Studies Towards the Synthesis of Thienamycin

Almost all successful syntheses of bicyclic beta-lactams involve the early synthesis of the monocyclic azetidin-2-one ring. Of the numerous methods developed to achieve this, the [2+2] cycloaddition of chlorosulphonyl isocyanate (CSI) to functionalised alkenes has proven to be particularly useful. In general, addition is performed on alkenyl acetates providing C-4 acetoxyazetidinones, which have found widespread use since the 4-acetoxy substituent can be replaced with various nucleophiles in an elimination/addition sequence. However, there are few functionalised alkenes which directly introduce the C-4 carbon substitution required for carbapenem synthesis upon cycloaddition with CSI. Earlier investigations within this group have shown that allylsilanes undergo regioselective cycloaddition with CSI to yield C-4 silylmethyl substituted beta-lactams.133,137 The regiochemistry of cycloaddition is controlled by the beta-effect of silicon, i.e., silicon's ability to stabilise the development of partial positive charge P to itself. Use of phenyldimethylsilyl substitution allows access, albeit in low yield, to the corresponding hydroxymethyl azetidinones, via oxidative cleavage of the C-Si bond. We were intrigued by reports from Fleming142 and Taddei141 that allylsilanes bearing a chiral centre directly adjacent to the double bond undergo reaction with various electrophiles, including CSI, with remarkably high stereoselectivity. The initial aim of this project was to prepare an ?-oxa-allylsilane, with such a chiral centre, which would undergo regio- and stereoselective cycloaddition with CSI to yield a C-3 hydroxyethyl substituted ?-lactam. Subsequent oxidative cleavage of the silylmethyl group would led to a useful precursor for the powerful carbapenem antibiotic Thienamycin. Unfortunately, all attempts to carry out cycloaddition with these substrates resulted in a rapid 1,4 silyl elimination to penta-l,3-diene. In an attempt to overcome this problem, an alternative allylsilane was designed and prepared. Disappointingly, however, this compound did not react with CSI. The second aim of this project was to improve the efficiency of the key oxidative cleavage step. Our interest was awakened by a report from Ito191 which briefly mentioned the use of iodine monochloride (ICl) for the iododesilylation of phenyldimethylsilyl moieties prior to oxidative cleavage. In order to study the applicability of this method to C-4 silylmethyl beta-lactams simple N-protected precursors were prepared. Gratifyingly, treatment with ICl resulted in cleavage of the Si-Ph bond and formation of the chlorodimethylsilyl beta-lactams which were hydrolysed to the corresponding silanols in high yield. Oxidation of these compounds using a modification of Tamao's191 procedure gave the potentially useful C-4 hydroxymethyl beta-lactams in good to moderate yield. Alternatively, one of the intermediate chlorosilanes could be directly oxidised using AcOOH/KF

Synthesis and biological activity of naturally occurring a-glucosidase inhibitors

In addition to their clinical importance in the treatment of type II diabetes, a-glucosidase inhibitors have attracted considerable attention from the synthetic community because of their profound effect on an array of cellular processes, including N-linked glycoprotein processing and maturation, oligosaccharide metabolism, and cell–cell and cell–virus recognition. Over the past decade, a number of structurally novel naturally occurring a-glucosidase inhibitors which do not conform to the classical iminosugar mold have been identified, including zwitterionic thiosugars and marine organosulfates. While these natural products are important leads in the development of new classes of glucosidase inhibitors, they have also attracted considerable attention as synthetic targets in of themselves. This article reviews the recent literature concerning the synthesis of these emerging natural product families, as well as the preparation of those polyhydroxylated alkaloids more traditionally associated with anti-a-glucosidase activity. 176 references are cited

Dehydrative Fragmentation of 5-Hydroxyalkyl-1<i>H</i>-tetrazoles: A Mild Route to Alkylidenecarbenes

The development of a mild, base-free method for the generation of alkylidenecarbenes is reported. Treatment of 5-hydroxyalkyl-1<i>H</i>-tetrazoles with carbodiimides generates products arising from the 1,2-rearrangement or [1,5]-C–H bond insertion of a putative alkylidenecarbene. Formation of this divalent intermediate is proposed to occur by way of a tetraazafulvene, which undergoes extrusion of 2 mol of dinitrogen. Details of this methodology, its application to the synthesis of combretastatin A-4, and an improved route to 5-hydroxyalkyl-1<i>H</i>-tetrazoles are described

Inhibition of influenza H7 hemagglutinin-mediated entry.

The recent outbreak of H7N9 influenza in China is of high concern to public health. H7 hemagglutinin (HA) plays a critical role in influenza entry and thus HA presents an attractive target for antivirals. Previous studies have suggested that the small molecule tert-butyl hydroquinone (TBHQ) inhibits the entry of influenza H3 HA by binding to the stem loop of HA and stabilizing the neutral pH conformation of HA, thereby disrupting the membrane fusion step. Based on amino acid sequence, structure and immunogenicity, H7 is a related Group 2 HA. In this work we show, using a pseudovirus entry assay, that TBHQ inhibits H7 HA-mediated entry, as well as H3 HA-mediated entry, with an IC50 ~ 6 µM. Using NMR, we show that TBHQ binds to the H7 stem loop region. STD NMR experiments indicate that the aromatic ring of TBHQ makes extensive contact with the H7 HA surface. Limited proteolysis experiments indicate that TBHQ inhibits influenza entry by stabilizing the H7 HA neutral pH conformation. Together, this work suggests that the stem loop region of H7 HA is an attractive target for therapeutic intervention and that TBHQ, which is a widely used food preservative, is a promising lead compound

Oxamidation of Unsaturated <i>O</i>‑Alkyl Hydroxamates: Synthesis of the Madangamine Diazatricylic (ABC Rings) Skeleton

A novel approach to the diazatricyclic madangamine ABC ring system and the synthesis of an advanced, differentially protected intermediate for the synthesis of madangamine D is reported. Central to the success of this approach is the iodine­(III)-mediated intramolecular oxamidation of an unsaturated <i>O-</i>methyl hydroxamate, a π–N^<b>+</b>-type cyclization which proceeds in high yield and with complete regioselectivity to generate the 2-azabicyclo[3.3.1]­nonane (morphan) system encompassing rings A and C