Intramolecular cycloadditions alkaloid systems

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>. 

Unique synthetic opportunities, particularly in alkaloid chemistry, are opened up on applying this protocol to diazo imides bearing a tethered heterocyclic ring. Thus, isomunchnone dipole, which is derived from these compounds, undergoes intramolecular cycloaddition across the heterocyclic CT-bond to produce bridged polyfused systems. Some examples of reactions with 2-furyl- and 1-indolyl-substituted substrates are shown in Schemes... 

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... 

The intramolecular oxidation using nitrogen nucleophiles was developed further by using an amide with the ability to undergo a twofold attack on the diene (Scheme 12). This leads to a bicyclic system and constitutes a useful [4 + 1] intramolecular cycloaddition, which gives access to pyrrolizidine and indolizidine alkaloids. " ... 

The Keck group described an approach to the pyrrolizidine alkaloids that revolved around acylnitroso Diels-Alder chemistry. The plan, outlined within the context of an approach to heliotridine (38), was to once again use an intramolecular N-alkylation to construct the N4-C3 bond. N-Alkylation substrate 39 was to be prepared by reduction of the N-O bond of 40, which was to result from an intramolecular cycloaddition of 41. It was hoped that the C7 substituent might induce relative stereochemistry at 07 by occupying a site on the convex face of the incipient azaoxabicyclo[4.3.0]nonane ring system in the cycloaddition transition state. Note that the cycloaddition of 41 establishes the olefin geometry needed to support the intramolecular N-alkylation. 

As a viable approach to the synthesis of lysergic acid, intramolecular cycloaddition of alkenyl- and alkynyl-substituted diazoimides 194 across a transient isomunchnone dipole was investigated, aiming at the construction of the ring system of the quinoline ring system (C and D rings) of the ergot alkaloids (79). 

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... 

Tandem, Double-Intramolecular Cycloaddition Toward the Synthesis of Daphnilactone B The structure of amide 420 resembles the core of the naturally occurring alkaloid daphnilactone B 421 (Figure 16.15) [165]. The B/C/D ring system of 421 is clearly present in 420. The total or even partial synthesis [46, 47, 83a, 147, 148] of such a complex alkaloid would demonstrate the power of the tandem, double-intramolecular cycloaddition of nitroalkenes for creating polycyclic natural products in a stereocontroUed fashion. 

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. 

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]. 

Padwa has reported an approach to the ring system of the ribasine alkaloids 98 [174], using an intramolecular 1,3-dipolar cycloaddition of the a-diazo ketone 99 to produce the pentacyclic skeleton 100 (Scheme 19.17). Wood [175] used an intermolecular 1,3-dipolar cycloaddition of a carbonyl ylide for the total synthesis of ( )-epoxysorbicilli-nol 101 (Scheme 19.18). The key cycloaddition in this approach is the conversion of 102 to the natural product core 103, which sets the substitution pattern around the entire ring system in a single step. 

In an approach to the clavine alkaloids [170] based on intramolecular nitrone-alkene cycloaddition, the condensed tetracyclic system is probably favored by steric factors. Equilibration at higher temperature leads to predominantly a bridged oxabicyclo-[3.2.1]nonae derivative in which a portion of the molecule contains polarity alternation sequence (OCOC=0, N-C-C-C=0). 

A novel route to the azepinone system in 93 and 94, based on an intramolecular nitrone-eneallene cycloaddition (in 91 and 92, which were accessed in turn from 88 via 89 and 90) and subsequent rearrangement via N-O bond homolysis and an electrocyclic recyclization step) has been described (Scheme 11) <2005EJ02715>. On heating 93 in toluene, equilibrium with the isomeric azepinone 95 was established, although comprising less than 3% of 95. The general synthetic approach was applied to the synthesis of an analogue of the alkaloid astrocasine. 

Scheme 75). The D/E ring system of these alkaloids has been constructed by the intramolecular [4 + 2]-cycloaddition of an oxadiene with an ot,P-unsaturated amide. Thermolysis of the diene 580 at 190°C in xylene produced a 4.5 1 mixture of the cis and trans- cycloadducts 581 and 582, respectively. They could be separated to provide cis-lactam (73%). Subsequent hydride reduction of 581 with aluminum hydride produced the tertiary amine 583. Acylation of 583 with trichloroacetyl chloride followed by a haloform cleavage gave the ester 584. Finally, hydrogenolysis of the iV-benzyl group provided the known bicyclic amine 585, which was previously converted to a mixture of 586 and 587. 

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. 

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