Nat. Prod. Rep., 2002, 19(3), 332 - 356   DOI: 10.1039/b009713f	Review Article
-Phenylethylamines and the isoquinoline alkaloids

Kenneth W. Bentley
Marrview, Tillybirloch, Midmar, Aberdeenshire, UK AB51 7PS

Contents
1	-Phenylethylamines
2	Isoquinolines
3	Naphthylisoquinolines
4	Benzylisoquinolines
5	Bisbenzylisoquinolines
6	Benzopyrrocolines
7	Pavines and isopavines
8	Berberines and tetrahydroberberines
9	Protopines
10	Phthalide–isoquinolines
11	Spirobenzylisoquinolines
12	Rhoeadines
13	Benzophenanthridines
14	Emetine and related alkaloids
15	Aporphinoid alkaloids
15.1	Proaporphines
15.2	Aporphines
15.3	Oxoaporphines
15.4	Dioxoaporphines
15.5	Aristolochic acids
15.6	Aristolactams
15.7	Azafluoranthenes and related tropolones
16	Alkaloids of the morphine group
17	Phenethylisoquinolines
18	Colchicine and related alkaloids
19	Erythrina alkaloids
19.1	Erythrinanes
19.2	Homoerythrinanes
19.3	Cephalotaxine and related alkaloids
20	Other isoquinolines

Covering: July 2000 to June 2001. Previous review: Nat. Prod. Rep., 2001, 18, 148

This review covers -phenylethylamines and isoquinoline alkaloids that are derived from them, including further products of oxidation, condensation with formaldehyde and rearrangement, some of which do not contain an isoquinoline system, together with naphthylisoquinoline alkaloids, which have a different biogenetic origin. The occurrence of the alkaloids, with the structures of new bases, together with their reactions, syntheses and biological activities are reported. The literature from July 2000 to June 2001 is reviewed, with 495 references cited.

-Phenylethylamines and amides have been isolated from the following plant species, the eleven marked with asterisks being new alkaloids:

Allium tuberosum¹

N-cis-feruloyldopamine (tuberosine A)* 1, N-trans-feruloyldopamine (tuberosine B)* 2 and N-trans-coumaroyltyramine* 3

Annona glabra²

N-trans-coumaroyltyramine and N-trans-feruloyltyramine

Aristolochia mollissima³

N-cis-coumaroyltyramine* 4 and N-trans-coumaroyltyramine

Balanites aegyptica⁴

N-cis-feruloyltyramine and N-trans-feruloyltyramine

Mollinedia marliae⁵

N-trans-feruloyltyramine

Paliurus ramossisimus⁶

paliurine A* 5a, paliurine B* 5b, paliurine C* 6, paliurine D* 7a, paliurine E* 7b and paliurine F* 8

Turbinicarpus alonsoi⁷

hordenine, N,O,O-trimethyldopamine and N-methyltyramine

Zanthoxylum integrifolium⁸

alfileramine and integramine* 10

Of the new alkaloids integramine 10 can be regarded as the product of Hofmann degradation of alfileramine and the paliurines (above) have obvious structural similarities to integerrimine 9 and waltherines A, B and C, reported in the previous review though, unlike these four compounds, they are not derived from tyrosine.

The chromium tricarbonyl complex of 1,2,3-trimethoxybenzene reacts with the anion of acetonitrile to give, after removal of the chromium tricarbonyl, the nitrile 11a, which can be reduced to mescaline 11b.⁹

The tartrate esters of ephedrine and pseudoephedrine have been found to be useful derivatives for the resolution of synthetic racemic mixtures of these alkaloids.¹⁰ Ephedrine has been acylated at the amino group rather than at the hydroxy group by N-acetylaminobenzenesulfonyl chloride¹¹ and by 4-nitrobenzoyl chloride.¹² Reduction of the dibenzylaminopropiophenone 12 with borane has afforded 80% excess of the erythro alcohol, hydrogenolytic cleavage of which yielded¹⁸ fluoronorephedrine 13.¹³ Methods of estimating ephedrine and of norephedrine in plasma have been reported.¹⁴

The pharmacological properties and physiological effects of ephedrine^15–18 and of pseudoephedrine^19–21 have been studied.

Simple isoquinoline alkaloids have been isolated from the following plant species:

Alangium lamarckii²²

salsoline

Annona purpurea²³

thalifoline

Iseia luxurians²⁴

iseluxine 14

Turbinicarpus alonsoi⁷

pellotine

Iseluxine, which is a new alkaloid, is the first of this group to be found with unsubstituted hydroxy groups at positions 6 and 7 and is a simple product of cyclisation of dopamine.

2-Bromohomoveratric aldehyde 15 has been condensed with the amino-alcohol 16 to give the cyclic carbinolamine ether 17, reduction of which afforded the amino alcohol 18. This has been further condensed with a variety of aldehydes to give the cyclic carbinolamine ethers 19a–19e, which have been cyclised by butyllithium, followed by a Lewis acid, to give the (1R)-tetrahydroquinolines 20 in three-fold excess over their (1S) isomers. The (1R) compounds derived from 19b–19e have been further converted into (R)-carnegine 21b, (R)-O-methylarmepavine 21c, (R)-laudanosine 21d and (R)-homolaudanosine 21e and the non-chiral O-methylcorpalline 21a has been prepared in the same way.²⁵

The imine 22, prepared from 2-allylveratraldehyde and 4-methoxy-1-naphthyltyramine, on treatment with methyllithium in the presence of the chiral ligand 23 forms, through a three-component complex, the (R) chiral amine 24. Hydroboration of this affords the alcohol 25, which can be cyclised to the tetrahydroisoquinoline 26a. This can be cleaved by ammonium cerium^III nitrate and acetic anhydride to 26b, hydrolysis of which yields (R)-salsolidine 26c.²⁶ A synthesis of (S)-salsolidine 27 in 86% enantiomeric excess has been achieved by an enantioselective protonation of the related lithium salt in the presence of the chiral amine 28.²⁷ A simple tetrahydrooxazaphenalene lactone containing the ABC ring system of the alkaloid stephaoxocanine 29 and the related excentricine has been synthesised.²⁸

Syntheses of the isomeric 4-aryltetrahydroisoquinoline alkaloids cherylline 30a and latifine 30b have been achieved by closure of the isoquinoline ring between an aryl halide and an amide enolate.²⁹

Naphthylisoquinoline alkaloids have been isolated from the following plant species, the ten marked with asterisks being new alkaloids:

Ancistrocladus ealaensis³⁰

ancistroealaine A* 31 and ancistroealaine B* 32

Ancistrocladus likoko³¹

ancistrolikokine A* 33, ancistrolikokine B* 34, ancistrolikokine C* 34 and korupensamine A

Ancistrocladus tectorius³²

ancistrotectoriline A* 36, ancistrotectoriline B* 37, 6-O-methyl-4-O-demethylancistrocladine* 38 and 6-O-methyl-4-Odemethylhamatine* 39

Triphyophyllum peltatum³³

dioncophylline D, 8-O-methyldioncophylline D, dioncophyllinol D and 8-O-methyldioncophyllinol D* 40a

Following the assignment of the structure 40a to 8-O-methyldioncophyllinol D, it was shown that dioncophylline D and 8-O-methyldioncophylline D have similar 7,6-coupled structures 41a and 41b respectively rather than the 7,8-coupled structures previously assigned to these alkaloids. Similarly dioncophyllinol D has been reformulated as 40b.³³

Jozipeltine A 44, a dimer of dioncopeltine A 42a not so far encountered in plants, has been prepared. Oxidation of N,O-dibenzyldioncopeltine A 42b with silver oxide gave the quinone 43, which was reduced to the diphenol and debenzylated to jozipeltine A 44. This compound shows greatly enhanced antimalarial activity compared with dioncopeltine A, its IC₅₀ against Plasmodium falciparum being 42 ng ml^–1.³⁴ A new, nonsymmetric 6,8-dimer, jozimine B 46 has been prepared in good yield by the nonphenolic oxidative dimerisation of ancistrocladine 45 by lead tetraacetate and boron trifluoride; the imine 47 is also produced as a minor product in this reaction. This dimer also has greatly enhanced antimalarial activity compared with its parent monomer.³⁵ Lead tetraacetate and phenyliodine^III bis(trifluoroacetate) have been used to achieve a convenient one-step dimerisation of dioncophylline B 48 to the unnatural dimer jozimine D 49, of korupensamine A to michellamine A and of korupensamine B to michellamine C.³⁶

The chromium carbonyl complex 50a has been combined with the naphthylboronic acid 51 to give, after removal of the chromium carbonyl, the phenylnaphthalene 52, the cyclic ketal of which was opened to give 53a, which was converted through 53b into 54a, 54b and 54c. Bischler–Napieralsky cyclisation of 54c afforded the dihydroisoquinoline 55, which was reduced to O,O-dimethylkorupensamine A, 56a and its C-1 epimer.³⁷ A similar sequence of reactions starting from 50b gave, after removal of the isopropyl groups, korupensamine A 56b and its C-1 epimer.³⁸ The amine 57 has been converted into a mixture of the tetrahydroisoquinolines 58 and 59 and 58 has been further converted through 60a, 60b and 60c into the 7-bromo compound 61. Coupling of this with the tributylstannylnaphthalene 62 by the Stille process afforded N-benzyl-O,O-bis(methoxymethyl)dioncophylline B 63, which was hydrolysed and debenzylated to dioncophylline B 48.³⁹

1-Benzylisoquinoline alkaloids have been isolated from the following plant species, that marked with an asterisk being a new alkaloid:

Annona purpurea²³

reticuline

Hernandia nymphaefolia⁴⁰

reticuline

Isopyrum thalictroides⁴¹

reticuline

Miliusa velutina⁴²

reticuline

Monodora junodii⁴³

norgorchacoine* 64

Papaver triniifolium⁴⁴

crykonisine

The structures of polysignine 67a and methoxypolysignine 67b have been confirmed by their preparations from O-methylarmepavine 65a and laudanosine 65b by the treatment of these alkaloids with methyl chloroformate, followed by reduction of the resulting carbamates 66a and 66b catalytically and with lithium aluminium hydride.⁴⁵

Nitration of N-formylnorlaudanosine 68 with nitric and acetic acids has afforded the dinitro compound 69, together with the simpler compounds 74 and 75. Direct nitration at C-5 and C-2 with hydrolysis of the C-6 methoxy group to give 69 is unexceptional, but compounds 74 and 75 must be formed by scission of the isoquinoline system, presumably through the intermediate 70, which could then suffer ring opening to the iminium salt 72, hydrolysis of which would give 74 and 75. The possibility that the dinitro compound could be 71, formed by recyclisation of the iminium salt 72ortho rather than para to the methoxy group, was eliminated by studies of NMR spectra.⁴⁶

Reaction of the lithium salt of 3,4-dimethoxybenzyl 1-methoxy-2-naphthyl sulfoxide with 6,7-dimethoxy-3,4-dihydroquinoline N-oxide has given the hydroxamine 76, from which (±)-laudanosine 65b was prepared by reduction.⁴⁷ (R)-(+)-Laudanosine 21d has been synthesised from 19d (see section 2).²⁵ 1,2-Dehydrolaudanosine hydrochloride reacts with the bromoketone 78 to give the pyrroloisoquinoline 79a, which may be converted into the aldehyde 79b, by the Vilsmeier reaction. Hydrolyis of the methanesulfonyl ester 79b yields the hemiacetal 80, mild oxidation of which affords O,O,O-trimethyllamellarin G 81. Oxidation of 80 with manganese dioxide gives only a poor yield of 81, the main product being the quinone 82.⁴⁸

The pharmacological properties and physiological effects of papaverine^49–54 and of atracurium^55–57 have been studied.

Bisbenzylisoquinolione alkaloids have been isolated from the following plant species, the nine marked with asterisks being new alkaloids:

Guatteria boliviana⁵⁸

(–)-antioquine* 83, guatteboline*84, pangkorimine, philogaline*85, puertogaline A* 86a, puertogaline B* 86b and sepeerine

Hernandia nymphaefolia⁴⁰

thalicarpine and vateamine 2-N-oxide

Isolona ghesquireina⁵⁹

chondrofoline, (–)-curine and isochondodendrine

Isopyrum thalictroides⁴¹

isopyruthaldine* 87, isopythaldine*88 and isothalmidine* 89

Sciadotenia toxifera⁶⁰

cavanine* 90

Thalictrum orientale⁶¹

fangchinoline

(–)-Antioquine is a new alkaloid, although the (+)-isomer has been encountered previously. The structures of the new alkaloids of the group have been determined on the basis of their NMR spectra and optical properties alone. The structures assigned to the alkaloids of Isopyrum thalictroides bear no obvious relationship to those of other alkaloids recently isolated from the same species. Isothalmidine 89 is the first bisbenzylisoquinoline to be reported with a head-to-tail biphenyl linkage. Isopyruthaldine 87 and isopythaldine 88 are likewise unusual in that they purportedly are tail-to-tail diners linked through a methylene group rather than directly or through oxygen as in all other cases. Presumably their biogenesis must involve condensation of two different benzylisoquinolines with formaldehyde or equivalent. Their nearest structural analogues are the head-to-tail dimers cycloatjehine and cycloatjehenine, in which the units are linked through -O-CH₂-. Further study of the of the structures of these alkaloids would be welcome.

A review of the bisbenzylisoquinoline alkaloids has ben published.⁶² The pharmacological properties and physiological effects of (–)-antioquine,⁵⁸ of cepharanthine,^64,65 of chondrofoline,⁵⁹ of curine,⁵⁹ of isochondodendrine,⁵⁹ of guatteboline,⁵⁸ of N-methylberbamine,⁶³ of philogaline,⁵⁸ of puertogalines A and B,⁵⁸ of tetrandrine,^66–80 of tiliacorine,⁸¹ and of tubocurarine^82–85 have been studied.

The 2-bromobenzyl-3,4-dihydroisoquinolines 91a and 91b have been cyclised, by heating with potassium carbonate, to the indolo[2,1-a]dihydroisoquinolinium salts 92a and 92b, which have been reduced catalytically and N-methylated to the benzopyrrocoline alkaloids (±)-cryptaustoline 93a and (±)-cryptowoline 93b.⁸⁶

Bromination of papaverine 94a to 2-bromopapaverine 94b, followed by reduction with tributyltin hydride, gave 2-bromo-1,2-dihydropapaverine 95a, which with ethyl chloroformate gave the carbamate 95b. This was cyclised by tetraphenylpalladium in the presence of sodium formate to N-ethoxycarbonylpavine 96a, which was reduced by lithium aluminium hydride to (±)-argemonine 96b.⁸⁷ In a related process the same alkaloid was synthesised from the methiodide of 94b by a radical cyclisation, followed by reduction and N-methylation.⁸⁸

Alkaloids of the berberine group have been isolated from the following plant species, the two marked by asterisks being new alkaloids:

Annona glabra²

dehydrocorydalmine and kikemanine

Asteropyrum cavaleriei⁸⁹

berberine, berberubine and palmatine

Isopyrum thalictroides⁴¹

columbamine and palmatine

Lindera glauca⁹⁰

canadine (tetrahydroberberine)

Papaver triniifolium⁴⁴

cheilanthifoline, isocorypalmine, sinactine and N-methylsinactine

Polyalthia longifolia⁹¹

8-oxopolyalthiaine* 97

Rollinia leptopetala^92,93

discretamine and tetrahydrojatrorrhizine

Thalictrum acutifolium⁹⁴

acutiaporberine* 98

Thalictrum orientale⁶¹

berberine

Zanthoxylum taediosum⁹⁵

isocorypalmine, kikemanine, scoulerine, tetrahydropalmatine and cis-N-methyltetrahydropalmatine

Acutiaporberine 98 is the first reported example of a dimer of an aporphine alkaloid and a tetrahydroberberine alkaloid similar to the bisbenylisoquinolines, aporphine–benzylisoquinoline dimers and aporphine dimers.

The influence of various media on the fluorescence of berberine chloride and implications for assays of the alkaloid⁹⁶ and the absorption and reduction of berberine at the mercury electrode⁹⁷ have been studied.

trans-Canadine N-oxide 99, when subjected to the Polonovski–Potier reaction has been shown to give a mixture of 7,8-dehydrocanadine 100 and the isomeric 13,14-dehydro compound 101, but in the presence of potassium cyanide 8-cyano-canadine 102a is formed. Both 8-cyanocanadine and 7,8-dehydrocanadine on treatment with methyl iodide yield 8-methylcanadine 102b Under similar conditions, in the absence or presence of potassium cyanide, cis-canadine N-oxide 103 gives only 7,8-dehydrocanadine 100, though on neutralisation of the reaction product small amounts of 5-hydroxycanadine 104a and 5-hydroxycanadine 104b are also formed. Similar results have been obtained with the N-oxides of thalictricavine and xylopinine.⁹⁸

The treatment of the 2-bromobenzyltetrahydroisoquinoline 105a with n-butyllithium affords the tetrahydroberberine 107a. 8-Oxotetrahydropalmatine 106, though not isolated from the reaction products, is assumed to be an intermediate in this reaction since it independently reacts very rapidly with n-butyllithium to give 107a in high yield. Under similar conditions 105a reacts with tert-butyllithium to give only 108 and with sec-butyllithium to give the analogue of 108, together with 109. With methyllithium 105a yields 107b, which is reduced by sodium borohydride to 110a. In a similar manner (±)-coralydine 110b has been prepared from 105b.⁹⁹

The 3-methoxytetrahydroisoquinoline 111 reacts with O-methyleugenol 112 and boron trifluoride to give 113, which may be oxidised by osmium tetroxide to the diol 114 and then further by periodic acid to the aldehyde 115a. Reduction of this to the alcohol 115b, followed by hydrolysis and debenzylation affords the amino-alcohol 116, which is cyclised to (±)-schefferine 117 by the Mitsunobu reaction.¹⁰⁰ 2-(2-Bromophenylethyl)isocarbostyrils 118 have been cyclised to 8-oxoberberines 119 in good yield by tributyltin hydride.⁸⁸

The pharmacological properties and physiological effects of berberine,^101–109 of canadine,^110,111 of stepholidine,^110,112 of tetrahydropalmatine^113–115 and of benzyltetrahydropalmatine¹¹⁶ have been studied.

Alkaloids of the protopine group have been isolated from the following plant species:

Glaucium corniculatum¹¹⁷

allocryptopine and protopine

Glaucium flavum¹¹⁷

allocryptopine and protopine

Zanthoxylum integrifolium⁸

allocryptopine and pseudoprotopine

-Narcotine has been isolated from Papaver triniifolium.⁴⁴N-Substituted derivatives of nornarcotine, such as 120, have been prepared as potential adjuvants for vaccines¹¹⁸ and simpler analogues, such as 121, have been shown to act as modulators of the GABA_A receptor.¹¹⁹

The physiological effects of bicuculline have been studied.^120–126

The new alkaloid 8-O-acetylcorysolidine 122 has been isolated, together with corysolidine and isoochotensine, from Corydalis ochotensis.¹²⁷

Rhoeadine, rhoeagenine, oreodine and oreogenine have been isolated from Papaver triniifolium, together with the new alkaloids O-ethylrhoeagenine 123a and O-ethyloreogenine 123b, which may be artefacts.⁴⁴

Benzophenanthridine alkaloids have been isolated from the following plants species, that marked with an asterisk being a new alkaloid:

Corydalis incisa¹²⁸

corynoline, acetylcorynoline, 6-oxocorynoline, corynoloxine, 12-hydroxycorynoloxine* 124 and luguine

Glaucium flavum¹¹⁷

chlerythrine and sanguinarine

The conformation of chelidonine in deuteriochloroform has been studied by NMR spectroscopy.¹²⁹O-(4-[¹⁸F]-Fluorobenzoyl)chelidonine has been prepared for possible use as an antitumour agent.¹³⁰

Reaction of the iododimethoxybenzoic acid 125a with the naphthylamine 126 gives the amide 127a, the methoxymethyl derivative of which 127b is cyclised in good yield by palladium^II acetate and triphenylphosphine to the benzophenanthridine 128a, together with a small amount of the alternative benzazepine 129.^131,132 The lactam 128a may be hydrolysed to 128b, which is convertible through 131 into norchelerythrine 130a by previously described methods. The trifluoromethylsulfonyloxy group has been shown to be as good a leaving group as iodine in this process.¹³¹ Nornitidine 131b may be prepared in a similar manner from 125b.^131,132 A similar cyclisation of 127c yields 128c, which has been converted into chelerythrine 132.¹³³ In approaches to alternative syntheses of benzophenanthridine alkaloids the isoquinolone 133 has been cyclised by acids to the simple unsubstitued analogue of 128c.¹³⁴

The physiological effects of chelerythrine¹³⁵ and of sanguinarine^136,137 have been studied.

Alangiside, alangine 134, cephaeline, 2-N-(1-deoxy-D-fructopyranosyl)-cephaeline, 10-O-demethylcephaeline, isocephaeline, neocephaeline, protoemetine, protoemetinol, psychotrine, tubulosine, 1,2-dehydrotubulosine, deoxytubulosine and isotubulosine have been isolated from Alangium lamarckii.²² Alangine is reported as an alkaloid for the first time. In the last review the structure 134 was incorrectly assigned to neocephaeline.

The proaporphine alkaloid stepharine has been isolated from Annona glabra² and from Annona purpurea²³ and the new alkaloid promucosine 135 has been isolated from Annona purpurea.²³

Aporphine alkaloids have been isolated from the following plant species, the nine marked with asterisks being new alkaloids:

anonaine, N-formylanonaine, annobraine*136a, nordomesticine and nornuciferine

apoglaziovine, isocorydine, lirindine, norglaucine, norpurpureine, northalbaicaline, romucosine F* 137, romucosine G* 138 and thalicsimidine

magnoflorine

xylopine and N-acetylxylopine

corydine, isocorydine, glaucine and thalicmidine

corydine, isoboldine, isocorydine and glaucine

N-(N-methylcarbamoyl)-O-methylbulbocapnine* 139, hernandaline and laurotetanine

isocorydine

lettowianthine* 136a and 11-methoxylettowianthine* 136b

boldine, norboldine, nantenine and 3-chloro-N-formylnornantenine* 140

isocorydine, isocorydine-N-oxide* 141 and norcorydine

anonaine and roemerine

corydine

acutiaporberine* 98

fuzitine

Annobraine and lettowianthine, isolated from different species, have been assigned the same structure 136a. The separation and identification of the components of a mixture of nine aporphine alkaloids by a coupled system of high pressure liquid chromatography and NMR spectroscopy has been demonstrated.¹⁴²

Glaucine 142 has been demethylated by hydrobromic acid at room temperature to a mixture of lirioferine 143a, thaliporphine 144a, N-methyllaurotetanine 144b and bracteoline 143b, though better yields were obtained at elevated temperatures.¹⁴³ Bischler–Napieralsky ring closure of the amide 145 has given the dihydroisoquinolinium salt 146, which was reduced to 147a, and on treatment with methyl chloroformate this yielded 147b, which was cyclised by tributyltin hydride to give (±)-cathaformine 148.¹⁴⁴ The efficacy of various oxidising agents in the dimerisation of dehydrowilsonirine 149 to bipowine 150 and the further oxidation of this to the extended quinone bipowinone 151 have been studied.¹⁴⁵

The pharmacological properties and physiological effects of boldine,^146–149 of dicentrine,¹⁵⁰ of nantenine and of apomorphine^151–169 have been studied. Two glucuronides of apomorphine have been prepared¹⁷⁰ and several (R)-aporphines related to apomorphine have been prepared by ring expansion of the ketone 152 in the quest for activity at serotonin 5-HT_1A and 5-HT₇ and dopamine D_2A receptors.¹⁷¹

Oxoaporphine alkaloids have been isolated from the following plant species, the three marked with asterisks being new alkaloids:

liriodenine and lysicamine

liriodenine, lysicamine, oxoglaucine and oxopurpureine

atherospermidine, fissiceine* 153, liriodenine, kuafumine, oxocrebanine and oxoglaucine

corunnine

lanuginosine

oxohernangine

lysicamine

liriodenine

dicentrinone, liriodenine, N-methyliriodendronine 154a and N,2-O-dimethylliriodendronine 154b

Dioxoaporphine alkaloids have been isolated from the following plant species:

cepharadione A and 4,5-dioxodehydroasimilobine

noraristolodine and norcepharadione B

noraristolodione and norcepharadione B

noraristolodione and norcepharadione B

Aristolochic acids and their esters have been isolated from the following plant species, that marked with an asterisk being a new acid:

7-hydroxyaristolochic acid* 155 and aristolochic acid III methyl ester

aristolochic acid Ia methyl ester

aristolochic acids I, II and IVa, aristoloterpenates I and III and aristophyllide A

Aristolactams have been isolated from the following plant species, the three marked with asterisks being new alkaloids:

cepharanone C* 156

aristoliukine C

aristolactam N--D-glucoside, aristolactams AII and AIIIa, aristolactam C N--D-glucoside* 157 and aristoliukines A and B

aristolactams AII, AIIIa, BII, BIII, and FII, enterocarpam I, goniothalactam, piperolactams A and C and stigmalactam* 158

aristolactams AII, BII and BIII, goniothalactam and piperolactam A

aristolactams AII, AIIIa, BII, BIII and FII, enterocarpam I, goniothalactam, piperolactams A and C and stigmalactam 158

Syntheses of the tropolone alkaloids imerubrine, isoimerubrine and grandirubrine have been achieved starting from 5,6,7-trimethoxyisoquinoline, following a successful synthesis of colchicine by similar methods (section 18). The isoquinoline 159a was converted through 159b, into the Reissert compound 160a, which was reduced and hydrolysed to 160b and this was converted by stages into the furan 161. A [4+3]cycloaddition of 3,3-dimethoxy-2-trimethylsilyloxypropene to 161 yielded a mixture of the adducts 162a and 163 and of these 162a suffered a ready elimination to the tropolone ether imerubrine 164, though a similar reaction could not be achieved with 163. Reaction of the furan 161 with 1,1,3-trichloropropanone, followed by reduction, gave the bridged cycloheptenone 165, from which the oxygen was eliminated to give the cycloheptatrienone 166. Oxidation of 165 with phenyliodine^III diacetate in methanolic potassium hydroxide afforded the dimethyl ketal of 162b, which was hydrolysed to 162b and elimination of the oxygen bridge from this yielded grandirubrine 167a. Methylation of grandirubrine afforded a mixture of imerubrine 164 and isoimerubrine 167b. O-Methylation of the dimethyl ketal of 162b, followed by hydrolysis, afforded a route to 162a without the formation of 163.¹⁷⁵

Pallidine, norpallidine and O-methylflavinantine have been isolated from Annona purpurea²³ and O-methylflavinantine has also been isolated from Croton menthodorus.¹⁷⁶ Hyserpine, a new alkaloid that may be regarded as a degradation product of hasubanonine, isolated from Hyserpa neocaledonica, is described in section 20.

Methods of estimating morphine,^177–179 esters of morphine,¹⁸⁰ buprenorphine,^181,182 norbuprenorphine,¹⁸² naltrexone¹⁸³ and naltrexol¹⁸³ have been described.

Photochemical N-demethylation of 14-acetoxycodeinone 168a in the presence of oxygen and tetraphenylporphin has been achieved with O,N-acyl migration to give N-acetyl-14-hydroxycodeinone 168b.¹⁸⁴ 1-Fluorocodeine 169a and 1-fluorodihydrocodeine have been prepared by the thermolysis of the diazonium fluoroborates derived from 1-aminocodeine 169b and 1-aminodihydrocodeine.¹⁸⁵ The 3-hydroxy group in morphine has been replaced by a series of amino groups. Morphine 170a was converted into the 3,6-tert-butyldiphenylsilyl ether 170b, which was hydrolysed to the 6-ether 170cc. The trifluoromethanesulfonyl ester of this 171, on heating with amines and sodium tert-butoxide suffered replacement of the ester group and desilylation of the products yielded the 3-amino-3-deoxymorphines 172a–172e.¹⁸⁶ Oxidation of 3-O-methylnaloxone with ammonium cerium^III nitrate has given 10-hydroxy-3-O-methylnaloxone 173 which on further oxidation yielded 10-oxo-3-O-methylnaloxone 174a, which was demethylated to 10-oxonaloxone 174b.¹⁸⁷ The preparation and use of these compounds and their 14-deoxy analogues has been covered by a patent.¹⁸⁸ The 14-aminodihydrocodeinone derivative 175a has been converted through 175b into 175c, the phenyltetrazolyl ether of which was cleaved to give 176. This was hydrolysed and converted into the amide 177.¹⁸⁹

Photochemical oxidation of thebaine affords the enedione-aldehyde 180 together with a smaller amount of the benzofuran 181. These compounds are believed to arise by the addition of singlet oxygen to the diene system of the alkaloid to give 178, which collapses through the related iminium salt to the enamine 179, followed by hydrolysis to 180. This enedione is stable to heat and is converted into the benzofuran 181 by a non-oxidative photochemical cleavage rather than by a retro Diels–Alder reaction. The enedione 180 is reduced by sodium borohydride in methanol to both diastereoisomers of the triol 182, catalytically to the alcohol 183 and finally to the isomers of the triol 184a, and by sodium borohydride and boron trifluoride to the alcohols 184b and 184c. The acetal 185 has been isomerised to the ketal 186, also available directly from 180, which is reduced by sodium borohydride to the disatereoisomeric alcohols 187. Sodium borohydride and boron trifluoride reduce the cis-diol 182 to a mixture of the cis-diol 184c and the alcohol 188. Although the 6,14-peroxide 178 has not been isolated from the oxidation of thebaine its quaternary N-methyl trifluoromethanesulfonate, which is stable at room temperature over an extended period, has been obtained by the photo-oxidation of N-methylthebaine trifluoromethanesulfonate. This peroxide is converted by warm trifluoroacetic acid into the quaternary salt 189b of 14-hydroxycodeinone and the hydroperoxide 189a has been spectroscopically identified as an intermediate in this hydrolysis.¹⁹⁰

The 7-ketone 190 and its 7-epimer have been equilibrated to a 2 1 mixture of the two by perchloric acid. The related tert-butyl ketones are similarly equilibrated to an equimolecular mixture. This equilibration occurs during the Schmidt reaction of the ketone 190 with perchloric acid and sodium azide, which gives a 2 1 mixture of the amide 191 and its 7-isomer.¹⁹¹

Details of the preparation of the following have been published: morphine 6-glucuronide,¹⁹² dihydromorphinone,¹⁹³ dihydrocodeinone,¹⁹³ 14-hydroxycodeinone,¹⁹⁰ 14-hydroxydihydrocodeinone,¹⁹⁴ hydrazones of general structure 192, derived from N-aminonorcodeine,¹⁹⁵ naltrexone O,O-distearate¹⁹⁶ the amide 193, derived from -naltrexamine,¹⁹⁷ pyrroles of general structures 194a and 194b,¹⁹⁸ the indoles 195¹⁹⁹ and 196,²⁰⁰ thiophenes, pyridines and quinolines of general structures 197,²⁰¹198, 199,²⁰² and 200,²⁰³ the normorphine derivative 201,²⁰⁴ dehydrobuprenorphine 202,²⁰⁵ alkyl ethers of alcohols of general structure 203,²⁰⁶ the phenols 204²⁰⁷ and 205,²⁰⁸ the amides 206, 207,²⁰⁹ and 208²¹⁰ and the quaternary indolinodeoxycodeine salt 209.²¹¹

Alternative approaches to intermediates in previously reported syntheses of morphine and its derivatives have been discussed,^212–214 and syntheses of the alkaloid have been reviewed.^215,216

The analgesic properties,^217–277 the pharmacokinetics and the metabolism^278–281 of morphine have been studied, as have the effects of the alkaloid on behaviour,^{234,282–295} on immune responses,^296–301 on the brain,³⁰² on the cardiovascular system,^303,304 on the gastrointestinal tract,^305–309 on neurones,^310–316 on blood cells,^317–320 on the regulation of temperature,^321,322 on respiration,³²³ on locomotor activity,^324,325 on the intake of food,³²⁶ on the thalamus,³²⁷ on the pituitary gland,³⁰¹ on the spinal cord,³²⁸ and spinal injuries,³²⁹ on lung receptors,³³⁰ on the foetus,³³¹ on the newborn,³³² on the utilisation of glucose,³³³ on the intake of saccharin,³³⁴ on pruritus,^335,336 on peritonitis,³³⁷ on feline immunodeficiency virus,³³⁸ on intracellular pH,³³⁹ on macrophage apoptosis,³⁴⁰ on calcium channels,³⁴¹ on adrenoreceptors,³⁴² on nicotinic receptors,³⁴³ on messenger RNA,^344–346 on nitrite production,^347–349 on gene expression,^350,351 on susceptibility to Salmonella typhimurum,³⁵² on levels of dopamine,³⁵³ of opioid peptides,³⁵⁴ of calcitonin,³⁵⁵ of corticosterone,³⁵⁶ of interleukins,^356,357 of oxytocin^358,359 and of substance P³⁵⁵ and on the effects of apomorphine,³⁶⁰ of amikacin,³⁶¹ of caffeine,³⁶² of cocaine,³⁶³ of N-methyl-3,4-methylenedioxyamphetamine,³⁶³ and of naloxone.³⁶⁴

The morphine-antagonist actions of naloxone have been studied,^365–369 as have the effects of this compound on behaviour,³⁶⁶ on the development of tolerance to morphine,³⁷⁰ on neurones,^371–375 on brain injuries,³⁷⁶ on cerebral blood flow,³⁷⁷ on reflexes,^378,379 on the spinal cord,³⁸⁰ on the cardiovascular system,³⁸¹ on lactate and pyruvate metabolism,³⁸² on antoxidant enzyme activity,³⁸² on levels of adrenocorticotropin,³⁸³ and of dopamine,³⁸⁴ and on the effects of amikacin,³⁶¹ of buprenorphine,³⁸⁵ of diazepam,³⁸⁶ of methotrexate³⁸⁶ and of pentobarbital.³⁸⁶

The pharmacological properties and physiological effects of the following have also been studied: O,O-diacetylmorphine (heroin),^387–404 morphine 3-glucuronide,^278,405 morphine 6-glucuronide,^{278,326,406,407} dihydromorphinone,^408,409 14-hydroxydihydromorphinone,⁴¹⁰ codeine,^411–418 dihydrocodeinone,⁴¹⁷ naltrexone,^{410,419–431} methylnaltrexone,⁴³² naloxone benzylhydrazone,⁴³³ nalbuphine,^434–436 nalmefene,^437–441 naltrindole,⁴⁴² 5-guanidinonaltrindole,⁴⁴³ 7-(2,3-diformylphenylcarboxamido)naltrindole [7-(phthalaldehydecarboxamido)naltrindole],⁴⁴⁴-funaltrexamine,⁴⁴⁵ norbinaltorphimine,⁴⁴⁶ etorphine,^447,448 dihydroetorphine,^449,450 buprenorphine,^{434,451–459}O-methylflavinantine,¹⁷⁶ and (+)-morphine.⁴⁶⁰

A review of the use of opiates in medicine has also been published.⁴⁶¹

(R)-Homolaudanosine 21e has been synthesised from 19e as described in section 2.²⁵

Atropisomeric colchicinoids have been prepared for the first time. Isocolchicine 210a and its relatives 210b and 210c, on treatment with ammonia and with amines, gives the atropisomeric amines 211 and 212, which in some cases are stable and in others are rapidly equilibrated. The isomers have been distinguished by their dichroic properties. Colchicine 213a, under similar conditions, affords the regioisomeric amines 214 and 215.⁴⁶²

9-Tolylsulfonyloxycolchicoside 210c reacts rapidly with the anion of dimethyl malonate in dimethyl sulfoxide to give the lactone 216, whereas the isomeric 10-tolylsulfonyloxy compound 213b reacts very slowly under identical conditions to give the isomeric lactone 217. Neither of these reactions occurs in hydroxylic solvents.⁴⁶³

A synthesis of colchicine 213a has been achieved from the alcohol 218a. This was converted into the acetylene 218b which was converted into the oxazole 219a and this was further converted through 219b and 219c into the furan 220a, also available by an alternative, though similar, route. The furan 220a was converted into the related 220b, which underwent a [4+3]cycloaddition reaction with the -methoxytrimethylsilyloxyallyl cation (generated in situ from the trimethylsilyl enol ether of pyruvic aldehyde) to give 221. This was smoothly cleaved to N-benzyloxycarbonyl-N-deacetylcolchicine, which was hydrolysed and acetylated to give colchicine 213a. The furan 220a also underwent [4+3]addition of 3,3-dimethoxy-2-trimethylsilyloxypropene, but the undesired regioisomer 222 was the sole product of the reaction.⁴⁶⁴

A patent for the preparation of ring-contracted colchinoids similar to colchibiphenyline 223a and salimine 223b of general structure 223 has been published.⁴⁶⁵

The physiological effects and other properties of colchicine have been studied.^466–477

The isomeric 15 and 16 -D-glucosides of erysopine have been isolated for the first time, together with erysodine -D-glucoside, erysotramidine, erysotrine, erysovine, erythraline and 8-oxoerythraline, from Erythrina latissima.⁴⁷⁸

A modified synthesis of (±)-erysotrine 228, with a three-fold increase in overall yield, has been reported. Diels–Alder addition of the dioxopyrroline 224 to 1-methoxy-3-trimethylsilyloxybutadiene, followed by reduction of the adduct with lithium borohydride and hydrolysis, afforded the erythrinane 225, which was converted into 226. Reduction of this with sodium borohydride gave the 3-alcohol 227a and its 3-isomer in a 9 1 ratio. O-Methylation of 227a gave (±)-erysotramidine 227b, which was reduced by lithium aluminium hydride to (±)-erysotrine 228. Peracid oxidation of 227a yielded the 4,5 -epoxide 229a, the methyl ether of which 229b was converted by samarium^II iodide into the allylic alcohol 230, which was reduced by lithium aluminium hydride and aluminium chloride to (±)-erythatidine 231 (80%) and (±)-erysotrine 228 (16%). The epoxide 229b could not be prepared from erysotramidine 227b The dienone 226 was oxidised by alkaline hydrogen peroxide to the 4,5 and 4,5 epoxides, which were reduced to 229a and its 3-epimer and to the 4,5-epoxide isomers of these alcohols.⁴⁷⁹

In a new approach to the erythrinane ring system the methylthioacetamide 232 has been oxidised by manganese dioxide in the presence of copper^II acetate to give a mixture of 233 and 234, whereas in the presence of copper^II trifluoromethanesulfonate the product was the saturated erythrinane 235.⁴⁸⁰

The effects of -erythroidine and of dihydro--erythroidine on behaviour have been studied.⁴⁸¹

3-Epischellhammericine and 3-epitaxodine have been isolated from Cephalotaxus harringtonia.⁴⁸²

Cephalotaxine, 11-hydroxycephalotaxine, demethylcephalotaxinone, drupacine, harringtonine, deoxyharringtonine, homodeoxyharringtonine, isoharringtonine and the new alkaloids cephalezomine A 236a, cephalezomine B 236b, cephalezomine C 237a, cephalezomine D 237b, cephalezomine E 238a and cephalezomine F 238b have been isolated from Cephalotaxus harringtonia. The structures of the new alkaloids were deduced from their spectra.⁴⁸² The mono- and di-acetyl esters of 11-hydroxycephalotaxine have been prepared.⁴⁸³ An improved preparation of the -keto-acid 239, an intermediate in the synthesis of homoharringtonine, has been reported.⁴⁸⁴

The physiological and antitumour effects of homoharringtonine have been studied.^485,486

Hyserpine 240, which is not an isoquinoline but which can be regarded as a degraded hasubanonine, has been isolated from Hyserpa neocaledonica.⁴⁸⁷

Buzonamine, a defensive secretion of the millipede Buzonium crassipes, has been assigned the octahydroisoquinoline structure 241.⁴⁸⁸

Antidesmone, from Antidesmona membranaceum and A. venosum, originally assigned the tetrahydroisoquinoline structure 242, has been shown to be the pyridone 243.⁴⁸⁹

Syntheses of aaptamine 244a, N-methylaaptamine 244b, isoaaptamine 245a and its regioisomer 245b have been reported.⁴⁹⁰

Jorumycin 246, which is a relative of the saframycins, has been isolated from the marine organism Jorunna funebris.⁴⁹¹ It is a cytotoxic agent slightly less potent than the related ecteinascidin E743 247. Syntheses of analogues of the saframycins^492,493 and ecteinascidins⁴⁹⁴ and a synthesis of ecteinascidin E743 247 from cyanosafracin B⁴⁹⁵ have been reported.