Total Synthesis of -y-Lycorane

Abstracted with permission from J. Org. Chem., 1995,60, 2016 01995 American Chemical Society 

---

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... 

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). 

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,... 

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 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... 

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). 

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... 

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. 

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... 

---