1,2-Metallate Rearrangement as a Toolbox for the Synthesis of Allylic Alcohols

The development of new methods and protocols for the synthesis of biologically active substances remains one of the most important pillars in organic chemistry, and one of these privileged structural motifs are allylic alcohols. The method of choice to date for the synthesis of these is the Nozaki–Hiyama–Takai–Kishi reaction. We describe here a valuable alternative to the synthesis of allylic alcohols via 1,2-metallate rearrangement. In this work, various vinyl boronic esters with different functional groups have been applied in the Hoppe–Matteson–Aggarwal reaction. In addition, two monoterpenoids were constructed via this convergent synthetic strategy.


2-2. Synthesis of carbamates General Procedure 3 (GP3): CbCl
The required primary alcohol (1.0 equiv) was dissolved in C2H4Cl2 (0.3 M) and Et3N (1.5 equiv) and N,N-diisopropylcarbamoyl chloride (1.5 equiv) were added successively. After heating to 70 °C overnight H2O was added. The phases were separated, and the aqueous phase was extracted with CH2Cl2 (3x), the organic layers were combined and dried over Na2SO4. The solvent was removed in vacuo and the crude material was purified by flash column chromatography to afford the corresponding carbamate.

General Procedure 4 (GP4): TIB esters
To a stirred solution of TIB ester (1.5 equiv) and diamine (1.5 equiv) in Et2O (0.2 M) at -78 °C was added sBuLi (1.3 M in hexanes, 1.4 equiv). The reaction mixture was stirred for 5 h at that temperature before a solution of vinyl boronic ester (1.0 equiv) in Et2O (0.5 M) was added. After stirring for further 3 h at -78 °C, the reaction mixture was warmed to 45 °C and stirred overnight. The reaction mixture was cooled to rt, sat. aq. NH4Cl was added, and the biphasic mixture was stirred for 15 min. The phases were separated, the organic layer was washed with sat. aq. NH4Cl (3x) and the combined aqueous phases were extracted with MTBE (3x). The combined organic phases were dried over Na2SO4, concentrated in vacuo and the crude material was purified by a short flash column chromatography (to remove TIBOH).

S7
The residue was dissolved in THF (0.2 M) and cooled to -20 °C. A premixed, ice-cooled solution of NaOH (2.0 M)/H2O2 (35%, 2/1 v/v, 0.12 M) was added dropwise. The reaction mixture was stirred for at rt before being quenched by the slow addition of sat. aq. Na2S2O3 at 0 °C after TLC showed full conversion. The solution was diluted with MTBE, the phases were separated, and the aqueous phase was extracted with MTBE (3x). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography to afford allylic alcohol.

General Procedure 5 (GP5): Carbamates
To a stirred solution of carbamate (1.5 equiv) and diamine (1.5 equiv) in Et2O (0.2 M) at -78 °C was added sBuLi (1.3 M in hexanes, 1.4 equiv). The reaction mixture was stirred for 5 h at that temperature before a solution of vinyl boronic ester (1.0 equiv) in Et2O (0.5 M) was added. The reaction mixture was stirred for 3 h at -78 °C. In parallel, magnesium turnings were activated (2x 1 M HCl, 2x H2O, 2x acetone, drying under high vacuum). The required amount (2.0 equiv) was dissolved in Et2O (0.8 M) and 1,2dibromoethane (2.0 equiv) was added under water bath cooling. The reaction mixture was stirred for 2 h at this temperature. The biphasic MgBr2•OEt2 solution was added dropwise to the main reaction mixture, which was then stirred for another 30 min at -78 °C before being warmed to 45 °C and stirred overnight. The reaction mixture was cooled to rt, sat. aq. NH4Cl was added, and the biphasic mixture was stirred for 15 min. The phases were separated, the organic layer was washed with sat. aq. NH4Cl (3x) and the combined aqueous phases were extracted with MTBE (3x). The combined organic phases were dried over Na2SO4 and concentrated in vacuo and the crude material was purified by a short flash column chromatography (to remove excess of the carbamate). The residue was dissolved in THF (0.2 M) and cooled to -20 °C. A premixed, ice-cooled solution of NaOH (2.0 M)/H2O2 (35%, 2/1 v/v, 0.12 M) was added dropwise. The reaction mixture was stirred at rt before being quenched by the slow addition of sat. aq. Na2S2O3 at 0 °C after TLC showed full conversion. The solution was diluted with MTBE, the phases were separated, and the aqueous phase was extracted with MTBE (3x). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography to afford allylic alcohol. The stereochemistry is assigned by the usual induction of (+)-sparteine and (-)-sparteine [4,5] due to no exerted substrate induction [6,7] of the used carbamates.

General Procedure 6 (GP6): TIB esters and TBS-protection
To a stirred solution of TIB ester (1.5 equiv) and diamine (1.5 equiv) in Et2O (0.2 M) at -78 °C was added sBuLi (1.3 M in hexanes, 1.4 equiv). The reaction mixture was stirred for 5 h at that temperature before a solution of vinyl boronic ester (1.0 equiv) in Et2O (0.5 M) was added. After stirring for further 3 h at -78 °C, the reaction mixture was warmed to 45 °C and stirred overnight. The reaction mixture was cooled to rt, sat. aq. NH4Cl was added, and the biphasic mixture was stirred for 15 min. The phases were separated, the organic layer was washed with sat. aq. NH4Cl (3x) and the combined aqueous phases were extracted with MTBE (3x). The combined organic phases were dried over Na2SO4, concentrated in vacuo and the crude material was purified by a short flash column chromatography (to remove TIBOH). The residue was dissolved in THF (0.2 M) and cooled to -20 °C. A premixed, ice-cooled solution of NaOH (2.0 M)/H2O2 (35%, 2/1 v/v, 0.12 M) was added dropwise. The reaction mixture was stirred for at rt before being quenched by the slow addition of sat. aq. Na2S2O3 at 0 °C after TLC showed full conversion. The solution was diluted with MTBE, the phases were separated, and the aqueous phase was extracted with MTBE (3x). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography to afford allylic alcohol. To a solution of the obtained allylic alcohol in CH2Cl2 (1.0 M) at -78 °C were added 2,6lutidine (4.0 equiv) and TBSOTf (2.0 equiv) successively. The reaction mixture was stirred for 20 min at -78 °C and at 0 °C until TLC showed full consumption. After the addition of sat. aq. NaHCO3 the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3x). The combined organic layers were washed with aq. KHSO4 (1.0 M) and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography to afford the TBS-protected allylic alcohol. The stereochemistry is assigned by the usual induction of (+)-sparteine and (-)-sparteine [4,5] due to no exerted substrate induction [6,7] of the used TIB esters.

2-4. Synthesis of (-)-sachalinol A Alcohol S1
To a stirred solution of ketone 61 (1.02 g, 3.06 mmol, 1.0 equiv) in THF (10.0 mL) at 0 °C was added MeMgBr (3.0 M in Et2O, 1.5 mL, 4.59 mmol, 1.5 equiv). The reaction mixture was was warmed to rt and stirred for 4 h at that temperature. The reaction mixture was cooled to 0 °C, sat. aq. NH4Cl was added, and the phases were separated. The aqueous layer was extracted with MTBE (3x). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (PE:MTBE 3:1) to afford alcohol S1 (0.91 g, 2.61 mmol, 85%) as a colorless oil.