Pumiliotoxin racemic synthesis

A third application of the Eschenmoser reaction in the synthesis of racemic perhydrogephyrotoxin (76) is based on an extension of the chemistry developed during the pumiliotoxin C synthesis. - Beginning with the bicyclic thiolactam (73), the sulfide-contraction reaction was used to append to the decahydro-isoquinoline a functionalized five-carbon side chain that would later be cyclized and become the a-hy-droxyethylpyrrolidine portion of the molecule. Alkylation of the thiolactam (73) with methyl 5-bromolevulinate followed by treatment with the Eschenmoser dual base-thiophile reagent (28) produced the vinylogous carbamate (74) in 81% yield from the starting thiolactam (73 Scheme 17). Reduction of the vinylogous amide (74), followed by equilibration of the amino ketones in the presence of... 

Decahydroquinoline Alkaloids.—Full details of a synthesis of ( )-pumiliotoxin-C hydrochloride and of its X-ray diffraction analysis, described briefly earlier,have been published. Two new syntheses of the racemic free base (31) have been described the first is outlined in Scheme 7. The final hydrogenation afforded the desired base (31) as major product, a consequence of a high order of stereoselectivity in this step. The second approach (Schemes 8 and 9) uses 1,3-bistrimethylsilyloxy-1,3-dienes as intermediates. In both of the latter pathways the final product is the lactam (32), the conversion of which to ( )-pumiliotoxin-C has already been documented. ... 

Another intramolecular version of the aza-Diels-Alder reaction was realized with the condensation of a dienyl aldehyde and benzylamine hydrochloride at 70 °C in 50% aqueous ethanol (Scheme 10) [59]. This methodology was used in the synthesis of racemic dihydrocannivonine [60] and substituted octahydro-quinolines related to pumiliotoxin C [61]. 

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. 

In his synthesis of the Dentrobatid alkaloid pumiliotoxin 25 ID 9, Timothy F. Jamison took (J. Org. Chem. 2007, 72, 7451) as his starting material another amino acid, prohne. Ni-mediated cyclization of the epoxide 8 proceeded with high geometric and regiocontrol, to give 9. The chemistry to convert 7 into 8 with high diastereocontrol and without racem-ization is a substantial contribution that wiU have many other applications. 

Synthesis of pumiliotoxin C has been accomplished by a number of routes. These are summarized in the Schemes XI— XVII. Most of the synthetic routes provided racemic pumiliotoxin C in overall yields of only 1—20%. A short and convenient route (Scheme XVII) has provided racemic pumiliotoxin C in an overall yield of about 50% 208, 209). Both enantiomers of pumiliotoxin C have been synthesized using either R-norvaline and S-norvaline as starting materials The latter afforded the levo-rotatory (2S)-pumiliotoxin C identical to the natural compound (Scheme XII) 200). An earlier publication erred in reporting that levo-rotatory pumiliotoxin C could be synthesized from l-(2-bromoethyl-lR)-butylamine (Scheme XIII) 122). In actuality the l-(2-bromoethyl-lS)-butylamine had been used and led to levo-rotatory (2S)-pumiliotoxin C. X-ray crystallographic analyses of synthetic pumiliotoxin hydrochloride have been reported 122, 203). The early syntheses of pumiliotoxin C have been reviewed 147). Earlier literature relevant to synthesis of decahydroquino-lines and to synthesis of octahydroquinolines has been cited by Oppolzer and Frostl (201). Syntheses of cw-decahydroquinolines with substituents at the 2- and 5-position other than n-propyl and methyl have been reported (Schemes XVII, XVIII). Certain of these were obtained during development of routes to perhydrogephyrotoxin (vide infra). 

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