Heck Diversification of Indole-Based Substrates under Aqueous Conditions: From Indoles to Unprotected Halo-tryptophans and Halo-tryptophans in Natural Product Derivatives.

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.

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] process.

Metal-free borylative ring-opening of vinyl epoxides and aziridines.

A rational approach towards the borylative ring-opening of vinylepoxides and vinylaziridines, by the in situ formed MeO(-)→bis(pinacolato)diboron adduct, has been developed. The enhanced nucleophilic character of the Bpin (sp(2)) moiety from the reagent favours the SN2' conjugated B addition with the concomitant opening of the epoxide and aziridine rings. The reaction proceeds with total chemoselectivity towards the polyfunctionalised (-OH or -NHTs) allyl boronate. Theoretical calculations have determined the transition states that come from the reaction of the vinylic substrates with the activated MeO(-)→bis(pinacolato)diboron adduct, and a plausible mechanism for the organocatalytic borylative ring opening reaction has been suggested.

Activation of diboron reagents with Brønsted bases and alcohols: an experimental and theoretical perspective of the organocatalytic boron conjugate addition reaction.

Bases play an important role in organocatalytic boron conjugate addition reactions. The sole use of MeOH and a base can efficiently transform acyclic and cyclic activated olefins into the corresponding ß-borated products in the presence of diboron reagents. Inorganic and organic bases deprotonate MeOH in the presence of diboron reagents. It is concluded, on the basis of theoretical calculations, NMR spectroscopic data, and ESI-MS experiments, that the methoxide anion forms a Lewis acid-base adduct with the diboron reagent. The sp(2) B atom of the methoxide-diboron adduct gains a strongly nucleophilic character, and attacks the electron-deficient olefin. The methanol protonates the intermediate, generating the product and another methoxide anion. This appears to be the simplest method to activate diboron reagents and make them suitable for incorporation into target organic molecules.

Essential role of phosphines in organocatalytic ß-boration reaction.

The use of phosphines to assist the organocatalytic ß-boration reaction of α,ß-unsaturated carbonyl compounds has been demonstrated with a selected number of substrates. The new method eludes the use of Brönsted bases to promote the catalytic active species and PR(3) becomes essential to interact with the substrate resulting in the formation of a zwitterionic phosphonium enolate. This species can further deprotonate MeOH when B(2)pin(2) is present forming eventually the ion pair [α-(H),ß-(PR(3))-ketone](+)[B(2)pin(2)·MeO](-) that is responsible for the catalysis.

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.

Skeletally Tunable Seven-Membered-Ring Fused Pyrroles.

We describe a copper-mediated method that enables the synthesis of seven-membered-ring fused pyrroles (7-mrFPs). The protocol proceeds via an in situ spiro-intermediate ring expansion and tolerates a library of 7-mrFP derivatives with a broad range of functional groups in a simple step with tangible parameters and substrate adaptations. These rare 7-mrFPs are now accessible on a millimolar scale, and selected examples exhibit high antioxidant activity.

A new context for palladium mediated B-addition reaction: an open door to consecutive functionalization.

Palladium metal-catalyzed boron addition to unsaturated carbon-carbon bonds provides an efficient and convenient route for the preparation of organoboranes, which are versatile intermediates for organic synthesis. Palladium complexes are responsible for the exclusive catalytic performance and eventually allow access to selectively functionalized molecules by catalytic consecutive tandem sequences. The final objective is to find suitable palladium complexes that make it possible to perform a one-pot sequential reaction (B-addition/functionalization) by means of a multifaceted palladium catalyst. Mechanistic insights into the concatenated reactions through B chemistry are required if one wants to understand the experimental results.

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

Blending synthetic biology and synthetic chemistry represents a powerful approach to diversity complex molecules. To further enable this, compatible synthetic tools are needed. We report the first Buchwald Hartwig amination reactions with unprotected halotryptophans under aqueous conditions and demonstrate this methodology is applicable also to the modification of unprotected tripeptides and the natural product barettin.

Living GenoChemetics by hyphenating synthetic biology and synthetic chemistry in vivo.

Marrying synthetic biology with synthetic chemistry provides a powerful approach toward natural product diversification, combining the best of both worlds: expediency and synthetic capability of biogenic pathways and chemical diversity enabled by organic synthesis. Biosynthetic pathway engineering can be employed to insert a chemically orthogonal tag into a complex natural scaffold affording the possibility of site-selective modification without employing protecting group strategies. Here we show that, by installing a sufficiently reactive handle (e.g., a C-Br bond) and developing compatible mild aqueous chemistries, synchronous biosynthesis of the tagged metabolite and its subsequent chemical modification in living culture can be achieved. This approach can potentially enable many new applications: for example, assay of directed evolution of enzymes catalyzing halo-metabolite biosynthesis in living cells or generating and following the fate of tagged metabolites and biomolecules in living systems. We report synthetic biological access to new-to-nature bromo-metabolites and the concomitant biorthogonal cross-coupling of halo-metabolites in living cultures.Coupling synthetic biology and chemical reactions in cells is a challenging task. The authors engineer bacteria capable of generating bromo-metabolites, develop a mild Suzuki-Miyaura cross-coupling reaction compatible with cell growth and carry out the cross-coupling chemistry in live cell cultures.

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.