Experimental and Theoretical Justification for the Regiospecific Cycloaddition of Levopimaric Acid to 2-Acetyl- or 2-(Methoxycarbonyl)-1,4-Benzoquinone

Effect of protic additives in Cu-catalysed asymmetric Diels–Alder cycloadditions of doubly activated dienophiles: towards the synthesis of magellanine-type Lycopodium alkaloids

“…1–3 In addition to being extremely reactive Michael acceptors in simple conjugate additions 3,4 and formal 2+2 cycloadditions, 5 their potential as dienophiles in Diels–Alder cycloadditions has been widely exploited, because of the ubiquity of the resulting hydrindane core in various classes of natural products when 5-membered cyclic analogs are used. 2 While many racemic and diastereoselective examples of Diels–Alder cycloadditions using alkylidene β-ketoesters as dienophiles have been reported, successful catalytic asymmetric variants remain scarce and typically lack generality with respect to the structure of the diene and dienophile. 6 Indeed, this subset of dienophiles is notoriously unstable to protic and Lewis acids, heat, and even simple dissolution in certain solvents, which has been attributed to their high propensity to polymerise following tautomerisation.…”

“…While this affords excellent asymmetric induction in Diels–Alder cycloadditions when the appropriate chiral bis(oxazoline) is employed, the synthesis of this dienophile and the additional steps required to install/cleave the imide auxiliary significantly impedes its practicality and general use in complex molecule synthesis. 2e In order to address this unresolved issue, we envisioned that similar rigidification might be achieved directly from the ester if an intermolecular hydrogen bond could be established using a catalytic amount of a protic additive (R–OH, Fig. 1, C).…”

“…Such additives were found to both accelerate the reaction and significantly improve the observed stereoselectivity, in accordance with a model such as C. The hydrindenone cycloadduct was employed as a key intermediate towards a synthesis of magellanine-type Lycopodium alkaloids. Given the versatility of the resulting hydrindenone products, 2 these initial forays into a general catalytic asymmetric Diels–Alder cycloaddition using cyclic alkylidene β-ketoesters should find broad applicability in the synthesis of complex natural products.…”

“…2 We envisioned that such a highly functionalised cycloadduct bearing three contiguous stereocenters could serve as an intermediate towards the synthesis of magellaninone, a tetracyclic Lycopodium alkaloid belonging to the fawcettimine class (Scheme 3). 12,13 Key to our synthetic strategy was masking the basic piperidine moiety present in the natural product as a pyridine.…”

“…This observation has introduced a new stereoinduction model for alkylidene β-ketoester dienophiles, and the development of a stereoselective synthesis of a functionalised hydrindenone commonly used in the synthesis of complex molecules relevant to natural product synthesis. 2 The utility of the hydrindenone cycloadduct was demonstrated in its application towards the synthesis of magellaninone. Key to the synthetic studies is a robust Stille cross-coupling of a highly congested enol triflate and a unique Meinwald rearrangement/cyclopropanation sequence.…”