Total Syntheses of Arylindolizidine Alkaloids (+)-Ipalbidine and (+)-Antofine

Abstract

This paper presents the first application of two recently developed reactions to natural product synthesis. The first method involves a 6-endo-trig cyclization to prepare a versatile chiral enaminone building block. The second is a direct C-H arylation reaction. As a showcase for the utility of these methods, (+)-antofine and (+)-ipalbidine were synthesized in only 8 steps and 24-26% overall yields.The indolizidine alkaloids are extraordinarily prevalent in nature and are endowed with a host of biological properties that are being harnessed to treat numerous diseases.1 For this reason, methods to prepare the indolizidine core, particularly in enantiomeric form, are valuable. We have recently developed a chiral pool approach to generate mono-and bicyclic enaminones, which has enabled the synthesis of a versatile indolizidine building block from Boc-L-proline.2 The multifaceted reactivity of the enaminone scaffold lends itself to many chemoselective transformations. Having established a practical route to these molecules, we next demonstrated that cyclic enaminones were viable C-H donors in a Pd(II)-catalyzed cross-coupling reaction with aryltrifluoroborates.3 Until now, these methods have not been applied to the synthesis of more complex molecules. Herein, we show for the first time that these two methods enable an efficient synthesis of aryl indolizidine alkaloids.Our interest in indolizidine alkaloids led us to prepare (+)-ipalbidine and (+)-antofine. These natural products were chosen not only by virtue of their prototypical structures but also by their remarkable biological profiles. (+)-Ipalbidine is a non-addictive analgesic, an oxygenfree radical scavenger, and has demonstrated inhibitory effects on the respiratory burst of leukocytes.4 (−)-Antofine, on the other hand, exhibits low nanomolar anti-proliferative activity (GI 50 ) in drug-sensitive and multi-drug resistant cancer cell lines5 and anti-viral activity.6 This phenanthroindolizidine is the only member in its class to have established DNA and RNA binding affinities,7 which may shed light on the elusive mechanism of action of these planar natural products. We chose to synthesize the unnatural enantiomer, (+)-antofine, considering that both natural products could be synthesized in a divergent * georg@umn.edu . Supporting Information Available.Full experimental details and copies of NMR spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. fashion from a late-stage intermediate derived from the Boc-L-proline. Although these natural products have been synthesized before,5b , 6 -8 this route gives access to these molecules in a remarkably concise and high-yielding fashion that will contribute to the ongoing search for their cellular target(s). NIH Public AccessTo begin our syntheses, diazoketone 1 was prepared from Boc-L-proline and was then treated with catalytic CF 3 CO 2 Ag in the presence of freshly distilled N,Odimethylhydroxylamine (Scheme 1).9 The resulting Weinreb amide 2 ...

Palladium-Catalyzed Direct C–H Arylation of Cyclic Enaminones with Aryl Iodides

“…Palladium(II) acetate, aryl iodides, all other chemicals and solvents were purchased and were directly used without further purification. Cyclic enaminones ( 1a , 1a 1q–1r , 3d,15 1s , 5b and 1t–1w 3d,15 ) were prepared according to the reported procedures and enaminone 1x is commercially available. Flash column chromatography was carried out on silica gel (230–400 mesh).…”

“…2 As our laboratory continues to investigate the pharmaceutical applications of phenanthropiperidine alkaloids, the syntheses of these natural products and analogs entail a regioselective C5-arylation of cyclic enaminones as a key step. 3 Our strategy has been employing direct C–H arylation reactions because of their convenience and efficiency.…”

2,3-Dihydropyridin-4(1H)-ones and 3-Aminocyclohex-2-enones: Synthesis, Functionalization, and Applications to Alkaloid Synthesis

“…39 Antofine exhibits low nanomolar antiproliferative activity against drug-sensitive and multidrug-resistant cancer cell lines, as well as antiviral activity. [43][44][45][46] The (+)-antofine enantiomer …”

Direct Hiyama Cross-Coupling of Enaminones With Triethoxy(aryl)silanes and Dimethylphenylsilanol

“…We have recently demonstrated the utility of this chemistry for the concise enantiospecific synthesis of the phenanthropiperidine alkaloids ipalbidine and antofine, 7 tylocrebrine, 8 and boehmeriasin A. 9 …”