Synthesis of Spirocyclic Glucose-Proline Hybrids (GlcProHs)

Abstract

A short synthetic route to polyhydroxylated spirocyclic glucose-based l-proline analogues is described from easily prepared 2,3,4,6 tetra-O-benzyl-d-glucono-lactone. The synthesis involves C-glycosylation of an exocyclic glucose-based epoxide with allyltributylstannane that affords functionalized C-ketosides containing an α-hydroxy ester moiety. Oxidation of the alcohol function, followed by stereoselective reductive amination provides an amine that undergoes iodine-induced aminocyclization to provide spirocyclic glucose-proline hybrids bearing an iodomethylene side-chain. The iodo function of the side-chain can be converted into ­other functional groups such as ester and hydroxyl groups, thereby allowing additional modifications to the pyrrolidine ring.

Key words

amino acids - carbohydrates - glycopeptides - glycosyl amino acids - proline

References

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22

It has been reported that substitution of d-proline by cis-3-hydroxy-d-proline (HypC3-OH) in the sequence Boc-Leu-Pro-Gly-Leu-NHMe resulted in novel pseudo β-turn-like nine-membered ring structure involving an intramolecular LeuNH Æ HypC3-OH hydrogen bond.

26

Analytical data for compounds 17, 19 and 21. Compound 17: ¹H NMR (500 MHz, C₆D₆, r.t., TMS): δ = 1.76 (s, 3 H), 2.20 (dd, H-9a, J = 13.7 Hz, J = 6.2 Hz), 2.38 (dd, H-9b, J = 13.7 Hz, J = 10.3 Hz), 3.00 (s, 3 H), 3.34 (m, H-10), 3.56-3.70 (m, 5 H, H-5, H-6, H-7, H-8a,b), 3.75 (s, H-2), 3.83-3.91 (m, H-4, 1 H, J = 9.0 Hz, J = 14.5 Hz), 4.12 (d, 1 H, J = 13.5 Hz), 4.28 (dd, H-11a, J = 10.6 Hz, J = 4.6 Hz), 4.44-4.53 (m, 2 H, H-11b), 4.54-4.58 (d, 2 H, J = 11.0 Hz), 4.60 (d, 1 H, J = 11.2 Hz), 4.80 (d, 2 H, J = 11.2 Hz), 4.83 (d, 1 H, J = 11.2 Hz), 5.17 (d, 1 H, J = 12.4 Hz), 6.98-7.21 (m, 25 H). ¹³C NMR (300 MHz, CDCl₃, r.t.): δ = 20.95, 29.99, 51.54, 60.41, 60.84, 67.20, 69.39, 72.48, 72.77, 73.52, 75.05, 75.52, 76.04, 76.69, 78.66, 86.14, 87.48, 126.01-128.79 (arom. C), 138.03, 138.04, 138.35, 138.91, 139.32, 170.99, 171.96. HRMS: m/z calcd for C₄₉H₅₄NO₉ [M + H]⁺: 800.3793; found: 800.3794.
Compound 19: ¹H NMR (500 MHz, C₆D₆, r.t., TMS): δ = 1.68 (s, 3 H), 2.14 (dd, H-9a, J = 14.2 Hz, J = 1.1 Hz), 2.82 (dd, H-9b, J = 14.2 Hz, J = 9.6 Hz), 3.07 (s, 3 H), 3.57 (dd, H-6, J = 9.4 Hz, J = 9.3 Hz), 3.63 (dd, H-5, J = 9.4 Hz, J = 9.2 Hz), 3.65-3.72 (m, H-4, H-8a), 3.75 (dd, H-8b, J = 11.1 Hz, J = 1.6 Hz), 3.77-3.81 (m, H-7, H-10), 3.84 (d, 1 H, J = 14.4Hz), 3.92 (s, H-2), 4.11 (d, 1 H, J = 14.2 Hz), 4.28 (dd, H-11a, J = 10.7 Hz, J = 7.8 Hz), 4.38 (dd, H-11b, J = 10.7 Hz, J = 5.4 Hz), 4.47 (d, 1 H, J = 12.5 Hz), 4.49-4.56 (m, 3 H), 4.58 (d, 1 H, J = 12.4 Hz), 4.76 (d, 1 H, J = 11.2 Hz), 4.77 (d, 1 H, J = 11.1 Hz), 5.20 (d, 1 H, J = 12.4 Hz), 7.00-7.28 (m, 25 H). ¹³C NMR (300 MHz, CDCl₃, r.t.): δ = 20.99, 27.69, 51.14, 53.04, 59.97, 67.23, 69.04, 72.86, 73.04, 73.21, 73.71, 75.12, 75.63 ( 2 C), 78.74, 85.88, 86.94, 126.03-128.49 (arom. C), 137.00 (2 C), 138.50, 138.90, 139.47, 170.91, 170.93. HRMS: m/z calcd for C₄₉H₅₄NO₉ [M + H]⁺: 800.3793; found: 800.3793.
Compound 21: ¹H NMR (500 MHz, C₆D₆, r.t., TMS): δ = 1.66 (s, 3 H), 2.67 (dd, 1 H, J = 13.6 Hz, J = 11.6 Hz), 2.81 (dd, J = 13.6 Hz, J = 4.1 Hz), 3.04 (s, 3 H), 3.10 (dd, H-11a, J = 10.2 Hz, J = 5.6 Hz), 3.41 (d, H-4, J = 9.1 Hz), 3.63 (s, H-2), 3.64-3.74 [m, H-11b, 2 H (NBn), H-6], 3.79 (dd, H-8a, J = 11.2 Hz, J = 4.4 Hz), 3.84-3.91 (m, H-5, H-8b), 4.07 (m, H-7,), 4.38 (d, 1 H, J = 12.5 Hz), 4.44 (d, 1 H, J = 12.0 Hz), 4.59 (d, 1 H, J = 12.0 Hz), 4.63 (d, 1 H, J = 11.4 Hz), 4.69 (d, 1 H, J = 12.0 Hz), 4.76 (d, 1 H, J = 11.1 Hz), 4.77 (d, 1 H, J = 11.4 Hz), 5.14 (d, 1 H, J = 12.5 Hz), 5.49 (m, H-10), 6.99-7.16 (m, 25 H). ¹³C NMR (300 MHz, C₆D₆, r.t.): δ = 21.56, 26.39, 50.15, 50.44, 59.47, 69.73, 72.78, 73.44, 74.35 (2 C), 75.38 (2 C), 75.82, 78.74, 79.36, 80.95, 85.26, 126.50-128.90 (arom. C), 138.78 (3 C), 139.24, 139.38, 170.71 (2 C). HRMS: m/z calcd for C₄₉H₅₄NO₉ [M + H]⁺: 800.3793; found: 800.3791.

27

Analytical data for compound 23.
¹H NMR (300 MHz, CD₃OD, r.t., TMS): δ = 2.13 (m, 1 H), 2.41 (m, 1 H), 3.23-3.21 (m, H-5, H-6), 3.49 (m, H-7), 3.60-3.71 (m, H-4, H-8a), 3.85 (s, 3 H), 3.87-4.00 ( m, H-10, H-8b, H-11a,b), 4.22 (s, H-2). ¹³C NMR (300 MHz, CD₃OD, r.t.): δ = 27.27, 54.30, 61.46, 61.85, 62.98, 68.74, 70.77, 71.57, 76.64, 77.03, 88.31, 168.49. HRMS: m/z calcd for C₁₂H₂₂NO₈ [M + H]⁺: 308.1340; found: 308.1343.

28

Subjection of the singlet H-2 proton in 2 to a one-dimensional GOESY [24] experiment showed interproton effects to H-5 (0.65% NOE) and H-7 (0.4% NOE) measured relative to the singlet H-2 signal. This is consistent with the epoxide structure 2.

29

Unreacted starting material was recovered in over 90% yield together with trace amounts of the corresponding amines and amides that were identified by HPLC-MS.

30

A 40 ms gaussian pulse with a 560 ms mixing time was used.

31

Synthetic Procedures for the Synthesis of Compounds 2, 4, 8, 10, 12, 17, 19, 21.
Synthesis of 2.
Methyl bromoacetate (4.1 mmol) was dissolved in dry THF (20 mL) and cooled to -78 °C before lithium bis(trimethylsilyl)amide (4 mL of a 1 M solution in THF) was slowly added. The reaction mixture was kept at -78 °C for an additional 30 min. Subsequently, a THF solution (5 mL) containing the lactone 1 (1 mmol) was added over a period of 10 min. After 1 h, the temperature was raised to r.t. and stirred for 15 min before sat. aq NH₄Cl solution (20 mL) was added. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in CH₂Cl₂ and partitioned with H₂O. The organic layer was dried over Na₂SO₄, concentrated and purified by flash column chromatography (hexane-EtOAc, 5:1) to provide 2 as a solid (488 mg, 80%).
Synthesis of 4.
To a mixture of epoxide 2 (480 mg, 0.79 mmol) and allyltributylstannane (0.995 mL, 3.15 mmol) in anhyd CH₂Cl₂ (15 mL) was added dropwise TMSOTf (0.427 mL, 2.36 mmol) at 0 °C. The mixture was stirred for 30 min at 0 °C before sat. NaHCO₃ solution (10 mL) was added to quench the reaction. The organic layer was dried (Na₂SO₄), concentrated and purified by flash column chromatography using hexane-EtOAc 8:1 → 2:1 to get 3 (449 mg) and 4 (53 mg) as a syrup. The trimethylsilyl ether 3 was converted to 4 (368 mg, quant.) by exposure to TFA (0.196 mL, 5 equiv) in aq THF (THF-H₂O, 5:1) overnight.
Synthesis of 8.
To a solution of dry DMSO (133 µL, 1.88 mmol)) in anhyd CH₂Cl₂ (12 mL) at -78 °C was added trifluoroacetic anhydride (200 µL, 1.41 mmol). After 10 min, a solution of compound 4 (307 mg, 0.47 mmol) dissolved in CH₂Cl₂ (8 mL) was added slowly and stirred for 40 min at -78 °C. Then, Et₃N (394 µL, 2.82 mmol) was added dropwise and the reaction was kept at -78 °C for 2 h. The cooling bath was removed and the reaction was quenched with H₂O (10 mL). The organic layer was separated and the aqueous solution was extracted with CH₂Cl₂ (2 × 15 mL). The combined organic solution was dried with anhyd Na₂SO₄, concentrated and purified by flash column chromatography (hexane-EtOAc, 6:1) to give 8 (244 mg, 80%).
Synthesis of 10.
To an ice-cooled solution of 8 (296 mg, 0.45 mmol) and benzylamine (148 µL, 1.36 mmol) in anhyd Et₂O (15 mL) was added dropwise TiCl₄ (0.544 mL of a 1 M solution in CH₂Cl₂, 0.54 mmol) at 0 °C. After complete addition, the ice bath was removed and the reaction mixture was stirred for 4 h. Then, sat. NaHCO₃ solution was added. The organic layer was separated and the water layer extracted with CH₂Cl₂ (2 × 15 mL). The combined organic layer was dried (Na₂SO₄), concentrated and purified by flash column chromatography (hexane-EtOAc, 6:1) to provide a mixture of 8 (30%) and 10 (70%). Complete conversion of 8 to 10 was achieved by repetition of the previous imination procedure to provide 10 (323 mg, 96%).
Synthesis of 12.
To an ice-cooled solution of 10 (240 mg, 0.32 mmol) in MeOH (9 mL) was added NaCNBH₃ (128 mg, 1.95 mmol), followed by 98% AcOH (39 µL, 0.65 mmol). The reaction mixture was stirred for 3 h at 0 °C and then quenched with H₂O (5 mL) and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic extracts were dried (Na₂SO₄), concentrated and purified by flash column chromatography (hexane-EtOAc, 5:1) to afford 12 ( 239 mg, quant.).
Synthesis of 17, 19 and 21.
To a solution of 12 (340 mg, 0.46 mmol) in a 50% mixture of CH₂Cl₂ in Et₂O (12 mL, 1:1) was added iodine (175 mg, 0.69 mmol) at 0 °C. After 5 min, the ice bath was removed and the reaction was stirred for 12 h. The organic layer was washed with sat. Na₂S₂O₃ solution, H₂O (2 mL) and dried (Na₂SO₄). The crude mixture (396 mg) was dissolved in toluene (15 mL), AgOAc (1.146 g, 6.88 mmol) was added and stirred for 12 h. Subsequently, the suspension was filtered and the solution was concentrated under reduced pressure to provide an inseparable mixture of 17, 19 and 21 (323 mg). The mixture was dissolved in MeOH (8 mL), K₂CO₃ (73 mg, 0.53 mmol) was added and stirred for 1 h before quenching with sat. NH₄Cl solution (1 mL) and H₂O (9 mL). The solvent was removed under reduced pressure and the dry residue was dissolved in CH₂Cl₂ (15 mL) and partitioned with H₂O (10 mL). The organic layer was concentrated, dried and purified by flash column chromatography (hexane-EtOAc, from 4:1 to 2:1) to yield 18 (135 mg, 44%), 20 (138 mg, 45%) and 22 (20 mg, 6.5%). Acetylation with a 1:1 mixture of pyridine in Ac₂O afforded compounds 17, 19 and 21 in quantitative yield.