Lycorane alkaloids

Other cases where the intramolecular variant has been usefully applied include the total syntheses of 9-isocyanopupukeane, lycorane alkaloids,torreyol, eremophilane, valencane, and the bridgehead olefin (131). ... 

An intramolecular version offers useful synthetic methods for heterocycles. The total syntheses of a- and 7-lycoranes (373 and 374) have been carried out by applying the intramolecular aminochlorination of the carbamate of 5-(2-aminoethyl)-l,3-cyclohexadiene (372) as a key reaction[312,313]. Interestingly, the 4,6- and 5,7-diene amides 375 and 377 undergo the intramolecular amina-tion twice via x-allylpalladium to form alkaloid skeletons ofpyrrolizidine (376) and indolizidine (378), showing that amide group is reactive[314]. 

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]. 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

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. 

Herrera MR, Machocho AK, Brun R et al (2001) Crinane and lycorane type alkaloids from Zephyranthes citrina. Planta Med 67(2) 191-193... 

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... 

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... 

Benzyl- and 2-phenethylenaminoketones (XXII Y = NR, n = 1,2) can be cyclized in good yields to quinolines and benzazepines (Table 7, numbers 14 and 15). The cyclization has also been used to prepare a precursor of the alkaloid lycorane [Eq. 

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 alkaloid lycorane (34) provides a more challenging example. It has three adjacent chiral centres, one next to nitrogen. We shall want to disconnect C-N bonds but it it bad strategy to disconnect the chiral centres from nitrogen as we should lose control over the stereochemistry. As (34) is an isoquinoline we can use the Mannich disconnection (Chapter 39) giving (35) and then a simple C-N disconnection to intermediate (36). 

The past year has witnessed a vast number of synthetic achievements. Details of the previously discussed synthesis of 5-lycorane (18) have been reported. In a novel and possibly general approach to lycorine-type alkaloids, the readily available compound (19) was directly cyclized to a single pentacyclic hydroxy-ketone (20) (Scheme 2) The identity of (20) was established by its four-step conversion into y-Iycorane (21), whose stereochemistry had been elucidated previously. 

The conversions of lycorine and caranine derivatives to a- and lycoranes take advantage of the stereoselective catalytic reduction of the 3—3a double bond. In these transformations, the configurations of the asymmetric centers at Cub and Cug are the same as in the parent alkaloids. Because of the trans relationship between the Ci-hydroxyl and the Ciiij-hydrogen, dehydration of the alkaloids and their a- and /3-dihydro derivatives occurs readily with phosphorus oxychloride and pyridine to give 1,11b unsaturation. Catalytic reduction of these olefins... 

Likewise, the P-azidation reaction has been applied to the enantioselective synthesis of the core structure of lycorane Amaryllidaceae alkaloids. The key intermediate 478 in this synthesis was obtained by p-azidation of the TIPS derivative 477 as a mixture of trans- and CM-diastereomers (3.5 1 ratio) (Scheme 3.189) [566]. 

Regioselective C-H activation is often used for intramolecular biaryl preparations in Pd-mediated transformations. Thus concise syntheses of a large collection of alkaloids have been reported using variations of this approach (239-241), which differ mainly in terms of the functionalization of the precursor, palladium catalysts, and ligands. An efficient synthesis of racemic y-lycorane was recently disclosed whereby the key step is the intramolecular a-arylation of a cyclohexanone derivative (242). Some heterocycKc synthetic precursors (e.g. substituted indoles, quinolines, quinolones, phenanthridines, and phenanthridinones) have also been prepared en route to the alkaloids [hippadine, trisphaeridine (70), and crin-asiadine] via Pd- and Cu-mediated reactions (243,244). 

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... 

Using rw-chloroalkenes (e.g., 42) in 1,3-dipolar cycloaddition reactions, Pearson et al. described the synthesis of several alkaloids [20-22]. The reaction proceeds by an intramolecular cycloaddition of an azide onto an alkene, producing an intermediate triazohne. Fragmentation of the triazoUne and rearrangement to a monocyclic imine occurs, which is internally N-alkylated by the alkyl chloride, resulting in iminium ion 43. Reduction with sodium borohydride leads to the racemic lycorane (44). 

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). 

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