The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• reaction that leads to the final cis-product 21. The thermodynamically favorable trans-product 21 can be obtained through a tetramethylguanidine (TMG)-catalyzed epimerization process. Other possible electrophiles have been contemplated in the Friedel–Crafts alkylation of indoles. For instance, Jørgensen’s

(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

• epimerization to the sole product 193. Their postulation is based on the fact that Henry reactions are typically reversible, so 194 and 195 could be involved in a retro-Henry and subsequent diastereoselective Henry reaction, where the stereochemical outcome is inducted by the C2 stereochemistry. This is further

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

• /epimerization can again be an issue in special cases [24]. However, the use of amines as chiral auxiliaries has been seldom exploited in peptidomimetic synthesis [16][25][26] because the need to remove the auxiliary reduces the number of diversity inputs and increases the number of synthetic steps. From the

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• additional modifying modules, e.g., epimerization domains, resulting in a greater structural variety than ribosomal peptides usually have. Two examples are the membrane disrupting decapeptide antibiotic tyrocidine A (14) [34] and teixobactin (15) [35], a recently discovered multi-target antibiotic rising

• promoter exchange [45] in the native host. Bioinformatics allowed for the annotation of several epimerization domains in the kollosin A NRPS, but it is hard to determine the actual activity of each of these functions. To overcome this problem, L-[2H8]valine, L-[2H10]leucin, L-[2H7,15N]tyrosine und L

• -[2H5,15N]threonine were fed to P. luminescens. The loss of one deuterium atom for an incorporated labeled amino acid (from Cα) directly supports an epimerase function within the corresponding NRPS module, and the incorporated building block can be assigned as D-configured. In this example, epimerization

Structure and conformational analysis of spiroketals from 6-O-methyl-9(E)-hydroxyiminoerythronolide A

• Ana Čikoš,
• Irena Ćaleta,
• Dinko Žiher,
• Mark B. Vine,
• Ivaylo J. Elenkov,
• Marko Dukši,
• Dubravka Gembarovski,
• Marina Ilijaš,
• Snježana Dragojević,
• Ivica Malnar and
• Sulejman Alihodžić

Beilstein J. Org. Chem. 2015, 11, 1447–1457, doi:10.3762/bjoc.11.157

• each of E isomers goes through an oxocarbenium type transition state that have different stereochemistry on C-8. That reflects in formation of the two isomeric products 3 and 4, with the latter anomerically stabilized and thermodynamically more stable. In this case the complete epimerization to 8S

Novel stereocontrolled syntheses of tashiromine and epitashiromine

• Loránd Kiss,
• Enikő Forró and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2015, 11, 596–603, doi:10.3762/bjoc.11.66

• -aminocyclooctenecarboxylate (±)-3 underwent epimerization at C-1, leading after 18 h to an equilibrium mixture of cis and trans amino esters (1:1 ratio determined by 1H NMR on the crude mixture), the required trans isomer (±)-7 being separated from the cis counterpart and isolated in a yield of 48% by means of column

• chromatography on silica gel (n-hexane/EtOAc 1:4) to give the dihydroxylated amino ester. General procedure for epimerization of the cis-amino ester To a solution of cis N-protected amino ester ((±)-3 or (−)-3) (3.3 mmol) in EtOH (30 mL), EtONa (1.5 equivalents) was added at 0 °C and the mixture was stirred at

C-5’-Triazolyl-2’-oxa-3’-aza-4’a-carbanucleosides: Synthesis and biological evaluation

• Roberto Romeo,
• Caterina Carnovale,
• Salvatore V. Giofrè,
• Maria A. Chiacchio,
• Adriana Garozzo,
• Emanuele Amata,
• Giovanni Romeo and
• Ugo Chiacchio

Beilstein J. Org. Chem. 2015, 11, 328–334, doi:10.3762/bjoc.11.38

• nucleosides and 2’-oxa-3’-aza-modified nucleotides. Triazolyl-2’-oxa-3’-aza-4’a-carbanucleosides. α–β Epimerization. Synthesis of triazolyl isoxazolidinyl-nucleosides 13 and 14. Reagents and conditions: a) Tosyl chloride, TEA, CH2Cl2, rt, 24 h; b) NaI, acetone, reflux, 72 h; c) NaN3, CH3CN/H2O (1:10) in the

Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization

• William H. Hersh

Beilstein J. Org. Chem. 2015, 11, 184–191, doi:10.3762/bjoc.11.19

• barrier was found to be high as no epimerization was detected up to 150 °C, and consistent with this, density functional theory calculations give an inversion barrier of over 40 kcal/mol. Keywords: acylphosphine; acyl phosphite; chiral; DFT; NMR; nucleic acids; oligonucleotides; Introduction Antisense

• P-chiral phosphorothioates, a trivalent dinucleoside phosphorus moiety is required that undergoes rapid epimerization under the sulfurization conditions – that is, the goal was to carry out a dynamic kinetic resolution with formation of a single epimeric phosphorothioate. In order to carry out the

• required dynamic kinetic resolution, it was hypothesized that acylphosphonites 1 might undergo rapid epimerization by comparison to their known acylphosphine analogs 2 (Figure 1). Mislow previously showed that trialkyl and triarylphosphines slowly undergo epimerization only at temperatures above

(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

• equivalent with aldehydes the situation is more complicated. The reaction of (S)-10 with acetaldehyde under strongly basic conditions led to the (R)-threonine complex 29 (inverse configuration relative to that of the proline moiety of (S)-10 due to epimerization on C-2), but when a weaker base such as

• Figure 4 and Supporting Information File 1) [28]. However, the product ratio changed in time from 95:5 after 30 s through 70:18 after 10 min to 5:95 after 24 h at ambient temperature. This epimerization comes along with a possible rearrangement in the Ni complex. The newly formed hydroxide group of the

• conditions at low temperature and to quench the reaction after a short time to avoid epimerization of 28. This modified protocol indeed gave the (R)-allo-threonine (4) in relatively poor yield [7.5% for the Ni complex, 91% (7% overall) for the amino acid], but with high enantiomeric purity in two steps

Total synthesis of the proposed structure of astakolactin

• Takayuki Tonoi,
• Keisuke Mameda,
• Moe Fujishiro,
• Yutaka Yoshinaga and
• Isamu Shiina

Beilstein J. Org. Chem. 2014, 10, 2421–2427, doi:10.3762/bjoc.10.252

• yield was improved from 60 to 71% by decreasing the substrate concentration from 2.0 to 1.0 mM (Table 1, entry 4). During the MNBA-mediated lactonization, no epimerization occurred at the α position of lactone carbonyl group. Thus, the total synthesis of the proposed structure of 1 was achieved. We next

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

• Naoya Oku,
• Miyako Matsumoto,
• Kohsuke Yonejima,
• Keijiroh Tansei and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2014, 10, 1808–1816, doi:10.3762/bjoc.10.190

• because of epimerization [12]. To circumvent this problem, we initially attempted to protect the ketone group prior to chemical conversion (Scheme 1). Compound 1 was acetylated (Supporting Information File 1) and subjected to protection as 1,3-dithiane [13] or 1,4-dinitrophenylhydrazone [14]; however

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• system), the catalytic effect of L-proline resulted in an increase in the reaction yield. Moreover, epimerization on the C-1 carbon atom of the starting aldehyde 88 was also suppressed. The latter effect was attributed to the preferential activation of methyl 3-aminocrotonate by L-proline via the

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

• potent Oxyma-based uronium salt. Dependent on the bulkiness of the amino acids to be coupled and the chemical conditions such as its solubility and its stability, the decision of the proper coupling reagent, offering enhanced reactivity by simultaneous reduction of epimerization, is of high relevance

Addition of H-phosphonates to quinine-derived carbonyl compounds. An unexpected C9 phosphonate–phosphate rearrangement and tandem intramolecular piperidine elimination

• Łukasz Górecki,
• Artur Mucha and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 883–889, doi:10.3762/bjoc.10.85

• solvent, instead of benzene, the reaction time was shortened to 7 hours while maintaining the same yield [35]. Epimerization, that occurred at the neighboring C8 atom, resulted in formation of two diastereomeric products: quininone 11 and quinidinone 12 in a 50:50 ratio. The mixture of ketones 11 and 12

Structure elucidation of female-specific volatiles released by the parasitoid wasp Trichogramma turkestanica (Hymenoptera: Trichogrammatidae)

• Armin Tröger,
• Teris A. van Beek,
• Martinus E. Huigens,
• Isabel M. M. S. Silva,
• Maarten A. Posthumus and
• Wittko Francke

Beilstein J. Org. Chem. 2014, 10, 767–773, doi:10.3762/bjoc.10.72

• position 2 underwent ca. 6% epimerization to yield 7 as a mixture of 4 stereoisomers. The synthesis of 2,6,8,12-tetramethyltrideca-2,4-diene (8) was completed by Wittig reaction using (3-methylbut-2-en-1-yl)triphenylphosphonium bromide [15]. As expected, the obtained mixture of all possible stereoisomers

• , followed by oxidation, yielded the aldehyde 10, which was chain elongated by Wittig reaction with [(2E)-1-methylbut-2-en-1-yl]triphenylphosphonium bromide [17] to afford the protected dienol 11 as a mixture of 4 racemates. This was due to partial epimerization at position 2 of the aldehyde 10 and the less

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

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

• Werner Telle,
• Gerhard Kelter,
• Heinz-Herbert Fiebig,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2014, 10, 316–322, doi:10.3762/bjoc.10.29

• was still active, because it had been shown in several SAR studies that limited variation of the amine or alcohol component at the C-terminal amide or ester moieties of the dolastatin family members can be tolerated without much loss of cytotoxicity. This includes epimerization of the thiazole

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• isomerization to the desired cis-isomer 9 at elevated temperature (≈200 °C [1][2], lowered for more conjugated systems). The isomerization pathways have been suggested to proceed either via the formation of intermediate diradical-species (pathway A, Scheme 3) [16][20][26][27] or through one-center epimerization

Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity

• Thomas A. Munro,
• Wei Xu,
• Douglas M. Ho,
• Lee-Yuan Liu-Chen and
• Bruce M. Cohen

Beilstein J. Org. Chem. 2013, 9, 2916–2924, doi:10.3762/bjoc.9.328

• affinity for opioid receptors [1]. In particular, most modifications of the furan ring tested to date dramatically reduce affinity for κ-OR [1], although small substituents at C-16 have little effect (Figure 1). Unexpectedly, epimerization at C-12, inverting the configuration of the furan ring, reduces

• chromatography, blocking the column. This was therefore extracted from the crude product with hot water. Our results conflict with a previous report that heating 1 in acetic acid led to deacetylation and epimerization [29]. In our hands, 1 was freely soluble in glacial acetic acid and was recovered unchanged

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

• deleterious epimerization of the existing stereocenter in Garner’s aldehyde. Keywords: asymmetric synthesis; Garner’s aldehyde; natural product synthesis; L-serine; Introduction “The universe is a dissymmetrical whole. I am inclined to think that life, as manifested to us, must be a function of the

• -toluenesulfonic acid and 2,2-dimethoxypropane (DMP) in refluxing benzene (Scheme 1) [24][25]. Reduction of the methyl ester 4 to aldehyde 1 was performed with DIBAL-H (175 mol %) at −78 °C. Garner later reported that they had detected some epimerization of the chiral center (5–7% loss of ee down to 93–95% ee) [26

• (Hünig’s base, DIPEA) inhibits the epimerization (Scheme 3) [28]. With DIPEA as the base they could isolate the aldehyde (S)-1 with an enantiopurity of 96–98% ee. The drawback of this route is an additional reaction step, the “overreduction” of the ester 4 to alcohol 6 and the necessary re-oxidation to

Stereodivergent synthesis of jaspine B and its isomers using a carbohydrate-derived alkoxyallene as C₃-building block

• Volker M. Schmiedel,
• Stefano Stefani and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2013, 9, 2564–2569, doi:10.3762/bjoc.9.291

• indicates that a (partial) epimerization at C-4 occurs under the reaction conditions employed. The diastereoselective reduction of the carbonyl group with L-selectride afforded the α-azidotetrahydrofuranones 9 and 10 in 66% yield over three steps. Subsequent hydrogenolysis of 9 and 10 afforded a mixture of

Bidirectional cross metathesis and ring-closing metathesis/ring opening of a C₂-symmetric building block: a strategy for the synthesis of decanolide natural products

• Bernd Schmidt and
• Oliver Kunz

Beilstein J. Org. Chem. 2013, 9, 2544–2555, doi:10.3762/bjoc.9.289

• quantitative recovery of unreacted starting material, the 6-MOM-protected precursor 29 underwent cyclization to the protected decanolide 38 [31] in 67% yield. Deprotection of 38 was accomplished with TFA in dichloromethane at ambient temperature without noticeable epimerization or elimination of water

Biosynthesis of rare hexoses using microorganisms and related enzymes

• Zijie Li,
• Yahui Gao,
• Hideki Nakanishi,
• Xiaodong Gao and
• Li Cai

Beilstein J. Org. Chem. 2013, 9, 2434–2445, doi:10.3762/bjoc.9.281

• rare sugar [25]. More interestingly, D-psicose has also been used to prepare several D-psicose containing disaccharides, aiming to learn the function of the rare sugar containing oligosaccharides and glycosides [27]. D-Psicose can be prepared through the epimerization of D-fructose at C-3 catalyzed by

• respectively. As these two enzymes showed high preference towards D-psicose, they were both renamed as DPEase as well. The activity of these two enzymes is strictly metal-dependent and requires Mn2+ as the optimum cofactor. Under optimal conditions, the epimerization yields were 32% and 28%, respectively [35

• galactitol catalyzed by Pseudomonas sp. ST 24 and the production yield was as high as 70%. The possible transformation route from galactitol to D-sorbose in this strain was deduced as follows (Scheme 4): the substrate galactitol is dehydrogenated at C-2 to afford D-tagatose followed by C-3 epimerization [43

Sequential Diels–Alder/[3,3]-sigmatropic rearrangement reactions of β-nitrostyrene with 3-methyl-1,3-pentadiene

• Peter A. Wade,
• Alma Pipic,
• Matthias Zeller and
• Panagiota Tsetsakos

Beilstein J. Org. Chem. 2013, 9, 2137–2146, doi:10.3762/bjoc.9.251

• . Epimerization occurred at C-6 (the C-atom attached to the nitronate O-atom). An intermediate cyclic zwitterion would seem to be present and is consistent with observed relative rates of isomerization. The rate (and success) of the thermal [3,3]-sigmatropic rearrangement of O-allyl nitronic esters appears to

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

• ]. Additionally, in the solid phase asymmetric alkylation reactions, in which Evans' 2-oxazolidinone chiral auxiliaries were used, the yield and stereoselectivity were too dependent on the base, reaction time, and supported resins. As an example, the base-catalyzed epimerization of the chiral center was

• responsible for epimerization was removed before adding the alkylated reagents [17], to obtain the high stereoselectivity control, the NCPS-supported 2-imidazolidinone chiral auxiliary 3 was simply prepared and asymmetric alkylations of it proceeded smoothly to produce the products in excellent

• acids 8a, 8b, and 8c in excellent ee values (Table 4, entries 1–3). To our surprise, although the asymmetric methylation proceeded very well with excellent diastereocontrol (>99 de), epimerization occurred under NaOH cleavage condition. Consequently, chiral acid 8d was obtained in only 89% ee (Table 4