Re-Evaluation of Product Outcomes in the Rh-Catalyzed Ring Expansion of Aziridines with N-Sulfonyl-1,2,3-Triazoles.

N-heterocycles are prevalent in pharmaceuticals and natural products, but traditional methods often do not introduce significant stereochemical complexity into the ring. We previously reported a Rh-catalyzed ring expansion of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. However, later studies employing ketone-containing carbene precursors showed that [3,9]-bicyclic aziridine formation competes with production of the desired heterocyclic scaffolds. In light of these surprising results, our initial findings were re-examined both experimentally and computationally to reveal how noncovalent interactions and restricted bond rotation in the aziridinium ylide intermediate promote this unexpected reaction pathway.

Rh-Catalyzed Aziridine Ring Expansions to Dehydropiperazines.

Piperazines are prevalent in pharmaceuticals and natural products, but traditional methods do not typically introduce stereochemical complexity into the ring. To expand access to these scaffolds, we report Rh-catalyzed ring expansions of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. Productive ring expansion proceeds via a pseudo-1,4-sigmatropic rearrangement of an aziridinium ylide species. However, the structural features of the carbene precursor are important, as pyridotriazoles undergo competing cheletropic extrusion to furnish ketimines.

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides.

The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new C-C bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.

α-Tetrasubstituted Aldehydes through Electronic and Strain-Controlled Branch-Selective Stereoselective Hydroformylation.

Hydroformylation utilizes dihydrogen, carbon monoxide, and a catalyst to transform alkenes into aldehydes. This work applies chiral bisdiazaphospholane (BDP)- and bisphospholanoethane-ligated rhodium complexes to the hydroformylation of a variety of alkenes to produce chiral tetrasubstituted aldehydes. 1,1'-Disubstituted acrylates bearing electron-withdrawing substituents undergo hydroformylation under mild conditions (1 mol % of catalyst/BDP ligand, 150 psig gas, 60 °C) with high conversions and yields of tetrasubstituted aldehydes (e.g., 13:1 regioselectivity, 85% ee, and <1% hydrogenation for 1-fluoromethyl acrylate). The scope also encompasses both acyclic 1,1'-disubstituted and trisubstituted, electron-poor alkenes as well as di- and trisubstituted alkenes composed of small rings with exocyclic and endocyclic unsaturation. For example, 1-methylene-ß-lactam furnished the tetrasubstituted aldehyde with 98% selectivity and up to 83% ee. Notably, chiral trisubstituted bicyclic methyleneaziridines are transformed with >99% regioselectivity and >19:1 diastereoselectivity to tetrasubstituted aldehydes at rates >50 catalyst turnovers/hour. NMR studies of the noncatalytic reaction of HRh(BDP)(CO)2 with methyl 1-fluoroacrylate enable interception of tertiary alkylrhodium intermediates, demonstrating migratory insertion to acyl species is slower than formation of secondary and primary alkylrhodium intermediates. Overall, these investigations reveal how the interplay of sterics, electronics, and ring strain are harnessed to provide access to valuable α-tetrasubstituted aldehyde synthetic building blocks by promoting branched-selective hydroformylation.

Oxidative allene amination for the synthesis of nitrogen-containing heterocycles.

The prevalence of stereochemically complex amines in natural products, pharmaceuticals and other bioactive compounds, coupled with the challenges inherent in their preparation, has inspired our work to develop new and versatile methodologies for the synthesis of amine-containing stereotriads ('triads'). The key step is a highly chemo-, regio-, and stereoselective transition-metal catalyzed nitrene transfer reaction that transforms one of the cumulated double bonds of an allene precursor into a bicyclic methyleneaziridine intermediate. This account summarizes our strategies to rapidly elaborate such intermediates into stereochemically rich, densely functionalized amine triads, nitrogen heterocycles, aminated carbocycles and other useful synthetic building blocks.

Regioselective Rh-Catalyzed Hydroformylation of 1,1,3-Trisubstituted Allenes Using BisDiazaPhos Ligand.

The efficient hydroformylation of 1,1,3-trisubstituted allenes is accomplished with low loadings of a Rh catalyst supported by a BisDiazaPhos (BDP) ligand. The ligand identity is key to achieving high regioselectivity, while the mild reaction conditions minimize competing isomerization and hydrogenation to produce ß,γ-unsaturated aldehydes and their derivatives in excellent yields.