Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.

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We describe an efficient regioselective formation of six-/seven-membered cyclic ethers based on goldcatalyzed intramolecular hydroalkoxylation. Sequential gold-catalyzed cyclization and palladium-catalyzed cross-coupling reactions afforded 6,6-bicyclic ethers, while reversing the reaction sequence (cross-coupling then cyclization) afforded 6,7-bicyclic ethers. This methodology should provide access to a range of functional polycyclic ethers.Key words gold-catalysis; cyclization; hydroalkoxylation; polyether; tandem reaction (Poly) cyclic ethers are key structural units in many natural products and materials of structural and biological interest [1][2][3][4][5] ( Fig. 1). Therefore, regio-and chemoselective construction of these structures has long been of interest in organic synthesis. Homogeneous gold catalysis has emerged over the last two decades as a powerful tool for heterocyclization reactions, and the gold-catalyzed intramolecular addition of alcohol across a carbon-carbon triple bond has been employed for the construction of cyclic ethers in various total syntheses. [6][7][8][9][10][11][12][13][14][15][16][17] However, its application to the formation of medium-sized cyclic ethers has been generally limited by 1) enthalpic and entropic difficulties, and 2) low regioselectivity in ringclosure to the triple bond.18) Furthermore, the applicability of the reaction to polycyclic ethers is not well established. 19) With total syntheses of polycyclic ether-containing natural products in mind, we therefore designed the alkyne alcohol (alkynol) 1 as a cyclization precursor obtainable within 10 steps from 2,3-dihydrofuran 20,21) (Chart 1). Herein, we report our investigations on the gold-catalyzed intramolecular hydroalkoxylation of 1, focusing in particular upon the influence of the electronic and/or steric properties of alkynes on the 6-exo/7-endo selectivity. We also show that changing the order in which gold-catalyzed cyclization and palladium-catalyzed cross-coupling reactions are carried out provides a means to rapidly diversify polyether structures. Results and DiscussionWe commenced our studies by treating 1a (X=3,5-syn-OMe; Y=Me) with various gold catalysts. After extensive experimentation, we found that the use of goldoxo complex, tris[(triphenylphosphine)gold]oxonium tetrafluoroborate ([(Ph 3 PAu) 3 O] BF 4 ) in the presence or absence of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) promotes the intramolecular cyclization smoothly to give 6-exo and 7-endo bicyclic ethers (2a and 3a) in high yields. Simple heating of 1a at 60°C in tetrahydrofuran (THF) in the presence of 5 mol% of [(Ph 3 PAu) 3 O] BF 4 (Condition A) afforded the desired cyclic ethers as a 13 : 87 mixture of 2a and 3a in 81% yield. Addition of 2 eq. of HFIP (Condition B) increased the total chemical yield of 2a and 3a to 92%, but lowered the 7-endo selectivity (Fig. 2). With these optimal conditions in hand, we then systematically examined the influence of the substituents at the propargylic (X) and terminal (Y) positions of alkynols 1 on the...

Successful vaccination, especially with safe vaccines such as component/subunit vaccines, requires proper activation of innate immunity and, for this purpose, adjuvant is used. For clinical use, alum is frequently used while, for experimental use, CFA, containing Mycobacterial components, was often used. In this report, we demonstrated that mycolic acids (MA), major and essential lipid components of the bacterial cell wall of the genus Mycobacterium, has adjuvant activity. MA plus model antigen-immunization induced sufficient humoral response, which was largely comparable to conventional CFA plus antigen-immunization. Importantly, while CFA plus antigenimmunization induced Th17-biased severe and destructive inflammatory responses at the injected site, MA plus antigen-immunization induced Th1-biased mild inflammation at the site. MA induced dendritic cell activation by co-stimulatory molecule induction as well as inflammatory cytokine/chemokine induction. MA plus antigen-immunization successfully protected mice from tumor progression both in prevention and in therapy models. We thus submit that MA is a promising adjuvant candidate material for clinical purposes and for experimental purposes from a perspective of animal welfare.