Homoaporphines

Appropriate phenolic 1,2,3,4-tetrahydro-l-phenethylisoquinolines gave miscellaneous C-homoaporphines by the same methodology as mentioned in Section II. 

Reagents a. Pb(OAc), AcOH b. CFjCOOH, CHjCIj C. PblOAcli, CFjCOOH. AcOH 

As in the case of 1-benzyl congeners, LTA oxidation in CHaCF of ( )-1,2,3,4-tetrahydro-7-methoxy-1 -(3,4-dimethoxyphenethyl)-2-methyl-isoquinolin-6-ol (172) was found to give quantitatively o-quinol acetate 175, the structure of which was readily determined by spectroscopy. However, treatment of the unpurified o-quinol acetate 175 with acetic anhydride containing concentrated sulfuric acid produced ( )-2-acetoxy-1,10,11-trimethoxy-C-homoaporphine (178) in 25.3% yield, accompanied by a comparable amount of a biphenyl compound (181) (58). The 

It is noteworthy that when the o-quinol acetate 177 derived from 174 was treated with acetic anhydride containing concentrated sulfuric acid, the product was ( )-C-homoaporphine 180, whose stereostructure was confirmed to be 186 by X-ray crystallographic analysis of a methiodide of 180 (59). Furthermore, 186 was heated at 60°C to give a more stable stereoisomer, which should be 187. 

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Oxidative coupling of aryl tetrahydroisoquinolines. This reagent is superior to thallium(III) trifluoroacetate or vanadium oxyfluoride for nonphenolic oxidative coupling of substrates such as 2 to provide aporphines and homoaporphines (3). 

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... 

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... 

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... 

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... 

Barolo, S.M., Teng, X., Cuny, G.D. and Rossi, R.A. (2006) Syntheses of aporphine and homoaporphine alkaloids by intramolecular ortho-arylation of phenols with aryl halides via SRn1 reactions in liquid ammonia. Journal of Organic Chemistry, 71, 8493—8499. 

The oxidation of non-basic and monophenolic tetrahydrobenzylisoquinolines with VOF3-TFA is a superior method for aporphine preparation. N-Trifluoroacetylnorcodamine (32), under these conditions, gives a 70% yield of N-trifluoroacetylnorthaliporphine, while the codamine-borane complex (33) provides thaliporphine (28) in 80% yield. The reaction has also been extended to the preparation of homoaporphines.2... 

On the other hand, the B-homo analog of the enamide 267 underwent smooth photocyclization under the same conditions as above to afford the B-homoaporphine skeleton, probably because of reduced steric congestion arising from involvement of the seven-membered ring in the enamide (134) (Scheme 98). 

Homoaporphins, 201 Homobenzoqulnones, 339 Homogeranic acid, 295 Homopropargylic alcohols, 279-280 Humulene-4,5-epoxide, 64 Hunsdiecker reaction, 293 Hydrastine, 214, 215 Hydrazides, 429 Hydrazine, 236-237, 351... 

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

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). 

Interestingly, LTA oxidation in AcOH and subsequent TFA treatment of ( )-l, 2,3,4-tetrahydro-6-methoxy-l-(3-methoxyphenethyl)-2-methylisoquinolin-7-ol (155) afforded ( )-l-hydroxy-2,10-dimethoxy-C-homoaporphine (156) in 11% yield (Scheme 17), a ( )-homomorphin-andienone 157 being the major product (30) (see Section V). 

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). 

Similar stereoselective acetoxylation at C-4 in C-homoaporphines was performed (JS). Thus, ( )-C-homoaporphines 127 and 128 were converted quantitatively to ( )-2,10,11-trimethoxy- and ( )-2-methoxy-... 

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