Synthesis of the Lycopodium Alkaloid (+)-Lycoflexine

Abstract

The first total synthesis of (+)-lycoflexine (1), a constituent of Lycopodium clavatum var. inflexum , has been accomplished in eight steps with 13% overall yield. Our synthesis covers four one-pot reactions, including a tandem Sakurai/aldol sequence, a novel hydroboration/oxidation procedure, a deprotection/transannular Mannich reaction, and as a highlight, a tandem catalysis cascade combining an enynene ring-closing metathesis and a selective hydrogenation.

Multi-Bond Forming Processes in Efficient Synthesis

“…[158] Two-fold ene-yne metathesis, pioneered by the group of Grubbs in the 1990s, [159] has also proven to be an efficient strategy for the synthesis of structures containing up to four new rings. [160,161] Some of the most recent examples feature in the work reported by the groups of Yang, [162] Fukuyama, [163] Metz, [164] Oguri, [165] Movassaghi, [166] Mulzer, [167] and Lee. [168] Olefin metathesis steps have also been combined with other transformations in independent reaction sequences.…”

5.27 Ene–Yne Metathesis

“…A concise tandem ring-closing dienyne metathesis was used to assemble the core polycyclic framework of the alkaloid lycoflexine. 177 The ring-closing event was initiated at the more reactive terminal alkene to first form the five-membered ring (Scheme 38). Strikingly, the second ring closure generated the nine-membered azacyclic ring.…”

Diversity-oriented synthesis of Lycopodium alkaloids inspired by the hidden functional group pairing pattern

“…SmI 2 reduction of a-ketol 28 successfully afforded diketone 33 as an inseparable mixture of two C4 epimers. A tandem deprotection/transannular Mannich reaction of diketone 33 using dilute aqueous HCl and formaldehyde 56 afforded the tetracyclic ( À )-Lycoposerramine-U (4) in moderate yield (44%), completing the E À F pair.…”