Aug. 5 , 1961
3323
SUBSTITUTED PYRROLIDINES AND PYRROLIZIDWES
The reduction' of 2,3-dimethylindole with tin and hydrochloric acid yielded a colorless, acid-soluble oil, b.p. 231-236', n 2 6 ~ 1.556, d25 0.994, which a vapor phase chromatogram showed to contain ca. 60% cis- and ca. 40y0 trans-2,3-dimethylindoline. The benzenesulfonamidelb of the cis isomer isolated from this mixture melts a t 70-71'. The acid-soluble product of the reaction of aniline with crotyl bromide was fractionated. AS shown by vapor
[CONTRIBUTIOS FROM THE N O Y E S CHEhIIC.4L
phase chromatogram, the fraction b.p. 230-240°, flzSD 1.554, dz5 0,990, contained besides three other compounds, ca. 55% trens-2,3-dimethylindoline and ca. 19% cis-2,3-
Acknowledgment.-We wish to thank Professor Martin G. Ettlinger for valuable advice.
LABORATORY, UXIVERsITY OF
ILLINOIS, URBAx& I L L
1
Synthesis of Substituted Pyrrolidines and Pyrrolizidines BY ROGERADAMS,SEIJIMIYANOAND M. D. NAIR RECEIVED FEBRUARY 17, 1961 Condema t~oriof S-substituted i3-aininopropionitriles with diethyl oxalate yields S-substituted 4-cyano-2,3-dioxopyrrolidines. Application of this reaction t o the synthesis of pyrrolizidine and octahpdropyrrocoline ring systems is described t o the Senecio bases macronecine, hastanecine or The relationship of synthetic dZ-l-hydroxymethyl-2-hpdroxypyrrolizidine turneforcidine is discussed.
The synthesis of 2,3-dioxopyrrolidines (I) and aminocrotonate (171). This structure is supported derivatives by means of the condensation of esters by its infrared spectrum which shows the presence of of oxalic acid with p-arninopropionic esters was a secondary non-cyclic aniide band3 a t 1507 cm.-'. X reaction of similar character is the condensation first reported by Southwick and co-workers.l z 2 This reaction now has been applied to the synthesis of 6-aminopropionitriles (\?II) with diethyl oxalate of pyrrolizidine derivatives, some of which represent to give 2,3-dioxo-4-cyanopyrrolidines(IX) . NMethyl-, N-ethyl-, N-o-cyanoethyl-, N-benzylthe basic moieties of certain Senecio alkaloids. (17111) conCondensation of ethyl aspartate (11)and ethyl /3- and N-cyclohexyl-/3-aminopropionitriles aminoglutaconate (111) with dimethyl oxalate densed smoothly with diethyl oxalate in the presyielded the expected 4,5-dicarbethoxy-2,3-dioxo-ence of sodium alkoxides to give the corresponding pyrrolidine (IV) and 4-carbethoxy-5-carbethoxy- N-substituted 4-cyano-2,3-dioxopyrrolidines(IX). methylene-2,3-dioxopyrrolidine(V), respectively. Reaction of N - /3 - cyanoethyl - 4 - cyano - 2,3 Diazomethane converted these dioso compounds dioxopyrrolidine with diazomethane yielded the enol ether. ;5 s these 8-aminopropionitriles are and 1-8,. into their enol ethers 11'~ conveniently prepared by cyanoethylation of amines, the oxalate condensation provides a very convenient route to substituted pyrrolidines. The CHR' parent compound, 8-aminopropionitrile, reacted I otherwise, however, and gave with diethyl oxalate NHR only p-cyanoethyloxamide (X), characterized by analysis and infrared spectrum. 111, R = H, R'=;CHCOOC,H~
IV, R = H , K ' = COOC,H, i V , K = H. K = 'CHCOOC'2Hj
CHJCS
/
\'Ill R
,
R
VI1
\'I
On the other hand, condensation of diethyl oxalate with ethyl 6-aminocrotonate in the presence of potassium ethoxide did not yield the cyclizat.ion product VI but instead a compound of molecular formula C1oH15NO6, presumably ethyl P-oxalyl11) Y
L
hLutbi-stallized frwn vtlianol; m.p. 160 - 151.5'. tl)tal. Calcd. for CsHljSO,~C~,HsS&: C, 51.31, 11, ;1.47;S, 16.52. Found: C, 51.39: H, 5.50; N. 16.36. 1-Carbethoxy-2,s-dioxopyrrolizidine(XII).-To a cooled solution of 1.4 g. of freshly cut sodium in 40 ml. of absolute ethanol was added vlith stirring a mixture of 6.8 g. of ethyl 2-pyrrolidylacetate and 7.0 g. of dry diethyl oxalate. The reaction mixture warmed up. I t was heated under reflux iur 4 h r . duriug which time the color changed to dark red. T h e ethanol was removed under reduced pressure, the gummy residue cooled and scratched with 30 nil. of 20:'; hydrochloric acid. The ivhite crystals that separated were removed by filtratioii, xished wit11 ice-colt1 water. dried and recrystallized from benzene-petroleum ether (11.1). 41-60") to give colorless needles, in.1). 119--120". Eatractinn of the aqueous mother liquor with chloroform yielded : I I I additional 0.9 g. nf product. The total yield was 7 . 3 L . (82%). .4nai. Calcd. for C1,.H13NOa: C, 56.86; H , 6.20; X , 6.63. Found: C,56.53; H,6.29; N,6.60. The 1-Carbethoxy-2-methoxy-3-oxopyrrolizid-1 ,2-ene .T o an ethereal suspension of 3 g. of l-carbethoxy-2,3-dioxopyrrolizidine was added an ethereal solution of 3 g. of (16) G. R. Clrnio, \V. \ l c G . 3 1 r ~ g n na t i d R 1743 (l!I%).
R x i w r , .I. Clr,.t,?. So'. ,
didzomethalic. In a few minutes most of the solid dissolved with effervescence. The solution was filtered, the ether removed, arid the residual oil distilled under reduced pressure; colorless oil. b.p. 185--187" (0.7 rnni.), yield 2.8 g. ( 77.870). Anal. Calcd. for C1lHlaNOa: S,6.22. Found: N,6.31. Reduction of l-Carbethoxy-2,3-dioxopyrrolizidine with Lithium Aluminum Hydride.-To a stirred solution of l.ti g. of lithium aluminum hydride in 50 ml. of anhydrous tetrahydrofuran was added droplrise a solution of 3.0 g. of l-carbethoxy-2,3-dioxopyrrolizidinein 20 ml. of anhgdrous tetrahydrofuran. .Ifter the addition m s complete, the reaction mixture LYas heated under reflux for 3 hr. A mixture of water and tetrahydrofuran then was added carefully to decompose the unreacted hydride. The mixture mas filtered through Super-cel, the filtrate dried over anhydrous sodium sulfate, arid the solvent removed under reduced pressure. The residual oil was distilled under reduced pressure t u give 0.9 g . (45.7c/0) of colorless liquid, b.p. 93-95" ( 1 . 7 mni.), which turned yellow on standing for a few hours. The picrate was prepared in ether and crystallized from absolute ethanol; 1n.p. 16rj--16S0. A t ~ i l . Calcd. for CsHlaSO,C6HaSaO;: C, 45.65; H , 4.25; S, 15.22. Found: C, 4S.36; H. 4.67; S , 15.03. Paper chromatography of the base using butauol-acetic :icid as the solvent slsteni indicated the presence of more than one compound. So attempt was made t r i separate the components. l-Carbethoxy-",3-dioxopyrrolizidirlc was unattacked bj. >odium borohydride. Lithium borohydride reduction 1-ieldeda mixture of products. Catalytic Reduction of the Lithium Aluminum Hydride Reduction Product.---A solution of 0.4 g . of the base in 25 i d . of absolute ethanol was shaken with 0.1 g. of platinum oxide catalyst and hydrogen at room temperature and ;ttmospheric pressure. The absorption of 58 ml. of hydrogen t calcd. for 1 mole, 64 i d . ) required 30 miti. and the absorption then ceased. The catalyst was removed :ind the solrent distilled off under reduced pressure. The residual oil ~ ; t converted s into its picrate in ether , i t i d crystallized from ethanol-ether; m.p. 18G-185". ;Innl. Calcd. for C ~ H L ~ N O ~ G H C, ~ N45.41; ~ O ~ :H, 4.8ti; S ,15.14. Found: C, 45.32; H , 5.16; S , 15.16. 1-Carbethoxy-2-hydroxy-3-oxopyrrolizidine(XX1):h sulution of 5.0 g. of 2,3-dioxo-l-carbethoxyp~-rrolizidine in 40 ml. of glacial acetic acid was hydrogenated in the prescnce of 1.5 g. of 570rhodium-on-alumina ;tiid a t an initial pressure of 20 p.s.i. Absorption of the theoretical ~ I I I I I I U I I ~ ( 1 rude) of hydrogen \vas complete in 30 niiti. T h c cwt:il y s t \w> filtered off and the solvent removed uiitler redured pressure. The residue crystallized on cnoling. I t \vas pttriiied b ~ .recrystallization from benzeue-petroleum ether (b.p. 4ibGO'i to give 4.2 g. (825;) of shining platelets, 1n.p. 137.5'. Arzal. Calcd. for CIOHISSOI:C, 56.32; H,7.08; S , 6.5;. Found: C,56.56; H, 7.31; S, 6.72. 1-Hydroxymethyl-'2-hydroxypyrrolizidine(XXII).-To a stirred slurry of 3.0 g. of powdered lithium aluminum hydride in 75 ml. of freshly purified tetrahydrofuran was added dropwise a solution of 5 .0 g. of l-carbethoxy-2-hydroxy-3oxopyrrolizidine in 75 ml. of tetrahydrofuran. After the :iddition 1ra.s over, the slurry was heated under reflux with itirriiifi for .1 hr., cnoled, excess of hydride clcconiposed
Aug. 5 , 1961
TOTAL SYNTHESIS OF CERASINE AND PHRENOSME
by addition of wet tetrahydrofuran, and the precipitate separated by filtration through Super-ccl. The filtrate was dried and evaporated to leave a gum which crystallized on trituration with acetone. Recrystallization from acetone yielded2.8g. (75.8%) of whiteprisms, m.p. 123-124". A ~ ~Calcd. J . for c ~ H ~ ~ cN, ~61.11; ~ : H, 9.61; s, 8.91. Found: C, 61.10; H , 9 . / 6 ; N,8.i6. The hydrochloride was prepared in ethanol and from ethanol-ether; m.p. 111-112.5". Anal. Calcd. for CSHI~NOVHCI:C, 49.60; H, 8.33. Found: C, 49.63; H, 8.62. The picrate prepared in ethanol and crystallized from ethanol-ether gave shilling yellow prisms, m.p . 166-167". Anal. Calcd. for C ~ H ~ S N O ~ . C ~ HC, ~ K43.52; ~ O ~ : H, 4.69; N, 14.50. Found: C, 43.50; H, 5.19; iV, 13.98.
[CONTRIBUTION FROM THE
3327
l-Chloromethyl-2-chloropyrrolizidine.--h misture of 1.3 l-hydroxymethy-l-2-h~~droxypyrrolizidine in 5 ml. of
g. of
chloroform and 3 ml. of thionyl chloride was heated under reflux for 4 hr. a t the end of which time most of the solvent and excess of thionpl chloride were removed under diminished pressure, the residue taken up in chloroforin, m s h e d with 10% aquebus sodium hydroxide, the organic layer dried and the solvent evaporated. The resulting oil was converted into its picrate in ethanol, and recrrstallized from ethanol; m.p. 1158-169". ilmz1. Calcd. for CSH&12S.CeHJXdO,: C, 39.72; H, 3.81; N , 13.24. FoUIld: 39.62; H , 3.7:; N, 13.*56. ]-H~droxynlethyl-2-hydro~~p~rrolizidilie failed to react with thionyl chloride a t 0 " . At the end of 30 min. the starting material was recovered as the hydrochloride.
c,
DAXIELSIEFF RESEARCR INSTITUTE,
THE WEIZMASX INSTITUTE O F SCIENCE,
REHOVOTH, ISRAEL]
Synthetic Studies on Sphingolipids. VI. The Total Syntheses of Cerasine and Phrenosine B Y DAVID SH.4PIRO
AXD
H. A I . FLURTRS
RECEIVEDFEBRUARY 3, 1961 The galactocerebrosides cerasine (VIIIa) and phrenosine (VIIIb) and the Gaucher spleen glucocerebroside have been synthesized and found identical with the natural products. The S-acS.l-3-O-benzoylsphingosine bases (VI), were condensed with the corresponding aceto-bromo sugars in the presence of mercuric cyanide, and the resulting acylated glycosides ( V I I ) were saponified to the glycosides V I I I . The @-configurationhas been assigned t o the natural cerebrosides.
The cerebrosides, first isolated from brain tissue in 1874,' were found to be composed of sphingosine, D-galactose and a long-chain fatty acid. The amide linkage of the acidic component and the glycosidic nature involving one of the two hydroxylic groups have long been recognized by early investigators."-j However, it was not until 1932 that structure TI was established for the two cerebrosides by Carter and co-workers,6who showed that the galactosyl group is attached to C-1 of the sphingosine molecule. The structure of sphingosine as trans-D-erythro- 1,3-dihydroxy-2-aminc-4-octadecene (I) was proven both by d e g r a d a t i ~ n ~and - ~ by synthesis. The term cerasine has been applied to the cerebroside I I a in which the acidic component is lignoceric acid, while phrenosine (IIb) contains cerebronic acid. Although these lipids certainly exist in nature as individual compounds, the fatty acids could not be obtained in a pure form by hydrolysis. Lignoceric (n-tetracosanoic) acid was found to contain small amounts of homologous acids. lo The (1) J. L. W. Thudichum, "Researches on the Chemical Configuration of the Brain," Report of the Medical OEcer of the Privy Council and Local Government Board 3, No. 5, 113 (1874). (2) J. L. W. Thudichum, "Die Chemische Konstitution (IPS Gehiriis des blenchen und der Tiere," Pietzcker, Tuebingen, 1901 (3) E. Klenk, 2.physioi. Chem., 163, 74 (1926) (4) E. Klenk and R . Haerle, ibid., 178,221 (1928). ( 5 ) I. Pryde and R. W. Humphreys, Biochem. J., 18, 661 (1924). (6) H. E. Carter and F. L. Greenwood, J . Biol. Chem., 199, 283 ( 1952). (7) H. E. Carter, F . J. Glick, W. P. Norris and G. E. Phillips, i b i d . . 170, 285 (1947). (8) H. E. Carter, F. J. Glick, W. P. Norris and G. E. Phillips, i b i d . , 142,449 (1942). (9) (a) D. Shapiro and H . Segal, J. A m . Chem. SOC., 76, 5894 (1954); (b) D. Shapiro, H. %gal and H. M. Flowers, i b i d . , 8 0 , 1194 (1958); (c) C. A. Grob and F. Gadient, Heis. Chim. A d a , 40, 1145 (1957). (10) A. Chibnall, S. H. Piper and E. F. Williams. Biochem .T , SO, 100 (1936).
identity and purity of natural cerebronic acid has been the subject of considerable discussion. Klenk's assumption"-'? that it is pure a-hydroxy-n-tetracosanoic acid was not substantiated by later investigators. -15 Indeed, Chibnall, et U Z . , ~ ~were able to show that the purified acid contained up to 155s of the C-%Ghomolog. Various melting-points and specific rotations have been reported for cerebronic acid. The optically active a-hydroxytetracosanoic acid synthesized in the present investigation closely corresponded to the physical data which characterize the purest cerebronic acid obtained from natural sources. lo In a preliminary comniunication16we reported a synthesis of dihydrocerebrosides which involved the Roenip-Knorr reaction17 of a DL-ceramidela of type VI with 2,3,4,6-tetra-O-acetyl-a-D-galactopyranosyl bromide in the presence of silver carbonate. The reaction proceeded sluggishly over a period of 41 hr., even with a large excess of the bromo-sugar. The products showed the expected infrared absorption spectra and gave good analytical values, including the percentage of galactose. The relatively low melting points of 125230' were attributed to the presence of a conglomerLite of 1)-galactosides instead of a racemic coinpound. Surprisingly, we later found that this reaction, when applied to the benzoyl-ceramides of D-sphingosine and D-dihydrosphingosine (VIa and (11) E. Klenk, Z. physioi. Chem., 174,241 (1928). (12) E. Klenk and TV Diebold, ibid., 216, 79 (1933). (13) F . A. Taylor and P. A Levene, J . Biol. Chem., 84, 23 (1929). (14) D. M Crowfoot, J . Chem. Soc., 716 (1936).
(15) J. C. Smith, ibid., 625 (1936). (16) D. Shapiro and H. M. Flowers, J. A m . Chem. SOC.,81, 2023 (1SSR).
(17) W. Koenigs and E. Knorr, Bev., 34, 957 (1901). (18) The f a t t y acid amides resulting from pnrtial hydrolysiq of I he sphingolipids are referred t o a s ceraluides.
