Sequential Nucleophilic Substitution of Phosphorus Trichloride with Alcohols in a Continuous-Flow Reactor and Consideration of a Mechanism for Reduced Over-reaction through the Addition of Imidazole.

We demonstrate a sequential nucleophilic substitution of highly electrophilic and inexpensive phosphorus trichloride with three different alcohols in a continuous-flow reactor. A variety of alcohols including ones that contained acid- and/or basic-labile functionalities were rapidly reacted. A over nucleophilic substitution that occurred during reaction of the second alcohol was suppressed by the addition of imidazole. Density functional theory calculations of the sequential nucleophilic substitutions of alcohols were performed both with and without imidazole, and Berry pseudorotation was suggested as a rate-limiting step in both cases. Herein, we discuss the reasons for the decreased selectivity in the absence of imidazole as well as those for improved selectivity in the presence of imidazole during the second nucleophilic substitution.

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor.

Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5-10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.

N-Methylated Peptide Synthesis via Generation of an Acyl N-Methylimidazolium Cation Accelerated by a Brønsted Acid.

The development of a robust amide-bond formation remains a critical aspect of N-methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N-methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N-methylated peptides, pterulamides I-IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate-limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.

Peptide-Chain Elongation Using Unprotected Amino Acids in a Micro-Flow Reactor.

Conventional peptide synthesis requires a deprotection step after each amidation step, which decreases synthetic efficiency. Therefore, peptide synthesis using unprotected amino acids is considered an ideal approach. Here, we report peptide chain elongation using unprotected amino acids via a mixed carbonic anhydride. Micro-flow technology enabled rapid mixing of an organic layer containing a protected amino acid or dipeptide and an aqueous layer containing an unprotected amino acid or dipeptide to accelerate the desired amidation, and this approach successfully suppressed undesired racemization/epimerization (≤0.4 %). Various di-, tri-, and tetra-peptides were obtained in good to high yields. This is the first report on peptide chain elongation that proceeds without severe racemization from unprotected amino acids using inexpensive, nonexplosive, less wasteful, and less toxic reagents.

Photochemical benzylic bromination in continuous flow using BrCCl3 and its application to telescoped p-methoxybenzyl protection.

BrCCl3 represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space-time-yield of 1.27 kg L-1 h-1.

Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides: Basic-to-Acidic Flash Switching in a Microflow Reactor.

Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.

Single-Step, Rapid, and Mild Synthesis of ß-Amino Acid N-Carboxy Anhydrides Using Micro-Flow Technology.

ß-Amino acid N-carboxy anhydrides (ß-NCAs) are rarely used in the synthesis of ß-peptides, which is due mainly to the poor availability of these potentially useful substrates. Herein, we describe the heretofore challenging synthesis of ß-NCAs via a single-step, rapid, and mild formation using pH flash switching and flash dilution, which are aspects of micro-flow technology. We synthesized 15 ß-NCAs in good to excellent yields that included acid-labile ß-NCAs that cannot be readily synthesized using the conventional Leuchs approach. Scaled-up synthesis using this process can be readily achieved via continuous operation.

Towards a Scalable Synthesis of 2-Oxabicyclo[2.2.0]hex-5-en-3-one Using Flow Photochemistry.

Cyclobutene lactones hold great potential as synthetic building blocks, yet their preparation by photochemical rearrangement in batch can often be a bottleneck in synthetic studies. We report the use of flow photochemistry as a tool to enable a higher-throughput approach to the synthesis of 2-oxabicyclo[2.2.0]hex-5-en-3-one, which reduces reaction times from 24 h to 10 min. Accordingly, a significantly improved throughput of 144 mg/h (vs 14-21 mg/h in batch) was achieved. Scale-out experiments showed problematic reactor fouling and steps were taken to explore and minimize this effect.

Peptide Synthesis Utilizing Micro-flow Technology.

Peptide drugs have garnered much attention in recent years. However, conventional peptide synthesis requires an excess amount of expensive reagents of low atom economy, and the large amount of waste produced by these reagents complicates the purification of desired peptides. Solid-phase approaches simplify the purification of these peptides, but these require expensive solid-phase, excess amounts of reagents, substrates, and solvents. This makes it important to develop high-yielding, cost-effective, and less wasteful synthetic approaches. Micro-flow technology (reaction space ≤1 mm) has produced many advantages over conventional batch synthesis. The advantages include precise control of short reaction time and temperature, high levels of light penetration efficiency, lowered risks of handling dangerous compounds, and ready scale-up with high reproducibility. Micro-flow peptide syntheses using these advantages have been reported in recent years. This review summarizes the solid-phase and solution-phase syntheses of α- and ß-peptides and of cyclic peptides using micro-flow technology.