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. 2020 Oct 21;142(42):18200-18212.
doi: 10.1021/jacs.0c08732. Epub 2020 Oct 5.

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

Juan Del Pozo  1 , Shaochen Zhang  1 , Filippo Romiti  1   2 , Shibo Xu  1 , Ryan P Conger  1 , Amir H Hoveyda  1   2
Affiliations

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

Juan Del Pozo et al. J Am Chem Soc. .

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.

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Figures

Scheme 1.
Scheme 1.
Bioactive Compounds Containing α-Substituted Ketones or Tertiary Alcohol Derivatives
Scheme 2.
Scheme 2.
The Initial Plan and Related Formerly Published Work
Scheme 3.
Scheme 3.
A Revised and More Flexible Strategy That Involves Nitriles as Substrates
Scheme 4.
Scheme 4.. Enantiomerically Enriched Ketones Bearing an α-Substituted C-Based Tertiary Stereogenic Centera
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.
Scheme 5.. Enantiomerically Enriched Ketones Bearing an α-Quaternary Carbon Stereogenic Centera
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.
Scheme 6.. Enantiomerically Enriched Ketones Bearing an α-Substituted O-Based Tertiary Stereogenic Centera
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.
Scheme 7.. X-ray Structures Show Minimal Carbonyl Oxygen to Boron Coordinationa
aSee the Supporting Information for details.
Scheme 8.
Scheme 8.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of an Alkyl Groupa
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.
Scheme 9.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of an Aryl Moietya
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.
Scheme 10.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of an Allyl Groupa
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.
Scheme 11.. Diastereoselective Synthesis of Tertiary Homoallylic Alcohols Through Addition of a Vinyl, an Alkynyl, or a Propargyl Groupa
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.
Scheme 12.. Representative Modifications of α-Substituted Ketones and Tertiary Homoallylic Alcohol Productsa
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.
Scheme 13.. Enantio- and Diastereoselective Gram Scale Synthesis of a Fragment of Rubriflordilactones A and Ba
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.
Scheme 14.. Enantio- and Diastereoselective Synthesis of a Fragment of epi-5-Rubriflordilactones A and Ba
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.
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References

    1. Ravindranath N; Venkataiah B; Ramesh C; Jayaprakash P; Das B Jatrophenone, a novel macrocyclic bioactive diterpene from Jatropha gossypifolia. Chem. Pharm. Bull. 2003, 51, 870–871. - PubMed
    1. Pimentel-Elardo SM; Gulder TAM; Hentschel U; Bringmann G Cebulactams A1 and A2, new macrolactams isolated from Saccaropolyspora cebuensis, the first obligate marine strain of the genus Saccharopolyspora. Tetrahedron Lett. 2008, 49, 6889–6892.
    2. Xie C-L; Niu S; Xia J-M; Peng K; Zhang G-Y; Yang X-W Saccharopolytide A, a new cyclic tetrapeptide with rare 4-hydroxy-proline moieties from the deep-sea derived actinomycete Saccharopolyspora cebuensis MCCC 1A09850. Nat. Prod. Res. 2018, 32, 1627–1631. - PubMed
    1. Cano R; Zakarian A; McGlacken GP Direct asymmetric alkylation of ketones: still unconquered. Angew. Chem., Int. Ed. 2017, 56, 9278–9290. - PMC - PubMed
    1. Yan X-X; Liang C-G; Zhang Y; Hong W; Cao B-X; Dai L-X; Hou X-L Highly enantioselective Pd-catalyzed allylic alkylations of acyclic ketones. Angew. Chem., Int. Ed. 2005, 44, 6544–6546. - PubMed
    2. Trost BM; Xu J Palladium-catalyzed asymmetric allylic α-alkylation of acyclic ketones. J. Am. Chem. Soc. 2005, 127, 17180–17181. - PMC - PubMed
    3. Zheng W-H; Zheng B-H; Zhang Y; Hou X-L Highly regio-, diastereo-, and enantioselective Pd-catalyzed allylic alkylation of acyclic ketone enolates with monosubstituted allyl substrates. J. Am. Chem. Soc. 2007, 129, 7718–7719. - PubMed
    4. Lundin PM; Esquivias J; Fu GC Catalytic asymmetric cross-couplings of racemic α-bromoketones with arylzinc reagents. Angew. Chem., Int. Ed. 2009, 48, 154–156. - PMC - PubMed
    5. Lou S; Fu GC Nickel/bis(oxazoline)-catalyzed asymmetric Kumada reactions of alkyl electrophiles: cross-couplings of racemic α-bromoketones. J. Am. Chem. Soc. 2010, 132, 1264–1266. - PMC - PubMed
    6. Cherney AH; Kadunce NT; Reisman SE Catalytic asymmetric reductive acyl cross-coupling: synthesis of enantioenriched acyclic α,α-disubstituted ketones. J. Am. Chem. Soc. 2013, 135, 7442–7445. - PubMed
    7. Bandar JS; Ascic E; Buchwald SL Enantioselective CuH-catalyzed reductive coupling of aryl alkenes and activated carboxylic acids. J. Am. Chem. Soc. 2016, 138, 5821–5824. - PMC - PubMed
    8. Zhou Y; Bandar JS; Buchwald SL Enantioselective CuH- catalyzed hydroacylation employing unsaturated carboxylic acids as aldehyde surrogates. J. Am. Chem. Soc. 2017, 139, 8126–8129. - PMC - PubMed
    9. Liu J; Vasamsetty L; Anwar M; Yang S; Xu W; Liu J; Nagaraju S; Fang X Organocatalyzed kinetic resolution of α-functionalized ketones: the malonate unit leads the way. ACS Catal. 2020, 10, 2882–2893.
    1. Chen J-P; Ding C-H; Liu W; Hou X-L; Dai L-X Palladium-catalyzed regio-, diastereo-, and enantioselective alkylation of acylsilanes with monosubstituted allyl substrates. J. Am. Chem. Soc. 2010, 132, 15493–15495. - PubMed

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