Biological active compounds stereoselectivity

The hydroxynitrile lyase (HNL)-catalyzed addition of HCN to aldehydes is the most important synthesis of non-racemic cyanohydrins. Since now not only (f )-PaHNL from almonds is available in unlimited amounts, but the recombinant (S)-HNLs from cassava (MeHNL) and rubber tree (HbHNL) are also available in giga units, the large-scale productions of non-racemic cyanohydrins have become possible. The synthetic potential of chiral cyanohydrins for the stereoselective preparation of biologically active compounds has been developed during the last 15 years. 

In general, the Henry reaction gives a mixture of diastereomers and enantiomers. The lack of selectivity is due to the reversibility of the reaction and the easy epimerization at the nitro-substituted carbon atom. Existing reviews have hardly mentioned the stereochemistry of the Henry reaction. Recently, Shibasaki has found that the modification of the Henry reaction can control the stereochemistry to give (3-nitro alcohols with high diastereo- and enantio-selectivity.6 In Section 3.3, the progress of the stereoselective Henry reaction and its application to biologically active compounds are discussed. 

The enantioselective hydrogenation of prochirai heteroaromatics is of major relevance for the synthesis of biologically active compounds, some of which are difficult to access via stereoselective organic synthesis [4], This is the case for substituted N-heterocycles such as piperazines, pyridines, indoles, and quinoxa-lines. The hydrogenation of these substrates by supported metal particles generally leads to diastereoselective products [4], while molecular catalysts turn out to be more efficient in enantioselective processes. Rhodium and chiral chelating diphosphines constitute the ingredients of the vast majority of the known molecular catalysts. 

Recent research deals with stereoselective 1,3-dipolar cycloadditions of nitrones for the syntheses of alkaloids and aza heterocycles asymmetric synthesis of biologically active compounds such as glycosidase inhibitors, sugar mimetics, /3-lactams, and amino acids synthesis of peptido-mimetics and peptides chemistry of spirocyclopropane heterocycles synthesis of organic materials for molecular recognition and photochemical applications. 

The transition metal cross-couplings of allenes described here offer practical solutions for the modification of 1,2-dienes and access to the preparation of highly functionalized 1,3-dienes, alkynes and alkenes, which are often not easily accessible in a regio- and stereoselective manner by classical methods. Some of the prepared alkynes or functionalized allenes serve as important intermediates in syntheses of natural products, biologically active compounds, e.g. enynes and enyne-allenes, and new materials. It can be predicted that further synthetic efforts will surely be focused on new applications of allenes in transition metal-catalyzed cross-coupling reactions. 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

Preparation of nonracemic epoxides has been extensively studied in recent years since these compounds represent useful building blocks in stereoselective synthesis, and the epoxide functionality constitutes the essential framework of various namrally occurring and biologically active compounds. The enantiomericaUy enriched a-fluorotropinone was anchored onto amorphous KG-60 silica (Figure 6.6) this supported chiral catalyst (KG-60-FT ) promoted the stereoselective epoxidation of several trans- and trisubstituted alkenes with ees up to 80% and was perfectly reusable with the same performance for at least three catalytic cycles. 

Microbially produced (2.S .3.S )-// .v-dihvdroxy-2.3-dihvdrobenzoic acid was used in the synthesis of enf-streptol, enf-senepoxide, and /so-crotepoxide (Fig. 33). The short and efficient synthesis of these biologically active compounds included the esterification of the carboxylic acid and protection of the diol moiety, delivering control of the regio- and stereoselectivity of the following epoxidation or dihydrox-ylation steps [178, 180]. 

The more recent work on this area deals predominantly with the asymmetric induction in aza Diels-Alder reactions in order to develop a novel powerful tool for the stereoselective synthesis of biologically active compounds. Thus, Wald-mann et al. demonstrated the utility of chiral imines derived from enantiopure amino acids by obtaining the cycloadduct 3-3 in very good diastereoselectivity from imine 3-1 and Brassard s diene 3-2 (Fig. 3-1) [181]. 

In principle, three approaches may be adopted for obtaining an enantio-merically pure compound. These are resolution of a racemic mixture, stereoselective synthesis starting from a chiral building block, and conversion of a prochiral substrate into a chiral product by asymmetric catalysis. The last approach, since it is catalytic, means an amplification of chirality that is, one molecule of a chiral catalyst produces several hundred or a thousand molecules of the chiral product from a starting material that is optically inactive In the past two decades this strategy has proved to be extremely useful for the commercial manufacture of a number of intermediates for biologically active compounds. A few recent examples are given in Table 9.1. 

By analogy to halolactonization, a methodology termed cyclocarbamation has been developed for the functionalization of double bonds. The stereoselective introduction of polyfunctional moieties, such as amino alcohols, starting from cyclic and acyclic substrates has been studied with the aim of synthesizing biologically active compounds. 

The versatility and efficiency of this method were demonstrated in the first catalytic asymmetric synthesis of (—)-phaseolinic acid 188 , a biologically active compound of the paraconic acid family (equation 50). Using the 1,4-addition-aldol pathway, the paraconic acid skeleton could be synthesized in only four synthetic transformations with excellent stereoselectivities and 54% overall yield. 

At the end of the 1980s, the phenylselones derived from nucleosides were successfully exploited by Chattopadhyaya and co-workers for a variety of stereoselective conversions in this family of biologically active compounds [88]. They elaborated high-yield syntheses of a series of 2, 3 -ene-3 -phenylselones and 2, 3 -ene-2 -phenylselones 200 and showed their synthetic utility as synthetic equivalents of the dication 201 shown below. 

Indeed, a transformation of alkenes to a-ketols was found to proceed highly efS-ciently. Thus, the low-valent ruthenium-catalyzed oxidation of alkenes with peracetic acid in an aqueous solution under mild conditions gives the corresponding a-ketols, which are important key structures of various biologically active compounds [127]. Typically, the RuCls-catalyzed oxidation of 3-acetoxy-1-cyclohexene (42a) and 3-azide-1-cyclohexene (42b) with peracetic acid in CH2CI2-CH3CN-H2O (1 1 1) gave (2S, 3R )-3-acetoxy-2-hydroxycyclohexanone (43a) and (2S, 3R )-3-azide-2-hydroxy-cyclohexanone (43b) chemo- and stereoselectively in 70% and 65% yield, respectively... 

Stereoselective synthesis of optically active ff-amino alcohols is highly desirable, because such units are seen ubiquitously in the structures of many biologically active compounds represented by neurotransmitter antagonists, antimicrobials, and pain killers. Hydroboration of the a-bromo ketone 51 promoted by the amino alcohol 54 gives a key intermediate 52 for the synthesis of the (i ,/ )-isomer of Formoterol (53), a long acting )52-agonist used in the treatment of asthma (Scheme 15) [52]. 

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