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. 2007 Nov 28;129(47):14556-7.
doi: 10.1021/ja076165q. Epub 2007 Nov 7.

Total synthesis of (-)-pseudolaric acid B

Barry M Trost  1 , Jerome Waser, Arndt Meyer
Affiliations

Total synthesis of (-)-pseudolaric acid B

Barry M Trost et al. J Am Chem Soc. .

Abstract

We report the enantioselective synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon, which displays interesting antifungal, antifertility, and cytotoxic activity against multidrug resistant cell lines. Our synthesis utilizes a highly efficient metal-catalyzed [5 + 2] vinylcyclopropane-alkyne intramolecular cycloaddition to construct the polyhydroazulene core of the natural product. Elaboration to the tricyclic scaffold of the pseudolaric acids was completed with an intramolecular alkoxycarbonyl radical cyclization to form the quaternary center and a highly diastereoselective cerium acetylide addition to a methyl ketone for introduction of the acid side chain.

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Figures

Scheme 1
Scheme 1
Retrosynthesis of Pseudolaric Acid B (1a)
Scheme 2
Scheme 2
Synthesis of the Polyhydroazulene Corea aConditions: (a) 1.4 mol% [RuI2(p-cymene)]2, 2.8 mol% (R)-BINAP, 1800 psi H2, methanol, CH2Cl2, 40 °C, 95%, >95:5 dr, >90% ee. (b) TBSCl, imidazole, DMAP, DMF. (c) DIBALH, toluene, −78 °C. (d) TMSCHN2, LDA, THF, −78 °C, then TMSCl, 73% over 3 steps. (e) PPh3, I2, imidazole, toluene, 90%. (f) TBDPSCl, imidazole, THF, 92%. (g) Et2Zn, DME, CH2I2, Charette’s auxiliary, CH2Cl2, −10→23 °C, 91%, >90% ee. (h) (COCl)2, DMSO, NEt3, CH2Cl2, quant. (i) 1) MePh3P+Br−, PhLi/LiBr, THF; 2) 7, 0 °C, then PhLi/LiBr; 3) 9, −78 °C, then PhLi/LiBr, 23 °C; 4) HCl, −78 °C, then KOtBu, 23 °C. (j) K2CO3, MeOH, 58% over 2 steps (53% (E)-4). (k) 23 mol% [CpRu(CH3CN)3]+PF6− (11), acetone, 48% 3, 15% 10 or 11 mol% [(C8H10)Rh(COD)]+SbF6− (12), DCE, 88% 3.
Scheme 3
Scheme 3
Introduction of the Quaternary Centera aConditions: (a) TBAF, 3Å MS, THF, 94%. (b) TESCl, imidazole, DMAP, DMF, 85%. (c) m-CPBA, NaHCO3, CH2Cl2, −20 °C. (d) LDA, THF, 0 °C, 72% over 2 steps. (e) DDQ, pH=7 buffer, CH2Cl2. (f) MnO2, KCN, AcOH, MeOH, 85% over 2 steps. (g) TBAF, AcOH, THF, 87%. (h) Dess-Martin periodinane, CH2Cl2, 85%. (i) Ac2O, pyridine, DMAP, quant. (j) TMSC≡CCeCl2, THF, −78 °C, then CDI, −78→23 °C, 91%, 8:1 dr. (k) Ph2Se2, NaBH4, DMF, 76% (84% brsm). (l) CDI, THF, quant. (m) Ph2Se2, NaBH4, DMF, 92%. (n) PMBOC(NH)CCl3, 2 mol% Sc(OTf)3, toluene, 0 °C, 94%. (o) Bu3SnH, 1,1′-azo(biscyclohexane carbonitrile), benzene, 70 °C, then DBU, 23°C, 85% (92% purity).
Scheme 4
Scheme 4
Completion of the Synthesisa aConditions: (a) KOTMS, toluene, 120 °C, 30 min, then Me2SO4, buffer (TsOH, Hünig’s base 1:2), 100 °C, 5 min. (b) Dess-Martin periodinane, NaHCO3, CH2Cl2, 0 °C, 59% over 2 steps (73% brsm). (c) DDQ, pH=7 buffer, CH2Cl2, 76%. (d) TMSC≡CCeCl2·2LiCl, THF, −78 °C, 87% (98% brsm). (e) Otera’s catalyst, toluene, 130 °C, 30 min, 94%. (f) TBAF, THF, 0→23 °C, 87%. (g) Ac2O, 8 mol% Sc(OTf)3, 0 °C, 98%. (h) Bu3SnH, 5 mol% Pd(PPh3)2Cl2, THF, 90%. (i) Iodide 21, 25 mol% Pd2dba3, Hünig’s base, NMP, 62%.
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