Danny Geerdink

Catalytic enantioselective syn hydration of enones in water using a DNA-based catalyst

The enantioselective addition of water to olefins in an aqueous environment is a common transformation in biological systems, but was beyond the ability of synthetic chemists. Here, we present the first examples of a non-enzymatic catalytic enantioselective hydration of enones, for which we used a catalyst that comprises a copper complex, based on an achiral ligand, non-covalently bound to (deoxy)ribonucleic acid, which is the only source of chirality present under the reaction conditions. The chiral β-hydroxy ketone product was obtained in up to 82% enantiomeric excess. Deuterium-labelling studies demonstrated that the reaction is diastereospecific, with only the syn hydration product formed. So far, this diastereospecific and enantioselective reaction had no equivalent in conventional homogeneous catalysis.

Total Synthesis of the Triglycosyl Phenolic Glycolipid PGL-tb1 from Mycobacterium tuberculosis†

Mycobacterium tuberculosis (M. tb) is one of the most important pathogens. Despite the availability of antibiotics and a vaccine (BCG), one third of the world s population is infected with M. tb, causing 8 million casualties and 1.5 million deaths yearly. Synergy with HIV and the appearance of M. tb strains that are multi-drug resistant or hypervirulent, poses further threats. The search for novel drugs and more effective vaccines entered a new era with the publication of the genome sequence of M. tb H37Rv. Based on this sequence, genes that code for enzymes involved in the critical steps of host– pathogen interaction were identified. Many of these enzymes are involved in the synthesis and transport of complex lipids, in particular phthiocerol dimycocerosates (DIM or PDIM) present in the outer layer of the M. tb cell envelope. Furthermore, several M. tb strains synthesize closely related phenolic glycolipids (PGL-tb1, Figure 1) in which the phthiocerol is connected to a glycosylated phenol. It has been shown that DIM/PDIMs are required for multiplication and persistence of M. tb in vivo. Next to this, PGLtb1 (1, Figure 1) is suspected to be involved in hypervirulence of specific M. tb strains. The interplay of M. tb with the human host is very complex, with PGL-tb1 as one of the most unusual virulence factors modulating its defense systems and causing disease. Thus, there is a great need for antigens that permit to distinguish between prior BCG vaccination and infection. Recently, an enzyme-linked immunosorbent assay (ELISA) based on PGL-tb1 has shown potential for the diagnosis of TB in HIV-infected patients. Furthermore, a lipidomics platform has been established for chemotaxonomic analysis of M. tb. Thus, access to pure, chemically synthesized PGL-tb1 (1) has become crucial for reliable immunological studies. Preluded by the first synthesis of phthiocerol dimycocerosate PDIM A we now report the first total synthesis of PGLtb1. The size and complexity of PGL-tb1 is impressive. The parent phenylphthiocerol has four stereocenters and is esterified to two molecules of mycocerosic acid (2), a longchain quadruple methyl-branched fatty acid. Through the phenol terminus, the aglycon is linked to a linear trisaccharide. To get PGL-tb1 within reach, a strongly convergent synthetic strategy had to be designed (see Scheme 1). Esterification with mycocerosic acid was planned for a late stage because of its precious nature. Instead of the glycosylation of the phenol terminus with the trisaccharide construct, we chose to connect the trisaccharide in the form of a para-iodophenoxy-substituted glycan to a terminal alkyne through Sonogashira coupling. This strategy avoids a stereoselective glycosylation step with an activated trisaccharide in a late stage of the synthesis. The alkyne function should be fully reduced to the corresponding aliphatic fragment together with the removal of the benzyl protecting groups in the final step. An additional advantage is that the bifunctional “spacer” of the required length, equipped with a terminal alkyne, would be readily accessible from commercially available alkynol 5 in a few steps. The right-hand side of phenylphthiocerol was planned to be prepared by using our asymmetric conjugate addition– Figure 1. PGL-tb1 (1).

Asymmetric total synthesis of a putative sex pheromone component from the parasitoid wasp Trichogramma turkestanica

Virgin females of the parasitoid wasp Trichogramma turkestanica produce minute amounts of a sex pheromone, the identity of which has not been fully established. The enantioselective synthesis of a putative component of this pheromone, (6S,8S,10S)-4,6,8,10-tetramethyltrideca-2E,4E-dien-1-ol (2), is reported as a contribution to this identification. Catalytic asymmetric conjugate addition of methylmagnesium bromide and stereoselective Horner-Wadsworth-Emmons olefinations are used as the key steps, and 2 was obtained in 16 steps with an overall yield of 4.4%.