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

Abstract

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-β-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) 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.

Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Dienes: An Experimental and DFT Study

“…Much to our surprise and delight, the cyclohexadienone-tethered 1,1-disubstituted terminal alkene 5a was also feasible for this transformation, albeit in low yield (Table , 6a ). This finding suggests that the involvement of a bulky tertiary alkyl-rhodium intermediate is capable of undergoing intramolecular conjugate addition . It is noteworthy that in all cases employing cyclohexadienone-tethered terminal alkenes, carboboration products were delivered with exclusive anti-Markovnikov regioselectivity, that is, C–B bond formation occurring at the terminal carbon atoms. , …”

Evolution in the metal-catalyzed asymmetric hydroformylation of 1,1′-disubstituted alkenes

“…The last example was reported by Landis, Schomaker and co-workers in 2018 (29). By using (S,S,S)-BisDiazaphos (L6) or (S,S)-Ph-BPE (L5) ligands they could expand the scope of 1,1 0 -disubstituted alkenes that can be hydroformylated with high branched selectivity under rather mild conditions (10 bar, 60 °C and 2-72 h).…”

Synthesis and applications of methyleneaziridines

“…More recently, a series of chiral bicyclic MAs were tested in hydroformylation. 88 In the presence of Rh(CO) 2 (acac) and chiral phosphine ligands, the hydroformylation afforded formyl functionalized aziridines in good yield (Scheme 65). Impressively, chiral trisubstituted bicyclic MAs were transformed to products with >99% regioselectivity and >19 : 1 diastereoselectivity at rates >50 catalyst turnovers per hour.…”