Oftentimes, in organic synthesis, the product of a chemical reaction or the starting material or key intermediate in a multi-step synthesis is only available in racemic form. The separation of these enantiomers could be effected through the use of enantiomerically enriched chiral auxiliaries. This project focuses on the separation of racemic mixtures of aldehydes and ketones, for several reasons: 1) these functionalities are prevalent, and 2) serve as ideal sites for temporary derivitization. One potentially useful application would involve chiral diols (figure, below) as auxiliaries in the formation of diastereomeric acetals from racemic mixtures of aldehydes and ketones. The resulting mixture of diastereomers could be separable either by differential recrystallization or by normal chromatographic methods. Once resolved, the chiral auxiliary can be removed to yield the enantiomerically enriched aldehyde or ketone. The auxiliary can be recycled for use in further resolutions. This project outlines the synthesis of several chiral diols, and their use as potential resolving agents. The diols will be derivatives of L- and D-tartaric acids, which are commercially available. Initially, only L-tartaric acid will be used, as this isomer is very inexpensive. With the addition of new students, the syntheses will be repeated with the D-isomer.
The synthesis of several related chiral diols would be carried out as indicated in Scheme 1 below. Initially, (L)-tartaric acid is treated with 2,2-dimethoxypropane to form dimethyl 2,3-O-isopropylidene-L-tartrate. Reduction of the resulting ester with lithium aluminum hydride to produce 2,3-O-isopropylidene-L-threitol is effected. The Williamson ether synthesis is used to produce the ether 1,4-di-O-benzyl-2,3-O-isopropylidene-L-threitol. Deprotection of the acetal with acid will yield the target diol 1,4-di-O-benzyl-L-threitol. A variety of aromatic halides will be used in the synthesis 1) to vary the steric demand of the R-groups in the diol, and 2) to explore what effect these groups have on the ability to crystallize the diastereomeric acetals.
Scheme 1.
The synthetic intermediate 2,3-O-isopropylidene-L-threitol can also serve as a route to new chiral diols as outlined in Scheme 2 below. The threitol intermediate is treated with methanesulfonyl chloride to make L-threitol 1,4-bismethanesulfonate. An intramolecular Williamson ether synthesis produces (S,S)-1,2,3,4-diepoxybutane. Epoxide ring opening with an appropriate Grignard reagent will yield the chiral diol, such as (2S,3S)-dihydroxy-1,4-diphenylbutane as in the scheme. These diols are expected to be more rigid (lacking the ether linkage of the R-group to the diol backbone), and may prove more useful as chiral resolving agents. An added benefit to this synthetic route is the ability to use a wider array of halogenated compounds in the epoxide ring-opening step. For instance, halogenated terpenes from the chiral pool could add additional chiral centers to these diols, enhancing the imposed chirality of the auxiliary.
Scheme 2.
To test the utility of these diols as resolving agents, several acetals will be formed from readily available racemic aldehydes and ketones. The general strategy is given below.
A racemic compound (2-methylcyclohexanone in this example) is mixed with a chiral diol ((2S,3S)-dihydroxy-1,4-diphenylbutane), an acid catalyst, solvent, and a water separator. The resulting diastereomeric acetals are separated (hopefully by differential recrystallization, less ideally by HPLC), and then treated with aqueous acid to remove the diol auxiliary to yield the enantiomerically enriched ketone. The chiral diol can be salvaged for future use.
Initial studies will center on aldehydes and ketones where the chiral center is close to the carbonyl functionality (as in the example above). Further studies will show if chiral discrimination is substantially reduced when the chiral center is remote from the carbonyl group. The axis of symmetry present in each of the chiral diols to be manufactured allows for only the two diastereomeric acetals pictured to be formed. Inspection of molecular models indicates that the diastereomer with the most sterically demanding group - to the carbonyl functionality oriented away from the bulky R-groups of the diols are most stable. It is hoped that with some of the diol derivatives (such as the anthracene derivative), reaction of one enantiomer of the carbonyl substrate may be precluded. A single, enantiomerically pure acetal will be formed, substantially simplifying the resolution protocol.
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