On the nitrile effect in l-rhamnopyranosylation

David Crich; Mitesh Patel

doi:10.1016/j.carres.2006.03.036

. Author manuscript; available in PMC: 2006 Sep 1.

Published in final edited form as: Carbohydr Res. 2006 Apr 27;341(10):1467–1475. doi: 10.1016/j.carres.2006.03.036

On the nitrile effect in l-rhamnopyranosylation

David Crich ^1,^*, Mitesh Patel ¹

PMCID: PMC1559506 NIHMSID: NIHMS10997 PMID: 16643872

Abstract

It is shown that the use of 5% acetonitrile or propionitrile in dichloromethane functions to increase the β-selectivity of a number of l-rhamnopyranosylation reactions conducted by the thioglycoside method with activation by the 1-benzenesulfinyl piperidine/trifluoromethanesulfonic anhydride couple. The use of more significant quantities of acetonitrile or propionitrile results in the formation of complex reaction mixtures containing little coupled product, but from which Ritter-type products can be isolated.

Keywords: Deoxy sugars, Acetonitrile, Nitrilium ion

1. Introduction

While significant advances have been made in the stereo-controlled formation of β-mannopyranosides in recent years, through both direct^† and indirect methods,¹^–¹⁹ their 6-deoxy congenors, the β-rhamnopyranosides, continue to pose significant challenges. In the d-series, characterized by the scarcity of d-rhamnose itself,²⁰ we have successfully devised methods based on stereochemically controlled β-mannosylation, followed by effcient deoxygenation at the 6-position by radical fragmentation of modified 4,6-O-acetals,²¹^–²³ but the l-series, while accessible by indirect methods,²⁴^–²⁶ continues to pose significant challenges to direct stereocontrolled synthesis. We report here on our attempts to use the ‘nitrile effect’ to enhance the β-selectivity of solution-phase rhamnosylation reactions.

2. Results and discussion

As we have discussed,⁶ based on our determination that a transient contact oxacarbenium ion/triflate anion pair (CIP) is the reactive species in our benzylidene acetal mediated β-mannosylation systems,²⁷ we considered the key to successful β-l-rhamnosylation to lie in the use of disarming non-participating protecting groups. The function of these groups is to destabilize the oxacarbenium ion, so as to shift the CIP/glycosyl triflate equilibrium toward the glycosyl triflate, which is the established resting state.⁶^,²⁸ In this manner, the concentration of the α-selective solvent-separated ion pair (SSIP), and of any free oxacarbenium ions is minimized resulting in enhanced β-selectivity (Scheme 1).

On this basis, following the early work of Schuerch,⁷ we surveyed of 2-O-sulfonyl protected rhamnosyl donors, ultimately arriving at the 4-O-benzoyl-2-O-sulfonyl system 1.⁶^,²⁹ A number of other non-participating electron-withdrawing protecting groups for O2, including phosphates, nitrate, cyanate, and a vinylous ester, were also surveyed but found to be less successful than the optimum sulfonate 1.⁶ Interestingly, 2,3-O-carbonyl and 2,3-O-alkylidene protected mannosyl and rhamnosyl thioglycosides were found to be highly α-selective in a number of homogeneous solution phase glycosylations.³^,³⁰^–³² This contrasts with their use in heterogenous glycosylations in the form of glycosyl bromides with activation by insoluble silver salts when they are β-selective.³³^–³⁷ We ascribe the α-selectivity of these 2,3-O-carbonates in homogeneous glycosylations to the half-chair conformation imposed on the pyranose ring, for which we have provided crystallographic evidence,³⁸ which reduces the energy barrier to oxacarbenium ion formation: the β-directing effect observed with the bromides and insoluble silver salts is simply a function of the mode of adsorption onto the promoter surface.³¹ This understanding of the reactivity of the 2,3-O-carbonates led us to the 3,4-O-carbonyl protected thioglycoside 2, which exhibits comparable β-selectivity in our systems to sulfonate 1.³¹

Although donors 1 and 2 gave moderate to excellent β-selectivity with simple secondary and tertiary alcohols, and with more reactive carbohydrate acceptors, they only afford modest selectivity with more typical secondary carbohydrate acceptors.⁶^,²⁹^,³¹^,³⁹ As a consequence, we turned our attention to the well-known β-directing effect of acetonitrile in glycosylation reactions.⁴⁰^–⁴⁴ We were encouraged in this endeavor by preliminary results from the Schmidt group in which it was found that 2,3,4,6-tetra-O-benzyl-α-d-mannopyranosyl trichloroacetimidate 3 gave approximately a 1:1 β:α mixture of anomers in good yield on coupling to methyl 2,3,4-tri-O-benzyl-α-d-glucopyranoside 4, and to methyl 2,4,6-tri-O-benzyl-α-d-glucopyranoside 5, in propionitrile at −80 °C on activation with trimethylsilyl triflate,⁴⁴ when high α-selectivity would have been expected in non-participating solvents.⁴⁵^,⁴⁶

Working with donor 2 and coupling to acceptor 4, we surveyed the effect of propionitrile^‡ under our BSP/Tf₂O/TTBP conditions,³^,⁴^,⁴⁷ with the formation of rhamnoside 6 (Table 1). In neat dichloromethane (Table 1, entry 1), 6 was formed in good yield with a 6:1 β:α ratio. By contrast, in neat propionitrile extensive decomposition of the donor was observed, most of the acceptor was recovered unchanged, and <10% of the coupled product 6 was discernible in the crude reaction mixture, albeit with a β:α ratio of at least 5:1 (Table 1, entry 2). This result was somewhat surprising as propionitrile had previously been demonstrated to be a satisfactory solvent for BSP type coupling reactions with other simple thioglycosides,³ and in the closely related sulfoxide couplings,⁴⁸ but was nevertheless reproducible. Reducing the amount of propionitrile until it was simply an additive in the main solvent resulted in the restoration of efficient coupling, and with some increase in β-selectivity, with a maximum approaching 8:1 for the solvent ratio of 5/95 (v/v) propionitrile/dichloromethane (Table 1, entry 4). It was subsequently shown that comparable results could be obtained with low proportions of acetonitrile in dichloromethane (Table 1, entries 6–8), and because of the greater ease of removal, the mixed acetonitrile/dichloromethane system was selected for use in further coupling reactions.

Table 1.

The effect of varying quantities of propionitrile and acetonitrile on the formation of 6 from 2 and 4 at −60 °C

Entry	Solvent (v/v)	Yield (%) 6	β:α ratio
1	EtCN/CH₂Cl₂ 0:100	81	6:1
2	EtCN/CH₂Cl₂ 100:0	<10	>5:1
3	EtCN/CH₂Cl₂ 10:90	69	6.8:1
4	EtCN/CH₂Cl₂ 5:95	80	7.9:1
5	EtCN/CH₂Cl₂ 2.5:97.5	78	6.6:1
6	CH₃CN/CH₂Cl₂ 5:95	76	7.2:1
7	CH₃CN/CH₂Cl₂ 2.5:97.5	80	8:1
8	CH₃CN/CH₂Cl₂ 1.25:98.75	98	4.5:1

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A further series of coupling reactions were then conducted with donor 2 in the 95/5 dichloromethane/acetonitrile solvent mixture with the results indicated in Table 2. In each a shift in the ratio of products, favoring the β-anomer, is observed on inclusion of acetonitrile, sometimes improving an already β-selective reaction, sometimes changing a previously α-selective reaction into a β-selective one, and other times reducing α-selectivity.

Table 2.

Coupling reactions with donor 2 in CH₂Cl₂/CH₃CN 95/5 (v/v) and in pure CH₂Cl₂

Entry	Yield^a (%) CH₂Cl₂	(β:α ratio)^b CH₂Cl₂/CH₃CN (95/5)
1	87 (5.8:1)	76% (7.2:1)
2	70 (1:1.1)	55% (2.1:1)
3	85 (1:8.1)	72% (1:4.2)
4	87 (1:2.1)	77% (1:1.2)

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Yields refer to isolated products.

Ratios were determined on the crude reaction mixtures by integration of the ¹H NMR spectra.

A similar series of experiments were conducted with donor 1 with similar consequences (Table 3). A comparison between the results presented in Tables 2 and 3 reveals donor 1 to be generally more β-selective than donor 2, whether the couplings are conducted in pure dichloromethane or with the inclusion of acetonitrile.

Table 3.

Further coupling reactions with donor 1 in CH₂Cl₂/CH₃CN 95/5 (v/v) and in pure CH₂Cl₂

Entry	Yield^a (%) CH₂Cl₂	(β:α ratio)^b CH₂Cl₂/CH₃CN (95/5)
1	87 (12.7:1)	88% (16:1)
2	85 (1:1.4)	78% (1.2:1)
3	92 (2.6:1)	88% (3.9:1)
4	74 (2.4:1)	42% (3.5:1)

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Ar = p-CF₃C₆H₄

Yields refer to isolated products.

Ratios were determined on the crude reaction mixtures by integration of the ¹H NMR spectra.

As is clear from the ensemble of results presented in Tables 1–3, the isolated yields of coupled products are generally lower when a nitrile is included in the solvent mixture, falling to a minimum with the use of pure propionitrile. In an attempt to shed further light on this problem, the coupling of donor 1 with the primary acceptor 4 was conducted in a 70/30 mixture of dichloromethane and acetonitrile. Examination of the crude reaction mixture by ¹H NMR spectroscopy revealed the almost complete absence of the anticipated coupled product 13 and the formation of one major product, which was isolated by chromatography on silica gel in 30% yield, and tentatively assigned structure 18. This assignment is based on the rhamnose anomeric hydrogen signal at δ 5.13 whose broad singlet nature is typical for an α-rhamnoside in this series, and on the 3H singlet at δ 1.99, attributed to the imidate methyl group. On standing in deuteriochloroform, this unstable compound underwent decomposition to acetate 19, thereby providing further support for product 18, which is obviously formed by attack of the acceptor on the intermediate nitrilium ion 20. Unfortunately, attempts to detect the formation of nitrilium ion 20, or its congenor arising from donor 2, by low temperature NMR spectroscopy have so far been unsuccessful. Presumably, the increased concentration of acetonitrile leads to a stabilization of nitrilium ion 20 and diverts nucleophilic attack away from the anomeric center toward the sp-hydrolized carbon. In support of this mechanism, we note that a variety of glycosyl nitrilium ions have been captured intramolecularly by this ‘Ritter-like’ capture mode by various nucleophiles and that this chemistry has been applied in the synthesis of sugar β-peptide libraries.⁴⁹^,⁵⁰

Finally, we note the unexpectedly high amounts of α-anomeric products 10α and 14α observed on coupling of acceptor 9 to donors 1 and, especially, 2. In our very extensive studies on the formation of the β-d-mannopyranosides,⁴ acceptor 9 typically delivers β-selectivities in excess of 10:1; certainly, it is usually a more β-selective acceptor than the glucose 4-OH derivative 7. However, comparison of Table 2, entries 2 and 3, reveals that the roles are reversed in coupling to l-rhamnopyranosyl donor 2. We believe this to be a manifestation of stereochemical matching/mismatching,⁵¹ a phenomenon that is gaining increasingly wide recognition in glycosidic bond forming reactions.⁵²^–⁵⁴

3. Experimental

3.1. General methods

All solvents were dried and distilled by standard procedures. Trifluoromethanesulfonic anhydride was distilled over P₂O₅. Acceptors and donors were dried at 40 °C under vacuum for 2 h before use. BSP and TTBP were dried at room temperature under vacuum for 2 h before use. Optical rotations were determined with an Autopol III polarimeter for solutions in CHCl₃. NMR spectra were recorded for CDCl₃ solutions with a Bruker Avance spectrometer at 500 MHz (¹H) or 125 MHz (¹³C). Chemical shifts are in parts per million downfield from tetramethylsilane. High resolution mass spectra were recorded with a Waters Q-TOF2 instrument. Microanalyses were conducted by Midwest Microlabs, Indianapolis, IN. The anomeric stereochemistry of all coupled products was assigned on the basis of the anomeric ¹J_CH coupling constants.⁵⁵

3.2. General procedure for coupling reactions

Tf₂O (0.40 mmol) was added dropwise to a stirred solution of donor (0.27 mmol), BSP (0.35 mmol), and TTBP (0.80 mmol) in CH₃CN (0.5 mL) and CH₂Cl₂ (7.0 mL) under argon at −60 °C. After stirring for 1 h at −60 °C, the acceptor (0.80 mmol) in CH₂Cl₂ (2.5 mL) was added slowly over a period of 1 min. The reaction mixture was stirred for 3 h at −60 °C, then quenched at −60 °C with saturated NaHCO₃, and extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layer was dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (EtOAc/hexane) afforded the corresponding α/β rhamnosides.

3.2.1. Methyl 6-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (6α)

[α]_D²¹ −3.6 (c 1.1, CHCl₃), lit.³¹ −32.7; IR: 1813 cm^{−1; 1}H NMR (CDCl₃): δ 7.38–7.21 (m, 20H, arom H), 5.01 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.86 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.81–4.77 (m, 2H, –CH₂Ph), 4.77 (s, 1H, H-1^II), 4.74 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.68 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.60 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.54 (d, 1H, J = 4.0 Hz, H-1^I), 4.50–4.48 (dd, 1H, J_2,3 = 11.5 Hz, J_3,4 3.0 Hz, H-3^II), 4.46 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.41–4.36 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^II) 4.05 (m, 1H, H-5^II), 4.02 (m, 1H, H-2^II), 3.98 (t, 1H, J_2,3, J_3,4 = 10.0 Hz, H-3^I), 3.83–3.81 (dd, 1H, J_6a,6b = 10.5 Hz, J_5,6a = 1.5 Hz, H-6^I), 3.71–3.68 (m, 1H, H-5^I), 3.54–3.50 (dd, 1H, J_6a,6b = 11.5 Hz, J_5,6b = 5.5 Hz, H-6^I), 3.50–3.47 (dd, 1H, J_2,3 = 9.5 Hz, J_1,2 = 3.5 Hz, H-2^I), 3.37 (t, 1H, J_3,4, J_4,5 = 10.0 Hz, H-4^I), 3.32 (s, 3H, –OCH₃), 1.34 (d, 3H, J_5,6 = 6.5 Hz, H-6^II); ¹³C NMR: δ 153.7, 138.6, 138.0, 136.8, 128.6, 128.52, 128.45, 128.18, 128.11, 128.00,127.98, 127.92, 127.80, 127.74, 127.71, 99.4 (¹J_CH = 172.3 Hz), 98.0 (¹J_CH = 167.1 Hz), 82.0, 80.5, 80.0, 77.9, 77.4, 75.8, 75.0, 74.1, 73.4, 72.9, 69.7, 68.6, 66.7, 55.2, 17.7; ESIMS m/z calcd for C₄₂H₄₆O₁₁Na [M+Na]⁺: 749.2938. Found: 749.2938.

3.2.2. Methyl 6-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamnopyranosyl)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (6β)

[α]_D²¹ +46.6 (c 1.0, CHCl₃), lit.³¹ +52.3; IR: 1810 cm^{−1; 1}H NMR (CDCl₃): δ 7.37–7.26 (m, 20H, arom H), 5.0 (d,1H, ²J = 11.0 Hz, –CH₂Ph), 4.89–4.80 (m, 5H, –CH₂Ph), 4.73 (d, 1H, ²J = 10.5 Hz, –CH₂Ph), 4.68 (d, 1H, ²J = 10.5 Hz, –CH₂Ph), 4.66 (s, 1H, H-1^II), 4.58 (d, 1H, J = 3.5 Hz, H-1^I), 4.48–4.44 (dd, 1H, J_3,4 = 11.5 Hz, J_4,5 = 9.0 Hz, H-4^II), 4.29–4.27 (dd, 1H, J_6a,6b = 11.5 Hz, J_5,6a = 3.0 Hz, H-6^I), 4.25 (d, 1H, J_2,3 = 2.0 Hz, H-2^II), 4.13–4.10 (dd, 1H, J_3,4 = 12.0 Hz, J_2,3 = 2.5 Hz, H-3^II), 3.99 (t, 1H, J_2,3, J_3,4 = 9.0 Hz, H-3^I), 3.76–3.69 (m, H-5^I, H-6^I, H-5^II), 3.61 (t, 1H, J_3,4, J_4,5 = 8.5 Hz, H-4^I), 3.46–3.43 (dd, 1H, J_2,3 = 10.0 Hz, J_1,2 = 4.0 Hz, H-2^I), 3.36 (s, 3H, –OCH₃), 1.39 (d, 3H, J_5,6 = 6.0 Hz, H-6^II); ¹³C NMR: δ 153.9, 138.8, 138.3, 138.1 137.2, 128.5, 128.41, 128.39, 128.1, 128.0, 127.9, 127.8, 127.6, 101.2 (¹J_CH = 157.5 Hz), 98.3 (¹J_CH = 166.9 Hz), 81.8, 81.6, 80.0, 77.9, 77.6, 75.6, 75.2, 73.8, 73.5, 73.4, 71.0, 70.0, 68.0, 55.3, 17.8; ESIMS m/z calcd for C₄₂H₄₆O₁₁Na [M+Na]⁺: 749.2938. Found: 749.2969.

3.2.3. Methyl 2,3,6-tri-O-benzyl-4-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-α-d-glucopyranoside (8α)

[α]_D²¹−11.7 (c 1.0, CHCl₃), lit.³¹ −19.6; IR: 1811 cm^{−1; 1}H NMR (CDCl₃): δ 7.33–7.21 (m, 20H, arom H), 5.09 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 5.0 (s, 1H, H-1^II), 4.76 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.63–4.56 (m, 4H, H-1^I –CH₂Ph), 4.52 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.45–4.41 (m, 2H, –CH₂Ph), 4.25–4.23 (m, 2H, H-3^II, H-4^II), 4.11–4.08 (m, 1H, H-5^II), 3.93 (s, 1H, H-2^II), 3.82–3.80 (m, 2H, H-3^I, H-4^I), 3.62 (m, 1H, H-5^I), 3.58–3.53 (m, 2H, H-2^I, H-6^I), 3.41–3.38 (dd, 1H, J_6a,6b = 11.0 Hz, J_5,6a = 3.0 Hz, H-6^I), 3.35 (s, 3H, –OCH₃), 0.97 (d, 3H, J_5,6 = 6.0 Hz, H-6^II); ¹³C NMR: δ 153.9, 138.2, 137.8, 137.5, 136.9, 128.7, 128.5, 128.4, 128.2, 128.08, 128.01, 127.90, 127.85, 127.75, 127.70, 98.6 (¹J_CH = 172.8 Hz), 97.9 (¹J_CH 166.1 Hz), 80.6, 80.2, 79.6, 78.2, 77.9, 77.5, 75.8, 74.1, 73.8, 73.6, 73.3, 72.6, 69.8, 69.0, 68.7, 55.3, 17.3; ESIMS m/z calcd for C₄₂H₄₆O₁₁Na [M+Na]⁺: 749.2938. Found: 749.2941.

3.2.4. Methyl 2,3,6-tri-O-benzyl-4-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamnopyranosyl)-α-d-glucopyranoside (8β)

[α]_D²¹ +18.8 (c 1.0, CHCl₃), lit³¹. +56.1; IR: 1811 cm^{−1; 1}H NMR (CDCl₃): δ 7.38–7.25 (m, 18H, arom H), 7.11 (m, 2H, arom H), 4.99 (d, 1H, ²J = 11.5 Hz, –CH₂Ph), 4.76–4.65 (m, 6H, H-1^I, H-1^II, –CH₂Ph), 4.61 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.52 (d,1H, ²J = 12.0 Hz, –CH₂Ph), 4.31–4.25 (m, 2H, H-4^II, –CH₂Ph), 3.86 (t, 1H, J_2,3, J_3,4 = 9.0 Hz, H-3^I), 3.82 (dd, 1H, J_6a,6b = 10.5 Hz, J_5,6a = 1.5 Hz, H-6^I), 3.73 (m, 1H, H-6^I), 3.69–3.62 (m, 2H, H-4^I, H-5^I), 3.53–3.48 (m, 4H, H-2^I, H-2^II, H-3^II, H-5^II), 3.44 (s, 3H, –OCH₃), 1.24 (d, 3H, J_5,6 = 6.0 Hz, H-6^II); ¹³C NMR: δ 154.0, 138.6, 138.4, 137.8, 137.5, 128.6, 128.5, 128.4, 128.2, 128.15, 128.09, 128.05, 128.00, 127.87, 127.85, 127.42, 127.37, 101.5 (¹J_CH = 165.0 Hz), 97.7 (¹J_CH = 163.1 Hz), 82.2, 81.5, 80.0, 77.9, 76.2, 75.7, 73.44, 73.37, 73.10, 72.98, 70.6, 69.5, 68.8, 55.5, 17.7; ESIMS m/z calcd for C₄₂H₄₆O₁₁Na [M+Na]⁺: 749.2938. Found: 749.2923.

3.2.5. Methyl 4-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-2,3-O-isopropylidiene-α-l-rhamnopyranoside (10α)

[α]_D^{21 −}68.5 (c 1.0, CHCl₃); IR: 1819 cm^{31; 1}H NMR (CDCl₃): δ 7.36–7.31 (m, 5H, arom H), 5.48 (d, 1H, J_1,2 = 1.0 Hz, H-1^II), 4.85 (s, 1H, H-1^I), 4.76 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.70 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.45 (m, 2H, H-3^II, H-4^II), 4.13 (m, 1H, H-2^II), 4.06 (m, 3H, H-2^I, H-3^I, H-5^II), 3.58 (m, 1H, H-5^I), 3.50 (m, 1H, H-4^I), 3.36 (s, 3H, –OCH₃), 1.51 (s, 3H, –C(CH₃)₂), 1.38 (d, 3H, J_5,6 = 6.0 Hz, H-6^II), 1.34 (s, 3H, –C(CH₃)₂), 1.26 (d, 3H, J_5,6 = 6.0 Hz, H-6^I); ¹³C NMR: δ 153.7, 136.9, 128.5, 128.1, 127.7, 109.6, 98.1 (¹J_CH = 174.9 Hz), 97.9 (¹J_CH = 167.4 Hz), 80.3, 78.4, 78.2, 77.9, 76.1, 74.6, 72.8, 69.2, 63.5, 54.9, 27.9, 26.3, 17.9, 17.8; ESIMS m/z calcd for C₂₄H₃₂O₁₀Na [M+Na]⁺: 503.1893. Found: 503.1892.

3.2.6. Methyl 4-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamno-pyranosyl)-2,3-O-isopropylidiene-α-l-rhamnopyranoside (10β)

[α]_D²¹ +5.6 (c 0.7, CHCl₃); IR: 1810 cm^{31; 1}H NMR (CDCl₃): δ 7.37–7.30 (m, 5H, arom H), 4.86–4.79 (q, 2H, ²J = 12.5 Hz, –CH₂Ph), 4.83 (s, 1H, H-1^I), 4.75 (d, 1H, J_1,2 = 1.0 Hz, H-1^II), 4.52–4.48 (dd, 1H, J_4,5 = 11.5 Hz, J_3,4 = 9.5 Hz, H-4^II), 4.37 (t, 1H, J_2,3, J_3,4 = 6.0 Hz, H-3^I), 4.21 (d, 1H, J_2,3 = 1.5 Hz, H-2^II), 4.13–4.11 (m, 2H, H-3^II, H-2^I), 3.76 (m, 1H, H-5^II), 3.70 (m, 1H, H-5^I), 3.39–3.36 (dd, 1H, J_4,5 = 10.0 Hz, J_3,4 = 7.0 Hz, H-4^I), 3.37 (s, 3H, –OCH₃), 1.48 (s, 3H, –C(CH₃)₂), 1.44 (d, 3H, J_5,6 = 6.0 Hz H-6^II), 1.33 (s, 3H, –C(CH₃)₂), 1.25 (d, 3H, J_5,6 = 6.5 Hz, H-6^I); ¹³C NMR: δ 153.9, 137.1, 128.4, 128.1, 128.0, 109.0, 100.9 (¹J_CH = 157.1 Hz), 98.2 (¹J_CH = 166.5 Hz), 83.4, 81.8, 77.9, 76.40, 75.8, 73.6, 73.2, 71.1, 63.9, 54.9, 28.0, 26.1, 17.8, 17.7; ESIMS m/z calcd for C₂₄H₃₂O₁₀Na [M+Na]⁺: 503.1888. Found: 503.1885.

3.2.7. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-α-d-manno-pyranoside (12α)

[α]_D²¹ 369.9 (c 0.9, CHCl₃); IR: 1810 cm^{−1; 1}H NMR (CDCl₃): δ 7.52 (dd, 2H, J = 8.5 Hz, J = 2.5 Hz, arom H), 7.40–7.30 (m, 13H, arom H), 5.65 (s, 1H, H-7^I), 4.87 (d, 1H, ²J = 11.5 Hz, –CH₂Ph), 4.83 (s, 1H, H-1^II), 4.82 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.67 (dd, 1H, J_3,4 = 11.0 Hz, J_2,3 = 2.5 Hz, H-3^II), 4.66 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.63 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.49 (d, 1H, J_1,2 = 2.0 Hz, H-1^I), 4.45 (m, 1H, H-5^II), 4.35 (dd, 1H, J_4,5 = 11.5 Hz, J_3,4 = 10.0 Hz, H-4^II), 4.25 (dd, 1H, J_6a,6b = 10.0 Hz, J_5,6a = 4.5 Hz, H-6^I), 4.21 (m, 1H, H-2^II), 4.1 (dd, 1H, J_2,3 = 3.5 Hz, J_1,2 = 1.5 Hz, H-2^I), 4.03 (t, 1H, J_3,4, J_4,5 = 10.0 Hz, H-4^I), 3.94 (dd, 1H, J_3,4 = 9.5 Hz, J_2,3 = 3.0 Hz, H-3^I), 3.84 (t, 1H, J_5,6a, J_6a,6b = 10.5 Hz, H-6^I), 3.76 (m, 1H, H-5^I), 3.35 (s, 3H, –OCH₃), 1.11 (d, 3H, J_5,6 = 6.0 Hz, H-6^II); ¹³C NMR: δ 153.8, 138.0, 137.4, 137.0, 129.0, 128.6, 128.4, 128.2, 127.9, 127.8, 126.0, 101.6 (¹J_CH = 162.4 Hz), 98.8 (¹J_CH = 165.9 Hz), 97.6 (¹J_CH 169.3 Hz), 80.2, 79.1, 77.9, 75.0, 74.4, 74.0, 73.8, 73.3, 68.9, 68.7, 63.9, 55.0, 17.5; ESIMS m/z calcd for C₃₅H₃₈O₁₁Na [M+Na]⁺: 657.2307. Found: 657.2306.

3.2.8. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamnopyranosyl)-α-d-manno-pyranoside (12β)

[α]_D²¹ +29.3 (c 0.6, CHCl₃); IR: 1811 cm^{−1; 1}H NMR (CDCl₃): δ 7.49 (dd, 2H, J = 8.5 Hz, J = 3.0 Hz, arom H), 7.45 (d, 2H, J = 7.5 Hz, arom H), 7.40–7.37 (m, 4H, arom H), 7.34–7.31 (m, 4H, arom H), 7.27 (m, 3H, arom H), 5.56 (s, 1H, H-7^I), 4.94 (m, 4H, H-1^I, –CH₂Ph), 4.79 (s, 1H, H-1^II), 4.60 (d, 1H, ²J = 11.5 Hz, –CH₂Ph), 4.44 (dd, 1H, J_4,5 = 11.5 Hz, J_3,4 = 9.5 Hz, H-4^II), 4.32 (m, 1H, H-6^I), 4.28 (d, 1H, J_2,3 = 2.0 Hz, H-2^II), 4.11 (t, 1H, J_1,2, J_2,3 = 2.5 Hz, H-2^I), 4.0 (m, 2H, H-3^I, H-4^I), 3.92 (dd, 1H, J_3,4 = 11.5 Hz, J_2,3 = 2.5 Hz, , H-3^II), 3.81 (m, 2H, H-5^I, H-6^I), 3.60 (m, 1H, H-5^II), 3.38 (s, 3H, –OCH₃), 1.42 (d, 3H, J_5,6 = 6.5 Hz, H-6^II); ¹³C NMR: δ 153.9, 138.5, 137.5, 137.4, 129.0, 128.5, 128.2, 128.0, 127.92, 127.86, 127.5, 126.0, 101.9 (¹J_CH = 164.8 Hz), 101.6 (¹J_CH = 160.5 Hz), 101.2 (¹J_CH = 174.8 Hz), 81.5, 79.4, 77.8, 76.4, 73.8, 73.7, 73.2, 71.0, 69.1, 63.7, 54.9, 17.8; ESIMS m/z calcd for C₃₅H₃₈O₁₁Na [M+Na]⁺: 657.2307. Found: 657.2307.

3.2.9. Methyl 6-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-2,3, 4-tri-O-benzyl-α-d-glucopyranoside (13α)

[α]_D²¹ +31.9 (c 1.0, CHCl₃), lit.²⁹ −30.2; ¹H NMR (CDCl₃): δ 8.22 (d, 1H, J = 7.5 Hz, arom H), 7.95 (d, 2H, J = 8.5 Hz, arom H), 7.73 (d, 1H, J = 8.0 Hz, arom H), 7.59–7.26 (m, 17H, arom H), 7.14 (m, 1H, arom H), 7.06 (t, 2H, J = 8.0 Hz, arom H), 6.94 (d, 2H, J = 7.5 Hz, arom H), 5.28 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^II), 5.12 (d, 1H, J_1,2 = 1.5 Hz, H-1^II), 5.03–5.01 (m, 2H, H-2^II, –CH₂Ph), 4.94 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.85 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.83 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.72 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.62 (d, 1H, J_1,2 = 3.0 Hz, H-1^I), 4.55 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.30–4.23 (q, 2H, J = 12.5 Hz, –CH₂Ph), 4.02 (t, 1H, J_2,3, J_3,4 = 9.5 Hz, H-3^I), 3.90–3.83 (m, 3H, H-6^I, H-3^II, H-5^II), 3.79–3.76 (m, 1H, H-5^I), 3.60–3.57 (dd, 1H, J_6a,6b = 11.0 Hz, J_5,6a = 6.5 Hz, H-6^I), 3.54 (dd, 1H, J_2,3 = 9.5 Hz, J_1,2 = 3.0 Hz, H-2^I), 3.40–3.36 (m, 4H, H-4^I, –OCH₃), 1.19 (d, 3H, J_5,6 = 6.0 Hz, H-6^II); ¹³C NMR: δ 165.3, 138.6, 138.0, 137.9, 137.0, 135.2, 133.5, 133.2, 132.0, 131.6, 129.8, 129.7, 128.52, 128.48, 128.37, 128.31, 128.26, 128.20, 128.16, 128.08, 128.07, 128.00, 127.96, 127.92, 127.8, 127.6, 97.9 (¹J_CH 172.9 Hz), 97.8 (¹J_CH 157.3 Hz), 82.0, 79.9, 77.8, 76.8, 75.9, 75.2, 73.6, 73.3, 72.5, 71.5, 70.2, 67.0, 66.8, 55.2, 17.3; ESIMS m/z calcd for C₅₅H₅₅O₁₃F₃NaS [M+Na]⁺: 1035.3213. Found: 1035.3218.

3.2.10. Methyl 6-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-2,3, 4-tri-O-benzyl-α-d-glucopyranoside (13β)

[α]_D²¹ +59.0 (c 1.0, CHCl₃), lit.²⁹ +22.9; ¹H NMR (CDCl₃): δ 8.22 (d, 1H, J = 7.5 Hz, arom H), 7.96–7.94 (dd, 2H, J = 7.5 Hz, J 0.5 Hz, arom H), 7.66 (d, 1H, J = 8.0 Hz, arom H), 7.59 (t, 1H, J = 7.0 Hz, arom H), 7.46–7.18 (m, 15H, arom H), 7.11 (t, 2H, J = 7.5 Hz, arom H), 7.04 (d, 2H, J = 7.0 Hz, arom H), 5.41 (d, 1H, J_2,3 = 3.0 Hz, H-2^II), 5.29 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^II), 4.98 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.86–4.82 (m, 2H, –CH₂Ph), 4.75 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.66 (s, 1H, H-1^II), 4.64 (d, 1H, J_1,2 = 3.5 Hz, H-1^I), 4.56–4.49 (m, 3H, –CH₂Ph), 4.37 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.27–4.24 (dd, 1H, J_6a,6b = 11.5 Hz, J_5,6a = 3.5 Hz, H-6^I), 3.91 (t, 1H, J_2,3, J_3,4 = 9.0 Hz, H-3^I), 3.69–3.63 (m, 3H, H-5^I, H-6^I, H-3^II), 3.56–3.52 (m, 2H, H-2^I, H-5^II), 3.43 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^I), 3.36 (s, 3H, –OCH₃), 1.26 (d, 3H, J_5,6 = 6.0 Hz, H-6^II); ¹³C NMR: δ 165.2, 139.1, 138.6, 138.4, 136.8, 136.5, 133.24, 133.22, 131.9, 130.9, 129.8, 129.6, 128.5, 128.4, 128.34, 128.26, 128.25, 128.17, 128.0, 127.92, 127.86, 127.74, 127.55, 127.52, 98.3 (¹J_CH 165.9 Hz), 97.8 (¹J_CH 156.8 Hz), 81.7, 79.6, 77.4, 77.2, 75.6, 74.9, 73.4, 72.5, 71.0, 70.9, 69.9, 67.1, 55.2, 17.6; ESIMS m/z calcd for C₅₅H₅₅O₁₃F₃NaS [M+Na]⁺: 1035.3213. Found: 1035.3209.

3.2.11. Methyl 4-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-2,3-O-isopropylidiene-α-l-rhamnopyranoside (14α)

[α]_D²¹ +21.5 (c 0.5, CHCl₃), lit.²⁹ −55.2; ¹H NMR (CDCl₃): δ 8.26 (d, 1H, J = 7.5 Hz, arom H), 7.94 (d, 2H, J = 7.5 Hz, arom H), 7.76 (d, 1H, J = 7.5 Hz, arom H), 7.58–7.50 (m, 3H, arom H), 7.42 (t, 2H, J = 8.0 Hz, arom H), 7.17 (t, 1H, J = 7.5 Hz, arom H), 7.1 (t, 2H, arom H), 6.99 (d, 2H, J = 7.5 Hz, arom H), 5.48 (d, 1H, J_1,2 = 1.5 Hz, H-1^II), 5.28 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^II), 5.19 (t, 1H, J_1,2, J_2,3 = 2.5 Hz, H-2^II), 4.86 (s, 1H, H-1^I), 4.39 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.30 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.12–4.11 (m, 2H, H-2^I, H-3^I), 3.91–3.86 (m, 2H, H-3^II, H-5^II), 3.66–3.63 (m, 1H, H-5^I), 3.48–3.45 (m, 1H, H-4^I), 3.39 (s, 3H, –OCH₃), 1.55 (s, 3H, –C(CH₃)₂), 1.37 (s, 3H, –C(CH₃)₂), 1.27 (d, 3H, J_5,6 = 6.5 Hz, H-6^I), 1.22 (d, 3H, J_5,6 = 6.5 Hz, H-6^II); ¹³C NMR: δ 165.2, 137.1, 135.5, 133.3, 133.1, 131.9, 131.7, 129.8, 129.7, 128.3, 128.24, 128.20, 128.1, 127.7, 127.5, 109.7, 98.0 (¹J_CH = 165.4 Hz), 97.2 (¹J_CH = 171.6 Hz), 79.3, 77.8, 77.1, 76.0, 73.7, 72.4, 71.4, 67.7, 63.9, 55.0, 28.0, 26.4, 17.7, 17.5. Anal calcd for C₃₇H₄₁F₃O₁₂S: C, 57.96; H, 5.39. Found: C, 57.66; H, 5.23.

3.2.12. Methyl 4-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-2,3-O-isopropylidiene-α-l-rhamnopyranoside (14β)

[agr;]_D²¹ +43.6 (c 0.7, CHCl₃), lit.²⁹ +30.7; ¹H NMR (CDCl₃): δ 8.28 (m, 1H, arom H), 7.96 (d, 2H, J = 8.0 Hz, arom H), 7.74 (m, 1H, arom H), 7.59–7.52 (m, 3H, arom H), 7.43 (t, 2H, J = 7.5 Hz, arom H), 7.16 (t, 1H, J = 7.0 Hz, arom H), 7.08 (t, 2H, J = 7.5 Hz, arom H), 7.0 (d, 2H, J = 7.5 Hz, arom H), 5.34 (d, 1H, J_2,3 = 3.0 Hz, H-2^II), 5.30 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^II), 4.80 (s, 2H, H-1^I, H-1^II), 4.82 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.34 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.16 (t, 1H, J_2,3, J_3,4 = 6.5 Hz, H-3^I), 4.05 (d, 1H, J_2,3 = 6.0 Hz, H-2^I), 3.70–3.68 (dd, 1H, J_3,4 = 10.0 Hz, J_2,3 = 3.0 Hz, H-3^II), 3.56 (m, 1H, H-5^II), 3.49 (m, 1H, H-5^I), 3.42–3.39 (m, 1H, H-4^I), 3.34 (s, 3H, –OCH₃), 1.50 (s, 3H, –C(CH₃)₂), 1.31 (s, 3H, –C(CH₃)₂), 1.30 (d, 3H, J_5,6 = 6.0 Hz, H-6^II), 1.26 (d, 3H, J_5,6 = 6.5 Hz, H-6^I); ¹³C NMR: δ 165.2, 136.83, 136.80, 133.3, 132.7, 131.8, 131.2, 129.8, 129.7, 128.4, 128.2, 128.0, 127.85, 127.80, 127.75, 127.70, 127.65, 127.61, 108.9, 98.0 (¹J_CH = 166.6 Hz), 97.6 (¹J_CH = 155.1 Hz), 82.8, 78.0, 76.3, 76.1, 75.7, 72.6, 71.06, 71.05, 63.8, 54.7, 28.1, 26.1, 17.7, 17.5. Anal calcd for C₃₇H₄₁F₃O₁₂S: C, 57.96; H, 5.39. Found: C, 58.03; H, 5.39.

3.2.13. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-α-d-mannopyranoside (15α)

[α]_D²¹ −24.3 (c 1.1, CHCl₃), lit.²⁹ −35.6; ¹H NMR (CDCl₃): δ 8.27 (d, 1H, J = 7.5 Hz, arom H), 7.92 (d, 2H, J = 7.5 Hz, arom H), 7.75 (d, 1H, J = 7.5 Hz, arom H), 7.57–7.39 (m, 10H, arom H), 7.34 (d, 2H, J = 7.0 Hz, arom H), 7.26–7.19 (m, 4H, arom H), 7.14 (t, 2H, J = 7.5 Hz, arom H), 6.99 (d, 2H, J = 7.0 Hz, arom H), 5.66 (s, 1H, H-7^I), 5.30 (t, 1H, J_3,4, J_4,5 = 10.0 Hz, H-4^II), 5.18 (d, 1H, J_1,2 = 1.0 Hz, H-1^II), 5.11 (t, 1H, J_1,2, J_2,3 = 3.0 Hz, H-2^II), 4.82 (d, 1H, ²J = 11.5 Hz, –CH₂Ph), 4.72 (s, 1H, H-1^I), 4.70 (d, 1H, ²J = 11.5 Hz, –CH₂Ph), 4.39–4.30 (m, 4H, H-6^I, H-5^II, –CH₂Ph), 4.19 (s, 1H, H-2^I), 4.02–3.98 (m, 3H, H-3^I, H-4^I, H-3^II), 3.88 (t, 1H, J_5,6a, J_6a,6b = 10.0 Hz, H-6^I), 3.81 (m, 1H, H-5^I), 3.41 (s, 3H, –OCH₃), 1.07 (d, 3H, J_5,6 = 6.5 Hz, H-6^II); ¹³C NMR: δ 165.4, 138.0, 137.5, 137.1, 135.0, 133.5, 133.1, 132.0, 131.7, 129.9, 129.7, 129.0, 128.4, 128.32, 128.26, 128.23, 128.18, 127.7, 127.6, 126.1, 101.6 (¹J_CH = 162.3 Hz), 99.0 (¹J_CH = 170.5 Hz), 96.5 (¹J_CH = 170.6 Hz), 78.7, 74.5, 74.1, 73.8, 73.1, 72.4, 71.7, 68.8, 67.2, 63.9, 55.1, 17.2; ESIMS m/z calcd for C₄₈H₄₇F₃O₁₃NaS [M+Na]⁺: 943.2587. Found: 943.2598.

3.2.14. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-α-d-mannopyranoside (15β)

[α]_D²¹ +51.1 (c 1.0, CHCl₃), lit.²⁹ +25.6; ¹H NMR (CDCl₃): δ 8.35 (m, 1H, arom H), 7.94–7.92 (dd, 2H, J = 8.0 Hz, 1.0 Hz, arom H), 7.77 (m, 1H, arom H), 7.59–7.26 (m, 15H, arom H), 7.16 (t, 1H, J = 7.5 Hz, arom H), 7.07 (t, 2H, J = 7.5 Hz, arom H), 6.96 (d, 2H, J = 7.0 Hz, arom H), 5.69 (s, 1H, H-7^I), 5.47 (d, 1H, J_2,3 = 2.5 Hz, H-2^II), 5.26 (t, 1H, J_3,4, J_4,5 = 10.0 Hz, H-4^II), 4.98 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.89 (s, 1H, H-1^II), 4.67 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.63 (d, 1H, J_1,2 = 1.5 Hz, H-1^I), 4.44 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.31 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^I), 4.25–4.19 (m, 2H, H-6^I, –CH₂Ph), 4.15 (m, 1H, H-2^I), 4.00–3.98 (dd, 1H, J_3,4 = 9.5 Hz, J_2,3 2.5 Hz, H-3^I), 3.81 (t, 1H, J_5,6a, J_6a,6b = 10.0 Hz, H-6^I), 3.75 (m, 1H, H-5^I), 3.49–3.46 (dd, 1H, J_3,4 = 9.5 Hz, J_2,3 = 2.5 Hz, H-3^II), 3.42 (m, 1H, H-5^II), 3.33 (s, 3H, –OCH₃), 1.29 (d, 3H, J_5,6 = 6.5 Hz, H-6^II); ¹³C NMR: δ 165.2, 138.9, 137.8, 137.0, 136.9, 133.2, 132.6, 132.0, 131.1, 129.8, 129.7, 128.8, 128.5, 128.4, 128.20, 128.17, 127.95, 127.91, 127.86, 127.81, 127.72, 127.65, 127.60, 127.57, 126.1, 101.5 (¹J_CH = 164.5 Hz), 100.9 (¹J_CH = 171.8 Hz), 98.6 (¹J_CH = 161.0 Hz), 79.0, 77.6, 76.6, 76.5, 75.9, 73.6, 72.3, 71.0, 70.8, 68.9, 64.0, 54.7, 17.6; ESIMS m/z calcd for C₄₈H₄₇F₃O₁₃NaS [M+Na]⁺: 943.2587. Found: 943.2542.

3.2.15. Methyl 3-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-2,4, 6-tri-O-benzyl-α-d-mannopyranoside (17α)

[α]_D²¹ +6.9 (c 0.7, CHCl₃), lit.²⁹ −23.1; ¹H NMR (CDCl₃): δ 8.16 (d, 1H, J = 8.5 Hz, arom H), 7.72 (m, 3H, arom H), 7.56–7.07 (m, 21H, arom H), 7.01 (t, 2H, J = 7.5 Hz, arom H), 6.88 (d, 2H, J = 7.5 Hz, arom H), 5.36 (s, 1H, H-1^II), 5.30 (t, 1H, J_3,4, J_4,5 10.0 Hz, H-4^II), 5.03 (s, 1H, H-2^II), 4.85 (s, 1H, H-1^I), 4.81–4.71 (m, 3H, –CH₂Ph), 4.62–4.55 (m, 2H, –CH₂Ph), 4.45 (d, 1H, ²J = 11.0 Hz, –CH₂Ph), 4.21–4.10 (m, 3H, H-3^I, –CH₂Ph), 4.03 (m, 1H, H-5^II), 4.00–3.93 (m, 3H, H-2^I, H-4^I, H-3^II), 3.82 (m, 1H, H-6^I), 3.78–3.72 (m, 2H, H-5^I, H-6^I), 3.34 (s, 3H, –OCH₃), 1.13 (d, 3H, J_5,6 = 6.0 Hz, H-6^II); ¹³C NMR: δ 165.2, 138.4, 138.3, 138.0, 136.7, 134.9, 133.5, 133.1, 131.9, 131.7, 129.7, 129.6, 128.5, 128.3, 128.1, 127.74, 127.71, 127.69, 127.64, 127.59, 127.54, 127.50, 127.3, 98.7 (¹J_CH 169.8 Hz), 93.5 (¹J_CH 171.6 Hz), 76.9, 75.0, 74.8, 73.9, 73.8, 73.6, 73.4, 73.2, 72.2, 71.5, 71.3, 69.0, 67.1, 54.9, 17.3; ESIMS m/z calcd for C₅₅H₅₅O₁₃F₃KS [M+K]⁺: 1051.2953. Found: 1051.2914.

3.2.16. Methyl 3-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-2,4, 6-tri-O-benzyl-α-d-mannopyranoside (17β)

[α]_D²¹ +68.9 (c 1.1, CHCl₃), lit.²⁹ +35.2; ¹H NMR (CDCl₃): δ 8.23 (d, 1H, J = 7.0 Hz, arom H), 7.90 (dd, 2H, J = 8.0 Hz, J = 0.5 Hz, arom H), 7.67 (d, 1H, J = 9.0 Hz, arom H), 7.56 (t, 1H, J = 7.0 Hz arom H), 7.45–7.24 (m, 19H, arom H), 7.15 (t, 1H, J = 7.5 Hz, arom H), 7.06 (t, 2H, J = 7.5 Hz, arom H), 6.90 (d, 2H, J = 7.5 Hz, arom H), 5.27 (t, 1H, J_3,4, J_4,5 = 9.0 Hz, H-4^II), 5.13 (d, 1H, J_2,3 = 2.5 Hz, H-2^II), 4.88 (d, 1H, ²J = 13.0 Hz, –CH₂Ph), 4.77 (t, 2H, ²J = 10.5 Hz, –CH₂Ph), 4.72 (s, 1H, H-1^II), 4.71 (d, 1H, ²J = 12.0 Hz, –CH₂Ph), 4.65 (d, 1H, J_1,2 = 1.5 Hz, H-1^I), 4.60–4.57 (m, 2H, –CH₂Ph), 4.30 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.13 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.02 (dd, 1H, J_3,4 = 9.5 Hz, J_2,3 = 2.5 Hz, H-3^I), 3.94 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-4^I), 3.89 (m, 1H, H-2^I), 3.79–3.75 (m, 3H, H-5^I, H-6^I), 3.48 (m, 1H, H-5^II), 3.41–3.39 (dd, 1H, J_3,4 = 9.5 Hz, J_2,3 = 3.0 Hz, H-3^II), 3.32 (s, 3H, –OCH₃), 1.26 (d, 3H, J_5,6 = 6.5 Hz, H-6^II); ¹³C NMR: δ 165.2, 139.1, 139.0, 138.4, 136.7, 136.5, 133.2, 132.7, 131.8, 131.0, 129.7, 129.6, 128.40, 128.37, 128.32, 128.25, 128.17, 128.10, 127.9, 127.8, 127.6, 127.55, 127.47, 127.2, 100.2 (¹J_CH = 155.4 Hz) (¹J_CH = 164.5 Hz), 83.4, 78.2, 76.7, 76.2, 75.0, 74.8, 73.5, 73.1, 72.3, 71.9, 71.2, 70.8, 69.4, 54.7, 17.7; ESIMS m/z calcd for C₅₅H₅₅O₁₃F₃KS [M+Na]⁺: 1035.3213. Found: 1035.3236.

3.3. Methyl 6-O-acetyl-2,3,4-tri-O-benzyl-α-d-gluco-pyranoside

Tf₂O (0.027 mL, 0.16 mmol) was added dropwise to a stirred solution of donor 1 (70 mg, 0.11 mmol) and BSP (29 mg, 0.14 mmol), in CH₃CN (1.2 mL) and CH₂Cl₂ (1.8 mL) under argon at −60 °C. After stirring for 1 h at −60 °C, acceptor 4 (150 mg, 0.32 mmol) in CH₂Cl₂ (1.0 mL) was added over a period of 1 min. The reaction mixture was stirred for 3 h at −60 °C, then quenched at −60 °C with saturated aqueous NaHCO₃, and extracted with CH₂Cl₂. (3 × 15 mL). The combined organic layer was dried (Na₂SO₄), and the solvent was removed under reduced pressure. Examination of the crude reaction mixture by ¹H NMR spectroscopy revealed the formation of one very major product, tentatively assigned as the imidate (18). Purification by silica gel column chromatography (EtOAc/hexane) afforded the unstable 18 (30 mg, 27%) and acetate 19 (10 mg, 6%). Compound 18 rapidly decomposed on standing in CDCl₃ to a mixture of 19 and several other compounds. It was characterized by the following signals: ¹H NMR (300 MHz, CDCl₃): δ 5.13 (s, 1H, H-1^II), 4.62 (d, 1H, J_1,2 = 3.6 Hz, H-1^I), 3.42 (s, 3H, –OCH₃), 1.99 (s, 3H, CH₃C(OR)=N), 1.17 (d, 3H J_5,6 = 6.3 Hz, H-6^II).

3.3.1. Methyl 6-O-acetyl-2,3,4-tri-O-benzyl-α-d-gluco-pyranoside (19)

[α]_D²¹ +18.0 (c 0.8, CHCl₃), lit.⁵⁶ +28.6; ¹H NMR (CDCl₃): δ 7.37–7.26 (m, arom H), 5.09 (d, 1H, ²J = 10.5 Hz, –CH₂Ph), 4.89–4.79 (m, 3H, –CH₂Ph), 4.68 (d, 1H, ²J = 12.5 Hz, –CH₂Ph), 4.59–4.55 (m, 2H, –CH₂Ph), 4.26–4.24 (m, 2H, H-6), 4.01 (t, 1H, J_3,4, J_4,5 = 9.5 Hz, H-3), 3.81 (m, 1H, H-5), 3.55–3.52 (dd, 1H, J_2,3 = 9.5 Hz, J_1,2 = 3.5 Hz, H-2), 3.48 (t, 1H, J_4,5, J_3,4 = 9.0 Hz, H-4), 3.37 (s, 3H, –OCH₃), 2.02 (s, 3H, CH₃CO); ¹³C NMR: δ 170.7, 138.6, 138.0, 137.8, 128.50, 128.48, 128.45, 128.13, 128.09, 128.01, 127.99, 127.92, 127.7, 98.1, 82.0, 79.8, 75.8, 75.0, 73.4, 68.5, 63.0, 55.2, 20.9.

Supplementary Material

Supplementary Data

NIHMS10997-supplement.pdf^{(155KB, pdf)}

Scheme 1 — Abbreviated glycosylation mechanism.

Acknowledgments

We thank the NIH (GM59335) for support of this work, and John Picione for first recognizing the α-selective coupling of donor 2 with acceptor 9.

Footnotes

^†

We distinguish between direct methods, which afford the desired glycosidic bond in a single step, and indirect methods, requiring either prior attachment of the acceptor to the donor, or correction of stereochemistry after formation of the glycosidic bond.

^‡

Propionitrile has a lower freezing point (−93 °C) than acetonitrile (−48 °C), making it the nitrile of choice when used in significant proportion in low temperature glycosylations. It was demonstrated by Schmidt that propionitrile and acetonitrile have similar directing effects in other glycosylation reactions.⁴⁴

Supplementary data

Copies of the ¹H and ¹³C NMR spectra for disaccharides. Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.carres.2006.03.036.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Data

NIHMS10997-supplement.pdf^{(155KB, pdf)}

[R1] 1.Crich D, Sun S. J Org Chem. 1997;62:1198–1199. [Google Scholar]

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[R12] 12.Ziegler T, Lemanski G. Angew Chem, Int Ed. 1998;37:3129–3132. doi: 10.1002/(SICI)1521-3773(19981204)37:22<3129::AID-ANIE3129>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]

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[R14] 14.Abdel-Rahman AA-H, El Ashry ESH, Schmidt RR. Carbohydr Res. 2002;337:195–206. doi: 10.1016/s0008-6215(01)00306-8. [DOI] [PubMed] [Google Scholar]

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[R16] 16.Hodosi G, Kovác P. J Am Chem Soc. 1997;119:2335–2336. [Google Scholar]

[R17] 17.El Ashry ESH, Rashed N, Ibrahim ESI. Curr Org Synth. 2005;2:175–213. [Google Scholar]

[R18] 18.Pozsgay, V. In Carbohydrate in Chemistry and Biology; Ernst, B., Hart, G. W., Sinaÿ, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, pp 319–343.

[R19] 19.Ito, Y.; Ohnishi, Y. In Glycoscience: Chemistry and Chemical Biology; Fraser-Reid, B., Kuniaki, T., Thiem, J., Eds.; Springer: Berlin, 2001; Vol. 2, pp 1589–1619.

[R20] 20.Ramm M, Lobe M, Hamburger M. Carbohydr Res. 2003;338:109–112. doi: 10.1016/s0008-6215(02)00353-1. [DOI] [PubMed] [Google Scholar]

[R21] 21.Crich D, Yao Q. J Am Chem Soc. 2004;126:8232–8236. doi: 10.1021/ja048070j. [DOI] [PubMed] [Google Scholar]

[R22] 22.Crich, D.; Bowers, A. A. J. Org. Chem., in press.

[R23] 23.Kwon YT, Lee YJ, Lee K, Kim KS. Org Lett. 2004;6:3901–3904. doi: 10.1021/ol048648u. [DOI] [PubMed] [Google Scholar]

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On the nitrile effect in l-rhamnopyranosylation

David Crich

Mitesh Patel

Abstract

1. Introduction

2. Results and discussion

Table 1.

Table 2.

Table 3.

3. Experimental

3.1. General methods

3.2. General procedure for coupling reactions

3.2.1. Methyl 6-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (6α)

3.2.2. Methyl 6-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamnopyranosyl)-2,3,4-tri-O-benzyl-α-d-glucopyranoside (6β)

3.2.3. Methyl 2,3,6-tri-O-benzyl-4-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-α-d-glucopyranoside (8α)

3.2.4. Methyl 2,3,6-tri-O-benzyl-4-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamnopyranosyl)-α-d-glucopyranoside (8β)

3.2.5. Methyl 4-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-2,3-O-isopropylidiene-α-l-rhamnopyranoside (10α)

3.2.6. Methyl 4-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamno-pyranosyl)-2,3-O-isopropylidiene-α-l-rhamnopyranoside (10β)

3.2.7. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-(2-O-benzyl-3,4-O-carbonyl-α-l-rhamnopyranosyl)-α-d-manno-pyranoside (12α)

3.2.8. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-(2-O-benzyl-3,4-O-carbonyl-β-l-rhamnopyranosyl)-α-d-manno-pyranoside (12β)

3.2.9. Methyl 6-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-2,3, 4-tri-O-benzyl-α-d-glucopyranoside (13α)

3.2.10. Methyl 6-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-2,3, 4-tri-O-benzyl-α-d-glucopyranoside (13β)

3.2.11. Methyl 4-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-2,3-O-isopropylidiene-α-l-rhamnopyranoside (14α)

3.2.12. Methyl 4-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-2,3-O-isopropylidiene-α-l-rhamnopyranoside (14β)

3.2.13. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-α-d-mannopyranoside (15α)

3.2.14. Methyl 3-O-benzyl-4,6-O-benzylidiene-2-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-trifluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-α-d-mannopyranoside (15β)

3.2.15. Methyl 3-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-α-l-rhamnopyranosyl)]-2,4, 6-tri-O-benzyl-α-d-mannopyranoside (17α)

3.2.16. Methyl 3-O-[(4-O-benzoyl-3-O-benzyl-2-O-(2-tri-fluoromethylbenzenesulfonyl)-β-l-rhamnopyranosyl)]-2,4, 6-tri-O-benzyl-α-d-mannopyranoside (17β)

3.3. Methyl 6-O-acetyl-2,3,4-tri-O-benzyl-α-d-gluco-pyranoside

3.3.1. Methyl 6-O-acetyl-2,3,4-tri-O-benzyl-α-d-gluco-pyranoside (19)

Supplementary Material

Scheme 1.

Acknowledgments

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

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