Harmalan

Canthin-6-one, which is a cytotoxic alkaloid, is synthesized in six steps from harmalane (Scheme 84) <1999TL7075>. The second step is a [4+2] cycloaddition with methyl 2-(dimethylamino)acrylate under singleelectron-transfer electrolysis. 

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). 

Ketone 166, the key intermediate of deplancheine was obtained in 63% overall yield by the reaction of harmalane (150) with l-bromo-2,3-epoxypropane, followed by sodium borohydride reduction and Moffat oxidation (116). Methods for the elaboration of the exocyclic, -configurated double bond are reviewed (117). 

In the other approach, again harmalane (150) was treated with methyl 2-(di-ethylphosphono)acrylate (174), resulting in iminophosphonate 175. By its sodium borohydride reduction and subsequent lactonization, the amidophospho-nate 176 has been obtained, Wittig-Homer reaction of 176 with acetaldehyde followed by selective reduction of the carbonyl group of the enamide function supplied ( )-deplancheine in good yield (116). 

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. 

To synthesize 6-methoxy-3,4-dihydro-beta-carboline (10-meth-oxy-harmalan), add 5-methoxy-tryptamine to acetic anhydride and let stand twelve hours at 10°. Dilute with water, basify and extract with methylene Cl and dry, evaporate in vacuum to get melatonin (I). Reflux (1) in xylene in the presence of P205 to get the title compounds. Other References JMC 7,136(1964) JPS 57,1364 (1968), 59,1446(1970) JACS 70,219(1948) JCS 1602(1921), 1203(1951), 4589,4593(1956) Organic Synthesis 51, 136... 

Since these molecules have been isolated and synthesized, a number of other p -carboline alkaloids have been developed in the laboratory. Michael Valentine Smith describes the preparation of several analogues in his Psychedelic Chemistry. The 6- or 10-methoxy isomer of harmaline, sometimes known as 10-methoxy-harmalan, is about half again as potent by weight as harmaline. 

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... 

By using the p-methoxy-substituted enamide (192), Ninomiya et al. (54) succeeded in a simple synthesis of alloyohimbone (196) via the unconjugated lactam 194, which has an enol ether structure. Lithium aluminum hydride reduction of the lactam 194, followed by hydrolysis with hydrochloric acid and subsequent catalytic hydrogenation over platinum dioxide, yielded alloyohimbone (196) stereoselectively in an overall yield of 59% from harmalane (54) this was the most convenient synthesis of alloyohimbone (196) so far reported (Scheme 75). 

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). 

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). 

As in the azaberbine synthesis described in Section IV,C, Ninomiya el al. (68) prepared the spirodihydropyridine 206 by acylation of harmalane with an excessive amount of isonicotinoyl chloride and then synthesized nauclefine (29) by photorearrangement of the corresponding N- nor derivative 207 (Scheme 81). 

DBC 34 (harmalan) is a rare mammalian alkaloid present in goat urine (67). The fully aromatic BC 35 (norharman), on the other hand, is an endogenous metabolite in man (44), and BC 36 (harman) was found to be present in tissues of rat and man (1,46,54,68,69). Carboxylic acid 37 was detected in cerebral fluids of monkeys (70), and analog 38 was detected in bovine milk and urine (71). 

To synthesize 6-methoxy-3,4-dihydro-beta-carboline (10-meth-oxy-harmalan), add 5-methoxy-tryptamine to acetic anhydride and let stand twelve hours at 10°. Dilute with water, basify and extract with methylene Cl and dry, evaporate in vacuum to get melatonin... 

Another approach to the indolo[2,3-a]quinolizine skeleton is the cyclization of enamide intermediates thus, photocyclization of (194) and subsequent elimination of methanol from the cyclized product (195) afforded a 35% yield of (196) based on harmalane (193) <84JCS(Pl)2035>, and enamide intermediate (198) obtained from (197) underwent cyclization efficiently in refluxing xylene to give (199) in high yield <80CC109>. 

Another well-known method is to utilize harmalane (193) as a three-atom fragment. Due to its... 

---