Asymmetric synthesis of furofurans

Furofurans are one of the largest sub-types of classical lignans which have been found to possess a broad range of important biological activities. Tremendous efforts have been directed to develop synthetic methodologies for the synthesis of furofurans, especially in a stereoselective manner, due to their interesting bioactivities associated with the structural and stereochemical complexity. This article summarizes the reports on asymmetric synthesis of furofurans disclosed during the period of 2004–2017.     

α-Hydroxylation of Carboxylic Acids and Amides Using Bis(Trimethylsilyl)Peroxide

Bis(trimethylsilyl)peroxide is shown to react with enolate anions derived from carboxylic acids and amides to give the corresponding α-hydroxy derivatives.     

Vicinal Dianion of Triethyl Ethanetricarboxylate: Syntheses of (±)‐Lichesterinic Acid, (±)‐Phaseolinic Acid, (±)‐Nephromopsinic Acid, (±)‐Rocellaric Acid,and (±)‐Dihydroprotolichesterinic Acid

The vicinal dianion 2 derived from triethyl ethanetricarboxylate reacted regioselectively with aldehydes and ketones at C(β) to provide paraconic acid derivatives 5a – f in moderate to high yields as mixtures of diastereoisomers. The paraconic acid derivatives 5e and 5f were utilized as the starting materials for the syntheses of (±)‐lichesterinic acid ( 12 ), (±)‐phaseolinic acid ( 13 ), (±)‐nephromopsinic acid ( 14 ), (±)‐rocellaric acid ( 15 ), and (±)‐dihydroprotolichesterinic acid ( 16 ).     

d5-Reactions of Doubly Deprotonated γ,δ-Unsaturated Carbonyl Derivatives with Electrophiles. A Novel Approach to the Synthesis of Tetrahydrofuran and Tetrahydropyran Derivatives

The dienone-dianion derivatives 1 react with all types of electrophiles tested (alkyl halide, silyl chloride, ester, ketone, aldehyde, epoxide) to give β, γ-unsaturated carbonyl compounds of type A (see Formulae 2 – 6 , 13 , 14 and Tables 1–5). The α- and β-hydroxyalkylation products obtained from 1a – 1d can be converted to tetra-hydrofuran and tetrahydropyran derivatives 7 and 16 , respectively (Tables 1 and 2), those from the sulfur analogues 1e and 1f to ketene thioacetals 9 and to dienone derivatives 10 and 12. The t-butyl and α-hydroxy-ketones are cleaved to give nitriles, amides, carboxylic acids and esters (Formulae 16 - 25 ). The reagents 1 allow to synthesize products with distant functional groups in one step (cf. 1,8-diketones 14 and Formulae 26 – 30 ); they correspond to the d⁵-synthons 31 – 33 ; in Table 6, they are compared with other d⁵-reagents.     

α,α-Difluoro-α-phenylsulfanylmethyl carbanion equivalent: a novel gem-difluoromethylenation of carbonyl compounds

α,α-Difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF₂SiMe₃) has been demonstrated as an α,α-difluoro-α-phenylsulfanylmethyl carbanion equivalent. gem-Difluorophenylsulfanylmethylation of carbonyl compounds has been successfully achieved by using PhSCF₂SiMe₃ in the presence of TBAF in THF. The adducts have been converted to the corresponding gem-difluoroalkenes by a novel pyrolytic and/or FVP elimination of the β-hydroxy-α-phenylsufinyl derivatives under reduced pressure.     

A general synthetic route to 1-azabicyclo[m.n.0]alkenes via cyclisation based on alpha-sulfinyl carbanions

The intramolecular nucleophilic addition of alpha-sulfinyl carbanions derived from the corresponding sufinyl lactams afforded 1-azabicyclo[m.n.0]alkenes in good yields.     

Morita-Baylis-Hillman reaction of masked 5-alkylidene-2-cyclopentenones: general entry to 5-alkylidene-2-(hydroxyalkyl)- 2-cyclopentenones

The reaction of masked 5-alkylidene-2-cyclopentenones with aldehydes catalyzed by tributylphosphine in the presence of phenol provided the corresponding Morita-Baylis-Hillman adducts, which were subjected to flash vacuum pyrolysis to afford 5-alkylidene-2-(hydroxyalkyl)-2-cyclopentenones.     

α,α-Difluoro-α-phenylsulfanyl-α-trimethylsilylmethane as a difluoromethyl building block: A general strategy to α,α-difluoromethyl aryl ketones

The synthetic utility of α,α-difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF₂SiMe₃; 1) as a difluoromethyl building block providing a general strategy to α,α-difluoromethyl aryl ketones was demonstrated. Oxidation, by using m-chloroperoxybenzoic acid, of the readily available 1-aryl-2,2-difluoro-2-phenylsulfanyl-1-trimethylsiloxyethanes obtained from fluoride-catalyzed nucleophilic addition of PhSCF₂SiMe₃ with aromatic aldehydes followed by flash vacuum pyrolytic elimination provided α,α-difluoromethyl aryl ketones in moderate overall yields.