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A new approach for the divergent total syntheses of (±)-vincaminorine, (±)-N-methylquebrachamine, (±)-quebrachamine, (±)-minovine and (±)-vincadifformine, each in less than 10 linear steps starting from a single δ-lactam building block, is reported. Key to our route design is the late-stage generation of reactive enamine functionality from stable indole-linked δ-lactams via a highly chemoselective iridium(I)-catalyzed reduction. The efficiently formed secodine intermediates subsequently undergo either a formal Diels-Alder cycloaddition or a competitive Michael addition/reduction to access aspidosperma-type alkaloids in excellent diastereoselectivities. Product selectivity could be controlled by changing the indole N-protecting group in the reductive cyclization precursors. An asymmetric variant of this synthetic strategy for the synthesis of (+)-20-epi-ibophyllidine is also described., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Daphniphyllum alkaloids are a diverse family of natural products rich in number and structural diversity that have been known for many decades. However, the structurally unique subclass of calyciphylline A-type alkaloids has only recently been discovered and is relatively unexplored. Several noteworthy core syntheses and the development of a wide range of novel synthetic strategies have been achieved. This includes strategies based on intramolecular Michael addition, Pd-catalysis, cycloaddition, and Mannich-type reactions. This review will provide an overview of these synthetic studies.

The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.2-7.5 mol% of a Mo- or W-based monoaryloxide pyrrolide (MAP) complex at 22 °C and proceed to complete conversion typically within two hours. Utility is demonstrated by synthesis of representative macrocyclic alkenes, such as natural products yuzu lactone (13-membered ring: 73% Z) epilachnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanced precursor to epothilones C and A (16-membered ring: up to 97% Z), and nakadomarin A (15-membered ring: up to 97% Z). We show that catalytic Z-selective cyclizations can be performed efficiently on gram-scale with complex molecule starting materials and catalysts that can be handled in air. We elucidate several critical principles of the catalytic protocol: 1) The complementary nature of the Mo catalysts, which deliver high activity but can be more prone towards engendering post-RCM stereoisomerization, versus W variants, which furnish lower activity but are less inclined to cause loss of kinetic Z selectivity. 2) Reaction time is critical to retaining kinetic Z selectivity not only with MAP species but with the widely used Mo bis(hexafluoro-tert-butoxide) complex as well. 3) Polycyclic structures can be accessed without significant isomerization at the existing Z alkenes within the molecule., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Total syntheses of three structurally complex marine natural products, manzamine A, ircinol A, and ircinal A, are reported. The route pivoted on the construction of a late-stage protecting-group-free pentacyclic enol triflate coupling partner, from which all three family members were accessed divergently via palladium-catalyzed reactions. The rapid synthesis of this key pentacyclic enol triflate was achieved by a highly convergent union of five fragments through a stereoselective Michael addition, a three-component nitro-Mannich lactamization cascade, an unprecedented and highly stereoselective reductive nitro-Mannich cyclization cascade, a stereoselective organometallic addition, and a Z-selective alkene ring-closing metathesis. Altogether this chemistry has allowed the shortest synthetic route to date for manzamine A (18-step longest linear sequence) via a late-stage diversification point that is ideal for future manzamine A analogue synthesis.

A synthetic strategy for the construction of the [7-5-5] all-carbon tricyclic core of numerous calyciphylline A-type Daphniphyllum alkaloids has been developed using a key intramolecular Pauson-Khand reaction. A subsequent base-mediated double-bond migration and a regio- and stereoselective radical late stage allylic oxygenation provide access to the substitution patterns of daphnilongeranin B and daphniyunnine D.

A new class of readily accessible chiral amino-phosphine precatalysts derived from 9-amino(9-deoxy) epicinchona alkaloids has been developed. In combination with Ag(I) salts, these amino-phosphines performed as effective cooperative Brønsted base/Lewis acid catalysts in the asymmetric aldol reaction of isocyanoacetate nucleophiles. Under optimal conditions, high diastereoselectivities (up to 98%) and enantioselectivities (up to 98%) were obtained.