Catalytic Enantioselective Synthesis of 2,5‐Dihydrooxepines

Abstract

A Michael addition initiated cyclopropanation/retro-Claisen rearrangement tandem reaction was developed for the enantioselective synthesis of highly functionalized 2,5-dihydrooxepines. In the presence of a chiral oxazaborolidinium ion (COBI) catalyst, the reaction proceeds to give good yields and high enantioselectivity.

One‐Pot Synthesis of Metastable 2,5‐Dihydrooxepines through Retro‐Claisen Rearrangements: Method and Applications

“…Pioneering reports by Vogel, [1] Dreiding, [2] and Rhoads [3] on the valence tautomerism between unsubstituted 2,5-dihydrooxepines 1 and syn-2-vinylcyclopropane-1-carboxaldehydes 2 (Scheme 1a,R= H) highlighted an equilibrium in favor of 2.I n the 1990s, Reißig, [4] Boeckman, [5] and Yamaguchi [6] demonstrated that the retro-Claisen( and also 1-oxa-Cope) seven-membered product can be strongly favoredby the presence of donor-acceptor stabilizing groupso nt he vinylcyclopropane (VCP) moiety. [7] More recently,t he use of stabilizing substituents allowed the development of catalytic enantioselective synthesis of 2,5-dihydrooxepines, [8] and their application as synthetic intermediates towards polysubstituted 5-membered rings. [9] However, these works only concern VCP-carboxaldehyde substrates (2,R = H), since for yet untargetedr easons, linear syn-VCP ketones (R ¼ 6 H) are unreactive towards [ 3,3]-sigmatropic rearrangements.…”

The Retro‐Claisen Rearrangement of 2‐Vinylcyclopropylcarbonyl Substrates and the Question of its Synthetic Potential

“…However, several questions arise on the selectivity with regard to the reaction conditions. The 2,5-dihydrooxepine products (37) are indeed in competition with other rearrangement products such as 2-vinyl-2,3-dihydrofurans (38) or cyclopentene-4-carbonyl derivatives (39), both arising from Cloke-Wilson-type rearrangements (Scheme 6). 7,8 Being in equilibrium with their cyclopropane precursors (cis-36), 2,5dihydrooxepines may thus be metastable, depending on the thermodynamic parameters of this transformation.…”

“…7,8 Being in equilibrium with their cyclopropane precursors (cis-36), 2,5dihydrooxepines may thus be metastable, depending on the thermodynamic parameters of this transformation. Their easy conversion to dihydrofuran products (38) has been observed 18b, 21 and it is questionable if this transformation (37→38) is direct, or if a cyclopropane intermediate from cycloreversion is a prerequisite to this rearrangement (37→cis-36→38). Finally, the literature has rarely mentioned the retro-Claisen rearrangement of 2vinylcyclopropyl ketones, 22,23 unlike that of carboxaldehyde.…”

Asymmetric Synthesis of Enantioenriched 2‐Aryl‐2,3‐Dihydrobenzofurans by a Lewis Acid Catalyzed Cyclopropanation/Intramolecular Rearrangement Sequence

“…Fort he ensuing Michael addition, the a-diazoester approached the b-methide carbon atom of the o-QM with the ester group positioned away from the carbonyl group of the quinone moiety because of dipole-dipole interaction between the two carbonyl groups.N ucleophilic addition of the a-diazoester from the re face (front) of the o-QM was thus facilitated, leading to intermediate 7,which could then cyclize with the loss of nitrogen to form the donor-acceptor cyclopropane 2. [8,9] Ther esulting cyclopropane 2 induced polarization in the C À C 1 bond with an electron-donating group (Ar 1 )a nd equilibrated with the zwitterion intermediate 2' '. Finally,t he alkoxy oxygen atom attacked the carbocation C 1 to afford the 2-aryl-2,3-dihydrobenzofurans 3 and 4.…”