Diastereopure Synthesis of Novel Cyclohexane-Ring-Based Constrained Lanthionine and α-Methyllanthionine through an S_N2 Reaction with a β-Bromoalanine as a Key Step

Abstract

Here we report the diastereopure synthesis of a novel protected lanthionine derivative substituted with a cyclohexane ring as well as the diastereopure synthesis of an α-methyllanthionine derivative. By starting from enantiopure α,β-cyclohexane-substituted cystine, or α-methylcysteine, we designed a straightforward route that permits the preparation of orthogonally protected modified lanthionines in diastereopure form. The key step of the methodology is the formation of a thioether bond through the use of an β-bromoalanine derivative. The strategy developed should be valuable in the preparation of a wide range of modified constrained lanthionines that might be finally attached to a peptide sequence, which would be especially useful in the syntheses of novel lantibiotics.

Key words

lanthionines - cysteine - cystine - asymmetric synthesis - medicinal chemistry

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• 27 N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-2-methyl-S-trityl-l-cysteine (6) A solution of FmocOSu (0.92 g, 2.6 mmol) in 1,4-dioxane (10 mL) was gently added to a solution of H-l-(αMe)Cys(Trt)-OH (5; 1.0 g, 2.7 mmol) and Na₂CO₃ (0.7 g, 6.6 mmol) in H₂O (10 mL) at 0 °C, and the mixture stirred for 1 d. H₂O (20 mL) and EtOAc (20 mL) were then added with stirring. The phases were separated, and the aqueous phase was extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with 0.2 M aq HCl (2 × 20 mL) and sat. aq NaCl (2 × 20 mL) then dried (MgSO₄), filtered, and concentrated. The resulting oil was purified by column chromatography (silica gel, 50% hexane–EtOAc) to give a white solid; yield: 1.3 g (2.2 mmol, 83%); mp 214–216 °C. [α]_D ²⁴ +47 (c 0.1, CH₃OH). IR (KBr): 3390, 2924, 2854, 1680, 1596, 1489, 1461, 1405, 1377, 1262 cm^–1. ¹H NMR (400 MHz, CD₃OD): δ = 7.78 (d, J = 7.6 Hz, 2 H, H_Ph), 7.70 (dd, J = 7.3, 2.2 Hz, 2 H, H_Ph), 7.40–7.30 (m, 8 H, H_Ph), 7.25–7.13 (m, 11 H, H_Ph), 4.34–4.21 (m, 3 H, CH ₂ + CH Fmoc), 2.98 (d, J = 11.0 Hz, 1 H, CH ₂), 2.74 (d, J = 11.2 Hz, 1 H, CH ₂), 1.35 (s, 3 H, CH ₃). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 174.9 (CO₂H), 154.0 (CONH), 144.8 (C_qPh), 144.0 (C_qPh), 143.9 (C_qPh), 140.8 (C_qPh), 129.3 (C_Ph), 127.9 (C_Ph), 127.7 (C_Ph), 127.22 (C_Ph), 127.16 (C_Ph), 126.6 (C_Ph), 125.4 (C_Ph), 125.3 (C_Ph), 120.2 (C_Ph), 65.4 (C_α or OCH₂), 65.0 (C_α or OCH₂), 58.2 (CH₂), 46.8 (CH), 23.8 (CH₃). HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₃₈H₃₃NNaO₄S: 622.2023; found: 622.2018. Dimethyl (1R,2R,1'R,2'R)-2,2'-Disulfanediylbis(1-{[(benzyl­oxy)carbonyl]amino}cyclohexanecarboxylate) (15) DIPEA (0.41 mL, 2.40 mmol) and TMSCl (0.20 mL, 1.60 mmol) were added to a solution of 11 ²² (0.14 g, 0.40 mmol) in anhyd CH₂Cl₂ (7 mL) at 0 °C, and the mixture was stirred for 30 min at 0 °C. CbzOSu (0.22 g, 0.88 mmol) was added and the mixture was stirred for 1 d. The mixture was then reloaded with 2.2 equivalents of CbzOSu (0.22 g, 0.88 mmol) and stirred for 4 d. The solvent was then evaporated off and the crude product was partitioned between 5% aq NaHCO₃ (5 mL) and Et₂O (5 mL). The organic layer was discarded and the aqueous phase was acidified with 1 N aq HCl to pH 1. The aqueous phase was extracted with EtOAc (3 × 15 mL), and the combined organic layers were washed with H₂O (5 mL), dried (MgSO₄), filtered, and concentrated under vacuum. Without purification, the resulting product 19 (0.22 g, 0.36 mmol) was dissolved in 2:1 toluene–MeOH (4.5 mL), TMSCHN₂ (1.07 mL, 2.14 mmol) was added, and the mixture was allowed to react for 2 h. Silica gel was added to quench the excess diazo compound, and the crude product was collected by filtration and dried under vacuum. The resulting solid was purified by column chromatography (silica gel 80% hexane–EtOAc) to give 15 as a colorless oil; yield: 0.17 g (0.26 mmol, 66% over two steps); [α]_D ²³ +125 (c 0.8; CHCl₃). IR (neat): 3362, 1714, 1497, 1450, 1280, 1225, 1055 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.29 (m, 10 H, H_Ph), 5.34 (br s, 2 H, NH), 5.13 (d, J = 12.2, 2 H, CH ₂Ph), 5.06 (d, J = 12.3, 2 H, CH ₂Ph), 3.68 (s, 6 H, OCH ₃), 3.36 (dd, J = 11.4, 3.4, 2 H, H₂), 2.83 (d, J = 12.0, 2 H, CH ₂), 2.03–1.98 (m, 2 H, CH ₂), 1.85–1.79 (m, 2 H, CH ₂), 1.74–1.73 (m, 2 H, CH ₂), 1.59–1.39 (m, 8 H, CH ₂). ¹³C NMR (100 MHz, CDCl₃): δ = 172.9 (CO₂Me), 155.6 (CONH), 136.5 (C_qPh), 128.6 (C_Ph), 128.22 (C_Ph), 128.18 (C_Ph), 66.8 (CH₂Ph), 62.9 (C₁), 55.1 (C₂), 52.8 (OCH₃), 32.1 (CH₂), 27.7 (CH₂), 25.4 (CH₂), 20.3 (CH₂). HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₃₂H₄₀N₂NaO₈S₂: 667.2118; found: 667.2131. Methyl (1R,2R)-1-{[(Benzyloxy)carbonyl]amino}-2-({(2R)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}sulfanyl)cyclohexanecarboxylate (18) PBu₃ (52 μL, 0.20 mmol) was added to a solution of 15 (0.12 g, 0.18 mmol) in THF (4 mL) and H₂O (0.2 mL), and the mixture was stirred for 5 min at r.t. The solvent was evaporated under vacuum and the crude product was purified by column chromatography [silica gel, EtOAc–hexane (10:90)]. The resulting thiol 16 was quickly used in the next reaction to prevent formation of the disulfide bridge. To a solution of thiol 16 (0.10 g, 0.32 mmol) and the β-bromoalanine derivative 17 ²⁶ (0.23 g, 0.65 mmol) in EtOAc (5 mL) were added a solution of Cs₂CO₃ (0.42 g, 1.32 mmol) in H₂O (2 mL, pH ≈ 12) and Bu₄N·HSO₄ (0.44 g, 1.30 mmol), and the mixture was stirred at r.t. for 20 h. The phases were then separated and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with sat. aq NaHCO₃ (5 mL) and brine (5 mL), and the final organic layer was dried (MgSO₄), filtered, and concentrated under vacuum. The resulting solid was purified by column chromatography (silica gel, 93% CH₂Cl₂–Et₂O) to give 18 as a colorless oil; yield: 0.10 g (0.19 mmol, 53% for the two reaction steps); [α]_D ²⁵ +39 (c 0.7; CHCl₃). IR (neat): 3358, 1710, 1497, 1452, 1280, 1222, 1160, 1054 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.37–7.29 (m, 5 H, H_Ph), 5.34 (d, J = 7.2, 1 H, NHBoc), 5.18 (s, 1 H, NHCbz), 5.12 (d, J = 12.2, 1 H, CH ₂Ph), 5.08 (d, J = 12.6, 1 H, CH ₂Ph), 4.50–4.49 (m, 1 H, CH–CH₂S), 3.74 (s, 3 H, OCH ₃), 3.73 (s, 3 H, OCH ₃), 3.26 (dd, J = 11.2, 3.7, 1 H, H₂), 2.93 (dd, J = 13.8, 4.5, 1 H, CH ₂), 2.87 (dd, J = 13.7, 4.9, 1 H, CH ₂S), 2.79 (d, J = 11.1, 1 H, CH ₂S), 1.93–1.80 (m, 2 H, CH ₂), 1.73–1.70 (m, 1 H, CH ₂), 1.61–1.51 (m, 2 H, CH ₂), 1.47–1.36 (m, 2 H, CH ₂), 1.44 [s, 9 H, C(CH ₃)₃]. ¹³C NMR (100 MHz, CDCl₃): δ = 173.1 (CO₂Me), 171.1 (CO₂Me), 155.8 (CONH), 155.1 (CONH), 136.5 (C_qPh), 128.6 (C_Ph), 128.2 (C_Ph), 80.4 [C(CH₃)₃], 66.8 (CH₂Ph), 63.5 (C₁), 53.9 (CH–CH₂S), 52.8 (OCH₃), 52.7 (OCH₃), 50.9 (C₂), 34.0 (CH₂), 31.8 (CH₂), 29.6 (CH₂), 28.4 [C(CH₃)₃], 25.2 (CH₂), 20.3 (CH₂). HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₅H₃₆N₂NaO₈S:547.2085; found: 547.2091.