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