Mattie S. M. Timmer

Protecting-Group-Free Synthesis of Amines: Synthesis of Primary Amines from Aldehydes via Reductive Amination

New methodology for the protecting-group-free synthesis of primary amines is presented. By optimizing the metal hydride/ammonia mediated reductive amination of aldehydes and hemiacetals, primary amines were selectively prepared with no or minimal formation of the usual secondary and tertiary amine byproduct. The methodology was performed on a range of functionalized aldehyde substrates, including in situ formed aldehydes from a Vasella reaction. These reductive amination conditions provide a valuable synthetic tool for the selective production of primary amines in fewer steps, in good yields, and without the use of protecting groups.

Total Synthesis Without Protecting Groups: Pyrrolidines and Cyclic Carbamates†

A protecting group free synthesis of 2,3-cis substituted hydroxypyrrolidines is reported. Two novel reaction methodologies allow for the stereoselective formation of cyclic carbamates from olefinic amines, and the formation of primary amines via a Vasella/reductive amination reaction, both performed in aqueous media.

Synthesis of phosphorus mono- and bicycles by catalytic ring-closing metathesis

A versatile route of synthesis of phosphorus oxide and phosphorus borane templates starting from the bifunctional phosphorylating agent bis(diisopropylamino)ethynylphosphine is presented. Ring-closing enyne metathesis using 4,5-dihydro-imidazol-2-ylidene ruthenium benzylidene complex 3 on these types of substrates led to the formation of mono- and bicyclic phosphorus heterocycles.

Long-Chain Lipids Are Required for the Innate Immune Recognition of Trehalose Diesters by Macrophages

Going to any length? Trehalose diesters of various chain lengths have been synthesised in order to determine the effect of lipid length on innate immune recognition, as determined by NO and cytokine production by macrophages. In this work, we show that longer lipids (C(20) -C(26)) are required for macrophage activation, with C(22) giving optimal activity.

The anti-cancer, anti-inflammatory and tuberculostatic activities of a series of 6,7-substituted-5,8-quinolinequinones

A variety of 6,7-substituted-5,8-quinolinequinones were synthesised and assessed for their anti-tumour and anti-inflammatory activities, and their ability to inhibit the growth of Mycobacterium bovis BCG. In particular, the introduction of a sulfur group at the 7-position of the quinolinequinone led to the discovery of two compounds, 6-methylamino-7-methylsulfanyl-5,8-quinolinequinone (10a) and 6-amino-7-methylsulfonyl-5,8-quinolinequinone (12), that exhibited selectivity for leukemic cells over T-cells, a highly desirable property for an anti-cancer drug. A number of anti-inflammatory (AI) compounds were also identified, with 6,7-bis-methylsulfanyl-5,8-quinolinequinone (18a) exhibiting the highest AI activity (0.11 microM), while 6,7-dichloro-5,8-quinolinequinone (7a), 6,7-dichloro-2-methyl-5,8-quinolinequinone (7b), and 6,7-bis-phenylsulfanyl-quinoline-5,8-diol (19) also exhibited good AI activity and specificity. Several quinolinequinone TB-drug candidates were identified. Of these, 6-amino-7-chloro-5,8-quinolinequinone (11) and 6-amino-7-methanesulfinyl-5,8-quinolinequinone (14), exhibited low MICs (1.56-3.13 microg/mL) for the 100% growth inhibition of M. Bovis BCG. Some general trends pertaining to the functional group substitution of the quinolinequinone core and biological activity were also identified.

Trehalose glycolipids—synthesis and biological activities

A variety of trehalose glycolipids have been isolated from natural sources, and several of these glycolipids exhibit important biological properties. These molecules also represent challenging synthetic targets due to their highly amphiphilic character, their large number of functional groups and additional chiral centres. This review highlights some of the recent advances made in the synthesis of trehalose glycolipids, and their associated biological activities.

On one leg: trehalose monoesters activate macrophages in a Mincle-dependant manner.

The C22 and C26 trehalose monoesters, each containing a single acyl chain, were synthesised in good overall yields and found to activate macrophages in a Mincle‐dependent manner. The activities of the monoesters paralleled those of their diester counterparts, and both mono‐ and diesters could activate the immune response in the absence of priming. This is the first time that trehalose monoesters have been found to activate macrophages, and these studies thus provide an important framework for the rational design of other Mincle agonists.

An expeditious route to phosphorus heterocycles based on ring-closing metathesis

A convenient route for the synthesis of phosphorus diolefinic templates starting from the bifunctional reagent bis(diisopropylamino)vinylphosphine is presented. Ring closing olefin metathesis on this type of diene substrate revealed that the newly developed 4,5-dihydro-imidazol-2-ylidene ruthenium benzylidene complex 4 is in all aspects superior to the previously developed Grubbs’ catalyst 1.

Isolation and structural characterisation of the major glycolipids from Lactobacillus plantarum

To date, the structures of the glycolipids from Lactobacillus plantarum, a commonly used beneficial probiotic, have not been conclusively assigned. Herein, we report for the first time, the full characterisation of the four principal glycolipids of the L. plantarum cell wall using sugar, linkage and FAME analysis, as well as ESI-MS/MS and 1D- and 2D-NMR spectroscopy, and assign the major glycolipids as being: α-D-Glcp-diglyceride, α-D-Galp-(1→2)-α-D-Glcp-diglyceride, β-D-Glcp-(1→6)-α-D-Galp-(1→2)-6-O-acyl-α-D-Glcp-diglyceride and β-D-Glcp-(1→6)-α-D-Galp-(1→2)-α-D-Glcp-diglyceride.

A fast, efficient and stereoselective synthesis of hydroxy-pyrrolidines

A five-step, protecting group free synthesis of 2,3-cis substituted hydroxy-pyrrolidines is presented. Key steps in the synthesis are the chemoselective formation of a primary amine via a Vasella reductive amination using ammonia as the nitrogen source, and the stereoselective formation of a cyclic carbamate from an alkenylamine. Improvement of the reductive amination, by way of the use of alpha-picoline borane as a more environmentally benign reducing agent, is also presented.