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