Conformationally Biased Ketones React Diastereoselectively with Allylmagnesium Halides

Abstract

The addition of the highly reactive reagent allylmagnesium halide to α-substituted acyclic chiral ketones proceeded with high stereoselectivity. The stereoselectivity cannot be analyzed by conventional stereochemical models because these reactions do not conform to the requirements of those models. Instead, the stereoselectivity arises from the approach of the nucleophile to the most accessible diastereofaces of the lowest-energy conformations of the ketones. High stereoselectivity is expected, and the stereochemical outcome can be predicted, with conformationally biased ketones that have sterically distinguishable diastereofaces wherein only one face is accessible for nucleophilic addition. The conformations of the ketones can be determined by a combination of computational modeling and, in some cases, structure determination by X-ray crystallography.

Acetal Substitution Reactions: Stereoelectronic Effects, Conformational Analysis, Reactivity vs Selectivity, and Neighboring-Group Participation

“…These Grignard reagents generally react with low diastereoselectivity with substrates that might be assumed to react either through a chelated transition state or one that might be considered to be a Felkin-Anh transition state. 131,132 At the same time, we showed that the assumption that chelation must correspond to acceleration of the…”

“…These Grignard reagents generally react with low diastereoselectivity with substrates that might be assumed to react either through a chelated transition state or one that might be considered to be a Felkin–Anh transition state. 131 132 At the same time, we showed that the assumption that chelation must correspond to acceleration of the rate 133 of a reaction is not strictly true. Reactions of alkoxy ketone 329 with LiAlH 4 , for example, did not occur with significant rate acceleration, but the major product was that expected from chelation control (Scheme 65 and Table 2 ).…”

“…122 Competition experiments showed that our hypothesis regarding the correlations between reactivity and selectivity in acetal substitution reactions is also true for reactions of carbonyl compounds. [126][127][128][129][130][131][132] Whereas alkyl and alkenyl Grignard reagents reacted with aldehydes more rapidly than with ketones, allylmagnesium halides did not differentiate between them (Scheme 63). 127 This lower chemoselectivity exhibited by allylmagnesium halides is consistent with the lower stereoselectivity observed when reacting them with -alkoxy ketones (Scheme 64).…”

Generation of Allylmagnesium Reagents by Hydromagnesiation of 2‐Aryl‐1,3‐dienes

“…[1] Non-substituted allylmagnesium halides I as well as those substituted with methyl groups such as crotylmagnesium halides II, methallylmagnesium halide III and prenylmagnesium halides IV are commercially available and their reactivities toward electrophiles have been examined in detail (Scheme 1A). [2] In the solution states, allylmagnesium species tend to adopt η 1 -allyl structures, in which a sterically less hindered η 1 -allyl structure is commonly predominant in unsymmetrical derivatives. [3] However, use of more complex allylmagnesium species in chemical synthesis has been elusive probably due to poor accessibility of the corresponding allyl halide precursors and their inefficient conversion to the allylmagnesium species via oxidative addition to magnesium metal.…”

“…Interestingly, when the reaction mixture was stirred at À 78 °C for 20 h, the product selectivity was switched to afford linear product 19 as the Scheme 2. Hydromagnesiation of 2-aryl-1,3-dienes and subsequent functionalization of the resulting allylmagnesium species with cyclohexanone (2). All the reactions were conducted using 0.5 mmol of 1,3dienes and isolated yields are reported.…”