ORGANIC CHEMISTRY.1. INTRODUCTION.Tms Report begins with a review of developments in theoretical organicchemistry. In this field, important studies of heats of hydrogenation ofcyclic molecules have advanced knowledge of the contributions of conjug-ation, hyperconjugation, and steric strain in such systems. Notable develop-ments in understanding of the detailed reaction paths of multi-stage reactionshave occurred during recent years through examination of isotope effects onrates and products of reaction, and by correlation of reactivities with acidityfunctions appropriate to various types of ionisation ; numerous exampleshave been noted in the present Report, which focuses particular attentionon aromatic substitution and on nucleophilic displacements at a saturatedcarbon atom, since these subjects were not discussed last year.Conformational analysis receives special attention in the Report onstereochemistry. Notable advances have been made in the aliphatic fieldby tracer studies which indicate the mode of incorporation of mevalonic acidinto a number of natural products related to squalene.Mechanistic studiesof the effects of neighbouring aryl groups in nucleophilic displacements haveled to the isolation of some interesting spiro-dienones.Successful syntheses of note include those of penicillin V, pentacyclo-squalene, and onocerin derivatives. In the terpene field sesquiterpenescontinue to attract attention. The products resulting from irradiation ofap-unsaturated ketones and cross-conjugated dienones are being intensivelystudied and often have unusual structures.Other intriguing compoundsare 1 : 2 : 3-triphenylcyclopropenyl fluoroborate and the macrocyclic poly-acetylene resulting from the trimerisation of o-diethynylbenzene.Much progress has been made in establishing the sequence of amino-acids in enzymes, particularly for ribonuclease. The Report of carbo-hydrates focuses attention on mechanistic and conformational aspects ofmono- and di-saccharide chemistry. Oligo- and poly-saccharides as well asnucleic acids will be discussed next year. -r. G. H.P. R. D. DE LA M.2. THEORETICAL ORGANIC CHEMISTRY.SEVERAL recent review articles and books are of considerable value to thoseinterested in the mechanisms of organic reactions.Steric effects in organicchemistry have been surveyed.l Leffler has discussed the properties andmethods of identification of transient intermediates in chemical reactions.Paul and Long’s reviews clarify consideration of the applicability of theHammett and related acidity functions to chemical problems.“ Steric Effects in Organic Chemistry,” ed. M. S. Newman, Wiley, New York,J. E. Leffler, “ The Reactive Intermediates of Organic Chemistry,” Intersciencea M. A. Paul and F, A, Long, Chem. Rev., 1957, 57, 1; F. A. Long and M. A. Paul,1956.Publ. Inc., New York, 1956.ibid., p. 93514s ORGANIC CHEMISTHY.Applications of Spectroscopy.-Equilibria of the types :Py + ICI * PyICI; 2PylCI * Py,l+- + ICI,--have been studied spectrophotometrically in carbon tetrachloride and aceto-nitrile as solvents.* Examination of equilibria of the benzoquinolines withbromine provides evidence for the existence of charge-transfer complexes inthese systems, as also in the related complexes with sodium.5 The lessfirmly bound complexes between aromatic compounds and halogens havebeen investigated in two ways: (a) through their infrared spectra; theobservations have been interpreted as indicating that these complexes havec 6 V axial symmetry,6 wherein the halogen axis is coincident with the benzeneC, axis; and (b) through their ultraviolet spectra; 7 a general theoreticaldiscussion of these and related systems is available.* Such complexes areimportant in that they may be involved in many chemical reactions ofhalogens with olefinic and aromatic compounds, such as the iodine-catalyseddimerisation of 1 : l-diphenylethylene.gThe degree of conjugation between the nuclei in derivatives of diphenyldepends partly on the magnitude of steric interactions between atoms andgroups in the 2 : 2'-positions.Careful spectroscopic investi-~ c ~ r k - ~ r gations show, however, that electronic effects are often so im-portant that spectral measurements do not always give a reliableestimate of the angle between the planes of the aromatic rings.1°The spectra of aromatic sulphides, sulphoxides, and related compoundshave been discussed,ll particularly with reference to conjugation betweensulphur and adjacent unsaturated groupings by way of expansion of theoctet of the sulphur atom.It was concluded, for example, that conjugationas indicated in formula (I) does not contribute significantly to the structureof such compounds as p-Me,N°C,H,*S*C6H,*No2-~.Stereochemical Effects on Mesomerism.-The ultraviolet spectra of nitro-substituted aromatic carbonyl compounds l2 give evidence for steric in-hibition of mesomerism by ortho-substituents. The dipole moments,partidarly of substituted nitro-compounds, also provide additional evidencefor this type of modification of conjugation.l39 l4 Comparison of ultravioletand infrared absorption spectra, molecular refraction, basic strength, andreactivities of derivatives of nitrobenzene and aniline all show deviationsFormylferrocene has been obtained by treatment of ferrocene with N -methylformanilide and phosphorus oxychloride,ll0* u and from ferrocenyl-methyltrimethylammonium iodide by treatment with hexamine 112 or byhydrolysis to ferrocenylmethanol followed by oxidation with manganesed i 0 ~ i d e .l ~ ~ While it shows many normal aldehyde reactions, fonnylferroceneis surprisingly basic and has not yet been successfully oxidised to thecarboxylic acid. The substance obtained by rearrangement of ferrocenyl-methyltrimethylammonium iodide by treatment with potassamide is now 11*assigned the structure (65). Ferrocenylmethanols have an unusually labilehydroxyl group ; thus a-ferrocenylbenzyl alcohol is converted into themethyl ether in boiling methan01.l~~ Cyclisation of p-ferrocenylpropionic101 K. L. Rinehart and K.L. Motz, Chem. and Ind., 1957, 1150.102 R. E. Benson and R. V. Lindsey, J. Amer. Chem. SOL, 1957, 79, 5471.108 D. S. Trifan and L. Nicholas, ibid., p. 2746.104 A. N. Nesmeyanov, Doklady Akad. Nauk S.S.S.R., 1957, 112, 439.lo6 M. Rausch, M. Vogel, and H. Kosenberg, J. Org. Chem., 1957, 22, 900.106 D. W. Mayo, P. D. Shaw, and M. Rausch, Chem. and Ind., 1957, 1388.107 M. Vogel, M. Rausch, and H. Rosenberg, J. Org. Chem., 1967, 22, 1016.108 A. N. Nesmeyanov and N. S. Kotchetkova, Duklady Akad. Nauk S.S.S.R.,lo9 K. L. Rinehart, K. L. Motz, and S. Moon, J. Amer. Chem. SOL, 1957, 79, 2749.111 P. J. Graham, R. V. Lindsey, G. W. Parshall, M. L. Peterson and G. M. Whit-112 G. D. Broadhead, J . M. Osgerby, and L. R. Pauson, Chem. and Ind., 1957, 209.l13 J.K. Lindsay and C. R. Hauser, J . Org. Chem., 1957, 22, 355.114 C. R. Hauser, J . K. Lindsay, D. Lednicer, and C. E. Cain, ibid., p. 717.116 N. Welicky and E. S. Gould, J. Amer. Chem. SOC., 1957, 79, 2742; M. Rausch,1956,109, 543.M. Rosenblum, Chem. and Ind., 1957, 72.man, J. Amer. Chem. SOC., 1957, 79, 3416.M. Vogel, and H. Rosenberg, J. Org. Chem., 1957, 22, 903SCHOFIELD HETEROCYCLIC COMPOUNDS. 239acid (66; n = 2) gives the bridged ketone (67), whereas y-ferrocenylbutyricacid (66; n = 3) and 6-ferrocenylvaleric acid (66; n = 4) undergo homo-annular cyclisation 116 to ketones of type (68). Ferrocenyl-substituteda-amino-acids have also been prepared.l17“ Sandwich ” structures have been obtained in which a metal atom islinked to both a cyclopentadiene ring and a benzene ring; e.g., the action ofphenylmagnesium bromide on methylcycZopentadienylmanganese chloride orbismet hylcyclopent adien ylmanganese gives the complex MeC,H,*Mn , C6H6 .llThe benzene-diphenylchromium cation , [C6H6-Cr(C6H,*C6H,)] +, is formed inthe reaction of phenylmagnesium bromide with chromium chloride or by thereductive Friedel-Crafts synthesis from a mixture of benzene and di~henyl.1~~Pyrolysis of the mercuri-iodide affords benzene and diphenyl in practicallyquantitative yield.120 The stability of the iron complexes of methylbenzenesincreases with the number of methyl groups attached to the benzene ring.121Attempts to apply typical aromatic substitution reactions to dibenzene-chromium(0) led to disruption of the molecule.122R.F. G.8. HETEROCYCLIC COMPOUNDS.MONOGRAPHS on polyazines and phenazines,l and two further volumes ofElderfield’s series have appeared. p - l a ~ t a m s , ~ phenanthridine~,~ hetero-aromatic N-oxides,h and meso-ionic compounds 46 have been reviewed.116 K. L. Rinehart and R. J. Curby, J . Amer. Chem. SOC., 1957, 79, 3290; K. L.Rinehart, R. J. Curby, and P. E. Sokol, ibid., p. 3420.117 K. Schlogl, Monatsh., 1957, 88, 601; C. R. Hauser and J. K. Lindsay, J . Org.Clzem, 1957, 22, 1246.118 T. H. Coffield, V. Sandel, and R. D. Closson, J . Amer. Chem. SOC., 1957, 79,5826.lls F. Hein and H. Muller, Chem. Ber., 1956, 89, 2722; F. Hein and K. Eisfeld, 2.anorg. Chem., 1957, 292, 162; F. Hein, P. Kleinert, and E.Kurras, ibid., 1957, 289,229; H. H. Zeiss and M. Tsutsui, J , Amer. Chem. SOC., 1957, 79, 3062.120 F. Hein and E. Kurras, 2. anorg. Chem., 1957, 290, 179.121 M. Tsutsui and H. H. Zeiss, Naturwiss., 1957, 44, 421.lZ2 H. P. Fritz and E. 0. Fischer, 2. Naturforsclz., 1957, 12b, 67.J. G. Erickson, P. F. Wiley, and V. P. Wystrach, “The Chemistry of Hetero-cyclic Compounds. Vol. 10. The 1 : 2 : 3- and 1 : 2 : 4-Triazines, Tetrazines, andPentazines,” Interscience Publ. Inc., New York, 1957, and “ Vol. 11. The Phenazines,”by G. A. Swan and D. G. I. Felton, in the same series.R. C. Elderfield (editor), “ Heterocyclic Compounds. Vol. 5. Five-MemberedHeterocycles Containing Two Hetero Atoms, and Their Benzo Derivatives,” and “ Vol.6. Six-Membered Heterocycles Containing Two Hetero Atoms, and Their BenzoDerivatives,” John Wiley and Sons, Inc., New York, 1957.Vol.IX,” p. 388, JohnWiley and Sons, Inc., New York, 1957.3 J. C. Sheehan, and E. J. Corey, “ Organic Reactions.4 J. Eisch and H. Gilman, Clzem. Rev., 1957, 57, 525.40 A. R. Katritzky, Quart. Rev., 1956, 10, 395.W. Baker and W. D. Ollis, ibid., 1957, 11, 15240 ORGANIC CHEMISTRY.Small Rings.-Alkaline hydrogen peroxide converts a-methylstyreneepoxide into acetophenone.6 Five- and six-membered cyclic ethers form1 : l-complexes with boron trichloride, whilst three- and four-memberedcompounds are cleaved to (chloroa1koxy)boron esters.6 Hydride reduction 7of oxetans (derivatives of 1) having two or fewer alkyl groups causescleavage between the oxygen and the less substituted carbon atom.3 : 3’-Bischloromethyloxetan with sodium sulphide gives the spiran (2) whichforms a sulphone.8More oxazirans (3) have been prepared,1° and a comprehensive accountof their properties has been given.ll Proof of structure depends onhydrolysis to aldehydes and N-alkylhydroxylamines, comparison with,and isomerisation to, nitrones, and resolution of 3-isobutyl-3-methyl-2-propyloxaziran.Ketens with azomethines have given a variety of @-lactams.12Five-membered Rings-Pyrroles. N-Substituted pyrroles result fromthe action of primary amines upon 1 : 4-bisdimethylaminobuta-1 : 3-diene,13ora’-dibromoadiponitrile,14 and 1 : 2 : 3 : 4-tetrabromob~tane.1~ Methyl-pyrroles can be prepared by reduction of pyrrole Mannich bases.16 Avariation of the Knorr pyrrole synthesis consists in the reduction of phenyl-azo-derivatives of p-dicarbonyl c0mpounds.1~ Porphobilinogen (4 ; R =CH,*NH,, R’ = H) has been synthesised by several methods 18 from thealdehydo-ester (diethyl ester of 4; R = CHO, R’ = C0,Et).Tripyrryl-methenes are readily obtained from pyrrolecarboxylk acids (or their tert.-butyl esters) and pyrroles in the presence of phosphoryl ch10ride.l~Treibs and his co-workers have demonstrated the basic properties ofmany pyrrole derivatives, and, contrary to current views, stress the impor-tance of these properties in influencing reactions in this series.20 In theC-acylation of N-methylpyrrole by ethylmagnesium bromide and acylJ. Hoffman, J . Amer.Chern. SOC., 1957, 79, 503.6 J. D. Edwards, W. Gerrard, and M. F. Lappert, J., 1957, 348.7 S. Searles, jun., K. A. Pollart, and E. F. Lutz, J . Amer. Chem. SOL, 1957, 79,* T. W. Campbell, J . Ovg. Chem., 1957, 22, 1029.0 Cf. Ann. Reports, 1956, 53, 229; Farbenfabriken Bayer, B.P. 743,940/1953 and948; S. Searles, jun., K. A. Pollart, and F. Block, ibid.. p. 952.other patents.10 L. Homer and E. Jurgens, Chem. Ber., 1957, 90, 2184.11 W. D. Emmops, J . Amer. Chem. SOL, 1957, 79, 5739.12 (a) W. Kirmse and L. Homer, Chem. Ber., 1956, 89, 2759; (b) R. Pfleger and A.13 M. F. Fegley, R. M. Bortnick, and C. H. McKeever, J . Amer. Chem. SOC., 195714 A. Treibs and F. Neumayr, Chem. Ber., 1957, 90, 76.16 A. Treibs and 0. Hitzler, ibid., p. 787.l6 A.Treibs and R. Zinsmeister, ibid., p- 87.17 A. Treibs, R. Schmidt, and R. Zinsmeister, ibid., p. 79.18 A. H. Jackson and S. F. MacDonald, Canad. J. Chem., 1957, 35, 715.1s A. Treibs and K. Hintermeier, Annulen, 1957, 605, 35.20 A. Treibs and H. G. Kolm, ibid., 1957, 606, 166; A. Treibs, E. Herrmann, E.Jager, ibid., 1957, 90, 2460.79, 4144.Meissner, and A. Kuhn, ibid., 1957, 60% 163SCHOFIELD : HETEROCYCLIC COMPOUNDS. 241chlorides, probably a Friedel-Crafts type reaction, ethylmagnesium bromidecan be replaced by magnesium bromide.21 Nitration of pyrrole gives 3-as well as 2-nitr0pyrrole,~~ and rather unexpectedly thiocyanation of pyrrolegives 3-thiocyanopyrrole.23Pyrrole trimer is proved to have structure (5) by degradation to 1 : 4-di-2 '-pyrrolylbutane .24 Netropsin (antibiotic T-1384, congocidine) is assignedMethe structure [6; R = C(:NH)*CH,*NH*C(:NH)*NH,J ; the chief products ofalkaline hydrolysis [6; R = H; and R = CO*CH2*NWC(:NH)-NH2] havebeen synthe~ised.~~Mild reduction of 4 : 4-dimethyl-5-nitropentan-%one gives 2 : 4 : 4-trimethyl-Al-pyrroline l-oxide (7). This and 4 : 5 : 5-trimethyl-Al-pyrrolinel-oxide 26 are the first non-aromatic monomeric nitrones.The 2-methylgroup in compound (7) undergoes base-catalysed condensation with aromaticaldehydes. Pyrrolid-3-one and 3-hydroxypyrrolidine have been preparedfrom l-ethoxycarbonylpyrrolid-3-0ne.~~Fzcrans. Adducts (8) from acetoacetic ester and a-nitro-olefins givefurans in the Nef reaction.28 Furans with free a-positions are readilyformylated by dimethylformamide and phosphoryl ch10ride.~~ Perillaketone has been synthesised from diisopentylcadmium and furan-l-carbonylchloride.30 The compound formed from pyruvic acid and benzylidene-aniline, previously taken to be a dioxopyrrolidine, has been re-formulated 31The reaction between furfuryl alcohol and methanolic hydrogen chloridegives, not 8-, but or-methoxylzvulaldehyde dimethyl a ~ e t a l .~ ~ Conversionof 5-aminomethylfurfuryl alcohol into 5-hydroxy-2-methyIpyridine byacid, and related reactions, have been reported.33(9).21 W. Herz, J. Org. Chem., 1957, 22, 1260.22 €3. j. Anderson, Canad. J. Chem., 1957, 35, 21.28 D. S. Matteson and H. R. Snyder, J. Org. Ghem., 1957, 22, 1500; J. Amer. Chew.SOL, 1957, 79, 3610.24 H.A. Potts and G. F. Smith, J., 1957, 4018.25 C. W. Waller, C. F. Wolf, W. 3. Stein, and B. L. Hutchings, J . Amer. Chem. SOC.,1957, 79, 1265; M. J. Weiss, J. S. Webb, and J. M. Smith, jun., ibid., p. 1266; seealso E. E. van Tamelen and A. D. G. Powell, Chem. and Ind., 1957, 365.26 R. F. C. Brown, V. M. Clark, and Sir Alexander Todd, Proc. Chem. Soc., 1957, 97.27 R. Kuhn and G. Osswald, Angew. Chem., 1957, 69, 60.28 F. Boberg and G. R. Schultze, Chem. Ber., 1957, 90, 1215.29 V. J. Traynelis, J. 3 . Miskel, jun., and J. R. Sowa, J. Org. Chew., 1957, 22, 1269.30 T. Matsuura, Bull. Chem. SOC. Japan, 1957, 30, 430.31 H. H. Wasserman and R. C. Koch, Chem. and Ind., 1957, 428.82 K. G. Lewis, J., 1957, 531; L. Birkofer and R.Dutz, Annaleua, 1957, 608, 7 .88 N. Elming and N. Clauson-Kaas, Acta Chem. Scand., 1956,10, 1603; N. Elming,ibid., p. 1664242 ORGANIC CHEMISTRY.Thiophens. Re-investigation of the oxidation of 3-thienylmagnesiumbromide disclosed a small yield of the unstable 3-hydroxythiophen which,unlike the 2-isomer, is appreciably phenolic. Hofmann decomposition of3-dimet hylaminomet hyl-4-methylenethiophan gave 3 : 4-dimethylthiophenrather than 3 : 4-dirnethylenethio~han.~~(10) ( I I) (12)Azoles. Details of an earlier synthesis of cycloserine (10) have beengiven and other new syntheses, one based on methyl N-triphenylmethyl-aziridine-2-carboxylate, are reported.36 Dichloroglyoxime with acetylenicGrignard reagents gives 3 : 3‘-diisoo~azolyl.~~ 4-Chloromethylene-2-phenyl-oxazol-&one reacts with organometallic reagents to give azla~tones.~~Oxazol-%ones, with organometallic reagents (e.g., R4MgBr) form ct-acyl-amino-ketones which are converted by strong acids into oxazoliumsalts 39 (1 1).A3-Thiazolines can be obtained from ketones by means of ammonia andsulphur, or from ammonia and ct-mercapto-ketones.With acetone theyield is poor and some dihydro-2 : 2 : 4 : 6 : 6-pentamethyl-1 : 3-thiazineis formed (see below). A3-Thiazolines with hydrogen atoms at andR-C -CR‘s-sare readily dehydrogenated to thia~oles.~~ Acid anhydrides (R’CO) 2Oconvert N-thiobenzoylsarcosine and N-ethyl-N-thiobenzoylglycine intomesoionic compounds (12; R = Me and Et respectively).*l 2 : 2’-Thia-zoloin exists as the orange e n e - d i ~ l .~ ~Degradation of bottromycin has provided the new amino-acid p-2-thia~olyl-p-alanine.~~ Among the products of acid degradation of another34 M. C . Ford and D. Mackay, J., 1956, 4985.35 C. S. Marvel, R. M. Nowak, and J. Economy, J . Awzer. Chem. SOL., 1956, 78,6171.86 Ann. Reeorts, 1955, 52, 232; C. H. Stammer, A. N. Wilson, C. F. Spencer,F. W. Bachelor, F. W. Holly, and K. Folkers, J . Amer. Chem. SOL, 1957, 79, 3236;J. Smrt, J. Beranek, J. Sicher, and F. Sorm, CoZZ. Czech. Chem. Comm., 1957, 22, 262;P. A. Plattner, A. Boller, H. Frick, A. Fiirst, B. Hegediis, H. Kirchensteiner, St.Majnoni, R. Schlapfer, and H. Spiegelberg, HeZv. Chim. Acta, 1957, 40, 1531.37 A. Quilico, G. Gaudiano, and A. Ricca, Gazzetta, 1957, 87, 638.38 H.Behringer and H. Taul, Chem. Ber., 1957, 90, 1398.39 R. Gompper, ibid., p. 374.40 F. Asinger, M. Thiel, and E. Pallas, AnnuZen, 1957, 602, 37; M. Thiel and F.Asinger, ibid., 1957, 610, 17; F. Asinger, M. Thiel, and I. Kalzendorf, ibid., p. 25;F. Asinger, M. Thiel, and G. Esser, ibid., p. 33; F. Asinger, M. Thiel, and L. Schroder,ibid., p. 49.41 A. Lawson and C . E. Searle, J., 1957, 1556.42 H. Beyerand U. Hess, Chem. Ber., 1957, 90, 2435.43 J. M. Waisvisz, M. G. van der Hoeven, and B. Te Nijenhuis, J . Amer. Chem.SOC., 1957, 79, 4524SCHOFIELD : HETEROCYCLIC COMPOUNDS. 243antibiotic, micrococcin P, are Z-propionyl- and (+)-2-( l-amino-Z-methyl-propyl)-thiazole-4-carboxylic acid, and a complex polythiazole, which areconsidered to arise from the incorporation of cysteine and other amino-acids in a peptide chain.44Bases convert arylsulphonylhydrazones of type (A) into pyra~oles.~~( A ) R*CH:CH*CN:N*NH*SO,*Ar (B) Ph*CH2*CH,*O*CO*CH,*NH*CH:NHn-Butyl-lithium metalates 4g N-substituted glyoxalines at position 2.Liberated from its hydrochloride, N- (phene t hylox ycarbonylme t hyl) amidine(B) cyclises to the highly reactive 4 : 5-dihydro-5-oxoglyoxaline (13) which isprobably an intermediate in the enzymic degradation of ~anthine.~’ 4-Nitro- and 4-amino-5-glyoxalinyl-sulphones , and 4-amino-1 : 2 : 3-triazole-5-carboxyamide, have been synthesised 48 as possible antagonists of the inter-mediate in purine biosynthesis, 4-aminoglyoxaline-5-carboxyamide.Thesuggestion that the glyoxaline nucleus of histidine is important in the activityof hydrolytic enzymes is supported by the peculiar effectiveness of glyoxalineas a catalyst of ester hydroly~is.~~ The urea, NN’-carbonyldiglyoxaline(14), and its triazole analogue are highly reactive, giving carbonic esterswith alcohols and phenols, and ureas with amines.jOOther systems.With nitrous fumes, P-methyl-a-methylaminobutyro-nitrile and y-methyl-a-methylaminovaleronitrile give sydnone iminenitrates (nitrates of 15; R = Pri or But, R’ = -NH). Acetic anhydridedehydrates the nitrates to nitro-imines (15; R’ = --N*N0,).51New syntheses of thioctic acid (16; 92 = 4) start from ethyl 6-oxo-oct-7-enoate and 2-acetoxymethylcycZohexanone. 52 Homologues (16 ; n = 3and 5) and analogues (16; n = 4, *SO,*NH, in place of *CO,H) have alsobeen synthesised as possible metabolite antagonist^.^^Six-membered Rings.-2 : 4 : 6-Triphenylpyryliurn fluoroborate givesl-nitro-2 : 4 : 6-triphenylbenzene with sodio-nitromethane, a reaction of somegenerality.5p a- and y-Pyrones, and their hydroxy-derivatives and sulphur an-alogues, can to some extent be regarded as pseudo-tropones and -tropolones. 55Ethylene glycol, butadiene, and a mercuric salt give cis- and trans-2 : 3-disubstituted dioxans (17) .56Pyridines and piperidines. Adducts (1 8) from a-carbonylacetylenesand enamines cyclise, when heated, to 2 : 3 : 6-trisubstituted pyridines.5744 P. Brookes, A. T. Fuller, and J. Walker, J., 1957, 689.45 A. Dornow and W. Bartsch, Annalen, 1957, 602, 23.46 D.A. Shirley and P. W. Alley, J . Amer. Chem. SOC., 1957, 79, 4922.47 K. Freter, J. C . Rabinowitz, and B. Witkop, Annalen, 1957, 607, 174.48 L. L. Bennett, jun., and H. T. Baker, J . Amer. Chem. SOL, 1957, 79, 2188; J .Org. Chem., 1957, 22, 707.40 M. L. Bender and B. W. Turnquest, J . Auner. Chem. SOC., 1957, 79, 1652; T. C.Bruice and G. L. Schmir, ibid., p. 1663; W. Langbeck and R. Mahrwald, Chem. Ber.,1957, 90, 2423.5 0 H. A. Staab, Annalen, 1957, 609, 75.51 P. Brookesand J. Walker, J., 1957, 4409.62 M. W. Bullock, J. J. Hand, and E. L. R. Stokstad, J . Amer. Chem. SOC., 1957,53 R. C. Thomas and L. J. Reed, ibid., 1956, 78, 6150, 6151.54 K. Dimroth, G. Brauninger, and G. Neubauer, Chem. Bey., 1957, 90, 1634;5 5 R.Mayer, Chem. Ber., 1957, 90, 2362.56 R. K. Summerbell and G. J. Lestina, J . Amer. Chem. SOC., 1957, 79, 3878.5 7 F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90, 2265.79, 1978; A. Segre, R. Viterbo, and G. Parisi, ibid., p. 3503.K. Dimroth, G. Neubauer, H. Mollenlramp, and G. Oosterloo, ibid., p. 1668244 ORGANIC CHEMISTRY.2-Pyridones are formed from 13-keto-nitriks, or from amides and ketones(and thus by hydrolysis of a-acylbenzyl cyanides),5s and also ham l-(carb-amoylmethy1)pyridinium chloride and Mannich bases (eg., 19 -20).6s(21)Me (22; R=H)3 : 5-Lutidine is conveniently synthesised from diethyl acetonedicarboxy-late.60 Hydrogen is evolved when sodium dissolves in pyridine, a factpreviously overlooked ; sodium pyridyls are presumably forrned.61 Criticalexamination of the Emmert-Asendorf reaction (co-reduction of pyridineand carbonyl compounds to pyridylcarbinols) led to the observation that,in the presence of aluminium or magnesium, esters can acylate pyridinedirectly.Acid anhydrides are not effective, but NN-dimethylbenzamidegives 2- (50%) and 4-benzoylpyridine (4%) .62 3- and 5-Amino-2-hydroxy-pyridines can be oxidised to hydroxyazaquinones (21) .633-Hydroxypicolinic acid occurs in the polypeptide antibiotic etamycin.B4The structure (22; R = Me) for muscopyridine (from the perfume glandof the musk deer), derived from biogenetic arguments, has been confirmed 65by the ingenious synthesis outlined in the formulae.Dipole-moment studies show that the oxide function in pyridine 1-oxidescan create a surfeit or a deficiency of electrons at position 4; the base-strengths and spectroscopic characteristic of 2- and 4-aminopyridine 1-oxidesshow them to exist in the m i n e forms, whereas the 4-hydroxy-compoundis a mixture of comparable amounts of both possible tautomers.66 %Nitro-pyridine l-oxides are formed by oxidation of the 2-amino-compounds.675 * J.F. M. Wajonand J. F. k e n s , Rec. Trav. chiwt., 1957, 76, 65, 79; C. R. Hauserand C. J. Eby, J . Amer. Chem. SOL, 1967, 79, 728.60 E. A. CouIson and J. €3. Ditcham, J., 1957, 356.6a G. B. Bachman, M. Hamer, E. Dunning, and K. M. Schisla, J . Org. Chem., 1957,64 J. C. Sheehan, H. G. Zachau, and W. B. Lawson, ibid., p. 3933.66 A. R. Katritzky, J., 1957, 191; A.R. Katritzky, E. W. Randall, and L. E.67 E. V. Brown, J . Awtev. Chem. SOL, 1957, 79, 3565.J. Thesing and A. Muller, Chem. Ber., 1957, 90, 711.R. Selton, Compt. rend., 1957, 244, 1205.22, 1296; G. B. Bachman and R. M. Schisla, ibid., pp. 858, 1302.J. H. Boyer and S. Kruger, J . Amer. Chem. SOC., 1957, 79, 3552.K. Biemann, G. Buchi, and B. H. Walker, ibid., p. 5558.Sutton, J., 1957, 1769; J. N. Gardner and A. R. Katritzky, J., 1957, 4375SCHOFIELD HETEROCYCLIC COMPOUNDS. 245The products of the Hantzsch pyridine synthesis are the non-basic1 : 4-dihydropyridines ; these do not react with dinitrophenylhydrazinein hydrochloric acid. In contrast, 1 : 2-dihydropyridines suffer ring-opening with dinitrophenylhydrazine.68 The 1 : 2-dihydropyridines (23)are converted 69 by hydrogenation and Grewe-cyclisation into benzomor-phans (24).Catalytic reduction of pyridinium salts in the presence of oneequivalent of alkali gives 2-hydroxy-l-methylpiperidine (25; R = OH) (inequilibrium with the open-chain form), which with benzoyl- or aceto-aceticacid gives the ketone; (25; R = -CH,*COPh or CH,*COMe). Furtherbasification gives A2-tetrahydro-1 : 1'-dimethylanabasine (26). isoQuino-linium salts produce the 3-substituted analogues of (26).70 Oxidation of1-alkylpiperidines with mercuric acetate has been systematically examined;1-methylpiperidine gave the dipyridyl derivative (26) .71 From the cupricacetate oxidation of l-hydroxypiperidine only the dimer of the resultingnitrone was obtained; in contrast, mercuric oxide oxidised l-hydroxy-1 : 2 : 3 : 4-tetrahydroisoquinoline to the nitrone (27).72Pyrimidine is formed in good yield from form-amide and 1 : 1 : 3-triethoxy-3-methoxypropane, and substituted pyrim-idines have been prepared from formamide and various p-dicarbonylDiazines and triazines.Me( 2 6 ) ( 2 7 ) ( 2 5 )R PhR "( 3 2 )derivatives.73 5-Fluoro-uracil and -orotic acid show antibacterial and anti-tumour activity.74 Icthiamine, formed by the action of clam tissue onthiamine, is 4-amino-5- (2-aminoethanesulphonylmethyl) -2-met hylp yrimidine(28); it has been synthesised.7568 L. Kuss and P. Karrer, Helv. Chim. Acta, 1957, 40, 740; H. Kiihnis, W. Traber,and P. Karrer, ibid., p. 751; H. Kiihnis, L. Kuss, and P. Karrer, ibid., p.1670; P. R.Brook and P. Karrer, Annalen, 1957, 6Q5, 1.E. L. May and E. M. Fry, J . Org. Chem., 1957, 22, 1366.7 0 C. Schopf, G. Herbert, R. Rausch, and G. Schroder, Angezv. Chem., 1957, 69, 391.71 N. J. Leonard and F. P. Hauck, jun., J . Amer. Chem. SOC., 1957, 79, 5279.72 J. Thesing and H. Mayer, Annalen, 1957, 609, 46.73 H. Bredereck, R. Gompper, and G. Morloclr, Chem. Ber., 1957, 90, 942.74 R. Duschinsky, E. Pleven, and C. Heidelberger, 3. Amer. Chem. Sot., 1957,79, 4559; C . Heidelberger, N.-K. Chaudhuri, P. Danneberg, D. Mooren, L. Griesbach,R. Duschinsky, R. J. Schnitzer, E. Pleven, and J. Scheiner, Nature, 1957, 179, 663.76 E. E. Kupstas and D. J. Hennessy, J - Amer. Chem. SOC., 1957, 79, 5217, 5220,6222246 ORGANIC CHEMISTRY.New syntheses of 1 : 2 : 4-triazines utilise the reaction between (3-acyl-amino-ketones and hydrazine, and the cyclisation of benzil monoarvl-hydrazones by ammonium acetate.76 With ammonia and carbonyl com-pounds p-mercapto-ketones give dihydro-1 : 3-thiazines (29). 77Large Rings.-Weak bases convert a-bromoacetophenone guanyl-hydrazone into the stable, orange triazacyclooctatetraene (30).78 Acidconverts methyl benzoylglyoxylate a-hydrazone into the tetra-azacyclo-octatetraene (31; R = *CO,Me). This and the parent (31; R = H) aresurprisingly stable; catalytic hydrogenation is slow, and the base (31 ;R = H) undergoes disubstitution with bromine.79Reaction between 2 : 2'-dilithiodiphenyl and mercuric chloride givesthe tetramercura-ring compound (32). The zinc analogue is obtainedsimilarly.80Condensed Ring Systems-%Amino- or 2-mercapto-thiazolines givep-lactams (33; R = *NHAc or *S*CO*CHPh,) with diphenylketen.12bSheehan's work has achieved a brilliant climax with the synthesis ofpenicillin V; D-penicillamine with tert.-butyl phthalimidomalonaldehydategave tert.-butyl ~-a-4-carboxy-5 : 5-dimethyl-a-phthalimido-2-thiazolidinyl-acetate [34; R' = But, R = *N(CO),C,H,]. Cleavage by hydrazine,acylation with phenoxyacetyl chloride, and hydrolysis with hydrogenchloride provided the acid (34; R' = H, R = PhO*CH,CO*NH) which wascyclised by NN'-dicyclohexylcarbodi-imide. *1@- @\ & ' \ N Lj-Jl R'O2C ".;"-f]":6,, ( 3 5 ) (36) Ac( 3 3 ) ( 3 4 )Compounds Ar*X*CH,*CO*Alkyl (X = 0 or S) can be cyclised to 3-alkyl-thionaphthens and -benzofurans, but substances Ar*X*CH,*COAr rearrangeto 2-aryl-thionaphthens and -benzofurans.82Indoles. Fischer cyclisation of arylhydrazones containing electron-releasing meta-substituents produces a preponderance of 6- over 4-substitutedindoles. The opposite is usually true for electron-attracting substituents. 83With ethyl oxalate and sodium ethoxide in pyridine, 4-cyanomethylindolegives the dipolar benzindole derivative (35), but neither 3 : 4-biscyano-methylindole nor the related diacid could be converted into a tricycliccompound.84 However, 4-acetonyl-l-acetyl-3-indolyacetaldehyde under76 V. Sprio and P. Madonia, Gazzetta, 1957, 87, 992; P. V. Laakso, Sir Robert77 F. Asinger, M. Thiel, and W.Horingklee, Annalen, 1957, 610, 1.78 H. Beyer and T. Pyl, Annulen, 1957, 605, 50. '* R. Pfleger and H.-G. Hahn, Chem. Ber., 1957, 90, 2411.*O G. Wittig and G. Lehmann, ibid., p. 875.81 J. C. Sheehan and K. R. Henery-Logan, J . Amer. Chem. SOC., 1957, 79, 1262.82 J. E. Banfield, W. Davies, N. W. Gamble, and S. Middleton, J , 1956, 4971;Robinson, and H. P. Vandrewala, Tetrahedron, 1957, 1, 103.W. Davies and S. Middleton, Chem. and Ind., 1957, 599.D. W. Ockenden and K. Schofield, J., 1957, 3175.H. Plieninger and K. Suhr, Chem. Ber., 1957, 90, 1980SCHOFIELD : HETEROCYCLIC COMPOUNDS. 247Mannich conditions gives the product (36),s5 and p-(6-methoxy-l : 2-di-methyl-3-indoly1)propionic acid can be cyclised at position 4. 86 Skatoleand 2-methylindole are oxidised by ferric chloride to dyes, represented bystructures such as (37).In the presence of amines different productsresult, 2-methylindole giving a product formulated as di-(2-methyl-3-indoleninyl). This is said to differ from di-(2-methyl-3-indolyl), which isconverted into it by hydriodic acid.87 The 3-alkylation of indoles byalcohols and alkoxides can be effected at ordinary pressures. 88 Accordingto conditions, indoles react with vinylpyridines at position 3 or at thenitrogen atom ; methyl vinyl ketone also effects C-alkylation. 89 Hydridereduction of 2-3'-indolylethylpyridinium salts 91 produces tetrahydro-pyridines without cyclisation to p-carbolines. 91Isatin blue, derived from isatin and pipecolic acid, is formulated as thehybrid (38).92Ozone converts heteroauxin into o-formamidobenzoylacetic acid, whichis cyclised by acid to 2 : 4-dihydro~yquinoline.~~ Ascorbigen, from Brassicaoleracw, gives, on hydrolysis, heteroauxin and ascorbic acid, and isrepresented as (39) (possibly the lower part should be Thecolourless acid from reductive hydrolysis of violacein, the pigment of Chromo-bacterium violaceurn, is formulated as (40), and the unstable yellow productof the action of alkali on the pigment as (40; double bond between starred85 H. Plieninger and G. Werst, C k . Berlin., 1956, 89, 2783.F. G. Mann and A. J. Tetlow, J., 1957, 3352.H. von Dobeneck and W. Lehnerer, Chem. Ber., 1957, 90, 161.E. F. Pratt and L. W. Botimer, J. Amer. Chem. SOC., 1957, 79, 5248.A.P. Gray and W. L. Archer, ibid., p. 3554; J. Szmuskovicz, ibid., p. 2819.J. Thesing, H. Ramloch, and C.-H. Willersinn, Chem. Ber., 1956, 89, 2896.Dl R. C. Elderfield, B. Fischer. and J. M. Lagowski, J . Org. Chem., 1957, 22, 1376.92 A. W. Johnson and D. J. McCaldin, J., 1957, 3470.93 C. Schopf, G. Koepke, B. Kowald, F. Schiilde, and D. Wunderlich, Chem. Ber.,94 2. ProchAzka, V. Sanda, and F. Sorm, Chem. Listy, 1956, 50, 333, 654; 1957,1956, 89, 2877.51, 1197; Coll. Czech. Chem. Comm., 1957, 22, 333248 ORGANIC CHEMISTRY.atoms) ; violacein then becomes represented by (41).g5 Oxidation of5 : 6-dihydroxyindoles suggests that a free 3- and a free 4- or 7-position isessential for melanin formation; the red solution formed by oxidising5 : 6-dihydroxy-2 : 3-dimethylindole may contain the related q ~ i n o n e .~ ~N-+-Toluenesulphon yldihydroisoindole is a convenient source of dihydr-is~indole.~’ Pyrrocoline can be obtained easily by treating 2-2’-hydroxy-ethylpyridine N-oxide with acetic anhydride, and pyrolysing the resultingacetate . gSQuinolines, isoquinolines, etc. The anomalous 3-nitration of quinolineis accounted for by initial 1 : %addition of the reagent. An importanttheoretical treatment of the nitration of nitrogen heterocyclics has beengiven.99 The imide (42), from butadiene and methyl glutaconate, can bereduced to trans-A6-octahydro- and trans-decahydro-isoquinoline.lOOPhosphoric oxide in pyridine is a promising reagent for Bischler-Napieral-ski cyclisation.lol 1 : 2-Dihydroquinoline is obtained by reduction ofquinoline with sodium-liquid ammonia.lo2 Reduction of isoquinoline bysodium and liquid ammonia gives initially the 1 : 2-dihydro- and then the1 : 2 : 3 : 4-tetrahydro-compound; the dihydro-compound can trimerise,probably by first isomerising to the 1 : 4-c0mpound.10~Bicyclic compounds with two OY more hetero-atoms. 6-Methoxybenzoxazol-one is partly responsible for the resistance of the maize plant to the cornborer.1“ Indazoles can be prepared by dehydrogenating the readilyavailable 5 : 6 : 7 : 8-tetrahydro-derivatives; indazole analogues of trypt-amine and serotonin have been synthesised.lo5 Oxidation of hydrazonesof 2-acylpyridines and related compounds gives 1 : 2 : 7a- (43) and otherpolyaza-indenes.lo6Hydroxypurines exist in the lactam form ; mercaptopurines havepredominantly thione structures.107 Much effort has been devoted to95 J.A. Ballantine, C. B. Barrett, R. J. S. Beer, B. G. Boggiani, K. Clarke, S.Eardley, B. E. Jennings, and A. Robertson, J., 1957, 2222; J. A. Ballantine, C. B.Barrett, R. J. S. Beer, S. Eardley, A. Robertson, B. L. Shaw, and T. H. Simpson,Proc. Chem. Soc., 1957, 340; R. J. S. Beer, Angew. Chem., 1957, 69, 676.s6 R. I. T. Cromartie and J. Harley-Mason, Biochem. J., 1957, 66, 713.g7 J. Bornstein, S. C . Lashua, and A. P. Boisselle, J . Org. Chem., 1957, 22, 1255.98 V. Boekelheide and W. Feely, J . Org. Chem., 1957, 22, 589.OD M. J. S. Dewar and P. M. Maitlis, J., 1957, 944, 2518, 2521.loo S. Heim&nck and J.TrojBnek, Chem. Listy, 1957, 51, 539; COX Czech. Chem.lol N. Itoh and S . Sugasawa, Tetrahedron, 1957, 1, 45.lo2 W. Hiickel and L. Hagedorn, Chem. Ber,, 1957, 90, 752.loS W. Hiickel and G. Graner, Chem. Ber., 1957, 90, 2017.lo4 E. E. Smissman, J. B. LaPidus, and S. D. Beck, J . Org. Chem., 1957, 22, 220.lo6 C . Ainsworth, J. Amer. Chem. Soc., 1957, 79, 5242, 5345.lo6 J. H. Boyer, R. Borgers, and L. T. Wolford, ibid., p. 678; J. D. Bower and G. R.lo7 D. J. Brown and S. F. Mason, J., 1957, 682.Gomm., 1957, 22, 1167.Ramage, J.. 1957, 4506; J. D. Bower and F. P. Doyle, J., 1957, 727SCHOFIELD HETEROCYCLIC COMPOUNDS. 240synthesising purines , deazapurines, thiazolo- and triazolo-pyrimidines , andbenzo-1 : 2 : 4-triazines as possible metabolite antagonists.lo8The Streptomyces antibiotics , echinomycin and X-948 , which givequinoxaline-2-carboxylic acid as well as amino-acids on hydrolysis , areprobably identical ; X-1008 also gives quinoxaline-2-carboxylic acid.logSome purines react under mild conditions with 1 : 2-dicarbonyl com-pounds , giving pteridines.110 8-Alkyl-2 : 8-dihydro-2-oxopteridines showstrong affinity for a molecule of water but it is argued that this is notstructurally bound.uf 'In aqueous solution lumazine exists as the dilactamform; a third hydroxyl group at C(,) exists predominantly as such, but atC(s) it assumes the lactam forrn.l12 Structure (44; R = CHO or CH,-OH)is suggested113 for a compound from the eyes of Drosophila melanogaster;three compounds have been isolated from this s0urce.1~~ Dihydro- andtetrahydro-pteroylglutamic acid appear to form, with formaldehyde,hydroxymethyl compounds of importance in the enzymic synthesis ofserine.115Cyclisation of the diacetal (45) gives the benzo-dithiophen (46) ; the linear analogue has also been synthesised.l16 Inter-mediates derived from 2-lithio-N-alkylindoles and amino-ketones can becyclised with formaldehyde to tetrahydro-y-carb~lines.~~~Acridinium salts with active methylene compounds give products oftype (4?).u8Glyoxalinophenazines , formed by oxidising o-phenylenediamines in thepresence of ketones, can be reduced to imino-compounds (48) possessinghigh antituberculosis activity .119With alkali, diacetyl gives 5-acetyltetrahydro-2-hydroxy-2 : 5-dimethyl-3-oxofuran which with 4 : 5-diaminouracil forms an intermediate convertedby alkali into lumichrome (49; X = Y = 0), a sequence possibly of bio-synthetic significance.120 The Kuhn-Cook synthesis of alloxazines from5 : 6-diaminopyrimidines and o-quinones succeeded only with polynuclearlo* R.K. Robins and H. H. Lin, J . Amer. Chem. SOC., 1957, 79, 490; J. A. Mont-gomery and C. Temple, jun., ibid., p. 5238; J. A. Montgomery and L. B. Holum, ibid.,p. 2185; W. Pfleiderer and H. Mosthaf, Chem. Bey., 1957, 90, 738; B. S. Gorton andW. Shive, J . Amev. Chem. SOL, 1957, 79, 670; L. Marchal and R. Promel, Bull. SOC.chim. belges, 1957, 66, 406: G. M. Timmis. D. G. I. Felton, H. 0. J. Collier, and P. L.Huskinson, J . Pharm. Pharmacol., 1957, 9, 46; R.F. Robbins and K. Schofield, J.,1957, 3186.lo9 R. Corbaz, L. Ettlinger, E. Gaumann, W. Keller-Schierlein, F. Kradolfer, L.Neipp, V. Prelog, P. Reusser, and H. Zahner, Helv. Chirn. Acta, 1957, 40, 199; J.Berger, E. R. La Sala, W. E. Scott, B. R. Meltsner, L. H. Sternbach, S. Kaiser, S.Teitel, E. Mach, and M. W. Goldberg, Experientia, 1957, 13, 434.Tricyclic comj5ounds.-4. Albert, Biochem. J., 1957, 65, 124.111 W. E. Fidler and H. C. S. Wood, J., 1957, 3980.112 W. Pfleiderer, Chem. Ber., 1957, 90, 2582.llS W. E. Fidler and H. C. S. Wood, J., 1957, 4157.11* M. Viscontini, E. Hadorn, and P. Karrer, Helv. Chzim. Acta, 1957, 40, 579.R. L. Blakley, Biochem. J., 1957, 65, 331.116 D. S. Rao and B. D. Tilak, J . Sci. I n d . Res., India, 1957, 16, B, 65.11' J.Kebrle, A. Rossi, and K. Hoflmann, Angew. Chem., 1957, 69, 683.0. D.imroth and R. Criegee, Chew. Bey., 1957, 90, 2207; F. Krohnke and H. L.119 V. C. Barry, J. G. Belton, M. L. Conalty, J. M. Dennery, D. W. Edward, J. F.lZo A. J. Birch and C . J. Moye. J., 1957, 412.Hohig, ibid., p. 2215.O'Sullivan, D. Twomey, and F. Winder, Nature, 1957, 179, 1013250 ORGANIC CHEMISTRY.quinones; however, it works well with '' dimeric " 4 : 5-dimethyl-o-benzo-quinone, giving derivatives resembling (49) .121Dilute alkali opens the phenoxazone nucleus of actinomycin,122 givingthe anil (50).123 Actinomycin D differs from actinomycin C, 122 only inX CO-NHR CO*NHR CO-NHR(50) (51)having valine in place of alloisoleucine in the peptide chains.lM Alkalinehydrogen peroxide cleaves actinomycins to two fragments, (51) andHO,C*CO*NHR, each having a complete peptide 125 Alkali opensthe lactone groups in the peptide chains of actinomycin C,, giving actino-mycin C, acid.A mixture of diastereoisomeric dimethyl esters of thissubstance has been obtained by constructing the peptide chain, condensingit with 3-benzyloxy-4-methyl-2-nitrobenzoyl chloride, then reducing theproduct and oxidising it .128Cinnabarin (polystictin) is believed to be 3-amino-4-carboxy-5-hydroxy-methylphenoxaz-2-one,127 a structure which accords with the evidencefrom light-absorption data of close similarity between actinomycin, ommo-chromes (see below), and cinnabarin. Gripenberg 128 suggested that thesubstance was 4-carbamoyl-3-hydroxy-5-hydroxymethylphenoxaz-2-one, butan amide group has not been dete~ted.1~' If the first suggestion is correctthe .degradation product which gives 2 : 5-dihydroxybenzoquinone onhydrolysis 128 is presumably 2-amino-5-hydroxybenzoquinone-3-carboxylicacid.Ommochromes are insect pigments, end-products of tryptophan meta-b0lism.1~~ They include ommines of high molecular weight, and ommatinesof low molecular weight.Three ommatines-xanthommatin, rhodommatin,and ommatin D-have been isolated from the butterfly, Vanessa urticae;ommatin C is probably an artefact. The structure of xanthommatin (52)121 T. J. Bardos, B. D. Olsen, and T. Enkoji, J. Amer. Chem. Soc., 1957, 79, 4704.122 Ann. Reports, 1956, 53, 234; A. W. Johnson, Chem.SOC. Spec. Publ. No. 5,123 S. J. Angyal, E. Bullock, W. G. Hanger, W. C. Howell, and A. W. Johnson,124 E. Bullock and A. W. Johnson, J., 1957, 3280.125 Idem, ibid., p. 1602.128 B. Franck, Angew. Chem.. 1957, 69, 237.127 G. W. K. Cavill, P. S. Clezy, and J. R. Tetaz, J., 1957, 2646; Proc. Chem. SOC.,12* J. Gripenberg, Proc. Chem. Soc., 1957, 233.l29 A. Butenandt, Angew. Chem., 1957, 69, 16; 'I Festschrift Arthur Stoll," Bade,1956, p. 82.J., 1957, 1592.1957, 346.1957, p. 869SCHOFIELD : HETEROCYCLIC COMPOUNDS. 261has been proved by degradation to xanthurenic acid (formed from hydroxy-kynurenine) and alanine, by its formation in the ferricyanide oxidation of( 5 2 ) (53)H O( 5 4 )hydroxykynurenine, and by its synthesis from hydroxykynurenine and5 : 8-dihydro-4 : 6-dihydroxy-5 : 8-dioxoquinoline-2-carboxylic acid.129Rhodommatin and ommatin D probably differ from xanthommatin only inthe side-chain~.~~~ As models for the oxidative self-coupling of hydroxy-kynurenine, similar phenoxazone syntheses from 3-hydroxyanthranilic acidand 2-amino-3-hydroxyacetophenone have been examined.131 The oxidationof 4 : 5-diacetyl-3-aminophenoxaz-2-one to 4-acetylbenzoxazolone 132 is inline with work on the actinomycins (see above).Ommochrome reactions 131asuggest that alkali will convert 4 : 5-diacetyl-3-amino- and -3-hydroxy-phenoxaz-2-one into 5-acetyl-3-hydroxyphenoxaz-2-one. Instead, all threesubstances give, through the intermediate (53), the trihydroxy-dibenz-azepinequinone imine (54) ; derivatives of this system are formed directlyfrom 2-amino-3-hydroxyacetophenone by oxidation at pH 8Ci-9.133Phenoxazones also result from oxidation of orcin in aqueous ammonia.Three of the products, a-, p-, and y-amino-orcein are formulated as theracemates (5!5), (56), and (56; with the 3-aryl substituent turned through180’) ; isomerism of the p- and y-compounds depends on restricted r0tation.13~Compounds with a seven-membered ring.2 : 2 : 3-Trimethoxy-l-benz-azepine (57), obtained by reducing methyl o-nitrobenzylidenepyruvate,could not be converted into an azabenzotr~polone.~~~ y-Keto-acids andanilines form the “ A4-homocarbostyrils ” (58) in presence of acids.136Derivatives of 2 : 3 : 4 : 5-tetrahydro-5-oxo-l-benzazepine have been pre-pared by Dieckmann cyclisation of y-o-methoxycarbonylanilinobutyrates.~37130 A.Butenandt, E. Biekert, and R. Beckmann, Annalen, 1957, 607, 207.lal (a) A. Butenandt, J . Keck, and G. Neubert, Annalen, 1957, 602, 61; (b) A.Butenandt, E. Biekert, and G. Neubert, ibid., p. 72.132 A. Butenandt, E. Biekert, and U. Baumann, Arch. Biochem. Biophys., 1957,69, 100.133 A. Butenandt, E. Biekert, and G. Neubert, Annabn, 1957, 603, 200.13* H. MUSSO, H. G. Matthies, H. Beecken, and H. Kramer, Angew. Chem., 1957,69, 178; H. Musso, ibid., p. 396; H. Musso and H. Beecken, Chem. Ber., 1957, 90,1808, 2190.M. Look, Diss. Abs., 1957, 17, 36.136 A. Bertho, Chem. Bey., 1957, 90, 29.lS7 B. D. Astill and V. Boekelheide, J . Amer. Chem. Soc., 1955, 77, 4079; G.R.Proctor and R. H. Thomson, J., 1957, 2302, 2312; J. T. Braunholtz and F. G. Mann,J., 1957, 4174; Chem. and Ind., 1957, 266252 ORGANIC CHEMISTRY.3-Benzoxepines and 3-benzazepines (59; X = 0 or NMe) can be obtained 138from phthalaldehyde and esters (EtO,C*CH,),X (X = 0 or NMe). Catalyticreduction of 2-acetylquinoxalines gives 139 red betaines derived from6-hydroxy-2 : 3-benzodiazepine (as 60). o-Phenylenediamine and o-amino-thiophenol with ctp-unsaturated ketones provide benzodiazepines andbenzothia~epines.~~~ Cyclisation of 2-phenoxyphenyl-pyruvic and -aceticacid gives dibenz[b, floxepins (derivatives of 61; X = 0, Y = CH), anddibenztb, flthiepins (61 ; X = S, Y = CH) are formed similarly. Sulphurcan be extruded from the latter, with the formation of phenanthrenes, andsimilarly dibenzo[b, f]-1 : 4-thiazepines (61; X = S, Y = N) can beconverted into ~henanthridines.1~1Complex oxygen heterocyclics. The pseudo-aromatic benzocyclopent apyran(62) and benzindenopyran resemble azulenes, spectroscopically andchemically.142The O-methyl derivative of dalbergin, from Dalbergia sissoo, is 6 : 7-di-methoxy - 4 - phenyl~oumarin.1~~ 3 : 5 : 7 : 2' : 4' - Pentahydroxyflavanone(dihydromorin) occurs in the heartwood of Morz~s Zactea.l* The flavourof bitter carrots is partly due to (-)-3 : 4-dihydro-8-hydroxy-6-methoxy-3-methylisocoumarin, whose racemic methyl ether has been ~ynthesised.~~~Polycladin and artemisetin are 4' : 5-dihydroxy-3 : 6 : 3' : 7-tetramethoxy-and 5-hydroxy-3 : 6 : 7 : 3' : 4'-pentamethoxy-flavone.1*6 Vitexin, frompuriri wood, is formulated as (63); its tri-0-methyl derivative can beoxidised to 8-f0rmyltri-O-methylapigenin.l~~ Seeding barley leaves containa glucoside, identical with saponarin, which gives vitexin on hydrolysis;analyses of vitexin agree moderately well with structure (63), but forsaponarin agree better with a hexahydroxy side-~hain.1~8 Completely138 K.Dimroth and H. Freyschlag, Chem. Ber., 1956, 89, 2602; 1957, 90, 1623.139 J. A. Barltrop and C. G. Richards, Chem. and Ind., 1957, 1011.140 W. Ried and P. Stahlhoffen, Chem. Ber., 1957, 90, 815, 825, 828; W. Xed and141 J. D. Loudon and L. A. Summers, J., 1957, 3809; J. D. Loudon, A. D. B. Sloan,142 G. V. Boyd, Chem. and Ind., 1957, 1244.145 V.K. Ahluwalia and T. R. Seshadri, J., 1957, 970.144 W. R. Carruthers, R. H. Farmer, and R. A. Laidlaw, J., 1957, 4440.Id6 E. Sondheimer, J . Amer. Chem. Soc., 1957, 79, 5036; W. R. Logan and G. T.1l6 G. B. Marini-Bettolo, S. Chiavarelli, and C. G. Casinovi, Gazzetta, 1957, 87,147 W. H. Evans, A. McGookin. L. Jurd, A. Robertson, and W. R. N. Williamson,lQ8 M. K. Seikel and T. A. Geissman, Arch. Biochem. Bioghys., 1957, 71, 17.W. Marx, ibid., p. 2683.and L. A. Summers, J., 1957, 3814; A. D. Jarrett and J. D. Loudon, J., 1957, 3818.Newbold, Chem. and Ind., 1957, 1485.1185; P. Tunmann and 0. Osaac, Arch. Pharm., 1957, 290, 37.J., 1957, 3510SCHOFIELD : HETEROCYCLIC COMPOUNDS. 253acetylated polyhydroxyflavones are preferentially alkylated at the7-po~ition.14~ That mollisacacidin, from Acacia naollisima, is cis-3 : 4 : 7 : 3' : 4'-pentahydroxyflavan is confirmed by reduction of f ~ s t i n .1 ~ ~Paper chromatography and the use of toluene-+-sulphonic acid as chromo-genic agent serves to identify 2eu~oanthocyanins.l~~Degradation of (-)-epicatechin tetramethyl ether to 1-(3 : 4-dimethoxy-pheny1)-3-(2 : 4 : 6-trimethylphenyl)propan-2-ol having excess of the (+)-enantiomorph, and similar degradation of (+)-catechin tetramethyl ether,shows that (+) <atechin and (-) -epicatechin have opposite configurationsat C(,). Application of Prelog's atrolactic acid method to (-)-epicatechintetramethyl ether confirms Freudenberg's conjectural absolute configuration(64) for (--)-efiicate~hin.l~~ This and other 153 deductions of absoluteconfiguration fix also the configuration of (+) -dihydroquercetin.laThe toxic constituent of immature Australian finger cherry is a tetra-hydroxydimethyldiisovaleryldibenzofuran.155 Alkaline degradation andhydride reduction of athamantin support the structure (65).156 Fulvicacid, a metabolite from Carpenteles crefeldianum, is assigned structure (66).Methyl di-0-methylfulvate readily loses water, and subsequent hydrolysisgave 2-acetyl-7-hydroxy-4 : 5-dimethoxyindane-1 : 3-dione, identical witha wrongly formulated derivative of ~itr0rnycetin.l~~ Conversion of[carboxy1*C]acetic acid into griseofulvin supports the theory of biosynthesisI49 L.Jurd, Chem. and Ind., 1957, 1452.l50 H. H. Keppler, J., 1957, 2721.l5l D.G. Roux, Nature, 1957, 180, 973.152 A. J. Birch, J. W. Clark-Lewis, and A. V. Robertson, J., 1957, 3586.lS3 E. Hardegger, H. Gempeler, and A. Ziist, HeZv. Chim. Acta, 1957, 40, 1819;154 J. W. Clark-Lewis and W. Korytnyk, Chena. am? Ind., 1957, 1418.155 S. Trippett, J., 1957, 414.15* 0. Halpern, P. Waser, and H. Schmid, Helv. Chim. Acta, 1957, 40, 758; cf.15' F. M. Dean, R. A. Eade, R. Moubasher, and A. Robertson, J., 1967, 3497.A. B. Kulkarni and C. G. Joshi, J . Indian Chem. Soc., 1957, 34, 217.Ann. Reports, 1941, 38, 223254 ORGANIC CHEMISTRY.by head-to-tail linkage of acetic acid units.15* 2-Acetyl-4 : 6-dimethoxy-coumaran-3-oneJ by addition to methyl vinyl ketone and cyclisation of theproduct gives the dioxogrisen (67).Degradation of tri-O-ethylwedelo-lactone proves the structure (68) for wedelolactone ; 160 tri-O-methyl-wedelolactone has been synthesised and converted into wedelolactone.161The structure (69) is suggested for the pigment sclerotiorin, from Peni-cillium sclerotiorum ; this compound exemplifies a group of substanceswhich, because of the ease with which they react with ammonia and primaryamines, giving isoquinoline derivatives, have been called azaphilones.162K. S.9. ALKALOIDS.SEVERAL interesting review articles have appeared in a publication 1 inhonour of A. Stoll’s seventieth birthday: one of these, on some biogeneticaspects of phenol oxidations, includes a number of interesting speculationson the biogenesis of alkaloids; those on pyrrolizidine alkaloids, on aromaticerythrina alkaloids, and on ajmaline have also been published in AngewandteChemie.Among the more interesting results of biosynthetic tracer work there isthe demonstration that, in barley, phenylalanine is the precursor ofhordenine ; this involves hydroxylation of a non-phenolic benzene ring.Further work has confirmed the hypothesis that ornithine is metabolised toa symmetrical CJ unit before incorporation as the pyrrolidine portion ofnicotine.* Ricinine, the alkaloid of the castor bean, has been shown to bederived from nicotinic acid.5Tropane Group.-Two reviews of recent developments in this group haveappeared.l, The absolute configuration of valeroidine (1) has been deducedby an application of Hudson’s rule to a derivative containing a a-lactonegrouping between the 6-hydroxyl and an N-carboxymethyl Thereare the beginnings of an absolute stereospecific synthesis in this group in thesynthesis of (S)-( +)-6 : 7-dihydroxytropan-3-one [( +)-alloteloidinone] fromdiethyl (+)-tartrate.8 A neat synthesis of scopoline (2) by thermal de-composition of teloidine carbonate has been a~hieved.~ A novel synthesis158 A.J. Bjrch, R. A. Massy-Westropp, R. W. Richards, and H. Smith, Proc. Chem.SOC., 1957, 98.15O F. M. Dean and K. Manunapichu, J., 1957, 3112.l60 T. R. Govindachari, K. Nagarajan, B. R. Pai, and P. C. Parthasarathy, J.,1957, 545.161 W. J. Bowyer, A. Robertson, and W. B. Whalley, J., 1957, 542; T. R.Govindachari, K. Nagarajan, and P. C. Parthasarathy, J., 1957, 548; N.R. Krishna-swamy and T. R. Seshadri, J . Sci. Ind. Res., India, 1957, 16, B, 268.162 A. D. G. Powell, A. Robertson, and W. B. Whalley, Chem. Soc. Sfiec. Publ. No.5, 1956, p. 27. (But see J., 1957, 4913 et seq.)1 Festschrift Arthur Stoll, Birkauser Verlag. Basel, 1957.2 Angew. Chem., 1957, 69, 5, 33, 40.J. Massicot and L. Marion, Canad. J . Chem., 1957, 35, 1.E. Leete and K. J. Siegfried, J. Amer. Chem. Soc., 1957, 79, 4529.5 E. Leete and F. H. B. Leitz, Chem. and Ind., 1957, 1572.6 G. Fodor, Tetrahedron, 1957, 1. 87.7 G. Fodor, I. Vincze, and J. Toth. Experientia, 1957, 13, 183.8 E. Hardegger and H. Furter, Helv. Chim. Acta, 1957, 40, 872; cf. K. Zeile and9 Idem, ibid., p. 2800.A. Heusner. Chem. Ber., 1957, 90, 1869SMITH : ALKALOIDS.255of the tropane system involves the interaction of cycloheptatriene-l-, -3-, or-4-carboxylic ester and methylamine.1° Structure (3) has been proposedfor dioscorine; 11 in this work, the presence of the spiro-6-lactone group wasproved, but not its position on the tropane system; the work leaves twopossible positions for it, 2 and 7, the former being preferred on biogeneticgrounds.Lupinane Group.-The structures of two further C,, lupin alkaloids havebeen elucidated: aphyllidine (4), by oxidative and spectral studies,12 andbaptifoline (5) by conversion into (-)-13-hydroxylupanine, the (+)-enantiomer of which is k n o ~ n . 1 ~ In a most interesting paper,l* Bohlmannand his co-workers repeat previous work by other workers15 up to thepreparation of a mixture of stereoisomers of compound (6), which is nowseparated chromatographically into the four possible stereoisomers.Thesestereoisomers, after oxidation of -CH,*OH to -C02H , are separatelyconverted into the four stereoisomers of the base (7). One of these, oxy-sparteine, had already been synthesised from the mixture; l5 another isnow found to be identical with (-+)-aphylline, which is thus synthesised forthe first time.The study of the rate of dehydrogenation of >N*CH< to >N+=C<by mercuric acetate, which has been applied with such success to con-formational analysis in the indole group,16 has been turned to the sparteinelo C. Grundmann and G. Ottmann, Annulen, 1957, 605, 24.l1 A. R. Pinder, Chem.and Ind., 1957, 1240.l2 F. Galinowski, P. Knoth, and E. Garisch, Monaish., 1957, 88, 143.l3 M. Martin-Smith and L. Marion, Canad. J . Chem., 1957, 35, 37.l4 F. Bohlmann, W. Weise, H. Sander, G.-G. Hanke, and E. Winterfeld, Chem. Ber.,l6 E. Wenkert and D. K. Roychaudhuri, J. Org. Chem., 1956, 21, 1315; F. L.1957, 90, 653.G. Clemo, W. Morgan, and R. Raper, J., 1949, 663.Weisenborn and P. A. Diassi, Chem. and Ind., 1956, 2022256 ORGANIC CHEMISTRY.and the matrine group: the stereochemistry deduced for matrine (8) andfor allomatrine (9) agrees with that deduced on other grounds by a differentschool.l* The latter workers also describe the synthesis of (&)-aZZo-matridine.Pyridine Group.-Anibine has been shown l9 to have the novel structure(10).The synthesis of gentianine has now been achieved.20 The absoluteconfiguration of the or-carbon in the monosubstituted piperidine alkaloidshas been shown to correspond with that of the L-amino-acids.21 Applicationof counter-current distribution to the separation of the mixture of minoralkaloids from Lobelia iny7ata has revealed the presence of at least thirtynew bases; the structures of six of these have been elucidated. A newnomenclature for the lobelia alkaloids, rendered necessary by the abovefindings, is proposed.22Quinoline Group.-A new type, 2-phenyl-4-methoxyquinoline, has beenisolated from the leaves of Lunasia amara B l a n ~ o . ~ ~isoQuinoline Group.-A new general synthesis of the protoberberinesystem has been described,% and has been used in the synthesis of (5)-ophiocarpine (11).By far the most interesting event in this group has beenthe isolation of the aldehydo-base (12) from ipecacuanha alkaloid mother-liquors: 25 this labile alkaloid forms the biogenetic link between thenumerous benzylisoquinoline alkaloids and the emetine bases, and givesstrong support to earlier speculations on the biogenesis of emetine.26 Theconversion of this aldehyde (12) into emetine further clearly demonstratesthe identity of the stereochemistry of the two molecules. This is furtherthe first authenticated occurrence of a free aldehyde group in an alkaloid:its analogues in the indole group, such as corynantheine, are all aldehydeenol ethers.Battersby and his co-workers have also achieved the elucidation of theabsolute configuration at position 1' of emetine (13), by molecular-rotation1 7 F.Bohlmann, Angew. Chem., 1957, 69, 641; F. Bohlmann, W. Weise, and D.Rahtz, ibid., p. 642.18 K. Tsuda and H. Mishima, Pharm. Bull. (Japan), 1957, 5, 285.1 9 W. B. Mors, 0. R. Gottlieb, and C. Djerassi, J . Amer. Chem. SOL, 1957, 79, 4507.20 T. R. Govindachari, K. Nagarajan, and S. Rajappa, J., 1957, 2725.21 H. C. Beyerman, J. Eenshuistra, and W. Eveleens, Rec. Trav. chim., 1957, 76,415; R. LukeS, J. Kloubek, K. BlAha, and J. KovAf, Coll. Czech. Chern. Comm., 1957,22, 286.22 C. Schopf and T. Kauffmann, with P. Berth, W. Bundschuh, G. Dummer, H.Fett, G. Habermahl, E. Wieters, and W. Wust, Annalen, 1957, 608, 88.23 S. Goodwin, A. F.Smith, and E. C. Homing, J . Amer. Chenz. SOL, 1957, 79, 2239.Z4 T. R. Govindachari and S. Rajadurai, J., 1957, 557; T. R. Govindachari, S.Rajadurai, M. Subramanian, and N. Viswanathan, ibid., p. 2943.86 A. R. Battersby, G. C. Davidson, and B. J. T. Harper, Chem. and Ind., 1967, 983.26 R. Robinson, Nature, 1948, 162, 624SMITH : ALKALOIDS. 257studies on the oxidation product (14), and of the relative configuration ofthe quinolizidine portion by conformational analysis of two products of thedegradation of 0-methylpsychotrine and by synthesis, from trans-3 : 4-diethylcyclopentanone, of the base (15), shown to be identical with the Wolff-Kishner reduction product of the aldehyde-alkaloid (12) .27 van Tamelen andOMeOMehis co-workers also arrived at the relative configuration of the quinolizidineportion of the emetine molecule 28 by a synthesis of the base (15), showing itto be identical with a compound obtained from an intermediate used in theRussian synthesis of emetine.29H E tIndole Group.-Flavopereirine, one of the alkaloids of GeissospermumZaeue Baill., has been given structure (16), most interesting because it is thefirst case in this group of a degraded structure, being obviously derived froma corynantheine-like precursor by loss of three skeletal carbon atoms.30 Inanother brilliant example of the art of separating complex mixtures ofalkaloids, H.Schmid, P. Karrer, and their co-workers have isolated twelvemore alkaloids from the bark of Strychnos melinonziana One ofthese is flavopereirine (16).One of the two which had previously beenisolated,32 melinonine-B, has been shown 33 most probably to have structure(17) ; dehydrogenation gives a noralstyrine, the 4'-ethyl group having beenreplaced by methyl, and, what is very disturbing, dehydrogenation bypalladium yields yobyrine (18)-this means that an isolation of yobyrine nolonger can be taken to indicate the presence of a homocyclic ring E.27 A. R. Battersby, R. Binks, D. Davidson, G. C. Davidson, and T. P. Edwards,Chem. and Ind., 1957, 982; A. R. Battersby and S. Cox, ibid., p. 983.28 E. E. van Tamelen, P. E. Aldrich, and J . B. Hester, jun., J . Amev. Chem. SOC.,1967, '79, 4817.29 R. P. Evstigneeva, R. S. Livshits, M. S. Bainova, L. I. Zakharin, and N. A.Preobrazhensky, J .Gen. Chem. (U.S.S.R.), 1952, 22, 1511 (U.S. translation).30 0. Bejar, R. Goutarel, and M.-M. Janot, Comfit. rend., 1957, 244, 2066.31 E. Bachli, C . Vamvacas, H. Schmid, and P. Karrer, Helv. Chim. Ada, 1957, 40,32 E. Schlittler and J. Holil, ibid., 1952, 35, 29.33 C. Vamvacas, W. von Philipsborn, E. Schlittler, H. Schmid, and P. Karrer, %id.,1167.1957, 40, 1793.REP.-VOL. LIV 258 ORGANIC CHEMISTRY.Elucidation of the stereochemistry of the alkaloids in the yohimbane andrelated groups is becoming an increasingly specialised activity, involvingmainly careful analysis of infrared spectra 34 and of rates of dehydrogen-ati0n.~5An interesting synthesis,36 that of 17-demethoxydeserpidine, involvesformation of a &-DIE ring junction as one of the last steps, this beingachieved by catalytic hydrogenation of compound (MA), which also bringsthe substituents in ring D into the required orientation.The stereochemistryof raunescine, i~oraunescine,~~ and psezdoreserpine 38 has been completelyworked out.Mainly on the basis of ultraviolet and infrared studies, corynoxeine hasbeen shown 39 to be the oxindole analogue (19) of corynantheine. This mostinteresting molecule looks very much like a " missing link '' between theyohimbine and the strychnine series, and may well point the way to asolution of the gelsemine problem. Corynoxine has an ethyl in place of thenvinyl, but has a different stereochemistry, for it is not identical with di-hydrocorynoxeine. The latter has been shown to be identical with rhyn-c ~ p h y l l i n e .~ ~ * ~ ~ Another member of the ajmaline group has been found invomalidine, to which structure (20) has been gi~en.~1 The structures ofsarpagine 42 and C-alkaloid-T 43 have been the subject of speculation:formula (21) has been proposed for sarpagine on the basis of the phenolicproperties of the base, its ultraviolet spectrum, and ozonolysis to acet-aldehyde ; in C-alkaloid-T, the methyl ether of sarpqgine contaminated with34 E. Wenkert and D. K. Roychaudhuri, J. Amer. Chem. SOC., 1956, 78, 6417;N. Neuss and H. E. Boaz, J. Org. Chem., 1957, 22, 1001.35 E. Wenkert and D. K. Roychaudhuri, J. Amer. Chem. SOC., 1957, 79, 1619.36 F. L. Weisenborn, ibid., 1957, 79. 4818.37 C. F. Huebner and E.Schlittler, ibid., p. 250; E. E. van Tamelen and C. W.38 M. W. Klohs, F. Keller, R. E. Williams, and G. W. Kusserow, ibid., p. 3763.39 N. An Cu, R. Goutarel, and M.-M. Janot, Bull. SOC. chim. France, 1957, 1292.40 J . C. Seaton and L. Marion, Canad. J. Chem., 1957, 35, 1102.4 1 A. Hofmann and A. J. Frey, Helv. Chim. Ada, 1957, 40, 1866.42 D. Stauffacher, A. Hofmann, and E. Seebeck, ibid., p. 508.4s W. Arnold, W. von Philipsborn, H. Schmid, and P. Karrer, ibid., p. 705.Taylor, ibid., p. 5256SMITH : ALKALOIDS. 2 59the vinyl isomer, the presence of the -CH,*OH grouping has been demons-trated. The proposed structures assume a relationship with the ajmalinegroup. Lochnerine is the pure methyl ether of sarpagine.& Some 80 yearsafter its isolation, aspidospermine has only now been found to contain anN-methyl group : 45 this was detected by nuclear magnetic resonancespectroscopy and its presence was then confirmed by standard methods.An analysis of available data, including a reversible BrCN degradationclaimed to involve a remarkable rearrangement, leads to the proposal ofthe novel structure (22) for the alkaloid as a working hypothesis.A newidea, ortho-meta-fission of the benzene ring in the phenylalanine unit, is used 45to derive a plausible scheme for the biogenesis of compound (22).Structures (23; R = H, R’ = OMe; R = OMe, R’ = H; and R = R’ =H), also of a completely new type, are proposed for ibogaine, tabernanthine,and ibogamine respe~tively.~~ This is the result of a brilliant deduction ofthe structure of the two selenium dehydrogenation products of ibogaine,N/ Me%Ec A - Me0 A-(24) and (25; R = OMe) : although neither has been synthesised, the authorreports the synthesis by another group of workers4’ of compound (25;R = H) which was obtained by dehydrogenation of ibogamine.Voacangine has been converted into ibogamine by decarboxylation ofvoacangic acid and by thermal elimination of formaldehyde from theproduct of reduction of voacangine by lithium aluminium hydride.Theseobservations have led to the proposal of structure (26) for the alkaloid.48An ingenious and convincing scheme for the biogenesis of the iboga alkaloidsand of voacangine has been proposed.49 Partial structure (27) has been putforward 50 for ulein, the alkaloid of Aspidosperma ulei, Mgf.; this does notseem to have any relation to the other indole alkaloids.The main degrad-ation product, an ethyl-n-propylcarbazole, has not yet been synthesised.44 J. Poisson, J . le Men, and M.-M. Janot, Bull. SOC. chim. France, 1957, 610.4 5 H. Conroy, Y. R. Brooks, M. K. Rout, and W. Silverman, J. Amer. Chem. SOL.,46 W. I. Taylor, ibid., p. 3298.47 MacPhillamy, Lucas, and Dzieman, unpublished work.48 F. Percheron, A. leHir, R. Goutarel, and M.-M. Janot, Compt. rend., 1957,49 W. I. Taylor, Experientia, 1957, 13, 454.6O J. Schmutz, F. Hunziker, and R. Hirt, Helv. Chim. Acta, 1957, 40, 1189.1957, 79, 1763.245, 1141260 ORGANIC CHEMISTRY.Four new alkaloids have been isolated from the ergot fungus growing ona tropical millet ; 5 l three of them are hydroxy-derivatives of agroclavineand elymoclavine; the fourth, chanoclavine, has been given structure (28).Pyrrolizidine Group.-Molecular-rotation arguments have led to proposalsfor the absolute configuration of the necines ; 52 thus, isoretronecanol hasbeen given structure (29).Phenanthridine Group.-The already large number of alkaloids in thisgroup is still increasing, eleven new ones having been added to it this yearby H.-G.Boit and his co-worker~.~~ Belladhe,% which has been givenstructure (30), is so far the simplest of the Amaryllidaceae alkaloids, andmay well represent the skeleton of the precursor of all the others. Biogeneticschemes on these lines are described.M*55 Galanthamine has been shown 56to have structure (31), which had been predicted on biogenetic grounds.55It is remarkable that the immediate precursor of the alkaloid (31) in thebiogenetic scheme,55 the corresponding a@-unsaturated ketone, ha5 sub-sequently turned out to be the alkaloid nar~edine.~'Diterpene Group.-Ajaconine has been shown to contain the atisineskeleton by degradation to an oxygen-free base obtainable from atisine; 58later work 59 has in fact shown it to be a hydroxyatisine. This is the firstdemonstration of the atisine skeleton in a delphinium alkaloid. Napellonine,an aconite alkaloid, has been shown to contain a modified Garrya-typeskeleton: e0 the main point of interest in the structure proposed, (32), is5l A.Hofmann, R. Brunner, H.Kobel, and A. Brack, Helv. Chim. Acta, 1957,40,1358.52 N. J. Leonard, Chem. and I n d . , 1957, 1455.6* H.-G. Boit and H. Emke, Chem. Ber., 1957, 90, 57, 369; H.-G. Boit, S. Uyeo,and H. Yajima, ibid., p.. 363; H.-G. Boit, W. Stender, and A. Beitner, ibid., p. 725;H.-G. Boit and W. Dopke, ibid., p. 1827; H.-G. Boit, W. Dopke, and W. Stender,ibid., p. 2203.64 E. W. Warnhoff, Chem. and Ind., 1957, 1385.55 D. H. R. Barton and T. Cohen, ref. 1, p. 126.5 6 Personal communication from S. Uyeo to H.-G. Boit in ref. 57.5' H.-G. Boit, W. Dopke, and A. Beitner, Chem. Ber., 1957, 90, 2197.5 8 D. Dvornik and 0. E. Edwards, Chem. and Ind., 1957, 952.5@ S. W. Pelletier, ibid., p. 1670.60 K. Wiesner, 2. Valenta, J. F. King, R. K. Maudgal, L. G. Humber, and Sh6 It6,ibid., p.173SMITH : ALKALOIDS. 261the presence of an extra ring postulated to involve the linking of positions17 and 8. The arguments for this are based largely on the interpretationof infrared spectra and pK, data.By assuming skeletal identity with lycoctonine, structures have beententatively proposed for delcosine 61 and aconitine.62 A structure proposed 63for delphinine has been withdrawn.64Miscellaneous.-The structure of muscarine has at last been elucidated: 65X-ray crystallography revealed it to be (33), in agreement with the formationof the rt-hexyltrimethylammonium ion by chemical degradati0n.6~0In other work on muscarine, a most interesting application of catalyticoxidation resulted in a good yield of the corresponding ketone, shown byits infrared spectrum to be of cyclopentanone type.66 Of three groups whohave reported synthetic work, one describes the formation of a mixture ofstereoisomers which contains about 30% of muscarine iodide, from whichno crystalline material could be i~olated,~' another a non-stereospecificsynthesis leading to crystalline (&)-muscarhe iodide,G8 and a third asynthesis which reveals the absolute configuration of muscarine 6@ to berepresented by (33).The last synthesis starts from L-glucosaminic acid andproceeds by L-chitaric acid, its dimethylamide (34) ,. the tritoluene-p-sulphonate of which on reduction by lithium aluminium hydride gives a lowyield of muscarine, isolated as the tetraphenylboronate.6Me ( 3 6 )The admirably systematic degradation of nupharidine, 70 one of thealkaloids of the rhyzome of the Japanese variety of the water-lily, hasbrought to light a novel sesquiterpenoid structure of quinolizidine type, (35).R. Anet, D.W. Clayton, and L. Marion, Canud. J . Chem., 1957, 35, 397.62 W. Schneider, Nuturwiss., 1957,44,492; W. Schneider and H. Tausend, ibid., p. 512.63 See Ann. Reports, 1956, 53, 249.64 W. A. Jacobs and S. W. Pelletier, J . Org. Chem., 1957, 22, 1428.65 F. Jellinek, Actu Cryst., 1957, 10, 277; F. Kogl, C. A. Salemink, H. Schouten,6 6 C. H. Eugster and P . G. Waser, Helv. Chim. Acta, 1957, 40, 888.87 F. Kogl, H. C . Cox, and C. A. Salemink, Annulen, 1957, 608, 81.6 8 C. H. Eugster, Helv. Chim. Actu, 1957, 40, 2462.6 s E. Hardegger and F.Lohse, ibid., p. 2383.7 0 M. Kotake, S. Kusumoto, and T. Ohara, Annalen, 1957, 606, 148.and I;. Jellinek, Rec. Trav. chim., 1957, 76, 109262 ORGANIC CHEMISTRY.A neat synthesis of cryptopleurine (36) has been de~cribed.~~ Very interest-ing is the appearance of an analogous structure in tylophorine, for whichformula (37) was advanced. 72Further oxidative experiments have enabled Wiesner and his co-workers 73to propose structure (38) for annotinine: this represents a completion of the0 ,q 0%.N N(38)partial structure proposed63 by the same school in 1956. This brilliantdeduction of structure (38) for annotinine was later spectacularly confirmedby X-ray crystallographic determination 74 of the structure of the corres-ponding bromohydrin (39).G.F. S.10. STEROIDS.A COMPILATION of the optical rotations of steroids1 has been produced,which is incidentally of great value in providing a survey of steroid literatureup to 1954.Physicochemical measurements. Optical rotatory-dispersion measure-ments have been used to correlate the absolute configurations of steroidswith those of other natural products.2Infrared spectroscopic studies have been made of the carbonyl absorptionin a-halogeno- steroid^,^ and in steroidal 16 : 17-ketols and keto-acetates!of the absorptions in the C-H stretching region modified by the presence ofepoxide groups and methoxyl group^,^ and of the absorption of 1 : 2-di-substituted cis-ethylenic centres.A mass spectrometer has been used in the determination of the molecularweights of steroids; the method also affords information on the length ofthe side chain (if any) which is split off in the process.General reactions.A method for the preparation of 3p-fluoro-A5-steroidsinvolves treatment of the corresponding toluene-P-sulphonates with mag-nesium iodide, and then with silver fluoride in acetonitrile and ~ y l e n e . ~7 1 C. K. Bradsher and H. Berger, J. Amer. Chem. SOC., 1957, 79, 3287.72 T. R. Govindachari, M. W. Lakshmikantham, K. Nagarajan, and B. R. Pai,73 K. Wiesner, W. A. Ayer, L. R. Fowler, and 2. Valenta, ibid., p. 564.74 M. Przybylska and L. Marion, Canad. J . Chem., 1957, 35, 1075.1 J. P. Mathieu and A. Petit, ‘‘ Tables de Constantes et Donnkes Numeriques,” 6,“Constantes SClectionn&, Pouvoir Rotatoire Nature], I, StCroYdes,” Masson et Cie,Paris, 1956.C. Djerassi, R.Riniker, and B. Riniker, J. Amer. Chem. SOC., 1956, ‘78, 6362.R. N. Jones and G. Roberts, Chem. and Ind., 1957, 1269.H. B. Henbest, G. D. Meakins, B. Nicholls, and K. J. Taylor, J., 1957, 1459. * H. B. Henbest, G. D. Meakins, B. Nicholls, and A. A. Wagland, ibid., p. 1463.7 H. B. Henbest, G. D. Meakins, B. Nicholls, and R. A. L. Wilson, ibid., p. 997. * P. de Mayo and R. I. Reed, Chem. and Ind., 1956, 1481.Chem. and Ind., 1957, 1484.3 E. G. Cummins and J . E. Page, J., 1957, 3847.T. N. Jacobsen and E. V. Jensen, ibid., 1957, 172; c f . C. W. Shoppee and G. H. R.Summers, J . , 1957, 4813BLADON : STEROIDS. 263The other 3p-halogeno-A5-steroids can be made by treating the corres-ponding alcohols with an aluminium halide.1° 17p-Hydroxyl groups areunaffected by aluminium chloride, and so this reagent is of value in selectivelyreplacing the 3p-hydroxyl group in 38 : 17p-diok.The solvolysis of salts and methyl esters of cholesteryl and cholestanylhydrogen sulphates has been studied, and the mechanism of the reactiondiscussed.llOxidation of A5-stenols with chromic anhydride-sulphuric acid in acetoneaffords good yields of A5-3-ketonesJ and after acid treatment, A4-3-ketones.12All the isomeric cholestane-2 : 3-diols are now known,13 and severall-oxygenated derivatives in the A/B-cis-series have been made from methyl1 f3 : 3~-dihydro~yetiocholanate.~~Reagents: I , Zn-&OH.2 , Zn-AcOH o n semicarbazone with subsequent regeneration ofketone.3, HCI-EtOH.Reductive removal of 17cc-, 17p-, and 21-acetoxy-groups in the corticalhormone series has been studied. The accompanying formulz (1-6) showthe chief transf 0rmations.lBoth allopregnane-3p : 17a : 20-triols (7) are converted into the 20-ketone(8) by acid treatment.lCExperiments with 2-, 3-, 4-, 6-, and 7-amino-steroidsJ and with 6-amino-3 : 5-cyclo-steroids have shown that the de-amination of equatorial amineswith nitrous acid gives the corresponding equatorial alcohols in good yield.The axial amines give the axial alcohols together with varying amounts ofelimination products. l7Representative saturated 3-, 12-, 17-, and 20-oxo-steroids, and A5-7-ketones and Als-20-ketones have been shown to react in the normal way withmethylenetriphenylphosphorane (the Wittig reagent) , to yield the corres-ponding methylene compounds.18lo J.Broome, B. R. Brown, and G. II. li. Summers, J., 1957, 2071.l1 J. McKenna and J. K. Norymberski, ibid., pp. 3889, 3893.l2 C. Djerassi, R. R. Engle, and A. Bowers, J . Org. Chem., 1956, 21, 1547.l3 H. B. Henbest and M. Smith, J., 1957, 926; C. W. Shoppee, D. N. Jones, andG. H. R. Summers, ibid., p. 3100.l4 W. Schlegel and C. Tamm, Helv. Chim. Acta, 1957, 40, 160.l6 R. S. Rosenfeld, J . Amer. Chem. SOC., 1957, 79, 5540; H. L. Slates and N. L.Wendler, J . Org. Chem., 1957, 22, 498.l6 D. K. Fukushima and T. F. Gallagher, J . Biol. Chem., 1957, 226, 725.l7 C. W. Shoppee, D. E. Evans, and G.H. R. Summers, J., 1957, 97; D. E. Evansand G. H. R. Summers, ibid., p. 906; C. W. Shoppee, R. J. W. Cremlyn, D. E. Evans,and G. H. R. Summers, ibid., p. 4364.F. Sondheimer and R. Mechoulam, J . Amer. Clzem. SOC., 1957, 79, 5029264 ORGANIC CHEMISTRY.Lithium tri-tert.-butoxyaluminium hydride reduces steroid 3-ketones togive equatorial alcohols in yields of over 90y0.19Lund 2o has shown that electrolytic reduction of A4-3-oxo-steroids givesrise to pinacols (9). In the particular case of the doubly unsaturatedl-dehydrotestosterone, either of two isomeric pinacols can be obtained,depending on the pH of the solution, but the arguments used by the authorto assign configurations to these pinacols are open to question.Chloranil has found a use as a dehydrogenating agent for A4-oxo-cortico-steroids.21 Double bonds are introduced at position 5 and under morevigorous conditions at position 1 (formulae 10-13).Reagents: I, Chloranil-xyfene at the b.p.2, Chloranif-n-pentyl alcohol at the b.p.Velluz and his collaborators22p23 have studied the reactions of the di-hydroperoxides formed by treating 3-, A4-3-, 17-, and 20-oxo-steroids withhydrogen peroxide. Those derived from 20-ketones (14) give 17-acetoxy-compounds (15) on treatment with foimic acid, while with mineral acids,derivatives of tetraoxacyclohexane (16) are formed.22The 17 : 17-di-hydroperoxide (18) derived from 3a-acetoxy-5P-androstane-11 : 17-dione (17), on treatment with acetic anhydride andpyridine, gives a lactone (19); when heated in an inert solvent it gives theOAc(14) (16)Reagents: I , H*CO,H.2, AcOH-H,SO,.stereoisomeric lactone (20). Both lactones are converted into the knownunsaturated acid (21) by base.23 The first of these lactones is also formedtogether with small quantities of the isomeric lactone (22) by oxidation ofthe 17-ketone (17) with peracids.=l9 0. H. Wheeler and J. L. Mateos, Chem. and Ind., 1957, 395.20 H. Lund, Acta Chem. Scand., 1957, 11, 283.21 E. J. Agnello and G. D. Laubach, J . Amer. Chem. Soc., 1957, 79, 1257.22 J. Warnant, R. Joly, 3. Mathieu, and L. Velluz, Bull. SOC. chim. Fvance, 1957,23 L. Velluz, G. Amiard, J. Martel, and J. Warnant, Compt. rend., 1957, 244, 1937.2* A. Lardon, J. Schmidlin, A. Wettstein, and T. Reichstein, Helv.Chim. Ada,1957, 40, 662; cf. N. L. Wendler, D, Taub, and H. L. Slates, J . Amer. Chem. SOC.,1955, 77, 3560; M. F. Murray, B. A. Johnson, R. L. Pederson, and A. C . Ott, ibid.,1956, 78, 982.331; L. Velluz, G. Amiard, J. Martel, and J. Warnant, ibid., p. 879BLADON : STEROIDS. 265The unsaturated acids (21) and (25; A/B-tYalaS, 3B-OAc) [obtained by asimilar Baeyer-Villiger reaction from (17) and the D-homo-ketone (23)],Reagents: I, H,O,-ButOH. 2, Xylene or Bu20 at b.p. 3, Ac20-pyridine. 4, Ph*C03H orAcOZH. 5, OH-. 6 , CFSCOSH. 7, Ph-CHO-HCI. 8, (COCI),; CH2N2; HI. 9, OH-. 10,LiAIH,; 0,.or -OH.In formulae 17-22, the suffix " a " 3 A/B-Cis, 3a-OAc or -OH; I ' b " = A/B-tfans, 3P-OAchave been used as intermediates in an attempted partial synthesis of aldo-sterone.The masked Waldehyde group was introduced via an inter-mediate benzylidene derivative (26), epimerization at position 14 occurringsimultaneously. The subsequent cyclisation steps (26 _t 28) were influencedmarkedly by the configuration at C(la (cf. 25 _t 30 - 31), and the desired(clD-trans, 14a-H : 17 p-CO-CH,) structure was not achieved.25The reactions of a wide range of steroid epoxides with the boron tri-fluoride-ether complex 26 (leading to ketones) and with metal-amine reducingsystems 27 have been studied.Steroids containing an 8 : 9-double bond (hitherto difficultly accessible)25 D. H. R. Barton, A. da S. Campos-Neves, and A. I. Scott, J., 1967, 2608.26 H. B. Henbest and T. I. Wrigley, ibid., p. 4596.'7 A.S. Halsworth and H. B. Henbest, &bid., p. 4604266 ORGANIC CHEMISTRY.are formed by reducing 1 l-oxygenated As(g)- or &oxygenated hg(l1)-com-pounds with lithium and ethylamine 28 (32 _t 34, R = H; 33 _t 34,R = OH).Interest in derivatives in which one or more of the ring junctions B/Cand C/D has an abnormal configuration has continued. The chart (formulae35-48) summarises the findings of two groups working in the sapogenin 29and ergostane 30 series. The former group extended the work to synthesesReagents: I, OH-. 2, Li-NH3 (liquid). 3, H,-Pd-C. 4, LiAIH,; Ac,O-AcOH. 5, Kishner-Wolff reduction. 6, Kishner-Wolff (forcing conditions). 7, LIAIH,; POC13-pyridine. 8, H,-Pt-AcOH.of 8cc-proges terone and 8a-tes tost e r ~ n e . ~ l Work on 14p-compounds hasincluded the total synthesis of 14p-cestrone methyl ether.32 An analysis ofthe conformations of all thirty-two isomeric 13p-methylstan-3~-ols has beenpublished.33to have the structure (49) " Ketone 104 " is now believed by Fieser28 A.S. Halsworth, H. B. Henbest, and T. I. Wrigley, J . 1957, 1969.2s C. Djerassi and G. H. Thomas, J . Amer. Chem. SOC., 1957, 79, 3835.80 J . B. Bream, D. C. Eaton, and H. B. Henbest, J . , 1957, 1974.3 l C. Djerassi, A. J. Manson, and H. Bendas, Tetrahedron, 1057, 1, 22.32 W. S. Johnson and W. F. Johns, J . Amer. Chevn. SOC., 1957, 79, 2006.33 J. Castells, Pub,?. Ivzst. Quim. Alonso Barba, 1956, 10, 84.34 L. F. Fieser, in " Festschrift Arthur Stoll," Verlag Birkhauser, Basel, 1957, p. 489BLADON : STEROIDS. 267and to be an oxidation product of cholesterol itself, and not of a companionof ch~lesterol.~~Photochemical oxygenation of cholesterol in pyridine solution in thepresence of sensitisers such as haematoporphyrin and Rose Bengal 36 givesHO 03 H 6the A6-5-hydroperoxide (50), proof of the structure of which rests on itsconversion into the known 37 cholest-6-ene-3P : 5a-diol.Cholesterol reacts with periodic acid to yield cholestane-3p : 501 : 6P-trio1and 38 : 5a-dihydroxycholestan-6-one (52).The reaction is presumed to gothrough the intermediate a-oxide which (a) under the influence of excess ofacid yields the triol or (b) by attack of periodic acid yields the 6p-periodate(51) which can decompose in the manner shown to give the 6-ketone (52).It is necessary to postulate such a mechanism, since the triol is not oxidisedto the ketone (52) by periodic acid.38Ozonolysis of cholesterol in inert solvents has long been known to givean amorphous ozonide of uncertain composition. Ozonolysis in the presenceof alcohols 39 (ROH), however, yields crystalline compounds formulated as(53).Both the amorphous ozonide and the crystalline products are reducedto the 5 : 6-secocholestane-3p : 5 : 6-triol (54) by lithium aluminium hydride.Molecular rearrangements. Further examples of the Wagner-Meerweinrearrangements of 17a-alcohols and 16a : 17a-epoxides have been reported,*Oand the reactions occurring may be rationalised as follows. Under theinfluence of acid, the 17-hydroxyl group is removed or the epoxide ringopened, to give the cation (57; R' = H and OH respectively).This isfollowed by migration of the 13P-methyl group to the 17p-position (the group35 L. F. Fieser, W-Y. Huang, and B. K. Bhattacharyya, J . Org. Chem., 1957,22,1380.36 G. 0. Schenck, K. Gollnick, and A. 0. Neumiiller, Annulen, 1957, 603, 46.37 H. B. Henbest and E. R. H. Jones, J., 1948, 1792.3* R. P. Graber, C . S. Snoddy, jun., H. B. Arnold, and N. L. Wendler, J . Org. Chem.,1956, 21, 1517.SB H. LettrC and A. Jahn, Annalen, 1957, 608, 43; Agigew. Claem., 1957, 69, 266;cf. H. Lettr6 and D. Hotz, ibid., p. 267.40 (a) 0. S. Madayeva and Yu. N. Sheinker, Zhur. obshchei Khim., 1956, 26. 2937,3198, 3201; ( b ) B. Camerino and A. Vercellone, Gazzettu, 1956, 86, 260, 1219; (c) H.L.Herzog, C . C . Joyner, M. J. Gentles, H. T. Hughes, E. P. Oliveto, E. B. Hershberg,and D. H. R. Barton, J . Org. Chem., 1957, 22, 1413; ( d ) K. Heusler and A. Wettstein,Chew. Ber., 1954, 87, 1301268 ORGANIC CHEMISTRY.R adopting the a-configuration) (58). According to Herzog and his col-leagues4OC in the particular case they dealt with (55; A/B-cZ'S, 301 : 11s : 2Op-triacetoxy), subsequent loss of a proton occurs from position 12 to give aMe12 : 13-double bond (cf. 59), in agreement with the formulation proposed byMadayeva for the compounds she was studying. The alternative, of lossof a proton from position 14 with consequent formation of the A13-structure(60), was discounted by nuclear magnetic resonance evidence. Earlierworkers had favoured this alternative structure (60) but had put forwardno evidence for it.It is worth noting that this type of rearrangement occurswith steroids unsubstituted at 11 or having an 11Q-hydroxyl group; anll-0x0 group inhibits the reaction.40cApplications of the Favorski reaction to 2a-bromocholestan-3-one (61),to 4 p-bromocoprost an-3-one 41 (U), and to 3 p-acet ox y-17 or-bromo-2 1 -iodo-pregn-5-en-20-one 42 (69) are illustrated in the accompanying formulae. TheReagents: I , OMe-. 2, Barbier-Wieland degradation. 3, OH-.structures assigned to the two acids (70) and (71) are based on the lowerintensity of light absorption in the ultraviolet region shown by the acid (71),41 D. El Evans, A. C. de Paulet, C. W. Shoppee, and F.Winternitz, J., 1957, 1451..43 J. Romo and A. Romo de Vivar, J. Amer. Chem. Soc., 1057,79, 1118BLADON : STEROIDS. 269presumably owing to inhibition of resonance by the interaction of thecarboxyl and the 13-methyl group.Beckmann rearrangement of the oximes of 17a-hydroxy-20-oxo-steroidsaffords 17-ketones 43 (cf. the similar transformation of oximes of A1s-20-0x0-steroids 44).Prednisone acetate on irradiation with ultraviolet light undergoes theinteresting rearrangement (72 __t 73) .45The structure of the products of the anthrasteroid rearrangement hasbeen shown to be (73a).450( 7 3'),OAc '1.Sterol side chain. A new method for the degradation of the stigmasterolside chain has been disc20sed.~~ 3~-Acetoxy-5a-chlorobisnorcholanaldehyde(74) was converted into a compound with the 17a-hydroxy-20-oxo-side chainby a series of reactions (74 _t 77).An unsaturated aldehyde similar t o (75)&CHO&{fi0 {5 O.CHO {fl"L L( 7 5 ) ( 7 6 ) ( 7 7 )Cl ( 7 4 )Reagents: Br,-CHCI,; H*CO*NMe,. 2, Perphthalic acid. 3, OW.has been converted into a 17-ketone by ozonolysis of the derived cyano-h y drin .4The synthesis of 24-methylenecholesterol from 24-oxocholesterol andmethylenetriphenylphosphorane has been reported by two groups.48Bergmann and Dusza 48e conclude that chalinasterol (from sea anemones)and ostreasterol (from oysters) which were previously known to be identical(and had been assigned the structure 24a-ethylcholesta-5 : 22-dien-3p-01 49),are in fact 24-methylenecholesterol (cf.ref. 48c). Idler and Fagerlund 48bhave also applied the Wittig reaction to the preparation of cholesta-43 J. Schmidt-ThomC, Annalen, 1957. 608, 43.44 E. Testa and F. Faua, Gazzetta, 1957, 87, 971; cf. Ann. Re$orts, 1956, 53, 222.45 D. H. R. Barton and W. C . Taylor, Proc. Chem. SOC., 1957, 147.45a A. W. Burgstahler, J. Amer. Chem. SOC., 1957, 79, 6047; cf. Ann. Re$orts, 1955,46 E. M. Chamberlin, E. Tristram, T. Utne, and J. M. Chemerda, J . Amer. Chem.4 7 R. L. Pederson, J. L. Johnson, R. P. Holysz, and A. C. Ott, ibid., p. 1115.4 8 (a) W. Bergmann and J. P. Dusza, Annalen, 1957, 603, 36; (b) D. R. Idler andU. H. M. Fagerlund, J . Amer. Chem. SOC., 1957, 79, 1988; (c) idem, Chem. and Ind.,.1957. 432.49 W. Bergmann and E. 11. Low, J .Org. Chem., 1947, 12, 67.52, 214.SOC., 1957, 79, 456270 ORGANIC CHEMISTKY.5 : 25-dien-3P-01 from 25-oxo-26-norcholesterol. The product differs from thesubstance previously assigned this structure 50 (formed by dehydration of a25-hydroxy-compound), which therefore must be 24-dehydrocholesterol.Bile acids. A series of three papers 51 describes the synthesis of a largenumber of bile acid derivatives, for possible use as serum-flocculating agents.Two new bile acids (“ Acid I ” and “ Acid I1 ”), isolated from the bile ofrats and pigs,52a have been shown to be respectively 3a : 6a : 7p- and3a : 6P : 7a-trihydroxycholanic Work on the related hyocholicacid and hyodeoxycholic acid has been reported.53The two stereoisomeric (at-position 25) 3a : 7a : 12a-trihydroxycoprostanicacids (81) have been synthesised.% The sodium salts of cholic acid (78) andmethyl hydrogen D- or L-a-methylglutarate (79) were electrolysed together.The additional carbon atom in the product (80) was removed by the Barbier-Wieland method.Vitamins D and Related Compounds.-The first partial synthesis ofcalciferol(85a) from the aldehyde (82) has been announced by Harrison andL y t h g ~ e .~ ~ It was carried through stages (83- 85) withmixtures of stereo-isomers which were separated after the last stage (as 3 : 5-dinitrobenzoates)into calciferol (85a) and eeicalciferol (85b), which was the major componentand was previously unknown. These workers questioned the validity ofthe earlier synthesis claimed by Inhoff en and his colleagues.56 The isomerscalciferol57 (85a), eeicalciferol 55 (85b), and 5 : 6-tra~zs-eeicalciferol 56 (87) allgive the same ketone (86) on Oppenauer oxidation. Inhoffen has alsoreviewed earlier work on partial synthesis of vitamins D.5850 A. I. Ryer, W. H. Gebert, and N. M. Murrill, J . Amer. Chem. Soc., 1950,72,4247;W. G. Dauben and H. L. Bradlow, ibid., p. 4248.51 F. C. Chang, R. T. Blickenstaff, A. Feldstein, J. R. Gray, G. S. McCaleb, andD. H. Sprunt, J . Amer. Chem. SOC., 1950, 72, 2161, 2164; F. C. Chang, A. Feldstein,J . R. Gray, G. S. McCaleb, and D. H. Sprunt, ibid., p. 2167.52 (a) J. T. Matschiner, T. A. Mahowald, W. H. Elliott, E. A. Doisy, jun., S. L.Hsia, and E. A. Doisy, J . Biol. Chem., 1957,225, 771 ; T. A. Mahowald, J.T. Matschiner,S. L. Hsia, R. Richter, E. A. Doisy, jun., W. H. Elliott, and E. A. Doisy, ibid., p. 781;( b ) S. L. Hsia, J. T. Matschiner, T. A. Mahowald, W. H. Elliott, E. A. Doisy, jun.,S. A. Thayer, and E. A. Doisy, ibid., p. 811; (c) idem, ibid., 1957, 226, 667.53 P. Ziegler, Canad. J . Chem., 1956, 34, 1528; A. Corbellini and G. Nathansohn,Gazzetta, 1956, 86, 1240.54 R. J. Bridgwater, Biochem. J., 1956, 64, 593.5 5 I. T. Hamson and B. Lythgoe, Proc. Chem. SOC., 1957, 261.5 6 H. H. Inhoffen, J. Kath, W. Sticherling, and K. Briickner, Annulen, 1957, 603,67 S. Trippett, J.. 195g: 370.Festschrift Arthur Stoll,,” Verlag Birkhauser, Basle, 1957,25.H. H. Inhoffen, inp. 419BLADON STEROIDS. 271By a similar series of reactions, the derivative of cholestanone (88) hasbeen converted into the analogue of calciferol (89) which is biologicallyactive.59R ROHC P ( 8 2 )epi-5:6-trons-V i t a m i n D/4,(85a(85bHOI ) 6-OH) a - O H(cis) Vitamin D and EpimerR = CsH1,. Reagents: I, 4-Acetoxycyc/ohexanone. 2, Ultraviolet light. 3, Ph,P=CHp,4, Oppenauer oxidation.Reagents : I , 4-Met hoxycyclo hexanone-NaOH. 2, Ph,P = CH 2 aMe / MeOHPre-vitamin DPrecalciferolR= C9H17iroTachyrterol isovitamin Di s o Calci fer o lTach y s t e r olAgreement seems to have been reached among the various groups ofworkers as to the formulz. of the B-seco-isomers of the vitamins D. Thestructures and preferred conformations (85, 87,90-93) are those put forwardb9 N. A. Milas and C.Priesing, J . Amer. Chem. Soc., 1957, 79, 3610272 ORGANIC CHEMISTRY.by Havinga and his co-workersJ60 on the basis of spectroscopic results andstudies of the reactivity of the compounds towards maleic anhydride(cf. refs. 58, 61). The structures suggested for the dihydrovitamin anddihydrotachysterol isomersEvidence has been produced 63 which leads to the formulze (94) and (95)for pho t oisop yrocalcif erol and pho t op yrocalci f erol respectively .seem to be less certain.R RSteroid Sapogenins-Much interest has centred on m~cogenin.~~ Thehydroxyl group previously thought to be at position 19 is now known to beat position 1, and has been assigned the P-configuration, largely on the basisof molecular-rotation data 65 and the degradation 66 to the known 67androst-5-ene-1 p : 3(3 : 17p-tri01.~~ Ruscogenin is usually contaminated byan isomer, neorus~ogenin.~~ Oxidation of pseudoruscogenin and pseudoneo-ruscogenin led to (-)- and (+)-=-methylglutark acid respectively.69bMeHHORuscogenin is therefore 22a : 25~-spirost-5-en-lp : Sp-diol (96; R = Me,R = H), and neoruscogenin is the corresponding 25~-isomer (96; R = H,R' = Me).Willagenin,'O a new sapogenin from Yucca$Zilifera, has been shown to be12-oxosarsasapogenin (97).6o A.Verloop, A. L. Koevoet, and E. Havinga, Rec. Trav. chim., 1957, 76, 689; cf.references 58 and 61.61 L. Velluz, G. Amiard, and B. Goffinet, Compt. rend., 1955, 240, 2076, 2156,2326; Bull. Soc. chim. France, 1955, 1341.62 P. Westerhof and J. A. K. Buisman, Rec.Trav. chim., 1956, 75, 453; 1957, 76,679; J. L. J. van de Vliervoet, P. Westerhof, J. A. K. Buisman, and E. Havinga, ibid.,1956, 75, 1179; F. van Werder, Naturwiss., 1956, 43, 380; Annalen, 1957, 603, 15.65 W. G. Dauben and G. J. Fonken, J . Amer. Chem. Soc., 1957, 79, 2971.1 3 ~ Cf. Ann. Reports.. 1955, 52, 223.6 s H. Lapin, Compt. rend., 1957, 244, 3065.e6 W. R. Benn, F. Colton, and R. Pappo, J . Amer. Chem. Soc., 1957, 79, 3920.13' R. M. Dodson, A. H. Goldkamp, and R. D. Muir, ibid., p. 3921.a Cf. A. L. Nussbaum, F. E. Carlon, D. Gould, E. P. Oliveto, E. B. Hershberg,6s ( a ) D. Burn, B. Ellis, and V. Petrow, Proc. Chem. Soc., 1957, 119; (b) C. Sanni67 O H. E. Kenney and M. E. Wall, J . Org. Chem., 1957, 22, 468.M. L. Gilmore, and W.Charney, ibid., p. 4814.and H. Lapin, Bull. Soc. chim. France, 1957, 1237BLADON : STEROIDS. 273The oxidation of cyclopseudotigogenin (20-isotigogenin) (98) was shownto give a 20~-hydroxy-derivative (99). The tertiary character of thehydroxyl group follows from its resistance to oxidising and acetylating42-( 9 8 )TS f p-C&i.+Me-S02 0(103) (102)Reagents: I , Cr0,-AcOH. 2, SOCl,pyridine. 3, 0 5 0 , . 4, H2-Pt-AcOH. 5, HIO,.6, 0,. 7, p-C,H,Me*SO,CI. 8, LIAIH,.agents, and its position is made certain by the transformations outlined inthe f0rmula2.~~ The similarity of the infrared spectrum of compound (100)to that of tigogenin acetate is cited as evidence that (in the 25~-series) thesole difference between the sapogenins and the cyclopseudosapogenins is theconfiguration of the 20-methyl group.That this conclusion is not acceptedby all workers is implied in the nomenclature scheme proposed by R ~ s e n . ~ ~The scheme can be criticised as not conforming to the accepted usages[e.g., the cyclopseudosapogenins are called 21-p(sic) -sapogenins] .Wall and his co-workers have reported studies on the isomeric 23-bromo-derivatives of diosgenin and tigogenin, 73 on gentrogenin (12-oxodiosgenin),and on correllogenin (12-0xoyarnogenin),~* as well as on the conversion ofgentrogenin into 3p-acetoxy-17~+hydroxypregn-5-ene-12 : 20-dione 75 andinto 1 l-oxodiosgenin.76Steroid Alkaloids.-A second elegant correlation of the alkaloidstomatidine and solasodine with the sapogenins neotigogenin and tigogeninrespectively has been reported. The N-acetyl derivatives of the dihydro-alkaloids were converted into the N-nitroso-compounds and thence, bythermal decomposition and hydrolysis, into the dihydrosapogenins.Theoccurrence together in Solanum tzlberoszkm of tomatid-5-en01 and the corres-ponding sapogenin, yamogenin, is of interest.7871 M. E. Wall and H. A. Walens, Chem. and Ind., 1957, 818.72 W. E. Rosen, ibid., p. 703.73 M. E. Wall and H. W. Jones, J . Amev. Chem. SOC., 1957, 79, 3222.74 H. A. Walens, S. Serota, and M. E. Wall, J . Org. Chem., 1957, 22, 182.76 E. S. Rothman and M. E. Wall, ibid., p. 223.76 Idem, J . Amer. Chem. Soc.. 1957, 79, 3228.77 Y . Sat0 and H. G. Latham, jun., J . Org. Chern., 1957, 22, 981; Y.Sato, H. G.Latham, jun., L. H. Briggs, and R. N. Seelye, J . Amer. Clzem. Soc.. 1957, 79, 6089;cf. Ann. Reports, 1956, 53, 226.78 K. Schreiber, Angew. Chem., 1957, 69, 483274 0 KG AN IC C H E bl 1 STH 1’.The glycosidic alkaloid, tomatine, forms an insoluble molecular complexwith cholesterol and other sterols, and has been suggested as an (expensive)alternative to digitonin as an analytical reagent.79The chemistry of jervine and veratramine has been reviewed.sOAttention is drawn to a review 81 of cardiac aglycones.Total Synthesis.-This subject was not dealt with in last year’s Report,and so work disclosed in the two years 1956 and 1957 is recorded here. Ofgreat interest is the monumental series of papers 82s83 detailing the work ofJohnson and his colleagues on the “ hydrochrysene ” approach.Most ofthe important results had been announced in preliminary communications.A modification of this synthesis which allows of more stereochemical controlin the introduction of the 13-methyl group involves the use of intermediateshaving a 9 : ll-double bond, the presence of which has a profound influenceon the stereochemistry of the cyclisation step. 83a Experiments on bicyclicmodels also suggested an adaptation to the synthesis of 18-oxygenatedsteroids. B bThe first stages of a modification of the Cornforth-Robinson synthesis,in which an extra oxygen function (at position 11) is present throughout,have been detailed by a second group of workers at the Merck laboratories.MA new synthesis starting from 6-methoxy-l-tetralone (104) (the B-c ring7Q G.Schulz and H. Sander, 2. fihysiol. Chem., 1957, 308, 122.8 0 0. Wintersteiner, in “ Festschrift Arthur Stoll,” Verlag Birkhauser, Basle, 1957,p. 166.C. Tamm, Fortschr. Chem. org. Naturstoffe, 1956, 13, 137.82 W. S. Johnson, J . Amer. Chem. Soc., 1956, 78, 6278; W. S. Johnson, J .Szmuszkovicz, E. R. Rogier, H. I. Hadler, and H. Wynberg, ibid., p. 6285; W. S.Johnson, E. R. Rogier, J. Szmuszkovicz, H. I. Hadler, J. Ackerman, B. K. Bhatta-charyya, B. M. Bloom, L. Stalmann, R. A. Clement, B. Bannister, and H. Wynberg,ibid., 6289; W. S . Johnson, J. Ackerman, J. F. Eastham, and H. A. DeWalt, jun.,ibid., 6302; W. S. Johnson, A. D. Kemp, R. Pappo, J. Ackerman, and W. F. Johns,ibid., 6312; W. S.Johnson, E. R. Rogier, and J. Ackerman, ibid., 6322; W. S. Johnson,B. Bannister, and R. Pappo, ibid., 6331; W. S. Johnson, R. Pappo, and W. F. Johns,ibid., 6339; R. Pappo, €3. M. Bloom, and W. S. Johnson, ibid., 6347; W. S. Johnson,B. Bannister, R. Pappo, and J. E. Pike, ibid., 6354.8s ( a ) W. S. Johnson and D. S. Allen, jun., ibid., 1957, 79, 1261; ( b ) W. S. Johnson,D. G. Martin, R. Pappo, S. D. Darling, and R. A. Clement, Proc. Chem. Soc., 1957, 58.84 W. F. Newhall, S . A. Hams, F. W. Holly, E. L. Johnston, J . W. Richter, E.Walton, A. N. Wilson, and K. Folkers, J . Amer. Chem. Soc., 1955, 77, 5646; E.Walton, A. N. Wilson, A. C. Haven, jun., C. H. Hoffman, E. L. Johnston, W. F.Newhall, F. N. Robinson, and F. W. Holly, ibid., 1956, 78, 4760BLADON STEROIDS.275moiety) has been described by Stork and his colleague^.^^ Ring D (six-membered) is introduced first, followed by ring A. The essential steps areshown in formulz (104 __t 109). The final product (109) is identical with acompound which has already been converted into cortisone.86 A similarapproach was also envisaged by M. J. T. Robinson 87 who arranged that the10-methyl group was present throughout.Details have appeared of the first total synthesis of aldosterone,*& andof a second synthesis following a somewhat similar approach,Sa both beingpart of a collaborative effort involving four laboratories.88cSteroid Biogenesis.-The discovery,sg that B-hydroxy-(3-methyl-&valero-lactone (110) (or the corresponding acid) is able to replace acetate in thesynthesis of squalene and cholesterol by rat-liver homogenate, has attractedmuch attention.g0 The yield of cholesterol from the lactone (110) is muchhigher than from other compounds (e.g., P-methylcrotonic acid andp-hydroxy-(3-methylglutaric acid) which have been postulated as inter-mediates in the acetate __t cholesterol pathway.Perhaps these other com-pounds are on an alternative route.g0dWhen the [2-14C]lactone (110) is transformed into squalene (lll), all theradioactivity appears 90a in the carbon atoms marked *. Further, incholesterol biosynthesised from similarly labelled material,g0e the radio-activity was detected in C(,) and (&, and in one of the terminal methylgroups of the side chain; it was absent from carbon at positions 20, 21, 23,24, and 25, and from the other terminal methyl group. From these resultsit can be concluded that the (head-to-tail) sequence of isoprene units isformed by condensation of the hydroxymethyl group of one molecule ofp6-dihydroxy-p-methylvaleric acid with the methylene group adjacent tothe carboxyl group in the next molecule.All the carboxyl groups areeliminated at some stage for, with carboxyl-labelled acid, no radioactivity isincorporated into cholesterol, but it is recovered as carbon dioxide. E9bThe conversion of lanosterol into cholesterol probably involves at leasttwo intermediates. The first is possibly a 4 : 4-dimethylcholestadienol (one85 G. Stork, H. J. E. Loewenthal, and P. C. Mukharji, J . Amer.Chem. Soc., 1956,a6 L. B. Barkley, M. W. Farrar, W. S. Knowles, H. Raffelson, and Q. E. Thompson,M. J. T. Robinson, Tetrahedron, 1957, 1, 49.88 ( a ) J. Schmidlin, G. Anner, J. R. Billeter, K. Heusler, H. Uebenvasser, P.Wieland, and A. Wettstein, Helv. Chim. Ada, 1957, 40, 1034, 1438, 2291; ( b ) A.Lardon, 0. Schindler, and T. Reichstein, ibid., p. 666; ( c ) cf. S. A. Szpilfogel, W. J.van der Burg, C. M. Siegmann, and D. A. van Dorp, Rec. Trav. chim., 1956, 75, 1043.(a) P. A. Tavormina, M. H. Gibbs, and J. W. Huff, J . Amer. Chem. SOL, 1956,78, 4498; ( b ) P. A. Tavormina and M. H. Gibbs, ibid., p. 6210.9~ ( a ) J. W. Cornforth, R. H. Cornforth, G. PopjBk, and I. Youhotsky-Gore,Biochem. J., 1957, 66, 10 P; ( b ) R. G. Gould and G. PopjAk, ibid., p.51 P; (c) D. L.,Azarnoff and G. L. Curran, J . Amer. Chem. Soc., 1957, 79, 2968; (d) cf. K. F. Gey,A. Pletscher, 0. Isler, R. Ruegg. and J. Wursch, Helv. Chim. Acla, 1957, 40, 2354;le) 0, Isler, J. Wiirsch, K. F. Gey, and A. Pletscher, ibid., p- 2369.78, 502.ibid., 1954, 76, 6014, 5017276 ORGANIC CHEMISTRY.double bond at position 24 : 25; another in the region of the B/C ringjunction) 01 and the second is probably zymosterol.92The details of the chemical degradation of cholesterol biosynthesisedfrom labelled acetate has appeared.93 With this, the biogenetic origin of allthe carbon atoms in cholesterol is known.It has been established that the 28-carbon atom of ergosterol (andeburicoic acid) is biosynthesised from f ~ r r n a t e .~ ~ Methionine is an inter-mediate and it appears that the methyl group in methionine is transferredintact to position 24 of the steroid side chain.Q5P. B.11. AMINO-ACIDS, PEPTIDES, AM) PROTEINS.THE two years since the last Report under this title 1 have seen remarkableprogress in the elucidation of the structures of natural peptides and proteinsand in the synthesis of peptides, and an attempt to give an adequate pictureof the achievements in these directions has left little space to devote towork on amino-acids, where development has chiefly been along establishedlines.those acids newly identified include 1-aminocyclopropane-1-carboxylic acid,spy-dihydroxyglutamic acid,* and S-methyl-~-cysteine,~ whose sulphoxide haspreviously been reported.It is interesting to note here that y-glutamyl-S-methylcysteine and its sulphoxide have also been found.g Timely warningshave been given of the danger of error in identifying amino-acids by paperchromatography alone. Homoserine and threonine have identical RP valuesin 5 out of 7 solvent systems investigated; Synge and Wood have pointedout that a change in chromatographic pattern after acid treatment is notalways due to the presence of a peptide,S whilst a mixture of eleven peptidesobtained from an aqueous extract of raw wool gave, both before and afteracid hydrolysis, two-dimensional chromatograms very similar to each otherand to that from a mixture of arnino-acid~.~Amino-acids.-Useful reviews of natural amino-acids have appeared;91 P.B. Schneider, R. €3. Clayton, and K. Bloch, J . Biol. Chem., 1957, 224, 175;9% J. D. Johnston and K. Bloch, ibid., 1957, 79, 1145.93 J. W. Cornforth, I. Y. Gore, and G. PopjAk, Biochem. J., 1957, 65, 94.94 H. Danielsson and K. Bloch, J . Amer. Chem. Soc., 1957, 79, 500; W. G. Dauben.G. J. Fonken, and G. A. Boswell, ibid., p. 1000.95 G. J. Alexander, A. M. Gold, and E. Schwenk. ibid., p. 2967; G. J. Alexanderand E. Schwenk, ibid., p. 4554.1 Ann. Reports, 1955, 52, 271.2 ( a ) F. C . Steward, R. M. Zacharius, and J. K. Pollard, Ann. Acad. Sci. Fenn., 1955,AII, 60, 321; (b) Festschrift Prof. Dr. Arthur Stoll, Birkhauser, Basel, 1957, p. 565;(c) H. Musso, Angew. Chem., 1956, 88, 313.3 L. F. Burroughs, Nature, 1957, 179, 360; M.-L. Vahatalo and A.I. Virtanen,Actu Chem. Scand., 1957, 11, 741.4 A. I. Virtanen and T. Ettala, ibid., p. 182.5 J. I?. Thompson, C. J. Morris, and R. M. Zacharius, Nature. 1956, 178, 593;J. B. Ragland and J. E. Liverman, Arch. Biochem. Siophys., 1956, 65, 574.7 J. A. Bakhuis, Nature, 1957, 180, 713.8 R. L. Synge and J. C. Wood, Biochem. J., 1956, 84, 252.9 K. R. Deane and E, V. Truter, Biochim. Biophys. Acta, 1955, 18, 435.F. Gautschi and K. Bloch, J . Amer. Chem. SOC., 1957, 79, 684.H. Rinderknecht, Chem. and Ind., 1967, 1384YOUNG : AMINO-ACIDS, PEPTIDES, AbiD PROTEINS. 277y- and 6-Aminovaleric acid have been synthesised by a route which maybe convenient for analogous amino-acids (not a) : loA simple synthesis of y-hydroxyproline (1) and y-allohydroxyproline (2)starts from the d y l derivative of acetamidomalonic ester.ll The diastereo-isomers were separated as their copper salts.In a series of investigationsof the stereochemistry of y-hydroxyproline and its derivatives, Witkop l2 has6;HO ( 1 )tested the validity of Hudson’s lactone rule for y- and 8-hydroxyamirlo-acids;the formation of a lactone from benzyloxycarbonyl-y-aZZohydroxy-L-proline(3) requires the stereochemistry of a D-sugar at C(,,, and in agreement with0-coDGHCSZO t= Ph.CHs*O*CO DG and LS relate the configuration to thatof D-glyceraldehyde and of I.-serine re-spectively.the rule the ladone has a-more positive specific rotation than the acid.An anomaly appeared in the case of the y-hydroxyornithine derivative (4),when pyridine was used as the solvent for the lactone, but in dimethylC ~ H I I .CO*NH*HzC c4° COiHL S C ~ H I ~ - C O .N ~ - $ ~ ~ H2i$L H L sH DG HO H LG HCH~.NH.CO*C~HII CHZ’NH2DG( 4 )( 5 )sulphoxide the rule was obeyed. On the basis of this rule, the erythro-configuration (5) is provisionally assigned to the 8-hydroxy-L-lysine derivedfrom collagen.lo Ng. Ph. Buu-Hoi and M. Sy, Cornpt. rend., 1966, 242, 2011.l2 B. Witkop, Ezpevientia, 1956, 12, 372.T. Wieland and U. Wintermeyer, Chem. Ber., 1957, 90, 1721278 ORGANIC CHEMISTRY.An interesting example of the direct resolution of a-amino-acids byl1 entrainment ” has been repo~3ed.l~ Crystallisation of DL-threonine towhich D-threonine had been added brought down the D-isomer in amountapproximately twice the weight added; a second crystallisation after theaddition of more racemate gave L-isomer, and after 10 such cycles two-thirdsof the racemate had been resolved, a final crystallisation giving opticallypure enantiomorphs.The purification of amino-mercapto-acids and -peptides is often effectedthrough insoluble metal mercaptides, but the regeneration of the thiol byhydrogen sulphide is tedious and not always satisfactory.An attractivealternative has been developed l4 in which mercury mercaptides are reducedquantitatively by electrolysis at a mercury cathode, in an apparatus of thetype used for the electrolytic removal of salts. For the regeneration ofpapain from its mercury derivative, E. L. Smith et aZ.15 recommend aninteresting procedure developed by Dintzis,lG in which thioglycollate isbound to a strong anion-exchange resin, which will then liberate thiols fromtheir mercapt ides.An unexpected observation is that when heated in phosphate buffer atpH 6.7 asparagine forms the p-lactam of aspartic acid (4-carboxy-2-azetidin-one) in 6 5 % yie1d.l’ The lactam was stable to boiling G~-hydrochloricacid and to @4~-barium hydroxide at room temperature.The reducedform of the lactam, azetidine-2-carboxylic acid, occurs naturally.18Purification of Peptides and Proteins.-Authoritative reviews of columnchromatography l9 and of counter-current distribution 2o have appeared.One of the most important developments in the separation of peptides hasbeen the use of sulphonated polystyrene cation-exchange resins with a lowdegree of cross-linking, to increase the effective surface area; thus, styreneco-polymerised with 2% of divinylbenzene (Dowex 50-X2) separated a seriesof peptides containing between 2 and 24 residues, obtained by tryptichydrolysis of oxidized ribonuclease.21 The effectiveness of the resolution isshown by the fact that two peptides, of 20 and 24 residues respectively,crystallised from their fractions.High-voltage electrophoresis on paper, inthe apparatus devised by Mich1,22 has proved to be a method with comparableresolving power, although the amounts separable are smaller ; the commercialavailability of apparatus for continuous paper electrophoresis will greatlyincrease the usefulness of this procedure.An interesting technique is the useof sponge rubber as the support in zone electroph~resis,~~ recovery of thematerial in each zone being simple and nearly quantitative. A modifiedstarch gel has been used as the supporting medium in the zone electrophoresisl3 G. Amiard, Bull, SOC. chim. France, 1956, 447.l* R. E. Benesch and R. Benesch, Biochim. Biophys. Actu, 1957, 23, 658.E. L. Smith, B. J . Finkle, and A. Stockell, Discuss. Faraduy SOL, 1955, 20, 96.€3. M. Dintzis, Thesis, Harvard, 1952.l7 E. A.Talley, T. J . Fitzpatrick, and W. L. Porter, J. Amer. Clzem. Soc., 1956,78,5836.l8 L. Fowden, Nature, 1955, 176, 347.l9 S. Moore and W. H. Stein, Adv. Protein Chem., 1956, 11, 191.2o P. von Tavel and R. Signer, ibid., p. 237.21 C.H. W. Hirs, W. H. Stein, and S. Moore, J. Biol. Chenz., 1956, 219, 623.22 H. Michl, Sitzungsber. osterr. Ahad. Wiss., Abt. 11, 1951, 160, 489.23 H. K. Mitchell and L. A. Herzenberg, Anulyt. Chew., 1957, 29, 1229YOUNG : AMINO-ACIDS, PEPTIDES, AND PROTEINS. 279of plasma proteins; the low solid content (<$yo) of the gel ensures a freerpath for migration than when solid fillers are used, and electro-osmosis isnegligible.% Zone electrophoresis on vertical columns of powdered cellulosehas been used to fractionate substances of both low and high molecularweight, in quantities up to 100 g., and the fractionation of serum proteins inthis way has recently been described.25 The chromatography of proteinspresents a complicated problem, since penetration into the adsorbent isdifficult , configurational changes may occur during adsorption and desorp-tion, and the multivalent nature of the molecule is likely to make elutiondepend critically on the composition of the eluent.The polymethacrylicacid cation exchanger Amberlite IRC-50 proved invaluable for the puri-fication of basic proteins of low molecular weight , such as ribonuclease,lysozyme , chymotrypsin , and chymotrypsinogen, and the anion-exchangeresin Dowex-2 (a quaternary ammonium base on a polystyrene skeleton) hasbeen used for the fractionation of several proteinsJ26 but a technique whichmay prove more generally applicable to proteins of higher molecular weightuses modified celluloses , such as carboxymethyl- and diethylaminoethyl-cellulose.These are cation- and anion-exchangers respectively, of highcapacity, and the latter has been used successfully for the fractionation ofserum proteins.27Structural Investigation of Peptides and Proteins.-The elucidation of thestructure of insulin28 has been followed by remarkable progress in the in-vestigation of natural peptides and proteins, using chiefly methods developedearlier. Sanger’s dinitrophenylation and Edman’s thiohydantoin procedureshave so far proved the most valuable for the identification of the N-terminalresidues; the latter procedure has been used, stepwise, to reveal the firstseven residues of a-corticotr~pin.~~ Edman 30 has shown that this degrad-ation proceeds through an intermediate 2-anilino-5-thiazolinone (6) , whichrearranges to the 3-phenyl-2-thiohydantoin (7).Ph.NH. CS. NH . CHR’. CO*NH.CHR“. CO2H Ph*NH*C-i a Ph.N-CSII OC, I I ,NHHN: ,COCHR’ ( 6 ) CHR’+ + N H 3 - C H R ” - C O x HtfSlowPh*NH*CS-NHA third and most promising method uses leucine aminopeptidase toremove N-terminal residues; 31 its action is far less specific than its nameindicates, and Hill and Smith32 have shown that it will remove in turnsome 120 N-terminal residues from the chain of 180 residues in mercuripapain24 P. Bernfeld and J. S. Nisselbaum, J . Bid. Chem., 1956, 220, 851.25 H. I. Gedin and J. Porath, Biochim. Biophys. Acta, 1957, 26, 159.26 H. G. Boman and L. E. Westlund, Arch. Biochem. Biophys., 1956, 64, 217.27 E. A. Peterson and H. A. Sober, J . Amer. Chem.Soc., 1956, 78, 751; H. A. Sober,28 Review: F. Sanger and L. F. Smith, Endeavour, 1957, 16, 48.29 J. I. Hams and C . H. Li, J . Amer. Chem. SOC., 1954, 76, 3607.31 R. L. Hill and E. L. Smith, J . BioZ. Chem., 1957, 228, 577.32 Idem, Biochim. Biophys. Acta, 1956, 19, 376.F. J. Gutter, M. M. Wyckoff, and E. A. Peterson, ibid., p. 756.P. Edman, Acta Chem. Scund., 1956, 10, 761280 ORGANIC CHEMISTRY.(and the regenerated peptide is still enzymically active towards benzoyl-L-arginine amide). For the identification of C-terminal residues, the use ofcarboxypeptidase 33 and cleavage by hydrazine 34 have been preferred.Determination of the sequence of amino-acids within the chain requiresfission into fragments which can then be separated and investigated in-dividually.Partial acid hydrolysis may provide useful frzpents, but oftenthe mixture obtained is undesirably complex. Experience has shown thatthe risk of transpeptidation during enzymic hydrolysis is more remote thanhad been supposed, and in recent work trypsin, chymotrypsin, and pepsinhave yielded the most valuable degradation products. A useful additon tothis list is the bacterial enzyme subtilisin, which has a wide range of activity,and it was used advantageously in the elucidation of the structure ofg l u ~ a g o n . ~ ~ Quantitative separation of the fragments has been greatlyfacilitated by the availability of the ion-exchange resins mentioned above,and extensive use has been made of counter-current extraction and ofMichl's high-voltage paper electrophoresis apparatus.22Two interesting attempts to control enzymic attack in order to yieldfragments of useful size deserve mention.Introduction of a dinitrophenylor (preferably) benzyloxycarbonyl group on the c-amino-group of a lysineresidue renders it immune to attack by trypsin, which then cleaves onlyarginylamino-linkages. Oxidized ribonuclease, for example, gave theexpected five peptides, which were readily separated by paper electro-p h ~ r e s i s . ~ ~ The second approach is so far tentative; the aim is to modifythe side chains of cysteine residues in the protein by reaction with 2-bromo-ethylamine, forming S-2-aminoethyl derivatives, in the expectation that thecysteinyl linkages will become susceptible to attack by trypsin, since theside chain closely resembles that of lysine.It has been shown that po1y-S-2-aminoethylcysteine is an excellent substrate for tryp~in,~' and the applic-ation of this ingenious method to a protein is now awaited.The general methods discussed above have been used with outstandingsuccess, particularly in the investigation of peptide enzymes and hormones,and some of the more important structures so revealed will now be given.A substantial portion of the structure of the (bovine) ribonuclease moleculeis already k n 0 ~ n , ~ 1 > ~ 8 ~ from work in the Rockefeller Institute for MedicalResearch, New York, and in the National Institutes of Health, Maryland,and the latest available information 38b is incorporated in structure (8).Thepositions of the disulphide bridges were determined 39 by degradation of the33 J. I. Harris, Chem. SOC. Spec. Pzcbl., No. 2, 1955, p. 71.34 E.g., C.-I. Niu and H. Fraenkel-Conrat, J . Amer. Chem. SOL, 1955, 77, 5882.35 W. W. Bromer, A. Staub, E. R. Diller, H. L. Bird, L. G. Sinn, and 0. K. Behrens,J . Amer. Chem. Soc., 1957, 79, 2794, 2798, 2801, 2805, 2807.313 R. R. Redfield and C. B. Anfinsen, J. B i d . Chem., 1956,221, 385; C. B. Anfinsen,M. Sela, and H. Tritch, Arch. Biochem. Biophys., 1956, 65, 156.37 H. Lindley, Nature, 1956, 178, 647.8 8 ( a ) J. L. Bailey, S. Moore, and W. H. Stein, J . B i d . Chem., 1956, 221, 143; C. H. W.Hirs, W. H. Stein, and S. Moore, ibid., p. 151; R. R. Redfield and C. B. Anfinsen, ibid.,p . 385; C.H. W. Hirs, Fed. Proc., 1957, 16, 196; ( b ) C. H. W. Hirs, W. H. Stein, andS. Moore, Symposium on Protein Chemistry, Paris, July, 1957. The Reporter isgrateful for permission to quote from the Proceedings, to be published by John Wiley.30 A. P. Ryle and C. €3. Anfinsen, Biochirn. Biophys. Acta, 1957, 24, 633; D. H.Spackman, S. Moore, and W. H. Stein, Fed. PYOC., 1957, 16, 252YOUNG AMINO-ACIDS, PEPTIDES, AND PROTEINS. 281enzyme with subtilisin, followed by electrophoretic separation of the cystine-containing fragments; these were oxidised with performic acid, and theresultant peptides of cysteic acid were similarly separated. Comparison ofLys.glu.thr.ala.ala.ala.lys.phe.glu,arg.ser.thr.ser.ser.asp. his.met.glu.ala.ala.ser.ser.asp.ser.tyr.c~s,-INH*(11) Iasp.lu.met.met.lys.ser.arg.asp.leu.thr.lys,asp.arg.(~slas~,v~l,~roltbrllys).phe.( lu,val,leu,ser,his).- 7I I f INH2INH2INH1 I P1HIN NHI(V> 1 (Iv) I (W I (asp glu,ola,vol).(cys,glu,olu,v~l,ser).lys.asp.val.ala.cys.lys.asp.gly.thr.asp. lu.cys.tyr.glu.ser.tyr.ser.-NH, HIN NHS NHI INH*INHI NH,(VII) I (W I thr.met.ser,ileu.thr.asp.cys.arg.glu.ser.thr.ser.gly.lys.tyr.pro.asp.ala.cys,tyr.lys.thr.thr.asp, lu.ala.- I ? H,N NH, INH,(Vlll) I I 24lys.(vol,ileu,,bis).(cys,osp glu,gly,a~o,pro).tyr.(va~~,~ro,his).phe.asp.ala.ser~val. I NHl(8) Ribonuclease 88bThe abbreviations used i n this and other structures are those of E. Brand and J. T. Edsall (Ann.Each amino-acid residue i s joined through i t s carboxyl group t o the Rev.Biochern., 1947, 16,223).residue which follows. 7"' Side-chain amides are indicated thus:NH2The arrangement of residues italicised and enclosed in brackets is not yet known. Romannumerals refer to the half-cystine residues below (see text).the structures of these peptides with the sequences already known establishedthe position of the bridges, between half-cystine residues I-VI, II-VIII,III-VII, and IV-V (see structure 8). It will be seen that the last bridgeinvolves an intra-chain disulphide ring system two residues larger than thatfound in insulin, oxytocin, and the vasopressins, and in order to accommodatethese bridges the protein must assume a closely folded form. The establish-ment of the chemical structure of an enzyme is a landmark which is nowclearly in sight. Considerable progress has been made in the investigation ofthe lysozyme from egg-white,4* pepsin and pepsinogen,*l and papain.42A major portion of the effort in this field has been directed to the study40 R.Acher, U.-R. Laurila, and C. Fromageot, Biochim. Biophys. Acta, 1956, 19,97; J. Thaureaux and R. Acher, ibid., 1956, 20, 559; J. Thaureaux and P. Jollds,Compt. rend., 1956, 243, 1926; P. Joll&s, J. Jollds-Thaureaux, and C. Fromageot,ref. 38 ( b ) .41 H. van Vunakis and R. M. Herriott, Biochim. Biophys. Acta, 1957, 23. 600;K. Heirwegh and P. Edman, ibid., 1957, 24, 219.4z E. L. Smith and J. R. Kimmel, Proc. Internat. Wool Textile Res. Conf., Australia,1955, Vol. C, p. 199282 ORGANIC CHEMISTRY.of peptides with hormonal activity.The structures of the insulins obtainedfrom pig, sheep, horse, and whale have been compared with that fromcattle; 43 the only differences lie within the intra-chain disulphide ring system,as shown in (9). A most notable achievement is the elucidation of the struc-ture of glucagon (10) , the hyperglycaemic-glycogenolytic hormone isolated6 r 7 8 9 1 0 s ~ l l . . . . . . CY.CY.ALA. SER.VAL. cy . . . . . . (cattle) I Sthr.ser.ileu. (pig and whale)thr.gly.ileu. (horse)1ala.gly.val. (sheep)(9) Variations in the disulphide ring system of the A-chain of insulins.The residues printed in small capitals are replaced by those below them.Hisser. lu.gly.thr.phe.thr.ser.asp.tyr.ser.lys.tyr.leu.~p.ser.arg,- B NHa 29arg.ala.glu.asp.phe.val.1u.try.leu.met.asp.thr INHlfNH*INHl( 10) Glucagon20Ser.tyr.ser.rnet.g/u.his.phe.arg.try.gly. lys.pro.va1 .gly.lys.lys.arg,arg.pro.val.lys.val.tyr,pro.-25 26 27 28 29 30 31 32 39ALA.GLY.GLu.AsP.asp.GLU.ALA.sER.g~U.a~a.phe.pro.~eu.giu.phe . . a (I I ) -- (4 (b)(a) asp.gly.ala.glu. (b) lu.leu.ala . . . . . . * B (12) r NH,The sequences o f a - and 8-corticotropin.Two amide groups remain t o be assigned in a-corticotropinI 2 3 4 5 6 7 8 9 1 0 l 1 1 2 1 3a ( I 3) R-ser.tyr.se r.met.glu. his.phe.arg.try.gly. l ys. pro.val .-N HI 2 3 4 5 6 7 8 9 10 II 1213 I4 1516 17 188 (I 4) asp.glu.gly.pro.tyr.lys.met.glu.his.phe.arg.try.gly.ser.pro.pro.1ys.asp.a- and p-Melanocyte-stimulating hormones.from hog pancreas.35 The details of the extensive investigations which led tothe determination of the structure of p-corticotropin (12) (from pigs) haveappeared,a and the complete sequence of the adrenocorticotropic hormone43 J. I.Harris, F. Sanger, and M. A. Naughton, Arch. Biochem. Bioehys., 1956,65,427.44 R. G. Shepherd, K. S. Howard, P. H. Bell, A. R. Cacciola, R. G. Child, M. C .Davies, J. P. English, B. M. Finn, J. H. Meisenhelder, A. W. Moyer, and J. van derScheer, J . Amer. Chem. SOL, 1956,78, 5051; P. H. Bell, K. S. Howard, R. G. Shepherd,B. M. Finn, and J. H. Meisenhelder, ibid., p. 5059; R. G. Shepherd, S. D. Willson,K. S. Howard, P. H. Bell, D. S. Davies, S. B. Davis, E. A. Eigner, and N. E. Shakespeare,ibid., p. 5067; R. A. Brown, M. Davies, M. Englert, and H.R. Cox, ibid., p. 5077YOUNG : AMINO-ACIDS, PEPTIDES, AND PROTEINS. 283from sheep, ct-corticotropin (1 1) , has been reported.45 a-Corticotropin willbe seen to differ from @-corticotropin in residues 25-28 and 31-32; twoamide groups, not yet located, are present in the a-compound. A com-prehensive review of the adrenocorticotropic hormones and of the growthhormone, somatotropin (also found in the anterior pituitary gland), hasappeared; 46 the latter is estimated to have a molecular weight of 45,000,and structural investigations have begun. Two peptide hormones whichstimulate the melanocytes (pigmented cells) and so darken the skin of cold-blooded vertebrates have been isolated from pig pituitary glands, and theamino-acid sequences of both (a- and p-melanocyte-stimulating hormones)have now been elucidated. The a-compound (13) has the sequence of thefirst 13 N-terminal residues of the corticotropins (which have slight melano-cyte-stimulating activity) but the N-terminal serine is acylated by an asyet unidentified group, and the C-terminal valine is in the form of its amide.*’The P-compound (14) 48a has a more distant, yet distinct, resemblance to thefirst portion of the corticotropin structures.The bovine analogue differsonly in the second residue, having serine in place of glutamic It isinteresting that, if the N-terminal serine of p-corticotropin is oxidised byperiodate or removed by alkali, the loss of the adrenocorticotropic hormoneactivity is accompanied by a significant increase in the melanocyte-stimulat-ing activity.The peptide ser.met. lu.his.phe.arg.try.gly, which has the 7 NH2sequence common to the corticotropins and to a- and p-melanocyte-stimulat-ing hormone, has recently been synthesised, and has some melanocyte-stimulating a~tivity.4~Physiological stimuli cause liberation of the enzyme renin from the renalcortex, and by the action of rabbit renin on ox serum Peart 50 isolated adecapeptide, hypertensin-I (ox), which raises the blood pressure in rats andhas been shown 51 to have structure (15). The analogue obtained from horseserum has isoleucine in place of valine in the fifth residue, “ileu5-hyper-tensin-I ” (16),52 and there is evidence that the active entities are in fact theoctapeptides va15- and ileu5-hypertensin-I1 (from ox and horse serumrespectively) resulting from the removal in vivo of the two C-terminalresidues.Val5-hypertensin-I has been ~ynthesised,~~ as have also thebiologically active aspartyl-P-amides of val5- and ileu5-hypertensin-11.45 C. H. Li, I. I. Geschwind, R. D. Cole, I. D. Raaclte, J . I. Harris, and J. S. Dixon,46 C. H. Li, Adv. Protein Ghepn., 1956, 11, 101.47 J . I. Harris and A. B. Lerner, Nature, 1957, 179, 1346.4t3 ( a ) J. I. Harris and P. ROOS, Nature, 1956, 178, 90; I. I. Geschwind: C. H. Li,and L. Barnafi, J. Amer. Chem. SOC., 1956, 78, 4494; 1957, 79, 620; ( b ) adem, abad.,p. 6394.49 K. Hofmann, T. A. Thompson, and E. T. Schwartz, ibid., 1957, 79, 6087.5 0 W. S. Peart, Biochem. J., 1956, 62, 520.51 D.F. Elliott and W. S. Peart, ibid., 1957, 65, 246.52 L. T. Skeggs, K. E. Lentz, J. R. Kahn, N. P. Shumway, and K. R. Woods,53 R. Schwyzer and P. Sieber, Chimia, 1956, 10, 265.54 W. Rittel, B. Iselin, H. Kappeler, B. Riniker, and R. Schwyzer, Angew. Chem.,Nature, 1955, 176, 687.J . Exp. Med., 1956, 104, 193.1957, 69, 179; Helv. Chim. Acta, 1957, 40, 614284 ORGANIC CHEMISTRY.I 2 3 4 5 6 7 8 9 1 0(15) Asp.arg.val.tyr.va/.his,pro.phe.HIS.LEu.Va16-Hypertensin-/ (ox): removal of residues 9 ond I0 yields Va15-Hypertensin-I/ (ox).I 2 3 4 5 6 7 8 9 1 0( I 6) Asp.arg.val.tyr.ileu.his.pro,phe.HIs.LEu./leu6-Hypertensin-l (horse); removal of residues 9 and I0 yields ileu6-Hypertensin-l/ (horse).R CHMea CHMe, CHMeBCHC0.N H*CH*CO*O*CH*CO*N H*CH*COI I I III0II 0~~OSCH-N H-COCH ~OCOCH~N H-COCH I I I ICHMe, CHMe, CHMel R( I 7) Vdinomycin: R = Me(18) Amidomycin: R = Pr*(For t h e stereochemistry, see text)CHMe, Me CHMe, 1 I 1ICHC0.N-CHCO0 0 IDABy-NHg + D-phe thrJ.DAB-7-N H 2 + y-N H e-DAB2 DAB +++thrD-DAB-y-NHlpelCHMe2 CHMea(19) Enniatin €5++++DA B-y-N H 2thrD-DAB-Y-NH,lpel(20) (21)DAB = my-diaminobutyric acid.lpei = isopelargonic acid.Amino-acid residues have the L-configuration unless otherwise stated. The carboxyl-group ofthe residue at the t a i l of the arrow is joined t o the amino-group of the residue a t i t s headYOUNG : AMINO-ACIDS, PEPTIDES, AND PROTEINS. 285It has been known for some time that peptides (strepogenins) present inpartial hydrolysates of certain proteins will stimulate the growth of micro-organisms such as Lactobacillus ~ a s e i .~ ~ Merrifield and Woolley have now iso-lated two pep tides, ser. his. leu .Val&. and ser. his.leu.va1. glu. ala.leu, withstrepogenin activity, from the partial hydrolysis of beef insulin by acid. 56The former has been ~ynthesised.~~Apart from glutathione, few small peptides have been isolated fromliving cells, but recent investigations suggest this scarcity is more apparentthan real. Turba and Esser 58 obtained evidence of the presence of some40 peptides in extracts of yeast cells, and Waley has now separated a numberof peptides from the lens of the calf, and has identified two components,y-L-glutamyl-L-a-aminobutyrylglycine (ophthalmic acid) and y-glutamyl-alanylglycine (norophthalmic acid), the former having been synthe~ised.~~The steric resemblance to glutathione is noteworthy.The investigation of peptides isolated from bacteria has continued toreveal structures significantly different in type from those from othersources.Recent work on the actinomycins is discussed elsewhere; Go butmention must be made here of the isolation from Stveptomyces species of twoantibiotic substances of quite a different structure, valinomycin 61 (probably17) and amidomycin 62 (18). The former contains two units of D-a-hydroxy-isovaleryl-D-valine, linked in a ring system by two units of L-lactyl-L-valine.The latter contains four units of D-a-hydroxyisovaleryl-D-vafine, in a ringof the same size. There is a clear resemblance.to the structure of theenniatins (19) , found in species of Fusa~izmz.~~Polymyxin-BI (separated by count er-current distribution from themixture of peptides secreted by Bacillzls fioljwzyxa) is considered to havestructure (20) or (21).64 During the continued investigation of bacitracin A,the remarkable resistance of e(wasparty1)lysine (and its p-isomer) to acidhydrolysis has been demonstrated,G5 prolonged attack giving the aspartimide(22). Another unusual type of structure occurs in phallaidin (23), a toxic5 6 H. Sprince and D. W. Woolley, J . Amer. C h e w SOC., 2945, 67, 1734.5 7 Idem, ibid., p. 4646.68 F. Turba and H. Esser, Biochem. Z., 1955, 327, 93.60 S. G. Waley, Biochem.J., 1956,64,715; 1957, 67, 172; 1958, 88, 189.6o This vol., p. 347.61 H. Brocltmann and H. Geeren, Annalen, 1957, 603, 216.62 L. C. Vining and W. A. Taber, Canad. J . Chem., 1957, 95, 1109.63 P. A. Plattner and U. Nager, Helv. Chim. Acta, 1948, 31, 2192.64 W. Hausmann, J . Amer. Chem. SOL, 1956, 78, 3663; G. Biserte and M.Dautrevaux, Bull. SOC. Chim. b i d , 1957, 39, 795.6 5 I. M. Lockhart and E. P. Abraham, Biochem. J., 1956, 62, 645: D. L. Swallowand E. P. Abraham, ibid., 1957, 65, 39P; D. Theodoropoulas and L. C. Craig, J . Org.Chem., 1956, 21, 1376. For,: review of the biochemistry of bacitracins and cephalo-sporins, see E. P. Abraham, Biochemistry o i Soxe Peptide and Steroid Antibiotics,”Wiley, New York, 1957.R. B. Merrifield and D.W. Woolley, ibid., 1956, 78, 358286 OKGANIC CHEMISTRY.cyclic peptide isolated from toadstools (Amanda phalloides) ; a full accountof the degradation evidence has appeared.66MeC = CH-CHeNH - CO.CH * NH.CO.CH - CH,I(23) PholloidinMe-CH. OHFor progress made in the establishment of amino-acid sequences in suchimportant proteins as the haemoglobins, serum albumens, tobacco mosaicvirus, silk frbroin, collagen, and wool keratin, reference should be made toAnfinsen and Redfield's stimulating review,67 and to a painstaking analysisof the amino-acid arrangements so far encountered in natural peptides andproteins given by $ o m and his co-workers.68It was mentioned above that by the action of leucine aminopeptidase onmercuripapain some 120 of the 180 amino-acid residues may be removedwhilst enzymic activity is still retained in the regenerated residue.This isthe most remarkable example of an increasing number of observations(summarised by Anfinsen and Redfield 67), in which biologically activepeptides and proteins have been degraded without loss of activity, and thereis the exciting prospect not only of a great simplification of structuralinvestigations in this way but also of discovering the essential requirementsfor activity. A parallel approach is the elucidation of the sequence ofamino-acids at the " active site " of an en~yme,~g and by degradation ofthe 32P-phosphorylated enzyme Koshland and Erwin 70 have found that theamino-acids at the active centre of phosphoglucomutase are the same asthose at the active centre of chymotrypsin, for which the sequenceasp.ser.gly.glu.ala has been proposed.71 This is consistent with a suggestionthat some bond-breaking mechanisms may be common to enzymes of widelydifferent specificities.The report of the Faraday Society Discussion on" The Physical Chemistry of Enzymes," which contains important contri-butions concerning the mechanism of enzymic action, appeared in the periodunder review.72 The report 73 of a recent symposium on the structure andfunction of proteins gives authoritative discussions of the present state ofour knowledge of the chemical basis of biological activity of the growthhormone (somatotropin) , ribonuclease, trypsinogen and chymotrypsinogen,66 T. Wieland and W.Schon, Annulen, 1955, 593, 157.67 C. B. Anfinsen and R. R. Redfield, A d v . Protein Chem., 1956, 11, 1.68 F. Sorm, B. Keil, V. HoleySovsky, V. KnezslovA, V. Kostka, P. Masiar, B. Meloun,0. Mikes, V. TomBSek, and J . VanECek, Coll. Czech. Chem. Comm., 1957, 22, 1310.68 See, e.g., W. N. Aldridge, Ann. Reports, 1956, 53, 301.70 D. E. Koshland and M. J . Erwin, J. Amer. Chem. Soc., 1957, 79, 2657.72 Discuss. Furuduy SOC., 1955, 20.73 Fed. Proc., 1957, 16, 774.F. Turba and G. Gundlach, Biochem. Z . , 1955, 327, 186YOUNG AMlNO-A4CIDS, PEPTIDE;S, AND PROTEINS. 257papain, and tobacco mosaic virus, and it is clear that we are on the thresholdof significant developments in this field.Synthesis of Peptides-The last two years have seen outstanding achieve-ments in this field also, largely by the methods developed previou~ly.~*Benzyloxycarbonyl remains the most generally useful amino-protectinggroup, but toluene-9-sulphonyl (tosyl) and triphenylmethyl (trityl) haveproved valuable in recent syntheses; the last has the advantage that it maybe removed under mild acid conditions; its steric effect affords alternativeroutes to a- and y-glutamyl-peptides, since partial saponification of thediester gives a-ethyl N-trityl-L-glutamate, and partial methanolysis ofdibenzyl N-trityl-L-glutamate yields the a-benzyl y-methyl ester.75 Morerecently it has been reported 76 that the N,-trityl group of N,N,-ditrityl-lysyl-peptides can be removed preferentially by acid, so providing a newsynthesis of peptides coupled through the a-amino-group of lysine.Amongnew suggestions, tert.-butoxycarbonyl and cyclopentyloxycarbonyl are likelyto be particularly useful amino-protecting groups since they are resistant tohydrogenation and to sodium in liquid ammonia but are removed byhydrogen bromide or hydrogen chloride in acetic acid or nitromethane."Some years ago, Ehrensvard 78 proposed the phenylthiocarbonyl groupfor amino-protection, but cleavage by lead tetra-acetate does not proceedsmoothly. 79 The discovery that aryl- and alkyl-thiocarbonyl groups canbe removed satisfactorily by perbenzoic acid 8o suggests that they will nowfind application in synthesis.The carbodi-imide method of coupling 8 l is proving very valuable; tofacilitate the separation from the urea co-product, carbodi-imides givingwater- or acid-soluble urea have been recommended : 82RC0,H + C,Hll*N=C=N~C,H,,*NEt, + R'*NH1 + RCO-NHR' + C6HIl*NH*CO*NHoC,,Hlo*NEt,An interesting application of the carbodi-imide method is in forming the4-membered cyclic amide during a total synthesis of penicillin-Vm and it hasbeen used to cyclise glycyl-DL-valylglycylglycyl-DL-valylglycine, in solutionin SO% methanol.@ A water-soluble carbodi-imide has been used to cross-link gelatin (by amide formation) in aqueous solution, yielding a gel in 30seconds.85T4 Reviews: H. D. Springall and H. D. Law, Quart. Rev., 1956, 10, 230; W. Grass-mann and E. Wunsch, Fortschr. Chem. org. Naturstofle, 1956, 13, 444; T. Wieland andB. Heinke, Angew.Chem., 1957, 69, 362; G. W. Kenner, J., 1956, 3689; M. Goodmanand G. W. Kenner, Adv. Protein Chem., 1957, 12, 465.75 G. Amiard, R. HeymAs, and L. Velluz, Bull. SOC. chim. France, 1956, 97.'13 G. Amiard and B. Goffinet, ibid., 1957, 1133.77 F. C. McKay and N. F. Albertson, J . Amer. Cheni. Soc., 1957, 79, 4686; G. W.79 A. Lindenmann, N. H. Khan, and K. Hofmann, J. Amer. Chem. SOC., 1952,74,476.82 J. C. Sheehan and J. J. Hlavka, J. Org. Chem., 1956, 21, 439.83 J. C. Sheehan and K. R. Henery-Logan, J. Amer. Chem. Soc., 1957, 79, 1262.8 5 J. C. Sheehan and J. J . Hlavka, J. ,4nzer. Chem. Soc., 1957, 79, 4528.Anderson and A. C. McGregor, ibid., p. 6180.G. C. H. Ehrensviird, Nature, 1947, 159, 500.J. Kollonitsch, A. Hajbs, and V. GAbor, Ghem. Bey., 1956, 89, 2288, 2293.J . C.Sheehan and G. P. Hess, J. Amer. Chem. SOL, 1955, 77, 1067.T. Wieland and K. W. Ohly, Annalen, 1957, 605, 179288 ORGANIC CHEMISTRY.The use of activated esters has been considerably developed. Afterexamination of a number of such esters, Schwyzer 86 recommended cyano-methyl esters; they are formed readily from the acylamino-acid by the actionof chloroacetonitrile in the presence of triethylamine, and react smoothlywith amino-esters giving high overall yields. In the same laboratory aninteresting attempt was made to use tetrahydropyranyl esters, prepared bythe addition of the carboxylic acid to 2 : 3-dihydropyra11,~~ but the amino-component combines with the 6-hydroxypentanal formed and so limits theyield of peptide from the amine:The same paper describes the protection of hydroxyl groups by means of theShydropyran, but a disadvantage is the presence of an additional asym-metric centre in the adduct. The usefulness of p-nitrophenyl and thiolesters has been limited by the methods available for their preparation,88but two interesting new methods for the preparation of aryl esters have beenreported,89 using diary1 sulphites or triaryl phosphites, in the presence ofpyridine :(0) R.CO2H(b) 2R.COZH + (P-NO2'CIH4*O)BP __t 2R.COaoC6Hp*NO2 + NOa*C6H4.OaPO2H2(p-NOsC6Hp'O)aSO + R.COI.C6H4*NOs + NO,*C,H4*OH + SO*In both cases the yields are nearly quantitative. This esterification has alsobeen effected by means of dicyclohexylcarbodi-imide; by using a largeexcess of p-nitrophenol, acylurea formation should be reduced.The use ofpropargyl esters, prepared by the action of propargyl bromide on the triethyl-amine salt of the acid, has been suggested in a preliminary communi~ation.~~Activated esters are proving valuable for the cyclisation of peptides, sincetheir stability permits the removal of amino-protecting groups such asbenzyloxycarbonyl and triphenylmethyl, as, for example, in the synthesis ofgramicidin-S 92 (24).The reactivity of acetylenic ethers (cf. the use of dihydropyran, above)is the basis of a method of coupling devised by Arens: 93R.CO,H + Et0.C-CH + R'-NH2 __t R.CO*NHR' + CH,*CO,EtSheehan has used both this method and a novel one involving the addition86 R. Schwyzer, B. Iselin, and M.Feurer, Helv. Chim. Acta, 1955, 38, 69;R, Schwyzer, M. Feurer, B. Iselin, and H. Kaigi, ibid., p. 80; R. Schwyzer, M. Feurer,and B. Iselin, ibid., p. 83.87 B. Iselin and R. Schwyzer, Helv. Chim. Acta, 1956, 39, 57.M. BodBnszky, Acta Chim. Acad. Sci. Hung., 1957, 10, 335; M. BodBnszky,M. Szelke, E. Tomorkhy, and E. Weisz, ibid., 1957, 11, 179; J. A. Farrington, P. J.Hextall, G. W. Kenner, and J. M. Turner, J., 1957, 1407.sg B. Iselin, W. Rittel, P. Sieber, and R. Schwyzer, Helv. Chim. Acfa, 1957, 40, 373.D. F. Elliott and D. W. Russell, Biochem. J., 1957, 66, 49P.B1 M. Bodhszky, Chem. and Ind., 1967, 524.92 R. Schwyzer and P. Sieber, Helv. Chim. Acta, 1957, 40, 624.g3 J. F. Arens, Rec. Trav. chim., 1955, '74, 769; ref. 2 ( b ) , p. 468YOUNG : AMINO-ACIDS, PEPTIDES, AND PROTEINS.289of the acid to the keten imine, cyclohexyliminomethylenecyclohexane, forthe cyclisation of D-a-phenoxymethylpenkilloic acid to penicillin V, but theyields were lower than that obtained with dicyclohexylcarbodi-imide. 83The preservation of optical activity is always an important considerationin peptide synthesis, and it is known than methods of coupling which givefully active products from benzyloxycarbonylamino-acids may lead toracemisation when benzyloxycarbonyl-peptides are further coupled. 94 Anexamination has been made of the optical activity of the products obtainedwhen various methods are used to couple acetyl-L-leucine with glycine ethylester.95 Methods involving mixed anhydrides led to considerable racemis-ation in this reaction, but the use of acid azides, cyanomethyl esters, ordicyclohexylcarbodi-imide gave active material ; an unexpected finding isthat racemisation of the acylating residue may result even when methods ofcoupling are used (such as the “ phosphorazo ” and the phosphoramideprocedure) which have been postulated to involve activation of the amino-component.In manycases, extensive use was made of counter-current distribution for the puri-fication of both intermediates and final product.One of the outstandingsyntheses during the period under review is that of an eicosapeptide methylester having the sequence of the first 20 N-terminal residues common toCC- and @-corticotropin, (11) and (12).g6 The product had positive, thoughlimited ’’ hormonal activity, although it is four residues shorter than thesmallest biologically active fragment so far obtained by degradation of thehormone.The antibiotic cyclic decapeptide gramicidin-S (24) has beensynthesised by Schwyzer’s group 92 and an outline of the final stages is givenin the accompanying chart. Preliminary announcements have been madeof the synthesis of the decapeptide va15-hypertensin-I ” (15),97 and of theaspartyl-p-amides of “ va15 ”- and “ ileu5-hypertensin-I1 ” (see above),98 anda full account of the last synthesis has appeared.99 Although the structuralevidence indicates an N-terminal aspartic acid residue in the hypertensins,these asparaginyl analogues have physiological activity comparable with thatof the natural products.An improved synthesis of lysine-vasopressin (25)has been reported,loO and two new syntheses of oxytocin (26),lo1 togetherwith syntheses of analogues in which the isoleucyl residue of oxytocin hasbeen replaced by phenylalanine, valhe, or leucine, and of one in which theasparagine residue has been replaced by glutamine; in each case so farSome of the important syntheses achieved will now be noted.94 Cf., e.g., J. R. Vaughan, J . Amer. Chem. SOC., 1952, 74, 6137.95 M. B. North and G. T. Young, Chern. and Ind., 1955, 159; M. B. North, N. A.Smart, and G. T. Young, Abs. Roc. 19th Internat. Congr. Pure Appl. Chem., Paris,1957, 11, p. 238.96 R. A. Boissonnas, St. Guttmann, J.-P. Waller, and P.-A. Jaquenoud, Experientia,1956, 12, 446.9’ R.Schwyzer and P. Sieber, Chimia, 1956, 10, 265.98 W. Rittel, B. Iselin, H. Kappeler, B. Riniker, and R. Schwyzer, Angew. Chem.,g9 Idem, Helv. Chim. A d a , 1957, 40. 614.loo V. du Vigneaud, M. F. Bartlett, and A. Johl, J . Amer. Chem. Soc., 1957, 79, 5572.l01 J. Rudinger, J. Honzl, and M. Zaoral, Coll. Czech. Chem. Cowam., 1956, 21, 202;L. Velluz, G. Amiard, J. Bartos, B. Goffinet, and R. HeymBs, Bull. SOC. chim. Fvance,1956, 1464.REP.-VOL. LIV K1957, 69, 179290 ORGANIC CHEMISTRY.CBzo.val.orn.leu.D.phe.pro.0MeITosT-va1.orn.leu.D-phe.pro I Tosval.orn.1eu.D-phe.pro.OMeITosT-val.orn.leu.D-phe.pro.;al.orn.leu.D-phe.pro.OMe I Tos I TosT-val.orn.leu.D-phe.pro.val.orn.leu.D-phe.pro.0NP I Tos I TosTos Tosval.orn.1eu.D-phe.pr0.val.orn.leu.D-phe.pro 1The later stages of the synthesis of gramicidin-S.Reagents: (a) Pd-Ha.(b) Ph3CCI. (c) NaOH. (d) I-cycloHexyl-3-(2-rnorpholinoethyl)-carbodi-imide. (e) Di-p-nitrophenyl sulphite in pyridine. ( f ) CFs*C02H. (g) Pyridine. (h) Na-NHS.CBZo = Ph*CH,*OCO-; TOS = p-C,H4Me*S02 = toluene-p-sulphonyl; T = Ph3C-; ONP =Amino-acids have the L-configuration unless otherwise shown.p-NO,.C,Hp'O.(26) OxytocinS S I IH2N NH,Arginine-vasopressin Phe(25) Lysine-vasopressin PheI' Oxypressin " (synthetic) PhYOUNG : AMINO-ACIDS, PEPTIDES, AND PROTEINS. 291reported, the products have modified biological activity.lo2 The analogueof oxytocin in which the asparagine residue is replaced by isoglutamine hasnow been synthesised,lo3 and it is interesting that the oxidation of thedithiol to the 22-atom cyclic disulphide proceeded even more smoothly thanin the case of the 20-atom ring of oxytocin.The product was biologicallyinactive. In this work a reminder has appeared that reagents which activatea carboxyl group may also attack less reactive parts of the molecule; whena peptide containing an asparagine residue was coupled by the tetraethylpyrophosphite method a by-product was formed which, in the simplestinterpretation, could have been the side-chain nitrile, since hydrolysis yieldedaspartic acid, while sodium in liquid ammonia gave a peptide which onhydrolysis gave ay-diaminobutyric acid.lM Other workers have obtainedconsiderable amounts of an anhydro by-product when coupling benzyloxy-carbonyl-L-asparagine with S-benzylcysteine methyl ester, using eithertetraethyl pyrophosphite or dicyclohexylcarbodi-imide ; this by-product wasabsent when coupling was effected through a mixed carbonic or carboxylicanhydride.lo5 The analogous reaction with benzyloxycarbonyl-L-glutaminegave a small amount of anhydro-material when the tetraethyl pyrophosphitemethod was used.The coupling of acylasparagines generally gives lowyields, probably owing to formation of the acylaspartimide ; the formationof the imide from c-aspartyl-lysines has been mentioned above. It isinteresting that dehydration of the asparaginyl or glutaminyl side chain,followed by hydrogenation, has been used for the synthesis of peptides ofay-diaminobutyric acid and of ornithine respectively; lo6 since the side chainof ornithine reacts with O-methylisourea to give the corresponding argininederivative, this sequence may provide a useful route to peptides of arginine.Three new syntheses of glutathione have been described; lo7 in the first,the triphenylmethyl group was used to protect both the amino- and thethiol group of the cysteine; and in the second these were protected byreaction with acetone to yield the 2 : 2-dimethylthiazolidine-4-carboxylicacid. The culmination of a long series of researches on the structure of theimmuno-specific capsular polypeptide formed by the anthrax bacillus hasbeen reached with the synthesis of a y-poly-D-glutamic acid, similar inC0,Me COsMe I I N H 2.C H [C H 21 ,*CO* N H*C H [C H ,CO*S P h (27)physical and immunological properties to the natural polymer.los This wasachieved by the polymerisation of the dimethylphenyl y-D-glutamyl-D-thiol-glutamate (27).It is interesting that the isomer in which y-L- and Y-D-102 P. G. Katsoyannis, J . Amer. Chem. SOC., 1957, 79, 109; R. A. Boissonnas, St.Guttmann, P.-A. Jaquenoud, and J.-P. Waller, Helv. Chim. Acta, 1956, 39, 1421 ;J. Rudinger, J. Honzl, and M. Zaoral, Coll. Czech. Chem. Comm., 1956, 21, 770.lo3 C . Ressler and V. du Vigneaud, J . Amer. Chem. SOC., 1957, 79, 4511.lo* C. Ressler, ibid., 1956, 78, 6956.lo5 D. T. Gish, P. G. Katsoyannis, G. P. Hess, and R. J. Stedman, ibid., p. 6954.lo6 M. Zaoral and J. Rudinger, Proc. Chem. Soc., 1957, 176.107 G.Amiard, R. Heymhs, and L. Velluz, Bull. SOC. chim. France, 1956, 698;F. E. King, J. W. Clark-Lewis, and R. Wade, J., 1957, 880; F. Weygand and R. Geiger,Chem. Ber., 1957, 90, 634.108 V. Bruckner, J. Wein, M. KajtAr, and J. KOVBCS, Naturwiss., 1955, 42, 463292 OKGANIC CHEMISTRY.glutamyl residues alternate also gave a precipitate with anti-anthrax~erurn.l0~, A valuable summary has appeared of the physicochemicalinvestigations of polypeptides of high molecular weight prepared bypolymerisat ion .ll1A full reportu2 has now been presented of the remarkable reaction bywhich amino-acid residues may be interpolated into a peptide chain throughthe intermediate formation of the O-aminoacylsalicyloyl-peptide (28) ;analogously, debenzylation of 0-(cebenzyloxycarbonylaminoacy1)salicylicacids yields salicylamido-acids quantitati~ely.~~ This reaction, termed‘ I Aminoacyjl Einlagerung, ’’ has been used to synthesise salicyloylglycyl-phenylalanylglycine, and has been extended to the use of O-aminoacylderivatives of aliphatic p-hydroxy-acids, although stronger bases are requiredto effect the rearrangement in these cases.The interesting suggestion ismade that serine, threonine, or cysteine residues may be used in this fashionin the biological synthesis of proteins, so lengthening the chain from thecentre rather than from the end.G. T. Y.12. CARBOHYDRATES.Stereochemical and Mechanistic Aspects-At present there is considerableinterest in both the stereochemistry of carbohydrates and the mechanismsof their reactions, and symposia on these subjects have been held recently.l,In an important publication further consideration has been given to theshapes of the pyranose ring and attention has been directed to the importanceof boat forms.In sodium hydroxide some glycosides show relatively largereversible changes in optical r ~ t a t i o n , ~ The hypothesis is put forward thataxial hydroxyl groups in neutral solutions tend to move to equatorialpositions at high alkalinity (when the ionised solvated sugar hydroxyl groupshave a greater effective volume) and this produces a rotational change.There is good correlation between experiment and theoretical predictions.As the changes would lad, in certain cases, to boat forms, the furthersuggestion is made that although chair forms are generally of lower energythan boat forms the difference is more than offset when a boat form allowsall ring substituents (other than hydrogen) to be equatorial.3 Geometricallyloo V.Bruckner, J. Wein, M. KajtAr, and J. KovAcs, Natztrwiss., 1957, 44, 89.110 Review: V. Brucknerand J. Kodcs, ActaChirn. A c e . Sci. HuHg., 1957,12,36!;111 C . H. Bamford, A. Elliott, and W. E. Hanby, Synthetic Polypeptides,Academic Press, New York, 1956.112 M. Brenner, J. P. Zimmemann, J. Wehrmiiller, P. Quitt, A. Hartman, v\i.Schneider, and U. Beglinger, Helv. Chim. Acta, 1957, 40, 1497; M. Brenner and J.Wehrmiiller, ibid., p. 2374.113 M. Brenner and J. P. Zimmermann, ibid., p. 1933.1 See G. R. Barker, Proc. Chem.Soc., 1957, 10.3 R. E. Reeves and F. A. Blouin, J . Amer. Chem. Soc., 1957, 79, 2261.4 R. E. Reeves, ibid., 1950, 72, 1499.Abs. Amer. Ckm. SOC. 132nd Meeting, 1957, KDOVEREND : CARBOHYDRATES. 293regular boat forms are unlikely in some simple pyranosides because of thehigh energy resulting from eclipsed valency angles on some of the adjacentatoms. Consequently the suggestion should be construed to mean that thering may take a shape approximating to that of a pure boat form, butdistorted in the region where the tendency of the large groups to move intothe equatorial plane is balanced by the repulsion brought3 ~ * * 2 ~ about by approach to the eclipsed-valency position. Boat-form rings are flexible, so that positions intermediate be- - #B3 tween Reeves’s designated forms can occur without greatlyincreased ring strain. There is a sequence in which oneboat form may be changed into another, e g ., (l), and,provided certain of the forms are not prohibited by steric interference ofsubstituents, boat forms may shift in either direction through the cycle ofchanges (1). As a result of this work further consideration of the designation ofring shapes is required, as Reeves’s descriptions are not sufficiently precise.Configurational and conformational effects in the proton magneticresonance spectrum of acetylated carbohydrates have been observed.5 Thespectra confirm the anomeric configurations of sugar acetates assigned onthe basis of Hudson’s rule of isorotation. There is evidence that hydrogenbonding of the 4-hydroxyl group to the ring-oxygen atom effectively fixesthe conformation of ~-erythro-3 : 4-dihydroxypyran (1 : 2-dideoxy-~-arabo-pyranose) in both carbon tetrachloride and aqueous solution.6 The re-fractive indices and densities of hexo- and pento-pyranosides (with theexception of methyl a-L-arabinoside) similarly substituted on correspondingring atoms increase with increasing number of axial substituents.’ Methyl4 : 6-O-ethylidene-cc-~-mannoside (2) and 1 : 6-anhydro-P-~-mannopyranose(3) (or its 4-methyl ether) undergo selective esterification at the equatorialhydroxyl group.8 The reaction of glyco-furanosides and -pyranosides withborate ions has been mea~ured.~ In certain pyran derivatives the reactionof vicinal cis-hydroxyl groups with borate ions is hindered by a vicinal cis-methoxy-group.10 Terdentate complex formation l1 is not responsible forthe effect and it is considered that conformations other than the preferredchair forms are involved.For example, methyl p-D-lyxopyranoside (4;R” = OMe, R’ = H) interacts with borate ions less than does the a-anomer(4; R‘ = OMe, R” = H).9 If the half-chair conformation (5) is involvedin the interaction, it is clear that in it the p-form leads to greater interactionbetween R” and the 2-hydroxyl group, and so the change (4) (5) willoccur less readily than for the a-isomer.3-0-Substituted aldoses and 4-0-substituted hexuloses take up hydrogenonly slowly from borohydride in borate buffer l2 because of steric hindrance.R.U. Lemieux, R. K. Kullnig, H. J. Bernstein, and W. Schneider, ibid., 1967,J. S. Brimacombe, A. B. Foster, and D. H. Whiffen, Abs. Amer. Chem. SOC.,R. B. Kelley, Canad. J. Chem., 1957, 35, 149. * G. 0. Aspinall and G. Zweifel, J., 1957, 2271.A. B. Foster, J., 1957, 1395.ti f C B?( 1 )79, 1005.132nd Meeting, 1957, 2D.lo Idem, ibid., p. 4214.l1 S. J. Angyal and D. J. McHugh, Chem. and Ind., 1956, 1147.l* P. D. Bragg and L. Hough, J., 1957,4347294 ORGANIC CHEMISTRY.Reduction to the hexitol(8) will be preceded by ring opening, e.g., (6) 4 (7)for a 3-O-substituted glucose, and in the acyclic staggered zig-zag conform-ation (7) a bulky 3-substituent hinders approach to the aldehyde group.H HH" O m R , ,Ho H( 4 ) ( 5 )There is correlation between the size of the group R and the rate of reduction.Smaller differences in reduction rates of other monosaccharides are attribut-able to borate-complex formation involving the cyclic form of the sugar.Steric hindrance of the carbonyl group in ketoses results in slower reductionthan with aldoses.The polarographic reduction of pentoses, hexoses, theirmethyl ethers, and 2-deoxy-analogues has been examined.13 Limitingcurrents are determined by the rates of transformation of the ap-equilibriummixtures of the sugars from ring to reducible form at the mercury surface.For some of the methylated derivatives the rate of transformation toreducible form is sufficiently high to render diffusion the rate-controlling( 6 ) Hstage.A correlation has been noted between bulk rate constantstransformations and the conformational instability units 4 of thesugars.for thevariousTreatment of a large excess of galactitol or mannitol with periodateafforded a tetrose or, mainly, glyceraldehyde respectively, indicatingpreferential oxidation of threo-glycol groups.14 The rates of periodateoxidation of methyl 4 : 6-O-benzylidene- and 4 : 6-O-ethylidene-a-~-aldo-hexosides can be correlated with the disposition of the hydroxyl groups inthe preferred conformations of the compounds.15 Periodate forms reversiblya complex with a cis-cis-1 : 2 : 3-trio1 system of a six-membered ring: 16 this13 W. G. Overend, A. R. Peacocke, and J. B. Smith, Chew. and Ind., 1957,113, 1383.14 J. C. P. Schwarz, J., 1957, 276.1 5 J.Honeyman, K. S. Ennor, C. J. G. Shaw, and T. C. Stening, Abs. Amer. Chem.16 G. R. Barker and D. F. Shaw, Proc. Chern. Soc., 1957, 259.Soc., 132nd Meeting, 2957, 4DOVEREND : CARBOHYDRATES. 295retards the rate of oxidation. Steric considerations suggest that the triolsreact in the conformation in which one hydroxyl group is equatorial and twoare axial, e.g., (9). The complex is thought to be more....- stable than that formed between periodate and di0ls.l' Itis unstable in acid. Decomposition of the ribose complexto give iodate and oxidation products follows first-orderkinetics up to 75% destruction of the pentose. Duringoxidation of glucose by alkaline iodine solution it isimportant to keep the concentration of potassium iodide as low as possible,consistent with the necessity of maintaining a sufficient excess of iodine untiloxidation is complete.18 The kinetics of oxidation of glucose, galactose,fructose, arabinose, and xylose by alkaline bivalent copper in the presenceof citrate and tartrate have also been investigated.lsThere is continuing interest in aspects of the halogen oxidation of sugars.Application of bromine oxidation to the study of ring conformation has been21 Bentley 21 concludes that the following generalization- can bedrawn : " for any pyranose of stable CI conformation regardless of member-ship in the D- or L-series, the more dextrorotatory member of the anomericpair will have the anomeric substituent in the axial position.Similarly, forany pyranose of stable IC conformation, regardless of membership in theD- or L-series, the more laevorotatory member of the anomeric pair will havethe anomeric substituent in the axial position.The anomer with theglycosidic substituent in the axial position will in general be the leastreactive. "The conclusion 22 that in the oxidation of glucose the rate-determiningattack by bromine occurs at the 1-hydroxyl group has been disproved bymeasurements of hydrogen-isotope effects.23 Oxidations of l-tritio-cc- and-p-D-glucose demonstrated that the rate-determining step involves ruptureof the C(,I--H bond. Bentley21 now suggests that an initial rapid andreversible formation of pyranose-halogen complex is followed by a rate-determining transfer of a hydride ion, as illustrated, the step RD beingrat e-det ermining.IO.;:......OH( 9 )HO *-. 270 - H 5 B r 2 H - +i0 0 - H + 0'2 zsz a B,Q* + "+The greater reactivity of the anomer in which the hydrogen at position Iis axial is considered to be due to the fact that the rate-determining step isfavoured by the release of strain. This is the reverse of the usual situationl7 G. J. Buist and C. A. Bunton, J., 1954, 1406.18 R. L. Colbran and T. P. Nevell, J., 1957, 2427.2o H. S. Isbell, Abs. Amer. Chem. SOC., 132nd Meeting, 1957, lo.21 R. Bentley, J . Amer. Chem. SOL, 1957, 79, 1720.Z2 Idem, Nature, 1955, 176, 870.23 F. Friedberg and L. Kaplan, Abs. Amer. Chem. SOC., 131st Meeting, 1957, 860.M. P. Singh and P. Ghosh, 2. phys. Chem.(Leipzig), 1957, 207, 187, 198296 ORGANIC CHEMISTRY.in cyclohexane compounds and is attributable possibly to the repulsive forcesassociated with the unshared electrons of the ring-oxygen atom.= Oxidationof methyl p-D-glucopyranoside with an aqueous chlorine system at pH 4.5yields, as maj or products, D-ghCOSe, D-arabinose, carbon dioxide, and oxalicacid; minor products include 2-0x0- and 2 : 5-dioxo-gluconic acid.25 Theglycoside is not hydrolysed under the conditions employed and it wasconcluded that either there is attack on the glycosidic bond in a combinedoxidation and hydrolysis or the oxidant attacks the methyl group yielding anew and more sensitive aglycone. D-Arabinose arises via its carbonate esterby cleavage of the 1 : 2-bond of the glycoside.The carbon dioxide andoxalic acid could not be attributed to any single definite source. 2 : 5-Dioxo-gluconic acid probably arises from oxidation of glucose via the 2-0x0-derivative.The action of phosphorus pentachloride on octa-0-acetylcellobiose and astudy of the anomeric acetates of sugars are reported.26 The known re-action 27 between sugar acetates and anhydrous aluminium chloride has beendeveloped into a general method for preparing 1 : 2-tram-acetylglycosylhalides, both pyranose and furanose, from 1 : 2-trans-acetates of p-D-aldoses.28The 1 : 2-cis-epimers of the sugars do not react under the conditions employed.Measurement of the rate of reaction with silver acetate in benzene offers aconvenient means for distinguishing between 1 : 2-cis-chlorides, 1 : 2-trans-chlorides, and orthoacetyl chlorides.28 In 2 : 3-di-0-acetyl-4 : 6-O-benzyl-idene-P-D-glucopyranosyl chloride (10; R = Ph) or the 4 : 6-O-ethylidenederivative (10; R = Me), which show behaviour typical of their class, thering junction prevents the conversion of the CI chair conformation of thepyranose ring into the IC chair conformation required for replacements atposition 1 according to Lemieux’s mechanism,29 but anchimeric assistance bythe %acetate group is still very apparent in reactions atposition 1.The antiparallel orientation of the chlorine atomCI and the acetate group 28 may be obtained without excessivesteric strains by conversion of the pyranose ring form of (10)into the appropriate boat form.The kinetics of the un-catalysed and catalysed solvolyses of 1 : 2-trans-2-0-acetylglycosyl halidesshow that the rate-determining stage is the removal of the halogen atom toform a cyclic carbonium i0n.30 Anchimeric assistance due to the 2-acetylgroup contributes to the enhanced solvolysis rates of 1 : 2-trans-2-0-acetyl-glycosyl 1 -halides compared with the corresponding 1 : 2-cis-compounds.Comparison of the solvolysis of tetra-0-acetyl-p-D-glucosyl chloride and tetra-O-acetyl-a-D-mannosyl chloride (both trans-compounds) illustrates the im-portance of other factors which govern reactivity. It has been suggestedthat these steric factors may be attributed either to hindrance by the large.‘:Tt,. H 3 2.(lo) AcO OAc84 Cf. J. T. Edward, Chem.and Ind., 1955, 1102.25 J. T. Henderson, J. Amer. Chem. SOL, 1957, 79, 5304.26 S. N. Danilova, 0. P. Koz’mina, and A. N. Shirshova, Zhur. obshchei Khim.,27 G. Zemplkn, L. Mester, and E. Eckhart, ActaChim. Acad. Sci. Hung., 1954,4, 73.s8 W. Korytnyk and J. A. Mills, Chem. and Ind., 1957, 817.29 R. U. Lemieux and C. Brice, Canad. J .Chew., 1956, 34, 1006; R. U. Lemieux8 0 G. L. Mattok and G. 0. Phillips, J., 1967, 268.1957, 27, 945.and J. D. T. Cipera, ibid., p. 906OVEREND : CARBOHYDRATES. 297groups to the realisation of a planar configuration of the ion, or to sterichindrance to the solvation of the ion.Conformational and mechanistic aspects of glycoside hydrolysis have beendiscussed in terms of a cyclic 1 and an acyclic 3 l carbonium ion intermediate.The influence of a keto-group on the stability of the glucosidic linkage hasbeen examined.32More measurements have been made33 of the rate of mutarotation ofD-glucose in unbuffered alkaline solutions.The reason for the establishedgreater acidity of p-D-glucose than of the a-form lies in the considerabledifference in entropy change upon ionization of the two isomers. Neutralsalts modify both the speed of mutarotation and the equilibrium rotation ofglucose, fructose, galactose, and maltose.34 The uncatalysed and acid-catalysed mutarotations of tetra-0-methyl-a-D-glucose in solvents D20 andH20 have been e~amined.~5 The results are very similar to those obtainedwith glucose, and it is reasonable to conclude that the large value of K=/JEDfor catalysis by strong acid is a characteristic of the mutarotation of glucose.Protons of the hydroxyl groups equilibrate instantaneously in an aqueoussolvent and hence in the mutarotation the slow step will involve rupture ofan O-H bond in water and of an O-D bond in D20 with simultaneous ringopening in both cases.This results in a slower rate-determining step inD,O. It has been suggested36 that the reason for the mutarotation ofsugar osazones lies in the electron-displacement which takes place in theirchelate structure upon the action of solvent, i.e., there is a structural shiftfrom somewhere near state (11) (osazone derived from a hexose) towardsstate (12).Molecular-rotation studies of sugar derivatives have been rep~rted.~'Calculations have been made according to Klyne's method 38 of molecularrotations of the isomeric trehaloses 39 and, except for the values obtainedfor aa-trehalose, there is good agreement with experimental values.To provide support for earlier generalizations40 the action of alkali onsugar derivatives has been further studied.41 The effect of the presence ofcalcium on the alkaline degradation of 4-O-substituted glucose derivatives31 F.Shafizadeh, Abs. Amer. Chem. SOC., 132nd Meeting, 1957, 6D.32 2. I. Kuznetsova, Y e . D. Kaverzneva, and V. I. Ivanov, Izvest. Akad. Nauk33 J. M. Los and L. B. Simpson, Rec. Trav. chim., 1957, '96, 267.34 A. de Grandchamp-Chaudun, Compt. rend., 1957, 244, 1564.35 B. C. Challis, F. A. Long, and Y. Pocker, J., 1957, 4679.38 L.Mester and A. Major, J . Amer. Chem. Sac., 1957, 79, 3232.3 7 S. Yamana, Bu.11. Chem. SOC. Japan, 1957, 30, 203, 207.38 W. Klyne, Biochem. J.. 1950, 47, xli.39 J. StanCik, Nature, 1957, 1'79, 97.40 J. Kenner, Chem. and Ind., 1955, 727.4 1 W. M. Corbett, G. N. Richards, and R. L. Whistler, J., 1957, 11; G. N. Richards,S.S.S.R., Otdel. khim. Nauk, 1957, 655.ibid., p. 3222; J. Kenner and G. N. Richards, ibid., p. 3019298 ORGANIC CHEMISTRY.is to favour the reaction sequence (13) -+s(16), leading to D-gh.ICOiS0-saccharinic acids at the expense of competing reactions.42 There is tentativeevidence that the effect results partly from catalysis of the benzilic acidrearrangement (15) --+ (16).CHO CHz.OH CHI*OH COPHI I II I II +-OR+ I __t II I 1I IC(OH)*CH 2.0HCH 0H-C-OHG OC’OG OHO-C-HIIIIIH-C-OHHO-C-HLf--H-C-OR CH * H-C-ORH-C-OH CH2*OH H-C-OH H-C-OHCHP*OH CHa*OH CH2’OH(13) (14) (15) (16)Full details are now published 43 of the alkaline degradation of xylobioseand xylotriose.The major product is xyloisosaccharinolactone (17 is theacid), but three other lactones, probably of the acids (18), (19), and (20),were also detected. It is probable that these lactones arise by conversionCHz*OH CO,H CO,H C02HH-C-OHCH2C(OH)*CO,HCH,-OHCHZICH,*OH1III IH-C-OH II CH 2 IH-C-OHI IIICH 2H-C-OHof the biose and triose into xylose which is the reaction intermediate.The alkaline degradation involves a ‘‘ peeling ” reaction of the type,xylotriose _+ xylobiose xylose, in which each successive reducingsugar residue gives rise to acidic products with the simultaneous exposureof a new reducing group.The action of hot dilute sodium hydroxide oncellulose under oxygen-free conditions and short reaction times yieldsD-ghcoisosaccharinic acid (44%), lactic acid (4.3y0), formic acid (7--8%),acetic acid (<2y0), and a range of other acidic materials.44 In additionthere is an alkali-stable polysaccharide residue which on acid hydrolysisyields a- and 8-glucometasaccharinic acid (as the lactones) and a-D-gluco-saccharinic acid (?).45 It was concluded that during the degradation ofcellulose by oxygen-free alkali two competitive reaction sequences occur,namely, the ‘‘ degradation ” and the “ stopping ” reaction.The scheme 46represents the probable course of the reactions. The “ degradation ”reaction (21) (31) represents a progressive stepwise degradation from42 M. J. Blears, G. Machell, and G. N. Richards, Chem. and Ind., 1957, 1150.43 G. 0. Aspinall, Mary E. Carter, and (in part) M. Los, J., 1956, 4807; Chem. andInd., 1955, 1553; cf. R. L. Whistler and W. M. Corbett, J . Amer. Chem. SOC., 1956,78, 1003.44 G. N. Richards and H. H. Sephton, J., 1957, 4492.45 G. Machell and G. N. Richards, ibid., p . 4500.413 G. Machell, G. N. Richards, and H. H. Sephton, Chem. and Ind., 1957, 467OVEREND CARBOHYDRATES. 299the reducing end of the cellulose molecule, while the " stopping " reaction(21) __t (25) competes with this process but occurs at a much slower overallrate, chiefly owing to the mass-law effect in reactions (22) + (23) andCHO CHOC-OHCHI IIII II ICHO-Ci=OIIIIIC-OHHO-C-H 1 - 1 L - 'iH2 .__tH-C-O-(G), H-C-O-(G), H-C-O-(G),H- -C-OH H-C-OH + OH- H-C-OHCH,.OH CH,*OH CH2*OH(22 (23) (24)COSHCH*OHIIH-C-O-(G),IIH-C-OH ICH2*OH CH,*OH CHa*OHc=oHO-C-H1 IIIII7-OC-O-II1 - 1 - II +IIHO-C HO-CH-C-O-(G), H-C-O-(G), CHH-C-OH I1 H-C-OH H-C-OHCHZ-OH CH,*OH CHz*OHI ICH,*OH c=o CO,H C=O I I C(OH)*CH,*OH G OI+ IICHaOHCH,.OH CH*OHCHO H-C-OHIi - O I 1 I FH2 - CH2 tH-C-OH H-C-0 H I CH ,.OHICH,.OH CH2.0HII H-C-OH(32) (31) (30) CHz-OHCHO III1IH-C-OHHO-C-HH-C-O-(G),-,H-C-OHCH ,*OH(29)Furtherdegrad n.COzH I C=O --+ CH-OHICHSICHS(33) (34) (21) = Cellulose molecule of D.P.n + I(25) = Alkali-stable cellulose molecule(27) __t (28) which are almost certainly rate-determining.A full accounthas now been published 47 of the action of bases on methanesulphonyl estersof reducing sugars.4 7 D. C . C . Smith, J., 1957, 2690; Chern. and Ind., 1955, 92300 ORGANIC CHEMISTRY.Esters.-There has been considerable interest this year in the chemistryof sugar phosphates : the subject was reviewed re~ently.~8Several sugar phosphates have been obtained by enzymic syntheses, e.g.,erythrose 4-pho~phate~~ ribulose 5-~hosphate,~O ribulose 1 : 5-dipho~phate,~lxylulose 2-deoxyribose 1 : 5-dipho~phate,~~ lactose 1-phosphate,54 and octulose The effects of temperature, pH,enzyme concentration, phosphate, and starch concentration on the potatophosphorylase-catalysed synthesis of glucose l-phosphate have beenstudied.56Mannitol l-phosphate has been isolated from LactobaciZZus arabinosus. 57A substance containing glycerophosphate and ribitol phosphate residues alsooccurs in fresh cells of this organism.58A number of chemical syntheses and transformations of sugar phosphateshave been described.59 By a micromethod involving successive periodateand bromine oxidations of the ribitol cyclic phosphate (35),579 6O glyceric acid2 : 3-(hydrogen phosphate) (36) was formed: this on mild hydrolysis affordsglyceric acid 2- and 3-phosphate (37 and 38).The acids were shown byenzymic assay to have the D-configuration.6lPeriodate oxidation of D-ribose 3-phosphate and saponification of theO-formyl ester so produced yield D-erythrose 2-ph0sphate.6~ The mono-phosphates of 4-deoxy-~-erythronic acid (~-erytho-or~-dihydroxybutyricCHS'OH IIIH-C-OHH-C-OH __tH-F-o\do CHI*O' \OH(35)ICOLH COPHH-C-O*POIHs H-C-OH I I+ I CH2-O*P0,Hp - ICH **OH(1 P a 4 (4 parts)(37) (38)acid) have been synthe~ized.~~ From the anomeric mixture resulting (afterremoval of protecting groups) from the addition of triethylammoniumdibenzyl phosphate to 5-O-acetyl-~-ribofuranosyl bromide 2 : 3-carbonate4 8 A. B. Foster and W. G. Overend, Quart. Rev., 1957, 11, 61.49 M. Schramm and E. Racker, Nature, 1957, 179, 1349.5O D.B. McNair Scott and S. S. Cohen, Biochem. J., 1957, 65, 686.51 J. Mayaudon, A. A. Benson, and M. Calvin, Biochim. Biophys. Acta, 1957,23,342.52 J. Hurwitz and 33. L. Horecker, J. Bid. Chem., 1956, 223, 993; J. Hickmanand G. Ashwell, J . Amer. Chem. Soc., 1956, 78, 6209.53 H. L. A. Tam, Chem. and Ind., 1957, 562.54 J. E. Gander, W. E. Petersen, and P. D. Boyer, Arch. Biochem. Biophys., 1957,69, 85.55 E. Racker and E. Schroeder, ibid., 1957, 88, 241.56 T. Suzuki and I. Hamada, J . Ckem. SOC. Japan, 1956, 77, 1681.57 J. Baddiley, J. G. Buchanan, B. Carss, A. P. Mathias, and A. R. Sanderson,68 J. Baddiley, J. G. Buchanan, and G. R. Greenberg, ibid., 1957, 68, 51P.5Q Cf. A. GebauerovA and K. TomfGek, Chem. Zvasti, 1957, 11, 562.6o J.Baddiley and A. P. Mathias, J., 1954, 2723.6* H. S. Loring, L. K. Moss, L. W. Levy, and W. F. Hain, Arch. Biockem. Biophys-,Biochem. J., 1956, 64, 599.J. Baddiley, J. G. Buchanan, and B. Carss, J., 1957, 1869.C. Ballou, J . Amer. Chem. Soc., 1957, 79, 984.G. M Tener and H. G. Khorana, ibid., p. 437,1956, 65, 578OVEREND: CARBOHYDRATES. 301the crystalline dicydohexylammonium salt of a-D-sbofuranose 1 -phosphatewas obtained a8 the main product.66 This ester is identical with that ob-tained by enzymic phosphordysis of ribonucleosides. Alternative synthesesemploying 3 : 5-di-O-benzoyl-~-ribofuranosyl halides gave moderate yieldsof anomeric ribofuranose l-phosphates. A prehmhary account has ap-peared66 of the synthesis according to the annexed scheme of a-D-ribo-furanose 1 : 5-diphosphate (39).Substitution in this scheme of triethyl-ammonium tribenzyl pyrophosphate far triethylammonium dibenzylPhO-P-0.H FI 2 C a * C H 2 P hH O . H z C O CHzPh I * PhO IH HHO OH HO OH0HO IIReagents: I , (Pt10)~PoCl in C,H,N. 2, Mild alkali and then COClz in C,H,N. 3, HBr in AcOHand then triethylammonium dibenzyl phosphate. 4, (a) Pd-Hs, (b) Pt03-H,, (c) LiOH.phosphate led to 5-0-phosphoryl-a-~-ribofuranose l-pyrophosphate. Amixture of the 5-pyrophosphate (20-25%) and 5-triphosphate (10%) ofribose is formed by the action of phosphoric acid and dicyclohexylcarbodi-imide in aqueous pyridine on ribose 5-pho~phate.~~ After chromatographicseparation both compounds were converted into ribulose derivatives byphosphoriboisomerase.Reduction of D-ribose &phosphate by sodium borohydride gives D-ribitol5-ph0sphate.6~ cycloHexy1ammoniu.m salts have been employed extensivelyto obtain crystalline forms of sugar phosphates, e.g., from the l-phosphatesof a- and P-D-glucose, a- and P-D-galactose, a- and P-L-arabinose and a- andp-D-xylose.68 It has been shown that a-D-xylose l-phosphate is formedwhen tri-0-acetyl-l-bromo-D-xylose is heated in benzene with silver diphenylphosphate and the protecting groups are then eliminated,69 whereas reactionat room temperature leads to the p-an~rner.~~ 1 : 2-@isoPropyfidene-~-xylofuranose 3 : &phosphate (40) has been synthesized in excellent yield bya number of methods.'l Mild action of acid on compound (40) gave a good66 G.M. Tener, R. S . Wright, and H. G. Khorana, J . Amev. Ckem. SOC., 1956, 78,*t~ G. M. Tener and H. G. Khorana, Chem. and Ind.. 1957. 562.506; 1957, 79. 441.67 B. L. Horecker, J. Hurtwitz, and L. A. Heppel, J . Amev..Chem. SOC., 1957,79, 701.68 E. W. Putman and W. 2. Hassid, ibid., p. 5057.6s N. J. Antia and R. W. Watson, C h m . and Ind., 1956, 1143.70 Idem, &id., 1957, 600.71 J. G. Moffatt and R. G. Khorana, J. Amer. C h m . SOC., 1957, 79, 1194302 ORGANIC CHEMISTRY.yield of D-xylose 3 : 5-phosphate (41). D-Xylose 3-phosphate has beenprepared for the first time by alkaline hydrolysis of the cyclic derivative(M), followed by mild acidic hydrolysis of the products (42) and (43) andseparation on a resin column.71 Attempts to synthesize glucose l-methyl-phosphonate and isopropyl glucose l-methylphosphonate were unsuccessful. 72A galactosamine phosphate has been prepared which is presumably the6-phosphate. 73 A colour reaction has been devised which differentiatesbetween pentose &phosphate, free pentose, and other pentose esters. 74Complex mixtures of inorganic and organic phosphates can be separated bytwo-dimensional ionophoresis and chromatography on paper. 75Application of Hudson's isorotation rules to the CI- and P-l-phosphatesof L-arabinose, D-xylose, D-glucose, and D-galactose shows the 2A values(average value = 25,400) to be consistent with the first rule, but the 2Bvalues are greater than those of the corresponding methyl glycosides byca.9000 molecular rotation units.68 The changes in optical rotation ofneutral solutions of D-xylose 5-phosphate are due to the ready partialconversion of the ester into D-xylulose 5-ph0sphate.~~~ 76 In various buffersin the pH range 7-0-9.5, xylulose 5-phosphate is destroyed more rapidlythan ribulose 5-phosphate. Changes in pH have less effect than differencesH203p.0.H2cQ H0.H2;Q7 X = 'PO3H2H( 4 2 ) H O-CMe2 H O-CMe, (43)in the nature of the buffer.77 The alkaline decomposition of phosphateesters having a reducing group in the p-position has been examined.78Elimination occurs and glucose 3-phosphate gives glucometasaccharinic acid.Similarly ribose 3-phosphate affords a C,-saccharinic acid, e.g. :CH-O- CHO CO,H I-----+I - I1 - IICH-OHIIC-OH I1ICHOOH- C-OH -pots-IC H.O*PO ,H a C H*O*PO 32- CH CH 2 I R R R RAcid treatment of ribitol 1 (5)-phosphate gives ribitol3- and 2(4)-phosphate 6172 F.C. G. Hoskin, Canad. J. Chem., 1957, 35, 581.73 J. M. Merrick and S. Roseman, Abs. Amer. Chem. SOC., 131st Meeting, 1957, 12D.74 2. Dische and E. Landsberg, Biochim. Biophys. Acta, 1957, 24, 193.7 6 Cf. R. W. Watson and J. L. Barnwell, Chem. and Ind., 1955. 1089.77 E. Borenfreund and 2. Dische, Biochem. Biophys. Acda, 1957, 25, 215.7 8 D. Brown, F. Hayes, and (Sir) A. Todd, Chem. Ber., 1957, 90, 936.V. C . Runeckles and G. Krotkov, Arch. Biochem. Biophys., 1957, 70, 442OVEREND : CARBOHYDRATES. 303and 1 : 4-anhydroribit01.~~ Formation of the last compound, which is themain product of prolonged treatment, is probably best represented byprotonation of the ester oxygen atom followed by the electronic displace-ments shown, leading to an intramolecular nucleophilic substitution.Al-though D-ribitol5-phosphate was used in the experiments, the acid-catalysedphosphate migration leads to considerable or even com- , , - YH plete racemisation, and it is likely that the DL-form of they 2 CHZ-~-~;-OH anhydride is produced. D-Xylitol 5-phosphate is con-At higher pH (e.g., pH 4) normal hydrolysisof ribitol 1 (5)-phosphate occurs and ribitol is formed.793The stereochemical requirements for cyclic ester formation from sugarmonophosphates have been discussed. A general procedure has beendeveloped for formation of five- and six-membered cyclic phosphates fromesters containing suitably placed hydroxyl functions, dicyclohexylcarbodi-imide being the reagent.Five- and six-membered cyclic phosphates can bedifferentiated, since the former undergo further reaction with the carbodi-imide to form N-phosphorylureas. From the behaviour of hexopyranosel-phosphates (in CI conformation) with the carbodi-imide it was concludedthat cyclisation is possible when both the relation of a phosphate group tothe adjacent hydroxyl group is axial to equatorial (e.g., 44) or is equatorialto equatorial (e.g., 45) (both a- and @-glucose l-phosphate form 1 : 2-cyclicphosphates). If the phosphate and hydroxyl groups are both axial (e.g., 46)cyclisation will not occur (a-D-mannose l-phosphate does not form a cyclicphosphate on addition of the reagent). Glucose 6-phosphate reacts in thepyranose form and yields the 4 : 6-cyclic phosphate. The reagent convertsD-xylose &phosphate into the six-membered 3 : 5-cyclic phosphate, butD-xylose 3-phosphate gives a five-membered cyclic ester. Obviously the&phosphate has a furanose structure and the 3-phosphate is a pyranosederivative. When the formation of both five- and six-membered cyclicphosphates is possible, the former is favoured.H H+ o verted similarly into an anhydride but slightly moreslowly.The r81e of hexose phosphates in the synthesis of cellulose by AcetobacterThe preparation and properties of organosilyl derivatives of sugars havexy2inu.m has been studied.81been reported.S2( b ) J. Baddiley, J. G. Buchanan, and B. Carss, J., 1957, 4058.SOC.. 1957, 79, 430.7 9 (a) J. Baddiley. J. G. Buchanan, B. Carss, and A. P. Mathias, J . , 1956, 4583;8 0 H. G. Khorana, G. M. Tener, R. S. Wright, and J. G. Moffatt, J . ,4mer. Chem.81 M. Schramm, 2. Gromet, and S. Hestrin, Nature, 1957, 179, 28.82 F. A. Henglein, G. Abelsnes, H. Heneka, K. Lienhard, P. Nakhre, and K.Scheinost, Makromol. Chena., 1957, 24, 1304 ORGANIC CHEMISTRY.D-Glucose 3-sulphate has been prepared according to the followingscheme : 83 1 : 2-6 : 6-di-O-isopropylidene-a-~-glucofuranose 3-(methylsulphite) 4 [by Ca(Mn0,)J 3-(methyl sulphate) -+ (by aq. AcOH at40") [l : 2-5 : 6-di-O-~sopropylidene-c~-~-glucofuranose 3-sulphate] --+ D-glucose 3-sulphate.Fully nitrated derivatives of allitol, L-arabitol, xylitol, adonitol, iso-mannide, isosorbide, and isoidide have been prepared.85 The action ofdry pyridine on the hexanitrates of D-mannitol and D-galactitol removesselectively the 3( =4)-nitrate group, yielding the alcohol without inversion.85Alkaline hydrolysis of glucose nitrates has been examined. 86 With mono-nitrates the amount of nitrite released is relatively small, but increases asthe number of nitrate groups is increased (Le., increase in the Eco reaction).Substitution of free hydroxyl groups by ethylidene or methyl residuesincreases the extent of the Eco reaction. Hydrolysis of acetyl derivatives ofsugar mono- and di-nitrates results in preferential cleavage of the acetylresidues, but removal of acetate and nitrate does not occur in controlledsteps with monoacetates of sugar trinitrates. The 2-nitrate group of methyl4 : 6-O-ethylidene-ot-~-mannoside 2 : 3-dinitrate is removed preferentially(yielding the alcohol) by (i) sodium methoxide in cold methanol-chloroform,(ii) sodium iodide in acetone at loo", or (iii), best, by sodium nitrite in boilingaqueous ethanol.*'Partial esterification of methyl 4 : 6-O-benzylidene-a-~-glucoside inpyridine with chlorides of carboxylic and sulphonic acids gives mainly the2-monoester. Likewise sulphonic anhydrides give the 2-monoester, butcarboxylic anhydrides give the 3 - e ~ t e r . ~ ~ For the glycoside the relativereactivity at positions 2 and 3 depends on the number of protons (eitherproduced by external addition or by release during the reaction) in thereaction medium. The results of this study are not in agreement with thegeneralization 89 that 2-hydroxyl groups are more reactive than othersecondary hydroxyl groups, especially in alkaline media.Amino-sugars.-N-Acetylglucosamine and N-acetylgalactosamine occurin a polysaccharide isolated from B. s ~ b t i l i s , ~ ~ and fucosamine is a componentof a polysaccharide from Chromobacterium v i o l a c e ~ r n . ~ ~ A growth-factor forL. biJidus var. Pennsylvanicus has been identified as ethyl N-acetyl-p-D-glu~osaminide.~2 " Trealoseamine," a new amino-sugar produced by astreptomycete, has been isolated. 93 Acid hydrolysates of chondroitinsulphate from hyaline cartilage contain an amino-sugar which is probablytal~samine.~~ Amino-sugars have been detected in hydrolysates of soya-bean83 A. B. Foster and E. B. Hancock, J., 1957, 968.84 A. B. Foster, E. B. Hancock, W. G. Overend, and J. Robb, J., 1956, 2589.85 L. D. Hayward, Abs. Amer. Chem. SOC., 132nd Meeting, 1957, 15D.86 D. O'Meara and D. M. Shepherd, J., 1957, 3377.87 J. Honeyman and T. C . Stening, ibid., p. 2278.88 R. W. Jeanloz and D. A. Jeanloz, J . Amer. Chsm. Soc., 1957, 79, 2579.89 J. M. Sugihara, Adv. Carbohydrate Chem., 1953, 8, 1.90 N. Sharon, Nature, 1957, 179, 919.91 D. A. L. Davies, ibid., 1957, 180, 1129.92 S. Pope, R. M. Tomarelli, and P. Gyorgy, Arch. Biockem. Bioghys., 1957, 68, 362.93 F. Arcamone and F. Bizioli, Gazzetta, 1957, 87, 896.94 H. Muir, Biochem. J., 1957, 65, 33POVEREND : CARBOHYDRATES. 305g l y ~ i n i n . ~ ~ The structure of muramic acid is 3-O-c+ethoxycarbonyl-~-glucosamine. 96 The dimethylamino-sugar (47) (amosamine) occurs in theantibiotic ame~etin.~' Mycosamine has structure (48).g8 The D-configur-ation is assigned to but the remainder of the stereochemistry is stillbeing investigated. The neobiosamine moiety of both neomycin B and Cconsists of a diaminohexosido-pento~e.~~Amino-sugar chromatograms developed with weakly basic or acidicsolvents require cautious interpretation.lO0 Methods are available for theseparation of talosamine from other 2-amino-hexoses lo1 and for the deter-mination of 10-100 pmg. of hexosamine.1o2 A determination of hexos-amines in conjunction with electrophoresis on starch has been outlined.lo3A review of amino-sugars has been published.lWW. G. 0.P. BLADON.R. C. COOKSON.L. CROMBIE.A. G. QAVIES.R. F. GARWOOD.T. G. HALSALL.W. G. OVEREND.K. SCHOFIELD.S. F. SMITH.G. H. WILLIAMS.G. T. YOUNG.P. B. D. DE LA MARE.0s B. N. Gladyshev, Doklady Akad. Nauk S.S.S.R., 1957, 112, 291.g6 L. H. Kent, Biochem. J., 1957, 67, 5P.07 C. L. Stevens, R. J . Gasser, T. K. Mukherjee, and T. H. Haskell, J . Amer. C k m .88 D. R. Walters, J . D. Dutcher, and 0. Wintersteiner, ibid., 1957, 79, 5076.99 K. L. Rinehart, P. W. K. Woo, A. D. Argoudelis, and A. M. Giesbrecht, ibid.,Soc., 1956, 78, 6212.p. 4567.100 D. H. Leaback and P. G. Walker, Biochem. J., 1957, 6'7, 22P.l01 M. J. Crumpton, Nature, 1957, 180, 605.102 D. Exley, Biochem. J., 1957, 67, 52.103 0. W. Newhaus and M. Letzring, Analyt. Chem., 1957, 29, 1230.104 R. Kuhn, H. H. Baer, W. Bister, R. Brossmer, A. Gauhe, H. J. Haas, F. Haber,G. Kriiger, T. Tiedemann, and D. Weiser, Angew. Chem., 1957, 89, 23