Enantioselective Synthesis of Highly Functionalized Dihydrofurans through Copper‐Catalyzed Asymmetric Formal [3+2] Cycloaddition of β‐Ketoesters with Propargylic Esters

Abstract

An enantioselective synthesis of highly functionalized dihydrofurans through a copper-catalyzed asymmetric [3+2] cycloaddition of β-ketoesters with propargylic esters has been developed. With a combination of Cu(OTf)2 and a chiral tridentate P,N,N ligand as the catalyst, a variety of 2,3-dihydrofurans bearing an exocyclic double bond at the 2 position were obtained in good chemical yields and with good to high enantioselectivities. The exocyclic double bond can be hydrogenated in a highly diastereoselective fashion to give unusual cis-2,3-dihydrofuran derivatives, thus further enhancing the scope of this transformation.

Scope and advances in the catalytic propargylic substitution reaction

“…Hu and co-workers in the year 2014 utilized their newly designed tridentate P,N,N ligand in conjunction with Cu(OTf) 2 catalyst for the enantioselective synthesis of highly functionalized dihydrofurans 141 by a [3 + 2] cycloaddition of bketoesters 140 with propargylic ester 123, Scheme 60. 88 Through ligand and copper salts screening identied chiral tridentate P,N,N ligand and Cu(OTf) 2 as the best combination, furnishing the product in 90% yield with 95% ee. No reaction occurred in the absence of a base and interestingly poor regioselectivity was observed when i Pr 2 NEt was used in place of Et 3 N.…”

Enantioselective Tandem Cyclization of Alkyne‐Tethered Indoles Using Cooperative Silver(I)/Chiral Phosphoric Acid Catalysis

“…[6] Some of these reactions were rendered enantioselective by using other carbophilic catalysts, such as iridium, [7] platinum, [5c,8] palladium, [9] and copper. [10] However, these strategies can only be applied to a limited number of transformations. Alternative approaches for highly enantioselective synthesis of complex carbo- and heterocyclic compounds are still in high demand.…”

Desilylation‐Activated Propargylic Transformation: Enantioselective Copper‐Catalyzed [3+2] Cycloaddition of Propargylic Esters with β‐Naphthol or Phenol Derivatives

“…Catalytic asymmetric propargylic transformations of terminal propargylic compounds with nucleophiles, transformations featuring metal allenylidene complexes as the key intermediates, have attracted much attention because of its high potential in the enantioselective formation of C−C and C–heteroatom bonds . Very recently, we disclosed the first copper‐catalyzed asymmetric formal [3+2] cycloaddition of propargylic esters as C 2 synthons with C,O‐bis(nucleophile)s, β‐ketoesters, by a sequential propargylic alkylation/intramolecular hydroalkoxylation process . However, the use of other bis(nucleophile)s for this cycloaddition remains unexplored .…”

“…Compared with the terminal alkyne 1 , as shown in Table , the target cycloaddition with 2 a in the presence of ( S )‐ L1 a proceeded smoothly, and exclusively gave the cycloadduct 4 aa in nearly quantitative yield and with a significantly improved enantioselectivity of 76 % ee (entry 4). The sterically hindered ( S )‐ L1 a , recently developed by us, has been demonstrated to be highly efficient in many copper‐catalyzed asymmetric propargylic transformations –,–. 3‐Triethylsilyl‐propargylic acetate ( 2 a′ ) also performed well (entry 5), however, 2 a′′ , bearing a tert ‐butyldimethylsilyl group, inhibited the cycloaddition, presumably because of the steric hindrance (entry 6).…”