Y -Lycorane

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]. 

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. 

H. Yoshizake, H. Satoh, Y., Satoh, S. Nukui, M. Shibasaki, M. Mori, Palladium-Mediated Asymmetric Synthesis of Cfs-3,6-Disubstituted Cydohexenes. A Short Total Synthesis of Optically Active (+)-Y-Lycorane , J. Org Chem 1995, 60, 2016-2021. 

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. 

The reduction of heterocyclic compounds is a versatile process of great use in the synthesis of alkaloids185. The choice of catalyst is crucial however, as illustrated by the indolizidine alkaloid synthesis shown in Scheme 34185a. The reduction of 37 to 38 proceeds with a very high degree of stereocontrol which sets up the correct framework for intramolecular cyclization to complete a short synthesis of y-lycorane 39186. 

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. 

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. 

An important advance was made when it was observed that photolysis of the (3-enamido ketone 165, which was readily available from the indoline 163 by Birch reduction followed by N-aryloylation, delivered the lactam 168 as the only photoproduct (Scheme 17) (125). Reduction of 168 with LiAlH4 gave ( )-a-anhydrodihydrocaranine (143), which was then converted to ( )--y-lycorane (93) on hydrogenation over Adams catalyst in acetic acid. In a similar fashion, irradiation of the bromo or iodo enaminones 166 (Z = Br, I), which were obtained by alkylation of the intermediate imino ether formed on Birch reduction of 163, afforded a mixture (approximately 3 2) of the lactam 168 together with the photoreduction product 167 (126). 

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). 

The total syntheses of clivonine (114) and clividine (138) have been achieved from the anhydride 75 already used in the syntheses of dihydrolycorine (85), y-lycorane (87), and S-lycorane (92). Treatment of 75 with MeOH mainly gave the half ester 127 which was converted into the urethane 131 via the acid chloride 128, the azide 129, and the isocyanate 130. The desired methyl ester 132 was obtained from 131 through the corresponding chloride and diazoketone. The... 

Stereochemistry has been a serious issue in all the syntheses of lycoranes but it dominates in one synthesis12 of y-lycorane 73. All three hydrogens at the chiral centres are on the same face so the idea is that two of them could be put in by catalytic hydrogenation of a pyrrole such as 104 or 105 from the less hindered side of the alkene. 

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 ... 

Finally, this mixture must be converted into y-lycorane suggest how this might be done. 

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... 

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... 

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