ORGANIC CHEMISTRY.1. INTRODUCTION.A GREAT volume of work continues to appear and the task of Reporters is notmade easier by a growing tendency for authors to disclose researches in apreliminary way and subsequently to give a full account of the same work.Sometimes the results are so significant that notice must be taken of thepreliminary account but more sparing use of this form of publication would bewelcomed.The topics dealt with in the theoretical organic chemistry section of thisyear’s Report were last reviewed in 1951. In the intervening year thefocus of current interest seems to have centred mainly upon stereospecificfeatures of chemical change. This is significant in connection with theGrignard reaction, with elimination reactions of homocyclic compounds, andwith rearrangement reactions of saturated molecules.In the two years that have elapsed since stereochemistry was last reviewedmuch significant work has appeared, and the importance of modern ideasconcerning the conformations of cyclic compounds is evident in all recentwork on homocyclic compounds, including steroids, and also in carbohydratechemistry.Attention may be drawn to the recent agreement to refer to“ equatorial ” and “ axial ” bonds and to drop the overworked term “ polarbond ” from the vocabulary of stereochemistry. Prelog’s elegant applicationof McKenzie’s pioneer work brings a welcome refinement to the diagnosis ofstereochemical configuration, and Cram’s treatment of asymmetric inductionis simple in its appeal and convincing in its results.Further examples ofmolecular dissymmetry have been discovered, the most striking being thatof 9 : 10-dihydro-3 : 4-5 : 6-dibenzophenanthrene with its surprisingly highrotation and optical stability.Steady progress is being made in the study of unsaturated long-chaincompounds and a number of novel acids have been isolated from naturalsources. Considerable, though not spectacular, advances continue to berecorded in aromatic chemistry, experimental work providing quite a fewinstances in which the structural wave-mechanics theories fail to accountadequately for observed chemical reactivity. Many outstanding problems ofterpene chemistry are being rapidly solved. A prodigious amount of work ofuniformly high quality continues to appear on steroids; much of it centresstill around cortisone and the introduction of oxygen substituents into the11-position, but one may note in particular a new and strikingly simple totalsynthesis leading to ( &)-e+iandrusterone, in which six asymmetric centresare created stereospecifically in virtually one operation.The biogenesis of porphyrins has been considerably clarified during theyear and a chemical synthesis of sucrose has been announced. Perhaps themost outstanding accomplishment, however, has been the elucidation of thestructure and the synthesis of oxytocin, which will surely rank for manyyears as one of the greatest achievements in peptide chemistry.J.W.W. A. WWATERS AND DE LA MARE: THEORETICAL ORGANIC CHEMISTRY.1252. THEORETICAL ORGANIC CHEMISTRY.A noteworthy feature of the year under review has been the appearanceof a number of books which have greatly clarified modern viewpoints inregard to theoretical aspects of organic chemistry. Outstanding amongstthese is undoubtedly C. K. Ingold’s “ Structure and Mechanism in OrganicChemistry ” which gives a comprehensive, fully referenced survey ofmechanisms of heterolytic reactions in the terminology of the very activeresearch school of University College, London. Structural organic chemistryis also dealt with in J. M. Robertson’s “ Organic Crystals and Molecules ”which, like Ingold’s treatise, also has as its basis a series of G. F. Bakerlectures at Cornell University.Implications of the modern mathematical approach to organic chemistryhave been summarised by M.J. S. Dewar in a chapter in Volume I1 of theEnglish series “ Progress in Organic Chemistry.” Two further volumes of“ Organic Chemistry,” * the well-known advanced treatise edited by H.Gilman, have been published in the U.S.A. In these the American viewpointin regard to organic reaction mechanisms has been set forth by P. D. Bartlett,and there is a chapter on mechanisms of oxidation processes by W. A. Waters.A chapter by F. A. Miller on “Applications of Infra-red and Ultra-violetSpectra to Organic Chemistry ” also deserves mention since it meets the realneed of the experimentalist by providing a concise guide to the interpretationof modern spectroscopic measurements.Two books from the previous year are also significant : “Valence ” byC.A. Coulson is a non-mathematical account of applications of wave-mechanics to structural organic chemistry, whilst J. W. Baker’s “ Hyper-conjugation ’’ details critically the experimental evidence in support of thisparticular theory. The Comprehensive textbook written by E. E. Turner andM. M. Harris also contains far more discussion of theories than is usual,stereochemistry in particular receiving detailed treatment.Heterolytic reactions.The calculation,by molecular-orbital methods, of reactivities in the various possible positionsin aromatic systems continues to arouse interest.cf.8 Of theoretical importanceis the conclusion Sa that, when an unsaturated snbstituent such as vinyl,phenyl, or butadienyl orients substitution in the benzene nucleus, the o-should be more reactive than the p-position. That $-substitution is actuallyfavoured experimentally, as in the nitration of diphenyl, is attributed tosteric hindrance of o-substitution.The steric influence of the larger tert.-butyl group has been demonstrated by the analysis of the partial rate-factorsfor o-, m-, and f-nitration of toluene and terl.-butylbenzene.9 It is difficult,however, to estimate reliably the effect of smaller alkyl and vinyl groups on1. Aromatic Substitution.-(a) General considerations.1 G. Bell and Sons, London, 1953.3 Butterworths Scientific Publications, London, 1953.4 John Wiley and Sons Inc., New York, U.S.A., 1953.6, Clarendon Press, Oxford, 1952.7 “ Organic Chemistry,” Longmans.Green and Co., London, 1952.8 ( a ) M. J . S. Dewar, J . Amer. Chem. Sac., 1952, 74, 3341; ( b ) R. D. Brown, ibid.,(a) H. Cohn, E. D. Hughes, M. H. Jones, and M. Peeling, Nature, 1952, 169, 291;Cornell Univ. Press, U.S.A., 1953.1953, 75, 4077.( b ) K. L. Nelson and H. C. Brown, J . Amer. Chem. Soc., 1951, 73, 5605126 ORGANIC CHEMISTRY.the rate of o-nitration. If R. D. Brown’s conclusion 8b is correct, then sterichindrance of o-substitution must in general be considerably larger than hashitherto been thought. On the other hand, a considerable body of opinionfavours the view that the quinonoid transition state for $-substitution will beenergetically more favourable than that for o-substitution. Thus W.A.Waters lo stresses the .analogy that P-quinones have a smaller energy contentthan o-quinones, and C. K. Ingold 1y p. 267 gives a qualitative quantum-mechanical justification for this view, concerning which there seems, there-fore, to be divergence of opinion.With regard to the nature of the intermediates involved in aromaticsubstitution, there have been a number of papers,ll dealing with the spectraof the complexes, ArH,X,, between aromatic substances and halogens.H. C. Brown and his co-workers l2 have studied the complexes formed byvarious alkylbenzenes with ( a ) hydrogen chloride and (b) aluminium chloride.Differences in the effects of structure of the aromatic compound on thestabilities of these complexes led these workers to conclude that two types areinvolved, namely, “ n-complexes,” in which the ring as a whole acts as a base,and “ o-complexes,” in which the “ acid ” is attached specifically to one ofthe aromatic carbon atoms.Analogies between the effects of structuralchanges on complex formation with aluminium chloride and on the rate ofaromatic substitution suggested that the latter type of reaction involvesG- rather than ~ i - complexes.G. Williams and his co-workers l3 showed that the changein rate of nitration of, e.g., the trimethylphenylamrnoniurn ion with solventcomposition in the range 82-90% sulphuric acid follows the extent ofionisation of 4 : 4’ : 4”-trinitrotriphenylmethanol in the same range ofmedia. Since such alcohols ionise according to the equation ROH +2H,SO,+ R+ + H,O+ + 2HS0,- (thus giving a measure of the J.acidity function),14 this result is taken as implying that nitration under theseconditions involves the nitronium ion, formed by the similar reaction :NO,*OH + 2H,S04 += NO,+ + H30f + 2HS04-.These workers haveshown that pentadeuteronitrobenzene is nitrated, in strong sulphuric acid, atthe same rate as nitrobenzene, thus confirming Melander’s conclusion l5 thatthe loss of a proton is not part of the process controlling the rate of nitration.A similar conclusion has been reached l6 from measurements of the rate ofnitration of monodeuteronitrobenzene; it can be taken that, contrary to aprevious Report,l7 a base is not kinetically required for nitration even of therelatively unreact ive subst rates.128 ORGANIC CHEMISTRY.methylaniline itself reacts with bromine much too rapidly for convenientmeasurement.A contribution has been made27 to the problem of the unexpected0, $-halogenation caused by the nitroso-group. I t has been shown that it isvery difficult to obtain a direct reaction of nitrosobenzene with bromine ;at first, substitution is extremely slow, but it becomes autocatalysed by theproduction of traces of hydrogen bromide.This, it is suggested, adds to thenitroso-group, thus producing intermediates, such as Ph*NBr*OH, which canparticipate in complex condensation and substitution reactions.Various workers 28 have studied the reactions of acidified hypochlorousacid with aromatic substances. With unreactive substrates, the kineticform is -d[ClOH]/dt = K[ArH][ClOH][H+] ; this result is consistent with theintervention of ClOH,+ or of C1’ in the reaction..With more reactive sub-stances, such as methyl p-tolyl ether, the rate of reaction, provided thatchloride ions are removed by added silver salts, may become of the form-d[ClOH]/dt = K[ClOH] + K’[ClOH][H+]. It is considered 28a that sincethe reaction velocity is independent of the concentration of aromatic com-pound the slow heterolysis of ClOH and C10H2+, giving Cl’, is being measured.With still more reactive aromatic compounds, such as phenol, the kineticequation becomes of the form :-d[ClOH]/dt = R[ClOH] + R’[ClOH][H+] + K”[CIOH][ArH][H+] . . ( 1 )The appearance, with very reactive aromatic compounds, of the last term inequation (l), taken in conjunction with the observation of a similar kineticterm with very unreactive substrates, is considered to be evidence that thesecond term in equation (l), observed with compounds of intermediatereactivity, does not represent the rate of a slow proton transfer to oxygen.Since added ions, X-, often powerfully catalyse chlorinations by ClOH, itis presumed that compounds C1X are in such cases the effective electrophilicreagents. Halogen acetates and related substances have been used pre-paratively,Z9 and further kinetic evidence for the existence and electrophilicbehaviour of chlorine acetate has recently been given.30The displacement reactions of arylboronic acids have been examinedkinetically : 31This reaction appears, from the effect of change in R on the rate, to involve anelectrophilic displacement by bromine on the aromatic system.Admirable summariesetc etc.Alicyclic compounds.Small and Large Rings.-Syntheses of n- and iso-propylcyclopropane,methylenecyclopropane,2 and nitrocyclopropane 3 have been described. Thelast, which was characterised by reduction to cyclopropylamine, does notform salts in strong alkaline media at 25°.3 The synthetic route to vinyl-cyclopropane derivatives has been extended by the condensation of 1 : 4-dibromobut-2-ene with ethyl cyano- and aceto-acetateJ5 and of 1 : 4-di-bromocyclopent-2-ene with ethyl malonateP6 the latter reaction giving abicyclo[3 : 1 : Olhexene derivative (I).Alkylated cyclopropanes can beprepared by the action of zinc on the addition products of hydrogen bromidet o a number of diene hydrocarbon^.^CH CMe(1) (11) (111)The adduct of phenylacetylene with 1 : l-dichloro-2 : 2-difluoroethyleneis the cyclobutene (II).8 This can be converted into derivatives of cyclo-butenone, cyclobutanone, and cyclobutane. Sulphuryl chloride and dimethyl-acetylene give the cyclobutene (III).g cis- and trans-l-Ethyl-3-methylcyclo-butane have been described.1° The heat capacities of solid and liquid cyclo-butane have been determined.lla-Carboxy- and a-cyano-adipic acid yield cyclopent anones when heatedwith hydrobromic acid.l2 The reaction is largely specific for the formationof a five-membered ring.The acyloin condensation leading to five- and95 F.A. Hochstein, C. R. Stephens, L. H. Conover, P. P. Regna, R. Pasternack,P. N. Gordon, F. J. Pilgrim, K. J. Brunings, and R. B. Woodward, J . Amer. Chem. SOC.,1953, 75, 5455.1 H. Pines, W. D. Huntsman, and V. N. Ipatieff, J . Amer. Chem. SOC., 1953, 75, 2311.J. T. Gragson, K. W. Greenlee, J. M. Derfer, and C. E. Boord, ibid., p. 3344.H. B. Hass and H. Shechter, ibid., p. 1382.R. W. Kierstead, R. P. Linstead, and B. C. L. Weedon, J., 1952, 3610.Idem, J., 1953, 1799.R. Ya. Levina and B. M. Gladshtein, Zhur. Obshchey Khim., 1952, 22, 585.* Idem, ibid., p . 1803.* J. D. Roberts, G. B. Kline, and H. E. Simmons, jun., J . Amer. Chem. SOC., 1953, 75,0 I. V. Smirnov-Zamkov, Doklady A k a d . N a u k S.S.S.R., 1952, 83, 869.lo B.A. Kazanskii and M. Yu. Lukina, Izvest. A k a d . N a u k S.S.S.R., Otdel. Khim.11 G. W. Rathjens, jun., and W. D. Gwinn, J . Amer. Chem. SOC., 1953, 75, 5629.l2 L. Crombie, J. E. H. Hancock, and R. P. Linstead, J., 1953, 3497.4765.N a u k , 1952, 314202 ORGANIC CHEMISTRY.six-membered rings is carried out effectively with sodium in liquid ammonia.13The two isomers of 1 : 3-dimethylcyclopentane have in the past had the wrongconfiguration ascribed to them, the lower-boiling isomer being, in fact,The preparation has been described of some cyclohexane-1 : 3-diones andtheir enol ethers,16 and their ultra-violet absorption spectra have beenreported.l7 An extension to various enolised a- and P-diketones of Wood-ward’s empirical rules for the calculation of A,,,.has been discussed.l71 : 2-Dimethylenecyclohexene l8 and 4-methyl-3-vinylcycZohex-3-enol l9have been prepared. The latter does not undergo the Diels-Alderreaction.19~20In recent years it has been realised that the properties of a substituenton a cyclohexane ring are profoundly influenced by its conformation. Therelation between conformation and reactivity has been well summarised byBarton.21 In the chair conformation of cyclohexane there are two types ofgeometrically distinct carbon-hydrogen bonds. Six of these bonds lieparallel to the three-fold axis of symmetry and until recently they havebeen designated “ polar.” It has now been proposed that the term “ axial ’’replace “ polar.” 22 The remaining six carbon-hydrogen bonds are stilltermed “ equatorial.”Conformational analysis indicates that cis-1 : 3-disubstituted cyclo-hexanes should be more stable than the corresponding tmns-isomers sincethe two substituents in the cis-arrangement can both be equatorial.Thegreater stability of the cis-isomer has been shown in the cases of the 3-methyl-~yclohexylamines,~~ 3-bromo- 24 and 3-hydroxy-cycZohexanecarboxylic acids,253-methyl~ycZohexanols,~~-~~ 3-methylcycLohe~ylmethanols,~~~ 29 and 1 : 3-bis-hydroxymethyl- 30 and 1 : 3-dimethyl-cy~Zohexanes,~~~ 31 and in some casesthe original stereochemical assignment has been reversed. The cis- andtrans-1 : 2- 32 and -1 : Pbishydroxymethyl-cy~lohexanes,~~ 1 : 2- and 1 : 4di-methylcy~lohexanes,~~ and 2- and 4-methylcycZohexylmethanols 34 have beendescribed.The most stable conformation of 2-bromo- and 2-chloro-cyclohexanone isthe chair form with the halogen atom axial, but that of 2-bromo-4 : Pdi-~is.14~15l 3 J.C. Sheehan and R. C . Coderre, J . Amer. Chem. SOC., 1953, 75, 3997.l4 S. F. Birch and R. A. Dean, J., 1953, 2477.l5 J. N. Haresnape, Chem. and Ind., 1953, 1091.l6 E. G. Meek, J. H. Turnbull, and W. Wilson, J., 1953, 811.l 7 Idem, ibid., p. 2891.lo G. Stork, S. S. Wagle, and P. C. Mukharji, ibid., p. 3197.2o Cf. P. A. Robins and J. Walker, J., 1952, 1610.21 D. H. R. Barton, J., 1953, 1027.22 D. H. R. Barton, 0. Hassel, K. S. Pitzer, and V. Prelog, Nature, 1953, 172, 1096.23 D. S. Noyce and J. R. Nagle, J . Amer. Chem. SOL, 1953, 75, 127.25 S. Siegel and J.G. Morse, ibid., p. 3857.25 S. Siegel, ibid., p. 1317.26 D. S. Noyce and D. B. Denney, ibid., 1952, 74, 5912.2 7 H. L. Goering and C . Serres, jun., ibid., p. 5908.28 G. A. Haggis and L. N. Owen, J., 1953, 408.29 L. H. Darling, A. K. Macbeth, and J. A. Mills, ibid., p. 1364.30 G. A. Haggis and L. N. Owen, ibid., p. 399.31 Cf. C. W. Beckett, K. S. Pitzer, and R. Spitzer, J . Amer. Cltem. SOC., 1947, fig, 2488.32 G. A. Haggis and L. N. Owen, J . , 1953, 389.33 Idem, ibid., p. 40-1. 34 Idem, ibid., p. 408.W. J. Bailey and H. R. Golden, J . Amer. Chem. SOC., 1953, 75, 4780HALSALL : ALICYCLIC COMPOUNDS. 203methylcyclohexanone has the bromine atom e q ~ a t o r i a l . ~ ~ ~ 36 The deamin-ation of cyclohexylamines with simple alkyl substituents on the ring is con-formationally specific ; equatorial amino-groups afford alcohols of the sameconfiguration while axial groups are, in the main, eliminated.37, 38 Theconfiguration of cydohexane derivatives with one to twelve mutually identicalsubstituents has been discussed.39cycZoHeptane-1 : 2-diol and a number of its derivative^,^^ cy~looctanone,~~cis- and trans-cycl~octene,~~ and cyclooctyne 43 have been prepared.Hydr-oxylation of cis-cyclooctene with performic acid, and hydrolysis or solvolysiswith formic acid of cis-cyclooctene epoxide, yield cyclooctane-1 : 4-dio1,formed by a transannular reaction, as a major p r o d u ~ t . ~ ~ ~ 45 cis- and trans-cycZoNonene undergo similar reactions with performic acid giving, in bothcases, the same two stereoisomeric cyclononane-1 : 5-di0ls.~~ The formationof two isomers is probably due to participation of hydrcgen atoms from twodifferent CH, groups in the transannular reaction (cf.IV, V, and VI). An-[ HzIz--CH2 CH ,-CH , - C q h 'AoH+7 1I FH'OH -HcH ICH ,-CH 2 - C w ' / ( ! g o Hi+ HOnHC HCH[CH213-cH2 HCH .[CH2] 2CH2HLH.[CH2] 2*CH2 I(Va and b)(2 Isomers)other example of this type of reaction is the conversion of the products fromthe action of two mols. of N-bromosuccinimide on cyclononanone and oncyclodecanone into 4 : 5 : 6 : 7-tetrahydroindan-4-one and a mixture of trans-or-decalone and 1 : 2 : 3 : 4 : 5 : 6 : 7 : 8-octahydro-l-oxonaphthalene respect-ively by the action of dimeth~laniline.~7 Treatment of 2-bromocyclo-decanone with sodium methoxide gives cyclononanecarboxylic acid.47Dehydration and dehydrogenation of cyclodecane derivatives such as cyclo-decanol, carried out either concurrently or consecutively, yield azulene andnapht halene.48Energy differences between the stereoisomers of perhydrophenanthreneand between those of perhydroanthracene have been c a l ~ u l a t e d .~ ~The rings of the bicycZo[3 : 3 : Oloctane-2 : 5-dione (VII) areSome 4-substituted bicyclo[2 : 2 : 2]octane-l-carboxylic acids (VIII ; X = H,Br, OH, NH,, CO,Et, and CN) and their ethyl esters have been ~ynthesised.~~bicycZo[5 : 3 : O]Dec-l(7)-en-S-one (IX ; R = H) and related compounds35 E. J . Corey, J . Amer. Chem. SOC., 1953, 75, 2301.36 Cf. E. J. Corey, Expericntia, 1953, 9, 329.38 M.Mousseron and M . Mousseron-Canet, Compt. rend., 1953, 237, 391.30 R. Riemschneider and P. Geschke, Angew. Chem., 1953, 65, 390.40 L. N. Owen and G. S. Saharia, J . , 1963, 2583.41 F. F. Rlicke, J. Azuara, N. J. Doorenbos, and E. B. Hotelling, J . Amer. Chem. Soc.,43 A. T. Blomquist and L. H. Liu, ibid., p. 2153.44 A. C. Cope, S. W. Fenton, and C. F. Spencer, ibid., 1952, 74, 5884.45 C f . Ann. Reports, 1952, 49, 178.4 6 V. Prelog, K. Schenker, and W. Kung, Helu. Chinz. Ada, 1953, 36, 471.4 7 K. Schenker and V. Prelog, ibid., p. 896.4* Idem, ibid., p . 1181. 49 Cf. p. 217.51 H.-W. Wanzlick, Chem. Ber., 1953, 86, 269.5* J. D. Roberts, W. J. Moreland, jun., and W. Frazer, J . Amer. Chem. SOC., 1953,37 J. A. Mills, J ., 1953, 260.1953, 75, 5418. 42 A. C. Cope, R. A. Pike, and C. F. Spencer, ibid., p. 3212.G. Schroeter and G. Vossen; c f . Annalen, 1922, 426, 1.75, 637204 ORGANIC CHEMISTRY.have been obtained from cycloheptanone (X) as shown.= cis- and trans-10-MethyIdecal-cis-2-01 have been prepared. 54Hot H,PO,-H.CO,H Hg(OAc), t\C=C*~HRNEt, 0" + HEC*yHR NEt, - UoH(XITerpenes-Ruzicka 55 has summarised the structural features of themono-, sesqui-, di-, and tri-terpenes and, together with Eschenmoser andHeusser, has shown how the natural terpenes may be formed in Naturefrom four possible precursors, geraniol (XI), farnesol (XII) , geranylgeraniol(XIII), and squalene (XIV). He has suggested that the original isoprenerule, which required that the carbon skeleton of a terpene should be divisibleinto isoprene units, should be modified.The modified rule (" biogeneticisoprene rule ") requires that the carbon skeleton should be such that it canbe formed by an accepted reaction mechanism from a limited number of" isoprenoid '' precursors, possibly the four compounds mentioned above.As a result of the modification, and by assuming the possibility of carbon-carbon rearrangements, it follows that terpenes need not have the carbonskeleton of their precursors and hence may not obey the original isoprenerule.Monoterpenes-The positions of the double bonds in the enol-acetates ofcitral and citronella1 have been determined 56 and hydrogenation of theseacetates has been studied.57 The chemistry of the P-menthane-2 : 3-diolshas been 59 (&)-cis- and (+)-trans-Piperitol 6o and (+)- 61 and(-)-cis-carveol 62 have been prepared by reduction of (&)-piperitone and(+)- and (-)-carvone respectively.Such a compound is the sesquiterpene eremophilone (XV).53 A.M. Islam and R. A. Raphael, J., 1953, 2247.54 A. S. Hussey, H. P. Liao, and R. H. Baker, J . Amer. Chem. SOC., 1953, 75, 4727.5 5 L. Ruzicka, Experientia, 1953, 9, 357. 6 6 A. Riser, Bull. SOC. chim., 1953, 570.5 7 Idem, ibid., p. 691. 6 8 A. K. Macbeth and W. G. P. Robertson, J . , 1953, 895.58 Idem, ibid., p. 3512. 6o A. K. Macbeth, B.Milligan, and J . S. Shannon, ibid., p. 901.61 D. Lloyd and J. Read, Chem. a.tzd Ind., 1953, 436.R. H. Reitsema, J . Amer. Chem. SOC., 1953, 75, 1996HALSALL : ALICYCLJC COMPOUNDS.205Syntheses of +unsaturated monoterpene alcohols by routes involvingeither allylic bromination of monoterpenes followed by conversion of thebromo-derivative into the alcohol through the f ~ r m a t e , ~ ~ or direct oxidationwith mercury salts 64 have been described. Oxidation of terpenes such ascarvomenthene and a-pinene with tert.-butyl chromate yields ap-unsaturatedThe hydrocarbon (XVI) has been synthesised 66 and found to differ fromis~carvestrene.~~ Structures (XVII) and (XVIII) have been proposed forumbellulone dibromide and bromodihydroumbellulone,68 and (XIX) forcamphenamine.@ apoisoFenchene has been synthesised and its hydrationstudied. 70%HZMe MeI( X W (XVII) (XVI 11) ( X WLavandulic (XX), citronellic (XXI), and ,By-dihydrolavandulic (XXII)acid can be cyclised by an intramolecular acylation reaction to piperitenone(XXIII), pulegone (XXTV), and piperitone (XXV).'l Cyclisation of thecis- and tram-compounds of the geranic acid series,72 and synthesis of 2 : 7-dimethylocta-2 : 6(or 2 : 7)-dienoic acid and its cyclisation to (XXVI) 73have been described.H2?To I III 0% II 9% \/ I" (XXIII) * (XXIV) (XXV) CHO (XXVII)Condensation of crotonaldehyde and formaldehyde gives the dialdehyde(XXVII).74 A large number of reactions have been carried out with com-pounds with the carbon skeleton of (XXVII).74-7863 A.K. Macbeth, B. Milligan, and J. S. Shannon, J., 1953, 2574.65 G. Dupont, R. Dulou, and 0. Mondou, Bull. Soc. chim., 1953, 60.66 P.Sengupta, J . Org. Chem., 1953, 18, 249.6 7 K. Fisher and W. H. Perkin, jun., J., 1908, 1876.6 8 R. H. Eastman and A. Oken, J . Amer. Chem. Soc., 1953, 75, 1029.G9 E. E. van Tamelen, TV. F. Tousignant, and P. E. Peckham, ibid., p. 1297.i o S. Beckmann and R. Bamberger, Annalen, 1953, 580, 198.71 W. Kuhn and H. Schinz, Helv. Chim. Actn, 1953, 36, 161.72 H. Kappeler, H. Grutter, and H. Schinz, ibid., p. 1862.73 H. Kappeler, A. Eschenmoser, and H. Schinz, ibid., p. 1877.74 R. Pummerer, F. Aldebert, F. Buttner, F. Graser, E. Pirson, H. Rick, and H.75 F. Buttner, ibid., p. 184.7 6 R. Pummerer, F. Aldebert, and H. Sperber, ibid., p. 191.7 7 R. Pummerer and F. Graser, ibid., p. 207. '* R. Pummerer, F. Aldebert, F. Graser, and H. Sperber, ibid., p.225.W. Treibs, G. Lucius, H. Kogler, and H. Breslauer, Annalen, 1953, 581, 59.Sperber, Annalen, 1953, 583, 161206 ORGANIC CHEMISTRY.Total syntheses of nerol and geraniol, of the geometrical isomers of$-ionone, and of the ionones have been reported.79 Recent progress in thechemistry of the irones has been reviewed 8o and further work on the synthesisof the irones has been described.81 The use of infra-red spectra enables theisomers of ionone and irone to be distinguished.82 A small quantity ofa-ionone in the presence of p-ionone can be estimated colorimetrically.83The cyclisation of $-ionone (XXVIII) with boron trifluoride leads to(XXIX), (XXX), and (XXXI) in addition to the ionones. Similar cyclis-ations occur with citronellylidene- and geranyl-acetone and with +-irone.8*? 85(XXXT) 'Y L 1Sesquiterpenes and Diterpenes-The ultra-violet spectrum of +antoninproves that it is not an ap-unsaturated y-lactone, whilst infra-red evidenceconcerning the lactone ring is inconclusive.86 #-Santonin is now formulated9 R0'\/OH Oh(XXXV) >I-'( /ICH, (DL I (XXXVI)/\as (XXXII).Syntheses of two optically inactive stereoisomerides ofsantonin (XXXIII) 87 and of some analogues 88 have been described. Anoxidat ion product of hydroxyeremophilone (XXXIV) , formerly regarded as79 G. I. Samokhvalov, M. A. Miropol'skaya, L. A. Vakulova, and N. A. Preobrazhen-skiy, Doklady Akad. Nauk S.S.S.R., 1952, 84, 1179.8o Y.-R. Naves, Bull. SOC. chim., 1953, 561.82 Y.-R. Naves and J . Lecomte, ibid., p.112.83 P. Karrer and U. Blass. Helv. Chim. Acta, 1953, 36, 463.84 Y.-R. Naves and P. Ardizio, Bull. SOC. chim., 1963, 494.8 5 Y.-R. Naves, R. Wahl, P. Ardizio, and C. Favre, ibid., p. 873.8 6 W. G. Dauben and P. D. Hance, J. Amer. Chem. SOC., 1953, 75, 3352.88 M. Yanagita and A. Tahara. J. Org. Chenz., 1953. 18, 792.Y.-R. Naves and P. Ardizio, ibid., p. 296.Y. Abe, T. Harukawa, H. Ishikawa, T. Miki, M. Sumi, and T. Toga, ibid., p. 2567HALSALL : ALICYCLIC COMPOUNDS. 207C12H1803,89 is C1CH2S04 and has structure (XXXV).90 Pure zingiberenehas been i~olated,~l and a compound with its gross structure has been~ynthesised.~~ Calamenene has been shown by synthesis to be (XXXVI).93* 94(3- and y-Caryophyllene are geometrical isomers differing about the endo-cyclic double b ~ n d .~ ~ ~ 96 It is proposed that the name " (3-caryophyllene "be replaced by caryophyllene and " y-caryophyllene " by iso~aryophyllene.~~Proof of the geometrical isomerism comes from the conversion of caryo-phyllene (XXXVII) and isocaryophyllene (XLII) into the same diketone(XLI) as shown. The glycols (XXXIX) and (XLIV) and the keto-alcohols(XL) and (XLV) are not i d e n t i ~ a l . ~ ~ - ~ ' Caryophyllene reacts much fasterwith perphthalic acid than isocaryophyllene and is therefore the trans-isomer.96 The two oxides (XXXVIII) and (XLIII) differ only at (&X-Ray analysis 98 of the chloride and bromide corresponding to p-caryo-phyllene alcohol leads to (XLVI) for the latter and to (XXXVII) for caryo-phyllene.H H Me Me(XXXVII)Me(XXXIX)+cro*Me<HO' 'p-Caryophyllene alcohol is not dehydrated by acid to clovene althoughWith phos-HenceThese results are explained(XLIV) (XLIII) (XLI I)both are formed when caryophyllene is cyclised with a~id.~7, 99phoric oxide isoclovene (suggested structure XLVII) is f0rmed.~7caryophyllene cyclises by at least two routes.89 A.E. Bradfield, N. Hellstrom, A. R. Penfold, and J. L. Simonsen, J., 1938, 767.O0 T. A. Geissman, J . Amer. Chem. Soc., 1053, 75, 4008.9 1 V. Herout, V. BeneSovA, and J . Pliva, Coll. Czech. Chem. Comm., 1953, 18, 248.92 S. M. Mukherji and N. K. Bhattacharyya, J . Amer. Chem. Soc., 1953, 75, 4698.93 F. Sorm, K. VereS, and V. Herout, Coll. Czech. Chem. Comm., 1953, 18, 106.94 Cf.W. Treibs, Ber., 1949, 83, 530.O 5 A. Aebi, D. H. R. Barton, and A. S. Lindsey, Chem. and Ind., 1953, 487.g6 Idem, J . , 1953,3124.99 A. W. Lutz and E. 13. Reid, ibid., p. 278.9 7 A. W. Lutz and E. B. Reid, Chem. and I n d . , 1953, 749.J . M. Robertson and G. Todd, ibid., p. 437208 ORGANIC CHEMISTRY.if clovene is (XLVIII) with its methylene bridge opposite in configurationto that of p-caryophyllene alcohol (XLVI) .loo Further chemical evidence-Me(XLVI) (XLVII) ( XLVI I I)for the grouping *CH,*CH:CMe*CH,* in caryophyllene has been described.101Synthetic (+)-tram-caryophyllenic acid (XLIX) is identical with the acidobtained from caryophyllene. lo2Further evidence concerning humulene l o 3 9 lo4 supports its formulationas (L) or a closely related isomer differing only in an endo-exo-cyclic bondarrangement.lo51 lo6 ’~ /CH 2C02 HM e 4 7The structures of cedrene lo8 (LI) and cedrol (LII) have been eluci-dated.1m- 110 The key step is the proof that ring A is six-membered and notfive-membered as had been thought previously.The most probable con-figuration of cedrene is (LIII).lo9 A mechanism has been proposed for theconversion of bromonorcedrenedicarboxylic acid (LIV) into (LV). 111(LI) h eMeMeOH- +\MeLongifolene 112 contains a vinylidene ()C=CH2) 113 rather than a vinylThe environment of the former group has beenloo A. Aebi, D. H. R. Barton, and A. S. Lindsey, Chem. and Ind., 1953, 748.lol N. W. Atwater and E. B. Reid, ibid., p. 688.102 A. Campbell and H.N. Rydon, J . , 1953, 3002. lo3 J. 0. Harris, ibid., p. 184.lo4 R. W. Fawcett and J. 0. Harris, Chem. and Ind., 1953, 18.lo5 G. R. Clemo and J. 0. Harris, J . , 1952, (565.lo6 F. Sorm, M. Streibl, J. Pliva, and V. Herout, Coll. Czech. Chem. Comm., 1951, 16,lo* Cf. Sir John Simonsen and D. H. R. Barton, ‘‘ The Terpenes,” Cambridge Univ.log P. A. Plattner, A. Fiirst, A. Eschenmoser, W. Keller, H. Klaui, S. Meyer, and M.110 G. Stork and R. Breslow, J . Amer. Chem. Soc., 1953, ‘75, 3291111 Idem, ibid., p. 3292. 112 Cf. Sir John Simonsen and D. H. R. Barton, op. cit., p. 92.113 P. Naffa and G. Ourisson, Chem. and Ind., 1953, 917.group a s hitherto thought.639.Press, Vol. 111, p. 75.Rosner, Helv. Chim. A d a , 1953, 36, 1845.lo’ Cf. Ann. Reports, 1947, 44, 158HALSALL : ALICYCLIC COMPOUNDS.209determined chemically and shown to be represented by (LVI) where theatoms marked * are either fully substituted or at bridge-heads.l13 Longi-folene hydrochloride, the formation of which involves a molecular rearrange-ment of the camphene _+ bornyl chloride type, has been shown by X-rayanalysis to be (LVII) with the chlorine atom in the ertdo-c~nfiguration.~~~The chemical and X-ray results enable longifolene to be formulated as(LVIII). Molecular-rotation data show that (+)-longifolene is related to(+)-camphene, and (LIX) represents its absolute configuration. Longi-folene may be compared with p-santalene (LX) which, however, is relatedto - ) -camphene. 115Klyne 116 has applied the method of molecular-rotation differences tosome sequiterpene and diterpene stereochemical problems.Structures(LX1)-(LXV) are proposed for a- and p-cyperone, eremophilone, a-selinene,and dihydroeudesmol respectively. The conclusions concerning the lasttwo are supported by conformational arguments. 117 In the diterpene groupthe stereochemistry of the fundamental (unknown) hydrocarbons is as shown&XI) (LXII) (LXIII) (LXIV)IAbietane Pimarane Podocarpane 7 : 8-secopimarane(LXVI) (LXVII) (LXVI 11) (LXIX)in formulz (LXV)-(LXIX). Structures (LXX)-(LXXIII) are proposedfor abietic, lzvopimaric, Izeoabietic, and dextropimaric acid respectively.The stereochemistry of some y- and &lactones is also discussed, formula(LXXIV) being suggested for the lactone C1@@2 obtained by oxidationof sclareol and ambrein, and (LXXV) for ambreinolide.l16114 R.H. Moffett and D. Rogers, Chem. and Ind., 1953, 916.115 G. Ourisson, ibid., p. 918. W. Klyne, J., 1953, 30722 10 ORGANIC CHEMISTRY.Sandarakopiniaric acid probably differs from either dextro- or isodextro-pimaric acid at C(l) [cf. (LXXIII)], having the opposite configuration atthis centre.ll7\(LXX)(LXXIV)(LXXI)\(LXXII) (LXXI I I)(LXXV)(LXXVI) (LXXVII) (LXXVI I I)Marrubiin is a y-lactone and is now formulated as (LXXVI).118~119Infra-red and ultra-violet data concerning cafestol, l*O C20H2803, and someof its transformation products show that it contains an a-glycol groupingattached to a five-membered ring [cf. (LXXVII)] and a furan nucleus fusedto a six-membered ring.121 A further furan compound, methyl vinhaticoate,C,, H3,O,, isolated from Plathymenin reticdata, 122 is formulated as(LXXVIII).123 This structure does not conform to the " classical I ' isoprenerule.An acidic diterpene, along with a sesquiterpene, a triterpene acid, anda triterpene alcohol have been obtained from copal resin.12*Triterpenes and Related Compounds.-Structure (LXXIX) representsthe absolute configuration at C(,,, of the 3p-hydroxy-5a-steroids on thebasis of ( a ) correlation between unsaturated terpenes of known con-figuration and unsaturated steroids which results from a study of molecular-rotation differences 125 and (b) Prelog's asymmetric-synthesis method.126* lZ7l l i F.Petrii and V. Galik, Coll.Czech. Chem. Comm., 1953, 18, 717.l l S W. Cocker, B. E. Cross, S. R. Duff, J. F. Edward, and T. F. Holley, J., 1953,2540.l l 9 D. G. Hardy and W. Rigby, Chem. and Id., 1953, 1150; cf. W. Cocker, J. T.Edward, and T. F. Holley, ibid., p.'!227.120 L. F. Fieser and M. Fieser, Natural Products Related to Phenanthrene," Rein-hold Publ. Corpn., New York, 3rd Edn., 1949, p. 79.n1 C. Djerassi, E. Wilfred, L. Visco, and A. J. Lemin, J . Org. Chem., 1953, 18, 1449.lZ2 F. E. King, T. J. King, and K. G. Neill, J., 1953, 1055.lZ3 F. E. King and T. J . King, ibid., p. 4158.P. Fournier, Bull. Soc. chim., 1953, 32.lZ5 J. A. Mills, J., 1952, 4982; see also idem, Chem. and Ind., 1953, 218.lZG V. Prelog, Helv. Chim. Ada, 1953, 36, 308.12' W. G. Dauben, D.F. Dicltel, 0. Jeger, and V. Prelog, ibid., p. 325HALSALL : ALICYCLIC COMPOUNDS. 21 1The relative st ereochemistry of lanosterol (LXXX) and p-amyrin (LXXXI)has already been elucidated and in both compounds the terminal ring A isof the same enantiomeric type as that of the 5a-ster0ids.l~~ Hence theabsolute configuration of lanosterol and p-amyrin must be as in (LXXX)and (LXXXI). This conclusion has been confirmed for lanosterol andu-amyrin,lZ7 ring A of which is the same as that of p-am~rin.l~~ A directrelation between lanosterol and p-amyrin has been established by the con-version of lanosterol and manool (LXXXII) into the same acid (LXXXIII) ,130manool having already been related to p - a m ~ r i n , ~ ~ ~ In view of the closestereochemical relation between steroids, lanosterol, and p-amyrin, steroidnumbering is now used for rings A and B of p-amyrin and related triterpenes(cf.LXXXI).131(LXXIX) (LXXX) (LXXXI)Tetracyclic. The evidence previously presented 132 concerning lanosterolhas, in some instances, been described more fully.133-135 Additional evidencesupporting structure (LXXX) has been p ~ b l i s h e d . l ~ ~ - l ~ ~ Lanosterol hasbeen converted into an analogue of provitamin D3,139 and into 14-methyl-pregn-4-ene-3 : 11 : 20-trione 140 which has the same activity in the Corner-Allen test as the corresponding progesterone derivative. 55cycZoArteno1 l4I7 142 is a ~ycZolanost-24-enol.~~~ The presence of an iso-propylidene group in a side chain, and of a cyclopropane ring had alreadybeen shown.l*l cycZoArtany1 acetate has now been isomerised by hydrogenchloride to a mixture of isomers, the major component of which is lanost-9(11)-enyl acetate.143 This suggests that the cyclopropane ring extendsfrom C(g), and infra-red data indicate that it contains a CH, group.144128 Cf. Ann.Reports, 1952, 49, 184. 129 Cf. L. Ruzicka, Experienlia, 1953, 9, 360.130 E. Kyburz, B. Riniker, H. R. Schenk, H. Heusser, and 0. Jeger, Heh. Chim.131 J. M. Guider, T. G. Halsall, and E. R. H. Jones, J., 1953, 3024.132 Ann. Reports, 1952, 49, 184.133 J . Fridrichsons and A. McL. Mathieson, J., 1953, 2159.13* C. S. Barnes, D. H. R. Barton, A. R. H. Cole, J. S. Fawcett, and B. R. Thomas,135 C . S. Barnes, D. H. R. Barton, J. S. Fawcett, and B.R. Thonas, ibid., p. 576.136 C. S. Barnes and D. H. R. Barton, ibid., p. 1419.lS8 S. A. Knight, J. F. McGhie, and M. J. Birchenough, Chem. and I n d . , 1953, 822.130 D. H. R. Barton and B. R. Thomas, J.. 1953, 1842.140 W. Voser, H. Heusser, 0. Jeger, and L. Ruzicka, Helv. C h i m . Acta, 1953, 36, 299.141 D. H. R. Barton, J., 1951, 1444.lb2 S. Chapon and S. David, Bull. Soc. chim., 1952, 456.143 H. R. Bentley, J . A. Henry, D. S. Irvine, and F. S. Spring, Chent. and I n d . , 1953,Acta, 1953, 36, 1891.ibid., p. 571.J. F. McGhie, M. K. Pradhan, and W. A. Ross, ibid., p. 305.217; J., 1953, 3673. 144 A. R. H. Cole, Chem. and I n d . , 1953, 946212 ORGANIC CHEMISTRY.cycZoArteno1 is therefore either (LXXXIV) or (LXXXV).may be cycloartenol.143Handianol 145\AOH/\/-Me(LXXXI I) (LXXXIII) (LXXXIV) (LXXXV)Eburicoic acid (LXXXVI) 146-148 and polyporenic acids A,149-154 B,155and C 156 (LXXXVII, LXXXVIII, LXXXIX) have been shown to possessthe 4 : 4 : 14-trimethylergostane skeleton with thirty-one carbon atoms.They thus form another group, distinct from the lanosterol group, of tri-met hyl-st eroids.Eburicoic acid has been converted into lano~t-8-ene.~~~ The methodinvolves removal of the C(,,-hydroxyl group by oxidation and Wolff-Kishnerreduction, removal of the methylene group by ozonolysis and reduction ofthe resulting ketone, and conversion of the carboxyl group into methyl.(LXXXVI) (LXXXVII) (LXXXVI 11)07-0(XC)The position of the methylene group is shown by addition of hydrogenchloride to methyl 0-acetyleburicoate, followed by dehydrochlorination andozonolysis of the product, methyl isopropyl ketone being obtained.14*Oxidation of 0-acetyleburicoic acid with selenium dioxide gives the lactoneG.A. Gonzalez and A. Calero, ibid., 1950, 46, B, 175.145 G. A. Gonzalez, ,4. Calero, and R. Calero, Anal. Fis. Quim., 1949, 45, B, 1441 ;146 R . M. Gascoigne, A. Robertson, and J . J. H. Simes, J . , 1953, 1830.14’ J. S. E. Holker, A. D. G. Powell, A. Robertson, J. J. H. Simes, and R. S. Wright,14* J. S. E. Holker, A. D. G. Powell, A. Robertson, J . J. H. Simes, R. S. Wright,149 R. G. Curtis, (Sir) Ian Heilbron, E. R. H. Jones, and G. F. Woods, ihid., p. 457.150 E. R. H. Jones and G. F. Woods, ibid., p. 464.151 T.G. Halsall, E. R. H. Jones, and A. J . Lemin, ibid., p. 468.15, T. G. Halsall and R. Hodges, ibid., p. 3019.153 M. Roth, G. Saucy, R. Anliker, 0. Jeger, and H. Heusser, Helv. Chim. Acts, 1953,lb4 T. G. Halsall, R. Hodges, and E. R. H. Jones, personal communication.155 T. G. Halsall and E. R. H. Jones, XIIIth Int. Congr. Pure Appl. Chem., Stock-156 A. Bowers, T. G. Halsall, E. R. H. Jones, and A. Lemin, J., 1953, 2548.ibid., p. 2414.and R. M. Gascoigne, ibid., p. 2422.36, 1908.holm, July 29th, 1953HALSALL : ALICYCLIC COMPOUNDS. 213(XC) which fixes the position of the carboxyl group. The position of thehydroxyl group has been shown by phosphorus pentachloride dehydration. 15'Polyporenic acid C has been converted into methyl O-acetyldehydro-eburicoate (XCII) as shown.lS5 The carbonyl-oxygen atom in acid C is atC(3) since infra-red data indicate that it is on a six-membered ring.156 Theinfra-red spectrum of (XCI) has a band characteristic of a keto-group in aMe polyporenate Eburicoic acidCrO, + t MeozCnJ1A A P CH,OP\/ A v (XCI) -4CO'X (XCII)Me02C X k ( i ) NaBH, ; *(ii) W.-K.redn *A V > : o ;i-< --y-7-& (iii) CH,NU,; (iv) Ac,O ,q(!(JI CH2(* Reduces C(,):O.) I3 I IIfive-membered ring. The hydroxyl group of acid C is therefore at eitheror Ccle). A decision in favour of c(16) can be made from molecular-rotation data.156 It has been suggested tentatively 156 that the hydroxylgroup has the p-configuration, but it is probable, in view of the change inrotation on a ~ e t y l a t i o n , ~ ~ ~ that the configuration is a (cf.LXXXIV).Polyporenic acid B is closely related to polyporenic acid C and both havebeen converted into (XCIII).155The evidence for the structure of polyporenic acid A is based partly onstudies of the oxidation of derivatives of methyl polyporenate A whichelucidated the nature of rings B and c,151 on dehydration experiments whichprove that there is a 3whydroxyl group,152 and on degradation of the sidechain as shown.152 These facts, together with the probable biogeneticS H 2 y; Heat 7H3 yH3 0, Y H 3 R.CH2*C- H C02H __t R*CH,.C=CH + R.CH,.C=O + CH,*CHO(i) PhMgBr ;(ii) -HIO I 0 sRC0,Me --- RCHO + R*CH=z?:relation of polyporenic acids A, B, and C, led to structure (LXXXVII) forpolyporenic acid A.152 The proof of this structure has been completed by(XCIV) Athe conversion of the acid and of lanosterol into the common degradationproducts (XCIV) 153 and (XCV).15*The action of hydrogen chloride on euphol 159 and butyrospermol 16015' R.M. Gascoigne, J. S. E. Holker, B. J. Ralph, and A. Robertson, J . , 1951, 2346.15* Cf. D. K. Fukushima and T. K. Gallagher, J . Amer. Chem. SOC., 1951, 73, 196.158 M. C. Dawson, T. G. Halsall, and R. E. H. Swayne, J., 1953, 590.160 M. C. Dawson, T. G. Halsall, E. R. H. Jones, and P. A. Robins, &id., p. 586214 ORGANIC CHEMISTRY.has been described, and the chemistry of the elemi acids discussed.161 Thestructure of euphol has been discussed in the light of its possible biogene~is.~~Tetracyclosqualene is (XCVI).162Olean-9( 11) : 13 (1 8)- and olean-9( 11) : 18-dienol have beenprepared and p-amyrin has been converted into germanic01.l~~ Taraxerol 164Pentacyclic.and skimmiol 165 are identical,166, 167 being probably 13a-olean-18-en-3p-01(1 3-isogermanicol) .166 Arjunolic acid, a new triterpene from Terminaliaarjuna, has been provisionally formulated as (XCVII).168The structure (XCVIII) suggested for quinovic acid 169 has been con-firmed,170 but a new structure (XCIX) has been advanced for its dehydrationproduct, novic acid.170 I t is suggested that the first stage of the Liebermannand the Salkowski colour reactions is the formation of a conjugated dienesystem.171 In support of this view ursolic acid has been converted withconcentrated sulphuric acid into a diene for which structure (C) is sug-gested.171 However, by analogy with the structure of novic acid, (CI)seems more likely.Phyllanthol 172 contains a cyclopropane ring and gives a-amyrin on treat-By a study of the oxidation of the deuterated a-amyrinobtained by treating phyllanthol with deuterium chloride it has been shownthat phyllanthol is not 9 : 12- or 11 : 13-cyclo-a-amyranol.Possible struc-tures have been discussed.Further evidence for structure (CII) for asiatic acid has been re~0rted.l‘~The location of the carboxyl group is not yet proved. It could be at C(14),ment with acid.173161 T. G. Halsall, G. D. Meakins, and R. E. H. Swayne, J., 1953, 4139.162 G. Buchi; cf. L. Ruzicka, Experientia, 1953, 9, 363.163 J .M. Beaton, J. D. Johnston, L. C. McKean, and F. S. Spring, J., 1953, 3660.164 S. Burrows and J. C. E. Simpson, J . , 1938, 2042.165 K. Takeda, J . Pharm. SOC. Japan, 1941, 61, 117, 506 (with S. Yosiki) ; 1942, 62,167 Cf. ‘‘ Elsevier’s Encyclopaedia of Organic Chemistry,” Vol. 14s (1952), p. 1190s.169 0. Jeger, “ Fortschritte der Chemie organischer Naturstoffe,” Springer-Verlag,Berlin, 1950, Vol. VII, p. 69; A. Brossi, B. Bischof, 0. Jeger, and L. Ruzicka, Helv. Chim.A d a , 1951, 34, 244.171 C. H. Brieskorn and L. Capuano, Chem. Ber., 1953, 86. 866.172 K. B. Alberman and F. B. Kipping, J., 1951, 2296.l i 3 D. H. R. Barton and P. de Mayo, J . , 1953, 2178.l T 4 J. Polansky, Bull. SOC. chim., 1953, 173.390; 1943, 63, 193, 197. 166 C.J. W. Brooks, Chem. and Ind., 1953, 1178.F. E. King, Chem. and Ind., 1953, 1325.D. H. R. Barton and P. de Mayo, J . , 1953, 3111HALSALL : ALICYCLIC COMPOUNDS. 215but this is unlikely since asiatic acid does not undergo the ready thermaldecarboxylation typical of a py-unsaturated acid. Ursa-ll(l3) : 18-dienolhas been prepared.175Lupene-I (CITI) and taraxastene (CIV) have been converted into acommon product (CV).176 At first it was thought that lupene-I had itsC<,,,-methyl group in the equatorial conformation, but it now appears thatit is in the axial conformation and that lupene-I and taraxastene have thestructures indicated.177INew triterpenes isolated include the alcohols resiniferol 178 and ilexol, 179a ketone C,,H,,O from Alnus g2utinosa,ls0 and the lactone thurberogeninC,,H,,O from the cactus Lemaireocereus Thurberi.181 Further evidence forthe existence of crataegolic acid has been put fonvard.ls2Triketones. The structure (CVI) for flavaspidic acid has been proved byits disproportionation to albaspidin (CVII) and by synthesis.183 A newsynthesis of filicinic acid (CVIII) is described. ls4 Cohumulone, whichresembles humulone in its behaviour, is converted by hot alkali into isobutyr-aldehyde, 4-methylpent-3-enoic acid, and cohurnulinic acid. 185hle\,Me2CH20 0 OH(CW (CVI I) (CVI I I)T. G. H.175 J. D. Easton, W. Manson, and F. S. Spring, J . , 1953, 943.176 J. L. Beton, A. Bowers, T. G. Halsall, and E. R. H. Jones, Chem. and Ind., 1953,17* G. Dupont, M.Julia, and W. R. Wragg, Bull. SOC. chim., 1953, 852.l i e H. Iseda, J . Pharm. SOC., Japan, 1952, 74, 1064; S. Iseda, ibid., p. 1611.180 S. Chapon and S. David, Bull. SOC. chim., 1953, 333.181 C. Djerassi, L. E. Geller, and A. J. Lemin, J . Amer. Chem. SOC., 1953, 75, 2254.lE2 R. Tschesche, A. Heesch, and R. Fugmann, Chem. Bey., 1953, 86, 626.lE3 A. XlcGookin, A. Robertson, and T. H. Simpson, J., 1953, 1828.E. B. Reid and T. E. Gompf, 1. Amer. Chem. SOC., 1953, 75, 1661.l o 5 G. A. Howard and A. R. Tatdhell, CJtem. and Ind.. 1953. 436847. 1 7 7 Cf. ibid., p. 1387216 ORGANIC CHEMISTRY.Steroids.Stereochemistry.-Important contributions were lately made to theproblem of absolute configuration. There is a fairly strong chain of evidencecorrelating D-glyceraldehyde with a number of cyclic terpeneslcollected data on the molecular optical rotation [MD] of several pairs ofepimeric, terpenoid cyclohex-2-enols and their esters ; by assuming thatthe ascribed configurations were correct it could be deduced that an alcoholrepresented as in (I) is more lzvorotatory than the epimer (11).The differ-ences are large, and are greatly enhanced by esterification.Mills(1) (11)When this rule was appliedsteroid alcohols, the differences(111) (IV)to seven known pairs of epimeric, allylicfound were those predictable if the con-vent ional steroid project ion represented truly the Bbsolute configuration.An eighth pair furnished a dubious exception. In a later note3 the con-figurational and conformational resemblances between (+)-menthol (111)and the conventional representation of ring B in a 7p-hydroxy-5a-steroid(IV) , and similarly between (-)-neomenthol and the 7a-steroid epimer,were pointed out.Here again the signs and magnitudes of the molecularrotation differences, when the steroid and terpenoid series were compared,supported the view that the steroid convention is spatially correct.Prelog and his associates advanced arguments which, if valid, permitthe assignment of configuration to certain optically active alcohols bydetermining the sign of rotation of the atrolactic acid produced from thephenylglyoxylic esters by reaction with methylmagnesium bromide andsubsequent hydrolysis. Androsten-l7p-01, cholestan-7a- and -7p-01, and5a-pregnan-20p-01 were examined. In each case the isolated atrolactic acidhad the sign of rotation to be expected if the conventional steroid projectionis assumed to be correct.These conclusions of Mills and of Prelog on the absolute configurationof steroids are in conflict with the view tentatively advanced by Lardon andReichstein and based on studies of a p-methoxyadipic acid derived fromcalcif erol.Turner computed the difference of internal energy (vapour phase, 25")between cis- and trans-decalin, using the values deduced by Pitzer for theenergy associated with different conformations of the n-butane portion of ahydrocarbon chain.The value obtained, 2.4 kcal., agreed well with experi-ment. observed that the result could be reached more simply byassigning the value zero to trans-decalin (V).Compared with (V), cis-A. J. Birch, Ann. Reports, 1950, 47, 191.J. A. Mills, J . , 1952, 4976; cf. W. Klyne, Helv. Chim. Acta, 1952, 35, 1224.J. A. Mills, Chew and Ind., 1953, 218.A. Lardon and T. Reichstein, Helv. Chim. Ada, 1949, 32, 2003.R. B. Turner, .T. Amer. Chem. SOL, 1952, 74, 2118.K. S. Pitzer, Chem. Reviews, 1940, 27, 39.W. S. Johnson, J . Amer. Chem. SOL, 1953, 75, 1498.JohnsoCORNFORTH : STEROIDS. 217decalin (VI) has three additional “skew” arrangements (shown by thebroken lines) of four-carbon portions of the molecule.associated with an energy-increase of 0-8 kcal.; the total energy differenceEach of theseis therefore 2.4 kcal. An analysis was made in this manner of the perhydroanthracenes and perhydrophenanthrenes : the relative values for internaenergy are given in the Table.Perhydro- Perhydro-anthracenes AE (kcal.) phenanthrenes AE (kcal.)trans-syn-trans 0 trans-anti-trans 0.8cis-syn-trans 2.4 trans-anti-cis 3.2cis-anti-cis 4.8 cis-syn-trans 3.2trans-anti-trans h5.6 cis-anti-cis 4.8cis-syn-cis - 6.4 cis-syn-cis - 7.2Ivans-syn-trans >/ 5.6Several papers were published on the configurations of x-bromo-ketones.Bromination products of several 3-oxosteroids were examined by FieseIand his collaborators.* The method may be exemplified : methyl 4-bromo-3-oxocholanate (VII) was reduced by sodium borohydride to a mixture oftwo bromohydrins (VIII, IX).With alcoholic alkali one of these gavea 3 : 4-epoxide (X), the other 3-oxocholanic acid (XI).The isomer (IX) wasalso converted by hydrogenation into 3p-hydroxycholanic acid (XII). Fromthe evidence obtained by Bartlett from cis- and trans-2-chlorocyclohexanol,the bromohydrin giving an epoxide is a trans-bromohydrin, and its epimerwhich yields a ketone is a cis-bromohydrin. From the conversion (IX __tXII) it follows that the bromine atom in (VII) is p-oriented. By similarmethods a 8-oriented bromine atom was attributed to 4-bromo-17p-hydroxy-testan-3-one. 2-Bromocholestan-3-one was a t first thought to have the28-configuration; but this erroneous conclusion was traced to a failure toseparate the two bromohydrins formed on reduction, and the evidence8 L. F. Fieser and R. Ettorre, J .Amer. Chem. SOC., 1953, 1700; L. F. Fieser and J. A.Dominguez, ibid., p. 1704. 0 P. D. Bartlett, ibid., 1935, 57, 224218 ORGANIC CHEMISTRY.actually established the 2a-configuration as correct. lo 2-Chlorocholestan-%one is also the 2a-epimer.llWhen the infra-red spectra of steroid a-bromo-ketones of known con-figuration were compared with the spectra of the parent ketones, it wasobserved l2 that where the carbon-oxygen and carbon-bromine bonds layapproximately in the same plane the carbonyl absorption band was shiftedto higher (13-25 cm.-l) frequencies; if the bonds were far from coplanarthe effect was slight. By applying this rule to 2-bromocyclohexanone andseveral alkyl-substituted analogues, Corey l3 concluded that the preferredconfiguration of the bromine atom in 2-bromocyclohexanone was axial, butthat this effect could be overcome by the steric repulsion from neighbouringaxial substituents.The information gathered from monocyclic ketoneswas applied to steroid a-bromo-ketones. Thus, in a pair of epimeric a-bromo-ketones the thermodynamically stable epimer could be indicated : this is theepimer which would preponderate after equilibration of either epimer withhydrogen bromide. This more stable epimer is not necessarily the initialproduct of bromination ; Corey proposed the rule that the epimer having anaxial bromine atom is always formed more rapidly. Complete agreementbetween predicted and proved configurations of a-bromo-ketones was claimed.Some evidence on the conformation of ring A in steroid ketones wasprovided by measurements l4 of the dipole moments of androstane-3 : 17-dione and testane-3 : 17-dione.If both these substances have the (' all-chair " conformation of the six-membered rings, calculation indicates thatthe dipole moments should be identical ( 3 . 0 4 ~ ) . The observed momentswere 3.1 and 3.5 respectively. It was suggested that the " boat " con-formation of ring A (calculated moment 5.28 D) appears to the extent ofsome 16% in testane-3 : 17-dione under the experimental conditions. Thedata do not exclude the possible presence of a similar proportion of " boat "form (calculated moment 3.58 D) in androstane-3 : 17-dione.In an important contribution to the stereochemistry of steroid sapogeninsit was shown l5 that sarsasapogenin and smilagenin (stereoisomers of struc-ture XIII) differ in configuration at C(25).The $-genins (XIV) and dihydro-genins (XV; R = OH) from the two sapogenins were found to be different,contrary to earlier reports; l6 moreover, the two $-genins were each recon-verted by acid quantitatively into the parent genin. Oxidation of $-sarsa-lo E. J. Corey, J . Amer. Chem. SOC., 1953, 75, 4833; L. F. Fieser and W.-Y. Huang,ibid., p. 4837.l 1 J. J. Beereboom, C. Djerassi, D. Ginsburg, and L. F. Fieser, ibid., p . 3500.l2 R. N. Jones, D. A. Ramsay, F. Herling, and K. Dobriner, ibid., 1952, 74, 2828;R. N. Jones, ibid., 1953, 75,4839. 13 E. J. Corey, ibid., p. 2301 ; Experientia, 1953,9,329.l4 H. R. Nace and R. B. Turner, J .Amer. Chem. SOC., 1953, '75, 4063.l6 R. E. Marker and E. Rohrmann, ibid., 1939, 61, 846; idem and E. M. Jones, ibid.,I. Scheer, R. B. Kostic, and E. Mosettig, ibid., p. 4871.1940, 62, 648CORNFORTH : STEROIDS. 219sapogenin afforded (+)-a-methylglutaric acid (containing all the carbonatoms of ring F), whereas $-smilagenin gave (-)-a-methyglutaric acid.Reduction of the 26-toluene-fi-sulphonates (XV ; R = +-C,H,Me-SO,*O) ofthe dihydrogenins by lithium aluminium hydride gave the same deoxy-compound (XV; R = H). Hence, unless formation of the dihydrogeninsis attended by inversion at C(22) in one series but not in the other, sarsa-sapogenin and smilagenin differ only at C(25). I t has been stated l6 thatisosarsasapogenin, formed by acid isomerisation of sarsasapogenin, is identicalwith smilagenin.If this is true, the acid isomerisation is an inversion at C(25).Such an inversion might possibly occur by addition of a proton to the oxygenatom of ring F ; then if the 27-methyl group had the axial configuration thisproton would be rather well placed to initiate a displacement reaction withinversion of configuration at CCz5) (XVI XVII). The reaction mightMebe reversibIe. Further research is undoubtedly needed to establish theexact relation between members of the " normal " and the " is0 "-series ofsapogenins, for the above evidence l5 suggests that other small differencesbetween non-identical substances may have been overlooked. Hecogeninand diosgenin were recently 1 7 correlated with smilagenin by oxidation ofthe +-genins to (-)-a-methylglutaric acid.From hecogenin by a differentroute, (+)-methylsuccinic acid was obtained. This incident ally correlates(+)-methylsuccinic acid with (-)-a-methylglutaric acid, as already inferredby Fredga.l*The formulation of lumisterol as 10-efiiergosterol was confirmed byX-ray crystallographic analysis of its 4iodo-5-nit robenzoat e.Total Synthesis.-A synthesis of ( &)-cortisone acetate was reported.20This is essentially a modification of the Harvard synthesis; 21 space doesnot permit an extended review, but it is remarkable that selection of experi-mental techniques made possible the elaboration of the 1 l-oxo-group froma 9 : ll-double bond, and the construction of ring D and its side-chain,while retaining a A4-3-oxo-group unprotected in ring A.The method usedto construct the side-chain after the characteristic closure of ring D~~ isnoteworthy ; it is illustrated in partial formula3 (XVIII _+ XIX).Details of the Oxford total synthesis 22 and of intermediate stages in theMerck total synthesis 23 were reported.l7 V. H. T. James, Chent. and I n d . , 1953, 1388.la A. Fredga, Arkiv Kemi Min., Geol., 1947, 24, A , No. 32.D. Crowfoot Hodgkin and D. Sayre, J., 1952, 4561.2o L. I3. Barkley, M. W. Farrar, W. S. Knowles, and H. Raffelson, J . Amer. Chem.SOC., 1963, 75, 4110. 21 A. J . Birch, Ann. Reports, 1951, 48, 200.22 H. M. E. Cardwell, J. W. Cornforth, S. R. Duff, H. Holtermann, and Sir R.Robinson, J . , 1953, 361 ; see ref.21.23 G. I. Poos, G. E. Arth, R. E. Beyler, and L. H. Sarett, J . Amer. Chem. Soc., 1953,75, 422; R. M. Lukes, G. I. Poos, R. E. Beyler, W. F. Johns, and L. H. Sarett, ibid.,p. 1707; L. H. Sarett, W. F. Johns, R. E. Beyler, R. M. Lukes, G. I. Poos, and G. E.Arth, ibid., p. 2112; see Ann. Reports, 1952, 49, 190220 ORGANIC CHEMISTRY.A total synthesis of striking simplicity, leading to (-+@androsterone,was announced24 by W. S. Johnson and his associates. 5-Methoxy-2-tetralone (XX) was condensed successively with l-diethylaminopentan-3-onemethiodide and with methyl vinyl ketone to give the tetracyclic methoxy-ketone (XXT). Reduction of this substance with lithium and ethanol inMe ,.‘? x2H CHOMe I,*‘? ‘I 1 /- - ‘IA; - /- /--(XVIII)Diazo-ketonesynthesisIiquid ammonia afforded a mixture containing the ketones (XXII), onehaving a 13 : 14-, the other a 16 : 17-, doubIe bond (homosteroid numbering).After hydrogenation, the hydroxy-ketone (XXIII) was isolated.The secondangular methyl group was introduced by methylation of a furfurylidene - - w Y eO A J U(XX)0 0Several___tstagesderivative : ozonolysis of the product (XXIV) gave a dicarboxylic acid whichwas cyclised to (-J=)-e$iandrosterone (XXV). The methylation also pro-duced, unfortunately, a larger amount of the undesired 13-epimer, which wassimilarly converted into ( &- ) -1umiepiandrost erone.24 W. S. Johnson, B. Bannister, B. M. Bloom, A. D. Kemp, R. Pappo, E. R. Rogier,and J . Szmuszkovicz, J . Amer.Chem. SOL, 1953, 75, 2275CORNFORTH : STEROIDS. 22 1The conversion of (XXI) into (XXIII) produces six new centres ofasymmetry, yet the desired stereoisomeride (XXIII) was the major product.This spectacular success is a measure of the increased knowledge, acquiredduring recent years, of the stereochemistry of fused alicyclic rings.Wilds and his collaborators 25 completed a total synthesis of which earlierstages have already been published.26 The monoethylene ketal (XXVI) ofa ketone which is available 26 from dihydroresorcinol by two ring-extensionsand a partial hydrogenation was methylated via the hydroxymethylenederivative. Sodiotriphenylmethane and methyl bromoacetate then gave,after hydrolysis, a mixture of two epimeric acids (XXVII) which wereseparated and converted into the methyl ketones (XXVIII) by reaction of(XXVI) (Two epimers)(XXXI) (XXW (XXIX)the acid chlorides with tert.-bu tyl malonate and acid-catalysed decarboxyl-ation.Cyclisation (sodium methoxide) to the cyclopentenones (XXIX) wasfollowed by carboxylation (methyl carbonate-sodium hydride) to the keto-esters (XXX) . Vigorous hydrogenation (platinum-acetic acid-hydro-chloric acid) and reoxidation (chromic acid) produced, from one isomer,methyl (&)-3-oxoetianate (XXXI). Thus another method for constructingring D has been successfully applied.A total synthesis of D-homosteroids, starting from 2-methylcyclohexane-1 : 3-dione, was reported from the Ciba 1ab0ratorie.s.~~ Condensation of thedione with ethyl 7-chloro-5-oxoheptanoate (obtained from ethylene, alumin-ium chloride, and the ester chloride of glutaric acid) in the presence of tri-ethylamine gave the trioxo-ester (XXXII).Conditions for cyclization to(XXXIII) needed careful choice, to avoid fission of the 1 : 3-dione : triethyl-amine benzoate in boiling xylene was found satisfactory. Hydrogenationand alkaline hydrolysis then gave two acids (XXXIV), which were separated.The more abundant isomer was found (see below) to have the desired con-figuration. Ring B was constructed by protecting the carbonyl groups (asethylene ketals) while the carboxyl group was converted into the ethyl25 A. L. Wilds, J. W. Ralls, D. A. Tyner, R. Daniels, S. Kraychy, and M. Harnick,2E A. L. Wilds, J. W. Ralls, W. C. Wildman, and K.E. McCaleb, ibid., 1950, 72, 5794.2 7 P. Wieland, H. Ueberwasser, G. Anner, and K. Miescher, Helv. Chim. Acta, 1953,J . Amer. Chem. SOC., 1953, 75, 4878.36, 376, 1231 ; P. Wieland, G. Anner, and K. Miescher, ibid., p. 646222 ORGANIC CHEMISTRY.ketone by reaction of ethylmagnesium bromide with the dimethylamide ;hydrolysis of the ketal groups and alkaline cyclization then gave the un-saturated tricyclic ketone (XXXV). The configuration of this substance was0 0 0__+(XXXII) (XXXIII) (XXXIV; two isomers)0 0 t o Atti+ Me,?$ + py$, Me1 ,q$ H{\I/H\i/HV AVVHVOP\/I0 9 V A V O P \ A /(XXXVII; two isomers) (XXXVI; two isomers) (XXXV)proved by correlation with an intermediate in the Harvard total synthesis.21Addition of ring A was then effected by means of methyl vinyl ketone; twost ereoisomerides (XXXVI) were produced, one of which could be hydro-genated, stepwise, to a mixture of (&)-D-homoandrostanedione and (-j)-~-homotestanedione (XXXVII).The optically inactive products of this andof the other total syntheses were identified by infra-red spectrography.11 -Oxygenated Steroids.-The transformation of readily accessible sub-stances into 11-oxygenated steroids was again the subject of a larger numberof papers than appeared on any other topic in this field.A series of papers gave details for the introduction of an lla-hydroxy-group into pregnane derivatives by incubation with growing cultures ofRihizopus nigricans.28 The substances hydroxylated in this way at Ctll)included deoxycorticosterone,29 17a-hydroxy-11-deoxycorticosterone (Reich-stein’s substance S ; XXXVIII),30 17cc-hydro~yprogesterone~~~ pregna4 : 6-diene-3 : 20-dioneJ32 and pregnane- and allopregnane-3 : 20-di0ne.~~ Pregna-4 : 16-diene-3 : 20-dione was transformed by the same organism into l l a -hydroxy-17a-progesterone, isomerized by acid to 11 a-hydroxypr~gesterone.~~Cortisone acetate (XXXIX) is thus available 30 from substance S (XXXVIII)28 See Ann.Reports, 1952, 49, 195-196; the sentence referring to R. nigricans ismisplaced and should precede the sentence on p. 185 beginning “ This microbiologicalhydroxylation . . .”29 S. H. Eppstein, P. D. Meister, H. C. Murray, H. M. Leigh, D. A. Lyttle, L. M.Reineke, and A. Weintraub, J . Amer.Chem. Soc., 1953, 75, 408.30 D. H. Peterson, S. H. Eppstein, P. D. Meister, B. J. Magerlein, H. C. Murray,H. M. Leigh, A. Weintraub, and L. M. Reineke, ibid., p. 412.31 P. D. Meister, D. H. Peterson, H. C. Murray, G. B. Spero, S. H. Eppstein, A. Wein-traub, L. M. Reineke, and H. M. Leigh, ibid., p. 416.32 D. H. Peterson, A. H. Nathan, P. D. Meister, S. H. Eppstein, H. C. Murray, A.Weintraub, L. M. Reineke, and H. M. Leigh, ibid., p. 419.33 S. H. Eppstein, D. H. Peterson, H. M. Leigh, H. C. Murray, A. Weintraub, L. M.Reineke, and P. D. Meister, ibid., p. 421.34 P. D. Meister, D. H. Peterson, H. C. hlurray, S. H. Eppstein, L. M. Reineke,A. Weintraub, and H. M. Leigh, ibid., p. 56CORNFORTH STEROIDS. 223in three stages, each proceeding in good yield : 11 a-hydroxylation, selectiveacetylation a t Ctzl>, and oxidation.COCH,*OH CO*CH,*OAcThe acetate (XLIII; R = Ac) of cortisol (“ Hydrocortisone,” 17a-hydroxy-corticosterone) was obtained 35 from 3a : 17a-dihydroxypregnane-11 : 20-di-one (XL) , readily available from 11 a-hydroxyprogesterone.28 Simultaneousoxidation and chlorination by tert.-butyl hypochlorite gave the chloro-ketone (XLI). The 3 : 20-di(ethylene ketal) of this was reduced (lithiumaluminium hydride) to the 11p-01, which was hydrolysed selectively to themonoketal (XLII). Introduction of a 21-acetoxy-group via a 21-bromidewas followed by hydrolysis of the remaining ketal group; the 4-chloro-ketone then gave cortisol acetate (XLIII ; R = Ac) by the successive actionof semi-carbazide and pyruvic acid.COMe COhfe1 c1 (XLI)CO*CH,*OR COMeSeveral - stages(XLIII) (XLII)The organism Rhizopzts arrhizus with some of the above substratesgenerally effected 6P-hydroxylation, with a subsidiary proportion of 1 la-hydroxylati~n.~~? 30, 31 Other microbiological oxidations of interest includethe conversion of substance S (XXXVIII) into cortisol (XLIII; R = H)directly by Cunninghamella bZake~Zeeana.~G Three independent communica-tions 37 described the oxidation of progesterone to androsta-1 : 4-diene-3 : 17-dione (XLIV), and the oxidation of testosterone, progesterone, 17a-35 R.H. Levin, B. J. Magerlein, A. V. McIntosh, A. R. Hanze, G. S. Fonken, J. L.Thompson, A.M. Searcy, M. A. Scheri, and E. S. Gutsell, J .Amer. Chem.Soc., 1953,75,502.36 F. R. Hanson, K. M. Mann, E. D. Nielson, H. V. Anderson, M. P. Brunner, J . N.Karnemaat, D. R. Colingsworth, and W. J. Haines, ibid., p. 5369.37 E. Vischer and A. Wettstein, Experientia, 1953, 9, 371 ; J. Fried, R. W. Thoma,and A. Klingsberg, 1. Amer. Chem. Soc., 1953, 75, 5764; D. H. Peterson, S. H. Eppstein,P. D. Meister, H. C. Murray, H. M. Leigh, A. Weintraub, and L. M. Reineke, ibid.,p. 6768224 ORGANIC CHEMISTRY.hydroxyprogesterone or substance S to “ testololactone ” (XLV) by variousorganisms.0Transformation of substance S (XXXVIII) into cortisol (XLIII ; R = H)by liver homogenates was reported.38Among the chemical methods for introducing an 1 l-oxygen atom, furtherprogress was made with the already highly refined conversion of 7 : 9-dienesinto ll-ketones.Treatment of a 9a : lla-epoxy-7-ene (XLVI) with borontrifluoride in ether gives a 7-en-9p-one (XLVII),399 40 isomerized by aluminasuccessively to the “normal ” 9a-one (XLVIII) and to the 8-en-ll-one(XLIX). The inversion at C(9) without rearrangement of the double bond(XLVII) (XLVIII) (XLIX)COMe(XLVI)is noteworthy and suggests simultaneous removal and addition of a proton.40In the 9p-one (XLVII), ring c has approximately the ‘‘ boat ” conformationand hence the angular methyl groups are farther apart than in the naturalsteroids. This difference is reflected in the ease of hydrogenation of the7 : %double bond in (XLVII) : it can, for example, be hydrogenated withoutreduction of the 22 : 23-double bond in an ergosterol ~ide-chain.~~, 41 Theresulting saturated ketone (L) is isomerized to the *‘ natural ” (9a) configur-ation (LI) by strong alkali.40This procedure was used in a new transformation of ergosterol intocortisone.42 The side-chain in 5 : 6-dihydroergosterol was shortened, advan-tage being taken of the inert nuclear double bond. The resulting ketone(LII) was dehydrogenated to the 7 : 9-diene; then by the above procedurethe 1 l-keto-group.was introduced.The remaining stages are known.38 D. Amelung, H. J. Hiibener, and L. Roka, 2. flhysiol. Chem., 1953, 294, 36.39 K. Heusler and A. Wettstein, Helv. Chim. Acta, 1953, 36, 398.40 P. Bladon, H. B. Henbest, B. J. Lovell, G. W. Wood, G. F. Woods, J. Elks,R. M. Evans, D.E. Hathway, J. S. Oughton, and G. H. Thomas, J., 1953, 2921.*l J. Elks, R. M. Evans, C. H. Robinson, G. H. Thomas, and L. J. Wyman, ibid.,p. 2933.4 2 D. Maclean, W. S. Strachan, and F. S. Spring, Chem. and Ind., 1953, 1259CORNFORTH STEROIDS. 225A series of papers 403 43 described a different approach to the ergosterol __tcortisone problem, the object being to preserve, during the other necessarystructural alterations, a potential 4 : 5-double bond in the form of a 5a-hydr-oxy-group. The technique may be exemplified by a synthesis of ll-oxo-progesterone. Dehydroergosterol epidioxide acetate (LIII) was hydrogen-SeveralstagesSeveral - stagesOH (Lv)CrO,; KOHfated over nickel directly to the 5a-hydroxy-7 : 9-diene (LIV), which isevidently formed by dehydration of an intermediate 8a-01.The 9cc : l l a -epoxide of (LIV) could be degraded, by way of a bisnorcholenal and its enolacetate, to the methyl ketone (LV). The procedure already describedthen gave the 11-ketone (LYI) which was converted into 11-oxoprogesterone(LVII) by chromic acid oxidation and dehydration with alkali.Several papers appeared, which amplified work already briefly reported,on 7 : 9-diene - 11-ketone processes. The Merck group described 44 atechnique for hydrogenating 5 : 7-dienes t o 7-enes over Raney nickel inbenzene, and published a study of the oxidation of 7-enes by mercuricacetate to 7 : g-diene~.~~ Details of later stages were also gi~en.~6 I t is43 P. Bladon, R. B. Clayton, C. W. Greenhalgh, H.B. Henbest, E. R. H. Jones,B. J . Lovell, G. Silverstone, G. W. Wood, and G. F. Woods, J . , 1952, 4553; H. B. Hen-best, E. R. H. Jones, G. W. Wood, and G. F. Woods, ibid., p. 4894; P. Bladon et idem,ibid., p. 4890; R. B. Clayton, A. Crawshaw, H. B. Henbest, E. R. H. Jones, B. J. Lovell,and G. W. Wood, J., 1953, 2009; R. B. Clayton, H. B. Henbest, and E. R. H. Jones,ibid., p. 2015; P. Bladon, H. B. Henbest, E. R. H. Jones, G. W. Wood, D. C. Eaton,and A. A. Wagland, ibid., p. 2916.44 W. V. Ruyle, E. M. Chamberlin, J. 31. Chemerda, G. E. Sita, L. M. Aliminosa,and R. L. Erickson, J . Amer. Chem. Soc., 1952, 74, 5929.4 5 W. V. Ruyle, T. A. Jacob, J. M. Chemerda, E. M. Chamberlin, D. W. Rosenburg,G. E. Sita, R. L. Erickson, L. M. Aliminosa, and M.Tishler, ibid., 1953, 75, 2604.4 6 E. M. Chamberlip, W. V. Ruyle, A. E. Erickson, J. $1. Chemerda, L. &I. Aliminosa,R. L. Erickson, G. E. Sita, and M. Tishler, ibid., p. 3477.REP.-VOL. L 226 ORGANIC CHEMISTRY.interesting that " 22a" : 5p-spirostan-7-en-3a-01 (LVIII) could not be oxidizedto a 7 : 9-diene, unlike corresponding substances in the 5a-~eries.~' Fieserand his collaborators have described various oxidations of 7 : 9-diene~.*~The elegant Ciba49 process for modifying a bile-acid side chain wasfurther improved : 50 when the diphenylcholene (LIX) was treated with twoequivalents of N-bromosuccinimide in allyl bromide, the bromo-diene (LX)was produced smoothly in at least 70% yield; no hydrogen bromide wasevolved, the allyl bromide being partly converted into dibromopropane.Curiously, when the bromo-compound (LXI) was heated in allyl bromide,evolution of free hydrogen bromide accompanied formation of a diene.RrMe II/\//CP1'2/ -- /-A simple conversion of cortisone into cortisol (XLIII; R = H) wasreported.51 Cortisone (but not its 21-acetate, which gave a 3-monoketal)with ethylene glycol gave the 3 : 20-di(ethylene ketal), which was reducedby lithium aluminium hydride to the llp-01 and hydrolysed to cortisol.A new method of transforming 12-oxo-steroids into ll-oxo- or 1 lp-hydr-oxysteroids was found independently in two laboratories ; 52* 53 hecogeninH? Br, C,H,,02BrCC13.C02 1 Me \/\//\/-(LXVII) I y- (LXV)I C II (LXVI)acetate (LXII) was in each case the initial material. The known 11 : 23-dibromohecogenin acetate (LXIII) was reduced by sodium borohydride 52or lithium borohydride 53 to a mixture of the lap- (LXIV) and the 12a-01,47 M.Velasco, J. Rivera, G. Rosenkranz, F. Sondheimer, and C. Djerassi, J . Org.Chem., 1953, 18, 92.48 L. F. Fieser, W.-Y. Huang, and J . C. Babcock, J . Amer. Chem. SOL, 1953, 75, 116;L. F. Fieser and J . E. Herz, ibid., p. 121; L. F. Fieser, W. P. Schneider, and \V.-Y.Huang, ibid., p. 124.49 C. Meystre, H. Frey, A. Wettstein, and K. Miescher, Helv. Chim. Acta, 1944, 27,1815, and later papers.51 R. Antonucci, S. Bernstein, M. Heller, R. Lenhard, R. Littell, and J. H. Williams,J . Org. Chem., 1953, 18, 70.52 J. W. Cornforth and J. M. Osbond, Chem. and. Ind., 1953, 919.53 J.Schmidlin and A. Wettstein, Helv. Chim. Acta, 1953, 36, 1241.50 J: Heer and A. Wettstein, ibid., 1953, 36, 891CORNFORTH : STEROIDS. 227the former predominating. On treatment of (LXIV) with sodium hydr-oxide 52 or silver oxide and pyridine 53 an l l p : 12p-epoxide (LXV) wasiormed (the 12a-01 with these reagents gave a 12-one; cf. refs. 8 and 0).Addition of hydrogen halides to the epoxide then gave a 12a-halogeno-llp-01 (LXVI) which could be changed into an ll-one by oxidation and zincdust reduction, or into an llp-01 by dehalogenation with Raney nickel. Theunreactive bromine atom at C(23) could be removed either a t the final stage 529 53or from the e p ~ x i d e . ~ ~Conversion of an l l a : 12a-epoxide into an l l p : 12p-epoxide, and thenceinto an ll-one, was illustrated in the cholanic acid series.54 The a-epoxidewith trichloroacetic acid gave an 11 p-trichloroacetoxy-l2a-01 (LXVII) ;the methanesulphonate of this underwent, with alkali, a trans-eliminationwhich gave the p-epoxide in 50% overall yield.Imitation of Hormones.-Several " artificial hormones " were found toshow biological activity.The high progestational activity of 19-norpro-gesterone 55 is now paralleled 56 by the mineralocorticoid activity of 19-nor-deoxycorticosterone acetate (LXVIII) : this is apparently about twice aspotent as deoxycorticosterone. " 9 : 11-Anhydrocorticosterone " acetate isalso active,57 and D-homodeoxycorticosterone acetate slightly Weakandrogenic activity was observed in the synthetic product (LXIX),59 but18-nor-D-homoandrostanedione (LXX), a by-product of the total synthesispreviously described, appeared to be as active an androgen, even in the(-+)-form, as androstane-3 : 17-di0ne.~~11 a : 17u : 21-Trihydroxypregn-4-ene-3 : 20-dione (LXXI ; readily avail-able by microbial oxidation of substance s) after acetylation at Ctzl) andtoluene-P-sulphonation at C(lr) was converted (sodium acetate in acetic acid)into the 4 : 9(11)-diene (LXXII) ; the reaction is a &elimination. N-Bromoacetamide then gave the 9a-bromo-1 1 p-hydroxy-compound whichpotassium acetate cyclized to the epoxide (LXXIII).This epoxide reactedwith hydrogen halides to give 9a-halogeno-llp-ols which were oxidized toll-ones (LXXIV). The method can, of course, be used to produce cortisoneor cortisol by dehalogenation of suitable intermediates, but it is interestingthat 9a-chlorocortisone acetate (LXXIV; X = C1) and its precursor, the9a-chloro-11 p-01, proved to have activity greater than that of cortisone itself54 A.Fiirst and R. Scotoni, Helv. Chim. Acta., 1953, 36, 1410.5 5 For details of preparation see C . Djerassi, L. Miramontes, and G. Rosenkranz,5 G A. Sandoval, L. Miramontes, G. Rosenkranz, C. Djerassi, and F. Sondheimer,5 7 R. Casanova, C. W. Shoppee, and G. H. R. Summers, J., 1953, 2983.5 8 R. M. Dodson, P. B. Sollman, and B. Riegel, J . Amer. Chem. SOC., 1953, 75, 6132.59 A. J. Birch and J. A. K. Quartey, Chem. and Ind., 1953, 489.60 W. S. Johnson, H. Lemajre, and R. Pappo, J .Amer. Chem. Soc., 1953, 75, 4866.J . Anzer. Chem. SOC., 1953, 7 5 , 4440.ibzd., p. 4117228 ORGANIC CHEMISTRY.in the rat-liver glycogen assay. 61was attributed to rapid reductionRearrangement Reactions.-Ahexalone (LXXV) showed thatThe activity of the 81-aldehyde of cortisonein vivo to cortisone.62CO*CH,*OAcThree___tstageso&&/' (LXXII)GO*CH,.OAcob\/'d (LXXIII)study of the aromatization of the methyl-aqueous mineral acids gave principaily5 : 6 : 7 : 8ltetrahydro-4-methyl-2-naphthol (LXXVI) whereas anhydrousacids in acetic anhydride favoured the alternative rearrangement to thetetrahydro-1-naphthol (LXXVII). Similar behaviour was observed withandrostan-1 : 4-diene-3 : 17-di0ne.~~ The rearrangement product from chol-estadienone and acetic anhydride-sulphuric acid gave on dehydrogenationwith selenium a hydrocarbon now identified, by synthesis,64 with 8 : 3'-dimethyl-1 : 2-cyclopentenophenanthrene.(LXXVI) (LXXV) (LXXVII)A remarkable and ready aromatization of dehydroergosterol (LXXVIII)was found to occur in chloroform containing a trace of hydrogen chloride.65The product is considered to have the structure (LXXIX) and on oxidationit furnished the methylbenzenetetracarboxylic acid (LXXX) previously(j9H1,pyYy- A?) __tHO/\/\/(LXXVIII)known as an abnormal oxidation product from ergosterol (with nitric acid).The assignment of structure to this acid is fortified by a synthesis 66 of theacid (LXXXI), which proved to be different.61 J.Fried and E.F. Sabo, J . Amer. Ckem. Soc., 1953, 75, 2273.62 J. J. Schneider, ibid., p . 2024.63 A. S. Dreiding, W. J. Pummer, and A. J. Tomasewski, ibid., p . 3159.64 R. B. Woodward, H. H. Inhoffen, H. 0. Larson, and K. H. Menzel, Chem. Bey.,66 K. Alder and B. Kruger, Chem. Ber., 1953, 86, 985.1953, 86, 594. 6 5 W. R. Nes and E. Mosettig, J . Amer. Chenz. SOC., 1953, 75, 2789CORNFORTH : STEROIDS. 229Acetolysis of 6p-bromocholest-4-en-3-one produced Za-acetoxycholest-4-en-3-one (LXXXII),67 the structure of which was proved by degradation(via a mercaptal) to cholestan-Za-01. Similar results were observed in thetestosterone series,68 and the reaction was used to effect a partial synthesisCO,H CO,HCO,H(LXXX) (LXXXI) (LXXXI I)of gitogenin from dio~genin.~~ Two interesting papers appearedstereochemistry of rearrangements among D-homosteroids.70on theReactions of Especial Iderest.-The resistance of an 11 p-hydroxy-groupto acetylation under ordinary conditions is notorious, but when 3a : l l p : 17a-trihydroxypregnan-20-one was treated a t room temperature with aceticacid-acetic anhydride containing perchloric or t oluene-fi-sulphonic acid allthree hydroxyl groups were acetylated. 71 Toluene-fi-sulphonic acid withisopropenyl acetate was also effective. The product could be hydrolysed bysodium carbonate in methanol to an llp-monoacetate, but data on thehydrolysis of the 11 p-acetoxy-group are not yet available.Manganese dioxide, already known in the vitamin A field as a ratherselective oxidizing agent for allylic alcohols, was applied 72 to oxidation ofA4-3p-01s to A4-3-ones ; e.g., testosterone was prepared rather simply fromandrostenedione by reduction with lithium aluminium hydride and selectiveoxidation by manganese dioxide a t room temperature.A4-3p : 6p-Diolswere oxidized t o 6p-hydroxy-h4-3-ones. Cholesterol under more vigorousconditions gave cholesta-4 : 6-dien-3-one ; 72 cholesteryl acetate on the otherhand was oxidized to 7-oxocholesteryl acetate. 73An interesting example of steric effects on the course of hydrogenationwas discovered : 74 efiicholesterol (or its acetate or methyl ether) was hydro-genated over platinum in acidic methanol to efiicoprosterol, addition ofhydrogen thus taking place, abnormally, on the p-side.(LXXXIV) (LXXXI I I) (LXXXV)Sa-Hydroxycholestan-3~-yl toluene-P-sulphonate (LXXXIII) with sod-ium tert.-butoxide gave a mixture of the 3cc : Scc-epoxide (LXXXIV) and the6 7 L.F. Fieser and M. A. Romero, J . Amer. Chem. SOG., 1953, 75, 4716.6 8 F. Sondheimer, S. Kaufmann, J. Romo, H. Martinez, and G. Rosenkranz, ibid.,p. 4712.60 J. Herran, G. Rosenkranz, and F. Sondheimer, Chem. and Ind., 1953, 824.70 R. J. W. Cremlyn, D. L. Garmaise, and C. W. Shoppee, J., 1953, 1847; R. B.Turner, J . Amer. Chem. SOG., 1953, 15, 3484.71 E. P. Oliveto, C. Gerold, and E. B. Hershberg, Arch. Biochem. Biophys., 1953, 43,234; idem with L. Weber, H. E. Jorgensen, and R. Rausser, J . Amer. Chem. SOG., 1953,75, 5486.72 F. Sondheimer and G. Rosenkranz, Experientia, 1953, 9, 62 ; idem and C.Amen-dolla, J . Amer. Chem. SOG., 1953, 75, 5930, 5932.73 P. Meunier, G. Zwingelstein, and J. Jouanneteau, Bull. SOG. Chim. biol., 1953,35, 495. 74 J . R. Lewis and C. W. Shoppee, Chenz. and Ind., 1953, 897230 ORGANIC CHEMISTRY.ketone (LXXXV).75 Studies of the methanolysis of various steroid toluene-fi-sulphonates were reported. 76The7-monoenol acetate of methyl 3a-acetoxy-7 : 12-dioxocholanate was shownto have a 6 : 7-double bond, and a 9 : ll-double bond was demonstrated inthe enol acetate of methyl 3~--acetoxy-ll-oxocholanate.~~ Cholestanoneenol acetate, after reduction with lithium aluminium deuteride, decom-position with water, and reoxidation, gave a cholestanone retaining nodeuterium. Reduction with lithium aluminium hydride, decomposition withdeuterium oxide, and oxidation gave a cholestanone having one atom ofdeuterium.This evidence suggests that a complex such as (LXXXVI), oran intermolecular equivalent, is formed in the reduction of enol acetates, thehydrogen atoms marked (*) being introduced by the reducing agent andthe atom marked ( 7 ) during decomposition by water.78 The action of N-iodosuccinimide on enol acetates was shown to give a-iodo-ketones. Theother product was N-acetylsuccinimide. 79There were several contributions to the chemistry of enol acetates./ItAcO/\LiAlH, -allBiosynthesis of Steroids.-The demonstration that acetic acid can furnishthe carbon atoms required for biosynthesis of cholesterol, and that fifteen(LXXXVI I)MeI- Ag20 1- KOH(KO,C*[CH,],*CH:CH,) 'O,C*[CH,],*CH (CH,) -NMe,+ 1.KOHSee ref. 82 1 s sHO,C-CH, + HO,t$H,-?H, __t to, + HO,??H," methyl " and twelve " carboxyl " carbon atoms are apparently needed,made it of interest to find ways of separating the carbon atoms of cholesterol7 5 R. B. Clayton and H. B. Henbest, Chem. and Ind., 1953, 1315.76 H. R. Nace, J . Amev. Chem. Soc., 1952, 7 4 , 5937; D. D. Evans and C. W. Shoppee,7 7 R. Hirschmann and N. L. Wendler, J - Amer. Chem. SOL, 1953,75,2361.78 W. G. Dauben and J. F. Eastham, ibid., p. 1718.79 C. Djerassi and C. T. Lenk, ibid., p. 3493.8 0 H. N. Little and K. Bloch, J . Biol. Chem., 1950, 183, 33.J., 1953,540CORNFORTH STEROIDS. 231biosynthesized from " labelled " [14C]acetic acid, in order to trace theorigin of individual carbon atoms.A new degradation of cholesterol *lmade possible the separation of eight carbon atoms from rings A and B.The decisive stage in this process was a pyrolysis of the keto-aldehyde(LXXXVII), obtained from cholest-5-ene by a manipulation of ring B whichalso separated c(6) as carbon dioxide, to 2-methylcyclohexanone. Thisketone, containing the carbon atoms of ring A, was degraded as shown tothree molecules of acetic acid and one of carbon dioxide; the carbon atomsof acetic acid were separated by well-established methods.In this way it was shown that carbon atoms 2, 4, 6, and 10 are derivedfrom acetate-carboxyl, and carbon atoms 1, 3, 5, and 19 from acetate-methyl. Previously,= the side-chain of cholesterol had been separated intoits constituent carbon atoms by adapting classical procedures.Carbonatoms, 25, 23, and 20 were identified as " carboxyl "-carbon, and 26, 27,24, 22, and 21 as " methyl "-carbon,Evidence that the terpenoid hydrocarbon squalene is a precursor ofcholesterol in vivo was mentioned in last year's Report (p. 201). Sir RobertRobinson's original suggestion 84 of a hypothetical cyclization of squaleneto cholesterol would give a distribution (if the construction of squalene fromacetate is assumed t o proceed as suggested for another terpenoid compound,the guayule rubber hydrocarbon 85) of " carboxy1"- and " methyl "-carbonLanosterolCholesterol6 and'' m " signifies " methyl "-carbon ; " c '' signifies " carboxyl "-carbon.as shown in (LXXXVIII). This agrees with the results of the two degrad-ations mentioned above.However, Woodward and Bloch,S6 impressed bythe close analogy between lanosterol and cholesterol, postulated another81 J. 14'. Cornforth, G. D. Hunter, and G. Popjiik, Biochem. J . , 1953, 54, 590, 597.a2 G. D. Hunter and G. PopjBk, ibid., 1951, 50, 163.83 J . Wursch, R. L. Huang, and K. Bloch, J . Biol. Chem., 1952, 185, 439.84 R. Robinson, J , SOC. Chem. Ind., 1934, 53, 1062.8 5 J. Bonner and B. Arreguin, Arch. Biochem., 1949, 21, 109.8 6 R. B. Woodward and K. Bloch, J . Amzer. Chem. SOC., 1953, 75, 2023232 ORGANIC CHEMISTRY.mode of cyclization involving migration of a methyl group. This gives apattern (LXXXIX) identical with (LXXXVIII) in the parts already knownbut differing elsewhere.Oxidation of a labelled androstane-3 : 17-diol bythe Kuhn-Roth method and examination of the carboxyl-carbon of theresulting acetic acid (this carbon originates from positions 10 and 13, andto be a " carboxyl "-carbon) now showed that carbon atom13 is a "methyl"-carbon, in harmony with the new hypothesis but notwith the old. Later, Bloch 87 separated carbon atom 7 of cholesterol. Thisproved to be a " methyl "-carbon, again supporting the new hypothesis.It was observed that (' squalene " regenerated from the hexahydro-chloride was not incorporated into cholesterol in vivo; however, the infra-red spectrum after regeneration is different and the product may not contain" natural " squalene.88$ s9published a series ofpapers dealing with the chromic acid oxidation of cholesterol and with theimpurities present in the commercial sterol.Cholestanol and lathosterol(cholest-7-en-3p-01) are common impurities ; so also is an unknown substance,isolated as a ketone C27H4403 (" ketone 104 ") after oxidation.Space is not available to review numerous papers on the isolation andchemistry of cardiac glycosides; the story here4-f is one of steady progress along established lines.\-/ The structure of scilliglaucosidin, a highly potentglycoside of squill, was elucidated : 91 the aglyconehas the structure (XC). The orientation of thehydroxyl groups in digoxigenin has been deter-mined by degradation to methyl 3 p : 12p-dihydroxy-etianate.92species was named markogenin, after R.E. Marker. It is " 22b "-spirostan-26 : 3p-di01.~~Identification of Steroids.-The absorption spectra of 220 steroids inconcentrated sulphuric acid under standard conditions were listed.94 Auseful study was made of steroid 2 : 4-dinitrophenylhydra~ones.~~ Papersappeared on the infra-red spectra of ~apogenins,~~ e p o x i d e ~ , ~ ~ chole~tenols,~~and other steroidsg9is knownNatural Steroids-Fieser and his collaboratorsItel-A new sapogenin from several YuccaJ. W. C.8 7 K. Bloch, Helv. Chim. Acta, 1953, 36, 1611.8 8 R. G. Langdon and K. Bloch, J . Biol. Chem., 1953, 200, 135.89 G. M. Tomkins, W. G. Dauben, H. Sheppard, and I. L. Chaikoff, ibid., 1953, 202,487, and earlier papers.90 L.F. Fieser, J . Amer. Chem. Soc., 1953, '75, 4377, 4386, 4395; L. F. Fieser andG. Ourisson, ibid., p. 4404; L. F, Fieser and B. K. Bhattacharyya, ibid., p. 4418;K. Nakanishi, B. K. Bhattacharyya, and L. F. Fieser, ibid., p. 4415.91 A. Stoll, A. von Wartburg, and J. Renz, Helv. Chim. Acta, 1953, 36, 1531.92 S. Pataki, K. Meyer, and T. Reichstein, ibid., p. 1295.93 M. E. Wall, C . R. Eddy, S. Serota, and R. F. Minigef, J . Amer. Chenz. Soc., 1953,94 S. Bernstein and R. Lenhard, J . Org. Chem., 1953, 18, 1146.95 H. Reich, K. F. Crane, and S. J. Sanfilippo, ibid., p. 822.9 6 C . R. Eddy, M. E. Wall, and M. K. Scott, AnaZyt. Chem., 1953, 25, 266; R. N.Jones, E. Katzenellenbogen, and K. Dobriner, J . Amer. Chem. Soc., 1953, 75, 168.9 7 H. H. Gunthard, H. Heusser.and A. Furst, Helv. Chim. A d a , 1953, 36, 1900.98 D. R. Johnson, D. R. Idler, V. W. Meloche, and C. A. Baumann, J . Amer. Chem.Soc., 1953, 75, 52.75, 4437.Q9 H. Rosenkrantz and L. Zablow, ibid., p. 903WALKER : HETEROCYCLIC COMPOUNDS. 2337. HETEROCYCLIC COMPOUNDS.Small Rings.-Unstable intermediates obtained in the Neber rearrange-ment 1 of oximes to a-amino-ketones are shown to be azirines, e g . , ( I ) ;reduction with lithium aluminium hydride gives the aziridine ; catalyticreduction of, e.g., (I) yields an acetylated propenylamine in the presence ofacetic anhydride and the arylacetone in the presence of water.2 2 : 2-Di-methyl-3 : 3-diphenylethylenimine has been obtained by the action ofphenylmagnesium bromide or phenyl-lithium on isobutyrophenone ~ x i r n e .~The epoxidation of ethylenic compounds with organic peracids has beenreviewed,4 and continued studies of the fission of the oxiran ring by avariety of reagents are reported.5 The ready formation of episulphidesfrom epoxides and thiourea and thiocyanates is clearly shown to involvetwo Walden inversions by the observation that D(+)-2 : 3-epoxybutaneaffords L( -)-2 : 3-epithiobutane. Trimethylene sulphide (thiacyclobutane),for which physical properties suggest a planar structure,8 affords a stablesulphone with hydrogen peroxide in contrast with propylene sulphide whichgives 2-hydroxypropane-l-sulphonic acid,s but, like the latter, it undergoescleavage with chlorine, giving bis-3-chloropropyl disulphide, the relatedsulphenyl chloride, or the sulphonyl chloride depending upon the amountof halogen used.lO A convenient synthesis of 1 : 3-epoxybutane has beendescribed.llFive-membered Ring Systems.-Vinylene carbonate (1 : 3-dioxol-2-one)(11), possibly the first example of a cyclic carbonate of an enediol, is obtainedby dehydrochlorination of chloroethylene carbonate, and acts as a dienophiletowards 2 : 3-dimethylbutadiene to give the cyclic carbonate of 4 : 5-di-methylcyclohex-4-ene-cis-1 : 2-dio1.12A new method for the synthesis of substituted pyrroles is basedon the Michael-type addition of N-substituted p-aminocrotonic esters tol-nitropropene, which leads directly to N-substituted ethyl 2 : 4-dimethyl-pyrrole-3-carboxylates in good yield ; the reaction involves a novel nucleo-philic displacement of nitrite ion and its subsequent use for dehydrogen-ation. l3Anomalous displacements have been observed in applying the Gatter-mann hydrogen cyanide-hydrogen chloride formylation method to 2-bromo-Pyrrole.1 P.W. Neber and A. Burgard, Annalen, 1932, 493, 281 ; P. W. Neber and G. Huh,ibid., 1935, 515, 283.2 D. J. Cram and M. J. Hatch, J . Amer. Chem. SOC., 1953, 75, 33; M. J. Hatch andD. J. Cram, ibid., p. 38.3 H. M. Kissman, D. S. Tarbell, and J. Williams, ibid., p. 2959; cf. K. N. Campbell,B. K. Campbell, J. F. McKenna, and E. P. Chaput, J . Org. Chem., 1943, 8, 103.4 D Swern, Org. Reactions, 1953, 7, 378.G. D. Zuidema, P. L. Cook, and G. VanZyl, J . Anzer. Chem. Soc., 1953, '95, 294-R.T. E. Schenck and S. Kaizerman, ibid., p. 1636; C. 0. Guss, R. Rosenthal, and R. I;.:Brown, ibid., p. 2393; N. R. Easton and V. B. Fish, J . Org. Chem., 1953, 18, 1071.6 F. G. Bordwell and H. M. Andersen, J . Amer. Chenz. SOC., 1953, 75, 4959.7 C. C. Price and P. F. Kirk, ibid., p. 2396.8 D. W. Scott, H. L. Finke, W. N. Hubbard, J. P. McCullough, C. Katz, M. E. Gross,Q J. M. Stewart and H. P. Cordts, ibid., 1952, 74, 5880.10 J. M. Stewart and C. H. Burnside, ibid., 1953, 75, 243.11 F. Sondheimer and R. B. Woodward, ibid., p. 5438.12 M. S. Newman and R. W. Addor, ibid., p. 1263.l3 C. A. Grob and K. Camenisch, Helv. Chim. Acta, 1953, 36, 49.J. F. Messerly, R. E. Pennington, and G. Waddington, ibid., p. 2795234 ORGANIC CHEMISTRY.4-et hoxycarbonyl-3-methylpyrrole, l4 as 2-chloro-4-ethoxycarbonyl-5-formyl-3-methylpyrrole was obtained along with 5-chloro-4-ethoxycarbonyl-2-formyl-3-methyl- and 4-ethoxycarbonyl-2-formyl-3-methyl-pyrrole.1~ Al-though an electron-attracting group in the ct-position of a pyrrole preventssubstitution in an adjacent free p-position by the Gattermann-Hoeschreaction,16 such a pyrrole can still take part in a Mannich reaction; l7 thelatter reaction also affords ready access to 2--2'-pyrrolylethylamine fromEt0,C- Me "ieYpyrrole by way of 2-cyanomethylpyrr01e.~~ The ultra-violet absorptionspectra of negatively substituted pyrroles are strongly dependent on theposition of the electron-attracting group(s) and have been used in the revisionof previously accepted structure^.^^ Light-absorption characteristics suggestthat 3-hydroxypyrroles exist in the oxopyrroline as do also 2-hydroxy-p yrroles .2Outstanding advances have been made in our knowledge of the biogenesisof porphyrins.Porphobilinogen, a labile substance present in porphyriaurines, has been crystallised 22 and shown conclusively to be the monocyclicpyrrole (111),239 24 which passes on mild treatment with acid into a porphyrinmixture Z3l 25 containing mainly uroporphyrin I11 (IV),23 and on treatmentwith haemolysed chicken red cells into proto-, copro-, and uro-porphyrin.26It has been known for some time that the protoporphyrin molecule is deriv-able from eight molecules of glycine and eight molecules of " active " suc-cinate, and the observation that 6-aminolaevulic acid (V) can replace boththese precursors 27 provides a simple and logical precursor of (111), as hasbeen demonstrated in vitro in the presence of hzemolysed chicken red cells.28The biosynthesis of chlorophyll has also been reviewed.29Carbonyl groups in the 3-position of steroids react preferentially with1 4 G.G. Kleinspehn and A. H. Corwin, J . Amer. Chem. SOC., 1953, 75, 5295.1 5 A. H. Corwin and G. G. Kleinspehn, ibid., p. 2089.16 S. F. MacDonald, .f., 1952, 4176.1 7 A. Treibs and W. Ott, Naturwiss., 1953, 40, 476.18 W. Herz. J . Amer. Chem. SOC., 1953, 75, 483.19 G. H. Cookson, J., 1953, 2789.21 C. A. Grob and P. Ankli, Helv. Chivtz. Acta, 1949, 32, 2010.22 R. G. Westall, Nature, 1952, 170, 614.23 G.H. Cookson and C. Rimington, Nature, 1953, 171, 875.24 0. Kennard. ibid., p. 876; G. H. Cookson, ibid., 1953, 112, 457; S. Granick and25 P. E. Brockman and C. H. Gray, Biochem. J . , 1953, 54, 22.2 6 J . E. Falk, E. I. B. Dresel, and C . Rimington, Nature, 1953, 172, 292.27 D. Shemin and C. S. Russell, J . Amer. Chem. SOC., 1953, 75, 4873: A. Neubergerand J. J. Scott, Nature, 1953, 172, 1093.28 E. I. B. Dresel and J. E. Falk, ibid., p. 1185.20 K. Egle, Naturwiss., 1953, 40, 569.2o J. Davoll, J., 1953, 3805.L. Bogorad, J . Amer. Chem. SOC., 1953, 75, 3610WALKER : HETEROCYCLIC COMPOUNDS. 235pyrrolidine to give the 3-(pyrrolidino)enamines, thus offering a useful methodfor the protection of 3-keto-groups during, for example, lithium aluminiumhydride reduction of other carbonyl groups in the molecule.30/co NH,*CH, NH,A P1-1A- --A A- _I,Fuuran.The stereochemistry of the furan-maleic anhydride reactioncontinues to receive a t t e n t i ~ n , ~ ~ and two stereospecific syntheses of canthar-idin (VI) have been described. In the first,32 dimethyl 3 : 6-epoxy-3 : 4 : 5 : 6-tetrahydrophthalate (VII) was condensed with butadiene to give the adduct(VIII), in which the two methoxycarbonyl groups were then converted intomethyl groups and the cyclohexene ring ultimately provided the dicarboxylicanhydride ring of (VI). In the second synthesis,33 1 : 2-dihydro-1 : 2-di-methylphthalic anhydride (IX) gave in over 50% yield a peroxide (X)having the peroxide bridge in the &-position to the anhydride ring.Cata-lytic reduction gave the saturated dihydroxy-compound (XI), and thence30 F. W. Heyl and M. E. Herr, J . Amev. Chem. SOL, 1953, 75, 1918; M. E. Herr and32 G. Stork, E. E. van Tamelen. L. J. Friedman, and A. W. Burgstahler, ibid., p. 384.33 G. 0. Schenck and R. Wirtz, Naturwiss., 1953, 40, 581.F. W. Heyl, ibid.. p. 5927. 31 J. A. Berson and R. Swidler, ibid., p. 1721236 ORGANIC CHEMISTRY.the lactone (XII), Gadamer’s hydrobromocantharic acid (XIII),34 andcantharidin (VI).Synthetic applications of furans include the widely applicable conversionof 2-f uryl ketones with ammonia into 2-subs t i t ut ed 3-hydro~ypyridines,~the conversion of 2-methylfuran by a four-stage process into the thiazolefragment (4-met hyl-5-2‘-hydroxyet h ylt hiazole) of vitamin B and thehydrolysis of difurfurylideneacetone to 4 : 7 : 10-trioxobrassylic acid ; 37a large number of miscellaneous reactions of furans has also been described.38Pyrolysis of 6-dimethylamino-4 : 4-diphenylheptan-3-one methiodide affords2-et hylidene-5-met hyl-3 : 3-diphen yltet rah ydro fThiopken.Thiophens are not readily oxidised to sulphones but oxidationin suitable cases can be effected with perbenzoic acid. In the case of thiophenitself the sulphone is accessible only indirectly; it is a very reactive sub-stance, combining with maleic anhydride and readily trimerising with lossof sulphur dioxide.40 The substance previously described as thiophensulphone is really a sesquioxide (XIV) produced by diene addition of theintermediate sulphoxide to the sulphone; (XIVa) is preferred to (XIVb) asBr, Br Br -2HBr ’\I __t IT,l * I l l 1 + \ /SO, SO, SO,l l ~ ~ l ~ ~ l l or !I /=ir”’ II JI IrAyI ’I\ ITfi),so \so, so, so2 so,(XIVa) (XIVb)the substance is stable towards excess of oxidising agent.40 In the vapour-phase bromination of thiophen the monobromo-product changes from 2- to3-bromothiophen as the temperature rises, but chlorination proceeds lessreadily ; 41 fluorination of thiophen has also been studied.42A number of ring-closures on to the thiophen ring have been reported.Cyclisation of 3-thienylthioacetic acid (XV) with sulphuric acid, followed byreduction of the product with lithium aluminium hydride, gave the solidthiophthen (XVI), which is obtained from acetylene and boiling sulphur.43Thieno(2,3-c)pyridine (XVII) and thieno(3,2-c)pyridine (XVIII) are obtainedby the Pomeranz-Frisch synthesis from thiophen-2- and -3-aldehyde byusing polyphosphoric acid, and the corresponding benzo-derivatives aresimilarly accessible from thianaphthen-2- and -3-aldehyde ; 44 the Bischler-34 J.Gadamer, Arch. Pharln., 1914, 252, 636.35 H. Leditschke, Chew Ber., 1952, 85, 202; 1953, 86, 123, 612; W. Gruber, Canad.J . Chem., 1953, 31, 564.36 T. E. Londergan, N. L. Hause, and W. R. Schmitz, J . Amer. Chem. Soc., 1953, 75,445 6.38 0. Moldenhauer, G. Trautmann. W. Irion, R. Pfluger, H. Doser, D. Mastaglio, and€3. Marwitz, Annalen, 1953, 580, 169; 1953, 583, 37.39 N. R. Easton, S. J. Nelson, V.B. Fish, and P. N. Craig, J . Amer. Chem. SOC., 1953,75, 3751.4 1 C. D. Hurd and H. J. Anderson, J . Amer. Chem. SOC., 1953, 76, 3617.4 2 J. Neudorffer, Ann. Chim., 1953, 8, 501.a3 F. Challenger and J. L. Holmes, J., 1953, 1837.44 W. Herz and L. Tsai, J . Amer. Chem. Soc., 1953, 75, 5122.37 H. Midorikawa, Bull. Chem. SOC. JapaN, 1953, 86, 317.40 J . L. Melles and H. J. Backer, Rec. Trav. chim., 1953, 72, 314, 491WALKER : HETEROCYCLIC COMPOUNDS. 237Napieralski reaction is also a p p l i ~ a b l e , ~ ~ and 4 : 5 : 6 : 7-tetrahydro-4-0~0-thionaphthen (XIX) results from cyclisation of p-2-thienylbutyric acid.46GZyo~aZine.~~ It is becoming increasingly evident that 4-aminoglyoxaline-5-carboxyamide occurs as a riboside or ribotide and that these pentosederivatives are important intermediates in the biosynthesis of purines andtheir derivative^.^^ New, naturally occurring glyoxalines accumulated bymutants of Neurospora and PeniciZZium have been shown to be 4-(trihydroxy-propy1)-, 4-(3-hydroxy-2-oxopropyl)-, 4 ( 2 : 3-dihydroxypropy1)-, and ~-4-(2-amino-3-hydroxypropy1)-glyoxaline (L-histidinol) ; two other products,which appear to be phosphate esters of the trihydroxy- and hydroxyketo-compounds, are considered to be directly involved in the biosynthesis ofh i ~ t i d i n e .~ ~ A physiologically interesting base, murexine, isolated fromMurex trunculus, has been shown to be 0-4-glyoxalinylacryloylcholine(urocanylcholine) (XX) . Formamide reacts with a-hydroxy-, a-halogeno-,a-amino-, and, under reducing conditions, also with a-hydroxyimino-ketonesto give 4 : 5-substituted gly~xalines,~~ which are also obtained in excellentyield from oxazoles and f ~ r m a m i d e .~ ~2-Thiazolylmagnesium bromides are obtained from thiazoleswith a free 2-position and ethylmagnesium bromide and can be used synthetic-ally, acetic anhydride, for example, affording the 2-acetyl derivatives ; 53similarly, phenyl-lithium gives, for example, 2-thiazolyl-lithium, which canbe carboxylated although it is only stable below -40°.54 5 : 5’-Dithiazolylhas been prepared by benzidine transformation of 2-hydrazothiazole inpresence of phthalic anhydride, hydrolysis to the free amine (2 : 2’-diamino-5 : 5’-dithiazolyl), diazotisation, and treatment of the diazo-compound withhypophosphorous acid.55 Ring-closure of the penicillamine derivative (XXI) ,which cannot azlactonise, with thionyl chloride has given the substance(XXII), showing the characteristic infra-red absorption of a p-lactamcarbonyl group but lacking the biological activity of penicillin.56 Recentapplications of mixed anhydrides for the synthesis of peptides 57 haveled to the preparation of benzylpenicillinic ethoxyformic anhydride (XXIII)Thiazole.45 D. B. Capps and C. S. Hamilton, J . Amer. Chem. SOC., 1953, 75, 697.4 6 M. C. Kloetzel, J. E. Little, and D. M. Frisch, J . Org. Chem., 1953, 18, 1511.47 “ Imidazole and its Derivatives. Part I.” by K. Hofmann, Intersci. Publ., New4 8 J. S. Gots, Nature, 1953, 172, 256.49 B. N. Ames, H.K. Mitchell, and M. B. Mitchell, J . Anzer. Chem. Soc., 1953, ‘95, 1016.50 V. Erspamer and 0. Benati, Biochenz. Z., 1953, 324, 66.5 1 H. Bredereck and G. Theilig, Chem. B e y . , 1953, 86, 88. 52 G. Theilig, ibid., p. 96.53 J , Metzger and B. Koether, Bull. SOC. d i m . , 1953, 702. 64 Idem, ibid., p. 708.5 5 M. Erne, L. Herzfeld, B. Prijs, and H. Erlenmeyer, Helv. Chim. Acta, 1953, 36 354.5 6 J. C. Sheehan, K. R. Henery-Logan, and D. A. Johnson, J . Amer. Chem.’Soc.,York, 1953.1953. 76, 3292. Ann. Reports, 1951, 48, 163; 1952, 49, 146238 ORGANIC CHEMISTRY.from which new derivatives of penicillin are acces~ible.5~ A novel type ofpenicillin has been isolated in which the phenylacetyl group of benzyl-penicillin has been replaced by one derived from D-a-aminoadipic acid.59(XXI) (XXI I)-?Me2c11H1002N2s{ <H*CO.OCO.OEt (XXIII)Keten and N-acetylcysteamine gave, besides NS-diacetylcysteamine, asubstance believed to be the enolic form of 2-acetonyl-A2-thiazoline (XXIV)and a substance considered to be (XXV).60 2-Thiothiazolidones are obtainedby an improved technique from ethyleneimines and carbon disulphide,61 anda full account has been given of the degradation and synthesis of actithiazicacid [ (-)-2-(5-carboxypentyl)thiazolid-4-one].62Miscellaneous Jive-membered ring compounds.The isolation and char-acterisation of a-lipoic acid,63 the interrelations of the lipoic a~ids,~4 and thesynthesis of (&)-a-lipoic acid (the cyclic disulphide from 4 : 8-, 5 : 8-, or6 : 8-dimercapto-octanoic acid) 65 have been described.The combined f o m ,for which biological and chemical evidence suggests structure (XXVI),66 isconcerned in the enzymic oxidative decarboxylation of pyruvate.67The equilibrium between 5-amino-l-aryl-1 : 2 : 3-triazoles (XXVII ;R = Aryl, X = CR') and 5-arylamino-1 : 2 : 3-triazoles (XXVIII; R=Aryl, X = CR') has been discussed,68 and is formally analogous to theisomerisation of 5-aminotetrazoles, recalling also the alkali-cat alysed con-version of 4 : 6-diamino-l-P-chlorophenyl-1 : 2-dihydro-2 : 2-dimethyl-1 : 3 : 5-triazine into 6-amino-4-~-chloroanilino-l : 2-dihydro-2 : 2-dimethyl-1 : 3 : 5-triazine.69 5-Aminotetrazoles substituted in the amino-group (XXVIII ;X = N) are formed by cyclisation of appropriate guanylazides but theprincipal products are the l-substituted 5-aminotetrazoles (XXVII ; X =N),70 which are also obtained from monosubstituted cyanamides and hydr-5 8 D.A. Johnson, J . Amer. Chem. SOC., 1953, 75, 3636; R. L. Barnden, R. hl. Evans,J . C. Hamlet, B. A. Hems, A. B. A. Jansen, M. E. Trevett, and G. B. Webb, J., 1953,3733. 59 G. G. F. Newton and E. P. Abraham, Nature, 1953, 172, 395.60 R. Kuhn, G. Quadbeck, and E. Rohm, Chem. Ber., 1953, 86, 468.61 L. B. Clapp and J. W. Watjen, J - Amer. Chem. SOC., 1953, 75, 1490.62 Ann. Reports, 1952, 49, 210; W. M. McLamore, W. D. Celmer, V. V. Bogert,F. C. Pennington, B. A. Sobin, and I. A. Solomons, J . Amer. Chem. SOC., 1953, 75, 105;F. C. Pennington, W. D. Celmer, W. M. McLamore, V. V. Bogert, and I.A. Solomons,6; Ann. Repovts, 1952, 49, 209; L. J. Reed, I. C. Gunsalus, G. H. F. Schnakenberg,Q. F. Soper, H. E. Boaz, S. F. Kern, and T. V. Parke, J . Amer. Chem. SOC., 1953, 75,1267.64 L. J. Reed, B. G. DeBusk, C. S. Hornberger, and I. C . Gunsalus, ibid., p. 1271.65 C. S. Hornberger, R. F. Heitmiller, I. C. Gunsalus, G. H. F. Schnakenberg, and6 6 L. J . Reed and B. G. DeBusk, J . Biol. Chem., 1952, 199, 873, 881.67 Idem, J . Amer. Chem. SOC., 1953, 75, 1261.6 8 B. €2. Brown, D. L1. Hammick, and S. G. Heritage, J., 195.3, 3820.69 H. C . Carrington, A. F. Crowther, D. G. Davey, A. A. Levi, and F. L. Rose, Nature,i o W. G. Finnegan, R. A. Henry, and E. Lieber, J . Org. Chem., 1953, 18, 779.ibid p. 109.L. J. Reed, zbzd., p. 1273.1951, 168, 1080WALKER HETEROCYCLIC COMPOUNDS.239azoic acid.71 When heated, all 5-alkylaminotetrazoles (XXVIII ; R =Alkyl, X = N) rearrange to l-substituted 5-amino-compounds (XXVII ;R = Alkyl, X = N), but, on the other hand, the reverse change occurswhen R is ~henyl,~Ot 72 and 5-alkylamino-l-phenyltetrazoles give 1-a11;yl-5-/CH-CO\Me. N-CH,C\CH-C/ I\S-CH, (XXV)[X = -PO(OH), or-PO(OH)*O*PO(OH),;HSix-membered Ring Systems.-Pyridine. 2 : 6-Di-tert.-butylpyridine isan interesting base which forms salts with protonic acids but does not com-bine with Lewis acids, such as boron trifluoride, because of the bulky sub-stituents ; for the same reason it undergoes smooth nuclear sulphoiiationwith sulphur trioxide in sulphur dioxide while pyridine and 2 : 6-lutidinegive sulphur trioxide addition products.73 The N-oxides of pyridine deriv-atives offer possibilities for substitution by electrophilic reagents that arenot generally appreciated and a good account has been given of recentJapanese work in this field.74 Nitration of 3 : lj-dibrorno-, like that of3-bromo- and 3-ethoxy-, pyridine oxide gives the 4-nitro-compound but3 : 5-diethoxypyridine oxide undergoes nitration in the 2-position.75 De-carbonylation of a-pyridil takes place on heating with lead oxide, givingdi-2-pyridyl ketone, 76 and the related a-pyridoin exists in neutral and faintlyacid solution as the pure enediol (XXIX).77The electron density in crystals of 2-pyridone has been measured withsufficient accuracy in two projections to establish the existence of the -,.- /NMe 'N*CH2??h\l.J(XXXI)molecule in the pyridone form; the pyridine ring departs considerably froma regular hexagonal shape but it is planar within experimental e~~0r.787 1 W.L. Garbrecht and R. M. Herbst, J. Org. Chem., 1953, 18, 1003, 1014, 1022.72 Idem, ibid., p. 1269; cf. also R. M. Herbst and W. L. Garbrecht, ibid., p. 1283.7 3 H. C. Brown and B. Kanner, J . Amer. Chem. Soc., 1953, 75, 3865.74 E. Ochiai, J. Org. Chem., 1953, 18, 534; C. C. J. Culvenor (Reviews Pure Appl.7 5 H. J. DenHertog, C. H. Henkens, and K. Dilz, Rec. Trav. chim., 1953, 72, 296.7 8 W. Mathes and W. Sauermilch, Chem. Ber., 1953, 86, 109.7 7 F. Cramer and W. Krum, ibid., p. 1586; W. Luttke and H. Marsen, 2.Elektro-7 8 B. R. Penfold, Acta Cryst., 1953, 0, 591 ; 2-thiopyridone, idem, ibid., p. 707.Chem., 1953, 3, 83) also gives a useful account of amine oxides.chew., 1953, 57, 680; H. Hensel, Angew. Chem., 1953, 65, 491240 ORGANIC CHEMISTRY,Reduction of 2-n-butyl-3-methylpyridine gives predominantly oneracemic 2-rt-butyl-3-methylpiperidine with sodium and ethanol, and theother racemate on hydrogenation over nickel ; from the relatively greaterease of dehydrogenation of the latter it is believed to be the cis-, and theformer the trans-form. 79 Dimethyl scopolinate (XXX) has been convertedinto 3-benzyl-9-methyl-3 : 9-diazabicycZo[3 : 3 : llnonane (XXXI) by way ofthe benzylimide and reduction with lithium aluminium hydride.sOSpectrophotometric confirmation has been provided forformulating potentially tautomeric aminopyrimidines as the amino- and notas the iminodihydro-forms,sl and attention has been directed to the con-venient synthesis of 5-nitroso- and thence of 5-amino-pyrimidines by con-densation of appropriate hydroxyimino-compounds, e g ., (XXXII), withPyrimidiize.suitable N-C-N components.82 A novel route to pyrimidine derivatives isexemplified by the formation, via N-p-aminocinnamoylacetamide, of 4-hydr-oxy-2-methyl-6-phenylpyrimidine (XXXIV) on catalytic hydrogenation of5-acetamido-3-phenylisooxazole (XXXIII) .83 Many pyrimidine derivativesform crystalline complexes with urea, thiourea, biuret, and di~yandiarnide,~~and many pyrimidine and purine derivatives, including naturally-occurringones, may be characterised by the melting points of eutectics formed withdicyandiamide.85In a revision of earlier work, products formed in the condensation ofalloxan with o-dimethylaminoaniline have been shown to be the spiran(XXXV), formed in an unusual ring-closure involving an N-methyl group,and a substance formed by linking of two molecules of (XXXV) through theposition indicated * by an ether linkage.86 Dealkylation of 5 : 5-dialkyl-barbituric acids has been observed in concentrated sulphuric acid, and thegroup extruded as a carbonium ion may, in the case of 5 : 5-dialkyl-2-thio-barbituric acids, effect alkylation of a 2-thio-group.87 Vicine, long thoughtto be a glucoside of 2 : 5-diamino-4 : 6-dihydroxypyrimidine, is really derivedfrom 2 : 4-diamino-5 : 6-dihydroxypyrimidine, which is the structure ofdivicine, and vicine is the 5-~-~-glucopyranoside.~~ A new antibiotic,79 N.J. Leonard and B. L. Ryder, J . Org. Chew., 1953, 18, 598.80 R. A. Barnes and H. M. Fales, J . Amer. Chem. Soc., 1953, 75, 975; B. H. Chaseand A. M. Downes (J., 1953, 3874) report an analogous piperazine synthesis.81 D. J . Brown and L. N. Short, J., 1953, 331.82 P. D. Landauer and H. N. Rydon, ibid., p. 3721.83 G. Shaw and G. Sugowdz, hrature, 1963, 172, 955.84 S. Birtwell, J . , 1953, 1725.8 5 K. Dimroth and H.-G. Meyer-Brunot, Biochem. Z . , 1952, 323, 343.8 6 F. E. King and J. W. Clark-Lewis, J., 1951, 3379; 1953, 172.E. W. Maynert and E. Washburn, J . Anzer. Chem. Soc., 1963, 75, 700.88 A.3endich and G. C. Clements, Biochim. Biofihys. A d a , 1953, 12, 462WALKER HETEROCYCLIC COMPOUNDS. 241ami~etin,*~ has been found to contain combined cytosine, as well as p-amino-benzoic acid and (+)-a-methyl~erine.~~Few monosubstituted triazines are known and two methodsfor the preparation of 2-phenyl-1 : 3 : 5-triazine have been de~cribed,~~ oneof which involves replacement of chlorine atoms in 4 : 6-dichloro-2-phenyl-1 : 3 : 5-triazine by methylthio-groups followed by Raney nickel desulphur-isation; it is noteworthy that an attempt to effect partial replacement ofchlorine atoms in cyanuric chloride by reduction with lithium aluminiumhydride gave 4 : 6-dichloro-2-dimethylamino-1 : 3 : 5-triazine as the soleproduct.92 Monosubstituted isocyanurates are obtained by condensation ofmono-N-substituted biurets and ethyl carbonate.93Condensed Ring Systems.-Indole.Recalling the behaviour of p y r r o l e ~ , ~ ~indole-3-aldehyde and -3-carboxylic acid and ethyl indole-3-carboxylate arereduced to skatole by lithium aluminium hydride and not to the hydroxy-methyl compound.95 Reaction of 1 : 3-dimethylindole with hexane-2 : 5-&one occurs at the p-position and the resulting indolenine (XXXVI) under-goes cyclisation in the a-position with an appropriately situated activatedmethylene group, to give (XXXVII) ; with heptane-2 : 6-dione, however,the product was the same as obtainable from 3-methylcyclohex-2-enone andwas obviously (XXXVIII) ,96Triazine.CMe-OH ob‘f:~H2 Me-OH ~ ~ $ ~ ~ ~ ~ ~ C O M / \Me H,.COMec1 w(XXXVI) (XXXVII) (XXXVIII) CH5 : 6-Dimethoxyindole is conveniently obtained by catalytic reductionof 3 : 4-dimethoxy-6 : p-dinitrostyrene and it has been converted into therelated harman (XXXIX; R = Me) and yobyrone (XXXIX; R = o-toluoyl) .97 Harman itself has been synthesised starting from the pyridinering by applying the Fischer indole synthesis to cyclohexanone 2-methyl-3-pyridylhydrazone, possibly the first application in the pyridine series, anddehydrogenation of the resulting 5 : 6 : 7 : 8-tetrahydro-l-rnethyl-$-carboline(XL) with palladised charcoal.98 Dehydrogenation of 2 : 3-cycloheptindoleto the benzaza-azulene (XLI) is conveniently effected with chl0ranil.9~The interconversions and rearrangements of sfiiro-oxindoles and -indoxylsJ.W. Hinman, E. L. Caron, and C. DeBoer, J . Amer. Chein. SOC., 1953, 75, 5864.E. H. Flynn, J. W. Hinman, E. L. Caron, and D. 0. Woolf, ibid., p. 5867.B1 C. Grundmann, H. Ulrich, and A. Kreutzberger, Chem. Ber., 1953, 86, 181.B2 A. Burger and E. D. Hornbaker, J . Amev. Chem. SOC., 1953, 75, 4579.B3 W. J. Close, ibid., p. 3617.O 5 E. Leete and L. Marion, Canad. J . Chem., 1953, 31, 775.O 6 Sir R. Robinson and J. E. Saxton, J., 1953, 2596.B7 C. F. Huebner, H. A. Troxell, and D. C. Schroeder, J . Amer. Chenz. SOC., 1953,94 Ann. Reports, 1952, 49, 206.75, 6887. g* G. R. Clemo and R. J. W. Holt, J . , 1953, 1313.W. Treibs, R. Steinert, and W. Kirchhof, Annalen, 1953, 581, 542 42 ORGANIC CHEMISTRY.have been reviewed, loo and alkylation of 3-formyl-1-methyloxindole has beenshown to give 3-alkoxymethylene derivatives and not 2-alkoxyindoles.lolOxindole and dibenzyl malonate gave the enol (XLII), yielding p-3-oxindolyl-propionic acid on catalytic reduction ; lo2 and analogously oxindole anddibenzyl oxalate gave the enol (XLIII), affording the long-sought 3-oxindolyl-acetic acid on reduction.lo3f)rrC(OH) CH,*CO,*CH,Ph f/),l=C(OH) *CO,*CH,Ph\/'#'?O (xLIII)(XLI I)\ / ' p OQuinoline. The Skraup synthesis has been reviewed.lo4 The so-called2 : 4-dihydroxyquinoline appears to exist as 4-hydroxy-2-quinolone in thesolid state and isomerises partly in solution to 2-hydroxy-4-quinolone butthere is no evidence for the lactim form; lo5 also the substance long thoughtto be 2 : 3-dihydroxy-4-quinolone is N : 4-dihydroxy-2-quinolone. lo6Benzoyl chloride reacts with quinaldine oxide to give 2-benzoyloxymet hyl-quinoline,1°7 and aqueous potassium dichromate converts tetrahydro-l-methylquinoline N-oxide into the lactam, 1 : 2 : 3 : 4-tetrahydro-2-oxoquin-oline.lO* Several examples of a novel ring contraction have been observed.Photodecomposition of quinoline-3 : 4-quinone-3-diazide (3-diazo-4-quin-olone) (XLIV), simply obtained from 3-amino-4-hydroxyquinoline, affordsindole-3-carboxylic acid ; in the pyridine series, however, the photodecom-position product (XLV) reacted with still unchanged material to give, afterspontaneous decarboxylation, (XLVI), but (XLV) could be obtained undersuitable conditions.10s Reaction of 3-aminolepidine with nitrous acid(XLIV) (XLV) (XLVI)(2 mols.) is reported to give 1 : 2 : 3 : 9-tetra-azaphenanthrene 3-0xide.l~~Further polycyclic bases have been isolated ll1 from coal-tar pitch : l-aza-pyrene,l12 4-aza-2 : 3-benzofluorene, quinindoline, and 13-azafluoranthene.isoQuinoZine. Considerable progress has been made in the synthesis ofreduced isoquinolines. Condensation of aldehydes with cyclohexenylethyl-amines gives decahydrohydroxy- or octahydro-isoquinolines directly,1l3 andN-methylmorphinan (XLVII; R = H) has been synthesised from isoquin-oline via l-benzyl-1 : 2-dihydro-5-hydroxy-2-methylisoquinoline,114 from100 B.Witkop and J. B. Patrick, J . Amer. Chem. SOC., 1953, 75, 2572.lo1 E. Wenkert, A.K. Bose, and T. L. Reid, ibid., p. 5514.loa P. L. Julian and H. C . Printy, ibid., p. 5301.lo3 P. L. Julian, H. C. Printy, R. Ketcham, and R. Doone, ibid., p. 8305.104 R. H. F. Manske and M. Kulka, Org. Reactions, 1953, 7 , 59.lo5 F. Arndt, L. Ergener, and 0. Kutlu, Chem. Ber., 1953, 86, 951.lo6 Idem, ibid., p. 957.l o 8 P. J . Scheuer, W. I. Kimoto, and K. Ohinata, ibid., p. 3029.log 0. Siis, M. Glos, K. Moller, and H.-D. Eberhardt, Annulen, 1953, 583, 150.110 D. W. Ockenden and K. Schofield, J., 1953, 1915.ll1 R. Oberkobusch, Chem. Ber., 1953, 86. 975.112 New synthesis : H. Medenwald, ibid., p. 287.113 R. Grewe, R. Hamann, G. Jacobsen, E. Nolte, and K. Riecke, Annulen, 1953, 581,114 C. F. Koelsch and N. F. Albertson, J . Amev. Chem. SOC., 1953, 75, 2095.lo7 I.J. Pachter, J . Amer. Chenz. SOC., 1953, 75, 3026.88WALKER : HETEROCYCLIC COMPOUNDS. 2432-phenyla~etyl-cyclohexanone,~~~ and from cyclohexenylacetonitrile via2-cyanomethyl-l-phenylacetylcyclohex-l-ene ; 115 the valuable drug 3-hydroxy-N-methyl-morphinan (XLVII ; R = OH) has been obtainedsimply from 9-meth-oxyphenylacetaldehyde and cy~lohexenylethylamine.~~~N-Methylmorphinan (XLVII; R = H) has been obtained from octa-hydrophenanthrene precursors by a method involving a fortuitous ring-X.Je*S-1 ' I R'CHO R' R'/\/\NR /\/'\NR /--\4,-\ / I 7 \ NHR - \-1 \-/(XLVI I) (A A H 2 'VIJ OH+ U J R CH,closure. 116 The parent ring-system of the erythrina alkaloids, erythrinane(XLIX), has been obtained by ring-closure of (XLVIII) with polyphos-phoric acid followed by reduction of the amide-carbonyl group with lithiumaluminium hydride.l17The von Pechmann reaction has beenreviewed.118 In a new synthesis, benzyl o-hydroxyphenyl ketones are con-densed with ethoxalyl chloride in pyridine to give Z-ethoxycarbonyliso-flavones, and thermal decarboxylation of the free acids gives the iso-flavones.ll9> lZo In the familiar synthesis using formic ester, methyl formateis reported to give 2-hydroxyisoflavanones while ethyl formate gives theisoflavone.lZ1 The isoflavones from the soya bean are possibly genistein anddaidzein.lz0, 122 In analogy with the flavones, examples of isomerisation of5 : 8-dihydroxyiso-flavones lZ3 and -flavonols lZ4 during demethylation ofmethyl ethers have been recorded, and vigorous demethylation of 2'-methoxy-flavones may cause rearrangement with interchange of the two benzenerings.lZ5 The occurrence of isomerisation is not readily predictable anddemethylation of 7-hydroxy-5 : 8 : 4'-trimethoxyflavylium chloride withhydriodic acid proceeds without isomerisation.126Oxygen-containing ring systems.115 H.Henecka, Annalen, 1953, 583, 110.116 D. Ginsburg and R. Pappo, J., 1953, 1624.117 B. Belleau, J. Amer. Chem. Soc., 1953, 75, 5765.118 S. Sethna and R. Phadke, Org. Reactions, 1953, 7, 1.119 W. Baker, J . Chadderton, J. B. Harborne, and W. D. Ollis, J., 1953, 1882.120 W. Baker, J . B. Harborne, and W. D. Ollis, ibid., p. 1860.121 X. Narasimhachari, D. Rajagopalan, and T. R. Seshadri, J .Sci. I n d . Aes., India,122 Cf. W. B. Whalley, J . Amer. Chem. Soc., 1953, 75, 1059.lZ3 \V. Baker, I. Dunstan, J. B. Harborne, W. D. Ollis, and R. Winter, Chenr. andInd., 1953, 277 ; W. B. Whalley, ibid. ; J., 1953, 3366.1 2 1 L. H. Briggs and R. H. Locker, J., 1949, 2157; D. M. Donnelly, E. M. Philbin,and T. S. Wheeler, Chenz. and Ind., 1953, 567.125 K. M. Gallagher, A. C. Hughes, M. O'Donnell, E. M. Philbin, and T. S. Wheeler,J., 1953, 3770.126 L. Ponniah and T. R. Seshadri, PYOC. Indian Acad. Sci., 1953, 38, A , 288.1953, 12, B, 287244 ORGANIC CHEMISTRY.Pachyrrhizon (L), isolated from " yam beans," provides a new variant ofthe rotenoid type with linear fusion of four rings instead of the usual linearfusion of rings B-C-D and opposed angular fusion of rings A and E.12'(R' = OH in tephrosin,otherwise H)IRotenone; R = H Elliptone; R = H Deguelin, tephrosin; R = HSumatrol; R = OH Malaccol; R = OH Toxicarol; R = OHPurine; Pteridine. Purine itself has been found in Nature for the firsttime in the form of its 9-p-D-ribofuranoside (nebularine) 129 in the mush-room Agaricm (CZitocybe) nebuZaris Batsch.; it is of biological interestbecause of its great toxicity to mice as compared with the parent unsubsti-tuted purine. Adenosine is involved in the biological transfer of methylgroups from methionine and the presence of adequate amounts of methioninein the media is necessary for microbiological accumulation of 5'-deoxy-5'-methylthioadenosine (" adenine thiomethyl pentoside ") ; 130 the " activeL+-l P YH* H-CH-€HCH,.S*CH,CH,*CH (NH,) *CO,- py\ +N ,/N\ INNOH"/\/ NH, (LI) N\/'X/ 1 11 ICH(OH)CH,-OHmethionine '' is formed from ATP and methionine 131 but contains nophosphate and is tentatively formulated as the thetin (LI).132Improved syntheses of pteroic and pteroylglutamic acid are reported inwhich an N-toluene-p-sulphonyl-p-amino-benzoate or -benzoylglutamate isallowed to react with a substituted propylene oxide (e.g.epichlorohydrin2 : 3-epoxypropaldehyde diethyl acetal) and the product is condensed with2 : 4 : 5-triamino-6-hydroxypyrimidine with subsequent removal of protect-ing groups.133 A belief that the lateral 3-carbon fragment of the pteridinepart of pteroic acid is of sugar origin is reinforced by the observation thatOH WI)127 H.Bickel and H. Schmid, Helv. Chirn. Acta, 1953, 36, 664.12* N. Lofgren and B. Liining, Acta Chew. Scand., 1953, 7, 225.lze G. B. Brown and V. S. Weliky, J . Biol. Chenz., 1953, 204, 1019.F. Weygand, R. Junk, and D. Leber, 2. physiol. Chem., 1952, 291, 191; R. L.Smith and F. Schlenk, Arch. Biochem. Biophys., 1952, 38, 167; F. Schlenk and R. L.Smith, J . Biol. Chem., 1953, 204, 27.152 J. Baddiley, G. L. Cantoni, and G. A. Jamieson, J . , 1953, 2662.133 D. 1. Weisblat, B. J. Magerlein, A. R. Hanze, D. R. Myers, and S. T. Rolfson,J . Amer. Chem. SOC., 1953, 75, 3625; D. I. Weisblat, B. J. Magerlein, D. R. Myers,A. R. Hanze, E. I. Fairburn, and S. T. Rolfson, ibid., p. 5893.131 G. L. Cantoni, ibid., p. 403BAILEY : ALKALOIDS.245fluorescyanin (ichthyopterin) 134 is 6-( 1 : 2-dihydroxyethy1)isoxanthopterin(LII) .135 Acetonyl, carboxyl, l-hydroxyethyl, and aminomethyl groupsare reductively removed from the 6-position of such substituted isoxantho-pterins by aluminium amalgam in alkaline media.13sNucleotides. Precise spectrophotometric studies have been carried outon cytidylic acids a and b,13’ which are respectively the 2’- and the 3’-phosphate,13* and there is general agreement that adenylic acids a and bare likewise the 2’- and the 3’-pho~phate.l~~-l~~ Thymidylic acid has beenidentified as thymidine 5’-ph0sphate.l~~ Methods for the synthesis ofunsymmetrical PP-diesters of pyrophosphoric acid have been discussedand their practical utility demonstrated by the syntheses of PP-diaden-osine 5‘-pyrophosphate and P1P2-diuridine-5’ pyrophosphate. 141 The struc-ture of coenzyme A la2 is now fairly certain and its chemistry and functionshave been reviewed.143J. W.Alkaloids.During the year under review volume 3 of Manske and Holmes’s “ TheAlkaloids ” has been published,l covering the cinchona, quinoline, quin-azoline, lupin, glyoxaline, solanum, veratrum, and ipecacuanha alkaloids,%phenylethylamines, and the ephedra bases up to 1952. The biogenesis ofthe pyrrocoline alkaloids has been discussed.2 Sprouting barley has beenfound to transform ( &)-[2-14C]tyrosine into radioactive N-methyltyramineand hordenine ; the methylenedioxy- and N-methyl groups of protopine areformed from the methyl group of [14C]methylmethionine.4 Neither nicotinicacid nor its ethyl ester is utilised in the biosynthesis of ni~otine.~More details of the work on the stereochemistry of thesealkaloids have appeared.6-Hydroxytropinone has been resolved andthen reduced, giving a 3 : 6-dihydroxytropane (I) identical with the productobtained by hydrolysis of valeroidine.’Lupinus sericeus Pursh. contains at least five alkaloids,8Tropane group.Lupinane group.134 M. Polonovski, R. G. Busnel, and M. Pesson, Compt. vend., 1943, 217, 163.135 R. Tschesche and F. Korte, Angew. Chem., 1953, 65, 600.136 S. Nawa, S. Matsuura, and Y . Hirata, J . Amer. Chem. SOC., 1953, 75, 4450.137 R. J. C. Harris, S. F. D. Orr, E. M. F. Roe, and J. F. Thomas, J., 1953, 489;J. J. Fox, L.F. Cavalieri, and N. Chang, J . Amer. Chem. Soc., 1953, 75, 4315.138 L. F. Cavalieri, ibid., p. 5268.139 D. M. Brown, G. D. Fasman, D. I. Magrath, A. R. Todd, W. Cochran, and M. M.Woolfson, Nature, 1953, 172, 1184; J. X. Khym, D. G. Doherty, E. Volkin, and W. E.Cohn, J . Amer. Chem. Soc., 1963, 75, 1262.l40 A. M. Michelson and A. R. Todd, J., 1953, 961.1 4 1 S. M. H. Christie, D. T. Elmore, G. W. Kenner, A. R. Todd, and F. J. Weymouth,142 Cf, Ann. Reports, 1952, 49, 280; J. Baddiley, E. M. Thain, G. D. Novelli, and143 G. D. Novelli, Fed. Proc., 1953, 12, 675; F. Lynen, ibid., p. 683.1 Ed. R. H. F. Manske and H. L. Holmes, Academic Press, New York, 1953.2 E. Wenkert, Chem. and Ind., 1953, 1088; Sir R. Robinson, ibid., p. 1317.3 E. Leete and L.Marion, Canad. J. Chem., 1953, 31, 126.4 M. Sribney and S. Kirkwood, Nature, 1953, 171, 931.ti R. F. Dawson, D. R. Christman, and R. C. Anderson, J . Amer. Chew Soc., 1953,7 A. Stoll, A. Lindenmann, and E. Jucker, Helv. Ckiw. Acta, 1953, 36, 1506.8 L. 3 5 a r . i ~ N. J. Leonard, and B. P. Moore, Canad. J. Chem., 1953, 31, 181.J., 1953, 2947.F . Lipmann, Nature, 1953, 171, 76.75, 5114. 6 Ann. Reports, 1952, 49, 219; cf. this ~ l . , p. 164246 ORGANIC CHEMISTRY.one of which, lupanoline Cl,H,,02N2 (11), appears to be new. It is a mono-acid base containing a hydroxyl and an amide group; the hydroxyl groupwas readily lost and could not be acylated. Lithium aluminium hydridereduction of the alkaloid gave an oily base C15H2,N2, different from sparteine(111) and from a-isosparteine (I11 ; but with both C(,,-H and C(,,,-H cis to the7-9 bridge), and was apparently the hitherto unknown p-isosparteine (IV ;Y = H2).This supposition was confirmed when dehydrogenation followedby hydrogenation gave sparteine (111). Ferricyanide oxidation of p-iso-sparteine (IV; Y = H,) gave (IV; Y = 0) identical with the substanceobtained from lupanoline by dehydration followed by catalytic hydrogen-a t i ~ n . ~(111) (IV)Structure (V) previously suggested for carpaine hasbeen disproved by the isolation of myristic acid from a two-stage Hofmanndegradation. Dehydrogenation yielded deoxycarpyrinic acid (VI) and2 mols. of hydrogen; permanganate oxidation of (VI) gave pyridine-2 : 6-dicarboxylic acid.lo Dehydrogenation of ethyl carpamate resulted in theloss of 3 mols. of hydrogen and the formation of a substance having theproperties of a 3-hydroxypyridine, indicating the presence in the alkaloidof a 3- or 5-hydroxypiperidine ring. l1 Finally, methyl N-methylcarpamatemethiodide (VII) was subjected to exhaustive methylation with hydrogen-ation at each stage, and the nitrogen-free product was oxidised to 12-oxo-tetradecanoic acid (VIII), showing that carpaine had structure (IX).127 CMefCH,] , 0 Me!&-[CHJ ,*C02H !:(J-[CHJ ,*C02MePyridine group./\Me, I- I,r, "i H(V) (VI) (VII)Yo 0MeCH,*CO.[CH,],,CO,H Me lh \N/-[CH21 7-(VIII) H (1x1isoQuinoZine group. A new alkaloid, thalictricavine, C2,H2,0,N (X),has been isolated from CorydaZis tuberosa DC.; demethylenation followedby methylation converted it into corydaline, and hydrastic acid was obtained10 H. Rapoport and H. D. Baldridge, J . Amer. Chem. Soc., 1951, 73, 343; 1952, 74,12 H. Rapoport, H. D. Baldridge, and E. J. Volcheck, J . A m y , Ckem. Soc., 1953, 75,9 B. P. Moore and L. Marion, Canad. J . Chem, 1953, 31, 187.5365.5290.11 T. R. Govindachari and N. S. Narasimhan, J., 1953. 2635BAILEY ALKALOIDS. 24ion permanganate oxidation. l3lodal and 6 : 7-methylenedioxyphthalide by the Hope-Robinson method.14Corlumine (XI) has been synthesised fromI I (XI (XI) O-CH,Emetine.15 The synthesis of emetine (XIII) has been described inThey were cyclised andR CH,-H C0,Et CH,-C;/< 'LO,Et 'CH,-CH C0,Et(i) NCCH,*CO,Et(ii) EtIdetail.16 Two isomers of (XII) were obtained.Et0,C /y!3 EtO,\ CH4 Eta *CO,Et E t C H c\ CN 'CNMe0OMeMeO'oc(i) POCl,; - (ii) H,-Pt Et.H NCH,*CH,(XW c\/ (XIII) CH,reduced to (XIII); one of the isomers obtained (racemic?) did not depressthe m. p. of natural emetine. (&)-Rubremetiniurn bromide has been syn-(i) H,-Pd; (ii) P,O,; (iiij Dil. H,SO,, -CO, i13 R. H. F. Manske, J . Amer. Chem. SOC., 1953, 75, 4928.14 W. M. Whaley and M. Meadow, J.. 1953, 1067. l5 Ann. Reports, 1952, 49, 220.1 4 R. P. Evstigneeva, R. S. Livshits, M. S. Bainova, L. I. Zakharkin, and N. A.Preobrazhenskii, Zhuv. Obshchey Khim., 1952, 22, 1467; Chem. Abs., 1953, 47, 5949248 ORGANIC CHEMISTRY.thesised 17 from the oxoquinolizine (XIV) by condensation with a-cyano-N-(2-3’ : 4‘-dimethoxyphenylethy1)acetamide to give (XV) which was thenconverted into (XVI) which is structurally identical with O-methylpsycho-trine; this was then oxidised to rubremetinium bromide (XVII).Tietz andMcEwen l8 repeated the experiments of Openshaw et aZ.15 on the reduction ofthe rubremetinium cation to compounds of structure (XVIII) and found anuptake of four hydrogen atoms instead of the two required by (XVII).These results have been explained in terms of structure (XIX) for therubremetinium cation, its optical activity being due to non-planaritybecause of crowding around the positions marked with an asterisk.(XVIII) (XIX) +Indole. Details of the infra-red spectra of alstonine l9 and its derivativeshave been published.2o Corynantheine (XX) and dihydrocorynantheine(XXI) may be separated by using Craig’s counter-current extraction method.21Corynantheidine has been shown 22 to be a stereoisomer of dihydrocoryn-antheine (XXI) and not of corynantheine (XX) since it contains a C-methylgroup and no XH,; it was dehydrogenated to alstyrine (XXII) and hydro-lysis afforded an amorphous aldehyde, Wolff-Kishner reduction of whichE t Et(XXIV)gave corynantheidane (XXIII).The stereochemistry of the yohimbine-type alkaloids has been studied by application of the methods of conform-1 7 A. R. Battersby, H. T. Openshaw, and H. C . s. Wood, J.. 1953, 2463.18 R. F. Tietz and W. E. McEwen, J . Amev. Chem. SOC., 1953, 75, 4945.10 Ann. Repovts, 1952, 49, 223. 2o F. E.Bader, Helv. Chem. Acta, 1953, 36, 215.21 R. Goutarel, M. M. Janot, R. Mirza, and V. Prelog, ibid., p. 337.22 M. M. Janot, R. Goutarel, and J. Chabasse-Massonneau, Bull. Soc. chim., 1953, 1033BAILEY : ALKALOIDS. 249ational analysis.23 Ozonolysis of yohimbine alkaloids leads to 9-memberedlactams which then form linear pyrroloquinolones (XXIV) .24The alkaloid reserpine has been isolated from RauwoZJia serpentinaBenth.25, 269 27 and from Rauwolfia heterophylla Roem. and Schult.28 An-alysis indicates a formula C3,H,oOgN,,25~ 27, 28 but C3,H,0,,N, has also beensuggested.26 The alkaloid contains six methoxyl groups and is hydrolysedto reserpic acid, 3 : 4 : 5-trimethoxybenzoic acid, and methanol; the alkaloidis re-formed by reaction of methyl reserpate with 3 : 4 : 5-trimethoxybenzoylchloride.25 Permanganate oxidation of reserpic acid afforded the acid (XXV),potash fusion yielded 5-hydroxyisophthalic acid (XXVI), and seleniumdehydrogenation gave yobyrine.From these observations structure(XXVII) has been suggested for reserpic acid.25C02HM e o / f \ l d ' l/\\/ HO,d llOH \ P I g y N )H\CO,HMeOl IJNHCO*C02H \/ mHO,C (,) OH(XXVI) (XXVII) OMeThe structure of the third alkaloid from Pentaceras australis Hook hasbeen shown to be 4-methylthio-6-oxocanthine (XXVIII ; R = SMe).29Mild alkaline hydrolysis gave the corresponding acid which readily re-cyclised to form the alkaloid ; prolonged hydrolysis yielded methanethiol and(XXVIII; R = OH) which did not react with o-phenylenediamine and wasoxidised t o p-carboline-l-carboxylic acid (XXIX).This was convertedinto (XXVIII; K = OH) by reaction of its acid chloride with diethylethoxymagnesiomalonate followed by hydrolysis of the resulting ester.Treatment of (XXVIII; R = OH) with phosphorus oxychloride gave(XXVIII; R = Cl), and heating the chloro-compound with potassiummethyl sulphide yielded the alkaloid (XXVIII ; R = SMe).Lysergic acid (XXX; R = C0,H) and its derivatives are readily isomer-ised by mineral acids to compounds containing a true naphthalene system(XXXI), the products being isolated as their acetyl derivatives. Structure(XXXI) has been proved by synthesis from 4-methoxynaphthostyril(XXXII). Reduction of (XXXIV) gave dihydronorlysergic acid (XXXV) ; 3023 R.C. Cookson, Chem. and Ind., 1953, 337 ; A. Le Hir and R. Goutarel, Bull. SOC.24 €3. Witkop and S. Goodwin, J . Amer. Chem. SOC., 1953, 75, 3371.25 L. Dorfman, C. F. Huebner, H. B. MacPhillamy, E. Schlittler, and A. F. St. And+,2 6 M. W. Klohs, M. D. Draper, F. Keller, F. J. Petracek, J . Amer. Chem. SOC., 1953,28 C. Djerassi, M. Gorman, A. L. Nussbaum, and J. Reynoso, ibid., p. 5446.29 E. R. Nelson and J. R. Price, Austral. J . Sci. Res., 1952, 5, A , 768; cf. Ann.30 A. Stoll and Th. Petrzilka, Helv. Chim. Ac~u, 1953, 36, 1125, 1137.chim., 1953, 1023, 1027; W. Klyne, Chem. and Ind., 1953, 1032.Experientia, 1953, 9, 368; cf. Helv. Chim. Acta, 1954, 3'9, 59.75, 4867. 2 7 N. Neuss, H. E. Boaz, and J. W. Forbes, ibid., p. 4870.Reports, 1952, 49, 224250 ORGANIC CHEMISTRY.the base (XXXIII; R = Me) has been converted into (XXXI) by reactionwith ethyl bischloromethylmalonate followed by hydrolysis and decarboxyl-at ion .31WH R/=\fLf\/ ‘2;(XXXIII)(i) NCCH(CHO),(ii) ZnCI, - (iii) EtOH-H,SO,(iv) Ac,O(i) LiAIH,;(ii) HBr, then Ac,O(iii) (NH,),SO, tC02EtAc(XXXIV)(i) Me1(ii) H,-PtNa- - BuOH(XXXV)OMe R(i) HCIf---(ii) Ac,OPyrrolizidine grozcfi.The structure (XXXVI) 32 previously accepted formonocrotaline is incorrect .33 The infra-red spectrum of the alkaloid showsonly a single ester-carbonyl band, and has no carbonyl band correspondingto a five-membered lactone ring ; hence structure (XXXVII) is preferred.Monocrotaline reacts with thionyl chloride, forming a cyclic sulphite ester(XXXVIII), indicating the presence of an a-glycol grouping; the alkaloid isMe qle Me YH TH HO ~ C H 2 * C O o 7 C - T - O H oc-y-y--$? co 1 H Me Me\CO-CHMe / ( O A r , w c (XXXVI I)’!(XXXVI)(XXXVIII) (XXXIX)rapidly oxidised by lead tetra-acetate ; addition of o-phenylenediamine tothe oxidation mixture gave 2-hydroxy-3-methylquinoxaline (XXXIX) .Similarly, structure (XL) has been suggested for di~rotaline,~~ and (XLI)31 F.R . Atherton, F. Bergel, A. Cohen, B. Heath-Brown, and A. H. Rees, Chem.32 R. Adams and F. B. Hauserman, J . Amer. Chem. SOC., 1952, 74, 694.33 R. Adams, P. R. Shafer, and B. H. Braun, ibid., p. 5612.34 R. Adams and B. L. VanDuuren, ibid.. 1953, 75, 2377.and I n d . , 1953, 1151BAILEY : ALKALOIDS.25 1for riddelline.35usaramoensine C, ,H,,O,N.sinecic acid, isomeric with integerrinecic acid.36Crotalaria zcsaramoensis E. G. Baker contains a new alkaloid,Hydrolysis gave retronecine and usaramoen-SHMe ?H,.OHO:C-C<H=CM~-C :O Ye O:C--CH,~-CH2-C:0 I OH I~ I0 I C H Z - O\N\/(XL) (XLI)Dihydrolycorineanhydrornethine (XLII) has been synthesised, andstructure (XLIII) suggested for l y ~ o r i n e . ~ ~ Another group of workersHOA HO/) HO-/O\/\/\/ I llEt /o\AA,\\O/\/\/NMe \o/\/\NHZC I II I HZC 1 II 11 HZC(XLI I) (XLIII) (XLIV)prefers (XLIV) and it is thought that the phenanthridine skeleton is formedby re-arrangement during the Hofmann degradation.38Quinazolone group. The optically active form of febrifugine (XLVI)has been synthesised from (-)-p-benzamido-p-tetrahydrofurfurylpropionicCH2H,C’ ‘CI3-q ( i ) NEt,;~ F H C H , - C O , H BrH,C YH-CH, ( i i ) BzC1__)I I I A 0 - NHBz NH2(XLV(XLVII)(i) Quinazol-4-one;(ii) HBr 1H(XLVI)acid (XLV).a9 The infra-red spectrum of febrifugine is in agreement withstructure (XLVI) ; the infra-red spectrum of isofebrifugine shows that it isthe cyclic ket a1 (XLVI I).35 R.Adams and B. L. VanDuuren, J . Amer. Chem. Soc., 1953, 75, 4638.36 Idem, ibid., p. 4631; cf. this vol., p. 187.37 R. B. Kelly, W. I. Taylor, and K. Wiesner, J . , 1953, 2094; I<. Wiesner, W. I.Taylor, and S. Uyeo, Chem. and I n d . , 1954, 46.38 E. J. Forbes, J. Harley-Mason, and Sir R. Robinson, Chem. and I n d . , 1963,946,1317.39 B.R. Baker, F. J. McEvoy, R. E. Schaub, J. P. Joseph, and J. H. Williams, J .Ovg. Chem., 1953, 18, 178; cf. Ann. Reports, 1952, 49, 226252 ORGANIC CHEMISTRY.A new alkaloid, arborine C1,HI4ON,, has been obtained from the leavesof Glycosmis arborea Correa. Alkaline hydrolysis yielded N-methyl-anthranilic acid, phenylacetic acid, and ammonia ; reduction of the alkaloidafforded a dihydro-derivative which gave phenylacet aldehyde on hydrolysis.Structure (XLVIII), thus indicated, was confirmed by synthesis from phenyl-R RA / \ N //\/\NH I II 1- A CO~NH,1, \/ IINMe.CO.CH,Ph - I \/\a; 11 lkH2Ph \/\E;-CHP1l(XLVI 11) (XLIX)acetyl chloride and N-methylanthranilamide.40 The same substance hasalso been isolated by Chatterjee and M a j ~ r n d a r , ~ ~ who found that ozonolysisor periodic acid oxidation of the alkaloid gave benzaldehyde and prefer thealternative formula (XLIX). The infra-red spectrum of the alkaloid shouldprovide a decision.Steroid alkaloids.A review of this group has recently appeared.42Kryptogenin (L; R = OH) has been converted into the iodide (L; R = I)via the monotoluene-p-sulphonate ; the iodide was then transformed intothe phthalimido-derivative (LI) and thence into solasodine (LII).43 A newMe , , C H , y a Me , /CHZ*cy,/"\PHMe CH-COYHz07L.- yoMe I /y/\:o/CHMeH-COp?):o ' RCH,ppY-' (LI) / / \ \-/AM7\/ -HO/\/\(L)HO/')\)\)glucosidic alkaloid, isorubijervosine, has been isolated from Veratrumeschscholtzii Gray and shown to be 3~-(D-g~ucosy~)solanid-5-en-lS-ol (LIII) .44Details of the degradation of jervine to a nitrogen-free pr0duct,4~ and ofthe acetolysis of dia~etyljervine,~~ have now been published.42The suggestion 47 that cevagenine is the true alkamine of cevidine andveratridine has been disproved by hydrolysis of the alkaloids at O", to a newalkamine, veracevine.This substance shows no carbonyl absorption in40 D. Chakravarti, R. N. Chakravarti, and S. C. Chakravarti, J., 1953, 3337; Ex-4 1 A. Chatterjee and S. G. Majumdar, J . Amer. Chem. SOC., 1953, 76, 4365.42 J . McKenna, Quart. Reviews, 1953, 7, 231.43 F. C . Uhle, J . Amer. Chem. SOC., 1953, '75, 2280.44 M. W. Klohs, M. D. Draper, F. Keller, W. Malesh, and F. J. Petracek, ibid., p.4 6 0. Wintersteiner and M. Moore, ibid., p.4938.4 7 Ann. Reports, 1952, 49, 228.perientia, 1953, 9, 333.2133. 4 6 J. Fried and A. Klingsberg, ibid., p. 4929OVEREND : CARBOHYDRATES. 253its ultra-violet or its infra-red spectrum ; further action of alkali convertsveracevine into cevagenine (which contains a carbonyl group) .48 Cevageninehas been shown to contain an a-ketol grouping, and a further isomer ofcevagenine, y-cevine, has been isolated.49 The physical properties of vera-cevine and y-cevine and their derivatives suggest that the two compoundsHO*YH,(LWare identical. y-Cevine has also been isolated from commercial veratrine,after removal of cevidine and veratridine, along with a new alkaloid cevacineC,,H4,09N, which is a monoacetate ester of y - ~ e v i n e . ~ ~ Jacobs and Pelle-tier 51 consider that a structure of type (LIV) for veracevine gives a betterexplanation of the type of hydrocarbon obtained by selenium dehydrogen-ation than does a conventional steroid-type formula.A.S. B.8. CARBOHYDRATES.Last year there was a comprehensive Report on polysaccharides, sothis Section will be restricted mainly to a consideration of the simpler sugarsand their derivatives, and then only to those topics which have attractedmost attention. Since the last account of monosaccharides, " Rules ofCarbohydrate Nomenclature " have been agreed by the Publication Com-mittee of the Chemical Society, and by the American Chemical Society.Detection, Estimation, and Separation.-To fill the need for methods toindicate the positions of sugars on chromatograms, several new colourreagents have been developed and known reagents have been made morespecific.A quantitative technique using benzidine in acetic acid is satis-factory for most common sugars and their methylated derivatives, exceptketoses. A slightly alkaline methanolic solution of sodium borate andphenol-red gives good definition with dihydroxyacetone, various pentoses,hexoses, and disaccharides, and a number of p01yols.~ Resorcinol-4 : 6-di-sulphonic acid and 9-anisidine phosphate in ethanol have been used for48 S. W. Pelletier and W. A. Jacobs, J . Amer. Chem. SOC., 1953, 75, 3248.40 A. Stoll and E. Seebeck, Nelv. Chim. A d a , 1953,36,189 ; A. Stoll, D. Stauffacher, andE. Seebeck, ibid., p. 2027 ; cf.N. Elming, C . Vogel, 0. Jeger, and V. Prelog, ibid., p. 2022.5O S. M. Kupchan, D. Lavie, C. 'CV. Deliwala, and R. Y . A. Andoh, J . Amer. Chew.SOC., 1953, 75, 5519; S. M. Kupchan and D. Lavie, ibid., 1954, 76, 314.51 W. A. Jacobs and S. W. Pelletier, .J. Org. Chem., 1953, 18, 765.1 E. J. Bourne, Ann. Reports, 1952, 49, 235.3 Editorial Report on Nomenclature, J . , 1952, 5108. * J. K. N. Jones and J. B. Pridham, Nature, 1953, 172, 161.D. J. D. Hockenhull, ibid., 1953, 171, 982.8 E. Lunt and D. Sutcliffe, Biochem. J., 1953, 55, 122.7 S. Mukherjee and H. C. Scrivastava, Nature, 1953, 169, 330.L. N. Owen, ibid., 1951, 48, 168254 ORGANIC CHEMISTRY.detection. Methods are now available for distinguishing deoxy-sugars,glycals, and methylpentoses from other sugars on paper chromatogramsand for estimating 2-deoxy-~-glucose colorimetrically.s Diethyl 9-phenylene-diamine sulphite, used in conjunction with hydrolysis on paper by in-vertase,1° can be employed for the identification of raffinose in the presenceof fructosylsucrose (kestose) .ll Pentoses may interfere appreciably withthe determination of hexoses by the anthrone reagent.l2 An improvedanthrone reagent has been described l3 and a procedure using a modifiedreagent has been developed as a specific test for ket0-s~gars.l~ A modifiedorcinol test can now be used to differentiate between ketoses and othersugars including keto-aldonic acids.l5 It is reported that the Elson-Morgantest, originally considered characteristic for hexosamines, is given by apentosamine.16 3 : 4-Dinitrobenzoic acid has been used for the quantitativecolorimetric estimation of sugars l7 and two improved copper reagents-onefor use in the colorimetric, the other for the iodometric technique-forquantitative work, have been described.l 8The use of ultra-violet and infra-red absorption spectra in structuraldetection of sugars is reported.lg3 2o Anomeric forms can be differentiatedsince measurements over the range 730-960 cm.-l enable derivatives ofD-glucopyranose to be assigned to either the CL- or @-series, no matter whetherthey are reducing sugars, methylglucosides, or polysaccharides : the a-anomers absorb at 844 -J-- 8 cm.-l and the @-anomers a t 891 & 7 crn.-l.Furthermore an indication may be obtained of the positions of the glycosidiclinkages in a polyglucose.21A neat procedure for correlating the structure of glycosides consists inthe reduction, either catalytically or with sodium borohydride, of thedialdehyde formed by periodate oxidation of the sugar glycoside, and anexamination of the resulting alcoho1.22 The dialdehydes (I) from the pento-furanosides and hexopyranosides give the alcohol (11). Pentopyranosidesyield the dialdehydes (111) and then the alcohol (IV).As there is only onecentre of asymmetry (*) in (11) or (IV) all the methyl C+D- and p-L-hexo-pyranosides should give the same optically active alcohol ( A ) . Similarly,all the methyl P-D- and a-L-hexopyranosides should furnish the enantio-morph of ( A ) . The relation will hold for the pentofuranosides, and similarlyit should exist among the alcohols (IV) produced from methyl a- and p-D-and -L-pentopyranosides.Experiments with the glycosides of D-glucose,D-mannose, D-galactose, D-XylOSe, and L-arabinose have confirmed theserelations and shown that glycosidic configurations can be correlated. The8 J. T. Edward and Deirdre M. Waldron, J., 1952, 3631.9 F. B. Cramer and G. A. Neville, J. Franklin Inst., 1953, 256, 379.10 I<. T. Williams and A. Bevanue, Science, 1951, 113, 582.11 H. C. S. De Whalley, Intern. Sugar J., 1952, 54, 158.12 R. Johanson, Nature, 1953, 171, 176.13 N. J. Fairbairn, Chern. and Iqzd., 1953, 86.14 R. Johanson, Nature, 1953, 172, 956.16 M. L. Wolfrom and K. Anno, J . Amer. Chern.SOL., 1953, 75, 1038.1 7 E. Bore1 and H. Deuel, Helv. Chim. Acta, 1953, 36, 801.la M. Somogyi, J. Biol. Chem., 1952, 195, 19.19 H. Bredereck, G. Hoschele, and W. Huber, Chem. Ber., 1953, 86, 1271.20 S. A. Barker, E. J. Bourne, M. Stacey, and D. H. Whiffen, J., 1954, 171;2 1 S. A. Barker, E. J. Bourne, M. Stacey, and D. H. Whiffen, Chem. and Ind., 1953,196.22 M. Abdel-Akher, J. E. Cadotte, R. Montgomery, F. Smith, J. W. Van Cleve, andl5 J. H. Williams, zbid., 1952, 170, 894.R. L. Whistler and L. R. House, Analyt. Chem., 1953, 25, 1463.B. A. Lewis, Nature, 1953, 171, 474OVEREND CARBOHYDRATES. 255method is also applicable to the glycosides of 6-deoxyhexopyranosides andoligosaccharides.Hexop yranosides, 10,- iFi ZH, *is] pentofuranosides 1 - - H,*OH7H.O H*OCH2*OH H2*OH(1) (11)To determine the rotation of an unknown a-glycoside it is usual to applyHudson's isorotation rules, by appropriate combination of the rotation ofthe p-anomer with the rotations of a related anomeric pair of glycosides.Ithas been suggested-and evidence provided 23 supports the idea-that, inthe related anomeric pair employed, the aglycone should bear the greatestpossible structural similarity to the aglycone of the unknown or-glycoside.Ring paper-chromatography for the separation of sugars has beendiscussed.24 I t is claimed 25 that limited use can be made of cellulose sheets(approx. Q in. thick) as chromatographic supports for separating a relativelylarge amount of a sugar mixture. Paper-chromatography and detection 26of phosphate esters 27 including phosphorylated hexose esters 28 have beendescribed.In a new method for oligosaccharides, the sugar is converted onthe chromatogram into the corresponding N-benzylglycosylamine,29 con-siderable increases in RF values of oligosaccharides being reported.Chromatography of un-neutralised polysaccharide hydrolysates is feasibleif aniline phosphate or phthalate spray is used for detection of the sugar.soMobility on the paper has been correlated with carbohydrate structure : 31regularities for homologous oligosaccharide series lead to a straight linecharacteristic of each series, when the logarithm of a partition function(obtained from single- or multiple-ascent experiments) is plotted againstmolecular size; the generalisation is proposed that increasing the size of asaccharide by one hexose unit will decrease the mobility by an amountwhich depends on the type of hexose unit being added and on its mode ofattachment. Examples included oligosaccharides of the starch, dextran,levan, inulin, and galactan types.Several workers have stressed that caremust be exercised in interpreting chromatograms. Apparently on unwashed23 W. A. Bonner, M. J. Kubitshek, and R. W. Drisko, J. Ames.. Chem. SOC., 1962, 74,25 L. S. Cuendet, R. Montgomery, and F. Smith, J . Attzer. Chem. SOC., 1963, 75, 2764.28 H. E. Wade and D. M. Morgan, Nature, 1953, 171, 529.2 7 E. Fletcher and F. H. Malpress, ibid., p. 838; S. Burrows, F. S. M. Grylls, and28 J. Dulberg, W. G.Roessler, T. H. Sanders, and C. R. Brewer, J . Biol. Cheln.,3O B. D. E. Gaillard, ibid., p. 1160.31 D. French and G. M. Wild, J . Awzer. Chent. SOC., 1953, 75, 2612.5082. 24 T. Bersin and A. Miiller, Helv. Chinz. A d a , 1952, 35, 475.J. S. Harrison, ibid., 1952, 170, 800.1962, 194, 199. 2B R. J. Bayly and E. J. Bourne, Nature, 1953, 171, 386256 ORGANIC CHEMISTRY.paper, heating to develop the spots results in interconversion of aldose andketose sugars 32 by alkaline impurities. When diabetic urines or glucosewas chromatographed with a butanol-ammonia system, two extra spotswere observed 33 and later identified 34 as glucosylamine and diglucosylamine.For methyl glycosides of fructose and galactose it was possible to separatein a single operation on a column of powdered cellulose not only ring-isomericglycosides, but also anomeric glyco~ides,~~ the eluting solvent being theupper phase of a mixture of ethyl acetate, technical pyridine, water, andbenzene (5 : 3 : 3 : 1). Many applications of the Whistler-Durso technique 36for sugar separations continue to appear.A gradient elution analysisprocedure, suitable for the separation of oligosaccharides has been de-scribedJ37 employing a continuously increasing concentration of ethanolin water. Methylpentoses, pentoses, and aldohexoses are separable on astarch column with butanol-propanol-water (4 : 1 : l).38 Favourable con-ditions have been determined for the selective separation on alumina of thetwo constituents of starches from maize, tapioca, and potatoes.39Ionophoretic separation of sugars, as their borate complexes, has beenin~estigated.~~ The value of the original method has been extended byimprovements in the apparatus, enabling potential gradients of 40-60vlcm. to be applied safely for 1-3 hours.41 Evidence has been adduced42suggesting that aldehyde-forms of sugar derivatives interact with borate ions,and hence migrate on ionophoresis.The method has been used43 forseparation of 2 : 3-, 2 : 4-, and 3 : 4-di-O-methylrhamnopyranose which aredifficult to resolve completely in other ways.The capacity of many sugars to form borate complexes also facilitatestheir separation by ion-exchange resins. The sugars are adsorbed on borate-treated strong base anion-exchange resin and eluted with boric-boratebuffers.44 Disaccharides are readily separated from monosaccharides, andcomponents of hexose and pentose mixtures are easily resolved as are hexose-pentose mixtures.The method is suitable for preparative purposes.45 Com-bination of the borate complex adsorption technique with elution by buffersprogressively adjusted for pH and ionic character is useful for separation ofthe commonly encountered monophosphorylated sugars.4G Although it hasbeen suggested 47 that columns of " Amberlite IRA 400 (OH-) " might beused for the separation of reducing and non-reducing carbohydrates, certainreducing sugars, and more particularly glucose and fructose, are degradedto organic acids by this resin.48 Furthermore some conversion of D-glucose32 R.B. Duff, Ckem. and Ind., 1953, 895.33 R. J. Ba.yly, E. J. Bourne, and M. Stacey, Nature, 1951, 168, 510.34 Idem, zbzd., 1952, 169, 876.3 5 J. A. Augestad, E. Berner, and E. Weigner, Chem. and Ind., 1953, 376.36 R. L. Whistler and D. F. Durso, J . Anzer. Chem. Soc., 1950, 72, 677.3 7 R. S. Alm, A d a Chem. Scand., 1952, 6, 1186. 38 S. Gardell, ibid., 1953, 7, 201.3O E. H. Fischer and W. Settele, Helv. Chim. Acta, 1953, 36, 811.40 R. Consden and W. M. Stanier, Nature, 1952, 169, 783 ; L. Jaenicke, Xaturwiss.,4 1 D. Gross, Nature, 1953, 172, 908.42 A. B. Foster, J., 1953, 982.44 J. X. Khym and L. P. Zill, J . Anzer. Chem. SOC., 1952, 74, 2090.45 L. P. Zill, J. X. Khym, and G. M. Cheniae, ibid., 1953, '45, 1339.4 6 J. X. Khym and \V.E. Cohn, ibid., p. 1153.4 7 S. Roseman, R. H. Abeles, and A. Dorfman, Arch. Biochem., 1952, 36, 232.4 8 J . D. Phillips and A. Pollard, Nature, 1953, 171, 41; L. I. Woolf, ibid., p. 841.1952, 39, 86; A. B. Foster and hl. Stacey, J . Appl. Chem., 1963, 3, 19.43 Idem, Chem. and Ind., 1952, 828OVEREND : CARBOHYDRATES. 257into D-fructose was observed49 on passage through a strongly basic anion-exchange resin [" IRA 400 (OH-) "]. Much lactic acid was produced whensolutions of glucose, sucrose, and fructose were passed through columns ofDowex 2 resin and eluted with dilute hydrochloric acid.50Anhydro-compounds.-Cleavage of epoxide rings in anhydro-sugars con-tinues to attract interest. The action of phenols on some ethylene oxidederivatives has been in~estigated.~~ In the examples studied (1 : 2-5 : 6-diepoxyhexane, 1 : 2-5 : 6-dianhydro-3 : 4-O-isopropylidenemannitol, and5 : 6-anhydro-1 : 3-2 : 4-di-O-ethylidene-~-sorbitol), rupture of the anhydro-ring(s) occurred and the aryl substituent entered the molecule at the primaryhydroxyl group.Further examples of the action of acidic reagents onethylene oxide anhydro-sugars have been reported. The chief product fromthe reaction of methyl 2 : 3-anhydro-4 : 6-O-benzylidene-a-~-mannoside (V)with hydrochloric acid is methyl 3-chloro-3-deoxy-a-~-altroside.~~ Treat-ment of methyl 3 : 4-anhydro-6-O-trityl- a-D-galactoside with the same acidaffords as expected methyl 3-chloro-3-deoxy-oc-~-guloside and methyl4-chloro-4-deoxy-a-~-glucoside.~~ The reaction of the 2-O-acetate of thelatter anhydride with hydrogen chloride in acetone has been re-investigated 54and the presence of both gulose and galactose derivatives in the product hasbeen confirmed.53 It is suggested that the galactose derivative is formed asillustrated. This reaction merits further investigation since it might providea route to cis-glycols from epoxides.+CMe, CMe,/ \ + H +Ho*(fMea CleavageMe,C-OH-+ H d ' O + yay + T><O$/ a t a \+ I/ q).pH HH H H H H 1-AThe view expressed in the Report for 1951 concerning the action ofGrignard reagents on sugar epoxides is supported by the finding that methyl2 : 3-anhydro-4 : 6-O-benzylidene-a-~-alloside is converted by phenyl-magnesium bromide into methyl 4 : 6-0-benzylidene-2-bromo-2-deoxy-a-~-altroside.Likewise, with ethylmagnesium bromide or iodide it furnishesthe 2-bromo- or 2-iodo-altroside derivative : no glucose isomer is obtained.55However, the overall picture is confused since, when the anhydro-allosidereacted with methylzinc iodide the product was methyl 4 : 6-O-benzylidene-3-deoxy-3-iodo-a-~-glucoside. 55 The action of diethylmagnesium on (V)under a variety of conditions has been in~estigated.~~ In ether the soleproduct is methyl 4 : 6-O-benzylidene-3-deoxy-3-C-ethyl-a-~-altro~ide (V1)-a novel branched-chain sugar. The reaction is not straightforward and intoluene leads to a complex mixture. Attempts have been made to explainthe nature of the products resulting from ring cleavage of sugar epoxides.For alkaline reagents and with an equatorial 6-hydroxymethyl group the'* L.Rebenfeld and E. Pacsu, J . Amer. Chem. SOC., 1953, 75, 4370.50 A. C. Hulme, Natuve, 1953, 171, 610.61 G. P. McSweeney, L. F. Wiggins, and D. J. C. Wood, J., 1952, 37.52 F. H. Newth and (in part) R. F. Homer, J., 1953, 989.53 V. Y. Labaton and F. H. Newth, J., 1953, 992.54 J. W. H. Oldham and G. J. Robertson, J., 1935, 685.5 5 G. N. Richards and L. F. Wiggins, J., 1953, 2442.56 A. B. Foster, W. G. Overend, M. Stacey, and G. Vaughan, J.. 1953, 3308.REP.-VOL. L 258 ORGANIC CHEMISTRY.preponderant isomer from the 2 : 3-anhydro-sugars is that which has theentering substituent in the polar ~onfiguration.~~ I t has been emphasised,58however, that in the present state of knowledge it is unsafe to presupposethe conformation of a monocyclic product resulting from epoxide fission.CH2 9 H r?o,HPhCH-0 (-1 OMe I I+ .:,I PhCH-0 ]Tl;:g 1-1 OMe(V) H H Et H (VI)That results in this field are still somewhat empirical is illustrated by theunexpected finding 59 that whereas treatment of methyl 2 : 3-anhydro-~-lyxofuranoside with sodium methoxide and subsequent hydrolysis affords2-O-methyl-D-xylose (1 part) and 3-O-methyl-~-arabinose (2 parts), similartreatment of the 5-O-methyl ether of the anhydropentoside gives only2 : 5-di-O-methyl-~-arabinose, no xylose derivative being detectedThe highlight of the year in sugar chemistry, undoubtedly was the chemicalsynthesis of sucrose.60 Dry tri-O-acetyl-D-glucosan<l : 5>a<l : 2>(1 : 2-anhydro-3 : 4 : 6-tri-O-acetyl-a-~-glucose) 1 : 3 : 4 : 6-tetra-O-acetyl-D-fructofuranose were heated together in a sealed tube at 100" for4 hours.Sucrose octa-0-acetate was isolated by Lo y--AC standard procedures in very low yield (56%) and onde-acetylation afforded sucrose. Likewise, maltoseocta-0-acetate was prepared (8% yield) by reaction ofAcO 1 H the anhydride with 1 : 2 : 3 : 6-tetra-O-acetyl-p-~-W1) glucopyranose 61 and subsequent further acetylation,etc. I t is believed that the 1 : 6-p-~-cyclic ion (VII) is formed as an inter-mediate in reactions of the Brig1 anhydride with alcohols at elevatedtemperatures.Methods have been described for the preparation of anhydro-compounds.andCH,\/I G A C T/'OHHOBz H(VIII)/"-\ OH H (IX)HCH,*OEIHO 1-1 EIOH H (XI1-Fluoro-p-D-glucose with barium hydroxide gives 1 : 6-anhydro-~-glucose.62Reduction of tetra-0-benzoyl-p-D-fructopyranosyl bromide (VIII) withlithium aluminium hydride affords a small amount of 1 : 5-anhydro-~-I 7 A. K. Bose, D. K. R. Chaudhuri, and A. K. Bhattacharyya, Chem. and Ind.,59 E. E. Percival and R. Zobrist, J . , 1953, 564.60 R. U. Lemieux and G. Huber, J . Amer. Chem. SOC., 1953, 75, 4118.61 R. U. Lemicux, Canad. J . Chem., 1953, 31, 949.62 F. Micheel and A. KIemer, Chem. Bcr., 1952, 85, 187.1953. 869. 5* F. H. Newth, ibid., p. 1257OVEREND : CARBOHYDRATES. 259mannitol (IX) together with a new hexitan as the major prcduct. This wasidentified as 1 : 5-anhydro-~-gulitol (X) .63The nature and yields of the products resulting from the action of coldconcentrated hydrochloric acid on L-sorbose 64 are similar to those for thetwo main products from the analogous reaction with D-fructose. Theseproducts have been designated diheterosorbosans I and I1 and shown to berespectively di-L-sorbopyranose 2 : 1'-2' : l-dianhydride (XI) and mostprobably L-sorbofuranose-L-sorbopyranose 2 : 1'-2' : l-dianhydride (XII) .From this reaction with fructose, in addition to diheterolevulosan I and 11,H OH HHO ~!--O,JH,--O 3'1 14r OH !/I \/A7&\lv (XI)A T q [ q O < H +\o-i[kOH H Ha new crystalline dianhydride has been isolated 65 which apparently is eitherdi-D-fructopyranose 1 : 2'-2 : 3'-dianhydride, or, more probably, an anomericform of diheterolevulosan 11.H OH HH /"\ 1\/H-o\/HTGo\ I i O H (XII)HO*H,C K H 1-1 ""/\o-~/\o-"/l l HOH H H HDeoxy- and Branched-chain Sugars.-A new deoxy-sugar, boivinose, hasbeen obtained by hydrolysis of a glycoside obtainable from Roupelinaboivini Pichon (Strophanthus boivini Bai11).66 I t has been identified as 2 : 6-dideoxy-D-xylohexose and its synthesis achieved.67 The conversion ofanhydro-sugars of ethylene oxide type directly into deoxy-sugars by treat-ment with lithium aluminium hydride has been exploited. Coupled withconventional sugar reactions methyl 2 : 3-anhydro-4 : 6-di-O-tosyl-a-~-alloside has been converted by this method into digitoxose and cymarose.68Reductive elimination of toluene-P-sulphonyloxy-groups can also beachieved by this reagent and treatment of 3 : 5-O-benzylidene-1 : 2-O-iso-propylidene-6-O-tosyl-~-glucofuranose and 1 : 2-0-isopropylidene-3 : 5-di-0-t osyl-D-xylofuranose affords derivatives of 6-deoxy-~-glucose (D-gluco-methylose) 69 and 5-deoxy-~-xylose (D-xylomethylose) 70 respectively.Thereactivity of groups in a sugar molecule towards the reagent is : anhydro-ring > primary tosyl ester > secondary tosyl ester.71Currently, attention is focused on the physiological action of 2-deoxy-D-glucose, especially as an inhibitor and antagonist of glucose,72 and so the63 R. K. Ness and H. G. Fletcher, jun., J . Amer. Chem. SOL, 1953, 75, 2619.64 M. L. Wolfrom and H. W. Hilton, ibid., 1952. 74. 5335.e 5 M. L. Wolfrom, H.W. Hilton, and W. W. Binkley, ibid., p. 2867.66 0. Schindler and T. Reichstein, Helv. Chim. Acta, 1952, 35, 730.6 7 H. R. Bolliger and T. Reichstein, ibid., 1953, 36, 302.6 8 H. R. Bolliger and P. Ulrich, ibid., 1952, 35, 93.69 P. Karrer and A. Boettcher, ibid., 1953, 36, 570.70 Idem, ibid., p. 837. 71 H. R. Bolliger and M. Thiirkauf, ibid., 1952, 35, 1426.72 F. B. Cramer and G. E. Woodward, J . Franklin Inst., 1052, 253, 354; J. 0. Ely,F. A. Tull, and J. A. Hard, ibid., p. 361; M. H. Ross and J . G. Archer, ibid., p. 525;G. E. Woodward, ibid., 1952, 254, 553 ; G. E. Woodward and F. R. Cramer, ibid., p. 259260 ORGANIC CHEMISTRY.glycal reaction for its preparation has been re-investigated. 73 Besidesyielding 2-deoxy-sugars, the reaction also affords furan derivatives. Meth-anolic hydrogen chloride and D-glUCal gave not only methyl 2-deoxy-ap-D-glucoside but other substances also, amongst which Z-hydroxymethyl-5-methoxymethylfuran was recognised.74 Of interest, was the conversionof D-glucose into %deoxy-~-xylose. 75 1 : 2-5 : 6-Di-O-isopropylidene-3-0-tosyl-D-glucofuranose was converted into 3-deoxy-1 : 2-5 : 6-di-O-isopropyl-idene-D-glucoseen (XIII) which on reduction and hydrolysis yielded 3-deoxy-D-galactose (XIV). The oxime of (XIV) on treatment with l-fluoro-2 : 4-dinitrobenzene in weakly alkaline solution gave the lower aldose, i.e.,2-deoxy-D-xylose.0A method is still sought for the synthesis of 2-deoxy-D-ribose in goodyield. Partial oxidation of 3-deoxy-~-g~ucose with periodate followed bydeformylation 76 gave some deoxypentose 77 (29% yield).Arabinose washeated in pyridine and converted into ribulose which was isolated as itso-nitrophenylhydrazone and reduced as such to the 2-amino-2-deoxy-pentitols. These were converted into 2-deoxyribose (3% overall yield) bytreatment with nitrous acid.78 To the Reporter the explanations proposedfor the reactions involved do not seem plausible. Application of the im-proved 79 Ruff method of degradation to calcium dextromet asaccharinateyielded 2-deoxy-~-ribose. Since carbohydrate precursors give poor yieldsof the deoxypentose an attempt has been made to build up the molecule fromsimpler units. 81 Allylmagnesium bromide and 2 : 3-O-isopropylidene-~-glyceraldehyde react to give 1 : 2-isopropylidenedioxyhex-5-en-3-01, appar-ently containing largely the erythro-isomer.Hydroxylation of this, followedby periodate oxidation and hydrolysis, afforded 2-deoxy-D-ribose, in pooroverall yield. Deoxyribose-5 phosphate has been synthesised enzymicallyfrom acetaldehyde and triose phosphate.82 There is a preliminary announce-ment 83 of the chemical synthesis of some phosphoric esters of 2-deoxy-L-ribose.Following the successful enzymic synthesis of 6-deoxy-~-fructose and-L-sorbose by addition of pea aldolase to DL-lactaldehyde and triose phos-phate 84 it has been shown that this enzyme converts triose phosphate and73 F. B. Cramer, J. F r a n k l i n I n s t . , 1952, 253. 277.74 F. Shafizadeh and M. Stacey, J ., 1952, 3608.75 F. Weygand and H. Wolz, Chem. Ber., 1952, 85, 256.7 6 G. R. Barker and D. C. C. Smith, Chem. and I n d . , 1052, 1035.7 7 P. A. J. Gorin and J. K . N. Jones, Nature, 1953, 172, 1051.79 H. G. Fletcher, jun., H. W. Diehl, and C. S. Hudson, J . Anzer. Chem. SOL, 1950,81 L. Hough, ibid., 1951, 406; J . , 1953, 3066.83 E. Racker, J . B i d . Chem., 1953, 196, 347; M. G. McGeown and F. H. Malpress,R. Allerton, W. G. Overend, and M. Stacey, Chem. and I n d . , 1952, 952.84 L. Hough and J . K. N. Jones, ibid., p. 715; J., 1952, 4052.Y. Matsushima and Y . Imanaga, ibid., 1953, 171, 475.72, 4546.Nature, 1952, 170, 575.G. N. Richards, Chem. and I n d . , 1953, 1035OVEREND : CARBOHYDRATES. 261acetaldehyde into 5-deoxyxylulose.85 Reductive desulphurisation of thediethyl mercaptal of the corresponding hexose 86 or pentose 87 leads to1 -deoxy-hexit 01s or -pentit 01s.The mechanism of formation of saccharinic acids has been studied with14C as a The action of lime-water on D-mannOSe and D-galactoseleads to the formation of " D-ghcosaccharinic acid " (XV) and " D-galacto-a-metasaccharinic acid " (XVI) respectively.Results obtained so farindicate that the branched-chain acid (XV) and the straight-chain acid (XVI)are formed by different mechanisms. (XV) is produced by a recombinationprocess, involving sugar fragments, the identity of which is not known withcertainty. Formation of (XVI) proceeds by a process of intra-molecularisomerisation and hydration, similar to the benzilic acid rearrangementmechanism, as suggested by Nef 89 and I ~ b e l l .~ ~C;O,H n:PMe nyHMe-OH H*O.COBui OQi:O." oG HH -HCH, CH,(XV) ( X V I ) (XVII) (XVIII)Methanolysis of the antibiotic " Magnamycin " 91 yielded a base and aneutral oil. Evidence presented 92 indicates that the neutral material 'isthe methyl 4-O-isovalerylglycoside (XVII) of a new branched-chain deoxy-sugar (XVIII), named mycarose. [The disposition of the groups in (XVII)and (XVIII) has no significance since the stereochemistry is not yet workedout.] The successful synthesis is reported s3 of cordycepose, a branched-chain sugar component of cordycepin, a metabolic product of Cordycefisrnilitaris (Linn.) Link.94 Another synthesis of a branched-chain sugar isdiscussed on p.258.Glycosylamines and Amino-Sugars.-1-Amino-derivatives of cellobioseand lactose are formed by the action of alcoholic ammonia (at high tem-perature and under pressure) on these sugars.95 D-Psicose, 4(5)-rnethyl-glyoxaline, and 2-methyl-5- and 2-methyl-6( ?)-(D-arabotetrahydroxybuty1)-pyrazine have been obtained from the complex mixture resulting fromtreatment of D-glUCOSe with aqueous ammonia.96 Lactose and maltose areisomerised in aqueous ammonia to lactulose and maltulose and also undergoalkaline fissi0n.~7 A general method has been devised for preparing, ascharacteristic derivatives, the crystalline N-P-tolylglycosylamines of theF M-V-OHH T - O HHY-OHH2L:HCH,.OH85 P. A. J. Grin, L. Hough, and J. K. N. Jones, J., 1953, 2140.8G E.Zissis and N. K. Richtrnyer, J . Amev. Chenz. Soc., 1952, 74, 4374.8 7 Idem, ibid., 1953, 75, 129.J. C. Sowden and D. J . Kuenne, ibid., p. 2788.89 J. U. Nef, A n n a l e n , 1907, 357, 294; 1910, 376, 1.B0 H. S. Isbell, J . R e s . Nut. Bur. Stand., 1944, 32, 45.B1 R. L. Wagner, jun., F. A. Hochstein, K. Murai, N. Messina, and P. P. Regna,B2 P. P. Regna, F. A. Hochstein, R. L. Wagner, jun., and R. B. Woodward, ibid.,94 H. R. Bentley, K. G. Cunningham, and F. S. Spring, J . , 1951, 2301.95 F. Micheel, R. Friei, E. Plate, and A. Hiller, Chem. Ber., 1952, 85, 1092.B6 L. Hough, J. K. N. Jones, and E. L. Richards, J., 1952, 3854.97 I d e m , J., 1953. 2005.J . Amer. Chern. SOC., 1953, 75, 4685.p. 4626. 93 R. A. Raphael and C . M. Roxburgh, Chem. and I n d ., 1953, 1034262 ORGANIC CHEMISTRY.common aldoses (except L-arabinose) .98 The influence of moisture on theformation of the two isomeric N-phenyl-D-ribosylamines has been estab-l i ~ h e d . ~ ~ By using anhydrous reactants new labile isomers of N-+-tolyl-D-glucosylamine and -D-galactosylamine were prepared.98 N-Substitutedglycosylamines have been derived from sulphanilamide and $-aminosalicylicacid.99 It is claimed that no solvent or catalyst is necessary for the pre-paration of glycosyl derivatives of highly basic amines.lOO Investigations,lOlin the glucose series, of the transglycosylation reaction, whereby the aryl-amine residue in a N-substituted aldosylamine is replaced by anotherarylamine, i.e.,Ar‘aNH,Ar-NH- H.[CH(OH)] *CHCH,.OH h4 Y-o”’Ar’*NH*CH-[CH (OH)] H*CH,*OH + Ar-NH, LoAhave revealed that the reaction depends on pH and in certain circumstancesis reversible.Solubilities of reactants and of possible products play a partin the change, which undoubtedly is transglycosylation rather than hydro-lysis followed by redistributive reglycosylation. Tetra-O-acetylglucosyl-amines also undergo this reaction. Piperidine with either a- or p-D-glUC0-pyranose penta-0-acetate affords N-D-glucosylpiperidine 3’ : 4’ : 6’-tri-O-acetate, deacetylation occurring at Ctl, and Ce,. The same tri-0-acetate isobtained by adding piperidine to either 3 : 4 : 6-tri-O-acetyl-D-g~ucosylchloride or D-glucose 2 : 3 : 4 : 6-tetra-O-acetate. Loss of acetyl a t Ct2>must accompany or precede formation of the C-N bond since N-D-glUCOSY1-piperidine 2’ : 3’ : 4’ : 6’-tetra-O-acetate is unaffected by piperidine.lo2The reaction of ammonia with a-D-glucose penta-0-benzoate to produceD-ghCOSe dibenzamide lo3 has been found lo4 to be of general application tothe acetates and benzoates of the monosaccharides; a series of competitivereactions is involved.There is now available an improved method for synthesising N-phenyl-and N-P-tolyl-D-fructosylamine and well-characterised cdmpounds have beenobtained for the first time.105 Unlike the corresponding glucosylamines,these are stable for years.Other N-substituted fructosylamines have beenprepared,1°6 but not in good yield. In the presence (but not in the absence)of warm dilute alcoholic hydrochloric acid, aldohexoses react with long-chain alkylureas.107 Ketohexoses do not react even in the presence ofacid.lo7 Ketoses condense more readily than aldoses with aliphatic amines.losReactions with long-chain primary aliphatic amines can go far past theamine-glycoside stage and solids of uncertain structure are formed byreaction of 4 - 5 molecules of amine with one of glucose or sorbose.lo8 Thestabilities and behaviour in solutions of N-arylglycosylamines have attracted98 G.P. Ellis and J. Honeyman, J.. 1952, 1490.g9 R. Bognar and P. NQnQsi, J., 1963, 1703.lo0 J. E. Hodge and C. E. Rist, J . Amer. Chem. Soc., 1952, 74, 1494.lol R. Bognar and P. NBnBsi, Nature, 1953, 171, 475.Io2 J. E. Hodge and C. E. Rist, J . Amer.Chem. Soc., 1952, 74, 1498.lo3 V. Deulofeu and J. 0. Deferrari, Nature, 1951, 167, 42.Io4 Idem, Chenz. and Ind., 1952, 272; J . Org. Chem., 1952, 17, 1087, 1093, 1097.lo5 C. P. Barry and J. Honeyman, J., 1952, 4147.lo6 B. Helferich and W. Portz, Chem. Ber., 1953, 86, 604.lo’ J. G. Erickson and J. S. Keps, J . Amer. Chem. SOC., 1953, 75, 4339.lo8 J. G. Erickson, ibid., p. 2784OVEREND : CARBOHYDRATES. 263attention. The stability of N-arylglucosylamines increases in the order,N-phenyl- , -P-tolyl-, -m-tolyl-, -o-tolyl.109 Amongst the N-chlorophenyl-and N-carboxyphenyl-glucosylamines, the ortho- are more stable than themeta- and the ;barn-isomers.lOg In weakly acidic solutions the ortlzo-com-pounds are the least readily converted into the corresponding isoglucos-amines.log The amounts of water and acid present are amongst the majorfactors involved in the darkening of methanolic solutions of N-phenyl-D-glucosylamine.l10 Atmospheric oxygen and the darkening of possiblehydrolysis products (glucose and aniline) do not contribute significantly tothe colour development. Darkening occurs rapidly in hot alcoholic solutionscontaining also compounds having active methylene hydrogen atoms-lllThe Amadori rearrangement isomer is amongst the products of darkeningof a glycosylamine.lllExamination of the chromatographic behaviour of 2-deoxy-N-P-tolyl-D-galactosylamine and its D-galactosyl analogue indicated that considerablehydrolysis occurs in aqueous solvents,112 and other studies 113 have shownthat glycosylamines may undergo rapid hydrolysis or isomerisation inaqueous solutions.Hydrolysis may only be partial a t equilibrium. Whencarefully purified, D-glucosylpiperidine does not mutarotate ill dry pyridine,but mutarotation was observed in this solvent with D-mannosyl- and D-galactosyl-piperidine.lOO Since in this solvent the production of a cationby the mechanism postulated by Kuhn and Birkofer 114 cannot be expected,it was suggested that an intramolecular rearrangement may have takenplace and there is some evidence for this with the mannose derivative.lWO-Methyl ethersJ1l5? 116 O-acetates,lO2? ll5? 117 and O-benzoates 115 of N-sub-stituted glycosylamines have been studied. Browning of solutions of thetetra-@acetates of N-phenyl-D-glucosylamine is much slower than forN-phenyl-D-glucosylamine but occurs eventually.l18 Acid hydrolysis of~-~-to~yl-~-D-g~ucosy~amine 2 : 3 : 4 : 6-tetra-O-acetate gives glucose2 : 3 : 4 : 6-tetra-O-acetate.115 For the preparation of such acetates this isan attractive alternative method to the use of the aldosylbromide acetate.It has been extended to the ketose series.In these reactions the N-aryl-glycosylamines behaved as pyranose compounds. The infra-red spectra ofsolid N-o-tolyl- and N-p-naphthyl-D-glucosylamine have been interpreted asindicating that these compounds have a Schiff-base structure,119 but theirelucidation is not yet complete.Addition of thiosemicarbazide or isonicotinoylhydrazine, or a number ofother reagents, to periodate-oxidised starch yielded polymeric productscontaining nitrogen,120 but there was only one molecule of base per hexoseunit.The aldehyde functions of the oxyhexose units are apparently modi-log S. Bayne and W. H. Holms, J . , 1952, 3247.110 L. Kosen, K. C. Johnson, and W. Pigman, J . Amer. Chem. SOC., 1953, 75, 3460.111 J. E. Hodge and C. E. Rist, ibid., p. 316.112 J. L.Barclay, A. B. Foster, and W. G. Overend, Chem. and Ind., 1953, 462.113 W. Pigman, E. A. Cleveland, D. H. Couch, and J. H. Cleveland, J. Amer. Chenz.115 G. P. Ellis and J . Honeyman, J., 1952, 2053.116 I. Ehrenthal, M. C. Rafique, and F. Smith, J . Amer. Chem. SOC., 1952, 74, 1341.11' J. Honeyman and A. R. Tatchell, J . , 1950, 967.11* W. Pigman and K. C. Johnson, J . Amer.Chem. SOC., 1953, 75, 3464.119 F. Legay, Compt. rend., 1952, 234, 1612.lZo V. C. Barry and P. W. D. Mitchell, J . , 1963, 3610.SOC.. 1951, 73, 1976. 114 R. Kuhn and L. Birkofer, Ber., 1938, 71, 621, 1535264 ORGANIC CHEMISTRY.fied and it is suggested 121 that they are united in a " hemialdal " linkage(cf. Hurd et ~ ~ 1 . l ~ ~ ) to give a seven-membered cyclic unit which reacts withthe base as shown.---7 I ---? yii EG*OH i !NH,RI - _ _ _ - L--- yq H.0 j - H,OH2*OH H2.0HSome of the non-enzymic browning which occurs in foods during concen-tration, dehydration, or storage can be attributed to reactions between re-ducing sugars and amino-compounds 123 (the Maillard reaction). Accordingto Hodge and Rist ll1 this non-enzymic browning can occur by condensationof reducing sugars and amino-compounds to form glycosylamines. Theserearrange spontaneously to deoxyaminoketoses which are dehydratedspontaneously to nitrogenous reductones.[The labile deoxyaminoketoses(via their scission and/or dehydration products) produce the Streckerdegradation of amino-acids, forming aldehydes and carbon dioxide.] Thenitrogenous reductones react slowly alone (in the presence of air) and rapidlywith amino-acids to produce brown pigments. For browning reactionsbetween amino-acids (glycine and alanine) and a reducing sugar (D-xylose)it is reported 124 that there is strong base-catalysis between the initial pHvalue of 6.5 and 8.5, solvent or weak base-catalysis between values of 3and 5, and acid inhibition in the range 1-3.The nature of the repeatingunit of browning polymers has been probed by radioactive tracertechniques.125 The rates of browning with glycine of the well-characterisedhexose phosphates of the glycolytic cycle have been rneasured.lz6 Thepresence of a phosphate ester at the primary alcohol group of both glucoseand fructose increases the rate of browning : there was no browning withglycosidic phosphate esters. The kinetics of the reaction between variousaldoses and amino-acids and peptides have been examined.12' The reactionof glucosamine with casein differs fundamentally from that of glucose.128There are recent accounts of the synthesis of 3 : 6-di-O-methyl-N-methyl-~-glucosamine,l29 and acetylated thioacetals of ~-glucosamine, 130 of the cata-lytic oxidation of glucosamine to glucosaminic acid,l31 and of the preparationof acyl derivatives of the acid.132 Experiments on the preparation of a- 133and p-glycosides 134 of N-acetylglucosamine have been reported.Reaction121 V. C. Barry and P. W. D. Mitchell, J . , 1953, 3631.122 C. D. Hurd, P. J. Baker, jun., R. P. Holysz, and W. H. Saunders, jun., J . Org.123 J. P. Danehy and W. Pigman, Adv. Food Res., 1951, 3, 241.124 M. L. Wolfrom, D. K. Kolb, and A. W. Langer, jun., J . Amer. Chem. Soc., 1953,125 M. L. Wolfrom, R. C. Schlicht, A. W. Langer, jun., and C. S. Rooney, ibid.,127 A. Katchalsky and N. Sharon, Biochim. Biophys. Acta, 1953, 10, 290.128 C. H. Lea and D. N. Rhodes, ibid., 1952, 9, 56.lZ9 J. Fried and D. E.Walz, J . Amer. Chem. SOC., 1952, 14, 5468.130 M. L. Wolfrom and K. Anno, ibid., p. 6150.131 K. Heyns and W. Koch, Chem. Ber., 1953, 88, 110.132 M. L. Wolfrom and M. J. Cron, J . Amey. Chem. Soc., 1952, 14, 1715.133 R. Kuhn, F. Zilliken, and A. Gauhe, Chem. Ber., 1953, 86, 466.134 R . Kuhn and H. H. Baer, ibid., p. 724; R. Kuhn and W. Kirschenlohr, ibid.,Chem., 1953, 18, 186.'45, 3471.p. 1013. 126 S. Schwimmer and H. S. Olcott, ibid., p. 4855.p . 1331OVEREND CARBOHYDRATES. 265of 1 : 3 : 4 : 6-tetra-O-acetyl-p-~-g~ucosamine with acylamino-acid chloridesaffords derivatives of D-glucosamine substituted on the nitrogen atom byacylamino-acid residues (i.e., “ gluco-peptide ” acetates).135 When anattempt was made 136 to acylate 1 : 3 : 4 : 6-tetra-O-acetyl-p-~-glucosamineby use of acylamino-acid azides, Curtius rearrangement took place in everycase. In the presence of aqueous sodium nitrite methyl a- and p-D-glucos-aminide hydrochloride were rapidly deaminated, but at different rates.13’The p-isomer reacted most rapidly, but in each case 2 : 5-anhydro-~-mannosewas the main product. I t was suggested that deamination of the a-formmay be hindered by the single axial group at the glycosidic centre and bythe cis-1 : 2-relation of the methoxyl and the amino-group. The influenceof the configuration of the glycosidic centre in glucosaminides on the rate ofdeamination may be of use in establishing the configuration of glucos-aminidic linkages in certain mucopolysaccharides.Two aminodeoxypentoses have been synthesised, namely, 2-amino-2-deoxy-D-xylose 138 (D-xylosamine) (XXII) and 3-amino-3-deoxy-~-ribose 139(XXIII) (both isolated as the hydrochloride).The former was obtainedby using ethyl 2-acetamido-2-deoxy-a-~-gIucothiofuranos~de (XIX) as theinitial material by submitting it to gIycoI cleavage with sodium meta-periodate and then reducing the product (XX) with sodium borohydrideto ethyl 2-acetamido-2-deoxy-a-~-xylothiofuranoside (XXI) from whichH NHAc H NHAc H NHAc H NH,( X W (XX) (XXI) (XXII)(XXII) was obtained by complete hydrolysis. The ribose derivative(XXIII) was synthesised as follows. (a) Methyl 2 : 3-anhydro-p-~-ribo-pyranoside was converted into methyl 3-amino-3-deoxy-~-~-xylopyranosideby heating it with aqueous ammonia.(b) Acetylation and subsequentmethanesulphonylation yielded methyl 3-acetamido-3-deoxy-2 : 4-di-0-methanesulphonyl-p-L-xylopyranoside. (c) This on treatment with boilingalcoholic sodium acetate and further acetylation afforded methyl 3-acet-amido-2-0-acetyl-3-deoxy-4-0-methanesulphonyl-~-~-lyxopyranoside. Re-petition of the process with 95% boiling “ Methyl Cellosolve ’’as solvent gave methyl 3-acetamido-2 : 4-di-0-acetyl-3-deoxy- ,OHa-D-ribopyranoside. Elimination of the methanesulphonyl re-sidues is accompanied by inversion and is reported to occur viaan oxazoline. (d) Hydrolysis furnished 3-amino-3-deoxy-~-ribose (XXIII), identical with the amino-pentose obtained as(xxlll) one of the hydrolysis products of “ Achromycin.” l40 It is note-worthy that this synthesis proceeds through all four pentose configurations.135 D.G. Doherty, E. A. Popenhoe, and K. P. Link, J . Amer. Chem. SOC., 1953,75,3466.136 E. A. Popenhoe, D. G. Doherty, and K. P. Link, zbid., p. 3469.137 A. B. Foster, E. F. Martlew, and M. Stacey, Chem. and Ind., 1953, 825.138 M. L. Wolfrom and K. Anno, J . Amer. Chem. SOC., 1953, 75, 1038.139 B. R. Baker and R. E. Schaub, i b i d . , p. 3864.140 C. W. Waller. P. W. Fryth, B. L. Hutchings. and J. H. Williams, ibid., p. 2025266 ORGANIC CHEMISTRY.Miscellaneous.-A new method of descent 141 in the aldose series in-volves oxidation of the diethyl mercaptal (XXIV) of the aldose acetate withmonoperphthalic acid in ether. Treatment of the main product (XXV) withhydrazine in methanol gives the lower aldose (XXVI) and bisethane-sulphonylmethane in good yield.p W W 2 ~ ( S O Z W , CH2( SO,*Et),K (XXIV) "2 (XXV) RCHO (XXVI)FH*OAc + + +Cation-exchange resins are effective in promoting the formation ofglycosides from pentoses, hexoses, uronic acids, and methylated sugars, andof isopropylidene derivatives of sugars and methyl g1y~osides.l~~ A newsynthesis of p-glucopyranosides has been outlined.143A convenient preparative method for polyols is to reflux aldoses andketoses in aqueous alcohol with Raney n i ~ k e 1 . l ~ ~ Sodium borohydride hasbeen used 145 in reductions in the sugar series. Chlorine-water oxidation ofanomeric pairs of methyl glycosides proceeds most readily with theP-isomer.lQ6 An interesting new method for masking the hydroxyl groupsat Sugar nitrates can beprepared by treatment a t 0" of a suspension of the sugar derivative in aceticanhydride, with acetic anhydride and ca.50% excess of fuming nitric acid.lQsThe syntheses and properties of some nitrate esters of alkyl D-glucosideshave been described.149 Syntheses of fructose-1 phosphate,150 a- andp-lactose-1 phosphate,151 a-D-mannose-1 and -6 phosphate, and -1 : 6 di-phosphate,152 and glucose-6 phosphate 153 have been described. Hydro-lysis of glucose-4 phosphate 154 and fructose-6 phosphate 155 has beenstudied.Rules have been published 156 which enable the condensation productsof polyhydric alcohols with acetaldehyde, benzaldehyde, and formaldehydeto be predicted.A detailed analysis has been made 157 of the stereochemicalfactors governing the synthesis of acetals of polyhydric alcohols.Solvolytic reactions of tetra-0-acetyl-a-D-glucopyranosyl 1-bromide havebeen examined kinetically.158a The reactivity of the halogen in the O-acyl-141 D. L. MacDonald and H. 0. L. Fischer, J . Aiizcr. Chem. SOC., 1952, 74, 2087;Biochem. Biophys. Acta, 1953, 12, 203.142 W. H. Wadman, J., 1952, 3051 ; J. E. Cadotte, F. Smith, and D. Spriestersbach,J . Amer. Chem. Soc., 1952, 74, 1501.143 R. U. Lemieux and W. P. Shyluk, Canad. J . Chem., 1953, 31, 528.144 J . V. Karabinos and A. T. Ballun, J . Amer. Chem. SOC., 1953, 75, 4501.145 M. L. Wolfrom and K. Anno, ibid., 1952, 74, 5583; L. Hough, J . I<. N. Jones,and E. L. Richards, Chcm.and Iwd., 1953, 1064; A. Meller, Chem. and Ind., 1953, 1204.146 B. Lindberg and D. Wood, Acta Chem. Scand., 1952, 6, 791.147 B. Helferich and E. von Gross, Chem. Ber., 1952, 85, 531.148 J . Honeyman and J. W. W. Morgan, Chem. and Ind., 1953, 1035.G. H. Williams, Chem. and Ind., 1952, 149; D. M. Shepherd, J., 1953, 3635.I5O B. M. Pogell, J . Bid. Chem., 1953, 201, 645.151 F. J. Reithel and R. G. Young, J . Amer. Chem. Soc., 1952, 74, 4210.152 T. Posternak and J. P. Rosselet, Helv. Chim. Acta, 1953, 36, 1614.153 M. Viscontini and C. Olivier, ibid., p. 466.154 H. R. Dursch and F. J. Reithel, J . Amer. Clzem. Soc., 1052, 74, 830.155 S. L. Friess, J . Amer. Chzm. SOC., 1952, 74, 5.521.15G S. A. Barker and E. J. Bourne, J., 1952, 905.l S 7 S.A. Barker, E. J. Bourne, and D. H. Whiffen, J., 1952, 3865.158 F. H. Newth and G. 0. Phillips, ( a ) J., 1053, 2896, (b) 2900, ( G ) 2904.and C(,) in aldopyranoses has been 0ut1ined.l~~E. G. Ansell and J. Honeyman, J., 1952, 2778; E. G. Ansell, J . Honeyman, anDVEREND : CARBOHYDRATES. 267glycosyl l-halides is due to its being part of an a-halogeno-ether system.1586The methanolysis rate of the halides is directly proportional to the amountof " crowding " about C(1).158cAs far as can be judged a t present arabitol occurs in all lichens of theorder Gyvnnocarpeae, but not in the lichens of the genera Dermatocarpon andE n d o c a ~ p o n . ~ ~ ~ These however contain volemitol which is not detectable inGymnocarpeae. Mannitol was found in all the lichens investigated and,amongst other components, umbilicin (3-~-arabitol p-D-galactopyr-anoside lc0), aa-trehalose, and sucrose were also detected.161 From thebrown alga Fucus vesicuZosus, D-mannitol l-0-acetate, D-mannitol 1 - @ - ~ -glucopyranoside, and D-mannitol 1 : 6-di-( p-~-glucopyranoside) have beenisolated,162 and the first two ~ y n t h e s i s e d .~ ~ ~ There is continued interest inthe synthesis of sugars from simple precursors in ~ i t r 0 . l ~ ~Po1ysaccharides.-An extensive survey 165 on the enzymic synthesisof polysaccharides concludes by stating that the problems of immediateinterest are the syntheses of pentosans, @-glucosans, mannans, and otherpolysaccharides containing essentially a single sugar component : in thesecases it will be necessary to consider how both the branched and the un-branched portions of the molecules arise.The biological significance andvarious chemical aspects of bacterial polysaccharides have been reviewedby Stacey,166 who has also surveyed the rdle of carbohydrates in immuno-chemistry. 167 Blom and Schwartz's conclusion 168 that molecules of starchcontain, in addition to the generally accepted or-1 : 4- and a-1 : 6-gluco-pyranosidic linkages, an additional type of glucosidic linkage has beencritically but concisely examined by Hopkins 169 who believes that it createsmore difficulties than it clears up; Lindberg 170 has also criticised the sug-gestion. During the past year there has been a symposium on " BiologicalTransformations of Starch and Cellulose " 171 and some of the meetings a tthe XIIIth International Congress of Pure and Applied Chemistry 172 weredevoted to cellulose chemistry.Publication of a textbook on " Poly-saccharide Chemistry" by R. L. Whistler and C. L. Smart 173 fills a long-standing gap.W. G. 0.IsQ B. Lindberg, A. Misiorny, and C. A. Wachtmeister. Acta Chem. Scand., 1953, 7 ,l80 B. Lindberg, C. A. Wachtmeister, and B. Wickberg, ibid., 1952, 8, 1052.lC1 B. Lindberg and B. Wickberg, ibid., 1953, 7 , 140.16* B. Lindberg, ibid., p. 1119.lb3 Idem, ibid., pp. 1123, 1218.164 L. Hough and J. K. N. Jones, J., 1952, 4047; J., 1953, 342; Chem. and Ind.,1b5 S. A. Barker and E. J . Bourne, Quart. Reviews, 1953, 7 , 56.167 I d e m , Biochem. SOC.Symp., No. 10, 1953.168 J. BIom and B. Schwarz, Acta Chenz. Scand., 1952, 6, 697.lGQ R. H. Hopkins, Il'ature, 1953, 171, 429.170 B. Lindberg, Acta Chenz. Scand., 1953, 7 , 237.171 Biochem. SOC. Symp., No. 11, 1953.172 Abst. of Papers, XI11 Int. Congr. Pure Appl. Chem., 1953, Group 22, p. 225,173 Academic Press, Inc., New York, 1953.501.1952, 907; P. A. J. Gorin and J . K. N. Jones, J., 1953, 1537.M. Stacey, Discovery, 1953, p. 271; Endeavour, 1953, 12, 38; Reseavch, 1953,0, 159268 ORGANIC CHEMISTRY.9. PEPTIDES, PROTEINS, AND AMINO-ACIDS.Oxytocin and Vasopressin.-These hormones can now be obtained pure.I t is possible to extract both hormones simultaneously from beef hyophyses ;their further purification involves similar methods for each.2 Bovine vaso-pressin can be purified by zone electrophoresis and is readily separated fromoxytocin (I) under these condition^.^ Bovine oxytocin can be obtained pureby counter-current distribution and, although itself non-crystalline, ityields a crystalline flavianate with specially purified flavianic acid.4 Bovineand porcine oxytocins appear to be identical in ~hemical,~ phy~ical,~ andbiological properties. The structure of oxytocin has been announcedalmost simultaneously from two separate laboratories.In the first G,partial hydrolysis with hydrochloric acid and the plakalbumin-formingenzyme from B. subtilis formed the basis of the investigations. The secondgroup used a variety of methods8CyS.Tyr.Ileu*Glu (NH,) -Asp (N H,) CyS.Pro.Leu.Gly( NH,)Investigations into the structure of these hormones have indeed bornea rich harvest in 1953 for, in addition to oxytocin, the structure of arginine-vasopressin (11) has been announced from two sources.g- lo An additionalform of the hormone, lysine-vasopressin, has an identical structure, withlysine replacing the a~-ginine.~CyS*Tyr*Phe.Glu (NH2).Asp(NH,).Cy7.Pro.Arg*Gly(NH,)Final confirmation of the validity of these investigations comes fromthe synthesis of oxytocin and probably that of lysine-vasopre~sin.~ Thiswork will surely rank as one of the greatest achievements in peptide chemistryfor many years.Lack of space precludes a detailed description of themethods used, but a feature of major interest must be mentioned. This isa novel and simple synthesis of glutamine and glutaminyl peptides (annexedscheme).HO2C.CHzCHz*qH*COzH pcI, HZY-VH, R C H (NH *)-CO,KOC\ /CH*coC1 - NHsTs +N-TsHZy-qH2 Aq,NH, qH2--CH2-YH*CO*NH.~H*CO2HOC CH*CO*NH.CHR*COzH -e CO-NH, NH*Ts K(Ts = p-C,H,Me*SO,) \ /PIIT-Ts1 H.Maier-Huser, H. Clauser, P. Fromageot, and R. Plongeron, Biochim. Biofihys.3 S . P. Taylor, V. du Vigneaud, and H. G. Kunkel, J . Biol. Chem., 1953, 205, 45.4 J. G. Pierce, S. Gordon, and V. du Vigneaud, ibid., 1952, 199, 929.Acta, 1953, 11, 252. 2 P. Fromageot, R. Acher, and H. Clauser, ibid., 12, 424.H. G. Kunkel, S. P. Taylor, and V. du Vigneaud, ibid., 1963, 200, 559.H. Tuppy, Bzochinz. Biophys. Acta, 1953, 11, 449.H. Tuppy and H. Michl, Monatsh., 1953, 84, 1011. * V.du Vigneaud, C. Ressler, J. M. Swan, C . W. Roberts, P. G. Katsoyannis, andS. Gordon, J . Amev. Chem. SOC., 1953, 75, 4879; V. du Vigneaud, C. Ressler, and S.Trippett, J . Biol. Chem., 1953, 205, 949.V. du Vigneaud, H. C. Lawler, and E. A. Popenoe, J . Amer. Chem. SOC., 1953, 75,4881.lo R. Acher and J. Chauvet, Biochim. Biophys. Ada, 1953, 12, 487ELLIOTT PEPTIDES, PROTEINS, AND AMINO-ACIDS. 269Oxytocin can be reduced by sodium in liquid ammonia to the mercapto-form, which is readily re-oxidised to the parent substance in aqueous solutionin the presence of air. This is a striking demonstration of the feasibility ofinternal disulphide bridges in polypeptide chains; in fact, the ease withwhich it occurs suggests a very favourable disposition of the two thiol groups.This would be the case if the molecule were in the form of a spiral or foldedstructure.I t has been reported that anti-diuretic and oxytocic substances areliberated from plasma proteins by the action of pepsin,lll l2 but the identityof these substances has not been established.During their structural investigations on oxytocin and vasopressin duVigneaud and his collaborators have discovered a specific peptide-bondcleavage.13-15 This occurs between tyrosine and the amino-acid joined toits carboxyl group when the hormones or their performic acid oxidationproducts are treated with bromine water.The tyrosine residue is convertedinto a ring-dibromo-derivative.Bacitracin A.-This polypeptide has been obtained pure by counter-current distribution l6, 1' and by carrier displacement analysis.l8 The mole-cular weight is 1460 l8 or 1470 l9 and the amino-acid composition is : *OPhe Leu Ileu, CySH Glu Asp, His Lys Orn-NH,Preparative isolation of each amino-acid by counter-current distributionrevealed that the phenylalanine, glutamic acid, and ornithine had theD-configuration, the aspartic acid was racemic, and the remaining amino-acids had the L-configuration.It is generally agreed 1 9 3 217 22 that the mole-cule has a cyclic structure, but it presents certain very unusual features.When the amino-acid units and the ammonia are joined with loss of theminimum number of water molecules a molecular weight much lower thanthe experimental value is obtained. An estimation of the elements presentby combustion analysis is also in disagreement with the formulaC60H,,01,N16S.It is probable that a 5-carbon residue of unknown natureis present in addition to the amino-acids.19 In addition to the glyosalinenucleus the antibiotic contains two carboxyl groups and two basic groups,one of which is the &-amino group of ~ r n i t h i n e . l ~ * ~ l There is uncertaintyabout the identity of the second basic group. It has been claimed 21 thatit is the amino-group of leucine or isoleucine. On the other hand Porath 22could find no N-terminal a-amino-acid group by the fluorodinitrobenzenemethod or the Edman degradation (see also ref. 57). The E-amino-group oflysine is not free.lg> 21, 22 The nature of the linkage with the sulphur atomis not clear a t present.A positive thiol reaction is obtained from the anti-l1 H. Croxatto, L. Barnafi, G. Rojas, A. Reyes, and A. Infante, h'atuve, 1953, 171, 82.l2 H. Croxatto and L. Barnafi, ibid., 172, 306.13 J. M. Mueller, J. G. Pierce, and V. du Vigneaud, J . Biol. Chern., 1953, 204, 857.l4 C. Ressler, S. Trippett, and V. du Vigneaud, ibid., p. 861.l5 E. A. Popenoe and V. du Vigneaud, ibid., 1953, 205, 133.l6 L. C. Craig, J - R. Weisiger, W. Hausmann, and E. J. Harfenist, J . B i o l . Chem.,l7 G. G. F. Newton and E. I?. Abraham, Biochern. J., 1953, 53, 597.l9 L. C. Craig, W. Hausmann, and J. R. Weisiger, J . B i o l . Chem., 1953, 200, 765.2o L. C. Craig, W. Hausmann, and J. R. Weisiger, ibid., 1952, 199, 865.21 G. G.F. h'ewton and E. P. Abraham, Biochem. J . , 1953, 53. €04.22 J . Porath, N a t u r e , 1953, 172, 871.1952, 199, 359.J. Porath, Acta Chem. Scand., 1952, 6, 1237270 ORGANIC CHEMISTRY.biotic only after mild treatment with acid and as a working hypothesis thepresence of a thiazoline ring (111) is suggested.21, 22 This explains the form-ation of an amino-alcohol and an alanine residue with its amino-group freeon Raney nickel hydrogenolysis, but other observations are not so readilyinterpreted.21 Partial hydrolysis 22 indicates the sequence (IV) of amino-acid residues.R-Lys-C;lu-C$S-Ileu-I;eu. . . NH.CHR.C/s-]Hz +SP The\r;-CH.CO.. . . Asp-His- Orn-Ileu(111) ( wThe Adrenocorticotrophic Hormones.-Several procedures have beenpublished for the preparation of highly active polypeptide material frompituitary glands, but the relation between these products is not yet clarified.A substance called corticotropin-B has been obtained in a highly purifiedstate from pepsin digests of partially purified pituitary extract from pigs.23-25Adsorption on oxycellulose, ion-exchange chromatography, and counter-current distribution were used.Amino-acid analysis and sedimentationstudies indicated a minimum molecular weight of 5000-7000.26 A value ofapproximately 23,000 has been found 27 for the adrenocorticotrophic hormoneof sheep.28 Chromatography on Amberlite XE 97,29 followed by counter-current distribution, of the crude hormone from hog pituitaries 30 yielded asubstance, which was apparently pure, called corticotropin-A. There is acertain amount of indirect evidence to suggest 29 that hormone preparationsfrom acid or pepsin digests of pituitary extracts may be hydrolysis productsof corticotropin-A, At present only 88.5% of the dry weight of this substancehas been accounted for by analyses.30 Degradative studies on cortico-tropin-A have been fairly extensive, the sequences Ser-Tyr andPro*Leu*Glu*Phe 32 having been found respectively at the amino- and thecarboxyl end of the molecule.Carboxypeptidase was used to determinethe latter sequence ; the presence of more than one polypeptide chain cannottherefore be excluded.An account of recent work on the chemistry and purifization of theadrenocorticotrophic hormone has appeared.33 The oxycellulose method ofpurification has been ~implified.~*Structure of Insulin.-The complete sequence of amino-acids in the A-chain of insulin has been worked This leaves only the positions ofthe amide groups and the disulphide bridges to be determined; the latter23 A.W. Bazemore, J. W. Richter, D. E. Ayer, J. Finnerty, N. G. Brink, and K.24 J . W. Richter, D. E. Ayer. A. W. Bazemore, N. G. Brink, and K. Folkers, ibid.,z 5 F. A. Kuehl, M. A. P. Meisinger, N. G. Brink, and K. Folkers, ibid., p . 1955.26 N. G. Brink, G. E. Boxer, V. C. Jelinek, F. A. Kuehl, J. W. Richter, and K.27 R. M. Mendenhall, Science, 1953, 117, 713.28 C. H. Li, H. M. Evans, and M. E. Simpson, J . Biol. Chenz., 1943, 149, 413.29 W. F. White and W. L. Fierce, J . Amer. Chem.SOC., 1953, 75, 245.30 W. F. White, ibid., p . 503.31 W. A. Landmann, M. P. Drake, and W. F. White, ibid., p. 4370.32 W. F. White, ibid., p . 4877.33 “ Recent Progress in Hormone Research,” Vol. VII, 1952, Chapters 1 and 2.34 K. J . Bartholomew, Proc. SOC. Exp. Biol. N.Y., 1953, 83, 334.35 F. Sanger and E. 0. P. Thompson, Biochem. J . , 1953, 53, 353, 366.Follters, J . Anzer. Chem. SOC., 1953, 75, 1949.p. 1952.Folkers, ibid., p. 1960ELLIOTT : PEPTIDES, PROTEINS, AND AMINO-ACIDS. 27 1problem may be very difficult to solve owing to the ease with which a mixtureof disulphides can undergo an interchange reaction.36 I t has been believedfor a long time that insulin consists of four chains and has a molecular weightof 12,000, but a recent determination by a novel method gives a value of6500.37 This method involves partial substitution of the reactive groupsin a molecule under conditions deliberately chcsen to prevent completereaction. The mixture of products is then submitted to counter-currentdistribution, the monosubstituted product being that found nearest to theparent substance. If a suitable substituent is used, the molecular weightof the parent substance can be readily calculated from the analytical datafor the monosubstituted product.38 The correct assignment of the disulphidebridges may be made possible from a consideration of atomic models ofinsulin.In at least two laboratories 397 40 the structure is being consideredon the basis of the 3.7-residue helix,41 but the work is a t an early stage.There is disagreement between the two groups as to whether or not a two-chain structure is possible.I t is now known that there are appreciable differences in compositionbetween the insulins obtained from various species.This confirms the sugges-tion made by Sange~-.~~ The six amino-acids, serine, threonine, glycine,alanine, valine, and isoleucine are present in different amounts in cattle, pig,and sheep i n ~ u l i n s . ~ ~ - 4 ~ In cattle insulin a component has been found whichhas five amide groups instead of six per two chains; this may be an artefactproduced from insulin during isolation.45Reaction of Diisopropyl Fluorophosphonate with En~ymes.~~-~-SerineO-(dihydrogen phosphate) (phosphoserine) has been isolated from partialhydrolysates of (diisopropyl phosphory1)chymotrypsin in about 30% yield.47The hydroxyl group of free serine is not reactive to diisopropyl fluorophos-phonate and only one atom of phosphorus is introduced per molecule ofenzyme.46 It could be assumed that some special configuration around aserine residue imparts to its hydroxyl group a reactivity much higher thannormal, but a more likely explanation is that the phosphorus becomesattached first to some other group and is transferred to serine duringhydrolysi~.~7? 48There is indirect evidence suggesting 4 7 7 48 that the primary site of phos-phorylation of the enzyme is a histidine residue.Photo-oxidation of chymo-trypsin destroys one histidine residue (and also 3 tryptophan residues),and the product is no longer reactive to diisopropyl fluoropho~phonate.~~The hydrolysis of the latter is accelerated in the presence of glyoxaline,histidine, pyridine, and certain of their derivatives and the suggestion is3G F.Sanger, Nature, 1953, 171, 1025.37 E. J. Harfenist and L. C. Craig, J . r3mer. Chem. Soc., 1952, 74, 3083, 3087.38 A. R. Battersby and L. C. Craig, ibid., 1951, 73, 1887; 1952, 74, 4023.39 U. W. Arndt and D. P. Riley, Nature, 1953, 172, 245.40 C. Robinson, ibid., pp. 27, 773.p2 F. Sanger, Nature, 1949, 164, 529.43 J . Lens and A. Evertzen, Biochim. Biophys. Acta, 1952, 8, 332.44 E. J . Harfenist and L. C. Craig, J . Amer. Chem. Soc., 1952, 74, 4216.4 5 E. J. Harfenist, ibid., 1953, 75, 5528.46 For a review of earlier work see A.K. Balls and E. F. Jansen, Adv. Enzymology,4 7 N. K. Schaffer, S. C. May, and W. H. Summerson, J . Biol. Chem., 1953, 202, 67.T. Wagner-Jauregg and B. E. Hackley, J . Amev. Chem. Soc., 1953, 75, 2125.4s L. Weil, S. James, and A. R. Buchert, Arch. Biochem., 1953, 46, 260.41 Ann. Reports, 1951, 48, 241.1952, 13, 321272 ORGANIC CHEMISTRY.made that this is due to formation of a quaternary complex 48 (cf. ref. 54). Ifthese views are correct such a complex must be present in the inhibitedenzyme and acts as a phosphorylating agent for the serine-hydroxyl group.48The acylating action of l-acylglyoxalines has been demonstrated re~ently.~OThe inhibition of cholinesterase by triesters of phosphoric acid appears to beclosely related to that of chymotrypsin.51These views on the mechanism of inhibition cannot be reconciled with thediscovery that diisopropyl fluorophosphonate reacts readily with the hydroxylgroup of tyrosine.The chloro-analogue, which reacts very much moreslowly, is also much less toxic; this suggests that the hydroxyl group oftyrosine may be involved in the active centre of the enzyme.52It is now known that inhibition of chymotrypsin can be reversed to asmall extent by hydroxylamine 53 and completely by nicotinohydroxamicacid methi~dide.~~ The effectiveness of the latter substance is ascribed tothe presence of an anionic site in the enzyme which survives the inhibitionprocess.Determination of Polypeptide and Protein End-groups.-N- Terminalresidues.The l3lI-labe1led P-iodobenzenesulphonyl group method 55 hasbeen applied to crystalline glyceraldehyde-3 phosphate dehydrogenase fromyeast and rabbit muscle. Both proteins contain two chains terminated byvaline residues. 56The free amino-groups of peptides can be reductively methylated withformaldehyde and the dimethylamino-acid, liberated from the terminalgroup on hydrolysis, can be identified by paper-chromatography. Thismethod gave satisfactory results on a number of peptides, including gluta-thione. No free a-amino-groups were found in bacitracin. 57The fluorodinitrobenzene (FDNB) technique has received further studyand improvement. Paper-chromatographic methods for identifying di-nitrophenyl(DNP)amino-acids are frequently used ; 58-623 31 X-ray powderdiffraction measurements provide additional confirmatory evidence.63 Acolumn procedure for acid-soluble DNP-amino-acids has been described.59The chromatographic behaviour of DNP-peptides on columns of silicic acid-Celite has been investigated in detail 64 and yields very satisfactory resultsin the separation of DNP-peptides from partial hydrolysates of gelatin.65Optimum conditions for the dinitrophenylation of amino-acids and peptideshave been worked out.66 It was not possible to cause some of the amino-6o T.Wieland and G. Schneider, Annalen, 1953, 580, 159.61 W. N. Aldridge, Biochenz. J., 1953, 54, 442.52 R. F. Ashbolt and H. N. Rydon, J . Amer. Chem. SOC., 1952, 74, 1865.53 L. W. Cunningham and H. Neurath, Biochim. Biophys.Acta, 1963, 11, 310.64 I. B. Wilson and E. K. Meislich, J . Amer. Chem. Soc., 1953, 75, 4628.5 5 A n n . Reports, 1951, 48, 239.5 6 S. F. Velick and S. Udenfriend, J . Biol. Chem., 1953, 203, 575.5 7 V. M. Ingram, ibid., 1953, 202, 193.5 8 C. Weibull, Acta Chem. Scand., 1953, 7, 335.59 E. F. Mellon, A. H. Korn, and S. R. Hoover, J . Amer. Chem. Sac., 1953, 75, 1675.6o C. H. Li and L. Ash, J . Biol. Chem., 1953, 203, 419.61 M. Rovery and C . Fabre, Bull. SOC. Chim. biol., 1953, 35, 541.62 J . H. Bowes and J. A. Moss, Biochem. J., 1953, 55, 735.63 H. M. Rice and F. J. Sowden, Canad. J . Chem., 1952, 30, 575.64 W. A. Schroeder and L. R. Honnen, J . Amer. Chem. Soc., 1953, 75, 4615.6 5 W. A. Schroeder, L. Honnen, and F. C. Green, Prac. U.S.Nut. Acad. Sci., 1953,39, 23. 6 6 W. A. Schroeder and J. Le Gette, J . Amer. Chem. SOL, 1953, 75, 4612ELLIOTT : PEPTIDES, PROTEINS, AND AMINO-ACIDS. 273acids and peptides to react quantitatively, aspartic acid being a particularlydifficult case. It is claimed 58 that quantitative estimation of protein end-groups can be achieved by the FDNB-method, with paper-chromatographyfor separation of DNP-amino-acids, followed by elution and spectrophoto-metric estimation at 360 mp.An important contribution to our knowledge of the FDNB methodhas been made in a study of the end-groups of tobacco mosaicalthough the validity of this work has been questioned.67a Dinitrophenolwas the only product isolated after hydrolysis of the DNP-virus and itwas shown that this arose almost exclusively from decomposition of DNP-proline (see also ref.68) in about 75% yield. If a molecular weight of40 x 106 is assumed for the virus, the results demonstrate that it contains2300-2700 peptide chains having N-terminal proline residues. Theseresults are in fairly good agreement with those for the C-terminal residues.69N-Terminal proline residues have been found in several protamines. 70The disturbing finding has been made 7 l that especially labile peptidebonds may be split during the preparation of DNP-proteins under the usualconditions. The sequence possibly concerned was the N-terminal asparagyl-serine in carboxypeptidase. It was found that during the reaction of theprotein with FDNB free DNP-asparagine was formed in an amountequivalent to the DNP-serine obtained on hydrolysis.In view of the factthat much less than one equivalent of DNP-serine is obtained per moleculeof enzyme, there may be an alternative explanation. It is known, forinstance, that peptide impurities are tenaciously held in crystallineproteins. 72-74Innovations in technique which have been made are : the removal ofartefacts from ether extracts of DNP-amino-acids,75 the differentiationbetween DNP-prolyl- and -hydroxyprolyl-peptides and other DNP-peptiilesby a spectrophotometric method,65 and the estimation of bis-DNP-lysine inthe presence of dinitrophenol by spectrophotometric measurement at 400 mpin 10whydrochloric acid.76 It has been reported that the destruction ofDNP-amino-acids which occurs on hydrolysis of DNP-proteins can beprevented by treating the protein first with xanthhydrol.77 Clupein can bepurified by chromatography of its DNP-derivative.78 2 : 4-Dinitrobenzene-sulphonic acid reacts with protein amino-groups at pH 10-11, to give DNP-derivatives which are water-soluble.The reaction is slower, but in the endnearly as effective as when FDNB is used.79C-Terminal residues. There is still no method available which is as6 7 G. Schramm and G. Braunitzer, 2. Naturforsch., 1953, 8b, 61.cia H. Fraenkel-Courat and B. Singer, J . Amer. Chem. SOC., 1954, 76, 180.6 8 R. Acher and U. Laurila, Bull. Soc. Chivn. biol., 1953, 35, 413.69 J. I. Harris and C. A. Knight, Nature. 1952, 170, 613.70 K. Felix and A. Krekels, 2.physiol. Chem., 1953, 295, 107.E. 0. P. Thompson, Biochim. Biophys. Acta, 1953, 10, 633.72 M. Rovery, C. Fabre, and P. Desnuelle, ibid., 1952, 9, 702.73 Idem, ibid., 1953, 10, 481.7$ P. Desnuelle, M. Rovery, and C. Fabre, ibid., 1952, 9, 109.75 Unpublished method of F. A. Isherwood and D. Cruickshank, quoted by H. M.7 6 M. Jutisz and L. Pknasse, Bull. SOC. Chinz. biol., 1952, 34, 480.7 7 S. R. Dickman and R. 0. Asplund, J . Amer. Chem. Soc., 1952, 74, 5208.78 E. Waldschmidt-Leitz and L. Pflanz, 2. physiol. Chew., 1953, 292, 150.7 9 H. N. Eisen, S. Belman, and M. E. Carsten, J . Amer. Chem. Soc., 1953, 75, 4583.Schwartz and C . H. Lea, Biochem. J . , 1952, 50, 713274 ORGANIC CHEMISTRY.effective generally for C-terminal residues as is the FDNB method for N-terminal residues.The method of reduction using mixed metallo-hydrides 55is potentially useful, but the difficulties associated with the quantitativeseparation of amino-alcohols from inorganic salts and amino-acids havenot yet been overcome. In the special case of ovornucoid, which containsterminal phenylalanine, the phenylalaninol (2-amino-3-phenylpropan-1-01)produced on reduction and hydrolysis was obtained almost quantitatively byadsorption on charcoal.80 Synthesis of the amino-alcohol from DL-cysteine 81and an improved synthesis of that from L-histidine 82 have been reported.The Schlack and Kumpf procedure 55 has received further study thisyear.s3-8G Now that a paper-chromatographic method is available 83 theidentification of the thiohydantoins is greatly simplified.Crystalline deriv-atives of serine, threonine, histidine, and arginine have not been prepared,S3and the method appears to fail with aspartic, glutamic, lysine, and arginineend-groups.@ Cleavage of the thiohydantoin by acid hydrolysis 84 is clearlypreferable to alkaline hydrolysis,85> 86 which leads to opening of the thio-hydantoin rings6 As a qualitative method it appears useful, for it has givenunequivocal results on lysozyme, 83 bovine plasma albumin,= and ovo-muc0id.8~ Alanine was found as an end-group in o v a l b ~ m i n . ~ ~ The yieldof thiohydantoin obtained by use of acetic anhydride and ammonium thio-cyanate was found to be far from quantitative,= but it is now possible toobtain high yields of thiohydantoin (VI) from simple N-acyl-peptides anddiphenyl phosphoroisothiocyanatidate (V) at room temperature.86 TheR*CO*NH*CHR*CO,- + (PhO),PO*NCS __t(V)R’CO*NH*CH RCO-NCS __t R’CO *$J- H R(VI) s(\ N H /Jooverall reaction is as shown.The phosphorus compound is readily avail-able. The suitability of this method for large polypeptides or proteins hasnot yet been ascertained.Carboxypeptidase is a valuable tool, but its limitations 87 need to bethoroughly appreciated. Of prime importance is the purity of the enzyme.ssIn favourable circumstances it yields very satisfactory result^.^*^^ Thetryptic activity which frequently accompanies the enzyme can be bbcked bytreatment with diisopropyl fluorophosphonate (DFP) .92 No C-terminalresidues were found in trypsinogen or in the DFP-complex of trypsin, orL.PBnasse, M. Jutisz, C. Fromageot, and H. Fraenkel-Conrat, Biochim. Biophys.8 1 J. C. Crawhall and D. F. Elliott, Biochem. J., 1953, 55, vii. Acta, 1952, 9, 551.88 P. Karrer and R. Saemann, Helv. Chim. Acta, 1953, 36, 570.83 J. T. Edward and S. Nielsen, Chem. and Ind., 1953, 197.84 V. H. Baptist and H. B. Bull, J . Amer. Chem. SOC., 1953, 75, 1727.8 5 R. A. Turner and G. Schmerzler, Biochim. Biophys. Acta, 1953, 11, 586.86 G. W. Kenner, H. G. Khorana, and R. J. Stedman, J., 1953, 673.J. A. Gladner and H. Neurath, J . Bid. Chem., 1953, 205, 345; cf. M. Rovery,D. Steinberg, J . Amer. Chern. SOL, 1953, 75, 4575.J. I. Harris, ibid., 1952, 74, 2944.C. Fabre, and P. Desnuelle, Biochim.Biophys. Acta, 1963, 12, 547.O0 A. R. Thompson, Nature, 1952, 169, 495.O1 F. Sanger and E. 0. P. Thompson, Biochem. J . , 1953, 53, 366.9s E. W. Davie and H. Neurath, J , Amer. Chem. SOC., 1952, 74, G305ELLIOTT PEPTIDES, PROTEINS, AND AMINO-ACIDS. 275when carbox y pep t idase was allowed to aut olyse .92 C h ymo t r ypsinogen didnot yield any amino-acids in the presence of carboxypeptidase, whereas theDFP-complex of a-chymotrypsin yielded leucine and tyrosine. I t is believedthat the formation of a-chymotrypsin from chymotrypsinogen involvesopening of a cyclic molecule with liberation of a basic ~eptide.~'At present an enzymic method is needed for the detection of a C-terminalcarboxyamide group. In the two cases so far studied, cleavage of glycineamide occurred readily in the presence of trypsin 99 lo or the plakalbumin-forming enzyme from B.~ubtiZis.~* 7Methods for Polypeptide Degradation.-Edman method. 93 Paper-chromatographic methods are now available for the identification of 3-phenyl-thiohydantoin derivatives of amino-a~ids.~~~ 95 The true thiohydantoinderivatives of serine 96 and threonine 95*96 have been prepared, but thecystine derivative is probably not a thioh~dantoin.~~ Phenyl isothiocyanatereacts incompletely with the free amino-groups of insulin in aqueous buffersolutions.97 The Edman method of stepwise degradation has been studiedmore fully than any other method; it has been used to determine theN-terminal pentapeptide sequences of ly~ozyme,~~ the result being in agree-ment with that of S ~ h r o e d e r , ~ ~ and of insulin,94~99 but in neither case was itpossible to continue the degradation.It was only partly successful in thedegradation of the hexapeptide, Ala-Gly*Val-Asp*Ala.Ala, liberated duringthe transformation of ovalbumin into plakalbumin,lm9 lol and of oxidisedvasopressin.15 These difficulties are due to the impossibility, at present, offorming the thiohydantoin ring without causing a small degree of peptide-bond fission. In the experiments described the techniques of ring closurehave varied widely; another and possibly more effective method has beensuggested recently. lo2 All these workers have applied successive steps ofthe degradation to the crude, degraded peptide from the previous stage.This is contrary to the general rule in organic syntheses.An increase in therange of the method would be expected if the degraded peptide could bepurified at every step, or every few steps of the degradation. This wouldbe a formidable task, but perhaps not an insuperable one in view of therapid advances being made in the techniques for purification of largemolecules.A modification of the Edman method in which 4-dimethylamino-3 : 5-dinitrophenyl isothiocyanate is the reagent has been briefly reported.lo3Thiohydantoin formation occurs in dilute acetic acid a t 40". The fullpublication of this work will be awaited with interest.A recent publication lo4 describes the stepwise degradation of a few simplepeptides by a method allied to the Edman technique, but as ring closure is93 Ann.Reports, 1950, 47, 165; 1952, 49, 148.94 W. A. Landmann, M. P. Drake, and J. Dillaha, J . Amer. Chem. SOC., 1953, 75, 3638.95 J. Sjoquist, Acta Chem. Scand., 1953, 7 , 447.s6 V. M. Ingram, J.. 1953, 3717.g7 E. Kaiser, L. C . Maxwell, W. A. Landmann, and R. Hubata, Arch. Biochenz., 1953,gg H. N. Christensen, Compt. rend. Trav. Lab. Carlsberg, SLY. Chim., 1953, 28, 265.loo M. Ottesen and A. WoIlenberger, Nature, 1952, 170, 801.101 Idem, Compt. rend. Trav. Lab. Carlsberg, SLY. Chim., 1953, 28, 463.lo2 I?. Edman, Acta Chem. Scand., 1953, 7 , 700.lo3 W. S. Reith and N. M. Waldron, Biochem. J., 1953, 53, xxxv.lo4 D. T. Elmore and I-'. A. Toseland, Ckenz. a i d Imd., 1953, 1227.42, 94. 98 W.A. Schroeder, J . Amer. Chem. Soc., 1952, 74, 5118276 ORGANIC CHEMISTRY.carried out under the conditions used in the Edman method it must sufferfrom the same disadvantages.If one surveys the literature in this field over the last few years it is pain-fully obvious that in spite of all the ingenuity and hard work there is not asingle stepwise method of degradation which approaches in usefulness thetechniques of partial hydrolysis used by Sanger and his collaborators (see,for instance, ref. 55). Something more specific is needed, however, to unravelprotein structures. I t is clear that experiments with simple peptides cando no more than establish the feasibility of a method; it is only afteradequate testing on naturally occurring polypeptides or proteins that its truevalue can be assessed.Effective methods have been developed for a study of the peptide linkagesin polyglutamyl-peptides. 105-107 The side-chain carboxyl groups are sub-mitted to Curtius lo5 or Hofmann degradation,loG9 lo7 and the product ishydrolysed to ay-diaminobutyric acid or p-formylpropionic acid, dependingon the nature of the linkage.The validity of the methods has been tested.... NH*YHCO * - - * . . . . NH.VH*CH,CH,CO*NH * 9 * *CH,.CH,.CO,H C0,Ht tt tNH,*qHCO,H CHOCH2CH,C0,1-ICH,CH,*NH,on a synthetic polypeptide.log Poly-D-glutamic acid from all the naturalsources so far examined appears to contain only y-glutamyl linkages. lo5-110By application of the isotopic dilution method to partial hydrolysates ithas been found that the sequence glycylalanylglycine occurs in silk fibroinmore frequently than would be the case with a random distribution of amino-acids.lll Evidence for a non-random structure in silk fibroin comes alsofrom another source.112Tri-iodothyronine.-Details of the synthesis of the L- and D-,l13 and114 forms of 3 : 5 : 3'-tri-iodothyronine have appeared. The L-form hasbeen obtained crystalline from the thyroid g1and.ll3 The mode of biologicalsynthesis is not k n 0 w n .l l ~ 3 ~ ~ ~ A high yield of monoiodotyrosine wasobtained by iodination of N-phthaloyltyrosine, but unfortunately this methodwas not successful for the preparation of tri-iodothyronine.l17lo5 J. KovAcs and V. Bruckner, J., 1952, 4255.loci V. Bruckner, J. KovAcs, and H.Nagy, J . , 1953, 148.lo7 V. Bruckner, J. KovBcs, K. KovAcs, and H. Nagy, Experientia, 1963, 9, 63.lo8 V. Bruckner, J. KovAcs, and K. KovBcs, J . , 1953, 146, 1512.log V. Bruckner, J. KovBcs, and I. Kandel, Naturwiss., 1953, 40, 243.110 V. Bruckner, J. KovAcs, and G. DCnes, Nature, 1953, 172, 508.ll1 E. Slobodian and M. Levy, J . Biol. Chent., 1953, 201, 371.112 B. Drucker, R. Hainsworth. and S. G. Smith, Shirley Inst. Mem., 1952-1963,lls J. Gross and R. Pitt-Rivers, Biochem. J , , 1953, 53, 645.11* J. Roche, S. Lissitzky, and R. Michel, Biochirrz. Biophys. A d a , 1953, 11, 215.115 Idern, ibid., p. 230. 116 J. Grossand R. Pitt-Rivers, Biochenz. J., 1953, 53, 652.117 A. Hillmann-Elies and G. Hillmann, Z. Naturforsch., 1953, 8b. 446.26, 191ELLIOTT : PEPTIDES, PROTEINS, AND AMINO-ACIDS.277Hydroxyamino-acids.-Additional examples have been found of thecis trans-oxazoline interconversion previously observed in the threonineseries; 118 these reactions appear to be stereospecific, as with the threonineisomers. cis-2-Phenyloxazoline esters (VII) are in every case convertedquantitatively into the trans-forms (VIII) under the influence of a strongbase in alcoholic solution. The R group may be methyl,l18 phenyl,llgpentadecyl,l20 or hydroxymethyl.121 The configuration of natural dihydro-sphingosine is now known to be erytlzro, as in allothreonine, on the basis ofthis interconversion and certain supporting physical evidence.120 The factthat the trans-oxazoline is much more stable than the cis-form probablyexplains why the thionyl chloride cyclisation occurs smoothly in the erythro-N-acyl derivatives of P-aryl-substituted serines 122 but not in the threo-series.123- 12* This reaction generally proceeds by an inversion mechanismafter intermediate formation of a chlorosulphinic ester and it is, presumably,necessary that rotation should occur at the bond joining the two asymmetriccarbon atoms until the distance between the chlorosulphinate group and theattacking amide group reaches a maximum. The transition complex in theerytlzro-series will then have R and C0,Et in the trans-position, the productof the reaction being a trans-oxazoline, whereas a cis-transition complexwould be formed from the threo-isomers. This inversion and cyclisation ofthe erythro-form is illustrated by the following tetrahedral models. That ofthe threo-form would have H and R in the lower tetrahedron interchanged,CL-soSynthesis of the P-phenylserines by condensation of benzaldehyde andglycine in the presence of alkali has been studied in detail; 125 both forms areobtained.Resolution of the two DL-isomers has been achieved by asym-metric hydrolysis of the trifluoroacetyl derivatives with carboxypeptidase. 126118 Ann. Reports, 1951, 48, 218.119 M. Viscontini and E. Fuchs, Helv. Chim. Acta, 1963, 36, 660.lZo H. E. Carter, J. B. Harrison, and D. Shapiro, J . Amer. Chem. SOC., 1953, 75,lz2 G. W. Moersch, M. C. Rebstock, A. C. Moore, and D. P. Hylander, zbid., 1952,la* D. 0. Holland, P.A. Jenkins, and J . H. C. Nayler, J . , 1953, 273.125 K. N. F. Shaw and S. W. Fox, J . Amer. Chem. Soc., 1953, 76, 3417, 3421.126 W. S. Fones, J . Biol. Chem., 1953, 204, 323.1007, 4703.74, 665.121 E. E. Hamel and E. P. Painter, ibid., p. 1362.123 W. A. Bolhofer, ibid., p. 5459278 ORGANIC CHEMISTRY.p-Phenylserine derivatives have been synthesised from aromatic acidchlorides and a-acylaminoacetoacetic esters. 127 In the presence of calciumhydroxide #-nitrobenzaldehyde condenses with glycine, to give threo-p-nitrophenylserine.128 The case of the condensation of P-nitrobenzaldehydewith glycine ester, about which there has been so much discussion in thepast, is clarified by the observation that the p-nitrobenzylidene derivativesof P-nitrophenylserine ethyl ester are interconvertible by prototropy undercertain conditions of condensation.124 The configuration of the productdepends on the reaction conditions,129 but it has been shown 122, 130 thatcondensation under the conditions of Dalgliesh 131 or Bermann and hisco-workers 132 gives the erythtro-form. The second diastereoisomeric form ofp-hydroxyglutamic acid has been prepared 133 and named allo-p-hydroxy-DL-glut amic acid in accordance with recent International rules, 13* although itappears to be configurationally related to threonine. Adjustment of therules may be necessary to avoid confusion in such cases.The four stereoisomers of 8-hydroxylysine have been prepared and theirconfigurations tentatively assigned.135Aspartic and Glutamic Acid.-Aspartic acid has been synthesised inalmost quantitative yield by the addition of benzylamine to the hydrolysisproduct of maleic anhydride, followed by hydrogenolysis of the benzylgroup ; asparagine was prepared by a similar route, the anhydride ring beingopened with ammonia.136 In addition to that already described a novel andsimple synthesis of L-glutamine from glutamic y-methyl ester is re~0rted.l~'Recent work l 3 * 5 139 has shown that dehydration of acetyl- and benzoyl-aspartic acid with acetic anhydride yields products with the properties ex-pected of anhydrides, although under certain conditions 1399 140 their chemicalreactivity suggests an oxazolone structure. Rearrangement to an oxazoloneprobably occurs in these instances. The profound effect of the solvent onH2y-qH.SJH Hzy----- YH-R\o/CR + CO,H OC O ~ o / c O CoRthe direction of ring opening of the anhydride with ammonia should benoted.141 The dehydration products of acylglutamic acids are also an-hydrides, which generally give a mixture of a- and y-amide on ring openingwith amines.l38, 142 Thiohydantoin formation can be used to distinguishbetween a- and y-amides.138Chromatography.-It is possible only to mention very briefly a few ofthe more significant or useful advances. Solvent systems of high resolvingla' G. Ehrhart, Chem. B e y . , 1953, 86, 713.1z9 E. D. Bergmann, H. Bendas, and C. Resnick, J., 1953, 2564.130 C. G. Alberti, B. Camerino, and A. Vercellone, Exflerientia, 1952, 8, 261 ; foot-132 E. D. Bergmann, M. Genas, and H. Bendas, Compt. rend., 1950, 231, 361.133 W. J. Leanza and K. Pfister, J . Biol. Chem., 1953, 801, 377.134 Int. Union Pure Appl. Chem., J., 1951, 3522.135 W. S. Fones, J . Anzer. Chem. Soc., 1953, 75, 4865.13* M. Frankel, Y. Liwschitz, and Y . Amiel, ibid., p. 330.137 S. Akabori and K. Narita, PYOC. Japan Acad., 1953, 29, 264.138 J. M. Swan, Nature, 1952, 169, 826.139 C. C. Barker, J., 1953, 453.S. W. Tanenbaum, J . Amer. Chem. Soc., 1953, 75, 1754.lP2 J. A. King, F. H. McMillan, and J. D. Genzer, ibid., 1952, 74, 5202.lZ8 Idem, ibid., p- 483.131 C. E. Dalgliesh, J . , 1949, 90. note 3, p. 262.140 A. Lawson, J., 1953, 1046ELLIOTT : PEPTIDES, PROTEINS, AND AMINO-ACIDS. 279power for paper-chromatography of amino-acid mixtures have been de-scribed,143* 144 as well as the separation on paper of the phenylserhes,126t hreonines,l25 nitrophenylserines, 124 and asparagine and isoasparagine. 141A new reagent for amino-acids which is especially sensitive for ornithine,sarcosine, proline, and hydr~xyproline,~~~ a sensitive test for guanidino-compounds on paper,146 and a new reagent for amino-acids, peptides, andproteins 147 after chlorination 1*8 have been described. A radiochemicalmethod of quantitative paper-chromatography with an accuracy of & 2%has been ev0lved.14~ A convenient apparatus has been made for washingof a large number of filter-paper sheets.150 Although it is not a chromato-graphic method attention should be drawn here to a beautifully designedapparatus for separation of amino-acids, peptides, and proteins by continuouselectrophoresis on paper. A multiple dipping technique has been recom-mended for the development of paper chromatograms. 152Remarkable advances have been made in the column-chromatography ofproteins. Two-phase systems have been evolved for the purification ofinsulin and other pr0teins.l5~ Separation of proteins on ion-exchange resinsseems very promising, but it may be applicable only to those of relativelyhigh stability andlow molecular weight. The resin IRC 50 has been exclusivelyused for the separation of ha3moglobin.s 154 and for the purification of ribo-n ~ c l e a s e , l ~ ~ y s o ~ y m e , l ~ ~ and chymotrypsinogen a.l57 In the last casecrude pancreatic extracts could be used.Miscellaneous.-The cyclic f o m of DL-phenylalanylglycylglycine has beenprepared by a novel method.158 Very high yields are obtained in a peptidesynthesis involving phosphorazo-compounds (IX) . These are easily preparedEtO,C*CHR*N:P*NH*CHR*CO,Et (IX) + 2CH ,Ph*O,C-NH.CH R’C0,HBCH,Ph*O,C*NH CH R’CO-I’U’HCH R’*CO,E tfrom phosphorus trichloride and amino-acid or peptide esters and reactsmoothly with benzyloxycarbonylamino-acids to give p e p t i d e ~ . l ~ ~ Opticalactivity is preserved. The value of the method is manifest from its use inthe synthesis of glutathione.lG0 A study has been made of the fission of tenprotecting groups under various conditions. Five of these are interesting143 A. L. Levy and D. Chung, Analyl. Cizem., 1953, 25, 396.14* R. R. Redfield, Biochina. Biophys. Acta, 1953, 10, 344.lg5 G. Curzon and J. Giltrow, Nature, 1953, 172, 356.146 H. Tuppy, Monatslz., 1953, 84, 342.14’ F. Reindel and W. Hoppe, Naturwiss., 1953, 40, 221.Ig8 Ann. Reports, 1952, 49, 149.14B S. Blackburn and A. Robson, Biochem. J . , 1053, 54, 295.150 F. A. Isherwood and C. S. Hanes, ibid., 1953, 55, 824.151 W. Grassmann and K. Hannig, 2. PJzysiol. Chem., 1953, 292, 32.lS2 J. B. Jepson and I. Smith, Nature, 1953, 172, 1100.153 K. R. Porter, Biochem. J . , 1953, 53, 320.154 N. K. Boardman and S. M. Partridge, Nature, 1953, 171, 208.lS5 C. H. W. Hirs, S. Moore, and W. H. Stein, J . Biol. Chem., 1953, 200, 493.ls6 H. H. Tallan and W. H. Stein, ibid., p. 507.157 C . H. W. Hirs, ibid., 1953, 205, 93.158 M. Winitz and J. S. Fruton, J . Amer. Chem. SOC., 1953, 75, 3011.159 S. Goldschmidt and H. Lautenschlager, Annalen, 1953, 580, 6 8 ; see also Ann.Reports, 1951, 48, 153. lG0 S. Goldschmidt and C. J u t z . Chem. B e y . , 1953, 86, 1116280 ORGANIC CHEMISTRY.on account of the possibility that they could be removed one after anotherfrom a molecule with which they were together combined.16l This know-ledge should be of value in the synthesis of complex peptides. Benzyloxy-carbonyl groups can be removed by the catalytic action of strong acids inanhydrous solvents. 161- 163A careful study has been made of the esterification of the free carboxylgroups of bovine serum albumin.16* A novel method has been devised forthe determination of protein thiol groups : the accuracy is &5y0 and onlysmall quantities of material are required.165Lithium aluminium hydride reduction has been used in a series of inter-conversions which establish the configurational relation between aliphaticamines and amino-acids.166 At the same time an independent proof wasobtained that L-alanine and L-valine have the same configuration.166 Theserelations had been established previously, but by less convenient and precisemethods.167 Amino-acids are conveniently converted into their methylesters by the action of methyl alcohol-thionyl chloride ; other esters may beprepared from these by alcoholysis.168 Alternative methods for amino-acidbenzyl esters are described.l637 169 It is now possible to isolate the basicamino-acids in the pure state and in good yield from protein hydrolysates bya very simple technique. 170 Cystine and lanthionine have been synthesisedin good yield by a neat method.lv1 The reader’s attention is drawn to theaccount of a Ciba Foundation Symposium on protein chemistry,172 which isrelevant to the matter in this section.D. F. E.A. S. BAILEY.I. G. M. CAMPBELL.N. CAMPBELL.J. W. CORNFORTH.P. B. DE LA MARE.D. F. ELLIOTT.T. G. HALSALL.W. G. OVEREND.J. WALKER.W. A. WATERS.B. C. L. WEEDON.161 R. A. Boissonnas and G. Preitner, Helv. Chim. A d a , 1953, 36, 875.162 N. F. Albertson and I;. C . McKay, J . Amer. Chem. Soc., 1953, 75, 5323.163 D. Ben-Ishai and A. Berger, J . Org. Chem., 1952, 17, 1564.164 H. A. Saroff, N. R. Rosenthal, E. R. Adamik, N. Hages, and H. A. Scheraga,165 T. C. Tsao and K. Bailey, Biochim. Biophys. A d a , 1953, 11, 102.166 P. Karrer and P. Dinkel, Helv. Chim. Acta, 1953, 36, 122.16’ F. Barrow and G. W. Ferguson, J., 1935, 410.1 6 * M. Brenner and W. Huber, Helv. Claim. Acta, 1953, 36, 1109.1 G 9 H. K. Miller and H. Waelsch, J . Amer. Chem. Soc., 1952, 74, 1092.170 W. Robson and A. S. M. Selim, Biochem. J., 1953, 53, 431.171 R. 0. Atkinson, F. Poppelsdorf, and G. Williams, J., 1953, 580.1 7 2 “The Chemical Structure of Proteins,” Edited by G. E. W. Wolstenholme andJ . Biol. Chem., 1953, 205, 255.M. P. Cameron, J. and A. Churchill Ltd., London, 1953