Enamides nonoxidative

Enamide photocyclization is basically of a nonoxidative nature, yielding the lactam isomeric to the starting enamide. 

Asymmetric photocyclization starting from a chiral enamide also proceeds smoothly under nonoxidative conditions to give a diastereo-differentiated product. 

According to the reaction conditions, nonoxidative, oxidative, and reductive and the variety of the structures of enamides, several types of lactams shown in Scheme 2 can be synthesized by the use of this cyclization. 

Most enamides, irrespective of their structures, are known to undergo photocyclization under nonoxidative conditions giving rise to lactams, whose structures are isomeric to the starting enamides, in good yields. One exception is the photocyclization of benzanilides that cyclize only under oxidative conditions to afford dehydrolactams (11). However, the stereochemical and regiochemical aspects of these photocyclizations are different, depending on the types of enamides, mainly either on A-a,/ -unsaturated acylenamine type or nsaturated acylanilide type. 

Since the enamide A affords the dehydrolactam E on irradiation in the presence of iodine, and no conversion from D to E is observed under nonoxidative conditions, the nonoxidative nature of the original enamide photocyclization is clearly established (Scheme 4). 

The above stereochemical and nonoxidative nature of photocyclization of this type of enamide is enough to propose the mechanism of this photocyclization as that of the electrocyclic nature of a six -electron... 

In the photocyclization of enamides of the A-benzoylenamine type and the A-acylanilide type, which are both capable of undergoing nonoxidative photocyclization, the presence of an oxidizing agent causes the abstraction of two hydrogens, therefore forming the dehydrolactam having a double bond, usually at the ring juncture. 

Therefore, the formation of a dehydrolactam by irradiation of enamides under nonoxidative or unrestrictive conditions can be assumed to proceed via the route involving a 1,5-hydrogen shift of the Hb proton from the cyclic intermediate A to afford a thermally very unstable lactam 10 with a dihydrobenzene structure. This compound (10) would then undergo facile dehydrogenation even at room temperature to afford the dehydrolactam (9) as the final product, although the actual role of the oxidizing agent remains to be clarified. 

In addition to the works on enamide photocyclization described in this chapter, there are some interesting reports on the mechanistic study (46,47) and also on the application of nonoxidative cyclization to the synthesis of pharmacologically active heterocyclic compounds (39,48-52). 

Various types of enamides are now shown to undergo ready photocyclization according to a mechanism of a six -electron conrotatory cyclization via a trans cyclic intermediate B, from which the photocyclized product is formed depending on the reaction condition, either oxidative or nonoxidative. 

Irradiation of enamides in the presence of a hydride (e.g., sodium borohy-dride) in a solution containing a protic solvent such as methanol, brought about reductive photocyclization (15,54-57). However, it is assumed that irradiation in the presence of aprotic solvent affords the photocyclized product (17) identical to that formed by irradiation under nonoxidative conditions according to the route suggested in Scheme 20. 

Furthermore, an asymmetric synthesis of natural xylopinine (20) by the route involving reductive photocyclization was successfully accomplished (16). Independently, Kametani et al. reported another asymmetric total synthesis of natural xylopinine via the route involving a diastereo-differen-tiated photocyclization of the chiral enamide (19) under nonoxidative conditions (66). Therefore, it is now established that enamide photocyclization is a reaction capable of not only undergoing a wide variety of cycliza-tions under various conditions but also having a high quality (Scheme 22). 

One of the major areas of research in enamide chemistry has been the application of enamide cyclization to the synthesis of natural alkaloids and related heterocyclic compounds. Ever since Ninomiya and co-workers discovered nonoxidative photocyclization of the A-benzoylenamine-type ena-mides in 1969 (9), several types of alkaloids have been synthesized, starting from enamides of rather simple structures, by applying enamide cyclization under both photochemical and thermal conditions. 

Crinane. A stereoselective synthesis of ( )-crinane was reported as the first application of nonoxidative photocyclization of an enamide to alkaloid synthesis (79,80). Acylation of the benzylimine of 2-allylcyclohexanone with piperonyloyl chloride gave a mixture of two isomeric enamides, 47 and 48, which were converted to the homogeneous enamide 48 by simple heating or irradiation with a high-pressure mercury lamp. Irradiation of the... 

Reduction of the cis lactam 61 with LAH afforded the cis amine 60, which was also obtained from either oxidative photocyclization of the enamide 56 or nonoxidative photocyclization of the bromoenamide 56, followed by successive reductions. Oxidative photocyclization of the enamide 56 in the presence of iodine afforded the corresponding dehydrolactam 59 in good yield, which is a useful intermediate for further conversion to various aromatized benzo[c]phenanthridines, the basic structure of many aromatic alkaloids (19,20). 

Photocyclization of the enamide 80 and the o-methoxy-substituted enamide 85 under nonoxidative conditions afforded the trans lactams 81 (52%) and 86 (53%) and the dehydrolactams 82 (41%) and 87 (50%), respectively. Since dehydrogenation of the trans lactams 81 and 86 with 30% Pd/C gave lactams 83 and 88, although in low yields, the dehydrolactams (82) and (87) were used for ready dehydrogenation with the same reagent, followed by reduction to the desired alkaloids dihydroavicine (84) and dihydronitidine (89), natural alkaloids that had been converted already to nitidine and avicine, respectively (1,2) (Schemes 44 and 45). 

Acylation of the well-known Bischler-Napieralski product, 1-benzyl-3,4-dihydroisoquinoline, with ethyl chloroformate gave a mixture of two carbamates, E isomer 118 and Z isomer 119 in the ratio of 1 2, which were readily assigned from their UV and NMR spectra and underwent cycliza-tion on irradiation under either nonoxidative or oxidative conditions to afford the 8-oxoberbine 120 or aporphine skeleton 121 (104,105). Irradiation of either the E or Z enamide, (118 or 119) or their mixture quickly... 

When the enamide 118 was irradiated in the presence of an oxidizing agent such as iodine, both the expected aporphine 121 in 65% yield and the 8-oxoberbine 120 in low yield were obtained the latter became the major product when enamide 118 was irradiated under nonoxidative conditions (Scheme 51). 

The enamide 127 that is substituted in an ortho position of the benzyli-dene group was prepared to investigate regioselective cyclization under nonoxidative conditions. However, irradiation brought about an exclusive cyclization to the unsubstituted position to afford the 2,3,9,12-tetrameth-oxy-substituted protoberberine iodide 128 (Scheme 54). 

Total synthesis of protoberberine alkaloids via the route involving enamide photocyclization consists of nonoxidative photocyclization of the 2-aroyl-l-methylene-3,4-dihydroisoquinolines and the subsequent metal-hydride reduction of the photocyclized lactams. This simple combination of reactions for alkaloid synthesis provides one of the most convenient synthetic routes to this group of popular alkaloids. 

Nonoxidative photocyclization of the enamide 133 in thoroughly degassed tert-butanol solution gave the lactam 155 in 93.5% yield as the sole product (31,44). Ninomiya et al. (21,23) carried out the same cyclization of 133 by passing an inert gas during the course of irradiation and obtained three different types of products 156,155, and 157 in yields of 40, 5, and 5%, respectively. 

Successful berbine synthesis summarized in Section IV,C prompted Nin-omiya s group (25,26,117,118) to extend enamide photocyclization to har-malane, therefore giving rise to a novel and facile synthesis of polycyclic heterocycles such as the yohimbine group of compounds. Before reductive photocyclization was introduced, the use of nonoxidative photocyclization with indole alkaloids was limited to simple systems and those possessing a large degree of aromaticity. 

Tryptamine was acetylated followed by cyclization to give harmalane in good yield harmalane was then acylated with benzoyl chloride to afford the enamide 14 that underwent smooth photocyclization under nonoxidative conditions to give the dehydrolactam 184 in 37% yield, even when passing an inert gass. The dehydrolactam 184, a basic skeleton of yohimbine, was... 

Nonoxidative photocyclization of enamides of benzanilide and acry-loylenamine types has offered useful routes for the synthesis of ergot alka-... 

Depyrrole analogs of clavines were readily synthesized by applying reductive photocyclization of the enamides of acryloyl and furoylenamine types, 229 and 233 (55,56). Irradiation of the enamide 229, prepared from 2-tetra-lonimine and methacryloyl chloride in the presence of triethylamine, under nonoxidative conditions, afforded the lactams 230 and 225 in yields of 45 and 10%, respectively. Their reductive photocyclization in the presence of sodium borohydride at a low temperature of 4-5°C led to the formation of... 

Alkaloids having a spiro-fused ring system, such as sesbanine and gramme, were also the targets of synthesis by the use of enamide photocycli-zation. Gramain et al. (49,50) succeeded in synthesizing various types of the spiro compounds 261 and 262 by applying nonoxidative photocycli-zation of the enamide 260 prepared from cyclohexanecarboxaldehyde (Scheme 93). 

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