Cells were treated with 10 M concentration of synthesized compound for 24 h in RPMI 1640 supplemented medium and 100 g/mL penicillin-streptomycin. aplysamine1,3verogamine2,4conessine3,5and dispyrin4,6,7have displayed both affinity for and inhibition of the histamine subtype 3 (H3) receptor (Figure1).810The H3receptor is a presynaptic autoreceptor within the Class A GPCR family, Goserelin but it also functions as a heteroreceptor modulating Goserelin levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA, and glutamate.810Thus, H3R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimers disease, neuropathic pain, and ADHD.810Importantly, conserved elements have been identified within small molecule H3ligand scaffolds that resulted in a highly predictive pharmacophore model, and many marine natural products conform to this model.810 == Figure 1. == Marine natural products14with significant affinity for and inhibition of H3, a target of interest for numerous CNS indications. Inset: refined H3pharmacophore model, to which synthetic small molecule and natural product H3antagonists conform. -Carboline alkaloids are a prevalent class of biologically active natural products from marine organisms. They exhibit diverse structural features and distinct neuropharmacological profiles.11,12Our lab has worked extensively in this arena,13,14and we were recently attracted to a class of -carboline alkaloids represented by the trypargines57(Figure2), as these alkaloids mapped well onto the H3pharmacophore model and offered a synthetic challenge.15,16Both trypargine5(15) and 6-hydroxytrypargine6(16) are highly toxic alkaloids. (+)-7-Bromotrypargine7, was only recently isolated by Quinn et al. from the Australian marine spongeAncorniasp. and found to possess antimalarial activity.176-Bromotyramine8was isolated along with7in similar quantities, and it is believed to be a Goserelin Goserelin key biosynthetic precursor.17Based on the neuropharmacological profiles of -carboline alkaloids, and the electron-deficient nature of7, relative to the electron-rich congeners5and6, which might diminish the cytotoxicity, the total synthesis of7and biological evaluation seemed warranted. == Figure 2. == Structures of the (+)-trypargines57and 6-bromotyramine8. Our retrosynthesis of7(Figure3) afforded two approaches to close the tricyclic ring: either utilizing the recently reported Brnsted-acid-catalyzed, enantioselective ProtioPictetSpengler reaction18,19or a BischlerNapieralski reaction,14followed by an asymmetric Noyori transfer hydrogenation protocol.20Both routes required the synthesis of 6-bromotyramine8. As shown in Scheme1, nitro-olefination of 6-bromo-1H-indole9, as prescribed by Bchi and Mak,21proceeded smoothly affording10in 98% yield. Exhaustive reduction then provided natural 6-bromotyramine8in 76% yield. == Figure 3. == Retrosynthesis of (+)-7-bromotrypargine (7). == Scheme 1. Synthesis of 6-Bromotyramine (8). == With large quantities of8in hand, we evaluated both the Jacobsen thiourea Brnsted-acid-catalyzed, enantioselective ProtioPictetSpengler reaction18as well as the Dixon chiral BINOL-derived phosporic acid variation19with known aldehyde11to produce the key, chiral -carboline core13(Scheme2). Interestingly, neither protocol afforded13; however, electron rich congeners of8, such as12, proceeded smoothly, providing14in good % ee and conversion. Thus, the Brnsted-acid-catalyzed, enantioselective ProtioPictetSpengler approach with the more electron deficient8was not tractable. Indeed, the original reports by Jacobsen and Klausen, and Dixon et al. utilized only electron rich substrates.18,19Conversion to13could be forced under both protocols (80% yield) at high temperatures, but enantioselectivity eroded. Thus, focus shifted toward a BischlerNapieralski/Noyori asymmetric transfer hydrogenation approach.14,20 == Scheme 2. GNAS Brnsted-Acid-Catalyzed, Enantioselective ProtioPictetSpengler Approach to -Carboline Core13. == Key acid17was prepared Goserelin in 98% yield by treating 4-aminobutanoic acid15with anhyride16under microwave conditions (Scheme3). Standard amide coupling conditions with8and17provided amide18. The BischlerNapieralski reaction14,20was facilitated by treatment with POCl3to imine19in 88% yield. Noyori asymmetric transfer hydrogenation with (S,S)-ruthenium catalyst20delivered the -carboline core13in 80% yield and 90% ee.20,22Removal of the phthalimide moiety with hydrazine to afford amine21, guanidation, and removal of the Boc protecting groups proceeded in 84% yield over the three steps, delivering, for the first time, (+)-7-bromotrypargine7. Synthetic7exhibited physical and spectoscopic data identical compared to that of organic7,17,22confirming the framework and overall stereochemistry. General, the synthesis proceeds in nine techniques, eight techniques longest linear series, in 36.9% overall yield which supplied significant material to allow complete biological evaluation. == System 3. Synthesis.