The first and asymmetric total syntheses of two C11-oxygenated hetisine-type diterpenoid alkaloids, namely, (+)-davisinol and (+)-18-benzoyldavisinol, is described. The concise synthetic approach features a HAT-initiated transannular redox radical cyclization, an ODI-Diels-Alder cycloaddition, and an acylative kinetic resolution. By incorporating an efficient late-stage assembly of the azabicycle, our strategy would streamline the synthetic design of C20-diterpenoid alkaloids and pave the way for their modular syntheses.

Asymmetric Total Syntheses of (+)-Davisinol and (+)-18-Benzoyldavisinol: A HAT-Initiated Transannular Redox Radical Approach.

Due to high ring strain energies, cyclopropanols and cyclobutanols have a strong tendency of breaking the endocyclic C–C bonds to participate in versatile organic transformations. With an inherent three-dimensional structure, cyclopropanols and cyclobutanols have the advantage of synthesizing linear or cyclic molecules with stereogenic centers via ring-opening asymmetric synthesis. There are three strategies for the ring-opening of cyclopropanols and cyclobutanols usually involved in asymmetric synthesis: 1) β-carbon elimination of metal alkoxide; 2) radical ring-opening; 3) ring-opening via semipinacol rearrangement. The present review has highlighted the progress developed in the last five years. 

Recent advances using cyclopropanols and cyclobutanols in ring-opening asymmetric synthesis

Catalyst- and solvent-free aminolysis of the asymmetric derivatives of Evans’ chiral <i>N</i>-acyloxazolidinones: enantioselective synthesis of chiral amides and its applications

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.

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

Carbon monoxide is a cheap and abundant C1 building block that can be readily incorporated into organic molecules to rapidly build structural complexity. In this Perspective, we outline several recent (since 2015) examples of palladium-catalyzed carbonylations in streamlining complex natural product total synthesis and highlight the strategic importance of these carbonylation reactions in the corresponding synthesis. The selected examples include spinosyn A, callyspongiolide, perseanol, schizozygane alkaloids, cephanolides, and bisdehydroneostemoninine and related stemona alkaloids. We also provide our perspective about the recent advancements and future developments of palladium-catalyzed carbonylations.

Palladium-Catalyzed Carbonylations: Application in Complex Natural Product Total Synthesis and Recent Developments

The concise, collective, and asymmetric total syntheses of four schizozygane alkaloids, which feature a "Pan lid"-like hexacyclic core scaffold bearing up to six continuous stereocenters, including two quaternary ones, are described. A new method of dearomative cyclization of cyclopropanol onto the indole ring at C2 was developed to build the ABCF ring system of the schizozygane core with a ketone group. Another key skeleton-building reaction, the Heck/carbonylative lactamization cascade, ensured the rapid assembly of the hexacyclic schizozygane core and concurrent installation of an alkene group. By strategic use of these two reactions and through late-stage diversifications of the functionalized schizozygane core, the first and asymmetric total syntheses of (+)-schizozygine, (+)-3-oxo-14α,15α-epoxyschizozygine, and (+)-α-schizozygol and the total synthesis of (+)-strempeliopine have been accomplished in 11-12 steps from tryptamines.

Asymmetric Total Syntheses of Schizozygane Alkaloids.

Here, we report the first asymmetric total synthesis of (+)-talassimidine and (+)-talassamine, two hetidine-type C20-diterpenoid alkaloids. A highly regio- and diastereoselective 1,3-dipolar cycloaddition of an azomethine ylide yielded a chiral tetracyclic intermediate in high enantiopurity, thus providing the structural basis for asymmetric assembly of the hexacyclic hetidine skeleton. In this key step, the introduction of a single chiral center induces four new continuous chiral centers. Another key transformation is the dearomative cyclopropanation of the benzene ring and subsequent SN2-like ring opening of the resultant cyclopropane ring with water as a nucleophile, which not only establishes the B ring but also precisely installs the difficult-to-achieve equatorial C7-OH group.

Tao Zhou

Papers

Asymmetric Total Syntheses of Schizozygane Alkaloids.

Asymmetric Total Synthesis of Hetidine-Type C20-Diterpenoid Alkaloids: (+)-Talassimidine and (+)-Talassamine.