Ring cleavage reactions of methyl α-D-allopyranoside derivatives with phenylboron dichloride and triethylsilane.

In the course of our studies on the regioselective carbon-oxygen bond cleavage of the benzylidene acetal group of hexopyranosides with a reducing agent, we found that a combination of a Lewis acid and a reducing agent triggered a ring-opening reaction of the pyranose ring of methyl α-D-allopyranosides. The formation of an acyclic boronate ester by the attachment of a hydride ion at C-1 indicated that the unexpected endocyclic cleavage of the bond between the anomeric carbon atom and the pyranose ring oxygen atom proceeded via an oxacarbenium ion intermediate produced by the chelation between O5/O6 of the pyranoside and the Lewis acid, followed by nucleophile substitution with a hydride ion at C1.

1. Introduction

Lewis-acid-induced regioselective carbon-oxygen bond cleavage of the benzylidene acetal group of hexopyranosides with a reducing agent is an important reaction in carbohydrate chemistry for the syntheses of complex oligosaccharides and glycoconjugates. Until now, various reagent systems [1,2,3,4,5,6,7,8,9,10,11,12] and investigations of the detailed mechanistic pathway [13,14] have been reported for the regioselective reduction of 4,6-O-benzylidene acetal groups.

Recently, we reported the synthesis of a new fluorous benzylidene acetal group for the protection of 1,3-diol compounds [15]. Efficient and expeditious syntheses of natural products [16], oligosaccharides [15], and modified monosaccharides have been accomplished by utilizing regioselective ring-opening reduction of fluorous benzylidene acetal groups and solid-phase extraction with a fluorous reverse-phase silica gel column. In the course of our studies on the expeditious synthesis of these products using fluorous benzylidene acetal groups, we isolated an interesting side product, the acyclic compound 3, during the regioselective ring-opening reduction of methyl 2,3-di-O-benzyl-4,6-O-Fbenzylidene-α-D-allopyranoside 1 with PhBCl2/Et3SiH (Scheme 1, Eq. 1). This unexpected side reaction is caused by the reductive cleavage of the fluorous benzylidene acetal group and subsequent endocyclic cleavage of the pyranosides. When methyl 2,3-di-O-benzyl-4,6-O-Fbenzylidene-α-D-glucopyranoside 4 and phenyl 2,3-di-O-benzyl-4,6-O-Fbenzylidene β-D-allopyranoside 6 were reacted under the same reaction conditions, this unexpected side reaction was not observed (Scheme 1, Eqs. 2,3).

Scheme 1

Reductive cleavage of fluorous benzylidene acetal group using PhBCl2/Et3SiH.

Only a few reports have been published so far on the anomerization [17,18,19,20,21,22,23,24] and attachment of nucleophiles at C1 [25,26,27,28,29,30,31,32] via the endocyclic cleavage of glycosides. To the best of our knowledge, the side reaction described here is the first example of the endocyclic cleavage of methyl α-D-allopyranoside derivatives with PhBCl2/Et3SiH. Here, we provide detailed results of the ring cleavage reaction of hexopyranosides bearing axial substituents at C1 and C3.

2. Results and Discussion

Initially, methyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-allopyranoside 8 was reacted with PhBCl2 (5.0 equiv.) and Et3SiH (4.5 equiv.) in CH2Cl2 at −78 °C. The purification of the crude product by silica gel column chromatography unexpectedly gave an acyclic derivative bearing a boronate ester as the main product [33]. Thus, to remove the phenylboronate group from the acyclic alditol derivative, an octadecyl silica gel (ODS) column was used instead of a fluorous reverse-phase silica gel column. The crude product was loaded onto the ODS column, after which the column was eluted successively with 40% aq. MeOH and then with MeOH. The methanol fraction subsequently was evaporated, and the residue was treated with Ac2O and pyridine to give acyclic derivative 19 in 78% yield. In the case of methyl β-D-allopyranoside 11, the acyclic derivative 19 and 4-O-benzyl derivative 23 were obtained in 17% and 46% yields, respectively. However, the endocyclic cleavage of methyl α-D-glucopyranoside 12and methyl α-D-galactopyranoside 13 was not observed. These results suggest that the hexopyranoside bearing axial substituents at C1 and C3 preferentially undergo endocyclic cleavage. To test the generality of this new finding, we examined the ring opening of various hexopyranosides bearing axial substituents at C1 and C3 under the same reaction conditions. The results are summarized in Table 1. When the reactions were carried out using methyl α-D-allopyranoside derivatives 9 and 10 bearing methoxymethyl ethers and benzoyl esters at C2 and C3, the number of spots observed by thin-layer chromatography (TLC) was so large that the spots could not be identified. In the cases of methyl α-D-gulopyranoside 14, allyl α-D-allopyranoside 15, and methyl α-D-ribo-hexopyranoside 16, the reactions proceeded smoothly to give the desired acyclic compounds 26, 27, and 28 in high yields. Additionally, the reaction involving hexopyranosides 17 and 18 bearing an axial substituent at C2 gave the acyclic compound 29 and the 4-O-benzylated compound 30 in 27% and 83% yields, respectively.

Table 1

Synthesis of acyclic derivatives from alkyl 4,6-O-benzylidene-α-D-hexopyranosides.

Entry	Substrate	Product (isolated yield)
		Acyclic derivative	4- O-benzylated derivative
1	8: R = Bn	19 (R = Bn): y. 78% a	20 (R = Bn): y. 7% a
2	9: R = MOM	21 (R = MOM): y. - b
3	10: R = Bz	22 (R = Bz): y. - b
4	11	19: y. 17%	23: y. 46%
5	12	-	24: y. 78%
6	13	-	25: y. 80%
7	14	26: y. 71%	-
8	15	27: y. 77%	-
9	16	28: y. 86%	-
10	17: R = OBn	29 (R = OBn): y. 27% c
11	18: R = N3	(R = N3): -	30 (R = N3): y. 83%

a When 3.4 equiv. of PhBCl2 and 3.0 equiv. of Et3SiH were used, acyclic compound 19 and 4-O-benzylated compound 20 were obtained in 59% and 19% yields, respectively; b Many spots were observed by TLC; c An inseparable mixture was obtained as a main product.

We expected the hydroxyl group at C6 of the hexopyranosides to play an important role in cleavage of the bond between the anomeric carbon C1 and the pyranose ring oxygen atom O5 during endocyclic cleavage of hexopyranosides bearing axial substituents at C1 and C3 with PhBCl2/Et3SiH because a 1,2-boronate ester derivative was isolated as an intermediate. Therefore, methyl 2,3,4,6-tetra-O-benzyl-α-D-allopyranoside 31 and methyl 2,3,4-tri-O-benzyl-α-D-allopyranoside 32 were reacted with PhBCl2 and Et3SiH. As shown in Table 2, compound 31 gave methyl 3,4,6-tri-O-benzyl-α-D-allopyranoside 33 and the starting material 31 in 28% and 52% yields, respectively. Although the reaction of 6-hydroxy-derivative 32 at −78 °C gave the desired acyclic derivative 34 with only a 10% yield, the yield reached 92% when the reaction was carried out at −19 °C.

Table 2

Synthesis of acyclic derivatives from methyl 2,3,4,6-tetra-O-benzyl-α-D-allopyranoside and 2,3,4-tri-O-benzyl-α-D-allopyranoside.

Entry	Reaction temperature (°C)	Yield of acyclic compound 34 (%)	Yield of recovered starting material 32 (%)
1	−78	10	80
2	−60	53	41
3	−50	70	24
4	−40	80	18
5	−19	92	-

On the basis of these experimental data, the pathway for PhBCl2-induced endocyclic cleavage of hexopyranosides with 1,3-diaxial substituents is speculated to be that shown in Scheme 2. The endocyclic cleavage is initiated by bond formation between the boron atom and oxygen atom O6 followed by chelation of the boron atom at ring oxygen atom O5. This interaction promotes cleavage of the endocyclic C1-O5 bond and formation of acyclic oxacarbenium ion V. Before or after rotation around the C1-C2 bond, the addition of chloride ion from PhBCl2 to cation V followed by nucleophilic substitution with hydride ion (Path A) or direct addition of hydride ion to cation V (Path B) gives boronate ester VII. The major factor in the endocyclic cleavage of methyl α-D-allopyranoside 8 is due to steric strain of pyranosidic ring caused by steric repulsions between the substituents at C1 and C-3. Hexopyranosides 12 and 13 in which the pyranosidic rings are stabilized by the equatorial substituent at C-3 do not produce the corresponding acyclic derivatives. In the case of the reaction of hexopyranoside 11, the equatorial methoxy group at C-1 sterically hinders bond formation between the boron atom and O5/O6 to give alditol derivative 19 in low yield. Since the 4C1 conformation of altropyranoside 17 or 18 bearing axial substituents at C1, C2, and C3 is rapidly converted into the more stable 1C4 conformation in which all the substituents are equatorial after the benzylidene acetal group is cleaved, the altropyranosides give alditol derivative 29 in low yield and 4-O-benzylated compound 30 in high yield. The endocyclic cleavage of 6-hydroxy-derivative 32 at −78 °C results in the lower yield because the formation of IV is inhibited at the lower temperature, although the reaction from III to IV proceeds smoothly at the higher temperature.

Scheme 2

Proposed reaction mechanism.

However, the above-mentioned mechanism is highly speculative because of the lack of enough experimental data for supporting it. Therefore, we are now making efforts to get essential data for clarifying the mechanism by several experiments. We will report the results in the near future.

3. Experimental

3.1. General

1H- and 13C-NMR spectra were measured using a Bruker Avance DPX-250 spectrometer. J values were recorded in Hertz, and the abbreviations used were s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Chemical shifts are expressed in δ values relative to the internal standard TMS. Octadecyl silica gel column chromatography was carried out using COSMOSIL 75C18-OPN (75 μm, Nacalai Tesque) column. TLC was carried out on Merck silica gel 60 F254 plates. PhBCl2 and Et3SiH were obtained from Sigma-Aldrich and Acros Organics, respectively.

3.2. General Procedure for Endocyclic Cleavage with PhBCl2 and Et3SiH

A suspension of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-allopyranoside 8 (50 mg, 0.108 mmol) and MS-4Å (250 mg) in dry CH2Cl2 (5.4 mL) was stirred for 1 h at room temperature under argon. Next, Et3SiH (77 μL, 0.486mmol, 4.5 equiv.) was added to the suspension at −78 °C, after which a solution of PhBCl2 (70 μL, 0.541 mmol, 5.0 equiv.) in CH2Cl2 (1 mL) was added over 1 h via a syringe pump. After stirring for 1 h at the same temperature, the reaction mixture was quenched with Et3N (0.5 mL) and MeOH (0.5 mL) and then filtered through Celite. The filtrate was subsequently washed with saturated NaHCO3 solution (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was then loaded onto an octadecyl silica gel column, which was eluted successively with 40% aq. MeOH and MeOH. Next, the MeOH fraction was concentrated to give the residue containing the acyclic diol. The residue was then redissolved in pyridine (0.5 mL), after which acetic anhydride (0.5 mL) was added. After stirring for 3 h at room temperature, the reaction mixture was poured into MeOH at 0 °C and stirred for 10 min. The mixture was evaporated and co-evaporated with toluene. Finally, the residue was subjected to preparative thin-layer chromatography(hexane/EtOAc = 3:2 v/v) to give allitol derivative 19 (46.7 mg, 78% yield).

(2S,3R,4R,5S)-1,2-Bis(acetoxy)-3,4,5-tris(benzyloxy)-6-methoxyhexane (19). Colorless syrup; Rf = 0.59 (hexane/EtOAc = 3:2 v/v); IR (NaCl, neat): 1745 cm−1; 1H-NMR (250 MHz, CDCl3): δ 7.33−7.25 (15H, m, ArH), 5.48 (1H, ddd, J2,3 = 4.0 Hz, J2,1 = 2.7 Hz, J2,1′ = 7.3 Hz, H-2), 4.73, 4.68 (2H, each d, J = 11.3 Hz, PhCH), 4.71, 4.58 (2H, each d, J = 11.6 Hz, PhCH), 4.60 (2H, s, PhCH), 4.43 (1H, dd, J1,2 = 2.7 Hz, J1,1′ = 12.2 Hz, H-1), 4.24 (1H, dd, J1′,2 = 7.3 Hz, J1,1′ = 12.2 Hz, H-1′), 3.93 (1H, dd t-like, J3,2 = 4.0 Hz, J3,4 = 4.4 Hz, H-3), 3.84 (2H, m, H-4, 5), 3.61 (1H, dd, J6,5 = 3.0 Hz, J6,6′ = 10.4 Hz, H-6), 3.54 (1H, dd, J6′,5 = 4.7 Hz, J6′,6 = 10.4 Hz, H-6′), 3.30 (3H, s, OCH), 1.99, 1.97 (6H, each s, CH × 2); 13C-NMR (63 MHz, CDCl3): δ 170.7, 169.8, 138.4, 137.9, 137.7, 128.3, 128.24, 128.22, 128.17, 128.08, 128.03, 127.97, 127.7, 127.63, 127.57, 127.4, 78.4, 78.2, 78.1, 73.8, 72.8, 72.3, 71.85, 71.79, 63.3, 58.9, 21.0, 20.7.

(2S,3S,4R,5S)-1,2-Bis(acetoxy)-3,4,5-tris(benzyloxy)-6-methoxyhexane (26). Colorless syrup; Rf = 0.63 (hexane/EtOAc = 3:2 v/v); IR (NaCl, neat): 1744 cm−1; 1H-NMR (250 MHz, CDCl3): δ 7.39−7.20 (15H, m, ArH), 5.38 (1H, ddd, J2,3 = 5.1 Hz, J2,1 = 3.6 Hz, J2,1′ = 7.1 Hz, H-2), 4.77 (2H, each d, J = 11.4 Hz, PhCH), 4.66, 4.44 (2H, each s, J = 11.8 Hz, PhCH), 4.64 (2H, s, PhCH), 4.30 (1H, dd, J1,2 = 3.6 Hz, J1,1′ = 12.0 Hz, H-1), 4.05 (1H, dd, J1′,2 = 7.1 Hz, J1′,1 = 12.0 Hz, H-1), 3.92−3.77 (3H, m, H-3, 4, 5), 3.74 (1H, dd, J6,5 = 3.6 Hz, J6,6′ = 10.1 Hz, H-6), 3.59 (1H, dd, J6′,5 = 4.0 Hz, J6′,6 = 10.1 Hz, H-1′), 3.35 (3H, s, OCH), 2.01, 1.97 (6H, each s, CH × 2); 13C-NMR (63 MHz, CDCl3): δ 170.5, 170.2, 138.4, 138.3, 138.0, 128.31, 128.29, 128.0, 127.9, 127.7, 127.60, 127.58, 127.52, 78.5, 78.3, 77.0 (overlapped with CDCl3), 74.5, 73.9, 72.0, 71.3, 71.2, 63.0, 58.9, 20.9, 20.7.

(2S,3R,4R,5S)-6-(Allyloxy)-1,2-bis(acetoxy)-3,4,5-tris(benzyloxy)hexane (27). Colorless syrup; Rf = 0.50 (hexane/EtOAc = 3:2 v/v); IR (NaCl, neat): 1744 cm−1; 1H NMR (250 MHz, CDCl3): δ 7.34−7.24 (15H, m, ArH), 5.87 (1H, ddt, J = 5.5 Hz, J = 10.4 Hz, J = 17.2 Hz, CH2CH=CH2), 5.49 (1H, ddd, J2,3 = 3.8 Hz, J2,1 = 2.7 Hz, J2,1′ = 7.3 Hz, H-2), 5.23 (1H, dq, J = 1.6 Hz, J = 17.2 Hz, CH2CH=CH), 5.14 (1H, dq, J = 1.3 Hz, J = 10.4 Hz, CH2CH=CH), 4.72, 4.60 (2H, each d, J = 11.7 Hz, PhCH), 4.70, 4.60 (4H, each s, PhCH × 2), 4.42 (1H, dd, J1,2 = 2.7 Hz, J1,1′ = 12.2 Hz, H-1), 4.24 (1H, dd, J1′,2 = 7.3 Hz, J1′,1 = 12.2 Hz, H-1′), 3.95−3.82 (5H, m, H-3, 4, 5, CHCH=CH2), 3.68 (1H, dd, J6,5 = 3.0 Hz, J6,6′ = 10.4 Hz, H-6), 3.59 (1H, dd, J6′,5 = 5.2 Hz, J6′,6 = 10.4 Hz, H-6), 1.99, 1.97 (6H, each s, CH × 2); 13C-NMR (63 MHz, CDCl3): δ 170.7, 169.8, 138.6, 138.0, 137.8, 134.8, 128.29, 128.26, 128.21, 128.12, 128.05, 127.8, 127.7, 127.6, 127.4, 116.7, 78.6, 78.4, 78.3, 73.8, 72.9, 72.5, 72.2, 71.9, 69.7, 63.3, 21.0, 20.8.

(2S,3S,4R)-1,2-Bis(acetoxy)-3,4-bis(benzyloxy)-6-methoxyhexane (28). Colorless syrup; Rf = 0.55 (hexane/EtOAc = 1:1 v/v); IR (NaCl, neat): 1745 cm−1; 1H-NMR (250 MHz, CDCl3): δ 7.38−7.25 (10H, m, ArH), 5.28 (1H, ddd, J2,3 = 4.8 Hz, J2,1 = 2.6 Hz, J2,1′ = 6.9 Hz, H-2), 4.72, 4.55 (2H, each d, J = 11.5 Hz, PhCH), 4.68, 4.63 (2H, each d, J = 10.5 Hz, PhCH), 4.48 (1H, dd, J1,2 = 2.6 Hz, J1,1′ = 12.2 Hz, H-1), 4.25 (1H, dd, J1′,2 = 6.9 Hz, J1′,1 = 12.2 Hz, H-1′), 3.80−3.73 (2H, m, H-3, 4), 3.54−3.35 (2H, m, H-6, 6′), 3.26 (3H, s, OCH), 2.04, 2.01 (6H, each s, CH × 2), 1.92−1.84 (2H, m, H-5); 13C-NMR (63 MHz, CDCl3): δ 170.6, 169.9, 138.2, 137.9, 128.3, 128.0, 127.7, 127.6, 79.3, 75.9, 73.3, 72.5, 71.4, 68.8, 63.2, 58.4, 30.6, 20.9, 20.7.

(2S,3R,4R,5R)-1,2-Bis(acetoxy)-3,4,5-tris(benzyloxy)-6-methoxyhexane (29). Colorless syrup; Rf = 0.46 (hexane/EtOAc = 3:2 v/v); IR (NaCl, neat): 1744 cm−1; 1H-NMR (250 MHz, CDCl3): δ 7.67−7.20 (15H, m, ArH), 5.40 (1H, ddd, J2,3 = 3.4 Hz, J2,1 = 2.8 Hz, J2,1′ = 7.3 Hz, H-2), 4.79, 4.70 (2H, each d, J = 11.3 Hz, PhCH), 4.66, 4.58 (2H, each d, J = 11.7 Hz, PhCH), 4.62, 4.51 (2H, each d, J = 11.6 Hz, PhCH), 4.54 (1H, dd, J1,2 = 2.8 Hz, J1,1′ = 12.2 Hz, H-1), 4.27 (1H, dd, J1′,2 = 7.3 Hz, J1′,1 = 12.2 Hz, H-1′), 3.93−3.85 (2H, m, H-3, 4), 3.79 (1H, ddd q-like, J5,4 = 4.8 Hz, J5,6 = 4.8 Hz, J5,6′ = 4.8 Hz, H-5), 3.57 (1H, dd, J6,5 = 4.7 Hz, J6,6′ = 10.2 Hz, H-6), 3.51 (1H, dd, J6′,5 = 4.8 Hz, J6′,6 = 10.2 Hz, H-6′), 3.30 (3H, s, OCH), 1.98 (6H, s, CH × 2); 13C-NMR (63 MHz, CDCl3): δ 170.7, 169.9, 138.6, 138.3, 137.9, 128.31, 128.28, 128.26, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 78.8, 78.2, 74.6, 73.0, 72.7, 72.0, 71.9, 63.3, 59.1, 21.0, 20.8.

(2S,3R,4R,5S)-1,2-Dihydroxy-3,4,5-tris(benzyloxy)-6-methoxyhexane (34). Colorless syrup; Rf = 0.24 (hexane/EtOAc = 3:2 v/v); IR (NaCl, neat): 3444 cm−1; 1H-NMR (250 MHz, CDCl3): δ 7.38−7.25 (15H, m, ArH), 4.73, 4.61 (2H, each d, J = 11.6Hz, PhCH), 4.71 (2H, s, PhCH), 4.68, 4.55 (2H, each d, J = 11.4 Hz, PhCH), 3.97 (1H, 1H, dd, J4,3 = 3.5 Hz, J4,5 = 6.1 Hz, H-4), 3.90 (1H, ddd, J5,4 = 6.1 Hz, J5,6 = 3.5 Hz, J5,6’ = 4.6 Hz, H-5), 3.93−3.84 (1H, m, H-2, overlapped with H-5), 3.76 (1H, dd, J3,4 = 3.5 Hz, J3,2 = 7.0 Hz, H-3), 3.71−3.60 (2H, m, H-1, 1′, overlapped with H-6, 6′), 3.66 (1H, dd, J6,5 = 3.5 Hz, J6,6′ = 10.4 Hz, H-6), 3.59 (1H, dd, J6′,5 = 4.6 Hz, J6′,6 = 10.4 Hz, H-6′), 3.35 (3H, s, OCH), 3.22 (1H, br d, J = 3.7 Hz, OH), 2.17 (1H, br s, OH); 13C-NMR (63 MHz, CDCl3): δ 138.02, 137.95, 137.90, 128.43, 128.41, 128.08, 128.06, 128.01, 127.9, 127.8, 79.4, 79.3, 78.1, 73.9, 73.2, 72.7, 71.81, 71.78, 63.9, 59.2.

4. Conclusions

The reaction of alkyl 4,6-O-benzylidene-α-D-allopyranoside, 4,6-O-benzylidene-α-D-gulopyranoside, and 4,6-O-benzylidene-α-D-altropyranoside derivatives carrying 1,3-diaxial substituents with PhBCl2/Et3SiH gave 4-O-benzyl ethers and alditol derivatives formed by C1/O5 bond cleavage. Because an acyclic boronate ester was isolated, the unexpected endocyclic cleavage is considered to proceed via an oxacarbenium ion intermediate produced by the chelation between O5/O6 of the pyranoside and PhBCl2 followed by nucleophilic substitution with a hydride ion at C1. The oxacarbenium ion could be employed as a valuable and versatile intermediate for stereoselective carbon-carbon, carbon-nitrogen, carbon-sulfur, and carbon-oxygen bond formations with a variety of nucleophiles. Further reactivity studies of this endocyclic cleavage are underway in our laboratory. The results of these studies will be reported in the near future.