(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• reduction. Deprotection of the alcohol followed by two-step oxidation to the carboxylic acid yielded the non-natural β-amino acid (±)-50, which could then be transformed into diamine (±)-51 by Curtius rearrangement. Recently, Mykhailiuk and co-workers also reported the synthesis of 1,2-BCHs using an

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• . Trapping of this enolate would lead to β-amino acid units, a class of compounds that has attracted a great deal of attention [19][20][21][22][23][24]. An obvious possible shortcoming that had to be considered was still that the generated zinc enolate III having a β-amino group could undergo β-elimination

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

• 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

• . We have recently reported the synthesis of various eight-membered aminocyclitols and their derivatives [19][20][21][22][23][24][25]. In the present paper, we describe the synthesis of some hydroxylated β-amino acid derivatives containing eight-membered rings starting from cis,cis-1,3-cyclooctadiene

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of β-amino acid

• into benzyl butyrate in view of facilitating the downstream purification of continuous flow Curtius rearrangement reactions [21]. In this paper, we will give a full account on this valuable approach and showcase the utility of the carbamate products towards generating sets of β-amino acid species

• after removal of BnOH, vide infra). The continuous flow set-up used. Side reaction during formation of product 3m. Flow set-up for the CALB-mediated impurity tagging approach. Strategies towards accessing β-amino acid derivatives 8. Complementary flow approaches towards the β-amino acid derivatives 8

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• -lactam, albeit functionalized in the side chain. The one-pot synthesis of the β-lactam steroid was achieved via the Ugi 3-component-4-center reaction using the dehydrocholic aldehyde 1 as carbonyl component. This variation of the Ugi reaction including a β-amino acid component allows the formation of the

Dirhodium(II)-catalyzed [3 + 2] cycloaddition of N-arylaminocyclopropane with alkyne derivatives

• Wentong Liu,
• Yi Kuang,
• Zhifan Wang,
• Jin Zhu and
• Yuanhua Wang

Beilstein J. Org. Chem. 2019, 15, 542–550, doi:10.3762/bjoc.15.48

• no cis product formed. After further removal of the para-methoxyphenyl (PMP) group using ammonium cerium nitrate (CAN), the cyclic β-amino acid ester 5b was obtained with a yield of 80%. Cyclic β-amino acids and derivatives have good bioactivity and are widely used as key synthetic intermediates in

• method has potential synthetic practicality by providing a convenient way to synthesize trans-cyclic β-amino acid derivatives. Further application of this method with other cycloaddition partners and asymmetric synthesis of the chiral ring with the help of chiral auxiliaries are currently underway

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• derived from cyclodienes were used as starting substances for further functionalization with ROM. We have described a stereocontrolled synthetic route to access difunctionalized cyclic β-amino acid derivatives [14] and β-lactams [15][16] based on ring-opening metathesis (ROM) through ethenolysis of the

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• trifluoromethyl group. It must be noted that this methodology represented the first efficient and general preparation of chiral β-trifluoromethyl β-amino acid derivatives containing a quaternary stereocenter adjacent to the amine function. In 2014, Linclau and Poisson reported the synthesis of chiral α,α-difluoro

• been described using chiral reagents. For example, the first efficient synthesis of chiral β-trifluoromethyl β-amino acid derivatives containing a quaternary stereocenter adjacent to the amine function has been reported with up to >98% de through diastereoselective Zn-mediated aza-Reformatsky reactions

Quinone-catalyzed oxidative deformylation: synthesis of imines from amino alcohols

• Xinyun Liu,
• Johnny H. Phan,
• Benjamin J. Haugeberg,
• Shrikant S. Londhe and
• Michael D. Clift

Beilstein J. Org. Chem. 2017, 13, 2895–2901, doi:10.3762/bjoc.13.282

• this reaction sequence, (thio)silyl ketene acetal 10 was united with 2-phenylglycinol and para-anisidine in a two-step, one-pot process to provide β-amino acid derivative 11 in a 60% yield. The overall reaction sequence provides a unique method for the production of the high-value β-amino acid

Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones

• Sergii V. Melnykov,
• Andrii S. Pataman,
• Yurii V. Dmytriv,
• Svitlana V. Shishkina,
• Mykhailo V. Vovk and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2017, 13, 2617–2625, doi:10.3762/bjoc.13.259

• malonic acid and its mono(thio)esters have been poorly investigated so far despite the potential to become a convenient route to β-trifluoromethyl-β-amino acid derivatives and to their partially saturated heterocyclic analogues. Results: In this paper we show that 4-trifluoromethylpyrimidin-2(1H)-ones

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence

• Attila Márió Remete,
• Melinda Nonn,
• Santos Fustero,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233

• dihydroxylated cyclic β-amino acid esters. Our study started with the fluorination of racemic dihydroxylated cyclopentane cis- or trans-β-amino acid esters (±)-1 and (±)-4 [23][24][25][26]. The preliminary investigations were performed with the commercially available fluorinating agents mentioned above in

• , heterocyclic natural products and nucleosides [29][30][31][32][33][34][35][36]. Therefore, the fluorinated β-amino acid derivative (±)-5, obtained through transformation of (±)-4 with chemodiscrimination of the alcoholic groups, might represent a promising bioactive framework. As the fluorination of the five

• example XtalFluor, Et3N·HF, and pyridine·HF and applying an efficient approach earlier developed by our group, proved to be unsuccessful ([18] and references cited therein). Due to the biological relevance of six-membered β-amino acid derivatives (e.g., tilidin, oryzoxymicin, BAYY9379) [19], we continued

Mechanochemical enzymatic resolution of N-benzylated-β³-amino esters

• Mario Pérez-Venegas,
• Gloria Reyes-Rangel,
• Adrián Neri,
• Jaime Escalante and
• Eusebio Juaristi

Beilstein J. Org. Chem. 2017, 13, 1728–1734, doi:10.3762/bjoc.13.167

• resolution; mechanochemistry; Introduction β-Amino acids are rather interesting molecules that frequently exhibit exceptional biological properties [1][2][3]; for instance, some of them are efficient inhibitors of several enzymes [4][5]. Furthermore, β-amino acid residues can be used to protect peptides and

• as the obtained with fresh catalyst (compare entries 1 and 2 in Table 3). This might suggest that the enzyme undergoes partial denaturation and/or partial destruction of the support, within each cycle (Table 3, entry 3). Interestingly, however, ee values of the isolated β-amino acid still resulted

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• biologically interesting β-amino acid derivatives (Table 2) [42]. In this work, the authors compared the results achieved by means of 4 with other urea- and thiourea-based organocatalysts in order to understand the effect of the acidity, the structural rigidity, and the bifunctionality of the promoter. These

Novel stereocontrolled syntheses of tashiromine and epitashiromine

• Loránd Kiss,
• Enikő Forró and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2015, 11, 596–603, doi:10.3762/bjoc.11.66

• pyrrole, followed by saturation [37]. The transformation of chiral functionalized pyrrole or pyrrolidine derivatives has served as the basis of the construction of (−)-epitashiromine [38][39] (Figure 4). The oxidative functionalization of cyclic β-amino acid derivatives has been reported to be a

• convenient route for the preparation of N-heterocyclic β-amino acid derivatives [40][41] or for the stereocontrolled synthesis of functionalized cispentacins [42] and their acyclic counterparts [43][44] (Figure 5). The oxidative ring cleavage of various vicinal diols and the transformation of the resulting

Stereoselective synthesis of perillaldehyde-based chiral β-amino acid derivatives through conjugate addition of lithium amides

• Zsolt Szakonyi,
• Reijo Sillanpää and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2014, 10, 2738–2742, doi:10.3762/bjoc.10.289

• addition was observed. Amino ester 11 was obtained as a single product and transformed to the corresponding amino acids 10A and 10D in good yields on the gram scale. Keywords: asymmetric synthesis; β-amino acid; chiral; Michael addition; monoterpene; Introduction In the past decade, cyclic β-amino acids

• secondary structure of foldamers, the introduction of well-designed hydrophilic or hydrophobic substituents on the alicyclic ring of β-amino acids can modify the fine structure of β-peptides. There are several powerful synthetic methods through which alicyclic or bicyclic β-amino acid enantiomers can be

• ][34]. From this aspect, chiral, monoterpene-based α,β-unsaturated esters might be excellent starting materials, in which the natural monoterpene skeleton may serve as the chiral origin for the stereoselective construction of the β-amino acid moiety. Our present aim was the synthesis of new, limonene

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• nucleophile preferentially attacks from the re-face as shown in TS 1 (Figure 4) to give 10b [48][55]. In the next step, ester saponification of 10a using lithium hydroxide afforded D-glucose derived β-amino acid 11a in 84% yield. Finally, N-terminal fluorenylmethoxycarbonyl (Fmoc) protection of the β-amino

• acid using Fmoc N-hydroxysuccinimidyl carbonate (Fmoc-OSu) under basic conditions gave sugar β-amino acid Fmoc-L-glycero-glucose(Bn)-OH 12a in 81% yield (Scheme 1). The C6-epimer Fmoc-D-glycero-glucose(Bn)-OH 12b was obtained by analogous procedures as performed for 12a. The synthesis of Fmoc-D-glycero

• protection using Fmoc-OSu afforded the required scaffold Fmoc-L-glycero-galactose-OH 12c (Scheme 2). The xylose derived N-Fmoc protected β-amino acid 1,2-O-isopropylidene-3-O-benzyl-5-deoxy-5-(N-9-fluorenylmethoxycarbonylamino)-β-L-ido-heptofuranuronic acid (Fmoc-L-ido-xylose-OH 12d) was prepared following a

Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non-proteinogenic amino acid segment of the linear pentapeptide microginin

• Rajendra S. Rohokale and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2014, 10, 667–671, doi:10.3762/bjoc.10.59

• -amino acid fragment in AHDA 2a is also present in linear peptides such as bestatin and valinoctin [5][6][7][8], which are isolated from the same species. In addition, the chiral α-hydroxy-β-amino acid constituent is an important component of protein kinase inhibitor compounds like balanol and the

• conclusion, we demonstrated a practical approach for the synthesis of both enantiomers of AHDA (2a and 2b) to obtain the stereochemistry required for the α-hydroxy-β-amino acid. Our method starts from D-glucose by an easy manipulation of its functional groups at C3 and C4. In addition, the chiral core (α

• -hydroxy-β-amino acid) in 2a is present in several biologically active compounds such as taxol, balanol and bestatin. Therefore, this methodology could be potentially exploited for the synthesis of the chiral segment of these compounds. Microginin (1) and (2S,3R)-AHDA (2a). Retrosynthetic analysis of AHDA

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

• , the group of Fülöp reported an efficient synthesis of bicyclic β-lactams from monocyclic β-amino acids via an Ugi four-center three-component reaction (U-4C-3R) [39]. Herein, the monocyclic β-amino acid acts as bifunctional moiety containing both an amino and carboxylic acid group. A variety of cyclic

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• synthetic chemists, thanks to their massive pharmacological potential [21][22]. For example, cispentacin ((1R,2S)-2-aminocyclopentanecarboxylic acid, 7) is a widely investigated naturally occurring carbocyclic β-amino acid with strong antifungal properties against Candida species (Figure 2) [23]. Its

• dipolarophiles to yield a library of novel 1,2,3-triazole-modified cyclic β-amino acid derivatives. Compounds 11–14 were racemates, the structures in Table 1 show their relative stereochemistry. The CF syntheses were carried out under both conditions A and B in order to obtain a clear comparison between the

• system. This resulted in around 100 mg of crude product, depending on the conversion and the molecular masses of the reactants. In the Cu(I)-catalysed reactions between phenylacetylene and the azido-substituted β-amino acid derivatives 11–14, 1,4-disubstituted 1,2,3-triazole isomers (15–18) were

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• step involves the use of a β-amino acid-forming three-component reaction (3CR), the scope of which defines its role in the synthetic strategy. Keywords: β-amino acid; benzimidazole; multicomponent reaction; Introduction Library syntheses and high-throughput screening can often be combined to enable

• studies of this compound as a biological probe [14][15]. The synthesis of 1 emanates from a one-pot, three-component reaction (3CR) of an arylaldehyde, malonic acid (5), and ammonium acetate, which assembles the β-amino acid core (Figure 2) [14][15][18]. In the reported synthesis of 1, a protected β-amino

• benzimidazole formation with Oxone furnished benzimidazole 17 in 47% yield over two steps [20][21]. The ester of 17 was smoothly reduced to the alcohol 18, in 74% yield, and immediately oxidized to the aldehyde 4, in 87% yield. Unfortunately, 4 produced none of the desired β-amino acid 3 under several different

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• site presumably by accessing a hydrophobic binding pocket [29][30]. A similar effect was seen with the substituted β-lactam analogue of PLG, compound 13, developed by Palomo et al. [31]. Other scaffolds have been employed successfully to generate PLG peptidomimetics. A β-amino acid approach to the

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

• H. Bauke Albada,
• Alina-Iulia Chiriac,
• Michaela Wenzel,
• Maya Penkova,
• Julia E. Bandow,
• Hans-Georg Sahl and
• Nils Metzler-Nolte

Beilstein J. Org. Chem. 2012, 8, 1753–1764, doi:10.3762/bjoc.8.200

• [14], trivalent lipidated short peptides with antifungal activity [15], peptoids [16], peptides containing D-amino acids [17], and foldamers based on β-amino acid residues with antibacterial activity [18] have been described. Whereas nature has to stick to products compatible with biosynthetic

Synthesis of trifunctional cyclo-β-tripeptide templates

• Frank Stein,
• Tahir Mehmood,
• Tilman Plass,
• Javid H. Zaidi and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2012, 8, 1576–1583, doi:10.3762/bjoc.8.180

• protection of the primary α-amino group. Therefore, tert-butyloxycarbonyl (Boc) protection was used to mask all α-amino groups during solid-phase synthesis of the tripeptide. Synthesis of the cyclo-β-peptide scaffold The Boc protected β-amino acid building blocks for SPPS of the cyclic β-tripeptide were

• silver benzoate and water as a nucleophile [19][20][21][22][23] yielding the homo-β-lysine derivatives 1 and 2 alongside the azide β-amino acid 3 (Figure 2). In previous studies, synthesis of the cyclic β-tripeptide scaffold was provided by cyclization of the linear β-tripeptide obtained by solution

• used for coupling (β-amino acid 5.00 equiv, HBTU 4.50 equiv, HOBt 5.00 equiv, DIEA 10.0 equiv, 2.80 mL DMF, 18 h) and Boc cleavage (3.00 mL TFA/m-cresole–95/5 v/v, 2 × 2 min) of β-amino acids Boc-β3-HLys(Fmoc)-OH, Boc-β3-HLys(Cbz)-OH and Boc-β3-HLys(N3)-OH. After N-terminal deprotection of the last

Synthesis of highly functionalized β-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines

• Melinda Nonn,
• Loránd Kiss,
• Reijo Sillanpää and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2012, 8, 100–106, doi:10.3762/bjoc.8.10

• cispentacin stereoisomer 2 into multifunctionalized β-amino acid derivative 12. Synthesis of multifunctionalized β-amino acid derivatives 13–16. Reaction conditions: NaBH4, NiCl2, Boc2O, EtOH/H2O, rt, 6 h. Acknowledgements We are grateful to the Hungarian Research Foundation (OTKA No. T81371) for financial

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• the cyanobacterium Microcystis aeruginosa [17][18][19]. Microcystins are produced by different genera of freshwater cyanobacteria and inhibit eukaryotic protein phosphatases of types 1 and 2A. A signature of this heptapeptide family is the unusual β-amino acid Adda (3-amino-9-methoxy-2,6,8-trimethyl