Synthesis of pyrrolizidines

Hudlicky and coworkers also reported a related 2-pyrroline formation from viny-laziridines [81], which are extremely useful for the synthesis of pyrrolizidine alkaloids such as the protected (+)-trihydroxyheliotridane 210 (Scheme 2.51). Since the pyrolysis of either diastereomer of 208 furnished the cyclized product 209 as a... 

With nonracemic chiral diazoacetates the insertion process occurs with evident match/mismatch characteristics. This has been demonstrated in reactions of optically pure 2-methylcyclohexyl diazoacetates (Eq. 9) [85] and in carbon-hydrogen insertion reactions of steroidal diazoacetates (Eq. 10) [86], as well as with the synthesis of pyrrolizidines 36 and 37 [84]. The mechanistic preference for formation of a /J-lactone in Eq. 10 over insertion into the 4-position is not clear,but there are other examples of /J-lactone formation [87]. In these and related examples, selectivities in match/mismatch examples are high, and future investigations are anticipated to show even greater applicability. 

As in the case of aminodialkenes (see above), hydroamination/bicyclizations of aminoalkenynes allow the regiospecific synthesis of pyrrolizidine skeletons (Eq. 4.87) [138, 303]. 

As discussed previously, radical ring-opening reactions of three-membered systems via cyclopropylmethyl and oxiranylmethyl radicals represent a fruitful method in organic synthesis [111]. De Kimpe and coworkers have now shown that azirid-ines can also be used, featuring a radical one-step synthesis of pyrrolizidines 3-280... 

The synthesis of pyrrolizidine alkaloid (-)-rosmarinecine illustrates the power of the fused mode tandem cycloaddition, as shown in Scheme 8.40.180 The all-cA relationship at the three contiguous centers C(l), C(7), and C(7a) can be constructed in a single-pot reaction with correct stereochemistry but C(6) cannot. 

An interesting strategy for the synthesis of pyrrolizidines and indolizidines has been developed by Brandi and co-workers. Cycloaddition between nitrones or nitrile oxides with methylenecyclopropanes generates strained tricyclic spiro compounds, which are prone toward further transformations, such as rearrangement, ring opening, and new ring closure (Scheme 10.17).116... 

Allenes have also been used as substrates in free radical cyclizations. Dener and Hart demonstrated that such entries are valuable in constructing pyrrolizidine and indolizidine ring systems [71]. In a total synthesis of pyrrolizidine base (+)-heliotri-dine (340), compound 338 possessing an allene functionality was used as a key intermediate (Scheme 19.62). Tri-n-butyltin radical-mediated carbon-selenium bond homolysis of 338 followed by the addition of the free radical to the allene moiety... 

More recently, Naidu and West have utilized a ring expansion reaction of spiro azetidinium ylide 167 in the synthesis of pyrrolizidine alkaloids. Spiro azetidinium ylide 167 is generated through a Cu(acac)2-catalyzed intramolecular reaction of a copper carbene complex with a pendant amino moiety. Subsequent [l,2]-shift gives fused bicyclic products 168 and 169 as a diastereomeric mixture. Each diastereomer was further converted to naturally occurring pyrrolizidines ( )-turneforcidine and ( )-platynecine, respectively (Scheme 18). ... 

A new synthesis of pyrrolizidine, which is based on the reaction of bis-tertiary glycols with co-chloronitriles, was reported by Meyers and Libano.28 The method involves three steps (a) condensation of 2,5-dimethyl-2,5-hexanediol (48) with 4-chlorobutyronitrile in the presence of sulfuric acid to give a derivative of A 1-pyrroline (49), (6) reduction of 49 with sodium borohydride to give the corresponding pyrrolidine (50), and (c) intramolecular cyclization of the pyrrolidine in the presence of alkali to give the pyrrolizidine derivative 51. The three-step synthesis was performed without isolation of the intermediate products. 

The synthesis of pyrrolizidine developed by LukeS and Sorm31 and by Micheel and Flitsch32 starts with furylacrylic acid (56) which is converted by the Markwald reaction into y-ketopimelic acid (57). The carbonyl group in 57 is replaced by an amino group via the oxime or by the Leuckart-Wallach reaction this substitution results immediately in the formation of the lactam 58, which can be converted by heat into 3,5-dioxopyrrolizidine (59). The latter compound yields pyrrolizidine... 

The synthesis of pyrrolizidine derivatives by condensation of di-(4-oxo-ra-butyl)amine is considered in Section V in conjunction with the biogenesis of naturally occurring pyrrolizidines. 

Silver ion catalysis has also been used with allenic oximes to generate cyclic nitrones, which are trapped by 1,2-dipolarophiles (equation 142).270 This reaction was used in a synthesis of pyrrolizidine alkaloids.270 5... 

F. Rulin, Microbial oxidation of chloro-aromatics in the enantiodivergent synthesis of pyrrolizidine alkaloids trihydroxyhelio-tridanes,/. Org. Chem. 1990, 55, 4683-4687. 

More effort was therefore invested in the application of synthetic methodologies for these alkaloids and some straightforward chemo-enzymatic approaches were recently developed [150]. An enzyme-catalysed aldol reaction was again a crucial step in that synthetic route and is strongly reminiscent of Wong s research strategy relating to the chemo-enzymatic synthesis of pyrrolizidines mentioned earlier. 

Mechanistically, it was suggested [92] that this cyclization does not involve the free a-amino radical formed by cleavage of the C—Si bond of the trimethylsilylmethyl-amine radical cation. Instead, it was pointed out that cleavage of the C—Si a-bond from the delocalized trimethylsilylmethylamine radical cation, produced by a vertical overlap of the C—Si bond and empty p-orbital of nitrogen, is assisted by the 71-orbitals of the olefin. This strategy was applied to the stereoselective synthesis of pyrrolizidine and indolizidine ring systems [93]. The synthetic utility of this reaction is also demonstrated by the synthesis of ( )-iso-retronecanol [94]. 

When oxygenated diene (175 X = OR) was utilized, a single isomer of pyrrolizidine (177) was formed on thermolysis.(The stereochemistry of the carboxylate was rationalized by the endo effect.) Thus a highly selective procedure for the exhaustive synthesis of pyrrolizidine alkadoids was developed (see Sections 8.1.8 and 8.1.9). ... 

Azides (175 X = OH) were resolved through microbial reduction of p-keto esters (181) with baker s yeast and provided the azido dienes (182) and (183) in about 70% ee in an approach to enantiocontrolled synthesis of pyrrolizidines (equation 55). In this series extensive racemization toc place prior to or during the vinylaziridine formation. A conversion of chlorobenzenediol (184) to lactone (185) and elaboration of this material to either enantiomer of trihydroxyheliotridane (187) constituted a fully enantiocontrolled approach to both enantiomeric series of highly oxygenated pyrrolizidine alkaloids (Scheme 41).2 ... 

Achiwa reported a short synthesis of pyrrolizidine derivatives by the cycloadditions using a nonstabilized azomethine ylide 23 (m = 1) (82CPB3167). When the trimer of 1-pyrroline is treated with a silylmethyl triflate, N-alkylation of the 1-pyrroline takes place. Then the resulting iminium salt is desilylated with fluoride ion in the presence of ethyl acrylate to give ethyl pyrrolizidine-l-carboxylate 295 as a mixture of stereoisomers (28%). After the epimerization of 295 with LDA, the ester moiety is reduced with lithium aluminum hydride in ether to provide (+ )-trachelanthamidine (296). A double bond can be introduced into 295 by a sequence of phenyl-selenylation at the 1-position, oxidation with hydrogen peroxide, and elimination of the selenyl moiety. The 1,2-dehydropyrrolizidine-l-carboxylate 297 is an excellent precursor of (+ )-supinidine (298) and (+)-isoretronecanol (299). Though in poor yield, 297 is directly available by the reaction of 23 with ethyl 3-chloropropenoate. 

The pyrrolidine synthon (48) is useful for the chiral synthesis of pyrrolizidine, pyrrolidine, indolizidine and azabicyclic alkaloids (see Scheme 23). 

Scheme 9. Synthesis of pyrrolizidine (+)-xenovenine using organolanthanide precatalysts.

Synthesis of pyrrolizidines by Dieckmann condensation continues to receive wide attention. It is a useful method for producing pyrrolizidines with oxygen substituents and has been exploited in a number of syntheses by Viscontini and co-workers. For their attempted preparation of 1,7-dioxopyrrolizidine, the very unstable 3-oxopyrrolidine was required as an intermediate. This compound was stabilized by ketalization (37), and by this means N-substituted 3-oxopyrrolidines are readily accessible. The... 

The opening of activated cyclopropanes with nitrogen nucleophiles has been widely rqiplied to the synthesis of pyrrolizidine and pyrroline alkaloids by Danishefsky this subject has been reviewed. A number of pyrroline armulations have been based on this principle, illustrated in equation (35a). Similar opening can be accomplished with halides, cuprates, and sulfur or selenium nucleophiles. ... 

Bicyclic 5-5 systems with one ring junction nitrogen atom and no extra heteroatoms were not covered in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I). Pyrrolizines <84AHC(37)i, 87Sio>, pyrrolizidines <88H(27)1465> and the asymmetric synthesis of pyrrolizidines <90H(30)l23l> have been reviewed. 

A synthesis of pyrrolizidine (109) from (108) by intramolecular carbene displacement has been described <88JCS(Pl)833>. 

This reagent was used to reduce 112 to the hydroxymethyl derivative (113) in 91%, without racemization of the stereogenic center at C5, taken from Smith s synthesis of pyrrolizidine alkaloids.Hojo showed that silica gel is an effective catalyst for several other reactions. 1 ... 

Quiroz T, Corona D, Covarruvias A, AvUa-Zaraga JG, Romero-Ortega M. A practical method for the synthesis of pyrrolizidine, indohzidine and pyrroloazepinohzi-dine nucleus. Tetrahedron Lett 2007 48(9) 1571-5. 

The isolation and synthesis of pyrrolizidine alkaloids originating from plants and animals have been reviewed [11,12],... 

An example of such structures is an a-haloamide skeleton bearing a double bond. In this context, Mori et al. [78] reported the synthesis of pyrrolizidine derivatives 103,104 and 105 from A-iodoacetyl-2-vinylpyrrolidine (102) (Scheme 6.27). 

As mentioned in an earlier section in this Report, free-radical carbon-carbon bond-forming processes are becoming increasingly important in synthesis, and this year they have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. Thus, Hart and his group have now applied their intramolecular tin hydride generated ot-acylamino radical to alkyne cyclization [viz. (97) - (98)] and to the synthesis of (-)-dehydrohastanecine (99), (+)-heliotridene (100), and (+)-hastanecine (101). In addition, free radical in mechanism is the photochemical cyclization of the -acylpyrrolidine (102) to the pyrrolizidene (103), a key intermediate in a synthesis of ( )-isoretronecanol (104). 

---