Enantioselective Aziridination of Unactivated Terminal Alkenes Using a Planar Chiral Rh(III) Indenyl Catalyst

Abstract

Chiral aziridines are important structural motifs found in natural products and various target molecules. They serve as versatile building blocks for the synthesis of chiral amines. While advances in catalyst design have enabled robust methods for enantioselective aziridination of activated olefins, simple and abundant alkyl-substituted olefins pose a significant challenge. In this work, we introduce a novel approach utilizing a planar chiral rhodium indenyl catalyst to facilitate the enantioselective aziridination of unactivated alkenes. This transformation exhibits a remarkable degree of functional group tolerance and displays excellent chemoselectivity favoring unactivated alkenes over their activated counterparts, delivering a wide range of enantioenriched high-value chiral aziridines. Computational studies unveil a stepwise aziridination mechanism in which alkene migratory insertion plays a central role. This process results in the formation of a strained four-membered metallacycle and serves as both the enantio- and rate-determining steps in the overall reaction.

Scheme 1. Functionalization of Activated and Unactivated Alkenes

Figure 1

Screening of electronically varied planar chiral Rh(III) indenyl catalysts. Reactions were performed on a 0.10 mmol scale. Isolated yields are reported, and enantiomeric ratios were determined by chiral HPLC on an AD-H column (3% isopropanol in hexanes).

Figure 2

Optimization of the Ag salt variable. Reactions were run on a 0.10 mmol scale. ^a Isolated yields. ^b Enantiomeric ratios were determined by chiral HPLC (see the Supporting Information for details).

Figure 3

Scope of functionalized alkene substrates. Reactions were run on a 0.10 mmol scale. Isolated yields are reported, and enantiomeric ratios were determined by chiral HPLC (see the Supporting Information for details). ^aDiastereomeric ratio was determined by chiral HPLC. ^b(S,S)-2 was used as the precatalyst. ^cDiastereomeric ratio was determined by integration of the crude ¹H NMR spectra.

Figure 4

Scope of varied alkyl chain length substrates. Reactions were run on a 0.10 mmol scale. Isolated yields are reported, and enantiomeric ratios were determined by chiral HPLC (see the Supporting Information for details). ^aNsNHOPiv was used as the nitrogen source. ^bMsNHOPiv was used as the nitrogen source. ^c(R,R)-8 was used as the precatalyst. ^dReaction was run at 60 °C.

Figure 5

Scope of competition substrates containing activated and unactivated alkenes. Reactions were run on a 0.10 mmol scale. Isolated yields are reported, and enantiomeric ratios were determined by chiral HPLC (see the Supporting Information for details).

Scheme 2. Plausible Reaction Pathways for Aziridine Formation

Figure 6

Free energy profile for the formation of A4 from A1. Blue and green traces represent direct nitrene formation via N–O bond cleavage.

Figure 7

Energy profile of the olefin insertion step and aziridination step. Structures for the (R) pathways are omitted in this figure.

Figure 8

Structures of (a) ^SA5-TS, (b) ^RA5-TS, and (c) distances between the atoms involved in the olefin insertion step. All hydrogen atoms in the structures have been omitted for clarity.