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

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’

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.

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

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

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

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

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

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

Identification of PPI Inhibitors

Peptide/Peptide mimics

High-throughput screening (HTS)Fragment-based screening

Virtual screening

9Chem. Soc. Rev. 2015, 44, 8238.

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.

Fragment-Based Lead Development

11Nat. Rev. Drug Disc. 2007, 6, 211.Drug Disc. Today 2005, 10, 987.Nat. Chem. 2009, 1, 187.

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.

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.

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

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

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

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

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.

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

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.

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

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

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

Asymmetric Alpha-Lithiation

24

(CH2)n

NDG

1. alkyllithium, chiral ligand

2. electrophile, low temp

(CH2)n

NDG

EH H

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

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

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

C-2 Direct Alkylation

n(H2C)

NDG

HHn(H2C)

NDGcatalyst

R R R

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%

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

Directing Group Free Direct Alkylation

Ta catalyst

R

X

HN H

X

HN R

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

C-2 Direct Arylation

n(H2C)

NDG

HHn(H2C)

NDG

Rcatalyst

(RO)2B R

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+

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

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

Enantioselective C-2 Direct Arylation

n(H2C)

NDG

HHn(H2C)

NDG

R(RO)2B R

Pd catalystChiral ligand

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)

Regio- and Stereospecific C-3 Functionalization

n(H2C)

NOR

n(H2C)

NDG

OR

R

Pd cat.

HI RDG

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

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

Regio- and Stereospecific C-5 Functionalization of 3-Aminopiperidine

Pd cat.

I R

NBoc

NHDG

H

NBoc

NHDG

R

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

Regiospecific C-4 Direct Functionalization of Piperidine

Pd catalyst

I RN

DGN

DG

RH

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

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

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

Thank you

48

Dr. Peter Wipf and Wipf group members