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Easy preparation of dehydroalanine building blocks equipped with oxazolidin-2-one chiral auxiliaries, and applications to the stereoselective synthesis of substituted tryptophans

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Abstract

Chiral dehydroamino acid building blocks are versatile starting materials for the preparation of optically active unusual amino acids and other compounds of pharmacological interest. Herein we disclose the expedient preparation of dehydroalanines (ΔAla) equipped with oxazolidin-2-one (Oxd) chiral auxiliaries, Ts-Oxd-ΔAla-OMe. These compounds have been obtained in high yields from dipeptides Ts-Ser/Thr/phenylSer-Ser-OMe by the one-pot cyclization–elimination reaction with N,N-disuccinimidyl carbonate and catalytic DIPEA. To test the efficacy of the chiral auxiliaries in controlling asymmetric transformations, the Friedel–Crafts alkylations of indoles carrying diverse substituents were performed in the presence of Lewis and Brønsted acids. The reactions proceeded with good to excellent diastereomeric ratios giving (S)- or (R)-tryptophan derivatives, isolated very conveniently by simple flash chromatography. To verify the utility of this approach, optically pure (S)-2-methyltryptophan and (S)-5-fluorotryptophan were obtained and utilized to prepare analogues of endogenous opioid peptide endomorphin-1, H-Tyr-Pro-Trp-PheNH2.

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References

  • Alemán C, Casanovas JCA (1995) Molecular conformational analyses of dehydroalanine analogues. Biopolymers 36:71–82. doi:10.1002/bip.360360107

    Article  Google Scholar 

  • Angelini E, Balsamini C, Bartoccini F, Lucarini S, Piersanti G (2008) Switchable reactivity of acylated α, β-dehydroamino ester in the friedel-crafts alkylation of indoles by changing the lewis acid. J Org Chem 73:5654–5657. doi:10.1021/jo800881u

    Article  CAS  PubMed  Google Scholar 

  • Artman GD, Grubbs AW, Williams RM (2007) Concise, asymmetric, stereocontrolled total synthesis of stephacidins A, B and notoamide B. J Am Chem Soc 129:6336–6342. doi:10.1021/ja070259i

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bacsa B, Horváti K, Bõsze S, Andreae F, Kappe CO (2008) Solid-phase synthesis of difficult peptide sequences at elevated temperatures: a critical comparison of microwave and conventional heating technologies. J Org Chem 73:7532–7542. doi:10.1021/jo8013897

    Article  CAS  PubMed  Google Scholar 

  • Bandini M, Melloni A, Tommasi S, Umani-Ronchi A (2005) A Journey across recent advances in catalytic and stereoselective alkylation of indoles. Synlett 8:1199–1222. doi:10.1055/s-2005-865210

    Article  Google Scholar 

  • Bittner S, Scherzer R, Harlev E (2007) The five bromotryptophans. Amino Acids 33:19–42. doi:10.1007/s00726-006-0441-8

    Article  CAS  PubMed  Google Scholar 

  • Blaser G, Sanderson JM, Batsanov AS, Howard JAK (2008) The facile synthesis of a series of tryptophan derivatives. Tetrahedron Lett 49:2795–2798. doi:10.1016/j.tetlet.2008.02.120

    Article  CAS  Google Scholar 

  • Blay G, Cano J, Cardona L, Fernández I, Muñoz MC, Pedro JR, Vila C (2012) NMR spectroscopic characterization and dft calculations of Zirconium(IV)-3,3-Br 2-BINOLate and related complexes used in an enantioselective Friedel–Crafts alkylation of indoles with α, β-unsaturated ketones. J Org Chem 77:10545–10556. doi:10.1021/jo3013594

    Article  CAS  PubMed  Google Scholar 

  • Bonauer C, Walenzyk T, König B (2006) α, β-Dehydroamino acids. Synthesis 1:1–20. doi:10.1055/s-2005-921759

    Google Scholar 

  • Bull SD, Davies SG, Garner AC, O’Shea MD (2001) Conjugate additions of organocuprates to a 3-methylene-6-isopropyldiketopiperazine acceptor for the asymmetric synthesis of homochiral α-amino acids. J Chem Soc Perkin Trans 1:3281–3287. doi:10.1039/B108621A

    Google Scholar 

  • Castellino S, Dwight WJ (1993) Et2AlCI complexes of an N-acyloxazolidinone: NMR investigation. J Am Chem Soc 115:2986–2987. doi:10.1021/ja00060a061

    Article  CAS  Google Scholar 

  • Castle SL, Srikanth GSC (2003) Catalytic asymmetric synthesis of the central tryptophan residue of celogentin C. Org Lett 5:3611–3614. doi:10.1021/ol035236x

    Article  CAS  PubMed  Google Scholar 

  • De Marco R, Tolomelli A, Campitiello M, Rubini P, Gentilucci L (2012a) Expedient synthesis of pseudo-Pro-containing peptides: towards constrained peptidomimetics and foldamers. Org Biomol Chem 10:2307–2317. doi:10.1039/C2OB07172J

    Article  PubMed  Google Scholar 

  • De Marco R, Tolomelli A, Spampinato S, Bedini A, Gentilucci L (2012b) Opioid activity profiles of oversimplified peptides lacking in the protonable N-terminus. J Med Chem 55(22):10292–10296. doi:10.1021/jm301213s

    Article  PubMed  Google Scholar 

  • De Marco R, Greco A, Rupiani S, Tolomelli A, Tomasini C, Pieraccini S, Gentilucci L (2013) In-peptide synthesis of di-oxazolidinone and dehydroamino acid-oxazolidinone motifs as β-turn inducers. Org Biomol Chem 11:4316–4326. doi:10.1039/c3ob40357b

    Article  PubMed  Google Scholar 

  • De Marco R, Bedini A, Spampinato S, Gentilucci L (2014) Synthesis of tripeptides containing D-Trp substituted at the indole ring, assessment of opioid receptor binding and in vivo central antinociception. J Med Chem 57(15):6861–6866. doi:10.1021/jm5002925

    Article  PubMed  Google Scholar 

  • Deng X, Mani NS (2006) A facile, environmentally benign sulfonamide synthesis in water. Green Chem 8(9):835–838. doi:10.1039/b606127c

    Article  CAS  Google Scholar 

  • Drury WJ, Ferraris D, Cox C, Young B, Lectka T (1998) A novel synthesis of α-amino acid derivatives through catalytic, enantioselective ene reactions of α-imino esters. J Am Chem Soc 120:11006–11007. doi:10.1021/ja982257r

    Article  CAS  Google Scholar 

  • Duhamel L, Duhamel P, Plaquevent JC (2004) Enantioselective protonations: fundamental insights and new concepts. Tetrahedron Asymmetry 15:3653–3691. doi:10.1016/j.tetasy.2004.09.035

    Article  CAS  Google Scholar 

  • Ferreira PMT, Maia HLS, Monteiro LS, Sacramento J (1999) High yielding synthesis of dehydroamino acid and dehydropeptide derivatives. J Chem Soc Perkin Trans 1(24):3697–3703. doi:10.1039/A904730A

    Article  Google Scholar 

  • Fichna J, Janecka A, Costentin J, Do Rego JC (2007) The endomorphin system and its evolving neurophysiological role. Pharmacol Rev 59(1):88–123. doi:10.1124/pr.59.1.3

    Article  CAS  PubMed  Google Scholar 

  • Galonić DP, van der Donk WA, Gin DY (2003) Oligosaccharide–peptide ligation of glycosyl thiolates with dehydropeptides: synthesis of s-linked mucin-related glycopeptide conjugates. Chem Eur J 9(24):5997–6006. doi:10.1002/chem.200305290

    Article  PubMed  Google Scholar 

  • Gentilucci L (2004) New trends in the development of opioid peptide analogues as advanced remedies for pain relief. Curr Topics Med Chem 4:19–38. doi:10.2174/1568026043451663

    Article  CAS  Google Scholar 

  • Gentilucci L, Squassabia F, Demarco R, Artali R, Cardillo G, Tolomelli A, Spampinato S, Bedini A (2008) Investigation of the interaction between the atypical agonist c[YpwFG] and MOR. FEBS J 275:2315–2337. doi:10.1111/j.1742-4658.2008.06386.x

    Article  CAS  PubMed  Google Scholar 

  • Gentilucci L, Cerisoli L, De Marco R, Tolomelli A (2010) A simple route towards peptide analogues containing substituted (S)- or (R)-tryptophans. Tetrahedron Lett 51:2576–2579. doi:10.1016/j.tetlet.2010.03.017

    Article  CAS  Google Scholar 

  • Gentilucci L, Tolomelli A, De Marco R, Spampinato S, Bedini A, Artali R (2011a) The inverse type II β-turn on D-Trp-Phe, a pharmacophoric motif for MOR agonists. ChemMedChem 6:1640–1653. doi:10.1002/cmdc.201100169

    Article  CAS  PubMed  Google Scholar 

  • Gentilucci L, Tolomelli A, De Marco R, Tomasini C, Feddersen S (2011b) Synthesis of constrained peptidomimetics containing 2-Oxo-1,3-oxazolidine-4-carboxylic acids. Eur J Org Chem 25:4925–4930. doi:10.1002/ejoc.201100346

    Google Scholar 

  • Goss RJM, Newil PLA (2006) A convenient enzymatic synthesis of L-halotryptophans. Chem Commun 47:4924–4925. doi:10.1039/B611929H

    Article  Google Scholar 

  • Greco A, Tani S, De Marco R, Gentilucci L (2014a) Synthesis and analysis of the conformational preferences of 5-aminomethyloxazolidine-2,4-dione scaffolds, first examples of β2- and β2,2-homo-Freidinger lactam analogs. Chem Eur J 20. doi:10.1002/chem.201402519

  • Greco A, De Marco R, Tani S, Giacomini D, Galletti P, Tolomelli A, Juaristi E, Gentilucci L (2014b) Convenient synthesis of the antibiotic linezolid via a oxazolidine-2,4-dione intermediate derived from the chiral building block isoserine. Eur J Org Chem submitted

  • He B, Hao S, Yu D, Yong Q (2009) Total synthesis of (-)-Ardeemin. J Org Chem 74:298–304. doi:10.1021/jo802216z

    Article  CAS  PubMed  Google Scholar 

  • Humphrey JM, Chamberlin AR (1997) Chemical synthesis of natural product peptides: coupling methods for the incorporation of noncoded amino acids into peptides. Chem Rev 97(6):2243–2266. doi:10.1021/cr950005s

    Article  CAS  PubMed  Google Scholar 

  • Irie K, Ishida A, Nakamura T, Oh-Ishi T (1984) Syntheses of substituted L- and d-tryptophans. Chem Pharm Bull 32(6):2126–2139. doi:10.1248/cpb.32.2126

    Article  CAS  Google Scholar 

  • Ishihara K, Nakashima D, Hiraiwa Y, Yamamoto HJ (2003) The crystallographic structure of a Lewis acid-assisted chiral Brønsted acid as an enantioselective protonation reagent for silyl enol ethers. J Am Chem Soc 125(1):24–25. doi:10.1021/ja021000x

    Article  CAS  PubMed  Google Scholar 

  • Ishihara K, Fushimi N, Akakura M (2007) Rational design of minimal artificial diels–alderases based on the copper(ii) cation–aromatic π attractive interaction. Acc Chem Res 40(10):1049–1055. doi:10.1021/ar700083a

    Article  CAS  PubMed  Google Scholar 

  • Javidan A, Schafer K, Pyne SG (1997) Diastereoselective michael reactions of azomethine ylides to chiral 4-methyleneoxazolidin-5-ones: synthesis of the four stereoisomers of 4-benzamindopyroglutamate. Synlett 1:100–102. doi:10.1055/s-1997-683

    Article  Google Scholar 

  • Jia YX, Zhong J, Zhu SF, Zhang CM, Zhou QL (2007) Chiral brønsted acid catalyzed enantioselective friedel–crafts reaction of indoles and α-aryl enamides: construction of quaternary carbon atoms. Angew Chem Int Ed 46:5565–5567. doi:10.1002/anie.200701067

    Article  CAS  Google Scholar 

  • Jones GB, Chapman BJ (1995) π stacking effects in asymmetric synthesis. Synthesis 5:475–497. doi:10.1055/s-002-328

    Article  Google Scholar 

  • Keresztes A, Borics A, Tóth G (2010) Recent advances in endomorphin engineering. ChemMedChem 5(8):1176–1196. doi:10.1002/cmdc.201000077

    Article  CAS  PubMed  Google Scholar 

  • Kieffer ME, Repka LM, Reisman SE (2012) Enantioselective synthesis of tryptophan derivatives by a tandem Friedel–Crafts conjugate addition/asymmetric protonation reaction. J Am Chem Soc 134:5131–5137. doi:10.1021/ja209390d

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Konda-Yamada Y, Okada C, Yoshida K, Umeda Y, Arima S, Sato N, Kai T, Takayanagi H, Harigaya Y (2002) Convenient synthesis of 7′ and 6-bromo-D-tryptophan and their derivatives by enzymatic optical resolution using D-aminoacylase. Tetrahedron 58(39):7851–7861. doi:10.1016/S0040-4020(02)00909-2

    Article  CAS  Google Scholar 

  • Krenske EH, Houk KN (2013) Aromatic interactions as control elements in stereoselective organic reactions. Acc Chem Res 46(4):979–989. doi:10.1021/ar3000794

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li X, Yin W, Srirama Sarma PVV, Zhou H, Ma J, Cook JM (2004) Synthesis of optically active ring-A substituted tryptophans as IDO inhibitors. Tetrahedron Lett 45(46):8569–8573. doi:10.1016/j.tetlet.2004.09.113

    Article  CAS  Google Scholar 

  • Lipkowski AW, Misicka A, Carr DB, Ronsisvalle G, Kosson D, Bonney MI (2004) Neuropeptide mimetics for pain management. Pure Appl Chem 76(5):941–950. doi:10.1351/pac200476050941

    Article  CAS  Google Scholar 

  • Ma C, Liu X, Li X, Flippen-Anderson J, Yu S, Cook J (2001) Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction. J Org Chem 66:4525–4542. doi:10.1021/jo001679s

    Article  CAS  PubMed  Google Scholar 

  • Mahrwald R (2004) Modern aldol reactions vol 1: enolates, organocatalysis, biocatalysis and natural product synthesis. Wiley, Weinheim, pp 1–328

  • Marcaccini S, Neo AG, Marcos CF (2009) Sequential five-component synthesis of spiropyrrolidinochromanones. J Org Chem 74(17):6888–6890. doi:10.1021/jo900992w

    Article  CAS  PubMed  Google Scholar 

  • Mocek U, Zeng Z, O’Hagan D, Zhou P, Fan LDG, Beale JM, Floss HG (1993) Biosynthesis of the modified peptide antibiotic thiostrepton in Streptomyces azureus and Streptomyces laurentii. J Am Chem Soc 115(18):7992–8001. doi:10.1021/ja00071a009

    Article  CAS  Google Scholar 

  • Ojima I, Kwon HB (1988) Remarkable effects of a pentafluorophenyl group on the stereoselective reactions of a chiral iron acyl complex. J Am Chem Soc 110:5617–5621. doi:10.1021/ja00225a004

    Article  CAS  Google Scholar 

  • Ousmer M, Braun NA, Bavoux C, Perrin M, Ciufolini MA (2001) Total synthesis of tricyclic azaspirane derivatives of tyrosine: FR901483 and TAN1251C. J Am Chem Soc 123:7534–7538. doi:10.1021/ja016030z

    Article  CAS  PubMed  Google Scholar 

  • Padmanabhan B, Dey S, Khandelwal B, Rao GS, Singh TP (1992) Design of peptide : synthesis, crystal structure, molecular conformation, and conformational calculations of N-Boc-L-Phe-Dehydro-Ala-OME. Biopolymers 32:1271–1276. doi:10.1002/bip.360321002

    Article  CAS  PubMed  Google Scholar 

  • Perry CW, Brossi A, Deitcher KH, Tautz W, Teitel S (1977) Preparation of R(+)- and S(-)-α-methyl-p-nitrobenzylamines and their use as resolving agents. Synthesis 7:492–493. doi:10.1055/s-1977-24459

    Article  Google Scholar 

  • Polinsky A, Cooney MG, Toy-Palmer A, Osapay G, Goodman M (1992) Synthesis and conformational properties of the lanthionine-bridged opioid peptide [D-AlaL2, AlaL5]enkephalin as determined by NMR and computer simulations. J Med Chem 35(22):4185–4194. doi:10.1021/jm00100a026

    Article  CAS  PubMed  Google Scholar 

  • Porter J, Dykert J, Rivier J (1987) Synthesis, resolution and characterization of ring substituted phenylalanines and tryptophans. J Pept Prot Res 30(1):13–21. doi:10.1111/j.1399-3011.1987.tb03307.x

    Article  CAS  Google Scholar 

  • Prieto M, Mayor S, Lloyd-Williams P, Giralt E (2009) Use of the SPhos ligand to suppress racemization in arylpinacolboronate ester Suzuki couplings involving r-amino acids. Synthesis of biaryl derivatives of 4-Hydroxyphenylglycine, tyrosine, and tryptophan. J Org Chem 74:9202–9205. doi:10.1021/jo901899w

    Article  CAS  PubMed  Google Scholar 

  • Pyne SG, Javidan A, Skeleton BW, White AH (1995) Asymmetric synthesis of proline derivatives from (2R) and (2S)-2-tert-butyl-3-benzoyl-4-methyleneoxazolidin-5-one. Tetrahedron 51(17):5157–5168. doi:10.1016/0040-4020(95)98711-P

    Article  CAS  Google Scholar 

  • Rajashankar KR, Ramakumar S, Chauhan VS (1992) Design of a helical motif using α,β-dehydrophenylalanine residues: crystal structure of Boc-Val-Δ-Phe-Phe-Ala-Phe-Δ-Phe-Val-Δ-Phe-Gly-OCH3, a 310-helical nonapeptide. J Am Chem Soc 114(23):9225–9226. doi:10.1021/ja00049a086

    Article  CAS  Google Scholar 

  • Royer CA (2006) Probing protein folding and conformational transitions with fluorescence. Chem Rev 106:1769–1784. doi:10.1021/cr0404390

    Article  CAS  PubMed  Google Scholar 

  • Rzeszotarska B, Siodlak D, Broda MA, Dybala I, Koziol AE (2002) Conformational investigation of α, β-dehydropeptides. X. Molecular and crystal structure of Ac-ΔAla-NMe2 compared with those of Ac-l-Ala-NMe2, Ac-dl-Ala-NMe2 and other dimethylamides. J Pept Res 59:79–89. doi:10.1034/j.1399-3011.2002.10951.x

    Article  CAS  PubMed  Google Scholar 

  • Schmidt U, Lieberknecht A, Wild J (1988) Didehydroamino acids (DDAA) and didehydropeptides (DDP). Synthesis 3:159–172. doi:10.1055/s-1988-27503

    Article  Google Scholar 

  • Sibi MP, Coulomb J, Stanley LM (2008) Enantioselective enolate protonations: Friedel-Crafts reactions with α-substituted acrylates. Angew Chem Int Ed 47(51):9913–9915. doi:10.1002/anie.200804221

    Article  CAS  Google Scholar 

  • Smith DR, Willemse T, Gkotsi DS, Schepens W, Maes BU, Ballet S, Goss RJ (2014) The first one-pot synthesis of l-7-iodotryptophan from 7-iodoindole and serine, and an improved synthesis of other l-7-halotryptophans. Org Lett 16(10):2622–2625. doi:10.1021/ol5007746

    Article  CAS  PubMed  Google Scholar 

  • Stammer CH (1982) In chemistry and biochemistry of amino acids, peptides, and proteins; Weinstein B (Ed) Dekker, New York. pp 33–74

  • Tabatabaeian K, Mamaghani M, Mahmoodi NO, Khorshidi A (2007) RuIII-catalyzed double-conjugate 1,4-addition of indoles to symmetric enones. J Mol Cat A 270:112–116. doi:10.1016/j.molcata.2007.01.038

    Article  CAS  Google Scholar 

  • Witt KA, Gillespie TJ, Huber JD, Egleton RD, Davis TP (2001) Peptide drug modifications to enhance bioavailability and blood-brain barrier permeability. Peptides 22:2329–2343. doi:10.1016/S0196-9781(01)00537-X

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Zhang F, Zhang L, Jia Y (2011) Total synthesis of (-)-indolactam V. Org Biomol Chem 9:2512–2517. doi:10.1039/C0OB01115K

    Article  CAS  PubMed  Google Scholar 

  • Yabe Y, Miura C, Horikoshi H, Miyagawa H, Baba Y (1979) Synthesis and biological activity of LH-RH analogs substituted by alkyltryptophans at position 3. Chem Pharm Bull 27(8):1907–1911. doi:10.1248/cpb.27.1907

    Article  CAS  PubMed  Google Scholar 

  • Yeh E, Garneau S, Walsh CT (2005) Robust in vitro activity of RebF and RebH, a two-component reductase/halogenase, generating 7-chlorotryptophan during rebeccamycin biosynthesis. Proc Natl Acad Sci USA 102:3960–3965. doi:10.1073/pnas.0500755102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zadina JE, Hackler L, Ge LJ, Kastin AJ (1997) A potent and selective endogenous agonist for the mu-opiate receptor. Nature 383:499–502. doi:10.1038/386499a0

    Article  Google Scholar 

  • Zappia G, Cancelliere G, Gacs-Baitz E, Delle Monache G, Misiti D, Nevola L, Botta B (2007) Oxazolidin-2-one ring, a popular framework in synthetic organic chemistry part 2. applications and modifications. Curr Org Synth 4:238–307. doi:10.2174/157017907781369306

    Article  CAS  Google Scholar 

  • Zheng BH, Ding CH, Hou XL, Dai LX (2010) Ag-catalyzed diastereo- and enantioselective synthesis of β-substituted tryptophans from sulfonylindoles. Org Lett 12:1688–1691. doi:10.1021/ol100161n

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank MIUR (PRIN 2010), Fondazione Umberto Veronesi, and the Italian Ministry for Foreign Affairs (bilateral project Italy-Mexico) for financial support; Krizia Scarpa and Marilena Campitiello for collaboration.

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The authors declare that they have no conflict of interest.

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  1. Department of Chemistry, G. Ciamician University of Bologna, via Selmi 2, 40126, Bologna, Italy

    Rossella De Marco, Lorenzo Cavina, Arianna Greco & Luca Gentilucci

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  1. Rossella De Marco
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  2. Lorenzo Cavina
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  3. Arianna Greco
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  4. Luca Gentilucci
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Correspondence to Rossella De Marco.

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De Marco, R., Cavina, L., Greco, A. et al. Easy preparation of dehydroalanine building blocks equipped with oxazolidin-2-one chiral auxiliaries, and applications to the stereoselective synthesis of substituted tryptophans. Amino Acids 46, 2823–2839 (2014). https://doi.org/10.1007/s00726-014-1839-3

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