(–)-Jorumycin (254)(+)-Cyanocycline A (256)NNOSiOTBSMeMeOOMeOOMeOOMeMeOOMeONMeMeOOMeOOMeOSOOFFFOTfNOSiOTBSOMeOOMeOOMe258259260+Pd(OAc)2 (20 mol%) P(t-Bu)2Me•HBF4 (50 mol%) CsOPiv (40 mol%) Cs2CO3 (3.5 equiv)PhMe, 130 °C, 5 h 93% yieldNNHOOMeOOMeMeOHOOMeOOMeMeOHNNOOMeMeOOMeOOMeOOMeMeOOMeOOH262261[Ir(cod)Cl]2 (10 mol%) BTFM-Xyliphos (21 mol%) TBAI (60 mol%)PhMe/AcOH (9:1) (0.02 M) H2 (60 bar) 60 °C, 18 h then, 80 °C, 24 h 83% yield >20:1 dr, 88% ee(–)-Jorumycin (254)(–)-Jorunnamycin A (257)NNOOOOMeMeOOOAcMeOOOOMeMeOHHNNOOOOMeMeOHMeOOOOMeMeNCNHEnantioselective Hydrogenation/LactamizationFagnou C–H Cross-CouplingNOHMeOOMeOOMeNOOMeMeOOMeNCNMeXYHABCEDNOHMeOOMeOOMeNHOOMeMeOOMeNCNHNMeOOMeOOMeNOOMeMeOOMeMeXYOHNOOOAcMeOOMeOOMeNOOMeMeOOMeNCNMeXYHNOOOAcFFNOOMeMeOOMeNCNMeHNZFFNFFNCNMeHNOOOAcMeOOMeOOMeNOOMeMeOOMeOHMeClClHNOHMeOOMeNOOMeMeONCNMeOOHOOMeOHTHIQ2 (264), X = Y = H THIQ3 (265), X = Y = Cl THIQ9 (271), X = Y = OH THIQ11 (273), X = OH, Y = H THIQ12 (274), X = H, Y = OH THIQ18 (280), X = OAc, Y = OHTHIQ1 (263)THIQ4 (266), X = Y = Cl THIQ8 (270), X = Y = BrTHIQ5 (267), X = Y = Cl THIQ7 (269), X = Y = Br THIQ17 (279), X = Y = OHTHIQ16 (278)THIQ13 (275), Z = OH THIQ14 (276), Z = OAc THIQ15 (277), Z = PhthTHIQ6 (268)THIQ10 (272)Pd(OAc)2 (20 mol%) P(t-Bu)2Me•HBF4 (50 mol%) CsOPiv (40 mol%) Cs2CO3 (3.5 equiv)PhMe, 130 °C, 4.5 h 70% yieldPd(OAc)2 (50 mol%) P(t-Bu)2Me•HBF4 (100 mol%) CsOPiv (2.0 equiv) Cs2CO3 (3 equiv)PhMe, 180 °C, 4.5 h 45% yield (excess N–O reduced)FFOOBnOOOOMeMeMe300BrFFOOBnOO298NH2OOMeMeMeOHSOOFFF• HOTfmethyl propiolate (1.1 equiv) [RhCp*Cl2]2 (2.5 mol%) CsOAc (2 equiv)MeOH (0.2 M) reflux, 18 h 87% yieldPd(OAc)2 (10 mol%) ligand (20 mol%) base (2 equiv)solvent (0.1 M) 130 °C, 18 hCOOOCsCsOOOKKOOOKKOOOKKOOOKKOOOKKOOOKKK2CO3 Cs2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3entryNMR Yield (%)solventbaseligand1 2 3 4 5 6 7a40 0 38 5 10 81 92 (88b)m-xylene m-xylene DMF m-xylene m-xylene m-xylene m-xylenecataCXium A cataCXium A cataCXium A P(t-Bu)3•HBF4 PCy3•HBF4 P(t-Bu)2Me•HBF4 P(t-Bu)2Me•HBF4NOHMeOOMeOOMeNOOMeMeOOMeNCNMeXYHABCEDNZFFNFFNCNMeHNOOOAcMeOOMeOOMeNOOMeMeOOMeOHMeClClHNOHMeOOMeNOOMeMeONCNMeOOHOOMeOHTHIQ2 (264), X = Y = H THIQ3 (265), X = Y = Cl THIQ9 (271), X = Y = OH THIQ11 (273), X = OH, Y = H THIQ12 (274), X = H, Y = OH THIQ18 (280), X = OAc, Y = OHTHIQ13 (275), Z = OH THIQ14 (276), Z = OAc THIQ15 (277), Z = NPhthTHIQ6 (268)THIQ10 (272)NOHFFNOOMeMeOOMeHNCNMeNH2THIQ21 (323)NOOOAcFFNOOMeMeOOMeHNCNMeNH2THIQ22 (324)NMeCNAc2O DMAPNOHFFNOOMeMeOOMeHOMeNH2322NOHFFNOOMeMeOOMeHOMeOH325NaNO2 Cu2O, Cu(NO3)2 H2SO4 (34% aq.)NOHFFNOOMeMeOOMeHNCNMeOHTHIQ23 (326)NOOOAcFFNOOMeMeOOMeHNCNMeOHTHIQ24 (327)NOHFFNOOMeMeOOMeHNCNMeNH2THIQ21 (323)NOHFFNOOMeMeOHNCNMeOTHIQ25 (328)acetone, H2OPd(OAc)2 (10 mol%) P(t-Bu)2Me•HBF4 (20 mol%) K2CO3 (2 equiv)m-xylene (0.1 M) 130 °C, 18 h 88% yieldFFBrOOIRIRRMSHRMSFFBrOOOFFOOOOOMeMeMeFFNOOHFFNOOSOOFFFOTfIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSNHOOOMeOOMeMeOOMeMeMeIRIRRMSHRMSMeOOMeOOMeNHOOOMeOIRIRRMSHRMSMeOOMeOOMeNClOOMeOIRIRRMSHRMSMeOOMeOOMeNSOOMeOOOMeOOOIRIRRMSHRMSFFNONOOMeOOOMeMeOOMeFFNOHNOOMeOOOMeMeOOMeFFNONMeOHOOMeMeOOMeFFNONHOHOOMeMeOOMeFFNONMeOOOMeMeOOMeN+OO-NO2N+OO-NO2FFNONMeOHOOMeMeOOMeNH2FFNNCNNMeOHOOMeMeOOMeNH2FFNONMeOHOOMeMeOOMeOHFFNNCNNMeOHOOMeMeOOMeOHFFNNCNNMeOOOAcOOMeMeOOMeNH2FFNNCNNMeOOOAcOOMeMeOOMeOHIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSIRIRRMSHRMSMeOOMeOOMeNSOOMeOOOMeOIRIRRMSHRMSeeopticalopticalopticalopticalopticalopticalopticalopticalopticalNNOOOOMeMeOOOAcMeOOOOMeMeOHHNNOOAcOMeMeOHOOMeMeOHHOSOONHOOOMeOHNNOOMeOOMeNONCNOHMeHHTHIQ9 (271)THIQ2 (264)THIQ11 (273)THIQ12 (274)NNHMeOOMeOHNOOMeMeOOMeNCNMeOOMeOHHONNNOOAcOMeMeOHOOMeMeOHHOSOONHOOOMeOHNYFFNOOMeMeOOMeNCNMeXHMeOOMeOOMeOOMeBrOIRIRRMSHRMSMeOOMeOOMeHBrOMeOOMeOOMeNHBrOOOMeOIRIRRMSHRMSNHOOOMeMeOOMeIRIRRMSHRMSFFNONMeOHOOMeMeOOMeClIRIRRMSHRMSopticalFFNONMeOOOAcOOMeMeOOMeClIRIRRMSHRMSopticalNOSOOFFFOTfFFMeNOOSiOTBSOOMeMeOOMeNFFMeNOSiOTBSOOOMeMeOOMeNFFNOOMeOOMeMeOOMeOHONNHFFOHOOMeOOMeMeOHNOSOOFFFOTfMeOOMeMeOOMeNOOOMeOOMeMeOOMeONMeOOMeMeNOOMeOOOMeMeOOMeOOOMe282283284285286258287288NYFFNOOMeMeOOMeNCNMeXHNOHFFNHOOMeMeOOMeHONFFNOOMeOOMeMeOOMeOOHNFFOOBnOSOOFFFOTfNMeOOMeSOOMeOOOOOMeOOOMe290291285289SiTMSOSOOFFFOTfFFFFOOMeOOOOBnOOMeOOOOBn292293294XBrBrFFBrFFOOOBnNOOOBnOMeMe296295297BrFFOOBnOO298OSiOTMSOSiOTMSZnBrZnBrOOMeMeMeO• THF299FFOOBnOOOOMeMeMe300FFNOHOOBn301FFNOSOOFFFOTfOOBn290XHOOOMeOOMeMeBrOOMeOOOMeOOMeMeBrNHOOOMeOOMeMeOOMeO302303NHONHAcOOMeO305304OHOOOMeOOMeMe308OOMeOOOMeOOMeMeBr303NHOOOMeOOMeMeBrOOMeO30661% yield, three stepsNOOOMeOOMeMeOOMeO305 (12% yield)OOMeOOMeMeNHO307 (87% yield)NHOOOMeOOMeMeOOMeMeMe310309NHOOOMeOOMeMeOOMeO305POClClClPOCl3reflux, 3 h 97% yieldNClOOMeOOMeMeOOMeO311SHOOMeO312NSOOMeOOMeMeOOMeOOOMeO313NSOOMeOOMeMeOOMeOOOMeOOO291NSOOMeOOMeMeOOMeOOOMeOOO291FFNOSOOFFFOTfOOBn290NNOOMeOFFOOBnOOMeMeOOMe314NNOOMeOFFOOBnOOMeMeOOMe314NNOOMeOFFOHOOMeMeOOMe285NOHFFNHOOMeMeOOMeHO286NOHFFNOOMeMeOOMeHOMe315NOHFFNOOMeMeOOMeHOMeCl316NSANCSAHFIP 0 °C, 5 min 64% yieldNOHFFNOOMeMeOOMeHOMeOH317NOHFFNOOMeMeOOMeHOMeCl316NOHFFNOOMeMeOOMeHOMeNHONHAc318XXNOHFFNOOMeMeOOMeHNCNMeClTHIQ19 (319)NOOOAcFFNOOMeMeOOMeHNCNMeClTHIQ20 (320)NOHMeOOMeOOMeNHOOMeMeOOMeNCNHNMeOOMeOOMeNOOMeMeOOMeMeXYOHNOOOAcMeOOMeOOMeNOOMeMeOOMeNCNMeXYHNOOOAcFFNOOMeMeOOMeNCNMeHTHIQ9 (271)THIQ2 (264)THIQ11 (273)THIQ12 (274)NOHFFNOOMeMeOOMeHOMe315NOFFNOOMeMeOOMeHOMeN+OO-NO2N+OO-NO2321NOHFFNOOMeMeOOMeHOMeNH2322NOHFFNOOMeMeOOMeHNCNMeNH2THIQ21 (323)NOOOAcFFNOOMeMeOOMeHNCNMeNH2THIQ22 (324)DDQDDQNMeCNNOAcFFNOOMeMeOHNCNMeOTHIQ26 (329)NSOOMeOOMeMeOOMeOOOMeOOO291FFNOSOOFFFOTfOOBn290NNOOMeOFFOOBnOOMeMeOOMe314NNOOMeOFFOHOOMeMeOOMe285NOHFFNHOOMeMeOOMeHO286NOHFFNOOMeMeOOMeHOMe315NSANCSAHFIP 0 °C, 5 min 64% yieldNOHFFNOOMeMeOOMeHOMeCl316NOHFFNOOMeMeOOMeHNCNMeClTHIQ19 (319)NOOOAcFFNOOMeMeOOMeHNCNMeClTHIQ20 (320)NOHFFNOOMeMeOOMeHOMeNH2322NOHFFNOOMeMeOOMeHNCNMeNH2THIQ21 (323)1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13C1H13C1H13C1H13C1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13C19F1H13CEcteinascidin 743 (Et-743) (255)FIgure A7.1FIgure A7.2FIgure A7.3A. Non-natural analogs.B. Biological assay data.BreastOvarianColonLungIC50 (29 Whole Cell Lines)= Not Determined100 nM500 nM> 800 nMC5C18Ecteinascidin 743 (Et-743) (255) A549 IC50 = 1.0 nM in vivo t1/2 = 96 hQuinaldic Acid Derivative (QAD) (281) (Myers, 2006) A549 IC50 = 10.7 nM in vivo t1/2 = 17 minA. Half-life comparison of a representative bis-THIQ derivative and Et-743.B. Targeted fluorinated derivatives.X = OH, NH2 Y = OH, OAc, PhthFIgure A7.41H13C1H1H13C1H13C1H13C19F1H13C19F+[Ir(cod)Cl]2 (10 mol%) BTFM-Xyliphos (21 mol%) TBAI (60 mol%)PhMe/AcOH (9:1) (0.02 M) H2 (60 bar) 60 °C, 18 h then, 80 °C, 24 h 45% yield >20:1 dr, 17% ee5 steps30% yieldA. Initial route toward di-fluorinated analogs.B. Incompatibility of oxidized coupling partners.+N-methylationarene/hydroxy functionalizationIr-catalyzed hydrogenation+desulfinative cross-couplingdebenzylationKF 18-crown-6 THF, 50 °Cor, CsF MeCN, 80 °C+Scheme A7.1Scheme A7.2Scheme A7.3n-BuLi (1.05 equiv)Et2O (0.2 M) –100 °C, 15 min 74% yieldTMSOTf (10 mol%)CH2Cl2 (0.4 M) 0–40 °C, 36 h 92% yield(1.1 equiv)Pd2(dba)3 (2.5 mol%) XPhos (5 mol%)THF (0.2 M) 65 °C, 18 h 98% yield1. HCl (4 N, dioxane) acetone (1 M) 50 °C, 5 h2. NH4OH (33%, aq.) MeCN (0.5 M) 60 °C, 18 hTf2O (1.5 equiv) pyridine (15 equiv)CH2Cl2 (0.15 M) 0–23 °C, 1 h 87% yield42% yieldFailed Li-Enolate Cross-Couplingt-butyl acetate (2.0 equiv) Pd2dba3 (5 mol%) P(t-Bu)3•HBF4 (20 mol%) LHMDS (2.5 equiv)PhMe, –78 to 23 °Ctrace yieldtrace yieldScheme A7.4Fe(ClO4)3•H2O (15 mol%) H2O2 (33% aq) (6 equiv)MeOH (0.3 M), 0–23 °C 60-90% yieldPd(dba)2 (5 mol%) DavePhos (12 mol%) Et3N (3 equiv)dioxane (0.2 M) 100 °C 34-47% yieldScheme A7.51. LiOH • H2O (10 equiv) THF/MeOH/H2O 2. (COCl)2, DMF (cat.) CH2Cl2 then, NH4OH3. methyl propiolate PPh3 (10 mol%) PhMe (0.2 M)Pd(dba)2 (10 mol%) DavPhos (12.5 mol%) Et3N (3 equiv)1,4-dioxane, 100 °C+B. Unexpected annulation.A. Initial attempts at Heck annulation.HATU (1.1 equiv) DIPEA (3 equiv)DCM:DMF (2:1, 0.2 M) 82% yieldPd2(dba)3 (2.5 mol%) XantPhos (5 mol%) DIPEA (3 equiv)1,4-dioxane 80 °C, 3 h 98% yieldH2O2 (10 equiv) Na2WO4•H2O (10 mol%)EtOH 60 °C, 5 h 99% yieldScheme A7.6+a140 °C. bIsolated yield, 0.1 mmol scale.Table A7.1Pd(OH)2/C (20 mol% wt) cat. HClMeOH:THF (1:1, 0.1 M) H2 (1 atm)[Ir(cod)Cl]2 (10 mol%) BTFM-Xyliphos (21 mol%) TBAI (60 mol%)PhMe/AcOH (9:1) (0.02 M) H2 (60 bar) 60 °C, 18 h then, 80 °C, 24 h 38% yield over two steps >20:1 dr, 17% eeCH2O (aq., 37%) Na(OAc)3BHDCE (0.1 M) 23 °C, 30 min 99% yieldPd G3 Dimer (50 mol%) AdBIppyPhos (2 equiv) CsOH•H2O (10 equiv)1,4-dioxane, 90 °C, 3 h 0% yieldacetamide (10 equiv) Pd(OAc)2 (1 equiv) t-BuBrettPhos (2.2 equiv) K3PO4 (3 equiv)t-BuOH (0.04 M), H2O (4 mol%) 100 °C, 16 h 0% yieldLi(EtO)2AlH2 THF, 0 °Cthen, AcOH aq. KCN 26% yieldAc2O DMAPMeCN 99% yieldB. Completed synthesis of THIQ19 and THIQ20.A. Attempted installation of phenol or acetamide.Scheme A7.7+analogA427H810H1437THIQ13 THIQ14 THIQ15 THIQ16 THIQ19 THIQ2019 8.3 6.8 21 9.7 5.418 5.0 6.3 16 7.4 4.615 19 33 37 17 10THIQ1 (263)THIQ4 (266), X = Y = Cl THIQ8 (270), X = Y = BrTHIQ5 (267), X = Y = Cl THIQ7 (269), X = Y = Br THIQ17 (279), X = Y = OHTHIQ16 (278)FIgure A7.3A. Non-natural analogs.B. Preliminary biological assay data.BreastOvarianColonLungIC50 (29 Whole Cell Lines)= Not Determined100 nM500 nM> 800 nMC5C18EC50 (uM)analogA427H810H1437THIQ1 THIQ2 THIQ3 THIQ5 THIQ6 THIQ7 THIQ9 THIQ11 THIQ12 THIQ13 THIQ14 THIQ15 THIQ16 THIQ17 THIQ1838 21 15 34 42 37 0.71 6.3 0.60 19 8.3 6.8 21 0.07 0.3234 11 18 >42 >42 >42 0.68 9.6 0.59 18 5.0 6.3 16 0.063 0.28>42 24 26 >42 >42 >42 3.0 21 1.5 15 19 33 37 0.2 1.3EC50 (uM)NNSA (12 equiv)HFIP 60 °C, 18 h 52% yieldPd/CTHF H2 (1 bar) 40 °C, 18 h 85% yieldLi(EtO)2AlH2 THF, 0 °Cthen, AcOH aq. KCN 44% yieldAc2O DMAPMeCN xx% yieldScheme A7.8A. Planned acetylation to access THIQ22.B. Planned route to phenolic derivatives.Ac2O DMAP+Pd(OH)2/C (20 mol% wt) cat. HClMeOH:THF (1:1, 0.1 M) H2 (1 atm)[Ir(cod)Cl]2 (10 mol%) BTFM-Xyliphos (21 mol%) TBAI (60 mol%)PhMe/AcOH (9:1) (0.02 M) H2 (60 bar) 60 °C, 18 h then, 80 °C, 24 h 38% yield over two steps >20:1 dr, 17% eeCH2O (aq., 37%) Na(OAc)3BHDCE (0.1 M) 23 °C, 30 min 99% yieldLi(EtO)2AlH2 THF, 0 °Cthen, AcOH aq. KCN 26% yieldAc2O DMAPMeCN 99% yieldLi(EtO)2AlH2 THF, 0 °Cthen, AcOH aq. KCN 44% yield