ENDOCYCLIC ENAMINE SYNTHESIS

Enamines, reaction with alkyl-enebisthiotosylates, 54, 39 Enamines, JV-bromomagnes ium-, alkylation of, 54, 46 Enamines endocyclic, synthesis of, 54, 93, 96... 

ENDOCYCLIC ENAMINE SYNTHESIS JV-METHYL- 2- PHENYL- A -TETRA-HYDROPYRIDINE, 54, 93 Enol acetates, acylation of,... 

ENDOCYCLIC ENAMINE SYNTHESIS N-METHYL-2-PHENYL-A2-TETRAHYDROPYRIDINE... 

Another application of this strategy is the construction of cyclic systems bearing 1,4-dissonant relationships. For example, the synthesis of the hasubanan alkaloid ring system 35. reported in 1972 by Evans [24], involves the Diels-Alder cycloaddition of a dienyl sulphoxide 32 with an endocyclic enamine 33, followed by a [2,3]-sigmatropic rearrangement of the resulting cycloadduct 34 (Scheme 5.21). 

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). 

This reaction has been developed by Stevens for a refined access to various alkaloid families. Equation 29 shows the short synthesis of mesembrine, where methyl vinyl ketone is annulated to the endocyclic enamine. The precursors for the imines are usually cyclopropyl aldehydes and the corresponding amines or cyclopropyl nitriles combined with suitable organometallics as demonstrated in a simple myosmine synthesis (equation 30). Additional examples will not be discussed here since excellent review articles exist on this topic ... 

In a further application of the methyl vinyl ketone annelation of endocyclic enamines, Stevens and Wentland21 report a simple three-step synthesis of the Erythrina alkaloid model ( )-15,16-dimethoxyerythrinane-3-one (11). 

The Stork-Dolfini synthesis of the amino ketone 458 requires some 11 steps clearly, this is an area for improvement. One method used has been that of methyl vinyl ketone annelation (237). This procedure had been used previously in a synthesis of mesembrine (238) involving 2- -rolines. Stevens hoped to extend this technique to endocyclic enamines to give compounds in the octahydroquinolone series. 3-Ethylpiperid-2-one (549) was prepared from the y-lactone 550 according to standard procedures (239). N-Benzylation followed by reduction with diisobutyl-aluminum hydride (DIBAL) gave enamine 473. Addition of the enamine to methyl vinyl ketone (551) gave an almost quantitative yield of a hydroquinoline 552, which could be readily debenzylated to the known amino ketone 458. As with the Stork method of synthesis, this route to the Aspidosperma nucleus is efficient for the parent compounds but appears to lack the potential for diversification required to synthesize the more complex alkaloids such as vindoline (101) or even tabersonine (28). 

Endocyclic enamines, such as pyrrolines and tetrahydropyridines are useful for the synthesis of complex heterocyclic compounds, as found in many alkaloids. Thus, reaction of the enamine 27 with methyl vinyl ketone gave the alkaloid mesem-brine(1.41). 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

Utilization of the endocyclic enamine 62 for the synthesis of mesembrine and mesembrenone Avas reported almost simultaneously from three different... 

The application of the annelation of endocyclic enamines to the Sceletium alkaloids is exemplified in the synthesis of ( )-Joubertiamine (33), ( )-0-... 

Scheme 17. Synthesis of joubertiamine (33) and related bases 38 and 35 by the endocyclic enamine route.

Scheme 29. Synthesis of Sceletium alkaloid and a related dihydropyridtme via the endocyclic enamine route.

---