Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described, starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10 (fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C. Finally fragment D was attached to the B + C fragment via aldol addition.

Three different routes are described for the synthesis of deoxylaulimalide (3), which is the immediate precursor of the marine sponge metabolite laulimalide (1). These routes mainly differ with respect to their ring closing step. Thus, route 1 uses a Still-Gennari olefination, route 2 a Yamaguchi lactonization, and route 3 an intramolecular allylsilane-aldehyde addition for establishing the macrocyclic structure. The unprotected deoxy derivative 3 was subjected to Sharpless' asymmetric epoxidation (SAE). With (R,R)-tartrate the 16,17-epoxide laulimalide (1) is formed selectively, whereas (S,S)-tartrate generates the 21,22-epoxide 142. This demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity. Laulimalide and some derivatives thereof have been tested with respect to antitumor activity and compared to standard compounds paclitaxel and epothilone B.

metalated and then acylated to afford triethyl 5-oxoortho-3-alkynoates (2), which can be converted into enol ethers of 3,5-dioxoalkanoic esters ( 3 ) by base-catalyzed addition of alcohols. Dimethylamine adds almost quantitatively to (2) giving triethyl 3-(dimethylamino)-5-oxoortho-3-alkenoates ( 4 ) which yield copper(r1) complexes of the P-polycarbonyl compounds on treatment with a solution of copper(rr) acetate in aqueous acetic acid. The reaction sequence ( I ) + (2) + (3) or ( 4 ) permits extension of a carboxylic acid chain by two acetyl units. The structures of compounds (I)-(4) are in agreement with their NMR spectra. [a] Bath temperature on distillation from a bulb-tube. A Simple Synthesis of a-Methylene y-Lactones Triethyl 5-oxoortho-3-hexynoate (2a) from triethyl ortho-3-butynoate ( I )A solution of propargylmagnesium bromide [21(43 g) in ether (160 ml) is dropped slowly under Nz into a solution of tetraethyl orthocarbonate (48 g) in anhydrous ether (80 ml) at -30 OC (internal temperature). When the temperature is slowly raised, an exothermic reaction sets in at 25 ' C ; external cooling is applied to prevent the temperature rising above 3OoC; after 30 min the mixture is hydrolyzed by saturated N H 4 C l solution, whereafter working up gives ( I ) (17.3 g).The orthoester ( I ) (6.9 g) is metalated in tetrahydrofuran (30 rnl) and ether (60 ml) under nitrogen and at -60 "C by an equivalent amount of a 2 N solution of butyIlithium in light petroleum. The mixture is allowed to warm to 0°C and then dropped into a solution of acetic anhydride (5 g) in ether (50 ml) kept at -60°C. Allowing the resulting mixture to warm to room temperature, shaking it with saturated NH4C1 solution, and then distillation afford (2a) (4.0 8). Triethyl 3-ethoxy-5-oxoortho-3-hexenoate (3a)The product (2a) (2.3 g) in ethanol (2 ml) is dropped into a solution of Na (0.23 g) in ethanol (10 ml) cooled to 0 "C and after a few min is warmed to room temperature. After 30 min, addition of HzO (50 ml),extraction with ether, and distillation afford (3a) (1.25 9). pounds which react with aldehydes and ketones to give methylene lactones ( 2 ) in very good yields. A single step technique in which the bromo ester is treated with zinc in the presence of the carbonyl compound has many advantages.

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