Divergent Protocol for the Synthesis of Isoquinolino[1,2-b]quinazolinone and Isoquinolino[2,1-a]quinazolinone Derivatives.

The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities. In this context, the development of an efficient strategy for their access is needed. Herein, we report a divergent metal-free operation to access a diverse collection of C6-substituted pyrrolo[4',3',2':4,5]isoquinolino[1,2-b]quinazolin-8(6H)-one and pyrrolo[4',3',2':4,5]isoquinolino[2,1-a]quinazolin-12(6H)-one architectures. The described cascade unites Friedel-Crafts and aza-Michael addition reactions. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the cascade features a promising approach for the design of unique compound libraries for drug design and discovery programs.

Stereodivergent Desymmetrization of Phenols En Route to Modular Access to Densely Functionalized Quinazoline and Oxazine Scaffolds.

The de novo assembly of stereochemically and skeletally diverse scaffolds is a powerful tool for the discovery of novel chemotypes. Hence, the development of modular, step- and atom-economic synthetic methods to access stereochemically and skeletally diverse compound collection is particularly important. Herein, we show a metal-free, stereodivergent build/couple/pair strategy that allows access to a unique collection of benzo[5,6][1,4]oxazino[4,3-a]quinazoline, quinolino[1,2-a]quinazoline and benzo[b]benzo [4,5]imidazo[1,2-d][1,4]oxazine scaffolds with complete diastereocontrol and wide distribution of molecular architectures. This metal-free process proceeds via desymmetrization of phenol derivatives. The cascade unites Mannich with aza-Michael addition reactions, providing expeditious entries to diverse classes of molecular shapes in a single operation.

Blue Light-Driven [4+2]-Cycloaddition: Diastereoselective Synthesis of Chromeno[4,3-b]quinoline and Chromeno[4,3-b][1,8]naphthyridine Scaffolds.

A one-pot, metal-free, light-driven [4+2]-cycloaddition reaction is described by accessing a diverse collection of chromeno[4,3-b]quinoline and chromeno[4,3-b][1,8]naphthyridine scaffolds in a diastereoselective manner. This process delivered stereoisomers, which were challenging to produce by an inverse-demand Diels-Alder reaction. The tetracyclic products were provided in good yields, promoted by rose bengal and blue light in a single operation. The developed protocol proceeded efficiently without the need for expensive photosensitizers such as Ir or Ru complexes. The cascade is modular and step-economic, and the substrate scope is wide. Polycyclic architectures can be assembled from readily available aniline, aminoazine, indole, and salicylaldehyde derivatives.

Stereodivergent Complexity-to-Diversity Strategy en Route to the Synthesis of Nature-Inspired Skeleta.

The complexity-to-diversity (CtD) strategy has become one of the most powerful tools used to transform complex natural products into diverse skeleta. However, the reactions utilized in this process are often limited by their compatibility with existing functional groups, which in turn restricts access to the desired skeletal diversity. In the course of employing a CtD strategy en route to the synthesis of natural product-inspired compounds, our group has developed several stereodivergent strategies employing indoloquinolizine natural product analogues as starting materials. These transformations led to the rapid and diastereoselective synthesis of diverse classes of natural product-like architectures, including camptothecin-inspired analogues, azecane medium-sized ring systems, arborescidine-inspired systems, etc. This manifestation required a drastic modification of the synthetic design that ultimately led to modular and diastereoselective access to a diverse collection of various classes of biologically significant natural product analogues. The reported strategies provide a unique platform that will be broadly applicable to other late-stage natural product transformation approaches.

A Double Activation Method for the Conversion of Vinyl Epoxides into vic-Amino Alcohols and Chiral Benzoxazine/Quinoxaline Derivatives.

A new method for the synthesis of 1,2-syn-vic amino alcohols (with double inversion of configuration) from vinyl epoxides, by the amination of a π-allyl palladium-borate complex generated by using Pd(0) and phenyl-o-phenylene borate (a double activation technique), is reported. Further, this new method with broad functional group compatibility was extended to a one-pot/two-step synthesis of chiral benzoxazine and quinoxaline derivatives.

Stereoselective total synthesis of dinemasone A by double intramolecular hetero-Michael addition (DIHMA).

The first total synthesis of dinemasone A, a bioactive metabolite with a spiroketal moiety, is described. The main strategy for the construction of the spiroketal unit involves a double intramolecular hetero-Michael addition (DIHMA) of an ynone moiety. The thus obtained axial-equatorial mono anomeric spiroketal, on spiroepimerization with ZnBr(2), was converted into the requisite axial-axial double anomeric spiroketal. The ynone moiety with four stereocentres, was prepared from a chiral propargylic alcohol (C5-C11 fragment) and a dihydroxy aldehyde (C1-C4 fragment), which in turn were obtained from D-mannitol and crotyl alcohol respectively.