Analogues of hepatotoxic pyrrolizidine alkaloids: synthesis and esterification of 1-methyl-2,3-bishydroxymethyl-pyrrolidines and -3-pyrrolines (synthanecines) and corresponding pyrrole derivatives

摘要

1974 707Analogues of Hepatotoxic Pyrrolizidine Alkaloids : Synthesis and Esteri-f ication of 1 - Methyl-2,3-bishydroxymethyl-pyrrol idines and -3-pyrrolines(Synthanecines) and Corresponding Pyrrole DerivativesBy A. Robin Mattocks, Toxicology Unit, Medical Research Council Laboratories, Woodmansterne Road,Several 2.3-bishydroxymethyl-pyrrolidine and -3-pyrroline derivatives (synthanecines) have been prepared asmonocyclic analogues of the bicyclic necine bases which constitute the alcohol portions of many pyrrolizidinealkaloids. Thus, reduction of 2.3-bisethoxycarbonyl-I -methyl-3-pyrroline (IX) and of 2,3-bisethoxycarbony1-4-methoxy-1 -methyl-3-pyrroline (XII) with lithium aluminium hydride gives mainly the pyrrolidine (XI) (syntha-necine B) while reduction using di-isobutylaluminium hydride gives the pyrrolines (X) and (XIII) (synthanecinesA and C, respectively).Some of the unsaturated synthanecine esters, such as the carbamate (XVII) have bio-logical effects similar to those of the toxic pyrrolizidine alkaloid monocrotaline (IV). Dehydrogenation of the3-pyrroline diesters (IX) and (XII) and reduction of the resulting pyrrole diesters (XXI) and (XXII) providesthe corresponding bishydroxymethylpyrroles (XXIII) and (XXV). which behave as bifunctional alkylatingCarshalton, Surreyagents.MANY pyrrolizidine alkaloids which are esters of un-saturated necine bases such as retronecine (I) are toxicto various animal species, causing damage to the liverand sometimes the lungs and other organ^.^.^ The acidportions of the natural alkaloids are often complex, asin monocrotaline (IV) but simpler, semisynthetic esterssuch as di-isovalerylretronecine (11) can cause similartoxic effects when given in larger doses and the dicarb-amate (111) is more active, having about the sametoxicity to rats as monocrotaline.6Synthetic analogues of the toxic alkaloids were re-quired for metabolic and toxicological studies.A syn-thesis of retronecine (I) has been described but it islengthy and the overall yield is poor (,),SO-CDCl, 2.41 (3H, s, picrolonate Me), 3-02 (3H, s, NMe), and3-76 (3H, s, OMe).The base, recovered from the picrolonate using anionexchange resin in methanol, was a gum, vmax. 3340s (OH) and1690s cm-l (C=C), 6 2-45 (3H, s, NMe), 3.3 (OH), 3.42 (H-5),3-63 (2H, d, J 3 Hz, 2-CH2), 3.71 (3H, s, OMe), and 4-2 (2H,m, 3-CH2), no U.V.absorption above 215 nm (in H,O).2,3-Bishydroxyrnethyl-l-methylpyrrolidine (SynthanecineB) (XI).-(a) Compound (XII) (8.4 g) and lithium aluniin-ium hydride ( I7 g) in ether (300 ml) were heated under refluxfor 1 h. The cooled mixture was decomposed with dilutesodium hydroxide solution, the ether was decanted, andthe wet solids stirred with hot ethanol (150 ml). Chloro-form (50 ml) and Hyflo supacel (15 g) were added, themixture filtered, and the filtrate concentrated t o a gumwhich was re-extracted with hot chloroform. This extracttogether with the original ether was dried and the solventsevaporated to give a brown gum (4.8 g).This was con-verted to a picrolonate (7-6 g) which formed yellow needles(from ethanol), m.p. 192" (Found: C, 49-9; H, 5.7; N, 17.1.C7Hl,N0,,C,,H8N40, requires C, 49.9; H, 5-6; N, 17.1).The base, recovered from the picrolonate using anion-exchange resin and purified by molecular distillation, was agum, RF 0.27 (Found: C , 57.9; H, 10.1; N, 9-8 C7Hl,N0,requires C, 57.9; H, 10.3; N, 9.7), vmx 3340s (OH) and2800s cm-l (5-CH2), 6 2.32 (3H, s, NMe), 3.5-343 (4H, 2-and 3-CH2), and 4.3 (2H, s, OH). The diacetate was an oil,nD2, 1.4580, b.p.90" at 0-25 mmHg (Found: C, 57-3; H,8.4; N, 6.4. Cl1Hl,NO4 requires C, 57.6; H, 8-3; N, 6.1 ),v, 2780m (5-CH2) and 1740s cm-l (ester), 6 2-08 (6H, s,acetyl Me), 2-40 (3H, s, NMe), 4.04 (2H, d, J 6 Hz, 3-CH2),and 4.15 (2H, d, J 5 Hz, 2-CH2).(b) Triethyl 4-methoxy-3-pyrroline- 1,2,3-tricarboxylate(3 g) and lithium aluminium hydride (2 g ) in tetrahydrofuran(THF) (30 ml) were heated under reflux for 4 h after theinitial reaction had subsided. The mixture was cooled,decomposed with dilute sodium hydroxide solution, andfiltered (pump). The solids were extracted with hotethanol (20 ml), then chloroform (10 ml), the combinedextracts evaporated t o dryness, and the residue re-extractedwith hot THF. This extract was combined with the THFfiltrate from the reaction mixture and the solvent removedunder reduced pressure t o give the product as a gum (1 g ,73y0), essentially the same (t.1.c.and spectra) as the crudeproduct of (a).Reduction of Pyrroline (IX) .-(a) W i t h lithium aluminiumhydride. The pyrroline (IX) (1 g) was reduced in the wayalready described for the 4-methoxy-analogue t o give a gum(0-39 g, 63) which contained about equal amounts of2,3-bishydroxymethyl-1-methyl-3-pyrroline and 2,3-bis-hydroxymethyl- I-methylpyrrolidine (synthanecines A andB) as shown by n.m.r. spectra (N-methyl signals at 6 2-46and 2-32 respectively).(b) W i t h lithium borohydride. Anhydrous lithium bro-mide (1.2 g) was added to a solution of sodium borohydride(0.5 g) in diethylene glycol dimethyl ether (diglyme; 15 ml)and the mixture stirred for 10 min.The pyrroline (IX)(1 g) was added and the mixture was heated on a steam-bathfor 1 h, cooled, poured into water (15 ml), and acidifieddropwise with HCl. The solution was washed with ether,basified (Na,CO,), washed again with ether, evaporated t odryness, and the residue extracted with 3 lots of warmchloroform. The combined chloroform extracts were con-centrated to give a gum which was re-extracted with ether.Evaporation of the ether gave a gum (0.23 g, 36), shownt o be 2,3-bishydroxymethyl-l-methylpyrrolidine (i.r. andn.m.r. spectra). The picrolonate had m.p. 189", not de-pressed by mixing with the authentic synthanecine Bpicrolonate.(c) W i t h sodium dihydrobis-( 2-methoxyethoxy) aluminate.To the pyrroline (IX) (1 g) in ether (50 ml) was added anexcess of the reagent (5 ml of 70 solution in benzene).-4fter the initial exothermic reaction, the solution was kept15 min a t room temperature and decomposed with enoughdilute HC1 (shaking) to give an acidic aqueous layer whichwas separated, washed with ether, made basic (Na,CO,), andevaporated to dryness under reduced pressure.The residuewas extracted with chloroform ( x 3 ) and the combinedextracts concentrated t o a gum (0.36 g, 56) which wasfound (i.r. and n.m.r.) to be mainly 2,3-bishydroxymethyl-1-methylpyrrolidine together with a small amount of un-reduced starting material.Dietltyl l-Methyl~5yrrole-2,3-dicarboxylate (XXI) .-Thepyrroline (IX) (3 g) was added to a part-solution, part-suspension of powdered DDQ (4 g) in warm chloroform (80nil) and the mixture stirred a t ca.50" for 10 min. Thechloroform solution was washed with aqueous potassiumcarbonate (10 ; 4 x 20 ml), dried and concentrated underreduced pressure, and the residue distilled to give thepyrrole as a pale yellow oil (2.86 g, 96y0), b.p. 128-131"at 0.6 mmHg, 1.5020 (Found: C, 58.7; H, 6.5; N, 6.6.C,,H,,TTO4 requires C, 58.7; H, 6.7; N, 6*2), vmaX. 3120w(ring) ancl 1703s cm-l (ester), 6 1.31 (3H, t, ester Me), 1-33(3H, t, ester Me), 3.81 (3H, s, NMe), 4.29 (2H, q, esterCH,), 4.32 (2H, q, ester CH,), 6.48 (IH, d, J 3 Hz, H-4), ancl4-Methoxy - 1 -met hylpyvrole-2,3-dicarboxylate(XXlI).-The pyrroline (XII) (3 g) was dehydrogenatedusing DDQ (4 g) in the same way as described above t o givethe crude pyrrole as an oil (2.55 g, 86), b.p.137-40" at0-2 mmHg, nD23 1.5120 (Found: C, 56.1; H, 6.8; N, 5.1.C,,H,,NO, requires C, 56-5; H, 6.7; N, 5.5), vmx. 3108w,3120w (ring), and 1710s cni--l (ester), 6 1-33 (6H, t, ester6.67 (lH, d, J 3 Hz, H-5).Diet hy1974 713Me), 3-73 (3H, s, OMe), 3-78 (3H, s, NMe), 4-29 (ZH, q,ester CH,), 4.31 (2H, q, ester CH,), and 6-30 (lH, s, H-5).2,3-BishydroxymethyZ- l-methylpyrrole (XXIII) .-The pyr-role (XXI) (1.5 g) was added to a suspension of lithiumaluminium hydride (1-2 g) in anhydrous ether (50 ml) andthe mixture was heated under reflux for 1.5 h, cooled, anddecomposed with water (3-4 ml). After 15 min the mix-ture was filtered (pump) and the solid washed several timeswith chloroform. The combined organic filtrates weredried, and concentrated under reduced pressure to give theproduct (0-85 g, 91) as an oil which crystallised when keptin a deep-freeze.Recrystallisation from ether gave prisms,m.p. 56-57', RF 0.49 (Found: C, 60.2; H, 7.9; N, 10.1.C,H1,NO2 requires C, 59.6; HI 7.8; N, 9.9yo), v , ~ 3320br,scm-, (OH), 6 3.3br variable (2H, s, OH), 3.62 (3H, s, NMe),4-H), and 6.58 (lH, d, J 3 Hz, H-5). The compound, inethanol, gave a magenta Ehrlich reaction, A,, 570 nm( E 71,900). The alkylation reaction gave an intense mauvecolour.2,3-BishydroxymethyZ-4-mzthoxy- 1 -methylpyrrole (XXV) .-The pyrrole (XXII) (1.2 g) was reduced with lithium alumin-ium hydride (1.2 g) in the same way as described above, t ogive the product as a gum (0-56 g, 70) which crystallisedon rubbing with ether.Recrystallisation from benzene-ether gave prisms, m.p. 92", RRF 0.48 (Found: C, 56.1; H,7.8; N, 8.0. C,H,,NO, requires C, 56-1; H, 7.6; N, 8.2y0),vmx. (KBr) 3270s cm-l (OH), 6 3.2br variable (2H, OH), 3-58(3H, s, NMe), 3-70 (3H, s, OMe), 4-47 (4H, s, CH,O), and6.10 (lH, s, H-5). The compound gave an immediatebright red precipitate with aqueous HC1. The alkylationreaction gave a strong mauve colour, A,, 560br nm. TheEhrlich reaction gave a magenta colour, A,, 546 nm ( E45,600).(XXIV).-The pyrrole (XXIII) (0.35 g) was heated underreflux with ethyl isocyanate (6 ml) for 2.5 h. 1,4-Diazabi-cyclo2.2.2octane (0.5 mg) was added and the mixtureheated for a further 20 min.Excess of reagent was re-moved under reduced pressure, the residue was dissolvedin anhydrous ether (10 ml) and the solvent again removed.The dicarbamate remained as a gum (0.65 g, 93) whichcrystallised. Recrystallisation from anhydrous ether-lightpetroleum (b.p. 60-80') gave blades, m.p. 85" (Found: C,4.45 (2H, S, 3-CH,), 4.50 (ZH, S, 2-CH,), 6.10 (lH, d, J 3 Hz,2,S-Bis- (N-et hylcarbamoyloxymet hyl) - l-met hylpyrrole55-2; HI 7.4; N, 15.0. C,,H,,N,O, requires C, 55-1; H,7.4; N, 14-8), vmX. 3310s (NH) and 1690s,br cm-l (CO);6 1.10 (6H, t, ethyl Me), 3.19 (4H, 2q, ethyl CH,), 3.61 (3H,s, NMe), 4-6br (NH), 5.05 (2H, s, 3-CH,), 5.15 (ZH, s,2-CH,), 6.16 (lH, d, J 3 Hz, H-4), and 6-60 (lH, d, J 3 Hz,H-5). The alkylation reaction gave an intense mauve colourwithout the addition of triethylamine. The Ehrlich re-action gave a magenta colour, Amxe 570 nm ( E 77,350).When a solution of the carbamate in NN-dimethylformamidewas added to water, a pale yellow polymer was precipitatedafter a few min. When added to dilute HCl, a red polymerwas precipitated immediately.2,3-Bisacetoxymethyl- l-methylpyrrole (XXVIII) .-Syn-thanecine A (0.25 g) in methanol (5 ml) and aqueous hydro-gen peroxide (0-3 ml) was kept a t room temperature for 16 h,then heated under reflux for 2 h. Excess of peroxide wasdecomposed by adding manganese dioxide, and the solutionwas filtered and concentrated under reduced pressure togive the crude N-oxide as a gum. This material was dis-solved in acetic anhydride (2 ml) at 30-35", and after 2 mintriethylamine (10 ml) was added and the mixture kept atroom temperature for 1.5 h in a stoppered flask. The tri-ethylamine and the excess of acetic anhydride were re-moved with cautious warming at 5-0.5 mmHg, furthertriethylamine being added frequently to maintain basicconditions. The residue was dissolved in anhydrous ether(5 ml), the solution diluted with light petroleum (b.p. 40-60"; 60 ml), charcoaled, filtered, and the solvents removedunder reduced pressure to give the diacetoxy-pyrrole deriva-tive as an oil (148 mg, 38) which was purified by moleculardistillation, vmX. 1735s cm-I (ester), 6 2.03 and 2-04 (6H, s,3- and 2-acetyl Me), 3-61 (3H, s, NMe), 5.04 (2H, s, 3-CH2),5-14 (2H, s, 2-CH,), 6-13 (lH, d, J 3 Hz, H-4), and 6.60(lH, d, J 3 Hz, H-5). The Ehrlich reaction gave an intensemagenta colour, A,, 570 nm. The alkylation reactiongave an intense mauve colour. The compound dissolved inwater to give a clear solution which became cloudy andpink after a few min. It gave a red polymer with diluteHCI.I thank Miss A. Mackintosh and hlr. R. Jones for technicalassistance, and Mrs. D. Butterworth (National PhysicalLaboratory) for microanalyses.3/1914 Received, 17th September, 1973