I. THREE CARBON ANNELATION: 1. ALKYLATION CHEMISTRY OF 3-BROMO-2-METHOXY-1-BUTENE. 2. REGIOCONTROLLED REACTIVITY OF TRIMETHYLSILYL AND ETHOXYETHYL PROTECTED CYANOHYDRINS. II. THE TOTAL SYNTHESIS OF (+, -) LITHOSPERMIC ACID

Part I. (1) Alkylation Chemistry of 3-Bromo-2-Methoxy-1-Butene. Cracking of 2,2-dimethoxy-3-bromobutane at 190(DEGREES)C in the presence of a catalytic amount of diisopropylethyl ammonium tosylate provides 3-bromo-2-methoxy-1-butene in 76% yield along with 2-5% of the starting ketal, 3-8% of 3-bromo-2-butanone and less than 1% methanol. None of the isomeric vinyl bromide is observed. The title compound has been found to undergo efficient alkylation of imines, esters, malonates and nitriles via competing modes of S(,N)2 and S(,N)2' alkylation. Specifically, hydrolysis of the imine and enol ether functionalities, under appropriate conditions produces 1,4-diketones suitable for the preparation of 2-methyl cyclopentenones. Variation of the hydrolysis conditions provides access to the derived furans and pyrroles. (2) Regiocontrolled Reactivity of Trimethylsilyl and Ethoxyethyl Protected Cyanohydrins. The trimethylsilyl and ethoxyethyl protected cyanohydrins of (alpha),(beta)-unsaturated aldehydes are utilized as three-carbon annelation reagents. The metalated trimethylsilyl reagents display exclusive (alpha) reactivity with ketones and aldehydes at -78(DEGREES)C. The observed addition products are (alpha)'-trimethylsilyloxy enones formed via an intramolecular silyl transfer with concomitant loss of lithium cyanide. The metalated ethoxyethyl reagents display exclusive (alpha) reactivity at -78(DEGREES)C and exclusive (gamma) reactivity at 0(DEGREES)C. The ethoxyethyl reagents thus allow for complete regiocontrol in their addition to aldehydes and ketones which permits selective addition of either a (DELTA)('2,3) acyl anion or homoenolate equivalent. Thus removal of the ethoxyethyl and cyanohydrin protecting groups for the (alpha) and (gamma) addition products affords (alpha)'-hydroxy enones and spirolactones respectively. Metalation of the ethoxyethyl (alpha) product at -78(DEGREES)C with subsequent warming to 0(DEGREES)C produces exclusively the (gamma) product, confirming the reversible nature of the addition to the carbonyl and the kinetic vs. thermodynamic nature of the reaction. The derived (alpha)'-trimethylsilylyloxy enones, (alpha)'-hydroxy enones, (alpha)'-acetoxy enones and spirolactones are cyclopentenone precursors. Treatment of the (alpha)'-hydroxy enones or its derivatives (i.e., trimethylsilyl or acetyl) with pTsOH in toluene at reflux affords cyclopentenones. The reaction proceeds via the postulated intermediacy of a pentadienyl cation which undergoes in situ electrocyclic ring closure.;Part II. A convergent total synthesis of ((+OR-)) lithospermic acid from the readily available isovanillin and 3,4-dihydroxybenzaldehyde is described. The synthesis involves preparation of: (a) the half malonic ester of 3-(3',4'-dihydroxyphenyl) lactic acid, (b) the requisite trans dihydrobenzofuran aldehyde and (c) coupling of these via a Doebner modified Knoevenagel condensation to afford a mixture of ((+OR-)) lithospermic acid and its diastereomer. The choice of phenolic protecting groups proved to be crucial for the preparation of these intermediates, with the t-butyldimethylsilyl and the methoxymethyl protecting groups being successfully employed. Purification of the natural and synthetic lithospermic acid was achieved using reversed phase chromatography. In addition a total synthesis of ((+OR-)) rosmarinic acid is described using the same strategy as that employed for the synthesis of ((+OR-)) lithospermic acid.