Process Mass Intensity (PMI): A Holistic Analysis of Current Peptide Manufacturing Processes Informs Sustainability in Peptide Synthesis.

Small molecule therapeutics represent the majority of the FDA-approved drugs. Yet, many attractive targets are poorly tractable by small molecules, generating a need for new therapeutic modalities. Due to their biocompatibility profile and structural versatility, peptide-based therapeutics are a possible solution. Additionally, in the past two decades, advances in peptide design, delivery, formulation, and devices have occurred, making therapeutic peptides an attractive modality. However, peptide manufacturing is often limited to solid-phase peptide synthesis (SPPS), liquid phase peptide synthesis (LPPS), and to a lesser extent hybrid SPPS/LPPS, with SPPS emerging as a predominant platform technology for peptide synthesis. SPPS involves the use of excess solvents and reagents which negatively impact the environment, thus highlighting the need for newer technologies to reduce the environmental footprint. Herein, fourteen American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) member companies with peptide-based therapeutics in their portfolio have compiled Process Mass Intensity (PMI) metrics to help inform the sustainability efforts in peptide synthesis. This includes PMI assessment on 40 synthetic peptide processes at various development stages in pharma, classified according to the development phase. This is the most comprehensive assessment of synthetic peptide environmental metrics to date. The synthetic peptide manufacturing process was divided into stages (synthesis, purification, isolation) to determine their respective PMI. On average, solid-phase peptide synthesis (SPPS) (PMI ≈ 13,000) does not compare favorably with other modalities such as small molecules (PMI median 168-308) and biopharmaceuticals (PMI ≈ 8300). Thus, the high PMI for peptide synthesis warrants more environmentally friendly processes in peptide manufacturing.

Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions.

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C-H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si-H bonds to yield an oxophilic silylium (R3Si+) equivalent along with a reducing (H-) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure-activity relationships.

Synthesis, structure, and reactivity of tris(amidate) mono(amido) and tetrakis(amidate) complexes of group 4 transition metals.

The syntheses of a series of tris(amidate) mono(amido) titanium and zirconium complexes are reported. The binding motif of the amidate ligand has been determined to depend on the size of the metal centre for these sterically demanding N,O-chelating ligands; the larger zirconium metal centre supports three κ(2)-(N,O) bound amidate ligands while the titanium analogue has one ligand bound in a κ(1)-(O) fashion to alleviate steric strain. Reactivity studies indicate that, despite high steric crowding about the tris(amidate) mono(amido) zirconium metal centre, transamination of the reactive dimethylamido ligand can be achieved using aniline. This complex is also an active precatalyst for intramolecular alkene hydroamination, in which protonolysis of one amidate ligand in the presence of excess amine is observed as an initiation step prior to catalytic turnover. Eight-coordinate homoleptic κ(2)-amidate complexes of zirconium and hafnium have also been prepared.

Tantalum catalyzed hydroaminoalkylation for the synthesis of α- and ß-substituted N-heterocycles.

Unprotected secondary amines are directly alkylated by C-H functionalization adjacent to nitrogen, thereby opening new routes toward the synthesis of α- and ß-alkylated N-heterocycles. α-Alkylated piperidine, piperazine, and azepane products are prepared from heterocycles and alkenes in an atom-economic reaction with excellent regio- and diastereoselectivity. ß-Alkylated N-heterocycles are synthesized via a scalable one-pot alkylation/cyclization procedure generating 3-methylated azetidines, pyrrolidines, and piperidines.

Broadening the scope of group 4 hydroamination catalysis using a tethered ureate ligand.

A broadly applicable group-4-based precatalyst for the hydroamination of primary and secondary amines was developed. Screening experiments involving a series of amide and urea proligands led to the discovery of a tethered bis(ureate) zirconium complex with unprecedented reactivity in the intermolecular hydroamination of alkynes and the intramolecular hydroamination of alkenes. This catalyst system is effective with primary and secondary amines, 1,2-disubstituted alkenes, and heteroatom-containing functional groups, including ethers, silanes, amines, and heteroaromatics. The gem-disubstituent effect is not required for cyclization. The catalyst is generally regioselective for the anti-Markovnikov product of intermolecular alkyne hydroamination, and chemoselective for hydroamination over alpha-alkylation when forming 6- and 7-membered rings from aminoalkenes.

Selective C-H activation alpha to primary amines. Bridging metallaaziridines for catalytic, intramolecular alpha-alkylation.

Selective alpha-C-H activation results in the synthesis of the first bridging metallaaziridine complex for the catalytic alpha-alkylation of primary amines. Reaction development led to the preparation of new Zr 2-pyridonate complexes for this useful transformation. No nitrogen protecting groups are required for this reaction, which is capable of assembling quaternary chiral centers alpha to nitrogen. Preliminary mechanistic investigations suggest bridging metallaaziridine species are the catalytically active intermediates for this alpha-functionalization reaction, while monomeric imido complexes furnish azepane hydroamination products.