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Synlett 2009(10): 1567-1570  
DOI: 10.1055/s-0029-1217329
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Improved Synthesis of Resorcylic Acid Macrolactone Inhibitors of Hsp90

James E. H. Day, Alexander J. Blake, Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: c.j.moody@nottingham.ac.uk;
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Publikationsverlauf

Received 23 March 2009
Publikationsdatum:
02. Juni 2009 (online)

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Abstract

A synthesis of resorcylic acid macrolactone analogues of the natural product radicicol is described in which the key steps are the acylation and ring opening of a homophthalic anhydride to give an isocoumarin, followed by a ring-closing metathesis to form the macrocycle.

Key words

macrocyclic lactones - isocoumarins - ring-closing meta­thesis reaction

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5-Chloro-6,8-bis(methoxymethoxy)isochroman-1,3-dione (8)
Mp 96-98 ˚C. MS: m/z calcd for C13H13 ³5ClNaO7: 339.0242; found: 339.0229 [M + Na]. IR (CH2Cl2): νmax = 1796, 1756, 1593 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.18 (1 H, s, ArH), 5.48 (2 H, s, OCH2O), 5.39 (2 H, s, OCH2O), 4.20 (2 H, s, CH2), 3.53 (3 H, s, OCH3), 3.52 (3 H, s, OCH3). ¹³C NMR (100 MHz, acetone-d 6): δ = 165.3 (C), 160.6 (C), 159.2 (C), 157.1 (C), 137.7 (C), 114.6 (C), 107.1 (C), 103.4 (CH), 96.3 (CH2), 96.1 (C), 57.0 (CH3), 56.9 (CH3), 34.2 (CH2). ESI-MS: m/z (%) = 341/339 (23/69) [M + Na], 327 (14), 309 (15).

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Ethyl 2-[5-Chloro-6,8-bis(methoxymethoxy)-1-oxo-1 H -isochromen-3-yl]hept-6-enoate (13)
Mp 50-52 ˚C. MS: m/z calcd for C22H27 ³5ClNaO8: 477.1292; found: 477.1326 [M + Na]. IR (CH2Cl2): νmax = 2987, 1736, 1661, 1585 cm-¹. ¹H NMR (400 MHz, acetone-d 6): δ = 7.15 (1 H, s, ArH), 6.85 (1 H, s, ArH), 5.89-5.77 (1 H, m, CH=CH2), 5.45 (2 H, s, OCH2O), 5.34 (2 H, s, OCH2O), 5.05-4.93 (2 H, m, CH=CH2), 4.18 (2 H, q, J = 7.1 Hz, CO2CH2CH3), 3.66 (1 H, t, J = 7.5 Hz, CHCH2), 3.51 (3 H, s, OCH3), 3.51 (3 H, s, OCH3), 2.13 (2 H, dt, J = 7.1, 7.5 Hz, CH2), 2.00-1.89 (2 H, m, CH2), 1.49 (2 H, quin, J = 7.1, CH2), 1.22 (2 H, q, J = 7.1 Hz, CO2CH2CH3). ¹³C NMR (100 MHz, CDCl3): δ = 171.1 (C), 160.5 (C), 159.2 (C), 157.2 (C), 158.15 (C), 139.1 (CH), 138.6 (C), 115.3 (CH2), 110.9 (C), 105.9 (C), 103.7 (CH), 101.2 (CH), 96.4 (CH2), 96.0 (CH2), 61.8 (CH2), 56.9 (CH3), 56.8 (CH3), 50.5 (CH), 34.0 (CH2), 27.2 (CH2), 14.5 (CH3), 1 × CH2 unobserved. ESI-MS: m/z (%) = 475/477 (36/100) [M + Na].

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( E )-1-Chloro-2,4-dihydroxy-7,8,11,12,13,14-hexahydro-6-oxa-16 H -benzocyclotetradecene-5,15-dione (3)
Mp 174-176 ˚C (lit.²5 mp 168-169 ˚C). MS: m/z calcd for C17H19 ³5ClNaO5: 361.0813; found: 361.0817 [M + Na]. IR (CH2Cl2): νmax = 3722, 3156, 1712, 1659, 1603 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 11.80 (1 H, s, OH), 6.61 (1 H, s, ArH), 6.17 (1 H, s, OH), 5.56-5.39 (2 H, m, CH=CH), 4.44 (2 H, t, J = 5.3 Hz, CO2CH2), 4.29 (2 H, s, CH2), 2.58 (2 H, t, J = 6.5 Hz, CH2), 2.44 (2 H, dt, J = 5.3, 5.3 Hz, CH2), 2.10 (2 H, dt, J = 6.2, 4.8 Hz, CH2), 1.71 (2 H, quin, J = 6.2 Hz, CH2), 1.58 (2 H, m, CH2). ¹³C NMR (75 MHz, CDCl3): δ = 206.2 (C), 170.7 (C), 163.0 (C), 156.4 (C), 136.2 (CH), 134.1 (C), 126.8 (C), 114.7 (C), 107.3 (CH), 65.8 (CH2), 46.8 (CH2), 41.0 (CH2), 32.2 (CH2), 31.54 (CH2), 25.5 (CH2), 22.1 (CH2). ESI-MS: m/z (%) = 363/361 (31/100) [M + Na], 341/339 (4/12).








( E )-1-Chloro-2,4-dihydroxy-7,8,11,12,13,14-hexahydro-8-methyl-6-oxa-16 H -benzocyclotetradecene-5,15-dione (17) Mp 163-164 ˚C. MS: m/z calcd for C18H21 ³5ClNaO5: 375.0970; found: 375.0959 [M + Na]. IR (CH2Cl2): νmax = 3686, 3512, 1720, 1658, 1604 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 11.78 (1 H, s, OH), 6.63 (1 H, s, ArH), 6.00 (1 H, br s, OH), 5.46 (1 H, dt, J = 15.6, 7.5 Hz, =CH), 5.34 (1 H, dt, J = 15.6, 7.3 Hz, =CH), 4.27 (1 H, dd, J = 10.7, 3.0 Hz, CO2CH), 4.28 (2 H, s, CH2), 3.99 (1 H, t, J = 10.7 Hz, CO2CH), 2.58 (3 H, m, CH2, CH), 2.13 (3 H, m, CH2, CH), 1.72 (3 H, m, CH2, CH), 1.04 (3 H, d, J = 7.0 Hz, CH3). ¹³C NMR (125 MHz, CDCl3): δ = 205.7 (C), 171.8 (C), 163.8 (C), 158.9 (C), 138.3 (C), 134.3 (CH), 132.5 (CH), 115.9 (C), 107.8 (C), 103.6 (CH), 71.1 (CH2), 47.1 (CH2), 41.2 (CH2), 36.7 (CH), 32.7 (CH2), 26.6 (CH2), 23.0 (CH2), 17.4 (CH3). ESI-MS: m/z (%) = 377/375 (33/100) [M + Na], 355/353 (8/23), 335/337 (31/10).

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Crystallographic data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB21EZ, UK; fax: +44 (1223)336033; or deposit@ccdc.cam.ac.uk].