ORGANIC CHEMISTRY.1. STEREOCHEMISTRY.Deutero-compounds.-A number of attempts have been made toascertain if a compound CHDRR' could exhibit optical activityowing to the difference between hydrogen and deuterium. H.Erlenmeyer and H. Gartner I. failed to resolve a partly deuteratedP-phenylpropionic acid, C6H2,,8D,.82'C2H,6,D,,8.C0,H, and laterphenylpentadeuterophenylacetic acid, C6D5*CHPh*C02H. E. Bid-man, K. A. Jensen, and E. Knuth at first concluded that decomposi-tion of Z-bornylmagnesium chloride with deuterium oxide gave aslightly active 2-deuterocamphane, but repetition of this workshowed that water and deuterium oxide gave products which werestereochemically indistinguishable. M. T. Leffler and R. Adamsreduced Z-bornylene with hydrogen and with deuterium, and foundthat, although 2 : 3-dideuterocamphane had a higher density thancamphane, it had the same optical rotation as the latter.The sameauthors also reduced ethyl maleate and ethyl fumarate catalyticallywith deuterium, and obtained from both the same ethyl aa'-dideutero-succinate, and this was found to be saponified to a single acid, thealkaloid salts of which showed no mutarotation. Similarly, J. B. M.Coppock and S. M. Partridge reduced y-phenyl-a-methylallylalcohol with hydrogen and with deuterium, and failed to observeany optical difference between the products. All the above authorsconcluded, therefore, that the formally " asymmetric '' carbonatom in CHDRR' does not give rise to optical activity.8On the other hand, G. R.Clemo and A. McQuillen have claimedthe resolution of pentadeuterobenzhydrylamine, C6D5*CHPh*NH2,prepared by reducing the oxime of pentadeuterobenzophenone,obtained by a Friedel-Crafts reaction from hexadeuterobenzene.etc. etc.48 ORQANIC CHEMISTRY.The reduction of the double bond in the side chain of ergosterolwithout disturbance of the nuclear system was accomplished in anelegant manner by A. Windaus and R. Langer.40 The adduct ofergosteryl acetate and maleic anhydride mas reduced to the dihydro-compou?d,4l which underwent thermal dissociation to give theacetate of 22-dihydroergosterol (XXI). Reduction of (XXI) withsodium and alcohol gives y-ergostenol (XXII), which is isomerisedby a palladium or platinum catalyst to the well-known a-ergostenol,containing an '( inert " double bond.42 Formula (XXIII) is nowfavoured for a-ergostenol 43 and on the basis of selenium dioxideoxidation experiments R.K. Callow 4.4 has derived an analogousstructure for the stereoisomeric a- and p-apocholic acids.HOp-Ergostenol, which arises by isomerisation of a-ergostenol withhydrochloric acid,45 has now been shown to have the structure(XXIV). P-Ergostenyl acetate was ozonised, and the ozonidesubmitted to reductive fission, followed by thermal decomposition.In this way 4G opening of ring IV was followed by splitting off of theside chain as an unsaturated aldehyde, C,,H,,O, with the productionof the acetate of a keto-alcohol, the structure of which (XXV)follows from its dehydrogenation with selenium to %methyl-p henant hrene .4340 Annalen, 1934, 688, 106.4 1 H.€3. Inhoffen, ibid., p. 81.4 2 Compare F. Reindel and E. Walter, ibid., 1928, 460, 214; S. v. Reichel,2. physiol. Chem., 1934, 226, 146.4 3 F. Laucht, ibid., 1935, 237, 236.44 J., 1936, 462; compare H. Wieland, E. Dietz, and H. Ottawa, 2. physiol.45 I. M. Heilbron and D. 0. Willrinson, J., 1932, 1708; compare I?. Reindel,46 Th. Achtermann, 2. physiol. Chem., 1934, 285, 141.Chem., 1936, 244, 194.E. Walter, and H. Rauch, Annalen, 1927, 452, 34COOK: NATURAL PRODUCTS OE* THE STEROL GBOUP. 349The Vitamin D Problem.There have been developments of outstanding importance in thisfield, and although it is evident that the problem is more complexthan was formerly suspected, we now have fairly precise knowledgeof the chemistry of at least some of the natural antirachitic vitamins.The main outlines of the chemistry of the photoisomerides ofergosterol have been established ; the structure of calciferol has beenelucidated ; new vitamins and provitamins have been preparedartificially from sterols, and the isolation of natural vitamins andprovitamins has been accomplished.Lumisterol, the first of the series of ultra-violet irradiation pro-ducts of ergosterol, appears to be stereoisomeric with ergoster01.~‘It contains intact the tetracyclic sterol ring system, as it is dehydro-genated to 3’-methyl- 1 : 2-cy~Zopentenophenanthrene~~ but unlikeergosterol it gives no insoluble precipitate with digitonin, althoughby epimerisation of their hydroxyl groups isolumisterol, dihydro-lurnisterol, and lumistanol are converted into isomerides which areprecipitated by digitonin.49 Dehydrolumisterol, obtained by milddehydrogenation of lumisterol with mercuric acetate,4’ was shownby K. Dimroth 5O to give it perhydro-derivative which differs fromlumistanol and also from ergostanol, but is identical with perhydro-pyrocalcif erol (p.35 I). If dehydrolumisterol (like dehydroergosterol)is correctly represented by formula (XXVII), the difference betweenthese two perhydro-compounds lies solely in the configuration of C,,and the experimental results are consistent with Dimroth’s con-clusion that the conversion of ergosterol into lumisterol (XXVI)consists solely in the inversion of con5guration of Clo.H.Lettrh’s s1 observation that calciferol (vitamin D,) gives no3’-methyl-l : 2-cyclopentenophenanthrene when dehydrogenatedwith selenium led him 60 a further study of tachysterol, which isintermediate between lumisterol and calciferol in the series ofirradiation products of ergosterol. This was shown to contain not4 7 I. M. Heilbron, F. S. Spring, and P. A. Stewart, J., 1935, 1221.dB K. Dimroth, Ber., 1935, 68, 539.49 A. Windaus, K. Dithmar, and E. Fernholz, Anmlen, 1932, 493, 259;60 Ber., 1936, 69, 1123.61 Anmlem, 1934, fill, 280.G. Ahrens, E. Fernholz, and W. StoU, ibid., 1932, 500, 109350 ORQANIC OHEMISTRY.three, but four double bonds (three of them conjugated). Hencetachysterol is tricyclic, which means that ring fiasion has occurred,and Lettr6 suggested that its structure is (XXVIII) or (XXIX).The essential accuracy of this conception has been demonstratedby investigations which have established the structure (XXX) forcalciferol (vitamin D2), the succeeding member in the photochemicalseries.I. M. Heilbron, K. M. Samant, and F. S. Spring 52 obtained,by oxidation of calciferol with chromic acid, an unsaturated aldehydeC21H380 (XXXI), the formation of which can only be interpretedby the assumption that fission of ring I1 has occurred in the con-version of ergosterol (XII) into calciferol. The location of thedouble bonds was elegantly shown by A. Windaus and W. Thiele,53who dehydrogenated the adduct of calciferol with maleic anhydride(XXXII), and obtained p-naphthoic acid with palladised charcoal,and 2 : 3-dimethylnaphthalene with selenium.Further, a saturatedketone, C,,H,,O (XXXIII), was obtained by ozonisation of thedihydro-derivative of this maleic anhydride adduct :52 Nature, 1935, 135, 1072.(xxxrI1.)63 Ammlm, 1935,521, 160COOK: NATURAL PRODUCTS OF THE STEROL GROUP. 351Pinally, Heilbron and his collaborators 54 and A. Windaus and W.Grundmann 55 isolated a keto-acid, C13H2003 (XXXIV), from theproducts of direct ozonolysis of calciferol (XXX). The chemicalevidence appears conclusive, although J. D. Bernal and D. Crow-foot 56 find difficulty in reconciling the X-ray crystallographic datawith this formdation.In connexion with these investigations the degree of unsaturationof calciferol and its derivatives has been re-examined. Althoughonly three double bonds could be detected in calciferol by perbenzoicacid titration ,s7 microhydrogenation has demonstrated 58 thepresence of the four double bonds required by the tricyclic structure(XXX) of the vitamin. Furthermore, dihydrocalciferol,69 whichmay also be obtained by reduction of tnchysterol,60 has been shownto contain three double bonds by perbenzoic acid titration 61 andby refractometric measurements.60 In the thermal transformationof calciferol to pyrocalciferol and " isopyrovitamin " 621 63 thetetracyclic sterol system is re-formed (compare p.349), 3'-methyl-1 : 2-cyclopentenophenanthrene being formed by subsequentselenium dehydrogenation.60 The epimerides of di- and hexa-hydropyrocalciferol are precipitated by d i g i t ~ n i n .~ ~ Suprasterols Iand 11, which arise by further irradiation of calciferol, are alsotetracyclic, but give no crystalline products on dehydrogenation.60In the meantime, it became apparent on biological grounds thatcalciferol is not the only antirachitic vitamin. For instance,J. Waddell 64 showed that irradiated cholesterol and cod-liver oilare more effective in curing rachitic chicks than irradiatedergosterol, compared on the basis of the same number of rat units.65905.64 I. M. Heilbron, R. N. Jones, K. M. Samant, and F. S. Spring, J., 1936,s5 Annulen, 1936, 524, 295.66 Chem. and Ind., 1935, 54, 701.67 A. Windaus, 0. Linsert, A. Luttringhaus, and G. Weidlich, Annrclen,6 8 R.Kuhn and E. F. MCiller, Angew. Chem., 1934,47, 145.69 E. Fernholz, Annalen, 1932, 499, 198.60 M. Miiller, 2. physiol. Chena., 1935, 233, 223.61 S. v. Reichel and M. Deppe, ibid., 1936, 239, 143.68 F. A. Askew, R. B. Bowdillon, H. M. Bruce, R. K. Callow, J. St. L.6s P. Busse, 2. physiol. Cherra., 1933, 214, 211.64 J . Biol. Chem., 1934,105, 711 ; for a discussion of " The Multiple Natureof Vitamin D " see C. E. Bills, Cold Spring Harbor Symposia on QuantitativeBiology, 1935, 3, 328.65 See also 0. N. Massengale and M. Nussmeier, J . Bid. C'hem., 1930, 87,415, 423; A. F. Hesa and G. C. Supplee, Proc. SOC. Exp. Biol. Med., 1930,27,S a m , Amer. J . Pharm., 1936,108,237.1932,492, 226.Philpot, and T. A. Webster, Proc. Roy. SOC., 1932, B, 109,488.609; M.J. L. Doh, 2. V'itMninf~t~h., 1936, 5, 161; A. Black a d €€. L352 ORGAN10 CHEMISTRY.The double bond in the side chain of calciferol is evidently notessential for activity, for 22-dihydroergosterol (p. 348) acquiresantirachitic properties on irradiati~n.~o This led to the suggestion 66that the analogous derivative of cholesterol, without the additionalmethyl group of the side chain, might be the provitamin normallypresent in cholesterol. This compound (XXXVI), for which theterm 7-dehydrocholesterol was suggested by C. E. Bills,64 wasprepared from cholesterol by A. Windaus, H. Lettr6, and Fr.Schenk O7 by oxidation of cholesteryl acetate to the 7-keto-compound(XXXV), followed by reduction with aluminium isopropoxide, andpyrolysis of the dibenzoate of the resulting A5-cholestene-3 : 7-diol.In a similar manner sitosterol and stigmasterol 69 have beenconverted into 7-dehydro-derivatives. In its absorption spectrum,07its photochemical oxidation and dehydrogenation, and its con-version into a series of dihydro-compounds, y-, a-, and ~-cholesten~ls,~~7-dehydrocholesterol shows a very close resemblance to ergosteroland 22-dihydroergosterol, and it acquires powerful antirachiticproperties on irradiation.The vitamin so formed has been isolatedin the pure state by A. Windeus, Fr. Schenk, and F. v. Werder 71and has been termed vitamin D,. Moreover, the irradiation pro-ducts of both 22-dihydroergosterol and 7-dehydrocholesterol arejust as effective in curing rachitic chickens, on the basis of thenumber of rat units which they contain, as the vitamin D of cod-liver oil and irradiated crude cholesterol.72 Irradiated 7-dehydro-sitosterol has antirachitic properties, but is less active than irradiatedergosterol, and it is remarkable that the antirachitic activity ofirradiated 7-dehydrostigmasterol is either feeble or nil ; for thissterol differs from ergosterol only by the presence of an additionalmethyl group in the side chain.The isolation from natural sources of the provitamin 7-dehydro-cholesterol (XXXVI), and also its irradiation product vitamin D,,6 6 R.K. Callow, Sei. J . Roy. Co2l. Science, 1934, 4, 41.6 7 Annalen, 1935, 5f10, 98.6 * W. Wunderlich, 2. phylsiol. Chem., 1936, 241, 116.69 0.Linsert, ibid., p. 125.70 Fr. Schenk, K. Buchholz, and 0. Wiese, Ber., 1936, 69, 2696.7 1 2. phy8iOE. Chem., 1936, 2 4 , 100.72 W. Grab, ibid., 1936, 243, 84COOK: NATURAL PRODUCTS OF !EIE STEROL GROUP. 353has now been achieved. Using the method of chromatographicadsorption on alumina and working with a cholesterol of unspecifiedorigin, containing as much as 4.5% of provitamin D, estimated fromthe intensity of its characteristic ultra-violet absorption, A. G. Boer,E. H. Reerink, A. van Wijk, and J. van Niekerk 73 isolated pure7-dehydrocholesterol. Actiniasterol, a sterol isolated in the previousyear by E. Klenk and W. Diebold 74 from the fat of the sea anemone,shows very close resemblance in its recorded properties to 7-dehydro-cholesterol, except that the optical rotations, measured in differentsolvents, show considerable divergence.Vitamin D,, which hasalmost the same absorption spectrum as calciferol (XXX) andpresumably has an analogous structure, was isolated from tunny-liver oil by H. Bro~krnann.?~ This is clearly not the only naturalvitamin, however, as A. Windaus and 0. Stange 76 have nowisolated ergosterol from cholesterol prepared from egg-yolk, althoughthese authors point out that ergosterol is not necessarily synthesisedby the hen, as there is e~idence,~7 which they could corroborate,that ergosterol, fed to hens in small quantities, is gradually absorbedand appears again in the eggs. There is evidence of the existenceof other antirachitic vitamins of a type chemically distinct fromcalciferol and vitamin D,.78Bile Acids.The stereochemical relationships of the bile acids have been tosome extent elucidated. Both lithocholic acid 79 and hyodeoxy-cholic acid 80 have been shown to belong to the epicoprosterol series(hydroxy-group at C, in the trans-position with respect to the methylgroup a t C,, ; cis-fusion of rings I and 11). Presumably this is alsotrue of the other bile acids. By analogy with the varying capacitiesof lactonisation shown by stereoisomeric hydroxycyclohexanecar-boxylic acids H. Lettri: 81 concluded that the hydroxyl group at C7of cholic and chenodeoxycholic (= anthropodeoxycholic) acids is inthe trans-position to the methyl group at Clo. The validity of this73 Proc. K. Akad. Wetensch.Amsterdam, 1936, 39, 622.74 8. physiol. Chem., 1935, 236, 141.75 Ibid., 1936,241,104; see also E. J. H. Shons and T. F. Zucker, J. Amer.76 2. physiol. Chem., 1936, 244, 218.7 7 R. Schoenheimer and H. Dam, ibid., 1932, 211,241 ; W. Menschick and78 0. Rygh, Nature, 1935, 136, 552.7B I,. Ruzicka and M. W. Goldberg, Hdv. Chim. Acta, 1935,18, 668.80 0. Dalmer, F. v. Werder, H. Honigaann, and K. Heyns, Ber., 1935, 68,81 Ibid., p. 766.Chem. Xoc., 1936, 58, 2655.I. H. Page, ibid., p. 246.1814.REP.-VOL. XXXIII. 354 ORGANIU CHEMISTRY.(XXXVII.)Me I(XXXVIII. )E02C PTy i iI co-0argument is supported by recent work on ursodeoxycholic acid,which is shown to be stereoisomeric with chenodeoxycholic acid,differing from it in the configuration of the hydroxyl group at C7.82Hypobrornite oxidation of chenodeoxycholic acid (XXXVII) givesa hydroxy-tricarboxylic acid which readily passes into a lactonicacid,s8 but the hydroxy-tricarboxylio acid similarly formed fromursodooxycholic acid (XXXVIII) shows no tendency to Iacfonise :P 3Me ~-CH,--CH,--CO,HThe isolation of new bile acids has been recorded,s4 and by aconvenient new method 3'.Cortese and L. Bauman 85 have preparedthe naturally occurring conjugated bile acids, glycocholic andglycodeoxycholic acids. Recognition that the hydroxyl group atC, of the bile acids has the opposite configuration from that in thesterols has led to speculation concerning the possible mode of bio-logicd conversion of cholesterol into the bile acids.The fact thatoholestenone is hydrogenated to coprostanone and then, in neutralsolution, to epicoprosterol 86 supports the view that these ketones,which have not been isolated from natural sources, are concernedin cholesterol rnetaboli~m.~~ In attempting to secure evidence onthis point R. Schoenheimer and his collaborators have adopted theinteresting device of " labelling " the molecule by introducingdeuterium. Cholestenone (V) was reduced with deuterium, and82 T. Iwasaki, Z. phpiol. Chem., 1936, 244, 181.83 A. Windaus and A. van Schoor, ibid., 1926, 167, 181.84 H. Wieland and S. Kishi, ibid., 1933, 214, 47; W. Gumlich, d6a'd., 1933,215, 18; E. Pernholz, ibid., 1935, 232, 202; S. Kishi, dbid., 1936, 238, 210.85 J . Amer. CRern. SOC., 1935, 57, 1393; J .Bid. Chem., 1936,113, 779.86 L. Ruzicb, H. Briingger, E. Eichenberger, and J. Meyer, Hdv. C'hin~.87 Compare 0. Rosenheim and T. A. Webster, Nature, 1935, 136, 474.Actct, 1934,17, 1407.CO,COOK: NATURAL PRODUCTS OJT TEE STEROL GROUP. 356when the resulting coprostanone-4 : 5-d, was fed to animals theyexcreted coprosterol containing deuferium,B* in confirmation of theview that chole~tenons and coproatanone are intermediates in thetransformation of cholesterol into coprosterol. However, when thesame coprostanone-4 : 5-d, was injected into dogs with bile fistulas,the Cholic acid subsequently recovered from the bile contained nodeuterium, so coprostanone had passed through the liver withoutthe formation of cholic acid.8Q Naturally, this negative evidencedoes not prove that the bile acids are not formed in the body fromcholesterol, with oxidative removal of three carbon atoms from theside chain.Of interest in this connexion is scymnol, present inthe bile of sharks, for which formula (XXXIX) is probable?* Ifthe hydroxyl group at C, is carrectly placed, a poinf which has notbeen established with certainty, this alcohol would appear torepreBent an arrested stage in the transition from cholesterol to thebile acids. A compound of somewhat similar type, containing anoxidised ergosterol side chain, is trihydroxybufosterocholenic acid(XL) isolated from the winter bile of toads; this acid was ozonisedto 3 : 7 : 12-trihydroxybisnorcholanic acid,91 which was also obtainedby “ Wieland degradation” of cholic acid.K. Wieland andG. HankeQ2 have commenced a study of the weak acids of ox-bileand have isolated an acid of the probable formula C,,H,,03, whichthey term sapocholic acid. The properties of this interesting acidare very similar to those of pyroquiiiovaic particularly inrespect to the reaction with bromine, which is characteristic of the88 R. Schoenheimer, D. Rittenberg, and M. Graff, J . Biol. Chem., 1935,111,183.89 R. Schoenheimer, D. Rithnberg, B. N. Berg, and L. Rousselot, ibid.,1936,115,635.90 A. Windaus, W. Bergmann, and G. Khig, 2. physiol. Chem., 1930, 189,91 T. Shimiza and T. Oda, ibid., 1934, 237, 74; T. S k i m and T. Kazuno,9% lbid., 1936, 241, 93.93 H. Wieland, A. Hartmann, and H. Dietrich, AnnaZm, 1936, 528, 191.148; R.Tschesche, {bid., 1931, 203,263.&id., 1936, 244, 167356 ORGANIC CHEMISTRY.triterpene sapogenins such as hederagenin and oleanolic acid. Itmay be that the triterpenes have a closer structural and biogeneticrelationship to the sterol group than has hitherto been demonstrated.Sex Hormones.It is now recognised that the terms '' male and female hormones "are unfortunate, as both groups of hormones are present in both sexes,and the biological effects of a hormone are not restricted to thereproductive organs of one sex. Moreover, the same compoundmay give rise t o the characteristic biological effects of both male andfemale hormones. In general, however, the male hormones areunderstood to be those compounds of which the essential functionis to promote growth of the secondary male organs, e.g,, the combin the capon or the seminal vesicles of castrated male rats, and thefemale hormones are those which are highly potent in promotingthe normal activities of the female reproductive organs, e.g., oestrusand uterine enlargement in rodents, An extraordinarily largenumber of physiologically active compounds have been preparedby the methods made available by the work of Ruzicka,g4 and manyinteresting studies have been made of the effect of changes ofstructure and configuration on the biological activity.95 The resultshere reported must be restricted largely to an outline of the structuralfeatures of the natural hormones.The oxidation of epicholestanol to androsterone was followed bythe oxidation of sitosterol,96 ch~lesterol,~~~t o the dehydroandrosterone which Butenandt 99 had isolated frommale urine.During oxidation of the sterols the hydroxyl group wasprotected by acetylation, and the double bond by addition ofbromine. These degradations showed that dehydroandrosterone(XLI), unlike androsterone, has the cis-configuration of the hydroxylgroup with respect to the methyl a t Cloy a conclusion already drawnby W. Schoeller, A. Serini, and M. Gehrkel from the fact thatdehydroandrosterone, but not androsterone, gives an insolublecompound with digitonin. Hence androsterone cannot be formedin the body by direct reduction of dehydroandrosterone. epiDehy-g p Ann. Reports, 1934, 31, 207.96 See, for example, E.Tschopp, Arch. internat. €'harm. Thdrap., 1936, 52,9 6 R. V. Oppenauer, Nature, 1935,135,1039.97 L. Ruzicka and A. Wettstein, Helv. Chim. Acta, 1935, 18, 986; E. S.Wallis and E. Fernhole, J . Amer. Chem. SOC., 1935, 67, 1379, 1504; I. A.Remesov, Compt. rend. Acad. Sci. U.R.S.S., 1936,1, 261.9s L. Ruzicka, W. Fisoher, and J. Meyer, Helv. Chim. Acta, 1935, 18, 1483.O9 A. Butenandt and H. Dannenbaum, 8. phyeiol. Chem., 1934, 229, 192.and stigmasterol 9 8 ~381 ; R. Deanesly and A. S. Parkes, Biochem. J., 1936,30,291.Naturui.s8., 1936, 23, 337COOK: NATURAL PRODUCfTS OF THE STEROL GROUP. 357droandrosterone has recently been obtained by L. Ruzicka andM. W. Goldberg2 as a product of partial hydrogenation with anickel catalyst of A5-androstenedione (compare formula VII) .(XLII.)The unsaturated chloro-ketone which is formed from dehydroandro-sterone by the action of hydrochloric acid used in the course ofisolation 99* 3 has also been prepared from cholesteryl chloride 4and directly from dehydroandr~sterone.~Certain biological and cheinical discrepancies rendered it uiilikelythat the hormone present in testicular extracts was either andro-sterone or dehydroandrosterone.The biological evidence dependedupon differences of activity towards capons and rats and was of asimilar nature to that which led to the conclusion that calciferol wasnot the vitamin D of irradiated crude cholesterol (p. 351). Moreover,T. F. Gallagher and F. C. Koch 7 showed that the active principle ofthe testis is destroyed by boiling alkali.This suggested an ap-un-saturated ketone and led to the preparation of androstene-3 : 17-dione (XLII),8 which had the expected high activity in rats. When,shortly afterwards, the testicular hormone (testosterone) was isolatedin the crystalline state and shown not to be androstenedione,”the alternative structure of A4-androsten-17-ol-3-one (XLIV) cameinto consideration; it was known already that reduction of the17-keto-group of androsterone results in a three-fold increase inbiological activity.1° This structure was rapidly confirmed by the2 Helv, Chim. AcM, 1936, 19, 1407.3 A. Butenandt, H. Dannenbaum, G. Hnisch, and €I. Kudszus, 8. phy&ol.4 R. E. Marker, F. C. Whitmore;O. Kamm, T. S.Oakwood, and J. M.6 A. Butenandt and W. Grosse, Ber., 1936,69,2776.6 See, for example, E. Dingemanse, J. Freud, and E. Laqueur, Nature,7 Endccrimology, 1934, 18, 107; J. Bwl. Chem.., 1924, 104, 611.8 L. Ruzicka and A. Wettsteiiij Helv. China. Acta, 1935,18,986; A. Buten-andt and G. Hanisch, Ber., 1935, 68, 1859; E. S. Wallis and E. Fernholz,J . Amer. Chem. SOC., 1935,57, 1511.9 K. David, E. Dirigemanse, J. Freud, and E. Lrzquour, 2. physwl. C’hem.,1935, 233, 281.10 L. Ruzicka, M. W. Goldberg, and J. Meyer, Helv. Chirn. Actct, 1935, 18,210.Chem., 1935,237, 57.Blatterman, J. Amer. Chern. SOC., 1936, 88,338.1935,135, 184358 ORGIANIO OHEMISTRY.oxidation of testosterone to androstene-3 : 17-dione (XLII) 11 andby the preparation of testosterone from dehydroandrosterone, inaccordance with the following scheme l2 :CrO, ondibromlde, ‘followed bydebrominationaod hydrolysisThe yields were subsequently much improved by the use of mixedesters of A5-androstene-3 : 17-dio1 (XLIII).r3 This diol was shownby A.Butenandt l4 to have pronounced oestrogenic activity as wellas male-hormone action; thus a, single molecule has two types ofbiological activity which are in some respects mutually antagonistic.Even more striking is the influence of the position of a double bondon the activity of androstenedione, for, whereas the A4-compound(XLII) has powerful male-hormone activity but no oestrogenicactivity, the isomeric Al-compound (XLV) is fairly strongly oestro-genic but has no male hormone action.15(XLV.)A Ogata and S.Hirano l6 isolated from testicuIar extracts acrystalline male hormone which differs in its properties from testo-sterone. L. Ruzicka and A. Wettstein l2 have suggested that this11 K. David, Acta Brew. Nierl., 1935, 5, 85.12 A. Butenandt and G. Hrtniach, Ber., 1935, 68, 1869; L. Ruzicka andA. Wettstein, Helv. Chim. Acta, 1936,18, 1204.13 L. Ruzicka, A. Wettstein, and H. Kagi, &bid., p. 1478.l4 Nuturwhe., 1936, 24, 15.16 A. Butenandt and H. Dannenberg, Ber., 1936, 60,1158.16 J . Pham. SOC. Japan, 1934, 54, 199UOOK: NATURAL PRODUCTS OF THE STEROL GROUP. 359ia androstane-3 : 17-dione (XLVI), which can be prepared by oxid-ation of androrsterone.lO* 17The most active natural male hormone is testosterone (XLIV),which shows high activity both in capons and in rats. It was shownby Laqueur and his collaborators that testosterone displays itsmaximum biological activity only in the presence of an “X-sub-stance ” present in testicular extracts, and consequent upon investiga-tions in which it was shown that many fatty acids can replace this“ X-substance ” l8 it was shown that by esterification of testosteroneits activity may be much enhanced and also considerably prolonged.This is especially so with the esters of the lower fatty acids and themost active of these esters is the propionate,lg which is now availablefor clinical use under the name of “ perandren.” It is evident thatthe function of the fatty acid or the “ X-substance ” is to promoteabsorption of the testosterone, the optimum effect being shown byan ester of testosterone which is slowly hydrolysed with constantproduction of biologically effective quantities of the hormone.Thisview is confirmed by the observation that, although 17-methyl-testosterone is highly active, its acetate, which contains a verydifficultly hydrolysable tertiary ester group, is completelyinactive.20In attempts to isolate cortin, the hormone of the adrenal cortexnecessary for the maintenance of life, E. C. Kendall, T. Reichstein,and 0. Wintersteiner, and their respective associates 21 haveisolated several crystalline compounds, some of which are apparentlyrelated to the pregnane (C2J group of sterol derivatives. One ofReichstein’s compounds, adrenostcrone, was an ap-unsaturateddiketone, CIBHB4O3 or Cl9H2,O3, having comb-growth promotingactivity.Reichstein also showed that three of his other compoundscould be degraded to the same saturated diketone, C19H2,0, orC19H2803, which had strong male hormone action in the capon test.This diketone, for which a structure of type (XLVII) is suggested,was reduced to 17-androstanone (XLVIII) and androstanc.1’ A. Butenandt and K. Tscherning, 2. physwl. Chem., 1934, 229, 185.1* K. Miescher, A. Wettstein, and E. Tschopp, Schweiz. med. Woch., 1936,66,310; Biochem. J., 1936,30, 1970.1Q L. Ruzicka and A. Wettstein, Helv. Chim. Acta, 1936, 19, 1141; K.Miescher, A. Wettstein, and E. Tsohopp, Biochem. J . , 1936, 30, 1977; A. S.Parkes, Lancet, 1936, 231, 674.20 Statement by Dr.K. Miescher at the meeting of the Biochemical Societyon December llth, 1936.2 l H. L. Mason, C. S. Myers, and E. C. Kendall, J. Biol. Chem., 1936, 114,613; 116, 267; T. Reiohstein, Helv. Chim. Acta, 1936, 19, 29, 223, 402, 979,1107 ; T. Reichstein and A. Goldachmidt, ibid., p. 401 ; 0. Wintersheher andJ. J. PWner, J . Biol. C‘hem., 1935, 111, 599; 1938, 116, 291360 ORGANIC CHEMISTRY.A compound, C21H2805, isolated by both Kendall and Winter-steiner, 'was stated to have qualitatively the biological action ofcortin by Kendall, who degraded it to a ketone, C19H2403, havingmale hormone activity. This and other observations support theview that cortin belongs to the pregnane-androstane group." Ofinterest in this connexion is the isolation from the urine of a manwith an adrenal tumour of relatively large amounts of an unsaturatedketone, C19H260, which was hydrogenated to 17-androstanone(XLVIII).23 The unsaturated ketone has since been shown (un-published experiments) to be A3: 5-androstadien-17-one.Thiscompound could be formed, during the acid hydrolysis used in itsisolation, by dehydration of epidehydroandrosterone (comparep. 342).I n view of the confusion introduced into the earlier literaturedealing with the oestrogenic hormones by the use of many names forthe same substance it is satisfactory that the European repre-sentatives a t the Second Conference on Standardisation of SexHormones agreed 23 to adopt the following nomenclature for thesehormones : hydroxy-ketonic form = oestrone ; trihydroxy-form =oestriol ; dihydroxy-form = oestradiol.The structures of thesehormones, and also of equilin and equilenin, have been establishedin every When, for instance, the methyl ether of oestradiol22 H. Burrows, J. W. Cook, and F. L. Warren, Chem. and Ind., 1936, 55,1031.23 Quart. Bull. Hlth. Org., League of Nations, 1035, 4, 625 ; see also J . Amer.x e d . Assoc., 1936,107, 1221.24 A. Cohen, J. W. Cook, and C. L. Hewett, J., 1935,445; W. Dirscherl andF. Hanusch, 2. physiol. Chem., 1935, 233, 13; 230, 131; J. W. Cook andE. Roe, Chem. and Ind., 1935, 54, 501. * One of Reichstein's compounds (" substance H ") was stated to be anap-unsaturated ketone, C18H2101 or C2,H,,0, (Helv. Chim. Acta, 1936, 19,1107).This has now been freed from a small amount of higher-meltingcontaminant, and the pure ketone, m. p. 180-182°, was found to have in avery high degree the biological activity of the cortical hormone (P. de Fremery,E. Laqueur, T. Reichstein, R. W. Spanhoff, and I. E. Uyldert, Nature, 1937,139, 26). It is stated in this important paper that the constitution of thehormone has been elucidated except for a few details, and it is evident fromthe name, corticosterone, which these authors give to the compound, that theyare satisfied that it is a ketone of the sterol groupCOOK : NATURAL PRODUCTS OF THE STEROL GROUP. 361(XLIX) was dehydrated, and the product dehydrogenated, therewas formed 7-methoxy-3'-met hyl- 1 : 2 - cyclopentenophenant hrene(L), identical with a synthetic specimen.By these and similar reactions in which dehydration of carbinolsof type (XLIX) is accompanied by methyl migration it was shownthat the earbonyl group of oestrone, equilin, and equilenin must be atC1,, and the quaternary methyl group a t CIS.The other structuralfeatures had been proved alreadyYz5 with the exception of theposition of the ethylenic linkage of equilin, which is now placed atC7 : (compare formula XLIX).The degradation of ergosterol (XII) to oestrone (LII) has beenaccomplished by R. E. Marker, 0. Kamm, T. S. Oakwood, andJ. F. Laucius,2G who reduced Honigmann's dehydroneoergosterol(XIV) to a tetrahydro-compound (LI) in which the phenolic hydroxylgroup is still present, so that, contrary to all analogies, ringbeen reduced.7-I1 has(LIT.)Oestrone (LTI) was isolated after oxidation of the acetate of (LI)with chromic acid.These reactions demonstrate only a partialstereochemical correspondence between the sterols and the oestro-genic hormones, for it is possible (though unlikely) that the con-figurations of the carbon atoms 8 and 9 of (LII) are different fromthose found in the original ergosterol.Both stereoisomeric oestradiols (XLIX), 111.p.'~ 172" and 209",which are formed by reduction of oestrone (LIQY2' have been isolatedfrom mares' urine.28 One of these (the principal reduction product,25 Ann. 12eports, 1934, 31, 214.26 J . Amer. Chem. Soc., 1936, 58, 1503 ; see, however, A. Windaus and M.27 E. Schwenk and F.Hildebrandt, Naturwiss., 1933, 21, 177.28 0. Wintersteiner, E. Schwenk, and B. Whitman, Proc. Xoc. Exp. Bid.Med., 1935, 82, 1087; see also 0. Wintersteiner, E. Schwenk, H. Hirschmann,and B. Whitman, J . Amer. Chem. Soc., 1936, 58, 2652.Deppe, Ber., 1937, 70, 76362 ORQANIU OHEMISTRY.m.p. 172") has been isolated from the ZiquorfoZZicuZi of sows' ovaries 29and is evidently the true follicular hormone. Its oestrogenic activityis several times that of oestrone.It is unlikely that the sex hormones are present in urine in thefree state, and the water-soluble complex of oestriol has beenisolated and shown to be probably a monoglucuronic acid 30; theglucuronic acid of pregnandiol 31 has also been isolated from humanpregnancy urine.32An unexpected development in the field of oestrogenic hormoneswas the isolation from ovarian tissue by R.H. Andrew and F.Fenger 33 of a crystalline nitrogenous compound which gave adelayed but prolonged oestrous response in rats in doses of 10-5 mg.( i e . , about 1/50 of the dose of oestrone necessary for oestrogenicaction). If the formula C,,H,102N suggested by analysis is correct,this compound cannot be a tetracyclic sterol derivative.Cardiac Aglycones.The chemistry of these substances was reviewed in these Reportsin terms of the modern structures in 1934, and more recent work,mainly by R. Tschesche, has amply confrmed the main structuralfeatures, and has filled in many of the details.Digoxigenin, a digitalis aglycone containing one tertiary and twosecondary hydroxyl groups, has not been correlated with the othermembers of the group, but resembles digitoxigenin very closely.Structure (1,111) is favoured for digoxigenin, the secondary hydroxylCH,*CO\O$!=zCH'(LIII.) H 2 e p i f q H*$lvHgroup being placed at C, mainly because no other position can bereadily reconciled with the chemical proper tie^.^^R. Tschesche 35 has shown that thevetigenin differs from uzarigenin29 D.W. MacCorquodale, S. A. Thayer, and E. A. Doisy, Proc. SOC. EXP.30 S. L. Cohen and G. F. Marrian, Biochem. J., 1936, 30, 57; S. L. Cohen,31 See Ann. Reports, 1931, 28, 237.32 E. M. Venning and J. S. E. Browne, Proc. SOC. Expo Biol. Med., 1936, 34,33 Science, 1936, 84, 18; Endrocrinology, 1936, 20, 563.34 S. Smith, J., 1935, 1305; R.Tschesche and K. Bohle, Bw., 1936, 09, 793,36 Hw., 1936, 69, 2368.Biol. Med., 1935, 32, 1182; J . Biol. Chem., 1936, 115, 435.G. F. Marrian, and A. D. Odell, ibid., p. 2250.792COOK : NATURAL PRODUCTS OF THE STEROL QROUP. 363(LIV) only in the configuration of C5 ; in thevetigenin there is acis-fusion, and in uzarigenin a tram-fusion of rings I and 11, and inboth genins the hydroxyl group at C, occupies the cis-position withrespect to the methyl at Clo. Digitoxigenin differs from them inthe latter respect; the C, hydroxyl group is trans to the methyla t Cl0, and there is a, cis-locking of rings I and 11. These stereo-chemical relationships suggested that the low biological activityof uzarin is due to the trans-fusion of rings 1 and 11, and as W.A.Jacobs and R. C. Elderfield 36 had suggested a similar confiaurationfor strophanthidine and probably also periplogenin, the latterquestion was reconsidered by R. Tschesche and K. B0hle.~7 Bysubmitting di h ydrostrophant hidine to the c yanoh ydrin synthesis ,W. A. Jacobs and R. C . EIderfield38 had obtained a hydroxy-acidwhich readily undergoes lactonisation involving the hydroxyl a tC,. Tschesche and Bohle infer from models that such a lactone (LV)can only be formed if there is a cis-fusion of rings I and 11.I 4-0,(LVII.)It is concluded that both strophanthidine and periplogenin havecis-fusions of rings I and 11, and that this configuration is presentin all the highly active heart poisons of the digitalis group.Sarrnent~genin,~~ a genin from the seeds of Stroplimnthus sar-mentosus, and other species of Strophanthus which have not beenidentified with certainty, has been converted by R.Tschesche andK. Bohle40 into a saturated lactone identical with that similarlyobtained from digitoxigenin by A. Windaus and G. Stein.41 Assarmentogenin gives no precipitate with digitonin, the hydroxylgroup assumed to be a t C, should be trans to the methyl group atClo. The corresponding diketone, sarmentogenone , like digoxi-genone, contains a non-reactive carbonyl group, which is likewise36 J . BioZ. Chem., 1935, 108, 506.37 Ber., 1936, 69, 2443.38 J . Biol. Chem., 1936, 113, 625.39 W. A. Jacobs and M. Heidelberger, ibid., 1929, 81, 765; R. Tschesche,40 Ber., 1936, 69, 2497.Ber., 1935, 68, 423.41 Ber., 1928,61, 2436364 ORGANIC CHEMISTRY.placed at Cll, and it is inferred that sarmentogenin is a stereo-isomeride of digoxigenin (LIII), differing only in the configurationabout C,.It is considered likely that in digoxigenin the con-figuration of C, is that of the sterols, since the genins of the glycosidesdigitoxin and gitoxin, from the same plant, have this configuration,and that sarmentogenin has the opposite configuration. If thisconception be correct, sarmentogenin is unique among the naturalproducts related to the sterols, in that rings I1 and I11 would belocked in the cis-position.The anomalous position of scillaridin-A has been partly removedby the demonstration 42 that this aglycone contains 84 carbonatoms in its molecule and not 25 as previously supposed, and thata-scillanic acid is identical with aZZocholanic acid.43Correlation of the toad poisons with the plant heart poisons hasbeen established by the dehydrogenation of cinobufagin to 3'-methyl-1 : 2-cycZ0pentenophenanthrene.~~ Nolecular weight determinationsof cinobufagin and two derivatives, employing X-ray crystallo-graphic measurements, have shown45 tha-t, this genin has theformula C26H3406, in close relationship to bufotalin C26H3606.46Chrysene has been obtained by selenium dehydrogenation ofb ~ f o t a l i n , ~ ~ and a provisional structure (LVI or LVII) has beenassigned to bufotalin by H.Wieland, G. Hesse, and R. Huttel,4?who discuss its relationship to the other toad poisons.Essentiallythe same formulation has been proposed for cinobufagin by R.Tschesche and H. A. Offe,48 who leave open the position of theacetoxy-group and the additional double bond.Xaponins.These are glycosides of plant origin which have the property offorming colloidal aqueous solutions which foam on shaking. I naddition, they are able to effect hBmolysis of the red blood cells,even in high dilution. Few of them are known in the pure state,but the sepogenins which result from their hydrolysis have beenwell characterised. These fall into two groups, of which onecontains such triterpenes as hederagenin and oleanolic acid ; theseare dehydrogenated by selenium to mixtures of naphthalene and42 A. Stoll, A. Hofmann, and 3.Peyer, Helv. Chim. Acta, 1935, 18, 1247.43 A. Stoll, A. Hofmann, and A. Helhstein, ibid., p. 644.4 4 €I. Jensen, J. Amer. Chem. SOC., 1935, 57, 2733; R. Tschesche arid45 ID. Crowfoot, Chem. and Ilzd., 1935,54,568; D. Crowfoot and H. Jensen,46 H. Wieland and G. Hesse, Alznalen, 1935, 517, 22.4 7 Ibid., 1936, 524, 203.48 Ber., 1936, 69, 2361.13. Offe, Ber., 1935, 68, 1998.J . Amer. Chent. SOC., 1936, 58, 2018COOK : NATURAL PRODUCTS OF THE STEROL GROUP. 365picene homologues, and do not come within the purview of thisreport. The other group contains sapogenins which are relatedin structure to the cardiac aglycones and sterols; some of thecorresponding saponins occur with the cardiac glycosides in theleaves of Digitalis purpurea. The most important genins fromdigitalis are digitogenin, C,,H4405, gitogenin, c&&&,, and tigo-genin, C2,Hd403, derived from digitonin, gitonin, and tigonin,respecti~ely.4~ Sarsasapogenin, C327H4403,49 from sarsaparilla root,has also been extensively investigated. An isomeric compound,smilagenin, has recently been de~cribed.~O It is surprising that thesegenins should be related to the characteristic animal sterol,cholesterol (C,,H,,O), rather than to the phytosterols, which contain29 carbon atoms in their molecules.W.A. Jacobs and J. C. E. Simpson showed that both sarsasapo-genin 51 and gitogenin 52 give, on dehydrogenation with selenium,3’-methyl-1 : 2-cyclopentenophenanthrene and a ketone, C,H,,O,not methyl isohexyl ketone, which evidently represents a side chaincommon to these genins.The close structural relationship betweenthe three digitalis genins was shown by R. Ts~hesche,~~ who foundthat chromic acid oxidation of both gitogenin and tigogenin leads,by opening of ring I, to gitogenic acid, which was also obtained byWolff-Kishner reduction of the keto-dicarboxylic acid arising fromthe oxidation of digitogenin. Digitogenin, gitogenin, and tigo-genin confain respectively three, two, and one secondary hydroxylgroups, the remaining two oxygen atoms being present in oxiderings.54The relationship of the genins of the digitalis group to the sterolswas completely demonstrated by R. Tschesche and A. Hagedorn,55who degraded the side chain of tigogenin (LVIII) and reduced thehydroxyl group in ring I (assumed to be at C,) with the formationof aetioctZZobilianic acid (LIX).F. A. Askew, S. N. Farmer, andG. A. R. Kon 50 conclude, on the basis of surface film measurements,that the hydroxyl group of sarsasapogenin is also at C,, and not a tC,, as originally suggested by J. C. E. Simpson and W. A. Jacobs,5649 For revision of empirical formulae, see J. C. E. Simpson and W. A. Jacobs,J . Biol. Chem., 1935, 109, 573; R. Tschesche and A. Hagedorn, Ber., 1935,68, 1412.50 F. A. Askew, S. N. Farmer, and G. A. R. Kon, J . , 1936, 1399.5 1 J. Biol. Chem., 1934, 105, 501.52 J . Amer. Chem. Xoc., 1934, 56, 1424.63 Ber., 1935,68,1090; see also W. A. Jacobs and J. C. E. Simpson, J . Biol.64 compare W. A. Jacobs and E. E.Fleck, ibid., 1930,88,545; A. Windaus,56 Ber., 1935, 68, 1412.66 J . Biol. Chem., 1935, 109, 673.Chem., 1935, 110,429.2. phyeiol. Chem., 1925, 150, 205; Nach. Ge%. Wiss. Gcittingen, 1935, 89366 ORGANIC CHEMISTRY.a conclusion since supported by ohemical e~idence.~' Using themethod of Tschesohe and Hagedorn, Kon and Farmer5* havedegraded sarsasapogenin to etiobilianic acid, a result which provesthat sarsasapogenin is a ooproshne derivative, and indioates that itis stereoisomeric with tigogenin (LVIII), differing from it in theconfiguration with respeat to C,.HW(LVIII.) (LIX.)The oxidation of gitogenin to gitogenic acid shows that the secondhydroxyl group of this geain is at C, or C,, and a6 the same acid i sformed by oxidation of tigogenin (LVIII) belonging to the cholestaneseries, opening of the ring should occur between C, and C, (seep.345). This and other evidence leads to the conclusion that thesecond hydroxyl group of gitogenin is a t C,. Both tigogenin50and sarsasapogenin 5O are precipitated by digitonin, 80 that thehydroxyl group a t C, has the same configuration (cis to methyl atCI,) as in the aterols. Incidentally it is of interest that neither ofthe epimeric 4-choleaterola gives an insoluble compound withdigitonin. 59The third hydroxyl group of digitogenin is placed at C,. Theearlier work on the degradation of this genin i s reviewed by R.Tscbesche and A. HagedorrQO who interpret the reactions in termsof formula (LX). Thus tho keto-dioarboxylic acid, digitogenic acid(LXI), resulting from the chromic acid oxidation of digitogenin 61may be further oxidised by permanganate to keto-triearbozsylicacid (LXXI) in which ring I1 is opened.This is a P-keto-acid whichreadily eliminetea a molecule of carban dioxide, and by thermaldecomposition loses a secgnd molecule of carbon dioxide. Thesechanges are expressed by the following partial formulae, analogiesfor the later stages being given by the experiments of H. Lettr6,6267 Private communication from Dr. Kon.6 8 Chern. and Ind., 1936, 55, 925.59 R. Tschesche and A. Hagedorn, Ber., 1935, 68, 2247,6o Ber., 1936, 69, 797.61 See, for example, €1. KUei, Rer., 1916, 49, 701; 1918, 51, 1613; A.Windau ctnd K. Wed, Z. p h y 8 W Chem., 1922, 121, 62; -4. Windaus aridU. Willerding, ibid., 1925, 143, 33.g* Ibid., 1933, 218, 67; 221, 73TURNER : HETEROCYCLIC COl@OtTNDS.367who, for example, obtained an unsaturated hydrocarbon bypyrolysis of a keto-acid of type (LXIII) formed by oxidation ofA5- cholestene :(LXI.)(LXIII.)The evidence for the structure of the side chain present in this groupof sapogenins (see formula LVIII) has been summarked by L. F.Pieser 1 (p. 341), in which connexion reference should also be madeto the critical discussion by Tschesche and Hagedorn.60By no means the least interesting development in the chemistryof the sterol group is the recognition that there is a class of alkaloidscontaining the sterol ring system, the side chain a t C,, being utilisedin the formation of heterocyclic systems containing nitrogen.'Reference to these compounds is made in another section of thisReport.J.W. C.8. HETEROCYCLIC COMPOUNDS.Large Oxygen Rings.-Large rings containing oxygen have beenprepared for the first time by M. Stoll and W. Scherrer.1 The mono-sodium derivative of tetradecane-1 : 14-diol was treated with oneequivalent of benzenesulphonyl chloride, and the resulting ester (1)was treated with sodium in boiling benzene (the sodium, to be effec-tive in this reaction, must be very finely divided, and the authorsprepared it by passing strictly dry ammonia into a mixture of sodiumand toluene, cooled in ether and solid. carbon dioxide. When themetal had dissolved, the ammonia was allowed t o evaporate; thesodium slowly formed very reactive, minute crystals).Under theseconditions, the benzenesulphonyl derivative passes into its sodiumderivative (II), which partly cycfises to 1 : 14-0~idotetradecane(oxacyclopentadecane) (111). Since (11) can only be formed S ~ O W ~ J T ,Helv. Chim. Acta, 1936, 19, 735368 OR(3 ANIC CHEMISTRY'.(I) has plenty of time to undergo side reactions, e.g., to give (IT).As a result, the yield of (111) is poor.OH*[CH,],4*ONa + Ph*S02C1 + OH~[CH,],,*O*SO,Ph (1.)Ph*SO,Na + ICH2]1z<~3>0 (In.)1 NaO [ CH,],,*O*SO,PhNaO*[CH,],,*O*[CH,],,*O~SO,Ph (IV.) 4 (11.12OH*[CH,],,~O*SOzPh G+=OH*[CH2],,*OH + Ph*S0z*O*~CH,]l,*O~S02Pl~ -+ (1V)A second method was to begin as follows :OH*[CH,],*O*[CH2]10~C0,Me --+ C1[CH,],~O~[CK,]10*C02Me --+(CO,Et),CH*[ CH,],*O*[CH2]lo*C0,Me -+Distillation of the cerium salt of the acid (V) gave 1 : 15-oxidopenta-decan-&one (VI), and this was reduced by the Wolff-Kishner processC02H*[CH,],*O'[CH,],o.Co,H (v.)to 1 : 15-oxidopentadecane (oxacycZohexadecane) (VII).The twooxacyclocompounds are low-melting solids, with a very feeble musk-like odour ; the oxide-ketone (VI), which is isomeric with " exalto-lide " (5-hydroxypentadecoic acid lactone),, has a powerful odour ofmusk, although of a modified type.G. Salomon3 has considered the kinetics of the formation of largerings of the cyclic imine and lactone series.Naturally Occurring Oxygen Ring Compounds.-Psoralene, fromthe oil of Phoralea cory-lijolia seeds, is (VIII), since the usual degrada-tive methods (methylation ; oxidation ; methylation), lead to methyl4 : 6-dimethoxyisophthalate (IX) . A substance, ficusin, apparentlyidentical with psoralene, has been extracted by K.Okahara fromthe leaves of Picus carica.(VIII.) (IX. 1 (X.1Xanthotoxin, isolated from Fagara xanthoxgloides and variousRzctaceae, is the methoxy-derivative (X) of psoralene (ficusin) .62 L. Ruzicka, and M. Stoll, HeZv. Chim. Acta, 1928, 11, 1159.4 E. Spiith, B. L. Manjunath, M. Pailer, and H. S. Job, Bey., 1936, 69,6 BuU. Chem. SOC. Japan, 1936,11, 389.Ibid., 1936, 19, 743.1087.E. Spiith and M. Pailer, Ber., 1936, 69, 767TURNER : HETEBOCYCLIC COMPOUNDS. 369H. Raistrick, R. Robinson, and D. E. White 7 have investigated ayellow pigment, ravenelin, produced during the metabolism of theplant Helminthsporium Waoendii, Curtis, and of H .Turcicum,Passerini. The pigment is shown to be 1 : 4 : 8-trihydroxy-3-methylxanthone (XI), and is the third hydroxyxanthone to be isol-ated from natural sources, euxanthorie and gentisin being the othertwo representatives of this class.Phenuxthionin.-It has been shown * that bromination, sul-phonation, and condensation with acyl chlorides (Friedel-Crafts)occurs in the 2-position in phenoxthionin (XII), the orienting effectof the oxygen thus outweighing that of the sulphur.Reduced Dipyridinobenxenes.-Some interesting results have beenobtained by P. Ruggli and A. Staub.9 When m-phenylenediacrylicacid is nitrated, 4-nitration occurs (contrast cinnamic acid).Re-duction of the nitro-compound (XIII) is unaccompanied by cyclis-ation, suggesting that the amino-acid (XIV) has the trans-configur-ation. Methyl m-phenylenediacrylate also gives only onenitro-derivative (as XIII), which, catalytically reduced, (a) in thecold, gives the methyl ester of (XIV), and ( 6 ) in the warm, givesmethyl 2-ketotetrahydroquinoline-6-propionate (XV), ring closureoccurring spontaneously .C O,H*CH: CH()!C$:CH*C 02H C 0,H CH : CH():CH&CH* C 0 $12(XiII.) (XIV.)CH,(XVI.)CO,Me*CH,-CH,(xv.) NHIn order to introduce a second nitro-group at the outset, it was foundnecessary to reduce the m-diacrylic ester to the m-dipropionic ester.The latter was readily dinitrated to give (XVI). Reduction of thisester, curiously enough, produced (XVII), and in order to effect7 Biochem.J., 1936,30, 1303.8 C. M. Suter, J. P. McKenzie, and C. E. Maxwell, J. Amer. Chem. Soc.,9 Helv. Chim. Acta, 1936, 19, 439.1936, 58, 717370 ORGANIC CHEMISTRY.ring closure in the 6 : 7-positions it was necessary to heat (XVII) to260°, or to treat it with boiling hydrochloric acid for some time. Theproduct (XVIII) was unaffected by distillation with zinc dust, andCH, CH,C02Me*CH2*CH2 @c3 H2?A(x>c" coNH2 oc\ NH NH NH( XVII . ) (XVIII. )(XIX.)the well-known method of reduction, starting with NHGO _jN:CCl, could not be applied. Recourse was made to the classicalreduction with phosphorus and hydriodic acid under pressure,but even this reaction only gave good results within a very narrowtemperature range.The reduced dipyridinobenzene (XIX) obtained' is a-crystalline solid.E. E. T.9. ALKALOIDS.Peganine ( Vasicine) .-The optical resolution of peganinc wasoffected by E. Spath, F. Kuffner, and N. Platzer,l who thought thealkaloid probably existed in the active condition in PeganumIzarmZa, but did not succeed in isolating it as such. A. D. Rosenfeldand D. G. Kolesnikov found that the active alkaloid can be ex-tracted from the plant, and in their later paper regard their productas probably identical with the Z-peganine isolated by E. Spath andP, Kesztler from Adhatoda vasim, Nees.A simple synthesis of peganine (I) has been described : 4The interesting work of Schopf and his co-workers on synthesesunder physiological conditions " has been extended to vasicine.5It is found that o-aminobenzaldehyde, allylamine, and formaldehyde,1 Ber., 1935, 68, 1384.2 Sixth Mendele'eff Congress, 1932 ; Ber., 1936, 69, 2022.a Ber., 1936, 69, 384.4 E.Spiith and N. Platzer, ibid., p. 255.6 C. Schopf and F. Oechler, Annalen, 1936, 523, 1TURNER : A L W f D S . 371c( )+c~H~*cH:cH~NHwhen left together in aqueous solution for three days at 2 5 O , condenseas in the annexed scheme, the product (11) behg ieolated in 73%yield as the picrate :r CH*OH 1+J RCOH(11.1'S.CH2* CH:CH2a : H a NHN€I,-GE,-CH:UHt and H.CO,H ~ (y~m*cH2nca:cH2The synthesis begins at pH 4.8 and ends at pE 5.2, and proceedssimilarly in phosphate-buffered solution at pE 7. The constitution of(11) is proved by the oxidation of its picrate to the picrate of 3-allyl-4-quinazolone, prepared independently from isatoic anhydride :R.CJOIE $hen heat co 1Moreover, the oxidation of /'H2 to vbH can be effected\I3under physiological conditions, by using potassium f erricyanideand a phosphate buffer at pE 7 at the ordinary temperature.It is concluded that the actual bioksynthesis of vasicine probablyoccurs between o-aminobenzaldehyde and y-amino-a-hydroxybut-aldehyde :CHaOHCH-OHf372 ORGANIC CHEMISTRY.Since the aminohydroxybutaldehyde is unknown, the authors carriedout the analogous synthesis (citrate buffer, 4 days, p3 5) :and obtained (111) in 75-78y0 yield, as the picrate.Its constitutionwas established by its oxidation to the known compound (IV).Further, if a condensation mixture containing (111) was shaken withpalladium and hydrogen, the originally yellow solution was decolor-ised and deoxyvasicine (V) could be isolated in 18% yield, suggestingthat biogenetic synthesis probably proceeds along these lines.Theauthors think it likely that the precursor in the plant of the o-amino-benzaldehyde is tryptophan, and that of the y-amino-a-hydroxybut-aldehyde is hydroxyornithine :1c /CHO*CH( OH)*CH2*CH2*NH2 CHO*CH( OH)*CH,*CO,HC. Schopf and G. Lehmann' had already suggested that thehydroxytropine (VI) isolated by 0. Wolfes and H. Hromatka 8 fromcocaleaves owed its biogenetic synthesis to malic dialdehyde, and this,and the aminohydroxybutaldehyde, would both come from hydroxy-ornithine.This may be compared with the derivation of hygrineand cuskhygrine from ornithine.Lupin AZkaloids.-in 1931, G. R. Clemo and G. R. Ramage9synthesised octahydropyridocoline (VIII) by performing a Dieck-mann condensation on (VII). The product was not identical withnorlupinane (A) obtained from lupinine.l* Later,ll however,6 R. C. Momis, W. E. Hanford, and R. Adams, J . Amer. Chem. Soc., 1935,67, 961.Annulen, 1935, 518, 1.J., 437 ; Ann. Reports, 1931, 174.8 Mercks Jahresber., 1934, 47, 45.lo G. R. Clemo, G. R. Ramage, andR. Raper, J . , 1931, 437, 3190.l1 Idem, J., 1932, 2959TURNER : ALKALOIDS. 373qHz vH*CO,EtCH, NCH,*CH,*CH,*CO,Et (VII.)\ /CH,norlupinane (A) was obtained by cyclisation of (IX) and morerecently 12 as follows :@\CH,*CW2*CQ,Et(X-1 I ll~*c~z*C()2E~ CH, N-CH,*CO,Et \/- BrCH, CH,p 2 QH-QH2CH, N CH, HC1 CH, N CO (XI.) ( V J q +zcg 9H2 ’\’ QH )H2\ / \ / CH, CH,\ / \ /CH, CHMeThis dismisses the possibility that norlupinane (A) is (XI), and sub-stantiates the &-trans relationship of the two octahydropyridoco-lines (VIII) obtained from (VII) and froin (IX) or (X). It has beenestablished by synthesis l3 that dl-oxysparteine is (XII).K. Winterfeld and H.E. ROnsberg,l4 by oxidising a-didehydro-sparteine with chromic anhydride, have isolated p-aminopropionicacid, which is regarded as indicating the presence (see XIII) of a4 : 5-ethylenic linkage in the norlupinane ring of sparteine. Whendidehydrosparteine is treated with benzoyl chloride and alkali, anunstable benzoyl derivative is formed, suggesting tKat the secondethylenic linkage is in the ccp-position to a nitrogen atom, and isjoined t o a tertiary carbon atom.This corresponds with unsatur-ation at C9-Cll or Cll-C12.12 G. R. Clemo, W. McG. Morgan, and R. Raper, J., 1935, 1743.l3 Idem, J., 1936, 1025.1 4 Arch. Pharm., 1936, 274, 48374 ORGANIC CHEMISTRY,Ergot Alkaloids (continued from Ann. Reports, 1935, 345).-In anexamination of their proposed constitution of lysergic acid, W. A.Jacobs and L. C. Craig l5 synthesised 3 : 4 : 5 : 6-tetrahydro-4-carboline-5-carboxylic acid and 3-phenyl-4-methyltetrahydro-4-carboline-5-carboxylic acid. These substances did not respond totests characteristic of lysergic acid.Later,16 a new formula wassuggested for this substance, since the tribasic acid, Cl,H,OsN,previously described l7 gave quinoline when it was distilled withsoda-lime. The same authors have confirmed their previousconclusion that ergotamine, and therefore ergotaminine, are de-rived from ergine, proline, phenylalanine and pyruvic acid. Theyhave also isolated d-proline (as its methyl ester) by hydrolysis notonly of ergotamine but also of ergotoxine. Ergoclavine is given thenew formula C,6H,o04N4. It is possible that this alkaloid is built upfrom ergine, I-leucine and pyruvic acid, but very little is really known,S. Smith and G. M. TimmisZ0 have shown that ergometrinine,like ergometrine, is lysergic acid hydroxyisopropylamide. The sameauthors 21 have obtained from ergot a new alkaloid, ergosinine,l5 Science, 1935, 82, 421.l6 Ibid., 1936, 83, 38.l7 J.Biol. Chem., 1932, 97, 739.I* J. Org. Chem., 1936, 1, 245.8o J., 1936, 1166.Science, 1936, 81, 256.Nature, 1936, 187, 111, 1075TURNER : ALKALOIDS. 375C&0HQ505N5, which is converted by acids into the isomericergosine.R. L. Grant and S. Smith 22 have found that ergometrine exists intwo physical forms.G . W. Holden and G. R. Diver 23 have isolated from ergot yetanother alkaloid, ergomonamine, C,9Hl,0,N, and an acid (citergic),which may be ccccpy-tetrahydroxypropane-a&-tricarboxylic acid.It is now agreed 24 that ergometrine, ergotocine, ergobasine andcrgostetrine are identical.S. Smith and G. M. Tirnmisz5 have used conditions (hot alcoholicphosphoric acid) under which ergotinine changes into ergotoxinefor the conversion of ergine ([0(]5461 + 635", in pyridine) into the newisomeric base, isoergine + 2 5 O ) , and conclude that the physio-logically active (lavorotatory) alkaloids ergotoxine, ergotamine,and ergometrine contain the isoergine structure. They furthershowed that alkalis rapidly isomerise ergine and isoergine to anequilibrium mixture.Again, using the conditions (action of pyrid-ine, or hot methyl alcohol, or hot ethyl alcohol, or sodium hydroxide)effecting the change of ergotoxine into ergotinine, or, better, by theaction of hot water, the authors have succeeded in converting lysergicacid into an isomeride, isolysergic acid. The latter has [a]5461 +365", as compared with [a15461 + 49" for lysergic acid.Possiblepartial formulae are suggested for lysergic acid, based on one putforward, but since rejected, by W. A. Jacobs and L. C. Craig.26W. A. Jacobs and L. C. Craig 27 altjo point out that the existenceof the pairs of ergot alkaloids depends on the ethylenic linkage inlysergic acid, since, while methyl lysergate mutarotates in warmmethyl-alcoholic solution, its dihydro-derivative does not. A freshmethod of attacking the problem is described by these authors, whohave obtained one and the same lysergic acid by hydrolysing anyof the alkaloids, whether of the dextro- or of the Iavo-rotatory class,On the other hand, reduction (2H) of the lavorotatory alkaloidsergotoxine, ergotamine, and ergometrine, followed by hydrolysis,gave a laevoro tatory acid, called a-diliydrolysergic acid ; similartreatment of the dextrorotatory alkaloids ergotinine and ergota-minine and also of ergine gave a dextrorotatory acid, .y-.dihydroly.sergic acid.Lysergic acid is not a mixture, but when it is reduced,23 Nature, 1936, 137, 154.23 Quart. J . Pharm., 1936, 9, 230.24 M. S. Kharasch, H. King, A. Stoll, and M..R. Thompson, Nature, 1936,2 5 J., 1936, 1440.26 J . Bid. Chem., 1936, 113, 771.2 7 Ibid., 115, 227.137, 403; Science, 1936, 83, 206; Ann. Reports, 1935, 349376 ORGANIC CHEMISTRY.it gives a mixture of the above t(- and y-dihydro-derivatives. Theauthors conclude that in this reduction new centres of asymmetryare produced, and suggest that lysergic acid isCH2*CH*Co2H (XIV), since this best accounts for the pro-stability of lysergic acid in presence of alkali.The above a-dihydro-acid (from ergotoxine))=Jm2 was identical with that previously obtainedby reducing lysergic acid with sodium andamyl alcohol; its methyl ester, on reductionwith sodium and butyl alcohol, gave a-di-hydrolysergol ; but methyl y-dihydrolysergate, similarly reduced,gave a new substance, y-dihydrolysergo1, different from thep-dihydrolysergol obtained previously from ergotinine.Neithermethyl a- nor y-dihydrolysergates gave p-dihydrolysergol onreduction.Aconitine.-Some advance hats been made in the chemistry of thisdifficult alkaloid. A. Lawsoii 28 has oxidised aconitine with chromicanhydride in acetone solution, and obtained a new substance,aconitoline, C,,H,,O(NMe)(OH)(OMe),(OAc)(OBz).The author'sresults support the formula C,2H,,01,N of E. Spiith and F. Galinov-sky 29 for oxonitin. W. Freudenberg and E. F. Rogers 3O showedthat dry distillation of aconitine hydrochloride with barium hydr-oxide gave hydrocarbons, methylamine, and Z-ephedrine, the struc-ture of the last therefore probably being present in aconitine. Ithas usually been assumed that aconitine contains the NMe group,but it is now found 31 that when aconitine hydrochloride is fused withpotassium or barium hydroxide, ethylamine is formed, and whenaconitine is heated with hydriodic acid ethyl as well as methyl iodideis obtained. It is thought that the NEt group is affected when aconi-tine is oxidised to oxonitin.This would fit in with the observedformation of acetaldehyde during this oxidation. W. Freudenberg 32has also identified ethylamine among the products of distillingaconitine with barium hydroxide, and gives the alkaloid the formulaVeratrurn Alkaloids.-B. K. Blount 33 showed that the verine ofC. R. A. Wright and A. P. Luff 34 was identical with cevine (veratrid-ine being veratroylcevine) , and that cevine, when dehydrogenateddH2 \ NMe duction of two dihydro-derivatives, and for the/=\ / / \-\ / NHCl~H19(NEt)(oH)3(oMe),(BAc)(oBz)'2B J., 1936, 80.30 J . Amr. Chem. Xoc., 1936, 58, 533.31 W. A. Jacobs and R. C. Elderfield, ibid., p. 105.9.32 Ber., 1936, 69, 1962.s3 J., 1935, 122.s4 J , , 1875, 33, 341.Ber., 1930, 63, 2994; 1931, 64, 2201TURNER : ALKALOIDS. 377with selenium, ga've a base, cevanthridine, possibly a phenanthridinederivative. I n conjunction with (Miss) D.Crowfoot 36 the sameauthor isolated cevanthrol, a phenol, from the dehydrogenationmixture, and concludes further, fro& X-ray crystallographicalexamination, that cevanthridine contains a benzphenanthrenc (XV)or benzanthracene (XVI) structure. The authors regard the con-ditions employed in the dehydrogenation as insufKciently drastic tobe conducivc to ring enlargement, that is, they appear t o have con-sidered, but rejected, the idea that cevanthridine might contain amet hylcyclopentenophenanthrene skeleton.Veratrzcm album (white hellebore) contains the alkaloid jervine,NH:CaF;H,,(OH)(CR,O,:), and amorphous materials of various kindsfrom which both angelic and tiglic acids have been is0lated.~6Heliotropium and Senecio AZkaEoids.-G.Menschikov 37 isolatedfrom HeZiotropium Zasiocarpum an alkaloid heliotrine, C,,H,,O,N,which by the action of barium hydroxide gave heliotric acid,OH*C,H,,( OMe)( CO,H) (a saturated aliphatic acid), and heliotridine,C,H1,O,N. The latter 38 contains two hydroxyl groups, replace-able (thionyl chloride) by two chlorine atoms. The (unstable)dichloro-compound was converted by a series of simple reactionsinto heliotridan, C,H1,N. Later work showed that heliotrine wasreducible to hydroxyheliotridan, which was probably a tertiarya,l~ohol,3~ and that heliotridan contained a pyrrolidine ring.40 Thesame author, with V.Rubinstein$l has also isolated from Tri-chodesma incanum the alkaloid trichodesmine, C18H,,Q,hT. Thiswith alkali gave methyl isobutyl ketone, dl-lactic acid, and a sub-stance, C,W130,N, trichodesmidine, which was not identical withheliotridine, but was convertible by simple reactions into helio-tridan. Heliotridine and trichodesmidine therefore differ in theposition of the hydroxyl group and possibly also that of the ethyleniclinkage. Later 42 it was found that lasiocarpine, a second alkaloid35 J., 1936, 414.38 K. Saito, H. Suginome, and M. Takaoka, Bulb. Cizern. SOC. Japan, 1934,9, 15; K. Saito and H. Suginome, ibid., 1936, 11, 168; K. Raito and M.Takaoka, ibid., p. 172.3 7 Ber., 1932, 65, 974.38 G.Menschikov, Ber., 1933, 66, 875.39 Ber., 1935, 68, 1081.40 Ibid., p, 1555.42 G. Menschikov and J. Schdanowitsch, Ber., 1936, 69, 1110.*l Ibid., p. 2039378 ORQANIO CHEMISTRY.from Heliotropiurn lasiomrpum, was hydrolysed by alkali to angelicacid and heliotridine. I n heliotrine, only one hydroxyl group ofheliotridine is esterified (with heliotric acid) , whereas in lasiocarpineone hydroxyl group of heliotridine is esterified with angelic acid andthe other with lasiocarpic acid, C8H,,05 : this is an unsaturated acidcontaining two hydroxyl and two methoxyl groups.Xenecio pZatyphyZlus contains two alkaloids, platyphylline,C18H2,05N, and ~eneciphylline.~~ Platyphylline on alkaline hydro-lysis gave platynecic acid, OH*C,H,,0*C02H, and platynecine,C8Hl,N(OH),. The two hydroxyl groups can under certain con-ditions be replaced by chlorine, and by simple reactions the authorsconverted the dichloro-compound into heliotr idan.Apparentlyseneciphylline is also derived from this substance. The Boraginucece(Heliotropium) and Senecio alkaloids therefore contain the sameC8H15N skeleton and differ in their degree of unsaturation, theposition of the hydroxyl groups, and the nature of the attachedacids.Solanum Alkaloids.-Solanidine-t (from the potato, Solanurntuberosum), when heated with selenium, gives phenanthrcne, chry-sene, and pyridine, together with other c0rnpounds.4~ A. Soltys andI<. Wallenfels 45 have shown that solaneine, described as occurringwith solanine, solanidine, and solanthrene in S.tuberosum, is amixture of solanidine and solanine. Having found that solanidinegives a flocculent precipitate with digitonin in alcoholic solution, areaction characteristic of sterols, they further found that seleniumdehydrogenation of solanidiene (obtained by elimination of waterfrom solanidine) gave methylcyclopentenophenanthrene. Fromthis, it follows that solanidine-t is (XVII), and the authors thinkthat a possible formula for the .alkaloid is (XVIII).OH( / g q ? 1 5 N /\yjjg)O I I C XVIII . ) ( XVII . ) O I I V J (XVIII.)Solanidine-s, from S. sodomaurn, contains structure (XIX),46 afact which explains the formation of ‘‘ tetra-acetylsolanidine ” when43 A. Or&hov, Ber., 1935, 68, 650; A.Or6khov and R. Konovalowa,ibid., p. 1186; R. Konovalowa and A. OrBfiov, Ber., 1936, 69, 1908.44 H. Dieter10 and H. Rochelmeyer, Arch. Pibarn., 1935, 273, 532.4 5 Ber., 1936, 69, 811.48 cf. Oddo and G. Caronna, {bid., p. 283TURNER : ALKALOIDS. 379the alkaloid is treated with a mixture of glacial acetic acid, aceticanhydride, and concentrated sulphuric acid :CXHc,,F126<~H*0H 4 c , AcQH.(XIX.)Eblanum pseudocapsicurn (winter cherry) may, 1 ike other Xolanums,contain a gluco-alkaloid, but this is not settled. The new alkaloids,solanocapsine, C25H4,O2N2 or C,,€I,,O,N,, and solanocapsidine,probably C2BH4204N2, have been isolated from it, and the former hasbeen i~ivestigated.~’ Solanocapsine contains NH, NH,, and OH(probably as iC*OH), the second oxygen probably being a member ofa heterocyclic ring.With nitrous acid, the NH is nitrosated, thearnino-group becomes h ydroxyl, one hydroxyl group, probably theone originally present, is eliminated as water, and an ethyleniclinkage is formed. Selenium dehydrogenation of solanocapsinegives hydrocarbons, pyridine bases, and methylcyclopentenophen-anthrene. This suggests that the struetiire of the alkaloid is Lzppros-imately expressed by formula (XX).The position of the ring oxygen atom recalls the oxygen bridge incertain saponins of Solangustidine, c27H4302N,49 differsfrom solanidine-t in having an extra oxygen atom, and in solano-capsine this difference is increased by an additional nitrogen atom(amino-group).I. Z. Saiyed and D.D. Kanga 50 have isolated from Solanurnxanthocarpum a sterol, C,,H5,0 (carpesterol) , an alkaloid, solan-carpidine, C26H,,0,N, and aC44H77019N, which, on hydrolysis,rhamnose, and (probably) galactose.gluco-alkaloid, solancarpine,gives solancarpidine, glucose,I d o l e Derivatives.-A base, gramine, was isolated from a chloro-phyll-defective strain of barley by H. voii Euler and H. Hellstrom.514 7 G. Barger and H. L. Fraenkel-Conrat, J . , 1936, 1537.48 Cf. J. C. E. Simpson and W. A. Jacobs, J . Biol. Chem., 1935, 109, 573;4s F. Tutin and H. W. B. Clewer, J., 1914, 105, 559.60 Proc. Indian Acad. Sci., 1936, 4, 283.61 Z . physiol. Chem., 1933, $217, 23.n. Tschesche and A. Hagedorn, Ber., 1935, 68, 1412; 1936, $9, 797380 ORUANIC CHEMISTRY.It was later thought to be identical with donaxine, isolated 52 fromArundo donax, and regarded as (XXI), but no proof of constitutionwas put forward. T. Wieland and C. Y. Hsing 53 have synthesised5-me thoxy- 3-dimethy laminome t hylindole (XXII) , which appears tobe identical with gramine, although the methiodide has a muchhigher melting point than that of the natural substance :+ CNC13,*NRle2 -+ CN*MgINHOMe(&CH2*NMe, (XXII.)-tNHTobacco Allca1oid.-Myosmine (XXIII), one of the tobacco a&a-loids, has been synthesised s4 as follows :NHN(XXIII.)isoQuinoliiae Alkaloids.-A synthesis has been recorded 55 of dl-bicuculline (XXIV), the d-form of which was isolated by R. H. F.Manske 56 from Dicentra cuczdlaria, Adlumia fungosa, Corydalissempervirens, and C . aurea.(XXVI.)O-CH,(XXIV.) (XXV.)52 A. Or6khov and S. Norkina, Ber., 1935,68, 436.53 Annalen, 1936, 528, 188.54 E. Sp&th and L. Mamoli, Ber., 1936, 69, 757.55 P. W. G. Groenewoud and R. Robimon, J., 1936, 199.56 Carutd.ian J . Res., 1932, 7, 258, 265; 1933, 8, 142TURNER: VITAMIN B1 (ANEURIN) AND THIOCHROME. 381It has been stated 57 tha6 the compound obtained " under physio-logical conditions " by G. Hahn and 0. Schales 58 is not (XXV) but(XXVI). The last-named authors 59 have, however, repliedsatisfactorily to the criticism.Tropinone Derivative.-Although there are many recorded casesin which Claisen coiidensations between carbonic esters and ketonesor ketonic esters have given very indifferent yields, it has now beenfound 6o that tropinone reacts vigorously with methyl or ethylcarbonate in presence of sodium or potassium, preferably when benz-ene or xylene is used as a medium. It thus becomes possible toprepare tropinonecarboxylic esters quickly and in good yields.E. E. T.10. VITAMIN B, (ANEURIN) AND THIOCHROME.Vitamin B, (I) has been synthesised by R. R. Williams and J. K.Cline1, according to the scheme :E G O E tC02Et*CH2*CH2* OEt --A COZEt *CH (CHO)*CH,*OEtNN hle0NtidJlr N CH,BrSSJ N AThe chloride was identical with the natural substance in ultra-violetabsorption and antineuritic potency, but had a melting point of232-234", whereas the natural product melts at 246". Possiblythe latter is a mixture of stereoisomeridea.6 7 E. Spath, F. Kuffner, and F. Kesztler, Ber., 1936, 69, 378.68 Ber., 1936, 68, 24. 68 Ber., 1936, 69, 622.80 N. A. Preobrashenski, M. N. Schtschukina, and R. A. Lapina, ibid.,J . Amer. Chem. Soc., 1936, 58, 1504. p. 1616382 ORUANIU CHEMISTRY.A. R. Todd and F. Bergel proposed formula (11) for thiochrome(obtained by the action of alkaline ferricyanide3 or of alkali aloneon aneuria) and later, with H. L. Frrtenkel-Conrat and Miss A.Jacob,5 effected its synthesis :60 XO,Et M0gE2*C0,Eti -~,,kX2*C0*N3NH, H*CH2*C0,EtNNH/CHONS CH,*C02*CH,*CH2Rr + CH,*CO*CHNa*CO,Et - .1 A NH,*sH fi*CH,*CH2*OHE-CMeCH,*C0,*CH2*CH2*CH( C02E t)*CO*CH,OH*CH,*CH,*CHCl.CO*CH,The encl-product of the synthesis was in all respects identical withthiochrome as obtained from vitamin B,.E. E. T.W. BAKER.J. w. COOK.R. D. HAWORTK.E. L. HIRST.R. P. LINSTEAD.S. PEAT.E. E. TURNER.2 J., 1936, 1559.3 G. Barger, F. Bergel, and A. R. Todd, Ber., 1935, 68, 2257.* R. Kuhn and H. Vetter, {bid., p. 2376. * J., 1936, 1601