Organocatalytic Enantioselective Synthesis of α-Hydroxyketones through a Friedel–Crafts Reaction of Naphthols and Activated Phenols with Aryl- and Alkylglyoxal Hydrates

Abstract

An efficient organocatalytic asymmetric synthesis of α-hydroxyketones has been developed. Quinine-derived thiourea catalyzed the enantioselective Friedel-Crafts alkylation of naphthols and activated phenols with aryl- and alkylglyoxal hydrates, providing the corresponding chiral α-hydroxyketones with high yields (up to 97%) and excellent enantioselectivities (up to 99% ee).

Base‐Free Asymmetric Transfer Hydrogenation of 1,2‐Di‐ and Monoketones Catalyzed by a (NH)2P2‐Macrocyclic Iron(II) Hydride

“…[5] Enantiomerically pure acyloins are frequent structural subunits in natural products [6] and bioactive molecules, [7] and act as chiral templates and building blocks [8] thanks to the combination of the highly directing hydroxy group with the easily functionalized prostereogenic carbonyl. [9] Their synthesis has been accomplished by an umber of chemical and biocatalytic [7] methods such as the stoichiometric [10] and catalytic [11] oxidation of enolates or enol ethers,a lkene ketohydroxylation, [9] oxidative kinetic resolution, [12] dynamic kinetic resolution, [13] monooxidation of 1,2-diols, [14] benzoin condensation, [15] Friedel-Crafts reactions, [16] enzymatic reductions, [17] and asymmetric hydrosilylation with chiral frustrated Lewis pairs. [18] Enantiopure propargylic alcohols can be converted to O-acylated a-hydroxyketones without racemization/epimerization.…”

“…[2] However,t he base additives that are required to activate the precatalyst [3] tend to limit the reaction scope.A ne minent example are ahydroxy ketones,f or example,b enzoin (A)o r, more generically,a cyloins (Figure 1), whose base-labile stereocenter easily racemizes upon heating or in basic media, [4] making the asymmetric hemihydrogenation of 1,2-diketones aformidable challenge. [9] Their synthesis has been accomplished by an umber of chemical and biocatalytic [7] methods such as the stoichiometric [10] and catalytic [11] oxidation of enolates or enol ethers,a lkene ketohydroxylation, [9] oxidative kinetic resolution, [12] dynamic kinetic resolution, [13] monooxidation of 1,2-diols, [14] benzoin condensation, [15] Friedel-Crafts reactions, [16] enzymatic reductions, [17] and asymmetric hydrosilylation with chiral frustrated [9] Their synthesis has been accomplished by an umber of chemical and biocatalytic [7] methods such as the stoichiometric [10] and catalytic [11] oxidation of enolates or enol ethers,a lkene ketohydroxylation, [9] oxidative kinetic resolution, [12] dynamic kinetic resolution, [13] monooxidation of 1,2-diols, [14] benzoin condensation, [15] Friedel-Crafts reactions, [16] enzymatic reductions, [17] and asymmetric hydrosilylation with chiral frustrated…”

Organocatalyzed Asymmetric Friedel‐Crafts Reactions: An Update

“…An organocatalytic enantioselective construction of α‐hydroxyketone derivatives was achieved in 2016 by Vila and co‐workers . Quinine‐obtained thiourea mediated the AF‐CA of naphthols and activated phenol derivatives along with aryl‐ and alkylglyoxal hydrates, giving the desired chiral α‐hydroxyketone derivatives with excellent yields and high ee s. Based on the optimal reaction condition, the generality of the reaction has been tested with respect to 1‐naphthols 121 and arylglyoxal hydrates 161 .…”

“…Groups at the para position, for example Me, F, Cl, Br, and NO 2 , have been well‐endured, affording desired α‐hydroxyketone derivatives 162 with 86–99 % enantioselectivity. Although, the existence of a OMe substituent at the para position had a detrimental influence on reactivity and enantioselectivity (53 % yield, 78 % ee ) (Scheme ) …”

“…Sesamol reacted easily with 162 a to afford the desired α‐hydroxyketone 164 a with 96 % enantioselectivity and 92 % chemical yield. 3,4‐Dimethoxyphenol 155 b and 3‐methoxyphenol 155 c with only one electron‐donating substituent, afforded desired chiral products 164 b,c in a reduced yield (Scheme ) …”