Alicyclic ?- and ?-Amino Acids: Useful Scaffolds for the Stereocontrolled Access to Amino Acid-Based Carbocyclic Nucleoside Analogs.
ABSTRACT: Stereocontrolled synthesis of some amino acid-based carbocyclic nucleoside analogs containing ring C=C bond has been performed on ?- and ?-lactam basis. Key steps were N-arylation of readily available ?- or ?-lactam-derived amino ester isomers and amino alcohols with 5-amino-4,6-dichloropyrimidine; ring closure of the formed adduct with HC(OMe)? and nucleophilic displacement of chlorine with various N-nucleophiles in the resulting 6-chloropurine moiety.
Project description:The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described. The key precursor, (3aS,4R,6R,6aR)-6-((methoxy-methoxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (5), was prepared from the commercially available compound, (1R,4S)-2-azabicyclo[2.2.1] hept-5-en-3-one (4). Our initial approach used intermediate 6, derived in three transformations from 5, for the key photolytic step to produce the desired ring-opened precursor to the target compound. This photochemical transformation was unsuccessful. However, an appropriately protected and related precursor was synthesized from 5 through the following side-chain functional group transformations: elaboration of the amino group through malonyl ester formation, oximation at the central carbon, conversion of ester to amide and catalytic reduction of the oxime group. This precursor, on treatment with triethylorthoformate and catalytic acetic acid in ethanol, underwent cyclization to produce the desired 4-carbamoyl-imidazolium-5-olate ring. Deprotection of the latter product proceeded smoothly to give the carbocyclic analog of bredinin. This target molecule exhibits antiviral activity, albeit low, against a number of RNA viruses. Further biological evaluations are in progress.
Project description:[reaction: see text] A fast and efficient synthetic route to novel Northern locked carbocyclic nucleosides (as precursors of carbocyclic locked nucleic acids or cLNAs) is described. The target nucleoside with a oxabicyclo[2.2.1]heptane ring system was prepared from a simple starting material, diethyl malonate. Ring closure by intramolecular O-alkylation provided the target ring system as the major isomer over the [3.2.0] oxetane system. The adenine moiety was introduced through a reactive triflate after inversion of the stereochemistry of the corresponding alcohol by oxidation and reduction.
Project description:A stereocontrolled synthesis of ?-amino-?'-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed cross-coupling of amino acid thiol esters and chiral nonracemic ?-alkoxyalkylstannanes gives ?-amino-?'-alkoxy ketones in good to excellent yields with complete retention of configuration at the ?-amino- and ?-alkoxy-substituted stereocenters.
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: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:The analogous imino-variant of the Nazarov reaction suffers from unfavorable energetics associated with the ring closure process, thereby limiting the utility of this class of reactions. In this report, the realization of the first intermolecular interrupted imino-Nazarov reaction utilizing silylated pyrimidine derivatives as nucleophilic trapping partners culminated in an expedient synthetic route to carbocyclic nucleoside analogues. The potential application of silylated nucleobases to intercept the oxyallyl cation in other variants of the Nazarov reaction provides vast opportunities to develop new strategies for the formation of carbocyclic nucleoside analogues.
Project description:In addition to the already known differences between adenosine deaminase (ADA) and cytidine deaminase (CDA) in terms of their tertiary structure, the sphere of Zn(+2) coordination, and their reverse stereochemical preference, we present evidence that the enzymes also differ significantly in terms of the North/South conformational preferences for their substrates and the extent to which the lack of the O(4') oxygen affects the kinetics of the enzymatic deamination of carbocyclic substrates. The carbocyclic nucleoside substrates used in this study have either a flexible cyclopentane ring or a rigid bicyclo[3.1.0]hexane scaffold.
Project description:Cytidine deaminase (CDA) catalyzes the deamination of cytidine via a hydrated transition-state intermediate that results from the nucleophilic attack of zinc-bound water at the active site. Nucleoside analogues where the leaving NH(3) group is replaced by a proton and prevent conversion of the transition state to product are very potent inhibitors of the enzyme. However, stable carbocyclic versions of these analogues are less effective as the role of the ribose in facilitating formation of hydrated species is abolished. The discovery that a 1,3-diazepinone riboside (4) operated as a tight-binding inhibitor of CDA independent of hydration provided the opportunity to study novel inhibitors built as conformationally locked, carbocyclic 1,3-diazepinone nucleosides to determine the enzyme's conformational preference for a specific form of sugar pucker. This work describes the synthesis of two target bicyclo[3.1.0]hexane nucleosides, locked as north (5) and south (6) conformers, as well as a flexible analogue (7) built with a cyclopentane ring. The seven-membered 1,3-diazepinone ring in all the three targets was built from the corresponding benzoyl-protected carbocyclic bis-allyl ureas by ring-closing metathesis. The results demonstrate CDA's binding preference for a south sugar pucker in agreement with the high-resolution crystal structures of other CDA inhibitors bound at the active site.
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: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.