Phenylacetic Acid → Phorbol
反応式
[C:1]([O-:4])(=O)[CH3:2].C([O-])(=[O:7])C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C1(CC(O)=O)C=CC=CC=1.N1CC=CN1.N=N.[CH3:35][C@H:36]1[C@:42]2([OH:56])[CH:43]3[C@:48]([OH:54])([CH2:49]C(CO)=[CH:51][C@H:41]2[C@H:40]([C:57]([CH3:59])=[CH2:58])[C:38](=[O:39])[CH2:37]1)[C:46](=[O:47])[C:45]([CH3:55])=[CH:44]3>>[CH3:35][C@H:36]1[C@:42]2([OH:56])[C@H:43]3[C@:48]([OH:54])([CH2:49][C:2]([CH2:1][OH:4])=[CH:51][C@H:41]2[C@@H:40]2[C:57]([CH3:58])([CH3:59])[C@:38]2([OH:39])[C@@H:37]1[OH:7])[C:46](=[O:47])[C:45]([CH3:55])=[CH:44]3参加物
6
実験手順
Another embodiment is shown in FIG. 8. In this embodiment, the acidic hydrolysis of phorbol produces crotophorbolone, which is then used as the starting material. First, treatment of crotophorbolone with hydrazine in the presence of acetic acid selectively affords the C13 hydrazone (not shown), which without isolation is cyclized to pyrazoline S5a. Oxidation of pyrazalone S5a with lead (IV) tetraacetate gives cyclic diazene S7a, allowing for concomitant direct introduction of a C13 acetate group and a diazene bridge between C13 and C15. Other C13 esters can also be directly introduced with this procedure by using the corresponding lead (IV) carboxylate or related oxidants. Photolysis of cyclic diazene S7a results in the extrusion of nitrogen and reestablishment of the C13-15 cyclopropane bond, providing prostratin in high yield and in a remarkably concise four—step sequence from crotophorbolone, or five steps from phorbol with a 12-16% overall yield, producing over 100 mg of prostratin from a single run. DPP can be made in a similar manner. In this case, the acetate ligands of lead tetraacetate are exchanged by premixing with an excess of phenylacetic acid. The resulting salt induces the oxidative conversion of pyrazoline S5a to diazene S7b. (in 36% yield for three steps from crotophorbolone). Subsequent photolysis affords the natural product and therapeutic lead DPP in 90% yield, or 13% overall yield from phorbol. Details of this embodiment are described below in EXAMPLES 7 and 11.