Stereocontrolled Debenzylative Cycloetherification Reaction as a Route to Enantiopure C-Furanosides with Amino Substituents in the Side Chain.
ABSTRACT: A highly efficient methodology of the preparation of synthetically important tetrahydrofuran derivatives with an amino substituent in the side chain is reported. This process is based on the stereocontrolled debenzylative cycloetherification (DBCE) reaction applied for chirons from the d-gluco- and d-manno-series and provides derivatives with new stereogenic centers. The influence of the electron-withdrawing group (EWG), present in the acyclic substrates with the mesyl leaving group, on the reactivity in the DBCE reaction was investigated both "in the flask" and by density functional theory (DFT) calculations. It was demonstrated that tetrahydrofuran derivatives with the benzoxime group (EWG = CHNOBn) are very good candidates for the subsequent highly stereoselective Grignard reaction.
Project description:By designing a novel chiral ion-pair organocatalyst composed of chiral phosphate and DABCO-derived quaternary ammonium, highly enantioselective 3-<i>exo</i> iodo-cycloetherification of allyl alcohols was achieved using NIS as a halogen source. Based on this reaction, one-pot asymmetric 3-<i>exo</i> iodo-cycloetherification/Wagner-Meerwein rearrangement of allyl alcohols en route to enantioenriched 2-iodomethyl-2-aryl cycloalkanones was subsequently developed. Due to the participation of adjacent iodine, the Wagner-Meerwein rearrangement of 2-iodomethyl-2-aryl epoxide proceeds with unusual retention of stereoconfiguration.
Project description:A stereocontrolled first total synthesis of muraymycin D1 (1) has been achieved. The synthetic route is highly stereoselective, featuring (1) selective ?-ribosylation of the C2-methylated amino ribose, (2) selective Strecker reaction, and (3) ring-opening reaction of a diastereomeric mixture of a diaminolactone to synthesize muraymycidine (epi-capreomycidine). The acid-cleavable protecting groups for secondary alcohol and uridine ureido nitrogen are applied for simultaneous deprotections with the Boc and tBu groups. Muraymycin D1 (1) and its amide derivatives (2 and 3) exhibited growth inhibitory activity against Mycobacterium tuberculosis (MIC50 = 1.56-6.25 ?g/mL) and strong enzyme inhibitory activities against the bacterial phosphotransferases (MurX and WecA) (IC50 = 0.096-0.69 ?M).
Project description:A flexible and convergent strategy for the stereoselective total synthesis of bioactive marine natural product cytospolide Q has been developed. The key features of this synthesis include Evans anti-aldol reaction for the installation of C-2 and C-3 stereocenters and cycloetherification via epoxide opening followed by concomitant lactonization for the construction of tetrahydrofuran and ?-butyrolactone scaffolds. This synthetic study also revealed that protected oxygenated functionality (methyl ester or benzyl ether) at C-1 position participated readily in epoxide opening.
Project description:A convergent and highly stereocontrolled synthesis of amphidinolide E (1) has been accomplished. The synthesis features a highly diastereoselective (>20:1) BF3.Et2O promoted [3+2] annulation reaction between aldehyde 3 and allylsilane 4 to afford substituted tetrahydrofuran 2.
Project description:Plagiogyrin A (1) was first isolated from the fronds of Plagiogyria matsumureana. Structurally, it features an ?-ketoaldehyde functional group in its hemiacetal form, fused in a cis-substituted lactone ring. We have successfully synthesized the skeleton of this natural product by employing a stereocontrolled aldol reaction followed by the installation of the ?-ketoaldehyde moiety derived from the mild oxidation of an ?-diazoketone. Finally, anhydrous acidic conditions released the protected diol and provided the required cyclized hemiacetal.
Project description:Through treatment with NaI and trifluoroacetic anhydride, which presumably forms trifluoroacetyl iodide in situ, epoxides can be converted to olefins. This reaction now has been shown to tolerate remote olefins without loss of their individual stereochemistry. A reaction sequence involving regiospecific epoxidation of an isoprenoid alcohol, conversion of the alcohol to an azide, and cycloaddition with an acetylene, followed by conversion of the epoxide back to the original olefin, has allowed stereocontrolled preparation of triazole bisphosphonates with a farnesyl or a geranylgeranyl substituent. This strategy may be applicable selective protection of an alkene in other polyolefins, including substrates for metathesis reactions.
Project description:The development of a simple, efficient, scalable, and stereocontrolled synthesis of a common intermediate en route to the axinellamines, massadines, and palau'amine is reported. This completely new route was utilized to prepare the axinellamines on a gram scale. In a more general sense, three distinct and enabling methodological advances were made during these studies: (1) an ethylene glycol-assisted Pauson-Khand cycloaddition reaction, (2) a Zn/In-mediated Barbier-type reaction, and (3) a TfNH(2)-assisted chlorination-spirocyclization.
Project description:Whereas complex stereoregular cyclic architectures are commonplace in biomacromolecules, they remain rare in synthetic polymer chemistry, thus limiting the potential to develop synthetic mimics or advanced materials for biomedical applications. Herein we disclose the formation of a stereocontrolled 1,4-linked six-membered cyclopolyether prepared by ring-closing metathesis (RCM). Ru-mediated RCM, with careful control of the catalyst, concentration, and temperature, selectively affords the six-membered-ring cyclopolymer. Under optimized reaction conditions, no metathetical degradation, macrocycle formation, or cross-linking was observed. Post-polymerization modification by dihydroxylation afforded a novel polymer family encompassing a poly(ethylene glycol) backbone and sugar-like functionalities ("PEGose"). This strategy also paves the way for using RCM as an efficient method to synthesize other stereocontrolled cyclopolymers.
Project description:We describe stereocontrolled semi-syntheses of deguelin and tephrosin, anti-cancer rotenoids isolated from Tephrosia vogelii. Firstly, we present a new two-step transformation of rotenone into rot-2'-enonic acid via a zinc-mediated ring opening of rotenone hydrobromide. Secondly, following conversion of rot-2'-enonic acid into deguelin, a chromium-mediated hydroxylation provides tephrosin as a single diastereoisomer. An Étard-like reaction mechanism is proposed to account for the stereochemical outcome. Our syntheses of deguelin and tephrosin are operationally simple, scalable and high yielding, offering considerable advantages over previous methods.
Project description:Here, we explored in detail an acid-catalyzed condensation of glyoxylic acid or its ethyl ester with several carboxamides of different basicity, or with mesyl amide, to furnish diaminoacetic acid derivatives. The most suitable synthesis conditions and the reaction catalysts were identified. Properties such as structure and basicity of the starting amides were demonstrated to influence the condensation process. Elemental iodine was used for the first time herein as an acid catalyst for the condensation of glyoxylic acid or its ester, which gave access to diaminoacetic acid derivatives in higher yields in most cases, as opposed to p-toluenesulfonic acid (PTSA). An abnormally high activity of mesyl amide when condensed with ethyl glyoxylate was noticed, which may evidence a special impact of the sulfonyl moiety in the amide molecule on the condensation.