Extended Enolates: Versatile Intermediates for Asymmetric C-H Functionalization via Noncovalent Catalysis

Abstract

Catalyst-controlled functionalization of unmodified carbonyl compounds is a relevant operation in organic synthesis, especially when high levels of site- and stereoselectivity can be attained. This objective is now within reach for some subsets of enolizable substrates using various types of activation mechanisms. Recent contributions to this area include enantioselective transformations that proceed via transiently generated noncovalent di(tri)enolate-catalyst coordination species. While relatively easier to form than simple enolate congeners, di(tri)enolates are ambifunctional in nature and so control of the reaction regioselectivity becomes an issue. This Minireview discusses in some detail this and other problems, and how noncovalent activation approaches based on metallic and metal free catalysts have been developed to advance the field.

Keywords: Brønsted base catalysis; C−H functionalization; asymmetric catalysis; dienolates; regioselectivity.

Figure 1

(a) Activation modes for enolizable carbonyl compounds in asymmetric catalysis. (b) Direct C−H functionalization pathways via dienolate intermediates (E=electrophile).

Scheme 1

Metal dienolate formation and reactivity trends.

Scheme 2

Substrate precomplexation to bulky Al‐phenoxides may override the innate α‐reactivity of metal dienolates leading to γ‐addition aldol products.

Scheme 3

The regioselectivity issue in reactions involving dilithium di‐ and trienolate dianions by Mestres.

Scheme 4

Recent example by Ito demonstrating that while deprotonation of skipped enones is suitable that of conjugate enones is reluctant.

Scheme 5

In‐ring C−H functionalization of enolizable heterocycles involving aromatic di(poly‐)enolate intermediates are not covered in this work.

Scheme 6

Cu(I)‐catalyzed reductive aldol between allenic esters and methyl ketones.

Scheme 7

Ba(II)‐catalyzed Mannich and aldol additions of allylic esters with concomitant double bond isomerization by Shibasaki.

Scheme 8

Cu‐catalyzed direct vinylogous aldol‐isomerization‐lactonization cascade to unsaturated δ‐lactones by Yin.

Scheme 9

Cu(I)‐catalyzed vinylogous and bisvinylogous Mannich reaction involving pyrazole amide di‐ and tri‐enolates by Yin.

Scheme 10

Cu(I)‐catalyzed vinylogous Mannich reaction of in situ formed halogen‐substituted pyrazole amide dienolates.

Scheme 11

Copper‐catalyzed direct enantio‐ and diastereoselective aldol additions of α‐vinyl (thio)amides by Shibasaki.

Scheme 12

Cu(I)‐catalyzed asymmetric Cα‐Mannich‐ and Cγ‐aldol‐type reactions of allylic nitriles developed by Shibasaki's group. Dpp: diphenylphosphinoyl.

Scheme 13

Acceptor‐dependent α vs γ regioselectivity in Cu‐catalyzed enantioselective aldol‐type additions of allyl nitriles to aldehydes by Shibasaki.

Scheme 14

Pd‐catalyzed tandem γ‐arylation/aza‐Michael route to fused indoles from β,γ‐unsaturated cyclohexanones by Buchwald.

Scheme 15

Rare earth/N,N‐dioxide catalysed α‐selective Michael and Mannich addition reactions of β,γ‐unsaturated 2‐acylimidazoles by Feng.

Scheme 16

Direct, catalytic and α‐selective Mannich reactions of unsaturated α‐fluoroketones involving crossed Zn(II)‐dienolates by Trost.

Scheme 17

Organocatalytic aldol addition reactions of acrylic ester and nitrile using Verkade's strong bases.

Scheme 18

Direct urea/tertiary amine catalysed Mannich reaction of β,γ‐unsaturated aryl esters proceeding through Cα as reported by Zhao.

Scheme 19

Tandem Michael addition/reduction/cyclisation involving symmetrical dienolates as key intermediates.

Scheme 20

Stereospecific γ‐amination of β,γ‐unsaturated thioesters catalysed by chiral guanidine C5.

Scheme 21

Asymmetric organocatalytic synthesis of spiroindoles through tandem γ‐selective aldol addition/lactonization by Wu.

Scheme 22

γ‐Selective Michael reactions of β,γ‐unsaturated N‐acyl pyrazoles triggered by bifunctional tertiary amine/H‐bond catalysts by Huang.

Scheme 23

Organocatalytic γ‐selective aldol additions involving acyclic ketone dienolates and active ketones as acceptors by Jiang.

Scheme 24

Organocatalytic tandem Michael/Michael processes initiated with γ‐addition of transiently formed ketone dienolates.

Scheme 25

Organocatalytic asymmetric α‐selective Michael additions of transiently formed ketone dienolates by Palomo.

Scheme 26

Catalyst‐ and substrate‐dependent reaction regioselectivity as reported by Palomo for transient dienolates from allyl alkynyl ketones.

Scheme 27

The glycosyl‐thiourea/amine catalysed α‐selective Mannich reaction between allyl ketones and activated ketimines by Ma.

Scheme 28

Organocatalytic α‐selective 1,2‐ and 1,4‐additions of α‐vinyl cycloalkanones leading to quaternary stereocenters developed by Palomo.

Scheme 29

Sequential Cα/Cα coupling of intermediate ketone dienolates leading to tetrasubstituted cyclopentenones from acyclic precursors.

Scheme 30

A thiourea/iminophosphorane catalytic approach to the enantioselective isomerization of .β,γ‐cyclohexenones by Paton and Dixon.

Scheme 31

γ‐Selective Michael addition of transiently generated bis(sulfonamide)‐stabilized dienolates from allyl ketones by Xu.

Scheme 32

Diastereodivergent organocatalytic synthesis of substituted cyclohexenes involving aldehyde dienolates by Xu.

Scheme 33

Tandem dienolate‐mediated addition/Henry reaction towards cyclohexene systems by Zhao.

Scheme 34

Ytterbium(III)‐catalyzed γ‐functionalization of 3‐alkylidene‐2‐oxindoles by Feng. DMAP: 4‐dimethylaminopyridine.

Scheme 35

Dienolates from alkylidene oxazolones en route to unsaturated α‐amino γ‐lactones by Xu and Singh, independently.

Scheme 36

Asymmetric Michael additions and allylic alkylations of dienolates transiently generated from alkylideneoxazolones.

Scheme 37

3‐Alkylidene‐2‐oxindoles as dienolate precursors and their enantioselective γ‐addition to different electrophiles.

Figure 2

Model proposed by Bencivenni et al. for the above catalytic reactions involving 3‐alkylidene‐2‐oxindole‐derived dienolates as intermediates.

Scheme 38

Enantioselective vinylogous aldol additions of azadienolates from o‐allyl azaarenes with activated ketones by Jiang.

Scheme 39

Ligand‐dependent azadienolate mediated vinylogous aldol‐type reactions of o‐allyl azaarenes by Yin.

Scheme 40

Trienolate‐mediated asymmetric one‐pot transformation of doubly unsaturated ketones/thioesters into substituted cyclohexenes by Palomo. MTBD: 7‐methyl‐1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene.

Scheme 41

Direct addition reaction of various in situ generated dienolates with transiently generated chiral iminium ion from aldehydes.

Scheme 42

α‐Selective coupling reaction of in situ formed ketone dienolates with chiral amine‐activated MBH carbonates 164 by Huang and Jiang.

Scheme 43

Ir‐catalyzed vinylogous allylic alkylation of β,γ‐unsaturated lactones by Yin.

Scheme 44

Umpolung strategies for the generation of ester and aldehyde metal dienolates in situ and their coupling with donor and acceptor reagents.

Scheme 45

Alkynylogous enantioselective aldol reactions of homopropargylic esters under Au(III) and Cu(I) catalysis.

Scheme 46

Asymmetric organocatalytic reducting coupling reactions between benzylidene pyruvates and aldehydes by Johnson.

Scheme 47

Catalytic asymmetric addition reactions involving nitrone‐derived azadienolates as intermediates.

Scheme 48

Recently reported enzymatic transformations involving dienolate intermediates.