Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated Amide Synthesis

Abstract

We describe a unified synthetic strategy for efficient assembly of four new heterocyclic libraries. The synthesis began by creating a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a simple one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. A newly developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic dienamides. The final stage of the process entailed diversification of each of the initially produced carboxylic acids using a fully automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity.

A Tandem Isomerization/Prins Strategy: Iridium(III)/Brønsted Acid Cooperative Catalysis

“…Despite the significant interest in these compounds for biological applications, an efficient and unified approach to obtain these products is lacking 20. Herein, we describe the development of a tandem catalytic isomerization/Prins‐type cyclization for the efficient construction of three types of pyran‐fused indoles geared toward bioactive compound library development 6a. 21…”

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…The rationalization of the observed diastereoselectivity of cyclization reactions is shown in Scheme 2e [46] . First, the conjugate addition of maleic and itaconic anhydrides results in intermediates B and E , respectively, where the imine moiety is located in close proximity to the anhydride group.…”

“…The rationalization of the observed diastereoselectivity of cyclization reactions is shown in Scheme 2e. [46] First, the conjugate addition of maleic and itaconic anhydrides results in intermediates B and E, respectively, where the imine moiety is located in close proximity to the anhydride group. Next, anhydride opening (intermediates C and F) and proton transfer steps would provide the final spirocycles 4 and 6 with the given diastereoselectivity.…”

“…[42] Recently Krasavin group reported several spirocyclization procedures based on α-diazolactam chemistry. [43,44] To the best of our knowledge, [3 + 2] and [3 + 3]-azaannulation reactions between enamines and maleic and itaconic anhydrides, [45][46][47][48] were not employed for the construction of spirocycles up to date, whereas such reactions would be advantageous from the standpoints of stereochemical control and prospects of post-synthetic modifications of the newly formed building blocks.…”

A Biocatalytic Route to Highly Enantioenriched β‐Hydroxydioxinones

“…Of particular note, dioxinones have extensive precedents in photocycloadditions to access fused cyclic structures common in diterpene natural products 5 , [34] thermal opening to provide macrocycles of varying sizes 6 , [35] and Lewis acid/Bronsted acid-catalysed reactions to form substituted tetrahydropyranones 7 [4,36] (Figure 6). …”