Cytoxazone [(4R,5R)-(-)-5-hydroxymethyl-4-(4-methoxyphen-employing the Sharpless asymmetric dihydroxylation as the key reaction in 26% overall yield (7 steps). yl)-2-oxazolidinone, 1], a new immunosuppressant, was synthesized by starting from p-methoxycinnamyl alcohol (2)
In 1998 Osada and co-workers isolated 140 mg of a novel cytokine modulator from 18 L of the culture broth of Streptomyces RK95Ϫ31 isolated from a soil sample in Hiroshima Prefecture. [1] That new immunosuppressant was named cytoxazone and its structure 1 was elucidated on the basis of its NMR, CD and X-ray analysis. [1] [2] Cytoxazone inhibits the cytokine production via the signaling pathway of Th2 cells, but not Th1 cells. We envisaged that 1 with a 2-oxazolidinone ring might readily be synthesized from pmethoxycinnamyl alcohol (2) by employing the Sharpless asymmetric dihydroxylation as the key reaction. Scheme 1 summarizes our synthesis of cytoxazone (1). The commercially available 2 was converted into the corresponding tert-butyldimethylsilyl (TBS) ether 3. This silyloxy olefin 3 was dihydroxylated by treatment with an osmium tetroxide based oxidant in the presence of 1,4-bis(9-O-dihydroquinidine)phthalazine [(DHQD) 2 PHAL] under the so-called AD-mix-α ® conditions to give (2S,3S)-4 (99.6% ee) in 99% yield. Conversion of such a 1,2-glycol as 4 to an azido alcohol 6 was reported to be feasible via a cyclic sulfate or a sulfite like 5. [5Ϫ7] In the present case, the cyclic sulfite 5 is thought to be reactive enough to give 6, because C-4 of 5 is the activated benzylic position to which the nucleophilic attack of the azide anion is expected. Accordingly, 4 was treated with thionyl chloride and triethylamine to afford 5, which was a mixture of two diastereomers 5a and 5b as revealed by its 1 H-NMR spectrum. Cleavage of the cyclic sulfite 5 was executed with lithium azide in hot Scheme 1. Synthesis of (Ϫ)-cytoxazone (1): reagents: (a) TBSCl, imidazole, DMF (97%); (b) AD mix-α ® [(DHQD) 2 PHAL, K 2 O s -N,N-dimethylformamide (DMF). [5] [6] The resulting azide 6 O 2 (OH) 4 , K 3 Fe(CN) 6 , K 2 CO 3 ], MeSO 2 NH 2 , tBuOH/H 2 O (99%); was fortunately a single stereoisomer as evidenced by its (c) SOCl 2 , Et 3 N, CH 2 Cl 2 (88%); (d) LiN 3 , DMF, 100°C, then H 2 O at 0°C (61%); (e) HCO 2 NH 4 , Pd/C, MeOH, 50°C (87%); (f) 1 H-NMR spectrum (see Experimental Section). This was CO(OEt) 2 , K 2 CO 3 (66%); (g) TBAF, THF (89%)
presumably caused by rapid S N 2-type ring cleavage at C-4 with the azide anion. The azide 6 was then hydrogenated with ammonium formate and palladium/charcoal to give 7.
Construction of the 2-oxazolidinone ring was achieved as usual [8] by treatment of 7 with diethyl carbonate in the presence of potassium carbonate to furnish 8. Removal of the TBS protective group of 8 with tetrabutylammonium fluoride (TBAF) yielded (4R,5R)-(Ϫ)-cytoxazone (1), whose