Synopsis of Research
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Transcript of Synopsis of Research
Phosphorylation of Functionalized Alcohols and Diols Using a Lewis
Acid Catalyst Kyle P. Pedretty and Bianca R. Sculimbrene
Department of Chemistry
April 19, 2013
Phosphorylated CompoundsPhosphorylated BiopolymersPhosphorylated Small Molecules
FostriecinNatural Product
Produced by Actinobacteria
FludarabineTreatment of Hematological MalignanciesManufactured by Genzyme Therapeutics
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
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
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.
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
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
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
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
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
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%
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
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.
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.
Catalytic Cycle