Highly complex molecules

Few known and thermodynamically feasible molecular structures are presently seen as impossible goals for synthesis. New transformations and effective strategies permit chemists to synthesize highly complex molecules, such as new natural compounds discovered in the continued chemical exploration of the natural world. Again, the point of such work is to develop new chemistry that permits an approach to structures of the type found in nature. This expands the power of chemistry and allows medicinal chemists to synthesize complex structures. 

The tandem Diels-Alder reaction of bisdiene 129 and bisdienophile 128 led to the production of a highly complex molecule as a single stereoisomer. Three new rings and six new stereogenic centers were created during the process [108]. 

The purity analysis of a recombinant produced product is difficult because the accuracy of protein purity is method-dependent and is influenced by the shortcomings of the analytical procedures (Chapter 2). Proteins are highly complex molecules therefore, it is generally very desirable to utilize more than one method to define a given protein s purity. To assure the purity of... 

An important fact inherent in the purity analysis of a recombinant pharmaceutical is that the absolute purity of any protein is an elusive, if not an unobtainable, measurement. For biopharmaceuticals, purity is a relative term. Protein purity is method-dependent and is defined by the shortcomings of the analytical procedure. Also, unlike small traditional drugs, proteins are highly complex molecules. For these two reasons, more than one method must be utilized to define a protein s purity. The greater the number of methods used in the purity analysis, the greater the assurance is that the product is pure. Furthermore, the purity determined by an analytical method can only be properly interpreted based on the method s validation. Analytical methods validation is critical to and inseparable from purity determinations. A detailed discussion on analytical methods validation is beyond the scope of this chapter but other sources of information are available for the interested reader.11 13... 

In the case of Tc pharmaceuticals, chemistry and safety have been compounded into kits, which have overcome the limitations set by radioactive decay and the risk of bacterial contamination. Kits are manufactured in advance in accordance with GMP requirements for the manufacture of sterile medicinal products, have a long shelf life, and facilitate ad hoc labeling whenever there is a demand in nuclear medicine. Kits provide safety and ease of preparation of highly complex molecules by using aseptic techniques for labeling. Consequently, quality control requirements for kit preparations rely merely on testing the radiochemical purity of a " Tc pharmaceutical to demonstrate stability in compliance with the purity requirements stated in the pharmacopeia. 

CoMpoarrioH.—They consist of C, N, H, O, and usually a small quantity of S, and form highly complex molecules whose exact composition is uncertain. Of their constitution nothing is definitely known, although there is probability that they arc highly complex amides, related to the ureids, aud formed by the combination of glycoUamine, leucine, tyrosine, etc., with radicals of the acetic and benzoic series-... 

Metal-catalyzed reactions have been of major importance in synthetic organic chemistry. Over the past decade, enantio- and diastereoselective metal-mediated domino catalysis has emerged as an effective tool to construct really highly complex molecules in one-pot processes [2, 4b,d]. Among them, enantioseletcive metal-catalyzed conjugate additions (in particular, Cu-catalyzed 1,4-addition to a,P-unsaturated carbonyl compounds) have been useful components of domino reactions [4d, 5]. The generated metal enolates 2 after the additions of nucleophiles readily react with a variety of electrophiles (Scheme 11.1). Enantioselectivity of 3 depends on the first addition of nucleophiles to the P-position of the unsaturated carbonyl compounds 1. 

This enzyme-like reactivity enables the synthesis of highly complex molecules from substrates containing carboxylic acids, such as picrotoxinin derivatives which, when exposed to the same oxidizing conditions, yield lactone and hydroxylactone products (Scheme 38). 

This chapter deals with three important classes of biotransformations. Firstly, those enzymes that catalyse the stereoselective formation of carbon-carbon bonds will be examined. These enzymes, whose natural functions often are to degrade carbohydrate-like molecules, have proved to be versatile catalysts for C—C bond synthesis. Secondly, we shall look at those enzymes that mediate the formation of C—X bonds, where X = O, N, S, Hal (halogen). These enzymes are termed lyases (see Table 2.1) and often carry out very simple reactions (e.g. the addition of water to a double bond) with very high stereoselectivity and regioselectivity. Finally, the application of a range of enzymes (including C—C bond formation) to carbohydrate synthesis will be examined. This chapter will conclude with some examples of the ways in which multienzyme reactions can be constructed to enable highly complex molecules to be assembled in an efficient manner. 

Under these circumstances, considerable efforts have been devoted toward their total syntheses over the past two decades [24-27]. In 1995, Nicolaou and co-workers completed the total synthesis of brevetoxin-B (1) after a 12-year endeavor, which is the first synthesis of a highly complex molecule of the polycyclic ether class [28-33]. This seminal work was followed by the synthesis of brevetoxin-A (2) by the same group in 1998 [34-38]. These outstanding achievements in the total synthesis of polycycUc ether natiual products revealed the power of contemporary organic synthesis and, at the same time. 

Much time has passed since the first organic synthesis of urea by Wohler in 1828, and the extraordinary ability of synthetic organic chemists has reached levels of real excellence in the research field of total syntheses of highly complex molecules with dramatic selectivities (e.g., palytoxin by Kishi in 1994 and brevetoxin B by Nicolaou in 1998). 

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