Scheme 1.

Synthesis of the bryostatin 9 northern and southern fragment coupling partners^a

^a A Reagents and Conditions: (a) BnBr, NaHMDS, 5:1 THF:DMF, 0 °C, 90%; (b) ethyl acetoacetate (2.5 eq.), LDA (5.0 eq.), THF, −78 °C; (c) PPTS, MeOH, 40 °C, 84% over 2 steps; (d) NaBH₄, EtOH, −15 °C, dr: 78:22, 61% isolated 8; (e) TESCl, imidazole, CH₂Cl₂, rt, 97%; (f) CeCl₃·2LiCl, TMSCH₂MgCl, THF, rt, 65%; (g) NaHMDS, THF, 0 °C, 91%; (h) lithium naphthalenide, THF, −30 °C → −10 °C, 87%; (i) TEMPO (30 mol %), PhI(OAc)₂ (3 eq.), 4:1 MeCN:H₂O, then NaH₂PO₄, NaClO₂, 2-methyl-2-butene, 0 °C; (j) Ac₂O, DMAP, CH₂Cl₂, 0 °C, then aq. NaHCO₃, 57% over 2 steps. B Reagents and Conditions: (a) O₃, CH₂Cl₂, −78 °C, then PPh₃, rt, 98%; (b) I₂CHCH₃, CrCl₂, DMF, THF, 0 °C, 76%, 93:7 E:Z; (c) K₂CO₃, methyl glyoxylate, THF:MeOH, rt, 81%; (d) NaBH₄, CeCl₃·7H₂O, MeOH, −49 °C; (e) butyric anhydride, DMAP, CH₂Cl₂, rt, 91% over 2 steps; (f) 3HF·Et₃N, THF, rt; (g) Dess-Martin periodinane, CH₂Cl₂, rt; (h) Z-1-bromo-2-ethoxyethylene, t-BuLi, Me₂Zn, Et₂O, −78 °C, then H₃O⁺, 64% over 3 steps; (i) K₂OsO₄·2H₂O (~0.5 mol %), DHQD₂PYR (1.5 mol %), K₂CO₃, K₃Fe(CN)₆, 4 °C, 78%, 83:17 (R,R):(S,S); (j) p-TsOH, 4:1 MeCN:H₂O, rt; (k) TBSCl, imidazole, CH₂Cl₂, 64% over 2 steps as a single diastereomer.