Stéphanie Essafi

Assembly-line synthesis of organic molecules with tailored shapes

Molecular assembly lines, where molecules undergo iterative processes involving chain elongation and functional group manipulation are hallmarks of many processes found in Nature. We have sought to emulate Nature in the development of our own molecular assembly line through iterative homologations of boronic esters. Here we report a reagent (α-lithioethyl triispopropylbenzoate) which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol. Through repeated iteration we have converted a simple boronic ester into a complex molecule (a carbon chain with ten contiguous methyl groups) with remarkably high precision over its length, its stereochemistry and therefore its shape. Different stereoisomers were targeted and it was found that they adopted different shapes (helical/linear) according to their stereochemistry. This work should now enable scientists to rationally design and create molecules with predictable shape, which could have an impact in all areas of molecular sciences where bespoke molecules are required.Molecular ‘assembly lines’, in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon–boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes—helical or linear—depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.

Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters

The cross-coupling of boronic acids and related derivatives with sp(2) electrophiles (the Suzuki-Miyaura reaction) is one of the most powerful C-C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.

Visible-Light-Mediated Generation of Nitrogen-Centered Radicals: Metal-Free Hydroimination and Iminohydroxylation Cyclization Reactions.

The formation and use of iminyl radicals in novel and divergent hydroimination and iminohydroxylation cyclization reactions has been accomplished through the design of a new class of reactive O-aryl oximes. Owing to their low reduction potentials, the inexpensive organic dye eosin Y could be used as the photocatalyst of the organocatalytic hydroimination reaction. Furthermore, reaction conditions for a unique iminohydroxylation were identified; visible-light-mediated electron transfer from novel electron donor–acceptor complexes of the oximes and Et3N was proposed as a key step of this process.

Construction of multiple, contiguous quaternary stereocenters in acyclic molecules by lithiation-borylation

Lithiation of carbamates followed by borylation provides a powerful method for the homologation of boron reagents. However, when applied to hindered systems (secondary carbamates with tBu-boronic esters) for the construction of two quaternary centers, this methodology fails. Instead, using mixed boranes (tBuBMe2), the synthesis of adjacent quaternary stereogenic centers with full stereocontrol was successful. The process can be repeated two or three times in one pot leading to carbon chains bearing multiple contiguous quaternary stereogenic centers. The boranes were converted into tertiary alcohols or C-tertiary amines using chloramine. The origin of the high selectivity for alkyl over Me group migration was determined computationally.

Development of enantiospecific coupling of secondary and tertiary boronic esters with aromatic compounds

The stereospecific cross-coupling of secondary boronic esters with sp2 electrophiles (Suzuki–Miyaura reaction) is a long-standing problem in synthesis, but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. To address this general problem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel–Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C–C bond. Elimination (preceded by further oxidation in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, and ethers). The reaction also worked well with other electron-rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found under which the B(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C(sp2)–C(sp3) and an adjacent C–B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases, the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations.

Highly Selective Allylborations of Aldehydes Using α,α‐Disubstituted Allylic Pinacol Boronic Esters

α,α-Disubstituted allylic pinacol boronic esters undergo highly selective allylborations of aldehydes to give tetrasubstituted homoallylic alcohols with exceptional levels of anti-Z-selectivity (>20:1). The scope of the reaction includes both acyclic and cyclic allylic boronic esters which lead to acyclic and exocyclic tetrasubstituted homoallylic alcohols. The use of β-borylated allylic boronic esters gave fully substituted alkenes bearing a boronic ester which underwent further cross-coupling enabling a highly modular and stereoselective approach to the synthesis of diaryl tetrasubstituted alkenes. Computational analysis revealed the origin of the remarkable selectivity observed.

Qualitative estimation of the single-electron transfer step energetics mediated by samarium(II) complexes: a "SOMO-LUMO gap" approach.

Lanthanide II organometallic complexes usually initiate reactions via a single-electron transfer (SET) from the metal to a bonded substrate. Extensive mechanistic studies were carried out for lanthanide III complexes in which no change of oxidation state is involved. Some case-dependent strategies were reported by our group in order to account for a SET event in organometallic computed studies. In the present study, we show that analysis of DFT orbital spectra allows differentiating between exothermic and endothermic electron transfer. This methodology appears to be general; it allows differentiating between lanthanide centers and substituent effects on metallocenes. For that purpose, we considered mainly various samarocene adducts as well as a SmI2 complex explicitly solvated by THF. Comparison between DFT methods and ab initio (CAS-SCF and HF) computational level revealed that the SOMO-LUMO gap computed at the DFT B3PW91 level, in combination with small-core RECPs and standard basis sets, offers a qualitative estimation of the energetics of the SET that is in line with both CAS-SCF calculations and experimental results when available. This orbital-based approach, based on DFT calculation, affords a fast and efficient methodology for pioneer exploration of the reactivity of lanthanide(II) mediated by SET.

Homologation of Boronic Esters with Organolithium Compounds: A Computational Assessment of Mechanism

Ab initio calculations are reported for the reaction of methyl boronic ester with organolithium reagents with α-leaving groups. The best calculations rely on density functional theory prediction of structures and coupled-cluster theory calculation of accurate potential energies. The results provide strong confirmation of the feasibility of a two-step mechanism with rapid initial formation of a boron-ate complex followed by slower migration of methyl from boron to carbon with loss of the leaving group. The calculated free energy of activation is consistent with observed kinetic behavior, and the calculations provide a framework for exploring substituent and other effects on reactivity. Obtaining reasonable agreement with experiment in this way is not trivial and requires careful treatment of level of theory (density functional theory calculations tend to yield inaccurate results), of conformational complexity, especially for the ate complexes, and of the nature of the microscopic model of reactants and solvent. The methodological challenges and possible pitfalls, many of which are relevant more broadly to computational modeling of organic reaction mechanisms, are discussed in detail.

Rates of Molecular Vibrational Energy Transfer in Organic Solutions

For condensed-phase reactions, commonly used kinetic models assume that energy exchange from and to solvent molecules is much faster than any reactive steps. However, it is becoming increasingly evident that this does not always hold true. In this work, we use molecular dynamics simulations to explore the time scale for energy transfer between solvent and solute in some typical organic solvents. As a reference, energy transfer between solvent molecules is also considered. The time scale is found to depend most strongly on the identity of the solvent. Energy transfer occurs fastest, with a time scale of roughly 10 ps, for ethanol, DMSO or THF, while it is noticeably slower in dichloromethane and especially supercritical argon, where a time scale well in excess of a hundred picoseconds is found. This suggests that the experimental search for nonthermal effects on selectivity and reactivity in organic chemistry should pay special attention to the choice of solvent, as the effects may occur more frequently in some solvents than in others.

Stereospecific conversion of alcohols into pinacol boronic esters using lithiation-borylation methodology with pinacolborane

The synthesis of primary and secondary pinacol boronic esters via lithiation-borylation of carbamates and benzoates with pinacolborane is described. This new protocol enables the highly selective synthesis of enantioenriched and geometrically defined boronic esters that cannot otherwise be accessed by alternative methodologies.