Gold-catalysed asymmetric net addition of unactivated propargylic C–H bonds to tethered aldehydes

Abstract

The asymmetric one-step net addition of unactivated propargylic C-H bond to aldehyde leads to an atom-economic construction of versatile chiral propargylic alcohols but has not been realized previously. Here we show its implementation in an intramolecular manner under mild reaction conditions. Via cooperative gold catalysis enabled by a chiral bifunctional phosphine ligand, this chemistry achieves asymmetric catalytic deprotonation of propargylic C-H (pK a > 30) by a tertiary amine group (pK a ~ 10) of the ligand in the presence of much more acidic aldehydic α-hydrogens (pKa ~ 17). The reaction exhibits a broad scope and readily accommodates various functional groups. The 5-/6-membered ring fused homopropargylic alcohol products are formed with excellent enantiomeric excesses and high trans- selectivities with or without a preexisting substrate chiral center. DFT studies of the reaction support the conceived reaction mechanism and the calculated energetics corroborate the observed stereoselectivity and confirm an additional metal-ligand cooperation.

Enantioselective C−H Functionalization Reactions under Gold Catalysis

“…However, to expand the horizon of such processes, the development of new designer ligands, such as PC-Phos, [129] TY-Phos, [140] TADDOL based ligands [133,[135][136][137][138] bearing cationic imidazolium unit or phosphoramidite moiety, helically chiral phosphines like HelPhos-V, [145] etc ., has recently started gaining pace. Moreover, the use of chiral bifunctional ligands [115] was observed to afford better regio-and stereo-control in such reactions. In addition, several innovative strategies are being adopted to overcome the need of bulky ligands.…”

“…Very recently, Qian, Zhang and co‐workers developed gold(I)‐catalyzed intramolecular addition of unactivated propargylic C−H bonds to aldehydes, thus providing access to the enantioenriched homopropargylic alcohols (Scheme 4). [115] Treatment of alkyne‐tethered aldehydes 4 a with bifunctional phosphine ligated cationic gold(I) complex L2 (AuCl) and NaBARF afforded five or six‐membered ring‐fused trans ‐homopropargylic alcohols 4 b in 34–87 % yields and up to >99 % ee. Initial study carried by the authors suggests that the destabilizing gauche interaction between the cyclohexyl and N−Me group in tetrahydroisoquinoline moiety of ( R )‐ L1 ligand hampers the yield of the reaction (55 %).…”

New‐Generation Ligand Design for the Gold‐Catalyzed Asymmetric Activation of Alkynes

“…Very recently, the same group reported the asymmetric intramolecular net addition of propargylic C−H bonds to aliphatic aldehydes 16 for the formation of synthetically useful 5‐ and 6‐membered‐fused homopropargylic alcohols 17 . [35] Remarkably, cooperative activation of the triple bond allowed for the preferential deprotonation of the propargylic C−H bond (p K a >30) by the remotely positioned basic unit (p K a ∼10) in the presence of much more acidic aldehyde α‐hydrogens (p K a ∼17) (Scheme 5 ).…”

Asymmetric Construction of α,γ-Disubstituted α,β-Butenolides Directly from Allylic Ynoates Using a Chiral Bifunctional Phosphine Ligand Enables Cooperative Au Catalysis

“…We recently reported a gold-catalyzed efficient synthesis of racemic α-allyl-α,β-butenolides via the cyclo-isomerization of allylic alkynoates (Scheme ). The achiral tert -amino-functionalized ligand L1 is essential in the cooperative gold catalysis. − As shown in Scheme , mechanistically the reaction initially undergoes catalyst-enabled isomerization of alkyne to allene, which is followed by gold-catalyzed cyclization and aromatization to generate the key 2-allyloxyfuran intermediate F . This intermediate then undergoes spontaneous Claisen rearrangement to generate the β,γ-butenolide G , which finally undergoes a gold-catalyzed double bond isomerization to afford the α-allyl-α,β-butenolide product.…”