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

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

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

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

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

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

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

An Example of a Simple StReCH Reaction 2 An Example of a Simple StReCH Reaction sulfoxide ligand exchange 1,2-metalate rearrangement ate-complex formation Blakemore, Burge J. Am. Chem. Soc. 2007, 129, 3068

Pregabalin (LyricaTM) 3 Pregabalin (LyricaTM) 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 LyricaTM (1.8 billion in 2007) First Pfizer pharmaceutical drug in a decade to gross over one billion dollars in a fiscal year

Pregabalin (LyricaTM) 4 Pregabalin (LyricaTM) pregabalin GABA 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

Planned Synthetic Approach to Pregabalin 5 Planned Synthetic Approach to Pregabalin ozonolysis / deprotection StReCH 65% methylene insertion amination

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

Synthesis of Allylboronate 7 Synthesis of Allylboronate Roush, Adam, Walts, Harris, D. J. J. Am. Chem. Soc., 1986, 108, 3422

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

StReCH Reaction Results: Attempted Ee Analysis 9 StReCH Reaction Results: Attempted Ee Analysis

StReCH Reaction Results: Attempted Ee Analysis 9 StReCH Reaction Results: Attempted Ee Analysis • no resolution of racemic standard with four standard chiral HPLC columns (Daicel AD, OD, AS, OJ)

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

10 Methylene Insertion model study

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

Summary and Future Work 11 Summary and Future Work ozonolysis / deprotection StReCH methylene insertion amination

Acknowledgements HHMI for funding Paul Blakemore Chris Emerson Kevin Ahern

Sulfoxide Chlorination: Mechanism