Lara R. Malins

A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents

Carbon links without helpful neighbors Its an irony of modern organic chemistry that the simplest-looking carbon-carbon bonds are often the hardest to make. Most reactions owe their efficiency to neighboring double bonds or oxygen and nitrogen atoms that linger in the products. Qin et al. now present a broadly applicable protocol for making C-C bonds in the absence of such surrounding help. The nickel-catalyzed process couples a zinc-activated carbon center to an ester thats poised to lose CO2. The ready availability of numerous carboxylic acids (which are easily converted to esters) contributes to the reactions versatility. Science, this issue p. 801 A versatile nickel-catalyzed reaction forms carbon–carbon bonds, with no need for adjacent functionality in the product. Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study demonstrates how the same activating principles used for decades to make simple C–N (amide) bonds from carboxylic acids with loss of water can be used to make C–C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).

Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins.

Native chemical ligation continues to play a pivotal role in the synthesis of increasingly complex peptide and protein targets twenty years after its initial report. This opinion article will highlight a number of recent, powerful extensions of the technology that have expanded the scope of the reaction, accelerated ligation rates, enabled chemoselective post-ligation modifications, and streamlined the ligation of multiple peptide fragments. These advances have facilitated the synthesis of a number of impressive protein targets to date and hold great promise for the continued application of native chemical ligation for the detailed study of protein structure and function.

Peptide Ligation–Desulfurization Chemistry at Arginine

The utility of a new β-thiol arginine building block in ligation-desulfurization chemistry has been demonstrated through reactions and kinetic studies with a range of peptide thioesters. Application of the method is highlighted by a one-pot, kinetically controlled, rapid ligation to generate a 7 kDa MUC1 glycopeptide.

One-Pot Peptide Ligation–Desulfurization at Glutamate

An efficient methodology for ligation at glutamate (Glu) is described. A γ-thiol-Glu building block was accessed in only three steps from protected glutamic acid and could be incorporated at the N-terminus of peptides. The application of these peptides in one-pot ligation-desulfurization chemistry is demonstrated with a range of peptide thioesters, and the utility of this methodology is highlighted through the synthesis of the osteoporosis peptide drug teriparatide (Forteo).

Rapid additive-free selenocystine-selenoester peptide ligation.

We describe an unprecedented reaction between peptide selenoesters and peptide dimers bearing N-terminal selenocystine that proceeds in aqueous buffer to afford native amide bonds without the use of additives. The selenocystine-selenoester ligations are complete in minutes, even at sterically hindered junctions, and can be used in concert with one-pot deselenization chemistry. Various pathways for the transformation are proposed and probed through a combination of experimental and computational studies. Our new reaction manifold is also showcased in the total synthesis of two proteins.

Strain-release amination

Opening one ring to tack on another Curious chemists have long sought to learn just how tightly carbon atoms can be bound together. For instance, its possible to form a bond between two opposite corners of an already strained four-membered ring to make an edge-sharing pair of triangles. Gianatassio et al. have now devised a general use for these and related molecular curiosities. They show that appropriately modified nitrogen centers can pop open the most highly strained bond, leaving the more modestly strained ring motif intact. In this way, small rings can emerge as a convenient diversifying element in compounds, including new pharmaceutical candidates. Science, this issue p. 241 Strained rings are appended to compounds of pharmaceutical interest through the use of even more highly strained precursors. To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C–C and C–N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.

Synthesis and Utility of β-Selenol-Phenylalanine for Native Chemical Ligation–Deselenization Chemistry

An efficient synthetic route to a suitably protected β-selenol-phenylalanine derivative from commercially available Garners aldehyde is described. The incorporation of this building block into peptides and its application in native chemical ligation reactions with peptide thioesters are demonstrated. Ligation products were chemoselectively deselenized (including in the presence of unprotected cysteine residues) to provide native peptides.

Chemoselective sulfenylation and peptide ligation at tryptophan

Peptide ligation–desulfurization chemistry at 2-thiol tryptophan (Trp) is described for the first time. Installation of a thiol auxiliary was achieved through late-stage chemoselective sulfenylation chemistry at the 2-position of the indole ring of Trp either in solution or on solid support, thus abrogating the need for the preparation of a pre-formed thiolated amino acid. Peptides possessing the 2-thiol Trp functionality on the N-terminus were shown to facilitate high yielding ligation reactions with a variety of C-terminal peptide thiophenyl thioesters. Efficient removal of the 2-thiol Trp auxiliary following the ligation reactions was achieved via reductive desulfurization and provided native peptide products in excellent yields. The utility of the methodology was demonstrated in the synthesis of a glycosylated fragment of the N-terminal extracellular domain of the chemokine receptor CXCR1.

Synthesis of MUC1-lipopeptide chimeras.

An efficient method for the convergent assembly of MUC1-lipopeptide vaccine candidates is described. Chimeras consisting of MUC1 glycopeptides (bearing multiple copies of the T(N) and T tumour-associated carbohydrate antigens) tethered to the lipopeptide immunoadjuvant Pam(3)CysSer were synthesised in high yields using a fragment-based condensation strategy.

Synthetic Amino Acids for Applications in Peptide Ligation-Desulfurization Chemistry

Native chemical ligation is a powerful tool for the convergent assembly of homogeneous peptide and protein targets from unprotected peptide fragments. The method involves the chemoselective coupling of a peptide thioester with a peptide bearing an N-terminal cysteine (Cys) residue and is mediated by the nucleophilic Cys thiol functionality. A widely adopted extension of the technique for the disconnection of protein targets at alanine (Ala) ligation junctions has been the application of post-ligation desulfurization protocols for the mild removal of the Cys thiol moiety. Recently, attention has turned to the construction of synthetic amino acid building blocks bearing suitably positioned β-, γ-, or δ-thiol ligation auxiliaries with a view to expanding the scope of the ligation–desulfurization manifold. To date, several thiol-derived amino acids have been prepared, greatly increasing the generality and flexibility of chemoselective ligation technologies for the chemical synthesis of diverse protein targets. This review will highlight the current synthetic approaches to these important amino acid building blocks.