Mosher esters, preparation

The submitters report obtaining the product in 99% yield. The enantiomeric excess of the Mosher ester of 3 was measured to be 98% using a Chiralcel OD column (40% 2-propanol/hexane). This optical purity measurement substantiated the optical purity assessment made by 111 NMR studies of 3 and racemic 3 prepared using a different method3. Addition of the chiral shift reagent tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium (III) resulted in clear resolution of the respective aromatic proton signals for the two enantiomers, which was demonstrated with the racemate. Under similar conditions, NMR analysis of 3 showed that within the detectable limits of the experiment (ca. <3%), there was none of the disfavored enantiomer. 

It was further shown that the nonracemic stannane 70 can be prepared from the Mosher ester derivative 69 through reductive cleavage and BOM protection (equation 28). Lithiation and methylation gave the nonracemic ether with retention of configuration59. 

General experimental procedure for preparation of Mosher esters 271... 

Pig liver esterase (PLE, E.C. 3.1.1.1) is one of the most successful enzymes for the enantiotopos-differentiating hydrolysis of dicarboxylic diesters and diacetates of diols as exemplified by the two examples, dimethyl cv. y-4-cydohexene-l,2-dicaiboxylate (I)100 - " 2 and (l/ ,2.S,3S)-l,3-di-acetoxy-2-nitrocyclohexane (3)113. The monoester 2 is obtained with the same results when prepared on a 100 mol scale114. The ee values of the monoester 2 may be determined conveniently by H-NMR spectroscopy in the presence of (+)- or ( )-ephedrine and that of the monoacetate 4, after conversion to the corresponding Mosher ester, by 19F-NMR spectroscopy. 

The ee of the alcohol was determined by analysis of the corresponding Mosher ester derivative6 by high resolution 1H NMR spectroscopy (400 MHz, C6D6). The preparation of the Mosher ester is described below. 

Aldrich Chemical Company, Inc., and were used without further purification. Dichloromethane used in the preparation of the Mosher ester was obtained from EM Science and was distilled from calcium hydride under a nitrogen atmosphere. (R)-(-)-a-Methoxy-a-(trifluoromethyl)phenyfacetyl chloride was prepared from (S)-(-)-a-methoxy-a-(trifluoromethyl)phenylacetic acid, as described in Note 21. 

The ee of this product was determined by reduction to the corresponding alcohol with lithium aluminum hydride followed by preparation and analysis of the Mosher ester derivatives by NMR spectroscopy (400 MHz, CeDe), as described in the following paragraph. 

Homochiral epoxides are versatile intermediates for the synthesis of a variety of natural products. The four-carbon bifiinctional chiron (i )-l- erNbutyldimethylsilyl-3,4-epoxybut-l-yne (228) is conveniently prepared from 141 as shown in Scheme 53. The conversion of 141 to chloride 225 followed by base-induced chloride elimination in liquid ammonia proceeds without any detectable epimerization (as determined by both hplc and nmr analysis of the corresponding Mosher ester) to provide the i -alcohol 226 in good yield. Subsequent silyl protection followed by treatment with boron tribromide results in a highly stereoselective bromination, together with simultaneous debenzylation to the bromohydrin 227, which under mild basic conditions is converted to epoxide 228. The optical purity of 228 (ee = 99%) demonstrates the high selectivity in this new bromination reaction [80,81]. 

To a stirred solution of 0.1 mmol (4R,VS)- and (45,l 5 )-4-(l -f rf-butoxycarbonyl-amino-2 -hydroxyethyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester in 1 mL anhydrous CH2CI2 were added 29 mg (R)-Qf-methoxy-a -(trifluoro-methyl)phenylacetic acid (0.12 mmol), 25 mg 1,3-dicyclohexylcarbodiimide (0.12 mmol), and a catalytic amount of 4-A, A-(dimethylamino)pyridine. The mixture was stirred for an additional 12 h at room temperature, then concentrated. The residue was taken into EtOAc, washed with saturated aqueous NaHCOs and brine, dried over Na2S04, and concentrated. The residue was purified by preparative TLC, affording the corresponding Mosher ester in almost quantitative yield. 

Both enantiomers of menthol are commercially available. Use the following H NMR chemical shift data for the Mosher esters of menthol to determine which enantiomer of menthol was used to prepare the samples. 

Determination of the absolute stereochemistry of the newly generated C(15) stereocenter of 2.353 was achieved by Mosher ester analysis of the major dia-stereomer following the procedure reported by Kakisawa and co-workers (Scheme 2.76) [225]. The Mosher esters of the organozinc addition reaction product were prepared as shown in Scheme 2.76. Analysis of the (S)- and (R)-MTPA esters prepared from 2.353 obviously indicated that the C(15) alcohol was of the desired configuration (/ ), which was consistent with the results via reagent controlled asymmetric organozinc addition reaction. 

Synthesis of (+)-lactacystin Lactacystin 7 is one of the most important biologically active pyrrolidinone-based natural products found in nature. It was isolated from the culture broth of a Streptomyces in 1991, and since that time, it has generated an enormous interest as a consequence of its highly selective and irreversible inhibition of the 20S pro-teasome. Its synthesis was first reported by Corey and Reichard, and an alternative more recent approach is based on the preparation of an oxazoline 8 that is produced via formation of a 2-ethynyl-allyl epoxide 10 via Sharpless asymmetric epoxidation of the allyl alcohol 9 (Scheme 34.3). The reaction was carried out in the presence of catalytic amounts of calcium hydride and silica gel (whose role is not described in the paper) at —40°C to — 18°C obtaining the desired product 10 in 89% yield and >95% ee determined by integration of the F resonances of the corresponding Mosher ester derivative. 

A precedent of this methodology can be found in the preparation of a ROMPgel support of activated Mosher ester (MTPA) as a means to performing the purification free synthesis of MTPA amides by the Barrett group. 

---