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; Carlos Cativiela

doi:10.1055/s-0039-1690790

Synlett, Table of Contents

Synlett 2020; 31(04): 383-387
DOI: 10.1055/s-0039-1690790

letter

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

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

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Abstract

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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

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References

References and Notes
1 Present address: Flemish Institute for Technological Research-VITO, Separation & Conversion Technology, Boeretang 200, 2400 Mol, Belgium.
2 Smith RA, M’ikanatha NM, Read AF. Health Commun. 2015; 30: 309
3 Field D, Cotter PD, Hill C, Ross RP. Front. Microbiol. 2015; 6: 1363

4a Sandiford SK. Expert Opin. Drug Discovery 2019; 14: 71
4b Magrone T, Russo MA, Jirillo E. Curr. Pharm. Des. 2018; 24: 1043

5a Moon K, Xu F, Seyedsayamdost MR. Angew. Chem. Int. Ed. 2019; 58: 5973
5b Halami PM. Microb. Pathog. 2019; 128: 139
5c Li Q, Montalban-Lopez M, Kuipers OP. Appl. Environ. Microbiol. 2018; 84: e00052-18
5d Brunati C, Thomsen TT, Gaspari E, Maffioli S, Sosio M, Jabes D, Løbner-Olesen A, Donadio S. J. Antimicrob. Chemother. 2018; 73: 414

6 Mattick AT, Hirsch A. Lancet 1947; 2: 5

7a Delves-Broughton J, Blackburn P, Evans RJ, Hugenholtz J. Antonie van Leeuwenhoek 1996; 2: 193
7b Hurst A. Adv. Appl. Microbiol. 1981; 27: 85

8 Jansen EF, Hirschmann DJ. Arch. Biochem. 1944; 4: 297
9 Kellner R, Jung G, Hörner T, Zähner H, Schnell N, Entian K.-D, Götz F. Eur. J. Biochem. 1988; 177: 53
10 Chatterjee S, Chatterjee S, Lad SJ, Phansalkar MS, Rupp RH, Ganguli BN, Fehlhaber HW, Kogler H. J. Antibiot. 1992; 45: 832
11 Allgaier H, Jung G, Werner RG, Schneider U, Zähner H. Eur. J. Biochem. 1986; 160: 9
12 Dvonch W, Shotwell OL, Benedict RG, Pridham TG, Lindenfelser LA. Antibiot. Chemother. 1954; 4: 1135

For selected recent papers, see ref. 4a and:

13a Wu C, Biswas S, Garcia De Gonzalo CV, van der Donk WA. ACS Infect. Dis. 2019; 5: 454
13b Halami PM. Microb. Pathog. 2019; 128: 139
13c De Luca S, Digilio G, Verdoliva V, Saviano M, Menchise V, Tovillas P, Jiménez-Osés G, Peregrina JM. Org. Lett. 2019; 20: 7478
13d Hetrick KJ, Walker MC, van der Donk WA. ACS Cent. Sci. 2018; 4: 458
13e Hegemann JD, van der Donk WA. J. Am. Chem. Soc. 2018; 140: 5743

14a Draper LA, Cotter PD, Hill C, Ross RP. Microbiol. Mol. Biol. Rev. 2015; 79: 171
14b Bierbaum G, Sahl H.-G. Curr. Pharm. Biotechnol. 2009; 10: 2
14c Héchard Y, Sahl H.-G. Biochimie 2002; 84: 545

15 Bakhtiary A, Cochrane SA, Mercier P, McKay RT, Miskolzie M, Sit CS, Vederas JC. J. Am. Chem. Soc. 2017; 139: 17803

16a Bengtsson T, Lönn J, Khalaf H, Palm E. MicrobiologyOpen 2018; e606
16b Dischinger J, Chipalu SB, Bierbaum G. Int. J. Med. Microbiol. 2014; 304: 51

For the most recent publications, see:

17a Jin X, Park O.-J, Hong SH. Appl. Microbiol. Biotechnol. 2019; 103: 2947
17b Kakkar N, Perez JG, Liu WR, Jewett MC, van der Donk WA. ACS Chem. Biol. 2018; 13: 951

For the latest publication, see:

18a Li Z, Gentry Z, Murphy B, VanNieuwenhze MS. Org. Lett. 2019; 21: 2200

For relevant reviews, see:

18b Denoël T, Lemaire C, Luxen A. Chem. Eur. J. 2018; 24: 15421
18c Tabor AB. Org. Biomol. Chem. 2011; 9: 7606

19a Denoël T, Zervosen A, Lemaire C, Joris B, Hervé M, Blanot D, Zaragoza G, Luxen A. Org. Biomol. Chem. 2014; 12: 9853
19b Denoël T, Zervosen A, Lemaire C, Plenevaux A, Luxen A. Tetrahedron 2014; 70: 4526

20 Smith ND, Goodman M. Org. Lett. 2003; 5: 1035
21 Haya L, Osante I, Mainar AM, Cativiela C, Urieta JS. Phys. Chem. Chem. Phys. 2013; 15: 9407
22 Narayan RS, VanNieuwenhze MS. Org. Lett. 2005; 7: 2655
23 Gracia-Vitoria J, Osante I, Cativiela C, Merino P, Tejero T. J. Org. Chem. 2018; 83: 12471

24a Michurin OM, Afonin S, Berditsch M, Daniliuc CG, Ulrich AS, Komarov IV, Radchenko DS. Angew. Chem. Int. Ed. 2016; 55: 14595
24b Tkachenko AN, Mykhailiuk PK, Radchenko DS, Babii O, Afonin S, Ulrich AS, Komarov IV. Eur. J. Org. Chem. 2014; 3584

For relevant examples, see:

25a Karas JA, Patil NA, Tailhades J, Sani M.-A, Scanlon DB, Forbes BE, Gardiner J, Separovic F, Wade JD, Hossain MA. Angew. Chem. Int. Ed. 2016; 55: 14743
25b Knerr PJ, Tzekou A, Ricklin D, Qu H, Chen H, van der Donk WA, Lambris JD. ACS Chem. Biol. 2011; 6: 753
25c Dmitrenko O, Thorpe C, Bach RD. J. Org. Chem. 2007; 72: 8298
25d Avenoza A, Busto JH, Jiménez-Osés G, Peregrina JM. Org. Lett. 2006; 8: 2855

26a Battenberg OA, Nodwell MB, Sieber SA. J. Org. Chem. 2011; 76: 6075
26b Oh JE, Lee KH. Bioorg. Med. Chem. 1999; 7: 2985

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.

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