Jordi Alsina

On the use of PyAOP, a phosphonium salt derived from HOAt, in solid-phase peptide synthesis

Abstract Phosphonium derivatives of HOAt such as PyAOP are useful for the solid-phase preparation of a range of peptides that include those incorporating hindered amino acids, difficult short sequences, and cyclic peptides. An advantage relative to uronium salts is that excess PyAOP does not undergo the detrimental side-reaction at the amino terminus which blocks further chain assembly.

Use of Alloc-amino acids in solid-phase peptide synthesis. Tandem deprotection-coupling reactions using neutral conditions

Abstract The use of Alloc group in SPPS for the Nα protection of amino acids is an alternative to the Boc and Fmoc protecting groups. The smooth removal of Alloc group in neutral conditions with catalytic amounts of Pd(PPh3)4 in the presence of PhSiH3 as a scavenger for the allyl system permits orthogonality with the most common protecting groups. Furthermore, a tandem deprotection-coupling reaction allows the suppression of DKP formation in cases where this side reaction is troublesome.

Solid-Phase Synthesis with Tris(alkoxy)benzyl Backbone Amide Linkage (BAL)[≠]

The novel and general BAL concept allows for solid-phase synthesis of C-terminal-modified and cyclic peptides, small organic molecules, and modified amino sugars, as single species or as part of combinatorial chemistry applications. A BAL anchor attached to resin is depicted.

SOLID-PHASE SYNTHESIS OF HEAD-TO-TAIL CYCLIC PEPTIDES VIA LYSINE SIDE-CHAIN ANCHORING

Abstract The N,N′ -disuccinimidyl carbonate (DSC) has been successfully used for the efficient conversion of conventional hydroxymethyl resins into active carbonate resins, which are suitable for the incorporation of protected amino acids via an amino function, allowing the preparation of “head-to-tail” cyclic lysine containing peptides.

Use of N-tritylamino acids and PyAOP1 for the suppression of diketopiperazine formation in Fmoc/tBu solid-phase peptide synthesis using alkoxybenzyl ester anchoring linkages

In order to suppress diketopiperazine formation in the solid-phase coupling of the thrid amino acid to dipeptides in Fmoc/tBu peptide synthesis using alkoxybenzyl ester resins, the Trt group was chosen for α-amino protection of the second amino acid since it can be removed by mild acid treatment. Subsequently, the coupling may be carried out without a prior neutralisation step using PyAOP as coupling reagent. This methodology also avoids diketopiperazine formation during the preparation of protected peptides with the HMPB handle since this is stable to the extremely mild acid treatment used to remove the Trt group.

Solid-phase synthesis of diketopiperazines, useful scaffolds for combinatorial chemistry

Abstract Diketopiperazines, which are cyclic dipeptides, are often formed by a side reaction of solid-phase peptide synthesis. Using the new “Backbone Amide Linker,” this chemistry can be conveniently harnessed for the intentional preparation of diketopiperazines. These products will be useful scaffolds for combinatorial chemistry, since they incorporate three different points of diversity: both amino acid side-chains and one (of the two) amide bonds.

Active carbonate resins for solid-phase synthesis through the anchoring of a hydroxyl function. Synthesis of cyclic and alcohol peptides

Abstract N , N ′-Disuccinimidyl carbonate (DSC) has been successfully used for the efficient conversion of 4-hydroxymethylpolystyrene and 4-hydroxymethyl-3-nitrobenzamido (Nbb) resins into active carbonate resins, which are suitable for the incorporation of molecules via a hydroxyl function. This methodology has been applied to the preparation of the growth hormone inhibitor, Sandostatin.

Active carbonate resins: Application to the solid-phase synthesis of alcohol, carbamate and cyclic peptides☆

Abstract N,N′-disuccinimidyl carbonate (DSC) has been successfully used to generate carbonates and carbamates on conventional hydroxymethyl and aminomethyl based resins. This methodology extends the applicability of such linkers, which were initially designed for the anchoring of carboxylic acids. Thus, amino and hydroxy groups have been attached onto classical resins to give straightforward access to the solid-phase synthesis of alcohols, carbamates, and cyclic peptides with an evident pharmaceutical interest.

Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D 3 Catalog Construction

Distributed Drug Discovery (D3) proposes solving large drug discovery problems by breaking them into smaller units for processing at multiple sites. A key component of the synthetic and computational stages of D3 is the global rehearsal of prospective reagents and their subsequent use in the creation of virtual catalogs of molecules accessible by simple, inexpensive combinatorial chemistry. The first section of this article documents the feasibility of the synthetic component of Distributed Drug Discovery. Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-bound unnatural amino acids 1, key intermediates in many combinatorial chemistry procedures. This global reagent rehearsal, coupled to virtual library generation, increases the likelihood that any member of that virtual library can be made. It facilitates the realistic integration of worldwide virtual D3 catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D3 catalog. It reports the enumeration of 24 416 acylated unnatural amino acids 5, assembled from lists of either rehearsed or well-precedented alkylating and acylating reagents, and describes how the resulting catalog can be freely accessed, searched, and downloaded by the scientific community.

A modified backbone amide linker (BAL) solid-phase peptide synthesis strategy accommodating prolyl, N-alkylamino acyl, or histidyl derivatives at the C-terminus

Abstract A new variation of the B ackbone A mide L inker (BAL) approach has been developed for N α -Fmoc solid-phase synthesis (SPS) of C-terminal modified peptides; this provides a convenient route to peptides containing prolyl, N -alkylamino acyl, or histidyl derivatives at the C-terminus. To illustrate the principles, several model peptides were prepared in high yields and excellent purities; diketopiperazines and racemized byproducts which otherwise form when alternative procedures are used were absent from the syntheses reported herein.