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.

Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production.

In recent years, there has been a growing interest in therapeutic peptides within the pharmaceutical industry with more than 50 peptide drugs on the market, approximately 170 in clinical trials, and >200 in preclinical development. However, the current state of the art in peptide synthesis involves primarily legacy technologies with use of large amounts of highly hazardous reagents and solvents and little focus on green chemistry and engineering. In 2016, the ACS Green Chemistry Institute Pharmaceutical Roundtable identified development of greener processes for peptide API as a critical unmet need, and as a result, a new Roundtable team formed to address this important area. The initial focus of this new team is to highlight best practices in peptide synthesis and encourage much needed innovations. In this Perspective, we aim to summarize the current challenges of peptide synthesis and purification in terms of sustainability, highlight possible solutions, and encourage synergies between academia, the pharmaceutical industry, and contract research organizations/contract manufacturing organizations.

A convergent synthesis of the tricyclic core of the dictyosphaeric acids.

The first synthetic route to the tricyclic core of the dictyosphaeric acids has been established starting from readily available (S)-(-)-4-(tert-butyldimethylsilyloxy)cyclohexenone and involving 9 steps, including a ring-closing metathesis to produce a 13-membered macrolactone, and a doubly tethered intramolecular Michael addition.

Tethered aminohydroxylation using acyclic homo-allylic sulfamate esters and sulfonamides as substrates.

Homo-allylic sulfamate esters and sulfonamides are shown to be useful substrates for the tethered aminohydroxylation (TA) reaction. The sulfamate esters undergo the TA reaction delivering 1,2,3-oxathiazinane products whereas the sulfonamides give 1,2-thiazinane products. A range of acyclic homo-allylic sulfamate esters were prepared and subjected to the TA reaction to establish the scope of the process. Nucleophilic ring-opening reactions of the 1,2,3-oxathiazinane products are also described.

Highly functionalized organolithium reagents for enantiomerically pure alpha-amino acid synthesis.

[reaction: see text] Highly functionalized l-serine-derived organolithium reagents have been generated and reacted with a variety of electrophiles, delivering novel enantiomerically pure adducts. These adducts were then converted into homochiral amino alcohols and novel nonproteinogenic alpha-amino acids, including an aspartic acid mimic that has been synthesized in an enantiomerically pure form for the first time.

Dearomatizing cyclization of arylsulfonylalkoxymethyl lithiums: a route to the podophyllotoxin skeleton.

[reaction: see text] The phenylsulfonyl group promotes the dearomatizing cyclization of tethered organolithiums onto aromatic rings. With an ether tether, the cyclizations create a new tetrahydrofuran ring, and both cyclization and subsequent electrophilic quenches proceed with high levels of diastereoselectivity. The sulfonyl group can be removed from the cyclized products oxidatively or reductively. The dearomatizing cyclization of a naphthyl sulfone was used in the synthesis of a close structural analogue of podophyllotoxin.

Dearomatizing annelation of five-membered rings to naphthalenes by organolithium cyclization.

[reaction: see text] gamma-Lithiopropylnaphthalenes and their oxa- and aza-tethered analogues cyclize by nucleophilic addition of the organolithium to the naphthalene ring. The resulting benzyllithiums react stereoselectively with electrophiles to give dearomatized tricyclic products with structural similarity to the arylnaphthalene lignans.