Enantioselective Synthesis of α‐Alkylidene‐γ‐Butyrolactones: Intramolecular Rauhut–Currier Reaction Promoted by Acid/Base Organocatalysts

Abstract

Teambildung: Die Titelreaktion bietet diastereoselektiven Zugang zu α‐Alkyliden‐γ‐butyrolactonen mit bis zu 98 % ee (siehe Schema; Ts=4‐Toluolsulfonyl). Der enantioselektive Prozess wird durch den Organokatalysator 1 katalysiert, der sowohl Lewis‐basische als auch Brønsted‐saure Einheiten enthält.

Domino Cyclization Initiated by Cross‐Rauhut–Currier Reactions

“…Recently, in work directed towards the medicinally important α‐alkylidene‐γ‐butyrolactone core, Sasai's group have creatively developed a straightforward and atom‐economic synthetic strategy based on an intramolecular cross‐RC reaction catalysed by bifunctional phosphane 24 (Scheme ) 11c,11d. Aliphatic‐ and aromatic‐substituted starting materials 25 were successfully cyclized to give the α‐alkylidene‐γ‐butyrolactones 26 in good yields (56–99 %) and with high enantioselectivities (70–98 % ee ).…”

Design, Synthesis, and Application of a Chiral Sulfinamide Phosphine Catalyst for the Enantioselective Intramolecular Rauhut–Currier Reaction

“…In our case,with the addition of 50 mol %ofphenol, the catalyst loading could be reduced to 10 mol %a nd the reaction could be completed within 12 hw ithout loss of efficiency and enantiopselectivity.Bycontrast, the phenol has aslightly negative effect on the reactivity in the work of Sasai and co-workers. [7] TheT BDMS-and TBDPS-derived XiaoPhos catalysts (R,R S )-X11 and (R,R S )-X12 delivered high reactivity and enantioselectivity.N otably,( À )-2a could be obtained in 76-90 %y ield and 46-81 % ee in the presence of (S,R S )-X10,( S , R S )-X11,a nd (S,R S )-X12.N ob etter results were obtained after the screening of various solvents and variation of reaction temperature (see Section S3 in the Supporting Information). Based on the results,t he optimal reaction conditions were identified:1 0mol %( R , R S )-X10 as the catalyst, 50 mol %phenol as an additive and CHCl 3 as the reaction medium at 25 8 8C.…”

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Abstract: An ovel class of chiral sulfinamide phosphine catalysts (Xiao-Phos) are reported, which can be easily prepared from inexpensive commercially available starting materials.The Xiao-Phos catalysts showed good performance in enantioselective intramolecular Rauhut-Currier reactions, generating a-methylene-g-butyrolactones in high yields with up to 99 %e eu nder mild conditions.M oreover,k inetic resolution and parallel kinetic resolution were also observed with the use of two different substituted racemic precursors.Over the past decade,a symmetric nucleophilic catalysis with chiral phosphines has emerged as apowerful approach to structurally diverse and synthetically valuable optically active organic building blocks.[1] Among the many types of chiral phosphines,c hiral b-aminephosphines represent one of the most attractive and have been utilized as nucleophilic catalysts [2] or chiral ligands [3] in ab road spectrum of useful organic transformations.Compared to the intensive attention focused on the utility of chiral b-aminephosphines in organic synthesis,only ahandful of methods have been reported so far for their synthesis.A mong these,t he approach from readily available natural or unnatural chiral amino acids is the most attractive.[4] Despite the fact that much progress has been made in the construction of chiral phosphine catalysts,t he development/design of highly efficient new types of chiral phosphines,e specially from inexpensive,c ommercially available chiral resources,r emains ac onsiderable challenge.Recently,o ur group developed an ew type of chiral sulfinamide phosphine (Ming-Phos ligands), which could be easily prepared in good yields from inexpensive commercially available chiral tert-butylsulfinamide in two steps.G ratifyingly,M ing-Phos ligands have shown good performance in asymmetric transition-metal catalysis and the sulfinamide plays asecond role in stereoselectivity control.[5] With aseries of chiral Ming-Phos ligands in hand and as ap art of our program for developing chiral-phosphine-catalyzed enantioselctive transformations, [6] we wished to expand the applications of Ming-Phos variants from transition-metal catalysis to nucleophilic phosphine catalysis.I nt his context, recent elegant work by Sasai and co-workers [7] attracted our attention. They successfully accomplished ac hiral-phosphine-catalyzed enantioselective intramolecular RauhutCurrier (RC) reaction, [8] efficiently furnishing synthetically valuable a-methylene-g-butyrolactones.

[9] However, the performance of the Ming-Phos variants was disappointing;i n most cases,the reaction did not give high conversions because of the low nucleophilic catalyst activity.W et hen envisaged that anew type of chiral sulfinamide phosphines,called XiaoPhos,should have better nucleophilic activity than the MingPhos variants.With two stereocenters,anH-bonding site,and tunable side chains,the Xiao-Phos series may be applicable to asymmetric nucleophilic catalysis for organic transformations such as RC reactions (Figure 1).

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Theoretical study on the reaction mechanisms and stereoselectivities of DABCO‐catalyzed Rauhut–Currier/cyclization reaction of methyl acrylate with 2‐benzoyl‐3‐phenyl‐acrylonitrile

“…The cross coupling versions of the RC reaction have also been documented . In recent years, the RC reaction has been developed for synthetic applications to make new molecules for natural product and organic synthesis …”