Absolute Configuration of Phorboxazoles A and B from the Marine Sponge Phorbas sp. 1. Macrolide and Hemiketal Rings

• Published in: Journal of the American Chemical Society Vol. 118; no. 39; pp. 9422 - 9423
• Main Authors: Searle, Philip A, Molinski, Tadeusz F, Brzezinski, Linda Joy, Leahy, James W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.10.1996; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Marine; Phorbas; Physical Sciences; Porifera; Science & Technology; PALYTOXIN; STEREOCHEMISTRY
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja962092r

Recently, we reported the structures of two new bis-oxazole macrolides, phorboxazoles A (1) and B (2), from the marine sponge. Phorbas sp. Both compounds exhibit exceedingly potent cytostatic activity against a variety of human solid tumor cell lines. For example, a recently completed round of in vitro testing in the National Cancer Institute's panel of 60 human tumor cell lines showed that 1 inhibited growth of colon tumor cells HCT-116 (GI sub(50) 4.36 x 10 super(-10) M) and HT29 (3.31 x 10 super(-10) M). The initially reported structures of 1 and 2 were solved by interpretation of MS and 2D NMR experiments. However, the absolute configuration was left undefined. Determination of the relative and absolute configurations of complex natural product macrolides by NMR methods is often made difficult by the need to assign independent molecular segments containing remote stereogenic centers. Our attention was drawn to 1 as an attractive target for total synthesis due to its extraordinary activity and unprecedented carbon skeleton. Consequently, we applied our efforts to determination of the complete stereochemistry, but unfortunately so far all attempts to obtain crystals of either compound suitable for X-ray diffraction studies have failed. We now report the elucidation of the absolute configurations of 14 out of the 15 stereocenters in both 1 and 2 by a combination of techniques including synthesis of a suitable model compound for NMR spectroscopic comparisons.