Rapid and column-chromatography-free peptide chain elongation a one-flow, three-component coupling approach.

Short peptides are extremely important as drugs and building blocks for the syntheses of longer peptides. Both solid- and liquid-phase peptide syntheses suffer from a large number of synthetic steps, high cost, and/or tedious purification. Here, we developed a rapid, mild, inexpensive, and column-chromatography-free peptide chain elongation a one-flow, three-component coupling (3CC) approach that is the first to use α-amino acid -carboxy anhydrides (α-NCAs) both as electrophiles and nucleophiles.

One-Flow Syntheses of Unsymmetrical Sulfamides and -Substituted Sulfamate Esters.

We developed one-flow syntheses of unsymmetrical sulfamides and -substituted sulfamate esters by changing a nucleophile and a tertiary amine from inexpensive and commercially available chlorosulfonic acid. In the synthesis of -substituted sulfamate esters, unexpected symmetrical sulfite formation was suppressed by changing the tertiary amine. The effect of tertiary amines was proposed using linear regression.

Peptide Cyclization by the Use of Acylammonium Species.

Although cyclic peptides have become increasingly important as drugs, the most conventional peptide cyclization method using moderately active coupling agents suffers from a lot of waste and high cost as well as long reaction times and burdensome purification. Herein, we report an unconventional approach to peptide cyclization that uses acylammonium species generated from inexpensive and less wasteful Me NBn and ClCO i-Pr. Using this approach, we observed the desired rapid activation of the C-terminus of cyclization precursors by an acylammonium ion for rapid and epimerization/dimerization-free cyclization of synthetically challenging peptides, including a difficult cyclization involving N-methyl amide bond formation.

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.

A micro-flow rapid dual activation approach for urethane-protected α-amino acid -carboxyanhydride synthesis.

This study demonstrated the rapid dual activation (10 s, 20 °C) of a combination of an α-amino acid -carboxyanhydride and alkyl chloroformate in the synthesis of a urethane-protected α-amino acid -carboxyanhydride in a micro-flow reactor. The key to success was the combined use of two amines that activated both substrates with proper timing. Three amines, -PrNEt, MeNBn, or -ethylmorpholine, were used with pyridine in accordance with the steric bulkiness of a side chain in the α-amino acid -carboxyanhydride.

Micro-flow synthesis of β-amino acid derivatives via a rapid dual activation approach.

Rapid dual activation (≤3.3 s) of both β-amino acid N-carboxy anhydride and alkyl chloroformate for the synthesis of a β-amino acid-derived scaffold was demonstrated. The key to success was the use of rapid mixing enabled by using a micro-flow reactor.

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

β-Amino acid N-carboxy anhydrides (β-NCAs) are rarely used in the synthesis of β-peptides, which is due mainly to the poor availability of these potentially useful substrates. Herein, we describe the heretofore challenging synthesis of β-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 β-NCAs in good to excellent yields that included acid-labile β-NCAs that cannot be readily synthesized using the conventional Leuchs approach.