Synthesis of Naturally Occurring Norlignan (±)-Nyasol

Abstract

The norlignans including nyasol 1, hinokiresinol 2, agatharesinol 3, sequirin C 4 and sugiresinol 5 have received widespread interest as pharmaceutically valuable compounds, mainly because of their various clinically important biological activities: e.g. antiplasmodial activity, antifungal activity, anticancer activity, antimalarial activity, anti-oomycete activity, and estrogen receptor binding activity. Nyasol is one of the naturally occurring norlignans, which constitute abundant classes of phenylpropanoids. Nyasol has been isolated from various species of plants (Asparagus africanus, Anemarrhena asphodeloides, Asparagus officinalis, and Asparagus cochinchinensis). Nyasol and hinokiresinol are geometrical isomers and the confusion concerning the nomenclature of the two compounds nyasol and hinokiresinol was settled by Oketch-Rabah et al., who agreed that the Z-isomer should be named nyasol and the Eisomer hinokiresinol. In particular, nyasol shows various biological activities. For example, nyasol stimulated the proliferation of estrogendependent T47D breast cancer cells, and their stimulatory effects were blocked by an estrogen antagonist. In addition, nyasol showed binding affinity for the bovine uterine estrogen receptor, but (+)-nyasol was found to bind approximately seven times more strongly than (−)-nyasol. It was reported that (−)-nyasol increases hexobarbital sleeping time in mice. Nyasol was also reported to possess antifungal activity and inhibit testosterone 5α-reductase. Furthermore, nyasol was found to exhibit antioxidant and antiatherogenic activities. These results have encouraged us to complete adaptable and scalable total synthesis of these classes of natural products for further pharmacological study. So far, hinokiresinol derivatives have been easily prepared from chalcones by using reduction and dehydration. However, few successful synthetic procedures for nyasol have been reported other than the recent report by the Hoveyda group, which limits a scalable synthesis of nyasol. Quan et al. also reported an approach to synthesis of di-O-methyl ethers of (+)-nyasol and related norlignans, however, they might fail deprotection of the methyl ethers to obtain the final nyasol since there