Chiral pool 346 General

Synthetic methods for enantiomers in a drug discovery programme differ appreciably from those used in their manufacture but the same basic principles are useful in both, for example, resolution by physical, chemical, or biocatalytic means, asymmetric synthesis, or use of the chirality pool. Generally, the method of choice ultimately used in manufacture of a pharmaceutical will be quite different from that first used to obtain the single-enantiomer material in a drug-discovery programme. 

The general syntheses of alkenes (p. 28 — 44) and 1,2-dihydroxy compounds (p. 50—54 and 123 — 132) are not repeated here. But there is an important chiral pool" for chiral 1,2-disubstituted compounds, namely a-amino acids. 

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. 

Although these definitions are vague, it appears that partial synthesis is restricted to those modifications which do not change the basic chemical structure, whereas ex-chiral-pool synthesis generally leads to a new type of compound. For instance, the introduction of new substituents into a steroid nucleus is partial synthesis , whereas the conversion of D-glucose into the pheromone e.vo-brevicomin is ex-chiral-pool synthesis . 

A chiral auxiliary must be easily obtained from the chiral carbon pool generally alcohols or amines are used, since they can be readily covalently bound to substrates e.g., carboxylic acids27, ketones or aldehydes in the form of esters, amides, ketals. or imino-derivatives. 

The use of chiral auxiliaries to impart dissymmetry has become a powerful tool for controlling the stereochemical outcome of chemical transformations. Many of these auxiliaries have been drawn from the chiral pool of natural materials. While high levels of asymmetric induction have been achieved in many cases, none of these natural products has emerged as a general agent, in part because typically only one enantiomer of the auxiliary is readily available. 

Crown ethers have given impressive enantioselectivites in Michael additions (Chart 10.2). Purely synthetic chiral crowns are of limited use on large scale based on cost although, in general, the crowns are less susceptible to catalyst degradation and, therefore, have higher catalyst turnover numbers than the chiral quaternary ammonium salts. Of interest are crowns with symmetry, aza-crowns, and those with sugars or other chiral-pool units as sources of chirality (Charts 2 and 4). 

General Three Carbon Chiral Synthons from Carbohydrates Chiral Pool and Chiral Auxiliary Approaches... 

The development of optically active biological agents, such as pharmaceuticals, has led to the increase in large-scale chiral syntheses. The chirality may be derived from the chiral pool or a chiral agent, such as an auxiliary, template, reagent, or catalyst. There are, however, relatively few general asymmetric methods that can be used at scale. 

The first chapter of the book is a general introduction. Chapters 2 through 5 discuss how the key subclasses of the chiral pool are obtained. The amino acid chapters are more specific as there are other examples of amino acid syntheses contained within other chapters. 

These are (1) The chiral substrate approach. This approach involves using chiral precursors that transfer their chirality to the final cyclopentenone. This implies the synthesis of chiral substrates, which has generally been made from classic chiral pools. Examples include carbohydrate derivatives like 40 that give 41 with variable yields depending on the substitution pattern. 41 is transformed into cyclopenta[c]pyrane 42, which is the skeleton of iri-doids [93]. In another example epichlorhydrin (43) is used to construct chiral enyne 44 which gives cyclopentenone 45 [94] (Scheme 14). 

The synthesis of chiral crown ethers is generally approached by exploiting the chiral pool, that is, naturally occurring materials which are available in enantiomerically pure form. 

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). ... 

Carbonyl functions often are protected as thioacetals, because these derivatives are stable to acids and bases. Dithio-acetals and -ketals generally are prepared by reaction of the carbonyl compound with a thiol in the presence of an acid catalyst. This transformation has been used in carbohydrate chemistry for a long time to lock aldoses in their acyclic forms (see equation 26). In recent years, this blocking principle for carbohydrates has been exploited in several chiral pool syntheses. Several other methods for... 

The sugars are generally both cheap and optically pure, and more compounds have been made from glucose 97 than any other member of the chiral pool. It is rare that a target molecule looks... 

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