Homoaporphine synthesis

An elegant synthesis of the neurotoxic alkaloid anatoxin has exploited the electrocyclic opening of the dibromobicyclo[5.1.0]octane followed by transannular cyclization (Scheme 13).238 Similarly, the thermal electrocyclic opening of the dichlorocyclopropane followed by intramolecular trapping of the developing allylic cation by a suitably positioned amine has been used in a homoaporphine synthesis.238... 

The c-ring expansion of aporphines via the dichlorocyclopropane ring opening238 induced by LAH has been utilized in a synthesis of homoaporphine alkaloids (equation 93). Reductive cleavage of 2-silyloxy-dibromocyclopropanes gives a,(3-unsaturated ketones directly (equation 96).239... 

The readily available reagent diphenyl selenoxide has been used as a mild and selective oxidant in the synthesis of aporphines (and homoaporphines). When the benzylisoquinoline (13) was treated with one equivalent of the reagent at room temperature in methanol, and the product was O- methylated with diazomethane, the aporphine (14) was obtained in 80% yield. The alternative use of chloranil, which is a commonly used oxidant for catechols, yielded less than 10% of (14).20... 

Marino and Schwartz have exploited the selectivity of this selenoxide in an intramolecular phenolic coupling in a synthesis of aporphines and homoaporphins. 

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. 

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. 

An application of the photolytic cyclodehydrobromination reaction to bromoamide 117 gave the 11-membered ring lactams 118 and 119, which could be useful compounds for the synthesis of homoaporphines (77). Cyclization of 119 with phosphorous oxychloride in acetonitrile afforded the expected homoaporphine 120 in excellent yield (72). 

An intramolecular SrnI reaction was used as key step in the synthesis of the alkaloid 0-demethyleupoularamine 3. The intermediately formed SrnI product is readily transformed by photochemical oxidative biaryl formation and subsequent methylation to the target compound 3 in good yield (Equation 13.7) [23]. The SrnI cyclization of l-(2-bromobenzyl)-l,2,3,4-tetrahydroisoquinolin-7-ol derivatives 4 was recently applied to the synthesis of aporphine alkaloids 5 (Equation 13.8) [24] and, by using the same approach, homoaporphine alkaloids can also be synthesized. 

Scheme 14.17 Photoinduced synthesis of aporphine and homoaporphine derivatives.

A novel non-phenol oxidative coupling of phenylethyltetrahydroisoquinolines using VOF3-TFA has been developed into a useful synthesis of homoaporphines thus (34 R, = H, Me) were prepared from the corresponding phenylethyltetra-... 

Base-catalyzed photolyses of 2 -bromo-7-hydroxytetrahydrophenethyl-isoquinolines have resulted in the synthesis of the homoaporphines kreysigine " and alkaloid CC-24. ... 

The first synthesis of a homoaporphine by dienone-phenol rearrangement of a homoneoproaporphine is that of Marino and Samanen. The phen-ethyltetrahydroisoquinoline trifluoroacetamide 5 was oxidized with vanadium oxytrichloride to supply the dienone 6 This dienone upon acid-catalyzed rearrangement furnished the homoaporphine trifluoroacetamide 7 in high yield. ... 

Like carbanions and anions from aryl amines, the anions from phenols have been used in intramolecular to obtain heterocycles by C—C bond formation [87]. One example of this approach is the photostimulated reaction of the phenoxide ion linked with a pendant bromoarene by Al-substi-tuted tetrahydroisoquinoline bridge such as 122. Under this reaction condition, aporphine alkaloid derivatives 123a,b (n=1) were obtained in good yields (Eq. 10.42). This approach was extended for the first time to the synthesis of a homoaporphine alkaloid 123c (w=2) [88]. 

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