In 2012, Sajiki and his colleagues of Gifu Pharmaceutical University reported that Stereo- and Regioselective Direct Multi-Deuterium-Labeling of Sugars can be realized by using the heterogeneous Ru/C-catalyzed H–D exchange reaction in D2O under a hydrogen atmosphere (scheme 1).
For example, a-d-methylglucoside (1 a) bearing an acetal moiety underwent the H–D exchange reaction by using 10% Ru/C (3 mol%) in D2O under a H2 atmosphere (1 atm), and deuterium atoms were incorporated at the 2–4 and 6 positions corresponding to the carbons atoms (a position) adjacent to the hydroxyl groups to give the multi-deuterated methylglycoside (1 a[D5]), although the deuterium efficiency was not satisfactory (Table 1, entry 1). Compound 1 a[D5] was isolated in its corresponding tetraacetate form (2 a) because the overlap of several peaks in the 1 H NMR spectra of the non-acetylated substrate (1 a[D5]) prevented a precise assignment. Intriguingly, the chirality of 1 a[D5] and 2 a was perfectly retained under the reaction conditions, which was indicated by the spectroscopic data, that is, the 1 H NMR analyses and further experimental results for the chirality. Whereas the increment of catalytic quantity to 5 or 10 mol% slightly revised the deuterium efficiency (Table 1, entries 2–4), a higher reaction temperature clearly affected the D efficiency (Table 1, entries 5 and 6). Although the temperature increased from 50 to 80 degree benifits the D efficient, a further temperature increasement from 80 to 110 degree reduces the D efficient. Consequently, the reaction using 5 mol% of 10% Ru/C at 80 oC and the following acetylation afforded the isolated 2 a in excellent yield and with quantitative D efficiency (Table 1, entry 7).
It was observed the ratio of D2O to the substrate governed the deuterium efficiency of the Ru/C-catalyzed H–D reaction (Table 2). Whereas the use of 2 to 0.5 mL of D2O versus 0.5 mmol of 1 a could produce satisfactory D efficiencies (Table 2, entries 1 vs. 2 and 3), the further decrease to 0.25 and 0.1 mL led to a significant reduction in the D incorporation.
The authors also proposed a mechanism for the demonstated H-D exchange. The H–D exchange reaction of sugars can be initiated by the formation of the H2- and D2O-activated Ru catalyst (Scheme 2, A) and it is gravitated by the hydroxyl group of the sugars as a directing group. The subsequent oxidative addition at the C-H bond adjacent to the hydroxyl group affords the intermediate (C). The intramolecular H– D exchange reaction, reductive elimination, and following aqueous workup to remove the acidic deuterium on the oxygen atoms give the regio- and stereoselectively deuterated sugar. Although the desired H–D exchange reaction and D–H (opposite) exchange reaction induced by the H2 gas and generated DHO must have formed an equilibrium relationship, the deuteration of the sugar preferentially proceeds. It is for this reason that the C-D bonds are thermodynamically more stable than the C-H bonds due to the H– D isotope effect, and the excess amount of D2O also effectively enhances the H–D exchange reaction as noted in Table 2. Whereas the Ru/C-catalyzed H–D exchange reaction of simple cyclic- and chiral aliphatic alcohols gave completely racemized deuterated alcohols probably generated through a redox process , the sugars used as substrates in this study were never epimerized at every position under the present reaction conditions. The authors deemed that a keto cyclic acetal structure formed by the oxidation (dehydrogenation) from the corresponding hydroxyl groups on the sugar is unfavorable due to the steric strain in the molecule, and the H–D exchange can proceed only through an oxidative insertion process as shown in Scheme 2 in restraint of a redox pathway.
Furthermore, the authors reported the reaction in H2O instead of D2O should facilitate the H–H or D–H exchange reactions of a-d-methylglucoside (1 a) or deuterated a-d-methylglucoside as a substrate [Eq. (2) and (3)]. Compound 1 a was completely recovered without any epimerization on all the chiral centers under the Ru/C-catalyzed reaction conditions in H2O as the solvent [Eq. (2)]. Additionally, 1 a[D5] underwent an incomplete D–H exchange reaction to give the partially hydrogenated (half-deuterated) product, because the D–H exchange reaction of 1 a[D5] was very ineffective compared with the corresponding H–D exchange reaction of 1 a due to the significant isotope effect of D. The chemical shifts in the 1 H NMR spectra of 1 a as the product of [Eq. (2)] were completely identical to that of the original 1 a as the starting material. These results clearly indicated that the D–H as well as the H–H and H–D exchange reactions on sugars proceed with perfect stereoselectivities.
A time-course study of the deuterium efficiencies in the respective positions of the a-d-methylglucoside (1 a) revealed that the Ru/C-catalyzed H–D exchange reaction was strongly influenced by the positional property (Figure 1). The H–D exchanges at the 4 and 6 positions were relatively slower than those at the 2 and 3 positions. Presumably, the thermodynamically stable six-membered coordination geometry formed by the Ru metal and two hydroxyl groups substituted at the 4 and 6 positions caused the slower reaction rate of their H–D exchanges, which prevented the oxidative addition process (B to C in Scheme 2). Meanwhile, the 1 and 5 positions bearing no hydroxy group were never deuterated, because the Ru/C catalyzed-H–D exchange reaction can only proceed at carbons adjacent to a hydroxyl group by a modest directing effect, as explained in Scheme 1 and Scheme 2.
The present methodology was adaptable to the direct deuteration of various pyranosides (Figure 2). Methyl-b-d-glucopyranoside (1 b), methyl-a-d-mannopyranoside (1 c), 1- deoxy-d-glucopyranoside (1 f) and methyl-b-d-galactopyranoside (1 g) also underwent the H–D exchange reaction at the 2–4 and 6 positions together with complete retention of the stereochemistry to afford the multi-deuterated 2 b,c,f and g with nearly quantitative yields and deuterium efficiencies (Figure 2). The H–D exchange reaction of the methyl-b-d-xylopyranoside (1 d) and methyl-a-l-frucopyranoside (1 e) lacking a hydroxyl moiety at the 6 position could effectively proceed at the 2–4 positions. Moreover, treharose (1 h), a disaccharide, and the nitrogen-containing methyl N-acetyl-b-d-glucosamine (1i) were also deuterated with excellent D contents and in high yields.
The authous also attempted to incorporae of deuterium atoms into the desired positions on sugars, because the site-selectively deuterated sugars would be useful as chiral building blocks for functional materials such as candidates for new medicines, and so on. As mentioned above, whereas the H–D exchange reaction only proceeded on the carbons bearing a free hydroxyl group, it never occurred on the vicinal carbons of a protected hydroxyl group. Although the H–D exchange reaction was attempted with methyl 4,6-O-isopropylidene-a-d-glucopyranoside (1 j: hydroxyl groups at 4 and 6 positions of 1 a were protected by an isopropylidene (Isop) group) under the same conditions as shown in Table 1, entry 7, compound 1 j was easily deprotected, probably due to the Lewis acidity of the Ru/C or residual acidic constituent from the preparation process of Ru/C; thus, this reaction did not afford the desired 2 j (Table 3, entry 1). Since acetals (the acetal-type protective groups) are well-known to tolerate basic conditions, the effect of basic additives was investigated by the authors.Whereas the use of 20 mol% NaOH as an additive also led to the complete deprotection of the Isop group (Table 3, entry 2), the increment in concentration of NaOH up to 40 mol% totally suppressed the deprotection of 1 j to afford the desired product (2 j) deuterated only at the 2 and 3 positions (Table 3, entry 3). Although the D efficiency at the 3 position was only 27%, the use of LiOH as a base slightly improved the D content (59%) and the addition of n-Pr3N as an organic base completely suppressed the H–D exchange reaction at the 3 position. In contrast, quantitative deuterium incorporation was achieved by the use of a b-isomer (1 k: methyl 4,6-O-isopropylidene-b-d-glucopyranoside) on both the 2 and 3 positions in the presence of 40 mol% of NaOH (Scheme 3). Namely, the intermediate F derived from the oxidative addition at the 3 position of 1 j develops a 1,3-diaxial interaction between the Ru functionality at the 3 position and methoxy group at 1 position to suppress the H–D exchange at the 3 position.
The investigators also expanded to construct regioselectively deuterated chiral compounds (Figure 3). The selective deuteration at the 2 and 6 positions was also accomplished by the use of methyl 3,4-O-isopropylidene-a-d-galactopyranoside (1l) as a substrate. Methyl 4,6-O-isopropylidene-a-d-galactopyranoside (1m) could undergo site-selective deuteration at the 2 and 3 positions, and only two deuterium atoms were selectively incorporated at the 6 position of 1,2:3,4-di-O-isopropylidene-a-d-galactopyranoside (1 n). Moreover, methoxymethyl (MOM) ether was also adaptable for the regioselective deuteration method to afford the deuterated product (2 o) from methyl 2,3-bis-O- (methoxymethyl)-a-d-glucopyranoside (1 o), although the deuterium efficiency was significantly reduced, especially at the 4 position, probably due to the greater affinity of the Ru metal to the two oxygen atoms of the MOM ether compared with the corresponding hydroxyl oxygen. In contrast, the corresponding methyl ether (1 p: methyl 2,3-bis-O- (methoxymethyl)-a-d-glucopyranoside) was smoothly and efficiently deuterated at both the 4 and 6 positions, because the coordination (directing) effect of the methyl ether moiety is weaker than that of the MOM ether and hydroxyl groups. 2,3:4,5-Di-O-isopropylidene-b-d-fructopyranose (1 q) also underwent the deuteration at the carbon adjacent to the primary free hydroxyl group, irrespective of the more acid-labile ketal-type moiety. A cyclic glucopyranoside (1 r: 1,6-anhydro-b-d-glucopyranoside) was efficiently deuterated at the 2, 3 and 4 positions and the following acid hydrolysis using TFA gave the corresponding glucose[D3], which was deuterated at the 2, 3 and 4 positions as a mixture of a and b anomers (a/b=76:24).
Finally, they investigated the H–D exchange reaction of furanosides represented by ribose and deoxyribose, which are easily hydrolyzed under heated aqueous conditions due to the poor structural relaxation (Figure 4). Ribose (1 s: methyl b-d-ribofuranoside) and deoxyribose (1 t: methyl 2-deoxyribofuranoside) were readily decomposed under the Ru/C catalyzed H–D exchange conditions, although the addition of an inorganic base, such as NaOH and LiOH, effectively enabled the deuterium-labeling reaction in nearly quantitative yields and with high D efficiencies. The site-selective deuteration using protected sugars was also applicable for the furanoside derivatives. Ribose that was only deuterated at the 5 position could be prepared from methyl 2,3-O-isopropylidene-b-d-ribofuranoside (1 u). 1,2:5,6-Diisopropylidene-a-d-ribofuranose (1 v) was regio- and stereoselectively deuterated at the 3 position and the subsequent acid hydrolysis using TFA afforded glucose[D1] (4) deuterated at only the 3 position as a mixture of a and b anomers (a/b= 45:55).
来自Chem. Eur. J. 2012, 18, 16436 – 16442
