Polycyclic natural product

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

An area of Diels-Alder Chemistry that has received a good deal of attention recently is in the synthesis of polycyclic natural products. This involves intramolecular variant. Thus a pseudotropine has been synthesized. The oxygen-nitrogen bond of isoxazoline can be cleaved by reduction. 

A practically identical retrosynthetic scheme was also worked out by Corey [33] for the synthesis of helminthosporal (36) a polycyclic natural product with somewhat greater structural complexity than compound 33. 

Polyene cyclizations have been of substantial value in the synthesis of polycyclic natural products of the terpene type. These syntheses resemble the processes by which terpenoid and steroidal compounds are assembled in nature. The most dramatic example of biological synthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, the enzyme presumably functions not only to induce the cationic cyclization but also to bind the substrate in a conformation corresponding to the stereochemistry of the polycyclic product.21... 

The most practically useful compound from oxepanes is -caprolactone, which is used as an important industrial monomer. Other oxepanes are considered following their structures from rather simple monocyclic to polyhetero-cyclic systems, the chemistry of the latter being now well developed in connection with investigation of complicated polycyclic natural products of marine origin. Below, only those data are cited that are absent in CHEC-II(1996). 

While virtually all of the research described above has focused on the inter-molecular cycloaddition of azomethine ylides, the intramolecular process holds considerable promise for the synthesis of polycyclic natural products. The Pfaltz group reported an intramolecular catalytic asymmetric cyclization of aryl iminoesters 112 using a complex of silver acetate with PHOX type ligand 100 (Scheme 2.29,... 

M. Ihara, K. Fukumoto, Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction, Angew. Chem. Int. Ed. Engl. 1993, 32, 1010-1022. 

Chelidonine. In 1971 Oppolzer and Keller (145) discovered and developed an intramolecular Diels-Alder reaction using oquinodimethane for the synthesis of polycyclic natural products. 

Addition of alkyllithium compounds at the ort/zo-position of oxazolines is possible with het-eroarenes as well as naphthalenes 24 (benzene derivatives usually tend to ort/zo-metallations) [12]. After reductive cleavage of the auxiliary, enantiopure aldehydes 26 are obtained, which have found wide application as versatile chiral precursors for complex polycyclic natural products. 

Ulaczyk-Lesanko A, Hall DG (2005) Wanted new multi-component reactions for generating libraries of polycyclic natural products. Curr Opin Chem Biol 9 266-276... 

The intramolecular Pauson-Khand reaction has been extensively used as a key step in total synthesis of fairly complex polycyclic natural products. The [2 + 2 + IJcycloaddition was, for example, used in recent syntheses of magellanine (Scheme 269), tecomanine, toward palau amines and styloguanidines (Scheme 270), Sa-hydroxystreptazolone (Scheme 271), ceratopicanol (Scheme 272), 13-deoxyserratine (Scheme 273), ABC-rings of nakadomarin and manzamine (Scheme 274), cedrone (Scheme 275), (-)-dendrobine (Scheme 276), " toward kalmanol (Scheme 277), and (+)-epoxydictymene (Scheme 278). 

ABSTRACT In the synthesis of relevant organic compounds such as natural products and analogues, the proportion of the number of steps coupled with the increase of complexity is now a universal paradigm to ascertain the quality and efficiency of a process. Alongwith providing accessibility to a multitude of diversified classes of natural products such as alkaloids, terpenoids, steroids and others, these criteria have been addressed by us via the application of domino processes. The acid-catalyzed intermolecular cyclization has been used as a viable synthetic tool for the stereospecific formation of different classes of polycyclic natural products. 

This methodology has been extended to the synthesis of the C-16 to C-26 fragment of the natural product mucocin in 81% yield and 15 1 diastereoselectivity as shown in Eq. (13.3). This cyclization can also be carried out sequentially. The methodology was extended towards the synthesis of polycyclic natural products [9]. Both cyclization steps proceeded in greater than 90% yield with diastereomer ratios of 6 1 for the formation of 11 and >19 1 for the formation of 13. 

Carbohydrates, which have recently been used extensively as chiral components in syntheses, have been transformed into diesters that, on cyclization, lead to precursors of polycyclic natural products. The tetrahydrofuran diester (135) was cyclized with potassium r-butoxide to an isomeric mixture (136) that was decarboxylated to (137). The related diester (138) was cyclized to a mixture (8 1) of (139) and (140), whereas the lactone (141) cyclized regioselectively to (142) and this was in turn methylated with iodomethane to the trans-syn-cis isomer (143 Scheme 43). ... 

The appreciable synthetic potential of the de Mayo reaction has been applied to the preparation of polycyclic natural products. Some recent developments are shown in Table 4. The de Mayo reaction was used as the key step in the synthesis of hirsutene (entry 1), fusicoccin H aglycone (entry 2), taxanes (entries 3 and 4), loganin (entries 8 and 9), sarracenin (entry 10) and iridoid intermediates (entry 11). 

Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. 

Transannular cyclizations are an important class of radical reactions that are nowadays frequently used as a key step in the synthesis of polycyclic natural product... 

Most applications of the intramolecular Diels-Alder reaction use 1-substituted butadienes and these reactions often form a key step in the synthesis of polycyclic natural products. Substituents in the connecting chain may influence the facial selectivity of the cycloaddition reaction, as well as the endo. exo selectivity. For example, in a synthesis of the antibiotic indanomycin, the triene 83 gave, on heating. 

Cycloaddition using an enol derivative of a cyclic 1,3-dicarbonyl compound, followed by retro-aldol reaction, results in ring expansion by two carbon atoms. Reactions of this kind have been applied to the synthesis of a number of polycyclic natural products. For example, irradiation of the enol benzoate 160 gave the tricyclic product 161 in almost quantitative yield (3.112). Dimethylation followed by hydrolysis and retro-aldol reaction gave the eight-membered ring diketone 162, used in a synthesis of the sesquiterpene ep/-precapnelladiene. 

Biomimetiepolyene cyclizations (5, 316). Johnson has reviewed cyclizations of polyenes to polycyclic natural products. 

The ring closure of cyclic 2-but-3-enylcycloalkyl radicals (Fig. 7.3) is similar to that of the open-chain system, except that the constraints of the ring impose an almost exclusive 1,2-cis stereochemistry [3, 4]. The critical 1,5-selectivity is still largely cis, and it is this selectivity that has found the most use in the synthesis of polycyclic natural products [5, 6]. In the context of the 2-but-3-enylcyclopentyl radical cyclization, it was argued [7] that the l,5-c stereochemistry is favored because the chair-like transition structure 8a (Fig. 7.4) can achieve effective overlap between the SOMO and the radical center and the olefin n orbitals, with less strain than the other possible chair Sb. 

Although this experiment indicated the likely mechanistic pathway for the formation of this polycyclic natural product, the more... 

If you have read the chapters on vancomycin and eveminomicin 13,384-1 in this book, then you aheady know that most polycyclic natural products are quite difficult to analyze retrosynthetically because they provide an almost limitless number of options for how, and in what order, to constmct their various domains. Superficially, okaramine N (1) appears to be essentially no different. However, it does possess one characteristic that, if recognized. 

In the years since the first reports in 1989 [4,5], the scope of the asymmetric intramolecular Mizoroki-Heck reactions has been substantially increased. This transformation has now been employed as a key strategic step in total syntheses of a wide variety of polycyclic natural products. Among the features that contribute to the broad utility of asymmetric Mizoroki-Heck cyclizations are the high functional group tolerance of palladium(O)-catalysed reactions, the remarkable capacity of this transformation to forge C—C bonds in situations of considerable steric congestion and the ability to orchestrate cascade or tandem processes that form multiple rings. 

Another approach is the use of multicomponent reactions (MCRs) to rapidly and efficiently construct structurally complex and varied polycyclic natural product-like compounds (Figure 1.5). A number of synthetic transformations played a key role in the rapid assembly of such molecules including isocyanide-based reactions, aza- and non-aza [4+2] cycloadditions, [3+2] cycloadditions, and dansition-metal-catalyzed reactions. Using isocyanide-based MCRs, pyrrolopyridines exemplified by mappicine represent an atttactive library target for their biological activity. Furthermore, the furoquinoline alkaloid tecleabine represents a common quinoline alkaloid core similar to strnctnres fonnd in a polycyclic library. ... 

Our overall objective is to explore the utility of the [2ti + 2tc + 2%] (homo Diels-Alder) cycloaddition reactions of norbomadiene as a route to synthesizing linearly and angularly fused polycyclic natural products... 

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