A Simple Entry to the 5,8-Disubstituted Indolizidine Skeleton via Hetero Diels-Alder Reaction

The 5,8-disubstituted indolizidines are the largest family of indolizidines isolated from the skin of amphibians. These compounds exhibit interesting biological activities such as noncompetitive blockers of nicotinic receptors. In this paper, we present a short, simple, and general synthesis of these alkaloids based on the hetero Diels–Alder reaction between suitable monoactivated dienes and Δ1-pyrroline as the dienophile. The selectivity of the process is explained based on computational studies. Concise synthesis of the indolizidine alkaloid 181B from a hetero Diels–Alder reaction was accomplished in four steps.


Introduction
Indolizidine alkaloids constitute a large family of heterocyclic compounds isolated from numerous sources, both terrestrial and marine [1][2][3].The basic structure of indolizidines is that of a five-membered ring fused with a six-membered ring, with a nitrogen atom at one of the fusion points (Figure 1).

Introduction
Indolizidine alkaloids constitute a large family of heterocyclic compounds isolated from numerous sources, both terrestrial and marine [1][2][3].The basic structure of indolizidines is that of a five-membered ring fused with a six-membered ring, with a nitrogen atom at one of the fusion points (Figure 1).Indolizidines exist with different substitution patterns-from the simple basic skeleton with some hydroxyl groups to more complex structures (Figure 2).Indolizidines exist with different substitution patterns-from the simple basic skeleton with some hydroxyl groups to more complex structures (Figure 2).Some of these alkaloids show interesting biological activities, such as antitumor, antiviral, antileukemic, and others [4,5].
A large number of indolizidines have been isolated from or detected on the skins of amphibians, and these are usually substituted with alkyl and hydroxyl groups, composing several families of alkaloids [6].The largest family is that of the 5,8- Some of these alkaloids show interesting biological activities, such as antitumor, antiviral, antileukemic, and others [4,5].
A large number of indolizidines have been isolated from or detected on the skins of amphibians, and these are usually substituted with alkyl and hydroxyl groups, composing several families of alkaloids [6].The largest family is that of the 5,8-disubstituted indolizidines, with more than 80 examples reported.These indolizidines come mainly from dietary sources since many have been isolated from mites that coexist with the amphibian [7,8].Many of these have tentative structures due to the difficulty of isolation because of the small amount present in samples obtained from natural sources.
Although some species of amphibians that contain these alkaloids are known to be toxic, the toxicity is not produced by the 5,8-disubstituted indolizidines.Their reported biological activity is as noncompetitive blockers of nicotinic receptors [9,10].
Numerous synthetic schemes aimed at the preparation of the indolizidine skeleton, both racemic and enantioselective, have been published.The most usual methodology is the cyclization of a suitable monocyclic intermediate, giving the bicyclic skeleton of the alkaloids [11].
A special mention must be made to Danishefsky and Vogel's synthesis of (±)-Ipalbidine [12], in which a hetero Diels-Alder reaction between an activated diene and ∆ 1 -pyrroline was used as the key step to prepare the target compound (Figure 3).Some of these alkaloids show interesting biological activities, such as antitumor, antiviral, antileukemic, and others [4,5].
A large number of indolizidines have been isolated from or detected on the skins of amphibians, and these are usually substituted with alkyl and hydroxyl groups, composing several families of alkaloids [6].The largest family is that of the 5,8disubstituted indolizidines, with more than 80 examples reported.These indolizidines come mainly from dietary sources since many have been isolated from mites that coexist with the amphibian [7,8].Many of these have tentative structures due to the difficulty of isolation because of the small amount present in samples obtained from natural sources.
Although some species of amphibians that contain these alkaloids are known to be toxic, the toxicity is not produced by the 5,8-disubstituted indolizidines.Their reported biological activity is as noncompetitive blockers of nicotinic receptors [9,10].
Numerous synthetic schemes aimed at the preparation of the indolizidine skeleton, both racemic and enantioselective, have been published.The most usual methodology is the cyclization of a suitable monocyclic intermediate, giving the bicyclic skeleton of the alkaloids [11].
In our group, the hetero Diels-Alder reactions of monoactivated dienes have been used for the synthesis of oxygen-containing compounds via reaction with aldehydes [19].We found that monoactivated dienes work well in those reactions in the presence of Lewis acids.Thus, we envisioned that the reaction between a suitable monoactivated diene and a cyclic imine (Δ 1 -pyrroline) could give quick access to the 5,8-alkyl-disubstituted indolizidine skeleton (Scheme 1), providing a simple method to prepare a variety of heterocyclic compounds in a few steps.The relative stereochemistry of the cycloadduct depends on the endo/exo selectivity of the cycloaddition, which in turn depends on the nature of the substituents on the diene.This aspect must be taken into account to match the relative stereochemistry of the natural compounds.This approach has been used in a few examples, with ∆ 1 -pyrroline derivatives and 1,3-diactivated dienes giving hydroxyl-substituted indolizidines [13][14][15][16], or ∆ 1 -pyrroline and allenyltrimethylsilylthioketenes acting as dienes [17,18].
In our group, the hetero Diels-Alder reactions of monoactivated dienes have been used for the synthesis of oxygen-containing compounds via reaction with aldehydes [19].We found that monoactivated dienes work well in those reactions in the presence of Lewis acids.Thus, we envisioned that the reaction between a suitable monoactivated diene and a cyclic imine (∆ 1 -pyrroline) could give quick access to the 5,8-alkyl-disubstituted indolizidine skeleton (Scheme 1), providing a simple method to prepare a variety of heterocyclic compounds in a few steps.The relative stereochemistry of the cycloadduct depends on the endo/exo selectivity of the cycloaddition, which in turn depends on the nature of the substituents on the diene.This aspect must be taken into account to match the relative stereochemistry of the natural compounds.In this article, we present our results in that direction, confirming the idea that the indolizidine skeleton can be accessed from easily prepared dienes and Δ 1 -pyrroline in a few steps.First, the conditions for the reactions between simple monoactivated dienes and Δ 1 pyrroline were studied.Then stereochemical issues were addressed, and finally, the In this article, we present our results in that direction, confirming the idea that the indolizidine skeleton can be accessed from easily prepared dienes and ∆ 1 -pyrroline in a few steps.First, the conditions for the reactions between simple monoactivated dienes and ∆ 1 pyrroline were studied.Then stereochemical issues were addressed, and finally, the racemic synthesis of the 5,8-disubstituted indolizidine 181B from the hetero Diels-Alder reaction was achieved in only four steps.

Results and Discussion
To simplify the synthesis of the indolizidine skeleton, we decided to use monoactivated dienes with a silyloxy group, which works well with hetero dienophiles such as aldehydes under Lewis acid catalysis [19].

Synthesis of the First Model: Mono-Substituted Indolizidine Skeleton
To test this idea, we decided to start with a simple mono-substituted alkyl indolizidine skeleton following the reactions shown in Scheme 2. Mono-substituted indolizidines with the substituent at position five were proposed as natural compounds; however, it was later determined that their structures were incorrect [6].This type of 5-substituted indolizidine has been the target of several synthesis efforts [20][21][22][23][24][25].In this article, we present our results in that direction, confirming the idea that the indolizidine skeleton can be accessed from easily prepared dienes and Δ 1 -pyrroline in a few steps.First, the conditions for the reactions between simple monoactivated dienes and Δ 1 pyrroline were studied.Then stereochemical issues were addressed, and finally, the racemic synthesis of the 5,8-disubstituted indolizidine 181B from the hetero Diels-Alder reaction was achieved in only four steps.

Results and Discussion
To simplify the synthesis of the indolizidine skeleton, we decided to use monoactivated dienes with a silyloxy group, which works well with hetero dienophiles such as aldehydes under Lewis acid catalysis [19].

Synthesis of the First Model: Mono-Substituted Indolizidine Skeleton
To test this idea, we decided to start with a simple mono-substituted alkyl indolizidine skeleton following the reactions shown in Scheme 2. Mono-substituted indolizidines with the substituent at position five were proposed as natural compounds; however, it was later determined that their structures were incorrect [6].This type of 5substituted indolizidine has been the target of several synthesis efforts [20][21][22][23][24][25].The simple monoactivated diene 1 was chosen to test the reaction.The alkyl chain on 1 contains a benzyloxy group since that group can serve as a reactivity point to make further transformations on the indolizidine skeleton [26,27].Additionally, these dienes tend to be volatile and somewhat difficult to work with.The presence of the benzyloxy group was expected to reduce the volatility.
Although the hetero Diels-Alder reaction was expected to proceed with high regioselectivity, the endo/exo ratio depends on the structure and degree of substitution on the diene, thus a complete study of the selectivity of the cycloaddition reaction was planned.
The diene was prepared following previous reports [28].The dienophile Δ 1 -pyrroline was prepared from the diethylacetal of 4-aminobutyraldehyde as described in the literature [29] and was freshly distilled before each use.The simple monoactivated diene 1 was chosen to test the reaction.The alkyl chain on 1 contains a benzyloxy group since that group can serve as a reactivity point to make further transformations on the indolizidine skeleton [26,27].Additionally, these dienes tend to be volatile and somewhat difficult to work with.The presence of the benzyloxy group was expected to reduce the volatility.
Although the hetero Diels-Alder reaction was expected to proceed with high regioselectivity, the endo/exo ratio depends on the structure and degree of substitution on the diene, thus a complete study of the selectivity of the cycloaddition reaction was planned.
The diene was prepared following previous reports [28].The dienophile ∆ 1 -pyrroline was prepared from the diethylacetal of 4-aminobutyraldehyde as described in the literature [29] and was freshly distilled before each use.
We tested BF 3 •OEt 2 , and In(OTf) 3 as Lewis acids since in our experience these two acids work well in hetero Diels-Alder reactions.The boron derivative gave the expected cycloadducts (±)-2 in a 40% yield and a 60:40 ratio of endo:exo isomers.The low yield was due to its reactivity with the diene, resulting in recovered unsaturated ketones.With the indium compound, the yield increased to 72% with the same endo:exo ratio.It must be noted that all compounds were slightly volatile even with the benzyloxy group present.The amount of BF 3 •OEt 2 needed for the reaction to proceed to completion was one equivalent, as is usual for this reagent, since the complex it forms with the dienophile is quite strong.As a comparison, three equivalents were needed for the Danishefsky and Vogel hetero Diels-Alder reaction [12].For the In(OTf) 3 , it was found that 0.5 equivalents were needed for the reaction to be complete.
The reaction was also studied computationally using the DFT level [30].These studies concluded that the mechanism is a cycloaddition reaction but with some asynchronicity.The low endo:exo selectivity correlated with the small difference in the energy of the corresponding transition states probably due to the low steric hindrance shown by the diene (for a discussion see the supporting information).
After extraction and purification, the structure and relative stereochemistry of the cycloadducts were studied using standard NMR experiments such as COSY, HMQC, HMBC, and ROESY.
Figure 4 shows the results of these experiments, which allowed us to ascertain that the major compound obtained in the cycloaddition was the endo isomer.This isomer has the same relative stereochemistry as most of the known mono-substituted indolizidines.
The amount of BF3•OEt2 needed for the reaction to proceed to completion was one equivalent, as is usual for this reagent, since the complex it forms with the dienophile is quite strong.As a comparison, three equivalents were needed for the Danishefsky and Vogel hetero Diels-Alder reaction [12].For the In(OTf)3, it was found that 0.5 equivalents were needed for the reaction to be complete.
The reaction was also studied computationally using the DFT level [30].These studies concluded that the mechanism is a cycloaddition reaction but with some asynchronicity.The low endo:exo selectivity correlated with the small difference in the energy of the corresponding transition states probably due to the low steric hindrance shown by the diene (for a discussion see the supporting information).
After extraction and purification, the structure and relative stereochemistry of the cycloadducts were studied using standard NMR experiments such as COSY, HMQC, HMBC, and ROESY.
Figure 4 shows the results of these experiments, which allowed us to ascertain that the major compound obtained in the cycloaddition was the endo isomer.This isomer has the same relative stereochemistry as most of the known mono-substituted indolizidines.

Synthesis of 8-Methyl-5-Alkyl Indolizidine Skeleton
Once we found a set of conditions to carry out the hetero Diels-Alder reaction with Δ 1 -pyrroline as the dienophile, we moved on to a system closely related to the most abundant indolizidine alkaloids from amphibious sources, the 5,8-disubstituted indolizidines [6].Several procedures for the syntheses of this family of indolizidines have been published [31][32][33].The most common among these are the indolizidines with a methyl group at the eighth position, and thus, we decided to prepare an example of a 5alkyl-8-methyl indolizidine.In these compounds, the stereochemistry of the stereogenic centers is usually cis for the hydrogens at the positions α to the nitrogen (C5 y C8a) and trans between these and the hydrogen at C8.This relative stereochemistry is expected from the endo adduct of a cycloaddition reaction in which the group at the eighth position has undergone epimerization.Since this position is adjacent to the silyloxy group in the expected cycloadducts, we envisioned that after cleaving the silyl group, the resulting carbonyl group could help to epimerize this position (Scheme 3).A computational study indicated that the epimerized ketone should be more stable than the ketone one coming from the cycloaddition reaction.For a discussion see the supporting information.

Synthesis of 8-Methyl-5-Alkyl Indolizidine Skeleton
Once we found a set of conditions to carry out the hetero Diels-Alder reaction with ∆ 1 -pyrroline as the dienophile, we moved on to a system closely related to the most abundant indolizidine alkaloids from amphibious sources, the 5,8-disubstituted indolizidines [6].Several procedures for the syntheses of this family of indolizidines have been published [31][32][33].The most common among these are the indolizidines with a methyl group at the eighth position, and thus, we decided to prepare an example of a 5-alkyl-8methyl indolizidine.In these compounds, the stereochemistry of the stereogenic centers is usually cis for the hydrogens at the positions α to the nitrogen (C5 y C8a) and trans between these and the hydrogen at C8.This relative stereochemistry is expected from the endo adduct of a cycloaddition reaction in which the group at the eighth position has undergone epimerization.Since this position is adjacent to the silyloxy group in the expected cycloadducts, we envisioned that after cleaving the silyl group, the resulting carbonyl group could help to epimerize this position (Scheme 3).A computational study indicated that the epimerized ketone should be more stable than the ketone one coming from the cycloaddition reaction.For a discussion see the supporting information.For this study, we decided to maintain the benzyloxy group in the alkyl chain to increase its polarity and facilitate its handling (Scheme 4).For this study, we decided to maintain the benzyloxy group in the alkyl chain to increase its polarity and facilitate its handling (Scheme 4).Scheme 3. Proposed synthesis of the 8-methyl-5-alkyl indolizidine skeleton with the most common relative stereochemistry found in natural compounds.

BnO
For this study, we decided to maintain the benzyloxy group in the alkyl chain to increase its polarity and facilitate its handling (Scheme 4).The diene needed for this synthesis was prepared according to the literature [28].After reacting with Δ 1 -pyrroline under In(OTf)3 catalysis, one cycloadduct (±)-4 was observed as the major compound (>90%) in an almost quantitative yield.NMR studies of this major cycloadduct (Figure 5) indicated that this compound corresponds to the endo adduct and thus, the three hydrogen atoms in the stereocenters of the molecule are in an all-cis relationship.The computational study of this reaction indicates a larger difference in energy between the respective transition states, favoring the endo one (see the supporting information).The subsequent step was the cleavage of the enol-silyl group to give the corresponding ketone, which was used to attempt the epimerization of the methyl group on carbon 8 (Scheme 5).The diene needed for this synthesis was prepared according to the literature [28].After reacting with ∆ 1 -pyrroline under In(OTf) 3 catalysis, one cycloadduct (±)-4 was observed as the major compound (>90%) in an almost quantitative yield.NMR studies of this major cycloadduct (Figure 5) indicated that this compound corresponds to the endo adduct and thus, the three hydrogen atoms in the stereocenters of the molecule are in an all-cis relationship.The computational study of this reaction indicates a larger difference in energy between the respective transition states, favoring the endo one (see the supporting information).Scheme 3. Proposed synthesis of the 8-methyl-5-alkyl indolizidine skeleton with the most common relative stereochemistry found in natural compounds.

BnO
For this study, we decided to maintain the benzyloxy group in the alkyl chain to increase its polarity and facilitate its handling (Scheme 4).The diene needed for this synthesis was prepared according to the literature [28].After reacting with Δ 1 -pyrroline under In(OTf)3 catalysis, one cycloadduct (±)-4 was observed as the major compound (>90%) in an almost quantitative yield.NMR studies of this major cycloadduct (Figure 5) indicated that this compound corresponds to the endo adduct and thus, the three hydrogen atoms in the stereocenters of the molecule are in an all-cis relationship.The computational study of this reaction indicates a larger difference in energy between the respective transition states, favoring the endo one (see the supporting information).The subsequent step was the cleavage of the enol-silyl group to give the corresponding ketone, which was used to attempt the epimerization of the methyl group on carbon 8 (Scheme 5).The subsequent step was the cleavage of the enol-silyl group to give the corresponding ketone, which was used to attempt the epimerization of the methyl group on carbon 8 (Scheme 5).

Synthesis of Indolizidine Rac-181B
Finally, once the validity of the basic strategy was confirmed, we carried out total synthesis of one natural indolizidine in racemic form.The synthesis could have been performed from the previously obtained keto-indolizidine (±)-6, eliminating the ketone group and transforming the benzyloxy group into a leaving group to introduce the required alkyl chain.However, we felt that it would be interesting to prepare the target molecule in as few steps as possible to check the validity of this fast approach to the 5, 8disubstituted indolizidine family.Thus, a diene with the required substituents in place was needed.Diene 8 was prepared as shown in Scheme 6 as a 9:1 mixture of Z:E isomers.The major isomer, easily separated by column chromatography using hexanes with 1% of Et3N as eluent, was reacted with Δ 1 -pyrroline in the presence of In(OTf)3 to give the expected cycloadducts (±)-9 in a 90:10 endo:exo ratio.This ratio is expected from the presence of the methyl group at the eighth position, which increases the selectivity favoring the endo approach as found from the calculation on compound 4. The yield was

Synthesis of Indolizidine Rac-181B
Finally, once the validity of the basic strategy was confirmed, we carried out total synthesis of one natural indolizidine in racemic form.The synthesis could have been performed from the previously obtained keto-indolizidine (±)-6, eliminating the ketone group and transforming the benzyloxy group into a leaving group to introduce the required alkyl chain.However, we felt that it would be interesting to prepare the target molecule in as few steps as possible to check the validity of this fast approach to the 5, 8-disubstituted indolizidine family.Thus, a diene with the required substituents in place was needed.Diene 8 was prepared as shown in Scheme 6 as a 9:1 mixture of Z:E isomers.The major isomer, easily separated by column chromatography using hexanes with 1% of Et 3 N as eluent, was reacted with ∆ 1 -pyrroline in the presence of In(OTf) 3 to give the expected cycloadducts (±)-9 in a 90:10 endo:exo ratio.This ratio is expected from the presence of the methyl group at the eighth position, which increases the selectivity favoring the endo approach as found from the calculation on compound 4. The yield was almost quantitative as judged by the 1 H-NMR spectra of the crude reaction mixture, although the isolated yield was 92%, probably due to some decomposition of compounds (±)-9 in contact with the silica gel.
The structures and relative stereochemistry of both cycloadducts were studied using NMR experiments, which confirmed that the major compound was the endo cycloadduct.
Based on the experience acquired, we decided to treat the endo cycloadduct directly with HBr to obtain the epimerized ketone in one step.
When the crude reaction mixture from the cycloaddition reaction was treated directly with HBr under the same conditions as before, ketone (±)-10 was obtained in a 90% isolated yield (Scheme 7).
almost quantitative as judged by the 1 H-NMR spectra of the crude reaction mixture, although the isolated yield was 92%, probably due to some decomposition of compounds (±)-9 in contact with the silica gel.Scheme 6. Synthesis of cycloadducts (±)-9.
The structures and relative stereochemistry of both cycloadducts were studied using NMR experiments, which confirmed that the major compound was the endo cycloadduct.
Based on the experience acquired, we decided to treat the endo cycloadduct directly with HBr to obtain the epimerized ketone in one step.
When the crude reaction mixture from the cycloaddition reaction was treated directly with HBr under the same conditions as before, ketone (±)-10 was obtained in a 90% isolated yield (Scheme 7).The structure was confirmed using NMR analysis.The relative stereochemistry was more difficult to prove since all three hydrogen atoms on the tertiary carbons present similar chemical shifts.Thus the assignment was tentatively established as shown in Scheme 7 based on similarity with compound 6 and some correlations observed in the ROESY spectrum.
The next step was the removal of the carbonyl group.In the literature, there are several examples of this transformation in similar compounds, and we tried some of them.The transformation of the ketone into a dithioketal and reduction with Ni-Raney/H2 [35], or treatment with TCDI and radical reduction of the thioester formed [36] gave complex mixtures.The structures and relative stereochemistry of both cycloadducts were studied using NMR experiments, which confirmed that the major compound was the endo cycloadduct.
Based on the experience acquired, we decided to treat the endo cycloadduct directly with HBr to obtain the epimerized ketone in one step.
When the crude reaction mixture from the cycloaddition reaction was treated directly with HBr under the same conditions as before, ketone (±)-10 was obtained in a 90% isolated yield (Scheme 7).The structure was confirmed using NMR analysis.The relative stereochemistry was more difficult to prove since all three hydrogen atoms on the tertiary carbons present similar chemical shifts.Thus the assignment was tentatively established as shown in Scheme 7 based on similarity with compound 6 and some correlations observed in the ROESY spectrum.
The next step was the removal of the carbonyl group.In the literature, there are several examples of this transformation in similar compounds, and we tried some of them.The transformation of the ketone into a dithioketal and reduction with Ni-Raney/H2 [35], or treatment with TCDI and radical reduction of the thioester formed [36] gave complex mixtures.Scheme 7. Synthesis of keto-indolizidine (±)-10.
The structure was confirmed using NMR analysis.The relative stereochemistry was more difficult to prove since all three hydrogen atoms on the tertiary carbons present similar chemical shifts.Thus the assignment was tentatively established as shown in Scheme 7 based on similarity with compound 6 and some correlations observed in the ROESY spectrum.
The next step was the removal of the carbonyl group.In the literature, there are several examples of this transformation in similar compounds, and we tried some of them.The transformation of the ketone into a dithioketal and reduction with Ni-Raney/H 2 [35], or treatment with TCDI and radical reduction of the thioester formed [36] gave complex mixtures.
We then resorted to the transformation of the ketone into an enol-triflate and the reduction of this moiety via catalytic hydrogenation (Scheme 8) [37].
Molecules 2023, 28, x FOR PEER REVIEW 8 of 13 We then resorted to the transformation of the ketone into an enol-triflate and the reduction of this moiety via catalytic hydrogenation (Scheme 8) [37].The enol-triflate was prepared using LDA as the base and N-phenyl bistrifluoromethanesulfonimide (PhNTf2), giving (±)-11 in an 82% yield.The hydrogenation step, using Pd/C as the catalyst, gave the reduced compound (±)-181B in an 81% yield.The 1 H NMR spectrum of this compound, after forming its salt with trifluoroacetic acid, was compared to that published by Schneider et al. [38]; the two were found to be Scheme 8. Synthesis of indolizidine (±)-181B.
The enol-triflate was prepared using LDA as the base and N-phenyl bistrifluoromethanesulfonimide (PhNTf 2 ), giving (±)-11 in an 82% yield.The hydrogenation step, using Pd/C as the catalyst, gave the reduced compound (±)-181B in an 81% yield.The 1 H NMR spectrum of this compound, after forming its salt with trifluoroacetic acid, was compared to that published by Schneider et al. [38]; the two were found to be identical.Thus, the relative stereochemistry assumed previously was correct and it was demonstrated that a 5,8-indolizidine such as 181B can be prepared in a very short synthetic sequence, namely, a hetero Diels-Alder reaction, desilylation-isomerization, formation of the enol-triflate, and catalytic hydrogenation in an overall yield of 49.5%.
The different substitutions in the indolizidine skeleton can be introduced by selecting the adequate diene.
This approach can also be used to confirm the proposed structures of the alkaloids isolated or detected in very small amounts from natural sources.

General Experimental Procedures
All moisture-sensitive reactions were carried out under an argon or nitrogen atmosphere with dry solvents under anhydrous conditions.All solvents and reagents were purified using standard techniques or used as supplied from commercial sources.Reactions under standard conditions were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 plates.Visualization was accomplished with UV light, stained with an ethanolic solution of phosphomolybdic acid or ninhydrin, and developed by heating.Silica gel (200-300 mesh) was used for column chromatography.NMR and spectra were recorded in CDCl 3 , C 6 D 6 , or CD 3 OD at 500 MHz for 1 H NMR and 125 MHz for 13 C NMR on a Bruker Avance instrument.Chemical shifts are given in (δ) parts per million and coupling constants (J) in Hz. 1H-and 13C-spectra were referenced using the solvent signal as an internal standard.The data are reported as (s = singlet, d = doublet, t = triplet, q = quartet, quintet = quintet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, and bs = broad singlet).High-resolution mass spectral analysis (HRMS) data were obtained using a VG AutoSpec spectrometer via electrospray ionization (ESI) or electron impact (EI).The 1 H NMR and 13 C NMR spectra and two-dimensional NMR spectroscopy of new compounds are provided in the Supplementary Materials.

Compound Synthesis
General Procedure for the Hetero Diels-Alder reaction with In(OTf) 3 To a solution of In(OTf) 3 (0.50 mmol) in dry acetonitrile was added a solution of ∆ 1 -pyrroline (1.00 mmol) in acetonitrile at 0 • C under argon.After 10 min, the mixture was cooled at −40 • C and a solution of diene (1.00 mmol) in acetonitrile was added.The reaction mixture was allowed to slowly warm to room temperature and stirred for 24 h, quenched with NaHCO 3 aqueous solution, extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.The residue was purified by flash chromatography to give the corresponding products.

Figure 1 .
Figure 1.Structure and numbering of the indolizidine skeleton.

Figure 1 .
Figure 1.Structure and numbering of the indolizidine skeleton.

13 Scheme 3 .
Scheme 3. Proposed synthesis of the 8-methyl-5-alkyl indolizidine skeleton with the most common relative stereochemistry found in natural compounds.

Scheme 3 .
Scheme 3. Proposed synthesis of the 8-methyl-5-alkyl indolizidine skeleton with the most common relative stereochemistry found in natural compounds.