Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• harbor non-canonical module architectures and cryptic domains [19][22]. As a result, the colinearity rule cannot be applied to predict trans-AT PKS-derived polyketide core structures [19]. Instead, it has been observed that the amino acid sequences of the ketosynthase domains in trans-AT PKSs correlate

• tryptorubin (9) biosynthesis only encodes a 26 amino acid precursor peptide and a single cytochrome P450 monooxygenase [33][79], and hence it was overlooked by genome mining algorithms. On the other hand, large PKS or NRPS BGCs can be split across multiple contigs. This mosaic-like distribution of a single

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• acids. Keywords: alkaloid; amino acid; aza-Prins reaction; cascade reaction; natural product; Introduction Marine sponges produce a large number of structurally diverse natural products, including many that exhibit biological activity [1][2][3]. In 2019, Tsukamoto and co-workers isolated the

• aminobisabolene sesquiterpenoid halichonic acid ((+)-1) from the sponge Halichondra sp. (Figure 1) [4]. This amino acid natural product features a rigid 3-azabicyclo[3.3.1]nonane ring system containing four stereogenic centers within the piperidine ring. In 2021, the same group re-isolated (+)-1 from the sponge

Solid-phase total synthesis and structural confirmation of antimicrobial longicatenamide A

• Takumi Matsumoto,
• Takefumi Kuranaga,
• Yuto Taniguchi,
• Weicheng Wang and
• Hideaki Kakeya

Beilstein J. Org. Chem. 2022, 18, 1560–1566, doi:10.3762/bjoc.18.166

• synthesis, and then hydrogenation of the double bond in 17 provided intermediate 18. Oxidation of the alcohol 18 to acid 10 was realized with the combination of Dess–Martin oxidation [17][18] and Pinnick oxidation [19]. Another unusual amino acid 7 was also synthesized from ᴅ-serine (20, Scheme 3). The

Characterization of a new fusicoccane-type diterpene synthase and an associated P450 enzyme

• Jia-Hua Huang,
• Jian-Ming Lv,
• Liang-Yan Xiao,
• Qian Xu,
• Fu-Long Lin,
• Gao-Qian Wang,
• Guo-Dong Chen,
• Sheng-Ying Qin,
• Dan Hu and
• Hao Gao

Beilstein J. Org. Chem. 2022, 18, 1396–1402, doi:10.3762/bjoc.18.144

• ATCC 26942. Further phylogenetic analysis of TadA and representative fungal DTSs showed that TadA falls within the clade of FC-type DTSs (Figure 2A). In light of showing low amino acid sequence identity (<50%) to reported fungal FC-type DTSs [20][22][24][25], TadA was annotated as a putative new FC

• , and the proposed bicyclic neutral intermediate was docked into the active pocket of TadA (Supporting Information File 1, Figure S20). We searched for the amino acid residues surrounding C2 or C3, which might be involved in the C2 protonation, and found the candidate residue Tyr91. In the corresponding

• chemical shifts, 3 was determined to be (3aS,5E,9E,12aR)-3,3a,4,7,8,11,12,12a-octahydro-3a,6,10-trimethyl-1-(1-methylethyl)cyclopentacycloundecene [31] (Supporting Information File 1, Figures S22–S24), indicating that Tyr91 is an essential amino acid residue involved in C2,6-cyclization. Intriguingly

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• , a universal naming system is crucial to group related CYPs and to facilitate functional predictions. Hence, CYPs from all kingdoms are systematically named according to their amino acid identity by the cytochrome P450 nomenclature committee (David Nelson: dnelson@uthsc.edu). CYPs are grouped into

• subfamily [14]. Typically, all CYPs in the same subfamily share more than 55% amino acid sequence identity, and all CYPs in the same family more than 40%, although exceptions exist [15][16]. These thresholds also underline the remarkable sequence variety of CYPs, as even enzymes with only 60–70% amino acid

• on triterpenoids and steroids. Amino acid sequences (149 triterpenoid CYPs, 266 non-triterpenoid CYPs) were aligned using MUSCLE [92], and a neighbour-joining consensus tree of 1,000 bootstrap replicates was generated using the Jukes–Cantor model. The final tree was visualised in Python using the

Make or break: the thermodynamic equilibrium of polyphosphate kinase-catalysed reactions

• Michael Keppler,
• Sandra Moser,
• Henning J. Jessen,
• Christoph Held and
• Jennifer N. Andexer

Beilstein J. Org. Chem. 2022, 18, 1278–1288, doi:10.3762/bjoc.18.134

• reaction where the terminal phosphate dissociates from the polyP chain before being attacked by the nucleotide [18]. Both mechanisms could proceed without a phosphate group transfer onto an amino acid side chain of the enzyme as in PPK1: here, the enzyme structure generates proximity and polarisation of

• parameters KM and vmax of selected enzymes (Table S6, Supporting Information File 1) [5][10][11][15][19][20][21]. A sequence-based classification of PPKs is in most cases straightforward and unambiguous. Nevertheless, there seem to be exceptions: regarding the amino acid sequence, the PPK1 from Vibrio

• cholerae is very similar to the one from E. coli with 82% similarity (64% identity) on the amino acid level; however, it was described to show kinetic preferences of a PPK2 [20]. While the PPK2 from P. aeruginosa catalyses both synthesis and usage of ATP with kinetic preference for ATP synthesis, the

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH₄I

• Shang-Feng Yang,
• Pei Li,
• Zi-Lin Fang,
• Sen Liang,
• Hong-Yu Tian,
• Bao-Guo Sun,
• Kun Xu and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2022, 18, 1249–1255, doi:10.3762/bjoc.18.130

• ) should be a key intermediate for this tandem reaction. On the basis of the above mechanistic studies and the previous works on iodide-mediated electrochemical transformation [37][38][39][40], a possible mechanism for this electrochemical reaction was proposed (Scheme 5). It is well known that amino acid

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• isolated. Moreover, the coupling of benzothiazines with amino acids was realized. In doing so, an enantioselective synthesis of the nonproteinogenic amino acid 2-amino-3-propylhexanoic acid was accomplished. Keywords: amino acid; benzothiazine; oxidative dimerization; peptide coupling; stereoselective

• our work, we aimed to utilize the carboxylic acid function of the prepared 4H-benzo-1,4-thiazines 10 by attaching them to nonproteinogenic amino acid 16a and ʟ-phenylalanine. Preparation of 3-propylnorleucin methyl ester (16a) started with the condensation reaction of heptan-4-one (12) and methyl

• isocyanoacetate (13). The palladium-catalyzed hydrogenation of intermediate 14 gave the racemic N-formyl-protected amino acid methyl ester 15 in good yield. Using either concentrated HCl (aq) or in situ-formed HCl from the reaction of MeOH and acetyl chloride, compound 15 could easily be deprotected to gain

Reductive opening of a cyclopropane ring in the Ni(II) coordination environment: a route to functionalized dehydroalanine and cysteine derivatives

• Oleg A. Levitskiy,
• Olga I. Aglamazova,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2022, 18, 1166–1176, doi:10.3762/bjoc.18.121

• Oleg A. Levitskiy Olga I. Aglamazova Yuri K. Grishin Tatiana V. Magdesieva Lomonosov Moscow State University, Dept. of Chemistry, Leninskie Gory 1/3, Moscow 119991, Russian Federation 10.3762/bjoc.18.121 Abstract The involvement of an α,α-cyclopropanated amino acid in the chiral Ni(II

• radical anions influenced by substituents in the cyclopropane ring are discussed. Optimization of the reaction conditions opens a route to the non-proteinogenic amino acid derivatives containing an α–β or β–γ double C=C bond in the side chain; the regioselectivity can be tuned by the addition of Lewis

• -activity and chirality provided by the Ni–Schiff base template, supported with the protection from redox-destruction of the amino acid skeleton, makes the suggested approach a convenient route to various types of non-proteinogenic amino acids [9][10][12][13]. Recently, several practical approaches to α,α

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• the unique methyl ester in azodyrecin The structural diversity of aliphatic azoxy natural products can be attributed to variations in the alkyl side chains and the amino acid-derived counterparts. The variation in the amino acid-derived units is considerably large, as it includes primary and secondary

• stepwise HMM-based search using models for “VlmA'' (PF09924: LPG_synthase_C) and the amino acid sequence of VlmH identified 179 pairs of VlmA/VlmH, indicating that approximately 5.7% of the actinobacteria present in the NCBI Refseq database are potential producers of aliphatic azoxy natural products. The

• . Biosynthetic gene clusters of aliphatic azoxy natural products. Conserved proteins are colored according to their functional annotations. Genes encoding homologous proteins with more than 30% amino acid sequence identities are linked. Structures of azodyrecins (a) and new azodyrecin derivatives, azodyrecins D

Identification of the new prenyltransferase Ubi-297 from marine bacteria and elucidation of its substrate specificity

• Jamshid Amiri Moghaddam,
• Huijuan Guo,
• Karsten Willing,
• Thomas Wichard and
• Christine Beemelmanns

Beilstein J. Org. Chem. 2022, 18, 722–731, doi:10.3762/bjoc.18.72

• , calculated mass of 31.9 kDa) (Figure 2) caught our attention due to its low sequence identity on the amino acid sequence level (coverage below 50%) with other characterized Ptases. To further explore the putative function of UbiA-297, we generated a phylogenetic tree using 444 Ptase sequences with already

• , Belgium). Bioinformatic analysis: Amino acid sequences of all described prenyltransferases were retrieved from the UniProtKB/Swiss-Prot database. Other Ptase amino acid sequences of marine Flavobacteria and Saccharomonopora strains were obtained using Blast searches against defined genome groups within

• . machipongonensis PR1 (NZ_CM001023), Saccharomonospora sp. CNQ490 (NZ_AZUM01000003), S. viridis DSM 43017 (NC_013159), and Nostoc punctiforme PCC 73102 (NC_010628). Percentage identities of homologous genes are given in the same colored arrow boxes (Maribacter sp. MS6 was set as reference). A) Amino acid alignment

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• ], which share ≈60% amino acid identity [33]. Both isoforms catalyze the incorporation of two oxygen atoms into arachidonic acid (AA) to form an endoperoxide between C9 and C11 and a peroxide at C15 to generate prostaglandin G2 (PGG2) (Scheme 1) [24][34]. Subsequently, the 15-hydroperoxide in PGG2 is

• endoperoxidase, NvfI shares a low amino acid sequence similarity with FtmOx1 (only 17%) and a phylogenetic analysis indicated that it is located in a different clade from FtmOx1. Prior to the structure–function analysis of NvfI, four pathways were proposed for the formation of fumigatonoid A from asnovolin A

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• moderate yields (37–63%), and a decreased yield was observed with an increase of the aliphatic chain length, which was more accentuated for the diacid derivatives, and more subtle for the amino acid derivatives (Scheme 30). The same methodology was applied during the synthesis of oligopeptides linked to 10

• (Scheme 30) [132][133][134]. In detailed studies, initiated by Commandeur and co-workers [135] and expanded by Naturale and co-workers [139], the alkylation capabilities of menadione (10) were evaluated, exclusively, with several amino acid types by Kochi–Anderson radical decarboxylation [76]. In the

Amamistatins isolated from Nocardia altamirensis

• Till Steinmetz,
• Wolf Hiller and
• Markus Nett

Beilstein J. Org. Chem. 2022, 18, 360–367, doi:10.3762/bjoc.18.40

• the end product of the pathway in N. altamirensis DSM 44997. Previous studies have demonstrated that, in nature, hydroxamates arise from the oxidation of terminal amino groups in amino acid side chains, followed by formylation or acylation of the resulting hydroxylamines. While the oxidations are

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• the active site of the enzyme. Once bound, substrate activation is carried out by specific amino acid side chains that adorn the inner surface of the cavity by means of a combination of covalent and/or weak intermolecular interactions leading to the stabilization of intermediate species and transition

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• as a pro-nucleophile in an enantioselective addition reaction. The mild reaction conditions allow the use of various functionalized malonamates. Given the importance of highly functionalized α-amino acid derivatives, the present strategy could be useful in generating a wide range of α-oxyamino

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• direct access to cyclopeptides related to naturally occurring histone deacetylase (HDAC) inhibitors Cyl-1 and Cyl-2. Late stage modifications on the unsaturated amino acid side chain allow the introduction of functionalities which might coordinate to metal ions in the active center of metalloproteins

• , non-proteinogenic amino acid (2S,9S)-2-amino-9,10-epoxy-8-oxodecanoic acid (Aoe) as a zinc-binding group. Interestingly, Aoe with its α-epoxyketone motif is wide-spread among this compound class as it is present in other natural products such as Cyl-1 and Cyl-2 [16][17], chlamydocin [18], and many

• (apicidin [19], microsporin A [20]), carboxylic acids (azumamides [21]), α-hydroxy ketones (FR235222 [22]) or thioesters (largazole [23]). These cyclopeptides mainly differ in the amino acid sequence of the peptide backbone, which causes selectivity towards the different HDAC isoforms. In fact, many

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254, Lithuania Vipergen ApS, Gammel Kongevej 23A, DK-1610 Copenhagen V, Denmark 10.3762/bjoc.18.11 Abstract A convenient and efficient synthesis of novel achiral and chiral heterocyclic amino acid-like building

• nonproteinogenic α-amino acids, have been used as excitatory amino acid receptor agonists [10][11][12][13]. For example, (S)-AMPA (III) and (S)-ACPA (IV) are specific agonists of an AMPA receptor that mimic the effects of the neurotransmitter glutamate [14][15][16]. Unnatural heteroarene amino acids have also been

• widely used as building blocks to prepare various heterocyclic peptides [17][18][19][20][21][22]. In particular, 1,2-oxazole amino acid derivatives, such as compounds V [20], VI [21], and VII, VIII [22], can be easily synthesized and are suitable for insertion with the corresponding heterocycle into a

Efficient and regioselective synthesis of dihydroxy-substituted 2-aminocyclooctane-1-carboxylic acid and its bicyclic derivatives

• İlknur Polat,
• Selçuk Eşsiz,
• Uğur Bozkaya and
• Emine Salamci

Beilstein J. Org. Chem. 2022, 18, 77–85, doi:10.3762/bjoc.18.7

• -en-10-one is described. cis-9-Azabicyclo[6.2.0]dec-6-en-10-one was transformed into the corresponding amino ester and its protected amine. Oxidation of the double bond in the N-Boc-protected methyl 2-aminocyclooct-3-ene-1-carboxylate then delivered the targeted amino acid and its derivatives. Density

• β-amino acid derivatives have antibiotic (oryzoxymycin) and antifungal activities (Figure 1) [12][13]. Among the cyclic β-amino acids, the most widely investigated derivatives are the five- and six-membered derivatives [8][9][10][14][15], but only a few synthetic methods are available for the

• -hydroxylated cyclooctane amino acids [14][18]. Also in other ring systems, only non-hydroxylated cyclic amino acids and derivatives were synthesized [8][9][10][15][16]. Therefore, we were inspired to develop new methods for the synthesis of hydroxylated β-amino acid derivatives containing eight-membered rings

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• signal. Danielson [48] found some errors in Folin’s analytical method and optimized it for better amino acid determination. Martin and Fieser [49] described an optimized method, analogous to Folin’s procedures, with temperature control, producing β-NQSNH4 16 and β-NQSK 20 in high yields (Scheme 2). It is

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• given next to the respective structure and backbone-atoms root mean square deviation with respect to the active conformation are indicated in parenthesis. RMSD reported and used in clustering were calculated from Pro to Met only. A schematic representation of the secondary structure of each amino acid

• , 1 h. In panel C), amino acids in R1 and R2 are with protecting groups and R2 is resin-bound (Rink amide resin); R3 = 4-phenylboronic acid or (4-ethylphenyl)boronic acid (P2–P5). Supporting Information Supporting Information File 6: Details on the amino acid and peptide synthesis, analytical data of

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• -Val5 and N-Me-ᴅ/ʟ-Phe2. Hoshinoamide C includes two N-methyl amino acids: N-Me-ᴅ-Phe2 and N-Me-ᴅ-IIe5. The C-terminal Pro is functionalized as methyl ester, while the N-terminal polypeptide is linked to the long alkyl chain amino acid Aha8/Ana8/Ama7 and p-hydroxybenzoic acid Hba9/Hba8. Hoshinoamides

GlycoBioinformatics

• Kiyoko F. Aoki-Kinoshita,
• Frédérique Lisacek,
• Niclas Karlsson,
• Daniel Kolarich and
• Nicolle H. Packer

Beilstein J. Org. Chem. 2021, 17, 2726–2728, doi:10.3762/bjoc.17.184

• ” is described by the National Human Genome Research Institute as “a subdiscipline of biology and computer science concerned with the acquisition, storage, analysis, and dissemination of biological data, most often DNA and amino acid sequences”. Adding the prefix “glyco-“ is about placing genomic and

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• ; separation of racemic nucleosides; stereoselectivity; Introduction Among all the biomolecules in an organism, nucleic acids, namely DNA and RNA, have the unique role of storing the genetic code – the nucleotide sequence that specifies the amino acid sequence of proteins that is essential for life on Earth

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• different approach for the use of cinchona-based organocatalysts. Instead of using the cinchona derivative alone, they employed a mixture of cinchona derivative and amino acid such as ᴅ-proline, termed as the modularly designed organocatalyst (MDO) for the synthesis of bridged tetrahydroisoquinoline