Natural products, total synthesis

Natural product total syntheses are particularly valuable when they are attended by the development of general utility methods of synthesis. In some instances, the successful completion of a natural product total synthesis requires the development and application of a new synthetic method. The total synthesis of erythronolide B by Corey et al. is one of these instances. The double activation macro-lactonization method was a fruitful innovation that was introduced in response to the challenge presented by the macrocyclic structures of the erythromycins. Several other methods to achieve the same objective, and numerous applications followed. 

The utility of the Suzuki reaction in the challenging arena of natural product total synthesis has been explored. The constitution of bombykol (106) (see Scheme 26), a well-known pheromone, lends itself to a Suzuki coupling. Indeed, in a short stereospecific synthesis of 106, Suginome et al. demonstrated that ( )-vinylboronic acid ( )-104 can be smoothly cross-coupled with (Z)-l-pentenyl bromide [(Z)-105] 44 the configurations of both coupling partners are preserved in the C-C bond forming process. 

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

Arimoto, H. Arimoto, Y. Okumura, S.N. Shosuke, Y. (1995) Synthetic studies on fiilly substituted y-pyrone-containing natural products total synthesis and structural revision of onchitriol I. Tetrahedron Lett., 36, 5357-8. 

The feasibility of multi-step natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first achieved by Nicolaou and co-workers in epothilone synthesis and in the synthesis... 

Enantioselective target-directed synthesis, which is important both for single-enantiomer pharmaceuticals and for natural product total synthesis, depends on the ability to form carbon-carbon bonds with absolute stereocontrol. An ideal method would be readily available, easy to practice, and proceed with high stereocontrol. In this column and the next one, we will review the most prominent recent developments. 

Sheldrake HM, Jamieson C, Burton JW (2006) The Changing Faces of Halogenated Marine Natural Products. Total Synthesis of the Reported Structures of Elatenyne and an Enyne from Laurencia majuscula. Angew Chem Int Ed 45 7199... 

Keywords Biocatalysis Biosynthesis In vitro reconstitution Natural products Total synthesis... 

B. Dounay, L. E. Overman, The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis, Chem. Rev. 2003, 103, 2945-2963. 

A different sequential DreM pathway involving O-carbamate ring switch-vinylogous tolyl amide cydization, 170 —> 171 —> 172 (Scheme 44), a formal bridging of a 2,2 -methyl diaryl dicarbanion with a carbonyl dication equivalent (173) has been affirmed in a model study (174 —> 175, Scheme 45) [73] and applied in natural product total synthesis [73, 74]. 

A. Total Synthesis of Natural Products Total Synthesis of Ikarugamycin... 

Thus, radical addition reactions provide a useful means of functionalising pyridines, quinolines and isoquinolines, particularly when it is reasonable to employ the heteroaromatic base in excess. Intramolecular variants of the reaction are devoid of that limitation and have been widely exploited in the synthesis of nitrogen-containing heteroaromatics. The mildness of the reaction conditions have found favour in natural products total synthesis and medicinal chemistry programs. These bare testament to the reactions worth and have raised its stature from academic curiosity to useful synthetic tool. 

Dounay AB, Overman LE. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 2003 103 2945-2963. 

The frequency with which the pinacol coupling process is employed in the synthesis of complex molecules is a testament to its tremendous utility. In this section, recent applications to natural products total synthesis are surveyed. These case studies simultaneously attest to the triumphs made possible by the pinacol coupling reaction, provide an indication of the functional-group compatibility of the process, and point to challenges that remain to be solved. 

The transition-metal catalyzed cross-coupling reaction of (hetero)aryl hahdes and triflates with primary and secondary amines or (hetero)aryl amines is know as the Buchwald-Hartwig reaction [144]. Mechanistically, this reaction is related to the crosscoupling reactions outlined thus far (Fig. 4.6). The modification arises at the point of transmetalation. This step in the process is substituted with the coordination of the amine reactant. Deprotonation of the amine nitrogen now precedes the reductive elimination step to generate the aryl amine product. This reaction has foimd utility in the academic setting, for use in natural product total synthesis, and in industry, for the preparation of materials up to the multi-hundred kilogram scale. 

The Asymmetric Intramolecular Heck Reaction in Natural Product Total Synthesis ... 

Diels-Alder reactions of glyoxylates have recently found application in natural product total synthesis. For example, Schmidt and Wagner used such a cycloaddition as a key step in synthesis of uracinine derivative 3, a component of the nucleoside antibiotic blasticidin S (Scheme 4-II).13 Interestingly, when unsymmetrical diene 1 undergoes [4 + 2] cycloaddition with a glyoxylate, only one series of regioisomers is produced, which has the incorrect orientation for synthesis of 3.14 However, if the o-benzoyl... 

Application to natural product synthesis. The application of Mn(III)-mediated radical reactions to natural product total synthesis provides an excellent demonstration of the scope and utility of these reactions since the method must be versatile enough to deal with complex skeletons and diverse functionality. Many examples of the use of Mn(III)-mediated radical reactions have already been presented above. Some other notable examples are described below. 

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