Recent encounters with atropisomerism in drug discovery

Glunz, Peter W.

doi:10.1016/j.bmcl.2017.11.050

Cited by 195 publications

(92 citation statements)

References 57 publications

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“…Pleasingly,aniline-based lactam 11 u was formed in quantitative yield;p resumably,t his system did not suffer from competing intermolecular reaction in view of the lower nucleophilicity of the aniline nucleophile relative to aliphatic amines.F inally,wefound that primary-amine-derived lactam 11 v could be formed in 52 %y ield using the standard conditions. [11] Atropisomerism can play av ital role in mediating ligand-target interactions in biology, [15] but while synthetic methods able to impart exquisite levels of control over stereogenic centres on asingle atom (usually referred to as point chirality) are very well established, methods designed to control other chirality elements (e.g.,p lanar, axial, and helical chirality) [16] are less well developed. The utility of the cyclisation/ring expansion cascade has therefore been well demonstrated by the synthesis of 34 medium-sized lactones or lactams using asimple and mild synthetic method, without requiring high dilution conditions.…”

Section: Resultsmentioning

confidence: 99%

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

et al. 2019

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Astrategy for the synthesis of medium-sized lactones and lactams from linear precursors is described in whicha n amine acts as an internal nucleophilic catalyst to facilitate an ovel cyclisation/ring expansion cascade sequence.T his method obviates the need for the high-dilution conditions usually associated with medium-ring cyclisation protocols,a s the reactions operate exclusively via kinetically favourable "normal"-sized cyclic transition states.T his same feature also enables biaryl-containing medium-sized rings to be prepared with complete atroposelectivity by point-to-axial chirality transfer.

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Section: Resultsmentioning

confidence: 99%

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

et al. 2019

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“…Zuschriften containing peptidyl catalysts can control enantioselective cyclodehydration to create highly enantioenriched benzimidazoles about as tereogenic C À Nb ond axis.G iven the evermore stereochemically complex compounds emanating from drug discovery campaigns, [25] and the increasing primacy of issues involving atropisomers, [26] we project that the findings presented herein may be of broad interest.…”

Section: Angewandte Chemiementioning

confidence: 88%

Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C−N Bond‐Forming Cross‐Coupling and Catalyst‐Controlled Atroposelective Cyclodehydration

et al. 2018

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Catalyst control over reactions that produce multiple stereoisomers is achallenge in synthesis.Control over reactions that involve stereogenic elements remote from one another is particularly uncommon. Additionally,c atalytic reactions that address both stereogenic carbon centers and an element of axial chirality are also rare.R eported herein is ac atalytic approach to each stereoisomer of as caffold containing as tereogenic center remote from an axis of chirality.N ewly developed peptidyl copper complexes catalyze an unprecedented remote desymmetrization involving enantioselective CÀNb ond-forming cross-coupling.T hen, chiral phosphoric acid catalysts set an axis of chirality through an unprecedented atroposelective cyclodehydration to form ah eterocycle with high diastereoselectivity.T he application of chiral copper complexes and phosphoric acids provides access to each stereoisomer of af ramework with two different elements of stereogenicity.Stereochemically complex molecules hold aspecial place in the development of bioactive substances.Often, their distinct chirality and topology allow for selective interactions with the intricate binding sites associated with their biological targets. [1] Scaffolds that possess two or more chiral centers pose particular challenges for design and synthesis. [2] Furthermore, in the formation of the additional stereogenic centers,match/ mismatch effects are introduced as the intrinsic selectivity of ac hiral substrate may influence the facile formation of all possible stereoisomers. [2,3] Thef ield of asymmetric synthesis deals with these situations,o ften masterfully,t hrough the application of chiral catalysts, [3] which can take the form of transition-metal complexes, [4] small organic molecules, [5] enzymes, [6] or combinations of am etal-based catalyst and an organocatalyst. [7] Ap articularly intriguing situation emerges when the scaffold of interest bears two different types of stereogenic elements. [8] Fore xample,w hen am olecule possesses both as tereogenic center (Figure 1a)a nd an axis of chirality (Figure 1b), four possible diastereomers exist (Figure 1c)i namanner rendering asymmetric synthesis of all possible stereoisomers quite complex. Therefore,d eveloping new approaches to address all of these issues not only contributes to answering fundamental questions in the area of asymmetric catalysis,b ut also creates avenues for the consideration of novel chemotypes in medicinal chemistry. [9] We chose to explore this stereochemically complex situation through examination of catalytic reactions that would combine an umber of challenging features,s everal of which, on their own, constituted unprecedented aspects of asymmetric synthesis.F irst, we endeavored to develop anew enantioselective CÀNb ond-forming cross-coupling reaction, [10] testing the generality of recently developed copper complexes employing guanidinylated peptidyl ligands. [11] We targeted ad esymmetrization process that would create ar emote stereogenic center on the nominally privileged diarylmeth...

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“…Thus the point chirality of the secondary nucleophile is able to fully control the formed atropisomer in the medium-sized cyclic biaryl product in all of these cases,v ia what is,t othe best of our knowledge,a nu nprecedented type of point-to-axial chirality transfer. [11] Atropisomerism can play av ital role in mediating ligand-target interactions in biology, [15] but while synthetic methods able to impart exquisite levels of control over stereogenic centres on asingle atom (usually referred to as point chirality) are very well established, methods designed to control other chirality elements (e.g.,p lanar, axial, and helical chirality) [16] are less well developed. [17] Atroposelective methods capable of delivering medium-sized rings or macrocycles are particularly rare, [18] which encouraged us to examine the atroposelectivity of our cascade reactions in more detail.…”

Section: Angewandte Chemiementioning

confidence: 99%

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

et al. 2019

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Recent encounters with atropisomerism in drug discovery

Cited by 195 publications

References 57 publications

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C−N Bond‐Forming Cross‐Coupling and Catalyst‐Controlled Atroposelective Cyclodehydration

Internal Nucleophilic Catalyst Mediated Cyclisation/Ring Expansion Cascades for the Synthesis of Medium‐Sized Lactones and Lactams

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