Kilo-Scale GMP Synthesis of Renewable Semisynthetic Vaccine-Grade Squalene.

Emulsions of the triterpene squalene ((6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene, CAS 111-02-4) have been used as adjuvants in influenza vaccines since the 1990s. Traditionally sourced from shark liver oil, the overfishing of sharks and concomitant reduction in the oceanic shark population raises sustainability issues for vaccine adjuvant grade squalene. We report a semisynthetic route to squalene meeting current pharmacopeial specifications for use in vaccines that leverages the ready availability of trans-ß-farnesene ((6E)-7,11-dimethyl-3-methylene-1,6,10-dodecatriene, CAS 18794-84-8), manufactured from sustainable sugarcane via a yeast fermentation process. The scalability of the proposed route was verified by a kilo-scale GMP synthesis. We also report data demonstrating the synthesized semi-synthetic squalene's physical stability and biological activity when used in a vaccine adjuvant formulation.

Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Syntheses of Indolizidine Alkaloids (-)-205A, (-)-207A, and (-)-235B.

Concise asymmetric syntheses of indolizidine alkaloids (-)-205A, (-)-207A, and (-)-235B were accomplished with a high degree of stereocontrol in eleven steps. Addition of 4-(1-butenyl)magnesium bromide to 1-acylpyridinium salt 5, prepared in situ from 4-methoxy-3-(triisopropylsilyl)pyridine and the chloroformate of (+)-trans-2-(alpha-cumyl)cyclohexanol, gave a 91% yield of diastereomerically pure dihydropyridone 6. Oxidative cleavage of 6 and subsequent reduction provided alcohol 7 in 81% yield. Removal of the chiral auxilliary and TIPS group (NaOMe; 10% HCl), N-acylation with BnOCOCCl, and treatment with NCS/Ph(3)P gave chloride 10. Methylation at C-3, copper-mediated conjugate addition of 4-(benzyloxy)butylmagnesium bromide, and vinyl triflate formation provided 13 in a stereoselective fashion. Catalytic reduction of the vinyl triflate moiety, simultaneous cleavage of the benzyl ether and Cbz groups, and cyclization to give amino alcohol 14 was effected via a one-pot reaction. Oxidation of 14 with the Dess-Martin reagent gave a 97% yield of amino aldehyde 4. Synthesis of each of the three title alkaloids was accomplished in one step from 4. The Seyferth-Gilbert reaction provided a 41% yield of (-)-205A. The appropriate Wittig olefination of 4 gave indolizidines (-)-207A and (-)-235B in 70% and 86% yield, respectively.

Synthesis of well-defined tower-shaped 1,3,5-trisubstituted adamantanes incorporating a macrocyclic trilactam ring system.

We describe the synthesis of two novel well-defined tower-shaped 1,3,5-trisubstituted adamantanes 30 and 33 that incorporate a macrocyclic trilactam ring system. Each nanoscale molecule has a broad tripodal base consisting of three identical sulfur-containing termini as the tripod feet, 4-acetylsulfanylmethylphenyl units in the case of 30 and 3,5-bis(acetylsulfanylmethyl)phenyl units in the case of 33. The sulfur atoms are designed to bind the molecules trivalently to the apex of a gold-coated commercial AFM tip through formation of three S-Au bonds. The rigid adamantane-derived head unit with a single hydrogen atom at the apex is designed to scan the sample. Molecules 30 and 33 are synthesized from 1,3,5-triethynyladamantane by a series of Sonogashira coupling reactions involving terminal alkynes and aryl iodides. A macrocyclic trilactam unit is included for added rigidity. We demonstrate that molecule 30 is sufficiently large and rigid to be visualized by a conventional AFM tip. These nanoscale molecules may also find application as chemically well-defined nanoscale objects for calibration of AFM tips.