Pyrroline alkaloids synthesis

Phenyl-1-pyrroline is useful for various purposes.10 11 In particular, its reduction product, 2-phenylpyrrolidine, is important in the synthesis of pyrroloisoquinoline antidepressants,20 12 and can be a starting point in alkaloid synthesis.13 The overall reaction sequence described here has been used to prepare nicotine derivatives such as myosmine.2a b... 

The opening of activated cyclopropanes with nitrogen nucleophiles has been widely applied to the synthesis of pynolizidine and pyrroline alkaloids by Danishefsky this subject has been reviewed. A number of pyrroline annulations have been based on this principle, illustrated in equation (35a). > Similar opening can be accomplished with halides, cuprates, and sulfur or selenium nucleophiles. ... 

Hudlicky and coworkers also reported a related 2-pyrroline formation from viny-laziridines [81], which are extremely useful for the synthesis of pyrrolizidine alkaloids such as the protected (+)-trihydroxyheliotridane 210 (Scheme 2.51). Since the pyrolysis of either diastereomer of 208 furnished the cyclized product 209 as a... 

The syntheses of flavanoid alkaloids also rest on A-l-pyrroline chemistry and on Friedel-Crafts-type reactions. In Govindachari s pioneering synthesis of ficine (167), pyrrolidine 126 is formed by condensation of trimethoxybenzene and y-aminobutyric acid in the presence of PPA (Scheme 19). Although the mechanism of this reaction has not been precisely determined, it may involve a A-l-pyrrolinium cation. These conditions were later used by Koch et al. in their synthesis of vochysine (Scheme 20) (108). 

Curiously, the synthesis of shihunine via a phenylcyclopropylimine (187) is the sole example of a simple pyrrolidine alkaloid obtained according to this general pyrroline synthesis (188) (Scheme 40). 

Volume 75 concludes with six procedures for the preparation of valuable building blocks. The first, 6,7-DIHYDROCYCLOPENTA-l,3-DIOXIN-5(4H)-ONE, serves as an effective /3-keto vinyl cation equivalent when subjected to reductive and alkylative 1,3-carbonyl transpositions. 3-CYCLOPENTENE-l-CARBOXYLIC ACID, the second procedure in this series, is prepared via the reaction of dimethyl malonate and cis-l,4-dichloro-2-butene, followed by hydrolysis and decarboxylation. The use of tetrahaloarenes as diaryne equivalents for the potential construction of molecular belts, collars, and strips is demonstrated with the preparation of anti- and syn-l,4,5,8-TETRAHYDROANTHRACENE 1,4 5,8-DIEPOXIDES. Also of potential interest to the organic materials community is 8,8-DICYANOHEPTAFULVENE, prepared by the condensation of cycloheptatrienylium tetrafluoroborate with bromomalononitrile. The preparation of 2-PHENYL-l-PYRROLINE, an important heterocycle for the synthesis of a variety of alkaloids and pyrroloisoquinoline antidepressants, illustrates the utility of the inexpensive N-vinylpyrrolidin-2-one as an effective 3-aminopropyl carbanion equivalent. The final preparation in Volume 75, cis-4a(S), 8a(R)-PERHYDRO-6(2H)-ISOQUINOLINONES, il lustrates the conversion of quinine via oxidative degradation to meroquinene esters that are subsequently cyclized to N-acylated cis-perhydroisoquinolones and as such represent attractive building blocks now readily available in the pool of chiral substrates. 

Figure 33. Synthesis of alkaloids from ornithine. Aikaioids are derived via putrescine or glutamic semialdehyde. At least two enzymes, ODL (Ornithine decarboxylase) or PDL (Pyrroline...

Many synthetic methods have been reported for the pyrrolidine alkaloids, including procedures based on the Hofmann-Loffler reaction 132,412), the metal hydride reduction of pyrrolines 413,414), the a-alkylation of N-nitro-sopyrrolidine 412,415), the catalytic hydrogenation of pyrroles 133), the reductive amination of 1,4-diketones 25,138), the direct alkylation of 1-methoxy-carbonyl-3-pyrroline 416), the versatile synthesis from the Lukes-Sorm dilac-... 

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

Tufariello has reviewed his strategy for the synthesis of alkaloids (including necine bases) using the 1,3-dipolar cycloaddition of nitrones to alkenes.5 This work began with the synthesis of ( )-supinidine (7) from 1-pyrroline 1-oxide (see these Reports, Vol. 2, Ch. 4). A related approach has been used by Iwashita et al. in their synthesis of ( )-isoretronecanol (5).6 The stereochemistry of the exo-product (8), formed by regiospecific 1,3-dipolar cycloaddition of 1-pyrroline 1-oxide to dihydrofuran (Scheme 2), was confirmed by its conversion into... 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

If the amino group forms part of the ketone, as it does with y-87, 88 and 8-amino-ketones,89,90 heterocyclic enamines are obtained. 1,2-Dialkyl-J2-pyrrolines and 1,2-dialkyl-J2-piperideines (15) are formed from secondary amino groups, whereas primary amino groups 91 lead to 2-alkyl-J pyrrolines and 2-alkyl-J -piperideines. Gabriel90 used the suitably substituted phthalimidoketone for the synthesis of the alkaloid y-coniceine (15 R = H, R = n-Pr, n = 2). 

Jatropham (surely better called jatrophine) is an alkaloid occurring in Jatropha macrorhiza (Euphorbiaceae) which has inhibitory activity towards leukaemia. Its racemic form (4) has been synthesized from 3-methyl-2-furoic acid, as outlined in Scheme l.5 This synthesis vindicates an earlier suggestion that the structure be revised to 5-hydroxy-3-methyl-3-pyrrolin-2-one (4), as opposed to the 4-methyl isomer.6... 

For synthesis of certain alkaloids, the requisite cyclopropylimines were prepared by bisalkylation of the appropriately substituted benzyl cyanide. Cyanides could be selectively reduced in high yield to the corresponding aldehydes by employing diisobutylaluminium hydride. Treatment of these aldehydes with a primary amine completes the synthesis of the imines. Rearrangement191,432-435 with acids afforded the 2-pyrrolines in high yield (equation 26). 

Dipolar cycloadditions. Nitrones such as 1 combine with alkenes to form isoxazolidines. Tufariello has employed these 1,3-dipolar cycloadditionS as key steps in the synthesis of several alkaloids. Monosubstituted olefins react with nitrones regioselectively to afford 5-substituted iSoxazolidines thus addition of 2 to 1-pyrroline-l-oxide produces the cycioadduct 3, which serves as an intermediate in a total synthesis of elaeocarpine (4). ... 

The synthesis of crinine, one of the Amaryllidaceae alkaloids, has been achieved by Whitlock and is based on an iodide ion-catalyzed rearrangement of iV-ketovinylaziridines to A -pyrroline (Scheme ). ... 

Two new syntheses of racemic mesembrine have been described. In the first, outlined in Scheme 1, an improved synthesis of the penultimate 2-pyrroline (8) was achieved annelation of this afforded ( )-mesembrine (9). The second (Scheme 2) incorporates a regioselective borohydride imide reduction. Investigations on the biosynthesis of mesembrine alkaloids have revealed that a stereospecific protonation occurs at C-7 [see formula (9)] as one of the late stages. ... 

The first step in the total synthesis of the alkaloid ( )-ipaIbidine 104 was the reaction of the diene 103 with A -pyrroline (eqnation 60) . The proportions of threo- and crytfiro-dihydro-a-pyridones, 106 and 107, respectively, prodnced in the diethylainmininm chloride-catalyzed reactions of the a-benzyloxyimines 105 (R = n-CsHu, i-Pr or t-Bn) with the diene 86 (equation 61), depend on the namre of R and the amonnt of imine... 

In an alternative approach to the nitrone method for the synthesis of Elaeocarpus alkaloids (cf. vol.ll, p.61), a 1,3 dipolar cycloaddition of 1-pyrroline 1-oxlde to a substituted enone gives the isoxazolidine (2), which was converted in a number of steps into the compound (3), the C-7 epimer of elaeokanine C. Oxidation of the epimer (3) afforded the diketone (4), an intermediate in a previously published synthesis of ( )-elaeokanlne C. 

---