J. Am. Chem. Soc. 1997, 119, 11217-11223
11217
Are Glycosyl Triflates Intermediates in the Sulfoxide Glycosylation Method? A Chemical and 1H, 13C, and 19F NMR Spectroscopic Investigation David Crich* and Sanxing Sun Contribution from the Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Room 4500, Chicago, Illinois 60607-7061 ReceiVed April 18, 1997X
Abstract: The title question is addressed by low-temperature 1H, 13C, and 19F NMR spectroscopies in CD2Cl2 as well as by the preparation of authentic samples from glycopyranosyl bromides and AgOTf. At -78 °C glycosyl triflates are cleanly generated with either nonparticipating or particpating protecting groups at O-2. The glycosyl triflates identified in this manner were allowed to react with methanol, resulting in the formation of methyl glycosides. Glycosyl triflates were generated at -78 °C in CD2Cl2 and allowed to warm gradually until decomposition was detected by 1H and 19F NMR spectroscopy. The decomposition temperature and products are functions of the protecting groups employed.
Introduction The use of anomeric sulfoxides as glycosyl donors has rapidly gained a position of prominence in the field of oligosaccharide synthesis since its introduction by Kahne in 1989. This popularity stems from the very mild conditions and the ability to glycosylate even the most hindered alcohols in high yield.1 The method has been successfully applied to an impressive variety of glycosyl acceptors including acetamide, phenols and hindered bile acids,1 hydroxylamines,2 hydroxylated amino acids,3 tertiary alcohols,4 and a broad selection of carbohydrates1,5,6 by the Kahne group. Solid-phase oligosaccharide synthesis has also been achieved through the use of glycosyl sulfoxides by the Kahne and Still laboratories.7,8 The formation of acyclic alkoxymethyl ethers by means of alkoxy methyl sulfoxides has also been demonstrated by the originators of the technique.9 Other groups have applied the sulfoxide glycosylation strategy in the syntheses of complex natural products10,11 as well as in oligosaccharide12-17 and nucleoside syntheses.18 The Stork variant on the intramolecular aglycone delivery X Abstract published in AdVance ACS Abstracts, November 1, 1997. (1) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem. Soc. 1989, 111, 6881-6882. (2) Walker, S.; Gange, D.; Gupta, V.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 3197-3206. (3) Hamilton Andreotti, A.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 3352-3353. (4) Yan, L.; Kahne, D. Synlett 1995, 523-524. (5) Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580-1581. (6) Yang, D.; Kim, S.-H.; Kahne, D. J. Am. Chem. Soc. 1991, 113, 47154716. (7) Yan, L.; Taylor, C. M.; Goodnow, R.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953-6954. (8) Liang, R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi, Y.; Sekanina, K.; Horan, N.; Gildersleeve, J.; Thompson, C.; Smith, A.; Biswas, K.; Still, W. C.; Kahne, D. Science 1996, 274, 1520-1522. (9) Silva, D. J.; Kahne, D.; Kraml, C. M. J. Am. Chem. Soc. 1994, 116, 2641-2642. (10) Boeckman, R. K.; Liu, Y. J. Org. Chem. 1996, 61, 7984-7985. (11) Ikemoto, N.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 25242536. (12) Sliedregt, L. A. J. M.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1994, 35, 4015-4018. (13) Zhang, H.; Wang, Y.; Voelter, W. Tetrahedron Lett. 1995, 36, 1243-1246. (14) Wang, Y.; Zhang, H.; Voelter, W. Z. Naturforsch. 1995, 50b, 661666. (15) Wang, Y.; Zhang, H.; Voelter, W. Z. Naturforsch. 1993, 48b, 11431145.
S0002-7863(97)01239-0 CCC: $14.00
approach to β-mannospyrannosides also makes use of the sulfoxide method.19,20 Despite all of this interest no detailed discussion of the mechanism of this reaction has yet been published. Stimulated by an unanticipated reversal of anomeric stereoselectivity on the coupling of the sulfoxide 1 to the acceptor 2 in the presence of triflic anhydride (Tf2O) and 2,6di-tert-butyl-4-methylpyridine (DTBMP) on simple reversal of the order of addition of the reactants to 1 (Scheme 1),21 which we have since developed into an efficient protocol for the stereoselective synthesis of β-mannopyranosides,22 we have investigated the mechanism of this reaction by low-temperature 1H, 13C, and 19F NMR spectroscopies and report here on our findings. Scheme 1
Results and Discussion In the initial paper, Kahne and Kim reported the glucosylation of sterically hindered secondary alcohols, phenols, and acetamides with the donors 5 and 6, of undefined stereochemistry, (16) Berkowitz, D. B.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1992, 114, 4518-4529. (17) Sarkar, A. K.; Matta, K. L. Carbohydr. Res. 1992, 233, 245-250. (18) Chanteloup, L.; Beau, J.-M. Tetrahedron Lett. 1992, 33, 53475350. (19) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087-1088. (20) Stork, G.; La Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-248. (21) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506-4507. (22) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198-1199.
© 1997 American Chemical Society
11218 J. Am. Chem. Soc., Vol. 119, No. 46, 1997
Crich and Sun Scheme 2
using Tf2O as the activator in the presence of DTBMP as the base. These reactions were carried out in either toluene, dichloromethane, or propionitrile by addition of the sulfoxide to Tf2O at -78 °C, followed by addition of the acceptor and the acid scavenger. Mixtures of R- and β-glucosides were obtained in excellent yield. For the pivalate-protected donor 5, pure β-glucosides were obtained in all cases, which the authors attributed to neighboring group participation. With the perbenzyl derivative 6, the β:R ratio increased with solvent polarity with the optimum selectivity seen in propionitrile. Reaction times and temperatures varied widely, ranging from a few minutes at -60 °C for hindered secondary alcohols to 12 h at room temperature for coupling to N-(trimethylsilyl)acetamide, prompting the authors to comment on the remarkable stability and reactivity of the undefined, intermediate glycosyl donor. The pattern of β-glycoside formation with donors containing equatorial pivaloxy groups in the 2-position is a recurring theme in subsequent papers as is the obtention of mixtures when nonparticipating protecting groups are used. In most subsequent papers Kahne and co-workers adhere to the original protocol in terms of the sequence of combining the reagents, but occasionally, as in the use of glycosyl acceptors immobilized on a solid support,7 Tf2O is added to a preformed mixture of the sulfoxide and the acceptor. The recent full paper generalizing the method recommends activation of the sulfoxide with Tf2O before addition of the glycosyl acceptor. Variations on the theme include activation with a catalytic amount of triflic acid5 or with trimethylsilyl triflate.12 When activation was achieved with catalytic TfOH, methyl propiolate was used as a sulfenic acid scavenger.5 Alcohols have sometimes been converted to their tributylstannyl ether derivatives prior to use as glycosyl acceptors in the sulfoxide method,23 presumably to increase their nucleophilicity.24 Most frequently, phenyl sulfoxides are employed, sometimes with their reactivity modified by the incorporation of electron-donating or -withdrawing groups,5 but as we have demonstrated through the use of ethyl sulfoxides,25 the reaction is by no means limited to aryl sulfoxides. Interestingly, and even frustratingly,26 Pummerertype chemistry is not a competing reaction in the sulfoxide glycosylation protocol but has been noted to occur to some extent with the acyclic sulfoxide 7.9 The observation (Scheme 1) that the stereoselectivity in the coupling of 2 to 1 could be reversed, depending on whether Tf2O was added to activate the sulfoxide 1 before or after the acceptor 2, first sparked our curiosity in the mechanism of this extremely useful reaction. Our interest was heightened when it became apparent that the closely related glycosyl donor 8 gave poor β:R ratios on coupling to simple alcohols, and this irrespective of the mixing sequence. To our knowledge, prior to our work, there were no previous reports of the synthesis of (23) Kim, S.-H.; Augeri, D.; Yang, D.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 1766-1775. (24) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663. (25) Crich, D.; Sun, S.; Brunckova, J. J. Org. Chem. 1996, 61, 605615. (26) Crich, D.; Ritchie, T. J. Tetrahedron 1988, 44, 2319-2328.
β-mannopyranosides, or other equatorial 1,2-cis-glycosides, using the sulfoxide method, although it was reported in a footnote to the original paper1 that the stereochemistry at C2 of the donor influences the stereochemical outcome. Prior to our work25 the use of 4,6-benzylidene acetals as protecting groups for the sulfoxide had also not been reported. The change in stereoselectivity on going from 1 to 8 as the donor suggests that this rigidifying system has a significant influence on the mechanism of the reaction. The questions foremost in our minds were therefore formulated as (i) what is the mechanism of β-mannoside formation with donor 1; (ii) why does the stereoselectivity of coupling to 1 change according to the sequence of mixing the reagents; (iii) what is the nature of the intermediate glycosyl donor, derived from 6, reactive enough to glycosylate hindered secondary alcohols at -60 °C, yet stable for many hours in toluene at room temperature;1 (iv) are oxonium ions key intermediates in the glycosylation as has been suggested;27 and (v) how does the 4,6-benzylidene protecting group influence the stereoselectivity of mannosylation. A working hypothesis which rationalizes the observations of Scheme 1 is set out in Scheme 2. According to this rationale, Tf2O serves to activate the donor 1 in the form of the sulfonium salt 9. This collapses immediately to the oxacarbenium ion 10 and the sulfenyl triflate 11. When the activation is carried out in the presence of the glycosyl acceptor, 10 is trapped directly, along the axial direction for the usual stereoelectronic reasons, to give the R-mannoside. When activation is conducted prior to addition of the glycosyl acceptor, 10 is trapped by triflate anion to give the R-mannosyl triflate 12. On subsequent addition of the glycosyl acceptor 12 participates in an SN2-like reaction with formation of the β-mannoside. To probe this hypothesis, the simplified sulfoxide 13 was prepared by standard means and its 1H NMR spectrum recorded in CD2Cl2 at -78 °C in the presence of DTBMP. A 10% excess of Tf2O was then added, still at -78 °C, and a new 1H NMR spectrum acquired. Inspection of this spectrum revealed that 13 was transformed quantitatively, within the
