- Beyond Chemoselectivity: Catalytic Site-Selective Aldolization of Diketones and Exploitation for Enantioselective Alzheimer's Drug Candidate Synthesis
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Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield.
- Nugent, Thomas C.,Najafian, Foad Tehrani,Hussein, Hussein Ali El Damrany,Hussain, Ishtiaq
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- Piperidine-derived γ-secretase modulators
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This Letter details the SAR of a novel series of piperidine-derived γ-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42, increase Aβ38 and have no effect on Aβ40 levels.
- Hall, Adrian,Elliott, Richard L.,Giblin, Gerard M.P.,Hussain, Ishrut,Musgrave, James,Naylor, Alan,Sasse, Rosemary,Smith, Beverley
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supporting information; experimental part
p. 1306 - 1311
(2010/06/15)
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- Fluorinated piperidine acetic acids as γ-secretase modulators
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We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor. Compounds 1f and 2c were selec
- Stanton, Matthew G.,Hubbs, Jed,Sloman, David,Hamblett, Christopher,Andrade, Paula,Angagaw, Minilik,Bi, Grace,Black, Regina M.,Crispino, Jamie,Cruz, Jonathan C.,Fan, Eric,Farris, Georgia,Hughes, Bethany L.,Kenific, Candia M.,Middleton, Richard E.,Nikov, George,Sajonz, Peter,Shah, Sanjiv,Shomer, Nirah,Szewczak, Alexander A.,Tanga, Flobert,Tudge, Matthew T.,Shearman, Mark,Munoz, Benito
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scheme or table
p. 755 - 758
(2010/05/19)
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- PIPERIDINES AND RELATED COMPOUNDS FOR THE TREATMENT OF DEMENTIA
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Compounds of formula I: modulate the action of gamma secretase, and hence find use in treatment of Alzheimer's disease and related conditions.
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Page/Page column 13
(2009/10/01)
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- SILYLATED PIPERIDINE DERIVATIVES
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Compounds of formula I: I wherein at least one of R4 and R5 comprises Si(R6)3 as a substituent selectively attenuate production of A?(1-42) and hence find use in treatment of Alzheimer's disease and related conditions.
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Page/Page column 21-22
(2008/12/07)
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- PIPERIDINES AND RELATED COMPOUNDS FOR TREATMENT OF ALZHEIMER’S DISEASE
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Compounds of formula (I) are modulators of gamma-secretase, and hence are useful in treatment of Alzheimer’s disease.
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- PIPERIDINE DERIVATIVES FOR TREATMENT OF ALZHEIMER'S DISEASE
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Compounds of formula (I) modulate the activity of gamma secretase and hence find use in treatment or prevention of Alzheimer's disease and related conditions.
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Page/Page column 21
(2008/06/13)
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- PIPERIDINES AND RELATED COMPOUNDS FOR THE TREATMENT OF DEMENTIA
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Compounds of formula I: modulate the action of gamma secretase, and hence find use in treatment of Alzheimer's disease and related conditions.
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