Synthesis of α-amino esters by dynamic kinetic resolution of α-haloacyl imidazolidinones

Caddick, Stephen; Afonso, Carlos A. M.; Candeias, Sara X.; Hitchcock, Peter B.; Jenkins, Kerry; Murtagh, Lorraine; Pardoe, D; Santos, A. Gil; Treweeke, Nigel R.; Weaving, Robert

doi:10.1016/s0040-4020(01)00550-6

Cited by 39 publications

(15 citation statements)

References 30 publications

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“…The resulting enantiomeric mixture was analysed by chiral-phase HPLC and was compared with a sample of the same compound, prepared by using substrate 7, following the literature procedure. [41] We determined that the major product obtained in our reaction is, as expected, (R)-methyl 2-(benzylamino)-propionate. All these results clearly show that there is a very high difference in reactivity between both epimers, which are in accordance with the molecular modelling predictions.…”

Section: Experimental Discussionsupporting

confidence: 69%

“…Theoretical studies: In our previous paper [19] we proposed a reaction mechanism for Caddicks system [32,41] based on calculated transition states at HF/3-21G*. The results were enthalpic values (DH), calculated by subtracting the enthalpy of the amine complex from that of the transition state ( Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…Under the same DKR conditions described before for substrate 6, using Bu 4 NBr, we were pleased to observe that the substitution occurs quantitatively and in a very high diastereoselectivity (entry 1, de 99 %). These results have to be compared with the ones obtained for substrate 6 under identical experimental conditions (de 58 %) [41] and also with the one for substrate 3 (de 88 %). [36] In case of BuNI the yield is also high and, more important, we were unable to detect by HPLC the minor epimer of 44 (entry 2) while in case of substrate 6 moderate diastereoselectivity was observed (de 74 %).…”

Section: Experimental Discussionmentioning

confidence: 97%

“…[36] In case of BuNI the yield is also high and, more important, we were unable to detect by HPLC the minor epimer of 44 (entry 2) while in case of substrate 6 moderate diastereoselectivity was observed (de 74 %). [41] In order to afford enough quantity of the minor epimer of 44 for characterization purposes and HPLC standard, the reaction was performed in the presence of AgNO 3 giving 44 and the corresponding epimer as the minor product but in lower stereocontrol (de 56 %, entry 3). To determine the absolute configuration of product 44, we prepared the corresponding methyl ester, by removing the chiral auxiliary via methanolysis.…”

Section: Experimental Discussionmentioning

confidence: 99%

“…A second amine would make another hydrogen bond, directing the attack through the less hindered face. [32] Our involvement in Caddicks work brought us to another proposal [19,41] where an interaction between the leaving group (bromide) and the aromatic ring in the auxiliary moiety ( Figure 2) can explain all the experimental observations; this would avoid the need for the formation of a rather unlikely complex as that in Scheme 4.…”

Section: Introductionmentioning

confidence: 98%

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New Chiral Auxiliaries for Dynamic Kinetic Resolution: From Theory to Experiment

Santos¹,

Pereira²,

Afonso³

et al. 2004

Chemistry A European J

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New efficient chiral auxiliaries for dynamic kinetic resolution (DKR) of bromides into amines are proposed, based on a theoretical rationalisation of known literature results. One example was synthesized and tested, affording diastereoselectivities up to 100%. Several results of DKR reactions are known, based on oxazolidinone or imidazolidinone units as chiral auxiliaries. Nevertheless, their behaviour was not fully understood until a recent paper that we published. We now used our proposed mechanism to rationalize the behaviour of other similar chiral auxiliaries and to propose small structure changes in imidazolidinone rings which could largely improve their performance. We could show that the good performance of these molecules as chiral auxiliaries for DKR reactions where bromine is the leaving group and a primary or secondary amine is the nucleophile is due, in a first step, to the formation of a hydrogen bond between the amine and the ring carbonyl oxygen and, in a second step, to the strong electrostatic interaction between the leaving bromide and the carbonyl oxygen in the C-3 substituent. Considering the behaviour of this substituent which rotates to minimize the electrostatic repulsion with the bromide when reaching the transition state, we proposed the introduction of a second substituent in the C-4 position of the imidazolidinone ring, which prevents such rotation, thus increasing the energy difference between the transition states of the two distereoisomers. With such an auxiliary we were able to increase the best de known in literature (88%), when benzylamine is used as nucleophile, to 99, or even 100%, when iodide replaces the bromide in the substrate.

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Section: Experimental Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Experimental Discussionmentioning

confidence: 97%

Section: Experimental Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

New Chiral Auxiliaries for Dynamic Kinetic Resolution: From Theory to Experiment

Santos¹,

Pereira²,

Afonso³

et al. 2004

Chemistry A European J

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Acid–Base Properties of Enols and Enolates

2010

Patai's Chemistry of Functional Groups

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An Alternative Mechanism for Diels–Alder Reactions of Evans Auxiliary Derivatives

Bakalova¹,

Duarte²,

Georgieva³

et al. 2009

Chemistry A European J

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The mechanism proposed by Evans for the dialkylaluminum chloride promoted Diels-Alder reaction of cyclopentadiene with alpha,beta-unsaturated N-acyloxazolidinones has been widely used as a basis for the rationalization of the experimental selectivities observed in many different types of reactions in which oxazolidinones or imidazolidinones are used as chiral auxiliaries. In this manuscript we introduce a new and more general model based on molecular modeling and NMR spectroscopy data that avoids several ambiguous concepts raised by the Evans model and fully explains all available experimental data. While the Evans proposal relies on the formation of high-energetic ionic chelates that promote the rotation of the amide bond in the N-acyloxazolidinone molecule, our model is based on the catalysis by means of low-energetic mono- or bicomplexes at the chain and the ring carbonyl groups that are easily observed by NMR spectroscopy measurements. The observed selectivities are explained by a chirality-transfer concept, in which an achiral Lewis acid works as a bridge for the transfer of chirality between a chiral auxiliary and a prochiral reactive center. Different to the Evans proposal, this mechanism fully explains the experimental selectivities for low Lewis acid concentrations, based on the catalysis by means of concurrent monocomplexes at the chain or the ring carbonyl groups, as well as the increased reaction rates and selectivities experimentally observed for high Lewis acid concentrations. The model can be extrapolated to nonchelating and other chelating Lewis acids, thereby allowing for the rationalization of much experimental data that were never explained by the Evans proposal.

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Synthesis of α-amino esters by dynamic kinetic resolution of α-haloacyl imidazolidinones

Cited by 39 publications

References 30 publications

New Chiral Auxiliaries for Dynamic Kinetic Resolution: From Theory to Experiment

New Chiral Auxiliaries for Dynamic Kinetic Resolution: From Theory to Experiment

Acid–Base Properties of Enols and Enolates

An Alternative Mechanism for Diels–Alder Reactions of Evans Auxiliary Derivatives

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