Synthetic Design

In character, in manners, in style in all things, the supreme excellence is simplicity. 

Pumiliotoxin C, a c/s-decahydroquinoline from poison-dart frogs, Dendrobates pumilio. 

Faced with the challenge to synthesize a new compound, how does the chemist approach the problem Obviously, one has to know the tools of the trade their potential and limitations. A synthetic project of any magnitude requires not only a thorough knowledge of available synthetic methods, but also of reaction mechanisms, commercial starting materials, analytical tools (IR, UV, NMR, MS), and isolation techniques. The ever-changing development of new tools and refinement of old ones makes it important to keep abreast of the current chemical literature. 

What is an ideal or viable synthesis, and how does one approach a synthetic project The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). Furthermore, the experimental ease of the transformations and whether they are environmentally acceptable must be considered. 

Synthesis of a molecule such as pumiliotoxin C involves careful planning and strategy. How would a chemist approach the synthesis of pumiliotoxin C This chapter outlines strategies for the synthesis of such target molecules based on retrosyn-thetic analysis. 

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The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

Discredited Synthetics. There are several materials that have in the past been considered to be synthetics, but were found on closet examination not to deserve such a designation, being merely imitations. Examples include imitation coral, lapis la2uli, and turquoise, all made by ceramic processes. This same point has been raised (17) with respect to synthetic opal, which does contain some substances not present in natural opal and somewhat less water. However, the composition of natural opal is quite variable and is usually intermixed with significant amounts of rock-derived materials hence the synthetic designation is usually retained. 

The Frasca method for obtaining 1-arylindazoles also involves a C(3)—C(3a) ring closure (67CJC697). It consists in the cyclization of p-nitrophenylhydrazones of ketones and aldehydes with polyphosphoric acid. The Barone computer-assisted synthetic design program has found several new methods for preparing indazoles (79MI40409). The selected method involves the transformation of jV, jV -diphenylhydrazides (596) into 1-phenylindazoles (597) by means of trifluoromethanesulfonic anhydride. The yields vary from 2% (R = H) to 50% (R = Ph). 

The last-mentioned property of a synthetic process, i.e. versatility, is frequently an important consideration in research on optimally effective therapeutic agents in which the synthesis of a large series of structural analogs from a single intermediate is desirable. This aspect of the problem-solving environment can play a decisive role in synthetic design. 

The title of this three-part volume derives from a key theme of the book—the logic underlying the rational analysis of complex synthetic problems. Although the book deals almost exclusively with molecules of biological origin, which are ideal for developing the fundamental ideas of multistep synthetic design because of their architectural complexity and variety, the approach taken is fully applicable to other types of carbon-based structures. 

Manzer, L. E. (1994). Chemistry and Catalysis. by Design Alternative Synthetic Design for Pollution Prevention, ed. P. T. Anastas, and C. A. Farris, 144-54. Washington, D. C. American Chemical Society. 

Thorough analyses of linear and convergent strategies for tetraene (3) are given by Corey. His approach is for computer-based synthetic design but the logic is helpful to humans. This would be a good example to look... 

Figure 36 Synthetic design of a molecular rod made of adamantanes the tetrameric 1,3-adamantane. Taken from Ref. [171] with permission.

For both these reasons, a strategy based simply on literature searching is unlikely to be competitive with the best synthetic chemists, who would, of course, use the literature to aid their synthetic designs. It may seem, then, that organic synthesis will remain a skill in which computers cannot compete with humans for some considerable time to come. However, this is not necessarily so. 

Owing to the low barriers to bond formation, reactant conformation often plays a decisive role in the outcome of these reactions. Carbocations, carbene, and radicals frequently undergo very efficient intramolecular reactions that depend on the proximity of the reaction centers. Conversely, because of the short lifetimes of the intermediates, reactions through unfavorable conformations are unusual. Mechanistic analyses and synthetic designs that involve carbocations, carbenes, and radicals must pay particularly close attention to conformational factors. 

The many efforts of synthesizing the thiepin system described in Section 2 have revealed that extremely mild conditions have to be employed for the construction of the thiepin skeleton in order to avoid thermal sulfur extrusion from the resulting thiepins. This is an especially important prerequisite for the synthetic designs aimed at obtaining simple (thermolabile) thiepin derivatives. In our own study in this field we have previously developed new versatile routes for the synthesis of the thiepin skeleton. In this section we summarize our synthetic approaches to the relatively simple thiepin derivatives. 

Musshoff, F., Lachenmeier, D.W., Kroener, L. and Madea, B. (2002) Automated headspace solid-phase dynamic extraction for the determination of amphetamines and synthetic designer drugs in hair samples. J. Chromatogr. A 958, 231-238. 

M. A. Marx, A.-L. Grillot, C. T. Louer, K. A. Beaver, P. A. Bartlett, Synthetic Design for Combinatorial Chemistry. Solution and Polymer-Supported Synthesis of Polycyclic Lactams by Intramolecular Cyclization of Azo-methine Ylides , J. Am. Chem Soc. 1997,119, 6153-6167. 

NMR spectroscopy derives its usefulness, in large measure, from its ability to detect constitutional symmetry. If constitutional symmetry is not taken into account in synthetic design computer programs, a redundancy of pathways may result. 

In the treatment of stereochemical aspects for many chemical problems such as synthetic design representation of tri- and tetracoordinate monocentric configurations by their parity descriptors suffices. The conformational aspect as well as higher coordinate and polycentric configurations can be neglected. Then, it is possible to reduce the CC-matrices to parity vectors Pn whose components +1,0, — 1 represent the configurational features. 

Synthesis of the Cl-Cll domain of the epothilones at first appeared quite forbidding because of the need to gain facile control over the stereocenters at C3, C6, C7, and C8. Indeed, this region has been the scene of many variations in strategy and synthetic design. [12] Our first generation synthesis of the Cl-Cll acyl domain, al-... 

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