Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• aldol reaction (Scheme 22B), which was confirmed by the observation of the aldol product in low yield. The ET step initially proposed by Baran has undergone insightful discussions about its nature, and a recent theoretical study postulated a proton-coupled electron transfer (PCET) pathway (Scheme 22C

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• been demonstrated to yield superior results to batch. Higher yields and rates of reaction, and greater selectivities can often be achieved in flow. For example, the rate of the aldol reaction of a silyl enol ether 13 with 4-bromobenzaldehyde (14) showed a marked increase upon transposition to flow [87

• to fragrance chemists. This section investigates the aldol reaction as this is a vital C–C and C=C bond forming tool within this class of reactions. Other sequences such as the Knoevenagel and Darzens condensation, however, will also be considered as part of the evaluation. The condensation of

• reaction [93]. A common synthesis of dihydrojasmone (35) uses an intramolecular aldol reaction to simultaneously form the cyclopentanone ring and the double bond in the correct positions [94][95]. Aldol reactions are most often exothermic, especially those involving highly reactive aldehydes (e.g

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• number of classical methodologies have been used for their synthesis, in which the key step is the generation of the six-membered ring, including the aldol reaction, the reductive amination, Mannich reaction, ring closing metathesis, Diels–Alder reaction with imines as dienophiles, aza-Prins cyclization

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• . A similar tandem strategy of an addition of vinylsilane 196, followed by silyl-Prins cyclization with an aldehyde 197 in the presence of 5 mol % BiBr3, was reported by Hinkle and co-workers to give the corresponding compound 198 (Scheme 47) [18]. The authors further investigated the Mukaiyama aldol

• reaction between the β,γ-unsaturated aldehyde 199 and acetal 200 in the presence of 10 mol % BiBr3 to obtain aldol product 201. However, the addition of 2 equiv of phenylacetaldehyde (189) and 10 mol % BiBr3 afforded dihydropyran 202 in 64% yield as a single isomer, as shown in Scheme 48 [91]. The cis-2,6

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• as the aldol reaction [30], Michael addition [31], Mannich reaction [32], and hydrogenation [33]. Results and Discussion Quite recently Xie and Dixon showed that it is possible to synthesize α-tetrazolylamines from simple and linear tertiary amides using an iridium-based catalytic protocol [19]. They

• widely used as organocatalysts. Such moieties are employed in a number of important synthetic transformations, including the aldol reaction [30], Michael addition [31], Mannich reaction [32], and hydrogenation [33]. We plan to test these possibilities in the near future. Stereochemistry and configuration

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• phosphonate reagent 50 proceeded stereoselectively to give ester 51 in excellent yield (94%). Subsequent DIBAL-H reduction of ester 51 followed by tetrapropylammonium perruthenate (TPAP) oxidation afforded aldehyde (Z,E)-52 as a single isomer in 83% yield over two steps. The asymmetric aldol reaction aldehyde

• ). The total synthesis of inthomycin C ((+)-3) was achieved by using a Stille coupling between (E,E,)-67 and vinyl iodide 48 followed by directed asymmetric aldol reaction under Mukaiyama–Kiyooka aldol reaction conditions (Scheme 6). Initially, (E)-3-(tributylstannyl)propenal (65) was converted into (E,E

• asymmetric aldol reaction in the presence of oxazaborolidinone derivative 68 and silyl ketene acetal 53 to produce the required α-hydroxy ester (+)-11 in 50% yield and 76% ee ((R)-stereochemistry of the major enantiomer). A competitive reduction of 71 was also observed to produce alcohol 72 in 43% yield

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• of the C=C double bond of 170b gave a keto aldehyde (not shown), which was subjected to an acid-mediated aldol reaction to give conidiogenone B (171) in 53% yield. The undesired isomer with β,γ-C=C double bond (not shown) was formed in 34% yield and can be isomerized to the more stable α,β

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• -aldol reaction affording the final product (Scheme 34). This mechanism was experimentally supported by the beneficial effect of water and the observation of HF-loss by 19F NMR. The catalytic version of this process was also studied. The best results in terms of efficiency and stereoselectivity were

• Diels-Alder reactions [70]. Tentative mechanism for the nucleophilic addition/retro-aldol reaction sequence. Catalytic PKR with norbornadiene [70]. Scope of the PKR of trifluoromethylalkynes with norbornadiene [72]. DBU-mediated detrifluoromethylation [72]. A simple route to enone 67, a common

A simple and easy to perform synthetic route to functionalized thienyl bicyclo[3.2.1]octadienes

• Dragana Vuk,
• Irena Škorić,
• Valentina Milašinović,
• Krešimir Molčanov and
• Željko Marinić

Beilstein J. Org. Chem. 2020, 16, 1092–1099, doi:10.3762/bjoc.16.96

• were synthesized through Wittig reactions and subjected to photochemical cyclization, in terms of obtaining the new annulated structures. As part of this study, the aldol reaction of the starting 2-substituted carbaldehyde with acetone was also performed, which produced the thieno-fused benzobicyclo

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• -metal-catalyzed transformations were needed to achieve the total synthesis of des-epoxy-amphidinolide N, including a palladium asymmetric allylic alkylation (Pd-AAA), a Mukaiyama aldol reaction (with Sn), and a Krische allylation (with Ir) [72]. As special feature of this procedure, an Evans aldol

• reaction generated the syn aldol adduct, having the steric configuration imposed in des-epoxy-amphidinolide N. Also, in the last step of their work, Trost et al. managed to install the C14-OH via a finely tuned Rubottom oxidation that finalized the total synthesis of des-epoxy-amphidinolide N. Strikingly

A green, economical synthesis of β-ketonitriles and trifunctionalized building blocks from esters and lactones

• Daniel P. Pienaar,
• Kamogelo R. Butsi,
• Amanda L. Rousseau and
• Dean Brady

Beilstein J. Org. Chem. 2019, 15, 2930–2935, doi:10.3762/bjoc.15.287

• alkoxide anions. This reduces the occurrence of undesirable side-reactions, e.g., intermolecular aldol reaction, lactone/ketonitrile product dimerization and ring-opening polymerization. The application of this method to produce the analogous hemiketal 6 from γ-butyrolactone was not as efficient. Although

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• the formal synthesis of triptolide (Figure 2, route N) [43]. This synthesis highlighted the palladium-catalyzed asymmetric addition of arylboronic acid 37 to 3-methylcyclohex-2-en-1-one (38) to form the C-10 quaternary chiral center, and a subsequent Claisen rearrangement and an aldol reaction to

Application of chiral 2-isoxazoline for the synthesis of syn-1,3-diol analogs

• Juanjuan Feng,
• Tianyu Li,
• Jiaxin Zhang and
• Peng Jiao

Beilstein J. Org. Chem. 2019, 15, 1840–1847, doi:10.3762/bjoc.15.179

• boronic acid had been widely utilized to disconnect the N–O bond as well as to hydrolyze the resulting imine into a ketone [52]. We applied this method to deprotect the isoxazoline 3. However, the desired β-hydroxy ketone was never obtained. In one instance, the methyl ketone from a retro-aldol reaction

New α- and β-cyclodextrin derivatives with cinchona alkaloids used in asymmetric organocatalytic reactions

• Iveta Chena Tichá,
• Simona Hybelbauerová and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2019, 15, 830–839, doi:10.3762/bjoc.15.80

• as the promoter (not in a catalytic amount) of a Henry reaction and obtained the product with 99% ee. Subsequently, Doyagüez et al. [17] attached L-proline to β-CD via different linkers (including a triazole linker) and used the resulting organocatalysts in an aldol reaction in water, albeit with a

• lower enantiomeric excess (54% ee). Conversely, Shen et al. [18] performed an aldol reaction in a buffer using L- and D-proline-derived CDs connected through a pyrrolidine skeleton as catalysts and observed 94% ee. More recently, Liu et al. [19] reported the excellent enantioselectivity of 99% ee in an

• aldol reaction catalyzed by β-CD with L-proline attached through a urea moiety. Therefore, mainly proline-derived CDs have been previously tested as organocatalysts and mainly in aldol-type reactions. The limited number of functional groups attached to CD comprising mainly L-proline restricts the

Mechanistic studies of an L-proline-catalyzed pyridazine formation involving a Diels–Alder reaction with inverse electron demand

• Anne Schnell,
• J. Alexander Willms,
• S. Nozinovic and
• Marianne Engeser

Beilstein J. Org. Chem. 2019, 15, 30–43, doi:10.3762/bjoc.15.3

• -proline-catalyzed aldol reaction. Organocatalysis has become a major research field with many applications and has proven to be a valuable complementary approach to organometallic or enzymatic catalysis [29][30][31][32][33][34]. The advantages especially in comparison to organometallic catalysis lie in a

• inexpensive and easily available. The work of List and Barbas in 2000 was groundbreaking for L-proline-catalyzed reactions [40]. They published a L-proline-catalyzed asymmetric aldol reaction and suggested that the essential catalytic step is the enamine formation between the secondary amine function of L

• aldol reaction [17]. In our case, it unfortunately does not accumulate in sufficient amounts for detection. Thus, the reaction was setup differently: instead of premixing L-proline (0.05 equiv) and tetrazine substrate 2 (1 equiv) in solution and then adding acetone (4 equiv) to start the reaction as

Stereodivergent approach in the protected glycal synthesis of L-vancosamine, L-saccharosamine, L-daunosamine and L-ristosamine involving a ring-closing metathesis step

• Pierre-Antoine Nocquet,
• Aurélie Macé,
• Frédéric Legros,
• Jacques Lebreton,
• Gilles Dujardin,
• Sylvain Collet,
• Arnaud Martel,
• Bertrand Carboni and
• François Carreaux

Beilstein J. Org. Chem. 2018, 14, 2949–2955, doi:10.3762/bjoc.14.274

• derivatives, from the same source of chirality. Results and Discussion Synthesis of vancosamine and saccharosamine glycals. The chiral (−)-lactic methyl ester was identified as the privileged starting material considering that the Evans aldol reaction via boron enolates [26][27][28] with an appropriately O

• -protected aldehyde should afford the desired aldol adduct with a syn relative configuration between the two newly created chiral centers [29][30]. Moreover, the boron-mediated stereoselective aldol reaction is all the more interesting for our synthetic plan as stereochemical diversity can be generated

• strategy based on an Evans’ aldol reaction. Mildly oxidizing conditions using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were used for the removal of the p-methoxybenzyl (PMB) group to provide alcohols 14 (Scheme 3). Several palladium(II) catalysts have been tested for the conversion of alcohols to

Cobalt- and rhodium-catalyzed carboxylation using carbon dioxide as the C1 source

• Tetsuaki Fujihara and
• Yasushi Tsuji

Beilstein J. Org. Chem. 2018, 14, 2435–2460, doi:10.3762/bjoc.14.221

• amount of reductant, as exemplified by the reductive aldol reaction of α,β-unsaturated nitriles catalyzed by cobalt using phenylsilane as the reductant [34]. Yamada found that the reductive carboxylation of α,β-unsaturated compounds with CO2 proceeded in the presence of Co catalysts and reductants

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• results clearly confirmed the cooperative effect and special role of the calixarene backbone. Aldol reaction Since chiral substituents and binding sites attached to the upper rim of the calixarene backbone can offer the full advantage of the unique inclusion properties of hydrophobic cavity, Wang et al

• prolinamide units located appropriate array on calixarene in the presence of 2 mol % of PhCOOH catalyzed the aldol reaction in excellent yield and high enantioselectivity. Under the optimized reaction conditions, the aldol reaction of aromatic aldehydes 72 with 70 and 71 afforded the adducts in moderate to

• respectively have been designed by Yilmaz et al. as shown in Figure 9 [65]. A new prolinamide derivative 92 with increased NH acidity has been synthesized from diformylcalixarene derivative 90 as shown in Scheme 24 [66]. Aldol reaction between 21 and 70 in water showed that catalyst 75 provided faster reaction

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• methods of C2' substitution that involve conversion of the C2'-OH to a ketone followed by Me or F substitution [87][88][89][90][91][92][93][94]. Using the Mukaiyama aldol reaction, Peifer obtained a C2'-substituted ribonolactone, which can then be employed in C-nucleoside synthesis [75]. This involves

• '-substituted D-ribonolactone via Mukaiyama aldol reaction. A series of 2'-O-alkyl, alkyl, cycloalkyl and deoxy D-ribonolactone were synthesized using this method. B. Use of Hantzsch ester to obtain the β-anomer of C-nucleosides. Synthesis of carbocyclic C-nucleosides using cyclopentanone [53]. A. Nucleophlic

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• depicted in Figure 2, PQS (4a) has an OH moiety that allows for its linkage to the organocatalyst proline 4b. Also, PQS has a lipophilic component that acts as a reaction solvent for hydrophobic dienes. The latter feature allows aldol reactions to take place efficiently in water. The aldol reaction between

• asymmetric aldol reaction of cyclohexanone and 4-nitrobenzaldehyde [83]. Cross-linked polymersome nanoreactors were also used to perform asymmetric cyclopropanation reactions in water [15]. These products are highly desired intermediates in the preparation of agrochemicals and pharmaceuticals [84][85][86

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• , reduction, nitro-aldol reaction, and dehydration (Scheme 1). Methylation of the ester 2 in the alpha position proceeded easily with LDA as a base and methyl iodide as an alkylating agent. The ester functionality was then reduced with DIBAL in dichloromethane to afford aldehyde 4 in 90% yield. A base

• -mediated addition of nitromethane to the aldehyde 4 provided nitro alcohol 5. The somewhat lower yield (58%) of the aldol product 5 is likely caused by the reversibility of the nitro-aldol reaction. The yield of this reaction did not improve with longer time and unreacted aldehyde was still present in the

Syn-selective silicon Mukaiyama-type aldol reactions of (pentafluoro-λ⁶-sulfanyl)acetic acid esters with aldehydes

• Anna-Lena Dreier,
• Andrej V. Matsnev,
• Joseph S. Thrasher and
• Günter Haufe

Beilstein J. Org. Chem. 2018, 14, 373–380, doi:10.3762/bjoc.14.25

• . The selectivity of these reactions depends on the geometry of the intermediate enolates. Here, we have reacted octyl pentafluoro-λ6-sulfanylacetate with substituted benzaldehydes and acetaldehyde under the conditions of the silicon-mediated Mukaiyama aldol reaction. The transformations proceeded with

• : aldol reaction; ester enolate; fluorine; SF5 compounds; stereochemistry; Introduction The classical acid- or base-catalyzed directed cross aldol reaction of an aldehyde and an enolizable second carbonyl compound is one of the most powerful and reliable carbon–carbon bond-forming transformations in

• chose the reaction of the less volatile octyl 2-(pentafluoro-λ6-sulfanyl)acetate (1) with p-nitrobenzaldehyde. Analogously to a protocol used by Ishihara et al. [35] for an Evans aldol reaction of trifluoropropanoic amides, we refluxed 1 equiv of ester 1 with 1.5 equiv trimethylsilyl

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• than the aldol reaction, especially in the case of heterogeneous conditions. Moreover, another limitation of the Reformatsky reaction is the requirement of an α-halogen in the Reformatsky reagent. Anyway, the Reformatsky reaction is versatile since it can occur through either intra- or intermolecular

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

• Yaochun Xu,
• Isabelle Correia,
• Tap Ha-Duong,
• Nadjib Kihal,
• Jean-Louis Soulier,
• Julia Kaffy,
• Benoît Crousse,
• Olivier Lequin and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2017, 13, 2842–2853, doi:10.3762/bjoc.13.276

• followed a general procedure to access to (2S,3S)-CF3-threonine through an aldol reaction of CF3CHO with the Ni(II) complex of the chiral Schiff base of glycine which was introduced by Belokon et al. [23][24]. The chiral auxiliary (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide (11) was obtained

• conditions gave the nickel Schiff base complex 12 in 71% yield as red crystals. The nucleophilic glycine equivalent 12 went through the aldol reaction with trifluoroacetaldehyde to give complex 13 in moderate yield (66%). Further hydrolysis of complex 13 led to the recovery of the chiral auxiliary 11 and

• obtained through the aldol reaction of trifluoroacetaldehyde with the Ni(II) complex of the chiral Schiff base of glycine. The conformational analysis of these pentapeptides was conducted by the combined use of NMR spectroscopy and molecular dynamics simulations. NMR conformational studies showed that the

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• protection. Xaa-ψ[CF=C]-Pro The first asymmetric synthesis of Xaa-ψ[CF=C]-Pro was reported in 2012 by Chang’s group with the synthesis of MeOCO-Val-ψ[(Z)-CF=C]-Pro 93 (Scheme 18) [52]. Their synthesis started with a stereoselective aldol reaction using (L)-threonine to furnish a chiral β-hydroxy