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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.
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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.
