The synthesis of carbon linked bis-benzylisoquinolines using Mizoroki–Heck and Sonagashira coupling reactions

Abstract

Novel laudanosine dimers in which two laudanosine units are linked at C-2′ via a two or three-carbon linker (alkane, alkene or alkyne) have been prepared using palladium-catalysed cross-coupling reactions (Mizoroki-Heck and Sonagashira reactions). In one example, a second three-carbon linker between the two isoquinoline N-atoms was also present leading to a novel macrocyclic ring system.

Synthesis of Vaniprevir (MK-7009): Lactamization To Prepare a 22-Membered Macrocycle

“…Given the vast array of potential cross-coupling reactions and ligands available to effect these transformations, we opted to examine ring closure via palladium catalysis. − The intermediates used to prepare the RCM substrate were easily manipulated to generate molecules that could be subjected to palladium-catalyzed macrocyclization conditions. In particular, we have made intermediates 10 , 12 , and 13 in Scheme and investigated Heck, Sonogashira, and Suzuki macrocyclizations .…”

Application of Ring-Closing Metathesis Strategy to the Synthesis of Vaniprevir (MK-7009), a 20-Membered Macrocyclic HCV Protease Inhibitor

“…In recent years, a wide array of metal-catalyzed coupling reactions has been effectively applied to C-C bond formation, including the C-C bond formation for the construction of macrocycle [7][8][9][10]. We next set out to explore ring-closing strategy via palladium-catalyzed intramolecular C-C bond formation.…”

Synthesis of 2′-aminoalkyl-1-benzylisoquinoline derivatives and medium sized ring analogues with mu opiod receptor binding activities

“…The structures of known CNS active compounds. [8][9][10][11][12] In our continuing project concerned with the discovery of new bioactive benzylisoquinoline derivatives, [13][14][15] the 2'-aminoalkyl-1-benzylisoquinoline compound 7 and the medium side ring analogues 8 were of interest. We report here our attempts to synthesise these compounds and the biological activities of four of these analogues on 48 different CNS receptors.…”

“…With the aim of preparing 2'-aminoethyl-1-benzylisoquinoline derivatives, we first examined the method reported by Seijas et al towards the preparation of phenylethylamines derivatives by addition of primary and secondary lithium amides to styrene. 16 The racemic 2'-vinyllaudanosine derivative 10 was prepared from the known N-TFA derivative 9 14,15 in 75% overall yield. Morpholine was treated with nbutyl lithium and the resulting solution of lithium morpholinamide in THF was added to compound 10 at 0 o C. The mixture was left at 0 o C for 18 h. 1 H NMR analysis only showed unreacted starting material 10 and no morpholine ethylene signals were observed.…”

“…and 12, [14][15] respectively, using the 2 step sequence of dihydroxylation, followed by oxidative cleavage. 17,18 N TFA The aldehydes 15 and 16 were subjected to reductive amination reactions with several amines to give the corresponding aminated products in moderate to good yields (Scheme 3, Table 1).…”