Homoproaporphine

Cyclization of (147 R = CH2Ph) by the action of trifluoroacetic acid yields androcymbine benzyl ether (148 R = CH2Ph), which has been converted into androcymbine (148 R = H) androcymbine methyl ether (148 R = Me) has been prepared from (147 R = Me) in a similar manner. Homoaporphines and homoproaporphines are produced, as well as homomorphinandienones, during this cyclization.378... 

A modification of the above procedure gave three types of products, C-homoaporphines 129-131, homoproaporphines 132 and 133 (see Section IV), and homomorphinandienones 134 and 135 (except for 118 see Section V) (57). LTA oxidation in AcOH of ( )-l-phenethyltetrahydro-isoquinolin-7-ol 117 gave a p-quinol acetate l20, TFA treatment of which in CH2CI2 produced the ( )-C-homoaporphine 129 in 44.2% yield. Similarly, the ( )-C-homoaporphines 130 and 131 were prepared in 55 and 35.2% yield, respectively, from the ( )-l-phenethyltetrahydro-isoquinolin-7-ols 118 and 119 (Scheme 15). 

As mentioned in Section III, we found that LTA oxidation in AcOH and subsequent TFA treatment of the ( )-l-phenethyltetrahydro-isoquinolin-7-ols 117 and 136 afforded ( )-l-hydroxy-2,10-dimethoxy-homoproaporphine (132) in 6.9 and 15.5% yield, respectively, which corresponded to dienone II 60, as well as ( )-C-homoaporphines 129 and 139 and ( )-homomorphinandienones 134 and 143 (see Section V) (57) (Scheme 15). The stereostructure of dienone II was determined as 197 by an X-ray crystallographic analysis of its derivative (,57,61,62). For another spiroisomer named dienone I, the naturally occurring ( )-kreysi-ginone (63), the above experiment in turn established the correct stereostructure as 198. In an analogous manner, the ( )-l-phenethyltetrahydro-isoquinolin-7-ols 137 and 138 afforded ( )-10-benzyloxy-l-hydroxy-2-methoxyhomoproaporphine (142) and ( )-12-methoxykreysiginone (133) in 11.4 and 15.9% yield, respectively, together with ( )-C-homo-aporphines 140 and 141 and ( )-homomorphinandienones 144 and 145 (see Sections III and V) (Scheme 15). 

On the other hand, LTA oxidation in a mixture of AcOH and TFA of ( )-l-phenethyltetrahydroisoquinolin-7-ols caused no appreciable improvement in the yields of ( )-homoproaporphines (57). Thus, 119 and 138 gave 133 in 15 and 10% yield, respectively. Dienone II 197 was obtained in 31 and 18% yield, respectively, from 117 and 136, whereas 142 was produced in 16% yield from 137 (Scheme 15). 

Phenethylisoquinoline alkaloids are classified into seven major alkaloid groups based on structural differences simple 1-phenethylisoquinolines (1), homomorphinanedienones (2), bisphenethylisoquinolines (3), homoproaporphines (4), homoaporphines (5), homoerythrines (6), and dibenz[benzylisoquinoline alkaloids. Although tropolone and Cephalotaxus alkaloids also belong to the... 

The oxidation of phenolic phenethylisoquinolines has been studied in some detail. With iron(iii) chloride the bases (68 R = H and R = OMe) have been oxidised to the homoproaporphine bases (69 R = H and OMe), and the base (70) has been oxidised to the homoproaporphine (71), which yielded the homoaporphine alkaloid multifloramine when subjected to dienone-phenol rearrangement. In this last process, when the dienone (71) was treated with concentrated hydrochloric acid in glacial acetic acid, the mixed acetal (72 R = Me), convertible into the hemiacetal (72 R = H), was isolated. ... 

The configuration of homoproaporphines at the spiro asymmetric centre may be deduced from circular dichroism data for the bases and their derivatives. ... 

Related work not directly dealing with total synthesis of proaporphine, aporphine, or homoproaporphine alkaloids has appeared. A series of homopro-aporphine-type compounds (110) have been prepared, as shown in Scheme 9.12 7 Compound (106), readily prepared from 3,4-dimethoxy-/ -phenethylamine and the appropriate keto-acid derivative, was transformed by reduction and acetylation to (107). Acetylation effectively blocked any complications from the cyclohexane oxygen function during the subsequent Bischler-Napieralski cyclization. Consecutive reduction, alkylation, and hydrolysis gave the key intermediate (109) which was transformed into the tetracyclic spiro-system (110) by reaction with polyphosphate ester under strictly defined conditions. Other conditions and... 

A surprising yield (60 %) of the more highly functionalized homoproaporphine derivative (112) has been obtained by the phenolic oxidative coupling reaction.128 On the other hand, application of the Pschorr sequence on (113) gave (114) as a mixture of diastereomers as well as anisaldehyde. Treatment of the diazonium salt corresponding to (113) with hypophosphorous acid also gave the diastereo-meric mixture (114) and, in addition, the deamination product and 4-methoxy-styrene.129... 

Phenethylisoquinoline alkaloids are classified into six major alkaloid groups based on structural differences, namely, simple 1-phenethyliso-quinoline (1), homomorphinandienone (2), bisphenethylisoquinoline (3), homoproaporphine (4), homoaporphine (5), and homoerythrina alkaloids (6). These alkaloids are related to the benzylisoquinoline alkaloids such as morphinandienone, bisbenzylisoquinoline, proaporphine, apor-phine, and erythrina alkaloids. Although colchicine and its derivatives also belong to the phenethylisoquinoline alkaloids group, these alkaloids are not included in this review as they have been reviewed earlier 1). 

Of the homoproaporphine alkaloids kreysiginone (19), dihydro-kreysiginone (21), and bulbocodine (22), the former two (19 and 21) were isolated from Kreysigia multiflora (2a). The last was isolated from Bulhocodium vernum (16) and its structure has been determined recently by Santavy (17). 

Although the biosynthesis of the homoproaporphines has not yet been elucidated, these alkaloids could be biosynthesized by phenolic oxidative coupling of the diphenolic isoquinoline 76. 

By analogy with the biosynthesis of several aporphine alkaloids (33-35) the homoaporphines could arise naturally by way of homoproaporphines 78a and 78b or by direct coupling of the diphenolic isoquinoline 77a. 

Diphenolic isoquinolines 100 and 101 were oxidized with ferric chloride to homoproaporphines 104 45) and 105 46), respectively, while 102 and 103 afforded the ortho dienones 106 and 107 47), respectively. 

An application of the photo-Pschorr reaction to the 2-aminoiso-quinolines 134 and 175 gave 0-benzylandrocymbine 138 which on debenzylation afforded (+ )-androcymbine (139) (58). The same reaction of diphenolio aminoisoquinoline 176, however, gave the abnormal product, homoproaporphine 93 (58), which would have been formed via the radical intermediates 178, 179, and 180, derived from the diazonium salt (177). 

Homoaporphines and Homoproaporphines.—A new homoaporphine from C. cornigerum is CC-24 (219). Photolysis of the appropriate bromotetrahydro-phenethylisoquinolines can lead to racemic multifloramine (218), kreysigine (220), or 0-methylkreysiginone (221). In each of these syntheses the bromine is situated either at C-8 or at C-2 of the tetrahydrophenethylisoquinoline precursor. ... 

The photo-Pschorr cyclization has been utilized to prepare kreysigine (220) and the homoproaporphine (222). °... 

A new method for the synthesis of reduced homoproaporphines involves Birch reduction of the phenethyltetrahydroisoquinoline (223). Further treatment with hot H3PO4 furnishes the tetracyclic species (224) (Scheme 14). ... 

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