Synthesis and Structure Revision of Nakiterpiosin

Abstract

This manuscript describes a convergent synthesis and the revision of the relative stereochemistry of nakiterpiosin, a marine C-nor-D-homosteroid. Our synthesis features a late-stage carbonylative Stille cross-coupling reaction and a photo-Nazarov cyclization reaction that deliver the complete nakiterpiosin skeleton efficiently. Nakiterpiosin (1) is a marine sponge metabolite that exhibits potent cytotoxicity against the P388 murine leukemia cell line (GI 50 10 ng/mL) ( Figure 1). 1 It was the first C-nor-Dhomosteroid isolated from a marine source. Its unique chemical structure and strong P388 growth inhibition property prompted us to initiate a research program to explore its laboratory synthesis 2 and biological function. We report herein the synthesis and structure revision 3 of nakiterpiosin.The C-nor-D-homosteroids are skeletally rearranged steroids with their C-ring contracted and D-ring expanded by one carbon. The veratrum alkaloid cyclopamine (3) and veratramine (4) are arguably the best known members. 4,5 The teratogenic alkaloid 3 inhibits the Hedgehog (Hh) signaling by binding to Smoothened (Smo), 6,7 and the chronotropic alkaloid 4 induces serotonin (5-HT) syndrome. 8 While 1 possesses potent cytotoxicity against P388, its molecular target is not known. Furthermore, the complete biological profile of 1 could not be obtained due to the scarcity of the material. From 30 kg of sponge T. hoshinota, only 0.4 mg of nakiterpiosin was obtained. Its chemical structure was assigned as 2 in the original reports. 1We were puzzled by the inconsistency between the C-20 stereochemistry reported for 2 and 3/4 and therefore set out to probe the relative stereochemistry of nakiterpiosin. Our model studies indicated potential misassignment of the C-6, C-20 and C-25 stereogenic centers. 9 We next considered the biogenesis of the halogen atoms 10 of nakiterpiosin to rationalize the C-6 and C-20 stereochemistry. We envisioned that the C-21 chlorine atoms of nakiterpiosin might be introduced by radical chlorination and the C-6 bromine atom by bromoetherification (as shown in 5) to result in retention of the C-20 configuration and the anti C-5,6 bromohydrin stereochemistry. Taken together, these considerations led us to propose 1 to be the correct structure of nakiterpiosin. Indeed, we found that the 1 H and 13 C NMR spectra of our synthetic sample of 1 agreed with those of the natural product. 11 In contrast, those of synthetic 2 9,11 and the natural product are significantly different. We thus revised the relative stereochemistry Chuo.Chen@UTSouthwestern.edu. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2010 February 4. Our synthetic strategy is outlined in Figure 2. We dissected 1 into fragments 6 and 7 and constructed the central cyclopentanone ring with a carbonylative cross-coupling reaction 12 and a photo-Nazarov cyclization reaction. 13 The electrophilic coupling component 6 was synthesized by an intramolecular Diels-Alder reaction, 14 and the nucleophilic coupling com...

Chemical and Biological Studies of Nakiterpiosin and Nakiterpiosinone

“…We recently proposed to revise their relative configuration to that shown in 1 and 2 by analyzing the spectroscopic data of their fragments. We further synthesized 1 and 3 and confirmed that the structure of nakiterpiosin should be 1 3. We present herein the details of our synthetic studies and spectroscopic analysis of nakiterpiosin ( 1 ) and 6,20,25- epi -nakiterpiosin ( 3 ).…”

“…Our first-generation approach3 is outlined in Figure 5. We opted to construct the central cyclopentanone ring at a late-stage for convergency reasons.…”

The Vinylogous Mukaiyama Aldol Reaction in Natural Product Synthesis

“…The highly diastereoselective character of the vinylogous aldolization, strongly favoring 23,24-syn-24,25-anti-configured isomer 262, may be rationalized based on a Diels-Alder-like transition state (cf. During the total synthesis of nakiterpiosin (271) and nakiterpiosinone (272), two related C-nor-D-homosteroids, an accurate screening of 14 different Lewis acid promoters, emerged Sn(OTf) 2 as the best performer in terms of both conversion and stereoselectivity (Scheme 2.69) [114,115]. Thus, the tin(II) triflate-catalyzed VMAR between aldehyde 269 (90% ee) and 3-methyl-2-(triisopropylsiloxy)furan (3-Me-TIPSOF) (268) yielded 270 with 83% conversion, as the only diastereomer in 80% isolated yield and 90% ee.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…In the latter case the reaction was performed in the presence of H 2 O (Scheme 10). 213,214 Water has also been used in other total syntheses using DMP in CH 2 Cl 2 , 97,121,122,215 because it accelerates the reaction. 13…”