Stereodefined trisubstituted enolates as a unique entry to all-carbon quaternary stereogenic centers in acyclic systems

Abstract

This protocol describes a new approach for the preparation of stereodefined trisubstituted chiral enolate species, avoiding conventional asymmetric enolization of carbonyl compounds. This protocol was developed as a single-flask synthetic sequence and therefore does not require isolation or purification of intermediate compounds. The sequence starts from a regioselective carbocupration reaction of readily accessible chiral ynamides; this is followed by oxidation of the generated vinylcuprate with a commonly available oxidizing reagent (tert-butyl hydroperoxide) in order to generate an enolate that completely retains its configuration. This synthetic protocol has been applied to the preparation of aldol and Mannich-type adducts. The procedure reported here requires a simple reaction setup commonly available in all synthetic laboratories and takes ∼6 h for completion and 2 h for isolation and purification. Final products are valuable diastereomerically and enantiomerically enriched building blocks for organic synthesis containing all-carbon quaternary stereocenters in acyclic systems.

Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres

“…65 In subsequent experiments, it was found that these trisubstituted stereodefined enolates could react with N-sulfonyl imines to generate Mannich-type adducts with similar diastereomeric ratios and isolated yields (Scheme 28). 65,76 The absolute configuration of the Mannich adducts was determined by X-ray crystallographic analysis and was consistent with a Zimmerman-Traxler transition state 79 with approach of the electrophilic imine from the stereoface opposite of the benzyl group of oxazolidinone. However, in this case the barrier of planar E to Z inversion of N-sulphonyl imines is low, 81 and steric factors most probably account for the favorable formation of the Z-isomer (the E-isomer of N-sulphonyl imine would generate 1,4-diaxial steric interactions with the chiral unit) in the sixmembered transition state (Scheme 28).…”

“…65 Despite this reaction provided the expected enolate intermediate in an efficient manner, a simple modification of the carbocupration step using Gilman-type organocuprates 74,75 R 2 CuLiÁLiX instead of organocopper reagents RCuÁMX n allowed the authors to perform the direct and selective oxidation by commercially available t-BuOOH (Scheme 25). 65,76 Thus, it was Scheme 24 Stereoselective construction of the quaternary stereocentre of (R)-puraquinonic acid using Gleason auxiliary. found that the oxidation reaction proceeds with a complete retention of configuration initially obtained during the carbocupration reaction, as determined by X-ray crystallographic analysis of the stereochemistry of the silylenol ether obtained by reaction of the copper enolate with triethylchlorosilane.…”

Enantioselective allylic alkylation of stereodefined polysubstituted copper enolates as an entry to acyclic quaternary carbon stereocentres

“…5 This approach was proven to be synthetically useful as it was successfully applied to the preparation of aldol and Mannich-type products in good overall yields and excellent diastereoselectivities (Scheme 1, path a). 6 Alternatively, the aldol reaction with aliphatic aldehydes could be subsequently achieved by using stereodefined disubstituted silyl ketene aminals through the Mukaiyama aldol reaction (Scheme 1, path b). 7 More recent studies have also shown that the preparation of stereochemically defined acyclic fully substituted enolates of ketones is now also possible from simple vinyl carbamates, and this has been successfully used in aldol and Mannich-type transformations (Scheme 1, path c).…”

Stereoselective Formation of Fully Substituted Ketone Enolates

“…Thesimple deprotonation of allylic alcohol 4a,possessing two identical substituents on the alkenyl group (R 1 = R 2 = Me, Scheme 3), with n-BuLi in THF induced, by raising the temperature of the reaction mixture from À30 to 0 8 8C, the migration of the carbamoyl group to generate in situ and quantitatively the enolate 1a.A ddition of tosyl imine gave the Mannich-type adduct 5a in 60 %y ield with a1 -4 diastereomeric ratio of 9:1, representing the diastereofacial choice in the Mannich reaction. [11,24] When the nature of the two alkyl groups is different (E4b,R 1 = Me,R 2 = Et, Scheme 3), the combined carbamoyl Scheme 2. Proposed strategy.…”

“…[11,12] Despite all these efforts,t he stereoselective formation of a,a-disubstituted enolate of ketones is still very challenging and remains in its complete infancy, as the regioselectivity and the E/Zselectivity of the enolization need to be concomitantly controlled (Scheme 1, Path A).…”