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