Diastereoselectivity Grignard reactions

Schmid and Maliakel [17] reported diastereoselective Grignard reactions in their synthetic scheme to sphydrofurans, secondary metabolites from various strains of Streptomycetes. Although Eq. (2) depicts the desired sequence as a single equation, the actual scheme has four steps. The authors used the silyl-protected carbonyl with D-threo... 

In 1991, Whitesides etal. reported the first application of aqueous medium Barbier-Grignard reaction to carbohydrate synthesis through the use of tin in an aqueous/organic solvent mixture (Eq. 8.48).106 These adducts were converted to higher carbon aldoses by ozonolysis of the deprotected polyols followed by suitable derivatization. The reaction showed a higher diastereoselectivity when there was a hydroxyl group present at C-2. However, no reaction was observed under the reaction conditions when there was an /V-acctyl group present at the C-2 position. 

Acetals as Chiral Auxiliaries. There have been many applications of acetals of 2,4-pentanediol as chiral auxiliaries to control the diastereoselectivity of reactions on another functional group. Examples include cyclopropanation of alkenyl dioxanes, lithium amide-mediated isomerization of epoxides to allylic alcohols, and addition of dioxane-substituted Grignard reagents or organolithiums to aldehydes. 

Conjugate additions. The diastereoselectivity of the copper(I)-catalyzed Grignard reaction on N-alkenoyloxazolidin-2-ones varies with the nature of the 4-substituent. ... 

Aziridine 2-carboaldimines, 201, have been used to provide ready access to a variety of diamines <05T9281>. A number of nucleophiles were added to imine 201 to provide products 202 and 203. Grignard reagents and a ketene sUyl acetal added to the imine in very good yields when catalyzed with BF3 OEt2- The Strecker product, R = CN, was obtained in very good yield but with only moderate diastereoselectivity by reaction with TMSCN and BFj OEtj. 

Diastereoselective additions. The y-substituents of allenyl carbonyl compounds exert stereodirecting effects on the Grignard reaction. On the other hand, the diastereoselectivity observed in the reactions of the aldehydes derived from a serine orthoester and 2-acyl-1,3-dithiane 1-oxides can be attributed to chelation control. 

The convergent synthesis of these compounds is rather simple. On the one side, the required a-keto ester may be synthesised from diethyl oxalate by a Grignard reaction. On the other side, alanine or trifluoroacetyllysine is coupled with proline via the oxazolidine-2,5-dione (the so-called Leuchs anhydride ). The two halves are combined by reductive amination. The diastereoselectivity of the hydrogenation is dependent on the choice of catalyst. With Raney nickel, the diastereoselectivity lies in case of enalapril at 87 13 and for Iisinoprii at 95 5 in favour of the desired diastereomers. In the case of Iisinoprii, there follows a final hydrolysis of the ester and amide function. The active material is ultimately purified by crystallisation. 

Impressively short is a total synthesis by Ian Paterson [281], who uses a lactate ester as chiral auxiliary. This is subsequently converted into a ketone via a Grignard reaction with its Weinreb amide. The boron-mediated aldol reaction, after an oxidative work-up, gives the aldol with a diastereoselectivity of >98 %. Since also the reaction with propionaldehyde shows the same diastereoselectiv-... 

Studies of Grignard reactions and hydride reductions of epi- and scyllo-inososes (11) indicate that the diastereoselectivity is determined by the orientation of the j0-hydroxyl group (or its derivative). ... 

Generally, in contrast to 2-substituted cyclopentanones, the diastereoselectivity of addition reactions to 3-substituted cyclopentanones is nearly independent of the nucleophile and the substituent in the 3-position. Thus, addition of various Grignard reagents, including ethynyl reagents, to 3-methyl- and 3-ferf-butylcyclopentanone leads to almost the same ratio of diastereomers (Table 3)3,4 6, 27,2s... 

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