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. 2022 May 20;12(10):6172-6179.
doi: 10.1021/acscatal.2c01647. Epub 2022 May 9.

Chiral α-Stereogenic Oxetanols and Azetidinols via Alcohol-Mediated Reductive Coupling of Allylic Acetates: Enantiotopic π-Facial Selection in Symmetric Ketone Addition

Nicholas P Stafford  1 , Melinda J Cheng  1 , Duong Nguyen Dinh  1 , Katherine L Verboom  1 , Michael J Krische  1
Affiliations

Chiral α-Stereogenic Oxetanols and Azetidinols via Alcohol-Mediated Reductive Coupling of Allylic Acetates: Enantiotopic π-Facial Selection in Symmetric Ketone Addition

Nicholas P Stafford et al. ACS Catal. .

Abstract

Iridium-tol-BINAP-catalyzed reductive coupling of allylic acetates with oxetanones and azetidinones mediated by 2-propanol provides chiral α-stereogenic oxetanols and azetidinols. As illustrated in 50 examples, complex, nitrogen-rich substituents that incorporate the top 10 N-heterocycles found in FDA-approved drugs are tolerated. In addition to 2-propanol-mediated reductive couplings, oxetanols and azetidinols may serve dually as reductant and ketone proelectrophiles in redox-neutral C-C couplings via hydrogen auto-transfer, as demonstrated by the conversion of dihydro-1a and dihydro-1b to adducts 3a and 4a, respectively. The present method delivers hitherto inaccessible chiral oxetanols and azetidinols, which are important bioisosteres.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Enantiotopic π-facial discrimination in the asymmetric allylation of non-symmetric and symmetric ketones.
Figure 2.
Figure 2.
Commercial oxetanes and azetidines.
Figure 3.
Figure 3.
General catalytic mechanism and proposed stereochemical model.
Scheme 1.
Scheme 1.
Enantioselective iridium-catalyzed reductive coupling of allylic acetate 2a with oxetanone 1a, azetidinone 1b and cyclobutanone 1c, experimentally determined LUMO energies and selected single crystal X-ray diffraction data.a aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.
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References

    1. For selected reviews on carbonyl addition chemistry, see:

    2. Noyori R; Kitamura M Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds: Chirality Transfer, Multiplication and Amplification. Angew. Chem. Int. Ed 1991, 30, 49–69.
    3. Soai K; Shibata T Alkylation of Carbonyl Groups. In Comprehensive Asymmetric Catalysis I-III; Jacobsen EN, Pfaltz A, Yamamoto H, Eds.; Springer-Verlag Berlin Heidelberg: Germany, 1999; Vol. 2, pp 911–922.
    4. Pu L; Yu H-B Catalytic Asymmetric Organozinc Additions to Carbonyl Compounds. Chem. Rev 2001, 101, 757–824. - PubMed
    5. Catalytic Enantioselective Addition of Allylic Organometallic Reagents to Aldehydes and Ketones. Chem. Rev 2003, 103, 2763–2793. - PubMed
    6. Trost BM; Weiss AH The Enantioselective Addition of Alkyne Nucleophiles to Carbonyl Groups. Adv. Synth. Catal 2009, 351, 963–983. - PMC - PubMed
    7. Comprehensive Organic Synthesis, 2nd ed.; Knochel P; Molander GA, Eds.; Elsevier: Oxford, 2014; Vols. 1 and 2.

    1. For selected reviews on catalytic enantioselective ketone addition, see:

    2. Betancort JM; Garcia C; Walsh PJ Development of the First Practical Catalyst for the Asymmetric Addition of Alkyl- and Arylzinc Reagents to Ketones. Synlett 2004, 5, 749–760.
    3. Ramon DJ; Yus M Chiral Tertiary Alcohols Made By Catalytic Enantioselective Addition of Unreactive Zinc Reagents to Poorly Electrophilic. Angew. Chem. Int. Ed 2004, 43, 284–287. - PubMed
    4. Garcia C; Martin VS Asymmetric Addition to Ketones: Enantioselective Formation of Tertiary Alcohols. Curr. Org. Chem 2006, 10, 1849–1889.
    5. Riant O; Hannedouche J Asymmetric Catalysis for The Construction of Quaternary Carbon Centres: Nucleophilic Addition on Ketones and Ketimines. Org. Biomol. Chem 2007, 5, 873–888. - PubMed
    6. Cozzi PG; Hilgraf R; Zimmermann N Enantioselective Catalytic Formation of Quaternary Stereogenic Centers. Eur. J. Org. Chem 2007, 36, 5969–5994.
    7. Hatano M; Ishihara K Recent Progress in the Catalytic Synthesis of Tertiary Alcohols from Ketones with Organometallic Reagents. Synthesis 2008, 11, 1647–1675.
    8. Shibasaki M; Kanai M Asymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C–C Bond Formation to Ketones and Ketimines. Chem. Rev 2008, 108, 2853–2873. - PubMed
    9. Adachi S; Harada T Catalytic Enantioselective Aldol Additions to Ketones. Eur. J. Org. Chem 2009, 22, 3661–3671.
    10. Wisniewska HM; Jarvo ER Enantioselective Propargylation and Allenylation Reactions of Ketones and Imines. J. Org. Chem 2013, 78, 11629–11636. - PubMed
    11. Rong J; Pellegrini T; Harutyunyan SR Synthesis of Chiral Tertiary Alcohols by CuI-Catalyzed Enantioselective Addition of Organomagnesium Reagents to Ketones. Chem. Eur. J 2016, 22, 3558–3570. - PubMed
    12. Thaima T; Zamani F; Hyland CJT; Pyne SG Allenylation and Propargylation Reactions of Ketones, Aldehydes, Imines, and Iminium Ions Using Organoboronates and Related Derivatives. Synthesis 2017, 49, 1461–1480.
    13. Liu Y-L; Lin X-T Recent Advances in Catalytic Asymmetric Synthesis of Tertiary Alcohols via Nucleophilic Addition to Ketones. Adv. Synth. Catal 2019, 361, 876–918.

    1. For examples of intermolecular catalytic enantioselective allylation of unactivated ketones using premetalated reagents, see:

    2. Allylboration: Wada R; Oisaki K; Kanai M; Shibasaki M Catalytic Enantioselective Allylboration of Ketones. J. Am. Chem. Soc 2004, 126, 8910–8911. - PubMed
    3. Lou S; Moquist PN; Schaus SE Asymmetric Allylboration of Ketones Catalyzed by Chiral Diols. J. Am. Chem. Soc 2006, 128, 12660–12661. - PubMed
    4. S. Shi-L.; Xu L-W; Oisaki K; Kanai M; Shibasaki M Identification of Modular Chiral Bisphosphines Effective for Cu(I)-Catalyzed Asymmetric Allylation and Propargylation of Ketones. J. Am. Chem. Soc 2010, 132, 6638–6639. - PubMed
    5. Zhang Y; Li N; Qu B; Ma S; Lee H; Gonnella NC; Gao J; Li W; Tan Z; Reeves JT; Wang J; Lorenz JC; Li G; Reeves DC; Premasiri A; Grinberg N; Haddad N; Lu BZ; Song JJ; Senanayake CH Org. Lett 2013, 15, 1710–1713. - PubMed
    6. Cu-Catalyzed Chemoselective Preparation of 2-(Pinacolato)boron-Substituted Allylcopper Complexes and their In Situ Site-, Diastereo-, and Enantioselective Additions to Aldehydes and Ketones. Meng F; Jang H; Jung B; Hoveyda AH Angew. Chem. Int. Ed 2013, 52, 5046–5051. - PMC - PubMed
    7. Alam R; Vollgraff T; Eriksson L; Szabo KJ Synthesis of Adjacent Quaternary Stereocenters by Catalytic Asymmetric Allylboration. J. Am. Chem. Soc 2015, 137, 11262–11265. - PubMed
    8. Lee K; Silverio DL; Torker S; Robbins DW; Haeffner F; van der Mei FW; Hoveyda AH Catalytic Enantioselective Addition of Organoboron Reagents to Fluoroketones Controlled by Electrostatic Interactions. Nature Chem. 2016, 8, 768–777. - PMC - PubMed
    9. Robbins DW; Lee K; Silverio DL; Volkov A; Torker S; Hoveyda AH Practical and Broadly Applicable Catalytic Enantioselective Additions of Allyl-B(pin) Compounds to Ketones and α-Ketoesters. Angew. Chem. Int. Ed 2016, 55, 9610–9614. - PMC - PubMed
    10. Fager DC; Lee K; Hoveyda AH 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. J. Am. Chem. Soc 2019, 141, 16125–16138. - PMC - PubMed
    11. Zanghi JM; Meek SJ Cu‐Catalyzed Diastereo‐ and Enantioselective Reactions of γ,γ‐Disubstituted Allyldiboron Compounds with Ketones. Angew. Chem. Int. Ed 2020, 59, 8451–8455. - PMC - PubMed
    12. Allylsilation: Wadamoto M; Yamamoto H Silver-Catalyzed Asymmetric Sakurai-Hosomi Allylation of Ketones. J. Am. Chem. Soc 2005, 127, 14556–14557. - PubMed
    13. Yamasaki S; Fujii K; Wada R; Kanai M; Shibasaki M A General Catalytic Allylation Using Allyltrimethoxysilane. J. Am. Chem. Soc 2002, 124, 6536–6537. - PubMed
    14. Allylstannation: Casolari S; D’Addario D; Tagliavini E Org. Lett 1999, 1, 1061–1063.
    15. Cunningham A; Woodward S Highly Enantioselective Catalytic Ketone Allylation with Sn(CH2CH=CH2)4/RSn(CH2CH=CH2)3 Mixtures (R = Et, Bu) Synlett 2002, 43–44.
    16. Kim JG; Waltz KM; Kwiatkowski D; Walsh PJ J. Am. Chem. Soc 2004, 126, 12580–12585. - PubMed
    17. Teo Y-C; Goh J-D; Loh T-P Catalytic Enantioselective Allylation of Ketones via a Chiral Indium(III) Complex. Org. Lett 2005, 7, 2743–2745. - PubMed
    18. Kim Jeung Gon; Camp Elizabeth H.; Walsh Patrick J. Catalytic Asymmetric Methallylation of Ketones with an (H8-BINOLate)Ti-Based Catalyst Org. Lett 2006, 8, 4413–4416. - PMC - PubMed
    19. Prieto O; Woodward S Enantioselective Catalytic Allylation of Aryl Methyl Ketones Using Tetraallyltin and Tin(IV) Chloride Mixtures. J. Organomet. Chem 2006, 691, 1515–1519.
    20. Zhang X; Chen D; Liu X; Feng X Enantioselective Allylation of Ketones Catalyzed by N,N′-Dioxide and Indium(III) Complex. J. Org. Chem 2007, 72, 5227–5233. - PubMed

    1. For selected reviews on the use of allene and diene pronucleophiles in metal-catalyzed carbonyl reductive coupling, see:

    2. Holmes M; Schwartz LA; Krische MJ Intermolecular Metal-Catalyzed Reductive Coupling of Dienes, Allenes and Enynes with Carbonyl Compounds and Imines. Chem. Rev 2018, 118, 6026–6052. - PMC - PubMed
    3. Xiang M; Pfaffinger DE; Brito GA; Krische MJ Allenes and Dienes as Chiral Allylmetal Pronucleophiles in Catalytic Enantioselective C=X Addition: Historical Perspective and State-of-The-Art Survey. Chem. Eur. J 2021, 27, 13107. - PMC - PubMed

    1. For examples of intermolecular catalytic enantioselective allylation of unactivated ketones under Nozaki-Hiyama-Kishi conditions, see:

    2. Miller JJ; Sigman MS Design and Synthesis of Modular Oxazoline Ligands for the Enantioselective Chromium-Catalyzed Addition of Allyl Bromide to Ketones. J. Am. Chem. Soc 2007, 129, 2752–2753. - PubMed
    3. Huang X-R; Chen C; Lee G-H; Peng S-M A Spirocyclic Chiral Borate for Catalytic Enantioselective Nozaki-Hiyama Allylation of Ketones. Adv. Synth. Catal 2009, 351, 3089–3095.