Planning Multistep Syntheses

Plan multistep syntheses using alcohols as starting materials and intermediates. 

The Expert System for Chemistry Planning Multistep Syntheses and Conversion of Polymeric and Hazardous Chemical Wastes to Useful Materials... 

It is in principle possible to plan multistep synthesis in two directions ... 

One of the surest wavs to learn organic chemistry is to work synthesis problems. The ability to plan a successful multistep synthesis of a complex molecule requires a working knowledge of the uses and limitations of a great many organic reactions. Not only must you know which reactions to use, you must also know when to use them because the order in which reactions are carried out is often critical to the success of the overall scheme. 

Protocols of peptide chemistry and, to some extent, biooligomer synthesis (e.g., nucleotides, saccharides) are valuable sources of information on this topic with regards to solid-phase synthesis peculiarities. Here we focus on a particular functional group transformation, which takes the role of depro-tecting a masked functionality, namely the nitro-to-amine reduction. This approach provides a versatile tool for planning multistep derivatizations of heterocycles, as exemplified in Fig. 15.45... 

As will be shown throughout this book, the outcome of organic reactions is highly dependent on all structural features of a given starting material, and unexpected products may readily be formed. Therefore, while planning a multistep synthesis, it is important to keep the total number of steps as low as possible. 

Carefully read the directions for each synthesis problem. Sometimes a starting material is specified, whereas at other times you must begin with a compound that meets a particular criterion for example, you may be asked to synthesize a compound from alcohols having five or fewer carbon atoms. These limitations are meant to give you some direction in planning a multistep synthesis. 

Another multistep synthesis, shown below, involves linking the synthesis of a chalcone in Experiment 61 with the epoxidation of the chalcone (Experiment 62) and/or the cyclopropanation of the chalcone (Experiment 63). If you plan for creating a multistep synthesis as described here, it may be a good idea to make a larger quantity of chalcone by scaling up the amounts of substituted acetophenone and substituted benzaldehyde used to prepare the chalcone. 

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. 

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

Adding the substituents in the correct order is crucial in mastering ciromatic synthesis problems. Examine the two reaction sequences given in Figure 8-4. Both sequences involve the same reagents however, the order is reversed. This shows that the reaction sequence is important. You need to plan ahead in any multistep reaction sequence. 

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