Natural products biomimetic synthesis

The enzymatic conversion of a-(aminomethyl)pyrroles is also used by nature to produce porphyrinogens like uroporphyrinogen III (see introduction, compound 8), which is the key building block in the biosynthesis of all known porphinoid natural products. This biomimetic method is a powerful tool for the synthesis of different porphyrins, e.g. for the preparation of JV,Af, V ,Ar"-tetramethylporphyrin-2,3,7,8,12,13,17,18-octaacetic acid dibromide 12.36... 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

Mannich reactions, or a mechanistic analog, are important in the biosynthesis of many nitrogen-containing natural products. As a result, the Mannich reaction has played an important role in the synthesis of such compounds, especially in syntheses patterned after the biosynthesis, i.e., biomimetic synthesis. The earliest example of the use of the Mannich reaction in this way was Sir Robert Robinson s successful synthesis of tropinone, a derivative of the alkaloid tropine, in 1917. 

Harring, S. R. Livinghouse, T. Sulfenium ion promoted polyene cyclizations in natural product synthesis. An efficient biomimetic-like synthesis of ( )-nimbidiol. Tetrahedron Lett. 1989, 30, 1499-1502. 

The original Robinson synthesis (66) of tropinone (124), which consists of a reaction between succinaldehyde (140), methylamine (141), and the calcium salt of acetonedicarboxylic acid (142), proceeds in low yield (Scheme 2). However, it has the great merit of being the pioneering achievement in the field of biomimetic syntheses of natural products. 

An impressive example of a multi-step biomi-metic domino process is the synthesis of codaphni-phyllin by Heathcock et al. (see scheme 14). Another example is the highly efficient biomimetic synthesis of (+)-hirsutine by my group (see scheme 13). In addition several other total syntheses of natural products have been developed using domino processes these are described in the different sections of this chapter. 

The synthesis of bicyclic molecules containing guanidinium subunits, such as 156 (Scheme 22), are of considerable interest due to the wide range of biological activities presented by this family of natural products (see Section 11.11.9). In one of the first biomimetic studies toward ptylomycalin A, a series of polycyclic compounds have been prepared through an intermediate l-imino-hexahydropyrrolo[l,2-f]pyrimidin-3(4//)-one such as 155. Succinaldehyde... 

Panacene (61) is a metabolite of the sea hare Aplysia brasiliana and acts as a fish antifeedent [61]. The synthesis of the racemic natural product, published by Feldman et al. [77] in 1982, takes advantage of the anti-selective SN2 -substitution of the propargylic mesylate 67 with LiCuBr2 (Scheme 18.21). In contrast, the later attempted biomimetic synthesis by treatment of the enyne 68 with NBS or 2,4,4,6-tetrabromocyclohexadienone did not proceed stereoselectively and led to a 1 1 mixture of the target molecule 61 together with its allenic epimer [78]. 

Two formal syntheses of (-)- [80] and (+)-kumausallene [81] followed this route and relied on the enantioselective preparation of the 2,6-dioxabicyclo[3.3.0]octane core 69 starting from diethyl tartrate or an appropriate chiral sulfoxide. In contrast, Evans et al. [82] used a distinct biomimetic approach in their enantioselective synthesis of the natural product (-)-62 (Scheme 18.23). 

A quite detailed review of transannular cyclizations was published201 wherein their important role in biomimetic syntheses of sesquiterpenes as well as explanation of the biogenetic formation of the polycyclic natural compounds from their monocyclic precursors is discussed. The great significance of these transformations for the synthesis of natural products is also emphasized in a series of reviews which describe the cyclizations to form terpene derivatives, e.g., of the germacrane and humulene systems202-206. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

Several natural products (Scheme 60) have been synthesized in vitro via singlet oxygen ene reactions. For example, clavukerin C was prepared in racemic form, in a biomimetic synthesis by Kim and Pak, whereas a-farnesene hydroperoxide was obtained starting from geraniol. 

The total synthesis of litseaverticillols D, F and G (172 and 173), which are natural products with anti-HIV activity, was achieved recently via a singlet oxygen initiated cascade proposed to be biomimetic (Scheme 64). Finally, allylic alcohols 174a and 174b (Scheme 64) were isolated in a 4/1 ratio via a stereoselective singlet oxygen ene reaction. Stereoisomer 174a is an intermediate in the synthetic route of staurosporine, which is a bioactive alkaloid with hypotensive, antimicrobial and cell cytotoxic properties. 

This methodology was applied to biomimetic diversity-oriented synthesis to discover galanthamine-like molecules (153) with biological properties beyond those of the natural product by Shair and co-workers [114] (Scheme 24). 

The oxidative activation of arenes is a powerful and versatile synthetic tactic that enables dearomatization to give useful synthons. Central to this chemistry are hydroxylated arenes or arenols, the phenolic functions of which can be exploited to facilitate the dearomatizing process by two-electron oxidation. Suitably substituted arenols can hence be converted, with the help of oxygen- or carbon-based nucleophiles, into ortho-quinone monoketals and ortho-quinols. These 6-oxocyclohexa-2,4-dienones are ideally functionalized for the construction of many complex and polyoxygenated natural product architectures. Today, the inherent and multiple reactivity of arenol-derived ortho-quinone monoketals and ortho-quinols species is finding numerous and, in many cases, biomimetic applications in modern organic synthesis. 

Pelish et al. [44] demonstrated the use of a biomimetic-based, diversity-oriented synthesis method to produce galanthamine-like molecules (Figure 15.14) with biological properties superior to those of natural product, galanthamine. As first... 

Porco, Jr. and coworkers also used this biomimetic domino approach for the synthesis of the quinone epoxide dimer torreyanic acid 7-151 as racemic mixture [67]. This natural product, isolated from the fungus Pestalotiopsis microspora, shows a pronounced cytoxicity to tumor cells. Its retrosynthetic analysis leads to the 2H-pyran 7-152 (Scheme 7.40). As substrate for the domino process, the epoxide... 

Intramolecular oxidative coupling of phenols (6, 516). A biomimetic synthesis of natural silybin (3), an interesting antihepatotoxic agent, involves oxidation of a mixture of optically active 1 and coniferyl alcohol (2) with AgO in a benzene-acetone mixture at 55°. This reaction affords a mixture of silybin (3) and isosilybin (4) in 78% yield. The products 3 and 4 are diastereomeric mixtures at C2 and Cs- relative to C2 and... 

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