A new approach to 4,6-disubstituted-3,4-dihydropyran-2-ones by Domino Michael addition-cyclization reaction under PTC conditions Nicoletta Gaggero a, * , Domenico C.M. Albanese b , Donatella Nava a a Dipartimento di Scienze Farmaceutiche (DISFARM), Sezione di Chimica Generale e Organica “Alessandro Marchesini” Universit a degli Studi di Milano, via Venezian 21, 20133 Milano, Italy b Dipartimento di Chimica, Universit a degli Studi di Milano, via Golgi 19, 20133 Milano, Italy article info Article history: Received 25 July 2014 Received in revised form 27 August 2014 Accepted 8 September 2014 Available online 18 September 2014 Keywords: Phase transfer catalysis 3,4-Dihydropyran-2-ones 1,3-Dithiane-2-carbothioate esters Domino reactions Thio-Michael addition Organocatalysis abstract Domino Michael addition-cyclization reactions of a,b-unsaturated carbonyl compounds with activated 1,3-dithiane-2-carbothioate esters under solid-liquid phase transfer catalysis conditions provide 4,6- disubstituted-3,4-dihydropyran-2-one-3,3-dithioacetals in good chemical yield. Desulfurization pro- ceeds chemoselectively under mild conditions affording 3,4-dihydropyran-2-ones in high yields. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction 3,4-Dihydropyran-2-ones are versatile synthetic intermediates in organic chemistry, widely employed in the synthesis of g-lac- tones, substituted benzenoids and pyridines. 1 Moreover, they constitute the key functionalized subunit of isocoumarins, a family of naturally occurring compounds, which show a broad spectrum of interesting pharmacological activities. 2 The Michael addition of enolates bearing good leaving groups to a,b-unsaturated carbonyl compounds, followed by intramolecular cyclization is one of the most straightforward, efficient and simple methods for constructing the 3,4-dihydropyran-2-one skeleton and is well precedented in the literature (Scheme 1 , path a). For example, Mukaiyama reported the use of silyl enolates derived from phenyl esters in the presence of catalytic achiral quaternary ammonium phenoxides 3 and cinchonidine-derived chiral ones. 4 Kobayashi employed silyl enolates from thioesters with excess of mercuric trifluoroacetate. 5 Katritzky developed lithiated acylbenzotriazoles as nucleophiles. 6 More recently, 1,4-conjugate additions promoted by catalytic N-heterocyclic carbenes were also reported. 7 An alter- native strategy exploited catalytic amounts of chiral isothioureas to generate suitable enolates for intra- and inter-molecular Michael addition-lactonization processes directly from carboxylic acids. 8 Although these methods provide good yields of the expected products, some of them suffer from limitations related to the use of toxic or expensive compounds, or troublesome synthetic steps. Therefore a practical method to carry out such transformations would be desirable. We envisioned the possibility of synthesizing enol lactones 4 by a Michael addition-cyclization sequence utilizing activated thio- ester enolates, generated in situ from 1,3-dithiane-2-carbothioate Scheme 1. Retrosynthesis of 4,6-disubstituted-3,4-dihydro pyran-2-ones. * Corresponding author. Tel.: þ39 02 50314470; fax: þ 39 02 50314476; e-mail address: nicoletta.gaggero@unimi.it (N. Gaggero). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet http://dx.doi.org/10.1016/j.tet.2014.09.022 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved. Tetrahedron 70 (2014) 8744e8749