Stereoselective synthesis of (R)- and (S)-1,2-diazetidine-3-carboxylic acid derivatives for peptidomimetics.

The stereoselective synthesis of both enantiomers of N-protected 1,2-diazetidine-3-carboxylic acid (aAze) from homochiral glycidol is described. Orthogonal protection of this novel cyclic α-hydrazino acid allows for selective functionalisation at either Nγ or Nδ. This novel peptidomimetic building block was incorporated into the pseudotripeptides Gly-γaAze-Ala and Gly-δaAze-Ala.

Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides.

Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.

Efficient N-Type Organic Electrochemical Transistors and Field-Effect Transistors Based on PNDI-Copolymers Bearing Fluorinated Selenophene-Vinylene-Selenophenes.

n-Type organic electrochemical transistors (OECTs) and organic field-effect transistors (OFETs) are less developed than their p-type counterparts. Herein, polynaphthalenediimide (PNDI)-based copolymers bearing novel fluorinated selenophene-vinylene-selenophene (FSVS) units as efficient materials for both n-type OECTs and n-type OFETs are reported. The PNDI polymers with oligo(ethylene glycol) (EG7) side chains P(NDIEG7-FSVS), affords a high µC* of > 0.2 F cm-1  V-1  s-1 , outperforming the benchmark n-type Pg4NDI-T2 and Pg4NDI-gT2 by two orders of magnitude. The deep-lying LUMO of -4.63 eV endows P(NDIEG7-FSVS) with an ultra-low threshold voltage of 0.16 V. Moreover, the conjugated polymer with octyldodecyl (OD) side chains P(NDIOD-FSVS) exhibits a surprisingly low energetic disorder with an Urbach energy of 36 meV and an ultra-low activation energy of 39 meV, resulting in high electron mobility of up to 0.32 cm2  V-1  s-1 in n-type OFETs. These results demonstrate the great potential for simultaneously achieving a lower LUMO and a tighter intermolecular packing for the next-generation efficient n-type organic electronics.

Synthesis of Benzofuropyridines and Dibenzofurans by a Metalation/Negishi Cross-Coupling/SNAr Reaction Sequence.

An efficient methodology for the synthesis of benzofuropyridines and dibenzofurans from fluoropyridines or fluoroarenes and 2-bromophenyl acetates is reported. This streamlined one-pot procedure consists of a four-step directed ortho-lithiation, zincation, Negishi cross-coupling, and intramolecular nucleophilic aromatic substitution, allowing for the facile assembly of a diverse set of fused benzofuro heterocycles.

Development of oxetane modified building blocks for peptide synthesis.

The synthesis and use of oxetane modified dipeptide building blocks in solution and solid-phase peptide synthesis (SPPS) is reported. The preparation of building blocks containing non-glycine residues at the N-terminus in a stereochemically controlled manner is challenging. Here, a practical 4-step route to such building blocks is demonstrated, through the synthesis of dipeptides containing contiguous alanine residues. The incorporation of these new derivatives at specific sites along the backbone of an alanine-rich peptide sequence containing eighteen amino acids is demonstrated via solid-phase peptide synthesis. Additionally, new methods to enable the incorporation of all 20 of the proteinogenic amino acids into such dipeptide building blocks are reported through modifications of the synthetic route (for Cys and Met) and by changes to the protecting group strategy (for His, Ser and Thr).

Readily accessible sp3-rich cyclic hydrazine frameworks exploiting nitrogen fluxionality.

Increased molecular complexity correlates with improved chances of success in the drug development process. Here, a strategy for the creation of sp3-rich, non-planar heterocyclic scaffolds suitable for drug discovery is described that obviates the need to generate multiple stereogenic centers with independent control. Asymmetric transfer hydrogenation using a tethered Ru-catalyst is used to efficiently produce a range of enantiopure cyclic hydrazine building blocks (up to 99% ee). Iterative C-N functionalization at the two nitrogen atoms of these compounds produces novel hydrazine and hydrazide based chemical libraries. Wide chemical diversification is possible through variation in the hydrazine structure, use of different functionalization chemistries and coupling partners, and controlled engagement of each nitrogen of the hydrazine in turn. Principal Moment of Inertia (PMI) analysis of this small hydrazine library reveals excellent shape diversity and three-dimensionality. NMR and crystallographic studies confirm these frameworks prefer to orient their substituents in three-dimensional space under the control of a single stereogenic center through exploitation of the fluxional behavior of the two nitrogen atoms.

Macrocyclisation of small peptides enabled by oxetane incorporation.

Cyclic peptides are an important source of new drugs but are challenging to produce synthetically. We show that head-to-tail peptide macrocyclisations are greatly improved, as measured by isolated yields, reaction rates and product distribution, by substitution of one of the backbone amide C[double bond, length as m-dash]O bonds with an oxetane ring. The cyclisation precursors are easily made by standard solution- or solid-phase peptide synthesis techniques. Macrocyclisations across a range of challenging ring sizes (tetra-, penta- and hexapeptides) are enabled by incorporation of this turn-inducing element. Oxetane incorporation is shown to be superior to other established amino acid modifications such as N-methylation. The positional dependence of the modification on cyclisation efficiency is mapped using a cyclic peptide of sequence LAGAY. We provide the first direct experimental evidence that oxetane modification induces a turn in linear peptide backbones, through the observation of d NN (i, i + 2) and d αN (i, i + 2) NOEs, which offers an explanation for these improvements. For cyclic peptide, cLAGAY, a combination of NMR derived distance restraints and molecular dynamics simulations are used to show that this modification alters the backbone conformation in proximity to the oxetane, with the flexibility of the ring reduced and a new intramolecular H-bond established. Finally, we incorporated an oxetane into a cyclic pentapeptide inhibitor of Aminopeptidase N, a transmembrane metalloprotease overexpressed on the surface of cancer cells. The inhibitor, cCNGRC, displayed similar IC50 values in the presence or absence of an oxetane at the glycine residue, indicating that bioactivity is fully retained upon amide C[double bond, length as m-dash]O bond replacement.

Short Enantioselective Total Synthesis of Tatanan†A and 3-epi-Tatanan†A Using Assembly-Line Synthesis.

Short and highly stereoselective total syntheses of the sesquilignan natural product tatanan A and its C3 epimer are described. An assembly-line synthesis approach, using iterative lithiation-borylation reactions, was applied to install the three contiguous stereocenters with high enantio- and diastereoselectivity. One of the stereocenters was installed using a configurationally labile lithiated primary benzyl benzoate, resulting in high levels of substrate-controlled (undesired) diastereoselectivity. However, reversal of selectivity was achieved by using a novel diastereoselective Matteson homologation. Stereospecific alkynylation of a hindered secondary benzylic boronic ester enabled completion of the synthesis in a total of eight steps.

Continuous-Flow Synthesis of Biaryls by Negishi Cross-Coupling of Fluoro- and Trifluoromethyl-Substituted (Hetero)arenes.

A continuous-flow method for the regioselective arylation of fluoroarenes and fluoropyridines has been developed. The telescoped procedure reported here consists of a three-step metalation, zincation, and Negishi cross-coupling sequence, providing efficient access to a variety of functionalized 2-fluorobiaryl products. Precise temperature control of the metalation step, made possible by continuous-flow technology, allowed for the efficient preparation of the arylated products in high yields and short residence times. Additionally, several examples of the regioselective arylation of benzotrifluoride derivatives are also provided.

Enantioselective installation of adjacent tertiary benzylic stereocentres using lithiation-borylation-protodeboronation methodology. Application to the synthesis of bifluranol and fluorohexestrol.

1,2-Diaryl ethanes bearing 1,2-stereogenic centres show interesting biological activity but their stereocontrolled synthesis has not been reported forcing a reliance of methods involving diastereomer and enantiomer separation. We have found that this class of molecules can be prepared with very high stereocontrol using lithiation-borylation methodology. The reaction of an enantioenriched benzylic lithiated carbamate with an enantioenriched benzylic secondary pinacol boronic ester gave a tertiary boronic ester with complete diastereo- and enantiocontrol. It was essential to use MgBr2/MeOH after formation of the boronate complex, both to promote the 1,2-migration and to trap any lithiated carbamate/benzylic anion that formed from fragmentation of the ate complex, anions that would otherwise racemise and re-form the boronate complex eroding both er and dr of the product. When the benzylic lithiated carbamate and benzylic secondary pinacol boronic ester were too hindered, boronate complex did not even form. In these cases, it was found that the use of the less hindered neopentyl boronic esters enabled successful homologation to take place even for the most hindered reaction partners, with high stereocontrol and without the need for additives. Protodeboronation of the product boronic esters with TBAF gave the target 1,2-diaryl ethanes bearing 1,2-stereogenic centres. The methodology was applied to the stereocontrolled synthesis of bifluranol and fluorohexestrol in just 7 and 5 steps, respectively.

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.

Enantioselective synthesis of (R)-tolterodine using lithiation/borylation-protodeboronation methodology.

The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation-protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.

Enantioselective syntheses of (+)-sertraline and (+)-indatraline using lithiation/borylation-protodeboronation methodology.

The lithiation/borylation-protodeboronation of a homoallyl carbamate was applied to the synthesis of (+)-sertraline and (+)-indatraline. Due to the presence of the alkene, significant modifications of the methodology were required (use of 12-crown-4, TMSCl, H(2)O), or a solvent switch to CHCl(3), to achieve high yields and high selectivities.

Synthesis and characterization of polycarbonyl compounds via their BF2-adducts.

A cobalt-catalyzed 1,4-hydrovinylation reaction is the key step in the synthesis of 1,3-dicarbonyl and higher tri- and tetracarbonyl compounds after ozonolysis of the 1,4-diene intermediates. For the isolation and characterization of the products, the 1,3-dicarbonyl subunits were complexed with a BF(2)- or a BR(2)-fragment eliminating the keto-enol tautomerisation. Other 2,3-disubstituted 1,3-butadienes can be generated by a Grubbs enyne metathesis of a symmetrical internal alkyne with ethene. After hydrovinylation and ozonolysis, other 1,3-diketones are accessible.