TheSenecioalkaloids. The structure and absolute configuration of isoline

摘要

1972The Senecio Alkaloids. The Structure and Absolute Configuration ofI sol i neBy E. D. Coucourakis, C. G. Gordon-Gray," and C. G. Whiteley, Department of Chemistry and ChemicalThe structure and absolute configuration of the alkaloid isoline has been determined by showing that its acidportion, isolinecic acid, is (2S.3R.5S) -5-ethyl-2.5-dihydroxy-2.3-dimethylhexanedioic acid (1 ). The stereo-chemistry was defined by degradation of the acid to 3-methylheptane-2.5-dione (4) of known absolute con-Technology, University of Natal, Pieterrnaritzburg, South Africafiguration.IN a previous communication1 it was shown thathydrolysis of the alkaloid isoline, obtained from Seneciootlzonnzformis Fourcade, afforded a new acid, isolinecicacid,? C,,H,,O,, which could be converted into itsmonolactone, and thence into the dilactone (ejD20-50.0") by distillation.Mainly on the basis of spectralstudies, isolinecic acid was tentatively assigned structure(1) or (2). We now present evidence which not onlyOH Me OH OH Me OHI I t I l lI I ICOzH C02H COzHEt -C-CH2-CH-C-Me Et -CH-CH-CH-C-Me( 1 1 ( 2 1confirms structure (1) but also defines its absolute con-figuration.Previously we mentioned that isolinecic acid dilactonediffered in m.p. and i.r. and n.m.r. spectra from thedilactone obtained by Danilova et aL2 from senecic acid(5-ethylidene-2-hydroxy-2,3-dimethylhexanedioic acid)by reduction of the derived bromo-dilactone. It wassuggested that these differences could be due t o stereo-chemistry.Since Danilova's work was available to usonly as an abstract and since correspondence with herwas not possible for us, it was decided to confirm thestructure of her dilactone. Treatment of senecic acidlact one (5-et hylidene-2,3-dimethyl-amp;oxotetrahydro-pyran-2-carboxylic acid) with bromine-water at 70"gave the bromo-dilactone, which was readily reduced tothe dilactone. A comparison of n.m.r. spectra con-firmed Danilova's structure for the bromo-compound.However, it seemed to us that the structure of thebromo-dilactone was unusual, in that the bromine, thepositive end of the polar HOBr molecule, appeared a t thep-position of an @-unsaturated system. We, therefore,decided to investigate this reaction.The halogenolactonization has been used successfullyfor the preparation of five- and six-membered lactonesfrom unsaturated acids3** The mechanism for ringclosure, in the case of double bonds not conjugated to acarboxy-group, seems perfectly normal in that the cyclict This was previously referred t o as 2,Bdihydroxy-3-methyI-heptane-2,5-dicarboxylic acid.2E.D. Coucourakis and C. G. Gordon-Gray, J . Chem. SOC.(C), 1970, 2312.A. V. Danilova, N. I. Koretskaya, and S. L. M. Utkin,Zhur. obshchei Khim., 1962, 32, 3823 (Chem. Abs., 1963, 58,12,504).bromonium ion, first formed by the electrophilic additionof bromine to the x-bond, is rapidly attacked by thenegative carboxy-group to give the most stable lactone.In the case of a double bond conjugated to a carboxy-group, however, the mechanism is not clear, and a studyof the literature shows that the initial step in the mechan-ism of this reaction has not been identified.5*6 Reeveand Israel6 in reacting hypochlorous acid with ethylcrotonate produced kinetic evidence to show that theinitial attack was that of ' positive chlorine ' derivedfrom chlorine monoxide.They proposed the unusualattack at the or-carbon to leave a carbonium ion a t thep-carbon. They did not invoke the formation of thecyclic chloronium ion nor did they give the structure ofthe chlorohydrin.In an attempt to get some insight into this halogeno-lactonization, ethyl crotonate was treated with bromine-water under the same conditions as those used for theformation of bromo-dilactone (see before).The bromo-hydrin was isoIated, reduced with Raney nickel, and theproduct was purified by distillation. An n.m.r. investi-gation showed the presence of ethyl 3-hydroxybutyrateas the only product. Thus, identical treatment ofsenecic lactone and ethyl crotonate with bromine-watershowed that the product from the former was the @-bromo- while that from the latter was a-bromo-com-pound.These reactions would seem to indicate that in bromo-lactonization some such species as the cyclic bromoniumion must be an intermediate. What constitutes theinitial attack is not clear. Is it a normal nucleophilicattack at the p-position by some such species as Br3-,which then in some way, not immediately clear, dis-proportionates to give the cyclic intermediate or, farmore likely, is it the ready electrophilic attack of thebromine atom from hypobromous acid (or the electro-philic chlorine atom from chlorine monoxide in the caseof hypochlorous acid) to give the intermediate cyclicbromonium ion as outlined in Scheme l?The second alternative is the more readily acceptable.In the case of ethyl crotonate, since no lactonization ispossible, a water molecule or hydroxide ion attacks thebromonium intermediate a t the p-position, the mostpositive carbon atom, whereas in the case of senecicP.N. Craig, J. Amer. Chem. SOC., 1952, 74, 129.E. E. van Tamelen and M. Shamma, J. Amer. Chem. SOC.,R. P. Bell and M. Pring, J. Chem. SOC. (23). 1966, 1119.I. D. Reeve and G. C. Israel, J. Chem. SOC., 1952, 2327.1964, 76, 23162340 J.C.S. Perkin Ilactone the intermediate is attacked by the negative Since the determination of the configuration at C-3carboxy-group at that carbon atom which will give the would automatically give the stereochemistry at C-2most stable lactone, namely the a-carbon atom.and C-5, it became essential to degrade both dilactones+ - C- C - C=OSCHEME 1Having confirmed the structure of the dilactonederived from senecic acid by Danilova, it was shown byc.d. spectra (see Figure) that this dilactone, and that200 220 210 260A / nmFIGURE C.d. curve of the dilactone derived from senecic acid(broken line) and isolinecic acid dilactone (solid line)from isolinecic acid, were diastereoisomers. Further-more the mass spectrum of each gave identical fragmenta-tion patterns.Hence the structure of isolinecic acidmust be (1).Since the absolute configuration of senecic acid isknown to be (2R,3R) , the dilactone derived from it mustto a common intermediate in which the asymmetry atC-2 and C-5 was lost. Oxidation with potassium per-manganate was successfully carried out on senecic acid-derived bromo-dilactone to give the y-valerolactone (3) ,but failed when repeated on the two dilactones. Proofof structure of (3) was obtained by oxidation of senecicacid with ozone.It was then necessary to convert both dilactones into3-met h ylhept ane-2,5-dione (4). Preliminary oxidationsMe(310 G c 0 p Me0Et CO 9 CH2-CHMe.CO*Me ( 4 1with sodium bismuthate on isolinecic acid, on a semi-micro-scale, failed to give the dione (a), and since thiscompound had, to our knowledge, not been reported inthe literature, it was decided to synthesize it in order toascertain its chemical and physical characteristics.The synthesis was accomplished by two differentmethods.The first method is shown in Scheme 2.Preparation of the p-keto-ester (6), however, by themethod of Riegel and LilienfieldJ9 was not successful;we obtained a mixture of products. This ester wasobtained pure, although in lower yield than that re-ported, by hydrolysis of a metal halide formed fromanhydrous tin(1v) chloride, propionitrile and ethyl aceto-acetate by hydrochloric acid in chloroform.1deg; Con--c02MeCHBr=CO*Me + EtCO*CH2-C02Et EtCO*CH(C02Etl~CHMe* COeMe -(amp;I15) (61 (7 1SCHEME 2have the (2R,3R,5R)-configuration as it is impossible toform the dilactone if C-5 has the opposite configurationto C-2.The same observation was made for hygro-phyllinecic acid dilactone which has the (2RJ3R,4R)-configuration.8 Consequently the dilactone from iso-linecic acid can have the configuration (2S,3R,5S) or(2R,3S,5R) ; the (ZS,3S,SS)-configuration is excludedsince the two lactones are not enantiomers.Tetrahedron Letters, 1960, 36.6707.67, 1273.7 J . Fridrichsons, A. McL. Mathieson, and J. D. Sutor,* F. D. Schlosser and F. L. Warren, J. Chem. Soc., 1966,0 B. Riegel and W. M. Lilienfield, J . Amer. Chem. Soc., 1946,densation of the ester and the bromo-ketone (5) l1 gavethe ester (7), which was decarboxylated to the dione (4)by heating with 20 aqueous potassium carbonateunder reflux.12Of themany routes to substituted furans 13-15 we chose that ofThe second method is shown in Scheme 3.l o Y.Isowa, Jap.P. 17,170/1968 (Chem. Abs., 1969, 70,11 C. Rappe and R. Kumar, Arkiv Kemi, 1966, 25, 476.12 V. M. Rodionov and E. F. Polunia, Doklady Akad. Nauk1s C. Paarl, Bey., 1884, 17, 2766.14 F. Feist, Bar., 1902, 85, 1637.16 P. A. Yoder and B. Tollens, Bey., 1901. 34, 3446.5 7,173h).S.S.S.R., 1949, 88, 636 (Chem. Abs., 1960, 44, 1030e)1972Gonzalezls modified by Hanson et a1.lrsquo; The furoatewas hydrolysed and the acid decarboxylated by heatingwith copper-barium chromite catalyst in quinoline.18Ring fission l9 gave the dione (4).The n.m.r.spectrum of the dione (4) gave the signalsT 9.0 (d and t), 7.8 (s) and 7.6 (9) for the MeCH,* andZnCL2MeCOCH(0H )Me + Et CO*CH2*COZEt -ion peaks at m/e 395 and 353, respectively. As in thecase of the analogous alkaloids floridanine, floricaline,and florosenine,m fragmentation of isoline gives fragment(9) at m/e 351, which corresponds to the loss of carbondioxide. This ion then loses an acetyl group to give anion (10) at m/e 308. In bisline the peaks correspondingSCHEME 3MeCH., MeCO., and MeCH,* groups respectively, asshown by decoupling. The other protons could not beclearly differentiated. The mass spectrum gave theaccurate mass of the molecular ion of 142.098558In order to didecarboxylate and oxidize the dilactonederived from senecic acid, it was reduced with lithiumaluminium hydride to give an oil which failed to give acrystalline derivative.Oxidation of the oil with sodiumbismuthate gave formaldehyde (1.8 mol) (as the dimedonederivative) together with the Gone (4). Such anoxidation of isolinecic acid on a macro-scale affordedcarbon dioxide (2 mol) and the dione (4).The dione from both sources were shown to haveidentical c.d. and 0.r.d. curves, thus establishing the3R-configuration in isolinecic acid (1) and hence givingthe absolute configuration for this acid as 2S,3R,5S).We suggested previously,l without any evidence, thatthe 5-hydroxy-group (in the acid portion) was acetylatedin the parent alkaloid, isoline. We now present evidencefrom n.m.r.and mass spectral data to show that theacetoxy-group exists at C-2.The n.m.r. spectrum of isoline differs from that ofbisline in two respects: the acetoxy methyl signal inisoline is clearly visible at T 8.0, and the 2-methyl groupis somewhat deshielded (7 8.6) by comparison with thesame methyl group in bisline ( T 8.8). A similar deshield-ing effect is observed when florosenine 20 and senkirk-ine 21 are compared with their O-acetyl derivatives.It has been shown 22-24 that in the mass spectrometerretronecine diesters undergo initial fragmentation byfission of the labile allylic ester bond, followed bysystematic fragmentation of the lsquo; necic rsquo; acid componentuntil only the lsquo;necinersquo; base remains. This thenundergoes fragmentation to give the well-known seriesof ions m/e 136, 120, 119, 95, 93, and 80, also found inisoline and bisline.The empirical formulae for isoline, CmHZ9NO,, andbisline, CI8H,,NO,, are consistent with the molecular( C8H 14O2) *l6 F.G. Gonzalez, J. L. Aparacio, and F. Sanchez-Laulke,l7 J. C. Hanson, J. H. C. Naylor, T. Taylor, and P. H. Gore,18 T. Reichstein, H. Zschokke, and W. Syz, Helv. Chim. Acta,Zo M. P. Cava, K. V. Rao, J. A. Weisbach, R. F. Raffauf, andAnales real SOC. espafi. Fls. Qulm., 1954, 50B, 407.J . Chem. SOC., 1966, 6984.1932, 15, 1112.H. Hunsdiecker, Ber., 1942, 75B, 447.B. Douglas, J . Org. Chem., 1968, 33, 3670.to this fragmentation pattern are at m/e 309 and 308,respectively .OH Me OAc OH MeIIcoI I o +I IIco0 rsquo;I I Et-C-CHTCH-AC E t -C-CHF CH - $-MeI CH2 1 CH2mle 351 m / e 308( 9 ) ( 1 0 )From the above discussion, and since the stereo-chemistry of retronecine is known, the absolute struc-ture of isoline is given as (11).Since bisline (12) wasdeduced from spectral data, its stereochemistry is un-defined. As far as we know, the only other pyrrolizidinealkaloid with the (2s)-configuration in the acid portionis clivorine (13) the structure of which was determinedby X-ray analysis.268rdquo; Me 1 : OH Me OH I t iE t -9- C- CH *- 5: - C 4 Me Et - C- C H 1 C H- C- MeI I coI I I ico: I I H CO coHaving determined the absolute configuration ofisoline, the one fact that still remains unexplained is why21 L. H. Briggs, R. C.Cambie, B. J. Candy, G. M. Orsquo;Donovan,R. H. Russell, and R. W. Seelye, J . Chem. SOC., 1965, 2492.22 C. K. Atal, K. K. Kapur. C. C. J. Culvenor, and L. W.Smith, Tetrahedron Letters, 1966, 637.t3 N. Neuner-Jehle, H. Nesvadba, and G. Spiteller, Monatsh.,1966, 96, 321.24 D. H. G. Crout, J. Chem. SOC. (C), 1969, 1379.25 F. L. Warren and M. E. von Klemperer, J . Chem. Soc.,26 K. B. Birnbaum, A. Klasek, P. Sedmera, G. Snatzke, L. F.1958, 4574.Johnson, and F. Santavy, Tetrahedron Letters, 1971, 34212342 J.C.S. Perkin Iisolinecic acid can be isolated as the free acid, whilesceleratinic and sceleranecic acids are only isolated as thedi-blactones. We note that the acid present in otosen-ine has the (2R)-configuration. It would be of interestto see whether floricaline (14), which must also have the(2R)-configuration, would yield the free acid on hydroly-sis. If not, then the stereochemistry of these acids atC-2 and C-5 must play an important part in the formationof the di-84actones.Me VAcI8-0 Me( 1 3 )AcO OH Me OAcI I I 1Me-CH-C- CHZCH-C-MeI I co coMeEXPERIMENTALHalogeno-dilactones from Senecic Acid (5-Ethylidene-2-hydroxy-2,3-dimethyZhexanedioic A cid) .-Intergerrinecic acidlactone 27 (4.0 g) was treated with an excess of bromine-witter at 70" to give pure 5-( l-bromoethyl)-2,3-dimethyl-hexane-2,5-diolide (5.1 g) as needles, m.p.115" (from ethanol)(lit.,2 114") (Found: C, 43.4; H, 4-8. Calc. for Cl0Hl3BrO,:C, 43.3; H, 4.7), M+, 277, vmx. (KBr) 1750 cm-1 (C=Olactone), T (CDCl,; 100 MHz) 8.8 (3H, d, MeCH), 8.4 (3H,s, MeC), 8-3 (3H, d, MeCHBr), 7-7 (IH, m, MeCH-CH,), and5.5 (lH, q, MeCHBr).Similar treatment of the lactone (1.0 g) with chlorine-water gave the 5-( 1-chloroethy1)-diolide (0.5 g), m.p.109"(from ethanol) (lit.,, 107-108") (Found: C, 51-5; H, 5.8.Calc. for C,,H,,ClO,: C, 51.5; H, 5.7).Preparation of the Dilactone derived from Senecic Acid.-The bromo-dilactone from senecic acid (1.0 g) with freshlyprepared Raney nickel was heated under reflux in ethanol(30 cm3) for 8 h. The solution was filtered, water (20 cm3)was added, the alcohol was removed, and the dilactone wasextracted into ether. The crude product, on sublimation(35" at 0.05 mmHg) afforded 5-ethyl-2,3-dimethylhexane-2,5-diolide, needles, m.p.51" (lit.,, 51") aiJD20 -55.3'(Found: C, 60.5; H, 7.1. Calc. for C,,H,,O,: C, 60.6; H,7.1 yo).27 M. Kropman and F. L. Warren, J. Chem. Soc., 1950,700.Oxidation of the Brom-dilactone from Seaecic Acia? wa3hPermangarrate.-To a stirred solution of the foregoingbromo-dilactone (2.5 g, 9 mmol) and potassium hydroxide(0-83 g, 18 mmol) in phosphate buffer (pH 7, 250 cm3) wasadded dropwise 2 potassium permanganate a t 60".The apparatus was flushed with nitrogen and the carbondioxide was collected as barium carbonate (2.8 g). Whenthe permanganate colour of the solution persisted, it wascooled to O", treated with sodium sulphite, and the mangan-ese dioxide was dissolved by adding concentrated sulphuricacid. The solution was concentrated (200 cms) and thedistillate afforded acetic acid, identified as its barium salt(1.4 g).The remaining aqueous solution yielded an oilygum (800 mg), which was distilled. The fraction boilingat 90" and 0.1 mmHg, on redistillation onto a cold finger,gave the pure hygroscopic 2,3-dimethyl-5-oxotetrahydro-2-furoic acid (3), m/e, 158, 113, 89, and 85, T (pyridine, 60MHz) 9-0 (3H, d, MeCH) and 8-5 (3H, s, Ac).p-Bromophenacyl 2,3-Dimethyl-5-oxotetraIzydro-2-furoale.-The foregoing acid (3) (124 mg) was neutralized with0-h-sodium hydroxide and the solution taken to drynessin vacuo. p-Bromophenacyl bromide (200 mg) and ethanol(5 cms) were added and the solution was heated underreflux (1 h). The alcohol was removed and the residue washeated under reflux with acetone, filtered hot, and thefiltrate was taken to dryness to yield the ester, plates, m.p.74-76" (from ethanol) (lit.,2B 82 and 109") (Found: C, 50.7;H, 4.3.Calc. for C,,H,,BrO,: C, 50.7; H, 4-3y0), v-(KBr) 1702, 1750, 1780, and 1580 cm-l.Ozonolysis of Senecic A cid.-Senecic acid (1 g) in dry ethylacetate (20 cm3) was ozonized at -76" for 4 h. Treatmentwith water and extraction with ether yielded a solid.Sublimation (80" at 0.1 mmHg) gave pure 2,3-dimethyl-5-oxotetrahydro-2-furoic acid (450 mg), identified by itsn.m.r. and i.r. spectra and by its pbromophenacyl ester.Ethyl 3-Oxopentanoate (6) .-Anhydrous tin(1v) chloride(74.5 g, 0-35 mol) followed by propionitrile (19.4 g, 0.35 mol)were dropped slowly onto ethyl acetoacetate (45.5 g,0.35 mol) and the whole was heated under reflux to effecta homogeneous solution.1deg; Chloroform (200 cm3) and 10hydrochloric acid (200 cm3) were added at 45" and thestirring was continued at room temperature (1 h).Theaqueous layer was extracted twice with chloroform (100cms) and the combined chloroform extract, after washingwith 10 hydrochloric acid and water, was dried anddistilled to give an oil. Fractional distillation gave theester (6), b.p. 54-59' at 4 mmHg.3-Bromobutan-2-ouze (5) .-N-Bromosuccinimide (53 g,0-295 mol) was added in portions to a boiling mixture ofethyl methyl ketone (85 g, 1.18 mol) in carbon tetrachloride(300 cm3).11 The solution was boiled for 1 h, cooled, andthe succinimide was filtered off at 0".Evaporation of thefiltrate gave an oil, which on fractional distillation yielded3-bromobutan-Z-one, b.p. 39" a t 13 mmHg.Ethyl 3-Methyl-4-oxo-2-propionylpentanoate (7) .-Theester (6) (24-0 g, 0.167 moll was added dropwise, with stir-ring, to a solution of sodium (3.7 g, 0.161 g atom) in absolutealcohol (48 g). The mixture was heated under reflux for30 min, cooled to below 40" and 3-bromobutan-2-one(24 g , 0.159 mol) added gradually at 30". The solution wasstirred for 1 h, first at 40" then at 50-60", filtered, con-centrated, and after water (18 cm3) had been added with28 R. Mozingo, Org. Synth., 1941, 21, 16.ZD R. B. Bradbury and S. Masamune, J. Amev. Chem. SOC.,1959, 81, 52011972shaking, extracted into ether. Evaporation and fractionaldistillation gave the ester (7), b.p.132-137O at 0.85 mmHg.3-Methylheptane-2,5-dione (4) .-The foregoing ester (7)(14.0 g, 0-065 mol) was heated under reflux for 3 h with25 aqueous potassium carbonate (140 g). The mixturewas cooled, solid potassium carbonate (26 g) was added, andthe product, an oil, was extracted into ether. Fractionaldistillation gave 3-methylheptane-2,5-dione (6 g) , b.p. 44-45' at 0.05 mmHg, M+ (mass spec.), 142.098559, m/e 142,113, 85, 71, 57, and 43, vmL (CHCl,) 1701 cm-l (GO), 7(CCI,; 60 MHz) 9.0 (6H, d and t, MeCH and MeCH,), 7.8(3H, s, Ac), and 7.6 (2H, q, MeCH,); bisthiosemicarbazone,m.p. 159" (from ethanol) (Found: C, 42.1; H, 7.8. C,,H,,-N,S, requires C , 41-7 ; H, 7-0y0) : bis-2,4-dinitrophenyLhydrazone, m.p.199-201" (from diglyme) (Found: C,47.5; H, 5-1. C20H22N808 requires C, 47.8; H, 4.4).Ethyl 2-Ethyl-4,5-dimethyZ-3-furoate.-The ester (6) (28.8g, 0.2 mol) was heated under reflux for 4 h with acetoin(16.0 g, 0.182 mol), anhydrous zinc chloride (18.2 g), and95 ethanol (27.2 cm*). The liquid was poured into water(50 cm3) and extracted with benzene. The benzenesolution, after washing successively with water, 5 sodiumhydroxide, dilute hydrochloric acid, and water, gave an oil.Fractional distillation gave the furoate (22.4 g , 64) , b.p.79-80" at 3 mmHg.2-Ethyl-4,5-dimethyL3-furoic Acid.-The foregoing esterwas heated under reflux for 6 h with 40 sodium hydroxide(60 cm3) containing alcohol ( 5 cm3). After evaporationand acidification, the furoic acid was collected, m.p.84"(from ethanol) (lit.,17 84-45") (Found: C, 64.4; H, 6.8.Calc. for C,H,,O,: C, 64.3; H, 7.2).2-Ethyl-4,5-dimethylfuran.-The furoic acid (8.7 g,5 1.9 mmol) was boiled with barium-copper chromitecatalyst (1.5 g) and quinoline (15.0 The temperaturewas raised and the fraction b.p. 14@-200deg; was collected.Fractional distillation gave 2-ethyl-4,5-dimethylfuranJ b.p.50" at 18 mmHg.3-Methylheptane-2,5-dione from 2-Ethyl-4,5-dimethylfuran.-2-Ethyl-4,5-dimethylfuran (10 g, 81 mmol) was heatedunder reflux a t 120" for 4 h with a mixture of glacial aceticacid (15 g), water (5 g), and 20 sulphuric acid (10 drops).The solution was made basic with 1 sodium carbonateand extracted into ether.Evaporation gave an oil, frac-tional distillation of which afforded 3-meth~lheptane-2~5-di-one (4.4 g, 50) , b.p. 4amp;45" a t 0.05 mmHg, identified byits n.ni.r. and i.r. spectra.Reduction of the DiEactone derived from Senecic Acidwith Lithium Aluminium Hydride.-The dilactone (seebefore) (1 g ) was dissolved in anhydrous tetrahydrofuran(100 cm3) and was heated under reflux with an excess oflithium aluminium hydride for 96 h. Water (50 cm3) wasadded at 0", and the resulting aluminium hydroxide filteredoff , dissolved in hydrochloric acid ( 2 ~ ) , and reprecipitatedwith sodium hydroxide. The combined filtrates weretaken to dryness under reduced pressure. Water (100 cm3)was added and the solution was continuously extracted withether (24 h) to yield a polyol after distillation (150" at 0.2mmHg) as a viscous oil (1.01 g).Oxidation of the Foregoing Polyol with Sodium Bismuthate.-Sodium bismuthate (840 mg) was added to a solution ofthe preceding polyol (240 mg) and 3.3~-phosphoric acid(6 cm3) in water (10 cm3).The mixture, after standing for48 h, was filtered and the filtrate was treated with dimedone(1.34 g) to give formaldehyde dimedone (563 mg), m.p.193". In a similar experiment the polyol (550 mg) wasoxidized with an excess of bismuthate (3 g). The aqueoussolution, after removal of the bismuth phosphate, was con-tinuously extracted with ether (24 h). After evaporation,making basic with 1 sodium carbonate, and re-extractionwith ether, the resulting mobile oil (300 mg) was distilled.The middle fraction, b.p. 42-44" a t 0.05 mmHg, gave pure3-meth~lheptane-2~5-dione (180 mg) , +47.8" (c30.74 g dm-3 in EtOH).Oxidation of Isolinecic Acid (5-Ethyl-2,5-dihydroxy-2,3-di-methylhexanedioic Acid) (l).-Sodium bismuthate (5 g) wasadded to a solution of the acid (1) (1.2 g ) and 3-3~-phosphoricacid (16 cm3) in water (50 cm3) and the mixture was keptunder a stream of nitrogen until evolution of carbon dioxideceased. Filtration and extraction of the filtrate with etherafforded an oil. The oil, in water, was made basic with 1sodium carbonate and re-extracted into ether to give pure3-meth~lheptane-2~5-dione (390 mg) after distillation (at43" and 0.05 mmHg), +48.7" (c 30432 g dm-a).We thank Dr. K. Pachler for n.m.r. spectra, Dr. S. Eggersand Dr. M. Toube for the mass spectra, Dr. L. Visser forc.d. and 0.r.d. spectra, and the South African Council forScientific and Industrial Research for grants (to E. D. C.and C. G. G.).2/545 Received, 8th March, 1972