Synthesis of pyrrolizidines and indolizidines by multicomponent 1,3-dipolar cycloaddition of azomethine ylides

Introduction

Natural and non-natural pyrrolizidine [1] and indolizidine [2] alkaloids show important biological properties especially polyhydroxylated systems, which are potentially glycosidase inhibitors and have antibacterial, antitumor, antiviral, anti-inflammatory and immunostimulatory properties (Fig. 1). For these reasons many synthetic strategies have been described being the intermolecular three-component 1,3-dipolar cycloaddition (1,3-DC) of azomethine ylides the most efficient approach for the generation of the common pyrrolidine unit in a single reaction step [3], [4], [5], [6]. This multicomponent reaction (MCR) involves the formation of a dipole formed by an iminium anion adjacent to a carbanion, by reaction of a cyclic amino acid with a carbonyl compound, which is trapped by a dipolarophile. This 1,3-DC can take place through two strategies depending on the amino acid derivative: (a) starting from the free amino acid, and (b) from the amino ester (Scheme 1). In the first case, a decarboxylative condensation occurs with the formation of a non-stabilized azomethine ylide, whereas in the second case a stabilized azomethine ylide is involved. Usually, the first multicomponent reaction must be performed under heating, where the second one needs milder reaction conditions. In this minireview, we highlight the development of intermolecular MCR 1,3-DC of azomethine ylides focused to the synthesis of pyrrolizidines and indolizidines including our contributions in this field, covering from its origin to recent contributions.

Fig. 1:

Selected pyrrolizidine and indolizidine alkaloids.

Scheme 1:

Strategies for three-component 1,3-DC.

Multicomponent synthesis of pyrrolizidines by decarboxylative 1,3-DC

Since the pioneering work of Grigg and co-workers [7] the decarboxylative routes of azomethine ylides has been widely used in 1,3-DC. This process can involve an intermediate oxazolidin-5-one, which loses carbon dioxide in a 1,3-dipolar cycloreversion reaction generating the non-stabilized azomethine ylide, but also by a 1,4-protropic rearrangement of the azomethine ylide [8], [9], [10]. The groups of Grigg et al [9], [10] and Orsini et al [11] described the synthesis of pyrrolizidines by MCR of proline with aldehydes and electrophilic olefins leading to mixtures of diastereomers. For instance, using benzaldehyde and N-propargyl maleimide under toluene reflux for 20 h a 3:1 mixture of endo/exo pyrrolizidines 1 were obtained via the anti-dipole I (Scheme 2) [12].

Scheme 2:

Multicomponent 1,3-DC of proline, benzaldehyde and N-propargyl maleimide.

Further applications of this process are depicted in Fig. 2. A four-component reaction of nihydrin, 1,2-phenylenediamine, proline and N-aryl maleimides gave after microwave (MW) irradiation (3–5 min at 600 W) exo-spiropyrrolizidines 2 in 85–95% yield through intermediacy of azomethine ylide II [13]. Dispiroindeno-quinoxaline-pyrrolizidine derivatives 3–6 have been prepared by subsequent in situ reaction of nihydrin with 1,2-phenylenediamine, then addition of L-proline and as carbonyl component: 2-arylidene-1,3-indanone, (E)-2-arylidenetetrahydronaphthalene-1-ones, (E)-3-arylidene-4-chromanones and (E)-2-oxoindolino-3-ylidene acetophenones using 20 mol % of heteropolyacid H₄[Si(W₃O₁₀)₃]-silica as catalyst in acetonitrile [14]. The same group described the synthesis of spiroheterocycles 7 by a three-component, under solvent free MW irradiation of proline, nihydrin and 9-arylidenefluorenes in high yields by means of azomethine ylides III derived from nihydrin [15]. Other spiro derivatives 8–10 (Fig. 2) have been synthesized using as cyclic ketones nihydrin, 11H-indeno[1,2-b]quinoxalin-11-one and acenaphthenequinone, respectively, being azomethine ylides II–IV the corresponding intermediates [16].

Fig. 2:

Spiro-fused pyrrolizidines and azomethine ylides.

Azomethine ylides derived from acenaphthenequinone IV and isatins V were the intermediates in the three-component 1,3-DC with a carbohydrate derived olefin providing spiro cycloadducts 11 and 12, respectively (Scheme 3) [17].

Scheme 3:

Three-component 1,3-DC of proline with isatins or acenaphthenequinone and a sugar-derived olefin.

Perumal and co-workers [18] have described the three-component 1,3-DC of proline with acenaphthenequinone and α,α′-bisalkylidenepyridinones under refluxed methanol affording spiropyrido-pyrrolizidines 13 in high yields (Fig. 2). Acenaphthenequinone has been allowed to react with proline and (E)-2-oxoindolino-3-ylidene acetophenones using MW irradiation and mediated by ZrOCl₂·8H₂O giving mainly products 14 [19] (Fig. 2). Nihydrin has been used as carbonyl component in the synthesis of spiropyrrolizidines 15 and 16 in the presence of chalcones and nitrostyrenes, respectively in methanol at rt [20] (Fig. 2). Korotaev and co-workers used 3-nitro-2H-chromenes as dipolarophiles leading to the formation of the corresponding spiropyrrolizidines 17 in good yields upon heating in ethanol [21] (Fig. 2).

Isatins have been widely used as carbonyl component for the multicomponent synthesis of spirooxindole-pyrrolizidines with potential biological activity using proline and different dipolarophiles. Raghunathan and co-workers firstly described the MCR of isatin with proline and 9-arylidenefluorene in a solvent-free MW assisted 1,3-DC affording the corresponding dispiro-oxindole-pyrrolizidines in very good yields 18 [22] (Fig. 3). Working under ultrasonication in the presence of silica as a catalyst dispiro-oxindole-pyrrolizidines 19 were formed using alkylidene-oxindoles as dipolarophile in acetonitrile [23] (Fig. 3). These reaction conditions were applied to the same MCR using nihydrin as carbonyl component. In the case of spirooxindoles 20 the pyrrolizidine unit has been prepared using benzo[b]thiophene dioxide under refluxing methanol for 45–110 min [16]. In this case the azomethine ylide V is participating giving only one regioisomer through the approach represented in Scheme 4.

Fig. 3:

Spirooxindole-pyrrolizidines.

Scheme 4:

Three-component 1,3-DC of isatins, proline and benzo[b]thiophene dioxide.

For the synthesis of spirooxindoles 21 the sugar-derived α,β-unsaturated lactones were employed as dipolarophiles under refluxing toluene by intermediacy of azomethine ylide V [24] (Fig. 3). Glyco-3-nitrochromenes 22 have been used as dipolarophiles by the same group in the MCR of isatin and proline under refluxing acetonitrile affording pyrrolidinyl spirooxindoles 23 [25] (Fig. 3). They also employed acenaphthalenones and indenoquinoxalines as carbonyl components affording the corresponding glycol 3-nitrochromane hybrid pyrrolizidinyl spiro-derivatives in 81–84% yield. Babu and co-workers have employed the Diels-Alder cycloadduct 24, derived from furan and methyl maleate, as dipolarophile in the three-component 1,3-DC of isatins and proline under refluxing ethanol or in a mixture of ethanol and 1,4-dioxane. The resulting norbornane-fused spirooxindolo-pyrrolizidines 25 were obtained in moderate yields [26] (Fig. 3). When (E)-3-benzylidenechroman-2-ones 26 were used as dipolarophiles the corresponding dispirooxindole-pyrrolizidines 27 were obtained under refluxing toluene in high yields [27] (Fig. 3). Yang and co-workers have used 1-benzyl-3-acetonylideneoxindole 28 as dipolarophile for the three-component 1,3-DC of N-benzylisatin and proline. The reaction took place at rt in methanol providing the dispirooxindole derivative 29 in high yield [28] (Fig. 3). The cycloadducts 30, derived from β-nitrostyrene, have been prepared from isatins and L-proline as well as (4S)-4-hydroxy-L-proline in a mixture of propylene carbonate and water as solvents at 90°C in very good yields [29] (Fig. 3). From LC₅₀ toxicity assays in zebrafish embryos, three molecules were identified as the most hepatotoxicity derivatives. By using α,β-unsaturated ketones 31 as dipolarophiles, the three-component 1,3-DC of isatin and proline afforded products 32 in very good yields [30] (Fig. 3). These spirooxindoles 32 bearing the furanyl moiety displayed good in vitro antibacterial activity against Gram-negative bacteria, especially compound 32 with Ar=MeOC₆H₄. Under refluxing methanol, a library of spirooxindole-pyrrolizidine derivatives 34 have been prepared in a MCR using enones 33 as dipolarophiles in good yield [31] (Fig. 3). Spirooxindole-pyrrolizidines 35 and 37 were obtained using acrylamides and aroyl acrylic acid 36 as dipolarophiles, respectively [32] (Fig. 3). These MCR were performed in refluxing aqueous methanol (1:3) in moderate to good yield in the case of compounds 35 and at rt for products 37. Montmorillonite has been used as a catalyst (10 mol %) for the 1,3-DC of isatins, proline and tetraethylvinylidenebis(phosphonate) (38) leading to mixture of spirooxindole-pyrrolizidines 39 in moderate to good yields [33] (Fig. 3). The andrographolide adducts 41 have been prepared under refluxing aqueous methanol (9:1) in moderate yields using angrapholide 40, the major labdane diterpene constituent of the medicinal plant Andrographis paniculate, as dipolarophile [34] (Fig. 3).

The MCR of acyclic 1,2-dicarbonyl derivatives, such as butane-2,3-dione and ethyl pyruvate, with L-proline and β-nitrostyrene in isopropanol (IPA) at rt gave the corresponding pyrrolizidines 42 and 43 as a mixture of regioisomers (Scheme 5) [35]. However, in the case of phenylglyoxal only product 42 was formed. On the other hand, (4S)-4-hydroxy-L-proline reacted with butane-2,3-dione giving a 1:4:1 mixture products 44:45:46, respectively, in 78% overall yield.

Scheme 5:

Three-component 1,3-DC of 1,2-dicarbonyl compounds, prolines and β-nitrostyrene.

Wu and co-workers used tetraethyl vinylbis(phosphonate) (38) in the three-component 1,3-DC of proline with benzaldehydes in toluene at 80°C catalyzed by cerium(IV) oxide (5 mol %) leading regioselectively to pyrrolizidines 47 in moderate yields [36] (Fig. 4). Trifluoromethylated pyrrolizidines 49 have been synthetized by reaction of aldehydes, proline and β-trifluoromethyl acrylamides 48 in DMSO at 80°C [37] (Fig. 4). Moderate regioselectivity (up to 1:6) was observed and excellent diastereoselectivity (>20:1) arose for compounds 49, being the anti-azomethine ylide VI the most stable intermediate according to DFT calculations.

Fig. 4:

Pyrrolizidines from L-proline, aldehydes and dipolarophiles.

When chalcones were employed as dipolarophiles in dry DMF at 90°C, endo-adducts 50 were obtained with excellent regio- and diastereoselectivity [38] (Fig. 4). However, oxazolidines were also formed by reaction of proline with 2 eq. of aldehyde. Both compounds were isolated in 65–89% overall yields. The MW-promoted (275°C, 300 W) three-component 1,3-DC of proline, aromatic aldehydes and 2-arylmethyleneindene-1,3-dione in 1,4-dioxane provided spiropyrrolizidines 51 and 52 in moderate yields [39] (Fig. 4).

The one-pot sequence aldol condensation of acetone with aldehydes catalyzed by proline, followed by 1,3-DC of the α,β-unsaturated ketone with proline, afforded racemic pyrrolizidines 53 (X=H) in moderate yields (Scheme 6) [40]. The reaction was performed in the presence of 10 mol % of MgSO₄ in DMSO at rt. Silylated (4S)-4-hydroxy-L-proline lead to the formation of enantiopure products 53 (X=OTBS) in moderate yields.

Scheme 6:

Three-component 1,3-DC of aldehydes, acetone and prolines.

Diederich and co-workers have prepared several tricyclic thrombin inhibitors by using a decarboxylative 1,3-DC of prolines with benzaldehydes and maleimides [41], [42], [43], [44], [45], [46]. The most active were those derived from trans-3-hydroxy-L-proline or trans-4-hydroxy-L-proline with 4-bromobenzaldehyde and N-(4-fluorobenzyl)maleimide as the key step (Scheme 7) [45], [46]. In the first case, the 1,3-DC was performed in MeCN at 80°C for 18 h, affording a mixture of separable enantiopure products endo,trans-54 and exo,trans-55 in 24 and 30%, respectively. The same process with trans-4-hydroxy-L-proline in DMF at 80°C for 48 h, provided two pairs of inseparable diastereomers, that means, a mixture 1:1 of endo-products 56 and 57 together with a mixture of exo-products 58 and 59. The desired product 56 was further isolated after several transformations.

Scheme 7:

Three-component 1,3-DC of 4-bromobenzaldehyde, N-(4-fluorobenzyl)- maleimide and (3S)- and (4S)-hydroxy-L-prolines.

Our group has recently prepared enantiopure nitropyrrolizidines 61–65 from chiral exo-4-nitroproline 60 [47], aldehydes and dipolarophiles (Scheme 8) [48]. These three-component 1,3-DC took place in toluene at rt or 70°C, depending on the dipolarophile, affording mixtures of diastereomers with de up to >99%. In the case of cinnamaldehyde and N-methyl or N-phenyl maleimides, pyrrolizidines endo-62 were mainly obtained, whereas N-(4-bromophenyl)maleimide gave exclusively compound 61 in 80% yield. Dimethyl fumarate also provided exclusively endo-63 and (E)-bis(phenylsulfonyl)ethylene gave a 2:1 mixture of 64 and 65. Other aldehydes, such as benzaldehyde and 3-phenylpropanal, provided compounds 61 and 62 in modest yield (23–47%). In these cases, the endo-selectivity was due to the participation of azomethine ylide VII.

Scheme 8:

Multicomponent 1,3-DC of cinnamaldehyde, nitroproline 60 and dipolarophiles.

A different multicomponent 1,3-DC has been described by Sridharan and co-workers [49] using benzylic alcohols instead of aldehydes. This reaction must be carried out under Ir catalysis, so a hydrogen autotransfer generated in situ the corresponding aldehyde, which by reaction with proline and maleimide, afforded a ca. 1:1 mixture of pyrrolizidines 66 (Fig. 4).

A four-component procedure has been carried out with isatin, proline, 3-(cyanoacetyl)indole and aldehydes under refluxing methanol affording spiropyrrolizidines 67 in moderate yields (Scheme 9) [50]. The corresponding dipolarophiles 68 were formed in situ via a Knoevenagel condensation between 3-(cyanoacetyl)indole and aldehydes.

Scheme 9:

Four-component 1,3-DC of isatin, proline, 3-(cyanoacetyl)indole and aldehydes.

Multicomponent synthesis of pyrrolizidines by 1,3-DC

Alkyl prolinate derivatives gave stabilized azomethine ylides by reaction with carbonyl compounds, which can be trapped by dipolarophiles giving substituted pyrrolizidines. Joucla and co-workers have described the three-component 1,3-DC of methyl prolinate with benzaldehyde and methyl (E)-cinnamate in refluxing toluene giving, regioselectively, a 1:1 mixture of pyrrolizidines 69 and 70 in 90% yield (Scheme 10) [51]. The relative configuration of compounds 69 and 70 can be attributed to the formation of the azomethine ylide VIII, which attacks to the dipolarophile by the α-position.

Scheme 10:

Multicomponent 1,3-DC of methyl prolinate, benzaldehyde and methyl (E)-cinnamate.

The former process was performed by Maiti and co-workers [52] with cinnamaldehydes and different dipolarophiles, in dichloromethane at rt, providing pyrrolizidines 71 in high yields through an azomethine ylide of type VIII, by an endo approach (Fig. 5). When β-nitrostyrenes were used as dipolarophiles, compounds 72 were regio- and diastereoselectively formed according to an endo-approach and similar behavior was observed with acrylates and acrylonitrile leading to products 73 in good yields (Fig. 5). Independently, our group studied the same multicomponent 1,3-DC between methyl prolinate hydrochloride in the presence of Et₃N, using toluene as solvent at rt, different aldehydes and dipolarophiles [53]. This process can be performed alternatively in the presence of AgOAc (5 mol %) affording similar results. The presence of AgOAc was crucial when benzaldehyde and isopentanal were allowed to react with methyl acrylate as dipolarophile giving mainly products 74 with up to 99:1 dr (Fig. 5). However, when ethyl glyoxylate was used as aldehyde the reaction only occurred in the presence of AgOAc affording exclusively the other regioisomer 75 as the only diastereomer. The formation of 75 can be explained by the participation of the azomethine ylide IX, which reacted by the less substituted γ-position (Fig. 5).

Fig. 5:

Pyrrolizidines from alkyl prolinates, aldehydes and dipolarophiles.

Methyl (4S)-4-hydroxyprolinate gave mainly the corresponding enantiomerically pure adducts 76 when cinnamaldehyde and acrylates were used working under refluxing toluene (Scheme 11) [48].

Scheme 11:

Three-component 1,3-DC of methyl (4S)-4-hydroxyprolinate with cinnamaldehyde and acrylates.

However, working in the presence, or in the absence of AgOAc, and N-methylmaleimide as dipolarophile, a 3:1 mixture of diastereomeric adducts 77 and 78 were obtained [54] (Fig. 6). Further studies about these processes, performed by our group with methyl (4S)-4-hydroxyprolinate, benzaldehyde and tert-butyl acrylate indicated that only compound 79 was isolated in the absence of AgOAc in 75% yield. In the case of using (E)-1,2-bis(phenylsulfonyl)ethylene, also the corresponding endo-pyrrolizidine 80 was exclusively obtained (Fig. 6) [54]. When N-crotonoyloxazolidinone was used as dipolarophile with methyl (4S)-4-hydroxyprolinate and cinnamaldehyde product 81 was obtained in 90% de (Fig. 6). From DFT calculations it can be deduced that the equilibrium between S-shape X and U-shape XI dipoles, derived from methyl prolinate and methyl (4S)-4-hydroxyprolinate and cinnamaldehyde, requires an activation barrier higher than 30 Kcal·mol⁻¹ (Fig. 6). On the other hand, the high observed diastereoselection with the methyl (4S)-4-hydroxyprolinate derivative is a consequence of the presence of a hydrogen bonding during the endo-approach.

Fig. 6:

Pyrrolizidines from methyl (4S)-4-hydroxyprolinate, aldehydes and dipolarophiles.

Consecutive three-component 1,3-DC were described by Shi and co-workers [55]. The initial multicomponent 1,3-DC was performed with glycine methyl ester, cinnamaldehyde and N-phenylmaleimide (NPM) giving racemic compound 82 in 73% yield (Scheme 12). Further treatment of these adducts 82 with the same reagents, under solvent-free conditions and heated with MW (700 W) for 10 min, afforded the tetracyclic product 83 in 59% yield.

Scheme 12:

Consecutive multicomponent 1,3-DC.

The same double 1,3-DC was performed by Zhang and co-workers in a single operation just under MW heating at 180°C in toluene (Scheme 13) [56]. Different aldehydes and maleimides have been used giving products 84 in good yields. When the former process was performed stepwise, it means first the formation of compound 82 (R²=Et) and then different aldehydes and maleimides were added to the reaction media, the corresponding unsymmetrical tetracyclic compounds 85 were formed (Scheme 13).

Scheme 13:

Three-component 1,3-DC of methyl glycinate, aldehydes and maleimides.

Reisman and co-workers [57] performed this double 1,3-DC, first by synthesizing prolines 87 in 44–96% ee using Schreiber’s conditions [58]. The 1,3-DC of glycine imino with tert-butyl acrylate using QUINAP (86) and AgOAc, as catalyst, provided prolinates 87 with ee up to 96%. Without isolation of adducts 87, cinnamaldehyde and tert-butyl acrylate were added to the reaction media at rt providing pyrrolizidines 88, with the same ee that for 87 by intermediacy of the azomethine ylide XII (Scheme 14).

Scheme 14:

Double consecutive 1,3-DC.

Our group has performed a double 1,3-DC using enantioenriched nitro prolinates 90 [59]. The first 1,3-DC was carried out with glycine imino esters and nitroalkenes using chiral phosphoramidite 89 and Cu(OTf)₂ [60], AgOTf, or AgO₂CPh [42] complexes providing exo-4-nitroprolinates 90 [47], [60], [61]. Representative exo-90 (R¹=R²=Ph, >99% ee) was allowed to react in a multicomponent 1,3-DC with cinnamaldehyde and different dipolarophiles under AgOAc catalysis in NMP at 70°C affording pyrrolizidines endo- and exo-91 in moderate to high diastereoselectivity by means of the azomethine ylide XIII, which reacts with dipolarophiles mainly through an endo-approach (Scheme 15 and Fig. 7) [59].

Scheme 15:

Double stepwise 1,3-DC.

Fig. 7:

Pyrrolizidines from exo-nitroprolinate 90 (R¹=R²=Ph), cinnamaldehyde and dipolarophiles.

In the case of N-methylmaleimide or maleimide, the diastereomeric products 91a and 91b were obtained in 2:1 dr, which could be separated by flash chromatography. However, in the case of N-phenylmaleimide exo-91c was mainly obtained in a 3:1 dr which, after chromatographic separation, gave the exo-diastereomer in 65% yield. Methyl acrylate gave regio- and diastereoselectively endo-91d in 92% de which, after purification, afforded the pure pyrrolizidine in 88% yield. Methyl fumarate gave a 2:1 mixture of endo and exo-91e which were separated after purification in 48 and 26% yield, respectively. When methyl or ethyl acetylenedicarboxylates were employed as dipolarophiles compounds 91f and 91g were obtained in moderate yields. The endo approach could be explained by means of model A in which the steric interactions between the two phenyl groups of the exo-nitroprolinate 90 were avoided. In the case of N-phenylmaleimide (NPM) the steric interactions between the phenyl group of NPM and the nitro group favors the exo-approach as indicated in model B. On the other hand, the stereochemistry observed with the methyl acrylate justified the α-attack of the azomethine ylide XIII to the dipolarophile (Fig. 7).

Sing and co-workers has recently performed a double consecutive 1,3-DC by synthesizing firstly prolinates 93 by enantiocatalyzed 1,3-DC of glycine imino esters with α,β-unsaturated pyrazolamides using the chiral complex formed by (R)-DM-SEGPHOS (92) and AgOTf (Scheme 16) [62]. Afterwards, cinnamaldehydes and maleimides were added to the reaction flask providing pyrrolizidines 94 in moderate to high endo-diastereoselectivity. Further reduction of compound endo-94 with NaBH₄ and LiAlH₄ gave different hydroxylated pyrrolizidines.

Scheme 16:

Double consecutive 1,3-DC.

A different multicomponent 1,3-DC has been performed by Coldham and co-workers using the aldehyde 95, glycine ethyl ester hydrochloride and dipolarophiles (Scheme 17) [63]. This process afforded pyrrolizidines 96 under refluxing toluene with good diastereoselectivity in favor of the endo-cycloadducts.

Scheme 17:

Three-component 1,3-DC of chloro aldehyde 95 with ethyl glycinate and dipolarophiles.

Multicomponent synthesis of indolizidines by decarboxylative 1,3-DC

The decarboxylative route to azomethine ylides from primary and secondary α-amino acids was first described by Grigg and co-workers [7], [8], [9], [10], [11], [12]. Starting from tetrahydrosioquinoline-3-carboxylic acid 98a and aldehydes and N-methylmaleimide in DMF at 120°C, the corresponding cycloadducts 99 were obtained as ca. 1:1 mixture of endo and exo-benzoindolizidines 99 derived from the syn-dipole XIV (Scheme 18). This process has been studied with tetrahydro-β-carboline-3-carboxylic acid giving a 1:1 mixture of endo/exo-products 100. In the case of pipecolinic acid the corresponding indolizidine 101 was formed by reaction with 2-pyridinecarboxaldehyde and N-methylmaleimide (NMM) in 70% yield. However, in the case of tetrahydroisoquinoline- and tetrahydro-β-carboline-1-carboxylic acid the reaction with benzaldehyde and NMM gave, through syn and anti-dipoles, mixtures of the four diastereomers.

Scheme 18:

Three-component 1,3-DC of tetrahydroisoquinoline-3-carboxylic acid, aldehydes and maleimides.

Grigg and co-workers also demonstrated that, in the case of cyclic α-amino acids intermediate oxazolidine-5-ones, 1,4-prototropic rearrangement of the azomethine ylide or formation of a stable azomethine ylide can occur during the decarboxylative 1,3-DC [10], [64].

Banerjee and co-workers studied the reaction of pipecolinic acid with isatin and a carbohydrate olefin (Scheme 3) [17]. In the case of pipecolinic acid the spiro compound was formed under refluxing toluene (Scheme 19).

Scheme 19:

Three-component 1,3-DC of pipecolinic acid, isatin and a carbohydrate-derived dipolarophile.

Other examples using isatins, already described in the case of pyrrolizidines, are compiled in Fig. 8 using pipecolic acid. In these cases, compound 103 has been isolated by a three-component 1,3-DC using an unsaturated carbohydrate lactone as dipolarophile [24]. Another example is the synthesis of spiro indolizidines 104 from nitro chromans 22 [25]. In the reaction of tetraethyl vinylidenebis(phosphonate) (38) [25] the corresponding indolizidines 105 were prepared in acetonitrile at 80°C in moderate yields. This spiro indole-indolizidine unit is present in the natural product strychnofoline 106.

Fig. 8:

Spirooxindole-indolizidines.

Our group has studied the multicomponent decarboxylative 1,3-DC of pipecolinic acid with cinnamaldehyde or benzaldehyde with different dipolarophiles providing indolizidines 107 (Scheme 20) [65]. The process took place in refluxing toluene giving mixtures of the four diastereomers due to the participation of anti- and syn-XVII azomethine ylides. In the case of NMM or NPM products 107a–c were formed whereas dimethyl and diisobutyl fumarates afforded indolizidines 108a–b. In the example of tert-butyl acrylate only regioisomeric products 109, resulted from the α-attack of azomethine ylides XV and XVI, were isolated. The same happened with β-nitrostyrene, providing the nitroindolizidines 110.

Scheme 20:

Three-component 1,3-DC of pipecolic acid, aldehydes and dipolarophiles.

Coldham and co-workers have used 111, the homologous aldehyde of 95 (Scheme 17), in the three-component decarboxylative 1,3-DC with α-amino acids and dipolarophiles, affording 1:1 mixtures of endo:exo indolizidines 112 under refluxing toluene, by intermediacy of the azomethine ylide XVII (Scheme 21) [63], [66].

Scheme 21:

Three-component 1,3-DC of aldehyde 111 with α-amino acids and dipolarophiles.

The former process has been performed with different halogen substituted aldehydes. In the case of ortho-2-(bromoethyl)benzaldehyde 113, the precursor 114 of crispine was prepared in 70% yield (Scheme 22) [66].

Scheme 22:

Three-component 1,3-DC of glycine, the aldehyde 113 and (E)-bis(phenylsulfonyl)ethylene.

Multicomponent synthesis of indolizidines by 1,3-DC

Joucla and co-workers reported the multicomponent 1,3-DC of ethyl pipecolinate with benzaldehyde and NMM giving a 3:1 mixture of endo/exo indolizidines 115a (Scheme 23) [51]. However, in the case of methyl fumarate a 1:1 mixture of endo/exo115b was obtained. The diastereomeric result was explained by the participation of the azomethine ylide XVIII.

Scheme 23:

Three-component 1,3-DC of ethyl prolinate, benzaldehyde and dipolarophiles.

As in the case of alkyl prolinates, Grigg and co-workers described the three-component 1,3-DC of methyl tetrahydroisoquinoline-3-carboxylate (98b) with (+)-menthyl glyoxylate (116) and NMM [67]. This 1,3-DC took place in DMF at 110°C providing a 5:1 mixture of endo/exo cycloadducts 117 in 73% yield arising from the azomethine ylide XIX (Scheme 24). Methyl tetrahydro-β-carboline-3-carboxylate gave a 3.5:1 mixture of isomeric cycloadducts, compound 118 being isolated in 51% yield. However, when 2-methoxybenzaldehyde was allowed to react with methyl tetrahydroisoquinoline-3-carboxylate a ca. 1:1 mixture of separable products 119 were obtained by the formation of the azomethine ylide XX.

Scheme 24:

Three-component 1,3-DC of methyl tetrahydroisoquinoline-3-carboxylate and methyl tetrahydro-β-carboline-3-carboxylate 98b with (+)-menthyl glyoxylate 116 and dipolarophiles.

Our group has described the three-component 1,3-DC of methyl pipecolinate hydrochloride with cinnamaldehyde and dipolarophiles, in toluene at 75°C, affording indolizidines 120–127 as mixture of diastereomers (Scheme 25) [65]. In the case of methyl acrylate, endo-120 was isolated in agreement with the α-attack of azomethine ylide XXI. Methyl fumarate gave a separable mixture of endo/exo-adducts 121 in 70 and 11% yield, respectively. However, chalcone afforded regioselectively exo-122. When β-nitro styrene was used as dipolarophile a 1:3 mixture of regioisomeric endo-123 and exo-124 was obtained. N-Methyl and N-phenylmaleimide gave a 7:3 mixture of products endo/exo125. When benzaldehyde was used as carbonyl component and maleic anhydride as dipolarophile, compound endo-126 was obtained in modest yield with total diastereoselectivity. In the case of the reactions performed with furfural and NMM, products endo/exo127 were isolated with 64% de. The major endo-products could be isolated and in the case of endo-127 the relative configuration was assigned according to X-ray diffraction analysis.

Scheme 25:

Three-component 1,3-DC of methyl pipecolate with cinnamaldehyde and dipolarophiles.

The multicomponent 1,3-DC of 1,2-diaza-1,3-diene 128 with formaldehyde and ethyl pipecolate gave regioselectively indolizidine derivatives 129 in moderate yield (Scheme 26) [68].

Scheme 26:

Three-component 1,3-DC of ethyl pipecolate, compounds 128 and formaldehyde.

Coldham and co-workers have described the three-component 1,3-DC of the γ-chloro aldehyde 95 for the synthesis of pyrrolizidines (Scheme 17) [63]. When the homologous aldehyde 111 was allowed to react with ethyl glycinate hydrochloride and different dipolarophiles, indolizidines 130 were prepared (Scheme 27) [66]. In the case of NMM and methyl maleate, a mixture of three separable diastereomers in ca. 2:2:1 and 94 and 74% yield were obtained, respectively, diasteromers 130a and 130b being mainly identified. For methyl acrylate, a 3.4:2.4 mixture of the corresponding regioisomers 130c was obtained in 77% overall yield.

Scheme 27:

Three-component 1,3-DC of ethyl glycinate, the aldehyde 111 and dipolarophiles.

Conclusions

Three-components 1,3-dipolar cycloadditions between cyclic α-amino acids, carbonyl compounds and electrophilic alkenes are an excellent, simple and powerful methodology for the thermal synthesis of the pyrrolizidine and indolizidine derivatives. The atom economy of these processes is total except for the reactions involving decarboxylations where a small molecule of carbon dioxide is lost. By means of proline and pipecolinic acid or related amino acids the intermediate azomethine ylides are formed by condensation with the carbonyl compound via a decarboxylative process. This metododology allows the synthesis of spiro-pyrrolizidines and -indolizidines when ketones are used as carbonyl component with high regio- and diastereocontrol. In particular, the synthesis of biological active spirooxindole-pyrrolizidines can be carried out using isatins as carbonyl components in only one step operation. The regio- and diastereoselectivity can be better controlled in the case of using cyclic α-amino acid derived esters than in the decarboxylative 1,3-DC giving the corresponding pyrrolizidines and indolizidines with an alkoxycarbonyl substituent in the bridge of the bicyclic systems. The last methodology can be also performed using a double 1,3-DC, first the asymmetric synthesis of the proline unit followed by the three-component 1,3-DC affording enantioenriched pyrrolizidines.