P-51 抗HIV活性を有する環状デプシペプチドパプアミド類の全合成研究(ポスター発表の部)
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Papuamides A (1) and B (2) are novel cyclic depsipeptides isolated from the sponges Theonella mirabilis and Theonella swinhoei collected at Papua New Guinea by Boyd and co-workers in 1999. They are known to inhibit the infection of human T-lymphoblastoid cells by HIV-1_<RF> in vitro. In addition to their novel biological activities, they have intriguing structures containing (4Z,6E)-2,3-dihydroxy-2,6,8-trimethyldecadienoic acid (Dhtda) and unusual amino acid residues, such as 3-methoxytyrosine (3-OMeTyr), O-methylserine (OMeSer), 3-hydroxyleucine (3-OHLeu) and homoproline (Hpr). The stereochemistry of papuamides remains to be determined because of the uncertainty regarding the 3-OMeTyr and Dhtda parts. The intriguing structures as well as the unique biological activities led us to initiate efforts towards the total synthesis. To determine the absolute stereochemistry of 3-methoxytyrosine, we synthesized four tripeptides (9a-d) derived from 3-OMeTyr with two unknown stereocenters at C2 and C3 position. Comparison of the ^1H NMR data reported for the natural hydrolysate (3) derived from papuamide A with the synthetic four tripeptides (9a-d) showed that the natural fragment is consistent with the (2R,3R)-isomer as shown in Scheme 3. The stereocontrolled syntheses of (2R,3R)-3-OHLeu and (2R,3R)-3-OMeTyr were achieved by the use of asymmetric hydrogenation via dynamic kinetic resolution catalyzed by the chiral ruthenium or iridium complex originally developed by us. For determination of the relative and absolute stereochemistry of Dhtda, we focused on synthesis of 8 diastereomers of Dhtda-peptide unit (10). Four diastereomers with the syn stereochemistry at the C2 and C3 stereocenters were synthesized by using stereoselective addition of alkynyl lithium generated from dibromoalkene (12) in situ to aldehyde (13) as a key step. Further synthesis of the diastereomers with the anti stereochemistry at the C2 and C3 stereocenters and structural determination of papuamides are in progress.
- 2006-09-15
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