Purinyl N-directed aroylation of 6-arylpurine ribo- and 2'-deoxyribonucleosides, and mechanistic insights.

The purinyl ring contains four embedded nitrogen atoms of varying basicities. Selective utilization of these ring nitrogen atoms can lead to relatively facile remote functionalization, yielding modified purinyl motifs that are otherwise not easily obtained. Herein, we report previously undescribed N-directed aroylation of 6-arylpurine ribo and the more labile 2'-deoxyribonucleosides. Kinetic isotope analysis as well as reaction with a well-defined dimeric, palladated 9-benzyl 6-arylpurine provided evidence for N-directed cyclometallation as a key step, with a plausible rate-limiting C-H bond cleavage. Radical inhibition experiments indicate the likely intermediacy of aroyl radicals. The chemistry surmounts difficulties often posed in the functionalization of polynitrogenated and polyoxygenated nucleosidic structures that possess complex reactivities and a labile glycosidic bond that is more sensitive in the 2'-deoxy substrates.

Two short approaches to the COVID-19 drug ß-D-N4-hydroxycytidine and its prodrug molnupiravir.

Molnupiravir, the prodrug for ß-D-N4-hydroxycytidine (NHC), is marketed by Merck as Lagevrio™ against mild-moderate COVID-19, under FDA emergency use authorization. It is the first oral drug against the disease. This work describes two synthetic approaches to NHC and molnupiravir by amide activation in uridine with a peptide-coupling agent and with a 4-chloropyrimidinone nucleoside intermediate.

Nitrene C-H Bond Insertion Approach to Carbazolones and Indolones, and a Reactivity Departure for 7-Membered Analogues.

A modular platform for facile access to 1,2,3,9-tetrahydro-4H-carbazol-4-ones (H4 -carbazolones) and 3,4-dihydrocyclopenta[b]indol-1(2H)-ones (H2 -indolones) is described. The requisite 6- and 5-membered 2-arylcycloalkane-1,3-dione precursors were readily obtained through a Cu-catalyzed arylation of 1,3-cyclohexanediones or by a ring expansion of aryl succinoin derivatives. Enolization of one carbonyl group in the diones, conversion to a leaving group, and subsequent azidation gave 2-aryl-3-azidocycloalk-2-en-1-ones. This two-step, one-pot azidation is highly regioselective with unsymmetrically substituted 2-arylcyclohexane-1,3-diones. The regioselectivity, which is important for access to single isomers of 3,3-disubstituted carbazolones, was analyzed mechanistically and computationally. Finally, a Rh-catalyzed nitrene/nitrenoid insertion into the ortho C-H bond of the aryl moiety gave the H4 -carbazolones and H2 -indolones. One carbazolone was elaborated to an intermediate reported in the total synthesis of N-decarbomethoxychanofruticosinate, (-)-aspidospermidine, (+)-kopsihainanine A. With 2-phenylcycloheptane-1,3-dione, prepared from cyclohexanone and benzaldehyde, the azidation reaction was readily accomplished. However, the Rh-catalyzed reaction unexpectedly led to a labile but characterizable azirine rather than the indole derivative. Computations were performed to understand the differences in reactivities of the 5- and 6-membered 2-aryl-3-azidocycloalk-2-en-1-ones in comparison to the 7-membered analogue, and to support the structural assignment of the azirine.

Nucleoside/Nucleotide or Nucleic Acid Modification & Applications.

"The field of nucleosides, nucleotides, and nucleic acids has been in existence for some decades, leading to a notion that the area is well-explored and/or specialized, but is that true? Despite the constant reliance on this field for various aspects of biochemical, biological, and biomedical research, recent advances have brought this area into a greater focus, with the potential and benefits becoming increasingly evident. Explore this Special Collection for rich, diverse, and state-of-the art research presented in the form of Personal Accounts, Reviews, and Research Articles."

Base Modifications of Nucleosides via the Use of Peptide-Coupling Agents, and Beyond.

Several naturally occurring purine and pyrimidine nucleosides contain an amide linkage as part of the heterocyclic aglycone. Enolization of the amide and conversion to leaving groups at the amide carbon atom permits base modification by addition-elimination types of processes. Although a number of methods have been developed over the years for accomplishing such conversions, the present Personal Account describes efforts from the Lakshman laboratories. Facile activation of the amido groups in nucleobases can be achieved with peptide-coupling agents. Subsequent reaction with nucleophiles then accomplishes the base modifications. In many cases, the activation and displacement steps can be done as two-step, one-pot processes, whereas in other cases, discrete storable activated nucleosides can be isolated for subsequent displacement reactions. Using such an approach a wide range of nucleoside base modifications is readily achievable. In many instances, mechanistic investigations have been conducted so as to understand the activation process.

Cross-dehydrogenative coupling of ethers and amides with tautomerizable quinazolinones and mechanistic studies.

Cross-dehydrogenative coupling reactions have been utilized to alkylate 4(3H)-quinazolinones with ethers and amides, using catalytic n-Bu4NI and t-BuOOH as oxidants. The reactions with amides represent the first examples under such conditions. Studies via inter- and intramolecular competitive experiments with protio and deuterio reactants, as well as radical inhibition experiments, provided mechanistic insight. Also, an understanding of the relative reactivities of ethers was obtained by pairwise competitions with 4(3H)-quinazolinone.

Recent developments in the utility of saturated azaheterocycles in peptidomimetics.

To a large extent, the physical and chemical properties of peptidomimetic molecules are dictated by the integrated heterocyclic scaffolds they contain. Heterocyclic moieties are introduced into a majority of peptide-mimicking molecules to modulate conformational flexibility, improve bioavailability, and fine-tune electronics, and in order to achieve potency similar to or better than that of the natural peptide ligand. This mini-review delineates recent developments, limited to the past five years, in the utility of selected saturated 3- to 6-membered heterocyclic moieties in peptidomimetic design. Also discussed is the chemistry involved in the synthesis of the azaheterocyclic scaffolds and the structural implications of the introduction of these azaheterocycles in peptide backbones as well as side chains of the peptide mimics.

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.

General Approach to N6,C5'-Difunctionalization of Adenosine.

Among the C6-halo purine ribonucleosides, the readily accessible 6-chloro derivative has been known to undergo slow SNAr reactions with amines, particularly aryl amines. In this work, we show that in 0.1 M AcOH in EtOH, aryl amines react quite efficiently at the C6-position of 2',3',5'-tri-O-(t-BuMe2Si)-protected 6-chloropurine riboside (6-ClP-riboside), with concomitant cleavage of the 5'-silyl group. These two-step processes proceeded in generally good yields, and notably, reactions in the absence of AcOH were much slower and/or lower yielding. Corresponding reactions of 2',3',5'-tri-O-(t-BuMe2Si)-protected 6-ClP-riboside with alkyl amines proceeded well but without desilylation at the primary hydroxyl terminus. These differences are likely due to the acidities of the ammonium chlorides formed in these reactions, and the role of AcOH was not desilylation but possibly only purine activation. With 50% aqueous TFA in THF at 0 °C, cleavage of the 5'-silyl group from 2',3',5'-tri-O-(t-BuMe2Si)-protected N6-alkyl adenosine derivatives and from 6-ClP-riboside was readily achieved. Reactions of the 5'-deprotected 6-ClP-riboside with alkyl amines proceeded in high yields and under mild conditions. Because these complementary methodologies yielded N6-aryl and -alkyl adenosine derivatives containing a free 5'-hydroxyl group, a variety of product functionalizations were undertaken to yield N6,C5'-doubly modified nucleoside analogues.

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.

Synthesis and Evaluations of "1,4-Triazolyl Combretacoumarins" and Desmethoxy Analogues.

1,4-Triazolyl combretacoumarins have been prepared by linking the trimethoxyarene unit of combretastatin A4 with coumarins, via a 1,2,3-triazole. For this, 4-azidocoumarins were accessed by a sequential two-step, one-pot reaction of 4-hydroxycoumarins with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), followed by reaction with NaN3. In the reaction with BOP, a coumarin-derived phosphonium ion intermediate seems to form, leading to an O 4-(benzotriazolyl)coumarin derivative. For the CuAAC reaction of azidocoumarins with 5-ethynyl-1,2,3-trimethoxybenzene, catalytic [(MeCN)4Cu]PF6 in CH2Cl2/MeOH with 2,6-lutidine, at 50 °C, was suitable. The 4-azidocoumarins were less reactive as compared to PhN3 and the NBO coefficients of the azido groups were compared by DFT analysis. Compound solubility was a problem in biological assays. On the basis of the biological and solubility data of one 1,4-triazolyl combretacoumarin, four analogues lacking one or two methoxy groups were synthesized. Reactivity differences among the phenylacetylenes were noted and the NBO coefficients of the alkynes were compared by DFT analysis. In antiproliferative assays, 1-phenyl-4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole showed activity in CEM and MDA-MB-231 cell lines, possibly by apoptosis. The desmethoxy 6-bromo-4-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-2H-chromen-2-one also showed cytotoxicity against the two cell lines, but this did not appear to be consistent with apoptosis. The antiviral activity of the compounds was unremarkable.

Facile Modifications at the C4 Position of Pyrimidine Nucleosides via In Situ Amide Activation with 1H-Benzotriazol-1-yloxy-tris(dimethyl-amino)phosphonium Hexafluorophosphate.

Two approaches for C4 modifications of silyl-protected thymidine, 2'-deoxyuridine, and 3'-azido-2',3'-dideoxythymidine (AZT) are described. In both, nucleoside amide activation with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and DBU yields O4 -(benzotriazol-1-yl) derivatives. These in situ-formed intermediates are reacted with various nucleophiles, resulting in C4 modifications. In the two-step, one-pot approach, the O4 -(benzotriazol-1-yl) nucleoside intermediates are initially produced by reactions of the nucleosides with BOP and DBU in THF. This step is fast and typically complete within 30 min. Subsequently, the O4 -(benzotriazol-1-yl) derivatives are reacted with nucleophiles, such as aliphatic and aromatic amines, thiols, and alcohols, under appropriate conditions. Workup, isolation, and purification lead to the desired C4-modified pyrimidine nucleosides in good to excellent yields. In the one-step approach, the nucleosides are reacted with BOP and DBU, in the presence of the nucleophile (only aliphatic and aromatic amines, and thiols have been tested). Where comparisons are possible, the one-step approach is generally superior. © 2019 by John Wiley & Sons, Inc.

The Disappearing Director: The Case of Directed N-Arylation via a Removable Hydroxyl Group.

A facile and broadly applicable method for the regiospecific N-arylation of benzotriazoles is reported. Copper-mediated reactions of diverse 1-hydroxy-1H-benzotriazoles with aryl boronic acids lead to 1-aryl-1H-benzotriazole 3-oxides. A N1-OH → N3 prototropy in the 1-hydroxy-1H-benzotriazoles is plausibly the underlying basis, where the tautomer is captured by the boronic acid, leading to C-N (not C-O) bond formation. Because the N-O bond in amine N-oxides and 1-hydroxy-1H-benzotriazoles can be easily reduced by diboron reagents such as (pinB)2 and B2(OH)4, exposure of the 1-aryl-1H-benzotriazole 3-oxides to B2(OH)4 then leads to facile reduction of the N-O bond resulting in diverse, regiospecifically-arylated benzotriazoles. Thus, the N-hydroxyl group in 1-hydroxy-1H-benzotriazoles acts as a disposable arylation director.

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.

Cross-dehydrogenative coupling and oxidative-amination reactions of ethers and alcohols with aromatics and heteroaromatics.

Cross-dehydrogenative coupling (CDC) is a process in which, typically, a C-C bond is formed at the expense of two C-H bonds, either catalyzed by metals or other organic compounds, or via uncatalyzed processes. In this perspective, we present various modes of C-H bond-activation at sp3 centers adjacent to ether oxygen atoms, followed by C-C bond formation with aromatic systems as well as with heteroaromatic systems. C-N bond-formation with NH-containing heteroaromatics, leading to hemiaminal ethers, is also an event that can occur analogously to C-C bond formation, but at the expense of C-H and N-H bonds. A large variety of hemiaminal ether-forming reactions have recently appeared in the literature and this perspective also includes this complementary chemistry. In addition, the participation of C-H bonds in alcohols in such processes is also described. Facile access to a wide range of compounds can be attained through these processes, rendering such reactions useful for synthetic applications via Csp3 bond activations.

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.

Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products.

Reactions of O-t-butyldimethylsilyl-protected thymidine, 2'-deoxyuridine, and 3'-azidothymidine (AZT) with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) leads to activation of the C4 amide carbonyl by formation of putative O4-(benzotriazol-1-yl) derivatives. Subsequent substitution with alkyl and aryl amines, thiols, and alcohols leads to facile functionalization at this position. Reactions with amines and thiols were conducted either as a two-step, one-pot transformation, or as a one-step conversion. Reactions with alcohols were conducted as two-step, one-pot transformations. In the course of these investigations, the formation of 1-(4-pyrimidinyl)-1H-benzotriazole-3-oxide derivatives from the pyrimidine nucleosides was identified. However, these too underwent conversion to the desired products. Products obtained from AZT were converted to the 3'-amino derivatives by catalytic reduction. All products were assayed for their abilities to inhibit cancer cell proliferation and for antiviral activities. Many were seen to be active against HIV-1 and HIV-2, and one was active against herpes simplex virus-1 (HSV-1).

Correction: Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products.

Correction for 'Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products' by Hari K. Akula, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02334g.

Pd-catalyzed versus uncatalyzed, PhI(OAc)2-mediated cyclization reactions of N6-([1,1'-biaryl]-2-yl)adenine nucleosides.

In this work we have assessed reactions of N6-([1,1'-biaryl]-2-yl)adenine nucleosides with Pd(OAc)2 and PhI(OAc)2, via a PdII/PdIV redox cycle. The substrates are readily obtained by Pd/Xantphos-catalyzed reaction of adenine nucleosides with 2-bromo-1,1'-biaryls. In PhMe, the N6-biarylyl nucleosides gave C6-carbazolyl nucleoside analogues by C-N bond formation with the exocyclic N6 nitrogen atom. In the solvent screening for the Pd-catalyzed reactions, an uncatalyzed process was found to be operational. It was observed that the carbazolyl products could also be obtained in the absence of a metal catalyst by reaction with PhI(OAc)2 in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Thus, under Pd catalysis and in HFIP, reactions proceed to provide carbazolyl nucleoside analogues, with some differences. If reactions of N6-biarylyl nucleoside substrates were conducted in MeCN, formation of aryl benzimidazopurinyl nucleoside derivatives was observed in many cases by C-N bond formation with the N1 ring nitrogen atom of the purine (carbazole and benzimidazole isomers are readily separated by chromatography). Whereas PdII/PdIV redox is responsible for carbazole formation under the metal-catalyzed conditions, in HFIP and MeCN radical cations and/or nitrenium ions can be intermediates. An extensive set of radical inhibition experiments was conducted and the data are presented.

Benzimidazopurine nucleosides from N6-aryl adenosine derivatives by PhI(OAc)2-mediated C-N bond formation, no metal needed.

The reaction of a variety of N6-aryl 2'-deoxyadenosine and adenosine derivatives with PhI(OAc)2 in 1,1,1,3,3,3-hexafluoro-2-propanol provides a facile access to benzimidazopurine nucleoside analogues by metal-free C-N bond formation with a purinyl nitrogen atom. These reactions likely proceed via radical-cation/radical processes as indicated by radical inhibition experiments.