Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• stereochemistry of the AT reaction was reported by Reiff and Aaron [29]. They used enantiopure O-isopropyl methylphosphonite 7-1 (Scheme 7-i) as a substrate. This substrate was purified by distillation with no racemization. However, rapid racemization was observed when 7-1 was treated with sodium methoxide in

• ; consequently, the (R) configuration is preserved in the course of this reaction). The authors also observed a racemization (Scheme 7-ii) when the same reaction was achieved without the addition of a nucleophile (aniline in the present case). The use of similar reaction conditions (CCl4, NEt3) led Mikolajczyk

• et al. [30] to observe the formation of a mixture of diastereoisomers due to a racemization at the phosphorus atom. However, this racemization was not always observed which points out the different stability of diastereoisomeric species (cyclic phosphite in the present case). Other conditions of

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• and Grignard addition. The enantiomeric purity of reisolated 3 was determined by HPLC analysis as its racemization can readily occur via silyl migration under the basic reaction conditions (see Supporting Information File 2 for HPLC chromatograms and for the synthesis of the racemic reference). After

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• . Most reactions gave 89 in low to good yields but in some cases the product could not be isolated, probably due to instability of the product. During the coupling reaction with 13h partial inversion of the phosphorus atom occurred, resulting in racemization. Nickel: Most research has focused on the use

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• points and they provide the Ugi-products 53a,b in high yields and mainly as trans-isomers (de >88%), without racemization. As an extension, two other enantiopure isocyanides were combined with a variety of carboxylic acids furnishing a small library of bicyclic dipeptide mimics (55a–d, Scheme 17) in good

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

• commercial application of chiral complex 1 is rather limited. The major shortcomings of compound 1 are: problematic scale up of its synthesis, partial racemization of the N-(benzyl)proline moiety and undesirable stereochemical outcomes. To overcome these deficiencies we initiated a project aiming to design a

Synthesis and biological activity of N-substituted-tetrahydro-γ-carbolines containing peptide residues

• Nadezhda V. Sokolova,
• Valentine G. Nenajdenko,
• Vladimir B. Sokolov,
• Daria V. Vinogradova,
• Elena F. Shevtsova,
• Ludmila G. Dubova and
• Sergey O. Bachurin

Beilstein J. Org. Chem. 2014, 10, 155–162, doi:10.3762/bjoc.10.13

• catalytic amounts of CsF (Scheme 1). The corresponding protected azidopeptides 5 [14][15] are accessible by the Ugi multicomponent reaction [16][17][18][19] of chiral isocyanoazides 4 [20] with carbonyl compounds, amines and Boc-protected amino acids (Scheme 2). As we showed before, the racemization of the

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• compound (i.e. cleaving off the proton) is done by the addition of Et3N at cold temperatures (–78 to –60 °C). According to Roush, the use of triethylamine for this transformation led to partial racemization of 1 (85% ee). Dondoni noticed that changing the base to the bulkier base N,N-diisopropylethylamine

• aldehyde 1. As a conclusion of the above results we see that reversing the order of the two first reaction steps has a significant effect on the overall yield (from Garner’s 86% to Dondoni’s 94–98%). Less racemization can be observed with the reduction–oxidation sequence. Of course, other methods for the

• olefinating reagents) and 2) E/Z-selectivity of the reaction. Moriwake et al. noticed in their synthesis of vinylglycinol 64 that the reaction of methyltriphenylphosphonium bromide with KH as the base provided 62 in fairly good yield, but with complete racemization of the product (Scheme 25) [101]. This

New developments in gold-catalyzed manipulation of inactivated alkenes

• Michel Chiarucci and
• Marco Bandini

Beilstein J. Org. Chem. 2013, 9, 2586–2614, doi:10.3762/bjoc.9.294

• diastereopure complex 35. Interestingly, the strong [Au(I)]–[Au(I)] aurophilic interaction in 35 prevented racemization even if chiral anions were removed (Scheme 10a). (S)-33 found application in the intramolecular hydroamination of 36, delivering 37 in quantitative yield (98%) and moderate enantioselectivity

Synthesis of enantiomerically pure N-(2,3-dihydroxypropyl)arylamides via oxidative esterification

• Akula Raghunadh,
• Satish S More,
• T. Krishna Chaitanya,
• Yadla Sateesh Kumar,
• Suresh Babu Meruva,
• L. Vaikunta Rao and
• U. K. Syam Kumar

Beilstein J. Org. Chem. 2013, 9, 2129–2136, doi:10.3762/bjoc.9.250

• any racemization under these optimized conditions. Higher dilutions of NMP resulted in longer reaction times and lower yields. A plausible mechanism for the ring opening of epoxide with a nitrogen heterocyclic carbene is presented in Scheme 3. Yadav and co-workers reported the ring opening of epoxide

Non-cross-linked polystyrene-supported 2-imidazolidinone chiral auxiliary: synthesis and application in asymmetric alkylation reactions

• Quynh Pham Bao Nguyen and
• Taek Hyeon Kim

Beilstein J. Org. Chem. 2013, 9, 2113–2119, doi:10.3762/bjoc.9.248

• % de). In almost cases, the recovery and recycling of this soluble polymer-supported chiral auxiliary were achieved to produce highly optical pure carboxylic acids (99% ee). The alkylated polymer 6a was also treated with LiAlH4 and NaOMe. Unexpectedly, racemization occurred under these cleavage

• . Unexpectedly, racemization occurred under these cleavage conditions to produce the corresponding chiral alcohol and ester in 80% and 77% ee, respectively. Synthesis of NCPS-supported 2-imidazolidinone chiral auxiliary 3 through direct copolymerization of 2-imidazolidinone derived monomer 2 with styrene

Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach

• Thi Thanh Huyen Trinh,
• Khanh Hung Nguyen,
• Patricia de Aguiar Amaral and
• Nicolas Gouault

Beilstein J. Org. Chem. 2013, 9, 2042–2047, doi:10.3762/bjoc.9.242

• the in situ deprotection of the amine function to permit the cyclization by Michael addition. However, in some instances partial racemization of the reaction products was observed [22]. Here, one major advantage of gold catalysis is the use of very mild conditions for the cyclization, thereby avoiding

• any racemization and obtaining N-protected compounds which may be useful for further transformations. In order to illustrate the efficiency of our method, we were interested in extending this methodology to quinolizidine privileged structures. Our retrosynthetic analysis is shown in Scheme 2. We

A practical synthesis of long-chain iso-fatty acids (iso-C₁₂–C₁₉) and related natural products

• Mark B. Richardson and
• Spencer J. Williams

Beilstein J. Org. Chem. 2013, 9, 1807–1812, doi:10.3762/bjoc.9.210

• a single diastereoisomer (as determined by 1H NMR) in 80% yield. Cleavage of the chiral auxiliary using LiOH/H2O2 (which occurs without racemization at the α-position) [64] afforded (S)-2,15-dimethylpalmitic acid (30) in 98% yield. 2-Hydroxy-15-methylpalmitic acid has been identified from a range of

Inter- and intramolecular enantioselective carbolithiation reactions

• Asier Gómez-SanJuan,
• Nuria Sotomayor and
• Esther Lete

Beilstein J. Org. Chem. 2013, 9, 313–322, doi:10.3762/bjoc.9.36

• formation of six-membered rings, though the slow cyclization rate results in racemization. The use of a phenylthio-substituted alkene favors the cyclization, and the faster reaction rate results in an improved optical purity of the indolizidines 35 and 36, though with moderate diastereo- and

• enantioselectivity. The addition of TMEDA increases the rate of racemization, resulting in an inversion of diastereoselectivity to obtain 36, albeit in racemic form [44]. The enantioselective cycloisomerization of achiral organolithiums in the presence of a chiral ligand has been reported with aryllithium reagents

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• known to limit racemization in peptide coupling reactions [16]. The enantiomeric excesses of the starting materials were ca. 95%. No erosion of stereochemistry in the products 12 was observed as determined by chiral HPLC. Recrystallization of 12 from ethanol did not increase the enantiomeric excess of

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

• Ricardo A. W. Neves Filho,
• Sebastian Stark,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2012, 8, 2085–2090, doi:10.3762/bjoc.8.234

• coupling with carbodiimides, HBTU, HATU, and PyBroP failed or resulted in very low conversions. The addition of a catalytic amount of DMAP to the carbodiimide-mediated reactions improved the conversions, but resulted in severe racemization. The best result was obtained by employing N-ethoxycarbonyl-2

Asymmetric desymmetrization of meso-diols by C₂-symmetric chiral 4-pyrrolidinopyridines

• Hartmut Schedel,
• Keizo Kan,
• Yoshihiro Ueda,
• Kenji Mishiro,
• Keisuke Yoshida,
• Takumi Furuta and
• Takeo Kawabata

Beilstein J. Org. Chem. 2012, 8, 1778–1787, doi:10.3762/bjoc.8.203

• associated with the higher mono/diacylation ratio in the asymmetric acylation of 22a promoted by 14 (Table 6, entries 6–8). (Notice: Enantioenriched 23a gradually undergoes partial racemization when it is kept as a CHCl3 solution probably via intramolecular acyl migration: e.g., from 88% ee to 71% ee after

On the mechanism of action of gated molecular baskets: The synchronicity of the revolving motion of gates and in/out trafficking of guests

• Keith Hermann,
• Stephen Rieth,
• Hashem A. Taha,
• Bao-Yu Wang,
• Christopher M. Hadad and
• Jovica D. Badjić

Beilstein J. Org. Chem. 2012, 8, 90–99, doi:10.3762/bjoc.8.9

• the gates in the process of the in/out guest exchange necessitates additional scrutiny. In particular, a careful inspection of the additivity of free energies [21] pertaining to the constrictive ΔG‡in/out and intrinsic ΔG° binding energies of the guests [11] as well as the racemization of the basket

• racemization of basket 1 The aromatic gates in basket 1 interact through hydrogen bonding, as exemplified by a large downfield shift of the signal corresponding to (O=C)N−H protons (δ = 11.6 ppm at 298.0 K, Figure 2) [13]. In addition, the aromatic gates are dynamic, each one revolving about its axis to give

• rise to two enantiomeric conformers 1A and 1B (Figure 7A). The interconversion kinetics of the 1A/B racemization can be followed by dynamic NMR spectroscopy in which a singlet corresponding to Ha/Hb nuclei at high temperatures is seen to split into two doublets at low temperatures. In particular, the

Valence isomerization of cyclohepta-1,3,5-triene and its heteroelement analogues

• Helen Jansen,
• J. Chris Slootweg and
• Koop Lammertsma

Beilstein J. Org. Chem. 2011, 7, 1713–1721, doi:10.3762/bjoc.7.201

• almost similar boat puckering for all. From the racemization of substituted benzene oxides (Scheme 2), the oxepine ring inversion barrier was estimated at 6.5 kcal·mol−1 at 135 K [45][46], which is similar to the 3.5 kcal·mol−1 calculated for the parent oxepine (3) at the QCISD(T)/6-31G(d) level [40

Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

• Elizabeth P. Jones,
• Peter Jones,
• Andrew J. P. White and
• Anthony G. M. Barrett

Beilstein J. Org. Chem. 2011, 7, 1570–1576, doi:10.3762/bjoc.7.185

• . Hydrolysis of the sterically less hindered adducts gave the corresponding quaternary amino acids with no racemization, whereas hydrolytic ring opening gave the corresponding valine dipeptides from bulkier bislactims. Keywords: aryl amino acids; arynes; asymmetric; multicomponent; quaternary; Introduction

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• % yield in optically pure form [16]. To alkylate the imide-moiety, glutarimide 3 was reacted with phenylethyl bromide in the presence of potassium carbonate at room temperature. The desired compound 4 was obtained in 98% isolated yield, but analysis revealed racemization. Indeed, the equilibration at the

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• immobilized Candida antarctica lipase B (Novozym 435) was used as a heterogeneous catalyst in the kinetic resolution of the alcohol 22 [30]. Racemization of the unreacted (S)-22 was achieved with acidic zeolite catalysts. Both heterogenous catalysts were coated with ionic liquids for improved stability of the

Efficient and selective chemical transformations under flow conditions: The combination of supported catalysts and supercritical fluids

• M. Isabel Burguete,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2011, 7, 1347–1359, doi:10.3762/bjoc.7.159

• mixture of zeolite CP811E-150 as the acid catalyst for the racemization and CALB supported on a SILLP based on bead-type PS-DVB resins [106]. Good results were obtained when the zeolite catalyst was coated with a small amount of an IL. This follows the same trend observed in the case of SILPs

Synthesis of enantiomerically enriched (R)-¹³C-labelled 2-aminoisobutyric acid (Aib) by conformational memory in the alkylation of a derivative of L-alanine

• Stephen P. Fletcher,
• Jordi Solà,
• Dean Holt,
• Robert A. Brown and
• Jonathan Clayden

Beilstein J. Org. Chem. 2011, 7, 1304–1309, doi:10.3762/bjoc.7.152

• e.r. of the products 5 and 6*) was strongly dependent on the conditions of the reaction and in particular on the time allowed between deprotonation of 3 and the addition of 13CH3I. Presumably, shorter reaction times minimise the extent of racemization of the intermediate enolate 4 [36]. Addition of

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• groups such as Cbz and Pht. The use of phosphorus pentaoxide for peptide synthesis was also reported, but racemization could occur under these reaction conditions [10][11]. Phosphorus oxychloride was another condensing agent used to synthesize various N-protected aminoacyl-pNAs in yields between 70% and

• 90% [12]. The proposed mechanism implies in situ activation of carboxylic acid by formation of the active mixed anhydride with phosphorodichloridic acid. Although the authors demonstrated that the synthesis was simple and free of racemization, this method required unfavorable anhydrous pyridine as a

• racemization, it does not result in satisfactory yields. Because of these limitations of the existing methods, there is still a need to develop a generally applicable method for the synthesis of aminoacyl-pNAs. Conjugation of Nα-protected amino acids with fluorogenic 7-amino-4-methylcoumarin (AMC) is similarly

A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction

• Christian Eidamshaus,
• Roopender Kumar,
• Mrinal K. Bera and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2011, 7, 962–975, doi:10.3762/bjoc.7.108

• form, but in methanol-d4 the equilibrium shifts completely to the pyridinol tautomer. Subsequent transformations of the prepared pyridine derivatives To prove the enantiopurity of the pyridines derived from carboxylic acids and nitriles, which are prone to racemization, i.e., substrates with tertiary

• diastereomeric compounds obtained from racemic starting materials unambiguously shows that the sequence proceeds without noticeable racemization, since 49, 50 and 51 were obtained in diastereomeric pure form (Table 2) as judged by 1H NMR analysis (estimated error 3–5%). For instance, the signal of the methoxy