Chemoenzymatic synthesis of the morphine skeleton via radical cyclization and a C10C11 closure

Comparison of Approaches to ent-Morphine via Radical, Cationic, and Heck-Type Cyclizations

“…The most significant event in our successful Heck closure is the "return" of the correct oxidation state into the ring C of morphine. The neopine-type ole- fin can be easily manipulated, following the C10-C11 closure, into the required C7-C8 position in codeinone, for example, as recently demonstrated by Rice 13 .…”

“…The crude product was purified by flash chromatography (hexanes-EtOAc 9 : 1) to yield pure 14 (0. 13 3-(2-(5aS,6S,9aR)-6-[tert-Butyl(dimethyl)silyloxy)]-4-methoxy-5a,6,7,9a-tetrahydrobenzo [b][1]benzofuran-9a-yl}ethyl)oxazol-2(3H)-one (16) A flame-dried heavy-walled Pyrex tube under static argon atmosphere was charged with 14 (40 mg, 0.08 mmol), Pd(PPh 3 ) 4 (9 mg, 0.008 mmol), PPh 3 (8 mg, 0.03 mmol), triethylamine (0.02 ml, 0.15 mmol), and toluene (5.0 ml). The tube was capped with a self-sealing, rubber-lined cap and heated to 120°C.…”

“…Because of the lack of stereoselectivity inherent in this approach, we executed a stepwise sequence from 2 (X = Y = Br) via isoquinoline derivative 9, also obtained with low stereocontrol 7 . The closure of 9 to 8 followed by further elaboration led to the complete morphine skeleton (in the ent-series) 8 .…”

“…Finally, the carbons at positions 9 and 10 as well as the N-methyl group can be derived from oxazol-2(3H)-one (6), prepared by anodic oxidation 7,8 .…”

The role of biocatalysis in the asymmetric synthesis of alkaloids

“…5 ) from arene cis -dihydrodiols. 70a , 83 Hudlicky's research group has first established a route to the complete morphinan core structure from two building blocks obtained with the help of biocatalytic dioxygenation: 84 The oxidation of 143 by TDO afforded the diol 144 , as the regio- and stereochemistry of the bioconversion is directed by the larger bromoethyl substituent. The diol was subsequently converted into compound 145 .…”