Dendrobatide synthesis

A stereoselective total synthesis of dendrobatide toxin 251 D was developed by Overman et al.237) involving an epoxidation of the (S)-proline derivative (237) to furnish the oxirane (238) as major product. In their approach towards the total synthesis of the same natural product Thomas et al.238) investigated the stereoselectivity of the epoxide formation from (S)-5-acetylpyrrolidin-2-one and dimethyloxosulfonium methylide. A diastereoselectivity of d.s. 50-60% was achieved 238. ... 

First Enantioselective Synthesis of Dendrobatid Alkaloids Indolizidine 2091 and 223J 53... 

The Dendrobatid poison arrow frogs of Central and South America exude a potent mixture of alkaloids from their skins. It was originally thought that the frogs biosynthesized these alkaloids, but it has since been shown that they are of dietary origin. The skin exudate of the Colombian frog Minyobates bombetes causes severe locomotor difficulties, muscle spasms and convulsions upon injection in mice. The major component of the alkaloid mixture is 251F3. Jeff Aube of the University of Kansas recently described (J. Am. Chem. Soc. 2004,126,5475) the enantioselective total synthesis of 3. The key step in the synthesis was the cyclization of the keto azide 2. 

Deacetoxyalcyonin acetate synthesis 76 Dendrobatid alkaloid 25 IF synthesis 112, 168... 

Dendrobatid toxins. The first step in a synthesis of ( )-perhydrogephyrotoxin (S, a poison-frog alkaloid) involves a Diels-Alder reaction of 1 and a suitable a.ft-unsulurated aldehyde, which proceeds selectively to give the erafo-adduct 2. Another key step is the selective reduction of a bicyclic imine (3) with LiAlH4 in about 9 1 ratio from the sterically more hindered a-face.2... 

The dendrobatid alkaloid 251F 213 (Figure 12.4) was isolated from the skin exudates of a Columbian dendrobatid poison frog, Minyobates bombetes [105]. The asymmetric total synthesis of this molecule has been reported by Aube and co-workers [106], The synthesis featured a Noyori-type three-component reaction to access an advanced bicyclopentenone intermediate, and also included a tandem ROM/RCM reaction sequence and a Schmidt rearrangement as key steps. 

An S 2 copper-catalyzed nucleophilic substitution of the chloride in a cyclic chloroacetate by butylmagnesium bromide was employed in a synthesis toward perhydrohistrionicotoxin [Eq.(47)] [79]. Histrionicotoxins are found in South American dart-poison frogs of the Dendrobatid family. Palladium-catalyzed chloroacetoxylation of 2-substituted diene 68 gave a highly regio- and stereoselective 1,4-addition product where the chloride ends up in the 1-position. Copper-catalyzed reaction of the chloroacetate 69 with butylmagnesium... 

A stereodivergent synthesis was developed by H. Nemoto and co-workers for the preparation of c/s-fused 2,5-disubstituted octahydroquinolines, which constitute the core structure of certain dendrobatid aikaioids. The instaiiation of the C5 methyi group was achieved by 1,4-cuprate addition and the resuiting enoiate was trapped with TMSCi. The siiyi enoi ether was then oxidized to the enone with Pd(OAc)2. 

Toyooka, N., Okumura, M., Nemoto, H. Stereodivergent process for the synthesis of the decahydroquinoiine type of dendrobatid aikaioids. J. Org. Chem. 2002, 67, 6078-6081. 

Wrobleski, A., Sahasrabudhe, K., Aube, J. Asymmetric Total Synthesis of Dendrobatid Alkaloid 251F. J. Am. Chem. Soc. 2002,124, 9974-9975. 

The power of Rh-mediated intramolecular C-H insertion can be seen in the cycli-zation of the a-diazo ester 1 (Scheme 1). Although four diastereomers could have been formed from this cyclization, only 2, the key intermediate for the synthesis of the dendrobatid alkaloid 251F 3, was in fact observed. This outcome, as explained in detail shortly, had first been predicted computationally. This chapter summarizes our computational approach toward understanding the transition state ( point of commitment ) for these Rh-mediated cyclizations. As we discuss at the end of this chapter, there is yet much left to be learned. 

Studies by Hart and Tsai have demonstrated that indolizidine 70 is stereoisomeric from the Dendrobatid alkaloid gephyrotoxin-223AB Hart, D.J. and Tsai, Y.-M. (1982) Stereoselective indolizidine synthesis preparation of stereoisomers of gephyrotoxin-223AB. J. Org. Chem., 41, 4403-9. 

An asymmetric total synthesis of the alkaloid dendroba-tid 251 F 192 using a Noyori-type three-component reaction was described by Aube and coworkers (Scheme 6.26) [55]. 1,4-Cuprate addition to enone 189 is achieved from the exo-face, and subsequent aldol condensation results in the formation of only one diastereoisomer 191 in 65% yield. Dendrobatid 251 F 192 is achieved in only six further steps. 

SCHEME 6.26 Noyori-type three-component reaction in the total synthesis of dendrobatid 251 F 192. 

An elegant application of vinylsilane chemistry reported this year is the clean and stereospecific iminium ion-vinylsilane cyclization to dendrobatid toxin 25 ID shown in Scheme and a spiroannulation synthesis has been described in which the final stage is Lewis-acid-catalysed cyclization of (111) to (112)/ °... 

An iminium ion-vinylsilane cyclization (Scheme 6) provides the basis for a very short synthesis of dendrobatid toxin 25 ID (85) as reported by Overman and Bell. A related iminium ion cyclization [(86) (87)] is a key step in a... 

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. 

Fora review of 7 recent approaches to pumiliotoxih-C [Habermehl (1998), Bach (1998), Comins (1993), Kunz (1999), Mori (2001), Stille (1993), Padwa (20(X))] see Sklenicka, H. M. Hsung, R. P. "Receht Approaches to c/s-Azadecalins Synthesis of Dendrobatid Alkaloid Pumiliotoxin C" Chemtracts-Organic Chemistry 2002, 15, 391-401. 

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