Chemoenzymatic Total Synthesis of (+)‐Galanthamine and (+)‐Narwedine from Phenethyl Acetate

Abstract

The stereoselective total synthesis of unnatural (+)-galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadi-enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)-galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)-galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds.

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

“…As previously described in our earlier publications on the preparation of ent -oxycodone [30,31], the synthesis began with the microbial dihydroxylation of phenethyl acetate 8 (Scheme 2) via a whole cell fermentation with E. coli JM109 (pDTG601A) to afford the known intermediate cyclohexadiene diol 7 (obtained in 5gL −1 yield) [52,53], which was subjected to a selective reduction of the more accessible alkene to afford the known diol 9 (85% yield) [54,55]. The distal, less hindered, hydroxyl in diol 9 was protected with tert -butyl dimethylsilyl chloride and the free allylic alcohol was then subjected to a Mitsunobu reaction with iodo phenol 10 [56], derived from isovanillin, to furnish the coupled product ether 6 (45% yield over two steps).…”

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

“… 81 Moreover, a structurally similar tricyclic intermediate, 151, served as precursor to the non-natural antipodes of the snowdrop alkaloids narwedine (153) and galantamine (154; Scheme 18b ). 82 The authors investigated two alternative Mitsunobu–Heck sequences, which both afforded 151 in good yield (61% over three steps, 68% over two steps) from diol 143. Elimination of the hydroxyl group, followed by iodoacetoxylation (Prévost reaction), reductive deiodination, and closure of the seven-membered D ring gave a 2 : 1 mixture of galantamine epimers (152), which was oxidised to (+)-narwedine (153) using pyridinium chlorochromate.…”

Recent Progress in Amaryllidaceae Biotechnology

“…As of the time of writing this review, there is no report on engineered plant or microbial system expressing target Amaryllidaceae alkaloids. It was suggested that a combination of enzyme catalyzed steps and chemical synthesis, or a combination of chemical synthesis of norcraugsodine as precursors and its conversion into nornarwedine by engineered microbial system expressing NR, N4OMT, and CYP96T1 could be effective for low cost production of galanthamine [ 75 , 76 , 77 , 78 , 79 ]. However, these processes must be implemented.…”