Transcript Bergman Cycloaromatization - University of Wisconsin–Madison

Bergman Cycloaromatization
∆
2 [H ]
Whitney M. Erwin
February 21, 2002
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
Bergman Cycloaromatization
200 ºC
0.01 M
2 [H ]
t1/2 = 30 s
100%
2,6,10,14-tetramethylpentadecane as solvent
Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc., 1972, 94, 660.
Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
Alkyne Termini Separation
A
Compound ring size
d
B
C
(CH2)n
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
Critical d range for spontaneous cyclization at rt = 3.4 – 2.9 Å
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.
Calculated Values
level
expt
∆HR°
(kcal/mol)
4.7
∆EST
(kcal/mol)
137.3 ± 3.3
-3.8 ± 0.5
138.0 ± 1.0
+
2
∆Hf°
(kcal/mol)
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
II.
Reaction Control
- Substituent Effects
- Variations
- Use of metals
- Triggers
III.
Applications
- Synthesis
- Materials Science
- Biology
IV.
Summary
Alkynyl Substituent Effects
RR
Monosubstituted

R
R
Strong σ–acceptors and /or πdonors lower the cyclization
barrier
R
R
 Ex. –F, -OH, -NH3+, -OH2+

 Ex. -BH2, -AlH2
Disubstituted


Barriers depend on steric
hindrance to substituents in the
TSs
Planar systems follow same
pattern as above
∆G
∆G(kcal/mol)
(kcal/mol)
π-Withdrawing groups raise the
cyclization barrier
R
R=
=
Reaction
Reaction coordinate
coordinate
H
H
Br
Cl
NO
Br 2
OH
NO2+
NH3
OH
F
F
OH2+
OH2+
Prall; M.; Wittikopp, A.; Fokin, A. A.; Schreiner, P. R. J. Comp. Chem. 2001, 22, 1605.
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
9-membered
Cl
10-membered
Cl
11-membered
10-membered dichloro
Cl
Cl
Cl
t1/2 = 8h/0°C
t1/2 = 60h/40°C
t1/2 = 2h/170°C
t1/2 = 24h/170°C
18h/50°C
5h/80°C
Cl
Cl
Cl
Cl
Cl
Jones, G. B.; Plourde II, G. W. Org. Lett. 2000, 2, 1757.
Benzannelation
Alters the kinetically important step in the cyclization of strained cyclic enediynes.
H-donor
Rate-limiting
Retro-cyclization barrier = 15.3 kcal/mol
H abstraction barrier = 12.7 kcal/mol
H-donor
Rate-limiting
Retro-cyclization barrier = 5.9 kcal/mol
H abstraction barrier = 11.8 kcal/mol
Kaneko, T.; Takahashi, M.; Hirama, M. Tet. Lett. 1999, 40, 2015.
Koseki, S.; Fujimura, Y.; Hirama, M. J. Phys. Chem. A 1999, 103, 7672.
Aza- and Protonated Aza-Bergmans
X
X
X
X
N
H
N
Reaction coordinate
Cramer, C. J. J. Am. Chem. Soc. 1998, 120, 6261.
X
Donors
∆
RH
CCl4
Cl
CH3OH
CH2OH
Cl
Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
Mg2+-induced Cyclization
2+
N
N
MeOH, MgCl2
N
N
Mg
N
0°C, 8h
N
N
N
70%
2+
MeOH
N
N
NaBH4, 5-10°C
N
DMF, EDTA, CH2Cl2
Mg
rt
N
40%
Rawat, D. S.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123, 9675.
H
N
N
N
H
N
Metal Coordination
O
O
194°C
N
N Cu N
N
O
N
N Cu N
N
S
S
O
N Cu N
N
N
116°C
O
N Cu N
N
N
O
O
S
S
S
S
O
Cl Cu N
Cl
N
O
152°C
Cl Cu N
Cl
N
O
S
O
O
S
Benites, P. J.; Rawat, D. S.; Zaleski, J. M. J. Am. Chem. Soc. 2000, 122, 7208.
CpRu as Accelerator / Inhibitor
Accelerator
THF, rt
0%
THF, 5h, rt
OTf
+
Ru
MeCN
MeCN
Cp*Ru
+
_
OTf
_
71%
NCMe
Inhibitor
hν, CH3CN
Cp*Ru
+
15%
_
OTf
hν, CD2Cl2
Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.; Cecil, T. L.
Am. Chem. Soc. 1996, 118, 3291.
0%
J.
O’Connor, J. M.; Lee, L. I.; Gantzel, P. J. Am. Chem. Soc. 2000, 122, 12057.
Redox Control
O
OCH3
O
OCH3
t½ = 15 h, 84°C
t½ > 24 h, 120°C
82%
O
OCH3
O
OCH3
Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038.
Tautomeric Trigger
O
N
HN
O
OH
Lumazine
N
N
N
H
N
Oxo tautomer
HO
N
N
Hydroxy tautomer
O
H3C
OCH3
N
N
O
N
N
N
N
H3CO
N
N
CH3
DMSO
165°C
t1/2 = 6.1 min.
DMSO
165°C
OCH3
O
N
N
37%
O
N
t1/2 = 10.1 min.
N
N
N
H3CO
N
Choy, N.; Russell, K. C. Heterocycles 1999, 51, 13.
N
0%
“Photo-Bergman”
H
H
n-Pr
OH
n-Pr
hν
n-Pr
n-Pr
+
i-PrOH
+
A-3 (cis)
n-Pr
n-Pr
A-1
n-Pr
n-Pr
H
A-2
A
H
n-Pr
H
n-Pr
A-3 (trans)
hν
i-PrOH
B
B-1
Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.
“Photo-Bergman”
H
H
n-Pr
OH
n-Pr
hν
n-Pr
n-Pr
+
i-PrOH
n-Pr
A-1
A
Product ratio 2 : 4 :
Mechanism:
A
+
A-3 (cis)
n-Pr
n-Pr
hν
n-Pr
H
2
1
A-2
H
n-Pr
H
n-Pr
A-3 (trans)
1[A]
A-1
n-Pr
n-Pr
ISC
3[A]
A-2 + A-3
[A]
Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.
“Photo-Bergman”
hν
i-PrOH
B
B-1
Mechanism:
hν
B
1[B]
B-1
Ph
ISC
3[B]
Ph
[B]
Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.
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
II.
Reaction Control
- Substituent Effects
- Variations
- Use of metals
- Triggers
III.
Applications
- Synthesis
- Materials Science
- Biology
IV.
Summary
Tandem Ring Annulation
O
O
MeO
O
n
MeO
n
MeO
n
PhCl, 210°C
R
R
R
19-24 h
n=1
n=2
72%
53%
If n = 1 and R = -CH2OTBS,
yield = 58%
OMe
O
R
42%
Grissom, J. W.; Calkins, T. L. Tet. Lett. 1992, 33, 2315.
Double Aromatization
H
H
170-190°C
H
< 0.005M
H
10%
Bharucha, K. N.; Marsh, R. M.; Minto, R. E.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 3120.
Radical Cascade
Path A
H
H
Path B
Br
Bu3SnH / AIBN
PhH, 80°C
36%
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.
Picenoporphyrins
Ph
Ph
R
N
N
N
Ni
R
N
N
Ni
N
R
N
N
Ph
R
Ph
Ph
N
R
Conditions
Recovered
s.m.
R
N
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.
------
Ni
N
R
N
Ph
Aihara, H.; Jaquinod, L.; Nurco, D. J.; Smith, K. M. Angew. Chem. Int. Ed. 2001, 40, 3439.
Morphine Synthesis

HO
Consumption of morphine in the
U.S. is approaching 100 metric
tons annually.
O
H

Produced by commercial
processing of raw opium from
Papaver somniferium
MeO
HO
Morphine
O
H


Most efficient synthesis by Rice
and coworkers gives 29% yield.
Skeleton of morphine can be used
to make other related molecules
such as codeine
NMe
HO
Codeine
NMe
AcO
O
H
AcO
Heroin
Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D.
Synthesis 1998, Sup. 1, 665.
NMe
Morphine Route
R
R
R
Si
R
O
Si
O
Si
HO
R
R
Si
H
O
Si
R
R
R
TBSO
O
O
R
R
R
O
N
TBSO
N
O
N
TBSO
Si
O
[O]
HO
∆
O
O
HO
O
O
Si
Si
O
N
H+
H
Si
< 225°C
TBSO
Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.; Gonzalez, D.
Synthesis 1998, Sup. 1, 665.
Si
Diasteroselective Radical Combination
OBn
BnO
BnO
OBn
O
PhCl
BnO
BnO
BnO
O Ph
H
H
O
230°C
BnO
BnO
O
BnO
BnO
OBn
BnO
BnO
OBn
BnO
BnO
O
H
O
H
Ph
OBn
BnO
BnO
O Ph
O
H
O
BnO
BnO
BnO
O
O
H
BnO
O
Ph
BnO
BnO
Ph
H
Ph
HO
O
55%
Xu, J.; Egger, A.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1996, 79, 2004.
Vasella, A. Pure Appl. Chem. 1998, 70, 425.
Fullerenes from Cyclic Polyynes
+
Retro [2+2]
Hunter, J. M.; Fye, J. L.; Roskamp, E. J.; Jarrold, M. F. J. Phys. Chem. 1994, 98, 1810.
Fullerenes from Cyclic Polyynes
n = 48
C60 fullerene
n = 58
C70 fullerene
n = 60
C76 fullerene
n = 62
C78 fullerene
n-1
n = # of carbons
in polyyne chain
n
n-5
Hunter, J. M.; Fye, J. L.; Roskamp, E. J.; Jarrold, M. F. J. Phys. Chem. 1994, 98, 1810.
Fullerenes from Cyclic Polyynes
Hunter, J. M.; Fye, J. L.; Roskamp, E. J.; Jarrold, M. F. J. Phys. Chem. 1994, 98, 1810.
Thin-film Lithography
Conventional Lithographic Process
SMIP Process
Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson; C. Macromolecules 2001, 34, 4104.
3,4-Bis(phenylethynyl)styrene Polymerization
n
n
initiator
50°C
250°C
m = 7-8
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
18
75
poly(1-vinylpyreneco-styrene)
Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson; C. Macromolecules 2001, 34, 4104.
Enediyne Antibiotics
SSSMe
O
O
OH
NHCO2Me
HO
O
Me
O
O
O
O
O
Me
SMe
O
Me
OH
NHCO2Me
HO
Me
O
O
O
OH
OH
O
I
OMe
O
Calicheamicin gI1
Me
O
MeO
OH
O
O
OMe
O
O
Me
O
H
OH
O
CO2H
HN
Me
O
O
O
OMe
H
Me
HN
O
HO
O
OH
O
OH
Dynemicin A
Me
OH
O
OMe
Me
Esperimicin A1
OMe
O
Me
HO
NH
S
OMe
NHEt
O
MeO
Me
O
NH
O
OMe
NH2
O
MeO
O
Me
NH
OH
SSSMe
Neocarzinostatin chromophore
Calicheamicin Bound to DNA
http://www.scripps.edu/chem/nicolaou/respages/bio20b.htm
Calicheamicin γ1I
Triggering device – initiates cyclization when the
O
SSSMe
NHCO2Me
HO
O
O
O
Me
O
Me
O
S
O
NH
OH
O
molecule reaches the target
OH
Me
OMe
I
OMe
OMe
NHEt
O
HO
Me
O
MeO
“Warhead” –
OH
enediyne capable of forming
damaging 1,4-diradical
Delivery system – targets molecule to DNA
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.
Calicheamicin Mechanism
O
H
N
O
O
COMe
HO
H
N
O
O
COMe
H
N
O
COMe
HO
HO
O-sugar
S
O-sugar
S
MeS
S
Nu
d = 3.35Å
O-sugar
S
d = 3.16Å
t1/2 at 37°C = 4.5 ± 1.5 s
O
DNA cleavage
H
N
O
COMe
HO
O-sugar
S
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.
DNA Cleavage
HO
P
O
HO
O
O
B
[Ar ]
P
O
HO
O
O
B
P
O
O
1. O2
B
O
HOO
2. [H ]
ArH
O
HO
P
O
HO
HO
P
P
HO
O
HO
O
O
O
Red.
O
O
B
P
OH
P
O
O
O
O
B
H O
O
HO
P
O
O
HO
P
O
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™
Gemtuzumab ozogamicin
Recombinant antibody
conjugated with
Calicheamicin
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
http://www.fda.gov/cder/foi/label/2000/21174lbl.pdf
Catalytic Antibody
catalytic antibody (“abzyme”)- an antibody capable of catalyzing specific
chemical reactions
Process of generating a catalytic antibody
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.
Antibody Catalysis
NHCOCF3
H
N
O
CO2H
Transition-state hapten analog
NHCOCF3
2H
NHCOCF3
NHCOCF3
OH
OH
OH
O2
F3COCHN
O
O
OH
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
O
OH
O
= a member of a library
of estrogenic probes
HO
Receptor
recognition
element
Receptor
cleavage
Target
receptor
Jones, G. B.; Wright, J. M.; Hynd, G.; Wyatt, J. K.; Yancisin, M.; Brown, M.
A. Org. Lett. 2000, 2, 1863.
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