The preparation of the first α-vinylidene-β-lactams

Buynak, John D.; Mathew, Jyothis; Rao, M. Narayana; Haley, Elizabeth; George, Christian; Siriwardane, Upali

doi:10.1039/c39870000735

Cited by 30 publications

(3 citation statements)

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“…Recently, allenamides have been suggested as bioisosteres of α,β-unsaturated amides for protein labeling purposes and inhibitor design. Although the reactivity of allenamides (general structure 8 , Figure ) toward thiols has been known for a long time, , Teck-Peng Loh and colleagues were the first to investigate these reagents for cysteine labeling applications . They found a high intrinsic reactivity toward the thiol(ate) of isolated cysteine as well as for terminal and internal cysteine residues in peptides and proteins at pH 8.…”

Section: Targeting the Cysteine Side Chainmentioning

confidence: 99%

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

2018

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Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheadsbeyond α,β-unsaturated amidesrecently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.

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Section: Targeting the Cysteine Side Chainmentioning

confidence: 99%

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

2018

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“…It is surprising, however, the former product has not yet been reported; the reaction between allenes and isocyanates leads to the 3-allylidene regioisomers only. 21,54,55 The solution to this problem was found in the mid-1990s by simulation of the reaction paths 30 which has shown the (chemically useful) allenes substituted by a p-donor substituent to follow the pathway favourable to the 3-methylene-b-lactams. In our study, the blactam (I) is more stable than its 3-methylene isomer (II) at each level of the theory used: by 5.7; 6.3 and 6.1 kcal mol À1 at the HF, DFT, and MP2 levels, respectively (Table 1, DG at normal conditions).…”

Section: Resultsmentioning

confidence: 99%

A theoretical study on the stability and spectra of cycloaddition products: Methylene-β-lactam isomers

Rode

Dobrowolski

Borowiak

et al. 2002

Phys. Chem. Chem. Phys.

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The theoretical thermodynamic stability was calculated for products of cycloaddition of vinylimine to ketene and isocyanic acid to allene by using the MP2, DFT(B3PW91), and HF methods involving the 6-311++G** basis set. These cycloaddition reactions could yield fourteen different molecules; practically however, free Gibbs energies calculated for the considered molecules suggest that only 4-and 3-methylene-b-lactams can be formed in observable amounts. For these particular isomers the heats of formation, geometry, rotational constants, harmonic vibrational frequencies, infrared intensities, Raman activities, depolarisation ratios, and 1 H, 13 C, 17 O and 15 N NMR spectra were evaluated and discussed. The PED analysis carried out for theoretical IR spectra allowed us to assign vibrations of the two isomers. The IR and NMR assignments form a basis for the elucidation of future experimental data.

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“…[47,48] However, we have recently carried out an experimental investigation on the reactivity of a new class of vinylketenes, the a-bromo-vinylketenes, with imines [49] and we have described successful synthetic routes toward a-bromo-substituted 4-alkyl-5,6-diyhdropyridin-2-ones. Halogen substituents [22,[50][51][52][53][54][55][56] dramatically affect the a-bromo-vinylketene reactivity in the cycloaddition to imines, promoting an unusual diene behaviour. A fine tuning of the substituents on both vinylketene and imine moieties allows us to selectively obtain [2 + 2] or [4 + 2] products (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

The Cycloaddition Reaction Between α‐Bromo Vinylketenes and Imines: A Combined Experimental and Theoretical Study

et al. 2008

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Abstract:The unusual behaviour of a-bromo vinylketenes in the cycloaddition reactions with imines is described. This class of vinylketenes behaves as dienophiles in [2 + 2] reactions, but also displays an unusual diene reactivity in [4 + 2] reactions. Interestingly, the reactivity of a-bromo vinylketenes can be modulated via a fine tuning of the substituents. For instance, a methyl group in the b-position completely inhibits the [2 + 2] reaction and the [4 + 2] pathway is almost exclusively followed. A more hindered ket-A C H T U N G T R E N N U N G imine (instead of a simple imine) is enough to activate again the [2 + 2] mechanism. We have carried out a DFT theoretical investigation to rationalise these experimental observations. We have considered two pathways for the [2 + 2] reaction involving imine, that is, the endo and exo pathways. The former is favoured in the case of a-bromo vinylketenes, while the latter is preferred for non-substituted vinylketenes. Since the [4 + 2] cycloaddition becomes possible only when the s-Z-conformation of vinylketene is significantly populated, the presence of bromine substituents in this substrate is crucial in determining the [2 + 2] or [4 + 2] mechanisms. For unsubstituted vinylketenes, the barrier connecting the s-E-to the s-Z-conformation is too high to be easily overcome. Thus, the s-Z-structure has a low population and the [2 + 2] mechanism is favoured. In the case of abromo vinylketenes (especially the b-methyl-substituted ones), this barrier can be surmounted and the [4 + 2] mechanism becomes available.

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The preparation of the first α-vinylidene-β-lactams

Abstract: The first examples of p-lactams having a fused exocyclic allene at the a-postion are reported and some of their chemistry is described.

Cited by 30 publications

References 1 publication

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

A theoretical study on the stability and spectra of cycloaddition products: Methylene-β-lactam isomers

The Cycloaddition Reaction Between α‐Bromo Vinylketenes and Imines: A Combined Experimental and Theoretical Study

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