Total Asymmetric Synthesis of Quinine, Quinidine, and Analogues via Catalytic Enantioselective Cascade Transformations

Abstract

A catalytic asymmetric strategy for the total synthesis of quinuclidine natural products, which includes the completed enantioselective synthesis of the classical targets quinine and quinidine is disclosed. It is based on catalytic asymmetric cascade transformations, which paves the road for the synthesis of both enantiomers of the crucial C4 stereocenter with high enantioselectivity (up to 99 % ee) in one pot. Next, developing a route to all possible stereoisomers of a common early‐stage intermediate sets the stage for the total synthesis of different enantiomers or epimers of quinine, quinidine and analogues with high selectivity.

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…[53] In 2019, Córdova and co-workers reported an enantioselective total synthesis of quinine (248) and quinidine (249) (Scheme 27). [54] They employed an asymmetric Michael reaction between methyl malonate 239 and aldehyde 240 catalyzed by compound 13, and the reductive amination of the primary Michael addition product led to the formation of the disubstituted piperidine 241. Further transformations of 241 afforded compound 247 via a multistep sequence, which served as the key intermediate for the synthesis of quinine (248) (Scheme 27).…”

“…This synthesis highlights the use of a common early-stage intermediate that can be used for the total synthesis of different enantiomers or epimers of quinine and quinidine. [54] In 2014, Ferjancic, Saicic, and co-workers developed an efficient asymmetric total synthesis of (+)-swainsonine (260) and (+)-8-epi-swainsonine (261) using L-proline [(S)-41] as the catalyst (Scheme 28). [55] The enantioselective aldol reaction between dioxanone 250 and α-aminoacetaldehyde 251 catalyzed by (S)-41 led to the formation of compound 252, which gave a highly functionalized heterocyclic system 253 after a reductive amination.…”

“…Further transformations of 241 afforded compound 247 via a multistep sequence, which served as the key intermediate for the synthesis of quinine ( 248 ) (Scheme 27). [54] Starting from compound 241 and through similar synthetic maneuvers, quinidine ( 249 ) was also synthesized. This synthesis highlights the use of a common early‐stage intermediate that can be used for the total synthesis of different enantiomers or epimers of quinine and quinidine [54] …”

Recent Advances in Total Synthesis of Alkaloids from α,β‐Unsaturated Aldehydes

“…[55] The demand for unique class of quinoline alkaloids determines the interest of chemists in the development of more efficient methods for their synthesis including from α,β-unsaturated aldehydes. [56][57][58] Wang et al reported the first total synthesis of broussonetine employing three-step reaction sequences (Scheme 18). [56] The preparation of key γ-butyrolactones 127 was performed via synergistic catalytic strategy by Brønsted acid and hindered prolinol diphenyl silyl ether 126.…”

“…A catalytic asymmetric strategy allowed the construction of y-lactam 132 for total synthesis of unnatural enantiomers of the cinchona alkaloids such as quinine, quinidine and 2 epimers of quinidine (Scheme 19). [57] In the early stage of the synthesis of (-)-quinine (135) and (-)-quinidine (136) and quinidine analogues 138, 140 the authors performed one-pot Michael/ cyclization cascade sequence from aldehyde 130 and dimethyl malonate 131 mediated by catalyst 39 to build the precursor 132 even multi-gram scale. The key intermediate 134 was obtained in 10 steps from heterocyclic substrate 132.…”