Aminolysis of 3-Phenyl Propylthiol Esters Leading to Diverse Sets of Amides

3-Phenyl propylthiol esters were investigated as “activatable” solution phase linkers. These linkers can be activated with silver salts and upon treatment with amines can be converted to the corresponding amides. Under unactivated conditions, the linker is stable to a variety of reagents and reaction conditions including treatment with amines.     

New stable backbone linker resins for solid-phase peptide synthesis

[reaction: see text] Two new 4-methoxybenzaldehyde backbone linker resins were developed for the solid-phase synthesis of peptides. The linkers are very stable during the cleavage of common protecting groups for amines (Fmoc, Boc) and carboxylic acids (Me, All, tBu) in peptide synthesis. Cleavage from the resin with refluxing TFA is sufficiently mild for peptides containing polar and nonpolar amino acids.     

Polymer-supported (2,6-dichloro- 4-alkoxyphenyl)(2,4-dichlorophenyl)methanol: a new linker for solid-phase organic synthesis

An acid and base stable hydroxytetrachlorodiphenylmethyl (HTPM) linker is developed for polymer-supported organic synthesis. The linkers reported here are utilized for loading carboxylic acids, amines, alcohols, and phenols, and are stable to Br?nsted and Lewis acids, Br?nsted bases, and a wide variety of nucleophiles. However, the HTPM linkers can conveniently be cleaved by the solvolytic displacement reactions with 20% TFA. [structure: see text]     

Application of base cleavable safety catch linkers to solid phase library production

We have used sulfide "Safety Catch" linkers to anchor typical medicinal chemistry functional groups to amine resins. Compounds are loaded as the ester, carbamate, or amine. At the end of the synthesis, the linker is activated by peracid. The sulfone resins are then cleaved by beta-elimination in the gas phase or in solution by secondary amines to produce acids and primary, secondary, or tertiary amines. Comparison of cleavage rates to other sulfone resins including SEM showed significantly faster cleavage for this system with conditions similar to Fmoc deprotection. Application of this strategy to a medicinal chemistry library gives good yields and purities of the resulting compounds.     

On DABAL-Me3 promoted formation of amides

The range and utility of DABAL-Me₃ couplings of methyl esters and free carboxylic acids with primary and secondary amines under a variety of conditions (reflux, sealed tube, microwave) has been compared for a significant range of coupling partners of relevance to the preparation of amides of interest in pharmaceutical chemistry. Commercial microwave reactors promote the fastest couplings and allow the use of significantly sterically hindered amines (primary and secondary) and carboxylic acids derivatives. The influence of microwave energy on the reaction system was shown to be typically related to thermal effects (over-pressuring and superheating).     

An acid-stable tert-butyldiarylsilyl (TBDAS) linker for solid-phase organic synthesis

[reaction: see text] A new, robust tert-butyldiarylsilyl (TBDAS) linker has been developed for solid-phase organic synthesis. This linker is stable to both protic and Lewis acidic reaction conditions, overcoming a significant limitation of previously reported silyl linkers. Solid-phase acetal deprotection, olefination, asymmetric allylation, and silyl protecting group deblocking reactions have been demonstrated with TBDAS-linked substrates.     

Thiophene backbone amide linkers, a new class of easily prepared and highly acid-labile linkers for solid-phase synthesis

Solid-phase synthesis is of tremendous importance for small-molecule and biopolymer synthesis. Linkers (handles) that release amide-containing products after completion of solid-phase synthesis are widely used. Here we present a new class of highly acid-labile backbone amide linkers (BAL handles) based on 3,4-ethylenedioxythiophene (EDOT), which we have termed T-BAL. These thiophene linkers are synthesized in three convenient steps from commercially available EDOT. In the linker design, the spacer was introduced to the EDOT core either via a carbon-carbon bond or via a thioether linkage. Introduction of the spacer via a C-C bond was performed by a chemoselective Negishi coupling without transient protection of the aldehyde group to provide the T-BAL1 handle. Introduction via a thioether linkage was performed by a facile nucleophilic aromatic substitution between the brominated EDOT aldehyde and unprotected mercapto acids to provide T-BAL2 and T-BAL3 handles. The minimal use of protecting groups gave the corresponding linker molecules in few synthetic steps and in good yields. After anchoring of the linker to a polymeric support, introduction of the first amino acid was achieved by reductive amination, giving a secondary amine. A following acylation of the secondary amine with a symmetrical amino acid anhydride resulted in a backbone amide linkage between the handle and the growing substrate (e.g., peptide chain). After solid-phase synthesis, the substrates could be released from the resin by either low acid conditions using 1% TFA in CH2Cl2 or high acid conditions such as 50% TFA in CH2Cl2. Peptide thioesters could be released from the T-BAL1 handle under very mild conditions using aqueous acetic acid. Tert-butyl based protecting groups, tert-butyl esters, tert-butyl ethers, and Boc groups, as well as dimethyl acetals were relatively stable to these mild conditions for release of the peptides.     

Strategy for the synthesis of polymeric supports with hydrazone linkers for solid-phase alkylation of ketones and aldehydes

A new approach to polymeric supports useful for the immobilization of aldehydes and ketones via hydrazone linkers is reported. The new strategy gives supports with better properties and is effective for the synthesis of all supports previously used for the alkylation of ketones anchored as hydrazones. In contrast to other approaches, the new strategy also provided a polymer with an economical C2 spacer linker. The supports were used for immobilization of ketones 3-pentanone, acetone, N-benzylpiperidone, and aldehydes hexanal and 3-phenylpropanal in the form of their hydrazones. The polymer-supported hydrazones were subjected to alpha-alkylation (LDA/RX) followed by acidic, reductive, or oxidative cleavage/workup procedures to provide alpha-alkylated aldehydes or ketones as well as corresponding primary amines, alcohols, nitriles or acids.     

Solid-phase synthesis of urea and amide libraries using the T2 triazene linker

Starting from Merrifield resin, primary amines were immobilized in two steps by triazene linkage (T2-linker). While reaction with isocyanates gave rise to resin-bound urea derivatives, acylation by acid chlorides or anhydrides furnished amides bound to solid support via the nitrogen atom, therefore representing a novel backbone amide linker. Cleavage from the resin was conducted using dilute trimethylsilyl chloride or trifluoroacetic acid, respectively, to yield ureas and amines/amides in a library format (altogether 60 examples; manual synthesis: 17 ureas, 6 mono-alkylated ureas [including dihydroxylation and ozonolysis/Wittig reaction]; automated synthesis: 15 ureas, 15 amides) in high purities and good overall yields. The synthesis of a small library (4 x 4 member) was successfully conducted on a Bohdan Neptune synthesizer.     

Tuning Cooperativity by Controlling the Linker Length of Silica-Supported Amines in Catalysis and CO(2) Capture

Cooperative interactions between aminoalkylsilanes and silanols on a silica surface can be controlled by varying the length of the alkyl linker attaching the amine to the silica surface from C1 (methyl) to C5 (pentyl). The linker length strongly affects the catalytic cooperativity of amines and silanols in aldol condensations as well as the adsorptive cooperativity for CO(2) capture. The catalytic cooperativity increases with the linker length up to propyl (C3), with longer, more flexible linkers (up to C5) providing no additional benefit or hindrance. Short linkers (C1 and C2) limit the beneficial amine-silanol cooperativity in aldol condensations, resulting in lower catalytic rates than with the C3+ linkers. For the same materials, the adsorptive cooperativity exhibits similar trends for CO(2) capture efficiency.     

Efficient amidation from carboxylic acids and azides via selenocarboxylates: application to the coupling of amino acids and peptides with azides

A facile one-pot procedure for the coupling of carboxylic acid and azide via selenocarboxylate and selenatriazoline has been developed and successfully applied to the coupling of amino acids and peptides with azides. Selenocarboxylates are readily prepared by the reaction of the activated carboxylic acids with LiAlHSeH under mild conditions. The selenocarboxylates formed in situ are used to react directly with azides to form the corresponding amides via a selenatriazoline intermediate. Excellent yields were obtained for electron-deficient azides, and moderate to good yields were obtained for electron-rich azides. The selenocarboxylate/azide amidation reaction is clean and chemoselective. It provides an attractive alternative method to the conventional acylation of amines when an amide bond needs to be formed without going through an amine intermediate.     

Lipase-catalyzed enantioselective reaction of amines with carboxylic acids under reduced pressure in non-solvent system and in ionic liquids

Lipase-catalyzed enantioselective acylation of 1-phenylethylamine and 2-phenyl-1-propylamine was performed by reacting the amines with carboxylic acids in a non-solvent system or in ionic liquids as reaction media. The reaction equilibrium was shifted toward amide synthesis by the removal of formed water under reduced pressure.     

Alternative and Uncommon Acylating Agents – An Alive and Kicking Methodology

Functionalizing and derivatising organic molecules is a centerpiece in organic synthesis. Succinctly manipulating and installing acyl moieties in organic molecules spurred the interest of chemists owing to its occurrence in natural products, bioactive molecules, pharmaceuticals, and advanced materials. Traditionally, access to acylation reaction was achieved by Friedel-Crafts reaction, Schotten-Baumann, and Vilsmeier-Haack acylation, however, these protocols own pitfalls. Further to make the acylation process attractive and environmentally friendly, toluene, aldehydes, alcohols, α-keto acids, amines, amides, esters, ethers, nitriles, alkynes, alkenes, ketenes, N-acylbenzotriazoles, ketones, thioacids, oximes, thiazolium carbinols, PIDA, diacyl disulfides and acyl salts were used as an acyl surrogates/reagents. Amusingly, these acylating reagents are considered uncommon and alternative to carboxylic acids, acid chlorides and acetic anhydrides. This short review aims to encompass the usage of acylating agents in transition-metal, metal-free, light-driven and other demanding conditions, and thus reveals their practicality.     

Practical synthesis of a dithiane-protected 3',5'-dialkoxybenzoin photolabile safety-catch linker for solid-phase organic synthesis.

The solution-phase preparation of the 3',5'-dialkoxybenzoin photolabile safety-catch linker 16 is described. Pivotal to this convenient synthesis is the selection of appropriate orthogonal protecting groups for the alkoxy functionalities present. The new linker can be readily loaded onto any standard amine-terminating resin under peptide-coupling conditions, without the need to protect the secondary alcohol functionality, and subsequently loaded with substrate. Alternatively, the loading efficiency of sterically hindered substrates can be enhanced by preloading the semiprotected linker variant 10 in solution prior to immobilization onto the resin. This second generation of benzoin photolabile safety-catch linkers provides greater control of both linker loading and resin attachment and should prove to be a more versatile and convenient form of the linker.     

N-Silylation of amines and amino acid esters under neutral conditions employing TMS-Cl in the presence of zinc dust

An expedient synthetic approach to N-silylamines has been developed. The protocol, using TMS-Cl/zinc dust instead of BSA, is useful for the conversion of amines or amino acid esters to the corresponding silyl derivatives, followed by acylation with an acyl chloride or Fmoc-amino acid chloride to give the corresponding amide or peptide. This procedure, affording products in good to excellent yields, is also efficient for the coupling of sterically hindered amino acids like α,α-dialkylamino acids and NMe-amino acids. Further, the use of an equimolar quantity of organic base, such as Et₃N/pyridine, is circumvented.     

pKa-dependent formation of amides in water from an acyl phosphate monoester and amines

Acyl phosphate monoesters are readily prepared biomimetically activated anionic derivatives of carboxylic acids that react rapidly with amines in water to form amides. A plot of the logarithms of the rate constants for the reactions of a series of primary amines with benzoyl methyl phosphate depends on the pKa of the conjugate acids of the amines (beta(nuc) approximately 0.9). This provides a simple and quantitative basis for regioselective acylation with these reagents.     

Dual linker with a reference cleavage site for information rich analysis of polymer-supported transformations

Two dual linker systems with specific reference cleavage sites were designed and synthesized to accelerate and simplify development and optimization of reaction conditions for solid-phase synthesis. The dual linker allows simple evaluation of cleavage rate of polymer-supported compounds from the linker and, at the same time, ensures that all resin-bound components are cleaved from the solid support. The dual linker 4 was assembled from two Wang linkers connected by a three carbon spacer. The linker 9 was synthesized using the PAL and HMPB linkers.     

An efficient synthesis of 2-amino alcohols by silica gel catalysed opening of epoxide rings by amines

Silica gel (60-120 mesh) efficiently catalyses the opening of epoxide rings by amines at rt under solvent-free conditions providing an easy method for the synthesis of 2-amino alcohols. Aromatic and aliphatic amines react with cyclohexene oxide with exclusive formation of the trans-2-aryl/alkylaminocyclohexanols in high yields. A complementary regioselectivity is exhibited by aromatic and aliphatic amines during the reaction with styrene oxide. The epoxide ring of non-styrenoidal unsymmetrical alkene oxide undergoes selective nucleophilic attack at the sterically less hindered carbon by aniline.     

Kinetic Comparison of Trifluoroacetic Acid Cleavage Reactions of Resin-Bound Carbamates, Ureas, Secondary Amides, and Sulfonamides from Benzyl-, Benzhydryl-, and Indole-Based Linkers

The kinetics of cleavage reactions of 16 resin-bound carbamates, ureas, secondary amides, and sulfonamides from four different acid labile linkers including benzyl, benzhydryl, and indole linkers has been investigated. The optimized cleavage conditions are generally milder than those commonly used and reported (e.g., 0.5% TFA as opposed to 5%). Among various linkers studied in this work, the indole linker has been found to be the most acid labile followed by the Rink linker. The rate of cleavage of compounds linked to the resin via various functional groups can be summarized as follows: sulfonamide >carbamate approximately urea > amide. This study shows that cleavages of 16 compounds from four different acid labile linkers have been optimized to much milder conditions in terms of TFA concentration and the reaction time. It also demonstrates that single bead FTIR is an effective tool for optimizing cleavage conditions.     

Solid phase synthesis of 6-acylamino-1-alkyl/aryl-4-oxo-1,4-dihydrocinnoline-3-carboxamides

6-Acylmino-1-alkyl/aryl-4-oxo-1,4-dihydrocinnoline-3-carboxamides were synthesized in parallel from 6-nitro-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid. The latter formed amides with amines bound to polystyrene-based resins via acid-labile linkers. N1 and N2-alkylation, followed by alkyl migration yielded only N1-alkylated products. Reduction of the 6-nitro group and acylation concluded the synthesis.