Stereoselective synthesis of (−)-cytoxazone

Synthesis of (−)‐Cytoxazone and (+)‐epi‐Cytoxazone: The Chiral Pool Approach

“…Physical Methyl (R)-N-benzoyl-4-methoxyphenylglycinate (6). To a solution of (R)-N-benzoyl-4-hydroxyphenylglycine 5 (12.00 g; 44 mmol) in acetone (420 mL) was added anhydrous K 2 CO 3 (18.30 g; 133 mmol) and dimethyl sulphate (13.95 g; 10.52 mL; 111 mmol).…”

Short-Step and Scalable Synthesis of (±)-Cytoxazone

“…The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residual brown viscous oil (1.294 g) was charged into a silica gel column (15 g (2R Ã ,3R Ã )-3-tert-Butoxycarbonylamino-3-(4-methoxyphenyl)propane-1,2-diol (6). Crude aminoalcohol HCl salt 5 (141.3 mg, 0.46 mmol was expected) was mixed with THF (2 ml) and Et 3 N (0.127 ml, 0.91 mmol) in the presence of 3A molecular sieves (714 mg), and the solid material of the amine salt was finely dispersed ultrasonically under Ar.…”

“…Chemical syntheses of the natural enantiomer 3,4) as well as the stereoisomers [5][6][7][8][9][10][11][12][13] have so far been reported. The fact that there was no difference between the stereoisomers in their bioactivity 10) prompted us to develop a short-step, scalable route to its racemic form for more advanced biological studies.…”

“…After acidification with aqueous HCl, precipitated Ph 3 PO could be simply removed by filtration, and we could avoid the previously reported extractive workup 16) with an organic solvent. Treatment of amino alcohol 5 with Boc 2 O under anhydrous reaction conditions provided N-Boc aminodiol (AE)-6, 6) a known precursor of cytoxazone, in a quantitative yield. An attempt at direct in situ transformation to desired 1 in the presence of either DBU or DMAP, 17) however, was unsuccessful.…”

Transformation of (+)-thiomicamine into the p-methylthio analogue of (+)-5-epi-cytoxazone

“…9 The C-C bond forming methodology, which relies on the chiral pool approach, uses commercially available amino acids 10,11 and carbohydrates 12,13 as substrates. Homologation can then be achieved by the addition of Grignard reagents 10,12,13 or cyanohydrin formation 11 via the corresponding aldehydes. The aldol-type reaction was also successfully applied in C-C bond forming methodology.…”