Catalytic activation of diboron reagents towards their addition to alkenes: experimental and theoretical approach

Els compostos organoborats són potencialment utilitzats en un extens nombre de camps, des de la medicina, en la teràpia de captura neutrònica amb bor o altres molècules amb activitat biològica, fins a l’ús de molècules funcionals com els polímers. A més a més, els compostos organoborats són curcials com a intermedis de síntesis per a productes d’alt valor afegit. El tema principal d’aquesta tesi és el desenvolupament de noves metodologies sintètiques per a l’obtenció de compostos organoborats de manera eficient. Ens hem centrat en entendre els diferents modes d’activació d’agents diborans i el mecanisme dels processos d’addició de diborans a alquens. Amb aquest propòsit s’han dut a terme estudis d’RMN juntament amb càlculs teòrics basats en la Teoria del Funcional de la Densitat (DFT).The organoborane products are highly used in a broad number of fields, from their use in medicine as a 10B carrier for neutron capture therapy, or other molecules with biological activity, to their use as functional molecules such as polymers. Importantly, organoboranes are very versatile and powerful intermediates in the synthesis of high value products. This thesis focuses on the development of novel methodologies for catalytic boron addition to alkenes, with particular attention to the understanding of the activation mode of the diboron reagent and the mechanism of their addition to olefins. For this purpose NMR studies together with DFT (Density Functional Theory) calculations are carried out

Origins of observed reactivity and specificity in the addition of B2Cl4 and analogues to unsaturated compounds

In 1954 Schlesinger and co-workers observed the direct reaction of diboron tetrachloride with simple organic compounds under mild conditions, the 1,2 addition product being formed with either ethylene or acetylene. In the following 25 years a series of addition reactions to simple alkenes, alkynes and dienes was demonstrated. B2F4 was shown to react in similar manner, albeit under more forcing conditions. Crucially, it was demonstrated that the addition to (E)- or (Z)-but-2-ene occurred with cis-stereospecificity. Only sporadic interest was shown in this field thereafter until catalysed addition reactions of diboron reagents were realized. Encouraged by this revival of interest through the discovery of transition-metal and nucleophilic catalysis of diboryl additions, DFT analysis of uncatalysed additions of B2X4 has been carried out and interpreted. This includes the relative reactivity of several B–B reagents with ethene, and that of B2Cl4vs. B2F4 additions, including benzene, naphthalene and C60 as reactants. This allows the analysis of relative reactivity vis-à-vis substitution on boron, and also direct comparison with hydroboration by HBCl2. [4 + 2] Addition of diboron reagents to dienes with B–B cleavage competes with direct [2 + 2] addition, favourably so for B2F4. The computational results demonstrate that the stereospecific addition to isomeric but-2-enes is a rare concerted [2σs + 2πs] proces

A one-pot synthesis of symmetrical and unsymmetrical dipeptide ureas

We gratefully acknowledge financial support from the BBSRC (Grant no. BB/I022910/1 and the European Commission (Seventh Framework Programme, Collaborative project "BlueGenics", Grant no. 311848).We describe a flexible and high yielding synthesis of 1,3-disubstituted ureas, that allows for the construction of both symmetrical and unsymmetrical dipeptide ureas, including easy access to 13C labelled ureas, from amino acids and carbon dioxide at atmospheric pressure.PostprintPostprintPeer reviewe

An expedient, mild and aqueous method for Suzuki–Miyaura diversification of (hetero)aryl halides or (poly)chlorinated pharmaceuticals

The development of mild, aqueous conditions for the cross-coupling of highly functionalized (hetero)aryl chlorides or bromides is attractive, enabling their functionalization and diversification. Herein, we report a general method for Suzuki–Miyaura cross-coupling at 37 °C in aqueous media in the presence of air. We demonstrate application of this general methodology for derivatisation of (poly)chlorinated, medicinally active compounds and halogenated amino acids. The approach holds the potential to be a useful tool for late-stage functionalization or analogue generation

Heck diversification of indole‐based substrates under aqueous conditions : from indoles to unprotected halo‐tryptophans and halo‐tryptophans in natural product derivatives

The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013/ERC grant agreement no 614779 GenoChemetics (to R.J.M.G). P. C. is supported by the European Union's Horizon 2020 research and innovation program through the SponGES project (grant agreement No. 679849). C.P-U. was supported by the Marie Sklodowska-Curie Fellowship C-XAq.The blending of synthetic chemistry with biosynthetic processes provides a powerful approach to synthesis. Biosynthetic halogenation and synthetic cross‐coupling have great potential to be used together, for small molecule generation, access to natural product analogues and as a tool for chemical biology. However, to enable enhanced generality of this approach, further synthetic tools are needed. Though considerable research has been invested in the diversification of phenylalanine and tyrosine, functionalisation of tryptophans thorough cross‐coupling has been largely neglected. Tryptophan is a key residue in many biologically active natural products and peptides; in proteins it is key to fluorescence and dominates protein folding. To this end, we have explored the Heck cross‐coupling of halo‐indoles and halo‐tryptophans in water, showing broad reaction scope. We have demonstrated the ability to use this methodology in the functionalisation of a brominated antibiotic (bromo‐pacidamycin), as well as a marine sponge metabolite, barettin.Publisher PDFPeer reviewe

Buchwald Hartwig diversification of unprotected halotryptophans, halotryptophan containing tripeptides and the natural product barettin in aqueous conditions

The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013/ERC grant agreement no 614779 GenoChemetics (to R.J.M.G) P. Cárdenas received support from the European Union's Horizon 2020 research and innovation program through the SponGES project (grant agreement No. 679849).Blending synthetic chemistry and biology is synthetically powerful. To further enable this, compatible synthetic tools are needed. We report the first Buchwald Hartwig amination reactions with unprotected halotryptophans in aqueous systems and demonstrate this methodology applicable to the modification of unprotected halotryptophans, simple tripeptides and the natural product barettin.Publisher PDFPeer reviewe

An expedient, mild and aqueous method for Suzuki–Miyaura diversification of (hetero)aryl halides or (poly)chlorinated pharmaceuticals

The development of mild, aqueous conditions for the cross-coupling of highly functionalized (hetero)aryl chlorides or bromides is attractive, enabling their functionalization and diversification. Herein, we report a general method for Suzuki–Miyaura cross-coupling at 37 °C in aqueous media in the presence of air. We demonstrate application of this general methodology for derivatisation of (poly)chlorinated, medicinally active compounds and halogenated amino acids. The approach holds the potential to be a useful tool for late-stage functionalization or analogue generation

Developing a bench-scale green diboration reaction toward industrial application

We report a new methodology for the organocatalytic diboration reaction using inexpensive, sustainable, nontoxic, commercially available halogen salts. This is an educative manuscript for the transformation of laboratory scale reactions into a sustainable approach of appeal to industry.</p

Rhodium–NHC complexes mediate diboration versus dehydrogenative borylation of cyclic olefins: a theoretical explanation†

In rhodium catalysed borylation of cyclic olefins, the synergy between bidentate NHC ligands, that modify cationic Rh(I) species, and the use of non-polar solvents, such as cyclohexane, is the key factor to favour a less energetically demanding route towards the formation of diborated products versus allyl boronate esters