Abstract
The scope and limitations of a tandem N-allylation/[2,3]-rearrangement protocol are investigated through the incorporation of a variety of functional groups within an allylic phosphate precursor. This method uses readily accessible N,N-dimethylglycine aryl esters and functionalized allylic phosphates, forming quaternary ammonium salts in situ in the presence of a palladium catalyst. Subsequent enantioselective [2,3]-sigmatropic rearrangement, promoted by the chiral isothiourea tetramisole, generates α-amino acid derivatives with two contiguous stereocenters. The incorporation of electron-withdrawing ester and amide groups gave the best results, furnishing the desired products in moderate to good yields (29–70%), with low diastereocontrol (typically 60:40 dr) but high enantioselectivity (up to 90:10 er). These results indicate that substrate–catalyst interactions in the proposed transition state are sensitive to the substitution pattern of the substrates.
Highlights
Enantioenriched α-amino acids are an important class of compounds, used in pharmaceuticals [1], as chiral building blocks in peptide chemistry [2] and total synthesis [3], and as chiral ligands and organocatalysts [4]
InInthis manuscript, we demonstrate the feasibility of incorporating varying substituents withinin a related dual catalytic system, employing chiral isothiourea and palladium catalysis in the the allylic phosphate, leading to the desired α-amino acid derivatives following N-allylationdirect and α-allylation of aryl acetic esters
The corresponding allylic observed syn-selectivity (Figure 1d, left). In recent work both by ourselves and Shiina and co-workers phosphates 14–17 and N,N-dimethyl 4-nitrophenyl ester hydrochloride salt 13 were subjected to relay catalysis conditions established in the previous work, using FurCat 3 (5 mol%) as a stable palladium catalyst precursor, (±)-BTM 5 as Lewis base catalyst and iPr2NH as base in MeCN at room concerning the isothiourea-catalyzed kinetic resolution of secondary and tertiary alcohols, a carbonyl group had been identified as a viable partner for a stabilizing C=Oisothiouronium interaction, which is primarily electrostatic in nature [15,16,17], leading to the postulate that this unit could be incorporated within the allylic fragment in this N-allylation/[2,3]-rearrangement protocol
Summary
Enantioenriched α-amino acids are an important class of compounds, used in pharmaceuticals [1], as chiral building blocks in peptide chemistry [2] and total synthesis [3], and as chiral ligands and organocatalysts [4]. In recent work both by ourselves and Shiina and co-workers phosphates 14–17 and N,N-dimethyl 4-nitrophenyl ester hydrochloride salt 13 were subjected to relay catalysis conditions established in the previous work, using FurCat 3 (5 mol%) as a stable palladium catalyst precursor, (±)-BTM 5 as Lewis base catalyst and iPr2NH as base in MeCN at room concerning the isothiourea-catalyzed kinetic resolution of secondary and tertiary alcohols, a carbonyl group had been identified as a viable partner for a stabilizing C=Oisothiouronium interaction, which is primarily electrostatic in nature [15,16,17], leading to the postulate that this unit could be incorporated within the allylic fragment in this N-allylation/[2,3]-rearrangement protocol Without such stabilizing interactions, [2,3]-rearrangements are proposed to proceed preferentially through an exo transition state, yielding the corresponding anti-products (Figure 1d, right). The stereochemical outcome of the rearrangement shows great sensitivity regarding the nature of the substituent within the allylic fragment
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