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

• researchers have developed methods for the stereoselective synthesis of tertiary carbon stereocenters. One aesthetically pleasing approach is the enantioselective protonation of prochiral enolates and enolate equivalents [1][2][3][4][5][6][7][8][9][10]. While an attractive strategy, the enantioselective

• manifold might possibly operate via different pathways. α,β-Unsaturated imides Lewis acids The catalytic generation of enolates in situ, while aesthetically attractive, presents its own set of challenges due to the potential for both E- and Z-enolate isomers that in some cases equilibrate under the

• thiourea catalyst 92 in high yield and modest enantioselectivity (Scheme 22) [45]. Tan and co-workers have investigated the conjugate addition–enantioselective protonation of N-arylitaconimides 95 using a C2-symmetric guanidine catalyst (Scheme 23) [24][46]. Because E- and Z-enolates can exhibit different

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

• of 10% of catalyst loading. Interestingly, the protocol employed gem-diols as equivalents of fluorinated aryl/alkyl methyl ketone enolates for the C–C bond formation accompanied the release of trifluoroacetate. This method showed a broad substrate scope including gem-diols with phenyl rings

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

• . The authors found that whilst the best results for allylation of oxazol-4-(5H)-ones were achieved from zinc enolates, thiazol-4-(5H)-ones produced the best outcome when the magnesium enolate was used. After optimization it was shown that the reaction was efficient with different cinnamyl tert-butyl

Scope and mechanism of the highly stereoselective metal-mediated domino aldol reactions of enolates with aldehydes

• M. Emin Cinar,
• Bernward Engelen,
• Martin Panthöfer,
• Hans-Jörg Deiseroth,
• Jens Schlirf and
• Michael Schmittel

Beilstein J. Org. Chem. 2016, 12, 813–824, doi:10.3762/bjoc.12.80

• ][10][11], stereoselective syntheses [12][13][14][15][16], and tandem reactions [17][18][19]. While the latter processes usually comprise only one aldol reaction, tandem reaction sequences containing two consecutive aldol steps are mostly limited to the trimerization of enolates [20][21][22]. Metal

• enolates (Ti [23], Zr [24], Si [25], and Sn [26]) and boron enolates [27] have adopted a considerable significance because of their high potential to control the stereochemical outcome of the bond formation [28][29][30]. However, the other group III metal enolates have been almost completely omitted over

• with benzaldehyde (PhCHO) is followed by the exergonic first aldol addition showing a small activation barrier of 1.82 kcal mol−1 via a half−chair like transition state (TS-C-A1), which is in accord with the anti-selective aldol addition of titanium enolates [53][54]. TS-C-A1 leads to the formation of

(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

• tetrasubstituted, in good yields and selectivities. In 2013, Luo, Xu and co-workers demonstrated an easy method for the synthesis of enantiomerically pure polysubstituted chromans 99, via the reaction of chalcone enolates 100 and nitromethane (101), catalyzed by quinine-derived thiourea 56 (Scheme 33) [52

My maize and blue brick road to physical organic chemistry in materials

• Anne J. McNeil

Beilstein J. Org. Chem. 2016, 12, 229–238, doi:10.3762/bjoc.12.24

• on a project aimed at understanding why a lithium enolate alkylation stalled at 70% conversion during a key step in the preparative scale synthesis of a factor Xa inhibitor at Aventis. At the time, identifying solution structures of lithium enolates by NMR spectroscopy was challenging owing to the

• declared that the “junk” was instead the complexity of higher aggregates. Sure enough, the “junk” showed a dependence on optical purity consistent with hexameric enolates (Figure 1). We recruited physics graduate student Gil Toombes to help us fit the data using an iterative parametric method and what

• emerged was a beautiful story [3][4][5] (and method) that is still being used to determine the aggregation state of lithium enolates [6][7][8][9] and alkoxides [10][11][12][13]. From Dave, I learned a tremendous amount about being a scientist. One of the most important take-home messages was that all data

Smart molecules for imaging, sensing and health (SMITH)

• Bradley D. Smith

Beilstein J. Org. Chem. 2015, 11, 2540–2548, doi:10.3762/bjoc.11.274

• lithium enolates in a weakly polar solvents using a range of multinuclear NMR methods [2]. The work involved vacuum line preparation of the samples and extensive measurements of NMR parameters. Jackman was a wonderful academic advisor, a passionate scientist who also enjoyed sports and recreation. He was

Lewis acid-promoted hydrofluorination of alkynyl sulfides to generate α-fluorovinyl thioethers

• Davide Bello and
• David O'Hagan

Beilstein J. Org. Chem. 2015, 11, 1902–1909, doi:10.3762/bjoc.11.205

• thioester enols and enolates, important intermediates in enzymatic C–C bond forming reactions. The method opens access to appropriate analogues for investigations in this direction. Keywords: alkynyl sulfides; α-fluorovinyl thioethers; hydrofluorination; Lewis acids; organofluorine; Introduction

• functional and complementary template in enzymatic DNA synthesis [6]. We have recently begun to explore synthesis methods to prepare α-fluorovinyl thioethers, to open up the possibility of exploring this motif as a mimetic for enols and enolates of biochemically relevant thioesters. Thioesters of low

• molecular weight carboxylic acids are found widely in metabolism, often as their co-enzyme A esters, and they then undergo condensation reactions through enols or enolates to generate C–C bonds typified by the processes of long chain fatty acid biosynthesis. α-Fluorovinyl thioethers, illustrated in Figure 2

SmI₂-mediated dimerization of indolylbutenones and synthesis of the myxobacterial natural product indiacen B

• Nils Marsch,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2015, 11, 1700–1706, doi:10.3762/bjoc.11.184

• ][28]. Thus, the indole NH group (pKa about 21 in DMSO) should be able to serve as a stoichiometric proton source that, after β,β'-coupling, would convert one of the Sm(III) enolates to the ketone. Attack of the remaining Sm(III) enolate would lead to Dieckmann-type ring closure, followed by

Highly selective palladium–benzothiazole carbene-catalyzed allylation of active methylene compounds under neutral conditions

• Antonio Monopoli,
• Pietro Cotugno,
• Carlo G. Zambonin,
• Francesco Ciminale and
• Angelo Nacci

Beilstein J. Org. Chem. 2015, 11, 994–999, doi:10.3762/bjoc.11.111

• times) was found to depend on the nucleophilic strength of the intermediate enolates, and ultimately on pKa values (reactivity scale: diethyl malonate pKa 13.5 > acetoacetate pKa 11.0 > acetylacetone pKa 8.9). As an example, diethyl malonate reacted with allyl methyl carbonate much faster than

DBU-promoted carboxylative cyclization of o-hydroxy- and o-acetamidoacetophenone

• Wen-Zhen Zhang,
• Si Liu and
• Xiao-Bing Lu

Beilstein J. Org. Chem. 2015, 11, 906–912, doi:10.3762/bjoc.11.102

• convenient access to the biologically important 4-hydroxy-2H-chromen-2-ones and 4-hydroxy-2(1H)-quinolinones in moderate to good yields under mild reaction conditions. While there are precedents for the carboxylation of enolates, a practical protocol was developed that relies on in situ cyclization to form

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• initial discovery [176][177], the Mukaiyama–Michael reaction has emerged as a reliable alternative to the use of metal enolates as nucleophiles in Michael reactions. Katsuki and co-workers reported the first application of this reaction to α,β-unsaturated amides [178]. Their reactions were promoted by

A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids

• Johanna Trenner and
• Evgeny V. Prusov

Beilstein J. Org. Chem. 2015, 11, 323–327, doi:10.3762/bjoc.11.37

• turned to the alternative oxidation of enolates with molecular oxygen in the presence of triethyl phosphite as originally described by Hartwig [12][13][14][15]. Application of these conditions resulted in a clean conversion to the 5-hydroxy-3-acyltetramic acid but again, the isolated yield of the product

Copper-catalyzed cascade reactions of α,β-unsaturated esters with keto esters

• Zhengning Li,
• Chongnian Wang and
• Zengchang Li

Beilstein J. Org. Chem. 2015, 11, 213–218, doi:10.3762/bjoc.11.23

• mainly based on the lactonization of γ-hydroxy esters, which were obtained through either addition of substituted succinate-derived enolates to carbonyls [3][4][5][6][7], or direct reduction of the corresponding γ-keto esters [8]. Usually they were carried out under acidic or basic conditions, which are

• the linker’s length is expected to yield δ-carboxymethyl-δ-lactones. Copper-catalyzed reductive intermolecular aldolization reactions have been discussed previously [17][18][19]. Constantino has demonstrated that aldol reactions of enolates with ketones or aldehydes are much faster than the Claisen

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• racemic trans-(2-fluoromethylcyclopropyl) iodides 11a–c as alkylating agents for the enolates of (R)-10 and (S)-10 (Figure 2). The initially intended preparations of the three precursors 14a–c to the iodides 11a–c all starting from the known dimethyl trans-cyclopropane-1,2-dicarboxylate (12) [21] through

• %, respectively). Upon treatment with the iodine/triphenylphosphine reagent in the presence of imidazole, the racemic trans-(2-fluoromethylcyclopropyl)methanols 25a–c were smoothly converted to the corresponding iodides 11a–c in very good yields (Scheme 3). Alkylation of the glycine equivalent enolates derived

• = methoxymethyl, Teoc = (2-trimethylsilylethyl)oxycarbonyl. Alkylation of the enolates of the Belokon'-type glycine equivalents (S)- and (R)-10 with the racemic trans-2-(fluoromethyl)cyclopropylmethyl iodides rac-11a–c (see Scheme 3). Yields in % based on converted (S)- and (R)-10. Substituted β

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• the nine-membered ring led to tricyclic compound 45. The pyrrole ring of 45 was formed by intramolecular condensation of cinnamyl amide 46, which is prepared via union of quaternary piperidinone 47 and cinnamyl electrophile 48. We envisioned that our allylic alkylation of lactam enolates would furnish

• control the stereoselectivity. We envisioned that an alternative way of constructing this motif would again make use of our recently developed palladium-catalyzed asymmetric alkylation of lactam enolates. The formal synthesis of (+)-quebrachamine commenced with benzoyl lactam 50 (Scheme 13), which was

(CF₃CO)₂O/CF₃SO₃H-mediated synthesis of 1,3-diketones from carboxylic acids and aromatic ketones

• JungKeun Kim,
• Elvira Shokova,
• Victor Tafeenko and
• Vladimir Kovalev

Beilstein J. Org. Chem. 2014, 10, 2270–2278, doi:10.3762/bjoc.10.236

• condensation, which comprises the C-acylation of the α-position of ketones in the form of their metal enolates, enamines or silyl ethers, with or without a catalyst. To appear as an acylating agent one of the following compounds could be required: acyl halides and acid esters, including formates and oxalates

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

A convenient enantioselective decarboxylative aldol reaction to access chiral α-hydroxy esters using β-keto acids

• Zhiqiang Duan,
• Jianlin Han,
• Ping Qian,
• Zirui Zhang,
• Yi Wang and
• Yi Pan

Beilstein J. Org. Chem. 2014, 10, 969–974, doi:10.3762/bjoc.10.95

• one point-binding aldehydes and two-point binding β-keto acids under mild reaction conditions. The lack of strong Lewis acids or very basic intermediates enabled it to tolerate functionalities that would normally be incompatible with ester enolates, for instance, hydroxy groups, phenols, enolizable

• enolates. Though in the case of enzymatic reactions, decarboxylation occurs first to form the enolates, followed by condensation with esters; it is believed that in the scandium-catalysed aldol process of β-keto acid, similar to the case of malonic acid half thioesters, decarboxylation happens after the

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• several substituents and enolates 33 can be generated from methyl- or ethyl vinyl ketone, the corresponding α,β-unsaturated esters being unreactive. Enamines 34 arise from cyclic or linear C3–C5 ketones, acetophenones and β-diketones. It is noteworthy, that the reactions are highly regiospecific for

Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen

• Hiroki Moriwaki,
• Daniel Resch,
• Hengguang Li,
• Iwao Ojima,
• Ryosuke Takeda,
• José Luis Aceña and
• Vadim A. Soloshonok

Beilstein J. Org. Chem. 2014, 10, 442–448, doi:10.3762/bjoc.10.41

• (S)-7a–f (5–20%) were observed in all cases. Compounds (S)-7a–f result from the reaction of atmospheric oxygen with the corresponding enolates derived from glycine complexes 5 and 6 and the basic reaction conditions [79][80]. Formation of 4-phenylquinazoline derivatives (S)-7a–f can be prevented by

• ) complexes should be conducted under oxygen-free conditions to avoid the formation of byproducts, resulting from the oxidation of the corresponding enolates. 5) The (SCRN) stereochemistry of the Ni(II) complexes is generally preferred. Drawing from these results, an improved design of new ligands is

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• -hydroxysuccinimide esters of N-acetylamino acids has been reported [19], we wished to exploit an alternative approach based upon C-acyloxylation of enolates followed by amine exchange, which had been shown to be very effective in a pyroglutamate series, since it offered synthetic simplicity and the potential 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

• the known allylic alcohol [58]. To synthesize ketone 57, we opted to utilize an asymmetric aldol reaction to set the stereochemistry of the β-hydroxy group. Since the report of Evans’s diastereoselective asymmetric aldol reaction using the boron enolates of N-acyloxazolidinones [59], numerous chiral

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• reaction of chiral imines with enolates derived from Weinreb amides [13][14]. In previous work on the asymmetric synthesis of 2,6-disubstituted piperidines by C–N bond formation, we demonstrated that intramolecular aza-Michael ”type” cyclisation [15] using a β'-carbamate-α,β-unsaturated ketone

Recent advances in transition-metal-catalyzed intermolecular carbomagnesiation and carbozincation

• Kei Murakami and
• Hideki Yorimitsu

Beilstein J. Org. Chem. 2013, 9, 278–302, doi:10.3762/bjoc.9.34

• ][51][52][53] or enolates [54] from simple alkynes by carbocupration reactions. Not only copper but also rhodium can catalyze carbometalation reactions. Hayashi applied carborhodation chemistry [55][56][57][58] to the reactions of aryl alkynyl ketones with arylzinc reagents, which provided enolates of