- kap 24 6 7 5 1 N N 8 2 N N 4 H 3 9 H N N N N HN N N N N N N N N N N N H H 9H 7H purine 1H purine 3H purine

two 6π elctron aromatic ring

Reaction with electrophiles at N - Protonation

N N N H N N N N N H+ N N N N N N N N N N N N N N H H H H H N pKa 2.5 major protonated form Reaction with electrophiles at N - Alkylation Me Me N N MeI N N N N

N N N N N H N Me Me Selectivity depends on substituents and conditions

NH2 NH N N RX N N major prod. N + N N N H - H H R Base NH 2 NH2 NH2 NH2 R N N N N N RX N N N

N N N N N N N N major R O isomer Cl Cl + N N H N N RX ≈ n.r. N N N N H O Base

complete Cl Cl Cl Cl R selectivity N N N N N RX N N N N N N N N N N N R N7/N9: - Sterical factors (Large 6-subst) Termodyn. control (reversible react.) X Time N9 / N7 X Base X X COMe Cl 1h 4.3 : 1 N N COMe N N N N Cl 24h 19 : 1 H N N N N N 2 H H2N N H2N N COMe Cl 24h 200 : 1 OMe 1h 1 : 1 X R X X R OMe 14 days Still mixt. N N N N N RX H2O N N N Y N N Y N O Y N O RO OR RO OR OR OR Electrophiles - cancer

X R X N N X N N Y N N N N Y N N N9 / N7 O α / β Y N N H RO OR NH OR R N N NH-R' RX N N N NH2 R NH R N R=H R N RX N N N N N MeOHN R R R=OMe N N N N N N R N N R Reaction with electrophiles at N - Acylation / Sulfonation Cl Acylation products generally unstable Cl KOH N N Sulfonation - Stable prod., selective N9 N ClSO2Ph N N H2O / acetone N N N H 64% O S O Ph Reaction with electrophiles at N - oxidation

X X NH2 O N N N N ROOH N ROOH N N N N N X=NH Y N Y N 2 R R R Y=H X="OH", Y=NH2 X=CN, Y=H O

O O O O O mCPBA N N N NH2 NH2 NHOMe N N N O N MeO N N N MeI N Me2NH, HI N N N N N N N N N Heat N R R N N N R R R R

NH2 NH2 MeO MeO N N N N H N N N N Me N Me N 2 R 2 H R Reaction with electrophiles at C

Electron rich N pyrole like N N Pyridine like N N N H H

δ+ More benzene like N + δ+ δ N Reaction with electrophiles at C E-fil Ar subst, generally not working Mechanism? NH NH Br 2 Br 2 Br 2 Br N H N N NaOAc N N N 2 N Br Br N Br N N N N N N -HBr R R R R R

Cl Cl

N N NXS N N X Radical mech.? N N N N R R Reaction with nucleophiles Reactivity towards Nu Cl N N N N N N Cl N N N N Cl N N Me Me Me Most probably react. on Cl Cl N N N N N N Cl N N N N Cl N N N N Cl N N H H H N N N N Nu

H N + N H N N Cl Cl activated for Nu attack N N N N Me Me Nu R R-Met Cl Cl cat. Pd N N N N Nu N N Cl Cl Nu N N N N N N R R R

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

N Cl N Nu N N Nu N N N Me3N N N N N N N N N N N R R R N N R from DABCO

N N N N Nu NH2 Me2N NMe2 N N TMS-Cl, pyridine Nu N N N N N

N N N N N N R R R Deprotonation at N

N N N N N N N N N N + N - H N N N N N H N N N N

pKa 8.9

N N

N N H H pKa 14.2 pKa 12.3 Deprotonation at C / C-metallation

D D D N N N D2O N N N N N H H + N N N - H N N N H N N H H H c.f. H-2 in imidazoles D+

D N N N N D D + N - D N N N H H OMe Me OMe Me N N CD OD N N H 3 D R R N N N N N N R' Me R' Me Heteromines

X X X + N "E " N N LDA or BuLi N N N H Li E Y N N Y N N Y N N R R R

X, Y: NH2, "OH" ; Excess base I Li E + N N n-BuLi N N "E " N N - 130 oC - 130 oC N N N N N N THP THP THP - 78 oC

+ N N "E " N N Li Li - 130 oC N N N N THP O

I ZnI Ar N N Riecke Zn N N ArX, cat. Pd N N N N N N N N R R R

Org. Lett, 2003, 4289 JOC 1997, 6833

Cl

N N N Bu3Sn N R 11

Cl 1) LDA Cl Cl N N 2) BrCN N N N N Br + Br N N N N Br N N R R R Nolsøe et al., Synth Commun 1998, 4303 -Oxo forms Oxy purines O O O H H N N N N HN HN N N HN HN O O N O N N N N N N O N N O N H H H H H H H Alkylation, acylation etc O O R N N N-alkylation N N R'-X N N O N N R N R HN Base N N R Me3SiCl, RSO2Cl, O OSiMe OSO R (RCO)2O 3 2 OCOR N N N N N N N N O-Silylation O-Sulfonation N N N N N N N N O-Acylation R R R R

Ph Ph Ph Ph Ph Base N N N N N N N HN N N N N PhCH2X O N N O N N N N O N N O N N O N O N H 26% 37% Ph 9% X% Ph Ph Ph Ph not detected Isolated yields Replacement of O with other hetero atoms

X I N N HI N N O POX3 Base N N X=Cl N N N HN R R X=Cl, Br N N (Me3Si)2NH R OSiMe3 NHR P S S 4 10 N N N NH2R N N HN N N N N R N N R R

Amino purines

NH2 O N N N N HN N Amino form NH2 N N H N N N N N H 2 H H Alkylation, acylation etc

NH

N N NH2 RX N N N H N R RCOX R N N H NHCOR NHCH2R N NH2 N N N LAH N N NaB(CN)H3 N RCHO N N + N N N N N H N H N H H N H Diazotation etc. X X N N N HBF4 N X NaNO 2 N F N N N N2 N N R R N H2N N R RONO CCl X X 4 X CHBr N 3 N N N N or N N CH2I2 N N N N N X N N R R R RO Synthesis of Purines

NH2 Carbonyl condensations N "C+" N NH Strategy A - Traube synth. etc a 2 N N NH CH(OEt)3 / HCONH2 2 O N + N N b H N N H H2N N N NH2 N N H "C+" Ac O H N N 2 2 H N N Me N N H

Cl Cl Cl

NH2 NH2 N N NH2R N N

N Cl N NH N N R R

Cl Cl Cl Cl Cl N Ar + NH N N N2Ar N N Zn/H N 2 N N

Y N Cl Y N NH Y N NH Y N NH Y N N R R R R

HNO3 CH(OEt) 3 N H SO NO NH + HN HN 2 4 HN 2 H2/cat. HN 2 H O N N O N NH2 O N NH2 O N NH2 H cytosin NH2 Carbonyl condensations N "C+" Strategy B a N NH2 N N b O O N N O O H H2N N H2N CH(OEt) (RCO) O 3 N "C+" HN N 2 N + HN H H2N N H N H R N N 2 N N N R R R Ph-N=C=S (EtO)2CO O O N HN N HN

O N N S N N N NH2 H R H R N N HCONH2 N H N 2 N N N Cycloadditions R R

CO2Et HO C CO Et 2 N CO2Et 2 N Diels Alder EtO C H N N 2 N N N H2N N N N EtO2C N CO2Et - CO EtO C N N R 2 EtO C N 2 2 H2N - EtO2CCN R R Bioactive Purines

DNA / RNA bases

NH2 O N N HN N

N N H N N N H 2 H Adenine Guanine

Anticancer / antiviral drugs

SH S O N N N HN N HN N N N N N H2N N H H NH2 O O HO HN 6-MP N N N HN N Acyclovir N F N N N N N H2N N HO HO O O HO OH

HO ddI Fludarabine Abacavir and adenosine reseptor ligands

NH2 O N N CH3 H C At least 4 sub-types. A1, A2A, A2B, A3 3 N N N N No drugs (yet)... N HO O N O CH3 Parkinston and selective A2A antag. ?? Coffein HO OH Antag. A1 & A2A Cytokinins - Plant growth hormones Ph

HN

N N

N N H

OMe Me Heteromines N N H R •Isolated from Heterostemma brownii N N N •Treatment of tumors in Taiwanese folk medicine R' Me Heteromines Purine-Containing Marine Natural Products

From marine algae, sponges, gorgonians (sea fans), ascidians (tunicates) etc., etc.

O CONH 2 Br Br

SO3H H HN N NH HN HN HN N N H H N N O N N OH OH N N OH H N N H Saxitoxin Microxine Aplidiamine (red tide)

O NH2 H N N HN N O N N O N N HO O

OH OH O H H Spongosine J Nat Prod 2005, 68, 1288 Purine-Containing Marine Natural Products

Agelasines Agelasimines Asmarines

OH

H H H

NH HO 2 N N N N N N N N Cl N N N N N N Agelasine A Agelasimine A Asmarine A Reversine

O HN N N N

N N N H H

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