Synthesis of clasto-lactacystin beta-lactone and analogs thereof

A process for forming a .gamma.-lactam carboxylic acid of Formula V:

• ##STR42## or a salt thereof, wherein R.sup.1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, where the ring portion of any of said aryl, aralkyl, or alkaryl can be optionally substituted;
• R.sup.2 is alkyl, cycloalkyl, aryl, alkaryl, aralkyl, alkoxy, hydroxy, alkoxyalkyl, or amido, where the ring portion of any of said aryl, aralkyl, or alkaryl can be optionally substituted;
• and
• said process comprising:
• (a) deprotonating a substituted aryl or heteroaryl oxazoline of Formula I:
• ##STR43## where R.sup.1 is as defined above;
• R.sup.3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, any of which can be optionally substituted;
• and
• R.sup.4 is aryl or heteroaryl, either of which may be optionally substituted;
• by treating said substituted aryl or heteroaryl oxazoline with a strong base to form an enolate;
• (b) transmetallating said enolate with a metal selected from the group consisting of titanium, aluminum, tin, zinc, magnesium and boron, and thereafter treating with a formyl amide of Formula XIV:
• ##STR44## where R.sup.2 is as defined above, and R.sup.5 and R.sup.6 are independently one of alkyl or alkaryl;
• or R.sup.5 and R.sup.6 when taken together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring, which may be optionally substituted, and which optionally may include an additional oxygen or nitrogen atom, to form an adduct of Formula II:
• ##STR45## where R.sup.1 through R.sup.6 are as defined above;
• c) catalytically hydrogenating said adduct of Formula II to form a .gamma.-lactam of Formula IV:
• ##STR46## where R.sup.1, R.sup.2 and R.sup.3 are as defined above;
• and d) saponifying said .gamma.-lactam of Formula IV to form a carboxylic acid of Formula V.