Methyl enantiomeric excess

Only reaction 1 provides a direct pathway to this chiral molecule the intermediate 2-methyl-butanal may be silylated and reacted with formaldehyde in the presence of the boronated tartaric ester described on page 61. The enantiomeric excess may, however, be low. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

The synthesis of 4-alkyl-y-butyrolactones 13 and 5-alkyl-<5-valerolactones 14 can be achieved in high enantiomeric excess by alkylation of ethyl 4-oxobutanoate and ethyl 5-oxopentanoate (11, n = 2, 3). The addition of diethylzinc, as well as dimethylzinc, leads to hydroxy esters 12 in high optical purity. When methyl esters instead of ethyl esters are used as substrates, the enantioselectivity of the addition reaction is somewhat lower. Alkaline hydrolysis of the hydroxy esters 12, followed by spontaneous cyclization upon acidification, leads to the corresponding y-butyro- and -valerolactones32. 

Control experiments, performed with the ( + )-(R)-diastereomer of 1, which differs only in the configuration of the stereogenic center at the metal, afford the enantiomeric homoallylic alcohol, (S)-3-methyl-1-phenyl-3-butenol, also with high enantiomeric excess, indicating that the chiral cyclopentadienyl ligand has no dominating influence1-2. 

Metalation ofa-sulfinyl dimethylhydrazones with terf-butylmagnesium bromide, butyllithium or lithium diisopropylamide, and reaction of the generated azaenolates with aldehydes, provides aldol adducts (e.g., 6) as mixtures of diastereomers. Reductive desulfurization leads to fi-hydroxy dimethylhydrazones (e.g., 7) which are cleaved to the desired /(-hydroxy ketones in 25% overall yield10 u. The enantiomeric excesses are about 50%, except for (- )-3-hydroxy-4-methyl-1-phenyl-1-pentanone (8) which was obtained in 88% ee. 

Addition of metalated, enantiomerically pure a-sulfinyl dimethylhydrazones (e.g., 9) to racemic a-chiral aldehydes 10 proceeds with good to excellent diastereo- and enantioselectivi-ty12. Diastereomeric ratios increase with increasing steric demand of the acetaldehyde substituent R1 compared to the methyl group, and each diastereomer is obtained with high enantiomeric excess. In the aldol-lype addition to 2-phenylpropanal, one of the four possible stereoisomers is formed selectively. The relative (syn) and absolute (R.R) configuration is in accord with Cram s and related rules as well as H-NMR data of closely related compounds. 

For the determination of the enantiomeric excess. 23 mg of the mi-hydroxy ester (containing 2 5% //-product) and 9 mg of tris[3-(heptafluoropropylhydroxymethylene)-a-camphorato]europium are dissolved in 0.5 mL of CDC13. The ec is calculated from the peak heights and areas of the resolved doublets, due to the methyl groups attached to C-2. of the minor (f) 1.74) and major (<5 1.98) enantiomers. 

By simply hydrolyzing the easily accessible 2-hydroxy-2-methylalkanenitriles with concentrated acid, 2-hydroxy-2-methylalkanoic acids are obtained without measurable racemization (Table 3). The reaction sequence from the starting ketone to the carboxylic acid can be carried out in one pot without isolation of the cyanohydrin. The enantiomeric excesses of the (/ )-cyanohydrins and the (ft)-2-hydroxyalkanoic acids are determined from the ( + )-(/T)-Mosher ester derivatives and as methyl alkanoates by capillary GC, respectively. The most efficient catalysis by (R)-oxynitrilase is observed for the reaction of hydrocyanic acid with 2-alkanoncs. 3-Alkanoncs are also substrates for (ft)-oxynitrilase, to give the corresponding (/ )-cyanohydrins32. 

Thus, the lithiated SAMP hydrazones of various methyl ketones on addition to 2-(aryl-methylene)- , 3-propanedionates and propanedinitriles provide, after the removal of the auxiliary, (R)-2-( l-aryl-3-oxobutyl)-1,3-propanedioates and -propanedinitriles with high enantiomeric excess (> 95%) in 50 82% yield (sec Table 6) 195,197. Using similar methods optically active (5-lactones (90% to > 96% ee) are obtained198. 

In one case, the addition of lithiated 1,3-dithiane to ( )-l-nitropropene gave an adduct in modest enantiomeric excess (43% ee). In an independent study chiral lithium [(S)-(l-(dimethylamino)-ethyl](methyl)phenylcupratc and lithium mcthoxy(methyl)eupratc were reacted with ( )-(2-ni-troethenyl)benzene to give adducts in 1-2% enantiomeric excess36. 

The addition of the lithium enolates of various acetic add esters to (S)-3-(4-methylphcnyl-sulfmyl)-2(5//)-liiranone and (,S)-5,6-dihydro-3-(4-methylphenylsulfinyl)-2//-pyran-2-one gives, after desulfurization with Raney nickel, 4-substituted dihydro-2(3//)-furanoncs and 4-substituted tetrahydro-2//-pyran-2-ones, respectively, in good to quantitative enantiomeric excess. Addition of the enolate occurs via the nonchelate mode. The enolate of methyl (phenylthio)acetatc is best overall in regards to chemical yields and enantiomeric purity of the final lactone product13. 

Enantioselective hydrogenation Z-2-methyl-pent-2-enoic and Z-2-ethyl-hex-2-enoic acids occurred over alkaloid-modified Pd/SiOa as described in Table 2 Enantioselectivity was favoured by an increase in hydrogen pressure to 50 bar The enantiomeric excess of 27% in Z-2-methyl-pent-2-enoic acid hydrogenation was the highest value recorded in this study. 

Although cinchona-modified Pd showed no enantioselectivity in the hydrogenation of the methyl esters of the unsaturated acids, the hydrogenation of methyl pyruvate occurred with a modest enantiomeric excess... 

The enantiomeric excess (ee) of the hydrogenated products was determined either by polarimetry, GLC equipped with a chiral column or H-NMR with a chiral shift reagent. Methyl lactate and methyl 3-hydroxybutanoate, obtained from 1 and 2, respectively, were analized polarimetry using a Perkin-Elmer 243B instrument. The reference values of [a]o(neat) were +8.4° for (R)-methyl pyruvate and -22.95° for methyl 3-hydroxybutcinoate. Before GLC analysis, i-butyl 5-hydroxyhexanoate, methyl 5-hydroxyhexanoate, and n-butyl 5-hydroxyhexanoate, obtained from 1, 5, and 6, respectively, were converted to the pentanoyl esters, methyl 3-hydroxybutanoate was converted to the acetyl ester, and methyl 4-methyl-3-hydroxybutanoate obtained from 2 was converted the ester of (+)-a-methyl-a-(trifluoromethyl)phenyl acetic acid (MTPA). 

For example, the hydrogenation of methyl (Z)-a-acetamidocinnamate gives a chiral product when conducted in the presence of a chiral diphosphine catalyst. The enantiomeric excess data for micro-reactor and batch operation are in line when performed imder similar conditions [169]. A very high reproducibility of determining data on enantiomeric excess was reported [170]. In addition, the ee distribution was quite narrow 90% of aU ee data were within 40-48% [170]. 

Chiral monodentate carbene complexes of Rh and Ir of the type [MCl(l,5-COD) (NHC)] (M = Rh, Ir) with the ligands 7-9 (Fig. 2.1) have been stndied as catalysts for the enantioselective hydrogenation of methyl-2-acetamido acrylate. Even though the activities were high, the enantiomeric excesses (ee) were poor [7, 8]. 

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