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Often referred to as the “Swiss Army knife” of the immune system, invariant natural killer T (iNKT) cells are a subpopulation of T lymphocytes stimulated by the synthetic glycolipid α-galactosylceramide (αGalCer) when in complex with the CD1d receptor of antigen presenting cells. Through their ability to produce TH1 and TH2 cytokines and co-stimulate several other lymphocytes, iNKT cells have emerged as central players in directing the immune response in a range of physiological processes, such as infections, autoimmune diseases, and cancer. Over the years, synthetic chemistry has advanced the field of iNKT cell stimulation with the development of more efficient approaches to prepare αGalCer, and, additionally, with the chemical synthesis of αGalCer analogs in the search of better TH1/TH2 cytokine skewing compounds for therapeutic applications. Here we review the strategies for the synthesis of αGalCer and its analogs, including synthetic probes, together with the most important advances in the understanding of the mechanism of action of these compounds, as a guide to the available tools for interrogating the iNKT cell–αGalCer–CD1d complex and inspiration for future research.

A series of fluorescein dyes have been prepared from a common precursor through a very simple synthetic procedure, giving access to important precursors for fluorescent probes. The method has proven an efficient access to regioisomerically pure 5- and 6-carboxyfluoresceins on a large scale, in good yields, and with high regioisomeric purity. Furthermore, we have applied the method to the development of a new type of mixed fluorescein derivatives of 5-carboxyfluorescein. We have demonstrated the scope of the procedure by synthesizing a new type of double chromophore within the fluoro-Jade family.

The Ritter-type reaction of arylnitriles and N-acyliminium ions generated in situ from dihydroxy-γ-lactams gave tetrahydropyrrolo[2,3-d]oxazol-5-ones in excellent yields. A subsequent acidic hydrolysis in EtOH/H2O/TFA (trifluoroacetic acid) yielded new (arylamido)pyrrolidinones with excellent cis diastereoselectivity. A combined one-step Ritter–hydrolysis procedure proved to be of equal efficiency. This versatile method, which was successfully used for the construction of a screening library containing 706 molecules within the European Lead Factory consortium, provides a simple way to access new compounds incorporating an arylamido and a pyrrolidinone moiety, both of which are widely found in marketed drugs and in biologically active molecules.

An efficient reductive cyclization strategy was employed for the synthesis of N-substituted β,γ-dihydroxy-γ-lactams. A subsequent Petasis-like reaction (PLR) through nucleophilic additions of boronic acids to intermediate N-acyliminium ions produced substituted γ-lactams. Overall, the application of this protocol provides β,γ-dihydroxy-γ-lactams and functionalized γ-lactams with potential interest for synthetic and bioorganic chemistry.

Macrocyclic compounds are attractive targets when searching for molecules with biological activity. The interest in this compound class is increasing, which has led to a variety of methods for tackling the difficult macrocyclization step in their synthesis. This microreview highlights some recent developments in the synthesis of macrocycles, with an emphasis on chemistry developed to generate libraries of putative biologically active compounds.

Treatment of the lysolipid 1-O-hexadecyl-sn-phosphatidylcholine with all-(E)-retinoic acid, DCC and DMAP resulted in poor acylation and caused (Z)/(E) isomerization of the α–β double bond. In the presence of a proton source, the carbodiimide-activated all-(E)-retinoic acid undergoes fast isomerization to give a final mixture of (13E)/(13Z) isomers in a 3:1 ratio. Similar treatment of (13Z)-retinoic acid leads to the same isomer ratio. The isomerization was circumvented successfully by using a Mitsunobu reaction, which provided an efficient synthesis of all-(E)-retinoic acid sn-2-conjugated to phosphatidylcholine and phosphatidylglycerol etherlipids.

The synthesis of two new α,α-difluoro ester phospholipid conjugates is described and the stability of their liposomal formulations in three different aqueous buffers (pH 4.5, 7.5 and 8.5) has been investigated. The studies confirmed that α,α-difluoro esters are much more prone to hydrolysis when positioned close to the hydrophilic head group of phospholipids than when the functionality is placed in the lipophilic part of the bilayer in liposomes. This observation lends further support to the concept of protecting hydrolysable functionalities by formulation as part of the membrane of liposomes.