Synopsis of Research
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Phosphorylation of Functionalized Alcohols and Diols Using a Lewis
Acid Catalyst Kyle P. Pedretty and Bianca R. Sculimbrene
Department of Chemistry
April 19, 2013
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Phosphorylated CompoundsPhosphorylated BiopolymersPhosphorylated Small Molecules
FostriecinNatural Product
Produced by Actinobacteria
FludarabineTreatment of Hematological MalignanciesManufactured by Genzyme Therapeutics
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Previous P(V) Phosphorylation Techniques and Limitations
• Reaction is limited to phenyl protecting groups, which are then removed under harsh conditions
• Reaction is not catalytic• Not compatible with base-sensitive compounds
Reliance on Phenyl Protecting Group
Reliance on Reactive Alkoxide
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Phosphorylation Work In The Sculimbrene Lab
Limitations overcome using Pyrophosphates• Not limited to phenyl protecting groups
• To date Sculimbrene Lab has synthesized 5 orthogonally protected pyrophosphates
• Catalyst lowers the energy of activation so the reactive alkoxide is no longer necessary
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Synthesis of Tetrabenzyl Pyrophosphate
Benefits of Pyrophosphate Synthesis• Urea byproduct crashes out of solution → Removed by filtration• No chromatography necessary → Recrystallized to obtain pure product
Benefits of Tetrabenzyl Pyrophosphate• Benzyl protecting groups removed under hydrogenolysis
84% Yield(15g Scale)
Nelson, T.D.: et al., “Tetrabenzyl Pyrophosphate” Organic Syntheses, 2003, 80, 219.
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Pyrophosphate Phosphorylation of Unfunctionalized Alcohols
• Previous exploration using Pyrophosphates as a phosphorylating agent was focused on alkyl and phenolic alcohols.
Goal:• Develop this chemistry with
functionalized alcohols and diols
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Amino Acid Phosphorylation
54% Conversion50% Yield
10 mol% Ti(OtBu)4
1.2eqv. TBPP, 1.5eqv. NiPr2Et
CH2Cl2
Protected Tyrosine
77% Conversion71% Yield
10 mol% Ti(OtBu)4
1.2eqv. TBPP, 1.5eqv. NiPr2Et
CH2Cl2
Protected Serine
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Phosphorylation of Allylic Alcohols
94% Conversion86% Yield
28% Conversion18% Yield
10 mol% Ti(OtBu)4
1.2eqv. TBPP, 1.5eqv. NiPr2Et
10 mol% Ti(OtBu)4
1.2eqv. TBPP, 1.5eqv. NiPr2Et
CH2Cl2
CH2Cl2
Geraniol
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FTY720: an immunomodulating drug
• In order to selectively phosphorylate one hydroxyl group over the other, we are looking into developing a chiral catalyst
Mirror plane
Rosen, H. et al., “Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists” Science 2002, 296, 346-349
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Development of an FTY720 analogue
Analogue
3.4eqv. Et3N
CH2Cl2
+
1.2 eqv. Boc protected FTY720 analogue
65% Yield
FTY720$315.00 for 50mg
2-amino-2-ethyl-1,3-propanediol$35.40 for 100g
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Phosphorylation of Diols
• Phosphorylation of diols can result in monophosphorylation or diphosphorylation
Reaction Conditions Monophosphorylated Yield
DiphosphorylatedYield
1.2eqv. TBPP, 1.5eqv. NiPr2Et 93% 0%
3.0eqv. TBPP, 3.2eqv. NiPr2Et 77% 7%
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Phosphorylation of Diols
41% Monophosphorylated Yield10 mol% Ti(OtBu)4
1.2eqv. TBPP, 1.5eqv. NiPr2Et
CH2Cl2
10 mol% Ti(OtBu)4
1.2eqv. TBPP, 1.5eqv. NiPr2Et
CH2Cl2
26% Diphosphorylated Yield
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Future Direction
Chiral Lewis Acid Catalyst
• We hope to use TADDOL bound to our catalyst to achieve asymmetric phosphorylation of FTY720
TADDOL
• Our lab plans to study the reactivity of diols to understand the factors that control selectivity.
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Acknowledgments
I would like to thank my research advisor, Professor Sculimbrene as well as the members of the Sculimbrene
lab; Emily Allen, Kelsey Poremba and Kyle Coppola, and all previous phosphorylation chemists in the Sculimbrene
Lab.
I would also like to thank the Alumni/Parent Summer Research Fellowship, Dr. & Mrs. Christopher Cheney P’10.
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Catalytic Cycle