1

Modern Techniques for the Synthesis of Small Molecule Libraries

- MAOS and Reagents/Scavengers on Solid Support -

Stefan WernerBiotage User Group Meeting, Copenhagen, Denmark,

November 7th, 2007

From Chemical Methodologies to Library Development

UPCMLD = University of Pittsburgh Center forChemical Methodologies and Library Development

UPCMLD-Core LC/MS, NMR, …Analysis

research groups in theDepartment of Chemistry,

University of Pittsburgh

reactions, techniques, instrument developmentChemical MethodologiesChemical

Methodologies

UPCMLD-Core SAR, QikPropLibrary Design

LibraryDevelopment

academic collaborations &screening institutes

antibacterial, antiviral, antifungal, oncogenic,HIV, orphan diseases…

Biological EvaluationBiologicalEvaluation

UPCMLD-Core Stability, Plating, Database, …

Compound Management

CompoundManagement

UPCMLD-Core Library Synthesis

standard chemistry, CombiChemtechniques, lots of Microwave

Chemistry and reagents/scavengers on solid support

Goal

Use of the unique opportunities of an academicenvironment for the synthesis of high-quality libraries of diverse

chemical structures to discover small molecules with architecturally novel scaffolds and a wide range of physico-

chemical properties and to develop innovative new methodologiesfor

Diversity-Oriented Organic Synthesis.

2

120 member library ofallyl and C-cyclopropylamides

Dimethylzinc-Mediated Addition of Alkenylzirconocenes to Imines

Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001, 123, 5122-5123.Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773-2776.

Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761-768.Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem. Soc. 2003, 125, 14694-14695.

Wipf, P.; Janjic, J.; Stephenson, C. R. Org. Biomol. Chem. 2004, 2, 443-445.

R2R1ClCpZr

R2

R1

Cp2ZrHCl

CbzHN

R1

NH

O

R6

R3

NH

R3

NH

O

R6R5

NH

R3

R5 HN

O

R6

R1

NH

R3

R2

R1

R5

NH

R3

R2

R1

R5

R4R2

NHP R2

NHP

R1R4

PHNR2

R3

ZnMe2CH2I2 imine

ZnMe2imine

quenchoxidation

ZnMe2imineCH2I2

oxidation

ZnMe2alkynylimineZn(CH2I)2

ZnMe2imineCH2I2

ZnMe2imine

quench

ZnMe2alkynylimineZn(CH2I)2

ChemicalMethodologies

R2

R1

R1

R2

N

R31. Cp2ZrHCl2. Me2Zn

3.

R3 H

NP

PhO

Ph

R1 R2 R3

Hn-Prc-Hex

n-Bun-PrMe

Php-Ph-C6H4p-Cl-C6H4m-Cl-C6H4p-F3C-C6H4o-F3C-C6H4p-MeOOC-C6H4

MeZn P(O)Ph2

R1

R2

HN

R3

O

R4

R1

R2

HN

R3

O

O

R1

R2

HN

R3

SR6

R5

O O

1. HCl, MeOH2. R4COCl

1. HCl, MeOH2. R5OCOCl

1. HCl, MeOH2. R6SO2Cl

Library Design

Wipf, P., Coleman, C. M., Janjic, J., Iyer, P. S., Fodor, M. F.,Shafer, Y. A., Stephenson, C. R. J., Kendall, C., Day, B. W. J. Comb. Chem. 2005, 7, 322-330.

R1

R2

R3

NHP(O)Ph2

aqueousquench

R1

R2

R3

NHP(O)Ph2

CH2I2

R1

R2

HN

R3

O

R4

R1

R2

HN

R3

O

O

R1

R2

HN

R3

SR6

R5

O O

R4 R5 R6

t-BuPhBnPhCH2CH2p-Ph-C6H4p-F3C-C6H4p-MeOOC-C6H42-furanyl2-thiophene3-pyridyl

i-BuHCCCH2PhCH2o-Cl-C6H4p-MeO-C6H4p-F-C6H4

Merac-camphorylPhp-Ph-C6H4p-Cl-C6H4p-F3C-C6H4p-MeO-C6H48-quinoline2-thiophene

1. HCl, MeOH2. R4COCl

1. HCl, MeOH2. R5OCOCl

1. HCl, MeOH2. R6SO2Cl

µW

µW

LibraryDevelopment

R2

R1

R1

R2

N

R31. Cp2ZrHCl2. Me2Zn

3.

R3 H

NP

PhO

Ph

R1 R2 R3

Hn-Prc-Hex

n-Bun-PrMe

Php-Ph-C6H4p-Cl-C6H4m-Cl-C6H4p-F3C-C6H4o-F3C-C6H4p-MeOOC-C6H4

MeZn P(O)Ph2

Microwave - Accelerated Divergent- Multi-Component Reaction (DMCR) Library Design

R1

R2

R3

NHP(O)Ph2

aqueousquench

R1

R2

R3

NHP(O)Ph2

CH2I2

µW

µW

EmrysOptimizer

Microwave

Allylic Amidesmicrowave irradiation of alkyne and zirconocene hydrochloride in toluene at 100 ºC for 1 min addition of 1 eq imine and 1.6 eqdimethylzinc at -78 ºCmicrowave irradiation at 100 ºC for 2 min aqueous quench

C-Cyclopropylalkylamidesalkyne and zirconocene hydrochloride are reacted for 20 min at r.t. in CH2Cl2addition of 1 eq imine and 3 eqdimethylzinc at -78 ºCmicrowave irradiation at 100 ºC for 5 min addition of 5-10 eq CH2I2, microwave irradiation at 60 ºC for 30 min

LibraryDevelopment

3

Dimethylzinc-Mediated Addition of Alkenylzirconocenes to Imines

Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001, 123, 5122-5123.Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773-2776.

Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761-768.Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem. Soc. 2003, 125, 14694-14695.

Wipf, P.; Janjic, J.; Stephenson, C. R. Org. Biomol. Chem. 2004, 2, 443-445.

92 member library ofcyclopropyl dipeptide isosteres

64 member library ofE-alkene dipeptide isosteres

R2R1ClCpZr

R2

R1

Cp2ZrHCl

CbzHN

R1

NH

O

R6

R3

NH

R3

NH

O

R6R5

NH

R3

R5 HN

O

R6

R1

NH

R3

R2

R1

R5

NH

R3

R2

R1

R5

R4R2

NHP R2

NHP

R1R4

PHNR2

R3

ZnMe2CH2I2 imine

ZnMe2imine

quenchoxidation

ZnMe2imineCH2I2

oxidation

ZnMe2alkynylimineZn(CH2I)2

ZnMe2imineCH2I2

ZnMe2imine

quench

ZnMe2alkynylimineZn(CH2I)2

ChemicalMethodologies

Dipeptide Isosteres

NH

Ri+1

R Ri+2

O

NH

Ri+1

R Ri+2

O

HN

O

R

NH

HN

Ri+1

O Ri+2

Oδ-amino-β,γ-unsaturated acids δ-amino-β,γ-cyclopropyl acids

γ-amino-α,β-cyclopropyl acids

ChemicalMethodologies

Me

MeOOS

N

O

HO

HN

NN

O

O

Me

MeOOS

N

O

HO

HN

NN

O

O

Me

MeOOS

N

O

HO

HN

NN

O

O

Me

MeOOS

N

O

HO

HN

NN

O

O

NH

R2

O

HN

R1

R2NH

NH

R1

O

2 enantiomers

2 diastereomers

Indexed Library Design

N-F

unct

iona

lizat

ion

C-Functionalization

N-F

unct

iona

lizat

ion

C-Functionalization

N-F

unct

iona

lizat

ion

C-Functionalization

N-F

unct

iona

lizat

ion

C-Functionalization

Cyclopropyl AminoAcid Derivative

CyclopropylDipeptide Isostere

LibraryDevelopment

4

Library Design

NH

O

HCl•H2N

NH

O

O

PNH

O

NH

O

NH

O

NH

O

NH

O

O

SNH

NH

O

NH

O

F

O O

SNH

O O

N

N

N

O N

N N

OH

O

OMe

O

NH

O

NH

O

NH

O

NH

O

NH

O

NH

ON

SOOMe

O

NH

O

NH

O

NH

O

NH

O

OH

NH

N N

C-FunctionalizationN-Functionalization

LibraryDevelopment

Synthesis of Peptidomimetic Scaffolds

Wipf, P.; Stephenson, C. R. J. Org. Lett. 2005, 7(6), 1137-1140.Wipf, P; Xiao, J. Org. Lett. 2005, 7(1), 103-106.

OTBDPS

1. Cp2ZrHCl2. Me2Zn3. PhCH=NP(O)Ph24. (CH2I)2Zn, 67 %

Ph2(O)PNH

PhOTBDPS

H3N

PhOMe

O

NH

PhOMe

O

R

1. TBAF, 83 %2. TEMPO, NaClO, NaClO4, 83 %3. HCl, MeOH, 96 %4. tartaric acid, resolution, 83 %

H3N

PhOMe

O

NH

PhOMe

O

R

R = P(O)Ph2 orCbz

tartrate tartrate

1. K2CO32. CbzCl, NaHCO3 or Ph2P(O)Cl, DIPEA, 95 %

R = P(O)Ph2 orCbz

OTBDPS

NH

OTBDPS

Ph

NH

OH

PhCbzN

HOH

PhCbz

Ph2(O)P

NH

OMe

PhCbz

NH

OMe

PhCbz

OO

1. Cp2ZrHCl2. Me2Zn3. PhCH=NP(O)Ph24. CH2I2, 60 %

1. HCl (g)2. CbzCl, 73 %

1. Dess-Martin, 67%2. NaClO2, NaH2PO4, 96%3. TMSCHN2, 87%

LibraryDevelopment

Derivatization

NH

PhOMe

O

R

NH

PhOMe

O

R

NH

OMe

PhCbz

NH

OMe

PhCbz

O

O

R = P(O)Ph2 or Cbz

R = P(O)Ph2 or Cbz

protocol A:1. amidation2. deprotection3. PS-DMAP, NEt3, R2Cl, µW 100ºC, 10 minworkup: 1. MP-Isocyanate, MP-Trisamine, µW 100ºC, 5 min 2. Chem Elut extraction

Wipf, P.; Werner, S; Woo, G.; Stephenson, C. R. J.; Walczak, M. A. A.; Coleman, C. M.; Twining, L. Tetrahedron (Symposium-in-Print on Multi Component Reactions) 2005, 61, 11488-11500.

Chen, Z.; Yang, Y.; Werner, S.; Wipf, P.; Weber, S. J. Am. Chem. Soc, 2006, 128, 2208-2209.

N-Functionalization C-Functionalization

protocol B:1. hydrolysis2. PS-DCC, HOBt3. R1NH2, µW 100ºC, 5 minworkup: Si-CO3

2- SPE

protocol C:1. hydrolysis2. DEPBT, NEt3, R1NH2,

r.t. 12 hworkup: ChemElut extraction or Phase Separator extraction and chromatography

LibraryDevelopment

5

Derivatization

92 Member Indexed Library95 % average purity by ELS74 % average yield24 mg average weight

Sauer, D. R.; Kalvin, D.; Phelan, K. M. Org. Lett. 2003,

5(24), 4721-4724.

protocol B:1. hydrolysis2. PS-DCC, HOBt3. R1NH2, µW 100ºC, 5 minworkup: Si-CO3

2- SPEprotocol A:1. amidation2. deprotection3. PS-DMAP, NEt3, R2Cl, µW 100ºC, 10 minworkup: 1. MP-Isocyanate, MP-Trisamine, µW 100ºC, 5 min 2. Chem Elut extraction

LibraryDevelopment

Derivatization

Techniquesmicrowavepolymer bound reagentsscavengingSPE workup ChemElut, Phase Separator, ALLEXis extractions

fast, parallel, automated

protocol C:1. hydrolysis2. DEPBT, NEt3, R1NH2,

r.t. 12 hworkup: ChemElut extraction or Phase Separator extraction and chromatography

LibraryDevelopment

Generating Skeletal DiversityThrough Transition Metal Catalyzed

Carbon-Carbon Bond Forming Reactions

Brummond, K. M.; Wan, H.; Kent, J. L J. Org. Chem. 1998, 63, 6535-6545.Brummond, K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem. Soc. 2002, 124, 15186-15187.Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2162-2163.

Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245-2248.Brummond, K. M.; Chen, D.; Org. Lett. 2005, 7, 3473-3475.

Mitasev, B.; Brummond, K. M. Synlett 2006, ASAP

*

*PN

COOR4R3

N

O

N

R8

R9R9

Library of 179 TricyclicPyrrole-2-carboxamides

Pravin S. Iyer, Matthew D. Fodor

*

PN

*

[Rh(CO)2Cl]2,PPh3, AgBF4CO (1 bar)

[Rh(CO)2Cl]2,toluene, N2

µw, 250ºC,ionic liquid,

toluene Mo(CO)6,DMSO, toluene

R1

R3

COOR4

R2CH2

PN

R1

R3

COOR4 CH2R2

PN

R4OOC

R3

R2

R1

O

R1

PN

COOR4R3

R2

O

R1

CH2R2

PN

R4OOC

R3

R1

CH2R2

PHN

R3COOR4

CH2R2

PN

COOR4R3

O

PN

R4OOC

R3

R1O

[Rh(CO)2Cl]2,toluene, N2

[Rh(CO)2Cl]2,toluene, N2

ChemicalMethodologies

6

Library Design

OMeF

H2N

COOH

H2N

COOH

H2N

COOH

3 amino acids

HN

O

O

HN

O

O

2 aldehydes

N N

R2

O

R3

O

H

HR1

OO

HO

NH

H2N Me

H2N H

H2N

H2N

H2N

OH

OH

H2N

H2N

H2N

H2N

H2N

H2N

H2N

H2N

F

OH

O

O

N

NNH

O

N O

H2N

H2N

H2N

H2NH2N

H2N

H2N

H2NH2N

N

SO

O

OO

OHO

O

ON

NHN

NHO

OH

N

H2N

H2N

H2NOH

OH

H2N

OH

O

NN

N

OO

H2N

H2N

H2N

H2N

S

OH

HN

N

Cl

F

F

F

O

O F

OMe

H2N

H2N

H2N

S

BrN

FF

F

F

F

H2N

N

N

H2N

O

H2N

Cl

F FF

H2N

FF

F

H2N

O

FF

F

NH

OH

H2N NH

OMe

H2N NH

F

NH

H2N NH

Br

41 primary amines

LibraryDevelopment

Synthesis of Tricyclic Pyrrole- 2- carboxamides

Brummond, K. M., Mitasev, B., Curran, D. P., Fischer, S. J. Org. Chem. 2005, 5, 1745-1753.Werner, S.; Iyer, P. S. Synlett 2005, 9, 1405-1408.

Werner, S.; Iyer, P. S.; Fodor, M. D.; Coleman, C. M.; Twining, L. A.; Mitasev, B.; Brummond, K. M. J. Comb. Chem., 2006, 8, 368-380.

H2N

40 - 50 %

COOMe

82 - 86 %

50 - 75 %

R1

34 - 62 %HCl

BzNH

O

R1

O

DMSO/tolueneNaH, DMF

1. NEt3, PPh3, CCl4 MeCN, r.t.2. MeOH, HCl

1. PhCOCl, NEt32. LiOH/H2O3. DCC, DMAP HCCCH2OH Bz

. NH

COOMe

R1

NBz

R1

COOMe

Br

NBz O

HR1

MeOOC

Mo(CO)6

•

•

88 - 99 %

75 - 93 %

1,4-dioxane,70 ºC

H2, Pd/CNBz O

HR1

MeOOC

N

O

OR2

R2

NBz O

HR1

MeOOC

N

O

OR2

R2

H

HN

R2

R2

O

O

THF, r.t.

N

S

Bn

HOCH2CH2 Cl

NEt3

NBz

HR1

MeOOC

H

NR3

N

O

R2R2

H2NREtOH/AcOH

19-81 %µW, 60-100 ºC

LibraryDevelopment

NBz O

Hp-F-C6H4CH2

MeOOC

N

O

O

H

NBz

Hp-F-C6H4CH2

MeOOC

H

NR

O

N

H2NREtOH/AcOH

(NEt3)

µW or oilbath

Microwave versus Oilbath

Aminetime yield H2NR time yield[min] [%] [min] [%]

5 76 15 58

7.5 74 20 57

15 80 45 72

5 74 20 55

3 57 10 56

Microwave Oilbath

H2NO

H2N

H2N

H2N

N

CH2OH

HO

2 HClH2O..

H2NO

O

HCl.

3-4 times fasteryields 10 % higher

same purityWerner, S.; Iyer, P. S.

Synlett 2005, 9, 1405-1408.

Emrys Optimizer Microwave

150 W, 80 ºC

Preheated Oilbath

80 ºC

LibraryDevelopment

7

Protocol

Emrys Optimizer Microwave600 µL EtOH, 60 µL glacial AcOH3 eq amine15 min 80 ºC, 150 W,

Radley’s GreenHouse BlowdownEvaporatorEvaporation under a flow of argon

ISCO CombiFlash Optix 10Purification on 4g RediSep Column

up to60 samples

up to24 samples

up to10 samples

Number of Scaffolds: 1Points of Diversity: 3Longest Linear Sequence: 10Library Matrix: 3 x 2 x 41Library Size: 179 compoundsAmounts obtained: 5-40 mgPurity by UV: 94%

LibraryDevelopment

Purity Criteria

LC-MS Analysis with a Thermo Finnigan LCQ AdvantageAlltech Prevail , 1 mL/min, 30 min runtime

35 % H2O/MeOH (95/5), 15 % MeOH, 50 % MeCN

< 85 %

Library179 compounds

Repurification with a Gilson Serial HPLCVarian C-18 (250 x 21.4 mm), 15 mL/min, 15 min runtime

70-100% MeOH/MeCN (1/3), 30-0 % H2O

> 85 %at 210, 220

and 240 nm or by ELS

LibraryDevelopment

Generating Skeletal DiversityThrough Transition Metal Catalyzed

Carbon-Carbon Bond Forming Reactions

Brummond, K. M.; Wan, H.; Kent, J. L J. Org. Chem. 1998, 63, 6535-6545.Brummond, K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem. Soc. 2002, 124, 15186-15187.Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2162-2163.

Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245-2248.Brummond, K. M.; Chen, D.; Org. Lett. 2005, 7, 3473-3475.

Mitasev, B.; Brummond, K. M. Synlett 2006, ASAP

Library of 115 3-Pyrroline-2-carboxamides

DhanalakshmiKasi

*N

R3

R4OOCCH2R2

R10

AgNO3

*

PN

*

[Rh(CO)2Cl]2,PPh3, AgBF4CO (1 bar)

[Rh(CO)2Cl]2,toluene, N2

µw, 250ºC,ionic liquid,

toluene Mo(CO)6,DMSO, toluene

R1

R3

COOR4

R2CH2

PN

R1

R3

COOR4 CH2R2

PN

R4OOC

R3

R2

R1

O

R1

PN

COOR4R3

R2

O

R1

CH2R2

PN

R4OOC

R3

R1

CH2R2

PHN

R3COOR4

CH2R2

PN

COOR4R3

O

PN

R4OOC

R3

R1O

[Rh(CO)2Cl]2,toluene, N2

[Rh(CO)2Cl]2,toluene, N2

ChemicalMethodologies

8

Synthesis of 3- Pyrroline- 2- carboxamides

NH

OHBOC

R1

O

R2

OH

TMS

NH

OBOC

R1

O

R2

TMSH

NHMeOOC

R1 R2

H

BOCDCC, DMAP, DCM, r.t.

80-100%

1. LDA, ZnCl2, THF -78ºC to r.t.2. MeI, KHCO3, r.t.3. TBAF, THF, r.t.

25-60%

racemic

N

MeR4HN

O R3

N

MeR4HN

O R3N

MeR4HN

O R3N MeR4HN

O R3NR4HN

O R3

H

NH2MeOOC

R1 R2

H

95%

for 5 different combinations of R1 and R2

TFA, DCM, r.t.

LibraryDevelopment

Werner, S.; Kasi, D.; Brummond, K. M. J. Comb. Chem. 2007, 9, 677.

Functionalization of 3- Pyrroline- 2- carboxamides

62-93%

ClCOOMe,NEt3 or K2CO3

DCM, r.t.

77-99%

PhCOCl, NEt3DCM, µW 100ºC

52-96%

MeCOCl, NEt3DCM, r.t.

1. LiOH, H2O, THF µW, 80ºC, 85-99%2. R4NH2, PS-DCC, HOBt, DCM, µW, 100ºC

1. LiOH, H2O, THF µW, 100ºC, 92-99%2. R4NH2, PS-DCC, HOBt, DCM, µW, 100ºC

1. LiOH, H2O, THF µW, 100ºC, 56-99%2. R4NH2, PS-DCC, HOBt, DCM, µW, 100ºC

N

R1

O

N R2

R1

O

N R2

R1

O O

R2R4NH

O

R4NH

R4NH

O

PhO

63-99%

83-99%

59-99%

NMeOOC

R1

O

NMeOOC R2

R1

Ph O

NMeOOC R2

R1

O O

R2

H

NH2MeOOC

R1 R2

H

NH

MeOOC R2R1

AgNO3,acetone,

r.t.54-99%

LibraryDevelopment

Werner, S.; Kasi, D.; Brummond, K. M. J. Comb. Chem. 2007, 9, 677.

Statistics

N

R1

R2R4HN

O R3

Physicochemical Properties (QikProp 2.1)

Average Molecular Weight: 311 ± 74 g/molAverage clogP: 2.3 ± 1.5Average logS: - 2.9 ± 1.4Average Number of HBD: 1.2 ± 0.6Average Number of HBA: 5.6 ± 1.5Average Number of Rotatable Bonds: 4.5 ± 1.2

Number of Scaffolds: 1Points of Diversity: 4Longest Linear Sequence: 9Library Matrix: 5 x 3 x 12Library Size: 115 compoundsAmounts obtained: average 20 mgPurity by ELSD: 97%

LibraryDevelopment

9

Generating Skeletal DiversityThrough Transition Metal Catalyzed

Carbon-Carbon Bond Forming Reactions

Brummond, K. M.; Wan, H.; Kent, J. L J. Org. Chem. 1998, 63, 6535-6545.Brummond, K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem. Soc. 2002, 124, 15186-15187.Brummond, K. M.; Chen, H.; Mitasev, B.; Casarez, A. D. Org. Lett. 2004, 6, 2162-2163.

Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245-2248.Brummond, K. M.; Chen, D.; Org. Lett. 2005, 7, 3473-3475.

Mitasev, B.; Brummond, K. M. Synlett 2006, ASAP

*

PN

*

[Rh(CO)2Cl]2,PPh3, AgBF4CO (1 bar)

[Rh(CO)2Cl]2,toluene, N2

µw, 250ºC,ionic liquid,

toluene Mo(CO)6,DMSO, toluene

R1

R3

COOR4

R2CH2

PN

R1

R3

COOR4 CH2R2

PN

R4OOC

R3

R2

R1

O

R1

PN

COOR4R3

R2

O

R1

CH2R2

PN

R4OOC

R3

R1

CH2R2

PHN

R3COOR4

CH2R2

PN

COOR4R3

O

PN

R4OOC

R3

R1O

[Rh(CO)2Cl]2,toluene, N2

[Rh(CO)2Cl]2,toluene, N2

ChemicalMethodologies

N-Heterocycles

Generating Skeletal DiversityThrough Transition Metal Catalyzed

Carbon-Carbon Bond Forming Reactions

unpublished

Library of 5,6-Dihydro-2H-pyran-2-carboxamides

Dhanalakshmi Kasi

OMe

CF3

R2

NH

OR10

O

R1

F3CCOOMe

R2CH2

HO

F3CCOOMe

CH2R2

OMe

CF3

COOMe

R2

OCOOMe

CF3

CH2R2

[Rh(CO)2Cl]2,toluene, N2

[Rh(CO)2Cl]2,toluene, N2

ChemicalMethodologies

O-Heterocycles

R2NH2, NaCN, MeOH,

µW, 100oC, 120 min

22-38%

Synthesis of 5,6- Dihydro- 2H- pyran- 2- carboxamides

Carbonyl-Ene Reaction

Transamidation

48h at 80oC in oilbathgives only 65% yield

unpublished

LibraryDevelopment

HydrolysisAmidation no product formation by stirring at r.t.

or heating in oilbath

F3C COOMe

OµW, 125oC, 45 min,

98% •

HO COOMe

•

O COOMe

CF3 •

O COOCH2CHCH2

CF3

1. NaH (95%), THF, 0oC2. Bu4NI, propargyl bromide +

[Rh(CO)2Cl]2toluene, r.t.

84%

78%

O

CF3

COOMeO

CF3

CONHR2

MeONH2

N

NH2

NH2

O

CF3

COOHLiOH, THF/water

µW, 100oC, 10min84%

R2NH2DEPBT, DCM, r.t. or

PS-DCC, HOBt, µW, 100oC, 10min<10%

10

Application of Fluorous Chemistry to the Synthesis of Compound Libraries

Fluorous Mixture Synthesise.g. synthesis of several

diastereomers of a natural product

Fluorous Reagents (FTI)e.g. F-DEAD, F-PPh3,

F-Dimethylsulfide, F-Grubbs

FluorousScavengers

FluorousBuilding Blocks

FluorousSynthesis

N N

NO O

RF

NC

Tos

O

RF

N

N

R2H

H R1

O

O

R3N

O

R4O

CnF2n+1

n = 4-8

Curran, D. P. Angew. Chem. 1998, 110, 1230-1255.Zhang, W. Tetrahedron 2003, 59, 4475-4489.

Werner, S.; Curran, D. P. Org. Lett. 2003, 5, 3293-3296.Curran, D. P.; Dandapani, S.; Werner, S.; Matsugi, M. Synlett 2004, 1545-1548.

Gladysz, J. A.; Curran, D. P.; Horváth, I. T. Handbook of Fluorous Chemistry, Wiley-VCH, New York, 2004.Fukui, Y.; Brückner, A.; Shin, Y.; Balachandran, R.; Day, B. W.; Curran, D. P. Org. Lett. 2006, 8, 301-304.

ChemicalMethodologies

FSPE

IT

FFF

O OO

Silica

O

Si(Me)2

Rf

TF FF

O

O

O

I

T

F

F

F

I

organic fraction

fluorous fraction

fluoroussilica gel

FluorophobicSolvent

(MeOH-H2O)

FluorophilicSolvent

(MeOH or Et2O)

Zhang, W.; D. P. Tetrahedron 2006, 62, 11837.Pictures provided by

ChemicalMethodologies

Fluorous Synthesis of Piperazinediones

NH2

ORF

O

NH2

ORF

O

Zhang, W.; Lu, Y.; Chen, C. H. T.; Curran, D. P.; Geib, S. Eur. J. Org. Chem. 2006, 2055, 2059.Werner, S.; Turner, D. M.; Nielsen, S. D.; Curran, D. P. unpublished.

CHO

CHOCHO CHO

N

CHO

ON OO N OON OO

O

O

H2NOH

H2N

H2N H2NH2N

H2N COOMe

HN

N

N

H2NH2N

H2N

CF3

NMe2

H2NN

LibraryDevelopment

NH2

ORF

OR1

R2+

NH

N

R2H

HR1

O

OR3

ORF

O

1. R4NH2 (10eq)2. AcOH, CHF2CF2CH2OH µW, 1h, 250°C

42-89%FSPE

50-85%chromatography

70-85%FSPE

N

N

R2H

HR1

O

OR3

ORF

O

ClO

N

N

R2H

HR1

O

OR3

N

O

R4O

CHO

ClCH2COCl (10eq),DMAP, molecular

sieves,DCE, 2h, 60°C

ORF = O(CH2)3C8F17

FSPE = Fluorous Solid Phase Extraction

1. NEt3 (3eq), DMF, 30min, r.t.2. R3-maleimide (1,5eq), µW, 30min 130°C

(1,2eq)

11

LibraryDevelopment

FSPE-Purification

NH2

ORF

OR1

R2+

NH

N

R2H

HR1

O

OR3

ORF

O

50-83%FSPE

CHO

1. NEt3, DMF, 30min, r.t.2. R3-maleimide (2eq), µW, 30min 130°C

(2eq)

Werner, S.; Turner, D. M.; Nielsen, S. D.; Curran, D. P. unpublished.

NH

N

H

H Me

O

OMe

O

O

O

C8F17

reaction mixture

150 mLMeOH/H2O 80/20

fluorophobic

150 mLEt2O

fluorophilic

DMF

30% EtOAc in hexanes

aldehyde

product

maleimide

Synthesis Workflow in the UPCMLD

1 mg 10 mg 100 mg 1 g 10 g 100 g

Synthesis

Workup

Purification

Evaporation

Greenhouse(Radley)

Phase Separator(Biotage)

Scavengers (Biotage)

AutomatedWorkstation

(Chemspeed)

Batch-ModeMicrowave

(CEM)Microwave(Biotage)

Chromatography System (ISCO)

Automated ParallelChromatography (ISCO)

HPLC(Gilson)

ChemElut(Varian) ALLEXis

(Mettler Toledo)

Blowdown Evaporator(Radley)

Carousel ReactionStation (Radley)

Speedvacs (Genevac/Christ)

LibraryDevelopment

Conclusion

During all presented library synthesesnot a single reaction was performed in an

oilbath. All reactions were carried out at room temperature, low temperature or

in a microwave reactor.

12

Five User Tips

1. Microwave heating is the first thing to try, not the last chance to get a reaction going.

2. Optimization is easy. Set up several reactions at the same time and queue them up. Run the reaction at three different temperatures (e.g. 80oC, 120oC, 160oC) and compare the results.

3. Solvents are distinguished as “good” or “bad” for microwave heating, but by having microwave energy absorbing reagents or by using passive heating elements “bad” solvents still can become the solvent of choice. There are no “bad” solvents, only unsuitable reaction conditions.

Passive Heating Elements

at room temperature very slow reactionunder microwave irradiation, the reaction is faster, but high temperatures are needednot more than 140-150oC can be reached with ethanol as solvent while applying 300 Waddition of silicon carbide, allows to reach 180oC within 30 s

O

Cl

F

O

Cl

F

NH

BnNH2 (20eq),quinidine, EtOH

Silicon CarbideµW, 180oC, 30min

Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651-4658.

change to a more polar solvent or use a mixture of solvents, e.g. trifluoromethylbenzene instead of toluene or benzeneadd ionic liquidsuse microwave energy absorbing reagents

beforeirradiation

afterirradiation

Five User Tips

4. You can use polymer beads in the microwave without any problem.Reaction time is generally short and grinding of the polymer no concern.We observed that preswelling is not necessary.

5. Microwave tubes are great sealable vessels for every type of reaction (room temperature, photochemistry, even refluxing DCM at 100ºC in the oil bath). Tubes fit in most test tube racks, e.g. for evaporation systems.

13

Acknowledgments

UPCMLD DOS CoreProf. Peter Wipf (Director of UPCMLD)Dr. Donna Huryn (Scientific Adviser)

Dr. Grace Woo (Synthesis)Dr. Shuli Mao (Synthesis)

David M. Turner (Synthesis)Pete G. Chambers (Synthesis, Analysis)

Dr. Dhana Kasi (Synthesis)Dr. Pravin S. Iyer (Synthesis)Leslie A. Twining (Analysis)

Matthew D. Fodor (Synthesis)

CollaboratorsProf. Kay M. Brummond,

Dr. Corey R. J. Stephenson, Dr. Christopher Kendall, Dr. Donald Probst, Dr. Branko Mitasev, Simon D. Nielsen,

Jingbo Xiao, Maciej Walczak

$$$NIH-Grant P50-GM067082

http://ccc.chem.pitt.edu/UPCMLD