Total synthesis of pukeleimide A, a 5-ylidenepyrrol-2(5H)-one from blue green algae

摘要

J. CHEM. soc. PERKIN TRANS. 1 1993 258 1 Total Synthesis of Pukeleimide A, a 5-Ylidenepyrrol-2(5H)-one from Blue Green Algae Gwyn D. Stuart D. Millsb and Gerald Pattenden*sa a Department of Chemistry, The University, Nottingham, NG 7 2RD, UK ICI Pharmaceuticals Division, Mereside Alderley Park, Macclesfield, SK I0 4TG, UK (ICI Pharmaceuticals is part of Zeneca Pharmaceuticals L td. in the UK) A total synthesis of pukeleimide A 5, a member of a rare family of naturally occurring 5-ylidenepyrrol-Z(5H) -ones produced by the marine blue alga Lyngbya majuscula, is described. The synthesis is based on elaboration of the ylidenepyrrolone lla from the maleimide 13a by a regio- and stereo-selective Wittig reaction with ethoxycarbonylmethylene(tripheny1)phosphorane. followed by conversion of 11 a into the amide 25, and oxidation of 25 with selenium dioxide.Certain strains of the marine blue-green alga Lyngbyu mujusculu contain lyngbyotoxin 1 have also provided minor amounts of are well known to be responsible for the contact dermatitis an interesting and rare class of 5-ylidenepyrrol-2(5H)-ones called lsquo;swimmerrsquo;s itchrsquo;. Two known irritants found in different known as pukeleimides, exemplified by pukeleimide A 5, C 6, samples of the algae are the indole alkaloid lyngbyotoxin 1and and E 7.rsquo; In the accompanying paper we described our the spiroketal debromoaphysiatoxin 2. The toxic, shallow- investigations of the use of substituted maleimides 8 and ofv2 water variety of L. mujuscuh produces malyngamide A 3,3an pyrrolinones 10 in the elaboration of 5-ylidenepyrrol-2(5H)- unusual chlorine-containing substituted 4-methoxypyrrol-ones 9 by appropriate carbanion reactiom6 In this paper, we 2(5H)-one which bears a strong structural resemblance to the describe the development of this chemistry and report a total sponge metabolite dysidin 4.4 Samples of L.mujusculu that synthesis of natural pukeleimide A 5.rsquo; ,OM0 #OMe 0 0 5 6 7 Rrsquo; R2 Rrsquo; R2 0 R3 60R3 R4 8 9 10 2582 Our overall strategy for a synthesis of pukeleimide A, was to use the substituted maleimides 13and 14 as key intermediates and to exploit the fundamental chemistry developed earlier for these molecules,6 i.e. Wittig olefination of 13 with ethoxy- carbonylmethylene(tripheny1)phosphorane was expected to be regio- and stereo-selective producing 11, and reduction of 14 should also be regioselective leading to 12 (Scheme 1).5 u R OMeL LI c,x,H 11 12 R 02)ko0 H Me 13 14 a R=H; b R=OH; c R=OCH2Ph Scheme 1 We first examined a synthesis of the 3-hydroxymethyl substituted maleimide 13b. Thus, reaction between citraconic anhydride and methylammonium acetate in hot glacial acetic acid first produced the maleimide 13a which could then be converted into 13b, albeit in low yield, by treatment with selenium dioxide in hot dioxane. Attempts to induce reaction of the maleimide 13b with ethoxycarbonylmethylene(tripheny1)-phosphorane (CMTP), however, were unsuccessful, and none of the required 5-ylidenepyrrol-2(5H)-one11b was produced.We also prepared the corresponding 3-benzyloxymethylmaleimide 13c as outlined in Scheme 2, but this maleimide also failed to react to any appreciable extent with CMTP under a variety of conditions. /OCH,Ph 15 16 Scheme 2 Reagents: i, LDA-DMPU, PhCHH,OCH,Cl; ii, aq. KOH-dioxane; iii, TFAA; iv, Me+NH,-OAc At this point we decided to modify our original strategy to pukeleimide A 5 (Scheme l), and instead synthesise the deoxypukeleimide 25 starting from the 3-methylmaleimide 13a, and then introduce the hydroxymethyl substituent in 25 as a final step. Hence, a Wittig reaction between the 3-methylmaleimide 13a and CMTP, as shown earlier,6 was found to be regio- and stereo-selective and produced the (E)-5-ylidenepyrrol-2(5H)-one 1la as needles (m.p.93-94 "C). The structure and stereochemistry of lla followed from inspection and comparison of 'H NMR chemical-shift data with related compounds, and from results of NOE signal enhancements from double-irradiation experiments. Saponification of the unsaturated ester group in lla, using aqueous potassium hydroxide in refluxing tetrahydrofuran was accomplished without stereomutation about the carbon-to-carbon double J. CHEM. SOC. PERKIN TRANS. 1 1993 bond and the resulting carboxylic acid 17a was then converted into the corresponding acid chloride 17b,using thionyl chloride in benzene, in readiness for conversion into the amide 25 by reaction with the pyrrolone 12.A number of routes were investigated for the synthesis of the pyrrolone 12. It was most conveniently obtained starting from the bromide 18, derived from ethyl acetoacetate, by reaction with ammonia,**' or alternatively by reaction with sodium azide, leading to 19, followed by reduction to the corresponding amine 20 and cyclisation. In model studies with the N-methylmaleimide 21, we found that its reduction with lithium aluminium hydride or sodium borohydride produced only the carbinol22a in low yields. Although the carbinol22a could be converted into the pyrrolinone 23, following chlorination and reduction of the resulting chloride 22b with tributyltin hydride, we were not attracted to this lengthy procedure as a method for the synthesis of 12 from reduction of the corresponding 3- methoxymaleimide 24.lie Me 17a R=OH b R=CI H2N C02Et CO2Et 19 20 0 Me a R=OH b R=CI 21 22 23 17c + 12 -0 Me 0 25 With a satisfactory synthesis of the pyrrolone 12 and of the acid chloride 1 we were now in a position to complete the synthesis of pukeleimide A 5. When the latter was added to a solution of the anion produced from the pyrrolone 12, using butyllithium, the deoxypukeleimide 25 was produced as yellow needles in a satisfying 71 yield. The synthesis of pukeleimide A was then achieved by reaction of the deoxy compound 25 with selenium dioxide in glacial acetic acid which gave the natural product as a solid (m.p. 192-193 "C). The synthetic pukeleimide A 5 showed spectroscopic data identical with those published for the natural metabolite isolated from L.mujusculu. Experimenta1 For general experimental details see ref. 6. 3-Hydroxymethyl-1 -methyl-1 H-pyrrole-2,5-dione 13b.-A solution of 1,3-dirnethylmaleimide (1 g)6 in glacial acetic acid (20 cm3) was heated in the presence of selenium dioxide (0.89 g) J. CHEM. SOC. PERKIN TRANS. 1 1993 for 3 h, and then concentrated under reduced pressure. The residue was purified by chromatography (ether-hexane, 3 :1) to give the hydroxymethylmaleimide 13b (0.14 g, 25 based on recovered starting material) as colourless crystals, m.p. 52- 53 "C; v,,,(CHCl,)/cm-l 3350, 1770, 1710 and 1630 m-'; SH 6.67 (t, J 2, =CH), 4.65 (d, J2, CH,OH), 3.32 (OH) and 3.05 (NMe) (Found: C, 51.1; H, 5.0; N, 9.9; M, 141.0430.C6H7N03 requires C, 5 1.5; H, 5.0; N, 9.9; M, 141.0425). 3-Benzyloxymethyl- 1 -methyl- 1 H-pyrrole-2,5-dione 13c.-A solution of diisopropyl malate 15 (6.5 g) and dry 1,3-dimethyl- 3,4,5,6-tetrahydro-2(1H)-pyrimidone(3.84 g) in dry THF (10 cm3) was added dropwise over 0.5 h to a stirred solution of LDA (2.05 equiv.) at -78 "C. The solution was warmed to -20 "C over a 45 min period and then recooled to -78 "C. Benzyl chloromethyl ether (4.77 g) was added slowly over 0.5 h to the solution which was then allowed to warm up to room temperature. The THF was evaporated under reduced pressure and 10 aqueous citric acid solution was then added to the residue until the pH was just acidic.The mixture was then extracted with ethyl acetate (4 x 50 cm3) to leave the impure alkylated malate diester 16 (5.1 g) as an orange oil. This (5.1 g) was dissolved in water and dioxane (1 :1; 100 an3)and 20 aqueous potassium hydroxide (20 cm3) was then added to it. The solution was heated under reflux for 16 h and then cooled when its pH was adjusted to 1.0 with 2 mol dmP3 hydrochloric acid. The mixture was evaporated under reduced pressure and the residue was then dissolved in trifluoroacetic anhydride (20 cm') and heated under reflux for 30 min. The mixture was concentrated under reduced pressure and glacial acetic acid (20 cm3) and methylammonium acetate (1.19 g) were then added to the residue. The solution was heated under reflux for 2 h and then cooled, diluted with water and extracted with ether (3 x 25 cm3).The combined extracts were dried and evaporated to leave a residue which was purified by chromatography using (hexane-ether, 1 :1) as eluent, to give the benzyloxymethyl- maleimide 13c(0.4 g, 6) as an off-white solid. Recrystallisation of this from hexane gave fine white needles, m.p. 8486deg;C; v,,,(CHCl,)/cm-' 1760,1700 and 1660; S, 7.33 (m, 5 x ArCH), 6.56 (t, J 1.5,=CH), 4.60 (OCH,Ph), 4.36 (d, J 1.5, CH,OCH,Ph) and 2.97 (NMe) (Found: C, 67.8; H, 5.7; N, 6.2; M, 125.0504. C13H13N03 requires C, 67.5; H, 5.7; N, 6.1; M 125.0477). (E)-5- Carboxymethylene- 1,3-dimethylpyrrol-2(5H)-one17a. -A solution of 5-ethoxycarbonylmethylene-1,3-dimethylpyr-rol-2(5H)-one (663 mg) ti and potassium hydroxide (286 mg, 1.5 equiv.) in THF-water (1 :1;50 cm3) was heated under reflux for 3 h.The pH was adjusted to 1.0 by the addition of 2 mol dmP3 hydrochloric acid, after which the mixture was extracted thoroughly with ethyl acetate (6 x 10 cm3). The combined extracts were dried and concentrated under reduced pressure to leave a white solid (567 mg, 100). Recrystallisation of this from chloroform gave the carboxylic acid 17a as colourless prisms, m.p. 195-196 "C; A.,,(EtOH)/nm 276; vmax(KBr)/cn-' 3300- 2500, 1700 and 1640; amp;,(C2H6acetone) 7.90 (=CH), 5.62 (=CHCO,H), 3.12 (NMe) and 1.98 (=Me) (Found: C, 51.6; H, 5.4; N, 8.4; M, 167.0587. C8H9NO3 requires C, 51.5; H, 5.5; N, 8.4; M, 167.0582). 4-Methoxypyrrol-2(5H)-one 12.-Method (a) A mixture of ethyl 4-bromo-3-methoxybut-Zenoate (46 g) and sodium azide (13.4 g) in dimethylformamide (250 cm3) was stirred at room temperature for 4 h and then poured into water (200 cm3) and extracted with ether (4 x 70 cm3).The combined extracts were washed successively with water (5 x 50 an3)and saturated brine (50 cm3), and then dried and evaporated under reduced pressure to leave the azide 19 (36.1 g, 98) as an orange oil. Purification of a small sample by Kugelrohr distillation gave a colourless oil, b.p. 68 "C/0.4 Torr; vmax(film)/mP1 2120 and 1705 cm-'; SH 5.14 (=CH), 4.38 (CHZN,), 4.14 (9, J 7, CO,CH,CH,), 3.71 (OMe) and 1.28 (t, J7, CO,CH,CH,) (Found: C, 45.2; H, 6.1; N, 22.7.C7H11N303 requires C 45.4; H, 6.0; N, 22.7). Hydrogen gas was passed through a solution of the undistilled azide (2.9 g) in methanol (50 cm3) in the presence of 10 palladium on charcoal (0.3 g) for 6 h. The mixture was concentrated under reduced pressure to leave a brown oil which was then heated at 120 "C for 1 h. The cooled residue was purified by chromatography (chloroform-methanol, 93 :7) to give the 4-methoxypyrrolone 12 (423 mg, 21) which recrystallised from benzene as colourless needles, m.p. 128- 129 "C (lit.,9 m.p. 129-131.4 "C); ,l,,,(EtOH)/nm 276 and 215 nm; v,,,(KBr)/cm-' 3460, 1670 and 1620; 6, 7.4 (NH), 5.13 (=CH), 3.97 (CH,N) and 3.88 (OMe);Sc 176.2,176.1,94.3 (CH), 58.3 (CH,) and 47.0 (CH,) (Found: C, 53.0; H, 6.5; N, 12.2; M, 113.0475. Calc.for C,H,NO,: C, 53.1; H, 6.2; N, 12.4; M, 11 3.0475). Method (b). According to the method of Kochlar and Pinnick,* a solution of ethyl 4-bromo-3-methoxybut-2-enoate (5 g) in aqueous ammonia (30 cm3) was stirred at room temperature for 24 h. The solution was extracted thoroughly with ether (2 x 30 cm3) and chloroform (4 x 25 cm3) and the combined extracts were then dried and evaporated to leave a residue which recrystallised from benzene to give the pyrrolone 12 (1.58 g, 67) as a white solid, m.p. 128-129 "C. The pyrrolone showed spectroscopic data identical with those described under method (a). 5-Hydroxy-4-methoxypyrrol-2(5H)-one22a.-Lithium alu-minium hydride (1 9 mg, 0.5 equiv.) was added in one portion to a stirred solution of 3-methoxy-1 -methylmaleimide (1 28 mg) '9'' in THF (1 2 cm3) at 0-5 "C for 30 min and then allowed to warm to room temperature over a 4 h period.Water (20 an3)was added to the mixture which was then extracted with ethyl acetate (3 x 20 cm3). The separated aqueous phase was extracted continually with ethyl acetate (30 cm3) for a further 24 h. The combined extracts were dried and then concentrated under reduced pressure to leave a brown oil (87 g). Recrystallisation from ethyl acetate gave the pure hydroxypyrrolone 22a (68 mg, 43) as white needles, m.p. 140-141 "C; v,,,(CHC~,)/~~-' 3350,1685 and 1640; BH 5.22 (=CH), 5.02 (CHOH), 3.89 (OMe) and 2.93 (NMe) (Found: C, 50.2; H, 6.4; N, 9.6; M, 143.0587. C6H9N0, requires C, 50.4; H, 6.3; N, 9.8; M, 143.0582).5-Chloro-4-methoxy-1-methylpyrrol-2( 5H)-one 22b.-A solution of the hydroxypyrrolone 22a (0.78 g) and thionyl chloride (2 cm3) in dry benzene (15 cm3) was heated under reflux for 2 h. The solution was concentrated under reduced pressure and the residue was then purified by chromatography (chloroform) to give the chloropyrrolone 22b (0.74 g, 84) as a pale yellow oil; v,,,(film)/cm-' 1680 and 1630; BH 5.1 1 (m, CHCl plus =CH), 3.83 (OMe) and 2.88 (NMe) (Found: M-Cl, 126.0558. C6H8N02 requires M-Cl, 126.0555). 4-Methoxy- 1 -methylpyrrol-2(5H)-one 23.-A solution of 5-chloro-4-methoxy-1-methylpyrrolone22b (0.34 g), tributyltin hydride (2 equiv.) and azoisobutyronitrile (0.2 g) in dry benzene (30 cm3) was heated under reflux for 56 h.The cooled solution was concentrated under reduced pressure and the residue was purified by chromatography (chloroform-methanol, 97 :3) to give the pyrrolone 23 (0.2 g, 74) which crystallised from benzene-hexane as prisms, m.p. 86-87 "C; v,,,(CHCl,)/cm~l 1670 and 1635; ~5~5.19 (=CH), 3.88 (OMe) and 2.98 (NMe); SC 173.2, 172.4,94.4 (CH), 58.1 (CH,), 52.5 (CH,) and 28.5 (CH,) (Found: C, 56.6; H, 7.4; N, 1 1.1; M, 127.0626. C6H9N02 requires C, 56.7; H, 7.1; N, 11.0; M, 127.0619). 1-( 1,5- Dihydro- 1,4-dimethyl-5-oxo-2H-pyrrol-2-ylidene)-acetyll-1,5-dihydr04methoxypyrrole-2-one(Deoxypukeleim-ide) 25.-A solution of (E)-5-carboxymethylene-1,3-dimethyl-pyrrol-2(5H)-one 17a (404mg) in thionyl chloride (10 cm3)was heated under reflux for 2 h.The solution was concentrated to afford the corresponding acid chloride 1 as a yellow solid. This solid was dissolved in dry THF (5 an3)and the solution added dropwise to a previously formed, stirred solution of 1- lithio-4-methoxypyrrol-2(5H)-one (305 mg) prepared by adding butyllithium (1.6 mol dm-' solution in hexane; 1.1 equiv.)to a solution of4-methoxypyrrol-2-(5H)-one12(1 equiv.) in THF (10 cm3)at 0 OC. The resulting suspension was stirred at 0deg;C for 2 h and then allowed to warm to room temperature overnight. The mixture was poured into water (20 cm3) and then extracted with ether (2 x 20 cm3) and chloroform (2 x 20 an3).The combined extracts were dried and evaporated to leave an oily solid.This was purified by chromatography (chloroform-methanol, 99 :1) to give E-deoxypukeleimide A 25 (447 mg, 7 1 ) which recrystallised from chloroform-hexane as yellow needles, m.p. 185.5-1 86 "C; h,,,(EtOH)/nm 262infl. (8670), 294 (16 500) and 325infl. (9070); v,(CHCl,)/cm-' 1715, 1670 and 1620; S, 7.80 (m, =CH), 7.15 (=CHCO), 5.18 (SH), 4.36 (CH,N), 3.94 (OMe), 3.17 (NMe) and 2.03 (d, J2, amp;Me); S, 176.1, 170.9, 169.7, 163.5, 152.2, 137.7, 130.3 (CH), 99.1 (CH), 94.8 (CH), 58.7 (CH,), 48.6 (CH,), 26.0 (CH,) and 11.1 (CH,) (Found: M, 262.0935. C1,H14N204 requires M, 262.0951). 1-( 1,5-Dihydr0-4-(hydroxymethyl)-1 -rnethyl-5-oxo-2H- pyrrol-2-ylidene)acetyl-1,5-dihydro-4-methoxypyrrol-2-one (Pukeleimide A) 5.-A stirred suspension of deoxypukeleimide A 25 (34 mg), selenium dioxide (50 mg) and glacial acetic acid (3 cm3)was heated under reflux for 1 h. The cooled solution was concentrated under reduced pressure to leave a green-black residue which was purified by chromatography (chloroform- methanol, 97 :3) to give: (i) recovered starting material 25 (20 mg, 59) and (ii) pukeleimide A 5 (9 mg, 25) as an off-white solid, m.p.192-193 "C (benzene); A,,(EtOH)/nm 330 and 292; J. CHEM. soc. PERKIN TRANS. 1 1993 v-(CHCl,)/cm-' 3400, 1715, 1675 and 1625-'; S, 7.91 (t, J 1.5, =CH), 7.21 (=CHCO), 5.16 (=CH), 4.56 (d, J 1.5, CH,OH), 4.35(CH2N), 3.91 (OMe)and3.17(NMe);SC 176.3,170.1,169.8, 163.2, 151.5, 140.0, 129.9 (CH), 101.0 (CH), 94.7 (CH), 59.0 (CH,), 57.7 (CH,), 48.6 (CH,) and 25.8 (CH,) (Found: M, 278.0889.Cl3HI4N2O5 requires M, 278.0903). Acknowledgements We thank the SERC for a studentship (CASE award to G. D. J.) and ICI Pharmaceuticals, which is part of Zeneca Pharma- ceuticals Ltd. for financial support. References 1 J. H. Cardellina 11, F. J. Marner and R. E. Moore, Science, 1979,204, 193. 2 J. S. Mynderse, R. E. Moore, M.Kashiwagi and T. R. Norton, Science, 1977,196,538. 3 J. H. Cardellina11, F. J. Marner and R. E. Moore,J.Am. Chem. SOC., 1979, 101, 240; R.E. Moore, A. J. Blackman, C. E. Cheuk, J. S. Mynderse, G. K.Matsumoto, J. Clardy, R. W. Woodard and J. C. Craig, J. Org. Chem., 1984,49,2484. 4 W.Hafheinz and W.E. Oberhbsli, Helu. Chim. Acta, 1977,60,660. 5 C. J. Simmons, F.J. Marner, J. H. Cardellina 11, R. E. Moore and K. Seff, Tetrahedron Lett., 1979, 22, 2003; J. H. Cardellina I1 and R. E. Moore, Tetrahedron Lett., 1979,22,2007. 6 G.B. Gill, G. D. James, K. V.Oates and G. Pattenden,J. Chem.Soc., Perkin Trans. I ,1993, preceding paper. 7 Preliminary communication: G. D. James, S. D. Mills and G. Pattenden, Tetrahedron Lett., 1985,26,3617. 8 K. S. Kochhar, H. J. Carson, K. A. Clouser, J. W. Elling, L. A. Gramens, J. L. Parry, H. L. Sherman, K. Braat and H. W. Pinnick, Tetrahedron Lett., 1984,25, 1871. 9 cf. D. J. Cram, 0.Theander, H. Jager and M. K. Stanfield,J. Am. Chem. SOC.,1963,85,1430. 10 A. Rothaas, Leibigs Ann. Chem., 1933,501,295. Paper 3/03239F Received 7th June 1993 Accepted 23rd June 1993