Lycorine type alkaloids

Major advances in the total synthesis of representative members of this family have been made. Several syntheses of lycorine (1) have been reported (108,109,112,113,117), although there remain problems in the development of a concise strategy for the stereoselective functionalization of the C ring. Substances prepared during the development of entries to the lycorine-type alkaloids have been exploited as key intermediates for the syntheses of clivonine (187) (110) and hippeastrine (180) (140). Several routes to the dihydrolycoricidines 270 and 271... 

This intermediate contained the correct stereochemistry and functionalization for further conversion into the lycorine-type alkaloids. However, 53 did react in the expected manner with a series of cyclic and open-chain dienes, but the reaction failed with 54 (6). 

Structures 98-112 (the stereochemistry at position 7 of compounds 99, 102, 104, 105, 109, and 112 was unsettled) were reported in Volume XI, p. 334, for the alkaloids possessing the [2]benzopyrano[3,4-gr]indole nucleus. Since that time experimental support for the in vivo derivation of this class of compounds from the lycorine-type alkaloids by benzylic oxidation and cleavage of the C-7—N bond has been presented (18, 19) thus strengthening the stereochemical relationships between the two groups of natural products. 

The Skeleton of Lycorine-Type Alkaloids. In the course of photochemical studies on 1-aroylindoles, Carruthers and Evans (76) synthesized pyr-rolo[3,2,l-i/,e phenanthridin-7-one (35), the basic skeleton of lycorine, in 10% yield by irradiation of 1-o-iodobenzoylindole (34). However, photocyclization of the corresponding indole analogs proceeded quite differently as shown in Scheme 29. 

An interesting synthesis of the lycorine-type alkaloids (46) and (47) using the photocyclization of an enamido-ketone (44) as the key step has been reported (Scheme 5). Benzyne reaction of the phenethylamine (41) provided the indoline... 

Lycorine-type alkaloids derived from pyrrolo[3,2,l-(ie] phenanthridine/ pyrrolophenanthridone ... 

The majority of the alkaloids that had affinity to the serotonin transporter (SERT) were crinine-type alkaloids. However, cherylline 4, tazettine 8 and 1-0-acetyllycorine 53 are the only alkaloids that showed affinity to SERT among the cheiylline-, tazettine- and lycorine-type alkaloids, respectively (80). The activity of the crinine-type alkaloids was attributed to the presence of a 1,3-dioxole moiety in common with the chnically used SSRI paroxetin (79). 

The flower stem fluid of Crinum latifolium 31) has been examined, from which numerous Amaryllidaceae alkaloids have been isolated. Among them, two lycorine-type alkaloids, 2-epi-lycorine (4) and 2-epi-pancrassidine (7), are included, structures of which were determined by spectroscopy. 

A new lycorine-type alkaloid named fortucine has been found in the leaves of Narcissus variety Fortune and its structure reported as 27 (87). From the bulbs of Crinum kirkii, two new alkaloids, kirkine (27) and 8-0-demethylvasconine (56), have been isolated and their structures established by physical and spectroscopic methods (29). In this study, the structure of kirkine was determined to be the same structure as that proposed for fortucine (87). Therefore, confirmation by direct comparison of each alkaloid remains to be conducted. 

C-Aromatic lycorine-type alkaloids have been discovered in the plants of the Amaryllidaceae family. Two new 2-oxo-pyrrolophenanthridinium alkaloids, zefbetaine (59) and zeflabetaine (60), together with several known Amaryllidaceae alkaloids, have been isolated from fresh mature seeds of Zephranthes flava by gradient solvent extraction, chromatography, and deri-vatization (108). Their structures were characterized by comprehensive spectroscopic methods, chemical transformations, and synthesis. They are listed in Fig. 9. 

The synthesis of lycorine-type alkaloids has received the attention of chemists as a target for exploration of new synthetic methods, because the stereoselective construction of the contiguous asymmetric centers reported until now is not always efficient. Since the previously published review (S), two investigations of the total synthesis of ( )-lycorine (1) (118), and the first total syntheses of optically active (+)-lycorine (1) and (+)-l-deoxylcorine (84) (119), the unnatural enantiomer of lycorine (1), were reported. Both of the synthetic strategies involve the construction of highly functionalized hexahydroindoline derivatives, followed by cyclization to form ring B. 

Hamayne (153), 3-O-acetylhamayne (154), crinamine (156), ambelline (161), and a new alkaloid named Josephine (144), together with the lycorine-type alkaloid stembergine (16), were isolated from the bulbs of Brunsvigia josephirute (//). The mass spectrum of 144 showed the molecular peak at m/z 331, and prominent fragments at m/z 289, 242, and 202 that are characteristic of a 1,2-disubstituted crinane alkaloid (140). Its spectroscopic ( H and NMR) evidence established the structure as 144. A new alka-... 

In a similar fashion, 2-aroyl-l-methylene-l,2,3,4-tetrahydroisoquinoline enamides yield on irradiation the corresponding 8-oxoberberines.18 Cyclization of analogous enamides containing or/Ao-substituents in the aryl residue is followed by elimination of the substituent leading to formation of the unsaturated oxyprotoberberines.19 Thus, for example, the enamide (23) is converted on irradiation in benzene into the oxyprotoberberine (24), presumably via the intermediate (25). An alternative pathway involving methoxyl migration has been observed by other workers.20 Related cyclizations have been employed in the syntheses of ( )-angustoline21 and of lycorine-type alkaloids.22... 

The past year has witnessed a vast number of synthetic achievements. Details of the previously discussed synthesis of 5-lycorane (18) have been reported. In a novel and possibly general approach to lycorine-type alkaloids, the readily available compound (19) was directly cyclized to a single pentacyclic hydroxy-ketone (20) (Scheme 2) The identity of (20) was established by its four-step conversion into y-Iycorane (21), whose stereochemistry had been elucidated previously. 

These alkaloids are among the most abundant of the bases derived from the [2]benzopyrano[3,4gf]indole nucleus in the Amaryllidaceae family, and the title of this section is derived from this fact. Lycorenine (LXVI) was one of the first Amaryllidaceae alkaloids to be studied and a summary of the chemical degradations leading to this structure (without stereochemical implications) has been given in Volumes II and VI. Lycorenine and the corresponding lactone, homolycorine (LXVII), not only serve as the reference alkaloids of the group for recent spectroscopic studies but also provides a chemical correlation with the lycorine-type alkaloids. Several important chemical interconversions are given below. 

Almost all of the lycorine-type alkaloids isolated from Narcissus present a trans-rmion between B/C rings, making them especially vulnerable to oxidative processes. It is interesting to observe that four of these alkaloids, namely vasconine (22), tortuosine (23), ungeremine (24), and roserine (25) possess an unusual quaternary nitrogen (67 71). The species N. pallidulus (section Ganymedes), unusual because it contains mesembrane-type alkaloids, is even more exceptional due to the presence of roserine. 

The alkaloids of the homolycorine series, formed by a restructuring of lycorine-type alkaloids, are absent from some tribes of the Amaryllidaceae, such as the Amaryllideae or Hemantheae (44). For that reason, the presence of these alkaloids is a distinctive feature of the Narcisseae tribe. Moreover, all the Narcissus alkaloids of the homolycorine series display a B/C ring junction with a cis stereochemistry. An exceptional homolycorine-type alkaloid is dubiusine (33), which has an unusual hydroxybutyryl substituent (72). 

It is well established that profiles of alkaloids vary with time, location, and developmental stage. In many instances, the site of biosynthesis is restricted to a single organ, but accumulation of the corresponding products can be detected in several other plant tissues. Long-distance transport must take place in these instances. There are only a few data on the ontogenic variations and distribution of alkaloids in species of the Amaryllidaceae family, and some results have been obtained in Narcissus species, such as N. assoanus (with only lycorine-type alkaloids) or N. confusus (with alkaloids of the homolycorine, hemanthamine, tazettine, and galanthamine types) 84,87). 

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