Benzylic deoxygenation

The synthesis of ABT-866 requires the nitro group reduction and benzylic deoxygenation of intermediate I. The goal was to define conditions for dependable catalytic reduction of I for use in a cGMP delivery of ABT-866. 

Benzylic deoxygenation. Benzylic alcohols are reduced by using McjSil in MeCN at room temperature. 

Stereoelectronic and conformational aspects of the Perrier rearrangement route leading to polysubstituted cyclohexanones have been studied and the cyclohexyl-fused anthracyclinone 22 has been synthesized using the branched sugar 21 (from D-glucose). A sequence involving two condensation/benzylic deoxygenation steps was employed. 

Deoxygenation of benzyl nitrosoformate, generated by retro-Diels-Alder reaction of its [4 + 2] cycloadduct 27 with 9,10-dimethylanthracene, with triphenylphosphane in anhydrous benzene yields the unstable benzyl 1//-azepine-1-carboxylate (28).143... 

Rajanikanth and Ravindranath44 have recently published a deoxygenation reaction for sulphoxides that uses metallic lithium in refluxing dimethoxyethane. Dialkyl and alkyl phenyl sulphoxides were reduced cleanly in yields around 70%, even if sterically hindered, but benzyl sulphoxides gave mixtures of products. For example, benzyl phenyl sulphoxide gave frans-stilbene (33%), benzyl phenyl sulphide (20%) and diphenyl disulphide (47%). These products can be rationalized by reaction pathways such as in equation (17) ... 

Co(TPP) has been demonstrated to act as a catalyst for the electrocarboxylation of benzyl chloride and butyl bromide with CO - to give PhCHiCfOiOCH Ph and Bu0C(0)C(0)0Bu, respectively. The propo.sed mechanism involved Co(TPP)R and [Co(TPP-N-R) as intermediates (the latter detected by spectroscopy) in the catalytic production of free R or R-, which then reacted directly with Co(TPP) precipitated on graphite foil has been successfully used for the determination of organic halides, including DDT and 1,2,3,4,5,6-hexachlorocyclohexane (lindane), to sub-ppm level in aqueous solution. Deoxygenation of the solutions is not required, and the technique is moderately insensitive to the ionic composition of the solution. ... 

Quebrachitol was converted into iL-c/j/roinositol (105). Exhaustive O-isopropylidenation of 105 with 2,2-dimethoxypropane, selective removal of the 3,4-0-protective group, and preferential 3-0-benzylation gave compound 106. Oxidation of 106 with dimethyl sulfoxide-oxalyl chloride provided the inosose 107. Wittig reaction of 107 with methyl(triphenyl)phos-phonium bromide and butyllithium, and subsequent hydroboration and oxidation furnished compound 108. A series of reactions, namely, protection of the primary hydroxyl group, 0-debenzylation, formation of A-methyl dithiocarbonate, deoxygenation with tributyltin hydride, and removal of the protective groups, converted 108 into 7. 

Paulsen and his coworkers first synthesized (-f-)-203 from L-quebrachitol (286) by a 21-step reaction as follows. The di-O-isopropylidene derivative was oxidized to the ketone (287), and then epoxidized with dimethyl sulfox-onium-methylide to give 288, which was subjected to benzoylation, mesyla-tion, and demethylation, followed by benzylation, to afford 289. Introduction of unsaturation was accomplished by epoxidation of 289 with sodium methoxide to 290 and 291, and deoxygenation to 292. The azido group was introduced with azobis(dicarboxylate) to give 293, which was hydrogeno-lyzed, followed by deprotection to afford 203. 

Organolithium reagent 35 was added to aldehyde 31 (Scheme 7.6) to obtain alcohol 36 as an inconsequential 1 1 mixture of diastereomers. The benzylic alcohol was removed using a Barton two-step radical deoxygenation protocol, followed by electrophilic aromatic bromination to provide the desired coupling partner 37. 

Treatment of 122 with (R,R)-tartrate crotyl-boronate (E.R.R)-W 1 provides the alcohol corresponding to 123 with 96% stereoselectivity. Benzylation of this alcohol yields 123 with 64% overall yield. The crude aldehyde intermediate obtained by ozonolysis of 123 is again treated with (Z,R,R)-111 (the second Roush reaction), and a 94 5 1 mixture of three diastereoisomers is produced, from which 124 can be isolated with 73% yield. A routine procedure completes the synthesis of compound 120, as shown in Scheme 3-44. Heating a toluene solution of 120 in a sealed tube at 145°C under argon for 7 hours provides the cyclization product 127. Subsequent debromination, deacylation, and Barton deoxygenation accomplishes the stereoselective synthesis of 121 (Scheme 3-44). 

Rhodium-catalyzed hydroformylation of -(substituted amino)benzyl-amines (387, X = H2) and -(substituted amino)benzamides (387, R = H, X = O) in the presence of rhodium(II) acetate dimer and triphenylphos-phine in deoxygenated ethyl acetate gave a 7 3 mixture of 1,2,3,4,4 ,5-hexahydro-6//-pyrido[l,2-a]quinazolines (388, X = H2,0) and isomeric 3-methyl-l,2,3,3fl,4,5-hexahydropyrrolo[l,2-a]quinazolines (389, X = H2, O) (94AJC1061). The methyl derivative of benzylamine 387 (R = Me, X = H2) afforded a mixture of diastereoisomers 390 and 391 (X = H2). Their ratio depended on the reaction time. Longer reaction times gave more 391 (X = H2), containing the methyl group in an equatorial position. Compound 390 isomerized into 391 (X = H2), under the aforementioned conditions. The benzamide derivative (387, R = Me, X = O) yielded only one isomer (391, X = O), independent of the reaction period. 

Synthesis and Deoxygenation of 3,4,6-Tri-0-benzyl-2-0-[(pentafluorophenoxy)thiocarbonyl]-fi-glycoside 46 [43a]... 

Debromination has been achieved by metallation followed by protonation (2002JOC3904). Finally, debromination has been effected using PC13, which in addition caused deoxygenation. Thus 2-benzyl-3,... 

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