Bergman Cycloaromatization Whitney M. Erwin February 21, 2002 ∆ 2 [H ]

Bergman Cycloaromatization

Whitney M. Erwin

February 21, 2002

∆ 2 [H ]

Outline

I. Background

II. Reaction Control- Substituent Effects- Variations- Use of metals- Triggers

III. Applications- Synthesis- Materials Science- Biology

IV. Summary

Robert G. Bergman

• 1963 – B.S. Carleton College

• 1966 – Ph.D. University of Wisconsin

• 1966 - Postdoc Colombia University

• 1968 - California Institute of Technology

• 1977 - University of California - Berkeley

2 [H ]

Bergman Cycloaromatization

Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc., 1972, 94, 660.Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.

200 ºC

t1/2 = 30 s

0.01 M

2,6,10,14-tetramethylpentadecane as solvent

Critical d range for spontaneous cyclization at rt = 3.4 – 2.9 Å

Alkyne Termini Separation

Schreiner, P. R. Chem. Commun. 1998, 4, 483.

Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184.

Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866.

C (CH2)n

Compound ring size d (Å) ∆H‡ (kcal/mol)

A ------ 4.548 28.4

B ------ 4.571 35.6

C 7 2.512

C 8 2.636

C 9 2.924 16.3

C 10 3.413 25.0

C 11 3.588 31.9

C 12 4.353 40.3

Calculated Values

level ∆HR° (kcal/mol)

∆Hf° (kcal/mol)

∆EST

(kcal/mol)

expt 4.7 137.3 ± 3.3 -3.8 ± 0.5

138.0 ± 1.0

CASSCF/aANO 3.0 139.6 -3.8

CASPT2(8,8)/aANO 4.4 138.2 -5.6

BPW91/cc-pVTZ -3.6 146.2 1.6

CCSD(T)/cc-pVTZ 5.4 137.2 -2.3

B3LYP/6-31G* -14.6 157.3 13.2

B3LYP/6-311+G** -12.6 155.3 11.1

BLYP/6-31G* -4.2 146.9 0.1

BLYP/6-311G** -2.6 145.3 -1.5

Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184.

Outline

I. Background

IV. Summary

Alkynyl Substituent Effects

Strong σ–acceptors and /or π-donors lower the cyclization barrier Ex. –F, -OH, -NH3

+, -OH2+

π-Withdrawing groups raise the cyclization barrier Ex. -BH2, -AlH2

Prall; M.; Wittikopp, A.; Fokin, A. A.; Schreiner, P. R. J. Comp. Chem. 2001, 22, 1605.

Monosubstituted

Disubstituted

Barriers depend on steric hindrance to substituents in the TSs

Planar systems follow same pattern as above

R = HBrClNO2

(kcal/mol)

Reaction coordinate

(kcal/mol)

Reaction coordinate

Vinylic Substituent Effects

Electron-withdrawing groups increase the cyclization barrier. Ex. –Cl, -NO2

σ-Donating groups decrease the cyclization barrier. Ex. -CH3, -(CH2)3

π-Conjugation has little effect.

Most annulations slightly raise or lower the cyclization barrier.

Jones, G. B.; Warner, P. M. J. Am. Chem. Soc. 2001, 123, 2134-2145.

Effect of Ring Size and Electronics

Cl ClCl

Jones, G. B.; Plourde II, G. W. Org. Lett. 2000, 2, 1757.

11-membered9-membered 10-membered

Cl ClCl

t1/2 = 8h/0°C t1/2 = 60h/40°C

18h/50°C

5h/80°C

t1/2 = 2h/170°C

t1/2 = 24h/170°C

10-membered dichloro

Benzannelation

Kaneko, T.; Takahashi, M.; Hirama, M. Tet. Lett. 1999, 40, 2015.

Koseki, S.; Fujimura, Y.; Hirama, M. J. Phys. Chem. A 1999, 103, 7672.

Alters the kinetically important step in the cyclization of strained cyclic enediynes.

Rate-limiting

H-donor

Rate-limiting

Retro-cyclization barrier = 15.3 kcal/mol

H abstraction barrier = 12.7 kcal/mol

Retro-cyclization barrier = 5.9 kcal/mol

H abstraction barrier = 11.8 kcal/mol

Aza- and Protonated Aza-Bergmans

Cramer, C. J. J. Am. Chem. Soc. 1998, 120, 6261.

Reaction coordinate

Donors

Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.

RH CH3OH

Mg2+-induced Cyclization

Rawat, D. S.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123, 9675.

MeOH, MgCl2

0°C, 8h

NaBH4, 5-10°C

DMF, EDTA, CH2Cl2

Metal Coordination

Benites, P. J.; Rawat, D. S.; Zaleski, J. M. J. Am. Chem. Soc. 2000, 122, 7208.

194°C

116°C

152°C

CpRu as Accelerator / Inhibitor

Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.; Cecil, T. L. J. Am. Chem. Soc. 1996, 118, 3291.

O’Connor, J. M.; Lee, L. I.; Gantzel, P. J. Am. Chem. Soc. 2000, 122, 12057.

Inhibitor

hν, CH3CN

hν, CD2Cl2

Cp*Ru OTf+ _

MeCNMeCN NCMe

THF, 5h, rt

Accelerator

THF, rt

Redox Control

Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038.

t½ = 15 h, 84°C t½ > 24 h, 120°C

Tautomeric Trigger

Choy, N.; Russell, K. C. Heterocycles 1999, 51, 13.

Oxo tautomer Hydroxy tautomer

Lumazine

165°C

165°Ct1/2 = 6.1 min. t1/2 = 10.1 min.

37% 0%

“Photo-Bergman”

H n-Pr

Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.

i-PrOH

A-1A-2

A-3 (cis)

A-3 (trans)

“Photo-Bergman”

H n-Pr

i-PrOH

A-3 (cis)

A-3 (trans)

Mechanism:

3[A] A-2 + A-3

A-11[A] n-Pr

Product ratio 2 : 4 :21

“Photo-Bergman”

i-PrOH

B-11[B] Ph

Mechanism:

Other Triggering Methods

• Release of ring strain

• Acid and base-induction

• Enzymatic protecting group cleavage

Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866-4868.

Nicolaou, K. C.; Dai, W.-M. Angew. Chem. Int. Ed. Engl. 1991, 30, 1387-1530. 16. Hay, M. P.; Wilson, W. R.; Denny, W. A. Bioorg. Med. Chem. Lett. 1999, 9, 3417-3422.

Outline

I. Background

IV. Summary

Tandem Ring Annulation

Grissom, J. W.; Calkins, T. L. Tet. Lett. 1992, 33, 2315.

PhCl, 210°C

19-24 h

n=1n=2

72%53%

If n = 1 and R = -CH2OTBS, yield = 58%

Double Aromatization

Bharucha, K. N.; Marsh, R. M.; Minto, R. E.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 3120.

170-190°C

< 0.005M

Radical Cascade

Chow, S.-Y.; Palmer, G. J.; Bowles, D. M.; Anthony, J. E. Org. Lett. 2000, 2, 961.

Bowles, D. M.; Palmer, G. J.; Landis, C. A.; Scott, J. L.; Anthony, J. E. Tetrahedron 2001, 57, 3753.

Bu3SnH / AIBN

PhH, 80°C

Path A

Path B

Picenoporphyrins

R Conditions

Recovered

s.m. Product

H 190°C, 8 h ------ 89%

nBu 190°C, 60 h 44% 50%

Ph 280°C, 18 h ------ 86%

TMS 190°C, 12 h quant. ------

Aihara, H.; Jaquinod, L.; Nurco, D. J.; Smith, K. M. Angew. Chem. Int. Ed. 2001, 40, 3439.

Morphine Synthesis

Consumption of morphine in the U.S. is approaching 100 metric tons annually.

Produced by commercial processing of raw opium from Papaver somniferium

Most efficient synthesis by Rice and coworkers gives 29% yield.

Skeleton of morphine can be used to make other related molecules such as codeine

Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D. Synthesis 1998, Sup. 1, 665.

Morphine

Codeine

Heroin

Morphine Route

Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D. Synthesis 1998, Sup. 1, 665.

Si< 225°C

Diasteroselective Radical Combination

BnOBnO

H PhHPh

Xu, J.; Egger, A.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1996, 79, 2004.

Vasella, A. Pure Appl. Chem. 1998, 70, 425.

230°C

Fullerenes from Cyclic Polyynes

Hunter, J. M.; Fye, J. L.; Roskamp, E. J.; Jarrold, M. F. J. Phys. Chem. 1994, 98, 1810.

Retro [2+2]

C60 fullerene

C70 fullerene

C76 fullerene

C78 fullerene

n = # of carbons in polyyne chain

n = 48

n = 58

n = 60

n = 62

Thin-film Lithography

Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson; C. Macromolecules 2001, 34, 4104.

Conventional Lithographic Process SMIP Process

3,4-Bis(phenylethynyl)styrene Polymerization

m = 7-8

initiator

50°C 250°C

Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson; C. Macromolecules 2001, 34, 4104.

Etch rate (nm/min.)

Material SF6 RIE O2 RIE

silicon 680

Novolac 32.3 153.5

poly(3,4-bis(phenylethynyl)styrene) 18.3 80

cured poly(3,4-bis(phenylethynyl)styrene) 11.6 52.5

poly(1-vinylpyreneco-styrene) 18 75

Enediyne Antibiotics

NHO Me

ONHCO2Me

MeO NH

Me OMe

NHCO2Me

HNCO2H

Esperimicin A1 Calicheamicin 1

Neocarzinostatin chromophoreDynemicin A

Calicheamicin Bound to DNA

http://www.scripps.edu/chem/nicolaou/respages/bio20b.htm

Calicheamicin γ1I

Me OMe

NHCO2Me

Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton, G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464.

Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. O.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3466.

Triggering device – initiates cyclization when the

molecule reaches the target

“Warhead” –

Delivery system – targets molecule to DNA

enediyne capable of forming

damaging 1,4-diradical

Calicheamicin Mechanism

O-sugar

DNA cleavage

Nicolaou, K. C.; Dai, W.-M. Angew. Chem. Int. Ed. Eng. 1991, 30, 1387.Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc.

1988, 110, 4866.

d = 3.35Å

d = 3.16Å

t1/2 at 37°C = 4.5 ± 1.5 s

DNA Cleavage

2. [H ]

De Voss, J. J.; Townsend, C. A.; Ding, W.-D.; Morton, G. O.; Ellestad, G. A.; Zein, N.; Tabor, A. B.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 9669.

Mylotarg™

antibody - a protein molecule produced by vertebrates that binds with high

specificity to a "foreign" entity (antigen) that has entered the system

by one means or another

Recombinant antibody conjugated with Calicheamicin

Gemtuzumab ozogamicin

http://www.fda.gov/cder/foi/label/2000/21174lbl.pdf

Catalytic Antibody

catalytic antibody (“abzyme”)- an antibody capable of catalyzing specific

chemical reactions

1) Design and synthesize a molecule whose charge and shape closely resemble those of the transition state of the reaction to be catalyzed.

2) Attach the molecule to a larger molecule and provoke an immune response to the complex in a living system.

3) Isolate the resultant antibodies for catalytic activity of the type desired.

Process of generating a catalytic antibody

Antibody CatalysisHN

NHCOCF3

Transition-state hapten analog

NHCOCF3

F3COCHN O

Jones, L. H.; Harwig, C. W.; Wentworth, Jr., P.; Simeonov, A.; Wentworth, A. D.; Py, S.; Ashley, J. A.; Lerner, R. A.; Janda, K. D. J. Am. Chem. Soc. 2001, 123, 3607.

Targeted Protein Degradation

Target receptor

Receptor cleavageReceptor

recognition element

Jones, G. B.; Wright, J. M.; Hynd, G.; Wyatt, J. K.; Yancisin, M.; Brown, M. A. Org. Lett. 2000, 2, 1863.

O = a member of a library

of estrogenic probes

Summary

• Bergman cycloaromatization can be tuned by:– Sterics

– Electronics

– Metals

– Triggering devices (eg. tautomerization, release of ring strain)

• Varied applications – Formation of polycyclic systems

– Biological (eg. antibiotics, protein degradation)

– Materials Science

Acknowledgements

Professor Charles T. Lauhon

Konstantin Levitsky

Jen Slaughter

Jason Pontrello

Lisa Jungbauer

Margaret Biddle

Wendy Deprophetis

John Herbert

Susie Martins

Scott Petersen

Bergman Cycloaromatization Whitney M. Erwin February 21, 2002 ∆ 2 [H ]

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