Chelation controlled Grignard reaction

The addition of vinylmagnesium bromide to methyl (S)-3-benzyloxy-4-oxobutanoate (5) in tetrahydrofuran proceeded with a slight preference for the nonchelation-controlled reaction product (40 60)5°. A reversal of the diastereoselectivity (80 20) could be observed when the Grignard reagent, as a solution in tetrahydrofuran, was added to a dichloromethane solution of the aldehyde which had been precomplexed with one equivalent of magnesium bromide. The almost exclusive formation of the chelation-controlled reaction product 6 was achieved when tetrahydrofuran was completely substituted by dichloromethane the presence of tetrahydrofuran interferes with the formation of the chelate complex, which is a prerequisite for high chelation-controlled diastereoselection. 

Addition of alkynes to a-alkoxy aldehydes is most favorably performed with the corresponding zinc reagents (Table 12)46. As with Grignard reagents, the chelation-controlled addition of zinc alkynes proceeds with higher diastereoselectivity when diethyl ether rather than tetrahydrofuran is used as reaction solvent. 

The nucleophilic addition of Grignard reagents to a-epoxy ketones 44 proceeds with remarkably high diastereoselectivity70. The chelation-controlled reaction products are obtained in ratios >99 1 when tetrahydrofuran or tetrahydrofuran/hexamethylphosphoric triamide is used as reaction solvent. The increased diastereoselectivity in the presence of hexamethylphos-phoric triamide is unusual as it is known from addition reactions to a-alkoxy aldehydes that co-solvents with chelating ability compete with the substrate for the nucleophile counterion, thus reducing the proportion of the chelation-controlled reaction product (vide infra). 

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. 

A successful approach to exploit the chelating ability of MeMgBr to control addition to the hydrazone 31 was discovered when the Grignard reaction was carried out in toluene solvent. Since toluene is a noncoordinating and nonpolar solvent, the magnesium coordinates with the substrate to activate the hydrazone and control the facial selectivity, as shown. A 94 6 selectivity for Re face attack to give 32 was observed after 1 hr at 20 C. There was no reaction after 48 hr at reflux temperature in THF [50]. 

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. 

Similar selectivities (>99 1) are observed in the cyclic chelation controlled reaction of a-benzyloxy carbonyls such as (4a equation 4) with Grignard reagents. However when the a-hydroxy group is protected as a silyl ether (4b), the selectivities observed in the addition reaction diminish (60 40), or reverse (10 90 Table 3). The nonchelating nature of a silyl group, as well as its steric bulk, are responsible for this change in selectivity. In the case of (4b), nucleophilic addition via the Felkin-Anh model effectively competes with the cyclic-chelation control mode of addition. 

Simple addition of n-decylmagnesium bromide to (7) yields an approximately equal ratio of products (8) and (9). The use of conditions which promote chelation (excess Grignard reagent) produces a shift in the pnxiuct ratio (63 37). Addition of ZnBr2 to the reaction mixture further increases the amount of chelation-controlled product formed (85 15 Table 4). 

A number of other examples have been reported which involve highly selective Grignard or organolithium additions to carbohydrates. Unfortunately, no general trends for these complex systems have been observed. Hie selectivities reported are often specific for one substrate under a particular set of reaction conditions. Reetz has reviewed the chelation and nonchelation control addition reactions (not confined to organolithium or organomagnesium reagents) of a- and 3-aUcoxycarbonyl compounds. ... 

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