Double agent: Switching the electronic nature of substituents on an aziridine ring induces the formation of the ring‐opened zwitterionic 1,3‐dipole through CN bond cleavage instead of the usual CC bond cleavage. This novel dipole reacts with alkenes, alkynes, nitriles, and carbonyl compounds to afford new types of [3+2] cycloadducts, thereby enhancing the diversity of nitrogen‐containing heterocycles accessible through 1,3‐dipolar cycloadditions. EWG=electron‐withdrawing group.

This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2+2 +2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the phosphoramidite ligand leads to tuning of enantio-and product selectivity, with a complete turnover in product selectivity seen with aliphatic alkynes when moving from Taddolbased to biphenol-based phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination of a series of competition experiments in combination with analysis of reaction outcome shed considerable light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that rationalizes the observed product selectivity.

Described is an efficient stereocontrolled route into valuable, densely functionalized fluorinated phosphonates that takes advantage of (i) a Clostridial enzyme to set the absolute stereochemistry and (ii) a new [3,3]-sigmatropic rearrangement of the thiono-Claisen variety that is among the fastest sigmatropic rearrangements yet reported. Here, a pronounced rate enhancement is achieved by distal fluorination. This rearrangement is completely stereoretentive, parlaying the enzymatically established β-C-O stereochemistry in the substrate into the δ-C-S stereochemistry in the product. The final products are of interest to chemical biology, with a platform for Zn-aminopeptidase A inhibitors being constructed here. The enzyme, Clostridium acetobutylicum (CaADH), recently expressed by our group, reduces a spectrum of γ,δ-unsaturated β-keto-α,α-difluorophosphonate esters (93–99% ee; 10 examples). The resultant β-hydroxy-α,α-difluorophosphonates possess the ‘L’-stereochemistry, opposite to that previously observed for the CaADH-reduction of ω-keto carboxylate esters (‘D’), indicating an unusual active site plasticity. For the thiono-Claisen rearrangement, a notable structure-reactivity relationship is observed. Measured rate constants vary by over three orders of magnitude, depending upon thiono-ester structure. Temperature-dependent kinetics reveal an unusually favorable entropy of activation (∆S‡ = 14.5 ± 0.6 e.u.). Most notably, a 400-fold rate enhancement is seen upon fluorination of the distal arene ring, arising from favorable enthalpic (∆∆H‡ = −2.3 kcal/mol) and entropic (∆∆S‡ = 4 e.u., i.e. 1.2 kcal/mol at RT) contributions. The unusual active site plasticity seen here is expected to drive structural biology studies on CaADH,, while the exceptionally facile sigmatropic rearrangement is expected to drive computational studies to elucidate its underlying entropic and enthalpic basis.

Thiocyanopalladation/carbocyclization chemistry: C–SCN bond installation, carbocyclization, and opportunities for structural diversification.