Phenethylisoquinoline alkaloid

Several genera in the lily family (Liliaceae) are found to synthesize analogues of the benzylte-trahydroisoquinoline alkaloids, e.g. autumnaline 

SCHEME 12.8 Main route to morphine (24) from thebaine (35). 

SCHEME 12.9 Route toward autumnaline (45) and phenethyhsoquinoline alkaloids. 

El Autunmaline cytochrome P-450 oxidase E2 0-Methylandrocymbine methyl transferase E3 0-Methylandrocymbine cytochrome P450 oxidase [yJeO E4 A-Formyldemecolcine deformylase E5 Colchicine A-acetyl transferase 

Oxidative para-para coupling of autumnaline (45) delivers the dienone isoandrocymbine (47), which is O-methylated in the subsequent enzymatic step. This very same para-para coupling reaction has also been biosyn-thetically employed in the route to reticuline (19), key intermediate for the preparation of morphine and other important tyrosine-derived alkaloids (see Section 12.2.3). Next, the tropolone ring is established via the aforementioned skeletal rearrangement. Most likely, this process is achieved by a cytochrome P-450-mediated oxidation with subsequent formation of an intermediary cyclopropane ring 

Because of the unprecedented tropolone ring, the structure elucidation of colchicine has been a highly challenging problem. In 1945, 125 years after its isolation, Dewar proposed the correct structure for this important alkaloid [36], which was confirmed by X-ray analysis a few years later [37]. The elucidation of the biosynthetic ronte proved to be equally troublesome. The currently accepted biosynthetic route has been deduced from extensive labeling experiments [38-43]. 

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Lilaceae also contain 1-phenethylisoquinoline alkaloids, it was suggested [82) that the homoerythrina derivatives are biosynthesized along a pathway analogous to that followed by the Erythrina alkaloids themselves (Scheme 35). Some preliminary results from feeding experiments (121) support this view ( )-[2-14C]tyrosine causes specific labeling of C-8 in 77a. 

Homopavinane (57) and homoisopavinane (58) ring systems represent examples of the phenethylisoquinoline alkaloid class. A synthesis of racemic... 

The chapter on phenethylisoquinoline alkaloids that appeared in Volume 14 of this treatise reviewed the literature up to the middle of 1972 (/). In the succeeding years covered in this review (1972-1988) significant advances have been made in all aspects of study regarding this family of alkaloids. 

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... 

Nearly 40 new phenethylisoquinoline alkaloids have been isolated and characterized since the last review in Volume 14 of this treatise (/). These alkaloids are listed in Table I together with their botanical sources and physical properties. 

II. Structural Elucidation, Chemical Reaction, and Stereochemistry of Phenethylisoquinoline Alkaloids... 

Of the simple phenethylisoquinoline alkaloids dysoxyline (8), (5)-(-t-)-homolaudanosine (9), and (-)-isoautumnaline (10), 8 and 9 were isolated from Dysoxylum lenticellare Gillespie (5). Alkaloid 10 was isolated from Colchicum ritchii R.B. (4). 

Although biosynthesis of the phenethylisoquinoline alkaloids has not yet been studied in full, that of androcymbines, homoaporphines, and homoerythrinans has been examined by work with radioactive tracers. In this section tracer experiments as well as hypothetical biogenetic routes in the synthesis of the phenethylisoquinoline alkaloids are discussed. 

This section describes various synthetic methods, each of which gives rise to a different type of phenethylisoquinoline alkaloid, depending on reactivity and reaction conditions. 

One-electron withdrawing inorganic reagents have been used to perform biomimetic syntheses of phenolic phenethylisoquinoline alkaloids. In order to obtain androcymbine compounds of type 85, the diphenolic isoquinoline 82a was subjected to phenol oxidation with manganese dioxide. The homoaporphine 83a coupled at the ortho-ortho position to the hydroxy group was the only product formed under these reaction... 

Since the total synthesis of O-methylandrocymbine (17) was accomplished via a photolytic cyclodehydrobromination reaction of a l-(2-bromophenethyl)-7-hydroxyisoquinoline (67), many phenethylisoquinoline alkaloids have been synthesized by this reaction. Irradiation of the bromoisoquinoline 113a,b with a Hanovia 450-W mercury lamp, using a Pyrex filter, in the presence of an excess of sodium hydroxide and sodium hydrogen sulfite gave alkaloid CC-24 (83a) (68) and the homoaporphine 114 (69), respectively. 

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