Alkenes chiral drugs

The body oxidizes the alkene components of drugs and other substances to epoxides, which are then hydrolyzed to diols by an epoxide hydrolase enzyme. The more reactive epoxides are rapidly converted to water-soluble diols and eliminated in the urine. Epoxide hydrolase enzymes are sometimes used in organic synthesis to produce chiral diols. 

Dihydrooxazoles continue to occupy an important place in organic synthesis and medicinal chemistry as they have found use as versatile synthetic intermediates, protecting groups/pro-drugs for carboxylic acids, and chiral auxiliaries in asymmetric synthesis. There are several protocols in the literature for the transformations of functional groups such as acids, esters, nitriles, hydroxyl amides, aldehydes, and alkenes to 2-oxazolines. Newer additions to these methods feature greater ease of synthesis and milder conditions. 

Topics of relevance to the content of this chapter which have been reviewed during the year include photoactive [2]rotaxanes and [2]catenanes, photochemical synthesis of macrocycles, phototransformations of phthalimido amino acids, photoaddition reactions of amines with aryl alkenes and arenes, photoreactions between arenenitriles and benzylic donors, photostability of drugs, polycyclic heterocycles from aryl- and heteroaryl-2-propenoic acids, photoreactions of pyrroles, photoamination reactions in heterocyclic synthesis, switching of chirality by light, photochromic diarylethenes for molecular photoionics and solid state bimolecular photoreactions. 

These examples show how the combinatorial peptoid approach holds enormous potential for the discovery of novel lead structures for drug development. In this context a postmodification on solid-phase of peptoid side chains, bearing alkene and alkyne moieties, via [3 + 2] cyclo-addition of nitrile oxides, enhances further the molecular diversity and the possibility to find new therapeutic agents [11]. Moreover, polymers of N-substituted glycines containing chiral side chains display interesting conformational preferences [12]. NMR and CD data indicate that the major species adopts in methanol a stable right-handed helical structure with o. v-amidc bonds. 

We sought to examine the enzymatic dioxygenation of aryl silanes using a number of different aromatic dioxygenases in order to determine if such transformations were possible and to define the substrate-specificity profile. We were also motivated by the rich chemistry of silicon-based materials, which includes the hydrosilylation of alkenes and ketones, the addition of electrophiles to vinyl and allyl silanes, and palladium catalyzed cross-coupling of vinyl silanes with aryl halides (13). As a result, silyl functional cw-diols have potential as chiral intermediates for drug development, as polymer precursors/modifiers and as elements in non-linear optical materials. 

Another auxiliary that proved to be useful as a base for enolate alkylations is cis-l-amino-2-indanol 37 developed by researchers at Merck, Sharp, and Dhome. Both enantiomers of the amino alcohol are commercially available in bulk. The alkylation method was elaborated for a synthesis of indinavir, the orally active HIV protease inhibitor that emerged as a major drug for treatment of AIDS. Thus, N-acylated Af,0-acetal 38 was converted into the lithium enolate and subsequently treated with allyl bromide to give the alkene 39 in excellent chemical yield and diastereoselectivity. The conversion into indinavir reveals that the amino alcohol 37 functions both as auxiliary and chiral building block (Scheme 4.8) [26]. 

Synthesis of candoxatril, a cardiovascular drug, involves asymmetric hydrogenation of the alkene 5.15. As shown by reaction 5.1.2.5, the first step of the overall synthetic scheme is asymmetric hydrogenation. The hydrogenation step must avoid isomerization and must be robust and also cost-effective. Keeping these considerations in mind, Ru- and Rh-based catalysts in combination with a variety of chiral chelating phosphines were evaluated. 

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