Poster session 1

The four Bromo and Extra-Terminal (BET) proteins, Brd2, Brd3, Brd4 and Brdt, play a crucial role in transcriptional regulation and other processes such as cell proliferation and inflammation. Each of the BET proteins contains two tandem bromodomains which are conserved across the family and are responsible for binding to acetylated lysine residues such as those at the N-terminus of histones. They have become an attractive therapeutic target as misregulation of BET proteins have been linked to diseases such as cancer, neurological disorders and inflammation. 

There are many examples of BET inhibitors, including JQ1¹ and I-BET762, ² however, due to the high homology of BET bromodomains, these inhibitors are pan-selective and cannot discriminate between the bromodomains within the BET family. Our group has previously established a bump-&-hole approach to overcome this by selectively targeting a conserved Leucine residue found in BET bromodomains with alkylated I-BET762 derived probes ET³ and 9-ME-1.⁴ A limitation to the current synthetic route of these probes is that they require chiral separation following any alkylation step. Separation can be costly and lead to low yields due to loss of material. 

We have achieved a new stereoselective route to obtain a key precursor which can be used in a divergent synthesis to yield a variety of bumped inhibitors containing a benzodiazepine scaffold. We demonstrate application of this new route to create novel bumped JQ1-analogues in >99% ee. Our new synthesis has also provided, for the first time, unambiguous evidence to the absolute stereochemistry of the active mutant-selective bumped ligand.

References 

1. P. Filippakopoulos et al., Nature, 2010, 468, 1067.

2. O. Mirguet et al., J. Med. Chem., 2013, 56, 19, 7501-7515.

3. M. G. J. Baud et al., Science, 2014, 346, 638-641. 

4. A. C. Runcie et al., Chem. Sci., 2018, 9, 2452-2468.

Substituted indolines are important motifs found in many drugs and natural products. Recently, research in our group has investigated the enantioselective synthesis of 2-substituted and 2,2-disubstituted indolines. This has been achieved by kinetic resolution of the N-tert-butoxycarbonyl (Boc) derivatives of 2-arylindolines 1 using the chiral base n-butyllithium/(+)-sparteine. Overall, the unreacted starting materials (S)-1 could be isolated with excellent enantiomer ratios along with the 2,2-disubstituted products (R)-2. In addition, the enantioenriched N-Boc-2-arylindolines (S)-1 could be converted to the corresponding 2,2-disubstituted products (S)-2 without significant loss in enantiopurity. Finally, removal of the Boc group using acid gave access to highly enantioenriched 2-aryl and 2,2-disubstituted indolines. To support the experimental results variable temperature NMR spectroscopy and density functional theory studies were carried out to investigate the rotation of the Boc group.

For related chemistry, see Synthesis and Kinetic Resolution of Substituted Tetrahydroquinolines by Lithiation then Electrophilic Quench, N. Carter, X. Li, L. Reavey, A. J. H. M. Meijer, I. Coldham, Chem. Sci. 2018, 9, 1352.

Molecular diphosphate tweezers are tools to selectively target specific amino acids, e.g. lysine and arginine. The aromatic scaffold shows the capability to host the side chain in the cavity and the negatively charged phosphates interact to the positively charged functional group.^[1] This interaction may lead to the inhibition of the function of proteins and be useful for the investigation of Protein-Protein-Interaction such as that of segregase p97 which is relevant for folding and unfolding of proteins. In this regard, the dynamic function of the pore which is in the center of the two ATPase domains, D1 and D2, of the protein, seems to play important role and raised our interest.^[2] 

Therefore, multivalent tweezer with defined distance and a rigid core containing aromatic systems have to be synthesized, which can target the amino acids on the border of the pore. This tailored hybrid tweezer will increase the affinity towards the protein and will prevent the penetration of the pore. The plugging of one as well as both side of the protein of p97 will help to understand the exact function of the pore. The novel multivalent tweezer will be achieved through a “clickable” azido function and would be the first synthesized molecule to plug a protein pore.

References:

[1] M. Fokkens, T. Schrader, F.-G. Klärner, Journal of the American Chemical Society 2005, 127, 14415.

[2] V. E. Pye, I. Dreveny, L. C. Briggs, C. Sands, F. Beuron, X. Zhang, P. S. Freemont: Going through the motions: The ATPase cycle of p97. Journal of Structural Biology 2006, 156, 12–28.

Hofmann elimination and substitution are concurrent reactions in alkaline media for tetraalkylammonium hydroxides that have protons in β-position. Moreover, in some cases, substitution products are the only products isolated. 

There are just few examples of quaternary ammonium salts that have phosphonic group attatched to the same carbon atom as the trialkylammonium group. However, no data about their reactivity in alkaline media can be found. 

Herein, studies on reactivity of novel (1-phosphonoalkyl)trimethylammonium salts in alkaline solutions are presented.

Reactions were carried out in 3.3M NaOH solutions and were heated in 100°C for 10 or 35 hours. The reaction mixtures were analyzed by ¹H and ³¹P NMR. Surprisingly, most of the examinated salts was stable in these reaction conditions while only 3 quaternary ammonium salts gave vinylphosphonic acid derivatives (elimination products) as well as 1-hydroxyalkylphosphonates (substitution products). 

In conclusion, if (1-phosphonoalkyl)trimethylammonium salts react in the alkaline media, elimination is always accompanied by substitution. Only unimolecular reaction mechanism is plausible explanation for these results. 

The title trifluoroacetonitrile imines 1 are highly reactive 1,3-dipoles readily available by base-induced dehydrohalogenation of the respective hydrazonoyl halides.¹ By judicious choice of trapping agents (dipolarophiles¹ or bifunctional reagents²) the corresponding 5- and 6-membered heterocycles as formal (3+2)-cycloadducts and (3+3)-annulation products can be accessed, respectively.

Here we summarize our recent efforts in applications of fluorinated nitrile imines of type 1 via (3+2)-cycloadditions by using electron-rich C=C (enol ethers, alkoxyallenes, arynes) and C=S (thioketones and thiochalcones) dipolarophiles as reaction partners.^3,4 Straightforward access to trifluoromethylated 1,3,4-thiadiazoles, pyrazoles, indazoles, and related heterocyclic systems will be presented. Based on the developed protocols, the synthesis of selected bioactive compounds such as anticancer pyrazole SC-560, and indazole-derived Lonidamine analogue will be presented.

References

[1] G. Mlostoń, K. Urbaniak, G. Utecht, D. Lentz, M. Jasiński, J. Fluorine Chem. 2016, 192, 147.

[2] G. Utecht-Jarzyńska, A. Michalak, J. Banaś, G. Mlostoń, M. Jasiński, J. Fluorine Chem. 2019, 222-223, 8.

[3] (a) G. Utecht, A. Fruziński, M. Jasiński, Org. Biomol. Chem. 2018, 16, 1252; (b) G. Utecht, G. Mlostoń, M. Jasiński, Synlett 2018, 29, 1753.

[4] (a) P. Grzelak, G. Utecht, M. Jasiński, G. Mlostoń, Synthesis 2017, 49, 2129; (b) G. Utecht-Jarzyńska, M. Jasiński, K. Świątek, G. Mlostoń, H. Heimgartner, Heterocycles 2020, 101, 251.

Selectively modifying C—H bonds has great potential in synthesis since it can shorten synthetic routes and offers alternatives complementarity to classical chemistry. One of the main challenges when working with reactions that functionalize C—H bonds is controlling regioselectivity. In metal-catalysed reactions, such as palladium catalysed functionalization, directing groups are often used to steer the reactivity to a particular position. However, predicting the regioselective outcome in cases where multiple directing groups are present in the same molecule is not trivial. Little data is available and no systematic study comparing multiple directing functional groups has been done.

Here we present a mechanistically based machine learning (ML) approach that allowed us to circumvent this problem and train a model, with the aim to accurate predict sites of reaction of directed palladium-catalysed aromatic functionalization.

We first formulated and validated a DFT-based approach to rank various directing groups by strength, to supplement experimental data extracted from literature. We then used these results to generate artificial training data.

The developed ML model is a binary classifier that, based on the chemical environment of an atom, predicts if this position is likely to be the site of reaction. Results obtained using a combination of experimental and artificial data were significantly better than training on experimental data only, with the final model displaying an accuracy of 95% and an F1-score of 0.9. As a final test, we have validated the approach by comparing the predicted results to experiment on a small set of drug molecules.

These results highlight how incompleteness of experimental data influences of the quality of predictive models. To produce more generalizable models, other methods may be needed in order to fill in the gaps in the training.

Multicellularity, the transition from a unicellular to a multicellular organism, is the foundational event in animal origins and was occurred in ocean filled with diverse bacteria^1-3. To illuminate the mechanism by which bacteria influence animal development, choanoflagellates, the closet living relatives of animals, has emerged as an ideal model system for reconstructing the transition to multicellularity.^{4, 5} Previous studies showed that the morphogenesis of choanoflagellates S. rosetta from a single cell into an embryogenesis-like colonies “rosettes” was regulated by rosette-inducing factors (RIFs), an unusual group of sulfonosphingolipids, produced by a Gram-negative Bacteroidetes bacterium, Algoriphagus machipongonensis.^6-8 However, further studies also displayed that the multicellular form “rosettes” can be inhibited by another morphogenetic factor – inhibitor-of-rosettes (IOR) produced by the same Bacteroidetes bacterium A. machipongonensis (Figure 1).⁹ To understand the complex chemical ecology and structure-activity relationship (SAR) behind S. rosetta and sulfonosphingolipids, we designed chemical probes for conducting the mechanistic studies, which eventually provide targets identification by activity based protein profiling (ABPP).

Figure 1. Morphogenesis of the choanoflagellate S. rosetta upon exposure to the prey bacterium A. machipongonensis

1. S.B. Carroll, Nature, 2001, 409(6823):1102–1109.
2. A.H. Knoll, Annu Rev Earth Planet Sci, 2011, 39(1):217–239.
3. M. McFall-Ngai, Am Zool, 1998, 38(4):592–608. 
4. M. Carr, B.S.C. Leadbeater, R. Hassan, M. Nelson, S.L. Baldauf, Proc. Nat. Acad. Sci USA, 2008, 105(43):16641–16646.
5. N. King et al., Nature, 2008, 451(7180):783–788. 
6. R. A. Alegado, L. W. Brown, S. Cao, R. K. Dermenjian, R. Zuzow, S. R. Fairclough, J. Clardy, eLife, 2012, e00013.
7. C. Beemelmanns, A. Woznica, R. A. Alegado, A. M. Cantley, N. King, J. Clardy, J. Am. Chem. Soc., 2014, 136, 10210-10213.
8. A. Woznica, A. M. Cantley, C. Beemelmanns, E. Freinkman, J. Clardy, N. King, Proc. Nat. Acad. Sci USA., 2016, 113, 7894-7899.
9. M. Cantley, A. Woznica, C. Beemelmanns, N. King, J. Clardy, J. Am. Chem. Soc., 2016, 138, 4326-4329.

Barnesin A is the first reported NRPS-PKS hybride-derived metabolite and first characterized secondary metabolite from anaerobic Epsilonproteobacteria (Sulfurospirillum barnesii). Genome comparison and phylogenetic analysis revealed the putative biosynthetic gene cluster responsible for barnesin A.¹

Barnesin A is a dipeptide containing a vinylogous arginine moiety and tyrosine, which is acetylated with (Z)-oct-2-enoic acid. A first total synthesis allowed the confirmation of its absolute structure and first structure-activity studies. To overcome synthetic difficulties a new solid-phase based synthetic approach was implemented which allowed us quick access to a synthetic compound library.² Bioactivity studies revealed that barnesin and derivatives are selective cysteine protease inhibitors of nanomolar activity. Here, we present our synthetic approaches and structure-activity relationship studies (SAR) of different barnesin derivatives.

References:

¹ Rischer, M.; Raguž, L.; Guo, H.; Keiff, F.; Diekert, G.; Goris, T.; Beemelmanns, C.; ACS Chem. Biol. 2018, 13(8), 1990-1995.

² Roman, D.; Raguž, L; Keiff, F.; Meyer, F.; Barthels, F.; Schirmeister, T.; Kloss, F.; Beemelmanns, C. Org. Lett. 2020, 22, 10, 3744-3748.

Mefloquine is known as a medicine under the name of Lariam. It is an antimalarial, which is very effective against Plasmodium parasite. Mefloquine is an analogue of Cinchona alkaloids such as quinine and quinidine. These quinoline-based antimalarial compounds possess two vital stereogenic centers and therefore can be present as four stereoisomers. However, they differ in chemical reactivity because of the differences in their structures. In contract to Cinchona alkaloids, Mefloquine possesses two electron withdrawing groups (-CF₃) in the quinoline ring. Moreover, it is a secondary amine, whereas the alkaloids are tertiary amines. Up to date, no Mefloquine derivative has been used as an asymmetric catalyst and only few modifications to the structure of Mefloquine are known.

Attempted replacement of the hydroxyl functionality with a primary amine moiety resulted in numerous problems and the usual ways of the Mitsunobu reaction with a nitrogen nucleophile or a path thru sulfonates were ineffective. Herein, we present a set of approaches with no straightforward stereochemistry, which have ultimately led us to develop scalable syntheses of all four stereoisomers of 11-amino-Mefloquine.

The used approaches rely on the enantiomer separation by crystallization, epimerization reactions, and choice of selective protective group. For some optically pure products, no chromatographic purification was required and yields of up to 73% for the overall transformation were achieved. 

The presentation includes synthesis, characteristic and application of 2-azabicycloalkane derivatives as novel organocatalysts in aldol condensation and Michael addition. Chiral 2-azanorbornyl scaffold is relatively easily obtained via aza-Diels-Alder cycloaddition. This rigid bicyclic analogue of various systems, e.g. piperidine or proline, is important from both biological and catalytic points of view.ⁱ

Proline is an example of a simple organocatalyst that has attracted a lot of attention, mainly due to its application in asymmetric synthesis, e.g. in Mannich, nitro-Michael and aldol reactions.^ii,iii,iv In the literature, numerous efficient bifunctional amide-based organocatalysts that contain proline fragment in the structure have been reported.^v To increase their solubility, acylsulfonamide group was introduced.^vi,vii Evaluation of obtained sulfonamides e.g. in asymmetric aldol reaction confirmed their superior or equal catalytic activity and enantioselectivity as compared to proline.

We decided to synthesize and test novel catalysts that combine proline molecule with 2-azabicyclo[2.2.1]heptane or 2-azabicyclo[3.2.1]octane skeletons in the structure. In another set of compounds 2-azabicycloalkane fragment was used to replace proline moiety in known organocatalysts. The novel enantio- and diastereomerically pure compounds were fully characterized and tested in aldol and Michael reactions.

.

Fig.1. Structures of synthesized compounds.

i E. Wojaczyńska, J. Wojaczyński, K. Kleniewska, M. Dorsz, T.K. Olszewski, Org. Biomol. Chem., 2015, 13, 6105-6408.

ii A. Cordova, C. F. Barbas, Tetrahedron Lett., 2002, 43, 7749-7752.

iⁱⁱ B. List, J. Am. Chem. Soc., 2000, 122, 9336-9337.

i^v Q. Wang, L. Peng, J. Fu, Q. Huang, L. Wang, X. Xu, Arkivoc, 2010, 340-351.

v X. Liu, L. Lin, X. Feng, Chem. Commun., 2009, 6145-6158.

vⁱ A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org. Biomol. Chem., 2005, 3, 84-96.

vⁱⁱ A. Berkessel, B. Koch, J. Lex, Adv. Synth. Catal., 2004, 346, 1141–1146.

N-heterocyclic carbenes (NHC) are widely used in the synthesis of various complex substances. NHC generated from appropriate salt effects on the reverse of the polarity of the carbonyl compound. Consequently, the electrophilic carbon atom is transformed into a synthetically appropriable nucleophile via the umpolung process.[1] Moreover, it exists another way to use Breslow intermediate in organocatalyzed reactions. It can be oxidized to acylazolium – very useful acylium cation synthon in esterification and annulation reactions of α,β-unsaturated carbonyl compounds.[2]

The aim of this work is the enantioselective synthesis of 3,4-dihydropyrano[3,2-b]chromene-2,10-diones and one-pot alcoholysis of obtained compounds. Developed synthetic procedure is based on a sigmatropic Claisen rearrangement and ring-opening of generated lactone. It is a very appropriable way to C-C bond formation and simple derivatization of chromenones with aryl-substituted propionic esters.

The project is co-financed by the National Science Center as part of the SONATA BIS program

(UMO - 2016/22/E/ST5/00469)

[1] D.M. Flanigan, F. Romanov-Michailidis, A. Nicholas. N.A. White, T. Rovis, J. Chem. Rev. 2015, 115, 9307-9387

[2] K. Dzieszkowski, Z. Rafiński, Catalysts 2018, 8, 549

Actinobacteria are versatile producers of bioactive natural products and their members are widely distributed in aquatic and terrestrial ecosystems. Besides the well-studied genus Streptomyces, members of the genus Amycolatopsis are known to produce various types of antibiotics, such as the glycopeptide vancomycin from Amycolatopsis orientalis. Recently, our group showed that Amycolatopsis sp. M39, isolated from the gut of a fungus-farming termite, is involved in the defense of their termite host against microbial pathogens by producing the antibacterial and antifungal macrolactams macrotermycins A-D.  Intrigued by the biosynthetic potential and its putative role as defensive symbiont, we started to explore members of the Amycolatopsis genus. Using a combination of ecology-guided metabolomics approach, we identified structurally diverse bioactive natural products, including polyunsaturated PKS-derived macrolactams, ribosomally-synthesized thiopeptides and hydroxylated lipopeptides. Despite the great potential as antibiotic producer, genetic manipulation procedures are established only for a few members of the genus. Hence, our current studies are directed towards the heterologous expression and genetic manipulation of their biosynthetic pathways to unravel novel biosynthetic transformations.

 References

Um S, Seibel E, Schalk F, Balluff S, Beemelmanns C (2021) Targeted Isolation of Saalfelduracin B-D from Amycolatopsis saalfeldensis Using LC-MS/MS-Based Molecular Networking J. Nat. Prod. [Accepted]

Hubert P, Seibel E, Beemelmanns C, Campagne JM, de Figueiredo RM (2020) Stereoselective construction of (E,Z)-1,3-dienes and its application in natural product synthesis. Adv Synth Catal 362(24), 5532-5575. (Review)

Beemelmanns C, Ramadhar TR, Kim KH, Klassen JL, Cao S, Wyche TP, Hou Y, Poulsen M, Bugni TS, Currie CR, Clardy J (2017) Macrotermycins A-D, Glycosylated Macrolactams from a Termite-Associated Amycolatopsis sp. M39. Org Lett 19(5), 1000-1003.

The structural features of glycome, its functions and interactions with the DNA and protein “machinery” can only be fully revealed by applying high-resolution separation and detection methods involving fluorescent tags. The capillary gel electrophoresis with laser-induced fluorescence detection (CGE-LIF) has become a key method in high-throughput glycan analysis. At present, CGE-LIF relies on 8-aminopyrene-1,3,6-trisulfonic acid (APTS), which has moderate reactivity in labeling of glycans, fixed selectivity profile and renders the detection to only green color. We introduce 8-aminopyrenes with three negatively charged acceptor groups in “active” positions (1, 3 and 6) of the aromatic system. For that, APTS was converted into tris-1,3,6-(w-hydroxyalkyl)-sulfonamides and -sulfones, then the free hydroxyl groups were phosphorylated and the negatively charged dyes used in reductive amination of glycans. The conjugates have absorption and emission maxima at ca. 505 nm and 560 nm, six negative charges (pH ≥ 8), low m/z ratios, higher mobilities in electric field and higher brightness, as compared to those of APTS.

Next we converted 3 sulfonic acid groups of APTS to 3 N-cyanosulfonamides, which provide 3 negative charges (pH ≥ 8) and shift the absorption maxima to the red. Conjugates of 8-amino-pyrene-1,3,6-tri-[(N-cyano)sulfonamide] with reducing sugars have absorption and emission maxima at ca. 480 nm and 545 nm.

The bright dyes of all these types (fluorescence quantum yields >90%, ε ~ 20000 M^-1 cm^-1) are intended for creating new analytical reagents and internal standards for glycan analysis by capillary electrophoresis, in particular in commercial DNA sequencers equipped with laser-induced fluorescence detectors and 488 nm or 505 nm excitation sources.

We demonstrate efficient labeling and separation of maltodextrin ladder by polyacrylamide gel electrophoresis. The new dyes are expected to cross-validate and increase the glycan identification precision in CGE-LIF and help to reveal “heavy” glycans, yet undetectable with APTS label.

The increasing interest in chiral thioureas has been recently noticed. Their capability to act as hydrogen donor allows wide use in asymmetric organocatalysis, as chelating agents, as well as application as drug candidates.^1-3 Parallelly, the 2-azabicycloalkane scaffold has found to be an easily synthetically available rigid and intrinsically chiral analogue of monocyclic nitrogen compounds which offers numerous possibilities of modification, substantiating its applications in various fields.⁴

In our contribution, we synthesised enantiomerically pure amines and isothiocyanates based on the 2-azabicycloalkane skeleton (2-azabicyclo[2.2.1]heptane and 2-azabicyclo[3.2.1]octane) successfully and used them as precursors with the complementary commercially available aliphatic or aromatic compounds to yield chiral thioureas.

The choice of such easily accessible chiral bicyclic system, comparable with the natural scaffold of Cinchona alkaloids, opens a route to novel versatile thiourea organocatalysts for asymmetric synthesis.

¹ O. V. Serdyuk, C. M. Heckel, S. B. Tsogoeva, Org. Biomol. Chem., 2013, 11, 7051.

² J. Li, L.-L. Shi, J. Chen, J. Gong, Z. Yang, Synthesis, 2014, 46, 2007.

³ A. Shakeel, A. A. Altaf, A. M. Qureshi, A. Badshah, J. Drug Des. Med. Chem., 2016, 2,10.

⁴ E. Wojaczyńska, J. Wojaczyński, K. Kleniewska, M. Dorsz,T. K. Olszewski, Org. Biomol. Chem., 2015, 13, 6116.

Alkyl amines have a rich chemistry in terms of their synthesis methods and applications in widespread organic reactions. Within the present study hydrogen transfer (HT) reactions of alkenes with internal double bond and alkynes with phenyl and alkyl substituents were examined with tertiary alkyl amines as hydrogen donors.

The saturation of a non-activated internal double bond containing compound, such as methyl oleate and trans-5-decene as substrates was observed in the presence of Pd/C, Pt/C and Rh/C (Figure 1A). The pre-reduced catalyst samples showed high activity, partial to complete conversion was detected at 140 °C in p-xylene as solvent. Alkyl amines such as trimethylamine, tributyl-, tripentyl-, trihexylamine and N,N-diisopropylethylamine, as well as cyclic 1-ethylpyrrolidine and 1-ethylpiperidine was investigated as possible hydrogen donors. Cyclic amines and diisopropyl derivatives as H-sources produced the highest conversion (99%), while amines with longer alkyl chains showed minor activity.

The promising outcome of the alkene HT reactions encouraged us to extend our substrate scope to alkynes as well. Alkyl- and phenyl-substituted derivatives were examined in the presence of Pt/C and Pd/C (Figure 1B). In case of substrate 1, 4 and 5 over-hydrogenation as a sequential reaction was observed under the given reaction conditions (Pt/C - (ⁱPr)₂NEt). In the presence of Pd/C – (ⁱPr)₂NEt), Pd/C – 1-EPyr and Pt/C – 1-EPyr catalyst systems C-C single bond formation was not observed, while the dominance of the cis-alkene of substrate 1, 2, 4 and 5 was detected (Z/E ratio up to 9/1). The calculated very negative entropies suggests the presence of a highly ordered transition state, which points to the formation of a surface complex and to a concerted pathway (Figure 1C, representing the catalytic cycle of eq. A and the second step of eq. B).

Figure 1. HT reactions of internal alkenes, alkynes.

Glucuronic acid (GlcA) is a component of several glycosaminoglycans (GAGs) occurring in chondroitin sulfates (CS), hyaluronic acid (HA) and heparin/heparin sulfates (H/HS). Chemical synthesis of GAG fragments[1] is central to investigation of interactions of GAG- mediated processes and interactions. This poster will describe evaluation of protecting group strategies and fragment approaches. Specifically, the synthesis and behaviour of GlcA reagents utilizing cyclohexane-1,2-diacetal CDA protection of the O2,O3 groups, aimed at conferring deprotection differentiation to other acyl or ether protections in GlcA derivatives to extend prior syntheses of IdoA-dominated GAG fragments.[2] Reactivity comparisons with other approaches and conversion into HS/CS-related disaccharide reagents will be discussed. This will report unexpected isomeric outcomes in these protection approaches, providing structural proof (including XRD) and a discussion of the mechanistic and synthetic consequences. Alternatives for synthesis of fragments using other GlcA reagents and coniugation-suitable reagents will be included. We also report structural studies of a sodiated GlcA derivative adopting an unusual 5-valent structure.

[1] Mende, M.; Bednarek, C.; Wawryszyn, M.; Sauter, P.; Biskup, M.B.;Schepers, U.;Bras̈e, S. Chem. Rev. 2016, 116, 8193−8255. 

[2](a) Jeanneret,  R. A.; Dalton, C. E.; Gardiner, J. M.  J. Org. Chem. 2019, 4, 15063-15078. 

 (b) Gardiner, J. M. et al. Chem. Commun. 2015, 51, 13846-13849. [4] Gardiner, J. M. et al Chemical Science 2015, 6, 6158-6164. 

References:

[1] Gardiner, J. M. et al. J. Org. Chem. 2015, 80, 3777-3789. [2] Gardiner, J. M. et al. OrgLett, 2013, 15, 88–91. [3] Jayson, G. C.; Gardiner, J. M. et al. Chem. Commun. 2015, 51, 13846-13849. [4] Jayson, G. C.; Gardiner, J. M. et al Chemical Science 2015, DOI: 10.1039/C5SC02091C. [5] Jayson, G. C.; Gardiner, J. M. et al. Chemical Science 2013, 4, 3218-3222. [6] (a) Gardiner, J. M. et al.Org. Biomol. Chem. 2015, 13, 10751-10761. [6] Jayson, G. C.; Gardiner, J. M. et al. Nature Commun. 2013, 4: 2345. [7] Dalton,C. E.; Gardiner,J. M.; Magennis, S. W. et al ChemPhysChem 2016, 21, 3442-3446. 

Nitrogen-containing heterocyclic compounds exhibit a broad spectrum of biological activities. 2-Azabicycloalkanes have found various applications as rigid analogues of piperidine alkaloids, proline, azepane and precursors of chiral substituted cyclopentane derivatives exhibiting biological activity.¹ Together with 1,2,3-triazoles, which are known for their versatile applications due to their bioactivity and use as functional materials², they offer great possibility of building up a scaffold of potential bioactive compounds.

In our contribution a series of mono-, di- and trivalent triazoles was prepared based on intrinsically chiral 2-azabicyclo[2.2.1]heptane and 2-azabicyclo[3.2.1]octane using copper-catalyzed azide-alkyne cycloaddition (CuAAC). The synthetic route included both, 2-azabicycloalkanes substituted with an azide group as well as those bearing a terminal alkyne reacted with different complementary materials.

The reactions proceeded in good yields (58-94%) with no changes at the chiral centers. Offering great opportunity for the development of a chiral pure scaffold bearing multiple active moieties in a rudimentarily modular system.

¹ E. Wojaczyńska, J. Wojaczyński, K. Kleniewska, M. Dorsz, T. K. Olszewski, Org. Biomol. Chem. 2015, 13, 6116.

² E. Wojaczynska, J. Wojaczyński Adv. Org. Synth. Vol. 11. Sharjah: Bentham Science Publishers, 2018, 156

The Rauhut-Currier (RC) reaction, also known as the vinylogous Morita-Baylis-Hillman reaction, is one of the methods of C-C bond formation, which involves the dimerization of electron-deficient alkenes in the presence of a nucleophilic catalyst. Initially, tertiary phosphines were used
in intermolecular variant. [1] Decades later, independently of each other, Krische and Roush for the first time carried out an intramolecular reaction of cyclization of α, β-unsaturated compounds with both electron donating- and electron-withdrawing groups. [2] [3] In the first asymmetric version of the IRC reaction, cysteine derivatives were used. [4] Based on the results of the mentioned authors, we started exploring the IRC reaction. Initial experiments allowed to obtain expected products with good yields based on lithium selenolates not yet described in this field.

The aim of the project is to optimize the conditions of the intramolecular RC reaction and applied it in stereoselective manner. We plan to expand a scope of substrates, including compounds with two nitrile, amide and ester groups, that cyclization by RC has not been described in the literature so far. These studies will allow to develop the range of methods used in organic synthesis and to find the missing fragment limiting the universality of the Rauhut-Currier reaction.

Figure 1. Scheme of the intramolecular RC reaction

Research financed by the National Science Center: Grant No. UMO-2017/27/B/ST5/01248

Bibliography:
[1] Rauhut, M. M.; Currier, H., U.S. Patent 307,499,919,630,122, 1963; Chem. Abstr. 1963, 58, 11224a

[2] Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402[3] Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404–2405[4] C. E. Aroyan.; Scott J. Miller, J. Am. Chem. Soc. 2007, 129, 256-257

The sulfoximine functional group continues to attract significant attention from medicinal chemistry programmes in the pharmaceutical industry.^1,2 Hence, new methods that access stereodefined, functionalised sulfoximines are desirable. There are virtually no examples of the α- and β-functionalisation of cyclic sulfoximines. These limitations in sulfoximine synthetic chemistry have inspired the present project and herein we present our enabling results.  

Initially, the use of direct lithiation-trapping was explored.^3,4 α-Substitution of 4-, 5- and 6-membered ring sulfoximines and a thiomorpholine sulfoximine via lithiation-trapping reactions worked well with a variety of electrophiles – a range of sulfoximines were generated as single diastereomers (29 examples, Panel A). Stereoselectivity arises from electrophilic attack on a lithiated intermediate opposite to the sterically hindered N-R substituent. 

There are only two previous reports on Negishi-type α-arylation of sulfoximines and there are no known examples with cyclic sulfoximines.^5,6 By transmetallating the lithiated sulfoximine to an organozinc species, it was possible to carry out stereoselective Pd-catalysed Negishi α-arylation of cyclic sulfoximines (34 examples, Panel B). The use of toluene as solvent and a higher temperature was required for better yields with medicinal chemistry-relevant heteroaryl bromides. 

We have also developed a synthetic route to the opposite diastereomer (Panel C). Thus, vinylic lithiation-bromination gave an α-vinyl bromosulfoximine which underwent a Suzuki-Miyaura cross-coupling reaction. Subsequent hydrogenation occurred opposite the N-TBDPS group to give complementary diastereoselectivity to the Negishi approach. 

To further explore 3-D chemical space around the cyclic sulfoximine scaffold, we have carried out lithiation-trapping and/or Negishi arylation sequences to deliver stereodefined di-, tri- and tetra-substituted cyclic sulfoximines (Panels D and E).

Finally, we have synthesised β-aryl sulfoximines via a rhodium catalysed Hayashi type⁷ cross-coupling reaction (Panel F). 

Overall, we have developed diastereoselective routes to α-functionalised cyclic sulfoximines via lithiation-trapping, Negishi cross-coupling reactions and Suzuki-Miyaura cross-coupling-hydrogenation. We are currently optimising the stereoselective β-functionalisation of cyclic sulfoximines.

(1)         Lücking, U. Angew. Chemie Int. Ed. 2013, 52, 9399–9408. 

(2)         Mäder, P.; Kattner, L. J. Med. Chem. 2020. 

(3)         Zhu, Y.; Rogers, R. B.; Huang, J. X. US 2005/0228027 A1, 2005.

(4)         Tota, A.; Fanelli, F.; Falcicchio, A.; Luisi, R.; Degennaro, L. Chem. Heterocycl. Compd. 2017, 53, 322–328. 

(5)         Sirvent, J. A.; Bierer, D.; Webster, R.; Lücking, U. Synthesis. 2017, 49, 1024–1036. 

(6)         Young Cho, G.; Bolm, C. Org. Lett 2005, 7, 1351–1354. 

(7)         Lim, K. M. H.; Hayashi, T. J. Am. Chem. Soc. 2015, 137, 3201–3204.

The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in regulation of body fluid and electrolyte homeostasis. In the clinic, the MR antagonists spironolactone and eplerenone are used for treatment of heart failure and hypertension. In addition, beneficial effects have been demonstrated for patients with chronic kidney disease.¹ MR belong to the oxo-steroid receptor family and bind the steroid hormones aldosterone and cortisol. The two clinical approved antagonists are both steroid based, however MR has proven itself to be a highly druggable target with multiple non-steroidal ligands reported in the literature,^2,3 often identified by high-throughput screening.

A new series of acylurea based MR antagonists were discovered from an internal HTS. The initial hit was optimized to decrease lipophilicity and improve MR potency. The first series of syntheses, using a T3P mediated condensation of urea with a chiral amino acid, were low yielding. In addition, substantial part of the chiral integrity of the starting material was lost in the reaction and  difficulties were experienced during purification as large amounts of material was required for detailed studies. In light of these challenges we searched for alternative conditions. In this work we present a novel, facile, high yielding and cheap route to generate acylureas with essentially conserved stereochemistry. Due to a clean reaction profile our final materials could easily be isolated as optically pure materials by simple crystallization. 

References

1. Bertocchio, J-P.; Warnock, D. G.; Jaisser, F. Kidney Int., 2011, 79, 1051-1060.
2. Nordqvist, A.; Granberg, K. L. Mineralocorticoid receptor antagonists in Aldosterone of Vitamins & Hormones, Academic press/Elsevier Edited by Gerald Litwack. 2019, 109, 151-188.
3. Martín-Martínez, M.; Pérez-Gordillo, F. L.; de la Rosa, D. A.; Rodríguez, Y.; Gerona-Navarro, G.; González-Muñiz, R.; Zhou, M.-M. J. Med. Chem. 2017, 60, 2629-2650.

Whilst the introduction of stereogenic centres close to other functional groups is well established, there are a limited number of studies that report the efficient installation of more remote stereocentres. A palladium-catalysed redox-relay oxidative Heck strategy has been applied to a number of acyclic systems, but far less attention has been given to the application of this methodology to cyclic systems, the more rigid nature of which is often beneficial in drug design. My PhD research focuses on the application of a novel redox-relay oxidative Heck process to dihydropyranyl (DHP) alcohols to deliver chiral, functionalised ε-trans-tetrahydropyrans bearing a remote aldehyde (trans-THP, Scheme 1). The exo-cyclic migration, required to furnish the aldehyde product, is novel to this substrate class. Furthermore, the resultant trans-THP motif is challenging to access via other methods, and the aldehyde formed acts as a synthetic handle for further functionalisation.

Scheme 1. DHP-alcohol system of study and associated challenges.

A strong kinetic resolution was observed when redox-relay oxidative Heck conditions were applied to the commercially available racemic DHP-alcohol starting material, generating the expected trans-THP-alcohols, following reduction, in moderate yield and moderate to good enantioselectivity. Variation in PyrOx ligand structure led to stark changes in yield and enantioselectivity, an explanation for which has been identified following computational studies.

Whilst the resolution of racemic DHP-alcohols is promising, 50% of the material is lost in the process. Therefore, investigations into the reaction of a single enantiomer of DHP-alcohol were subsequently initiated. Under optimised conditions, the resultant trans-THP-aldehyde products are delivered in excellent diastereoselectivity (>20:1 d.r.) and enantioselectivity (99:1->99:1 e.r.) across a broad substrate scope in yields of 8-68%. 

In summary, the scope of substrates for use in redox-relay oxidative Heck methodologies has been successfully expanded to the formation of ε-trans-THPs, which are of high synthetic value to the pharmaceutical industry.

The development of reactions promoted by N-heterocyclic carbenes enables the synthesis of various complex substances, including compounds with one or more stereogenic centers. The phenomenal success of NHCs can be attributed primarily to their ability to reverse the typical electrophilic nature of aldehydes (umpolung). N-heterocyclic carbenes (NHC) are commonly used as organocatalysts in various umpolung reactions such as benzoin condensation or Stetter reaction.[1,2] Therefore, the synthesis of chiral NHC precatalysts enables the synthesis of enantiomerically enriched substances.[3,4,5]

The aim of this work is the synthesis of chromanones with the trifluoromethyl group bonded to the quaternary stereogenic center. The incorporation of lipophilic trifluoromethyl groups in bioactive compounds is a popular strategy to increase their ability to cross membranes. Products of intramolecular Stetter reaction were obtained with good yields and excellent enantiomeric excesses. In conclusion, it is worth adding that the obtained products are derivatives of chromanone, containing the structural motif of many different biologically active compounds.[6]

The project is co-financed by the National Science Center as part of the SONATA BIS program

(UMO - 2016/22/E/ST5/00469)

[1] D.M. Flanigan, F. Romanov-Michailidis, A. Nicholas. N.A. White, T. Rovis, J. Chem. Rev. 2015, 115, 9307-9387.

[2] J. L. Moore, T. Rovis, Top Curr Chem, 2010, 291, 77-144.

[3] Z. Rafinski, A. Kozakiewicz, K. Rafinska, ACS Catal., 2014, 4, 1404-1408.

[4] Z. Rafinski, A. Kozakiewicz, J. Org. Chem., 2015, 80, 7468-7476.

[5] Z. Rafinski, ChemCatChem, 2016, 8, 2599-2604.

[6] B. Mayuri, P. Kavitha, S. Basavoju, G. Bhargavi, K.L. Reddy, J. Mol. Struct., 2017, 1145, 1-9.

Disulfide/dithiol equilibria are fundamental for most cellular protein folding and highly depend on a balanced redox homeostasis. All eukaryotes share a key set of highly conserved and specialised disulfide/dithiol redox effector proteins (e.g. thioredoxin) and their upstream oxidoreductases (e.g. thioredoxin reductase) to ensure the correct functioning and status of the cellular redox environment. However, while genetic engineering approaches have delivered ratiometric-response fusion proteins that report on the redox status of the enzymes themselves, no exogenous chemical sensor systems have yet succeeded to monitor cellular redox enzymatic activity or the redox status that they reflect, within the native cellular context. In particular, while substrate-inspired designs exploiting disulfide redox triggers offer the potential for high turnover, reported designs have so far failed to resist nonspecific transthiolation, and therefore one expects that all disulfides are reduced nonspecifically upon entry into cells. We recentely created robust and selective substrate-competitive motifs to probe cellular redox processes. We rationally designed a series of disulfide-based probes by independently tuning the thermodynamics and kinetics of disulfide transthiolation, while modifying the substrate-competitiveness of disulfide-trigger/payload conjugates, to achieve outstanding enzymatic specificity and redox environment selectivity in cell biology assays. We anticipate that these probes can than be further applied in the minimally-invasive monitoring of endogenous cellular redox processes as well as in diagnostics and therapeutics that discriminate for abnormal redox environments (as found in e.g. cancer).

Iminosugars (also called azasugars) are naturally occurring sugars analogs with endocyclic oxygen atom replaced by nitrogen. This “small” difference diametrically changes the biological activity of azasugars in comparison to sugars as they cannot undergo a glycosylation reaction catalyzed by glycosidases, but exhibit strong enzyme inhibition.^[1]

A bicyclic member of the iminosugars family – tertiary amine Castanospermine (1) isolated from Castanospermum Australe shows prominent anti-HIV and anti-cancer activity. However, due to its high toxicity 1 has been excluded from clinical trials, but a number of Castanospermine analogs (2,3) such as 1-deoxy-6-epi-castanospermine (2) and their epimers are still investigated as potent drugs.^[2]

As a part of our recent investigation in de novo synthesis of monocyclic iminosugars via asymmetric aldol reaction of isoserinal (5) with aliphatic ketones, we developed an effective method for synthesis of the iminosugar core structure.^[3] Applying the same methodology with additional cyclization we present a synthetic pathway to analogs 2 and 3. Application of a chiral bimetallic complex (4) as a catalyst in asymmetric aldol reaction leads to the formation of the main isomer of 7 with appropriate stereochemistry in good yield up to 75%, while the total yield of all possible isomers is up to 95%. Deprotection and cyclization of aldol products lead to bicyclic iminosugars.

Financial support from the Polish National Science Centre (MINIATURA Grant No. 2017/01/X/ST5/01122) is gratefully acknowledged.

[1] Compain, P.; Martin, O.R.; Iminosugars From synthesis to therapeutic application, John Wiley & Sons, 2007.
[2] (a) Gajare, V.S.; Khobare, S.R.; Datrika, R.; Reddy, K.S.; Rajana, N.; Babu, B.K.; Rao, B.V.; Kumar, U.S. Tetrahedron Letters, 2016, 57, 1486–1488. (b) Durantel, D.; Curr Opin Investig Drugs, 2009, 10, 860-70.
[3] (a) Nicolas, C.; Pluta, R.; Pasternak-Suder, M.; Martin, O.R.; Młynarski, J. Eur. J. Org. Chem. 2013, 1296-1305. (b) Baś, S.; Kusy, R.; Pasternak-Suder, M.; Nicolas, C.; Młynarski, J.; Martin, O.R. Org. Biomol. Chem., 2018, 16, 1118-1125.

Chiral organophosphorus compounds, especially those containing C-stereogenic carbons in the proximity of the phosphorus atom, are known for their unique properties and have found wide applications that span from medicinal chemistry to enantioselective catalysis. However, the synthesis of such chiral molecules, especially the precise control of the stereochemistry at chiral carbon atom, still remains a very challenging task. In that aspect, the use of H-P reagents bearing chiral alcohol moiety attached to the phosphorus atom and serving as chiral auxiliary represent an interesting synthetic approach. During our presentation we will report on recent results from our laboratory on the utility of such chiral H-P reagents in the synthesis of substituted phosphonates.

The carboxylic acid group is a ubiquitous functional group in organic chemistry. The importance of such group is easily justified not only by its prevalence, but through the number of endogenous biological processes, reliant on its intrinsic chemical nature (Pajouhesh and Lenz, 2005). It has been estimated that well over 450 marketed drug candidates contain the carboxylic acid moiety, including Amoxicillin, Diclofenac and Cerivastatin. The carboxylic acid moiety can be seen to influence both pharmacodynamic and pharmacokinetic properties. It is, for example, part of the pharmacophore for both β-lactam antibiotics and COX inhibitors (Hajduk et al., 2000; Kalgutkar and Scott Daniels, 2010). In terms of pharmacokinetics, the carboxylic acid group is often introduced into drug candidates to increase its solubility in the aqueous environment of the body. It should be noted, however, that due to its high polarity it is far too hydrophilic to cross the lipophilic membrane of the blood brain barrier and is largely metabolised via Phase II conjugation reactions (Kalgutkar and Scott Daniels, 2010).

To circumnavigate the above issues, medicinal chemists have conducted extensive research into the development of carboxylic acid bio-isosteres (Lassalas et al., 2016). One such isostere is squaric acid. 3,4-Dihydroxycluclobut-3-ene-1,2-dione, commonly referred to as quadratic/squaric acid, is a planar aromatic framework which has been seen to possess an almost perfect square shape (Perez and Perez, 2000; Chasák et al., 2021). Though squaric acid derivatives were first synthesised in the mid 1950’s they were not considered druggable moieties until the last decade (Chasák  et al ., 2021). Functionalisation of the squaric acid core revolves around the formation of the corresponding squarate ester or amine substituted squaramides.

The results presented in this work illustrate the methodology for the development of a library of monosubstituted squaramide-based compounds, which could be used to develop novel drug candidates.

Inconsistencies in published photochemical transformations, which do not contain sufficient information to reproduce results, represents a challenge from a process chemistry perspective. Herein, we introduce a versatile photoreactor for high-throughput screening, preparative scale batch reactions and flow, all with a single light source (Figure 1). The reactor utilises interchangeable arrays of pseudo-monochromatic high-power LEDs in a range of synthetically useful wavelengths, combined with excellent temperature control. Moreover, light intensity can be modulated in an accurate and straightforward manner. This system has subsequently been tested on a range of literature methodologies (C-S cross‑couplings, [2+2]-cycloadditions, Norrish type 1 rearrangement, benzylic brominations) using our newly developed workflow.^1,2 This commercially available platform, which can be utilised with high levels of reproducibility, by medicinal chemists in an expeditious manner to generate arrays of compounds and understood by process chemists and engineers for efficient scale-up, allows for the development of new synthetic strategies within the pharmaceutical industry.

Figure 1: Photochemistry LED Illuminator as a standardised photochemical platform.

References:

1. H. E. Bonfield, J. D. Williams, W. X. Ooi, S. G. Leach, W. J. Kerr, L. J. Edwards. ChemPhotoChem 2018, 2, 938.
2. H. E. Bonfield, K. Mercer, G. C. Cook, B. S. J. McKay, P. Slade, G. M. Taylor, W. X. Ooi, J. D. Williams, S. G. Leach, J. P. M. Roberts, W. J. Kerr, J. A. Murphy, L. Schmermund, L. J. Edwards. ChemPhotoChem 2020, In press.

Predicting reaction outcomes has a huge potential for accelerating discovery and optimization in synthetic organic chemistry. In particular, predictive models can be used to rank suggested synthetic steps ahead of experimental testing. It becomes even more important when many and long routes are considered. In this work, we combine traditional mechanistic modelling using density functional theory with machine learning on experimental rate constant data for the nucleophilic aromaticity substitution reaction. Our fully automated method provides accurate activation free energies with a mean absolute error below 1 kcal/mol, and the model is also successfully validated on regio- and chemoselectivity prediction of reactions from patent data. This level of accuracy is particularly attractive for prediction in process chemistry with high demands on reaction optimization and low tolerance for by-products. Models with a mechanistic component appear especially promising in the low-data regime of below ca 150 data points, which is common in synthetic organic chemistry. In addition, we present the open-source ᴍᴏʀғᴇᴜs Python package which enables non-experts to calculate molecular features for use in machine learning models. It includes well-established ligand features such as buried volume, Sterimol parameters and much more. We recently used ᴍᴏʀғᴇᴜs to parametrize 1,558 experimentally accessible monodentate phosphine ligands and construct machine learning models for a virtual library of 300,000. We anticipate that this extensive mapping of phosphine chemical space will find widespread use in catalyst discovery and optimization.

GPR81 is a novel drug target that is implicated in the control of glucose and lipid metabolism. GPR81 is a member of the hydroxyl-carboxylic acid receptor family of G-protein coupled receptors, and lactate is its endogenous ligand. The aim of the GPR81 project is to develop an orally active GPR81 agonist that lowers free fatty acids to improve insulin sensitivity and glucose control without flushing. The lack of potent GPR81 modulators suitable for in vivo studies has limited the pharmacological characterization of this receptor. There are only two studies published showing effects in vivo after repeated dosing of a GPR81 agonist.¹

We performed a high throughput screen and only one viable GPR81 agonist chemical series was identified. An acyl urea containing cluster originating from an inhouse growth hormone secretagogue receptor type 1a inverse agonist project. The medicinal chemistry work focused on exploring SAR, generating in vivo tools, improving DMPK and selectivity profiles. During SAR building two additional new series were evolved, one containing cyclic acyl urea bioisosteres (constrained analogues) and another a central amide bond. These three novel series, acyl urea-, constrained analogue- and amide-series, provide different selectivity and physicochemical properties suitable for in-vivo studies.²

References

1.(a) Sakurai, T.; Davenport, R.; Stafford, S.; Grosse, J.; Ogawa, K.; Cameron, J.; Parton, L.; Sykes, A.; Mack, S.; Bousba, S.; Parmar, A.; Harrison, D.; Dickson, L.; Leveridge, M.; Matsui, J.; Barnes, M. Eur. J. Pharm. 2014, 727, 1-7. (b) Wallenius, K.; Thalén, P.; Björkman, J-A.; Johannesson, P.; Wiseman, J.; Böttcher, G.; Fjellström, O.; Oakes, N. D. JCI Insight. 2017, 19, 1-18.

2. Davidsson, Ö.; Nilsson, K.; Brånalt, J.; Andersson, T.; Berggren, K.; Chen, Y.; Fjellström, O.; Gradén, H.; Gustafsson, L.; Hermansson, N-O.; Jansen, F; Johannesson, P.; Ohlsson, B.; Tyrchan, C.; Wellner, A.; Wellner, E.; Ölwegård-Halvarsson, M. Bioorg. Med. Chem. Lett. 2020, 30, 126953.

The casbane diterpene natural product family consists of many derivatives with a complex oxygenation pattern. Structural characteristics are a 14-membered unsaturated macrocycle and the fused gem-dimethyl-cyclopropane. Casbanes are used in traditional Chinese medicine “Lang Du”, and are produced by sessile soft corals as well as higher plants. The fascinating diversity of casbanes inspired us to design a novel approach for a collective diversity-oriented synthesis strategy. The successful strategy combines flexibility with late-stage diversification, bringing a number of casbane diterpenes into reach. Step and atom economical principles were considered when the adaptable building blocks were assembled. This strategy provided an excellent access to casbane diterpenes. The highly efficient and selective synthesis is based upon the following key design elements: catalytic cyclopropanation, chemoselective hydroboration, Suzuki cross coupling, ring-closing alkyne metathesis (RCAM), and directed trans-hydrostannation.

Figure 1. Diversity-Oriented Total Synthesis Strategy of Casbane Diterpenes.

Herein, the concise collective total synthesis of depressin, yuexiandajisu A and ent-pekinenin C, which was identified as the misassigned euphorhylonal A, was achieved.

Reference: L. E. Löffler, C. Wirtz, A. Fürstner, Angew. Chem. Int. Ed. 2021, 60, 5316-5322. (https://doi.org/10.1002/anie.202015243)

The discovery of aggregation-induced emission (AIE) by Tang in 2001 led to a considerable interest in dyes due to possible applications in biological and medicinal analytics and in optoelectronic devices.^[1] AIE-active chromophores are characterized by the absence of luminescence in solution but fluoresce strongly in aggregated state and thus avoid the obstacle of aggregation-caused quenching (ACQ).^[1]

Previously, we introduced a novel class of AIE-active chromophores with strong and tuneable solid-state emission properties, namely N-benzyl aroyl-S,N-ketene acetals.^[2]

Herein, we propose the conception of a novel consecutive three-component condensation-Suzuki cross coupling one-pot sequence furnishing novel bichromophores on the basis of aroyl-S,N-ketene acetals. With this protocol in hand, a diversified substance library of bichromophores is readily accessible in moderate to excellent yields (Scheme 1).

Scheme 1: Synthesis of aroyl-S,N-ketene acetal-based bichromophors.

These bichromophores show strong fluorescence properties as well as AIE-active behavior. Energy-transfer processes were observed with switchable fluorescence upon aggregation by intertwined ACQ and AIE effects. Possible applications as alcohol concentration sensors by exploiting aggregation are outlined.^[3]

[1] J. Mei, N. L. Leung, R. T. Kwok, J. W. Lam, B. Z. Tang, Chem. Rev. 2015, 115, 11718-11940.

[2] L. Biesen, N. Nirmalananthan‐Budau, K. Hoffmann, U. Resch‐Genger, T. J. Müller, Angew. Chem. Int. Ed. 2020, 59, 10037-10041.

[3] L. Biesen, L. May, N. Nirmalananthan-Budau, K. Hoffmann, U. Resch-Genger, T. J. J. Müller, manuscript submitted.

Catalytic desymmetrization of prochiral substrates provides useful blocks for chiral synthesis. Furthermore, combination of desymmetrization and further reactions introduce new products with multiple stereogenic centres. However, reports of highly effective stereoselective intermolecular desymmetrization of 1,3-diketones are limited as opposed to reactions involving anhydrides and monosubstituted ketones [1]. In a search for effective desymmetrization tool, we decided to investigate bifunctional organocatalysts bearing hydrogen-bond forming units.

Scheme 1. Cascade reaction of desymmetrization of 1,3-cyclohexanediones – Michael addition with intramolecular hemiacetalization and further transformations. 

The efficient desymmetrization of prochiral 5-substituted 1,3-cyclohexanediones involving chiral squaramides will be presented. Further transformations of obtained products open new routes for synthesis of new chiral 1,4-dihydropyridine, pyridine and indol derivatives (Scheme 1).

ACKNOLEDGEMENTS

National Science Center, Poland is acknowledged for financial support (Grant No. 2016/22/E/ST5/00046).

REFERENCES

[1] a) A. Borissov, T. Q. Davies, S. R. Ellis, T. A. Fleming, M. S. W. Richardson, D. J. Dixon, Chem. Soc. Rev. 2016, 45, 5474-5540; b) N. Di Orio, S. Crotti, G. Bencivenni, Chem. Rec. 2019, 19, 2095–2104.

[2] M. Dajek, A. Pruszczyńska, K. A. Konieczny, R. Kowalczyk, Adv. Synth. Catal. 2020, 362, 3613– 3620.

The Suzuki-Miyaura reaction is a transformation wherein organohalides react with boronic acids in the presence of a palladium(0) catalyst to form cross-coupling products.¹ Being one of the most widely used processes in academia and industry, it has attracted a significant amount of research on the optimisation of the conditions, scope, and mechanism. Within the catalytic cycle (Figure 1A), the efficiency of transmetalation is key for the success of the overall process. In this context, previous works evidence the Suzuki-Miyaura reaction to occur via oxo-palladium(II) intermediates.^2-4 However, the formation of these intermediates from the corresponding halidopalladium(II) complexes via X→OH anion metathesis is not yet well understood. Recent research by Carrow and Hartwig demonstrated the relevant intermediates to be in an equilibrium, which is reached instantaneously.² The rapid nature of the equilibration has limited further understanding of the process.

Herein, we demonstrate the application of ¹⁹F and ³¹P NMR spectroscopy in a kinetic and mechanistic analysis of this complex equilibrium system (Figure 1B). By using simple pulsed experiments (2D EXSY and selective inversion-recovery), we interrogated the exchange pathways of the complexes. Our results provide insight into their stability, and the influence of various parameters (water, temperature, and exogenous ligand) on the rates of exchange between relevant spins.

Figure 1. A) General scheme and mechanism of the Suzuki-Miyaura reaction. B) Our work: the mechanistic study on multiple equilibria between relevant palladium(II) complexes.

References:

1. N. Miyaura, K. Yamada, H. Suginome and A. Suzuki, J. Am. Chem. Soc., 1985, 107, 972–980.

2. B. P. Carrow and J. F. Hartwig, J. Am. Chem. Soc., 2011, 133, 2116–2119.

3. C. Amatore, G. Le Duc and A. Jutand, Chem. Eur. J., 2013, 19, 10082–10093.

4. A. F. Schmidt, A. A. Kurokhtina and E. V. Larina, Russ. J. Gen. Chem., 2011, 81, 1573.

Introduction: Bis-quinolines are reported to bind and stabilize G-quadruplex (G4) DNA structures. However, in order to bind G4 DNA structures, they are forced into a crescent-shaped conformation, limiting the number of possible conformations, which results in an entropic penalty. The aim of this work is to investigate if the macrocyclization of bis-quinolines will render compounds closer to the bioactive conformation and thereby reduce the energetic penalty of binding. Furthermore, we hypothesize that the selectivity for G4 DNA structures over double-stranded DNA should increase for these macrocycles by avoiding flexible bis-quinoline compounds.  

Methods: The design of the macrocycles was based on known features of existing G4 binding compounds and studies made within the research group. The synthetic route to the macrocycles consists of 11 steps involving radical-mediated quinoline formation and macrocyclizations using amide couplings (see below). In total, 8 different macrocycles were synthesized and evaluation of their binding and stabilization of G4 DNA was conducted using; fluorescence intercalator displacement (FID) assay, fluorescence resonance energy transfer (FRET) melting assay, microscale thermophoresis (MST), circular dichroism (CD) spectroscopy, NMR experiments, and molecular dynamic (MD) simulations. 

Results & Discussion: Unanimous results from the assays show that the synthesized macrocycles strongly bind and stabilize G4 DNA structures, with improved selectivity over dsDNA. This supports the initial hypothesis that macrocycles can reduce the energetic penalty upon binding to G4-structures. In addition, our MD simulations (see above) show that the macrocycles likely can be further enhanced by optimizing their ring size to better accommodate the G4 surface. These compounds demonstrated that macrocycles can improve G4 binding and stabilization with increased selectivity over dsDNA.

Enantiopure 1,2-aminoalcohols and derivatives are essential structure motifs in many natural products or biological active molecules and they are often used as chiral catalyst in asymmetric synthesis.^{[1, 2]} Known asymmetric procedures for this substance class are still rare and limited in regio- or stereoselectivities and functional group tolerance.^[3]

Herein we described a highly diastereoselective synthesis of anti-1,2-amino alcohols via nucleophilic addition to 2,5-dimethylpyrrolo-protected amino aldehydes, which can synthesize from ex-chiral pool reagents.^[4]  Starting from commercially available amino acid methyl ester hydrochlorides to obtain the aldehydes in a 3-4 step sequence via Paal-Knorr synthesis, synthesis of Weinreb amides followed by DIBAL-H reduction. The strategy focuses on the use of bulky, base stable 2,5-dimethylpyrrolo-group in alpha position to the carbonyl group, which direct the reaction to the anti-product via Felkin-Anh like transition state with good diastereomeric ratios up to >99:1. Slightly acidic microwave assisted cleavage of 2,5-dimethylpyrrolo-group lead to the corresponding amino alcohols with yields of 81 to 96% without racemization. This method could use as key step in the straightforward synthesis of sphingolipid-type natural products, which have a crucial role in many physiological processes like protein kinase C inhibitor D-erythro-sphinganine or antitumor agent (+)-spisulosine.^[5]

[1]   D. J. Ager, I. Prakash, D. R. Schaad, Chem. Rev. 1996, 96, 835-876.

[2]   D. Frantz, R. Fässler, C. Tomooka, E. Carreira, Acc. Chem. Res. 2000, 33, 373-381.

[3]   C.-X. Ye, Y. Y. Melcamu, H.-H. Li, J.-T. Cheng, T.-T. Zhang, Y.-P. Ruan, X. Zheng, X.         Lu, P.-Q. Huang, Nat. Commun. 2018, 9, 1-9.

[4]   M. Sauer, C. Beemelmanns, manusscript in preparation

[5]   C. Snook, J. Jones, Y. Hannun, Biochim. Biophys. Acta 2006, 1761, 927-946.

The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. Diversity-oriented synthesis is a particularly attractive strategy for the delivery of complex molecules in which the 3-dimensional architecture varies across the collection. Here we describe a folding cascade approach to complex polycyclic systems bearing multiple stereocentres mediated by reductive single electron transfer (SET) from SmI₂. Simple, linear substrates undergo three different folding pathways triggered by reductive SET. Two of the radical cascade pathways involve the activation and functionalization of otherwise inert secondary alkyl and benzylic groups by 1,5-hydrogen atom transfer (HAT). Combination of SmI₂, a privileged reagent for cascade reactions, and 1,5-HAT can lead to complexity-generating radical sequences that unlock access to diverse structures not readily accessible by other means.¹

¹Plesniak, M. P.; Garduño-Castro, M. H.; Lenz, P.; Just-Baringo, X.; Procter, D. J. Nat. Commun. 2018, 9, 4802

Introduction

As ketoses like D-fructose find diverse applications, they are produced via biocatalytic isomerization of abundant aldoses. However, due to drawbacks of biocatalysts, the development of efficient chemo-catalysts is required. Currently, many known chemo-catalysts suffer from low yield due to decomposition of monosaccharides.¹ Detailed knowledge of the molecular mechanism and the kinetics of the base-catalysed isomerization will facilitate design of tailor-made catalysts and efficient catalytic processes. Therefore, our work focuses on mechanistic and kinetic investigations, employing the isomerization of D-glucose to D-fructose as an exemplary system.

Methods

We employ a combination of kinetic studies at various conditions (e.g. pH, temperature, substrate concentration, addition of salts) and operando NMR- and UV/Vis-spectroscopy to provide further insight into the base-catalysed isomerization.

Results

Kinetic investigations identified D-mannose, D-allulose and D-tagatose as co-products during the isomerization of D-glucose into D-fructose in the presence of NaOH. Moreover, the addition of neutral salts was found to accelerate the isomerization. As previously described,¹ the isomerization occurs through enediol-anion intermediates (Scheme 1), showing an absorbance at 312 nm, shifting to 308 nm under the influence of disodium carbonate.

Scheme 1. Enediol species.

To facilitate the evaluation of the operando NMR-experiments, we synthesized partially deuterated glucose and fructose species (Scheme 2).²

Scheme 2. Partial deuteration of D-fructose and D-glucose.

Discussion

The addition of salts to the reaction mixture was found to have a benign influence on the rate and the isomerization of D-glucose. Moreover, the added salts have an influence onto the selectivity for D-fructose. This impact seems to be dependent on the nature of the salt and reaction conditions. Our current research focuses on elucidating the reasons causing such impacts. Different partially deuterated sugars were successfully synthesized and will be employed in operando NMR investigations.

References

1.Delidovich, I.; Palkovits, R. ChemSusChem 2016, 9, 547-561.

2.Sawama, Y.; Yabe, Y.; Iwata, H.; Fujiwara, Y.; Monguchi, Y.; Sajiki, H. Chemistry 2012, 18, 16436-42.

Introduction: Highly toxic nerve agents such as sarin and tabun are known for their use in chemical warfare and terrorist attacks.^[1] They covalently inhibit the enzyme acetylcholinesterase (AChE), an important player in neuronal signalling. Inhibition of AChE leads to neural overstimulation and ultimately, death.^[2] To reactivate the enzyme, oxime antidotes are commonly applied alongside symptomatic treatments.^[3] The current drugs, however, have several drawbacks, including poor pharmacokinetics and nerve agent specificity.^[4] Through a compound screening and follow-up work, we found a new antidote 1. It contains a molecular anchor as well as an oxime warhead connected via an alkyl linker as structural motifs. From there, we aim to explore antidotes with improved properties as well as the poorly understood reactivation mechanism.

Methods: We design and synthesise libraries of new antidotes based on oxime 1. Since such nerve agent antidotes work similarly to covalent drugs, a large focus of our work revolves around kinetic characterisation which we assess in steady-state reactivation experiments.^[5] Furthermore, stopped-flow-techniques have made it possible to investigate pre-steady-state kinetics. Together with crystallographic investigations of nerve-agent inhibited AChE with antidotes, aided by computational methods, these techniques provide a deeper understanding of the reaction mechanism.

Results and discussion: Crystallographic investigation of antidote 1 revealed that its anchor fixates it in AChE’s peripheral site, resulting in the oxime being positioned further down the active site gorge to where the nerve agent is located. We found that both the length of the alkyl linker, in agreement with the crystal structures, as well as the nature of the oxime warhead played a crucial role in its reactivation profile. Interestingly, oxime 1 surpassed obidoxime, one of the currently used antidotes, in its in vitro reactivation capabilities regarding the hard‑to‑reactivate nerve agent tabun. Moving on from these initial studies, we now investigate similar antidotes, based on an anchor-warhead design, with more flexible linkers and non-charged oxime moieties.

References: [1] F. Worek, T. Wille, M. Koller, H. Thiermann, Arch. Toxicol. 2016, 90, 2131-2145 [2] G. Testylier, N. Micoud, S. Martinez, G. Lallament, J. Neurosci. Methods 1998, 81, 53-61 [3] M. P. Stojilikovic, M. Jokanovic Arh. Hig. Rada. Toksikol. 2006, 57, 435-443 [4] D.E. Lorke, H. Kalasz, G.A. Petroianu, K. Tekes, Curr. Med. Chem. 2008, 15, 743-753 [5] N. M. Hrvat, T. Zorbaz, G. Sinko, Z. Kovarik Toxicol. Lett. 2018, 293, 222-228

In the present project, the lipids produced by the surface-dwelling springtail Hypogastrura viatica are being studied. The major lipid component, viaticene A, was isolated by column chromatography and its structure was elucidated based on NMR- and IR-spectroscopy, mass spectrometry and microderivatization (hydrogenation and ozonolysis). The configuration of the two stereogenic centers of the core ozonolysis fragment could be elucidated by synthesis of the candidate stereoisomers and comparison with the natural derivative by chiral GC, while the configuration of the remaining three stereocenters is unknown so far.

To provide access to greater amounts of this natural product, a total synthesis of viaticene A is being developed at present, relying on the use of carbometallations for the stereoselective introduction of the two triple-substituted double bonds and cross-coupling reactions for the buildup of the carbon skeleton. Of the five stereogenic centers, three are planned to be established from citronellyl-units, while the remaining two can be introduced using pseudoephedrine as chiral auxiliary, enabling the synthesis of all possible stereoisomers.

Viaticene A represents a new class of irregular tetraterpenes with a highly branched, ‘Y-shaped’ [6+2]-connectivity. After conclusion of the total synthesis, the physical properties and ecological significance of this unique lipid will be explored.

Phenol functionalization strategies are dominated by ortho- and para-selective electrophilic aromatic substitution and ortho-directed catalytic C-H activation.¹ Access to the meta-position remains challenging and demands elaborate directing ‘templates’ or ‘blocking’ groups, superstoichiometric additives, and high catalyst loadings. Furthermore, these meta-functionalisation approaches cannot be applied to phenols featuring ortho-substituents.^2,3 We have developed an ‘outside-the-box’ approach to these hard to access structures using organobismuth chemistry.

Starting from a versatile bismuth(III) precursor that can be synthesised on a decagram scale, we show that meta-selective arylation of ortho-substituted phenols is achieved in good to excellent yields. The reaction tolerates a wide range of electronically diverse substrates and is compatible with functionality that is orthogonal to conventional cross-coupling methods. In this way it is now possible to access both the elusive meta‑position of phenols, and under-represented 1,2,3-trisubstituted benzenoid motif.

As well as expediting access to previously unexplored structures, mechanistic studies provide a rationale for the observed chemoselectivity. This fast, easy, and air stable chemistry opens the door to a previously poorly explored area of chemical space.

1. Z. Huang et al., ACS Catal., 2019, 9, 521–555.
2. R. J. Phipps et al., Science, 2009, 323, 1593–1597.
3. P. Wang, et al., J. Am. Chem. Soc., 2016, 138, 9269–9276.
4. D. H. R. Barton, et al., Tetrahedron, 1987, 43, 323–332.

Introduction:

We combine machine learning (ML) with mechanistically based modelling to extend the scope and accuracy of selectivity predictions. We have previously shown that mechanistic models can achieve selectivity predictions within ca. 2-3 kJ/mol. Such models can be constructed without experimental data, but have limited scope. Pure machine learning models, built upon many thousands of experimental data points, cover a wide scope, but are so far unable to make quantitative predictions. By combining the two methods, we utilize limited data without sacrificing accuracy.

Methods:

A mechanistic framework enables predictive ML models from limited reaction data. Methods tested include ML-models built on quantum mechanical (QM) descriptors; augmentation of the experimental data set with QM-generated data points; and training an ML model to compensate for systematic errors in QM calculations.

Results:

Different reaction types require different approaches. An ML model based on local descriptors was well suited to rank directing groups in ortho-metallation, if the training set was augmented with QM-based selectivity predictions. For reactions dependent on long-range conjugation, such as electrophilic aromatic substitution, we instead utilized QM-calculated descriptors based on reactants or intermediates. Finally, for nucleophilic aromatic substitution, we required knowledge about the transition state. An automated transition state finder was implemented and utilized with semi-empirical and DFT methods. An ML model trained on these structures was shown to outperform DFT activation energies by a wide margin.

Discussion:

We still do not have a global model, encompassing all chemical reactions, with an accuracy necessary to support chemical development. However, combining QM and ML for several frequently utilized reaction types, we are achieving the required accuracy/cost ratio to be of use to developers of experimental routes. The models are being implemented in automated workflows within AstraZeneca, and can be utilized by experimental chemists without training in computational methods.

Carbasugars are a wide group of carbohydrate mimetics in which the ring oxygen had been replaced by a methylene group.[i] The high importance of these compounds is related to their interesting biological and pharmacological properties which are the matter of current studies. 

Due to the fact of increasing application of carbasugars is not surprising that much effort has been put into the synthesis of these highly functionalized cyclohexane derivatives.

In our work, concise synthesis of carbasugars from naturally occurring D-pentoses is presented. The one-pot seleno-Michael reaction connected with intramolecular aldol reaction is a key step of the carbasugar core asymmetric synthesis. Further transformation of obtained carbasugar moiety led to different bioactive compounds.[ii,iii]

Tandem seleno-Michael reaction conjugated with oxidation/elimination step of in situ generated nucleophile has been described a few years ago in the intermolecular variant.[iv] In our work, we present the first example of this reaction in an intramolecular way which leads to a previously inaccessible cyclic product of Morita-Baylis-Hillman reaction. Conducted experiments allowed to receive cyclic products with high yields and good to great diastereoisomeric excesses.[v]

Further research on the developed method allows applying trimethylsilyl ethers as temporary protecting groups. This protocol drastically decreased synthesis time and resulted in total yields up to 40% from naturally occurring pentoses.[vi]

The use of catalytic reagents is a means of reduced waste production, lower energy consumption and improved atom economy. As such catalysis touches on several of the other Principles of Green Chemistry. Recently, the term “metal criticality” was established to evaluate metals beyond their relative abundance to include environmental implications of mining operations and supply risk. In line with those new trends in Green Chemistry, new solutions are sought to provide metals resources in an environmentally friendly fashion. During the presentation we will show that biomass issued from plants used in phytoremediation of metal contaminated sites can be used for production of polymetallic catalysts suitable for applications in organic synthesis and preparation of a variety of structurally diverse molecules.

 Malaria is one of the various infectious diseases that are transmitted by mosquitoes (called vectors). Vector control with insecticides is a very important preventing measure to save millions of people each year. The present work aims to develop insecticidal organic molecules that selectively inhibit the function of acetylcholinesterase 1 (AChE1) in mosquitoes, with a focus on the malaria mosquito Anopheles gambiae (Ag). Acetylcholinesterase (AChE) is an essential enzyme for cholinergic signaling in mammals, insects, and other animals. Mosquitoes have two kinds of AChE (AChE1 and AChE2), where AChE1 is the catalytically active one. In the present work, a series of indole-based analogous has been synthesized and explored as selective inhibitors of AgAChE1 over human AChE (hAChE) as well as acetylcholinesterase 2 (AChE2) of honeybee (Apis mellifera (Apm), an important pollinator. 

Crystal structures of mouse AChE (mAChE) in complex with indole-based inhibitors were used in MD simulations to study the dynamics of the compound class in off-target species (mAChE) and target species (AgAChE). The results were then exploited to design and synthesize new analogues. Using the in vitro Ellman assay, potency and selectivity of the analogues were analyzed for the enzymes AgAChE1, hAChE, mAChE, AgAChE2, and ApmAChE2. 

The non-substituted indole-based compound AL226 showed some inhibitory potential (AgAChE IC₅₀ = 31.6 µM, hAChE IC₅₀ =1 mM). SAR of AL226 has been explored with small chemical changes either in a benzyl moiety e.g. AL227 (AgAChE IC₅₀ = 2.6 µM, hAChE IC₅₀ = 92µM) or in the indole moiety AL417 (AgAChE IC₅₀ = 0.06 µM, hAChE IC₅₀ = 1.6 µM) resulting in substantial increase in potency. The comparison of mouse and mosquito MD simulations revealed differences in the binding position of the indole-based compounds in different species. Newly designed and synthesized indole analogues proved to be potent as well as selective inhibitors of AgAChE1 over hAChE. Besides, we recently were able to successfully express ApmAChE2 and AgAChE2 in a baculoviral protein expression system.

 Analysis of differences in the AChE protein in target and off-target species allowed the design and synthesis of new highly potent and selective inhibitors. Small changes in chemical structures resulted in remarkable differences in inhibition potency as well as selectivity. The indole-based compounds show potential as insecticide candidates in the combat against malaria.

Organochlorine compounds are ubiquitous in the pharmaceutical industry, as they have found use in several different therapeutics, namely anti-cancer drugs, and in the agrochemical industry. The incorporation of fluorine to make vic-chlorofluorides could yield bioactive compounds with higher metabolic stability and biocompatibility [A]. Syntheses of the vic-chlorofluoride is surprisingly rare in the literature, as these often combine a chloronium source with hydro fluoride, which have several disadvantages, including limited substrate scope and use of wasteful atom uneconomic reagents. Furthermore, the mechanism necessarily leads to the anti diasteroisomer, and access to the syn-diastereomer is unprecedented [B]. The use of electrochemically generated hypervalent iodine mediators can circumvent these issues by offering a mildly reactive and 'green' solution. The physical separation of the oxidation and reduction reactions in electrochemistry, allows for a selective oxidation on the anode and a milder and waste-free oxidant to be reduced on the cathode. Herein, we report an electrochemical diastereoselective methodology whereby access to both the syn- and anti-diastereomers is possible for the first time [C]. The substrate scope was extended to several new functionalities, such as anilines, secondary amines, tri, and tetra substituted alkenes. Additionally, the reaction has been shown on several pharmaceutical drugs to indicate its wide functional group tolerance.

Mucins are densely O-glycosylated membrane-bound or secreted proteins ubiquitously found on the epithelial cell surface.^[1] They are part of the innate immune system and play major roles as protective barriers to defend the host against invading pathogens.^[2] However, bacteria and viruses have co-evolved with the human host and developed strategies to promote virulence for instance by adhering to carbohydrate ligands on the host cell-surface via pathogenic lectins. Therefore, the study of these carbohydrate-lectin interactions is essential to gain insights into the disease process and progress, and to develop novel treatment strategies. In order to improve our understanding of the pathogenic adhesion processes on a molecular level, we study the interactions between pathogenic lectins and carbohydrate ligands using microarray-based techniques. In this study, we determined the fine binding specificities two bacterial lectins that recognize and bind to fucose containing glycans: LecB from Pseudomonas aeruginosa, an opportunistic bacterium that is a major player in airway diseases^[3-5], and toxin A from Clostridium difficile (TcdA), a bacterium that causes gastro-intestinal disorders.^[6] Therefore, we enzymatically modified selected synthetic mucin glycopeptides with Lewis a, Lewis x, or H-type core motifs as well as bi-fucosylated Lewis b and Lewis y structures. Then, we generated glycopeptide microarrays which we applied to evaluate the LecB and TcdA binding preferences. Whereas TcdA specifically bound to Lewis x structures, LecB recognized all fucosylated structures with preference of Lewis a over H-type and Lewis x modified glycans. Additionally, we found that the glycosylation sites, glycan core structures and the number of fucose units attached to the cores strongly impacted lectin binding. Based on our findings, diagnostic biomarkers can be identified, and novel drugs and strategies can be developed to fight Pseudomonas aeruginosa and Clostridium difficile infections.

References:

[1] J. Dekker, Trends in Biochemical Sciences 2002, 27, 126. [2] D. J. Thornton, Proc. Am. Thorac. Soc. 2004, 1, 54. [3] R. L. Gibson, Am. J. Respir. Crit. Care Med. 2003, 168, 918. [4] S. L. Gellatly, Pathog. Dis. 2013, 67, 159. [5] V. E. Wagner, Clin. Rev. Allergy Immunol. 2008, 35, 124. [6] R.N. Pruitt, Proc Natl Acad Sci U S A. 2010, 107, 13467.

Given their manifold applications in mechanistic experiments, drug development, and metabolism studies, methodologies for the selective exchange of hydrogen for its heavier isotope deuterium continue to be of interest for many scientists. The current toolbox for labeling reactions mainly relies on iridium catalysis. However, methodologies catalyzed by the more abundant 3d metals gain increasing importance. Further, there is a need to circumvent the laborious pre-installation and removal of complex directing groups. In this context, we show here how catalytic transient directing groups can enable manganese-catalyzed hydrogen isotope exchange of aromatic aldehydes. Using D₂O as a cheap and convenient source of deuterium, the reaction proceeds with excellent functional group tolerance. High ortho-selectivity is achieved in the presence of catalytic amounts of specific amines, which in situ form a transient directing group. Extending the scope of transient directing group-mediated deuteration of aromatic carbonyl compounds to ketones, we further present an improved hydrogen isotope exchange methodology using a ruthenium catalyst along with a catalytic aniline. Here, a high degree of deuteration is achieved for α-carbonyl and aromatic ortho-positions. In addition, appropriate choice of conditions allows for exclusive labeling of the α-carbonyl position while a procedure for the preparation of merely ortho-deuterated compounds is also reported. Lastly, we demonstrate how our novel methodology can be applied for the deuteration of pharmaceuticals.

A convenient protocol for stereoselective synthesis of a wide range of unnatural α-amino acids has been achieved through addition of C-radicals to a chiral glyoxylate-derived N-sulfinyl imine. In the developed photocatalytic system, an organic acridinium-based photocatalyst mediates formation of C-radicals from ubiquitous carboxylic acids without prior derivatization under visible light irradiation. The disclosed protocol tolerates a range of highly functionalized substrates and displays excellent diastereoselectivity at the α-position of the formed α-amino acids, while also simplifying separation of β-diastereoisomers. Alternative mechanisms for the developed transformation are delineated and supported by computational and experimental studies.

Protein based hydrogels are three-dimensional networks formed by crosslinking of e.g. aqueous BSA (bovine serum albumin) or GM10 (methacrylated gelantin) with photoreactive molecules (photoresists). Being structurally similar to the extracellular matrix, hydrogels are an appealing material for various biomedical applications.^[1]

                                  _{Scheme 1. Route towards functionalized 3D scaffolds in a “one-step” procedure.}

Furthermore, microfabrication techniques, such as two photon stereo-lithography allow for the direct sculpturing of native protein material into micron scale shapes. Hereby, 3D tissue scaffolds and tissue replicas, cell micropatterns, and bioelectronic components can be manufactured.^[2] Although hydrogels already display a stunningly versatile spectrum of possible applications little effort has been made to functionalize its surface to e.g. immobilize biomolecules.

Here we present functionalized 3D scaffolds fabricated in a “one-step” procedure derived from novel functionalized crosslinkers.

[1] A. Upadhyay et al., ACS Sustainable Chem. Eng., 2018, 6, 3321–3330.

[2] J. V. Hoorick, H. Ottevaere, H. Thienpont and P. Dubruel, Polymer and Photonic Materials Towards Biomedical Breakthroughs. (Springer, 2018)

Hoot loops, composed of peptide sequences with their C- and N-terminus in spacial proximity, have been identified as frequently occurring structural protein motifs which contribute crucially to protein-protein interactions (PPIs). Macrocyclic peptides have been explored to inhibit PPI mediated by hot loops. However, peptide macrocyclization is currently restricted to classical methods such as lactam, disulfide, olefin, triazole and simple aromatic bridges. Moreover, their lengthy synthetic routes and lack of conformational tuning limit their diversity, availability and efficient adjustment of the peptide epitope conformation.

Herein, we report de novo combination of peptide sequences from hot loops and natural product (NP)-inspired structures to afford macrocyclic Peptide-Natural Product modalities (PepNats) to modulate PPIs.¹ Efficient access to PepNats is obtained via intramolecular imine cyclization followed by a late stage diastereoselective cycloaddition on solid support. Rapid structural variation of both the Csp3 moiety and the peptidic unit is enabled by leveraging the power of solid phase synthesis in combination with stereoselective synthesis of a NP-like scaffold. These macrocyclic modalities adopt a preferred conformation in solution as revealed by NMR and conformational analysis. Further, we provide proof of principle by the design, synthesis and analysis of two macrocyclic PepNat collections using the DINNN and RFF peptide loop epitopes from the inducible nitric oxide synthase (iNOS) and human agouti-related protein (AGRP) respectively. The PepNats derived from the iNOS hot loop are nanomolar binders of the SPSB2 adaptor protein in the E3 ubiquitin ligase complex. Flexible modification of the NP unit in the RFF containing PepNats gives modulable selectivity profile for the different melanocortin receptor sub-types. Taken together, the unprecedented combination of NP scaffolds with a hot loop on solid support enables the rapid identification of novel hot loop mimics with conformationally constrained and biologically relevant structure.

(1) Guéret, S. M.; Thavam, S.; Potowski, M.; Carbajo, R. J.; Larsson, N.; Dahl, G.; Dellsen, A.; Grossmann, T. N.; Plowright, A. T.; Valeur, E.; Lemurell, M.; Waldmann, H. Under Revision for The Journal of American Chemican Society.

Developing new ways to selectively functionalise compounds has become increasing important in organic synthesis. Allowing diverse libraries of compounds to be accessed through elaboration of a small group of core scaffolds. In order to achieve selective functionalisation, new reagents are required which can interact with particular functional groups whilst leaving others untouched. We have a long-standing interest in the use of perfluoroinated aromatics and their interesting properties when it comes S_NAr and displacement chemistries. We have found that compounds such as hexafluorobenzene and pentafluoropyridine can have uses in functionalisation of diverse chemical scaffolds from small molecules to peptides.^[1] Pentafluoropyridine (PFP) for example is an interesting reagent as not only can it readily react with nucleophiles, but it can also dramatically change the electronics of aromatic systems with its highly electron deficient nature. Due to these properties, we have utilised PFP in a range of functionalisation reactions including modification of peptides, amino acids and asymmetric bi-aryls. Our developed synthetic methodologies allow for easy to conduct and selective modification using cheap commercially available reagents which can be used under mild reaction conditions.

In this presentation a range of applications of pentafluoropyridine in molecular functionalisation will be discussed. This will include work on the selective protection of phenols along with remote regioselective functionalisation of bisphenols. It will also touch on other areas such as modification of biologically relevant scaffolds.

[1]         a) W. D. G. Brittain, S. L. Cobb, Org Biomol Chem 2019, 17, 2110-2115; b) W. D. G. Brittain, S. L. Cobb, J. Org. Chem 2020, 85, 6862-6871; c) D. Gimenez, C. A. Mooney, A. Dose, G. Sandford, C. R. Coxon, S. L. Cobb, Org Biomol Chem 2017, 15, 4086-4095.

Chiral tetrahydrothiophenes are valuable building blocks for compounds exhibiting various biological activities [1]. Elaborated addition of mercaptoacetic aldehyde to the unsaturated electron-poor system of Michael acceptor resulted in the formation of the multifunctional tetrahydrothiophenes with three contiguous stereocenters in a one-pot reaction (Scheme 1.). A crucial step to this transformation was a decomposition of the stable 1,4-dithiane-2,5-diol into reactive thiol promoted by a tertiary amine unit in a catalyst and the temperature increase to 333 K, followed by the cascade Sulfa-Michael/ aldol reaction. An undeniable advantage of this strategy is the possibility of further transformations of obtained chiral products bearing additional double or triple bonds or another electron-withdrawing group to even more complex structures.

Scheme.1 Addition of 1,4-dithiane-2,5-diol to functionalized enone-based π-conjugated systems

The perfect fit of the catalyst and the electrophile via N-H hydrogen bonding was essential for the chirality. Only 2 mol% of the carefully designed Cinchona alkaloid-based squaramides provided multifunctional products with enantioselectivities up to 99% and diastereoselectivities up to 20:1 [2]. 

ACKNOWLEDGEMENTS 

We thank National Science Center, Poland for financial support (Grant No. 2016/22/E/ST5/00046).

REFERENCES:

[1] P. Chauhan, S. Mahajan, D. Enders, Organocatalytic Carbon-Sulfur Bond-Forming Reactions Chem. Rev. 2014, 114, 18, 8807-8864

[2] Ż. A. Mała, M. J. Janicki, N. H. Niedźwiecka, R. W. Góra, K. A. Konieczny, R. Kowalczyk, Stereoselectivity Enhancement During the Generation of Three Contiguous Stereocenters in Tetrahydrothiophenes ChemCatChem 2021, 13, 574-580

AZD9977 is a neutral, non-steroidal and selective mineralocorticoid receptor (MR) modulator in clinical development for heart failure.^1-2 During profiling of the series, we expanded the SAR to include a range of sulfonamide derivatives as represented by compound 1, which showed excellent binding affinity to hMR. However, the preparation of these sulfonamide analogs posed a significant synthetic challenge . Herein, we report on the preparation of these sulfonamide analogs and detail the route development of 1, which led to a relatively short and scalable chemistry route on a 100-gram scale to support preclinical profiling.

1.Bamberg, K., et al. Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion. PLoS One 2018, 13, e0193380, https://doi.org/10.1371/journal.pone.0193380

2.Granberg, K. L., et al. Identification of Mineralocorticoid receptors with low impact on electrolyte homeostasis but maintained organ protection, J Med Chem 2019, 62, 1385-1406

An increasing interest in the development of the chemistry and applications of N-oxides has been observed in the last decade. Chiral heteroaromatic N-oxides can work as powerful electron-pair donors, providing suitable electronic environments in the transition state formed within the reaction [1]. The nucleophilicity of the oxygen atom in N-oxides, coupled with a high affinity of silicon to oxygen, represent ideal properties for the development of synthetic methodology based on nucleophilic activation of organosilicon reagents [2]. However, catalytically efficient heteroaromatic N-oxides usually are quite complex, sophisticated structures that require long and tedious synthesis. Therefore, the developing of new structures, readily available and efficient as chiral organocatalysts for the reaction of trichlorosilyl compounds is still very active. On the other side, azoles, specifically the 2-oxazoline sub-class of azoles, represent an important group of chiral auxiliaries and metal-binding agents that are used extensively in both enantioselective catalysis and materials science [3]. Despite the numerous uses of either N-oxides or oxazolines, chiral structures containing both active fragments have not been described. 

Within our investigations, several azaaromatic oxazolines, and their N-oxides based on frameworks of pyridine, alkyl-substituted pyridine, 2,2’-bipyridine and isoquinoline were synthesized in aim to combine the unique properties of both moieties. Various synthetic pathways have been designed and tested according to the properties and limitations imposed by the target products. Using the ability of the N-oxide moiety to activate the silane compound, and an additional coordination center in the oxazoline ring we examined a few selected compounds in the allylation of benzaldehyde with alliltrichlorosilane which has become the testing ground for catalytic properties of new chiral Lewis bases. The differences in the effectiveness of the obtained compounds as catalysts, resulting from their different structure, were shown.

Scheme 1. Possible ways from heteroaromatic cyanides to chiral oxazoline derived N-Oxides.

[1] Malkov, A.V.; Kočovský, P. Chiral N-Oxides in Asymmetric Catalysis. Eur. J. Org. Chem. 2007, 29–36. 

[2] Koukal, P.; Ulč, J.; Nečas, D.; Kotora, M. Pyridine N-Oxides and Derivatives Thereof in Organocatalysis. Top Heterocycl Chem 2017, 53, 29-58.

[3] Gómez, M.; Muller, G.; Rocamora, M. Coordination chemistry of oxazoline ligands. Coord. Chem. Rev. 1999, 193–195, 769–835; 

Thorough exploration of chemical space relevant for medicinal chemistry requires synthetic methods, which open access to potential lead compounds in an efficient manner. Multicomponent reactions are especially promising in this view since they provide sufficient diversity of the compound libraries with minimum synthetic efforts required. In particular, Castagnoli-Cushman reaction (CCR), i.e. condensation of imines with cyclic andydrides, has been considered as an efficient tool for synthesis of pyrrolidones and piperidones, as well as their fused and heteroatom-substituted analogues. Our last investigation added azepinones to this list.

In our ongoing research in discovering of the scope and limitation of this useful reaction the trifluoracetaldehyde monohydrate was utilized. This opened a door for such rare types of benzpiperidones and benzazepinones as 1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids and 4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylic acids and their derivatives.

In this report, the specificities of the methodology of the using of fluoral in this reaction are shown. The correlation between regioselectivity of the reaction and type of the anhydride used is described, unusual rearrangement of trifluoroethylideneamines is determined. The stereochemistry of the process is detected.

The well-known electrochemical Shono oxidation of Boc-protected cyclic amines was revised. Boc-protected morpholine 1, which in described conditions gives the mixture of products, was as model compound. The process was optimized for the synthesis of carbamate 3 in 500g from 1 synthetic run. The optimized procedure was applied to the multigram synthesis of carbamates 6-11. Further electrophilic functionalization of the carbamates leads to latent 1,3-bielectrophilic compounds type 12, which was subjected into classical heterocyclization with binucleophilic reagents. In a case of hydrazine the corresponding pyrazoles 13, decorated by unusual manner were prepared. The proposed methodology appears straightforward tools for the design and synthesis of MedChem relevant building blocks. For example using commercially available cyclic α-aminoacids type 14 the 5 step synthesis leads to the formation of α-aminoacids 15 with different linkers between aminoacids fragment and pyrazole nuclei. In the report the scope and limitation of above mentioned methodology will be discussed.

Introduction: Salicylic acid is used on the skin to treat common skin and foot (plantar) warts and other skin diseases. After application of a particular preparation, there is occurs the interaction between the formulation and the skin. In this work is presented dissolution test for patches with salicylic acid.

Methods. The method was performed at USP dissolution apparatus 5 in 300 mL of KH₂PO₄ buffer with pH=5.0. Dissolution was done after 48 hours at the 32±0.5 °C with 100 rotations per minute for samples 1, 2 and 3. Then was carried out HPLC-UV determination at 238 nm and extraction was done in methanol. Used column was LiChrospher 100, RP-18 endcapped (5µm), 125x4mm.

Results. We made two calibration graphs because of different concentrations of salicylic acid in three samples. Concentration ranges were 0.002-0.32 mg/ml and 0.0001-0.008 mg/ml. Sampling was done after different times of dissolution when was continued with HPLC analysis. Results show that sample 1 was release 11.78% of salicylic acid after 48 h, 90.82% and 82.35% after 48 h from sample 2 and 3 respectively.

Discussion. These tests have shown that, based on the Paddle over Disc of the used pharmacopoeial assay, different formulations from the market can be successfully compared and evaluated for quality. Sample 1 has the lowest concentration of salicylic acid and the worse quality of plasters.