3. Conclusion
In summery, we have developed a stereo- and regioselective allylic substitution on simple Neu5Ac2en derivatives that ensures the control of the regio- and stereoselectivity and affords the C-2 or C-4 products with high efficiency. I. The simple replacement of the protecting group on the glycerol chain might induce certain conformational changes which further promote the reactivity. II. The more reactive catalyst cooperated with the appropriate ligands and even the ratio between ligand and catalyst can be finely tuned to investigate the optimal conditions, especially for the retest of the unsuccessful cases. III. The selected additives for the improvement of efficiency, such as phase transfer reagent, base, metal, etc., could be possible. IV. The functionalized products provide an easy entry to a variety of modified sialic acid derivatives, which can serve as useful sialyl building blocks for biological research.
4. Experimental
General. Unless otherwise stated, all reactions were carried out under argon. THF and DCM were purified using a PureSolv solvent purification system (Innovative Technology Inc.).
Reactions were monitored with analytical thin-layer chromatography (TLC) on silica gel 60 F254 plates and visualized under UV (254 nm) and/or by staining with KMnO4. Silica gel SDS 60 ACC 35-70 mm was used for column chromatography. NMR spectra were recorded with AM 300, AVANCE 300 and AVANCE 500 Brüker spectrometers. Chemical shifts are given in parts per million, referenced to the solvent peak of CDCl3, defined at 77.0 ppm (13C NMR) and 7.26 ppm (1H NMR). Melting points (uncorrected) were determined with the aid of a Büchi B-540 apparatus. IR spectra were recorded on a Perkin-Elmer Spectrum BX instrument with an FT-IR system. Optical Rotations were measured on a JASCO-810 polarimeter using a cell of 1 dm-length path.
O COOMe
OAc OAc AcO
AcO AcHN
8
Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto -non-2-enonate (8)
Preparation of (8): To a solution of Neu5Ac (3.5 g, 6.67 mmol) in anhydrous ethyl acetate (30 mL) was added dropwise TMSOTf (2.68 mL, 14.82 mmol) at 0 oC over a period of 5 mins. The mixture solution was warmed to room temperature and stirred for another 4 hrs. The reaction was monitored by TLC, quenched by Et3N (5 mL) and water (50 mL) and then extracted by ethyl acetate (2 ° 30 mL). The combined organic layer was washed with brine (30 mL), dried (Na2SO4) and concentrated to obtain the crude product which was purified by silica gel
chromatography (DCM/MeOH : 97/3) to afford Neu5Ac2en (2.73 g, 5.84 mmol, 89 %) as a white solid.70
O COOMe
OBz O O
OH AcHN
11
Methyl 5-acetamido-2,6-anhydro-4-O-benzoyl-3,5-dideoxy-8,9-O-isopropylidene-
D-glycero-D-galacto-non-2-enonate (11)
Preparation of (11): Neu5Ac2en (5.9 g, 12.63 mmol) was dissolved in freshly-distilled methanol (100 mL) and sodium (38 mg, 0.61 mmol) was added at room temperature. While the clear solution turned to be cloudy (1 h), the reaction was completed. Dowex 50 (H+) resin was added and the reaction mixture was filtered and washed with hot methanol. The filtrates were evaporated in vacuo to give a pale-yellow foam (3.85 g), which was used directly for the next step. To the crude mixture of de-acetylated product (3.85 g) and CSA (0.15 g, 0.73 mmol) in anhydrous acetone (200 mL) was added 2,2-dimethoxypropane (12 mL). The reaction mixture was heated to reflux for 2 hrs. After being cooled, the solvent was evaporated. To a solution of the crude product (4.50 g) in DCM (100 mL) was added pyridine (10 mL) followed by dropwise addition of BzCl (2.14 ml, 18.50 mmol) at 0oC. The reaction was completed (1~2 hrs) monitoring by TLC and co-evaporated with toluene (3 ° 50 mL). The residue was diluted with DCM (200 mL), washed with HCl (0.5% in water, 3 ° 10 mL), water (10 mL), and saturated NaHCO3 aqueous solution (2 ° 10 mL). After evaporation of the solvents, the crude residue was purified by silica gel chromatography (DCM/MeOH : 100/0 to 98/2) gave the expected product 8 (4.09 g, three steps 72%) as a white solid. m.p. 230-232ºC; [α]D25 = + 69.8 (c = 1.05 in CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ = 8.02 (d, 3JH,H = 7.0 Hz, 2H, H-Ph), 7.60 (dd,
3JH,H = 7.4 Hz, 3JH,H = 8.4 Hz, 1H, H-Ph), 7.45 (dd, 3JH,H = 7.3 Hz, 3JH,H =8.4 Hz, 2H, H-Ph), 6.07 (d, 3JNH,H-5 = 7.0 Hz, 1H, NH), 5.96 (d, 3JH-3,H-4 = 2.6 Hz, 1H, H-3), 5.95 (dd, 3JH-4,H-3 = 2.6 Hz, 3JH-4,H-5 = 11.5 Hz, 1H, H-4), 4.78 (d, 3JOH,H-7 = 4.5 Hz, 1H, OH), 4.44-4.31 (m, 2H, H-5, H-8), 4.19- 4.08 (m, 3H, H-6, H-9, H-9’), 3.79 (s, 3H, OCH3), 3.50 (dd, 3JOH,H-7 = 4.5 Hz, 3JH,H
= 8.3 Hz, 1H, H-7), 1.99 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.36 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3, 25°C): δ = 173.2 (CO), 167.5 (CO), 161.9 (CO), 146.6 (C-2), 133.9 (Ph), 129.9 (Ph), 128.7 (Cq-Ph), 128.6 (Ph), 109.2 (Cq-acetonide), 106.7 (C-3), 77.9 (C-6), 74.0 (C-8), 69.7 (C-7), 69.1 (C-4), 67.3 (C-9), 52.4 (OCH3), 49.4 (C-5), 27.1 (CH3), 25.2 (CH3), 23.1 ppm (NHCOCH3) ppm; IR (neat): ν bar = 3280, 3093, 2924, 1727, 1667, 1638, 1562, 1556, 1454, 1439, 1390, 1250, 1127, 1067, 1043, 975, 860, 801 cm–1 ; ESI HRMS for C22H27O9NNa [M + Na]+ : found 472.1589, calcd 472.1578; elemental analysis calcd (%) for C22H27O9N: C 58.79, H 6.06, N 3.12, O 32.04; found: C 59.01, H 6.08, N 3.05, O 31.99.
12
O COOMe
OBz O O
TBSO AcHN
Methyl 5-acetamido-2,6-anhydro-4-O-benzoyl-7-O-tertbutyldimethylsilyl-3,5-dideoxy -8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate (12)
Preparation of (12): To a solution of 7 (168 mg, 0.37 mmol) in anhydrous DCM (1.5 mL) was added 2,6-Lutidine (0.22 mL, 1.89 mmol) followed by slow addition of TBSOTf (0.30 mL, 1.31 mmol) at room temperature. After being stirred overnight, the reaction mixture was quenched by Et3N and poured into water, washed by HCl (0.5% in water, 3 ° 3 mL), water (3 mL), saturated NaHCO3 aqueous solution (3 mL), brine (3 mL) and dried (MgSO4). After
concentration under reduced pressure, the residue was purified by silica gel chromatography (DCM/MeOH : 100/0 to 97.5/1.5) to furnish 12 (185 mg, 88%) as a white solid. m.p.
152-154ºC; [α]D25 = + 103.5 (c = 0.8 in CHCl3); 1H NMR (300 MHz, CDCl3, 25°C): δ = 8.02 (d, 3JH,H = 7.9 Hz, 1H, H-Ph), 7.57 (dd, 3JH,H = 7.6 Hz, 3JH,H = 8.0 Hz, 1H, H-Ar), 7.44 (dd, 3JH,H
= 7.6 Hz, 3JH,H = 7.9 Hz, 2H, H-Ph), 6.13 (d, JH-3,H-4 = 4.0 Hz, 1H, H-3), 5.70 (dd, 3JH-4,H-3 = 4.0 Hz, 3JH-4,H-5 = 5.4 Hz, 1H, H-4), 5.55 (d, 1H, NH, JNH,5 = 7.7 Hz), 4.49-4.32 (m, 4H, H-5, H-6, H-7, H-8), 4.06 (dd, 3JH-9,H-8 = 6.4 Hz, 2JH-9,H-9’ = 7.7 Hz, 1H, H-9), 3.93 (t, 3JH-9’,H-9 = 3JH-9’,H-8 = 7.6 Hz, 1H, H-9’), 3.79 (s, 3H, OCH3), 1.93 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.26 (s, 3H, CH3), 0.90 (s, 9H, CH3), 0.11 (s, 3H, CH3), 0.06 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3, 25°C):
δ =169.7 (CO), 165.9 (CO), 162.1 (CO), 145.2 (C-2), 133.4 (Ph), 129.9 (Ph), 129.3 (Cq-Ph), 128.5 (Ph), 108.6 (Cq-acetonide), 106.7 (C-3), 79.0 (C-6), 75.6 (C-7), 70.0 (C-8), ), 67.7 (C-4), 64.9 (C-9), 52.4 (OCH3), 47.5 (C-5), 26.6 (CH3), 25.9 (SiC(CH3)3), 25.2 (CH3), 23.3 (NHCOCH3), 18.3 (SiC), -3.6 (SiCH3), -4.5 (SiCH3) ppm; IR (neat): ν bar = 2929, 2854, 2870, 1746, 1734, 1725, 1643, 1530, 1450, 1370, 1249, 1225, 1058, 1093, 1024, 918, 851, 834, 772, 711 cm–1 ; ESI HRMS for C28H41O9NNaSi [M + Na]+ : found 586.2455, calcd 586.2443;
elemental analysis calcd (%) for C28H41NO9Si: C 59.66, H 7.33, N 2.48; found: C 59.69, H 7.35, N 2.44.
General procedures for palladium-mediated allylic substitution
A- with sodium malonate as nucleophile: In a Schlenk tube, a solution of the palladium source and the appropriate ligand in degassed THF (0.25 M) was added to 11 or 12. After stirring for 10 min, a solution of freshly-prepared sodium malonate in THF (0.33 M) was added and the resulting mixture was heated at 50°C for 0.5 - 18h. After cooling, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography
on silica gel.
B-with other nucleophiles: In a Schlenk tube, a mixture of 12, Pd2(dba)3.CHCl3, the appropriate ligand, the nucleophile and the base or the additive in degassed solvent (0.07 M) were heated at the indicated temperature. After cooling, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel.
O
COOMe O O
OH AcHN
COOMe COOMe
13
Methyl 5-acetamido-2,6-anhydro-2-C-(1-di-methoxycarbonyl-methyl)-8,9-O-isopropy -lidene-3,4,5-trideoxy-D-glycero-D-galacto-non-3-enonate (13)
(13) : m.p. 158-160 ºC; [α]D25 = -1.7 (c = 0.4 in CHCl3); 1H NMR (500 MHz, CDCl3, 25°C):
δ = 6.04 (dd, 3JH-3,H-4 = 9.5 Hz, 4JH-3,H-5 = 2.0 Hz, 1H, H-3), 5.92 (dd, 3JH-4,H-5 = 2.0 Hz, 3JH-4,H-3
= 9.5 Hz, 1H, H-4), 5.56 (d, 3JNH,H-5 = 9.5 Hz, 1H, NH), 4.66 (tt, 3JH-5,H-4 = 4JH-5,H-3 = 2.0 Hz,
3JH-5,NH = 3JH-5,H-6 = 9.5 Hz, 1H, H-5), 4.25 (q, 3JH-8,H-9 = JH-8,H-9’ = 6.5 Hz, 1H, H-8), 4.09 (s, 1H, H-malonyl), 4.05 (dd, 3JH-9,H-8 = 6.5 Hz, 2JH-9,H-9’ = 8.5 Hz, 1H, H-9), 3.99 (dd, 3JH-9’,H-8 = 6.5 Hz,
2JH-9’,H-9 = 8.5 Hz, 1H, H-9’), 3.75-3.77 (m, 1H, H-6), 3.74 (s, 3H, OCH3), 3.72 (s, 6H, OCH3), 3.65-3.67 (m, 1H, H-7), 3.54-3.58 (br, 1H, OH), 1.99 (s, 3H, NHCOCH3), 1.37 (s, 3H, CH3), 1.33 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δ = 171.4 (CO), 170.1 (CO), 166.6 (CO), 166.4 (CO), 131.7 (C-4), 127.0 (C-3), 108.5 (Cq), 78.7 (C-2), 76.4 (C-8), 75.3 (C-6), 69.5 (C-7), 66.0 (C-9), 58.6 (C-malonyl), 53.0 (OCH3), 52.9 (OCH3), 41.3 (C-5), 26.8 (CH3), 25.7 (CH3), 23.3 (NHCOCH3); IR (neat): ν bar = 3476 (br), 3267 (br), 2957, 2358, 1735, 1643, 1550, 1433, 1370, 1331, 1246, 1155, 1111, 1058, 1012, 890, 853, 757, 710 cm–1 ; ESI HRMS for
C20H29NO11Na [M + Na]+ : found 482.1642, calcd 482.1638; elemental analysis calcd (%) for C20H29 NO11: C 52.28, H 6.36, N 3.05, O 38.31; found: C 51.99, H 6.32, N 3.01, O 38.05.
14
MeOOC COOMe
O COOMe
O O
OH AcHN
Methyl 5-acetamido-2,6-anhydro-4-C-(1-di-methoxycarbonyl-methyl)-8,9-O-isopro -pylidene-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonate (14)
(14) : mp 191-193 ºC; [α]D25 = + 20.2 (c = 0.43 in CHCl3) ; 1H NMR (500 MHz, CDCl3): δ = 5.97 (d, 3JNH,H-5 = 8.0 Hz, 1H, NH), 5.88 (d, 3JH-3,H-4 = 2.5 Hz, 1H, H-3), 4.67-4.58 (bs, 1H, OH), 4.39 (m, 1H, H-8), 4.18 (dd, 2JH-9,H-9’ = 8.5 Hz, 3JH-9,H-8 = 6.0 Hz, 1H, H-9), 4.12 (dd, 3JH-9’,H-8 = 5.0 Hz, 2JH-9’,H-9 = 8.5 Hz, 1H, H-9’), 4.05 (td, 3JH-5,NH = 3JH-5,H-4 = 8.0 Hz, 3JH-5,H-6 = 10.5 Hz, 1H, H-5), 3.85 (d, 3JH-6,H-5 = 10.5 Hz, 1H, H-6), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.59 (d, 3JH-malonyl,H-4 = 5.5 Hz, 1H, H-malonyl), 3.55 (d, JH-7,H-8 = 8.0 Hz, 1H, H-7), 3.30 (ddd, 3JH-4,H-3 = 2.5 Hz, 3JH-malonyl,H-4 = 5.5 Hz, 3JH-4,H-5 = 8.0 Hz, 1H, H-4), 2.06 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.38 (s, 3H, CH3) ppm; 13C NMR (75 MHz, CDCl3): δ = 172.8 (CO), 168.7 (CO), 168.3 (CO), 162.3 (CO), 145.3 (C-2), 109.1 (Cq), 108.9 (C-3), 77.9 (C-6), 74.4 (C-8), 69.5 (C-7), 67.2 (C-9), 53.9 (OCH3), 53.1 (C-malonyl, OCH3), 52.3 (OCH3), 46.7 (C-5), 37.9 (C-4), 27.0 (CH3), 25.3 (CH3), 23.0 (NHCOCH3) ppm; IR (neat): ν bar = 3271 (br), 2955, 2359, 1754, 1726, 1641, 1556, 1435, 1370, 1311, 1256, 1227, 1158, 1043, 920, 862, 777, 731 cm–1; ESI HRMS for C20H29NO11Na [M + Na]+: found 482.1634, calcd 482.1638; elemental analysis calcd (%) for C20H29NO11: C 52.28, H 6.36, N 3.05, O 38.31 ; found: C 52.17, H 6.36, N 3.11, O 38.05.
15 O
COOMe O O
TBSO AcHN
COOMe COOMe
Methyl 5-acetamido-2,6-anhydro-7-O-tertbutyldimethylsilyl-2-C-(1-di-methoxycarbonyl -methyl)-8,9-O-isopropylidene-3,4,5-trideoxy-D-glycero-D-galacto-non-3-enonate (15) Preparation of (15): In a Schlenk tube, a solution of [Pd2(dba)3]•CHCl3 (5.1 mg, 5 mmol) and dppb (8 mg, 20 mmol) in degassed THF (0.2 mL) was added to 8 (28.1 mg, 50 mmol). After stirring for 10 min, a solution of freshly-prepared sodium dimethyl malonate in THF (0.3 mL, 0.1 mmol) was added and the resulting mixture was heated at 50 oC for 3 h. After cooling, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 1:0 to 49:1) to give 15 as a colorless solid (24 mg, 84%). m.p. 143 oC; [α]D25 =-3.3 (c=1.3 in CHCl3); 1H NMR (300 MHz, CDCl3): δ = 6.02 (dd,
3JH-3,H-5 =1.5 Hz, 3JH-3,H-4 =10.4 Hz, 1H; H-3), 5.99 (dd, 3J H-4,H-5 =1.5 Hz, 3J H-4,H-3 = 10.4 Hz, 1H; H-4), 5.48 (d, 3J NH,H-5 =7.5 Hz, 1H; NH), 4.36 (ddt, 3J H-5,H-3 = 3J H-5,H-4 =1.5 Hz, 3J H-5,NH = 7.5 Hz, 3J H-5,H-6 = 9.3 Hz, 1H; H-5), 4.25 (td, 3J H-8,H-7 =3.0 Hz , 3J H-8,H-9 = 3J H-8,H-9’ = 7.5 Hz, 1H; H-8), 4.15 (dd, 3JH-7,H-6 =1.5 Hz, 3J H-7,H-8 =3.0 Hz, 1H; H-7), 3.96 (t, 3J H-9,H-9’ = 3J H-8,H-9’
= 7.5 Hz, 1H; H-9), 3.95 (s, 1H; H-malonyl), 3.88 (dd, 3J H-6,H-7 =1.5, 3J H-6,H-5 = 9.3 Hz, 1H;
H-6), 3.82 (t, 3JH-9’,H-8= 3J H-9,H-9’ = 7.5 Hz, 1H; H-9’), 3.74 (s, 3H; OCH3), 3.71 (s, 3H; OCH3), 3.70 (s, 3H; OCH3), 1.94 (s, 3H; NHCOCH3), 1.40 (s, 3H; CH3), 1.31 (s, 3H; CH3), 0.89 (s, 9H;
CH3), 0.12 (s, 3H; CH3), 0.11 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3): δ =170.1 (CO), 169.8 (CO), 166.2 (CO), 166.0 (CO), 132.3 (C-4), 125.1 (C-3), 107.7 (Cq), 78.9 (C-2), 77.4 (C-8), 76.6 (C-6), 70.8 (C-7), 64.7(C-9), 59.0 (C-malonyl), 52.7 (OCH3), 52.5 (OCH3), 44.3
(C-5), 26.3 (CH3), 26.0 (SiC(CH3)3), 24.8 (CH3), 23.3 (CH3 NHCOCH3), 18.2 (SiC), -4.9 (SiCH3), -3.9 ppm (q, SiCH3); IR (neat): ν bar = 2951, 1740, 1646, 1542, 1433, 1243, 1156, 1015, 835, 776, 714 cm-1; ESI HRMS: m/z: calcd for C26H43NO11SiNa [M+Na]+: 596.2503;
found 596.2500; elemental analysis calcd (%) for C26H43NO11Si: C 54.43, H 7.55, N 2.44;
found: C 54.51, H 7.53, N 2.36.
16
MeOOC COOMe
O COOMe
O O
TBSO AcHN
Methyl 5-acetamido-2,6-anhydro-4-C-(1-di-methoxycarbonyl-methyl)-8,9-O-isopropyli -dene-7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonate (16) Preparation of (16): In a Schlenk tube, a solution of [Pd2(dba)3]•CHCl3 (51 mg, 0.05 mmol) and PBu3 (50 mL, 0.2 mmol) in degassed THF (2 mL) was added to 12 (281 mg, 0.5 mmol).
After stirring for 10 min, a solution of freshly-prepared sodium dimethyl malonate in THF (3 mL, 1 mmol) was added and the resulting mixture was heated at 50 oC for 15 h. After cooling, the solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 1:0 to 99:1) to give 16 as a colorless solid (261 mg, 92%). m.p.78 oC; [α]D25 = +30.2 (c=1 in CHCl3); 1H NMR (300 MHz, CDCl3, 25 oC): δ = 6.02 (d, 3JH-3,H-4 = 2.5 Hz, 1H; H-3), 5.62 (d, 3JNH,H-5 = 8.0 Hz, 1H; NHAc), 4.38 (dd, 3JH-6,H-7 = 1.2, 3J H-6,H-5 = 10.0 Hz, 1H; H-6), 4.29 (td, 3JH-8,H-7 = 5.0 Hz, 3JH-8,H-9 = 3J
H-8,H-9’ = 6.6 Hz, 1H; H-8), 4.14 (dd, 3JH-7,H-6 =1.2 Hz, 3JH-7,H-8 = 5.0 Hz, 1H; H-7), 4.09(dd,
3JH-9,H-8 = 6.6, 3JH-9,H-9’ = 8.1 Hz, 1H; H-9), 3.96 (dd, 3JH-9’,H-8 = 6.6 Hz, 3JH-9’,H-9 = 8.1 Hz, 1H;
H-9’), 3.83 (td, 3JH-5,NH = 8.0 Hz, 3JH-5,H-6 = 3JH-5,H-4 =10.0 Hz, 1H; H-5), 3.78 (s, 3H; OCH3),
3.77 (s, 3H; OCH3), 3.75 (s, 3H; OCH3), 3.72 (d, 3JH-malonyl,H-4 = 4.5 Hz, 1H; H-malonyl), 3.54 (ddd, 3JH-4,H-3 = 2.5 Hz, 3JH-4, H-malonyl = 4.5, 3JH-4,H-5 =10.0 Hz, 1H; H-4), 1.96 (s, 3H; CH3), 1.40 (s,3H; CH3), 1.30 (s, 3H, CH3), 0.87 (s, 9H; 3 x CH3), 0.12 (s, 3H; CH3), 0.11 ppm (s, 3H;
CH3); 13C NMR (75 MHz, CDCl3, 25 oC): δ = 170.2 (CO), 168.7 (CO), 167.9 (CO), 162.3 (CO), 144.1 (C-2), 109.9.1 (C-3), 108.3 (Cq), 77.5 (C-6), 76.3 (C-8), 71.5 (C-7), 65.6 (C-9), 52.8 (OCH3), 52.6 (OCH3), 52.1 (C-malonyl, OCH3), 47.7 (C-5), 38.2 (C-4), 26.6 (CH3), 26.0 (SiC(CH3) 3), 24.9 (CH3), 23.6 (CH3), 18.4 (SiC), -3.3 (SiCH3), -4.3 ppm (SiCH3); IR (neat):
ν bar = 3476 (br), 3267 (br), 2957, 2358, 1735, 1643, 1550, 1433, 1370, 1331, 1246, 1155, 1111, 1058, 1012, 890, 853, 757, 710 cm-1; ESI HRMS: m/z: calcd for C26H43NO11SiNa [M+Na]+: 596.2503; found 596.2503; elemental analysis calcd (%) for C26H43NO11Si: C 54.43, H 7.55, N 2.44; found: C 54.31, H 7.54, N 2.38.
22
O COOMe
O O
TBSO AcHN
SO2Ph PhO2S
Methyl 5-acetamido-2,6-anhydro-7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-4-C-(1-diben -zenesulfonyl-methyl)-8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate (22) (22): m.p. 177-179 ºC; [α]D25 = + 2.3 (c = 0.3 in CHCl3); 1H NMR (300 MHz, CDCl3): δ 8.05 (d, 2H, J = 7.8 Hz, Ph), 7.80 (d, 2H, J = 7.7 Hz, Ph), 7.67-7.56 (m, 2H, Ph), 7.45-7.54 (m, 4H, Ph), 6.18 (d, 1H, J3,4 = 2.1 Hz, H-3), 5.68 (d, 1H, JNH,5 = 7.8 Hz, NH), 5.65 (s, 1H, HC(SO2Ph)2), 4.71 (td, 1H, J5,NH = 7.8 Hz, J5,4 = J5,6 = 9.5 Hz, H-5), 4.28-4.18 (m, 2H, H-7, H-8), 4.05 (dd, 1H, J9,8 = 5.8 Hz, J9,9’ = 7.5 Hz, H-9), 3.94 (d, 1H, J6,5 = 9.5 Hz, H-6), 3.88 (t, 1H, J9’,8 = J9’,9 = 7.5 Hz, H-9’), 3.77 (s, 3H, CH3), 3.58 (dd, 1H, J4,3 = 2.1 Hz, J4,5 = 9.5 Hz,
H-4), 1.86 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.23 (s, 3H, CH3), 0.89 (s, 9H, 3 x CH3),0.14 (s, 6H, 2 x CH3); 13C NMR (75 MHz, CDCl3): δ 171.3 (CO), 161.8 (CO), 144.9 (C-2), 140.0 (Cq Ph), 137.2 (Cq Ph), 134.7 (Ph), 134.1 (Ph), 129.7 (Ph), 129.4 (Ph), 129.3 (Ph), 108.3 (Cq), 107.6 (C-3), 80.7 (C(SO2Ph)2), 78.1 (C-7), 75.9 (C-8), 71.9 (C-6), 65.2 (C-9), 52.3 (OCH3), 47.5 (C-5), 41.4 (C-5), 26.5 (CH3), 26.0 (SiC(CH3)3), 25.0 (CH3), 23.5 (NHCOCH3), 18.3 (SiC), -3.8 (SiCH3), -4.5 (SiCH3); IR (neat): ν bar = 2927, 1730, 1666, 1650, 1536, 1309, 1277, 1253, 1145, 1078, 832, 745, 727, 625 cm–1; ESI HRMS for C34H47NO11S2SiNa: found 760.2247, calcd 760.2258.
34 N3
O COOMe
O O
TBSO AcHN
Methyl 5-acetamido-2,6-anhydro-4-azido-7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-8,9 -O-isopropylidene-D-glycero-D-galacto-non-2-enonate (34)
(34): [α]D25 = +65.6 (c = 1.2 in CHCl3); 1H NMR (500 MHz, CDCl3): δ 5.97 (d, 1H, J3,4 = 2.5 Hz, H-3), 5.69 (d, 1H, JNH,5 = 8.5 Hz, NH), 4.68 (dd, 1H, J6,7 = 3 Hz, J6,5 = 8.5 Hz, H-6), 4.65 (dd, 1H, J4,3 = 2.5 Hz, J4,5 = 8.5 Hz, H-4), 4.29 (q, 1H, J8,9 = J8,9’ = J8,7 = 7.0 Hz, H-8), 4.18-4.14 (m, 1H, H-7), 4.11 (t, 1H, J9,8 = J9,9’ = 7.0 Hz, H-9), 3.94 (t, 1H, J9’,8 = J9’,9 = 7.0 Hz, H-9’), 3.82 (s, 3H, OCH3), 3.61 (q, 1H, J5,4 = J5,NH = J5,6 = 8.5 Hz, H-5), 2.04 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.35 (s, 3H, CH3), 0.91 (s, 9H, 3 x CH3), 0.16 (s, 3H, CH3), 0.14 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 170.4 (CO), 161.8 (CO), 145.3 (C-2), 108.5 (Cq), 106.7 (C-3), 77.5 (C-6), 76.3 (C-8), 70.7 (C-7), 65.5 (C-9), 56.6 (C-4), 52.4 (OCH3), 50.5 (C-5), 26.5 (CH3), 26.0 (SiC(CH3)3), 24.9 (CH3), 23.5 (NHCOCH3), 18.5 (SiC), -3.2 (SiCH3), -4.3
(SiCH3); IR (neat): 2927, 2854, 2357, 2096, 1731, 1650, 1659, 1537, 1438, 1370, 1249, 1129, 1070, 832, 776, 712 cm–1; ESI HRMS for C21H36N4O7Si Na: found 507.2271, calcd 507.2251;
35 N
O COOMe
O O
TBSO AcHN
O
Methyl 5-acetamido-2,6-anhydro-7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-4-N-morpho -lino-8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate (35)
(35): m.p. 61-63 ºC; [α]D25 = +45.8 (c = 1.5 in CHCl3); 1H NMR (300 MHz, CDCl3): δ 6.07 (d, 1H, J3,4 = 3.6 Hz, H-3), 5.46 (d, 1H, JNH,5 = 7.2 Hz, NH), 4.38-4.24 (m, 3H, H-6, H-7, H-8), 4.07 (q, 1H, J5,6 = J5,NH = J5,4 = 7.2 Hz, H-5), 4.06 (t, 1H, J9,8 = J9,9’ = 7.3 Hz, H-9), 3.95 (t, 1H, J9’,8 = J9’,9 = 7.3 Hz, H-9’), 3.81 (s, 3H, OCH3), 3.72-3.68 (m, 4H, 2 x CH2), 3.34 (dd, 1H, J4,3 = 3.6 Hz, J4,5 = 7.2 Hz, H-4), 2.76-2.58 (m, 4H, 2 x CH2), 1.96 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.31 (s, 3H, CH3), 0.87 (s, 9H, 3 x CH3), 0.08 (s, 3H, CH3), 0.04 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 170.1 (CO), 162.5 (CO), 144.9 (C-2), 108.6 (Cq), 108.1 (C-3), 79.2 (C-8), 76.2 (C-6), 70.5 (C-7), 67.5 (OCH2), 65.2 (C-9), 61.3 (C-4), 52.4 (OCH3), 50.2 (CH2N), 45.6 (C-5), 26.8 (CH3), 26.2 (SiC(CH3)3), 25.4 (CH3), 23.7 (NHCOCH3), 18.6 (SiC), -3.1 (SiCH3), -4.2 (SiCH3); IR (neat): ν bar = 2929, 2854, 1731, 1650, 1537, 1437, 1369, 1250, 1152, 1114, 1004, 832, 776, 692 cm–1; ESI HRMS for C25H44N2O8SiNa: found 551.2767, calcd 551.2765; Anal. Calcd for C25H44N2O8Si: C, 56.79; H, 8.39; N, 5.30; Found:
C, 56.67; H, 8.51; N, 5.07.
N
O COOMe
O O
HO AcHN
NBoc 36 (-TBS)
Methyl 5-acetamido-2,6-anhydro-3,4,5-trideoxy-4-(4-tertbutoxycarbonyl-piperazin-1-yl) -8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate
(36 - TBS): mp: 183 ºC; [α]D25 = +40.6 (c 0.81, CHCl3) ; 1H NMR (300 MHz, CDCl3): δ 5.93 (d, 1H, H-3, J3,4 = 3.9 Hz); 5.87 (d, 1H, NH, JNH,5 = 7.7 Hz), 4.24-4.32 (m, 2H, H-5, H-7), 4.09-4.17 (m, 2H, H-9’, H-8), 4.01 (dd, 1H, H-9, J = 5.0, 8.7 Hz), 3.75 (s, 3H, OCH3), 3.52 (d, 1H, H-6, J = 8.3 Hz), 3.38 (br, 4H, piperazine), 3.17 (dd, 1H, H-4, J = 5.0, 5.0 Hz), 2.59 (br, 4H, piperazine), 2.00 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.36 (s, 3H, CH3),1.32 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): 171.5 (CO); 162.2 (CO), 154.5 (CO), 146.0 (C-2), 109.2 (Cq), 105.2 (C-3), 77.5 (C-8), 74.4 (C-5), 72.1 (C-6), 67.4 (C-9), 60.7 (C-4), 52.4 (OCH3), 49.4 (CH2 of piperazine), 45.3 (C-7), 43.4 (CH2-piperazine), 28.4 (CH3-Boc), 27.0 (CH3-acetonide), 25.3 (CH3-acetonide), 23.7 (NHCOCH3); IR (neat): ν bar = 3282(br), 2980, 2931, 1728, 1690, 1646, 1552, 1409, 1367, 1246, 1153, 1120, 1062, 1004, 914, 847, 764, 719 cm–1; ESI HRMS for C24H39N3O9Na:: found: 536.2572 calcd 536.2584;; Anal. Calcd for C24H39N3O9: C, 56.13; H, 7.65; N, 8.18; O, 28.04; Found: C, 55.43; H, 7.18; N, 7.57; O, 27.68.
37 N
O COOMe
O O
TBSO AcHN
N
Methyl 5-acetamido-2,6-anhydro-7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-4-(4-(hex- 5-ynyl)-piperazin-1-yl)-8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate (37) (37): m.p. 55-56 ºC; [α]D25 = +53.2 (c = 0.9 in CHCl3); 1H NMR (500 MHz, CDCl3): δ 6.08 (d, 1H, H-3, J3,4 = 3.0 Hz), 5.52 (d, 1H, JNH,5 = 7.0 Hz, NH), 4.36-4.31 (m, 1H, H-8), 4.31-4.26 (m, 1H, H-7), 4.24-4.18 (m, 1H, H-6), 4.01 (t, 1H, J9,8 = J9,9’ = 7.0 Hz, H-9), 3.98 -3.92 (m, 1H, H-5), 3.91 (t, 1H, J9’,8 = J9’,9 = 7.0 Hz, H-9’), 3.76 (s, 3H, OCH3), 3.44-3.40 (m, 1H, H-4), 2.75-2.62 (m, 4H, NCH2), 2.52-2.39 (m, 4H, NCH2), 2.38-2.32 (m, 2H, CH2), 2.24-2.20 (m, 2H, CH2), 1.95 (s, 3H, CH3), 1.91 (s, 1H, CH-alkyne), 1.72-1.48 (m, 6H, CH2), 1.40 (s, 3H, CH3), 1.31 (s, 3H, CH3), 0.88 (s, 9H, CH3), 0.09 (s, 3H, CH3), 0.06 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): δ 170.0 (CO), 162.4 (CO), 144.3 (C-2), 108.7 (Cq), 108.3 (C-3), 84.3 (Calkyne), 79.1 (C-6), 76.1 (C-8), 70.0 (C-7), 68.5 (CH-alkyne), 64.8 (C-9), 60.2 (C-4), 58.0 (CH2), 53.5 (CH2), 52.2 (OCH3), 49.4 (CH2), 45.9 (C-5), 26.5 (CH3), 26.4 (CH2), 26.0 (CH3), 25.9 (CH2), 25.4 (CH3), 23.5 (NHCOCH3), 18.3 (SiC, CH2), -3.0 (SiCH3), -4.5 (SiCH3); IR (neat): ν bar = 3268, 2930, 1731, 1650, 1436, 1369, 1251, 1119, 1070, 1006, 833, 776, 695 cm–1; ESI HRMS for C31H54N3O7Si: found 608.3730, calcd 608.3731;
O CO2CH3
O O O
TBSO N
H5
H4
H6
39
Methyl 2,6-anhydro-7-O-tertbutyldimethylsilyl-8,9-O-isopropylidene-4',5'-dihydro-2'- methyloxazolo<5.4-d>-2,3,5-trideoxy-D-glycero-D-galacto-non-2-enonate (39)
Preparation of (39): In a Schlenk tube, the mixture of 12 (11.2 mg, 20 µmol), [Pd2(dba)3.CHCl3] (4 mg, 4µmol), dppb (6.8 mg, 16 µmol) and potassium hexamethyl -disilazide (KHMDS, 20 mg, 100 µmol) in degassed DCM (1 mL) was heated at 80 oC for 15 h. After purification via column chromatography over silica gel (DCM/MeOH = 99:1 to 98:2), the bicyclic oxazoline 39 was obtained as a colorless syrup (12.5 mg, 71%). For 39, [α]D25 = -7.4 (c 1.48, CHCl3) ; 1H NMR (300 MHz, CDCl3): δ 6.32 (d, 1H, H-3, J3,4 = 4.0 Hz), 4.79 (dd, 1H, H-4, J4,3 = 3.7 Hz, J4,5 = 8.0 Hz), 4.23-4.28 (m, 2H, H-7, H-8), 4.11-4.15 (m, 2H, H-5, H-9’), 3.98 (dd, 1H, H-9, J9,8 = 7.6, 8.9 Hz), 3.79 (s, 3H, OCH3), 3.22 (d, 1H, H-6, J6,5 = 10.4 Hz), 1.97 (s, 3H, NAc), 1.40 (s, 3H, CH3), 1.31 (s, 3H, CH3), 0.89 (s, 9H, CH3), 0.19 (s, 3H, CH3), 0.13 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 166.4 (CO), 162.4 (CO), 147.8 (C-2), 108.1 (Cq), 106.7 (C-3), 79.6 (C-6), 77.1 (C-8), 72.6 (C-4), 70.2 (C-7), 65.7 (C-9), 61.2 (C-5), 52.4 (OCH3), 26.5 (CH3), 26.0 (SiC(CH3)3), 25.2 (CH3), 18.4 (SiC), 14.1 (NHCOCH3), -3.7 (SiCH3), -4.0 (SiCH3). ESI HRMS for C21H35NO7SiNa: found 464.2079, calcd 464.2080;
43 HN
O COOMe
O O
TBSO AcHN
Methyl 5-acetamido-2,6-anhydro-7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-4-phenyl -amino-8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate (43)
(43): [α]D25 = +31.6 (c = 0.6 in CHCl3) ; 1H NMR (500 MHz, CDCl3): δ 7.21 (dd, 2H, J = 8.0, 8.5 Hz, Ph), 6.76 (t, 1H, J = 8.0 Hz, Ph), 6.66 (d, 2H, J = 8.0 Hz, Ph), 6.10 (d, 1H, J3,4 = 2.5 Hz, H-3), 5.89 (d, 1H, JNH, 5 = 8.5 Hz, NH), 4.61 (d, 1H, JNH,4 = 6.5 Hz, NH), 4.30 (dd, 1H, J6,7 = 2.0 Hz, J6,5 = 8.5 Hz, H-6), 4.30-4.23 (m, 3H, H-4, H-7, H-8), 4.10 (q, 1H, J5,NH = J5,4 = J5,6 = 8.5 Hz, H-5), 4.06-4.02 (m, 1H, H-9), 3.92-3.88 (m, 1H, H-9’), 3.79 (s, 3H, OCH3), 1.97 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.30 (s, 3H, CH3), 0.93 (s, 9H, 3 x CH3), 0.18 (s, 3H, CH3), 0.17 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 171.2 (CO), 162.4 (CO), 146.7 (Cq), 143.5 (C-2), 129.5 (Ph), 118.1 (Ph), 113.2 (Ph), 110.7 (C-3), 108.5 (Cq), 78.4 (C-8), 75.6 (C-6), 71.8 (C-7), 65.3 (C-9), 53.5 (C-4), 52.2 (OCH3), 49.4 (C-5), 26.5 (CH3), 25.7 (SiC(CH3)3), 25.1 (CH3), 23.4 (NHCOCH3), 18.3 (SiC), -3.7 (SiCH3), -4.5 (SiCH3); IR (neat):
3284, 2929, 2855, 1731, 1650, 1601, 1504, 1435, 1370, 1307, 1249, 1143, 1069, 835, 748, 730 cm–1 ; ESI HRMS for C27H42N2O7SiNa: found 557.2695, calcd 557.2659;
44 HN
O COOMe
O O
TBSO AcHN
Methyl 5-acetamido-2,6-anhydro-4-benzylamino-7-O-tertbutyldimethylsilyl-3,4,5-tride -oxy-8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate (44)
(44): m.p. 90-92 ºC; [α]D25 = +41.1 (c = 0.5 in CHCl3); 1H NMR (500 MHz, CDCl3):
δ 7.37-7.27 (m, 5H, Ph), 6.11 (d, 1H, J3,4 = 3.0 Hz, H-3), 5.57 (d, 1H, JNH,5 = 6.0 Hz, NH), 4.29 (td, 1H, J8,7 = 3.5 Hz, J8,9 = J8,9’ = 6.5 Hz, H-8), 4.25 (t, 1H, J7,6 = J7,8 = 3.5 Hz, H-7), 4.19 (dd, 1H, J6,7 = 3.5 Hz, J6,5 = 8.5 Hz, H-6), 4.03 (dd, 1H, J9,8 = 6.5 Hz, J9,9’ = 8.0 Hz, H-9), 3.95-3.86 (m, 3H, H-5, H-9’, NCH2Ph), 3.80-3.74 (m, 5H, NH, NCH2Ph, OCH3), 3.48 (dd, 1H, J4,3 = 3.0 Hz, J4,5 = 7.0 Hz, H-4), 1.93 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.29 (s, 3H, CH3), 0.88 (s, 9H, 3 x CH3), 0.10 (s, 3H, CH3), 0.07 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
δ 170.2 (CO), 162.7 (CO), 143.6 (C-2), 140.0 (Cq), 128.6 (Ph), 128.5 (Ph), 128.3 (Ph), 127.1 (Ph), 126.8 (Ph), 110.9 (C-3), 108.4 (Cq), 78.8 (C-6), 76.0 (C-8), 70.8 (C-7), 65.3 (C-9), 54.6 (C-4), 52.2 (OCH3), 50.4 (NCH2Ph), 48.8 (C-5), 26.6 (CH3), 26.0 (SiC(CH3)3), 25.2 (CH3), 23.5 (NHCOCH3), 18.3 (SiC), -3.4 (SiCH3), -4.4 (SiCH3); IR (neat): 3320 (br), 2930, 2854, 1713, 1650, 1537, 1436, 1370, 1252, 1138, 1027, 832, 776, 742, 695 cm–1; ESI HRMS for C28H44N2O7SiNa: found 549.2997; calcd 549.2996.
45 N
O COOMe
O O
TBSO AcHN
Methyl 5-acetamido-2,6-anhydro-4-(N-benzyl-N-methyl)amino-8,9-O-isopropylidene -7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonate (45)
(45): m.p. 95-97 ºC; [α]D25 = +59.8 (c = 0.65 in THF); 1H NMR (500 MHz, CDCl3):
δ 7.33-7.27 (m, 5H, Ph), 6.14 (s, 1H, H-3), 5.31 (bs, 1H, NH), 4.36 (d, 1H, J6,5 = 7.0 Hz, H-6), 4.29 (q, 1H, J8,7 = J8,9 = J8,9’ = 6.5 Hz, H-8), 4.14 (d, 1H, J7,8 = 6.5 Hz, H-7), 4.12 (dd, 1H, J9,8
= 6.5 Hz, J9,9’ = 8.0 Hz, H-9), 3.99 (dd, 1H, J9,8 = 6.5 Hz, J9,9’ = 8.0 Hz, H-9), 3.97-3.91 (m, 1H, H-5), 3.84-3.74 (m, 4H, NCH2Ph, OCH3), 3.72-3.66 (m, 1H, H-4), 3.59 (d, 1H, J = 13.0 Hz, NCH2Ph), 2.25 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.29 (s, 3H, CH3), 0.87 (s, 9H, 3 x CH3), 0.11 (s, 3H, CH3), 0.10 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 170.0 (CO), 162.4 (CO), 145.5 (C-2), 139.2 (Cq), 128.7 (Ph), 128.4 (Ph), 127.2 (Ph), 109.0 (Cq), 108.3 (C-3), 78.2 (C-8), 76.3 (C-6), 71.1 (C-7), 65.8 (C-9), 59.3 (C-4), 58.6 (NCH2Ph), 52.1(OCH3), 46.6 (C-5), 37.7 (NCH3), 26.6 (CH3), 26.0 (SiC(CH3)3), 25.0 (CH3), 23.7 (NCOCH3), -3.1 (SiCH3), 18.5 (SiC), -4.1 (SiCH3); IR (neat): 2927, 2854, 1736, 1650, 1547, 1454, 1369, 1250, 1133, 1071, 832, 776, 741, 697 cm–1; ESI HRMS for C29H47N2O7Si: found:
563.3156, calcd 563.3152; Anal. Calcd for C29H47N2O7Si: C, 61.89; H, 8.24; N, 4.98; Found:
C, 62.19; H, 8.45; N, 4.31.
46 O
O COOMe
O O
TBSO AcHN
Methyl 5-acetamido-7-O-tertbutyldimethylsilyl-3,5-trideoxy-2,6-anhydro-4-O-phenyl -8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enonate (46)
(46): m.p. 87-89 ºC; [α]D25 = +62.0 (c 0.9 in CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.28 (dd, 2H, J = 7.2 Hz, J = 7.2 Hz, 8.7 Hz, Ph), 7.02-6.95 (m, 3H, Ph), 6.16 (d, 1H, J3,4 = 3.9 Hz, H-3), 5.72 (d, 1H, JNH,5 = 6.0 Hz, NH), 5.19 (dd, 1H, J4,3 = 3.9 Hz, J4,5 = 6.0 Hz, H-4), 4.55 (t, 1H, J6,5 = J6,7 = 6.0 Hz, H-6), 4.38 (dd, 1H, J7,8 = 3.9 Hz, J7,6 = 6.0 Hz, H-7), 4.21 (ddd, 1H, J8,7 = 3.9 Hz, J8,9 = 6.6, J8,9’ = 7.8 Hz, H-8), 4.15 (q, 1H, J5,6 = J5,NH = J5,4 = 6.0 Hz, H-5), 3.96 (dd, 1H, J9,8 = 6.6 Hz, J9,9’ = 7.8 Hz, H-9), 3.93 (t, 1H, J9’,9 = J9’,8 = 7.8 Hz, H-9’), 3.82 (s, 3H, OCH3), 1.93 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.18 (s, 3H, CH3), 0.90 (s, 9H, 3 x CH3), 0.11 (s, 3H, CH3), 0.06 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 170.2 (CO), 162.4 (CO), 156.9 (Ph), 144.5 (C-2), 129.8 (Ph), 121.8 (Ph), 115.7 (Ph), 108.4 (Cq), 106.9 (C-3), 79.1 (C-6), 76.1 (C-8), 69.3 (C-7), 68.9 (C-4), 64.4 (C-9), 52.4 (OCH3), 48.8 (C-5), 26.4 (CH3), 26.0 (SiC(CH3)3), 25.0 (CH3), 23.4 (NHCOCH3), 18.4 (SiC), -3.4 (SiCH3), -4.6 (SiCH3); IR (neat):
2928, 2854, 1731, 1705, 1650, 1537, 1370, 1251, 1219, 1114, 1069, 1004, 834, 776, 691 cm–1; ESI HRMS for C27H41NO8SiNa: found 558.2491, calcd 558.2499; Anal. Calcd for C27H41NO8Si: C, 60.54; H, 7.71; N, 2.61; Found: C, 60.35; H, 7.82; N, 2.51.
O
COOMe O O
TBSO AcHN
OCH3
47
Methyl 5-acetamido-2,6-anhydro-7-O-tertbutyldimethylsilyl-8,9-O-isopropylidene-2-O- methyl-3,4,5-trideoxy -D-glycero-D-galacto-non-2-enonate (47)
Preparation of (47): In a Schlenk tube, to the mixture of 12 (56.3 mg, 100 µmol), [Pd2(dba)3.CHCl3] (20 mg, 20 µmol), dppb (34 mg, 80 µmol) in degassed THF (0.56 mL) was added a suspension of Zn(OMe)2 (500 µmol) in cosolvent of THF and hexane [Zn(OMe)2 was freshly prepared from MeOH (48 µL), Et2Zn (1 M in hexane, 0.6 mL) in degassed THF (0.48 mL)]. The reaction mixture was heated at 60 oC for 15 h. The cooled residue was directly subjected to column chromatography over silica gel and the product 47 was obtained as a colorless syrup (29.2 mg, 62%). For 47, 1H NMR (300 MHz, CDCl3): δ 5.98 (d, 1H, H-4, J4,5
= 9.8 Hz), 5.87 (dd, 1H, H-3, J3,5 = 2.4 Hz, J3,4 = 10.1 Hz), 5.38 (d, 1H, NH, JNH,5 = 7.6 Hz), 4.63 (dt, 1H, H-5, J5,3 = 1.8 Hz, J5,6 = J5,NH = 8.5 Hz), 4.29 (ddd, 1H, H-8, J8,7 = 6.1, 6.7, 6.7 Hz), 3.87 (dd, 1H, H-9, J9,8 = 7.0, 8.1 Hz), 4.05 (dd, 1H, H-9’, J9’,8 = 6.7, 7.9 Hz), 3.92 (d, 1H, H-7, J7,8 = 6.7 Hz), 3.84 (d, 1H, H-6, J6,5 = 10.5 Hz), 3.76 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 1.97 (s, 3H, NAc), 1.38 (s, 3H, CH3), 1.30 (s, 3H, CH3), 0,89 (s, 9H, CH3), 0.15 (s, 3H, CH3), 0.11 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): δ 169.8 (CO), 169.1 (CO), 133.2 (C-4), 126.0 (C-3), 108.7 (Cq), 96.3 (C-2), 74.9 (C-8), 73.0 (C-7), 71.2 (C-6), 66.8 (C-9), 52.6 (OCH3), 51.6 (OCH3), 44.2 (C-5), 26.7 (CH3), 25.9 (SiC(CH3)3), 25.1 (CH3), 23.3 (NHCOCH3), 18.4 (SiC), -4.3 (SiCH3), -3.8 (SiCH3); ESI HRMS for C22H39NO8SiNa: found 496.2338, calcd 496.2343.
N3
O N
O COOMe
N O O
TBSO AcHN
52
Methyl 5-acetamido-2,6-anhydro-7-O-tertbutyldimethylsilyl-3,4,5-trideoxy-4-N-[4-(3- azido-propionylamino)-piperazin-1-yl]-8,9-O-isopropylidene -D-glycero-D-galacto-non- 2-enopyranosonate (52)
(52): m.p. 77 ºC; [α]D25 = +73.9 (c 0.89 in CHCl3); 1H NMR (300 MHz, MeOD) δ 6.07 (d, J
3,4 = 2.7 Hz, 1H, H-3), 4.42-4.30 (m, 2H, H-5, H-8), 4.18 (dd, J6,7 = 2.1 Hz, J 6,5 = 10.2 Hz, H-6), 4.14 (dd, J 9,8 = 6.3 Hz, J9,9= 8.1 Hz, 1H, H-9), 4.06 (dd, J7,6 = 1.5 Hz, J7,8 = 6.9 Hz, 1H, H-7), 3.99 (dd, J9’,8 = 6.0 Hz, J9’,9 = 8.4 Hz, 1H, H-9'), 3.81 (s, 3H), 3.64-3.52 (m, 7H, CH2-piperazine, CH2CH2CH2N3, H-4), 2.76 (br, 2H, CH2-piperazine), 2.68 (t, J = 6.3 = 6.3 Hz, 2H, CH2CH2CH2N3), 2.55 (br, 2H, CH2-piperazine), 2.00 (s, 3H, NHCOCH3), 1.41 (s, 3H, acetonide), 1.34 (s, 3H, CH3), 1.21 (t, J = 7.0 Hz, J = 7.0 Hz, 2H, CH2CH2CH2N3), 0.92 (s, 9H, CH3), 0.18 (s, 3H, CH3), 0.14 (s, 3H, CH3); 13C NMR (75 MHz, MeOD): δ 173.97 (CO), 171.9 (CO), 164.5 (CO), 147.2 (C-2), 111.0 (C-3), 110.8 (Cq), 80.4 (C-6), 77.7 (C-8), 74.1 (C-7) , 68.6 (C-9), 64.8 (C-4), 53.5 (O CH3), 51.0 (CH2) , 49.1 (CH2), 48.1 (CH2), 45.6 (H-5), 44.4 (CH2), 34.0 (CH2), 27.9 (CH3), 27.5 (SiC(CH3)3), 26.2(CH3), 23.7 (NHCOCH3), 20.3 (SiC), -1.7 (SiCH3), -2.7 (SiCH3).
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Chapter 2
An Easy Access to α-Glycosyl Chloride via TCT/DMF
1. Introduction
1.1. Previous methods in preparations of α-glycosyl chlorides
In the past decades, glycosyl halides are widely employed as donors in constructions of O-, C-, N-glycosides.1-3 A vast number of methods have been established. Among them, glycosyl chloride received much less attention and elaborated studies towards its advantage are rarely described.4 Usually, per-O-acetylated sugars are straightforwardly converted to the corresponding glycosyl chlorides by treatment of anhydrous HCl in various sovlents, AcCl, SOCl2/AcOH, SOCl2/SnCl4, PCl5, AlCl3, ZnCl2, TiCl4, BiCl3/MeSiCl3, triphosgene or α-dichloromethyl methyl ether (DCMME) (Figure 1).5-9 Unfortunately, the acid-labile groups can not survive under those harsh conditions, and the generally-adopted reagent (DCMME) is a lachrymatory, quite expensive and toxic, which impedes its large-scale preparation.10-11
Viehe's salt
N+ Cl Cl
Cl
-Vilsmeier-Haack reagent triphosgene Cl Cl Cl O O Cl O
Cl Cl
α-dichloromethyl methyl ether HO
Cl
Cl N+
H Cl
Cl
-Figure 1 - Common chlorinating reagent for preparation of glycosyl chlorides
Activation of thioglycoside via ICl to prepare glycosyl chlorides also has been reported, however, the instant realease of HCl may impair the acid-sensitive groups, which limit its scope.12 Recently, a mild protocol through chlorosulfonium chloride reagent converting thioglycoside to α/β mixed glycosyl chloride at –78 oC has been disclosed and the crude chloride was directly subjected to the following Koenigs-Knorr glycosylation with the several acceptors (Scheme 1).13
O PO SR
P = Protecting group
O PO
Cl R1 S
Cl
R1 Cl
-Cl2 O
PO S
Cl
+ R Cl
-acceptor + i n-si tu prepar ed f rom oxalyl chlori de
and phenyl sulf oxi de
sequential glycosyl ati on α/β mixture
-78oC
Koenigs-Knorr conditions
Scheme 1 - Conversion from thioglycoside to glycosyl chloride via chlorosulfonium chloride
The other basic or neutral methods derived from sugar hemiacetals, such as PPh3/CCl4, (Me2N)3P/CCl4,14 n-BuLi/ClPO(OPh)2,15 chloroenamines (Viehe’s salt or Vilsmeier-Haack reagent),16 TsCl/DMAP/Et3N,17 have been mentioned (Figure 1). In those aforementioned procedures, handling hazardous, costly, and excess reagents, even sometimes at lower temperature might arouse several potential drawbacks. Therefore, developing a milder, bench-top and cheap reagent to transform hemiacetals to the corresponding glycosyl chlorides is highly desirable.
Therefore, we envisaged that a new method to prepare glycosyl chloride from hemiacetal using Vilsmeier-Haack (VH) reagent in-situ generated from 2,4,6-trichloro-1,3,5-triazine (TCT) and N,N-dimethylformamide (DMF) (Scheme 2). Using the complex TCT/DMF converting amide to nitrile was firstly reported by Rodriguez et al. in 1997,18and many applications using TCT appeared in the past decade.19-25 A mild chlorination and
chemoselective formylation of alcohol via TCT/DMF complex have been reported by Giacomelli et al.26, 27 Their findings prompted us to consider its use in synthetic carbohydrate chemistry (Scheme 2).
O PO OH
N N
N Cl
Cl Cl
P = Protecting group
O PO
Cl
TCT + DMF