1 -Phenylethylamines

Hordenine has been isolated from Anomianthus dulcis 1 and the new alkaloid armatamide 1, which has been hydrolysed to -(4-methoxyphenyl)ethylamine and 3,4-methylenedioxycinnamic acid, has been isolated from Zanthoxylum armatum. ²

The conformational analysis of ephedrine and of pseudo- ephedrine ³ and the crystal structure of ephedrine (S)-tert-butylsulfinylacetate ⁴ have been studied. The reaction of ephedrine 2a with thionyl chloride in the absence of a solvent has been shown to proceed by the S_N2 mechanism with 100% inversion, to give 3a, whereas the corresponding N-toluenesulfonyl compound 2b reacts by the S_Ni mechanism, with 100% retention of configuration, to give 4b. Pseudoephedrine 5a, under the same conditions, gives a mixture of the erythro and threo compounds 4a and 3b by S_N1 substitution and the N-toluenesulfonyl compound 5b gives a mixture of 4b and 5a. ⁵ Ephedrine and pseudoephedrine have been found to add to propargyl (prop-2-ynyl) alcohol, with oxidation, in the presence of manganese dioxide, to give the isomeric aldehydes 6 and 7. ⁶ A method for the estimation of N-methylephedrine has been published. ⁷

The pharmacological and physiological effects of ephedrine ^8-15 and of N,N-dimethyltryptamine ¹⁶ have been studied.

2 Isoquinolines

Simple isoquinolines have been isolated from the following plant species:Annona cherimola 17 doryphornine and thalifolineBerberis turcomanica ¹⁸ turcomanine 8Berberis vulgaris ¹⁹ thalifolineFumaria bastardii ²⁰ corydaldine and oxohydrastinineHypecoum leptocarpum ²¹ oxohydrastinineThalictrum przewalskii ²² N-methylcorydaldine.
Of these turcomanine is a new alkaloid derived from 7,8-dihydroxyisoquinoline, the only other alkaloids of that type being lemaireocerine, dehydrolemaireocerine, bisdehydrol- emaireocerine (isobackebergine) and tepenine. In addition the new 1-phenyltetrahydroisoquinoline alkaloid 9 (unnamed) has been isolated from Adhatoda vasica ²³ and the novel 5,6,7,8-tetrahydroisoquinolines hyeronine A 10a and hyeronine B 10b, in which the stereochemistry at C-6 has not been determined, have been isolated from Hyeronima oblonga. ²⁴

Racemic coreximine 13 has been synthesised by the reaction of hydrastinine 11 with the lithium salt 12, followed by hydrolysis of the product; a 6% excess of the (+)-isomer was obtained using the menthyl ester analogue of 12. ²⁵

3 Naphthylisoquinolines

Naphthylisoquinoline alkaloids have been isolated from the following plant species, the six marked with asterisks being new alkaloids:Ancistrocladus korupensis 26 korundamine A* 14Ancistrocladus robertsonorium ²⁷ ancistrobrevine B, ancistrocladine, ancistrorobertsonine A* 15 and hamatineTriphyophyllum peltatum ^28-30 dioncophylline D* 16a, 8-O-methyldioncophylline D* 16b, 5-O-demethyldioncophylline A* 17a and dioncophyllinol* 18.

Of the new alkaloids the absolute stereochemistry of dionocophylline D was determined by oxidation to D-alanine and (R)-3-aminobutyric acid ²⁸ and of 5-O-methyldioncophylline A by an X-ray crystallographic study of its 5-bromo-N,O,O-tribenzyl derivative and by partial synthesis from dioncopeltine A. ²⁹ The absolute configurations of the known isoancistrocladine 19 and its rotamer, isohamatine, have been determined from their CD spectra. ³¹ Dionocophyllinol is the first 4-hydroxytetrahydroisoquinoline reported in this series, and korundamine A is the first unsymmetrical dimer of a 5-naphthyl and a 7-naphthylisoquinoline. The latter alkaloid shows antiviral activity against HIV-1 and antimalarial activity against Plasmodium falciparum. ²⁶ Michellamines A, B and C and korupensamines A and B have been separated by HPLC, and the enzymatic oxidation of korupensamine B to michellamine C has been confirmed. ³²

The bromo-acid 20 and the phenol 21 have been coupled through the ester 22 to give the lactone 23a, which was converted through 23b into dioncolactone A 23c. Reduction of 23b with the complex of borane and the (S)-oxazaborolidine 24 afforded over 95% enantiomeric excess of N-benzyldioncopeltine A, easily converted into dioncopeltine A 17b and into 5-O-dimethyldioncophylline A 17a. The unwanted atropomer produced in the reduction of 23b was easily converted back into 23b for further use. ³³ Using a similar approach the lactone 25 was reduced to the alcohol 26, from which the naphthalene system was constructed to afford a synthesis of korupensamines A and B 27, ³⁴ which have also been synthesised by the palladium-mediated coupling of the bromo-compound 28 with the boronic acid 29, followed by removal of the protecting benzyl group. ³⁵


Octadehydromichellamine 32, which contains no asymmetric carbon atom, is not preparable by the dehydrogenation of michellamines A, B or C, but has been synthesised by the coupling of 30, available from previous syntheses of michellamines, with the boronic acid 31. It shows antiviral and cytotoxic activity against HIV-1 of the same order as that of michellamine B, but its activities against both chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum are significantly greater than those of the alkaloid. ³⁶ Other syntheses of alkaloids of this group have been reviewed. ³⁷

4 Benzylisoquinolines

1-Benzylisoquinoline alkaloids have been isolated from the following plants species, the two marked with asterisks being new alkaloids:Anonianthus dulcis 1 reticulineBerberis turcomanica ³⁸ turcomanidine* 33Fumaria bastardii ²⁰ juziphineOrophea hexandra ³⁹ reticulineThalictrum przewalskii ²² thalprzewalskiinone* 34

The new 2-benzylisoquinoline alkaloid heterocarpine 35 has been isolated from Ceratocapnos heterocarpa and its structure has been confirmed by its synthesis from the iminium salt 36, through the tetrahydroisoquinolines 37a, 37b and 37c. ⁴⁰

It was reported in the previous review that dehassiline, assigned the structure 39, is not identical with the base of this structure prepared by synthesis; a further study has shown that it is not identical with the isomeric base 38, prepared by the stereoselective reduction of the related 3,4-dihydroisoquinolinium salt. ⁴¹ The bis-quaternary salt 40, which is an analogue of atracurium has been prepared from tetrahydropapaverine. ⁴² Electrolytic cyclisations of the halides 41a, 41b and 41c have afforded the aporphine alkaloid dehydroroemerine 42. ⁴³



A review of the isolation, determination of structure and syntheses of alkaloids of Papaver species has been published. ⁴⁴ The pharmacological and physiological effects of papaverine ⁴⁵ and of atracurium ^46-51 have been studied.

5 Bisbenzylisoquinolines

Bisbenzylioquinoline alkaloids have been isolated from the following plant species, the four marked with asterisks being new alkaloids:Berberis vulgaris 19 aromoline, baluchistanamine 43a, berbamine, isotetrandrine, obaberine, obamegine, oxyacanthine and tejedine* 43b.Stephania tetrandra ⁵² fenfangjine A* 44, fenfangjine B* 45a and fenfangjine C* 45b.

The pharmacological and physiological effects of berbamine, ^53-57 of O-(4-ethoxybutyl)berbamine, ⁵⁸ of cepharanthine, ^59,60 of dauricine, ^61,62 of daurisoline, ^63-65 of fangchinoline, ^66-68 of tetrandrine ^66,68-81 and of tubocurarine ^82,83 and the esterolytic activity of tubocurarine ⁸⁴ have been studied.

6 Dibenzopyrrocolines

A new alkaloid of the dibenzopyrrocoline group, mangochinine, which is 10-O-demethylcryptaustoline 46, has been isolated from Magnolia chingii. Its structure was deduced from the spectra of its O,O-diacetyl ester and its absolute configuration from ORD studies. 85

7 Pavines and isopavines

The new alkaloid isothalisopavine 47, which has been isolated from Thalictrum minus, 86 is the first unsymmetrically substituted isopavine alkaloid to be reported, though a similar orientation of substituents has been observed in the pavine alkaloids munitagine, neocaryachine, platycerine and O-methylplatycerine. N-Methylcaryachine and N-methylneocaryachine salts have been isolated from cultures of callus cells of Cryptocarya chinensis. ⁸⁷

The substituted formamide 48 has been cyclised by tetrafluoroacetic anhydride and boron trifluoride to give N-formylisopavine 49a, which was reduced to (±)-thalisopavine 49b, and N-formylpavine 50a and hence (±)-argemonine 50b has been prepared by the similar cyclisation of the 1,2-dihydroisoquinoline 51. ⁸⁸

8 Berberines and tetrahydroberberines

Alkaloids of the berberine group have been isolated from the following plant species, the four marked with asterisks being new alkaloids:Anomianthus dulcis 1 capaurine, caseamine and discretamineBerberis turcomanica ³⁸ N-methylcorydaline chlorideBerberis vulgaris ¹⁹ berberine, 8-oxyberberine, jatrorrhizine and palmatineCroton hemiargyreus ⁸⁹ hemiargyrine* 52Enantia chlorantha ⁹⁰ hydroxydihydropalmatine* 53Fissistigma balansae ⁹¹ columbamine, dehydrodiscretamine, fissiaine* 54, kikemanine and thaipetalineFumaria agraria ⁹² coptisine, palmatine, sinactine, stylopine and N-methylstylopine chlorideFumaria bastardii ²⁰ stylopine and tetrahydropalmatineFumaria capreolata ⁹² coptisine, sinactine and stylopineFumaria densiflora ⁹² coptisine, palmatine, sinactine, stylopine and N-methylstylopine chlorideFumaria muralis ⁹² coptisine, palmatine, sinactine and stylopineFumaria officinalis ⁹² coptisine, palmatine, sinactine, stylopine and N-methylstylopine chlorideFumaria parviflora ⁹² coptisine, sinactine, stylopine and N-methylstylopine chlorideFumaria vaillantii ⁹² coptisine, palmatine, sinactine and stylopinePhellodendron amurense ⁹³ berberineStephania rotunda ⁹⁴ tetrahydropalmatineThalictrum przewalskii ²² berberine and pseudocoptisineTinospora hainanensis ⁹⁵ N-methyltetrahydrocolumbamine chloride* 55

In addition 8-trichloromethyldihydroberberine 56a and 8-trichloromethyldihydropalmatine 56b, which are presumed to be artifacts of the solvent extraction process, have been isolated from Berberis oblonga and Berberis integerrima. ⁹⁶ The structures of these ⁹⁶ and of tetrahydropalmatine hydrate ⁹⁴ were confirmed by X-ray crystallographic studies.

Govadine 57a has been synthesised by the photo-catalysed cyclisation of 58, ⁹⁷ and bharatamine 57b has been synthesised in the same way from the simpler 59. ⁹⁸ Cyclisation of the acetylenes 60a and 60b has afforded the macrocyclic lactams 61 and 62 respectively, both of which were stereospecifically cyclised by hydriodic acid to the oxyberberine analogue 63 in very good yield. In marked contrast with this the cyclisation of 60b with tetrabutylammonium fluoride gave a quantitative yield of the isoindolobenzazepine 64, which is an analogue of the alkaloid lennoxamine (section 13). ⁹⁹ The silylated lactam 62 has been oxidised by the dimethyldioxirane 65a to the epoxide 66, which was cyclised by hydrochloric acid to the unsaturated lactam 67. The same sequence of reactions with the unsilylated lactam 61 afforded the hydroxylated lactam 68. The (Z)-isomer of the (E)-lactam 61 reacted more sluggishly with an excess of the oxidising agent 65a, eventually giving a mixture of the tetrahydroberberine 69 and the isoindolobenzazepine 70, which are analogues of the alkaloids prechilenine and chilenine respectively. Oxidation of 62 with 65a involved some fission of the veratrole ring to give 71 in addition to 66, but the bulkier dioxirane 65b was unable to attack the styrenoid double bond and only the diester 72 was obtained. ¹⁰⁰





The pharmacological properties and physiological effects of berberine, ^101-103 of palmatine, ^104,105 of tetrahydropalmatine, ¹⁰⁶ and of stepholidine ^106-108 have been studied, and the synthetic berberine 73 and its close analogues have been tested as potential antimicrobial agents. ¹⁰⁹

9 Secoberberines

Four new secoberberine alkaloids, leptopine 74a, leptopidine 74b, leptopinine 75 and leptopidinine 76, have been isolated from Hypecoum leptocarpum. 21 Their structures were deduced from their spectra. Leptopine 74a and leptopidinine 76 would be expected to be readily interconverted, but their ultraviolet spectra, and their behaviour on thin layer chromatography, in both aqueous and methanolic sodium hydroxide and hydrochloric acid were not identical. ²¹

(±)-Coreximine 13 has been synthesised from hydrastinine 11 as described in section 2, and a similar synthesis of (±)-corydalisol 77 has also been achieved. ¹¹⁰

10 Protopines

Alkaloids of the protopine group have been isolated from the following plant species:Fumaria agraria 92 cryptopine and protopineFumaria bastardii ²⁰ protopineFumaria capreolate ⁹² cryptopine and protopineFumaria densiflora ⁹² cryptopineFumaria muralis ⁹² protopineFumaria officinalis ⁹² protopineFumaria parviflora ⁹² cryptopine and protopineFumaria vaillantii ⁹² cryptopine and protopineHypercoum leptocarpum ²¹ protopineThalictrum triternatum ¹¹¹ allocryptopine and protopine.
X-Ray crystallographic studies of and -allocryptopine confirm that these are polymorphic forms of the same substance. ¹¹²

11 Phthalide-isoquinolines

Phthalide-isoquinoline alkaloids have been isolated from the following plant species:Fumaria agraria 92 adlumiceine and adlumidiceineFumaria bastardii ²⁰ bucuculline, corlumine and -hydrastineFumaria capreolata ⁹² adlumiceine and adlumidiceineFumaria densiflora ⁹² adlumiceine and adlumidiceineFumaria muralis ⁹² adlumiceine and adlumidiceineFumaria officinalis ⁹² adlumiceine and adlumidiceineFumaria parviflora ^92,113 adlumiceine, adlumidiceine, corledine, corlumidine and -hydrastineFumaria vaillantii ⁹² adlumiceine and adlumidiceine
The pharmacological properties and physiological effects of bicuculline ^114-116 and of narcotine ¹¹⁷ have been studied.

12 Spirobenzylisoquinolines

Spirobenzylisoquinolines alkaloids have been isolated from the following plant species:Fumaria agraria 92 fumaricine, fumariline, fumaritine, fumarophycine, O-methylfumarophycine and parfumineFumaria bastardii ²⁰ fumariline, fumaritine and O-methylfumarophycineFumaria capreolate ⁹² fumaricine, fumariline, fumaritine, fumarophycine, O-methylfumarophycine and parfumineFumaria densiflora ⁹² fumaricine, fumariline, fumarophycine, O-methylfumarophycine and parfumineFumaria muralis ⁹² fumaricine, fumaritine, fumariline and parfumineFumaria officinalis ⁹² fumaricine, fumariline, fumaritine, fumarophycine, O-methylfumarophycine and parfumineFumaria parviflora ⁹² fumariline, fumaritine, O-methylfumarophycine and parfumineFumaria vaillantii ⁹² fumaricine, fumarophycine, O-methylfumarophycine and parfumineHypecoum leptocarpum ²¹ isohyperectine.

13 Other modified berberines

Chilenine has been isolated from Berberis vulgaris 19 and a new alkaloid, leptocarpinine, which has been assigned the arylbenzazepine structure 78 on the basis of its spectra, has been isolated from Hypercoum leptocarpum. ²¹ Apart from the additional methylene group, 78 has the skeleton of a hydrolysed chilenine 79 and might be expected to be derived from a secoberberine alkaloid in a manner similar to the derivation of chilenine from berberine. However the orientation of substituents in 78 and 79 is different and the substitution pattern of any putative precursor of 78, such as 80, which could be converted into 78 through 81 and 82, is observed only in the alkaloid caseadine 83. The very much more common 2,3,9,10-substitution pattern is observed in all of the alkaloids (protopine 84, isohyperectine 85, leptopine 74a, leptopinine 74b, leptopidine 75 and leptopidinine 76) isolated together with leptocarpinine, from Hypecoum leptocarpum suggesting that this alkaloid more probably has the structure 86. Structures deduced entirely from spectra have occasionally had to be revised, most recently those of fumarizine and dehassiline. Though 13a C-methylated tetrahydroberberines have not so far been reported, alkaloids with C-methyl groups in the other benzylic positions 8 and 13 are known and the introduction of such a group into 80 or an isomer presents no biogenetic problem.



The acetylenic amide 87 has been cyclised to the isoindole 88, oxidation of which gave the vicinal diol 89a, the monomethyl ether of which 89b was cyclised to the isoindoloquinoline 90. Rearrangement of this afforded dehydrolennoxamine 91, which was hydrogenated to lennoxamine 92. ¹¹⁸ The synthesis of analogues of chilenine and lennoxamine from macrocyclic acetylenes is reported in section 8.

14 Benzophenanthridines

Chelilutine and chelirubine chlorides 93a and 93b have been converted into the bimolecular alkanolamine ethers 94a and 94b by aqueous sodium carbonate and into the bimolecular amines 95a and 95b by aqueous ammonia. The simple alkanolamines 96a and 96b have been detected only in solutions of the alkaloids in deuteriochloroform on shaking with aqueous sodium carbonate. 119 The NMR spectrum of 6-hydroxydihydrosanguinarine 96c, obtained in deuteriochloroform in the same way from sanguinarine, has been studied. ¹²⁰


The assignment of structures 99a and 99b to fagaridine and isofagaridine respectively has been confirmed by detailed studies of their UV spectra ¹²¹ and by syntheses of both alkaloids by internal aryl-aryl couplings of 97a and 97b in the presence of tri-n-octyltin iodide to give 98a and 98b, followed by oxidation to the related isoquinolines with manganese dioxide and N-methylation. ^121,122 Similar aryl-aryl cyclisations of the trifluoromethane sulfonates 100a, 100b and 100c by palladium(II) acetate, 3-bis(diphenylphosphino)propane and tributylphosphine have afforded dihydrochelerythrine 101a, dihydronitidine 101b and oxonitidine 101c, which were converted into chelerythrine 99c and nitidine 99d. ^123,124



An alternative approach, using the Suzuki coupling of an aryl halide with an arylboronic acid, used so successfully in the synthesis of naphthylisoquinoline alkaloids, has afforded a range of benzophenanthridine alkaloids. The required 2-bromo-1-aminonaphthalene was difficult to prepare, but was finally obtained from the 1-tetralone 102a by bromination to 102b and dehydrobromination to the 2-bromo-1-naphthol 103a, followed by Smiles rearrangement of the ether 103b to the amide 104a, which was hydrolysed to the amine 104b. This was found to react only sluggishly and inefficiently with the aldehydic boronic acids 105a and 105b, in attempts to generate the tetracyclic system directly, but the formamide 104c and the simpler boronic acids 106a and 106b readily coupled to give good yields of 107a and 107b. These were then subjected to Bischler-Napieralsky ring closure to give nornitidine 108a and noravicine 108b. N-Methylation of 107a and 107b gave 107c and 107d and cyclisations of these afforded nitidine 99d and avicine 99e. Similar syntheses of chelerythrine 99c and chelilutine 93b were achieved from the boronic acids 109a and 109b and the amide 104c. ¹²⁵


The 4-phenylisoquinoline alkaloid decumbenine B 116, ¹²⁶ which can be regarded as a degraded benzophenanthridine, has been synthesised from piperonal, the lithium salt of which 110a, when treated with ethyl chloroformate yielded 110b. Protection of the aldehyde group of this as the cyclic dithioketal, followed by reduction of the ester with lithium aluminium hydride and hydrolysis of the ketal, afforded 110c, which was benzylated to give 110d. Condensation of this with benzylamine yielded the imine 111, to which the anhydride 112 added to give the lactam 113. This was decarboxylated to 114a and the protecting groups were then removed to give 114b, which was reduced to the amine 115, dehydrogenation of which gave decumbenine B 116. ¹²⁷


The pharmacological properties and physiological effects of chelerythrine ¹²⁸ and the binding of fagaronine to DNA ¹²⁹ have been studied

15 Aporphinoid alkaloids

16 Alkaloids of the morphine group

Alkaloids of the morphine group have been isolated from the following plant species, the two marked with asterisks being new alkaloids:Croton hemiargyreus 89 salutaridine and norsalutaridineElastostema sinuata ¹³⁴ amurineMenispermum dauricum ¹⁶¹ dechloroacutumine* 149bPachygone dasycarpa ¹⁶² 14-hydroxyisostephodeline* 148

Dechloroacutumine 149b was only isolated from Menispermum dauricum grown in chloride-free media. In the presence of chloride ion only acutumine 149a is produced. ¹⁶¹
The O-demethylation of codeine to morphine has been effected in 91% yield with boron tribromide and in 73% yield using L-Selectride. The latter reagent has also proved effective (30%) in the more sensitive demethylation of thebaine 151 to oripavine and in the demethylation of 14-hydroxycodeinone and of O-methylnaltrindole. ¹⁶³ Codeine has been converted into thebaine 151 by oxidation to codeinone 150, followed by enol methylation; ¹⁶⁴ it has also been rearranged by butyllithium to thebainone A 152 in 74% yield, which is much superior to earlier yields by rearrangement over palladium. ¹⁶⁵ The acid-catalysed condensation of morphine with paraformaldehyde has been shown to give a mixture of the 1,1-methylenebis-compound 153 and the bases 154a and 154b. ¹⁶⁶ Ethers of 1,2-dimorphine and of trimorphine and tetramorphine have been obtained by the oxidation of morphine 3-ethers with potassium ferricyanide. ¹⁶⁷


Dihydrocodeinone 155a on treatment with diaryliodonium iodides affords the 7-aryl and 7,7-diaryldihydrocodeinones 155b and 155c, ¹⁶⁸ and has been converted by the Wittig reaction into the olefins 156a-156e. Of these 156b and 156c were hydrolysed to the aldehyde 157, which readily suffered base-catalysed cleavage of the oxygen bridge to give the phenol 158, and 156d and 156e on catalytic reduction afforded a mixture of 159 and 160, though the non-phenolic dihydro compound 161 was obtained by reduction with diimide. Attempts to prepare the olefins 156f and 156g by the Wittig reaction resulted in a mixture of the dienes 162 and 163 and in production of the phenolic dimer 164 respectively, and use of the ylide from isopropyltriphenylphosphonium bromide resulted in the formation of the aldol 165. ¹⁶⁹




6-Bromodihydrocodide 166 has been converted by tributyltin hydride into a mixture of deoxycodeine C 167 and dihydrodeoxycodeine D 168, ¹⁶⁹ and the same reagent has been used to cyclise 6-O-(2-bromophenyl)isocodeine 169 to the dibenzofuran 170. ¹⁷⁰ Morphine reacts with 4-dimethylaminobenzaldehyde in the presence of perchloric acid to give the triarylmethane derivative 171, but in concentrated sulfuric acid the reaction leads to the apomorphine derivative 122. ¹³⁶

5-Methylthebaine reacts with trifluoroacetaldehyde to give the 14-substituted codeinone 173, presumably by way of the Diels-Alder adduct 172, and this has been epoxidised with alkaline hydrogen peroxide to 174, which gave 175 on reduction with sodium borohydride. ¹⁷¹ The Diels-Alder adducts of thebaine 176a-176d and their 6,14-endo-ethano analogues have been equilibrated with their C-7 epimers by non-nucleophilc bases in dipolar aprotic solvents, the equilibrium in all cases favouring the 7 epimers. The 7 epimer of 176c has been reacted with phenylmagnesium bromide to give the dimeric base 177. ¹⁷² The adduct 176b has been rearranged by chromium iminodiacetate to the dihydro-8,14-cyclopentathebaine 178. ¹⁷³ It has been shown that the acid-catalysed rearrangement of alcohols of structure 179 to tetrahydrofurans 180 proceeds with retention of configuration at C-7. ¹⁷⁴ This has been held to vitiate the mechanism originally proposed for this reaction ¹⁷⁵ but nothing in that mechanism necessarily requires scrambling at this centre. X-Ray crystallographic studies of the alcohol 181 and its C-7 epimer have confirmed their structures. ¹⁷⁶



In Diels-Alder reactions other than those of thebaine the diene 182, prepared from 6-O-trifluoroacetylcodeine and tri- butylvinyltin, afforded poor yields of the adducts 183 and 184 with tetracyanoethylene and diethyl acetylenedicarboxylate respectively. ¹⁷⁰


Details of the preparation of the following have been published: the 14-aminodihydrocodeinone derivatives 185a-185c, ¹⁷⁷ N-benzyl-14-hydroxydihydronormorphinone, ¹⁷⁸ 14-O-benzylnaltrexone, ¹⁷⁹ 3-deoxy-14-O-benzylnaltrexone, ¹⁷⁹ the 7-arylidenenaltrexones 186a-186k, ¹⁸⁰ the indole 187a, the benzofuran 187b and related compounds, ^181-184 the quinolines 188a-188d and related bases, ¹⁸⁵ the diamine 189 and related bases, ¹⁸⁶ the amide 190, ¹⁸⁷ buprenorphine, ¹⁸⁸ 4,5-deoxythebaine 191 and its analogues, ¹⁸⁹ ethers of morphine and of 14-hydroxymorphine, ^190,191 14-hydroxydihydromorphinone, 14-hydroxydihydrocodeinone and their derivatives, ^{192 3}H-labelled morphine and codeine ¹⁹³ and ¹⁸F-labelled naltrindole. ¹⁹⁴


The bacterial oxidation ¹⁹⁵ and the gluronidation ¹⁹⁶ of morphine and of codeine and methods for the detection and estimation of morphine, ^197-201 of codeine ^201,202 of 6-O-methylcodeine, ²⁰² of thebaine ²⁰² and of buprenorphine ²⁰³ have been studied, and the crystal structure of the complex of morphine and (S)-2-phenylhydracrylic acid has been examined. ²⁰⁴ The hydrogenation of methyl pyruvate in the presence of dihydrocodeine or of thebaine has been found to favour the formation of an excess of the (S)-lactate, whereas in the presence of 14-hydroxydihydrocodeinone or of naloxone an excess of the (R)-lactate is formed. ²⁰⁵
An asymmetric synthesis of ()-dihydrocodeinone (and hence a formal synthesis of morphine) has been achieved from 5-chloro-7,8-dimethoxy-1-tetralone. Claisen condensation of this with ethyl formate afforded 192, which, with methyl vinyl ketone followed by retro-Claisen cleavage, yielded racemic 193, together with 10% of the achiral 194, which could be separately equilibrated with 193. Racemic 193 gave 193 on resolution by chromatography on cellulose triacetate and the unwanted enantiomer was easily converted into the equilibrium mixture of racemic 193 and 194 for further use. Reaction of 193 with vinylmagnesiocuprate gave 195a in very good yield and bromination of this gave 195b, which was cyclised to 196 in dimethylformamide at 140 °C. The cyclic ketal of this ketone on hydroboration and oxidation afforded the alcohol 197a, reduced to 197b and this was converted directly into 198 by N-methylbenzenesulfonamide. Bromination of 198 with N-bromosuccinimide and dehydrobromination of the product afforded the olefin 199, which was cyclised to 200, and hydrolysis of this ketal yielded ()-dihydrocodeinone 155a. ²⁰⁶


(+)-Cepharamine, the mirror image of the natural alkaloid, has been synthesised for pharmacological screening in comparison with morphine, which has the same absolute stereochemistry. Alkylation of the Birch reduction product of 201 with the halide 202 gave the enol ether 203, which was hydrolysed, reduced and cyclised to the lactone 204a. The formyl ester of this 204b was oxidised to the enone 205a, which was ketalised and cyclised by tributyltin hydride to 205b. The derived 205c was then subjected to Hofmann rearrangement to 206 and this was reduced with lithium aluminium hydride to the cyclic amine 207. Oxidation of this to 208 and conversion into the enol ether afforded 209, which was hydrolysed to (+)-cepharamine 210. ²⁰⁷


Approaches to the synthesis of compounds of the morphine, morphinan and hasubonine groups have been reviewed. ²⁰⁸
The analgesic properties, ^209-260 metabolism ²⁶¹ and pharmacokinetics ^229,262-265 of morphine have been studied, as have the effects of the alkaloid on behaviour, ^266-270 on immune responses, ^271-278 on locomotor activity, ^279-281 on the brain ²⁸² on the cardiovascular system, ^283,284 on the gastro-intestinal tract, ^285,286 on respiration, ^287,288 on neurones, ²⁸⁹ on spinal receptors, ²⁹⁰ on the jaw reflex, ²⁹¹ on appetite, ²⁷⁹ on post-operative recovery, ²⁹² on the hippocampus, ^293,294 on the newborn, ^295,296 on the progression of sepsis, ²⁹⁷ of inflammation ²⁹⁸ and of fever, ²⁹⁹ on the activation of neutrophils, ³⁰⁰ on the activity of lymphocytes, ³⁰¹ on levels of cholecystokinin, ^302,303 of dopamine, ³⁰⁴ of enkaphalins, ³⁰⁵ of oxytocin, ³⁰⁶ of adenylcyclase, ³⁰⁷ and of intracellular calcium ³⁰⁸ and on the effects of amphetamine ³⁰⁹ and of lignocaine. ³¹⁰ The effects of diazepam on the development of tolerance to morphine have also been studied. ³¹¹
The narcotic antagonist actions of naloxone ^312-317 and the effects of this compound on behaviour, ^318-323 on the cardiovascular system, ³²⁴ on immune responses, ³²⁵ on temperature, ³²⁶ on arterial gas concentrations, ³²⁷ on platelets, ³²⁸ on the effects of acute alcohol poisoning, ^329,330 on levels of adrenocorticotrophin, ³³¹ of calcitonin, ³³² and of endothelin-I, ³³² on the relief of testicular torsion, ³³³ on the gastro-intestinal tract, ³³⁴ and on the effects of ()-clausenamide ³³⁵ have been studied.
The pharmacological properties and physiological effects of the following have also been studied: 3,6-O,O-diacetylmorphine (heroin), ^230,336-339 morphine 3-glucuronide, ^265,340 morphine 6-glucuronide, ^{222,230,237,246,265,339,341,342} codeine, ^247,343-347 codeine glucuronide, ³⁴⁸ dihydromorphinone glucuronide, ³⁴⁹ thebaine, ³⁵⁰ oripvine, ³⁵¹ 14-hydroxydihydrocodeinone, ^346,352-354 naloxone methiodide, ³²⁴ naltrexone, ^355-366 naltrexone methiodide, ^367-369 7-benzylspiroindanylnaltrexone, ³⁷⁰ naltrexol, ³⁶⁶ naltrindole, ^371,372 nalbuphine, ^{285,316,373-375} nalmefene, ³⁷⁶ -funaltrexamine, ^377-380 norbinaltorphimine, ³⁸¹ 14-hydroxymorphindole, ³⁸² buprenorphine, ^{233,313,357,383-393} dihydroetorphine, ³⁹⁴ sinomenine, ³⁹⁵ and stephodeline. ³⁹⁶

17 Colchicine and related alkaloids

The absolute configuration of colchicine has been further confirmed. 397 A method for the hydrolysis of colchicine to N-deacetylcolchicine without isomerisation of the tropolone system has been described. ³⁹⁸ Colchicine undergoes a Diels-Alder reaction with the acetylenic dienophiles benzyne, dimethyl acetylenedicarboxylate and cyclooctyne to give the 8,12-adducts 211a, 211b and 211c. In marked contrast, ethylthiocochicide undergoes a [3 + 2] cycloaddition of benzyne to the enol thioether system to give 212 (not isolated) which suffers hydrogen shift and cleavage of the carbon-sulfur bond to give 213. ³⁹⁹ Thiocolchicine has been demethylated to 214a, 214b and 214c, and of these 214a and 214b have been oxidised to the 1,4-quinone 215 and the quinomethane 216 respectively. ⁴⁰⁰ Colchicinoid and isocolchicinoid compounds react with amidines in dry benzene to give 1,3-diazazulenes, of type 217 from ring deactivated compounds such as colchicine and of type 218 from ring activated compounds such as 9-tolylsulfonylisocolchicine. ⁴⁰¹


Thiocolchicone 219 has been converted into the lactams 220a and 220b by heating in benzene with methylamine and butylamine respectively, whereas with aniline the product was the simpler ketone 221, which was reduced to the racemic alcohol 222, resolved through its ()-(1S)-camphamate ester. ^402,403 Colchicine has been converted into the colchicein- amide 223a by heating with piperidine ⁴⁰⁴ and phenolic colchiceinamides of general formula 223 have been prepared by the demethylation of 223b and claimed to form a new class of topoisomerase-II inhibitors. ⁴⁰⁵ Complex ethers of 3-O-demethylcolchicine 224a-224d have been prepared as potential pharmaceuticals. ⁴⁰⁶


The physiological effects of colchicine, ^407-412 of analogues of colchicine, ⁴¹³ of colchiceine, ⁴⁰⁸ of colchemid ⁴¹⁴ and of esters of the alcohol 222 ⁴⁰² have been studied.

18 Erythrina alkaloids

19 Other isoquinolines

The new base aaptosamine 243, which is not an isoquinoline but, like the similarly constituted aaptosine reported in the previous review, is probably derived from the isoquinolone aaptamine, has been isolated from the sponge Aaptos aaptos. 424 Syntheses of aaptamine have been reviewed. ⁴²⁵ The effects of ecteinascidin 743 on human ovarian carcinoma xenografts have been studied. ⁴²⁶