Enantiopure <i>N</i>-Acyldihydropyridones as Synthetic Intermediates:  Asymmetric Synthesis of (−)-Septicine and (−)-Tylophorine

Comins, Daniel L.; Chen, Xinghai; Morgan, Lawrence A.

doi:10.1021/jo9711495

Cited by 77 publications

(24 citation statements)

References 19 publications

(22 reference statements)

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“…In this second approach, enaminone 7 was again reduced with L-Selectride only the resulting enolate was trapped in situ with 2-[ N,N -bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (Comins’ reagent) 16. The methyl group was then installed by subjecting this triflate to Negishi cross-coupling conditions17 to furnish common intermediate 9 in 69% yield over two steps. As before, upon methyl deprotection, the natural product was obtained.…”

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confidence: 99%

“…Thus, (+)-antofine was synthesized in two steps from triflate 10 (Scheme 4), whose synthesis has already been discussed. Firstly, antofine’s seco-analog was prepared using Negishi cross-coupling conditions17 to install the 3,4-dimethoxyphenyl group in 95% yield. In the final step, the phenanthrene system was established with a PhI(O 2 CCF 3 ) 2 -mediated biaryl coupling to furnish (+)-antofine in 70% yield.…”

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

Niphakis

Georg

2010

J. Org. Chem.

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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 ...

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

Niphakis

Georg

2010

J. Org. Chem.

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“…7, 8 The C 5 position can also be halogenated using NBS and a subsequent palladium-mediated coupling provides various 5-substituted derivatives (Scheme 3). 9 A widely used method for the synthesis of the dihydropyridone system involves the reaction of carbon nucleophiles with various 1-acylpyridinium salts (12). 4,10 Because of the abundance of piperidine-containing natural products, 11 this method has been extensively utilized by Comins and coworkers for the asymmetric synthesis of many quinolizidine, indolizidine and perhydroquinoline alkaloids.…”

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confidence: 99%

A high yielding oxidation method for the preparation of substituted 2,3-dihydro-4-pyridones from 4-piperidones

Flick¹,

Padwa²

2008

Arkivoc

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“…The use of VOF 3 in a mixture of CH 2 Cl 2 and TFA allowed Comins and co-workers to complete the total synthesis of tylophorine (102), first in racemic form and then as a chiral compound [74,75]. The oxidative cyclization of septicine (101) leads directly to tylophorine in 68 % yield (Scheme 24).…”

Section: Substratementioning

confidence: 99%

Oxidative Aryl‐Coupling Reactions in Synthesis

Lessène

Feldman

2002

Modern Arene Chemistry

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The oxidant-mediated coupling of electron-rich arene rings has served over several decades as a valuable procedure to access biaryl units. The complex mixtures of isomers that often plagued the earliest studies have gradually given way to synthetically useful product distributions upon application of more selective coupling protocols. Continual advances in the nature of the oxidant (and its attendant ligands) and more precisely defined reaction conditions have led to increasing levels of control upon CaC bond formation. Chemoselective (CaC vs. CaO bond formation with phenols; suppression of product oxidation), regioselective (o-o 0 , vs. o-p 0 vs. p-p 0 CaC bond formation), and, more recently, stereoselective (atropisomer-selective) biaryl bond formation can now be achieved in many well-defined systems. A survey of the more recent advances in these areas is presented.14.1

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Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Synthesis of (−)-Septicine and (−)-Tylophorine

Cited by 77 publications

References 19 publications

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

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

A high yielding oxidation method for the preparation of substituted 2,3-dihydro-4-pyridones from 4-piperidones

Oxidative Aryl‐Coupling Reactions in Synthesis

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