Antineoplastic Agents. 561. Total Synthesis of Respirantin^1a

Abstract

Total synthesis of the eighteen-membered ring cyclodepsipeptide believed to be respirantin (1b) has been achieved. The key step in the synthesis is an intramolecular transesterification of the β-ketoester alcohol 6 to afford the protected macrocycle 5. The synthetic product was shown to be identical to a natural product presumed to be respirantin (1b) and the absolute stereochemistry of 6 of the 7 asymmetric centers of cyclodepsipeptide 1b was unequivocally established. Respirantin (1b) was found to be a remarkable inhibitor of cancer cell growth and related to the antimycin family of antibiotics.In the preceding report, we summarized the isolation and structures of three exceptional cancer cell growth inhibitory cyclodepsipeptides from the bacterium Kitasatospora sp. found on the Beaufort Sea coast of the Alaska North Slope. 1a One of these corresponded to a unique structure and was designated kitastatin 1 (1a) (Figure 1) while the other two cyclodepsipeptides on the basis of reported NMR assignments were presumed to be respirantin (1b) and a valeryl modification (1c). 1b Respirantin (1b) was first reported in 1993 1b as an insecticidal antibiotic isolated from a Streptomyces species found in a soil sample from Japan and shown to have cyclodepsipeptide structure 1b based on analysis of its spectroscopic properties. The stereochemistry was not determined. Kitastatin 1 (1a) and respirantin (1b) contain a blastmycic acid unit also found in the antimycins 2 such as 2 and neoantimycin 3 . An unusual structural feature is the β-ketoester linkage (carbons 6-8) in the 18-membered depsipeptide macrocycle. In order to obtain sufficient material for more extensive biological evaluation as well as overall to determine the stereochemistry and absolute configuration of kitastatin 1 (1a) and respirantin (1b), we undertook research to develop a total synthesis of 1b with flexibility to enable future SAR development. Herein we report the successful results. Results and DiscussionInspection of the kitastatin 1 (1a) and respirantin (1b) macrocycle revealed that they are composed of common amino acids, or α-hydroxycarboxylic acids derived from them, along with the β-ketoester unit. Since the absolute stereochemistry of 1a and 1b was undetermined at the onset of this study, our initial target 1b was selected by assuming the most common Sconfiguration for the constituent amino acids and their presumed α-hydroxy derivatives. Fortunately, that proved to be the correct choice among the 256 possible optical isomers. A retrosynthetic analysis of the ultimately successful route to respirantin (1b) is presented in Scheme 1. Prior antimycin syntheses 2 offered good precedent for appending the protected benzoic acid 3 to amino substituted macrocycles. However other issues that needed to be * To whom correspondence should be addressed. Tel: (480) . E-mail: bpettit@asu.edu. NIH Public AccessAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2008 December 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Autho...

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

“…3,50 In particular, 68 showed substantial growth inhibition against a pancreas cancer cell line with a GI 50 value of $7 ng mL À1 , 3 while 66 displayed signicant growth inhibition against a prostate cancer cell line with a GI 50 value of $2 ng mL À1 . 3,50 In particular, 68 showed substantial growth inhibition against a pancreas cancer cell line with a GI 50 value of $7 ng mL À1 , 3 while 66 displayed signicant growth inhibition against a prostate cancer cell line with a GI 50 value of $2 ng mL À1 .…”

“…50 The 18-membered tetralactone core was completed via an intramolecular b-ketoester transesterication method, and the gem-dimethyl groups were introduced aer formation of the b-ketoester linkage because of epimerization occurring during deprotection of a silyl ether. 50 The 18-membered tetralactone core was completed via an intramolecular b-ketoester transesterication method, and the gem-dimethyl groups were introduced aer formation of the b-ketoester linkage because of epimerization occurring during deprotection of a silyl ether.…”

“…In particular, JBIR-06 (49) and JBIR-52 (50) were recently isolated from Streptomyces sp. In particular, JBIR-06 (49) and JBIR-52 (50) were recently isolated from Streptomyces sp.…”

Antineoplastic Agents. 560. Isolation and Structure of Kitastatin 1 from an Alaskan Kitasatospora sp.

“…The comprehensive analyses of 1 H-, 13 C-and 2D-NMR spectra allowed assignment of the following units: lactyl, 2-hydroxy-3-methylvaleryl, 4-amino-2,2,6-trimethyl-3-oxoheptanoyl, 2-hydroxy-4-methylvaleryl, 2-hydroxy-3-formylaminobenzoyl, and a threonine unit. The connection of the fragments by HMBC-NMR analyses led to assignment of depsipeptide 1 with unknown stereochemistry, as reported for the Streptomyces sp.…”

“…High-resolution mass spectra were obtained with a JEOL LCmate magnetic sector instrument by APCI in positive ion mode with a poly(ethylene glycol) reference. The NMR experiments were conducted using a Varian Unity INOVA-500 spectrometer operating at 500 MHz or 400 MHz for 1 H NMR as well as 2D NMR referenced to tetramethylsilane and at 100 MHz for 13 C NMR referenced to tetramethylsilane.…”