Pyrrolizidine 1-hydroxy

Xia et al. reported on the metabolism of lasiocarpine (prototype heliotridine pyrrolizidine alkaloids) by F344 rat liver microsomes, and isolated 6,7-dihydro-7-hydroxy-l -hydroxymcthyl-5//-pyrrolizinc (DHP)-derived DNA adducts, thus showing the potential use of such DHP-derived DNA adducts as biomarkers of exposure and tumorigenicity for all pyrrolizidine alkaloids <2006MI1001-02>. 

An intermediate 5-hydroxy-5,6-dihydro-2/7-pyrrolo[l,2- ][l,2]oxazin-7(4a//)-one 142 has been described in the total synthesis of (—)-loline, a pyrrolizidine alkaloid extracted from rye grass Lolium cuneatum. The key step of the synthesis was an intramolecular cycloaddition of acylnitrosodienes (obtained by in situ oxidation of the corresponding hydroxamic acids 143). This reaction generated predominantly the rro/o-stereoisomer that was further cleaved at the N-O bond with Na(Hg) and further elaborated in several steps to reach the target compound (Scheme 19) <2001J(P 1)1831 >. 

A chiral pyrrolizidine (53) catalyses asymmetric Baylis-Hillman reactions. Important structural features include an accessible nitrogen lone pair and a strategically placed hydroxy group the latter may also interact with alkali metal cations, which catalyse the reaction. 

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). 

Sorm and Beranek39 used an intramolecular acylation in their synthesis of l-azoniumtricyclo[3.3.3.0]undecane (66). Condensation of nitromethane with acrylonitrile in the presence of an alkaline catalyst resulted in the formation of tris-(2-cyanoethyl)nitromethane (60), which afforded the triethyl ester 61 on hydrolysis followed by esterification. The ester was reduced catalytically to give a pyrrolidone (62). The derivative (62) gave rise to 8-(j8-carboethoxyethyl)-3,5-dioxo-pyrrolizidine (63) on heating. Reduction of 63 resulted in the formation of 8-(y-hydroxypropyl)pyrrolizidine (64). Replacement of the hydroxy group by bromine (65), followed by cyclization, afforded the tricyclic compound 66. 

As already mentioned, this route has been especially important for the preparation of naturally occurring pyrrolizidine bases. Recently, it afforded synthetic 1-hydroxymethylpyrrolizidine, 1-hydroxy-methyl-7-hydroxypyrrolizidine,andl-hydroxymethyl-7-hydroxy-l,2-dehydropyrrolizidine (retronecine). 

The absolute configuration was also established unequivocally for C-8 of naturally occurring pyrrolizidine bases.88 It was demonstrated in the course of the structural analysis of isoheliotridene (146), obtained by degradation of the alkaloid monocrotaline, that ozonolysis of this compound affords 2-acetylpyrrolidine-l-acetic acid (147).66 The (— )-methyl ester of this acid was condensed with methylmagnesium iodide to give (— )-l-(2-hydroxy-2-methylpropyl)-2-(l-hydroxy-l-methylethyl)pyrrolidine (148). The same glycol (148) was obtained... 

B) Reactions of hydroxy-, oxo-, car boxy-, and other substituted pyrrolizidines. 

B. Reactions of Hydroxy,- Oxo-, Carboxy-, and Other Substituted Pyrrolizidines... 

The hydroxy groups of pyrrolizidine amino-alcohols are readily replaced by chlorine atoms upon treatment with thionyl chloride (see, e.g., refs. 101 and 103). In this reaction, the allylic hydroxyl group is more reactive and can be selectively replaced by chlorine.79 In some particular cases, methoxyl groups can also be substituted for halogen e.g., l/3-methoxymethyl-8a-pyrrolizidine, when treated with hydro-bromic acid, gives rise to the corresponding bromo derivative.104... 

Pyrrolizidine amino-alcohols are readily dehydrated for example, hydroxyheliotridane and retronecanol, when treated with sulfuric acid, afford heliotridene (see e.g., refs. 105 to 107). A more complicated dehydration reaction is the transformation of the alkaloid rosmarinine into the alkaloid senecionine.83 Dehydration of 1-hydroxy-l-carbethoxypyrrolizidine53 in the presence of phosphorus oxychloride in pyridine results mainly in the formation of the A1,8-unsaturated ester (see Section II, E). The authors61,62 claimed that the dehydration product of l-carbethoxy-2-hydroxy-3-oxopyrrolizidine contained a A1,2-double bond (159). Later, however, the UV, IR, and NMR spectra67 revealed that the double bond had migrated the... 

Biogenetic pathways leading to naturally occurring pyrrolizidine bases were proposed by Robinson, Schopf, and Lukefi (see, e.g., refs. 119-121) in their publications concerned with the biogenesis of alkaloids. The most probable precursors of the pyrrolizidine system are commonly accepted to be ornithine (176), hydroxyomithine (177), and their biogenetic equivalents. It is noteworthy that ( + )- -hydroxy-jV-methylnorvaline (178) (structurally related to ornithine) was isolated... 

Aaron s group has studied various hydroxy derivatives of both indolizidines and pyrrolizidines and assigned conformations, mainly on the basis of infrared data. The isomers of 8- (240, 241) and 7-hydroxy-indolizidine (242, 243) were separated as racemates after chemical or catalytic reduction of the ketones.282... 

The number of synthetic routes to the natural 1-hydroxymethyl-pyrrolizidines continues to increase. Robins and Sakdarat have achieved the first synthesis of these necines in optically active form, using natural (-)-4-hydroxy-L-proline as a chiral template.2 The dihydropyrrolizine ester (2) was prepared by regiospecific 1,3-dipolar cycloaddition of ethyl propiolate to the N,0-diformyl derivative (1) of (-)-4-hydroxy-L-proline, followed by deformylation (Scheme 1). Addition... 

Heliotrine (161) Small Gram-ve coccus 7 a-Hydroxy-1 -methylene-8a-pyrrolizidine (173) (-) 165... 

Europine (165) Peptococcus heliotrinreducans (7a-Hydroxy-l-methylene-8a-pyrrolizidine) (173) (-) 166... 

Enantioselectivities of 21-70% ee were observed in the reaction of ethyl- and methyl-vinylketone with aromatic aldehydes 22 using the chiral hydroxy-pyrrolizidine-catalyst 24 which was prepared in four steps starting from BOC-I-prolinol (Scheme 5) [32]. The enan-tioselectivity was explained by the predominant formation of intermediate 26-A, which is less sterically hindered than the isomeric intermediate 26-B. The employment of a reaction temperature of -40 °C, the use of NaBF4 as a co-catalyst, and the presence of a hydroxy group in the base (which allows the formation of intramolecular hydrogen bonds) resulted in good conversions and rates. 

Scheme 5. Enantioselective Baylis-Hillman reaction using a chiral hydroxy-pyrrolizidine-catalyst (Barrett et al.).

Using established methods, pyrrolizidines with 1- and 2-hydroxy and 1- and 2-hydroxymethyl substituents have been synthesized.3 The racemates were separated by chromatographic techniques, and resolved by classical methods. 

Another synthetic route to ( )-retronecine (27) has been developed by Vedejs and Martinez.11 The protected hydroxy-lactam (22) was prepared from 2-methoxy-1-pyrroline by known methods. The key ylide intermediate (24) was then generated from the salt (23) by desilylation with caesium fluoride (Scheme 6). This ylide (24) reacted with methyl acrylate in a 1,3-dipolar cycloaddition to afford the unsaturated pyrrolizidine (25) in 57% yield from the lactam (22). Catalytic hydrogenation of the ester (25) gave an unstable endo-product, which epimerized to the exo-form (26). Introduction of the 1,2-double-bond into (26) was carried out by insertion and thermal elimination of a phenylseleno-group.12 Reduction then yielded ( )-retronecine (27). 

Pyrrolizidine alkaloids or, more specifically, the mono or diesters of 1 -hydroxymethyl-7-hydroxy-l,2-dehydropyrroUzine (Figure 13.8) are a diverse class of naturally occurring alkaloids. 

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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