Reaction of enamines and mediated anodic oxidation of carbohydrates with the 2,2,6,6-tetramethylpiperidine-1-oxoammonium ion (TEMPO+)

Electrochimica Acta 50 (2005) 4956–4972

Reaction of enamines and mediated anodic oxidation of carbohydrates with the 2,2,6,6-tetramethylpiperidine-1-oxoammonium ion (TEMPO+) M. Sch¨amann, H.J. Sch¨afer ∗,1 Organisch-Chemisches Institut der Universit¨at M¨unster, Corrensstraße 40, D-48149 M¨unster, Germany Received 23 November 2004; received in revised form 25 February 2005; accepted 25 February 2005 Available online 6 July 2005

Abstract TEMPO+ is obtained by anodic oxidation or disproportionation of 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO). TEMPO+ reacts in acetonitrile with the enaminoester: ethyl (Z)-3-benzylamino-2-methyl-2-butenoate to an imidazolium cation. The reaction possibly involves the trimer of the enaminoester as intermediate. The enamine: 1-pyrrolidino-cyclohexene and TEMPO+ combine to an intermediate cation, which is hydrolyzed to the ␤-ketoalkoxyamine: 2-(2,2,6,6-tetramethyl-piperidine-1-oxy)-cyclohexanone. Cyclovoltammograms of TEMPO and the enaminoester or the enamine support the proposed mechanisms. The primary hydroxy group of carbohydrates can be selectively oxidized at the anode with TEMPO as mediator. This conversion is applied to the disaccharides: d-maltose, d-lactose, d-cellobiose and the trisaccharide: d-raffinose. d-maltose and d-raffinose are converted in good yields and selectivity to tricarboxylic acids, the oxidations of d-lactose and d-cellobiose are less selective due to cleavages of the disaccharides. For the mediated oxidation of d-maltose a scale-up to 67.5 mmol (24.3 g) has been developed for a current controlled electrolysis in an undivided cell. © 2005 Elsevier Ltd. All rights reserved. Keywords: Enaminoester; Imidazolium cation; Uronic acid; Maltose; Raffinose; TEMPO+

1. Introduction Electrochemistry contributes strongly to organic synthesis by providing C,C-bond forming reactions and functional group interconversions [1]. Many of these reactions occur by direct electron transfer from the electrode to the substrate or from the substrate to the electrode. Others proceed as indirect electrolysis with a mediator [2], whereby the substrate is oxidized or reduced by an electrocatalyst, whose active form is subsequently regenerated at the anode or cathode. TEMPO and its derivatives have been used frequently as mediators in indirect electrolyses for the selective oxidation of primary alcohols [3], carbohydrates [4] or naphthol [5]. In nonelectrochemical oxidations TEMPO and its derivatives ∗ 1

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have been employed with cooxidants in many conversions of hydroxy [6] and other functional groups [7]. The active forms: TEMPO+ -salts have also been applied as selective stoichiometric oxidants [8]. TEMPO and its 4-substituted derivatives are readily available and produced in a technical scale [9]. The redox potentials of several nitroxyl radicals from the TEMPO type have been determined and the values correlated with their structures by AM1-SM2 calculations [10]. The electrochemical reduction and oxidation of TEMPO and substituted TEMPO derivatives has been studied by cyclovoltammetry in water, methanol and acetonitrile [11]. The acid-promoted disproportionation of TEMPO was investigated by potentiometry and voltammetry in order to elucidate the role of TEMPO in the catalytic oxidation of alcohols by nitroxides [12]. Further electrochemical studies of nitroxyls are reported in Ref. [13]. In this study the reaction of TEMPO with enamines is analyzed by cyclovoltammetry. These electron-rich alkenes

M. Sch¨amann, H.J. Sch¨afer / Electrochimica Acta 50 (2005) 4956–4972

should undergo an electrochemically induced reaction with TEMPO, which has not been studied before. In order to get additional insight into the mechanism and to explore the synthetic use of this reaction the enamines are also converted in a preparative scale with TEMPO+ , the oxidized form of TEMPO. Furthermore the scope of the TEMPO-mediated carbohydrate oxidation is extended, by exploring the selectivity for the conversion of the trisaccharide: d-raffinose and of the unprotected disaccharides: d-cellobiose, d-lactose and d-maltose.

2. Experimental 2.1. General remarks Chemicals from Acros, Aldrich, Fluka, Merck were used without further purification. TEMPO was supplied from Degussa AG. All solvents were purified by distillation and in some cases traces of water were removed. All products were identified by mass spectrometry, 1 H, 13 C NMR and FTIR spectroscopy. 2.2. Electrochemistry Cyclovoltammetry was performed in an undivided microcell (7 ml, Metrohm) with a Ag/AgCl-reference electrode (3 M aqueous KCl + 0.21 V versus NHE), a glassy carbon rod as counter electrode and a glassy carbon or platinum disc electrode (d = 3 mm) as working electrode. Current source was the potentiostat PG-STAT 20 in combination with VA 663 (Metrohm), as software the programme GPES 4.6 (EcoChemie B.V.) was used. For digital simulation Digisim® 3.0 (BAS) was applied. Preparative potential controlled electrolyses were performed in an undivided, double walled beaker cell with a volume of 40–100 ml. The cell was closed with a Teflon stopper, which contained borings for the current feeders and the Luggin capillary. Reference electrode was the Ag/AgCl-electrode. As anode material graphite P127 (Sigri, Meitingen) or a platinum foil on a teflon holder was used, cathode material was always platinum, if not otherwise stated. Larger scale constant current electrolyses with carbohydrates were performed in an undivided beaker cell (600 ml) with different electrode materials (see Section 3.2.2). As current source for the potential controlled electrolyses served the potentiostats: Wenking HP 88 and Wenking ST 88 (Bank Elektronik). For constant current (galvanostatic) electrolyses the potentiostat/galvanostat TNs 300-1500 (Heinzinger) was applied. 2.2.1. Ethyl (Z)-3-benzylamino-2-methyl-2-butenoate (1c) A mixture of benzylamine (6.42 g, 60 mmol) and ethyl 2methylacetoacetate (8.65 g, 60 mmol) was refluxed in 50 ml toluene for 6 h in a water separator. Thereafter the solution

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was dried, the toluene rotaevaporated (removal of the solvent at the rotary evaporator at reduced pressure), the product purified by flash chromatography to yield enaminoester 1c (13.81 g, 59.2 mmol, 99%). Rf -value: 0.64 (cyclohexane:ethylacetate = 1:2). FT-IR (film): ν˜ (cm−1 ) = 3260 (br., N H), 3030 (s, C Harom. ), 2979, 2932 (s, C H), 1644 (C O), 1599 (s, C C), 1495 (s), 1453 (s, C H-def.), 1236 (s), 1098 (s), 1025 (s, C O), 779 (s), 733 (s), 697 (s). 1 H NMR (CDCl3 ): δ (ppm) = 1.27 (t, 3 J = 7.1 Hz, 3H, CH3 CH2 ), 1.80, 1.90 (2 s, 6H, 2-CH3 , 3-CH3 ), 4.13 (q, 3 J = 7.1 Hz, 2H, CH3 CH2 ), 4.40 (d, 3 J = 5.9 Hz, 2H, C6 H5 CH2 ), 7.23–7.31 (m, 5H, Harom. ), 9.65 (br. s, 1H, N H). 13 C NMR (CDCl3 ): δ (ppm) = 12.7 (q, CH3 CH2 ), 14.6, 15.2 (2 q, 2-CH3 , 3-CH3 ), 47.0 (t, C6 H5 CH2 ), 58.6 (t, CH3 CH2 ), 87.7 (s, C-2), 126.6, 127.0, 128.6 (5 d, CHarom. ), 139.4 (s, Carom. ), 159.4 (s, C-3), 171.2 (s, C-1). MS (direct inlet, 70 eV, EI): m/z (%) = 233 (60) [M+ ], 218 (4) [M+ − CH3 ], 204 (7) [M+ − C2 H5 ], 188 (21) [M+ − OC2 H5 ], 186 (15), 160 (38) [M+ − COOC2 H5 ], 132 (7), 106 (6) [HNC7 H7 + ], 91 (100) [C7 H7 + ], 65 (10) [C5 H5 + ]. C14 H19 NO2 (233.1): calcd. C 72.07, H 8.21, N 6.00; found C 71.91, H 8.09, N 5.85. 2.2.2. Ethyl (Z)-3-benzylamino-2-ethyl-2-butenoate (1d) Enaminoester 1d was prepared as enaminoester 1c. From benzylamine (5.82 g, 54.3 mmol) and ethyl 2-ethylacetoacetate (8.60 g, 54.0 mmol) was the enaminoester 1d (12.02 g, 48.6 mmol, 90%) obtained. Rf -value: 0.56 (cyclohexane:ethyl acetate = 1:2 + 1% diethylamine). FT-IR (film): ν˜ (cm−1 ) = 3170 (br., N H), 3030 (s, C Harom. ), 2978, 2933 (s, C H), 1643 (C O), 1597 (s, C C), 1496 (w), 1454 (m, C H-def.), 1283 (m), 1231 (s), 1172 (m), 1104 (s, C O), 1027 (m), 965 (m), 788 (s), 732 (s), 697 (s). 1 H NMR (CDCl3 ): δ (ppm) = 0.96 (t, 3 J = 7.3 Hz, 3H, 2-CH3 CH2 ), 1.26 (t, 3 J = 7.1 Hz, 3H, CH3 CH2 O), 1.94 (s, 3H, 3-CH3 ), 2.23 (q, 3 J = 7.3 Hz, 2H, 2-CH3 CH2 ), 4.12 (q, 3 J = 7.1 Hz, 2H, CH3 CH2 O), 4.40 (d, 3 J = 6.2 Hz, 2H, C6 H5 CH2 ), 7.17–7.34 (m, 5H, Harom. ), 9.63 (br. s, 1H, N H). 13 C NMR (CDCl3 ): δ (ppm) = 14.6 (q, CH3 CH2 O), 15.2, 20.5 (2 q, 3CH3 , 2-CH2 CH3 ), 43.6 (t, 2-CH2 CH3 ), 47.1 (t, C6 H5 CH2 ), 58.5 (t, CH3 CH2 O), 95.2 (s, C-2), 126.6, 127.2, 128.6 (5 d, CHarom. ), 139.5 (s, Carom. ), 159.1 (s, C-3), 171.0 (s, C-1). MS (direct inlet, 70 eV, EI): m/z (%) = 247 (42) [M+ ], 232 (58) [M+ − CH3 ], 219 (7) [M+ − C2 H4 (McLaff.)], 202 (14) [M+ − OC2 H5 ], 190 (5), 186 (7), 174 (15) [M+ − COOC2 H5 ], 172 (12), 158 (5), 156 (2) [M+ − C7 H7 ], 132 (3), 106 (3) [HNC7 H7 + ], 91 (100) [C7 H7 + ], 65 (10) [C5 H5 + ]. The spectroscopic data correspond to these in Refs. [14,15]. 2.2.3. (E)-1-Pyrrolidino-cyclohexene (7) Enamine 7 was prepared as enaminoester 1c. Pyrrolidine (4.62 g, 65.0 mmol) and cyclohexanone (5.89 g, 60.0 mmol) afforded enamine 7 (7.73 g, 85%). b.p. 96–97 ◦ C (11 mbar). FT-IR (film): ν˜ (cm−1 ) = 2934, 2871 (s, C H), 1647 (s, C C), 1541 (s), 1521 (m), 1435 (s, C H-def.), 1228 (s), 1202 (s), 1032 (s), 914 (s), 875 (s), 818 (s). 1 H NMR (CDCl3 ): δ (ppm) = 1.55 (m, 2H, 4-H), 1.58 (m, 2H, 5-H), 1.84 (m,

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4H, 8-H, 8 -H), 2.10 (m, 4H, 3-H, 6-H), 2.92 (m, 4H, 7H), 4.29 (s, 1H, 2-H). 13 C NMR (CDCl3 ): δ (ppm) = 23.0, 23.3 (2 t, C-4, C-5), 24.5 (2 t, C-8), 27.5 (2t, C-6, C-3), 47.4 (t, C-7), 93.5 (d, C-2), 143.4 (s, C-1). MS (GC/MS, 70 eV, EI): m/z (%) = 151 (93) [M+ ], 150 (100) [M+ − H], 136 (57) [M+ − CH3 ], 123 (58) [M+ − C2 H4 ], 108 (24) [M+ − C3 H7 ], 95 (39) [M+ − C2 H4 C2 H4 ], 81 (12) [M+ − NC4 H8 ], 80 (19), 70 (21) [NC4 H8 + ], 68 (12), 54 (18), 53 (16) [C4 H5 + ], 41 (23) [C3 H5 + ]. The spectroscopic data correspond to these in Ref. [16].

2.2.4. Ethyl 3-[4-(1-ethoxycarbonylethyl)-1,3dibenzylimidazolium-2-yl]-benzylamino-2-methylacryloate-tetrafluoroborate (10a) To enaminoester 1c (1.88 g, 8.1 mmol) in acetonitrile (10 ml) was added oxopiperidinium salt 4 (2.01 g, 8.1 mmol) in acetonitrile (5 ml), then the mixture was stirred for 6 h at room temperature. After extraction with pentane (3× 20 ml) the acetonitrile was removed in the rotary evaporator and the residue dried in vacuum. The crude product (3.22 g) was purified by flash chromatography first with diethyl ether as solvent and then with cyclohexane:ethylacetate (1:4), the latter eluted the imidazolium salt 10a (0.79 g, 1.2 mmol, 45%). Rf -value: 0.12 (cyclohexane:ethylacetate = 1:4 + 1% diethylamine). FT-IR (film): ν˜ (cm−1 ) = 3380 (s, N H), 3060, 3027 (m, C Harom. ), 2980, 2956 (s, C H), 1736 (s, C Osat. ), 1683 (s, C Ounsat. ), 1597 (s, C C), 1499 (s, C C), 1455 (s, C Hdef.), 1367 (m), 1300 (s), 1059 (s, br., BF4 ), 916 (m), 862 (m), 736 (s), 701 (s). 1 H NMR (CDCl3 ): δ (ppm) = 1.07, 1.08 (2 t, 2 3 J = 7.1 Hz, 6H, 11-H, 16-H, numbering see Scheme 6), 1.37, 1.53 (d, 3 J12,13 = 7.3 Hz, 3H, 13-H), 2.04, 2.09 (s, 8-H, 3H), 3.66 (q, 3 J12,13 = 7.3 Hz, 1H, 12-H), 3.86 (2 q, 3 J = 7.1 Hz, 4H, 10-H, 15-H), 4.02 (dd, 2 3 J = 6.6 Hz, 2H, 19-H), 4.29 (d, 2 J = 14.4 Hz, 1H, 18-H), 4.80 (d, 2 J = 14.4 Hz, 1H, 18H), 4.84 (d, 2 J = 16.5 Hz, 1H, 17-H), 5.03 (d, 2 J = 16.5 Hz, 1H, 17-H), 6.18, 6.59 (dd, 2 3 J = 6.6 Hz, 1H, NH), 6.84, 7.04 (s, 1H, 5-H), 7.07–7.34 (m, 15H, Harom. ). 13 C NMR (CDCl3 ): δ (ppm) = 12.3 (q, C-8), 13.6 (q, C-11), 14.0 (q, C-16), 17.7 (q, C-13), 36.3 (d, C-12), 47.7 (t, C-19), 50.2, 52.1 (2 t, C-17, C-18), 60.5 (2 t, C-10, C-15), 105.0 (s, C7), 120.1 (d, C-5), 127.9, 128.6, 128.9, 129.1, 129.3, 129.5, 129.7, 131.4, 132.1 (15 d, CHarom. ), 131.8, 134.3 (2 s, Carom. ), 134.7 (s, C-4), 135.6 (s, C-6), 138.8 (s, Carom. ), 141.1 (s, C-2), 167.0 (s, C-9), 170.9 (s, C-14). MS (ESI/MS, ES+): m/z (%) = 566 (21) [M+ ], 538 (3) [M+ − C2 H4 (McLaff.)], 520 (5) [M+ − HOC2 H5 ], 493 (2) [M+ − COOC2 H5 ], 475 (1) [M+ − PhCH2 ], 446 (8) [M+ − C2 H4 PhCH3 ], 428 (10), 402 (28) [M+ − COOC2 H5 PhCH2 ], 384 (29), 354 (22), 349 (4) [M+ − PhCH2 NHC C(CH3 )COOC2 H5 ], 338 (13), 312 (11), 297 (9) [M+ − COOC2 H5 PhCH2 PhCH2 N], 275 (11) [M+ − PhCH2 NHC C(CH3 )COOC2 H5 HCOOC2 H5 ], 259 (11), 233 (3) [M+ − PhCH2 NH(CNCH2 Ph)C C(CH3 )COO C2 H5 ], 185 (11), 181 (32), 129 (11), 91 (100) [PhCH2 + ]. C35 H40 N3 O4 + (HR-MS, ESI, ES+): calcd. 566.3019; found 566.3029.

2.2.5. Ethyl 3-[4-(1-ethoxycarbonyl-propyl)-1,3dibenzyl-imidazolium-2-yl]-3-benzylamino-2ethylacryloate-tetrafluoroborate (10b) To enaminoester 1d (0.161 g, 0.65 mmol) in acetonitrile (2 ml) a solution of oxopiperidinium salt 4 (0.159 g, 0.65 mmol) in acetonitrile (2 ml) was added drop by drop, then the mixture was stirred for 6 h at room temperature. After extraction with pentane (3× 5 ml) the acetonitrile was removed at the rotary evaporator and the residue dried in the vacuum. The crude product (0.298 g) was purified by flash chromatography the same way as salt 10a, to afford imidazolium salt 10b (28.6 mg, 0.04 mmol, 19%). Rf -value: 0.17 (cyclohexane:ethyl acetate = 1:4 + 1% diethylamine). FT-IR (film): ν˜ (cm−1 ) = 3372 (s, N H), 2971, 2934 (s, C H), 1734 (s, C Osat. ), 1680 (s, C Ounsat. ), 1592 (s, C C), 1497 (s, C C), 1454 (s, C H-def.), 1367 (m), 1302 (s), 1133 (s), 1060 (s, br., BF4 ), 913 (m), 733 (s), 701 (s). 1 H NMR (CDCl3 ): δ (ppm) = 0.95 (t, 3 J14,15 = 7.3 Hz, 3H, 15-H), 1.08, 1.09 (3 t, 3 J11,12 = 7.2 Hz, 3 J17,18 = 7.2 Hz, 3J 8,9 = 7.6 Hz, 9H, 9-H, 12-H, 18-H), 1.93 (m, 2H, 14-H), 2.50 (q, 3 J8,9 = 7.6 Hz, 2H, 8-H), 3.48 (t, 3 J13,14 = 7.4 Hz, 1H, 13-H), 3.88 (q, 3 J11,12 = 7.2 Hz, 2H, 11-H), 3.92 (q, 3J 3 17,18 = 7.2 Hz, 2H, 17-H), 4.04 (dd, 2 J = 6.6 Hz, 2H, 212 H), 4.37 (d, J = 14.4 Hz, 1H, 20-H), 4.83 (d, 2 J = 14.4 Hz, 1H, 20-H), 4.95 (d, 2 J = 16.3 Hz, 1H, 19-H), 5.14 (d, 2 J = 16.3 Hz, 1H, 19-H), 6.21 (dd, 2 3 J = 6.6 Hz, 1H, NH), 6.98 (s, 1H, 5-H), 7.08–7.38 (m, 15H, Harom. ). 13 C NMR (CDCl3 ): δ (ppm) = 11.7 (q, C-15), 12.4 (q, C-9), 13.8 (q, C-12), 14.1 (q, C-18), 19.9 (t, C-8), 26.5 (t, C-14), 43.2 (d, C-13), 48.0 (t, C-21), 50.0 (t, C-19), 52.2 (t, C-20), 60.5 (2 t, C-11, C-17), 111.3 (s, C-7), 120.0 (d, C-5), 127.2, 127.5, 127.8, 128.2, 128.6, 128.7, 128.9, 129.0, 129.1, 129.3, 129.5, 129.6, 129.7 (15 d, CHarom. ), 131.3, 132.3 (2 s, Carom. ), 133.6 (s, C-4), 135.1 (s, C-6), 138.8 (s, Carom. ), 141.5 (s, C-2), 166.6 (s, C-10), 170.3 (s, C-16). MS (ESI/MS, ES+): m/z (%) = 594 (10) [M+ ], 566 (1) [M+ − C2 H4 (McLaff.)], 548 (2) [M+ − HOC2 H5 ], 521 (1) [M+ − COOC2 H5 ], 503 (1) [M+ − PhCH2 ], 474 (4) [M+ − C2 H4 PhCH3 ], 456 (3), 430 (7) [M+ − COOC2 H5 PhCH2 ], 428 (4), 412 (8), 382 (5), 366 (5), 363 (3) [M+ − PhCH2 NHC C(C2 H5 )COOC2 H5 ], 341 (3), 338 (2), 325 (2) [M+ − COOC2 H5 PhCH2 PhCH2 N], 289 (3), 273 (3), 248 (3) [M+ − PhCH2 NHC C(C2 H5 ) COOC2 H5 H5 C2 CHCOOC2 H5 ], 199 (4), 181 (9), 143 (4), 91 (100) [PhCH2 + ]. C37 H44 N3 O4 + (HR-MS, ESI, ES+): calcd. 594.3332; found 594.3295. 2.2.6. Trimethyl d-raffinose-trisuronate (25) d-Raffinose-pentahydrate (24) (1200 mg, 2.00 mmol) and TEMPO (3, 156 mg, 1.00 mmol) were dissolved in 50 ml of an aqueous sodium carbonate buffered solution (pH 10) and were electrolyzed at 20 ◦ C in an undivided cell with a graphite anode (area: 8 cm2 ) and a platinum cathode (area: 8 cm2 ) potential controlled at 0.53 V versus SCE. After consumption of 3965 ◦ C (20.5 F for 12 electrons per mole) at currents between 150 and 20 mA the electrolyte was treated with 80 ml amberlite IR 120. After removal of

M. Sch¨amann, H.J. Sch¨afer / Electrochimica Acta 50 (2005) 4956–4972

the cation exchanger by filtration the solvent was removed first at a rotary evaporator at 10 Torr and later at 0.1 Torr, not exceeding a temperature of 50 ◦ C. This afforded the crude product (1124 mg) as a pale yellow, viscous liquid. From that 146 mg were converted into the ester by treatment with 2,2-dimethoxypropane (1.0 ml, 8.2 mmol) and a drop of conc. HCl in 10 ml abs. methanol. After stirring for 1 day the solvent was removed, the crude ester purified by flash chromatography (ethyl acetate:methanol = 3:1) to yield the trimethyl ester 25 as a colourless, viscous liquid (97 mg from 146 mg crude product, which corresponds to 747 mg,1.27 mmol, 63% from 1124 mg crude product). [α]20 D : +67.7 (c = 1.03, MeOH). Rf -value: 0.05 (ethyl acetate:methanol = 3:1). FT-IR (film): ν˜ (cm−1 ) = 3389 (s, br., O H), 2956 (w, C H), 1743 (s, C O), 1645 (w), 1442 (m, C H-def.), 1234 (m), 1151 (m), 1083 (s, C O), 1024 (m), 921 (m), 795 (m). 1 H NMR (600 MHz, CD3 OD): δ (ppm) = 3.40–3.43 (m, 4 -H, numbering see Scheme 12), 3.48 (dd, 3 J2 ,3 = 9.4 Hz, 1H, 2 -H), 3.71–3.92 (m, 14H, 3 -H, 6a -H, 3× COOCH3 , 2 -H, 6b -H, 3 -H), 4.23–4.25 (m, 2H, 4 -H, 5 -H), 4.27 (d, 3 J3,4 = 5.6 Hz, 1H, 3-H), 4.38 (d, 3 J4,5 = 5.4 Hz, 1H, 4-H), 4.44 (d, 1H, 5-H), 4.59 (d, 3 J   = 5.5 Hz, 1H, 5 -H), 5.02 (d, 3 J   = 3.7 Hz, 1H, 1 4 ,5 1 ,2 H), 5.26 (d, 3 J1 ,2 = 3.8 Hz, 1H, 1 -H).13 C NMR (151 MHz, CD3 OD): δ (ppm) = 53.0, 53.1, 53.9 (3 q, COOCH3 ), 67.3 (t, C-6 ), 69.3 (d, C-2 ), 70.5 (d, C-3 ), 71.2 (d, C-4 ), 71.7 (d, C-4 ), 72.0 (d, C-5 ), 72.9 (d, C-2 ), 74.8 (d, C-3 ), 77.2 (d, C-4), 80.0 (d, C-3), 82.2 (d, C-5), 96.8 (d, C-1 ), 99.7 (d, C1 ), 105.5 (d, C-2), 169.9 (s, C-1), 171.7 (s, C-6 ), 171.9 (s, C-6). MS (ESI/MS, ES+): m/z (%) = 611 (25) [M + Na+ ], 375 (45) [M + Na+ H3 COOC C4 H6 O4 COOCH3 , ␣-cleavage], 259 (100) [H3 COOC C4 H6 O4 COOCH3 + Na+ ], 199 (5) [259 − CO CH3 OH], 141 (7) [199 − CO CH2 O], 23 (12) [Na+ ]. C21 H32 O19 (588.47): calcd. C 42.86, H 5.48; found C 41.57, H 5.34. C21 H32 O19 + Na+ (M = 588.47 + 22.98) HR-MS (ESI, ES+): calcd. ion mass 611.1436; found 611.1453. 2.2.7. Dimethyl 4-O-(methyl-α-dglucopyranosyluronate)-d-glucuronate (37a) d-Maltose-monohydrate (36) (720 mg, 2.00 mmol) and TEMPO (3, 156 mg, 1.00 mmol) in 80 ml sodium carbonate buffer (pH = 10) were electrolyzed as raffinose 24, until 5617 C (29.1 F for 12 electrons per mole) were consumed at currents between 170 and 2 mA. In the work-up, as with 24, 829 mg of crude product was obtained, from which 177 mg were converted into the ester and purified by flash chromatography (ethyl acetate:methanol = 6:1) to yield the triester 37a (104 mg from 177 mg crude product, which corresponds to 487 mg, 1.14 mmol, 57% from 829 mg crude product) as a colourless, viscous liquid. [α]20 D : −69.8 (c = 1.00, MeOH). Rf -value: 0.11 (ethyl acetate:methanol = 6:1). FT-IR (film): ν˜ (cm−1 ) = 3388 (s, br., O H), 2959 (w, C H), 1740 (s, C O), 1645 (w), 1442 (m, C H-def.), 1230 (m), 1147 (m), 1045 (s, C O), 964 (m),

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923 (m). 1 H NMR (400 MHz, CD3 OD): δ (ppm) = 3.52–3.57 (m, 2H, 2 -H, 4 -H, numbering see Scheme 16), 3.65–3.69 (m, 1H, 5 -H), 3.81, 3.82 (2 s, 9H, 3× COOCH3 ), 4.09 (dd, 3 J4,5 = 3.2 Hz, 1H, 4-H), 4.29 (dd, 3 J3,4 = 7.5 Hz, 3J 3  2,3 = 1.9 Hz, 1H, 3-H), 4.35 (d, J2 ,3 = 10.3 Hz, 1H, 3 -H), 3 4.44 (d, 1H, 2-H), 4.51 (d, 1H, 5-H), 5.15 (d, J1 ,2 = 3.6 Hz, 1H, 1 -H). 13 C NMR (100 MHz, CD3 OD): δ (ppm) = 53.0, 53.1 (3 q, COOCH3 ), 72.6 (d, C-2), 73.3 (2 d, C-4 , C-5), 73.7 (d, C-2 ), 73.8 (d, C-3), 73.9 (d, C-3 ), 74.6 (d, C-5 ), 86.0 (d, C-4), 103.6 (d, C-1 ), 172.3 (s, C-6 ), 173.9 (s, C-6), 174.7 (s, C-1). MS (ESI/MS, ES+): m/z (%) = 451 (65) [M + Na+ ], 391 (9) [M + Na+ CH3 OH CO], 361 (15) [391 − CH2 O], 261 (100) [CH3 OOC C4 H8 O4 COOCH3 + Na+ , ␣-cleavage], 201 (5), 171 (7), 23 (43) [Na+ ]. C15 H24 O14 (428.35): calcd. C 42.06, H 5.65; found C 40.74, H 5.56. C15 H24 O14 + Na+ (M = 428.35 + 22.98) HR-MS (ESI, ES+): calcd. ion mass 451.1064; found ion mass 451.1065.

2.2.8. Pentaacetyl-37a Crude sodium salt 37c (2.84 g) was converted into the trimethylester, which was transformed into the white solid pentaacetate 37a (1.56 g). For that the crude product was dissolved in methanol (100.0 ml) and then 2,2dimethoxypropane (10.0 ml, 82 mmol) and 10 drops of conc. HCl were added. After stirring for 1 day the solution was neutralized with triethanolamine and the solvent rotaevaporated. To the remaining solid pyridine (40 ml) and acetic anhydride (20 ml) were added. After 1 day stirring at room temperature most of the solvent was rotaevaporated and residual solvent removed by azeotropic distillation with toluene (3× 100 ml). The remaining product was purified by flash chromatography (cyclohexane:ethyl acetate = 1:1). Rf -value: 0.17 (cyclohexane:ethyl acetate = 1:1). m.p. 56–57 ◦ C. FT-IR (film): ν˜ (cm−1 ) = 3064, 2959, 2853 (w, C H), 1742, 1733 (s, C O), 1643 (w), 1439 (m, C H-def.), 1375 (m), 1228 (m), 1044 (s, C O), 964 (m), 930 (m), 736 (s). 1 H NMR (400 MHz, CDCl3 ): δ (ppm) = 2.00–2.16 (6 s, 18H, CH3 ), 3.73, 3.75, 3.89 (3 s, 9H, 3× COOCH3 ), 4.31–4.33 (m, 1H, 4-H), 4.66 (d, 3 J4 ,5 = 3.2 Hz, 1H, 5 -H), 4.88 (dd, 3 J1 ,2 = 3.6 Hz, 3 J   = 10.4 Hz, 1H, 2 -H), 5.12 (t, 3 J   = 9.6 Hz, 1H, 2 ,3 3 ,4 4 -H), 5.24–5.29 (m, 2H, 1 -H, 2-H), 5.36–5.41 (m, 2H, 5-H, 3 -H), 5.70 (dd, 3 J2,3 = 2.2 Hz, 3 J3,4 = 7.7 Hz, 1H, 3-H). 13 C NMR (100 MHz, CDCl3 ): δ (ppm) = 20.3–20.6 (6 q, CH3 ), 52.8, 53.0 (3 q, COOCH3 ), 68.5 (d, C-3 ), 69.0 (d, C-5 ), 69.3 (d, C-4 ), 70.0 (d, C-2 ), 70.6 (2 d, C-1 , C-2), 71.3 (d, C-5), 71.5 (d, C-3), 76.4 (d, C-4), 96.7 (d, C-1 ), 166.6 (s, C-6), 167.1 (s, C-1), 168.0 (s, C-6 ), 169.3-170.3 (6 s, COO). MS (ESI/MS, ES+): m/z (%) = 703 (62) [M + Na+ ], 643 (43) [M + Na+ HOAc], 583 (18) [M + Na+ 2HOAc], 541 (15) [M + Na+ 2HOAc CH2 CO], 387 (100) [CH3 OOC C4 H5 O(OAc)3 COOCH3 + Na+ , ␣-cleavage], 357 (5) [CH3 OOC C4 H3 (OAc)3 CH(OH)O + Na+ ], 327 (15) [387 − HOAc], 203 (65), 185 (82), 141 (67), 23 (38) [Na+ ]. C27 H36 O20 (680.57): calcd. C 47.65, H 5.33; found C 47.89, H 5.35.

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2.2.9. Dimethyl 4-O-(α-d-glucopyranosyl)-dglucuronate (38a) and methyl 4-O-(methyl α-dglucopyranosyluronate)-d-glucosyluronate (38b) Maltose-monohydrate (36, 12.16 g, 33.75 mmol) and TEMPO (3, 1.76 g, 11.3 mmol) in carbonate buffer (450 ml, pH 11.5) were electrolyzed at 5 ◦ C and 0.84 A as raffinose 24. After 5.3 F the electrolysis was interrupted for 16 h and then continued until further 5.0 F were consumed, after that the electrolysis was again interrupted for 16 h. Then it was electrolyzed with further 3.1 F and the reaction worked up as in the case of 24. From 12.36 g crude product 1.52 g were converted to esters, from which by flash chromatography (ethyl acetate:methanol = 6:1) trimethyl ester 37a (150 mg, 0.35 mmol, 8%) and the dimethyl esters 38a,b (321 mg, 0.80 mmol, 19%) were isolated as colourless, viscous liquids. Rf -value: 0.05 (ethyl acetate:methanol = 6:1). 1 H NMR (400 MHz, CD OD): δ (ppm) = 3.5–3.6 (m, 1H, 4 3 H), 3.65–3.8 (m, 1H, 2 -H), 3.8–3.95 (m, 3H, 5 -H, 6-H, 6 H), 3.96–4.08 (m, 6 H, CH3 ), 4.1–4.15 (m, 1H, 3 H), 4.28–4.35 (m, 1H, 4-H), 4.42–4.5 (m, 1H, 3-H), 4.6–4.7 (m, 1H, 2-H), 4.78–4.82 (m, 1H, 5-H), 4.98–5.05 (m, 7H, OH), 5.26–5.31, 5.37–5.41 (m, 1H, 1 -H). ESI/MS (ES+): m/z (%) = 423 (10) [M + Na+ ], 261 (16) [M + Na+ HOH2 C C5 H8 O3 ], 23 (100) [Na+ ].

3. Results and discussion 3.1. Oxidation of enaminoesters 1b–d and enamine 7 with TEMPO+ (4) 3.1.1. Cyclovoltammetry Enaminoesters have been anodically dimerized to symmetrical pyrroles. For instance methyl (Z)-3-benzylamino2-butenoate (1a, Scheme 1) yielded 47% of 1-benzyl-2,5dimethyl-3,4-dimethoxycarbonyl-pyrrole (2) upon electrolysis in methanol/sodium perchlorate at a graphite anode (Scheme 2) [17]. The indirect electrolysis of enaminoesters

Scheme 3. Redox-reaction between TEMPO (3) and TEMPO+ (4).

has not been studied yet. It therefore appeared of interest to investigate their TEMPO-mediated conversion and compare the products with these of the direct anodic oxidation. In cyclovoltammetry a 9 mM solution of TEMPO (3) in acetonitrile (0.1 M TBAClO4 ) exhibits at a platinum electrode a chemically reversible (ip,c /ip,a = 1.0) oxidation to TEMPO+ (4, Scheme 3, insert in Fig. 1b). The forward scan shows the oxidation potential Ep,a = 0.81 V (versus Ag/AgCl, scan rate 0.1 V/s) and on the reverse scan this for the reduction of TEMPO+ (4) to TEMPO (3) at Ep,c = 0.71 V. Enaminoester 1c shows under identical conditions a first oxidation peak at Ep,a = 1.03 V with a (Ep − Ep/2 ) of 58 mV, which suggests a quasireversible electron transfer. A missing reduction peak in the reverse scan indicates a fast reaction of the anodically generated intermediate (Fig. 1a). In the cyclovoltammogram of a 1:0.9-mixture of enaminoester 1c and TEMPO (3) (Fig. 1b) the oxidation peak of 3 is cathodically shifted by 90 mV to 0.72 V. The cyclovoltammogram of the mixture can be interpreted as follows: TEMPO (3) is oxidized to TEMPO+ (4). A fast follow-up reaction between the cation 4 and enaminoester 1c decreases the concentration of 4 at the electrode surface, which causes a cathodic shift of the oxidation potential of TEMPO. The cation 4 possibly reacts in an electrophilic addition with the double bond of 1c to afford the intermediate cation 5 (Scheme 4, path (a)). Electrophilic additions of TEMPO+ and analogous oxopiperidinium salts to enols, silylenolethers and other olefins have been reported [8d,18]. Conceivable, but less probable, is also an endergonic electron transfer between enaminoester 1c and 4 to yield TEMPO and the radical cation 6 followed by a fast heterocoupling (Scheme 4, path (b)).

Scheme 1. Selected enaminoesters used in this study.

Scheme 2. Anodic dimerization of enaminoester 1a (Bzl = benzyl) to pyrrole 2.

Scheme 4. Heterocoupling of TEMPO+ (4) and enaminoester 1c by (a) electrophilic addition or (b) electron transfer and radical combination.

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Fig. 1. Anodic oxidation in acetonitrile (0.1 M TBAClO4 ), v = 0.1 V/s vs. Ag/AgCl: (a) 0.01 M enaminoester 1c; (b) 0.009 M TEMPO (3) and 0.01 M enaminoester 1c; dotted line TEMPO without 1c.

The CV of enaminoester 1c and TEMPO (3) was simulated with Digisim® 3.0 using the mechanism proposed above [19]. There the simulated values (Ep = 0.725 V and ip = 0.340 mA) agreed well with the experimental ones (Fig. 1b) and the oxidation peak for enaminoester 1c as well as the reduction peak for TEMPO+ had disappeared in the simulation. Enaminoester 1b shows an Ep,a = 1.32 V with a (Ep − Ep/2 ) of 66 mV. The missing +I-effect (inductive effect of an electron donating substituent) of the 2-Me group in 1c causes in 1b the shift of Ep,a by 0.29 V to a more positive potential. The cyclovoltammogram (CV not shown) of 0.01 M of enaminoester 1b and 0.009 M of TEMPO shows a broadened oxidation peak of TEMPO and neither an oxidation peak of enaminoester 1b, nor a reduction peak of TEMPO+ . This behaviour again suggests a chemically irreversible reaction of TEMPO+ with enaminoester 1b. With enaminoester 1b the potential shift of TEMPO (3) is very small, which is in accord with a lower reaction rate between 1b and 3 due the smaller nucleophilicity

of enaminoester 1b in the electrophilic addition or a slower electron transfer due to the higher oxidation potential of 1b. The enamine: 1-pyrrolidino-cyclohexene (7) is oxidized at a much lower potential than enaminoester 1b or 1c namely at 0.49 V, which is due to the missing electron attracting ester group (Fig. 2a). The CV of a 0.9:1-mixture of TEMPO (3) and enamine 7 shows two peaks at 0.39 and 0.46 V (Fig. 2b). The peak at Ep,a = 0.39 V is assigned to the oxidation of enamine 7 to its radical cation 8, which reacts with TEMPO (3) to afford the adduct 9 (Scheme 5). This fast follow-up reaction, compared to the slower reaction of the radical cation 8 in the absence of TEMPO (3), leads to a cathodic shift of the oxidation potential. The experimental CV of the mixture of enamine 7 and TEMPO (3) with Ep = 0.38 V, ip = 0.35 mA could be calculated with Digisim® 3.0 using the proposed mechanism [20]. The second peak (Ep = 0.46, ip = 0.32 mA) in the CV can be assigned to the oxidation of enamine 7 to the radical cation

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Fig. 2. Anodic oxidation in acetonitrile (0.1 M TBAClO4 ), v = 0.1 V/s vs. Ag/AgCl: (a) 0.01 M enamine 7; (b) 0.009 M TEMPO (3) and 0.01 M enamine 7; dotted line TEMPO without 7.

8, when TEMPO near the electrode has been totally consumed. An increase of the concentration of the enamine 7 in the experimental CV as well as in the simulated CV increases this peak [20]. Thus in the mixtures of the enaminoesters 1b,c and the enamine 7 no mediated oxidation with TEMPO as catalyst is detected, but instead an irreversible reaction with the formation of a covalent bond between the substrate and TEMPO is

Scheme 5. Coupling of enamine 7 with TEMPO via the radical cation 8.

found. In the case of the enaminoesters 1b,c, which are harder to oxidize than TEMPO (3), this is converted to TEMPO+ , which reacts with the enaminoesters 1b,c. In the case of enamine 7, which is more facile oxidized than TEMPO, the enamine 7 is oxidized to its radical cation 8, which combines with TEMPO. To get some information on the follow-up reactions of the first formed intermediates, which were suggested from the cyclovoltammograms, the enaminoesters 1c,d and the enamine 7 were reacted with stoichiometric amounts of TEMPO+ (4) in a preparative scale. These conversions were done with TEMPO+ (4) to avoid direct anodic oxidations of the enamines and the intermediates. 3.1.2. Preparative scale conversion of the enaminoesters 1c,d with TEMPO+ (4) TEMPO+ BF4 − (4-BF4 ) was prepared in 87% yield as yellow salt by disproportionation of TEMPO (3) into TEMPO+

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Scheme 6. Reaction of enaminoester 1c with TEMPO+ (4).

(4) and the hydroxylamine 12 [21]. The reaction of stoichiometric amounts of 4-BF4 and enaminoester 1c in acetonitrile at room temperature afforded 45% of the imidazolium salt 10a, the piperidinium salt 11 and the hydroxylamine 12 (Scheme 6). The structure of 10a has been assigned by means of IR, 1 H, 13 C NMR-spectroscopy and mass spectrometry. In the IR-spectrum two ester carbonyl absorptions at 1736 and 1683 cm−1 refer to an ester group at a saturated and an unsaturated carbon atom, respectively. Two C C stretching vibrations appear at 1597 cm−1 for the double bond in the enaminoester and at 1499 cm−1 for the imidazolium ring. The 1 H NMR shows two singlets at 2.04 and at 2.09 ppm for the vinylic methyl group at C7. The methyl group at C12 appears in two doublets at 1.37 ppm and 1.53 ppm. The vinylic hydrogen in the imidazolium ring is visible in two singlets at 6.84 and 7.04 ppm. The N H proton is found at 6.18 and 6.59 ppm. The 13 C NMR supports with a doublet at 120.1 ppm and a singlet at 134.7 ppm the C C double bond in the imidazolium ring. The signals for the C C double bond in the enamino ester appear as singlets at 105.0 and 135.6 ppm. The methine group at the saturated ester is present as doublet at 36.3 ppm. The chemical shifts in the 13 C NMR correspond to assignments made for the corresponding imidazolium structures in [22,23], which are shown in Table 1. Further support of the structure was obtained by C,H-correlations using long range NMR-couplings and NOE-experiments [24]. The 1 H NMR signals are doubled (ratio 1:1.46 to 1:1.78). The reason is unclear. The compound has only one stereogenic center and the double bond of the enaminoester has only the E-configuration, which excludes diastereomers and E/Z-mixtures. Possibly the free rotation around the C2 C6 bond (numbers in Scheme 6) is restricted for electronic and/or steric reasons.

Finally the structure of 10a is supported by the ESI(+)-MS with the M+ at m/z = 566 and in the ESI(−)-MS the BF4 -anion appears at m/z = 87. The exact mass of 10a agreed with the empirical formula. Crystals of the imidazolium 10a-salts for an X-ray diffraction analysis could not be obtained. With 10a-BF4 and 10aClO4 diffusion experiments of diethyl ether or of petroleum ether into acetonitrile or dichloromethane solutions of the salts or the slow cooling of saturated acetonitrile, methanol or dimethyl sulfoxide solutions did not lead to crystals. To explain the unexpected formation of the imidazolium cation 10a the following pathway (Scheme 7a and b) is tentatively proposed: the reaction starts with the electrophilic addition of TEMPO+ to the enaminoester 1c to form cation 5, as was already proposed in Scheme 4. The adduct 5 then can undergo a number of consecutive reactions. An intramolecular proton transfer forms the protonated O-allylhydroxylamine 13, whose SN 2 -reaction with enaminoester 1c as nucleophile and the hydroxylamine 12 as leaving group affords the enaminoester-dimer 14. This

Table 1 Chemical shifts of the atoms in the imidazolium ring in 10a and 10b

Compound 10a Compound 10b Al Mourabit [22] Gouesnard and Dorie [23] a

C-2

C-4

C-5

5-H

141.1 141.5 137.6 138.4

134.7 133.6 134.9 –a

120.1 120.0 127.7 –a

7.04 6.98 7.94 –a

Ref. [23] gave no chemical shifts for these atoms.

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Scheme 7. (a) Proposed reaction of enaminoester 1c to the enaminoestertrimer 15. (b) Proposed conversion of the enaminoester-trimer 15 to the imidazolium cation 10a.

repeats the reaction with enaminoester 1c, which leads to the enaminoester-trimer 15 (Scheme 7a). At the trimer 15 the hydroxylamine 12 can initiate a cleavage at the terminal enaminoester group, which produces the substituted enaminoester-dimer 17, piperidine 11 and ethyl 2-methyl-3oxobutanoate (16). Addition of TEMPO+ (4) to the dimer 17 generates the protonated O-allylhydroxylamine 18, that cyclizes to the dihydroimidazole 19. Dehydrogenation of 19 by addition of TEMPO+ and elimination of hydroxylamine

12 followed by a final 1,3-proton shift leads to the imidazolium cation 10a (Scheme 7b). In the reaction of enaminoester 1c with TEMPO+ perchlorate it was possible to isolate imidazolium cation 10a-perchlorate by flash chromatography in 89% yield. With enaminoester 1c and 4-acetylamino-TEMPO+ tetrafluoroborate 45% of 10a-BF4 together with 45% of piperidine 11-HBF4 and 37% of hydroxylamine 12-HBF4 were obtained. The mediated electrolysis of enaminoester 1c with TEMPO was also investigated. From an electrolysis in acetonitrile (0.1 M TBABF4 ) at 0.7 V in an divided cell after 1 F a possibly formed imidazolium 10a-BF4 could not be separated from the supporting electrolyte. However, the perchlorate of the imidazolium cation 10a could be prepared electrochemically. For that TEMPO was first oxidized in acetonitrile (0.1 M LiClO4 ) in the anode chamber of a divided cell and subsequently one equivalent of enaminoester 1c was added. In the work-up the supporting electrolyte could be extracted into the aqueous phase and 27% of 10a-ClO4 could be isolated. With enaminoester 1d and TEMPO+ the imidazolium salt 10b was obtained in 21% yield. Further products except for the hydroxylamine 12 could not be isolated. The spectra of 10a and 10b are nearly identical except for the signals of the ethyl group in 10b, which replace this of the methyl group in 10a. The structure of 10b was also assigned using NMRspectroscopy by C,H-correlations with long range couplings and NOE-experiments. In 10b as in 10a the signals are doubled (ratio 1:2). In contrast to the direct anodic oxidation of methyl enaminoester 1a which affords 47% of the pyrrole 2 (Scheme 2) [17], the TEMPO+ oxidation of the corresponding ethyl enaminoester 1b led to many uncharacterized products and only traces of the corresponding imidazolium salt could be detected by ESI-MS. In a further preparative scale conversion 3.0 mM of TEMPO+ (4) and 3.0 mM of enamine 7 were reacted at room temperature in acetonitrile. An ESI-MS taken after 6 h from the reaction solution showed m/z = 307, pointing to the formation of the cation 9, which was already postulated from the CV-experiment (Fig. 2, Scheme 5). The aqueous workup afforded 50% of the alkoxyamine 20a, which is produced by hydrolysis and elimination of pyrrolidine from the cation 9 (Scheme 8). The formation of alkoxyamine 20a by reaction of TEMPO+ (4) with enamine 7 indicated a short route

Scheme 8. Reaction of enamine 7 with TEMPO+ to alkoxyamine 20a.

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Scheme 9. Alkoxyamine 20b by reaction of the sodium salt of ethyl acetoacetate (21) with TEMPO+ (4).

to alkoxyamines, namely the reaction of enolates with TEMPO+ . This was indeed the case. The sodium salt of ethyl acetoacetate (21) and TEMPO+ (4) afforded alkoxyamine 20b in 87% yield (Scheme 9). Subsequently further alkoxyamines were obtained similarly [25]. This method supplements nicely alkoxyamine syntheses by reaction of TEMPO+ with enolizable ketones via their enols [18a] or the coupling of lithium enolates and TEMPO with CuCl2 as stoichiometric oxidant [26]. Alkoxyamines are of timely interest because they are used as mediators in the living radical polymerization of styrene and acrylates leading to polymers with a low polydispersity [27]. Furthermore they can be applied to the free radical addition of substituted alkyl groups and TEMPO to aliphatic alkenes [28]. 3.2. TEMPO-mediated oxidations of carbohydrates 3.2.1. Oxidation of d-raffinose (24), d-cellobiose (26), d-lactose (30) and d-maltose (36) The selective oxidation of primary hydroxy groups in carbohydrates has received great interest [29]. Most frequently applied methods are the catalytic oxidation with noble metals and oxygen [29c,30–32] or stable nitroxyl radicals with cooxidants (often sodium hypochlorite) [6a,33]. For the latter method the use of the anode as cooxidant is an alternative. Recently several examples of anodic carbohydrate oxidations with TEMPO as mediator have been reported [4]. The oxidation of alcohols with TEMPO+ is a base catalyzed reaction and involves nucleophilic addition of the alcohol to the N O group followed by an intramolecular ␤elimination leading to the aldehyde (Scheme 10) [6a]. In aqueous medium the hydrate of the aldehyde is further oxidized in a similar way to the carboxylic acid. In alkaline medium the hydroxylamine 12, the reduction product of TEMPO+ , symproportionates with TEMPO+ to TEMPO, which is anodically regenerated to TEMPO+ . The increase

Scheme 10. Mechanism of the base catalyzed oxidation of alcohols with TEMPO+ [6a].

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of the catalytic efficiency with pH in the TEMPO-mediated anodic oxidation of methyl-␣-d-glucopyranoside has been shown by cyclovoltammetry [4a]. With 0.2 equiv. of TEMPO (3) in an undivided cell at a graphite anode in a carbonate buffer several methyl glycosides of monosaccharides, nonreducing disaccharides as trehalose and saccharose, cyclodextrins and starch have been oxidized to the corresponding uronic acids in fair to good yield [4a]. Recently results on the oxidation of methyl glycosides of ketohexoses, of methyl 2-acetylamino-␤-dglucoside, of methyl glycosides of reducing disaccharides (Scheme 11) and of 1-azido disaccharides have been reported [4c]. Here the more complex carbohydrates d-raffinose, dcellobiose, d-lactose and d-maltose are studied to probe the scope of the TEMPO-mediated anodic oxidation. Raffinose is a trisaccharide and contains a furanoside structure with two primary hydroxyl groups, whose behaviour in anodic oxidation is barely characterized. In the disaccharides the laborious four-step protection of the anomeric center has been omitted, to probe, whether a loss of selectivity is caused by this significant simplification of the method. For d-maltose a scale-up is intended. Raffinose (24), a nonreducing trisaccharide, that consists of galactose, glucose and fructose units, is found in larger amounts in cotton seed. It could be oxidized with high selectivity at the three primary hydroxy groups in the presence of eight secondary hydroxy groups (Scheme 12). The disaccharide: d-saccharose, that contains also a furanoside unit afforded only 39% of the corresponding trisuronic acid [4a]. For carbohydrate oxidations the following reactivity of substituents (ordered with increasing reactivity) at the carbohydrate skeleton has emerged: ␣- and ␤alkoxy, ␤-azido, equatorial N-acetylamino, equatorial secondary hydroxy ≤ axial secondary hydroxy, C C-double bond < primary hydroxy < hemiacetal hydroxy. This means, that for the selective oxidation of the primary hydroxy group with retention of the hemiacetal this group needs to be protected. The usual protection, which is glycosidation, involves four synthetic steps, namely peracetylation, C1-bromination, substitution of the bromide by methoxide and deacylation. If one can accept the oxidation of the hemiacetal to a lactone, the avoidance of these additional steps would improve the value of the oxidation method. Therefore the selectivity for the oxidation of reducing disaccharides with an unprotected hemiacetal was investigated for d-cellobiose (26), d-lactose (30) and d-maltose (30). d-Cellobiose can be obtained enzymatically from cellulose. It was oxidized in an undivided cell with 0.5 equiv. of TEMPO at 20 ◦ C and potential controlled at 0.53 V (versus SCE) until 8 F were consumed. This corresponds to 0.8 oxidation equivalents for the conversion of the hemiacetal to the lactone (2 F) and the two primary hydroxy groups to carboxylic acids (8 F). Analysis of the crude product by GC–MS (after trifluoroacetoxylation with MSTFA) and ESI-MS showed six peaks for products derived from

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Scheme 11. TEMPO-mediated selective anodic oxidation of methyl ␣-d-cellobiose (22) and methyl ␣-d-maltose (23) [4c].

monosaccharides and seven peaks for products derived from disaccharides with a ratio of monosaccharides:disaccharides of about 1:2. From the ESI-MS the lactone of glucaric acid (27), tartaric acid (28) and hydroxymalonic acid (29) could be identified by comparison of their MS-spectra with these of authentic compounds (Scheme 13). Furthermore nine more or less oxidized disaccharide structures could be deduced from the mass spectra (Scheme 14).

d-Lactose (30), the disaccharide: 4-(␤-d-galactopyranosyl)-glucopyranose is available in large quantities (about 300,000 t/year). In a controlled potential electrolysis (0.53 V versus SCE), as this of d-cellobiose (26), with 0.25–1 equiv. of TEMPO and a current consumption of 10–20 F (theoretical amount 10 F) a full conversion of d-lactose (30) was achieved with a mass balance of 96–115% [34]. At least five products were indicated by

Scheme 12. TEMPO-mediated selective anodic oxidation of d-raffinose (24) to trimethyl d-raffinose trisuronate (25).

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Scheme 13. Lower molecular weight compounds from the TEMPO-mediated oxidation of d-cellobiose (26) by comparison of the ESI-MS spectra with those of authentic compounds [26 appeared as sodium adduct, 27–29 as carboxylates in (−)ESI, in parenthesis relative intensities].

thin layer chromatography, which, however, could not be separated by preparative chromatography. The most probable product structures were assigned by ESI-MS (Scheme 15). The relative product distribution is indicated by the ion currents (in parenthesis). Besides the disaccharide structures as the mono-, di- and tricarboxylic acids 32–34 and the diketoproduct 35 mainly the cleavage product, the monosaccharide:galactaric acid (31) is found. This unselective conversion of d-lactose, a ␤(1–4)-disaccharide, corresponds to the behaviour of d-cellobiose, which is also a ␤(1–4)-connected disaccharide. d-Maltose (36) can be obtained enzymatically with amylase from starch. It was oxidized under the same conditions as d-cellobiose (26, Schemes 13 and 14) until the current had decreased to 5 mA. At this point 29.1 F had been consumed corresponding to 2.91 oxidation equivalents (10 F for the conversion of two primary hydroxyl groups to two carboxylic acids and one hemiacetal to one lactone). After work-up and treatment with dimethoxypropane (DMP/HCl/MeOH) the trimethyl ester 37a could be isolated in 57% yield (Scheme 16). No d-maltose could be detected in the crude product and besides the triacid 37b with M = 386 g/mol in the mass spectrum no products with M = 384 or 382 g/mol were found, which indicated that no additional oxidation at secondary OH groups had occurred. This way the tricarboxylic acid 37b could be obtained in one step from d-maltose avoiding the four-step protection of the hemiacetal. The yield of 37a is with 57% similar to the 61% found in the oxidation of methyl ␤-d-maltose (23) (Scheme 11). Whilst the ␣(1–4)-disaccharide: d-maltose (36) is selectively oxidized at the primary hydroxy groups and the hemiacetal to the tricarboxylic acid 37b, the oxidation of the ␤(1–4)-disaccharides: d-cellobiose (26) and d-lactose (30) is accompanied by the conversion of secondary hydroxy groups and disintegration to lower molecular weight carboxylic acids. This result is in contrast to the oxidation of

the methyl glycosides of d-maltose and d-cellobiose, which are oxidized with similar yields, namely 61 and 69%, respectively (Scheme 11) [4c]. This result points to the hemiacetal function in 26, 30 and 36 as a possible reason for the different selectivity. Depolymerization of polysaccharides has been reported during TEMPO-mediated oxidations, whose extent increases at pH values above 10 [35]. If this finding is applied to disaccharides it would mean a cleavage of the glycosidic bond by way of a ␤-elimination [35a], whose extent would be dependent on the pH and could be different for ␣(1–4)- and ␤(1–4)-disaccharides. Taking this into account possibly a more selective mediated oxidation of d-cellobiose (26) and d-lactose (30) can be developed by an adaptation of the pH. 3.2.2. Scale-up of the mediated oxidation of d-maltose (36) Up to now we had always oxidized 2 mmol of the carbohydrates. To demonstrate a larger scale conversion of an unprotected disaccharide, d-maltose was chosen, because it is readily available and can be selectively oxidized (Scheme 16). At first the quantitative determination of the tricarboxylic acid 37b in the crude product was established. For that either triacid 37b was precipitated as sodium salt or the triacid was converted into the trimethylester, which was isolated by chromatography. The first procedure affords a product, which also contains the sodium salts of the mono- and diacids as side products, the second method yielded the pure triester. Accordingly the yields of the less pure sodium salt are higher than these of the triester, which also are lowered by losses in the chromatographic separation. The sodium salts were prepared, by first removing all sodium cations of the buffer with a cation exchanger. Thereafter the pH was adjusted with sodium hydroxide to 8–9 and this way the free uronic acids were converted into their sodium salts. From the concentrated solutions the sodium salts were precipitated

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Scheme 14. Proposed structures of higher molecular weight compounds in the TEMPO-mediated oxidation of d-cellobiose (26) [26 appeared as sodium adduct, the uronic acids as carboxylates in (−)ESI, in parenthesis relative intensities].

by addition of methanol. The results of the electrolyses are summarized in Table 2. At the beginning of the scale-up experiments the small scale oxidation of d-maltose (electrolysis 0, Table 2) was reproduced (electrolysis 1). Then the platinum cathode in the undivided cell was exchanged for a graphite electrode (electrolysis 2). A graphite anode and cathode would be needed, to perform the electrolysis later in a capillary gap cell. This exchange reduced the yield from 52 to 39% of ester 37a, although the amount of the mediator TEMPO had been doubled from 0.5 to 1 equiv. Thereafter with the same portion of the mediator and an increased electrode surface a six-fold amount of maltose was

electrolyzed at a graphite anode and a platinum cathode (electrolysis 3), which led to a fair yield of ester 37a. Exchange of the platinum cathode against a graphite cathode decreased again the yield of ester 37a (electrolysis 4). Subsequently the amount of d-maltose (36) and the area of the anode surface was increased three-fold, the area of the platinum cathode was left unchanged and the TEMPO portion was decreased to 0.33 equiv. (electrolysis 5). The yield corresponded to this in electrolysis 4. With the protocol of the current versus time values in the potential controlled electrolysis 5 the following electrolysis 6 was conducted current controlled, which would be a technically feasible procedure. The result was a smaller current consumption, but also a

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Scheme 15. Anodic oxidation of lactose (30) with TEMPO as mediator [30 appeared as sodium adduct, the uronic acids as carboxylates in (−)ESI, in parenthesis relative intensities].

decreased yield. By increasing the current density in the different time intervals the duration of the electrolysis could be further decreased, however, the selectivity for the triacid 37b decreased too and the electrolyte changed its colour to brown (electrolysis 7, not shown in the table). The product consisted of mono-, di- and triacid, from which the latter could not be isolated. The insufficient oxidation indicated a decreased current yield. The reason could be an electrochemical short circuit by cathodic reduction of TEMPO+ , as the rate of its formation was increased, whilst the consumption

Scheme 16. TEMPO-mediated anodic oxidation of d-maltose (36).

through the carbohydrate oxidation remained constant. To overcome this drawback the cathode surface was decreased from 90 to 16 cm2 (quasi-divided cell), which should lead to a preferred reduction of protons instead of TEMPO+ cations. However, neither could the colouring be prevented, nor was the yield increased (electrolysis 8 and 9). In a further scale-up 48.6 g (135 mmol) of d-maltose (36) were electrolyzed at a constant current of 1.3 A up to a consumption of 11 F, which led to an intensely brown coloured electrolyte und the increased formation of side products, which were detected by ESI-MS (electrolysis 10). A reason for the lower selectivity could be the decrease of pH due to the exchange of the carbonate anion in the buffer against the salts of the more acidic uronic acids in the course of the electrolysis, which leads to a decreased reaction rate of TEMPO+ . This apparently favours a direct anodic oxidation, which is less selective and competes with the oxidation by TEMPO+ . To adapt the oxidation rate of TEMPO to this of the carbohydrate, d-maltose (36, 24.5 g, 67.5 mmol) was electrolyzed in electrolysis 11 with a smaller current (1 A for 3.6 h, 0.5 A for 14.4 h and 0.2 A for 36.2 h). After 10 F the colouring still appeared and all three carboxylic acids (mono-, di- and tricarboxylic acid) were found in about equal portions. To increase the pH in electrolysis 12, d-maltose was oxidized under the same conditions as in electrolysis 11, but with addition of two portions of sodium carbonate (5 g each). The colouration now had decreased considerably and 34% of triester 37a could be isolated. In the current controlled

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Table 2 Conditions and yields in the optimization of the d-maltose (36) oxidation Electrolysisa

Scale amount of 36 (mmol)

Ratio 36:3

Anode area (cm2 )

Yield of ester 37a (%)

Yield of salt 37cb (%)

0 (p)c 1 (p) 2 (p) 3 (p) 4 (p) 5 (p) 6 (g) 8 (g) 9 (g) 10 (g) 11 (g) 12 (g) 15 (g) 16 (g) 19 (g) 20 (g)

2.00 2.00 2.00 11.25 11.25 33.75 33.75 33.75 33.75 135.0 67.5 67.5 67.5 33.75 33.75 at 45 ◦ C 33.75 at 5 ◦ C

2:1 2:1 1:1 1:1 1:1 3:1 3:1 3:1 3:1 12:1 6:1 6:1 6:1 3:1 3:1 3:1

8 8 8 45 45 90 90 90 90 90 90 90 90 90 90 90

57 52 39 49 42 42 31 15 17 – – 34 (m)d 39 (m) or 32(am)b,d 31 (m) 32 (m) + 10 diesterb 8 (m) + 19 diesterb

– – – 74 75 84 68 – – – – 70 – – – –

a b c d

Current consumption (F) 29.1 26.3 17.9 25.9 19.8 17.6 9.8 11.0 11.0 11.0 10.0 13.4 13.4 13.4 13.4 13.4

p = potential controlled; g = current controlled. See text. d-Maltose oxidation in Scheme 16. m = methylester; am = acetylated methylester.

electrolysis 15, additional to the carbonate buffer after each decrease of the current density, aqueous sodium hydroxide was added (at first electrolysis at 1 A [11.1 mA/cm2 ] in buffer for 2.07 F, then addition of 2.7 g NaOH and 0.5 A [5.6 mA/cm2 ] for 5.32 F, then addition of 3.6 g NaOH and 0.2 A [2.2 mA/cm2 ] for 2.61 F, then addition of 1.8 g NaOH and electrolysis at the same current for 3.4 F). This way the colouration could be totally suppressed and the yield of triester 37a could be increased to 39%. In order to leave time for TEMPO+ to react, the electrolysis was periodically interrupted (electrolysis 16: 6.6 F at 1 A, then 18 h without current, thereafter 5.5 F at 1.0 A, then 18 h without current, thereafter 1.3 F at 1.0 A). This procedure afforded a 31% yield of triester 37a. So far maltose had been always electrolyzed at room temperature. To study the effect of temperature on yield and selectivity maltose was oxidized additionally at 45 and 5 ◦ C. The electrolysis at 45 ◦ C (electrolysis 19, first 4.6 F at 0.835 A, then 16 h without current, thereafter 8.8 F at 0.835 A) afforded 32% of triester 37a and 10% of diester 38 (two isomers in which only one of the two primary hydroxyl groups is oxidized to a carboxylic acid). At 5 ◦ C (electrolysis 20, first 5.3 F at 0.84 A, then 16 h without current, thereafter 5 F at 0.84 A, then 16 h without current, thereafter 3.1 F at 0.84 A) afforded 8% triester 37a and 19% of diester 38. Thus at temperatures above or below room temperature the selectivity and the yield decreased. In summary for the oxidation of maltose the scale could be increased by a factor of 33 from 0.72 g (2 mmol) to 24.3 g (67.5 mmol) to afford the tricarboxylic acid isolated in 39% yield as trimethylester 37a (electrolysis 15). Further experiments for optimization of yield and selectivity in the scale-up have to consider the mediator concentration, the pH of the electrolyte, the duration of the current interruption,

or the development of a flow system with a divided cell for the TEMPO+ regeneration and a separate chemical reactor.

4. Conclusion The reaction of TEMPO and TEMPO+ with the enaminoesters 1 and the enamine 7 has been studied by cyclovoltammetry and preparative scale conversions. The primary hydroxy groups in the trisaccharide: d-raffinose and the disaccharides: d-cellobiose, d-lactose and d-maltose have been oxidized to tricarboxylic acids by mediated anodic oxidation with TEMPO. The following results were obtained: 1. TEMPO can be readily oxidized in acetonitrile at 0.81 V versus Ag/AgCl to TEMPO+ (4), which is fairly stable in this solvent. 2. According to cyclic voltammetry experiments and their simulation TEMPO+ reacts fast with enaminoester 1b and 1c. The enamine 7 is oxidized at a lower potential than TEMPO to a radical cation, that combines rapidly with TEMPO. 3. In a preparative scale conversion TEMPO+ reacts with enaminoester 1c to an imidazolium cation 10a. The product formation can be rationalized by an electrophilic addition of TEMPO+ at the enaminoester. Deprotonation can then lead to an allyloxyamine, which reacts with the enaminoester 1 in a SN 2 -reaction to a dimer. This sequence can repeat to form a trimer, which after a cleavage can undergo cyclization to the imidazolium cation 10a. Contrary to that the direct anodic oxidation of enaminoester 1a leads to a pyrrole derivative, whose formation can be explained by dimerization of two radical cations.

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4. The enamine 7 reacts with TEMPO+ to an addition product, which is hydrolyzed to an alkoxyamine. This result has led to a simplified synthesis of alkoxyamines, by the reaction of TEMPO+ with enolates [25]. Alkoxyamines are used as initiators for living radical polymerizations. 5. In an anodic oxidation mediated by TEMPO the trisaccharide: d-raffinose, which contains a galactose, glucose and fructose unit, has been selectively oxidized at the three primary hydroxyl groups to afford 63% of trimethyl draffinose trisuronate. 6. The disaccharides d-cellobiose, d-lactose and d-maltose have been oxidized, mediated by TEMPO, without protection of the anomeric center. Omitting the four-step protection strongly simplifies the oxidation. All disaccharides are selectively oxidized at the primary hydroxyl groups and the anomeric center. d-Cellobiose and d-lactose with a ␤(1–4) linkage, however, are cleaved to a larger extent. d-maltose with an ␣(1–4)-linkage affords the trisuronic acid without side reactions. In this case a 33-fold scale-up for the conversion of 24.3 g (67.5 mmol) d-maltose has been developed. In summary TEMPO is a stable radical, which is produced in a technical scale. Its anodic oxidation affords TEMPO+ , which is fairly stable in acetonitrile. TEMPO+ can react as electrophile and selective oxidant, which can be recycled in a number of cases. These properties offer interesting applications in synthesis and mediated oxidations.

Acknowledgements This work was supported through the Arbeitsgemeinschaft Industrieller Forschungsvereinigungen (AIF project No 13227N/1) by the Bundeswirtschaftsminister. We thank the Degussa AG for samples of TEMPO.

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[14] K.H. Chung, K.Y. Cho, Y. Asami, N. Takahashi, S. Yoshiba, Heterocycles 32 (1991) 99. [15] S.I. Yakimovich, V.A. Khrustalev, T.A. Favorskaya, J. Org. Chem. USSR (Engl. Transl.) 9 (1973) 1411. [16] M.E.F. Braibante, H.S. Braibante, L. Missio, A. Andricopulo, Synthesis (1994) 898. [17] D. Koch, H.J. Sch¨afer, Angew. Chem. 12 (1973) 841. [18] (a) T. Ren, Y.-Ch. Liu, Q.-X. Guo, Bull. Chem. Soc. Jpn. 69 (1996) 2935; (b) V.A. Golubev, R.V. Miklyush, Z.G. Rozantsev, Izvest. Akadem. Nauk SSR, Ser. Khim. (1972) 656; Chem. Abstr. 77 (1972) 101344. [19] The simulation is provisional, but it is sufficient for the interpretation of the cyclovoltammograms in the context of the investigation. The following mechanism, written in the terms of Digisim® 3.0, was used: B + e = A with E0 = 1.06 V, α = 0.5, ks = 100 cm/s; E + e = D with E0 = 1.35 V, α = 0.5, ks = 100 cm/s; H + e = G with E0 = 0.76 V, α = 0.5, ks = 100 cm/s. B = C, Keq = 500, kf = 500 s−1 ; B + A = D, Keq = 1E+5 M−1 , kf = 5E+4 M−1 s−1 ; E = F, Keq = 10, kf = 1 s−1 ; H + A = I, Keq = 1E+7 M−1 , kf = 5E+5 M−1 s−1 . D(A − F, I) = 3E−5 cm2 s−1 ; D(G) = 5E−5 cm2 s−1 , D(H) = 3.5E−5 cm2 s−1 . CV-parameters: Estart = 0 V, Erev = 1.6 V, Eend = 0 V; v = 0.1 V s−1 ; cycles: 1; Ru = 50 , T = 25 ◦ C; geometry: planar; area: 0.070651 cm2 . The following values were simulated, in parenthesis are the experimental values: (a) G = TEMPO (3) = 0.0 M, A = enaminoester 1c = 0.01 M: Ep,a = 1.035 V (1.03 V), ip = 0.269 mA (0.270 mA); Ep,a = 1.38 V (1.38 V), ip = 0.138 mA (0.140 mA); (b) G = TEMPO (3) = 0.009 M, A = enaminoester 1c = 0.01 M: Ep,a = 0.72 V (0.72 V), ip = 0.337 mA (0.330 mA). [20] The simulation is provisional, but it is sufficient for the interpretation of the cyclovoltammograms in the context of the investigation. The following mechanism, written in the terms of Digisim® 3.0, was used: B + e = A with E0 = 0.52 V, α = 0.5, ks = 100 cm/s; E + e = D with E0 = 0.69 V, α = 0.5, ks = 100 cm/s; I + e = G with E0 = 0.76 V, α = 0.5, ks = 100 cm/s. B = C, Keq = 500, kf = 500 s−1 ; B = D, Keq = 30, kf = 30 s−1 ; E = F, Keq = 40, kf = 40 s−1 ; B + G = H, Keq = 1E+8 M−1 , kf = 5E+8 M−1 s−1 . D(B − F, H) = 3E−5 cm2 s−1 ; D(G) = 5E−5 cm2 s−1 ; D(I) = 3.5E−5 cm2 s−1 ; D(A) = 3.2E−5 cm2 s−1 . CV-parameters are the same as in Ref. [19]. The following values were simulated, in parenthesis are the experimental values: (a) G = TEMPO (3) = 0.0 M, A = enamine 7 = 0.01 M: Ep,a = 0.5 V (0.5 V), ip = 0.353 mA (0.340 mA); Ep,a = 0.665 V (0.68 V), ip = 0.174 mA (0.205 mA); (b) G = TEMPO (3) = 0.009 M, A = enamine 7 = 0.01 M: Ep,a = 0.39 V (0.39 V), ip = 0.322 mA (0.350 mA); (c) G = TEMPO (3) = 0.009 M,

[21] [22] [23] [24]

[25] [26] [27]

[28] [29]

[30] [31] [32] [33] [34] [35]

A = enamine 7 = 0.013 M: Ep,a = 0.39 V (0.39 V), ip = 0.379 mA (0.350 mA); Ep,a = 0.495 V (0.46 V), ip = 0.269 mA (320 mA). J.M. Bobbitt, M.C. Flores, M. Zhenkum, T. Huitong, Heterocycles 30 (1990) 1131. A. Al Mourabit, M. Beckmann, C. Poupat, A. Ahond, P. Potier, Tetrahedron: Asymm. 12 (1996) 3455. J.-P. Gouesnard, J. Dorie, Bull. Soc. Chim. Fr. 2 (1986) 253. Using the numbering in 10a (Scheme 6) a C,H-correlation is found for: C-13 to C-4 and C-14; C-12 to C-13 and C-5; C-5 to C-12 and C-18; C-18 to C-2; C-17 to C-2 and C-4; C-19 to C-6 and C-2; NH to C-2 and C-7; C-8 to C-9 and C-6; NOE-enhancement between: NH and H at C-8 (E-configuration); H at C-5 and H at C-18; H at C-12 and H at C-17. M. Sch¨amann, H.J. Sch¨afer, Synlett (2004) 1601. R. Braslau, L.C. Burill II, M. Siano, N. Naik, R.K. Howden, L.K. Mahal, Macromolecules 30 (1997) 6445. (a) C.J. Hawker, W.A. Bosmann, E. Harth, Chem. Rev. 101 (2001) 3661; (b) Ch. Wetter, J. Gierlich, Ch.A. Knoop, Ch. Mueller, T. Schulte, A. Studer, Chemistry 10 (2004) 1156; (c) Ch.A. Knoop, A. Studer, J. Am. Chem. Soc. 125 (2003) 16327. Ch. Wetter, K. Jantos, K. Woithe, A. Studer, Org. Lett. 5 (2003) 2899. (a) H. van Bekkum, in: F.W. Lichtenthaler (Ed.), Carbohydrates as Organic Raw Materials, VCH Verlagsgesellschaft, Weinheim, 1991, p. 289; (b) H. R¨oper, in: F.W. Lichtenthaler (Ed.), Carbohydrates as Organic Raw Materials, VCH Verlagsgesellschaft, Weinheim, 1991, p. 267; (c) A. Abbadi, H. van Bekkum, Carbohydrates as Organic Raw Materials III, VCH Verlagsgesellschaft, Weinheim, 1996, p. 37. T. Mallat, A. Baiker, Catal. Today 19 (1994) 247. K. Heyns, H. Paulsen, G. R¨udiger, J. Weyer, Fortschr. Chem. Forsch. 11 (1969) 285. D.F. Hinkley, A.M. Hoinowski, DE 1813757 (1967); Chem. Abstr. 72 (1970) 32177r. Refs. [11–30] in [4c]. Experiments done by T. Breton, University of Poitiers, France, during a stay in M¨unster. (a) A.E. de Nooy, A.C. Besemer, H. van Bekkum, J.A.A.P. van Dijk, J.A.M. Smit, Macromolecules 29 (1996) 6541; (b) I. Shibata, A. Isogai, Cellulose 10 (2003) 335; (c) J.-F. Thaburet, N. Merbouh, M. Ibert, F. Marsais, G. Queguiner, Carbohydr. Res. 330 (2001) 21.