A solution to the anti-Bredt olefin synthesis problem

Abstract

The π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be distorted, leading to heightened reactivity of the π-bond. Although π-bond-containing compounds with bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of π-bond-containing compounds that display twisting or pyramidalization remains underdeveloped. We report a study of perhaps the most notorious class of geometrically distorted molecules that contain π-bonds: anti-Bredt olefins (ABOs). ABOs have been known since 1924, and conventional wisdom maintains that ABOs are difficult or impossible to access. We provide a solution to this long-standing problem. Our study also highlights the strategic manipulation of compounds that display considerable distortion arising from the presence of geometrically constrained π-bonds.

Fig. 1.. Geometric distortions of unsaturated compounds and historical perspective of anti-Bredt olefins.

(A) Twisting of alkene and pyramidalization of carbon termini. (B) Historical timeline of anti-Bredt olefins. (C) Prior efforts to generate anti-Bredt olefins using silyl halide precursors.

Fig. 2.. Structural analysis of [2.2.1] ABO 12 and synthesis of a precursor for ABO generation.

(A) Structural features of 12 with respect to the geometric distortion about the C–C double bond. Olefin strain energy calculated at the CCSD(T)/cc-pVTZ level of theory. Ground-state geometry calculated at the ωB97XD/def2-TZVP level of theory. (B) Synthetic route to isomers 27 and epi-27 from acrylate 22. (C) Syntheses of silyl sulfonates 28, 29a, and epi-29a. Diastereomeric silyl nonaflate epi-29a is not a viable ABO precursor experimentally, likely because of an unfavorable torsion angle that precludes formation of the ABO π-bond as suggested by calculated structures 29b and epi-29b (OTf and Me₃Si substituents used to simplify computations). Calculations were performed at the ωB97XD/def2-TZVP level of theory. (D) Survey of reaction conditions for generation and trapping of ABO 12.

Fig. 3.. Scope of trapping reactions with [2.2.1] anti-Bredt olefin 12.

Asterisk symbol indicates the following conditions: 29a (1 equiv), trapping partner (3 to 10 equiv), CsF (10 equiv), TBAB (1 equiv), toluene (0.1 M), 120°C, 14 hours, sealed vessel. Single-dagger symbol indicates the following conditions: 29a (1 equiv), trapping partner (2 equiv), TBAF (1 M in THF, 5 equiv), DMF (0.05 M), 0°C, 3 hours. Observed diastereomeric ratios (d.r.) and regioselectivities (% r) to indicate distribution of constitutional isomers are provided, with the major isomer being depicted. In all cases, the stereochemistry at C2 of the bicycle fragment is as shown in structure 33. For product 49, 1.3:1 d.r. is observed for the major constitutional isomer and 6:1 d.r. is observed for the minor constitutional isomer.

Fig. 4.. Validation of anti-Bredt olefins by trapping with anthracene (30).

Different combinations of silyl group and bridgehead leaving group are indicated in the entry column. Average twist angle (τ) and pyramidalization angle at the bridgehead carbon (Φ_p) are given for each ABO and were obtained from the ground-state geometry-optimized structures calculated at the ωB97XD/def2-TZVP level of theory. Reaction conditions: Asterisk symbol indicates the following conditions: precursor (1 equiv), anthracene (2 equiv), TMAF (5 equiv), DMF (0.05 M), 23°C, 2 to 17 hours. Single-dagger symbol indicates the following conditions: precursor (1 equiv), anthracene (2 equiv), CsF (10 equiv), TBAB (1 equiv), toluene (0.1 M), 120°C, 14 hours. Double-dagger symbol indicates the following conditions: precursor (1 equiv), anthracene (2 equiv), CsF (10 equiv), TBAB (1 equiv), xylene (0.1 M), 140°C, 22 hours.

Fig. 5.. Studies pertaining to reactivity, electronic structure, and stereochemistry of ABOs.

(A) A concerted asynchronous cycloaddition is proposed for the formation of cycloadduct 31. ABO 12 is predistorted in a manner that resembles the geometry seen in TS-1, leading to a facile reaction. Calculations were performed at the ωB97XD/def2-TZVP/SMD(DMF) level of theory. (B) FMOs of ABO 12, with structures reoriented to best visualize the alkene portion of the molecule. Calculations of stepwise geometric distortions of ethylene are used to assess the influence of the twisting and pyramidalization present in ABO 12 on energetics and frontier molecular orbitals. Geometry optimizations were performed at the ωB97XD/def2-TZVP level of theory. MO structures and energies were obtained at the HF/6–31G(d) level of theory. (C) Explanation for diastereoselectivity in the formation of 31. Calculations were performed at the B3LYP/6–311+G(d,p) level of theory. (D) ABO 63 and its enantiomer ent-63 are depicted with a mirror plane. Use of enantioenriched silyl bromide (+)-73 leads to enantioenriched cycloadduct (+)-64 in high optical yield.