Pyrrolizidines, hydroxy-, reactions

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. 

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... 

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.).

A frequently used intermediate in pyrrolizidine syntheses is the hydroxy-alkylpyrrolidine (3). This has been prepared in an improved yield of 40% from pyrrole by Kray and Reinecke, by Grignard reaction of pyrryl magnesium chloride with trimethylene oxide, followed by catalytic reduction [Eq. (2)]. Some 20% of the product was the isomeric compound (4). Cyclization of the mixture gave the two azabicyclic derivatives (1) and (5). A similar... 

The 2-aza-Cope N-acyliminium ring closure of hydroxy lactone (131) proceeds in a stereoselective fashion via primary N-acyliminium intermediates (132), which may also be obtained from hydroxymethyl lactam (133). From a reaction of (131) in HCO2H at room temperature for 18 h 77% of diastereomeric pyrrolizidines (134) were obtained <83TL2109>. 

Six articles cover general aspects of heterocyclic chemistry 1,3-dipolar cycloreversions, syntheses with arylnitrenes and a-metallated isocyanides, and photo-oxygenation of nitrogen heterocycles,while others deal with more specialized subjects, i.e. preparation and use of halogeno-lactones, aspects of the chemistry of furan, 1-hydroxy-indoles, ring-opening of azoles by the action of amines, " the use of 2-chlorobenzoxazolium (1) and other heterocyclic onium salts for dehydration and condensation reactions," the synthesis of monosub-stituted tetrathiafulvalenes (2), cycloadditions of azoles containing three heteroatoms,sydnone imines (3), the conversion of acyl-benzofuroxans into nitro-indazoles (cf. p. 199), and advances in the chemistry of pyrrolizidine " and indolizine." ... 

As expected from the depicted mechanism, early attempts to control the stereoselectivity of the MBH reaction was focused on the application of chiral amines (Fig. 4.48). Thus, using high pressure conditions (5 kbar) to accelerate the reaction and a C -symmetric DABCO derivative 245 (15 mol%), product 241a (R =Me, R sq-NO CgH ), was obtained in 45% yield and 47% ee (1 mol% hydroquinone, THF, 30°C) [318]. When used with pyrrolizidine derivative 246 (10 mol%, acetonitrile, 0°C) improved results (17-93% yield, 39-72% ee) were obtained in reactions between methyl or ethyl vinyl ketone (237a R =Me and 237b R =Et) and aromatic aldehydes. The presence of NaBF as co-catalyst was required to achieve these results, due to the coordination of aldehyde and hydroxy group of the catalyst to the alkali metal, which fixed the orientation for the attack of the nucleophile to the electrophile in the transition state [319]. 

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