Towards the development of continuous, organocatalytic, and stereoselective reactions in deep eutectic solvents

• Davide Brenna,
• Elisabetta Massolo,
• Alessandra Puglisi,
• Sergio Rossi,
• Giuseppe Celentano,
• Maurizio Benaglia and
• Vito Capriati

Beilstein J. Org. Chem. 2016, 12, 2620–2626, doi:10.3762/bjoc.12.258

• synthesis of enantiomerically enriched products by testing different experimental set-ups. L-Proline-catalysed cross-aldol reactions were efficiently performed in continuo, with high yield (99%), anti-stereoselectivity, and enantioselectivity (up to 97% ee). Moreover, using two different DES mixtures, the

• diastereoselectivity of the process could be tuned, thereby leading to the formation, under different experimental conditions, to both the syn- and the anti-isomer with very high enantioselectivity. The excess of cyclohexanone was recovered and reused, and the reaction could be run and the product isolated without the

• interaction, nitrogen was used as a diffusor, thus realizing in set-up III a better mixing of the two phases (Figure 1, III). By monitoring the transformations performed with the above-described different set-ups, it was observed that both the diastereoselection and the enantioselectivity were constant during

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• /bjoc.12.222 Abstract A dipeptide-based urea-amide tertiary amine (DP-UAA) was shown to be an effective Brønsted base catalyst for the first asymmetric annulation reaction between 5H-thiazol-4-ones and N-itaconimides. High levels of enantioselectivity (up to 99% ee) and diastereoselectivity (>19:1 dr

• devised and demonstrated as a competent catalyst to furnish excellent chemo- and stereoselectivity [10]. Therefore, we examined catalyst III for this reaction (Table 1, entry 3); annulation adduct 3a was obtained in 60% yield with 70% ee. The increased in enantioselectivity indicates the potential of

• dipeptide-based tertiary amine for this type of reaction. By modifying the thiourea moiety of III to urea lead us to catalyst DP-UAA IV, which could further increase the enantioselectivity (Table 1, entry 4). Subsequently, we screened the solvent effect with IV as the catalyst (Table 1, entries 5–7), and

The direct oxidative diene cyclization and related reactions in natural product synthesis

• Juliane Adrian,
• Leona J. Gross and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200

• the key step (right, Scheme 8) [79]. After reduction of the ester 26, a Sharpless asymmetric dihydroxylation (AD) [86][87][88] reaction furnished diol 31 with a high degree of both regio- and enantioselectivity. Osmium-promoted oxidative type B cyclization of 31 proceeded in high yield (81%) and with

Chiral ammonium betaine-catalyzed asymmetric Mannich-type reaction of oxindoles

• Masahiro Torii,
• Kohsuke Kato,
• Daisuke Uraguchi and
• Takashi Ooi

Beilstein J. Org. Chem. 2016, 12, 2099–2103, doi:10.3762/bjoc.12.199

• . Conclusion In summary, we have clearly demonstrated that chiral ammonium betaine 1c acts as a uniquely effective catalyst in promoting a Mannich-type reaction between 3-aryloxindoles and N-Boc aldimines with high levels of diastereo- and enantioselectivity under mild conditions. This study greatly expands

Enantioconvergent catalysis

• Justin T. Mohr,
• Jared T. Moore and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2016, 12, 2038–2045, doi:10.3762/bjoc.12.192

• %. Three mechanistically distinct approaches to effecting enantioconvergent catalysis are identified, and recent examples of each are highlighted. These processes are compared to related, non-enantioconvergent methods. Keywords: asymmetric catalysis; enantioselectivity; synthetic methods; Review

• . Additionally, there must be a significant difference in the rates of product formation (i.e. k3 > k4). If this condition is not met, enantioselectivity will suffer. Stoltz and co-workers have reported an approach for the preparation of enantioenriched oxindole derivatives from racemic oxindole halides using a

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• enantioselectivity encouraged the Inomata group to further investigate the reaction [152]. Their investigation of enantioselective hetero-Diels–Alder reactions resulted in an enantioselectivity of up to 92% ee, when nitrosobenzene and a dienol were reacted in the presence of tartaric acid ester as a chiral auxiliary

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• -phenylmaleimide (22). For the remaining combinations (20 + 23; 20 + 24; 21 + 24) only the Michael products 29–31 could be observed (0.1 equiv of 10, CH2Cl2, −15 °C). To determine the enantioselectivity of guanidine 10 we started with the structurally simplest case, the reaction of anthrone 20 and N

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

• Hee Seung Jang,
• Yubin Kim and
• Dae Young Kim

Beilstein J. Org. Chem. 2016, 12, 1551–1556, doi:10.3762/bjoc.12.149

• reaction time, and low temperature required for good enantioselectivity. Thus, new approaches for the organocatalytic enantioselective addition of diphenyl phosphonate to isatin imines are highly desired. In connection with our ongoing research program on the design and application in asymmetric catalysis

• initially investigated a reaction system with ketimine 1a derived from N-allylisatin and diphenyl phosphonate (2) with organocatalyst in the presence of 4 Å molecular sieves. We first surveyed the effect of the structure of bifunctional organocatalysts I–VI (Figure 1) on enantioselectivity in ethyl acetate

• methanol were used as the solvent (Table 1, entries 7–11). Under low catalyst loading of 2.5 mol %, this enantioselective addition reaction proceeded successfully to give 3a without compromising the reactivity and enantioselectivity (Table 1, entries 3 and 12–14). Finally, lowering the reaction temperature

Stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)”s: functionalization, rotational barriers and non-covalent interactions

• Golo Storch,
• Sebastian Pallmann,
• Frank Rominger and
• Oliver Trapp

Beilstein J. Org. Chem. 2016, 12, 1453–1458, doi:10.3762/bjoc.12.141

• long as their chirality can be controlled by chiral additives or auxiliaries. In addition, the simultaneous presence of both axially chiral BIPHEP enantiomers can be beneficial as this allows bidirectional control of enantioselectivity depending on temperature [14][15]. In this approach, both product

Development of chiral metal amides as highly reactive catalysts for asymmetric [3 + 2] cycloadditions

• Yasuhiro Yamashita,
• Susumu Yoshimoto,
• Mark J. Dutton and
• Shū Kobayashi

Beilstein J. Org. Chem. 2016, 12, 1447–1452, doi:10.3762/bjoc.12.140

• (SiMe3)2 (CuHMDS) and the FeSulphos ligand, with the latter being related to the system reported by Carretero et al. [15]. The reaction produced 3aa smoothly with 3 mol % catalyst loading at −40 °C, and high endo selectivity and high enantioselectivity were obtained (Table 1, entry 1). On the other hand

• loading (Table 1, entry 3), and similar results were obtained in other solvents such as Et2O and toluene, although the reactivity and enantioselectivity both decreased slightly in dichloromethane (DCM, Table 1, entries 4–6). It was found that the use of the chiral CuHMDS catalyst also afforded the product

• with high enantioselectivity at lower catalyst loadings of 0.1 mol % (Table 1, entry 7). The effect of the amide part of the structure was then examined. Copper dialkylamides were not as reactive as CuHMDS, and lower yields were obtained (Table 1, entries 8 and 9). Interestingly, mesitylcopper also

Selective bromochlorination of a homoallylic alcohol for the total synthesis of (−)-anverene

• Frederick J. Seidl and
• Noah Z. Burns

Beilstein J. Org. Chem. 2016, 12, 1361–1365, doi:10.3762/bjoc.12.129

• regio- and enantioselectivity. Disclosed herein, this discovery has enabled the first total synthesis of (−)-anverene (1) (Scheme 1, bottom), a secondary metabolite from the algae Plocamium cartilagineum with selective antibiotic activity against vancomycin-resistant Enterococcus faecium (VREF) [10

• . Unlike Table 1, entry 1, which was taken to completion, bromochlorinations quenched at low conversion exhibited high enantioselectivity for 6, but also constitutional isomer ratios (cr) as low as 2:1 for 6:7 (not shown). These observations are consistent with a highly selective catalytic reaction

• , and can adopt both monomeric and oligomeric structures, several of which can be catalytically active [12]. When Cl2Ti(OiPr)2 is used in place of ClTi(OiPr)3, bromochloride 7 forms very quickly with no enantioselectivity and with inherent substrate regioselectivity. The additional Ti(OiPr)4 may limit

Synergistic chiral iminium and palladium catalysis: Highly regio- and enantioselective [3 + 2] annulation reaction of 2-vinylcyclopropanes with enals

• Haipan Zhu,
• Peile Du,
• Jianjun Li,
• Ziyang Liao,
• Guohua Liu,
• Hao Li and
• Wei Wang

Beilstein J. Org. Chem. 2016, 12, 1340–1347, doi:10.3762/bjoc.12.127

• , entry 8). It was found that the reaction took place to afford the desired cyclopentane 3a. Encouraged by this result, we carried out further investigations of the co-catalysts promoted process (Table 2). First, we determined the diastereo- and enantioselectivity of the reaction. The 1H NMR of the

• performed in THF was interesting: No reaction occurred at rt (Table 2, entry 8), but at 50 °C, 54% yield with high enantioselectivity for both isomers while 3a’’ as the major product (dr: 3a’’:3a’ = 5:1, Table 2, entry 9) was obtained. We decided to further optimize the reaction in CHCl3 accordingly (Table

• high yields and excellent enantioselectivities for major isomer 3’ and minor 3’’’ products, while the electronic effect on enantioselectivity is more pronounced for minor 3’’ (Table 3, entries 1–5). A similar trend is observed with the aromatic α,β-unsaturated aldehydes with electron-withdrawing at

Artificial Diels–Alderase based on the transmembrane protein FhuA

• Hassan Osseili,
• Daniel F. Sauer,
• Klaus Beckerle,
• Marcus Arlt,
• Tomoki Himiyama,
• Tino Polen,
• Akira Onoda,
• Ulrich Schwaneberg,
• Takashi Hayashi and
• Jun Okuda

Beilstein J. Org. Chem. 2016, 12, 1314–1321, doi:10.3762/bjoc.12.124

• influence the endo/exo ratio as well as the enantioselectivity [30]. Artificial Diels–Alderases have also been reported to show good endo/exo selectivities as well as high enantioselectivities in a benchmark reaction of azachalcone with cyclopentadiene [22][23][24][25][26][27]. The artificial Diels

• absence of any enantioselectivity suggests that no preferential orientation of the substrate at the active site within the barrel structure is possible. Notably, no protein precipitated during catalysis, showing the advantageous feature of membrane proteins in terms of robustness as compared to soluble

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

• , catalytically generated from 1, to α-substituted acrylates 2 followed by enantioselective protonation of the resulting lithium enolate (Scheme 1) [14]. The ortho-trimethylsilyl substituent on the phenyl ring was necessary for achieving high levels of enantioselectivity. All of the reactions proceeded in high

• stoichiometric chiral Mg-(bis)oxazoline complex was required to achieve high enantioselectivity. Higher enantioselectivity was generally observed for reactions using secondary or tertiary alkyl halides. When performing radical conjugate additons to give 2-hydroxymethyl esters 7c, the authors observed a complete

• nucleophiles for the conjugate addition–enantioselective protonation of α-aminoacrylates (vide infra). In 2010, Mikami and co-workers reported a hydrogen atom transfer strategy for the synthesis of β-perfluorobutyl-α-amino ester 13 in low yield and modest enantioselectivity, and the absolute configuration of

NeoPHOX – a structurally tunable ligand system for asymmetric catalysis

• Jaroslav Padevět,
• Marcus G. Schrems,
• Robin Scheil and
• Andreas Pfaltz

Beilstein J. Org. Chem. 2016, 12, 1185–1195, doi:10.3762/bjoc.12.114

• efficiency and excellent enantioselectivity. Among the many oxazoline-derived ligands that have been reported in the literature, SimplePHOX [17] and ThrePHOX [18] have emerged as some of the most versatile and most easily accessible ligand classes. However, although iridium complexes derived from these

• various test substrates were much lower than those induced by the tert-butyloxazoline analog with the exception of the result obtained with the allylic alcohol S2 (Table 1). Surprisingly, the presence of two geminal phenyl substituents at C(5) had a negative impact on the enantioselectivity, as shown by

• the enantioselectivity and catalytic activity of the corresponding iridium complexes. Initial attempts to introduce a silyl or acetyl group by deprotonation with potassium hydride and subsequent reaction with silyl triflates or acetyl chloride failed. The NeoPHOX ligand 14 showed no reaction under

Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization

• Barry M. Trost,
• Michael C. Ryan and
• Meera Rao

Beilstein J. Org. Chem. 2016, 12, 1136–1152, doi:10.3762/bjoc.12.110

• and enantioselectivity of this reaction, as there was a severe matched/mismatched effect observed with another diastereomer. In contrast to the ruthenium-catalyzed [5 + 2] cycloaddition of enynes, which is thought to proceed through a ruthenacyclopentene intermediate [26], it has been proposed that

• that, upon coordination to ruthenium, create diastereomeric, chiral-at-ruthenium complexes (Figure 1c). It was unclear a priori whether this transfer of stereochemical information would have an adventitious, negligible, or detrimental impact on the enantioselectivity of the reaction. With this

• that the sulfoxide must be bound to the metal in order for the reaction to proceed. Raising the temperature to 60 °C had a negligible impact on enantioselectivity (Table 1, entry 2). Our proposed mechanism of the racemic redox bicycloisomerization reaction necessitates the decomplexation of one

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• reported cinchonine-derived bifunctional thiourea catalyst 12 afforded the addition product 13 in high yield with good levels of diastereo- and enantioselectivity (95:5 dr, 90:10 er for the major diastereomer 13). The relative stereochemical configuration of the minor diastereomeric product 14 was

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• situ, giving the corresponding products with 93–99% ee. This modified protocol was also extended to electron-rich heteroarene substrates. Interestingly, hexafluoroisopropanol (HFIP) was found to be able to improve the enantioselectivity significantly. The authors also proposed a possible transition

• were used for the reaction. The phenolic hydroxy group of the catalyst was thought to be crucial in controlling the enantioselectivity by forming hydrogen bonds with reactants. Besides, enantioselective additions of allenes to isatins were also achieved under these conditions, giving the desired

• effects on the enantioselectivity. Compared to acetone and cycloheptanone, good enantioselectivities were obtained for cyclohexanone. Based on the previously observed catalytic performance of amino acid metal salts in asymmetric catalysis, Luo and co-workers reported that phenylalanine lithium salt (cat

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• catalyst control for these reactions should be pursued. Ideally, the catalyst would dictate the diastereoselectivity, the enantioselectivity, and the location of C–H bond insertion to provide any of the possible product isomers selectively on demand. Bridged polycyclic natural products. Strategic

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• (Scheme 2, compounds 13–15) proceeded with poor diastereocontrol but the results were improved by changing to catalyst C2 [62]. Nonetheless, in both cases the enantioselectivity for the major diastereomer was excellent. Finally, and starting from the corresponding bicyclic imidazolones, quaternary proline

• demonstrated to be either less reactive and/or less stereoselective in their addition reaction to nitrostyrene thus affording the corresponding Michael adducts with no diastereoselectivity and/or poor enantioselectivity (Scheme 3). Useful applications of the Michael adducts coming from the Michael addition of

• tetrasubstituted Michael adducts in high diastereo- and enantioselectivity. The efficiency of the previous 2-thio-imidazol-4(5H)-ones as pronucleophiles in Michael reactions has also been corroborated in the addition to these α-silyloxyenones as Michael acceptors [55]. First attempts to carry out the Michael

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• is an important tool for the synthesis of complex molecules due to the high control of enantioselectivity in the formation of stereogenic centers. This paper presents a brief review of the early issues, related mechanistic studies and recent applications on this chemistry area. Keywords: C–H

• coworkers (Scheme 4) [38]. In addition to the novelty of the use of the chiral copper complex 11 for controlling the enantioselectivity, the authors proposed the participation of the copper carbenoid 13, formed from the reaction between the copper complex 11 and methyl diazoacetate 9 as active intermediate

• reaction. The catalyst 17c showed opposite enantioselectivity when compared to the catalysts 17a and 17b, with the S-enantiomer formed as the major product. In 1991, Doyle and coworkers published asymmetric synthesis of lactones from alkyl diazoacetates in high enantioselectivity by intramolecular rhodium

Recent advances in C(sp³)–H bond functionalization via metal–carbene insertions

• Bo Wang,
• Di Qiu,
• Yan Zhang and
• Jianbo Wang

Beilstein J. Org. Chem. 2016, 12, 796–804, doi:10.3762/bjoc.12.78

• (I) complexes. In some cases, high regioselectivity and enantioselectivity have been achieved in the C–H bond insertion of small alkanes. This review highlights the most recent accomplishments in this field. Keywords: alkane; diazo compounds; C–H bond functionalization; C–H bond insertion; metal

• methyl ethers [21]. The use of 2,2,2-trichloroethyl aryldiazoacetates, in combination with sterically crowded chiral Rh(II) catalysts Rh2(R-BPCP)4, enhances the site-selectivity and the enantioselectivity of the reaction. Interestingly, the C–H bonds of a methyl group show high reactivity over the

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• transformation (Table 1, entry 4). Different from N-Boc-oxindole, using N-unprotected oxindole and N-benzyl-substituted oxindole as the substrates, accomplished the reaction with every low enantioselectivity (Table 1, entries 7 and 8), incidated the N-Boc protecting group is crucial for this system. Next, the

• -trichloroethane or the less polar solvent toluene gave no improvement in enantioselectivity in comparison to the originally used DCM (Table 2, entries 1–9). To our delight, lowering the reaction temperature increased the reaction yield significantly (Table 2, entries 10–16), while the highest ee value (90%) with

• DEAD was obtained at −30 °C (Table 2, entry 13). Interestingly, the use of other azodicarboxylates with larger R group as amination reagent revealed different optimum reaction temperatures for the best enantioselectivity, and −78 °C was identified as optimal for di-tert-butyl azodicarboxylate (2d, DBAD

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• McDermott et al. in 2008 (Figure 6) [41]. In two steps (asymmetric deprotonation followed by a carbon dioxide quench and coupling with N-benzylpiperazine, 22) product 23 was produced in 48% yield with 89:11 enantioselectivity favoring the R-configuration of the newly generated carbon center. In contrast to

• enantioselectivity were obtained for N-Boc-pyrrolidines when (−)-sparteine or (+)-sparteine surrogate 28 was used. The reactions could be conducted at −30 or −20 °C with a slight drop of the enantiomeric ratio in comparison to the results at −78 °C. They also reported one example of asymmetric lithiation trapping of

• was found to be problematic. Similar to the Coldham discovery, they also noted that the distal N-alkyl substituents have a profound effect on the overall reaction yield and enantioselectivity, with the bulkier alkyl substituents giving better results. The rationale is that the bulky alkyl substituent