€rythrina and Related Alkaloids A. S. Chawla Department of Pharmaceutical Sciences Panjab University Chandigarh 7 60074 India A. H. Jackson Department of Chemistry University College Cardiff CF 7 7XL Wales Reviewing the literature published between July 1985 and June 1987 (Continuing the coverage of literature in Natural Product Reports 1986 Vol. 3 p. 555) 1 Isolation and Structure Determination 2 Synthesis 2.1 Erythrina Alkaloids 2.2 Homoerythrina Alkaloids 2.3 Abnormal Erythrina Alkaloids 3 References (1) a; R1= H R2= R3=Me This Report embodies the work published during the past two b; R'=R2=H,R3=Me years on the isolation structure determination and synthesis of Erythrina Cocculus Cephalotaxus and other related alkaloids.c;R1=R3=Me,R2=H d;R'=R2= R3=Me e ; R' R2= CH2 R3=Me 1 Isolation and Structure Determination f;R'=RZ=Me,R3=H The alkaloids in the seeds of the four Erythrina species E. g; R'=Me,R2=R3=H brucei E. cochleata E. tholloniana and E. caribaea have been screened by gas chromatography-mass Spectrometry.' The commonly occurring alkaloids erysodine (1 a) erysopine (1 b) h; R' =R3=H,R2 =Me i ; R'R2= CHz,R3=H and erysovine (lc) were found in all four species. In contrast to the earlier studies of E. brucei,2 erythraline (le) and ery- thratidine (2a) have been found in addition to (la) (lb) and (lc); 11-methoxyerythratidine (2c) was also identified in both E. brucei and E. cochleata. Erysotrine (Id) and erythratidine (2a) were found in substantial amounts in E. cochleata and this was the only one of the four species which contained erythravine (If).The major constituents of E. tholloniana were the a-and P-erythroidines (3) and (4) although erysotine (2b) was also present. A new alkaloid erythrocarine (li) has been isolated from E. caribaea and characterized as a methylenedioxy- analogue of the known dienoid alkaloids erysoline (lg) and erysonine (1 h). N-Nororientaline (5) has been isolated from the leaves of E. herbacea.3 The X-ray structure of P-erythroidine (4) has been reported4 and its conformation compared with those of other Erythrina alkaloids. The common feature of these molecules is the possession of a convex positively charged hydrophobic surface. It is suggested that this characteristic feature plays a dominant role in the interaction between Erythrina alkaloid nicotinic antagonists (such as B-erythroidine) and the nicotinic acetyl- choline receptor.Two alkaloids of the homoerythrinane group namely 1,2- dihydrocomosidine and holidinine leaves of Phelline lucida.5 were isolated from the (3) (4) Variations in the alkaloidal constituents of the leaves of CoccuIus laurifolius in different seasons in a year have been studied.6 The results reveal that the total yield of alkaloids and the concentrations of individual alkaloids vary markedly from January to December. The variations in the concentrations of the individual constituents of the alkaloidal mixture that was obtained from the leaves of C. Iaurifofius were monitored by ammonium chemical-ionization mass spectrometry.A review has appeared on Cephalotaxus alkaloids' which covers the isolation synthesis biosynthesis and biological activity of the principal alkaloids. The alkaloids present in OMe Cephalotaxus .fortunei include cephalotaxine cephalotaxinone (5) 55 NATURAL PRODUCT REPORTS 1989 __c SiMe3 (6) (11) vi or vii I Reagents i hv MeOH; ii LiAlH, Et,O; iii MsC1 Et,N Et,O; iv OsO, NaIO, p-dioxane H,O; v 1,8-diazabicyclo[5.4.0]undec-7-ene, THF; vi LiAlH, THF; vii L-Selectride (LiBus3BH) THF; viii H, Pd/C Scheme 1 0 bJog &-Lre N I Me I CH2 CH2 I I CH2 OMe 6OMe OoMe OMe (16) Me0 H" SMe -0 (18) NATURAL PRODUCT REPORTS 1989-A. S. CHAWLA AND A.H. JACKSON OMe C02H C02Me 5 I Reagents i heat; ii HI; iii 0,,CH,Cl, at -78 "C;iv AcOH heat; v NaOH NaBH, H+; vi hv NH,OH Scheme 2 acet ylcephalotaxine demethylcep halo taxine epicep halo taxine harringtonine and homoharringtonine.8 Harringtonine proved to be effective as a neoplasm inhibitor against leukaemia in mice. Chemical analysis of C. sinensis indicated the presence of cephalotaxine wilsonine epiwilsonine hydroxycephalotaxine harringtonine deoxyharringtonine homoharringtonine and dr~pacine.~ A review on the use of Chinese herbal medicines in the treatment of leukaemias including harringtonine from C. fortunei has been published. lo 2 Synthesis 2.1 Erythrina Alkaloids Investigations have been conducted to probe the application of diradical cyclization methods in synthetic approaches to members of the family of Erythrina a1kaloids.l' a-Keto-imidoyl halides which can be obtained by the reaction of representative 2-phenylethyl and related isocyanides with acyl halides undergo facile cyclization (induced by silver salts) to afford the corresponding heterocycles in good yield.An efficient synthesis of the erythrinane skeletal system which relies upon the sequential utilization of this method followed by an azomethine ylide (3 +2) cycloaddition reaction has been reported.l2 A novel strategy based upon an electron-transfer-induced spirocyclization methodology represents a method for con- structing the tetracyclic skeleton that is common to the members of the Erythrina alkaloid family.l3The key tricyclic intermediate (7) was generated in 60% yield by irradiation of the (silylalkenyl)-3,4-dihydroisoquinoliniumperchlorate (6) and transformed via intermediates @)-(lo) into the ketone (1 1) by an intramolecular alkylation process (Scheme 1). Reduction of (1 1) with LiAlH provided the diastereoisomeric alcohols (12a) and (12b) in the ratio 2.3 1 respectively whereas the reaction with the more bulky reducing agent L-Selectride@' (LiBu",BH) gave the a-alcohol (12a) exclusively. The alcohols (12a) and (12b) were converted into methanesulphonate esters (1 3a) and (1 3b) which on treatment with 1,8-diazabicyclo[5.4.O]undec-7-ene (DBU) followed by catalytic hydrogenation afforded 15,16-dimethoxy-cis-erythrinane (15) (Scheme 1).N-[2-( 3,4-Dimethoxyphenyl)ethyll-N-(3 -oxocyclohex- 1-eny1)-a-(methylsulphiny1)acetamide (1 6) when heated with toluene-p-sulphonic acid in 1,2-dichIoroethane gave 3,5,6,7- tetrahydro -1-[2-(3,4- dimethoxypheny1)ethyll- 3 -methylthio -1H-indole-2,4-dione (1 7).14 The latter on treatment with 85 YO phosphoric acid afforded 15,16-dimethoxy-7-methylthio-cis-erythrinane- 1,8-dione (1 8) and 6,7-didehydro- 15,16-dimeth- oxyerythrinane- 1,8-dione (19) in 53 and 15 YOyields respecti- vely. On the other hand heating the tetrahydroindoledione (17) in boiling formic acid afforded the erythrinanedione (19) in 43 YOyield. Interestingly if the precursor (16) of the dione (17) was itself heated in formic acid the erythrinanediones (18) and (19) were formed by double cyclization in 7 and 47 YOyields respectively.A synthesis of 15,16-dimethoxyerythrin-6-en-8-one has been accomplished by using an intramolecular Wadsworth-Emmons rea~ti0n.l~15,16-Dimethoxyerythrinan-8-onewas smoothly reduced to 15,16-dimethoxyerythrinaneeither with KH and AlH (65%) or with AlH alone (73%).16 Isobe et a1." have reported the synthesis of the P-erythroidine skeleton (26) by two different routes. One route started from 15,16,17-trimethoxy-cis-erythrinan-8-one (22) which had been prepared by the condensation of 2-(2,3,4-trimethoxy- pheny1)ethylamine (20) and 2-(ethoxycarbonylmethy1)-cyclohexanone (21) followed by cyclization with hydriodic acid. Selective ozonolytic cleavage of the aromatic ring of (22) gave the diester (23) (33YO), which on heating with 70 YOacetic acid in a sealed tube yielded the pyrone derivative (24) (57 YO).Alkaline hydrolysis of the latter followed by treatment of the resulting keto-acid with sodium borohydride gave (after acidification) a mixture of the epimeric &lactones (25) (66 YO). Photochemical removal of the carboxyl group then yielded 14,17-dihydro- 16( 1SH)-oxaerythrinane-8,15-dione(26) (1 8 YO) (Scheme 2). NATURAL PRODUCT REPORTS. 1989 OH (29) ... Ill I OH Iv Reagents i N-bromosuccinimide; ii H, Pd/C; iii Ph,P=CH,; iv SeO,; v heat AcOH Ac,O AgOAc Scheme 3 The second route involved the treatment of D-furano-erythrinane (27) with N-bromosuccinimide to yield the hydroxy- y-lactone (28) (72 Yo) which on hydrogenation over 10YO Pd/C in ethanol afforded an epimeric mixture of keto-acids (29).Wittig reaction of the mixture with methylene-triphenylphosphorane yielded the exomethylene derivative (30) (93%) as the sole product. Oxidation of the latter with selenium dioxide gave two hydroxy-derivatives (3 1) (50 YO)and (32) (49 YO).Heating the former in AcOH and Ac,O with silver acetate (or with tetrabutylammonium acetate) in a sealed tube effected allylic rearrangement and cyclization of the resultant primary alcohol gave the compound (26) (Scheme 3). Sano and co-workersls have achieved the total synthesis of erythrinane alkaloids by a strategy that is based on the Diels-Alder reaction of activated butadienes to a dioxo-pyrroline.The reaction of isoquinolinopyrrolinedione (33) prepared from an arylethylamine (cf. ref. 19) with 1,3-di-0- substituted butadienes proceeded in a regiospecific and regio- selective manner to give erythrinane derivatives (34) and (35) (Scheme 4). Reduction of either derivative with lithium borohydride in THF at -70 OC followed by dehydration of the resulting product with hydrochloric acid afforded the hydroxy-enone (36). Mesylation of (36a) with methane-sulphonyl chloride gave the mesylate (37) which on de-methoxycarbonylation in the presence of MgCI in DMSO yielded the dione (38) (77 "/o). Meerwein-Ponndorf reduction of this dione proceeded stereoselectively to give the epimeric alcohols (39) and (40) in 70% and 25% yields respectively.Methylation of the alcohol (39) with methyl iodide in the presence of a phase-transfer catalyst (KOH with Et,NBr) furnished (+)-erysotramidine (41) (84 YO);this on reduction with aluminium hydride20 (generated from AICl and LiAlH in THF at room temperature) gave (+)-erysotrine (Id) (Scheme 4). The total synthesis of (+)-erythraline (le) (86%) was also achieved from the enedione (36b) by the same sequence of reactions as described above. The identity of the synthetic compounds was confirmed by spectral comparisons with the natural alkaloids. These results clearly showed that a Diels-Alder strategy was an effective method for the synthesis of erythrinane alkaloids ; the overall yields of erysotrine (1 d) and erythraline (1 e) were 10YOand 13YOrespectively.These ten-step processes from commercially available arylethylamines represent the shortest route and the highest yield of any of the currently known met hods. The dibenzazonine alkaloids laurifonine (42a) and laurifine (42b) which are related to a biosynthetic precursor of Erythrina alkaloids have been prepared in 29% and 15% yields re- spectively by variations of existing rnethods.,l 3-Azaerythrinanes that are useful as central-nervous-system depressants and as analgesics have bzen synthesized., NATURAL PRODUCT REPORTS 1989-A. S. CHAWLA AND A. H. JACKSON (34) R = C02R2 (33) (36) vi -Me0 (36a) 0~~ MeO\ __f -C02Me (37) (38) vii HO (40) Iix a; R1= R2=Me b; R1R1=CH2,R2=Me Reagents i H,C=C(OSiMe,)CH=C(H)OSiMe,; ii H,C=C(OSiMe,)CH=C(H)OMe; iii LiBH,; iv H+; v MsCl; vi MgCI, DMSO ; vii AI(OPr’), Pr’OH; viii MeI KOH Et,N+ Br-; ix AIH Scheme 4 OMe / Meo%NR\ (42)a; R=Me b; R=H NATURAL PRODUCT REPORTS 1989 (48) and (49) phcHzow Me0 \ Me0 R°CQvo li -(431 MeO@ NH ii :Gpo \ (45) R = CHzPh Me0 ' \ (46) R =H (55) R =H (54) Me0a iii C(56) R =Me (44) / (58) (57) Me0CY 1 vi (47) + Reagents i Na NH (liq.); ii 5% HC1; iii CH,N,; iv OH HOCH,CH,OH; v LiAlH,; vi 2% HCl Scheme 6 2.2 Homoerythrina Alkaloids A review has appeared on the total synthesis of homoery- thrinane alkaloids.23 Tanaka et aI.24have reported the synthesis A MeOv of the homoerythrina base cis-16,17-dimethoxyhomo-erythrinan-3-one (53) (Scheme 5).Condensation of 3-(3-ii G(48)X =O ii G(49) x = 0 benzyloxy-4-methoxypheny1)propylamine(43) and 6-bromo-4- (50)X =H2 (51) X = Hz methoxyphenylacetic acid (44)in decalin gave the amide (45) (73 YO),which on debenzylation yielded the bromophenolic compound T46) (84%). Irradiation of the latter in methanol OH afforded a mixture of the phenol (47) and two isomeric phenolic lactams (48) and (49) which were separated by chromatography over silica gel. Reduction of the mixture of lactams (48) and (49) with diborane in THF followed by column chromatography over silica gel gave the cyclic amines (50) and (51). The major and more polar product (51) on Birch reduction at -70 "C afforded the 1,5-diene (52) which on treatment with 5% hydrochloric acid followed by methylation with diazomethane gave cis-16,17-dimethoxyhomoerythrinan-3-6ne(53) (21 Yo).The erythrinane base (53) was also prepared via Birch reduction of the amide (49). The mixture of amides (48) and (49) on reduction with sodium in liquid ammonia followed by fractional crystallization yielded the diene (54) (43 YO);see Scheme 6. This on treatment with 5% hydrochloric acid afforded the homoerythrinane derivative (55) (79 O/O> which was methylated with diazomethane to give the keto-amide MeoQ dimethyl ether (56). The corresponding ethylene ketal (57) Me0 \ (84 YO),which was formed by acid-catalysed condensation with ethylene glycol in benzene was then reduced with LiAlH to give the amine (58) and subsequent deprotection of the latter with 2 YOhydrochloric acid gave the desired homoerythranone (53) (80 YO).Thus a convenient synthesis of the homoerythrina (53) ring-system by Birch reduction of dibenzazecine bases followed by treatment with an acid has been achieved.Reagents i hv MeOH; ii B,H,; iii Na NH (liq.); iv 5% HCl; v The first stereo-controlled total synthesis of the naturally CHP occurring homoerythrinane alkaloids schelhammericine (77a) Scheme 5 and its 3-epimer (77b) has been reported (Scheme 7).25 4-(3,4- NATURAL PRODUCT REPORTS 1989-A. S. CHAWLA AND A. H. JACKSON (59) (60) II Me3SiO. 0 0 0 (68) xvi ~(69) a; R =Et b; R =Me xx ii -Me0 COzMe ( 0O9 Me0 bR xx .xx i (74) (73) (71) R =H 1 3xix xxiii (72) R =CS2Me xx iv (0 9 0 xxv xxvi __c __c (=P HO RZ' RL (75) a; a-OH (76) a; R1 =H,RZ= OMe (77) a; R1=H,R2=OMe b; p-OH b;R1=OMe,R2=H b; Rl=OMe,R*=H Reagents i Et,N ClC0,Et; ii NaN,; iii heat in toluene; iv POCl, SnCl,; v P,S, benzene; vi BrCH,CO,Et; vii KHCO,; viii PPh, ButOK DMF; ix ClC(O)C(O)Cl Et,O; x H,C=C(OSiMe,)CH=C(H)OMe; xi NaBH,; xii Bu",N+ F- THF; xiii H, Pd/C; xiv MsCl pyridine; xv 1,8-diazabicyclo[5.4.0]undec-7-ene,toluene heat; xvi 2 YONaOMe MeOH ;xvii PhSeCl BF * Et,O THF ;xviii Hg(ClO,), MeOH ;xix NaH CS, MeI; xx Bu",SnH heat; xxi 2% HCI acetone; xxii CaCl, DMSO Et,CSH heat; xxiii Bu",N+ BH,- MeOH; xxiv NaBH, CeCl, MeOH; xxv NaH MeI (Bu",N),SO,; xxvi LiAlH, AlCl, THF Scheme 7 NATURAL PRODUCT REPORTS 1989 (O0 I __t 00 \ (78) X =O (80)"-iv.v ... Vlll -0 (83) (81) vi .vii I - - iv ix.x Me0 Me0 0 OR (85) a;R=H -J b ;R =CS2Me xi ( 84) (82) 1xii.v (86) (87) a ; R1=OMe,R2=H (88) a ; R' = OMe,R2=H b;R'=H,RZ=OMe b; R1=H,R2=OMe Reagents i DMSO Ac,O; ii HOCH,CH,OH TsOH; iii MgCl, DMSO Et,CSH heat; iv NaBH,; v HCl acetone; vi MsCl pyridine; vii K,CO, MeOH; viii MeOH TsOH; ix PhSeCl BF Et,O; x Hg(ClO,), MeOH; xi NaH CS, MeI; xii Bu",SnH; xiii NaBH, CeCI, MeOH; xiv NaH MeI (Bu",N)HSO,; xv LiAlH, AlCl Scheme 8 (89) a ; R' = R2=H (90) a; R'=Me,R2=H b ; R' = Me R2=H b ;R1=R2=Me c; R'=R2=Me Methylenedioxypheny1)butyric acid (59) was converted into the isocyanate (60) and then cyclized to the benzazepinone (61) (63%).This was treated with P,S, and then Eschenmoser's alkenylation procedure26 afforded the thiolactam (62) (96 YO) which was converted into the benzazepino-pyrrolinedione (64) (80%) via the amino-acrylate (63). Irradiation of a mixture of the pyrrolinedione (64) and 1 -methoxy-3-trimethyl- silyloxybutadiene gave a stereospecific [2+21 adduct (65) (81 %). This on reduction with sodium borohydride followed by treatment of the resulting alcohol (66) with tetra-n-butylammonium fluoride gave the homoerythrinane derivative (67) (91 %). Hydrogenation of the latter gave the dione (68) methanesulphonylation of which followed by treatment with DBU yielded the cyclohomoerythrinane (69a) (81 YO).This was transesterified to the methyl ester (69b) and this on heating with PhSeCl and BF;Et,O in THF followed by treatment with mercury(1r) perchlorate gave the a,a-dimethoxy-ketone (70) (76%).This was reduced to the a-alcohol (71) and converted into the dithiocarbonate (72) which on reduction with tributyltin hydride afforded the dione (73). Hydrolysis of NATURAL PRODUCT REPORTS 1989-A. S. CHAWLA AND A. H. JACKSON I Me0 ' Me0 L Me0 ' + Meo% "*a RO2C U 0 (91) a;R = Et (92) (93) b;R =H iior iii X (95) a; X = H (9L)a; X = H b; X = CI b; X = Cl n Me0-O R' vi R2 __c vii CI O/ (97) R1=R2=Me (98) R1= R2=Me (96) (101) R' =R2=H Jxi (103) R' R2= CH2 (102) R1R2= CH2 1viii ix t- HO Ho OMe Me0 OMe (100) R' =R2=Me (99) R1= R2= Me (105) R'R~=CH* (104) R'R2= CH 2 Reagents i polyphosphoric acid; ii H,C=CHCH,Br; iii H,C=CClCH,CI NaOH DMF; iv heat at 150 "C; v NaBH, MeOH CH,CI,; vi 90% H,SO, at 55 "C; vii PhIO KOH MeOH; viii LiAlH, THF; ix TsOH; x BBr, CH,CI, at -78 "C; xi CH,Br, KF DMF Scheme 9 (73) and decarboxylation gave the enone (74) (83 %) which on mixture of unsaturated alcohols which were separated after reduction afforded the epimeric alcohols (75a) and (75b); they had been methylated to the 0-methyl derivatives (87a) reduction with tetrabutylammonium borohydride gave mainly (54 YO)and (87b) (25YO).Reduction of (87a) gave the product the P-alcohol(75b) whereas NaBH and CeC1 afforded mainly (83a) and (87b) similarly afforded the 3-epimer (88b).Both the a-alcohol (75a).Both alcohols were converted into the compounds were identical with the corresponding naturally corresponding methyl ethers (76a) and (76b) the reduction of occurring alkaloids. which with LiAlH and AlCl led to racemic 3-epi-schel- Two new hexahydrodibenz[dJlazecines (90a) and (90b) hammericine (77b) and racemic schelhammericine (77a) re- related to a biosynthetic precursor of the homoerythrina spectively in excellent yields; the n.m.r. spectrum of the latter alkaloids have recently been synthesized;,' their 60x0-proved to be identical with that of the natural product. derivatives exist in two conformations in solution. The The stereo-controlled total synthesis of 6,7-dihydro-homoerythrinanenone (74) on treatment with NaOH or 1,8-schelhammeridine (88a) and its 3-epimer (88b) have been diazabicyclo[5.4.O]undec-7-ene (DBU) underwent ring-cleav- described (Scheme 8).27The homoerythrinane derivative (68) age to give the azecine (89a).Methylation of (89a) with on oxidation with DMSO and Ac20 yielded the trioxo- diazomethane gave the 0-methyl ether (89b) which on further compound (78) (95Y0) which was then converted into the methylation with methyl iodide and sodium hydride afforded mono-ethylene acetal (79) (99 YO).This was hydrolysed and the N,0-dimethyl derivative (89c). Reduction of (89b) and decarboxylated and then converted into the cyclohomo-(89c) with LiAlH and AlCl yielded the 5,6,7,8,9,10-hexahydro- erythrinane (82)through the intermediates (80) and (81). The 2-methoxy-12,13-methylenedioxydibenz[dJlazecines(90a) and (6R) stereochemistry of (81) and (6s) of (82) was rigidly (90b) respectively in quantitative yields.established by a quantitative formation of the cyclic acetal(83). Model studies directed towards the synthesis of cephalotaxine The keto-amide (82) was converted into the enone (86) (in an have been A novel and highly stereoselective overall yield of 50%) via intermediates (84) and (85) (Scheme synthesis of cephalotaxine (105) and its analogue (100) has been 8); reduction of (86) with NaBH and CeCl,'* yielded a 2:1 achieved from proline (Scheme 9).31 Condensation of ethyl NPR 6 NATURAL PRODUCT REPORTS 1989 (106) (108) iiii - M e O s o R V,V~ MeOQ R O vii 0 (111) / COzMe a ;R = OH b ;R =Ms v iii (112) (113) a; R'= H RZ =OH b;R1=OH,R2=H Reagents i ClC(O)CH,CO,Me; ii polyphosphate ester; iii ClC(O)C(O)Cl; iv H,C=C(OSiMe,)CH=C(H)OSiMe ; v LiBH ; vi H' ; vii MsCl pyridine; viii MgCl, heat; ix Al(OPr'), Pr'OH; x MeI phase-transfer catalyst; xi AIH Scheme 10 prolinate with 3,4-dimethoxyphenylacetylchloride yielded the amide ester (91a) (89 YO),which on hydrolysis with potassium hydroxide in ethanol gave the carboxylic acid (91b) (100Y0).The latter on treatment with polyphosphoric acid cyclized to the pyrrolobenzazepine (92) (74 YO),and a small amount of the pyrroloquinolinone (93) (2 YO)was also formed. Treatment of (92) with ally1 bromide or 2,3-dichloropropene in the presence of sodium hydroxide in dimethylformamide afforded the enol ethers (94a) (73 YO)or (94b) (91 YO)respectively.On heating (94a) or (94b) at 150 "C Claisen rearrangement occurred yielding the products (95a) (8 1 YO)or (95b) (97 YO)respectively. Reduction of (95b) with sodium borohydride in methanol and dichloromethane gave the alcohol (96) (100 YO),which under- went cationic cycli~ation~~ to yield the tetracyclic ketone (97) (69 YO).Oxidation of (97) with iodosobenzene afforded the hydroxy-ketal (98) (80%) as the sole product. Reduction of (98) with lithium aluminium hydride gave the amine (99) (85 YO),which on treatment with toluene-p-sulphonic acid afforded the cephalotaxine analogue (100) (78 YO). The tetracyclic ketone (97) on treatment with boron tribromide in dichloromethane underwent demethylation to afford the compound (101) (79 YO),which was converted into the methylenedioxy-derivative (102) (33 YO)and hydroxylated with iodosobenzene at 0 "C to afford stereoselectively the hydroxy-ketal(lO3) (79 YO).Reduction of the latter with lithium aluminium hydride gave the amine (104) (86 YO)and treatment with toluene-p-sulphonic acid in THF afforded ( f)-cephalo-taxine (105) (91 YO).Partial syntheses of isoharringtonine analogues have also been reported., 2.3 Abnormal Eryihrina Alkaloids Sano and co-worker~~~ have developed a new synthetic route for the preparation of the abnormal erythrinane alkaloids (L)-coccolinine (1 14) and (i-)-coccuvinine (1 15) (Scheme 10). Condensation of 2-(4-methoxyphenyl)ethylamine (106) with methyl chloroformylacetate afforded the amide (107) in good NATURAL PRODUCT REPORTS 1989-A.S. CHAWLA AND A. H. JACKSON (118) iv .v1 0 Reagents i heat; ii polyphosphoric acid; iii 0, at -78 "C; iv AcOH HCl; v Ac,O; vi K-Selectride (KBu",BH) Scheme 11 yield which underwent Bischler-Napieralski cyclization with polyphosphate ester (PPE) to give 1,2,3,4-tetrahydr0-7-meth-oxy-1-methoxycarbonylmethylideneisoquinoline(1 08) (51YO). This on treatment with oxalyl chloride yielded the iso-quinolinopyrrolinedione (109) (78YO).Diels-Alder reaction of the latter with 1,3-bistrimethylsilyloxybutadieneafforded the adduct (1 10) (71 YO),which on reduction with lithium boro- hydride followed by treatment of the resulting alcohol with hydrochloric acid afforded the enone (1 1 la). Formation of the mesylate (1 1 1 b) and removal of the methoxycarbonyl group at C-6 (by elimination caused by heating with magnesium chloride) produced the dienone (1 12) (72 YO).Meerwein-Ponndorf reduction of (1 12)gave the a-alcohol (1 13a) and the P-alcohol (1 13b) in 76 and 18YOyields respectively.Methyl- ation of the a-alcohol (1 13a) with methyl iodide in the presence of a phase-transfer catalyst afforded (i-)-coccolinine (1 14) (93 YO).Reduction of this with aluminium hydride yielded (i-)-coccuvinine (1 15) (93 YO).The synthesis of 15-demethoxy-coccuvinine which is an unnatural erythrinane compound has also been achieved via the same route starting from phenyl- ethylamine. Cocculolidine (121)is an alkaloid with insecticidal properties that has been isolated from Cocculus trilobus.Structurally it is a lower homologue of P-erythroidine. The synthesis of the cocculolidine skeleton (1 20) has now been described (Scheme 11).35 Condensation of 2-(2,4,5-trimethoxyphenyl)ethylamine (1 16) and 2-(ethoxycarbonylmethyl)cyclohexanone (2l) fol-lowed by cyclization with an excess of polyphosphoric acid gave 14,15,17-trimethoxyerythrinan-8-one(1 17)(5 1 YO),which on ozonolysis at -78 "C,gave the bisnor-diester (1 18) (63 YO). Hydrolysis of the latter with 70YOacetic acid containing 10YO HCI yielded the diacid which on heating with acetic anhydride afforded the anhydride (1 19) in quantitative yield. Reduction of this with potassium tri-s-butylborohydride (K-Selectridem) gave the cocculidine derivative (120) (70%) as the sole product.3 References 1 A. S. Chawla F. M. J. Redha and A. H. Jackson Phyto-chemistry 1985 24 1821. 2 I. Barakat A. H. Jackson and M. I. Abdullah Lloydia 1977,40 471. 3 Q. N. Saqib K. Usmanghani and V. U. Ahmad J. Pharm. (Univ. Karachi) 1985 4 39 (Chem. Abstr. 1987 106 2899). 4 R. C. Hider M. D. 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