Epoxide, chiral building blocks

Dong and Lin [68, 69] did not start with a sugar as chiral building block, but a product from an asymmetric Sharpless epoxidation commonly used... 

Enantiopure epoxides and vicinal diols are important versatile chiral building blocks for pharmaceuticals (Hanson, 1991). Their preparation has much in common and they may also be converted into one another. These chirons may be obtained both by asymmetric synthesis and resolution of racemic mixtures. When planning a synthetic strategy both enzymic and non-enzymic methods have to be taken into account. In recent years there has been considerable advance in non-enzymic methods as mentioned in part 2.1.1. Formation of epoxides and vicinal diols from aromatics is important for the break down of benzene compounds in nature (See part 2.6.5). 

The synthetic application of the a-chloro aldehydes has been demonstrated by the preparation of a variety of important chiral building blocks (Scheme 2.35) [26b]. The a-chloro aldehydes could be reduced to the corresponding optically active a-chloro alcohols in more than 90% yield, maintaining the enantiomeric excess by using NaBFU. It was also shown that optically active 2-aminobutanol - a key intermediate in the synthesis of the tuberculostatic, ethambutol - could be obtained in high yields by standard transformations from 2-chlorobutanol. Furthermore, the synthesis of an optically active terminal epoxide was demonstrated. The 2-chloro aldehydes could also be oxidized to a-chloro carboxylic acids in high yields without loss of optical purity, and further transformations were also presented. 

Ot-Hydroxy Acid and Epoxide as Building Blocks. Deamination of an a-amino acid with nitrous acid is known to give the corresponding a-hydroxy acid with retention of configuration. An a-hydroxy acid can be converted to an epoxide. Both a-hydroxy acids and epoxides are versatile chiral building blocks in natural products syntheses (3). Alcohol as a Chiral Building Block... 

Terminal epoxides of high enantiopurity are among the most important chiral building blocks in enantioselective synthesis, because they are easily opened through nucleophilic substitution reactions. Furthermore, this procedure can be scaled to industrial levels with low catalyst loading. Chiral metal salen complexes have also been successfully applied to the asymmetric hydroxylation of C H bonds, asymmetric oxidation of sulfides, asymmetric aziridination of alkenes, and the asymmetric alkylation of keto esters to name a few. 

Nucleophilic epoxidation of chiral a,/i-unsaturated carbonyl compounds allows the synthesis of potentially useful chiral building blocks. 

A synthetic strategy based on Jacobsen s hydrolytic kinetic resolution of readily available racemic epoxide 345 offers the possibility to produce in a good yield enantiomerically enriched (R,R) and (A,A)-epoxides 345 as chiral building blocks for the preparation of (R)-lipoic acid and (A)-lipoic acid (Scheme 66) <200681863>. 

Stable and easily handled, protected forms of l- and D-glyceraldehyde were obtained by the Sharpless asymmetric dihydroxylation [56] of the benzene-1,2-dimethanol acetal of acrolein (Scheme 13.23). The method produces either diol (7 )-32 or (S)-32 with 97% ee after recrystallization from benzene. These diols can be converted into useful C-3 chiral building blocks such as epoxides (7 )-33 and (5)-33, respectively [28,57]. 

These results have led to an interesting industrial apphcation for the synthesis of the j5-blockers Metoprolol and Atenolol. Thus, epoxidation of the prochiral allyl ethers by several bacteria, including the P. oleovorans strain mentioned above, led to the corresponding (S)-epoxides which showed excellent enantiomeric purities (Fig. 3). Further on, these chirons (i.e. chiral building blocks) were transformed into the corresponding (S)-enantiomers of the drugs developed by the Shell and Gist-Brocades companies [44]. Refinement of this approach... 

This is not the case for a Rhodococcus rhodochrous strain that affords 1,2-epoxyalkanes from short-chain terminal olefins. Indeed, in the latter case, no product inhibition has been observed [106]. However, the ee s obtained were not determined, and it seems probable that they were quite low. On the other hand, a Nocardia corallina strain was described that afforded the corresponding 1,2-(i )-epoxy-2-methylalkane with ee s as high as 90% depending on the chain length [ 107]. These epoxides were used as chiral building blocks to prepare prostaglandin co-chains. 

The hydrolytic kinetic resolution (HKR) of racemic terminal epoxides catalyzed by chiral (salen)-Co(III) complexes provides efficient access to epoxides and 1,2-diols, valuable chiral building blocks, in highly enantioenriched forms. While the original procedure has proved scalable for many substrates, several issues needed to be overcome for the process to be industrially practical for one of the most useful epoxides, epichlorohydrin. Combined with kinetic modelling of the HKR of epichlorohydrin, novel solutions were developed which resulted in linearly scalable processes that successfully addressed issues of catalyst activation, analysis and reactivity, control of exothermicity, product isolation, racemization, and side-product formation. 

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