Pyrrolizidine acid chloride

Pyrolysis of the N-chloroethyl-substituted enaminone 183, however, gives the pyrrolizidine acid chloride 184, which may be converted to the ester 185, Scheme 49 (87TL885 90H1251). 

Australian workers have prepared a number of semisynthetic pyrrolizidine esters as part of a major investigation of pyrrolizidine alkaloid toxicity. 7,9-Diacetylheliotridine (52), 7-acetylheliotridine (53), 7,9-divalerylheliotridine (54), and 7-pivalyl-(55), 9-pivalyl-(56) and 7,9-dipivalylheliotridine (57) were prepared by acylation of heliotridine with the appropriate acid chloride. The three last-... 

Many esters, both naturally occurring and semisynthetic, have been prepared by esterification of hydroxy-substituted pyrrolizidine bases. Mattocks synthesized a range of retronecine diesters by heating retronecine (127) hydrochloride with acid chlorides.Mattocks also converted retronecine into the corresponding amine, retronamine, from which amide analogs of pyrrolizidine esters were prepared [Eq. (35)]. 

Formation of a vinyl-substituted pyrrolizidine derivative is also observed in case of an allylstan-nane cyclization94. Since the allylstannane moiety is acid sensitive, the iV-acyliminium ion is generated by exposure of the hydroxylactam to methanesulfonyl chloride and triethylamine in dichloromethane. The very rapid cyclization produces the endo-vinyl compound with very high stereoselectivity. 

The properties and reactions of amino-alcohols, obtained largely by hydrolysis of naturally occurring alkaloids, were investigated primarily for the purposes of structural analysis and the preparation of physiologically active derivatives. Many authors have described acylation of pyrrolizidine alcohols with benzoyl chloride and acetic anhydride (see, e.g., refs. 83 and 101). Trachelanthamidine benzoate and p-aminobenzoate were prepared especially for testing of their physiological activity.102 The p-aminobenzoate was obtained by treatment of trachelanthamidine with p-nitrobenzoyl chloride and subsequent reduction of the nitro group with iron in 20% acetic acid. The compound exhibited an anesthetic activity close to that of cocaine. 

Konovalova and Orekhov103 demonstrated that the primary hydroxyl group in platynecine is more reactive to acylation than the secondary. For example, use of more or less drastic conditions yields platynecine di- or mono-benzoate, respectively. Pyrrolizidine alcohols can be esterified with inorganic acids e.g., mild treatment of platynecine with thionyl chloride yields the cyclic sulfite ester hydrochloride79 (see Section III, A). 

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... 

Surzur and Stella, in a paper mainly concerned with the free radical cyclization of pyrrolizidines, reported the formation of the benzindol-izidine 171 from iV-benzyl-iV-chloropentenylamine (170) when treated with titanium(III) chloride in aqueous acetic acid (Scheme 23),230... 

A new type of pyrrolizidine alkaloid has been isolated from the leaves of Ehretia aspera Willd. by Suri et al.n The structure (39) for ehretinine was established by spectroscopic evidence and by hydrolysis to give retronecanol and p-methoxy-benzoic acid. Confirmation of the structure (39) was obtained by synthesis of ehretinine from retronecanol and pmethoxybenzoyl chloride. This is the first reported occurrence of a retronecanol ester, although it should be pointed out that retronecanol esters can be produced by hydrogenolysis of retronecine diesters. The authors do not appear to have considered the possibility that ehretinine could have been formed by hydrogenolysis of the common type of ester (40) on treatment with the zinc and sulphuric acid that are used in their extraction procedure. 

Separation of mono- and di-ester pyrrolizidine alkaloids has been achieved by ion-pair adsorption t.l.c., using chloride (or iodide) as the counter-ion.48 Chloranil has been used to oxidize pyrrolizidine alkaloids on t.l.c. The pyrrole derivatives that were formed were then detected with Ehrlich s reagent49 or sulphuric acid.50 Mixtures of pyrrolizidine alkaloids have been separated by h.p.l.c. on a reversed-phase styrene-divinylbenzene resin.51 In a sensitive method for the detection of pyrrolizidine alkaloids, the protonated alkaloids were complexed with aqueous methyl orange. The dye was then released from the complex and estimated spectrophotometrically.52... 

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. 

Another example is provided by the quaternization of a saturated pyrrolo[l,2-6]isoxazole with methanesulfonyl chloride and further treatment with Zn powder in aqueous acetic acid <82T2627>. When compound (152) was treated with Zn in aqueous acetic acid at 50-60 °C, the isoxazolidine underwent reductive N—O bond cleavage with in situ cyclization to afford pyrrolizidine (153) in 86% yield. When (152) is treated directly with Zn in 90% aqueous acetic acid at higher temperature (130-140°C) and prolonged reaction time, pyrrolizidine (154) is obtained (Scheme 28) <85CPB351>. 

Epoxidation of the N-formyl enaminone 190 with m-chloroperbenzoic acid at high temperature gives the epoxyazocine 191. Interestingly, deformy-lation of 191 generates in high yield the bicyclic amino ether 192, which on exposure to pyridinium chloride gives the pyrrolizidine 193, Scheme 51 (77JOC2903),... 

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