Synthetic planning

Both items are repeated until the intermediates are reasonably priced commercial starting materials. The resulting antithetic schemes are then evaluated and the most promising ones can be converted into synthetic plans and be investigated in the laboratory. 

A critical feature of synthetic planning is to reason backward from the target to the starting material A second is to always use reactions that you know will work... 

Often more than one synthetic route may be available to prepare a particular com pound Indeed it is normal to find m the chemical literature that the same compound has been synthesized m a number of different ways As we proceed through the text and develop a larger inventory of functional group transformations our ability to evaluate alternative synthetic plans will increase In most cases the best synthetic plan is the one with the fewest steps... 

E J Corey (Section 14 9) invented the word synthon in connection with his efforts to formalize synthetic planning... 

The prevalence of diols in synthetic planning and in natural sources (e.g., in carbohydrates and nucleosides) has led to the development of a number of protective groups of valuing stability to a substantial array of reagents. Dioxolanes and diox-anes are the most common protective groups for diols. The ease of formation follows the order ... 

It is a common experience in synthetic chemistry that a truly optimal ordering of a synthetic route may not be possible in the planning stage, but may have to determined experimentally. The precise information necessary for the complete and unambiguous evaluation of each step in a possible synthesis is hardly ever available. Nonetheless it is clearly wise to try to optimize a synthetic plan on the basis of available information before the experimental approach begins. Such an effort may suggest certain preliminary or "model" experiments that can be helpful in the choice or refinement of a synthetic plan. It is also obviously desirable to devise and consider alternate or bypass paths for each problematic step of a synthetic sequence. 

The antibiotic aplasmomycin serves as a receptor or transporter for borate. Retrosynthetic simplification of the boron-free macrocycle to identical hydroxy acid subunits is clearly appropriate. Further retrosynthetic dissection produced fragments A, B and oxalate and provided a workable synthetic plan. 

Part Two, a collection of multistep syntheses accomplished over a period of more than three decades by the Corey group, provides much integrated information on synthetic methods and pathways for the construction of interesting target molecules. These syntheses are the result of synthetic planning which was based on the general principles summarized in Part One. Thus, Part Two serves to supplement Part One with emphasis on the methods and reactions of synthesis and also on specific examples of retrosynthetically planned syntheses. 

Retrosynthetic analysis (Section 14.9) Technique for synthetic planning based on reasoning backward from the target molecule to appropriate starting materials. An arrow of the type designates a retrosynthetic step. 

In their general synthesis of quinoline-2,5,8(lf/)-triones, Avendano and coworkers use this modified protocol to access the key 2,5-dimethoxyanilide systems 11 required in their synthetic plan." For more examples, see reference 11 and references cited within. 

The parent TMM precursor (1), now commercially available, has played a pivotal role in the execution of many synthetic plans directed at natural and unnatural targets. Reaction of (1) with 2-(methoxycarbonyl)cyclohexenone (14, R=C02Me) in the presence of palladium acetate and triethyl phosphite produced the adduct (15) in near quantitative yield. This cycloadduct is a critical intermediate in the total synthesis of a hydroxykempenone (16), a component of the defensive substances secreted by termites (Scheme 2.5) [12]. In accord with a previous observation by Trost that unactivated 2-cyclohexenone reacts poorly with TMM-Pd [13], the substrate (14, R=Me) was essentially inert in the cycloaddition. 

The second synthesis follows an entirely different synthetic plan—one dependent upon a double-Michael reaction to establish the spiran junction. Chlorophenol, 7, is reacted with chloro-acetylchloride to give coumaranone, 16. This is treated with methoxyethynyl propenyl ketone (17) (itself prepared by 1,2-... 

The aziridine-2-carboxaldehyde 56 can also serve as synthon for the synthesis of sphingosines, which are important biomembrane constituents [64]. One possible route involves the addition of an alanate to the aldehyde. In a later stage of this synthetic plan the aziridine can be opened, either via the intermediacy of an oxazoline or directly with dilute acid. Unfortunately, the reaction of aldehyde 56 with a vinylalanate has a poor diastereoselectivity of 3 2. Therefore, an alternative approach was considered, namely one involving the addition of a vinylzinc reagent to the aldehyde thereby employing our N-tritylaziridinediphenyl-methanol 51 as the chiral catalyst. Gratifyingly, only one diastereomer was obtained. Reductive removal of the trityl function, acetylation of the hydroxy... 

Minimize overall number of steps and stages preferably using nested MCRs as far as possible as the main strategy in a synthetic plan to a complex target. Overall convergence is maximized dramatically if a plan contains a late-stage MCR that involves components that are themselves terminal products of independent parallel linear sequences. 

The opiate alkaloid, papaverine, from Papaver somniferum is an anti-spasmodic, vasodilator, and smooth muscle relaxant. Its total synthesis has been studied since Pictet and Gams early work in 1909 and has since been followed up by various industrial syntheses up till the early 1950s using important industrial commodities as vanillin, acetovanillone, veratraldehyde (methylvanillin), and homoveratric acid as starting materials (see Figure 4.50). Table 4.23 summarizes the results of the five synthetic plans for this natural product. All are convergent... 

The initial step in creating a synthetic plan involves a retrosynthetic analysis. The structure of the molecule is dissected step by step along reasonable pathways to successively simpler compounds until molecules that are acceptable as starting materials are identified. Several factors enter into this process, and all are closely interrelated. The recognition of bond disconnections allows the molecule to be broken down into key intermediates. Such disconnections must be made in such a way that it is feasible to form the bonds by some synthetic process. The relative placement of potential functionality strongly influences which bond disconnections are preferred. To emphasize that these disconnections must correspond to transformations that can be conducted in the synthetic sense, they are sometimes called antisynthetic transforms, i.e., the reverse of synthetic steps. An open arrow symbol, = , is used to indicate an antisynthetic transform. 

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