A Local‐Desymmetrization‐Based Divergent Synthesis of Quinine and Quinidine

Abstract

Herein we report an ovel synthetic entry to the legendary quinuclidine natural products quinine and quinidine.T he developed strategy is based on the use of as ymmetrical and nonstereogenic precursor to access quinine and quinidine through a" local-desymmetrization" approach,i n stark contrast conceptually to the preparation of stereodefined disubstituted piperidines (or their acyclic precursors) as featured in all past syntheses.T he developed strategy also provided quinine and quinidine derivatives that could not be readily obtained through previous total syntheses or by modification of the naturally occurring substances.Quinine and quinidine are two flagship alkaloid natural products that have captivated the imaginations of generations of organic chemists,with respect to both their synthesis [1] and applications in asymmetric catalysis. [2] In the former context, although both natural products are abundant in natural and commercial supply,s ynthetic studies dedicated toward quinine and quinidine remain vibrant today more than 70 years after the landmark achievement of Woodward and Doering. [1a] On the other hand, the application of these "pseudoenantiomeric" gifts of nature in asymmetric transformations has often delivered enantiomeric products with comparable levels of optical purity,while novel analogues of quinine and quinidine continue to emerge particularly in the context of multifunctional catalysis. [3] With great appreciation for the valuable lessons from the past quinine/quinidine syntheses, [1] and as part of our continued investigations in desymmetrization-based target-oriented synthesis, [4] we embarked on ar esearch program aimed at the development of an ovel and divergent strategy for both quinine and quinidine and designed analogues.Upon cursory examination, ac ommon feature shared by the past quinine/quinidine syntheses is the early preparation of astereodefined disubstituted piperidine or astereocenterbearing acyclic piperidine precursor (Figure 1a). More specifically,a ll of these synthetic endeavors required thoughtful orchestration of diastereocontrol, whereby some met with more difficulties than others.W ef urther recognized that the relative stereochemical arrangement within quinine (1)a nd quinidine (2)( more precisely,q uinine and ent-quinidine) simply differs in the spatial relationship between the methoxyquinoline domain and the vinyl substituent ("syn"or"anti", Figure 1b). These observations prompted us to propose ah ypothetical symmetrical and nonstereogenic precursor 3 that may offer synthetic entry to both quinine (1)a nd Figure 1. a) Reported intermediates and their diastereochemical integrity in the synthesis of quinine (1)a nd quinidine (2); b) structural comparison between quinine (1)a nd quinidine( 2); c) proposed divergent synthetic strategy towards quinine (1)and quinidine (2) based on a"local-desymmetrization" approach. Bz = benzoyl, TBS = tert-butyldimethylsilyl, TBDPS = tert-butyldiphenylsilyl, Teoc = 2-(trimethysilyl)ethyloxycarbonyl.

Early and Late Steps of Quinine Biosynthesis

“…Quinine 1 is an alkaloid produced by Cinchona trees of the Rubiaceae family, historically used as an antimalarial drug and as a flavor ingredient in beverages such as tonic water. 1 − 3 Although the total synthesis of quinine has been achieved, 4 the enzymes of this biosynthetic pathway remain undiscovered. In the present work, we combined metabolomics and transcriptomics data from different tissues of Cinchona pubescens to identify genes involved in the biosynthesis of quinine and related compounds.…”

Liquid chromatographic resolution of natural and racemic Cinchona alkaloid analogues using strong cation- and zwitterion ion-exchange type stationary phases. Qualitative evaluation of stationary phase characteristics and mobile phase effects on stereoselectivity and retention

“…In nature, the genuine enantiomers of ( −)QN, of ( −)DHQN and of ( −)CD, do not exist, which qualified them as highly interesting targets for total synthesis concepts. These challenges could recently be mastered for ( −)QN and ( + )QN by Lee and Chen [4] , and for racemic ( ±)QN by the Maulide group [5,] via two different synthesis strategies and diastereocontrolled reaction cascades. The protocol developed by Maulide [5] allowed also the straightforward synthesis of racemic QN derivatives (see CF 3 PQN in Fig.…”

“…1 ), but not that of QD derivatives. In contrast, the synthesis way of Chen [4] opens up conceptually the production of ( −)QN and ( + )QD including the unnatural enantiomers, namely ( + )QN and ( −)QD. The synthesis of unnatural epi -QN/ epi -QD was also published in detail [6] .…”