Asymmetric induction in thia-Diels-Alder reactions of chiral polyfluoroalkylthionocarboxylates Vadim M. Timoshenko a, *, Sergiy A. Siry a , Alexander B. Rozhenko a,b , Yuriy G. Shermolovich a a Institute of Organic Chemistry NAS of Ukraine, Murmanska str. 5, 02660 Kyiv, Ukraine b University of Bielefeld, Universita ¨tstr. 25, 33615 Bielefeld, Germany 1. Introduction Synthetic methodologies based on the Diels-Alder reaction are widely employed in organic chemistry and have an enormous spectrum of application. Using heterodienes or heterodienophiles in the [4 + 2] cycloaddition reaction makes it possible to construct complex natural products or their analogues containing a six- membered heterocyclic framework [1]. Thiocarbonyl compounds are well known representatives of heterodienophiles which have found applications in total syntheses [2,3], for preparation of thioglycoside derivatives [4] and thiashikimic acid [5]. Electron- withdrawing groups in a-position to the thiocarbonyl group lower the LUMO energy of the heterodienophile and significantly facilitate the cycloaddition. Therefore, polyfluroalkyl thioalde- hydes [6], thioketones [7], dithioesters [6–9] are excellent dienophiles and can be used for syntheses of diverse sulfur- containing heterocycles. For symmetrical dienes, at least one new stereogenic centre is generated by Diels-Alder reaction. Therefore, the application of a proper chiral dienophiles could influence the stereochemical outcome of the cycloaddition and can be used in the construction of optically active compounds. Continuing our studies on applications of polyfluoroalkylthi- nocarboxylic acids derivatives in syntheses of new fluorine–sulfur- containing compounds, we were interested to study an asymmet- ric variant of the thia-Diels-Alder reaction of alkyl polyfluoro dithioesters with dienes. For this purpose suitable dithioesters bearing chiral groups were necessary. In this paper we describe a preparation of such chiral substrates, a study of their cycloaddition reactions and a comparison of the diastereoselectivity in these reactions. Additionally, O-alkyl polyfluorothionoates have been synthesized for comparison, dienophilic properties of which have not been described to date. 2. Results and discussion Several synthetic methods are known for the preparation of perfluoroalkyldithiocarboxylates, developed in our laboratory [8– 10] and by others groups [11–14]. In order to obtain a series of dithioesters involving a chiral group we have developed another, new and simple method which consists in nucleophilic displace- ment of chlorine in polyfluorothioalkanoyl chlorides 1 by sulfur in reactions with optically active mercaptanes. Trifluorothioacetyl chloride 1a and 2,2,3,3-tetrafluorothiopropionyl chloride 1b were prepared according to the known procedure [15] from correspond- ing benzyl 1,1-dichloropolyfluoroalkyl sulfides [16] (Fig. 1). The following chiral thiols prepared according to the described procedure we have chosen as nucleophiles for reactions with chlorides 1: (1S)-10-mercaptocamphor 2a [17], (1S)-thioisobor- neol 2b [18], (1S)-thioborneol 2c [19], (1S,2S,5R)-thioneomenthol 2d [20] and racemic a-phenethylthiol 2e [21]. Journal of Fluorine Chemistry 131 (2010) 172–183 ARTICLE INFO Article history: Received 22 July 2009 Received in revised form 16 November 2009 Accepted 18 November 2009 Available online 24 November 2009 Keywords: Thioesters Fluorine Thia-Diels-Alder reaction Dihydrothiopyrans Asymmetric induction DFT Transition state ABSTRACT A series of chiral S- or O-alkyl thionoesters have been synthesized by treatment of trifluorothioacetyl- or 2,2,3,3-tetrafluorothiopropionyl chloride with corresponding thiols or alcohols. The thia-Diels-Alder reaction of the thionoesters with symmetrical 1,3-dienes proceeds with diastereoselectivity up to 60%. Structures of cycloaddition products and corresponding transition states have been studied at the DFT level of approximation. The experimentally observed diastereomeric excess has been referred to differences in activation energies of transition states, preceding formation of the diastereomeric cycloaducts. ß 2009 Elsevier B.V. All rights reserved. * Corresponding author. Tel.: +380 44 499 4938; fax: +380 44 573 2643. E-mail address: vadim@ioch.kiev.ua (V.M. Timoshenko). Contents lists available at ScienceDirect Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor 0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2009.11.011