Total synthesis approaches

During the first total synthesis of taxol by Holton [179], a sequence of phosgenation reactions was performed in forming both a carbonate 243 and a cydocarbonate 245 with phosgene. The cydocarbonylation of the triol 244 with phosgene is re-gioselective and yields the six-membered ring 245. 

Nicolaou s approach to the total synthesis of taxol [182] employed phosgene to form the 1,2-cyclocarbonate 247 from 246 at the taxane scaffold as a protective group for the next 15 steps. Then, a regioselective ring-opening reaction with phe-nyllithium elegantly afforded the 2-0-benzoyl derivative 249 from 248. A further three steps led to taxol 241. 

A cydocarbonylation reaction akin to 246 — 247, forming 251 from 250, was accomplished with CDI in a taxoid synthesis by Nicolaou [187]. 

Mesyl chloride has been employed in the construction of the taxinine AB ring system [187] as well as of the taxane BC substructure [188]. The stereoselective construction of the taxinine AB system through a novel tandem aldol-Payne rearrangement annulation involves dehydration of the formamide 252 with mesyl chloride to give 253, followed by reductive cleavage of the isocyano function in 253 to afford 254 [188], 

Stereoselective construction of the taxane BC substructure requires an intermediate isocyano function in 256. Intermediate 256 is obtained in 100% yield by dehydration of the formamide 255 with mesyl chloride [189]. 

Fullerene generation by vaporization of graphite or by combustion of hydrocarbons is very effective and certainly unbeatable what facile production in large quantities is concerned. However, total synthesis approaches are attractive because (a) specific fullerenes could be made selectively and exclusively, (b) new endohedral fullerenes could be formed, (c) heterofullerenes and (d) other cluster modified fullerenes could be generated using related synthesis protocols. 

In a third approach substituents were removed from a preformed dodecahedrane cage. In this way the synthesis of [20-fJfullerene was possible in the gas phase [154]. However, extensions of this approach to syntheses of fullerenes consisting of 60 or more C-atoms are conceptually very difEcult. 

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Hydroxyquinine 97 was prepared recently in the course of a novel total synthesis approach toward cinchona alkaloids (Scheme 12.27). Interestingly, studies on stereocontrolled synthesis of quinine, apart from that of Uskokovic [66], were not published until 2001 and 2004, again underlining the fact that cinchona alkaloid... 

Alternatively, some of the prototypes of fullerene derivatives shown in Fig. 1 can be obtained directly during the fullerene formation out of graphite in the presence of foreign elements, by particle implantation methods or by total synthesis approaches. Most of the endohedral metallofullerenes are currently generated during the fullerene formation whereas partial structures are basically provided from total syntheses. For total synthesis approaches of fullerenes and their derivatives see [7]. 

Heterofullerenes like 3 [13-16] were synthesized via specific addition/elimina-tion sequences starting from C o or C70. As an example for a partial structure, semibuckminsterfullerene 4 was prepared exclusively using total synthesis approaches [17]. 

Rearrangement reactions have been well used in several total synthesis approaches for the construction of otherwise hard-to-access molecular frameworks, and in the past few years the first asymmetric organocatalytic versions of several synthetically useful sigmatropic rearrangements have appeared in the literature [78]. 

A chiral amine-catalyzed transfer hydrogenation was recently employed successfully by Lear and co-workers to obtain a key intermediate for die total synthesis of (—)-platensimycin (245) (213). (—)-Platensimycin (245) was identified from Streptomyces platensis in 2006 (214, 215). Due to its impressive antibacterial properties, it has generated considerable interest within the scientific and medical communities as a potential powerful new therapy against dmg-resistant bacteria (214, 215). Accordingly, several (formal) total synthesis approaches have been... 

Monoterpenes and iridoids are important classes of secondary metabolites, and their biosynthesis as well as total synthesis approaches to access these compounds has attracted the interest of chemists for a long time. This overview will summarize the most important biosynthesis pathways and in addition will illustrate how one of the most important recent developments in organic chemistry, asymmetric organocatalysis, contributed in the development of total synthesis approaches toward these compounds. Therefore, a comprehensive introduction to asymmetric organocatalysis will be given as well. However, it should be noted that the applicability of this methodology to the synthesis of natural products is of course not only limited to monoterpenes and iridoids but holds much promise for other classes of primary and secondary metabolites as well. 

Pharmaceutically useful steroids may be either obtained by total synthesis or by degradation and functional group conversions from inexpensive natural steroids. Both approaches will be discussed in this section (H. Langecker, 1977 R.T. Blickenstaff, 1974). 

Covalent synthesis of complex molecules involves the reactive assembly of many atoms into subunits with aid of reagents and estabUshed as well as innovative reaction pathways. These subunits are then subjected to various reactions that will assemble the target molecule. These reaction schemes involve the protection of certain sensitive parts of the molecule while other parts are being reacted. Very complex molecules can be synthesized in this manner. A prime example of the success of this approach is the total synthesis of palytoxin, a poisonous substance found in marine soft corals (35). Other complex molecules synthesized by sequential addition of atoms and blocks of atoms include vitamin potentially anticancer KH-1 adenocarcinoma antigen,... 

S. Hanessian, "Total Synthesis of Natural Products The Chiron Approach" (Pergamon Press, Oxford, 1983). 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

Boger developed his pyridine synthesis out of a need to eonstruet a pentasubstituted pyridine in an approach to the formal total synthesis of antitumor antibiotic streptonigrin 44. The requisite triazine 48 was produeed by using this methodology in an iterative sense with two different aza-heteroeyeles. Reaetion of thioamidate 46 with tetrazine 47, in a eyeloaddition/eyeloreversion sequenee, afforded 1,2,4-triaziene 48. Exposure of enamine 49 to 48 resulted in the formation of 50. This compound was elaborated into a eompound that intereepted Kende s synthesis of 44. ... 

Although morphine has been prepared by total synthesis, the complexity of the molecule makes such an approach unattractive on a commercial scale. The drug in fact is obtained by fractionation of opium obtained from the poppy morphine in turn is used as starting material for various derivatives. If it were not for the importance of these drugs in the clinic, some progress might have been made in eradication of the plant. 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

Based on the successful series of transformations summarized in Scheme 1, Schreiber and Santini developed an efficient and elegant synthesis of periplanone B (1),8 the potent sex pheromone of the American cockroach, Periplaneta americana. This work constitutes the second total synthesis of periplanone B, and it was reported approximately five years after the landmark periplanone B synthesis by W.C. Still9 (see Chapter 13). As in the first synthesis by Still, Schreiber s approach to periplanone B takes full advantage of the facility with which functionalized 5-cyclodecen-l-one systems can be constructed via anionic oxy-Cope rearrangements of readily available divinylcyclohexanols.5 7 In addition, both syntheses of periplanone B masterfully use the conformational preferences of cyclo-decanoid frameworks to control the stereo- and regiochemical course of reactions carried out on the periphery of such ring systems.10... 

For excellent discussions of the use of optically active starting materials in synthesis, see (a) Hanes-sian, S. The Total Synthesis of Natural Products. The Chiron Approach, Pergamon Press New York, 1983 (b) Scott, J.W. In Asymmetric Synthesis, Morrison, J.D. Scott, J. W., Eds., Academic Press San Diego, 1984, Vol. 4, p. 1. 

Due, in large part, to the promising antitumor activity of gilvocarcin V (2), it was of interest to modify the approach outlined above so that a total synthesis of 2 could also be achieved. Not surprisingly, the gilvocarcin V synthesis exercised the same basic strategy that was so successful in the synthesis of gilvocarcin M... 

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