Diastereoselective addition Grignard reagent

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

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... 

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). 

Besides the addition of vinylation reagents, methyllithium and methyl Grignard reagents can react with a,/1-epoxy aldehydes in a nonchelation-controlled mode79. However, the level of diastereoselectivity is moderate. 

The fact that only Grignard reagents add with high diastereoselectivity to the phenylmenthyl ester of glyoxylic acid, whereas methyllithium reacts nonstereoselectively, may be the result of a different aggregation of the reagents. This is supported by the tremendous improvement of the stereoselectivity when the addition of methyllithium is undertaken in the presence of lithium perchlorate13. 

The high diastereoselectivity which is found in the nucleophilic addition of Grignard reagents to chiral 2-0x0 acetals can be explained by a chelation-controlled mechanism. Thus, coordination of the magnesium metal with the carbonyl oxygen and the acetal moiety leads to a rigid structure 3A in the transition state with preferred attack of the nucleophile occurring from the S/-side. 

Enantiomerically pure of-dibenzylamino-/V-tosylimines 2 arc accessible from amino acids. Since they are not suitable for storage it is advantageous to prepare them in situ from the corresponding aldehydes 1 and A-sulfmyl-4-toluenesulfonamide immediately before use. Addition of Grignard reagents affords the protected 1,2-diamines 3 in good yields (57-95%) and diastereoselectivities (d.r. 85 15 >95 5)8. Deprotection is achieved without racenuzation by reductive methods, see 4-6. 

The diastereoselectivity of the reaction may be rationalized by assuming a chelation model, which has been developed in the addition of Grignard reagents to enantiomerically pure a-keto acetals7,8. Cerium metal is fixed by chelation between the N-atom, the methoxy O-atom and one of the acetal O-atoms leading to a rigid structure in the transition state of the reaction (see below). Hence, nucleophilic attack from the Si-face of the C-N double bond is favored4. 

The diastereoselectivity of the nucleophilic addition to nitrone 2 may be rationalized by assuming that magnesium bromide preferentially coordinates with the nitrone oxygen. The Grignard reagent is therefore forced to interact with the acetal oxygen in position 3. 

Substantially high diastereoselectivity was accomplished by the conjugate addition of Grignard reagents to the amide 1 derived from 1-ephedrine32. The reagent attacked from the Re-face of the double bond, as shown in 2, via a chelated intermediate. Low asymmetric induction was observed when butyllithium was used instead of butylmagnesium bromide. 

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>. 

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