Post on 02-Nov-2020
RODOLFO LAVILLA GRIFOLS
Barcelona, May 2015
Biology-Oriented
Organic Chemistry
UNIVERSITAT DE BARCELONA
Preparation of Bioactive Compounds
Facilitated
Synthetic
Chemistry
Biological
Response
Feed back
New Chemical Entities
Small Molecules
Biologics
BioProbes
New Reactivity
Multicomponent Reactions
Heterocyclic Chemistry
Biopolymer Modification
Multicomponent Reactions
• Atom Economy-BFE
• Exploratory Power
• Feasibility
• Selectivity
• Versatility
CRITERIA
Stepwise Approach
SolventActivationWork up
SolventActivationWork up
SolventActivationWork up
+ + +
Multicomponent Approach
1 Solvent1 Activation1 Work up
MCRs: Processes in which 3 or more compounds react to yield an adduct displaying essential parts of the starting materials through a unified reaction mechanism
Dr. Nico Isambert
Chem. Eur. J.
2008, 14, 8444
� Discovery of New MCRs
(Rational Speculation)
� Med Chem with the
MCR Processes/Adducts
(Fast, Complex, drug-like)
Reactivity of Heterocycles in MCRs
NH2R
CHO
R''
R'
R''
R'
NH
R
Acid
Povarov MCR
Povarov, L. S.; Mikhailov, B. M.
Izv. Akad. Nauk SSR, Ser. Khim. 1963, 953.
Dr. Oscar Jiménez
Angew. Chem. Int. Ed. 2005,44, 6521
Interrupted
Povarov MCR
R4
NH2
N
R2
R1
N
NH
R3
R1
R2
R4
+ R3 +
H
H
DHP
Lewis AcidCHO
Org. Lett. 2003, 5, 717
Dr. Inés CarrancoDr. José Luis Díaz
DHP Participation
Passerini and Ugi MCRs
UgiReaction
R1-CHO R2-COOH R4-NH2R3-N=C+ ++
Ugi
4CR
R2
R1
N
O
O
R4
HN R3
R1
O
C
O
N
N
R2
R4H
R3
α-addition
R1
O
C
O
N
N
R2
R4H
R3
R1-CHO R2-COOH R3-N=C+ +Passerini
3CRR2
R1
O
O
O
HN
R3
R1
O
C
O
O
N
R2
H
R3α-addition
R1
O
C
O
O
N
R2
H
R3
PasseriniReaction
MCRs with Isocyanides (II)
N-Acyl Pyridinium Salts
N
ONH
O
Cl
O
Cl
N N
O
N=C
H2O
DHP
Reissert-Ugi Reaction
Mechanism
R2-N=C
NCH2Cl2-H2O
R1-OCOCl
N
O NHR2
O
O
R1
N
O
O
R1
Cl
R2-N=C
N
O
O
R1
N
R2
R1-OCOCl
H2O
J. Org. Chem. 2004, 69, 3550
Dr. José Luis DíazDr. Miriam Miguel
Polyarylated motifs as
scaffolds in MedChem
A. D. Hamilton et al. Angew. Chem. Int. Ed.
2005, 44, 2704
N
S
N
S
O O
COOCH3
Cystothiazole Aantifungal
N
S
N
O
NH
HN
O
O
N
AO H
N
N
O
O
Leucamide Aanticancer
NH
OOSN
O
NH
S
N
O
S
O
n-C7H15
Largazoleanticancer
O
NO
N
N
O
ON
S
NO
N
N
O
O N
Telomestatineanticancer
Bioactive NPs containing
oxa/thiazole moieties
Merging
privileged
structures
New Heterocyclic Scaffolds
Biological studies:
� Proapoptotical activity independent of p53
� Compounds 3 and 4 (low µM) are more cytotoxic than 1 and 2
X-ray structure of 3
Proapoptotic Fluorescent
Antitumoral Arylated Thiazoles
I) Mitochondrial Inner Membrane
Gottlieb Cell,
2006, 126, 27
II) Mitochondrial Outer Membrane
Cristae junction
wideningSpierings et al, Science,
2005, 310, 66
Destabilize OPA1
by inhibiting PHBs
Mechanism of Actrion
Post-synthetic Modification of Peptides
Arylation of Tryptophans by C-H Activation.
Indole (tryptophan)
in peptides
� High natural abundance (Trp)
� Privileged structure in MedChem
� Chemical modification desirable
� 1% occurrence in Protein/peptide sequences
Celogentin C Complestatin
NH
N NCOOH
NHO
NH
NH
NH
H2NO
N
OHN
O
NH
O
HN
O
HN
O
HNO
N
O
CH3
HN
O
HN
O
NH
OHN
O
NH
O
O
HN
O
OH
Cl Cl
OH
Cl
OH
ClCl
OH
Cl
HO2C
OH
aan
aan
- Customized Peptides
- Selective Labelling
- Optimized bioactivity
- From I-Phenylalanine (commercially available)
- Stapled Peptides
Post-synthetic Modification of Peptides
Arylation of Indoles
C-H activation processes
� Catalyzed by transition metals
� Selective transformation of C-H bonds
� Doesn’t require prefunctionalized
organometallic precursors
HNH N
H
Ar
I Ar
Pd(OAc)2,
2-NO2Bz, AgBF4
DMF, 150ºC,
24-48 h
4.0 equiv+
� Not extended to functionalized derivatives!!
� Drastic Conditions
(unsuitable for biomolecules)
Prof. Fernando AlbericioDr. Javi RuizChem. Eur. J.2010, 16, 1124