Tandem Palladium and Isothiourea Relay Catalysis: Enantioselective Synthesis of α-Amino Acid Derivatives via Allylic Amination and [2,3]-Sigmatropic Rearrangement.

Stéphanie S M Spoehrle,Andrew D Smith,James E Taylor,Alexandra M Z Slawin,Thomas H West

doi:10.1021/jacs.7b05619

Stéphanie S M Spoehrle, Andrew D Smith + Show 3 more

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https://doi.org/10.1021/jacs.7b05619

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Abstract

A tandem relay catalytic protocol using both Pd and isothiourea catalysis has been developed for the enantioselective synthesis of α-amino acid derivatives containing two stereogenic centers from readily accessible N,N-disubstituted glycine aryl esters and allylic phosphates. The optimized process uses a bench-stable succinimide-based Pd precatalyst (FurCat) to promote Pd-catalyzed allylic ammonium salt generation from the allylic phosphate and the glycine aryl ester. Subsequent in situ enantioselective [2,3]-sigmatropic rearrangement catalyzed by the isothiourea benzotetramisole forms syn-α-amino acid derivatives with high diastereo- and enantioselectivity. This methodology is most effective using 4-nitrophenylglycine esters and tolerates a variety of substituted cinnamic and styrenyl allylic ethyl phosphates. The use of challenging unsymmetrical N-allyl-N-methylglycine esters is also tolerated under the catalytic relay conditions without compromising stereoselectivity.

Highlights

The functionalization of α-amino acids through enantioselective α-alkylation is an enduring challenge in synthetic chemistry.1 For example, the direct stereoselective transitionmetal-catalyzed α-alkylation of amino acid ester derivatives through allylic substitution has received considerable attention.2 In such processes, the use of palladium-based catalysts typically results in formation of the linear substitution product,3,4 whereas catalysts based on either molybdenum,5 ruthenium,6 rhodium,7 or iridium8 can be branched selective (Scheme 1a)
In 2014, we reported the first catalytic enantioselective [2,3]-rearrangement of allylic quaternary ammonium salts 5 using the isothiourea BTM 1 as a Lewis base and cocatalytic hydroxybenzotriazole (HOBt) to form syn-α-amino acid derivatives 6 with excellent stereoselectivity (Scheme 2b)
We hypothesized that the counterion generated from Pd-promoted allylic ammonium salt formation could play a key role in this area

Summary

INTRODUCTION

The functionalization of α-amino acids through enantioselective α-alkylation is an enduring challenge in synthetic chemistry. For example, the direct stereoselective transitionmetal-catalyzed α-alkylation of amino acid ester derivatives through allylic substitution has received considerable attention. In such processes, the use of palladium-based catalysts typically results in formation of the linear substitution product, whereas catalysts based on either molybdenum, ruthenium, rhodium, or iridium can be branched selective (Scheme 1a). In 2014, we reported the first catalytic enantioselective [2,3]-rearrangement of allylic quaternary ammonium salts 5 using the isothiourea BTM 1 as a Lewis base and cocatalytic hydroxybenzotriazole (HOBt) to form syn-α-amino acid derivatives 6 with excellent stereoselectivity (Scheme 2b).17 In this process the HOBt additive (i) aids catalyst turnover through interception of a post-[2,3]-rearrangement acylammonium species and (ii) leads to increased diastereoand enantioselectivity of the [2,3]-rearrangement products.. Building upon the precedent of Tambar, we questioned the feasibility of merging a Pd-catalyzed allylic amination with an enantioselective isothiourea-catalyzed [2,3]-rearrangement (Scheme 2c) Such a process would allow for the rapid generation of complex enantiomerically enriched α-amino acids 7 bearing two new stereocenters from readily available allylic alcohol derivatives and glycine esters, avoiding the problematic isolation of ammonium salts. The inherent substrate bias for [2,3]-rearrangement under the basic Pd-

RESULTS AND DISCUSSION

CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES