A Concise Synthesis of Isocryptolepine by C–C Cross-Coupling Followed by a Tandem C–H Activation and C–N Bond Formation

Abstract

Isocryptolepine (1), a potent antimalarial natural product, was prepared in three steps from 3-bromoquinoline and 2-aminophenylboronic acid hydrochloride. The key transformations were a SuzukiMiyaura cross-coupling reaction followed by a palladium-initiated intramolecular C-H activation/C-N bond formation between an unprotected amine and an aromatic C-H group. The two key reactions can also be performed in one pot.

Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioisomers for Antimalarial, Antiproliferative and Antimicrobial Activities

“…We recently reported a concise synthesis of isocryptolepine ( 3a ) and some regioisomers in which the two key synthetic steps were a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization [ 52 , 62 ]. The most unexpected result of our previous endeavor was the formation of a pyridophenanthridine scaffold 4a , when biaryl 7a was treated with palladium under our intramolecular cyclization conditions (Path A, Scheme 1 ).…”

“…Modification of our previously reported conditions for the N -methylation of tetracycle 14 to furnish isocryptolepine ( 3a ) [ 62 ], allowed the formation of two novel isocryptolepine analogues 3b and 3c , albeit in lower yields than the parent alkaloid ( Scheme 4 ). Of the remaining tetracycles, namely compounds 16 , 18 , and 20 , only compound 16 was successfully N -methylated using the same conditions as reported in our previous work [ 62 ]. Efforts to explain the failure of tetracycles 18 and 20 to undergo N -alkylation at the most reactive ring-nitrogen, presumably the quinoline moiety, is currently under way in our laboratories.…”

“…Detailed experimental procedures and full characterizations for compounds 3a, 4, 5b, 7, 15, 17, and 19 are available through our previous works [52,62] The appropriate biaryl (1 equiv.) in a suitable amount of glacial acetic acid was added to a premixed solution of PdCl 2 (dppf) (10 mol%), 1,3-bis(2,4,6-trimethylphenyl)imidazolium (IMes) (5 mol%), H 2 O 2 (35 wt%, 29 mol%) and a suitable amount of glacial acetic acid.…”

“…Detailed experimental procedures and full characterizations for compounds 3a , 4 , 5b , 7 , 15 , 17 , and 19 are available through our previous works [ 52 , 62 ].…”

“…Modification of our previously reported conditions for the N-methyl cle 14 to furnish isocryptolepine (3a) [62], allowed the formation of two no pine analogues 3b and 3c, albeit in lower yields than the parent alkaloid (18) and 7Hpyrido [3,2-c] carbazole (20) using a diazotization-azidation-nitrene insertion approach. In brackets: yields from our previous endeavors [52].…”