Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2008 Nov 25.
Published in final edited form as: Tetrahedron Lett. 2007 Jan 22;48(4):559–562. doi: 10.1016/j.tetlet.2006.11.126

An armed-disarmed approach for blocking aglycon transfer of thioglycosides

Zhitao Li 1, Jeffrey C Gildersleeve 1,*
PMCID: PMC2587334  NIHMSID: NIHMS16399  PMID: 19043616

Abstract

Thioglycosides are used frequently as glycosyl donors and as mimetics of O-glycosides. While being very useful, thioglycosides are prone to a detrimental side reaction referred to as aglycon transfer. In this paper, it is shown that aglycon transfer can be blocked by matching thioglycoside-containing acceptors with more armed glycosyl donors.

Thioglycosides are extremely useful derivatives for the synthesis of oligosaccharides and glycosylated natural products.1,2 The sulfide group is easy to install and stable to a wide range of reaction conditions. In addition, thioglycosides can be activated directly as glycosyl donors using a variety of activating agents such as mercury salts, sulfenyl triflates, and alkylating agents.1,2 Moreover, thioglycosides can be readily converted into other glycosyl donors such as glycosyl sulfoxides,3 sulfones,4 and halides.5 As a result, they are versatile intermediates for carbohydrate synthesis. Thioglycosides have also been investigated extensively as mimetics of biologically relevant O-glycosides.6 S-glycosides are much more stable than O-glycosides to both chemical and enzymatic degradation and are typically much easier to synthesize. As a result, S-glycosides have been developed as glycosyl transferase inhibitors, agonists/antagonists for lectins, and as carbohydrate-based vaccine antigens.7

While being extremely useful, compounds containing thioglycoside aglycon groups are prone to a detrimental side reaction referred to as aglycon transfer.8-22 Strong electrophilic species such as activated glycosyl donors can react with the sulfur atom of a thioglycoside to produce a sulfonium ion (see Scheme 1). Cleavage of the bond between the anomeric carbon and the sulfur atom results in transfer of the aglycon to the electrophilic species. In the case of a glycosylation reaction, the aglycon is transferred to the glycosyl donor.

Scheme 1.

Scheme 1

Open in a new tab

Aglycon Transfer of Thioglycosides

One strategy to block aglycon transfer is to introduce aglycon groups that decrease the nucleophilicity of the sulfur atom through steric hindrance and/or electronic deactivation such as the dicyclohexylmethyl group or 2,6-dimethylphenyl (DMP) group.16,17,22 While this approach is effective in many synthetic routes, there are a number of situations where the aglycon group cannot be modified. For example, many S-glycoside inhibitors and vaccine antigens have strict structural requirements for the aglycon group. Therefore, an alternative strategy that minimizes or eliminates aglycon transfer without modifying the aglycon is needed.

Several reports have shown that the aglycon transfer process is affected by the protecting groups on the glycosyl acceptor and donor. For one to effectively utilize a protecting group strategy for blocking aglycon transfer, it is critical to understand how changes to protecting groups affect transfer and how best to implement this approach.

Aglycon transfer is thought to proceed via glycosylation of the sulfur atom to form a sulfonium ion followed by cleavage to give the transfer product. In principle, this process is reversible, which raises two important issues. First, the transfer process provides a pathway for cleavage and reformation of the bond between the anomeric carbon and the sulfur atom. Therefore, it provides a pathway for anomerization of the linkage. We recently showed that anomerization does in fact occur.22 Second, the transfer process permits equilibration between the activated species derived from the glycosyl donor and the activated species derived from the thioglycoside. Therefore, the relative energies of the two activated intermediates could have a significant effect on the transfer process with the reaction driven to the more stable intermediate(s). If this were true, one could avoid transfer by controlling the relative stabilities of the activated intermed iates.

To effectively implement this approach, two important challenges must be addressed. First, one would have to prevent anomerization. This could be achieved by addition of a group that controls stereoselectivity via neighboring group participation. Second, one would like a rational means to control the relative reactivities of the activated species. However, the nature of the activated intermediate(s) and the factors that determine the relative stabilities are not well understood. Nevertheless, one can approximate the relative stabilities via an armed/disarmed analysis. The terms armed and disarmed refer to the relative ease or difficulty of activating a sugar as a glycosyl donor.23,24 In general, disarmed sugars have protecting groups that would destabilize an oxocarbenium ion such as electron withdrawing esters and azides. Armed sugars typically have protecting groups that are less destabilizing such as benzyl ethers or silyl ethers. Since the rates of activation can be evaluated experimentally, there is extensive information in the literature regarding factors that affect the armed/disarmed nature of a sugar.25

To evaluate the armed-disarmed strategy, a series of glycosylations were arried c out with the aim of synthesizing a GalNAcα1−3Gal derivative. This disaccharide is known to be expressed in humans and was needed as a glycan for our group's carbohydrate microarray.26-28 The relative armed/disarmed nature of the glycosyl donor and acceptor was systematically varied. First, the disarmed donor 129 was coupled with armed acceptor 230 (see Scheme 2).31 One would anticipate that an oxocarbenium ion (or other activated intermediate) derived from the armed 2 would be more stable than an oxocarbenium ion derived from the disarmed 1. Therefore, aglycon transfer was expected to be favorable. In fact, aglycon transfer was the major pathway (85% of 332, α:β = 2.5:1) and no disaccharide was formed. Next, we examined disarming the thioglycoside by substituting the benzyl ethers with electron withdrawing benzoyl esters. In addition to disarming the thioglycoside, the benzoyl ester at the 2 position should maintain the beta stereochemistry at the anomeric center via neighboring group participation. Glycosylation of disarmed acceptor 426 with disarmed donor 1 produced the desired disaccharide (5)26 in 40% yield along with 30% transfer product 3 (α:β = 1:1). Next, armed donor 629 was coupled with armed acceptor 2. The reaction produced a very complex mixture of products. From this mixture, the transfer product (7, all β)33 could be isolated in 30% yield, but the desired product was not obtained. The extensive formation of side products may have resulted from polymerization and/or anomerization. Finally, we coupled the disarmed thioglycoside 4 with the armed donor 6. Based on the mechanistic analysis, this is the preferred matching and transfer should be unfavorable. Indeed, disaccharide 834 was produced in 79% yield and no transfer product was observed.

Scheme 2.

Scheme 2

Open in a new tab

Effects of varying the armed/disarmed nature of the glycosyl donor and acceptor on the outcome of the glycosylation reaction

The results demonstrate that aglycon transfer can be avoided by modifying the protecting groups on the glycosyl donor and acceptor to ensure that the thioglycoside acceptor is more disarmed than the glycosyl donor. The approach provides a complement to existing strategies based on modifying the aglycon group. Given the work involved in changing protecting groups, this approach is best implemented in the planning stages of a synthesis.

Acknowledgments

Financial support from the intramural research program of the NIH, NCI is gratefully acknowledged.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.Garegg PJ. In Advances In Carbohydrate Chemistry And Biochemistry. Vol. 52. Academic Press; New York: 1997. pp. 179–205. [DOI] [PubMed] [Google Scholar]
  • 2.Toshima K, Tatsuta K. Chem. Rev. 1993;93:1503–1531. [Google Scholar]
  • 3.For some examples and key references, see Kahne D, Walker S, Cheng Y, Engen D. J. Am. Chem. Soc. 1989;111:6881–6882.; Kakarla R, Dulina RG, Hatzenbuhler NT, Hui YW, Sofia MJ. J. Org. Chem. 1996;61:8347–8349. doi: 10.1021/jo961478h.; Chen MY, Patkar LN, Chen HT, Lin CC. Carbohydr. Res. 2003;338:1327–1332. doi: 10.1016/s0008-6215(03)00164-2.; Chen MY, Patkar LN, Lin CC. J. Org. Chem. 2004;69:2884–2887. doi: 10.1021/jo035698o.; Agnihotri G, Misra AK. Tetrahedron Lett. 2005;46:8113–8116.
  • 4.For examples, see Chang GX, Lowary TL. Org. Lett. 2000;2:1505–1508. doi: 10.1021/ol005579k.; Brown DS, Ley SV, Vile S, Thompson M. Tetrahedron. 1991;47:1329–1342.
  • 5.For some examples and key references, see Nicolaou KC, Dolle RE, Papahatjis DP, Randall JL. J. Am. Chem. Soc. 1984;106:4189–4192.; Kartha KPR, Field RA. Tetrahedron Lett. 1997;38:8233–8236.; Sugiyama S, Diakur JM. Org. Lett. 2000;2:2713–2715. doi: 10.1021/ol0063050.
  • 6.For some recent reviews, see Driguez H. Thiooligosaccharides in glycobiology. Glycoscience Synthesis Of Substrate Analogs And Mimetics. 1997;187:85–116.; Witczak ZJ. Curr. Med. Chem. 1999;6:165–178.; Pachamuthu K, Schmidt RR. Chem. Rev. 2006;106:160–187. doi: 10.1021/cr040660c.
  • 7.For some recent examples, see Knapp S, Myers DS. J. Org. Chem. 2002;67:2995–2999. doi: 10.1021/jo0110909.; Bundle DR, Rich JR, Jacques S, Yu HN, Nitz M, Ling CC. Angew. Chem. Int. Ed. Engl. 2005;44:7725–7729. doi: 10.1002/anie.200502179.; Thayer DA, Yu HN, Galan MC, Wong CH. Angew. Chem. Int. Ed. Engl. 2005;44:4596–4599. doi: 10.1002/anie.200500090.
  • 8.Kihlberg J, Eichler E, Bundle DR. Carbohydr. Res. 1991;211:59–75. doi: 10.1016/0008-6215(91)84146-6. [DOI] [PubMed] [Google Scholar]
  • 9.Knapp S, Nandan SR. J. Org. Chem. 1994;59:281–283. [Google Scholar]
  • 10.Leigh DA, Smart JP, Truscello AM. Carbohydr. Res. 1995;276:417–424. doi: 10.1016/0008-6215(95)00182-s. [DOI] [PubMed] [Google Scholar]
  • 11.Belot F, Jacquinet JC. Carbohydr. Res. 1996;290:79–86. doi: 10.1016/0008-6215(96)00116-4. [DOI] [PubMed] [Google Scholar]
  • 12.Du YG, Lin JH, Linhardt RJ. J. Carbohydr. Chem. 1997;16:1327–1344. [Google Scholar]
  • 13.Zhu T, Boons GJ. Carbohydr. Res. 2000;329:709–715. doi: 10.1016/s0008-6215(00)00252-4. [DOI] [PubMed] [Google Scholar]
  • 14.Yu H, Yu B, Wu XY, Hui YZ, Han XW. J. Chem. Soc. Perkin Tran. 1. 2000;9:1445–1453. [Google Scholar]
  • 15.Sherman AA, Yudina ON, Mironov YV, Sukho va EV, Shashko v AS, Menshov VM, Nifantiev NE. Carbohydr. Res. 2001;336:13–46. doi: 10.1016/s0008-6215(01)00213-0. [DOI] [PubMed] [Google Scholar]
  • 16.Cheshev PE, Kononov LO, Tsvetkov YE, Shashkov AS, Nifantie v NE. Russ. J. Bioorg. Chem. 2002;28:419–429. [Google Scholar]
  • 17.Geurtsen R, Boons GJ. Tetrahedron Lett. 2002;43:9429–9431. [Google Scholar]
  • 18.Tanaka H, Adachi M, Takahashi T. Tetrahedron Lett. 2004;45:1433–1436. [Google Scholar]
  • 19.Xue J, Khaja SD, Locke RD, Matta KL. Synlett. 2004:861–865. [Google Scholar]
  • 20.Codee JDC, Stubba B, Schiattarella M, Overkleeft HS, van Boeckel CAA, van Boom JH, van der Marel GA. J. Am. Chem. Soc. 2005;127:3767–3773. doi: 10.1021/ja045613g. [DOI] [PubMed] [Google Scholar]
  • 21.Sun JS, Han XW, Yu B. Org. Lett. 2005;7:1935–1938. doi: 10.1021/ol050324y. [DOI] [PubMed] [Google Scholar]
  • 22.Li Z, Gildersleeve JC. J. Am. Chem. Soc. 2006;128:11612–1161. doi: 10.1021/ja063247q. [DOI] [PubMed] [Google Scholar]
  • 23.Fraser-Reid B, Wu ZF, Udodong UE, Ottosson H. J. Org. Chem. 1990;55:6068–6070. [Google Scholar]
  • 24.Mootoo DR, Konradsson P, Udodong U, Fraser-Reid B. J. Am. Chem. Soc. 1988;110:5583–5584. [Google Scholar]
  • 25.For some nice examples, see Zhang Z, Ollmann IR, Ye X-S, Wischnat R, Baasov T, Wong C-H. J. Am. Chem. Soc. 1999;121:734–753.; Jensen HH, Nordstrom LU, Bols M. J. Am. Chem. Soc. 2004;126:9205–9213. doi: 10.1021/ja047578j.
  • 26.Manimala J, Li Z, Jain A, VedBrat S, Gildersleeve JC. ChemBioChem. 2005;6:2229–2241. doi: 10.1002/cbic.200500165. [DOI] [PubMed] [Google Scholar]
  • 27.Manimala JC, Roach TA, Li Z, Gildersleeve JC. Angew. Chem. Int. Ed. Engl. 2006;45:3607–3610. doi: 10.1002/anie.200600591. [DOI] [PubMed] [Google Scholar]
  • 28.Podolsky DK. J. Biol. Chem. 1985;260:8262–8271. [PubMed] [Google Scholar]
  • 29.Schmidt RR, Grundler G. Angew. Chem. Int. Ed. Engl. 1982;21:781–782. [Google Scholar]
  • 30.Kanie O, Ito Y, Ogawa T. Tet. Lett. 1996;37:4551–4554. [Google Scholar]
  • 31.Procedure for the glycosylation reactions: A mixture of donor 6 (98 mg, 0.16 mmol, 2 eq) and acceptor 4 (46 mg, 0.08 mmol, 1 eq) was dried under vacuum for 1 hr and then dissolved in dichloromethane (1 mL). Molecular sieves was added to the solution and the reaction was cooled to −20 °C. TMSOTf (1 drop) was added and the mixture was stirred at −20 °C for 0.5 hr. The reaction was quenched by addition of saturated NaHCO3 (1 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (1:1 ethyl acetate/hexanes) to give the desired product, phenyl (2-azido-3,4,6-tri-O-benzyl-2-deoxy-α-D-galactopyranosyl)-(1→3)-2,4,6-tri-O-benzoyl-1-thio-β-D-galactopyranoside (8), (64 mg, 79% yield).
  • 32.Andreotti AH, Kahne D. J. Am. Chem. Soc. 1993;115:3352–3353. [Google Scholar]
  • 33.Suzuki K, Ohtsuka I, Kanemitsu T, Ako T, Kanie O. J. Carbohydr. Chem. 2005;24:219–236. [Google Scholar]
  • 34.Phenyl (2-azido-3,4,6-tri-O-benzyl-2-deoxy-α-D-galactopyranosyl)-(1→3)-2,4,6-tri-O-benzoyl-1-thio-β-D-galactopyranoside (8), (64 mg, 79% yield): Rf = 0.4 (1:2 ethyl acetate/hexanes); 1H NMR (CDCl3) δ 8.08−8.01 (m, 6H), 7.61−7.50 (m, 5 H), 7.48−7.43 (m, 4 H), 7.33−7.17 (m, 18 H), 7.10−7.08 (m, 2 H), 5.91 (d, J = 3.2 Hz, 1 H), 5.64 (t, J = 10.0 Hz, 1 H), 5.24 (d, J = 3.6 Hz, 1 H), 4.85 (d, J = 10.0 Hz, 4.66 (d, J = 11.2 Hz, 1 H), 4.58 (dd, J = 11.6, 7.2 Hz, 1 H), 4.46−4.36 (m, 3 H), 4.30−4.21 (m, 4 H), 4.12 (m, 1 H), 3.74 (m, 1 H), 3.70 (dd, J = 10.4, 3.2 Hz, 1 H), 3.44 (dd, J = 10.8, 2.8 Hz, 1 H), 3.38 (dd, J = 9.6, 7.2 Hz, 1 H), 3.23 (d, J = 1.2 Hz), 3.17 (dd, J = 9.6, 5.6 Hz, 1 H); 13C NMR (CDCl3) δ 166.0, 165.7, 164.7, 138.1, 138.0, 137.5, 133.3, 133.2, 131.9, 130.1, 129.9, 129.8, 129.5, 129.4, 129.1, 128.8, 128.5, 128.44, 128.42, 128.36, 128.32, 128.16, 128.1, 127.97, 127.8, 127.7, 127.6, 127.5, 94.2, 86.0, 77.4, 75.0, 74.4, 73.7, 73.3, 73.2, 72.5, 70.1, 69.1, 68.9, 65.6, 62.7, 59.2; HRMS, C alcd for [MNH4]+ C60H59N4O12S: 1059.3850. Found: 1059.3873.

RESOURCES