Alkaloids intramolecular cycloadditions

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

The intramolecular cycloaddition has proven to be the method of choice for the preparation of steroids. A diastereomeric mixture of 204, prepared from 191 and tosylate 203 has been cleanly converted to dl-estra-1,3,5(10)-trien-17-one (205) in 85% yield (equation 130). A second example of the intramolecular cycloaddition reaction is the formation of the cycloadduct (209), the key intermediate in a synthesis of the As-pidosperma alkaloid aspidospermine, upon heating 208 at 600 °C (equation 131)124. The sulfone 208 can be prepared by reaction of 3-ethyl-3,4,5,6-tetrahydropyridine (206) with the acid chloride 207. 

Oppolzer and Robbiani have reported highly stereoselective total syntheses of alkaloids such as chelidonine by an intramolecular o-quinodimethene/nitrostyrene-cycloaddition (Scheme S.7).34 (Benzocyclobutane is used as a source of quinodimethene). The high regio- and stereoselectivity in the intramolecular cycloaddition is remarkable a strong preference for transition state, exo-N02, over transition state, emfo-N02, is responsible for the stereoselectivity. 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

An intermediate 5-hydroxy-5,6-dihydro-2/7-pyrrolo[l,2- ][l,2]oxazin-7(4a//)-one 142 has been described in the total synthesis of (—)-loline, a pyrrolizidine alkaloid extracted from rye grass Lolium cuneatum. The key step of the synthesis was an intramolecular cycloaddition of acylnitrosodienes (obtained by in situ oxidation of the corresponding hydroxamic acids 143). This reaction generated predominantly the rro/o-stereoisomer that was further cleaved at the N-O bond with Na(Hg) and further elaborated in several steps to reach the target compound (Scheme 19) <2001J(P 1)1831 >. 

When propargylamine 183 was subjected to a homologative allenylation (Crabbe reaction) at 100 °C, the resulting allene underwent a spontaneous Diels-Alder reaction to give the adduct 184. This intramolecular cycloaddition-oxidation sequence provided a simple route to indole alkaloids such as hippadine and ds-trikentrin B [148]. 

Manzamine alkaloids can be isolated from marine sponges. They often contain /3-carboline. This group has a diverse range of bioactivities. It also has its own way of establishing its structures. An intramolecular Diels-Adler reaction for manzamines has been proposed. The a is bisdihydropyridine (derived probably from amonia), and the (3 is intramolecular cycloaddition in a pentacyclic... 

Natural (—)-actinidine (9a) is prepared from nepetalinic acid imide (262) via dichloropyridine (263) 403) and from iridodial (264) via bis (2,4-dinitrophe-nyl)hydrazone 404) or treatment with ferric ammonium sulfate (Scheme 19) 405). (+)-Actinidine (9b), the enantiomer of natural alkaloid, is synthesized from acid chloride 265, derived from (+)-pulegone, via vinylketone 267 (Scheme 20) 406). Racemic actinidine (9) is prepared by intramolecular cycloaddition of an acetylene across a pyrimidine ring in 5-(hept-5-yn-2-yl)-4,6-dihydroxypyrimidine (268) followed by chlorination and hydrogenation (Scheme 21) 407). 

Confalone et al. (85) also made use of an intramolecular cycloaddition step in the construction of a range of tri- and tetracyclic products. Phenyl allyl ethers, of the type shown in Scheme 3.94, underwent dehydrative condensation with the requisite amine to furnish the intermediate ylides, which suffered cycloaddition resulting in 285 and 286 in essentially quantitative yield. The ratio of cis/trans fused products was in the range of 10 1. Such a process has been developed to construct the alkaloid (+ / ) sceletium A4 by reaction of the intermediate 287 with amine 288 via the cycloaddition protocol already developed, followed by further chemical manipulation, in an efficient five step synthesis (Scheme 3.94). 

Cha and co-workers (50) reported a short enantioselective synthesis of the indo-lizidine alkaloid, (—)-swainsonine (247) involving an intramolecular cycloaddition... 

Pearson et al. (68) reported a versatile approach to pyrrolizidine and indolizidine alkaloids such as 355, 247, and 362 using intramolecular cycloadditions of azides with electron-rich dienes (Scheme 9.68). Azido dienes 353, 357, and 360 that possess a electron-donating group on the diene were prepared from the respective compounds 352, 356, and 359. On heating at 100 °C, the azido diene 353 underwent smooth intramolecular 1,3-dipolar cycloaddition in a stereoselective... 

The intramolecular cycloaddition reaction of enamides has recently been exploited in alkaloid synthesis (81JOC3763). Application of A2-piperideine derivatives resulted in the... 

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. 

A synthesis of the monoterpene alkaloid ( )-actinidine has been accomplished through the intramolecular cycloaddition of a substituted pyrimidine (81JCS(P1)1909). Condensation of the diester (756) with formamidine provided the pyrimidine precursor (757) which when heated at its melting point (203 °C) underwent cycloaddition with elimination of isocyanic acid to produce the pyridone (758). Conversion of the pyridone into the chloropyridine was effected with phosphoryl chloride. The chlorine atom was then removed by hydrogenoly-sis over palladium on charcoal to afford the racemic alkaloid (759 Scheme 175). 

The decomposition of 368 catalysed by Rh perfluorobutyrate and subsequent intramolecular cycloaddition give 370 in high yield (93%) as the key step in the total synthesis of lysergic acid (371), and is believed to involve the intramolecular reaction of the ylide intermediate 369 at the alkene. No C—H insertion takes place [122], Another elegant example is the efficient construction of the aspidosperma alkaloid skeleton 374. The Rh-catalysed domino cyclization cycloaddition of diazo irnide 372 afforded cycloadduct 374 in 95% yield as a single diastereomer via the dipole 373, and desacetoxy-4-oxo-6,7-dihydrovindorosine (375) has been synthesized from 374 [123]. 

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>. 

Tetrahydroalstonine 7-7, a heteroyohimboid alkaloid, has been synthesised in enantiopure form by Martin et al. by means of an oxa Diels-Alder reaction as key step. The trienic precursor 7-5 underwent a thermal intramolecular cycloaddition to form a 5 1 mixture of 7-6 and its 15/J-epimer. The main cycloadduct was then subjected to a straightforward sequence to yield the natural product 7-7 (Fig. 7-2) [483-485]. In earlier work, Ogasawara et al. have employed a con-ceptionally different domino Knoevenagel-hetero Diels-Alder approach to this alkaloid and other natural products [486-488]. 

Two very elegant alkaloid syntheses basing on intramolecular cycloadditions of imino dienophiles have been published by Grieco and his coworkers. The preparation of ( )-eburnamonine 7-32 is very efficient since imine 7-31, available from (5-valerolactam in a straightforward sequence, is directly converted into the desired alkaloid 7-32 by aza Diels-Alder reaction and subsequent isomerisation of the newly formed double bond. (Fig. 7-8) [506],... 

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