Synthesis of Chiral Tertiary Alcohols by Cu^I‐Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones

Abstract

Catalytic enantioselective addition of organometallic nucleophiles to ketones is among the most straightforward approaches to the synthesis of chiral tertiary alcohols. The first such catalytic methodologies using the highly reactive organomagnesium reagents, which are the preferred organometallic reagents in terms of cost, availability, atom efficiency, and structural diversity, were developed only during the last five years. This Concept article highlights the fundamental breakthrough that made the development of methodologies for highly enantioselective Cu(I) -catalyzed alkylation of ketones using organomagnesium reagents possible.

Preparation and Reactivity of Acyclic Chiral Allylzinc Species by a Zinc‐Brook Rearrangement

“…[16] We used this strategy to prepare various substrates (1)i ne xcellent yields and enantiomeric ratios and the absolute configurations of 1 were determined by transforming 1a (R 1 = R 2 = Me,R 3 = Et), by aR iley-type oxidation using SeO 2 and tBuOOH, into crystalline oxaselenolane 2-oxide, [17] which was characterized by X-ray crystallography (see the Supporting Information). [16] We used this strategy to prepare various substrates (1)i ne xcellent yields and enantiomeric ratios and the absolute configurations of 1 were determined by transforming 1a (R 1 = R 2 = Me,R 3 = Et), by aR iley-type oxidation using SeO 2 and tBuOOH, into crystalline oxaselenolane 2-oxide, [17] which was characterized by X-ray crystallography (see the Supporting Information).…”

“…Zuschriften hydroxy allylsilanes (1)b yt he enantioselective coppercatalyzed Grignard addition to acylsilanes in good yields and high enantiomeric ratios. [16] We used this strategy to prepare various substrates (1)i ne xcellent yields and enantiomeric ratios and the absolute configurations of 1 were determined by transforming 1a (R 1 = R 2 = Me,R 3 = Et), by aR iley-type oxidation using SeO 2 and tBuOOH, into crystalline oxaselenolane 2-oxide, [17] which was characterized by X-ray crystallography (see the Supporting Information). [18] Having aw ell-established procedure in hand for the preparation of 1 through asymmetric catalysis,wethen investigated the critical step,n amely the allyl Zn-Brook rearrangement and subsequent reaction with electrophiles.…”

Catalytic Synthesis of Enantiopure Chiral Alcohols via Addition of Grignard Reagents to Carbonyl Compounds

“…Another step forward has been made by the groups of Harutyunyan and Minnaard, who proved Cu(I)-based chiral catalysts to be successful for the direct use of Grignard reagents (without additives) as nucleophiles in the catalytic asymmetric alkylations of ketones. 11 This Perspective outlines efforts towards the synthesis of enantiopure chiral alcohols via the addition of Grignard reagents to aldehydes and ketones. Approaches using (super)stoichiometric amounts of chiral additives or ligands as well as recently developed titanium and copper(I)-catalyzed enantioselective additions will be highlighted.…”

Method for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents as Alkyl Sources

“…Accordingly, an asymmetric version of the Grignard reaction that enables the enantioselective preparation of chiral secondary and tertiary alcohols has been of considerable interest for a long time. , However, the use of Grignard reagents in catalytic enantioselective addition is difficult because to their high activity that concurrently induces noncatalytic racemic reaction. Recently, Harutyunyan and Minnaard have shown for the first time that the enantioselective addition of alkyl Grignard reagents to ketones can be realized by chiral Cu­(I) catalysts. − Despite such advancement, the enantioselective addition to the significantly more reactive aldehydes remains a challenging problem.…”