Unnatural natural products

Recent Applications in Natural and Unnatural Product Synthesis... 

Copper-Mediated Synthesis of Natural and Unnatural Products... 

Conjugate addition [2] to Midiael acceptors is die most important and usefid reaction in orgatiocopper diemistiy, and die reaction is ofien used as die key step in die syndiesis of numerous natural and unnatural products. Perhaps one of die most efficient methods for die syndiesis of quaternary carbon centers is organo-copper-mediated conjugate addidon to /, / -disubstituted enones. 

As described above, many copper-mediated reactions play important roles in tlie syntlieses of natural and unnatural products. To date natural product syntlieses using organocoppet reagents have beeti accomplisbed, and w ill undoubtedly be increasing greatly from now on. 

The cis dihydroxylation of olefins (10—>11, Scheme 2), one of organic chemistry s most venerable reactions, was first reported by Makowaka in 1908.9 It is also one of the most useful reactions, since it converts an olefin, itself a pivotal functional group, to a vicinal diol, another pivotal functional group present in many natural products and unnatural molecules. The original dihydroxyl-... 

Application of an aldolase to the synthesis of the tricyclic microbial elicitor (-)-syringolide (Figure 10.34) is another excellent example that enzyme-catalyzed aldolizations can be used to generate sufficient quantities of enantiopure material in multistep syntheses of complex natural and unnatural products [159]. Remarkably, the aldolase reaction established absolute and relative configuration of the only chiral centers that needed to be externally induced in the adduct (95) from achiral precursor (94) during the subsequent cyclization events, all others seemed to follow by kinetic preference. 

Pyroglutamic acid is a useful starting material for the synthesis of several natural products, such as pyrrolidine alkaloids, kainoids, and other unnatural amino acids. Interesting chemose-lective Michael additions of anions derived from pyroglutamates have been reported (see Eqs. 4.54 and 4.55).69... 

The Barton-Zard pyrrole synthesis has now been extensively applied to synthesis of natural and unnatural products containing pyrrole units. Methyl 4-methylpyrrole-2-carboxylate is the trail-maker pheromone of the Texas leaf-cutting ant Atta texana.24 It is readily prepared by the Barton Zard method in 60% yield (Eq. 10.22).22... 

Pyrrolidines are structural subunits found in many natural and unnatural products, which have important biological activity.102 Depending on the substitution pattern and functionalization, pyrrolidines have been shown to be effective antibacterials,103 neuroexcitatory agents,104 potent venom,105 and glyosidase inhibitors.106... 

Since the first description was only two decades ago, combinatorial biosynthesis has advanced from a limited set of proof-of-principle experiments into a more mature scientific discipline. To reach the maximal potential of natural product structural diversity, the combination of this approach with other established and emerging technologies will ultimately provide access to a rich variety of unnatural natural products with improved properties or new biological activities for future drug discovery and development. 

McDaniel, R., Thamchaipenet, A., Gustafsson, C. et al. (1999) Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel unnatural natural products. Proceedings of the National Academy of Sciences of the United States of America, 96, 1846. 

The natural product westiellamide (158) and other unnatural cyclopeptide alkaloids were synthesised by cyclooligomerisation reactions <00T9143>. The benzene-based tripodal tris(oxazolines) 159 were developed as new selective receptors toward alkylammonium ions <00CEJ3399>. 

The utility of small ring conjunctive reagents in total syntheses appears to be very great. The convulated structural correlations between the target and a starting material hamper its ready adaptation. The facility and stereochemical implications make the rethinking of retrosynthetie analysis well worth the effort. To illustrate some of this potential, several applications in the total synthesis of natural and unnatural products are analyzed. 

The availability of cyclopentenones from butanolides allows the lactone annulation to facilitate the synthesis of cyclopentyl natural and unnatural products. An example that highlights the latter is dodecahedrane (178) for which 179 constitutes a critical synthetic intermediate 136,137). Lateral fusion of cyclopentenones as present in 179 can arise by acid induced reorganization and dehydration of 180. While a variety of routes can be envisioned to convert a ketone such as 182 into 180, none worked satisfactorily137 On the other hand, the cyclobutanone spiro-annulation approach via 181 proceeds in 64 % overall yield. Thus, the total carbon cource of dodecahedrane derives from two building blocks — cyclopentadiene and the cyclopropyl sulfonium ylide. 

Strained molecules such as cyclopropanes and cyclobutanes have emerged as important intermediates in organic synthesis. We have already demonstrated here that cyclobutane derivatives can indeed serve as starting materials for the synthesis of natural as well as unnatural products. Unlike cyclopropanes, which can be prepared asymmetrically in a number of ways 175 -182>, the asymmetric synthesis of cyclobutane derivative has received less attention, and, to our best knowledge, very few reports were recorded recently 183). Obviously, the ready availability of chiral cyclobutane derivatives would greatly enhance their usefulness in the enantioselective synthesis of natural products. The overcome of this last hurdle would allow cyclobutane derivatives to play an even more important role in synthetic organic chemistry. 

This article provides a brief overview of several recent total syntheses of natural and unnatural products that have benefited from the use of catalytic asymmetric processes. The article is divided by the type of bond formation that the catalytic enan-tioselective reaction accomplishes (e.g C-C or C-0 bond formation). Emphasis is made on instances where a catalytic asymmetric reaction is utilized at a critical step (or steps) within a total synthesis however, cases where catalytic enantioselective transformations are used to prepare the requisite chiral non-racemic starting materials are also discussed. At the close of the article, two recent total syntheses are examined, where asymmetric catalytic reactions along with a number of other catalyzed processes are the significant driving force behind the successful completion of these efforts (Catalysis-Based Total Syntheses). 

The above methodology should enable control of product configuration by mere change in the reagent. Preparation of natural and unnatural amino acid... 

Dioxin vinylogous esters derived from cyclic 1,3-diketones (e.g., 4) are valuable building blocks for the construction of natural and unnatural carbocyclic products.2 In connection with a synthesis of plant-growth regulators, Crow and... 

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