Pumiliotoxin hydrochloride

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). 

Extracts from skins of the neotropical frog Dendrobates tricolor from Ecuador have given the alkaloid 8-hydroxy-6-(2-methylhexylidene)azabicyclo[4.3.0]non-ane (4), the structure and absolute configuration of which have been determined by X-ray crystallography of the hydrochloride salt. This alkaloid is the first structurally defined member of the pumiliotoxin A class of dendrobatid alkaloids. Spectroscopic studies (m.s. and n.m.r.) have allowed the formulation of the... 

The decahydroquinoline has been released from the carbohydrate auxiliary by acid-catalyzed hydrolysis. After introduction of the A-benzyloxycarbonyl (Z) group, the above-mentioned two-step reduction of the carbonyl group and the subsequent hydrogenolytic removal of the Z-group furnished enantiomerically pure 4a-epi pumiliotoxin C hydrochloride 57. 

Decahydroquinoline Alkaloids.—Full details of an earlier briefly described synthesis of ( )-pumiliotoxin C have been published.28 Other total syntheses of the same compound have been documented, starting from trans-4-hexenal,29 and from ethyl tra s-buta-l,3-diene-l-carbamate.30 An enantioselective synthesis of natural (-)-pumiliotoxin-C hydrochloride (34) has also been described (Scheme 6),... 

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]. 

Decahydroquinoline Alkaloids.—The structure of pumiliotoxin-C (26) has been confirmed by an X-ray diffraction analysis of its hydrochloride/ and by two total syntheses of the racemic base/ The syntheses are outlined in Schemes 5 and 6/ ... 

Explain the formation of the product pumiliotoxin C (as its hydrochloride salt) in the following reaction. 

C13H26CIN, Pumiliotoxin C hydrochloride, 43B, 746 C14H8N2O2 H2O, Amarorine monohydrate, 46B 575 C14H18INO2, Phyllochrysine methiodide, 31B, 240 C14H18N2O6, Pukeleimide C, 45B, 627... 

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). 

Fig. 6. Structure of pumiliotoxin C. Configuration depicted at the right is based on x-ray analysis of the hydrochloride salt 87)...

Fig. 7. Proton magnetic resonance spectral assignments for pumiliotoxin C hydrochloride. Chemical shifts in ppm for deuterochloroform with coupling constants in parentheses (data from 87, 143, 200, 209). Chemical shifts for the free base are 2-H, 2.64 8a-H, 2.95. The spectrum of the HCl salt (100 MHz) is given by Daly etal. (57)...

Fig. 8. Carbon-13 magnetic resonance spectral assignments for pumiliotoxin C, hydrochloride Chemical shifts are in ppm for deuterochloroform (data from 209 similar data reported...

A synthesis of optically active pumiliotoxin 251D, identical in physical and spectral properties with the natural compound has been realized using L-proline as starting material (Scheme L) 206). The overall yield was about 20%. One important comparison has not been carried out, namely optical rotation, due to the present lack of sufficient quantities of the natural compound. The hydrochloride of synthetic pumiliotoxin 251D was dextrorotatory, while the free base appeared to be weakly levorotatory (Table 20). The chiral precursor for the side chain of pumiliotoxin 251D was prepared in an overall yield of about 80% (reactions H, 1). 

Flippen, j. L. 2-n-Propyl-7-methyl-/r i 5-decahydroquinoline hydrochloride, a synthetic isomer of pumiliotoxin C. Acta Crystallogr. B30, 2906—2907 (1974). 

Ibuka, T., Y. Inubushi, I. Saji, K. Tanaka, and N. Masaki Total synthesis of dl-pumiliotoxin C hydrochloride and its crystal structure. Tetrahedron Letters 1975,323— 326. 

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