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.
In a flash: Rapid (0.1 s) and mild (20 °C) synthesis of N‐carboxy anhydrides (NCAs) using basic‐to‐acidic flash switching and subsequent flash dilution was demonstrated. This process enabled the synthesis of acid‐labile NCAs, which are impossible to access using conventional batch conditions. The developed process requires simple phase separations and recrystallization to yield pure NCAs. This microflow approach could pave the way to on‐demand, on‐site NCA synthesis.
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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.
Who needs protection! Peptide synthesis using unprotected amino acids via mixed carbonic anhydride was demonstrated (see figure). 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 without severe racemization/epimerization (≤0.4 %). Various peptides were obtained in good yields using inexpensive, less toxic, and less wasteful reagents.
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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 β-peptides and of cyclic peptides using micro-flow technology.
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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.
A variety of N‐methylated peptides were synthesized in high yield without severe racemization via the generation of acylN‐methylimidazolium cations. Brønsted acids dramatically accelerated the reaction. The developed amidation reaction enabled the synthesis of a bulky peptide in higher yield and shorter reaction time in comparison with conventional amidation reactions. The first total synthesis of pterulamides I–IV was also achieved.
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The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the ...concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less‐toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74 %–quant.) without significant epimerization (≤3 %). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents.
In the fast lane: The title reaction is described for the synthesis of peptides. Various carboxylic acids including easily epimerizable amino acids were rapidly converted into highly electrophilic species, and then reacted with various amines, including less nucleophilic N‐methyl amino acids, to afford the desired peptides in high yields without significant epimerization.
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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.
Go with the microflow: Methods that accomplish rapid (0.5–10 s) and mild lactamization with highly electrophilic triphosgene in a microflow reactor are described. Various lactams as well as a cyclic peptide containing acid‐ and/or heat‐labile functional groups were synthesized in good to high yields (72–95 %). The developed approach enabled safe, rapid, mild, inexpensive, and less‐wasteful synthesis of lactams without the need for tedious purification.
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Acyl ammonium cations can be readily prepared from inexpensive and commercially available nucleophilic tertiary amines and acid chlorides or chloroformates. The significantly electrophilic nature of ...these cations allows rapid acylations to occur. However, it also causes undesired reactions. The emergence of micro-flow technologies has enabled precise control of reaction time (< 1 s) and temperature that cannot be achieved by conventional batch technologies. In this account, we describe high-yielding, rapid, less wasteful, and low-cost syntheses of peptides and amino acid derivatives via highly electrophilic acyl ammonium cations in which undesired reactions were suppressed by micro-flow technologies. These technologies not only enabled the development of highly efficient synthetic processes, but also provided us deeper insights into the highly active acyl ammonium cation species involved. This is leading to novel discoveries regarding their value in synthesis.
Feglymycin is a naturally occurring, anti-HIV and antimicrobial 13-mer peptide that includes highly racemizable 3,5-dihydroxyphenylglycines (Dpgs). Here we describe the total synthesis of feglymycin ...based on a linear/convergent hybrid approach. Our originally developed micro-flow amide bond formation enabled highly racemizable peptide chain elongation based on a linear approach that was previously considered impossible. Our developed approach will enable the practical preparation of biologically active oligopeptides that contain highly racemizable amino acids, which are attractive drug candidates.
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•Micro-flow technology enables highly efficient photo reactions.•Integrated micro-flow reaction enables efficient synthesis of complex compounds.•Integrated, multi-step micro-flow ...synthesis containing photo reactions were reviewed.
Micro-flow photochemical reactions have great advantage over batch photochemical reactions due to its high light-penetration efficiency. Integrated micro-flow reaction enables efficient synthesis of structurally complex compounds from simple starting materials and it can avoid handling of explosive, toxic, unstable, or odorous intermediates. Combination of micro-flow photochemical reactions with integrated micro-flow synthesis enhances their benefits. Here we summarize recently reported integrated multi-step micro-flow synthesis containing various photochemical reactions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A direct functionalization of unsubstituted isoxazole (1) was achieved by generation of 4‐isoxazolyl anion species (3). An efficient 4‐iodination of isoxazole and halogen–metal exchange reaction ...using a turbo Grignard reagent (iPrMgCl⋅ LiCl) were essential for the generation of 3, which reacted with various electrophiles to give 4‐functionalized isoxazoles in good to high yields. Isoxazolyl boronate, boronic acid, and stannane were also synthesized as useful building blocks from 1. The current methods enabled us to synthesize multi‐functionalized isoxazoles by introducing each substituent into the desired positions. Furthermore, total synthesis of triumferol, which was isolated from Triumfetta rhomboidea, was achieved from 1 in only three steps.
Taking position: Preparation of a 4‐isoxazolyl anion species from 4‐iodoisoxazole using iPrMgCl⋅LiCl enabled introduction of a wide variety of functional groups into the 4‐position of the isoxazole ring in good to excellent yields. This approach provides various isoxazolyl metal species which can be used for multifunctionalization of isoxazoles. The step‐by‐step synthesis of 3,4,5‐trisubstituted isoxazoles was achieved by using the this 4‐isoxazolyl anion method.
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