Diversely C8-functionalized adenine nucleosides via their underexplored carboxaldehydes.

The potentially versatile N-unprotected 8-formyl derivatives of adenosine and 2'-deoxyadenosine are highly underexploited for C8 modifications of these nucleosides. Only in situ formation of 8-formyladenosine is known and a single application of an N-benzoyl derivative has been reported. On the other hand, 8-formyl-2'-deoxyadenosine and its applications remain unknown. Herein, we report straightforward, scalable syntheses of both N-unprotected 8-formyladenine nucleoside derivatives, and demonstrate broad diversification at the C8 position by hydroxymethylation, azidation, CuAAC ligation, reductive amination, as well as olefination and fluoroolefination with modified Julia and a Horner-Wadsworth-Emmons reagents.

Catalytic Reductions Without External Hydrogen Gas: Broad Scope Hydrogenations with Tetrahydroxydiboron and a Tertiary Amine.

Facile reduction of aryl halides with a combination of 5% Pd/C, B2(OH)4, and 4-methylmorpholine is reported. Aryl bromides, iodides, and chlorides were efficiently reduced. Aryl dihalides containing two different halogen atoms underwent selective reduction: I over Br and Cl, and Br over Cl. Beyond these, aryl triflates were efficiently reduced. This combination was broadly general, effectuating reductions of benzylic halides and ethers, alkenes, alkynes, aldehydes, and azides, as well as for N-Cbz deprotection. A cyano group was unaffected, but a nitro group and a ketone underwent reduction to a low extent. When B2(OD)4 was used for aryl halide reduction, a significant amount of deuteriation occurred. However, H atom incorporation competed and increased in slower reactions. 4-Methylmorpholine was identified as a possible source of H atoms in this, but a combination of only 4-methylmorpholine and Pd/C did not result in reduction. Hydrogen gas has been observed to form with this reagent combination. Experiments aimed at understanding the chemistry led to the proposal of a plausible mechanism and to the identification of N,N-bis(methyl-d 3)pyridine-4-amine (DMAP-d 6) and B2(OD)4 as an effective combination for full aromatic deuteriation.

When nucleoside chemistry met hypervalent iodine reagents.

There has been increasing use of hypervalent iodine reagents in the field of nucleoside chemistry. Applications span: (a) synthesis of nucleoside analogues with sulfur and seleno sugar surrogates, (b) synthesis of unusual carbocyclic and ether ring-containing nucleosides, (c) introduction of sulfur and selenium into pyrimidine bases of nucleosides and analogues, (d) synthesis of isoxazole and isoxazoline ring-containing nucleoside analogues, (e) involvement of purine ring nitrogen atoms for remote C-H bond oxidation, and (f) metal-catalyzed and uncatalyzed synthesis of benzimidazolyl purine nucleoside analogues by intramolecular C-N bond formation. This review offers a perspective on developments involving the use of hypervalent iodine reagents in the field of nucleoside chemistry that have appeared in the literature in the 2003-2017 time frame.

Generating Stereodiversity: Diastereoselective Fluorination and Highly Diastereoselective Epimerization of α-Amino Acid Building Blocks.

Diastereoselective fluorination of N-Boc ( R)- and ( S)-2,2-dimethyl-4-((arylsulfonyl)methyl)oxazolidines and a previously unknown diastereoselective epimerization at the fluorine-bearing carbon atom α to the sulfone was realized. Diastereoselectivities of both reactions were excellent for benzothiazolyl sulfones, allowing access to two enantiomerically pure diastereomers from one chiral precursor. To demonstrate synthetic utility, the benzothiazolyl sulfones were converted to diastereomerically pure ( S, S)- and ( R, S)-benzyl sulfones via sulfinate salts and to amino acids. To understand the diastereoselectivities, DFT analysis was performed.

KHF2, a mild and selective desilylating agent for phenol t-butyldimethylsilyl (TBDMS) ethers.

TBDMS (t-BuMe2Si, t-butyldimethylsilyl) ethers of a variety of phenols have been deprotected with KHF2 in MeOH, at room temperature. Carboxylic ester and labile phenolic acetate were unaffected under these conditions. In competition reactions between TBDMS ethers of a phenol and two primary benzylic alcohols, the phenolic ether underwent cleavage whereas the alcohol ethers remained intact. From a substrate containing both a phenolic hydroxyl group and a secondary, doubly benzylic hydroxyl group protected as TBDMS ethers, the phenol was rapidly and selectively released. Cleavage of TBDMS, TBDPS, and TIPS ethers of a phenol was also compared. TBDMS and TBDPS ethers underwent cleavage at room temperature within 30 min, whereas removal of the TIPS ether required 2.5 hours. Ease of cleavage appears to be TBDMS ≈ TBDPS > TIPS. At 60 °C, TBDMS ethers of primary benzylic, allylic, and unactivated alcohols can be efficiently desilylated over a prolonged period (13-17 h). Thus, KHF2 proves to be a mild and effective reagent for the selective desilylation of phenol TBDMS ethers at room temperature.

Regiospecifically Fluorinated Polycyclic Aromatic Hydrocarbons via Julia-Kocienski Olefination and Oxidative Photocyclization. Effect of Fluorine Atom Substitution on Molecular Shape.

A modular synthesis of regiospecifically fluorinated polycyclic aromatic hydrocarbons (PAHs) is described. 1,2-Diarylfluoroalkenes, synthesized via Julia-Kocienski olefination (70-99% yields), were converted to isomeric 5- and 6-fluorobenzo[c]phenanthrene, 5-and 6-fluorochrysene, and 9- and 10-benzo[g]chrysene (66-83% yields) by oxidative photocyclization. Photocyclization to 6-fluorochrysene proceeded more slowly than conversion of 1-styrylnaphthalene to chrysene. Higher fluoroalkene dilution led to a more rapid cyclization. Therefore, photocyclizations were performed at higher dilutions. To evaluate the effect of fluorine atom on molecular shapes, X-ray data for 5- and 6-fluorobenzo[c]phenanthrene, 6-fluorochrysene, 9- and 10-fluorobenzo[g]chrysene, and unfluorinated chrysene as well as benzo[g]chrysene were obtained and compared. The fluorine atom caused a small deviation from planarity in the chrysene series and decreased nonplanarity in the benzo[c]phenanthrene derivatives, but its influence was most pronounced in the benzo[g]chrysene series. A remarkable flattening of the molecule was observed in 9-fluorobenzo[g]chrysene, where the short 2.055 Å interatomic distance between bay-region F-9 and H-8, downfield shift of H-8, and a 26.1 Hz coupling between F-9 and C-8 indicate a possible F-9···H-8 hydrogen bond. In addition, in 9-fluorobenzo[g]chrysene, the stacking distance is short at 3.365 Å and there is an additional interaction between the C-11-H and C-10a of a nearby molecule that is almost perpendicular.

E- or Z-Selective synthesis of 4-fluorovinyl-1,2,3-triazoles with fluorinated second-generation Julia-Kocienski reagents.

A highly modular approach to N-substituted 4-(1-fluorovinyl)triazoles is described. In situ desilylation and Cu-catalyzed ligation reaction of TMS-protected α-fluoropropargyl benzothiazole sulfone with aryl, alkyl, and metallocenyl azides furnished second-generation Julia-Kocienski reagents in good to excellent yields. Condensation reactions of these reagents with aldehydes can be tuned to yield E or Z-alkenes selectively. Under mild conditions with DBU as the base, reactions of aldehydes furnished E-alkenes as the major isomer. On the other hand, in condensation reactions with LHMDS as the base and in appropriate solvents, both aldehydes and ketones reacted to yield fluoroalkenes with Z-selectivity. Stereochemical assignment of E/Z olefins obtained in the reaction of a ketone with two Julia reagents was performed via X-ray crystallographic analysis and comparisons of NMR data. The method allows efficient and ready diversification of the N1-substituent and substituents at the double bond.

Synthesis of regiospecifically fluorinated conjugated dienamides.

Modular synthesis of regiospecifically fluorinated 2,4-diene Weinreb amides, with defined stereochemistry at both double bonds, was achieved via two sequential Julia-Kocienski olefinations. In the first step, a Z-a-fluorovinyl Weinreb amide unit with a benzothiazolylsulfanyl substituent at the allylic position was assembled. This was achieved via condensation of two primary building blocks, namely 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylacetamide (a Julia-Kocienski olefination reagent) and 2-(benzo[d]thiazol-2-ylthio)acetaldehyde (a bifunctional building block). This condensation was highly Z-selective and proceeded in a good 76% yield. Oxidation of benzothiazolylsulfanyl moiety furnished a second-generation Julia-Kocienski olefination reagent, which was used for the introduction of the second olefinic linkage via DBU-mediated condensations with aldehydes, to give (2Z,4E/Z)-dienamides in 50%-74% yield. Although olefinations were 4Z-selective, (2Z,4E/Z)-2-fluoro-2,4-dienamides could be readily isomerized to the corresponding 5-substituted (2Z,4E)-2-fluoro-N-methoxy-N-methylpenta-2,4-dienamides in the presence of catalytic iodine.

Modular synthesis of N-vinyl benzotriazoles.

A modular approach to N1-vinyl benzotriazoles by azide-aryne cycloadditions and Julia-Kocienski reactions is described. Reactions of azidomethyl phenyl-1H-tetrazol-5-yl (PT) sulfide with arynes gave methyl(PT-sulfanyl)-substituted benzotriazoles in 68-89% yields. Oxidation of the sulfides to the sulfones gave the benzotriazole-substituted Julia-Kocienski reagents. Olefination reactions of aldehydes and a ketone with reagents derived from benzyne, 2,3-naphthyne, and 4,5-dimethoxybenzyne precursors proceeded to give various N1-vinyl benzotriazole derivatives. Olefination stereoselectivities are tunable for electron-rich aldehydes, but not for electron-deficient aldehydes and alkanals, where they proceed with good to excellent Z-stereoselectivity.

Julia-Kocienski Approach to Trifluoromethyl-Substituted Alkenes1.

A Julia-Kocienski approach to trifluoromethyl-substituted alkenes was evaluated in the reactions of 1,3-benzothiazol-2-yl, 1-phenyl-1H-tetrazol-5-yl, and 1-tbutyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfones with aldehydes. Among the various conditions tested, the best yields were obtained with 1-phenyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfone, in CsF-mediated, room temperature olefinations in DMSO. Aromatic aldehydes gave (trifluoromethyl)vinyl derivatives in 23-86% yields, with generally moderate stereoselectivity. Straightforward synthesis of the Julia-Kocienski reagent, and conversion to trifluoromethyl-substituted alkenes under mild reaction conditions, are the advantages of this approach.

Stereoselective synthesis of conjugated fluoro enynes.

Metalation-electrophilic fluorination of TMS- and TIPS-protected 1,3-benzothiazol-2-yl (BT) propargyl sulfones gave corresponding BT fluoropropargyl sulfones, Julia-Kocienski reagents for the synthesis of fluoro enynes. Both reagents reacted with aldehydes under mild DBU- or LHMDS-mediated conditions, giving high yields of conjugated fluoro enynes with E-stereoselectivity. In comparison to DBU-mediated reactions, stereoselectivity was higher in low-temperature LHMDS-mediated reactions. Two ketones were shown to react as well, using LHMDS as base. In situ removal of the TMS group gave terminal conjugated 2-fluoro 1,3-enynes. Synthetic utility of the fluoro enynes was demonstrated by conversion to internal alkynes and to stereoisomeric fluoro dienes via Sonogashira and Heck couplings.

Expedient synthesis of α-substituted fluoroethenes.

A mild and efficient synthesis of 1-aryl-1-fluoroethenes from benzothiazolyl (aryl)fluoromethyl sulfones and paraformaldehyde, under DBU- or Cs(2)CO(3)-mediated conditions at room temperature, is described. A comparable diethyl fluoro(naphthalen-2-yl)methylphosphonate reagent does not react with paraformaldehyde under these mild conditions. The utility of the methodology for synthesis of terminal α-fluoroalkenes bearing electron-withdrawing functionalities is also shown.

Facile synthesis of 4-vinyl- and 4-fluorovinyl-1,2,3-triazoles via bifunctional "click-olefination" reagents.

Modular synthesis of vinyl and fluorovinyl triazoles can be achieved from bifunctional propargyl and fluoropropargyl sulfones by Cu-catalyzed azide-alkyne ligation and Julia-Kocienski olefination. Competitive click reactions of the protio and fluoropropargyl sulfones show higher reactivity of the latter, and a preliminary DFT analysis was performed.

Synthesis of Fluoroolefins via Julia-Kocienski Olefination.

The Julia-Kocienski olefination provides a versatile platform for the synthesis of fluorovinyl compounds. This review describes our efforts as well as those of others in the synthesis of various fluorinated aryl and heteroaryl sulfones and their utility as olefination reagents for the modular assembly of fluoroalkenes. Where data is available, the influence of the fluorine atom on the reactivity of the olefination reagents and the stereochemical outcome of the olefination are described.

Fluorinated 1-phenyl-1H-tetrazol-5-yl sulfone derivatives as general reagents for fluoroalkylidene synthesis.

Julia-Kocienski olefination reagents 1-fluoropropyl, (cyclopropyl)fluoromethyl, 1-fluoro-2-methyl-2-propenyl, and 1-fluoro-5-hexenyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfones were prepared by metalation followed by electrophilic fluorination. Although metalation-fluorination of n-propyl, 5-hexenyl, and (cyclopropyl)methyl PT-sulfones proceeded under homogeneous conditions, fluorination of 2-methyl-2-propenyl PT-sulfone required heterogeneous fluorination conditions. Condensation reactions of fluoro PT-sulfones with aldehydes resulted in fluoroalkylidenes in high yields. Screening of olefination conditions showed that stereoselectivity depended on reagent and carbonyl structure and can in many cases be tuned either toward E- or Z-selectivity. For example, LHMDS-mediated condensations of 1-fluoropropyl PT-sulfone in the presence of MgBr(2) x OEt(2) were Z-selective with electron-rich aromatic aldehydes, a hindered aromatic aldehyde, and cinnamaldehyde. Low-temperature KHMDS-mediated condensations were E-selective with electron-rich and electron-deficient aromatic aldehydes and Z-selective with n-octanal. Dialkyl, aryl alkyl, and diaryl ketones reacted as well to give fluoro olefin products in 71-99% yields.

Alpha-fluorovinyl Weinreb amides and alpha-fluoroenones from a common fluorinated building block.

Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic ketones to give alpha-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E- or Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are > or = 98% Z-stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents, namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU, these compounds react with aldehydes tested to give alpha-fluoroenones with high Z-selectivity. The use of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermediate in the synthesis of alpha-fluorovinyl Weinreb amides and alpha-fluoroenones has been demonstrated. Application of the Weinreb amide to alpha-fluoro allyl amine synthesis is also shown.

Fluoro-Julia olefination as a mild, high-yielding route to alpha-fluoro acrylonitriles.

Synthesis of a novel, stable reagent (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile from readily synthesized ethyl alpha-(1,3-benzothiazol-2-ylsulfanyl)-alpha-fluoroacetate is reported. Aldehydes undergo condensations with (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile in the presence of DBU leading to alpha-fluoro acrylonitriles in high yields and with good Z-stereoselectivity. Lowering of reaction temperature increases the Z selectivity.

Julia Olefination as a General Route to Phenyl (alpha-Fluoro)vinyl Sulfones.

Mild and efficient synthesis of phenyl (alpha-fluoro)vinyl sulfones via condensation of aldehydes and a ketone with a novel benzothiazolyl based bis-sulfone reagent is reported and this proceeds with moderate to good Z-stereoselectivity.

Direct synthesis of 8-fluoro purine nucleosides via metalation-fluorination.

A straightforward access to protected 8-fluoro nucleosides via metalation-electrophilic fluorination under heterogeneous reaction conditions is reported. This is the first synthesis of 8-fluoro-2'-deoxyribonucleoside derivatives. Phenylsulfonyl substituted nucleosides are accompanying byproducts, possibly indicating a competing radical process. Higher yields of 8-fluoro derivatives were obtained with 2'-deoxyribonucleosides, as compared to ribonucleosides. Deprotection of the hydroxyl groups leading to 8-fluoro-2'-deoxyadenosine using TASF in methylene chloride demonstrates the compatibility of desilylation with 8-fluoro substituted nucleosides. NMR data indicate a syn conformation of the 8-fluoro derivatives.