Absolute configuration racemic alcohol

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

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. 

As described in the section dealing with liquid chromatographic methods, the reaction of 0,0-di-substituted tartaric anhydrides with racemic amino alcohols in acidic solution leads exclusively to the corresponding diastereomeric monoesters, which are easily separated by reversed-phase HPLC. However, H- and sometimes 13C-NMR spectra of these compounds are in many cases also highly useful for determining the diastereomeric ratio and in many cases the absolute configuration. 

BINAP-ruthcnium(II)-catalyzed hydrogenation of the racemic cyclic / -oxo ester, methyl 2-ox-ocyclopentanecarboxylate, was found to lead to alcohol 3, one of the four possible stereoisomers135. The reaction is both enantioselective (kinetic resolution) and diastereoselective. Since racemization of the substrate is sufficiently faster than hydrogenation, the yield of the hydroxy ester was almost quantitative. Whereas the relative configuration was probably clear from NMR spectra (not reported), the absolute configuration of 3 had to be determined (see p 438)135. 

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. 

After decarboxylation, enolization in the alternative mode would cause racemization. However, this reasoning does not explain why 199 was racemized. The racemic a-aminoketones were eventually resolved via their bromocamphorsulfonates. Optically pure (—)-indolizidin-l-one (196) was reduced with lithium aluminum hydride to the alcohol, tosylated, and again reduced to (+)-indolizidine [Eq. (28)]. Since indolizidine obtained from R-pipecolic acid [Eq. (29)] was levorotatory, it followed that the absolute configuration of the original ketone was S.254 The optical rotatory dispersion (ORD) curve of the S(-)-ketone showed a strong negative Cotton effect as predicted by the octant rule. 

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. 

Others CPSs have been prepared in a similar way and characterized at different steps by physicochemical methods. For example, the structure of the chiral selector iV-[2 -(5)-hydroxypropyl]-Ar, /V -bis(3,5- dichlorobenzoyl)-(f ,f )-tra i- 1,2-diamino-cyclohexane was solved by X-ray analysis and its absolute configuration confirmed unambiguously [73]. These CPS phases were used to resolve a large number of racemic mixtures belonging to different classes of organic compounds, such as a-aryloxyacetic acids, alcohols, sulfoxides, selenoxides, phosphinates, amino acids, amino alcohols, etc. 

This procedure required but one resolution of the acetylenic alcohol 40 which then served to resolve the remaining chiral portion of the molecule. The resolution of octyn-3-ol 40 therefore was the start of the synthesis of the optically active 7-oxaprostanoids. Reaction of the racemic octyn-3-ol 40 with phthalic anhydride gave the phthalyl acid 41 which formed the crystalline salt 42 by reaction with ( )-o -phenethylamine with the absolute configuration shown. 

The absolute configuration of methyl 4-methyl-6-(2-methylprop-l-enyl)cyclohexa-l,3-dienecarboxylate (24) was assigned on the basis of a study with Eu(fod)3. 24 was first converted to its corresponding alcohol (24 ), which was then converted to its mtpa derivative. Relative shifts of the methoxy signal of the (S)- and (/f)-mtpa derivative in the presence of Eu(fod)3 were used in assigning the absolute configuration. The NMR method was compared to a hydrolysis method using pancreatic lipase with the racemic ester. Porcine pancreatic lipase is known to hydrolyze the ester enantioselectively ". 

The stereochemistry of the olefin is crucial for the enantioselectivity of the carbolithiation. Whereas the asymetric carbolithiation of ( )-cinnamyl alcohol gives the (S)-alkylated product 93, the reaction of the (Z)-isomer, under the same experimental conditions, leads to 92 Li, the enantiomer of 92Li. After acidic hydrolysis, 92 Li was converted to 93 with an (/ ) absolute configuration in 70% ee. Addition of diphenyl disulfide to 92 Li leads to the fonnation of two vicinal chiral centers with a diastereoselectivity of 98 2 and an enantioselection of 70% [128], as described in Scheme 7-109. However, a racemic product is obtained when the allylic alcohol is not substituted, as is the case with prop-2-en-l-ol. 

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