Synthesis of Conformationally North-Locked Pyrimidine Nucleosides Built on an Oxabicyclo[3.1.0]hexane Scaffold

Beginning with a known 3-oxabicyclo[3.1.0]­hexane scaffold (I), the relocation of the fused cyclopropane ring bond and the shifting of the oxygen atom to an alternative location engendered a new 2-oxabicyclo[3.1.0]­hexane template (II) that mimics more closely the tetrahydrofuran ring of conventional nucleosides. The synthesis of this new class of locked nucleosides involved a novel approach that required the isocyanate II (B = NCO) with a hydroxyl-protected scaffold as a pivotal intermediate that was obtained in 11 steps from a known dihydrofuran precursor. The completion of the nucleobases was successfully achieved by quenching the isocyanate with the lithium salts of the corresponding acrylic amides that led to the uracil and thymidine precursors in a single step. Ring closure of these intermediates led to the target, locked nucleosides. The anti-HIV activity of <b>29</b> (uridine analogue), <b>31</b> (thymidine analogue), and <b>34</b> (cytidine analogue) was explored in human osteosarcoma (HOS) cells or modified HOS cells (HOS-313) expressing the herpes simplex virus 1 thymidine kinase (HSV-1 TK). Only the cytidine analogue showed moderate activity in HOS-313 cells, which means that the compounds are not good substrates for the cellular kinases

The Conformationally Constrained <i>N</i>-Methanocarba-dT Analogue Adopts an Unexpected C4′-<i>exo</i> Sugar Pucker in the Structure of a DNA Hairpin

Incorporation of a bicyclo[3.1.0]­hexane scaffold into the nucleoside sugar was devised to lock the embedded cyclopentane ring in conformations that mimic the furanose North and South sugar puckers. To analyze the effects of North-methanocarba-2′-deoxythymidine (N-MCdT) on the B-form DNA, we crystallized d­(CGCGAA­[mcTmcT]­CGCG) with two N-MCdTs. Instead of a duplex, the 12mer forms a tetraloop hairpin, whereby loop N-MCdTs adopt the C4′-exo pucker (NE; P = 50°). Thus, the bicyclic framework does not limit the pucker to the anticipated C2′-exo range (NNW; P = −18°)

Synthesis of Conformationally Locked l-Deoxythreosyl Phosphonate Nucleosides Built on a Bicyclo[3.1.0]hexane Template

Two conformationally locked versions of l-deoxythreosyl phosphonate nucleosides (2 and 3) were synthesized to investigate the preference of HIV reverse transcriptase for a conformation displaying either a fully diaxial or fully diequatorial disposition of substituents. Synthesis of the enantiomeric 4-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-2-ol carbocyclic nucleoside precursors (diaxially disposed) proceeded straightforwardly from commercially available (1R,4S)-4-hydroxy-2-cyclopent-2-enyl-1-yl acetate employing a hydroxyl-directed Simmons−Smith cyclopropanation that culminated with a Mitsunobu coupling of the purine base. For the more complicated 1-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-3-ol carbocyclic nucleoside precursors (diequatorially disposed), the obligatory linear approach required the syntheses of key 1-aminobicyclo[3.1.0.]hexan-3-yl benzoate precursors that were assembled via the amide variant of the Kulinkovich reaction involving the intramolecular cyclopropanation of a substituted δ-vinylamide. Completion of the purine ring was achieved by conventional approaches but with much improved yields through the use of a microwave reactor. The syntheses of the phosphonates and the corresponding diphosphates were achieved by conventional means. None of the diphosphates, which were supposed to act as nucleoside triphosphate mimics, could compete with dATP even when present in a 10-fold excess

Synthesis of Conformationally Locked l-Deoxythreosyl Phosphonate Nucleosides Built on a Bicyclo[3.1.0]hexane Template

Two conformationally locked versions of l-deoxythreosyl phosphonate nucleosides (2 and 3) were synthesized to investigate the preference of HIV reverse transcriptase for a conformation displaying either a fully diaxial or fully diequatorial disposition of substituents. Synthesis of the enantiomeric 4-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-2-ol carbocyclic nucleoside precursors (diaxially disposed) proceeded straightforwardly from commercially available (1R,4S)-4-hydroxy-2-cyclopent-2-enyl-1-yl acetate employing a hydroxyl-directed Simmons−Smith cyclopropanation that culminated with a Mitsunobu coupling of the purine base. For the more complicated 1-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-3-ol carbocyclic nucleoside precursors (diequatorially disposed), the obligatory linear approach required the syntheses of key 1-aminobicyclo[3.1.0.]hexan-3-yl benzoate precursors that were assembled via the amide variant of the Kulinkovich reaction involving the intramolecular cyclopropanation of a substituted δ-vinylamide. Completion of the purine ring was achieved by conventional approaches but with much improved yields through the use of a microwave reactor. The syntheses of the phosphonates and the corresponding diphosphates were achieved by conventional means. None of the diphosphates, which were supposed to act as nucleoside triphosphate mimics, could compete with dATP even when present in a 10-fold excess

Synthesis of Conformationally Locked l-Deoxythreosyl Phosphonate Nucleosides Built on a Bicyclo[3.1.0]hexane Template

Two conformationally locked versions of l-deoxythreosyl phosphonate nucleosides (2 and 3) were synthesized to investigate the preference of HIV reverse transcriptase for a conformation displaying either a fully diaxial or fully diequatorial disposition of substituents. Synthesis of the enantiomeric 4-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-2-ol carbocyclic nucleoside precursors (diaxially disposed) proceeded straightforwardly from commercially available (1R,4S)-4-hydroxy-2-cyclopent-2-enyl-1-yl acetate employing a hydroxyl-directed Simmons−Smith cyclopropanation that culminated with a Mitsunobu coupling of the purine base. For the more complicated 1-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-3-ol carbocyclic nucleoside precursors (diequatorially disposed), the obligatory linear approach required the syntheses of key 1-aminobicyclo[3.1.0.]hexan-3-yl benzoate precursors that were assembled via the amide variant of the Kulinkovich reaction involving the intramolecular cyclopropanation of a substituted δ-vinylamide. Completion of the purine ring was achieved by conventional approaches but with much improved yields through the use of a microwave reactor. The syntheses of the phosphonates and the corresponding diphosphates were achieved by conventional means. None of the diphosphates, which were supposed to act as nucleoside triphosphate mimics, could compete with dATP even when present in a 10-fold excess

Synthesis of a Conformationally Locked Version of Puromycin Amino Nucleoside

A conformationally locked carbocyclic version of puromycin amino nucleoside was synthesized via Mitsunobu coupling of a 3-azido-substituted carbocyclic moiety with 6-chloropurine without interference from the azido group reacting with triphenylphosphine. The requisite 3-azido-substituted carbocyclic pseudosugar was prepared by a double inversion of configuration at C3‘ (nucleoside numbering) involving a nucleophilic displacement with azide

Synthesis of Enantiomerically Pure (<i>S</i>)-Methanocarbaribo Uracil Nucleoside Derivatives for Use as Antiviral Agents and P2Y Receptor Ligands

We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]hexane system. d-Ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5′-hydroxymethyl group. An ester group appended to a tertiary carbon (C1) was transformed to an amino group as a nucleobase precursor

Conformationally Constrained Analogues of Diacylglycerol. 30. An Investigation of Diacylglycerol-lactones Containing Heteroaryl Groups Reveals Compounds with High Selectivity for Ras Guanyl Nucleotide-Releasing Proteins

Using a diacylglycerol-lactone (DAG-lactone) template previously developed in our laboratory as a scaffold with high binding affinity for C1 domains, we describe herein a series of novel DAG-lactones containing heterocyclic moieties (pyridines, quinolines, and indoles) as α-arylidene fragments. Some of the DAG-lactones obtained show selective binding to RasGRP3 as compared to PKCα by more than 2 orders of magnitude and possess subnanomolar affinities. Because activated C1 domains bound to their ligands (DAG or DAG-lactones) insert into membranes, the lipid composition of membranes (cellular, nuclear, and those of internal organelles) is an important determinant for specificity. Therefore, reaching a proper hydrophilic/lipophilic balance for these molecules is critical. This was achieved by carefully selecting partnering acyl fragments for the DAG-lactones with the appropriate lipophilicity. The results clearly show that the combination of chemical and physical properties in these molecules needs to be perfectly balanced to achieve the desired specificity

Synthesis of Bicyclo[3.1.0]hexanes Functionalized at the Tip of the Cyclopropane Ring. Application to the Synthesis of Carbocyclic Nucleosides

A general synthetic strategy for the preparation of functionalized bicyclo[3.1.0]hexanes is described. The new approach employs a cross metathesis step designed to functionalize the appropriate terminal olefin of the bicyclo[3.1.0]hexane precursor and a carbene-mediated intramolecular cyclopropanation reaction on the corresponding diazo intermediate. This combined methodology allowed the diastereoselective introduction of chemically diverse substituents at the tip of the cyclopropane group, except in cases where the substituents consisted of electron-withdrawing groups where a competing [3 + 2] cycloaddition predominated

Synthesis of Bicyclo[3.1.0]hexanes Functionalized at the Tip of the Cyclopropane Ring. Application to the Synthesis of Carbocyclic Nucleosides

A general synthetic strategy for the preparation of functionalized bicyclo[3.1.0]hexanes is described. The new approach employs a cross metathesis step designed to functionalize the appropriate terminal olefin of the bicyclo[3.1.0]hexane precursor and a carbene-mediated intramolecular cyclopropanation reaction on the corresponding diazo intermediate. This combined methodology allowed the diastereoselective introduction of chemically diverse substituents at the tip of the cyclopropane group, except in cases where the substituents consisted of electron-withdrawing groups where a competing [3 + 2] cycloaddition predominated