Enantioselective Organocatalytic Synthesis of a Secoyohimbane-Inspired Compound Collection with Neuritogenic Activity.

Natural products provide evolutionary validated core structures to inspire the synthesis of new compound collections endowed with neurite growth-promoting activity. Rhynchophylline is the major component of Uncaria species, and has been used to treat neurological diseases in Chinese traditional medicine. Based on the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide a tetracyclic secoyohimbane scaffold incorporating a quaternary and three tertiary stereogenic centers, in a one-pot multistep reaction sequence. A compound collection of derived secoyohimbanes was synthesized and expanded by decorating the periphery of the basic scaffold with additional substituents to increase the diversity. Evaluation of the different subcollections of secoyohimbanes for modulation of neurite outgrowth in the SH-SY5Y human cell line led to the discovery of new compounds that promote neurite outgrowth.

Propargyl Vinyl Ethers and Tertiary Skipped Diynes: Two Pluripotent Molecular Platforms for Diversity-Oriented Synthesis.

During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4-O-C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB' three-component reaction for PVEs; A2BB' four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile. The PVEs are defined by the presence of an alkyne (alkynoate) function and a conjugated enol moiety and their mutual through-bond/through-space connectivity. This functional array accommodates a number of domino reactions launched either by a Michael addition on the alkynoate moiety (conjugated alkynes) or by a [3,3]-propargyl Claisen rearrangement (conjugated and nonconjugated alkynes). The reactivity profile of the TSDs is defined by the two connected alkynoate moieties (Michael addition) and the bispropargylic ester group ([3,3]-sigmatropic rearrangement). Using these first reactivity principles, each platform selectively delivers one unique and different skeleton (topology) from each domino transformation. Thus, through the use of 11 instrumentally simple and scalable domino reactions, we have transformed these two linear (rod-symmetric) pluripotent molecular platforms into 16 different scaffolds incorporating important structural motifs and multifunctional decorative patterns. The generated scaffolds entail carbocycles, heterocycles, aromatics, ß,γ-unsaturated esters and acids, and fused polycycles. They can be transformed into more elaborated molecular skeletons by the use of chemical handles generated in their own domino reactions or by appending different functionalities to the pluripotent molecular platform (secondary reactivity principles).

Synthesis of fully substituted pyrimidines.

A novel approach to the synthesis of fully substituted pyrimidine derivatives armed with an oxy-functionalized acetate chain at the ring is described. The manifold uses amidines as the nitrogen source and activated skipped diynes as the electrophilic reactive partners in a coupled domino strategy. In the first domino reaction, two consecutive aza-Michael additions assemble the six-membered ring heterocycle, while in the second domino process, a [H]-shift and a [3,3]-sigmatropic rearrangement lead to the aromatization of the product.

Acetylides from alkyl propiolates as building blocks for C3 homologation.

Alkyl propiolates are reagents with a versatile reactivity profile that entirely remains in the C(3)-homologated product for further elaboration. To be effective, this C(3) homologation requires suitable methods for the generation of the acetylide anion that are compatible with both the conjugated ester and the electrophilic partner. Recent advances include catalytic procedures for the in situ generation of these acetylides in the presence of suitable electrophiles. Whereas the organometallic methods have brought stereoselectivity to these reactions, the organocatalytic methods laid the ground for new efficient domino processes that generate complexity.

Highly enantioselective catalytic synthesis of neurite growth-promoting secoyohimbanes.

Natural products endowed with neuromodulatory activity and their underlying structural scaffolds may inspire the synthesis of novel neurotrophic compound classes. The spirocyclic secoyohimbane alkaloid rhynchophylline is the major component of the extracts of Uncaria species used in Chinese traditional medicine for treatment of disorders of the central nervous system. Based on the structure of rhynchophylline, a highly enantioselective and efficient organocatalyzed synthesis method was developed that gives access to the tetracyclic secoyohimbane scaffold, embodying a quaternary and three tertiary stereogenic centers in a one-pot multistep reaction sequence. Investigation of a collection of the secoyohimbanes in primary rat hippocampal neurons and embryonal stem cell-derived motor neurons led to discovery of compounds that promote neurite outgrowth and influence the complexity of neuronal network formation.

Metal-free access to fully substituted skipped diynes. An efficient chemodifferentiating A2BB' 4CR manifold.

A metal-free chemodifferentiating A2BB' 4CR manifold for the modular synthesis of tertiary skipped diynes is described. The manifold performs a triethylamine triggered reaction of alkyl propiolates and acid chlorides to assemble two units of each component in the form of two propargylic alkynoates, a tertiary alcohol, and an ester. A differentiated incorporation of the two acid chloride components ensures functional diversity in the final structure. In addition, the presence of two connected propargylic alkynoates provides a reactive platform for complexity generation.