Synthesis of 3-amino-2,3,6-trideoxy-D-ribo-hexose hydrochloride.

The title sugar, the 5-epimer of daunosamine, was prepared in a sequence of high-yielding steps from methyl alpha-D-mannopyranoside (1). Conversion of 1 into methyl 3-acetamido-4-O-benzoyl-6-bromo-2,3,6-trideoxy-alpha-D-ribo-hexopyranoside (2), followed by reduction with hydrogen and Raney nickel, gave the 4-benzoate (3) of methyl 3-acetamido-2,3,6-trideoxy-alpha-D-ribo-hexopyranoside (4). Saponification of 3 gave 4 as an oil that gave a crystalline 4-acetate (8). N-Deacetylation of 4 was effected with barium hydroxide, and the resultant glycoside was hydrolyzed to give 3-amino-2,3,6-trideoxy-D-ribo-hexose hydrochloride (7). The 3-benzamido analogue (5) of 4 was prepared from 4 by N-deacetylation and subsequent benzoylation, and hydrolysis of 5 gave crystalline 3-benzamido-2,3,6-trideoxy-D-ribo-hexose (6). The crystalline 3-acetamido analogue (9) of 6 was obtained by acid hydrolysis of the glycoside 4.     

A preparative synthesis of 3-amino-2,3,6-trideoxy-L-lyxo-hexose (daunosamine) hydrochloride from D-mannose.

A simple, preparative route in nine steps from methyl alpha-D-mannopyranoside (1) is described that affords, in 40% overall yield, the title amino sugar 11, the sugar constituent of the antitumor antibiotics adriamycin and daunorubicin. The 2,3:4,5-dibenzylidene acetal (2) of 1 is converted by butyllithium into the 2-deoxy-3-ketone 3, whose oxime 4 is reduced with high stereoselectivity to the D-ribo amine, isolated as its N-acetyl derivative 5 and converted by action of N-bromosuccinimide into the 4-O-benzoyl-6-bromide 7. Dehydrohalogenation of gives the 5,6-unsaturated glycoside 8, which, after O-debenzoylation to 9, undergoes stereospecific reduction by hydrogen with net C-5 inversion to give the crystalline, N-acetylated methyl beta-glycoside (10) of daunosamine, readily converted into daunosamine hydrochloride (11) and into the crystalline N-benzoyl (14) and N-acetyl(15) derivatives. No chromatographic procedures for isolation are required in any of the steps.     

Synthesis of 3-amino-2,3,6-trideoxy-ll-lyxo-hexose (daunosamine) hydrochloride from d-glucose

Three different approaches starting from 1,2-O-isopropylidene-α-d-glucofuranose were tested for the synthesis of daunosamine hydrochloride (24), the sugar constituent of the antitumor antibiotics daunomycin and adriamycin. The third route, affording 24 in ~5% overall yield in 11 steps, constitutes a useful, preparative synthesis, 3,5,6-Tri-O-benzoyl-1,2-O-isopropylidene-α-d-glucofuranose was converted via methyl 2,3-anhydro-β-d-mannofuranoside into methyl 2,3:5,6-dianhydro-α-l-gulofuranoside, the terminal oxirane ring of which was split selectively on reduction with borohydride, to afford methyl 2,3-anhydro-6-deoxy-α-l-gulofuranoside (31). Compound 31 was converted into methyl 2,3-anhydro-5-O-benzyl-6-deoxy-α-l-gulofuranoside, which was selectively reduced at C-2 on treatment with lithium aluminum hydride, affording methyl 5-O-benzyl-2,6-dideoxy-α-l-xylo-hexofuranoside. Subsequent mesylation, and replacement of the mesoloxy group by azide, with inversion, afforded methyl 3-azido-5-O-benzyl-2,6-dideoxy-α-l-lyxo-hexofuranoside, which could be converted into either 24 or methyl 3-acetamido-5-O-acetyl-2,3,6-trideoxy-α-l-lyxo-hexofuranoside, which can be used as a starting material for the synthesis of daunomycin analogs.     

Synthesis of derivatives of 3-amino-2,3-dideoxy-l-hexoses related to daunosamine (3-amino-2,3,6-trideoxy-l-lyxo-hexose)

The synthesis is described of 3-amino-2,3-dideoxy-l-arabino-hexose (10), methyl 2,3-dideoxy-3-trifluoroacetamido-α-l-lyxo-hexopyranoside (17), methyl 3-amino-2,3-dideoxy-α-l-ribo-hexopyranoside (21), methyl 2,3-dideoxy-3-trifluoroacetamido-α-l-xylo-hexopyranoside (26), and certain derivatives from methyl 4,6-O-benzylidene-2-deoxy-α-l-arabino-hexopyranoside (3). Conversion of 2-deoxy-l-arabino-hexose into 3 by modified, standard procedures, and on a large scale, gave a 75% yield.     

Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel mu opioid receptor ligands

3-Amino-3-phenylpropionamide derivatives were produced as small molecule mimics of the cyclic octapeptide octreotide from readily available imine 1. The compounds exhibit high affinity for the mu opioid receptor.     

An approach to branched-chain amino sugars,particularly derivatives of l-vancosamine (3-amino-2,3,6-trideoxy-3-C-methyl-l-lyxo-hexose) and its d enantiomer,via the cyanohydrin route

Methyl 4,6-O-benzylidene-2-deoxy-α-d-erythro-hexopyranosid-3-ulose reacted with potassium cyanide under equilibrating conditions to give, initially, methyl 4,6-O-benzylidene-3-C-cyano-2-deoxy-α-d-ribo-hexopyranoside (7), which, because it reverted slowly to the thermodynamically stable d-arabino isomer, could be crystallised directly from the reaction mixture. The mesylate derived from the kinetic product 7 could be converted by published procedures into methyl 3-acetamido-2,3,6-trideoxy-3-C-methyl-α-d-arabino-hexopyranoside, which was transformed into methyl N-acetyl-α-d-vancosaminide on inversion of the configuration at C-4. A related approach employing methyl 2,6-dideoxy-4-O-methoxymethyl-α-l-erythro-hexopyranosid-3-ulose gave the kinetic cyanohydrin and thence, via the spiro-aziridine 27, methyl 3-acetamido-2,3,6-trideoxy-3-C-methyl-α-l-arabino-hexopyranoside, a known precursor of methyl N-acetyl-α-l-vancosaminide.     

The synthesis, physicochemical properties and immunological activity of 5-amino-3-methylisoxazolo[5,4-d]4-pyrimidinone derivatives

A series of 5-amino-3-methylisoxazole[5,4-d]4-pyrimidinone derivatives were obtained by reacting substituted 5-amino-3-methylisoxazol-4-carboxylic acid hydrazide with ethyl ortho-formate. The compounds were tested using the models of in vivo cellular and humoral immune response in mice and pokeweed mitogen-induced (PWM-induced) polyclonal antibody production in a culture of human peripheral blood mononuclear cells (PBMC). The compounds exhibited differential inhibitory activities in the described models, depending on the character and location of the substituted groups. We suggest that the compounds affect the early stages of the immune response.     

Synthesis and structure of 6-amino-2,3,6-trideoxy-D-erythro-hexono-1,6-lactam and 6-amino-3,6-dideoxy-D-xylo-hexono-1,6-lactam

Solid-state conformations of 6-amino-2,3,6-trideoxy-D-erythro-hexono-1,6-lactam (3a) and 6-amino-3,6-dideoxy-D-xylo-hexono-1,6-lactam (7a) were determined using X-ray diffraction. Conformations of the compounds 3a, 7a, and their per-O-acetyl derivatives 4,5-di-O-acetyl-6-amino-2,3,6-trideoxy-D-erythro-hexono-1,6-lactam (3b) and 2,4,5-tri-O-acetyl-6-amino-3,6-dideoxy-D-xylo-hexono-1,6-lactam (7b) in solutions were deduced from the analysis of NMR spectra using a modified Karplus equation and compared with the results of circular dichroism measurement of lactams 3a and 7a. Conformation 4C(1,N) was revealed for solid lactams 3a and 7a and for lactams 7a and 7b in solution, while lactams 3a and 3b in solution exist in the approximately 1:1 equilibrium of the conformers 4C(1,N) and (1,N)C4.     

Efficient synthesis of 3'-amino-3'-deoxythymidine derivatives

An efficient method of reduction of 3'-azido-3'-deoxythymidine and its 5'-protected derivatives to 3'-aminothymidine derivatives on a palladium catalyst using ammonium formate as a source of hydrogen was suggested.     

Piperazine: An excellent catalyst for the synthesis of 2-amino-3-cyano-4H-pyrans derivatives in aqueous medium

An improved, forthright, and highly efficient one-pot synthesis of a wide range of pharmaceutically exciting diverse kind of functionalized 2-amino-3-cyano-4H-pyrans and especially bis-pyrans compounds is developed using piperazine as a low-cost and environmentally benign commercially available basic catalyst in aqueous media. The attractive features of this process are simple procedure, short reaction times, high yields, no column chromatographic separation and commercial availability and recyclability of the catalyst. Also, piperazine can catalyze the synthesis of the target compounds on a larger scale. Furthermore, rational mechanism was suggested via GC-Mass analysis of the trapped intermediates.     

The synthesis of trifluoromethylated N-nitroaryl-2-amino-1,3-dichloropropane derivatives and their evaluation as potential anti-cancer agents

Six N-nitroaryl-2-amino-1,3-dichloropropane derivatives have been prepared and evaluated against 18 cancer cell lines and two non-cancerous cell lines. Analysis of cell viability data and IC₅₀ values indicated that the presence of a trifluoromethyl group in the nitroaryl moiety is an important structural feature associated with the compounds’ cytotoxicities.     

Stereoselective synthesis of 2-amino-1-hydroxy-3-phenylpropylphosphonic acid

A highly stereoselective synthesis of 2-amino-1-hydroxy-3-phenylpropylphosphonic acid was achieved by simple addition of diethyl phosphite to enantiomeric N-blocked phenylalaninals. These compouds exhibit significant herbicidal activity.     

An approach to branched-chain amino sugars, particularly derivatives of -vancosamine (3-amino-2,3,6-trideoxy-3-C-methyl- -lyxo-hexose) and its enantiomer, via the cyanohydrin route

Methyl 4,6-O-benzylidene-2-deoxy-α- -erythro-hexopyranosid-3-ulose reacted with potassium cyanide under equilibrating conditions to give, initially, methyl 4,6-O-benzylidene-3-C-cyano-2-deoxy-α- -ribo-hexopyranoside (7), which, because it reverted slowly to the thermodynamically stable -arabino isomer, could be crystallised directly from the reaction mixture. The mesylate derived from the kinetic product 7 could be converted by published procedures into methyl 3-acetamido-2,3,6-trideoxy-3-C-methyl-α- -arabino-hexopyranoside, which was transformed into methyl N-acetyl-α- -vancosaminide on inversion of the configuration at C-4. A related approach employing methyl 2,6-dideoxy-4-O-methoxymethyl-α- -erythro-hexopyranosid-3-ulose gave the kinetic cyanohydrin and thence, via the spiro-aziridine 27, methyl 3-acetamido-2,3,6-trideoxy-3-C-methyl-α- -arabino-hexopyranoside, a known precursor of methyl N-acetyl-α- -vancosaminide.