Enantioselective Synthesis of Chiral Piperidines via the ...ccc.chem.pitt.edu/wipf/Current...
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EnantioselectiveSynthesisofChiralPiperidinesviatheStepwiseDearomatization/BorylationofPyridinesKojiKubota,YutaWantanabe,KeiichiHayama,andHajameItoJACSASAP10.1021/jacs.6b01375WipfGroup|CurrentLiterature4-9-16JamesJohnson
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PiperidinesaPrivilegedHeterocycle
FromaselecQonof640FDAapproveddrugs.J.Med.Chem.2014,57,10257−10274
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HOPh
O
ON
O
scopolamine
OHO H
HHN
morphine
OH HN
N
SMe
H
pergoline
H
N
NH
H
(-)-sparteineN
NH
NH
HO
HO
juliflorine
N
OHH OH
OH
swainsonine
N OH N NO N OPh
NN
NH2
N
PhNO
N N N
CO2H
N O
Ph
Ph
OO
zamifenacine
(-)-preclamol
HN O
O
O
F
(-)-paroxetine
N
N
O
fentanyl
ibrutinib KDM2A inhibitor
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J.Med.Chem.2014,57,10257−10274Nat.Prod.Rep.2008,25,139–165
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CommonSynthesisofPiperidines• NucleophilicsubsQtuQon• ReacQonofamineswithhalides,acQvatedalcohols,threememberedrings
• ReducQveaminaQon• Intra/intermolecularreducQveaminaQon
• ReacQonofamideswithalkenesandalkynes• IntramolecularMichaeladdiQon,radical1,4reacQonofamineswith
alkenes,hydroaminaQon,reacQonofamineswithalkynes• ReacQonofdienes,enynesanddiynes• Ring-closingmetathesisIntramolecularenereacQons,enereacQons(typeI),ene
reacQons(typeIII)• FormalenereacQons(enehalogenocyclizaQon,π-allylcomplexes,palladium
cross-coupling,iminiumcaQons)• RadicalcyclizaQons• RadicalcyclizaQonofN-chloroaminoalkenes,radicalcyclizaQonusingsamarium
orQn• DieckmanncondensaQon• CycloaddiQons• IminoDiels-Alder,Aza-dieneDiels-Alder
• DearomaQzaQonofpyridinesTetrahedron2004,60,1701–1729,Nat.Prod.Rep.2008,25,139–165Synthesis2000,13,1781–1813
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DearomatizationofPyridines
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Cu,Sn,
Mg,Zn,Sn,Li,H-,CN
R1 R3
OSiR3
R2
-OH
Chem.Rev.2012,112,2642−2713James Johnson @ Wipf Group Page 5 of 19 6/19/2016
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ItoGroupPreviouswork
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Chem.Commun.2016ASAP.Chem.Eur.J.2015,21,25,9236–9241,Angew.Chem.Int.Ed.2015,54,8809–8813.J.Am.Chem.Soc.2015,137,1,420–424.,J.Am.Chem.Soc.2014,136,47,16515–16521NatureChemistry2010,2,972-976
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TitlePaper
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DOI:10.1021/jacs.6b01375
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ReactionOptimization
CondiQons:CuCl(0.025mmol),ligand(0.025mmol),2(0.5mmol),bis(pinacolato)diboron3(0.6mmol),alcohol(1.0mmol),andK(O-t-Bu)(0.1mmol)inTHF.BNMRyield.CTheeevaluesof(R)-4aweredeterminedbyHPLCanalysisofthecorrespondingbenzoateester.DThereacQonwascarriedoutat30°C.EThereacQonwascarriedoutona5mmolscale.F1mol%CuClandligandwereused.GThereacQonQmewas16h.HThereacQonwascarriedoutat0°CandthereacQonQmewas1h.
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DOI:10.1021/jacs.6b01375
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SubstrateScope
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DOI:10.1021/jacs.6b01375
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SubstrateScope:Limitations
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DOI:10.1021/jacs.6b01375
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DerivatizationofTetrahydropyridines
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DOI:10.1021/jacs.6b01375
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Synthesisof(-)-Paroxetine
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DOI:10.1021/jacs.6b01375
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DFTCalculationsforBorylationPathway
(B3PW91/cc-pVDZ).RelaQveGvalues(kcal/mol)at298K,1.0atominthegasphase.
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DOI:10.1021/jacs.6b01375
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N B(pin)MeO2C
(R)-enantiomer
N B(pin)MeO2C(S)-enantiomer
DOI:10.1021/jacs.6b01375
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DeuteriumLabeling
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DOI:10.1021/jacs.6b01375
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ProposedMechanism
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DOI:10.1021/jacs.6b01375
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Conclusions
• DevelopedanoveldearomaQzaQon/enanQoselecQveborylaQonofdihydropyridines.
• InteresQngstereoretenQveprotonaQonoftheallylcopper(I)intermediate• SubstratelimitaQons• Expeditedsynthesisofchiral3subsQtutedpiperidines• PotenQalMedChemapplicaQons
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Thanks
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Aggarwal’sCrossCoupling
N B(pin)R
Li OMe
N B(pin)
R OMe
Br+
N B(pin)
R OMe
Br
1,2-Shift
NRB(pin)
OMeBr
Nu-
NR OMeElimination
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