Alkaloids, synthesis 3 + 3-cycloaddition

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

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. 

Ethyl 4-hydroxycrotonate has proven to be a valuable Intermediate in synthetic chemistry. It has been used in alkaloid synthesis or as a dipolarophile in dipolar cycloadditions.7 Furthermore, ethyl 4-hydroxycrotonate can be readily oxidized to ethyl 4-oxocrotonate, which has also served as a valuable precursor in synthesis. ... 

Porphobilinogen and Studies of Its Biosynthesis, ft. Neier. Synthesis and Cycloaddition Reactions of Iso-Condensed Heteroaromatic Pyrroles, C. K. Sha. Azacyclopentadienyl Metal Compounds Historical Background and Recent Advances, C. Janiak and N. Kuhn. Recent Developments in the Synthesis of Marine Pyridoacridine Alkaloids, A. M. Echavar-ren. Alkaloid Synthesis Using 1-Acylpyridinium Salts as Intermediates, D. L. Comins and S. P. Joseph. Index. S S... 

Aza Diels-Alder reactions ofW-acyl-l-aza-1,3-butadienes have also been studied and applied in synthesis [236-239]. Interestingly, Jung et al. demonstrated the possibility to generate N-acyl- 1-aza-l,3-butadienes like 3-27 by flash vacuum pyrolysis of 2-azetines such as 3-26. Subsequent cycloaddition yielded the bicyclic product 3-28 which is a useful intermediate in alkaloid synthesis [240] (Fig. 3-9). 

Cycloadditions involving nitroalkenes as heterodiene have been employed as part of Denmark s domino [4 + 2] / [3 + 2] cycloaddition protocol for the synthesis of natural products. Since also this methodology has just been exhaustively reviewed [5], its value for alkaloid synthesis might be exemplarily demonstrated... 

The intramolecular Diels-Alder reaction promises to become widely used in the synthesis of natural products from reports of recent research (142-144). In natural alkaloid synthesis by a Diels-Alder reaction, an enamide was utilized as either a suitable dienophile or diene group. There exist numerous examples of bimolecular and intramolecular Diels-Alder reactions of enamides with various dienophiles as well as bimolecular (4 + 2) cycloadditions of enamines with electron-deficient dienes. On the other hand, there appear to be only few reports of the (4 + 2) cycloaddition reactions of enamides with unactivated dienes. 

Dehydrogliotoxin, synthesis, 57, 204 Dehydrophenylalanine, cycloaddition of benzonitrile oxides, 60, 277 (-)-Deoxynupharidine (alkaloid), synthesis, 57, 19... 

More recently, dioxopyrrolines have been introduced as classical , electron-deficient dienophiles. For example, the addition of (in situ prepared) 3-aryldioxopyrroline (43) to butadiene afforded the hexahy-droindole (44), a key precursor in a synthesis of Amaiyllidaceae alkaloids (Scheme IS). Similarly, highly regioselective [4 -i- 2] cycloaddition of isoquinolinodioxopyrroline (46) to l,3-bis(tiimethylsily-loxy)butadiene (45) afforded the tetracyclic adduct (47) with excellent control over the relative configuration of two quaternary and one tertiary stereogenic centers. Cycloadduct (47) served as a pivotal intermediate in erythrina alkaloid synthesis. ... 

Simple, neutral electron-rich imines are generally not useful dienophiles unless q>propriately reactive dienes are used. Thus it is possible to effect cycloadditions of neutral imines with some electron-deficient dienes. - In a series of p rs, Langlois and coworkers have described Diels-Alder reactions of cyclic imines and methyl 2,4-pentadienoate to afford adducts used in alkaloid synthesis. For example, the cycloadditicMi shown in equation (IS) was used in a total synthesis of the indole alkaloid vincamine (45). 

In the last decade a variety of catalytic asymmetric DA reactions wifh alkenes has been developed most, however, involve the use of a cychc diene, particularly cyclopentadiene. There are a few examples of catalytic asymmetric reactions of siloxydienes with alkenes. Corey et al. have reported enantioselective cycloaddition of sil-oxydiene 106 to mefhacrolein as the key step of fhe asymmetric synfhesis of cassiol (Scheme 10.116) [314]. Recently, Rawal et al. have demonstrated that Cr(III)-salen complex 108a catalyzes the cycloaddition of l-amino-3-siloxy-l,3-dienes to a, -unsa-turated aldehydes wifh high enantioselectivity [315]. The highly functionalized cyclohexene products have been used for alkaloid synthesis. Ghosez et al. have introduced asymmetric DA reaction of siloxy-substituted azadienes 109 under catalysis by Cu(II)-box complex 70a [316]. 

Nitrogen-containing heterocyclic enone systems also reacted with allene to give (2 + 2)-cycloadducts, as was shown in alkaloid synthesis.178 As the keystep in the synthesis of an annotinine derivative, allene was added to 157 and the adduct 158 was obtained in quantitative yield. Various uracils have been modified by photochemical (2 + 2)-cycloaddition with olefins, e.g., vinylene carbonate,17,18° vinyl ethers, vinyl acetates, and (cetene acetals yielded 159.181 Very recently the photochemical addition of cyanoethylenes to 2-pyridones has been observed to yield mixtures of tetrahydroazocin-2-ones (160) and (2 + 2)-cycloadducts (161).182... 

The methodology based on nitroso DieIs-alder reaction that proved useful in the synthesis of tropane alkaloids also seemed to open an attractive route to some other alkaloids. Compared to the intramolecular imino Diels-Alder reaction (ref. Ic) the intramolecular variant of the nitroso Diels-Alder reaction has received far less attention (refs. 6b 12), despite the enormous potential it holds for alkaloid synthesis. With this in mind we proceeded to examine the application of the intramolecular nitroso Diels-Alder cycloaddition in the synthesis of alkaloids possessing saturated nitrogen heterocyclic ring systems. 

Recent Advances of 1,3-Dipolar Cycloaddition Chemistry for Alkaloid Synthesis ... 

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