Cycloaddition reactions alkaloid systems

Mejla-Oneto and Padwa have explored intramolecular [3+2] cycloaddition reactions of push-pull dipoles across heteroaromatic jr-systems induced by microwave irradiation [465]. The push-pull dipoles were generated from the rhodium(II)-cata-lyzed reaction of a diazo imide precursor containing a tethered heteroaromatic ring. In the example shown in Scheme 6.276, microwave heating of a solution of the diazo imide precursor in dry benzene in the presence of a catalytic amount of rhodium I) pivalate and 4 A molecular sieves for 2 h at 70 °C produced a transient cyclic carbonyl ylide dipole, which spontaneously underwent cydoaddition across the tethered benzofuran Jt-system to form a pentacyclic structure related to alkaloids of the vindoline type. 

The reader was given a taste of the power of isomiinchnone dipolar cycloaddition chemistry in Section 10.2.1. As discussed by Potts (1) and Gingrich and Baum (10), the isomiinchnone ring system—a masked carbonyl dipole—is exceptionally reactive as a 1,3-dipole in 1,3-dipolar cycloaddition reactions. In the intervening years since these two excellent reviews the major research efforts in isomiinchnone chemistry have entailed synthetic applications to specific targets such as alkaloids and other natural and unnatural products. 

In summary, the cycloaddition reactions of 1,2-dihydropyridines have proven to be very useful in the total synthesis of natural products. The primary reasons for their utility are that they have electron-rich reactive 7r-systems, they contain a heterocyclic nitrogen atom for alkaloid synthesis, and the stereochemistry is controlled in their cycloaddition reactions. 

A synthesis of the antitumor agent elliptidne has utilized the indolyl-substituted oxazole (351) as a key intermediate (77JOC2039). Diels-Alder reaction of (351) with acrylonitrile in acetic acid afforded a pyridinecarbonitrile (352) which was reacted with methyllithium, and the ketimine salt was hydrolyzed and cyclized to ellipticine (353 Scheme 76). Other Diels-Alder reactions of this type, particularly intramolecular cycloadditions of oxazoles with alkenic dienophiles should provide rapid access to a variety of alkaloid systems. 

Intramolecular cycloaddition reactions have been performed on the furan-containing indoles 143, to provide an efficient route to numerous derivatives of the tetracyclic ring system 144, a structural motif of Aspidosperma and Strychnos alkaloids <02OL4643>. 

The ABCD ring system of the diterpene alkaloid atisine was constructed by T. Kametani et al using an intramolecular Diels-Alder cycloaddition reaction as the key step. The dienophile was obtained by the traditional Hofmann degradation of the corresponding dimethylamino precursor. The diene was prepared by the kinetic enolization of the cyclohexenone system with LDA. 

Padwa A, Price AT (1995) Tandem cyclization-cycloaddition reaction of rhodium carbenoids as an approach to the aspidosperma alkaloids. J Org Chem 60 6258-6259 59. Padwa A, Price AT (1998) Synthesis of the pentacyclic skeleton of the aspidosperma alkaloids using rhodium carbenoids as reactive intermediates. J Org Chem 63 556-565 Mejia-Oneto JM, Padwa A (2004) Intramolecular [3+2]-cycloaddition reaction of push-pull dipoles across heteroaromatic p-systems. Org Lett 6 3241-3244 61. Padwa A, Lynch SM et al (2005) Cycloaddition chemistry of 2-vinyl-substituted indoles and related heteroaromatic systems. J Org Chem 70 2206—2218... 

Hetero-substituted dienes and dienophiles have been used extensively in intramolecular cycloaddition reactions, for example towards the synthesis of alkaloid ring systems (e.g. see Scheme 3.40). A synthesis of the alkaloid manzamine A makes use of the substituted triene 90, which cycUzes to the tricyclic ring system 91 (3.77). In this example, the one stereocentre in the triene 90 controls the formation of the three new chiral centres in the product 91. 

Intramolecular cycloaddition reactions with 2-azadienes have found limited apphcation in organic synthesis, however an efficient route to the daphniphyllum alkaloids makes use of such a cycloaddition. " The 2-azadiene 101 was formed in situ from the diol 100 by Swern oxidation (to the dialdehyde) and addition of ammonia (3.82). Cycloaddition in the presence of acetic acid at room temperature gave the complex ring system 102. If the reaction mixture is warmed to 70 °C... 

Herein, three syntheses of morphine or related alkaloids are discussed in detail, which utilize completely different protocols for the coupling of the ring motifs of the alkaloid. Rice published a biomimetic approach with an acid-mediated electrophilic cyclization strategy as key step [144]. Mulzer employed a Friedel-Crafts acylation and a Robinson annulation to construct the phenanthrenone ring system [145]. The D ring of the alkaloid was elaborated with a 1,4-cuprate addition as key step. In his most recent contribution to morphine research, Hudlicky employed a Diels-Alder cycloaddition reaction to construct the ABCE ring system of the natural product. The requisite diene was obtained after oxidative dearomatization of the A ring precursor [146]. 

Very recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core ring system of indole alkaloids (Scheme 16) (174-178). Intramolecular cycloaddition reactions often benefit from higher reactivity and greater control of stereoselectivity relative to their intermolecular counterparts. Unlike Bodwell s lEDDA reaction (Scheme 13), the reaction of an electron-rich furan moiety with an N-acyl indole moiety required only a single tether. His synthesis also involved... 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

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