Synthesis of Chiral Chromans by the Pd-Catalyzed Asymmetric Allylic Alkylation (AAA):  Scope, Mechanism, and Applications

Abstract

The Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol allyl carbonates serves as an efficient strategy to construct the allylic C-O bond allowing access to chiral chromans in up to 98% ee. The effect of pH and the influence of olefin geometry, as well as substitution pattern on the ee and the absolute configuration of the chiral chromans were explored in detail. These observations suggest a mechanism involving the cyclization of the more reactive pi-allyl palladium diastereomeric intermediate as the enantiodiscriminating step (Curtin-Hammett conditions). This methodology led to the enantioselective synthesis of the vitamin E core, the first enantioselective total synthesis of (+)-clusifoliol and (-)-siccanin, and the synthesis of an advanced intermediate toward (+)-rhododaurichromanic acid A.

Preparation and chemical reactivity of 2-chromanols

“…8,10,[38][39][40] The Pechmann condensation of a phenol and a carboxylic acid or ester containing a β-carbonyl group in the presence of an acid has been widely used for the preparation of coumarins. 41,42,43 For more complex 2-chromanol derivatives the preparation will be described.…”

“…27,36 Esterification of the phenol group was used for the synthesis of chiral chromans. 40,68 The synthesis of chiral chromans via Pd-catalyzed intramolecular asymmetric allylic alkylation (named AAA) of phenol allyl carbonates has been extensively studied. 69,70,40 Trost's group explored in detail this reaction and obtained high yields and enantioselectivities under the conditions described in Scheme 22.…”

“…40,68 The synthesis of chiral chromans via Pd-catalyzed intramolecular asymmetric allylic alkylation (named AAA) of phenol allyl carbonates has been extensively studied. 69,70,40 Trost's group explored in detail this reaction and obtained high yields and enantioselectivities under the conditions described in Scheme 22. First, acetal 88 was prepared by the reaction of phenol 89 with methylvinylketone 76 (see section 3.4).…”

Regioselective bromination of 1,4-dimethoxy-2,3-dimethylbenzene and conversion into sulfur-functionalised benzoquinones

“…Because of the two activating methoxy groups, compound 1 is reactive towards electrophilic ring bromination as well as radical bromination of the two methyl groups and previous studies have reported the formation of various mono-, di-and tribrominated derivatives. The earliest derivative, the mono ring-brominated product 4 was reported in 1944 from reaction of 1 with bromine in chloroform, 4 and is also formed by the reaction with bromine in acetic acid 5 or hexafluoropropan-2-ol 6 and with NBS in dichloromethane. 7 In the first attempt at radical bromination, 2 reaction with NBS in the presence of benzoyl peroxide in boiling carbon tetrachloride for 1 h gave a 60% yield of the mono bromomethyl compound 5 accompanied by 9% of the dibromide 2.…”

“…Simply substituting trichloroethane for CCl4 gave an identical crude product composition and after chromatographic purification led to a slightly improved yield of 2 (entry 2). By varying the conditions with this solvent, conditions were found to maximise the yield of each product and thus isolate each of 8, 9 and 4 (entries [3][4][5]. Increasing the amount of NBS gave the tribromide 8 while ring bromination was favoured by using photochemical initiation rather than benzoyl peroxide with 4 formed after 1 h which reacted further to give 9 after 3 h. The initial attempt using benzotrifluoride and conditions otherwise similar to before gave only ring bromination (entry 6) and prolonging the reaction time (entry 7) led to 4 being further brominated to 8 and 9 but none of the desired dibromide 2 was formed.…”