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

• straightforward method for accessing a wide array of chiral indoline skeletons [5][6][7][8]. The most common strategy in this approach is to utilize an oxindole enolate as a nucleophile, because facile deprotonation from the C-3 carbon is ensured by the inductive effect of the α-carbonyl group and by the enolate

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

• carbon stereocenter to form achiral enolate intermediate 22. Since no kinetic resolution of the racemic starting material was observed, yields in excess of 90% with up to 92% ee could be obtained. In further studies, it was found that the putative enolate intermediate could also be trapped by a proton

• source to yield α-tertiary cycloalkanones in high ee (e.g., (±)-20 → (–)-24) [30]. Interestingly, in the reactions of certain substrates the enolate face functionalized by the electrophilic allyl group is opposite to the face functionalized by the proton (Scheme 5). This observation indicates that the

• two enantioconvergent reactions, though related, must proceed through substantially different mechanisms of enantioinduction. The differential reactivity demonstrated by the enolate intermediate 22 highlights the power of accessing different mechanistic pathways via stereoablative initiation. Examples

Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe

• Motoyuki Isoda,
• Kazuyuki Sato,
• Yurika Kunugi,
• Satsuki Tokonishi,
• Atsushi Tarui,
• Masaaki Omote,
• Hideki Minami and
• Akira Ando

Beilstein J. Org. Chem. 2016, 12, 1608–1615, doi:10.3762/bjoc.12.157

• Mannich-type reaction; rhodium–hydride; zinc enolate; Introduction The Mannich reaction is an important and classical C–C bond-forming reaction between an enolizable carbonyl compound and an imine to give the corresponding β-aminocarbonyl compound. For example, Shibasaki and his colleague reported the

• enolate 7 involved the 1,4-reduction of α,β-unsaturated ester 2 by 6 and the transmetalation with a zinc species to give the Reformatsky-type reagent Int A. This intermediate Int A reacts immediately with the imine to give the corresponding intermediate Int B. Subsequently, intramolecular cyclization of

• ). Furthermore, we reported in the previous paper that the configuration of the Int A species was identified as that of the E-enolate by the trapping procedure of tert-butyl acrylate (2k) with TMS-Cl. In addition, the same reaction gave only the syn-β-amino ester syn-4Ak in 86% and it was speculated that the

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

• + 2] adducts in high yields with high selectivities. Notably, the chiral CuHMDS catalyst worked well with catalyst loadings of both 0.1 and 0.01 mol %. A proposed catalytic cycle is shown in Figure 1. Thus, the chiral CuHMDS deprotonates Schiff base 1a to generate the corresponding chiral Cu enolate B

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• acid (Figure 4C). This is formed by sequential Michael-type cyclisations [57][60], where a conventional lanthionine thioether is first formed by the attack of cysteine onto Dha. The resulting enolate then attacks another Dha residue to stereospecifically form the carbocycle (Figure 4D), and the

Stereoselective synthesis of tricyclic compounds by intramolecular palladium-catalyzed addition of aryl iodides to carbonyl groups

• Jakub Saadi,
• Christoph Bentz,
• Kai Redies,
• Dieter Lentz,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2016, 12, 1236–1242, doi:10.3762/bjoc.12.118

• intramolecular enolate arylation, a reaction that has been discovered by our group some years ago [11][12]. Apparently, under the reaction conditions a ketone enolate of 2 reacts with the iodoarene moiety to form the five-membered ring of 10. The configurational assignments of compounds 7 and 8 are in agreement

• groups [20][21]. Very extensive investigations with a variety of o-haloaniline derivatives as precursors have been reported by the group of Solé, Bonjoch and Fernández [22][23]. They also analyzed this reaction and the competing enolate arylation by computational studies [24][25] (for a review, see [26

• precursor compounds or elimination of water in the products. However, in general none of these byproducts has been isolated. For compound 2 the bulky isopropyl group slows down the addition to the carbonyl group and an enolate arylation was observed instead as major reaction pathway. Although the scope of

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

• are further classified according to whether catalysis is achieved with chiral Lewis acids, organocatalysts, or transition metals. Keywords: asymmetric catalysis; conjugate addition; enantioselective protonation; enolate; Introduction Due to their ubiquity in natural products and drugs, many

• 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

• stabilize the carbanion intermediate, also increases the stereocenter’s susceptibility to racemization under the reaction conditions. Moreover, enolate intermediates can adopt E- or Z-geometries that, upon protonation, generally lead to opposite stereoisomers. Because enantioselective protonation is a

Synthesis of 2-oxindoles via 'transition-metal-free' intramolecular dehydrogenative coupling (IDC) of sp² C–H and sp³ C–H bonds

• Nivesh Kumar,
• Santanu Ghosh,
• Subhajit Bhunia and
• Alakesh Bisai

Beilstein J. Org. Chem. 2016, 12, 1153–1169, doi:10.3762/bjoc.12.111

• as the presence of an o-halogen, an o-selenium, or an o-xanthate, respectively. One of the direct approaches to 2-oxindoles could be a one-electron oxidation of an amide enolate as shown in Scheme 1. Toward this end, in 2009, Kündig and co-workers have developed a novel route to 3,3-disubstituted-2

• to the phenyl ring. The α-carbonylalkyl radicals were formed by Cu(II)-mediated oxidation of the respective enolate precursors. In 2010, Yu and co-workers have reported the synthesis of 3-acetyloxindoles via Ag2O-mediated intramolecular oxidative coupling [45]. For the past few years, our group is

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

• -controlled Michael reaction remained present. Accordingly, we chose to probe reactivity and establish relative stereocontrol using a close model system comprising pronucleophile 8 and furanyl nitroolefin 11 (Scheme 1). The δ-valerolactone pronucleophile 8 was synthesised by the enolate acylation of δ

Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(−)-myrtenol nitrate

• Sean P. Bew,
• Glyn D. Hiatt-Gipson,
• Graham P. Mills and
• Claire E. Reeves

Beilstein J. Org. Chem. 2016, 12, 1081–1095, doi:10.3762/bjoc.12.103

• chloroacetone in THF. It was important in establishing high yields of (E)-58 and (Z)-59 to use a syringe pump. This helped to minimise the number and amounts of side-products formed via, presumably, the enolate of chloroacetone which likely undergoes rapid secondary reactions. Subsequent work-up and

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

• ) and their analogues (Figure 1a) and oxazol-4-(5H)-ones and their thiazolone and imidazolone analogues (Figure 1b). These heterocycles show very interesting characteristics: i) easy deprotonation under soft enolization conditions (aromatic enolate formation); ii) the geometry of the resulting starting

• enolate or equivalent is fixed due to their cyclic nature, thus facilitating the control of the stereoselectivity; iii) they are substituted at the α-position of the carbonyl and therefore, after reaction with an electrophile, a tetrasubstituted stereocenter is created and, iv) the resulting adducts can

• ]. The main advantages of these pronucleophiles over the previous known templates are: i) the NR group can be installed in the heterocycle previous to the asymmetric reaction, ii) they are easily deprotonated under soft enolization conditions (aromatic enolate formation), and iii) unlike azlactones and

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

• ; domino aldol; metal enolate; tetrahydropyran; Introduction Since its discovery in the late nineteenth century the aldol reaction has become one of the most powerful tools in the field of carbon–carbon bond formation [1][2][3][4][5]. It is widely used in the formation of many natural products [6][7][8][9

• benzaldehyde (3a: Ar = Ph) (Scheme 2). The enolate was generated from propiophenone by deprotonation with lithium diisopropylamide (LDA) at −40 °C in tetrahydrofuran (THF) and was subsequently reacted with 0.33 equivalents of MCl3 or 0.25 equivalents of MCl4, respectively. The resulting metal enolate was then

• . Additionally, there are alternating inter- and intramolecular hydrogen bonds between the hydroxy groups. Mechanistic aspects To shed light on the mechanism, the metal to enolate ratio was varied (Table 2), while keeping the optimum temperature for each metal as determined in the previous experiments. 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

• product (Scheme 3). We propose that after deprotonation by the basic in situ generated zwitterion, the resultant enolate form of 3-aryloxindoles might interact with the catalyst by both hydrogen bonding as well as static interaction. The presence of the 3,5-CF3-substituted benzene ring may block the Re

• face of the enolate, driving the electrophile to attack from the Si face. Conclusion In summary, we have realized enantioselective α-aminations of 3-substitued oxindoles with azodicarboxylates by using amino acid-derived bifunctional phosphine catalysts. These reactions afford a variety of chiral 2

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• catalytic cysteine. Subsequently, lactonization can take place. It is assumed that an enolate exists as an intermediate in the formation of the C–O bond [88]. Even though for both enzymes no experimental evidences for the chronological order of the two condensation reactions exist, it can be expected that

(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

• resulting enolate is directed to the upper face of the 3-nitro-2H-chromene due to hydrogen bonding of the enolate with the ammonium cation. The thiourea moiety, firstly activates the 3-nitro-2H-chromene through two hydrogen bonds, making it more electrophilic (LUMO lowering effect) and secondly it orients

• it near the enolate. In 2011, You and co-workers described the intramolecular desymmetrization of cyclohexadienones 69 catalyzed by thiourea 71, derived from cinchonine to give a bicyclic system 70 containing two chiral centers, utilizing an aza-Michael reaction (Scheme 24) [34]. The reaction

• amine of the organocatalyst to provide an enolate, which in turn reacts with the Michael acceptor 111. Cascade/domino/tandem reactions producing six-membered rings initiated by Michael addition of activated methylenes and derivatives In 2004, Takemoto and co-workers demonstrated the enantioselective

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

• -aminoketones 39 in high enantioselectivity [41]. Notably, the homoenolate or enolate reactivity of the NHC-enal adduct was not observed in this case. The presence of a tertiary alcohol functionality and the steric bulk of the NHC-precatalyst 40 were essential for the selective formation of the aza-benzoin

• afforded chiral quaternary aminooxindole derivatives. The NHC–enal adduct prefers to react via the acyl anion pathway and the competing homoenolate/enolate reactivity was not observed. The sterically non-congested, electron-deficient NHC-catalyst 42 presumably does not hinder bond formation at the catalyst

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

• a cinchona organocatalyst with a 6’-OH functionality came from Hatakeyama and co-workers in 1999 who demonstrated the use of β-ICPD in an asymmetric Morita–Baylis–Hillman (MBH) reaction [15][16][17][18] what is essentially an asymmetric C3-substituted ammonium enolate reaction (Scheme 1) [19][20

• processes, the tertiary amine adds into the conjugate ester as with the MBH reaction, but instead of the resulting C3-ammonium enolate reacting with an electrophile, an E1cB elimination of the carbonate occurs to generate another conjugated system. This can then undergo an attack by a Michael donor

• been developed by Frontier and co-worker using β-ICPD through a mechanism that is reminiscent of the MBH reaction (Scheme 7) [31]. In this process however, the tertiary amine adds to the conjugated system 25 in a 1,6-fashion to generate intermediate enolate 26. This undergoes a single bond rotation to

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

• mode of nitromethane with different electrophiles [14][17][39], we propose a possible model to explain the stereochemistry of this transformation. As shown in Figure 2, nitromethane is activated by the tertiary amine to form the nitro enolate. Simultaneously, the 1H-pyrrole-2,3-diones 1 are orientated

• by the multiple hydrogen bonds of the catalyst. Thus, the nitro enolate attacks the keto carbonyl group of 1H-pyrrole-2,3-diones (to the si-face) to furnish the corresponding product with S-configuration (Figure 2). Conclusion In conclusion, we have developed an asymmetric Henry reaction of 1H

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

• heterochiral 50:50 R/S aggregate. We suspected a dimeric aggregate because our rate studies revealed a first-order dependence on enolate concentration. A major breakthrough occurred when Dave saw spectroscopic data wherein the “baseline junk” emerged as two additional resonances on warming; he excitedly

• a great mentor who knew exactly when to push, when to provide assistance, and when to disappear and let me figure it out on my own. A fortuitous and unusual observation during my graduate work led me into the field of organic materials: I observed an enolate alkylation wherein the rate correlated

Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

• Minami Odagi,
• Yoshiharu Yamamoto and
• Kazuo Nagasawa

Beilstein J. Org. Chem. 2016, 12, 198–203, doi:10.3762/bjoc.12.22

• expected that guanidine–bisurea bifunctional organocatalyst 1 would be effective in promoting α-amination of β-keto esters as a result of interactions between guanidine and enolate of the β-keto ester, and between urea and azodicarboxylate (Figure 1b). Herein, we describe the catalytic asymmetric α

• moieties in the catalyst 1f are mandatory for obtaining high enantioselectivity, presumably interacting with the enolate of 4a and DEAD, respectively. Conclusion In conclusion, we have developed an asymmetric α-amination of β-keto esters 4 by using guanidine–bisurea bifunctional organocatalyst 1f in the

Facile synthesis of 4H-chromene derivatives via base-mediated annulation of ortho-hydroxychalcones and 2-bromoallyl sulfones

• Srinivas Thadkapally,
• Athira C. Kunjachan and
• Rajeev S. Menon

Beilstein J. Org. Chem. 2016, 12, 16–21, doi:10.3762/bjoc.12.3

• the enone unit to afford the enolate 12. Isomerization of the exocyclic olefin moiety of 12 into the endocyclic position may be assisted by internal proton transfer. Tautomerization of the resultant enol 13 to its keto form affords the final product 8aa. It may be noted that the key carbon–carbon bond

A convergent, umpoled synthesis of 2-(1-amidoalkyl)pyridines

• Tarn C. Johnson and
• Stephen P. Marsden

Beilstein J. Org. Chem. 2016, 12, 1–4, doi:10.3762/bjoc.12.1

• substitution of suitably-activated pyridine N-oxides by azlactone nucleophiles, followed by decarboxylative azlactone ring-opening. The synthesis obviates the need for precious metal catalysts to achieve a formal enolate arylation reaction, and constitutes a formally ‘umpoled’ approach to this valuable class

• particular has developed methods for the preparation of α-aryl variants by palladium-catalysed enolate arylation reactions [13][14][15]. More recently, we have sought to develop more sustainable methods for the arylation of amino acid enolate equivalents that avoid the use of precious metal salts and

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

• latter being generated after the initial deprotonation of the pronucleophile. The different possibilities offered by the two catalysts 4 and 6 to form geometrically different H-bonded complexes with the nitroacetate enolate would account for the different simple diastereoselection observed in each case

Iron complexes of tetramine ligands catalyse allylic hydroxyamination via a nitroso–ene mechanism

• David Porter,
• Belinda M.-L. Poon and
• Peter J. Rutledge

Beilstein J. Org. Chem. 2015, 11, 2549–2556, doi:10.3762/bjoc.11.275

• situ along with chiral oxazolines [16][17], N-oxides [19] or amines [18][20][21] as ligands or organocatalysts. In these nitrosoaldol contexts, the chiral agents induce asymmetry by virtue of their influence over the enolate reaction partner. Achieving asymmetric induction in the nitroso–ene reaction

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• afforded lactone 64. For the introduction of the side chain, the enolate derived from lactone 64 was treated with 1-bromo-4-methylpent-2-ene, giving a 1:6 mixture of coraxeniolide A (10) and its epimer 65. By equilibration with triazabicyclodecene (TBD), the ratio of 10:65 could be inverted to 3:1. In

• -catalyzed conjugate addition of silyl ketene acetal 81a to enone ent-80. Deprotonation and trapping of the resulting enolate with formaldehyde furnished lactone 82 in a regio- and stereoselective fashion. Introduction of the exocyclic double bond proved to be challenging and therefore salt-free, highly