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.
Claims23
A process for forming a substituted aryl oxazoline compound of Formula Ia:
- wherein
- R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, where the ring portion of said aryl, aralkyl, or alkazyl can be optionally substituted;
- R3 is alkyl, cycloalkyl, aryl, alkaryl, any of which can be optionally substituted;
- and
- R4 is optionally substituted aryl or optionally substituted heteroazyl;
- said method comprising:
- (a) asymmetrically dihydroxylating an alkene intermediate of Formula XV:
- to form an optically active diol of Formula XVIa:
- (b) reacting said optically active diol of Formula XVIa with an orthoester under acid catalysis to give a mixed orthoester, and thereafter reacting the resulting mixed orthoester intermediate with a reagent selected from the group consisting of acyl halides, HCl, HBr, HI, Me3SiCl, Me3Sil, Me3SiBr and halogen-containing Lewis acids to form a haloester derivative of Formula XVIIa:
- wherein X is Cl Br, or I;
- (c) reacting said haloester derivative with an alkali metal azide to form an azide of Formula XVIIIa:
A process for forming a substituted aryl oxazoline compound of Formula Ib:
- to form an optically active diol of Formula XVIb:
- (b) reacting said optically active diol of Formula XVIb with an orthoester under acid catalysis to give a mixed orthoester, and thereafter reacting the resulting mixed orthoester intermediate with a reagent selected from the group consisting of acyl halides, HCl, HBr, HI, Me3SiCl, Me3SiI, Me3SiBr and halogen-containing Lewis acids to form a haloester derivative of Formula XVIIb:
- wherein X is Cl, Br, or I;
- (c) reacting said haloester derivative with an alkali metal azide to form an azide of Formula XVIIIb:
- (d) hydrogenating said azide to form a compound of Formula XIXb:
- (e) subjecting the compound of Formula XIXb to ring closing conditions to form said substituted phenyloxazoline of Formula Ib;
- wherein for each of Formulae XVb, XVIb, XVIIb, XVIlIb and XIXb, R1, R3 and R4 are as defined above for Formula Ib.
Dependencies are inferred from the claim text.