Catalytic Enantioselective Addition of Organozirconium Reagents to Aldehydes

Abstract

A catalytic enantioselective addition reaction of alkylzirconium species to aromatic aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with Ti(OiPr)4, proceeds under mild and convenient conditions, and no premade organometallic reagents are required since the alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The methodology is compatible with functionalized nucleophiles and a broad range of aromatic aldehydes.

Catalytic Enantioselective Addition of Alkylzirconium Reagents to Aliphatic Aldehydes

“…The in-situ preparation of the alkylzirconium nucleophile allows the synthesis of chiral secondary aliphatic alcohols bearing functional groups that are not compatible with other premade organometallic reagents. This work is an extension of our previous, recently published work [ 67 ], where only aromatic aldehydes were employed as substrates.…”

“…Thus, the addition of organozirconium reagents to aldehydes [ 43 , 44 , 45 , 46 , 47 , 48 , 49 ], ketones [ 50 , 51 ], enones [ 52 , 53 , 54 ], epoxides [ 55 ] and isocyanates [ 56 ] is possible in the presence of Ag(I), ZnBr 2 or Me 2 Zn; although these protocols are rarely enantioselective [ 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. The addition of alkenylzirconocenes to aldehydes and ketones, reported by Wipf [ 45 , 64 , 65 ] and Walsh [ 66 ], respectively; together with our recent work on the addition of alkylzirconium reagents to aromatic aldehydes [ 67 ], are, to the best of our knowledge, the only catalytic asymmetric methodologies for the addition of organozirconium reagents to carbonyl compounds.…”

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

“…However, the aldehyde substrate 75 could also be additionally activated by Lewis acids that were present in the reaction mixture. 98 A different approach for the 1,2-addition of alkylzirconium compounds 4 to aromatic aldimines 77 was reported by our group. 99 This strategy shadowed our long-standing efforts in the field of asymmetric Cu(I/II)-catalyzed addition of organozirconium reagents.…”

“…97 In 2018, Fernández-Ibáñez and Maciá described the first enantioselective addition of alkylzirconium species 4 to aromatic aldehydes 75 in which the catalytic system consisted of Ti(IV)-Ph-BINMOL complex L12 in the presence of ZnBr 2 (Scheme 21, a). 98 The reaction most likely occurs via transmetalation of the organozirconium reagent with the organozinc species. This was followed by a second transmetalation with the organotitanium compound which subsequently coordinates with the chiral ligand to provide enantioenriched products 76.…”

Stereogenic Centers

“…In this regard, Fernández-Ibáñez, Maciá and co-workers describe the use of a chiral complex between 1,1-binaphthalene-2- α -arylmethan-2-ols (Ar-BINMOLs) and Ti(O i Pr) 4 acting as a catalyst for the enantioselective addition of organozirconium reagents, generated in situ, to aldehydes. The corresponding alcohols were obtained in moderate to good yields and high enantioselectivities [ 5 ]. In the other article related to the use of metal catalysts, Huang and Chang reported the use of an iridium-phosphoramidite chiral complex for the direct asymmetric reductive amination of O -protected 3-hydroxyacetophenone as a key step for the total synthesis of ( S )-Rivastigmine, an active drug against Alzheimer’s disease.…”