Alkaloids using benzynes

Alternative approaches to aporphine alkaloids using benzyne intermediates have been reported.113-118 For example, treatment of the readily available bromo-benzylisoquinoline derivative (98 X = Br, Y = H) with potassium amide gave the corresponding amino-compound (98 X = H, Y = NH2), which upon... 

The benzyne route to 1-cyanobenzocyclobutenes has been employed for the synthesis of a myriad of complex natural products. The cyano group in (74) was used to attach the dienophile as well as for building die imino bridge of (75), an important precursor for some diterpene alkaloids (Scheme 15).110... 

Another important entry to the skeletal framework of the alkaloids related to lycorine has involved the formation of the B ring from an ACD precursor by different arylation protocols. Although the first examples of these processes typically involved photocyclizations of substituted A-benzoyl indolines such as 158-160 and enamides such as 165-167, cyclizations of benzyne intermediates and electrochemical oxidative cyclizations have recently proved to be useful. Early workers in this area noted that when 158 was irradiated, it suffered... 

An interesting synthesis of the lycorine-type alkaloids (46) and (47) using the photocyclization of an enamido-ketone (44) as the key step has been reported (Scheme 5). Benzyne reaction of the phenethylamine (41) provided the indoline... 

The benzyne reaction of the bromoisoquinoline 140 was examined by using sodium methylsulfinylmethanide, and dibenz[6,g]azecine 141 was obtained (80,81). An attractive modification appeared to be the expansion of the central ring of ( )-homoargemonine (143), since it seemed possible that 143 could be a representative of a new, as yet undiscovered alkaloid class originating from a 1-phenethyltetrahydroisoquinoline precursor. The synthesis of 143 was accomplished by reaction of the 1,2-dihydroisoquinoline 142 and formic acid-phosphoric acid (82). 

More recently, the preparative value of VOCl3 and VOF3-TFA in chemical oxidation has been demonstrated (see Section III, on the pro-aporphine and promorphinane alkaloids) (415,462). Some other authors used the purified enzyme horseradish peroxidase (463). By this method the aporphine base (besides the quaternary dibenzopyrrocoline) is readily obtained from (S)-( + )-laudanosoline hydrobromide or from (/ )-(—)-laudanosoline methiodide with retention of the absolute configuration. The synthesis of 6a,7-dehydroaporphine bases was also carried out by making use of the benzyne reaction (439). Reduction of these substances affords the corresponding aporphine bases (439). The synthesis of isoquinoline alkaloids by lead tetraacetate oxidation was reviewed by Umezawa and Hoshino (343). 

Furthermore, the following compounds were synthetically prepared racemic cheilanthifoline (58c) (47), kikemanine (58d) (129), canadine (58e), berberine (59a) (590, 614), tetrahydropalmatine (58g) (475), sinac-tine (58h), cavidine (68d) (616,617), nandinine (58i) (590, 614, 615), capaurine (58p) (618), capaurimine (58o) (128, 618a), xylopinine (60c) (610, 615, 619), O-methylcaseanadine (62b) (70, 620), thalictricavine (68b), and corydaline (68h) (615). Xylopinine (60c) and some other alkaloids were synthesized by benzoylation of 1-alkyl-3,4-dihydroisoquinolines followed by photocyclization. This method provides a useful route to the synthesis of other protoberberine alkaloids (619). It is also applicable to the synthesis of cularine (51) and spirobenzyltetrahydroisoquinoline alkaloids (188). Xylopinine was also synthesized from the corresponding enamide under benzyne reaction conditions (615). Kametani etal. summarized their findings on the synthesis of these alkaloids and described the formation of protoberberines by debenzylation and photolysis of tetrahydroisoquinolines (622, 623). The total stereospecific synthesis of racemic ophiocarpine (70a) from the 3,4-dihydroisoquinoline derivative by Mannich cyclization was also described (624). 

Synthetic work on morphine and morphinandienone alkaloids continues unabated. Amurine " and O-methylflavinantine have been obtained by the benzyne reaction of appropriate benzyl isoquinoline precursors. A review concerning new synthetic derivatives of dihydrocodeinone is not readily available.Codeine has been prepared in 98% yield from morphine using... 

An intramolecular benzyne cycloaddition to a styrenic diene has been used to simultaneously construct two carbon-carbon bonds of the central ring of a phenanthrene moiety, in a new approach to aristolactam alkaloids 679. Treatment of jE -alkene 677 (R =... 

Nucleophilic aromatic substitution, based on an intramolecular attack of the phenoxide ion in the benzyne intermediate 87 (generated by dimsyl sodium treatment of 86), has been used by Castedo et al. (66) in a versatile synthesis of cularine alkaloids. However, N-attack competes with 0-attack in all instances to give dibenzopyrrocoline derivates (88), together with tetradehydrocularines (89). The main value of this approach is the easy conversion of 89 to norcularines, by catalitic hydrogenation to cularines, by quatemization with methyl iodide fol-... 

This methodology has since been applied to constructing [6]-an-nelated carbazoles, and benz[/]indole, and the tetracyclic skeleton of the benzophenanthridine alkaloids. Arynes used in this type of reaction include 3,4-didehydropyridine in the synthesis of ellipticine 8 and isoellipticine 9," 3,4-(methylenedioxy)benzyne, and 2,3-naphthalyne. ... 

Funk and Huntley converted divinylpyrrolidine 10 to diene 11, and thence to an indole precursor 12 of )-cis-trikentrin B. A similar sequence was used to synthesize ( )-ci5 -trikentrin B. Dihydropyrrole 10 was assembled in five steps from A-Boc-2-pyrrolidinone. Fiirstner and coworkers synthesized several pyrrolo[2,3-c]carbazole alkaloids, the dictyodendrins B, C, and E, that featured a photochemical 6it-elecirocyclization and in situ dehydrogenation (equation 2) [21], Danheiser and colleagues effected an intramolecular benzyne generation and cycloaddition onto an alkynylpyrrole to afford a polycyclic indole (equation 3) [22],... 

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