PMC

a) Suzuki coupling conditions: a. Et₃N/DCM; b. PrI, Buli, B-methoxy-9-BBN/ Et₂O, THF; c. K₃PO_4(aq), 29, PdCl₂(dppf)⋅CH₂Cl₂/DMF. b) Mannich condensation: d. H₂C = N⁺(CH₃)₂, CF₃CO₂-/DCM; e. MeI/MeOH.

Synthesis of cyclization precursors 76, 81, 83 and 85. Reagents and conditions: a) n‐BuLi, BF₃ ⋅ OEt₂, THF, −78 °C to 0 °C, 80 %; b) I₂, PPh₃, imH, Et₂O, MeCN, 22 °C, 78 %; c) t‐BuLi, B‐methoxy‐9‐BBN, THF, −78 °C to 22 °C, then 19, SPhos Pd GII, SPhos, Cs₂CO₃, DMF, H₂O, 40 °C, 76 %; d) TBAF, THF, 0 °C to 22 °C, 82 %; e) CuI, (CH₂O)_n, Cy₂NH, 1,4‐dioxane, 103 °C, 57 %; f) n‐BuLi, THF, −78 °C to 22 °C; g) TBSOTf, 2,6‐lutidine, CH₂Cl₂, 0 °C; h) p‐TsOH ⋅ H₂O, MeOH, 22 °C, 56 % over three steps; i) I₂, PPh₃, imH, Et₂O, MeCN, 22 °C, 92 %; j) t‐BuLi, B‐methoxy‐9‐BBN, THF, −78 °C to 22 °C, then 19, SPhos Pd GII, SPhos, Cs₂CO₃, DMF, H₂O, 40 °C; k) TBAF, THF, 0 °C to 22 °C, 69 % over two steps; l) PhSCl, NEt₃, THF, −78 °C to 22 °C, 98 %; m) Ac₂O, DMAP, NEt₃, 22 °C, 95 %; n) [(Ph₃P)CuH]₆, toluene, 22 °C, 46 %; o) LiHMDS, MeI, THF, −78 °C to 22 °C, 36 %; p) CuI, LiBr, MeMgBr, THF, 0 °C to 22 °C, 91 %. Ac=acetyl, B‐methoxy‐9‐BBN=9‐methoxy‐9‐borabicyclo[3.3.1]nonane, Cy=cyclohexyl, DMAP=N,N‐dimethylpyridin‐4‐amine, DMF=N,N‐dimethylformamide, imH=imidazole, LiHMDS=lithium hexamethyldisilazide, SPhos=2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl, SPhos Pd GII=chloro(2‐dicyclohexylphosphino‐2′,6′‐dimethoxy‐1,1′‐biphenyl)[2‐(2′‐amino‐1,1′‐biphenyl)]palladium(II), TBAF=tetra‐n‐butylammonium fluoride, TBS=t‐butyldimethylsilyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran, THP=tetrahydropyranyl, TIPS=tri‐iso‐propylsilyl, Ts=toluenesulfonyl.

Synthesis of cyclization precursors 42 a/b, 54, 55, 64 and 65. Reagents and conditions: a) BnOCH₂PPh₃Cl, n‐BuLi, THF, −78 °C to 22 °C; b) NEt₃ ⋅ 3HF, MeCN, 22 °C, 72 % over two steps; c1) MsCl, NEt₃, CH₂Cl₂, 0 °C to 22 °C, then TBAI, benzene, 80 °C, 41 % of 41 a/b (1 : 1); c2) I₂, PPh₃, imH, CH₂Cl₂, 0 °C, inseparable mixture of 41 b with PPh₃; c3) I₂, pol−PPh₃, imH, CH₂Cl₂, 0 °C to 22 °C, 9 % of 41 a/b (1 : 6); c4) DEAD, PPh₃, LiI, THF, 0 °C, 59 %; c5) DEAD, PPh₃, LiI, THF, 0 °C, 80 %; d) t‐BuLi, B‐methoxy‐9‐BBN, THF, −78 °C to 22 °C, then 19, SPhos Pd GII, SPhos, Cs₂CO₃, DMF, H₂O, 40 °C, 53 % of 42 a, 74 % of 42 b; e) EtAlCl₂, CH₂Cl₂, −78 °C; f) SnCl₄, CH₂Cl₂, −78 °C; g1) 44, MeMgBr, Ni(acac)₂, AlMe₃, THF, 22 °C; g2) 44, AlMe₃, Cp₂ZrCl₂, CH₂Cl₂, 0 °C to 22 °C; g3) 46, AlMe₃, Cp₂ZrCl₂, CH₂Cl₂, 0 °C to 22 °C; g4) 49, AlMe₃, Cp₂ZrCl₂, CH₂Cl₂, 22 °C to 40 °C, traces; g5) 49, AlMe₃, Cp₂ZrCl₂, H₂O, CH₂Cl₂, −40 °C to 40 °C, 40 %; h) I₂, PPh₃, imH, CH₂Cl₂, 0 °C, 60 %; i) t‐BuLi, B‐methoxy‐9‐BBN, THF, −78 °C to 22 °C, then 52 or 53, SPhos Pd GII, SPhos, Cs₂CO₃, DMF, H₂O, 40 °C, 88 % of 54, 60 % of 55; j) EtAlCl₂, CH₂Cl₂, −78 °C; k) SnCl₄, CH₂Cl₂, −78 °C; l1) t‐BuLi, CuCN ⋅ 2LiCl (10 mol%), allyl bromide, THF, −78 °C, 60/61/62 (7 : 3 : 1) determined by ¹H NMR analysis of the crude reaction mixture; l2) t‐BuLi, CuCN ⋅ 2LiCl (10 mol%), allyl iodide, THF, −78 °C, 60/61/62 (10 : 10 : 1) determined by ¹H NMR analysis of the crude reaction mixture; l3) i‐PrMgBr, n‐BuLi, CuCN ⋅ 2LiCl (10 mol%), allyl bromide, THF, −78 °C to 0 °C, 60/61/62 (25 : 1 : 3) determined by ¹H NMR analysis of the crude reaction mixture, 66 % of 60; m) PPTS, MeOH, 22 °C, 85 %; n) I₂, PPh₃, imH, CH₂Cl₂, 0 °C, 78 %; o) t‐BuLi, B‐methoxy‐9‐BBN, THF, −78 °C to 22 °C, then 19 or 53, SPhos Pd GII, SPhos, Cs₂CO₃, DMF, H₂O, 40 °C, 63 % of 64, 79 % of 65; p) EtAlCl₂, CH₂Cl₂, −78 °C, traces. Acac=acetylacetone, B‐methoxy‐9‐BBN=9‐methoxy‐9‐borabicyclo[3.3.1]nonane, Bn=benzyl, Cp=cyclopentadienyl, DEAD=diethyl azodicarboxylate, DMF=N,N‐dimethylformamide, imH=imidazole, MsCl=methanesulfonyl chloride, n.d.=not determined, pol−PPh₃=diphenylphosphino−polystyrene, PPTS=pyridinium p‐toluenesulfonate, py=pyridine, SPhos=2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl, SPhos Pd GII=chloro(2‐dicyclohexylphosphino‐2′,6′‐dimethoxy‐1,1′‐biphenyl)[2‐(2′‐amino‐1,1′‐biphenyl)]palladium(II), TBAI=tetrabutylammonium iodide, TBS=t‐butyldimethylsilyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran, THP=tetrahydropyranyl.

Synthesis of 25 a/b via polyene tetracyclization of 21. Reagents and conditions: a) Corey–Noe–Lin ligand 18, MeSO₂NH₂, K₂OsO₄ ⋅ 2H₂O, K₂CO₃, K₃[Fe(CN)₆], t‐BuOH, H₂O, 0 °C, 73 %, 94 % ee; b) MsCl, pyridine, CH₂Cl₂, 22 °C, then K₂CO₃, MeOH, 22 °C, 80 %; c) 20, t‐BuLi, B‐methoxy‐9‐BBN, THF, −78 °C to 22 °C, then SPhos Pd GII, SPhos, Cs₂CO₃, DMF, H₂O, 40 °C, 84 %; d) SnCl₄, CH₂Cl₂, −78 °C, 16 % 22 a, 10 % 22 b; d) EtSH, NaH, DMF, 120 °C, 94 % of 25 a, 84 % of 25 b; e) BzCl, DMAP, py, 22 °C, 9 % 23 over two steps, 12 % 24 over two steps. B‐methoxy‐9‐BBN=9‐methoxy‐9‐borabicyclo[3.3.1]nonane, Bz=benzoyl, DMAP=N,N‐dimethylpyridin‐4‐amine, DMF=N,N‐dimethylformamide, ee=enantiomeric excess, MsCl=methanesulfonyl chloride, py=pyridine, SPhos=2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl, SPhos Pd GII=chloro(2‐dicyclohexylphosphino‐2′,6′‐dimethoxy‐1,1′‐biphenyl)[2‐(2′‐amino‐1,1′‐biphenyl)]palladium(II), THF=tetrahydrofuran.