CATALYTIC ENANTIOSELECTIVE SYNTHESIS OF A SPIROFUSED AZETIDINONE

摘要

A process for catalytic enantioselective synthesis of a compound of the formula (1.0) wherein: R1, R2 and R3 are independently selected from: (a) H; (b) halo; (c) -OR5 wherein R5 is selected from: H, C1 to C6 alkyl, aryl, aralkyl, alkaryl, heteroaryl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C7 cycloalkyl, C3 to C7 cycloalkenyl, and -C(O)R6 wherein R6 is selected from C1 to C6 alkyl, aryl, and -OR7 wherein R7 is C1 to C6 alkyl or aryl; and (d) -C(O)R8 wherein R8 is selected from C1 to C6 alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, -OR9 (wherein R9 is selected from C1 to C6 alkyl or aryl), and -N(R10)2 (wherein each R10 is independently selected from H, C1 to C6 alkyl and aryl); R4 is selected from H and -OH; said process comprising: (a) reacting, under an inert atmosphere, in a suitable organic solvent, a compound of the formula with an enolization base and a silylation reagent to produce a compound of the formula (3.0) 1706 כ" ג בתמוז התש" ס - July 26, 2000 wherein n is 1 or 2, R11 is a C1 to C4 alkyl group, R12 is a C1 to C4 alkyl group; (b) reacting, under an inert atmosphere, in a suitable organic solvent, the compound of Formula 3.0 with a chiral catalyst and a compound of the formula: wherein R2 is defined above, with the proviso that R2 is not OH, and then reacting the resulting product with a deprotecting reagent to remove the -Si(R12)3 protecting group, thereby forming a compound of the formula: (5.0)or or an enantiomeric mixture of 5.0 and 5.1; said chiral catalyst being a cyclic condensation product of borane and a compound of the formula: (6.0) wherein R13 is selected from aryl and fused aryl, and R14 represents an amino acid R17-CH(NH2)-CO2H bound to the sulfur of formula 6.0 through the nitrogen atom; wherein R17 is a lower alkyl group which can be substituted with a lower alkoxy, lower alkylthio, diloweralkylamino, or diloweralkylaminocarbonyl group, an aryl group, a heteroaryl group, or an aralkyl 1707 כ" ג בתמוז התש" ס - July 26, 2000 group; or an aryl, heteroaryl or aralkyl group that can be substituted with one to three groups selected from halogen, lower alkyl, lower alkoxy, -CF3, -NO2, and diloweralkylamino; (c) reacting a compound of formula 5.0 or 5.1 or an enantiomeric mixture of 5.0 or 5.1, in a suitable organic solvent, with a compound of the formula wherein R1 is as defined above, with the proviso that R1 is not OH, with a Lewis acid and with a strong acid, to produce a compound of the formula (8.1) (8.0) or an enatiomeric mixture of 8.0 or 8.1; (d) reacting a compound of Formula 8.0 or 8.1 or an enantiomeric mixture of 8.0 and 8.1, in a suitable solvent, with a reagent that converts hydroxy groups into leaving groups with a strong base, and with a phase transfer catalyst, to produce a compound of the formula (9.0) (e) reacting a compound of formula 9.0, in a suitable solvent, with a compound of the formula (1.0) 1708 כ" ג בתמוז התש" ס - July 26, 2000 wherein R3 is as defined above, with the proviso that R3 is not OH, to produce a compound of the formula wherein R4 is OH; with the proviso that R1, R2 and R3 are not -OH; (f) when R1, R2, and/or R3 in formula 1.0 in (e) above is -OR5, wherein R5 is an arylmethyl or allyl group, optionally hydrogenating said compound of formula 1.0 in an appropriate alkanol solvent with a hydrogenation catalyst and a Lewis acid selected from MgX2, TiX4, and ZnX2, wherein X is Cl or Br, thereby converting said -OR5 to -OH; and (g) when is R5 -OH, optionally converting said -OH R4 substituent to H by heating a compound of formula 1.0 (wherein R4 is -OH) with an acid to produce a dehydrated compound of the formula (1.2) and then hdyrogenating the compound of formula 1.2 in a C1 to C6 alkanol solvent using a hydrogenation catalyst to produce a compound of formula 1.0 wherein R4 is H.