合成路线1

The tosylate precursor (I) can be prepared by a number of different methods. Microbial dihydroxylation of chlorobenzene (XIII) gives (1S,2S)-3-chlorocyclohexa-3,5-diene-1,2-diol (XIV), which is further hydrogenated to (XV) in the presence of Rh/Al 2O3. Regioselective tosylation of (XV), followed by hydrogenation of the resulting monotosylate (XVI) over Pd/C, leads to (1S,2R)-2-hydroxycyclohexyl tosylate (XVII). Subsequent coupling of (XVII) with imidate (X) provides the target intermediate (I) (1). In a different method, ketalization of (S,S)-1,2-cyclohexanediol (XVIII) with 2,2-dimethoxypropane provides the acetonide (XIX), which is oxidized to 2(S)-hydroxycyclohexanone (XX) by treatment with bis(trifluoromethyl)-dioxirane (BTDO). Subsequent tosylation of (XX) furnishes 2(S)-tosyloxycyclohexanone (XXI). Alternatively, the chiral tosyl ketone (XXI) can be obtained by monotosylation of diol (XVIII) in the presence of Bu2SnO to afford the hydroxy tosylate (XXII), which is subjected to Jones oxidation, giving ketone (XXI). The diastereoselective reduction of ketone (XXI) then provides an alternative route to 2(R)-hydroxy tosylate (XVII). Alternatively, the chiral tosyl ketone (XXI) is condensed with the sodium alkoxide of 3,4-dimethoxyphenethyl alcohol (XI) to yield the 2(R)-ether (XXIIIa). Stereoselective reduction of ketone (XXIIIa) utilizing bulky reducing agents such as L-Selectride, LS-Selectride or alpine boranes gives the (S)-cyclohexanol (XXIV), which can be further converted to tosylate (I) under the usual conditions. Similarly, the phenethyl alcohol (XI) can be reacted with 2-chlorocyclohexanone (XXV) by means of NaH to yield the racemic ketone ether (XXIIIb), which is enantioselectively reduced to the (1S,2R)-phenethoxycyclohexanol (XXIV) under Noyori’s asymmetric hydrogenation conditions. A further route to the phenethoxy ketone (XXIIIa) consists of the enantioselective α-oxyamination of cyclohexanone (XXVI) with nitrosobenzene in the presence of L-proline to produce the chiral hydroxylamine derivative (XXVII), which is subsequently cleaved to 2(R)-hydroxycyclohexanone (XXVIII) by treatment with CuSO4, and then coupled with imidate (X) in the presence of boron trifluoride etherate. Optionally, 2(R)-hydroxycyclohexanone (XXVIII) can be obtained by oxidation of the (1R,2R)-cyclohexanediol acetonide (XXIX) with BTDO. Another method for obtaining the (1S,2R)-phenethoxy cyclohexanol (XXIV) is based on the asymmetric reduction of (3,4-dimethoxyphenyl)acetaldehyde cyclohexanediol acetal (XXX) by means of triethylsilane in the presence of chiral Lewis acids (2). Scheme 2.