Lycorane, total synthesis

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 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,... 

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... 

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. 

Cobalt-mediated [2-I-2-I-2] cycloaddition of an alkyne to the double bond of an enamide has been found to give spontaneously the lycorane ring system 127). Thus, a formal total synthesis of ( )--y-lycorane (100) has been achieved by this methodology. Also, ( )-y-lycorane (100) has been synthesized starting with pyrrole 128) or homophthalimide 129). 

The next series of syntheses is based on conjugate additions. A 2-arylcyclo-hexanone was regio- and stereoselectively added to nitroethylene to access the octahydroindole core present in the alkaloids. This has enabled the total synthesis of (+j-y-lycorane and (+)-crinane (280). Tomioka described a chemoselective conjugate addition - nitro Michael reaction sequence to prepare a- and -lycoranes in their racemic form (281). The addition of an arylcuprate to a D-mannitol-derived... 

Acetaldehyde also engaged in other conjugate additions with poly-conjugated substrates, such as nitrodienynes and nitroenynes. Interestingly, only 1,4-additions were observed and no 1,6- or 1,8-addition occurred. The utility of the products was demonstrated by the enantioselective total synthesis of (- -)-a-lycorane (Scheme 8.2). ... 

Further utihzation of this general method for the preparation of other alkaloids was subsequendy demonstrated by Pearson and Schkeryantz in the total synthesis of ( )-lycorane (118) (1992JOC6783). The intramolecular 1,3-dipolar cycloaddition of azide 115 in benzene at 140 °C followed by extrusion of nitrogen gave the unstable iminium salt 117. This intermediate was then reduced with sodium borohydride to afford ( )-y-lycorane 118 in 63% yield from azide 115 (Scheme 27). 

We start the retrosynthetic analysis of structures 1-3 related to lycoranes and then discuss some examples of non-asymmetric and asymmetric total synthesis of these target molecules. 

Another inventive total synthesis of ( )-a- and ( )- lycorane is completed by sequential chemoseleclive conjugate addition-stereoselective nitro-Michael cyclization of a to-nitro-a,p,< ),a)-unsaturated ester [32]. This approach is based on the following retrosynthelic analysis (Scheme 9.21). 

A short total synthesis of enantiopure of (+)-y-lycorane, based on the asymmetric alkylation of cyclohexene 1,4-diol derivative, was first reported in 1995 [35] and... 

Magnus developed also a combination of iodosyl benzene and trimethylsilyl azide to azidate the j8-carbon of silyl enol ethers (Scheme 8.22). ° ° The total synthesis of lycorane amaryllidaceae alkaloids takes advantage of this process. A tentative ionic mechanism is proposed for this process. However, involvement of radicals cannot be totally excluded. Under the same reaction conditions, anilines and amides lead to the isolation of C-H substituted products at carbon atoms adjacent to nitrogen (Scheme 8.23). These azidoamines/azidoamides are precursor of iminium/acycliminium ions that are useful intermediates for C-C bond formation. 

H-)-y-Lycorane, isolated from plants of the Amaryllidacae family, has attracted substantial attention for its total synthesis, due to its unique pentacyclic structure [45]. In 1995, Yoshizaki et al. reported the first asymmettic synthesis of (-rj-y-lycorane... 

Yoshizaki H, Satoh H, Sato Y, Nukui S, Shibasaki M, Mori M. Palladium-mediated asymmetric synthesis of cis-3,6-disubstituted cyclohexenes. A short total synthesis of optically active (- -)-7-lycorane. J. Org. Chem. 1995 60(7) 2016-2021. 

Chapsal BD, Ojima I. Total synthesis of enantiopure (+)-7-Lycorane using highly efficient Pd-catalyzed asymmetric allylic alkylation. Org. Lett. 2006 8(7) 1395-1398. 

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