Re-Engineering Organocatalysts for Asymmetric Friedel-Crafts Alkylation of Indoles through Computational Studies.

The discovery of efficient organocatalysts is generally carried out by thorough experimental screening of different candidates. We recently reported an efficient organocatalyst for iminium-ion-based asymmetric Diels-Alder reactions following a rational design approach. This result encouraged us to test this optimal catalyst in the mechanistically related Friedel-Crafts alkylation of indoles, but to our surprise, almost null enantioselectivity was observed. The results did not significantly improve with structurally related catalysts, and a totally unexpected facial selectivity inversion was also noticed. Using DFT calculations by modeling the competing transition structures with ONIOM, we could unravel the origins of those findings, further employed to predict the most efficient catalyst for this new transformation. The computational results were validated experimentally (up to 92:8 er), providing another successful example of a general strategy to accelerate catalyst development which still remains underexplored.

Design, synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents.

A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.

Synthesis of Triazole Derivatives of Levoglucosenone As Promising Anticancer Agents: Effective Exploration of the Chemical Space through retro-aza-Michael//aza-Michael Isomerizations.

The design and synthesis of biomass-derived triazoles and the in vitro evaluation as potential anticancer agents are described. The discovery of base-catalyzed retro-aza-Michael//aza-Michael isomerizations allowed the exploration of the chemical space by affording novel types of triazoles, difficult to obtain otherwise. Following this strategy, 2,4-disubstituted 1,2,3-triazoles could be efficiently obtained from the corresponding 1,4-disubstituted analogues.

Advice from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons on riot control agents in connection to the Chemical Weapons Convention.

Compounds that cause powerful sensory irritation to humans were reviewed by the Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) in response to requests in 2014 and 2017 by the OPCW Director-General to advise which riot control agents (RCAs) might be subject to declaration under the Chemical Weapons Convention (the "Convention"). The chemical and toxicological properties of 60 chemicals identified from a survey by the OPCW of RCAs that had been researched or were available for purchase, and additional chemicals recognised by the SAB as having potential RCA applications, were considered. Only 17 of the 60 chemicals met the definition of a RCA under the Convention. These findings were provided to the States Parties of the Convention to inform the implementation of obligations pertaining to RCAs under this international chemical disarmament and non-proliferation treaty.

Determination of the Relative Configuration of Terminal and Spiroepoxides by Computational Methods. Advantages of the Inclusion of Unscaled Data.

The assignment of the relative configuration of spiroepoxides or related quaternary carbon-containing oxiranes can be troublesome and difficult to achieve. The use of GIAO NMR shift calculations can provide helpful assistance in challenging cases of structural elucidation. In this regard, the DP4 probability is one of the most popular methods to be employed when only one set of experimental data is available, though modest results were obtained when dealing with spiroepoxides. Recently, we introduced an improved probability (DP4+) that includes the use of both scaled and unscaled NMR data computed at higher levels of theory. Here, we report a comprehensive study to explore the scope and limitations of the DP4+ methodology in the stereoassignment of terminal or spiroepoxides bearing a wide variety of molecular complexity and conformational freedom. The excellent levels of correct classification achieved were interpreted on the basis of a constructive compensation of errors upon using both scaled and unscaled proton and carbon data. The advantages of the DP4+ methodology in solving two case studies that could not be unequivocally assigned by NOE experiments are also provided.

Mechanistic insight into the acid-catalyzed isomerization of biomass-derived polysubstituted pyrrolidines: an experimental and DFT study.

The 1,3-dipolar cycloaddition reactions of azomethine ylides is one of the preferred methods for the synthesis of polysubstituted pyrrolidines. The use of chiral dipolarophiles derived from carbohydrates yields enantiomerically pure pyrrolidines, usually in good to excellent endo selectivities, along with other minor stereoisomers. Recently, we found an unusual isomerization event that allowed the isolation of useful pyrrolidines with relative stereochemistries difficult to obtain otherwise. Although a simple and efficient protocol to promote these transformations was developed, the mechanism was not fully unravelled. Herein, after a combination of experimental, spectroscopic and computational studies (using DFT methods) we propose that this isomerization event takes place through a retro-Mannich//Mannich cascade, via the formation of an iminium ion with E geometry.

Experimental and theoretical insights in the alkene-arene intramolecular π-stacking interaction.

Chiral acrylic esters derived from biomass were developed as models to have a better insight in the aryl-vinyl π-stacking interactions. Quantum chemical calculations, NMR studies and experimental evidences demonstrated the presence of equilibriums of at least four different conformations: π-stacked and face-to-edge, each of them in an s-cis/s-trans conformation. The results show that the stabilization produced by the π-π interaction makes the π-stacked conformation predominant in solution and this stabilization is slightly affected by the electron density of the aromatic counterpart.

Synthesis of a 3-Thiomannoside.

An efficient and straightforward synthesis of a novel 3-thiomannoside derivative (1,2,4,6-tetra-O-acetyl-3-S-acetyl-3-thio-ß-d-mannopyranoside) was developed starting from levoglucosenone. A xanthate-thiocarbonate exchange under acidic conditions was the key step for the new C-S bond. The product was obtained enantiospecifically in very good overall yield.

Joint Experimental, in Silico, and NMR Studies toward the Rational Design of Iminium-Based Organocatalyst Derived from Renewable Sources.

An efficient organocatalyst for iminium-ion based asymmetric Diels-Alder (DA) reactions has been rationally designed. The most influential structure-activity relationships were determined experimentally, while DFT calculations and NMR studies provided further mechanistic insight. This knowledge guided an in silico screening of 62 different catalysts using an ONIOM(B3LYP/6-31G*:AM1) transition-state modeling, which showed good correlation between theory and experiment. The top-scored compound was easily synthesized from levoglucosenone, a biomass-derived chiral enone, and evaluated in the DA reaction between (E)-cinnamaldehyde and cyclopentadiene. In line with the computational finding, excellent results (up to 97% ee) were obtained. In addition, the catalyst could be easily recovered and reused with no loss in its catalytic activity.

Montmorillonite K-10 promoted synthesis of chiral dioxa-caged compounds derived from levoglucosenone.

A short and efficient methodology for the synthesis of chiral dioxa-caged compounds from levoglucosenone, a biomass-derived enone, is herein presented. The key transformation, that involves a cascade 3-step cationic cyclization, was efficiently carried out in high yields and selectivities by Montmorillonite K-10 catalysis. The usefulness of K-10 in related semi-pinacol rearrangements to obtain pyran-3-ones is also shown. Interesting differences in the reactivity pattern was found for epimeric alcohols, and the origins of these findings were determined by DFT calculations.

Efficient production of the flavoring agent zingerone and of both (R)- and (S)-zingerols via green fungal biocatalysis. Comparative antifungal activities between enantiomers.

Zingerone (1) and both chiral forms of zingerol (2) were obtained from dehydrozingerone (3) by biotransformation with filamentous fungi. The bioconversion of 3 with A. fumigatus, G. candidum or R. oryzae allowed the production of 1 as the sole product at 8 h and in 81%-90% at 72 h. In turn, A. flavus, A. niger, C. echinulata, M. circinelloides and P. citrinum produced 1 at 8 h, but at 72 h alcohol 2 was obtained as the major product (74%-99%). Among them, A. niger and M. circinelloides led to the anti-Prelog zingerol (R)-2 in only one step with high conversion rates and ee. Instead, C. echinulata and P. citrinum allowed to obtain (S)-2 in only one step, with high conversion rates and ee. Both chiral forms of 2 were tested for antifungal properties against a panel of clinically important fungi, showing that (R)-, but not (S)-2 possessed antifungal activity.

Synthesis of tri-O-acetyl-D-allal from levoglucosenone.

Tri-O-acetyl-D-allal has been enantiospecifically synthesized in six steps from levoglucosenone in 55% overall yield. A key step in the synthesis is the anhydro bridge ring-opening with concomitant formation of a 1,3-oxathiolane-2-thione ring.

1,3-Dipolar cycloaddition reactions of azomethine ylides with a cellulose-derived chiral enone. A novel route for organocatalysts development.

Cellulose-derived chiral pyrrolidines were synthesized in excellent yields, regioselectivities, and stereoselectivities via a 1,3-dipolar cycloaddition reaction between levoglucosenone and azomethine ylides. An unprecedented isomerization event led to a new family of pyrrolidines with an unusual relative stereochemistry. Preliminary results showed that these compounds are promising organocatalysts for iminium ion-based asymmetric Diels-Alder reactions.

Experimental and theoretical study of a Diels-Alder reaction between a sugar-derived nitroalkene and cyclopentadiene.

The Diels-Alder reaction of a pyranose-derived nitroalkene 1 with cyclopentadiene is described, and the unexpected facial selectivity of the cycloaddition is analyzed by a computational study.

Pi-stacking effect on levoglucosenone derived internal chiral auxiliaries. A case of complete enantioselectivity inversion on the Diels-Alder reaction.

Detailed quantum chemical calculations, experimental evidence, and NMR data rationalize the participation of pi-stacking interaction in the highly asymmetric Diels-Alder reaction using levoglucosenone derived internal chiral auxiliaries, including the appealing effect of inversion of the enantioselectivity by coordination of the substrate with Et 2AlCl.

Microwave-assisted regioselective cycloaddition reactions between 9-substituted anthracenes and levoglucosenone.

The cycloaddition reactions of 9-substituted anthracenes and levoglucosenone were investigated under microwave irradiation and conventional heating conditions. Considering time, yields, and regioselectivity, microwave technology has proven to be an ideal tool to achieve this chemical transformation. [reaction: see text].

Highly diastereoselective Diels-Alder reaction using a chiral auxiliary derived from levoglucosenone.

[reaction: see text] A new chiral auxiliary derived from levoglucosenone is reported. The compound is obtained by a cycloaddition reaction with 9-methoxy methylanthracene followed by a diastereoselective reduction of the C-2 keto function. The auxiliary has been used as a chiral template in an asymmetric Diels-Alder reaction of the corresponding acrylic ester derivative with cyclopentadiene. The results showed excellent diastereomeric excess even at room temperature when the reaction was promoted by Et(2)AlCl as the Lewis acid.

Synthesis of methyl 4,6-O-benzylidene-2,3-dideoxy-2-C-formyl-alpha-D-erythro-hex-2-enopyranoside.

The synthesis of the title compound was achieved in seven steps and 61% overall yield from methyl alpha-D-glucopyranoside.

Neighboring-group participation in benzylidene acetal ring-opening of a 2-cyano-2-deoxypyranoside derivative by diethylaluminum cyanide.

The oxirane ring-opening of an anhydro sugar with diethylaluminum cyanide (Et(2)AlCN) is a direct approach for obtaining a cyano derivative. Methyl 2,3-anhydro-4,6-O-benzylidene-alpha-D-allopyranoside showed anomalous chemical behavior when treated with Et(2)AlCN. The reaction afforded the corresponding beta-cyanohydrin as the minor component from a mixture of compounds resulting from the benzylidene acetal ring-opening caused by the attack of ethyl or cyano groups.