ORGANIC LETTERS
Synthesis of N-Glycosides. An Alternative Approach Based on Diastereoselective Base Coupling and SN2 Cyclization
2002 Vol. 4, No. 2 241-244
Yvan Guindon,* Marc Gagnon, Isabelle Thumin, Daniel Chapdelaine, Grace Jung, and Brigitte Gue´rin Institut de recherches cliniques de Montre´ al (IRCM), Bio-organic Chemistry Laboratory, 110 aVenue des Pins Ouest, Montre´ al, Que´ bec, Canada H2W 1R7, and Department of Chemistry and Department of Pharmacology, UniVersite´ de Montre´ al, C.P. 6128, succursale Centre-Ville, Montre´ al, Que´ bec, Canada H3C 3J7
[email protected] Received November 1, 2001
ABSTRACT
Acyclic diastereoselection is achieved for the formation of thioaminyl acetals. The highly intramolecular stereocontrolled SN2 displacement of the thioaminyls allows for the formation of cyclic nucleoside derivatives. This versatile approach may provide easy access to a large variety of N-glycosides.
N-Glycosides and their acyclic derivatives are compounds of great medicinal interest.1 The synthesis of nucleosides1,2 generally involves both SN1 and SN2 displacements of a leaving group by a silylated purine or pyrimidine (the Vorbru¨ggen modification2b) at the anomeric carbon of a fivemembered ring carbohydrate derivative (Scheme 1). SN1type processes occur more frequently because the presence of an oxygen on the carbon bearing the leaving group generally allows for the stabilization of any developing carbon-centered positive charge through the formation of an (1) (a) Vorbru¨ggen, H.; Ruh-Pohlenz, C. In Organic Reactions; Paquette, L. A., et al., Eds.; John Wiley & Sons: New York, 2000; Vol. 55, pp 3-111. (b) Wilson, L. J.; Hager, M. W.; El-Kattan, Y.; Liotta, D. C. Synthesis 1995, 1465. (c) Lukevics, E.; Tablecka, A. In Nucleoside Synthesis Organosilicon Methods; Horwood, E., Ed.; New York, 1991. (2) (a) Mukaiyama, T.; Katsurada, M.; Takashima, T. Chem. Lett. 1991, 985. (b) Anchimeric assistance of neighboring groups: Vorbru¨ggen, H.; Kroilkiewicz, K.; Bennua, B. Chem. Ber. 1981, 114, 1234. (c) Mukaiyama, T.; Matsubara, K.; Suda, S. Chem. Lett. 1991, 891. (d) Paulsen, H.; Tietz, H. Angew. Chem. 1985, 97, 118; Angew. Chem., Int. Ed. Engl. 1985, 24, 128. (e) Nicolaou, K. C.; Sietz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc. 1983, 105, 2430. (f) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881. (g) Ratcliffe, A. J.; Konradsson, P.; FraserReid, B. J. Am. Chem. Soc. 1990, 112, 5665. 10.1021/ol016991i CCC: $22.00 Published on Web 12/21/2001
© 2002 American Chemical Society
Scheme 1
oxonium ion. In the SN1-type process, facial differentiations can be achieved using, for example, the anchimeric assistance of neighboring groups2b or internal base delivery.3 The SN2-type process2b has been observed in approaches such as fluoride displacement or electrophilic addition involving glycals. The intermediates formed in the latter reaction include glucal epoxides,4 iodonium ions,5 and (3) Sujino, K.; Sugimura, H. Tetrahedron Lett. 1994, 35, 1883. (4) Chow, K.; Danishefsky, S. J. Org. Chem. 1990, 55, 4211. (5) Kim, C. U.; Misco, P. F. Tetrahedron Lett. 1992, 34, 5733.
phenylselenium ions.6 Dominant in the approaches used to date for the synthesis of N-glycosides has been the fact that the base is always introduced on the cyclic sugar. Acyclic N-glycosides have even been prepared from cyclic intermediates through ring cleavage of the sugar.7 Lacking in literature have been strategies involving a base coupling step that precedes a cyclization as illustrated in Scheme 2. A rare example of such an approach is Liotta’s
Scheme 2
synthesis of AZT (R1 ) OBz, R3 ) N3, R4 ) H, X)OBn), wherein an SN1 pathway is responsible for the anomeric stereochemistry (Scheme 2a).8 The challenging strategy we propose (Scheme 2b) is based on a diastereoselective introduction of the silylated base to an acyclic dithioacetal intermediate and a subsequent SN2-like intramolecular displacement. A few years ago, we became interested in inducing on acyclic molecules stereogenic centers bearing a C-N bond. One of the approaches we have developed in this context is based on a diastereoselective transformation of thioacetals. The first step of the approach to be depicted herein involves the formation of a thionium ion intermediate to which an amine is added in order to generate the thioaminyl acetal (Scheme 3).
Scheme 3
Diastereoselectivity is induced through the transfer of stereochemical information originating from the stereogenic center adjacent to the thioacetal (1,2-induction). The resulting thioaminyl acetal is further transformed through an SN2-type process to preserve chirality. For the latter to occur, tactically (6) (a) Dı´az, Y.; El-Laghdach, A.; Matheu, M. I.; Castillo´n, S. J. Org. Chem. 1997, 62, 1501. (b) Dı´az, Y.; El-Laghdach, A.; Castillo´n, S. Tetrahedron 1997, 53, 10921. (7) Elkattan, Y.; Gosselin, G.; Imbach, J. L. J. Chem. Soc., Perkin Trans. 1 1994, 10, 1289. (8) Hager, M. W.; Liotta, D. C. J. Am. Chem. Soc. 1991, 113, 5117. 242
speaking, an electron-withdrawing group should be present on the nitrogen to render the nitrogen electron deficient, making more energy demanding the creation of an iminium ion intermediate in a competitive SN1-like process. We hypothesized that silylated purines and pyrimidines would be judicious choices of amines and that an intramolecular SN2 displacement of the sulfur on the thioaminyl by the hydroxyl group at C4 should lead to N-glycosides (Scheme 2b).9 The preliminary results of our study are depicted herein. Dithioacetal 1 was used to evaluate the reactivity of different thiol activating reagents in the silylated base coupling step. Hg(OAc)2/TMSOTf 10 and dimethyl(methylthio)sulfonium tetrafluoroborate (Me2S(SMe)BF4)11 have both proven to be successful conditions as seen in Table 1. Promising ratios of 4:1 and 13:1 were obtained in favor of syn product 2a when silylated uracil was used (Table 1, entries 1 and 2). Replacing the methyl with a silyl ether (OTBS) resulted in a significant increase in diastereoselectivity (cf. entries 1 and 3 as well as entries 2 and 4, Table 1).12 Similarly, excellent diastereoselectivity and yield were obtained when thioacetal 3 was treated with either thymine (Table 1, entries 5 and 6) or cytosine (Table 1, entries 7 and 8). The silylated adenine was coupled effectively with dithioacetal 3 using Hg(OAc)2/TMSOTf (Table 1, entry 9).13 Substrates bearing a primary or secondary alkoxy group at C4 were also considered. With the exception of 12 (Table 1, entry 12),14,15 all substrates tested gave excellent results (Table 1, entries 10, 11, 13, and 14).16 A couple of conclusions can be drawn at this point. The use of Hg(OAc)2/TMSOTf and Me2S(SMe)BF4 in the first step was effective in selectively activating the sulfur. Additionally, the presence of an alkoxy group (OR1, 1,2induction, Scheme 3) on the stereogenic center R to the dithioacetal17 during addition of the silylated base was successful in promoting excellent diastereoselectivity. Two (9) The synthesis of disaccharide proposed by Hindsgaul bears a similarity to our approach in that cyclization occurs as the final step: McAuliffe, J. C.; Hindsgaul, O. J. Org. Chem. 1997, 62, 1234. (10) Bra˚nalt, J.; Kvarnstro¨m, I.; Niklasson, G.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. J. Org. Chem. 1994, 59, 1783. (11) Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529. (12) Proof of the structure was obtained through crystallization of 4a followed by X-ray analysis. See Supporting Information. (13) The coupling of this base was less successful in the presence of Me2S(SMe)BF4, giving complex mixtures of thioaminyl acetals. Similar results were obtained with guanine in the presence of either thiol activating reagent, an issue that will have to be revisited with modified purine bases. Regioselectivity in the synthesis of purine nucleosides is discussed in ref 1a. Additional approaches such as the blocking of nitrogen functions were not considered in this study. (14) Bernardi et al. have shown that allylmagnesium bromide addition to 2,3-syn- and 2,3-anti-dialkoxy aldehydes also takes place with different degrees of stereocontrol, the syn substrate giving the highest ratio: Bernardi, R.; Fuganti, C.; Grasselli, P. Tetrahedron Lett. 1981, 22, 4021. (15) A mixture of SEt/SMe compounds was obtained from 12. A control experiment involving cyclization of the corresponding isolated SEt and SMe products in the presence of Me2S(SMe)BF4 gave products 23a:23b with similar ratios, indicating that the SMe/SEt exchange does not occur after the introduction of thymine and is not responsible for the erosion of diastereoselectivity. (16) The 1,2-anti relative stereochemistry of 9b was confirmed by X-ray analysis. See Supporting Information. (17) For more on the use of dithioacetals in diastereoselective processes, see: (a) Shibata, N.; Fujita, S.; Gyoten, M.; Matsumoto, K.; Kita, Y. Tetrahedron Lett. 1995, 36, 109. (b) Mori, I.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 5966. Org. Lett., Vol. 4, No. 2, 2002
Table 1. Introduction of the Silylated Base, Model Study
Figure 1. Proposed transition states for the base coupling.
substrate 18a in the presence of Me2S(SMe)BF4 was highly stereocontrolled, and an excellent yield of trans product 19a was obtained (Table 2, entry 1). Similarly, the cyclization of 18b gave exclusively product 19b (Table 2, entry 2). Mixtures of 1,2-syn/anti thioaminyl acetals were reacted with Me2S(SMe)BF4. The corresponding trans and cis N-glycosides were obtained in the same ratios as the starting products (Table 2, entries 3-5).18 This and the reversal of stereo-
Table 2. Cyclization of Various Substrates
a Conditions A: Silylated base, Hg(OAc) , TMSOTf, CH Cl , 23 °C, 2 2 2 24 to 48 h. B: Silylated base, Me2S(SMe)BF4, CH3CN, -20 to 0 °C, 2 to b 1 c 12 h. Ratios were determined by H NMR spectroscopy. A mixture of SEt:SMe (3:1) products was obtained.
transition states involving thionium ions can be proposed to account for the anti and syn products in the base coupling step (Figure 1). In the lowest-energy syn-predictive transition state A, the hydrogen at C2 is almost in the same plane as the thionium ion,17b and the incoming nucleophile reacts on the face opposite the alkoxy group. The second step of the sequence involved the intramolecular displacement of the activated SR group by the hydroxyl group at C4. As seen in Table 2, the cyclization of Org. Lett., Vol. 4, No. 2, 2002
a Conditions: Me S(SMe)BF , THF, 25 °C, 1 h. b Ratios were determined 2 4 by 1H NMR spectroscopy. c SMe thioaminyl acetal was used as the starting material.
243
chemistry observed at the carbon center bearing the heterocycles were strong indicators of the SN2-like character of this reaction. In conclusion, this study shows that reversing the normally accepted order of carbon heteroatom bond formation (i.e., the C-N bond prior to the C-O bond) is as a strategy viable for the formation of N-glycosides. Also shown is that acyclic diastereoselection can be achieved for the formation of thioaminyl acetals, compounds with potential medicinal significance. The highly stereocontrolled SN2 displacement of the thioaminyls can allow for the formation of cyclic nucleoside derivatives. This versatile approach may provide easy access to different N-glycosides (L, D, R, and β). The (18) Relative configuration of the cyclized products was established by correlation of NMR chemical shifts. See Supporting Information. The NMR assignments were verified by the X-ray crystallographic structure of 25a and by NOESY experiments of cyclized products 19a and 19b as well as 23a and 23b.
244
scope of these reactions will be studied further as will the possibility of using other nucleophiles in both intra- and intermolecular displacements for the second step of the reaction sequence. Acknowledgment. The authors thank NSERC for its financial support as well as Ms. LaVonne Dlouhy for her assistance in the preparation of this manuscript. Supporting Information Available: Experimental procedures and characterization data for compounds 1-33; determination of the relative configuration for compounds 4a, 9b, 19a, 19b, 21a, 21b, 23a, 23b, 25a, and 25b; and NMR spectra for compounds 2a, 2b, 3, 5-7, 9a, 11a, 11b, 13-18, 20-25, and 29-32. This material is available free of charge via the Internet at http://pubs.acs.org. OL016991I
Org. Lett., Vol. 4, No. 2, 2002
