Pederin synthesis

As shown in Scheme 11.72, direct lithiation of protected glucal 346 using tBuLi to form 347 has been proposed [258]. From the lithium anion 347 it was also possible to prepare the vinyl stannane 348, which can be isolated and retreated with nBuLi to give the lithio derivative 347 [259,260]. This anion has been condensed with aldehydes and esters. Lithiation of 2-phenyl-thioglycal was also effective [261]. A good example of the use of such a dihydropyran anion could be found in a pederin synthesis [262]. 

SCHEME 10 Synthesis of the nitrile component for the pederin synthesis. 

The successful completion of the pederin synthesis gave us the appropriate level of confidence to apply the method to the synthesis of psymberin (Scheme 13)." We were unable to effect a cyanation reaction of diol 25 under the conditions that were effective in the pederin synthesis, forcing us to activate the hydroxyl group prior to ionization. Concerns about the compatibility of an acetate group in the nitrile fragment from our original approach led us to... 

Pederin (104), the powerful cytotoxin of staphylinid beetles of the genus Paederus, has been the object of renewed interest due to the unexpected discovery of a series of closely related compounds in marine sponges that display antitumor activities. The latter, as well as pederin, were prepared by total synthesis and their biological activities were reported [219,220]. A recent review summarizing present knowledge on this family of compounds has been published [221]. 

Beside this dermatoxic activity pederin (147) has various biological activities (92). When administered in appropriate doses to partially hepatectomized rats, this compound stimulates development of hepatic tissues. The inhibitory effect at the cellular level has been found in chicken heart fibroblast cultures, and mice embryo, dog kidney, HeLa, and KB cell lines. In plants, root growth of Lupinus albus is inhibited and mitosis in Allium cepa blocked at the metaphasic stage. Also, pederin (147) inhibits protein synthesis and growth of yeast cells. In addition, the treatment of rat ascites sarcoma with purified extracts of P. fuscipes produces almost complete regression. 

Many approaches to the synthesis of pederin have been tried (473,474). Total synthesis of (-l-)-pederin (147) was finally accomplished by two research groups (475-477) on the basis of a method joining pedamide, the right-hand half of pederin, and a pederic acid derivative, the left-hand half. 

Pedamide 536 was converted by treatment with trimethyloxonium tetrafluoro-borate to methyl pedimidate (549) (475), which was connected by the reaction sequence shown in Scheme 69 to (-l-)-acetylpederic acid (550), prepared via a route similar to that to the racemic pederamide (536) from (—)-(2/ ,3/ )-2,3-butanediol. The ratio of the resulting (-l-)-pederin (147) to (+)-10-epipederin (551) was 1 3. This ratio can be inverted to 60 14 by a stereocontrolled synthesis (476) including connection of methyl pedimidate (549) and (+)-selenoacid (552)... 

The synthesis of (-t-)-benzoylselenopederic acid (569) (477) (Scheme 71), the left-hand half of pederin (147), began with (-f-)-3-keto imide 570, which was subjected to the recently developed syn-directing Zn(BH4)2 reduction (482) to give 5yn-a-methyl-3-hydroxy acid derivative 571. Imide 571, after protection of the hydroxyl group as the THP ether, was reduced with DIBAH, and the resulting aldehyde was treated with lithium enolate of tm-butyl acetate to give the p-... 

Zn(BH4)2 reduction and phenylselenation. The methyl ester of 582 was selectively hydrolyzed hy PrSLi treatment to yield (-t-)-selenoacid (569) (Scheme 71). The total synthesis of (+)-pederin (147) from (-t-)-536 and (+)-569 was accomplished in a manner similar to Matsumoto s. 

Pederin (735) is one of the most potent poisons known to man, with an LDso for rats of ca. 2 p.g per 100 g body weight. The pyran, which causes severe blistering of the skin, is part of the defence system of the beetle Paederus fuscipes. It inhibits chromosome division by first blocking protein synthesis and subsequently halting DNA synthesis. 

Narquizian R, Kocienski PJ. The pederin family of antitumor agents structures, synthesis and biological activity. In The Role of Natural Products in Drug Discovery, Vol. 32. Mulzer R, Bohlmann R, eds. 2000. Springer, Heidelberg, Germany, pp. 25-56. 

Applications of the same enolate alkylation procedure to furnish gem-dialkylated compounds have been used in the synthesis of onnamide A [118]. This type of gem-2-C-dimethyl group is also found in pederin and mycalamides A and B. As shown from the retrosynthetic analysis of some members of this class of compounds (Scheme 11.38), C-glycosidic structure 158 could be obtained from the a-glycoside 159. The latter could be prepared from the ketone 160 via gem-dialkylation of the corresponding enolate, as described for the synthesis of 8. 

Jarowicki, K, Kocienski, P, Marczak, S, Willson, T, A synthesis of (+) pederin, the metallated dihydropyran approach. Tetrahedron Lett., 31, 3433-3436, 1990. 

The total synthesis of pederin, a potent insect toxin was achieved by T. Takemura and co-workers. One of the key steps of the synthesis was an intramolecular samarium diiodide induced Reformatsky reaction to construct the lactone subunit of the molecule. The transformation was carried out in tetrahydrofuran at 0 °C without the use of additives or catalysts. 

Takemura, T., Nishii, Y., Takahashi, S., Kobayashi, J. i., Nakata, T. Total synthesis of pederin, a potent insect toxin the efficient synthesis of the right half, (+)-benzoylpedamide. Tetrahedron 2002, 58, 6359-6365. 

Amino nitriles are useful for conjugate addition Acyl anion equivalents of the ester d1 synthon - C02R Methods Based on Vinyl (Enol) Ethers and Enamines Lithium derivatives of cyclic vinyl ethers The synthesis of pederin and related anti-tumour agents Lithium derivatives ofallenyl ethers Oxidative Cleavage of Allenes... 

Previous synthetic studies that have employed ozonolysis as a means for cleaving oxabicydic substrates include Meinwald s studies toward pederin [138], Just s synthesis of showdowmycin [139], Masamune s synthesis of avenaciolide [140], and Ohno s asymmetric syntheses of (+)-showdowmycin, (-)-cordycepin C, and (-)-6-azapseudouridine [141 a]. 

The avmlability of these chiral 3-d>cafbonyl synthons has been put to good use by Evans and Di Mare in an asymmetric synthesis of premonensin (166) and by a Japanese group in the synthesis of (+)-pederin (167). 

N-(l-Alkoxyalkyl)-aniides or -carbamates (2 X = OR), most frequently used as stable precursors for A -acyliminium ions, are usually prepared by one of the following routes (equations 7-13). For five- or six-membered cyclic cases a simple acid-catalyzed solvolysis of the hydroxy compound provides the alk-oxy derivative (equation 7). A silicon-assisted approach involves the TMSOTf-catalyzed reaction of bis(trimethylsilyl)formamide with aldehydes (equation 8). /V-(l-Trimethylsilyloxyalkyl)formamides are thus formed in good yields, which on TMSOTf-catalyzed solvolysis lead to the /V-( 1-alkoxyalkyl)form-amides. A third method is based on the NaBH4 reduction of imidates (equation 9), and has proved useful for a total synthesis of the insect poison pederine. Addition of reactive acid derivatives to imines constitutes another method (equations 10 and 11). Acylation with acid chlorides followed by treatment with ethanol in the presence of base leads to N-(l-alkoxyalkyl)amides. A one-step protocol using diethyl dicarbonate provides the corresponding carbamates. 2... 

The trienamide onnamide A (43) is a metabolite isolated from the marine sponge Theonella sp. found in Okinawan waters [84]. It belongs to the pederin family like mycalamides and theopederins [85], and shows a potent antiviral activity against herpes simplex virus type-1, vesicular stomatitis virus, and coronavirus A-59. The complete determination of the structure was carried out during the total synthesis of onnamide A (43)... 

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