Pumiliotoxin syntheses

These reactions contain stereoselective and stereospecilic components. The starting materials 20 and 22 are chiral and racemic and the faces of the double bonds (in both cases) are diastereotopic. Epoxidation is stereospecilic since there is only one extra atom in the epoxide it must react with the two carbon atoms on the same side if the reaction is concerted. But, with allylic alcohols the reactions are also stereoselective since the OH will form a hydrogen bond with the peracid and hence deliver the oxygen syn to the alcohol. It could in principal react to give the anti product but it is not possible to make (as the major product anyway) the anti isomers 24 and 25 by this method. Another example of a reaction that has both stereoselective and stereospecilic components appears in the pumiliotoxin synthesis in Chapter 21. 

When the reaction was carried out by treating the aldehyde (-)-105 with ammonium chloride, the cycloaddition took place under quite mild conditions (75 °C in aqueous ethanol) with complete regiochemical control but gave a mixture of two diastereoisomers 108 and 109 in a 70 30 ratio but none of the right isomer for the pumiliotoxin synthesis.17 The major product 108 has three of the chiral centres correct but is epimeric with pumiliotoxin C 102 at C-8a. Grieco has used this reaction successfully for other alkaloids.18... 

The catalytic oxidative carbonylation of allene with PdCb and CuCh in MeOH affords methyl a-methoxymethacrylate (559)[499]. The intramolecular oxidative aminocarbonylation of the 6-aminoallene 560 affords the unsaturated J-amino ester 561. The reaction has been applied to the enantioselective synthesis of pumiliotoxin (562)[500]. A similar intramolecular oxycarbonyla-tion of 6-hydroxyallenes affords 2-(2-tetrahydrofuranyl)acrylates[501]. 

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

Within a total synthesis of the neurotoxin (-)-pumiliotoxin C [52], Minnaard, Fer-inga and coworkers used a domino Heck/Tsuji-Trost reaction of 6/1-93 and 6/1-94 to give the perhydroquinoline 6/1-95 in 26% yield after hydrogenation [53] (Scheme 6/1.24). 

Perhydropyrido[l,2-A][l,2]oxazines have been utilized as key intermediates in a stereospecific total syntheses of (—)-pumiliotoxin C and 5-< />z-pumiliotoxin C <1996J(P1)1113>, and the marine alkaloids (—)-lepadins A, B, and C and macrocyclic dilactones, (+)-azimine and (+)carpaine <20000L2955, 2001JOC3338, 2003OL3839>. In the total synthesis of the marine alkaloids ( )-fasicularin and ( )-lepadiformine, perhydro[l,2]oxazino[3,2 /]quinolines were used to control the stereochemistry <2000JA4583, 2000TL1205>. 

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

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>. 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

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

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... 

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 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... 

For alkenyl nitrile oxides having the alkene in a cyclic structure, such as compound 141, high diastereoselectivities can be obtained (Scheme 12.47). Compound 141 is formed in situ, and undergoes a spontaneous cyclization to furnish 142 as the sole diastereomer. Toyota et al. (239) used the tricyclic isoxazoline 143 in the synthesis of (+)-pumiliotoxin C. 

Thus, (2R)-pumiliotoxin C (214) has been prepared from (R)-norvaline (212). The asymmetric center in the triene (213) controls the configuration at three carbon atoms 210). a-Kainic acid, isolated from the algae Digena simplex and Centrocerus clavulatum, was prepared by total synthesis. Its enantioselective synthesis involved a stereocon trolled intramolecular cycloaddition of a (S)-glutamic acid211). Asymmetric cycloadditions also play a decisive role in the synthesis of chiral cytochalasins. In this case 212> the primary chiral information was carried by (S)-alanine and (S)-phenylalanine, respectively. 

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... 

A very recent synthesis of ( )-pumiliotoxin C employed the nitrone cyclization product (29), obtained in 74% overall yield from the nitrone precursors.12b Reduction of (29) with zinc-acetic acid provided a trisubstituted piperidine which was converted in several steps to ( )-pumiliotoxin C. 

This sequence was used for an efficient synthesis of rf/-pumiliotoxin C (2), a frog toxin, from 1. 

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

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... 

Meyers, A. I. Milot, G. a-Alkylation and stereochemistry of cis- and trans-decahydroqui-nolines mediated by the formamidine and Boc activating groups. Synthesis of pumiliotoxin C.J. Am. Chem. Soc. 1993, 335, 6652-6660. Elworthy, T. R. Meyers, A. I. The configurational stability of chiral lithio a-amino carbanions. The effect of Li-O vs Li-N complexa-tion. Tetrahedron 1994, 50, 6089-6096. 

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),... 

An interesting application of this protocol was utilized in the total synthesis of ( )-pumiliotoxin.82 Intramolecular acylation of the a-anion of vinyl sulfone 128 gave enaminone 129 which was readily converted to the desired alkaloid pumilio-toxin 130 (Scheme 35). 

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