Dilgam Ahmadli T£¼rkmen Group Meeting Bergman Cyclization 21.04 Bergman Cyclization 21.04.2020 1942--Born

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    Türkmen Group Meeting Dilgam Ahmadli

    21.04.2020 Bergman Cyclization

    1942--Born (Chicago, USA)

    1963--BSc at Carleton College

    1966--PhD at Wisconsin (w/ Jerome. A. Berson)

    1977-present--Professor at UC Berkeley

    2002--Gerald.E.K Branch Distinguished Professor

    Main Interests -Investigation of reaction mechanisms

    -Generation and study of unusual reactive molecules

    such as 1,3-diradicals and vinyl cations.

    -Organometallic Chemistry

    -known for his discovery of the first soluble organometallic

    complexes that undergo intermolecular insertion of transition metals

    into the carbon-hydrogen bonds of alkanes

    J. Mayer F. Sondheimer, 1966

    J. Am. Chem .Soc. 1966, 88 (3), 603–604

    J. Chem. Soc. D, 1971, 1516-1517

    S. Masamune, 1971

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    Türkmen Group Meeting Bergman Cyclization

    R. Bergman, 1972, Bergman Cyclization

    J. Am. Chem .Soc. 1972 , 94 (2): 660–661

    Possible intermediates

    Acc. Chem. Res. 1973, 6, 25-31

    Mechanistic Studies: Deuterium scrambling upon

    pyrolysis

    In transition state or intermediate C-1, C-3, C-4, and C-6 are chemically

    equivalent

    No scrambling in trans isomer

    S. Masamune’s work revisited

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    Calicheamicins and Espiramicins, 1980’s

    (a) Subpicogram potency against Gram positive bacteria,

    (b) Activity in the biochemical induction assay at very low

    concentrations,

    (c) high potency against a number of animal tumor models

    (d) induction of double-stranded DNA cleavage with minimal

    concurrent single-stranded breakage.

    Biological activities

    J. Am. Chem. Soc. 1987, 109, 11, 3464-3466

    Calicheamicin 𝛾1𝛼 Esperamicin A 1

    J. Am. Chem. Soc. 1987, 109, 3461-3462

    Dynemicin A

    J. Am. Chem. Soc. 1990, 112, 9, 3715-3716

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    Geometrical Factors

    J. Am. Chem. Soc. 1988, 110, 14, 4866-4868

    Angew. Chem. Int. Ed. 1992, 31, 1044.

    J. Am. Chem. Soc. 1992, 114, 7360.

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

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    Türkmen Group Meeting Bergman Cyclization

    Initial strategy used for the synthesis of the cyclic conjugated

    Enediynes (n= 2-8) based on Ramberg-Bäcklund Reaction

    .

    J. Am. Chem. Soc. 1988, 110, 14, 4866-4868

    Simple structures that can mimic the DNA cleavage

    J. Am. Chem. Soc. 1988, 110, 21, 7247-7248

    Electronic Factors (Synlett 2004(3): 393-421)

    Redox-controlled Bergman cyclization

    J. Am. Chem. Soc. 1992, 114, 9279.

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    ∆𝐺𝑎 ∓ = 22.6

    𝑘𝑐𝑎𝑙

    𝑚𝑜𝑙 , 30 ℃ ∆𝐺𝑏

    ∓ = 25.7 𝑘𝑐𝑎𝑙

    𝑚𝑜𝑙 , 37 ℃

    Electronic Effect: Effect of benzannulation.

    J. Am. Chem. Soc. 1993, 115, 7944

    Electronic Effect: Effect of double bond character.

    Tetrahedron Lett. 1992, 33, 3277.

    J. Org. Chem. 1994, 59, 5038.

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    Exception

    𝐸𝑎 = 27.4 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙 J. Am. Chem. Soc. 1980, 102, 5976.

    𝐸𝑎 = 25.1 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙 J. Org. Chem. 1994, 59, 5833-5835

    Mechanistic studies, Trapping the Radical Intermediate

    Mechanism a

    Mechanism b

    Mechanism c

    J. Org. Chem. 1993,58, 5422-5427

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    Indirect proof for biradical formation

    J. Org. Chem. 1993,58, 5422-5427

    Effect of vinyl substitution

    𝑅 = 𝑝 − 𝑀𝑒𝑂𝐶6𝐻4 ∆𝐺 ∓= 111 𝑘𝐽/𝑚𝑜𝑙

    R = H ∆𝐺∓= 98.7 𝑘𝑗/𝑚𝑜𝑙

    Electron deficient heteroarynes

    J. Org. Chem. 1998, 63, 8229-8234

    Liebigs Ann. 1992, 855

    𝑡1/2 = 13 𝑚𝑖𝑛, 155℃

    𝐸𝑎 = 21.5 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙

    𝑡1/2 = 7 𝑚𝑖𝑛, 154 ℃

    𝐸𝑎 = 16.1 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙

    𝑡1/2 = 148 𝑚𝑖𝑛, 152 ℃

    𝐸𝑎 = 33.6 𝑘𝑐𝑎𝑙/𝑚𝑜𝑙

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    𝑡1/2 = 8ℎ, 0 °𝐶 X = Cl, Y = H

    X = Cl, Y = Cl

    𝑡1/2 = 5ℎ, 60 °𝐶

    𝑡1/2 = 24ℎ, 170 °𝐶

    Org. Lett. 2000, 2, 1757

    Ortho-substitutent effects

    Transition state or ground state may be stabilized or

    destabilized depending on the interaction between R and

    orbital.

    Groups that make Hydrogen bonding stabilizes Ground

    state.

    Purely steric factors has minimal net effect.

    Org. Lett. 2002, 4, 1119-1122

    Substitution at alkyne termini

    a) Tetrahedron Lett. 1993,34, 4121.

    b) Chem. Lett. 1995, 953.

    c) Comp. Chem. 2001, 22, 1605.

    Steric Effects

    Chem. Commun., 2000, 2493–2494

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    Metal complexation

    J. Org. Chem. 1984, 49, 1564.

    Volhardt, 1984

    Magnus, 1988, Esperamicin Model

    J. Am. Chem. Soc., 1988, 110, 6921-6923

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    Buchwald, 1995

    Science 1995, 269, 814. J. Org. Chem. 1996, 61, 4258.

    König, 1996

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    Zaleski, 2001

    J. Am. Chem. Soc. 2001, 123, 9675.

    Photochemical Bergman Cyclization

    Tetrahedron Lett. 1994,35, 8089.

    Funk, 1996 Turro, 1994

    -Another example of unsaturated molecule undergoes rearrangement with thermal and photochemical mechanism

    -Would allow controlled activation of drug

    Dilgam Ahmadli 21.04.2020

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    Türkmen Group Meeting Bergman Cyclization

    J. Am. Chem. Soc. 1996, 118, 3291-3292

    Bergman Cyclization in Polymer Chemistry

    Macromolecular Rapid Communications, 2011, 32, 1688–1698.

    Bergman Cyclization in Total Synthesis

    Angew. Chem. Int. Ed. 2018, 130, 9255 –9259

    Dilgam Ahmadli 21.04.2020