Dendrobatid alkaloids synthesis

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

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

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. 

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. 

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. 

Wrohleski A, Sahasrabudhe K, Aube J. Asymmetric total synthesis of dendrobatid alkaloids preparation of indolizi-dine 25 IF and its 3-desmethyl analogue using an intramolecular Schmidt reaction strategy. J. Am. Chem. Soc. 2004 126(17) 5475-5481. 

The present review summarizes current knowledge of the properties, occurrence, synthesis and biological activity of the dendrobatid alkaloids. 

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. 

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... 

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. 

In the last decade, aza-Diels Alder reactions were used effectively to synthesize chiral six-member cyclic systems. Maloney and Danheiser reported on a strategy for the total synthesis of quinolizidine alkaloid (—)-217A 285 where aza-Diels-Alder reaction was used as the key step to induce the chirality in the molecule. The sulfonamide 282 prepared from 5-hexenol 281 by multistep procedures was converted into the aza-Diels Alder precursor 283. It underwent an intramolecular hetero Diels-Alder reaction at 130°C to afford cyclic a-amino nitrile 284 with 56-59% yield. From 284 quinolizidine (—)-217A 285 was prepared following simple steps (Scheme 40.63). This alkaloid is present in the skin of small dendrobatid frog, Dendrobates pumilio ... 

Overman, L. E., and K. L. Bell Enantiospecific total synthesis of dendrobatid toxin 25ID. A short chiral entry to the cardiac-active pumiliotoxin A alkaloids via stereospecific iminium ion — vinylsilane cyclizations. J. Amer. Chem. Soc. 103, 1851— 1852 (1981). 

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