Ir-catalyzed Sequential Asymmetric Allylic Substitution/Olefin Isomerization for the Synthesis of Axially Chiral Compounds

Abstract

Axially chiral compounds represent an important class of chiral molecules. In this regard, many methods have been developed to access these compounds. However, efficient methods for the synthesis of axially chiral styrenes are limited to date, mainly due to their relative instability compared to axially chiral biaryl compounds. Iridium-catalyzed asymmetric allylic substitutions have evolved as a powerful tool in constructing C-C or C-X bonds at the allylic position. We developed an efficient sequential strategy to access a series of axially chiral styrenes by iridium-catalyzed allylic substitution and central-to-axial chirality transfer via olefin isomerization. With the iridium complex derived from [Ir(cod)Cl]2 and Alexakis ligand L1 as catalyst, and β-naphthol as nucleophiles, a broad range of axially chiral styrenes were obtained with moderate to excellent yields (28%～97% yields) and enantioselectivity (59%～98% ee). A general procedure for the asymmetric allylation of β-naphthol is described as the following: A flame-dried Schlenk tube was cooled to room temperature and filled with argon. To this flask were added [Ir(cod)Cl]2 (2.6 mg, 0.004 mmol, 2 mol%), (S,S,Sa)-L1 (4.8 mg, 0.008 mmol, 4 mol%), freshly distilled tetrahydrofuran (THF, 0.5 mL) and propylamine (0.5 mL). The mixture was stirred at 50 ℃ for 30 min and then the low-boiling solvents were removed in vacuo to give a pale yellow solid. The solid was stirred at 50 ℃ again under vacuum until it became a powder. After that, β-naphthol 1 (0.22 mmol, 1.1 equiv.), allyl carbonate 2 (0.2 mmol, 1.0 equiv.), 1,4-diazobicyclo(2.2.2)octane (DABCO) (67.3 mg, 0.6 mmol, 3.0 equiv.) and freshly distilled Et2O (2.0 mL) were added to this flask under argon atmosphere. The reaction mixture was stirred at 20 ℃ until the starting material was consumed (monitored by thin layer chromatography, TLC). The crude reaction mixture was diluted with water (5 mL), and extracted with dichloromethane (DCM, 5 mL×3). The organic layers were collected, dried over Na2SO4 and then concentrated in vacuo to afford the crude product. The residue was purified by preparative TLC to afford the product.

Transition-metal-catalyzed atroposelective synthesis of axially chiral styrenes

“…A similar conversion has also been achieved in moderate to good enantioselectivity by You and co-workers using a similar ligand L12 (Scheme 16b). 51 Further mechanism studies supported that iridium and organic base DBU are both essential in the centralto-axial chirality transfer.…”

Enantioselective Synthesis of Cyclobutane Derivatives via Cascade Asymmetric Allylic Etherification/[2 + 2] Photocycloaddition

“…Complex molecules could be built rapidly and conveniently from simple starting materials via a cascade reaction. Iridium-catalyzed asymmetric allylic substitution reactions represent a powerful tool for the construction of C–C and C–X bonds, especially furnishing terminal alkenes bearing a stereogenic center at the allylic position. , A variety of useful downstream cascade reactions based on the formed terminal CC bond have been realized, introducing new stereocenters in a rapid fashion via chirality induction or translocation process . Given our ongoing interest in asymmetric allylic substitution reactions, we intend to integrate it with [2 + 2] photocycloaddition reactions in a cascade protocol to provide a practical asymmetric synthesis of cyclobutane derivatives.…”