Chiral Grignard reagents, synthesis

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

For the preparation of aspartic proteinase inhibitors, Jones et al. [7] needed epimeric A -protected alcohols (see Table 1, entry 2). In this stereocontrolled synthesis of hydroxyethylene dipeptide isoteres, a chiral Grignard reagent was used in a reaction with a protected aminoaldehyde [7]. In this reaction, a 6 1 ratio of diastomers 4SAR) was obtained. The stereochemistry of the products was controlled by the complexation of the reagent with the protected amine the S-epimer predominates because of a chelation-controlled addition of the Grignard. 

A tetrahydropyran that inhibits leukotriene biosynthesis Asymmetric synthesis of2-methyl-tetrahydropyran-4-one by kinetic resolution Part VI - Asymmetric Desymmetrisation of a Diels-Alder Adduct Ifetroban sodium a thromboxane receptor antagonist A laboratory synthesis starting with a Diels-Alder reaction Desymmetrisation of a symmetrical anhydride with a chiral Grignard reagent Laboratory and process routes compared Part VII - Asymmetric Synthesis of A Bicyclic 3-Lactone Lactacystin a naturalproteasome inhibitor... 

Insofar as the closely related asymmetric synthesis with an asymmetric P-N chelate is concerned, the crucial step is the one in which the chiral Grignard reagent reacts with the palladium (or nickel)-haloalkyl complex with displace-... 

Further utility of the Andersen sulphoxides synthesis is demonstrated by the preparation of optically active unsaturated sulphoxides which were first prepared by Stirling and coworkers359 from sulphinate 276 and the appropriate vinylic Grignard reagents. Later on, Posner and Tang360 prepared in a similar way a series of ( )-l-alkenyl p-tolyl sulphoxides. Posner s group accomplished also the synthesis of (+)-(S)-2-(p-tolylsulphinyl)-2-cyclopentenone 287, which is a key compound in the chiral synthesis of various natural products361 (equation 159). 

Simple 1,2,4-triazole derivatives played a key role in both the synthesis of functionalized triazoles and in asymmetric synthesis. l-(a-Aminomethyl)-1,2,4-triazoles 4 could be converted into 5 by treatment with enol ethers <96SC357>. The novel C2-symmetric triazole-containing chiral auxiliary (S,S)-4-amino-3,5-bis(l-hydroxyethyl)-l,2,4-triazole, SAT, (6) was prepared firmn (S)-lactic acid and hydrazine hydrate <96TA1621>. This chiral auxiliary was employed to mediate the diastereoselective 1,2-addition of Grignard reagents to the C=N bond of hydrazones. The diastereoselective-alkylation of enolates derived from ethyl ester 7 was mediated by a related auxiliary <96TA1631>. 

Wang used method D to fashion a key intermediate for the synthesis of rishirilide B (Fig. 4.20).21 The 2,4-bis-OBoc-3-methyl-benzyl alcohol (31) undergoes the addition of two equivalents of corresponding Grignard reagent to afford phenol 32 in 75% yield (Fig. 4.20). This material was subsequently elaborated by Mejorado in three steps (61% yield) to the corresponding 2,5-chiral cyclohexadienone 33, which was ultimately transformed into ( + )-rishirilide B (34).22... 

Aromatic and vinylic sulfides take part in cross-coupling reactions with Grignard reagents in the presence of Ni catalysts.336,337 This reaction has been applied to the enantioselective synthesis of binaphthyls using a standard chiral oxazoline ligand (Equation (25)) 338... 

In the first systematic study on nucleophilic substitutions of chiral halides by Group IV metal anions, Jensen and Davis showed that (S )-2-bromobutane is converted to the (R)-2-triphenylmetal product with predominant inversion at the carbon center (Table 5)37. Replacement of the phenyl substituents by alkyl groups was possible through sequential brominolysis and reaction of the derived stannyl bromides with a Grignard reagent (equation 16). Subsequently, Pereyre and coworkers employed the foregoing Grignard sequence to prepare several trialkyl(s-butyl)stannanes (equation 17)38. They also developed an alternative synthesis of more hindered trialkyl derivatives (equation 18). 

Preparation of the chiral biphenyls and binaphthyls with high enantiose-lectivity can be achieved via substitution of an aromatic methoxyl group with an aryl Grignard reagent using oxazoline as the chiral auxiliary.38 Schemes 8-10 and 8 11 outline the asymmetric synthesis of such chiral biaryl compounds. 

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