Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

Abstract

Aldehydes constitute a main class of organic compounds widely applied in synthesis. As such, catalyst-controlled enantioselective α-functionalization of aldehydes has attracted great interest over the years. In this context, α-branched aldehydes are especially challenging substrates because of reactivity and selectivity issues. Firstly, the transient trisubstituted enamines and enolates resulting upon treatment with an aminocatalyst or a base, respectively, would exhibit attenuated reactivity; secondly, mixtures of E- and Z-configured enamines/enolates may be formed; and third, effective face-discrimination on such trisubstituted sp² carbon intermediates by the incoming electrophilic reagent is not trivial. Despite these issues, in the last 15 years, several catalytic approaches for the α-functionalization of prostereogenic α-branched aldehydes that proceed in useful yields and diastereo- and enantioselectivity have been uncovered. Developments include both organocatalytic and metal-catalyzed approaches as well as dual catalysis strategies for forging new carbon-carbon and carbon-heteroatom (C-O, N, S, F, Cl, Br, …) bond formation at Cα of the starting aldehyde. In this review, some key early contributions to the field are presented, but focus is on the most recent methods, mainly covering the literature from year 2014 onward.

Keywords: aldehydes; asymmetric catalysis; dual catalysis; organocatalysis; quaternary carbon; reaction umpolung.

Scheme 1

Pioneering reports on catalytic asymmetric α-functionalization of α-branched aldehydes.

Figure 1

Representative primary and secondary amine catalysts used for enamine-mediated synthesis of α-quaternary aldehydes until the year 2014.

Scheme 2

Enamine-mediated α-amino, α-oxy, α-thio, and α-halo-functionalization of aldehydes.

Scheme 3

α-Fluorination of chiral γ-nitroaldehydes.

Scheme 4

An unnatural α-minoester-catalyzed aldehydes α-fluorination.

Scheme 5

Reagent-dependent enantioswitch of the aldehyde α-fluorination.

Scheme 6

α-Hydrazination of aldehyde applied to synthesis.

Scheme 7

Primary amine-catalyzed α-hydrazination of aldehydes.

Scheme 8

Sequential α-hydrazination/N-alkylation towards atropisomeric hydrazines.

Scheme 9

Aldehydes α-chlorination and the origin of low stereoselectivity.

Scheme 10

α-Alkylthiolation of α-branched aldehydes.

Scheme 11

Diarylmethylation of α-branched aldehydes catalyzed by thiourea-primary amines.

Scheme 12

Enantioselective reactions of α-amino aldehydes with indolyl-aryl-methanols.

Scheme 13

α-Amino acid-catalyzed C-benzylation of branched aldehydes.

Scheme 14

Optimizing conditions for the α-amino acid-catalyzed benzylic alkylation of branched aldehydes.

Scheme 15

Aminocatalytic α-alkylation of branched aldehydes under phase transfer conditions.

Scheme 16

Enantioselective Michael reaction of α-branched aldehydes with enones.

Scheme 17

Aminocatalytic asymmetric addition of branched aldehydes to succinimides.

Scheme 18

Polymer-supported chiral aminocatalysts for the enantioselective conjugate addition of branched aldehydes to nitrostyrenes.

Scheme 19

A secondary amine-catalyzed asymmetric addition of branched aldehydes to nitrostyrenes.

Scheme 20

Asymmetric conjugate addition of branched aldehydes to vinyl bis-sulfone.

Scheme 21

A tripeptide-catalyzed asymmetric crossed-aldol reaction of branched aldehydes with glyoxylates.

Scheme 22

Bifunctional Brønsted base/H-bonding catalyst activation approach for Michael additions of α-amino-aldehydes.

Scheme 23

Extension of the above catalytic addition to α-alkyl α-aryl aldehydes.

Scheme 24

Rhodium-phosphite catalyzed asymmetric allylic alkylation of α-branched aldehydes.

Scheme 25

Dinuclear zinc-aminoalcohol catalyzed Mannich addition reactions.

Scheme 26

Pd-catalyzed [3+2] coupling as a general approach for preparation of chiral α-quaternary aldehydes.

Scheme 27

Chiral organophosphoric acid (R)-TRIP (C56) and Pd(PPh₃)₄ as the cocatalyst for α-allylation of aldehydes.

Scheme 28

Three different catalytic species approaches for the asymmetric allylation of aldehydes.

Scheme 29

Dual catalysis using chiral primary amine/iridium-phosphoramidite organometallic complexes for the asymmetric allylation of aldehydes.

Scheme 30

Asymmetric counterion catalysis in combination with palladium-catalyzed allylic C-H activation.

Scheme 31

Deconjugative α-allylic alkylation reaction of α,β-unsaturated aldehydes.

Scheme 32

Nickel/enamine cooperative dual catalysis for highly enantioselective allylic α-alkylation of branched aldehydes.

Scheme 33

Enamine-mediated α-allylation reaction of branched aldehydes with allenamides.

Scheme 34

Asymmetric allylation using Cu(I) complex as the metallic cocatalyst with bis(3,5-trifluoromethylphenyl) prolinol.

Scheme 35

Dual catalysis approach to the α-alkylation of branched aldehydes using a proline-based tripeptide as the catalyst.

Scheme 36

Dual activation approach using a primary amine chiral catalyst and a palladium complex co-catalyst for the coupling with allenes.

Scheme 37

Dual catalysis protocol for reactions of branched aldehydes with aryl-methyl alkynes using rhodium hydride-catalyzed hydrometallation.

Scheme 38

Complex dissociation renders two independent catalysts for Michael additions of branched aldehydes.

Scheme 39

Photochemically driven aminocatalytic asymmetric α-alkylation of aldehydes with reactive alkyl bromides.

Scheme 40

EDA complexation-induced photochemical α-perfluoroalkylation of aldehydes.

Scheme 41

Enantioselective α-fluorination of α-substituted α,β-enals with NSFI via dienamine intermediate.

Scheme 42

α-Benzoyloxilation of aldehydes/enals using cinchona alkaloid-derived primary amine as the catalyst and an acid cocatalyst.

Scheme 43

Boronic acid cocatalyzed dual catalysis strategy for allylic α-alkylation of branched aldehydes with allylic alcohols.

Scheme 44

Three- and two-component self-assembled systems containing a primary α-amino acid for catalyzed Mannich/Michael addition reactions.

Scheme 45

Michael additions of branched aldehydes catalyzed by (a) lithium salt of primary α-amino acids, (b) a mixture of free α-amino acid and its lithium salt.

Scheme 46

Combination of oxidant and aminocatalysts for (a) the homocoupling reaction of branched aldehydes, and (b) the aldehydes α-acyloxylation.

Scheme 47

Umpolung approach for various catalytic α-oxidations (O, S, Cl) of branched aldehydes: (a) proof-of-concept, and (b) optimization of the α-aryl(alkyl)thiolation.

Scheme 48

Oxidative cross-coupling of indoles with aldehydes.

Scheme 49

Asymmetric catalytic coupling of aldehydes with various O- and N-centered nucleophiles: (a) coupling with α-amino acids and oligopeptides; (b) coupling with alcohols; (c) coupling with secondary amines.

Scheme 50

Dual catalysis conditions for the reaction between o-aryl-tethered vinyl aminoalcohols and aldehydes.

Scheme 51

Iminium ion-mediated cyclopropanation of methacrolein with α-diazophosphonate.