Total Synthesis of (+)-Rubriflordilactone A

Abstract

Two enantioselective total syntheses of the nortriterpenoid natural product rubriflordilactone A are described, which use palladium- or cobalt-catalyzed cyclizations to form the CDE rings, and converge on a late-stage synthetic intermediate. These key processes are set up through the convergent coupling of a common diyne component with appropriate AB-ring aldehydes, a strategy that sets the stage for the synthetic exploration of other members of this family of natural products.

Keywords: cyclotrimerization; domino reactions; natural products; total synthesis; transition metal catalysis.

Scheme 1

Retrosynthetic analysis of rubriflordilactone A.

Scheme 2

Reagents and conditions: a) (S,E)-pent-3-en-2-ol, EDC⋅HCl, Et₃N, DMAP, THF, RT, 16 h, 81 %; b) LiHMDS, Et₃N/toluene (3:1), −78 °C→RT, 5 h, 95 %, d.r.>20:1; c) LDA, TMSCl/Et₃N (1:1), THF, −78 °C→0 °C, 3 h, 92 %, d.r. 9:1; d) TMSCHN₂, toluene/MeOH (5:1), RT, 30 min, 88 %; e) DIBALH, CH₂Cl₂, −78 °C→−30 °C, 2 h, 97 %; f) DMP, NaHCO₃, CH₂Cl₂, 0 °C→RT, 1 h, 90 %; g) [Ph₃PCH₂I]⁺I⁻, NaHMDS, THF, −78 °C→RT; then NaHMDS, −78 °C→RT, 84 %; h) LiHMDS, THF, −78 °C, 30 min; then BnMe₂SiCl, −78 °C→RT, 3 h, 98 %; i) DDQ, CH₂Cl₂/H₂O (4:1), RT, 1 h; j) DMP, NaHCO₃, CH₂Cl₂, 0 °C→RT, 30 min, 83 % (2 steps); k) CBr₄, PPh₃, CH₂Cl₂ −30 °C→0 °C, 1 h, 85 %; l) nBuLi, THF, −78 °C→RT, 40 min, 98 %. Bn=benzyl, DIBALH=diisobutylaluminium hydride, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMAP=4-dimethylaminopyridine, DMP=Dess–Martin periodinane, EDC=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, HMDS=1,1,1,3,3,3-hexamethyldisilazane, LDA=lithium diisopropylamide, PMB=para-methoxybenzyl, TMS=trimethylsilyl.

Scheme 3

Reagents and conditions: a) TMSCαCCH₂MgBr, CuBr⋅SMe₂, THF, −78 °C→−40 °C, 40 min; 13, −78 °C; b) DIBALH, CH₂Cl₂, −78 °C→RT, 3 h, 90 % (2 steps); c) Ti(OiPr)₄, d-(−)-diethyl tartrate, tBuOOH, 4 Å MS, CH₂Cl₂, −20 °C, 22 h, 92 %, 92 % ee; d) AllylMgBr, THF, 0 °C, 10 min, 97 %; e) SO₃⋅py, DMSO, iPr₂EtN, CH₂Cl₂, 0 °C→RT, 2 h; f) NaOCl, NaH₂PO₄, 2-methylbut-2-ene, tBuOH/H₂O (3:1), RT, 18 h, 92 % (2 steps); g) BOPCl, py, MeCN, RT, 3 h, 83 %; h) MeMgBr, THF, −5 °C→RT, 1.5 h, 64 %+31 % ketone, recycled to give 75 % overall; i) OsO₄, NaIO₄, 2,6-lutidine, dioxane/H₂O (4.6:1), RT, 2 h, 88 %; j) (±)-camphorsulfonic acid, MeOH, RT, 18 h, 98 %; k) SO₃⋅py, DMSO, iPr₂EtN, CH₂Cl₂, 0–10 °C, 1 h, 84 %; l) (PhO)₂POCH₂CO₂Et, KHMDS, THF, 0 °C; m) TFA, CH₂Cl₂, 0 °C, 15 min, 47 % (from 17, and 18); n) K₂CO₃, MeOH, RT, 2 h, 99 %. BOPCl=bis(2-oxo-3-oxazolidinyl)phosphinic chloride, MS=molecular sieves, py=pyridine, TBS=tert-butyldimethylsilyl, TFA=trifluoroacetic acid.

Scheme 4

Reagents and conditions: a) nBuLi, 7, −78 °C; then add 6, −78 °C→−10 °C, 2 h, 67 %; b) TBSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C→RT, 4 h 75 %; c) [Pd(PPh₃)₄] (10 mol %), Et₃N, MeCN, 80 °C, 18 h, 91 %; d) TBAF, THF, RT, 30 min; then H₂O₂, KHCO₃, MeOH, RT, 12 h; e) Et₃SiH, ZnCl₂, CH₂Cl₂, RT, 3 h; then TBAF, THF, RT, 20 min, 51 % (2 steps); f) nBuLi, 7, −78 °C; then add 8, −78 °C→−10 °C, 4 h, 85 %; g) [CpCo(CO)₂] (20 mol %), PPh₃ (40 mol %), PhCl, MW (300 W), 150 °C, 25 min, 67 %; h) TBAF, THF, RT, 30 min; then H₂O₂, KHCO₃, MeOH, RT, 12 h, 84 %; i) Et₃SiH, ZnCl₂, CH₂Cl₂, RT, 3 h, 77 %; j) TBSCl, imid., DMAP, CH₂Cl₂, RT, 6 h, 98 %; k) [CpCo(CO)₂] (20 mol %), PPh₃ (40 mol %), PhCl, MW (300 W), 150 °C, 25 min, 54 %. Cp=cyclopentadienyl, MW=microwave irradiation, OTf=trifluoromethanesulfonate, TBAF=tetra-n-butylammonium fluoride.

Scheme 5

Reagents and conditions: a) OsO₄ (2 mol %), NMO, acetone/H₂O (3:1), RT, 3 h; b) NaIO₄/SiO₂, CH₂Cl₂, RT, 15 min, 85 % (2 steps); c) ZnCl₂, SOCl₂, CDCl₃, RT, 3 h; d) 29, ZnCl₂, CH₂Cl₂, −30 °C→RT, 12 h, 38 % of 1 and 33 % of 30 (2 steps). NMO=N-methylmorpholine-N-oxide, TIPS=triisopropylsilyl.