From Oxygen to Sulfur and Back: Difluoro -H-phosphinothioates as a Turning Point in the Preparation of Difluorinated Phosphinates: Application to the Synthesis of Modified Dinucleotides.

A simple, two-step procedure to convert α,α-difluorinated H-phosphinic acids into the corresponding H-phosphinothioates is described. The usefulness of these species is demonstrated by their transformation into difluorinated phosphinothioyl radicals and their addition onto alkenes. Additionally, sequential treatment of H-phosphinothioates by a strong base and a primary alkyl iodide constitutes an alternate route to the formation of the C-P bond. Both methods efficiently deliver difluorinated phosphinothioates. Similar reactions carried out with the fully oxygenated counterparts clearly indicate the superiority of the sulfur-based species and emphasize the crucial role played by sulfur in the construction of the second C-P bond. Oxidation easily transforms the thereby obtained phosphinothioates into the corresponding phosphinates. The whole strategy is applied to the stereoselective preparation of dinucleotide analogues featuring either a difluorophosphinothioyl or a difluorophosphinyl unit linking the two furanosyl rings.

Addition of 4-(cyclohex-1-en-1-yl)morpholine on 3-nitroindole: an unprecedented dearomatizing process.

Nucleophilic enamines add spontaneously on heteroarenes 3-nitroindole and benzofuran to form a new C-C bond. With nitroindole and enamine , an unprecedented dearomatizing formal ene reaction occurs in a totally regio- and diastereo-selective manner. With 3-nitrobenzofuran and enamine , the reaction course is different and leads to the generation of a dienylphenol.

Aromatic C=C bonds as dipolarophiles: facile reactions of uncomplexed electron-deficient benzene derivatives and other aromatic rings with a non-stabilized azomethine ylide.

Non-stabilized azomethine ylide 4a reacts smoothly at room temperature with a variety of uncomplexed aromatic heterocycles and carbocycles on the condition that the ring contains at least one or two electron-withdrawing substituents, respectively. Aromatic substrates, including pyridine and benzene derivatives, participate as 2π components in [3+2] cycloaddition reactions and interact with one, two, or three equivalent(s) of the ylide, depending on their structure and substitution pattern. Thus, this process affords highly functionalized polycyclic structures that contain between one and three pyrrolidinyl ring(s) in useful yields. These results indicate that the site selectivity of the cycloaddition reactions strongly depends on both the nature and the positions of the substituents. In most cases, the second 1,3-dipolar reaction occurs on the opposite face to the one that contains the first pyrrolidinyl ring. DFT calculations on model compounds indicate that a concerted mechanism features a low activation barrier.

Benzofurans as efficient dienophiles in normal electron demand [4 + 2] cycloadditions.

Dearomatization of electron-poor benzofurans is possible through involvement of the aromatic 2,3-carbon-carbon double bond as dienophile in normal electron demand [4 + 2] cycloadditions. The tricyclic heterocycles thereby produced bear a quaternary center at the cis ring junction, a feature of many alkaloids such as morphine, galanthamine, or lunaridine. The products arising from the reaction have been shown to depend on different factors among which the type of the electron-withdrawing substituent of the benzofuran, the nature of the reacting diene, and the method of activation. In the presence of all-carbon dienes, the reaction yields the expected Diels-Alder adducts. When thermal activation is insufficient, a biactivation associating zinc chloride catalysis and high pressure is required to generate the cycloadducts in good yields and high stereoselectivities, for instance, when cyclohexadiene is involved in the process. The use of more functionalized dienes, such as those bearing alkoxy or silyloxy substituents, also shows the limits of the thermal activation, and hyperbaric conditions are, in this case, well-suited. The involvement of Danishefsky's diene induces a competition in the site of reactivity. The aromatic 2,3-carbon-carbon double bond is unambiguously the most reactive dienophile, and the 3-carbonyl unit becomes a competitive site of reactivity with benzofurans bearing substituents prone to heterocyloaddition, in particular under Lewis acid activation. The sequential involvement of both the aromatic double bond and the carbonyl moiety as dienophiles is then possible by using an excess of diene under high-pressure activation. In line with the experimental results, DFT computations suggest that the Diels-Alder process involving the aromatic double bond is preferred over the hetero-Diels-Alder route through an asynchronous concerted transition state. However, Lewis acid catalysis appears to favor the heterocycloaddition pathway through a stepwise mechanism in some cases.

Multicomponent domino [4+2]/[3+2] cycloadditions of nitroheteroaromatics: an efficient synthesis of fused nitrogenated polycycles.

Activation by high pressure allows 3-nitroindole and 3-nitropyrrole derivatives to behave as electron-poor heterodienes in multicomponent domino [4+2]/[3+2] cycloaddition processes. The primary [4+2] inverse demand cycloaddition appears to be completely endo selective, while the subsequent [3+2] process shows a total facial selectivity, setting the stereochemistry at ring junction, and an endo/exo selectivity depending on the nature of the heterocycle. In two operations, a polycyclic diamine featuring a quaternary center at ring junction is efficiently generated.

Sulfonyl vs. carbonyl group: which is the more electron-withdrawing?

Unexpectedly high reactivity of nitrogenated aromatics protected as amides or carbamates, when compared to sulfonamides, can be explained by a decrease of the aromaticity due to a greater ability of the carbon-centered groups to achieve delocalisation of the nitrogen lone pair, resulting in stronger global withdrawing effects.

1-Triflylpyrroles as efficient dienophiles in normal electron demand [4+2] cycloaddition reactions under pressure.

1-Triflylpyrroles bearing acetyl group(s) on position 3, or 2 and 4, are efficient dienophiles in normal electron demand Diels-Alder reactions activated by high pressures and Lewis acids.

The preparation of new phosphorus-centered functional groups for modified oligonucleotides and other natural phosphates.

Efforts to develop synthetic methodologies allowing the preparation of alpha,alpha- difluorophosphonothioates, alpha,alpha-difluorophosphonodithioates, alpha,alpha-difluorophosphono- trithioates, and alpha,alpha-difluorophosphinates are reviewed in the light of applications in the field of modified oligonucleotides and cyclitol phosphates. Two successful approaches have been developed, based either on the addition of phosphorus-centered radicals onto gem-difluoroalkenes or on a process involving the addition of lithiodifluorophosphono- thioates 91 onto a ketone and the subsequent deoxygenation reaction of the adduct. The radical route successfully developed a practical route to alpha,alpha-difluoro-H-phosphinates which proved to be useful intermediates to a variety of phosphate isosters. The ionic route led to the first preparation of phosphonodifluoromethyl analogues of nucleoside- 3'-phosphates.

Efficient synthesis of 3-furanosyl-6'-furanosylphosphinate through a tandem sequential radical process.

The sodium salt of hypophosphorous acid is shown to act as a double radical precursor in a double, sequential radical addition on 3-exo-methylenefuranose derivative 14 and 4-ethylenefuranose 10 to furnish phosphinates 18d in good overall yields. Unambiguous structural assignment establishes the high diastereoselection of the process.

Cross-Diels-Alder reactions of 6-oxo-1-sulfonyl-1,6-dihydropyridine-3-carboxylates.

Electron-poor 6-oxo-1-sulfonyl-1,6-dihydropyridine-3-carboxylates 1b-d undergo cross-Diels-Alder reactions with electron-rich dienes 4a-f under hyperbaric conditions, reacting either as dienophiles to yield normal-electron-demand (NED) cycloadducts 10 and/or 11 or as dienes to give inverse-electron-demand (IED) cycloadducts 12 and/or 13. The latter are converted into 14 and/or 15 through an NED cycloaddition with a second equivalent of electron-rich diene. Acyclic dienes display a propensity to yield NED products, whereas cyclic dienes tend to favor IED cycloadducts. High-pressure activation compares favorably with thermal or microwave activation in terms of both yields and suppression of the transformation of 1 into unreactive pyridines 3. Whereas the Cope rearrangement from IED to NED occurs under thermal conditions, no evidence of its involvement under high pressure could be detected. These and other data point to similar activation energies for the NED and IED processes under these conditions.

Phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals. Generation and addition onto alkenes and alkynes.

[reaction: see text] Selanylated difluoromethylphosphonates and difluoromethylphosphonothioates are good precursors to phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals, respectively. When generated in the presence of alkenes and a hydrogen donor, the corresponding alpha,alpha-difluorinated alkylphosphonates or alkylphosphonothioates are produced in fair to good yields. The use of alkynes results in the formation of alpha,alpha-difluorinated allyl derivatives in useful yields. The presence of the sulfur atom in phosphonothiodifluoromethyl radicals usually translates into higher isolated yields.

Nucleotides and nucleic acids: a source of inspiration for the development of new, phosphorus-centered functional groups.

Synthetic methodologies aiming at the creation of new phosphorus-centered functional groups are reported, as well as applications to the field of nucleotide chemistry. Thus, difluorophosphonothioate-based, ionic reagents 3b and 3d are shown to allow the stereocontrolled and efficient synthesis of phosphonodifluoromethyl analogues of nucleoside-3'-phosphates. An alternate, radical approach describes the use of hypophosphorous acid to stereoselectively link two furanosyl units in positions 3 and 5, and to provide an access to alpha,alpha-difluoro-H-phosphinates. These intermediates are shown to be precursors to the corresponding fluorinated phosphonic acids, phosphonothioic acids and variously substituted phosphinates.

Development of cross-linked polystyrene-supported chiral amines featuring a fluorinated linker for gel-phase 19F NMR spectrometry monitoring of reactions.

Ten cross-linked polystyrene-supported, protected chiral amines featuring both a spacer, comprising from 5 to 15 atoms, and a fluorinated linker have been successfully prepared. The development of the monitoring technique by gel-phase 19F NMR spectrometry on cross-linked polystyrene derivatives proved to be of high value in four steps of the process, as shown by the comparison of data gathered from both a classic NMR spectrometer and elemental analysis. Gel-phase 19F NMR spectrometry, thus, constitutes a useful technique that complements IR and 13C NMR spectrometries for the qualitative monitoring of reactions. In addition, quantitative determination of the conversion in a given transformation is possible, provided that 19F chemical shifts of the substrate and the product be different enough (Deltadelta>base width), as illustrated by the Mitsunobu coupling process (16-->17). The technique is nondestructive, and the samples used to monitor the reactions may be returned to the reaction medium. Deprotection of the above amines was achieved and furnished eight of the final resins in good to acceptable purity for future applications.

Inhibition of human immunodeficiency virus type 1 reverse transcriptase, RNase H, and integrase activities by hydroxytropolones.

Human immunodeficiency virus type I reverse transcriptase (RT) possesses distinct DNA polymerase and RNase H sites, whereas integrase (IN) uses the same active site to perform 3'-end processing and strand transfer of the proviral DNA. These four enzymatic activities are essential for viral replication and require metal ions. Two Mg2+ ions are present in the RT polymerase site, and one or two Mg2+ ions are required for the catalytic activities of RNase H and IN. We tested the possibility of inhibition of the RT polymerase and RNase H as well as the IN 3'-end processing and transfer activities of purified enzymes by a series of 3,7-dihydroxytropolones designed to target two Mg2+ ions separated by approximately 3.7 angstroms. The RT polymerase and IN 3' processing and strand transfer activities were inhibited at submicromolar concentrations, while the RNase H activity was inhibited in the low micromolar range. In all cases, the lack of inhibition by tropolones and O-methylated 3,7-dihydroxytropolones was consistent with the active molecules binding the metal ions in the active site. In addition, inhibition of the DNA polymerase activity was shown to depend on the Mg2+ concentration. Furthermore, selective inhibitors were identified for several of the activities tested, leaving some potential for design of improved inhibitors. However, all tested compounds exhibited cellular toxicity that presently limits their applications.

First and efficient synthesis of phosphonodifluoromethylene analogues of nucleoside 3'-phosphates: crucial role played by sulfur in construction of the target molecules.

Phosphoric esters of secondary alcohols are ubiquitous in biological systems. However, despite the obvious interest of the corresponding difluoromethylene phosphonates as isopolar mimics, a single example of such an analogue featuring this particular substitution pattern has so far been reported in the literature, due to synthetic problems associated with their preparation. The lithium salt of diethyl difluoromethylphosphonothioate 28d provides a solution to this problem, as demonstrated by an 8-step synthesis of all five fully protected analogues of nucleoside 3'-phosphates in 9-18% overall yield, from readily available ketones. Sulfur is shown to play a crucial role in the introduction of the phosphorus-substituted difluoromethylene unit onto the furanose ring. Complete diastereoselectivity is observed in the three steps of the process requiring stereocontrol. The key conversion of the P=S bond into its oxygenated analogue is simply achieved by use of m-chloroperoxybenzoic acid. It is noteworthy that the synthesis can be carried out on large scale: a 31-g batch of compound 26b has been prepared. The deprotected nucleoside 3'-phosphate analogues can be liberated from their precursors as exemplified by the conversion of 7b, 8b, and 9b into the corresponding difluorophosphonic acids, isolated in the form of their disodium salts.

Phosphonyl, phosphonothioyl, phosphonodithioyl, and phosphonotrithioyl radicals: generation and study of their addition onto alkenes.

The treatment of benzyl dialkyl phosphites and dithiophosphites with benzeneselanyl chloride generates an Arbuzov-type transformation leading to the dialkyl selenophosphates 19a and 19b and to selenophosphorodithioates 21a and 21b. Interaction of these substrates with Lawesson's reagent yields the corresponding selenophosphorothioates 20a and 20b and the selenophosphorotrithioates 22a and 22b. When treated with a radical initiator in the presence of a hydrogen donor and an alkene, all eight phosphorus(V) precursors undergo homolytic cleavage of the P-Se bond to generate the phosphonyl, phosphonothioyl, phosphonodithioyl, or phosphonotrithioyl radicals. Most of these are shown to add onto electron-rich and electron-poor alkenes to deliver the expected adducts in fair to excellent yields. Cyclic precursor 19b displays peculiar behavior and, under the reaction conditions, produces only the corresponding cyclic phosphite. Application of this radical chain process is carried out on furanosyl 3-exo-methylene derivative 37 to diastereoselectively furnish five new 3-phosphonomethyl-, 3-phosphonothiomethyl-, and 3-phosphonodithiomethyl-3-deoxofuranoses 38a-c and 38f,g. The possibility of conducting tandem processes is also discussed through experiments involving (1R)-(+)-alpha-pinene (39) and diallylamine 41.

Complete and remarkable reversal of chemoselectivity in [4 + 2] cycloadditions involving electron-poor indoles as dienophiles. Diels-Alder versus hetero-Diels-Alder processes.

The reaction between indole-3-carboxaldehyde 1a or indole-3-glyoxalate 1b and 2,3-dimethylbutadiene under thermal activation leads exclusively to the Diels-Alder cycloadducts resulting from the participation of the indole 2,3-carbon-carbon double bond. The concomitant use of zinc chloride and high pressure (16 kbar) induces the primary cycloadduct to react further, and biscycloadducts 11 and 12 are now isolated in high yields, the result of two consecutive [4 + 2] processes on, first, the indole 2,3 C=C bond and, second, the 3-carbonyl unit. The possibility of using two different dienes in a tandem, sequential process is demonstrated by the preparation of tetracycle 13. Interactions between the carbonyl dienophile and Danishefsky diene yield exclusively yet another type of product, namely the gamma-dihydropyranones arising from the sequential [4 + 2] heterocycloaddition, hydrolysis of the silyl enol ether, and loss of methanol. Isolation of the Mukaiyama-type adduct 16 indicates that a stepwise mechanism may be involved, at least under zinc chloride catalysis. N,N-Disubstituted indole-3-glyoxamides undergo the expected, usual Diels-Alder process, with the 2,3 C=C bond acting as dienophile, and cycloadducts of the type 3 are obtained in high yields, regardless of the mode of activation. Remarkably, however, N-monosubstituted indole-3-glyoxamides react almost exclusively as heterodienophiles, the 3-carbonyl unit being now the preferred site of reactivity, and gamma-dihydropyranones of the type 6 are isolated in yields ranging from 72 to 92%. Conformational analysis of the Diels-Alder adducts based on both (1)H NMR spectrometry and X-ray diffraction data indicates that the newly created cyclohexene and cyclohexanone rings adopt a pseudoboat conformation.