Direct and Stereoselective Synthesis of α-Linked 2-Deoxy-Glycosides

Abstract

α-Linked 2-deoxy-glycosides were conveniently obtained by employing a glycosyl donor having a participating (S)-(phenylthiomethyl)benzyl moiety at C-6, whereas 2,6-di-deoxy-α-glycosides could be prepared by BF₃•Et₂O promoted activation of allyl glycosyl donors.

Many medically important natural products are modified by oligosaccharides composed of 2-deoxy-sugars and examples of such compounds include antibiotics such as erythromycin, anti-parasite agents such as amphotericin, insecticides such as the avermectins and anti-cancer drugs such as doxorubicin.[1-4] The sugar moiety of these compounds can wield a remarkable influence on pharmacological and pharmacokinetic properties and can dictate the molecular recognition at the drug target site. Not surprisingly, considerable efforts are directed to the development of tools that make it possible to diversify natural product glycosylation.[5-7] This approach, which has been coined glycodiversification or glycorandomization, can be achieved by metabolic, enzymatic and chemical means.[8-14]

The stereochemical introduction of 2-deoxy glycosides is a key step in chemical glycodiversification and has mainly been achieved by indirect methods that employ a participating functionality as C-2 of a glycosyl donor such as halides and aryl selenyl and sulfenyl derivatives.[15-18] The drawback of this approach is that the introduction and removal of the participating functionality requires additional steps that need to be performed in a stereoselective manner often leading to time-consuming synthetic procedures. On the other hand, several methods are available for direct β-selective glycosylation in which α-glycosyl halides, glycosyl phosphites and trichloroacetimidates are employed as glycosyl donors in combination with a mild promoter.[19-24] α-Glycosides of 2-deoxysaccharides have been obtained in moderate yield by acid catalyzed activation of glycals and anomeric esters and silyl ethers.[25-28] Furthermore, diastereoselective Pd-promoted glycosylations followed by reduction of a 2,3-double bond of the resulting compound has been employed to prepare unnatural 2,3-di-deoxy glycosides.[29, 30] Reasonable anomeric selectivities have also been achieved by remote assistance of a p-methoxybenzoyl ester at C-3 of a glycosyl donor. Remote particpiation has also been implicated in the stereoselective introduction of α-galactosides, α-glucosides and β-mannosides.[31-37]

Recently, we demonstrated that glycosylations with glycosyl donors modified at C-2 with a (S)-(phenylthiomethyl)benzyl moiety give exclusively α-anomeric selectivity due to neighboring group participation resulting in an intermediate trans-fused 1,2-sulfonium ion.[38-40] We were curious to explore whether remote participation by a (S)-(phenylthiomethyl)benzyl moiety can be exploited in the stereochemical synthesis of 2-deoxy-glycosides. Thus, trichloroacetimidates 1-3 were prepared that have either a (S)-(phenylthiomethyl)benzyl, a benzyl ether or acetyl ester at C-6 (Table 1). Interestingly, a TMSOTf-mediated glycosylation of donor 1 with glycosyl acceptor 4 gave the expected disaccharide 8 in good yield as almost exclusively the α-anomer. Similar glycosylations employing glycosyl donors 2 and 3, having a benzyl ether or acetyl ester at C-6, provided the disaccharides 9 and 10, respectively as mixtures of anomers. The use of (R)-(phenylthiomethyl)benzyl ether at C-6 of the glycosyl donor also led to excellent anomeric selectivity indicating that the chirality of the auxiliary did not influence the anomeric outcome of the glycosylation. We were unable to identify the intermediate sulfonium ion by NMR experiments in which 1 was activated with TMSOTf probably due to the high reactivity of the intermediate. However, glycosylations of 1 with 5-7 led to the isolation of the corresponding disaccharides 11, 13 and 15 in excellent yields with almost exclusively α-anomeric selectivity. The alternative use of benzylated derivative 2 gave the disaccharides 12, 14 and 16 as mixtures of anomers. Glycosylations of 2 and 3 promoted by BF₃•Et₂O did not lead to an improvement of anomeric selectivity. Thus, it appears that a (phenylthiomethyl)benzyl ether at C-6 promotes high α-selectivity.

Table 1.

Glycosylations with trichloroacetimidate donors 1-3.

donor	Acceptor	Product	yield (%)	α/β
1	4	8	94	15:1
1	5	11	93	12:1
1	6	13	95	10:1
1	7	15	92	8:1
2	4	9	96	1:1
2	5	12	95	1:1
2	6	14	92	5:1
2	7	16	93	4:1
3	4	10	90	4:1

All reactions were performed at -78 °C in DCM.

Next, attention was focused on anomeric control by employing a glycosyl donor that has a (S)-(phenylthiomethyl)benzyl ether at C-4. Surprisingly, an attempt to introduce the auxiliary at C-4 by treatment of sugar alcohol 17 with (S)-(phenylthiomethyl)benzyl acetate 18 in the presence of BF₃•OEt₂ led to the formation of disaccharide 19 (Scheme 1). Thus, unexpected activation of the allyl glycoside of 17 led to self-condensation. However, the allyl glycoside of disaccharide 19 did not undergo further activation indicating that 17 (or its auxiliary modified counter-part) is more reactive than 19.

Scheme 1.

Direct activation of a 2,6-dideoxy allyl glycoside.

Allyl glycosides are attractive building blocks in glycoside chemistry because the allyl moiety provides convenient protection of the anomeric center but can easily be removed by isomerization to a vinyl glycoside, which can be hydrolyzed under mild conditions to give a lactol. The latter compound can be converted into various glycosyl donors such as trichloroacetimidates, phosphites and halides. The intermediate vinyl glycoside can also directly be employed as a glycosyl donor in TMSOTf-promoted glycosylations.[41, 42]

We envisaged that allyl 2-deoxy-glycosides would be interesting building blocks for oligosaccharide assembly because the results presented here indicate that these compounds can be employed in direct glycosylations using BF₃•Et₂O as the promoter or converted into various conventional glycosyl donors using standard procedures. To explore the direct glycosylation of allyl 2-deoxy-glycosides in more detail, compounds 20, 21 and 22, which have either benzyl ether or ester at C-3 and C-4, were employed in BF₃•Et₂O mediated glycosylations with glycosyl acceptors 4-7 to give the corresponding disaccharides 23-34 (Table 2). Interestingly, the highly activated glycosyl donor 20 having benzyl ethers at C-3 and C-4 could be activated at -78 °C to provide the expected disaccharides 23, 26, 29, and 32 in excellent yields (Table 2). The somewhat less reactive glycosyl donor 21, having a benzoyl ester C-4, required a temperature of -30 °C for activation whereas the least reactive derivative 22 was only reactive at 0 °C. Importantly, each glycosylation resulted in the formation of the expected disaccharide (23-34) as mainly the α-anomer. Thus, these results indicated that the high α-anomeric selectivity observed in the formation of disaccharide 19 is not due to participation by the C-4 (S)-(phenylthiomethyl)benzyl ether but probably a result of the BF₃•Et₂O promoted activation of the allyl glycoside. Furthermore, it was observed that the corresponding methyl glycosides of 20-22 were less reactive than allyl glycosides because higher reaction temperatures and a larger excess of BF₃•Et₂O (4 eq) was required for activation. The use of catalytic TMSOTf as the promotor to activate 20-22 lead to good anomeric selectivities, however, the yields were significantly lower compared to BF₃•Et₂O promoted glycosylations.

Table 2.

Glycosylations with allyl glycosyl donors 20-22.

donor	accept	temp	prod	yield (%)	α/β
20	4	-78 °C	23	85	8:1
20	5	-78 °C	26	80	5:1
20	6	-78 °C	29	68	7:1
20	7	-78 °C	32	62	5:1
21	4	-30-0 °C	24	83	10:1
21	5	-30-0 °C	27	82	8:1
21	6	-30-0 °C	30	68	11:1
21	7	-30-0 °C	33	65	10:1
22	4	0 °C-rt	25	85	14:1
22	5	0 °C-rt	28	82	13:1
22	6	0 °C-rt	31	73	15:1
22	7	0 °C-rt	34	72	10:1

All reactions were performed in DCM.

Attempts were also made to introduce β-glycosides by treatment compounds 20-22 with TMSI or TMSBr to form the intermediate halides, which can then be displaced by a sugar alcohol to form β-glycosides.[24] However, these attempts led to formation of disaccharides in good yields but with poor anomeric selectivities (see supporting information).

Finally, the direct activation of allyl 2-deoxy-glycosides was employed in an armed-disarmed strategy to synthesize more complex compounds.[43-45] Thus, it was envisaged that benzylated 2,6-di-deoxy-glycoside 20 would be more reactive than compound 35, which has a deactivating acetyl ester at C-3. Indeed, a BF₃•Et₂O mediated glycosylation of 20 with 35 in DCM at -20 °C gave clean formation of disaccharide 36, which was isolated in a yield of 56% (α/β = 6/1) and led to the recovery of a small amount of starting materials (Scheme 2). However, further activation of allyl glycoside 36 at a higher reaction temperature led to decomposition of the disaccharide. It is possible to convert the allyl glycoside of the latter compound into another leaving group for conventional glycosylation. We aimed, however, to minimize manipulations during oligosaccharide assembly and therefore the less reactive glycosyl donor 21 was employed in a coupling with glycosyl acceptor 35 and in this case disaccharide 37 was obtained in a yield of 62% (α/β = 8/1). The successful formation of this compound indicates that the benzoyl ester at C-4 of 21 is less deactivating than the acetyl ester at C-3 of 35. Fortunately, the allyl glycoside of 37 could be activated with BF₃•Et₂O at 0 °C and coupling with cyclohexanol, which was used as a mimic of the aglycon of compounds such as avermectin B_1a, gave disaccharide 38 as mainly the α-anomer.

Scheme 2.

Armed-disarmed glycosylation strategy.

In conclusion, it has been demonstrated that 2-deoxy-glycosyl donors having a (S)-(phenylthiomethyl)benzyl moiety at C-6 can be employed for the chemical synthesis of α-linked glycosides. In addition, it was found that allyl 2,6-di-deoxy-glycosides could easily be activated with BF₃•Et₂O and couplings with a variety of sugar alcohol provided mainly α-glycosides. It is to be expected that the methodology will be attractive for glycorandomization of medically important natural products.

Supplementary Material

1_si_001. Supporting Information Available.

Experimental procedures and ¹H and ¹³C NMR spectra. This information is available free of charge via the Internet at http://pubs.acs.org.