“…Attempts to demethylate both methoxy groups in the amine ent -24 with HBr at 100 °C both with and without the addition of sodium iodide led to partial isomerization of the trans -1,3-dimethyl-THIQ to the cis isomer. This C(1)-epimerization can be viewed as proceeding either through a reverse Michael-like reaction of the ammonium ion 31 or via a reversible retro-Mannich fragmentation of the keto-tautomer 32 4 5 …”
Efficient syntheses of the title compounds have been developed. Several strategies for preparation
of each of the naphthalene and tetrahydroisoquinoline (THIQ) portions were developed. Initial
attempts to use benzyne plus furan cycloaddition reactions were thwarted by the unfavorable sense
of the regiochemical outcome. An interesting annulation reaction of benzynes derived from 2,4-dibromophenol derivatives formed the core of the shortest naphthalene synthesis. An alternative
annulation initiated by the addition of a benzylic sulfone anion to methyl crotonate led to an efficient
naphthol synthesis amenable to large scale. The THIQ synthesis of Bringmann was used initially
and subsequently complemented by a route whose key step involved the opening of N-tosyl-2-methylethyleneimine by a 3,5-dimethoxyphenylcuprate reagent. The results from a variety of aryl
cross-coupling reactions are described. Suzuki coupling of the boronic acid derived from the
naphthalene moiety with a THIQ-iodide was the most generally effective method for forming the
hindered biaryl bond. The korupensamines and ancistrobrevine B were then revealed by deprotection. The oxidative coupling of several 4-aryl-1-naphthols to indigoids (cross ring naphthoquinones) with silver oxide effected the critical dimerization reaction needed to establish the
michellamine skeleton. For the perbenzylated precursor, hydrogen over palladium on carbon both
reductively bleached the indigoid and hydrogenolyzed the benzyl ethers and amines to release the
free michellamines. The synthesis of several michellamine analogues, including ent-michellamines,
is outlined. Results of anti-HIV assays are presented.
“…Attempts to demethylate both methoxy groups in the amine ent -24 with HBr at 100 °C both with and without the addition of sodium iodide led to partial isomerization of the trans -1,3-dimethyl-THIQ to the cis isomer. This C(1)-epimerization can be viewed as proceeding either through a reverse Michael-like reaction of the ammonium ion 31 or via a reversible retro-Mannich fragmentation of the keto-tautomer 32 4 5 …”
Efficient syntheses of the title compounds have been developed. Several strategies for preparation
of each of the naphthalene and tetrahydroisoquinoline (THIQ) portions were developed. Initial
attempts to use benzyne plus furan cycloaddition reactions were thwarted by the unfavorable sense
of the regiochemical outcome. An interesting annulation reaction of benzynes derived from 2,4-dibromophenol derivatives formed the core of the shortest naphthalene synthesis. An alternative
annulation initiated by the addition of a benzylic sulfone anion to methyl crotonate led to an efficient
naphthol synthesis amenable to large scale. The THIQ synthesis of Bringmann was used initially
and subsequently complemented by a route whose key step involved the opening of N-tosyl-2-methylethyleneimine by a 3,5-dimethoxyphenylcuprate reagent. The results from a variety of aryl
cross-coupling reactions are described. Suzuki coupling of the boronic acid derived from the
naphthalene moiety with a THIQ-iodide was the most generally effective method for forming the
hindered biaryl bond. The korupensamines and ancistrobrevine B were then revealed by deprotection. The oxidative coupling of several 4-aryl-1-naphthols to indigoids (cross ring naphthoquinones) with silver oxide effected the critical dimerization reaction needed to establish the
michellamine skeleton. For the perbenzylated precursor, hydrogen over palladium on carbon both
reductively bleached the indigoid and hydrogenolyzed the benzyl ethers and amines to release the
free michellamines. The synthesis of several michellamine analogues, including ent-michellamines,
is outlined. Results of anti-HIV assays are presented.
“…As expected, the one-pot reaction produced the piperidine ring to furnish O -TBS misramine 31 as a single diastereomer. The high stereoselectivity was considered to be thermodynamically controlled . For proaporphines with the S configuration of C-6a, the C-1 phenol is closer to C-11 than to C-9 .…”
The enantioselective total synthesis of an unusual pentacyclic proaporphine alkaloid, (-)-misramine, was achieved. The synthetic strategy relied on an enantioselective intramolecular Friedel-Crafts-type 1,4-addition using an asymmetric organocatalyst to construct a spiroindane skeleton containing an all-carbon quaternary stereocenter and a double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. This work is the first example of asymmetric synthesis of a proaporphine alkaloid.
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