Catalytic Enantioselective Hosomi–Sakurai Conjugate Allylation of Cyclic Unsaturated Ketoesters

Abstract

Despite impressive advances over the years, [1] there are still important transformations that lack catalytic asymmetric variants. While Lewis acid catalyzed additions of allylsilanes to carbonyl compounds [2] and acetals [3] have been well studied using catalytic, [4] as well as auxiliary-based methods to control absolute configuration, [5] to the best of our knowledge, there are no effective methods for catalyzing the asymmetric 1,4-addition of allyltrimethylsilane to unsaturated carbonyl compounds. [6] In that regard, we report herein a catalytic enantioselective conjugate addition of allyltrimethylsilane to various activated cyclic enones with selectivities surpassing 98 % ee. The 1,4-addition of the air-and moisture-stable nucleophile to unsaturated carbonyl compounds proceeds to > 95 % conversion in the presence of Cu(OTf) 2 (10 mol %) with the commercially available di(tert-butyl)bis(oxazoline) (box) ligand (2). [7] We show how these products can be functionalized to a variety of useful enantiomerically enriched systems.Our initial studies into the development of a chiral Lewis acid catalyst indicated that simple cyclic and acyclic a,bunsaturated carbonyls (ketones and esters) did not react with a variety of metal-ligand combinations.[8] We therefore sought to activate the substrate by installation of a second electron-withdrawing/chelating group at the a-position of the enone (i.e., 1). In the presence of Cu(OTf) 2 (7 mol %) and bis(oxazoline) ligand 2 (8 mol %) in Cl(CH 2 ) 2 Cl, we obtained the desired 1,4-allyl-addition product 3 in > 95 % conversion (after 30 min at 0 8C) and 72 % ee as a mixture of keto-enol tautomers (Scheme 1). Alternative solvents (CH 2 Cl 2 , Et 2 O, toluene, EtOAc, etc.) and metal salts, including other copper salts, resulted in lower selectivities.[9] Other chiral ligands (e.g., peptide-based, [10] salen, [11] Trost ligand [12] ) led to high conversion (> 95 %), but with low selectivity (< 5 % ee).To identify a more effective catalyst, we prepared and screened approximately 40 mono-and bis(oxazoline) ligands.

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

“…[21] Firstly,avariety of metal salts combined with L 3 -PiPr 2 were tested in DCM at 35 8 8C (entries [1][2][3][4][5]. Encouraged by these results,various chiral N,N'-dioxide ligands coordinated with Ni(OTf) 2 were evaluated (entries [5][6][7][8][9][10]. Encouraged by these results,various chiral N,N'-dioxide ligands coordinated with Ni(OTf) 2 were evaluated (entries [5][6][7][8][9][10].…”

“…It was found that many typical Lewis acids, except Cu(OTf) 2 ,c ould promote the reaction, among which Ni(OTf) 2 provided promising results,g iving the formal 1,4allylation product g-allyl-a-ketoester 4aa in 48 %y ield with 71 % ee (entry 5). [22] Since L 3 -RaPr 2 was superior in terms of enantioselectivity,t he efficiencies of other N,N'-dioxide ligands derived from l-ramipril were evaluated (entries [8][9][10]. Compared with L 3 -PiPr 2 ,d erived from S-pipecolinic acid, l-proline-derived L 3 -PrPr 2 and l-ramiprilbased L 3 -RaPr 2 displayed higher activities,y ielding the desired products with 85 and 86 %yields,respectively (entry 5 vs.entries 6and 7).…”

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

“…It was found that many typical Lewis acids, except Cu(OTf) 2 ,c ould promote the reaction, among which Ni(OTf) 2 provided promising results,g iving the formal 1,4allylation product g-allyl-a-ketoester 4aa in 48 %y ield with 71 % ee (entry 5). Encouraged by these results,various chiral N,N'-dioxide ligands coordinated with Ni(OTf) 2 were evaluated (entries [5][6][7][8][9][10]. Compared with L 3 -PiPr 2 ,d erived from S-pipecolinic acid, l-proline-derived L 3 -PrPr 2 and l-ramiprilbased L 3 -RaPr 2 displayed higher activities,y ielding the desired products with 85 and 86 %yields,respectively (entry 5 vs.entries 6and 7).…”

“…In this context, Snapper and co-workers developed copper(II)-catalyzed enantioselective Hosomi-Sakurai conjugate silylallylation of cyclic unsaturated ketoesters (Scheme 1a). [9] Our group reported catalytic asymmetric conjugate allylation of coumarins with tetraallyltin. [10] However,o nly simple allyl reagents,w ithout substituents,were investigated in these cases.…”

Concise Total Synthesis of Albaflavenone Utilizing Sequential Intramolecular Aldol Condensation: Determination of Absolute Configuration

“…In summary, we have achieved the first total synthesis of tricyclic sesquiterpene albaflavenone 1 in racemic form in 9 steps from 2-cyclopenten-1-one (9). The overall yield was 15% from 2-cyclopenten-1-one (9) (84% average yield per step).…”