A Stereodivergent Strategy for the Preparation of Corynantheine and Ipecac Alkaloids, Their Epimers, and Analogues: Efficient Total Synthesis of (−)‐Dihydrocorynantheol, (−)‐Corynantheol, (−)‐Protoemetinol, (−)‐Corynantheal, (−)‐Protoemetine, and Related Natural and Nonnatural Compounds

Abstract

Here we present a general and common catalytic asymmetric strategy for the total and formal synthesis of a broad number of optically active natural products from the corynantheine and ipecac alkaloid families, for example, indolo[2,3-a]- and benzo[a]quinolizidines. Construction of the core alkaloid skeletons with the correct absolute and relative stereochemistry relies on an enantioselective and diastereodivergent one-pot cascade sequence followed by an additional diastereodivergent reaction step. This allows for enantio- and diastereoselective synthesis of three out of four possible epimers of the quinolizidine alkaloids that begin from common and easily accessible starting materials by using a common synthetic route. Focus has been made on excluding protecting groups and limiting isolation and purification of synthetic intermediates. This methodology is applied in the total synthesis of the natural products (-)-dihydrocorynantheol, (-)-hirsutinol, (-)-corynantheol, (-)-protometinol, (-)-dihydrocorynantheal, (-)-corynantheal, (-)-protoemetine, (-)-(15S)-hydroxydihydrocorynantheol, and an array of their nonnatural epimers. The potential of this strategy is also demonstrated in the synthesis of biologically interesting natural product analogues not accessible through synthetic elaboration of alkaloid precursors available from nature, for example, thieno[3,2-a]quinolizidine derivatives. We also report the formal synthesis of (+)-dihydrocorynantheine, (-)-emetine, (-)-cephaeline, (-)-tubulosine, and (-)-deoxytubulosine.

Efficient Organocatalytic Construction of C4‐Alkyl Substituted Piperidines and Their Application to the Synthesis of (+)‐α‐Skytanthine

“…Upon deprotonation, 2 isomerizes to the highly reactive enamine form 3 , which decomposes through reactions such as self‐condensation. Thus, to promote the desired initial Michael reaction with aliphatic α,β‐unsaturated aldehydes, highly reactive nucleophiles such as nitromethane,4 malonic esters,5 bis‐sulfonyl methane,6 or β‐ketoamide3e are required.…”

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…It should be noted that, under thermodynamic control, diastereomer ratios depended on the reaction time and temperature, thus authors supposed that the α-epimer (kinetic product) was formed initially, and then it epimerized to the thermodynamically more-stable β-epimer. This strategy was then applied to the synthesis of many indole alkaloids by the use of 5-hydroxypent-2-enal as the unsaturated aldehyde [68]. Depending on the reaction conditions, three out of four possible epimers of the corresponding quinolizidine alkaloids were enantio-and diastereoselectively prepared.…”

“…Two points are worth noting: (i) conversely from the products obtained by Franzén, the C-2 was not asymmetric, because the enol form of the ketone was always recovered; (ii) pent-2-enal also worked in this reaction, although an inseparable 1:1 mixture of keto and enol form was recovered in 81% yield. This strategy was then applied to the synthesis of many indole alkaloids by the use of 5-hydroxypent-2-enal as the unsaturated aldehyde [68]. Depending on the reaction conditions, three out of four possible epimers of the corresponding quinolizidine alkaloids were enantio-and diastereoselectively prepared.…”

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis

“…[94] The construction of the core alkaloid skeletons, with the correct absolute and relative stereochemistry, relies on an enantioselective 48 and diastereodivergent one-pot cascade sequence followed by an additional diastereodivergent reaction step. Starting from common and easily accessible starting materials and using a common synthetic route this approach gives access to the total synthesis of the indolo [ …”