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Synlett 2020; 31(04): 383-387
DOI: 10.1055/s-0039-1690790
letter
© Georg Thieme Verlag Stuttgart · New York

Diastereopure Synthesis of Novel Cyclohexane-Ring-Based Constrained Lanthionine and α-Methyllanthionine through an SN2 Reaction with a β-Bromoalanine as a Key Step

Jaime Gracia-Vitoria 
,
Ángel Carretero
,
Iñaki Osante∗
Departamento de Quimica Organica, Instituto de Sintesis Quimica y Catalisis Homogenea (ISQCH), CSIC-Universidad de Zaragoza, 50009 Zaragoza, Spain   eMail: iosante@unizar.es   eMail: cativiela@unizar.es
,
Carlos Cativiela∗
Departamento de Quimica Organica, Instituto de Sintesis Quimica y Catalisis Homogenea (ISQCH), CSIC-Universidad de Zaragoza, 50009 Zaragoza, Spain   eMail: iosante@unizar.es   eMail: cativiela@unizar.es
› InstitutsangabenFinancial support to this work was provided by MINECO (Ministerio de Economía y Competitividad, grant CTQ2013-40855-R), Gobierno de Aragon–FEDER (Grupo Aminoacidos y Peptidos E19_17R; FEDER 2014-2020 ‘Construyendo Europa desde Aragón’), and Gobierno de Aragon-FSE (Predoctoral fellowship to J.G.-V.).
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Publikationsverlauf

Received: 02. Oktober 2019

Accepted after revision: 17. Dezember 2019

Publikationsdatum:
13. Januar 2020 (online)

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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690790.
  • Supporting Information
 

  • References and Notes

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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, HPh), 7.70 (dd, J = 7.3, 2.2 Hz, 2 H, HPh), 7.40–7.30 (m, 8 H, HPh), 7.25–7.13 (m, 11 H, HPh), 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 (CqPh), 144.0 (CqPh), 143.9 (CqPh), 140.8 (CqPh), 129.3 (CPh), 127.9 (CPh), 127.7 (CPh), 127.22 (CPh), 127.16 (CPh), 126.6 (CPh), 125.4 (CPh), 125.3 (CPh), 120.2 (CPh), 65.4 (Cα or OCH2), 65.0 (Cα 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, HPh), 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 (CqPh), 128.6 (CPh), 128.22 (CPh), 128.18 (CPh), 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, HPh), 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 (CqPh), 128.6 (CPh), 128.2 (CPh), 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.