Grignard reagents chiral ketones

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. 

The reactions of 2-propenyltitanium reagents with chiral aldehydes (0) or ketones ( and ) usually exhibit enhanced induced diastereoselectivities compared to allyl Grignard reagents. This enhanced diastereoselection is mainly attributed to the greater bulk and lower reactivity of the reagent. Some examples are collected ( )52. 

SCHEME 16. The observed stereochemistry of the reported reactions by the use of (a) chiral ketones and (b) Grignard reagents in Grignard reactions. Asymmetric carbon atoms are denoted by i or 5... 

Compared with aldehydes, ketones and esters are less reactive electrophiles in the addition of dialkylzincs. This makes it possible to perform a unique reaction that cannot be done with alkyllithium or Grignard reagents, which are too reactive nucleophiles. For example, Watanabe and Soai reported enantio- and chemoselective addition of dialkylzincs to ketoaldehydes and formylesters using chiral catalysts, affording enantiomerically enriched hydroxyketones 30 (equation 12)43 and hydroxyesters 31 in 91-96% , respectively (equation 13). The latter are readily transformed into chiral lactones 3244. 

Chiral 2,2-disubstituted cyclobutanones have been obtained by asymmetric rearrangement of chiral sulfinyl- 177,178 and sulfanylcyclopropanes.179 Using readily available cyclopropyl 4-tolyl (/ )-sulfoxide (l),180 the requisite sulfinylcyclopropanes 3 and 3 were obtained by a sequence of lithiation, reaction with carboxylic acid esters and stereoselective addition of Grignard reagents to the ketones 2 thus formed.178 The corresponding sulfanylcyclopropanes 4 and 4 resulted from a sequence of protection, reduction and deprotection.179... 

Addition to a-aikoxy carbonyl compounds. n-Butylmagncsium bromide reacts stercosclcctivcly with protected, chiral a-hydroxy ketones. For example, reaction of the Grignard reagent with the MEM ether of 3-hydroxy-2-decanone in THF leads to the f/ireo-product [>95% isolated yield (equation I)]. The stereoselectivity is much lower when n-butyllilhium is used in addition the solvent plays an important role. Stereoselectivity is lower in C5H, 2, CH2CI2, and ether. A number of protective... 

These reagents add to the chiral ketones 3 with high 1,5-asymmetric induction. Grignard and organolithium reagents show slight diastereoselectivity.3 Example ... 

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