Pumiliotoxin total synthesis

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]. 

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). 

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. 

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... 

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). 

Overman has shown that camphorsulfonic acid can also be used in nucleophile-promoted alkyne-iminium cyclizations. Alky-lamines can react with formaldehyde and sodium iodide to yield piperidines in good yield. This methodology has been applied in the total synthesis of pumiliotoxin A (eq 4). ... 

During the enantioselective total synthesis of denrobatid alkaloid (-)-pumiliotoxin C by C. Kibayashi et al., an aqueous acyinitroso Diels-Alder cycloaddition was used as the key step. In the endgame of the total synthesis, the c/s-fused decahydroquinolone was subjected to the Clemmensen reduction conditions to give a 2 1 epimeric mixture of deoxygenated products in 57% yield. Subsequent debenzylation converted the major isomer into 5-ep/-pumiliotoxin C. 

Naruse, M., Aoyagi, S., Kibayashi, C. Total synthesis of (-)-pumiliotoxin C by aqueous intramolecular acyinitroso Diels-Alder approach. Tetrahedron Lett. 1994, 35, 9213-9216. 

Overman, L.E., and Jessup. P.J.. Synthetic applications of V-acylamino-l,3-dienes. An efficient stereospecific total synthesis of (//-pumiliotoxin C. and a general entry to cw-decahydroquinoline alkaloids, J. Am. Chem. Soc.. 100. 5179. 1978. 

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... 

Decahydroqninoline Alkaloids.—Full details of two earlier briefly reported total syntheses of ( )-pumiliotoxin-C have been disclosed. A third total synthesis... 

Diels-Alder reaction This diene reacts with ethyl crotonate to give a single adduct (2), which was converted as shown into the keto lactam (5). The lactam (5) was also synthesized by an initial Diels-Alder reaction of the related cyclic diene (6). This work was carried out in connection with a total synthesis of a ncurotoxin, pumiliotoxin (8), isolated from neotropical frogs. 

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],... 

As part of the total synthesis of the neurotoxin (-(-pumiliotoxin C [69], Minnaard and coworkers [70] used a domino Mizoroki-Heck/Tsuji-Trost reaction as the key step to prepare the perhydroquinoline 124 in 26% yield from 122 and 123 after hydrogenation (Scheme 8.31). Similarly, acyclic tosyl amides with vinyl bromides have been used to give the corresponding lactams in 49-82% yield [71]. 

Homopumiliotoxin and Pumiliotoxin were totally synthesized in the late twentieth century by Kibayashi s goup [73-75]. Intramolecular alkoxycarbonylation for the formation of lactone frames were taken as a fundamental step (Scheme 10.12). Negishi and Liao reported a palladium-catalyzed carbonylative lactonization of (Z)-cr-iodoalkenols and applied that in the total synthesis of (h-)-hamabiwalactone B [76]. 

Murahashi SI, Sasao S, Saito E, Naota T (1993) Ruthenium-catalyzed hydration of nitriles and transformation of 8-keto nitriles to ene-lactams Total synthesis of (—)-pumiliotoxin C. Tetrahedron 49 8805... 

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. 

Overman, L. E. Jessup. P. J. "Synthetic Applications of A/-Acylamino-1,3-dienes. An Efficient Stereospecific Total Synthesis of c/Z-Pumiliotoxin C, and a General Entry to c/s-Decahydroquinoline Alkaloids" J. Am. Chem. Soc. 1978, 100, 5M9. 

Ibuka, T. Inubushi, T. S i, I. Tanaka, K. Masaki, N. "Total Synthesis of c//-Pumiliotoxin C Hydrochloride and its Crystal Structure" Tatrahadron Latt. 1975, 323-326. See also Inubushi, Y. Ibuka, T. "Synthesis of Pumiliotoxin C, AToxb Alkaloid from Central Amerban Arrow Poison Fnog, Dentrobates Pumlllo and D. Auratus" Heterocyclas 1977, 8, 633-660 (this is a brief review). 

Bonin, M. Royer, J. Grierson, D. S. Husson, H.-P. "Asymmetric Synthesis VIII Biogenetically Patterned Approach to the Chiral Total Synthesis of (-)-Pumiliotoxin-C" Tetrahedron Lett. 1986, 27, 1569-1572. For a review discussing this "general approach" to alkaloids see Husson, H.-P. "A New Approach to the Asymmetric Synthesis of Alkaloids" J. A/af. Prod. 1985, 6, 894-906. 

An interesting way of enolate trapping has been realized by Feringa and coworkers under the form of a palladium-catalyzed allylic alkylation [210]. By applying this consecutive reaction to cyclohexenone, the alkene 427 was accessible in 96% enantiomeric excess in the trans-diastereomer that formed predominantly [211]. The product was carried on in a total synthesis of the potent neurotoxin (-)-pumiliotoxin C (Scheme 5.109) [210c]. 

The pumiliotoxins are a group of more than 60 alkaloids isolated from the toxic skin secretions of the frog Dendrobates pumilis and related species. Many of the alkaloids have, as a central feature, the unusual c/s-decahydroquinoline structure, and since they possess interesting neurological activities they are an attractive target for total synthesis. A new total synthesis of rf,/-pumiliotoxin C has been reported. The main feature of the new synthesis is the Diels-Alder reaction of an activated N-acylaminodiene and a crotonaldehyde derivative leading to an intermediate with two chiral centres which can be utilized to control the introduction of the third chiral centre (Scheme 67). The method, which is short and efficient, should be useful in the synthesis of other cis-decahydroquinoline alkaloids. The overall yield of c/,/-pumiliotoxin C was 51%. 

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