A new synthesis of Tyrian purple (6,6’-dibromoindigo) and its corresponding sulfonate salts

• Holly Helmers,
• Mark Horton,
• Julie Concepcion,
• Jeffrey Bjorklund and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2026, 22, 167–174, doi:10.3762/bjoc.22.10

• Scheme 5A, dimethyl sulfoxide (DMSO) did not react with the benzyl bromide and instead only returned the starting material. The addition of 1.2 equivalents of silver nitrate promoted the substitution of the benzyl bromide with DMSO to yield an alkoxysulfonium ion 8 [22]. Following substitution, the

• addition of 1.2 equivalents of triethylamine mediated the formation of 4 in moderate yield, as shown in Scheme 5B (57% isolated, 67% based on NMR). The crude product was sufficiently pure (84 wt % by quantitative NMR) to carry on without purification, but further purification was possible by

Circumventing Mukaiyama oxidation: selective S–O bond formation via sulfenamide–alcohol coupling

• Guoling Huang,
• Huarui Zhu,
• Shuting Zhou,
• Wanlin Zheng,
• Fangpeng Liang,
• Zhibo Zhao,
• Yifei Chen and
• Xunbo Lu

Beilstein J. Org. Chem. 2026, 22, 158–166, doi:10.3762/bjoc.22.9

• group compatibility. The reaction was further applicable to naphthyl sulfenamides, as demonstrated by the successful conversion of a 2-naphthyl derivative to 3p in 70% yield. In addition, alkyl sulfenamides derived from thiols, including cyclohexyl (3q) and linear alkyl chains (3r), gave the desired

• and 2-phenylethanol, were well tolerated. These substrates afforded the corresponding sulfinimidate esters 3m’–q’ in 70–90% yields. In addition to linear alcohols, cycloalkyl-substituted primary alcohols such as cyclobutylmethanol and cyclopentylmethanol were also examined. These small-ring systems

• , the sulfenamide-based oxidative coupling proceeded smoothly, delivering sulfilimidate ester 4 in 53% yield. In addition, the transformation was applied to a chiral secondary alcohol, ʟ-menthol, to generate the sulfilimidate ester 5 in 67% yield. A diastereomeric analysis revealed a modest dr of 1.6:1

Asymmetric Mannich reaction of aromatic imines with malonates in the presence of multifunctional catalysts

• Kadri Kriis,
• Harry Martõnov,
• Annette Miller,
• Mia Peterson,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2026, 22, 151–157, doi:10.3762/bjoc.22.8

• with the steric effect of the tert-butyl group of the catalyst, is responsible for the high stereoselectivity of the reaction. Keywords: aromatic imine; asymmetric catalysis; Mannich reaction; noncovalent interactions; organocatalysis; Introduction The Mannich reaction, i.e., the addition of an

• malonate. It is known that N-atoms are the strongest XB acceptors in electroneutral compounds [26]. It has also been shown that imines protected with heteroarylsulfonyl groups provide higher enantioselectivity than those protected with the more commonly used phenylsulfonyl or tosyl groups in addition

Design and synthesis of an axially chiral platinum(II) complex and its CPL properties in PMMA matrix

• Daiki Tauchi,
• Sota Ogura,
• Misa Sakura,
• Kazunori Tsubaki and
• Masashi Hasegawa

Beilstein J. Org. Chem. 2026, 22, 143–150, doi:10.3762/bjoc.22.7

• %. Synthesis of S/R-3 Under an argon atmosphere. S-2 (197 mg, 0.389 mmol) in tetrahydrofuran (1.7 mL) was treated with a dropwise addition of 1 M TBAF solution (16.7 mL, 16.7mmol), and the resulting solution was stirred at room temperature for 2 hours. After the addition of water, the mixture was extracted

Symmetrical D–π–A–π–D indanone dyes: a new design for nonlinear optics and cyanide detection

• Ergin Keleş,
• Alberto Barsella,
• Nurgül Seferoğlu,
• Zeynel Seferoğlu and
• Burcu Aydıner

Beilstein J. Org. Chem. 2026, 22, 131–142, doi:10.3762/bjoc.22.6

• theory (DFT) methods. The dyes also exhibit chemosensor properties, showing selectivity for cyanide via a Michael addition mechanism that causes the disappearance of the ICT band, and a significant color change was observed in both organic and aqueous media. In addition, the interaction mechanism between

• ). The vinyl bridges were added to the design, which have the potential to open nucleophilic addition reactions (Michael type) due to their electron deficiencies, in addition to acting as π-bridges for the D–A conjugation. Furthermore, a symmetric design with increased π-conjugation was planned to shift

• under ambient light. In addition, interaction mechanisms of dyes with cyanide were studied using the 1H NMR titration method, and it was determined that they interacted through an addition mechanism. Photophysical properties and interaction mechanisms of the compounds were also supported through density

Highly electrophilic, gem- and spiro-activated trichloromethylnitrocyclopropanes: synthesis and structure

• Ilia A. Pilipenko,
• Mikhail V. Grigoriev,
• Olga Yu. Ozerova,
• Igor A. Litvinov,
• Darya V. Spiridonova,
• Aleksander V. Vasilyev and
• Sergey V. Makarenko

Beilstein J. Org. Chem. 2026, 22, 123–130, doi:10.3762/bjoc.22.5

• –C2H protons of the cyclopropane ring (3JH(1)H(2) = 5.7–7.5 Hz) indicate their transoid arrangement [38][39][45]. This makes it possible to assign 1SR,2RS configurations to the stereocenters. The proposed mechanism for this transformation is depicted in Scheme 6. Michael addition of the CH-acid anion I

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• -art systems depend on expensive transition metals such as platinum, ruthenium, or palladium, inflating the cost of large-scale applications. In addition, precious-metal catalysts often display poor selectivity, while heteroatoms in heteroarenes – acting as Lewis bases – tend to coordinate to the metal

• systems. In addition, converting a planar sp2-hybridized-atoms-enriched framework into three-dimensional sp3-hybridized-atoms-enriched architectures inherently generates new stereocenters, making stereocontrol essential in asymmetric variants. As highlighted in the methods below, recent advances in

• of axially chiral cyclic compounds with high enantioselectivity could be synthesized. In addition, the authors also obtained central chiral cyclic compounds by asymmetric hydrogenation of phenanthrene with directing groups. In 2022 and 2024, Chirik and co-workers reported the use of molybdenum as a

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• intramolecular addition to the olefin, affording the cyclized acetal product 4. The reaction proceeded efficiently across a range of substrates bearing various substituents at R¹–R⁴, delivering the desired cyclized products 4a–f in good yields. The proposed mechanism is illustrated in Scheme 1C. Initially

• transmetallation with a NiII complex generated by oxidative addition of the thioester to Ni0. Finally, reductive elimination from NiII furnishes the ketone. Given the strong Zr–S bond (BDE = 137 kcal/mol) [12], zirconocene is thought to play a key role in facilitating the oxidative addition of Ni0 to the thioester

• its subsequent radical addition to 2-methylene-1,3-dithiane (14) proceeded, affording radical intermediate 15. This radical intermediate rapidly underwent homodimerization to give vic-bis(dithiane) 16. The reaction could be applied to both tertiary and secondary alkyl halides, providing the

Reactivity umpolung of the cycloheptatriene core in hexa(methoxycarbonyl)cycloheptatriene

• Dmitry N. Platonov,
• Alexander Yu. Belyy,
• Rinat F. Salikov,
• Kirill S. Erokhin and
• Yury V. Tomilov

Beilstein J. Org. Chem. 2026, 22, 64–70, doi:10.3762/bjoc.22.2

• further transformation in the case of allylation. Reactions with diazonium salts mainly involve a vicinal addition of the reagent to the anion and subsequent 1,5-sigmatropic shift, 6π-electrocyclization, and azocyclopropane rearrangement into dihydroindazole derivatives. Analysis of the reaction

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• Vertex Pharmaceuticals describes the synthesis of alkenyl chloride 21 on a 360 and 580 mmol scale (Scheme 6A) [51]. The addition of a few drops of DMF was not commented. Surprisingly a significant decrease in yield was observed at the larger 580 mmol scale compared to the 360 mmol scale. Scott reported a

• is generated in situ and likely present only in trace amounts. All our attempts to accelerate the reaction through addition of various mono- and bidentate phosphorus ligands were unsuccessful. A similar trend was observed with NEt3, which afforded optimal yields at 20–30 mol % loading (not shown

• unable to efficiently separate 61 from side product 94, which was likely formed via addition of acetyl chloride to 61 followed by conversion of the ketone to the alkenyl chloride. Regarding the mechanism (Scheme 18B), acid-catalyzed enolization of the ketone is proposed (enol I), followed by acetylation

One-pot synthesis of ethylmaltol from maltol

• Immanuel Plangger,
• Marcel Jenny,
• Gregor Plangger and
• Thomas Magauer

Beilstein J. Org. Chem. 2025, 21, 2755–2760, doi:10.3762/bjoc.21.212

• through fermentation, or a synthetic intermediate derived thereof is being utilized. For example, the 1969 Pfizer patent describes the oxidation of kojic acid (3) with molecular oxygen to comenic acid, which is then decarboxylated to yield pyromeconic acid. An aldol addition with acetaldehyde followed by

• reduction of the newly introduced secondary hydroxy group affords ethylmaltol (1) in four steps overall [1][4]. Different modifications of this approach have been developed, including performing the aldol addition before decarboxylation [5] or using different feedstock chemicals such as furfuryl alcohol

• procedure, maltol (2) was deprotonated with sodium hydride followed by treatment with TBSCl to in situ obtain silyl ether 8e, which was subsequently deprotonated with LiHMDS and C-methylated with methyl iodide at 0 °C. Addition of aqueous hydrochloric acid enabled silyl deprotection to ethylmaltol (1) in 52

Sustainable electrochemical synthesis of aliphatic nitro-NNO-azoxy compounds employing ammonium dinitramide and their in vitro evaluation as potential nitric oxide donors and fungicides

• Alexander S. Budnikov,
• Nikita E. Leonov,
• Michael S. Klenov,
• Andrey A. Kulikov,
• Igor B. Krylov,
• Timofey A. Kudryashev,
• Aleksandr M. Churakov,
• Alexander O. Terent’ev and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2025, 21, 2739–2754, doi:10.3762/bjoc.21.211

• approaches focus mainly on intramolecular radical cyclizations [42][54][55][56][57][58][59][60][61][62][63], while intermolecular [1][64][65][66][67][68] N–N coupling remains a poorly studied area. In addition to the preparation of azo compounds [69][70], intermolecular N–N coupling reactions are of

• very important, as it overcomes one of the major obstacles to the sustainability and scalability of organic electrosynthesis: the need for a supporting electrolyte in addition to reactants. The synthesized nitro-NNO-azoxy arenes were discovered as a novel class of fungicides, with in vitro activity

• our study [87], ADN exhibits two irreversible oxidation peaks (red curve) at +1.8 V and +2.1 V, which are higher than or comparable to those of S2–S4 (Figure 2). Upon the addition of ADN to a solution of 1a (Figure 2, green curve), a single oxidation peak was observed at +1.89 V. Finally, the reaction

Competitive cyclization of ethyl trifluoroacetoacetate and methyl ketones with 1,3-diamino-2-propanol into hydrogenated oxazolo- and pyrimido-condensed pyridones

• Svetlana O. Kushch,
• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess,
• Pavel A. Slepukhin,
• Alexandrina S. Volobueva,
• Vladimir V. Zarubaev and
• Victor I. Saloutin

Beilstein J. Org. Chem. 2025, 21, 2716–2729, doi:10.3762/bjoc.21.209

• ethylenediamine [27] as well as with 2-(aminomethyl)aniline and 1,3-diaminopropane [28]. In addition, we have found another route for the three-component cyclization of 3-polyfluoroalkyl-3-oxo esters with α-methylene ketones involving mono- and dialkylamines, leading to 5-polyfluoroalkylaminocyclohexen-2-ones [29

• fragment of the neighboring molecule also participate in the pattern of 4att crystal packing. In addition, in the cis-configuration of the pseudo-axially located NH and OH groups in the structures 4acc, 4act and 4dct, a strong intramolecular N–H···O hydrogen bond is observed. The crystal packing of

• compound ribavirin (Table 5, entry 2). In addition, this entire series of compounds is distinguished by the absence of cytotoxicity towards MDCK cells. Conclusion To sum up, we have, for the first time, demonstrated the possibility of 1,3-diaminopropan-2-ol being involved in cyclization as an ambident N,N

Mechanistic insights into hydroxy(tosyloxy)iodobenzene-mediated ditosyloxylation of chalcones: a DFT study

• Jai Parkash,
• Sangeeta Saini,
• Vaishali Saini,
• Omkar Bains and
• Raj Kamal

Beilstein J. Org. Chem. 2025, 21, 2703–2715, doi:10.3762/bjoc.21.208

• -ditosyloxy ketones. It is found that the mechanism for the formation of α,β-ditosyloxy ketone involves only electrophilic addition of HTIB, and the mechanism is the same for all studied chalcones, irrespective of whether an electron-donating or electron-withdrawing substituent is present on the aryl ring

• . However, the detailed mechanism for the formation of β,β-ditosyloxy ketones is different and depends on the nature of the substituent. Broadly, the formation of β,β-ditosyloxy ketones involves electrophilic addition followed by 1,2-aryl migration. Our study shows that the presence of an electron-donating

• results for the two pathways are compared to draw the inferences. The main focus of the current study is to understand the addition mechanism and the migratory aptitude of the aryl ring (present at β-position of reactant – chalcone) depending on the nature of the substituent present at para-position. The

Tandem hydrothiocyanation/cyclization of CF₃-iminopropargyl alcohols with NaSCN in the presence of AcOH

• Ruslan S. Shulgin,
• Ol’ga G. Volostnykh,
• Anton V. Stepanov,
• Igor’ A. Ushakov,
• Alexander V. Vashchenko and
• Olesya A. Shemyakina

Beilstein J. Org. Chem. 2025, 21, 2694–2702, doi:10.3762/bjoc.21.207

• ) in reaction with the NaSCN/AcOH system failed to afford the corresponding isothiazolium salts 2f,g, and dihydrofurans 3f,g were isolated as the only products (Table 2, entries 5 and 6). In addition, the reaction mixture underwent strong resinification, as primary and secondary propargyl alcohols

• thiocyanic acid at the triple bond – vinylthiocyanate A (Scheme 2). Isothiazolium thiocyanate 2 is formed by the attack of the imino nitrogen atom on the sulfur atom and the elimination of the CN anion in the Z-isomer of intermediate A. On the other hand, intramolecular addition of the hydroxy group to the

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

• 3-position, a copper-mediated C–H activation of position 12 and subsequent protection of the introduced hydroxy moiety to give compound 25 (Scheme 6). Installation of the lactone moiety in 22 was carried out in a three-step sequence via a 1,2-addition of organocerium reagent 26 to the ketone

• rearrangement was carried out with trifluoromethanesulfonic anhydride leading to a mixture of regioisomers 23 and 27, with 23 being convertible to 27 by addition of DBU. The A–E-rings have, thus, been installed with correct stereoconfiguration, therefore the last steps of the sequence focused on the

• alkylation was diasteroselective. In the next steps, addition of isopropenyllithium to the lactone moiety led to a hemiketal, which was then opened and a protecting group on the hydroxy group was installed, furnishing fragment 42. Key convergent coupling of this total synthesis was performed by lithium

Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• absorption and metabolism, and specific moieties like rhamnose can enhance CG potency markedly by more than 25 times [1][7]. In addition, the -OH groups on the steroids’ structure also play an important role on their activity. However, these compounds are mainly isolated from plants or animals, which not

• [19]. In addition, rhodexin A exhibits a strong antiproliferation activity due to the ability to inhibit the synthesis of hypoxia inducible factor 1 (HIF-1α) [20]. Thus, rhodexin A shows high value in medicinal research. Structurally, rhodexin A consists of two parts, the cardenolide aglycon

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• ) [63]. Glacial acetic acid (AcOH) was initially selected as a hydrophilic (polar) protic solvent due to its high dipole moment, which makes it ideal for microwave reactions, as well as its ability to facilitate simple work-up procedures by simple addition of water [64]. Using sodium acetate (NaOAc) as

• an additive resulted in low reaction yields of the desired product 3a (Table 1, entries 1 and 2). The addition of an aliphatic amine (piperidine) to the reaction medium significantly improved the yields (Table 1, entries 3 and 4). In the absence of NaOAc, only a slight decrease in yield was observed

• condensation reactions involving rhodanine derivatives (26 examples). In addition, it requires a lower catalyst loading (10 mol %) and eliminates the need for further purification steps. EDDA has also been employed in reactions for the synthesis of heterocyclic compounds such as tetrahydroquinolines [67

Silica gel with covalently attached bambusuril macrocycle for dicyanoaurate sorption from water

• Michaela Šusterová and
• Vladimír Šindelář

Beilstein J. Org. Chem. 2025, 21, 2604–2611, doi:10.3762/bjoc.21.201

• 1 M KOH, followed by addition of dicyanoaurate ([Au(CN)2]−) to the supernatant. It was shown previously that the absorption spectrum of dicyanoaurate in aqueous solution changes upon formation of an inclusion complex between the anion and a bambusuril macrocycle [17]. A solution of dicyanoaurate in

• is only physically adsorbed on SG. However, upon addition of chloride anions, either as tetrabutylammonium (TBA) or sodium salt, BnBU formed a complex with the anion and dissolved in chloroform and dichloromethane and even in methanol. Thus, SG-BnBU remained stable only in water in the absence and

• presence of salt showing it is suitable for applications in an aqueous environment. SG-BU1 proved to be stable in chloroform, dichloromethane, and methanol even after addition of TBACl or NaCl, respectively. We did not detect any release of BU1 from SG-BU1 in aqueous phosphate buffer by NMR, but we

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• system involves the efficient nucleophilic addition of an imidazolyl anion B to radical cation species A, generated via single-electron oxidation of electron-donating arenes 31. The azolide anion B is released from acylimidazole 9 through an addition/elimination sequence in the presence of an NHC

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• enantioenriched compound 33, a nickel-catalyzed hydrocyanation of the terminal alkyne was performed. Subsequent protection of the tertiary alcohol with TESOTf and reduction of the resulting cyanide to an aldehyde afforded compound 34 (Scheme 4). Addition of isopropenyllithium to aldehyde 34, followed by TES

• , deprotonation, and intramolecular addition to ketone. Treatment of the silacycle with MeMgCl cleaved the Si–O bond and subsequent intramolecular nucleophilic substitution of the chloride with the adjacent hydroxy group yielded TMS-epoxide 41. Protonic acid-mediated opening of the TMS-epoxide, accompanied by TES

• -mediated N–O bond cleavage afforded carbamate 90. The carbamate was converted to a carbonyl group via Boc deprotection with TFA, oxidation of the resulting amine to the oxime with Na2WO4 and H2O2, and subsequent reduction with TiCl3·HCl to give 91. The LaCl3·2LiCl-mediated methyl addition to the carbonyl

Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• -alkoxy bridgehead radical addition then installed an allyl fragment, and ring-closing metathesis (RCM) smoothly formed the C ring to complete the core skeleton. The total synthesis was finalized by installing the four remaining stereocenters (C2, C3, C9, and C10). The specific synthetic route is as

• hemiacetalization to construct the oxa[3.2.1]-bridged ring system, thereby forming the D and E rings. Subsequently, the introduction of a tertiary hydroxy thiocarbonate at C11 afforded compound 38. Under thermal conditions, 38 underwent smooth introduction of an allyl fragment via intermolecular radical addition

• route commenced from (−)-pulegone. After introducing oxidation states at C6 and C10 and installing an alkynyl group at C11, oxidative cleavage of a double bond yielded the key propargylic alcohol intermediate 66. This compound underwent a 1,2-addition with alkynyl Grignard reagent 67, and the resulting

Ni-promoted reductive cyclization cascade enables a total synthesis of (+)-aglacin B

• Si-Chen Yao,
• Jing-Si Cao,
• Jian Xiao,
• Ya-Wen Wang and
• Yu Peng

Beilstein J. Org. Chem. 2025, 21, 2548–2552, doi:10.3762/bjoc.21.197

• Abstract The total synthesis of bioactive (+)-aglacin B was achieved. The key steps include an asymmetric conjugate addition reaction induced by a chiral auxiliary and a nickel-promoted reductive tandem cyclization of the elaborated β-bromo acetal, which led to the efficient construction of the

• aryltetralin[2,3-c]furan skeleton embedded in this natural product. Keywords: aryltetralin; conjugate addition; cyclolignan; nickel; reductive coupling; Introduction Proksch and co-workers isolated aglacins A, B, C, and E (1–4, Figure 1) from the methanolic extract of stem bark of Aglaia cordata Hiern from

• that the diarylmethine stereocenter at C7′ in 6 could be formed by an Evans’ auxiliary-induced asymmetric conjugate addition of α,β-unsaturated acyl oxazolidinone 7 with 3,4,5-trimethoxyphenylmagnesium bromide (8). Both of these two building blocks could be conveniently prepared from commercially

Pentacyclic aromatic heterocycles from Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles

• Kaylen D. Lathrum,
• Emily M. Hanneken,
• Katelyn R. Grzelak and
• James T. Fletcher

Beilstein J. Org. Chem. 2025, 21, 2524–2534, doi:10.3762/bjoc.21.194

• ring itself to also include benzophenanthridine, dibenzonaphthyridine, and benzophenanthroline heterocycles of previously unreported identity (Figure 2). In addition to studying how naphthalene, quinolone, and isoquinoline incorporation impact click and annulation efficiency, characterizing the

Isoorotamide-based peptide nucleic acid nucleobases with extended linkers aimed at distal base recognition of adenosine in double helical RNA

• Grant D. Walby,
• Brandon R. Tessier,
• Tristan L. Mabee,
• Jennah M. Hoke,
• Hallie M. Bleam,
• Angelina Giglio-Tos,
• Emily E. Harding,
• Vladislavs Baskevics,
• Martins Katkevics,
• Eriks Rozners and
• James A. MacKay

Beilstein J. Org. Chem. 2025, 21, 2513–2523, doi:10.3762/bjoc.21.193

• addition of the acyl chloride to excess 9 was important to avoid forming bis-acylation of the phenylenediamine. The carboxylic acid 13 was formed using a microwave-promoted ring opening of glutaric anhydride (11) and benzyl-protected PNA backbone 12 [38]. A series of optimizations was performed in a

• . Db3 Synthesis The synthesis of Db3 was originally envisioned to be completed with an unprotected aniline nitrogen, however, this proved problematic in the PNA synthesis. The ultimate route was developed to have an N-Boc protected monomer (Scheme 3). The synthesis started with a conjugate addition of m