Convergent Total Synthesis of (±)-Apomorphine via Benzyne Chemistry: Insights into the Mechanisms Involved in the Key Step

Abstract

Convergent total synthesis of (±)-apomorphine hydrochloride was accomplished by an approach that employs in the key step a sequence of transformations involving a [4+2]-cycloaddition reaction followed by a hydrogen migration. Through this sequence of transformations, the desired aporphine core was obtained regioselectively in 75% isolated yield. Since only one regioisomer was produced in the key step of the synthesis, a polar [4+2]-cycloaddition mechanism was proposed. Furthermore, NMR experiments and theoretical calculations were carried out to elucidate the hydrogen migration mechanism. (±)-Apomorphine hydrochloride was achieved after 9 steps in an overall yield of 8% involving benzyne chemistry.

Total Synthesis of Aporphine Alkaloids via Benzyne Chemistry: Progress Towards a Late‐Stage Enantioselective Hydrogenation and Neuroprotective Activity Evaluations

“…Castedo et al [16] . and our research group [17] have employed the approach involving benzyne chemistry in the synthesis of achiral, [16b,17c] racemic, [17b] and enantiomerically enriched [17a,d] aporphine compounds. Particularly, enantioenriched aporphinoids have been obtained by a small‐scale racemate resolution [17d] and a chiral auxiliary‐based strategy [17a] (Figure 1).…”

Structure–Functional–Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands

“…The synthesis of these compounds was achieved by a regioselective [4 + 2] cyclization of aryne precursor and isoquinoline derivative as a key step to afford the core aporphine ring as described in Scheme . The aryne precursor I and the isoquinoline derivatives II-A and II-B were synthesized following a previously reported procedure . The CsF-promoted [4 + 2]-cyclization of isoquinoline II-A and II–B with 2-trimethylsilylaryl triflate I delivered the core intermediates III-A and III-B , which were hydrolyzed to free amines IV-A and IV-B under microwave heating.…”

“…The aryne precursor I and the isoquinoline derivatives II-A and II-B were synthesized following a previously reported procedure. 27 The CsFpromoted [4 + 2]-cyclization of isoquinoline II-A and II−B with 2-trimethylsilylaryl triflate I delivered the core intermediates III-A and III-B, which were hydrolyzed to free amines IV-A and IV-B under microwave heating. Finally, reductive methylation yielded analogs 3 and 4 which bear a bromine at C-1 and at C-3, respectively.…”