Asymmetric Synthesis Via Chiral Vinyl Sulfoxides: New Applications Of The Sulfoxide-directed Lactonization.

Abstract

New routes to optically active (alpha)- and (beta)-amino acid precursors from optically pure (E)-2-phthalimidovinyl p-tolyl sulfoxide are descibed. This chiral vinyl sulfoxide is converted to a 3-phthalimido-4-p-tolylthio-(gamma)-butyrolactone enantiospecifically, and the lactone is solvolytically opened to a dimethyl acetal ester. Conversion of this latter compound to phthalimido aspartic acid, (beta)-methyl ester, proceeds with high enantiomeric excess (80%). Lactone ring opening is also effected by treatment with an alcohol, thiocresol, and boron trifluoride etherate to afford dithioacetal esters. The Pummerer reaction of the bissulfoxide of methyl 4,4-bis(p-tolylthio)-3-phthalimidobutanoate affords the corresponding thioester, which is converted to the same (alpha)-amino acid precursor in an overall 75% ee. The enantiospecificity of the lactonization/dithioacetalization sequence is confirmed spectroscopically by opening the phthalimidolactone with an optically pure alcohol. Also, the use of 2-(trimethylsilyl)ethanol to open the lactone directly affords a (beta)-amino acid presursor. Amino acid synthesis via bicyclic (alpha)-chlorolactones was unsuccessful. The stereochemical outcome of the reaction of monochloroketene and cyclic vinyl sulfoxides is described. Stereochemical assignments were made by NMR analysis after conversion of the (gamma)-arylthio-(gamma)-lactones to their corresponding sulfones. A series of optically pure N-protected, (beta)-azavinyl sulfoxides are prepared via treatment of (E)-2-bromovinyl p-tolyl sulfoxide with nitrogen nucleophiles. Each sulfoxide was subjected to the lactonization conditions, and it was found that the phthalimidovinyl sulfoxide gave the best results. An enantiospecific, intramolecular displacement of the arylthio moiety of (beta)-alkyl-(gamma)-arylthio-(gamma)-butyrolactones is described. The use of activated aromatic rings as nucleophiles affords optically pure, tricyclic lactones in moderate yield; the use of a double bond affords a mixture of bicyclic lactones in low yield. This transformation is effected by treatment of the (gamma)-arylthio-(gamma)-lactones with tributylstannyl triflate. The (beta)-alkyl appendages of the lactones are derived from appropriately substituted malonate esters. Addition of substituted malonate anions to (E)-2-bromovinyl p-tolyl sulfoxide affords the requisite vinyl sulfoxides which are then converted to their corresponding lactones.