A Racemization Test in Peptide Synthesis Using 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium Chloride (DMT-MM).

Abstract

Recently, we introduced 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) as a new dehydrating condensing agent.1) Practical features of DMT-MM are as follows: 1) the reaction proceeds by a convenient one-step procedure in which DMT-MM is simply added to a mixture of acids and amines in a solvent; 2) no additives are required; 3) DMT-MM is a stable but not hygroscopic solid; 4) no irritating properties to the eye and nose, nor allergenic properties were observed in our laboratory; 5) the highly water-soluble co-products can be readily removed by washing with water; 6) DMT-MM can be prepared at a low cost from inexpensive cyanuric chloride. In addition, it is noteworthy that DMT-MM enables us to carry out the direct onepot condensation of carboxylic acids and amines in protic solvents like methanol, ethanol, 2-propanol, or water, as well as in a variety of aprotic organic solvents. 2)In order to evaluate the usefulness of DMT-MM in peptide synthesis, the degree of racemization with this reagent should be examined. We have already reported that no diastereomeric isomer resulting from racemization was detected in the coupling of tert-butoxycarbonyl (Boc)-L-Leu-OH and H-L-Phe-OMe with DMT-MM in both tetrahydrofuran (THF) and MeOH.2) Taddei and co-workers recently found that DMT-MM is a useful alternative to benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) with regard to reaction yields and the purity of products in solid phase peptide synthesis using N-Fmoc amino acids.3) In contrast to the coupling of amino acids with a urethane-type N-protecting group that are known to be almost free from racemization, the C-terminal amino acids of Nishi-ku, Kobe 651-2180, Japan. Received November 26, 2001 accepted January 7, 2002 Racemization of the C-terminal amino acid (Ala) has been studied in various solvents during coupling between 4-methoxybenzyloxycarbonyl (Z(OMe))-Gly-L-Ala-OH and phenylalanine benzyl ester (H-Phe-OBzl) with 4-(4,6-dimethoxy-1,3,5-thiazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). The reaction occurred without substantial racemization in AcOEt, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), CH 3 CN, and 2-PrOH, while a slight racemization was observed in dimethyl sulfoxide (DMSO), EtOH, and MeOH. The extent of racemization may correlate with the polarity of the solvents.

Racemisation of N‐Fmoc phenylglycine under mild microwave‐SPPS and conventional stepwise SPPS conditions: attempts to develop strategies for overcoming this

“…(1998) and which has been applied to the synthesis of esters , amides , and simple peptides . Of direct relevance to the present study are the reports that DMTMM‐Cl yields peptide and peptidomimetic products with much lower levels of racemisation (in some instances, with complete suppression of the undesired formation of diastereoisomers) in comparison to those produced using other activating agents such as 2‐chloro‐4,6‐dimethoxy‐1, 3, 5‐triazine (CDMT) and HBTU/HOBT .…”

Immobilized Triazine-Type Dehydrocondensing Reagents for Carboxamide Formation: ROMP-Trz-Cl and ROMP(OH)-Trz-Cl

“…In addition, the weight proportion of the solid carrier relative to the amount of solidsupported reagent is generally high, which inevitably results in the generation of large amounts of waste; this is a serious problem common to solid-supported reagents. To resolve this issue, we developed a new immobilized triazine-type dehydrocondensing reagent by polymerizing the dehydrocondensing reagent itself.19) This polymer reagent is based on the condensing agent, 4,6-dimethoxy-1,3,5-triazinyl-2-methylmorpholinium chloride (DMT-MM) [20][21][22][23][24][25][26] and is a crosslinked polymer prepared by co-polymerizing tetra(ethylene glycol) bis(4-chloro-6-methoxy-1,3,5-triazin-2-yl) ether and tris(2-aminoethyl)amine, which is easily substituted onto the triazine ring under weakly basic conditions.In this work, we developed another application for polymer-type triazine condensing reagents: immobilization by well-established ROMP (ring opening metathesis polymerization) method, in which the reaction proceeds rapidly and with high yield under mild neutral conditions. The dramatically expanded ROMP methodology, based on the work of Grubbs et al in the 1990s, has been developed as an effective method for acquiring high-loading polymer reagents by polymerizing the reagent unit as a monomer.…”

“…To resolve this issue, we developed a new immobilized triazine-type dehydrocondensing reagent by polymerizing the dehydrocondensing reagent itself. 19) This polymer reagent is based on the condensing agent, 4,6-dimethoxy-1,3,5-triazinyl-2-methylmorpholinium chloride (DMT-MM) [20][21][22][23][24][25][26] and is a crosslinked polymer prepared by co-polymerizing tetra(ethylene glycol) bis(4-chloro-6-methoxy-1,3,5-triazin-2-yl) ether and tris(2-aminoethyl)amine, which is easily substituted onto the triazine ring under weakly basic conditions.…”

Synthesis of heptapeptides and analysis of sequence by tandem ion trap mass spectrometry

“…In addition, another puzzling problem concerning racemization should also be minimized through optimizing experimental conditions. The factors leading to racemization are variable, which mainly contain coupling reagents [6], solvent polarity [7], reaction temperature [8], base strength [9] and coupling protocols [10]. Recently a novel concept about the effect of preactivation step on racemization brings an effective outcome for avoiding racemization [11][12][13][14][15].…”