Synthesis of clasto-lactacystin β-lactone and analogs thereof
AssigneeMillennium Pharmaceuticals, Inc.
InventorsFrançois Soucy, Louis Plamondon, Mark Behnke, William Roush
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Abstract
The present invention is directed to an improved synthesis of clasto-lactacystin-β-lactone, and analogs thereof, that proceeds in fewer steps and in much greater overall yield than syntheses described in the prior art. The synthetic pathway relies upon a novel stereospecific synthesis of an oxazoline intermediate and a unique stereoselective addition of a formyl amide to the oxazoline. Also described are novel clasto-lactacystin-β-lactones, and analogs thereof and their use as proteosome inhibitors.
Claims6
A process for forming a substituted oxazoline compound of Formula II:
- said method comprising:
- (a) deprotonating a substituted aryl or heteroaryl oxazoline of Formula I:
- by treating said substituted aryl or heteroaryl oxazoline with a strong base to form an enolate;
- and
- (b) transmetallating said enolate with a metal selected from the group consisting of titanium, aluminum tin, zinc, magnesium and boron, and thereafter reacting with a formyl amide of Formula XIV:
- wherein for each of Formulae I, II and XIV:
- R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, where the ring portion of any of said aryl, aralkyl, or alkaryl can be optionally substituted;
- R2 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;
- R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, any of which can be optionally substituted;
- R4 is optionally substituted aryl or optionally substituted heteroaryl;
- and
- R5 and R6 are independently one of alkyl or alkaryl;
- or R5 and R6 when taken together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring, which can be optionally substituted, and which optionally include an additional oxygen or nitrogen atom.
A compound of Formula II:
- or a salt thereof, wherein
- R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, where the ring portion of any of said aryl, aralkyl, or alkaryl can be optionally substituted;
- R2 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;
- R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, any of which can be optionally substituted;
- R4 is optionally substituted aryl or optionally substituted heteroaryl;
- and
- R5 and R6 are independently one of alkyl or alkaryl;
- or R5 and R6 when taken together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic ring, which can be optionally substituted, and which optionally include an additional oxygen or nitrogen atom.
A method of treating cancer, comprising administering to a subject an effective antitumor or antimetastatic amount of a compound of Formula VII:
- or a salt thereof, wherein:
- R1 is C1-12 alkyl, C3-8 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl C6-14 aryl, C6-10 ar(C1-6)alkyl or C1-6alk(C6-10)aryl:
- R2 is C2-6 alkyl;
- and
- R7 is alkyl, aryl, aralkyl, alkaryl, wherein any of said alkyl, aryl, aralkyl or alkaryl can be optionally substituted.
Dependencies are inferred from the claim text.