Alcohol secondary, absolute configuration

It is always advisable to examine the complete molecular topology in the neighborhood of the chiral carbon atom and to confirm the results by employing another analytical method before the final assignment. In conclusion, Prelog s rule does predict the steric course of an asymmetric synthesis carried out with a chiral a-keto ester, and the predictions have been found to be correct in most cases. Indeed, this method has been widely used for determining the absolute configuration of secondary alcohols. 

Another method for determining the absolute configurations of secondary alcohols is Horeau s method, which is based on kinetic resolution. As shown in Scheme 1-14, an optically active alcohol reacts with racemic 2-phenylbutanoic anhydride (54), and an optically active 2-phenylbutanoic acid (52) is obtained after hydrolysis of the half-reacted anhydride. 

Procedures for using this method to determine the absolute configuration of secondary alcohols can be outlined as follows (Fig. 1-2IB) ... 

Figure 1-21. Model to determine the absolute configurations of secondary alcohols. Reprinted with permission by Am. Chem. Soc., Ref. 75.

The absolute configuration of a secondary alcohol can also be determined through the NMR spectra of a single methoxyphenylacetic ester derivative... 

Version A A secondary alcohol or amine has the absolute configuration (L LJs, if the H-NMR signal of the group L, of the alcohol of the ester or amino part of the amide of (7 )-PBA appears at higher field than the corresponding (S)-PBA derivative. 

Version B In the case of an (7fi-PBA ester (amide) of a secondary alcohol (amine) of absolute configuration (Ljh L,) the H-NMR signal of L appears at a higher field and that of L2 at a lower field than in the corresponding (5)-PBA derivative. 

O-Methylmandelic acid has also been used to prepare esters with the aim of assigning the configuration of optically active alcohols by X-ray analysisl89. However, O-methylmandelates are mainly used for the establishment of absolute configurations of secondary alcohols by NMR. Problems associated with the ester formation are, therefore, covered in Section 4.3.4.1.1.3. 

The absolute configuration of chiral nonracemic compounds can be established by forming a complex which can bind to the axial position of [Rh2(02CCF3)4] and thus induce circular dichroism within its electronic absorption bands. This method works well for chiral secondary alcohols and monoolefins. For these compounds tentative rules were proposed, which correlate the configuration of the starting materials with the sign of certain Cotton effects of their complexes178. 

The basic method uses the kinetic resolution of racemic 2-phenylbutanoic acid (1, present in excess). Alcohols of configurational type 2 react preferentially with (S)-2-phenylbutanoyl groups to give 3, hence the residual anhydride is relatively deficient with respect to this form. On hydrolysis the residual anhydride yields 2-phenylbutanoic acid enriched in the (- )-(R)-form 4. Thus, if the 2-phenylbutanoic acid isolated is levorotatory, the secondary alcohol has the absolute configuration depicted in 2. The method has authoritatively been reviewed234. 

For secondary acyclic allylic alcohol benzoates, resolved by Sharpless enantioselective epoxida-tion, there is a similar relation between the sign of the benzoate Cotton effect and absolute configuration, as in 7 and 8149. 

This simple method for determining the absolute configuration of allylic alcohols is undoubtedly operative due to strong conformational preference of benzoates of secondary allylic alcohols for a rotamer with coplanar H —C(0R) and C = C bonds. 

In the initial discovery of the asymmetric synthesis of a-chloro boronic esters 3, the diastereomeric ratios of 3 were estimated by reaction with Grignard reagents to form secondary alkyl boronic esters 5 and deboronation with hydrogen peroxide to secondary alcohols of known absolute configuration and rotation40. 

Distal C-C bond formation can also be used to construct cyclic ethers, but this demands that methods be developed for the enantioselective assembly of complex acyclic ethers. P. Andrew Evans of Indiana University has demonstrated (Angew. Chem. Jnt. Ed. 2004, 43,4788) that Rh-mediated coupling of secondary allylic carbonates such as 7 with secondary alcohols such as 8, both enantiomerically pure, proceeds with clean retention (double inversion) of absolute configuration. Alkene metathesis then delivers the cyclic ether 9 in high diastereomeric and enantiomeric purity. 

Viridifloric /3-lactone, 143, has been identified as one of the pheromone components of a complex mixture of volatiles released by the pheromone glands of the male Idea leuconoe butterfly during courtship <1996BMC341>. A racemic mixture of both diastereoisomers was synthesized in four steps from the dilithio salt of 3-methylbutyric acid 144 alkylation with ethanal, dehydration of the secondary alcohol with phosphorus pentoxide, dihydroxylation of the C-C double bond with osmium tetraoxide, and finally formation of the /3-lactone by cyclization with sulfonyl chloride. By comparison with the sample isolated from I. leuconoe, the absolute configuration was established to be (2V,3V)-2-hydroxy-2-(l-methylethyl)-3-butanolide 143. 

When the alcohol is secondary, the possibility for kinetic resolution exists if the titanium tartrate complex is ctqxiUe of catalyzing the enantioselective oxidation of the amine to an amine oxide (or other oxidation product). The use of the standard asymmetric epoxidation complex, i.e. Ti2(tartrate)2, to achieve such an enantioselective oxidation was unsuccessful. However, modification of the complex so that the stoichiometry lies between Ti2(tartrate)i and Ti2(tartrate)i.s leads to very successful kinetic resolutions of p-hydroxyamines. A representative example is shown in equation (13). " The oxidation and kinetic resolution of more than 20 secondary p-hydroxyamines provi s an indication of the scope of the reaction and of some structural limitations to good kinetic resolution. These results also show a consistent correlation of absolute configuration of the resolved hydroxyamine with the configuration of tartrate used in the catalyst. This correlation is as shown in equation (13), where use of (+)-DIPT results in oxidation of the (5)-P-hydroxyamine and leaves unoxidized the (/ )-enantiomer. 

Shifts in the spectra of camphanate esters with secondary alcohols with Eu(fod)3 exhibited a consistent trend that correlated with absolute configuration. ... 

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