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