Application of the PIFA–mediated alkyne amidation reaction to the formal synthesis of ( ± )-clausenamide

The hypervalent iodine reagent PIFA promotes the intramolecular electrophilic cyclization of easily accessible N -aryl and N -methylalkynylamides leading to the formation of the pyrrolidinone skeleton in a very efficient way. This strategy has found application in the preparation of a key intermediate in the total synthesis of (±)-clausenamide alkaloid.


Introduction
When properly substituted amides are treated with the hypervalent iodine reagent PIFA, 1 [bis(trifluoroacetoxy)iodo]benzene, an acylnitrenium ion (B and E) is formed provided that an electron-releasing group is attached to the nitrogen to stabilize such deficient species (see Scheme 1). 2 If under such conditions the substrate contains an additional nucleophilic group, a heterocyclic compound can be formed after an intramolecular cyclization process.We have applied this strategy to amides containing olefins (A) or alkynes (D), as the nucleophilic component of the reaction, to afford, respectively, a series of 5-hydroxymethylpyrrolidinones (C) 3

Scheme 1
Such pyrrolidine nucleus is found in many natural products and it constitutes an interesting motif with pharmaceutical interest.Some selected examples include the liver protecting agent (-)clausenamide, 5 the antibiotic (-)-anisomicine, 6 and the potent fungicide (+)-preusine 7 (see Figure 1).Considering its close structural similarity to pyrrolidinones of type F, we embarked in the formal synthesis of one of these related natural products by using our PIFA-mediated strategy that transforms alkynylamides into 5-aroylpyrrolidinones as the key step of the synthesis.

Results and Discussion
(±)-Clausenamide is the main component of aqueous extract of the leaves of Clausena lansium, a plant extensively employed in chinese folk medicine. 8This alkaloid has shown efficiency as a liver-protecting agent against chemical toxins, 9 as an inductor effect over P450 cytochrome, 10 and also as a protector against cerebral hypoxia. 11In fact, the possible application of this compound for the prevention and/or treatment of degenerative processes, such as Alzheimer's disease, is under study. 12Due to the low concentration of the alkaloid in the natural media, an efficient chemical synthesis is highly desirable. 13Therefore, to accommodate its preparation to our synthetic design, in combination with previous procedures, properly substituted substrates had to be prepared.
Our first attempt (see Scheme 2) started with the cyclization of the preformed 14 alkynylamide 1a, which on treatment with PIFA in trifluoroethanol 15 at 0 ºC afforded the desired pyrrolidinone 2a in 62% yield.Location of the methyl group at nitrogen required further removal of the PMP group and a subsequent N-methylation process.Although elimination of the aryl group was easily accomplished by using ceric ammonium nitrate, all efforts to N-methylate pyrrolidinone 3 furnished the C-alkylated product 4.At this moment we were considering that the presence of an aryl group (i.e.PMP) in substrate 1a was essential for the stabilization of the acylnitrenium intermediate of type B presumably formed after treatment with PIFA. 16But to the view of the difficulties associated with the N-methylation step, and trying to simplify the synthesis, we designed a second attempt starting from the N-methylalkynylamide 1b.To our delight, treatment of 1b with the hypervalent iodine reagent under the same reaction conditions yielded the corresponding Nmethylpyrrolidinone 2b in a superior 78% yield.Conversely to this anticipated mechanistic scenario, the success on the cyclization of N-alkynylamides of type 1b, where a positive charge on nitrogen would not be adequately stabilized, led us to propose an alternative mechanism (see Scheme 3).Thus, activation of the triple bond by PIFA (instead of nitrogen oxidation) gives an electrophilic intermediate that reacts intramolecularly with the nucleophilic amide.Substitution by a trifluoroacetate ligand, with concomitant release of PhI, renders the corresponding enol acetate, which after basic work up yields the final Nmethylpyrrolidinone 2b.Considering this new piece of information, the synthetic design towards the clausenamide alkaloid was modified according to Scheme 4 in which a more elaborated precursor 9 that includes the N-methyl and the phenyl groups had to be prepared.Therefore, alkylidene adduct 6 was satisfactorily prepared by condensation of commercially available Meldrum's acid (5) with benzaldehyde in EtOH under sonication.Conjugate addition of phenylacetylene to 6 yielded 7, which after a decarboxylation process led to the formation of the required -alkynyl carboxylic acid 8 in 45% yield over two steps.Then, carboxylic acid 8 was transformed into the Nmethylamide 9 in high yield employing HOBt and EDC•HCl as activating reagents.Finally, application of our PIFA-mediated cyclization conditions afforded pyrrolidinone 10 as a cis/trans mixture (1:2 ratio). 17The desired cis-isomer could be separated by flash column chromatography (EtOAc/hexanes, 8/2) as a solid that was crystallized from Et2O, and its stereochemical identification was achieved by comparison with the previously reported data that claimed a coupling constant of 8Hz for protons H-4 and H-5 in a cis relationship.Finally, pyrrolidinone 10cis can be easily transformed into (±)-clausenamide in two steps following procedures previously described in the literature.reported in hertz.DEPT experiments were used to assist with the assignation of the signals.
HRMS spectra were measured by using a Waters GCT Mass Spectrometer.
Figure 1 Scheme 2 Scheme 3 13e All reagents were purchased and used as received.Melting points were measured using open glass capillaries and are uncorrected.Infrared spectra were recorded as KBr plates or as thin films and peaks are reported in cm -1 .Only representative absorptions are given.NMR spectra were recorded at ambient temperature on a Bruker ACE-250 apparatus at 250 MHz (250 MHz for 1 H and 62.83 MHz for 13C).Chemical shifts () were measured in ppm relative to chloroform (=7.26 for 1 H or 77.00 for13C) as internal standard.Coupling constants, J, are ISSN 1551-7012 Page 11  ARKAT USA, Inc.