25143-95-7Relevant academic research and scientific papers
A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo
Lee, Sang M.,Cheng, Qiang,Yu, Xueliang,Liu, Shuai,Johnson, Lindsay T.,Siegwart, Daniel J.
supporting information, p. 5848 - 5853 (2021/02/05)
Lipid nanoparticles (LNPs) represent the leading concept for mRNA delivery. Unsaturated lipids play important roles in nature with potential for mRNA therapeutics, but are difficult to access through chemical synthesis. To systematically study the role of unsaturation, modular reactions were utilized to access a library of 91 amino lipids, enabled by the synthesis of unsaturated thiols. An ionizable lipid series (4A3) emerged from in vitro and in vivo screening, where the 4A3 core with a citronellol-based (Cit) periphery emerged as best. We studied the interaction between LNPs and a model endosomal membrane where 4A3-Cit demonstrated superior lipid fusion over saturated lipids, suggesting its unsaturated tail promotes endosomal escape. Furthermore, 4A3-Cit significantly improved mRNA delivery efficacy in vivo through Selective ORgan Targeting (SORT), resulting in 18-fold increased protein expression over parent LNPs. These findings provide insight into how lipid unsaturation promotes mRNA delivery and demonstrate how lipid mixing can enhance efficacy.
Complex Carbocyclic Skeletons from Aryl Ketones through a Three-Photon Cascade Reaction
Bach, Thorsten,Jandl, Christian,N?sborg, Line,Zech, Andreas
supporting information, p. 5656 - 5659 (2020/02/11)
Starting from readily available 7-substituted 1-indanones, products with a tetracyclo[5.3.1.01,704,11]undec-2-ene skeleton were obtained upon irradiation at λ=350 nm (eight examples, 49–67 % yield). The assembly of the structurally complex carbon framework proceeds in a three-photon process comprising an ortho photocycloaddition, a disrotatory [4π] photocyclization, and a di-π-methane rearrangement. The flat aromatic core of the starting material is converted into a functionalized polycyclic hydrocarbon with exit vectors in three dimensions. Ring opening reactions at the central cyclopropane ring were explored, which enable the preparation of tricyclo[5.3.1.04,11]undec-2-enes and of tricyclo[6.2.1.01,5]undecanes.
Regioselective Epoxidations by Cytochrome P450 3A4 Using a Theobromine Chemical Auxiliary to Predictably Produce N-Protected β- or γ-Amino Epoxides
Polic, Vanja,Cheong, Kin Jack,Hammerer, Fabien,Auclair, Karine
supporting information, p. 3983 - 3989 (2017/11/30)
N-Protected β- and γ-amino epoxides are useful chiral synthons. We report here that the enzyme cytochrome P450 3A4 can catalyze the formation of such compounds in a regio- and stereoselective manner, even in the presence of multiple double bonds or aromatic substituents. To this end, the theobromine chemical auxiliary is used not only to control the selectivity of the enzyme, but also as a masked amine, and to facilitate product recovery. Theobromine predictably directed epoxidation at the double bond of the fourth carbon from the theobromine group. Unlike with most catalysts, the selectivity did not depend on electronic or steric factors but rather on the position of the olefin relative to the theobromine group. (Figure presented.).
Organolanthanide-Catalyzed Intramolecular Hydroamination/Cyclization/Bicyclization of Sterically Encumbered Substrates. Scope, Selectivity, and Catalyst Thermal Stability for Amine-Tethered Unactivated 1,2-Disubstituted Alkenes
Ryu, Jae-Sang,Marks, Tobin J.,McDonald, Frank E.
, p. 1038 - 1052 (2007/10/03)
This paper reports the organolanthanide-catalyzed intramolecular hydroamination/cyclization of amine-tethered unactivated 1,2-disubstituted alkenes to afford the corresponding mono- and disubstituted pyrrolidines and piperidines using coordinatively unsaturated complexes of the type (η5-Me5C5)2LnCH(TMS)2 (Ln = La, Sm), [Me2Si(η5-Me4C5) 2]SmCH(TMS)2, and [Me2Si(η 5-Me4C5)(tBuN)]LnE(TMS)2 (Ln = Sm, Y, Yb, Lu; E = N, CH) as precatalysts. [Me2Si(η 5-Me4C5)(tBuN)]LnE(TMS)2 mediates intramolecular hydroamination/cyclization of sterically demanding amino-olefins to afford disubstituted pyrrolidines in high diastereoselectivity (trans/cis = 16/1) and good to excellent yield. In addition, chiral C 1-symmetric organolanthanide catalysts of the type [Me 2Si(OHF)(CpR*)]LnN(TMS)2 (OHF = η 5-octahydrofluorenyl; Cp = η5-C5H 3; R* = (-)-menthyl; Ln = Sm, Y), and [Me2Si(η 5-Me4C5)(CpR*)]SmN(TMS)2 (Cp = η5-H3C5; R* = (-)-menthyl) mediate asymmetric intramolecular hydroamination/cyclization of amines bearing internal olefins and afford chiral 2-substituted piperidine and pyrrolidine in enantioselectivities as high as 84:16 er at 60 °C. The substrate of the structure NH2CH2CMe2CH2CH=CH(CH 2)2CH=CH2 is regiospecifically bicyclized by [Me2Si(η5-Me4C5)( tBuN)]LnE(TMS)2 to the corresponding indolizidine skeleton in good yield and high diastereoselectivity. Thermolysis of (η 5-Me5C5)2LaCH(TMS)2 in cyclohexane-d12 at 120 °C rapidly releases CH 2(SiMe3)2 and leads to possible formation of fulvene (η6-Me4C5CH2-) species. The thermolysis product readily reverts to active catalysts upon protonolysis by substrate and exhibits the same catalytic activity as the (η 5,η1-Me5C5) 2LaCH(TMS)2 precatalyst at 120 °C in the cyclization of cis-2,2-dimethylhept-5-enylamine. Catalytically-active lanthanide-amido complexes (η5-Me5C5) 2La(NHR)(NH2R)n and [Me2Si(η 5-Me4C5)(tBuN)]Sm(NHR)(NH 2R)n are shown to be thermally robust species.
Iodide-catalysed cyclization of unsaturated N-chloroamines: A new way to synthesise 3-chloropiperidines
Noack, Michael,Goettlich, Richard
, p. 3171 - 3178 (2007/10/03)
Tetrabutylammonium iodide is a very efficient catalyst for the cyclization of unsaturated N-chloroamines. The catalysis seems to proceed through N-iodoamine intermediates, which act as a source of iodonium ions. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
Cyclization of N-butyl-4-pentenylaminyl: Implications for the cyclization of alkenylaminyl radicals
Maxwell, Brendan J.,Tsanaktsidis, John
, p. 4276 - 4283 (2007/10/03)
The utility of arenesulfenamides as aminyl radical precursors has been clearly demonstrated. The cyclization of N-butyl-4-pentenylaminyl is shown to be a slow and irreversible process that is accelerated significantly by small amounts of bis(tributyltin) oxide.
Regiochemical and Stereochemical Studies on Halocyclization Reactions of Unsaturated Sulfides
Ren, Xiao-Feng,Turos, Edward,Lake, Charles H.,Churchill, Melvyn Rowen
, p. 6468 - 6483 (2007/10/03)
The regiochemistry and stereochemistry for the halocyclization reactions of unsaturated benzyl sulfides have been examined as a function of tether length, type of unsaturation (carbon-carbon double bond versus carbon-carbon triple bond), substituents, and halogenating agent.Alkenyl sulfides were found to react with iodine or bromine at room temperature to give five-membered ring cycloadducts exclusively over those having four-membered rings, while for larger systems, six-membered ring products are formed preferentially over their five-membered ring isomers and exclusively over the seven-membered ring adducts.The endo- versus exo-regioselectivity of these alkenyl sulfide ring closure most likely reflects the difference in thermodynamic stabilities of the β-halo sulfide cycloadducts, which are able to equilibrate via a common episulfonium intermediate.The efficiency of cyclization process markedly drops off for these alkenyl sulfides as the tether length increases beyond four intervening carbon centers.Thus, while the halogenations of 3-butenyl sulfides and 4-pentenyl sulfides give high yields of cycloadducts, those of 5-hexenyl sulfides afford only small amounts of cyclized products and large quantities of acyclic dibromides.Conversely, the reactions of acetylenic sulfides with iodine give uniformly high yields and regiochemical control regardless of the tether length.Thus, 3-butynyl and 4-pentynyl sulfides cyclize cleanly to the five-membered ring while 5-hexynyl sulfides give exclusively the six-membered ring.The products arising from these alkynyl sulfide ring closures are believed to be formed under kinetic control.The methodology has been applied to the synthesis of unusual bicyclic β-lactams related to the penicillin family of antibiotics.
