Modular Access to Chiral 2,3-Dihydrofurans and 3,4-Dihydro-2H-pyrans by Stereospecific Activation of Formylcyclopropanes through Combination of Organocatalytic Reductive Coupling and Lewis-Acid-Catalyzed Annulative Ring-Opening Reactions

Abstract

An organocatalytic reductive coupling and Lewis-acid-catalyzed annulative ring-opening strategy is developed as a two-step protocol for the stereoselective synthesis of dihydropyrans as the major products from the chiral formylcyclopropanes, CH acids, and Hantzsch ester. It is an efficient, catalytic, two-step protocol for the chiral synthesis of dihydropyrans and dihydrofurans. Structurally important and challenging functionally rich cyclopropanes containing cyclic-1,3-diones were synthesized in very good yields with excellent chemo-, enantio-, and diastereoselectivities from the readily available starting materials, chiral formylcyclopropanes, cyclic-1,3-diones, or CH acids and Hantzsch ester through an organocatalytic reductive coupling reaction at ambient conditions, especially without harming the cyclopropane ring. Chiral cyclopropanes containing cyclic-1,3-diones were stereospecifically transformed into dihydropyrans and dihydrofurans found in many bioactive natural products and drugs through an annulative ring-opening reaction by using Lewis-acid (BF·OEt) or cesium carbonate (CsCO) catalysis. Highly diastereo- and regioselective ring opening of cyclopropanes was explained through a stereospecific intimate ion pair pathway.

The Chemistry of Cyclopropanes and New Insights into Organocatalyzed Asymmetric Cyclopropanation

“…This cyclopropanation method, has been one of the most studied with different metals such as cooper, rhodium or ruthenium [23] . The reaction proceeds through the formation of a metallocarbene complex between ethyl diazoacetate 47 and the metal (CuOTf), (where to obtain the reaction enantiocontrol, the metal is bound to the chiral catalyst bisoxazolidine 48 [27] .…”

“…This transformation was carried out via ring‐expansion, annulation, and cycloaddition reactions. Recently, Peraka and co‐workers [23] described a compilation of different donor‐acceptor formylcyclopropane reactions. They also described an organocatalytic reductive coupling reaction carried out on a chiral formylcyclopropane to produce a new cyclopropane, which was converted to its respective 3,4‐dydro‐2H‐pyrane with Lewis acid (Scheme 9).…”

Recent Advances in the Synthesis of 2-Hydroxy-1,4-naphthoquinone (Lawsone) Derivatives

“…In earlier reports it has been discussed that lawsone and its derivatives serve as synthons for several asymmetric synthesis of biologically active molecules. 117 Among these, recently, Ramachary and co-workers 118 developed a protocol for the synthesis of chiral naphthoquinone-fused pyran derivative 290. The synthesis involves the stereoselective Knoevenagel condensation or Ramachary reductive coupling between the starting material lawsone (1) and chiral formylcyclopropane (287) in the presence of Hantzsch ester (288).…”

Creating Stereocenters within Acyclic Systems by C–C Bond Cleavage of Cyclopropanes

“…Regio- and diastereoselective direct nucleophilic attack on activated cyclopropanes produced diastereomerically enriched open-chain products (Scheme ). Many different Lewis acids as well as nucleophiles could be used on variously activated cyclopropane derivatives (Scheme a–e). − Strikingly, weak nucleophiles such as ketones can open the cyclopropyl core in an intramolecular manner, and aromatization of a quinone-type spiro system may serve as a strong enough driving force for ring opening, sparing the use of any Lewis acid (Scheme e–g). , This strategy was used for the diastereoselective copper-catalyzed addition of benzyl alcohol to activated cyclopropane 96 , resulting in the formation of the key intermediate 97 en route to the total synthesis of tupichilignan A (Scheme ). …”