Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions.

The Petasis reaction is a multicomponent reaction of aldehydes, amines and organoboron reagents and is a useful method for the construction of substituted amines. Despite the significant advancement of the Petasis reaction since its invention in 1993, strategies for asymmetric and non-directed Petasis reactions remain limited. To date, there are very few catalytic asymmetric Petasis reactions and almost all asymmetric reports employ a chiral auxiliary. Likewise, the aldehyde component often requires a directing group, ultimately limiting the reaction's scope. In this Concept, key methods for asymmetric and non-directed Petasis reactions are discussed, focusing on how these conceptual advances can be applied to solve long-standing gaps in the Petasis literature.

Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers through a Convergent Petasis Borono-Mannich Reaction.

Strempeliopidine is a member of the monoterpenoid bisindole alkaloid family, a class of natural products that have been shown to elicit an array of biological responses including modulating protein-protein interactions in human cancer cells. Our synthesis of strempeliopidine leverages palladium-catalyzed decarboxylative asymmetric allylic alkylations to install the requisite all-carbon quaternary centers found in each of the two monomeric natural products, aspidospermidine and eburnamine. Initial studies employing Suzuki-Miyaura cross-coupling followed by diastereoselective hydrogenation provided evidence for a structural reassignment of the natural product. Our final synthetic sequence employs a diastereoselective Petasis borono-Mannich reaction to couple eburnamine to a trifluoroborate aspidospermidine derivative. These convergent approaches enabled the synthesis of eight diastereomers of this heterodimer and offer support for the reassignment of the absolute configuration of strempeliopidine.

Development of a Non-Directed Petasis-Type Reaction by an Aromaticity-Disrupting Strategy.

The Petasis-type reaction, which couples an imine and boronic acid, is an important tool for C-C bond formation in organic synthesis. However, the generality of this transformation has been limited by the requirement for a directing heteroatom to enable reactivity. Herein, we report the development of a non-directed Petasis-type reaction that allows for the coupling of trifluoroborate salts with α-hydroxyindoles. By disrupting aromaticity to generate a reactive iminium ion, in conjunction with using trifluoroborate nucleophiles, the method generates a new C-C bond without the need for a directing group. This reaction is operationally simple, providing α-functionalized indoles in up to 99 % yield using sp, sp2 , and sp3 -hybridized trifluoroborate nucleophiles. Finally, this reaction is applied as a novel bioconjugation strategy to link biologically active molecules and toward the convergent synthesis of non-natural heterodimeric bisindole alkaloid analogs.

Enantioselective 1,3-Dipolar Cycloadditions of α-Methylene Lactams to Construct Spirocycles.

Spirocyclic scaffolds are important motifs due to their potential to bestow favorable effects on pharmaceutical compounds. However, there is a need for efficient methods for their enantioselective construction. We report a method for the asymmetric 1,3-dipolar cycloaddition of diazoacetates or nitrile oxides with α-methylene lactams to prepare chiral spirocyclic heterocycles. The methodology is high yielding (up to 91% yield) and enantioselective (up to 89% ee) for a wide range of N-substituents and 6- and 7-membered ring lactam substrates.

Predicting the stability of homotrimeric and heterotrimeric collagen helices.

Robust methods for predicting thermal stabilities of collagen triple helices are critical for understanding natural structure and stability in the collagen family of proteins and also for designing synthetic peptides mimicking these essential proteins. In this work, we determine the relative stability imparted on the collagen triple helix by single amino acids and interactions between amino acid pairs. Using this analysis, we create a comprehensive algorithm, SCEPTTr, for predicting melting temperatures of synthetic triple helices. Critically, our algorithm is compatible with every natural amino acid, can evaluate both homotrimers and heterotrimers, and accounts for all possible helix compositions and registers, including non-canonically staggered helices. We test and optimize our algorithm against 431 published collagen triple helices to demonstrate the quality of our predictive system. Finally, we use this algorithm to successfully guide the design of an ABC heterotrimer possessing high assembly specificity.