with NG-benzoyl-2',3'-Oisopropylidene- adenosine-5'-a1dehyde (49) and nitromethane (37) or O-methy1-N-acety1-S-nitro-OL norvaline were used to develop formation of the nucleoside 5'-6' bonds. Reaction between (94) and (49) catalysed by tetrabuty1ammonium fluoride was followed by acetylation of the 5'-hydroxyl group, elimination and reduction to give !!6-benzoyl-9- [[O-benzhydryl-9' (5) - ( (tert-bu tyloxy) carbonyl) amino-G' (R)-nitro]-S',G',7',8',9'-pentadeoxy-2',3'-O-isopro py1idene-~-0-ribo-decafuranosy1uronate]adenine (133) and the corresponding 6' (5) isomer (134). o-N-Acety1-0-ornithine (144) cyclised to 0-0- acetamido-2-piperidone (149) when treated with 2-ethoxy-lcarboethoxy dihydroquinoline. Reduction of the nitro group of (133) or (134) whether in fully protected form or partially protected form (178) could not be achieved satisfactorily.Deprotection of (133) and (134) in two steps provided 9- [9' (5) -amino-G' (R,S) nitro] -5' ,G' ,7',8' ,9'-pentadeoxy-B-Dr ibo-decafuranoysluronate] adenine (201). Reduction of 201 with Raney Nickel T-4/ammonium formate provided sinefungin (1) and the corresponding G'-epimer (153). (201) was inactive against Candida Albicans in vitro. The mixture of sinefungin (1) and 6'-epimer (153) was of cmparable activity to naturally occurring sinefungin against C. Albicans.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry