Synthesis Of Chiral Tertiary Alcohols Research Articles

DFT investigation of Cu(i)-catalyzed addition of 1,4-pentadiene to acetophenone: mechanism and selectivity for the synthesis of a chiral tertiary alcohol with a 1,3-diene unit

DFT calculations show a clear understanding of the reaction mechanism and the origin of selectivity in the chiral phosphoric acid ligand-controlled Cu(i)-catalyzed addition of 1,4-pentadiene to acetophenone.

Biocatalytic hydroxylation tertiary C-H bonds for synthesis of chiral tertiary alcohols by cytochrome P450

In view of the importance and beneficial characteristics of enantioenriched tertiary alcohols in pharmaceutical chemistry, efficient and green strategies for their synthesis are highly sought after. Here, we report a simple synthesis of the elusive chiral tertiary alcohols. A cytochrome P450 monooxygenase called P450PL2 was developed to enable chiral tertiary alcohols by the benzylic CH bonds asymmetric hydroxylation of the racemic tertiary carbon substrates. This P450-catalyzed protocol provides various chiral tertiary alcohols with unexpectedly functional group tolerance and excellent enantioselectivities (up to >99 % ee). The method features mild reaction and employs molecular oxygen as an oxidant, avoids the use of pre-oxygen functionalized substrates. Preliminary molecular dynamics simulation studies were carried out to reveal the possible reasons for the exceptional selective hydroxylation of substrate during P450PL2 catalysis.

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

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12′ together with the previously reported L0 and L0′ define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Copper-Catalyzed Synthesis of Chiral Tertiary Alcohols from 1,3-Dienes and Ketones

Copper-Catalyzed Synthesis of Chiral Tertiary Alcohols from 1,3-Dienes and Ketones

Synthesis of Chiral Tertiary Alcohols by Asymmetric Cyanosilylation

Key words cyanosilylation - chiral tertiary alcohols - chloromethyl(di-methyl)silyl cyanide - ketones

ChemInform Abstract: Synthesis of Chiral Tertiary Alcohols by CuI‐Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones

AbstractReview: [35 refs.

Cover Picture: Synthesis of Chiral Tertiary Alcohols by CuI‐Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones / Emergence of the First Catalytic Oligonucleotides in a Formamide‐Based Origin Scenario / Intermolecular Peptide Cross‐Linking by Using Diaminodicarboxylic Acids / Smart Polymeric Nanoparticles as Emerging Tools for Imaging—The Parallel Evolution of Materials / Transition Metal Nitrides for Electrocatalytic Energy Conversion: Opportunities and Challenges

Cover Picture: Synthesis of Chiral Tertiary Alcohols by Cu^I‐Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones / Emergence of the First Catalytic Oligonucleotides in a Formamide‐Based Origin Scenario / Intermolecular Peptide Cross‐Linking by Using Diaminodicarboxylic Acids / Smart Polymeric Nanoparticles as Emerging Tools for Imaging—The Parallel Evolution of Materials / Transition Metal Nitrides for Electrocatalytic Energy Conversion: Opportunities and Challenges

Synthesis of Chiral Tertiary Alcohols by CuI‐Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones

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.

Enzymatic Synthesis of Tertiary Alcohols

AbstractTertiary alcohols are found as a motif in many pharmaceuticals and natural products. Elucidation of their biosynthesis is thus a good starting point for the identification of enzymes for the synthesis of chiral tertiary alcohols. To date, however, relatively few enzymatic methods for such syntheses have been established in biotechnological processes. Whereas secondary alcohols can be efficiently synthesized via the (asymmetric) reduction of ketones, a generally applicable method for the enzymatic synthesis of tertiary alcohols has been more difficult to identify. Herein, a survey of the biocatalytic methods for the synthesis of (chiral) tertiary alcohols is presented. Advantages and disadvantages of the respective methods are discussed from a synthetic point of view.

Addressing Challenges in the Stereospecific Lithiation-Borylation of Carbamates

The enantioselective synthesis of chiral tertiary alcohols remains a challenge in organic synthesis. The authors have previously developed an approach based on the lithiation of chiral secondary carbamates and their subsequent reaction with organoboron reagents (V. K. Aggarwal and co-workers Nature 2008, 456, 778). In the present report the authors address factors which are important to the enantio­selectivity of the process and provide solutions to overcome the poor selectivity observed with challenging substrates.

Toward the continuous-flow synthesis of chiral tertiary alcohols by enantioselective addition of organozinc reagents to ketones using nanosize isoborneol ligands

The catalytic enantioselective addition of different organozinc reagents, such as alkyl or in situ generated phenylzinc derivatives to simple aryl ketones, was accomplished using titanium tetraisopropoxide and chiral ligands derived from trans-1-arenesulfonylamino-2-isoborneolsulfonylamidocyclohexane and Fréchet-type dendrons with up to 2.5 nm of diameter, giving the corresponding tertiary alcohols with enantioselectivities up to >99%. A simple and efficient procedure for the synthesis of the ligands used is also described, involving the radical addition of the corresponding thiol dendron to the chiral styryl-isoborneol derivative.

Polymer-Support Synthesis of Chiral Tertiary Alcohols

Polymer-Support Synthesis of Chiral Tertiary Alcohols