Diastereoselectivity chiral auxiliaries, drug synthesis

Major interest has been expressed in the synthesis of chiral sulfoxides since the early 1980s, when it was discovered that chiral sulfoxides are efficient chiral auxiliaries that are able to bring about important asymmetric transformations [22]. Sulfoxides are also constituents of important drugs (e.g., omeprazole (Losec , Priso-lec )) [23]. There is a plethora of routes of access to enantioenriched sulfoxides, and many involve metal-catalyzed asymmetric oxidations [24]. Examples of ruthenium metal-based syntheses of sulfoxides are scarce, presumably due to the tendency of sulfur atoms to bind irreversibly to a ruthenium center. Schenk et al. reported a dia-stereoselective oxidation of Lewis acidic Ru-coordinated thioethers with dimethyl-dioxirane (DMD) (Scheme 10.16) [25[. Coordination of the prochiral thioether to the metal is followed by diastereoselective oxygen transfer from DMD in high yield. The... 

Enantioselective as well as diastereoselective synthesis of axially chiral biaryls is the subject of a rapidly growing interest, due to its role as a cmcial motif in a great number of drug candidates, chiral polymers, chiral auxiliaries, catalysts, etc. 

Diastereoselective synthesis of biaryls is important field in organic chemistry due to a number of natural products and a significant number of drug candidates, chiral ligands and auxiliaries that are axially chiral biaryls. One can expect great results in this chemistry, concerning both new reactions and approaches, as well as more effective methodology. 

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]. 

A number of processes involving chiral acetals have been examined in the synthesis of pharmaceutically important compounds. In one example, a synthesis of the antiinflammatory drug naproxen (80) includes a diastereoselective bromination reaction to furnish bromide 78 (dr 93 7, Scheme 6.15) [45]. Intramolecular rearrangement gives ester 79 with >99 1 diastereo-selectivity after recrystallization. Subsequent acidic cleavage of the auxiliary followed by reduction (H2 Pd-C) of the bromide that is adventitiously introduced on the naphthyl core afforded naproxen (80). 

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