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<A NAME="RG03307ST-16">16</A> Other vinylmetal species such as vinylstannane and vinylzinc only gave reduced
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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.
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Gradillas A.
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McErlean CSP.
Proisy N.
Davis CJ.
Boland NA.
Sharp SY.
Boxall K.
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Workman P.
Moody CJ.
Org. Biomol. Chem.
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<A NAME="RG03307ST-21">21</A>
Tetra-n-butylammonium fluoride (TBAF) turned out to be too basic for inducing the elimination
of the siloxy group at C-3.
<A NAME="RG03307ST-22">22</A>
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.
We tested oxidation [(NH4)2Ce(NO3), MeCN] of the aromatic moiety present in the silyl-protected precursor of 6 but could only isolate the ortho-quinone 20 (Figure 2 in 71% yield instead of the para-quinone present in geldanamycin. See also:
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Andrus MB.
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Meyer, A.; Brünjes, M.; Taft, F.; Frenzel, F.; Sasse, F.; Kirschning, A.; unpublished
results.
