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

100%

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.

A

B

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

d

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.

+

2

Outline

I. Background



IV. Summary

R

R

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

OHNH3

+

FOH2

+

∆G

(kcal/mol)

Reaction coordinate

R

R

R =

HCl

Br

OHNO2

FOH2

+

∆G

(kcal/mol)

R

R

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

Cl

Cl

Cl

Cl

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

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

N

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

NH

X

X

XX X

Reaction coordinate

Donors

Cl

Cl

CCl4

∆

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

RH CH3OH

CH2OH

Mg2+-induced Cyclization

N

N

N

N

N

N

N

N

Mg

2+

N

N

N

N

Mg

2+

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

N

N

N

NH

H

MeOH, MgCl2

0°C, 8h

70%

MeOH

rt

NaBH4, 5-10°C

DMF, EDTA, CH2Cl2

40%

Metal Coordination

N

CuNN

N

O

O

N

CuNN

N

O

O

Cu NN

NN

S

S

O

O

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

Cu NN

NN

S

S

O

O

Cu NN

ClCl

S

S

O

O

Cu NN

ClCl

S

S

O

O

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+ _

Cp*Ru OTf+ _

Ru

MeCNMeCN NCMe

+OTf

_

THF, 5h, rt

71%

Accelerator

THF, rt

15%

0%

0%

Redox Control

O

O

O

O

OCH3

OCH3

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

OCH3

OCH3

t½ = 15 h, 84°C t½ > 24 h, 120°C

82%

Tautomeric Trigger

N

NHN

NH

O

O N

NN

N

OH

HO

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

N

NN

N

OCH3

H3CO

N

NN

N

OCH3

H3CON

NN

N

O

O

N

NN

N

O

O

H3C

CH3

Oxo tautomer Hydroxy tautomer

Lumazine

DMSO

165°C

DMSO

165°Ct1/2 = 6.1 min. t1/2 = 10.1 min.

37% 0%

“Photo-Bergman”

n-Pr

n-Pr

n-Pr

n-Pr

H

n-Pr

n-Pr

OH

H n-Pr

H

n-Pr

H H

n-Pr

n-Pr

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

i-PrOH

i-PrOH

hν

hν

A

B

A-1A-2

A-3 (cis)

A-3 (trans)

B-1

+ +

“Photo-Bergman”

n-Pr

n-Pr

n-Pr

n-Pr

H

n-Pr

n-Pr

OH

H n-Pr

H

n-Pr

H H

n-Pr

n-Pr


i-PrOH

AA-1

A-2

A-3 (cis)

A-3 (trans)

+ +

Mechanism:

A

3[A] A-2 + A-3

A-11[A] n-Pr

n-Pr

[A]

hν

hν

ISC

Product ratio 2 : 4 :21

“Photo-Bergman”


i-PrOH

B B-1

B

3[B]

B-11[B] Ph

Ph

[B]

Mechanism:

hν

hν

ISC

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

R

MeO

O

nMeO

O

n

R

MeO

O

R

n

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

R

OMe

O

PhCl, 210°C

19-24 h

n=1n=2

72%53%

42%

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

Double Aromatization

H

H

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

H

H

10%

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.

Br

Bu3SnH / AIBN

PhH, 80°C

36%

H

H

Path A

Path B

Picenoporphyrins

N

N N

R

R

N

Ph

Ph

Ni

N

N N

N

Ph

Ph

Ni

R

R

N

N N

N

Ph

Ph

Ni

R

R

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

HO

O

HO

HNMe

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

MeO

O

HO

HNMe

AcO

O

AcO

HNMe

Morphine

Codeine

Heroin

Morphine Route

HO

TBSO

O

Si

Si

N

O

O

RR

RR

O

TBSO

Si

Si

N

O

O

O

H

R

R

R

R O

TBSO

Si

Si

HO

N

O

O

RR

R R

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

HO

O

TBSO

HN

O

O

Si

SiSi

Si< 225°C

[O]

∆

H+

Diasteroselective Radical Combination

O

BnOBnO

BnO

OBn

O

BnO

OBn

BnO

BnO

OBnO

BnO

O

OBn

O

BnO

O

BnOH

HPh

Ph

HH

BnO

O

BnOBnO

OBn

O

BnO

O

BnO

O

H PhHPh

BnO

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

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

OBnO

BnO

O

OBn

O

BnO

O

BnOH

Ph

PhH

BnO

55%

PhCl

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

n

n-1

n-5



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

nn

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

OOH

MeO

NHO Me

OH

OO

O

SSSMe

HO

ONHCO2Me

MeO

MeO NH

OMeO

O

O

O

O

OH

Me

MeMe

OMe

SMe

NH2

O

O

OH

HO

MeO

I

Me OMe

OMe

S OO

OHO

NHO

OH

OO

OOMe

SSSMe

HO

O

NHCO2Me

Me

NHEt

Me

Me

O

OOH

OH OH

HNCO2H

OMe

O

MeH

O

O

OMe

Me

O

O

O

O

O

O

O

OH

HO

Me

N

Me

H H

Esperimicin A1 Calicheamicin 1

Neocarzinostatin chromophoreDynemicin A

Calicheamicin Bound to DNA

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

Calicheamicin γ1I

O

O

OH

HO

MeO

I

Me OMe

OMe

S OO

OHO

NHO

OH

OO

OOMe

SSSMe

HO

O

NHCO2Me

Me

NHEt

Me

Me

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

HN

O

HO

O-sugar

Nu

COMe

O

SS

MeS

HN

O

HO

O-sugar

COMe

O

S

HN

O

HO

O-sugar

COMe

O

S

HN

O

HO

O-sugar

COMe

O

S

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

OB

O

O

P OHO

P OHO

OB

O

O

P OHO

P OHO

OB

O

O

P OHO

P OHO

HOO

OB

O

P OHO

OOH

P OHO

OB

O

O

P OHO

P OHO

OH

[Ar ]

ArH

1. O2

2. [H ]

Red.

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

OCO2H

NHCOCF3

OH

NHCOCF3

OH

NHCOCF3

Transition-state hapten analog

OH

NHCOCF3

OH

F3COCHN O

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.

O2

2 H

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.

OH

HO

O

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

Documents

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