Exploring chemical diversity via a modular reaction pairing strategy

Abstract

The efficient synthesis of an 80-member library of unique benzoxathiazocine 1,1-dioxides by a microwave-assisted, intermolecular nucleophilic aromatic substitution (S(N)Ar) diversification pathway is reported. Eight benzofused sultam cores were generated by means of a sulfonylation/S(N)Ar/Mitsunobu reaction pairing protocol, and subsequently diversified by intermolecular S(N)Ar with ten chiral, non-racemic amine/amino alcohol building blocks. Computational analyses were employed to explore and evaluate the chemical diversity of the library.

Keywords: benzoxathiazocine 1,1-dioxides; chemical diversity; informatics; nucleophilic aromatic substitution (SNAr); sultams.

Figure 1

Biologically active benzofused sultams.

Scheme 1

Proposed library generation by microwave-assisted intermolecular S_NAr diversification reaction.

Scheme 2

Utilization of a reaction pairing strategy for the synthesis of benzoxathiazocine 1,1-dioxides core scaffolds 1–8.

Figure 2

Benzoxathiazocine 1,1-dioxides 1–8 and amine library building blocks {1–10}.

Figure 3

(i) Simple cartoon of the library compounds, with a core of MW ~ 80, based on Lipinski’s rules (MW < 500), and comprising three substituents, each having MW < 140, to establish different functional groups. (ii) This cartoon demonstrates that the substituents extend out of the core in a circular motion. (iii) Overlay images exhibiting the common core in these 80 compounds. (iv) and (v) both overlay images revealing that the substituents are extending outwards in the circular motion as mentioned in (ii).

Figure 4

Distribution of 80 compounds (colored spheres) relative to the set of 771 known orally available drugs (black dots) [43].

Figure 5

Comparison of a small set of our representative compounds versus two sultams synthesized by our group as well as a biological active compound [11].

Figure 6

Three representative compounds with high QED values.

Figure 7

Representation of Z-scores for the 80 compounds.