Dilgam Ahmadli Türkmen Group Meeting Bergman Cyclization 21.04€¦ · Bergman Cyclization...

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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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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


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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.


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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.


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∆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.


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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


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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 ℃


𝑡1/2 = 148 𝑚𝑖𝑛, 152 ℃



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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


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Metal complexation

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

Volhardt, 1984

Magnus, 1988, Esperamicin Model

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


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Buchwald, 1995

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

König, 1996


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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


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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 Türkmen Group Meeting Bergman Cyclization 21.04€¦ · Bergman Cyclization...

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