Lycorane, synthesis

T 40. A recent synthesis of lycorane also uses the Dlels -Alder as a key reaction but approaches it... 

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. 

The synthesis of lycorane (13) by Mori and Shiba-saki121 is breathtaking for its use of three consecutive Pd catalyzed C-C bond forming reactions. Thus, Pd-catalyzed asymmetric allylic substitution of a benzoate in meso 7 in the presence of the chiral bisphos-phine 8 leads to the regioselective formation of 10 in 40 % ee It is easy to overlook this low level of enantioselectivity when we are faced with the subsequent elegant Pd-catalyzed reactions Pd-catalyzed intramolecular animation is followed by a Pd-catalyzed Heck coupling to afford 12, which is then readily converted to the target molecule... 

Scheme 2. Pd-catalyzed asymmetric allylic alkylation of 7 is followed by a Pd-catalyzed intramolecular C-N bond formation and a Pd-catalyzed intramolecular Heck-type alkylation in Mori and Shibasaki s total synthesis of lycorane (1995).

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. 

Pearson and Schkeryantz (56) developed a novel approach for synthesis of (i)-lycorane (280) using an intramolecular cycloaddition of an azide with an co-chloro alkene (Scheme 9.56). The bromide 276 was smoothly converted into the required chloro azide 277 in several steps. 1,3-Dipolar cycloaddition of the azide 277 in benzene at 140 °C followed by extrusion of nitrogen gave the unstable... 

Radical cyclization is an effective approach to the synthesis of isoquinolines (Scheme 8). In some cases these offer an alternative to the palladium-catalyzed reactions with aryl halide intermediates <99EJOC1925, 99TL1125>. For example, the radical cyclization of the iodide 37 onto the vinylsulfide moiety was followed by a cascade cyclization to form the benzo[n]quinolizidine system <99TL1149>. In some cases the radical cyclization can take place without the need for a halo intermediate. The reactive intermediate of 38 was formed on the nitrogen as an amidyl radical, which underwent tandem cyclizations to the lycorane system <99TL2125, 99SL441>. 

Carbanions derived from side chain tertiary amides have also been cyclized to provide isoquinolones and isoindoles (equation 36).125 126 While benzyne intermediacy in the formation of the former is likely, the latter seems to arise through a SrnI reaction pathway. Synthesis of indole from the meta bromo compound (87), on the other hand, clearly involves an aryne cyclization. 27 A more versatile route to indoles is based on intramolecular addition of aminyl anions to arynes (equation 38).128 A somewhat similar dihydroindole preparation constitutes the first step in a synthesis of lycoranes (equation 39).129 The synthesis of (88) also falls in the same category of reactions, but it is noteworthy because only a few examples of ring closure of heteroarynes are mentioned in literature.27 28... 

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. 

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... 

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 intramolecular [3 + 2] dipolar cycloaddition reaction has also been exploited in the design of a concise, stereospecific synthesis of ( )-a-lycorane (57) (119). Thus, cyclization of the azomethine ylide 145, which was produced in situ by the reaction of 144 with IV-benzylglycine, in refluxing toluene furnished the cw-hydroindole 146 as the exclusive product (Scheme 14). The transformation of 146 to racemic a-lycorane (57) was then achieved by N-debenzylation via catalytic, transfer hydrogenation and subsequent Pictet-Spengler cyclization. 

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). 

An alternative is to put the alkene in another place 84 and discover a different pair of diene 86 and dienophile 85. Again the -isomers will be easier to make and this time we get the right stereochemistry 88 for a-lycorane 71. This strategy was followed in an early synthesis by Hill.9 Another synthesis using the Diels-Alder reaction is by Irie.10 More details appear in the workbook. 

Among other important reactions that build up a molecule rapidly are aldol and conjugate addition. Together with Diels-Alder and Wittig reactions they are major players in organic synthesis. Another synthesis of lycoranes uses these reactions.11 Similar preliminary disconnections with the addition of a carbonyl group 89 lead to the amino acid 90. 

Reductive removal of the amide carbonyl with borane and Mannich closure of the middle ring give P-lycorane 72. A feature of this synthesis is that by changing the order of events and by adding ArLi with chelation control, all three lycoranes can be made selectively. 

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... 

Synthesis This is the method used in the synthesis of TM271 as an intermediate for a-lycorane (j. Amer. Chem. Soc.. 1962,, 4951). 

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 ... 

The last example consists of the synthesis of lycorane skeletons by an intramolecular cycloaddition of the azomethine ylide generated by the decarboxylation route (Section II,E). Thus, 3,4-(methylenedioxy)phenyIaceto-nitrile is deprotonated with LDA and then alkylated with 5-bromo-l-pentene... 

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