ORGANIC CHEMISTRY.1. INTRODUCTION.THE following report on organic chemistry covers work published duringthe year except for the theoretical topics which are better reviewed at longerintervals than one year, so that the work discussed can be considered critic-ally in relation to contemporary views. The section on theoretical organicchemistry, therefore, deals with the more salient features of the chemistryof free radicals in solution, since that rapidly advancing field has not beenreviewed since 1948. The mechanism of the ozonisation of aromatic com-pounds, which was last reported in 1947, now merits special attention inview of the wider application of recent theories to other contemporary studiesof the reactivity of polynuclear aromatic systems.Perhaps the most novel discoveries of the year are the recognition ofiron dicyclopentadienyl as a new type of symmetrical structure showingtypical aromatic behaviour, and the use of clathrate compounds for opticalresolutions.In synthetic organic chemistry the year has been notable fora stereospecific total synthesis of cortisone, a synthesis of flavin-adenine-dinucleotide, a synthesis of morphine, and a synthesis of all-trans-methyl-bixin; each of these considerable achievements exemplifies in some way orother the high degree of specificity of modern techniques in organic chemistry,to which has been added a welcome catalytic hydrogenation method forreducing triple bonds to double bonds. The structure of lanosterol has nowbeen established and the stereochemistry of the p-amyrin and lupeolgroups of triterpenes has been elucidated, while appreciation of the richvariety of types of substance found to occur naturally is increased by theisolation of an antibiotic incorporating every known type of carbon-carbonunsaturation.The increasing use of enzymic methods for the study of organic chemicalproblems is seen in recent work on nucleotides and macromolecules, whileexpanding facilities for infra-red spectroscopy are reflected in the increasinguse being made of this tool in structural problems.J.W.W. A. W.2. THEORETICAL ORGANIC CHEMISTRY.Bromonium Cations.-Though iodonium salts have long been known,stable bromine and chlorine analogues (I) and (11) have been prepared byR. B. Sandin and A.S. Hay only in the year under review.sponding iodonium salts were made by L. Mascarelli in 1907.2The corre-Previously,1 J . Amer. Chew. SOC., 1952, 74, 274.2 AttiR. Accad. Lincei, 1907, 16,11, 562; 1908, 17,'11, 580; 1912, 21, 11, 617; Gazzetta,1908, 38, 624WATERS : THEORETICAL ORGANIC CHEMISTRY. 111cyclic bromonium catihs (111) had been postulated by I. Roberts andG. E. Kimball3 in order to explain trans-addition to olefins. Their theoryhad received strong support from the work of S. Winstein and H. J. Lucas *and other American investigators of the stereochemistry of the reactions ofolefins, 1 : 2-glycolsJ and their derivative^.^ M. J. S. Dewar has advocatedthe x-bond formula (IV) but there now seems to be no special need for it,since it depends on the assumption that a halogen atom can only form asingle covalent bond.6 Related studies of neighbouring group displacementreactions have led D. J. Cram to postulate the transient existence of aphenonium ion ” (V), but a detailed report of this subject is deferred untilnext year.RZC--C / R f f Rf\c=C /Rf Rf\c-C/RffR/ \G~/ \Rf I f R/ J. \,,ff R/ / \,fffBr + ?+\ I: ;I(111) (IV) \*/ (V)Ozonisation. The Action of Double-bond Reagents.-Continuation ofthe detailed studies of ozonisation by J. P. Wibaut and his school in Amster-dam 8 has in the past two years led to results of major theoretical significance.Kinetic measurements of the velocities of ozonisation of several benzene,pyridine, quinoline, and isoquinoline derivatives have been made.+l4 Thevelocity of addition of ozone to benzene is proportional to the concentrationof the ozone as well as to that of the benzene.11-13 Apparently benzenetriozonide is formed in successive stages, the velocity of the first being muchless than that of the subsequent ones.Alkyl substituents increase thereaction vel~city,~, lo whilst halogens have the opposite effect, as the followingC,H,Me2 > C,H5Me; C,H5Me >C6H,*CH2C1 > C,H5*CHC12 CI,H,*CC1,. Anisole is attacked exceedinglyrapidly whilst pyndine derivatives do not react as fast as their benzeneanalogues.14 This has led J. P. Wibaut and F. L. J. Sixma to concludethat the first stage in the ozonisation of an aromatic compound is an electro-philic reaction in which the central, electropositively polarised, oxygen atomof the ozone molecule (VI) becomes attached to the activated aromaticsystem, giving the primary transition state (VII).In this, only four electronsremain distributed over the five carbon centres, 2-6, of the benzene ring,which is thus positively charged, whilst the two terminal oxygen atoms ofthe ozone residue are negatively charged. Consequently, stabilisation of(VII) occurs very rapidly, to give the structures (VIII) and (IX) which, inthe case of benzene alone, will be identical and correspond to H. Staudinger’ssequences show 1oy14 C6H6 < C6H5Me < CGHSEt; P-C6H4Me2 > m(o)-C,H6 > C,H,F > C6H5C1 N C6H5Br;J . Amer. Chem. Soc., 1937, 59, 947.See E. R. Alexander, ‘‘ Ionic Organic Reactions,” J .Wiley & Sons, New York,J. Anzer. Chem. Soc., 1949, 71, 3863, 3871, 3883; 1952, 74, 2129, 2137, 2149,J . van Dijk, Rec. Trav. chim., 1948, 67, 945.lo J. P. Wibaut, F. L. J . Sixma, L. W. F. Kampschmidt, and H. Boer, ibid., 1950,11 H. Boer, F. L. J . Sixma, and J . P. Wibaut, ibid., 1951, 70, 509, 1006.l2 H. Boer and F. L. J . Sixma, ibid., p. 997.lo F. L. J . Sixma, ibid., p. 1124.16 J. P. Wibaut and F. L. J. Sixma, Proc. K. Ned. Akad. Wet., 1948, 51, 776.Ibid., 1939, 61, 1576.1950, pp. 100-102.2152, 2159.69, 1355.See Ann. Reports, 1950, 47, 133; 1951, 48, 118.* Ann. Reports, 1947, 44, 127.J . P. Wibaut and F. L. J. Sixma, ibid., 1952, 71, 761112 ORGANIC CHEMISTRY.“ molozonides.” l6 The conversion of these initial molozonides of olefins(X) into the stable structures (XI), which have been established by the workof A.Rieche with simple olefins l7 and of B. Witkop and J. B. Patrick 18in the indole series, has been explained by R. Criegee as an intramolecular~hange.1~ This completes the fission of the carbon-carbon double bond;opening up of the ozonide finally occurs by an acid-base-catalysed hydro-lysis 2.0 which has a mechanism similar to that involved in the acid-catalyseddecompositions of hydroperoxides.21The electrophilic nature of the attack of ozone on aromatic compounds(VI --+ VII) has been substantiated by showing that the reaction canbe catalysed by the ‘‘ Lewis acids ’’ aluminium chloride, ferric chloride, andboron fluoride. These electron-deficient molecules enhance the electrophiliccharacter of the ozone :+ -O=O-0 + AICl, O=6--O-~lC13The view that the initial stage in the ozonisation of an aromatic compoundresembles nitration, or the Friedel-Crafts reaction, has been challenged byG.M. Badger 22 who maintains that ozone, osmium tetroxide, and diazo-acetic ester differ from cations such as NO2+ in that they attack the n-elec-trons of double bonds and not localised electrons a t the site of individua!carbon atoms.23 It is characteristic of these “ double-bond reagents ” thatthey can often attack polycycfic aromatic systems a t bonds of high electrondensity which sometimes do not correspond to the carbon centres attackedby typical electrophilic substituting agents. Pyrene exemplifies this ;ozonisation occurs a t the “ K ” bonds 1-2 and 6-7 whereas nitration occursalmost exclusively at atoms 3 or 5.Though they concede that the fonn-ation of a “x-complex” 24 may possibly precede the formation of thetransition structure, Sixma and Wibaut 25 counter Badger’s argument bypointing out that the reversible formation of the transition structure (VII)is followed in ozonisation by a process different from that which occurs inCf. RCl + AlCI, R+[AlCI,]-16 Ber., 1925, 58, 1088. l7 Ibid., 1932, 65,.1274; Annalen, 1942, 553, 187.18 J . Amer. Chem. Soc., 1952, 74, 3855.19 Annalen, 1948, 560, 127; cf. J. E. Lefler, Chem. Reviews, 1949, 45, 38520 B. Witkop and J. B. Patrick, J . Amer. Chem. Soc., 1952, ‘74, 3801. :: gVef:l29. 22 Rec.Trav. chim., 1952, 71,468. 23 Quart.Reviews, 1951, 6,147.S . Dewar, “ Electronic Theory of Organic Chemistry,” Oxford Univ. Press,1949,pp. 17,169. 26 Rec. Trav. chim., 1952, 71, 473.Cf. thls vol., p. 123WATERS THEORETICAL ORGANIC CHEMISTRY. 113bromination or nitration. Ozonisation involves ring closure by stabilisationof vicinal electrostatic charges of opposite sign (VII+VIII, IX), whereasbromination involves stabilisation by extrusion of a proton, (XII), and there-formation of the aromatic sextet. The Dutch workers calculate that ifthe stabilising effects of vicinal charges are taken into account then thetransition structure (XIII) has a slightly lower energy content than (XIV),though in pyrene itself the electron density is higher at atom 3 than atatom 1, since the localisation of the nuclear positive charge in (XIII) givesan activated phenanthrene structure with an energy level below that of theactivated naphthalene arrangement in (XIV).Ring closure of (XIII) thus-0 0-0- \;/&b/ + I H\ /-H.i;G,&t,fi)A)+ 1 /v\1\r-. II p \A&(XW ( X W CYY A/ 'V\/ (XIV) (XV)B y ? )H"C;r! Lgives a more stable product than that which could be derived from (XIV),and consequently ozonisation of pyrene is to be expected at bond 1-2.Sixma and Wibaut 25 suggest that the whole conception of mechanisticallydistinct " double-bond reagents " is untenable.Ethyl diazoacetate has been considered to be another reagent of thistype26 since it adds to the 1 : 2-positions of anthracene.However, thereaction products, e.g., (XV), which have locaked double bonds since theyeasily add on bromine, are much less reactive towards ethyl diazoacetatethan are the aromatic molecules from which they have been formed : hereagain " double-bond character " cannot be a satisfactory explanation of thechemical reactivity. It is evident to the Reviewer that ethyl diazoacetateis typically a reagent which attacks 9oZarisabZe bonds and that the final ringclosure would favour reaction via a particular transition state ; osmiumtetroxide is a reagent with similar characteristics. All these reagents thusexemplify the theoretical dangers inherent in attempts to assess the energylevels of the transition states of organic reactions by calculations whichtake into account the detailed electronic structure of only one of the par-t icipat ing molecules.Free radicals and their reactions.Triphenylmethyl and Related Compounds.-Of the methods availablefor determining the degree of dissociation of compounds of the hexaphenyl-ethane series, most reliance has, in recent years, been placed on magneticsusceptibility measurements.G. W. Wheland27 and P. W. Selwood andR. M. Dobres28 have pointed out that this method has a serious inherenterror : molecular diamagnetic susceptibility is compounded of both atomicand resonance terms, and the latter, which may be large for stable mesomericradicals, is incalculable and has hitherto been neglected. Consequently ifthe paramagnetism, Xp, due to an unpaired electron is estimated as X, =X cu~c.it gives results which may be much too found -l- x diumag.,26 G. M. Badger, J. W. Cook, and A. R. M. Gibb, J., 1951, 3456.2 7 " Advanced Organic Chemistry," J. Wiley & Sons, New York, 1949, p. 696.28 J . Amer. Chern. soc., 1950, 72, 3860114 ORGANIC CHEMISTRY.low. The discrepancy is noticeable when observations are made over arange of temperatures. This difficulty may however be overcome bymeasuring the paramagnetic resonance ab~orption.~~ Colorimetric measure-ments, on absorption bands characteristic of the free radicals themselves,show the expected temperature dependence and are considered to be trust-worthy.28 Magnetic-susceptibility methods however are still valuable formeasuring reaction velocities 30 and for the qualitative detection of freeradicals.New radicals which have been examined in this way includepentaphenylpyrrolium perchlorate (XVI) 31 and the uncharged reductionproduct of the tetrazolium salt (XVII).32 Somewhat similar in reactions arethe free radicals obtained by reducing triphenylmethane dyes with zinc dustin pyridine solution.33Stepwise polarographic reduction of triphenylmethane and acridine dyeshas been studied by R. C. Kaye and H. I. Stonehil134 who consider that thefree-radical stage is of biological significance. They point out that thechemotherapeutically active dyes give radicals which are stable over a con-siderable pH range, and they suggest that these radicals may act by stoppingreaction chains essential for bacterial metab0lism.~5 Polarographic reduc-tion of coenzymes has also been examined from this viewpoint.36 Chemicalone-electron reduction of pyridinium salts has also been disc~ssed.~'K. Ziegler and W.Deparade 38 have shown that many compounds suchas 2 : 3-dimethyl-2 : 3-diphenylbutane slowly evaporate at temperatures wellbelow their normal boiling points owing to dissociation and disproportion-ation :Barton and Holness in a brilliant exposition g2 of the problem havediscussed the relative configurations in rings c, D, and E of p-amyrin andconcluded that the junction D-E is cis, and that the C,lo)-hydrogen atomand the C(,,)-methyl group are both trans to the C,,,)-methyl group(cf. LXXIV and LXXV). The junction B-c is in the more stablearrangement .92p 93Making the probable assumption that the Ct5)- and the C,,)-methylgroup are cis, Barton concluded that there are only two structures (LXXIVand LXXV) for P-amyrin which will accommodate the facts describedabove.Now, (LXXIV) and (LXXV) have terminal ring E units which areenantiomeric. Klyne 67 has distinguished between these two structures8 8 Cf. D. H. R. Barton, Quart. Reviews, 1949, 3, 36; 0. Jeger, l r Fortschritte derL Y dF. A. Alves, Exfierientia, 1952, 8, 10.D. H. R. Barton, Experientia, 1950, 6, 316.T. G. Halsall, E. R. H. Jones, and G. D. Meakins, J., 1952, 2862.n1 Cf. A. Lardon and T. Reichstein, Helv. China. Acta, 1949, 33, 2003.Q1c J. A. Mills, J., 1952, 4982.92 D. H. R. Barton and N. J. Holness, J., 1952, 78.s3 R.Budziarek, W. Manson, and F. S. Spring, J., 1951, 3336.Chemie organischer Naturstoff e," Springer-Verlag, 1950, VoI. VII188 ORGANIC CHEMISTRY.by showing that the terminal ring E of p-amyrin is of the same enantiomerictype as that in (LXXIV), which therefore is the correct formulation ofp-am yrin .(LXXIV) (LXXV)The configurations of C(Q C(5)r C(e>, C,), C(lo), C(14))t and C(1,) of lupeol(cf. LXXVI) are the same as in p - a m ~ r i n . ~ ~ Lupeol has also been convertedinto germanicol (LXXVII) in which the hydrogen atom at and-1 IMe Me(LXXVI) (LXXVII)the methyl group at are cis.95 Finally it has been proved that thejunction D-E is trans, and that the isopropenyl group and the C(l,l-methylgroup are trans.90 Lupeol is therefore (LXXVI).(LXXIX)Asiatic acid, the aglycone of asiaticoside, has been shown to beThis structure is supported by proof of the presence of94 T.R. Ames, T. G. Halsall, and E. R. H. Jones, J., 1951, 450.9 5 D. H. R. Barton and C. J. W. Brooks, J., 1951, 257.913 (Mme.) Judith Polonsky, Bull. SOC. chirn., 1952, 649, 1015; Compt. vend., 1949,228, 1450; 1950, 280, 485, 1784; 1951, 5338, 1878; 1951, 233, 93, 671.(LXXVIII).gHALSALL ALICYCLIC COMPOUNDS. 189an a-glycol group, the formation of a lactone involving the carboxyl groupand the double bond, and the conversion of (LXXVIII) into 23-nor-a-amyrene (LXXIX) as shown.Zeorin, a pentacyclic secondary-tertiary diol, has been fully character-i ~ e d . ~ ' It forms a monoacetate, dehydration of which with phosphorusoxychloride in pyridine gives isozeorinin acetate.This contains the group-ing (>C=CH,). The secondary hydroxyl group is not at the typical tri-terpene 2-position.New triterpenes isolated include gratiogenin (as its glycoside gratioside)which may be 21-keto-olean-12-ene-2 : 19 : 29-tri01,~~ and psidiolic acid,C3,H,,0,.99 S-Amyrin, hitherto not found in Nature, has been isolatedfrom Spanish broorn.100 The so-called crataegolic acid lol is a mixture ofknown triterpenes. 102p-Triketones.-Considerable progress has recently been made in thechemistry of the group of naturally occurring alkali-soluble substances whichowe their acidity to the presence of a p-triketone system. Birch lo3 hasconsidered the evidence concerning angustione, dehydroangustione, andcalythrone, and concluded that they are best represented by structuresMeCO <ge g&CO*CH2CHMe2Me Me 0II0II0If0(LXXX) (LXXXI) (LXXXII)Me Me Me Me Me0 \,i\/ocHzoy Pri-CO o\@o =CH- O\& CO*Pri pri.COIA 1- CO-Pri \/II I10II0II0 0(LXXXIII) (LXXXIV)(LXXX), (LXXXI), and (LXXXII) .Flavaspidic acid, which was formul-ated by Boehm lo4 as (LXXXIII) with a cydobutane ring, is now believedto be (LXXXIV),103 the quinonoid nature of which would account for theyellow colour of the acid.Protokosin, isolated from the anthelmintic drug kousso, was originallyformulated as C,,H,,O, and also thought to have a cyclobutane ring. Theformula has now been modified to C,5H,0,, and structure (LXXXV) hasbeen proposed.lo5 (LXXXVI) and (LXXXVII) follow for a- and 8-kosinwhich result from the action of zinc and alkali on protokosin.The hop constituents lupulone and humulone have been synthesised : 106O7 D.H. R. BartonandT. Bruun, J., 1952, 1683.98 R. Tschesche and A. Heesch, Chem. Ber., 1952, 85, 1067.99 G. Soliman and M. K. Farid, J., 1952,134; H. R. Arthur and W. €3. Hui, Chem.loo 0. C . Musgrave, J. Stark, and F. S . Spring, J., 1952, 4393.lo1 R. Tschesche and R. Fugmann, Chenz. Ber., 1951, 84, 810.lo2 T. Bersin and A. Miiller, HaZv. Chim. Acta, 1952, 85, 1891.lo3 A. J. Birch, J., 1951, 3026.lo5 A. J. Birch and A. a. Todd, J., 1952, 3102.lo6 W. Riedl, Chsm. Bey., 1952, 85, 692.and Ind., 1952, 693.lo* R. Boehm, Awnden, 1903, 329, 310190 ORGANIC CHEMISTRY.lupulone by trialkylation of 2 : 4 : 6-trihydroxyisovalerophenone withl-bromo-3-methylbut-2-ene, and humulone by similar dialkylation of thesame trihydroxyisovalerophenone followed by oxidation of the product withMe MeOH0(LXXXV) (LXXXVI)0 0 I1 II(LXXXVIII) o ; Q y H 2 - f e 2 QyH2*CHMe2 (LXXXIX)0R R R OHR = -CH,*CH:CMe,.oxygen.in the presence of lead acetate in methanol. These syntheses areconsistent with, but do not prove, structures (LXXXVIII) and (LXXXIX)which have been proposed for lupulone lo'* lo8 and humulone.lo61 l0*lloThese structures, however, are said not to provide a satisfactory explanationof all the properties of these substan~es.1~~~ 1 1 1 9 112T. G. H.7. STEROIDS.Total Syntheses.-The year's outstanding achievement in syntheticchemistry is a stereospecific total synthesis of cortisone by Sarettand his associates " Stereo-specific " is defined by the authors to mean that in each reaction producinga fixed asymmetric centre the ratio, to all other isomers, of the isomer havingthe configuration of the end product is greater than unity; they add thatin the present synthesis there is no such ratio less than 8 : 1.An account of earlier stages in the synthesis, leading to the hydroxy-diketone monoketal (I) is still in the press.This ketone was alkylated, firstwith methyl iodide and then with 2-methylallyl iodide. The product (11)after oxidation to the diketone was condensed with ethoxyethynylmagnesiumbromide ; rearrangement of the acetylenic ether (111) gave the unsaturatedat the Merck Laboratories in New Jersey.lo7 M.Verzele and F. Govaert, Bull. SOC. chim. Belg., 1950, 68.l o * J. F. Carson, J . Amer. Chem. SOC., 1951, 73, 4652.lo* G. Harris, G. A. Howard, and J. R. A. Pollock, J., 1952, 1906.l10 A. H. Cook and G. Harris, J., 1950, 1873.ll1 Cf. G. A. Howard and J. R. A. Pollock, J , , 1952, 1902.lla Cf. S. David and C. Imer, Bull. SOC. chim., 1951, 634.1 L. H. Sarett, R. M. Lukes, R. E. Beyler, G. I. Poos, W. F. Johns, and J. M. Con-stantin, J . Amer. Chem. SOC., 1952, 74, 4974CORNFORTH : STEROIDS. 191ester (IV). This was hydrolysed to the acid and reduced stepwise by threeselective reagents : first, sodium borohydride (carbonyl group), then potas-sium and isopropanol in liquid ammonia (conjugated double bond), andfinally lithium aluminium hydride (carboxyl group).The resulting diol(V ; R = H) formed a monotoluene-9-sulphonyl derivative (V ; R =C,H,Me*SO,) which was then oxidized stepwise by three selective reagents :chromium trioxide-pyridine (>CH*OH __+ >CO), osmium tetroxideCMeXH,IYMeXH,(11)Oxidn. ;EtOCpMg BrCMe:CH2(i) Hydrol.(ii) NaBH,(iii) K-NH,-PriOH(iv) LiAlH,YMeXH,(VW[ > CXH, ---+ > C( OH) *CH,*OH] , and periodic acid [ > C (OH) *CH,*OH --+>CO + CH,O]. Cyclization with sodium methoxide of the toluene-p-sulphonyloxy-ketone (VI) and isomerization with alkali of the initiallyformed 17a-stereoisomer gave the 3-ethylene ketal (VII ; R = H) of (&)-ll-ketoprogesterone.Resolution was achieved by way of the strychnine sal192 ORGANIC CHEMISTRY.of the 21-oxalyl acid (VII; R = CO*CO,H) : the (+)-acid, on removal ofthe oxalyl group and hydrolysis of the ketal, gave 1 l-ketoprogesterone.Synthesis of cortisone from the (+)-oxalyl acid (VII ; R = CO*CO,H) wascompleted by idination and acetoxylation to the 21-iodo-compound (VII ;R = I) and 21-acetate (VII ; R = OAc) ; the remaining stages followedestablished procedures. Comparison of the synthetic compounds withmaterial derived from natural sources was made at several of the intermediatestages as well as with the final product.Earlier stages of this synthesis may be discerned in two papers 2l deal-ing with the condensation of benzoquinone with 3-ethoxypenta-1 : 3-diene.The diene was obtained by pyrolysis of 1 : 3 : 3-triethoxypentane,CH3*CH2*C(OEt),*CH2-CH2*OEt --+ CH,*CH:C(OEt)CH:CH,, as a mixtureof geometrical isomers. The major constituent reacted easily with benzo-quinone. The adduct (VIII) was stereochemically unstable, contact withalkaline alumina giving two trans-decalin isomers ; however, neutral Raneynickel in benzene reduced the double bond of the enedione system withoutcausing isomerization. Further reduction by lithium aluminium hydrideand hydrolysis with acid then gave the diol (IX). The configuration ofMe 0!I(IX) b Hthis substance was carefully studied and the structure shown was assignedon various grounds (e.g., steric hindrance of one hydroxyl group ; formationof lactol ethers between the carbonyl group and both hydroxyl groups).Other papers of the same series*, 5 describe the preparation of somecyclohexene-2 : 5-diones (e.g., X) and their condensation with ethoxy-pentadiene.In a different approach, still involving the Diels-Alder re-action, Robins and Walker found that l-vinylcyclohex-l-ene condensedreadily with benzoquinone, affording the decahydrophenanthrenedione (XI ;R = H). When this procedure was applied to a mixture of methylvinyl-(XI) (XII) (XIII)cyclohexenes prepared from 2-methyl-l-vinylcycZohexanol, the product(XI; R = Me) was shown to arise from 3-methyl-2-vinylcycZohexene, themore important l-methyl isomer failing to react. Catalytic reduction ofL. H. Sarett, R. M. Lukes, G. I. Poos, J.M. Robinson, R. E. Beyler, J. M. Vande-grift, and G. E. Arth, J . Amer. Chem. SOC., 1952, 74, 1393.R. E. Beyler and L. H. Sarett. ibid., p. 1406.P. A. Robins m d J. Walker,,a Idem, ibid., p. 1397.ti R. M. Lukes, G. I. Poos, and L. H. Sarekt, Qbid., p. 1401. ., 1952, 642, 1610; see also N. C. Deno and J. D.Johnston, J. Org. Chem., 1062, 17, l 468CORNFORTH : STEROIDS. 193(XI; R = H and Me) was studied : it is interesting that of the two keto-groups that a t C(41 was reduced preferentially.A partial synthesis of the " Windaus acid " (XIII ; derived from, andreconvertible into, cholestenone) from the -ketone (XII) is reported.' Itwas necessary to block the methylene group at position 6 (steroid numbering)with a methylanilinomethylene group in order to induce reaction with acrylo-nitrile at position 10.Direct angular methylation of a methoxyhexalone (XIV --+ XV) canbe effected with potassamide and methyl iodide in liquid ammonia.Theproduct is a potentially useful intermediate in further syntheses.Hydrolytic procedures then gave the acid (XIII).MeA novel method of building a steroid ring D is indicated 8a by the conver-sion of dimethyl marrianolate methyl ether (XVa) into 16-keto-a-oestradiol3-methyl ether in 60% yield with sodium in liquid ammonia. The methodwas also successfully applied to the recyclization of ring c from an 11 : 12-seco-dioic ester.OHDetailed accounts have been given of work reported in earlier years :the Harvard steroid synthesi~,~ the preparation of some androsteronestereoisomerides,1° and a total synthesis of oestrone.llProduction of Cortisone.-The problem of producing cortisone economic-ally in large quantity from naturally occurring steroids continues to attractmuch attention, most of the papers being concerned with introducing anll-oxygen atom into molecules unsubstituted in ring c.Chemical methodsof achieving this continue to be centred on the 7 : 9(11)-dienes. Contri-butions from several laboratories have notably simplified the transformationof these dienes into lla-hydroxy- and ll-keto-steroids. ' The primaryproduct of epoxidation of a 7 : 9(11)-diene in the 5-allo-series appears tobe a 7-ene-9a : lla-epoxide (XVI) ; when this is treated with dilute sulphuricacid the products, under progressively less gentle conditions, are the 8(9)-ene-7E : lla-diol (XVII), the 9(11)-en-7-one (XVIII), and the 8-en-7-one7 A.R. Pinder and Sir Robert Robinson, J., 1952, 1224. * A. J. Birch, J. A. K. Quartey, and H. Smith, ibid., p. 1768.*a J. C. Sheehan, R. C. Coderre, L. A. Cohen, and R. C. O'Neill, J . Amer. Chem. Sot.,9 R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, and W. M. McLamore,lo J. R. Billeter and K. Miescher, Helv. Chim. Acta, 1951, 34, 2053.11 W. S. Johnson, D. K. Bannerjee, W. P. Schneider, C . D. Gutsche, W. E. Shelberg,1952, 74, 6155.J . Amer. Chem. Sot., 1962, 74, 4223.and L. J. Chin, J . Amer. Chem. Sot., 1952, 74, 2833.REP.-VOL. XLIX. 1 94 ORGANIC CHEMISTRY.(XIX).12y 133 1 4 9 l5 When, however, the epoxide is treated with the borontrifluoride-ether complex,l2* 13 or with ferric chloride,14 in benzene, theHO, /(XXII) (XX) (XXI)product is the 8-en-ll-one (XX) and this can be reduced to the saturatedketone of natural ” configuration (XXI) by lithium in liquid ammonia ; 1 5 9 16when ethanol is present, reduction proceeds as far as the lla-01 (XXII).[It is interesting that reduction of an 1 l-keto-group (ergostane series) withsodium and rt-propanol l7 also gives the lla-01, in contrast to the stereo-chemical course of catalytic or metal-hydride reduction.] Thus a way ofintroducing the ll-oxygen atom has been found which does not involveelimination of a 7-keto-groupJ and this has been carried out in the ergostaneand the allospirostane series.Catalytic reduction l6 of the unsaturatedketone (XX ; allospirostane series) gives a stereoisomeric 1 l-ketone thoughtto have the “ unnatural ” configuration at Ctsl and C(91.On the other hand, epoxidation of 7 : 9(11)-dienes in the 5-normal (bileacid) series seems to occur preferentially at the 7 : 8-double bond.This isindicated both by molecular-rotation differences between the diene and itsepoxide and by the formation of an 8-en-7-one from the epoxide with borontrifluoride.l2S l4Improvements and elucidations of methods for making 1 l-oxygenatedsteroids from 7 : 9(11)-dienes via 7 : ll-dioxygenated derivatives have beenp~blished,l*-~~ but space to review them is lacking. A method which doesnot start from the usual diene involves oxidation of ergosta-7 : 22-dienylacetate (XXIII) with tert.-butyl chromate; the 8 : 9-epoxy-7-one (XXIV) is1% H.Heusser, K. Eichenberger, P. Kurath, H. R. Dallenbach, and 0. Jeger, Helv.Chim. Acta, 1951, 34, 2106.18 H. Heusser, K. Heasler, K. Eichenberger, C. G. Honegger, and 0. Jeger, ibid.,1952, 35, 295.14 H. Heusser, R. Anliker, K. Eichenberger, and 0. Jeger, ibid., p. 936.15 E. Schoenewaldt, L. Turnbull, E. M. Chamberlin, D. Reinhold, A. E. Erickson,W. V. Ruyle, J . M. Chemerda, and M. Tishler, J . Amer. Chem. SOL, 1952, 14, 2696.16 F. Sondheimer, R. Yashin, G. Rosenkranz, and C. Djerassi, ibid., p. 2696.17 H. Heusser, R. Anliker, and 0. Jeger, Helv. Chim. A d a , 1952, 35, 1537.16 C. Djerassi, E. Batres, M. Velasco, and G. Rosenkranz, J . Amer.Chern. SOC.,20 R. Budziarek, G. T. Newbold, R. Stevenson, and F. S. Spring, J . , 1952, 2892.21 R, C. Anderson, R. Stevenson, and F. S. Spring, ibid., p. 2901.22 R. Budziarek, F. Johnson, and F. S. Spring, ibid., p. 3410.23 R. Budziarek and F. S. Spring, Chem. and Ind., 1952, 1102.1952, 14, 1712. l@ J. Romo, G. Stork, G. Rosenkranz, and C. Djerassi, ibid., p. 2918CORNFORTH : STEROIDS. 195formed (along with the 8 : 14epoxy-7-one in comparable amount) and thisis reduced to the 8-en-7-one (XXV) by zinc and acetic acid.24 A methodalready exists 25 for the conversion of 8-en-7-ones into ll-ones.(XXIII) (XXIV) (XXV) (XXVI)Some important work has appeared on the biosynthetic hydroxylationof ring c. A detailed study has been made of optimum conditions forhydroxylation, by adrenal homogenates, of deoxycorticosterone and its17a-hydroxy-analogue to corticosterone and 17a-hydroxycorticosterone(hydrocortisone) respectively.26 A similar hydroxylation in the 11 p-positionwas effected by the mould Stre$tomyces fradiae, 17a-hydroxy-1 l-deoxy-corticosterone being converted in small yield into hydrocortis~ne.~~ Certainmoulds of the order Mucurales, on the other hand, are capable of hydroxyl-ation in the lla-position : thus when progesterone was introduced into agrowing culture of Rhizupzcs arrhtiz.us, 11 a-hydroxyprogesterone (XXVI)could later be isolated in 10% yield.28 An unidentified strain of Rhizupushas been found to effect the same oxidation in 45% yieId.29 This micro-biological hydroxylation is of great potential importance, for progesterone isreadily available from diosgenin, and 11 a-hydroxyprogesterone (XXVI) hasspecial advantages as an intermediate for cortisone synthesis.Hydrogen-ation of the double bond in A4-3-ketones having an 11/3-hydroxy-S* or ll-keto-COMe COMesubstituent 31 affords largely the 5-dlU(A/B trans)-configuration, but with11 a-hydroxyprogesterone the product is the 5-normal(~/~ cis)-compoundand on oxidation affords pregnane-3 : 11 : 20-trione (XXVII),29 and a later24 H. Heusser, G. Saucy, R. Anliker, and 0. Jeger, Helu. Chim. Acta, 1952, 35, 2090.25 C. Djerassi, 0. Mancera, G. Stork, and G. Rosenkranz, J . Amer. Chem. Suc.,1951, 73, 4496; idem and M. Velasco, ibid., 1952, 74, 3321.28 F. W. Kahnt and A.Wettstein, Helu. Chim. Acta, 1951, 34, 1790.27 D. R. Collingsworth, M. P. Brunner, and W. J , Haines, J . Amer. Chem. SOC.,1952, 74, 2381. 28 D. H. Peterson and H. C. Murray, ibid., p. 1871.2s 0. Mancera, A. Zaffaroni, B. A. Rubin, F. Sondheimer, G. Rosenkranz, and C.Djerassi, ibid., p. 3711.ZsoD. H. Peterson, H. C. Murray, S. H. Eppstein, L. M. Reinecke, A. Weintraub,P. D. Meister, and H. M. Leigh, ibid., p. 5933.30 J. Pataki, G. Rosenkranz, and C. Djerassi, J . Bid. Chem., 1952, 195, 751.31 J. M. Chemerda, E. M. Chamberlin, E. H. Wilson, and M. Tishler, J . Amer. Cham.SOL, 1951, 73, 4052; E. Wilson and M. Tishler, ibid., 1952, 74, 1609; E. P. Oliveto,C. Gerold, and E. B. Hershberg, t v d . , p. 2248. A trace of alkali favours formation ofthe (AIB cis)-isomer : cf.Julian, Recent Progress in Hormone Research,” AcademicPress, New York, 1951, Vol. VI, pp. 207, 212106 ORGANIC CHEMISTRY.paper 29a reports 85-95% yields with Rhixopzts nigricans. Preferentialreduction of the 3-keto-group is possible with sodium borohydride in pyr-idine; 29 the resulting 3a-01 (XXVIII) can be converted into cortisone(see below).The biologically important 17-hydroxycorticosterone (hydrocortisone)has been synthesized 32 by modifying a known cortisone synthesis : in theintermediate (XXIX) the 3-keto-group is protected (dimethyl ketal orsemicarbazone) so that the ll-keto-group may be reduced (lithium or sodiumborohydride) to the 11p-01. The protecting group is removed and thesynthesis then proceeds by known paths to hydrocortisone (XXX).The 11 ct-epimer of hydrocortisone has also been ~ynthesised.~~Further progress is reported with methods for elaborating the cortisoneside chain.From 3a-hydroxypregnane-11 : 20-dione (XXVIII) with aceticanhydride-toluene-fi-sulphonic acid a dienol triacetate (XXXI ; or theA11(12)-isomer) is obtainable which can be epoxidized with perbenzoic acidCMeCN COCH,.OHCMe. OAc COMeIH d H (XXXII)selectively at the 17(20)-double bond. Alkaline hydrolysis then gives3a : 17a-hydroxypregnane-11 : 20-dione (XXXII), into which the 21-hydroxyl group can easily be introd~ced.~~ This method has also beenapplied 35 for preparation of the 3p : 5a-stereoisomer of (XXXII). Fulldetails have been given 36 of another method involving formation andepoxidation of a 16 : 17-double bond.The tertiary 17ct-hydroxyl group in (XXXII) has been acetylated (aceticanhydride-toluene-fxulphonic acid) ; the 17-acetoxy- is comparable with a21-acetoxy-group in ease of h y d r ~ l y s i s .~ ~ ~ ~ * The CH,*OH group in thecortisone side chain has been oxidized 39 to CHO : pyridine and toluene-fi-sulphonyl chloride , followed by p-nitrosodimethylaniline gave the nitrone,-CH=N(+O)C,H,*NMe, ; this was hydrolysed by dilute acid to the aldehyde,32 N. L. Wendler, R. B. Graber, R. E. Jones, and M. Tishler, J . Amer. Chem. SOC.,1952, 74, 3630.33 J. Romo, A. Zaffaroni, J. Hendrichs, G. Rosenkranz, C. Djerassi, and F. Sond-heimer, Chem. and Ind., 1952, 783.34 T. H. Kritchevsky, D. L.Garmaise, and T. F. Gallagher, J . Amer. Chem. SOC.,1952, 74, 483.36 F. B. Colton, W. R. Nes, D. A. van Dorp, H. L. Mason, and E. C. Kendall, J.Biol. Chem., 1952, 194, 235; F. B. Colton and E. C . Kendall, ibid., p. 247.37 Huang-Minlon, E. Wilson, N. L. Wendler, and M. Tishler, J . Amer. Chem. SOC.,1952, 74, 5394.30 E. F. Rogers, J. B. Conbere, K. Pfister, and W. J. Leanza, ibid., p. 2946.s5 J. Pataki, G. Rosenkranz, and C. Djerassi, ibid., p. 5615.38 R. B. Turner, ibid., p. 4220CORNFORTH : STEROIDS. 197which proved approximately as effective as cortisone in the rat-liver glycogentest.A radioactive cortisone labelled with tritium has been prepared 40 in aninteresting manner. 3a-Acetoxypregnane-l l : 20-dione with a platinumcatalyst and tritium-enriched water gave a product " permanently " labelledin the 16-position, and this was converted into cortisone as already described.Modification of Individual Groups.-Protection of steroid hydroxylgroups as tetrahydropyranyl ethers (XXXIII) by reaction with dihydropyranhas been examined.41~ 42 The carbethoxylation (" cathylation ") of steroidhydroxyl groups by ethyl chloroformate is shown to be a selective process,esters (R*O*CO,Et) being formed preferentially from " equatorial " hydroxylgroups.Thus of the three hydroxyl groups in methyl cholate only one (theequatorial 3cc) reacts even when excess of reagent is available.43 Experiencewith the formation of thioketals (XXXIV or XXXV) from cyclic steroidketones and ethanethiol (EtSH) or ethanedithiol (HS*CH,*CH,*SH) may besummarized thus: 44 the ketones which reacted with both thiols had thecarbonyl group in ring A or D ; ketones with a carbonyl group in ring B or creacted with ethanedithiol only, except the ll-keto-group which was inert toboth thiols.M~(oAc):CHz ?b 'ICMe* OAcEtS\ / CH,-S\ /C/-I(XXXVII)()OR EtS/\ CH,-S/ \ /(XXXIII) (XXXIV) (XXXV) (XXXVI)Some interesting data on the formation of enol acetates are now available.20-Ketones are well known to give A17(20)-enol acetates (XXXVI) withacetic anhydride-toluene-9-sulphonic a ~ i d , 4 ~ but with isopropenyl acetatethe isomeric A20-enol acetates (XXXVII) are f ~ r m e d .~ ~ ~ 47 An 11-keto-groupgives an enol acetate with the former reagent 34 but not with the latter.46With a 12-keto-group, both reagents are reported to fail."? 48 These curiousresults seem consistent with the idea that the isopropenyl acetate reagent ismore susceptible to steric hindrance than is acetic anhydride, and thatformation of an enol acetate is inhibited if the removal of the cc-hydrogenatom is sterically hindered.The inertia of the 12-keto-group may beutilized to eliminate the 7-substituent in 3a-hydroxy-7 : 12-diketocholanicacid by catalytic hydrogenolysis of the 7-monoenol acetate which it forms.48Shoppee and Summers 49 have devised a route to the efiicholesterylhalides. 3p-Hydroxycholestan-6-one (XXXVIII) with phosphorus penta-chloride or pentabromide gave the 3cc-halides (XXXIX) which were reducedwith lithium aluminium hydride to the 6p-01s; these were dehydrated to thedesired halides (XL).The normal (3p) cholesteryl halides were obtainable40 D. K. Fukushima, T. H. Kritchevsky, M. L. Eidinoff, and T. F. Gallagher, J .Amer. Chem. SOC., 1952, '44, 487.44 A. C. Ott, M. F. Murray, and R. L. Pederson, ibid., p. 1239.43 L. F. Fieser, J. E. Herz, M. W. Klohs, M. A. Romero, and T. Utne, ibid., p. 3309.44 H. Hauptmann and M. Moura Campos, ibid., p. 3179.45 T. F. Gallagher and T. H. Kritchevsky, J . Bid. Chem., 1949, 1'79, 507.4 6 R. B. Moffett and D. I. Weisblat, J . Amer. Chew Soc., 1952, 74, 2183.4 7 H. Vanderhaeghe, E. R. Katzenellenbogen, K. Dobriner, and T. F. Gallagher,48 R. Hirschmann, M. Brown, and N. L. Wendler, ibid., 1951, '43, 5373. ** C. W.Shoppee and G. H. R. Summers, J., 1952, 1786, 1790.41 W. G. Dauben and H. L. Bradlow, ibid., p. 559.ibid., p. 2810198 ORGANIC CHEMISTRY.by a modification of the same process : 3 : 5-cycZocholestan-6-one (XLI)[from the toluene-fi-sulphonyl derivatives of (XXXVIII) and potassiumhydroxide] with hydrogen halides gave 3P-halogenocholestan-6-ones (XLII)which were reduced and dehydrated.X(XXXVIII) (XXXIX)A discovery 50 which may prove generally useful is that steroid 3-ketonesundergo " reductive methylation " on catalytic hydrogenation in methanolcontaining hydrogen bromide, the product being a methyl ether : >CO -+> CH-OMe. 3p-Methoxy-compounds were produced from both cholestanone(do-series) and methyl 3-keto-A9(11)-cholenate (normal series).In a studyof non-catalytic reduction of cholestanone, Nace and O'Connor 51 showedthat whereas with lithium aluminium hydride the ratio of 3p-01 to 3a-01 inthe product was 7-3 : 1, with aluminium alkoxides Al(OR), more of the 3a-01was formed. This effect could be exaggerated by increasing the bulk of theR group : with di-tert.-butylcarbinol Me,C*CH(OH)*CMe, and its aluminiumalkoxide the reduction product contained 55% of 3a-01. The results areattributed to steric hindrance in formation of an intermediate complex. -Some Reactions involving Double Bonds.-The diacetate of androst-7-enediol (XLIII) was found 52 to be rearranged by hydrogenation catalystsin the known manner to the AKl4)-isomeride (XLIV), but further isomeriz-ation by hydrogen chloride to the A14-isomeride (XLV) did not occur.Thisfailure to isomerize, in contrast to the results obtained with cholesterol andergosterol analogues, has also been observed with A8(14)-aZZ~pregnen~lone andwith dehydro t igogenin. 53Me?*' M e yM e C b p!fP/": J AcO H -+ /c"" M e P 5/HVAcOPh /\/HVAcO(XLIII) (XLIV) (XLV)Two methods of obtaining A5: '-steroids from A4-3-ketones (XLVI) havebeen elaborated. By bromination and dehydrobromination the 4 : 6-dien-%one can be made, the enol acetate (XLVII) of which with sodium boro-50 J. C. Babcock and L. F. Fieser, J. Amer. Chem. SOC., 1952, 74, 5472.61 H. R. Nace and G. L. O'Connor, ibid., 1951, 73, 6824.52 R. Antonucci, S. Bernstein, D. Giancola, and K. J. Sax, J.Org.Chem., 1961,16,1891.63 0.Mancera, D. H. R. Barton, G. Rosenkranz, and C. Djerassi, J., 1952, 1021CORNFORTH : STEROIDS. 199hydride affords the 5 : 7-dien-3p-01 (XLVIII). This has been done in thecholestane and 22-iso-allospirostane 55 series. Alternatively one canobtain the A5-ketal (XLIX) from the unsaturated ketone (XLVI ; cholest-enone, progesterone, 21-acetoxyprogesterone) and ethylene glycol ; 56bromination and dehydrobromination then give an unusually high yield ofthe 5 : 7-diene (L)563 57___,0 AcO HO(XLVI) (XLVII) (XLVIII)3 : 5-cycloSteroids.-A hydrocarbon obtained from ergosterol withtoluene-$-sulphonyl chloride and pyridine, and formerly thought to be anergostatetraene, is now shown 58 to be 3 : 5-cycloergosta-6 : 8(14) : 22-triene(LI).By working at -lo", ergosterol and 7-dehydrocholesterol can beconverted into toluene-9-sulphonyl derivatives (LII) and these with lithiumaluminium hydride give 3 : 5-cyclo-7-enes (LIII) .59(LIII)Wagner, Wolff, and Wallis report 60 that both epimers of 3 : 5-cyclo-cholestan-6-01 (LIV) are rearranged under acidic conditions to give the same(3P) cholesterol derivatives, and have advanced arguments that the 3 : 5-64 W. G. Dauben, J. F. Eastham, and R. A, Micheli, J . Amer. Chem. SOG., 1951,73,4496.6 5 H. J. Ringold, G. Rosenkranz, and C. Djerassi, ibid., 1952, 74, 3441.6 6 R. Antonucci, S. Bernstein, R. Littell, K. J. Sax, and J. H. Williams, J . 9%.cf. E. Fernholz and H. E. Stavely, Abstr. 102nd meeting,57 R. Antonucci, S. Bernstein, R. Lenhard, K.J. Sax, and J. H. Williams, J . OYg.s8 M. Fieser, W. E. Rosen, and L. F. Fieser, J . Amer. Chem. SOL, 1952, 74, 5397-69 P. Karrer and H. Asmis, Hek. Chim. A d a , 1952, 35, 1926.6o A. F. Wagner, N. E. Wolff, and E. S. Wallis, J . Org. Chem., 1952, 17, 529; N- E.Chewz., 1952, 17, 1341;Amer. Chem. Soc., Sept. 1941, M39.Chem., 1952, 17, 1369.WoIff and E. S . Wallis, ibid., p. 1361200 ORGANIC CHEMISTRY.cycEo-6-01s (the iso-steroids) prepared by rearrangement of 3P-hydroxy-A5-steroids have the 6ceconfiguration. However, isocholesterol can be hydro-genated61 to cholestan-6p-01 (its epimer gives cholestan-6a-01) and shouldtherefore be 3 : 5-cycZocholestan-6~-01. The mechanisms of isocholesterolrearrangements have been discussed.60*The structure of the unsaturated hydrocarbon obtained 62 by acid treat-ment of 3 : 5-cycZocholestane has been established as (LV) by an unequivocalsynthesis.63Naturally Occurring Steroids.-There have been several advances inthe chemistry of steroid saponins.Infra-red absorption measurementsindicate 64 that the spiroketal side chain present in the sapogenins, and the12-keto-group present in some of these, occur also in the original saponinsand are not artefacts of hydrolysis, as has been suggested.65 A method hasbeen given 66 for detecting steroidal sapogenins in hydrolysates of planttissue by means of the characteristic infra-red absorption of the seiroketalside chain. The effect of several catalysts on the opening of the 6-memberedheterocyclic ring in sapogenins by acetic anhydride has been studied.67Reductive fission of this ring (to give a primary alcohol) can be effected withlithium aluminium hydride and ether saturated with hydrogen chloride.Without the acid no cleavage occurs.68Manogenin (2a ? : 3~-dihydroxy-22-isoaZZospirostan-12-one 69) has beenconverted into hecogenin (3~-hydroxy-22-isoaZZospirostan-12-one) via theA3-analogue and its epoxide.70The 3-(hydrogen succinate) 12-methanesulphonate (LVI ; R =HO,C*CH,*CH,*CO) of rockogenin suffers rearrangement of the carbonskeleton under remarkably mild conditions (boiling methanol). The struc-ture (LVII ; R = HO,CCH,*CO) is indicated for the product ; the exocyclicmethylene group was demonstrated by two-stage oxidation to formaldehyde.CH2 M2 -4- (q,;+A>-MeM e * s 0 2 0 7 M e M ~ ~ ~ M eRo d&ho (LVI) RO -" (LVII)The corresponding 1%-derivative was unchanged under similar con-d i t i o n ~ .~ ~ A carbon skeleton identical with that of (LVII) has been postul-ated for the alkaloid jer~ine.~,61 C. W. Shoppee and G. H. R. Summers, J., 1952, 3361.62 H. Schmid and K. Kagi, Helv. Chim. Acta, 1950, 33, 1582; cf. F. S. Prout and63 C. W. Shoppee and G. H. R. Summers, J . , 1952, 2528.64 E. S. Rothman, M. E. Wall, and C. R. Eddy, J . Amer. Chem. SOC., 1952, 74, 4013.66 R. E. Marker and J. Lopez, ibid., 1947, 69, 2390.66 M. E. Wall, C. R. Eddy, M. L. McClennan, and M. E. Klumpp, Analyt. Chem.,6 7 D. H. Gould, H. Staeudle, and E. B. Hershberg, J . Amer. Chem. Soc., 1952, 74,For some evidence of configuration see J.Pataki, G. Rosenkranz, and C. Djerassi,71 R. Hirschmann, C. S. Snoddy, and N. L. Wendler, ibid., p. 2694.73 J- Fried, 0. Wintersteiner, M. Moore, B. M. Iselin, and A. Klingsberg, ibid., 1951,B. Riegel, J . Amer. Chem. SOC., 1952, 74, 3190.1952, 24, 1337.3685.&id., p. 5375.73, 2970.H. M. Doukas and T. D. Fontaine, ibid., 1951, 73, 5918.70 N. L. Wendler, H. L. Slates, and M . Tishler, ibid., 1952, 74, 4894CORNFORTH : STEROIDS. 201Reichstein and his collaborators have published numerous papers add-ing to the systematic knowledge of naturally occurring cardiac glycosides.Two glycosides from Gomphocarpzls fruticosus, gofruside and frugoside, wererespectively hydrolysed 73 to the aglycones corotoxigenin and corogluaci-genin previously obtained by Stoll, Pereira, and Renz '4 from Coronkllaglauca.Corotoxigenin has been identified as a 5-deoxystrophanthidin(LVIII ; R = CHO), and coroglaucigenin as the corresponding strophanthidol(LVIII; R = CH,*OH), by degradation to an ester (LIX) obtainable alsofrom strophanthidin.The cholesterol isomer, cholest-7-en-3p-01, has been isolated from the skinof albino rats.75Biogenesis of Steroids.-Langdon and Bloch 76 have shown that 14C-labelled squalene, obtained from the tissues of rats fed with l*C-label€edacetic acid, when fed to other rats is converted into cholesterol more effici-ently than any previously known precursor. This observation, indicatinga close relation between steroid and terpenoid biogenesis, lends additionalinterest to the recent elucidation of the structure of lanosterol. Evidenceon the point of attachment of the side-chain has been obtained by chemical 77and by X-ray crystallographic 78 methods, and lanosterol may now beregarded as 4 : 4 : 14-trimethylzymosterol (LX), a steroid with some terpenoidfeatures.Me IMe I CH.CH,.CH,*CH:CMe,Me,Physical Properties of Steroids.-Several papers on the infra-red spectraof steroids have appeared, and features of the spectra have been correlatedwith the configuration of 3-hydroxyl groups,79 with methyl and methylenegroups,8o and with the A5-3p-hydroxy-system.81 Several methods for paper73 A.Hunger and T. Reichstein, Helv. Chim Acta, 1952, 35, 1073.74 A. StolI, A.Pereira, and J. Renz, ibid., 1949, 32, 293.7 6 D. R. Idler and C. A. Baumann, J . Biol. Chem., 1952, 195, 623.76 R. G. Langdon and K. Bloch, J . Amer. Chem. SOC., 1952, 74, 1869.7 7 W. Voser, M. V. Mijovic, H. Heusser, 0. Jeger, and L. Ruzicka, Hclv. Chim. Ada,7 8 R. G. Curtis, J. Fridrichsons, and A. McL. Mathieson, Natuve, 1952, 170, 321.70 A. R. H. Cole, B. N. Jones, and K. Dobriner, J. Amer. Chem. Soc., 1952, 74, 5571.R. N. Jones and A. R. H. Cole, ibid., p. 5648; idem and B. N o h , ibid., p. 506281 H. Hirschmann, ibid., p. 5357.1952, 35, 2414202 ORGANIC CHEMISTRY.chromatography of steroids have been reported.82 A fractionation of oxbile by counter-current distribution showed, among other things, that nounconjugated bile acids are present in fresh bile.=Stereochemistry of Steroids.-Chemical evidence for the assignmentof configurations to the two 7-hydroxycholesterols has been provided byHeymann and Fieser; the seco-3 : 4-dioic acid (LXI) obtained by hydro-genation and oxidation of the more dextrorotatory epimer forms a y-lactone,which is only possible with a 7p-hydroxyl group.Klyne B5 has published a paper correlating the stereochemistry of thetriterpenoids with that of the steroids on the basis of molecular-rotationcontributions.J. W.C.8. HETEROCYCLIC COMPOUNDS.Further volumes in the series edited by R. C. Elderfield and byA. Weissberger have appeared, and a comprehensive tabular survey ofthiazoles has been published.Three- and Four-membered Ring Systems.-Studies on the fission of theoxiran ring by a variety of reagents * continue to be reported.o-, m-, and$-Nitrostyrene oxides react with the phenoxide ion to give predominantly thesecondary alcohols,5 while, under suitable conditions in the presence ofexcess of phenol as solvent, styrene oxide can give the primary alcohol almostexclusively.6 The secondary alcohol is the major product from styreneoxide and benzylamine, and p-nitrostyrene oxide and diethyl sodiomalonategive the lactone (I),8 indicating- steric factors to be then a controlling in-fluence.9 The reaction between Grignard reagents and the oxiran ring havebeen reviewed.10 The stereochemistry of the opening and closure of thering in 2 : 3-dimethylethyleneimine,ll 2 : 3-epoxybutane,12 and cyclo-hexeneimine (2 : 3-cyclohexanoaziridine) l3 has been studied, both re-82 R.B. Davis, J. M. McMahon, and G. Kalnitsky, J . Amer. Chem. Soc., 1952, 74,4483; R. Neher and A. Wettstein,Helv. Chim. A d a , 1952, 35, 276; I. E. Bush, Biochem. J., 1952, 50, 370.83 E. H. Ahrens and L. C. Craig, J . Biol. Chem., 1952, 195, 763.8 1 H. Heymann and L. F. Fieser, Helv. Chim. Acta, 1952, 35, 631.86 W. Klyne, J., 1952, 2916; cf. W. M. Stokes and W. Bergmann, J . Org. Chem.,1951, 16, 1817.1 “ Heterocyclic Compounds. Vol. I11 : Polycyclic Derivatives of Pyrrole ; Poly-cyclic Systems with One Nitrogen Common to Both Rings; Pyrindene and RelatedCompounds. Vol. IV : Quinoline, Isoquinoline, and Their Benzo Derivatives.” J .Wiley and Sons, Inc., New York, 1952.2 “ Thiophene and its Derivatives,” by H.D. Hartough. ’ ‘ Five-membered Hetero-cyclic Compounds with Nitrogen, Sulphur and Oxygen (except Thiazole),” by L. L.Bambas.9 Kartothek der Thiazolverbindungen (in 4 vols.), by B. Prijs. S. Karger, Basel,1951.6 C. 0. Guss, J . Org. Chem., 1952, 17, 678.6 C. 0. Guss and H. R. Williams, ibid., 1951, 16, 1809.7 C. L. Browne and R. E. Lutz, ibid., 1952, 17, 1187.8 S. J. Cristol and R. I;. Helmreich, J . Amer. Chem. Soc., 1952, 74, 4083.9 Cf. also R. Rothstein and J. Ficini, Compt. rend., 1952, 234, 1293, 1694.l o N. G. Gaylord and E. I. Becker, Chem. Reviews, 1951, 49, 413.l1 F. H. Dickey, W. Fickett, and H. J. Lucas, J . Amer. Chem. Soc., 1952, 74, 944.l2 G. K. Helmkamp and H. J. Lucas, ibid., p.961.l3 0. E. Paris and P. E. Fanta, ibid., p. 3007.D. Kritchevsky and M. R. Kirk, ibid., p. 4484;Intersci. Publ., New York, 1952.4 Cf. Ann. Reports, 1950, 47, 220WALKER : HETEROCYCLIC COMPOUNDS. 203actions being accompanied , as would be expected, by Walden inversion.Alkaline hydrolysis of either the 0- or the S-acetyl derivative of Z-mercapto-ethanol gives ethylene sulphide and polymeric material, and cyclohexenesulphide is similarly 0btainab1e.l~ Glycidol (11) is obtained in high yieldfrom glycerol and ethylene carbonate, or phenyl carbonate, a cross-linkedpoly(glycero1 carbonate) being presumably an intermediate.14uR*CH:C-CHR I I 0-coNO,C,H,*CHCH *CH*CO,Et CH,--CHCH,*OH0- I ' i co '0'In analogy with the formation of coumaranone in the decomposition ofo-ani~oyldiazomethane,1~ I-oxas$iro[3 : 51nonan-3-one (111) has been ob-tained by the decomposition of l-acetoxycyclohexane-l-carbonyldiazo-me thane.l6Further examples of the condensation of indoles with P-propiolactone havebeen described, and pyrrole gave p-2-pyrrolylpropionic acid. l7 Confirmatoryevidence has been produced to show that monosubstituted keten dimers areP-lactones (IV) containing a semicyclic double bond. l8Five- and Six-membered Ring Systems.-A detailed analysis has beenmade of the stereochemical factors governing the synthesis of cyclic acetals ofpolyhydric alcohols, and a theoretical basis has been provided l9 for certainempirical rules 2O developed to enable the pattern of condensation between agiven carbonyl compound and a given polyhydric alcohol to be predicted.y-Valerolactone has been used in the Friedel-Crafts reaction with theisomeric xylenes for the synthesis of various polymethylnaphthalenes.21Perfluorobutyrolactone, the main product of the degradation of silverhexafluoroglutarate with excess of iodine, is a highly reactive compound andreacts with water, ethanol, ammonia, hydriodic acid, and ethanethiol to givederivatives of perfluorosuccinic acid.22The stereochemical course of the temperature-dependent re-action 23 between furan and maleinimide is similar to that between furan andmaleic anhydride,24 the endo-adduct (V) being formed at 25" and the exo-com-pound (VI) a t higher temperatures ; both adducts are relatively unstable,having endo-bridges ,25 but hydrogenation to the hexahydro-3 : 6-endo-oxophthalimides permitted further investigation.% Electrolytic methodshave been described for the alkoxylation of furan and substituted furans withFuran.l4 L.W. C. Miles and L. N. Owen, J., 1952, 817.140 H. A. Bruson and T. W. Riener, J. Amer. Chem. SOC., 1952, 74, 2100.l6 E. R. Marshall, J . A. Kuck, and R. C. Elderfield, J. Org. Chem., 1942, 7 , 444;A. K. Bose and P. Yates. J. Amer. Chem. SOC., 1952, 74, 4703.J . R. Marshall and J . Walker, J., 1952, 467.J . Harley-Mason, J., 1952, 2433.l 8 C. M. Hill, M. E. Hill, H. I. Schofield, and L. Haynes, J. Amer. Chew%. Soc., 1952,S. A. Barker, E. J. Bourne, and D. H. Whiffen, J., 1952, 3865.2o S. A. Barker and E. J . Bourne, ibid., p, 905.21 W.L. Mosby, J. Amer. Chem. Soc., 1952, 74, 2564.22 M. Hauptschein, C. S. Stokes, and A. V. Grosse, ibid., p. 1974.23 H. Kwart and I. Burchuk, ibid., p. 3094.24 R. B. Woodward and H. Baer, ibid., 1948, 70, 1161.25 Cf. Ann. Reports, 1950, 47, 179; M. Kloetzel, Organic Reactions, 1948, 4, 9.74, 166. 204 ORGANIC CHEMISTRY.the production of 2 : 5-dialkoxy-2 : 5-dihydrofurans ; 26 with methanol,maleinaldehyde tetramethylacetal is a by-product. Acyloxylation of furansis effected with lead tetra-acyloxylates 27 and pyrolysis of 2 : 5-diacetoxy-2 : 5-dihydrofuran gives 2-acetoxyf~ran,~S while conversion of thedialkoxydihydrofurans into l-arylpyrroles proceeds in good yield.%The Willgerodt reaction is applicable in the furan series if lower temper-atures are used than is customary.30 Formation of a 1 : 2-adduct (VII) offurfuraldehyde and batadiene has been reported,31 and appears to be theonly known example of furfuraldehyde acting as a dienophile in a dienereaction. Another product is formed in the reaction and appears, fromvarious degradations, to be (VIII).32 The reaction of diazonium salts withfurylacrylic acid 33 leads mainly to 5-aryl-2-styrylfurans, 2-styrylfurans andp-(5-aryl-2-furyl)acrylic acids being formed as by-products.The methylenedihydrofuran, obtained together with 2-methylfuran byapplying the Wolff-Kishner reaction to furfuraldehyde, has been shown by 4y l-&cohH <?/\ /\/ CH* \p+OHco’ \p0,/ d! (Ao/..CO-NH CHO(V) t VI 1 ( V W (VIII)ultra-violet absorption to be the conjugated 2 : 5-dihydro-2-methylene-f ~ r a n .~ ~ The reaction between the two stereoisomeric forms of tetrahydro-5-hydroxy-3-methyl-2-propenylfuran and aniline is said to give selectively thetwo forms of the corresponding anilino t e trahydrof urans.Further experience has been obtained of the use of dihydropyranfor the protection of secondary alcohol groups in steroids.36 Other novelreactions in this series include the reaction of 2-alkoxy-3 : 4-dihydropyrans 37with ammonia over alumina a t 400°, which gives pyridine, and thermalcleavage over an alumina-silica catalyst to isomeric 5-alko~ypent-4-enals.~~Addition of alcohols, carboxylic acids, phenol, and hydrogen cyanide yieldsthe appropriate 6-alkoxy-, 6-acyloxy-, 6-phenoxy-, and 6-cyano-derivativesof 2-alkoxy t e trahydropyran .3 Hydrogenation of 2-alkoxydih ydropyransover Raney nickel gave 2-alkoxytetrahydropyrans and hydrolysis followedby hydrogenation gave the corresponding pentane-1 : 5-di0ls.~~ The latterPyran.26 N.Clauson-Kaas et al., Acta Chem. Scand., 1952, 8, 531, 545, 551, 556, 569;27 N. Elming and N. Clauson-Kaas, ibid., p. 535; N. Elming, ibid., p. 578.28 N. Clauson-Kaas and N. Elming, ibid., p. 560.29 N. Elming and N. Clauson-Kaas, ibid., p. 867; N. Clauson-Kaas and 2. Tyle,30 J. A. Blanchette and E. V. Brown, J . Amer. Chem. Sac., 1952, 74, 2098.31 J . C. Hillyer, S. Swadesh, M. L. Leslie, and A. P. Dunlop, I n d . Eng. Chem., 1948,33 W. Freund, J., 1952, 3068; cf. D. M. Brown and G.A. R. Kon, J . , 1948, 2150.34 H. L. Rice, J . Amer. Chem. SOC., 1952, 74, 3193.3 5 C. Glacet, Compt. rend., 1952, 234, 2371,36 A. C. Ott, M. F. Murray, and R. L. Pederson, J . Amer. Chem. SOC., 1952, 74, 1239;37 Ann. Reports, 1950, 47, 226; 1951, 48, 211.38 C. W. Smith, D. G. Norton, and S. A. Ballard, J . Amer. Chem. SOC., 1952, 74, 2018.39 R. I. Longley, W. S. Emerson, and T. C. Shafer, ibid., p. 2012.N. Elming, ibid., p. 572.ibid., p. 667.40, 2216. 12 J. C. Hillyer and J. T. Edmonds, J . Org. Chern., 1952, 17, 600.E . Elisberg, H. Vanderhaeghe, and T. F. Gallagher, ibid., p, 2814WALKER : HETEROCYCLIC COMPOUNDS. 205are also obtained directly by hydrogenation over copper chromite in thepresence of water,39 the saturated S-lactone being a by-product in the caseMe Meof dihydro-2-methoxy-4-methylpyran. Dihydrodeoxypatulinic acid (IX)has been synthesised from A3-dihydropyran and formaldehyde by way ofthe methylene ether (X) or the diacetate (XI)J41 and tetrahydro-3 : 4-dihydroxypyran is accessible from erythrol (but-l-ene-3 : 4-diol) and form-aldehyde.42Dieckmann ring-closure of ethyl y-carbethoxymethylthiobutyrate givesethyl tetrahydro-3-ketothiapyran-2-carboxylate (XII), converted by aseries of stages into A2-dihydrothiopyran 1 : l-dioxide (XIII) ; the latterreadily passes irreversibly into the A3-sulphone (XIV) 43 in contrast with thesituation arising with isoprene sulphone (XV) .Vapour-phase reaction oftetrahydropyran with primary aromatic amines gives l-arylpiperidines inhigh yield,&Deuterated y-pyrones have been prepared by exchange and synthesis,and exchange, rather surprisingly, takes place only at the cc-p0sition.4~Pyrrole.The molecular structures of pyrrole and some of its simplederivatives have been studied by electric dipole-moment measurements 46and fit into a general pattern with indole derivatives.4' Pyrroles react withisocyanates with C-substitution at previously unsubstituted positions in thenucleus. The imino-group is unreactive and no reaction takes place withH H1-methylpyrrole in accordance with the rule that N-substitution deactivatesthe pyrrole nucleus generally.48 Similarly, diketen reacts with pyrroles togive C-acetoacetylpyrroles (e.g. , XVI), hydrolysed by alkali to C-acetyl-40 Cf.L. P. Kyrides and F. B. Zienty, J . Amer. Chem. SOL, 1946, 68, 1385.41 S. Olsen, Acta Chem. Scand., 1951, 5, 1326.43 E. Fehnel, J . Amer. Chem. SOL, 1952, 74, 1569.44 A. N. Bourns, H. W. Embleton, and M. K. Hansuld, Canad. J . Chem., 1952, 30, I .4 5 R. C. Lord and W. D. Phillips, J . Amer. Chem. Soc., 1952, 74, 2429.4 6 H. Kofod, L. E. Sutton, and J. Jackson, J . , 1952, 1467.4 7 E. F. J , Janetzk andM. C . Lebret, Rcc. Trav. chzim., 1944, 63, 123.48 A. Treibs and d Ott, Annabn, 1952, 577, 119.42 Idem, ibid., p. 1339206 ORGANIC CHEMISTRY.pyrr~les.*~ Hydroxymethylpyrroles containing only alkyl groups as othersubstituents are unknown and are not even accessible by lithium aluminiumhydride reduction of suitable precursors ; the reaction either fails completelywith recovery of starting material, even with excess of reagent in boilingtetrahydrofuran, or reaction occurs with subsequent destruction of thelabile product.Analogous secondary alcohols are also not accessible by thismeans, 3-acetyl-2 : 4-dimethylpyrrole, for example, yielding cryptopyrrole(3-ethyl-2 : 4-dimethylpyrrole) . 50 When the reducible functional groupsare not directly attached to the pyrrole nucleus reduction with lithiumaluminium hydride proceeds normally. 51Substituted pyrrolidines are prepared by the addition of aliphatic nitro-compounds to acrylic ester, followed by reduction of the y-nitro-esters, ringclosure, and further reduction of the resulting pyrrolidones with lithiumaluminium hydride. 52 Similar reduction of alkylsuccinimides proceedsnormally.53 The relative ease of formation of the pyrrolidine ring is shownby the ready cyclisation, under the conditions of amidine formation, of3-chloro-l-phenyl-, 3-chloro-1 : l-diphenyl-,= and 3-dimethylamino-1 : 1-diphenyl-propyl cyanide 55 to iminopyrrolidines, ring closure in the lastinstance being accompanied by loss of a methyl group.Evidence has beenNHII /C-NMe + Ph,C I Ph,C PN\CH,*CH,.NMe, \CH,-CH,obtained to suggest that the biosynthesis of proline follows the path:glutamic acid --+ glutamic acid y-semialdehyde -+ Al-pyrroline-5-carboxy-lic acid --+ pr0line,~6 and it has been shown that natural hydroxy-L-prolinecan be converted into the other three stereoisomeric modifications by selectiveinversions.57Pyridine. The Tschitschibabin synthesis of pyridines has been improvedby carrying out the reaction in acetic acid-ammonium acetate,58 and certain2 : 3 : 5-trisubstituted pyridines are conveniently prepared by disproportion-ation of 2 : 3 : 5-trisubstituted l-benzyl-1 : 2-dihydropyridines obtained bycondensation of aldehydes with N-ben~ylaldimines.~~ A kinetic study hasbeen carried out on the reaction between butadiene and cyanogen, by which2-cyanopyridine is formed.60 Although N-bromosuccinimide would beexpected to introduce bromine atoms into the methyl groups, 2-hydroxy-,2-amino-, and 2-acetamido-4 : 6-dimethylpyridine undergo nuclear bromin-ation even in presence of benzoyl peroxide.61 2-Vinylpyridine, being a49 A.Treibs and K. H. Michl, Annalen, 1952, 577, 129.50 A. Treibs and H. Scherer, ibid., p. 139.51 0. Klamerth and W. Kutscher, Chem. Ber., 1952, 85, 444; W. Kutscher and0. Klamerth, 2. physiol. Chem., 1952, 289, 229.52 R. B. Moffett and J. L. White, J . Org. Chem., 1952, 17, 407.53 D. E. Ames and R. E. Bowman, J.. 1952, 1057.54 F. E. King, K. G. Latham, and M. W. Partridge, ibid., p. 4268.5 5 W. Wilson, J . , 1950, 2173; 1952, 3524; J. Cymerman and W. S. Gilbert, ibid.,5 7 D. S. Robinson and J . P. Greenstein, J . Biol. Chem., 1952, 195, 383.5 8 M. Weiss, J . Amer. Chem. SOC., 1952, 74, 200.58 T. M. Patrick, ibid., p. 2984.61 R. P. Mariella and E. P. Belcher, ibid., p. 1916.p. 3529. 56 H. J. Vogel and B. D. Davis, J . Amer. Chem. SOL, 1952, 74, 109.6o P.J. Hawkins and G. J. Janz, ibid., p. 1790WALKER HETEROCYCLIC COMPOUNDS. 207vinylogue of acrylonitrile, takes part in Michael addition reactions to giveappropriate pyridylethyl derivatives.62 Ultra-violet absorption charac-teristics have shown the existence of restricted rotation in 4-aryl-3 : 5-di-carbethoxy-2 : 6-1~tidines.~~A synthesis of pyridoxine based on biogenetic considerations has beendescribed,6* and pyridoxal5-phosphate (codecarboxylase) (XVII) , which maybe purified as the acridine salt ,65 has 'been obtained from 00-isopropylidene-pyridoxine (XVIII) by reaction with phosphoric oxide in phosphoric acid,and subsequent oxidation of pyridoxine 5-phosphate. 66 Anhydrous phos-phoric acid also converts pyridoxamine into the crystalline 5-pho~phate.~'(-)-Pipecolinic acid has been recognised as a natural amino-acid of relativelywide occurrence.68CHOHO/~H~.O-PO,H,(XVII) Me!! N' '-H27 YH2(XIX) Me& h'Me,,HClph\/CN+ Q + NMe,(XX) Me,HC1Convenient syntheses of alkylpiperidines, 53 piperidin-4-01,~~ 3 : 3-di-substituted 2 : 6-diketopiperidine~,~* substituted 3-piperidones 71 and 1-alkyl-3-hydroxypiperidines 72 have been described, while a novel ring-closure of a=-bis-2-dimethylaminoet hyl- =-phenylacet onitrile hydrochloride(XIX) proceeds with loss of trimethylamine and formation of 4-cyano-1-methyl-4-phenylpiperidine hydrochloride (XX) in 78 yo yield.73Monocyclic compounds with more than one hetero-atom. PreliminarylfX1, 'Y'(XXII)EtO(XXIV)/s(XXVI)i!s>OAc/N=CHC2BH3808)C\ I C28H3808}C0 f NH3 $- [HS'CH2'CH01S-CH,Uscharin Uscharidinstudies of the series (XXI) and (XXII) have been reported where X = S,Y = 0, and X = Y = S.Monothioglycol(2-mercaptoethanol) and chloro-62 R. Levine and M. H. Wilt, J . Amer. Chem. SOC., 1952, 74, 342.64 A. Cohen, J. W. Haworth, and E. G. Hughes, J.. 1952, 4374.66 M. Viscontini and P. Karrer, Helv. Chim. Acta, 1952, 35, 1924.66 J . Baddiley and A. P. Mathias, J., 1952, 2583.97 E. A. Peterson, H. A. Sober, and A. Meister, J . Amer. Chem. Soc., 1952, 74, 570.68 R. M. Zacharius, J. F. Thompson, and F. C. Steward, ibid., p. 2949; G. Harris6s K. Bowden and P. N. Green, J., 1952, 1164.7O E. Tagmann, E. Sury, and K. Hoffmann, Helv. Chim. Acta, 1952, 35, 1235.7l F.F. Blicke and J. Krapcho, J . Amer. Chem. Soc., 1952, 74, 4001.73 J . H. Biel, H. L. Friedman, H. A. Leiser, and E. P. Sprengeler, ibid., p. 1485.73 F. F. Blicke, J. A. Faust, J . Krapcho, and E. Tsao, ibid., p. 1844.A. P. Phillips and P. L. Graham, ibid., p. 1552.and J. R. A. Pollock, Chem. and Ind., 1952, 931808 ORGANIC CHEMISTRY.acetaldehyde dimethyl acetal gave 2-methoxy-1 : 4-oxathian (XXIII), con-verted by catalytic decomposition over phosphoric oxide into 1 : 4-oxathien(XXI; X = S, Y = O).74 2-Mercaptoacetal, HS*CH,*CH(OEt),, passesslowly into 2 : 5-diethoxy-1 : 4-dithian (XXIV). The latter is hydrolysed tomercaptoacetaldehyde, which dimerises to give the two stereoisomericforms of 2 : 5-dihydroxy-1 : 4-dithian (XXV), and the derived acetatespass when heated into the same acetoxy-1 : 4-dithien (XXVI).75 Theheterocyclic fragment of the African arrow poison uscharin consists appar-ently of a thiazoline ring since hydrolysis gives uscharidin, ammonia, anddimeric mercaptoacetaldehyde (XXV).76Applications of intermediate oxazoline formationin stereochemical problems have already been reviewed. 77 Analogousstudies based on the intermediate formation of the tetrahydro-1 : 3-oxazinering have clarified the stereochemistry of tropine and pseudotropine. 78 Anovel application of N-acyl + O-acyl migration via the oxazoline is in thedegradation (XXVII) of silk fibroin at serine residue^,'^ and an account hasbeen given of cyclisation, ring-fission, and acyl-migration reactions involvingthiazolines.80 Preservation of spatial configuration during various pro-cedures for closing the hetero-ring in hexahydrobenzoxazolones (XXVIII ;X = 0) and related compounds (XXVIII; X = S, or NH) has beendemonstrated, and both cis- and trans-series are obtainable. 81Oxaxoline ; thiazolirze.R(XXVII) (XXVIII) (XXIX)Further studies of the ultra-violet light absorption ofpyrimidine derivatives have been reported,S2 and an empirical rule has beenfound for calculating the wave-length of absorption maxima of polysub-stituted compounds containing not more than one potentially tautomericgrouping. 83 Infra-red absorption characteristics of a wide range of deriv-atives have been published,8* and a novel technique in this field, with possiblewide application^,^^ uses the substance embedded in a plate of potassiumbromide formed under high pressure.86 The infra-red absorption data aremore in accord with amino- than with imino-dihydro-structures for potentialaminopyrimidines, in line with conclusions reached on similar evidence foraminopyridines.87Pyrimidim.74 W. €3. Parham, I. Gordon, and J. D. Swalen, J . Amer. Chem. SOC., 1952, 74, 1824.75 G. Hesse and I. Jorder, Chem. Ber., 1952, 85, 924.7 8 G. Hesse and H. W. Garnpp, ibid., p. 933.7 7 Ann. Reports, 1951, 48. 217; cf. G. Fodor and K. Koczka, J., 1952, 860.713 G. Fodor and K. NAdor, Nature, 1952, 169, 462; A. Nickon and L. F. Fieser,J. C. Crawhall and D. F. Elliott, J., 1952, 3094.81 M. Mousseron, F.Winternitz, and M. Mousseron-Canet, Compt. rend., 1952,235,373.82 D. Shugar and J. J. Fox, Biochim. Biophys. Acta, 1952, 9, 199; M. P. V. Boarland84 L. N. Short and H. W. Thompson, ibid., p. 168.85 Cf. U. Schiedt and H. Reinwein, 2. Naturforsch., 1952, 7b, 270.86 M. M. Stimson and M. J . O’Donnell, J . Amer. Chem. Soc., 1952, 74, 1805.C. L. Angyal and R. L. Werner, J., 1952, 2911; J. D. S. Goulden, ibid., p. 2939;J . Amer. Chem. Soc., 1952, 74, 5566. 79 D. F. Elliott, Biochem. J., 1952, 50, 542.and J. F. W. McOmie, J., 1952, 3716. *3 Idem, ibid., p. 3722.cf. also S. J. Angyal and C. L. Angyal, ibid., p. 1461WALKER : HETEROCYCLIC COMPOUNDS. 209Although 5-aminopyrimidine itself fails to undergo diazotisation,88 thepresence of other suitable substituents allows normal diazonium salt form-ation to occur, and in the presence of a 4(6)-mercapto-, -hydroxy-, orprimary-amino-group, ring closure to pyrimidino-thiadiazoles (XXIX ;X = S), Loxadiazoles (XXIX; X = 01, and -triazoles (XXIX; X = NH)occurs; 89 ring closure even takes place with a 4(6)-alkyl group, giving1 : 2 : 4 : 6-tetra-azaindenes (XXIX; X = CH,), isomeric with purines.A new reaction of acetylene with nitriles, e g ., propionitrile, results in theformation of 2 : 4-diethylpyrimidine and the isomeric aminopyridine ;a carbanion mechanism is suggested for the reaction.90Insight into the mechanism of formation of s-triazines fromnitriles has been obtained since all nitriles which form triazines readily giveprimary products containing two molecules of nitrile to one of hydrogenhalide, their properties being compatible with ionic ~ t r u c t u r e s .~ ~ Besides theuse of strong acids, nitriles may also be trimerised in the presence of methanolor weak bases at high pressures (7000-8500 atm.) ; besides the triazine, theisomeric 4-amino-2 : 6-dimethylpyrimidine is also obtained from acet~nitrile.~~The novel formation of aminotriazines has been observed in the reactionbetween a-cyano-carbonyl compounds and g ~ a n i d i n e . ~ ~a-li$oic (thioctic) acid. A new growth factor has been isolated anddescribed under several names : protogen A,% thioctic acid,g4 and ol-lipoicacid.95 Degradation 94-96 and synthesis 97, 98 of a-lipoic acid (from y-tetrahydro-2-furylbutyric acid) and of some of its isomersg9 have shownit to be “ 5 : 8-dithio-octanoic acid ” (3-3’-carboxypropyl-l : 2-dithian)(XXX).Another growth factor, protogen B, is possibly a closely relatedTriazine.~-~H.[CH2] ,*CO,HH,C NH ‘c6 (XXXI)sulphoxide.lO0 (95) The amide of cc-lipoic acid with thiamine pyrophosphateappears to be a coenzyme in the oxidative decarboxylation of a-keto-acids,lo1and it may also be concerned in photosynthesis.lo28 8 M. P. V. Boarland and J. F. W. McOmie, J., 1951, 1218.89 F. L. Rose, J . , 1952, 3448.T. L. Cairns, J. C. Sauer, and W. K. Wilkinson, J . Amer. Chem. Soc., 1952, 74, 3989.y1 C. Grundmann, G. Weisse, and S. Seide, Annalen, 1952, 577, 77.92 T. L. Cairns, A. W. Larchar, and B. C. McCusick, J . Amer. Chem. Soc., 1952, 74, 5633.93 P.B. Russell, G. H. Hitchings, B. H. Chase, and J . Walker, ibid., p. 5403.g4 J. A. Brockman, E. L. R. Stokstad, E. L. Patterson, J. V. Pierce, M. Macchi, and95 L. J. Reed, B. G. DeBusk, I. C. Gunsalus, and G. H. F. Schnakenberg, ibid.,96 L. J. Reed, Q. F. Soper, G. H. F. Schnakenberg, S. F. Kern, H. Boaz, and I. C.9 7 M. W. Bullock, J . A. Brockman, E. L. Patterson, J . V. Pierce, and E. L. R. Stok-98 C. S. Hornberger, R. F. Heitmiller, I. C. Gunsalus, G. H. F. Schnakenberg, and9g M. W. Bullock, J . A. Brockman, E. L. Patterson, J . V. Pierce, and E. L. R.loo E. L. Patterson, J. A. Brockman, F. P. Day, J. V. Pierce, M. E. Macchi, C. E.lol L. J. Reed and B. G. DeBusk, ibid., 1952, ‘94, 3457, 3964, 4727; J . Biol. Chern.,lo2 hl.Calvin and J. A. Barltrop, ibid., p. 6153.F. P. Day, ibid., p. 1868.1951, 73, 5920.Gunsalus, ibid., 1952, 74, 2383.stad, ibid., p. 1868.L. J. Reed, ibid., p. 2382.Stokstad, ibid., p. 3455.Hoffman, C. T. 0. Fong, E. L. R. Stokstad, and T. H. Jukes, ibid., 1951, 73, 5919.1952, 199, 881210 ORGANIC CHEMISTRY.Actithiazic acid. Two other groupslo3 have independently isolated a novelantibiotic, CsHl,O,NS, from Strefitomyces spp. Treatment with mercuricchloride lo* or alkali lo5 removed the nitrogen, the sulphur, and two carbonatoms to give the semialdehyde of pimelic acid; the substance was therefore(-)-2-5~-carboxypentylthiazolid-4-one (XXXI), and the (&)-form wassynthesised by condensation of this aldehyde with thioglycollamide w lo6and resolved with brucine.104Dihydroquinoline is obtainablefrom quinoline by reduction with lithium aluminium hydride, a reagent whichgenerally converts heterocyclic compounds into dihydro-derivatives whichare often difficult of access and ~ n s t a b l e .1 ~ ~ Several instances of lability ofhalogen substituents in the Bx-ring of quinoline have been reported : thebromine atoms in S-amino-5 : 7-dibromoquinoline are replaced by chlorineduring diazotisation and deamination in hydrochloric acid ; lo8 S-amino-5-bromo-6-methoxyquinoline is converted into the 7-bromo-isomer byboiling hydrobromic acid ; los 5-chloro-8-hydroxy-7-iodoquinoline is saidto undergo disproportionation in boiling dioxan to give 8-hydroxy-5 : 7-di-iodo- and 5 : 7-dichloro-S-hydroxy-quinoline.110 Reactive halogen atomsin the heterocyclic rings of 2-chloro- and 4 : 7-dichloro-quinoline, and of2-chlorobenzothiazole, undergo the Friedel-Crafts reaction with resorcinol togive the corresponding dihydroxyphenyl derivatives.lllThe base-catalysed condensation of quinolinium methiodide with sub-stances containing a reactive methylene group is now well-established, theproducts being derivatives (XXXII) of 1 : 4-dihydro-l-methyl-4-methylene-quinoline.1l2 y-Aminotropolone (XXXIII) undergoes the Gould- JacobsCondensed Ring Systems.--QuinoZine.(XXXII) (XXXIII) (XXXIV) (XXXV)modification c f the Conrad-Limpach reaction,l13 the Doebner-Miller re-action,l13 and +he Skraup reaction 114 to give the apEjropriate pyridino-tropolones (XXXIV).Three of five antibiotics produced by Pseudomonas aeruginosa have beenlo3 W.E. Grundy, A. L. Whitman, E. G. Rdzok, E. J. Rdzok, M. E. Hanes, andJ. C. Sylvester, Antibiotics and Chemotherapy, 1952, 2, 399; B. A. Sobin, J . Amev. Chem.SOC., 1952, 74, 2947.lo4 W. M. McLamore, W. D. Celmer, V. V. Bogert, F. C. Pennington, and I. A.Solomons, ibid., p. 2946.lo5 J. R. Schenck and A. F. De Rose, Arch. Biochem. Biophys., 1952, 40, 263.lo@ R. K. Clark and J . R. Schenck, ibid., p. 270.lo7 F. Bohlmann, Chem. Ber., 1952, 85, 390.lo8 R. C. Elderfield and E. F. Claflin, J . Anzer. Chem. SOC., 1952, 74,2953.log W. M. Lauer, C . J. Claus, R. W. Von Korff, and S. A. Sundet, zbzd., p. 2080.110 T. N6grAdi. Chem. Ber., 1952, 85, 104.ll1 G. Illuminati and H.Gilman, J . Amer. Chem. SOC., 1952, 74, 2896.11* N. J. Leonard, H. A. DeWalt, and G. W. Leubner, J . Amer. Chem. Soc., 1951,73, 3325; N. J. Leonard and R. L. Foster, ibid., 1952, 74, 2110, 3671.113 R. Slack and C. F. Attridge, Chem. and Ind., 1952, 471.114 J. W. Cook, J. D. Loudon, and D. K. V. Steel, ibid., p. 562WALKER : HETEROCYCLIC COMPOUNDS. 211shown by degradation 115 and synthesis to be 2-heptyl-, 2-nonyl-, and2-non-l'-enyl-quinolin-4-01. 1 : 2-Dihydro-2-keto-l-azapyrene (XXXV) hasbeen isolated from the pitch fraction, b. p. 470°, of coal tar.l17The infra-red absorption spec-tra of 4-hydroxy-, 2 : 4-dihydroxy-, and 4-mercapto-quinazolines supportthe tautomeric carbonyl and thiocarbonyl structures.118Relatively high pH values have been found to favour the formation ofmonoacyl derivatives of tetrahydroquin~xaline,~~~ which is convenientlyprepared from o-amino-N-2-hydroxyethylaniline.120Elegant methods for the removal of terminal protecting N-chloroacetylgroups or terminal amino-acid residues from peptides have been described.Reaction of the chloroacetyl derivatives with o-phenylenediamine affords1 : 2 : 3 : 4-tetrahydro-2-ketoquinoxaline (XXXVI) and the free 'peptidedirectly.121 The reaction is not conveniently applied by reduction ofdinitrophenyl peptides prepared by the standard method,122 but condens-ation of a peptide with methyl 4-fluoro-3-nitrobenzoate affords the appropriatesubstituted phenylpeptide (XXXVII), passing on reduction into the tetra-hydroket oquinoxaline (XXXVI I I), characteristic of the terminal amino-acidresidue, and the lower peptide (XXXIX) .123s 124 Terminal o-nitrophenoxy-Quinazoline ; quinoxaline ; benzoxazine.1 fjNH2 + CI-CH,*CO*NH-CHRCO. .. -+ [alNHz ~\NH,CH,CO-NH-CHR.CO . , ,\/"HZybNH'yHR + NH,CHR'.CO.. . ~\NH-CHRCO.KH.CHR~.CO . . .MeO,Ci)! NO, --+ Me0,C' \\/\NH/CO '1(XXXVII) ( XXXVI I I) (XXXIX)acetyl groups are similarly eliminated from peptides, reduction affording the1acta.m (XL; R = H) of o-aminophenoxyacetic acid and theOHHO Me(XL) (XLI) (XLII)123 The ready formation of the ring system (XL) wasfree pep-also seenin the formation of 2 : 3-dihydro-3-keto-4-methylbenz-1 : 4-oxazine (XL ;R = Me) when the normal conditions for the StolI6 oxindole synthesis wereapplied to N-cc-halogenoacetyl-N-methyl-o-anisidine, though rearrangement116 I.C. Wells, W. H. Elliott, S. A. Thayer, and E. A. Doisy, J . Biol. Chem., 1952,11' 0. Kruber and R. Oberkobusch, Chem. Ber., 1952, 85, 433.118 H. Culbertson, J. C. Decius, and B. E. Christensen, J . Amer. Chem. Sot., 1952,G. R. Ramage and G. Trappe, ibid., p. 4406.lZ1 R. W. Holley and A. D. Holley, J . Amer. Chem. SOL, 1952, 74, 3069.lZ2 F. Sanger, Biochem. J., 1945, 39, 507.lZ3 R. W. Holley and A. D. Holley, Zoc. cit., p. 1110.12'. Idem, ibid., p. 5445.190, 321.74, 4834.116 I. C. Wells, ibid., p. 331.ll9 J. S. Morley, J . , 1952, 4004212 ORGANIC CHEMISTRY.to the isomeric oxindoles (XLI) and, surprisingly, (XLII) took place at highertemperatures.125Miscellaneous sulphur-containing compounds.The properties of aninteresting compound, C,H,,S, from Middle East oil distillates recall adaman-tane in some respects and, as desu-lphurisation gave bicycZo[l : 3 : Slnonane,it is formulated as thia-adamantane (XLIII).126 Raney nickel desulphuris-CH2-CH- I I(XLIII) (XLIV) (XLV)ation of 1 : 2-dihydro-l-keto-2-thianaphthalenes (e.g. , XLIV) gave indanones(e.g., XLV).127Full details have now been given of the isolation 128 of biocytin fromyeast and its recognition by degradation 129 and synthesis 130 as c-N-biotinyl-L-lysine.Ring systems with a nitrogen atom common to two rings. The reductivecyclisation of nitro oo'-dicarboxylic esters, previously used for pyrroliz-idines,131 has been extended. The addition of methyl y-nitrobutyrate tomethyl sorbate gave the ester (XLVI), which passed on hydrogenation overcopper chromite into 2-methyl-7-azabicycZo[5 : 3 : Oldecane (XLVII) .132The method has been extended to the synthesis of tricyclic systems (XLIX)Me cs"I PI-J \/\\ ('y qH I/CHMe.CH( 7 3 2 - p\P(LI) (L)/CHz LIJ CH NO, \" C0,Me C0,Me(XLVI) (XLVII).""; "YCz2], \" -j [CH,], /"?y/cY lCH21,\ /g\ /HF: YHCCH2Iz \ /c\ /HC: YH H,C-[CH2], (XLIX) (XLVIII) H,C---[CH,],from the oximes of keto-dicarboxylic esters (XLVIII) under similar con-d i t i o n ~ .~ ~ ~ The hexahydrojulolidine obtained in this way (where x = y = z= 2) was identical with one of the stereoisomers obtained on catalytic re-duction of julolidine,l3* and gave evidence of resolution 133 over a column125 J.W. Cook, J. D. L'oudon, and P. McCloskey, J., 1952, 3904.lZ6 S. F. Birch, T. V. Cullum, R. A. Dean, and R. L. Denyer, Nature, 1952, 170, 629.lZ7 D. J. Dijksman and G. T. Newbold, J . , 1952, 13; J. J. Brown and G. T. Newbold,L. D. Wright, E. L. Cresson, H. R. Skeggs, T. R. Wood, R. L. Peck, D. E. Wolf,ibid., p. 4397.and K. Folkers, J . Amer. Chem. SOC., 1952, 74, 1996.129 R. L. Peck, D. E. Wolf, and K. Folkers, ibid., p. 1999.13* D. E. Wolf, J. Valiant, R. L. Peck, and K, Folkers, ibid., p. 2002.131 N. J. Leonard and D. L. Felley, ibid., 1950, 72, 2537.133 N. J. Leonard and W. J. Middleton, ibid.. p. 5114.134 M. Protiva and V. Prelog, Helv. Chim. Acta, 1949, 32, 621.N. J. Leonard, D. L.Felley, and E. D. Nicolaides, ibid., 1952, 74, 1700WALKER : HETEROCYCLIC COMPOUNDS. 213of D-lactose, indicating the cis : trans-structure (L), the cis : cis- andtrans : trans-stereoisomers being meso-forms.(-)-Octahydropyrrocoline (LI) has been correlated with (+)-coniine andD( +)-pipecolinic acid and therefore belongs to the ~ - s e r i e s . l ~ ~The electrolytic reduction of a-amino-ketones 136 has now been appliedto bicyclic representatives in a new synthesis of medium-sized nitrogen-containing rings, octahydro-l-ketopyridocoline (LII) giving 5-hydroxyaza-cyclodecane (LIII) .13’Et Me 0 4x2\Hi/R MeII Me/\/PA I I I I + t I\/ Y/ i Y 5 + P5Me\/N\/ \/&/(LII) (LIII) (LIV) (LV)The “ ethiodide ” of 1 : 5 : 8-trimethyl-2 : 3-benzopyrrocoline (LIV;R = Me) and the “ methiodide ” of l-ethyl-5 : 8-dimethyl-2 : 3-benzo-pyrrocoline (LIV; R = Et) are identical, indicating alkylation at the p-carbon atom of the indole ring system and the salt is therefore the pyridiniumcompound (LV) .l3 *Indole. The mechanism of the Fischer indole synthesis is still the subjectof discussion 139 though the general correctness of the Robinson mechanismis not disputed, and an analog9 is seen between the Fischer indole synthesisand the conversion of 1-phenylthiosemicarbazide (LVI) into Z-aminobenzo-thiazole (LVII) . 141 The conversion of 2 : 6-dichlorophenylhydrazanes(LVIII) into 7-chloroindoles (LIX) in presence of stannous chloride and 5 : 7-dichloroindoles (LX) with zinc chloride has been discussed.142 Polyphos-phoric acid is also usefully emp10yed.l~~(LVI) (LVII) (LXI)C f h &ZnC1,FH2RSnCh /\ci E*R’ -+ A1 lmIz/ +- 1 11, ,,N \cp$ \d M NC(y(LIX) (LVIII) (LX)Indole-3-aldehyde has been obtained by improved methods ; these arethe reaction of potassium indole with carbon monoxide at high temperaturesand pressures,l4 a modification of the N-methylformanilide process,145136 Ann. Reports, 1951, 48, 223.l37 N. J. Leonard, S. Swann, and J. Figueras, J . Amsv. Chew. SOC., 1952, 74, 4620.138 Sir R. Robinson and J. E. Saxton, J., 1952, 976.139 R. B. Carlin, J . Amer. CEtem. SOC., 1952, 74, 1077.14* G. M. Robinson and R. Robinson, J., 1924, 125, 827.141 K. Clusius and H. R. Weisser, Helv. Chim. Acta, 1952, 35, 400.14, R.B. Carlin, J. G. Wallace, and E. E. Fisher, J . Amev. Chew. Soc., 1952, 74, 990.143 H. M. Kissman, D. W. Farnsworth, and B. Witkop, ibid., p. 3948.144 F. T. Tyson and 3 . T. Shaw, ibid., p. 2273.14s A. C. Shabica, E. E. Howe, J. B. Ziegler, and M. Tishler, ibid., 1946, 68, 1156.N. J. Leonard and W. J. Middleton, loc. cit., p. 5776214 ORGANIC CHEMISTRY.and the reaction between hexamethylenetetramine and gramine (LXI) inaqueous acetic or propionic a~id.1~6 The red pigment (urorosein) obtainedby the action of acids on indole-3-aldehydes has been shown to be the methene(LXII), recalling pterorhodin formation amongst pterins, and the carbonatom which is lost is eliminated as formic acid.lP7 ad-Di-indolyl-methaneand -methene have also been described.148Although “ gramine methiodide ” has frequently been used, its recordedproperties have varied and no significant analytical data have hitherto beenrecorded.It has now been shown that “gramine methiodide,” as usuallyobtained, is really a mixture of 3 : 3‘-bis(indolylmethyl)dimethylammoniumiodide, [ (RCH,),N+Me,]I- (R = 3-indolyl) and tetramethylammoniumiodide ; 149 the authentic methiodide has, however, now been prepared.149(LXII)The oxidation of indoles has been further extensively studied and re-viewed with special reference to the biological oxidation of tryptophan.lMHydrogen peroxide in the presence of ammonium molybdate affords deriv-atives of anthranilic acid in the case of indoles unsubstituted in the 3-position,and the appropriate ketones from 3-substituted derivatives.151 Treatmentwith osmium tetroxide followed by hydrolysis of the resulting esters gave2 : 3-dihydro-2 : 3-dihydro~yindoles,l~~ and further study of the autoxidationof tetrahydrocarbazoles to give derivatives of cycZopentanes#iro-2-+indoxylis r e ~ 0 r t e d .l ~ ~ The reactions of the stable ozonide (LXIII) formed by2-phenylskatole have been interpreted in terms of an equilibrium betweenthis structure (LXIII) and the tautomeric hydroperoxide form (LXIV),while numerous reductive transformations have been carried out linking theozonide with the hvdroperoxide (LXV) derived from the same parent com-pound, and acid- a i dbeen examined.lUMeI I( o,To ‘’a Ph(LXIII)base-catalysed rearrangements of the ozonide have alsoA novel synthetic route to the eserine (physostigmine) ring system hasemerged ; lM S-methyl- or -hydroxy-indolenines with an alanine side-chainundergo an internal condensation at pH < 6 to give eseroline derivatives and146 H.R. Snyder, S. Swaminathan, and H. J. Sims, J . Amer. Chew. Soc., 1952,74,5110.14’ J. Harley-Mason and J. D. Bu’Lock, Biochem. J., 1952, 51, 430.14* H. Dobeneck and G. Maresch, 2. physiol. Chem., 1952, 289, 271.149 T. A. Geissman and A. Armen, J . Amer. Chem. So;., 1952, 74, 3916.150 A. Ek, H. Kissman, J. B. Patrick, and B. Witkop, Experiential 1952, 8, 36.151 C. Mentzer and Y . Berguer, Compt.rend., 1952,234,627 ; Bull. Soc. chim., 1952,218.152 D. W. Ockenden and K. Schofield, Nature, 1951, 168, 603.153 R.J. S. Beer, T. Broadhurst, A. Robertson, and L. McGrath, J., 1952, 4351;154 B. Witkop, J. B. Patrick, and H. M. Kissman, Chem. Ber., 1952, 85, 949; B.R. J. S. Beer, T. Broadhurst, and A. Robertson, ibid.,’p. 4946.Witkop and J. B. Patrick, J . Amer. Chem. Sac., 1952, 74, 3855, 3861WALKER : HETEROCYCLIC COMPOUNDS. 215it is impossible to synthesise P-methyl-$-tryptophan by the Fischer indolesynthesis from (LXVI), as (LXVII) results instead.(LXVI) (LXVI I )Evidence is now available to show that the molecule of the toxic cyclicpeptide phalloidin, obtained from Amanita phalloides, may consist not ofsix but of seven amino-acid residues,155 and that, as already suggested,156 theformation of oxindolylalanine (2-hydroxytryptophan) (LXVIII) on hydrolysisis an artefact.Treatment of phalloidin with Raney nickel and subsequenthydrolysis have afforded t r y p t ~ p h a n , l ~ ~ indicating the presence of the frag-ment (LXIX) in phalloidin, and, as the ratio, after hydrolysis, of oxindolyl-alanine to cysteine appears to be 2 : 1, it may be that the hydroxyl group ofthreonine or that of allohydroxyproline may participate in an analogousstructure, while the amino-acid residue next to the cysteine may be ala-nine.15' A simple new synthesis of oxindolylalanine has been described.15sYH ...CH,*CH-CO . . .I @\-~H*CH,*CH(NH,)CO,H II f > d\/\gCO ~/'~'\s-cH,.FH.co.. .(LXVIII) (LXIX) N H . . .Convenient syntheses of 5- and 7-hydroxyindole have been recorded 159and bufotenine (LXX), the pressor amine from the skin of the toad, hasbeen obtained from 2 : 5-dimethoxybenzyl cyanide by way of the nitrile(LXXI) and the derived phenylethylamine.160 The biological effects ofserotonin (5-hydroxytryptamine)161 are reversed by 2 : 3-dialkyl-&amino-indoles.162M~o//\-cH(cN).cH,.cH,.N~~, (ii) H B ~ . HOfh,CH2*CH,*NMe,(i) H,-Ni;\/\a' (LXX)I IIOMe -jzjT&$ v (LXXI)3-Indolylacetonitrile has been recognised as a naturally occurring plant-growth hormone163 and the related aldehyde has been synthesised andstudied for such activity. lG4156 T. Wieland and G. Schmidt, Annalen, 1952, 577, 215.156 J. W. Cornforth, C. E. Dalgliesh, and A. Neuberger, Biochem. J . , 1951, 48, 598.157 F. Sorm and B. Keil, Coll. Czech. Chem. Comm., 1951, 16, 366.158 H.Behringer and H. Weissauer, Chem. Ber., 1952, 85, 743; this vol., p. 163.15n R. I. T. Cromartie and J. Harley-Mason, J., 1952, 2525; J. Harley-Mason, Chem.lb0 J. Harley-Mason and A, H. Jackson, Chem. and Znd., 1952, 954.161 New synthesis: B. Asero, V. Colb, V. Erspamer, and A. Vercellone, Annalen,lBz D. W. Woolley and E. Shaw, J . Amev. Chem. Soc., 1952, 74, 2949; cf., however,lbS E. R. H. Jones, H. B. Henbest, G. F. Smith, and J . A. Bentley, Nutwe, 1952,and Ind., 1952, 173.1952, 576, 69.T. D. Spies, and R. E. Stone, J . Amer. Med. Assoc., 1952, 150, 1599.169, 485. 164 J. B. Brown, H. B. Henbest, and E. R. H. Jones, J., 1952, 3172216 ORGANIC CHEMISTRY.Pteridirte. The pteridines have recently been reviewed 165 and progresshas been made in the study of some of the simpler representatives.All fourmonohydroxypteridines are now known and 6-hydroxypteridine (LXXII)shows on titration a hysteresis loop ascribed to slow tautomerism.166 6- and7-Hydroxypteridine (LXXIII) were obtained simultaneously by con-densation of ethyl glyoxylate hemiacetal with 4 : 5-diaminopyrirnidine, thelatter predominating in condensations carried out a t low pH values.166Similarly, xanthopterin (LXXIV) is obtained from 2 : 4 : 5-triamino-6-hydroxypyrimidine and diacetoxyacetic acid in concentrated sulphuric acidat 90” ; 167 xanthopterin is also conveniently obtained from leucopterin(2-amino-4 : 6 : 7-trihydroxypteridine) via dihydroxanthopterin.1“8 ‘ ‘ p-Di-hydroxanthopterin ’ ’ has now been identified as 2 : 6-diamino-5‘-hydroxy-1’ : 4‘-oxazino(2’ : 3’-4 : 5)pyrimidine (LXXV),169 and attempts to preparepteridines by reduction and cyclisation of 4 : 2’-chloroethylamino-5-nitro-pyrimidines gave instead the tetrahydroglyoxalinopyrimidines (LXXVI) .170(LXXII) (LXXIII) (LXXIV) .(LXXV) (LXXVI)The action of alkylamines on 4-amino-2-mercapto- and 4-hydroxy-2-mercapto-pteridines gives either 2-alkylamino-4-amino- or 2 : 4-bisalkyl-amino-pteridines,171 and evidence has been obtained supporting the viewthat these replacements occur with ring cleavage to a thioureidopyrazineintermediate (LXXVII) and subsequent ring-closure ; a similar mechan-ism is advanced for the formation of 2 : 4-bisalkylamino- from 2 : 4-diamino-pteridines and alkylamines.178Pterorhodin formation from pterins, linking two pteridine ring-systemsthrough the 7-position by a methine bridge, is possible if there is present amolecule capable of providing the methine bridge under oxidative con-ditions,l7* and a novel formula (LXXVIII) 175 for erythropterin is believedto account for the notable stability of this ene-diol compound.lS6 A. Albert, Quart. Reviews, 1952, 6, 197.le6 A. Albert, D. J . Brown, and G. Cheesman, J., 1952, 1620.167 F. Korte, Chcm. Ber., 1952, 85, 1017; F. Korte and E. G. Fuchs, ibid., 1953, 86,lBS A. Albert and H. C. S. Wood, J. Appl. Chem., 1952, 2, 591.lsg G. B. Elion and G. H. Hitchings, 3. Amer. Chem. SOC., 1952, 74, 3877.170 G. R. Ramage and G. Trappe, J., 1952, 4410.171 E. C.Taylor and C. K. Cain, J. Amer. Chem. SOC., 1951, 73,4384; 1952,74, 1644.174 R. Tschesche and F. Korte, Chew. Ber., 1952, 85, 139.175 Due to H. G. Khorana; cf. R. Tschesche and F. Korte, Zoc. cit.114.E. C. Taylor, ibid., p. 1651. Idem, ibid., p. 1648WALKER : HETEROCYCLIC COMPOUNDS. 217Further descriptions of the chemistry 176 and the synthesis 177 of leuco-vorin (LXXIX) have been published. In the preparation of leucovorinfrom pteroyl-L-glutamic acid by formylation, reduction and rearrangement,a new asymmetric centre is created at C(61 (marked *), and partial separationof the resulting diastereoisomerides has been eff e ~ t e d . ~ ~ ~ The 7-isomer ofpteroylglutamic acid has also been synthesised.HNucleotides and related compoumis. Physical and physico-chemicalaspects of pyrimidines, purines, and nucleic acids have been reviewed,together with such other studies as bear on structure.lm Spectrophoto-metric patterns have been presented enabling distinction to be made betweenribofuranosides and their deoxyribofuranoside analogues ; similarly, differ-ences are reported between pyrimidine glycopyranosides and glycofurano-sides.181 Riboflavin-5’ phosphate is simply obtained by warming ribo-flavin with metaphosphoric acid,lg2 and diphosphopyridine nucleotide(cozymase) has been obtained in the form of a crystalline quinine salt.ls3Substantial progress has been made during the year in the synthesis ofnycleotides.Condensation of 5’-trityl adenosine with dibenzyl chloro-phosphonate (phosphorochloridate) and removal of protecting groups gavetwo adenylic acids, identical with adenylic acids a and b from ribonucleicacids ; these are formulated as adenosine-2’ phosphate and -3’ phosphate(not necessarily respectively), and ready phosphoryl migration under acidconditions enables interconversion to take place by way of the cyclic 2’ : 3’-phosphate.ls4 Cyclic 2’ : 3’-phosphates of adenosine, cytidine, and uridinehave been synthesised.The cytidine and uridine derivatives have beenidentified as products of incomplete ribonuclease digestion of ribonucleicacids lS6 but they are converted respectively into cytidylic acid b anduridylic acid b by further action of the enzyme, and cytidylic acid b isdeaminated by alkali to uridylic acid b, so that in these two substancesthe phosphoryl group occupies the same position.lS6 It has been suggestedon physico-chemical grounds that cytidylic acid b is cytidine-3‘ phosphate.lS7176 D. B. Cosulich, B. Roth, J. M. Smith, M. E. Hultquist, and R. P. Parker, J .Amev. Chem. SOC., 1952, 74, 3252.177 B. Roth, M. E. Hultquist, M. J. Fahrenbach, D. B, Cosulich, H. P. Broquist,J. A. Brockman, J. M. Smith, R. P. Parker, E. L. R. Stokstad, and T. H. Jukes, ibid.,p. 3247.178 D. B. Cosulich, J . M. Smith, and H. P. Broquist, ibid., p. 4215.170 C . W. Waller, M. J. Fahrenbach, J. H. Boothe, R. B. Angier, B. L. Hutchings,J. H. Mowat, 3 . F. Poletto, and J. Semb, ibid., p. 5405; cf. J. H. Boothe, J. H. Mowat,C. W. Waller, R. B. Angier, J. Semb, and A.L. Gazzola, ibid., p. 5407.18* D. 0. Jordan, Ann. Rev. Biochem., 1952, 21, 209.lal J. J. Fox and D. Shugar, Biochem. Biophys. A d a , 1952, 9, 369.lS3 K. Wallenfels and W. Christian, Angew. Chem., 1952, 64, 419.185 D. M. Brown, D. I. Magrath, and A. R. Todd, ibid., p. 2708.lS6 D. M. Brown, C. A. Dekker, and A. R. Todd, ibid., p. 2715.187 L. F. Cavalieri, J . Amer. Chem. Soc., 1952, 74, 5804.M. Viscontini, C. Ebnother, and P. Karrer, Helv. Chim. Acta, 1952, 35, 457.D. M. Brown and A. R. Todd, J., 1952, 44218 ORGANIC CHEMISTRY.Uridine-5' pyrophosphate has been synthesised 188, 189 and found to beidentical with " uridine diphosphate " from the naturally occurring coenzyme" uridine-diphosphate-glucose, " lgo and uridine-5' pyrophosphate linkedto an amino-sugar through the reducing group has been isolated from peni-cillin-treated Staphylococcus aureus cells.lgl Adenosine-5' uridine-5' phos-phate has been synthesised from a suitably protected silver adenosine4phosphate and 2' : 3'4sopropylidene 5'-deoxy-5'-iodouridine lg2 but this typeof method has limitations. A new method for the preparation of mixedsecondary phosphites (LXXX) lS3 and the fact that these could be chlorinatedwith N-chloro-amides, rather than with more vigorous reagents, to the chloro-phosphonates (LXXXI) 189 paved the way for the synthesis of unsymmetricaldiribonucleoside pyrophosphates, culminating in an outstanding achieve-ment : 194 the synthesis of flavin-adenine-dinucleotide ( PI-riboflavin-5'P,-adenosine-5' dihydrogen pyrophosphate, FAD) (LXXXII) , identicalwith the naturally occurring coenzyme, by condensation of 2' : 3'-isopro-pylidene adenosine-5' benzyl chlorophosphonate with the monosilver saltof riboflavin-5' phosphate and subsequent removal of protecting groups.RO'\p//OCH,Ph/ \ c l (LXXXI)r----o------ IyH,*[CH( OH)],*CH,*O.PO( OH)*O*PO( OH).O*CH,CH*[CH( OH)] 2*qHVitamin B,,.In this field the situation has been complicated by theappearance of Pseudovitamin B,,,1955 lg6 which contains adenine instead of5 : 6-dimethylbenziminazole in the nucleotide portion of the r n o l e ~ u l e . ~ ~ ~Fresh spectroscopic evidence has been produced, however, to show that thebenziminazole chromophore is present in intact vitamin B,, itself,l97 and thespectroscopic examination of authentic synthetic benziminazolo-cobaltousand -cobaltic co-ordination compounds has proved the validity of criteriapreviously employed in establishing the presence of the related complex inthe vitamin.Ig8 Details have been published of the degradation of vitaminB,, to 5 : 6-dimethyl-l-a-~-ribofuranosylbenziminazole (cr-ribazole) lg9 andof the syntheses of the four l-D-ribosides of 5 : 6-dimethylbenziminaz0le.~~~N.Anand, V. M. Clark, R. H. Hall, and A. R. Todd, J., 1952, 3665.189 G. W. Kenner, A. R. Todd, and F. J. Weymouth, ibid., p. 3675.lg0 A. C. Paladini and L. F. Leloir, Biochem. J., 1952, 51, 426.191 J. T. Park, J . Biol. Chem., 1952, 194, 885.lg2 D. T. Elmore and A. R. Todd, J., 1952, 3681.lg3 N. S. Corby, G. W.Kenner, and A. R. Todd, ibid., p. 3669.19* S. M. H. Christie, G. W. Kenner, and A. R. Todd, Nature, 1952, 170, 924.lS5 H. W. Dion, D. G. Calkins, and J. J. Pfiffner, J . Amer. Chem. Soc., 1952, 74,1108.lg6 U. J. Lewis, D. V. Tappan, and C. A. Elvehjem, J . BioE. Chem., 1952, 194, 539;lS7 G. H. Beaven and E. R. Holiday, J . Pharm. Pharmacol., 1952, 4, 344.198 M. T. Davies, P. Mamalis, V. Petrow, B. Sturgeon, G. H. Beaven, E. R. Holiday,lS9 N. G. Brink and K. Folkers, J . Amer. Chem. Soc., 1952, 74, 2856.m0 F. W. Holly, C. H. Shunk, E. W. Peel, J. J. Cahill, J. B. Lavigne, and K. Folkers,1952, 199, 517.and E. A. Johnson, ibid., p. 448.ibid., p. 4521BAILEY : ALKALOIDS. 219A crystalline 2’- or 3’-phosphate of a-ribazole has now been obtained both bydegradation of vitamin B,, and by synthesis.%lMacrocyclic Compounds.-A report on this field must be deferred becauseof limitations of space, but it may be noted that the subject of chlorophyllhas been reviewed exhaustively for the period 1938-1951.202J.W.9. ALKALOIDS.has appeared.This covers the chemistry of the morphine, colchicine, acridine, indole,erythrina, strychnos, and amaryllidaceae groups of alkaloids up to 1951.The biogenesis of alkaloids has been reviewed 3 and has been investigated bymeans of radioactive ~ a r b o n . ~Simple Bases.-Cornforth and Henry have isolated ( -)-stachydrine fromthe fruit of Capparis tomentosa Lam. and from the fruit of Courbonia virgataA. Brongn. ; both cis- and trans-3-hydroxystachydrine (I) have been i~olated.~Both compounds were dehydrated to the same optically inactive anhydro-compound which was reduced to (-J-)-stachydrine and oxidised to P-dimethyl-aminopropionic acid.Since the last Report,l volume 2 of ‘‘ The Alkaloids ’’CH,-CH-CH,I I I SJMey-o\COCH,--CH-CH-C/II(1) (11) CMe,Simple syntheses of mezcaline and trichocereine (NN-dimethyl-mezcaline) 67 7 and of arecoline 8 have been described.Mezcaline containing14C has been pre~ared.~Tropane Group.-The stereochemistry of the tropane alkaloids has beendiscussed.10 Lithium aluminium hydride reduction of tropinone givesentirely $-tropine.ll The Robinson synthesis has been used for the pre-paration of 6-hydroxytropinone 12, l3 and 6 : 7-dihydroxytropinone,13 theintermediate aldehydes being obtained from furan.Pinder has isolated201 E. A. Kaczka, D. Heyl, W. H. Jones, and K. Folkers, J . Amer. Chem. SOC., 1952,2oa A. Stoll and E. Wiedemann, Fortschr. chem. Forsch., 1952, 2, 538.74, 5549.Ann. Reports, 1951, 48, 228.Ed., R. H. F. Manske and H. L. Holmes; Academic Press, New York, 1952.(Sir) R. Robinson, Bull. World Hlth. Org., 1952, 6, 211.K. Bowden and L. Marion, Canad. J . Chem., 1951, 29, 1037, 1043; E. Leete,S. Kirkwood, and L. Marion, ibid., 1952, 30, 749; S. A. Brown and R. U Byerrum,J . A6 J. W. Cornforth and A. J. Henry, J., 1952, 597, 601.K. Banholzer, T. W. Campbell, and H. Schmid, Helv. Chim. Acta, 1952, 35, 1577.L. Reti and J. A. Castrill6n, J . Amer. Chem. SOC., 1951, 73, 1767.A.Dobrowsky, Monatsh., 1952, 83, 443.W. Block and K. Block, C h e w Ber., 1952, 85, 1009.mey. Chem. SOC., 1952, 74, 1523.lo G. Fodor, Nature, 1952, 170, 278; G. Fodor, 0. KOV~CS, and L. Mkszdros, Research,1952, 5, 534; B. L. Zenitz, C. M. Martini, M. Priznar, and F. C. Nachod, J . Amer. Chem.Soc., 1952, 74, 5564; A. Nickon and L. F. Fieser, ibid., p. 5566.l1 R. Mirza, Nature, 1952, 170, 630.la A. Stoll, B. Becker, and E. Jucker, Helv. Ckim. Ada, 1952, 35, 1263.l3 J. C. Sheehan and B. M. Bloom, J . Amer. Chem. SOC., 1952, 74, 3826220 ORGANIC CHEMISTRY.an alkaloid, probably dioscorine, from Dioscorea hzispida Dennst. ; l4 thealkaloid does not appear to have the structure (11) suggested by Gorter l5since it gave no acetone on ozonolysis. It is an ap-unsaturated lactone (atleast a six-membered ring) containing a C-methyl group.Lupinane Group.-Rhombifoline has been shown to possess structure(111 ; R = CH2*CH2*CH:CH2).When heated with hydrogen iodide it gavecytisine (I11 ; R = H) ; and the latter re-formed rhombifoline on alkylationwith but-3-enyl bromide.16 Deoxytetrahydrocytisine (V) has been syn-thesised from 1 : 3-dicarbethoxy-4-quinolizone (IV) and resolved via thetartrate.17C0,EtCH, I’\/ ‘CH, NR I /\’\ H,-Pt *CH-~,yjl,)-COzEt * II 1\(N\ \ II, CH,-CH-CH, II(111) 0 0 (IV)CH,*OH CH- CH,b&\ \ I CH,-CH-CH,(V)isoQuinoline Group.-Manske has deduced formula (VI) for corpaverine ;oxidation gave p-anisic acid, and ethylation followed by Hofmann degradationand oxidation led to 3-ethoxy-4 : 5-dimethoxyphthalic acid.18H,-Pt(VIIIEmetine (VII ; R = Et).19 Openshaw and Wood have shown 2o thatrubremetinium chloride (VIII) is reduced to two dihydrorubremetines (IX) ,both substances giving identical colour reactions and differing in stereo-chemistry at C*.These authors’ observations on the oxidation productsof emetine differ from those reported by HazIett and M~Ewen.~1 A prelimi-nary account of the synthesis of (&)-“ c-noremetine ” (VII; R = H) hasl4 A. R. Pinder, J., 1952, 2286.l6 W. F. Cockburn and L. Marion, Cmad. J . Chem., 1952, 30, 92.l7 F. Galinovsky, 0. Vogl, and W. Moroz, Monatsh., 1952, 83, 242.lS Cf. Ann. Beports, 1949, 46, 202.2o H. T. Openshaw and H, C. S. Wood, J., 1952, 391.21 R.N. Hazlett and W. E. McEwen, J . Amer. Chem. SOL, 1951, 73, 2578.16 K. Garter;Rec. Trav. chim., 1911, 30, 161.R. H. F. Manske, J . Auzer. Chem. SOC., 1952, 14, 2864BAILEY : ALKALOIDS. 221appeared.22 Oxidation of laudanosoline (X) yields dehydrolaudanosoline(XI ; R = H) which is methylated to (XI ; R = Me).23* A new alkaloid,C,H2404NI , related to dehydrolaudanosoline, has been isolated 25 from thebark of Cryptocarya bowiei (Hook), Druce, of Northern Queensland. Thesubstance contains three methoxyl groups and yields a monomethyl ether.The latter, on treatment with alkali, gave an optically active methine (A) ;Hofmann degradation of A led to an optically inactive methine (B) identicalwith the compound from (XI; R = Me).23924 Pyrolysis of the O-methylalkaloid chloride gave the known 23 indole (XII).Bark from SouthernQueensland contained an alkaloid, C,gH,,O,NI, probably of this type, butcontaining one methylenedioxy-group and one methoxyl group.been announced.26 (&)-p-was resolved, the (+)-formMorfihine. The synthesis of morphine hasA6-Dihydrodeoxycodehe methyl ether (XIII) 27being identical with the substance obtained from natural sources: ' Hydr-ation of (XIII) with dilute sulphuric acid gave p-dihydrothebainol methylether (XIV; R Me) ; alkaline demethylation then yielded 8-dihydro-thebainol (XIV ; R = H) which was oxidized to p-dihydrothebainone (XV),Bromination (2 mols.) of this, followed by treatment with 2 : 4-dinitro-phenylhydrazine, gave a 2 : 4-dinitrophenylhydrazone (XVI) , identicalwith the product obtained from thebainone (XVII) or p-thebainone (XVII ;C(,,,-epimer) by treatment with 2 : 4-dinitrophenylhydrazine followed bybromination.This reaction involves epimerisation at C(14) of the p-series(trans --+ cis) , leading to the natural configuration at C(14) (B-c cis). Cleavageof (XVI) with acetone produced l-bromothebainone which was then reducedto dihydrothebainone (XVIII). Bromination (3 mols.) of (XVIII) , followedby treatment with 2 : 4-dinitrophenylhydrazine, gave a small yield ofl-bromocodeinone 2 : 4-dinitrophenylhydrazone (XIX) which was cleavedby acetone to l-bromocodeinone; the latter was reduced to codeine (XX;R = Me) which had previously been demethylated to morphine (XX;R = H) .28 The biogenesis 29 and the absolute stereochemical configuration 30of morphine have been discussed.Evidence has been obtained that theethanamine chain and the C(,]-hydroxyl group are trans in codeine.31 Anaccount of the reactions of phenyldihydrothebaine has been published.3222 M. Pailer and H. Strohmayer, Monatsk., 1951, 82, 1125; 1952, 83, 1198; cf. M.Pailer, K. Schneglberger, and W. Reifschneider, ibid., 1952, 83, 513.23 R. Robinson and S. Sugasawa, J., 1932, 789.24 C. Schopf and K. Thierfelder, Annalen, 1932, 497, 22.25 J. Ewing, G. K. Hughes! E. Ritchie, and W. C. Taylor, Nature, 1952, 169, 618.26 M. Gates and G. Tschudi, J . Amer. Chern. Soc., 1952, 74, 1109.2 7 Idem, ibid., 1950, 72, 4839.28 H. Rapoport, C. H. Lovell, and B. M. Tolbert, ibid., 1951, 73, 5900.29 C.Schopf, Naturwiss., 1952, 39, 241. 30 I. R. C . Bick, Nature, 1952, 160, 755.31 H. Rapoport and G. B. Payne, J . Amer. Chern. SOL, 1952, 74, 2630.32 K. W. Bentley and (Sir)- R. Robinson, J., 1952, 947; cf,., ref. 2 and L. F: FieserReiahold Publ. Corp., and M. Fieser, I' Natural Products Related to Phenanthrene,New York, 1949, p. 19222 ORGANIC CHEMISTRY.Reduction of thebaine by sodium in liquid ammonia gives dihydrothebaine-4(XXI) (phenolic dihydrothebaine) ; 33 this structure is preferred to (XXII) asa result of a study of ultra-violet and infra-red spectra 34 and because it does/\Meoll IHo\//\,Meal AII/ivy I l J 4 I----CH*(XXI) Meo\/I(XXII)H O f YMeo\/ (XXIV)not add dienophile~.~~ Formula (XXII) is that of the p-dihydrothebaineprepared by Karrer and S~hmid.~5 The isomerism of the thebainones has83 K.W. Bentley, (Sir) R. Robinson, and A. E. Wain, J., 1952, 958.34 G. Stiork, J . Amer. Chem. SOC., 1952, 74, 768.35 P. Karrer and H. Schmid, Helv. Chim. Acta, 1950, 33, 863BAILEY : ALKALOIDS. 223been studied, their nomenclature revised, and structures allotted on thebasis of their ultra-violet and infra-red spectra. A fourth thebainone,thebainone-B (XXIII), has been obtained by hydrolysis of dihydro-thebainone-4 (XXI) .36Aporphine Group.-The structure suggested for artabotrine 37 is in-correct, the substance is identical with isocorydine (XXIV) .38Indole Group.-Alstonine (ref. 1, p. 233) has now been isolated fromvarious species of Rauwolja; 39 structure (XXV) is preferred to (XXVI) onthe basis of the infra-red spectrum.Serpentine (ref. 1, p. 233) has beenfound to contain a C-methyl group and is now formulated as (XXVII), adihydro-derivative of alstonine (XXV) .40 Two new quaternary salts,melinonine A, C,,H,,O,N,Cl, and B, C,H,g.ON,Cl, have been isolated fromStrychnos melinonzana Baillon.41 Melinonine A lost methyl chloride onbeing heated, giving a tertiary base, normelinonine A (identical with tetra-hydroalstonine, XXVIII) ; the latter re-formed the alkaloid on methylation.The ultra-violet spectrum of melinonine B suggests it is an ctp-substitutedindole. It is suggested that S-yohimbine and mayumbine are stereoisomersof tetrahydroalstonine (XXVIII) .42 Hydrogenation of sempervirine (XXIX)/ L A /\AI A II B I1 c I+ I II II I f\/‘?+@\ \/‘?’\,P\MeO,C’(XXV) (XXVI) (XXVII)IJ,MeI D 1\/OMe0,C v<hMe \/O M~o,c\/O MMe(XXVIII) (XXIX) (XXX)gave (&)-alloyohimbane (XXX) which was resolved via the tartrate 43 andfound to be identical with the product obtained by Wolff-Kishner reductionof aUoyohimbone (corynanthidone) .44 Corynantheine (XXXI) appearsalways to be admixed with dihydrocorynantheine (XXXII) ,45 and thisexplains the results obtained by various workers : 46 (XXXI) gives form-aldehyde on ozonolysis, and (XXXII) gives acetic acid on Kuhn-Rothoxidation.Lithium aluminium hydride reduction of dihydrocorynantheine36 K. W. Bentley and A. E. Wain, J., 1952, 967.37 G. Barger and L. J . Sargent, J., 1939, 991.3B E.Schlittler and H. U. Huber, Helv. Chim. Acta, 1952, 35, 111.39 E. Schlittler, H. Schwarz, and F. Bader, ibid., p. 271.40 F. Bader and H. Schwarz, ibid., p. 1594.41 E. Schlittler and J. Hohl, ibid., p. 29.42 R. Goutarel and A. Le Hir, Bull. SOC. chim., 1951, 18, 909; M. M. Janot, R.A. Le Hir, R. Goutarel, and M. M. Janot, ibid., 1952, 235, 63; Bull. SOC. chim.,Goutarel, and J. Massonneau, Compt. rend., 1952, 234, 850.1952, 19. 1091. 44 A. Le Hir, Compt. rend., 1952, 234, 2613.45 P. Karrer, R. Schwyzer, and A. Flam, Helv. Chim. Acta, 1952, 35, 851.46 Ref. 1, p. 232; cf. M. M. Janot and R. Goutarel, Compt. rend., 1952, 234, 1562224 ORGANIC CHEMISTRY.followed by catalytic hydrogenation gave tetrahydrodemethoxycoryn-antheine alcohol (XXXIII).Dehydrogenation of the last with seleniumgave alstyrine (XXXIV; R = H) and a small quantity of methylalstyrine(XXXIV ; R = Me) ; however, palladium dehydrogenation afforded flavo-corynanthyrine (XXXV) .457 47 Similarly, yohimbyl alcohol (XXXVI)with selenium gives a little yobyrine (XXXVII; R = H) and mainlymethylyobyrine (XXXVII; R = Me), but use of palladium leads only toyobyrine (XXXVII ; R = H).48MeO,C.C:CH.OMe MeO,C*kCH*OMe HO*CH,kHMe(XXXI) (XXXII) (XXXIII)(XXXIV) (XXXV) (XXXVI) (XXXVII)5-Methoxy-1 : 9-dimethyl-p-carboline (XXXVIII) has been synthesised 49and shown to be identical with a degradation product of mitragynine.50Three new alkaloids, (A) canthin-6-one, C,,H,ON, (XXXIX; R = H),(B) 5-methoxycanthin-6-one, C,,H,,0,N2 (XXXIX ; R = OMe), and(C) C1,Hl0OSN2 have been isolated from Pentaceras australis Hook.f.The bases A and B were oxidised by permanganate to p-carboline-l-carb-oxylic acid, and were hydrolysed to acids which readily re-formed the alkaloids ;the acid from A was isomerised by alkali to an acid which did not re-formthe lactam ring; both isomers gave the same dihydro-derivative on reduc-tion. The position of the methoxyl group in B was established by the reactionof the demethylated substance (XXXIX; R = OH) with o-phenylene-diamine.52 This ring system has not been previously observed in Nature.OMe / L AI I1 ll 1 L/\ ‘\/“/\dN\/‘i&\&N \g I I1 II 1 0:I I(XXXVIII) (XXXIX)Gelsemine. Application of the Hofmann degradation to gelsemine (ref.1,p. 234) is complicated by the fact that >NMe(b) alkylates CO*NH(a),+4 7 R. Schwyzer, Helv. Chim. A d a , 1952, 35, 867.4 * P. Karrer, R. Schwyzer, A. Flam, and R. Saemann, ibid., p. 865.49 J. W. Cook, J. D. Loudon, and P. McCloskey, J., 1952, 3904.50 H. R. Ing and C. G. Raison, J., 1939, 936.51 H. F. Haynes, E. R. Nelson, and J. R. Price, Austral. J. Sci. Res., 1952, 5 , A , 387.52 E. R. Nelson and J. R. Price, ibid., p. 563BAILEY : ALKALOIDS. 225giving CO-NMe(a) ; for example, the substance described as N-demethyl-gelsemine 53 is actually N(a)-methylgelsemine. It is reduced by lithiumaluminium hydride to deoxydihydro-N(a)-methylgelsemine. The latter isalso obtained from deoxydihydrogelsemine by formylation, followed bylithium aluminium hydride reduction.54 Heating gelsemine with tetra-methylammonium hydroxide yields N(a)-methylgelsemine.55None of the structures suggested for p-erythroidine(ref. 1, p. 230) has been accepted by Boekelheide and his colleagues.56 Theseworkers find that a@-p-erythroidine, C,,H,,O,N, is readily dehydrogenatedto dehydroapo-P-erythroidine, C,,H,,O,N ; the latter is a lactone, giving anindole colour reaction (Ehrlich) . Alkaline permanganate oxidises dehydro-ape-p-erythroidine to 2-aminoisophthalic acid, isatin-7-carboxylic acid (XL) ,and 4-hydroxyquinoline-3 : 8-dicarboxylic acid (XLI), the last not giving2-aminoisophthalic acid on oxidation. Similar oxidation of a@- p-erythroidineafforded (XL) and (XLI). These observations indicate that a@-p-erythro-p-Erythroidine.(XL) (XLI) (XLII)idine contains a structure of type (XLII).Contrary to earlier claims, apo-p-erythroidine does not appear to contain a :CH,.group, and oxidativedegradation of p-erythroidine derivatives gave phthalic acid and not 3-meth-oxyphthalic acid. Hofmann degradation of apo- p-erythroidine 57 shows thepresence of (*CH,*CH,*) ,N-. Dc-N-met hyldihydro- p-eryt hroidinol (XLI I I ;R = OH) on two-stage Hofmann degradation gave a substance C15H1802,and reduction of this, followed by permanganate oxidation, gave o-ethyl-benzoic acid. Hydrogenolysis of (XLIII; R = OH) yielded (XLIII;R = H); Hofmann degradation of the latter with reduction at each stageshowed the presence of (*CH,*CH,:),N*, and ozonolysis of the end productgave ethyl methyl ketone.A consideration of these results lead to structure(XLIV) for p-erythroidine, and (XLV) for ape-p-erythroidine.f% ,/\CH,.CH,.NMe \\/\N( \/”<MeOZ c, C,H2 I ,CH,H+’ ‘Y-CH, H 2 y Q ~ . ~ ~HO-H,C*H,C CH2R OCwCH, OC,(yCH,I \ , ~ ~ : F - C H , C H , II I(XLIII) (XLIV) (XLV)Strychnos Alkaloids.-The long suspected relation between a-colubrine(XLXVI ; R = H, R’ = OMe), p-colubrine (XLVI ; R = OMe, R’ = H), andstrychnine (XLVI; R = R’ = H) has been e~tablished.~~ Lithium alu-m R. Goutarel, M. M. Janot, V. Prelog, and R. P. A. Sneeden, Helv. Chirn. Acfa, 1951,64 T. Habgood, L. Marion, and H. Schwarz, ibid., 1952, 35, 638.66 V. Prelog, J. B. Patrick, and B. Witkop, ibid., p. 640.56 M. F. Grundon and V.Boekelheide, J . Awzer. Chem. SOC., 1952, 74, 2637.67 V. Boekelheide, M. F. Grundon, and J. Weinstock, ibid., p. 1866.34, 1962.S. P. Findlay, ibid., 1951, 13, 3008.REP.-VOL. XLIX. 226 ORGANIC CHEMISTRY.minium hydride reduction of the colubrines gave the corresponding colu-bridines which were then oxidised to 2 : 3-diketonucidine, the oxidation pro-duct of stry~hnidine.~~ A new alkaloid, novacine (N-methyl-sec.-pseudo-brucine), has been isolated from Strychnos utux-vomica seeds.60 Boit hascontinued his degradative studies on pseadobrucine. 61 Phenols have beenfound to form solid complexes with certain strychnine derivatives.62 TheCH,-OH(XLVI) (XLVII)Wieland-Gumlich aldehyde (XLVII) has been condensed with malonic acid,forming isostrychnic acid (XLVIII ; inversion at C* relative to strychnine).63isoStrychnic acid had previously been converted into isostrychnine-1(XLIX),64 and hence into strychnine (XLVI; R = R' = H).G5 Theoxidation of strychnine with osmium tetroxide,66 and that of strychnine andbrucine N-oxides with permanganate has been described.67I A I I B I c \fir?dG I A I I B I C \/y$,qAH 7" o:"' '6.CH,*OHH0,C O-CH,(XLVIII) (XLIX)Quinazolone Group.68-Koepfli, Brockman, and Moff at 69 considerfebrifugine and isofebrifugine, Cl6HIgO3N,, to be isomers of (L), the semi-ketal of (LII), differing in stereochemistry at C*. This explains the ready(L) (LI)interconversion of the two alkaloids. Both are oxidised by periodate to thesame optically inactive substance, C16H1703N3, which yields the pyrazole(LI) on treatment with semicarbazide.However, the alkaloids are reducedto different dihydro-derivatives, and febrifugine forms carbonyl derivatives6D H. Leuchs and H. S. Overberg, Ber., 1931, 64, 1009.80 W. F. Martin, H. R. Bentley, J. A. Henry, and F. S. Spring, J . , 1952, 3603.61 H. G. Boit, Chem. Ber., 1952, 85, 19, 106.62 J. T. Edward and (Sir) R. Robinson, J., 1952, 1080.63 (Sir) R. Robinson and J. E. Saxton, J., 1952, 982.64 H. G. Boit, Ber., 1951, 84, 16.6 5 V. Prelog, J. Battegay, and W. I. Taylor, Helv. Chim. Acta, 1948, 31, 2244.6 7 K. Hirayama, ibid., p. 45.1 3 ~ J. B. Koepfli, J. A. Brockman, and J. Moffat, J . Amev. Chem. SOC., 1950, 73, 3323.A. Kogure and M. Kotake, J . Inst. Polytech.Osaka City Univ., 1951, sec. C2, 39Cf. Ann. Reports, 1949, 46. 210.(Chem. A h . , 1952, 46, 6131)BAILEY : ALKALOIDS. 227whilst isofebrifugine does Febrifugine has also been isolated fromhydrangea leaves71 Pennanganate oxidation gave 3-carboxymethyl-4-quinazolone (LII; R = CO,H), zinc dust distillation afforded the ketone(LII; R = Ac), and the alkaloid contained a carbonyl group, a hydroxylgroup, and a sec.-amino-group, indicating a structure of type (LIII).72The racemic form of the alkaloid (LV) has been synthesised by treating ethyl2-3'-bromoacetonyl-3-methoxypiperidine- 1 -carboxylate (LIV) with quin-azol-4-one and then removing the protecting groups. 73QC,H,*OH n 0II/V\N.CH,COCH,.CHI II I \,2H2\/"/ (LIII) H( L W C0,Et (LV)Steroid Alkaloids.-A 3p-dimethylaminopregn-5-ene structure (LVI ;R = Me) has been suggested for conessine.'* This is in agreement with theoptical rotation, ultra-violet, and infra-red spectral data.Degradation ofconessine by von Braun's method affords isoconessimine (LVI; R = H).75Hofmann degradation of the N-acetyl derivative (LVI; R = Ac), followedby Emde reduction, gave (LVII; R = Ac) identical with the substanceprepared by reaction of 3~-toluene-~-sulphonyloxypregna-5 : 20-diene withmethylamine followed by acetylation of the resulting amine (LVII ; R = H).The presence of a sec.-amino-group in solasodine (LVIII) has been con-firmed ; molecular-rotation differences indicate that solasodine has the samestereochemical configuration as cholesterol ; N-nitrososolasodine has beenconverted in small yield into diosgenin (LIX), confirming structure (LVIII).76A new alkaloid, solamargine, has been isolated 77 from Solanunz marginaturn ;complete hydrolysis gave rhamnose, glucose, and solasodine (LVIII) ;partial hydrolysis yielded solasodine p-glucoside.Tomatidine yields a diacetyl derivative (m.p. 194') containing >NAc,7O J. B. Koepfli, J. F. Mead, and J. A. Brockman, J . Ameu. Chem. SOC., 1949, 71, 1048.7 l F. Ablondi, S. Gordon, J . Morton, and J. H. Williams, J . Org. Chem., 1952, 17, 14.7a B. L. Hutchings, S. Gordon, F. Ablondi, C. F. Wolf, and J. H. Williams, abid.,73 B. R. Baker, R. E. Schaub, F. J. McEvoy, and J. H. Williams, ibid., p. 133.74 R. D. Haworth, J. McKenna, R. G. Powell, and H.G. Whitfield, Chem. and Ind.,7 5 S. Siddiqui, Proc. Indian Acad. Sci., 1936, 3, A , 249, 257.7 f ~ L. H. Briggs and T. O'Shea, J . , 1952, 1654.7 7 L. H. Briggs, E. G. Brooker, W. E. Harvey, and A'. D. Odell, ibid., p. 3587.p. 19.1952, 215228 ORGANIC CHEMISTRY.which is isomerised by light to a compound (m. p. 92”) containing -NHAc.The former product is oxidised by chromic acid to 3-acetyltigogenin lactoneMeIHO AN (LVIII)(LX); 78 the lower-melting isomer is oxidised to a mixture of (LX) and3~-acetoxyaZZopregn-16-en-20-one (LXI),78, 79 suggesting that tomatidinemay be (LXII), the nitrogen analogue of tigogenin.’8MeM$All.o Me 1 /----\-Me/q+,>NH-/ Mqd9AH AT%-(LXII) NH, (LXIII)HO h/.J HSolanocapsine , C,,H4602N2,H20, contains no double bonds, two or threeC-methyl groups, three active hydrogen atoms, one amino-, and one secondarycyclic imino-group.Treatment with nitrous acid gives an unsaturatednitroso-compound and nitrogen ; one oxygen atom is present as a tertiary orhindered secondary hydroxyl group, and the other as an ether linkage.80Selenium dehydrogenation yielded Diels’ hydrocarbon and 2-ethyl-5-methyl-pyridine, observations differing from those of earlier workers.81 These re-actions lead to a formula of type (LXIII ; stereochemistry unknown). Infra-red spectral studies indicate that salt formation by this type of structureinvolves opening of the ether ring.Careful hydrolysis of cevadine gives cevagenine and angelic acid ; simi-larly veratridine gives veratric acid and cevagenine.82 Further action of78 R. Kuhn and I. Low, Chem. Ber., 1952, 85, 416.79 Y . Sato, A. Katz, and E. Mosettig, J . Amer. Chem. SOC., 1952, 74, 538.81 G. Barger and H. L. Fraenkel-Conral, J., 1936, 1537.82 A. Stoll and E. Seebeck, Helv. Chim. Acfa, 1952, 35, 1270, 1942; cf. N. Elming,E. Schlittler and H. Uehlinger, HeEv. Cham. Acta, 1952, 35, 2034, 2608.C. Vogel, 0. Jeger, and V. Prelog, ibid., p. 2541BAILEY : ALKALOIDS. 229alkali isomerises cevagenine to the known cevine. Hence cevagenine is thetrue alkamine; its infra-red spectrum is similar to that of the alkaloids andshows the presence of a carbonyl group. This group is absent in cevine.Reduction of cevadine produces two dihydrocevadines ; both these yieldcevagenine on hydrolysis, but one gives (+)-a-methylbutyric acid and theother the (-)-isomer.Cevagenine contains a keto-group and seven hydroxylgroups ; a consideration of its reactions lead to a formula of type (LXFV).The skeleton of isorubijervine (LXV; R = OH) has been established bythe oxidation of dihydroisorubij ervine to the corresponding aldehyde and0Me OH IIMe(LXV)MeHO’ d g G Q M e H (LXVI) HO N ereduction of the latter to solanidan-3p-01 (LXVI),s3 and also by reaction ofthe toluene-$-sulphonic ester of isorubijervine with potassium iodide to give(LXV ; R = I). Reduction of this iodide gave solanidine (LXV ; R = H). 84Further evidence for the presence of an aromatic ring in veratramine(LXVII) has been obtained by the nitration of triacetyldihydroveratramineMe Me1 I AcMe MeAcO (LXX)Me Mep2Me MeMe0Ac,O-AcOAcO -.v (LXXI)(LXVIII) ; the resulting nitro-compound was reduced to a diazotisableamine.N-Acetylveratramine has been oxidised to an +-unsaturated83 D. Burn and W. Rigby, Chem. and Ind., 1952, 668.04 S. W. Pelletier and W. A. Jacobs, J . Amer. Chem. Soc., 1952, ’44, 4218230 ORGANIC CHEMISTRY.ketone, indicating that ring B is not aromatic. 85 Triacetyldihydroveratr-amine (LXVIII) has been oxidised by chromic acid to a ketone (LXIX)whose chemical and spectral properties indicate a carbonyl group atON-Diacetyljervine (LXX) is converted on acetolysis into a triacetatehaving an indanone structure (LXXI).S6 This has now been reduced to(LXIX), identical with the product from veratramine, establishing therelation between veratramine and j ervine.87A. S. B.10. NATURALLY-OCCURRING OXYGEN RING COMPOUNDS.Furans and Benzofurans-The chemistry of usnic acid has been re-viewed.l Details of the work leading to the determination of the structureof griseofulvin3 have now been given. Contributions to the chemistry ofcournaranones include work on the synthesis of the naturally occurringleptosidin (2-benzylidene-6 : 3’ : 4’-trihydroxy-7-methoxycoumaranone) andits 6-glycoside, leptosin ; the rearrangement of 2-benzylidenecoumaranonesunder weakly alkaline conditions to flavones, a change that may prove usefulin flavone synthesis ; and the formation of 2-arylidenecoumaranones in theattempted conversion of some arylidenephloracetophenone derivatives intoflavonols by treatment with alkaline hydrogen peroxide.’The structure of ipomeamarone (I),8 a furan produced in sweet potato byinfection with Ceratostomella~fimbriata Elliot, has been elucidated by JapaneseH,C-----CH, H,C-CH, H,C--CH,H\l I I t >L,o,CMeCH,R I‘O/CMe*CH2R H0,CC CMeCH,R OC II I1 \O/\n/H,C-CH,H\I 1MeO,CCH,CH,*CMe:CHR CH2XH-C\ /CMe.CH,R(IV) 0 .,(R = - CO*CH,*CHMe,) (V)chemists.9 Preliminary work indicated the presence of a carbonyl group,two double bonds, and two oxide rings. Ozonolysis gave as chief productsipomic lactone (11) and ipomeanic acid (111). The lactone gave isovalericacid and lzevulic acid on oxidation, and ozonolysis of the semicarbazone of8 5 C. Tamm and 0.Wintersteiner, J . Amer. Chem. SOG., 1952, 74, 3842. ** J. Fried, 0. Wintersteiner, A. Klingsberg, M. Moore, and B. M. Iselin, ibid.,1 F. M. Dean, Sci. Progr., 1952, 40, 635.8 J. F. Grove, J. MacMillan, T. P. C. Mulholland, and M. A. T. Rogers, J., 1952,3949; J. F. Grove, D. Ismay, J. MacMillan, T. P. C. Mulholland, and M. A. T. Rogers,ibid., p. 3958; J. F. Grove, J. MacMillan, T. P. C. Mulholland, and J. Zealley, ibid.,p. 3967; J. F. Grove, J. MacMillan, T. P. C. Mulholland, and M. A. T. Rogers, ibid.,p. 3977; T. P. C. Mulholland, ibid., p. 3987, 3994.1951, 73, 2970. 87 0. Wintersteiner and N. Hosansky, ibid., 1952, 74, 4474.Ann. Reports, 1951, 48, 210,,T. A. Geissman and C. D. Heaton, ibid., 1943, 65, 677.D. M. Fitzgerald, E.M. Philbin, and T. S. Wheeler, Chem. and Ind., 1952, 130.* T. A. Geissman and W. Mole, J . Amer. Chem. Soc., 1951, 73, 5765.7 H. Ozawa and M. Kawanishi, J . Pharm. SOG. Japan, 1951, 71, 1186.8 I. Oze and M. Hiura, Ann, Rep. Jup. Veget. Path., 1939, 9, 123.9 T. Kubota and T. Matsuura, Proc. Japan Acad., 1952, 8, 44, 83, 198KING : NATURALLY-OCCURRING OXYGEN RING COMPOUNDS. 231the compound (IV) obtained by dehydration of the methyl ester formedon ring-opening of the lactone gave chiefly methyl lzvulate and isobutyl-glyoxal semicarbazone. The structure (IV) of the keto-acid, thus deduced,was confirmed by synthesis, and the point of attachment of the carboxylgroup in (111) was proved by degradation to the lactone (11). The furanstructure of the remaining C(*) moiety was shown by colour tests, the form-ation of Diels-Alder adducts, and by a degradation lo typical of acc'-un-substituted furans, in which the adduct with acetylenedicarboxylic ester waspartially reduced and heated, giving furan-3 : 4-dicarboxylic ester and anolefin (V).The olefin, on oxidative decomposition of its ozonide, gaveformic acid, ipomeanic acid, and ipomic lactone. Further work l1 is de-scribed which independently confirmed the position of the carbonyl groupin the side chain of ipomeamarone.Flavones-Several useful papers have appeared on the separation andidentification of flavone derivatives by paper partition chromatography.Gage, Douglas, and Wender l2 give the RF values of 38 flavone derivativesin 11 solvent systems and also the colours produced on paper by each com-pound with 8 sprays in both visible and ultra-violet light.Paris13 givesR F values in various solvents of 41 flavone derivatives. In two papers l4the R M [log (1/RF - l)] values of many natural and synthetic flavones(including 13 new compounds) are reported, and the interactions ofsubstituent groups, in particular hydrogen bonding, are discussed in thelight of the results. Partition chromatography has also been applied to theidentification 15 of flavanones in extracts of various Pinus species. Theultra-violet absorption spectra of flavones have been studied in relation totheir structure by Briggs and Locker l6 who also discuss the effects of struc-ture on the acidity and basicity of flavones.The determination of theultra-violet absorption spectra of substances, including flavones, iso-flavones, and coumarins, present as spots on paper after chromatographyhas been investigated 1' as an analytical method.The literature concerning colour reactions of flavones is notoriouslyconfused and many conclusions about the specificity of certain reactionshave been reached on insufficient evidence. One aspect of this field hasbeen clarified l8 by an investigation of the colours given by 57 flavonederivatives with two reagents (magnesium-hydrochloric acid and zinc-hydrochloric acid 19). Whereas the first reagent appears to give stableanthocyanidin-like colours with all flavone derivatives, the second givesstable colours only with flavonols substituted in the 3-position ; fadingcolours are produced with flavones and 3-hydroxyflavanones.A furthercolour test,20 reported as specific for flavanones, depends on the formation10 K. Alder and H. F. Rickert, Ber., 1937, 70, 1354.l1 T. Kubota and T. Matsuura, J . Chem. SOC. Japan, 1952, 73, 530.l2 T. B. Gage, C. D. Douglass, and S. H. Wender, AnaZyt. Chem., 1951, 23, 1582.13 R. Paris, Bull. SOC. Chim. biol., 1952, 34, 767.14 T. H. Simpson and (in part) L. Garden, J., 1952, 4638; B. L. Shaw and T. H.16 G. Lindstedt and H. Misiorny, Acta Chem. Scand., 1952, 6, 744.16 L. H. Briggs and R. H. Locker, J., 1951, 3136.l7 A. E. Bradfield and A. E. Flood, J., 1952, 4740.l8 M. Shimizu, J. Pharm. SOC. Japan, 1951, 71, 1329; 1952, 72, 338.Is J .C. Pew, J . Amer. Chem. SOC., 1948, 70, 3031.a. S. Shibata and A. Kasahara, J. Pharm. SOC. Japan, 1952, 72, 1386.Simpson, ibid., p. 5027232 ORGANIC CHEMISTRY.of a blue fluorescent spot (ultra-violet light) when the compound, on paper,is sprayed with magnesium acetate.Experiments on the isolation, identification, and synthesis of flavonescontinue. New flavone derivatives isolated include ayanin 21 from thetimber of Distemonanthus Benthamianus, shown by degradation and synthesisto be 3 : 7 : 4’-trimethylquercetin ; 3-O-rhamnoglucosidylk~mpferol22 fromthe leaves of Hyptis capitata and Dryopteris oligophlebia ; rhoifolin (7-0-rhamnoglucosidylapigenin) from both the Japanese wax tree 23 (Rhussuccedenia) and the peel of the ripe fruit of Japanese varieties of Citrusauyantium 24 where it is accompanied by naringin (the peel of Europeanvarieties of this plant contains only hesperidin 25) ; a new glycoside ofgenkwanin from the bark of the Japanese cherry; 26 and astilbin (a rhamnos-ide of 3 : 5 : 6 : 3’ : 4’-pentahydroxyflavanone) from Astilbe Thwbergii 27which also contains quercetin and the isocoumarin, bergenin.The substancearomadendrin, long known to occur in the kinos of many Eucalyptus species,has been identified 28 as dihydrokzempferol which is also identical withk a t ~ r a n i n . ~ ~ In the light of new evidence the structure of meliternatin hasbeen m0dified.3~Several known flavones have been isolated from new sources, includingquercetin and its 3-glucoside (by the use of ion-exchange resins) fromgrapes 31 and black currants,32 and from a variety of Rosa polyantha; 33rutin from date-palm pollen 34 and the leaves of GreviElea robusta; 35 andnaringenin from the timber of Ferreirea ~pectabilis.~~Synthetic investigations in the field include the synthesis of 5 : 4’-di-methoxyfurano(3” : 2”-6 : 7)flavone and 7 : 4’-dimethoxyfurano(2” : 3”-5 : 6)flavone,37 possibly isomeric with, but shown not to be identical with, ging-keti11.3~ During experiments on the solubilising of flavones with boricacid 39 an observation has been made which may prove useful in the synthesisof partially methylated compounds.In the presence of borate, diazo-methane fails to methylate not only the 5-hydroxyl, but also vicinal hydroxyl,groups; rutin can thus be methylated to the 7-methyl ether, and quercetinto the 3 : 7-dimethyl ether.Addition of boric acid also improves the reduc-tion 40 of flavonols to hydroxyflavanones by dithionite.19isoF1avones.-A new isoflavone, muningin (6 : 4’-dihydroxy-5 : 7-di-21 F. E. King, T. J. King, and K. Sellars, J . , 1952, 92.22 K. Kobayashi, J . Pharm. SOC. Japan, 1952, 72,l; K. Kob.ayashi and K. Hayashi,24 S. Hattori, M. Shimokoriyama, and M. Kanao, J . Amer. Chem. Soc., 1952, 74, 3614.26 F. Kolle and K. E. Gloppe, Pharm. Zentralh., 1936, 77, 421.2 6 T. Ohta, J . Pharm. SOC. Japan, 1952, 73, 456.2 7 H. Shimada, T. Sawada, and S. Fukuda, ibid., p. 578.28 W. E. Hillis, Austral. J . Sci. Res., 1952, 5, 379.29 H. Voda, B. Fukushima, and T.Kond6, J . Agric. SOC. Japan, 1943, 19, 467.30 L. H. Briggs and R. H. Locker, J., 1951, 3131.31 B. L. Williams and S. H. Wender, J . Amer. Chem. SOC., 1952, 74, 4372.32 R. L. Williams, C. H. Ice, and S. H. Wender, ibid., p. 4566.33 T. Ohta and T. Myazaki, J . Pharm. SOC. Japan, 1951, 71, 1281.34 M. S. El Ridi, L. A. Strait, and M. H. Aboul Wafa, Arch. Biochem., 1952, 39, 317.35 K. Kobsyashi, J . Pharm. SOC. Japan, 1951, ‘21, 1493.38 F. E. King, M. F. Grundon, and K. G. Neill, J . , 1952, 4580.37 A. Kogure, J . Chem. SOC. Japan, 1952, 73, 271, 308.3 8 W. Baker and W. H. C. Simmonds, J., 1940, 1370.3g M. Shimizu et al., J . Pharm. SOC. Japan, 1951, 71, 875 st seq.40 M. Shimizu and T. Yoshikawa, ibid., 1952, 72, 331.ibid., p. 3. 23 S.Hattori and H. Matsuda, Arch. Biochem., 1952, 37, 85KING : NATURALLY-OCCURRING OXYGEN RING COMPOUNDS. 233rnethoxyisaflavone) has been isolated 41 from the heartwood of Pterocarpusangalemis which also contains a small amount of p r ~ n e t i n . ~ ~ Formo-nonetin and genistein have been isolated from subterranean clover,43 andgenistein has been shown to be estrogenic. Two independent groups ofworkers have isolated simple dihydroisoflavones, previously known in Natureonly as complex derivatives, from natural sources. Indian workers on theconstituents of Prunus +uddum, known to contain prunetin as well asgenkwanin and sakuranetin,u have isolated two new substance^,^^ theglycoside padmakastin and its aglycone padmakastein. The latter wasidentified as dihydroprunetin (2 : 3-dihydro-5 : 4’-dihydroxy-7-methoxyiso-flavone) by synthesis and by dehydrogenation to prunetin derivatives (bythe action of selenium dioxide on the acetate).British workers36 isolatedfrom Ferreirea spectabikis, in addition to biochanin-A (4-methylgenistein) andnaringenin, two compounds ferreirin and homoferreirin. Dehydrogenation(palladised charcoal), oxidation, and synthesis of the fully methylatedderivatives established both compounds as derivatives of 5 : 7 : 2’ : 4’-tetra-hydroxyisoflavanone ; investigation of the ethyl ethers established thestructures 46 of the natural compounds as, respectively, 5 : 7 : 2’-trihydroxy-4‘-methoxy- and 5 : 7-dihydroxy-2’ : 4’-dimethoxy-isoflavanone.‘A new synthetic route to isoflavones has been developed 47 which isparticularly useful for the direct preparation of hydroxylated derivatives.The appropriate deoxybenzoin is treated, in pyridine, with ethoxalyl chloride,giving the 2-carbethoxyisoflavone, readily hydrolysed and decarboxylatedunder mild conditions.By this method biochanin-A, genistein, $-bapti-genin, and 5 : 7 : 2‘-trihydroxyisoflavone 48 have been made. The lastwas not identical with an aglycone from a soya-bean glycoside whichhad been allotted this structure.49 The synthesis 42 from biochanin-A of7 : 4‘-dihydroxy-5-methoxyisoflavone, the so-called prunusetin 44 fromPrunus fiuddum, does not give the substance described as occurring naturally,which was probably impure prunetin. The method of nuclear oxidationwith persulphate, well known in the flavone field, has been successfullyapplied to several isoflavone~.~~Miscellaneous Benzopyrones and Coumarins.-The first natural naphtho-pyrone, eleutherinol, has been found 51 in Eleuthera bulbosa; 52 only 500 mg.were obtained but the structure has been unambiguously established as (VI).Analysis, colour tests, the formation of a piperonylidene derivative of thedimethyl ether, and alkaline degradation [which gave acetone, acetic acid,a trihydroxy-ketone (VII; R = Ac, R’ = H), and a small amount of atrihydroxy-compound (1711; R = R‘ = H)] indicated that the substance4 1 F.E. King, T. J. King, and A. J. Warwick, J., 1952, 96.42 F. E. King and L. Jurd, J., 1952, 3211.43 R. B. Bradbury and D. E. White, J., 1951, 3447.44 D.Chakravarti and C. Bhar, J . Indian Chem. Soc., 1945, 22, 301.46 N. Narasimhachari and T. R. Seshadri, Proc. Indian Acad. Sci., 1952, 35, A, 202.46 F. E. King and K. G. Neill, J., 1952, 4752.47 W. Baker and W. D, Ollis, Nature, 1952, 169, 706.48 W. Baker, J. H. Harborne, and W. D. Ollis, Cham. and Ind., 1952, 1058.49 K. Oliano and I. Beppu, J . Agric. Chem. SOC. Japan, 1939, 16, 645.50 N. Narasimhachari, L. R. Row, and T. R. Seshadri, Proc. Indian Acad. Sci., 1952,5 1 A. Ebnother, Th. M. Meijer, and H. Schmid, Helv. Chim. A d a , 1952, 35, 910.62 Cf. Ann. Reports, 1950, 47, 226.35, A , 46234 ORGANIC CHEMISTRY.was a dihydroxy-2-methylchromone with one further methyl group (Kuhn-Roth) . Alkaline degradation of dimethyleleutherinol gave the correspondingderivatives (VII; R = Ac, R’ = Me, and R = H, R = Me) ; oxidationof the former gave 3 : 5-dimethoxyphthalic anhydride, and of the latter(VI) (VII) (VIII) (IX)(lead tetra-acetate) gave a mixture of a 2-hydroxy-dimethoxy-methyl-1 : 4-naphthaquinone and the corresponding dimethoxy-methyl-1 : 2-naphtha-quinone. The data thus obtained did not distinguish between the twostructures (VIII) and (IX) for the 1 : 4-quinone, but an unambiguoussynthesis 53 of both quinones identified the degradation product as (VIII),and the structure (VI) for eleutherinol followed.Some analogous naphtho-pyrones have been synthesised by standard methods.54Several papers concerning the chemistry of khellin and its analogueshave appeared ; visnagin has been converted into the more physiologicallyactive khellin by a process which makes use of nuclear oxidation withpersulphate ; 55 khellol 66 and a visnagin isomer [5-methoxy-Z-methyl-furano(2’ : 3’-7 : 8)(2 : 3-benzopyrone)] 57 have been prepared by standardmethods.Work on natural coumarins has been largely confined to the analyticalfield. Paper chromatographic studies of coumarins have been published bytwo school^.^*^^^ Spectral studies are represented by a paper 6o on thevariation of fluorescence spectrum with pH of 59 coumarin derivatives, anda variety of coumarins and furanocoumarins have been investigated polaro-graphically.61Lactones and Lacto1s.-A series of closely argued paperss2 on thestructure of picrotoxin has appeared but the investigations described arenot yet sufficiently complete to allow final conclusions to be reached.Further details 63 have now appeared concerning the synthesis of picrotoxa-diene and its production from picrot~xinin.~~ The lignan arctigenin (a-3 : 4-dimethoxybenzyl-a-4-hydroxy-3-methoxybenzylbutyrolactone) 65 has beensynthesised.6653 H. Schmid and M. Burger, Helv. Chim. Acta, 1952, 35, 928.54 H. Schmid and H. Seiler, ibid., p. 1990.5 5 S. K. Mukherjee and T. R. Seshadri, Proc. Indian Acad. Sci., 1952, 35, A , 323.56 T. A. Geissman and J. W. Bolger, J . Amer. Chem. SOC., 1951, 73, 5875.5 7 G. H. Phillips, A. Robertson, and W. B. Whalley, J., 1952, 4951.58 K. Riedl and N. Neugebauer, Monatsh,, 1952, 83, 1083.69 A. B. Svendsen, Pharm.Acta Helv., 1952, 27, 44.60 R. H. Goodwin and F. Kavanagh, Arch. Biochem., 1952, 36, 442.61 R. Patzak and L. Neugebauer, Sitzungber. Akad. Wiss. Wien, 1952, 161, 776.62 J . C. Benstead, H. V. Brewerton, J. R. Fletcher, M. Martin-Smith, S . N. Slater,and A. T. Wilson, J., 1952, 1042; S. N. Slater and A. T. Wilson, ibid., p. 1597; J. C.Benstead, R. Gee, R. B. Johns, M. Martin-Smith, and S. N. Slater, ibid., p. 2292.63 H. Conroy, J . Amer. Chem. SOL, 1952, 74, 491, 3047.64 Cf. Ann. Reports, 1951, 48, 211.$6 R. D. Haworth and W. Kelly, J., 1936, 998.e6 T. Ozawa, J. Pharm. SOC. Japan, 1952, 73, 285, 551BOURNE : MACROMOLECULES. 235Gladiolic acid, a metabolic product of Penicillium gladioli, has beenshown 67 to have the tautomeric structure (X; R = CHO).The presenceof a formyl group was proved by the formation of carbonyl derivatives andMe0 CO Me0by the existence of reducing properties which(XI)disameared on mild oxidationduring which a new carboxyl group appeared. TLL 0, product so obtainedhad two carboxyl groups and one methoxy-group, and showed both carbonyland hydroxyl properties, which are best explained by assuming a tautomericsystem as shown. Rearrangement under alkaline conditions t o give acarboxy-lactone (XI; R = C0,H) was best explained by an ortho-arrange-ment of formyl and lactol grouping, and vigorous oxidation gave 4-methoxy-benzene-1 : 2 : 3 : 5-tetracarboxylic acid (structure by synthesis). The finalorientation of the substituents followed from detailed arguments for whichthe original paper should be consulted; they depend chiefly on the inter-pretation of infra-red spectra and the isolation 68 from the phthalide (XI;R = Me), obtained by Clemmensen reduction of gladiolic acid, of 2 : 4 : 5-trimethylphenol.T.J, K.11. MACROMOLECULES.During 1952, workers engaged in the study of macromolecules mournedthe deaths of C. S. Hudson and K. H. Meyer, whose researches laid thefoundations of so much of the work reported below.Poly saccharides.It is the turn of polysaccharides to receive the main emphasis in a yearwhich, in addition to furnishing its full quota of studies on new and rarepolysaccharides, has seen some readjustments in widely accepted conceptsof the structures of certain " simple " and well-known polysaccharides, suchas starch, glycogen, and dextran.Structural studies have been facilitatedby the continued use of chromatographic techniques for the fractionation ofmixtures of oligosaccharides on filter paper, on charcoal col~mns,l-~ and, astheir acetates, on columns of " Silene EF." 4 It has been shown that caremust be exercised in interpreting paper dhromatograms of sugar solutionscontaining ammonium salts, or other nitrogenous compounds, becauseglycosylamines formed, in certain circumstances, on the paper itselfmay produce extra spots.5 Studies of filter-paper ionophoresis of sugars inborate buffers have demonstrated that this new method is potentially very6 7 J. F. Grove, Biochem. J., 1952, 50, 648.6 s H. Raistrick and D.J. Ross, ibid., p. 635.* S. A. Barker, E. J. Bourne, G. T. Bruce, and M. Stacey, Chem. and Ind., 1952,1156.4 M. L. Wolfrom and J. C. Dacons, J . Amer. Chem. Sot., 1952, 74, 6331.R. L. Whistler and Chen-Chuan Tu, J . Amer. Cham. Sot., 1952, 74, 3609.S. Peat, W. J. Whelan, and G. J. Thomas, J., 1952, 4546.R. J. Bayly, E. J. Bourne, and M. Stacey, Nature, 1952, 169, 876236 ORGANIC CHEMISTRY.valuable for characterisations; there is no doubt that it will shortly bewidely used to unravel the complexities of polysaccharide structures, as alsowill electrokinetic ultra-filtration analysis. Infra-red absorption, havingyielded valuable results with dextran and hyaluronic acid,g likewise willprobably find extensive application in the polysaccharide field.A usefulmethod of structural analysis, involving periodate oxidation of a poly-saccharide, reduction of the newly formed aldehyde groups, and acidichydrolysis of the product to give readily identifiable fragments, has beenreported. loStarch and Glycogen.-Maple-sapwood starch has been shown, bypotentiometric titration with iodine, to contain ca. 19% of amylose.11Hydrolysis of the trimethyl ether gave 2 : 3 : 4 : 6-tetramethyl and 2 : 3 : 6-trimethyl glucose (3.3-3.4 and 92-93y0, respectively), together withdimethyl glucoses (4-5y0), a result which indicated that the principal gluco-sidic linkages involved positions 1 and 4, and that the average chain lengthof the amylopectin fraction was 26 glucose units. A somewhat lowerfigure (22 units) was derived from a determination of the formic acid liberatedduring oxidation of the starch with periodate.The presence of xylose in thestarch was attributed to an associated xylan.lf Nuclear-substituted tri-carbanilates of maize starch, amylose, and amylopectin have been preparedby treatment of the polysaccharides, in pyridine, with derivatives of phenylisocyanate.12 The greatly differing optical rotations and melting points ofthe ortho-substituted products, as compared with the meta- and para-isomers,were consistent with their different intramolecular bondings. Alkaline ferri-cyanide, in the presence of cyanide, has been used for measurement ofmolecular weights of amylodextrins and other substances of the starch type.13Determinations of the molecular weight of an amylopectin acetate, byosmotic and light-scattering methods, have given approximate values of6 x lo6 and 400 x lo6, respectively, the former being a number-averageand the latter a weight-average.14 The swelling of starch granules, causedby the sorption of water vapour,l5 and the effect of temperature and aggre-gation on the absorption spectrum of the amylose-iodine complex,16 havebeen studied.Important advances have been made concerning the finer structures ofthe starch components.A detailed account has been given of the propertiesof Z-enzyme, which occurs in impure samples of soya-bean p-arnyla~e.~'Whereas the purified soya-bean p-amylase, like the crystalline p-amylasefrom sweet potatoes, effects only a 70% conversion of potato amylose intomaltose (and not ca.lOOyo, as was believed previously), in the presence ofA. B. Foster, Chern. and Ind., 1952, 828; R. Consden and W. M. Stanier, Nature,S. F. D. Orr, R. J. C. Harris, and B. SylvCn, Nature, 1952, 169, 544.1952, 169, 783. D. L. Mould and R. L. M. Synge, Biocham. J., 1951, 50, xi. * S. C. Burket and E. H. Melvin, Science, 1952, 115, 516.lo M. Abdel-Akher, J. K. Hamilton, R. Montgomery, and F. Smith, J . Amev. Chem.11 C. E. Ballou andE. G. V. Percival, J., 1952, 1054.l2 I. A. Wolff, P. R. Watson, and C. E. Rist, J . Amer. Chew. Soc., 1952, '44,3061,3064.Is S. Nussenbaum and W. 2. Hassid, Analyt. Chem., 1952, 24, 501.l4 B. H. Zimm and C. D. Thurmond, J . Auner. Chem. Soc., 1952, 14, 1111.l6 N.N. Hellman, T. F. Boesch, and E. T. Melvin, ibid., p. 348.l6 J.. F. Foster and E. F. Paschall, ;bid., p. 2105.l7 S. Peat, S. J. Pic, and W. J. Whelan, J., 1952, 705, 714; S. Peat, G. J. Thomas,Soc., 1952, 74, 4970.and W. J. Whelan, zbad., p. 722BOURNE MACROMOLECULES. 237Z-enzyme an almost complete conversion into the disaccharide results. Theamyloses of sago, tapioca, and maize behave simi1arly.l' It was concluded(a) that some degree of branching occurs in amyloses, and that the branches,which serve as obstructions to pure p-amylase (and also to phosphorylase),are removed by Z-enzyme, (b) that Z-enzyme is a p-glucosidase, and (c) thatthe branches consist of single p-glucose units attached to the main chain.17If the Z-enzyme-sensitive links are, in fact, at branch points, it seems thatthe enzyme responsible for their synthesis still remains to be found.Alter-natively, the anomalous links may not be branches, but may occur at thenon-reducing ends of 30% of the amylose molecules, and may resultfrom imperfections in the synthesis by phosphorylase. Branching in amylosehas been postulated also on the basis of the rates of sugar production withamylo-glucosidase and with p-amylase ; l8 it appears that potato amylosehas 1-2, and tapioca amylose 2-3, branches per molecule.Evidence that amylopectin and glycogen have structures similar to that(I) suggested by Meyer, rather than the simpler " laminated " formula (11)due to Haworth, or the " comb-like " structure (111) proposed by Freuden-berg, has been obtained by two methods 2$ l9 (cf.ref. 20). In the first, thepolysaccharides were treated with salivary or-amylase and then with R-enzyme (which hydrolyses the 1 : 6-=-branch linkages), and the resultingmixtures of linear saccharides were analysed on charcoal columns. Fromthe analytical figures, it was deduced that multiple branching occurred inthe polysaccharide ~ t r u c t u r e s . ~ ~ ~ 21 The second method entailed a similar0 boPossible structural formule f o r anzylopectin.0 0-Rb(1) (11)o = Non-reducing chain end, = a-1 : 6-Link,(WR = Free reducing chain end.analysis of the amylosaccharides formed when the P-limit dextrin fromamylopectin was treated with R-enzyme.2A new procedure for the determination of polysaccharide structureshas been illustrated by its application to amylopectin.1° Periodate-oxidisedamylopectin (IV) was hydrogenated and hydrolysed, and the resultingmixture was analysed for glycerol and erythritol.Since the former- arisesonly from the non-reducing terminal units, and the latter from the remainingunits, the molar ratio glycerol : erythritol is related to the chain length ofthe polysaccharide. In addition, about 0.5% of the sugar units resistedperiodate, and gave glucose on hydrolysis, from which it was concluded 10that some 1 : 3-linkages occur in amylopectin. Glycogen (1%), amylosel8 R. W. Kerr and F. C. Cleveland, J . Amer. Chem. SOC., 1952, 74, 4036.1 9 W. J. Whelan and P. J. P. Roberts, Nature, 1952, 170, 748.20 G. T.Cori and J. Larner, J . Biol. Chem., 1951, 188, 17.21 P. J. P. Roberts and W. J . Whelan, Biochem. J., 1952, 51, xviii238 ORGANIC CHEMISTRY.(0.2-0.5%) , and cellulose ( 0 - 1 4 - 2 ~ 0 ) likewise contain periodate-resistantunits. loH,-OH ,Other studies have been devoted to the determination and purificationof amylases. An improved method has been developed for the preparationof hog pancreatic amylase.22 Adsorption indicators have been used for thedetermination of p-amylase a~tivity.~3 Earlier reports that indole deriv-atives, and other plant hormones, inhibit human a-amylase have been dis-proved.24 Crystalline malt P-amylase is a very soluble albumin, which canbe stored in the cold for long periods without loss of activity; it is totallyand irreversibly destroyed by the salts of heavy metals, but is relativelystable to low pH; its isoelectric point is at pH 6.1, and it displays itsoptimum activity at pH 5.2.25 An interesting observation is that cell-freehomogenates of Tetrahymena pyriformis contain, in addition to phosphorylase,an enzyme capable of hydrolysing starch, glycogen, and maltose to glucme.26Enzymic syntheses of the starch components have continued to receiveattention.Potato phosphorylase has been prepared in a highly purifiedform, following a new method of purification; 27 the enzyme, which had anactivity nine times greater than that of any sample described previously,was free from phosphatase, amylases, and Q-enzyme. It is believed thata two-fold increase in purity remains to be achieved,27 so that the crystallis-ation of the enzyme at last seems to be imminent.A detailed study hasbeen made of the equilibrium ratio [orthophosphate] : [glucose-1 phosphate]established by potato phosphorylase, and the effect of Mg++ ions on thisratio has been explained in equations relating it to the concentration ofMg++ ion, and to the dissociation constants of magnesium complexes withorthophosphoric and glucose-1 phosphoric acids2* Magnesium ions arebelieved to have little effect on the ratio under physiological conditions.The second dissociation constant of glucose-1 phosphoric acid has beenredetermined as 3.09 x at 30°.28 The free-energy change, at 30°, ofthe reaction glucose-1 phosphate -> acid orthophosphate + polysaccharideis -1460 ca1.28 Additional support for the current theory that potato22 M.L. Caldwell, M. Adams, J. T. Kung, and G. C. Toralballa, J . Amer. Chenz. SOG.,24 E. H. Fischer and J. Fellig, ibid., 1952, 115, 684.26 A. Piguet and E. H. Fischer, HeEv. Chim. Acta, 1952, 35, 257.26 J. F. Ryley, Biochem. J., 1952, 52, 483.27 G. A. Gilbert and A. D. Patrick, ibid., 1952, 51, 186.z8 W. E. Trevelyan, P. F. E. Mann, and J. S. Harrison, Arch. Biochem., 1952, 39,1952, 74, 4033. 23 B. Carroll and J. W. Van Dyk, Scieme, 1952, 116, 168.419, 440BOURNE : MACROMOLECULES. 239phosphorylase functions by lengthening the chains of all primer moleculessimultaneously, and not by converting one primer molecule into amyloesbefore attacking another, has resulted from measurements of the spectra ofthe iodine stains of the products formed when different proportions ofglucose-1 phosphate and primer molecules are employed, and also fromelectrokinetic ultra-filtration analysis of the products.29 Chromatographicanalysis of the non-protein fraction of crystalline muscle phosphorylase hasrevealed uridylic acid, cystine, and (probably) 2-methyl-1 : 4-naphtha-quinone; 30 the cystine was isolated in sufficient quantity to suggest thatcysteine may constitute an end group of the protein molecule, and serve as aconnecting link with the prosthetic The crystalline enzyme isinhibited significantly by D-glucose, and by a-methyl- and a-phenyl-D-gluco-pyranoside, but not by a variety of other sugars, including p-methylglucosideand p-D-glucose-1 p h ~ s p h a t e .~ ~Details have been given of the preparation and properties of crystallinepotato Q-en~yme.~Z ( Q-enzyme converts the slightly branched amylosecomponent of starch into the highly branched amylopectin structure.) Likeearlier, less pure, samples of the enzyme, the crystalline enzyme is rapidlyinactivated in solution at 30"; it is more stable in the presence of starch.32In support of the hypothesis that Q-enzyme is a transglucosylase, it has beenshown by two independent groups of workers 339 34 that the potato enzymecannot utilise amylose-type molecules as substrates unless they containmore than ca. 42 glucose units. For the synthesis of starch from acetate,Polytomella coeca utilises inter alia a phosphorylase and a Q-enzyme, thesebeing very similar in their actions to the potato enzymes.35 Productsformed from amylose by the protozoal Q-enzyme have been shown, bychemical and enzymic methods, to be members of the amylopectin-glycogenclass ; they were readily distinguishable from amylose-fatty acid c0mplexes.~6This amylase+ amylopectin conversion is more rapid in the presence ofamylosaccharides having a small average chain length, presumably becausesuch molecules serve as receptors of the transferred chains.Confirmatory evidence has been obtained3' of the presence in E.coli ofamylomaltase, which catalyses the reaction : n maltose -e (glucose), + nglucose. The extra-cellular saccharides, formed when washed cells of theorganism were incubated with maltose in the presence of iodoacetate, werefractionated on a charcoal column into glucose, unchanged maltose, and thelower members of the homologous series of 1 : 4-c~-glucosans.~~ Improvedconditions for the production of Schardinger dextrinogenase by B. macerans 38have facilitated the preparation of an enzyme sample which behaves asessentially one component in solubility tests, in electrophoretic analysis, andin the ~ltra-centrifuge.~~20 J.M. Bailey and W. J . Whelan, Biochem. J., 1952, 51, xxxiii.30 M. V. Buell, Fed. Proc., 1952, 11, 192.81 P. N. Campbell, N. H. Creasey, and C. W. Pam, Biochem. J., 1952, 52, 448.3 I G. A. Gilbert and A. D. Patrick, ibid., 1952, 51, 181.33 S. Nussenbaum and W. Z. Hassid, J . Biol. Cheun., 1952, 196, 785.34 J.M. Bailey, S. Peat, and W. J. Whelan, Biochem. J., 1952, 51, xxxiv.56 A. Bebbington, E. J. Bourne, M. Stacey, and I. A. Wilkinson, J., 1952, 240.36 A. Bebbington, E. J. Bourne, and I. A. Wilkinson, ibid., p. 246.37 S. A. Barker and E. J. Bourne, ibid., p. 209.ae S. Schwimmer and J . A. Garibaldi, Cereal Cheun., 1952, 29, 108.S. Schwimmer, Fed. Proc., 1962, 11, 283240 ORGANIC CHEMISTRY.Interest has been focussed on glycogen in papers additional to thosementioned above. A polysaccharide synthesised by Tetrahymena pyriforrnishas been proved to be a glycogen, having a molecular weight of 9.8 x lo6(light-scattering method) and an average chain length of 13 glucose residuesMThe molecular weights of other glycogens have been determined41 by alight-scattering method as 3-15 x lo6 (cf. ref.14). Maltulose has beenfound in the saccharides resulting from the action of salivary a-amylase ona glycogen obtained from the livers of .pregnant rabbits.42 This importantobservation raises the question of the possible occurrence of fructose in otherglycogens, and perhaps in starches. By periodate oxidation, and deter-mination of the liberated formic acid, chain lengths of 13 units were foundfor cat-liver and fetal-Sheep-liver glycogens, while three samples of glycogenfrom Mytilus edulis had chain lengths of 5, 12, and 17.43 The structuresof these and other glycogens were discussed in the light of their behaviourduring P-amyl~lysis.*~gThe liver “ branching factor,” freed from cc-amylase, has been shown toconvert amylopectin into a polysaccharide giving a reddish-brown, ratherthan a purple, iodine stain ; it was believed that the reaction entailed branch-ing of the outer chains of amyl~pectin.~~ As confirmation of this, a syntheticpolysaccharide, prepared from glycogen by lengthening the outer chains bymeans of phosphorylase and [14C] glucose-1 phosphate, was treated withthe “ branching factor,” and the product was proved by an enzymic methodto possess radioactivity at the new branch points. The liver enzyme, whichfunctions in the absence of added phosphate, probably detaches a short chainof glucose residues by scission of a 1 : 4-link and attaches the chain, as abranch, through a 1 : 6-link; 45 this mechanism is similar to that establishedfor Q-enzyme.The syntheses of glycogen and other carbohydrates duringfermentation of glucose by baker’s yeast have been studied and discussed interms of the enzymic processes of fermentati~n.~~Cellulose.-A polysaccharide from Posidonia australis, previously thesubject of conflicting reports, is now known to be a cellulose; when methyl-ated and hydrolysed, it gives 2 : 3 : 6-trimethyl glucose almost excl~sively.~~An important recent contribution to cellulose chemistry is the isolation ofcellodextrins containing 2-7 glucose residues ; this notable achievementwas accomplished by fractionating, on a column of ‘‘ Silene EF,” the dextrinacetates produced by acetolysis of cellulose, and then deacetylating them.It seems certain that studies of these cellodextrins will lead to a betterunderstanding of the properties of cellulose.It has been demonstrated thata certain amount of re-esterification occurs during the hydrolysis of celluloseacetate with aqueous acetic acid,48 and that the heterogeneous hydrolysis ofhighly methylated cotton cellulose causes scission in the non-crystallineregions, followed by more rapid destruction of the smaller fragrnent~.~~4O D. J. Manners and J. F. Ryley, Biochem. J., 1952, 52, 480.41 B. S. Harrap and D. J. Manners, Nature, 1952, 170, 419.42 S. Peat, P. J. P. Roberts, and W. J. Whelan, Biochem. J., 1952, 51, xvii.43 D. J. Bell and D. J. Manners, J., 1952, 3641.44 D. J. Manners, Biockem. J., 1952, 51, xxx.4 5 J. Larner and G. T. Cori, Fed. PYOC., 1952, 11, 245.46 W.E. Trevelyan, J. N. Gammon, E. H. Wiggins, and J. S. Harrison, Biochem. J.,48 C. J. Malm, L. J. Tanghe, B. C. Laird, and G. D. Smith, J . Amer. CAem. SOL,1952, 50, 303.1952, 74, 4105.4 7 D. J. Bell, J . , 1952, 3649.49 R. E. Reeves, B. J. Barrett, and L. W. Mazzeno, ibid., p. 4491BOURNE MACROMOLECULES. 241Other papers have dealt with the molecular dimensions of cellulose tri-butyrate and trio~tanoate,~O the alcoholysis of cellulose and its derivativeswith 2-methoxyethan01,~l and the oxidation of hydrocellulose withhypoiodite. 52Limnoria Zignorum, a marine wood-boring isopod, has been found tosecrete a cellulase which converts cellulose into reducing substances ; 53earlier work had failed to detect this enzyme.The cellulase of Myrotheciumverrucaria is stimulated by proteins.= An investigation of the relationbetween the action of brown rot fungi, cellulose degradation, and lignincomposition in bagasse has been made.55 An observation which may be offundamental importance with regard to the enzymic synthesis of cellulose isthat an enzyme from Neisseria meningitidis catalyses the reversible reaction :maltose + phosphate p-D-glucose-1 phosphate + glucose.56 This tran-sition from the a- to the @-series may well be the key to the synthesis ofp-glucose polymers.Dextran.-The common tacit assumption that the branches of all dextransinvolve positions 1 and 4 has been proved to be invalid by several inde-pendent groups of workers. Periodate oxidations of the dextrans fromLeuconostoc mesenteroides NRRL B-742 and NRRL B-512 have shown thepresence of periodate-resist ant units, which yield glucose on hydrolysis.l0y 57It was suggested that these units carried branches at position 3, or positions2 and 4.Similar observations have since been made on other dextransss Insuch cases there are anomalous optical rotations and infra-red spectra.** 57* 58A full structural analysis of a Betacoccus arabinosaceous dextran (used inBritain for the production of a blood plasma substitute) has revealed thatthe branches are attached at position 3 almost excl~sively.~ Methylationand end-group assay gave 2 : 3 : 4 : 6-tetramethyl, 2 : 3 : 4-trimethyl, and2 : 4-dimethyl glucose, in proportions corresponding to an average chainlength of ca. 6 glucose residues.Partial acidic hydrolysis of the dextran andfractionation of the resulting oligosaccharides on a charcoal column yielded,inter alia, isomaltose and 3-glucosyl glucose ; there were periodate-resistantunits giving glucose on hydr~lysis.~ An added complication is that somedextrans can be separated, by graded precipitation with ethanol, into frac-tions with no 1 : 3-branches and with an increased proportion of suchbranches.57. 58 In the thermal degradation of dextran, there is a iotableabsence of reducing oligosaccharides when oxygen is excluded.59 Thetoxicity and blood anticoagulant properties of dextran sulphates have beenexamined over a range of molecular weights and sulphate contents.60The optimum conditions for the production of dextran sucrase byLeuconostoc mesenteroides NRRL B-512 have been ascertained ; from50 L.Mandelkern and P. J . Flory, J . Amer. Chem. Soc., 1952, 74, 2517.51 M. G. Blair, ibid., p. 3411.52 M. G. Blair and R. E. Reeves, ibid., p. 2622.53 D. L. Ray and J. R. Julian, Nature, 1952, 169, 32.54 D. R. Whitaker, Scie~zce, 1952, 116, 90.5 5 G. de Stevens and F. F. Nord, J . Amsr. Chem. Soc., 1952, 74, 3326.5 G C . Fitting and M. Doudoroff, J . Biol. Chem., 1952, 199, 153.67 R. Lohmar, J . Anzsr. Chem. Soc., 1952, '94, 4974.5 8 A. Jeanes and C. A. Wilham, ibid., p. 5339.5D M. Stacey and F. G. Pautard, Chem. and Ind., 1962, 1058.6O C. R. Ricketts, Biochem. J., 1952, 51, 129.61 H. J. Koepsell and H. M. Tsuchiya, J .Bact., 1952, 63, 293242 ORGANIC CHEMISTRY.sucrose the culture filtrates produce small amounts of levan, in addition todextran. High sucrose levels in the culture medium lead to viscous cultures,from which the separation of the cells is dificult.sl It has been claimed 62that a new disaccharide, leucrose [5-~-(glucopyranosyl)-~-fructopyranose]," plays a role in the polymerisation process " ; this hypothesis is at variancewith the accepted mechanism of dextran synthesis, and, if substantiated,would cast doubt on current concepts of the formation of other polysacchar-ides from sucrose. Perhaps the disaccharide arises in a side reaction in-volving the transfer of a glucose residue to fructopyranose, instead of toa growing dextran molecule.Cell-free culture filtrates of certain bacteriafrom the human intestine,63 and of an Aspergillus strain isolated fromdisplay dextranase activity, inasmuch as they decrease the average mole-cular weights of dextrans (to ca. 75,000 in the latter case) without liberatingsignificant quantities of reducing sugar.1 : $Linked G1ucosans.-It appears that 1 : 3-linked glucosans occurmore widely in Nature than has been believed hitherto; studies of three ofthem have been reported this year. Confirmation that laminarin is com-posed of p-glucopyranose units, mutually linked through positions 1 and 3,was obtained when it was proved that the disaccharide (laminaribiose), towhich it gives rise when partially hydrolysed with acid, is identical with asynthetic specimen of 3-p-~-glucopyranosyl-~-glucopyranose.65 The syn-thesis was accomplished by condensing 2 : 3 : 4 : 6-tetra-acetyl glucosylbromide with 1 : 2-5 : 6-diisopropylidene glucofuranose, and then removingthe protecting sub~tituents.~~ The flesh of the bracket fungus, PolyporusbetuZinus, when methylated and hydrolysed, has given 2 : 3 : 4 : 6-tetra-methyl, 2 : 4 : 6-trimethyl, 4 : 6-dimethyl, and a monomethyl glucose, in themolar ratio 1 : 13 : 4 : 1, and would thus seem to contain a highly branched1 : 3-gl~cosan.~~ An interesting polysaccharide (" mycodextran ") separateswhen hot-water extracts of AspergiZlus niger 152, grown on a sucrose medium,are cooled ; 67 it has [a]= +283" in alkali, an unusually high figure.68 Chemi-cal analyses of the products of partial hydrolysis of the polysaccharide, andof the methyl glucoses formed by hydrolysis of its trimethyl ether, haveshown " mycodextran " to be a glucosan containing 1 : 3-a- and 1 : 4-a-linkages in approximately equal amount.68Garactans and Ga1actomannans.-Methylation of the galactan of beeflung has indicated that a main chain of 1 : 6-~-galactopyranose units carriesa single D-galactopyranose residue, as a branch, at position 3 of every alternateunit ; in addition, there is one titratable acid function, probably carboxyl,per 3 5 4 0 sugar residues. 69A structure has been proposed for guaran on the basis of enzymicand acidic hydrolyses; 71 the former gave Gal la-6 Man (0.5%) andMan 1 p-4 Man l p 4 Man (7-5%), and the latter, Gal la-6 Man 1 p 4 Man(3%) (where Gal and Man are galactopyranose and mannopyranose residues,62 F.H. Stodola, H. J . Koepsell, and E. S. Sharpe, J. Amer. Chem. SOL, 1952, 74,3202.64 V. Whiteside-Carlson and W. W. Carlson, Science, 1952, 115, 43.65 P. Bachli and E. G. V. Percival, J., 1952, 1243.6 6 R. B. Duff, ibid., p. 2592.68 S. A. Barker, E. J . Bourne, and M. Stacsy, ibid., p. 756.69 M. L. Wolfrom, G. Sutherland, and M. Schlamowitz, J. Amer. Chem. Soc., 1952,'1 R. L. Whistler and D. F. Durso, ibid., p. 5140.a3 E. J. Hehre and T. W. Sery, J . Bact., 1952, 63, 424.6 7 J . L. Yuill, Chem. and I n d . , 1952, 755.74, 4883. 70 R. L. Whistler and C. G. Smith, ibid., p. 3795BOURNE : MACROMOLECULES. 243respectively). It was concluded that guaran consists of a chain of 1 : 4-linked p-D-mannopyranose units, with an a-D-galactopyranosyl group a tposition 6 of every other (average) mannose residue of the chain.Thegalactomannans of lucerne and clover seed resemble guaran in that they arehighly branched, and contain D-galactopyranose end-groups united tochains of 1 : 4(or 1 : 6)-linked D-mannose residues (probably in the pyranose~OX-I-II).~~ A similar structure has been assigned to the galactomannan offenugreek seed, but in this case the galactose : mannose ratio is appreciablyhigher (5 : 6), as also is the degree of branching.73 2-Cyanoethyl ethers havebeen prepared from guaran with acrylonitrile, and have been hydrolysedwith alkali to the corresponding 2-carboxyethyl ethers. 74Fructosans.-A polysaccharide from elecampane has been proved to beof the inulin class by hydrolysis of its methyl ether to 1 : 3 : 4 : 6-tetramethyl,3 : 4 : 6-trimethyl, and a dimethyl fructose (molar ratio, 1 : 32.7 : 1 ~ 5 ) .~ ~Polysaccharides from leaf cocksfoot and I talian rye grass have been classifiedas levans, because their methyl ethers yield 1 : 3 : 4 : 6-tetramethyl, 1 : 3 : 4-trimethyl, and a dimethyl fructose (molar ratios, 1 : 12 : 2 and 1 : 11 : 1,re~pectively).~~ It is interesting, in view of the enzymic studies reportedbelow, that each of these three polysaccharides contained ca. 3% of glucoseresidues. However, the glucose did not appear to be present as non-reducingend-groups (as it is in the inulin of dahlia tubers),76 because it was isolatedduring the end-group assays principally as trimethyl glucose.75Studies of transfructosidases have extended the work of Bacon andEdelman,77 and Blanchard and Albon; 78 they provide possible routes tothe synthesis of inulin and levan." Difco " invertase solution catalyses theconversion of sucrose into a reducing disaccharide, two trisaccharides, and atetrasaccharide, all containing fructose unit(s) linked to a single glucoseresidue. 79 p-Methylfructofuranoside has been prepared from sucrose and25% methanol with yeast invertase.80 With an enzyme from Aspergillusoryzae, sucrose has been converted into a trisaccharide containing oneglucose and two fructose units, and a tetrasaccharide composed of oneglucose and three fructose residues.81 All of these reactions conform withthe equation :Sucrose + HOR Fructosyl-O-R + Glucosewhere ROH is sucrose, glucose, methanol, or a growing oligosaccharide chainwith a non-reducing terminal fructofuranose group, A related phenomenonappears to be responsible for the occurrence, in barley leaves and stems, ofglucose, fructose, sucrose, and at least four higher oligosaccharides withdecreasing glucose : fructose ratioss2Xy1an.-A valuable contribution to the chemistry of xylan has been72 P.Andrews, L. Hough, and J. K. N. Jones, J . Anzev. Chem. Soc., 1952, 74, 4029.73 Idem, J . , 1952, 2744.74 0. A. Moe, S. E. Miller, and M. I. Buckley, J . Amer. Chem. Soc., 1952, 74, 1325.7 5 D. J. Bell and A. Palmer, J., 1952, 3763.76 E. L. Hirst, D.I. McGilvray, and E. G. V. Percival, J., 1950, 1297.7 7 J. S. D. Bacon and J. Edelman, Arch. Biochem., 1950, 28, 467.7 8 P. H. Blanchard and N. Albon, ibid., 1950, 29, 220.79 L. M. White and G. E. Secor, ibid., 1952, 36, 490.81 J. H. Pazur, Fed. Proc., 1952, 11, 267; J , Biol. Chem., 1952, 199, 217.82 H. K. Porter and J. Edelman, Biochem. J . , 1952, 50, xxxiii.J. S . D. Bacon, Biochem. J., 1952, 50, xviii244 ORGANIC CHEMISTRY.made by Whistler and his colleagues, who separated, on charcoal columns,the oligosaccharides resulting from partial acidic hydrolysis of the poly-saccharide.% 83 They isolated a series of five oligosaccharides, all crystalline,extending from the dimer to the hexamer, and obtained evidence that allwere composed of unbranched chains of 1 : 4-linked p-D-xylopyranose units;each of them gave a crystalline p-acetate.Hemicel1uloses.-European beech hemicellulose A gives xylose and auronic acid (not glucuronic acid) when hydrolysed ; the pentosan and uronicacid anhydride contents are 81.4 and 10.4%, respectively.a Hydrolysis ofextractive-free aspen sawdust yields L-rhamnose, L-arabinose, D-xylose,D-galactose, xylobiose, xylotriose, 4-methyl D-glucuronic acid, D-galacturonicacid, ~-a-(4-methy~-~-g~ucuronosy~)-a-D-xy~ose, and several unidentifiedacidic fractions of higher molecular weight.85 The uronic acid anhydrideand pentosan contents of hemicellulose fractions of hays and straws havebeen compared for different plant families and for members of the samefamilies.86Pectic Substances, Gums, and Mucilages.-Chromatographic methods areassisting the elucidation of enzyme actions on pectic substan~es.~~-8~ Withtheir aid crystalline mono-, di-, and tri-galacturonic acids have been isolatedfrom the products of polygalacturonase action on pectic a ~ i d . 8 ~ ~ 8* Bysso-chlamys fulva has been shown to produce a pectin esterase and a poly-galacturonase.% This year has revealed that the problems to be faced instudies of the enzymic degradation of pectic materials are even more complexthan had been realised previously, as the following four examples show.First, a pectin depolymerase of Neurospora crassa differs from others reportedearlier in that it yields lower polyuronides, rather than galacturonic acid, asend products, and also in that it degrades pectin without preliminary de-rnethylati~n.~~ Secondly, Aspergillus foetidus utilises at least two enzymesto effect the conversion of pectic acid into galacturonic acid; one producesdi- and tri-uronides, which serve as substrates for the other.89 Thirdly, apolymethylgalacturonase from commercial " hydralase,' which attackspectin more rapidly than pectic acid, cannot hydrolyse more than 26% ofthe available uronide bonds of the pectin.92 Fourthly, Schubert 93 claimsto have shown with certainty the presence of at least four different poly-galacturonases in extracts of a single culture of Aspergillus niger.The monomethyl aldobiuronic acid which, together with 4-methylD-glucuronic acid, results from controlled hydrolysis of mesquite gum,%is now known to be 6-p-(4-methyl D-glucuronosyl) ~-galactopyranose.~~Acidic hydrolysis of Khaya grandifolia gum gives galactose and a degraded83 R.L. Whistler, J. Bachrach, and Chen-Chuan Tu, J . Amer. Chem. Soc., 1952, 74,3059 ; R. L. Whistler and Chen-Chuan Tu, ibid., p. 4334.84 I. R. C. McDonald, J . , 1952, 3183.s 5 J. K. N. Jones and L. E. Wise, ibid., pp. 2750, 3389.8 6 C. A. Flanders, Arch. Biochem., 1952, 36, 421, 425.87 H. J. Phaff and B. S. Luh, ibid., p. 231.8 8 H. Altermatt and H. Deuel, Helv. Cham. Acta, 1952, 55, 1422.8s A. Ayres, J. Dingle, A. Phipps, W. W. Reid, and G. L. Solomons, Nature, 1952,~41 E. Roboz, R. W. Barratt, and E. L. Tatum, J . Biol. Chem., 1952, 195, 459.93 E. Schubert, Nature, 1952, 169, 931.y* F.Smith, J., 1951, 2646.95 M. Abdel-Akher, F. Smith, and D. Spriestersbach, J., 1952, 3637.170, 834. W. W. Reid, Biochenz. J., 1952, 50, 289.C. G. Seegmiller and E. F. Jansen, ibid., p. 327BOURNE : MACROMOLECULES. 245polysaccharide containing galactose, rhamnose, and galacturonic acid units ;Anogeissus schiwperi gum yields arabinose, galactose , and a degraded poly-saccharide containing arabinose , galactose, and glucuronic acid residuesg6A polysaccharide of Lapinus termis seeds consists of D-galactose, L-arabinose,and galacturonic acid residuesg7Hyaluronic Acid.-Methods for the isolation of hyaluronic acid withtrichloroacetic acid,98 and for the determination of hyaluronidase activity 99have been reported.The polysaccharide has been obtained from the callustissue of healing rabbit fractures.lW Attempts have been made to find thebest method for the isolation, without degradation, of the protein-hyaluronicacid complex of ox sinovial fluid.lo1 About 93% of the complex wasaccounted for in terms of N-acetylglucosamine, glucuronic acid, protein, andash; its particle weight is ca. lo7. Methylation and methanolysis of hyal-uronic acid have been studied.lo2 The crystalline disaccharide, preparedpreviously from hyaluronic acid,lo3 has been shown to be 3-p-D-glUCO-pyruronosyl-D-glucosamine by its conversion into 2-p-~-glucopyranosyl-D-arabinose, which has been obtained also from laminaribio~e.1~~ Infra-redspectroscopy has confirmed the presence in hyaluronic acid of free carboxylgroups and monosubstituted amides ; none of the hydroxyl groups is acetyl-ated.g Purified testicular hyaluronidase converts the polysaccharide intoa mixture of oligosaccharides, but the crude testicular extract givesglucuronic acid and N-acetylglucosamine.1°5 A trisaccharide constituent ofthe oligosaccharide mixture, when treated with glucosaminidase, affordsN - ace t y lglucosamine and a glucuronosy1-N- ace t y lglucosamine .lo Tracerexperiments suggest that the glucosamine moiety of the polysaccharide arisesfrom glucose during biosynthesis.lo6Other Po1ysacchandes.-Alginates have been examined with respect toviscosity 107 and electrolyte absorption.108 It has been confirmed that theirmain structural feature is a chain of 1 : 4-linked p-D-mannuronic acidresidues.lo9 A useful method developed for fractionation of the cell carbo-hydrates of yeast is applicable to as little as 10 mg.of material.ll* Theoccurrence of L-fucose, rhamnose, and methylated carbohydrates in soil hasbeen reported.111 It is interesting that, whereas L-arabinose had been foundpreviously in polysaccharides only in the furanose form, independentresearches have now revealed the presence of the pyranose form in larchE-galactan, 112 and in sapote gum. 113 An electrophoretically pure non-s6 R. J. McIlroy, J., 1952, 1918.s8 W. E. Jancsik and E. Kaiser, Nature, 1952, 169, 114.8s R. L. Greif, J . Biol. Chem., 1952, 194, 619; J. G. Bachtold and L. P. Gebhardt,100 P. H. Maurer and S. S. Hudack, Arch.Biochem., 1952, 38, 49.Iol A. G. Ogston and J. E. Stanier, Biochem. J., 1952, 52, 149.lo2 R. W. Jeanloz, J . Biol. Chem., 1952, 19'9, 141; Helv. Chim. Acta, 1952, 35, 262.lo3 M. M. Rapport, B. Weissmann, F. Linker, and K. Meyer, Nature. 1951, 168, 996.lo4 B. Weissmann and K. Meyer, J . Amer. Chem. SOC., 1952, 74, 4729.1°5 A. Linker and K. Meyer, Fed. Prac., 1952, 11, 249.Io6 S. Roseman et al., ibid., p. 276.lo' M. L. R. Harkness and A. Wassermann, J., 1952, 497.lo8 I. L. Mongar and A. Wassermann, ibid., pp. 492, 500, 510.lo9 S. K. Chanda, E. L. Hirst, E. G. V. Percival, and A. G. Ross, ibid., p. 1833.110 W. E. Trevelyan and J. S. Harrison, Biochem. J., 1952, 50, 298.D7 W. Tadros and M. Kamel, ibid., p. 4532.ibid., p. 635.R. B. Duff, Chem.and Ind., 1952, 1104;J. K. N. Jones, Chem. and Ifid., 1952, 954!E. V. White, J. Amer. Chem.-Soc., 1952, 74, 3966.. Sci. Food Agric., 1952, 3, 140246 ORGANIC CHEMISTRY.reducing oligosaccharide from the cell wall of Corynebacterium diphtheriaeappears to contain two D-galactose residues, one of D-mannose, and three ofD-arabinose, but the molecular weight of such a molecule is only ca. 75% ofthat actually f0und.11~ Polysaccharides isolated from three fresh-wateralgz, NiteZZa, Oscillatoria, and Nostoc, were, respectively, a cellulose-likepolyglucosan, a polyglucosan of the amylopectin class, and a mucilaginousacidic polysaccharide containing at least six different monosaccharideunits. 115 Chondrosine, the component disaccharide of chondroitin sulphuricacid, has been characterised as 4-~(?)-[~-amino-2-deoxy-~-ga~actopyranosy~]D-glucuronic acid ; 116 in the heteropolymer, which is very probably linear,one sulphate acid ester group and the glycosidic attachment of the adjacentD-glucuronic acid unit are yet to be assigned between positions 3, 4, and 6of each chondrosamine residue.l16Nucleic acids.This year has been an important one in the development of nucleic acidchemistry, mainly as a result of contributions by Brown and Todd, and byMarkham and Smith.The former workers 117 showed that phosphorylationof 5’-trityl adenosine with dibenzyl chlorophosphonate (phosphorochloridate),followed by removal of the protecting groups, yielded two adenylic acids,seemingly identical with the isomeric adenylic acids a and b derived fromribonucleic acids ; evidence was presented for their formulation as adenosine-2’ and adenosine-3’ phosphate, although not necessarily respectively.Theirix$erconversion under acidic conditions into an equilibrium mixture of thetwo was explained by ready phosphoryl migration via an intermediate cyclicortho-structure ; there was no rearrangement under alkaline conditions.In these respects, there is a close parallel with the behaviour of glycerolmonopho~phates.~~7 On the other hand, it was recalled that glycerol a-(methylhydrogen phosphate) and triesters of phosphoric acid are unstable to alkali ;in the former case, the reaction probably proceeds via the neutral cyclictriester (V), which is hydrolysed immediately to methanol and the cyclicCH,*O\ yoFH-O/ \OH (VI)I P‘I ICH,.OH CH,*OHphosphate (VI), and this, in turn, gives glycerol a- and p-phosphate.l17Dialkyl phosphates, devoid of a hydroxyl function in proximity to thephosphoryl group, are stable to alkali.For these and other reasons, a simplestraight-chain polynucleotide sequence was represented as (VII), in whichthe individual nucleoside residues are shown briefly as C~F~--C~r~-Cp~ ;alkaline degradation was regarded as proceeding through an intermediate(VIII), followed by ready fission of the triester groups exchsively at theP-O-C,,, linkage, to give eventually a mixture of nucleoside-2’ and -3’phosphates.117 In addition to structure (VII) , in which -the polymericlinkage is shown joining the 3’- and 5’-positions, other structures withE.S. Holdsworth, Biochim. Siophys. Acta, 1952, 8, 110; 1952, 9, 19; T. J.Bowen, ibid., p. 29. 115 L. Hough, J. K. N. Jones, and W. H. Wadman, J . , 1952,3393.l l s M. L. Wolfrom, R. K. Madison, and M. J. Cron, J . Amer. Chew. Soc., 1952, 74,1491. 117 D M. Brown and A. R. Todd, J., 1952, 44, 52BOURNE MACROMOLECULES. 247C(,.)-C(,) or C,)-C,,.) links, or mixed C,)-C,, and C(r)-C(y) units insequence would all show alkali lability. A C(5')-C(5' linkage, however,cannot occur anywhere in the molecule as this would be stable to alkali andwould lead to the appearance of dinucleotides in ribonucleic acid hydro-1 y ~ a t e s . l ~ ~ Reasons were given for believing that CC5,) is involved in themain internucleotide linkage of both ribonucleic and deoxyribonucleic acids,thus restricting the choice of linkage to C,,)-C,,) and C(r)-C,,).Sincedeoxyribonucleic acids cannot be of the former type, it was regarded asadvantageous, at the moment, to represent the " backbone " of ribonucleicacids as (VII). Deoxyribonucleic acids are not degraded to small moleculesby mild treatment with alkali because the essential formation of a cyclicstructure is prec1uded.l'Brown and Todd 1 1 7 pointed out that, although deoxyribonucleic acidsappear to be largely straight-chain polynucleotides, ribonucleic acids probablyhave a branched-chain structure. They considered the known productionof large amounts of pyrimidine nucleotides during ribonuclease treatment ofribonucleic acids to suggest that these nucleotides are derived from short sidechains, which occur at frequent intervals and probably for the most partcontain only one nucleoside residue.Accordingly, they envisaged a possiblegeneral structure for ribonucleic acid as (IX), an extension of (VII).(IX) a and b are pyrimidine nucleoside residues; P represents a phosphate group.Further experimental support for the above concepts of the architectureof the ribonucleic acid molecule was obtained subsequently. The cyclic2' : 3'-phosphates of adenosine, cytidine, and uridine were prepared 118 fromthe corresponding 2'- and 3'-phosphates, by the widely applicable esteri-D. M. Brown, D. I. Magrath, and A. R. Todd, J., 1952, 2708248 ORGANIC CHEMISTRY.fication process promoted by trifluoroacetic anhydride.l19 With acid oralkali, the cyclic esters gave mixtures of the a and b nucleotides.ll* Ribo-nuclease converted cytidine-2’ : 3’-phosphate into cytidylic acid b, anduridine-2’ : 3’ phosphate into uridylic acid b, but it hadno action on adenosine-2’ : 3’ phosphate; 120 these observations accord well with the fact that thereis little or no purine nucleotide in the mononucleotide fraction of ribonucleasedigests of ribonucleic acids.120p 121 The conversion of cytidylic acid b intouridylic acid b, by alkaline deamination, indicated that the phosphorylgroup in each of these two compounds occupies the same position in theribofuranose residue.12*Markham and Smith, who had already observed 122 that a new class ofnucleotide appears during the digestion of ribonucleic acid with ribonuclease,have extended their studies 123 and have provided excellent confirmation ofpart of the theory of Brown and Todd.l17 They have shown 123 that thenew class of nucleotide is, in fact, composed of nucleoside-2‘ : 3’ phosphates,which are formed also by mild alkaline hydrolysis of ribonucleic acid, andhave confirmed that the cyclic phosphates of pyrimidine, but not of purine,nucleosides are substrates for ribonuclease.In a more detailed analysis,based on chromatography and paper electrophoresis, methods were givenfor the isolation of fifteen of the smaller products formed from ribonucleicacid by ribon~clease.12~ The general structure of the dinucleotides was toy i-I’P voYr ‘1-1Py ’ O y‘1-1 Peither (X) or (XI) (Py = pyrimidine ; X = pyrimidine or purine) ; the3‘-phosphate groups shown may in fact have been 2’-phosphate groups.Thedinucleotides with a cyclic phosphate group were the first liberated, andwere then slowly transformed into the 3’(or 2’)-phosphates. The trinucleo-tides all contained at least one pyrimidine nucleotide residue. 123 Adenosine-2’ : 3’ phosphate, guanosine-2’ : 3’ phosphate, and adenylic, guanylic,cytidylic, and uridylic acids were all identified as end-groups in the ribo-nucleic acids of yeast and turnip yellow mosaicAC:U:C:U:C:C:AGAGC:U:C:C:AAGU:U:GU:U:C:C:GC:C:U:AGC:A(=I)In spite of such a large measure of agreement, Markham and Smith werenot able to accept the branched structure (IX) advanced by Brown and Toddfor ribonucleic acid. They believed the acid to be composed of a mixture110 E.J. Bourne, M. Stacey, J. C. Tatlow, and J. M. Tedder, J., 1949, 2976.l a o D. M. Brown, C. A. Dekker, and A. R. Todd, J . , 1952, 2715.I a r R. Markham and J. D. Smith, Nature, 1951, 168, 406.lee Idem, Research, 1951, 4, 344. lfS Idem, Bioclzem. J., 1952, 52, 552, 558, 585BOURNE : MACROMOLECULES. 249of many kinds of comparatively short chains, with the general features of(XII) in which A, G, C, and U represent adenylic, guanylic, cytidylic, anduridylic acid residues, respectively, each nucleoside being joined at position-2‘ (or -3‘) through a phosphate ester link to the adjacent residue on theright-hand side, and at position-5’ through a similar link to its neighbouron the left ; the bonds which are broken by ribonuclease are shown as colons.A purine nucleoside-2’ : 3‘ phosphate can be liberated only if it is situated atone end of the chain.la3 The ribonuclease-resistant “ core ” appears to bea mixture of polynucleotides about three to five residues in length, eachpolynucleotide consisting of a chain of purine nucleotides terminated by apyrimidine nucleotide residue, with the terminal phosphoryl group on C(z?or C,).The failure of this “ core ” to dialyse through Cellophane is dueapparently largely to its charge, rather than to its molecular size 123 (see alsoref. 127). Methylation evidence has been claimed to demonstrate that yeastribonucleic acid possesses internucleotide linkages between ribose andphosphoryl residues, and also that there is a high degree of branching, dueto triply phosphorylated ribose units.12* Several dinucleotides have beenisolated in an analytically pure state from acid-ireated yeast ribonucleicacid.la5 Studies have been made of the splitting of purine ribosides by botha hydrolytic and a phosphorolytic system found in autolysates of driedbaker’s yeast.126 A promising method for the degradation of ribonucleicacid, catalysed by methoxide ion, has been announced.126aDeoxyribonucleic acids have continued to receive considerable attention.Samples derived from animal, plant, and bacterial sources have been analysedcarefully,127* 128 as also have the enzyme-resistant “ cores ” produced there-from by deoxyribonuclease ; 127 a new pyrimidine base, 5-hydroxymethyl-cytosine, is present in bacteriophage nucleic acids. 128 The deoxypentose-nucleic acids from three different strains of E. coli possess unusual purine andpyrimidine ~ 0 n t e n t s . l ~ ~ Light-scattering techniques have revealed that themethod for the isolation of calf-thymus deoxyribonucleic acid developed bySchwander and Signer 130 is reproducible, and that the product has a highermolecular weight (6-7-8.0 x lo6) than have samples prepared in otherways 13’ (see also ref. 144) ; the shape of the molecule is greatly dependenton pH.I3l The irreversible decrease in the viscosity of deoxyribonucleicacid solutions, caused by phenol or urea, is attributed to the breakage ofhydrogen bonds.132 Ultrasonic waves have a similar effect, but in additionthere is some scission of the polynucleotide ~hain.l3~ Dilute acid and alkaliincrease the intensity of colour given by Schiff’s reagent ; this might possiblybe due to the rupture of labile C(r)-phosphate l i n k ~ . l ~ ~ Under mild acidic124 A. S. Anderson, G. R. Barker, J. M. Gulland, and M. V. Lock, J., 1952, 369.1z6 L. A. Heppel and R. J. Hilmoe, ibid., 1952, 198, 683.1260 D. Lipkin and J. S. Dixon, Science, 1952, 116, 525.lZ7 S. G. Laland, W. G. Overend, and M. Webb, J., 1952, 3224.lz8 G. R. Wyatt and S. S. Cohen, Nature, 1952, 170, 846, 1072.lz9 B. Gandelman, S. Zamenhof, and E. Chargaff, Biochim. Biophys. Acta, 1952, 9,399.130 H. Schwander and R. Signer, Helv. Chim. Acta, 1950, 33, 1521.131 M. E. Reichmann, R. Varin, and P. Doty, J . Amar. Chern. Soc., 1952, 74, 3203;132 B. E. Conway and J. A. V. Butler, J . , 1952, 3075.133 S. G. Laland, W. G. Overend, and M. Stacey, ibid., p. 303.134 W. A. Lee and A. R. Peacocke, ibid., p. 130.R. B. Merrifield and D. W. Woolley, J . Biol. Chem., 1952, 197, 521.I?. Doty and B. H. Bunce, ibid., p. 5029250 ORGANIC CHEMISTRY.conditions purines can be removed quantitatively from calf-thymus deoxy-ribonucleic acid, without completely destroying the original highly poly-merised structure and without changing the distribution of the pyrimidinenucleo t ides. 135The nucleotides and dinucleotides resulting from deoxyribonucleaseaction on the deoxyribonucleic acids of calf thymus,136 wheat embryo, 137and herring sperm 137* 138 have been examined; in one case 5'-deoxycytidylicacid was identified in the digest. 139 An ion-exchange chromatographicprocedure, suitable for use on a large scale, has been described for theseparation of deoxyrib~nucleosides.~~~ Earlier assumptions that sodiumarsenate, sodium citrate, and sodium borate (known inhibitors of pancreaticdeoxyribonuclease) inhibit intra-cellular deoxypentosenucleases of mam-malian tissues have been shown to be invalid.140It has been demonstrated, by indirect methods, that enzyme preparationsfrom Lactobacillus helveticus, Lactobacillus delbrueckii, and Thermobacteriumacidoplzilus R. 26 catalyse the transfer of the deoxyribose residue from onepurine or pyrimidine to another.141 These enzyme(s) are trans-N-glycos-idases ; they are unable to utilise either deoxyribose or deoxyribose-1ph0~phate.l~~ Among other topics studied are (a) the binding of sodiumchloride 142 and mercuric chloride 143 with calf-thymus deoxypentosenucleate,and (b) the spectrophotometry of this nucleic acid,144 and of natural andsynthetic pyrimidine ribo- and deo~yribo-nucleosides,1*~ as a function of pH.Proteins.Since the chemistry of proteins was covered very fully in the AnnualReports for 1951, only brief reference to the subject will be made this year.The formidable task of condensing such a vast field into so small a space canbest be accomplished by drawing attention to useful reviews of currentresearches; five such reviews, published during 1952, give a fairly compre-hensive picture of the present position. Writing from the viewpoint of theorganic chemist, Khorana 146 has surveyed structural investigations, andchemical methods of synthesis of polypeptides and proteins. Edsall 147has provided a concise account of a Royal Society Discussion, in which themain emphasis was on the contributions of X-ray and infra-red techniquesto the problem of the structural pattern of the polypeptide chains in proteins.Particular attention was paid to synthetic poly-y-methyl L-glutamate fibres,and it was concluded 147 that, although further work is certainly needed, thebalance of evidence on these synthetic polypeptides seems to be in favour ofthe a-helix. In a survey of recent developments in the separations of pro-teins and enzymes by paper chromatography, Boman 148 laid stress on theR. L. Sinsheimer and J . F. Koerner, J. Amer. Chem. SOG., 1952, 74, 283.J . D. Smith and R. Markham, Nature, 1952, 170, 120; Biochim. Biophys. Acta,139 J . L. Potter, K. D. Brown, and M. Laskowski, Biochim. Biophys. Acta, 1952,141 W. S. Macnutt, Biochem. J., 1952, 50, 384.142 J. Shack, R. J. Jenkins, and J. M. Thompsett, J . Biol. Chem., 1952, 198, 85.143 S. Katz, J. Amer. Chem. SOG., 1952, 74, 2238.144 J. Shack and J. M. Thompsett, J . Biol. Chem., 1952, 197, 17; G. Frick, Biochim.14* H. G. Khorana, Quart. Reviews, 1952, 6, 340.147 J. T. Edsall, Nature, 1952, 170, 53.135 C: Tamm, M. E. Hodes, and E. Chargaff, J. Biol. Chem., 1952, 195, 49.1952, 8, 350.9, 150.138 W. Andersen, C. A. Dekker, and A. R. Todd, J., 1952, 2721.140 M. Webb, Nature, 1952, 169, 417.Biophys. Ada, 1952, 8, 625. 145 D. Shugar and J. J . Fox, ibid., 1952, 9, 199, 369.148 H. G. Boman, ibid., p. 703BOURNE MACROMOLECULES. 251phenomenon of ‘‘ double-fronting.” An interesting discussion u9 of thephysical chemistry of proteins ranged over such topics as the globular-fibrous protein transformation, zone electrophoresis in filter-paper, mechan-isms of muscular action, the conversion of fibrinogen into fibrin, muco-proteins, nucleopro teins , ant igen-an t ibod y reactions, and protein inter-actions with heavy metals, alkaline earths, heparin, and other organicmolecules. The biogenesis of proteins was the subject of a symposium inParis. 150E. J. B.A. S. BAILEY.E. J. BOURNE.J. W. CORNFORTH.T. G. HALSALL.T. J. KING.J. F. W. MCOMIE.R. A. RAPHAEL.J. WALKER.W. A. WATERS.B. C. L. WEEDON.149 The Physical Chemistry of Proteins, Discuss. Faraday Soc., 1952.lLo Symposium on the Biogenesis of Proteins, 2nd Internat. Congr. Biochem., Paris,1952