Alkaloids syntheses electrocyclic reactions

Thermal and photochemical electrocyclic reactions are particularly useful in the synthesis of alkaloids (W. Oppolzer, 1973,1978 B K. Wiesner, 1968). A high degree of regio- and stereoselectivity can be reached, if cyclic olefin or enamine components are used in ene reactions or photochemical [2 + 2]cycloadditions. 

A new benzannulation methodology was developed in order to overcome the limitations of electrocyclic ring closure of divinylindoles. The cyclization is achieved via an allene-mediated electrocyclic reaction of 2,3-difunctionalized indoles. This method is more efficient for the synthesis of highly substituted 2-methyl carbazole alkaloids (559). The 3-alkenyl-2-propargylindole 557, a precursor for the allene intermediate, was prepared from 2-formylindole over several steps using simple functional group transformations (536,537) (Scheme 5.20). 

The photochemical electrocyclic reaction of acrylamides represents a versatile strategy for alkaloid synthesis. Thus, (S)-pipecoline has been synthesized using the photochemical cyclization of enantiomerically pure acrylamide derivatives in the presence of NaBH4, which causes reduction of the imonium intermediate. The lactam may then easily be transformed into the desired heterocyclic compound (Scheme 9.26) [38]. 

A photocyclization which may involve a similar electrocyclic reaction and which may be useful for benzophenanthridine alkaloid synthesis has been described in preliminary form.239 For example, irradiation of the enamide (257) gave an approximately 1 1 mixture of the octahydrophenanthridines (258 R1 = H, R2 + R3 = 0CH20) and (258 R1 + R2 = 0CH20, R3 = H). In this connection, an alternative synthesis of phenanthridines (260) by the reaction of diazonium salts (259) with sodium iodide in acetone may be noted.240 A series of compounds, e.g. (261), temptingly related to benzophenanthridine alkaloids, have been synthesized.241... 

The photocyclization of enamides to quinolines or isoquinolines has become an important reaction in the synthesis of alkaloids 219,358). It has recently been applied in the preparation of the isoquinoline alkaloid polycarpine 359). The principle of the reaction is demonstrated in the preparation of dihydroquinolines 360> (3.39) and of spirocyclohexaneisoquinoline derivatives (3.40) 361K In each case the electrocyclic ring closure product undergoes a subsequent 1,5-hydrogen shift. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The photochemical electrocyclization of conjugated iminium salts 160, formed by protonation of 2-azadienes 159, led to isoquinolin-4-ones 162, presumably through hydrolysis and oxidation of the dihydroisoquinoline intermediates 161 (85TL5213) (Scheme 39). A closely related reaction served as the key step for a short synthesis of the pentacyclic marine alkaloid ascididemin as reported by Moody, Rees, and Thomas [90TL(31)4375 92T3589] the central reaction involves a 67r-electron pho-tocyclization of a syn- aza stilbene in sulfuric acid. 

The electrocyclic cyclization was investigated by heating the sample in o-dichlorobenzene (o-DCB), both under conventional heating conditions and under microwave irradiation in a dedicated monomode apparatus. It was found that the microwave-assisted cyclization provided slightly elevated yields at the lower reaction temperature of 150 °C, in comparison with the conventional heating experiment conducted at 180 °C (Scheme 14). The intermediate isoquinoline was then converted to the final alkaloid using known synthetic manipulations to complete the synthesis. 

This methodology was employed for the synthesis of the reported structure of the alkaloid jamtine (02OL715, 02JOC929). The key sulfoxide intermediate 307 was heated with CSA to produce several tricyclic products (98% yield) as a mixture (5 2 1 1) of diastereomers in which 308 predominated (Scheme 57). The stereochemistry of 308 was secured by X-ray crystallographic analysis and is consistent with a Nazarov-type conrotatory 47i-electrocyclization followed by attack of the nucleophilically disposed aromatic ring from the least hindered side of the intermediate iminium ion. Reaction of a-ethylthio amide 308 with NaH effected an intramolecular alkylation to provide tetracycle 309. 

A new synthesis of ( )-crinan (43), a compound possessing the basic ring skeleton of the alkaloid crinine, using a stereoselective photocyclization reaction has been devised.28 The imine (39), readily prepared from 2-allylcyclohexanone and benzylamine, was acetylated with piperonyloyl chloride to give the AT-acylena-mine (40). Photolysis of (40) in methanol solution gave compound (41) (15% yield) whose structure and stereochemistry were established by spectral means and by consideration of the proposed electrocyclic nature of the reaction. 

The usefulness of benzocyclobutenyl derivatives for the synthesis of isoquinoline alkaloids (see Vols. 2—4 of these Reports) has been extended to the preparation of the protoberberine bases (Schemes 9 and 10). In one case (Scheme 9), compound (155) was thermolysed to afford the protoberberinium salt (157), the reaction plausibly proceeding via the ortho-quinonoid intermediate (156), which then undergoes electrocyclization and dehydrogenation to give the product. Reduction of (157) then provided the protoberberine (158 R = H, R = R = Me). This route was used for the synthesis of (+ )-discretine (158 R = H,... 

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