Numbers of natural products

Chiral oxazoline-based synthetic methods have been employed in the asymmetric synthesis of a large number of natural products. A few representative examples of these applications are shown below. 

Indeed, great emphasis was placed on the presentation of compounds in crystalline form for many years, early chromatographic procedures for the separation of natural substances were criticized because the products were not crystalline. None the less, the invention by Tswett (3) of chromatographic separation by continuous adsorption/desorption on open columns as applied to plant extracts was taken up by a number of natural product researchers in the 1930s, notably by Karrer (4) and by Swab and lockers (5). An early example (6) of hyphenation was the use of fluorescence spectroscopy to identify benzo[a]pyrene separated from shale oil by adsorption chromatography on alumina. 

M-Acyliminium cyclizations of optically active mono- and di-oxygenated hydroxylactam derivatives have been used in the synthesis of a number of natural products. In case of a five-membered lactam the oxygen function adjacent to the iminium carbon directs attack of the internal nucleophile from the least hindered side, opposite to the substituent. In the examples given the size of the newly formed ring is determined by the electronic bias of the alkene substituent. 

The macrocyclization has proven useful in the formation of a number of natural products.245 These conditions have been used to prepare 36- and 72-membered rings. 

Employing their catalytic system, the group of Oltra and Cuerva demonstrated that 7-endo cyclizations can be performed in surprisingly high yields. Moreover, 7-endo-cyclizations were used by the same group in elegant catalytic cyclization cascades for the preparation of a number of natural products as shown in Scheme 33 [125]. Barreo et al. reported similar methodology [105]. 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Batcho indole synthesis is a useful tool for synthesis of natural products. As outlined in Scheme 10.6, the Batcho indole synthesis is used for total synthesis of the slime mold alkaloid arcyriacy anin.67 Such indolocarbazole alkaloids represent a growing number of natural products isolated from soil organism, slime molds, and marine sources. They are important as antitumor compounds and protein kinase C and topoisomerase inhibitors. 

The number of natural products containing these tricyclic systems is relatively small, viz. a few alkaloids from marine (compound 293), fungal (compound 282), amphibian (compound 395), insect (compound 387), and plant sources (compound 288) and also some iridoid molecules (compounds 98-100). Some of those Myrmkaria alkaloids (from ants Section 12.16.6.5.2) which contain the 5 5 6 fused-ring system are perhaps the most extensively studied of these natural products, with several successful syntheses now recorded. 

As a whole, the Lycopodium alkaloids consist of over 270 members, and the number of natural products in this family continues to grow [1], The natural products are divided into four structural classes, three of which are represented by the parent... 

Synthetic activity associated with the carbonyl-ene reaction is extensive. During the past decade, the trend has been to perform these reactions in the presence of a Lewis acid in an enantioselective fashion. Efforts to find a general catalyst that affords homoallylic alcohols in high yields and enantioselectivities are continual. The synthetic utility of this reaction has been validated by its application to the synthesis of a number of natural products (see Section 10.12.6) and many structurally novel motifs that have found a place in drug discovery vide infra). It is the latter application that has resulted in research efforts aimed at large-scale production of carbonyl-ene adducts. 

The merit of Fischer s convention is that it enables the systematic stereochemical presentation of a large number of natural products, and this convention is still useful for carbohydrates or amino acids today. Its limitations, however, become obvious with compounds that do not resemble the model reference compound glyceraldehyde. For example, it is very difficult to correlate the terpene compounds with glyceraldehyde. Furthermore, selection of the correct orientation of the main chain may also be ambiguous. Sometimes different configurations may even be assigned to the same compound when the main chain is arranged in a different way. 

Bridging of macrolides.1 A number of natural products are known to consist of oxapolycyclic systems. A potential route to such systems involves bridging of the more readily available macrolides (or the corresponding dithionolides, available by thionation with Lawesson s reagent) by electron-transfer reactions initiated with sodium naphthalenide (Scheme I). 

The transformation has been employed extensively in the preparation of precursors to a number of natural products including dihydrojasmone, rosaprostol, valeranone, and hirsutene [20]. Its use en route to guaiazulene (23) is illustrated in Scheme 5. 

Occasionally, however, things can go awry and examples exist in the chemical literature (albeit very few in number) of natural products whose structures, even after the "structure confirmation" by total synthesis, were shown to be incorrect in the light of the results obtained by X-ray crystallographic analysis. Patchouli alcohol, a natural sesquiterpene of some interest in the perfumery industry, provides an illuminating example. 

The silylcuprate conjugate addition reaction has been used for the protection of an enone double bond, which can be regenerated with CuBr2 [22a], and for the strategic introduction of the silyl substituent for stereocontrol and regiocontrol purposes. Enantiopure 5-trimethylsilyl-2-cyclohexenone can be prepared by conjugate addition reaction [44] and the appropriate enantiomer has been converted into a number of natural products (Scheme 3.4) [38]. These synthetic strategies exploit... 

As six-membered heterocycles are present in a number of natural products and biologically important molecules, solid-phase synthesis of these has been reported very often (Fig. 3.9). Solid-phase synthesis for nearly every six-membered ring including one nitrogen atom are known piperidines (272) [376], tetrahydropyridines (273) [377, 378], dihydropyridines (274) [219, 379, 380], pyridines (275) [349, 381-386], (Scheme 3.37), piperidinones (276) [387], dihydropyridones (277-279) [313, 378, 388-390], pyridinones (280-281) [328, 329] and piperidindiones (282) [391] derivatives. In contrast, the synthesis of six-membered rings with one single oxygen is rarely described. Nevertheless, solid-phase synthesis of dihydropyrans (283-284) [392-394] and tetrahydropyrans (285) [335, 336] has been reported. 

A number of natural products have been found to be useful as drugs. 

Building on Inoue s pioneering work and using Andersson s versatile diamine, Kozmin and coworkers have described a catalytic base-induced isomerization of silacyclopentene oxide 139 [Eq. (10.41)] as a potential route to acyclic polyol domains, important components of a number of natural products. Epoxida-tion of 140, epoxide ring opening, and oxidation of the C—Si bonds provides tetra-ols in good overall yield and selectivity ... 

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. 

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