Contrary to the established literature, ' isocubebinic ether *, ' cubebinic ether ', and ' cubebinol ' are acid-catalysed cyclisation products, (IV), ( V I I ; R = OAc), and (VII: R = H), respectively. Their formation from (-)-cubebin (I) is discussed.The first synthesis of cubebin is described. (-+) -a-(3,4-Methylenedioxybenzyl)-~-(3,4-methylenedioxybenzylidene)succinic acid (XIII) is prepared by a double Stobbe approach and resolved with quinine. Reduction to the diol ( X X I ) and oxidation with manganese dioxide gives (+)-, (-)-, and (*)-hibalactone (XXII) [the first synthesis of the natural (-)-form] ; selective oxidation with this reagent gives dehydrocubebin (XXIII). (+)-, (-)-, and(+) -1sohinokinin (XXV) are obtained by hydrogenation of the corresponding hibalactones ; epimerisation of (+)and (-) -isohinokinin gives (-) and (+)-hinokinin (XXVI) respectively. By selective reduction with sodium aluminium hydride the lactone (-) -hinokinin is converted into the hemiacetal (-) -cubebin (I).THE structure and absolute stereochemistry of the lignan cubebin (I), a constituent of cubeb fruits (Piper cuubeba) was elucidated by the work of Haworth,l Mameli,2 and I~higuro.~ The accepted chemistry 495 of cubebin contains certain unusual features. Treatment of cubebin with halogen acids in acetic acid is said to give ' cubebinic ether ' (11), which is reported to be reduced to an alcohol, cubebinol (111), with sodium and alcohol. Further, a compound of unknown structure, ' isocubebinic ether ', is obtained from cubebin by reaction with sulphuric-acetic acid; this gives ' cubebinol ' with methanolic hydrochloric acid. In this paper the three named compounds are shown to be cyclisation products and their chemistry is rationalised. Later, the complete synthesis of natural (-)-cubebin is described. A r (11) -fCH20H + Ar (111) Ar = Lo O PN.m.r. and other spectral data (Experimental section) for natural (-)-cubebin are in agreement with structure (I), and show that it exists, in chloroform solution, as the hemiacetal. Although Jz.3 (4 Hz) can be measured, this value is not decisive in determining the orientation of the hydroxy-function. Treatment of (-)-cubebin with acetic and sulphuric acids, as described by Mameli,2c

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SzcmnzaryThe structures of the acid-catalysed reaction products from cubebin have been elucidated. CUBEEIN (I)f*2 is reported to be dehydrated to 'cubebinic ether' (11)2 when treated with halogen acids in acetic acid; this ether is said to be reduced to 'cubebinol' (111) by sodium and alcoh01.2~~ On the other hand, cubebin gives a compound of unknown structure 'isocubebinic ether' when treated with sulphuric acid-acetic acid.3 Surprisingly, this gives 'cubebinol' with methanolic hydrochloric acid.3 ReimFestigation now shows that all three named products are in fact cyclisation products, and the accepted chemistry4 of this lignan must be superseded.N.m.r. and other spectral data for cubebin are compatible with structure (I) and show that it exists, in chloroform, almost entirely as the hemiacetal. 'Isocubebinic ether', C,,H,,O,, m.p. 156-157"' [a]? + 26.9" (CHCl,) was chromophorically similar to cubebin in the U.V. region,