PURINES - kap 24 Reaction with electrophiles at N - Protonation

Reaction with electrophiles at N - Alkylation Selectivity depends on substituents and conditions

N7/N9: - Sterical factors (Large 6-subst) Termodyn. control (reversible react.) Electrophiles - cancer

Reaction with electrophiles at N - Acylation / Sulfonation Acylation products generally unstable Sulfonation - Stable prod., selective N9 Reaction with electrophiles at N - oxidation

Reaction with electrophiles at C

E-fil Ar subst, generally not working Reaction with nucleophiles

Nu.Ar.Subst: Reactivity F>Cl>Br>I Other leaving groups

Deprotonation at N

Deprotonation at C / C-metallation

Org. Lett, 2003, 4289

JOC 1997, 6833

Oxy purines -Oxo forms Alkylation, acylation etc

Replacement of O with other hetero atoms Amino purines Amino form

Diazotation etc. Alkylation, acylation etc

Synthesis of Purines Carbonyl condensations Strategy A - Traube synth. etc

Carbonyl condensations Strategy B Cycloadditions

Bioactive Purines DNA / RNA bases Anticancer / antiviral drugs

Adenosin og adenosinreseptorligander AKB PhD-lecture, august 05 Cytokinins - Plant growth hormones Sel. A 2A antag. Parkinston /Alsheimer?

Natural products Agelasine D Agelasines from marine sponges (Agelas spp) Asmarines for marine sponges Heteromines Isolated from Heterostemma brownii Treatment of tumors in Taiwanese folk medicine

Reversine

Heterocycles cont. more than 2 heteroatoms in one ring kap 26 5-membered rings Triazoles and tetrazoles 6-membered rings Triazines and tetrazines

5-membered rings Triazoles and tetrazoles (pentazoles highly unstable) More acidic - less basic comp to diazoles Bioisostere - CO 2 H

React. at N 1,2,3-Triazole

React. at C

Benzo-1,2,3-Triazole

1,2,4-Triazole React. at N React. at C

Tetrazole Bioisostere - CO 2 H Small diff. stab. taut. React. at N

React. at C

Oxadiazoles and thiadiazoles (thiatriazole) Aromaticity (NMR shifts, bond lenghts) - No acidic NH -Generally low basicity (cf triazoles) -Some examles N-quart. -Few ex. Introd of E-fils on C -Prone to Nu attack

Ring opening (esp. O-cont. rings) C-lithiation easy, but often low stab of lithiated prod

6-membered rings Triazines and tetrazines Highly activated for Nu attack No simple react with electrophiles

Diels Alder react. Leading to azines with fewer N (see synth of pyridines, diazines)