Total Synthesis of the Schisandraceae Nortriterpenoid Rubriflordilactone A

Abstract

Full details of the total synthesis of the Schisandraceae nortriterpenoid natural product rubriflordilactone A are reported. Palladium- and cobalt-catalyzed polycyclizations were employed as key strategies to construct the central pentasubstituted arene from bromoendiyne and triyne precursors. This required the independent assembly of two AB ring aldehydes for combination with a common diyne component. A number of model systems were explored to investigate these two methodologies, and also to establish routes for the installation of the challenging benzopyran and butenolide rings.

Keywords: cascade cyclization; cyclotrimerization; natural products; total synthesis; transition-metal catalysis.

Figure 1

Schinortriterpenoid natural products prepared by total synthesis, and common structural features.

Scheme 1

Retrosynthetic analysis of rubriflordilactone A.

Scheme 2

Reagents and conditions for large scale synthesis of 19 and 23. Masses indicate the scale reactions were conducted on. a) PdCl₂(PPh₃)₂. (3 mol %), Bu₃SnH, THF; b) TBSCl, imid., DMF, 0 °C to RT; c) Pd(dba)₂. (4 mol %), 2,3‐dibromopropene, toluene, 70 °C; d) PMBTCA, Sc(OTf)₃ (5 mol %), PhMe; e) CSA (10 mol %), MeOH; then NEt₃; f) Ti(OiPr)₄, d‐(−)‐diethyl tartrate, tBuOOH, 4 Å MS, CH₂Cl₂, −20 °C; g) allylMgBr, THF, 0 °C; h) Dess–Martin periodinane, NaHCO₃, CH₂Cl₂; i) 2‐methyl‐2‐butene, NaClO₂, NaH₂PO₄, tBuOH/H₂O (2:1); j) BOPCl, py, MeCN; k) MeMgBr, THF −50 °C to RT; l) TBSCl, imid., DMAP, CH₂Cl₂; m) nBuLi, THF, −78 °C; EtOCOCl, −78 °C to RT; n) TMSC≡CCH₂MgBr, CuBr⋅SMe₂, THF, −40 °C; then 24, THF, −78 °C; o) DIBALH, CH₂Cl₂, −78 °C→rt; p) MeMgBr, THF, −5 °C. BOPCl=bis(2‐oxo‐3‐oxazolidinyl) phosphinic chloride; CSA=(±)‐camphorsulfonic acid; dba=dibenzylidene acetone; DIBALH=diisobutylaluminium hydride; DMAP=4‐dimethylamino pyridine; PMB=4‐methoxybenzyl. PMBTCA=4‐methoxybenzyl trichloroacetimidate, TBS=tert‐butyldimethylsilyl.

Figure 2

a: Attempted optimization of π‐allyl Stille coupling of stannane 26. All reactions were carried out on a 150 mg scale. [a] Addition of stannane to a solution of bromide. [b] Catalyst formed in situ from Pd(dba)₂/2 PPh₃ on treatment with H₂. [c] 32 % yield of a mixture of 28 and 29. b: Addition of MeMgBr to β‐lactones 20 and 30.

Scheme 3

Reagents and conditions: a) OsO₄ (2 mol %), NaIO₄, 2,6‐lutidine, 1,4‐dioxane/ H₂O; b) TFA, CH₂Cl₂, 0 °C; c) CSA (10 mol %), MeOH, 0 °C; d) SO₃⋅py, iPr₂EtN, DMSO, CH₂Cl₂, 0 °C; e) (PhO)₂P(O)CH₂CO₂Et, KHMDS, THF −20 °C→0 °C; f) TFA, CH₂Cl₂/H₂O, 0 °C; g) K₂CO₃, MeOH. KHMDS=potassium bis(trimethylsilyl)amide; TFA=trifluoroacetic acid.

Scheme 4

Reagents and conditions: a) EDC⋅HCl, NEt₃, DMAP; b) LiHMDS, NEt₃, PhMe, −78 °C→RT; then 5 % NaOH; then conc. HCl; c) TMSCHN₂, MeOH/PhMe, 0 °C→RT; d) DIBALH, CH₂Cl₂, −78 °C→RT; e) DMP, NaHCO₃, CH₂Cl₂; f) NaHMDS, [Ph₃PCH₂I]I, THF, −78 °C→RT; NaHMDS, −78 °C→RT; g) LiHMDS, THF, −78 °C; BnMe₂SiCl, −78 °C to RT, 88 %; h) DDQ, CH₂Cl₂; i) DMP, NaHCO₃, CH₂Cl₂; j) CBr₄, PPh₃, CH₂Cl₂, 0 °C; then 50, NEt₃, −30 °C→0 °C; k) nBuLi, THF, −78 °C→RT. DDQ=2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone; DMP=Dess–Martin periodinane; EDC=1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide.

Scheme 5

Reagents and conditions: a) 13, LiHMDS, THF, −78 °C; then add aldehyde; b) TBSCl, imid., DMAP, CH₂Cl₂; c) Pd(PPh₃)₄ (5 mol %), NEt₃, MeCN, 80 °C; d) CpCo(CO)₂ (20 mol %), PPh₃ (40 mol %), PhCl, MW (300 W), 150 °C; e) TBAF, THF; then MeOH, H₂O₂, KHCO₃; f) Et₃SiH, ZnCl₂, CH₂Cl₂; TBAF, THF; g) OsO₄ (4 mol %), NMO, acetone/H₂O (3:1); h) NaIO₄/SiO₂, CH₂Cl₂. Cp=cyclopentadienyl; NMO=N‐methylmorpholine‐N‐oxide; TBAF=tetrabutylammonium fluoride.

Scheme 6

Reagents and conditions: a) Ph₃PCHCO₂Me, PhMe, 110 °C; b) H₂, Pd/C, MeOH; c) TESCl, imid., DMAP, CH₂Cl₂; d) DIBAL‐H, CH₂Cl₂, −78 °C; e) BF₃⋅OEt₂, Et₂O, −78 °C→0 °C; f) MsCl, NEt₃, CH₂Cl₂, 0 °C→RT; g) TBAF, THF; h) Conditions (see text); i) Tf₂O, iPr₂EtN, CH₂Cl₂, 0 °C; j) Pd(OAc)₂ (10 mol %), dppf or (S)‐tolBINAP (12 mol %), K₂CO₃, PhMe, 90 °C; k) DIAD, PPh₃, CH₂Cl₂, 0 °C. DIAD=diisopropyl azodicarboxylate; dppf=1,1′‐bis(diphenylphosphino)ferrocene; Ms=SO₂Me; TES=SiEt₃; TES=triethylsilyl; Tf=SO₂CF₃.

Scheme 7

Reagents and conditions: a) SOCl₂, ZnCl₂, PhMe, 0 °C→RT; b) ZnCl₂, CH₂Cl₂, −40 °C→RT; c) TIPSOTf, Et₃N, CH₂Cl₂, 0 °C. TIPS=triisopropylsilyl.

Scheme 8

Reagents and conditions: a) SOCl₂, ZnCl₂, PhMe, 0 °C→RT; b) ZnCl₂, CH₂Cl₂, −40 °C→RT. Graph a: Reaction profile (monitored by ¹H NMR for conversion of lactol 64 to chloropyran 80 via dimer 81; Graph b: Reaction profile for conversion of 81 to 80; Graph c: Example ¹H NMR timecourse experiment.

Scheme 9

Reagents and conditions: a) 13, nBuLi, THF, −78 °C; then add aldehyde 14 or 15, −78 °C→−10 °C; b) TBSOTf, 2,6‐lutidine, CH₂Cl₂, 0 °C→RT; c) Pd(PPh₃)₄ (10 mol %), NEt₃, MeCN, 80 °C; d) TBSCl, imid., DMAP, CH₂Cl₂; e) CpCo(CO)₂ (20 mol %), PPh₃ (40 mol %), PhCl, MW (300 W), 150 °C; f) TBAF, THF; then MeOH, H₂O₂, KHCO₃; g) Et₃SiH, ZnCl₂, CH₂Cl₂; h) TBAF, THF; i) OsO₄ (2 mol %), NMO, acetone/H₂O (3:1); j) NaIO₄/SiO₂, CH₂Cl₂; k) SOCl₂, ZnCl₂, PhMe, 0 °C→RT; l) 67, ZnCl₂, CH₂Cl₂, −40 °C→RT.