The MARDi Cascade: A Michael‐Initiated Domino‐Multicomponent Approach for the Stereoselective Synthesis of Seven‐Membered Rings

Abstract

The MARDi cascade is a recently invented three-component Michael-initiated condensation involving 1,3-dicarbonyl derivatives. It allows regio- and stereocontrolled access to a variety of functionalised and substituted seven-membered rings. The substitution array can be diastereoselectively modulated by appropriate choice of the reaction partners, and the reaction allows the control of up to five newly created stereocentres and a complete chiral induction in the case of an optically active ketone precursor. The high level of diastereoselectivity observed has been attributed to total thermodynamic control of the reaction. The attractiveness of the present domino three-component approach to seven-membered rings resides in the diversity of carbo- and heterocyclic structures that can be accessed with total regiocontrol and high stereocontrol by starting from simple substrates, under user and environmentally friendly conditions, as now required in modern organic chemistry.

Synthetic Studies towards Guaianolide Sesquiterpene Lactones

“…The MARDi cascade with the β‐oxo ester 3 and crotonaldehyde yields the cycloheptanol 4 in 94 % yield as the only detectable isomer (Scheme ) 6. Of crucial importance for the synthetic applications of the MARDi cascade to target‐oriented synthesis is the chemo‐differentiation of the two carboxylate groups in the product.…”

“…They usually exhibit a trans ‐γ‐lactone ring fused to the C 6 –C 7 bond of the bicycle or, less often, to the C 7 –C 8 bond, and have been the subject of considerable synthetic4 and biological studies 1,5. In our continuous effort towards eco‐compatible synthetic routes to valuable molecules involving domino and/or multicomponent reactions (MCRs), we have recently developed the MARDi cascade, a Michael‐initiated MCR which allows a diastereoselective access to a variety of carbo‐ and heterocyclic seven‐membered rings under user‐ and environmentally friendly conditions 6. The application of multicomponent/domino reactions7 to target‐oriented synthesis has been conceptualized as early as 1917 by Robinson, and its advantages have been demonstrated with the efficient one‐pot synthesis of the bridged bicyclic alkaloid tropinone by using a double Mannich three‐component reaction 8.…”

Asymmetric Domino Reactions Based on the Use of Chiral Substrates

“…129 Thus, a range of substituted cycloheptanols was regio-and diastereoselectively synthesised through the reaction of b-substituted acroleins with 2oxo-cyclopentanecarboxylate methyl esters in the presence of DBU as a base in methanol at room temperature. These products, containing up to five stereogenic centres, were produced in moderate to high yields and relatively high diastereoselectivities of 492% de, as shown in Scheme 1.84.…”

Expeditious Divergent Synthetic Approach to Polycyclic Terpene‐Like Molecules

“…[18] For this purpose, we used our previously developed conditions for the domino Michael-aldol-retroDieckmann sequence (MARDi cascade). [19] Thus, the treatment of compound 7 a with DBU in methanol, followed by aqueous acidic workup, afforded directly the cycloheptenes 15 a and 15 b as a 7:1 mixture of diastereomers (62 % yield), with the major isomer exhibiting a cis-fused d-lactone. The formation of 15 is believed to result from a six-step process: first, the domino Michael-aldol sequence from 7 a afforded 6 a in a comparable manner as described in Scheme 2.…”