Synthesis of Large-Volume Products

The purpose of this chapter is to discuss the syntheses of top-selling chiral compounds so that a perspective may be obtained about the merits of the various asymmetric approaches discussed elsewhere in this book. Of course, the majority of these drugs are mature, which means that a considerable amount of time and money has been expended to reduce costs and optimize the syntheses. In addition, asymmetric synthesis is a new approach and, although the potential may exist today to use an asymmetric oxidation, this was not a serious option 20 years ago. To help with the development of asymmetric synthesis, a discussion has been included on the difference between the top-selling drugs discussed in the first edition of this book and in the current one. In addition to pharmaceuticals, some large volume products in the food and agricultural areas are also discussed. 

The whole-cell biocatalysis approach is typically used when a specific biotransformation requires multiple enzymes or when it is difficult to isolate the enzyme. A whole-cell system has an advantage over isolated enzymes in that it is not necessary to recycle the cofactors (nonprotein components involved in enzyme catalysis). In addition, it can carry out selective synthesis using cheap and abundant raw materials such as cornstarches. However, whole-cell systems require expensive equipment and tedious work-up because of large volumes, and have low productivity. More importantly, uncontrolled metabolic processes may result in undesirable side reactions during cell growth. The accumulation of these undesirable products as well as desirable products may be toxic to the cell, and these products can be difficult to separate from the rest of the cell culture. Another drawback to whole-cell systems is that the cell membrane may act as a mass transport barrier between the substrates and the enzymes. 

While this route furnished 14 from inexpensive, readily available starting materials in the early stages of development, the following drawbacks prompted the quest for a better synthesis (1) the multiple manipulations to the oxidation state at the 3-position of the piperidine ring were tedious (2) the hydroboration/oxidation sequence required the use of large volumes of solvent during the work-up and isolation (3) the Parikh-Doering oxidation resulted in product that was contaminated with dimethyl sulfide and (4) the overall yield from this sequence was less than ideal. 

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