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

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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SubstrateScope:Limitations

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DerivatizationofTetrahydropyridines

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DOI:10.1021/jacs.6b01375

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Synthesisof(-)-Paroxetine

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DFTCalculationsforBorylationPathway

(B3PW91/cc-pVDZ).RelaQveGvalues(kcal/mol)at298K,1.0atominthegasphase.

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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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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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