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
Tetrahydrolipstatin (1) and its analogue 2 are representatives of a new class of pancreatic-lipase inhibitors. Two stereoselective synthetic approaches are described.
de ces deux sch+mas ne nous a permis d'interpr&er correctement les valeurs des F o. Ce fait nous a conduit penser que le site 8(b) n'est pas un puits de potentiel pour le thallium. L'occupation de positions 32(e) par le thallium nous avait 6t6 sugg6r6e par des calculs de potentiel 61ectro-statique qui incluaient le terme d'origine dipolaire, ici tr6s important compte tenu de la grande polarisabilit6 du thallium (Fourquet, 1977). La d~termination structurale precise et confirme doric cette hypoth6se; elle permet en outre de corr6ler entre elles d'autres observations sur T1Nb205F: ~t la temperature ambiante l'existence d'une bande de relaxation dipolaire di~lectri-que (Fourquet, 1977) ainsi que le r6tr6cissement tr~s sensible de la largeur de raie du signal RMN du thallium en fonction de la temperature (Sleight, Gulley & Berzins, 1977). Ces deux derniers r~sultats trouvent leur interpretation darts un mouvement des ions thallium darts leurs cages; ceux-ci passeraient d'un type de position 32(e) h un autre avec un temps de relaxation de l'ordre de l0 -5 s. Cette mobilit~ est en relation &roite avec le ph6nom~ne de conduction ionique par le thallium observ~ sur TINbEO5F par Fourquet (1977)et Sleight, Gulley & Berzins (1977
AbstractIn the MA1C14 family, the salts of voluminous cations (NO, NH4, Rb) and CsA1CI 4 have the BaSO 4 barytestype structure (space group Pnma). It is possible to describe the KA1CI 4 (space group P21) and the NaA1CI 4 (space group P212~2~) structures as deformations of this basic structure; the LiAICI 4 structure (space group P2~/c) is built up from LiC16 octahedra 0567-7408/79/071573-08501.00 layers linked together by A1C14 tetrahedra. The mean A1-C1 lengths, corrected for thermal-motion effects, range from 2.141 /~, (NOA1CI4) to 2.150 A (NHaA1CI4).
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