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BIOASSAY DIRECTED ISOLATION STUDIES ON PLUMERIA RUBRA AND SOLID PHASE SYNTHESIS OF MURAMYL DIPEPTIDES VIA AMINOMETHYL LINKER RESINS

Nizami, Tanveer Ahmad (1998) BIOASSAY DIRECTED ISOLATION STUDIES ON PLUMERIA RUBRA AND SOLID PHASE SYNTHESIS OF MURAMYL DIPEPTIDES VIA AMINOMETHYL LINKER RESINS. PhD thesis, University of Karachi, Karachi.

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Abstract

The present doctoral thesis comprises of two parts. The part A describes the syntheses of four new aminomethyl anchors, and their effective utilization has been demonstrated by high yielding syntheses; of the isomeric muramyl-dipeptides (MDP).The part B describes the isolation and structural elucidation of two new long chain esters of sarsapogenin and hecogenin, re5pectively, from Plumeria rubra. Part A: Solid phase synthesis of muramyl dipeptides via aminomethyl linker resins. The aminomethyl anchors have been synthesized via Friedal Craft reaction of 3,5-dimethoxyphenol with N-chloromethylphthalimide using anhydrous zinc chloride as catalyst. The reaction yielded two monosubstituted (la & 1b) and two disubstituted products (2a & 2b) which were separated through column chromatography over silica gel (Scheme). The four isomers were separately loaded on chloromethylcopoly (styrene-l %-divinylbenzene) in presence of sodium methoxide as catalyst. The monosubstituted la & 1b were loaded on Merrifield resin (1.34 mmol/g), while the disubstituted derivatives 2a & 2b were loaded on Merrifield resin (0.75 mmol/g).------------------------------------------------------------ Hydrozinolysis liberated the free amino groups to provide resin coupled anchors 3a-3d (Scheme 2). For the synthesis of carbohydrate moiety, N-acetyl glucosamine was benzylated with benzyl alcohol in acidic condition, followed by the protection of hydroxyl groups at C-4 and C-6 through benzylidene formation. The free hydroxyl group at C-3 was reacted with racemic a-chloropropionic acid to obtain crystalline benzyl N-acetyl-3-0-(D-l-carboxyethyl)-2-deoxy-D-glucose (7) (Scheme 3)------------------------------------------------------------------------------------ Synthesis of N-(9-fluorenylmethoxycarbonyi)-γ-tert-butyl-D-glutamic ester was achieved through standard strategy in seven steps (Scheme 4). The L-isomer was also obtained through the similar methodology.------------------------------------------ The synthesis of N-(9-fluorenylmethoxy carbonyl) 0 and L alanine was achieved in one step by reaction of Oor L alanine with N-(9-fluorenylmethoxy succinimide (FmocONSu) (Scheme 5).---------------------------------------------------- The solid phase synthesis of muramyldipeptides (MOP) was carried out by standard OCC/HOBt strategy which is illustrated in Fig I.------------------------------ Both the D and L isomers derived from glutamine and alanine were utilized using different aminomethyl anchors 3a-3d, respectively. For the cleavage TFA/anisol was used which took 3-5 h for complete detachment. The products 18-21 (Fig 2)were purified through HPLC.-------------------------------------------------- Debenzylation was achieved through hydrogenation over palladium in presence of charcoal. It resulted in the formation of both the a and β-anomers in a ratio of2:l (determined by HPLC).---------------------------------------------------------------------- Although muramyldipeptides have also been obtained by other routes, but we have synthesized these through solid phase methodology to demonstrate the utility of our newly synthesized aminomethyl linkers. These can easily be synthesized and cleaved with TFA/anisol under mild conditions during which the side chain protecting groups are stable. Z. Naturforsch. 53b, 753-764 (1998). Part B: I3ioassay directed isolation studies on Plumeria rubra. This part describes the phytochemical studies on Plumeria rubra which resulted in the isolation and structural elucidation of 12 compounds out of which two spirostanes namely (25s)-5/3-spirostane-3/3-palmitate (57) and (25R)-5a-spirostane-12-one-3f3-octanoate (58) have been characterized as new compounds.------------------------------------ Besides, the following reported compounds have also been isolated and identified 13α, 27-Dihydroxy-12-oleanene(47) 2Rubrinol(48) 36 α-Hydroxy-3-epi-oleanolic acid(49) 4Taraxarsteryl acetate (50) 5Cycloart-22-ene-3 α, 25-diol(51) 6Oleanolic acid(52) 7Lupeol(53) 8α-Amyrine(54) 9β-Sitosterol(55) 10Stigmasterol(56)

Item Type:Thesis (PhD)
Uncontrolled Keywords:plumeria rubra, muramyl dipeptides, aminomethyl linker resins, aminomethyl anchors, esters, sarsapogenin, hecogenin
Subjects:Physical Sciences (f) > Chemistry(f2)
ID Code:1358
Deposited By:Mr. Muhammad Asif
Deposited On:14 Feb 2007
Last Modified:04 Oct 2007 21:06

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