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

• phenylalanine and LiOH and the ratios of phenylalanine and LiOH were found to be crucial in determining the enantioselectivity; an excess of LiOH caused racemization of the final products. Besides, the solvent, catalyst loading, the reaction time and temperature were also important for the reaction

• designed the bifunctional bisurea catalysts (cat. 27 and 28) that promoted the reactions of isatins with tert-butylhydrazones through hydrogen bond interactions, affording the functionalized 3-hydroxy-2-oxindoles in low enantioselectivity because of the racemization of the adduct products, albeit with high

One-pot synthesis of enantiomerically pure N-protected allylic amines from N-protected α-amino esters

• Gastón Silveira-Dorta,
• Sergio J. Álvarez-Méndez,
• Víctor S. Martín and
• José M. Padrón

Beilstein J. Org. Chem. 2016, 12, 957–962, doi:10.3762/bjoc.12.94

• (dia)stereoselectivity (within limits of 1H NMR detection in the crude reaction mixture) of the process was affected neither by the reaction solvent nor by the amount of DIBAL-H employed. It is known from the literature that some racemization of enantiomerically pure aldehydes occurs during the DIBAL-H

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

• Samantha Caputo,
• Andrea Basso,
• Lisa Moni,
• Renata Riva,
• Valeria Rocca and
• Luca Banfi

Beilstein J. Org. Chem. 2016, 12, 139–143, doi:10.3762/bjoc.12.15

• , no report of valuable diastereocontrol by them has appeared so far. Successful examples of diastereoselective Ugi reactions have been reported only with chiral amines [15][16][17][18][19] or with chiral cyclic imines (Ugi–Joullié reaction) [20][21][22][23], although in the latter case, racemization

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• )malonate ((S)-7), according to Scheme 2. We firstly focused on two well-known mild procedures in order to avoid the classical harsh acidic conditions. Disappointingly, modifications of the Krapcho decarboxylation performed with a LiCl/H2O/DMF mixture under reflux [36][37] led to partial racemization of the

• in ee (Table 3, entries 4 and 8). On the other hand, partial racemization was detected at longer reaction times (Table 3, entries 2, 3 and 7). This somewhat matched the time-dependent loss in ee observed by Allin et al. in the N-deprotection with H2SO4 of other chiral 3-substituted isoindolinones [39

• ]. The racemization probably occurs on the product 9, via the mechanism reported in Scheme 3, as a slower process than the decarboxylation itself. The cleavage of the C–N bond and the formation of the acyclic intermediates 11 with the consequent loss of chirality is probably favored by the protonation of

Stereoselective synthesis of hernandulcin, peroxylippidulcine A, lippidulcines A, B and C and taste evaluation

• Marco G. Rigamonti and
• Francesco G. Gatti

Beilstein J. Org. Chem. 2015, 11, 2117–2124, doi:10.3762/bjoc.11.228

• (+)-β-hydroxyhernadulcin isomer (Figure 1), which has been described as a sweetener [39]. Intrigued by the behavior of 3a we prepared the epimer 3d ([α]D −107° (c 1.2, CHCl3) vs lit. [8] [α]D −118.4° (c 0.5, CHCl3)) by the acid catalyzed racemization of C(6) stereogenic center. Remarkably, the absolute

Radical-mediated dehydrative preparation of cyclic imides using (NH₄)₂S₂O₈–DMSO: application to the synthesis of vernakalant

• Dnyaneshwar N. Garad,
• Subhash D. Tanpure and
• Santosh B. Mhaske

Beilstein J. Org. Chem. 2015, 11, 1008–1016, doi:10.3762/bjoc.11.113

• succinimide 10 without any racemization at the C-3 centre. Finally, reduction of the imide and deprotection of the acetyl moiety was done in a single step by LiAlH4 to obtain vernakalant (11) as the free base. The synthesis was completed in 5 steps with 51% overall yield. A preliminary mechanistic study

Chiroptical properties of 1,3-diphenylallene-anchored tetrathiafulvalene and its polymer synthesis

• Masashi Hasegawa,
• Junta Endo,
• Seiya Iwata,
• Toshiaki Shimasaki and
• Yasuhiro Mazaki

Beilstein J. Org. Chem. 2015, 11, 972–979, doi:10.3762/bjoc.11.109

• switchable by tuning the electronic structure of the tetrathiafulvalene (TTF) moieties. However, compound 1 exhibited slow racemization in solution under daylight. The chirality of an allene is configurationally firm in general, because the barrier of the rotation of the allenic double bonds is quite high

• (ΔG‡ = 180 kJ mol−1 for CH3CH=C=CHCH3) [11]. In contrast, several allenes directly connected with electron-donating groups occasionally underwent photoracemization [12][13]. Although the mechanism of the photoracemization is not clear, a comparative examination of the racemization rate in 1 and 2, the

• latter of which is a dissymmetric allene having a TTF and a pyrenyl group at 1,3-position, suggests that the direct connection of the TTF units may strongly affect the fast racemization [14]. From this point of view, we decided to employ a 1,3-diphenylallene derivative (3) as a stable chiral framework

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• Previero, Barry and Coletti-Previero, detailed previously, regarding the stability of most of the common amino acids under acidic, non-hydrolytic reaction conditions (Table 1). The acidic conditions also guard the unprotected amino acid moiety against racemization through protonation close to the chiral

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

• ketones, under the reaction conditions, resulting in the partial racemization [186]. Good results were achieved in the oxidative C–O coupling of ketones, aldehydes and β-dicarbonyl compounds 198 with carboxylic acids 199 in the presence of the Bu4NI/t-BuOOH system [194] (Scheme 41). The coupling can be

A facile synthesis of functionalized 7,8-diaza[5]helicenes through an oxidative ring-closure of 1,1’-binaphthalene-2,2’-diamines (BINAMs)

• Youhei Takeda,
• Masato Okazaki,
• Yoshiaki Maruoka and
• Satoshi Minakata

Beilstein J. Org. Chem. 2015, 11, 9–15, doi:10.3762/bjoc.11.2

• information of 1a through rapid racemization of optically active 2a or of the reaction intermediates. Having identified the optimized conditions for the oxidative ring-closure of 1a, we then turned our attention to applying this method to the preparation of functionalized 7,8-diaza[5]helicenes (Scheme 3

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

• Paweł Borowiecki,
• Daniel Paprocki and
• Maciej Dranka

Beilstein J. Org. Chem. 2014, 10, 3038–3055, doi:10.3762/bjoc.10.322

• identified as a key step in optimizing the process to avoid racemization. To save one step less, we initiated our efforts by direct transformation of the sec-alcohol functionality in afore-obtained compound (±)-3 under modified Mitsunobu [78][79] reaction conditions using Ph3P (1.1 equiv), DEAD (1.1 equiv

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• development of racemization suppressants such as the most popular HOBt (1-hydroxybenzotriazole) [55]. HOBt traps the O-acylisourea, an intermediate, which tends to racemization, and forms the activated species. Nowadays, a great variety of coupling reagents are commercially available reaching from traditional

• reflected in rapid heating on a molecular level [73]. The strength of the heating is influenced by solvents, reactants, sample volumes and the mode of mixing. It has to be noted that an optimization of temperature is mandatory in order to avoid racemization and side reactions [74]. Application of automated

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