β-Mannosylation with 4,6-benzylidene protected mannosyl donors without preactivation

Abstract

Mannosylations with benzylidene protected mannosyl donors were found to be β-selective even when no preactivation was performed. It was also found that the kinetic β-product in some cases anomerizes fast to the thermodynamically favored α-anomer under typical reaction conditions.

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Chemical glycosylation, a reaction for the synthesis of oligosaccharides and other biologically or medicinally crucial glycosides, is a very important reaction.¹ Many excellent glycosylation protocols that lead to high yield and stereocontrol have been developed, even when alcohol and the glycosylation agent are used in equimolar amounts.² Nevertheless, stereochemistry is always an issue in glycosylation reactions and this simple fact leaves the impression that they are largely S_N1-type reactions.^2d,3 It was therefore remarkable when the Crich laboratory discovered that β-mannosides, a stereochemical pattern that is notoriously difficult to obtain by direct glycosylation, could be obtained directly when a 4,6-benzylidene protective group was present in the mannosyl donor.^4,5 It was also remarkable that a special pre-activation procedure was critical for β-selectivity: when the sulfoxide donor 1 was pre-activated with triflic anhydride at −78 °C before the addition of the acceptor, β-selectivity (β-mannoside 3) was obtained (Scheme 1), but if alcohol was present when triflic anhydride was added α-mannoside 4 was formed.⁶ These observations, together with the low temperature observation of an α-triflate 2 upon pre-activation, led to the proposal that the β-manno selectivity is a result of an S_N2 substitution (Scheme 1),^7,8 albeit several papers have reported that preactivation is not necessary.⁹ We were therefore surprised when we recently performed mannosylation reactions with a 4,6-silylene protected thiomannoside 5 and found that β-mannoside 7 was formed by simple direct activation of the thioglycoside with NIS/TfOH (cat.) in the presence of an acceptor (Scheme 2) – this worked even at room temperature, regardless of the anomeric configuration of the thiomannoside. This indicates that the oxocarbenium ion 6 was the glycosylating species and was attacked from the β-face.¹⁰

Scheme 1 The crucial effect of the order of addition order on stereoselectivity in mannosylation reactions observed (ref. 4 and 6).

Scheme 2 The use of the 4,6-di-tert-butylsilylene tethered donor for selective β-mannosylation using direct activation.

Conclusions made with this 4,6-silylene protected thiomannoside may not hold for the commonly used 4,6-benzylidene protected mannosyl donors. Indeed the literature, including the results reported above, indicated that it did not; NIS-promoted glycosylations with 4,6-benzylidene protected phenyl thiomannosides, as an example, were less β-selective than when using the pre-activation procedure.¹¹ So we were interested in seeing if the apparent indiscriminate β-selectivity of the 4,6-silylene protected thiomannoside 5 was also found for the commonly used benzylidene protected mannosyl donors (such as 1) and if this would also hold for other common donor types such as trichloroacetimidates and sulfoxides. The results of this investigation are reported in the present paper. Benzylidene protected mannosyl donors give β mannosides as the kinetic products and significant α mannoside formation in some cases may be a result of subsequent anomerisation.

As seen above the benzylidene analogue of 5, the α-thioglycoside 8, was reacted with a series of relevant acceptors 11–15 (Scheme 3) promoted by NIS/TfOH. These reactions gave mostly high yield and high β-selectivity (Table 1, entries 1–5).¹²

Scheme 3 Donors, acceptors and products.

Table 1 Results of glycosylation with sulfur containing mannosyl donors 1, 8 & 9

Entry	Dnr	Ac	Conditions	Yield/β : α
0.1 equiv. TfOH was used, ND: not determined, TTBP: 2,4,6-tri-tert-butylpyrimidine, NIS: N-iodosuccinimide and DTBMP = di-tert-butyl-4-methylpyridine. CH2Cl2 is used as solvent in all glycosylations.a Literature reference reaction >9/1 88%.^13a,bb 34% 1.c 30% 9.d Preactivation.
1	8	11	NIS, TfOH, −78 → 0 °C	98%/7 : 1^a
2	8	11	NIS, TfOH, 0 °C	94%/6 : 1
3	8	11	NIS, TfOH, 25 °C	93%/6 : 1
4	8	12	NIS, TfOH, 25 °C	26%/5 : 1
5	8	15	NIS, TfOH, 25 °C	34%/2 : 1^b
6	1	14	Tf2O, TTBP, −78 °C^d	82%/>9 : 1
7	1	14	Tf2O, TTBP, −78 °C	47%/9 : 1^b
8	1	15	Tf2O, DTBMP, −78 °C^d	ND/>20 : 1
9	1	15	Tf2O, DTBMP, −78 °C	64%/>20 : 1
10	1	13	Tf2O, DTBMP, −78 °C^d	67%/5 : 1
11	1	13	Tf2O, DTBMP, −78 °C	42%/5 : 1
12	9	14	Tf2O, DTBMP, −78 °C^d	ND/β-only
13	9	14	Tf2O, DTBMP, −78 °C	33%/4 : 1^c
14	9	13	Tf2O, DTBMP, −78 °C	ND/3 : 1
15	9	14	Tf2O, DTBMP, −78 °C	41%/7 : 2
16	9	14	Tf2O, DTBMP, −78 → rt	34%/1 : 12

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This is essentially the same outcome as with the silylene-tethered donor 5¹⁰ and comparable to what one obtains with a pre-activation procedure.¹³ It is noteworthy that β-selectivity is obtained at 0 °C or 25 °C (Table 1, entries 2 & 3) even though α-triflate is not stable at such high temperatures.^5c

We now reinvestigated the original protocol for β mannosylation,^4,6 which uses α-anomeric sulfoxide 1 that is activated using Kahne's method,¹⁴ and included the corresponding β-sulfoxide 9 in the study. When the anomeric set of donors 1 and 9 were preactivated and allowed to react with cyclohexanol 14 at −78 °C both donors gave the β-mannoside 17 with high selectivities (9 : 1 and β-only respectively – Table 1, entries 6 & 12). When alcohol 14 was present from the beginning, prior to activation, the β : α ratio remained high (9 : 1 for the α-sulfoxide 1 and 4 : 1 for the β-sulfoxide 9, Table 1, entries 7 & 13). The acceptor alcohols 13 and 15 gave similar results (Table 1, entries 8–11 & 14). When pre-activation was omitted the yields were significantly lower, which we suspect is due to some triflation of the acceptor alcohol.^5c This side reaction becomes a larger problem when the alcohol is a better nucleophile or when the glycosylation is hampered.¹⁵ So while preactivation is a good idea as it provides better yields it is not a requirement for β-mannoside formation.

The experiments without pre-activation (Table 1, entries 7, 9, 11 and 13) appears to contradict earlier findings^4,6 where such conditions gave either α-mannosides or low selectivity. We speculated that the α-mannoside formation sometimes may be caused by an acid catalyzed anomerisation if insufficient amount of base was present. To test this hypothesis, two reactions were carried out with activation of 9, in the presence of the acceptor 14 (2 equiv.), at −78 °C using sub-stoichiometric amounts of base (1 equiv.) relative to Tf₂O (1.7 equiv., Table 1, entries 15 & 16). One reaction was quenched at −70 °C, whereas the other was allowed to reach 0 °C and kept there for 5 min. before quenching it with Et₃N. The change in stereoselectivity was dramatic: The first experiment gave mainly β (7 : 2) and the latter mainly α (1 : 12). It is clear that, similar to what was observed with the silylene donor,¹⁰in situ anomerisation has occurred and obviously led to an erosion of β-selectivity.

We also investigated the popular trichloroacetimidate (TCA) donors. Schmidt has already reported that TCA donor 10 gave β-mannosides promoted by excess TMSOTf,^8a but in light of the findings above we wished to see if triflate could be omitted. First we carried out 7 glycosylations with donor 10 and acceptors 11–13 (Table 2, entries 1–7) using TMSOTf catalysis (0.1 equiv.). These experiments confirmed the β-selectivity and yield were high, provided the reaction was run in a nonpolar solvent and quenched at low temperature (entries 1, 3–4) or an acid scavenger (1 equiv. 2,4,6-tri-tert-butylpyrimidine (TTBP))¹⁶ was added (entries 2, 5 and 6). If no such precaution against anomerisation was taken the α-anomer was predominant (Table 2, entry 7).

Table 2 Results of glycosylation with trichloroacetimidate donor 10

Entry	Dnr	Ac	Conditions	Yield/β : α
Dnr: donor, Ac: acceptor, ND: not determined, NR: no reaction; HFIB: 1,1,1,3,3,3-hexafluoro-2-propanol and TTBP: 2,4,6-tri-tert-butylpyrimidine.a 21 sideproduct.b Quenched after 10% conversion.
1	10	11	TMSOTf, CH2Cl2, −78 °C	Quan./>6 : 1
2	10	11	TMSOTf, TTBP, CH2Cl2, rt	ND/>6 : 1
3	10	11	TMSOTf, HFIP, −78 °C → rt	0%
4	10	11	TMSOTf, PhMe, −78 °C → rt	92%/>10 : 1
5	10	12	TMSOTf, TTBP, CH2Cl2, 25 °C	ND/8 : 1
6	10	13	TMSOTf, TTBP, CH2Cl2, 0 °C	ND/2.2 : 1
7	10	13	TMSOTf, CH2Cl2, −78 → rt	ND/1 : 2.5
8	10	11	BF3·OEt2, CH2Cl2, −78 °C	<5%/>6 : 1^a
9	10	11	BF3·OEt2, CH2Cl2, LiOTf^b	10%/>10 : 1
10	10	11	LiOTf (0.1 equiv.), TTBP, BF3	ND/>10 : 1
11	10	15	BF3, CH2Cl2, −78 °C	21
12	10	15	BF3, CH2Cl2, LiOTf, TTBP	ND/∼5 : 1
13	10	12	BF3, TTBP, CH2Cl2, 25 °C	21
14	10	12	TTBP, LiOTf, CH2Cl2, 25 °C	NR
15	10	12	TTBP, LiOTf, CH2Cl2, 25 °C, BF3	ND/>8 : 1^a
16	10	12	AgClO4, TTBP, CH2Cl2, 25 °C	NR
17	10	12	AgClO4, TTBP, CH2Cl2, 25 °C, BF3	21
18	10	12	LiClO4, TTBP, CH2Cl2, 25 °C	NR
19	10	12	LiClO4, TTBP, CH2Cl2, 25 °C, BF3	21
20	10	13	BF3, CH2Cl2, 25 °C	77%/1 : 2^a

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To investigate the necessity of triflate in these reactions 13 glycosylations using BF₃·OEt₂ activation were performed (Table 2, entries 8–20). At low temperature only a small amount of the glycosylation product was obtained, but with β-selectivity (Table 2, entries 8, 11 and 12), while a major sideproduct was mannosyl fluoride 21. At room temperature it was possible to obtain good yield, but now the β-selectivity was lost due to anomerisation (entry 20); adding TTBP did not work here (entry 13). Remarkably, adding LiOTf significantly enhanced the reaction rate. The β-anomer was the kinetic product (entry 9), and adding an acid scavenger allowed full conversion with high β-selectivity (Table 2, entries 10 and 15). LiOTf alone did not activate (entry 14) and silver or lithium perchlorate could not substitute the effect of triflate (entries 16–19).

The above studies show that preactivation is not necessary in order to get good yield and β-selectivity. Regardless of the configuration of the donor the β-mannoside appears to be the kinetic product; however acid catalysed anomerisation, especially at prolonged reaction times at ambient temperature, can erode the stereoselectivity as it gives α-mannoside. This can be prevented by the addition of an acid scavenger.

While triflate is not always necessary in order to get β-selectivity we find it has a clear catalytic effect that appears, at least in some cases, to be caused by the triflate ion itself (Table 2, entry 10). This suggests that formation of a tight ionpair with triflate¹⁷ facilitates formation of the oxocarbenium ion and indeed, in accordance with the Crich mechanism,^18,19 is an intermediate in the reaction. Recent work with gold-catalyzed glycosylations also indicate that the role of triflate in these reactions is non-trivial.^20,21 Perhaps, β-selectivity is attributed to the intermediacy of an oxocarbenium ion ionpair in B_2,5 conformation²² either solvent separated as we proposed for the 4,6-silylene donor,¹⁰ or as a contact ion pair with triflate in the α-position as recent calculations support.^22c This ion pair is glycosylated with β-selectivity either for steric reasons or simply due to the shielding effect of the triflate.

Notes and references

1. P. Stallforth, B. Lepenies, A. Adibekian and P. H. Seeberger, J. Med. Chem., 2009, 52, 5561–5577.
2. (a) R. R. Schmidt, Angew. Chem., Int. Ed., 1986, 25, 212–235; (b) S. C. Ranade and A. V. Demchenko, J. Carbohydr. Chem., 2013, 32, 1–43; (c) J. Guo and X.-S. Ye, Molecules, 2010, 15, 7235–7265; (d) X. Zhu and R. R. Schmidt, Angew. Chem., Int. Ed., 2009, 48, 1900–1934.
3. (a) H. Paulsen, Angew. Chem., Int. Ed., 1982, 21, 155–173; (b) K. Toshima and K. Tatsuta, Chem. Rev., 1993, 93, 1503–1531; (c) G. J. Boons, Tetrahedron, 1996, 52, 1095–1121.
4. D. Crich and S. Sun, J. Org. Chem., 1996, 61, 4506–4507.
5. The importance of the 4,6-O-benzylidene for β-selectivity was later investigated: (a) D. Crich and A. Banerjee, Org. Lett., 2005, 7, 1395–1398; (b) H. H. Jensen, L. U. Nordstrøm and M. Bols, J. Am. Chem. Soc., 2004, 126, 9205–9213; (c) T. G. Frihed, M. T. C. Walvoort, J. D. C. Codée, G. A. van der Marel, M. Bols and C. M. Pedersen, J. Org. Chem., 2013, 78, 2191–2205.
6. D. Crich and S. Sun, Tetrahedron, 1998, 54, 8321–8348.
7. (a) D. Crich, Acc. Chem. Res., 2010, 43, 1144–1153; (b) A. Aubry, K. Sasaki, I. Sharma and D. Crich, Top. Curr. Chem., 2011, 301, 141–188.
8. An S_N1-type mechanism has been suggested for C-glycosylations: (a) M. Moumé-Pymbock and D. Crich, J. Org. Chem., 2012, 77, 8905–8912; (b) M. Huang, P. Retailleau, L. Bohé and D. Crich, J. Am. Chem. Soc., 2012, 134, 14746–14749.
9. For some studies that appear inconsistent with S_N2 hypothesis and are precedent to the present work, see: (a) R. Weingart and R. R. Schmidt, Tetrahedron Lett., 2000, 41, 8753–8758; (b) J. D. C. Codée, L. A. Hossain and P. H. Seeberger, Org. Lett., 2005, 7, 3251–3254; (c) J. Y. Baek, T. J. Choi, H. B. Jeon and K. S. Kim, Angew. Chem., Int. Ed., 2006, 45, 7436–7440; (d) K. S. Kim, J. H. Kim, Y. J. Lee, Y. J. Lee and J. Park, J. Am. Chem. Soc., 2001, 123, 8477–8481; (e) T. Tsuda, R. Arihara, S. Sato, M. Koshiba, S. Nakamura and S. Hashimoto, Tetrahedron, 2005, 61, 10719–10733; (f) S. Tanaka, M. Takashina, H. Tokimoto, Y. Fujimoto, K. Tanaka and K. Fukase, Synlett, 2005, 2325–2328; (g) H. Nagai, S. Matsumura and K. Toshima, Carbohydr. Res., 2003, 338, 1531–1534; (h) K. Worm-Leonhard, K. Larsen and K. J. Jensen, J. Carbohydr. Chem., 2007, 26, 349–368.
10. M. Heuckendorff, J. Bendix, C. M. Pedersen and M. Bols, Org. Lett., 2014, 16, 1116–1119.
11. (a) M. You, Y. Shin, K. H. Chun and J. E. N. Shin, Bull. Korean Chem. Soc., 2000, 21, 562–566; (b) C. T. Tanifum and C.-W. T. Chang, J. Org. Chem., 2009, 74, 634–644; (c) S. Wang, D. Lafont, J. Rahkila, B. Picod, R. Leino and S. Vidal, Carbohydr. Res., 2013, 372, 35–46; (d) D. Crich, M. de la Mora and A. U. Vinod, J. Org. Chem., 2003, 68, 8142–8148.
12. The selectivities are determined from crude NMR obtained after a simple work-up. The spectra corresponding to the α- or β-products are superimposed with the crude spectra to analyze the product distribution. Reference spectra were obtained from purified samples, which were fully assigned and the anomeric stereo-chemistry is determined from the ¹J_C1,H1-coupling constant and literature references to the known compounds. See K. Bock and C. Pedersen, J. Chem. Soc., Perkin Trans. 2, 1974, 293–297.
13. BSP and Ph₂SO are the most common: (a) D. Crich and M. Smith, J. Am. Chem. Soc., 2001, 123, 9015–9020; (b) J. D. C. Codée, R. E. J. N. Litjens, R. den Heeten, H. S. Overkleeft, J. H. van Boom and G. A. van der Marel, Org. Lett., 2003, 5, 1519–1522.
14. D. Kahne, S. Walker, Y. Cheng and D. B. Engen, J. Am. Chem. Soc., 1989, 111, 6881–6882.
15. The method was originally developed for poor acceptors; see ref. 14. It has however also been observed that a less nucleophilic 4-OH acceptor has been triflated (see ref. 5c).
16. Addition of TTBP slows down the reaction, but does not inhibit it. As TTBP has a pK_a of 1.0 it can potentially be the promotor. For pK_a see: H. C. van der Pas and A. Koudijs, Recl. Trav. Chim. Pays-Bas, 1978, 97, 159–161.
17. For a discussion of the formation and interconversion of contact and solvent separated ion pairs in glycosylations, see: T. Hosoya, T. Takano, P. Kosma and T. Rosenau, J. Org. Chem., 2014, 79, 7889–7894.
18. M. M. Huang, G. E. Garrett, N. Birlirakis, L. Bohé, D. A. Pratt and D. Crich, Nat. Chem., 2012, 4, 663–667.
19. L. Bohé and D. Crich, Carbohydr. Res., 2015, 403, 48–59.
20. Y. Zhu and B. Yu, Chem. – Eur. J., 2015, 21, 8771–8780.
21. P. Sun, P. Wang, Y. Zhang, X. Zhang, C. Wang, S. Liu, J. Lu and M. Li, J. Org. Chem., 2015, 80, 4164–4175.
22. For studies where a boat conformation has been proposed in β-glycoside formation, see: (a) T. Nukada, A. Bérces and D. M. Whitfield, Carbohydr. Res., 2002, 337, 765–774; (b) H. Satoh, H. S. Hansen, S. Manabe, W. F. van Gunsteren and P. H. Hünenberger, J. Chem. Theory Comput., 2010, 6, 1783–1797; (c) T. Hosoya, P. Kosma and T. Rosenau, Carbohydr. Res., 2015, 411, 64–69.

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Footnote

† Electronic supplementary information (ESI) available: General experimental procedures and analysis data. See DOI: 10.1039/c5cc04716a

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