Novel stereocontrolled amidoglycosylation of alcohols with acetylated glycals and sulfamate ester

Abstract

A regio- and stereo-controlled, one-pot amidoglycosylation of alcohols has been achieved using O-acetylated glycals, trichloroethoxysulfonamide, and iodosobenzene in the presence of a rhodium(II) catalyst. The reaction would proceed via stereoselective intermolecular aziridination of the glycal.

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2-N-Acetamido-2-deoxyglycosides, most commonly of the D-glucose and D-galactose series, are widely distributed in living organisms as glycoconjugates (glycolipids, glycoproteins) and glycosaminoglycans. Aminosugars on cell surfaces are assumed to play an important role as receptor ligands for protein molecules such as enzymes, antibodies, and lectins. Except D-glucosamine, most aminosugars, e.g., D-galactosamine, D-mannosamine, disaccharide lactosamine, are rather expensive as starting materials for the chemical synthesis of glycoconjugates and oligosaccharides.

Glycals (1,2-dehydro-sugar derivatives) have proved to be useful synthetic precursors of 2-amino-2-deoxy-O-glycosides by way of N-functionalisation at C-2 accompanied by addition of alcohols to C-1 (aza-glycosylation), and a variety of methods have been developed for the nitrogen transfer to glycals over the last few decades.¹ Among them, azido-nitration reactions developed by Lemieux and co-workers² have been widely used since the reaction of O-protected glycals with sodium azide and cerium(IV) ammonium nitrate provides 2-azido-2-deoxy-1-O-nitro-glycoses regioselectively. However, the stereoselectivities are dependent on the structure of the glycal substrate; the azidonitrations of acetylated glucal derivatives often proceed non-stereoselectively to give both epimers of the azido group at C-2 (gluco-N and manno-N isomers).^2,3

In recent years, transition metal-catalysed inter- and intra-molecular aziridinations of alkenes have been developed by using nitrenes as a nitrogen source.⁴ The highly reactive nitrene species are generated in situ from several types of precursors, e.g., sulfonyliminoiodinanes,⁵ sulfonamides⁶/sufamate esters⁷/carbamate esters⁸ with iodine(III) compounds, N-(sulfonyloxy)carbamates with base,⁹ chloramine-T,¹⁰ and azido-compounds.¹¹ When the aziridination reactions are applied to glycal derivatives, the corresponding 1,2-aziridines would be formed. The anomeric C-1 position of N-sulfonyl or N-carbonyl 1,2-aziridino-glycosides would be highly electrophilic to react readily with nucleophiles providing 2-amino-2-deoxy-glycoside derivatives. There have been several reports on such aminoglycosylation reactions via aziridine intermediates.^4c Rojas and co-workers reported intramolecular aziridinations of 3-O-azidoformyl-^12a and 3-O-carbamoyl-D-allal derivatives^12b and subsequent reactions with alcohols to access 2-amino-2-deoxy-β-D-allopyranosides stereoselectively. Liu and co-workers reported stereoselective synthesis of glucosamine derivatives via rhodium-catalysed, substrate-controlled aziridination of 4-O- or 6-O-sulfamoyl-D-glucal derivatives.¹³ However, these precedents require preparation of the appropriate substrates for intramolecular aziridinations. Stereoselective synthesis of 2-amino-2-deoxy-1-O-glycosides from glycals via intermolecular aziridination¹⁴ should be more challenging since it would likely afford a mixture of stereoisomers. Indeed, to our knowledge, this type of glycosylation has been reported only by Descotes' group; addition of photochemically generated N-ethoxycarbonyl-nitrenes to acetylated glycals in methanol gave the methyl 2-amino-glycosides as a mixture of three stereoisomers.¹⁵

We report here a regio- and stereo-controlled amidoglycosylation of alcohols via intermolecular aziridination in a one-pot manner using simple O-acetylated glycals (D-glucal, D-galactal, D-lactal), which are readily prepared in 3 steps from the parent sugars. In their research on rhodium-catalysed olefin aziridination with PhI(OAc)₂ and sulfamate esters, Du Bois and co-workers found a stereospecific amido-acetoxylation of tri-O-acetyl-D-glucal 1a to give 2-deoxy-2-(trichloroethoxysulfonyl)amino-glucopyranosyl 1β-O-acetate 2a-β in a regiospecific manner in high yield,¹⁶ though they have not described the reaction in detail. We were interested in the amido-acetoxylation, and confirmed that the reaction of 1a with Cl₃CCH₂OSO₂NH₂, PhI(OAc)₂, MgO in the presence of a Rh(II) catalyst [Rh₂(NHCOCF₃)₄] afforded the β-acetate 2a-β only. The amidoacetoxylation was applied to acetyl-protected galactal 1b and lactal 1c under identical conditions. As shown in Table 1, Ac-galactal 1b gave a 2 : 1 mixture of the α- and β-acetates, whereas Ac-lactal 1c gave the β-acetate 2c-β predominantly. In all cases, the stereoisomers at C-2 were not detected.

Table 1 Amidoacetoxylation of acetylated glycals 1a–c^a

1	Yield (%)
	2-β	2-α
a Reagents and conditions: Cl3CCH2OSO2NH2 (1.8 equiv.), PhI(OAc)2 (1.8 equiv.), Rh2(NHCOCF3)4 (0.1 equiv.), MgO (4 equiv.) in PhCl, 5 °C, 2 h to rt, 10 h.b Isolated yield by silica gel chromatography.c The yields were determined by ^1H-NMR integration of the α/β mixture.
a: R^1 = AcO, R^2 = H	91^b	0
b: R^1 = H, R^2 = AcO	33^b	61^b
	84^c	8^c

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We next examined a direct synthesis of 2-sulfonamido-1-O-glycosides¹⁷ from glycals by adding alcohols in the reaction mixture. As shown in Table 2, the reaction of 1a and tetradecanol (4 equiv.)¹² with Cl₃CCH₂OSO₂NH₂ in the presence of PhI(OAc)₂ and catalytic Rh₂(NHCOCF₃)₄ in chlorobenzene afforded the desired tetradecyl-β-glucoside 3a in 58% yield with no α-glucoside. However, the 1-O-acetate 2a-β was also formed (entry 1). Formation of 2a was suppressed by using iodosobenzene with 4 Å molecular sieves (as dehydration agent) in place of PhI(OAc)₂ with MgO (entry 2). Reduction of the amount of alcohol improved the yield of 3a (entry 3). For the aziridination catalyst, Rh₂(OAc)₄ was less effective than Rh₂(NHCOCF₃)₄, and copper(I)^6a and silver¹⁸ catalysts were much less effective (entries 4–6).

Table 2 Amidoglycosylation of tetradecanol with acetylated glucal 1a and trichloroethoxysulfonamide

Entry	Equiv. of C14H29OH	Oxidant^a	Catalyst	3a Yield^b (%)
a The oxidant (solid, 1.8 equiv.) was added in ca. 6 portions to the mixture of other reactants for ca. 1 h at 5 °C.b Isolated yield by silica gel chromatography. In all cases, unreacted 1a remained.c MgO (4 equiv.) was used in place of MS4A.d 1-Acetate 2a-β was obtained in 22% yield.e tBu3tpy: 4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-terpyridine.
1^c	4	PhI(OAc)2	Rh2(NHCOCF3)4	58^d
2	4	PhI=O	Rh2(NHCOCF3)4	66
3	2	PhI=O	Rh2(NHCOCF3)4	78
4	4	PhI=O	Rh2(OAc)4	45
5	2	PhI=O	Cu(CH3CN)4PF6	17
6	2	PhI=O	AgNO3, tBu3tpy^e	25

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With the optimised reaction conditions in hand, we investigated the scope and generality of this Rh-catalysed one-pot amidoglycosylation, and the results are summarized in Table 3. Reactions of 12-bromododecanol and 2-phenylethanol with the glycals 1a–c proceeded smoothly to afford the corresponding β-glycosides 4a, b, c, 6a in good yields (entries 1, 2, 3 and 5). In contrast, 12-acetylthio-1-dodecanol gave the galactoside 5b in poor yield under identical conditions, indicating that the acetylthio group would suppress the reaction (entry 4). Reaction of 1b with 4-penten-1-ol gave the β-galactoside 8b in somewhat lower yield along with a byproduct‡ derived from 4-pentenol, indicating that pentenol was also aziridinated, but would be less reactive than 1b (entry 7).

Table 3 Amidoglycosylation of alcohols with acetylated glycal 1a–c and trichloroethoxysulfonamide^a

Entry	Glycal	R–OH	Product	Yield^b (%)
a General procedure: to a mixture of glycal 1, ROH (2 equiv.), Cl3CCH2OSO2NH2 (1.7 equiv.), Rh2(NHCOCF3)4 (0.1 equiv.), molecular sieves 4 Å (0.8 g mmol^−1) in PhCl (1: 0.05–0.10 M) under nitrogen at 5 °C was added PhIO (1.8 equiv.) in several portions for 1 h, and the resulting suspension was stirred at 5 °C for 1 h and then at rt for 5–15 h.b Isolated yield by silica gel chromatography.
1	1a	Br(CH2)12–OH	4a	77
2	1b	Br(CH2)12–OH	4b	84
3	1c	Br(CH2)12–OH	4c	70
4	1b	AcS(CH2)12–OH	5b	11
5	1a	Ph(CH2)2–OH	6a	75
6	1b	PhCH2–OH	7b	62
7	1b	H2C=CH–(CH2)3–OH	8b	63
8	1a	Cyclohexanol	9a	57
9	1b	Cyclohexanol	9b	78
10	1a		10a	74
11	1b	L(−)-Menthol	10b	76
12	1c	L(−)-Menthol	10c	67
13	1b		11b	74
14	1b		12b	21
15	1b		13b	56

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Cyclic secondary alcohols: cyclohexanol and L(−)-menthol reacted with the glycals 1a–c to give the corresponding β-glycosides in good yields. Ac-galactal 1b appeared to be more reactive and gave the glycosides in better yields than 1a and 1c (entries 8–12 and 1–3). For sugar-derived alcohols, 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose afforded the galactoside 11b in good yield, whereas methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside gave the galactoside 12b in low yield, and substantial amounts of some byproducts: de-O-benzylated glucoses and benzaldehyde were obtained. In all the cases examined, no α-anomer was detected by ¹H- and ¹³C-NMR. Small amounts (3–8%) of hydrolysed products (1-OH) were formed in most cases.

The reaction would proceed via the generation of sulfonyl-nitrene followed by formation of the α-oriented aziridine intermediate (14) presumably due to the presence of β-acetoxy group at C-3.¹⁹ The aziridine would be opened with the alcohol at C-1 from the β-face to afford 1,2- and 2,3-di-trans-product (Scheme 1).

Scheme 1 Proposed reaction pathway.

The trichloroethoxysulfonyl group in 3a was removed by treatment with zinc and acetic acid in the presence of CuSO₄ to give the free amine 15. When the desulfonylation was carried out in the presence of acetic anhydride, the acetamide 16 was obtained in good yield (Scheme 2).

Scheme 2 Deprotection of the trichloroethoxysulfonyl group.

In conclusion, we have developed a regio- and stereo-selective synthesis of 2-amino-2-deoxy-1-O-β-glycosides from acetylated glycals via rhodium(II)-catalysed intermolecular aziridination with trichloroethoxysulfonamide and iodosobenzene. This amidoglycosylation proceeds smoothly under mild conditions without the use of usual O-glycosylation promoters such as Lewis acids, and is applicable to a variety of primary and secondary alcohols.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, analytical data, copies of ¹H and ¹³C NMR, and mass spectra. See DOI: 10.1039/c4ra02367f

‡ 2-(Trichloroethoxysulfonylamino)methyltetrahydrofuran was obtained in ca. 0.5 molar ratio to major product 8b.

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