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Biotage User Group Meeting, 12 th October 2004, Basel Doris Dallinger User Group Meeting, 12 th October 2004, Basel Rapid Scaffold Decoration of Privileged Dihydropyrimidine Cores Using Microwave-Assisted Synthesis Doris Dallinger Institute of Chemistry, Organic & Bioorganic Chemistry Karl-Franzens University Graz, Austria [email protected] www.maos.net

Rapid Scaffold Decoration of Privileged Dihydropyrimidine ...data.biotage.co.jp/pdf/presentations/1191_dallinger.pdf · Rapid Scaffold Decoration of Privileged Dihydropyrimidine Cores

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Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

User Group Meeting, 12th October 2004, Basel

Rapid Scaffold Decoration of Privileged Dihydropyrimidine Cores Using Microwave-Assisted Synthesis

Doris DallingerInstitute of Chemistry, Organic & Bioorganic Chemistry

Karl-Franzens University Graz, [email protected]

www.maos.net

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Privileged Heterocyclic Structures:Dihydropyrimidines (DHPMs)

SQ 32926

R6

E

N

N

R4

ZR1

R3

“a single molecular framework able to provide ligands for diverse receptors”(Evans, et al. 1988)

Privileged Heterocyclic Structures:Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Biologically Active Dihydropyrimidines

NH

Ni-PrO2C

Me O

CONH2

NO2

NH

Ni-PrO2C

Me S

F3C O

O

N

F

NH

NMeO2C

O

FF

MeO

O

NH

NN

NH

NHEtO2C

Me S

OH

MeO2C

MeN

F

NH

N

F

Cl

FBay 41-4109SQ 32,926

antihypertensive

SQ 32,547antihypertensive

L-771,688 (SNAP 6,383)α1A-adrenergic antagonists

monastrol

mitotic kinesin Eg5 inhibitor (Science 1999, 286, 971)

HBV replication inhibitor (Science 2003, 299, 893)

Eur. J. Med. Chem. 2000, 35, 1043

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Dihydropyrimidines (DHPMs) via the Biginelli Reaction

+OR6

E H+

R1

ZHN

NH2

Z = O, SR1 = H, alkyl, arylR4 = alkyl, aryl, heterocycleE = ester, amide, acyl nitroR6 = alkyl, aryl

R6

ER4

H

R1

Z

N

N

OH

R4

(17)

(25)

(8) (3400)

conventional conditions: 3-12 h reflux (EtOH/HCl)

Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360

Reviews: Kappe, C. O. Tetrahedron 1993, 49, 6937Kappe, C. O. Acc. Chem. Res. 2000, 33, 879Kappe, C. O. QSAR Comb. Chem. 2003, 22, 630Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Generation of DHPM Libraries

Automated solution phase synthesisPolymer-assisted solution phase synthesisSolid-phase strategiesFluorous synthesisSoluble polymers / dendrimersParallel synthesis

Possible Attachment Points of DHPM Scaffolds for Solid-, Soluble Polymer- or Fluorous Supports

N

NH

O

O

R6 Z

R4

R1N

NHE

R6 Z

R4

NH

NE

R6

R4

S N

NHE

Z

R4

R1

A B C D

Review: Kappe, C. O. QSAR Comb. Sci. 2003, 22, 630

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

High Throughput Sequential Synthesis in Single-Mode Cavities

Emrys™ Synthesizer+ sample robot+ up to 120 reactions+ magnetic stirring+ 12-15 reactions per hour+ 0-300 W+ 60-250 °C, 0-20 bar

J. Comb. Chem. 2001, 3, 624

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Optimization of Reaction Conditions

Model Reaction

1. Select Catalyst

0 20 40 60 80 100

5 mol%Yb(OTf)3

FeCl3

LaCl3

InCl3

Isolated Yield (%)

2. Time & Temp Optimization

0

20

40

60

80

100

5 min10 min

15 min

100°C

120°C

130°C

140°C

Isol

ated

Yiel

d (%

)

catalyst

AcOH/EtOH (3:1)OH

Ph

Me

EtO2C

Ph

H

H

O

N

NOH2N

NH2

OMe

EtO2C+

cf. Tye, H. Drug Discov. Today 2004, 9, 485

10 mol%

120 °C, 10 min, AcOH/EtOH (3:1) Yb(TfO)3, AcOH/EtOH (3:1)

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Automated Software-Driven Library Production

+ prepare stock solutions+ enter building blocks and

conditions into software+ generate dispensing strategy+ run automated protocol+ work-up

experimentalprogress

ISIS Draw platform

creating toolsprotocol generation

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Summary for DHPM Library Generation

OR6

E

R4

O HNH2

HN ZR1

∆ R6

E

N

NH

R4

ZR1

+

solvent/catalyst

Z = O, SR1 = H, alkyl, arylR4 = aryl, alkyl, heterocycleE = ester, acyl, amide nitroR6 = alkyl, aryl

(25)

(17)

(8)(3400)

48 member DHPM library generated within 12h (52% average yield)DHPMs produced in 200-1000 mg quantities Reaction times reduced from 3-12 hours to 10-20 minutesReaction optimization within hoursEstablishing of library production protocol within daysSequential treatment allows for individually optimized conditions

J. Comb. Chem. 2001, 3, 624

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

High-Speed, High-Throughput DHPM ScaffoldDecoration using Microwave-Chemistry

R = benzyl, allyl:deprotection

R = H: F-Mitsunobu

X = NO2: CTHX = Br: C-C coupling

acylationarylation

Z = S: alkylation,arylation

alkylation (Mitsunobu)

1. bromination2. substitution

Me

RO2C

NH

NH

Z

X

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

N1-Alkylation of DHPMs

Selective N1-Alkylation Using Mitsunobu Conditions

N

N

R6

ER4

OH

H

N

N

R6

ER4

O

H

R1

R1OH (5 equiv)TMAD, TBP (2.5 equiv each)

dioxane, rt, 1-15 h

(for primary alcohols)

35-89% yield(17 examples)

R1 = Me, Et, n-Pr, n-hexyl, PhCH2, 3-F-PhCH2

TMAD = N,N,N',N'-tetramethylazodicarboxamide, TBP = tributylphosphine

Synlett 2002, 1901

N1-Alkylation of N3-Protected Derivatives

N

N

Me

EtO2CPh

OH

Ac

N

N

Me

EtO2CPh

O

Ac

CH2Ph

PhCH2Cl (1.5 equiv) Cs2CO3, DMF

MW, 160 °C, 5 min

95% conversion

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Liebeskind-Srogl C-C Bond Formations

Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979

SR'

NMe SMe

MeCN

N

N

SMe

Me

S

NSMe

R

SOEtO2C

SMe

S COOCu

Het + R-B(OH)2

Pd2dba3/TFPCuTC, (Zn(OAc)2) THF

50 °C, 18 h

Het

CuTC =

TFP = tris(2-furyl)phosphine

e.g.

12 examples (53-87%)

NH

N

Me

O

O

NO2

SMe NH

N

Me

O

O

NO2

Ph

2-3 mol% Pd(PPh3)4 2.5 equiv CuTC THF

MW, 130 °C, 25 min

84 % yield

+ Ph-B(OH)2

Org. Lett. 2004, 6, 771

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Tunable Carbon-Carbon versus Carbon-Sulfur Coupling

A Novel Carbon-Carbon Bond Forming Reaction !

Pd(0)/Cu(I)

NH

NH

Me

EtO2C

S

Ph

NH

N

Me

EtO2C

Ph

Ph PhB(OH)2Pd(PPh3)4, CuTC THF

MW, 100 °C, 25 min

NH

N

Me

EtO2C

S

Ph

Ph

PhB(OH)2Cu(OAc)2, phenanthroline DCE, MW, 85 °C, 45 min

72%

81%

Org. Lett. 2004, 6, 771

Cu(II)

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Application for the Generation of Bay 41-4109 Libraries

F

ClCHO

OMe

MeO2CNH2

H2N S

NH

NH

Me

MeO2C

S

F

Cl Yb(OTf)3, MeCN

MW, 120 °C, 20 min+

(87 %)

ArB(OH)2 Pd(PPh3)4, CuTC THF

MW, 100 °C, 25-60 minNH

N

Me

MeO2C

F

Cl

Ar

NH

NMeO2C

Me

F

Cl

N

F

FBay 41-4109

14-81%

Ar = Ph, 4-ClPh, 3-MePh, 2,6-F2Ph, 2-thiopheneScience 2003, 299, 893

Org. Lett. 2004, 6, 771

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

N3-Arylation via Goldberg Reaction

EtO2C

Me

Ph

N

NH

O

EtO2C

Me

Ph

N

N

O

CuI, Cs2CO3, DMF

MW, 180 °C, 40 minI

R3

R3

R1 R1 R1 = H, Me

13-83 % yield

10 examples

N

NEtOOC

Me OH

N

N

Me OMe

N

NEtOOC

Me OMe

OMe

N

NEtOOC

Me OMe

EtOOC

COOEt COOEt

COOMe

13 % 80 % 63 % 83 %

unpublished results

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

N3 Protection and Deprotection using Polymer Bound Reagents

Selective N3-Acylation with Electrophiles

NH

N

Me

EtO2CPh

O

O

Me

N

N

NH

NH

Me

EtO2CPh

O+ Ac2O

MeCN/THFMW, 130 °C, 15 min

EtOH/HClMW, 130 °C, 15 min

Mol. Diversity 2003, 7, 229

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

N3-Acylation of DHPMs with Anhydrides, Acid Chlorides, and Isocyanates.........

High-Throughput Synthesis

N

N

R6

ER4

XR1

H

N

N

R6

ER4

XR1

A.(R3CO)2O, or R3COClTEA, DMAP, MeCN

MW, 5-20 min 100-180 °C

O

R3

N

N

R6

ER4

X

O

R3+

O R3

SPE: Al2O3/K2CO3 (2:1), SiO2

44 member N3-acyl-DHPM library 32-99 % isolated yield66-99 % purity

C. (for R1 = H)

MW, 5 min, 100 °C

B. scavenger

10 DHPMs

Org. Lett. 2003, 5, 1205

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

....In Combination with Microwave-AssistedScavenging Techniques

Kinetics of Benzoic Anhydride Sequestration using Amine-Functionalized Resin:a: polystyrene / b: functionalized silica / c: Plugs / d: Lanterns

Room Temperature (25 °C) Microwave Heating (80-100 °C)

0

10 60

120

240

360

480

ab

cd

0

20

40

60

80

100

% B

z 2O

t [min]

0 150 300 450 600 a b c d0

20

40

60

80

100

t [s]

Si

HNNH2

(3.02 mmol N/g)

HNNH2(3.26 mmol N/g)

HNNH NH2

(915 µmol / unit)

NH2 (TFA salt)

(100 µmol / unit)

Org. Lett. 2003, 5, 1205; Mol. Diversity 2003, 7, 229

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Pd-Catalyzed Transfer Hydrogenations.Derivatization of Anilines

ARKIVOC 2002, (8), 71

NH

NH

O

EtO2C

Me NH

NH

O

EtO2C

Me

EtOHHCOONH4, Pd/C

MW, 120 °C (12 bar)2 min

NH

N

O

MeO2C

Me

HN

CO2Me

O

HN N

OMe

BMS (WO 98/33791)

NO2 NH2

steps

91 %

neuropeptide Y antagonist

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Transition Metal-Catalyzed C-C Bond Formations

Intramolecular Heck Reaction

NH

N

O

EtO2C

Me

OBr Herrmann's palladacycle DMF/H2O MW, 130 °C, 15 min

NH

N

O

EtO2C

MeO

Aminocarbonylations

NH

NH

O

EtO2C

Me

Br

NH

NH

O

EtO2C

Me

O

NR1R2 R1R2NH, Mo(CO)6Pd(OAc)2+ P(o-tolyl)3 Bu3P.HBF4, DBU THF MW, 130 °C, 15 min

80%Collaboration with M. Larhed and J. Wannberg

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Pd-Catalyzed Debenzylation and Deallylation of C5 Esters

N

N

Me XR1

HO

OPh

N

N

Me XR1

HO

HO

N

N

Me XR1

HO

O

Pd(PPh3)4, THF Et2NH

MW, 100 °C, 10 min (45-61 %)

Pd/C, MeOHHCOONH4

MW, 100 °C, 20 min (62%)or rt, 12 h (75%)

Z

Z

Z

Acid Functionalization

10 examples

cf. J. Chem. Soc., Perkin Trans. 1, 2000, 4382

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Amidation Involving Resin-Bound Carbodiimide

N

N

R6 XR1

HO

HO

Z

NHR2R3N

N

R6 XR1

HO

NR2

R3

Z

+

BtOH, MeCN/DMA

MW, 100-120 °C, 10-15 min

then SPE(Si-carbonate)

O NC

NPS-Wang

N

N

Me SH

HO

NH

Cl

Ph

N

N

Me OH

HO

NH

Ph

Me

N

N

Me OMe

HO

NH

Ph

N

N

Ph OH

HO

NH

Ph

Early Examples

cf. Sauer, D. R. et al. Org. Lett. 2003, 5, 4721

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Solid Phase Synthesis of C5 Acids

OH

Wang resin

O

O

DMAP, DCM 0 °C -> rt

MeO R

O OO

O

OR

O H

Ar

NH2

H2N X

solventHCl (cat)18h

O

O

NH

R

NH

O

ArTFA/DCM30 min, rtHO

O

NH

R

NH

O

Ar

1,2 dichlorobenzene MW, 170 °C, 10 min (open vessel)

11 examples

J. Comb. Chem. 2002, 4, 154Synlett 2001, 6, 741

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Alkylation of C5 Acids via F-Mitsunobu

N

N

Me OH

HO

HO THF, rt, 1h

1. R5OH, F-TPP, F-DEAD (1.8 equiv each)

2. F-SPE MeOH:H2O (80:20) N

N

Me OH

HO

R5O

R5 = Et: 93 %

O N N OC6F13C6F13

O OF-DEAD:

PhPC6F13

2

F-TPP:

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Triazolyl-Dihydropyrimidone Libraries

Merging MCR and Click Chemistry

O

N

NH

R2

O

OR3

R1

NNN

R4

O

N

NH

R2

O

OR3

R1Me

HR4

Me O

O

OR3

O

N

NH

R2

O

OR3

R1

N3

R2

O HNH2

HN OR1

+Biginelli MCR

Azide-Acetylene Ligation "Click Chemistry"

Installment of Azide Functionality

Azide – Alkyne Ligation: Rostovtsev, V. V. et al. Angew. Chem. Int. Ed. 2002, 41, 2596Click Chemistry: Kolb, H. C.; Finn, M. G.; Sharpless, K. Angew. Chem. Int. Ed. 2001, 40, 2004

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

A) Bromination / Azidation Sequence

NMe3 Br3+ _

DMF, rt, flow conditionsca 1 min residence time

then SPE (basic alumina)

NMe3 Br+ _

Br2, CCl4, rt, flow conditions O

NH

NH

Ph

O

EtONu

NuH

O

NH

NH

Ph

O

EtON3MW, 60 °C, 20 min

NaN3, DMF

Azidation: Kappe, C. O. Liebigs Ann. 1990, 505

Batch Bromination: Zigeuner, G. et al. Monatsh. Chem. 1966, 97, 1408

O

NH

NH

Ph

O

O

Me

O

EtO

BrEt

NH

NH

Ph

O

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

B) Azide-Acetylene Ligation (Click Chemistry)

O

NH

NH

Ph

O

EtO

N3

HPhO

NH

NH

Ph

O

OEt

NNN

Ph

CuSO4, Na ascorbate, DMF

MW, 80 °C, 1 min

O

N

NH

R2

O

OR3

R1

NNN

R4

• 27 library compounds• 4 diversity points• 15-46% overall purified yield

J. Comb. Chem. 2004, ASAP

Azide – Alkyne Ligation: Rostovtsev, V. V. et al. Angew. Chem. Int. Ed. 2002, 41, 2596Click Chemistry: Kolb, H. C.; Finn, M. G.; Sharpless, K. Angew. Chem. Int. Ed. 2001, 40, 2004

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Solid-Phase Synthesis of Bicyclic DHPMs

OH

NH

NH

R1

OO

O

ON

O

NH

NH

R1

OH2NR3

OCl

O

NH

NH

R1

O

OCl

O

O

HNN

O

NH

NH

R1

OR3

ON

O

NH

NH

R1

OR2 H

NH

NH

R1

ON

O

R2

Me 4-Cl-acetoacetate

1,2-dichlorobenzeneMW, 170°C, 15 min

R1CHO, ureadioxane/HCl70°C o/n

R2NH2, DMFrt to 70°C, o/n

R3NHNH2, DMFrt, 30 min

DMF, MW

150 °C, 10 min

150 °C, 10 min

DMF, MW

DMF, MW

150 °C, 10 min

PS-OH

J. Comb. Chem. 2002, 4, 501

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Generation of Diversity-Oriented DHPM Libraries

R = benzyl, allyl:deprotection

R = H: F-Mitsunobu

X = NO2: CTHX = Br: C-C coupling

acylationarylation

Z = S: alkylation,arylation

alkylation (Mitsunobu)

1. bromination2. substitution

Me

RO2C

NH

NH

Z

X

ca 211

43.252.003.274.489.856.000

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Combination of Microwave Chemistry and Automated Flash Chromatography

Bromination of a Quinolin-2-one

N

Ph

OMe

NBS (1.5 equiv) MeCN

MW, 60 °C, 5 min N

Ph

OMe

N

Ph

OMe

Br Br

Product (56 %) Byproduct (44 %)

HPLC at 254 nm:

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Combination of Microwave Chemistry and Automated Flash Chromatography

Flash Chromatography (SP4)

TLC:

Product

Byproduct

Eluent: PE:EtOAc/1:1

SP4 at 254 nm:

Product Byproduct

Biotage User Group Meeting, 12th October 2004, Basel Doris Dallinger

Acknowledgements

Supervisor

C. Oliver Kappe

Colleagues

Alexander StadlerMykola Gorobets Rolando PerezBimbisar Desai Alenka Lengar Bogdan Khanetskyy Elise Gunnarson

Collaborators

M. Larhed (Uppsala)

Personal Chemistry/BiotageAustrian Science FundCERC3, EU (COST D32)Austrian Academy of SciencesÖsterreichische NationalbankAustrian Academic Exchange Service