Organocatalytic enantioselective synthesis of double S-shaped quadruple helicene-like molecules

Abstract

Helicene-shaped molecules are compelling chemical structures with unique twisted helical chirality and remarkable properties. Although progress occurs in the catalytic asymmetric synthesis of helicene (-like) molecules, the enantioselective synthesis of multiple helicenes, especially four or higher helicity, is still challenging and has yet to be achieved. Herein, we report an organocatalytic [4 + 2] cycloadditions to achieve double S-shaped quadruple helicene-like molecules with high enantioselectivity (up to 96% e.e.). The enantioselective synthesis of (P,P,P,P) and (M,M,M,M) configurational quadruple helical molecules can be achieved by modulating the structure of the catalyst. Density functional theory (DFT) calculations show that the reaction involves the formation of a duplex vinylidene ortho-quinone methide (VQM) intermediate and two successive cycloaddition reactions. Configurational stability studies elucidate the isomerization process between the isomers. In addition, the structural features and optical properties of the quadruple helicene-like molecules were investigated to explore their potential applications.

Fig. 1. Research background and our strategy for synthesizing double S-shaped helicene-like molecules.

a The research status of catalytic enantioselective synthesis of chemicals with helical chirality. b Current status of enantioselective synthesis of multiple helicenes and helicene-like molecules. The helicene units are indicated with semicircles in light blue and the fused rings are indicated with rectangles in pink. c Synthesis of axially chiral molecules by organocatalyzed [4 + 2] cycloadditions and our vision for the synthesis of multi-helical chiral compounds. d Strategies for the enantioselective synthesis of double S-shaped helicene-like molecule and key issues to be addressed. e Our design blueprint: enantioselective synthesis of double S-shaped helicene-like molecules via organocatalyzed [4 + 2] cycloadditions. E⁺, electrophilic reagent.

Fig. 2. Optimization of reaction conditions.

Reaction conditions: 1a (0.02 mmol, 1.0 equiv), catalyst (0.004 mmol, 20 mol%) in 2-MeTHF (1.0 mL) at corresponding temperature for 1.5 h and then N-bromo-phthalimide (NBP) (0.04 mmol, 2.0 equiv) at corresponding temperature for 2 h. Yield is that of the isolated product and enantiomeric excess (e.e.) value is determined by chiral HPLC analysis. Only one dominant diastereomer was formed under all conditions. n.d., not detected.

Fig. 3. Substrate scope and synthetic transformations.

a Substrate scope of (P,P,P,P)-2 and (M,M,M,M)-2. Reaction conditions: 1 (0.02 mmol, 1.0 equiv), catalyst (0.004 mmol, 20 mol%) in 2-MeTHF (2.0 mL) at corresponding temperature for 1.5 h and then N-bromo-phthalimide (NBP) (0.04 mmol, 2.0 equiv) at −60 °C for 2 h. ^aThe reaction was conducted at -78 °C for 24 h. ^bThe reaction was conducted in cyclopentyl methyl ether (CPME) at -78 °C for 24 h. b Synthetic transformations of (P,P,P,P)−2a. t-Bu, tert-butyl. TMS, trimethylsilyl. i-Pr, isopropyl.

Fig. 4. Preliminary mechanistic study.

a Isolation of single-cyclized product. b Control experiments. c Proposed mechanistic pathway.

Fig. 5. DFT calculations and proposed mechanism.

a DFT-computed Gibbs free energies of key transition states and the independent gradient model based on Hirshfeld partition (IGMH) analyses. b The catalytic cycle commences with substrate 1 and NBP being activated by the hydrogen bonding of catalyst F. It proceeds through stereocontrolled two successive electrophilically brominated and rapid proton transfer and concludes with the release of the chiral VQM intermediate and catalyst regeneration. The generated axially chiral VQM intermediate then undergoes two consecutive [4 + 2] cycloaddition reactions to give the final chiral product via axial to helical chirality transfer.

Fig. 6. Configurational stability.

a Stereoisomers and calculated energies of 2a. b The most plausible diastereomerization pathway from (P,P,P,P)−2a to (M,M,P,P)−2a. Relative Gibbs free energy profile for interconversion among diastereoisomers of 2a calculated at the B3LYP/6-31 G(d)//M06−2x/6-311 + G(d,p) level^–. The energy diagram of the process from (P,P,P,P)−2a to (P,P,M,M)−2a is equal to that of the process from (M,M,M,M)−2a to (M,M,P,P)-2a. Helical substructures that invert in transition states are highlighted in green. c Isomerization of (P,P,P,P)-2a to (M,M,P,P)-2a. d ¹H-NMR traces for time course of isomerization of (P,P,P,P)-2a to (P,P,M,M)-2a in toluene-d₈ at 100 °C. e Plot of the decreasing integration of (P,P,P,P)-2a in the ¹H-NMR spectra in toluene-d₈ upon heating at 100 °C, where [(P,P,P,P)-2a]₀ and [(P,P,P,P)-2a]_t are the ratios of the integration of (P,P,P,P)-2a to the sum of the integration of (P,P,P,P)-2a and (P,P,M,M,)-2a at the initial stage and at a certain time t (s) during the conversion, respectively. The integration of the signal peak at 8.31 ppm for (P,P,P,P)-2a was used as a reference. RDS, rate-determining step.

Fig. 7. Crystal structures of (P,P,P,P)-2a and (P,P,M,M)-2a.

ORTEP drawings are shown showing 50% probability of thermal ellipsoids. Hydrogen atoms are omitted for clarity. a Different viewings of (P,P,P,P)-2a and (P,P,M,M)-2a in the crystals. b Torsion angles of (P,P,P,P)-2a and (P,P,M,M)-2a. c Twisting angles relative to the central anthracyclic core. d Packing structures of (P,P,P,P)-2a and (P,P,M,M)-2a.

Fig. 8. Photophysical properties of 2a-c.

a UV/Vis spectra of 2a-c (2.0 × 10⁻⁵M in DCM). b Fluorescence spectra of 2a-c (Excitation wavelength = 375 nm, 2.0 × 10⁻⁴M in DCM). c Fluorescence lifetime decay curves of 2a-c. d CD spectra of 2a-c (2.0 × 10⁻⁵ M in DCM).