Download PDF
Synlett 2008(15): 2355-2359  
DOI: 10.1055/s-2008-1078209
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of Arylomycin A2, a Signal Peptidase I (SPase I) Inhibitor

Jeremy Dufour, Luc Neuville*, Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax: +33(1)69077247; e-Mail: neuville@icsn.cnrs-gif.fr; e-Mail: zhu@icsn.cnrs-gif.fr;
Further Information

Publication History

Received 23 May 2008
Publication Date:
22 August 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

A concise total synthesis of arylomycin A2 has been accomplished featuring a key intramolecular Suzuki-Miyaura reaction for the formation of the 14-membered meta,meta-cyclophane and direct coupling of a fully elaborated peptide side chain with the macrocyclic core.

Key words

total synthesis - cross-coupling - palladium - macrocycles - antibiotics

    References and Notes

  • 1a Höltzel A. Schmid DG. Nicholson GJ. Stevanovic S. Schimana J. Gebhardt K. Friedler HP. Jung GJ. J. Antibiot.  2002,  55:  571 
    Google Scholar
  • 1b Schimana J. Gebhardt K. Höltzel A. Schmid DG. Süssmuth R. Müller J. Pukall R. Friedler HP. J. Antibiot.  2002,  55:  565 
    Google Scholar
  • 2 Kulanthaivel P. Kreuzman AJ. Strege MA. Belvo MD. Smitka TA. Clemens M. Swartling JR. Minton KL. Zheng F. Angleton EL. Mullen D. Jungheim LN. Klimkowski VJ. Nicas TI. Thompson RC. Peng S.-B. J. Biol. Chem.  2004,  279:  36250 
    Google Scholar
  • 3 Paetzel M. Karla A. Strynadka NC. Dalbey RE. Chem. Rev.  2002,  102:  4549 
    CrossrefPubMedGoogle Scholar
  • 4a Brown ED. Wright GD. Chem. Rev.  2005,  105:  759 
    Google Scholar
  • 4b Zhu J. Expert Opin. Ther. Pat.  1999,  9:  1005 
    Google Scholar
  • 4c Nicolaou KC. Boddy CNC. Bräse S. Winssinger N. Angew. Chem. Int. Ed.  1999,  38:  2096 
    Google Scholar
  • 4d Williams D. Bardsley B. Angew. Chem. Int. Ed.  1999,  38:  1172 
    Google Scholar
  • 4e Kahne D. Leimkuhler C. Lu W. Walsh CT. Chem. Rev.  2005,  105:  425 
    Google Scholar
  • For reviews on aryl-bridged natural products, see:
  • 5a Feliu L. Planas M. Int. J. Pept. Res. Ther.  2005,  11:  53 
    Google Scholar
  • 5b Zhu J. Islas-Gonzalez G. Bois-Choussy M. Org. Prep. Proced. Int.  2000,  32:  505 
    Google Scholar
  • 6 Paetzel M. Goodall JJ. Kania M. Dalbey RE. Paghe MG. J. Biol. Chem.  2004,  279:  30781 
    CrossrefPubMedGoogle Scholar
  • For biaryl-containing macrocycles, see:
  • 7a Carbonnelle A.-C. Zhu J. Org. Lett.  2000,  2:  3477 
    Google Scholar
  • 7b Boisnard S. Carbonnelle A.-C. Zhu J. Org. Lett.  2001,  3:  2061 
    Google Scholar
  • 7c Jia X. Bois-Choussy M. Zhu J. Org. Lett.  2007,  9:  2401 
    Google Scholar
  • 7d Lépine R. Zhu J. Org. Lett.  2005,  7:  2981 
    Google Scholar
  • 7e Bois-Choussy M. Cristau P. Zhu J. Angew. Chem. Int. Ed.  2003,  42:  4238 
    Google Scholar
  • 7f Jia X. Bois-Choussy M. Zhu J. Angew. Chem. Int. Ed.  2008,  47:  4167 
    Google Scholar
  • 8 Roberts TC. Smith PA. Cirz RT. Romesberg FE. J. Am. Chem. Soc.  2007,  129:  15830 
    Google Scholar
  • 9a Freidinger RM. Hinkle JS. Perlow DS. Arison BH. J. Org. Chem.  1983,  48:  77 
    Google Scholar
  • 9b Aurelio L. Browlee RTC. Hughes AB. Sleebs BE. Aust. J. Chem.  2000,  53:  425 
    Google Scholar
  • 9c Aurelio L. Browlee RTC. Hughes AB. Chem. Rev.  2005,  104:  5823 
    Google Scholar
  • 10 Barnett R. Andrews LJ. Keefer RM. J. Am. Chem. Soc.  1972,  94:  6129 
    CrossrefGoogle Scholar
  • 12 Chiarello J. Joullié MM. Synth. Commun.  1988,  18:  2211 
    CrossrefGoogle Scholar
  • 14 Ishiyama T. Murata M. Miyaura M. J. Org. Chem.  1995,  60:  7508 
    CrossrefGoogle Scholar
  • 15 For a related methylation of boron-containing peptide, see: Deng H. Jung J.-K. Liu T. Kuntz KW. Snapper ML. Hoveyda AH. J. Am. Chem. Soc.  2003,  125:  9032 
    CrossrefPubMedGoogle Scholar
  • 16a Elder AM. Rich DH. Org. Lett.  1999,  1:  1443 
    Google Scholar
  • 16b Li W. Burgess K. Tetrahedron Lett.  1999,  40:  6527 
    Google Scholar
  • 16c Lobrégat V. Alcaraz G. Bienaymé H. Vaultier M. Chem. Commun.  2001,  817 
    Google Scholar
  • 16d Kaiser M. Siciliano C. Assfalg-Machleidt I. Groll M. Milbradt AG. Moroder L. Org. Lett.  2003,  5:  3435 
    Google Scholar
  • 16e Shinohara T. Deng H. Snapper ML. Hoveyda AH. J. Am. Chem. Soc.  2005,  127:  7334 
    Google Scholar
  • For recent reviews, see:
  • 18a Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 
    Google Scholar
  • 18b de la Hoz A. Diaz-Ortiz A. Moreno A. Chem. Soc. Rev.  2005,  34:  164 
    Google Scholar
  • 19 For a review on conformation-directed macrocyclization, see: Blankenstein J. Zhu J. Eur. J. Org. Chem.  2005,  1949 
    CrossrefGoogle Scholar
  • 20 We synthesized isolauric acid following a Cu-catalyzed coupling of a Grignard reagent with an alkylbromide according to: Cahiez G. Chaboche C. Jézéquel M. Tetrahedron  2000,  56:  2733 
    CrossrefGoogle Scholar
  • 21a Furlan RLE. Mata EG. Mascaretti AO. J. Chem. Soc., Perkin Trans. 1  1998,  355 
    Google Scholar
  • 21b Nicolaou KC. Estrada AA. Zak M. Lee SH. Safina BS. Angew. Chem. Int. Ed.  2005,  44:  1378 
    Google Scholar
  • 22 Bigot A. Tran Huu Dau ME. Zhu J. J. Org. Chem.  1999,  64:  6283 
    CrossrefGoogle Scholar
  • 23 Li H. Jiang X. Fan C. Romoff T. Goodman M. Org. Lett.  1999,  1:  91 
    CrossrefPubMedGoogle Scholar
11

Selected Physical and Spectroscopic Data
Compound 10: [α]D ²5 +86 (c 0.9, MeOH). ¹H NMR (300 MHz, MeOD): δ = 7.61 (d, J = 2.0 Hz, 1 H), 7.12 (dd, J = 8.3, 2.0 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 5.47 (s, 1 H), 2.66 (s, 3 H), 1.48 (s, 9 H) ppm. HRMS (ES+): m/z calcd for C14H18NO5NaI [M + Na]+: 430.0127; found: 430.0128.
Compound 5: [α]D ²5 +16 (c 1.0, CHCl3). ¹H NMR (300 MHz, CDCl3, 1:1 mixture of rotamers): δ = 7.72 and 7.71 (d, J = 2.2 Hz, 1 H), 7.42 and 7.30 (d, J = 2.3 Hz, 1 H), 7.29-7.24 (m, 0.5 H, overlapped with solvent), 7.22 (dd, J = 8.5, 2.2 Hz, 0.5 H), 7.22 (dd, J = 8.5, 2.2 Hz, 0.5 H), 7.10 (dd, J = 8.5, 2.2 Hz, 0.5 H), 6.78 (d, J = 8.5 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H), 6.58-6.32 (m, 1 H), 6.54 and 6.37 (d, J = 7.3 Hz, 1 H), 5.67-6.57 (m, 1 H), 4.81-4.70 (m, 1 H), 4.59-4.46 (m, 1 H), 3.88 and 3.87 (s, 3 H), 3.79 and 3.77 (s, 3 H,), 3.72 and 3.71 (s, 3 H), 3.11-2.96 (m, 2 H), 2.71 and 2.69 (s, 3 H), 1.48 and 1.47 (s, 9 H), 1.41-1.24 (m, 15 H) ppm. MS (ES+): m/z = 832 [M + Na]+. Anal. Calcd for C35H49N3O10IB: C, 51.93; H, 6.10; N, 5.19. Found: C, 51.83; H, 6.30; N, 5.10.
Compound 15: [α]D ²6 +44 (c 1.1, CHCl3). ¹H NMR (500 MHz, CDCl3, 1:1.9 mixture of rotamers): δ = 7.20-7.25 (m, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.94 and 6.93 (d, J = 8.5 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.78 and 6.73 (s, 1 H), 6.75 and 6.68 (s, 1 H), 6.34-6.27 (m, 1 H), 6.26 and 6.21 (d, J = 8.5 Hz, 1 H), 5.93 and 5.61 (s, 1 H), 4.95-4.87 (m, 1 H), 4.77-4.67 (m, 1 H), 3.83 (s, 3 H), 3.82 and 3.81 (s, 6 H), 3.58-3.47 (m, 1 H), 3.05 and 3.04 (dd, J = 15.9, 6.9 Hz, 1 H), 2.71 and 2.70 (s, 3 H), 1.51 and 1.49 (br s, 9 H), 1.42-1.37 (m, 3 H) ppm. ¹H NMR (500 MHz, DMSO-d 6, 1:1 mixture of rotamers): δ = 9.06-9.01 (m, 1 H), 8.37 and 8.31 (d, J = 8.3 Hz, 1 H), 7.24-7.11 (m, 2 H), 7.10-7.05 (m, 1 H), 7.00 (d, J = 8.5 Hz, 1 H), 6.70-6.60 (m, 2 H), 5.92 and 5.74 (s, 1 H), 4.91-4.79 (m, 1 H,), 4.78-4.65 (m, 1 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.33-3.27 (m, 1 H, overlapped with solvent), 3.07-2.96 (m, 1 H), 2.53 (s, 3 H, overlapped with solvent), 1.44 and 1.41 (s, 9 H), 1.18 (d, J = 6.8 Hz, 3 H) ppm. HRMS (ES+): m/z calcd for C29H37N3O8Na [M + Na]+: 578.2478; found: 578.2490.
Arylomycin A2 ( 1): [α]D ²4 +29 (c 0.3, MeOH). ¹H NMR (500 MHz, MeOD, 1:6.4 mixture of isomers): δ = 8.91 (d, J = 8.0 Hz, 1 H), 8.61 (d, J = 8.1 Hz, 1 H), 8.17-8.05 (m, 2 H), 7.23 and 7.13 (d, J = 8.3 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 7.03 (br s, 1 H), 7.00 (br s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.35 and 5.87 (s, 1 H), 4.99-4.94 (m, 1 H), 4.57-4.51 (m, 2 H, overlapped with solvent), 4.56-4.46 (m, 1 H), 4.25 (d, J = 17.1 Hz, 1 H), 4.08-4.00 (m, 2 H), 3.95-3.85 (m, 1 H), 3.46-3.36 (m, 1 H), 3.16-3.07 (m, 1 H), 3.11 and 2.89 (s, 3 H), 2.80 and 2.76 (s, 3 H), 2.57-2.42 (m, 2 H), 1.67-1.58 (m, 2 H), 1.52 (sept, J = 6.6 Hz, 1 H), 1.41 (d, J = 7.0 Hz, 3 H), 1.35 (d, J = 6.6 Hz, 3 H), 1.42-1.26 (m, 10 H), 1.21-1.15 (m, 2 H), 0.88 (d, J = 6.6 Hz, 6 H) ppm. ¹H NMR (500 MHz, DMSO-d 6, 1:3.1 mixture of isomers): δ = 12.81 (br s, 1 H), 9.69 (br s, 2 H), 9.07-8.95 and 8.35-8.27 (m, 1 H), 8.62-8.54 (m, 1 H), 8.03-7.87 (m, 2 H), 7.14 and 7.10 (d, J = 7.8 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.95 and 6.93 (br s, 1 H), 6.91-6.80 (m, 3 H), 6.29 and 5.85 (s, 1 H), 5.03-4.98 and 4.91-4.84 (m, 1 H), 4.97 and 3.44 (dd, J = 8.2, 5.8 Hz, 1 H), 4.83-4.73 (m, 1 H), 4.69-4.61 (m, 1 H), 4.41-4.30 (m, 1 H), 4.20 and 4.02 (d, J = 17.3 Hz, 1 H), 3.96 (dd, J = 17.3, 4.4 Hz, 1 H), 4.85-4.74 (m, 1 H), 3.71-3.62 (m, 1 H), 3.28-3.20 (m, 1 H), 3.16-3.07 (dd, J = 16.7, 12.1 Hz, 1 H), 2.93 and 2.76 (s, 3 H), 2.69 and 2.63 (s, 3 H), 2.39-2.27 (m, 2 H), 1.56-1.45 (m, 3 H), 1.25 (d, J = 7.3 Hz, 3 H), 1.32-1.20 (m, 10 H), 1.18 (d, J = 6.7 Hz, 3 H), 1.18-1.11 (m, 2 H), 0.85 (d, J = 6.6 Hz, 6 H). HRMS (ES-): m/z calcd for C42H59N6O11 [M - H]- 823.4242; found: 823.4269.

13

Abbreviations: DEPBT = 3-(diethyloxyphosphoryloxy)-1,2,3-benzotriazin-4 (3H)-one; EDC = 1-[3-(eimethyl-amino)propyl]-3-ethylcarbodiimide; HOBt = N-hydroxy-benzotriazole, SPhos = 2-dicyclohexylphosphino-2′,6′-di-methoxybiphenyl; MOP = (diphenylphosphino)-2′-meth-oxy-1,1′-binaphtyl; NMP = N-methylpyrolidinone.

17

Microwave experiments were conducted using a Discover microwave reactor from CEM. All experiments were performed in sealed tubes (capacity 10 mL) under argon atmosphere. Microwave irradiation of 300 W was used, the temperature being ramped from r.t. to 90 ˚C or 110 ˚C in 1 min. Once this temperature was reached, the reaction mixture was held at 90 ˚C or 110 ˚C for the indicated time.