Tertiary Homoallylic Alcohols Research Articles

Organic Dye Photocatalyzed Synthesis of Functionalized Lactones and Lactams via a Cyclization-Alkynylation Cascade.

An organic dye photocatalyzed lactonization-alkynylation of easily accessible homoallylic cesium oxalates using ethynylbenziodoxolone (EBX) reagents has been developed. The reaction gave access to valuable functionalized lactones and lactams in up to 88% yield via the formation of two new C-C bonds. The transformation was carried out on primary, secondary, and tertiary homoallylic alcohols and primary homoallylic amines and could be applied to the synthesis of spirocyclic compounds as well as fused and bridged bicyclic lactones.

A catalytic process enables efficient and programmable access to precisely altered indole alkaloid scaffolds.

A compound's overall contour impacts its ability to elicit biological response, rendering access to distinctly shaped molecules desirable. A natural product's framework can be modified, but only if it is abundant and contains suitably modifiable functional groups. Here we introduce a programmable strategy for concise synthesis of precisely altered scaffolds of scarce bridged polycyclic alkaloids. Central to our approach is a scalable catalytic multi-component process that delivers diastereo- and enantiomerically enriched tertiary homoallylic alcohols bearing differentiable alkenyl moieties. We used one product to launch progressively divergent syntheses of a naturally occurring alkaloid and its precisely expanded, contracted and/or distorted framework analogues (average number of steps/scaffold of seven). In vitro testing showed that a skeleton expanded by one methylene in two regions is cytotoxic against four types of cancer cell line. Mechanistic and computational studies offer an account for several unanticipated selectivity trends.

Stereoselective Construction of Tertiary Homoallyl Alcohols and Ethers by Nucleophilic Substitution at Quaternary Carbon Stereocenters

AbstractAn efficient method for the stereoselective construction of tertiary C−O bonds via a stereoinvertive nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl carbinol derivatives using water, alcohols and phenols as nucleophiles has been developed. This substitution reaction proceeds under mild conditions and tolerates several functional groups, providing a new access to the stereoselective formation of highly congested tertiary homoallyl alcohols and ethers.

Stereoselective Construction of Tertiary Homoallyl Alcohols and Ethers by Nucleophilic Substitution at Quaternary Carbon Stereocenters.

An efficient method for the stereoselective construction of tertiary C-O bonds via a stereoinvertive nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl carbinol derivatives using water, alcohols and phenols as nucleophiles has been developed. This substitution reaction proceeds under mild conditions and tolerates several functional groups, providing a new access to the stereoselective formation of highly congested tertiary homoallyl alcohols and ethers.

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

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.

Cu‐Catalyzed Diastereo‐ and Enantioselective Reactions of γ,γ‐Disubstituted Allyldiboron Compounds with Ketones

AbstractA catalytic diastereo‐ and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1‐diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.

Cu-Catalyzed Diastereo- and Enantioselective Reactions of γ,γ-Disubstituted Allyldiboron Compounds with Ketones.

A catalytic diastereo- and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1-diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.

Copper-Catalyzed Synthesis of Tertiary Homoallylic Alcohols

Copper-Catalyzed Synthesis of Tertiary Homoallylic Alcohols

Catalytic Enantioselective Addition of an Allyl Group to Ketones Containing a Tri-, a Di-, or a Monohalomethyl Moiety. Stereochemical Control Based on Distinctive Electronic and Steric Attributes of C-Cl, C-Br, and C-F Bonds.

We disclose the results of an investigation designed to generate insight regarding the differences in the electronic and steric attributes of C-F, C-Cl, and C-Br bonds. Mechanistic insight has been gleaned by analysis of variations in enantioselectivity, regarding the ability of electrostatic contact between a halomethyl moiety and a catalyst's ammonium group as opposed to factors lowering steric repulsion and/or dipole minimization. In the process, catalytic and enantioselective methods have been developed for transforming a wide range of trihalomethyl (halogen = Cl or Br), dihalomethyl, or monohalomethyl (halogen = F, Cl, or Br) ketones to the corresponding tertiary homoallylic alcohols. By exploiting electrostatic attraction between a halomethyl moiety and the catalyst's ammonium moiety and steric factors, high enantioselectivity was attained in many instances. Reactions can be performed with 0.5-5.0 mol % of an in situ generated boryl-ammonium catalyst, affording products in 42-99% yield and up to >99:1 enantiomeric ratio. Not only are there no existing protocols for accessing the great majority of the resulting products enantioselectively but also in some cases there are hardly any instances of a catalytic enantioselective addition of a carbon-based nucleophile (e.g., one enzyme-catalyzed aldol addition involving trichloromethyl ketones, and none with dichloromethyl, tribromomethyl, or dibromomethyl ketones). The approach is scalable and offers an expeditious route to the enantioselective synthesis of versatile and otherwise difficult to access aldehydes that bear an α-halo-substituted quaternary carbon stereogenic center as well as an assortment of 2,2-disubstituted epoxides that contain an easily modifiable alkene. Tertiary homoallylic alcohols containing a triazole and a halomethyl moiety, structural units relevant to drug development, may also be accessed efficiently with exceptional enantioselectivity.

Ligand-controlled diastereodivergent, enantio- and regioselective copper-catalyzed hydroxyalkylboration of 1,3-dienes with ketones.

A copper-catalyzed three-component coupling of 1,3-dienes, bis(pinacolato)diboron, and ketones allows for the chemo-, regio-, diastereo- and enantioselective assembly of densely functionalized tertiary homoallylic alcohols. The relative configuration of the vicinal stereocenters is controlled by the chiral ligand employed. Subsequent transformations illustrate the versatility of these valuable chiral building blocks.

Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions.

Organofluorine compounds are central to modern chemistry, and broadly applicable transformations that generate them efficiently and enantioselectively are in much demand. Here we introduce efficient catalytic methods for additions of allyl and allenyl organoboron reagents to fluorine-substituted ketones. These reactions are facilitated by readily and inexpensively available catalysts and deliver versatile and otherwise difficult-to-access tertiary homoallylic alcohols in up to 98% yield and >99:1 enantiomeric ratio. Utility is highlighted by a concise enantioselective approach to synthesis of anti-parasitic drug Bravecto™ (presently sold as the racemate). Different forms of ammonium-organofluorine interactions play a key role in controlling enantioselectivity. The greater understanding of various non-bonding interactions afforded by these studies should facilitate future development of transformations involving fluoro-organic entities.

ChemInform Abstract: Design of a New Bimetallic Catalyst for Asymmetric Epoxidation and Sulfoxidation.

A new chiral tethered 8-quinolinol-based ligand class is developed. The binuclear titanium complex of the ligand operates through a novel mechanism allowing for the regio- and stereoselective epoxidation of primary and tertiary homoallylic alcohols (up to 98% ee), as well as first examples of 2-allylic phenols (up to 92% ee). The new catalyst system also promotes the asymmetric oxidation of γ-hydroxypropyl sulfides giving an important class of chiral sulfoxides that have been inaccessible to date (up to 95% ee).

Design of a New Bimetallic Catalyst for Asymmetric Epoxidation and Sulfoxidation.

A new chiral tethered 8-quinolinol-based ligand class is developed. The binuclear titanium complex of the ligand operates through a novel mechanism allowing for the regio- and stereoselective epoxidation of primary and tertiary homoallylic alcohols (up to 98% ee), as well as first examples of 2-allylic phenols (up to 92% ee). The new catalyst system also promotes the asymmetric oxidation of γ-hydroxypropyl sulfides giving an important class of chiral sulfoxides that have been inaccessible to date (up to 95% ee).

ChemInform Abstract: Concise Enantioselective Synthesis of δ,δ‐Disubstituted δ‐Valerolactones.

Abstract Efficient access to enantioenriched δ,δ-disubstituted δ-valerolactones is described. A soft Lewis acid/hard Bronsted base cooperative catalyst allowed for direct catalytic asymmetric γ-addition of allyl cyanide to ketones, producing tertiary homoallylic alcohols with a Z -configured α,β-unsaturated nitrile. Electrophilic activation of the nitrile functionality triggered 6- exo - dig cyclization, and subsequent N -acylation gave rise to the δ-valerolactone skeleton via C N bond cleavage.

Concise enantioselective synthesis of δ,δ-disubstituted δ-valerolactones

Efficient access to enantioenriched δ,δ-disubstituted δ-valerolactones is described. A soft Lewis acid/hard Brønsted base cooperative catalyst allowed for direct catalytic asymmetric γ-addition of allyl cyanide to ketones, producing tertiary homoallylic alcohols with a Z-configured α,β-unsaturated nitrile. Electrophilic activation of the nitrile functionality triggered 6-exo-dig cyclization, and subsequent N-acylation gave rise to the δ-valerolactone skeleton via CN bond cleavage.

Chemoenzymatic route to various spirocyclic compounds based on enantiomerically enriched tertiary allylic, homoallylic, and homopropargylic alcohols

A ring closing metathesis (RCM) reaction of dienes and an intramolecular Pauson–Khand (PKR) reaction of enynes derived from tertiary allyl, homoallyl, and homopropargyl alcohol backbones to afford the corresponding spirocyclic dihydrofuran and dihydropyrans and spirocyclic cyclopentenone pyrans, respectively, are described. Cyclopent-2-ene anchored tertiary allyl, homoallyl, and homopropargyl alcohols 1a–c have been efficiently resolved via enzymatic resolution with high ee (up to 90%) with 44%, 40%, and 43% chemical yields, respectively. Moreover, the cyclohex-2-ene anchored tertiary allyl, homoallyl, and homopropargyl alcohols 3a–c have also been resolved in the same manner with high ee (up to 97%) and in 42%, 45%, and 49% chemical yields. Enantiomerically enriched dienes derived from tertiary homoallyl alcohols yield the corresponding enantiomerically enriched spirocyclic dihydropyran derivatives via RCM with 74% and 78% chemical yields and with 90% and 97% ee, respectively. Moreover, enantiomerically enriched enynes derived from tertiary homoallyl alcohols afford the corresponding enantiomerically enriched cyclopentenone pyrans with spirocyclic motifs via PKR with 80% and 81% chemical yields, respectively, and as single diastereomers.

ChemInform Abstract: Rhodium‐Catalyzed Redox Allylation Reactions of Ketones.

AbstractKetones (I) react with allyl acetate (II) to generate tertiary homoallylic alcohols (III) in the presence of a rhodium catalyst and bis(pinacolato)diboron.

Highly diastereoselective addition of allyltitanocenes to α-chiral ketones

The addition of allyltitanium reagents, generated by the desulfurizative titanation of allylic sulfides with the titanocene(II) reagent Cp2Ti−1-butene, to α-chiral ketones produced tertiary homoallylic alcohols bearing three adjacent chiral centers with high diastereoselectivity.

Rhodium-catalyzed redox allylation reactions of ketones

Ketones react with allyl acetate to generate tertiary homoallylic alcohols in the presence of a rhodium catalyst and bis(pinacolato)diboron. A range of substrates, including aryl, alkyl and cyclic ketones react smoothly under these conditions. Diastereoselective allylation reactions of functionalized ketones such as pregnenolone acetate are also reported.

ChemInform Abstract: Regio‐ and Stereoselective Preparation of Highly Substituted Tertiary Homoallylic Alcohols.

Abstractα‐(Benzyldimethylsilyl)allylic sulfides undergo a titanocene(II)‐promoted reaction with ketones to give δ‐silylhomoallylic alcohols with high regio‐ and stereoselectivity.