Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations

Abstract

Herein, recent developments in the field of organocatalytic asymmetric transfer hydrogenation (ATH) of C=N, C=O and C=C double bonds using chiral phosphoric acid catalysis are reviewed. This still rapidly growing area of asymmetric catalysis relies on metal-free catalysts in combination with biomimetic hydrogen sources. Chiral phosphoric acids have proven to be extremely versatile tools in this area, providing highly active and enantioselective alternatives for the asymmetric reduction of α,β-unsaturated carbonyl compounds, imines and various heterocycles. Eventually, such transformations are more and more often used in multicomponent/cascade reactions, which undoubtedly shows their great synthetic potential and the bright future of organocatalytic asymmetric transfer hydrogenations.

Keywords: Asymmetric Transfer Hydrogenation; Catalysis; Chiral Phosphoric Acids; Metal-Free Hydrogenation; Organocatalysis.

Figure 1

The most typically used chiral phosphoric acids (top) and hydrogen sources (bottom) for asymmetric transfer hydrogenations.

Scheme 1

Typical reaction mechanism of CPA‐catalyzed asymmetric transfer hydrogenations, illustrated with the ATH of ketimine A.

Scheme 2

ATH of enals via asymmetric counteranion directed catalysis.

Scheme 3

ATH of cyclic enones via asymmetric counteranion directed catalysis (A) and via “counterion enhanced catalysis” (B).

Scheme 4

ATH of electron rich stryrenes (left) and the plausible intermediates (right bottom).

Scheme 5

Asymmetric hydroarylation of electron rich stryrenes.

Scheme 6

C ₂‐symmetric imidodiphosphoric acid‐catalyzed ATH of aromatic ketals.

Scheme 7

CPA‐catalyzed asymmetric transfer hydrogenation of prochiral ketones.

Scheme 8

A CPA‐catalyzed asymmetric transfer hydrogenation of bulky aryl ketones.

Scheme 9

Asymmetric transfer hydrogenation of ethyl ketimines.

Scheme 10

Asymmetric transfer hydrogenation of fluorinated alkynyl ketimines.

Scheme 11

Asymmetric transfer hydrogenation of fluorinated alkynyl ketimines via Ru/CPA combined catalysis.

Scheme 12

Chiral DSI‐catalyzed asymmetric transfer hydrogenation of N‐alkyl imines.

Scheme 13

Chiral DSI‐catalyzed asymmetric reductive condensation of N−H imines.

Scheme 14

Synthesis of β‐aryl amines via reductive amination, relying on Hantzsch ester (A) or benzothiazoline reductants (B).

Scheme 15

Strategies for the synthesis of α‐amino ketones via ATH and reductive amination.

Scheme 16

Synthesis of polyheterocycles via reductive amination.

Scheme 17

Reductive amination of β‐tetralones.

Scheme 18

CPA‐catalyzed, ammonia borane‐mediated ATH of ketimines and β‐enamino esters.

Figure 2

Various biological activity of saturated N‐heterocycles.

Scheme 19

Recent advances for the ATH of 49.

Scheme 20

Formation of tetrahydroquinolines via AOX‐formation.

Scheme 21

ATH of quinoline‐3‐amines.

Scheme 22

pThr‐containing peptides with CPA scaffold for the ATH of 8‐aminoquinolines.

Scheme 23

ATH of 3‐(trifluoromethyl)quinolines (top) and 3‐(trifluoromethyl‐thio)quinolines (bottom).

Scheme 24

ATH of various N‐heterocycles catalyzed by SPINOL‐derived acid (S)‐CPA 8.

Scheme 25

ATH of N‐heterocycles via Ru/CPA catalysis.

Scheme 26

ATH of 1,4‐benzoxazines with in situ formed Hantzsch esters.

Scheme 27

Catalyst immobilization strategies for the ATH of 1,4‐benzoxazines.

Scheme 28

Synthesis of DHPDs.

Scheme 29

Dehydroxy‐hydrogenation of 3‐indolylmethanol derivatives.

Scheme 30

Synthesis of piperidines via asymmetric dearomatization/aza‐Friedel‐Crafts alkylation cascade reaction.

Scheme 31

Dearomatization/ATH cascade for the synthesis of highly functionalized indole moieties (top) and the possible activation modes (bottom, A and B).

Scheme 32

CPA‐mediated synthesis of 5,6‐dihydroindolo[1,2‐c]quinazolines (top) and its application for the preparation of α‐diamino acid derivatives (bottom).

Scheme 33

Different concepts for the synthesis of spiroindolines via CPA‐catalyzed cascade reactions.

Scheme 34

Synthesis of tetrahydroquinolines via dehydrative cyclization/ATH cascade reaction.

Scheme 35

One‐pot synthesis of chiral quinolines via reduction of nitroarenes in a reduction/cyclization/reduction cascade.