Harmalane enamide photocyclization synthesis

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). 

Simple synthesis of demethoxycarbonyloxogambirtannine (347) was reported by Ninomiya and co-workers (188) via enamide photocyclization. N-Benzoyla-tion of harmalane (150) afforded enamide 348, which could be photocyclized to 347 in 37% yield. 

Yohimbine. Ninomiya et al. (118) reported a formal total synthesis of yohimbine by applying enamide photocyclization. Harmalane was acylated with 4-methoxy-3-methoxycarbonylbenzoyl chloride to yield the enamide 198, which was found to be so unstable that it was irradiated without purification. Of two photocyclized products thus obtained, 199 in 32% yield and 200 in 5% yield, the latter product was identical to a known key intermediate (119) of yohimbine when their spectral data were compared (Scheme 76). 

The considerable amount of new synthetic work reported in this area during the past year includes a new synthesis of nauclefine (72) by a modification of the enamide photocyclization route. The reaction of harmalan (73) with an excess of isonicotinoyl chloride gave the spirodihydropyridine derivative (74), which on hydrolysis followed by irradiation gave nauclefine (72) (Scheme 8). 

Other research groups have also investigated the viability of strategies based on enamide photocyclizations to prepare yohimbines. For example, Kametani and his coworkers tested this approach in a formal asymmetric synthesis of yohimbol (390) (Scheme 3.66) (74). The optically active harmalane derivative 383, prepared from L-trytophan, was condensed with anisoyl chloride (352) to afford enamide 384. Irradiation of 384 yielded a mixture of the desired pentacyclic lactam 385 in addition to enamide 386. The amide carbonyl in 385 was reduced to provide 387 as well as its C(3)-epimer 388. 

Nauclefine. In 1975 Sainsbury and Webb (122) and Hotellier et al. (71) reported the isolation and synthesis of nauclefine. Hotellier et al. (71) obtained nauclefine in 6% by treating harmalane with an excessive amount of nicotinoyl chloride. Alternatively, Sainsbury and Webb (122) carried out photocyclization of the enamide 201, prepared from harmalane and the above acid chloride, to obtain a mixture of two lactams, 29 and 202, in the ratio of 100 9, with 48% yield. The major product thus obtained was identical to parvine, whose name was first proposed by Sainsbury (122) but later changed to nauclefine (123) (Schemes 77 and 78). 

In the first part of my talk, it is demonstrated that we have successfully applied reductive photocyclization of the enamide prepared from harmalane and p-methoxybenzoyl chloride to the synthesis of yohimbine group of alkaloids, which have a common ben-zoindoloquinolizidine skeleton. 

Enamide and enamine photocyclizations (9, 13, 14, 113) are central to yet another strategy which has been successfully employed by Ninomiya (9, 13, 14, 61-71), Kametani (74), and Atta-ur-Rahman (72, 73) in the synthesis of yohimbine alkaloids. These approaches typically begin with harmalane (336) which contains the ABC unit of the pentacyclic yohimbine targets (Scheme 3.56). Condensation of harmalane with an appropriately substituted cyclohexene carboxylic acid or benzoyl chloride 337 affords seco D-ring intermediate 338. To effect D-ring closure, the enamide chromophore in 338 is photocyclized to form pentacyclic enamide 339. Alternatively, photoreaction... 

The synthesis of yohimbane (120) and alloyohimbane (82) was improved by using a modified sequence which featured reductive photocyclization as the key step (Scheme 3.58) (63,69). Condensation of harmalane (336) with benzoyl chloride afforded enamide 348 which upon irradiation in the presence of sodium borohydride afforded a mixture of functionalized yohimbanes 349, 350, and 351. The overall yields and product distribution were found to be dependent on the solvent employed with the maximum yield of 350 (98%) being obtained in a mixture of MeCN and MeOH. Hydrogenation of 349... 

---