A- and y-lycorane

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

An alternative synthesis of ( )-a- and ( )--y-lycoranes (57 and 93) commenced with the 2-oxocyclohexyl acetic acid derivative 114 obtained by the alkylation of the enamine derived from 113 (Scheme 10) (116). Refluxing the oxime of 114 with zinc dust in glacial acetic acid afforded a mixture of the lactams 115, 116, and 117 in an approximate ratio of 4 6 3. The structure of 115 was verified by catalytic hydrogenation to give the lactam 118, which had previously been converted to ( )-a-lycorane (57). When the lactam 116 was subjected to sequential catalytic hydrogenation, hydride reduction, and Pictet-Spengler cyclization, ( )-y-lycorane (93) was obtained. A more efficient route to ( )-a-lycorane (57) involved refluxing the ketone 114 first with benzylamine in xylene and then with 87% formic acid to furnish the unsaturated lactam 119. 

Tlie intramolecular 1,4-chloroamination of 89 was applied to the synthesis of the amaryllidaceae alkaloids a- and y-lycorane (Scheme 8-34) [114]. The hexahydroindole 90... 

Alternative syntheses of a-lycorane (23) and y-lycorane (25) depend on the preparation of unsaturated lactams (20) and (21) whereby ring c is derived from an aryl-cyclohexanone (17) (Scheme 2). Reduction of the oxime of the 2-... 

C.ii.c. Cyclizations Involving Nitrogen Nucleophiles. Heterocyclization catalyzed by palladium complexes has also been applied in nitrogen series for the synthesis of several alkaloids such as ( )-alchomeine, ( )-isoalchomeine, a- or y-lycorane, ( )-heUotridane, ( )-cephalotaxine, and (-)-anatoxin-a (Scheme 33). 

Total syntheses of three tetraacychc diastereomeric alkaloids, a-lycorane TM 9.4, -lycorane TM 9.5 and y-lycorane TM 9.6, have attracted the attention of chemists and pharmacologists for many years. Absolute configurations indicated in the formulae are present in natural products. 

Compounds 1-3 comprise a perhydroindole ring connected to the (3,4-methylenedioxo)aryl unit. This unit is annulated to a tetracyclic structure in lycoranes TM 9.4-TM 9.6. Both sets of compounds comprise three chiral centers in 1 and a-lycorane, their relative configuration is trans,cis, in 2 and P-lycorane it is tram,trans and in 3 and y-lycorane cis,cis. 

Padwa s group has not only developed highly efficient domino reactions using transition metal catalysis, but they are also well known for their unique combinations of a cycloaddition and a N-acyliminium ion cyclization. An example of this strategy, which is very suitable for the synthesis of heterocycles and alkaloids, is the reaction of 4-98 to give 4-101 via the intermediates 4-99 and 4-100 (Scheme 4.22). Furthermore, 4-101 was transformed into the alkaloid (+)-y-lycorane 4-102 [32]. 

A formal synthesis of y-lycorane was accomplished by Vollhardt and colleagues by employing a [2 + 2 + 2] cycloaddition between enyne 589 and 568h (equation 169)344. The reaction afforded a mixture of syn and anti adducts 590 and 591 in a 80 20 ratio when the reaction was conducted at room temperature. When the reaction was conducted in refluxing 568h/THF (1 1, v/v), a syn anti ratio of 60 40 was obtained. A small amount of [2 + 2] adduct 592 was also isolated. This product became the dominant product when the enamide double bond was substituted. The additional steric hindrance probably prevented the enamide double bond from participating in the cycloaddition reaction. 

One facile entry to intermediates possessing the y-lycorane skeleton involved the alkoxide-catalyzed cyclization of the isocarbostyril 34b, which was readily accessible by the N-alkylation of 34a, to provide the y-lycorane derivative 35 (104). The amino derivative 36 was available in three steps from the isocarbostyril 37 by a similar sequence of reactions, but several attempts to prepare the p-unsubstituted enone lactam 38 by this approach resulted in the loss of the N-(4-oxobutyl) appendage by a retro-Michael reaction and were unsuccessful. 

A total synthesis of dihydrolycorine (85), y-lycorane (87) and 8-lyco-rane (92), has been achieved starting from the indanone carboxylic acid 77. This, in turn, was obtained, like the tetralone ester 76, from the known anhydride (75) via Friedel-Crafts cyclization of the monomethyl esters obtained from 75 by treatment with 1 mole of methanol. Reduction of the methyl ester of 77 (LiAlH4), followed by Mn02 oxidation,... 

The compound 77 proved to be a key intermediate for further synthesis in this field. Indeed, ( )-y-lycorane (87) was obtained from 77 through the acid lactam 80. The latter, on treatment with acetic anhydride, gave the imide 86 readily converted upon LiAlH4 reduction and hydrogenation into 87 (10). 

Natural products have always been attractive targets for the application of newly developed synthetic strategies. In this field, only a few examples have been reported, in which intramolecular aryl radical addition reactions occur to non-activated carbon-carbon double bonds [69]. One of the early examples is the first total synthesis of (—)-y-lycorane [70]. More recently, formal total syntheses of aspidos-permidine [71] and vindoline [72] have been accomplished by an aryl radical... 

A synthesis of the natural product y-lycorane starts with a palladium-catalysed reaction. What sort of a reaction is this, and how does it work ... 

Tn and coworkers reported on both kinetically and thermodynamically controlled Michael addition of the lithinm enolates of ketone 135 to nitroethylene 136 as the key step in the total syntheses of the alkaloids ( )-y-lycorane (139) and ( )-crinane (142) (equation 39) °. Both reactions started from the same Michael donor (135) with nitroethylene (136) as a C-C-NH2 synthon for the construction of aryl-substituted... 

Liu et al. [79] further developed a Ru-catalyzed hydrogenation of racemic a,a -disubstituted cycloketones through DKR for the one-step synthesis of chiral diols with three contiguous stereocenters with high diastereoselectivity and enantioselectivity (Scheme 23). This new strategy facilitates the enantioselective total synthesis of alkaloid (-H)-y-lycorane. 

The syntheses of (-l-)-a -lycorane (92) and (+)-trianthine (97) using the retro-Cope elimination step 122), and of (-l-)- y-lycorane (100) using the palladium-mediated reaction 123), have been reported. 

Other groups have reported free-radical approaches to lycoranoids less richly decorated than 66. For example, Rigby has reported a short synthesis of ot-lycorane (67) via an aryl radical-enamide cyclization that constructs the C 2a-Ci2b bond [42]. Padwa focused on the same bond construction via an aryl radical-dihydroindole cyclization in his synthesis of anhydrolycorin-7-one (68) [43]. Both Zard [44] and Cossy [45] have reported syntheses of y-lycorane (69) that involve initial construction of the N-Ci2a bond via cyclization of nitrogen-centered radicals. Both ap-... 

A short synthesis of the tetracyclic y-lycorane derivatives (13a) and (13b) from isocarbostyrils has been reported (Scheme 2). N-Alkylation of (11a) and (11b) with 5-bromo-2-pentanone ethylene ketal gave the ketals (12a) and (12b), respectively. Acid hydrolysis provided the corresponding ketones which upon base-catalysed cyclization yielded compounds (13a) and (13b), respectively. 

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