Alkaloids metal-mediated reactions

Today, many heterocyclic systems (including indole derivatives which are useful precursors for alkaloid synthesis) have been prepared by transition metal-mediated reactions. 

Angew. Chem. Int. Ed. Engl. 44, 3668-3688, 2005 Kent, M. and Tepe, J.J., One-pot Friedel-Crafts/ Robinson-Gabriel synthesis of oxazoles using oxazolone templates, J. Org. Chem. 70, 4211 213, 2005 Movassaghi, M. and Ondrus, A.E., Enantioselective total synthesis of tricyclic myrmicarin alkaloids, Org. Lett. 7, 4423 426, 2005 Paizs, C., Katona, A., and Retey, J., The interaction of heteroaryl-acrylates and alanines with phenylalanine ammonia-lyase form parsley. Chemistry 12, 2739-2744, 2006. Cuprous ions have been observed to promote a Friedel-Crafts acylation reaction (Kozikowski, A.P. and Ames, A., Copper(l) promoted acylation reactions. A transition metal-mediated version of the Friedel-Crafts reaction, J. Am. Chem. Soc. 102, 860-862, 1980). 

The discussion about the possible formation of metalla-2-oxetanes in transition metal-mediated oxidation reactions began with the ground breaking work of Sharpless in the field of enantioselective dihydroxylation of olefins with osmium tetraoxide using cinchona alkaloids as ligands [6]. The transfer of the stereochemical information of the chiral ligand to the substrate was explained by Sharpless with a two-step mechanism for the addition reaction, which should occur rather than a concerted [3+2] addition as originally proposed [110] (Fig. 15). 

Heteroatom-assisted metallation reactions are very common and especially useful for the selective o-functionalisation of aromatic compounds. More recently, activation of non-aromatic substrates has attracted attention but only a few examples pertinent to protecting groups will be cited here. Kerrick and Beak [Scheme 1.53] showed that pyrrolidine protected with a /err-butoxycarbonyl (Boc) group 53.1 is enantioselectively deprotonated by 5cc-BuLi activated by the alkaloid (-)-Sparteine (533). Enantioselective deprotonations mediated by (-)-Sparteine were first exploited by Hoppe and co-workers for the metallation of saturated and allylic - carbamates. 

Abstract An overview of recent transition metal-catalyzed syntheses of pyrroles and carbazoles is presented. The focus is on methods which have been applied to the preparation of biologically active namrally occurring pyrrole and carbazole alkaloids. For pyrroles, special attention is paid to silver(I)-catalyzed cyclization reactions. For carbazoles, iron(0)-mediated and palladium(0/ll)-catalyzed cychza-tion reactions are highlighted and their broad range of applications is discussed. 

Transition metals, especially palladium, have been used for the stereoselective synthesis of these alkaloids with remarkable success. Since Overman s approach to (+)-tazettine (62) using an intramolecular Heck reaction (225), this methodology for the construction of the critical quaternary stereogenic center has been implemented for the preparation of many alkaloids. Grigg later reported access to (R,R)-crinane via regiospecific palladium-mediated cyclization (226). An efficient total synthesis of racemic galanthamine (75) following this approach has been recently disclosed (227). After the key intramolecular Heck reaction, deprotection of the... 

In N-acyliminium ion-mediated functionalization of 2- or 6-alkoxy-substituted piperidines, Sc(OTf)3 was found to be an excellent Lewis acid with a silyl enol ether nucleophile, and moderate diastereoselectivities were obtained (trans/cis = 26/74 and 78/22, respectively) [158]. Sc(OTf)3 was found to be a more efficient metal tri-flate in the nucleophilic substitution of N-benzyloxycarbonyl-2-methoxypiperidine and 3-substituted-2-acyloxy-N-benzyloxy-carbonylpiperidine with silylicon enolates [159]. 2-Acetoxy-3-benzyloxy-N-benzyloxycarbonylpiperidine afforded the 2-alkylat-ed adducts in high cis selectivity (cis/trans = 71/29), while 2,3-diacyloxy-N-benzyl-oxycarbonylpiperidines showed trans selectivity (trans/cis = 80/20-100/0). Febri-fugine, a potent malarial alkaloid, was successfully synthesized from 2,3-diacetoxy car bony Ipiperidine on the basis of these diastereoselective nucleophilic substitution reactions. 

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