Collective total synthesis

MacMillan and co-workers demonstrated the capabilities of collective total synthesis in combination with organocascade catalysis very recently [53], which provided them a new synthetic strategy to achieve large collections of complex molecular architectures from a common molecular scaffold [54]. The power of this... 

FIGURE 14.12 Evolution in total synthesis from target to diversity-oriented synthesis and collective total synthesis. 

Syntheses targeting an advanced core structure for the construction of closely related natural products are frequently reported. The discovery of common scaffolds, however, and its application in the synthesis of structurally diverse natural products in the so-called collective total synthesis is much less present in the literature. In the following section some of the most elegant collective syntheses of indole and bisindole natural products are presented. 

COLLECTIVE TOTAL SYNTHESIS OF TRYPTOPHAN-DERIVED ALKALOIDS... 

Collective total synthesis has been gathering more and more attention recently. Prof Jieping Zhu s divergent synthesis toward five members of Aspidosperma alkaloids represent one of the most recent advancement (Fig. 14.14) [49]. The advantages in Prof Zhu s synthesis plan include (i) to construct the indole unit at a late stage of the synthesis instead... 

A recent extension of the DTS is the concept of collective total synthesis, which has been introduced by MacMillan in 2011 [94]. Collective total synthesis aims for the generation of structurally diverse natural products by transformation of a common synthetic scaffold through biomimetic-like pathways [95]. MacMillan et al. employed the common tetracyclic scaffold 120 for the complex total synthesis of six different opium alkaloids of considerable structural complexity (Scheme 15.25) [94]. 

The fungus Streptomyces erythreus is the source of a number of structurally related macrolide antibiotics that are collectively known as the erythromycins. The erythromycins occupy a prominent position in medicine by virtue of their useful antibacterial properties. Their use in therapy over the course of the last three decades has been widespread, and has resulted in the saving of many human lives. In this chapter, we address the landmark total synthesis of erythronolide B (1), the biosynthetic precursor of all the erythromycins, by E.J. Corey and his coworkers which was carried out at Harvard in the 1970s.1... 

Corey s solution to the intimidating structural and stereochemical complexities of ginkgolide B features an impressive collection of powerful bond-forming strategies. The first total synthesis of ginkgolide B by the Corey group is a major achievement of contemporary organic synthesis. 

As mentioned by the authors in their preface, the achievements in total synthesis have been so numerous and so important that it is clearly impossible to include them all in a single volume. My hope is that Classics in Total Synthesis will be successful and that it will be followed by a continuing series. Such a collection will add to our reading pleasure and further encourage and inspire new generations of chemists to dare the impossible (or even the unfashionable). There is much still to be learned and to be discovered. Humanity will be enriched beyond measure if the twenty-first century is a period of continued vigorous development of synthetic chemistry. 

The table, which collects representative examples, shows that monosubstituted epoxides afford homoaUyhc alcohols resulting from the attack to the less substituted carbon atom (runs 1, 5 and 7). HomoaUyhc alcohols are useful intermediates in several important total synthesis." Disubstituted epoxides fail to react (run 4). Styrene oxide leads to a mixture of homoaUyhc alcohols (run 2) and ally lie epoxides give mixture of 1,2- and 1,4-opening product, with predominance of the 1,4 product (run 3, 6 and 8). 

Cyclodidemnamide (60) is a weakly cytotoxic, heptapeptide from D. molle from the Philippines [90]. Total synthesis of the proposed structure of cyclodidemnamide gave a product with different spectral data to those of the natural product, which is thought to be a stereoisomer [91]. The stereochemistry of one of the two valine residues in cyclodidemnamide was revised from L-valine to D-valine as a result of the total synthesis of both isomers [92] and the configuration was also reassigned as a result of total synthesis [93]. The hexapeptides, comoramides A (61) and B (62), were isolated from D. molle from Mayotte lagoon in the Comoros Islands, while the heptapeptides, mayotamides A (63) and B (64) were isolated from a separate collection of D. molle from the Comoros Islands [94]. 

Bioassay directed isolation of serine protease inhibitors from Coscinoderma mathewsi yielded the 1-methylherbipoline salts (366-367) of known sesterterpenes halisulfate-1 (359) and suvanine (358) [321]. Coscinosulfate 1 (368), a sesquiterpene sulfate, was isolated from a New Caledonian collection of C. mathewsi. It displayed significant activity as an inhibitor of the protein phosphatase Cdc25 [322]. A total synthesis starting from (+)-sclareolide was described [323]. 

An Oceanapia sp. collected off the northern Rottnest Shelf, Australia, has yielded three novel dithiocyanates, thiocyanatins A-C (623-625). The structures were determined by spectroscopic analysis and confirmed by total synthesis. The thiocyanatins contain an unprecedented dithiocyanate functionality and an unusual 1,16-difunctionalised n-hexadecane carbon skeleton. They possess nematocidal activity [496]. 

---