Stereoselective Conjugate Addition Reactions Using In Situ Metallated Terminal Alkynes and the Development of Novel Chiral P,N-Ligands

Abstract

In this account, new methods for the catalytic and stereoselective conjugate addition of terminal alkynes are described. Our laboratories have disclosed asymmetric addition reactions to aldehydes and imines using a combination of a zinc or copper salt and a terminal alkyne. Under these conditions, terminal alkyne is transformed in situ into an alkynyl metal species. Recently, it was found that these in situ generated alkynyl metal species can undergo conjugate additions to alkylidene malonate-type acceptors. In the zinc(II) triflate-catalyzed system, a highly diastereoselective conjugate addition has been realized using a chiral oxazepene acceptor. Subsequently, alternative conjugate addition protocols have been developed which employ a terminal alkyne, substoichiometric amounts of copper and a highly eletrophilic Meldrum's acid derived acceptor. This reaction can be made enantioselective using a novel atropisomeric P,Nligand (PINAP). With this ligand, excellent enantioselectivities can be achieved for the conjugate addition of aromatic alkynes to various Meldrum's acid derived acceptors.

Cu‐ and Ni‐Catalyzed Conjugated Additions of Organozincs and Organoaluminums to α,β‐Unsaturated Carbonyl Compounds

“…Among phosphine-based ligands, phosphaferrocene-oxazoline ligands L28 [95] may also be included, with the asymmetric induction in the Cu(OTf ) 2 -catalyzed addition of Et 2 Zn to various chalcones at up to 91% ee in the presence of L28a. It should be also noted that Carreira et al [10] have utilized chiral phosphines as a ligand for the Cu-catalyzed enantioselective addition of terminal alkynes to Meldrum's acid derivatives.…”

Cooperative Activation of Alkyne and Thioamide Functionalities; Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to α,β‐Unsaturated Thioamides

“…In this study, we envisioned simultaneous activation of both reaction partners by using the soft Lewis acid/hard Brønsted base cooperative catalyst, which can be represented by a catalytic asymmetric conjugate addition of soft Lewis basic a,b-unsaturated thioamides as the Abstract: A detailed study of the direct catalytic asymmetric conjugate addition of terminal alkynes to a,b-unsaturated thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst, comprising [CuA C H T U N G T R E N N U N G (CH 3 CN) 4 ]PF 6 , bisphosphine ligand, and Li(OC 6 H 4 -p-OMe) simultaneously activated both substrates to compensate for the low reactivity of copper alkynylide. A series of control experiments revealed that the intermediate copper-thioamide enolate functioned as a Brønsted base to generate copper alkynylide from the terminal alkyne, thus driving the catalytic cycle through an efficient proton transfer between substrates.…”

Asymmetric Conjugate Alkynylation of Cyclic α,β‐Unsaturated Carbonyl Compounds with a Chiral Diene Rhodium Catalyst

“…[1] While an umber of efficient reaction systems have been reported on the asymmetric conjugate addition of sp 3 -a nd sp 2 -carbon nucleophiles by use of chiral metal catalysts and organocatalysts, [2] thed evelopment has been slow on the asymmetric introduction of sp-carbon atoms (alkynyl groups). [1] While an umber of efficient reaction systems have been reported on the asymmetric conjugate addition of sp 3 -a nd sp 2 -carbon nucleophiles by use of chiral metal catalysts and organocatalysts, [2] thed evelopment has been slow on the asymmetric introduction of sp-carbon atoms (alkynyl groups).…”

“…Asymmetric conjugate alkynylation of a,b-unsaturated carbonyl compounds is one of the most efficient methods of producing alkynes bearing stereogenic carbon centers at the propargyl position. [1] While an umber of efficient reaction systems have been reported on the asymmetric conjugate addition of sp 3 -a nd sp 2 -carbon nucleophiles by use of chiral metal catalysts and organocatalysts, [2] thed evelopment has been slow on the asymmetric introduction of sp-carbon atoms (alkynyl groups). Thecatalytic asymmetric conjugate alkynylation has been reported with nickel, [3] copper, [4] rhodium, [5][6][7][8] and other metal [9] complexes as catalysts.A lthough high yields and high enantioselectivities have been reported for some of acyclic a,b-unsaturated carbonyl compounds,t here have been only af ew reports on successful asymmetric alkynylation of cyclic substrates,t ypically 2-cyclohexenone and 2-cyclopentenone.O ne of them is the nickel-catalyzed addition of alkynylaluminum reagents reported by Corey and co-workers,w herein 3-alkynylcyclohexanones were obtained with 85-90 % ee.…”