Starting with the ω-hydroxy and ω-amino acid derivatives 13 and 21, the two closely related geodiamolide analogs 32 and 35, respectively, were prepared. Compared to the natural cyclodepsipeptide geodiamolide (1), the macrocycles 32 and 35 have a smaller ring size (17-vs. 18-membered). Conformational analysis by ROESY spectroscopy and molecular dy-
The synthesis of the omega-amino acid 4 is described utilizing a two-dimensional synthesis strategy combined with an enzymatic differentiation of homotopic ester groups. The amino acid 4 features two non-bonded interactions that result in conformational constraints on a cyclic construct. This amino acid was incorporated into the four macrolactams 17, 22, 31, and 37. The ring in 17 and 22 is 18-membered, whereas 31 and 37 have a 19-membered ring. The pairs with the same ring size differ in a N-methyl group. For the larger macrolactams (31 and 37) conformational analysis showed that the macrocyclic rings are somewhat more rigid than in the natural lead, the depsipeptide jasplakinolide. Nevertheless, their conformations are comparable to the natural product. There are no intramolecular hydrogen bonds, neither is the cis-rotamer populated in the N-methyl compound 37. Due to the increased flexibility of the smaller macrolactams 17 and 22 and signal overlap, a distinct solution structure could not be obtained for these compounds. The amino acid 4 should be useful for restricting the conformation of other small peptides.
Synthesis of Jasplakinolide Analogues Containing a Novel ω-Amino Acid. -The novel amino acid (III) incorporates conformational constraints due to non-bonded interactions. It is part of cyclodepsipeptide analogues (I) and (II) of geodiamolide A. Whereas (I) are devoid of any cytotoxic effects, weak activity is observed for (IIa) and a moderate one for (IIb). -(MARIMGANTI, S.; YASMEEN, S.; FISCHER, D.; MAIER*, M. E.; Chem. Eur. J. 11 (2005) 22, 6687-6700; Inst. Org. Chem., Eberhard-Karls-Univ., D-72076 Tuebingen, Germany; Eng.) -Klein 15-185
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