Diversity-oriented synthesis of stereodefined tetrasubstituted alkenes via a modular alkyne gem-addition strategy

Abstract

Stereocontrolled construction of tetrasubstituted olefins has been an attractive issue yet remains challenging for synthetic chemists. In this manuscript, alkynyl selenides, when treated with ArBCl₂, are subject to an exclusive 1,1-carboboration, affording tetrasubstituted alkenes with excellent levels of E-selectivity. Detailed mechanistic studies, supported by DFT calculations, elucidates the role of selenium in this 1,1-addition process. Coupled with subsequent C-B and C-Se bond transformations, this 1,1-addition protocol constitutes a modular access to stereodefined all-carbon tetrasubstituted alkenes. The merit of this approach is demonstrated by programmed assembly of diverse functionalized multi-arylated alkenes, especially enabling the stereospecific synthesis of all six possible stereoisomers of tetraarylethene (TAE) derived from the random permutation of four distinct aryl substituents around the double bond. The diversity-oriented synthesis is further utilized to explore different TAE luminogenic properties and potential Se-containing antitumor lead compounds.

Fig. 1. Diversity-oriented synthesis of stereodefined olefins with up to four different substituents.

a Functionalized multi-arylated all-carbon tetrasubstituted alkenes. b Stereocontrolled synthesis of all-carbon tetrasubstituted alkenes from alkynes. c 1,1- vs. 1,2-selective carboboration of electron-rich alkynes. d This work: Modular alkyne gem-addition to access functionalized tetrasubstituted alkenes.

Fig. 2. Examinations on electron-rich alkynes.

a Reaction yields and selectivity. b ¹³C-labeled experiment. c Isosurface of condensed dual descriptors (CDD) for 1a, 1b, and 1c. Blue indicates nucleophilicity, while green represents electrophilicity. The negative and positive values (in a.u.) correspond to the overall nucleophilicity and electrophilicity condensed on each atom, respectively.

Fig. 3. Computational mechanistic study of carboboration of 1c.

Free-energy profiles of reaction pathways for carboboration of alkynyl selenide (1c) computed at the B3LYP(D3BJ)/def2-TZVP/PCM(DCE)//M06-2X/def2-TZVPP/SMD (1,2-DCE) level of theory. The geometries of the key transition states are illustrated below, with the bond lengths indicated in Angstrom (Å).

Fig. 4. Computational mechanistic study of carboboration of 1a.

Free-energy profiles of reaction pathways for carboboration of alkynyl sulfide (1a) computed at the B3LYP(D3BJ)/def2-TZVP/PCM(DCE)//M06-2X/def2-TZVPP/SMD (1,2-DCE) level of theory. The geometries of the key transition states are illustrated below, with the bond lengths indicated in Angstrom (Å).

Fig. 5. Substrate scope.

General reaction conditions: alkynes (0.2 mmol), ArBCl₂ (0.4 mmol), 1,2-DCE (1 mL), room temperature, 12 h, then quenching with pinacol/Et₃N. Isolated yield. Except for commercially available PhBCl₂, another ArBCl₂ was generated in situ through the reaction of ArTMS with BCl₃. PMP p-methoxyphenyl.

Fig. 6. Synthesis of polysubstituted 1,3-dienes.

General reaction conditions: alkynes (0.2 mmol), R³BCl₂ (0.4 mmol), 1,2-DCE (1 mL), room temperature, 12 h, then quenching with pinacol/Et₃N. Isolated yield. In situ generation of p-MeO-PhBCl₂ through the reaction of p-MeO-PhTMS with BCl₃.

Fig. 7. Derivations.

a Scale-up synthesis. b Transition metal-free Suzuki-type cross-coupling. c Downstream transformations of alkenyl boronate: (i) KOAc (3 equiv.), 30% H₂O₂ (3 equiv.), 0 °C to rt, 20 h; (ii) TBAF•3H₂O, 45 °C, 16 h; (iii) CuCl₂ (5 equiv.), MeOH/H₂O, 24 h; (iv) 5 mol% Pd₂(dba)₃, 20 mol% P(furan)₃, NaO^tBu, (bromoethynyl)triisopropylsilane (3 equiv.), THF/PhMe, 75 °C, 20 h; (v) 10 mol% PdCl₂(dppf), Cs₂CO₃ (2 equiv.), 4-iodobenzonitrile (3 equiv.), 50 °C, 1,4-dioxane, 36 h.

Fig. 8. Modular synthesis of drug molecules based on the C-Se bond transformation:

(i) 10 mol% PdCl₂(dppf), 9 M aqueous NaOH (4 equiv.), aryl iodide (2 equiv.), in THF, rt, 1 h; (ii) 15 mol% NiCl₂(dppe), 1 M Et₂Zn in ether, 50 °C, 15 h; (iii) ICl (2 equiv.), in DCM, −50 °C to 0 °C, 36 h.

Fig. 9. Programmed synthesis of up to six TAE isomers and fluorescence determinations.

a Fluorescence photographs of 100 in THF/H₂O mixtures with different H₂O fractions, [c] = 2 µM. b FL intensity of 100 with different H₂O fractions, [c] = 2 µM. c UV–Vis spectra of 100–105, [c] = 20 µM, 95% H₂O. d Fluorescence spectra of 100–105, [c] = 2 µM, 95% H₂O. e Solid-state molecular structure of 104 and 105.

Fig. 10. Diversified construction of Se-containing antitumor compound library and evaluation of antitumor activities.

a Tumor volume changes by treatment with different dosages of compound 109 in MCF-7 xenograft model mice compared to Tamoxifen. All values were presented as mean ± SEM. Significance was determined using Two-way ANOVA followed by Tukey’s multiple comparison test with two-tailed adjusted p-values displayed in the figure (con vs. TAM, p = 0.0000827, 95% confidence interval (CI): 92.91 to 147.4; con vs. 109-L, p = 0.0000632, 95% CI: 109.1 to 163.1; con vs. 109-M, p = 0.0000554, 95% CI: 135.1 to 189.2; con vs. 109-H, p = 0.0000671, 95% CI: 132.5 to 187.6; TAM vs. 109-L, p = 0.4860, 95% CI: −11.08 to 42.99; TAM vs. 109-M, p = 0.0003, 95% CI: 15.00 to 69.06; TAM vs. 109-H, p = 0.0008, 95% CI: 12.32 to 67.47). Data are n = 6 (con group and TAM group) or n = 7 (109-L, 109-M, and 109-H group) biological replicates, one independent experiment. b Photographs of all MCF-7 xenograft tumors resected on day 28. c Measured weight of the resected MCF-7 xenograft tumors on day 28. All values were presented as mean ± SEM. Significance was determined using a two-tailed unpaired t-test with p-values displayed in the figure (con vs. TAM, p = 0.0022; con vs. 109-L, p = 0.0001; con vs. 109-M, p = 0.000006; con vs. 109-H, p = 0.00001). Data are n = 6 (con group and TAM group) or n = 7 (109-L, 109-M, and 109-H group) biological replicates, one independent experiment. TAM = 13.4 µmol/kg; 109-L = 6.6 µmol/kg; 109-M = 13.3 µmol/kg; 109-H = 26.6 µmol/kg.