Gurpreet S. Bhatia

Enantioselective synthesis of (3R)- and (3S)-piperazic acids. The comparative unimportance of DMPU mediated retro-hydrazination

Abstract In response to a recent literature report by Decicco and Leathers (Ref. 13), the work of Hale, Delisser, and Manaviazar (1992) on the asymmetric synthesis of (3R)- and (3S)-piperazic acids has been reinvestigated, and the originally claimed product yields fully substantiated. The claims made in reference 13 about the proportions of cyclised product 6 and starting bromide 20 isolated from the low temperature electrophilic hydrazination-nucleophilic cyclisation of 20 with di-t-butylazodicarboxylate (DBAD) and DMPU as an additive are inaccurate. The retro-hydrazination reaction that they claim is problematic when DMPU is added to the hydrazinated reaction mixture has been demonstrated not to have a seriously detrimental effect on cyclisation product yield and to be unimportant. The other main assertion of reference 13, that the electrophilic hydrazination and nucleophilic cyclisation of 20 gives 6 in 91% isolated yield when n-Bu4NI is employed as an additive (instead of DMPU) has also been shown to be in error. We have carefully repeated a scaled-down version of the n-Bu4NI catalysed procedure (Ref. 13) and have found that 6 is generally isolated in yields of 50–56% after flash chromatography. We have concluded that n-Bu4NI does not significantly increase the yields of cyclisation products 6 or 17 when it is employed as a cyclisation additive. Herein, we report details of our two preferred “crude” experimental procedures for preparing the enantiomers of piperazic acid in high optical purity, neither of which requires chromatographic purification of the reaction intermediates en route. Both these preferred “crude” methods for preparing 11 and 19 have been consistently reproduced many times in these laboratories over the past few years. In our view, they remain the most expedient and highest yielding methods currently available for obtaining 11 and 19 in high optical purity.

Synthetic studies on the azinothricin family of antibiotics. 2. Asymmetric synthesis of the C(28)–C(47) subunit of A83586C

Abstract An asymmetric synthesis of the C(28)–C(47) segment of the antitumour antibiotic A83586C is described.

Synthetic studies on the azinothricin family of antibiotics. 3. Enantioselective synthesis of a hexapeptide precursor for antitumour antibiotic A83586C

Abstract A “3+2+1” fragment condensation strategy to a precursor of the hexapeptide found in antibiotic A83586C is described.

Synthetic studies on the A83586C and bryostatin antitumor macrolides and the monamycin antibiotics

After a brief summary of our asymmetric total syntheses of A83586C and 4-epi-A83586C, we will go on to describe some of our synthetic work on the monamycins, and our most recent total synthesis studies on the bryostatin antitumor macrolides.

Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb.

The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of beta-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).