Streamlined Catalytic Enantioselective Synthesis of α-Substituted β,γ-Unsaturated Ketones and Either of the Corresponding Tertiary Homoallylic Alcohol Diastereomers

Abstract

A widely applicable, practical, and scalable strategy for efficient and enantioselective synthesis of β,γ-unsaturated ketones that contain an α-stereogenic center is disclosed. Accordingly, aryl, heteroaryl, alkynyl, alkenyl, allyl, or alkyl ketones that contain an α-stereogenic carbon with an alkyl, an aryl, a benzyloxy, or a siloxy moiety can be generated from readily available starting materials and by the use of commercially available chiral ligands in 52-96% yield and 93:7 to >99:1 enantiomeric ratio. To develop the new method, conditions were identified so that high enantioselectivity would be attained and the resulting α-substituted NH-ketimines, wherein there is strong C═N → B(pin) coordination, would not epimerize before conversion to the derived ketone by hydrolysis. It is demonstrated that the ketone products can be converted to an assortment of homoallylic tertiary alcohols in 70-96% yield and 92:8 to >98:2 dr-in either diastereomeric form-by reactions with alkyl-, aryl-, heteroaryl-, allyl-, vinyl-, alkynyl-, or propargyl-metal reagents. The utility of the approach is highlighted through transformations that furnish other desirable derivatives and a concise synthesis route affording more than a gram of a major fragment of anti-HIV agents rubriflordilactones A and B and a specific stereoisomeric analogue.

Scheme 1.

Bioactive Compounds Containing α-Substituted Ketones or Tertiary Alcohol Derivatives

Scheme 2.

The Initial Plan and Related Formerly Published Work

Scheme 3.

A Revised and More Flexible Strategy That Involves Nitriles as Substrates

Scheme 4.. Enantiomerically Enriched Ketones Bearing an α-Substituted C-Based Tertiary Stereogenic Center^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). ^b22 °C, 20 min. ^c2.2 mol % ligand (ent-phos-1 for 4k), 2.0 mol % CuMes, 1.2 equiv. nitrile, 8 h. ^dFor 16 h, −25 °C. ^eFor 36 h, −40 °C. See the Supporting Information for details.

Scheme 5.. Enantiomerically Enriched Ketones Bearing an α-Quaternary Carbon Stereogenic Center^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 6.. Enantiomerically Enriched Ketones Bearing an α-Substituted O-Based Tertiary Stereogenic Center^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 7.. X-ray Structures Show Minimal Carbonyl Oxygen to Boron Coordination^a

^aSee the Supporting Information for details.

Scheme 8.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of an Alkyl Group^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 9.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of an Aryl Moiety^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 10.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of an Allyl Group^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 11.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of a Vinyl, an Alkynyl, or a Propargyl Group^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 12.. Representative Modifications of α-Substituted Ketones and Tertiary Homoallylic Alcohol Products^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 13.. Enantio- and Diastereoselective Gram Scale Synthesis of a Fragment of Rubriflordilactones A and B^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to isolated and purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.

Scheme 14.. Enantio- and Diastereoselective Synthesis of a Fragment of epi-5-Rubriflordilactones A and B^a

^aReactions were performed under N₂ atm. Conversion (nitrile disappearance; >98% in all cases) was determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields correspond to isolated and purified products (±5%). Enantioselectivities were determined by HPLC analysis (±1%). See the Supporting Information for details.