Dataset Information

Catalytic Asymmetric Synthesis of meta Benzene Isosteres

ABSTRACT: Aromatic rings are common elements in pharmaceutically active compounds; however, their ready oxidation can present a liability with respect to a drug's metabolic stability. Replacing these aromatic rings in pharmaceutical compounds with non-aromatic isosteric motifs can enhance properties such as potency, metabolic stability, solubility, and lipophilicity. Since the binding pockets of most pharmaceutical targets are chiral, the stereochemical configuration of the isosteric replacements are expected to have an impact on the affinity of derived ligands for target receptors. A significant impediment to this approach is the lack of simple, and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. In this work, we present a heretofore unknown palladium-catalyzed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that that shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalyzed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold will render this platform a useful foundation for assembly of new biologically active agents.

INSTRUMENT(S): Orbitrap Exploris 240

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Bingcong Xiong

LAB HEAD: Eranthie Weerapana

PROVIDER: PXD051400 | Pride | 2024-09-11

REPOSITORIES: Pride

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			Action	DRS
	072223_MBM_URB597_TMT_B1T1.msf	Msf
	072223_MBM_URB597_TMT_B1T1.raw	Raw
	072223_MBM_URB597_TMT_B1T2.raw	Raw
	082623_MBM_MZV096RR_10uM_TMT_B1T1.msf	Msf
	082623_MBM_MZV096RR_10uM_TMT_B1T1.raw	Raw

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Catalytic asymmetric synthesis of meta benzene isosteres.

Zhang Mingkai M Chapman Matthew M Sarode Bhagyesh R BR Xiong Bingcong B Liang Hao H Chen James K JK Weerapana Eranthie E Morken James P JP

Nature 20240821 8028

Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug<sup>1</sup>. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs<sup>2</sup>. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceuti ...[more]

PMID: 39169193

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