Multicomponent Domino Reaction in the Asymmetric Synthesis of Cyclopentan[c]pyran Core of Iridoid Natural Products

The asymmetric synthesis of a compound with the cyclopentan[c]pyran core of iridoid natural products in four steps and 40% overall yield is reported. Our methodology includes a one-pot tandem domino reaction which provides a trisubstituted cyclopentane with five new completely determined stereocenters, which were determined through 2D homo and heteronuclear NMR and n.O.e. experiments on different compounds specially designed for this purpose, such as a dioxane obtained from a diol. Due to their pharmaceutical properties, including sedative, analgesic, anti-inflammatory, CNS depressor or anti-conceptive effects, this methodology to produce the abovementioned iridoid derivatives, is an interesting strategy in terms of new drug discovery as well as pharmaceutical development.


Introduction
Iridoids are a very extensive family of secondary metabolites. They are found in both terrestrial and marine flora and fauna [1][2][3]. Although usually found in their glucoside form, free iridoids as well as secoiridoids are also abundant in Nature. As free iridoids, they are precursors of biologically active alkaloids and several studies have demonstrated their interesting pharmaceutical properties, as hematoprotective or N-oxide inhibitor agents [4][5][6]. As glycosides, they are commonly found in plants, such as in the genus Nepeta, and, since they are structurally cyclopentane pyran monoterpenoids, they represent a link between terpenes and alkaloids [7]. Recent studies also suggest they are cell proliferation inhibitors, opening an interesting window into cancer treatment [8,9] as well as viral protein P (Vpr) inhibition [10]. Finally, as secoiridoids, they possess lots of biological activities such as antioxidant, anti-inflammatory, or anti-atherogenic properties, among others [11][12][13]. This family of compounds has also been extensively used in folk medicine plant treatments, all around the globe, as a remedy against coughs, wounds or skin disorders, as well as bitter tonics, antipyretics or sedatives [14,15].
The genus Nepeta, with its bigger diversity located in the Mediterranean area, have demonstrated, in recent studies, that some extracts from different plants possess very interesting therapeutic properties, such as anti-inflammatory or analgesic effects, due to the abundant presence of nepetalactone derivatives [16,17]. This opens a promising researching area, since morphine use, nowadays, is responsible a lot of dependency and deaths. Also, recent studies have demonstrated the high diversity of pharmacological properties of nepetalactone compounds [8,18,19]. They show both sedative and analgesic properties, as well as anti-inflammatory and CNS depressor effects, as new studies suggest this kind of compound is able to pass through the blood brain barrier [16]. Plus, recent studies have demonstrated nepetalactone derivatives present anticonceptive activity as well as insect repellent ability [19][20][21][22].
We have developed an asymmetric synthesis-based route, which enabled us to obtain the 4β,4aα,7α,7aα-dihydronepetalactone analogue 26 (Figure 1,) in very good yield while controlling all chiral centers. This compound is an advanced intermediate towards nepetalactone and iridoid skeletons which have been demonstrated to possess very interesting analgesic properties. Some examples of nepetalactones and iridoids accessible using our methodology are illustrated in Figure 1, where the relevance of the recently isolated secoiridoid I from Fraxinus americana L. [23] with an identical cyclopentane core can be mentioned, highlighting the importance of 26 for its synthesis [23][24][25].
Molecules 2019, 24, x FOR PEER REVIEW 2 of 26 therapeutic properties, such as anti-inflammatory or analgesic effects, due to the abundant presence of nepetalactone derivatives [16,17]. This opens a promising researching area, since morphine use, nowadays, is responsible a lot of dependency and deaths. Also, recent studies have demonstrated the high diversity of pharmacological properties of nepetalactone compounds [8,18,19]. They show both sedative and analgesic properties, as well as anti-inflammatory and CNS depressor effects, as new studies suggest this kind of compound is able to pass through the blood brain barrier [16]. Plus, recent studies have demonstrated nepetalactone derivatives present anticonceptive activity as well as insect repellent ability [19][20][21][22]. We have developed an asymmetric synthesis-based route, which enabled us to obtain the 4β,4aα,7α,7aα-dihydronepetalactone analogue 26 (Figure 1,) in very good yield while controlling all chiral centers. This compound is an advanced intermediate towards nepetalactone and iridoid skeletons which have been demonstrated to possess very interesting analgesic properties. Some examples of nepetalactones and iridoids accessible using our methodology are illustrated in Figure  1, where the relevance of the recently isolated secoiridoid I from Fraxinus americana L. [23] with an identical cyclopentane core can be mentioned, highlighting the importance of 26 for its synthesis [23][24][25].  [26][27][28], dealing with all the characteristics of the asymmetric addition, and recently, we have published a chapter describing methods for the synthesis of lithium amides and their applications in C-N and C-C bond formation reactions, including stereoselective transformations [29].
We have demonstrated the use of chiral lithium (α-methylbenzyl)benzylamide (R)-or (S)-1) in different domino reactions. We first published that a chiral lithium amide could initiate an asymmetric conjugate addition cyclization of nona-2,7-diendioate to generate chiral cyclohexane  [26][27][28], dealing with all the characteristics of the asymmetric addition, and recently, we have published a chapter describing methods for the synthesis of lithium amides and their applications in C-N and C-C bond formation reactions, including stereoselective transformations [29].
derivatives (Scheme 1, II) [30][31][32][33], and applied it to the synthesis of (1R,5R,9R)-2-azabicyclo-[3.3.1]nonane-9-carboxylic acid (morphanic acid), with a morphan scaffold [34], which was used in the synthesis of a new class of opioid receptor ligands [32]. In the same way, when octa-2,6-diendioate was used we stereoselectively obtained the 2-amino-5-carboxy-methyl-cyclopentane-1-carboxylate skeleton (Scheme 1, III) [35][36][37], and applied it to the synthesis of (R) and (S)-methyl(methoxycarbonylcyclopent-2-enyl)acetate IV and (R)-and (S)-2-(2-hydroxymethyl-cyclopent-2enyl)ethanol, useful homochiral synthons for monoterpenes [35] and to the asymmetric synthesis of all the stereoisomers of 2-amino-5-carboxymethyl-cyclopentane-1-carboxylic acid [36]. We have later shown a novel domino reaction: allylic acetate rearrangement stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition [38][39][40][41]. A protocol starting from Baylis-Hillman adducts using chiral lithium amide (R)-1 to afford δ-aminoacids, which can be transformed into piperidines [40] Furthermore we get ready access to phenethylamines from (N-α-methylbenzyl)-Nbenzyl β-aminoacids obtained by Michael addition of (R)-1 to α-β-unsaturated ester, by domino reaction initiated in a Barton decarboxylation followed by a 1,4-phenyl radical rearrangement (1,4-PhRR) [42]. Herein, as shown in retrosynthetic Scheme 2, following the aforementioned domino reaction access to cyclopentane derivatives, now in a three component version, we report the synthesis of highly functionalized cyclopentanes VIII with total stereocontrol of the four new stereocenters generated in one-pot and their application via cyclization (VII) to the synthesis of important derivatives from the point of view of their pharmaceutical activities, such as nepetalactones and iridoids. Herein, as shown in retrosynthetic Scheme 2, following the aforementioned domino reaction access to cyclopentane derivatives, now in a three component version, we report the synthesis of highly functionalized cyclopentanes VIII with total stereocontrol of the four new stereocenters generated in one-pot and their application via cyclization (VII) to the synthesis of important derivatives from the point of view of their pharmaceutical activities, such as nepetalactones and iridoids.

Domino and Tandem Reaction with Benzaldehyde
Cyclopentane derivative III has been synthesized, as already mentioned, by adding (R)-1 to 2 without a subsequent electrophile addition [35][36][37]. We wanted to introduce an additional carbon atom in the α-position of the alkoxycarbonylmethyl group, so an electrophile was necessary after performing the abovementioned domino reaction in a tandem multicomponent reaction protocol.

Domino and Tandem Reaction with Benzaldehyde
Cyclopentane derivative III has been synthesized, as already mentioned, by adding (R)-1 to 2 without a subsequent electrophile addition [35][36][37]. We wanted to introduce an additional carbon atom in the α-position of the alkoxycarbonylmethyl group, so an electrophile was necessary after performing the abovementioned domino reaction in a tandem multicomponent reaction protocol. Thus, we decided initially to use benzaldehyde as electrophile so the reaction scope, as well as the stereochemistry of the two new generated stereocenters, could be studied.
When the addition of (R)-1 (1.6 eq) to di-3-pentyl octa-2,6-diendioate is performed at −78 • C and then after one hour, benzaldehyde is added and the reaction allowed to reach room temperature, a mixture from which alcohol 3 (23%) and the C-1"' epimer 4 (45%) (Scheme 3b, showing the numbering of these derivatives) are isolated by column chromatography is obtained. The 3-pentyl ester was chosen as it largely prevents the 1,2 addition reactions of the lithium amide to the ester (methyl) group, leading to the corresponding amide and, at the same time, it is easy to hydrolyze under basic conditions. In addition, with the pentyl ester in the domino reaction to obtain the cyclic compound III, we have observed an increase in d.r.: 92:8 vs. 91:9 when using the methyl ester [36].

Domino and Tandem Reaction with Benzaldehyde
Cyclopentane derivative III has been synthesized, as already mentioned, by adding (R)-1 to 2 without a subsequent electrophile addition [35][36][37]. We wanted to introduce an additional carbon atom in the α-position of the alkoxycarbonylmethyl group, so an electrophile was necessary after performing the abovementioned domino reaction in a tandem multicomponent reaction protocol. Thus, we decided initially to use benzaldehyde as electrophile so the reaction scope, as well as the stereochemistry of the two new generated stereocenters, could be studied.
When the addition of (R)-1 (1.6 eq) to di-3-pentyl octa-2,6-diendioate is performed at −78 °C and then after one hour, benzaldehyde is added and the reaction allowed to reach room temperature, a mixture from which alcohol 3 (23%) and the C-1 ‴ epimer 4 (45%) (Scheme 3b, showing the numbering of these derivatives) are isolated by column chromatography is obtained. The 3-pentyl ester was chosen as it largely prevents the 1,2 addition reactions of the lithium amide to the ester (methyl) group, leading to the corresponding amide and, at the same time, it is easy to hydrolyze under basic conditions. In addition, with the pentyl ester in the domino reaction to obtain the cyclic compound III, we have observed an increase in d.r.: 92:8 vs. 91:9 when using the methyl ester [36]. The results of the 1 H-13 C heteronuclear correlation experiments at one and several bonds (normal and long range HMQC and HMBC), shown in Table 1 and in Supplementary Materials, allow to corroborate their structure and the full assignment of the 1 H-and 13 C-NMR data. The results of the 1 H-13 C heteronuclear correlation experiments at one and several bonds (normal and long range HMQC and HMBC), shown in Table 1 and in Supplementary Materials, allow to corroborate their structure and the full assignment of the 1 H-and 13 C-NMR data.
The observed n.O.e ( Figure 2a) between H2 and H5 for these compounds and the coupling constant in 4 for H1 at 3.23 ppm (dd, J = 10.1 and 9.3 Hz) confirm the predicted trans, transtrisubstituted cyclopentane ring. Compounds 3 and 4 show very similar 1 H and 13 C data according to the C1 " different configuration, but full stereochemical characterization was possible by chemical transformations and spectroscopic analysis, as it will be detailed later.
Once the stereochemistry of all sterocenters of 3 and 4 was known (vide infra), it was possible to explain the experimental observations, such as the J of the hydroxyl hydrogen at 3.92 ppm (d, J = 9.1) and H1 " at 4.87 ppm (dd, J = 9.1 and 3.7 Hz) in 3 and 3.04 ppm (d, J = 3.5 Hz); 4.64 ppm (dd, J = 10.0 and 3.5 Hz) respectively for 4.  The n.O.e with H1 by saturation of H7 and a hydrogen of the benzyl C2′ in 3 allowed us to conclude the existence of a hydrogen bridge in a cyclooctane system formed between the hydroxyl group and the C6 carbonyl as shown in Figure 2b. These observations could be used for the stereochemical determination of the centers generated in the aldol condensations of these systems.
Then, different reductions were performed as shown in Scheme 4. When 4 was treated both with LiAlH4 (2 eq.) at 0 °C and with DIBALH (3 eq.) at -78 °C; 5, 6 and the triol 7 were obtained. HMQC and HMBC studies (Table 1) show correlation between H7 and C-8 ester in diol 5, and correlations between C-6 and H1 and H2 in 6. Thus, suggesting that the formation of the proposed hydrogen bond ( Figure 2b) is favorable at low temperatures, because of both entropic contributions and the Boltzmann distribution, and, therefore, favors the reduction of the C6 ester and, additionally, because of the C-8 ester within this structure is blocked by the phenyl and cyclopentyl groups, bringing on the formation of 5.   The n.O.e with H1 by saturation of H7 and a hydrogen of the benzyl C2 in 3 allowed us to conclude the existence of a hydrogen bridge in a cyclooctane system formed between the hydroxyl group and the C6 carbonyl as shown in Figure 2b. These observations could be used for the stereochemical determination of the centers generated in the aldol condensations of these systems.
Then, different reductions were performed as shown in Scheme 4. When 4 was treated both with LiAlH 4 (2 eq.) at 0 • C and with DIBALH (3 eq.) at −78 • C; 5, 6 and the triol 7 were obtained. HMQC and HMBC studies (Table 1) show correlation between H7 and C-8 ester in diol 5, and correlations between C-6 and H1 and H2 in 6. Thus, suggesting that the formation of the proposed hydrogen bond (Figure 2b) is favorable at low temperatures, because of both entropic contributions and the Boltzmann distribution, and, therefore, favors the reduction of the C6 ester and, additionally, because of the C-8 ester within this structure is blocked by the phenyl and cyclopentyl groups, bringing on the formation of 5. The n.O.e with H1 by saturation of H7 and a hydrogen of the benzyl C2′ in 3 allowed us to conclude the existence of a hydrogen bridge in a cyclooctane system formed between the hydroxyl group and the C6 carbonyl as shown in Figure 2b. These observations could be used for the stereochemical determination of the centers generated in the aldol condensations of these systems.
Then, different reductions were performed as shown in Scheme 4. When 4 was treated both with LiAlH4 (2 eq.) at 0 °C and with DIBALH (3 eq.) at -78 °C; 5, 6 and the triol 7 were obtained. HMQC and HMBC studies (Table 1) show correlation between H7 and C-8 ester in diol 5, and correlations between C-6 and H1 and H2 in 6. Thus, suggesting that the formation of the proposed hydrogen bond (Figure 2b) is favorable at low temperatures, because of both entropic contributions and the Boltzmann distribution, and, therefore, favors the reduction of the C6 ester and, additionally, because of the C-8 ester within this structure is blocked by the phenyl and cyclopentyl groups, bringing on the formation of 5.   When the reduction of the mixture 3+4 (2:3 ratio) was performed with excess DIBALH, the triols 7 and 8 were obtained accordingly, and, under these conditions, reduction of 4 afforded 7 in 85% isolated yield that was converted in dioxane derivative 9 (61%) under standard condition when it was treated with dimethoxypropane (Scheme 4). Homonuclear COSY and n.O.e. (Figure 3) experiments allowed to determine the stereochemistry in the newly generated centers within the dioxane ring (see Supplementary Materials). Coupling constants J = 12.1 Hz for H8β and H8α and 0 and 2.9 Hz, respectively, for H7, therefore indicating an equatorial disposition for these protons (H7 and H8α). The most relevant n.O.es: H1-H7, H7-H1 ", H1 "-H8β, H1 "-Meβ, H8β-Meβ and H7-H8β, indicate a cis arrangement for H7, H1 ", H8β and Meβ (1.49 ppm), thus, fixing all stereocenters for 9 as: (1R,2R,5S, 7R,1 R,1 "R) and the same remains for compounds 7 and 4. When the reduction of the mixture 3+4 (2:3 ratio) was performed with excess DIBALH, the triols 7 and 8 were obtained accordingly, and, under these conditions, reduction of 4 afforded 7 in 85% isolated yield that was converted in dioxane derivative 9 (61%) under standard condition when it was treated with dimethoxypropane (Scheme 4).
Homonuclear COSY and n.O.e. (Figure 3) experiments allowed to determine the stereochemistry in the newly generated centers within the dioxane ring (see Supplementary Materials). Coupling constants J= 12.1 Hz for H8β and H8α and 0 and 2.9 Hz, respectively, for H7, therefore indicating an equatorial disposition for these protons (H7 and H8α). The most relevant n.O.es: H1-H7, H7-H1′'', H1′''-H8β, H1′''-Meβ, H8β-Meβ and H7-H8β, indicate a cis arrangement for H7, H1′'', H8β and Meβ (1.49 ppm), thus, fixing all stereocenters for 9 as: (1R,2R,5S, 7R,1′R,1′''R) and the same remains for compounds 7 and 4. As 3 (minor adduct) was presumed to be C1′'' epimer of 4, both the mixture and each compound separately was oxidized with TPAP, always providing the ketone 10 quantitatively, as shown in Scheme 5, so the configuration in 3 was established as (1R,2R,5S,7R,1′R,1′''S). When a mixture of 3 and 4 was oxidized with PDC the diketone 11 was obtained together with 10, due to further oxidation of the benzylic carbon. Thus, in summary, we have corroborated by n.O.e experiments the stereochemistry of the three stereocenters of the cyclopentane (achieved by, and related to, the auxiliar chiral (R)-1), that we have already described and settled by x-ray crystallography [36]). Likewise, the stereochemistry of the two new stereocenters generated in the subsequent aldol reaction were established by n.O.e experiments on a dioxane derivative of the major diastereoisomer. The other diastereoisomer was the C1 " epimer of the previous one, since the same compound was obtained by oxidation of this center in both epimers.

Proposed Mechanism
We have reported an exhaustive mechanistic revision [43] of the originally proposed mechanism [44], developing a quantum mechanics/molecular mechanics protocol for the asymmetric aza-Michael reaction of homochiral lithium benzylamides to α-β-unsaturated esters resulting in a Z-enolate prior to electrophilic quenching [45].
The second Michael addition in the domino reaction gives rise to the living Z-enolate (IX, Scheme 6) with the Si face accessible for the electrophile. Two approaches are possible for the incoming benzaldehyde: like, throughout its Si face (X) or unlike, Re face of the aldehyde (XI), a 1:2 ratio for 3/4 is observed, probably, due to the contrast of unfavourable axial position of the phenyl group in X, over steric impediment of the cycle substituents in XI. This ratio changes with the size of the aldehyde (vide infra).

Reaction Scope
The next step was to react new electrophiles such as different aldehydes, ketones, epoxide and chloroformate to explore the reaction scope. Formaldehyde is an interesting substrate in regards to this methodology due to the possibility of its applications to the synthesis of iridoid natural products.
Results are shown in the following table. When using cinnamaldehyde as electrophile ( Table 2, entry 2), 12 (30%) and 13 (27%) were obtained. The NMR signals, taking into account the additional double bond, are similar to those of 3 and 4, and, based on the spectroscopic considerations established above, especially the hydrogen bridge bond, allow us to establish the stereochemistry of these compounds, the hydroxyl proton in 12 at 3.33 ppm (d, J= 10 Hz) and in 13 at 2.85 ppm (d, J= 2.5 Hz) accordingly. In this case the epimer ratio is close to 1:1, in accordance to the proposed mechanism (Scheme 6) due to increased interaction in TS XI.

Reaction Scope
The next step was to react new electrophiles such as different aldehydes, ketones, epoxide and chloroformate to explore the reaction scope. Formaldehyde is an interesting substrate in regards to this methodology due to the possibility of its applications to the synthesis of iridoid natural products.
Results are shown in the following table. When using cinnamaldehyde as electrophile ( Table 2, entry 2), 12 (30%) and 13 (27%) were obtained. The NMR signals, taking into account the additional double bond, are similar to those of 3 and 4, and, based on the spectroscopic considerations established above, especially the hydrogen bridge bond, allow us to establish the stereochemistry of these compounds, the hydroxyl proton in 12 at 3.33 ppm (d, J = 10 Hz) and in 13 at 2.85 ppm (d, J = 2.5 Hz) accordingly. In this case the epimer ratio is close to 1:1, in accordance to the proposed mechanism (Scheme 6) due to increased interaction in TS XI. When formaldehyde was used (entry 3), 14 (80%) was the only compound isolated after column chromatography. Now the C6 configuration is S, contrary to previous one, as determined in subsequent derivatives (vide infra). Due to the small size of the formaldehyde molecule, it approaches the Re face probably in a tricoordinate Li TS within IX, producing 14.
To explore the reaction scope acetone and diphenylketone (entry 4 and 5) were used, giving rise to the multicomponent adducts 15 (27%) and 17 (52%) respectively, together with the reported [36] domino adduct 16 in 25% and 15% respectively, due to the lower reactivity of ketones.
Finally, when ethyl chloroformate was used as electrophile, the mixture of epimers in C7 19 (54%) was obtained as the only isolable compounds, in this case 1 H-and 13  When formaldehyde was used (entry 3), 14 (80%) was the only compound isolated after column chromatography. Now the C6 configuration is S, contrary to previous one, as determined in subsequent derivatives (vide infra). Due to the small size of the formaldehyde molecule, it approaches the Re face probably in a tricoordinate Li TS within IX, producing 14.
To explore the reaction scope acetone and diphenylketone (entry 4 and 5) were used, giving rise to the multicomponent adducts 15 (27%) and 17 (52%) respectively, together with the reported [36] domino adduct 16 in 25% and 15% respectively, due to the lower reactivity of ketones.
Finally, when ethyl chloroformate was used as electrophile, the mixture of epimers in C7 19 (54%) was obtained as the only isolable compounds, in this case 1 H-and 13  When formaldehyde was used (entry 3), 14 (80%) was the only compound isolated after column chromatography. Now the C6 configuration is S, contrary to previous one, as determined in subsequent derivatives (vide infra). Due to the small size of the formaldehyde molecule, it approaches the Re face probably in a tricoordinate Li TS within IX, producing 14.
To explore the reaction scope acetone and diphenylketone (entry 4 and 5) were used, giving rise to the multicomponent adducts 15 (27%) and 17 (52%) respectively, together with the reported [36] domino adduct 16 in 25% and 15% respectively, due to the lower reactivity of ketones.
Finally, when ethyl chloroformate was used as electrophile, the mixture of epimers in C7 19 (54%) was obtained as the only isolable compounds, in this case 1 H-and 13  When formaldehyde was used (entry 3), 14 (80%) was the only compound isolated after column chromatography. Now the C6 configuration is S, contrary to previous one, as determined in subsequent derivatives (vide infra). Due to the small size of the formaldehyde molecule, it approaches the Re face probably in a tricoordinate Li TS within IX, producing 14.
To explore the reaction scope acetone and diphenylketone (entry 4 and 5) were used, giving rise to the multicomponent adducts 15 (27%) and 17 (52%) respectively, together with the reported [36] domino adduct 16 in 25% and 15% respectively, due to the lower reactivity of ketones.
Finally, when ethyl chloroformate was used as electrophile, the mixture of epimers in C7 19 (54%) was obtained as the only isolable compounds, in this case 1 H-and 13 C-NMR spectra showed

19: 54%
When formaldehyde was used (entry 3), 14 (80%) was the only compound isolated after column chromatography. Now the C6 configuration is S, contrary to previous one, as determined in subsequent derivatives (vide infra). Due to the small size of the formaldehyde molecule, it approaches the Re face probably in a tricoordinate Li TS within IX, producing 14.
To explore the reaction scope acetone and diphenylketone (entry 4 and 5) were used, giving rise to the multicomponent adducts 15 (27%) and 17 (52%) respectively, together with the reported [36] domino adduct 16 in 25% and 15% respectively, due to the lower reactivity of ketones.
Finally, when ethyl chloroformate was used as electrophile, the mixture of epimers in C7 19 (54%) was obtained as the only isolable compounds, in this case 1 H-and 13 C-NMR spectra showed signals corresponding to the mixture. Nevertheless, this could be an interesting triorthogonal derivative to achieve the objectives of the project.
The results obtained indicate that this is an effective methodology capable of supporting the addition of different electrophiles, which allows the incorporation of different potential functionalities in the synthesis of interesting organic molecules and natural products.

Application to the Synthesis of the Iridoid Natural Product Core
It was shown in the retrosynthetic Scheme 2 that iridoid natural products are available from intermediate VII with cyclopentan[c]pyran skeleton, which is available from intermediate VIII, which is the one obtained in the domino reaction and subsequent tandem addition of formaldehyde (compound 14). Key steps towards achieving the objective are: cyclization reaction and substitution of the amine with a methyl group. The first approach was to try cyclization in an acidic medium (pTsOH) but little transformation (5%) was observed, then, when basic conditions were used, either with NaOMe or NaH, the dehydration product 20 was obtained quantitatively (Scheme 7), which is an interesting synthon within this methodology. As from our experience the lone pair electrons in amine group prevents reactivity in acidic media, we treated the solution with HCl (g) prior to the pTsOH acid addition to obtain in 30% yield the lactone 21, the precursor of iridomyrmecin (Figure 1). COSY 2D correlation experiments and significant n.O.es (Figure 4) have allowed us to establish both the absolute stereochemistry and the conformation of the molecule. Relevant n.O.es are H5 with H9 and H4 and this last one with H3α, showing that these four hydrogens are cis. Also, the H9 with H3β n.O.e is due to a boat conformation for the δ-lactone with the ester group equatorial and H4 axial (3.08 ppm, ddd, J = 9.8, 9.8 and 7.5 Hz), which explains its coupling constants and those of H3α and H3β. The (4S,5S,8R,9R,1 R) stereochemistry assigned for 21 matches those from 14.
Taking into account that the lone pair electrons in the amine complicate the cyclization reaction, the stereospecific syn concerted elimination reaction of Cope was tried first, so when 14 was treated with mCPBA, compound 22 was obtained in 82% isolated yield. When the reaction was carried out directly from the diunsaturated diester 2 and after the addition of the (R)-1 amide and formaldehyde, and the reaction crude mixture was treated directly with mCPBA, 22 and 23 were separated by column chromatography with 69% and 6% yield, respectively. Then, cyclization of each derivative was performed with pTsOH, and 24 and 25 were obtained in 77% and 65% yield respectively. The observed n.O.e (Figure 4) sets the stereochemistry for these compounds, which are C4 epimers [36] and therefore corroborates those deduced from adduct 14.
Finally, the methylation of 25 was performed with Me 2 CuLi, so 26 was obtained stereoselectively in 80% yield [46]. The shift of the methyl group at 1.20 ppm is consistent with the one described for mitsugashiwalactone [47]  Taking into account that the lone pair electrons in the amine complicate the cyclization reaction, the stereospecific syn concerted elimination reaction of Cope was tried first, so when 14 was treated with mCPBA, compound 22 was obtained in 82% isolated yield. When the reaction was carried out directly from the diunsaturated diester 2 and after the addition of the (R)-1 amide and formaldehyde, and the reaction crude mixture was treated directly with mCPBA, 22 and 23 were separated by column chromatography with 69% and 6% yield, respectively. Then, cyclization of each derivative was performed with pTsOH, and 24 and 25 were obtained in 77% and 65% yield respectively. The observed n.O.e (Figure 4) sets the stereochemistry for these compounds, which are C4 epimers [36] and therefore corroborates those deduced from adduct 14. Taking into account that the lone pair electrons in the amine complicate the cyclization reaction, the stereospecific syn concerted elimination reaction of Cope was tried first, so when 14 was treated with mCPBA, compound 22 was obtained in 82% isolated yield. When the reaction was carried out directly from the diunsaturated diester 2 and after the addition of the (R)-1 amide and formaldehyde, and the reaction crude mixture was treated directly with mCPBA, 22 and 23 were separated by column chromatography with 69% and 6% yield, respectively. Then, cyclization of each derivative was performed with pTsOH, and 24 and 25 were obtained in 77% and 65% yield respectively. The observed n.O.e (Figure 4) sets the stereochemistry for these compounds, which are C4 epimers [36] and therefore corroborates those deduced from adduct 14.

Conclusions
In summary, the total asymmetric synthesis of the iridoid 26, with a methylcyclopentan[c]pyran skeleton, has been carried out in four reaction steps from the affordable octadiendioate 2 and chiral lithium amide (R)-1 and with an overall yield of 40%. This compound is a very advanced analogue of natural products such as: dihydronepetalactone, deoxyloganin or mitsugashiwalactone (by decarboxylation) [42] and it is identical to the cyclopentane system of a new secoiridoid isolated from Fraxinus americana L., so a very effective asymmetric synthesis methodology of iridoidal natural product is developed, providing access to a great diversity of these derivatives. The key step of the synthesis is the initial multicomponent domino reaction, where six sterocenters are developed in one pot, the initial four in the domino reaction of Michael addition and intramolecular cyclization and the subsequent two by aldol condensation. Importantly, the analogue series of reactions using the enantiomer of lithium amide (S)-1 in the domino reaction step will allow simple access to the corresponding enantiomers of the aforementioned compounds. Spectroscopic analysis, including homo and heteronuclear two-dimensional correlation experiments have allowed full data assignment and n.O.e and ROESY experiments were performed to determine stereochemistry, especially in derivative products such as dioxolane 9, or in the case of formaldehyde as electrophile by obtaining the δ-lactones: 21, 24 and 25. A mechanistic proposal for the reaction course has been postulated and the application to the synthesis of such important natural derivatives as: iridomyrmecin, mitsugashiwalactone and dihydronepetalactone, is underway in our laboratory. Rotatory Power: Rotatory power data was recorded using CHCl 3 as solvent and sodium D line as polarized light ray.

General Information
Infrared Spectrometry: IR data was recorded using liquid IR spectrometer and NaCl crystal as supporting material.

General Procedure for the Synthesis of Compounds 3-11
n-Buli in THF (1.6 M, 1.0 mL,1.60 mmol) was added under Ar atmosphere and at -78 • C to a solution of (R)-1, (357 mg, 1.69 mmol) in THF (7.0 mL). After 50 min of reaction, a solution of 2 (238 mg, 0.77 mmol) in THF (2.5 mL) was added. After 1 h, PhCHO (2.7 mL) was added and the reaction mixture was stirred until it reached room temperature. Then, a saturated solution of NH 4 Cl (6 mL) was added. The reaction mixture was dissolved in EtOAc and washed with H 2 O, brine and 10% aqueous Na 2 S 2 O 3 solution. Then, the mixture was dried with Na 2 SO 4 and, after being filtered, the solvent was evaporated. The resulting mixture (4.41 g) was chromatographed and the desired compounds eluted with hexane/EtOAc 95:5. Yield: 141 mg (23% yield) of 3 and 217 mg (45% yield) of 4.
To a solution of 3 + 4 (2:3 ratio) (86 mg, 0.137 mmol) in DCM (3 mL), 1.5 M DIBALH (1.12 mL, 1.680 mmol) was added at -78 • C under an Ar atmosphere. After 1 h, the reaction flask was allowed to reach room temperature and H 2 O (1.5 mL) was added. Then, the reaction mixture was placed in an Erlenmeyer flask with ether, NaHCO 3 (3 g) and Na 2 SO 4 (3 g) and the resulting mixture left stirring for 5 h. Then, it was chromatographed and the desired products were eluted with hexane/EtOAc 8:2 to give 26 mg of 7 (yield 38%) and 18 mg of 8 (yield 27%). To a solution of 7 (22 mg, 0.048 mmol) in acetone (5 mL), a catalytic amount of camphorsulfonic acid (CSA) and 2,2-DMP (5 mL) were added. The reaction was heated up to reflux for 7 h. The reaction mixture was solved in ether and washed with NaHCO 3 saturated solution, brine and H 2 O. The resulting solution was dried with Na 2 SO 4 and, after being filtered, 42 mg of crude product were obtained and chromatographed. The desired compound was eluted with hexane/EtOAc 95:5, and 12 mg of 9 were obtained (yield 65%).