asymmetric catalysis of unnatural amino acids · unnatural amino acids used in production of orally...

Susan Wortas, Michigan State University, November 29, 2006

Asymmetric Catalysis of Unnatural Amino Acids

OutlineUnnatural Amino Acids Asymmetric Phase Transfer CatalysisSynthetic Approaches

Optimizing Phase Transfer CatalystDeveloping libraries of Unnatural Amino AcidsUses in natural product synthesis

Unnatural Amino AcidsUsed in production of orally administered peptide-based drugs:

Building Blocks Membrane permeability Metabolically stable Conformational constraints

Used as intermediates in the synthesis of Natural productsHeterocycles

Fluka ChemFiles Unnatural Amino Acids Vol. 1, No. 5 2006

Unnatural Amino AcidsGlycopeptide antibiotic

Vancomycin

Unnatural Amino Acids

Enantiomeric purityLarge scale productionEnvironmentally friendly reagentsInexpensive catalystsHigh atom economy

OutlineUnnatural Amino Acids Asymmetric Phase Transfer CatalysisSynthetic Approaches

Optimizing Phase Transfer CatalystDeveloping libraries of Unnatural Amino AcidsUses in natural product synthesis

C. M. Starks J. Am. Chem. Soc. 1971, 93, 195

C. M. Stark’s Discovery

C. M. Starks J. Am. Chem. Soc. 1971, 93, 195

C. M. Stark’s Discovery

Q+ X- + R YOrganic Phase

Aqueous or Solid Phase

+ Q+ Y-R X

Q+ X- + + Q+ Y-Y-

M+X-

M+

C. M. Stark’s Discovery

C. M. Starks J. Am. Chem. Soc. 1971, 93, 195

Q+ X- + R YOrganic Phase

Aqueous or Solid Phase

+ Q+ Y-R X

Q+ X- + + Q+ Y-Y-

M+X-

M+

Q+ would be the chiral catalyst

C. M. Stark’s Discovery

C. M. Starks J. Am. Chem. Soc. 1971, 93, 195

Ulf Dolling’s Catalyst

U. Dolling J. Am. Chem. Soc. 1984, 106, 446M. O’Donnell Acc. Chem. Res. 2004, 37, 506

Cinchona Plant$0.91/gram $1.28 /gram

Ulf Dolling’s Catalyst

Cinchona Plant

Ion pairing between indanone anion and benzyl cinchonium cation

U. Dolling J. Am. Chem. Soc. 1984, 106, 446M. O’Donnell Acc. Chem. Res. 2004, 37, 506

EnantioselectiveSimple & safe reaction proceduresCatalytic amounts of organocatalystsInexpensive reagents and solventsEasy to scale up reactionsEnvironmentally friendlyHigh Yield

Asymmetric Phase-Transfer Catalysis

Shioiri, T. Arai, S. Stimulating Concepts in Chemistry; Vogtle, F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley: New York, 2000

OutlineUnnatural Amino Acids Asymmetric Phase Transfer CatalysisSynthetic Approaches

Optimizing Phase Transfer CatalystDeveloping libraries of Unnatural Amino AcidsUses in natural product synthesis

Martin O’Donnell’s Schiff Base

M. O’Donnell J. Am. Chem. Soc. 1989, 111, 2353

Three Generations

U. Dolling J. Am. Chem. Soc. 1984, 106, 446 M. O’Donnell Tetrahedron 1994, 50, 4507

M. O’Donnell Acc. Of Chem. Res. 2004, 37, 506

E. J. Corey J. Am. Chem. Soc. 1997, 119, 12414B. Lygo Tet. Let. 1997, 38, 8595

B. Lygo Acc. of Chem. Res. 2004, 37, 518

NN

O-

O

H N+RO

Leads to desired enantiomer Leads to undesired enantiomer

Martin O’Donnell 2005

M. O’Donnell J. Am. Chem. Soc. 2005, 127, 13450

Martin O’Donnell 2005

M. O’Donnell J. Am. Chem. Soc. 2005, 127, 13450

Martin O’Donnell 2005

Synthesis of 4-Substituted Pyroglutamates

M. O’Donnell J. Am. Chem. Soc. 2005, 127, 13450

Synthetic Applications of the Glycine Schiff Base

M. O’Donnell Acc. Of Chem. Res. 2004, 37, 506

Asymmetric Two-Center Catalysts

M. O’Donnell J. Am. Chem. Soc. 1989, 111, 2353M. Shibasaki Tetrahedron 2004, 60, 7743

U. Dolling’s Catalyst M. Shibasaki’s Catalyst

TaDiAS 3: Tartrate-derived Diammonium Salt

Ring could be formed from inexpensive L- or D-Tartrate($0.63 per gram)Needed appropriate distance between two ammonium salt moietiesNeed for 2 bulky groups off of the ammonium salts

M. Shibasaki Tetrahedron 2004, 60, 7743

TaDiAS 3 interacting with a Glycine Schiff Base Enolate

M. Shibasaki Tetrahedron 2004, 60, 7743

Optimization by molecular orbital calculations

M. Shibasaki Tetrahedron 2004, 60, 7743

Optimization by molecular orbital calculations

M. Shibasaki Tetrahedron 2004, 60, 7743

Crystal structure of (S,S)-TaDiAS

M. Shibasaki Angew. Chem. Int. Ed. 2005, 44, 4564

top view side view

M. Shibasaki Tetrahedron 2004, 60, 7743

Alkylation Optimization Conditions

M. Shibasaki Tetrahedron 2004, 60, 7743

Alkylation Optimization Conditions

M. Shibasaki Tet. Lett. 2002, 43, 9539

Alkylation with Optimized Catalyst

M. Shibasaki Tet. 2004, 60, 7743; B. Lygo Acc. of Chem. Res. 2004, 37, 518; E. J. Corey J. Am. Chem. Soc. 1997, 119, 12414

Asymmetric Michael Addition

M. Shibasaki Tet. Lett. 2002, 43, 9539

Asymmetric Michael Addition

M. Shibasaki Tetrahedron 2004, 60, 7743

Asymmetric Michael Addition

M. Shibasaki Tet. Lett. 2002, 43, 9539

Asymmetric Michael Addition

M. Shibasaki Tetrahedron 2004, 60, 7743

Synthetic Application of the Michael Reaction

M. Shibasaki Angew. Chem. Int. Ed. 2006, 45, 4635

Synthetic Application of the Michael Reaction

M. Shibasaki Angew. Chem. Int. Ed. 2006, 45, 4635

α-β Diamino acidsKey structural components of peptides and β-lactam antibiotics:

TuberactinomycinBleomycinCapreomycinNocardicinMonobactamLavendomycinAntrimycinGlumamycinAspartocin

M. Shibasaki Angew. Chem. Int. Ed. 2005, 44, 4564G. Lajoie /J. Org. Chem. 1999, 64, 6160

Bleomycin

Asymmetric Mannich Reaction

OH

HHN

CH3

CH3

N

H

HO

HH+

N

H

H

N

H

HO

R1R2

HHR1

O

R2

H H

N

Base

Mannich-type reaction

NPh

Ph

OtBu

O

+

Schiff BaseKetone

Base

Ph

Ph N

Ph

NH

R2

OtBuO

N

R2

Ph

* *

M. Shibasaki Angew. Chem. Int. Ed. 2005, 44, 4564

Mannich-type reaction

M. Shibasaki Angew. Chem. Int. Ed. 2005, 44, 4564

Mannich-type reaction

M. Shibasaki Angew. Chem. Int. Ed. 2005, 44, 4564

Mannich-type reaction

M. Shibasaki Angew. Chem. Int. Ed. 2005, 44, 4564

Synthetic Applications of the Mannich Reaction

*S. Chandrasekhar Tet. Let. 1999, 40, 5071M. Shibasaki Angew. Chem. Int. Ed. 2005, 44, 4564

ConclusionDevelopment of asymmetric catalystCatalyst can be optimizedInexpensive starting materials & environmentally friendly reagents Enantio- and diasterioselectiveUp to 99:1 syn selectiveAchieve up to quantitative yieldsProven synthetic usefulness

AcknowledgementsAdvisor Dr. GeigerGeiger Group Members & Friends

XiofeiSuzyLeiAdam

Thank you!

Proposed Catalytic Cycle

M. Shibasaki, Angew. Chem. Int. Ed. 2005, 44, 4564-4567