Lycoricidine radical synthesis

Total synthesis of (-l-)-lycoricidine, (—)-lycoricidine and (-l-)-narciclasine via 6-exo cyclization of substituted vinyl radicals with oxime ethers has been reported . Thus, interaction of oxime ether 321 with thiophenol and then with Sml2 and TFA afforded (-l-)-lycoricidine 322 in good overall yield (equation 139). 

Furthermore, this methodology was developed to afford the synthesis of e t-lycoricidine (248) using photolysis instead of a chemically mediated radical reaction (160). Photolysis of 4-(4/ )-hydroxy-6-[(2-methoxycar-bonyl-4,5-methylenedioxy)phenyl]-25,35-0-isopropylidenehex-5-ynal O-benzyloxime 245 (derived from D-glucose) in the presence of thiophenol under went intramolecular cyclization to produce l-(A-benzyloxy-amino)-5-phenylthiocyclohex-5-ene 246. Cleavage of the N-O bond and reductive elimination of the phenylthio group in 246 with Sml2 in THF... 

Keck has reported a short, enantioselective synthesis of lycoricidine as outlined in Scheme 10 [70]. The synthesis began with the acetonide of D-gulonolactone (104). This material was converted in 6 steps to oxime ether 105. Irradiation of 105 with thiophenol in toluene gave a 90% yield of 106, resulting from addition of a thio-phenoxy radical to the alkyne and cyclization of the resulting vinyl radical onto the oxime ether. It is notable that tri- -butylstannyl radicals failed to mediate this ad-dition-cyclization sequence. The synthesis of lycoricidine was completed from 106 in two steps. Keck also reported that the enantiomer of lycoricidine could be prepared in a similar manner starting from D-lyxose [71], and also described a modification of this route that provided (+)-narciclasine [70]. 

The synthesis of natural products has been accomplished by this strategy examples are shown in Eqs. (18), (19). The key step used by Keck and Wager in the total synthesis of en/-lycoricidine [43a] relies on the addition of phenylthiyl radical to the... 

Radical addition. In the context of a synthesis of ent-lycoricidine, the addition of PhSH to a dehydrocinnamyl alcohol leading to a cyclohexene unit is the key step. The use of BujSnH-EtjB is not viable, because of reverse regioselectivity, and there is no cyclization. 

The key step in the total synthesis of e/ir-lycoricidine, recently accomplished by Keck and Wager [55] consisted of the thiy] radical addition to a triple bond of a suitable precursor followed by cyclization onto a pendant oxime moiety, as shown in Scheme 7. Then the alkoxyaminyl radical abstracts hydrogen from PhSH, when R=C02Me, or attacks intramolecularly the carbonyl moiety, when R = CHO. Following the former strategy, the target compound was obtained after two other transformations and in an overall yield of 11.1 % starting from lyxo.se, in 14 steps. 

Keck GE, Wager TT. Total synthesis of enl-lycoricidine via a thiyl radical addition-cyclization sequence. J. Org. Chem. 1996 61(24) 8366-8367. 

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