Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• cyclization modes that provide entries to various N-heterocycles, some of which serve as key structural motifs in natural alkaloids. This review highlights recent advancements in enamide-based cyclization reactions, including enamide–alkyne cycloisomerization, [3 + 2] annulation, and polycyclization, with a

• particular emphasis on their pivotal role as a strategy in the total synthesis of natural products. Keywords: alkaloid; cyclization; enamide; natural product; total synthesis; Introduction The use of enamines as surrogates for enols in nucleophilic reactions has been well-documented for decades since their

• enamides contain an N-acyl group in place of the original alkyl group. The electron-withdrawing effect of the amide group delocalizes the nitrogen lone pair, thereby reducing the electron density and nucleophilicity of the enamide double bond. These features significantly diminish the reactivity of

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• were tolerated, while a dioxazolone containing bromobenzene displayed lower reactivity (26c). The enamide 26d, derived from lobatamide, was successfully produced without altering the stereochemistry of the oxime ether. Terminal alkynes with linear alkyl group, protected alcohol, and sulfonamide

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• the final step of the reaction, ring opening by the C–C bond cleavage yields the desired product 203. The first phosphoric acid C39-catalyzed asymmetric cycloaddition–elimination cascade reaction of 2-naphthol or phenol enamide derivatives 204 with azonaphthalenes 205 was done by Xu et al. in 2021

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• and pivalamide 7j were formed in trace quantities whereas the benzyl derivative 7k was isolable. The enamide 7l was not observed. Intriguingly, cyclopropyl and cyclohexyl derivatives 7m and 7n, respectively, were formed and isolated in moderate yields. Furyl derivative 7o was isolated in 63% yield

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• a simple enol ether was reactive in the transformation, we attempted to use glucal 1l but no conversion was observed. Enamide 1m could be azido-alkynylated in low yield and the product was inseparable from impurities. When dehydroalanine 1n was used in the reaction no product was formed and only

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• , the authors proposed that (R)-TRIP-Li has the capability to engage enamide 51 through H-bonding and NHPI ester 3 through Li-promoted Lewis acid activation, acting as a pocket that facilitates the formation of charge-transfer complex 52 (Scheme 11B). This complex can be excited either by direct

• irradiation at 390 nm or through RuII-mediated EnT under blue light irradiation (456 nm). Following excitation, SET from the enamide to the active ester forms intermediate 53, which undergoes fragmentation and radical recombination to afford intermediate 54. At this stage, the indole nucleophile substitutes

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• the final targets. With regard to the mechanism, it is hypothesized that it commences with the formation of a nitrogen-centered radical. The carbon radical 139 is then formed after the aforementioned nitrogen radical attacks the enamide group. The α-amide positioning is theorized to improve

Ligand-dependent stereoselective Suzuki–Miyaura cross-coupling reactions of β-enamido triflates

• Tomáš Chvojka,
• Athanasios Markos,
• Svatava Voltrová,
• Radek Pohl and
• Petr Beier

Beilstein J. Org. Chem. 2021, 17, 2657–2662, doi:10.3762/bjoc.17.179

• Information File 1). Subsequently the optimized conditions for preferential formation of 3 were used in the scope study and in all cases, isomeric products 3 formed preferentially (Scheme 2). The highest selectivity in favor to enamide 3 was noted in the Suzuki coupling of vinyl triflate 1d bearing a 2

• first step, vinyl triflate undergoes oxidative addition to give complex 4, which subsequently transmetalates with arylboronic acid to form palladium complex 5. In the case of Pd(PPh3)4, reductive elimination occurs to give enamide 2. However, using catalysts with very bulky ligands, such as Pd(dppf)Cl2

• causes the tautomerization of complex 5 [30] to zwitterionic carbene 6 which can now isomerize through the C–C bond rotation to the thermodynamically more stable palladium complex 7, followed by reductive elimination to enamide 3. A possible isomerization of enamides 2 or 3 in the presence of a catalyst

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

A complementary approach to conjugated N-acyliminium formation through photoredox-catalyzed intermolecular radical addition to allenamides and allencarbamates

• Olusesan K. Koleoso,
• Matthew Turner,
• Felix Plasser and
• Marc C. Kimber

Beilstein J. Org. Chem. 2020, 16, 1983–1990, doi:10.3762/bjoc.16.165

• it was observed that the predominant product in each case was Z-30 and Z-31, respectively, which presumably result from γ-addition of the nucleophile. This was confirmed by 1H NMR NOE analysis of Z-30, where an enhancement between the enamide proton and the methylene proton were observed, as shown in

• nucleophilic addition at the α-position giving the observed N,N’-allylaminal product 43. Conversely, addition of a nucleophile at the γ-position of E-42 gives the observed Z-enamide 44; and addition at the γ-position of Z-42’ gives the same observed Z-enamide 44 after C–N bond rotation. Conclusion In

Towards the total synthesis of chondrochloren A: synthesis of the (Z)-enamide fragment

• Jan Geldsetzer and
• Markus Kalesse

Beilstein J. Org. Chem. 2020, 16, 670–673, doi:10.3762/bjoc.16.64

• Hannover, Germany 10.3762/bjoc.16.64 Abstract The stereoselective synthesis of the (Z)-enamide fragment of chondrochloren (1) is described. A Buchwald-type coupling between amide 3 and (Z)-bromide 4 was used to generate the required fragment. The employed amide 3 comprising three chiral centers was

• ′-dimethylethane-1,2-diamine. Keywords: cross coupling; myxobacteria; natural product; ribolactone; Z-enamide; Introduction In the course of our program to provide synthetic access to biologically active natural products we targeted complex polyketides and depsipetides [1][2][3][4][5][6][7][8][9][10]. One

• particular group of compounds of particular focus in our research activities are natural products with enamide moieties [11]. Among these, chondrochloren having a (Z)-enamide moiety features a rare structural motif. The myxobacterial metabolite chondrochloren A (1) was isolated from Chondromyces crocatus

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• , and branched aliphatic substituents in the δ-position afforded preferably the 1,4-products. Importantly, when the morpholine moiety was used as N-substituent, the addition of diethylzinc to the enamide afforded the 1,6-addition product with 78% isolated yield and 91% ee. It is worth to underline that

AgNTf₂-catalyzed formal [3 + 2] cycloaddition of ynamides with unprotected isoxazol-5-amines: efficient access to functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives

• Ziping Cao,
• Jiekun Zhu,
• Li Liu,
• Yuanling Pang,
• Laijin Tian,
• Xuejun Sun and
• Xin Meng

Beilstein J. Org. Chem. 2019, 15, 2623–2630, doi:10.3762/bjoc.15.255

• silver catalyst from E along with the formation of enamide motif affords 3H-pyrrole F. A final aromatization step by isomerization provides the desire cyclic product 10aa. Notably, two possible cyclization routes from D’ (or D) to give 7-membered rings G and H cannot be achieved through the attack of the

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 60:40) to provide the CM product (E)-N-benzyloxy)undec-2-enamide (6a, 133 mg, 81%) as a colourless viscous liquid. IR (neat): 3183

Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins

• Christiane Schultze and
• Bernd Schmidt

Beilstein J. Org. Chem. 2018, 14, 2991–2998, doi:10.3762/bjoc.14.278

• . Starting point was the 7-acetamido-substituted coumarin 18 [29], which was first N-allylated to the allylamide 19. Dual double bond migration was accomplished with the Ru–hydride complex used previously and furnished the enamide 20 in high yield and predominantly as the E,E-isomer. In light of previous

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• using PIDA (15) at 4 °C (Scheme 41). This oxidative cyclization of enamide substrate 113 afforded synthetically useful spiroenamide 114, which was used as key intermediate for total synthesis of annosqualine (1). The synthesis of natural product 1 was achieved in two steps starting from synthesized

• oxazoline derivatives 41 to spirolactams 42 using PIDA (15). Oxidative cyclization of oxazoline 43 to spirolactam 44 using PIDA 15 as oxidant. PIFA-mediated spirocyclization of amides 46 to N-spirolactams 47 using PIFA (31) as an electrophile. Synthesis of spirolactam 49 from phenolic enamide 48 using PIDA

Atom-economical group-transfer reactions with hypervalent iodine compounds

• Andreas Boelke,
• Peter Finkbeiner and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2018, 14, 1263–1280, doi:10.3762/bjoc.14.108

• anion. Next, a SET from the enamide 45 to Fe(III) affords again Fe(II) and a further reaction with the radical A or A’ leads to the formation of carbocation B or iminium ion B’, respectively. Recombination of these positively charged intermediates with the azide anion finally affords the oxyazidated

Palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides

• Tao Fan,
• Wei-Dong Meng and
• Xingang Zhang

Beilstein J. Org. Chem. 2017, 13, 2610–2616, doi:10.3762/bjoc.13.258

• alkene did not interfere with the reaction efficiency, providing 3l in 83% yield. The reaction was not restricted to aromatic alkenes, enamide was also applicable to the reaction and afforded 3m in 61% yield. To demonstrate the generality of this method further, reactions of alkenes with various

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• between the phosphate moiety and the enamide [57], which gives a very convincing explanation for the observed stereochemical outcome of this reaction. In 2014, the same group then succeeded in carrying out this transformation by starting directly from ketones 10 [83]. Crucial to access high yields and

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• mechanism of their reaction through a combination of DFT calculations, deuterium labeling studies, and control experiments (Scheme 13) [34]. The authors proposed that after migratory insertion of the rhodium–aryl bond across the acrylate, 58 undergoes β-hydride elimination of the enamide proton to generate

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• consist of a 3'-deoxyuridine unit with a unique enamide linkage and the non-proteinogenic N-methyl-2,3-diaminobutyric acid, which branches into two peptide moieties. They differ in the amino acid residues AA2, AA4 and AA5, with AA2 and AA5 being aromatic in all four classes. The amino acid residue AA4 is

Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation

• Franziska Gille and
• Andreas Kirschning

Beilstein J. Org. Chem. 2016, 12, 564–570, doi:10.3762/bjoc.12.55

• -dimethylethylenediamine 16 (4.05 equiv), 1,4-dioxane, 90 °C) we did not encounter the formation of enamide 14 but instead only the hydrolysis product 15 was isolated which might have resulted from the presence of oxygen in the solvent. Therefore, we decreased the temperature and only degassed 1,4-dioxane was used in

• protecting groups are not compatible for this enamide forming protocol. The best results were obtained by using the Boc-protected amide 30 and ornithine-containing vinyl iodides 24 and 28 (Scheme 5). It needs to be noted that the presence of a Cbz protecting group in dehydrooligopeptides is problematic

• , because it cannot be cleaved without simultaneously reducing the acyl enamide. We found that the Teoc protecting group is better suited to be removed from oligoamides 39 and 40, respectively, which were formed from amide 38 and vinyl iodides 29 and 35 (Scheme 5) [17]. Facile removal of the Teoc group was

Hydrogenation of unactivated enamines to tertiary amines: rhodium complexes of fluorinated phosphines give marked improvements in catalytic activity

• Sergey Tin,
• Tamara Fanjul and
• Matthew L. Clarke

Beilstein J. Org. Chem. 2015, 11, 622–627, doi:10.3762/bjoc.11.70

• require quite different ligands to those needed for enamide hydrogenation. From a synthetic perspective, large scale reduction processes generally prefer the use of hydrogen gas to any other reductant, since it potentially saves on cost, waste, atom-economy, solvent and water use; the catalysts identified

Aza-Diels–Alder reaction between N-aryl-1-oxo-1H-isoindolium ions and tert-enamides: Steric effects on reaction outcome

• Amitabh Jha,
• Ting-Yi Chou,
• Zainab ALJaroudi,
• Bobby D. Ellis and
• T. Stanley Cameron

Beilstein J. Org. Chem. 2014, 10, 848–857, doi:10.3762/bjoc.10.81

• ; cyclization; Diels–Alder; inverse electron demand; N-acyliminium ion; tert-enamide; Introduction Fused indoline, isoindoline, quinoline and isoquinoline substructures are found in many natural products and bioactive synthetic compounds (Figure 1). For example, nuevamine is a naturally-occurring isoindolo[1,2

• reported reaction conditions for imino [4 + 2] Diels–Alder reactions [13][14] were employed here for the electrocyclization of N-acyliminium ions from N-aryl-3-hydroxyisoindolinones and tert-enamide analogues namely N-vinylpyrrolidone and N-vinylcaprolactam as the electron-rich dienophiles. Sixteen

• position. The polarized form of the tert-enamide dienophile, on the other hand, will have a positive and negative charge on carbons α and β to N, respectively. Such polarization can only lead to the regioisomer with the substitution at position 5 of the isoindoloquinoline ring. Even with this

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• that the lower electrophilicity of arylimines and the possible enamide conjugation could account for this. Furthermore, it was shown that the pKa of the carboxylic acid significantly influenced the reaction rates, in which TFA gave the best results (2 days vs. 5 days for benzoic acid). No