Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C:9]([C:11]([NH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20](O)=[C:21]([CH2:23][CH:24]=[C:25]([CH3:27])C)[CH:22]=3)=[O:16])=[C:12](O)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:29][C@H:30]1[O:35][C:34]([CH3:37])([CH3:36])[C@H:33]([O:38][CH3:39])[C@@H:32]([O:40]C(N)=O)[C@@H:31]1[OH:44])=[O:10].N1[C:54]2[C:49](=CC=CC=2)C=CC=1.CC1C=CC=C2C=1[O:64][C:63](=O)C=C2.O1C2C(=CC=CC=2)C=CC1=O.C1(O)C=CC=CC=1.C(OC(=O)[O-])(C)(C)C>>[OH:44][C@@H:31]1[C@H:32]([OH:40])[C@@H:33]([O:38][CH3:39])[C:34]([CH3:36])([CH3:37])[O:35][C@H:30]1[O:29][C:3]1[C:2]([CH3:1])=[C:7]2[C:6]([CH:12]=[C:11]([NH:14][C:15]([C:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[CH:25][CH:27]=[CH:49][CH:54]=4)[C:20]([O:64][CH3:63])=[CH:19][CH:18]=3)=[O:16])[C:9](=[O:10])[O:8]2)=[CH:5][CH:4]=1
Reactant: CO[C@@H]1[C@@H](OC(N)=O)[C@H](O)[C@@H](Oc2ccc3c(O)c(NC(=O)c4ccc(O)c(CC=C(C)C)c4)c(=O)oc3c2C)OC1(C)C
Reactant: Cc1cccc2ccc(=O)oc12
Reactant: c1ccc2ncccc2c1
Agent: CC(C)(C)OC(=O)[O-]
Agent: O=c1ccc2ccccc2o1
Solvent: Oc1ccccc1
Product: COc1ccc(C(=O)Nc2cc3ccc(O[C@@H]4OC(C)(C)[C@H](OC)[C@@H](O)[C@H]4O)c(C)c3oc2=O)cc1-c1ccccc1
Yield: 46 %

Procedure:
In this example, novobiocin analogues containing a quinoline or naphthalene ring in lieu of the 8-methylcoumarin of novobiocin were synthesized to probe the importance of the coumarin lactone moiety in binding the Hsp90 C-terminus, as well as to potentially circumvent the limited solubility of coumarin-containing analogues. Protection of the phenol in 27 as the t-butyl-carbonate served two purposes as shown in the scheme below. See Hansen, M. M.; Riggs, J. R. Tetrahedron Lett. 39 2705-2706 (1998). Not only did phenol protection remove the quinolone-like properties of 27, introduction of the sterically-hindered t-butyl-carbonate also decreased the relative amount of 6-bromo and 8-bromo regioisomers normally produced upon bromination of 28. Thus, the isolable percentage of desired 3-bromo regioisomer was enriched to 46% yield. See Zymalkowski, F.; Tinapp, P. Justus Liebigs Ann. Chem. 699 98-106 (1966). One-pot t-butyl-carbonate deprotection, followed by immediate reprotection with benzyl bromide afforded intermediate 30. N-arylation of 30 was accomplished with p-methoxybenzylamine under Ullman-like conditions employing CuI and L-(−)-proline as a catalyst to provide 31. See Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 70 5164-5173 (2005). Acylation of the secondary aniline with the desired benzoyl chloride, generated in situ from the appropriate benzoic acid, afforded PMB-protected amide 32. See Ulbrich, H. K.; Luxenburger, A.; Prech, P.; Eriksson, E. E.; Soehnlein, O.; Rotzius, P.; Lindbom, L.; Dannhardt, G. J. Med. Chem. 49, 5988-5999 (2006); Jin, Y.; Zhou, Z.-Y.; Tian, W.; Yu, Q.; Long, Y.-Q. Bioorg. Med. Chem. Lett., 16, 5864-5869 (2006). Interestingly, subjection of 32 to aluminum trichloride in anisole57 resulted solely in the formation of 7-hydroxy 33; the PMB-protected amide remained intact. Global removal of the PMB and benzyl groups was ultimately accomplished with trifluoroacetic acid, to provide phenol 34. See Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.; Moquin, R. V.; Shen, Z.; Cook, L. S.; Doweyko, A. M.; Pitt, S.; Pang, S.; Shen, D. R.; Fang, Q.; de Fex, H. F.; McIntyre, K. W.; Shuster, D. J.; Gillooly, K. M.; Behnia, K.; Schieven, G. L.; Wityak, J.; Barrish, J. C. J. Med. Chem. 49 6819-6832 (2006).