Enantio‐ and Diastereoselective Access to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho‐Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalysis

Abstract

A protocol for the highly enantioselective synthesis of 9-substituted tetrahydroxanthenones by means of asymmetric Brønsted acid catalysis has been developed. A chiral binol-based N-triflyphosphoramide was found to promote the in situ generation of ortho-quinone methides and their subsequent reaction with 1,3-cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio- and diastereoselective Brønsted acid catalyzed desymmetrization of 5-monosubstituted 1,3-dicarbonyl substrates with ortho-quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

“…Recently, ortho ‐hydroxybenzyl alcohols have emerged as active reaction partners in asymmetric catalysis for their characteristic of being readily converted into ortho ‐quinone methide ( o ‐QM) intermediates7 in the presence of a Brønsted acid (Scheme ),8 and should serve as a suitable diene for catalytic asymmetric IED oxa‐DA reactions. However, previous reports on catalytic enantioselective transformations of ortho ‐hydroxybenzyl alcohols only included conjugate additions (Scheme )8b–d and stepwise cyclizations (Scheme ) 8e,f. During the preparation and submission of this manuscript, Schneider and co‐workers reported an elegant tandem cyclization using highly reactive cyclic enamides as nucleophiles (Scheme ) 8g,h.…”

Cinchona Squaramide‐Catalyzed Intermolecular Desymmetrization of 1,3‐Diketones Leading to Chiral 1,4‐Dihydropyridines

“…An exception is the enantioselective Michael reaction of 5substituted cyclohexane-1,3-diones to ortho-quinone methides (Scheme 1, eq. c) [7] and (Z)-bromonitrostyrenes (Scheme 1, eq. d) [8] followed by tandem cyclization of the intermediate adducts.…”

Catalytic Asymmetric (4+3) Cyclizations of In Situ Generated ortho‐Quinone Methides with 2‐Indolylmethanols

“…[1][2][3] Among them, o-hydroxybenzyl alcohols have recently been recognized as powerful precursors of o-QMs (Scheme 1), which can easily be transformed into o-QMs in the presence of aB rønsted acid (B-H). [4,5] Consequently,u nder the catalysis of chiral catalysts,as eries of enantioselective conjugate additions [4] and (4+ +2) cyclizations [5] have been established [Scheme 1,Eq. (1), (2)].…”

“…After establishing the optimal reaction conditions,w e examined the generality of the catalytic asymmetric (4+ +3) cyclization. As shown in Table 1, this reaction could be applicable to awide range of 2-indolylmethanols 1 (entries [1][2][3][4][5][6][7][8] and o-hydroxybenzyl alcohols 2 (entries 9-22) bearing different substituents,g enerating products 3 with regiospecificity in high yields and excellent enantioselectivity.Itisworth noting that 2-indolylmethanol 1h bearing two alkyl groups (i-Pr) could serve as asuitable substrate to give product 3ha in an acceptable yield and good enantioselectivity (entry 8). Notably,apart from aromatic groups (entries [13][14][15][16][17][18][19][20], aliphatic groups such as methyl and iso-propyl groups could successfully serve as suitable R 3 groups for substrates 2,w hich participated in the (4+ +3) cyclization in good yields and high enantioselectivity (entries 21-22).…”