Tunable aziridinium ylide reactivity: non-covalent interactions enable divergent product outcomes

Abstract

Methods for rapid preparation of densely functionalized and stereochemically complex N-heterocyclic scaffolds are in demand for exploring potential new bioactive chemical space. This work describes experimental and computational studies to better understand the features of aziridinium ylides as intermediates for the synthesis of highly substituted dehydromorpholines. The development of this chemistry has enabled the extension of aziridinium ylide chemistry to the concomitant formation of both a C–N and a C–O bond in a manner that preserves the stereochemical information embedded in the substrate. The chemistry is tolerant of a wide range of functionalities that can be employed for DNA-encoded library (DEL) synthesis to prepare diverse libraries of heterocycles with potential bioactivity. In addition, we have uncovered several key insights that describe the importance of steric effects, rotational barriers around the C–N bond of the aziridinium ylide, and non-covalent interactions (NCIs) on the ultimate reaction outcome. These critical insights will assist in the further development of this chemistry to generate novel and complex N-heterocycles that will further expand complex amine chemical space.

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

“…Our calculations indicate that the features of the key metal-free ylide play a crucial role in determining the reaction outcome. According to previous calculations on related systems, 15,16,18 the ylide derives from the nucleophilic addition of the aziridine 1a′ (where the Et group of 1a was modeled as a Me group for simplicity) to the Rh accessed, no 4′ will be obtained, which is in line with experimental observations. In addition, even if INT1′ could be accessed, the transition state associated with the possible transformation of INT1′ to the expected dehydropiperazine 4′ (TS2) also lies above than that associated with the formation of the [3,9]-adduct (TS1) from INT1.…”

“…Therefore, although both 3′ and 4′ are thermodynamically more stable than the observed 3aa′, the formation of the latter species takes place under kinetic control, which is in line with our recent findings on related transformations involving rather different ylide intermediates. 18…”

“…13 In 2017, we reported that aziridinium ylides generated from strained aziridines and Rh-supported carbenes undergo concerted [2,3]-Stevens rearrangement to give methyleneazetidines in good yields and dr with broad scope (Scheme 1A). 14,15 We also reported an intermolecular carbene transfer between Rh-bound vinyl carbenes and aziridines via a pseudo- [1,4]-sigmatropic rearrangement to furnish dehydropiperidines in excellent yields and dr. 16 We previously attempted to extend this work to the synthesis of dehydropiperazines; 17 however, later investigations of the factors leading to divergent product outcomes in the Rh-catalyzed reactions of diazoketones and bicyclic aziridines 18 caused us to reassess our earlier findings. 19 In this communication, we correct initial structural misassignments and provide insight into the reasons for the unexpected product outcomes (Scheme 1B).…”