Exploiting orthogonally reactive functionality: synthesis and stereochemical assignment of (-)-ushikulide A

Abstract

In spite of the tremendous advances in modern spectroscopic methods, organic synthesis continues to play a pivotal role in elucidating the full structures of complex natural products. This method has the advantage that, even in the absence of a firm structural assignment, a combination of logic and spectroscopic comparison can arrive at the correct structure. Herein, we report execution of this strategy with respect to ushikulide A, a newly isolated and previously stereochemically undefined member of the oligomycin-rutamycin family. To maximize synthetic efficiency, we envisioned chemoselective manipulation of orthogonally reactive functional groups, notably alkenes and alkynes as surrogates for certain carbonyl and hydroxyl functionalities. This approach has the dual effect of minimizing the number of steps and protecting groups required for our synthetic route. This strategy culminated in the efficient synthesis and stereochemical assignment of ushikulide A.

Figure 1. Tentative Assignment of Ushikulide A

Scheme 1. Retrosynthesis of Ushikulide A

Scheme 2. Toward the Synthesis of the Spiroketal Fragment^a

^aConditions: (a) 0.1 mol% (R)-BINAP, 0.05 mol% [RuCl₂(C₆H₆)]₂, MeOH, H₂ 1800 psi, 92%, 99% ee (b) PMBO(C=NH)CCl₃, 1 mol% Cu(OTf)₂, toluene, 85% (c) DIBAL-H, CH₂Cl₂, 82% (d) i.) cis-2-butene, n-BuLi, KOt-Bu, THF ii.) (+) Ipc₂BOMe iii.) BF₃·OEt₂ then 10, >20:1 d.r. (e) TBSCl, imid., DMF, 87% over 2 Steps (f) 9-BBN, THF then I₂, NaOCH₃, MeOH, 85% (g) THF, DMPU, LiCCTMS, then KOH, MeOH, 81% (h) TiCl₄, EtN(i-Pr)₂, NMP, CH₂Cl₂, single diastereomer, 90%, (i) TBSOTf, 2,6-lutidine, CH₂Cl₂, 96% (j) DIBAL-H, CH₂Cl₂, 87% (k) 10 mol% (S,S) ProPhenol, Me₂Zn, toluene, 88%, 95% ee (l) LiOH, THF, H₂O then CuCl, CH₃CN, 75% (m) MsCl, Et₃N, CH₂Cl₂, 95%.

Scheme 3. Completion of the Spiroketal Fragment^a

^aConditions: (a) n-BuLi, THF, 90%, 1.5:1 syn:anti (b) for syn: DEAD, PhCOOH, PPh₃, toluene, 92%, for anti: BzCl, pyridine, 95% (c) HCl, H₂O, THF (d) 10 mol % AuCl, PPTS, THF, 63% (e) MeI, NaHCO₃, CH₃CN, H₂O, 80% (f) 10 mol% Pd(OAc)₂, ZnEt₂, PPh₃, THF, 7, 90%, 3.8:1 d.r. (g) TBSOTf, 2,6-lutidine, CH₂Cl₂ (h) K₂CO₃, MeOH (i) Bu₃SnH, 5 mol% PdCl₂(PPh₃)₂, THF, then I₂, 90% over 3 steps.

Scheme 4. Synthesis of the Aliphatic Fragment^a

^aConditions: (a) PMBO(C=NH)CCl₃, 0.5 mol% Sc(OTf)₃, toluene, 88% (b) 10 mol% PdCl₂, CuCl, O₂, DMF, H₂O, 60% (c) allyl bromide, tin (II) catecholate, DBU, CuI, (−)-diisopropyl tartrate, CH₂Cl₂, 92%, 99% ee (d) PMBO(C=NH)CCl₃, 1 mol% Sc(OTf)₃, toluene, 85% (e) DIBAL-H, CH₂Cl₂, 90% (f) 60 mol% Et₂Zn, t-BuOH, dioxane, 30 mol% (S,S) ProPhenol, 65% b.r.s.m. (g) NaBH₄, MeOBEt₂, MeOH, THF (h) p-TsOH, CH₂Cl₂, 2,2-dimethoxypropane, 71% over 2 steps (i) n-Bu₄NF, THF (j) Dess-Martin reagent, CH₂Cl₂, (k) n-BuLi, (EtO)₂P(O)CH₂CO₂TMS, THF, 92% over 3 steps.

Scheme 5. Completion of the Synthesis^a

^aConditions: (a) 3, 9-BBN, THF; then 2, DMF, H₂O, 10 mol% PdCl₂(dppf), 10 mol% Ph₃As, Cs₂CO₃, 67% (b) 2-methyl-6-nitrobenzoic anhydride, 4-DMAP, DCE, 65% (c) HF·pyridine, pyridine, THF (d) Dess-Martin reagent, CH₂Cl₂ (e) DDQ, H₂O, CH₂Cl₂ then dilute with 3:2 AcOH, H₂O, 52% over 3 steps.