Alkaloid branched-chain

In summary, the pumiliotoxin-A class alkaloids are unique to certain genera from four different families of amphibians. Pumiliotoxins and allo-pumiliotoxins often occur together. Homopumiliotoxins occur much less often. The unique and complex structures and the phylogenetic distribution of pumiliotoxin-A class alkaloids argue for the independent evolutionary development of a complex suite of biosynthetic enzymes. The branched-chain structures of the pumiliotoxin-A class also suggest the incorporation of isoprene units, unlike the preponderance of bicyclic den-drobatid alkaloids, which appear to be derived from straight-chain precursors. 

The pyrrolizidine alkaloids are not all poisonous. Schoental (42) has postulated that for an alkaloid to be toxic it must have a double bond between C-1 and C-2. The cyclic diesters are twice as toxic as the open diesters, and four times as toxic as the open monoesters. Esters of branched-chain acids are toxic while esters of straight-chain acids are not... 

Most pyrrolizidine alkaloids are esters constructed from an aminoalco-hol called a necine unit (pyrrolizidine derivative), and straight or branched chain fatty acid, called a necic acid. Necine is the derivative of pyrrolizidine, i.e., azabicyclo[3,3,0]octane, and a hydroxymethyl (-CH2OH) moiety is always attached at the C-1 position. Necines can be classified into two groups, either with or without a double bond between the C-1 and C-2 positions. The stereochemistry of the H-8 position is usually H-8a.When the C-8 position is oxidized, as in the case of otonecine, it becomes an eight-membered ring by decychzation. 

Fig. 6.4 Branched-chain capsaicinoids, acid amide type alkaloids from Capsicum spp. all unsaturated acyl residues are tr

Various carboxylic acids are found as the necic acid parts of the pyrrolizidine alkaloids, e.g. senecionine 6.77), monocrotaline 6.78) and heliosupine 6.79). Available evidence [61, 62] points to the derivation of these acids from the branched-chain amino acids isoleucine and valine (see dotted lines). [In the case of monocrotaline C-4, C-5, and C-8 apparently derive from propionic acid. Carbon atoms 5 and 6 of the echimidinic acid fragment in 6.79) apparently derive from acetate.] The basic fragment in these alkaloids, retronecine 6.80), is formed [63] from two molecules of... 

Some natural products outside the carbohydrate field - particularly those with highly hydroxylated cyclohexane ring components - have been subject to synthetic studies which are dependent on the mercury-based rearrangement reaction the alkaloid (+)-lycoricidine (30) [12] and the cycloheptane-based (+)-calystegine 62(31) which stimulates growth of nitrogen-fixing Rhizobia [29] are examples, and compound 32 which offers novel access to the anthracyclinone components of anthracyclin anti-cancer compounds, has been produced by cycloaddition of a naphthalene-based o-xylylene to a 2,3-unsaturated hex-4-uloside followed by carbocyclization of the product by use of the mercuration procedure [30]. Studies on HMG-CoA reductase inhibitors like compactin have afforded the tetra-carbon-substituted 33 made from a hex-5-enopyranoside with deoxy-branch chains at C-2, C-3 and C-4 [31]. 

Deoxy-branched chain sugars are also referred to as precursors for alkaloid and polyketide synthesis in Chapter 24, and branched-chain sugar nucleosides are mentioned in Chapter 20. 

Necine bases are esterified by different carboxylic acids. With the exception of acetic acid, these acids have 5 10 carbon atoms and include mono- and dicarboxylic acids with branched chains substituted with hydroxyl, methoxyl (other alkoxyl), epoxy, carboxy and acetoxy groups. Necines with two hydroxyls, such as 7,9-necinediol, may be esterified with carboxyhc acids in positions C-7 and C-9 or in both positions. Esterification with dicarboxyhc acids produces macrocyclic alkaloids with 11 to 14-membered rings. Depending on the ester type, the following alkaloids can be recognised ... 

A synthesis of the ring skeleton of the alkaloid histrionicotoxin involves condensation of the lyxodialdose (63) with a 5-nitropent-anol derivative followed by cyclization to the branched-chain nitro-... 

On the chemical side it has long been the practice of the chemist to attempt to discern common denominators within a class of natural products by a process which can best be regarded as a visual dissection of the structural formulae. The most well-known example of such an exercise has been the recognition of repeating branched chain five carbon units in terpenes and the subsequent use of this observation in reverse in order to frame structures which could then be tested against the experimental results. Mevalonic acid has turned out to be the biochemical equivalent of the hypothetical branched five carbon unit. In the case of indole alkaloids not quite so much progress has been made. 

Most of the necic acids are Cio-acids. Because they can apparently be divided into two isoprene units, they were originally believed to be derived from mevalonate, even though the oxidation patterns and mode of coupling of the Cs units were quite different from those of terpenoid compounds. Indeed, acetate and mevalonate were found not to be specific precursors for the Cio-necic acid portions of pyrrolizidine alkaloids (J4,123). All of the acids investigated so far have been shown to be formed from common branched-chain amino acids. 

This is the branch-poiat differentiatiag phenylalanine (25, R = H) from tyrosiae (25, R = OH). Both phenylalanine and tyrosiae contain an aryl ring, a three-carbon side chain (a Cg—Cg fragment), and a nitrogen. Decarboxylation yields a two-carbon side chain (a Cg—Cg fragment), eg, 2-phenethylamine (59, R = H) from phenylalanine and tyramine (59, R = OH) from tyrosiae, although it is not certain that ia all cases decarboxylation must precede use ia alkaloid constmction. 

The evidence for dioscorine biosynthesis is consistent likewise with the intermediacy of (4) (see Scheme 1). The sequences of saturation and condensation leading to dioscorine, and also anatabine, cannot yet be specified, but are clearly well worth exploring. Of interest too, in the case of dioscorine, is the way in which the branched acetate chain originates (stepwise introduction of acetoacetate units in the course of the biosynthesis of the alkaloid ). 

NMR measurements have resulted in a diagnostic to differentiate pyridine and pyridinium moieties and to define the presence of branched or unsaturated alkyl chains, as for example in the cases of halitoxin (74) [1] or amphitoxin (75) [31], respectively. However they are of limited value for establishing the number of linked subunits, since natural 3-AP alkaloids are usually isolated as mixtures of oligomers and polymers, that... 

Tabemaemontana corymbosa also provided several new bisindole alkaloids, conodiparines A-D (362-365) which are constituted from union of iboga and vobasinyl moieties [237]. The spectral data indicated that in conodiparines A (362) and C (364), the dimers are branched from C(3) of the vobasinyl unit to C(IO ) of the iboga unit whereas in conodiparines B (363) and D (365), the connection is from C(3) to C(12 ). The configuration of C( 19 ) in conodiparines A (362) and B (363) was determined to be 5 from examination of the carbon shifts of C(15 ) and C(2r) which corresponds to those of the iboga alkaloid heyneanine (345), exemplifying the 19(5) series in iboga alkaloids with a hydroxylethyl side chain [238]. 

The results may be summarized as follows Necine bases and alkaloids of saturated necine bases are non-toxic esters of the monohydroxy-neclne, supinldine, are only slightly toxic monoesters of dihydroxy-necines are slightly more toxic and diesters are considerably more so macrocycllc diester alkaloids are the most toxic. Necine bases esterifled synthetically with n-aliphatlc acids are non-toxic indicating that branching of the acid side chain is required for toxicity (58,62,70). Relative toxicities also appear to be inversely related to water solubilities of the alkaloids. 

The C27-steroid alkaloids contain two heterocyclic rings attached to a steroid nucleus. Either one or both contain a nitrogen atom. The alkaloids are glycosides with the sugars attached to the hydroxy group in position 3. A well-known representative is oc-tomatine, which contains a branched sugar chain frequently found also with steroid saponins (D 6.4.2). 

---