Grignard reagents chelation controlled addition

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. 

Stereoselective chelate-controlled addition of Grignard reagents to tetrahydrooxepine derivatives (Equation 3) involves Zr-catalyzed kinetic resolution with (i )-[EBTHI]Zr-BINOL (BINOL= l,l -bi-2-naphthol) <1996JA4291, 1997JA6205, 1999JOC854>. 

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. 

Systematic studies on the chelation-controlled additions were carried out, varying the type of alkoxy group, the carbon nucleophile, the solvent and the temperature. It was found that a-alkoxy ketones react highly stereoselectively with Grignard reagents in THF (equation 24). Alkyllithiums were not effec-tive. -6 The generalization was made use of in the synthesis of the polyether antibiotic monensin. ... 

As described above, the reactions of Grignard or oiganolithium reagents to a-hydroxy or a-amino-carbonyls can proceed with extremely high stereoselectivities (>99 1) when cyclic chelation control is in effect. However, attempts to generate products arising from the C ram-Felkin-Anh mode of addition exclusively have been much less successful. These products are available by the use of conditions which favor nonchelation-controlled processes however, until recently, the selectivities of these reactions (up to 80-90%) never reached those observed in cyclic chelation control additions. 

Most of the examples in this chapter have been disubstituted alkenes, a few have been trisubstituted, but none so far has been tetrasubstituted (except cyclic alkenes) as this is the most difficult case of all. One solution49 starts with ethyl lactate 228 and uses a HWE reaction on the enantiomerically pure phosphonate 229 to make the / -enone 230 with very high selectivity. Chelation-controlled addition of a Grignard reagent gives the stereochemically pure allylic alcohol 231. Chelation control is explained in chapter 21. 

In a second chelation-controlled addition, 286 is converted to 287 by addition of Grignard reagent to the acetyl carbonyl (80 1 diastereoselectivity) followed by lactonization. Di-oxanone-dihydropyran Claisen rearrangement (287- 288) establishes the desired carbon skeleton. It is ironic that the original (iS)-lactate stereocenter, which was responsible for all the stereochemistry, is ultimately destroyed in 289. An additional 11 steps is required to reach the target C-7 to C-13 fragment [103]. 

Grignard reagents add to 658 in a fashion similar to that previously described for lactaldehydes to give predominantly syn alcohols as a result of chelation-controlled addition to the aldehyde. Consequently, when methyl Grignard is added to 658, a 75 25 mixture of alcohols 659 and 660 is formed [199] (Scheme 90). 

A strategically similar approach has been used for the synthesis of tetrasubstituted acyclic olefins [201] (Scheme 91). The initial addition of a Grignard reagent to 658 followed by Swem oxidation of the intermediate mixture of alcohols affords enone 664. Chelation-controlled addition of methyl Grignard to 664 gives the anti tertiary alcohol 665 as a single diastereomer. 

The central fragment (281) of monensin is prepared from 275 as outlined in Scheme 38 [62]. The key step in the sequence is addition of 3-methyl-3-butenylmagnesium bromide to 279. Since 279 contains the necessary features for chelation-controlled addition of the Grignard reagent to the carbonyl group, product 280a is formed with high diastereoselectivity (50 1). 

The a-chelation-controlled addition of Grignard reagents to aldehyde 624 to provide in some cases exclusively syn addition products suggests the possibility of utilizing either a- or ) -chelation-controlled addition of hydride to the ketone derivative 642 for efficient and stereoselective preparation of either the L-lyxo (anti)-643 or L-jcy/o (syn)-644 alcohols [201] (Scheme 141). 

The alcohol 5 arises from chelation-controlled addition to the ketone 4. Draw a Newman projection, as shown in A, to illustrate this, with attack by the isopropyl group from the less-hindered face. The alcohol 6 is formed by p-hydride delivery from the Grignard reagent. In this case, there must be no O—Mg—N chelation, and the stereochemistry can be explained by using the Felkin-Anh transition state - see the Newman projection B. See Schemes 1.125, 1.127 and 1.128. 

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. 

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). 

An excess of Grignard reagent (4 equivalents) or the addition of strong Lewis acids promotes the preference for chelation-controlled. vvn-products (Table 20)22 21 u. In addition, the use of diethyl ether or dichloromethane instead of tetrahydrofuran improves the yield of the chelation-derived syn-product24. 

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