Chiral synthons synthetic applications

All the optically active terpenes mentioned in this chapter are commercially available in bulk (>kg) quantities and are fairly inexpensive. Although many of them are isolated from natural sources, they can also be produced economically by synthetic methods. Actually, two thirds of these monoterpenes sold in the market today are manufactured by synthetic or semi-synthetic routes. These optically active molecules usually possess simple carbocyclic rings with one or two stereo-genic centers and have modest functionality for convenient structural manipulations. These unique features render them attractive as chiral pool materials for synthesis of optically active fine chemicals or pharmaceuticals. Industrial applications of these terpenes as chiral auxiliaries, chiral synthons, and chiral reagents have increased significantly in recent years. The expansion of the chiral pool into terpenes will continue with the increase in complexity and chirality of new drug candidates in the research and development pipeline of pharmaceutical companies. 

Malic acid, although useful itself in many synthetic applications, achieves its true potential as a versatile chiral synthon when converted to one of its simple analogs. Rudimentary manipulations of 1 allow rapid access to esters, amides, and various 0-protected derivatives. Each of these is widely used as a starting point in the tactical synthesis of medicinal agents, natural products, and agrochemicals as discussed in the remainder of this chapter. 

Synthetic utility of five-membered heterocycles - chiral functionalization and applications (2-oxazolone, l,3-dihydro-2-imidazolone, 2-thiazo-lone, chiral synthons, chiral auxiliaries, chiral ligands) 05T8073. 

Ishizuka T, Morooka K, Ishibuchi S, Kunieda T (1996) Synthetic Application of Chiral 4-Methoxy-2-oxazolidinone Synthons to 2-Amino Alcohols of Biological Interest. Heterocycles 42 837... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Asymmetric hydroboration of enamines with chiral diboranes, followed by oxidation with hydrogen peroxide, in aqueous sodium hydroxide, gives /1-amino alcohols in good yields and high ee (equation 29)153. The products of this reaction are useful in medicinal applications and as synthons for further synthetic elaboration. 

Despite several synthetic approaches to the cyciopentane moiety of carbocyclic nucleosides, starting from noncarbohydrate synthons or readily available meso intermediates, no universally applicable methodology is yet available for the asymmetric synthesis of these compounds (28-31). An efficient access to chirality is via enantioselective resolution of a prochiral or a meso intermediate prior to the addition of the purine or pyrimidine base. For example, pig liver esterase (PLE) has been used in a chemoenzymatic approach to the synthesis of optically active (-l-aristeromycin and (-)-neplanocin (32), whereas cyclic y-acetamido esters were resolved to obtain (-)-4 d5-amino-2,3-trflTis-dihy-droxy hydroxymethyl cyciopentane as a key intermediate in the synthesis of carbocyclic nucleosides (33). Although hydrolytic enzymes often display a limited degree of enan-tiospecificity with such unnatural substrates, reaction conditions can in many cases be optimized to improve the enantioselectivity (34). 

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