Method for the synthesis of heteroyohimbine natural products

NU 2015-009

INVENTORS

Karl Scheidt*
Herbert Meltzer
Ashkaan Younai
Bi-Shun Zeng

SHORT DESCRIPTION

Enantioselective synthetic methods for preparing heteroyohimbine alkaloid intermediates using a novel cooperative hydrogen bonding/enamine-catalyzed Michael addition reaction as a key step to access complex natural products, including alstonine and serpentine.

BACKGROUND

Heteroyohimbine alkaloids, such as alstonine and serpentine, have long intrigued researchers due to their unique structural features and promising pharmacological properties, including antipsychotic and anticancer activities. Natural isolation methods yield scarce and impure material, and total syntheses has not been previously reported due to the synthetic challenges posed by their complex stereochemistry and ring systems. Thus, there is a critical need for enantioselective synthesis methods that provide sufficient access to these complex molecules for further study and development.

ABSTRACT

The invention provides scalable enantioselective synthetic routes to heteroyohimbine alkaloids and their intermediates through a novel cooperative catalysis approach employing catechol as a hydrogen-bond donor and chiral primary amines like (R)-1-(naphthalen-1-yl)ethanamine for asymmetric intramolecular Michael addition reactions. The key transformation converts keto-enamine esters into trans-piperidinyl compounds with >99:1 enantiomeric ratio, which serve as common intermediates for divergent synthesis of both cis- and trans-bicyclic dihydropyran scaffolds. These bicyclic intermediates can be elaborated through a series of transformations including lactone formation, Korte acyl-lactone rearrangement, reductive amination with indole-3-acetaldehyde, and oxidative iminium ion cyclization to provide access to tetrahydroalstonine, akuammigine, and ultimately the natural products alstonine and serpentine through palladium-mediated dehydrogenation, enabling the first total syntheses of these challenging alkaloids.

APPLICATIONS

Development of antipsychotic medications based on alstonine, which has been identified in traditional Nigerian medicine for treating psychotic disorders.
Production of anticancer and antimalarial agents derived from serpentine and related heteroyohimbine alkaloids.
Synthesis of diverse heteroyohimbine natural product libraries through divergent routes from common intermediates, enabling structure-activity relationship studies and medicinal chemistry optimization.
Access to complex indole alkaloid scaffolds for neurotherapeutics research, as the bicyclic dihydropyran intermediates and piperidinyl building blocks can be functionalized and modified to create novel bioactive compounds.

ADVANTAGES

High enantioselectivity with enantiomeric ratios exceeding 99:1 through the cooperative catechol/chiral amine catalysis system
Scalable multi-gram synthesis enabling production of sufficient quantities of alstonine, serpentine, and related alkaloids for further pharmacological studies, clinical development, and mechanistic investigations.
Divergent synthetic strategy allowing access to both cis- and trans-bicyclic dihydropyran diastereomers from a single common trans-piperidinyl intermediate.
Novel catalytic methodology solving the long-standing challenge of asymmetric intramolecular Michael additions into simple unsaturated esters.

PUBLICATIONS