Multidirectional desymmetrization of pluripotent building block en route to diastereoselective synthesis of complex nature-inspired scaffolds

Vunnam Srinivasulu,Anusha Sebastian,Paul Schilf,Matthew John O'Connor,Scott Mcn Sieburth,Raed A Alqawasmeh,Saleh Ibrahim,Hany Omar,Monther A Khanfar,Taleb H Al-Tel

doi:10.1038/s41467-018-07521-2

Abstract

Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly, is underdeveloped. Here we show a one-step build/couple/pair strategy that uniquely allows access to diverse octahydroindolo[2,3-a]quinolizine scaffolds with more than three contiguous chiral centers and broad distribution of molecular shapes via desymmetrization of the oxidative-dearomatization products of phenols. The cascade demonstrates excellent diastereoselectivity, and the enantioselectivity exceeded 99% when amino acids are used as chiral reagents. Furthermore, two diastereoselective reactions for the synthesis of oxocanes and piperazinones, is reported. Phenotypic screening of the octahydroindolo[2,3-a]quinolizine library identifies small molecule probes that selectively suppress mitochondrial membrane potential, ATP contents and elevate the ROS contents in hepatoma cells (Hepa1–6) without altering the immunological activation or reprogramming of T- and B-cells, a promising approach to cancer therapy.

Highlights

Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products
Natural products encompass a wealth of structural diversity within defined, nonplanar scaffolds; there are well-documented hurdles to their use in screening campaigns because of their limited availability relative to the quantities needed for structure activity relationship (SAR) development and clinical trials[1,2,3]
The recent decade has witnessed an upsurge in the development of privileged substructure diversity-oriented synthesis (DOS) strategies for the de novo construction of nature-inspired compounds needed for phenotypic-screening campaigns[4,5,6]

Summary

Introduction

Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. These investigations have spurred a growing belief in the advantage of increasing the percentage of sp3-hybridized atoms within a compound collection used for phenotypic screening In this context, one of the important classes of natural products is the octahydroindolo[2,3-a]quinolizine monoterpene indole alkaloids, comprised of more than 2000 members and among the most studied natural product classes owing to their diverse biological activities and synthetic potential associated with these scaffolds[13,14,15,16]. Here we describe a one-step chemo-, diastereo- and enantio-selective protocol for the construction of densely functionalized octahydroindolo[2,3-a]quinolizine systems with three to five contiguous chiral centers This protocol employs tandem cycloaddition processes utilizing Pictet-Spengler/aza-Michael addition, the products of which constitute the basic framework of the biologically significant natural products yohimbine, venenatine, alstovenine and tangutorine (Fig. 1)[15,18]. The discovery of oxocanes via aza-Michael addition/Mannich cascade using aniline derivatives as one of the

Objectives

Methods

Results