Bicyclic Alkaloids

Most amphibian alkaloids are not as complex in structure as the steroidal batrachotoxins and samandarines. Of the 300 known amphibian alkaloids, most have been characterized from the skin extracts of frogs of the family Dendrobatidae and, hence, have been referred to as dendrobatid alkaloids. The major bicyclic classes of dendrobatid alkaloids are the histrionicotox-ins, decahydroquinolines, and pumiliotoxin-A class. Because of the presence of a piperidine ring in most dendrobatid alkaloids, they also have been referred to as piperidine-based alkaloids. 

The structures of histrionicotoxin (283A) and dihydroisohistrionicotoxin (285A) were determined by X-ray crystallography 54) to be as shown in III and rv. Structures of most of the other histrionicotoxins have been 

The properties of the natural histrionicotoxins are presented below in a format introduced in 1978 60) for the dendrobatid alkaloids. The entries are as follows (1) the code designation based on molecular weight and identifying letter(s) in boldface (2) the trivial name, if any (3) an empirical formula based on high-resolution mass spectrometry (tentative formulas 

Other physical and spectral properties of the histrionicotoxins are presented in Table III. Proton and carbon-13 magnetic resonance assignments have been presented (57-59) and reviewed (5). For proton spectra, see Refs. 3,57-59 for carbon-13 assignments, see Ref. 55. The diagnostic infrared peaks for various histrionicotoxins in solution have been tabulated 

3 as determined by titration. Butylboronic acid derivatives of histrionicotoxins can be easily prepared and provide several advantages for gas chromatographic-mass spectral and FTIR analysis (55). 

The tosylate of epilupinine (XIV) is thermally stable, whereas that of lupinine (XVIII) is quarternized, the structure of the resulting salt (XIX) 

A synthesis of epilupinine under physiological conditions was accomplished as follows (42). Ethyl A-benzyliminodivalerate (XXII) yields an acyloin (XXIII) which was reduced with lithium aluminum hydride to the diol XXIV, the benzyl group of which was removed by hydro-genolysis. Subsequent oxidation with periodic acid at 25°, pH 5, gave an intermediate dialdehyde which cyclized to lupinaldehyde (XXV). This unstable aldehyde on reduction with lithium aluminum hydride gives only the more stable epilupinine (XIV). 

A mixture of lupinine and epilupinine is obtainable by the following series of reactions. The betaine XXVI on cyclic hydrogenation and subsequent decarboxylation with 20 % hydrochloric acid gives a mixture of epimeric lupininic acids (XXIX). The dicarboxylic ester XXVIII is also obtained by the mercuric acetate dehydrogenation of the piperidine derivative XXX and by the alkylation of monomeric piperideine with a y-bromopropylmalonic ester. The last route is presumably a first Mannich condensation followed by an alkylation. Hydrolysis of the malonic esters, decarboxylation (XXIV), esterification, and reduction with lithium aluminum hydride complete the synthesis of a mixture which consists of 80% dZ-epilupinine and 20% dMupinine. Thermal 

A simple synthesis of the lupininic acids has been reported as follows 43) ethyl a-pyridylacetate and an acrylic ester or acrylic nitrile undergo a simple Michael addition and hydrogenation of the product generates an epimeric mixture (7 3 or 1 4, respectively) of epilupininic and lupininic acids. 

The reduction of d. S-imonium salts (XXXII) of substituted quinolizidines with sodium borohydride is influenced by substituents at position 3 44). The stereochemical course of the reaction is dependent upon the more stable conformation of the imonium salt. Quasiaxial hydrogen in position 3 hinders the approach of the reducing agent on that side and there result the energetically less stable quinolizidines XXXIII. 

---

Bicyclic alkaloids. Nagao et al. have developed a general synthesis of chiral bicyclic alkaloids with a nitrogen atom at the ring juncture, such as pyrrolizidines [5.5], quinolizidines [6.6], and indolizidines [6.5], based on a highly diastereose-lective alkylation of 3-a>-chloroacyl-(4S)-isopropyl-l,3-thiazolidine-2-thiones (1, m = 1,2) with 5-acetoxy-2-pyrrolidinone (2, n = 1) or 6-acetoxy-2-piperidinone (2, n = 2). Thus the tin enolate of 1 (m = 1), prepared with Sn(OTf) and N-... 

In addition, deoxoprosphylline [36], pipecolic acids, izidines [37], and the bicyclic alkaloids ( )-isoretronecanol, ( )-trachelanthamidine [38] and 6-epi-poranthellidine [39] were synthesized via tandem hydroformyla-... 

The antibacterial and cytotoxic bicyclic alkaloid phloeodictine B (473) was isolated from a New Caledonian species of Phloeodictyon and is unusual as it contains a cyclic aminoketal functionality. The structure was proposed on the basis of spectral data [398], A Phloeodictyon sp. from New Caledonia contained the cytotoxic and antibiotic alkaloids, phloeodictines Ci (474) and C2 (475). Their structures were elucidated by mass spectrometry and NMR spectroscopy [399]. 

The amphibian alkaloids considered to be 3,5-disubstituted indolizidines are tabulated below. Two other bicyclic alkaloids, proposed as monosub-stituted indolizidines in an earlier review, are included. These are 167B, which was considered likely to be a 5-n-propylindolizidine, based on its mass spectrum and biosynthetic considerations, and 209D, which was considered likely to be a 5-n-hexylindolizidine. These two indolizidines have been synthesized (130,131), but efforts to compare the synthetic indolizidines to natural 167B and 209D were thwarted when the natural trace alkaloids could no longer be detected in extracts. Structures of relatively well-characterized 3,5-disubstituted indolizidines from amphibians are shown in Fig. 11. 

The monocyclic 2,6-disubstituted piperidines have been considered as possible precursors for dendrobatid alkaloids containing piperidine rings, such as the histrionicotoxins, decahydroquinolines, and gephyrotoxins (see Ref. J). Similarly, the monocyclic 2,5-disubstituted pyrrolidines have been considered as possible precursors for dendrobatid alkaloids containing pyrrolidine rings, such as the pumiliotoxins, the indolizidines, and now the pyrrolizidines (see Ref. 5). It should be noted that 2,6-disubstituted piperidines and 2,5-disubstituted pyrrolidines occur only rarely in dendrobatid frogs, while in ants they appear as major venom constituents, along with pyrrolizidines and indolizidines. It has been proposed that the monocyclic piperidines and pyrrolidines may serve as biosynthetic precursors of the bicyclic alkaloids in ants 125,134). 

Amino-i3-carbolines, 136 2-Amino-6-hydroxymethyl-8-hydroxyquinazoline, 264-265 Amphibian alkaloids, 185-281, see also Bicyclic alkaloids analytical protocol, 280-281 flame ionization—gas chromatograms. 278-280... 

Batrachotoxins, 187-194 biological activity. 189, 191 occurrence, 192-194 structures, 187-190 Benzylisoquinolines, 142-144 biosynthesis, 153 Berbines, acetaldehyde, 153, 155 Betaine, fluorescent, 135 Bicyclic alkaloids, 199 decahydroquinolines, 206-212 histrionicotoxins, 200-206... 

A new convenient procedure for the chiral alkylation of 5-acetoxy-2-pyrrolidinone (91) and 6-acetoxy-2-piperidinone (92) has been developed. This procedure should be useful for an extremely short chiral synthesis of the bicyclic alkaloids involving pyrrolizidine, indolizidine, and quinolizidine skeletons (88JA289). 

There have been numerous papers related to the total synthesis of bicyclic alkaloids, such as pyrrolizidines, indolizidines, and quinolizidines, because of their interesting biological activities (e.g., anticancer activity). 

We reported a new general method for an extremely short chiral synthesis of the bicyclic alkaloids having a nitrogen atom ring juncture utilizing a highly diastereoselective alkylation to the cyclic acylimines, followed by reductive annulation of the resultant cyclic imines (88JA289). 

Thus, a one-pot and one-reagent (LiAlH4) synthesis of the chiral bicyclic alkaloids 100 from 93 was designed. cu-Halolactams 93a-d were treated with LiAlH4 (4 mol equiv) in THF first at 0°C for 5 min to reduce the active amide moiety without epimerization at the asymmetric methine carbon and then at reflux for 2 hr to achieve reductive cyclization. After the usual treatment of the reaction medium, the desired bicyclic products lOOa-d (41-69% yield) were obtained directly together with the corresponding hydrogenated byproducts lOla-d (Scheme 18 and Table IV). Cyclization products lOOa-d... 

Not included in the Table are the results of a colossal GC-MS chemotaxonomic survey of the alkaloidal profiles of 56 Lupinus species (embracing 90 subspecies and chemotypes) representing both Old World and New World taxa 337). Of interest in this survey is the finding that bicyclic alkaloids of the lupinine class occurred mainly in Old World species. Genetic evidence has also been obtained for a close relationship between (and probably a common ancestry for) lupines that produce the lupinine complex of metabolites 33S). 

By far the most popular asymmetric deprotonation uses sparteine as a ligand for lithium.28 Sparteine 154 is a bicyclic alkaloid from lupins and gorse and has two nitrogen atoms that can, in one favourable conformation 154a, chelate a lithium atom. In spite of appearances, it is not (quite) C2-symmetric and only one enantiomer is available. 

B. Bicyclic Alkaloids.—Full details of the syntheses of lupinine and epilupinine, first reportedin 1960, have now been published this paper also includes the synthesis of sparteine. 

A Occurrence, and Isolation of New Alkaloids B Bicyclic Alkaloids C Tricyclic and Tetracyclic Alkaloids... 

DAB, DNJ, and DMJ. However, the pyrrolidine and piperidine alkaloids in species co-occur with a number of polyhydroxypyrrolizidines none of these bicyclic alkaloids were isolated from A. triphylla. 

Direct reaction of 191 with acrylic acid resulted in efficient formation of 192 (eq. 41).66 Subsequent dehydrogenation at elevated temperatures provided the aromatic species 193, which was a key intermediate in the synthesis of 194, a compound that displays strong p-blocking activity. Under similar conditions, reaction of 191 with crotonic acid, cinnamic acid, and ethyl acrylate did not generate the corresponding bicyclic alkaloid skeletons. 

The synthesis of nitrogen-containing natural products is also possible via diols such as these. Hudlicky and co-workers prepared the bicyclic alkaloid (+)-kifunensine, for example, from 284. 0 More complex molecules can also be prepared, as illustrated by the conversion of 285 into (+)-pancratistatin (291), via synthetic intermediate 290. Banwell et al. reported an asymmetric synthesis of (-)-patchoulenone from 287... 

---