Rhodium‐Catalyzed Cyclization of Terminal and Internal Allenols: An Atom Economic and Highly Stereoselective Access Towards Tetrahydropyrans

Abstract A comprehensive study of a diastereoselective Rh‐catalyzed cyclization of terminal and internal allenols is reported. The methodology allows the atom economic and highly syn‐selective access to synthetically important 2,4‐disubstituted and 2,4,6‐trisubstituted tetrahydropyrans (THP). Furthermore, its utility and versatility are demonstrated by a great functional‐group compatibility and the enantioselective total synthesis of (−)‐centrolobine.

To a suspension of magnesium (1.2 equiv.) and iodide (catalytic amount) in THF (1.0 M) corresponding bromide (15 mmol) was added dropwise. After the reaction stopped refluxing, the mixture was heated to 80 °C for 1 h. Afterwards the solution was cooled to room temperature and directly used in the substrate synthesis or was stored in the freezer. ) was added at this temperature. The mixture was stirred for 15 min before the GRIGNARD reagent in THF (1.5 equiv.) was added dropwise, stirred for 30 minutes at −78 °C and then slowly warmed to −30 °C. The reaction was quenched by the addition of aqueous saturated NH4Cl-solution. The layers were separated, the aqueous layer was extracted with Et2O (4 × 30 mL), the combined organic layer were washed with brine (40 mL) and dried over Na2SO4.
The solvent was removed and the residue was purified by flash chromatography on silica gel using a mixture of pentane and ether.

General procedure internal allenes
General procedure 5: Synthesis ethyl 3,4-dienoate derivate: I) A solution of the Aldehyde (1.0 equiv.) in THF (0.5 M) was added to ethynylmagnesium bromide (0.5 M in THF, 1.1 equiv.) within 1 h at 0 °C. The reaction mixture was then stirred for 1 h at room temperature and quenched via addition of saturated aqueous NH4Cl solution. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered over a short silica pad and concentrated.

II)
To a solution of the crude alcohol (step I) (0.5 equiv.) in triethyl orthoacetate (1.05 equiv.) was added dropwise propionic acid (4.0 mol%) at 100 °C. The mixture was heated to 160 °C and resulting EtOH was continuously distilled off under atmospheric pressure for 1 h. Then another aliquot of crude alcohol (step I) (0.5 equiv.) and propionic acid (0.80 mL, 0.80 g, 11 mmol, 4.0 mol%) were added dropwise and the mixture was stirred for another 1 h before a third portion of propionic acid (4.0 mol%) was added.
The reaction was stirred for an additional hour and then cooled to room temperature and quenched by addition of aqueous HCl-solution (2 M). The organic layer was separated and the aqueous layer was extracted with Et2O (× 3). The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was either purified by fractional distillation CH2Cl2 (× 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered over a silica pad and concentrated under reduced pressure.

II)
A suspension of NaH (60% in mineral oil, 1.1 equiv.) in dry THF (0.25 M) was cooled to 0 °C and triethyl phosphonoacetate (1.3 equiv.) was added dropwise to the reaction mixture. After complete addition, the suspension was stirred for 1 h at 0 °C and was then cooled to −78 °C. A solution of penta-4,5-dienal (1.0 equiv.) was added to the reaction mixture at this temperature. The mixture was slowly warmed to −20 °C over 3 h and then quenched by the addition of aqueous saturated NH4Cl-solution.
The layers were separated, the aqueous layer was extracted with Et2O, the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Pentane:Et2O). General procedure 7: 1,4-Addition and reduction: I) A mixture of CuI (10 mol%) and LiBr (20 mol%) was carefully dried and cooled to room temperature under vacuum and backfilled with argon using a standard SCHLENK line apparatus, before extra dry or freshly distilled THF (1.0 M) was added. The mixture was stirred at room temperature for 15 min and then cooled to −78 °C. A solution of ethyl (E)-hepta-2,5,6-trienoate derivative (1.0 equiv) in extra dry or freshly distilled THF (0.3 M) and TMSCl (1.1 equiv.) was added at this temperature. The mixture was stirred for 15 min before the GRIGNARD reagent in THF (1.5 equiv.) was added dropwise, stirred for 30 minutes at −78 °C and then slowly warmed to −30 °C over 3 h. The reaction was quenched by the addition of aqueous saturated NH4Cl-solution. The layers were separated, the aqueous layer was extracted with Et2O (× 4), the combined organic layer were washed with brine and dried over Na2SO4.
The solvent was removed and the residue was filtered over a shirt silica pad II) The crude product was dissolved in Et2O () and added dropwise to a suspension of LAH () in dry Et2O at 0 °C. The reaction was stirred at this temperature for 1 h and then warmed to room temperature and stirred for another hour. The mixture was quenched through the addition of H2O and aqueous HCl (2.0 M). The layers were separated, the organic layer was washed with H20 and brine. The aqueous layer was extracted with Et2O (× 4). The combined organic layer were dried over Na2SO4, the solvent was removed. The solvent was removed and the residue was purified by flash chromatography on silica gel using a mixture of pentane and ether.
The crude product from step I was treated with LAH (0.19 mg, 5.1 mmol, 1.5 equiv.). The crude product from step II was purified by flash chromatography on silica gel (10:1 to 3:1 pentane/Et2O). The desired product was obtained as a colorless liquid (0.48 g, 1.5 mmol, 53%). Analytical Data [
The crude product from step I was treated with LAH (0.19 mg, 5.1 mmol, 1.5 equiv.). The crude product from step II was purified by flash chromatography on silica gel (10:1 to 3:1 pentane/Et2O). The desired product was obtained as a colorless liquid (0.59 g, 1.7 mmol, 59%).
The crude product from step I was treated with LAH (0.19 mg, 5.1 mmol, 1.5 equiv.). The crude product from step II was purified by flash chromatography on silica gel (10:1 to 3:1 pentane/Et2O). The desired product was obtained as a colorless liquid (0.43 g, 1.2 mmol, 43%). [
Analytical Data [
Analytical Data [

Synthesis of (S)-3-methylhepta-5,6-dien-1-ol 53
A suspension of LAH () in dry Et2O was cooled to 0 °C then a solution of 3-ethylhepta-5,6-dienoate in Et2O (2 mL) was added dropwise. The reaction was stirred at this temperature for 1 h and then warmed to room temperature and stirred for another hour. The mixture was quenched through the addition of H2O and aqueous HCl (2.0 M). The layers were separated, the organic layer was washed with H20 (20 mL) and brine (20 mL). The aqueous layer was extracted with Et2O (4 × 20 mL). The combined organic layer were dried over Na2SO4, the solvent was removed. The crude product was used without further purification.

Synthesis of (S)-3-methylhepta-5,6-dien-1-ol 54.
A suspension of LAH () in dry Et2O was cooled to 0 °C then a solution of 3-ethylhepta-5,6-dienoate in Et2O (2 mL) was added dropwise. The reaction was stirred at this temperature for 1 h and then warmed to room temperature and stirred for another hour. The mixture was quenched through the addition of H2O and aqueous HCl (2.0 M). The layers were separated, the organic layer was washed with H20 (20 mL) and brine (20 mL). The aqueous layer was extracted with Et2O (4 × 20 mL). The combined organic layer were dried over Na2SO4, the solvent was removed. The crude product was used without further purification.
Analytical Data [
The solvent was removed under reduced pressure and the crude product was purified by column chromatography (pentane: Et2O = 2:1) to afford the desired product (374 mg, 0.94 mmol, 85 %) as a yellow liquid.

Analytical data:
mL) nad conc. HCl (100mL). The layers were separated, and the aqueous layer was extracted with EE (3 x 50 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM to DCM/EE = 90/10) the residue was recrystallized from Et2O to obtain the pure title combined as white solid (12.5 g, 36.8 mol, 75%) using a mixture of pentane/ether. 480 L, 1.19 mmol, 2.2 equiv.) were added dropwise to a stirred solution of (C5H5)2Fe (100 mg, 0.540 mmol, 1.0 equiv.) in hexane (10 mL) under a argon atmosphere at room temperature. The solution was stirred at room temperature overnight. The orange slurry was allowed to settle, and the hexane layer was removed with a syringe. The remaining orange powder was washed with dry hexane (5 mL) and dissolved in dry THF (10 mL). Chlorobis(4-(trifluoromethyl)phenyl)phosphane (578 mg, 1.62 mmol, 3.0 equiv.) was diluted with dry THF (2 mL) and added to the orange solution at -78 °C. The solution was slowly warmed to room temperature and stirred for 4 hours. The reaction was quenched with water and diluted with DCM (10 mL). The layers were separated and the aqueous layer was extracted with DCM

Analytical
(3 x 10 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (pentane/Et2O = 60/1) the orange residue was recrystallized in heptane to obtain the pure title combined as orange needles (149 mg, 0.178 mmol, 33%) using a mixture of pentane/ether.

II)
To a suspension of NaH (2.16 g, 54.0mmol, 1.1 equiv. (60%)) in dry THF (30 mL) was carefully added diethylphosphite (67.9 g, 63.3 mL, 49.1 mmol, 1.0 equiv) dropwise. After completed addition the mixture was stirred for 1 h and then cooled to 0 °C. The Grignard solution (step I) was added the reaction was allowed to warm to room temperature and was then refluxed for 30 minutes. The reaction mixture was cooled to room temperature and stirred for 3 h before it was quenched through the addition of H2O (100 mL) nad conc. HCl (100mL). The layers were separated, and the aqueous layer was extracted with EE (3 x 50 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM to DCM/EE = 90/10) the residue was recrystallized from Et2O to obtain the pure title combined as white solid (16.3g, 34.7 mol, 70%) using a mixture of pentane/ether.  was slowly warmed to room temperature and stirred for 4 hours. The reaction was quenched with water and diluted with DCM (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (pentane/Et2O = 60/1) the orange residue was recrystallized in heptane to obtain the pure title combined as orange needles (178 mg, 0.162 mmol, 30%) using a mixture of pentane/ether.