An approach to new chiral bicyclic imines and amines <i>via</i> Horner–Wadsworth–Emmons reaction

Iwanejko, Jakub; Sowiński, Mateusz; Wojaczyńska, Elżbieta; Olszewski, Tomasz K.; Górecki, Marcin

doi:10.1039/d0ra02646h

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…To ensure that the obtained results are comparable, we also simulated the electronic and vibrational CD spectra at different levels of approximation; however, for the discussion here, we selected only the ones that demonstrate the best fit with the experimental spectra, i.e., obtained at the ωB97X-D/6–311+G(d,p) level of theory with the PCM solvent model. Additional motivation for using this approximation level was prior identification of its effectiveness and accuracy in reproducing chiroptical spectral features of various organic molecules of synthetic and natural origin [ 26 , 39 , 40 , 41 , 42 , 43 , 44 ]. In our previous work on β-lactams, we also showed that using the PCM solvent model significantly impacted the assignments’ credibility [ 22 , 31 , 33 , 45 , 46 , 47 ].…”

Section: Resultsmentioning

confidence: 99%

A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases

Górecki

Frelek

2021

IJMS

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This paper’s main objective is to show that many different factors must be considered when solving stereochemical problems to avoid misleading conclusions and obtain conclusive results from the analysis of spectroscopic properties. Particularly in determining the absolute configuration, the use of chiroptical methods is crucial, especially when other techniques, including X-ray crystallography, fail, are not applicable, or give inconclusive results. Based on various β-lactam derivatives as models, we show how to reliably determine their absolute configuration (AC) and preferred conformation from circular dichroism (CD) spectra. Comprehensive CD analysis, employing both approaches, i.e., traditional with their sector and helicity rules, and state-of-the-art supported by quantum chemistry (QC) calculations along with solvation models for both electronic (ECD) and vibrational (VCD) circular dichroism ranges, allows confident defining stereochemistry of the b-lactams studied. Based on an in-depth analysis of the results, we have shown that choosing a proper chiroptical method/s strictly depends on the specific case and certain structural features.

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Section: Resultsmentioning

confidence: 99%

A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases

Górecki

Frelek

2021

IJMS

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“…We next examined the bases used in the Horner–Wadsworth–Emmons reaction (Table ). Sodium hydride used in the preliminary manufacturing route gave a good yield (entry 1), but it is not applicable for large-scale production due to safety concerns.…”

Section: Resultsmentioning

confidence: 99%

Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

Matsuura

Sato

Nishino

et al. 2020

Org. Process Res. Dev.

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We describe the development of a one-pot preparation process of (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (3), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide (LDA), formylation using N-formylmorpholine, followed by olefination employing the Horner−Wadsworth−Emmons reaction with triethyl 2-phosphonopropionate. This method enabled kilogram-scale manufacturing of carboxylic acid 3, a key intermediate of lusutrombopag with high purity, together with a reduced number of steps, improvement of yield, and avoidance of a cumbersome procedure for isolation of the intermediate.

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“…In addition, the use of bicyclic iminium salts has been reported for the asymmetric preparation of cyclic α-aminophosphonates 90 ( Scheme 17 ). Chiral cyclic imines 89 are synthesized from diamine 88 and ketoesters and their subsequent treatment in toluene with dialkyl phosphites gives tetrasubstituted α-aminophosphonates 90 in high yields and diastereoselectivities (78–95%, 68:32–98:2 dr) [ 51 , 52 ] . However, if imines 89 are activated with bromotrimethylsilane, they are supposed to form an iminium ion, which is reactive towards tris(trimethylsilyl) phosphite and then, α-aminophosphonic acid derivatives 91 can be obtained in high yields and diastereoselectivities (70–99%, 85:15–98:2 dr) [ 51 ].…”

Section: Diastereoselective Synthesis Of Tetrasubstituted α-Aminophosphonic Acid Derivativesmentioning

confidence: 99%

Asymmetric Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives

et al. 2021

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Due to their structural similarity with natural α-amino acids, α-aminophosphonic acid derivatives are known biologically active molecules. In view of the relevance of tetrasubstituted carbons in nature and medicine and the strong dependence of the biological activity of chiral molecules into their absolute configuration, the synthesis of α-aminophosphonates bearing tetrasubstituted carbons in an asymmetric fashion has grown in interest in the past few decades. In the following lines, the existing literatures for the synthesis of optically active tetrasubstituted α-aminophosphonates are summarized, comprising diastereoselective and enantioselective approaches.

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An approach to new chiral bicyclic imines and amines via Horner–Wadsworth–Emmons reaction

Abstract: New chiral cyclic imines and enamines were prepared via HWE reaction, with selectivity dependent on the carbonyl substrate.

Cited by 8 publications

References 35 publications

A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases

A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases

Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction

Asymmetric Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives

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