Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• enantioselectivity of the three-component coupling of glyoxylic acid (employed as its solid, easy-to-handle monohydrate) with 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonylamide, and an arylboronic acid was significantly affected by the nature of the boronic acid. Whereas the reaction with phenylboronic acid

• afforded the Pbf-protected [23] phenylglycine derivative 10a in high yield and enantioselectivity, an almost racemic mixture of 10b was obtained from the corresponding (p-methoxyphenyl)boronic acid (2b, Scheme 2a). This decrease in enantioselectivity can be attributed to a faster racemic background

• increase in enantioselectivity. Decreasing the arylboronic acid to active catalyst ratio could be one possible opportunity to decrease the rate of the background reaction. Thus, we envisioned that this could be achieved by the slow generation of small amounts of the boronic acid from a suitable precursor

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• using acyclic enones 14 [27]. Their tandem conjugate addition/Mannich reaction methodology offers access to various non-cyclic β-aminoketones 16 with multiple contiguous stereocenters in high diastereo- and enantioselectivity (Scheme 5a). Additionally, chiral isoindolinones 18 and 2,3,4-trisubstituted

• three-step reaction sequence resulting in trisubstituted nitropyrrolidinones 24 with exceptional enantioselectivity (Scheme 6B). In contrast to conjugate additions to nitroolefins, these activated alkenes can also be utilized in the enolate trapping step. In the last decade, several highly

• (diallylation) because the strongly basic R2Zn can form the enolate from the monoallylated product 32. Therefore, using only 1 equiv of dialkylzinc, the desired allylated products 32 were isolated in good yields and excellent diastereo- and enantioselectivity. Soon after, Jarugumilli et al. investigated the

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

• Alena V. Dmitrieva,
• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• -Cl [21], 3,4-di-Cl [21][22], 2/3/4-F [23]) were inserted in the N-benzyl moiety as well as in the aromatic rings of the benzophenone fragment [24][25][26] (selected examples are given in Scheme 1). Insertion of halogen atoms increased enantioselectivity, e.g., in alkylation reactions [27][28

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• noted decreasing the steric bulk of the amide moiety of the substrate from isopropyl to ethyl to methyl decreased the enantioselectivity of the reaction. Carbon- and nitrogen-bridging bicyclic alkenes were also identified as competent substrates. In this respect, norbornadiene was found to give the

• desired carboaminated product in slightly diminished yields while azabicyclic alkenes generated the targeted products in excellent yield, albeit with slightly reduced enantioselectivity. To showcase the synthetic capabilities of this methodology, the authors synthesized the non-natural amino acid

• reduced yield and enantioselectivity. Bridgehead-substituted, non-benzo-fused oxabicycles, as well as azabicyclic alkenes failed to produce the desired product. When the benzo-fused moiety was unsymmetrically substituted, little regioselectivity was observed. Based on X-ray crystallographic data for their

Computational studies of Brønsted acid-catalyzed transannular cycloadditions of cycloalkenone hydrazones

• Manuel Pedrón,
• Jana Sendra,
• Irene Ginés,
• Tomás Tejero,
• Jose L. Vicario and
• Pedro Merino

Beilstein J. Org. Chem. 2023, 19, 477–486, doi:10.3762/bjoc.19.37

• alkenes under chiral BINOL-derived Brønsted acid catalysis has been studied by Houk and Rueping in 2014 [33]. These authors established the origin of the enantioselectivity and the differences between the catalyzed and uncatalyzed reactions, suggesting that the catalyzed reaction is, actually, a so-called

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• gave the corresponding epoxide 51 in low enantioselectivity and only 44% yield. The subsequent deprotection reaction led to compound 1 in 86% yield (Scheme 9). Besides the low enantioselectivity, the authors observed that the optical rotation value of the synthesized compound ([α]D +36.9, c 0.55, CHCl3

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• achieved. When AgOTf was replaced with silver (R)-BINOL phosphate, the asymmetric allylation proceeded in a moderate yield (60%) and enantioselectivity (40% ee). The structure of the ‘GaIOTf’ species was explored in more detail by Slattery, and a monovalent [GaI(18-crown-6)OTf] complex was isolated and

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• of each strategy, as well as the challenges remaining to be tackled. Keywords: enantioselectivity; grayananes; oxidation; 1,2-shift; total synthesis; Introduction The Ericaceae are a large plant family, with over 4250 known species all around the world [1]. While Ericaceae’s toxicity has been known

• structure of grayananes. Nevertheless, this approach is somehow lower yielding than the previous ones. Regarding enantioselectivity, both Newhouse’s and Luo’s syntheses rely on an enantioenriched precursor obtained in 86% ee. On the other hand, while Ding’s syntheses were performed in racemic form, the

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• electrophile and the nucleophile with the specific preorganization of the substrates by the catalyst is crucial for high enantioselectivity [67] (as in example A in Scheme 4). However, in example B the transition state without specific interactions between the sulfide and the catalyst is proposed. In this case

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• ]. Based on the fact that the cis-configuration between the sulfur and the pivalate was absolutely required for enantioselectivity, an interaction between both the sulfur and pivalate carbonyl oxygen with the hydrogen of Hantzsch ester's NH was proposed (Scheme 5). Thus, rather weak interactions might

• still be important in the assembly of a ternary complex and the enantioselectivity of the reaction. The evaluation of the catalysts is shown in Table 1. CPA 4 was completely ineffective at inducing chirality (Table 1, entry 1) and catalyst 2 was not much better (entry 2). Catalyst 3 on the other hand

Supramolecular approaches to mediate chemical reactivity

• Pablo Ballester,
• Qi-Qiang Wang and
• Carmine Gaeta

Beilstein J. Org. Chem. 2022, 18, 1463–1465, doi:10.3762/bjoc.18.152

• tetraaminobisthiourea chiral macrocycles as catalysts in decarboxylative Mannich reactions. Low macrocycle loading was used to catalyze the decarboxylative addition of malonic acid half thioesters to isatin-derived ketimines with excellent yields and good enantioselectivity. It was reported that effective activation

Mechanochemical synthesis of unsymmetrical salens for the preparation of Co–salen complexes and their evaluation as catalysts for the synthesis of α-aryloxy alcohols via asymmetric phenolic kinetic resolution of terminal epoxides

• Shengli Zuo,
• Shuxiang Zheng,
• Jianjun Liu and
• Ang Zuo

Beilstein J. Org. Chem. 2022, 18, 1416–1423, doi:10.3762/bjoc.18.147

• epichlorohydrin and provided α-aryloxy alcohols in an overall high yield and a complete enantioselectivity. Conclusion In summary, we mechanochemically synthesized unsymmetrical salens 1 for preparing metal–salen catalysts 2 for the first time. The use of grinding technology provided salens 1 in an overall higher

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• (25), formaldehyde (26), and aniline (27) and 10 mol % of the organocatalyst to yield β-aminoketone 28 in 85% yield (88% ee), in less than 1 h. Although a significantly higher yield was achieved compared to the batch experiment, a slight reduction in enantioselectivity was observed. The Petasis or

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• enantiopure tetrahedral Pt12 cage has been previously studied for catalytic Michael addition reactions, but no enantioselectivity was detected because the chiral building blocks were located at peripheral positions thus not sufficiently breaking symmetry within the cavity [73]. Therefore, it was envisioned

• trans-styrylboronic acid (43, Figure 10). The catalytic reaction inside the chiral cavity of (S)-40 provided a yield up to 91% with a very high enantioselectivity (94% ee). In contrast, the larger chiral macrocycle (S)-41 afforded a slightly lower catalytic activity (87%), however, at a similar

• enantioselectivity (94% ee). Using similar reaction conditions, the non-assembled BINOL derivative (S)-3,3'-dibromo-[1,1'-binaphthyl]-2,2'-diol acted as a superior catalyst (99% yield) but achieved a lower enantioselectivity (84% ee). Therefore, this result indicates that the incorporation of multiple catalytic

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• % conversion) which were used as reference catalysts. With regard to enantioselectivity, it was found the less bulky rotaxanes (S)-56a/b performed even worse than the reference systems (14%/14% ee for (S)-56a/b, 23%/22% ee for the reference catalysts). However, an introduction of the bulky iPr substituents on

• )/K(R) = 5.7. In comparison, the free chiral axle alone displayed no significant enantioselectivity (K(S)/K(R) = 0.96). With the rotaxane host, it was also possible to discriminate between the double-bond isomers fumarate and maleate, with strong preference for fumarate (Kfum/Kmal = 4.4, see Figure 19

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• . Only 5 mol % of the optimal macrocycle catalyst efficiently catalyzed the decarboxylative addition of a broad scope of malonic acid half thioesters to isatin-derived ketimines with excellent yields and good enantioselectivity. The rigid macrocyclic framework and the cooperation between the thiourea and

• outcome (Table 3, entries 4 and 5). Performing the reaction at 0 °C led to a very slow conversion, while at 40 °C the reaction became much faster but gave a diminished yield due to the competitive decarboxylation side reaction (Table 3, entries 6 and 7). In both cases, the enantioselectivity did not turn

• mechanism The above results showed that the tetraamino-bisthiourea chiral macrocycles can efficiently catalyze the decarboxylative addition reactions with good yields and enantioselectivity. To check the role of the macrocyclic framework, two acyclic compounds (9 and 3c) containing the similar structural

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban

• Martin Vrbický,
• Karel Macek,
• Jaroslav Pochobradský,
• Jan Svoboda,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2022, 18, 438–445, doi:10.3762/bjoc.18.46

• linezolid (1) and rivaroxaban (2). The main aim of this study was the evaluation of the catalytic activity and enantioselectivity of several established enantioselective catalysts applicable to the asymmetric Henry reaction, which were used for the preparation of chiral intermediates of these drugs. Various

• enantioselectivity was achieved with the copper(II) complexes of ligands Ia, IIa, IIIa, and IV. Fortunately, these catalysts provided the R-enantiomer of nitroaldol 21 as the major product, which can be subsequently transformed to S-linezolid (1) (the active stereoisomer). On the other hand, the catalysts derived

• from 2-(pyridin-2-yl)imidazolidine-4-ones Ib–IIIb, bisoxazoline ligands V–VII, and (+)-sparteine (VIII) showed only insufficient enantioselectivity and therefore, they were excluded from further studies. A higher catalyst loading (10 mol %) slightly increased the enantioselectivity in some cases (i.e

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

• from cinchonine PTC 44 as catalyst. Despite of good yields, the method did not demonstrate good enantioselectivity results [104]. Berkessel and co-workers, in turn, described the use of asymmetric Weitz–Scheffer-type epoxidation of menadione (10), mediated by cinchona alkaloid PTC 45, showing high

• enantioselectivity (85% ee) (Scheme 12) [105]. Exploring a different epoxidation reaction approach, Lattanzi and co-workers reported a methodology using a (+)-norcamphor hydroperoxide 46, to generate the menadione-derived epoxide 40 in 51% ee, under optimized reaction conditions employing n-BuLi/THF [106]. The

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

• of enantioselectivity, and the corresponding optically active oxyaminated malonamates were obtained in reasonably good yields. Keywords: enantioselective; malonamate; nitroso aldol reaction; N-selectivity; Takemoto catalyst; Introduction Nitrosoarenes are versatile building blocks frequently

• better result furnishing the product in 90% yield and 90% enantiomeric excess (Table 1, entry 2). Further lowering of the reaction temperature did not improve the enantioselectivity and slowed down the reaction (Table 1, entries 3 and 4). Our next attempts on the improvement of enantioselectivity focused

• squaramide catalyst 3c, however, with low enantioselectivity (Table 1, entry 6). Disappointingly, the reaction catalyzed by ʟ-proline-derived catalysts gave very low enantioselectivity (Table 1, entries 7 and 8). Having identified Takemoto’s catalyst as the most efficient one for this transformation, our

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• to be more selective catalysts than thioureas. When squaramide C was used as a catalyst, the product was isolated in 80%/87% ee (major/minor diastereoisomer) (Table 1, entry 3). The enantioselectivity was even higher with the cinchonine-derived squaramide D, 85%/92% (major/minor) (Table 1, entry 4

• increase the yield the substrate concentration was varied. A substantial excess of CPD (five equivalents) led to a very slow reaction and a decrease in enantioselectivity (Table 1, entry 8). It was assumed that the binding between CPD and the catalyst was stronger than the binding between the substituted

• oxindole and the squaramide decreasing the effective concentration of the catalyst. Taking this into consideration, 2 equiv of substituted oxindole was used and the reaction proceeded smoothly in 2 h in high enantioselectivity (90%/94% ee), in high yield (74%) but in moderate diastereoselectivity (Table 1

Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins

• Jiang-Song Zhai and
• Da-Ming Du

Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3

• improve the reaction yield and enantioselectivity, but it did not meet our expectations (Table 1, entry 16). Taking into account the ease of operation of the experiment and for economic reasons, we did not explore the effect of increasing the catalyst loading and changing the reaction temperature on the

• the product 3ba was higher than that of the model reaction, but the enantioselectivity was partially reduced. When the 5-position of the indanone was substituted by either F or a MeO group, the yield remained nearly unchanged, however, the enantioselectivity was slightly reduced. On the other hand

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• diphosphine ligand. Preliminary results demonstrated the chiral iron species moderately controlled the enantioselectivity of the aryl Grignard cross-coupling. This work provided a proof-of-concept towards the use of vinylcyclopropanes as useful 1,5-synthons in asymmetric Fe-catalyzed cross-coupling reactions

• . Although poor enantioinduction was observed, several Fe-catalyzed non-sequential cross-coupling protocols have been established with yields and enantioselectivity rivaling Pd-catalyzed reactions [64][65]. Mechanistically, these reactions differ by not including a π-system which allows for propagation of

• asymmetric carboazidation of styrene derivatives 115 (Scheme 33) [135]. The authors propose the enantioselectivity originates from the diastereoisomeric azido group transfer from the Fe(III) center to the benzylic radical. Not only did the described methodology produce enantiopure products in up to 90% ee

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• excellent enantioselectivity [31]. The widespread use of phosphoric acids and phosphates as chiral acids, chiral anions, and ligands is one of the most important achievements of modern enantioselective catalysis. The atropochiral BINOL, H8-BINOL and SPINOL [32] derived phosphoric acids (Figure 4) [33][34

• ′-binaphthalenes (BINAMs) from achiral N,N′-binaphthylhydrazines (Scheme 1). In the presence of chiral phosphoric acids (CPA 1), the reaction undergoes a simple [3,3]-sigmatropic rearrangement, giving the corresponding products 2 in good yield (up to 88%) and enantioselectivity (up to 93:7 er). The density

• ) (Scheme 2). The electronic properties of the substituents on the 2-naphthylamine showed remarkable effects on the chemical yield but had negligible impact on the enantioselectivity [42]. The direct arylation reaction of quinones 6 and 2-naphthols 7 was described by Tan and co-workers in 2015. The

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

• ). Enantioselectivity for a wide range of substrates was achieved in good yield with rigorous optimization of the reaction conditions by utilization of wild-type CAL-B. Synthetic N-glycosylation strategies for glycosidic C–N bond formation in 1,3-oxathiolane nucleosides This section will discuss the methods for

• cytosine or 5-fluorocytosine. Further, hydrolysis of the 5'-O-acetyl group was evaluated with respect to reactivity and enantioselectivity utilizing several enzymes. They found that the butyrate ester derivative was hydrolyzed with a higher rate than the 5'-O-acetate derivative during the synthesis of ʟ

Solvent-free synthesis of enantioenriched β-silyl nitroalkanes under organocatalytic conditions

• Akhil K. Dubey and
• Raghunath Chowdhury

Beilstein J. Org. Chem. 2021, 17, 2642–2649, doi:10.3762/bjoc.17.177

• % yield with 60% ee (Table 1, entry 1). Catalyst II was found to be unproductive as only 25% conversion of β-TMS enone 1a was observed (Table 1, entry 2). Gratifyingly, catalyst III furnished product ent-3a in 85% yield (Table 1, entry 3) with excellent enantioselectivity (94% ee). Whereas catalyst IV

• gave ent-3a in 85% yield with slightly lower enantioselectivity (91% ee) as compared to catalyst III (Table 1, entry 4). Catalyst V also led to product 3a in 66% yield and 78% ee (Table 1, entry 5). Catalyst VI, a pseudoenantiomer of catalyst V delivered ent-3a in 78% yield with 80% ee (Table 1, entry

• solvent-free conditions, and was complete within 24 h without affecting the enantioselectivity of product 3a (Table 1, entry 10). Reducing the loading of nitromethane (2) to 5 equivalents, a slight drop in yield (82%) of product 3a was observed whereas the enantioselectivity (97% ee) remained the same