Pyrrolidinyl peptide nucleic acids bearing hydroxy-modified cyclobutane building blocks: Synthesis and binding properties.

The conformationally constrained pyrrolidinyl PNA with a dipeptide consisting of an alternating nucleobase-modified D-proline and a cyclic ß-amino acid "spacer" exhibited improved nucleic acid binding properties compared to the original PNA. The pyrrolidinyl PNA with the four-membered ring spacer (1S,2S)-2-aminocyclobutanecarboxylic acid (acbcPNA) are among the best performed members of the pyrrolidinyl PNA family. However, these PNA suffer some limitations such as aqueous solubility and non-specific interactions due to their extreme hydrophobicity. In the present work, a hydroxy group is introduced onto the cyclobutane ring spacer of the acbcPNA with the aim of decreasing its hydrophobicity. To this end, a Fmoc/tBu ether-protected 4-hydroxy-2-aminocyclobutanecarboxylic acid building block was synthesized and resolved by chiral HPLC. Each enantiomer was used to synthesize the hydroxy-modified acbcPNA employing Fmoc solid-phase peptide synthesis. DNA/RNA binding studies indicated that the introduction of the hydroxy group to the acbcPNA decreases the binding affinity toward complementary DNA and RNA while maintaining the sequence and directional specificity of unmodified acbcPNA. The hydrophobicity of the hydroxy-modified acbcPNA decreased with the number of hydroxy groups added as indicated by the decrease in the logP values. Only two modifications were sufficient to decrease the logP by an order of magnitude without excessively lowering the binding affinity nor the specificity. This work thus demonstrated that the specific structural modifications for this type of PNA model can be performed in a modular fashion, which paves the way toward the future realization of improving hydrophilicity and nucleic acid binding affinity as well as specificity.

Stereocontrolled Preparation of Diversely Trifunctionalized Cyclobutanes.

The expedient and stereoselective syntheses of small libraries of trifunctionalized cyclobutane scaffolds bearing an acid, an amine, and a third functional group are described. Starting from a single precursor, the readily available protected derivative of all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid, cis-trans stereoisomers are obtained following an SN2-type reaction, while all-trans stereoisomers are obtained using the same strategy preceded by a C1 epimerization reaction.

A Photochemical Route to 3- and 4-Hydroxy Derivatives of 2-Aminocyclobutane-1-carboxylic Acid with an all-cis Geometry.

Short gram-scale syntheses of both enantiomers of 2-amino-3-hydroxycyclobutane-1-carboxylic acid and of 2-amino-4-hydroxycyclobutanecarboxylic acid with an all-cis geometry are described. The sequences feature highly endo-selective [2 + 2]-photocycloaddition reactions followed by fully regioselective ring opening/Hofmann rearrangement/nitrogen protection, in a consecutive or one-pot protocol, followed by efficient resolution using a chiral oxazolidinone.

Preparation of Cyclobutene Acetals and Tricyclic Oxetanes through Photochemical Tandem and Cascade Reactions.

We describe a photochemical reaction using two starting materials, a cyclopent-2-enone and an alkene, which are transformed in a controlled manner via the initial [2+2]-photocycloaddition adducts into cyclobutene aldehydes (conveniently trapped as stable acetals) or unprecedented angular tricyclic 4:4:4 oxetane-containing skeletons. These compounds are formed through tandem or triple cascade photochemical reaction processes, respectively. Small libraries of each compound class were prepared, thus suggesting that this photochemistry approach opens new opportunities for synthesis design and for widening molecular diversity.

Synthesis of 2,2-bis(pyridin-2-yl amino)cyclobutanols and their conversion into 5-(pyridin-2-ylamino)dihydrofuran-2(3H)-ones.

A two-step protocol is presented for the preparation of 5-(pyridin-2-ylamino)dihydrofuran-2(3H)-ones from 2-hydroxycyclobutanone and some 2-aminopyridines via a catalyst-free synthesis of 2,2-bis(pyridin-2-ylamino)cyclobutanols followed by Dess-Martin periodinane mediated ring expansion.

Synthetic Access to All Four Stereoisomers of Oxetin.

A short synthesis of all four stereoisomers of 3-amino-2-oxetanecarboxylic acid (oxetin) is described. The oxetane core is built using a Paternò-Büchi photochemical [2 + 2] cycloaddition; from the key intermediates, complementary resolution protocols provide access to enantiomerically pure oxetin and epi-oxetin on gram-scale.

A stable N-heterocyclic carbene organocatalyst for hydrogen/deuterium exchange reactions between pseudoacids and deuterated chloroform.

It was observed that the stable and commercially available N-heterocyclic carbene (NHC) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, the so-called IDipp, catalyzes hydrogen/deuterium exchange reactions between pseudoacids and chloroform-d1, while the analogous saturated NHC 1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene, the so-called SIMes, is inefficient for the same transformation. Experimental and computational DFT studies allowed these differences of reactivity to be attributed to the relative stability of the corresponding azolium­trichloromethyl anion ion pairs: in the former case, the complex evolves toward dissociation of the ions to produce an aromatic azolium cation and a basic trichloromethyl anion, while in the latter case, it evolves by ion recombination to give the product of formal carbene C­H insertion into the C­H bond of chloroform. These results provide a rationale for some early intuitions and observations of Wanzlick, Arduengo, and others on the reactivity of NHCs with chloroform as well as a simple organocatalytic method for the deuteration of pseudoacids (pKa,DMSO = 14­19) with chloroform-d1.

Anionic access to silylated and germylated binuclear heterocycles.

A simple access to silylated and germylated binuclear heterocycles, based on an original anionic rearrangement, is described. A set of electron-rich and electron-poor silylated aromatic and heteroaromatic substrates were tested to understand the mechanism and the factors controlling this rearrangement, in particular its regioselectivity. This parameter was shown to follow the rules proposed before from a few examples. Then, the effect of the substituents borne by the silicon itself, in particular the selectivity of the ligand transfer, was studied. Additionally, this chemistry was extended to germylated substrates. A hypervalent germanium species, comparable to the putative intermediate proposed with silicon, seems to be involved. However, a pathway implicating the elimination of LiCH2Cl was observed for the first time with this element, leading to unexpected products of the benzo-oxa (or benzo-aza) germol-type.

Engineering the structure of an N-terminal ß-turn to maximize screw-sense preference in achiral helical peptide chains.

Oligomers of α-aminoisobutyric acid (Aib) are achiral peptides that typically adopt 310 helical conformations in which enantiomeric left- and right-handed conformers are, necessarily, equally populated. Incorporating a single protected chiral residue at the N-terminus of the peptide leads to induction of a screw-sense preference in the helical chain, which may be quantified (in the form of "helical excess") by NMR spectroscopy. Variation of this residue and its N-terminal protecting group leads to the conclusion that maximal levels of screw-sense preference are induced by bulky chiral tertiary amino acids carrying amide protecting groups or by chiral quaternary amino acids carrying carbamate protecting groups. Tertiary L-amino acids at the N-terminus of the oligomer induce a left-handed screw sense, while quaternary L-amino acids induce a right-handed screw sense. A screw-sense preference may also be induced from the second position of the chain, weakly by tertiary amino acids, and much more powerfully by quaternary amino acids. In this position, the L enantiomers of both families induce a right-handed screw sense. Maximal, and essentially quantitative, control is induced by an L-α-methylvaline residue at both positions 1 and 2 of the chain, carrying an N-terminal carbamate protecting group.

Foldamer-mediated remote stereocontrol: >1,60 asymmetric induction.

An N-terminal L-α-methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac6 c. The persistent right-handed screw-sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16-, 1,31-, 1,46- and even 1,61-asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm.

Preparation of Thietane Derivatives through Domino Photochemical Norrish Type II/Thia-Paternò-Büchi Reactions.

This work describes straightforward access to a large collection of thietane derivatives through an innovative two-step domino photochemical reaction involving a Norrish type II fragmentation and a thia-Paternò-Büchi reaction. Starting from stable phenacyl sulfides, unprecedented thiocarbonyl intermediates were generated in situ and reacted with diverse electron-deficient alkene partners to form a thietane core. The rules governing the regio- and diastereoselectivity of this [2+2] photocycloaddition have been rationalized and fully controlled for many substrates.

N-heterocyclic carbene-catalyzed Michael additions of 1,3-dicarbonyl compounds.

A study of the organocatalytic activity of N-heterocyclic carbenes (NHCs) in the Michael addition of 1,3-dicarbonyl compounds has allowed us to identify 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) as an excellent catalyst for this transformation (up to 99 % yield with a 2.5 mol % catalyst loading), and the reaction was found to be of broad scope. Two early applications of this unprecedented catalytic activity of NHCs are described, that is, the domino carbocyclization reactions of simple cyclic 1,3-dicarbonyl and malonic acid derivatives, which allow stereoselective access to bridged bicyclic compounds, and the stereoselective synthesis of cyclohexanols (or cyclohexene). Early mechanistic investigations are also reported.

Formation of Tetrahydrothiophenes via a Thia-Paternò-Büchi-Initiated Domino Photochemical Reaction.

We have established photochemical access to thietane or tetrahydrothiophene compounds from thiobenzophenone derivatives and acrylonitrile, wherein the product selectivity is controlled by a simple adjustment of the reagent concentration in solution. Small libraries of five-membered ring sulfur-containing compounds were prepared through a thia-Paternò-Büchi reaction, followed by a previously unknown regioselective photochemical ring enlargement reaction in a domino process or a stepwise fashion. A mechanism is proposed to rationalize this ring enlargement reaction via a carbene species provided from photoexcited thiocarbonyl compounds.

A Selective Deprotection Strategy for the Construction of trans-2-Aminocyclopropanecarboxylic Acid Derived Peptides.

A procedure allowing access to unprecedented tripeptides containing a trans-2-aminocyclopropanecarboxylic acid residue in their central position has been established. The key features of the strategy are the use of a masked trans-2-aminocyclopropanecarboxylic acid monomer equivalent for C-terminal coupling and full N-Boc protection of all amide groups until the final step.

Acid-catalyzed synthesis of functionalized arylthio cyclopropane carbaldehydes and ketones.

A general strategy for the synthesis of arylthio cyclopropyl carbaldehydes and ketones via a Brønsted acid catalyzed arylthiol addition/ring contraction reaction sequence has been exploited. The procedure led to a wide panel of cyclopropyl carbaldehydes in generally high yields and with broad substrate scope. Mechanistic aspects and synthetic applications of this procedure were investigated.

Cooperative 5- and 10-membered ring interactions in the 10-helix folding of oxetin homo-oligomers.

Homo-oligomers of the natural product oxetin (cis-3-amino-2-oxetanecarboxylic acid) were prepared and their conformational behaviour studied in solution and solid state and by molecular modelling. The predominant secondary structure was a 10-helix, propiciously stabilized by a network of 5-membered ring H-bonds implicating ring oxygens and neighboring amide hydrogen atoms.

Synthesis of functionalized tryptamines by Brønsted acid catalysed cascade reactions.

An original synthetic protocol has been developed for the preparation of highly functionalized tryptamines from 2-hydroxycyclobutanone and secondary arylamines via a solvent-free Brønsted acid catalysed two-step reaction sequence.

Chemical communication: conductors and insulators of screw-sense preference between helical oligo(aminoisobutyric acid) domains.

(1)H NMR studies quantify the abilities of achiral amino acids to communicate a left-handed screw-sense preference from one helical Aib(4) domain to another: certain quaternary amino acids (e.g. Ac(6)c) act as effective conductors of conformational preference while others (e.g. diphenylglycine) acts as insulators.

Intramolecular sila-Matteson rearrangement: a general access to silylated heterocycles.

A series of new silylated heterocycles has been efficiently prepared using an intramolecular silicon version of the Matteson rearrangement, providing two isomers of binuclear heterocycles. This method applies to a large variety of substrates, a direct relationship between the Hammett constants of the aromatic substituents and the isomer ratio being observed. Complementary experiments suggest that a common pentaorganosilicate species is involved.