Easy Access to Configurationally Controlled C-Glycofuranoside-Based Building Blocks by Means of Formyl C-Glycofuranosides

LETTER 271 Easy Access to Configurationally Controlled C-Glycofuranoside-Based Building Blocks by Means of Formyl C-Glycofuranosides C -Glycofuranoside-Based Building Blocks Yolanda Vera-Ayoso,a Pastora Borrachero,a Francisca Cabrera-Escribano,*a Manuel Gómez-Guillén,a Joaquim Caner,b Jaume Farrásb aDepartamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado de Correos No. 1203, 41071 Sevilla, Spain Fax +34(95)4624960; E-mail: [email protected] bDepartamento de Química Orgánica, Universidad de Barcelona, Av. Diagonal 647, 08028 Barcelona, Spain Received 24 September 2009 SYNLETT 2010, No. 2, pp 0271–0275 xx.xx.2010 Advanced online publication: 09.12.2009 DOI: 10.1055/s-0029-1218552; Art ID: D27109ST © Georg Thieme Verlag Stuttgart · New York Abstract: A general approach to enantiopure C-glycofuranoside- based hybrid a/b-amino acids and nitrones, among other valuable building blocks, has been established via formyl C-glycofurano- sides, easily available from hexose-derived equatorial-2-OH-glyco- pyranosides by DAST-promoted ring contraction. Key words: C-glycofuranoside-based building blocks, formyl C- glycofuranosides, DAST-promoted ring contraction, C-glycofura- nosyl nitrones, C-glycofuranosyl amino acids The replacement of the exocyclic carbon–oxygen or carbon–nitrogen bond of native glycoconjugates with a carbon–carbon bond creates compounds which are resistant to chemical and enzymatic degradation with minimal loss or enhancement in biological activity with respect to the parent O- or N-glycosides.1 Therefore the ready access to C-glycosides is of great interest in carbohydrate chemistry.2 A major problem to prepare functionalized C-glycosides relies on the few available anomeric carbon–carbon bondforming reactions endowed with both chemical efficiency and stereocontrol. This problem could be avoided by the use of C-functionalized carbohydrate derivatives bearing an a- or b-linked highly reactive carbon functionality at the anomeric center. Following this idea, we have developed by means of formyl C-glycofuranosides 1, a widescope method for the synthesis of configurationally controlled C-glycofuranoside-based building blocks containing the substructures 2–4 (Scheme 1), from which an easy access to biologically relevant more complex C-glyco- furanoside-based molecules (C-oligosaccharides and C- glycoconjugates) is provided. The key step in this strategy is clearly a DAST-mediated rearrangement reaction that involves ring contraction of hexose-derived equatorial 2- OH-glycopyranosides, and leads to formyl C-glycofura- nosides under remarkably mild conditions. This methodology allowed us to prepare a series of formyl C- glycofuranosides,3 and from the point of view of atom economy4 it can be considered in the carbohydrate field as a greener formylation methodology than those strategies that are based on the use of formyl anion equivalents.5 We have employed formyl C-glycofuranosides 1 as key intermediates via reductive amination of the formyl group for the synthesis of enantiopure N-substituted 1-C-amino- methyl glycofuranosides 5 (Figure 1).6 Herein we describe the synthesis of some enantiopure biologically relevant C-glycofuranoside-based building blocks (C-GfBB), in particular 1-C-alkoxymethyl glycofuranosyl amino acids 2, C-glycofuranosylcarbonyl amino acids 3, and C-glycofuranosyl nitrones 4 in good to high yields. Scheme 1 Compounds of types 2 and 3 are structural and configurationally related to the natural antifungal antibiotic cispentacin (6),7 which has been used as a peptidomimetic for proline. Amino acids 2 and 3 are of potential interest in the field of peptide foldamers as heterogeneous a/b-peptide subunits. a/b-Hybrid peptides containing a- and b-amino acid constituents in 1:1 backbone alternation display a variety of helical structures8 and some of these peptides elicit substantial biological activity.9 Diversity is supplied by readily available a-amino acids, while conformational stability and specificity are provided by the preorganized b-amino acid residues (e.g., 6 and 7, Figure 1).10 Figure 1 O H R O O H N R O O N+ R Bn O– O OR1 HN O 1 4 3 2 O HOOMe R O HO ROMe CO2R4 R2 NHR3 R2 R = N3, OH O NR1R2 R 5 R = N3, OH, F H2N O OH X H2N O OH cispentacin ( 6 ) 7 X = CH2, NH Downloaded by: Universidad de Sevilla. Copyrighted material. 272 Y. Vera-Ayoso et al. LETTER Synlett 2010, No. 2, 271–275 © Thieme Stuttgart · New York The synthetic utility of nitrones 4 as 1,3-dipolar systems11 is demonstrated by the highly stereoselective preparation of C-disaccharides, sugar moieties of which are tethered through a rigid five-membered heterocycle. Scheme 2 summarizes our synthetic strategy for the preparation of C-glycofuranoside-based building blocks (C- GfBB) with substructures 2–5 via formyl C-glycofurano- sides, readily available as their synthetic equivalents, from a hexose-derived equatorial 2-OH-glycopyranoside, for example, methyl a-D-allopyranoside 8.12 Treatment of compound 8 with diethylaminosulfur trifluoride (DAST) in refluxing acetonitrile for 12 minutes as described previously6 gave the 2,5-anhydro-1-fluoro-1-O- methyl-D-altritol 9 (73%), as an epimeric mixture which contains a masked formyl function, and therefore can be considered as a synthetic equivalent of the formyl C-gly- cofuranoside 13 (Table 1, entry 1). To obtain the methoxymethyl glycofuranosyl glycine derivative 16, having the substructure 2, and its precursor the vicinal amino alcohol 15 we followed route A starting from compound 9 (Table 1). Thus, reduction of 9 dissolved in dry THF, with sodium cyanoborohydride (12.7 mol equiv) in the presence of 3 Å molecular sieves (r.t., 15 min, and then HCl–Et2O, 5 min), afforded compound 1013 in 64% yield, which was subjected to Staudinger reaction to give the amine 15 (95%, entry 3). On its turn, Staudinger reaction of 10, by using Boc- Gly-OH, gave the dipeptidomimetic 16 in high yield (entry 4). It is noteworthy that the 1H NMR coupling constants of compound 16 contrast sharply with those expected for a furanose ring, suggesting a conformational deviation. Thus, the J2,3 value of 8 Hz observed matched with a dihedral angle H2–C2–C3–H3 next to 0°, and the J4,5 = 3 Hz is remarkably lower than the corresponding usual value (7.5–8.5 Hz) observed for a furanose ring.3,6 Preliminary molecular-mechanic calculations14 show a sole low-energy conformer (below 10 kJ/mol, Figure 2) with a dihedral angle (17–23°) in agree with NMR data indicated above. Targeting the formyl C-glycofuranoside synthetic equivalent 12,6 which is a key product for the synthesis (route B) of C-GfBB having substructures 3–5, compound 9 was transformed (PTSA–MeOH) into the 4,6-O-deprotected dimethyl acetal 11 (93%). When this crude product was subjected in situ to standard acetylation conditions, the 4,6-di-O-acetyl derivative 12 was obtained in high yield (94%).6 Hydrolysis of 12 with TFA–H2O (9:1) gave aldehyde 14 (entry 2), from which a variety of protected C- glycofuranosyl diamines 17 (substructure 5) were obtained by reductive amination with diverse primary or secondary amines (entry 5).6 The C-glycofuranosyl b-amino acid precursor 19 (entry 7) was obtained from the key compound 12 by hydrolysis of the acetal function and subsequent oxidation with Jones reagent or starting from the primary alcohol 18 (Jones reagent, –30 °C, r.t., 1 h, 72%). On its turn, 18 was prepared (entry 6) by treatment of the crude aldehyde 14 obtained in situ by hydrolysis [TFA–H2O (9:1), r. t., 1 h] of the dimethyl acetal 12, with imidazole (1.4 mol equiv) and NaBH(OAc)3 (1.4 mol equiv) in dry DCE.6 Transformation of 19 into 20 was easily achieved for protected glycine (EDCI, HOBt, DIPEA, HCl·EtO-Gly-NH2, CH2Cl2, r.t., 18 h) in good yield (entry 8). The C-glycofuranosyl nitrone 21 was obtained in poor yield (22%, entry 9) by treatment of the crude aldehyde 13 prepared in situ (PTSA, acetone, r.t., 1 h) from 9, with Bn- NHOH·HCl and NaHCO3 (MgSO4, dry CH2Cl2, 4 Å MS, r.t., 5 h). However, starting from the di-O-acetylated dimethyl acetal 12, the nitrone 22 was obtained (entry 10) in good yield (67%), thus opening potential access to longchain functionalized C-disaccharides through isoxazolidine derivatives.15 For instance, the 1,3-dipolar cycloaddition reaction of 22 with the D-galactose derived nitroolefin 23 led to the 3,5-di-C-glycosyl-4-nitroisoxazo- Scheme 2 Synthetic routes to C-glycofuranoside-based building blocks (C-GfBB, types 2–5) via formyl C-glycofuranosides (see Table 1) 9 (73%) O O O N3 Ph OMe H F O O OPh N3HOOMe DAST, MeCN, reflux, 12 min 8 [ref. 6] 10 (64%) O HO N3 Na(CN)BH3, THF, HCl/Et2O, r.t., 20 min route A reagents and conditions route B 11 R = H (93%) O RO N3 OMe OMe Ac2O, pyridine, 0 ºC 12 R = OAc (94%) reagents and conditions MeOH, PTSA, r.t., 1 h product (C-GfBB type 2) product (C-GfBB types 2, 3, 4, and 5) BnO RO OMe Figure 2 Lowest energy conformer and relative energy (0.0 kJ/mol) of compound 1614 Downloaded by: Universidad de Sevilla. Copyrighted material. LETTER C-Glycofuranoside-Based Building Blocks 273 Synlett 2010, No. 2, 271–275 © Thieme Stuttgart · New York lidines 24 and 25 (60%, Scheme 3) as a 10:1 mixture (1H NMR).16 The configuration assignment was made on the basis of the stereospecificity of the cycloaddition reactions, and the exo/endo and facial stereoselectivities observed for related reactions.17 In summary, a practical approach to the synthesis of enantiopure, biologically relevant C-glycofuranosides, in particular protected 1-C-alkoxymethyl glycofuranosyl amino acids, C-glycofuranosyl amino acids, and C-glycofurano- syl nitrones, via formyl C-glycofuranosides is reported. Moreover, the synthetic utility of some of them for the preparation of more complex C-glycofuranoside-based molecules is provided. Our strategy: 1) offers operational simplicity, 2) allows complete stereocontrol at the anomeric center, and 3) has the potential to enable the preparation of a wide range of multifunctional C- glycofuranoside-based building blocks from diverse easily available hexose-derived equatorial 2-OH-glycopyra- nosides, by a DAST-promoted ring contraction as the key step. Scheme 3 O O O O O NO2 23 O O O O O NO Bn NO2 O N3 AcO AcO 24 + NO Bn O O O O O NO2 O N3 AcO AcO 25 (10:1 mixture) toluene, reflux, 1 h 22 O AcO N3 AcO N+ Bn O– (60%) 34 5 1' 1'' Table 1 Formyl C-Glycofuranosides and C-Glycofuranoside-Based Building Blocks (C-GfBB) Entry Route Substrate Reagents and conditions Products (yield, %)a 1– 9PTSA, acetone, r.t., 1 h 13 (83) 2B12 TFA–H2O (9:1), r.t., 1 h 14 (90) 3A10 1. Ph3P, THF, r.t., 8 h 2. H2O, 20 h 15 (95) O HO N3 HHO O O AcO N3 HAcO O O HO NH2 BnO OMe Downloaded by: Universidad de Sevilla. Copyrighted material. 274 Y. Vera-Ayoso et al. LETTER Synlett 2010, No. 2, 271–275 © Thieme Stuttgart · New York Acknowledgment We thank the European Commission, Directorate General for Science and Development (FP6-508430), the Spanish ‘Ministerio de Ciencia y Tecnología’ (predoctoral fellowship to Y. V.-A.), and the ‘Junta de Andalucía’ (FQM142) for financial support. References and Notes (1) (a) Taylor, E. A.; Clinch, K.; Kelly, P. M.; Li, L.; Evans, G. B.; Tyler, P. C.; Schramn, V. L. J. Am. Chem. Soc. 2007, 129, 6984. (b) Pellisier, H. Tetrahedron 2005, 61, 2947. (c) Schmieg, J.; Yang, G.; Franck, R. W.; Tsuji, M. O. J. Exp. Med. 2003, 198, 1631. (d) Levy, W.; Chang, D. The Chemistry of C-Glycosyl Compound; Elsevier: Cambridge, 1995. (2) (a) Kaliappan, K. P.; Subrahmanyam, A. V. Org. Lett. 2007, 9, 1121. (b) Moreno, B.; Quehen, C.; Rose-Helene, M.; Leclerc, E.; Quirion, J.-C. Org. Lett. 2007, 9, 2477. (c) Taillefumier, C.; Chapleur, Y. Chem. Rev. 2004, 104, 263. (3) (a) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Carmona, A. T.; Gómez-Guillén, M. Tetrahedron: Asymmetry 2005, 16, 889. (b) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Carmona, A. T.; Gómez-Guillén, M. Tetrahedron: Asymmetry 2004, 15, 429. (c) Borrachero, P.; Cabrera-Escribano, F.; Carmona, A. T.; Gómez-Guillén, M. Tetrahedron: Asymmetry 2000, 11, 2927. (d) Borrachero, P.; Cabrera-Escribano, F.; Gómez-Guillén, M.; Madrid-Díaz, F. Tetrahedron Lett. 1997, 38, 1231. (4) One of most important principles of Green Chemistry is that of atom economy. Rearrangements are considered as atom economic reactions: Anastas, Y.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. (5) Kirchning, A.; Kujat, C.; Luiken, S.; Schaumann, E. Eur. J. Org. Chem. 2007, 2387. (6) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Gómez-Guillén, M.; Vogel, P. Synlett 2006, 45. (7) (a) Aye, Y.; Davies, S. G.; Garner, C.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 2195. (b) Benedek, G.; Palkó, M.; Wéber, E.; Martinek, T. A.; 4A 10 1. Ph3P, THF, r.t., 8 h 2. EDCI, HOBt, DIPEA, Boc-Gly-OH, CH2Cl2, r.t., 20 h 16 (82) 5B 12 1. TFA–H2O (9:1), r.t., 1 h 2. RNH2 or R1R2NH, NaBH(OAc)3, DCE, 25 °C 176 (35–88) 6B 12 1. TFA–H2O (9:1), r.t., 1 h 2. NaBH(OAc)3, imidazole, DCE, 25 °C, 20 h 186 (56) 7B 12 1. TFA–H2O (9:1), r.t., 1 h 2. Jones’ reagent, –30 °C to r.t. 193 (65) 8B 12 1. TFA–H2O (9:1), r.t., 1 h 2. Jones reagent, –30 °C to r.t. 3. EDCI, HOBt, DIPEA, HCl·EtO-Gly-NH2, CH2Cl2, r.t., 18 h 20 (67) 9– 91. PTSA, acetone, r.t., 1 h, 83% 2. BnNHOH·HCl, NaHCO3, MgSO4, MS 4 Å, CH2Cl2, r.t., 5 h, 26% 21 (22) 10 B 12 1. TFA–H2O (9:1), r.t. 1 h 2. BnNHOH·HCl, NaHCO3, MgSO4, MS 4 Å, CH2Cl2, r.t., 40 min 22 (67) a All products were fully characterized by their IR, 1H NMR (500 MHz), 13C NMR (125.7 MHz), and HRMS spectral data.18 Table 1 Formyl C-Glycofuranosides and C-Glycofuranoside-Based Building Blocks (C-GfBB) (continued) Entry Route Substrate Reagents and conditions Products (yield, %)a O HO H N OMe N HO O O BnO O AcO N3 NR1R2 AcO O AcO N3 OHAcO O AcO N3 AcO OH O O AcO N3 AcO H NCO2Et O O HO N3 HO N+ Bn O– O AcO N3 AcO N+ Bn O– Downloaded by: Universidad de Sevilla. Copyrighted material. LETTER C-Glycofuranoside-Based Building Blocks 275 Synlett 2010, No. 2, 271–275 © Thieme Stuttgart · New York Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008, 3724. (c) Forró, E.; Fülöp, F. Chem. Eur. J. 2007, 13, 6397. (8) (a) Sharma, G. V. M.; Babu, B. S.; Chatterjee, D.; Ramakrishna, K. V. S.; Kunwar, A. C.; Schramm, P.; Hofmann, H.-H. J. Org. Chem. 2009, 74, 6703. (b) Choi, S. H.; Guzei, I. A.; Spencer, L. C.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130, 6544. (c) Prabhakaran, P.; Kale, S. S.; Puranik, V. G.; Rajamohanan, P. R.; Chetina, O.; Howard, J. A. K.; Hofmann, H.-J.; Sanjayan, G. J. J. Am. Chem. Soc. 2008, 130, 17743. (d) Schmitt, M. A.; Choi, S. H.; Guzei, I. A.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 4538. (9) (a) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366. (b) Sadowsky, J. D.; Schmitt, M. A.; Lee, H. S.; Umezawa, N.; Wang, S.; Tomita, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11966. (10) Fülöp, F.; Martinek, T. A.; Tóth, G. K. Chem. Soc. Rev. 2006, 35, 323. (11) (a) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (b) Ratner, D. M.; Adams, E. W.; Disney, M. D.; Seeberger, P. H. ChemBioChem 2004, 5, 1375. (12) Baer, H. H.; Gan, Y. Carbohydr. Res. 1991, 210, 233. (13) Preparation and More Relevant Data of Compound 10 A soln of 9 (105 mg, 0.340 mmol) in dry THF (4.8 mL) containing 3 Å MS was treated with NaCNBH3 (273 mg, 4.35 mmol). The mixture was stirred for 15 min, and then Et2O–HCl (3.5%, 6 mL) was added. After 5 min, the reaction was diluted with H2O (20 mL) and CH2Cl2 (20 mL). After separation, the organic layer was successively washed with sat. aq NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated. Column chromatography (hexane– EtOAc, 3:1) gave pure 10 (64 mg, 64%). Analytical Data [a]D24 +16.2 (c 0.63, CH2Cl2). IR: nmax = 2108 (N3) cm–1. 1H NMR (500 MHz, acetone-d6): d = 7.36–7.26 (m, 5 H, Ph), 4.75 (s br, 1 H, OHC4), 4.55 (s, 2 H, CH2Ph), 4.55–4.53 (m, 1 H, H-4), 4.17 (ddd, 1 H, J1,2 =J1¢,2 =5.7 Hz, J2,3 =3.7 Hz, H-2), 4.14 (dd, 1 H, J3,4 = 4.2 Hz, H-3), 3.93 (ddd, 1 H, J4,5 =7.5 Hz, J5,6¢=4.5 Hz, J5,6 = 3.0 Hz, H-5), 3.65 (dd, 1 H, J6,6¢= 11.0 Hz, H-6), 3.58 (dd, 1 H, H-6¢), 3.56 (dd, 1 H, J1,1¢= 10.0 Hz, H-1), 3.43 (dd, 1 H, H-1¢), 3.31 (s, 3H, OCH3) ppm. HRMS (CI): m/z calcd for C14H19N3O4 + H: 294.1454; found: 294.1462. (14) The calculations were performed at the University of Barcelona. Lowest-energy conformer were calculated by performing Monte Carlo conformational searches (50000 steps) with MacroModel 8.5 (MM2*, CHCl3, GB/SA): (a) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufied, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comp. Chem. 1990, 11, 440. (b) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J. Am. Chem. Soc. 1990, 112, 6127. (15) Borrachero, P.; Cabrera, F.; Diánez, M. J.; Estrada, M. D.; Gómez-Guillén, M.; López-Castro, A.; Moreno, J.; Paz, J.; Pérez-Garrido, S. Tetrahedron: Asymmetry 1999, 10, 77. (16) The ratio of 24/25 was calculated by the 1H NMR (CDCl3) of the mixture, in particular from the signals of H-4 of both stereoisomers: d = 5.65 ppm (dd, 1 H, J4,5 = 7.8 Hz, J3,4 =4.5 Hz, H-4) observed for the major stereoisomer 24, and that observed at d = 4.80 ppm (dd, 1 H, J4,5 = 7.2 Hz, J3,4 =4.8 Hz, H-4) for 25. (17) Torres-Sánchez, M. I.; Borrachero, P.; Cabrera-Escribano, F.; Gómez-Guillén, M.; Angulo-Álvarez, M.; Sánchez, E.; Favre, S.; Vogel, P. Tetrahedron 2007, 18, 1089. (18) More Relevant Data Compound 16: [a]D21 +37 (c 0.77, acetone). 1H NMR (500 MHz, acetone-d6): d = 7.36–7.33 (m, 5 H, Ph), 7.09 (d, 1 H, JNH,3 = 7.0 Hz, CCONH), 6.43 (s br, 1 H, OCONH), 4.58– 4.53 (m, 1 H, H-3), 4.57 and 4.58 (each 2 d, 1 H, JH,H¢= 12.9 Hz, CH2Ph), 4.45 (d, 1 H, JOH,4 = 8.0 Hz, OHC4), 4.31 (ddd, 1 H, J2,3 = 8.0 Hz, J1¢,2 = 4.5 Hz, J1,2 = 3.0 Hz, H-2), 4.17– 4.14 (m, 1 H, H-4), 4.01 (ddd, 1 H, J5,6 =J5,6¢= 4.0 Hz, J4,5 = 3.0 Hz, H-5), 3.77 (dd, 1 H, Jgem = 16.5 Hz, JNH,CH2a = 6.0 Hz, NHCHa2), 3.72 (dd, 1 H, JNH,CH2b =6.0 Hz, NHCHb2), 3.55 (dd, 1 H, J6,6¢= 10.5 Hz, H-6), 3.52 (dd, 1 H, H-6¢), 3.50 (dd, 1 H, J1,1¢= 10.5 Hz, H-1), 3.40 (dd, 1 H, H- 1¢), 3.35 (s, 3 H, OCH3), 1.43 [s, 9 H, C(CH3)3] ppm. 13C NMR (125.7 MHz, acetone-d6): d = 170.5, 157.0, 139.6- 128.2, 85.2, 79.6, 78.9, 73.8, 73.1, 72.9, 72.0, 59.3, 53.9, 44.9, 28.6 ppm. HRMS (CI): m/z calcd for C21H32N2O7 + H: 425.2288; found: 425.2291. Anal. Calcd for C21H32N2O7: C, 59.42; H, 7.60; N, 6.60. Found: C, 59.12; H, 7.45; N, 6.72. Compound 20: [a]D24 +52 (c 0.66, CH2Cl2). IR: nmax = 2114 (N3) cm–1. 1H NMR (500 MHz, CDCl3): d = 7.07 (dd, 1 H, JNH,CH2a = 5.0 Hz, NH), 5.22 (dd, 1 H, J4,5 = 8.5 Hz, J3,4 =4.5 Hz, H-4), 4.68 (dd, 1 H, J2,3 = 4.5 Hz, H-3), 4.62 (d, 1 H, H- 2), 4.40–4.36 (m, 1 H, H-5), 4.36 (dd, 1 H, J6,6¢= 12.5 Hz, J5,6 = 2.5 Hz, H-6), 4.23 (q, 2 H, J=7.0, C 2H5), 4.13 (dd, 1 H, J5,6¢= 4.0 Hz, H-6¢), 4.11 (dd, 1 H, Jgem = 18.0 Hz, NHCHa2), 4.07 (dd, 1 H, NHCHb2), 2.16, 2.09 (2 s, each 3 H, COCH3), 1.29 (t, 3 H, C2H5) ppm. HRMS (CI): m/z calcd for C14H20N4O8 + H: 373.1359; found: 373.1349. Compound 22: [a]D24 –1.2 (c 0.75, CH2Cl2). IR: nmax = 2112 (N3) cm–1. 1H NMR (500 MHz, CDCl3): d = 7.41 (s, 5 H, Ph), 6.79 (d, 1 H, J1,2 = 4.5 Hz, H-1), 5.20 (dd, 1 H, J4,5 =8.0 Hz, J3,4 = 5.0 Hz, H-4), 5.15 (dd, 1 H, J2,3 = 4.5 Hz, H-2), 4.94 (dd, 1 H, H-3), 4.91 (s, 2 H, CH2Ph), 4.34 (dd, 1 H, J6,6¢= 12.0, J5,6 = 3.0 Hz, H-6), 4.24 (ddd, J5,6¢= 4.5 Hz, H- 5), 4.04 (dd, 1 H, H-6¢), 2.14, 2.08 (2 s, each 3 H, 2 COCH3) ppm. 13C NMR (125.7 MHz, CDCl3): d = 170.7, 170.2, 136.2, 132.0-129.2, 77.2, 77.0, 73.5, 69.3, 63.3, 62.7, 20.9, 20.4 ppm. HRMS (CI): m/z calcd for C17H20N4O6 + H: 377.1461; found: 377.1454. Downloaded by: Universidad de Sevilla. Copyrighted material.