Stereoselective synthesis of C-glycosides by addition of titanium enolates from a chiral N-glycolyl thiazolidinethione to glycals Erik Gálvez a , Miriam Sau a , Pedro Romea a,⇑ , Fèlix Urpí a,⇑ , Mercè Font-Bardia b,c a Departament de Química Orgànica, Universitat de Barcelona, Carrer Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain b Departament de CristalÁlografia, Mineralogia i Dipòsits Minerals, Universitat de Barcelona, Carrer Martí i Franqués s/n, 08028 Barcelona, Catalonia, Spain c Unitat de Difracció de RX, Centres Científics i Tecnològics de la Universitat de Barcelona (CCiTUB), Universitat de Barcelona, Carrer Solé i Sabarís 1-3, 08028 Barcelona, Catalonia, Spain article info Article history: Received 16 November 2012 Revised 28 December 2012 Accepted 8 January 2013 Available online 16 January 2013 Keywords: Stereoselective reactions C-Glycosidations Titanium enolates Glycals Chiral thiazolidinethiones abstract The Lewis acid-mediated addition of the titanium enolate from the pivaloyl-protected (S) N-glycolyl-4- isopropyl-1,3-thiazolidine-2-thione to glycals affords the corresponding syn C-a-glycosides in high yields and excellent diastereomeric ratios. Further removal of the chiral auxiliary permits access to enantiome- rically pure C1 0 -pivaloyloxy pyrans in a straightforward manner. Ó 2013 Elsevier Ltd. All rights reserved. The ubiquitous presence of 2,6-disubstituted tetrahydropyrans in natural products has inspired the development of a rich array of strategies and synthetic methodologies. 1 One of the most effec- tive approaches to the stereoselective synthesis of such structural motifs relies on the Lewis acid-mediated addition of carbon nucle- ophiles to glycals, 2 followed by the appropriate transformation of the resultant dihydropyran adducts. Unfortunately, and in spite of the success of such an approach, the simultaneous installation of a chiral center flanking the pyran ring is still challenging. In par- ticular, methods for the introduction of an oxygenated stereocen- ter at this position, 3,4 as occurs in amphidinol 3 (Fig. 1), are limited. 5 In this context, and taking advantage of our experience on the reaction of titanium enolates with oxocarbenium intermedi- ates, 6–8 we envisaged that the Lewis acid-mediated addition of titanium enolates from valine-derived O-pivaloyl protected N-gly- colyl thiazolidinethiones to glycals might permit the stereoselec- tive construction of such structural motifs (Scheme 1). 9 Indeed, the configuration of the heterocycle would depend on the a-bias usually observed in C-glycosidation processes involving glycals, 2 whereas the configuration of the oxygenated stereocenter would be controlled by the chiral auxiliary. 6,7,10 Therefore, the anti and the syn relationships affecting the tetrahydropyran moieties embedded in the structure of amphidinol 3 could arise from the appropriate choice of the glycal and the chiral auxiliary (routes a or b in Scheme 1). Herein, we report our findings on the stereose- lective addition of the titanium enolates from an O-pivaloyl pro- tected N-glycolyl thiazolidinethione to a wide array of glycals (route a in Scheme 1) that provides the corresponding syn a-C-gly- cosides in high yields and in a straightforward manner. Application of experimental conditions used in former studies to the SnCl 4 -mediated reactions of titanium enolates from (S) 4- isopropyl-N-(2-pivaloyloxyacetyl)-1,3-thiazolidine-2-thione (1) 6c with tri-O-acetyl glucal (a) revealed that the expected a-C-glyco- side 2a was formed diastereoselectively but in a low yield after long reaction times (entry 1 in Table 1). Considering that such a low yield was likely due to the poor reactivity of the titanium enolate possessing an electron withdrawing group and taking advantage of the thermal stability of such a titanium enolate, the reaction was carried out at 0 °C. Under these conditions, we were pleased to observe that yields increased significantly while diaste- reomeric ratios remained higher than 95:5 (entries 2–9 in Table 1). Finally, a further optimization led us to recognize that decreasing the amount of glucal a and the Lewis acid slightly improved both the yields and the diastereoselectivity (compare entries 3, 5, and 8, and also entries 6 and 9 in Table 1). Therefore, the simple stirring of the reaction mixture at 0 °C for 5 h and the final purification of the reaction mixture through a pad of silica provided diastereo- merically pure adduct 2a in 94% yield (entry 8 in Table 1) and per- mitted the recovery of most of the unreacted starting material 1. 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.01.028 ⇑ Corresponding authors. Tel.: +34 93 4039106; fax: +34 93 3397878 (P.R.); tel.: +34 93 4021247; fax: +34 93 3397878 (F.U.). E-mail addresses: pedro.romea@ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpí). Tetrahedron Letters 54 (2013) 1467–1470 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet