Grignard reagent racemic

The carbonyl carbon of an unsymmetrical ketone is a prochiral center reaction with a Grignard reagent 2 (R 7 R, R") can take place on either face of the carbonyl group with equal chance. The products 8a and 8b are consequently formed in equal amounts as racemic mixture, as long as no asymmetric induction becomes effective ... 

By treatment of a racemic mixture of an aldehyde or ketone that contains a chiral center—e.g. 2-phenylpropanal 9—with an achiral Grignard reagent, four stereoisomeric products can be obtained the diastereomers 10 and 11 and the respective enantiomer of each. 

Johnson s classic synthesis of progesterone (1) commences with the reaction of 2-methacrolein (22) with the Grignard reagent derived from l-bromo-3-pentyne to give ally lie alcohol 20 (see Scheme 3a). It is inconsequential that 20 is produced in racemic form because treatment of 20 with triethyl orthoacetate and a catalytic amount of propionic acid at 138 °C furnishes 18 in an overall yield of 55 % through a process that sacrifices the stereogenic center created in the carbonyl addition reaction. In the presence of propionic acid, allylic alcohol 20 and triethyl orthoacetate combine to give... 

Reaction of racemic a-alkyl-a-(l H-1,2,4-triazol-l-yl)acetophenones with Grignard reagents in boiling diethyl ether affords exclusively the (RS/S -enantiomeric pairs. On the other hand, reaction of racemic a-alkoxy-x-(17/-l,2,4-triazol-l-yl)acetophenonc with Grignard reagents leads, under chelation control, to the (R/ /5S)-enantiomeric pair82. 

Chelation control does not operate in the addition of 2-butenyl Grignard reagents to a-oxyalkanals, since with (racemic) 2-benzyloxy-, 2-(benzyloxymethoxy)- and 2-(t< rt-butyldi-methylsilyoxy)propanal similar ratios of isomers are formed28. Several cations were investigated, but the best choices, e.g., allylboronates or allylsilanes, were not included in this study. 

Racemic l-methyl-2-butenylboronates (E)- and (Z)-3 may be prepared selectively via reactions of the l-methyl-2-butenyl Grignard reagent with the appropriate borate ester. Use of triisopropyl borate provides a 96 4 mixture of (E)-3l(Z)-3 on a 0.36 mol scale15. Use of a bulkier borylating agent, such as 2-isopropyloxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane, reverses the selectivity, enabling a 91 9 mixture of (Z)-3/( )-3 to be obtained on a 0.5 mol scale. The diastereomeric purity of this mixture may be enhanced to 95 5 by treatment with 0.15 equivalents of benzaldehyde, since ( )-l-mcthyl-2-butenylboronatc ( )-3 is more reactive than (Z)-3. Repetition of this process provides (Z)-3 that is 98% isomerically pure. 

Sturmer via the reaction of the chiral borate ester (45, 5S)-4,5-dicyclohexyl-2-isopropyloxy-1,3,2-dioxaborolane, and racemic Grignard reagent (l-methyl-2-butenyl)magnesium chloride16. A 97 3 mixture of (S)-4 and its tf-diastereomer was obtained in 89% yield. 

The reaction gives unsatisfactory yields using R2CuLi in the presence of lib, or Grignard reagents. b The reaction fails with RLi using TFIF as the solvent. c The dcprotcction is accomplished without any racemization. 

Grignard reagents add to racemic AT-(2-phcnylpropylidene)alkylamine A-oxides 2 to afford hydroxylamines 3a and 3b in good yield (68-90%) but modest diastereoselectivity (d.r. 67 33 — 83 17)7. The major product 3a is the diastereomer predicted by Cram s rule. 1 shows the attack of the Grignard reagent according to the T elkin-Anh explanation of Cram s rule. 

Addition of Grignard reagents to enimines prepared from acyclic or cyclic a,/J-unsaturated aldehydes and tert-butyl (.S )-2-ami no-3,3-dimethylbutanoate gives, after acid hydrolysis, non-racemic /1,/1-disubstituted aldehydes in high enantiomeric excess1"5. 

The chiral auxiliary can be recovered without any racemization. A chelated transition state has been suggested in which the Grignard reagent is delivered to the 7t-face more distal from the sterically demanding toy-butyl group1 2. 

Few racemic alkyl p-tolyl sulphoxides were prepared in rather low yields (16—40%) by the reaction of Grignard reagents with mixed anhydrides 108, 109 and compound HO formed in situ from p-toluenesulphinic acid and 3-phthalimidoxy-l,2-benzoisothiazole 1, 1-dioxide167 (equation 59). The mixed anhydrides 109 or 110 when reacted with cyclopen-tene and cyclohexene enamines 111 gave the corresponding a-ketocycloalkyl sulphoxides 112 in low yields (10-41%) along with small amounts of several by-products such as disulphides and thiosulphonates167 (equation 60). 

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). 

The use of a chiral alcohol to prepare diastereomeric alkoxystannanes from racemic triorganostannyl halides, then displacement with a Grignard reagent, constitutes a general route to nonracemic tetraorganostannanes. Chinconine has proven particularly effective as the chiral alcohol (equation 7)19. 

The availability of non-racemic oxepins through tandem catalytic RCM and Zr-catalyzed kinetic resolution has additional important implications. Optically pure heterocycles that carry a heteroatom within their side chain (cf. (S)-14 in Scheme 3) can be used in stereoselective uncatalyzed alkylations. The alcohol, benzyl ether or MEM-ethers derived from (S)-14 readily undergo directed [10] and diastereoselective alkylations when treated with a variety of Grignard reagents [11]. 

Another approach to chiral sulfinates was developed by Pirkle and Hoekstra (108) it is based on incomplete but stereoselective reaction of racemic sulfinates with chiral Grignard reagents. This kinetic resolution affords the unreacted sulfinates enriched in the (5 -enantiomers with optical purities in the 8-64% range. The chiral cyclic sulfinates 66 and 67 were first obtained by this method. 

---