Racemisation, chiral alcohols

Dynamic Kinetic Resolution. Another typical acid-catalysed reaction is the racemisation of chiral alcohols, due to inversion at the chiral carbon. This can actually be made use of in the formation of enantiopure compounds, by dynamic kinetic resolution using an enzyme, such as a lipase, that catalyses enantioseleetive esterification in an organic medium. By coupling zeolite Beta-catalysed intereonversion of benzylic alcohol enantiomers with enzyme-catalysed esterifieation of only one of the enantiomeric alcohols, almost complete eon version to enantiopure ester ean be achieved. ... 

Chiral acids react with chiral alcohols or amines to form diastereoisomeric esters or amides respectively. Mislow andRabanl l first described chemical shift non-equivalence in the proton NMR spectra for diastereoisomeric 1-methylphenylethanoic acid esters of l-(2-fluorophenyl)-ethanol and observed some racemisation during the reaction. A systematic study was made thereafter of a series of substituted phenylethanoic acids as CDAs for the assay of alcohols (Table 3.1). Epimerisation a to the acid carbonyl was the cause of the racemisation observed by Mislow and Raban. In order to avoid this problem Mosher developed a-methoxy-a-trifluoromethyl-phenyl-acetic acid (MTPA), (10), as a CDA.f l It is stable to racemisation because it lacks an a-hydrogen. Induced chemical shift nonequivalence is typically 0.15 ppm (in CDCI3,298 K). A NMR study... 

In the reciprocal experiment, the chiral alcohol methylmandelate, (13), is used as a CDA for the study of the enantiomeric purity of acids. Esterification is effected without racemisation with N, N-dicyclohexylcarbodiimide in the presence of the acyl transfer catalyst,... 

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

In reactions of chiral compounds requiring the use of a base, the proton sponge practically causes no racemisation and favours the retention of high optical purity. An example is the conversion of optically active alcohols into ethers under the action of trialkyloxonium tetrafluoroborates (equation 19)218-220. 

The same reaction works well with chloride as nucleophile to give 14 and, after reduction of the acid group and cyclisation of the alcohol 15, the epoxide 16. Such epoxides, made from many of the amino acids, now count as members of the new chiral pool. The diazonium salt 11 and the chloroacid 14 are susceptible to racemisation by enolisation and it is only after two distillations that the epoxide 16 has 97% ee. There are very detailed Organic Syntheses procedures for both these steps.6... 

In 2002, a novel aminocyclopentadienyl ruthenium chloride complex was introduced by Park s group involving a new mode of catalytic racemisation which allowed use of the more reactive isopropenyl acetate as an acyl donor and much less lipase. This catalytic system was particularly efficient for the DKR of various aliphatic or aromatic alcohols as shown in Scheme 4.9. Not only simple alcohols, but also functionalised alcohols such as allylic alcohols, alkynyl alcohols, diols, hydroxyl esters and chlorohydrins were successfully transformed into the corresponding chiral acetates. ... 

It has been demonstrated that the combination of metal-catalysed racemisation and enzymatic kinetic resolution is a powerful method for the synthesis of optically active compounds from racemic alcohols and amines. There are many metal complexes active for racemisation, but the conditions for enzymatic acylation often limit the application of the metal complexes to DKR. In the case of DKR of alcohols, complementary catalyst systems are now available for the synthesis of both (R)- and (5)-esters. Thus, (R)-esters can be obtained by the combination of an R-selective lipase, such as CAL-B or LPS, and a racemisation catalyst, whereas the use of an A-selective protease, such as subtilisin, at room temperature provides (5)-esters. The DKR of alcohols can be achieved not only for simple alcohols but also for those bearing various additional functional groups. The DKR of alcohols has also been applied to the synthesis of chiral polymers and coupled to tandem reactions, producing various polycyclic compounds. 

The chiral auxiliary is the oxazolidinone (24) derived from IS,2R) norephedrine. Acylation with propionyl chloride gives (25) and this is deprotonated to afford exclusively the internally chelated Z-enolate, which reacts with methallyl iodide from the face opposite the methyl and phenyl groups of the auxiliary. The product (26), a 97 3 mixture of diastereomers, is purified to a ratio of better than 500 1. Reductive removal of the auxiliary and careful oxidation of the primary alcohol under non-racemising conditions affords the chiral (5)-aldehyde (27). This in turn is reacted with the boron enolate of (25), which furnishes with remarkable selectivity the u aldol product (28). The reason for the choice of boron rather than lithium is to invert the facial selectivity of the reaction— the enolate is no longer constrained to be planar by internal chelation and rotates in order to place the bulky dibutyl borinyl group on the opposite side to the methyl and phenyl ... 

On the other hand, Kita et al. reported a combination of the domino reaction concept and the DKR protocol, comprising the first lipase-catalysed domino process that combined the DKR of alcohols by using l-etho QAanyl esters and the Diels-Alder reaction of the intermediates. The finding that ruthenium catalysts produced a rapid racemisation of the slow-reacting (S)-enantiomers was the key to the success of this process, which provided useful chiral intermediates for natural products, such as compactin and forskolin (Scheme 8.28). 

---