Total syntheses of strychnine

The development of highly efficient asymmetric catalysts is one of the most intensively investigated research fields today.1 Catalytic asymmetric reactions are extremely powerful in terms of the practicality and atom economy.2 The power of asymmetric catalysis is rapidly growing, so as to be applicable to syntheses of natural products with complex structures. We call total syntheses using catalytic asymmetric reactions in key steps catalytic asymmetric total syntheses . In this chapter, we describe our recent success in catalytic asymmetric total syntheses of (-)-strychnine and fostriecin. Both of the total syntheses involve catalytic asymmetric carbon-carbon bond forming reactions using bifunctional catalysts developed in our group3 as key steps. 

We describe herein our recent achievement of total syntheses of (-)-strychnine and fostriecin. The key stereocenters were constructed using catalytic asymmetric reactions developed in our group. Catalytic asymmetric reactions that can produce versatile chiral building blocks with high practicality should ensure further efficient total synthesis of complex molecules in future. 

Since the monumental accomplishments of Woodward s total syntheses of strychnine in 1954 [I] and rcserpinc in 1958 (2], the arsenal of synthetic methods in indole alkaloid synthesis has greatly expanded. In the same time period, the use of palladium chemistry in organic syntheses has also witnessed tremcndou- growth with an ever-expanding repc loire of synthetic methods and their applications to total synthesis. The use of palladium chemistry for the synthesis of indole alkaloids has been explored, and several examples have been included in recent reviews [3-6]. This account attempts to present a comprehensive collection of total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. 

The influence of the total syntheses of strychnine on the evolution of strategy and tactics of organic synthesis 12AG(E)4288. 

Strychnine is the most challenging target molecule in the total synthesis of alkaloids because it has seven rings in spite of the 24 skeletal atoms. The first total synthesis of (-)-strychnine (89, Scheme 18) was achieved by Woodward in 1954. After about 40 years, the second total synthesis was reported by Magnus. Several groups then reported unique and elegant total syntheses of strychnine by utilization of organometallic complexes. One... 

Since then, many synthetic chemists have been confronted with strychnine, which is a classic among the classics of total synthesis. Overall, 18 total syntheses of strychnine have been reported so far [58a-r], the shortest one in only 7 linear steps from tryptamine by Vanderwal [58r], to be compared with the earliest total synthesis of Woodward in 29 linear steps from phenylhydrazine [53a], The efficiency of these works can be evaluated by looking at the overall yields, from 0.00014% [58a] to nearly 10% yield [58e]. For sure, these improvements not only took benefits from Corey s retrosyn-thetic Logic of Chemical Synthesis but also from those famous chemists s creativity and from new achievanents in synthetic and catalytic methodologies. Indeed, new methodological concepts have arisen by the last 20 years, such as those of ideal synthesis [59], atom economy, step economy, redox economy, and sustainable approaches [60]. 

To demonstrate the power of these cascade sequences this methodology was successfully applied to total syntheses of several indole-derived alkaloids, for example, minfiensine [113]. By implementation of organocatalyzed cascade reactions the MacMillan group was able to dramatically reduce the number of reaction steps in total syntheses of strychnine, aspidospermidine, and kopsinine [114]. 

Sirasani G, Paul T, Dougherty Jr.W, Kassel S, Andrade RB. Concise total syntheses of ( )-strychnine and ( )-akuammi-cine. J. Org. Chem. 2010 75(10) 3529-3532. 

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. 

Fused carbazoles related to pyrido[4,3-6]carbazole alkaloids were prepared by a Diels-Alder route, and a 3-aza bioisostere of the antitumor alkaloid olivacine was synthesized <02CPB1479>. Indoloid [3.3]cyclophane 40a gave the pentacyclic indoloid 41a upon heating <02OL127>. This led to a concise formal total synthesis of ( )-strychnine in 12 facile steps from tryptamine when a similar transannular inverse-electron-demand Diels-Alder reaction of indoloid [3.3]cyclophane 40b gave 41b <02AG(E)3261>. 

Deshpande [74], has carried out carbon-carbon bond formation on a solid support using a polymer-supported aryl iodide and vinyl (or aryl) tins. In the area of natural-product synthesis. Overman and co-workers have carried out total syntheses of (—) and (+)-strychnine which include an aryltin/CO/alkenyltin coupling step [75] (a technique introduced earlier by Stille [1]). Very recently, Heathcock and co-workers have reported total syntheses of (—)-papuamine and (—)-haliclonadiamine which include a key step in which a 1,3-diene unit is constructed by coupling two alkenyltin moieties thus reaction (Scheme 4-27) only proceeds in the presence of copper (I) iodide [76]. 

During the enantioselective total syntheses of (-)- and (+)-strychnine and the Wieland-Gumlich aldehyde, L.E. Overman and co-workers used the tandem aza-Cope rearrangement/Mannich reaction as a key step. This central aza-Cope/Mannich reorganization step proceeded in 98% yield. 

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. 

Total syntheses of the complex molecule of strychnine have been carried out by several groups applying intramolecular HR as key reactions. The first elegant Pd-based total synthesis of stryclmine (237) has been achieved by Rawal. An intramolecular Diels-Alder reaction and HR were key reactions. The Pd-catalyzed cyclization of the pentacyclic lactam 238 under Jeffery s conditions gave isostrychnine 239 in 74% yield. Conversion of 239 to 237 is known [106]. 

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... 

Vollhardt s total synthesis of strychnine successfully demonstrated the power of the cobalt-mediated [2+2+2]cycloaddition (111) for the construction of complex polycyclic molecules (Scheme 11). This key reaction was originally developed by his group in the 1970s, and widely utilized for the syntheses of complex natural and unnatural products (112-116). Here, this reaction was used for the simultaneous closure of the E and G rings with formation of the C7 quaternary center (117-119). To accomplish total synthesis, five synthetic approaches were investigated, but only the successful one is shown here. 

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). 

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