Natural pumiliotoxin

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),... 

Oppolzer, W. FrostI, W. Weber, H. P. "The Total Synthesis of d/-Pumiliotoxin-C" Helv. Chim. Acta 1975, 58, 593. Oppolzer, W. Flaskamp, E. "An Enantioselective Synthesis and the Absolute Configuration of Natural Pumiliotoxin-C" Helv. CNm. Acta 1977, 60, 204. Oppolzer, W. Flaskamp. E. Bieber. L. W. "Efficient Asymmetric Synthesis of Pumilbtoxin C via Intramolecluar [4+2] Cycloaddition" Helv. Chim. Acta 2001, 84,141-145. Eor a related approach to pumiliotoxin-C and other Dendrobatid alkaloids see Banner, E. J. Stevens, E. D. Trudell, M. L. Tetrahedron Lett. 2004,45,4411-4414. 

Further properties of pumiliotoxin C are documented in Figs. 7 and 8 and Table 6. These include nuclear magnetic resonance spectral assignments and optical rotations. Natural pumiliotoxin C is the /-enantiomer. 

Structure-activity correlations for pumiliotoxin-A class alkaloids have not been delineated because of the limited supplies available from nature. Pumiliotoxin B is more active in potentiating frog muscle contraction than is pumiliotoxin A, which in turn is much more active than pumiliotoxin 251D (cited in 24). Thus, hydroxyl groups in the side chain appear important to at least one biological activity of this class of alkaloids. 

Oppolzer, W., and E. Flaskamp An enantioselective synthesis and the absolute configuration of natural pumiliotoxin-C. Helv. Chim. Acta 60, 204—201 (1977). 

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. 

An enantioselective synthesis of the natural venom pumiliotoxin C 98 and its unnatural enantiomer was achieved from (/ )-norvaline in a multistep... 

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. ... 

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... 

The first enantioselective Brpnsted acid catalyzed cascade reduction of pyridines provides the corresponding products in good yields and with excellent enantioselectivities (up to 92% ee). The hexahydroquino-linones and tetrahydropyridines isolated are not only known starting products for various natural products such as pumiliotoxin C but also for numerous interesting biologically active compounds. As previously only metal catalyzed hydrogenations of pyridines have been described, and these did not result in the valuable products described herein and gave lower enantioselectivities, our newly developed metal-free Brpn-sted acid catalyzed procedure represents an important contribution to the enantioselective reduction of pyridines. 

The effects of pumiliotoxin B on sodium channels appear to be due to interaction with a subdomain of the site at which batrachotoxin acts scorpion toxins and brevetoxin can potentiate the effects of pumiliotoxin B and of congeneric pumiliotoxins and allopumiliotoxins (102,112). Certain pumiliotoxin congeners appear to block sodium channel activation and may act as antagonists or reverse agonists (106). Structure-activity relationships with respect to stimulation of sodium flux and phosphoinositide breakdown have been studied (106). The nature of the side chain is critical to activity. For example, whereas pumiliotoxin B is one of the most potent of these alkaloids, its 15,16-erythro isomer has much lower activity (106,112). 

General Considerations. In addition to its use in peptide chemistry, (S)-proline is often applied as a chiral precursor in the total syntheses of natural products, e.g. odorin, pumiliotoxin, petasinecine," or threonine. Some highly effective pharmaceuticals, such as optically pure ACE inhibitors, are prepared from L-proline. In the last two decades, (S)-proline has attracted much attention as an optically active auxiliary in asymmetric synthesis. 

Thus optically pure shikimic acid (347) has been synthesized via the addition of 1,4-diacetoxybuta-diene (345) to (340a), whereas the Diels-Alder reaction of )V-dienylcarbamate (348) to hydroxy enone (340b) served as the key step for a synthesis of the enantiomer (350) of naturally occurring pumiliotoxin C (142) (c/. Scheme 35). 

Treatment of a wide variety of oxime sulfonates with several equivalents of alkyl-aluminum reagents in CH2CI2 resulted in formation of the imines, which were directly reduced with excess DIBAH to give the corresponding amines, as shown in Sch. 19. This organoaluminum-promoted Beckmann Rearrangement of oxime sulfonates has been successfully applied to the stereoselective synthesis of naturally occurring alkaloids, pumiliotoxin C, and solenopsin A and B, as illustrated in Sch. 20 [43]. 

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. 

Finally the benzyl group was removed, the primary alcohol oxidised to the aldehyde, and an ii-selective Wittig reaction performed with the enantiomerically pure stabilised ylid 137. No racemisation of either partner occurred and the product was almost pure E at the new alkene. Stereoselective reduction gave (+)-pumiliotoxin B 129 identical to the natural product in all respects, including biological effects. 

Mannich-type cyclizations of vinylsilanes have found considerable application in the area of alkaloid total synthesis. Cyclizations that occur in the exocyclic mode with respect to the vinylsilane nucleophile have been widely employed to assemble 3-alkylidenepiperidine substructures with high stereocontrol. Overman and coworkers have made extensive use of the acid-promoted conversion of bicyclic oxazolidines to alkylideneindolizidines in their total syntheses of pumiliotoxin A alkaloids (Scheme 36). - " - An illustration of the mild nature of iminium ion-vinylsilane cyclizations is provided in the conversion of (101) to (102), the penultimate precursor of (-i-)-pumiliotoxin A. This conversion was accomplished in 71% yield by heating (101) at 80 C in a methanolic pyridine-pyridinium tosylate buffer (pH 4.5). More strongly acidic conditions had to be avoided since they led to competitive solvolysis of the allylic benzyl ether functionality of the pumiliotoxin A side chain. To the limits of detection by high... 

The efficiently chelated (zinc chloride, boron trifluoride diethyl ether complex), rigid five-mem-bered-ring dienophiles la and lb have been used in the enantioselective syntheses of several natural products. Thus, the reaction of (S)-l with 1,3-butadiene (5), promoted by zinc chloride (1 equiv) produces the cycloadduct ( + )-6 (83% d.r. 99 1), later converted to a precursor of (S)-sarkomycin (7). Cycloaddition of (S)-la with l,4-diacetoxy-l,3-butadicnc (8), catalyzed by boron trifluoride-diethyl ether complex (0.5 equiv) gives (-)-9 (72%) as a single diastercomer, further converted into (-)-shikimic acid (10) in a six-step procedure. Similarly, addition of (/ )-lb to 1,3-butadiene carbamate 11 in the presence of boron trifluoride-diethyl ether complex (1 equiv) produces ( + )-12 (95% d.r. 99 1), which was converted into ( + )-pumiliotoxin. 

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