Studies in the synthesis of sinefungin
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
A total synthesis of sinefungin (1) and its 6'epimer
(153) is described in a total of 19 steps by a convergent
(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-
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)
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
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.