Synthesis of clasto-lactacystin beta-lactone and analogs thereof

A process for forming a substituted oxazoline compound of Formula II:

• 52
• said method comprising:
• (a) deprotonating a substituted aryl or heteroaryl oxazoline of Formula I:
• 53
• 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:
• 54
• 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 process for forming a substituted aryl oxazoline compound of Formula Ia:

• 57
• wherein
• R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, where the ring portion of said aryl, aralkyl, or alkaryl 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 heteroaryl;
• said method comprising:
• (a) asymmetrically dihydroxylating an alkene intermediate of Formula XV:
• 58
• to form an optically active diol of Formula XVIa:
• 59
• (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, Me3SiI, Me3SiBr and halogen-containing Lewis acids to form a haloester derivative of Formula XVIIa:
• 60
• wherein X is Cl, Br, or I;
• (c) reacting said haloester derivative with an alkali metal azide to form an azide of Formula XVIIIa:
• 61
• (d) hydrogenating said azide to form a compound of Formula XIXa:
• 62
• (e) subjecting the compound of Formula XIXa to ring closing conditions to form said substituted phenyloxazoline of Formula Ia;
• wherein for each of Formulae XVa, XVIa, XVIIa, XVIIIa and XIXa, R1, R3 and R4 are as defined above for Formula Ia.

A process for forming a substituted aryl oxazoline compound of Formula Ib:

• 63
• wherein
• R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, where the ring portion of said aryl, aralkyl, or alkaryl 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 heteroaryl;
• said method comprising:
• (a) asymmetrically dihydroxylating an alkene intermediate of Formula XV:
• 64
• to form an optically active diol of Formula XVIb:
• 65
• (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:
• 66
• wherein X is Cl, Br, or I;
• (c) reacting said haloester derivative with an alkali metal azide to form an azide of Formula XVIIIb:
• 67
• (d) hydrogenating said azide to form a compound of Formula XIXb:
• 68
• (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, XVIIIb and XIXb, R1, R3 and R4 are as defined above for Formula Ib.

A process for forming a compound of Formula XIXa:

• 69
• said method comprising:
• hydrogenating an azide compound having Formula XVIIIa:
• 70
• wherein for each of Formulae XIXa and XVIIIa:
• 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;
• R3 is alkyl, cycloalkyl, aryl, alkaryl, any of which can be optionally substituted;
• and
• R4 is aryl or heteroaryl, either of which may be optionally substituted.

A process for forming a compound of Formula XIXb:

• 72
• said method comprising:
• hydrogenating an azide compound having Formula XVIIIb:
• 73
• wherein for each of Formulae XIXb and XVIIIb:
• 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;
• R3 is alkyl, cycloalkyl, aryl, alkaryl, any of which can be optionally substituted;
• and
• R4 is aryl or heteroaryl, either of which may be optionally substituted.

A compound of Formula VI or VII:

• 75
• 76
• or a salt thereof, wherein:
• R1 is C1-2 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.

An enantiomerically-enriched formyl amide of Formula XIV:

• 77
• or a salt thereof, wherein
• R2 is C1-8 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;
• and
• R5 and R6 are independently C1-6 alkyl, C6-10 ar(C1-6)alkyl or C1-6alk(C6-10)aryl, or together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle which can be optionally substituted, and which optionally can include an additional oxygen or nitrogen atom.

A compound of Formula II:

• 78
• 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 compound of Formula III:

• 79
• 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;
• 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 can optionally include an additional oxygen or nitrogen atom.

A compound of Formula XVIIa or XVIIb:

• 80
• 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;
• R2is Cl, Br or I;
• R3 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, any of which can be optionally substituted;
• and
• R4 is optionally substituted aryl or optionally substituted heteroaryl.

A compound of Formula XVIIIa or XVIIIb

• 81
• or a salt thereof, wherein
• R1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, wherein 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;
• and
• R4 is optionally substituted aryl or optionally substituted heteroaryl.

A process for forming an enantiomerically-enriched formyl amide of Formula XIV:

• 82
• or a salt thereof, wherein
• 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;
• 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;
• said method comprising:
• (a) acylating an anion of a compound of Formula VIII.
• 83
• where R8 is isopropyl or benzyl, with R2CH2COCl to form an acyloxazolidinone of Formula IX:
• 84
• where R2 and R8 are as defined above;
• (b) stereoselectively reacting the acyloxazolidinone of Formula IX with benzyloxymethyl chloride to form a protected alcohol of Formula X:
• 85
• where R2 and R8 are as defined above;
• (c) hydrolyzing the protected alcohol of Formula X to form a carboxylic acid of Formula XI:
• 86
• where R2 is as defined above;
• (d) coupling said acid of Formula XI with an amine R5R6NH2 to provide an amide of Formula XII:
• 87
• where R2, R5 and R6 are as defined above;
• (e) catalytically hydrogenating, the amide of Formula XII to form an alcohol of Formula XIII:
• 88
• where R2, R5 and R6 are as defined above;
• and
• (f) oxidizing the resultant alcohol of Formula XIII to give a formyl amide of Formula XIV.