Strychnine enantioselective syntheses

Kuehne, M.E., and Xu, F., Syntheses of strychnan- and aspidospermatan-type alkaloids. Part 10. An enantioselective synthesis of (-)-strychnine through the Wieland-Gumhch aldehyde, 7. Org. Chem., 63, 9427, 1998. 

Whether the four new total syntheses represent a fundamental improvement over Woodward s strychnine synthesis can certainly be debated, as well as the extent of this improvement. It cannot, however, be contested that Overman et al. accomplished the first and only enantioselective synthesis of the natural product, and that Kuehne and Rawal with their respective 17- and 15-step syntheses devised approaches with markedly fewer reaction steps than Woodward s 28-, Magnus 27-and Overman s 25-step syntheses. The considerable improvement in the overall yields relative to that of the first total synthesis is also noteworthy. Whereas Magnus improved the yield by a factor 1000, Overman, Kuehne and Rawal upped the overall yield by a factor of 100000 These impressive numbers cannot be attributed solely to improved synthetic methods and modem reagents, but emphasize the importance that sequential reactions [17] have achieved in the construction of complex natural products. 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

A novel procedure for the synthesis of an indole skeleton 81 was developed by Mori s group (Scheme 13).16e,16f Enantioselective allylic amination of 78 with A-sulfonated < r/ < -bromoaniline 79 followed by Heck cyclization of 80 provided chiral indoline 81. The treatment of a cyclohexenol derivative 78 with 79 in the presence of Pd2(dba)3-GHGl3 and ( )-BINAPO gave compound 80 with 84% ee in 75% yield. Total syntheses of (—)-tubifoline, (—)-dehydrotubifoline, and (—)-strychnine were achieved from compound 80. 

The alio series of the pumiliotoxin A class have an additional hydroxyl group that has been placed at C-7 on the indolizidine ring, without assignment of configuration. Three members of the alio series have been assigned the tentative structures (7), (8), and (9).3 Pumiliotoxins A and B are relatively toxic, and comparable in potency to strychnine. Pumiliotoxin B has a potent cardiotonic and myotonic activity.3 An enantioselective total synthesis of pumiliotoxin A alkaloids from L-proline has already been announced.4... 

Enantioselective total syntheses based on asymmetric catalysis including total synthesis of strychnine, asymmetric epoxidation of a,/l-unsaturated acid derivatives, and ring opening of oxiranes 04CPB1031. 

The third total synthesis of strychnine (1), so far the only enantioselective route to the natural product, was accomplished by Overman et al. [10] The key to their approach to 1 is the sequential cationic aza-Cope rearran-gement/Mannich cyclization, which is frequently employed with success in alkaloid synthesis. With the synthesis of akuammicine rac-19 the authors proved that this strategy offers an efficient route to the strychnos alkaloids. [8g]... 

Owing to their structural complexity, Strychnos alkaloids, especially strychnine itself, are a benchmark in synthetic organic chemistry and have been prepared numerous times ]92]. Another alkaloid of the Strychnos family that enjoys increasing popularity nowadays is (+)-minfiensine. It was isolated from Strychnos minfimsis and features a l,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole motif, and hence is closely related to echitamine and vincorine [93]. A total synthesis of this beautiful structure was accomplished by MacMillan and coworkers [94]. Their key step was a highly efficient enantioselective domino Diels-Alder/isomerization/amine cycHzation reaction (Scheme 14.35). In this process, the chiral organocatalyst 226-TBA (TBA, tribromoacetic acid) was used, which reacted first with propargyl aldehyde 225 to form i minium ion 229 as intermediate, which underwent an endo-selective Diels-Alder reaction with 224... 

In 1993, Overman achieved the first enantioselective total synthesis of (—)-strychnine using the optically pure monoacetate (+)-36, which was prepared by the enzymatic hydrolysis of 35 (70,71), as a starting material (Scheme 5). The key reaction in this synthesis is the cationic aza-Cope-Mannich rearrangement, which was previously developed by Overman et al. for the syntheses of various alkaloids, such as akuammicine (72-76), to assemble the CDE core ring system. The... 

Pd-catalyzed reactions have been used quite often in the syntheses of natural products (120). Indeed, in Mori s total synthesis of (—)-strychnine, all cyclizations for the synthesis of (+)-isostrychnine were performed using Pd-catalyzed reactions, including the first enantioselective allylic substitution (121-124) (Scheme 12). The strategy used for this synthesis was previously developed by this group for the synthesis of (—)-tubifoline (124). 

Ohshima T, Xu Y, Takita R, Shimizu S, Zhong D, Shibasaki M. Enantioselective total synthesis of (—)-strychnine using the catal3ftic asymmetric Michael reaction and tandem cyclization. J. Am. Chem. Soc. 2002 124(49) 14546-14547 (Erratum 2003 125(7) 2014). 

Ohshima T, Xu Y, Takita R, Shimizu S, Zhong D, Shihasaki M. Enantioselective total synthesis of ( )-strychnine using... 

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