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Synlett 2007(8): 1264-1268  
DOI: 10.1055/s-2007-977441
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Syntheses of New Proansamitocin Derivatives by Ring-Closing Metathesis

Axel Meyer, Andreas Kirschning*
Institut für Organische Chemie und Zentrum für Biomolekulare Wirkstoffchemie (BMWZ), Leibniz Universität Hannover, Schneiderberg 1b, 30167 Hannover, Germany
e-Mail: andreas.kirschning@uni-hannover.de;
Further Information

Publication History

Received 6 February 2007
Publication Date:
18 April 2007 (online)

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Abstract

The enantioselective synthesis of two new proansamitocin derivatives is described. Macrocyclization is achieved by ring-closing metathesis of appropriate alkene and diene precursors.

Key words

ansamitocins - natural product synthesis - macrolactam antibiotics - ring-closing metathesis

    References and Notes

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19

General Procedure for the Preparation of Amides 17 and 19: Ketoacid 18 (1 equiv) was dissolved in CH2Cl2, then treated with BOPCl (1 equiv) and DIPEA (1 equiv) and stirred at r.t. for 3 h. A solution of aniline 8/9 (1 equiv) and DIPEA (1 equiv) in CH2Cl2 was added over a period of 2 h. After completion (ca. 18 h), the reaction was terminated by addition of aq phosphate buffer (pH 7) and CH2Cl2. The organic phases were combined, dried over Na2SO4 and the solvent was removed under reduced pressure. Flash column chromatography over silica eluting with hexanes-EtOAc (20:1) furnished the corresponding amide 17/19.
Spectroscopic data for 17: [α]D 20 -59.0 (c = 1.2, CHCl3). 1H NMR (400 MHz, CDCl3; CHCl3 = 7.26 ppm): δ = 7.69-7.71 (m, 4 H, OTBDPS), 7.50 (s, 1 H, NH), 7.33-7.43 (m, 6 H, OTBDPS), 6.95 (s, 1 H, ArH), 6.83 (s, 1 H, ArH), 6.27 (s, 1 H, ArH), 5.73 (ddt, J = 6.7, 10.2, 16.9 Hz, 1 H, 2′-H), 5.67 (ddd, J = 6.9, 10.3, 17.2 Hz, 1 H, 11-H), 5.44 (ddd, J = 1.3, 1.3, 17.2 Hz, 1 H, 12-H), 5.37 (ddd, J = 1.3, 1.3, 10.3 Hz, 1 H, 12-H′), 5.33-5.37 (m, 1 H, 5-H), 4.92 (ddd, J = 1.6, 1.6, 17.1 Hz, 1 H, 3′-H), 4.89 (ddd, J = 1.6, 1.6, 17.1 Hz, 1 H, 3′-H′), 4.39 (dd, J = 3.5, 7.3 Hz, 1 H, 3-H), 4.01-4.06 (m, 2 H, 7-H, 10-H), 3.33 (s, 3 H, 10-OCH3), 3.13 (s, 1 H, 1′-H), 3.12 (s 1 H, 1′-H′), 2.66 (dd, J = 6.7, 17.2 Hz, 1 H, 8-H), 2.57 (dd, J = 4.6, 17.2 Hz, 1 H, 8-H′), 2.47-2.52 (m, 1 H, 6-H), 2.42 (dd, J = 3.8, 13.8 Hz, 1 H, 2-H), 2.36 (dd, J = 7.8, 13.8 Hz, 1 H, 2-H′), 1.59 (d, J = 1.6 Hz, 3 H, 4-CH3), 1.08 (s, 9 H, OTBDPS), 0.86 (d, J = 7.0 Hz, 3 H, 6-CH3), 0.84 [s, 9 H, OSiC(CH3)3], 0.82 [s, 9 H, OSiC(CH3)3], 0.05 (s, 3 H, OSiCH3), -0.02 (s, 3 H, OSiCH3), -0.03 (s, 3 H, OSiCH3), -0.06 (s, 3 H, OSiCH3). 13C NMR (100 MHz, CDCl3 = 77.0 ppm): δ = 206.8 (s, C-9), 169.1 (s, C-1), 155.9 (s, Ar), 141.7 (s, Ar), 138.7 (s, Ar), 136.8 (d, C-2′), 136.5 (s, C-4), 135.5 (d, Ph), 132.9 (s, Ph), 132.4 (d, C-11), 129.8 (d, Ph), 128.3 (d, C-5), 127.7 (d, Ph), 120.3 (t, C-12), 115.9 (d, Ar), 115.8 (t, C-3′), 112.7 (d, Ar), 108.9 (d, Ar), 88.8 (d, C-10), 75.2 (d, C-3), 71.4 (d, C-7), 57.0 (q, 10-OCH3), 46.1 (t, C-2), 43.4 (t, C-8), 39.9 (t, C-1′), 38.2 (d, C-6), 26.5 [q, OSi(Ph2)C(CH3)3], 26.0 {q, OSi[(CH3)2]C(CH3)3}, 25.8 {q, OSi[(CH3)2]C(CH3)3}, 19.5 [s, OSi(Ph2)C(CH3)3], 18.1 {s, OSi[(CH3)2]C(CH3)3}, 18.0 {s, OSi[(CH3)2]C(CH3)3}, 16.2 (q, 6-CH3), 12.5 (q, 4-CH3), -4.5 [q, 2 × OSiC(CH3)3], -4.7 [q, OSiC(CH3)3], -5.2 [q, OSiC(CH3)3]. HRMS (ESI): m/z [M + H]+ calcd for C52H79Si3NO6: 898.5294; found: 898.5288. 19: [α]D 20 -37.5 (c = 0.8, CHCl3). 1H NMR (400 MHz, CDCl3; CHCl3 = 7.26 ppm): δ = 7.97 (s, 1 H, ArH), 7.77 (s, 1 H, NH), 5.99 (ddt, J = 6.1, 10.3, 16.7 Hz, 1 H, 2′-H), 5.68 (ddd, J = 6.9, 10.3, 17.2 Hz, 1 H, 11-H), 5.45 (ddd, J = 1.3, 1.3, 17.2 Hz, 1 H, 12-H), 5.40-5.43 (m, 1 H, 5-H), 5.38 (ddd, J = 1.3, 1.3, 10.3 Hz, 1 H, 12-H′), 5.00 (ddd, J = 1.6, 3.3, 10.3 Hz, 1 H, 3′-H), 4.89 (dd, J = 1.6, 3.3, 16.7 Hz, 1 H, 3′-H′), 4.51 (dd, J = 3.8, 8.2 Hz, 1 H, 3-H), 4.07 (dt, J = 5.0, 6.6 Hz, 1 H, 7-H), 4.05 (ddd, J = 1.3, 1.3, 6.9 Hz, 1 H, 10-H), 3.83 (s, 3 H, ArOCH3), 3.78 (s, 3 H, ArOCH3), 3.69 (s, 3 H, ArOCH3), 3.42 (dd, J = 1.4, 6.0 Hz, 2 H, 1′-H, 1′-H′), 3.34 (s, 3 H, 10-OCH3), 2.69 (dd, J = 6.6, 17.1 Hz, 1 H, 8-H), 2.60 (dd, J = 4.8, 17.1 Hz, 1 H, 8-H′), 2.50 (m, 1 H, 6-H), 2.51 (dd, J = 3.8, 13.7 Hz, 1 H, 2-H), 2.44 (dd, J = 8.2, 13.7 Hz, 1 H, 2-H′), 1.65 (d, J = 1.0 Hz, 3 H, 4-CH3), 0.85 (d, J = 4.4 Hz, 3 H, 6-CH3), 0.84 [s, 9 H, OSiC(CH3)3], 0.83 [s, 9 H, OSiC(CH3)3], 0.05 (s, 3 H, OSiCH3), 0.02 (s, 3 H, OSiCH3), 0.01 (s, 3 H, OSiCH3), -0.03 (s, 3 H, OSiCH3). 13C NMR (100 MHz, CDCl3 = 77.0 ppm): δ = 206.8 (s, C-9), 169.1 (s, C-1), 149.1 (s, Ar), 143.3 (s, Ar), 140.8 (s, Ar), 137.1 (s, C-2′), 136.4 (s, C-4), 132.4 (d, C-11), 128.4 (d, C-5), 127.4 (s, Ar), 126.4 (s, Ar), 120.3 (t, C-12), 115.0 (t, C-3′), 103.4 (d, Ar), 88.9 (d, C-10), 75.4 (d, C-3), 71.4 (d, C-7), 61.5 (q, ArOCH3), 60.9 (q, ArOCH3), 56.9 (q, 10-OCH3), 55.9 (q, ArOCH3), 46.5 (t, C-2), 43.4 (t, C-8), 38.1 (d, C-6), 28.7 (t, C-1′), 25.9 {q, OSi[(CH3)2]C(CH3)3}, 25.8 {q, OSi[(CH3)2]C(CH3)3}, 18.1 {s, OSi[(CH3)2]C(CH3)3}, 18.0 {s, OSi[(CH3)2]C(CH3)3}, 16.0 (q, 6-CH3), 12.4 (q, 4-CH3), -4.5 [q, 2 × OSiC(CH3)3], -4.6 [q, OSiC(CH3)3], -5.2 [q, OSiC(CH3)3]. HRMS (ESI): m/z [M + Na]+ calcd for C39H67Si2NO8: 756.4303; found: 756.4306.

21

Tetra-n-butylammonium fluoride (TBAF) turned out to be too basic for inducing the elimination of the siloxy group at C-3.

22

General Procedure for the Preparation of Macrocycles 5 and 6: Amide 17/19 (1 equiv) was dissolved in anhyd CH2Cl2, treated with Grubbs’ 2nd generation catalyst (0.2 equiv) and heated to reflux. After completion (ca. 6 h), the reaction was terminated by the addition of aq phosphate buffer (pH 7). The organic phases were combined, dried over Na2SO4 and the solvent was removed under reduced pressure. Flash column chromatography over silica with hexanes-EtOAc (20:1) as eluent yielded the corresponding protected macrolactams which were dissolved in anhyd THF and treated with HF·Py (ca. 70% HF, excess) at r.t. After completion (ca. 16 h), the reaction mixture was neutralized with a sat. NaHCO3 solution. The aqueous phase was extracted with EtOAc, the organic phases were combined, dried over Na2SO4 and the solvent was removed under reduced pressure. Flash column chromatography over silica with CH2Cl2-MeOH (50:1) as eluent yielded the corresponding macrolactam 5/6.
Spectroscopic data for 5: [α]D 20 -134.6 (c = 1.0, MeOH). 1H NMR (400 MHz, CD3OD; CH3OH = 3.31 ppm): δ = 7.90 (s, 1 H, NH), 7.10 (dd, J = 1.6, 1.6 Hz, 1 H, ArH), 6.51 (dd, J = 2.1, 2.1 Hz, 1 H, ArH), 6.39 (dd, J = 1.6, 2.1 Hz, 1 H, ArH), 6.06 (dddd, J = 0.9, 6.7, 8.0, 15.5 Hz, 1 H, 12-H), 5.41 (psd, J = 9.3 Hz, 1 H, 5-H), 5.26 (ddt, J = 1.1, 8.1, 15.5 Hz, 1 H, 11-H), 4.31-4.37 (m, 2 H, 3-H, 10-H), 3.96 (ddd, J = 3.6, 8.5, 8.5 Hz, 1 H, 7-H), 3.32-3.35 (m, 2 H, 13-H, 13-H′), 3.33 (s, 3 H, 10-OCH3), 2.75 (dd, J = 3.6, 13.7 Hz, 1 H, 2-H), 2.62 (dd, J = 6.6, 13.7 Hz, 1 H, 2-H), 2.50-2.54 (m, 2 H, 8-H, 8-H′), 2.44-2.49 (m, 1 H, 6-H), 1.66 (d, J = 0.9 Hz, 3 H, 4-CH3), 0.96 (d, J = 6.3 Hz, 3 H, 6-CH3). 13C NMR (100 MHz, CD3OD = 49.0 ppm): δ = 209.2 (s, C-9), 171.5 (s, C-1), 158.9 (s, Ar), 142.5 (s, Ar), 140.4 (s, Ar), 138.7 (s, C-4), 137.9 (d, C-12), 127.0 (d, C-5), 126.7 (d, C-11), 113.1 (d, Ar), 112.9 (d, Ar), 105.7 (d, Ar), 89.9 (d, C-10), 74.3 (d, C-7), 73.0 (d, C-3), 57.0 (q, 10-OCH3), 44.7 (t, C-8), 42.6 (t, C-2), 40.0 (d, C-6), 39.3 (t, C-13), 17.7 (q, 6-CH3), 14.7 (q, 4-CH3). HRMS (ESI): m/z [M - H+] calcd for C22H29NO6: 402.1917; found: 402.1923.
6: 1H NMR (400 MHz, CD3OD; CH3OH = 3.31 ppm): δ = 8.01 (t, J = 1.51 Hz, 1 H, ArH), 5.92 (dddd, J = 0.6, 3.4, 7.9, 15.5 Hz, 1 H, 12-H), 5.58 (psd, J = 8.5 Hz, 1 H, 5-H), 5.26 (dd, J = 7.0, 15.5 Hz, 1 H, 11-H), 4.40 (m, 1 H, 3-H), 4.21 (d, J = 7.0 Hz, 1 H, 10-H), 3.93 (ddd, J = 1.6, 8.9, 10.5 Hz, 1 H, 7-H), 3.82 (s, 3 H, ArOCH3), 3.70-3.81 (m, 1 H, 13-H), 3.75 (s, 3 H, ArOCH3), 3.68 (s, 3 H, ArOCH3), 3.33 (s, 3 H, 10-OCH3), 3.13-3.26 (m, 1 H, 13-H′), 2.92 (dd, J = 4.5, 16.7 Hz, 1 H, 2-H), 2.77 (dd, J = 3.1, 16.7 Hz, 1 H, 2-H′), 2.54 (dd, J = 1.6, 16.9 Hz, 1 H, 8-H), 2.29 (dd, J = 10.5, 16.9, 10.5 Hz, 1 H, 8-H′), 2.31 (m, 1 H, 6-H), 1.62 (s, 3 H, 4-CH3), 1.01 (d, J = 6.3 Hz, 3 H, 6-CH3). 13C NMR (100 MHz, CD3OD = 49.0 ppm): δ = 208.2 (s, C-9), 171.8 (s, C-1), 150.5 (s, Ar), 143.9 (s, Ar), 142.7 (s, Ar), 136.8 (s, Ar), 134.3 (d, C-12), 129.5 (s, C-4), 127.4 (d, C-5), 127.3 (s, Ar), 125.0 (d, C-11), 104.5 (d, Ar), 88.7 (d, C-10), 72.9 (d, C-7), 70.7 (d, C-3), 61.7 (q, ArOCH3), 61.4 (q, ArOCH3), 57.3 (q, 10-CH3), 56.4 (q, ArOCH3), 44.9 (t, C-2), 42.6 (t, C-8), 39.4 (d, C-6), 27.9 (t, C-13), 18.1 (q, 6-CH3), 14.4 (q, 4-CH3). HRMS (ESI): m/z [M + Na+] calcd for C25H35NO8: 500.2260; found: 500.2260.

24

Meyer, A.; Brünjes, M.; Taft, F.; Frenzel, F.; Sasse, F.; Kirschning, A.; unpublished results.