Lavanduquinocin

Using (R)-propene oxide as a chiral building block a convergent enantioselective synthesis of the potent neuronal cell protecting alkaloid lavanduquinocin has been accomplished by the iron-mediated one-pot construction of the carbazole framework.

Lavanduquinocin (LDQ) is a potent neuroprotective carbazole alkaloid from Streptomyces species that features a rare cyclic monoterpene/cyclolavandulyl moiety attached to the tricyclic carbazole nucleus. We elucidated the biosynthetic logic of LDQ by enzymatically reconstituting the total biosynthetic pathway and identified the genes required for generating the cyclolavandulyl moiety in LDQ based on mutagenetic analysis, including a cyclolavandulyl diphosphate synthase gene ldqA and a squalene synthase-like aromatic prenyltransferase gene ldqG. LdqG is homologous to carbazole prenyltransferases, NzsG and CqsB4, discovered from the biosynthetic pathways of two bacterial carbazoles, neocarazostatin and carquinostatin. Based on analysis of the sequences and modeled protein structures, further in vitro and in vivo site-directed mutagenetic analyses led to identification of two residue sites, F53 and C57 in NzsG vs I54 and A58 in LdqG, which play crucial roles in governing the prenyl donor specificities toward cyclolavandulyl, dimethylallyl, and geranyl diphosphates. By applying this knowledge in strain engineering, prenyl donor delivery was rationally switched to produce the desired prenylated carbazoles. The study provides an opportunity to rationally manipulate the prenylation modification to carbazole alkaloids, which could influence the biological activities by increasing the affinity for membranes as well as the interactions with cellular targets.

An asymmetric synthesis of the core carbazole structure, 6-desprenyl-carquinostatin 3 and 6-descycloavandulyl-lavanduquinocin 3, toward a total synthesis of carquinostatin A (1) and lavanduquinocin (2), has been established. Lipase QLM (Meito) catalyzed enantioselective acetylation of the racemic alcohol 6 gave the (-)-acetate 7 and the (+)-alcohol 6 with high enantioselectivity. The absolute stereochemistry of the (-)- and (+)-alcohol 6 have been determined to be R- and S-configurations, respectively, by the advanced Mosher method. In the same manner, the (-)-acetate 13 and the (+)-alcohol 12 have been obtained from the racemic alcohol 12. The (R)-(-)-acetate 13, derived from the (R)-(-)-acetate 7, was the same as the (-)-acetate 13, which has been determined to be (R)-configuration. Oxidation of the (R)-(-)-acetate 13 followed by hydrolysis afforded (R)-(-)-6-desprenyl-carquinostatin [and (R)-(-)-6-descycloavandulyl-lavanduquinocin] 3. In addition, oxidation of the (S)-(+)-alcohol 12 provided (S)-(+)-3, which is the enantiomer of 6-desprenyl-carquinostatin A (R)-(-)-3.