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Lipopeptides, carrying the N-terminal lipoamino acid 2-(palmitoylamino)-6,7-bis(palmitoyloxy) heptanoic acid (Pam3Adh-OH, 1), were obtained by solid-phase synthesis and by synthesis in solution. 2-Amino-6,7-dihydroxyheptanoic acid (Adh) can be regarded as a methylene analogue of S-glycerylcysteine, the N-terminal amino acid of lipoprotein from the outer cell membrane of Escherichia coli (a methylene group substitutes for the sulfur atom). The lipopeptides Pam3Adh-Ser-Ser-Asn-Ala 2a-d, in which the four possible stereoisomers of Pam3Adh-OH (2S,6S)-1 (1a), (2S,6R)-1 (1b), (2R,6S)-1 (1c), and (2R,6R)-1 (1d) are linked to the naturally occurring sequence Ser-Ser-Asn-Ala of the N-terminus of lipoprotein, and also Pam3Adh-Ser-(Lys)4 [2S,6S)-3), with a peptide part rendering the molecule water soluble, were capable of stimulating murine splenocytes polyclonally in vitro, as determined in a proliferation assay and in a hemolytic plaque assay against trinitrophenylated sheep erythrocytes. The diastereomers (2S,6S)-2 and (2R,6S)-2 with S-configurated C-6 were more active than the diastereomers (2S,6R)-2 and (2R,6R)-2 with R-configurated C-6; a change of the configuration at C-2 had less effect on the stimulatory activity. (2S,6S)-2 and (2S,6S)-3 are potent immunoadjuvants. A significantly enhanced primary immune response against trinitrophenylated sheep erythrocytes was obtained in vitro at lipopeptide concentrations of about 5 micrograms/mL and an immunization dose of 10(7) sheep erythrocytes/mL. Balb/c mice, which were immunized with a mixture of ovalbumin and (2S,6S)-2 or (2S,6S)-3, respectively, had a substantially higher antiovalbumin titer 28 days after immunization than mice which had received ovalbumin, (2S,6S)-2 or (2S,6S)-3 alone. Finally, the novel lipopeptides constitute potent macrophage activators: (2S,6S)-3 was able to induce tumor cytotoxicity against the tumor cell line L929 in bone marrow derived macrophages.

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The pentacyclic Aspidosperma alkaloid dZ-16-methoxytabersonine (1) has been synthesized by an efficient convergent sequence. The key step in the synthesis is the "ring-enlarging pyrrolidine annulation" reaction of 7-styrylhydropyridin-7-ols 17 and 18 to give 9a-arylhydrolilolidine 19 and 16-methoxy-l,2,6,7-tetradehydroaspidospermidine (20), respectively.

The reported preparation of the p-ansa compound frangulanine, previously isolated f r o m Rhamnus frangula L., also constitutes the first total synthesis of a fourteen-membered cyclopeptide alkaloid.

of DIEA (1 X 10 min); (13) wash, methylene chloride (3x); ( 14) wash, ethanol/methylene chloride (1:2; 3x). Recoupling was performed after each coupling of AocArg(Tos). The resulting hexapeptide resin (3.0 g, 0.89 mmol based on the substitution level of the first amino acid attached to the resin) was suspended in 50 mL of trifluoroethanol, which had been saturated at 0 °C with ammonia freshly distilled from sodium. The suspension was sealed in a pressure bottle and shaken for 3 days at room temperature. The flask was then cooled to 0 °C and the trifluoroethanol removed by filtration. The peptide resin was washed several times with methanol, and then the peptide was eluted from the resin with warm DMF. Evaporation of the solvent and trituration of the residue with ether gave 850 mg of peptide (60%). This product was dissolved in 7 mL of DMF, applied to a 2.5 X 80 cm column of LH-20 Sephadex, and eluted with DMF. The major peak corresponding to the appropriate molecular weight was collected, and the solvent was removed under reduced pressure; yield 737 mg (52%). The peptide was still heterogeneous by criteria of TLC, so the product was dissolved in hot methanol, and upon cooling a homogeneous product precipitated: yield 0.42 g (30%); mp 133-136 °C; Rf(F) 0.38, Rf(G) 0.80.Acknowledgment. We acknowledge financial support by USPHS Program Project HL-18577. We express our appreciation to Dr. Rei Matsueda for many helpful discussions, to Drs.