Macrocyclization

and

Baeyer-Villiger Oxidation

Greg Lackner

Overman Group Topics Presentation

June 18, 2012

Diverse Applications of Macrocycles

azithromycin

Macrocycles as drug candidates

“Compromise between structural organization and flexibility”

Candidates typically contain little modification of natural macrocycles

amphotericin B

cyclosporin

rifampicin

Driggers, E.; Hale, S.; Lee, J.; Terrett, N. Nat. Rev. Drug Discov. 2008, 7, 608-624

Diverse Applications of Macrocycles

Macrocycles in nature

Macrocycles in chelation chemistry

chlorin

heme B

macrocycle shown to coordinate Cu2+

10,000 times more strongly!

Cabbiness, D.; Margerum, D. J. Am. Chem. Soc. 1969, 91, 6540-6541

Cabbiness, Margerum, 1969

Macrolactonization

Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106, 911-939

Simple disconnection in macrolide synthetic targets

May require alcohol protecting groups, dilute conditions

Alcohol epimerization and olefin isomerization may occur under

activation conditions

Requires activation of alcohol or carboxylic acid

Macrolactonization: Ring Size and

Reactive Conformation

Substituents play an important role in directing cyclization

Andrus et al., 1996

Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006, 106, 911-939

Macrolactonization: Ring Size and

Reactive Conformation

Mulzer et al. J. Am. Chem. Soc. 1991, 113, 910

White et al. J. Am. Chem. Soc. 2001, 123, 8593

Reactive conformation can provide regioselective cyclization

Mulzer, 1991

White, 2001

Carboxylic Acid Activation

Corey & Nicolau, 1974 (biomimetic) Yamaguchi, 1979 (>200 refs!)

Yamamoto, 1996

a “diolide”

Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989

Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614

Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996, 61, 4560

Alcohol Activation

Mitsunobu conditions,

(Steglich operational

modification, 1991)

Evans, 2002

Justus, K.; Steglich, W. Tetrahedron Lett. 1991, 32, 5781

Evans, D.A.; Hu, E.; Burch, J.D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654

Iodonium- And Epoxide-Mediated

Lactonizations

Competing cyclization pathways can make

these strategies problematic

Rousseau, 2004 Hoye, 2003

Simonot, B.; Rousseau, G. J. Am. Chem. Soc. 1993, 58, 4

Hoye, T.R.; Hu, M. J. Am. Chem. Soc. 2003, 125, 9576

Translactonization

Corey & Nicolau, 1977

“Interconversion rate decreases as ring size increases”

Vedejs, 1987

Corey, E. J.; Brunelle, D. J.; Nicolaou, K. C.; J. Am. Chem. Soc. 1997, 99, 7359

Vedejs, E.; Powell, D. W. J. Am. Chem. Soc. 1982, 104, 2046

Macrolactamization

Almost exclusively via carboxylic acid activation

Many peptide coupling reagents suitable for macrolactamization

Often accelerated by metal ions

Boger, 2003

Chlorofusin

Lee, S. Y.; Clark, R. C.; Boger, D. L. J. Am. Chem. Soc. 2007, 129, 9860

Macrolactamization

Phosphonium-type reagents – more resistant to α-epimerization

than carbodiimides

PyBop

VanNieuwenhze, 2007

Patellamide A

Garcia-Reynaga, P.; VanNieuwenhze, M. S. Org. Lett. 2008, 10 (20), 4621-4623

Diels-Alder and NHK Macrocyclizations

Advantage over macrolactonization/macrolactamization:

Generation of skeletal bonds and stereochemical information

Sorensen, 2005

1

2

Kishi, 2005

Zapf, C. W.; Harrison, B. A.; Drahl., C.; Sorensen, E. J. Angew. Chem., Int. Ed. 2005, 44, 6533-6537

Namba, K.; Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382-15383

Prins-Driven Macrocyclization

Wender, P. A. et al. J. Am. Chem. Soc. 2002, 124, 13648-13649

Wender, P. A.; DeChristopher, B. A.; Schrier, A. J. J. Am. Chem. Soc. 2008, 130, 6658-6659

Wender, 2002 and 2008

Alkyne Haloallylation Macrocyclization

Hoye, 2005

A proposed mechanism:

Hoye, T. R.; Wang, J. J. Am. Chem. Soc. 2005, 127, 6950-6951

Olefination/Macrocyclization

Phillips, 2006

Velazquez, 2007

• RCM macrocyclizations common and reliable

88% (2 steps)

O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340-5341

Velazquez, F. et al. Org. Lett. 2007, 9, 3061-3064

Multicomponent Macrocyclizations

Wessjohann, 2007

Michalik, D.; Schaks, A.; Wessjohann, L. A. Eur. J. Org. Chem. 2007, 149-157

Wessjohann, 2007

Multicomponent Macrocyclizations

Michalik, D.; Schaks, A.; Wessjohann, L. A. Eur. J. Org. Chem. 2007, 149-157

Macrocyclic Ketone Oxidation

Clyne, D. S.; Weiler, L. Tetrahedron 1999, 55, 13659-13682

Weiler, 1999

1899: An Unexpected Discovery

Adolf von Baeyer, Victor Villiger

Examining ring cleavage of cyclic ketones

Many experiments established composition of Caro’s reagent

Search for comparable oxidants led to first synthesis of organic peracids

Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625

Determining the Mechanism

Baeyer and Villiger believed their oxidation to be mechanistically similar to the

Beckmann rearrangement (dioxirane intermediate?) at that time

Dilthey, Inkel, Stephan, 1940

*Dimer must be a byproduct, not an intermediate

Dilthey, W.; Inckel, M.; Stephan, H. J. Prakt. Chem. 1940, 154, 219-237

Labeling Experiments

Doering & Dorfman, 1953

only product observed

Doering, W. v. E.; Dorfman, E. J. Am. Chem. Soc. 1953, 75, 5595-5598

Determining The Stereochemical Outcome

Turner, 1950

Products saponified and derivitized to phthalates

Mixed with natural phthalate samples and melting point measured

Migration occurs with retention of stereochemistry

Mislow & Brenner, 1953 Rozzell & Benner, 1983

Turner, R. B.; J. Am. Chem. Soc. 1950, 72, 882-885

Mislow, K.; Brenner, J. J. Am. Chem. Soc. 1953, 75, 2318-2322

Rozzell, J. D. Jr.; Benner, S. A. J. Org. Chem. 1983, 48, 1190-1193

Migrating Group Preference

Migratory aptitude has largely been elucidated experimentally

Directly related to positive charge-stabilizing ability

3o alkyl > cyclohexyl > 2o alkyl > benzyl > phenyl

> primary alkyl > cyclopropyl ≈ cyclopentyl > methyl

Hawthorne, 1957

Doering & Speers, 1950

Hawthorne, M. F.; Emmons, W. D.; McCallum, K. S. J. Am. Chem. Soc. 1958, 80, 6393-6398

Doering, W. v. E.; Speers, L. J. Am. Chem. Soc. 1950, 72, 5515-5518

Peracid oxidant can influence migration

Hawthorne, 1957

Murray, Johnson, Pederson, Ott, 1958

Migrating Group Preference: Inconsistencies

Baeyer & Villiger, 1899

Migratory aptitudes are strong predictions, not rigid laws

Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625

Hawthorne, M. F.; Emmons, W. D.; McCallum, K. S. J. Am. Chem. Soc. 1958, 80, 6393-6398

Murray, M. F. Johnson, B. A.; Pederson, R. L.; Ott, A. C. J. Am. Chem. Soc., 1956, 78, 981-984

Oxidant Considerations

Peracids are effective oxidants, but too unstable for large-scale applications

Noyori, 1983

Thompson, 1987

Newer peroxide reagents less chemoselective;

alkenes, amines, phosphines, sulfides incompatible

Suzuki, M.; Takada, H.; Noyori, R. J. Org. Chem. 1982, 47 (5), 902-904

Brougham, P.; Cooper, M. S.; Cummerson, D. A.; Heaney, H.; Thompson, N. Synthesis, 1987, 11, 1015-1017

cyclohexanone to caprolactone: 76%

cyclohexanone to caprolactone: 57%

Hydrogen Peroxide As The Oxidant

Cheaper, greener reagent than peracids

Water byproduct simplifies purification

but,

Water can hydrolyze ester/lactone product

Hydrogen peroxide is relatively unreactive; requires activation

Williams, 1961

Brinck, 2001

McClure, J. D.; Williams, P. H. J. Org. Chem. 1962, 27 (1), 24-26

Carlqvist, P.; Eklund, R.; Brinck, T. J. Org. Chem. 2001, 66, 1193

“Aerobic” Baeyer-Villiger Reaction

Ishii, 2001

H2O2 (the true oxidant) generated in situ

Caprolactone is a desirable intermediate for polymer production

Fukuda, O.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2001, 42, 3479

Transition Metal Catalysis

Early transition metals form electrophilic peroxo complexes

MTO shows promise; catalyzes both epoxidations and Baeyer-Villiger

Jacobsen, 1978

Jacobsen, S. E.; Tang, R.; Mares, F. J. Am. Chem. Soc., Chem. Commun. 1978, 888

Hermann, W. A.; Fischer, R. W.; Correia, J.D.G. J. Mol. Catal. 1994, 94, 213

Herrmann, 1994

Asymmetric Variants

Strukul, 1993

Bolm, 1994

(±)

4

(±)

Seebach, 2001

(±)

D. T. Frisone, M.; Pinna, F.; Strukul, G. Organometallics, 1993, 12, 148-156

Bolm, C.; Schlingloff, G.; Weikhardt, K. Angew. Chem. 1994, 106, 1944

Aoki, M.; Seebach, D.Helv. Chim. Acta 2001, 84, 187

Biocatalytic Variants

Baeyer-Villiger Monooxygenases (BVMOs) are selective

enzyme catalysts from many yeasts and E. coli

Require NADPH as a cofactor; O2 is oxidant

t. Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev., 2004, 104, 4105-4123

Cyclohexane monooxygenase (CHMO)

BVMOs In Synthesis

Mihovilovic, 2006

Mihovilovic, Marko D.; Bianchi, D. A.; Rudroff, F. Cheminform, 2006, 37

Baeyer-Villiger In Total Synthesis

Demnitz, 1995

Demnitz, F. W. J.; Philippini, C.; Raphael, R. A. J. Org. Chem. 1995, 60, 5114-5120

Baeyer-Villiger In Total Synthesis

Iwata, 1994

Iwata, 1997

Iwata, C. et al. Tetrahedron Lett. 1994, 35 (24) 4125-4128

Iwata, C. et al. Tetrahedron Lett. 1997, 38 (10) 1801-1804

Summary

Macrocyclizations efficiently construct large, biologically relevant molecules

Macrolactonizations and macrolactamizations are the most straightforward

and most common, but introduce little structural complexity compared to

other methods

Molecular preorganization will determine macrocyclization success

The Baeyer-Villiger reaction uses a peroxide reagent to oxidize ketones to esters

In general, the most substituted carbon atom migrates in the rate-determining step

Enzymes can be used for selective, green Baeyer-Villiger reactions