No abstract

The structure 7-chloro-4 : 6-dimethoxycoumaran-3-one-2-s~iro-l'-(2'methoxy-6'-methylcycZohex-2'-en-4'-one) (IX ; R = Me) accounts for the known physical and chemical properties of griseofulvin and for the degradation products described in Parts 1-111 (preceding papers). FROM the oxidative degradations described in Part I1 (J., 1952, 3958), it was concluded that griseofulvin possesses a benzenoid ring (A) and a hydroaromatic six-membered ring (c) thereby confirming the views of Oxford, Raistrick, and Simonart (Bioclzem. 3979and C1,Hl,O,C1, which were shown in Parts I1 and I11 to be (VIII; R = H and OH respectively). These acids, derived from griseofulvic acid by alkaline peroxide and by permanganate respectively, are substituted coumaran-3-ones in which the carbonyl and oxygm ether bridges from partial structure (VI) are linked to the same carbon atom, adjacent to a C-methyl group. Union of partial structures (VI) and (VII) in a like manner leads to the two spiran structures (IX) and (X) which are isomeric methyl ethers of the Me0 CO CO-CH CH,

Pyrrolidine-2.4-dione (tetramic acid) has been obtained by heating its 3-ethoxycarbonyl derivative with water or nitromethane. Prolonged heating with water yields 4-hydroxy-3,4'-bi-A3-pyrrolinyl-2,2'-dione, the anhydroderivative of the dione. Iand 5-Methylpyrrolidine-2,4-diones and their anhydro-derivatives have been obtained, similarly. Previously reported syntheses of these pyrrolidine-2,4-diones are shown to be in error; the products obtained appear to have been the corresponding anhydro-derivatives, or their hydrates. Other derivatives of the diones are described. Condensation of ethyl-4-hydroxy-2-oxo-A3-pyrroline-3-carboxylate with aromatic aldehydes yields mainly the (€) -5-arylmethylene derivatives. PYRROLIDINE-2,4-DIONE (tetramic acid) (XVII) and its 1-and &methyl derivatives [(XVIII) and (XIX)]have been synthesised (Scheme l), apparently for the first time, although their synthesis has been claimed previously. Pyrrolidine-2,4-dione has hitherto been obtained1 only as its enol methyl ether, 4-methoxy-A3-pyrrolin-2-one (I) The first reported synthesis a s 3 of the corresponding dione (XVII) was shown e5 later to give the isomeric compound (11) (' iminotetronic acid I); the correction has not always been More recently Isowa and Ohtag have reported that hydrolysis of methyl 4-hydroxy-2-oxo-A3-pyrroline-1 D. J. Cram, 0. Theander, H.

The structures proposed for griseofulvin, C17H1706Cl, by Oxford, Raistrick, and Simonart (Biochem. J., 1939, 33, 240) and by Grove and McGowan (Nature, 1947, 160, 574) are inconsistent with the ultra-violet and infra-red absorption spectra. Grove and McGowan's suggestion (Chew. and Ind., 1949, 647), based on spectroscopic data, that griseofulvin is the methyl ether of a 1 : 3-diketone has been proved conclusively by catalytic reduction of griseofulvic acid, Cl,H ,O,Cl, to two neutral non-lactonic alcohols, C,,Hl,O,C1 and C,,Hl,O,Cl, and by other evidence. The formation of decarboxygriseofulvic acid by the action of alkali on griseofulvic acid is shown by ultra-violet and infra-red spectroscopic evidence to involve a rearrangement of the molecule. GRISEOFULVIN, C,,H,,O,Cl, m. p. 220°, [a]:& +354", a colourless neutral compound containing three methoxyl groups, was isolated from the mycelium of Penicilliuutz griseofuluum Dierckx by Oxford, Raistrick, and Simonart (Biochem. J., 1939, 33, 240). Subsequently, it was isolated from P. jnnczeuskii Zal. [= P. nigricans (Bainier) Thom] and its unique biological activity on moulds noted by Brian, Curtis, and Hemming (Trans. Brit. 2tlycoZ. SOC., 1946, 29, 173; see also Brian, A m . Bat., 1949, 13, 59) and McGowan (Trans. Brit. Mycol. SOC., 1946, 29, 188) who originally called it ' I curling factor " before the identity with griseofulvin was established (Grove and McGowan, Nature, 1947, 160, 574; Brian, Curtis, and Hemming, Trans. Brit. Mycol . SOC., 1949, 32, 30).Although the chemical and biological properties of ' I curling factor " and griseofulvin were identical, the analytical data and molecular-weight determinations quoted by McGowan (Zoc. cit.) in support of his original formula C,,H,,O, agreed more closely with C,,H,,O,Cl than with C,,H,,O,Cl. However, a careful reinvestigation has established the empirical formula as C1,H,,O,C1, in agreement with the earlier work of Oxford ei al. and this is supported by molecular-weight determinations by both the Rast and crystallographic methods (the latter by Dr. A. F. Wells). Nevertheless, the structure (I) tentatively proposed by Oxford et al. (loc. cit.) is not entirely satisfactory even on the basis of the facts which they reported, and we have accumulated considerable evidence which cannot be reconciled with it. We have repeated practically all the experimental workRecent work on the correlation of absorption frequency and structure for the C=O and -OH stretching vibrations has been summarised by Grove and Willis (J., 1951, 877). Normal carboxylic esters generally absorb between 1715 (conjugated) and 1745 cm.-l (unconjugated). These frequencies may be raised by the presence of powerful electronattracting substituents (e.g., NO,) or lowered by intramolecular hydrogen bonding (chelation) ; however, neither of these complications is present in the griseofulvin molecule. Griseofulvin (Fig. 3b) has no absorption bands in the carboxylic ester range, and the Derivatives. Griseofulvin (0.4 g.) and bromine (0.6 g.) were dissolved ...

Allogibberic acid and epiallogibberic acid, stereoisomeric degradation products of gibberellic acid, are shown to have the absolute configurations (111) and (XX) respectively.GIBBERELLIC ACID 1 (I), on treatment with dilute mineral acid, yields 233 allogibberic acid 4 (111). Allogibberic acid has also been obtained by heating gibberellic acid with water, and from 2,7-dihydroxy-l-methyl-S-methylene-lOa~-gibba-3,4a(4b) -diene-1 ,lo-dicarboxylic acid t (gibberellenic acid 19596) (11) with boiling water or cold mineral acid.* Part XI, J . Sci. Food Agric., in the press.t By agreement with the Editor the name gibbane is used for the fully saturated tetracyclic systemThe ring system derived from gibbane by inversion at positions 7 and 9a is called