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DOI: 10.1055/s-2008-1078209
Total Synthesis of Arylomycin A2, a Signal Peptidase I (SPase I) Inhibitor
Publication History
Publication Date:
22 August 2008 (online)
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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
-
1a
Höltzel A.Schmid DG.Nicholson GJ.Stevanovic S.Schimana J.Gebhardt K.Friedler HP.Jung GJ. J. Antibiot. 2002, 55: 571 -
1b
Schimana J.Gebhardt K.Höltzel A.Schmid DG.Süssmuth R.Müller J.Pukall R.Friedler HP. J. Antibiot. 2002, 55: 565 - 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 - 3
Paetzel M.Karla A.Strynadka NC.Dalbey RE. Chem. Rev. 2002, 102: 4549 -
4a
Brown ED.Wright GD. Chem. Rev. 2005, 105: 759 -
4b
Zhu J. Expert Opin. Ther. Pat. 1999, 9: 1005 -
4c
Nicolaou KC.Boddy CNC.Bräse S.Winssinger N. Angew. Chem. Int. Ed. 1999, 38: 2096 -
4d
Williams D.Bardsley B. Angew. Chem. Int. Ed. 1999, 38: 1172 -
4e
Kahne D.Leimkuhler C.Lu W.Walsh CT. Chem. Rev. 2005, 105: 425 - For reviews on aryl-bridged natural products, see:
-
5a
Feliu L.Planas M. Int. J. Pept. Res. Ther. 2005, 11: 53 -
5b
Zhu J.Islas-Gonzalez G.Bois-Choussy M. Org. Prep. Proced. Int. 2000, 32: 505 - 6
Paetzel M.Goodall JJ.Kania M.Dalbey RE.Paghe MG. J. Biol. Chem. 2004, 279: 30781 - For biaryl-containing macrocycles, see:
-
7a
Carbonnelle A.-C.Zhu J. Org. Lett. 2000, 2: 3477 -
7b
Boisnard S.Carbonnelle A.-C.Zhu J. Org. Lett. 2001, 3: 2061 -
7c
Jia X.Bois-Choussy M.Zhu J. Org. Lett. 2007, 9: 2401 -
7d
Lépine R.Zhu J. Org. Lett. 2005, 7: 2981 -
7e
Bois-Choussy M.Cristau P.Zhu J. Angew. Chem. Int. Ed. 2003, 42: 4238 -
7f
Jia X.Bois-Choussy M.Zhu J. Angew. Chem. Int. Ed. 2008, 47: 4167 - 8
Roberts TC.Smith PA.Cirz RT.Romesberg FE. J. Am. Chem. Soc. 2007, 129: 15830 -
9a
Freidinger RM.Hinkle JS.Perlow DS.Arison BH. J. Org. Chem. 1983, 48: 77 -
9b
Aurelio L.Browlee RTC.Hughes AB.Sleebs BE. Aust. J. Chem. 2000, 53: 425 -
9c
Aurelio L.Browlee RTC.Hughes AB. Chem. Rev. 2005, 104: 5823 - 10
Barnett R.Andrews LJ.Keefer RM. J. Am. Chem. Soc. 1972, 94: 6129 - 12
Chiarello J.Joullié MM. Synth. Commun. 1988, 18: 2211 - 14
Ishiyama T.Murata M.Miyaura M. J. Org. Chem. 1995, 60: 7508 - 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 -
16a
Elder AM.Rich DH. Org. Lett. 1999, 1: 1443 -
16b
Li W.Burgess K. Tetrahedron Lett. 1999, 40: 6527 -
16c
Lobrégat V.Alcaraz G.Bienaymé H.Vaultier M. Chem. Commun. 2001, 817 -
16d
Kaiser M.Siciliano C.Assfalg-Machleidt I.Groll M.Milbradt AG.Moroder L. Org. Lett. 2003, 5: 3435 -
16e
Shinohara T.Deng H.Snapper ML.Hoveyda AH. J. Am. Chem. Soc. 2005, 127: 7334 - For recent reviews, see:
-
18a
Kappe CO. Angew. Chem. Int. Ed. 2004, 43: 6250 -
18b
de la Hoz A.Diaz-Ortiz A.Moreno A. Chem. Soc. Rev. 2005, 34: 164 - 19 For a review on conformation-directed
macrocyclization, see:
Blankenstein J.Zhu J. Eur. J. Org. Chem. 2005, 1949 - 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 -
21a
Furlan RLE.Mata EG.Mascaretti AO. J. Chem. Soc., Perkin Trans. 1 1998, 355 -
21b
Nicolaou KC.Estrada AA.Zak M.Lee SH.Safina BS. Angew. Chem. Int. Ed. 2005, 44: 1378 - 22
Bigot A.Tran Huu Dau ME.Zhu J. J. Org. Chem. 1999, 64: 6283 - 23
Li H.Jiang X.Fan C.Romoff T.Goodman M. Org. Lett. 1999, 1: 91
References and Notes
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.
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.
17Microwave 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.