Pyrrolizidine- 1-carboxylic acids

Pyrrolizidine alcohols are readily oxidized. Stereoisomeric 1-hydroxymethylpyrrolizidines when oxidized with chromic acid afford stereoisomeric pyrrolizidine-1-carboxylic acids (see Section III, C).81,90 Secondary alcohols, when subjected to Oppenauer oxidation or chromic acid treatment, yield amino-ketones (cf. refs. 72, 77, and 81). 

For the synthesis of the pyrrolizidine fragment (2), we identified maleic anhydride (5, 7 /kg), aminobutyric acid (6, 120 /kg) and trienal 7 as readily available starting materials. In the most ambitious disconnection, the racemic pyrrolizidine carboxylic acid 4a, could be assembled, in principle, in a single step from 4-aminobutyric acid (6) and maleic anhydride (5). A subsequent kinetic resolution via oxa-Michael addition would then generate an enantiomerically enriched enolate equivalent, which could in turn add to the aldehyde 3. However,... 

Scheme 2. One-step synthesis of the desired pyrrolizidine carboxylic acid rac-4a...

If a molecule contains several asymmetric C atoms, then the diastereomers show diastereotopic shifts. Clionasterol (28a) and sitosterol (28b) for example, are two steroids that differ only in the absolute configuration at one carbon atom, C-24 Differing shifts of C nuclei close to this asymmetric C atom in 28a and b identify the two diastereomers including the absolute configuration of C-24 in both. The absolute configurations of carboxylic acids in pyrrolizidine ester alkaloids are also reflected in diastereotopic H and C shifts which is used in solving problem 54. 

In a more recent paper Menschikov assigns to trachelantamidine formula (VI, p. 611), which makes it structurally identical with iso-retronecanol (p. 609). He also provides experimental evidence for the view that trachelantic acid is 2-methyl-3 4-dihydroxypentane-3-carboxylic acid, Me CH. C(OH)(COjH). CHOH. CHg, and trachelanta-mine becomes C HjaN. CHaO. OC. C(OH)Pr. CHOH. CHg, C,HjaN being the pyrrolizidine residue (1947). 

Monocarboxylic [as in heliotrine (5) and trachelanthamine (6)] and dicarboxylic acids [in senecionine (7) and thesine (8)] are found among the carboxylic acid moieties. All the pyrrolizidine alkaloids afford pyrrolizidine alcohols under conventional conditions of ester hydrolysis. Formerly, these alcohols were used as starting materials for all the studies dealing with pyrrolizidine chemistry synthetic approaches have now been developed. Some pyrrolizidine alcohols, and other derivatives like 1-methylenepyrrolizidine, occur in plants in the free state, forming the special group of the so-called non-ester pyrrolizidine alkaloids. 

Fig. 13.8 General structures of some pyrrolizidine alkaloids. A Pyrrolizidine alkaloid esters, B 1,2-dehydro pyrrolizidine alkaloid esters, C the N-oxide of 1,2-dehydro pyrrolizidine alkaloid esters, and D an otonecine-based alkaloid. Ri and R2 can be H or esters of carboxylic acids that may or may not be cyclized forming a macrocyclic diester.

RETENTION TIMES OF PYRROLIZIDINE ESTERS WITH MONO CARBOXYLIC ACIDS ON A 4 % SE-30 PACKED COLUMN ON GAS CHROM P AT 205°C1... 

Hydrogenation of (11) gave the IjS-hydroxymethyl isomer (12), since it afforded dihydroxyheliotridane (2) on hydrolysis. Jones oxidation of (12) gave the corresponding carboxylic acid, the ethyl ester of which epimerised at C-1 and also suffered transesterification when treated with sodium methoxide, to give la-methoxycarbonyl-7a-hydroxy-8a-pyrrolizidine (13). Reduction of (13)... 

A useful summary of data on pyrrolizidine alkaloids has appeared, although the presence of a number of mistakes was noted (e.g. necic acids are referred to as terpenoid carboxylic acids ). A review (in Japanese) on the chemistry of the pyrrolizidine alkaloids has been published. ... 

Examples of SB formation are outlined in Figure 1.28. The reaction of 4-aminobutanal and succinaldehyde yields an SB which is the intermediate of dialdehyde amine, likely a precursor of the pyrrolizidine ring system. Another example is the piperidine-2-carboxylic acid (a precursor of anabasine) obtained from a-keto- -aminocapronic acid. 

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... 

An important lower unsaturated carboxylic acid is ( )-but-2-enoic (crotonic) acid (8-62). This acid occurs in small quantities, together with other unsaturated acids with 5-10 carbon atoms in the molecule, in beer and fermented drinks and foods. Examples of acids with five carbon atoms in the molecule are (Z)-2-methylbut-2-enoic (angelic) (8-62) and ( )-2-methylbut-2-enoic acid (tiglic) acids, the precursor of which is threonine (8-62). Valine is converted into (Z)-3-methylbut-2-enoic (senecioic) acid with five carbon atoms (8-62). These acids, along with a number of other related acids, are a frequent component of pyrrolizidine alkaloids known as senecio alkaloids (see Section 10.3.2.1.3). 

The skeletons of pyrrolizidine alkaloids are derived from 2,3,5,6,7,8-hexahydro-lH-pyrrolizine, known as pyrrolizidine (10-11), and from pyrrolizidine-M-oxide (10-12). The bases of the pyrrolizidine alkaloids are necines (necine bases) derived from bicyclic amino alcohols, which have their origin in 1-hydroxymethylpyrrolizidine. Necines may be saturated or may have a double bond at C-1 of ring B and may also have an additional one or two hydroxyl groups at C-2, C-6 or C-7. Necines are esterified with carboxylic acids, which are called neck acids. Biosynthesis takes place in the roots, where the alkaloids occur as the corresponding JV-oxides. They are then transported to the aerial parts of the plant and stored in vacuoles. 

A novel synthesis of (+)-mtegerrinecic acid lactone, the necic acid component of the macrolactone pyrrolizidine alkaloid integerrimine 53, has been reported by White and Jayasinghe, wherein lactonization of a 6-hydroxy acid was used for the ring closure [46] (Scheme 9). Reduction of epoxide 49 derived from / -(+)-P-citronellol and subsequent protection gave bis-3,5-DNB ester 50. Oxidative cleavage of the double bond afforded the carboxylic acid which upon saponification of the esters and acidification resulted in spontaneous lactonization to provide lactone 52. 

The examples illustrated employ a lactamization to construct the left (as drawn) ring of pyrrolizidines from atoms provided by the dipolarophile. This construction requires that substituent A (Scheme 16.53) contain a carboxylic acid derived electrophile. Alternatively, an alkylation can be used to construct pyrrohzidines 253 (Scheme 16.55) if substituent A contains an appropriate electrophile. Moreover, a six-membered ring can be built via a similar route providing access to indolizidines, such as 255. This structural motif is also present in many natural products. 

Structurally, the pyrrolizidine alkaloids are composed of a necine base (two fused five-membered rings with a nitrogen at one of the vertices) and one or more branched carboxylic acids attached as esters to one or two of the necine hydroxyl groups. The esterified branched mono-and di-carboxylic acids are unique to the pyrrolizidine alkaloids. The alkaloids are represented by three major structural groups saturated bases (i.e. platyphylline [29]), 1,2-unsaturated necines (i.e. senecionine [30]) and seco necines (i.e. (otosenine [31]). The N-oxides of these alkaloids frequently co-occur with the free alkaloids (Roitman and Panter, 1995). 

Pyrrolizidine alkaloids are usually composed of two moieties-the pyrrolizidine alcohol and a carboxylic (usually hydroxy) acid, which are combined by an ester linkage. The pyrrolizidine moieties may appear as monohydric (trachelanthamidine, 2), dihydric (platynecine, 3), or trihydric alcohols (rosmarinecine, 4). 

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

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