Tadashi Akita

Efficient removal of N-benzyloxycarbonyl group by a ‘push–pull’ mechanism using thioanisole–trifluoroacetic acid, exemplified by a synthesis of Met-enkephalin

The N-benzyloxycarbonyl group can be smoothly cleaved under mild conditions, using thioanisole–trifluoroacetic acid, which can deprotect O-benzyltyrosine without the formation of O-to-C rearrangement products; this deblocking method was successfully applied to the synthesis of Met-enkephalin.

Syntheses of two tyrosine-sulphate containing peptides. Leucosulfakinin (LSK)-II and cholecystokinin (CCK)-12, using the 0-p-(methylsulphinyl)benzyl serine for the selective sulphation of tyrosine

Abstract A novel approach for the synthesis of tyrosine sulphate [Tyr(SO 3 H)]-containing peptides was developed. In this approach, trifluoroacetic acid stable O-p-(methylsulphinyl)-benzyl group was used as a key protecting group for serine to achieve the selective sulphation of tyrosine.

Deprotection of O-methyltyrosine by a ‘push–pull’ mechanism using the thioanisole–trifluoromethanesulphonic acid system. Application to the convenient synthesis of a potent N-methylenkephalin derivative

The methyl group attached at the phenolic oxygen of tyrosine can be smoothly cleaved by a thioanisole–trifluoromethanesulphonic acid system; this deblocking method was successfully applied to the synthesis of a new potent enkephalin derivative, MeTyr-Gly-Gly-Phe-Metol (Metol = L-methioninol residue).

Use of dimethylformamide–sulphur trioxide complex as a sulphating agent of tyrosine

Dimethylformamide–sulphur trioxide (DMF–SO3) complex was found to be more suitable for tyrosine sulphation than pyridine–sulphur trioxide (Pyr–SO3) complex, the most commonly used sulphur trioxide complex for sulphation. The work-up after sulphation using DMF–SO3 was also easier than with Pyr–SO3. The usefulness of DMF–SO3 complex was demonstrated through the synthesis of two tyrosine sulphate [Tyr(SO3H)]-containing peptides, leucine-enkephalin sulphate and leucosulfakinin-II.

An ‘active ester’-type mixed anhydride method for peptide synthesis. Use of the new reagent, norborn-5-ene-2,3-dicarboximido diphenyl phosphate (NDPP)

Norborn-5-ene-2,3-dicarboximido diphenyl phosphate (NDPP) is a convenient activating reagent for peptide synthesis.

Neo‐kyotorphin (Thr—Ser—Lys—Tyr—Arg), a new analgesic peptide

The amino acid sequence of a newly isolated pentapeptide, neo‐kyotorphin from bovine brain was synthetically verified to be Thr‐Ser‐Lys‐Tyr‐Arg corresponding to the C‐terminal portion of hemoglobin α‐chain. The synthetic neo‐kyotorphin showed the dose‐dependent analgesia in mice which was approximately equal to that of Leu‐enkephalin.

Syndyphalin-33, a synthetic tripeptide alkylamide with prolonged analgesic activity

Pentapeptides, Metenkephalin (ENK) and LeuENK [l] with opiate agonist activity produce only weak and short-lived analgesia even after intracerebroventricular (i.c.v.) administration [2,3] and no analgesia follows their subcutaneous (s.c.) administration. This is due to their rapid enzymatic degradation, and various attempts have been made to obtain ENK derivatives with high and prolonged analgesic activity by protecting the Nand C-terminals and the peptide bond of the molecule [4]. in SD-20 also produce analgesia after S.C. administration [8]. These findings indicate that all 5 amino acids in ENK are not necessary for S.C. analgesic activity. We therefore sought the ‘minimal segment’ of ENK required for S.C. analgesia and could find a tripeptide alkylamide with S.C. analgesia [ 121. Here, we report the synthesis of a simple tripeptide Tyr-D Met(O)-Gly-MPA named ‘syndyphalin (SD)33’ (fig.1) which exhibits potent opioid activity in vitro

Efficient deprotection of NG-tosylarginine with a thioanisole–trifluoromethanesulphonic acid system

The tosyl group attached at the guanidino function of arginine can be efficiently cleaved by a thioanisole–trifluoromethanesulphonic acid system, which can deprotect O-2,6-dichlorobenzyltyrosine without the formation of O-to-C rearrangement products; the NG-mesitylene-2-sulphonyl group was also cleaved by a thioanisole–trifluoroacetic acid system.

Facile reduction of methionine sulfoxide with sulfur trioxide/thiol system

Abstract A new condition for effective reduction of methionine sulfoxide (sulfur trioxide/thiol) was developed and the usefulness of this reduction was demonstrated in the synthesis of methionine-enkephalin.

Sulphur trioxide/thiol: a novel system for the reduction of methionine sulphoxide

A new method for the effective reduction of methionine sulphoxide in protected peptides with sulphur trioxide and thiol has been developed. In practice, a combination of dimethylformamide–sulphur trioxide complex and ethane-1,2-dithiol was found effective, the presence of pyridine in the reaction medium being found necessary for the reduction to proceed. Methionine sulphoxide in two types of protected methionine–enkephalins was efficiently reduced to methionine by this reduction system at 20 °C in an hour. The (p-methylsulphinyl)benzyl protecting group was also reduced to (p-methylthio)benzyl simultaneously with the reduction of methionine sulphoxide. Subsequent deprotection afforded methionine–enkephalin of high purity in each case.