ChemInform Abstract: DIRECTED CHIRAL SYNTHESIS BY WAY OF α‐CHLORO BORONIC ESTERS

Matteson, Donald S.; Ray, Rahul; Rocks, Richard R.; Tsai, David J. S.

doi:10.1002/chin.198406217

Cited by 6 publications

(7 citation statements)

References 1 publication

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“…Chloro-containing alkyl-substituted internal enol ester underwent the desired hydroalkylation reaction to give 6n in 68% yield with 94% ee. The absolute configuration of the chiral ester was confirmed to be R by comparison to literature [53][54][55] . Furthermore, literature procedures proved unprotected chiral aliphatic amines and alcohols could be obtained via hydrolysis without erosion of enantioselectivities 53,54 , which further enhanced the synthetic utility of this method.…”

Section: Resultsmentioning

confidence: 66%

Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

Wang

Zhang

et al. 2021

Nat Commun

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Chiral aliphatic amine and alcohol derivatives are ubiquitous in pharmaceuticals, pesticides, natural products and fine chemicals, yet difficult to access due to the challenge to differentiate between the spatially and electronically similar alkyl groups. Herein, we report a nickel-catalyzed enantioselective hydroalkylation of acyl enamines and enol esters with alkyl halides to afford enantioenriched α-branched aliphatic acyl amines and esters in good yields with excellent levels of enantioselectivity. The operationally simple protocol provides a straightforward access to chiral secondary alkyl-substituted amine and secondary alkyl-substituted alcohol derivatives from simple starting materials with great functional group tolerance.

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Section: Resultsmentioning

confidence: 66%

Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

Wang

Zhang

et al. 2021

Nat Commun

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“…>98%, 96%). 18 − 22 Treatment with lithium bis(trimethylsilyl)amide, performed at −100 °C to minimize elimination reaction, produced the intermediate 4 (80%) with clean inversion of the configuration. This latter compound was then deprotected at nitrogen with a stoichiometric amount of methanol and coupled with thiophenacetyl chloride to afford compound 5 (62%).…”

Section: Methodsmentioning

confidence: 99%

Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii

et al. 2014

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β-Lactam resistance in Acinetobacter baumannii presents one of the greatest challenges to contemporary antimicrobial chemotherapy. Much of this resistance to cephalosporins derives from the expression of the class C β-lactamase enzymes, known as Acinetobacter-derived cephalosporinases (ADCs). Currently, β-lactamase inhibitors are structurally similar to β-lactam substrates and are not effective inactivators of this class C cephalosporinase. Herein, two boronic acid transition state inhibitors (BATSIs S02030 and SM23) that are chemically distinct from β-lactams were designed and tested for inhibition of ADC enzymes. BATSIs SM23 and S02030 bind with high affinity to ADC-7, a chromosomal cephalosporinase from Acinetobacter baumannii (Ki = 21.1 ± 1.9 nM and 44.5 ± 2.2 nM, respectively). The X-ray crystal structures of ADC-7 were determined in both the apo form (1.73 Å resolution) and in complex with S02030 (2.0 Å resolution). In the complex, S02030 makes several canonical interactions: the O1 oxygen of S02030 is bound in the oxyanion hole, and the R1 amide group makes key interactions with conserved residues Asn152 and Gln120. In addition, the carboxylate group of the inhibitor is meant to mimic the C3/C4 carboxylate found in β-lactams. The C3/C4 carboxylate recognition site in class C enzymes is comprised of Asn346 and Arg349 (AmpC numbering), and these residues are conserved in ADC-7. Interestingly, in the ADC-7/S02030 complex, the inhibitor carboxylate group is observed to interact with Arg340, a residue that distinguishes ADC-7 from the related class C enzyme AmpC. A thermodynamic analysis suggests that ΔH driven compounds may be optimized to generate new lead agents. The ADC-7/BATSI complex provides insight into recognition of non-β-lactam inhibitors by ADC enzymes and offers a starting point for the structure-based optimization of this class of novel β-lactamase inhibitors against a key resistance target.

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“…We then moved our attention to automating the Matteson homologation, a reaction which allows the insertion of a methylene unit to the carbon chain of a boronic ester. [18][19][20][21] Using phenethyl boronic acid pinacol ester (1) as the model substrate, the Matteson homologation using chloromethyllithium was targeted (Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

Automated Stereocontrolled Assembly-Line Synthesis of Organic Molecules

Fasano

Mykura

Fordham

et al. 2022

Preprint

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Automation has fuelled dramatic advances in fields such as proteomics and genomics (e.g., in preparation of proteins and nucleic acids),1,2 enabling non-experts to prepare, test and analyse complex biological molecules. However, the field of automated organic synthesis lags far behind, partly because of the complexity and variety of organic molecules. As a result, only a handful of relatively simple organic molecules, requiring a small number of synthetic steps, have been made in an automated fashion. Herein, we report an automated assembly-line synthesis that allows iterative, stereocontrolled formation of C(sp3)–C(sp3) bonds with high stereochemical fidelity and reproducibility, enabling access to complex organic molecules even by non-synthesis experts. This was achieved on a commercially available robotic platform capable of handling air sensitive reactants and performing low temperature reactions, which enabled six sequenced one-carbon homologations of organoboron substrates to be performed iteratively without human intervention. Together with other automated functional group manipulations, this methodology has been exploited to rapidly build the core fragment of the natural product (+)-kalkitoxin, thus leading the way towards automated organic synthesis.

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ChemInform Abstract: DIRECTED CHIRAL SYNTHESIS BY WAY OF α‐CHLORO BORONIC ESTERS

Abstract: Die Homologisierung der (+)‐Pinandiolboronsäureester (I) mit Dichlormethyl‐Li führt über die intermediären Borat‐Komplexe (II) zu den αS‐α‐Chlorboronsäureestern (III) mit einer diastereomeren Reinheit von 74‐98%.

Cited by 6 publications

References 1 publication

Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii

Automated Stereocontrolled Assembly-Line Synthesis of Organic Molecules

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