Chiral pool asymmetric synthesis with

The Chiral Pool—Asymmetric Synthesis with Natural Products as... 

Use the chiral pool in synthesis and synkinesis. The common monosaccharides provide three or four asymmetrical carbon atoms per unit (an orgy in precious chiral center at very low cost). Carbohydrates together with amino acids therefore constitute the principal components of the chiral pool, the most rewarding and renewable source of fine chemicals and stereoselective membrane surfaces. 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

In planning the synthesis of biologically active compounds, strategies using aldonolactones or other compounds from the chiral pool should therefore continue to be considered, since they can provide attractive routes in comparison with alternative methods by asymmetric synthesis. 

The use of chiral oxazolines as ligands for catalytic asymmetric synthesis is undoubtedly the most important development in oxazohne chemistry. Compared with other ligands, oxazolines offer the advantage of being easily accessible from chiral amino alcohols that are, in turn, readily available from a chiral pool of amino acids. There have been numerous reports on this exciting use of oxazolines during the last 10 years. Many of the ligands studied to date contain at least two oxazoline units. The synthesis and reactions of bis(oxazohnes) are discussed in detail in Chapter 9 the discussions in this section are limited to mononuclear oxazolines. 

The third approach is the main topic of this volume. According to the definition given above it involves enantiomerically pure starting materials which at some point must be provided by resolution or ex-chiral-pool synthesis. It is more or less equivalent to the term asymmetric synthesis defined by Marckwald in 19047 as follows Asymmetric syntheses are those reactions which produce optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes . In today s language, this would mean that asymmetric syntheses are those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation. 

Around 70% of the pharmaceuticals on the market are chiral, and approximately one third of these are chiral amines [1], This represents a substantial number of achve drug substances that are typically manufactured at a scale of 1-100 l y . The three main manufacturing processes used to introduce these homochiral centers are from optically active starting materials (the so-called Chiral Pool approach), by asymmetric synthesis and by resolution. The last technique is widely practiced but results in waste of the undesired enantiomer. This chapter deals with developments in asymmetric transformations, that is to say methods for augmenting the yield of amine resolution processes to theory 100%, resulting in an alternative to asymmetric synthesis and a practical Green Chemistry solution to the synthesis of optically active amines. Figure 13.1 shows different approaches to the asymmetric transformation that will be discussed in the chapter. 

The structurally novel antimitotic agent curacin A (1) was prepared with an overall yield of 2.5 % for the longest linear synthesis. Three of the four stereogenic centers were built up using asymmetric transformations one was derived from a chiral pool substrate. Key steps of the total synthesis are a hydrozirconation - transmetalation protocol, the stereoselective formation of the acyclic triene segment via enol triflate chemistry and another hydrozirconation followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A (1) the oxazoline - thiazoline conversion provides efficient access to the sensitive marine natural product. 

There are many problems associated with carrying out asymmetric synthesis at scale. Many asymmetric transformations reported in the literature use the technique of low temperature to allow differentiation of the two possible diastereoisomeric reaction pathways. In some cases, the temperature requirements to see good asymmetric induction can be as low as -100°C. To obtain this temperature in a reactor is costly in terms of cooling and also presents problems associated with materials of construction and the removal of heat associated with the exotherm of the reaction itself. It is comforting to see that many asymmetric catalytic reactions do not require the use of low temperature. However, the small number of robust reactions often leads development chemists to resort to a few tried and tested approaches, namely chiral pool synthesis, use of a chiral auxiliary, or resolution. In addition, the scope and limitations associated with the use of a chiral catalyst often result in a less than optimal sequence either because the catalyst does not work well on the necessary substrate or the preparation of that substrate is long and costly. Thus, the availability of a number of different approaches helps to minimize these problems (Chapter 2). 

Although nature has been the primary source of the proteinogenic amino acids through extraction processes, many of the unnatural analogues have to be synthesized. Modem asymmetric synthetic methodology is now in the position to provide cheap, pure, chiral materials at scale. Some of the unnatural amino acids are now made at scale and have been used to extend the chiral pool. To avoid duplicating sections of this book, this chapter discusses the problems associated with the synthesis of unnatural amino acids at various scales. This illustrates that a single, cheap method need not fulfill all of the criteria to provide a chiral pool material to a potential customer, and a number of approaches are required. 

Sometimes the natural products that are needed are immediately obvious from the structure of the target molecule. An apparently trivial example is the artificial sweetener aspartame (marketed as Nutrasweet), which is a dipeptide. Clearly, an asymmetric synthesis of this compound will start with the two members of the chiral pool, the constituent (natural) (S)-amino acids, aspartic acid and phenylalanine. In fact, because phenylalanine is relatively expensive for an amino acid, significant quantities of aspartame derive from synthetic (S)-phenylalanine made by one of the methods discussed later in the chapter. 

Starting from the chiral pool (/f-(+)-hmonene), the total synthesis of natural (-f)-3,4-epoxycembrene A (56) has been achieved by Liu et al. with the low-valent titanium-mediated intramolecular pinacol couphng of the corresponding sec-keto aldehyde precursor 171 (Scheme 6-25). A more general and efficient enantioselective synthesis of (+)-3,4-epoxy-cembrene A (56) with a chiral pool protocol and Sharpless asymmetric epoxidation for the introduction of three chiral centers has also been reported by the same authors in 2001 (Scheme 6-26). ... 

As resolution procedures are often tedious, and asymmetric synthesis provides chiral products with only limited enantiomeric excess, it seems an obvious strategy to use an enantiomerically pure material from the chiral pool to construct chiral ferrocenes by incorporating these compounds in the final product. As such chiral materials, cheap terpenes (menthone, a- and -pinene, and camphor) were chosen. The reaction of ferrocene with carbonyl compounds under acidic conditions is a very convenient way to obtain directly a-ferrocenylalkyl carbocations. The starting materials were therefore converted to aldehydes or their enol ethers (menthone and camphor are too sterically hindered and do not react with ferrocene). Joint dissolution of the aldehydes and ferrocene in trifluoroacetic acid or in the trichloroacetic acid/ fluorosulfonic acid system gives a-ferrocenylalkyl carbocations, which can either... 

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