Pumiliotoxin alkaloids

This cyclization has been used in a stereospecific synthesis of a pumiliotoxin alkaloid (6).2... 

Perhydropyrido[l,2-A][l,2]oxazines are applied as key intermediates in a stereospecific total syntheses of (-)-pumiliotoxin C and 5-e/ /-pumiliotoxin C(96JCS(P1)1113), and the marine alkaloid)—)-lepadins A, B, C (OOOL2955). (2-Pyridyl)propionic acids 13 can be regioselectively prepared via 2,3,4, 4fl,7,8-hexahydropyrido[l,2-A][l,2]oxazin-2-ones 12 (00OL4007). 

According to this scheme, a wide variety of naturally occurring alkaloids [331], for example onychine (2-640) [332] dielsiquinone (2-641) [333], costaclavin (2-642) [334] and pumiliotoxin C (2-643) [335] have been prepared starting from 2-638a-c via the cycloadducts 2-639a-c (Scheme 2.146). 

The pumiliotoxins, alio- and homopumiliotoxins, are alkaloids isolated from the skin of amphibians, such as neotropical frogs of the Dendrobatidae family, and are believed to serve as a chemical defence against predators. These natural products have interesting pharmacological properties, including myotonic and cardiotonic activities. 

Three syntheses of homopumiliotoxin alkaloids are compared below, and one more reaction leading to homo-pumiliotoxin-related compounds was mentioned in Section 12.01.9.3.7. The strategies involved for the ring-closure procedures leading to the quinolizidine system involved the formation of a- or 7-bonds from piperidine precursors and are summarized in Scheme 97. 

The isoxazoline 355 (Table 27, entry 9) served as precursor for the total synthesis of the amphibian alkaloid ( + )-Pumiliotoxin C 358 (Scheme 50) [89]. 

SAM, samandarines BTX, batrachotoxins HTX, histrionicotoxins PTX, pumiliotoxins aPTX, allopumiliotoxins hPTX, homopumiliotoxins DHQ, 2,5-disubstituted decahydroquinolines 3,5-P, 3,5-d [substituted pyrrolizidines 3,5-1 and 5,8-1, disubstituted indolizidines 1,4-Q, 1,4-disubstituted quinolizidines Epi, epibatidine Pseudophry, pseudophrynamines. With the exception of 3,5-P and 3,5-1, these alkaloids are not known to occur in arthropods (see text). Histrionicotoxins may occur in Minyobates and Mantella, but the evidence is not conclusive. 

Another class of these amphibian alkaloids, the pumiliotoxins, contain an alkylidene side chain on C-6 of the indolizidine ring (Table 2). Due to their myotonic and cardiotonic activity, and challenging structure, they also have been the object of synthetic interest. A review points out the state of the art at the beginning of the decade <1996CRV505>. 

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. 

The active principle of dart frog poisons is alkaloids. The study of the den-drobatid poisons led to the discovery of over 200 new alkaloids, including batrachotoxins Pig. 10.5), pumiliotoxins, histrionicotoxins, gephyrotoxins, and decahydroquinolines (Daly et al., 1994). The most common compounds have the basic structure of piperidine and include histrionotoxin. In Phyllobates, the synthesis of other alkaloids is suppressed in favor of batrachotoxins. These are... 

Frogs of the genus Dendrobates are ant specialists. Of the more than 20 structural classes of lipophilic alkaloids found in the frogs, six occur in myrmicine ants. However, many dendrobatid alkaloids such as the batrachotoxins, histri-onicotoxins, and pumiliotoxins, have not yet been found in insects and other leaf-litter prey such as beetles and millipedes (Daly et al., 2000). The snake Lio-phis epinephelus feeds on Dendrobates and may further bioaccumulate alkaloids. 

Iminium ion-vinylsilane cyclizations closely related to the one described here have been used to prepare indolizidine alkaloids of the pumiliotoxin A and elaeokanine families, indole alkaloids, amaryllidaceae alkaloids, and the antibiotic (+)-streptazolin. The ability of the silicon substituent to control the position, and in some cases stereochemistry, of the unsaturation in the product heterocycle was a key feature of each of these syntheses. 

The Beckmann rearrangement was used as a key step (41% yield, under standard conditions) for the synthesis of the natural alkaloid Pumiliotoxin C 359, which was originally isolated from the skin extracts of Dendrobates pumilio (a strikingly coloured Panamanian poison arrow frog) (equation 139). ( )-Pumiliotoxin C was also synthesized by a similar ring formation process by Mehta and Praveen. ... 

Moreover, it is known that toads belonging to the genus Melanophryniscus contain toxic alkaloids in their skin °°. From Melanophryniscus montevidensis, alkaloids of the pumiliotoxin (PTX) group and indolizidines were isolated. 

As mentioned in Section 10.1.2, Padwa and co-workers (40,41) employed the Pummerer reaction to generate and trap isomtinchnones. This group (190,191) has now adapted the intramolecular version of this tactic to the synthesis of several alkaloids of the pyridine, quinolizidine, and clavine classes. In each case, a 2-pyridone serves as the keystone intermediate. For example, Kuethe and Padwa (190) employed this Pummerer reaction of imidosulfoxides that contain tethered iz-bonds in a formal synthesis of the frog alkaloid ( )-pumiliotoxin C. They also used this methodology to synthesize the azafluorenone alkaloid onychine (295) (Scheme 10.42) (191). Generation of the thionium ion 291 under standard... 

As shown in Table I, this reaction sequence has wide generality and is readily applicable to the straightforward synthesis of various naturally occurring alkaloids such as coniine,9 pumiliotoxin C,11 1 and solenopsin A and B.11 Oxime sulfonates of either linear or cyclic structures may be used. Obviously, the regioselectivity of the reaction follows the general rule of... 

Extracts from skins of the neotropical frog Dendrobates tricolor from Ecuador have given the alkaloid 8-hydroxy-6-(2-methylhexylidene)azabicyclo[4.3.0]non-ane (4), the structure and absolute configuration of which have been determined by X-ray crystallography of the hydrochloride salt. This alkaloid is the first structurally defined member of the pumiliotoxin A class of dendrobatid alkaloids. Spectroscopic studies (m.s. and n.m.r.) have allowed the formulation of the... 

The alio series of the pumiliotoxin A class have an additional hydroxyl group that has been placed at C-7 on the indolizidine ring, without assignment of configuration. Three members of the alio series have been assigned the tentative structures (7), (8), and (9).3 Pumiliotoxins A and B are relatively toxic, and comparable in potency to strychnine. Pumiliotoxin B has a potent cardiotonic and myotonic activity.3 An enantioselective total synthesis of pumiliotoxin A alkaloids from L-proline has already been announced.4... 

Decahydroquinolines are another important class of alkaloids isolated from the skin of tropical frogs. Frogs of the family Dendrobates pumilio produce highly toxic alkaloids, the pumiliotoxins [58]. Pumiliotoxin C, one of the prominent members of this class of compounds, has a ds-annulated decahydroquinoline structure, whereas toxins of the related family of Dendrobates histrionicus have fraras-annulated decahydroquinoline structures [49]. These decahydroquinoline systems can be synthesized from the galactosylamine auxiliary 2 in a 12-step pathway(see Scheme 33) [59]. 

Decahydroquinoline Alkaloids.—Full details of an earlier briefly described synthesis of ( )-pumiliotoxin C have been published.28 Other total syntheses of the same compound have been documented, starting from trans-4-hexenal,29 and from ethyl tra s-buta-l,3-diene-l-carbamate.30 An enantioselective synthesis of natural (-)-pumiliotoxin-C hydrochloride (34) has also been described (Scheme 6),... 

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