Transition‐Metal‐Free [4+3]‐Cycloaddition of ortho‐Quinone Methides and Isomünchnones: Catalytic and Diastereoselective Assembly of Oxa‐bridged Oxazocine Scaffolds

Abstract

Cycloadditions are powerful processes to synthesize complex polycyclic scaffolds. Herein, we disclose a [4+3]‐cycloaddition between an in situ generated ortho‐quinone methide and an isomünchnone to yield oxa‐bridged oxazocine cores, generating N2 and H2O as the sole by‐products. Using only catalytic amounts of camphorsulfonic acid, it is possible to generate both reactive intermediates in one step, eliminating the need for rhodium catalysts generally employed for isomünchnone formation. Spectroscopic data and X‐ray crystallography indicate the formation of the syn diastereomer, with the main side‐product arising from a hydrate participating in a competing [4+2]‐cycloaddition pathway.

Kooperative Katalyse für die diastereo‐ und enantioselektive [4+3]‐Cycloanellierung von ortho‐Chinonmethiden und Carbonylyliden

“…über die erste Phosphorsäure‐katalysierte, enantioselektive Reaktion von o ‐QM mit 2‐Indolylmethanolen als 1,3‐Dipolkomponenten zur Synthese von Indolylbenzoxepinen . In einem weiteren bemerkenswerten Beispiel konnte die Gruppe von Lautens zeigen, dass sauerstoffverbrückte Oxazocine durch Brønsted‐Säure‐katalysierte, diastereoselektive Cycloaddition von o ‐QM und Isomünchnonen zugänglich sind …”

Asymmetric Synthesis of Oxa‐Bridged Oxazocines through a Catalytic RhII/ZnII Relay [4+3] Cycloaddition Reaction

“…In particular, Padwa and co‐workers have carried out a series of studies in this field, and several alkaloids have been synthesized using the methodology (Scheme a) . In addition, Lautens and co‐workers realized a [4+3]‐cycloaddition through Brønsted acid catalyzed in situ formation of ortho ‐quinone methides ( o ‐QM) and isomünchnones (Scheme b). This transition‐metal‐free reaction produced several [4+3]‐products smoothly in good yields as racemates, and up to 15 % ee could be achieved by using chiral phosphoric acid, albeit with a significant decrease in yield.…”

Asymmetric Synthesis of Oxa‐Bridged Oxazocines through a Catalytic RhII/ZnII Relay [4+3] Cycloaddition Reaction

“…Based on the crystal structure of the catalyst, as well as the determination of absolute configuration of products,apossible transition-state model was proposed to explain the origin of the stereoinducement (Scheme 3). In Lautens models, [6] the E/Z-o-QM determines the diastereoselectivity of the reaction. In contrast, only the E ketoester was used in our work.…”

“…[4] In particular,Padwa and co-workers have carried out aseries of studies in this field, and several alkaloids have been synthesized using the methodology (Scheme 1a). [5] In addition, Lautens and co-workers realized a[ 4 + +3]-cycloaddition through Brønsted acid catalyzed in situ formation of orthoquinone methides (o-QM) and isomünchnones [6] (Scheme 1b). This transition-metal-free reaction produced several [4+ +3]-products smoothly in good yields as racemates,and up to 15 % ee could be achieved by using chiral phosphoric acid, albeit with asignificant decrease in yield.…”

“…Changing the ester group (R 1 )from methyl to abulkier aliphatic isopropyl, cyclopentyl, or benzyl group,the yields and ee values could still remain (entries 1-4). b,g-Unsaturated a-ketoesters with electron-withdrawing or electron-donating substituents at different positions of the phenyl group can react smoothly to afford the corresponding products in good yields (71-90 %y ield) and excellent ee values (97-99 % ee;e ntries [5][6][7][8][9][10][11][12][13][14][15][16]. It was worth mentioning that a-ketoester 1j,which contains ahydroxy group,was also compatible,p roducing the product 3ja in 88 %y ield with 97 % ee (entry 10).…”