Abstract
An improved practical synthesis of L-vancosamine-related glycosyl donors is described. The key steps include (1) stereoselective addition of methylcerium reagent to oximino ether and (2) stereoselective hydrogenation of exocyclic unsaturated glycoside in the presence of Wilkinson catalyst with C(5) inversion to give L-vancosamine derivatives. Three glycosyl donors were prepared, and their reactivities in the aryl C-glycoside formation were compared. Conversion of primary amine and azide to the corresponding N,N-dimethyl derivative is also described.
Similar content being viewed by others
Introduction
L-Vancosamine and its N,N-dimethyl derivative are found as the sugar constituents of several antibiotics. For example, L-vancosamine1, 2 is included in vancomycin, a glycopeptide antibiotic that is important for the treatment of methicillin-resistant Staphylococcus aureus.3 The N,N-dimethyl analog occurs as an O-glycoside in the nocardicyclin antibiotics4, 5 and as a C-glycoside in the pluramycin–hedamycin class antibiotics (Figure 1).6, 7, 8
L-Vancosamine in antibiotic structures.
Many methods have been recorded for synthesizing the vancosamine derivatives starting either from carbohydrates9, 10, 11, 12, 13, 14, 15, 16 or non-carbohydrates.17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 However, most of the methods had problems on practicality; for example, use of toxic reagents or expensive starting materials. Herein, we record a viable method for preparing glycosyl donors of L-vancosamine derivatives.
Results and discussion
The route is primarily based on the report by Thang et al.,29 which has been improved30 in terms of the stereoselectivity, and thus overall efficiency. The starting material was a known ketone 1 31 derived from commercially available methyl α-D-mannopyranoside, treatment of which with O-methyl hydroxylamine hydrochloride (NaOAc, MeOH, room temperature, 6 h) gave oximino ether 2 in 86% yield. Treatment of 2 with the methylcerium species,32, 33 generated by mixing MeLi and anhydrous CeCl3 (tetrahydrofuran (THF), –78 °C→0 °C, 4 h), gave amine 3 as a single product. The stereostructure of 3 was assigned by the NOE experiment as shown in Figure 2. After conversion of amine 3 to trifluoroacetamide 4 [(CF3CO)2O, pyridine, 4-(dimethylamino)pyridine (DMAP), CH2Cl2, 30 min], the N–O bond was cleaved with samarium iodide34, 35 (MeOH, THF, 0 °C, 30 min), giving amide 5 in 95% yield. Recrystallization (EtOAc, hexane) gave nice single crystals of 5 suitable for X-ray analysis, confirming the stereochemical identity (Figure 3 and Scheme 1).
NOE study of amine 3.
X-ray structure of trifluoroacetamide 5.
The benzylidene acetal in 5 was cleaved with N-bromosuccinimide36, 37 (pyridine, CCl4, reflux, 4 h) to give bromide 6 in 87% yield. Note that this process should be conducted at low concentration (<30 mM): When performed at higher concentration the yield was not reproducible, and unidentified products were produced presumably by the competing bromination of the trifluoroacetamide in 5.38 Recrystallization (Et2O, hexane) gave nice single crystals of 6 suitable for X-ray analysis (Figure 4), confirming that the benzylidene acetal in 5 was regioselectively cleaved. Dehydrobromination of 6 was effected by using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (N,N-dimethylformamide (DMF), 90 °C, 4 h) to give enol ether 7 in 80% yield,39 which was subjected to catalytic hydrogenation of the exocyclic 5,6-double bond.
X-ray structure of bromide 6.
Our previous protocol30 using 10% Pd/C (MeOH, room temperature, 12 h) suffered from the low stereoselectivety (<7:3). The main product 8 was produced in 67% yield, and the C(5)-epimer, epi-8 in 29% yield (Table 1, run 1). Although these stereoisomers (8 and epi-8) were easily separable by silica-gel chromatography, we sought for a better protocol to improve the stereoselectivity and the yield. In spite of the originally reported protocol,29 use of Raney Ni as the catalyst gave no hydrogenated products in our hands (run 2). Pearlman’s catalyst (Pd(OH)2/C) gave products 8 and epi-8 in a better stereoselectivity (run 3). On the other hand, the combination of triethylsilane with Lewis acids gave no desired compound (run 4). Finally, we found that the hydrogenation of 7 over Wilkinson catalyst40 (5 mol%, toluene, EtOH, room temperature, 10 h) proceeded in an excellent stereoselectively to give the desired stereoisomer 8 in 96% yield (run 5; Scheme 2).
Having the key intermediate 8 in hand, we prepared three vancosaminyl acetate donors 9, 12 and 15, differing in the protection of 3-amino and 4-hydroxy groups (Figure 5). Preparation of 4-O-benzoyl donor 9 was previously described,30 and the routes to amide acetate 12 and azide 15 are outlined in Schemes 3 and 4, respectively.
Glycosyl donors 9, 12 and 15.
Scheme 3 shows preparation of amide acetate 12. The 4-O-benzoyl group in 8 was selectively removed by treatment with Mg(OMe)2 (MeOH, 0 °C, 1.5 h) to give the corresponding alcohol 10,41 which was protected with a benzyl group (BnBr, NaH, DMF, room temperature, 2 h) to give benzyl ether 11 in 80% yield (two steps). Hydrolysis of 11 in 20% aqueous AcOH (100 °C, 3.5 h)42 followed by acetylation (Ac2O, DMAP, pyridine, room temperature, 11 h) gave glycosyl acetate 12 in 92% yield (two steps).
In our synthetic study on the pluramycin-class antibiotics, we needed the glycosyl donors with different protection for the C(3)-amino group. One of the promising donors was azide 15. After hydrolysis of 11 by 5 M aqueous NaOH (MeOH, 40 °C, 9 h), the resulting free amine 13 was subjected to the diazo-transfer reaction by treatment of TfN343, 44, 45 in the presence of CuSO4 (MeOH, H2O, room temperature, 2.5 h), giving the desired azide 14 in 95% yield (two steps). Recently, Kitamura et al.45 have developed diazo-transfer reagent 16, which is stable against heat and impact. Indeed, use of 16 for the same conversion (13→14) proceeded smoothly (DMAP, MeCN, room temperature, 1 h), giving azide 14 in 91% yield. Recrystallization (hexane, EtOAc) gave nice single crystals of 14 amenable for the X-ray analysis (Figure 6). Hydrolysis of 14 (20% aqueous AcOH, 100 °C, 3.5 h) followed by acetylation (Ac2O, DMAP, pyridine, room temperature, 11 h) gave glycosyl actetate 15 in 81% yield (two steps).
X-ray structure of azide 14.
With three glycosyl donors 9, 12 and 15 in hand, their reactivities were assessed by the aryl C-glycosidation with phenol 17 in the presence of 25 mol% of Sc(OTf)3 (Drierite, 1,2-dichloroethane). In the case of C(3)-trifluoroacetamide-substituted acetates 9 and 12, C-glycosides 18 and 19 were obtained in 94% and 88% yield, respectively (runs 1 and 2). However, the azide acetate 15 gave poor result, giving C-glycoside 20 in 48% yield (run 3; Table 2).
Finally described is a reliable protocol for converting these amino and azido compounds into the N,N-dimethyl derivatives. Primary amine 13 was converted to the dimethylamino sugar 21 in excellent yield by treatment with formalin and sodium cyanoborohydride (MeCN, 0 °C, 15 min). Azide 14 could also be converted in one pot to N,N-dimethylamine 21 (74% yield) by a modified protocol of our previous report46, 47 (PMe3, CH2Cl2, room temperature, 4 h; aq HCHO, NaBH3CN, AcOH, MeCN, room temperature, 1 h; Scheme 5).
In conclusion, an improved synthesis of L-vancosamine donors has been described. Conversion of primary amine and azide to the corresponding N,N-dimethyl derivative is also described.
Experimental Procedure
General
All experiments dealing with air- and moisture-sensitive compounds were conducted under an atmosphere of dry argon. Ethereal solvents (anhydrous; Kanto Chemical Co., Inc., Tokyo, Japan) were used as received. Dichloromethane and 1,2-dichloroethane were distilled successively from P2O5 and CaH2, and stored over 4A molecular sieves. For TLC analysis, Merck pre-coated plates (Merck, Darmstadt, Gemany) (silica gel 60 F254, Art 5715, 0.25 mm) were used. For flash column chromatography, silica gel 60N (Spherical, neutral, 23–210 μm) from Kanto Chemical was used. Preparative TLC was performed on Merck silica gel 60 PF254 (Art 7747). Determinations of m.p.were performed by using a Yanako MP-500 (Yanako, Kyoto, Japan) instrument. 1H NMR and 13C NMR spectra were measured on a JEOL JNM ECX-500 (JEOL, Tokyo, Japan) (500 MHz), a JEOL JNM AL-400 (400 MHz), a JEOL JNM Lambda-400 (400 MHz) or a JEOL JNM AL-300 (300 MHz) spectrometer, and are reported in p.p.m. using tetramethysilane as an internal standard (tetramethysilane=0 p.p.m.). 1H NMR spectra data are reported as: (δ shift) ((s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, m=multiplet, br=broad), (integration) and (J=coupling constant in Hz)). IR spectra were recorded on a Jasco IR-Report 100 (Jasco, Tokyo, Japan) or a Perkin Elmer Spectrum 100 FTIR spectrometer (Perkin Elmer, Waltham, MA, USA). Attenuated total reflectance (ATR) FTIR spectra were recorded on a Perkin Elmer 100 spectrometer. Optical rotations ([α]D) were measured on a Jasco DIP-1000 polarimeter. Elemental analyses were recorded on an Elementar vario MICRO cube analyzer (Elementar, Tokyo, Japan).
O-Methyl methyl 4,6-O-benzylidene-2,3-dideoxy-α-D-erythro-hexopyranosid-3-ulose oxime (2)
A solution of ketone 1 (52.0 g, 197 mmol), O-methylhydroxylamine hydrochloride (29 g, 347 mmol) and NaOAc (29.3 g, 358 mmol) in MeOH (1040 ml) was stirred at room temperature for 6 h. After cooling to 0 °C, the mixture was poured into water (2 l). The precipitates were collected by filtration to provide O-methyl oxime 2 (49.5 g, 86%) as white solids, which were used in the next step without further purification. An analytical sample of 2 was obtained by recrystallization from MeOH as colorless needles.
Rf 0.40 (hexane/EtOAc=7/3); m.p. 209–210 °C (MeOH); [α]D30 +173 (c 1.03, CHCl3); 1H NMR (CDCl3, 400 MHz): 2.24 (dd, 1H, J=4.6, 15.4 Hz), 3.37 (s, 3H), 3.52 (dd, 1H, J=1.0, 15.4 Hz), 3.83 (dd, 1H, J=10.0, 10.5 Hz), 3.92 (s, 3H), 4.05 (ddd, 1H, J=4.9, 9.8, 10.0 Hz), 4.24 (d, 1H, J=9.8 Hz), 4.31 (dd, 1H, J=4.9, 10.5 Hz), 4.90 (brd, 1H, J=4.6 Hz), 5.63 (s, 1H), 7.34–7.39 (m, 3H), 7.51–7.55 (m, 2H); 13C NMR (CDCl3, 100 MHz): 30.8, 54.8, 61.9, 64.7, 69.4, 78.1, 98.4, 102.4, 126.5, 128.2, 129.1, 137.0, 148.8; IR (ATR): 3059, 2943, 2866, 1643, 1367, 1124, 1049, 991, 748, 698 cm–1. Anal. calcd for C15H19NO5: C, 61.42; H, 6.53. Found: C, 61.72; H, 6.77.
Methyl 4,6-O-benzylidene-2,3-dideoxy-3-C-methyl-3-(methoxyamino)-α-D-ribo-hexopyranoside (3)
Cerium chloride heptahydrate (36.8 g, 98.8 mmol) was dried under vacuum (0.1 mm Hg) by the Imamoto procedure.33 The resulting powders were cooled under vacuum, and the flask was flushed with argon. Dry THF (400 ml) was added, and the resulting suspension was stirred vigorously at room temperature for 12 h. The mixture was cooled at –78 °C, to which MeLi (1.09 M in Et2O, 90 ml, 98.1 mmol) was added dropwise. The yellow suspension was stirred for 1 h, and a solution of O-methyl oxime 2 (10.1 g, 34.4 mmol) in THF (100 ml) was added dropwise. After 1 h at –78 °C, the reaction mixture was gradually warmed to 0 °C, and the stirring was continued for 3 h. To the resulting brown suspension saturated aqueous NH4Cl was added, and the products were extracted with EtOAc (3 × ). The combined organic extracts were successively washed with brine, saturated aqueous NaHCO3 and brine, and then dried (Na2SO4). Filtration and concentration in vacuo gave amine 3 (11.4 g) as light brown oil, which was used in the next step without further purification. An analytical sample of 3 was obtained by column chromatography (hexane/EtOAc=7/3) and recrystallization from Et2O/hexane.
Rf 0.53 (hexane/EtOAc=7/3); m.p. 87–88 °C (Et2O/hexane); [α]D30 +105 (c 1.02, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.29 (s, 3H), 1.57 (dd, 1H, J=4.6, 14.9 Hz), 2.36 (dd, 1H, J=0.6, 14.9 Hz), 3.38 (s, 3H), 3.49 (d, 1H, J=9.8 Hz), 3.59 (s, 3H), 3.65 (dd, 1H, J=10.2, 10.2 Hz), 4.16 (ddd, 1H, J=5.1, 9.8, 10.2 Hz), 4.27 (dd, 1H, J=5.1, 10.2 Hz), 4.69 (brd, 1H, J=4.6 Hz), 5.49 (s, 1H), 6.05 (brs, 1H, NH), 7.33–7.39 (m, 3H), 7.46–7.49 (m, 2H); 13C NMR (CDCl3, 100 MHz): 23.1, 36.9, 55.3, 56.2, 58.8, 62.5, 69.6, 84.1, 98.5, 102.1, 126.2, 128.1, 128.9, 137.6; IR (ATR): 2968, 2933, 2860, 1456, 1375, 1132, 1082, 1043, 760, 698 cm–1. Anal. calcd for C16H23NO5: C, 62.12; H, 7.49; N, 4.53. Found: C, 62.31; H, 7.69; N, 4.48.
Methyl 4,6-O-benzylidene-2,3-dideoxy-3-(N-methoxytrifluoroacetamido)-3-C-methyl-α-D-ribo-hexo-pyranoside (4)
To a solution of the crude amine 3 (11.4 g), pyridine (5.9 ml, 73 mmol) and DMAP (0.20 g, 1.6 mmol) in CH2Cl2 (100 ml), trifluoroacetic anhydride (10.2 ml, 73.4 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and quenched with water and then 1 M HCl. The products were extracted with CH2Cl2 (3 × ). The combined organic extracts were successively washed with brine, saturated aqueous NaHCO3 and brine, and then dried (Na2SO4), filtered and concentrated. The residue was triturated with (hexane/EtOAc=9/1) to give trifluoroacetamide 4 (10.9 g) as white solids. The mother liquer was concentrated, and the residue was purified by column chromatography (hexane/EtOAc=9/1) to give 2.34 g of 4. The combined yield of these materials was 95% in two steps. An analytical sample of 4 was obtained by recrystallization from Et2O/hexane as colorless prisms.
Rf 0.52 (hexane/EtOAc=7/3); m.p. 119–120 °C (Et2O/hexane); [α]D28 +138 (c 1.06, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.53 (s, 3H), 1.65 (dd, 1H, J=3.7, 15.4 Hz), 3.27 (s, 3H), 3.48 (dd, 1H, J=1.0, 15.4 Hz), 3.61–3.69 (m, 2H), 3.81 (s, 3H), 4.36 (dd, 1H, J=5.6, 10.7 Hz), 4.54 (ddd, 1H, J=5.6, 10.0, 10.0 Hz), 4.63 (brd, 1H, J=3.7 Hz), 5.53 (s, 1H), 7.37–7.41 (m, 3H), 7.49–7.52 (m, 2H); 13C NMR (CDCl3, 100 MHz): 24.1, 35.4, 54.7, 59.9, 63.4, 68.5, 69.8, 85.7, 97.8, 102.8, 116.2 (q, JCF=289 Hz), 126.1, 128.2, 129.1, 137.3, 157.5 (q, JCF=37 Hz); IR (ATR): 2950, 2837, 1701, 1379, 1203, 1153, 1115, 1066, 903, 746, 700 cm–1. Anal. calcd for C18H22F3NO6: C, 53.33; H, 5.47; N, 3.46. Found: C, 53.11; H, 5.77; N, 3.45.
Methyl 4,6-O-benzylidene-2,3-dideoxy-3-C-methyl-3-trifluoroacetamido-α-D-ribo-hexopyranoside (5)
To a solution of trifluoroacetamide 4 (6.99 g, 17.3 mmol) in MeOH (30 ml), SmI2 (prepared from Sm (10.2 g, 68.1 mmol) and 1,2-diiodoethane (17 g, 60.5 mmol) in THF (600 ml))35 was added at 0 °C. After stirring for 0.5 h, the reaction was quenched by the addition of 2 M HCl, and the products extracted with EtOAc (3 × ). The combined extracts were successively washed with saturated aqueous NaHCO3, 10% aqueous Na2S2O3 and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, the crude residue was purified by column chromatography (hexane/EtOAc=75/25) to give amide 5 (6.13 g, 95%) as white solids. An analytical sample of 5 was obtained by crystallization from EtOAc/hexane as colorless prisms.
Rf 0.43 (hexane/EtOAc=7/3); m.p. 120–121 °C (EtOAc/hexane); [α]D25 +73 (c 1.01, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.58 (s, 3H), 1.70 (dd, 1H, J=3.9, 15.1 Hz), 2.99 (dd, 1H, J=0.5, 15.1 Hz), 3.33 (s, 3H), 3.51 (d, 1H, J=9.8 Hz), 3.76 (dd, 1H, J=10.0, 10.4 Hz), 3.95 (ddd, 1H, J=4.9, 9.8, 10.0 Hz), 4.30 (dd, 1H, J=4.9, 10.4 Hz), 4.71 (brd, 1H, J=3.9 Hz), 5.61 (s, 1H), 7.14 (brs, 1H, NH), 7.34–7.41 (m, 3H), 7.45–7.48 (m, 2H); 13C NMR (CDCl3, 100 MHz): 22.9, 37.2, 53.5, 55.1, 59.6, 69.0, 82.9, 98.1, 101.9, 115.6 (q, JCF=291 Hz), 125.9, 128.3, 129.1, 136.8, 156.4 (q, JCF=36 Hz); IR (ATR): 3346, 3066, 2939, 2841, 1736, 1545, 1379, 1213, 1159, 1047, 903, 752, 698 cm–1. Anal. calcd for C17H20F3NO5: C, 54.40; H, 5.37; N, 3.73. Found: C, 54.16; H, 5.66; N, 3.77. Crystallographic data: C17H20F3NO5, MW=375.34 Da, 0.30 × 0.30 × 0.10 mm, orthorhombic, space group P=212 121, Z=4, T=173(2) K, a=9.6053(5), b=12.3369(6), c=15.1350(7) Å, V=1793.49(14) Å3, λ(Mo Kα)=0.71075 Å, μ=0.121 mm–1. Intensity data were collected on Rigaku R-AXIS Rapid IP area detector system (Rigaku, Tokyo, Japan). The structure was solved by direct methods and refined by the full-matrix least-squares on F2 (SHELXL-97 (Sheldrick, 1997)). A total of 17 480 reflections were measured and 4058 were found to be independent. Final R1=0.0386, wR2=0.0967 (3356 references; I>2σ(I)), and goodness of fit (GOF)=1.098 (for all data, R1=0.0474, wR2=0.1021).
Methyl 4-O-benzoyl-6-bromo-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-α-D-ribo-hexopyranoside (6)
To a mixture of trifluoroacetamide 5 (10.0 g, 26.7 mmol) in dry carbon tetrachloride (900 ml), N-bromosuccinimide (5.72 g, 32.1 mmol) and pyridine (5 ml, 61.8 mmol) were added. The mixture was heated under reflux for 4 h under normal room light illumination. Solvents were removed in vacuo to some extent, and the residue was dissolved in CH2Cl2 and washed successively with 5% aqueous NaHSO3, saturated aqueous NaHCO3 and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, the residue was purified by column chromatography (hexane/EtOAc=9/1) to give bromide 6 (10.5 g, 87%) as white solids. Recrystallization from Et2O/hexane gave 6 as colorless prisms.
Rf 0.65 (hexane/EtOAc=7/3); m.p. 118–119 °C (Et2O/hexane); [α]D29 −14 (c 1.02, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.68 (s, 3H), 1.94 (dd, 1H, J=3.8, 15.1 Hz), 2.29 (d, 1H, J=15.1 Hz), 3.41–3.51 (m, 2H), 3.52 (s, 3H), 4.10 (ddd, 1H, J=2.7, 7.7, 10.2 Hz), 4.94 (d, 1H, J=3.8 Hz), 5.12 (d, 1H, J=10.2 Hz), 7.45–7.49 (m, 2H), 7.58–7.62 (m, 1H), 8.00–8.02 (m, 2H), 8.24 (brs, 1H, NH); 13C NMR (CDCl3, 100 MHz): 23.3, 32.1, 40.8, 55.5, 56.4, 67.1, 74.8, 97.7, 115.8 (q, JCF=291 Hz), 128.5, 130.1, 133.6, 156.1 (q, JCF=36 Hz), 165.7; IR (ATR): 3334, 3072, 2943, 2841, 1739, 1558, 1450, 1263, 1217, 1178, 1045, 960, 877, 710 cm–1. Anal. calcd for C17H19BrF3NO5: C, 44.95; H, 4.22; N, 3.08. Found: C, 44.73; H, 4.51; N, 3.01. Crystallographic data: C17H19BrF3NO5, MW=454.24 Da, 0.60 × 0.30 × 0.20 mm, monoclinic, space group P=21, Z=2, T=168(2) K, a=10.2351(6), b=7.6213(5), c=13.1952(7) Å, V=967.64(10) Å3, λ(Mo Kα)=0.71075 Å, μ=2.179 mm–1. Intensity data were collected on Rigaku R-AXIS Rapid IP area detector system. The structure was solved by direct methods and refined by the full-matrix least-squares on F2 (SHELXL-97). A total of 9422 reflections were measured and 4368 were independent. Final R1=0.0340, wR2=0.0774 (3810 references; I>2σ(I)), and GOF=1.069 (for all data, R1=0.0432, wR2=0.0850).
Methyl 4-O-benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-α-D-erythro-hex-5-enopyranoside (7)
To a solution of bromide 6 (19.7 g, 43.3 mmol) in DMF (220 ml), DBU (12.2 ml, 86.5 mmol) was added. The mixture was heated to 90 °C for 4 h. After cooling to room temperature, the mixture was quenched with 10% aqueous KHSO4. The products were extracted with EtOAc (3 × ), and the combined extracts were washed with saturated aqueous NaHCO3 and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, the residue was purified by column chromatography (hexane/EtOAc=9/1) to give enol ether 7 (13 g, 80%) as white solids. Recrystallization from Et2O/hexane gave 7 as colorless prisms.
Rf 0.61 (hexane/EtOAc=7/3); m.p. 117–118 °C (Et2O/hexane); [α]D28 +29 (c 0.92, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.69 (s, 3H), 2.07 (dd, 1H, J=4.0, 14.9 Hz), 2.53 (dd, 1H, J=1.0, 14.9 Hz), 3.48 (s, 3H), 4.69 (dd, 1H, J=1.7, 1.7 Hz), 4.85 (dd, 1H, J=1.7, 1.7 Hz), 4.96 (brd, 1H, J=4.0 Hz), 5.55 (dd, 1H, J=1.7, 1.7 Hz), 7.48–7.52 (m, 2H), 7.60–7.64 (m, 1H), 7.77 (brs, 1H, NH), 8.09–8.11 (m, 2H); 13C NMR (CDCl3, 100 MHz): 22.7, 39.3, 55.5, 56.7, 74.2, 98.0, 99.4, 115.8 (q, JCF=291 Hz), 128.6, 128.7, 130.0, 133.6, 150.0, 156.5 (q, JCF=36 Hz), 165.3; IR (ATR): 3332, 3072, 2941, 2843, 1736, 1662, 1560, 1452, 1267, 1215, 1161, 1113, 1045, 987, 870, 712, 677 cm–1. Anal. calcd for C17H18F3NO5: C, 54.69; H, 4.86; N, 3.75. Found: C, 54.93; H, 5.12; N, 3.90.
Methyl 4-O-benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-β-L-lyxo-hexopyranoside (8)
A mixture of enol ether 7 (10.3 g, 27.6 mmol) and RhCl(PPh3)3 (1.20 g, 1.30 mmol) in toluene (250 ml) and EtOH (25 ml) was stirred under a hydrogen atmosphere (balloon) at room temperature for 10 h. After filtration through a Cerite pad followed by concentration in vacuo, purification by column chromatography (hexane/EtOAc=9/1→7/3) gave benzoate 8 (9.94 g, 96%) as a colorless syrup and the stereoisomer epi-8 (0.31 g, 3%) as white solids.
Rf 0.37 (hexane/EtOAc=7/3); [α]D29 +15 (c 1.05, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.29 (d, 3H, J=6.3 Hz), 1.74 (s, 3H), 1.93 (dd, 1H, J=9.5, 15.1 Hz), 2.45 (dd, 1H, J=2.2, 15.1 Hz), 3.56 (s, 3H), 4.03 (dq, 1H, J=1.0, 6.3 Hz), 4.63 (dd, 1H, J=2.2, 9.5 Hz), 5.14 (brs, 1H), 6.79 (brs, 1H, NH), 7.45–7.49 (m, 2H), 7.59–7.64 (m, 1H), 8.11–8.13 (m, 2H); 13C NMR (CDCl3, 100 MHz): 17.3, 21.4, 37.1, 56.7, 57.1, 68.2, 73.4, 99.4, 115.2 (q, JCF=291 Hz), 128.5, 128.6, 130.0, 133.8, 156.1 (q, JCF=37 Hz), 167.3; IR (neat): 3336, 3074, 2989, 2846, 1728, 1556, 1452, 1271, 1203, 1070, 739, 714 cm–1. Anal. calcd for C17H20F3NO5: C, 54.40; H, 5.37; N, 3.73. Found: C, 54.34; H, 5.58; N, 3.57.
Methyl 4-O-benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-α-D-ribo-hexopyranoside (epi-8)
Rf 0.60 (hexane/EtOAc=7/3); m.p. 104–105 °C (colorless plates from MeOH); [α]D20 –6.4 (c 0.89, CHCl3);1H NMR (CDCl3, 400 MHz): 1.22 (d, 3H, J=6.0 Hz), 1.65 (s, 3H), 1.89 (dd, 1H, J=4.1, 15.1 Hz), 2.28 (brd, 1H, J=15.1 Hz), 3.44 (s, 3H), 4.03 (dq, 1H, J=10.1, 6.0 Hz), 4.83 (brd, 1H, J=4.1 Hz), 4.98 (d, 1H, J=10.1 Hz), 7.26–7.47 (m, 2H), 7.56–7.59 (m, 1H), 8.00–8.02 (m, 2H), 8.26 (brs, 1H, NH); 13C NMR (CDCl3, 100 MHz): 17.5, 23.3, 40.9, 55.2, 56.3, 63.1, 77.5, 97.7, 116.0 (q, JCF=295 Hz), 128.4, 129.1, 130.0, 130.1, 156.1 (q, JCF=36 Hz), 166.1; IR (ATR): 3348, 2937, 1737, 1715, 1583, 1556, 1450, 1323, 1266, 1216, 1181, 1128, 1027, 993, 963, 879, 708 cm–1. Anal. calcd for C17H20F3NO5: C, 54.40; H, 5.37; N, 3.73. Found: C, 54.18; H, 5.13; N, 3.44.
4-O-Benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-α,β-L-lyxo-hexopyranosyl acetate (9)
Benzoate 8 (756 mg, 2 mmol) was dissolved in 20% aqueous AcOH (40 ml), and the mixture was heated under reflux for 3.5 h. After cooling to 0 °C, the mixture was basified by saturated aqueous NaHCO3. After extraction (EtOAc, 3 × ), the combined organic extracts were washed with brine and then dried (Na2SO4). After filtration and evaporation in vacuo, the residue was dissolved in pyridine (8 ml), to which was added Ac2O (2 ml), and DMAP (6 mg) at 0 °C. After 11 h at room temperature, the reaction was quenched by 1 M HCl. After extraction (EtOAc, 3 × ), the combined organic extracts were sequentially washed with brine, saturated aqueous NaHCO3 and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, purification with column chromatography (hexane/EtOAc=6/4) gave acetate 9 (715 mg, 88%, α/β=1/5) as white solids. Recrystallization from CH2Cl2/hexane gave 9 as white powders.
Rf 0.45 (hexane/EtOAc=6/4); m.p. 168–169 °C (CH2Cl2/hexane); 1H NMR (CDCl3, 400 MHz) for the β-anomer: 1.29 (d, 3H, J=6.3 Hz), 1.77 (s, 3H), 2.10 (dd, 1H, J=10.3, 12.6 Hz), 2.15 (s, 3H), 2.61 (dd, 1H, J=2.7, 12.6 Hz), 4.17 (dq, 1H, J=1.0, 6.3 Hz), 5.03 (brs, 1H), 5.96 (dd, 1H, J=2.7, 10.3 Hz), 6.99 (brs, 1H, NH), 7.48–7.67 (m, 3H), 8.13–8.16 (m, 2H); for the selected α-anomer: 1.25 (d, 3H, J=6.9 Hz), 4.38 (q, 1H, J=6.9 Hz), 5.07 (brs, 1H), 6.34 (brd, 1H, J=4.0 Hz), 7.10 (brs, 1H, NH); 13C NMR (CDCl3, 100 MHz): 17.2, 21.0, 21.2, 35.3, 57.2, 69.1, 73.4, 90.6, 115.2 (q, JCF=290 Hz), 128.3, 128.7, 130.0, 134.1, 156.3 (q, JCF=37 Hz), 167.7, 169.1; IR (ATR): 3334, 3076, 2989, 1728, 1556, 1452, 1273, 1161, 1049, 908, 758, 715 cm–1. Anal. calcd for C18H20F3NO6: C, 53.60; H, 5.00; N, 3.47. Found: C, 53.39; H, 5.25; N, 3.37.
Methyl 2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-β-L-lyxo-hexopyranoside (10)
To a solution of Mg(OMe)2 in MeOH (prepared from magnesium (1.12 g, 46 mmol) and MeOH (230 ml)), a solution of benzoate 8 (6.24 g, 16.6 mmol) in MeOH (100 ml) was added at 0 °C. After stirring for 1.5 h, the mixture was acidified by carefully adding aqueous 2 M HCl, and MeOH was removed under reduced pressure. The products were extracted with EtOAc (5 × ), and the combined organic extracts were washed with brine and then dried (Na2SO4). After filtration, solvents were evaporated in vacuo, and purification by column chromatography (hexane/EtOAc=8/2) gave alcohol 10 (3.75 g, 83%) as white solids. Recrystallization from Et2O gave 10 as colorless plates.
Rf 0.35 (hexane/EtOAc=7/3); m.p. 104–106 °C (Et2O); [α]D24 +56 (c 1.1, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.33 (d, 3H, J=6.4 Hz), 1.61 (s, 3H), 1.62 (dd, 1H, J=9.2, 14.0 Hz), 2.30 (d, 1H, J=10.4 Hz), 2.46 (dd, 1H, J=2.0, 14.0 Hz), 3.24 (d, 1H, J=10.4 Hz), 3.49 (s, 3H), 3.88 (q, 1H, J=6.4 Hz), 4.43 (dd, 1H, J=2.0, 9.2 Hz), 7.06 (s, 1H, NH); 13C NMR (CDCl3, 100 MHz): 17.0, 20.3, 36.4, 56.6, 56.7, 68.5, 72.3, 100.0, 115.5 (q, JCF=287 Hz), 156.2 (q, JCF=35 Hz); IR (ATR): 3380, 2986, 2950, 1719, 1549, 1463, 1448, 1394, 1332, 1259, 1187, 1164, 1145, 1122, 1104, 1070, 1006 cm–1. Anal. calcd for C10H16 F3NO4: C, 44.28; H, 5.95; N, 5.16. Found: C, 44.50; H, 6.02; N, 4.86.
Methyl 4-O-benzyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-β-L-lyxo-hexopyranoside (11)
To a mixture of NaH (63% dispersion in oil, 1.8 g, 48 mmol) in DMF (50 ml), a solution of alcohol 10 (3.75 g, 13.8 mmol) in DMF (20 ml) was added. After stirring for 2 h, benzyl bromide (5.66 g, 33.1 mmol) was added, and the mixture was allowed to warm to room temperature. After stirring for 2 h, water and Et2NH were successively added at 0 °C. After 0.5 h, aqueous 2 M HCl was added, and the products were extracted with Et2O (3 × ). Combined organic extracts were washed successively with brine, saturated aqueous NaHCO3 and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, the residue was purified by column chromatography (hexane/EtOAc=8/2) to give benzyl ether 11 (4.52 g, 91%) as a colorless oil.
Rf 0.45 (hexane/EtOAc=7/3); [α]D29 –30 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.40 (d, 3H, J=6.4 Hz), 1.64 (s, 3H), 1.80 (dd, 1H, J=9.2, 12.4 Hz), 2.05 (dd, 1H, J=2.4, 12.4 Hz), 3.44 (s, 1H), 3.49 (s, 3H), 3.86 (q, 1H, J=6.4 Hz), 4.48 (dd, 1H, J=2.4, 9.2 Hz), 4.50 (d, 1H, J=11.2 Hz), 4.81 (d, 1H, J=11.2 Hz), 6.42 (brs, 1H, NH), 7.29–7.38 (m, 5H); 13C NMR (CDCl3, 100 MHz): 17.6, 21.3, 37.5, 56.2, 56.8, 69.2, 75.9, 79.2, 99.0, 115.2 (q, JCF=287 Hz), 127.7, 127.9, 128.4, 137.0, 156.1 (q, JCF=36 Hz) cm–1; IR (ATR): 3326, 3091, 3068, 2989, 2938, 2877, 1723, 1553, 1520, 1498, 1454, 1397, 1371, 1355, 1278, 1258, 1171, 1128, 1111, 1071, 1028, 1016 cm–1. Anal. calcd for C17H22 F3NO4: C, 57.55; H, 5.27; N, 2.82. Found: C, 57.71; H, 5.31; N, 2.58.
4-O-Benzyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-α,β-L-lyxo-hexopyranosyl acetate (12)
Benzyl ether 11 (1.50 g, 4.15 mmol) was dissolved in 20% aqueous AcOH (200 ml, 0.68 mol), and the mixture was heated under reflux for 3.5 h. After cooling to 0 °C, the mixture was basified by adding KOH (3 M, 220 ml, 0.66 mol) and saturated aqueous NaHCO3. After extraction with EtOAc (3 × ), the combined organic extracts were washed with brine and then dried (Na2SO4). After filtration, solvents were removed in vacuo. The residue was dissolved in pyridine (5 ml), to which was added Ac2O (1 ml) and DMAP (10 mg) at 0 °C. After 1.5 h, the reaction was quenched by adding 1 M HCl. The products were extracted with EtOAc (3 × ), the combined organic extracts were washed successively with brine, saturated aqueous NaHCO3 and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, purification with column chromatography (hexane/EtOAc=8/2) gave acetate 12 (1.48 g, 92%; α/β=45/55) as a colorless gummy syrup.
Rf 0.32 (hexane/EtOAc=7/3); 1H NMR (CDCl3, 400 MHz) for the β-anomer: 1.41 (d, 3H, J=6.6 Hz), 1.66 (s, 3H), 2.04 (dd, 1H, J=9.0, 12.4 Hz), 2.08 (s, 3H), 2.11 (dd, 1H, J=2.9, 12.4 Hz), 3.45 (s, 1H), 4.02 (q, 1H, J=6.6 Hz), 4.51 (d, 1H J=11.7 Hz), 4.83 (d, 1H, J=11.7 Hz), 5.84 (dd, 1H J=2.9, 9.0 Hz), 6.51 (s, 1H, NH), 7.33–7.39 (m, 5H); for the selected α-anomer: 1.39 (d, 3H, J=6.6 Hz), 6.17 (dd, 1H, J=1.6, 3.6 Hz); 13C NMR (CDCl3, 100 MHz) for the α- and β-mixture: 17.6 (2 × ), 21.0, 21.2, 21.4, 22.8, 34.1, 35.9, 54.9, 56.4, 66.5, 70.2, 76.0, 76.1, 79.0, 79.8, 90.5, 90.9, 115.3 (q, JCF=291Hz), 128.0, 128.1, 128.4 (2 × ), 128.7, 128.8, 136.8, 156.4 (q, JCF=37 Hz), 169.2 (2 × ); IR (neat): 3338, 3092, 3068, 3033, 2988, 2939, 2920, 2883, 1754, 1723, 1556, 1521, 1498, 1455, 1386, 1370, 1355, 1312, 1232, 1201, 1187, 1162, 1130, 1107, 1085, 1049, 1007 cm–1. Anal. calcd for C18H22F3NO5: C, 55.53; H, 5.70; N, 3.60. Found: C, 55.83; H, 5.47; N, 3.42.
Methyl 4-O-benzyl-2,3,6-trideoxy-3-C-methyl-3-amino-β-L-lyxo-hexopyranoside (13)
To a solution of amide 11 (4.69 g, 13 mmol) in MeOH (55 ml), 5 M NaOH (14 ml, 60 mmol) was added and the reaction mixture was stirred at room temperature for 9 h. The reaction mixture was concentrated in vacuo to some extent, was diluted with H2O and EtOAc, and the was extracted with EtOAc (5 × ). The combined organic extracts were washed with brine and then dried (Na2SO4), and concentration in vacuo gave amine 13 (3.22 g, 93%) as a colorless oil.
Rf 0.24 (CHCl3/MeOH=9/1); [α]D20 +2.5 (c 1.66, CHCl3); 1H NMR (CDCl3, 500 MHz): 1.17 (s, 3H), 1.32 (d, 3H, J=6.6 Hz), 1.55 (dd, 1H, J=2.5, 12.8 Hz), 1.68 (dd, 1H, J=9.7, 12.8 Hz), 2.08–2.25 (brs, 2H, NH), 2.89 (s, 1H), 3.47 (s, 3H), 3.76 (q, 1H, J=6.6 Hz), 4.39 (dd, 1H, J=2.5, 9.7 Hz), 4.68 (d, 1H, J=15.2 Hz), 4.77 (d, 1H, J=15.2 Hz), 7.25–7.40 (m, 5H); 13C NMR (CDCl3, 125 MHz): 17.5, 24.9, 42.2, 52.4, 56.3, 69.8, 83.9, 100.5, 127.6, 127.8, 128.2, 128.3, 138.2 cm–1; IR (neat): 3361, 2929, 1722, 1586, 1497, 1455, 1392, 1224, 1164, 1070, 1011, 965, 876, 755, 704 cm–1. Anal. calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C, 67.83; H, 9.03; N, 5.01.
Preparation of TfN3 in toluene44
To a mixture of NaN3 (5.92 g, 91.1 mmol) in toluene (15 ml) and H2O (15 ml), Tf2O (7.76 ml, 45.5 mmol) was added at 0 °C; the mixture was stirred at 10 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3, and the mixture was extracted by toluene (10 ml 2 × ) to give a toluene solution of TfN3, which was used in the subsequent diazo-transfer reaction. (warning: TfN3 has an explosive nature and requires very careful treatment.)
Methyl 4-O-benzyl-2,3,6-trideoxy-3-C-methyl-3-azido-β-L-lyxo-hexopyranoside (14)
To a suspension of a mixture of amine 13 (3.22 g, 12.2 mmol), CuSO4 (208 mg, 1.30 mmol), NaHCO3 (5.44 g, 64.8 mmol) in MeOH (28 ml) and H2O (7 ml), a freshly prepared TfN3 solution (28 ml) was added at 0 °C. After stirring for 2.5 h at room temperature, the mixture was diluted with H2O and EtOAc, and the products extracted with EtOAc (3 × ). The combined organic extracts were washed with brine, and it was then dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc=85/15) to give azide 14 (3.51 g, 99%) as white solids. Recrystallization from MeOH gave 14 as colorless needles.
Rf 0.45 (hexane/EtOAc=4/1); m.p. 108–110 °C (MeOH); [α]D28 +54.9 (c 1.07, CHCl3); 1H NMR (CDCl3, 500 MHz): 1.19 (d, 3H, J=6.3 Hz), 1.30 (s, 3H), 1.77 (dd, 1H, J=2.3, 12.6 Hz), 2.11 (dd, 1H, J=9.2, 12.6 Hz), 3.01 (s, 1H), 3.48 (s, 3H), 3.67 (q, 1H, J=6.3 Hz), 4.45 (dd, 1H, J=2.3, 9.2 Hz), 4.57 (d, 1H, J=11.5 Hz), 4.92 (d, 1H, J=11.5 Hz), 7.28–7.37 (m, 3H), 7.39–7.43 (m, 2H); 13C NMR (CDCl3, 125 MHz): 17.1, 23.3, 36.1, 56.4, 62.8, 69.8, 75.8, 81.1, 99.8, 128.0, 128.3, 128.7, 137.5; IR (ATR): 2866, 2097, 1458, 1390, 1352, 1252, 1156, 1116, 1062, 1010, 977, 876, 813, 764, 697 cm–1. Anal. calcd for C15H21 N3O3: C, 61.84; H, 7.27; N, 14.42. Found: C, 61.98; H, 7.11; N, 14.31. Crystallographic data: C15H21N3O3, MW=291.35 Da, 0.20 × 0.15 × 0.15 mm, orthorhombic, space group P=212 121, Z=4, T=173(2) K, a=10.5718(13), b=11.5146(11), c=12.8642(14) Å, V=1566(3) Å3, λ(Cu Kα)=1.54187 Å, μ=0.713 mm–1. Intensity data were collected on Rigaku VariMax Rapid-II IP area detector system. The structure was solved by direct methods and refined by the full-matrix least-squares on F2 (SHELXL-97). A total of 17 995 reflections were measured, and 2852 were found to be independent. Final R1=0.0452, wR2=0.1124 (2399 references; I>2σ(I)), and GOF=1.018 (for all data, R1=0.0513, wR2=0.1168).
Alternative synthesis of 14 by using reagent 16
To a solution of amine 13 (34.3 mg, 0.13 mmol) and DMAP (47.1 mg, 0.39 mmol) in MeCN (1.3 ml), 16 (45.2 mg, 0.16 mmol) was added at 0 °C. After stirring for 1 h at room temperature, the reaction was quenched with saturated aqueous NaHCO3 at 0 °C, and the products were extracted with EtOAc (3 × ). The combined organic extracts were successively washed with H2O and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, the crude residue was purified by preparative TLC (hexane/EtOAc=8/2) to give azide 14 (34.3 mg, 91%) as white solids.
4-O-Benzyl-2,3,6-trideoxy-3-C-methyl-3-azido-α,β-L-lyxo-hexopyranosyl acetate (15)
Azide 14 (4.06 g, 13.9 mmol) was dissolved in 20% aqueous AcOH (250 ml), and the mixture was heated under reflux for 3.5 h. After cooling to 0 °C, the mixture was basified by adding KOH (46 g) and saturated aqueous NaHCO3. After extraction (AcOEt, 3 × ), the combined organic extracts were washed with brine and then dried (Na2SO4). After filtration and evaporation in vacuo, the residue was dissolved in pyridine (65 ml), to which was added Ac2O (17 ml), and 4-DMAP (18 mg) at 0 °C. After 11 h at room temperature, the reaction was quenched by 1 M HCl. After extraction (EtOAc, 3 × ), the combined organic extracts were sequentially washed with brine, saturated aqueous NaHCO3 and brine, and then dried (Na2SO4). After filtration and concentration in vacuo, purification with column chromatography (hexane/EtOAc=8/2) gave azide acetate 15 (3.63 g, 81%; α/β=1/2.5) as a colorless gummy syrup.
Rf 0.39 (hexane/EtOAc=4/1) for the β-anomer, Rf 0.44 (hexane/EtOAc=4/1) for the α-anomer; 1H NMR (CDCl3, 500 MHz) for the β-anomer: 1.19 (d, 3H, J=6.4 Hz), 1.35 (s, 3H), 1.79 (dd, 1H, J=2.3, 12.4 Hz), 2.10 (s, 3H), 2.29 (dd, 1H, J=9.6, 12.4 Hz), 3.04 (s, 1H), 3.82 (dq, 1H, J=1.4, 6.4 Hz), 4.59 (d, 1H J=11.0 Hz), 4.92 (d, 1H, J=11.0 Hz), 5.80 (dd, 1H J=2.3, 9.6 Hz), 7.28–7.43 (m, 5H); for the selected α-anomer: 1.79 (dd, 1H, J=1.4, 13.7 Hz), 2.42 (dd, 1H, J=4,2, 13.7 Hz), 3.17 (s, 1H), 4.10 (dq, 1H, J=1.4, 6.4 Hz), 6.24 (dd, 1H, J=1.4, 4.2 Hz); 13C NMR (CDCl3, 125 MHz) for the α- and β-mixture: 17.1 (2 × ), 21.1, 21.2, 23.0, 24.2, 33.4, 34.8, 61.0, 62.4, 67.5, 70.8, 75.6, 75.7, 80.6, 81.0, 91.2, 91.5, 127.9, 128.3 (2 × ), 128.4, 128.6, 137.5, 137.6, 169.1, 169.3; IR (neat): 2982, 2938, 2099, 1750, 1455, 1368, 1235, 1208, 1168, 1143, 1103, 1048, 1003, 917, 756, 700, 598, 531 cm–1. Anal. calcd for C16H21N3O4: C, 60.17; H, 6.63; N, 13.16. Found: C, 60.20; H, 6.36; N, 12.96.
Typical procedure for C-glycosylation reaction
To a mixture of Sc(OTf)3 (612 mg, 1.24 mmol), phenol 17 (2.02 g, 9.70 mmol) and powdered Drierite (8.16 g) in 1,2-dichloroethane (40 ml), acetate 12 (2.23 g, 5.73 mol) in 1,2-dichloroethane (10 ml) was added at –30 °C. After gradual warming to 0 °C, the mixture was quenched with saturated aqueous NaHCO3 at 0 °C. After filtration through a Celite pad, the products were extracted with CH2Cl2 (3 × ). The combined organic extracts were washed with brine and then dried (Na2SO4). After filtration, solvents were removed in vacuo, and the residue was purified by column chromatography (hexane/EtOAc=95/5→8/2) to give C-glycoside 19 (2.72 g, 88%) as a colorless oil.
Methyl 2-hydroxy-3-(4-O-benzoyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-β-L-lyxo-hexopyranosyl)-6-(prop-2-ene-1-yloxy)benzoate (18)
Colorless plates, 94%; Rf 0.40 (hexane/EtOAc=3/1); m.p. 71–73 °C (EtOH/hexane); [α]D22 –65 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.29 (d, 3H, J=6.0 Hz), 1.88 (s, 3H), 1.95 (dd, 1H, J=11.6, 12.4 Hz), 2.58 (dd, 1H, J=2.0, 12.4 Hz), 3.97 (s, 3H), 4.17 (q, 1H, J=6.0 Hz), 4.58–4.59 (m, 2H), 5.10 (dd, 1H, J=2.0, 11.6 Hz), 5.21 (s, 1H), 5.31 (dd, 1H, J=0.8, 10.8 Hz), 5.51 (dd, 1H, J=0.8, 17.2 Hz), 6.06 (ddt, 1H, J=10.8, 17.2, 4.8 Hz), 6.49 (d, 1H, J=8.8 Hz), 6.74 (s, 1H, NH), 7.48–7.52 (m, 2H), 7.61–7.65 (m, 1H), 7.62 (d, 1H, J=8.8 Hz), 8.13–8.15 (m, 2H), 11.8 (s, 1H, OH); 13C NMR (CDCl3, 125 MHz): 18.1, 20.6, 37.7, 52.5, 57.1, 69.5, 69.6, 70.8, 103.2, 103.7 (q, JCF=271 Hz), 113.8, 116.9, 121.9, 128.6, 128.9, 129.8, 132.1, 132.5, 133.7, 156.0 (q, JCF=36 Hz), 159.0, 159.3, 167.3, 171.5; IR (neat): 3340, 2980, 2950, 1720, 1650, 1615, 1550 cm–1. Anal. calcd for C27H28F3NO8: C, 58.80; H, 5.12; N, 2.54. Found: C, 58.59; H, 4.89; N, 2.24.
Methyl 2-hydroxy-3-(4-O-benzyl-2,3,6-trideoxy-3-C-methyl-3-trifluoroacetamido-β-L-lyxo-hexopyranosyl)-6-(prop-2-ene-1-yloxy)benzoate (19)
Colorless oil, 88%; Rf 0.60 (hexane/EtOAc=7/3); [α]D25 –72 (c 1.3, CHCl3); 1H NMR (CDCl3, 400 MHz): 1.40 (d, 3H, J=6.4 Hz), 1.77 (dd, 1H, J=11.6, 12.4 Hz), 1.79 (s, 3H), 2.13 (dd, 1H, J=2.0, 12.4 Hz), 3.58 (s, 1H), 3.95 (s, 3H), 4.00 (q, 1H, J=6.4 Hz), 4.53–4.55 (m, 2H), 4.56 (d, 1H, J=11.6 Hz), 4.82 (d, 1H, J=11.6 Hz), 4.94 (dd, 1H, J=2.0, 11.6 Hz), 5.29 (dd, 1H, J=1.6, 10.8 Hz), 5.49 (dd, 1H, J=1.6, 17.2 Hz), 6.03 (ddt, 1H, J=10.8, 17.2, 4.4 Hz), 6.37 (s, 1H, NH), 6.42 (d, 1H, J=8.8 Hz), 7.30–7.40 (m, 5H), 7.54 (d, 1H, J=8.8 Hz), 11.60 (s, 1H, OH); 13C NMR (CDCl3, 100 MHz): 18.5, 20.6, 38.5, 52.4, 56.9, 69.4, 69.4, 72.1, 75.9, 79.6, 103.3, 103.5, 115.4 (q, JCF=287 Hz), 116.8, 122.0, 127.6, 127.9, 128.5, 132.1, 132.5, 137.5, 156.2 (q, JCF=35 Hz), 158.7, 159.0, 171.3; IR (neat): 3330, 2920, 1718, 1648, 1616, 1436, 1352, 1298, 1198, 1156, 1080 cm–1. Anal. calcd for C27H30F3NO7: C, 60.33; H, 5.63; N, 2.61. Found: C, 60.12; H, 5.38; N, 2.39.
Methyl 2-hydroxy-3-(4-O-benzyl-2,3,6-trideoxy-3-C-methyl-3-azido-β-L-lyxo-hexopyranosyl)-6-(prop-2-ene-1-yloxy)benzoate (20)
Colorless oil, 48%; Rf 0.51 (hexane/EtOAc=4/1); [α]D20 –76 (c 1.15, CHCl3); 1H NMR (CDCl3, 500 MHz): 1.23 (d, 3H, J=6.3 Hz), 1.45 (s, 3H), 1.88 (brd, 1H, J=12.6 Hz), 2.12 (dd, 1H, J=11.5, 12.6 Hz), 3.08 (s, 1H), 3.84 (q, 1H, J=6.3 Hz), 3.94 (s, 3H), 4.53–4.55 (m, 2H), 4.61 (d, 1H, J=10.9 Hz), 4.90 (brd, 1H, J=11.5 Hz), 4.96 (d, 1H, J=10.9 Hz), 5.28 (dd, 1H, J=1.2, 10.9 Hz), 5.49 (dd, 1H, J=1.2, 17.2 Hz), 6.02 (ddt, 1H, J=10.9, 17.2, 5.8 Hz), 6.43 (d, 1H, J=8.6 Hz), 7.26–7.46 (m, 5H), 7.58 (d, 1H, J=8.6 Hz), 11.66 (s, 1H, OH); 13C NMR (CDCl3, 125 MHz): 17.9, 22.5, 36.6, 52.3, 62.8, 69.4, 69.8, 72.4, 75.6, 81.8, 103.2, 103.7, 116.8, 122.3, 127.6, 128.2, 128.3, 132.5, 132.7, 138.1, 158.8, 159.1, 171.6; IR (neat): 2891, 2101, 1736, 1654, 1618, 1439, 1357, 1301, 1259, 1206, 1151, 1084, 984, 812, 755, 697, 664, 548 cm–1. Anal. calcd for C25H29N3O6: C, 64.23; H, 6.25; N, 8.99. Found: C, 64.07; H, 6.38; N, 9.25.
Methyl 4-O-benzyl-2,3,6-trideoxy-3-C-methyl-3-dimethylamino-β-L-lyxo-hexopyranoside (21)
To a solution of amine 13 (76.0 mg, 0.29 mmol) in MeCN (4 ml), formalin (37%, 0.64 ml, 8.6 mmol) and NaBH3CN (138 mg, 2.19 mmol) were added at 0 °C. After stirring for 15 min, the reaction was quenched with 2 M aqueous NaOH. After extraction (CH2Cl2, 6 × ), the combined organic extracts were successively washed with water and brine, and then dried (Na2SO4). Filtration and concentration in vacuo gave dimethylamine 21 (82.4 mg, 98%) as a colorless oil. An analytical sample of 12 was obtained by preparative TLC (hexane/EtOAc/NEt3=6/4/0.5) as a colorless oil.
Rf 0.65 (hexane/EtOAc/NEt3=6/4/1); [α]D28 +44 (c 0.91, CHCl3); 1H NMR (CDCl3, 500 MHz): 0.98 (s, 3H), 1.25 (d, 3H, J=6.3 Hz), 1.65 (dd, 1H, J=2.3, 11.5 Hz), 1.91 (dd, 1H, J=9.8, 11.5 Hz), 2.25 (s, 6H), 3.11 (s, 1H), 3.50 (s, 3H), 3.66 (q, 1H, J=6.3 Hz), 4.51 (dd, 1H, J=2.3, 9.8 Hz), 4.64 (d, 1H, J=11.5 Hz), 4.96 (d, 1H, J=11.5 Hz), 7.23–7.32 (m, 3H), 7.41–7.46 (m, 2H); 13C NMR (CDCl3, 125 MHz): 14.0, 18.1, 37.1, 37.8, 56.3, 59.4, 70.0, 74.4, 78.7, 100.7, 127.1, 127.8, 128, 139.3; IR (neat): 2982, 2882, 1453, 1391, 1335, 1256, 1207, 1131, 1072, 1014, 965, 884, 736, 700, 592 cm–1. Anal. calcd for C17H27NO3: C, 69.59; H, 9.28; N, 4.77. Found: C, 69.49; H, 9.15; N, 4.57.
One-pot conversion of azide 14 to dimethylamine 21
To a solution of azide 14 (25.3 mg, 86.8 μmol) in CH2Cl2 (1.7 ml), PMe3 (1 M in toluene, 0.26 ml, 0.26 mmol) was added at room temperature. After stirring for 4 h, the solvent was removed in vacuo, and the residue was dissolved in MeCN (1.7 ml). Formalin (37%, 210 μl, 2.8 mmol) was added at room temperature, and the mixture was stirred for 30 min. The pH was adjusted to pH 4 with AcOH and NaBH3CN (27 mg, 0.43 mmol) was added at room temperature. After stirring for 1 h, the reaction was quenched with saturated aqueous NaHCO3 at 0 °C. After extraction with EtOAc (3 × ), the combined organic extracts were washed with brine and then dried (Na2SO4). After filtration, solvents were removed in vacuo, and the residue was purified by preparative TLC (hexane/EtOAc/NEt3=6/4/0.5) to give dimethylamine 21 (18.9 mg, 74%) as a colorless oil.
Preparation of trifluoroacetamide 5.
Preparation of benzoate 8.
Preparation of amide acetate 12.
Preparation of azide acetate 15.
Conversion of amine 13 and azide 14 into N,N-dimethylamino derivative 21.
References
Johnson, A. W., Smith, R. M. & Guthrie, R. D. Vancosamine: the structure and configuration of a novel amino-sugar from vancomycin. J. Chem. Soc. Perkin Trans. 1, 2153–2159 (1972).
Weringa, W. D., Williams, D. H., Feeney, J., Brown, J. P. & King, R. W. The structure of an amino-sugar from the antibiotic vancomycin. J. Chem. Soc. Perkin Trans. 1, 443–446 (1972).
Williams, D. H. & Bardsley, B. The vancomycin group of antibiotics and the fight against resistant bacteria. Angew. Chem. Int. Ed. 38, 1172–1193 (1999).
Tanaka, Y., Gräfe, U., Yazawa, K., Mikami, Y. & Ritzau, M. Nocardicyclins A and B: new anthracycline antibiotics produced by Nocardia pseudobrasiliensis. J. Antibiot. 50, 822–827 (1997).
Tanaka, Y., Gräfe, U., Yazawa, K. & Mikami, Y. Production of nocardicyclins by clinical isolates of Nocardia pseudobrasiliensis and in vivo antitumor activity of the antibiotic. J. Antibiot. 51, 589–591 (1998).
Maeda, K. et al. A new antitumor substance, pluramycin. J. Antibiot. 9, 75–81 (1956).
Kondo, S, Miyamoto, M., Naganawa, H., Takeuchi, T. & Umezawa, H. Structures of pluramycin A and neopluramycin. J. Antibiot. 30, 1143–1145 (1977).
Bililign, T., Griffith, B. R. & Thorson, J. S. Structure, activity, synthesis and biosynthesis of aryl C-glycosides. Nat. Prod. Rep. 22, 742–760 (2005).
Thang, T. T., Winternitz, F., Olesker, A., Lagrange, A. & Lukacs, G. Synthesis of a derivative of vancosamine, a component of the glycopeptide antibiotic vancomycin. J. Chem. Soc. Chem. Commun. 153–154 (1979).
Thang, T. T., Winternitz, F., Lagrange, A., Olesker, A. & Lukacs, G. Stereospecific access to branched-chain carbohydrate synthons. Tetrahedron Lett. 21, 4495–4498 (1980).
Ahmad, H. I., Brimacombe, J. S., Mengech, A. S. & Tucker, L. C. N. The synthesis of some derivatives of L-vancosamine (3-amino-2,3,6-trideoxy-3-C-methyl-L-lyxo-hexose). Carbohydr. Res. 93, 288–293 (1981).
Brimacombe, J. S., Mengech, A. S., Rahman, K. M. M. & Tucker, L. C. N. An approach to branched-chain amino sugars, particulary derivatives of L-vancosamine (3-amino-2,3,6-trideoxy-3-C-methyl-L-lyxo-hexose) and its D enantiomer, via the cyano-hydrin route. Carbohydr. Res. 110, 207–215 (1982).
Dyong, I., Weigand, J. & Thiem, J. Synthesen ungesättigter Aminozucker und Aminoalkyl-verzweigter Kohlenhydrate durch sigmatrope Umlargerung von Trichloracetimidaten. Liebigs Ann. Chem. 577–599 (1986).
Klemer, A. & Wilbers, H. Neue Synthesen von Derivaten der Antibiotikazucker 3-Amino-2,3,6-tridesoxy-3-C-methyl-L-xylo-hexopyranose, L-Vancosamine, D-Rubranitrose und von Vorläufen der L-Decilonitrose und D-Kijanose. Liebigs Ann. Chem. 815–823 (1987).
Greven, R., Jütten, P. & Scharf, H.-D. Stereoselective synthesis of L-vancosamine methyl β-glycoside by addition of an organocerium reagent to O-benzyloxime ethers. Carbohydr. Res. 275, 83–93 (1995).
Smith, G. R. & Giuliano, R. M. Synthesis of methyl α-L-vancosaminide. Carbohydr. Res. 323, 208–212 (2000).
Dyong, I. & Friege, H. N-Acetyl-1,4-di-O-acetyl-β-DL-vancosamin. Chem. Ber. 112, 3273–3281 (1979).
Dyong, I., Friege, H., Luftmann, H. & Merten, H. Totalsynthese und Konfigurationsbestimmung Me-C(3)-NHR-verzweigter 2,3,6-tridesoxyhexosen. Chem. Ber. 114, 2669–2680 (1981).
Fronza, G., Fuganti, C., Grasselli, P. & Pedrocchi-Fantoni, G. Synthesis of the N-benzoyl derivatives of L-arabino, L-lyxo (L-vancosamine) isomers of 2,3,6-trideoxy-3-C-methyl-3-aminohexose from a non-carbohydrate precursor. Tetrahedron Lett. 22, 5073–5076 (1981).
Fronza, G., Fuganti, C., Grasselli, P. & Pedrocchi-Fantoni, G. Synthesis of the four configuratonal isomers of N-benzyl-2,3,6-trideoxy-3-C-methyl-3-amino-L-hexose from the (2S, 3R)-diol obtained from α-methylcinnamaldehyde by fermentation with Baker’s yeast. J. Carbohydr. Chem. 2, 225–248 (1983).
Hamada, Y., Kawai, A. & Shioiri, T. New methods and reagents in organic synthesis. 50. A stereoselective synthesis of a derivative of L-vancosamine, a carbohydrate component of the antibiotics vancomycin and sporaviridin. Tetrahedron Lett. 25, 5413–5414 (1984).
Hauser, F. M., Ellenberger, S. R., Glusker, J. P., Smart, C. J. & Carrell, H. L. Stereoselective syntheses of (±)-daunosamine, (±)-vancosamine, and (±)-ristosamine from acyclic precursors. J. Org. Chem. 51, 50–57 (1986).
Hamada, Y., Kawai, A., Matsui, T., Hara, O. & Shioiri, T. 4-Alkoxycarbonyloxazoles as β-hydroxy-α-amino acid synthons: efficient, stereoselective synthesis of 3-amino-2,3,6-trideoxyhexoses and a hydroxy amino acid moiety of AI-77-B. Tetrahedron 46, 4823–4846 (1990).
Nicolaou, K. C., Mitchell, H. J., van Delft, F. L., Rübsam, F. & RodrÃguez, R. M. Expeditious routes to evernitrose and vancosamine derivatives and synthesis of a model vancomycin aryl glycoside. Angew. Chem. Int. Ed. 37, 1871–1874 (1998).
Nicolaou, K. C. et al. Total synthesis of vancomycin—Part 4: attachment of the sugar moieties and completion of the synthesis. Chem. Eur. J. 5, 2648–2667 (1999).
Nicolaou, K. C., Baran, P. S., Zhong, Y.-L. & Vega, J. A. Novel IBX-mediated processes for the synthesis of amino sugars and libraries thereof. Angew. Chem. Int. Ed. 39, 2525–2529 (2000).
Cutchins, W. W. & McDonald, F. E. Stereoselective synthesis of vancosamine and saccharosamine glycals via tungsten-catalyzed alkynol cycloisomerization. Org. Lett. 4, 749–752 (2002).
Parker, K. A. & Chang, W. A synthesis of L-vancosamine derivatives from non-carbohydrate precursors by a short sequence based on the Marshall, McDonald, and Du Bois reactions. Org. Lett. 5, 3891–3893 (2003).
Thang, T. T. et al. Synthesis and antitumor activity of 3’-C-methyl-daunorubicin. Carbohydr. Res. 135, 241–247 (1985).
Hsu, D.-S., Matsumoto, T. & Suzuki, K. Synthesis of L-vancosamine derivatives from methyl α-D-mannopyranoside. Synlett 469–471 (2006).
Horton, D. & Weckerle, W. A preparative synthesis of 3-amino-2,3,6-trideoxy-L-lyxo-hexose (daunosamine) hydrochloride from D-mannose. Carbohydr. Res. 44, 227 (1975).
Imamoto, T. et al. Carbon–carbon bond forming reactions using cerium metal or organocerium(III) reagents. J. Org. Chem. 49, 3904–3912 (1984).
Takeda, N. & Imamoto, T. Use of cerium(III) chloride in the reactions of carbonyl compounds with organolithium or Grignard reagents for the suppression of abnormal reactions: 1-butyl 1,2,3,4-tetrahydro-1-naphthol. Org. Synth. 76, 228–233 (1999).
Keck, G. E., McHardy, S. F. & Wager, T. T. Reductive cleavage of the N–O bonds in hydroxylamine and hydroxamic acid derivatives using SmI2/THF. Tetrahedron Lett. 36, 7419–7422 (1995).
Imamoto, T. & Ono, M. The reaction of samarium(III) iodide with samarium metal in tetrahydrofuran. A new method for the preparation of samarium(II) iodide. Chem. Lett. 501–502 (1987).
Hanessian, S. The reaction of O-benzylidene sugars with N-bromosuccinimide I. Methyl 4,6-O-benzylidenehexopyranosides. Carbohydr. Res. 2, 86–88 (1966).
Hanessian, S. & Plessas, N. R. The reaction of O-benzylidene sugars with N-bromosuccinimide. II. Scope and synthetic utility in the methyl 4,6-O-benzylidenehexopyranoside series. J. Org. Chem. 34, 1035–1044 (1969).
Duhamel, L., Plé, G., Angibaud, P. & Desmurs, J. R. New chiral brominating and chlorinating agents. Synth. Commun. 23, 2423–2433 (1993).
Wang, L.-X., Sakairi, N & Kuzuhara, H. Synthesis of 1D-(1,3,5/2,4)-4-acetamido-5-amino-1,2,3-cyclohexanetriol and its incorporation into a pseudo-disaccharide. Carbohydr. Res. 275, 33–47 (1995).
Lee, Y. J., Kubota, A., Ishiwata, A. & Ito, Y. Synthesis of pseudaminic acid, a unique nonulopyranoside derived from pathogenic bacteria through 6-deoxy-AltdiNAc. Tetrahedron Lett. 52, 418–421 (2011).
Xu, Y.-C., Bizuneh, A. & Walker, C. Selective deprotection of alkyl esters using magnesium methoxide. Tetrahedron Lett. 37, 455–458 (1996).
Kimura, Y., Matsumoto, T., Suzuki, M. & Terashima, S. An improved synthesis of N-trifluoroacetyl-L-daunosamine. Bull. Chem. Soc. Jpn 59, 663–664 (1986).
Alper, P. B., Hung, S.-C. & Wong, C.-H. Metal catalyzed diazo transfer for the synthesis of azides from amines. Tetrahedron Lett. 37, 6029–6032 (1996).
Titz, A., Radic, Z., Schwardt, O. & Ernst, B. A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines. Tetrahedron Lett. 47, 2383–2385 (2006).
Kitamura, M. et al. Direct synthesis of organic azides from primary amines with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate. Eur. J. Org. Chem. 458–462 (2011).
Kato, H., Ohmori, K. & Suzuki, K. Convenient procedure for one-pot conversion of azides to N-monomethylamines. Synlett 1003–1005 (2001).
Ben, A., Hsu, D.-S., Matsumoto, T. & Suzuki, K. Total synthesis and structure revision of deacetylravidomycin M. Tetrahedron 67, 6460–6468 (2011).
Acknowledgements
This work was supported by Grant-in-Aid for Specially Promoted Research (No. 23000006) from JSPS, Japan. We are grateful to Dr Hidehiro Uekusa and Ms Sachiyo Kubo for X-ray analysis.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Dedicated to Professor Kuniaki Tatsuta for his great synthetic expeditions, having conquered 101 peaks, including the 4 major antibiotics.
Rights and permissions
About this article
Cite this article
Kitamura, K., Shigeta, M., Maezawa, Y. et al. Preparation of L-vancosamine-related glycosyl donors. J Antibiot 66, 131–139 (2013). https://doi.org/10.1038/ja.2013.2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ja.2013.2
