Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• exhibiting comparable electrophilicity to activated esters; however, with considerably fewer steric restrictions [9][10]. Acylations with acyl fluorides also typically proceed with fewer side-reactions while derivatives bearing an α-stereocentre generally undergo little racemisation [11][12]. The combination

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• hangtaimycin, TDD and the hangtaimycin degradation product HTM222 are given. Keywords: antibiotics; enantioselective synthesis; peptides; racemisation; Streptomyces; Introduction Hangtaimycin (1, Scheme 1) was first isolated from Streptomyces spectabilis and shown to possess weak antimicrobial activity

• proceeded with a high diastereoselectivity (Z/E = 8:1), giving access to 4 in a satisfactory yield of 29% over 6 steps. However, the optical rotation of the obtained material showed only a small positive value ([α]D25 = +1.9, c 0.27, EtOH), suggesting that 4 had undergone racemisation during the prolonged

• integration, Figure 1B). Further improvement of the enantiomeric excess of 4 (90% ee, Figure 1C) was possible by performing the elimination reaction with 14 and KH and 18-crown-6 under ice cooling. This helped to suppress basic racemisation of 4, but required prolonged reaction times and gave a slightly

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• . Also, a higher C–H acidity of the proton at the stereogenic centre and possible racemisation can’t be excluded. A heteroaromatic oxindole derivative afforded the product 3j in lower yield and high ee values. 4- and 5-bromo oxindole derivatives (2l and 2k, respectively) were also used as starting

Kinetics of enzyme-catalysed desymmetrisation of prochiral substrates: product enantiomeric excess is not always constant

• Peter J. Halling

Beilstein J. Org. Chem. 2021, 17, 873–884, doi:10.3762/bjoc.17.73

• enzymatic desymmetrisation. These show that the mechanisms necessarily include a pathway of elementary reactions catalysed by the enzyme that brings about racemisation of the product. This will always be possible unless either the reaction is completely irreversible, or the reactions leading to the less

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• by Bach to the deracemisation of allenes rac-194 (Scheme 29) [85]. The proposed mechanism proceeds through configurationally isomeric hydrogen bonding complexes 195 and 195’, with subsequent photoexcitation of the thioxanthone chromophore leading to racemisation of the allene through a triplet state

• ). As the efficiency of Dexter energy transfer decreases exponentially with distance, the larger gap results in lower sensitisation rates for 190. This, in combination with the difference in association constants, leads to greater racemisation of ent-194 and, therefore, a deracemisation with excellent

• reversible reductive quenching step to give two enantiomeric radical cations 236•+ and ent-236•+. The acidified adjacent proton can then be abstracted by a base to give the racemic radical 236•, which then undergoes HAT with a thiol HAT catalyst to complete the racemisation. If an appropriate chiral base is

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• chromatography. Pleasingly, the sequence proceeded in high yields (63–83%) for all substrates with no chromatography required. Despite relatively high yields, significant racemisation was seen in the synthesis of piperidine 20 and pyrrolidine cores 23. Pyrrolidine 23 was obtained with an ee of only 30

• %, representing a significant loss of enantiopurity. It is believed that racemisation occurred during the olefination step, caused by a base mediated keto–enol tautomerisation. It was proposed that the use of lithium hydroxide would promote hydrate formation, mitigating racemisation of the aldehyde. However, this

• was unsuccessful as complete racemisation was observed, with olefination requiring five days to complete. No olefination was seen using DIPEA under refluxing conditions. As such, this sequence, as currently performed, is suitable for substrates lacking an acidic α-proton (fluoropyrrolidine core 6) or

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• surprised to observe compound 10 had undergone racemisation under these conditions. The exact cause of racemisation is unknown, but may possibly be due to the four equivalents of DIPEA used to ensure 5 is converted to its free base. This will be investigated further for the synthesis of future conjugates

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

• Pavel Yanev and
• Plamen Angelov

Beilstein J. Org. Chem. 2018, 14, 2602–2606, doi:10.3762/bjoc.14.238

• improve the yields of 3k,l to 77% and 60%, respectively, only by using the corresponding N-phthaloyl amino acid chlorides [35][36] as acylating reagents. The increased yield however came at the expense of chiral integrity, with nearly full racemisation. After the series of α-aminoacyl (3) and ω-aminoacyl

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• , which were synthesised according to Brieke et al. [18][36]. It has to be noted that the Hpg-residue at position 7 of all heptapeptides is highly racemisation prone. In case of the Tei7 peptide effective separation by preparative HPLC was possible, so that pure L-Hpg7 and D-Hpg7 peptide could be used [13

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

• intermediate from the acylsilane followed by a cross-coupling with the imine [39]. In 2005, Miller and co-workers used the chiral thiazolium salt 38 to catalyse an enantioselective cross-aza-benzoin reaction. Racemisation of the products under the reaction conditions caused erosion of enantioselectivity. This

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

• Beatrice Bechi,
• David Amantini,
• Cristina Tintori,
• Maurizio Botta and
• Romano di Fabio

Beilstein J. Org. Chem. 2014, 10, 1114–1120, doi:10.3762/bjoc.10.110

• ratio: 49%, 33%), the others minor (12%, 3%, 1.8% and 1.2%, respectively). The presence of two unexpected additional diastereoisomers can be explained based upon a partial racemisation of the chiral center next to the nitrogen, most likely occurring during the Petasis olefination reaction of

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• achieved a yield of 44% over two steps (59% and 74%, respectively) compared to 70% according to our direct conversion from 1a to 2a. Next the carboxylic acids 2 were transformed to the Weinreb amides 5 with DCC and MeONHMe in 77–91% yield (Scheme 2). While no racemisation occurred with substrates 2a, 2b

• desired amide 5c was isolated with a very good ee of 95% (entry 6) [64]. The high racemisation sensitivity of 2c is further underlined by a T3P/pyridine (n-propylphosphonic acid anhydride) [65][66] mediated amidation, which has been reported to suppress racemisation [67]. With substrate 2c the

• condensation product 5c was formed in a moderate ee of 74% (Table 1, entry 7). The configurational lability of the phenylglycine derivative was not surprising, as phenylglycine itself is 60 times more prone to racemisation than alanine [68]. The optical purity of amides 5a–c, hydroxyketone 7c and piperidins

The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow

• Kimberley A. Roper,
• Malcolm B. Berry and
• Steven V. Ley

Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207

• contamination between substrates run in sequential reactions through a single monolith (with the exception of the nicotinaldehyde substrate explained above). An important test of this methodology was the application to α-chiral aldehydes, to ensure that racemisation of the sensitive chiral centre is avoided in

• aldehydes were also successfully transformed, without racemisation of the stereocentre and two ketones bearing electron-withdrawing groups were converted into the desired dibromoolefins in high yield. It was further demonstrated that the same monoliths could be applied to the Appel reaction, giving a small

Synthesis of the calcilytic ligand NPS 2143

• Henrik Johansson,
• Thomas Cailly,
• Alex Rojas Bie Thomsen,
• Hans Bräuner-Osborne and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2013, 9, 1383–1387, doi:10.3762/bjoc.9.154

• . Similar to a previously reported synthesis of (R)-3 [13], we decided to activate epoxide 5 as the m-nosyl derivative that has been shown to minimise racemisation during epoxide ring opening [15]. The synthesis of amine 6 was accomplished from commercially available 2-cyanonaphthalene (7) in four steps

• ’ attack thereby suppressing racemisation [15]. m-Nosylate 5 was synthesised by using nosyl chloride at low temperature [19]. Upon cooling, the reaction mixture became a viscous slurry, and it was important to maintain vigorous stirring to ensure full conversion. In this manner, a spectroscopically pure

Intramolecular carbenoid ylide forming reactions of 2-diazo-3-keto-4-phthalimidocarboxylic esters derived from methionine and cysteine

• Marc Enßle,
• Stefan Buck,
• Roland Werz and
• Gerhard Maas

Beilstein J. Org. Chem. 2012, 8, 433–440, doi:10.3762/bjoc.8.49

• , so that the reaction could be performed in toluene under reflux. For phenylalanine, it was reported that no racemisation occurred under these conditions [21]. However, with some other α-aminoacids we have noted a small degree of racemisation [18]. In this work, we can confirm the reported specific

• rotation value for N,N-phthaloyl-L-methionine (6a), but racemisation occurred to a significant extent in the case of S-benzyl-N,N-phthaloyl-L-cysteine (6b) (Supporting Information File 1). Practically complete racemisation took place during conversion of N-protected aminoacids 6a–c to the β-ketoesters 7a–c

• racemisation. A sample of 8a, which was prepared from a slightly racemised sample of 6a (HPLC: 90:10 enantiomeric ratio of the derived methyl ester, which was prepared from 6a and dry methanol in the presence of excess chlorotrimethylsilane) on the latter route, had an enantiomeric ratio of 83:17. Rhodium

Carbamate-directed benzylic lithiation for the diastereo- and enantioselective synthesis of diaryl ether atropisomers

• Abigail Page and
• Jonathan Clayden

Beilstein J. Org. Chem. 2011, 7, 1327–1333, doi:10.3762/bjoc.7.156

• organolithiums may again be to blame. Enantiomerically enriched stannane returned enantiomerically enriched product, showing that racemisation (which necessarily involves either rotation about the Ar–O–Ar axis or deprotonation–reprotonation) is also slow. Discussion Due to the gummy nature of the products, it

• turned out to be impossible to establish unequivocally the relative or absolute stereochemistry of the products obtained from the lithiations. However, we can make several important conclusions from this work. Firstly, racemisation of the intermediate organolithiums is demonstrably slow, because an

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• products 16 with complete inversion of configuration [16][17]. Acid catalysed cleavage of a thioether or thioacetate yields tert-thiols 17 in good yield. 1.1.2 Epoxide ring opening SN2 displacements from quaternary electrophiles require specific structural features to avoid competing racemisation

• ]. Equilibration of the diastereoisomers of 71 favoured axial methylation of the lithiated intermediate to give 72. Studies by both Hoffmann and co-workers [59][60] and by Reich and co-workers [61] showed that the rate determining step for racemisation of α-thio, α-seleno and α-telluroorganolithiums is rotation

• about the C–S, Se or Te bond [62]. Simple inversion in α-thio-substituted carbanions has a barrier as low as 0.5 kcal·mol−1 [63] making inversion itself unlikely to comprise the rate determining step of the racemisation. Consistent with this explanation, the barrier to racemisation increases with

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• crystallisations. In addition, the racemisation of the undesired enantiomer via methyl ester formation and treatment with sodium hydroxide was found to be feasible allowing efficient recycling of this material [47]. Imidazoles Imidazole is an important biological building block being present in the amino acid

Asymmetric synthesis of biaryl atropisomers by dynamic resolution on condensation of biaryl aldehydes with (−)-ephedrine or a proline- derived diamine

• Ann Bracegirdle,
• Jonathan Clayden and
• Lai Wah Lai

Beilstein J. Org. Chem. 2008, 4, No. 47, doi:10.3762/bjoc.4.47

• reduction allows isolation of related compounds bearing hydroxymethyl groups, whose barriers to racemisation are somewhat higher than those of the corresponding aldehydes [37] obtained by hydrolysis alone. After trial reactions to establish optimal conditions, purified imidazolidines 9a were treated with

A convenient allylsilane- N-acyliminium route toward indolizidine and quinolizidine alkaloids

• Roland Remuson

Beilstein J. Org. Chem. 2007, 3, No. 32, doi:10.1186/1860-5397-3-32

• , (-)-lasubine II and (+)-subcosine II A similar strategy was attempted from (+)-(3R)-ethyl 3-hydroxy-3-(3,4-dimethoxyphenyl)propionate but racemisation was observed during the Mitsunobu reaction. [69] So we developed another strategy to prepare these natural optically active compounds based on the