Pumiliotoxin derivatives

The addition of a titanium homoenolate 115 to a proline derivative 114 proved to be a feasible approach for the formal synthesis of pumiliotoxin 251D. The addition proceeded with high stereoselectivity (Scheme 30) <1999JOC1410>. 

The pyrrolobenzodiazepine-5,11 -diones II have been utilized in asymmetric syntheses of both the cis- and tra i-decahydro-quinoline alkaloids (Schemes 21 and 22). For example, reduction of 100 with 4.4 equiv. of potassium in the presence of 2 equiv. of t-BuOH, followed by protonation of the resulting enolate with NH4CI at —78 °C gave the cA-fused tetra-hydrobenzene derivative 101.Amide-directed hydrogenation of 101 gave the hexahydrobenzene derivative with diastereo-selectivity greater than 99 1. Removal of the chiral auxiliary and adjustment of the oxidation state provided aldehyde 103 which was efficiently converted to the poison frog alkaloid (+)-pumiliotoxin C. 

As a current example of a stereoselective intramolecular Diels-Alder reaction using nitroso dienophiles, Kibayashi s studies aimed at the enantioselective total sysnthesis of (-)-pumiliotoxin C 4-31 shall be discussed here [356, 357]. The chiral nitroso compound 4-30 derived from L-malic acid was generated in situ... 

The Panamanian frog Dendrobates pumilio yielded not only pumiliotoxin C (vide ante) but also pumiliotoxins A and B. The instability of pumiliotoxins A and B under acid conditions has interfered with the preparation of a crystalline salt and many years after the isolation of these alkaloids the structural formulas remained unknown. Pumiliotoxins A and B and many related alkaloids are widely distributed in frogs of the genus Dendrobates. Serendipitously, in searching for a different alkaloid, a major alkaloid with a molecular weight of 251 (pumiliotoxin 25 ID) was isolated from the skin of the Ecuadorian poison frog Dendrobates tricolor. It proved to be a simpler analog of pumiliotoxins A and B, but most importantly, it was possible to crystallize the HC1 salt and consequently to derive its structural formula by X-ray diffraction analysis (37). 

Fig. 15. Structures of pumiliotoxin A (left) and pumiliotoxin B (right) based on the structure of pumiliotoxin 25 ID, as derived from X-ray analysis and spectral data (37).

Once the structure of pumiliotoxin 25ID was known from crystal structure analysis, the structures of a number of other alkaloids of the pumiliotoxin A class were derived from mass spectra and NMR spectra (see e.g., Fig. 15). A problem still remains in assigning the stereoconfigurations of the hydroxyl groups in the long side chains. This kind of problem could be easily resolved by crystallography, if it were possible to grow a crystal. 

Alkali metal in ammonia reductions of pyrrolobenzodiazepine-5,11-diones give trans-2-aminocyclohexanecarboxylic acid derivatives (e.g., 4) in enantiomerically pure form.2 3 A method for preparation of cis-2-aminocyclohexanecarboxylic acids related to 4 is based on the enantioselective hydrolysis of symmetrical diesters with pig liver esterase.4 cis-2-Aminocyclohexane derivatives have been used for syntheses of aminocyclitol antibiotics.4 5 6-Alkyl-cis-2-aminocyclohexanecarboxylic acids can be prepared by alkali metal in ammonia reduction of pyrrolobenzodiazepine-5,11-diones followed by olefin hydrogenation the cis-decahydroquinoline alkaloid (+)-pumiliotoxin C has been prepared by this methodology.2... 

In summary, the pumiliotoxin-A class alkaloids are unique to certain genera from four different families of amphibians. Pumiliotoxins and allo-pumiliotoxins often occur together. Homopumiliotoxins occur much less often. The unique and complex structures and the phylogenetic distribution of pumiliotoxin-A class alkaloids argue for the independent evolutionary development of a complex suite of biosynthetic enzymes. The branched-chain structures of the pumiliotoxin-A class also suggest the incorporation of isoprene units, unlike the preponderance of bicyclic den-drobatid alkaloids, which appear to be derived from straight-chain precursors. 

For the synthesis of the trans-mmulsitQd 4a- p/-pumiliotoxin C 195 (Scheme 10.66), the imine prepared from galactosyl amine 150 and 5-hexenal was reacted with Danishefsky s diene to give the 2-substituted dehydropiperidinone derivative 196 with high diastereoselectivity. The subsequent addition of propyl cuprate promoted by borontrifluoride etherate furnished the 2,6-c/5 -disubstituted... 

Indolizidine and quinolizidine alkaloids found in amphibians and ants were studied by Daly and co-workers who classified them in two different classes, A and B, Fig. (1) [2,15-17]. The former include 3,5- and 5,8-disubstituted indolizidines, 5,6,8-trisubstituted indolizidines and 1,4- and 4,6-disubstituted quinolizidines that can be derived from straight-chain carbon precursors. The latter contain one or more isoprene units, and include pumiliotoxins (PTX-A), allopumiliotoxins (a//o-PTX-A or... 

W-phenoxycarbonyl bicyclic enone, which was structurally similar to 61, exclusively provided a cw-annulated octahydroquinoline derivative. From the trans-annulated decahydroquinoline 62, fraw5 -4a-e/7t-pumiliotoxin C 63 was S5uithesized in a 5-step reaction sequence, including hydrogenolytic desulfurization of the dithiolane prepared by treatment of the carbonyl group in 62 with 1,2-ethanedithiol. 

The usefulness of nucleophile-promoted Iminium Ion-alkyne cyclizations derives from the ready availability of alkynylamines and the subsequent transformations of the cyclization products made possible because of their vinylic functionality (e.g., equations 1 and 2). Equation 2 illustrates use of this chemistry to elaborate an exocyclic tetrasubstituted double bond with complete stereooontrol. Net "reductive iminium ion alkyne cyclizations can be accomplished by dehalogenation of vinyl halide cyclization products. The conversion illustrated in equation 3 is a key step in an efficient, practical synthesis of the cardiotonic frog alkaloid pumiliotoxin A. ... 

Addition of this homoenolate to the ketone 23, a single enantiomer derived from natural proline, gives the tertiary alcohol 24 with high stereoselectivity.7 Removal of the Cbz protecting group leads to spontaneous cyclisation to give 25, an intermediate on the way to the neurotoxin pumiliotoxin 251D 26. 

Inversion of the hydroxyl center with oxygen nucleophiles allows one to gain access to R) lactic acid derivatives. This strategy has been used to establish the correct stereochemistry in the alkylidene side chain of pumiliotoxin B (108) [37], a cardiac agent isolated from the Panamanian poison frog (Scheme 16). In the key reaction, conversion of 2 to R)-p-nitrobenzoyl ester 104 proceeds in high yield and with essentially complete inversion of configuration. 

Synthesis of N-heterocycles (indole, quinoline, pyrrole, pyrrolizine, indo-lizine derivatives, lactams, pumiliotoxin C, and lycopodine) using Ti-activated molecular nitrogen 04JOM(689)4210. 

Total synthesis of (+)-pumiliotoxin A (39) has been achieved based on the Negishi coupling of the alkylzinc chloride 37, derived from the alkyl iodide, with the alkenyl iodide 38 at room temperature, and subsequent deprotection [58], The alkylzinc reagent 41 was prepared conveniently by the reaction of the alkyl iodide 40 with Zn/Cu couple, and treated with 2-iodoimidazole 42 to afford the adduct 43 [47],... 

From the numerous ir-systems investigated, nitrogen-containing dienophiles are the most typical carbonyl derivatives for hetero Diels-Alder reactions. Simple imines, however, are quite unreactive and require highly reactive dienes as counterparts. - In contrast, electron-deficient species, such as iminium salts (134 Scheme 63) or N-acylimines (137 Scheme 64), do undergo [4 -t- 2] cycloadditions with normal nonactivated dienes. Thus, the intramolecular Diels-Alder reaction of the iminium species (134), created in situ from the aldehyde (133) and ammonia, gives the octahydroquinoline (135), which can be hydrogenated to afford the 8a-epimer of pumiliotoxin C (Scheme 63). ... 

The nitroso functionality is a powerful dienophile and N-alkyl- and N-acylnitroso compounds give inter- and intrahetero Diels-Alder reactions easily. The cycloadditions also occur in aqueous medium although some nitroso compounds (i.e. N-acylnitroso derivative) are short-lived in the presence of water. The NO functionality is generated in situ by periodate oxidation of the hydroxylamine group and the cycloaddition with butadienes gives a 1,2-oxazine ring. Scheme 5.16 illustrates the utility of the nitroso Diels-Alder cycloaddition for the synthesis of (—l-swainsonine/ (—)-pumiliotoxin and BCX-1812... 

The next synthesis uses a chiral auxiliary approach in which the auxiliary is not sacrificed. The synthesis begins with anthranihc acid derivative 157. A potassium-ammonia reduction provided a mixture of diastereomers 158 and 159. A directed hydrogenation of the major diastereomer (159), using Crabtree s cationic iridium catalyst, provided 160. This material was moved forward to pumiliotoxin-C through intermediates we encountered in the Overman approach (compare the substitution pattern and relative stereochemistry of 160 with 131 on Pumihotoxin-3). 

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