Asymmetric Synthesis of Axially Chiral C-N Atropisomers

Abstract

Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C-C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C-N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C-N axes. The preparation of different families of C-N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.

Figure 1

A) Naturally occurring and bioactive C−N‐bonded axially chiral compounds. B) Selected ligands and complexes featuring C−N axially chirality.

Figure 2

Representative families of atropisomers featuring a C−N chiral axis.

Figure 3

Strategies for the catalytic asymmetric synthesis of axially chiral C−N atropisomers.

Scheme 1

Seminal studies toward the synthesis of axially chiral anilides. Enantiomers of 2  a and 2  b not shown.

Scheme 2

Kinetic resolution for the synthesis of 2‐(t‐butyl)anilides.

Scheme 3

Chiral pool approach to axially chiral anilide derivatives.

Scheme 4

Synthesis and reduction of axially chiral acetoxy anilides.

Scheme 5

Chiral pool approach for the synthesis of atropisomeric anilides.

Scheme 6

Asymmetric synthesis of atropisomeric anilides.

Scheme 7

Axially chiral enantiopure anilides by crystallization‐induced asymmetric transformation.

Scheme 8

Kinetic resolution of sulfanyl ureas.

Scheme 9

Palladium‐catalyzed asymmetric allylic alkylation for the synthesis of atropoisomeric anilides.

Scheme 10

N‐arylation of achiral anilides.

Scheme 11

Atroposelective N‐allylation of sulfonamides.

Scheme 12

Atroposelective acylation of sulfonamides

Scheme 13

Atroposelective hydroamination to axially chiral sulfonamides

Scheme 14

Phase‐transfer‐catalyzed N‐alkylation of axially chiral o‐iodoanilide.

Scheme 15

Pd‐Catalyzed asymmetric allylic alkylation of ortho‐anilides.

Scheme 16

Lewis base organocatalyzed allylic alkylation of anilides

Scheme 17

Atroposelective N‐allylic alkylation of phosphamides.

Scheme 18

Rhodium‐catalyzed enantioselective intermolecular [2+2+2] cycloaddition.

Scheme 19

Atroposelective Pd^II‐catalyzed C−H functionalization of N‐aryl picolinamides via DKR.

Scheme 20

Synthesis of N‐aryl quinoids by CPA‐catalyzed direct C−H halogenation.

Scheme 21

Organocatalyzed synthesis of naphthamides by the group of Jørgensen.

Scheme 22

Atroposelective CPA‐catalyzed C−H amination of N‐aryl‐2‐naphthylamides and anilides.

Scheme 23

Total synthesis of Murrastifoline‐F.

Scheme 24

Stereoselective synthesis of axially chiral N‐aryl indoles.

Scheme 25

Catalytic asymmetric Paal‐Knorr reaction for the synthesis of axially chiral N‐arylpyrroles.

Scheme 26

Pd‐Catalyzed enantioselective synthesis of axially chiral indoles.

Scheme 27

Palladium‐catalyzed intramolecular N‐arylation for the synthesis of enantioenriched N‐aryloxindoles.

Scheme 28

Organocatalyzed heteroannulation reaction for the synthesis of N‐arylindole esters.

Scheme 29

Rhodium(III)‐catalyzed C−H activation of anilines for the synthesis of axially chiral N‐isoquinolyl indole derivatives.

Scheme 30

Organocatalytic construction of complex azepines featuring C−N axial chirality.

Scheme 31

Palladium‐catalyzed atroposelective C−H alkynylation.

Scheme 32

Atroposelective C−H olefination of N‐aryl indoles.

Scheme 33

Satoh‐Miura‐type reaction of N‐aryloxindoles and alkynes.

Scheme 34

Atroposelective synthesis of N‐aryl‐tetrahydro‐β‐carbolines.

Scheme 35

Atroposelective alkylation using a chiral at‐rhodium catalyst.

Scheme 36

Axially chiral N‐arylated indolines by Cu‐catalyzed Ullmann coupling.

Scheme 37

Atroposelective C−H amination of arenes for the synthesis of chiral N‐aryl carbazoles and indoles.

Scheme 38

Asymmetric Rh‐catalyzed carbene insertion reaction for the synthesis of axially chiral N‐arylindolocarbazoles.

Scheme 39

Enantioselective ring‐closing metathesis for the synthesis of N‐arylindoles.

Scheme 40

Resolution of phenyl triazole derivatives.

Scheme 41

Synthesis of axially chiral N‐arylurazole derivatives.

Scheme 42

NHC‐catalyzed atroposelective desymmetrization of urazoles.

Scheme 43

Cyclization approaches for the synthesis of axially chiral N‐aryl benzimidazoles.

Scheme 44

Atroposelective construction of axially chiral N‐aryl benzimidazoles involving carbon−carbon bond cleavage.

Scheme 45

Atroposelective construction of axially chiral N‐aryl benzimidazoles involving carbon−carbon bond cleavage.

Scheme 46

Enantioselective deprotonation for the synthesis of axially chiral imides.

Scheme 47

Rhodium‐catalyzed asymmetric 1,4‐addition for the synthesis of axially chiral N‐arylsuccinimides.

Scheme 48

Synthesis of N‐arylsuccinimides by a guanidine‐catalyzed thia‐Michael addition/ protonation sequence:

Scheme 49

A: Scandium‐catalyzed Michael addition of 3‐substituted‐2‐oxindoles to arylmaleimide derivatives. B: Organocatalytic atroposelective desymmetrization of maleimides.

Scheme 50

NHC‐catalyzed synthesis of axially chiral N‐Aryl succinimides.

Scheme 51

Synthesis of axially chiral N‐Aryl succinimides: Ni‐catalyzed desymmetrization of norbornene derivatives by hydrocyanation.

Scheme 52

Asymmetric intramolecular N‐arylation for the synthesis of atropoisomeric lactams.

Scheme 53

Base‐catalyzed isomerization–Michael addition for the synthesis of axially chiral lactams

Scheme 54

Atroposelective cycloaddition of diynes with isocyanates for the synthesis of axially chiral N‐aryl‐2‐pyridones.

Scheme 55

Ullmann‐type amination to obtain axially chiral lactams.

Scheme 56

Atroposelective synthesis of phenanthridin‐6‐ones.

Scheme 57

Axial‐to‐axial chirality transfer approach for the synthesis of axially chiral N‐arylphenanthridinones.

Scheme 58

Atroposelective synthesis of N‐styryl pyridones.

Scheme 59

Classical resolution of racemic quinazolinones.

Scheme 60

Diastereoselective dehydrative cyclization for the synthesis of quinazolinone derivatives.

Scheme 61

Atroposelective tribromination of N‐arylquinazolinones.

Scheme 62

Reductive desymmetrization of chiral quinazolinones.

Scheme 63

Asymmetric synthesis of heterobiaryl cyclic carbamates.

Scheme 64

Hydroamination/cyclization sequence for the synthesis of axially chiral quinazolinones.

Scheme 65

Atroposelective synthesis of axially chiral uracil derivatives.

Scheme 66

Atroposelective synthesis of axially chiral thiazine derivatives.