Diastereo‐ and Enantioselective Access to Stereotriads through a Flexible Coupling of Substituted Aldehydes and Alkenes

Abstract A flexible redox‐neutral coupling of aldehydes and alkenes enables rapid access to stereotriads starting from a single stereocenter with perfect levels of enantio‐ and diastereoselectivity under mild conditions. The versatility of the method is highlighted by the installation of heteroatoms along the tether, which enables a route to structurally diverse building blocks. The formal synthesis of (+)‐neopeltolide further demonstrates the synthetic utility of this approach.


General Information
Unless otherwise stated, all glassware was flame-dried before use and all reactions were performed under an atmosphere of argon. All solvents were distilled from appropriate drying agents prior to use. All reagents were used as received from commercial suppliers unless otherwise stated. All aldehydes were distilled or purified via flash column chromatography before use. Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminium plates coated with silica gel F254 with 0.2 mm thickness. Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining using potassium permanganate. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck and co.). Neat infra-red spectra were recorded using a Perkin-Elmer Spectrum 100 FT-IR spectrometer.
Splitting patterns that could not be interpreted or easily visualized were designated as multiplet (m) or broad (br). 3

Synthesis of unsaturated alcohol substrates (Method A)
To a flame-dried Schlenk flask containing a suspension of Mg powder (15 mmol, 1.5 equiv.) in dry Et2O (10.0 mL) were added 5 drops 1, 2-dibromoethane and 5 drops of alkyl bromide at ambient temperature and the mixture was stirred for 5 minutes. Then alkyl bromide (12.0 mmol) was slowly added and the reaction was kept stirring at room temperature for 30 minutes.
The Grignard reagent was added to a suspension of (S)-(-)-Propylene Oxide (10 mmol) and CuCN (10 mol%) in THF (20 mL) at -78° C. The reaction mixture was allowed to warm to room temperature over 3 h. Then sat. NH4Cl solution was slowly added, extracted with ether and the combined organic phases were dried with anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (heptane/ethyl acetate 4:1).
(S)-6-methylhept-6-en-2-ol (1f) 1f was prepared according to the general procedure and obtained as colorless oil in 78% yield.    S-1 was prepared in 55% yield according to a known procedure. [1] General procedure for the synthesis of trisubstituted alkene-substrates The required vinyl bromides are commercially available or were synthesized based on a previously reported procedure. [2] Vinyl bromide (15 mmol, 1.5 equiv.) and dry THF (20.0 mL) were added to a flame dried Schlenk flask. The flask was placed in a -78 °C dry ice-acetone bath, n-BuLi was slowly added and the reaction was kept at the same temperature for 30 minutes. Then CuCN (10 mol%) was added in one portion, the reaction was allowed to warm to r.t. and stirred at this temperature for 1h. S-1 was added in one portion at -78 °C, the reaction was stirred at the same temperature for 2 h and quenched with sat. NH4Cl solution. The biphasic mixture was extracted with ether, the combined organic phased were dried with anhydrous MgSO4, filtered and the solvent was removed under reduced pressure to afford the crude products. Purification by silica gel chromatography (Heptane/Ethyl acetate = 3/1) gave the desired products.
Allylic alcohol (30 mmol) was added dropwise. After completion of addition of allyl alcohol, the reaction mixture was further stirred for 30 minutes and HMPA (5 equiv.) was added. Then (S)-(-)-Propylene Oxide (35 mmol) was added in one portion at r.t. and the reaction mixture was stirred at 50 °C for 12 h. Upon completion of the reaction, sat.
NH4Cl solution was added and extracted with pentane. The combined organic phases were dried with anhydrous MgSO4, filtered and the solvent was removed under reduced pressure to afford the crude product. Purification by silica gel chromatography (Pentane/DCM = 1/1) afforded the clean product as colorless oil in 50% yield.  The aldehyde was prepared based on a previously reported procedure in 75% yield as colorless sticky oil. [  Water (0.2 mL) was added and the reaction was allowed to cool to room temperature with stirring. The reaction mixture was filtered over silica, eluted with dichloromethane and the solvent was removed under reduced pressure to obtain crude sticky product.
Purification by flash column chromatography afforded the pure products.
GP 2: Alcohol (0.2 mmol) was diluted with 2 mL dichloromethane. Aldehyde (0.24 mmol, 1.2 eq.) and FeCl3 (0.04 mmol, 20 mol%) were successively added and the reaction was stirred at r.t. until Alcohol was consumed. Water (0.2 mL) was added and the reaction was allowed to cool to room temperature with stirring. The reaction mixture was filtered over silica, eluted with dichloromethane and the solvent was removed under reduced pressure to obtain crude sticky product. Purification by flash column chromatography afforded the pure products.
for 2 h. Water (0.2 mL) was added and the reaction was allowed to cool to room temperature with stirring. The reaction mixture was filtered over silica, eluted with dichloromethane and the solvent was removed under reduced pressure. Purification by flash column chromatography afforded the pure products.
Caution! To make stereotriads, the reactions are sensitive to the purity of the aldehydes.
In order to obtain the reported results, the aldehyde must always be distilled or purified by column chromatography before use. If an impurity is present in the starting materials, the reaction does not reach full conversion. In this case, another dose of catalyst can be added without dramatically influencing the yield and ee-values.
Previously obtained silyl enol ether and Pd(OAc)2 (0.03 mmol, 10 mol%) were dissolved in 3 mL DMSO, frozen in a bath of liquid nitrogen, evacuated and backfilled with pure oxygen using a balloon. The Schlenk tube was directly taken out of the nitrogen bath, warmed to room temperature and heated at 80° C for 13 h. Upon completion, the reaction mixture was diluted with water and extracted with dichloromethane three times. The combined organic phases were dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was purified using flash column chromatography (20:1-9:1 heptane/EtOAc) to give (6R,8R,E)-8-hydroxy-6-methyl-10-phenyldec-3-en-2-one in 57% yield over 2 steps.   Synthesis of (4R,6R)-4-methyl-8-phenyloctane-1,6-diol (4e) Procedure: Compound 4e was prepared with slight modifications according to a reported procedure. [4] An approximately 1M solution of trifluoroperacetic acid was prepared according to the following procedure: to a 25-mL, round-bottomed flask was added urea hydrogen peroxide (5 mmol) and anhydrous 1, 2-dichloroethane (5.0 mL). The suspension was cooled to 0 °C in an ice/water bath and trifluoroacetic anhydride (5.5 mmol) added dropwise by syringe. The solution was stirred at 0°C for 1 h, then the ice bath removed and stirred at room temperature for 1 h, by which time the white suspension had changed into a biphasic mixture. Stirring was stopped to allow the layers to separate. To achieve more reproducible results, the biphasic mixture was placed in a -20°C freezer for 1 h to freeze trifluoroacetic acid before addition.
This solution was vigorously stirred as a solution of potassium hydroxide (2 mmol, 10 eq.) in H2O (2.0 mL) and a solution of iodine (0.6 mmol, 3 eq.) and potassium iodide (2.4 mmol, 12 eq.) in H2O (2.0 mL) were added via syringe at similar rates over 10 min. This mixture was stirred for 2 h and the reaction was quenched with 1M aqueous Na2SO3 (2 mL). The pH of the mixture was adjusted to 14 with 1M aqueous potassium hydroxide, diluted with water (5 mL) and washed with dichloromethane. The pH of the aqueous layer was adjusted to 3 with 1M aqueous NaHSO4 and extracted with ether (2x20 mL).
The combined organic layers were dried over MgSO4, filtered and concentrated.
Previously obtained silyl enol ether and Pd(OAc)2 (0.015 mmol, 10 mol%) were dissolved in 1.5 mL DMSO, frozen in a bath of liquid nitrogen, evacuated and backfilled with pure oxygen using a balloon. The Schlenk tube was directly taken out of the nitrogen bath, warmed to room temperature and heated at 80° C for 13 h. Upon completion, the reaction mixture was diluted with water and extracted with dichloromethane three times. The combined organic phases were dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was purified using flash column chromatography (20:1-9:1 heptane/EtOAc) to give a colorless oil (35% yield over 2 steps). 1 H NMR (400 MHz, CDCl3) δ 7.37 -7.24 (m, 5H),

35
Synthesis of (3S,5S,7S)-7-(benzyloxy)-5-methoxy-3-methyldecanal (11) Procedure: Unsaturated ketone (0.023 mmol) was dissolved in 1 mL dichloromethane and cooled to -78° C. Ozone was bubbled through the solution until a blue color was observed (ca. 5 minutes). The ozone generator was turned off and oxygen was bubbled through until the solution became colorless. The reaction was quenched with dimethyl sulfide (0.05 mL), slowly warmed up and stirred at room temperature for 5 h. The solvent and excess DMS were removed using a high vacuum pump with a liquid nitrogen cooling trap. The remaining yellow oil was dissolved in 3 mL diethyl ether, 3 mL saturated aqueous Na2CO3 was added and the biphasic mixture was vigurously stirred at room temperature for 3 h. The mixture was extracted with ether, dried over Na2SO4 and the solvent removed under reduced pressure. Purification by flash column chromatography (20:1 -9:1 heptane/EtOAc) afforded the product as colorless oil (85% yield). Dissolving the sample in pentane, then slowly evaporating the solvent to obtain the crystal is suitable for X-Ray analysis. The X-ray intensity data were measured on Bruker D8 Venture and on a Bruker X8 Apex2 diffractometer equipped each with multilayer monochromator, Mo K/a INCOATEC micro focus sealed tube and Oxford Cryostream respectively Kryoflex cooling systems. The structures were solved by direct methods and refined by full-matrix least-squares techniques. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were inserted at calculated positions and refined with riding model and as rotating groups. The following software was used: Bruker SAINT software package i using a narrow-frame algorithm for frame integration, SADABS ii for absorption correction, OLEX2 iii for structure solution, refinement, molecular diagrams and graphical user-interface, Shelxle iv for refinement and graphical user-interface SHELXS-2013 v for structure solution, SHELXL-2013 vi for refinement, Platon vii for symmetry check. Experimental data and CCDC-Codes can be found in Table S-3. Crystal data, data collection parameters, and structure refinement details are given in Tables S-4    4.60 6.04 6.04 6.04 6.08 6.08 6.08 6.71 6.73 6.75 6.75 6.77 6.79