Lipstatin (l), a natural product, and tetrahydrolipstatin (2) are pancreatic lipase inhibitors. Non-stereoselective and partially stereoselective syntheses of 2 are used to establish the absolute configuration of tetrahydrolipstatin and lipstatin Lipstatin (1) is a pancreatic lipase inhibitor of microbial origin [l] [2] which, by catalytic hydrogenation, has yielded tetrahydrolipstatin (2) [ 11 [3]. Because of our interest in the biological activity of these compounds, we became interested in the synthesis of this class of p-lactones, and the synthetic intermediates served to establish the absolute configuration of 1 and 2.") For systematic atom numbering, see Exper. Part. (2) Starting from Ethyl @)-3-Hydroxy-6-heptenoate (Scheme I ) . -The known ethyl (R)-3-hydroxy-6-heptenoate was protected as its tetrahydropyranyl ether 3 [4] which, by ozonolysis, gave aldehyde 4. Wittig reaction yielded ester 5 which was reduced with diisobutylaluminium hydride (DIBAH) to aldehyde 6. Aldol condensation of the aldehyde with the anion of lithium octanoate gave hydroxy acid 7. Cyclisation yielded P-lactone 8 as a mixture of diastereoisomers which, by deprotection followed by careful chromatography of the mixture 9, yielded trans-hydroxy-P-lactone lo') as well as trans-hydroxy-P-lactone 11, the cis-isomers being discarded. Esterification of 10 with (S)-N-formylleucine using Mitsunobu's conditions (inversion of configuration at the OH-substituted center) yielded compound 12 which, by catalytic hydrogenation, gave tetrahydrolipstatin (2). ~~~ ') Absolute configuration as established later in this paper Synthesis of Tetrahydrolipstatin

471250 ml. of saturated ethanolic ammonia was heated in an autoclave a t 135' for 12 hr. The resulting solution was evaporated to dryness and the residue recrystallized from butanol. A final recrystallization from aqueous ethanol afforded an analytically pure product.The structural assignment (see Discussion part) in this group of compounds was further substantiated by paper chromatographic measurements (one spot in each case). Rr values for 2,4-diamino-6-( p-bromoanilino)-5-pyrimidinecarbonitrile: 0.71 (isopropyl alcohol-water, 7 : 3), and 0.80 (butanol saturated with acetic acid); for 2,4-diamino-6-(p-iodoanilino)-5-pyrimidinecarbonitrile: 0.73 and 0.81, respectively.2,4-Diamino-6-( substituted-anilino) -5-pyrimidinecarboxamide (Table I). General Procedure.-With good stirring, 2,4-diamino-6-(substituted-anilino)-5-pyrimidinecarbonitrile (0.05 mole) was added slowly to 50 ml. of concentrated sulfuric acid a t 30-35". The solution was stirred a t this temperature for 12 hr. and then added, with stirring, to 500 g. of flaked ice. The precipitated product was separated by filtration and washed well with icewater. The crude product was dissolved in hot, dilute sulfuric acid, treated with charcoal, and filtered. The filtrate was adjusted to pH 8 with aqueous ammonia and the product filtered while hot, washed with water, and dried at 100'. Repeated reprecipitation afforded product of analytical purity. 4,6-Dichloro-2-methylaminopyrimidine.-In a flask equipped with two modified Friedrichs condensers designed to retain low boiling liquids was added 23 g. (0.23 mole) of triethylamine and 7 g. (0.23 mole) of methylamine diluted with 200 ml. of ethyl acetate. To this solution was added 30 g. (0.154 mole) of 4,6dichloro-2-( methyl~ulfony1)pyrimidine~~ dissolved in 200 ml. of ethyl acetate.The temperature was kept below 35" during the entire reaction. After 2 hr. of stirring the reaction mixture was evaporated and the pale yellow residue recrystallized from ethanol to give 13 g. (77%) of white crystals, m.p. 162-163". The product was found to be identical with that reported by Winkelmann'4* and B 0 0 n . l~~ 4-Amino-6-chloro-2-methylaminopyrimidine.-A mixture of 4,6-dichloro-2-methylaminopyrimidine ( 10.8 g.) and ethanolic ammonia wm heated a t 80' for 8 hr. in a sealed vessel. Evaporation of the reaction mixture and purification of the product from methanol afforded 7 g. (657,) of white crystals, m.p. 193-194". Anal. Calcd. for CsH7ClN4.H20: N, 31.8. Found: N, 31.9. General Preparations of 4-(Substituted-anilino)-5-nitrosopyrimidines (V).A.-A mixture of the appropriate 4chloropyrimidine, an equivalent amount (plus a 10% excess) of the substituted aniline, and several milliliters of concentrated hydrochloric acid was heated in an oil bath. A clear, dark colored melt was observed around 150" followed by an exothermic reaction that caused the temperature to rise to ca. 200". The reaction mixture was held at this temperature for several minutes. It was then cooled, dissolved in boiling ethanol, treated with charcoal, and filt...

1,3‐Dipolar Additions to 7‐Methylthieno[2,3‐c]pyridine 1,1‐dioxide 1,3‐Dipolar additions of diazomethane, diazoethane, ethyl diazoacetate, phenyldiazomethane and phenyl azide to 7‐methylthieno[2,3‐c]pyridine 1,1‐dioxide have been examined. The structures of the primary products e.g. 2, 8, 18, 25 have been established and their behaviour towards elevated temperatures and/or basic conditions was investigated. Under these conditions the primary products lost SO2 or N2 to yield e.g. 4, 11, 19, 21, 23, 27, 28.

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