Structural Features of Diacyldodecaheterocycles with Pseudo-C2-Symmetry: Promising Stereoinductors for Divergent Synthesis of Chiral Alcohols.

Pseudo-C2-symmetric dodecaheterocyclic structures, which possess two acyl/aroyl groups disposed on either a cis- or trans-relative configuration, were prepared from the naturally occurring (-)-(1R)-myrtenal. Addition of Grignard reagents (RMgX) to the diastereoisomeric mixture of these compounds unexpectedly showed that nucleophilic additions to the two prochiral carbonyl centers gave the same stereochemical result in both cis/trans diastereoisomers, making unnecessary the separation of this mixture. Noticeably, both carbonyl groups showed different reactivity because one of them is attached to an acetalic carbon and the other to a thioacetalic carbon. Furthermore, addition of RMgX to the carbonyl attached to the former carbon takes place through the re face, while addition to the second one proceeds through the si face, thus affording the corresponding carbinols in a highly diastereoselective process. This structural feature allowed the sequential hydrolysis of both carbinols, yielding separately (R)- and (S)-1,2-diols after reduction with NaBH4. The mechanism of the asymmetric Grignard addition was explained by density functional theory calculations. This approach contributes to the development of the divergent synthesis of structurally and/or configurationally different chiral molecules.

The Chameleonic Nature of the Nitro Group Applied to a Base-Promoted Cascade Reaction To Afford Indane-Fused Dihydrofurans.

We disclose a Michael/Conia-ene/SN2 cascade reaction for the synthesis of Indane-fused dihydrofurans from 1,3-dicarbonyl compounds and 2-alkynylnitrostyrenes promoted by potassium carbonate in DMSO at room temperature. In this reaction, the nitro group has a chameleonic role, first as an electron-withdrawing group for the Michael addition, then the nitronate behaves as a nucleophile, and finally, the allylic nitro acts as a leaving group. The product is obtained as a single diastereomer, affording up to 82% with 1,3-keto esters and 58% with 1,3-diketones. Furthermore, DFT calculations of the reaction mechanism explained the chemoselective addition of the nitronate over the enolate to the unactivated triple bond, with the enolate addition being highly endothermic.

Stereoselective synthesis of highly substituted 1-isomorphans (1-azabicyclo[3.3.1]nonanes).

We describe the first enantioselective synthesis of highly functionalized 1-azabicyclo[3.3.1]nonanes (1-IM). The 1-IM scaffold is present in natural products and drugs and is an isomer of the morphan moiety. The proposed methodology is based on an organocatalytic Michael addition of N-protected piperidine ketoesters to nitroalkenes and an intramolecular nitro-Mannich reaction as key transformations. The 1-IMs feature 6 contiguous stereocenters, substituents at positions 2 and 4, and nitro, ester, and hydroxyl functional groups at positions 3, 5, and 6 respectively. The synthesis is straightforward, highly stereoselective (up to 98% ee, >99 : 1 d.r.), with overall yields of up to 83% and requires only two purification steps.

Incorporation of Conjugated Diynes in Perovskites and their Post-Synthetic Modification.

Two-dimensional (2D) organic-inorganic hybrid perovskites have rapidly become an attractive alternative to three-dimensional (3D) perovskites as solar cell absorbers, owing to their improved stability, versatility, and ease of processing. Despite their advantages, the insulating nature of the organic cations makes these materials have lower absorbing and conducting properties, resulting in lower device efficiencies. A way to circumvent these issues is the integration of functional molecules that help mitigate these limitations. In this study, six new perovskites composed of three distinct diynes are synthesized, all of which can be thermally polymerized to form conjugated polymers within the perovskite layers. The incorporation of conjugated polymers results in drastic changes in these materials' optoelectronic properties and their overall stability. Furthermore, depending on the nature of the diyne and the inorganic layers, the materials show varying polymerization yields, optical bandgaps, and charge carrier densities. These results afford significant insight into the chemical nature of the polymerized species and thus highlight the versatility of this approach to post-synthetically generate conducting polymers within the layers of 2D perovskites, paving the way toward their use in optoelectronic devices.

SO2 capture and detection using a Cu(II)-metal-organic polyhedron.

The SO2 adsorption-desorption capacity at room temperature and 1 bar of the metal-organic polyhedron MOP-CDC was investigated. In addition, the qualitative solid-state absorption-emission properties of this material (before and after SO2 exposure) were measured and tested, and it demonstrated remarkable capability for SO2 detection. Our results represent the first example of fluorimetric SO2 detection in a MOP.

Stereocontrolled Synthesis of Enantiopure cis-Fused Octahydroisoindolones via Chiral Oxazoloisoindolone Lactams.

Kinetically controlled cyclocondensation of stereoisomeric and ring-chain tautomeric mixture of (±)-hydroxylactone 1 and 0.5 equiv of (R)-phenylglycinol provided tricyclic oxazoloisoindolone lactam (3R,5aS,9aR,9bS)-2a, a versatile intermediate for further stereocontrolled transformations to access enantiopure cis-fused octahydroisoindolones. An extension of this methodology was successfully applied to the synthesis of the 5,6-dihydroxy derivative (3aR,5R,6S,7aS)-17.

Water clusters as bifunctional catalysts in organic chemistry: the hydrolysis of oxirane and its methyl derivatives.

This contribution explores the bifunctional catalytic activity of water clusters ((H2O)n with n = 1-5) in organic chemistry similar to that observed in the formation of H2SO4 in acid rain (Chem. Commun., 53, 3516, (2017)). We considered for this purpose the Hydrolysis of Epoxides (HE), in particular, that of oxirane and its methyl derivatives. Surrounding water molecules with H-bond cooperative effects decrease the activation energy of the rate-limiting step of HE in condensed phase, especially when they lead to an anti-periplanar attack on the alkoxide leaving group. Furthermore, the water molecules have a bifunctional catalytic role in HE by (i) increasing the nucleophilic and electrophilic character of the attacking oxygen atom and the leaving group of the reaction, respectively, and (ii) placing the reactants in a suitable disposition for the substitution to occur. Overall, this investigation provides relevant insights into the collective action of water molecules on organic reactions in neutral, basic and acid media.

The effect of chiral N-substituents with methyl or trifluoromethyl groups on the catalytic performance of mono- and bifunctional thioureas.

We evaluated thiourea organocatalysts that incorporate a chiral group which includes a trifluoromethyl moiety and contrasted their performance with non-fluorinated analogs. The comparison between such systems allows the direct study of the NH acidity of a thiourea bonded to an aliphatic substituent. In principle, -CF3 systems feature an enhanced hydrogen bond (HB) donor capacity that is undoubtedly beneficial for HB-catalysis applied to the Baylis-Hillman reaction. We found that the thiourea substituted on both nitrogens with this group accelerates this reaction like Schreiner's thiourea. On the other hand, we observed a different behavior in reactions promoted by bifunctional catalysts (thiourea-primary amine). In the Michael addition of isobutyraldehyde to methyl benzylidenepyruvate, the -CF3 containing catalysts were better than the -CH3 systems, whereas the conjugate addition to N-phenylmaleimide showed the opposite behavior. Theoretical calculations of the transition states indicated that the phenylethyl group in fluorinated and non-fluorinated compounds have different kinds of interactions with the electrophile. These interactions are responsible for a different arrangement of the electrophile and thereby the selectivity of the catalyst. Therefore, it cannot be generalized that in all cases NH acidity correlates with the performance of the catalyst, particularly, with aliphatic substituents that unlike the aromatic ones possess groups that are outside the plane of the thiourea.

Stability of doubly and triply H-bonded complexes governed by acidity-basicity relationships.

We used our recently proposed acidity-basicity interplay (ABI) model (Chem. Sci., 2018, 9, 4402) and the Jorgensen secondary interactions hypothesis (JSIH) to rationalise the experimentally observed trends in the formation constants of doubly and triply H-bonded systems with -NHO[double bond, length as m-dash]C- and -NHN- interactions. Unlike the JSIH, the ABI interpretation can explain the trends in the complexation of amide/imide homo- and heterodimers as well as ADA-DAD clusters. We found that the strongest H-bonds play a very important role, a condition which offers an alternative to the well established JSIH to modulate the stability of these relevant systems.

Thousand-fold Conductivity Increase in 2D Perovskites by Polydiacetylene Incorporation and Doping.

Two-dimensional (2D) organic-inorganic perovskites have rapidly become an attractive alternative to traditional three-dimensional (3D) perovskite solar-cell absorbers owing to their improved stability and processability. Despite their advantages, the insulating nature of the organic cations and diminished light absorption limit their overall performance. Herein, it is demonstrated that the incorporation of conjugated diynes in hybrid 2D perovskites, and subsequent thermal treatment results in the formation of 2D perovskites that incorporate polydiacetylenes in their structure. Furthermore, it is shown that oxygen or iodine doping results in the formation of stable radicals within the material alongside a drastic shift of the band gap from 3.0 to 1.4 eV and in-plane conductivity improvements of up to three orders of magnitude, which lead to record conductivities for 2D halide perovskites (n=1).

Acidity and basicity interplay in amide and imide self-association.

Amides dimerise more strongly than imides despite their lower acidity. Such an unexpected result has been rationalised in terms of the Jorgensen Secondary Interactions Hypothesis (JSIH) that involves the spectator (C[double bond, length as m-dash]OS) and H-bonded (C[double bond, length as m-dash]OHB) carbonyl groups in imides. Notwithstanding the considerable body of experimental and theoretical evidence supporting the JSIH, there are some computational studies which suggest that there might be other relevant intermolecular interactions than those considered in this model. We conjectured that the spectator carbonyl moieties could disrupt the resonance-assisted hydrogen bonds in imide dimers, but our results showed that this was not the case. Intrigued by this phenomenon, we studied the self-association of a set of amides and imides via 1H-NMR, 1H-DOSY experiments, DFT calculations, QTAIM topological analyses of the electron density and IQA partitions of the electronic energy. These analyses revealed that there are indeed repulsions of the type OS···OHB in accordance with the JSIH but our data also indicate that the C[double bond, length as m-dash]OS group has an overall attraction with the interacting molecule. Instead, we found correlations between self-association strength and simple Brønsted-Lowry acid/base properties, namely, N-H acidities and C[double bond, length as m-dash]O basicities. The results in CDCl3 and CCl4 indicate that imides dimerise less strongly than structurally related amides because of the lower basicity of their carbonyl fragments, a frequently overlooked aspect in the study of H-bonding. Overall, the model proposed herein could provide important insights in diverse areas of supramolecular chemistry such as the study of multiple hydrogen-bonded adducts which involve amide or imide functional groups.

Identification of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate-nitrostyrene hybrid as potent antiproliferative and apoptotic inducing agent against cervical cancer cell lines.

The present study seeks to describe the design and synthesis of six new Michael adducts of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate with nitrostyrenes and their in vitro antiproliferative activity against human cervical cancer cell lines [HeLa (HPV 18 positive), CaSki (HPV 16 positive) and ViBo (HPV negative) cervical cancer cell lines]. Virtual screening of the physicochemical properties of all compounds have also been presented. All the compounds exploited significant antiproliferative activity on the three cervical cancer cell lines. Compound 8a was found to be most potent, displaying in vitro antiproliferative activity against HeLa, CaSki and ViBo cervical cancer cell lines superior to Cisplatin and Paclitaxel with IC50 values 0.99 ±â€¯0.007, 2.36 ±â€¯0.016 and 0.73 ±â€¯0.002 µM respectively. In addition, compound 8a did not trigger the necrosis cell death to the test cancer cell lines. Further mechanistic study revealed that compound 8a could inhibit the cancer cell proliferation by inducing apoptosis through caspase-3 activation. Moreover, cell cycle analysis indicated that compound 8a could arrest the cell cycle at the G1 phase for HeLa and CaSki cancer cells. At the predetermined IC50 values on cancer cells, compound 8a did not induce any necrotic (cytotoxic) death to the normal human lymphocytes. In the present design, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane system was found to be superior than the piperazine counterpart 11.

Hydrogen-Bond Weakening through π Systems: Resonance-Impaired Hydrogen Bonds (RIHB).

Redefining interactions: The concept of the resonance-impaired hydrogen bond (RIHB) as an interaction in which a conjugated π system strongly impairs the formation of a hydrogen bond (HB) is introduced. A typical HB involving charged species can have a formation energy of tens of kcal mol-1 , whereas the corresponding value for the examined RIHB is only 2.6 kcal mol-1 . Quantum chemical topology tools are used to analyse the low formation energy of the studied RIHBs.

Stereodivergent Mannich reaction of bis(trimethylsilyl)ketene acetals with N-tert-butanesulfinyl imines by Lewis acid or Lewis base activation, a one-pot protocol to obtain chiral ß-amino acids.

We report a one-pot synthesis of chiral ß2,2,3-amino acids by the Mannich addition of bistrimethylsilyl ketene acetals to N-tert-butanesulfinyl imines followed by the removal of the chiral auxiliary. The synthesis and isolation of pure ß-amino acid hydrochlorides were conducted under mild conditions, without strong bases and this method is operationally simple. The stereoselective reaction was promoted by two different activation methods that lead to different stereoisomers: (1) Lewis Acid (LA) catalysis with boron trifluoride diethyl etherate and (2) Lewis Base (LB) catalysis with tetrabutylammonium difluorotriphenylsilicate. The reaction presented good diastereoselectivity with LB activation and moderate to good dr with LA catalysis. The exceptions in both protocols were imines with electron donating groups in the aromatic ring.

Stereocontrolled Nucleophilic Addition to Five-Membered Oxocarbenium Ions Directed by the Protecting Groups. Application to the Total Synthesis of (+)-Varitriol and of Two Diastereoisomers Thereof.

A stereodivergent C-glycosidation of carbohydrate-derived lactones can be mediated by the protecting groups and applied to the total synthesis of (+)-varitriol and of two diastereoisomers thereof, which represent an unprecedent use of the protecting groups in the synthesis of a naturally occurring compound. In particular, the stereoselective nucleophile attack for 2,3-trans-substituted five-membered ring oxocarbenium ions is strongly influenced by the presence of aromatic rings in the protecting groups. According to quantum chemical calculations, the stereoselectvity depends on the π-π interactions between the aromatic ring of the C-2 protecting group with the exocyclic triple bond and the oxocarbenium ion. These interactions account for the stabilization of the conformer in which the C-2 and C-3 substituents adopt pseudoaxial orientations. When protecting groups do not contain an aromatic ring, the sterochemical outcome is dictated by stereoelectronic factors established by the Woerpel's model. Based on these findings, a concise total synthesis of the natural product (+)-varitriol and of two diastereoisomers was acomplished.

The bifunctional catalytic role of water clusters in the formation of acid rain.

State-of-the-art chemical bonding analyses show that water clusters have a bifunctional catalytic role in the formation of H2SO4 in acid rain. The embedded H2O monomers mitigate the change in the chemical bonding scenario of the rate-limiting step, reducing thereby the corresponding activation energy in accordance with Hammond's postulate. We expect that the insights given herein will prove useful in the elucidation of the catalytic mechanisms of water in inorganic and organic aqueous chemistry.

Bifunctional Thioureas with α-Trifluoromethyl or Methyl Groups: Comparison of Catalytic Performance in Michael Additions.

Thioureas are an important scaffold in organocatalysis because of their ability to form hydrogen bonds that activate substrates and fix them in a defined position, which allows a given reaction to occur. Structures that enhance the acidity of the thiourea are usually used to increase the hydrogen-bonding properties, such as 3,5-bis(trifluoromethyl)phenyl and boronate ureas. Herein, we report the synthesis of bifunctional thioureas with a chiral moiety that include either a trifluoromethyl or methyl group. Their catalytic performance in representative Michael addition reactions was used in an effort to compare the electronic effects of the fluorination at the methyl group. The observed differences concerning yields and ee values cannot be attributed solely to the different steric environments; theoretical results indicate distinct interactions within the corresponding transition states. The calculated transition states show that the fluorinated catalysts have stronger N-H···O and C-H···F hydrogen bonds, while the nonfluorinated systems have C-H···π contacts. These results have shown that a variety of hydrogen-bonding interactions are important in determining the yield and selectivity of thiourea organocatalysis. These details can be further exploited in catalyst design.

Mapping the landscape of potentially primordial informational oligomers: (3'→2')-D-phosphoglyceric acid linked acyclic oligonucleotides tagged with 2,4-disubstituted 5-aminopyrimidines as recognition elements.

The (3'→2')-phosphodiester glyceric acid backbone containing an acyclic oligomer tagged with 2,4-disubstituted pyrimidines as alternative recognition elements have been synthesized. Strong cross-pairing of a 2,4-dioxo-5-aminopyrimidine hexamer, rivaling locked nucleic acid (LNA) and peptide nucleic acid (PNA), with complementary adenine-containing DNA and RNA sequences was observed. The corresponding 2,4-diamino- and 2-amino-4-oxo-5-aminopyrimidine-tagged oligomers were synthesized, but difficulties in deprotection, purification, and isolation thwarted further investigations. The acyclic phosphate backbone structure of the protected oligomer seems to be prone to an eliminative degradation owing to the acidic hydrogen at the 2'-position--an arrangement that renders the oligomer vulnerable to the conditions used for the removal of the protecting groups on the heterocyclic recognition element. However, the free oligomers seem to be stable under the conditions investigated.