Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• Marc Paul Beller Ulrich Koert Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße 4, 35032 Marburg, Germany 10.3762/bjoc.18.129 Abstract This review summarizes examples for the application of vicinal ketoesters such as α-ketoesters, mesoxalic esters, and α,β-diketoesters as key

• stabilization of reactive conformations by chelation or dipole control. Keywords: aldol addition; ketoesters; natural products; total synthesis; Introduction Vicinal ketoesters contain a carbonyl group adjacent to an ester group. One keto group results in α-ketoesters 1 and two vicinal keto groups lead to α,β

• were used as key intermediates. For reasons of clarity and better comparability all syntheses are strongly summarized highlighting the key step only. The presentation of the examples is structured in three parts: α-Ketoesters as key intermediates: (+)-euphorikanin A, (−)-preussochromone A

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

• conjugate addition of 4-hydroxycoumarin (1) to β,γ-unsaturated α-ketoesters 106 was reported the Kim’s group [69]. In this case, a bifunctional binaphthyl-modified thiourea organocatalyst 108 was used, and among the solvents probed (such as CH2Cl2, CH3CN and toluene), the best results were achieved when the

• [dihydrofurocoumarin/pyrazolone] 83. Michael/hemiketalization addition enantioselective of hydroxycoumarins (1) to: (a) enones 2 and (b) α-ketoesters 86. Synthesis of 2,3-dihydrofurocoumarins 89 through Michael addition of 4-hydroxycoumarins 1 to β-nitrostyrenes 88. Synthesis of pyrano[3,2-c]chromene derivatives 93

• . Enantioselective synthesis of functionalized pyranocoumarins 99. 3-Homoacylcoumarin 70 as 1,3-dipole for enantioselective concerted [3 + 2] cycloaddition. Synthesis of warfarin derivatives 107 through addition of 4-hydroxycoumarins 1 to β,γ-unsaturated α-ketoesters 106. Asymmetric multicatalytic reaction sequence

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

Enantioselective Diels–Alder reaction of anthracene by chiral tritylium catalysis

• Qichao Zhang,
• Jian Lv and
• Sanzhong Luo

Beilstein J. Org. Chem. 2019, 15, 1304–1312, doi:10.3762/bjoc.15.129

• the carbocation precursor [20][21]. In this latent strategy, the carbocation precursor can undergo facile ionic dissociation upon mild external stimulation such as polar substrates (such as α-ketoesters) to form a catalytically active chiral ion pair for substrate activation and chiral induction

• α-ketoesters 4 was subjected to the reaction with anthracene (3a) to give the desired cycloadducts 5a–n in moderate to good yields and with up to 93% ee. The bulkier isopropyl ketoester resulted in a lower yield and enantioselectivity (Table 2, entry 3 vs 1 and 2). Variations on the aromatic group

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

• Herman O. Sintim,
• Hamad H. Al Mamari,
• Hasanain A. A. Almohseni,
• Younes Fegheh-Hassanpour and
• David M. Hodgson

Beilstein J. Org. Chem. 2019, 15, 1194–1202, doi:10.3762/bjoc.15.116

• deprotect the TBDPS ether more slowly than FeCl3, and adjustment of the reaction conditions with AlCl3 (to 2 equiv in CH2Cl2, −78 °C, followed by slow warming to −50 °C) cleanly provided α-ketoester 20 (Scheme 6). α-Ketoesters can be prone to hydrate easily (2D TLC analysis of 20 indicated decomposition

DABCO- and DBU-promoted one-pot reaction of N-sulfonyl ketimines with Morita–Baylis–Hillman carbonates: a sequential approach to (2-hydroxyaryl)nicotinate derivatives

• Soumitra Guin,
• Raman Gupta,
• Debashis Majee and
• Sampak Samanta

Beilstein J. Org. Chem. 2018, 14, 2771–2778, doi:10.3762/bjoc.14.254

• construction of pyridines bearing a carboxylate or CN group at C3 position has been a lucrative target for chemists due to the pharmaceutically privileged status (Figure 1). In this context, Rodriguez’s group successfully established a one-pot three-component reaction between β,γ-unsaturated α-ketoesters, 1,3

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• -aminopyrazole derivatives 16/126 with β,γ-unsaturated-γ-alkoxy-α-ketoesters 175 for the regioselective synthesis of pyrazolo[1,5-a]pyrimidines 177 in refluxing ethanol. The reaction provided high regioselectivity compared to other 1,3-dielectrophiles like 1,3-dicarbonyl compounds. The reaction was proposed to

Regiochemistry of cyclocondensation reactions in the synthesis of polyazaheterocycles

• Patrick T. Campos,
• Leticia V. Rodrigues,
• Andrei L. Belladona,
• Caroline R. Bender,
• Juliana S. Bitencurt,
• Fernanda A. Rosa,
• Davi F. Back,
• Helio G. Bonacorso,
• Nilo Zanatta,
• Clarissa P. Frizzo and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 257–266, doi:10.3762/bjoc.13.29

• compounds 11a–e were washed with acetonitrile (1 × 1 mL). The reactions done with non-symmetric dinucleophiles 8b, 8e, and 8f furnished isomeric product mixtures. Data obtained from DFT-B3LYP theoretical calculations showed that in the three α-ketoesters 5–7, the carbonyl of the ketone has a larger LUMO

• condensation reaction between the α-ketoester fragment in polyazaheterocycles and amidines. The experimental results and theoretical calculations of HOMO/LUMO coefficients, together with charge density and energetic stability of the intermediates, indicate that reactions between α-ketoesters and dinucleophiles

• ,f’), and from 1.44 to 1.47 kcal mol−1 for compounds containing 1,2-diaminopropane (b,b’) in the structure. These data suggest that there is no formation of a preferential isomer, thus corroborating the experimental results. In order to synthesize imidazolones, reactions of the previously obtained α

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

• [68], most efforts still focus on the development of unsaturated ester/amide surrogates [69][70][71], which involve α,β-unsaturated imides, N-acyl heterocycles, α-oxophosphonates, α-ketoesters, 3-methyl-4-nitro-5-alkenylisoxazoles and α’-hydroxyenones. These latter substrates have proven to be very

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

• , 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

• -unsaturated α-ketoesters was reported (Table 1) [41]. In the presence of catalyst ent-4, 1-methyleneaminopyrrolidine (28) reacted with the different β,γ-unsaturated α-ketoesters 26 in dichloromethane at low temperature to give the corresponding products 29, which are useful masked 1,4-dicarbonyl compounds

(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

• 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

• (Scheme 42) [62]. The resulting (R)-3-nitro-2H-chromene was isolated in rather moderate optical purity. In 2010, a domino Michael hemiacetalization reaction was reported between cyclic 1,3-dicarbonyl compounds 134 and β-unsaturated α-ketoesters 87 utilizing a novel tyrosine-derived thiourea 135 (Scheme 43

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

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

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

• 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

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 [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

N-Heterocyclic carbene/Brønsted acid cooperative catalysis as a powerful tool in organic synthesis

• Rob De Vreese and
• Matthias D’hooghe

Beilstein J. Org. Chem. 2012, 8, 398–402, doi:10.3762/bjoc.8.43

• -unsaturated aldehydes [18], the enantioselective synthesis of cyclopentenes from α,β-unsaturated aldehydes and α,β-unsaturated ketones [19], and the preparation of cyclopentanes through the reaction of enals and β,γ-unsaturated α-ketoesters [20]. Discussion Recently, Rovis et al. reported that the acetate

Continuous flow based catch and release protocol for the synthesis of α-ketoesters

• Alessandro Palmieri,
• Steven V. Ley,
• Anastasios Polyzos,
• Mark Ladlow and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2009, 5, No. 23, doi:10.3762/bjoc.5.23

• , Melbourne, Australia, 3169 Uniqsis, Shepreth, Cambridgeshire, SG8 6GB, United Kingdom 10.3762/bjoc.5.23 Abstract Using a combination of commercially available mesofluidic flow equipment and tubes packed with immobilised reagents and scavengers, a new synthesis of α-ketoesters is reported. Keywords: catch

• and release; flow synthesis; α-ketoesters; mesoreactor; polymer supported reagents; Introduction Organic synthesis is changing rapidly owing to the discovery of processes that challenge current dogma and lead to the invention of new chemical reactions [1][2]. Likewise, new synthesis tools are

• chemical syntheses [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. In this work we report the use of the Uniqsis FlowSyn™ continuous flow reactor [55] (Figure 1) to effect a flow-based preparation of α-ketoesters. The key feature of this process is the application of a catch and