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

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• well as enantioselectivity remained unchanged. We have used thiourea (S,R)-C1 for this Michael addition, too, but the catalyst was not successful for this reaction (not shown). Only traces of the Michael adduct were obtained in the solution reaction of butanal (6a) with 1-methoxy-4-(2-nitrovinyl

• ). The aliphatic aldehydes propanal (6d) and hexanal (6b) provided medium yields and diastereoselectivity and enantioselectivity. The Michael addition of 3-phenylpropanal (6c) to (E)-3-(2-nitrovinyl)pyridine (11) required long reaction times (120 h) in solution, similar to those for the reaction with (E

• (7a) using sulfinylurea catalyst (S,R)-C2. A relatively high yield (81%) of Michael adduct 8a was formed in 3 hours of milling, with triethylamine as the base (Table 3, entry 1). The diastereoselectivity and enantioselectivity reached comparable values as in the solvent conditions. The chemical yield

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

• of carbamates, sulfonamides and acetamides 13 bearing an α,β-unsaturated ketone to synthesize a series of 2-substituted five- and six-membered heterocycles in good yields (up to 99%) and excellent enantioselectivity (92–97.5% ee) (Table 3). As in an earlier case [29], several acids were tested as co

• afforded the corresponding adducts in good yields ranging from 72–99% with excellent diastereoselectivity (up to >99:1 dr) and enantioselectivity (>99% ee) (Table 6) [36]. In another report, Yang et al. accomplished a highly asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of

• for the synthesis of dihydroisoquinoline and tetrahydropyridines from Michael reaction of ortho-homoformyl chalcone with various amines by using squaramide catalyst. The reaction occurred with good yields and excellent enantioselectivity [39]. Similarly, Li et al. reported an asymmetric cascade aza

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• -pipecolinic acid, was the most effective. Optimized conditions for substrate 3 (11, m = 1; Ar = 2,6-iPr2C6H3) led to yields approaching 99% with 91% ee. Addition of substituents on the phenyl group maintained excellent enantioselectivity, with 84% to 92% ee. Most of the twelve derivatives tested also had

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• (13% ee) was observed, pointing to the formation of (R)-8 with 16% ee (average of both experiments). The enantiomeric composition of the products 8 and 9 from the other enzyme variants was analysed following the same strategy, revealing that (R)-nephthenol was produced with high enantioselectivity

• enantiomeric ratios through (R)- and (S)-A. Compound 9 may be obtained with a high enantioselectivity, because an active site water could be near to the cationic centre in (R)-A, but distant in (S)-A. Supporting Information Supporting Information File 354: Amino acid sequence alignment, details about the

Enantioselective PCCP Brønsted acid-catalyzed aminalization of aldehydes

• Martin Kamlar,
• Robert Reiberger,
• Martin Nigríni,
• Ivana Císařová and
• Jan Veselý

Beilstein J. Org. Chem. 2021, 17, 2433–2440, doi:10.3762/bjoc.17.160

• stereogenic carbon center with good enantioselectivity (ee up to 80%) and excellent yields (up to 97%). Keywords: aminalization; Brønsted acid; organocatalysis; PCCP; pentacarboxycyclopentadiene; Introduction Nitrogen-containing heterocyclic compounds are commonly occurring in nature and constitute the core

• organocatalytic synthesis of molecules with this moiety uses the reaction between aldehydes and anthranilamide building blocks. The advantage of this methodology lies in the fact that both starting materials are readily available, and the enantioselectivity of such cyclization reactions can be controlled by

• the enantioselectivity of the aminalization reaction. While most solvents tested showed to be effective at room temperature, the enantiomeric purity of the corresponding aminal 3a was low in all cases (Table 1, entries 1–5). On the other hand, the yield of 3a was satisfactory in all reactions. In

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• other hand, such electron-withdrawing groups, α to the reactive centre, dramatically changes the acidity of the substrate (and thus the reactivity of the enolate conjugate base) and as consequence its reactivity which can drastically impact the enantioselectivity in SN2 alkylation processes. In this

• catalytic reaction exhibited poor enantioselectivity and none of the catalysts employed were able to promote the reaction with product ee higher than 22% (Scheme 1C – for more details see Supporting Information File 1). Over the last decade, Maruoka and co-workers discovered that phase-transfer-catalysed

• process. In preliminary studies, we observed that a substituent at the catalyst C-2' position was enhancing the enantioselectivity of the reaction. Initial attention was therefore focused on the influence the other catalyst subunits (i.e., catalysts 7–9, Table 1) exerted over both reactivity and

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• cyclization reaction of succinimide and glutarimide-derived hydroxylactams 7 (Scheme 3) [33]. This system was designed in a way that key experimental observations could be made to analyze whether a SN1 or SN2-type mechanism takes place. A strong dependence of the enantioselectivity on the counterion and

• enantioselectivity, but this system also allowed the control over regioselectivity (C2 vs C4 cyclization) through alteration of the N-substituent of the pyrrole substrate and the acylating reagent (Scheme 4a) [34]. This example showcases that next to the counterion, the acylating group can have a major influence on

• existence of two competing Brønsted acid and Lewis acid mechanistic pathways leading to the same product with high enantioselectivity was then uncovered. Jacobsen et al. reasoned that the key for this highly selective transformation lies in attractive cation–π and cation–dipole secondary interactions

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

• Zara M. Seibel,
• Jeffrey S. Bandar and
• Tristan H. Lambert

Beilstein J. Org. Chem. 2021, 17, 2077–2084, doi:10.3762/bjoc.17.134

• Michael adduct 2 was generated in a 4:1 ratio along with the cycloadduct 3 [43], which we had not observed in our previous study of glycinate imine substrates. The aminoindanol-derived catalyst 5 was more reactive and resulted in improved enantioselectivity (89% ee), but afforded the same 4:1 ratio of the

• ) improved the reactivity somewhat but was detrimental to enantioselectivity (Table 1, entry 4), while changing the relative stereochemistry of the hydroxy substituent resulted in an inactive catalyst (8, entry 5 in Table 1). Likewise, catalysts such as 9 lacking a hydrogen-bonding substituent were not

• approximately equal enantioselectivities but resulted in slightly worse ratios of 2 and 3. 1,4-Dioxane was notably detrimental to the reactivity and selectivity (Table 1, entry 9). On the other hand, the use of diethyl ether as solvent resulted in a high reactivity, enantioselectivity of 93%, and no erosion of

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• was synthesized by Kumagai et al. and applied in the Michael addition of 4-hydroxycoumarin 1 with α,β-unsaturated ketones 2 [42]. This chiral primary amino amide organocatalyst 32 afforded the desired products 3, including warfarin (3a) in 86% yield, although in moderate enantioselectivity (up to 56

• a high diastereoisomeric control and in most cases with good enantioselectivity of the products. It becomes even more attractive, since it allows an in situ rearrangement of the acyl group that can be used in other functionalization methodologies. However, it presents a limitation relative to the

• , with moderate to excellent enantioselectivity followed by two decarboxylations (Scheme 21). Huang’s group has used azadienes to perform an enantioselective 1,4-addition to afford benzofuran-fused six-membered heterocycles with a squaramide catalyst [56]. Based on their previous work, the authors