Palladium–(S,_pR)‐FerroNPS‐Catalyzed Asymmetric Allylic Etherification: Electronic Effect of Nonconjugated Substituents on Benzylic Alcohols on Enantioselectivity

Abstract

The development of efficient methods for enantioselective synthesis remains at the center of modern-day organic chemistry, as such methods have many important applications, from the total synthesis of natural products [1] to the preparation of analogues of lead compounds in the pharmaceutical industry. The ability to prepare compounds by a carbon-heteroatom bond-forming process from a common intermediate is of great significance to the drug-discovery process. In particular, the stereoselective construction of an ether linkage adjacent to a stereogenic carbon center is important for the synthesis of many biologically active targets.[2] However, this process requires further development. For example, the conventional formation of a CÀO bond by a direct S N 2-type O alkylation (Williamson ether synthesis) is sometimes impractical synthetically owing to the strong basicity of the alkoxide anion, which may be incompatible with other functional groups present in the system. It would clearly be advantageous to construct C À O bonds in a catalytic manner under mild conditions rather than through traditional organic synthesis. Enantioselective transitionmetal-catalyzed allylic substitution [3] has become one of the most powerful tools for the generation of carbon-carbon and carbon-heteroatom bonds with various nucleophiles. The development of the synthesis of chiral compounds containing carbon-carbon or carbon-nitrogen bonds from racemic allylic electrophiles has been documented well [Eq. (1)]. In contrast, the enantioselective allylic substitution of unactivated allylic acetates with relatively hard oxygen nucleophiles has only been studied sporadically. [4] Enantioselective iridium-catalyzed [5] allylic substitution reactions with a broad range of phenols (relatively soft nucleophiles) have been reported. They generally proceed with good selectivity with monodentate phosphoramidite ligands. Asymmetric palladium-catalyzed C À O bond formation between phenols and various allylic substrates to give ethers has also been studied. [6][7][8] In a separate study, Kim and Lee demonstrated that the palladium-catalyzed etherification of allylic acetates with aliphatic alcohols afforded achiral ethers by using zinc alkoxides generated from diethyl zinc and an alcohol.[9] Haight et al. reported an asymmetric variant of the protocol described by Kim and Lee. However, the more reactive allylic carbonate and harsher conditions (reflux in THF) were required, and the observed enantioselectivities were rather poor.[7c] Spurred by these findings, we undertook the challenge to develop an efficient etherification process that can proceed under mild reaction conditions with good stereoselectivity. Herein, we report a general palladiumcatalyzed asymmetric allylic substitution of racemic 1,3-diphenyl-2-propenyl acetate with aliphatic alcohols in the presence of newly developed fine-tunable phosphinamiditethioether ligands with a ferrocene motif (Scheme 1) to generate chiral ethers in high yields with excellent enantioselectivities.We recently ...

A Highly Efficient, Metal‐Free and Convenient Diarylallyl Ether/Thioether Formation via Oxidative C‐H Activation

“…However, this protocol is sometimes synthetically impractical owing to the strong basicity of the alkoxide anion, which may be incompatible with other functional groups presented in the system. [3] Therefore some modified methods were developed, [4,5,6] for example, transition metal-catalyzed cross-coupling of aryl halides with phenols or alcohols.…”

Development of a Novel Multifunctional N,P Ligand for Highly Enantioselective Palladium‐Catalyzed Asymmetric Allylic Etherification of Alcohols and Silanols

“…In this context, although numerous chiral ligands has been reported for regioselective and enantioselective allylic alkylation with relatively good performance,4, 5 the palladium‐catalyzed asymmetric allylic alkylation or etherification (AAE) of alcohols and 1,3‐diphenyl‐2‐propenyl acetate has not been widely reported with high levels of enantioselectivity owing to the mismatch of poor nucleophilicity of alcohols with respect to chiral metal–ligand complexes 4a. 6 Notably, in 2008, Chan and co‐workers reported a palladium‐catalyzed asymmetric allylic etherification of 1,3‐diphenyl‐2‐propenyl acetate with alcohols in moderate to high yields (58–98 %) and good to excellent levels of enantioselectivity (83–96 % ee ) by using the ( S , p R )‐FerroNPS ligand 7. Meanwhile, the research groups of Hou, Ding, Fukuzawa, Du, and others8 have also demonstrated independently that various bidentate phosphine or phosphite ligands associated with palladium centers afford chiral allylic ethers in moderate to good levels of enantioselectivity and diastereoselectivity.…”

“…[4a, 6] Notably, in 2008, Chan and co-workers reported a palladium-catalyzed asymmetric allylic etherification of 1,3-diphenyl-2-propenyl acetate with alcohols in moderate to high yields (58-98 %) and good to excellent levels of enantioselectivity (83-96 %ee) by using the (S, p R)-FerroNPS ligand. [7] Meanwhile, the research groups of Hou, Ding, Fukuzawa, Du, and others [8] have also demonstrated independently that various bidentate phosphine or phosphite ligands associated with palladium centers afford chiral allylic ethers in moderate to good levels of enantioselectivity and diastereoselectivity. However, this useful process to provide chiral allylic ethers still needs substantial improvement in its level of enantioselectivity and chemical yield to be more practical.…”

Asymmetric Hydroalkynylation of Norbornadienes Promoted by Chiral Iridium Catalysts

“…This functional‐group compatibility potentially offers the opportunity for additional functionalization of the chiral alkyne product by using well‐established cross‐coupling protocols 16. Some nonconjugate electronic effects of the alkene moiety on the product enantioselectivity were observed (entries 3, 6–8) 17. Electron‐donating groups on the benzonorbornadiene provided a better stereochemical outcome,18 possibly because of a more favorable coordination of CC to the chiral iridium center (entries 6 and 8).…”