Asymmetric Counteranion-Directed Halogen Bonding Catalysis

Abstract

Halogen bonding has been established as a promising tool in organocatalysis. Asymmetric processes are nevertheless scarce, and their applications are limited to a few studies applying chiral halogen bond donors. Herein, we combine halogen bonding with asymmetric counteranion-directed catalysis, providing the first highly enantioselective example of such an approach. A strong bidentate iodine(III)-based catalyst with chiral disulfonimides as counteranions is applied in the first asymmetric organocatalysis of the Diels-Alder reaction between cyclopentadiene and trans-β-nitrostyrene, the key step in the synthesis of the drug fencamfamine, which was prepared with high enantioselectivity.

Figure 1

Concepts of previous approaches to XB-ACDC^, versus the concept of this work (red: XB catalyst, blue: chiral counteranion, green: substrate) and our catalyst system.

Scheme 1. Catalysis of the Diels–Alder Reaction between trans-β-Nitrostyrene (1a) and Cyclopentadiene (2) Using an Achiral XB Donor Salt (XBD) with Chiral DSI Additives

For clarity, endo- and exo-3a are depicted as defined enantiomers.

Figure 2

Transition state of the Diels–Alder reaction (Scheme 1) catalyzed by XB donor 4, calculated using DFT (M06-2X-D3,^, def2-TZVP(D)⁻). Graphic via CYLview20.

Scheme 2. Substrate Scope (at 100 μmol Scale, 50 mM Concentration; e.r. Determined via Chiral HPLC; Products Isolated with >100:1 d.r.)

Performed at 50 and 100 μmol scale, at 12.5 mM concentration. 9:1 d.r. The depicted absolute configuration (1R,4S,5R,6S) was proven for endo-3a by VCD spectroscopy.

Scheme 3. Scale-up and Isolation of Enantiopure (−)-Fencamfamine

The depicted absolute configuration (1R,4S,5R,6S) was proven for endo-3a by VCD spectroscopy.