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Abstract

A total synthesis of the monoterpene iridodial, in 12 steps and 13% overall yield from 1,3-cyclohexadiene, is described. The known (-)-tricyclo[3.3.0.~~8]octan-3-one, which is readily available in multigram batches and in high enantiomeric purity, served as the key intermediate. The subsequent transformations involved standard procedures, and separations were only necessary in the two final steps.A preceding contribution' has dealt with the transformation of the intermediate (-)-2, obtained by regio-and stereoselective methylation2 of tricycl0[3. 3.0.O~~~]octan-3one [(-)-lI3s4into loganin aglucon 6-acetate. It required, in particular, an oxidative enlargement and other structural modifications of ring A, which were initiated by the isomerization of the cyclopropyl ketone moiety into the 7,8unsaturated ketone. The starting material, (+l, and its enantiomer are available in multigram batches, each with >98% enantiomeric excess and in ca. 17% overall from 1,3-cyclohexadiene via a photochemical oxadi-7methane rearrangement as the key step.a4We now report the first selective total synthesis of iridodialThe compound is found as a constituent of anta' and other insects: and it has been shown also to (1) Demuth, M.; Chandrasekhar, S.; Schaffner, K. For a review on the preparation of the tricyclooctanone enantiomers and their use in total syntheses of cyclopentanoids and related products, see: Demuth, M.; Schaffner, K. Angew. Chem. 1982,94,809; Angew. Chem., Znt. Ed. Engl. 1982,21,820. For more recent work, see: Demuth, M.; Canovas, A.; Weigt, E.; KrGger, C.; Tsay, Y.-H.Di-and tripeptide analogues containing (2-amin0ethyl)phosphonic acid [H-A~P(OH)~], which has been discovered in a wide variety of living organisms, were prepared. As starting materials for incorporating the amino phosphonic acid into a peptide chain, the N-phthalylated diethyl ester [Pht-Ae~(OEt)~l and the N-carbobenzyloxylated monoalkyl ester [Cbz-Aep(OR)(OH), R = Me, Et, and Bzl] were used. A phosphonamide bond between the amino phosphonic acid unit and amino acid unit was formed by reaction of Pht-Aep(0Et)Cl with amino acid ethyl ester or coupling reaction between Cbz-Aep(OR)(OH) and amino acid ethyl ester using diphenylphosphoryl azide-triethylamine as a condensing agent. Removal of the protecting groups was studied in connection with the acid-labile phosphonamide bond in the abnormal peptides.

SummaryA total synthesis of the antitumor sesquiterpene coriolin (9; racemic) in 11 steps from 3,3,6-trimethylbicyclo[2.2.2]oct-7-ene-2,.5-dione (2a/2b) is described (yield 2a/ 2b-t8: 28 "/o). The sequence is unprecedentedly short and avoids difficult separation problems. The key step in the scheme is a novel facet of oxadi-n-methane photochemistry, i.e., the steering by subtle steric effects of the P,y-unsaturated E-diketone to undergo a regioselective photorearrangement involving one P,y -enone partial chromophore. Furthermore, the overall phototransformation, which can be carried out at unusually high concentrations ( > 20% solutions), involves also a Norrish type 1 process equilibrating the two epimeric starting enediones 2a and 2b in favour of the desired stereoisomer.The antitumor sesquiterpene coriolin, (-)-(9)'), has become a testing case for the design of syntheses of medium-sized natural products of complex structures, and notably for the development of new methodologies aiming at cyclopentanoid annulation procedures [4]. We have previously demonstrated that the use of the optically active forms of tricyc1o[3.3.0.0*~*]octan-3-one provides for a versatile synthetic approach to cyclopentanoid natural products [3] [5] [6], including one towards the total synthesis of coriolin, (-)-(9) [6]. Scheme 1 summarizes an alternative to this concept which is characterized by an unprecedentedly short route to the intermediate 8 in common with previous total syntheses of (f)-coriolin (9) [2]. The key step in this scheme is a novel facet of oxadi-n-methane photochemistry, i e . , the steering by subtle steric effects of a P,y -unsaturated E -diketone to undergo a regioselective photorearrangement involving one P,y-enone partial chromophore.') Synthetic work directed towards ( * )-9, see [I]; synthesis of 8 and its conversion into (%)-9, see [4. For the isolation of (-)-9 and its biological importance, see Footnote 82 in [3].

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