Diastereoselective Alkylation of β-Amino Esters:  Structural and Rate Studies Reveal Alkylations of Hexameric Lithium Enolates

McNeil, Anne J.; Toombes, Gilman E. S.; Grüner, Sol M.; Lobkovsky, Emil; Collum, David B.; Chandramouli, Sithamalli V.; Vanasse, Benoit; Ayers, Timothy A.

doi:10.1021/ja045144i

Cited by 51 publications

(56 citation statements)

References 52 publications

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“…Product 13 was prepared following the procedure reported in Reference [32]. Product 14 was prepared following the procedure reported in Reference [33]. Product 15 is known.…”

Section: Chemical Synthesismentioning

confidence: 99%

Azetidinones as Zinc‐Binding Groups to Design Selective HDAC8 Inhibitors

et al. 2009

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2-Azetidinones, commonly known as beta-lactams, are well-known heterocyclic compounds. Herein we described the synthesis and biological evaluation of a series of novel beta-lactams. In vitro inhibition assays against HDAC isoforms showed an interesting isoform-selectivity of these compounds towards HDAC6 and HDAC8. The isoform selectivity changed in response to modification of the azetidinone-ring nitrogen atom substituent. The presence of an N-thiomethyl group is a prerequisite for the activity of these compounds in the micromolar range towards HDAC8.

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“…Product 13 was prepared following the procedure reported in Reference [32]. Product 14 was prepared following the procedure reported in Reference [33]. Product 15 is known.…”

Section: Chemical Synthesismentioning

confidence: 99%

Azetidinones as Zinc‐Binding Groups to Design Selective HDAC8 Inhibitors

et al. 2009

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“…Differences in the aggregation states of lithium enolates may also account for the observed differences in both the 7 Li NMR spectra and the differential reactivity. 13 To the best of our knowledge, these studies in the blebbistatin system are the first time that the enolate of a quinolone system, which can potentially have the lithium atom coordinated to the oxygen or the nitrogen in the transition state for hydroxylation, has been used in the Davis reaction. Our results suggest that this may prove an interesting system for more detailed study including computational analysis.…”

Section: (S)-(-)-blebbistatin (1) Analogue Synthesismentioning

confidence: 99%

“…Purification by flash column chromatography on silica gel eluting with (50-100% ethyl acetate-PE 40-60) gave the desired compound. Methyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-one (15) 13 Methyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-one (16 …”

Section: General Procedures For the Synthesis Of Quinolones 13 15-17mentioning

confidence: 99%

The small molecule tool (S)-(−)-blebbistatin: novel insights of relevance to myosin inhibitor design

et al. 2008

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The small molecule blebbistatin is now a front line tool in the study of myosin function. Chemical modification of the tricyclic core of blebbistatin could deliver the next generation of myosin inhibitors and to help address this we report here on the impact of structural changes in the methyl-substituted aromatic ring of blebbistatin on its biological activity. Chemical methods for the preparation of isomeric methyl-containing analogues are reported and a series of co-crystal structures are used to rationalise the observed variations in their biological activity. These studies further support the view that the previously identified binding mode of blebbistatin to Dictyostelium discoideum myosin II is of relevance to its mode of action. A discussion of the role that these observations have on planning the synthesis of focused libraries of blebbistatin analogues is also provided including an assessment of possibilities by computational methods. These studies are ultimately directed at the development of novel myosin inhibitors with improved affinity and different selectivity profiles from blebbistatin itself.

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“…A key step in the preparative scale synthesis involves an enolization/alkylation sequence wherein the use of an unprotected amino group provides intermediate 22 with a high level of diastereoselectivity (17:1). Rate studies along with x-ray crystal structure and x-ray powder diffraction data by Collum et al [11] suggest that enolate alkylation occurs directly from the hexamer with participation by THF. An x-ray crystal structure of otamixaban 3 with fXa is illustrated in Fig.…”

Section: Structure-activity Relationship Studies On -Aminoestersmentioning

confidence: 99%

The Discovery of the Factor Xa Inhibitor Otamixaban: From Lead Identification to Clinical Development

Guertin¹,

Choi²

2007

CMC

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Factor Xa (fXa) is a critical serine protease situated at the confluence of the intrinsic and extrinsic pathways of the blood coagulation cascade. FXa catalyses the conversion of prothrombin to thrombin via the prothrombinase complex. Its singular role in thrombin generation, coupled with its potentiating effects on clot formation render it an attractive target for therapeutic intervention. Otamixaban is a synthetically derived parenteral fXa inhibitor currently in late stage clinical development at Sanofi-Aventis for the management of acute coronary syndrome. Otamixaban is a potent (Ki = 0.5 nM), selective, rapid acting, competitive and reversible fXa inhibitor that effectively inhibits both free and prothrombinase-bound fXa. In vivo experiments have demonstrated that Otamixaban is highly efficacious in rodent, canine and porcine models of thrombosis. In addition, recent clinical findings indicate that Otamixaban is efficacious, safe and well tolerated in humans and therefore has considerable potential for the treatment of acute coronary syndrome. This review article chronicles the discovery and pre-clinical data surrounding the fXa inhibitor Otamixaban as well as the recent clinical findings in humans.

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Diastereoselective Alkylation of β-Amino Esters: Structural and Rate Studies Reveal Alkylations of Hexameric Lithium Enolates

Cited by 51 publications

References 52 publications

Azetidinones as Zinc‐Binding Groups to Design Selective HDAC8 Inhibitors

Azetidinones as Zinc‐Binding Groups to Design Selective HDAC8 Inhibitors

The small molecule tool (S)-(−)-blebbistatin: novel insights of relevance to myosin inhibitor design

The Discovery of the Factor Xa Inhibitor Otamixaban: From Lead Identification to Clinical Development

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