kapakahine-b and chaetominine

A common dearomative strategy toward the kapakahines B/F and chaetominine natural products is reported. The proposed biomimetic strategy generates the tetracyclic α-carboline core in a single step, featuring a selectfluor-mediated dearomatization of preactivated N-Phth-Trp-Xaa-OR dipeptides at the C-terminus. The pivotal cascade includes a double annulation and the formation of three carbon-heteroatom bonds while gaining, for the first time, some insight on the diastereoselectivity outcome during the formation of the α-carboline fragment.

Topics: Biological Products; Diazonium Compounds; Indole Alkaloids; Molecular Conformation; Oligopeptides; Peptides, Cyclic; Stereoisomerism; Tryptophan

We demonstrated, for the first time, that on the basis of chemistry principles, the hexacyclic peptidyl alkaloid (−)-chaetominine (1) can be synthesized in a straightforward manner from L-Trp. The approach features the efficient generation of molecular complexity via a tandem C3/C14 syn-selective epoxidation (dr = 3:2)–annulative ring-opening reaction and a regioselective epimerization at C14. The successful production of (−)-chaetominine (1) from L-Trp could be helpful for revealing how the configuration of L-tryptophan becomes inverted in the biosynthetic pathway of (−)-chaetominine (1).

Topics: Biosynthetic Pathways; Chemistry, Organic; Indole Alkaloids; Peptides, Cyclic; Tryptophan

A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available D-tryptophan methyl ester, based on a short and straightforward (nine steps) sequence. The early stage introduction (first step) of the quinazolinone moiety and the late stage introduction (penultimate step) of the hydroxy group allowed a synthetic strategy devoid of protective groups. The key step of the process is the a-c tricyclic ring construction via an unprecedented NCS-mediated N-acyl cyclization on an indole ring to give tetrahydro-1H-pyrido[2,3-b]indole 11. In the penultimate step, oxidation of the tetracyclic intermediate 14 with oxaziridine 15 gave only one of the four possible diastereoisomers, the cis-diastereoisomer 16 resulting from the attack of the oxaziridine to the double bond face opposite to the c-d ring substituents. In the last step, the complete stereocontrol of the Et(3)SiH/TFA reduction of compound 16, probably involving a N-acyliminium ion, can be attributed to ring constrain, which forces the b-c ring junction in the more stable cis-orientation. (-)-Chaetominine (1) showed a negligible inhibitory activity on several cancer cell lines.

Topics: Drug Screening Assays, Antitumor; Humans; Indole Alkaloids; Molecular Structure; Peptides, Cyclic; Quinazolines; Stereoisomerism