Enamide photocyclization reductive

A new total synthesis of flavopereirine perchlorate (148) has been reported by Ninomiya et al. (109) via enamide photocyclization. Harmalane (150) was acy-lated with 3-methoxyethacryloyl chloride to enamide 151 which was irradiated in benzene solution without purification to yield the unstable lactam 152. The latter was treated with hydrochloric acid, resulting in dehydrolactam 153 in a yield of 35% from harmalane (150). Lithium aluminum hydride reduction of 153, followed by dehydrogenation, afforded flavopereirine (148), isolated as its perchlorate (109). 

The structure of this cyclic intermediate B, which contains an immonium structure, suggests the possibility of undergoing a facile reduction by hydride, if present during the course of photocyclization. This expectation was visualized as expected on the various enamides and therefore opened up a new phase of the application of enamide photocyclization (15) (Scheme 16). 

The use of a chiral hydride complex has been central to the asymmetric reduction of ketones such as acetophenone (58). A number of excellent chiral metal hydride complexes have been introduced by many researchers, including Noyori (59,60), Meyers (61), Mukaiyama (62,63), Terashima (64,65), and others (58). It is apparent that there is a close similarity in structure between acetophenone and the proposed intermediate in enamide photocyclization, therefore suggesting the possibility of undergoing photocyclization in an asymmetric manner. 

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). 

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. 

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. 

As an unavoidable situation we faced from smooth application of enamide photocyclization to alkaloid synthesis, we have investigated a new developement in enamide photocyclization and found a very efficient and most useful synthetic methodology in what we called " reductive photocyclization ". 

An early application of enamide photocyclizations to yohimbine alkaloid synthesis is illustrated by Ninomiya and coworkers synthesis of yohimbane (120), epiyohimbane (347) and alloyohimbane (82) (Scheme 3.57) (61, 63, 69). These compounds were prepared by a short sequence starting with har-malane (336) which was condensed with acid chloride 341 to provide enamide 342. Irradiation of 342 in benzene followed by reduction afforded a mixture of the stereoisomeric pentacyclic lactams 344, 345, and 346 which were reduced to provide yohimbane (120), epiyohimbane (347), and alloyohimbane (82), respectively. While the yield of the photocyclization process was modest, this route demonstrated how enamide photocyclizations can be used to rapidly construct pentacyclic yohimbane targets. 

Ninomiya s group has also utilized the enamide photocyclization strategy to prepare alloyohimbone (247) and yohimbone (358) (Scheme 3.59) (9,64,65, 70). In these syntheses, harmalane (336) was condensed with anisoyl chloride 352 to provide enamide 353. Reductive photocyclization of this substance... 

A further application of the enamide photocyclization in yohimbine synthesis is demonstrated by Ninomiya s preparation of naucleficine (378) (Scheme 3.64) (68) Enamide 376, prepared from 336 and aroyl chloride 375, was irradiated under non-reducing conditions to form oxygambirtannine (127). Finally, a reduction-oxidation sequence afforded the target. 

Reductive photocyclization of the enamide 261 by irradiating a methanolic solution containing sodium borohydride results in a mixture of four products the hexahydrophe-nanthridone 262, two geometrically isomeric octahydrophenanthridones, 263 and 264, and the structurally isomeric octahydrophenanthridone 265 (equation 111)135. 

In the presence of metal hydride, the enamide can undergo reductive photocyclization to give the dihydrolactam in good yield. 

From the synthetic point of view, oxidative photocyclization of these two types of enamides has a definite advantage in the construction of a polycyclic ring system with a double bond at the ring juncture in one step from the starting compounds. The photocyclized product can be readily converted to the cis-fused ring system by a facile catalytic reduction or to the fully aromatized lactam on dehydrogenolysis (19,20) as in the case of vV-benzoy-lenamines. 

The reaction course of the reductive photocyclization of enamides in Scheme 17 was firmly established by the experiments using deuterated reagents (75). When enamide 14 was irradiated in the presence of sodium borodeuteride in acetonitrile-methanol (10 1) solution, the isolated product 15 in 93% yield was deuterated at the 3 position, whereas irradiation in the presence of sodium borohydride in acetonitrile-deuterium methoxide solution afforded lactam 16, deuterated in the benzene ring as shown in Scheme 18 (55). 

Discovery of reductive photocyclization of enamides has certainly increased its importance as a general and useful synthetic tool. 

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. 

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). 

Reductive photocyclization of the enamide 18 in ether-ethanol solution in the presence of an excessive amount of sodium borohydride afforded two... 

Regioselective photocyclization of the o-methoxy-substituted enamide 133 (32) or the obromoenamide 133 (29,30) gave only the dehydrolactam 156 in 85 or 80% yield, respectively. Reduction of the lactam 155 with LAH... 

On the assumption that asymmetric reduction of an intermediate by a chiral metal hydride complex could occur during the course of photocycli-zation of the enamide 133, as exemplified by reductive photocyclization, Ninomiya et al. (16) have undertaken and completed the photochemical asymmetric synthesis of (—)-xylopinine. 

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... 

Similarly, photocyclization of the /i-methoxy-substituted enamide 229, followed by two-step hydride reduction with LAH and sodium borohydride, furnished the depyrrole analog of agroclavine (55) (Scheme 87). 

The crucial step in this synthetic route is the use of the furoyl moiety in the enamide that facilitated reduction of the number of stereoisomers expected from the photocyclization of enamide and that also was suited for the following modification of the resultant dihydrofuran ring (Scheme 88). 

Epicostaclavine (248) and pyroclavine (250) were also synthesized by applying reductive photocyclization of the enamide (243) as shown in Scheme 91 (53). 

Lysergic Acid. Based on the results of the synthetic route using benzo[/]quinoline derivatives (55,56), Ninomiya et al. (57) applied reductive photocyclization to the enamide 251, prepared from the tricyclic imine 242 and 3-furoyl chloride. 

Reductive photocyclization of the enamide 251 afforded a mixture of two hydrogenated lactams 252a and b in 81% combined yield as a mixture of two... 

Oxidative photocyclization of the enamide 273 gave the same aporphine (271) in 15% yield this was then converted to ( )-nuciferine by LAH reduction of the carbamate, followed by catalytic hydrogenation of ring C (136) (Scheme 100). 

Novel synthetic applications of the photocyclization of enamides have been reported. Preparation of the fused quinolone (23) from the enaraide (24) was achieved by photocyclization and subsequent elimination of a suitably positioned methoxyl group Reductive photocyclization of enamides, usually carried out in the presence of sodium borohydride, is of particular value in the synthesis of alkaloids. Cyclization of the enamide (25) to the... 

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