Frontiers Seminar - ccc.chem.pitt.educcc.chem.pitt.edu/wipf/Frontiers/Evan.pdf · Regulate the...
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Frontiers Seminar
Targeting Protein-Protein Interactions – the Pursuit ofAsymmetric Direct Functionalization of Saturated N-Heterocycles for Efficient Development of TopologicallyComplex Chemical Fragments for Fragment-Based DrugDiscovery
Evan CarderWipf Group Frontiers Seminar
September 30, 2017 0
(CH2)nNH
(CH2)nNH
R
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Part I. Current Reality of Drug Discovery
Nat. Rev. Drug Disc. 2015, 14, 475.Nat. Rev. Drug Disc. 2016, 15, 817.Nat. Rev. Drug Disc. 2016, 15, 447.
Reason for Clinical Trial Failure 2013-2015
EfficacyOperational SafetyStrategyCommercial
52%
Reason for Clinical Trial Failure 2013-2015
EfficacyOperational SafetyStrategyCommercial
52%
1996
-1999
2000
-2003
2004
-2007
2008
-2011
2012
-2014
0
5
10
15
20
Perc
enta
ge (%
)
Cumulative Success Rate Phase I to Launch
11.6
7.510.010.8
16.4
Lead
Develo
pmen
t
Pre-Clini
cal
Phase
I
Phase
II
Phase
III
FDA Approv
al0
1
2
3
4
5
Tim
e (y
ears
)
Drug Development Timeline
1.5
2.5
1.51.0
4.5
2.5
‘Valley of Death’
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Lack of Clinical Efficacy – Poor Target Identification and Validation
2
Tissuesample
Patient
Brit. J. Pharm. 2011, 162, 1239. Nat. Rev. Drug Disc. 2013, 12, 581.Nat. Rev. Cancer 2017, 17, 441.
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Tractable Disease Targets
3Nat. Rev. Drug. Disc. 2017, 16, 19.Nat. Rev. Drug Disc. 2006, 5, 993. Nat. Rev. Drug Disc. 2006, 5, 821.
EnzymesOxidoreductasesTransferasesProteasesHydrolasesIsomerasesLigases
Ion-ChannelsCa2+ channelsK+ channelsNa+ channelsCl- channels
ReceptorsGPCRCytokine receptorIntegrin receptorNuclear receptor
Nucleic Acids and RibosomesDNARNASpindle Ribosomes
I. Clinically Validated
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Tractable Disease Targets
4The Nobel chronicles. Lancet 2000, 355, 1022.
II. Druggability
“the most fruitful basis for the discovery of a new drug is to start with an old drug”
– James Black
N
NH
H2N
O
NH
N NH
NH
O
CO2H
CO2H
Folic Acid(Substrate of DHFR)
N
NH2N N
N N
NH
O
CO2H
CO2H
NH2
Me
Methotrexate(DHFR Inhibitor)
PDB: 5EAJ
DHFR
FolicAcid
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New Drug Target Category
§ There is an estimated 130,000 –650,000 types of protein-proteininteractions (PPI) in the humaninteractome.
§ The interactome is very complex anddiverse and their extensive networkregulate most biochemcal pathwaysinvolved in cell signaling, growth, andsurvival.
§ Protein-protein interactions are nowrecognized as potential therapeutictargets
§ Identifying therapeutically relevant PPIsis considerably difficult.
Chem. & Biol. 2012, 19, 42.Nature 2007, 450, 1001.Nat. Methods 2009, 6, 83. 5
The Interactome - the extensive network of Protein-Protein Interactions
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6
§ PPI display fewer well-defined concave bindingsites than classical enzymes and receptors.
§ Protein-protein interfaces tend to be flat withlarge surface area (1,500 – 3,000 A2) anddominated by hydrophobic and complementarycharge interactions.
§ Not all residues at the protein-protein interfacecontribute equally toward binding. Only a smallsubset of contact residues contribute toward thebinding free energy.
§ “Hot spot” residues or regions are significantlyresponsible for the majority of the PPI bindingfree energy
Side-view
Nat. Rev. Drug. Disc. 2004, 3, 301.Annu. Rev. Pharmacol, Toxicol. 2014, 54, 435.Chem. Biol. 2014, 9, 1102. Bioorg. Med. Lett. 2014, 24, 2546.Chem. Soc. Rev. 2015, 44, 8238. Nat. Rev. Drug Disc. 2016, 15, 533.
Protein Interface
Characteristics of Protein-Protein Interactions
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7Chem. Soc. Rev. 2015, 44, 8238.
Disrupting hot spot residues
1. Orthosteric inhibition2. Allosteric regulation3. Interfacial binding/stabilization
Strategies towards Modulating a Protein-Protein Interaction
Hot spot identification
1. Alanine scanning mutagenesis 2. Nuclear magnetic resonance 3. X-ray crystallography
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8Chem. Soc. Rev. 2015, 44, 8238.
Protein-Protein Interaction
§ No natural small molecule partners§ Fewer well-defined binding sites§ Flat and featureless surface§ Lack of hydrogen-bond donors and
acceptors§ Conformational plasticity
Classical Drug Target
§ Natural small molecule partners§ Well-defined binding sites§ Concavity§ Hydrogen-bond donors and acceptors
Druggability: Challenges Developing PPI Inhibitor
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Identification of PPI Inhibitors
Peptide/Peptide mimics
High-throughput screening (HTS)Fragment-based screening
Virtual screening
9Chem. Soc. Rev. 2015, 44, 8238.
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Part II. Fragment-Based Drug Discovery (FBDD)
10
§ Begin with low molecular weight subunits
§ Greater diversity and complexity
§ Access to more chemical space
§ Better physiochemical properties
§ High-quality intermolecular interactions
§ Opportunity for novel intellectual property
Advantages of FBDD:
Nat. Rev. Drug Disc. 2007, 6, 211.Trends Pharm. Sci. 2012, 33. 5. Drug Disc. Today 2005, 10, 987 J. Med. Chem. 2017, 60, 89.Nat. Chem. 2009, 1, 187.
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Fragment-Based Lead Development
11Nat. Rev. Drug Disc. 2007, 6, 211.Drug Disc. Today 2005, 10, 987.Nat. Chem. 2009, 1, 187.
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Greater Survey of Chemical Space
12
Protein Interface:
§ Fewer well-defined binding sites
§ Flat and featureless surface
§ Lack of hydrogen-bond donors andacceptors
§ Conformational plasticity
Importance:
§ Structural and stereochemical diversity
§ Enhanced complexity
§ High-quality intermolecular interactions
Lead fragment Fragment expansionFragment expansion
Growth vectors – possible sites to incorporate functionality or substituents
Angew. Chem. Int. Ed. 2016, 55, 488.Nat. Rev. Drug Disc. 2007, 6, 211.Nat. Chem. 2009, 1, 187.
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Success Story – Development of Navotoclax (ABT-263)
13
§ B cell lymphoma 2 (BCL-2)
Regulate the intrinsic apoptotic pathway
Inhibit essential pro-apoptotic effectors BAK and BAX by binding to their BH3 domain and preventing oligomerization.
Upregulated in cancer
Associated with chemoresistance and cancer cell survival
Targeting the anti-apoptotic BCL-2 protein is an attractive therapeutic strategy in cancer.
Nat. Rev. Drug. Disc. 2017, 16, 273.
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BCL-2 and BAX Protein-Protein Interaction
14
BCL-2
BAX
PDB: 2XA0
Nat. Rev. Drug. Disc. 2017, 16, 273.Nat. Rev. Drug Disc. 2016, 15, 533.
BCL-2
BAX
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Medicinal Chemistry Efforts of Navotoclax (ABT-263)
15J. Med. Chem. 2006, 49, 1165..J. Med. Chem. 2008, 51, 6902.
F
OH
O
Fragment 32Kd = 300 uM
LE = 0.30
OH
Fragment 34Kd = 6000 uM
LE = 0.23
F
OH
O
Kd = 1.4 uMLE = 0.27
F
NH
O
Kd = 0.036 uMLE = 0.27
SOO
NO2
NHS
N
NH
O
SOO
NO2
NHS
N
NCl
ABT-737Kd = 0.0008 uMLE = 0.22
N
NH
O
SOO
SO2CF3
NHS
N
NCl
ABT-263 or NavitoclaxKd = 0.0005 uM
LE = 0.20
O
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Success Story – Development of Navotoclax (ABT-263)
16Nat. Rev. Drug. Disc. 2017, 16, 273.Nat. Rev. Drug Disc. 2016, 15, 533.
BCL-2
PDB: 4LVT
ABT-263
Hot spot P4
Hot spot P2
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Challenges to FBDD – Escape from the Flatland
17
Fragments libraries
§ Commercially available
§ Substantial sp2-rich compounds
§ Flat molecules lacking dimensionality
§ Improve physiochemical properties to conserve drug-likeness
Angew. Chem. Int. Ed. 2016, 55, 488.Nat. Chem. 2013, 5, 21.Med. Chem. Commun. 2013, 4, 515.PNAS 2011, 108, 6799. J. Med. Chem. 2009, 52, 6752.
Improve 3-Dimensionality
§Incorporate structural and stereochemical diversity
§Emulate natural product structural motifs
§Sp3 carbons can increase the number and scope of vectors for fragment growth.
§“Chiral sp3-rich heterocycles are greatly underrepresented”
F
OH
O
OH
OH
N
CO2H
S
CO2Me
N NCO2Me
HNHON H
N
CO2Me N
N
H HN
NH
HN
CO2H
O
O
NH
CO2H
OO
HN
NH2
HN
HO
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Challenges to FBDD – Efficient Synthetic Methodology
18
“Precision Synthesis”
§Synthetic vectors Methodology that allows synthetically accessible vectors to incorporate substituents
§Molecular recognition Methodology that enables incorporation of heteroatoms and tolerates polar H-bonding functionality.
Angew. Chem. Int. Ed. 2016, 55, 488.J. Med. Chem. 2016, 59, 8189.
Structure-guided medicinal chemistry
X-ray informed fragment-design requires tailor synthetic transformations to the central core of the fragment
§ ShapeControl of stereo- and regio-chemistry.
§ Synthetic tractabilityEfficient synthesis (few steps) usingcommercially available reagents.
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Part III. Asymmetric Direct-Functionalization of Saturated N-Heterocycles
19
NH
pyrrolidine
NH
piperidine
NH
azepane
NH
azocane
NHazonane
morpholine
NH
O
NH
S
thiomorpholine
1,4-piperazine
NH
HN
NH
O
1,4-oxazepane 1,4-diazepane
NH
NH
Saturated N-Heterocycles:
§Biologically relevant
Natural productsPharmaceuticals Agriculture
§Biological handle – hydrogen bonding capabilities
§Significant opportunity for growth vectors to enhance intermolecular interactions
§Synthetically undeveloped
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Synthesis of Saturated N-Heterocycles
20
Direct Functionalization
Cyclization
Ring Transformation C-H Amination
Hydroamination/ArylaminationR’
XR
R
XH
N
N
X
H2NR
X
H
XR
N
NR’
X
N3H
J. Org. Chem. 2014, 79, 2809.
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Not all C-H bonds are equal
§Electronics§Steric§Stereoelectronics§Directed-proximal effects – for site selectivity
Saturated N-Heterocycles
§Alpha-Lithiation§Cationic §Radical §Transition-metal
21
Direct Functionalization
J. Org. Chem. 2014, 79, 2809.Chem. Eur. J. 2012, 18, 10092Chem. Soc. Rev. 2007, 36, 1069..
(CH2)n
NDG
(CH2)n
NDG
R
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Alpha-Lithiation
22
NBoc
ENtBuO O Li
sBuN
N
R2
R2
NtBuO O
NN
R2
R2
LiH
NtBuO O
sBuLi
NR2R2N
electrophilealpha-lithiation
(CH2)n
NDG
1. alkyllithium, ligand
2. electrophile, low temp
(CH2)n
NDG
E
(CH2)n
NDG
Li L
H H
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23
(CH2)n
NBoc
Me(CH2)n
NBoc
Me Li Ls-BuLi, TMEDA
-78 oC
E+
-78 oC
(CH2)n
NBoc
Me E
Tetrahedron Lett. 1989, 1197
Substrate Major product E % Yield
NBoc
NBoc
EMeMeTMSD
72%93%81%
NBoc
NBoc
EMe
Me
Me
MePhCH(OH)DCHO
71%96%90%87%
NBoc
Men N
Boc
Men E
Me 83%
NBoc
Men N
Boc
Men E
SnBu3 83%
t-Bu t-Bu
BocNMe
BocNMe E
MeTMSCHO
41%67%63%
Substrate Major product E % Yield
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Asymmetric Alpha-Lithiation
24
(CH2)n
NDG
1. alkyllithium, chiral ligand
2. electrophile, low temp
(CH2)n
NDG
EH H
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J. Am. Chem. Soc. 1994, 3231.Acc. Chem. Res. 1996, 522.Tetrahedron: Asymmetry 2005, 661.J. Am. Chem. Soc. 2010, 132, 7260. 25
E % Yield, (er)
TMSCH3Bu3SnCO2HPh2C(OH)
71%, (97:3)76%, (98:2)70%, (97:3)55%, (94:6)75%, (95:5)
N
H N
H(-)-Sparteine(Beak 1994)
s-BuLi, (-)-Sparteine
-78 oC NBoc
Li L-E+
-78 oC NBoc
Es-BuLi, (+)-Sp. Surr.
-78 oCNBoc
E+
-78 oCNBoc
Li L+E NBoc
HH
N
HHN
(+)-Sparteine surrogate (O’Brien 2002)
E % Yield, (er)
84%, (95:5)TMS
s-BuLi, (+)-L
-78 oC, 6 h
E+
-78 oC - rt
E % Yield, (er)
(R)-TMS(R)-Bu3Sn(S)-CO2(S)-MeO2C(R)-PhMe2Si(R)-Me
73%, (86:14)82%, (88:12)92%, (88:12)78%, (88:12)85%, (73:27)45%, (64:36)
N
HNMe
(+)-L
NBoc
NBoc
Li L NBoc
E
s-BuLi, (+)-L
-78 oC, 6 h
E+
-78 oC - rt
E % Yield, (er)
(R)-TMS(R)-Bu3Sn(S)-CO2(S)-MeO2C(R)-PhMe2Si(R)-Me
73%, (86:14)82%, (88:12)92%, (88:12)78%, (88:12)85%, (73:27)45%, (64:36)
N
HNMe
(+)-L
NBoc
NBoc
Li L NBoc
E
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J. Org. Chem. 2004, 69, 3076.26
CO2Bn
I
NBoc
79% (80:20)O
O
NBoc
CO2Bn 95%, (50:50)
E+ Product % Yield (er)
H CO2Et NBoc
CO2Et 56%, (72:28)
Ph
OP(OPh)2 NBoc
CH287%, (85:15)dr (56:44)
Ph
E+ Product % Yield (er)
NBoc
I Ph Ph 85%, (90:10)
I
OTBS NBoc
OTBS84%, (94:6)
XX = IX = TfX = Nf
NBoc
56%, (72:28)65%, (94:6)50%, (92:8)
R
I CO2EtNBoc R
CO2Et
R = HR = n-Bu
89%, (95:5)53%, (91:9)
NBoc
Li (-)SpNBoc
s-BuLi, (-)-Sparteine
-78 oC NBoc
CuCuCN 2LiCl E+
-78 oC NBoc
EHH
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J. Am. Chem. Soc. 2006, 128, 3538.
27
N
Br
Boc
NH
Br
81% (96:4)NBoc N
Boc
77% (96:4)NBoc
NH
N
60%, (96:4)NBoc N
Br
Ar-Br Product % Yield (er)
NBoc
Li (-)SpNBoc
s-BuLi, (-)-Sparteine
-78 oC NBoc
ZnClZnCl2
-78 to 25 oC
Pd(OAc)2tBu3P-HBF4
Ar-Br25 - 60 oC
NBoc
ArHH
Ar-Br Product % Yield (er)
NBoc
82%, (96:4)75%, (96:4)78%, (96:4)81%, (96:4)87%, (97:3)80%, (96:4)70%, (96:4)
RR Br H
FNMe2CO2MeSO2MeCNNH2
R:
71%, (96:4)72%, (96:4)N
BocBr
MeOMe
R:R R
78% (96:4)NBoc
Br
MeO O
Me
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C-2 Direct Alkylation
n(H2C)
NDG
HHn(H2C)
NDGcatalyst
R R R
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J. Am. Chem. Soc. 2001, 123, 44.
Ru3(CO)12, ethylene
CO, iPrOH, 140 oC, 20 h
n(H2C)
N2-Py
n(H2C)
NPy
Ru3(CO)12,
CO, iPrOH, 140 oC, 40-60 hN2-Py
NPy
RR R
Alkene
Bu
di: 53%mono: 29%
tBu
di: 73%mono: 21%
Ph
di: 58% di: 33%mono: 39%
Substrate scope
NPy73%
NPy73%
N
85%
Py
90%
N Py NPy
47%
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Angew. Chem. Int. Ed. 2017, 56, 10530.
O N
S [Ir(cod)2]OTf,
Degassed PhCl 85 oC, Ar, 6 h
RO N
S R
R
CO2Et
di: 44%mono: 24%
CN
< 5%
Ph
di: 23%mono: 19%
di: 6 %mono: 31%
F
di: 34%mono: 28%
di: 34%mono: 22%
di: 52%
di: 62%
Ph
di: 59%
OMe
di: 96%
F
di: 62%*
Br
di: 40%
CN
di: 73%O
di: 55%
SO2Ph
di: 70%
N
O
O
Alkene
O N
S
CH2)n
[Ir(cod)2]OTf,
Degassed PhCl 85 oC, Ar, 6 or 24 h
R1
O N
S
(CH2)nR
R1
R
Substrate Scope
NDG
42%
NDG
76%dr: 1.2:1
OMe NDG
68%dr: 1:1
OPh
NDG
30%dr: 1.3:1
O
BocHN
NDG
48%dr: 6:1
Ph
O
OEt
NDG O
OEt
30%*
N
O
OEt
35%*
DG
NDG
35%dr: 3.3:1
Ph
O
OEtHO
Ph
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Directing Group Free Direct Alkylation
Ta catalyst
R
X
HN H
X
HN R
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Org. Lett. 2013, 15, 2182.
Product t(h) % Yield, dr
HN n-hexyl
H143 h 76%, >20:1
HN H 72 h 79%, >20:1
HN n-hexyl
H69 h 59%, >20:1
O O
HN H
165 h 64%, >20:1OTBS3
N
HN n-hexyl
H72 h 43%, >20:1
R
R = Me
Ph
PMP
72 h 68%, >20:172 h 84%, >20:1
n-hexylH
72 h 60%, 10:1HN
N
Ot-Bu(NMe2)4Ta
i-Pr i-Pr
Tantalum Amidate CatalystX
HN
R+ Ta catalyst
toluene, 165 oC X
HN R
H
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C-2 Direct Arylation
n(H2C)
NDG
HHn(H2C)
NDG
Rcatalyst
(RO)2B R
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N
N
PhCF3
N
N
PhCOCH3
76%trans/cis = 3:1
45%trans
N
N
PhOCH3
70%trans/cis = 4:1
N
N
Ph N
N
Ph
62%trans/cis = 6:1
62%trans/cis = 5:1
N
N
PhN
72%trans/cis = 3:1
H3C
NMe
N
N
PhN
N
N
63%trans/cis = 3:1
57%trans
38%
F
TBSON
N OMe
J. Am. Chem. Soc. 2006, 128, 14220.
Ru3(CO)12
t-BuCOMe, 150 oC, 4-19 h
NR ArN
N NR
OB
OAr+
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Chem. Eur. J. 2010, 16, 13063..Chem. Eur. J. 2013, 19, 10378.
NPyr
mono: 38%bis: 38%, trans/cis 3:1
NPyr
70%, trans/cis 3:1
Me
NPyrmono: 48%
bis: 26%, trans/cis 3:1
Cl
NPyr
mono: 49%bis: 12%, trans/cis 3:2
CF3
NPyr
mono: 35%bis: 36%, trans/cis 5:2
F
NPyr
58%, trans/cis 5:4
Me
OMe
NPyr
48%, trans/cis 5:1
Me
Me
NPyr91%
NPyr83%
CF3
Ru3(CO)12
3-ethyl-3-pentanol reflux, 24 h
OB
OAr+
N2-Py
N2-Py
ArAr
mono: 39%bis: 8%, trans/cis 3:1
F
mono: 27%bis: 10%, trans
OMe
mono: 28%bis: 22%, trans/cis 5:1
Me
NN
44%NN
63%
O S
N
65% 37%
33%N 52%
N 50%
Cl
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J. Am. Chem. Soc. 2015, 137, 11876.
N
(HO)2BR
Pd(TFA)2, 1,4-BQKHCO3, t-AmylOH, air
100 oC, 4 hStBu
N
StBu
R
72%51%
Me
Me
72%
Me
76%64% 78%
NHAc
OMe
OMe
79%75% 70%
Cl
Cl
F
62%
NN
51% 69%
N
F
F
OMe
N
(HO)2BX
Pd(TFA)2, 1,4-BQKHCO3, t-AmylOH, air
100 oC, 4 hStBu
N
StBu
X
(HO)2BY
1,4-BQ100 oC, 12 h
(one pot)
Y
N
StBuF
77% (dr >20:1)
N
StBuF
65% (dr >20:1)
Me
OMe
N
StBu
74% (dr >20:1)
MeMeOC
N
StBuF3CO
52% (dr >20:1)
N
StBu
82% (dr >20:1)
Me
Cl
N
StBu
80% (dr >20:1)MeOC
Cl
Cl
OMe
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Enantioselective C-2 Direct Arylation
n(H2C)
NDG
HHn(H2C)
NDG
R(RO)2B R
Pd catalystChiral ligand
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Nat. Chem. 2017, 9, 140. R
R
OO
PO
OH
(R)-PA
N
(HO)2BR
Pd(dba)3, (R)-PA1,4-BQ, KHCO3, t-AmylOH
N2, 65 oC, 16 hStBu
N
StBu
R
71%, 97:3 er
MeMe
Me
Me
88%, 97:3 er 61%, 93:7 er
OMe
84%, 99:1 er
78%, 99:1 er
F
F
F
80%, 99:1 er 87%, 96:4 er
CF3
71%, 96:4 er
50%, 93:7 er 71%, 97:3 er 79%, 97:3 er
CH3
47%, 88:12 er
Br
CHO COMe
N
StBu
40%, 98:2 er
N
StBu
84%, 98:2 er
N
StBu
62%, 96:4 er
N
StBu
54%, 99:1 er
N
(HO)2B
Pd(dba)3, (R)-PA1,4-BQ, KHCO3, t-AmylOH
N2, 65 oC, 16 hStBu
N
StBu
n(H2C) n(H2C)
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Regio- and Stereospecific C-3 Functionalization
n(H2C)
NOR
n(H2C)
NDG
OR
R
Pd cat.
HI RDG
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Org. Lett. 2014, 16, 4956.Eur. J. Org. Chem. 2016, 139.
Ar-I % Yield Ar-I % Yield
86%
91%Me
88%F
90%CO2Et
22%OH
44%F
76%
45%
34%
N34%
N28%
87%
CF3Me
MeOMe
OMe
OMe
S
Ar-I % Yield
96%
98%OMe
90%
N98%
Cl
Cl
N
HN
OCbzN
AQ
OCbz
R
IR
Pd(OAc)2, AgOAcneat, 110 oC, 24 h
N IR
Pd(OAc)2, AgOActoluene, 110 oC, 24 h
NCbz O
HN N
Cbz O
AQ
R
N
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Chem. Eur. J. 2016, 22, 4748.
IR
Pd(TFA)2, AgOAc, Lhexafluorobenzene
100 oC, 24 h
NTFA O
HN
FF
FF
CF3
NTFA
DG
R
N N+AdAd
Cl-
4,5-dihydroimidazolium ligand (L)
98% 98% 90%
Me OMe Ph
92%
84% 83% 79%
Cl Br CF3
77%
53% 92%
CO2Me
CHO
40%
Ac
OMe
40% 83%
70%
93%
FCO2Me
MeO
AcHN
89%
F
54%
NTs
60%
NTs
48%
NN
Ts
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Regio- and Stereospecific C-5 Functionalization of 3-Aminopiperidine
Pd cat.
I R
NBoc
NHDG
H
NBoc
NHDG
R
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ACS Catal. 2016, 6, 4486.
IR
Pd(OAc)2, Ag2(OAc)32,6-dimethylbenzoic acid
120 oC, 24 hNBoc
NH
O2-Py
NBoc
NH
O2-PyR
Ar-I % Yield Ar-I % Yield
71%
65%Me
78%OMe
67%CO2Me
70%F
68%
60%
62%
Cl
CO2Et
OMe
72%Cl
9%
Cl
IR
Pd(OAc)2, Ag2(OAc)32,6-dimethylbenzoic acid
120 oC, 24 hNBoc
NH
O2-Py
NBoc
NH
O2-PyRHAr
HAr
HAr-I % Yield
N72%
98%
CF3
NSO2Ph
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Regiospecific C-4 Direct Functionalization of Piperidine
Pd catalyst
I RN
DGN
DG
RH
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Nature 2016, 531, 220.
N NDG
HN
O
FF
CF3F
F
I
Pd(OAc)2, CsOPiv150 oC, 18 h, air
NDG
OMe
55%
N DGOMe62%
N DGOBn66%
N DGPh35%
ON DG
33%
N DG
OMe
46%
N DG
34%
Ph
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46
n(H2C)
NOR
n(H2C)
NDG
OR
R
Pd cat.
HI RDG
Pd cat.
I R
NBoc
NHDG
H
NBoc
NHDG
R
(CH2)n
NDG
1. alkyllithium, chiral ligand
2. electrophile, low temp
(CH2)n
NDG
EH H
n(H2C)
NDG
HHn(H2C)
NDG
R(RO)2B R
Pd catalystChiral ligand
n(H2C)
NDG
HHn(H2C)
NDG
Rcatalyst
(RO)2B R
Ta catalyst
R
X
HN H
X
HN R
(CH2)n
NDG
1. alkyllithium, ligand
2. electrophile, low temp
(CH2)n
NDG
EH H
Alpha-lithiation
Transition metal-catalyzed
n(H2C)
NDG
HHn(H2C)
NDGcatalyst
R R R
Pd catalyst
I RN
DGN
DG
RH
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Future Efforts
47
III. Asymmetric Direct Functionalization
§ Enhance stereo- and regioselective control
§ Expand scope and substitutional diversity
§ Scope: 2-atom heterocycles§ Subsitutions: heteroatoms
§ Efficient and robust
I. Drug Development
§ Lack of drug efficacy is a significant barrier towards advancing modern medicine.
§ Protein-protein interactions offer a new category of possible drug targets; however, identifying therapeutically relevant PPIs is considerably difficult.
§ Modulating a protein-protein interaction with a small molecule is feasible; however, the identification and development of such a molecule is rather difficult and requires the advancement in modern drug development.
II. Fragment-Based Drug Development
§ Improve 3-Dimensionality
§ Incorporate structural and stereochemicaldiversity
§ Emulate natural product structural motifs
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Thank you
48
Dr. Peter Wipf and Wipf group members