Creation and manipulation of common functional groups en route to a skeletally diverse chemical library

Abstract

We have developed an efficient strategy to a skeletally diverse chemical library, which entailed a sequence of enyne cycloisomerization, [4 + 2] cycloaddition, alkene dihydroxylation, and diol carbamylation. Using this approach, only 16 readily available building blocks were needed to produce a representative 191-member library, which displayed broad distribution of molecular shapes and excellent physicochemical properties. This library further enabled identification of a small molecule, which effectively suppressed glycolytic production of ATP and lactate in CHO-K1 cell line, representing a potential lead for the development of a new class of glycolytic inhibitors.

Fig. 1.

(A) Synthetic strategy for assembly of a skeletally diverse chemical library. The approach relies on the initial series of cycloisomerizations of acyclic enyne, followed by subsequent [4 + 2] cycloadditions and alkene diversifications via dihydroxylation and carbamylation. (B) Transformations of enyne 1 into a series of 1,3-dienes. (C) Structures and isolated yields of products of [4 + 2] cycloadditions of dienes 5, 6, 7, and 8 with dienophiles 9, 10, 11, 12, and 13.

Fig. 2.

(A) Selected chemical transformations of alkene 14. Such reactions were designed to enable subsequent structural diversification of this representative cycloadduct. (B) Results of Os-catalyzed dihydroxylations of alkenes 14–32. Structures of major diastereomers of each product are shown, as well as isolated yields following by silica gel chromatographic purification. Diastereoselectivity of each transformation was determined by analysis of crude reaction mixtures by ¹H NMR. Structures of 35, 36, 37, 38, 39, 42, 43, 49, and 50 were determined by X-ray crystallography of either the parent diol or the corresponding acetal (SI Appendix and Tables S1–S10).

Fig. 3.

(A) Representative transformations of diol 35. Such reactions were investigated to enable subsequent diversification of all the initially produced diols. (B) Carbamylation of a selected subset of diols using n-hexyl isocynate. Depending on the structure of the diol, either mono- or bis-carbamates were selectively produced.

Fig. 4.

(A) Carbamylation of diols 35–50. Reactions were performed on 18–20 mg scale to deliver final compounds, which were purified by preparative LCMS. (B) Structures, yields, purities, and selected physicochemical properties of four selected library members. (C) Molecular shape analysis using PMI computational method. The graph shows broad shape distribution of the 191-member library using a standard triangular plot.

Fig. 5.

Effects of compound 57 on ATP synthesis, lactate production and cell proliferation. (A) Chemical structure of 57. (B) Inhibition of intracellular ATP level in CHO-K1 cells upon treatment with 57 in the presence or absence of antimycin A. (C) Inhibition of lactate production in CHO-K1 cells upon treatment of 57. (D) Effect of 57 on the growth of CHO-K1 cells. All values are presented as percentage of vehicle treated samples. Each value is the mean ± SEM of duplicate or triplicate values from a representative experiment.