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Target Directed Synthesis via StReCH Chemistry: Pregabalin (Lyrica TM ) Bryan D. Beall, Paul R. Blakemore Department of Chemistry, Oregon State University.

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Presentation on theme: "Target Directed Synthesis via StReCH Chemistry: Pregabalin (Lyrica TM ) Bryan D. Beall, Paul R. Blakemore Department of Chemistry, Oregon State University."— Presentation transcript:

1 Target Directed Synthesis via StReCH Chemistry: Pregabalin (Lyrica TM ) Bryan D. Beall, Paul R. Blakemore Department of Chemistry, Oregon State University

2 substratecarbenoid reagent intermediate metalate complex new substrate Stereospecific Reagent Controlled Homologation (StReCH) 1

3 substrate intermediate metalate complex new substrate carbenoid reagent Stereospecific Reagent Controlled Homologation (StReCH) 1

4 substrate intermediate metalate complex new substrate carbenoid reagent Stereospecific Reagent Controlled Homologation (StReCH) 1

5 substrate intermediate metalate complex new substrate Requirement 1 configurational and chemical stability of carbenoid during ate-complex formation carbenoid reagent Stereospecific Reagent Controlled Homologation (StReCH) 1

6 substrate intermediate metalate complex new substrate Requirement 2 stereospecific formation and break-down of ate-complex carbenoid reagent Stereospecific Reagent Controlled Homologation (StReCH) 1

7 substrate intermediate metalate complex new substrate Requirement 3 greater stability of ate-complex than carbenoid (to prevent oligomerization) carbenoid reagent Stereospecific Reagent Controlled Homologation (StReCH) 1

8 An Example of a Simple StReCH Reaction sulfoxide ligand exchange ate-complex formation 1,2-metalate rearrangement Blakemore, Burge J. Am. Chem. Soc. 2007, 129,

9 Discovered by Richard B. Silverman of Northwestern University First drug approved by the FDA for wide spread pain of fibromyalgia Also treats epilepsy and neuropathic pain disorders Sales of Lyrica TM (1.8 billion in 2007) First Pfizer pharmaceutical drug in a decade to gross over one billion dollars in a fiscal year Pregabalin (Lyrica TM ) 3

10 Analogue of gamma-aminobutyric acid (GABA) Binds to the  protein subunit of voltage-sensitive calcium channels, modifying calcium transduction and neurotransmitter release Acts as a agonist of GABA receptors Increases GABA levels by increasing glutamic acid decarboxylase (GAD) activity GAD is an enzyme that synthesizes glutamate to GABA in one step 4 GABA pregabalin

11 Planned Synthetic Approach to Pregabalin StReCH methylene insertionamination ozonolysis / deprotection 5 65%

12 Synthesis of  Chlorosulfoxide Drago, Caggiano, Jackson Angew. Chem., Int. Ed. 2005, 44, 7221 Satoh, Oohara, Ueda, Yamakawa Tetrahedron Lett. 1988, 29, 313 6

13 Synthesis of Allylboronate Roush, Adam, Walts, Harris, D. J. J. Am. Chem. Soc., 1986, 108,

14 StReCH Reaction Results: Yield Analysis %yield 33-48% 16% t-BuLi 2 eq 1.1 eq chlorosulf. 2 eq 1 eq boronate 1 eq 2 eq 8

15 StReCH Reaction Results: Attempted Ee Analysis 9

16 no resolution of racemic standard with four standard chiral HPLC columns (Daicel AD, OD, AS, OJ) 9

17 StReCH Reaction Results: Attempted Ee Analysis alternate determination via NMR analysis of Mosher ester derivative in progress 9

18 Methylene Insertion 10 model study

19 Methylene Insertion 10 model study 73% ≈ 64%, product was volatile as an alcohol StReCH and methylene insertion

20 Summary and Future Work StReCH methylene insertionamination ozonolysis / deprotection 11

21 Acknowledgements HHMI for funding Paul Blakemore Chris Emerson Kevin Ahern

22 Sulfoxide Chlorination: Mechanism


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