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Department of Organic Pharmaceutical Chemistry
Rapid Metal-Catalysis in Organic and Medicinal Chemistry
Frankfurt am Main, June 9, 2005
Mats LarhedUppsala University
Organic Pharmaceutical ChemistryDepartment of Medicinal Chemistry
Disposition
• Introduction• Metal-mediated microwave-heated organic reactions
– Instant chemistry– Carbonylations– HIV-1 protease inhibitors– AT2 selective peptidomimetics– Heck and Grignard reactions– Plasmepsin inhibitors– Pulsed microwave irradiation - PCR
• Acknowledgement• Extra material
Larhed et al. Drug Discovery Today 2001, 406Larhed et al. Acc. Chem. Res. 2002, 717Olofsson et al. Microwaves in Organic Chemistry, Ed.Loupy, Wiley VCH, 2002, 379Ersmark et al. Current Opinion in Drug Discovery & Development, 2004, 417
Microwave Flash-Heating. Pressurized System
• 2450 MHz• Two mechanisms:
– dipole oscillation – ionic conduction
• Rapid heating• Superheating• In situ heating• Non-thermal effects?
20
40
60
80
100
120
140
0 30 60 90 120 150 180 210 240 270 300 330Time (s)
Tem
pera
ture
(o C)
500 W x 15 s120W x 30s90 W x 60 s30 W x 120 s10 W x 300 s 5 W x 300 s
Kaiser et al. J. Organomet. Chem. 2000, 2Gabriel et al. Chem. Soc. Rev. 1998, 213
CH3CN bp 81-82 oC
Heating Profile of Single-Mode Microwave Heating vs. Pre-Heated
Oil-Bath
Microwave-heating Classic wall-heatingSchanche et al.
Microwave-Assisted OrganicChemistry
• Pressurized system• Solvent-free (open vessel reactions)• Reflux system• Continuous flow system
Kaiser et al. Angew. Chem. 2000, 3595.
Rapid Iterations with Microwave Chemistry
Positive outcomePositive outcome
ClassicalHeating Hypothesis Reaction Hypothesis
Negative outcome
Reaction
Negative outcome
Hypothesis HypothesisReaction
Positive outcome Positive outcome
Negative outcome
Time
Reaction
Negative outcome
Hypothesis HypothesisReaction
Positive outcome Positive outcome
Negative outcome
Reaction
Negative outcome
Hypothesis HypothesisReaction
Positive outcome Positive outcome
Negative outcome
Reaction
Negative outcome
Hypothesis HypothesisReaction
Positive outcome Positive outcome
Negative outcome
Reaction
Negative outcome
thesis HypothesisReaction
Positive outcome Positive outcome
Negative outcome
MicrowaveHeating
Reaction
Negative outcome
Hypo
Lidström et al. Curr. Top. Med. Chem. 2004, 773
Rapid Optimization using Microwaves
Microwave heating and multivariate experimental design is a good combination for rapid chemical optimization!
http://pubs.acs.org/cen/
Solid Phase Synthesis
• Palladium-catalyzed Suzuki reaction– TentaGel, 100 mg resin (23 µmol).– 84-99% isolated yields, >99% conversion, 14 examples
RAMHN
OX
O
H2N
O
H2NOMe
O
H2N
O
H2N
S
O
H2NF
O
H2N
NSO2Ph
O
H2NMeO
O
H2NNO2
1) ArB(OH) 23.8 min 45 W
2) TFA
X = I or Br
Larhed et al. Tetrahedron Lett. 1996, 8219
Heck-Coupling Reactions
Larhed et al. J. Org. Chem. 1996, 9582
I
IMeO
BrNC
I
CN
O
OMe
O
OMePd(OAc)2, DMF
Pd(OAc)2, DMF
OTfO NMe2
IBr
OTft-Bu O
Pd(OAc)2, DMF
Pd(OAc)2, DMF Br
Me
Ot-Bu
CN
O
OMe
MeO
O
OMe
NC
O NMe2
3.8 min 60 W
3.8 min 60 W
2.8 min 90 W
3.8 min 80 W
2.8 min 55 W
Pd(OAc)2, DMF o-(Tol)3P
Pd(OAc)2, Ph3 PDMF
Pd(OAc)2, DPPP DMF, H2O
4.8 min 60 W
7.0 min 35 W
87% (120 min 75%)
63% (1020 min 64%)
77%
87% (540 min 93%)
90%
94% (120 min 70%)
70% (300 min 68%)
(traditional cond.)
Instant CarbonylationChemistry
RI Co2(CO)8
R
O
RMicrowaves 6-10 s, rt → 130 oC
• 6-10 s Irradiation time• 10 Examples• 57-97% Isolated yields• No product without heating
Enquist et al. Org. Lett. 2003, 4875
Instant CarbonylationChemistry
• Temperature, pressure and powerprofiles for the 10 s synthesis ofbenzophenone with0.66 or 0.44 equiv Co2(CO)8
• The IR-thermometer lags behind
• Higher temperaturewith higher amountof Co2(CO)8
Enquist et al. Org. Lett. 2003, 4875
Instant Urea Synthesis
R NH2Co2(CO)8
Et3N, CH3CN Microwaves 10 s to 40 min
NH
NH
OR R2
NR
CO
• Isocyanate as key intermediate:
Enquist et al. Tetrahedron Lett. 2005, 3335
Instant Urea Synthesis
Enquist et al. Tetrahedron Lett. 2005, 3335
Entry Amine Time (s) Product Yield (%)________________________________________________________________
________________________________________________________________
1NH2
HN
HN
O
NH2 NH
C6H11 NH
OC6H11
NH2 NH
NH
O
NH2O
NH
NH
O
O O
NH2F3C
NH
NH
O
F3C CF3
NH2O NH
O NH
OO
NH2 NH
NH
O
NH2 NH
NH
O
NH2 NH
NH
O
NH2
O
HN
HN
OO O
2
3
4
5
6
7
8
9
10
10
10
13600
10
10
10
10
1200
1200
2400
8475
8381
7475
66
68
86
10
61
38
46
Temp (ºC)
Flash
Flash
Flash
Flash
Flash
Flash
130
rt
Flash
120
120
150
rt5 h
5 h
Microwave-Assisted in situGeneration of Carbon Monoxide
In principle:
• Combinatorial chemistry applications limited to manipulations of solids and liquids
• Microwave-assisted organic transformations limited to manipulations of solids and liquids
Can controlled release of gases from solid or liquid reagents be achieved?
An Improved in situ Amino-Carbonylation Protocol – Chemical
CO-liberation• Cr(CO)6 80%• Mo(CO)6 84%• W(CO)6 77%• Fe3(CO)12 0%• Co2(CO)8 28%
• DBU mediated CO release
• Improved method with sluggish amines and amino acids
Wannberg et al. J. Org. Chem. 2003, 5751Wan et al. J. Comb. Chem. 2003, 82Wan et al. J. Org. Chem. 2002, 6232Kaiser et al. J. Comb. Chem. 2002, 109
FAB-MS
M(CO)6 Yield
X
Mo
O
O
OO
O
O
HNR'R''
Mo
N
N
OO
O
O
N
N
O
NR'R''
2 CO
[Pd], Mo(CO)6
Air, 15 minDBU, THF
+
10 equiv DBU+
R RX = I, Br23 examples35-95%
Novel in situ Aminocarbonylations
HNR2R3O
NR3
R2
[Pd], Mo(CO)6Na2CO3
170 oC x 15 minwater
+Br
R1 R1
33 Examples, 44-97% yield
Wu et al. Submitted andIn preparation
• Only minor amounts of benzoic acid formed
NH2OH x HClO
NH2
[Pd], Mo(CO)6DBU, i-Pr2EtN
150 oC x 20 mindioxane
+Br
R1 R1
18 Examples, 70-85% yield
• Hydroxylamine reduced in situ by Mo(CO)6
Fast Syntheses of Esters by in situCarbonylation
O
OBr
O
O
F3C
O
O
HOR2
O
O R2
Pd/C or palladacycle
Mo(CO)6
150-190 oC15-20 min
+X
R1
R1
23 Examples, 33-89% yield
OO
O
OSiBr
O
O
O
OOSi
O
O
O
O
O
O
O
O
O
OBr
O
O
F3C
OO
• Fast palladium-catalyzed ester synthesisfrom aryl iodides and bromides under air
• Focus on common protecting groupsO
O
OSi
O
O
F3C
SiO
OSi
Georgsson et al. J. Comb. Chem. 2003, 350
In situ Aminocarbonylation of Aryl Chlorides
ClR
NH
OR'
NH2R'
R+
[Pd]Mo(CO)6
170 oC, Air15-25 min
50-89%10 Examples
(SmithSynthesizer, Biotage AB)
• The combination of Fu-salt, [(t-Bu)3PH]BF4, and Herrmann’s palladacycle results in a highly active and thermostable catalytic system suitable for microwave chemistry
• First method for aminocarbonylation of aryl chlorides?Lagerlund et al. Submitted
Catalyst Recycling in Carbonylation Chemistry with Fluorous Ligand
I
Pd(OAc)2, DBU,
Hydrazide, air P(PhCH2CH2C8F17)3
Mo(CO)6
THF, CF-84
NH
HN
OPh
O
Pd(P(PhCH2CH2C8F17)3)nMicrowaves, 5 min, 110 °C
+
NH
NH2
O
I
THF
micro-wave
P(Ph-C 2H 4
F 17) 3
Pd(OAc)2
FC-84
THF
Pd(P(P
hC 2H 4
C 8F 17
) 3) n
NH
HN
OO
FC-84
coolingRecycling 6 timeswith 64-79 % yield
Herrero et al. Synlett, 2004, 2335
Synthesis of Acyl Sulfonamides with Mo(CO)6
O
NH
OS
O O
O
IH2N
SO O
INH
OS
O O
INH
OS
O O
I
Ph
O
NH
OS
O O
F3C
I
F3C
NH
OS
O O
S I NH
OS
O O
S
S
I
NH
OS
O O
S
H2NS
O O
NH
OS
O O
H2NS
O O
Br
NH
OS
O O
Br
H2NS
O ONH
OS
O O
H2NS
O O
CF3
NH
OS
O O
CF3
NH
OS
O OI
NH
OS
O O
Ph
O
Entry Iodide Sulfonamide Product Isolated yield (%)
1 88
87
88
80
70
76
88
65
79
88
84
72
71
2
3
4
5
6
7
8
9
10
11
12
13
I
HNS
O O14 N
OS
O O
47
NH
OS
O OBr
H2NS
O O
Br
F
F
F
F3C
NH
OS
O O
BrNH
OS
O O
S Br NH
OS
O O
S
NH
OS
O OBr
NC
NH
OS
O O
NC
Br
H2NS
O O
H2NS
CF3
O O
NH
OS
O O
NH
OS
CF3
O O
Entry Bromide Sulfonamide Product Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
O
Br
O
NH
OS
O O
Br
O
NH
OS
O O
O
BrNH
OS
O O
93
94
91
93
95
96
95
83
79
88
80
ArX
H2NS
R
O O
NH
SR
O O
Ar
O
+ microwaves15 min
[Pd], Mo(CO)6DBU, dioxane
Wu et al. J. Org. Chem. 2005, 3094
Synthesis of a Hepatitis C Virus NS3 Protease Inhibitor
O
NH
BocHN SO O
Br
N
O
N
O
OOH
OBocHN
NH
O
SO
O
N
O
N
O
O
HN
OBocHN
ONH
SO
O
O
NH
BocHN SO O
HN
OS
O O
1. HCl/1,4-dioxane
2. HBTU, DIEA, DMF
[Pd], Mo(CO)6DBU, 1,4-dioxane
microwaves 15 min
H2NS
O O
Ki-value of 85 ± 7 nM
52%
76%
Wu et al. J. Org. Chem.2005, 3094
HCV Full-length NS3(protease-helicase/NTPase)
Metal-Catalyzed Functionalizations of the 4-Aryl-Dihydropyrimidone Template
[Pd] , Mo(CO)6, HNu
N O
NHO
O
R1
Y
N O
NHO
O
R1
N O
NO
OAr
R1
[Pd] , H2N R
O
[Cu]Ar-I
NHR
O
N O
NHO
O
R1
O
NuEsters and amides:Herrman's palladacycle[(t-Bu)3PH]BF415 min, 21-87%
Pd(OAc)2, XantphosCs2CO315 min, 62-85%
CuI, Cs2CO340 min, 34-83%
Y = Br or H 110-140 oC
120-150 oC
180 oCR1 = H or Me
• All reactions performed with microwave heatingWannberg et al. J. Comb. Chem. In print
Enamides in Reductive Heck Chemistry
OH
NHR
R
ROTf
Br
Br
NR' O
R''
NR' O
R''
Mo(CO)6Pd(OAc)2 Fu-salt Microwaves
Pd(OAc)2
R
NR'
O
R''
O
+dppp
8 examples26-63%
8 examples36-84%
P2 Indanol amine
• Carbonylative / reductive Heck cyclizations with in-situ CO iiirelease
Wu et al. J. Org. Chem. 2005, 346
00003-E-4 – December 2004
Adults and children estimated to be living Adults and children estimated to be living with HIV as of end 2004with HIV as of end 2004
Total: 39.4 (35.9 – 44.3) million
Western & Central Europe
610 000610 000[480 000 [480 000 –– 760 000]760 000]
North Africa & Middle East540 000540 000
[230 000 [230 000 –– 1.5 million]1.5 million]
Sub-Saharan Africa25.4 million25.4 million
[23.4 [23.4 –– 28.4 million]28.4 million]
Eastern Europe & Central Asia1.4 million 1.4 million
[920 000 [920 000 –– 2.1 million]2.1 million]
South & South-East Asia7.1 million7.1 million[4.4 [4.4 –– 10.6 million]10.6 million]
Oceania35 00035 000
[25 000 [25 000 –– 48 000]48 000]
North America1.0 million1.0 million
[540 000 [540 000 –– 1.6 million]1.6 million]Caribbean440 000440 000
[270 000 [270 000 –– 780 000]780 000]
Latin America1.7 million1.7 million
[1.3 [1.3 –– 2.2 million]2.2 million]
East Asia1.1 million1.1 million
[560 000 [560 000 –– 1.8 million]1.8 million]
AIDS – Epidemicupdate. Dec 2004
Target: HIV-1 Protease
HIV-proteaseC2 symmetric dimer
Concerns: 1) Active mutants2) Improved bioavailability
Microwave-assisted synthesis of protease inhibitors:Alterman et al. J. Med. Chem. 1999, 3835; Schaal et al. J. Med. Chem. 2001, 155;Nöteberg et al. J. Med. Chem. 2003, 734; Nöteberg et al. J. Comb. Chem. 2003, 456;Ersmark et al. J. Med. Chem. 2004, 110; Ax et al. Bioorg. Med. Chem. 2005, 755.For a summary see: Ersmark et al. Current Opinion in Drug Discovery & Development, 2004, 417
High-Speed Microwave-Assisted Library Generation
Wannberg et al. J. Comb. Chem. In print
NH
NHOH
OH
O
O
O
O
NH
ONH
O
I
I
NH
NHO
O
O
O
O
O
NH
ONH
O
I
IOO
NH
NHO
O
O
O
O
O
NH
ONH
O
(H)R'N
O
NR'(H)
O
R
R
NH
NHOH
OH
O
O
O
O
NH
ONH
O
(H)R'N
O
NR'(H)
O
R
R
10-CSA
CH2Cl2
AmineMo(CO)6
Pd(OAc)2DBU, THF
100 oC, 15 min
HCl /Diethylether
MeOH2 h
HIV-1 proteaseinhibitors
Biological Evaluation Against HIV-1 Protease and Work in Progress
NH
O
NH
O
NH
ON
S
NH
O
NH
O
NH
O
NH
O
NO
NO
O
NO
NH
ON
NH
O
N
653 nM
668 nM
1840 nM
863 nM
7.0 nM
16 nM
23 nM
>5000 nM
602 nM
392 nM
3.1 nM
678 nM
177 nM
65 nM
170 nM
1.6 nM
298 nM
7.2 nM
>5000 nM
ortho Ki meta Ki
O
HN N
H
HN
O
O
O
O
OH
OHNH
O
R1
R1
O
HN N
H
HN
O
O
O
O
OH
OHNH
O
R2
R2
R1
Metal-catalyzedintroduction ofmetabolically stableR-groups
Wannberg et al. J. Comb. Chem. In print
New previously “unknown”iiibinding site exploited?
O
HN N
H
HN
O
O
O
O
OH
OHNH
O
O
HN N
H
HN
O
O
O
O
OH
OHNH
O
Microwaves15 min
I
IKi= 117 nM
NH
HN
O
O
O
O
OH
OHHO
OH
Ki= 4.1 nM
[Pd]
Wannberg et al. In preparation
High-Speed Microwave-Assisted Library Generation of HIV-1 Protease Inhibitors
24 Examplesof coupling reactions
• Introduction of metabolicallyiiistable amide isosteres• Indanol amide optimal iiiP2/P2´?• Three probable binding iiiregions for the P1 and P1’iiisubstituents
One-Pot Generation of Protected Aminoindanones
CHO
OTf
O
OH
NH
R''R'
N R''R'
OORR
NHR
OH
+ +
Pd(OAc)2 dppp, PMP
80 °C
R R' R''H4-methoxy6-methoxy
butylisoamylisobutylethylethylbenzyl
butylisoamylisobutylcyclohexylbenzylbenzyl
51-71%
NH
OOH
H
R' R''
+
Arefalk et al. J. Org. Chem. 2005, 938
• Three-component annulation• Immonium ion intermediate
Via
P2 Indanol aminein Indinavir
High-Speed Syntheses of Aryl Triflates
R
OH O
H Tf2NPh, K2CO3R
OTf O
HMicrowaves 6.0 min, 120 oC
• 10 Different aryl triflates• 69-91% Isolated yields
Bengtson et al. Org. Lett. 2002, 1231
Dibenzylamine as an Ammonia Equivalent
CHO
OTf
O
OH NH2
OO
NH NH2
OO
+ +
Pd(OAc)2 dppp, PMP
90 °C
Pd/C, HCO2NH4 20 min, 100 °C
MicrowavesNH
OH
O
ONH
O
O
Compare
D29
D30
D29
D30
Arefalk et al. J. Org. Chem. 2005, 938
Cyclic Sulfamide HIV-1 Protease Inhibitors
• History
N NS
HO OH
OO
O O
N N
HO OH
O O
OP2
P1
P2
P1
S2 S2
P2'
P1'
P2'
P1'
S2'
S2'Ki = 12 nM Ki = 23 nM
Diol TS-mimic
Water mimicking groups
1994 Lam 1997 Hallberg
Lam et al. Science 1994, 380Hulten et al. J. Med. Chem. 1997, 885
Cyclic Sulfamide HIV-1 Protease Inhibitors
N NS
HO OH
OO
0-2 0-2
P2
P1
P2'
P1'R R
N NS
HO OH
OO
O O
Ki = 530 nM
O
N NS
HO OH
OO
NHO
HNO
R R
N NS
HO OH
OO
HN NH
R
O
R
O
R = phenyl or benzyl
• The elongation concept:
Aminocarbonylation product N-Amide arylation productAx et al. Bioorg. Med. Chem. 2005, 13, 755
Cyclic Sulfamide HIV-1 Protease Inhibitors
• Synthetic strategies for unsymmetrical inhibitors
HN NHS
HO OH
OO
O O
N NH
HO OH
OR
P1P1 P1'P1'
HN NHS
O O
OOAg2O2-Bromobenzyl bromide
97%isolatedyield
N NHS
O O
OOBr
CH2Cl2MW, 100 °C, 60 min
• Remarkable silver coordination method
Gold et al.In preparation
Cyclic HIV-1 Protease Inhibitors
N NS
O O
OOBr Br
HN NHS
O O
OO
N NS
O O
OOBr
HN NS
O O
OOBrAg2O,
2-Bromobenzyl bromide
CH2Cl2MW, 100 °C, 60 min
N NS
HO OH
OOR R
N NS
HO OH
OOR
K2CO32-Bromobenzyl bromideDMF, 100 °C, ON
K2CO3Benzyl bromide100 °C, 60 min
97%
95%99%
Palladium-Catalyzed Amidation Reactions
MW, 15-60 minDeprotection
R-group
Symmetric Yield
Ki (nM)
Nonsymmetric Yield
Ki (nM)
NH
O
59% > 20 000
77% > 20 000
NH
O
80% 8580
74% > 20 000
NH
O
77%
> 20 000 72%
> 20 000
NH
O
53% 1150
51% > 20 000
NH
O
O 54% 1270
68% 7730
NH
O
57% 19
66% 144
N NS
HO OH
OO
NHHN O O
N NS
HO OH
OO
O O
Ki = 530 nMGold et al. Submitted
The Renin-Angiotensin SystemAngiotensinogen
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Tyr-Ser-protein
RENINAngiotensin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
vasodilatationantiproliferation
apoptosisdifferentiation
carbonate secretion
Asp-Arg-Val-Tyr-Ile-His-Pro-PheAngiotensin II
ACE
AT1 AT2
vasoconstrictionsalt/water reabsorption
aldesteron secretionsympathetic activation
cell growth and proliferation
ACE inhibitorsAT1 receptorantagonists
Can AT2 receptoragonists serve asa new class of drugs?
From Angiotensin II to AT2 Receptor Selective Peptide Mimetics
H2NO
NH
HN
O
NH
HN
O
NH
NHN
O
OHOO
NHN
OO
NH
H2N NH
O
HO
OH
O
NH
HN
O
NH
NHN
O
OHOO
NHN
O
OH
O
NH
HN
O
NH
NHN
O
OHOO
NHN
O
OH
AT1 = 1.0 nMAT2 = 0.2 nM
Angiotensin II
AT1 = inactiveAT2 = 3.1 nM
AT1 = inactiveAT2 = 38 nM
From Angiotensin II to Peptide Mimetics
Minimize N-terminal Optimize C-terminal
Molecular recognition points at the C-terminal
O
NH
HN
O
NH
NHN
O
OHOO
NH
N
O
OH
NH
OO
RNH
N
O
NH
HN
O
O
OH
NH
SOO
Lead optimization to Peptide Mimetics
- 170 compounds made- Suzuki couplings key reactions
Microwave heating applied:
M24• Lowers blood pressure • Induces neurite outgrowth• Enhances carbonate secretion • Exhibits 20-30% bioavailabilityffafter oral administration in rat• No acute toxicity
AT2 = 0.4 nMThe first nonpeptidicselective AT2 agonist
NH
OO
R2
R3
R1
S
SOO
NHO
ON
N
O
NH
HN
O
NH
NHN
O
OHOO
NH
N
O
OH
SOO
Pd(OAc)2
Cs2CO3, DMFCuI,
Zn(CN)2Pd(PPh3)4
S
SNH
O O
N
N
S
SNH
O O
NO
R
R
S
SNH
O O
CN
180 oC, 2 min
180 oC, 40 min
76%27%
With Pd(0)no amination
DMF,dppfimidazole,KOt-Bu190 oC, 15-20 min
Microwave-Heated Suzuki Benzylation, Cyanation and Ullman Couplings
Suzuki
Ullman
Cyanation
Rosenström et al. J. Med. Chem. In printWan et al. J. Med. Chem. 2004, 5995Wan et al. J. Org. Chem. 2002, 6232Wan et al. J. Comb. Chem. 2003, 82Microwave-assisted homogeneous catalysis: Larhed et al. Acc. Chem. Res. 2002, 717
Carbonylation
S
SNH
O O(HO)2B
Pd(PPh3)4,
N
Br
N
KOHS
SNH
O O
N
N
150 oC, 5 min
75%
S
SNH
O O(HO)2B Br
Br
Pd(PPh3)4, Na2CO3
S
SNH
O O
Br
+110 oC, 30 min
78%
Suzuki benzylation
AT2-Selective γ-Turn Mimetics
IBr
OHO
Br
O
I
O
1) SOCl2, reflux
2) Anisole, AlCl3 DCM
para = 73 %Br I
O
Et3SiH, TFATriflic acid
94 %O
O
O
Si
Br
Mo(CO)6,Pd/CTrimethylsilanyl-ethanol
DIEA, DMAP,Dioxane15 min, 130 oCMicrowaves 55 %
O
O
O
Si
NC
Zn(CN)2,Pd2(dba)3P(o-tolyl)3
DMF, 10 min180 oCMicrowaves
72 %
O
O
O
Si
NH
1) H2, Pd/C EtOH
2) Fmoc-Cl, Na2CO3 Dioxane
52 %
Fmoc
OH
OH
ONH
91 %
BF3-SMe2
DCM
Fmoc
NHN
O H
OR2
R1
NH
R3
ONHO
γ−turn
OH
O
NH
ArgAsp His Pro Phe
Ki (nM)AT1 = >10000AT2 = 10
Georgsson et al. Submitted
A New Route to 4-(2-Alkyloxyethyl)phenol by Terminal Arylation of Vinyl Ethers
Strategy:
NO2
Cl
OH
OR
NH2
OR
OHN CH(CH3)2
OH
OR
β1 selective β-blockers
Key Step
• Key Step - Regioselective Heck coupling with p-nitrophenyl f chloride and alkyl vinyl ethers followed by in situffhydrogenation? Datta et al. In preparation
The Development of Regioselective HeckArylations of Vinyl Ethers with Aryl
Chlorides
R
Cl
OBu R
OBuMicrowaves
[(t-Bu)3PH]BF4[Pd], Base
αβ
60-78% yields
• Key Methodology – Rapid reaction optimization withffautomated microwave reactor• More than 200 reaction conditions investigated• (t-Bu)3P both activates aryl chlorides and controls ffthe regioselectivity Datta et al. In preparation
Grignard Reagents from Aryl ChloridesGold et al. Synlett2005, 1596ArCl + Mg 1) Iodine Ar-MgCl 2) Benzaldehyde Alcohol
Entry Aryl Halide Cond. Temp Product Yield
(%)
1 Chloroben-zene
A 150 °C
OH
94
2 1-Chloro-4-fluorobenzene
A 150 °C
F
OH
91
3 1-Chloro-naphthalene
A 150 °C
OH
c
99
4 2-Chloro-naphthalene
A 150 °C
OH
99
5 2-Chlorotoluene
A 150 °C
OH
e
93
6 4-Chlorotoluene
A 150 °C
OH
93
7 2-Chloro-m-
xylene
A 175 °C
OH
89
8 2-Chloroanisole
A 150 °C
O OH
h
89
9 4-Chloroanisole
A 150 °C
O
OH
93
10 2-Bromo-trifluorobenzene
A 100 °C
CF3 OH
97
11 1-Bromo-naphthalene
A 100 °C c 99
12 2-BromotolueneA
100 °C e 99
13 2-Bromoanisole A 100 °C h 99
14 2-ChlorotolueneB
150 °C e 58
15 2-Chloroanisole B
150 °C h 61
16 2-BromotolueneB
100 °C e 81
Microwave Synthesis of a Novel HIV-1 Protease Inhibitor
THF, I2, MW 100 °C, 60 min
Mg (turnings)
MW, 80 °C, 30 minN NS
O O
OO
Br MgBr
1) 2 mol% Pd(dba)2
4 mol% t-Bu3PHBF4
2) 2.2 M HCl/Ether rt, 45 min
N NS
HO OH
OOBr
67 %2-step yield
A
A+
Victor Grignard
Gold et al. Synlett 2005, 1596
Arylation of an α,β-Epoxyketone
O
O
O
OH
O
OH
ArPd(0), Ar-BrBase
Pd(0), Ar-BrBase
OOH
O
Ar
OH
• Hypothesis: Pd(0) catalyzed generation of the 1,3-diketone followed by one-pot Heck arylation
Svennebring et al. J. Org. Chem. 2005, 4720
• iReality: Base mediated generation of 1,2-diketone lkland subsequent Heck arylation
Microwave-Heated Arylations in Aqueous PEG
O
O
O
Ar
OHArBr, NaOAc0.05% Pd(OAc)2
15% aq. PEGMicrowaves150 oC, 20 min 58-80%
• Rapid and ”green” protocol• NaOAc accelerates both the diketone generation and
the Heck arylationSvennebring et al. J. Org. Chem. 2005, 4720
Chelation-Assisted Heck Reactions
• Basic concept: Use the ability of intramolecularfactors to overcome the reluctance of substituted alkenes to participate in Heck couplings
• Chelation-accelerated presentation of the oxidative addition complex
PdX
L
LPd X
Z
IntramolecularHeck reaction
Chelation-acceleratedHeck reaction
Z
Nilsson et al. J. Am. Chem. Soc. 2001, 8217Nilsson et al. J. Am. Chem. Soc. 2003, 3430Svennebring et al. J. Org. Chem. 2004, 3345
Chelation-Controlled Heck Vinylation
PdPR3
R3P
Vinyl
Nx
O
PdPR3
NxVinyl
OONxPdPR3
PR3Vinyl
ONxVinyl
Pd(0) / PR3
Vinyl OTfONx
π-complex
σ-complex
β-elimination
chelation andreorganization
vinylpalladium(II) complex
Diels-Alderproducts
Dienophile
ONMe2 O
NEt2
ON
OTf OTf
OTf
OTf
MeO
N
OTf
Ph
OTf
Vinyl triflates
Chelating vinyl ethers
Stadler et al. Adv. Synth. Catal. 2004, 1773
Microwave-Heated Terminal Heck Vinylations
Product ProductIsolated Yield Isolated Yield
ON
N
O NR2
Ph
ONR2
ONR2
ONR2
ONR2
ONR2
MeO
ON
R = MeR = Et
R = MeR = Et
R = MeR = Et
R = MeR = Et
R = MeR = Et
R = MeR = Et
30 %
28%
60%64%
59%65%
51%51%
47%45%
50%44%
46% 55%
Conditions: 1 mol% Pd(OAc)2, 3 mol% PPh3, DMSO, 120 °C, 30 min, 0.2 mmol scale. E/Z ~75:25
DFT-Calculations
• Calculated Coordination strengths
PdPR3
NxVinyl
O
PdPR3
Vinyl
ONx
dissociated π-complex B´
π-complex B
∆E
∆E [kcal/mol]
LigandPR3
ChelatingN-auxiliaries
PH3 PH3 PH3
22.7 18.9 17.128.6 25.0 23.2
ON O
NO
NN N
N
PH3 PH3 PH3
15.1 10.7 4.1
PPh3 PPh3 PPh3
Stadler et al. Adv. Synth. Catal. 2004, 1773
Competitive Experiments• Experimental support for computational results
Comp. Alone
ONMe2
OTf
ONEt2
ONEt2
ONMe2
++
50 % (60 %)
17% (64 %)
ONMe2
OTf
ON
ON
ONMe2
+ +
11 %
---
(60 %)
(30 %)
ONEt2
OTf
ON
ON
ONEt2
+ +
10 % (64 %)
--- (30 %)
Plasmepsin I and II –Plasmodium falciparum
• Aspartic proteases (common target class in drugdiscovery, e.g. HIV-PR, renin)
• Relatively little research, although the crystal structure of Plasmepsin II has been solved
• Similar to human enzyme Cathepsin D (possible selectivity problem)
Plasmepsin II Cathepsin D
Plasmepsin Inhibitors
• A few lead substances:
1. Ki Plm II, 0.56 nM; Ki Cat D, 21 nM 1 2. Ki Plm II, 4.3 nM; Ki Cat D, 63 nM 2
Important for selectivity Important for activity1 Silva et al. Proc. Natl. Acad. Sci. USA. 1996, 93, 100342 Haque et al. J. Med. Chem. 1999, 42, 1428
3. Generic structure of new inhibitors
HN
OH
NH
ON
NH
O HN
ONH2
O
O
HN
OHN
O
NH
O
O
Cl
O
Basic nitrogen, will promote accumulation in the acidicfood vacuoleSites of variation to
improveactivity/selectivity
NNH2
OHN
OH
NH
R3
O
R1 R2O
R4
Diversity Strategy
HN
OH HN
NH2
O
NH O
R1
O
R2
Diversity byamide formation
Diversity by microwave-assistedPd-chemistry
• Selection of R1 and R2 based on the “maximum-dissimilarity” method
Nöteberg et al, J. Med. Chem. 2003, 734, Nöteberg et al, J. Comb. Chem. 2003, 456, Muthas et al, Submitted
Microwave-Assisted Decorations. R1.
HN
NH2
OHN
OH
NH O
R1
Br
HN
NH2
OHN
OH
NH O
R1
(HO)2B
Pd(PPh3)2Cl2140 °C, 20 min
28 - 46 %
FF
FF
F
OHN
O
NN
N
N
OO
HN O
OCF3
HN
N
O OO O
O O OO
OO
xNöteberg et al, J. Comb. Chem. 2003, 456
Ki (Plm I / nm) = 2Ki (Plm II / nm) = 120Ki (Cat D / nm) = 1400
Microwave-Assisted Lead-Optimization
(HO)2B
N
OHO
O
(HO)2B
(HO)2BCF3
CF3
(HO)2BNH2(HO)2B
HN O
OO
(HO)2B
(HO)2B
OHO
N
N
(HO)2BO
O S
(HO)2B
HN
NH2
OHN
OH
NH O
ON
Br
HN
NH2
OHN
OH
NH O
ON
R2
NO
(HO)2B
(HO)2B (HO)2B
O
(HO)2B
NH2
SH
O
BO
O
(HO)2B
BrZn
R2-B(OH)2
Pd(PPh3)2Cl2140 °C, 20 min
20 - 51 %
*
x xxxNöteberg et al, J. Comb. Chem. 2003, 456
Ki (Plm I / nm) = 13Ki (Plm II / nm) = 30Ki (Cat D / nm) = 1400
*Other reaction conditions: Pd(PPh3)2Cl2, THF, 130 °C, 30 min
NH
HN
N
O
NH
OH O HN
ONH2
OpBrBnO
O
Ki (nM) Plm I = 0.5, Plm II 2.2, Cat D 4.9Johansson et al. J. Med. Chem. 2004, 3353
Plasmepsin I and II Inhibitors
Not selective:
NNH O
HN
NH O
HN
NH2
O
O
Br
OH O O
S1
spacerP1
Improved inhibitors by extension of the P1’ arm ?
Ki (nM), Plm I = 0.5 Plm II 2.2, Cat D 4.9
S1’Attach spacer-P1’?
water
Johansson et al. J. Med. Chem. 2004, 3353
Decoration of Plasmepsin Inhibitors
H
H
NH
NOH
OHO
OO
OHO
OH
R''
R''
NH
NOH
OHO
OO
OHO
OH
Br
Br
O
O
NH
NOH
OHO
OO
OHO
OH
R'
R'
ON
O
F
OOS
N
N
O
O
NH
NOH
OHO
OO
OHO
OH
R
R
Si
KF
SONOGASHIRAPd(PPh3)4, CuI, HNEt2, DMFa) 120oC, 10 min, 91% yieldb) 90oC, 30 min, 46% yield
SUZUKIPd(PPh3)4, R'-B(OH)2, Na2CO3 DME:H2O:EtOH (12:4:3)90oC, 30 min, 33-63% yield
HECKHerrmann's palladacycle DIEA, DMF:H2O (17:3)a) 170oC, 25 min, 46% yieldb) 150oC, 30 min, 84% yield
R= R'=R''=
Ersmark et al. J. Med. Chem. 2004, 110
Ki (Plm I / nm) = 1.4Ki (Plm II / nm) = 29Ki (Cat D / nm) =2000
Selectivity!
Vinyl bromidesIndanol amide
Microwave-Assisted PCRM 1 2 3 4 5 M
Lane Microwave power pulses
Template DNA No. of cycles
Relative band intensity
1 75W/120W Plasmid 25 0.11 2 90W/120W Plasmid 25 0.42 3 100W/130W Plasmid 25 0.67 4 100W/130W Chromosomal 35 0.20 5 Conventional
PCR Plasmid 25 1.0
• Manual protocol iii“proof-of-principle”• Faster heating cycles
with microwaves • 25 cycles of
amplification in 1 h –lll50 × 15 s irradiationlllpulses• Large-scale ikautomated PCR?
Fermér et al, Eur. J. Pharm. Sci. 2003, 129
Polymerase chain reaction (PCR) is a technique which is used to amplify the number of copies of a specific region of DNA
Experimental PCR Set Up
• Automated milliliter-scale amplifications?Orrling et al, Chem. Commun. 2004, 790
Coolingairstream
Fluoroptictemperature measurement
IR-pyrometer
Controlledmicrowaves
Single-modemicrowaveapplicator
Coolingairstream
Fluoroptictemperature measurement
IR-pyrometer
Controlledmicrowaves
Single-modemicrowaveapplicator
Microwave-Assisted ThermocyclingMicrow ave-heated PCR, 2.5 mL
0
10
20
30
40
50
60
70
80
90
100
0 1000 2000 3000 4000 5000 6000Time (s)
Tem
p (o
C)
4 05 0
6 07 0
8 09 0
10 0
2 8 5 0 3 0 0 0 3 15 0 3 3 0 0
IR -s ens o r
F O -p ro b e
Microwave-Heated PCR, 2.5 mLTe
mp
(°C
) IR-pyrometer
FO-probe
• 2.5 mL scale in Emrys Optimizer EXP• Amplification efficiency over 95%• One microwave pulse per cycle Orrling et al, Chem. Commun. 2004, 790
Microwave-Assisted Thermocycling
Microwave-Heated PCR, 15 mL
40
50
60
70
80
90
100
4000 4200 4400 4600 4800 5000Time (s)
Tem
pera
ture
(°C
)
4 Cycles out of 33 cycles
• 15 mL microwave-assisted thermocycling• 33 cycles with more than 95% efficiency• No detected deactivation of the Taq polymerase• ~0.1 mg DNA – 150 times increased amplification scale
Orrling et al, Chem. Commun. 2004, 790
Acknowledgement
– Dr. Daniel Nöteberg– Dr. Peter Nilsson– Dr. Karl Vallin– Dr. Karolina Ersmark– Dr. Johan Wannberg– Dr. Anna Ax– Jennie Georgsson– Andreas Svennebring– Per-Anders Enquist– Gopal Datta– Kristina Orrling– Anna Arefalk– Maria Antonia Herrero– Olle Lagerlund
– Prof. Anders Hallberg– Prof. Christina Moberg– Prof. Bertil Samuelsson– Prof. Åke Pilotti– Dr. Mathias Alterman– Dr. Kristofer Olofsson– Dr. Yiqian Wan– Dr. Ulf Bremberg – Dr. Nils-Fredrik Kaiser– Dr. Xiongyu Wu– Dr. Alexander Stadler– Dr. Murugaiah Andappan
Acknowledgement
• Swedish Foundation for Strategic Research• The Swedish Research Council• Knut och Alice Wallenbergs Foundation• Biotage AB• Medivir AB
Generation of the Starting Organopalladium(II) Intermediate
Pd XM X
Pd XH
Pd XX
[Pd(II)]
[Pd(II)]
[Pd(0)]
Transmetallation
Electrophilic palladation
Oxidative addition
Oxidativecoupling
Classiccoupling
• In the classic Pd(0)-catalyzed Heck coupling Pd(0) is regenerated after every turnover
• In order for the Pd(II)-mediated Heck couplings to be catalytic; a reoxidant must be added to generate Pd(II) from Pd(0)
Larhed et al. Handbook of Organopalladium Chemistry for Organic Synthesis, E. Negishi, Ed.; John Wiley & Sons, Volume I, 2002, 1133
Oxidative Heck Couplings
Heck
Pd(0) Pd(II)
Pd(0)
R1
B(R2)2
OxidativeHeck
Ar1 XAr1
R1
Ar2
R1
Suzuki
Ar1 Ar2
Ar2
• Boronic acids readily undergoes transmetallation
• Microwave-assisted Oxidative Heck chemistry?
• Which reoxidant to use?
• Can we use ligands to improve the per-formance of the catalyst?
Relation between the classic Heck, the Oxidative Heck and the Suzuki coupling
Andappan et al. Mol. Div. 2003, 97
Oxidative Heck Couplings
O2 H2O2
M RLLPd (II)
LLPd
HPd(II)
L
X
L
RPdLL
L'
R'
R
RPdLL
Pd
R'
L
X
L
HH
RH R'
R'
1. Trans-metallation
2. π-Complexformation
4. Internal rotationand β-hydride elimination 3. 1,2-Insertion
Base
HBaseX
5. Generation of Pd(0)
6. Generation of Pd(II) byreoxidation with dioxygen
+
(0)
+
L' = Ligand, OAc-
or Solvent
M = B, Sn, Hg ...
Medium-Scale Oxidative Heck Couplings with Microwaves
Andappan et al. J. Org. Chem. 2004, 5212
B(OH)2
N
ON
O
[Pd(II)]
5% Pd(OAc)2, 6% dmphen
αβ
~3 bar O2, EtCN + [Pd(0)]
Oxidation
dmphenNN
• Dmphen ligand enables direct reoxidation of Pd(0) by O2• Pressurized O2 gas used• High reactivity and regioselectivity with electron-rich arylboronic acids• Emrys Optimizer, 1 mmol, 80 %, α/β = 93/7 at 100 oC, 1 h• Emrys Advancer, 10 mmol, 66 %, α/β = 97/3 at 80 oC, 1 h
DFT Calculations - Regioselectivity
PdN N CH3H3C
+
NO
R
PdN N CH3H3C
+
R
PdN N CH3H3C
+
R
NO
NO
PdN N CH3H3C
+
R
NO
NO
NO
R
R
β-Product
α-Product
α
β
‡
‡
p-Substituent
∆Eπ ∆E*α ∆E*β ∆∆E*
-OCH3 -27.5 9.8 13.5 -3.7 -CH3 -27.9 12.4 14.8 -2.4 -H -29.0 13.9 15.3 -1.4
-CF3 -30.8 15.3 16.4 -1.1 -CHO -30.8 15.4 15.8 -0.5
-COCH3 -31.2 15.9 16.4 -0.5
Calculated π-complexation energies and insertion barriers for selected p-substituted phenyl rings [kcal/mol]
Andappan et al. J. Org. Chem. 2004, 5212
• Reduced dmphen model; the ...olefin and aryl fully represented• Electron donating groups favor …the α-product• High insertion barrier with electronn…withdrawing substituents
Geometries were optimized at the B3LYP/lanl2dz level
Suggested Catalytic Mechanism forPd(0) to Pd(II) Oxidation
L2Pd(II)
O
O
2 H+
H2O2
O2
H2O2
2 H2O L2Pd(0)
L2Pd
PalladiumCatalyzed
Stahl, S. S. et al. J. Am. Chem. Soc. 2002, 766.
Conclusions
A highly selective, Ag2O-mediated monoalkylation was developed
Rapid microwave-promoted, palladium-catalyzed N-amide arylationprotocol was developed
Highly potent symmetrical inhibitor (19 nM)
Bulky substituents and three-atom spacer
Nonsymmetrical inhibitor / three subsites (144 nM)
