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

• in the catalytic cycle of this transformation. From the 1990s, the enantioselective carbenoid insertion into C(sp3)–H bonds starts to be better discussed in the literature. Ikegami and coworkers reported the enantioselective insertion of α-diazo-β-ketoesters into C(sp3)–H bonds catalyzed by rhodium

• porphyrin-based catalyst for enantioselective carbenoid insertion into C(sp3)–H bond. Rhodium porphyrin-based catalyst for enantioselective carbenoid insertion into benzylic C(sp3)–H bond. Enantioselective insertion of α-diazo-β-ketoesters into C(sp3)–H bonds catalyzed by chiral rhodium(II) complexes 17a

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

• -type acceptor, by weak hydrogen-bonding interaction between the oxygen atom of the hydroxy group and the indolic proton (Figure 5). Recently, the conjugated addition of indole derivatives to β,γ-unsaturated α-ketoesters was explored [40]. To this end, the catalytic activity of several chiral thioureas

• -ketoesters 26a–f reacted with the substituted indoles 2 in the presence of ent-4 to achieve the corresponding adducts 27 with good yields and enantioselectivities (up to 88% yield, up to 76% ee) (Scheme 11). Although the absolute configuration was unknown at that point, the authors envisioned a plausible

• , establishing a hydrogen bond with the indolic proton. This would conduct its attack over the Re face of the β,γ-unsaturated α-ketoesters, producing the addition in a stereocontrolled fashion. Some additional experimental proofs provided in the article supported this hypothesis [40]. Michael addition to α,β

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• same nucleophile 81, Wang and his group combined it with β,γ-unsaturated α-ketoesters 87, as the electrophile, catalyzed by bifunctional indane-derived thiourea 88, to produce derivatives of 3,4-dihydro-2H-pyran 89 (Scheme 30) [49]. This reaction sequence involved a Michael reaction, followed by a

• tandem Michael addition of γ,δ-unsaturated-β-ketoesters 114 to trans-β-nitrostyrene 115 which produced tetrasubstituted cyclohexenols 116 and 117 utilizing Takemoto’s catalyst 77 (Scheme 37) [56]. In a paper that described in more detail the transformation, the authors showed that the substitution of the

• dihydropyrans 122. They utilized the novel tyrosine-derived tertiary amine-thiourea 123 in quite low catalyst loading to catalyze the reaction between α-cyanoketones 118 and β,γ-unsaturated α-ketoesters 87 (Scheme 39) [59]. Initially a Michael reaction occurs, followed by a hemiacetalization reaction, providing

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• trifluoromethyl ketones were later developed using the chiral catalyst 27 (Scheme 13) [29]. The electron-deficient triazolium-derived NHC 23 mediated efficient and chemoselective cross-benzoin reactions of aldehydes and α-ketoesters to produce acyloin products endowed with a quaternary stereocentre [30

• ]. Remarkably, the competing hydroacylation reaction was not observed under these reaction conditions. A variety of aliphatic and aromatic aldehydes functioned as acyl donors, whereas several α-ketoesters could be employed as the electrophilic coupling partner to afford the desired products in moderate to good

• cross-benzoin reaction of aliphatic aldehydes and α-ketoesters. Notably, the reaction affords enantiomerically enriched tertiary alcohols. Excellent levels of enantioselection were obtained by using an electron-deficient valine-derived triazolium salt precatalyst 28 (Scheme 15) [31]. Moreover

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• (Scheme 11a) [38]. Subsequent reports by Deng and co-workers include, amongst many varieties of Michael acceptor and donor with various CPN/CPD derivatives [39][40][41], an example where β-ketoesters are used as the nucleophilic component [42]. It is on the basis of this work that Lin and co-workers were

Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors

• Ming-Liang Zhang,
• Deng-Feng Yue,
• Zhen-Hua Wang,
• Yuan Luo,
• Xiao-Ying Xu,
• Xiao-Mei Zhang and
• Wei-Cheng Yuan

Beilstein J. Org. Chem. 2016, 12, 295–300, doi:10.3762/bjoc.12.31

• amino-alcohols, amino acids and carbonyl compounds [15]. Much attention has been devoted to the development of an efficient catalytic asymmetric version of this reaction from readily accessible nitroalkanes and carbonyl compounds [16], such as aldehydes [17][18][19], α-ketoesters [20], α

Catalytic asymmetric formal synthesis of beraprost

• Yusuke Kobayashi,
• Ryuta Kuramoto and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285

• -ketoesters and diazoesters, a reactivity that could be further extended to various other molecular transformations. We believe that these findings could be applied to the synthesis of other biologically active oxo-heterocycles, and thus this is currently under investigation in our laboratory and will be

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

• Jose I. Martínez,
• Uxue Uria,
• Maria Muñiz,
• Efraím Reyes,
• Luisa Carrillo and
• Jose L. Vicario

Beilstein J. Org. Chem. 2015, 11, 2577–2583, doi:10.3762/bjoc.11.277

• ][25][26]. In this context, we have recently reported a catalytic and enantioselective Michael/Michael cascade reaction in which α-nitro-δ-ketoesters react with nitroalkenes to provide densely functionalized cyclohexanes in excellent yield and stereoselectivity (Scheme 1) [27]. This reaction made use

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

• Thibault E. Schmid,
• Sammy Drissi-Amraoui,
• Christophe Crévisy,
• Olivier Baslé and
• Marc Mauduit

Beilstein J. Org. Chem. 2015, 11, 2418–2434, doi:10.3762/bjoc.11.263

• studied the reactivity of various β,γ-unsaturated α-ketoesters, which remain to date the only report dealing with such substrates in Cu-catalyzed ACA of trialkylaluminium [41]. Using the (R)-Binap-based system L4/CuTC, an excellent 1,4-selectivity was achieved with mono-unsaturated substrates. Dienic

• breakthroughs. Nowadays, a number of ACA procedures with a various electron-deficient polyenic substrates (linear and cyclic dienones, dienoates, conjugated thioesters, nitroolefins and nitroenynes, enynones, unsaturated acyl-N-methylimidazoles and conjugated ketoesters) and nucleophiles (dialkylzinc, Grignard

• cyclohexanone from a polyunsaturated cyclic Michael acceptor. Selective conversion of β,γ-unsaturated α-ketoesters in copper-catalyzed asymmetric conjugate addition. Addition of trialkylaluminium compounds to nitroenynes catalyzed by L9/CuTC. Addition of trialkylaluminium compounds to nitrodienes catalyzed by

Azirinium ylides from α-diazoketones and 2H-azirines on the route to 2H-1,4-oxazines: three-membered ring opening vs 1,5-cyclization

• Nikolai V. Rostovskii,
• Mikhail S. Novikov,
• Alexander F. Khlebnikov,
• Galina L. Starova and
• Margarita S. Avdontseva

Beilstein J. Org. Chem. 2015, 11, 302–312, doi:10.3762/bjoc.11.35

• , rhodium carbenoids derived from α-diazocarbonyl compounds transform 2H-azirines 1 to azirinium ylides 5 (Scheme 1) which undergo facile N–C2 bond cleavage to give 2-azabuta-1,3-dienes 3. Recently we showed that the use of α-diazo-β-ketoesters 2 in these reactions, which are finished by 1,6-cyclization of

• cyclize into oxazine 4a under the reaction conditions. According to our previous computational and experimental results for transformations of 3,4-diphenyl-substituted 2-azabuta-1,3-dienes derived from α-diazo-β-ketoesters, oxazine 4a formed via rapid cyclization of azadiene E-3a [15], whereas 2-azabuta

• -ketoesters; b) a high reactivity of azirenooxazole 10j toward acetyl(methyl)ketene (12); c) two competing modes of the attack of 10j on ketene 12, leading to adducts 6j,7j via two short-lived betaine intermediates 13j,13′j and 14j,14′j. It is worthy to notice that the distribution of products 6,7 strongly

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

• was used as the OH-reagent along with 1,3-ketoesters. However, the reaction with 1,3-cyclohexanedione gave products in low yields (19–26%). The coupling of a number of substituted salicylaldehydes with formamides was performed; the aldehyde group, which is prone to oxidation, remaining intact [157

• was used [181]. The reaction time is 18 h at 90 °C, the yields of α-ketoesters vary from 42 to 88%. The unusual C–O cross-coupling of primary alcohols 184 with secondary alcohols 185 in the absence of oxidants was performed in the presence of ruthenium complex 186 as the catalyst; the reaction

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• reactants, even though these are present in the solution in excess to all other species, a fact that is due to the poor ESI response of ketoesters and even more so of aldehydes. In the case of the proline-catalyzed solution (Figure 4a), the catalyst is not visible either, because of an instrumental

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• in 28–64% ee [5]. In a similar fashion, Denmark’s oxazaphosphorinane cis-44a yielded keto esters 46a–c in high optical purities via conjugate addition to enones 41 followed by ozonolysis and oxidative esterification. Using diastereomer trans-44b on the other hand provided ketoesters 46a–c with only

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• olanzapine [105]. The preparation of unsymmetrical 1,4-DHPs by the Hantzsch reaction involving two different β-ketoesters has been reported [106]. The literature survey revealed that the Hantzsch reaction served as a tool for the preparation of C-nucleosides with the C-4-substituted 1,4-DHP moiety as a

Synthesis of chiral N-phosphinyl α-imino esters and their application in asymmetric synthesis of α-amino esters by reduction

• Yiwen Xiong,
• Haibo Mei,
• Lingmin Wu,
• Jianlin Han,
• Yi Pan and
• Guigen Li

Beilstein J. Org. Chem. 2014, 10, 653–659, doi:10.3762/bjoc.10.57

• Research Institute of Nanjing University, Changzhou, 213164, China Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, 79409-1061, USA 10.3762/bjoc.10.57 Abstract A variety of chiral N-phosphinyl α-imino esters have been synthesized for the first time from ketoesters and

Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

• Jie-Ping Wan,
• Yunfang Lin,
• Kaikai Hu and
• Yunyun Liu

Beilstein J. Org. Chem. 2014, 10, 287–292, doi:10.3762/bjoc.10.25

• attractiveness in biological and medicinal researches, DHPMs have also been demonstrated as quite flexible precursors for the synthesis of many other derived heterocyclic scaffolds [13]. For a rather long period, the Biginelli reaction involving the condensation of aldehydes, β-ketoesters and ureas (thioureas

• ) [14] has been dominantly employed for DHPMs synthesis in both racemic [15][16][17][18] and asymmetric versions [19][20][21][22][23]. Despite of many recognized advantages of the Biginelli reaction, the product diversity suffered from limitations because β-ketoesters or 1,3-diketones are intrinsically

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters

• Lin Yan,
• Zhiqiang Han,
• Bo Zhu,
• Caiyun Yang,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2013, 9, 1853–1857, doi:10.3762/bjoc.9.216

• conjugate addition and Mannich reaction of α-fluoro-β-ketoesters with excellent results [38][39][40]. Herein, we wish to report the first allylic alkylation of MBH carbonates with α-fluoro-β-ketoesters in excellent enantioselectivities and moderate diastereoselectivities, furnishing enantiopure fluorinated

• (entry 19). A slight increase in enantio- and diastereoselectivity could be obtained when the reaction temperature was decreased to 10 °C, but the reaction rate became too sluggish to be useful (Table 1, entry 20). Using the established conditions, allylic alkylations of α-fluoro-β-ketoesters 1b–g with

• MBH carbonate 2a were found to afford the products 3ba–ga in 67–79% yield with 88–96% ee and 3:1 to 4:1 dr (Table 2, entries 1–6). The results showed that the introduction of various aryl substituents in α-fluoro-β-ketoesters did not affect the reactivity and stereoselectivity. Subsequently, the scope

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• -ketoesters and aromatic aldehydes to yield dihydropyrimidines has received significant attention, these products having pharmacological activity including calcium channel modulation, mitotic kinesin Eg5 inhibition, and antiviral and antibacterial activity [49][50]. The Biginelli reaction has been performed

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• (3% ee). The usage of Boc for the N-protected group in aziridine resulted in no enantioselectivity under the optimum conditions. The organocatalytic enantioselective ring-opening of N-protected aziridines by β-ketoesters by means of cinchona alkaloid-derived PTCs (Figure 3, OC-12 to OC-19) for

A reductive coupling strategy towards ripostatin A

• Kristin D. Schleicher and
• Timothy F. Jamison

Beilstein J. Org. Chem. 2013, 9, 1533–1550, doi:10.3762/bjoc.9.175

• obtained for either of the individual steps from the methyl series that it replaced. The cleavage of TMSE β-ketoesters with TBAF·3H2O has been described in the literature as a chemoselective method for decarboxylation in the presence of other types of β-ketoesters [64]. Comparable yields for the

• elimination could sometimes be observed; however, this typically occurred in less than 10%. Given these results, it seems that the fluoride-mediated deprotection of TMSE β-ketoesters is deserving of further exploration and utilization as a method for the decarboxylation of sensitive synthetic intermediates

Mechanistic studies on the CAN-mediated intramolecular cyclization of δ-aryl-β-dicarbonyl compounds

• Brian M. Casey,
• Dhandapani V. Sadasivam and
• Robert A. Flowers II

Beilstein J. Org. Chem. 2013, 9, 1472–1479, doi:10.3762/bjoc.9.167

• -electron oxidations employing δ-aryl-β-dicarbonyl compounds have been carried out on arenes containing pendant β-ketoesters [10][11]. When Mn(III)-based oxidants are employed, secondary oxidations of the 2-tetralone products can occur [10][11]. Cerium(IV) ammonium nitrate (CAN) is a versatile, inexpensive

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• ) under ball-milling (400 rpm) to provide an easy access to Michael adducts 10 in good to high yield (63–95%) and excellent enantioselectivity (91–99% ee). The chiral squaramide IX also catalyses the Michael reaction of β-ketoesters 11 with nitrostyrene to provide Michael adducts 12 in 73–95% yield, 1.4:1

• nitrogen activates and orients the dicarbonyl compounds to provide the Michael adduct in high enantioselectivity. Application of grinding with pestle and mortar for highly stereoselective Michael addition of trisubstituted β-ketoesters to nitroalkene derivatives was reported by Chimni’s group (Scheme 8

• ) [48]. Grinding an equimolar quantity of six/five-membered cyclic β-ketoesters 13 and various nitroalkenes 7, including nitrodienes, in the presence of 5 mol % of cupreine-derived organocatalyst X provided Michael adducts 14 in good to high yield (72–99%) and good to excellent stereoselectivity (85–99

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225