Enantioselective N-heterocyclic carbene-catalyzed Michael addition to α,β-unsaturated aldehydes by redox oxidation

Enantioselective N-heterocyclic carbene-catalyzed Michael addition reactions to α,β-unsaturated aldehydes by redox oxidation were realized. With 10 mol % of camphor-derived triazolium salt D, 15 mol % of DBU, 5 mol % of NaBF(4), and 100 mol % of quinone oxidant, the reactions of various dicarbonyl compounds with α,β-unsaturated aldehydes led to 3,4-dihydro-α-pyrones in good yields and excellent ee's.     

Two-carbon homologation of aldehydes and ketones to α,β-unsaturated aldehydes

Phosphonate reagents were developed for the two-carbon homologation of aldehydes or ketones to unbranched- or methyl-branched α,β-unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl ethylformyl-2-phosphonate dimethylhydrazone, contained a protected aldehyde group instead of the usual ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde, followed by removal of the dimethylhydrazone protective group with a biphasic mixture of 1 M HCl and petroleum ether. This robust two-step process worked with a variety of aldehydes and ketones. Overall isolated yields of unsaturated aldehyde products ranged from 71% to 86% after the condensation and deprotection steps.     

Palladium-catalyzed 1,4-addition of diarylphosphines to α,β-unsaturated aldehydes

A highly stereoselective asymmetric 1,4-addition of diarylphosphines to α,β-unsaturated aldehydes catalyzed by a bis(phosphine) pincer-Pd complex has been developed for the synthesis of chiral phosphines with excellent stereoselectivity (up to 98% ee) under mild conditions. The application of the current method to the synthesis of enantiopure bisphosphine and its pincer-Pd complex has also been demonstrated.     

Deacylative 1,6-addition of Bestmann-Ohira reagent to p-quinone methides for the synthesis of α-diazo-β-diarylphosphonates and cis-stilbenyl phosphonates

The role of Bestmann-Ohira Reagent (BOR) as a conjugate addition partner is reported for the first time. Deacylation of BOR in the presence of ethanolic KOH and 1,6-addition of the resulting diazophosphonate anion to p-quinone methides (PQMs) provides β-disubstituted α-diazophosphonates in good to excellent yields in most cases. Such 1,6-adducts further undergo Rh-catalyzed elimination of the diazo group and 1,2-migration of the phenolic group to afford cis-stilbenylphosphonates with high E-selectivity. The migration of the phenolic group presumably takes place via a spirocyclopropane intermediate derived from the Rh-carbenoid.     

Olefination of α,α'-divinyl ketones through catalytic Meyer-Schuster rearrangement

The direct olefination of 1,4-dien-3-ones remains a synthetic challenge. A two-step protocol, employing acetylide addition followed by catalytic Meyer-Schuster rearrangement has been developed for the olefination of 1,4-pentadien-3-ones to afford [3]dendralenes. Many of the traditional methods for the Meyer-Schuster rearrangement of alkynyl carbinols are not suitable with these highly unsaturated substrates because of their acid sensitivity. Unexpected reactivity during attempted rearrangement, including Nazarov-type electrocyclizations, is presented, along with conditions to promote the Meyer-Schuster rearrangement of ethoxyacetylene adducts using catalytic VO(acac)(2).     

NHC–copper-catalyzed asymmetric 1,4-addition of diarylphosphines to α,β-unsaturated ketones

N-Heterocyclic carbene–copper-catalyzed asymmetric 1,4-addition of diarylphosphines to α,β-unsaturated ketones was developed for the synthesis of chiral phosphorus derivatives in high yields with moderate enantioselectivity under mild conditions.     

Access to spirocyclic oxindoles via N-heterocyclic carbene-catalyzed reactions of enals and oxindole-derived α,β-unsaturated imines

A diastereoselective access to β-lactam fused spirocyclic oxindoles and related compounds bearing all carbon spiro centers is described. This N-heterocyclic carbene-catalyzed process employed challenging β,β-disubstituted α,β-unsaturated imines to react with enals.     

Electronic tuning of chiral diene ligands in iridium-catalyzed asymmetric 1,6-addition of arylboroxines to δ-aryl-α,β,γ,δ-unsaturated ketones

Asymmetric addition of arylboroxines to δ-aryl-α,β,γ,δ-unsaturated ketones proceeded in the presence of an iridium catalyst coordinated with a chiral diene ligand to give high yields of δ-diaryl ketones with very high enantioselectivity.     

Enantioselective conjugate addition of donor-acceptor hydrazones to α,β-unsaturated aldehydes through formal diaza-ene reaction: access to 1,4-dicarbonyl compounds

Donor-acceptor monosubstituted hydrazones participate as suitable reagents able to undergo an enantioselective formal diaza-ene reaction with α,β-unsaturated aldehydes under chiral secondary amine catalysis. This constitutes a new approach for the enantioselective conjugate addition of hydrazones to enals under metal-free conditions and leads to the formation of γ-hydrazono carboxylic acids after oxidation/[1,3]-H shift. The methodology is also useful for the synthesis of enantioenriched β-substituted α-keto-1,5-diesters by using the hydrazone moiety as a masked carbonyl group.     

Copper(I) catalyzed asymmetric 1,2-addition of Grignard reagents to α-methyl substituted α,β-unsaturated ketones

The first catalytic enantioselective 1,2-addition of Grignard reagents to ketones is presented. This additive-free copper(I) catalyzed 1,2-addition provides chiral allylic tertiary alcohols with an er of up to 98:2 and excellent yields due to the complete shift of overwhelming 1,4-selectivity of copper(I)-catalysts towards 1,2-selectivity in the addition reaction to enones.     

N-heterocyclic carbene catalyzed reactions of α-bromo-α,β-unsaturated aldehydes/α,β-dibromoaldehydes with 1,3-dinucleophilic reagents

Carbenes ring true: N-Heterocyclic carbene (NHC) catalyzed reactions of α-bromo-α,β-unsaturated aldehydes/α,β-dibromoaldehydes with 1,3-dinucleophilic reagents, such as 1,3-dicarbonyl compounds, β-enamino ketones, and β-enamino esters through umpolung processes gave functionalized 3,4-dihydropyranones and 3,4-dihydropyridinones. The availability of the starting materials, lack of external oxidant, and usefulness of the products make this strategy attractive.     

Catalytic asymmetric α-alkylation of ketones and aldehydes with N-benzylic sulfonamides through carbon-nitrogen bond cleavage

A range of ketones and aldehydes smoothly undergo asymmetric S(N)1 α-alkylation with N-benzylic sulfonamides in the presence of 10 mol % of a chiral imidazolidinone and trifluoroacetic acid to give the corresponding products in good to excellent yields and with good enantioselectivity. This chemistry has been successfully extended to the asymmetric desymmetrization of 4-substituted cyclohexanones, which exhibits greater than 99:1 diastereoselectivity and good enantioselectivity.     

Organoselenium-mediated reduction of α,β-epoxy ketones to β-hydroxy ketones: A new access to inter- and intramolecular aldols

The organoselenium-mediated reduction of α,β-epoxy ketones has been demonstrated to be a promising entry to a variety of cyclic and acyclic aldols.     

An expedient synthesis of α,α-difluoro-β-hydroxy ketones via decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes

A novel decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes in the absence of any base and metal catalysts has been developed. This reaction provides a highly convenient and efficient method for the synthesis of structurally diverse α,α-difluoro-β-hydroxy ketones in good to excellent yields.     

Lipase-catalyzed kinetic resolution of α,β-unsaturated α′-acetoxy ketones

The lipase-catalyzed kinetic resolutions of the α,β-unsaturated α′-acetoxy ketones 3a,b have been investigated. Of the lipases examined, CAL-B from Candida antarctica (fraction B) has been shown to be an efficient biocatalyst, which may be used effectively in preparative scale reactions.