Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.

Catalytic, Enantioselective Sulfenofunctionalization of Alkenes: Development and Recent Advances.

The last decade has witnessed a burgeoning of new methods for the enantioselective vicinal difunctionalization of alkenes initiated by electrophilic sulfenyl group transfer. The addition of sulfenium ions to alkenes results in the generation of chiral, non-racemic thiiranium ions. These highly reactive intermediates are susceptible to attack by a myriad of nucleophiles in a stereospecific ring-opening event to afford anti 1,2-sulfenofunctionalized products. The practical application of sulfenium ion transfer has been enabled by advances in the field of Lewis base catalysis. This Review will chronicle the initial discovery and characterization of thiiranium ion intermediates followed by the determination of their configurational stability and the challenges of developing enantioselective variants. Once the framework for the reactivity and stability of thiiranium ions has been established, a critical analysis of pioneering studies will be presented. Finally, a comprehensive discussion of modern synthetic applications will be categorized around the type of nucleophile employed for sulfenofunctionalization.

Enantio- and Diastereoselective, Lewis Base Catalyzed, Cascade Sulfenoacetalization of Alkenyl Aldehydes.

A catalytic, enantio-, and diastereoselective formation of sulfenyl acetals bearing multiple stereogenic centers is reported. Alkenyl aldehydes undergo a chiral thiiranium ion initiated cascade starting with intramolecular capture by a formyl group and termination by capture with HFIP solvent. This method provides a one-pot synthesis of dihydropyran and 1,3-disubstituted isochroman acetals in good to excellent yield and with high levels of diastereo- (up to >99:1 dr) and enantiocontrol (up to 99:1 er).

Aryloxide-Facilitated Catalyst Turnover in Enantioselective α,ß-Unsaturated Acyl Ammonium Catalysis.

A new general concept for α,ß-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,ß-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,ß-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,ß-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

Enantioselective Stereodivergent Nucleophile-Dependent Isothiourea-Catalysed Domino Reactions.

α,ß-Unsaturated acyl ammoniums generated from the reaction of α,ß-unsaturated 2,4,6-trichlorophenol (TCP) esters bearing a pendent enone with an isothiourea organocatalyst are versatile intermediates in a range of enantioselective nucleophile-dependent domino processes to form complex products of diverse topology with excellent stereoselectivity. Use of either 1,3-dicarbonyls, acyl benzothiazoles, or acyl benzimidazoles as nucleophiles allows three distinct, diastereodivergent domino reaction pathways to be accessed to form various fused polycyclic cores containing multiple contiguous stereocentres.

Synthesis of Highly Functionalized 4-Iodo-7-azaindazoles via Condensation/Diels-Alder/Retro-Diels-Alder Cyclization of Iodoalkynones and 2-Hydrazineylpyrimidines.

A method for the preparation of highly functionalized 4-iodo-7-azaindazoles is reported. These valuable heterocycles are synthesized via condensation of 2-hydrazineylpyrimidines with various iodoalkynones followed by Diels-Alder/retro-Diels-Alder cyclization. The method is general to the formation of products with a variety of C3, C5, and C6 substituents while preserving the C4 iodide functional handle for further late-stage functionalization. The utility of this transformation is demonstrated through the rapid synthesis of several bioactive azaindazole targets.

Enantioselective Inter- and Intramolecular Sulfenofunctionalization of Unactivated Cyclic and (Z)-Alkenes.

A method for the enantioselective, Lewis base-catalyzed sulfenofunctionalization of cyclic and (Z)-alkenes is reported. The intermediate thiiranium ion generated in the presence of a selenophosphoramide catalyst is intercepted by a variety of nucleophiles. A diverse array of inter- and intramolecular functionalizations proceed in high yield and good to high enantioselectivity (86:14-98:2 er). Prior experimental and computational studies indicated such enantiotopic face discrimination to be poor; however, the results disclosed herein remediate the previous findings. Control experiments were performed to investigate the different behavior of (Z)-alkenes and their more established (E)-counterparts.

Unanticipated Silyl Transfer in Enantioselective α,ß-Unsaturated Acyl Ammonium Catalysis Using Silyl Nitronates.

The use of silyl nitronates is reported for the isothiourea-catalyzed synthesis of γ-nitro-substituted silyl esters containing up to two contiguous stereocenters in good yields with excellent enantioselectivities (up to 93% yield and 99:1 er). The serendipitously discovered formation of silyl ester products in this reaction demonstrates a novel platform for catalyst turnover in α,ß-unsaturated acyl ammonium catalysis.

Four into one: organocatalyzed stereoselective conjugate addition of unprotected and unactivated carbohydrates.

This paper proposes a new and stereoselective access to glycosides. This operationally simple approach achieved via base-catalyzed conjugate additions of unprotected and unactivated carbohydrates to activated alkenes or alkynes is described.