Practical access to axially chiral sulfonamides and biaryl amino phenols via organocatalytic atroposelective N-alkylation

Shenci Lu,László Kürti,Yu Zhao,Shawn Voon Hwee Ng,Kaitlyn Lovato,Si Bei Poh,Xiao Qian Ng,Jun-Yang Ong

doi:10.1038/s41467-019-10940-4

Abstract

The importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.

Highlights

The importance of axial chirality in enantioselective synthesis has been widely recognized for decades
In contrast to the ubiquitous central chirality, axial chirality stems from hindered rotation around a bond axis, which was overlooked for many years in drug delivery due to the dynamic nature of such chiral compounds
We present our recent efforts in the development of a unified and practical catalytic procedure to deliver two important classes of axially chiral molecules (i.e., NOBIN analogs and chiral sulfonamides) in high efficiency and excellent enantiopurity (Fig. 1d)

Summary

Results

Access to enantiopure NOBIN analogs by N-alkylative kinetic resolution. Kinetic resolution is a highly effective strategy to produce a general library of enantiopure NOBIN analogs. Our previous work resulted in a highly practical and scalable organocatalytic preparation of a wide range of racemic biaryl sulfonamide phenols in high yields (see below)[29,30] If this racemic synthesis can be combined with a catalytic kinetic resolution using a commercial and inexpensive catalyst, this sequence may provide a practical access to enantiopure NOBIN library. To further explore the scope of this catalytic method beyond the NOBIN analogs available from our previous synthesis[30], other NOBIN analogs bearing different anilines such as 1l29 or binaphthyl-derived NOBINs including 1m–1o were prepared using alternative syntheses These analogs were subjected to the kinetic resolution and gratifyingly, similar or even higher levels of reactivity and enantioselectivity could be achieved.

New axially chiral entity?

Discussion

Methods