Reactivity and Application of Pyridinium Salts in Organic ... Pyridinium Salts in Organic Synthesis

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  • Reactivity and Application of Reactivity and Application of Pyridinium Salts in Organic Synthesis

    Elizabeth Cline

    February 12 2010February 12, 2010

    2ndYear Literature Seminar

    Alexanian Lab

  • Pyridinium Salts Useful Synthetic Building BlocksUseful Synthetic Building Blocks

    NuNu

    N NuN

    Nu

    N N Nu

    Nu

    Nu

    RR substituted piperidine

    substituted pyridine

    N R

    N R

    Nu

    R substituted

    dihydropyridine

  • Ubiquity in Medicinal Compounds

    NexiumPlavix

    Actos AbilifyAvandia

    Risperdal

    Aricept

    Concerta Actonel

    Aciphex Singulair

  • Ubiquity in Nature

    Haliclonin A Sarain A

    Lonijaposide Aj p

    Manzamine AKeramaphidin BGeissoschizine

    Halicyclamine A

    N

    N

    N

    HO O

    N H

    H

    O N H

    DL-Febrifugine NH

    CHO

    Norfluorocurarine (-)-Cephalotaxine Akagerine

  • Pyridinium Salts in Nature

    R1

    N

    HO

    N

    N

    R2

    NH2

    2 OH

    R1=R2=H njaoamine A R1=R2=Me njaoamine B R1=H R2=Me njaoamine C

    Reyes, F.; Fernández, R.; Urda, C.; Francesch, A.; Bueno, S.; de Eguilior, C.; Cuevas, C. Tetrahedron 2007, 2432. R. Laville; G. Genta-Jouve; C. Urda; R Fernandez; O. Thomas; F. Reyes; P Amade. Molecules 2009, 4716.

  • Pyridinium Salts from Pyridine Electrophilic reactions on nitrogenElectrophilic reactions on nitrogen

    N

    X

    RX

    N R

    RX

    R NHR NH2 N R

    Cl

    Zincke Reaction

    T. Eicher, S. Hauptmann, The Chemistry of Heterocyles, p 272, New York, 1995.

  • General Reactivity

    Electrophilic at the 2, 4, and 6 positions

    Synthetic Challenges •Control of regioselectivity •Difficult to differentiate t o faces of the p ridinium salt•Difficult to differentiate two faces of the pyridinium salt

  • General Rules

    +0.165

    +0.241

    Grignards, organolithium compounds, heteroatom

    nucleophiles Electron deficiency at C-2 and C-4

    T. Eicher, S. Hauptmann, The Chemistry of Heterocyles, p 272, New York, 1995. D. M. Stout; A.I. Meyers Chem. Rev. 1982, 82, 223.

  • General Rules MO DiagramCuprates, carbanions,

    enolates, thiols

    LUMO

    T. Eicher, S. Hauptmann, The Chemistry of Heterocyles, p 272, New York, 1995. D. M. Stout; A.I. Meyers Chem. Rev. 1982, 82, 223.

  • Application to Total Synthesis Synthesis of GeissoschizineSynthesis of Geissoschizine

    TsOH, LiI N N

    SPh

    N N Br

    SPh

    ,

    THF O

    CO2Me

    O

    CO2Me

    Geissoschizine

    M.L. Bennasar; J.M. Jimenez; B. Vidal; B.A. Sufi; J. Bosch . J. Org. Chem 1999, 64, 9605.

  • Face-Selective Addition

    S. Yamada; C. Morita. J. Am. Chem. Soc. 2002, 124, 8184.

  • Asymmetric Addition Use of Chiral N-Acylpyridinium SaltsUse of Chiral N Acylpyridinium Salts

    Dihydropyridone

    79% yield 34% de34% de

    88% yield 94% de

    •TIPS group blocks 2 position allowing

    for greater diastereoselectivity

    D. Comins, S. Joseph, R Goehring, J. Am. Chem. Soc. 1994, 116, 4719.

  • Asymmetric Addition Removal of the Chiral Auxiliary and Silyl GroupRemoval of the Chiral Auxiliary and Silyl Group

    Dihydropyridone

    81% – 88% yield

    D. Comins, S. Joseph, R Goehring, J. Am. Chem. Soc. 1994, 116, 4719.

  • Asymmetric Addition Use of Chiral N Acylpyridinium SaltsUse of Chiral N-Acylpyridinium Salts

    RMgX Yield (%) deRMgX Yield (%) de PhMgCl 80 94

    p-MePhMgBr 75 82 p MeOPhMgBr 68 73p-MeOPhMgBr 68 73

    MeMgCl 85 91

    i-BuMgBr 86 92

    c-HexMgBr 83 81

    1-hexynylMgCl 74 83

    i lM Cl 75 85vinylMgCl 75 85

    D. Comins, S. Joseph, R Goehring, J. Am. Chem. Soc. 1994, 116, 4719.

  • Total Synthesis of (+)-Cannabisativine OZ Cl

    OMe TIPS

    O O

    Et Et

    OZnCl

    1. O

    H

    N

    NH

    H C5H11

    OH

    OH H O

    N CO2R*

    Cl 2. H3O+ N CO2R*

    O

    O O

    Et

    Et

    H

    85%

    NH

    NH

    (+) C bi i i 85% de > 95%

    (+)-Cannabisativine

    D. Comins, J. Kuethe, J. Org. Chem. 2004, 69, 5219.

  • Total Synthesis of (+)-Cannabisativine

    D. Comins, J. Kuethe, J. Org. Chem. 2004, 69, 5219.

    (+)-Cannabisativine

  • Regioselectivity Use of Directing GroupUse of Directing Group

    RMgX 1:2 Yield (%) MeMgBr >95:5 83

    >95:5 86 2-FurylMgBr >95:5 96

    90:10 70

    94:6 76

    A.B. Charette; M. Grenon; A. Lemire; M. Pourashraf; J. Martel. J. Am. Chem. Soc. 2001, 123, 11829.

  • Stereoselectivity Use of Directing GroupUse of Directing Group

    RMgX 1:2 dr Yield (%) MeMgBr >95:5 >95:5 77

    Et2Zn >95:5 >95:5 73 2-FurylMgBr >95:5 >95:5 68y g

    A.B. Charette; M. Grenon; A. Lemire; M. Pourashraf; J. Martel. J. Am. Chem. Soc. 2001, 123, 11829.

  • Total Synthesis of (+)-Lepadin B Application of Chiral Directing Group

    O

    NAux M

    Application of Chiral Directing Group

    BF3-Et2O 50°C

    OMe

    N

    NAux

    Ph

    Me H

    OMO OMeO

    N Bz

    Me H 5 steps

    OBn

    (+)-Lepadin B

    A.B. Charette. J. Am. Chem. Soc. 2008, 130, 13873.

  • Regioselectivity Use of PyridiniumYlidesUse of PyridiniumYlides

    Ylides have counterion linked directly to the pyridinium ring •Serves as a Lewis base and as a directing groupServes as a Lewis base and as a directing group

    Considerations for choosing X: •N-X bond strength – must be easily cleaved

    •Directing ability•Directing ability

    A.B. Charette; C. Legault. J. Am. Chem. Soc. 2003, 125, 6360.

  • Regioselectivity Use of PyridiniumYlidesUse of PyridiniumYlides

    1. RMgX, CH2Cl2 rt, 25 min N

    R

    NBz N

    rt, 25 min

    2. NaBH4, MeOH NBz

    N

    R NBz

    N

    1 2

    RMgX 1:2 Yield (%) MeMgBr >95:5 91 EtMgBr >95:5 83t g 95 5 83

    n-PrMgCl >95:5 87 i-PrMgCl >95:5 81 t-BuMgCl 43/57 39 28t BuMgCl 43/57 39, 28 BnMgCl 93/7 71

    AllylMgBr >95:5 79

    A.B. Charette; C. Legault. J. Am. Chem. Soc. 2003, 125, 6360.

    Bulky Grignards usually give predominantly 1, 4 addition

  • Asymmetric Hydrogenation Use of PyridiniumYlidesUse of PyridiniumYlides

    N

    I2 (2 mol%) H2 (400 psi)

    Toluene, rt, 6h

    NN NBz

    P N

    O

    Ir COD

    N NHBz

    R R

    Ar Ar BArF

    R Yi ld (%) (%)

    COD t-Bu

    Ar = p-F

    R Yield (%) ee (%) 2-Me 84 97 2-nPr 75 95 2-Bn 97 58

    2-CH2OBn 85 76 2-(CH2)3OBn 88 88

    A.B. Charette; C. Legault. J. Am. Chem. Soc. 2005, 127, 8966.

  • Catalytic Enantioselective Addition of TMSCNAddition of TMSCN

    OH

    S Ph O

    Additional chirality on sulfur atom Sulfoxide acts as OH

    S O

    Ph ligand

    Sulfoxide acts as Lewis base to activate

    TMSCN 98% ee

    E. Ichikawa; M. Suzuki; K. Yabu; M. Albert; M. Kanai; M. Shibasaki. J. Am. Chem. Soc. 2004, 126, 11809.

  • Addition of Terminal Alkynes Copper Catalyzed Addition to 1-Acylpyridinium SaltsCopper Catalyzed Addition to 1 Acylpyridinium Salts

    N

    10 mol% CuI, L 10 mol%

    i-Pr2NPr-n CH2Cl2 -78°C R

    NN CO2Me

    i Pr2NPr n, CH2Cl2, 78 C N CO2Me R

    Bis(oxazoline)

    R Yield (%) ee (%) CO2CH3 74 95 CO Bn 81 86CO2Bn 81 86 COCH3 69 93

    COCH2CH3 65 99 CO(CH ) CH 70 91Increasing Decrease in CO(CH2)3CH3 70 91 CO(CH2)4CH3 68 90 CO(CH2)3OBn 70 77

    Ph 75 1

    Increasing steric bulk

    Decrease in enantioselectivity

    Carbonyl Ph 75 1 (CH2)3CH3 63 11

    Carbonyl necessary to get enantiocontrol

    Z. Sun; S. Yu; Z. Zing; D. Ma. J. Am. Chem. Soc. 2007, 129, 9301.

  • Catalytic Enantioselective Addition Addition of Dialkylzinc ReagentsAddition of Dialkylzinc Reagents

    First example of catalytic enantioselective addition of organometallic reagents

    Phosphoramidite

    R Yield (%) ee (%) Et 69 95 Bu 63 93

    CH2CH2Ph 50 97 iPr 65 56

    M. A. Fernandez-Ibanez; B. Macia; M. G. Pizzuti; A. J. Minnaard; B. L. Feringa; Angew. Chem. Int. Ed. 2009, 48, 9339

  • Pyridine N-Oxides Synthesis of trans-2,3-Substituted Piperidinesy , p

    Prior knowledge

    R1MgX

    Addition of Grignard and Addition of Grignard results

    NR1 OH

    RT

    Pyridine N-Oxides are g subsequent addition of electrophilein ring-opening dienal oximes both nucleophilic and

    electrophilic

    H. Andersson; M. Gustafsson; D. Bostrom; R. Olsson; F. Almqvist. Angew. Chem. Int. Ed. 2009, 48, 3288

  • Pyridine N-Oxides Synthesis of trans-2 3-Substituted PiperidinesSynthesis of trans 2,3 Substituted Piperidines

    N-Oxide E+ Yield (%) R Yield (%)( )

    81

    e d (%)

    72

    MgCl

    80

    71

    76

    60

    F

    MgCl

    96

    60

    H. Andersson; M. Gustafsson; D. Bostrom; R. Olsson; F. Almqvist. Angew. Chem. Int. Ed. 2009, 48, 3288