Strategy Chapters

One route is by reductive amination of ketone (10) available by Friedel-Crafts reaction from acid (11) which we can make by an FGA strategy (Chapter T 24). 

Alternating with instructional chapters, like the last one, will be strategy chapters, like this one, which discuss reasons for choosing one route rather than another in other words the overall plan rather than the individual steps. In this chapter we shall examine the order of events, using the synthesis of aromatic compounds as examples. The details are specific but the guidelines general. 

This is the first of four General Strategy chapters in which we discuss important points that apply to the whole of synthetic design rather than one particular area. This chapter concerns general principles to help you choose one C-C disconnection rather than another. Even a simple molecule like the alcohol 1, introduced in chapter 1 as a component of the elm bark beetle pheromone, can be disconnected at any of the five marked bonds. 

This strategy chapter is rather different. We shall look at one class of starting material—alkynes or acetylenes—and see what special jobs they can do in synthesis. In particular, we shall see how they can solve some problems we have already met. Acetylene itself 3 is readily available and its first important property is that protons on triple bonds are much more acidic than most CH protons. Acetylene forms a genuine anion 4 with sodium in liquid ammonia, a lithium derivative 1 with BuLi and a Grignard reagent 2 by reaction with a simple alkyl Grignard such as EtMgX. 

You will notice that all these methods depend on the carbonyl group and interspersed with these chapters will be strategy chapters relevant to them culminating in a general strategy chapter on carbonyl chemistry ... 

This extension, known as the Amdt-Eistert procedure,1 is useful if the relationship between functional groups is unhelpful in the TM but becomes helpful if the chain is retrosynthetically shortened. Other methods, such as cyanide displacement, also increase the chain length by one carbon and we saw a chain extension by two carbon atoms in the last chapter. The disconnections are strange both C-C bonds between R and CO are made in the reaction so we must disconnect both 5a. You might like to think of this as a reconnection strategy (chapter 26) or as an extrusion of a CH2 group. 

Disconnection of the bicyclic diketone 21 starts reasonably to reveal 22 but the two carbonyl groups are now 1,6-related suggesting a reconnection strategy (chapter 27). But this is impossible as the bridgehead alkene 23 is too strained to exist. However, if we extrude the carbon atom in the seven-membered ring between the ketone and the branchpoint 22a, we get a new ketoester 24 with a 1,5 relationship that can be made by conjugate addition (chapter 21). 

The plan of the original book is the same in the second edition. It alternates chapters presenting new concepts with strategy chapters that put the new work in the context of overall planning. The 40 chapters have the same titles some chapters have hardly been changed while others have undergone a thorough revision with considerable amounts of new material. In most cases examples from recent years are included. 

Each strategy chapter ends with a point-by-point summary that captures the most important points. The summaries are a convenient way to review the content of these strategy chapters. 

During the scale-up of an asymmetric synthesis of lotrafiban 228, a drug for the prevention of thrombotic events , racemisation proved to be a problem. The synthesis used the chiral pool strategy (chapter 23), the fragment in the frame of the intermediate 229 being derived from aspartic acid. 

Two methods were promising enough for serious consideration but were eventually rejected on practical grounds. They both amount to chiral pool strategies (chapter 25) though the first starting material, styrene oxide 7, is not a natural product. Both enantiomers of 7 are commercially... 

The synthesis is necessarily long and we shall concentrate on the tandem aspects. The three enantiomerically pure starting materials were the acetylenic silane 135 for C-6, prepared by resolution (chapter 22), the epoxide 136, for C-l and 2, prepared from proline (chiral pool strategy, chapter 23) and the Wittig reagent 137, prepared from ethyl lactate (chiral pool again), for C-ll. 

A commoner way to make heterocycles by pericyclic reactions is to use 1,3-dipolar cycloadditions. These often occur without catalysis and so are compatible with many other reactions. The starting material 182 for this asymmetric synthesis of swainsonine was derived from a natural sugar (chiral pool strategy, chapter 23). An exceptionally stereoselective Wittig reaction gave the Z-alkene 183 (chapter 15) and the alcohol was converted into the azide 184 with diphenylphos-phoryl azide.24... 

As pointed out in the preceding reviews of separator function and separator materials (Chapters 6 and 7, respectively) and of charging strategies (Chapter 9), the separator plays a crucial role in VRLA cells. Provision of a separator with the appropriate microstructure can constrain the rate of oxygen arrival at the negative plate and thus restrict the suppression of the plate potential caused by the oxygen-recombination reaction. 

Chapters of instruction in types of disconnections alternate with strategy chapters which aim to put the instruction in a broader context. At four points, general strategy chapters (11, 28, 37, 40) of exceptional importance are inserted into this scheme. If you are a student, you will probably need to read all the chapters, though you may find much familiar chemistry at first. If you arc a practising organic chemist, you will find the early instructional chapters elementary but, I hope, worthwhile in their relationship to the early strategy chapters. 

This is a long synthesis. Though the yields are good, the overall yield is only A second successful and much shorter synthesis comes from the FGA strategy Chapter 24). Introducing unsaturation throughout the whole skeleton of (34) gives an aromatic compound (38) with an obvious ct, 3-disconnection. 

Some of the guidelines established in earlier general strategy chapters (12, 28,37) amount to convergence disconnections in the middle of a molecule or a at a branch point are likely to lead to convergent syntheses. Examples of convergent syntheses appear in Chapters 5,6,10,21,23, and 39. 

Office of National Drug Control Policy, 1998. The national drug control strategy. Chapter III Strategic goals and objectives, http //www.ncjrs.org/ondcppubs/... 

---