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Synlett 2007(2): 0303-0307  
DOI: 10.1055/s-2007-967993
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Serendipitous Discovery of a New C-Furanosyl Glycine Synthesis via Thiazole-Based Aminohomologation of Hexopyranoses

Alessandro Dondoni*, Alessandro Massi, Andrea Nuzzi
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
Fax: +39(053)2291167; e-Mail: adn@dns.unife.it;
Further Information

Publication History

Received 8 September 2006
Publication Date:
24 January 2007 (online)

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Abstract

Ring closure via microwave-assisted intramolecular OMs displacement by a γ-OBn group (O-nucleophilic attack) in protected polyhydroxylated N-Boc-thiazolylalkyl amines afforded C-furanosides (37-81%) featuring a chiral thiazolylmethylamino side chain, which, upon thiazole to carboxylate (through aldehyde) transformation, furnished enantiopure C-furanosyl glycines.

Key words

amino acids - cyclization - glycopeptides - glycosides - ring closure

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The open-chain amino alcohol 1 was obtained by reduction of the minor product that was formed by addition of thiazolylmagnesium bromide to the sugar hydroxylamine-nitrone mixture derived from the reaction of N-benzylhydroxylamine with tetra-O-benzyl-d-mannopyranose.

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For a critical discussion on this issue, see section IIA in ref. 2a.

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Typical Procedure for Entry N -Boc-Amines 5a-c, 7a-c.
To a stirred solution of N-benzyl-N-glycosylhydroxylamines 4a-c, 6a-c (0.50 g, 0.69 mmol) in MeOH (9.0 mL) was added a 12% HCl solution of TiCl3 (1.22 mL, 1.71 mmol). Stirring was manteined for an additional 15 min at r.t., then 5 M NaOH was added dropwise until pH 7 (the solution became white). After stirring for an additional 5 min, the primary amine was extracted with EtOAc (3 × 25 mL). The organic phase was washed with brine (2 × 20 mL), dried over Na2SO4, and concentrated. Crude primary amine was dissolved in dioxane (6.0 mL) and Boc2O (330 mg, 1.50 mmol) was added in one portion. Then some drops of a sat. solution of NaHCO3 were added to the mixture until pH 7.5. Stirring was mantained for 18 h, then the reaction was quenched with a 10% citric acid solution (4.0 mL). The protected amine was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and H2O (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was eluted from a column of silica gel with the suitable elution system to give the N-Boc-protected amines 5a-c,7a-c. Column chromatography with 3:1 cyclohexane-EtOAc afforded 5a (278 mg, 56%) as a syrup. [α]D 5.9 (c 0.7, CHCl3). 1H NMR (CDCl3): δ = 7.78 (d, 1 H, J = 3.2 Hz, Th), 7.42-7.00 (m, 21 H, 4 Ph and Th), 5.86 (d, 1 H, J NH,6 = 9.0 Hz, NH), 5.59 (dd, 1 H, J 6,5 = 1.0 Hz, J 6,NH = 9.0 Hz, H-6), 4.72 and 4.62 (2 d, 2 H, J = 11.0 Hz, CH 2Ph), 4.72 and 4.59 (2 d, 2 H, J = 11.0 Hz, CH 2Ph), 4.58 (dd, 1 H, J 5,4 = 8.0 Hz, J 5,6 = 1.0 Hz, H-5), 4.54 and 4.51 (2 d, 2 H, J = 11.0 Hz, CH 2Ph), 4.23 and 3.99 (2 d, 2 H, J = 11.0 Hz, CH 2Ph), 4.10 (br s, 1 H, H-2), 3.97 (dd, 1 H, J 4,3 = 3.5 Hz, J 4,5 = 8.0 Hz, H-4), 3.88 (dd, 1 H, J 3,2 = 8.0 Hz, J 3,4 = 3.5 Hz, H-3), 3.72 (dd, 1 H, J 1a,1b = 9.5 Hz, J 1a,2 = 3.0 Hz, H-1a), 3.64 (dd, 1 H, J 1b,1a = 9.5 Hz, J 1b,2 = 5.5 Hz, H-1b), 2.65 (s, 1 H, OH), 1.45 (s, 9 H, t-Bu). 13C NMR (CDCl3): δ = 173.9, 155.4, 143.2, 138.5, 138.2, 137.9, 137.5, 128.6, 128.5, 128.4, 128.3, 127.9, 127.8, 127.7, 127.5, 127.0, 118.9, 80.9, 80.1, 78.4, 78.1, 74.9, 73.8, 73.4, 72.8, 71.2, 70.0, 60.4, 53.5, 28.3, 21.1, 14.2. MALDI-TOF MS (724.9): m/z 747.1 [M + Na], 763.1 [M + K]. Anal. Calcd for C42H48N2O6S: C, 71.16; H, 6.82; N, 3.95. Found: C, 71.17; H, 6.79; N, 3.97.

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Typical Procedure for Entry C -Furanosides 8a,b, 9a-c, 14. To a cooled (0 °C), stirred solution of N-Boc-protected amines 5a-c, 7a-c, 13 (175 mg, 0.24 mmol) in pyridine (6.0 mL) was added mesyl cloride (56 µL, 0.72 mmol) in one portion. The mixture was stirred for an additional 2 h, then some drops of MeOH were added and the solvent was removed in vacuo. The residue was taken up in EtOAc (10 mL) and washed with a sat. solution of NaHCO3 (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. A 0.5-2.0 mL process vial was filled with the above crude mesylated intermediate, DIPEA (83 µL, 0.48 mmol), and anhyd DMF (2.0 mL). The vial was sealed with the Teflon septum and aluminium crimp by using an appropriate crimping tool. The vial was then placed in its correct position in the Biotage Initiator cavity where irradiation for 20 min at 150 °C was performed. After the full irradiation sequence was completed, the vial was cooled to r.t. and then opened. The solution was transferred into a round-bottomed flask and the solvent was removed in vacuo. The residue was taken up in EtOAc (10 mL), and washed with a sat. solution of NaHCO3 (2 × 15 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was eluted from a column of silica gel with the suitable elution system to give the C-furanosides 8a,b, 9a-c, 14. Column chromatography with 3:1 cyclohexane-EtOAc afforded 8a (112 mg, 73%) as a syrup. [α]D 42.8 (c 1.0, CHCl3). 1H NMR (C6D6): δ = 7.52 (d, 1 H, J = 3.2 Hz, Th), 7.20-7.00 (m, 15 H, 3 Ph), 6.50 (d, 1 H, J = 3.2 Hz, Th), 6.36 (d, 1 H, J NH,2 = 7.5 Hz, NH), 5.69 (br s, 1 H, H-2), 4.90 (br s, 1 H, H-3), 4.42 and 4.18 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.26 (s, 2 H, CH2Ph), 4.21 and 4.14 (2 d, 2 H, J = 11.0 Hz, CH2Ph), 4.14 (dd, 1 H, J 4,3 = 1.5 Hz, J 4,5 = 4.0 Hz, H-4), 4.11 (ddd, 1 H, J 6,5 = 1.5 Hz, J 6,7a = 6.5 Hz, J 6,7b = 5.0 Hz, H-6), 3.83 (dd, 1 H, J 5,4 = 4.0 Hz, J 5,6 = 1.5 Hz, H-5), 3.66 (dd, 1 H, J 7a,6 = 6.5 Hz, J 7a,7b = 9.5 Hz, H-7), 3.52 (dd, 1 H, J 7b,6 = 5.0 Hz, J 7b,7a = 9.5 Hz, H-7b), 1.35 (s, 9 H, t-Bu). 13C NMR (C6D6): δ = 172.1, 155.6, 142.9, 138.5, 137.9, 128.3, 128.2, 128.1, 127.9, 127.7, 127.4, 118.4, 110.3, 98.2, 85.4, 83.0, 82.4, 80.0, 73.0, 71.6, 71.3, 67.4, 55.3, 35.5, 28.0. MALDI-TOF MS (616.7): m/z 655.2 [M + K]. Anal. Calcd for C35H40N2O6S: C, 68.16; H, 6.54; N, 4.54. Found: C, 68.22; H, 6.60; N, 4.59.

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Typical Procedure for Entry C -Glycosyl Glycines 10a,b, 11a-c, 15. A mixture of the thiazole derivative 8a,b, 9a-c, 14 (164 mg, 0.26 mmol), activated 4 Å MS (400 mg) and MeCN (4.0 mL) was stirred at r.t. for 10 min then methyl triflate (32 µL, 0.28 mmol) was added in one portion. The suspension was stirred for an additional 15 min then the solvent was removed under reduced pressure. The residue was taken up in MeOH (4.0 mL), cooled to 0 °C and treated with NaBH4 (22 mg, 0.56 mmol). The mixture was stirred at r.t. for 15 min, diluted with acetone, filtered through a pad of Celite®, and concentrated in vacuo. The residue was taken up in 10:1 MeCN-H2O (4.0 mL) and then treated with CuO (60 mg, 0.78 mmol), and CuCl2·2H2O (48 mg, 0.28 mmol). The resulting suspension was stirred at r.t. for 10 min, then filtered through a pad of Celite® and concentrated in vacuo at a temperature below 30 °C. The residue was partitioned between brine (30 mL) and Et2O (30 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (2 × 30 mL). The combined organic extracts were washed with sat. aq EDTA (disodium salt), brine, dried over Na2SO4, filtered, and concentraed to give the essentially pure α-amino aldehyde which was taken up in MeCN (2 mL). The resulting solution was treated with 35% aq H2O2 (40 µL), 1.2 M aq KH2PO4 (0.2 mL) and 0.17 M aq NaClO2 (1.4 mL). After 2 h the reaction was acidified with 1 N aq HCl till pH = 2 and the resulting mixture was extracted with EtOAc (3 × 20 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated. The crude carboxylic acid was taken up in Et2O, the solution was kept at 0 °C and treated with an ethereal solution of CH2N2 until a pale yellow colour persisted. The solution was stirred for an additional 15 min, then the residue was dried in vacuo. The residue was eluted from a column of silica gel with the suitable elution system to give the corresponding C-glycosylglycines 10a,b, 11a-c, 15. Column chromatography with 3:1 cyclohexane-EtOAc afforded 10a (104 mg, 67%) as a syrup. [α]D 32.1 (c 1.0, CHCl3). 1H NMR (C6D6): δ = 7.20-7.00 (m, 15 H, 3 Ph), 5.96 (d, 1 H, J NH,2 = 9.0 Hz, NH), 4.85 (dd, 1 H, J 2,NH = 9.0 Hz, J 2,3 = 2.5 Hz, H-2), 4.65 (dd, 1 H, J 3,2 = 2.5 Hz, J 3,4 = 4.0 Hz, H-3), 4.42 and 4.12 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.26 and 4.22 (2 d, 2 H, J = 11.0 Hz, CH2Ph), 4.21 (s, 2 H, CH2Ph), 4.14 (t, 1 H, J 4,3 = J 4,5 = 4.0 Hz, H-4), 4.12 (br s, 1 H, H-6), 3.82 (dd, 1 H, J 5,4 = 4.0 Hz, J 5,6 = 1.5 Hz, H-5), 3.64 (dd, 1 H, J 7a,6 = 6.5 Hz, J 7a,7b = 10.0 Hz, H-7a), 3.54 (dd, 1 H, J 7b,6 = 5.0 Hz, J 7b,7a = 10.0 Hz, H-7b), 3.25 (s, 3 H, CH3), 1.37 (s, 9 H, t-Bu). 13C NMR (C6D6): δ = 170.2, 156.0, 138.4, 138.0, 137.9, 128.3, 128.2, 128.1, 127.9, 127.7, 127.6, 127.4, 127.3, 83.7, 83.2, 82.5, 80.2, 79.1, 73.0, 71.9, 71.3, 67.4, 55.7, 53.0, 51.6, 28.0. MALDI-TOF MS (591.7): m/z = 614.6 [M + Na], 630.3 [M + K]. Anal. Calcd for C34H41NO8: C, 69.02; H, 6.98; N, 2.37. Found: C, 69.04; H, 6.97; N, 2.37.

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Compound 11a: [α]D 27.9 (c 0.3, CHCl3). 1H NMR (C6D6): δ = 7.25-7.00 (m, 15 H, 3 Ph), 5.94 (d, 1 H, J NH,2 = 6.5 Hz, NH), 4.92 (dd, 1 H, J 2,NH = 6.5 Hz, J 2,3 = 5.0 Hz, H-2), 4.45 and 4.15 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.35-4.20 (m, 7 H, 2 CH2Ph, H-3, H-4 and H-6), 3.83 (br s, 1 H, H-5), 3.79 (dd, 1 H, J 7a,6 = 6.5 Hz, J 7a,7b = 10.0 Hz, H-7a), 3.68 (dd, 1 H, J 7b,6 = 5.5 Hz, J 7b,7a = 10.0 Hz, H-7b), 3.22 (s, 3 H, CH3), 1.35 (s, 9 H, t-Bu).
Compound 10b: [α]D 10.9 (c 1.0, CHCl3). 1H NMR (C6D6): δ = 7.25-7.00 (m, 15 H, 3 Ph), 5.42 (d, 1 H, J NH,2 = 8.5 Hz, NH), 4.92 (dd, 1 H, J 2,NH = 8.5 Hz, J 2,3 = 4.5 Hz, H-2), 4.75 (t, 1 H, J 3,2 = J 3,4 = 4.5 Hz, H-3), 4.32 (ddd, 1 H, J 6,5 = 4.0 Hz, J 6,7a = 6.5 Hz, J 6,7b = 5.0 Hz, H-6), 4.28 and 4.19 (2 d, 2 H, J = 11.5 Hz, CH2Ph), 4.26 and 4.21 (2 d, 2 H, J = 11.0 Hz, CH2Ph), 4.21 and 4.12 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.01 (dd, 1 H, J 4,3 = 4.5 Hz, J 4,5 = 2.0 Hz, H-4), 3.87 (dd, 1 H, J 5,4 = 2.0 Hz, J 5,6 = 4.0 Hz, H-5), 3.71 (dd, 1 H, J 7a,6 = 6.5 Hz, J 7a,7b = 9.5 Hz, H-7a), 3.58 (dd, 1 H, J 7b,6 = 5.0 Hz, J 7b,7a = 9.5 Hz, H-7b), 3.20 (s, 3 H, CH3), 1.40 (s, 9 H, t-Bu).
Compound 11b: [α]D 2.3 (c 1.0, CHCl3). 1H NMR (C6D6): δ = 7.22-7.00 (m, 15 H, 3 Ph), 5.77 (d, 1 H, J NH,2 = 10.0 Hz, NH), 5.33 (dd, 1 H, J 2,NH = 10.0 Hz, J 2,3 = 5.0 Hz, H-2), 4.76 (t, 1 H, J 3,2 = J 3,4 = 5.0 Hz, H-3), 4.49 (ddd, 1 H, J 6,5 = 4.0 Hz, J 6,7a = 7.0 Hz, J 6,7b = 5.5 Hz, H-6), 4.32 and 4.25 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.20 and 4.15 (2 d, 2 H, J = 11.5 Hz, CH2Ph), 4.09 (s, 2 H, CH2Ph), 4.00 (dd, 1 H, J 4,3 = 5.0 Hz, J 4,5 = 1.5 Hz, H-4), 3.84 (dd, 1 H, J 5,4 = 1.5 Hz, J 5,6 = 4.0 Hz, H-5), 3.81 (dd, 1 H, J 7a,6 = 7.0 Hz, J 7a,7b = 9.5 Hz, H-7a), 3.68 (dd, 1 H, J 7b,6 = 5.5 Hz, J 7b,7a = 9.5 Hz, H-7b), 3.15 (s, 3 H, CH3), 1.40 (s, 9 H, t-Bu).
Compound 11c: [α]D -28.5 (c 0.6, CHCl3). 1H NMR (CDCl3): δ = 7.40-7.20 (m, 15 H, 3 Ph), 6.07 (d, 1 H, J NH,2 = 9.0 Hz, NH), 4.83 (t, 1 H, J 3,2 = J 3,4 = 5.0 Hz, H-3), 4.74 (dd, 1 H, J 2,NH = 9.0 Hz, J 2,3 = 5.0 Hz, H-2), 4.64 and 4.59 (2 d, 2 H, J = 10.5 Hz, CH2Ph), 4.56 and 4.39 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.54 and 4.47 (2 d, 2 H, J = 11.0 Hz, CH2Ph), 4.28 (br s, 2 H, H-4 and H-6), 4.03 (t, 1 H, J 5,4 = J 5,6 = 5.0 Hz, H-5), 3.54 (s, 3 H, CH3), 3.53 (dd, 1 H, J 7a,6 = 4.0 Hz, J 7a,7b = 10.5 Hz, H-7a), 3.46 (dd, 1 H, J 7b,6 = 3.0 Hz, J 7b,7a = 10.5 Hz, H-7b), 1.40 (s, 9 H, t-Bu).
Compound 15: [α]D -6.9 (c 0.7, CHCl3). 1H NMR (C6D6): δ = 7.20-7.00 (m, 15 H, 3 Ph), 5.79 (d, 1 H, J NH,2 = 9.0 Hz, NH), 5.30 (dd, 1 H, J 2,NH = 9.0 Hz, J 2,3 = 6.0 Hz, H-2), 4.47 (dd, 1 H, J 3,2 = 6.0 Hz, J 3,4 = 4.0 Hz, H-3), 4.31 and 4.24 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.30 and 4.29 (2 d, 2 H, J = 12.0 Hz, CH2Ph), 4.21 (br s, 1 H, H-6), 4.14 (s, 2 H, CH2Ph), 4.01 (br s, 1 H, H-5), 3.95 (br s, 1 H, H-4), 3.59 (dd, 1 H, J 7a,6 = 5.0 Hz, J 7a,7b = 10.0 Hz, H-7a), 3.51 (dd, 1 H, J 7b,6 = 7.5 Hz, J 7b,7a = 10.0 Hz, H-7b), 1.39 (s, 9 H, t-Bu).

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Cyclization of the N-Boc amino alcohol 7c required two cycles of microwave irradiation to get an acceptable yield of the C-furanoside 9c. On the other hand, microwave irradiation of 5c for prolonged time periods (single or repeated cycles) did not afford the corresponding furanoside 8c.

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Reduction of 12 by NaBH4 at lower temperatures and by L-Selectride (THF, -78 °C) afforded the undesired alcohol 7b as major product.