Bjorn ter Horst

Iterative strategies for the synthesis of deoxypropionates

This feature article gives an overview of iterative synthetic methods for the construction of deoxypropionates, an important class of polyketides. The catalytic and non-catalytic methodologies discussed are based on highly stereoselective reactions which can be carried out in an iterative fashion. Non-catalytic methods are described first, followed by state of the art catalytic iterative protocols. The application of the iterative methods in the synthesis of natural products is discussed as well.

Catalytic asymmetric synthesis of mycocerosic acid

The first catalytic asymmetric total synthesis of mycocerosic acid was achieved via the application of iterative enantioselective 1,4-addition reactions and allows for the efficient construction of 1,3-polymethyl arrays with full stereocontrol; further exemplified by the synthesis of tetramethyl-decanoic acid, a component of the preen-gland wax of the graylag goose, Anser anser.

Stereoselective synthesis of syn and anti 1,2-hydroxyalkyl moieties by Cu-catalyzed asymmetric allylic alkylation

A stereoselective synthesis of 1,2-hydroxyalkyl moieties is described herein. These valuable building blocks are obtained with complete regiocontrol and excellent stereocontrol both for the syn or the anti products, by choosing the appropriate enantiomer of the ligand in a copper-catalyzed asymmetric allylic alkylation of δ-alkoxy-substituted allyl bromides.

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 synthesis and structure elucidation of a glycerophospholipid from Mycobacterium tuberculosis

A glycerophospholipid (1-O-tuberculostearoyl-2-O-palmitoyl-sn-glycero-3-phosphoethanolamine) from Mycobacterium tuberculosis was isolated from the reference strain H37Rv. The molecular structure of this tuberculostearoyl [(R)-10-methyloctadecyl] and palmitoyl containing phosphatidylethanolamine (PE) has been resolved. The substitution pattern on the glycerol backbone could be determined by comparison of the isolate to the two synthetically prepared regioisomers. MS/MS analysis was used to determine its molecular structure. Production of this synthetic version of mycobacterial PE in high yield, with a stereochemically correct and pathogen-specific fatty acyl group, can be used as a standard in LC-MS based lipidomic analyses to detect trace amounts of mycobacterial PE in human blood, sputum, or tissues as a marker of infection by mycobacteria.

Stereoselective synthesis of 2,3,7-trimethylcyclooctanone and related compounds and determination of their relative and absolute configurations by the M alpha NP acid method

The copper/chiral phosphoramidite (L(1))-catalyzed conjugate addition of dimethylzinc to cycloocta-2,7-dienone 4, followed by the methylation of the intermediate enolate, yielded a single isomer of 7,8-dimethylcyclooct-2-enone (+)-5. Compound (+)-5 was subjected to the second conjugate addition with ent-L(1) giving only one stereoisomer of 2,3,7-trimethylcyclooctanone (+)-6, which was converted to 2,3,7-trimethylcyclooctanol 7. To determine the relative and absolute configurations of these compounds, the (1)H NMR anisotropy method using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid {(S)-(+)-MalphaNP acid} 1 was applied. Racemic alcohol (+/-)-7 was esterified with (S)-(+)-MalphaNP acid 1 yielding diastereomeric esters, which were efficiently separated by HPLC on silica gel affording the first-eluted MalphaNP ester (-)-10a and the second-eluted one (-)-10b. The relative and absolute configurations of ester (-)-10a were determined to be (S;1R,2S,3R,7S) by analyzing the (1)H and (13)C NMR spectra of (-)-10a and (-)-10b, especially their HSQC-TOCSY and NOESY spectra, and by applying the MalphaNP anisotropy method. The alcohol 7 formed from (+)-6 was similarly esterified with (S)-(+)-MalphaNP acid 1 yielding an MalphaNP ester, which was identical with (-)-10a, and the relative and absolute configurations of 2,3,7-trimethylcyclooctanone (+)-6 were determined to be (2S,3R,7S).