Facial-Selective Allylation of Methyl Ketones for the Asymmetric Synthesis ofα-Substituted Tertiary Homoallylic Ethers

Abstract

The asymmetric synthesis of enantiomerically pure a-substituted tertiary homoallylic ethers 4a, 11 and 12a-c by the allylation of ethyl methyl ketone (la) with gamma-substituted allylsilanes 9a-h is described. The allylsilanes were obtained by a nickel-catalysed Grignard cross-coupling reaction of (E)- and (Z)-(3-iodoallyl)trimethylsilane with various Grignard reagents. The reaction of the allylsilanes with la in the presence of the trimethylsilyl ether of N-trifluoroacetylnorpseudoephedrine (3), and catalytic amounts of a mixture of trimethylsilyl triflate and trifluoromethanesulfonic acid led to the homoallylic ethers 4a, 11 and 12a-c with two new stereogenic centres, with a selectivity of 1:9 to >20:1 for the homoallylic and of 1:99 to >60:1 for the allylic centre. The facial selectivity does not depend on the configuration of the allylsilane, and in all reactions the anti product is preferentially formed. Interestingly, a pronounced switch of facial selectivity takes place with increasing length of the alkyl group of the allylsilane.

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“…Experimental elucidation of the minor isomer stereochemistry : To assess the validity of the computational results, the predicted and observed ratios of both the main and minor isomer must be compared. In the original publication, only the major isomer stereochemistry was determined by X‐ray crystallography, while the minor isomer was argued to be the second anti isomer by analogy reasoning 6. Computational results for the crotylation with ( E )‐ 2 b however predict the minor isomer to be ( RR )‐ 4 b and not the originally published ( RS )‐ 4 b , while the main isomer is correctly predicted to have ( SR )‐configuration.…”

“…We have expanded the scope of the reaction by employing both E ‐ and Z ‐configured γ‐substituted allyl silanes ( 2 b – e ) (Table 1, entries 2–9) 6. In each case, only two out of the four possible isomers of 4 b – e are formed (in the following, termed major and minor isomer).…”

Origin of Syn/Anti Diastereoselectivity in Aldehyde and Ketone Crotylation Reactions: A Combined Theoretical and Experimental Study

“…When the enantiopure chiral norpseudoephedrine-derived silyl ether 7 is used, very high induced diastereoselectivities (up to >99:1) could be obtained for a number of aliphatic aldehydes and ketones. , For ketone allylation, Me 3 SiOTf has to be replaced by trifluoromethanesulfonic acid (TfOH) to initiate the reaction.…”

Diastereoselective Additions of Nucleophiles to α-Acetoxy Ethers Using the α-(Trimethylsilyl)benzyl Auxiliary

“…Oxocarbenium ions are important intermediates in various reactions, including Prins cyclizations, cation−olefin cyclizations, and addition reactions. Efforts to impart high diastereofacial control in these reactions have led to the development of a number of chiral auxiliaries . We recently reported the synthesis of a new oxocarbenium ion chiral auxiliary, α-(trimethylsilyl)benzyl alcohol ( 4 ) .…”

“…This auxiliary offers several desirable features, including facile preparation of both enantiomers, high diastereofacial selectivity in addition reactions, and direct deprotection or conversion to a benzyl ether. In a preliminary demonstration of the auxiliary's utility, we found that allylations of auxiliary-based oxocarbenium ions, generated in situ according to Marko's protocol, proceeded with high diastereoselectivity (Scheme ). 1h, The facial selectivity could be rationalized by Linderman's model, in which α-silyl oxocarbenium ions adopt a rigid conformation due to a stereoelectronic effect similar to the β-silyl effect . While Marko's procedure is operationally convenient, it is limited to nucleophiles with reactivity sufficiently low to permit the formation of oxocarbenium ions in situ.…”