Grignard reagents, alkyl stereoselectivity

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

The availability of non-racemic oxepins through tandem catalytic RCM and Zr-catalyzed kinetic resolution has additional important implications. Optically pure heterocycles that carry a heteroatom within their side chain (cf. (S)-14 in Scheme 3) can be used in stereoselective uncatalyzed alkylations. The alcohol, benzyl ether or MEM-ethers derived from (S)-14 readily undergo directed [10] and diastereoselective alkylations when treated with a variety of Grignard reagents [11]. 

The availability of oxepins that bear a side chain containing a Lewis basic oxygen atom (entry 2, Table 6.4) has further important implications in enantioselective synthesis. The derived alcohol, benzyl ether, or methoxyethoxymethyl (MEM) ethers, in which resident Lewis basic heteroatoms are less sterically hindered, readily undergo diastereoselective uncatalyzed alkylation reactions when treated with a variety of Grignard reagents [17]. The examples shown below (Scheme 6.7) demonstrate the excellent synthetic potential of these stereoselective alkylations. 

The same nitrone 241 was employed in a stereoselective alkylation with a Grignard reagent by Petrini et al. <1995JOC5706> for another synthesis of lentiginosine. 

An enantioselective approach to both enantiomers of a-alkyl-a-methoxyarylacetic acid derivatives has been described from L-(- -)-tartaric acid. Key steps include stereoselective addition of Grignard reagents to 1,4-diketones derived from tartaric acid. This methodology has been applied in synthesizing the pine beetle pheromone frontalin. 

A different type of reaction, in which the intermediate formation of a chelate ring is crucial, is the reaction of pyridyl thioates with Grignard reagents, which achieves an overall conversion of an alkyl or aryl halide to a ketone (Scheme 105).378 Grignard reactions are highly susceptible to chelation factors and stereoselectivity is observed in the addition of organomagnesium or... 

Nucleophilic alkylation with Grignard reagents (mediated by Et2AlCl) on chiral perhydropyrido(2.1 A]pyrrolo[l,2-ii][l,3,4]oxadiazinc (25) proceeds via an 5 2 mechanism below — 80 °C, forming the inversion product (26) with high stereoselectivity.22 At higher temperatures the stereoselectivity shifts in favour of retention. 

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