Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (−)-Napelline, (+)-Dehydronapelline, (−)-Songorine, (−)-Songoramine, (−)-Acoapetaldine D, and (−)-Liangshanone

Abstract

The napelline-type alkaloids possess an azabicyclo[3.2.1]­octane moiety and an ent-kaurane-type tetracyclic skeleton (6/6/6/5) along with varied oxidation patterns embedded in the compact hexacyclic framework. Herein, we disclose a divergent entry to napelline-type alkaloids that hinges on convergent assembly of the ent-kaurane core using a diastereoselective intermolecular Cu-mediated conjugate addition and subsequent intramolecular Michael addition reaction as well as rapid construction of the azabicyclo[3.2.1]­octane motif via an intramolecular Mannich cyclization. The power of this strategy has been demonstrated through efficient asymmetric total syntheses of eight napelline-type alkaloids, including (−)-napelline, (−)-12-epi-napelline, (+)-dehydronapelline, (+)-12-epi-dehydronapelline, (−)-songorine, (−)-songoramine, (−)-acoapetaldine D, and (−)-liangshanone.

Asymmetric Synthesis of Chiral 2-Cyclohexenones with Quaternary Stereocenters via Ene-Reductase Catalyzed Desymmetrization of 2,5-Cyclohexadienones

“…Due to the strong preference for the pro-S orientation of cyclohexadienone substrates in YqjM and OPR3, cyclohexenones carrying quaternary stereocenters could be generated with excellent enantioselectivities (>99% ee), which surpass previously described methods using enantioselective transition-metal catalysis in respect to both enantioselectivity as well as catalytic efficiency (TON). YqjM was even capable of discriminating between sterically similar methyl- and nitrile-substituents with a high degree of stereoinduction (85% ee) for an intermediate, which can function for the formal total synthesis of napelline-type C-20 diterpenoid alkaloids . This biocatalytic desymmetric hydrogenation using accessible wild type ene-reductases adds a highly stereoselective and environmentally benign biocatalytic method to the synthetic toolbox, delivering quaternary stereocenters.…”

Deciphering the quest in the divergent total synthesis of natural products

“…Another convergent entry to the ent -kaurane core with conjugate addition, followed by intramolecular Michael addition enabled easy excess for the divergent and telescoped synthesis to an array of eight napelline-type alkaloids reported by Ma and coworkers 95 based on intramolecular Mannich cyclization (Scheme 32). The two fragments 394 and 395 (prepared in few steps) were employed for conjugate addition, followed by the in situ reduction of nitrile to give amine 396 and its tautomer 397 .…”

Recent Advances in the Chemistry of Saturated Annulated Nitrogen-Containing Polycyclic Compounds

“…Most of C 19 -diterpene alkaloids belong to the aconitine and lycoctonine types. The main representatives of C 20 -diterpene alkaloids correspond to atisine and napelline types [ 58 , 59 , 60 , 61 , 62 , 63 ]. Diterpene alkaloids exhibited a pronounced cytotoxic effect against human tumor cells (A-549, DU-145, MDA-MB-231, MCF-7, HER2, and KB) [ 64 , 65 ].…”