C. Compounds with Four Heteroatoms
The A 1 adenosine receptors fulfill a largely inhibitory role. Research has
thus recently focused on agonist with structures based on adenosine
itself as agents that will overcome responses due to inappropriate exci-
tation, such as tachycardia and some arrhythmias. Replacement of one of
the hydrogen atoms on the exocyclic amine in adenosine by a tetrahydro-
furyl group provides an effective A 1 adenosine agonist. Preparation of this
fragment as a single enantiomer starts with a modern version of the Curtius
reaction. Thus, reaction of tetrahydrofuroic acid ( 47 ) with triphenyl-
phosphoryl azide leads to isocyanate ( 48 ). Treatment of this intermediate
with benzyl alcohol then affords the corresponding carbamate ( 49 ).
Catalytic hydrogenation removes the benzyloxy group leading to the free
primary amine 50. The product is then resolved by way of its camphorsul-
fonyl salt to afford 51. Reaction of this intermediate with desamino chloro-
adenosine ( 52 ) affordstecadenoson( 53 ).^8
O CO 2 H
47Ph 2 PON 3
O NCO
48C 6 H 5 CH 2 OH
O NH OCH 2 C 6 H 5O49H 2
O NH 2
50Resolve
O NH 2
51N
N NNHOHO OHCl52N
N NNHOHO OHO NH53Another approach to preparing A 1 adenosine receptors agonists involves
converting the hydroxymethyl group on the sugar moiety to an amide in
addition to adding a substituent to the amine of adenosine. The starting
material ( 56 ) is arguably obtainable by oxidation of inosine acetonide
( 54 ), followed by acetylation of the hydrolysis product. Reaction of the
acid ( 55 ) with thionyl chloride followed by ethanol affords the correspond-
ing ethyl ester ( 56 ). The ring oxygen on this intermediate is next replaced
by chlorine by means of phosphorus oxychloride to yield 57. Reaction of
57 with cyclopentylamine displaces the halogen to form the cyclopentyla-
mino derivative ( 58 ). Treatment with triethylamine under somewhat more
strenuous conditions effects ester–amide interchange to form the
amide; the acetyl protecting groups are cleaved under those reaction
- COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS 195