Catalytic Enantioselective Desymmetrization of Norbornenoquinones via C(sp²)–H Alkylation

Abstract

The enantioselective Diels-Alder (DA) reaction with monosubstituted p-benzoquinones is an unmet challenge. A new approach for the enantioselective synthesis of monosubstituted quinone-DA adducts is presented based on C(sp)-H alkylative desymmetrization of meso-DA adducts. Catalyzed by a tertiary amino-thiourea derivative, this reaction utilizes nitroalkanes as the alkylating agents and generates densely functionalized products bearing at least four contiguous stereogenic centers remote from the reaction site with excellent enantioselectivities.

Atropisomerism as inspiration for new chemistry

“…While the addition of thiophenols did not prove fruitful, we found that we could affect atroposelective methylation on this scaffold using nitromethane as the methyl source (Scheme 11), 86 in line with chemistry from Mukherjee. 87,88 In this work, sterically hindered ureas containing quinine derivatives such as 61 were found to effect the alkylation in good yields and moderate to good enantioselectivity (up to 85:15 e.r.). The moderate enantioselectivity was perhaps due to the products existing as Class-2 atropisomers with barriers to racemization between 25-28 kcal/mol due to the aforementioned gearing mechanism to racemization.…”

Recent advances towards organocatalytic enantioselective desymmetrizing reactions

“…Norbornenoquinones are valuable building blocks for the synthesis of quinonoid natural products, which renders the construction of enantiomerically pure norbornenoquinones highly in demand. Accordingly, on the basis of previous work [49], in 2016 Mukherjee exploited the use of bifunctional thiourea as the catalyst and nitroalkanes as the alkylating reagents to perform the desymmetrization of meso-substrates (30) [50]. As demonstrated in Figure 3D, the conversion starts with the enantioposition-selective conjugate addition of nitroalkanes on the olefin moieties to form chiral intermediates ( 30-A).…”

“…Owing to the flexible O-or ortho C-functionalization, achiral bisphenols ( 49) are another sort of potential candidate for desymmetrizing reactions and a diverse range of methodologies to construct chiral C-and P-stereogenic centers have been developed (Figure 4F). In 2016, Chi introduced bisphenol phosphinates as reactants and disclosed a pioneering carbene-catalyzed desymmetrization to afford P-stereogenic phosphinates (50) in moderate to excellent yields and enantioselectivities [66]. Subsequently in 2018, the Li group presented an NHC-catalyzed desymmetrization reaction of diarylalkane-bisphenols with aldehydes [67].…”

Copper-Catalyzed N-Arylation of Nitroenamines with Diaryliodonium Salts

“…2-Nitro-1-phenylethan-1-one (1a″). 30 Prepared according to the general procedure A from 2-nitro-1-phenylethan-1-ol. White crystalline solid (4.83 g, 29.3 mmol, 36%).…”