Synthesis Of Multisubstituted Chiral β-Lactams With Asymmetric Interrupted Kinugasa Reaction

In 1972,Kinugasa and Hashimoto reported the coupling of copper(I)phenylacetylides and nitrones to synthesize β-lactams,a facile method to produce cis-β-lactams in pyridine.In 1993,the first catalytic Kinugasa reaction of terminal alkynes and nitrones was described by Miura and co-workers.At the start of this century,the asymmetric catalytic Kinugasa reaction was realized by the Fu group and others,and provides a diastereo-and enantioselective synthesis of β-lactams from two readily available starting materials efficiently.Among numerous approaches,the Kinugasa reaction has been the most straight forward and atom-economic one to rapidly assemble chiral β-lactams.Despite significant advances made by researchers,the asymmetric catalytic Kinugasa reaction has not been widely investigated.However,the normal Kinugasa reactions can only produce a 3,4-cis-disubstituted product and the aryl substrates are more favorable than other functional groups.A domino sequences in a one-pot reaction involving Kinugasa reaction and subsequent functionalization,provide the synthesis strategy towards diverse functional β-lactams.Thus,we have developed an interrupted Kinugasa reaction in this thesis,with some approptiate electrophiles introduced to intercept the enolate copper(Ⅰ)intermediate,forming some multisubstituted chiral β-lactams.There are several challenges involving chemo-,regio-,diastereo-,and enantioselectivity that need to be addressed.The thesis includes four parts:The first part,a copper(Ⅰ)-catalyzed asymmetric interrupted Kinugasa reaction to construct α-thiofunctional chiral β-lactams is described.This reaction developed a novel side-arm bis-oxazoline ligand(HM-BOX)bearing six methoxyl groups at the 3,4,5-positions of the pendant aromatic rings,combined with copper(Ⅰ)as the catalytic system.The asymmetric alkynes-nitrones cycloaddition and subsequent rearrangement generated the key copper(Ⅰ)enolate intermediate,and various sulfur electrophiles were introduced to intercept the intermediates to produce diverse α-thiofunctional multisubstituted β-lactams with excellent diastereo-and enantioselectivity and in good yields.The new thiofunctional chiralβ-lactams could be useful for the discovery of new antibiotics in medicinal chemistry.The second part,an asymmetric interrupted Kinugasa allylic alkylation(IKAA)reaction has been established with a synergistic Cu/Pd-catalyzed multicomponent reaction system to synthesize α-quaternary chiral β-lactams.An achiral phosphine ligand DPEPHOS coordinated with palladium catalyst reacted with an allylic electrophile forming an allylic palladium intermediate,and meanwhile a chiral bis-oxazoline ligand HM-BOX coordinated with copper generated the chiral four-membered enolate intermediate from alkyne and nitrone.Stereoselective coupling of two catalytic amounts of transient organometallic intermediates formed in situ,produced the target α-quaternary chiral β-lactams and provided new concepts for the development of some challenging asymmetric transformations.The third part,we have developed a synergistic Cu/Ir-catalyzed asymmetric IKAA reaction for stereodivergent synthesis of α-branched allylation β-lactams.A range of unsaturated chiral β-lactams containing three vicinal stereocenters were produced and controlled by using a chiral copper complex derived from bis-oxazoline ligand and a chiral iridium complex derived from phosphoramidite.The pairwise combination of chiral metal catalysts allows for control over the absolute and relative configuration,and synthesizes four of the eight possible stereoisomers from the same starting materials under identical reaction conditions,with excellent enantioselectivity(up to>99%ee).The fourth part,a gold-catalyzed cascade reaction of alkynyl alcohols and alkynyl enones to access polysubstituted spiro cyclopenta[c]furans has been realized.With the independently activation of two substrates by a single gold catalyst,alkynyl alcohol generated electron-rich vinyl ether intermediate and alkynyl enone formed a furanyl gold cation intermediate,simultaneously.The cyclization of two reactive intermediates afforded multisubstituted furans in excellent yields with good diastereoselectivities.The practical method constructed three rings in one pot from simple acyclic starting materials.In summary,we have developed an interrupted Kinugasa reaction.The enolate copper(Ⅰ)intermediate can be intercepted by sulfur electrophiles through electrophilic attack directly,or by allylic metal intermediate through synergistic bimetallic catalysis strategy.The well-programmed reaction sequence can cascade more functional reaction and offer a variety of multisubstituted chiral β-lactams.