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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, Austriado.dallinger@uni-graz.at
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
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