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The AD Catalytic Cycle

This comprehensive review by Sean Parris discusses the advancements in olefin bisfunctionalization, focusing on strategies to suppress the secondary cycle in various catalytic processes. It delves into the Cinchona alkaloids and the effectiveness of different ligand systems in reactions such as Sharpless Asymmetric Aminohydroxylation (AA) and diamination of conjugated dienes. Insights into regioselectivity, substrate compatibility, and mechanism modifications are presented, highlighting the challenges and successes encountered in the field. This article serves as a valuable resource for chemists seeking to enhance olefin transformations.

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The AD Catalytic Cycle

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  1. The AD Catalytic Cycle Chem. Rev. 1994, 94, 2483-2547 Sean Parris, Olefin Bisfunctionalisation

  2. Shutting Down the Secondary Cycle Sean Parris, Olefin Bisfunctionalisation

  3. The Cinchona Alkaloids (DHQ)2PHAL “AD-a” Sean Parris, Olefin Bisfunctionalisation

  4. The AD-Mix Mnemonic • Works best for: • trans alkenes • terminal olefins quite bad • with aromatic ring to sit in • “attractive area” Sean Parris, Olefin Bisfunctionalisation

  5. Which Ligand System? Sean Parris, Olefin Bisfunctionalisation

  6. Racemic Dihydroxylation – Beyond Upjohn Upjohn (NMO, OsO4) can be slow & prone to over-oxidation J. Eames, H. Mitchell, A. Nelson, P. O’Brien, S. Warren, P. Wyatt, Perkin 1 1999, p1095 Sean Parris, Olefin Bisfunctionalisation

  7. Sharpless Asymmetric Aminohydroxylation (AA) Sean Parris, Olefin Bisfunctionalisation

  8. Sharpless Asymmetric Aminohydroxylation (AA) Sharpless et al. Angew. Int.1997 438 Sean Parris, Olefin Bisfunctionalisation

  9. AA –Mechanism Review: McLeod et al, Perkin 1, 2002, 2733 Sean Parris, Olefin Bisfunctionalisation

  10. AA – Standard Conditions? Review: P. O’Brien, Angew. Int,1999, 326 Sean Parris, Olefin Bisfunctionalisation

  11. Competing Dihydroxylation • First turnover of catalyse is AD • Can reduce AD with slow addition of substrate Sean Parris, Olefin Bisfunctionalisation

  12. AA – Best Substrates Cinnamates best using (DHQ)2PHAL (as drawn) (DHQ)2AQN (regioisomer) a,b-unsat’d (DHQ)2PHAL (as drawn) effect ligand unknown Sean Parris, Olefin Bisfunctionalisation

  13. AA – More Substrates • Styrenes, a,b-unsat’d esters & vinyl arenes only work with acetamide & carbamate • Other egs where DHQ vs DHQD give regioisomers in similar ee of opposite stereoinduction! Sean Parris, Olefin Bisfunctionalisation

  14. Sharpless Aminohydroxylation – Further Work • a,b-unsat’d amides & carboxylic acids found to be good substrates for a racemic AH (Angew.1997, p2751; Angew.2001 3455) because exist solely in “secondary cycle” • Start to develop a AA using the secondary cycle only which places far more stringent requirements on the ligand, with only partial success: 50-70% ee for AD, 25-60% ee for AA (Angew. 2002, 474) • Muniz et al got around the problem of a racemic AH for acrylamindes by using chiral substrate (Tet. Asymm. 2005, 3492) • Hergenrother et al found could change regioselectivity in AA of styrenes by controlling pH with modest ee (Org. Let.2003, 281) Sean Parris, Olefin Bisfunctionalisation

  15. Other Aminhydroxylations - TA Tethered Aminohydroxylation (TA) • Stereochemistry comes from allylic alcohol • Stereoinduction requires cyclic system Donohoe et al, JACS2002, 12934 Sean Parris, Olefin Bisfunctionalisation

  16. Tethered Aminohydroxylation Sean Parris, Olefin Bisfunctionalisation

  17. Tethered Aminohydroxylation - Mechanism Sean Parris, Olefin Bisfunctionalisation

  18. Diamination to Conjugated Dienes (1) disfavour 3 (2) favour Nu addn to give diamine (3) amine souce that won’t react with other species Sean Parris, Olefin Bisfunctionalisation

  19. Question Time – Predict the Products Sean Parris, Olefin Bisfunctionalisation

  20. Diamination – Initial Results • Conditions are modified Wacker conditions • - Regioselectivity of first complexation • Unsymmetric ureas (solubility also a problem) • needs chloride Pd pre-catalyst Sean Parris, Olefin Bisfunctionalisation

  21. Question Time – Wacker Oxidation Sean Parris, Olefin Bisfunctionalisation

  22. Diamination – Further Results • Benzoquinone (method A) is superior oxidant • best for symmetric dienes Sean Parris, Olefin Bisfunctionalisation

  23. Enatioselective Diboronation of Olefins 50-98% 50-96% ee • Works for terminal & di-substiuted alkene, not tri subst • Works best for trans alkenes • Tolerates protected alcohols Morken et al, JACS2003, 8702; JOC 2005 9538 Sean Parris, Olefin Bisfunctionalisation

  24. Enatioselective Diboronation of Olefins Morken et al, JOC 2005 9538 Sean Parris, Olefin Bisfunctionalisation

  25. Carbohyroxyltion of Olefins One-pot diboronation-Suzuki cross coupling Morken et al, Org. Lett. 2004,131 Sean Parris, Olefin Bisfunctionalisation

  26. Diboronation Mechanism Sean Parris, Olefin Bisfunctionalisation

  27. Regioselective Aminoacetoxylation • Racemic addition • Requires adjacent ether in substrate • Interesting IIII reagent oxidises Pd-C bond… Stahl et al, JACS2006, 7179 Sean Parris, Olefin Bisfunctionalisation

  28. Regioselective Aminoacetoxylation Sean Parris, Olefin Bisfunctionalisation

  29. Hydroxysulfenation Sean Parris, Olefin Bisfunctionalisation

  30. Hydroxysulfenation • R1 = Ar, alk • R1=R2 = c-hex, Ar • R3 = Ar, Cy • Complete diastereoselectivity • can also replace S-Ar with Si-iPr, SePh & SnBu Taniguchi, JACS 2006, 7876 Sean Parris, Olefin Bisfunctionalisation

  31. Hydroxysulfenation Sean Parris, Olefin Bisfunctionalisation

  32. Hydroxysulfenation Sean Parris, Olefin Bisfunctionalisation

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