Natural product synthesis Strychnine

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]. 

One classic application of the Tsuji-Trost reaction in natural products synthesis is found in the synthesis of strychnine by Overman and co-workers in 1993. Reaction of acetoacetate derivative 138 with enantiopure allylic carbonate 137 in the presence of Pd2(dba)3, PPh3, and NaH in THF yielded the cw-adduct 139 in 91%. It is worth noting that the selective displacement of carbonate group occurs with retention of the configuration and proceeds via the reactive 7i-allyl intermediate (see. Scheme 13.38). Derivative 139 could then be elaborated in a number of steps, to complete the total synthesis of strychnine. 

Among the recent outstanding contributions to the chemistry of natural products is the conformational analysis designed by Derek Barton. He used it for the structural determinations of many complex molecules such as P-amyrin and cycloartenol. Robert B. Woodward was involved in the structural determinations of penicillin, strychnine, patalin, terramycin, aureomycin and the synthesis ofVitamin B12. 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

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]... 

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. 

Amongst natural products, the oxepin structure occurs only in senoxepin 19, a norsesquiterpene lactone of the groundsel Senecio platiphylla its structure has been established by synthesis [8]. Hydrogenated oxepins and oxepanones are often found in natural products, e.g. in the alkaloids strychnine (20, R = H) and brucine (20, R = OCH3), and in the brassinosteroids, e.g. the growth regulator brassinolid 21. 

The total synthesis of the complex natural product strychnine (Section 25-8), containing seven fused rings and six stereocenters, has been steadily improved over a half-century of development of synthetic methods. The first synthesis, reported in 1954 by R. B. Wo ward (Section 14-9), started from a simple indole derivative (Section 25-4) and required 28 synthetic steps to give the target in 0.00006% overall yield. A more recent synthesis (in 2011) took 12 steps and proceeded in 6% overall yield. 

Strychnine as a Case Study A Classic among the Classics Herein, we would like to illustrate the evolution of total synthesis by one of the most famous natural products, strychnine (Scheme 1.12). For decades, strychnine was regarded as one of the most challenging natural products to be synthesized [56]. The correct structure of strychnine was determined by Woodward and Brehm in 1948, one century after its discovery [57]. Since then, this remarkable natural product witnessed the evolution of total synthesis. 

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). 

Once again, this volume of "The Alkaloids Chemistry and Biology is comprised of four quite different chapters, from three different continents, on mechanisms of c)dotoxic action, the calystegines, strychnine synthesis, and substituted quinoline alkaloids. This diversity reflects the need to see alkaloids as a class of natural product having tremendous biological potential and of continued broad scientific interest. 

It was only about 40 years ago that chemists had the tedious task of identifying and characterizing unknown organic compounds especially in the area of natural products. This may involve degradation of the molecule followed by synthesis involving many steps. For example Woodward elucidated the structure of strychnine in 1947 and seven-years later successfully synthesized this compound. 

---