ring fusion. The amide nitrogen in the product, which still contains a small
amount of cis isomer, is next alkylated with methyl chloride in the presence
of base to yield 46. Reaction of that intermediate with methanol opens the
lactam ring to yield the corresponding methyl ester 47 ; the small amount
of cis isomer can be separated at this stage since it resists methanolysis.
The amino–ester is then resolved via its ditoluyl tartrate salt. Heating the
resolved aminoester ( 48 ) with sodium carbonate then regenerates the
lactam ring to afford 49.^6
The scheme used to produce a somewhat more complex 5-a-reductase
inhibitor relies on a chiral auxiliary to yield the final product as a single
enantiomer. The first step in a sequence similar to that above, starts with the
reaction of bromotetralone ( 50 ) with (R)-a-phenethyl amine ( 51 ) to afford
the enamine ( 52 ). Reaction with methyl iodide adds the methyl group at
what will be a steroid-like AB ring junction. This product is then treated
with acryloyl chloride. The initial step in this case probably involves acy-
lation of nitrogen on the enamine; conjugate addition completes formation
of the lactam ring. Treatment of 54 with triethylsilane then reduces the ring
unsaturation and cleaves the benzylic nitrogen bond to yield 55 as the opti-
cally pure trans isomer. Displacement of bromine with the mercapto-
benzthiasole ( 56 ) completes the synthesis ofizonsteride( 57 ).^7
BrO
50C 6 H 5NH 2
H+51BrC 6 H 5HNH 52CH 3 I
H 3 C
H 3 CH 3 CH 3 CH 3 CH 3 C H^3 CH 3 CBrC 6 H 5HN53COClBrC 6 H 5N54OEt 3 SiHBrO NH
55NS
NS
S HSO NH
5756HHHHThe aggregation of blood platelets, the prelude to formation of blood
clots, is a very necessary process for preserving the integrity of the circu-
latory system. Inappropriate platelet aggregation on the other hand can
result in the formation of clots that block vital organs leading to strokes
and heart attacks. Various approaches have been followed in the search
- COMPOUNDS WITH THREE FUSED RINGS 223