Keiji Hemmi

PAF inhibitory activity of diketopiperazines: Structure-activity relationships

FR900452, a natural product isolated from the culture broth ofStreptomyces phaeofaciens No. 7739, was found to inhibit PAF-induced rabbit platelet aggregation with an IC50 of 3.7×10−7M. FR900452, 1-methyl-3-[1-[5-methylthiomethyl-6-oxo-3-(2-oxo-3-cyclopenten-1-ylidene)-2-piperazinyl]ethyl]-2-indoline, has an oxocylopentylidene group incorporated as a vinylogous amide in a diketopiperazine skeleton. This unique structure led us to synthesize diketopiperazine derivatives, 3-arylalkyl-6-substituted-piperazine-2,5-diones. their observed PAF inhibitory activity suggest that the D-D configuration of diketopiperazine is an important factor for anti-PAF activity and that the hydrophobic aromatic portion may play a specific role in the binding of the diketopiperazine to the PAF receptor.

An efficient method for selective amino acid protection of meso-2,2′-diaminodicarboxylic acid: An improved synthesis of FK-156

Abstract An efficient method for selective amino acid protection with proper differentiation between the two amino acid groups in meso-2,2′-diaminopimelic acid has been achieved [ 7 → 8 → 9 → 10 → 11 ] and applied to the synthesis of FK-156 [ 10 → 12 → 14 → 1 ].

Synthesis of 2-oxocephalosporins

A synthesis of the 2-oxocephalosporin nucleus (12) has been achieved starting from penicillin V. Some physical and chemical properties of this new ring system and the preparation of the corresponding free acid 2 (R1 = CH2OC6H5) for biological testing are also described.

Total synthesis of urogastrone (human epidermal growth factor, h-EGF). Part 1. Synthesis of the fully protected urogastrone

The first total synthesis of urogastrone (h-EGF) has been achieved by the segment condensation method in solution applying the maximum protection strategy with a two-step deprotection procedure. The polypeptide chain was constructed from 10 small segments which were synthesized in a conventional fashion using Boc for the amino protecting group, Acm for the thiol protecting group, and Pac for the carboxy protecting group except for segments (48–53) and (1–5), which were protected with Bzl and Troc hydrazide, respectively. The larger fragment condensation reactions were successfully carried out by the WSCD-HOBt method and the azide method to obtain the fully protected tripentacosapeptide corresponding to the sequence of urogastrone.

Total synthesis of urogastrone (human epidermal growth factor, h-EGF). Part 2. Synthesis of urogastrone having the structure proposed for the natural compound

Deprotection of the fully protected urogastrone was carried out by a two-step deprotection strategy. In the first step the protecting groups of all side-chain functional groups except for the cysteine thiol were removed by treatment with HF and the resulting (S-Acm)6-urogastrone was purified by ion-exchange chromatography prior to the disulphide bond formation. In the second step the six Acm groups of the purified (S-Acm)6-urogastrone were removed by Hg(OAc)2. After formation of disulphide bonds by air oxidation, the synthetic urogastrone was purified by ion-exchange chromatography and gel filtration. The structure of the synthetic urogastrone was further characterized by amino acid analysis, tryptic peptide mapping, thermolytic peptide mapping, and fast atom bombardment mass spectroscopy.

Slow ring-inversion of the nine-membered lactam in 4-azabicyclo[5,2,2]-undeca-8,10-dien-3-one systems

The kinetic parameters for hindered inversion of the nine-membered lactam ring in 4-azabicyclo[5,2,2]undeca-8,10-dien-3-one systems have been determined by n.m.r. total line-shape analysis. These data may provide an example of hindered ring-inversion of a medium-sized ring caused by hindered rotation of the amide group.

Transannular formation of 1,10-dimethoxy-4-azatricyclo[6,2,2,04,8]dodeca-9,11-dien-3-one

Photolysis of N-chloroacetyl-3,4-dimethoxy-phenylpropylamine (1) gave the eight-membered lactam (2) and the novel aza-azulene derivatives (4 and 5); the nine-membered lactam (9) was synthesized similarly from N-chloroacetyl-3,4-dimethoxyphenylbutylamine (8).