Target Directed Synthesis via StReCH Chemistry: Pregabalin (LyricaTM)

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Target Directed Synthesis via StReCH Chemistry
Pregabalin (LyricaTM)

• Bryan D. Beall, Paul R. Blakemore
• Department of Chemistry, Oregon State University

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Stereospecific Reagent Controlled Homologation
(StReCH)
1
intermediate metalate complex
substrate
carbenoid reagent
new substrate
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Stereospecific Reagent Controlled Homologation
(StReCH)
1
intermediate metalate complex
substrate
carbenoid reagent
new substrate
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Stereospecific Reagent Controlled Homologation
(StReCH)
1
intermediate metalate complex
substrate
carbenoid reagent
new substrate
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Stereospecific Reagent Controlled Homologation
(StReCH)
1
intermediate metalate complex
substrate
carbenoid reagent
new substrate
configurational and chemical stability of
carbenoid during ate-complex formation
Requirement 1
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Stereospecific Reagent Controlled Homologation
(StReCH)
1
intermediate metalate complex
substrate
carbenoid reagent
new substrate
stereospecific formation and break-down of
ate-complex
Requirement 2
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Stereospecific Reagent Controlled Homologation
(StReCH)
1
intermediate metalate complex
substrate
carbenoid reagent
new substrate
greater stability of ate-complex than carbenoid
(to prevent oligomerization)
Requirement 3
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An Example of a Simple StReCH Reaction
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sulfoxide ligand exchange
1,2-metalate rearrangement
ate-complex formation
Blakemore, Burge J. Am. Chem. Soc. 2007, 129, 3068
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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

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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

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Planned Synthetic Approach to Pregabalin
65
methylene insertion
amination
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Synthesis of ??Chlorosulfoxide
Drago, Caggiano, Jackson Angew. Chem., Int. Ed.
2005, 44, 7221 Satoh, Oohara, Ueda, Yamakawa
Tetrahedron Lett. 1988, 29, 313
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Synthesis of Allylboronate
Roush, Adam, Walts, Harris, D. J. J. Am. Chem.
Soc., 1986, 108, 3422
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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
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StReCH Reaction Results Attempted Ee Analysis
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StReCH Reaction Results Attempted Ee Analysis
no resolution of racemic standard with four
standard chiral HPLC columns (Daicel AD, OD, AS,
OJ)

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

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Methylene Insertion
model study
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Methylene Insertion
model study
StReCH and methylene insertion
64, product was volatile as an alcohol
73
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Summary and Future Work
methylene insertion
amination
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Acknowledgements

• HHMI for funding
• Paul Blakemore
• Chris Emerson
• Kevin Ahern

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Sulfoxide Chlorination Mechanism