Lycorine alkaloids synthesis

This method can be applied to the total synthesis of natural products. The lycorine alkaloids anhydrolycorinone and hippadine have a pyrrolo[3,2,l-de]phenanthridine framework and have been isolated from Amaryllidaceae plants [26]. Hippadine exhibits reversible inhibition of fertility in male rats. Diverse synthetic approaches to the pyrrolophenanthridine alkaloids have been developed because of their potent biological activities [27[. We applied the iron(O)-mediated arylamine cydization described above to a concise synthesis of anhydrolycorinone and hippadine (Scheme 15.7) [28]. 

Although one-electron oxidation of arenes by thallium trifluoroacetate presumably does not proceed via formation of a discrete aiylthallium bond, some examples involving oxidative cyclization mediated by thallium trifluoroacetate will be considered here. Schwartz and Hudec employed thallium trifluoroacetate to effect an intramolecular cyclization of the amide (41) to give a key intermediate (42) in their projected synthesis of lycorine alkaloids (Scheme 16). Interestingly, when the bromine was replaced by a hyctogen the yield was poorer. 

A photochemical ring construction similar to that described in Scheme 5 was used in the synthesis of the aromatic lycorine alkaloid ungeremine (51) (Scheme 6). Photocyclization of the somewhat inaccessible imine (48) gave the phenanthridine derivative (49) in 21 % yield which upon metal hydride reduction and cyclization with phosphorus tribromide afforded the quaternary salt (50) which was shown to be identical with the methyl ether of ungeremine (51) obtained as shown. 

Fortucine 112, first isolated from the Fortune variety of narcissus by Tokhtabaeva et al. [43] in 1987, is a Lycorine alkaloid. To clarify the structure, Zard and coworkers [44] carried out the first total synthesis of ( )-fortucine using a radical domino process as the key step (Scheme 5.23). It was suggested that an amidyl-nitrogen radical is generated from 110, followed by a 5-exo-trig cyclization in sequence with... 

Amide Formation. The synthesis of an amide can be accomplished by initial reaction of an acid with PhsP-CCU and then reaction of the intermediate with 2 equiv of the appropriate amine. A tertiary amine, such as Diisopropylethylamine, can be employed as the HCl scavenger in cases where one would not want to waste any of a potentially valuable amine.This method has been used in the construction of an amide in the synthesis of the skeleton of the lycorine alkaloids (eq 29). ... 

Lycorine is the most abundant alkaloid in plants of the Amaryllidaceae. Several syntheses of racemic lycorine had been reported prior to our initiation of studies directed at an asymmetric synthesis of the unnatural enantiomer 64. 2 a common theme in all of the syntheses of ( )-lycorine has been the utilization of either an intermolecular or intramolecular Diels-Alder construction of the key C-ring of the alkaloid. This six-membered ring presents a rather formidable synthetic challenge because of the four contiguous stereogenic centers, the trans 1,2-diol moiety, and the juxtaposition of the aromatic substituent and the carbon-carbon double bond. 

Lycorine. Boeckman s particularly elegant synthesis [65] (Scheme 41) of the most abundant Amaryllidaceae alkaloid, (-)-lycorine (245) [66], known since 1877 [67], involved an intramolecular Diels-Alder reaction of an appropriately functionalised azatrienic system. This approach (A + D - AD - ADCB) somewhat reminiscent of the one used by Stork for ( )-7-oxo-a-lycorane [68], possessed the virtue of establishing the correct stereochemistry of four... 

A recently published full account of another synthesis [69] of the same alkaloid starting from the /rans-cinnamic ester 264 represented a different approach (ACD -> ACDB) to ( )-lycorine (Scheme 42). An intramolecular Diels-Alder reaction of 264 in o-dichlorobenzene furnished the two diastereomeric lactones 265 (86%) and 266 (5%) involving the endo and exo modes of addition respectively. The transposition of the carbonyl group of 265 to 267 was achieved by reduction with lithium aluminium hydride, followed by treatment of the resulting diol with Fetizon s reagent, which selectively oxidised the less substituted alcohol to give isomeric 5-lactone 267. On exposure to iodine in alkaline medium 267 underwent iodolactonisation to afford the iodo-hydroxy y-lactone 268. The derived tetrahydropyranyl ether... 

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... 

Recent advances in the chemistry of alkaloids of the Amaryllidaceae have been mostly concerned with synthesis, and substantia] progress has again occurred in this area during the year now under review two new syntheses of the lycorine ring system and a synthesis of tazettine are particularly noteworthy. 

Umezawa and co-workers9 have reported a new synthesis of the tetracyclic lactam (19), which is a key intermediate in Torssell s synthesis of lycorine (cf. Vol. 9, p. 139) the Japanese work (Scheme 2), therefore, represents a formal synthesis of the alkaloid. The cyclohexyl isocyanate (15) (trans-diequatorial aryl and isocyanate groups) cyclized to a tricyclic lactam, which by reduction with a hydride and hydrolysis gave the ketone (18). The tetracyclic ketone (16) was converted into the 2,3-ene (17) by a Cope elimination reaction, and the synthesis of compound (19) was completed by transposition of the lactam carbonyl group from C-5 to C-7. 

This group has been included in a review that describes the synthesis of several types of alkaloids by intramolecular radical-coupling reactions.1 A review of the total synthesis of lycorine and related alkaloids is not easily accessible.2... 

A number of Amaryllidaceae alkaloids, including haemanthamine, lycorine, narciclasine, and pretazettine, have been shown to inhibit the fundamental step of the formation of a peptide bond in protein synthesis.14... 

The phenanthridine alkaloid lycorine (narcissine, galanthidine) (MD—Phe G5N C6) has a widespread occurrence and inhibits protein synthesis. Like lycorine, the structurally similar alkaloids dihydrolycorinine, haemanthamine, narciclasine, pretazettine and pseudolycorine also inhibit protein synthesis at the level of peptide bond formation. Galanthamine (lycorimine) (Phe C6N C40 C6 ), from daffodil bulbs but also of widespread occurrence, is both a nACh-R allosteric modulator and an inhibitor of AChE. Galanthamine is clinically employed in the treatment of Alzheimer s disease (dementia linked to deficiency in acetylcholine-mediated signalling in the central nervous system). 

The use of enamide photocyclization in the synthesis of Amaryllidaceae alkaloids has remained a basic study and so far limited only to the synthesis of the skeletons of lycorine and crinine, as well as intermediates in the total synthesis of haemanthidine and nortazettine, and some of the degradation products of these alkaloids. 

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... 

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. 

The total synthesis of dihydrolycorine (38), the sole hydrogenation product of lycorine (6 R1 + R2 = CH2, R3 = R4 = H) and an alkaloid in its own right, has been reported.27 Scheme 3 shows how treatment of the Diels-Alder adduct (33) with methanol gave a mixture of two half-esters which were directly subjected to Friedel-Crafts cyclization to give the indanone ester (34) and a rearrangement product. Attempted Schmidt ring expansion on (34) failed, but a prior reduction-oxidation sequence followed by treatment with sodium azide and hydrolysis produced the desired lactam (35) and an isomeric compound whose structure remains undetermined. Lactam (35) was readily converted into a chain-extended... 

Finally, lycorine inhibited the growth of rho+, mit and rho strains of Saccharomyces cerevisiae, while rho0 strains (devoid of mitochondrial DNA) were resistant to high concentrations of the alkaloid. Total protein synthesis and mitochondrial protein synthesis are only slightly inhibited by lycorine. It had, however, an inhibitory effect on DNA and RNA [172],... 

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. 

A synthesis of the alkaloid narseronine 53 that highlights yet another novel mode of cyclisation of arylated cyclohexenes derived from compound 67 is shown Scheme 9 (White et al., unpublished work [45]). Thus, nitrile 73 (generated from precursor 67 during the course of our synthesis of the lycorine degradation product 79 as shown in Scheme 6) was reduced with dihydrogen in the presence of Raney-cobalt and the resulting primary amine was then protected as the corresponding... 

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