REACTIONS

Meyer-Schuster Rearrangement Reaction, Dihydroxylation And Nucleophilic Addition Reaction

Dihydroxylation And Nucleophilic Addition Reaction

Phoslactomycins (PLMs) A-F are six antibiotics isolated in 1989 by Seto et al. from the culture broth of a strain of Streptomyces nigrescens (SC-273), which were found to be active against resistant phytopathogenic fungi. In the same year, phospholine, a compound which turned out to be identical to PLM B, was isolated from the fermentation broth of Streptomyces hygroscopicus. This compound showed strong in vitro cytotoxicity against L1210, P388, and EL-4 tumor cell lines. A few years later, while using a new screening method for colony-stimulating factors (CSFs) inducers, researchers from the Sankyo group identified three active compounds, leustroducsins (LSNs) A-C, isolated from cultures of Streptomyces platensis SANK 600191. Finally, LSN H, a synthetic analogue prepared by saponification, was also found to possess thrombopoietic activity. PLMs and LSNs feature a common backbone comprising an a,ß-unsaturated d-lactone (C1-C5), a disubstituted olefin of E configuration (C6-C7), a tertiary alcohol at C8 substituted by an aminoethyl side-chain, a phosphorylated secondary alcohol at C9, a secondary hydroxyl group at C11, and a conjugated diene (C12-C15) consisting of two olefins of Z configuration (Fig. 1).

Figure 1. Phoslactomycins, leustroducsins, and fostriecin.

Naturally occurring PLMs and LSNs only differ by the nature of the substituent attached to the cyclohexyl ring at C18 (a hydrogen for PLM B or an acyloxy group for the other members), which does not seem to exert a marked effect on the biological activity. These compounds are also structurally related to the natural product fostriecin from which they differ by the presence of an ethyl group at C4, a 2-aminoethyl side-chain at C8 rather than a simple methyl group and a (Z,Z)-diene substituted by the cyclohexyl group at C15 instead of a labile (Z,Z,E)-triene subunit (Fig. 1).

Like fostriecin, PLMs and LSNs are potent selective inhibitors of protein phosphatase 2A (PP2A), an enzyme playing important roles in the regulation of cell growth and division, signaling pathways, inhibition of metastasis through activation of natural killer cells, and also in the transcription and regulation of HIV-1. It is therefore not surprising that PLMs and LSNs have elicited considerable interest from the synthetic community. To date, two total syntheses of both PLM B and LSN B and one total synthesis of PLM A have been reported. Formal syntheses of LSN B and PLM B have also been recently disclosed.

Herein, we report a full account of our studies on the development of convergent approaches toward members of the phoslactomycins/leustroducsins family that have resulted in the formal synthesis of phoslactomycin B.

The C1-C13 subunit A, common to all PLMs and LSNs, was selected as the target. With the aim of developing a convergent route, an appropriate disconnection appears to be at the C7-C8 bond. In the forward sense, the tertiary alcohol at C8 would be created by nucleophilic addition of an alkenyl Grignard reagent B, containing a cyclic mixed acetal as a temporarily masked form of the lactone (with the C4 and C5 stereocenters in place), to an a,?-dialkoxy ketone ...