Stereoselective synthesis of 2,3,7-trimethylcyclooctanone and related compounds and determination of their relative and absolute configurations by the M alpha NP acid method

摘要

The copper/chiral phosphoramidite (L-1)-catalyzed conjugate addition of dimethylzinc to cycloocta-2,7-dienone 4, followed by the methylation of the intermediate enolate, yielded a single isomer of 7,8-dimethylcyclooct-2-enone (+)-5. Compound (+)-5 was subjected to the second conjugate addition with ent-L-1 giving only one stereoisomer of 2,3,7-trimethylcyclooctanone (+)-6, which was converted to 2,3,7-trimethylcyclooctanol 7. To determine the relative and absolute configurations of these compounds, the H-1 NMR anisotropy method using (S)-(+)-2-methoxy-2-(1-naphthyl)-propionic acid {(S)-(+)-M alpha NP acid} 1 was applied. Racemic alcohol (+/-)-7 was esterified with (S)-(+)-M alpha NP acid 1 yielding diastereomeric esters, which were efficiently separated by HPLC on silica gel affording the first-eluted M alpha NP ester (-)-10a and the second-eluted one (-)-10b. The relative and absolute configurations of ester (-)-10a were determined to be (S;1R,2S,3R,7S) by analyzing the H-1 and C-13 NMR spectra of (-)-10a and (-)-10b, especially their HSQC-TOCSY and NOESY spectra, and by applying the M alpha NP anisotropy method. The alcohol 7 formed from (+)-6 was similarly esterified with (S)-(+)-M alpha NP acid 1 yielding an M alpha NP ester, which was identical with (-)-10a, and the relative and absolute configurations of 2,3,7-trimethylcyclooctanone (+)-6 were determined to be (2S,3R,7S).