Important Pharmaceuticals and Intermediates

Harnessing the Power of the Asymmetric Grignard Synthesis of Tertiary Alcohols: Ligand Development and Improved Scope Exemplified by One-Step Gossonorol Synthesis

“…Tertiary alcohols and their derivatives are among the most important structural motifs in both natural and synthetic bioactive organic compounds, and numerous enantioselective syntheses have been reported. However, often the most highly selective of these are indirect and therefore inherently inefficient .…”

From oximes to tertiary alcohols in water, at room temperature and under air: a hybrid one-pot tandem assembly of enzymatic deoximation and RLi/RMgX reagents

“…The following features of our hybrid one-pot tandem protocol are noteworthy: (i) an aqueous medium is used as the solvent for the combination of both biocatalysed and main-group-promoted organic transformations; (ii) the global one-pot tandem protocol proceeds at room temperature and under aerobic conditions; (iii) no isolation of any reaction intermediate (ketones in this case) is needed, thus reducing the chemical waste and energy/time costs; and (iv) it is an effective and chemoselective methodology for the synthesis of highly-substituted tertiary alcohols (conversions up to 91%), which are often considered components of active pharmaceutical ingredients (APIs), natural products, agrochemicals and synthetic materials. 20 This new methodology overcomes the aforementioned drawbacks of our previous chemoenzymatic methodology based on the catalytic oxidation of secondary alcohols by the laccase/TEMPO system followed by the addition of organolithium reagents to the in situ formed ketones, 8 b as: (i) it tolerates a large variety of starting oximes; (ii) better isolated yields (up to 82%) have been obtained for tertiary alcohols; and (iii) for the first time, Grignard reagents have been successfully employed, thereby expanding the scope of main-group reagents which can be amalgamated with enzymes.…”

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols

“… 3 Among the variety of applications offered by organomagnesium species, 4 the asymmetric 1,2-addition of Grignard reagents to prochiral ketones has emerged as a powerful strategy providing access to non-racemic tertiary alcohols, 5 widespread structural motifs and valuable synthetic intermediates for the preparation of complex chiral scaffolds, bioactive targets and APIs. 6 Owing to the synthetic flexibility of the 3-disconnection approach, the Grignard synthesis enables the straightforward and modular construction of molecular complexity from simple and cheap substrates ( Scheme 1 ). However, the 1,2-addition of organomagnesium nucleophiles to ketones entails substantial challenges, due to the reduced reactivity of ketones and the presence of competing enolization pathways, 7 which have posed a major limit to the development of effective synthetic methods to date.…”