How to Approach Synthesis Problems

In this chapter, we have seen many reactions. In order to solve synthesis problems, you will need to have all of these reactions at your fingertips. In the beginning of this chapter, we saw a few ways to make aldehydes and ketones. Do you remember those reactions If you don t, then you are in trouble. This is why organic chemistry can get tough at times. It is not sufficient to be a master of mechanisms. That is an excellent start, and it builds an excellent foundation for understanding the material. But at the end of the day, you have to be able to solve synthesis problems. And in order to do that, you must have all of the reactions organized in your mind. 

It sounds like a lot of work. And it is. It wiU take you a whUe. But when you are done, you wUl be in an exceUent position to start tackling synthesis problems. If you get lazy, and you decide to skip this advice, then don t complain later if you are frustrated with synthesis problems. It would be your own fault for trying to run before you have mastered walking. 

Once you get to the point where you have aU of the reactions at your fingertips, then you can come back to here, and try to prove it, by doing some simple problems. These problems are designed 

EXERCISE 5.80 What reagents would you use to achieve the following transformation  

Answer By inspecting the product, we can immediately determine that we will need a nitrogen nucleophile. We just need to decide what kind of nitrogen nucleophile. Since our product is an enamine, we will need a secondary amine. When we look at the product, we can determine that we would need to use the following secondary amine  

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Joining the effort at this time were Drs. Kai Rossen and Phil Pye, specifically to work on a practical carbonate synthesis. In thinking about how to approach this problem (Figure 8), their thoughts led back to the acetoxyazetidinone, which, in fact, was defined as a viable carbapenem synthon by Dr. Paul Reider and yours truly back in the early 1980 s. In the intervening years it has become an article... 

In order lo learn how to devise sensible ways to make large organic molecules from small ones (a typical task of synthesis), you need to approach the problem systematically. First, note that the reactions you are learning can be classified into two categories ... 

One has to pinpoint why chemists react to certain synthesis problems in a distinct way and not otherwise. For this reason, the development of a logic of chemical synthesis [3] brought significant progress, which was in due course recognized in 1990 with the Nobel Prize. However, the notion of such a logical approach to synthesis is hke a sermon in church one listens and accepts how one ought to behave, but the next day one s reality reflects a different story. 

The use of AR theory is somewhat different from many other optimization techniques, and hence it is useful to provide a guideline for how to approach reactor network synthesis problems from this viewpoint. This framework outlines five key steps, with the level of difficulty involved in each step placed in parentheses. 

Acid Derivatives 14.2 How to Approach Multistep Synthesis Problems... 

The synthesis of complex molecules requires an in-depth knowledge of chemical reactions, as well as an understanding of synthetic strategy for various types of structural motifs. An entire course is usually required to introduce the fundamentals of synthesis theory, and that is well beyond the scope of this book. However, a discussion of how to approach several common problems in the synthesis of complex molecules is appropriate. This will give a glimpse into the power and flexibility of the disconnection approach to develop a synthetic route to the most complex targets. 

In order to illustrate this approach, we next consider the optimization of an ammonia synthesis reactor. Formulation of the reactor optimization problem includes the discretized modeling equations for a packed bed reactor, along with the set of knot placement constraints. The following case study illustrates how a differential-algebraic problem can be optimized efficiently using (27). In addition, suitable accuracy of the ODE model can be obtained at the optimum by directly enforcing error restrictions and adaptively adding elements. Finally, bounds on the continuous state profiles can be enforced directly in the optimization problem. 

There have been two major developments in the past decade that make the total synthesis of proteins a practical reality the first developed and refined by people trained in classical solution chemistry and the second developed and refined by people trained in solid-phase chemistry. There are fundamental differences in the two approaches, but it is most interesting to see how they have converged into a unified approach to a common problem. 

In this appendix, we consider how an organic chemist systematically approaches a multistep synthesis problem. As with mechanism problems, there is no reliable formula that can be used to solve all synthesis problems, yet students need guidance in how they should begin. 

The main problem of catenane or rotaxane synthesis can be formulated as follows how to hold together the non-reacting partners, like 104 and 105, or 107a and 108, in an orientation to secure the formation of catenane or rotaxane, respectively Below we will consider several examples illustrative of the modern approach to solving this problem. 

Another approach that addresses the reduction of size of the MINLP is the state space approach by Bagajewicz and Manousiouthakis (1992). The basic idea of this strategy is to partition the synthesis problem into two major subsystems, the distribution network and the state space operator. The objective in the former is to make the decisions related to the distribution of flows in the superstructure, while the objective in the latter is to perform the optimization for the decisions selected in the distribution network. At the level of the state space operator one can consider the process either in its detailed level or simply as a pinch-based targeting model. While this strategy has the advantage of reducing the size of the MINLP, it is unclear how to develop automated procedures based on this approach. 

In 1971, Sumitomo started to apply this reaction to the chrysanthemic acid synthesis (Scheme 2). The first problem was how to choose a suitable catalyst which would achieve the highest ee of the product. Here we describe our approach to this problem [10,11,12,13,14,15,16,17,18]. Other effective catalysts... 

HMM synthesis is an effective solution to the problem of how to map fi om the specification to the parameters. While most approaches aim to generate cepstral parameters, some generate formants and in this sense the HMM approach can be seen as a direct replacement for the provision of these rules by hand as described in Chapter 13. Issues still remain regarding the naturalness parameter-to-speeeh part of HMM synthesis, but as confidence gains in the ability to solve the specification-to-parameter part, new techniques will be developed to solve these naturalness problems. 

The final further issue concerns the specification-to-parameters problem. In going from formant synthesis to LP synthesis the key move was to abandon an explicit specification-to-parameters model of vocal-tract configurations and instead measure the required parameters from data. From this we can use at synthesis time a lookup table that simply lists the parameters for each unit (typically a diphone). The cost in doing so is firstly that we lose explicit control of the phenomenon and secondly of course that we incur significant extra storage costs. If we now, however, look at how closely the LP parameters for one diphone follow parameters for lots of examples of that same diphone in many different real situations, we see that in fact even this purely data-driven approach is severely lacking, and in many cases the set of parameters for our diphone will match... 

In an introductory organic chemistry laboratory course, the student learns how to run organic reactions in cookbook fashion. The transition from this level of achievement to the competence required to carry out a synthesis from a vaguely defined procedure in a research journal or to develop a new synthesis is substantial. The general information given in Secs. 1.1 to 1.7 should help the student to bridge the gap between organic reactions at introductory and advanced levels. It is supplemented in Sec. 1.8 by a series of case studies in which the experimental approaches that were used to solve some special problems are examined. 

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