Chiral compounds carboxylic acids, absolute

Strains of Pseudomonas putida are very versatile in metabolizing aromatic compounds, particularly to the corresponding 1,2-dihydro-l,2-diols. The hydroxylating enzyme of the P. putida mutant is not strongly substrate specific and alkyl, aryl and halogen functionalities are usually readily tolerated380. Thus, 4-bromobenzoic acid (1, R = Br) is converted to a. v-4-bro-mo-5,6-dihydroxy-l, 3-cyclohexadiene-l-carboxylic acid (2, R = Br) in 80% yield with 98% cc (determined by chiral NMR shift experiments on the 4-nitrobenzyl ester) 375. The absolute stereochemistry, (5R,6R), was determined by a single crystal X-ray analysis. 

The optical resolution of racemates 22a, 25a, and 27a was carried out by chromatographic separation of their (4/ ,5S)-MPOT-amide derivatives 22b, 25b, and 27b. The absolute stereochemistry of each pure diastereoisomer was confirmed by comparing the physical data of its derivative with those of the authentic compound in each case. Thus, (4i ,5S)-MPOT (5) proved to be a satisfactory chiral reagent useful for analytical separation and optical resolution of racemic carboxylic acids and amino acids (85JCS(P1)2361). 

We have recently developed chiral carboxylic acids as novel molecular tools useful for enantioresolution and simultaneous determination of the absolute configuration of various alcohols. These chiral molecular tools are very powerful for the facile preparation of enantiomers with 100% ee and also for the absolute configurational assignment. Methods using these chiral tools have been successfully applied to various compounds, and their methodologies and applications are explained throughout this chapter. 

Axially chiral carboxylic acids such as [2] and [3] can be used to prepare diastereoisomers of secondary alcohols. The NMR spectra of the diastereoisomers show enantiomeric resolution and it is possible to assign absolute configurations. Monocyclic, chiral carboxylic acid compounds such as tetrahydro-5-oxo-2-furancarboxylic acid and 2,2-diphenylcyclo-propane-carboxylic acid have been used to derivatize secondary alcohols for the purpose of enantiomeric resolution. Similarly, bicyclic derivatizing agents such as camphanic acid, camphanic acid chloride, or camphor sulfonyl chloride have been used to derivatize amines or alcohols to their respective amides or esters for the purpose of enantiomeric resolution. 

We have developed some chiral carboxylic acids as novel molecular tools useful for both enantioresolution of various alcohols and simultaneous determination of their ACs (Figure 55.1). These chiral molecular tools are powerful for facile preparation of chiral compounds with 100% ee and for the absolute configurational assignment. The so-called asymmetric syntheses are useful for preparation of chiral compounds, but reaction products are not always enantiopure, and in some cases, it is necessary to determine their ACs by independent chemical and/or physical methods. The methodologies explained in this chapter are useful for preparation of enantiopure authentic sample and for determination of their ACs in an unambiguous manner. The protocols using these chiral reagents have been successfully applied to various compounds, and their principle and applications are explained in this chapter. 

Carboxylic acids are frequently found in nature as optically active compounds with the chiral center at the a-position, and general approaches for the determination of the absolute stereochemistry of these systems are rare. 

Control over the absolute configuration in cyclohexenone photocycloadditions has been achieved by auxiliary-induced diastereoselectivity. In particular, esters related to compound 26, which are derived from a chiral alcohol but not from methanol, lend themselves as potential precursors, from which the chiral auxiliary can be effectively cleaved [42, 43]. In a recent study, the use of additives was advertised to increase the diastereomeric excess in these reactions [44], An intriguing auxiliary-induced approach was presented by Piva et al., who employed chiral 13-hydroxy-carboxylic adds as tethers to control both the regioselectivity and the diastereoselectivity of intramolecular [2 + 2]-photocycloaddition reactions [45]. In Scheme 6.14 the reaction of the (S)-mandelic acid derived substrate 38 is depicted, which led with very good stereocontrol almost exclusively to product 39a, with the other diastereoisomer 39b being formed only in minor quantities (39a/39b = 96/4). Other acids, such as (S)-lactic acid, performed equally well. The chiral tether could be cleaved under basic conditions to afford enantiomerically pure cydobutane lactones in good yields. 

---