2612-32-0Relevant articles and documents
A Case Study in Catalyst Generality: Simultaneous, Highly-Enantioselective Br?nsted- And Lewis-Acid Mechanisms in Hydrogen-Bond-Donor Catalyzed Oxetane Openings
Strassfeld, Daniel A.,Algera, Russell F.,Wickens, Zachary K.,Jacobsen, Eric N.
supporting information, p. 9585 - 9594 (2021/07/19)
Generality in asymmetric catalysis can be manifested in dramatic and valuable ways, such as high enantioselectivity across a wide assortment of substrates in a given reaction (broad substrate scope) or as applicability of a given chiral framework across a variety of mechanistically distinct reactions (privileged catalysts). Reactions and catalysts that display such generality hold special utility, because they can be applied broadly and sometimes even predictably in new applications. Despite the great value of such systems, the factors that underlie generality are not well understood. Here, we report a detailed investigation of an asymmetric hydrogen-bond-donor catalyzed oxetane opening with TMSBr that is shown to possess unexpected mechanistic generality. Careful analysis of the role of adventitious protic impurities revealed the participation of competing pathways involving addition of either TMSBr or HBr in the enantiodetermining, ring-opening event. The optimal catalyst induces high enantioselectivity in both pathways, thereby achieving precise stereocontrol in fundamentally different mechanisms under the same conditions and with the same chiral framework. The basis for that generality is analyzed using a combination of experimental and computational methods, which indicate that proximally localized catalyst components cooperatively stabilize and precisely orient dipolar enantiodetermining transition states in both pathways. Generality across different mechanisms is rarely considered in catalyst discovery efforts, but we suggest that it may play a role in the identification of so-called privileged catalysts.
Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additions to Oxetanes
Strassfeld, Daniel A.,Wickens, Zachary K.,Picazo, Elias,Jacobsen, Eric N.
supporting information, p. 9175 - 9180 (2020/07/13)
A precisely designed chiral squaramide derivative is shown to promote the highly enantioselective addition of trimethylsilyl bromide (TMSBr) to a broad variety of 3-substituted and 3,3-disubstituted oxetanes. The reaction provides direct and general access to synthetically valuable 1,3-bromohydrin building blocks from easily accessed achiral precursors. The products are readily elaborated both by nucleophilic substitution and through transition-metal-catalyzed cross-coupling reactions. The enantioselective catalytic oxetane ring opening was employed as part of a three-step, gram-scale synthesis of pretomanid, a recently approved medication for the treatment of multidrug-resistant tuberculosis. Heavy-atom kinetic isotope effect (KIE) studies are consistent with enantiodetermining delivery of bromide from the H-bond-donor (HBD) catalyst to the activated oxetane. While the nucleophilicity of the bromide ion is expected to be attenuated by association to the HBD, overall rate acceleration is achieved by enhancement of Lewis acidity of the TMSBr reagent through anion abstraction.
S - Cis Diene Conformation: A New Bathochromic Shift Strategy for Near-Infrared Fluorescence Switchable Dye and the Imaging Applications
Chen, Hsiang-Jung,Chew, Chee Ying,Chang, En-Hao,Tu, Yu-Wei,Wei, Li-Yu,Wu, Bo-Han,Chen, Chien-Hung,Yang, Ya-Ting,Huang, Su-Chin,Chen, Jen-Kun,Chen, I-Chia,Tan, Kui-Thong
, p. 5224 - 5234 (2018/04/23)
In this paper, we present a novel charge-free fluorescence-switchable near-infrared (IR) dye based on merocyanine for target specific imaging. In contrast to the typical bathochromic shift approach by extending π-conjugation, the bathochromic shift of our merocyanine dye to the near-IR region is due to an unusual S-cis diene conformer. This is the first example where a fluorescent dye adopts the stable S-cis conformation. In addition to the novel bathochromic shift mechanism, the dye exhibits fluorescence-switchable properties in response to polarity and viscosity. By incorporating a protein-specific ligand to the dye, the probes (for SNAP-tag and hCAII proteins) exhibited dramatic fluorescence increase (up to 300-fold) upon binding with its target protein. The large fluorescence enhancement, near-IR absorption/emission, and charge-free scaffold enabled no-wash and site-specific imaging of target proteins in living cells and in vivo with minimum background fluorescence. We believe that our unconventional approach for a near-IR dye with the S-cis diene conformation can lead to new strategies for the design of near-IR dyes.
New pseudodimeric aurones as palm pocket inhibitors of Hepatitis C virus RNA-dependent RNA polymerase
Meguellati, Amel,Ahmed-Belkacem, Abdelhakim,Nurisso, Alessandra,Yi, Wei,Brillet, Rozenn,Berqouch, Nawel,Chavoutier, Laura,Fortuné, Antoine,Pawlotsky, Jean-Michel,Boumendjel, Ahcène,Peuchmaur, Marine
, p. 217 - 229 (2016/04/05)
The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 Combining double low line 1.3 1/4M). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives.
Enzymatic desymmetrization of prochiral 2-substituted-1,3-diamines: Preparation of valuable nitrogenated compounds
Rios-Lombardia, Nicolas,Busto, Eduardo,Garcia-Urdiales, Eduardo,Gotor-Fernandez, Vicente,Gotor, Vicente
supporting information; experimental part, p. 2571 - 2574 (2009/07/25)
A wide range of prochiral 1, 3-diamines were first efficiently synthesized and subsequently desymmetrized by using lipase from Pseudomonas cepacia as catalyst and diallyl carbonate as alkoxycarbonylating agent. In all cases, the amino carbamates of R-configuration were recovered. Final selective cleavage of the N-allyloxycarbonyl moiety was carried out under mild reaction conditions, which demonstrates the high versatility and potential of this chemoenzymatic route as a source of intermediates in the synthesis of related optically active nitrogenated derivatives.
Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: A new class of KDR kinase inhibitors
Fraley, Mark E.,Hoffman, William F.,Rubino, Robert S.,Hungate, Randall W.,Tebben, Andrew J.,Rutledge, Ruth Z.,McFall, Rosemary C.,Huckle, William R.,Kendall, Richard L.,Coll, Kathleen E.,Thomas, Kenneth A.
, p. 2767 - 2770 (2007/10/03)
We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC50=19 nM), respectively. The synthesis and SAR of these compounds are described.
LIQUID CRYSTALLINE PROPERTIES OF 2-(trans-4-n-ALKYLCYCLOHEXYL)-PROPANE-1,3-DIOLS
Tschierske, C.,Altmann, H.,Zaschke, H.,Brezesinski, G.,Kuschel, F.
, p. 295 - 300 (2007/10/02)
The liquid crystalline properties of the homologous series of 2-(trans-4-n-alkylcyclohexyl)propane-1,3-diols 1 is described.These compounds exhibit thermotropic and after addition of small amounts of water also lyotropic liquid crystalline properties.The phase behaviour is described and explained by a general model, whereby hydrogen-bonding and hydrophobic interactions are considered.
SYNTHESIS OF BOTH ENANTIOMERIC FORMS OF 2-SUBSTITUTED 1,3-PROPANEDIOL MONOACETATES STARTING FROM A COMMON PROCHIRAL PRECURSOR, USING ENZYMATIC TRANSFORMATIONS IN AQUEOUS AND IN ORGANIC MEDIA
Tombo, G. M. Ramos,Schaer, H.-P.,Busquets Fernandez I,Ghisalba, O.
, p. 5707 - 5710 (2007/10/02)
A direct entry to both enantiomeric forms c and ent-c based on enzyme catalyzed transformations of prochiral compounds of type a and b is described.The catalysts used are carboxyl esterase preparations obtained from crude porcine pancreas lipase.
