Unprecedented Elimination Reactions of Cyclic Aldols: A New Biosynthetic Pathway toward the Taiwaniaquinoid Skeleton

The acid treatment of 6,7-seco-abietane dialdehydes gives, in high yield, the corresponding derivatives with the 4a-methyltetrahydrofluorene skeleton of taiwaniaquinoids. A mechanism involving the elimination of formic acid from the cyclic aldol intermediate is proposed here. This process can be postulated as a new biogenetic pathway from abietane diterpenes to taiwaniaquinoids. Using this novel reaction, the first enantiospecific synthesis of bioactive natural cupresol and taxodal has been obtained.


Introduction
Taiwaniaquinoids belong to a group of terpenoids with an unusually rearranged 5(67) or 6-nor-5(67)abeo-abietane skeleton, which have been isolated from species of East Asian conifers during the last 20 years [1]. Although little is known about their biological activities, preliminary studies have revealed some interesting properties, including cytotoxic and trypanocidal effects [2][3][4][5][6][7]. The other structurally related compounds are the bioactive seco-taiwaniquinoids cupresol [8] and taxodal [9]. The promising biological activities and the uncommon structural features of such compounds have motivated the development of several synthetic approaches over the past few years. Thus, diverse total syntheses have been reported, including Pd-catalyzed The promising biological activities and the uncommon structural features of such compounds have motivated the development of several synthetic approaches over the past few years. Thus, diverse total syntheses have been reported, including Pd-catalyzed intramolecular reductive cyclization [10,11], a domino intramolecular acylation carbonylα-tert-alkylation reaction [12], intramolecular Heck cyclization [13], Nazarov cycliza-tion [14], tandem acylation-Nazarov cyclization [15], acid-promoted Friedel-Crafts acylation/alkylation [16,17], cyclization of aryldienes [18][19][20], and thermal ring expansion/4electrocyclization [21]. Asymmetric syntheses have also been reported for these compounds, including enantioselective Tsuji allylation [22], enantiospecific thermal 6-electrocycliza tion [23,24], enantioselective Heck reaction [25,26], iridium-catalyzed borylation, and palladium-catalyzed asymmetric α-arylation [27], as well as the enantioselective conjugate addition of arylboronic acids that are catalyzed by palladium [28]. The synthesis of taiwaniaquinoids, starting from abietane diterpenes, deserves a special mention. On the one hand, the abundance of abietane derivatives in their natural sources, such as (-)-abietic acid, means that these raw materials are inexpensive, which lends commercial interest to this approach, due to the few step sequences that are usually involved. Alternatively, the search for a practical means of transforming abietane terpenoids into taiwaniaquinoids could be of interest in regard to establishing possible biogenetic pathways, because of the structural relationship between the two types of metabolites and their simultaneous presence in their natural sources. A few syntheses of taiwaniaquinoids from abietane derivatives, such as 6,7-dehydroferruginol (1, R: H) and (-)-abietic acid (2) (see Figure 2), which involve the B ring contraction as the key step, have been reported, and biosynthetic pathways have been proposed on the basis of these transformations. Three biosynthetic proposals have been made, which postulate a 6,7-dehydroferruginol (1) derivative as the precursor. The pinacol rearrangement of a 6,7-diol derived from 1 could afford the corresponding cyclopentane carboxaldehyde, which is a possible precursor of the C20 taiwaniaquinoids, such as taiwaniaquinone A and D; however, this conjecture, which was postulated by Cheng [29], could not be experimentally confirmed in a recent study [30,31]. Node et al. postulated the transformation of the seco-abietane dialdehyde, resulting from the oxidation of the C6-C7 double bond of compound 1, into standishinal (see Figure 1), through a Friedel-Crafts-type cyclization, which was experimentally corroborated by these authors [32]. A third proposal involving the benzylic acid rearrangement of hydroxydione 3 induced by an intramolecular nucleophilic attack has also been supported experimentally by Gademann et al. [33,34]. More recently, our group reported the synthesis of C20 taiwaniaquinoids, such as taiwaniaquinone A, and a wide variety of existing taiwaniaquinoids, based on the cleavage of the C6-C7 double bond of the abietane diterpenes that are derived from (-)-abietic acid (2), via the hydroxyaldehyde intermediate 4, and proposed this process as the key step in a possible biosynthetic pathway [30,31]. Recently, two syntheses, which use a Wolff-type reaction in order to achieve the B ring contraction of the abietane skeleton, have been reported [34,35].
Molecules 2023, 28, x FOR PEER REVIEW 2 of 16 intramolecular reductive cyclization [10,11], a domino intramolecular acylation carbonylα-tert-alkylation reaction [12], intramolecular Heck cyclization [13], Nazarov cyclization [14], tandem acylation-Nazarov cyclization [15], acid-promoted Friedel-Crafts acylation/alkylation [16,17], cyclization of aryldienes [18][19][20], and thermal ring expansion/4electrocyclization [21]. Asymmetric syntheses have also been reported for these compounds, including enantioselective Tsuji allylation [22], enantiospecific thermal 6-electrocyclization [23,24], enantioselective Heck reaction [25,26], iridium-catalyzed borylation, and palladium-catalyzed asymmetric α-arylation [27], as well as the enantioselective conjugate addition of arylboronic acids that are catalyzed by palladium [28]. The synthesis of taiwaniaquinoids, starting from abietane diterpenes, deserves a special mention. On the one hand, the abundance of abietane derivatives in their natural sources, such as (-)-abietic acid, means that these raw materials are inexpensive, which lends commercial interest to this approach, due to the few step sequences that are usually involved. Alternatively, the search for a practical means of transforming abietane terpenoids into taiwaniaquinoids could be of interest in regard to establishing possible biogenetic pathways, because of the structural relationship between the two types of metabolites and their simultaneous presence in their natural sources. A few syntheses of taiwaniaquinoids from abietane derivatives, such as 6,7-dehydroferruginol (1, R: H) and (-)-abietic acid (2) (see Figure 2), which involve the B ring contraction as the key step, have been reported, and biosynthetic pathways have been proposed on the basis of these transformations. Three biosynthetic proposals have been made, which postulate a 6,7-dehydroferruginol (1) derivative as the precursor. The pinacol rearrangement of a 6,7-diol derived from 1 could afford the corresponding cyclopentane carboxaldehyde, which is a possible precursor of the C20 taiwaniaquinoids, such as taiwaniaquinone A and D; however, this conjecture, which was postulated by Cheng [29], could not be experimentally confirmed in a recent study [30,31]. Node et al. postulated the transformation of the seco-abietane dialdehyde, resulting from the oxidation of the C6-C7 double bond of compound 1, into standishinal (see Figure 1), through a Friedel-Crafts-type cyclization, which was experimentally corroborated by these authors [32]. A third proposal involving the benzylic acid rearrangement of hydroxydione 3 induced by an intramolecular nucleophilic attack has also been supported experimentally by Gademann et al. [33,34]. More recently, our group reported the synthesis of C20 taiwaniaquinoids, such as taiwaniaquinone A, and a wide variety of existing taiwaniaquinoids, based on the cleavage of the C6-C7 double bond of the abietane diterpenes that are derived from (-)-abietic acid (2), via the hydroxyaldehyde intermediate 4, and proposed this process as the key step in a possible biosynthetic pathway [30,31]. Recently, two syntheses, which use a Wolff-type reaction in order to achieve the B ring contraction of the abietane skeleton, have been reported [34,35].

Results and Discussion
Continuing our research on the synthesis of taiwaniaquinoids from abietane diterpenes, and the related biosynthetic pathway, and after our unsuccessful attempt to achieve the B ring contraction via pinacol rearrangement [30], we focused on the transformation of 6,7-dehydroabietane derivatives, which are similar to compound 1, into taiwaniaquinoids. Thus, we considered the oxidative degradation of the C6-C7 double bond

Results and Discussion
Continuing our research on the synthesis of taiwaniaquinoids from abietane diterpenes, and the related biosynthetic pathway, and after our unsuccessful attempt to achieve the B ring contraction via pinacol rearrangement [30], we focused on the trans-formation of 6,7-dehydroabietane derivatives, which are similar to compound 1, into taiwaniaquinoids. Thus, we considered the oxidative degradation of the C6-C7 double bond and the subsequent acid-mediated cyclization of the resulting seco-abietane dialdehyde, through a Friedel-Crafts-type reaction process, as reported by Node [32], or via an intramolecular aldol condensation, providing the desired B ring contraction (Scheme 1). and the subsequent acid-mediated cyclization of the resulting seco-abietane dialdehyde, through a Friedel-Crafts-type reaction process, as reported by Node [32], or via an intramolecular aldol condensation, providing the desired B ring contraction (Scheme 1). Scheme 1. Abietane B ring contraction via C6-C7 cleavage.
In a previous study by Node et al. [32], the seco-abietane dialdehyde resulting from the reductive ozonolysis of the 6,7-dehydroderivative was isolated and, after the deprotection of the phenolic hydroxyl group, was subjected to acid treatment, affording standishinal as the sole product; this compound results from a Friedel-Crafts-type cyclization, which is probably due to the activation of the aromatic ring by the hydroxyl group. Several Brønsted and Lewis acids were assayed, and (+)-camphorsulfonic acid was found to provide the best results [32].
Taking into account these antecedents, seco-abietane dialdehyde 5 was synthesized and its behavior under the previously reported acidic conditions was investigated. First, the reaction with camphorsulfonic acid (1.1 equiv.) was assayed at room temperature for 14 h, following the procedure of Node et al. [32]. Surprisingly, standishinal (8) (5%), which was described by Node et al. as the sole product of this reaction, was obtained as the minor product, together with phenol 6 (80%), and aldehyde 7 (7%). Compound 7, which is the dehydration product of standishinal (8), has the characteristic 4a-methyltetrahydrofluorene skeleton of C20 taiwaniaquinoids, such as taiwaniaquinone H. This interesting result encouraged us to investigate the behavior of dialdehyde 5 under different acid conditions (Table 1). Some conclusions can be obtained from these results. Thus, the use of trifluoroacetic acid (entry two) favored the formation of C20 compound 7, resulting from a Friedel-Crafts cyclization. The C19 compound 6 is the major product when camphorsulfonic acid, which is a less strong acid, is used (entry one). Under weaker acid conditions (entries three and four), compound 6 was the only product. Treatment with BF3·Et2O afforded a 1:1 mixture of C19 and C20 compounds 6 and 7 (entry five). Moreover, a mixture of these compounds, in which C20 terpenes were predominant, was obtained when metal triflates were used (entries six to eight). In a previous study by Node et al. [32], the seco-abietane dialdehyde resulting from the reductive ozonolysis of the 6,7-dehydroderivative was isolated and, after the deprotection of the phenolic hydroxyl group, was subjected to acid treatment, affording standishinal as the sole product; this compound results from a Friedel-Crafts-type cyclization, which is probably due to the activation of the aromatic ring by the hydroxyl group. Several Brønsted and Lewis acids were assayed, and (+)-camphorsulfonic acid was found to provide the best results [32].
Taking into account these antecedents, seco-abietane dialdehyde 5 was synthesized and its behavior under the previously reported acidic conditions was investigated. First, the reaction with camphorsulfonic acid (1.1 equiv.) was assayed at room temperature for 14 h, following the procedure of Node et al. [32]. Surprisingly, standishinal (8) (5%), which was described by Node et al. as the sole product of this reaction, was obtained as the minor product, together with phenol 6 (80%), and aldehyde 7 (7%). Compound 7, which is the dehydration product of standishinal (8), has the characteristic 4a-methyltetrahydrofluorene skeleton of C 20 taiwaniaquinoids, such as taiwaniaquinone H. This interesting result encouraged us to investigate the behavior of dialdehyde 5 under different acid conditions (Table 1). Some conclusions can be obtained from these results. Thus, the use of trifluoroacetic acid (entry two) favored the formation of C 20 compound 7, resulting from a Friedel-Crafts cyclization. The C 19 compound 6 is the major product when camphorsulfonic acid, which is a less strong acid, is used (entry one). Under weaker acid conditions (entries three and four), compound 6 was the only product. Treatment with BF 3 ·Et 2 O afforded a 1:1 mixture of C 19 and C 20 compounds 6 and 7 (entry five). Moreover, a mixture of these compounds, in which C 20 terpenes were predominant, was obtained when metal triflates were used (entries six to eight). Table 1. Treatment of dialdehyde 5 under different acidic conditions. and the subsequent acid-mediated cyclization of the resulting seco-abietane dialdehyde, through a Friedel-Crafts-type reaction process, as reported by Node [32], or via an intramolecular aldol condensation, providing the desired B ring contraction (Scheme 1).
In a previous study by Node et al. [32], the seco-abietane dialdehyde resulting from the reductive ozonolysis of the 6,7-dehydroderivative was isolated and, after the deprotection of the phenolic hydroxyl group, was subjected to acid treatment, affording standishinal as the sole product; this compound results from a Friedel-Crafts-type cyclization, which is probably due to the activation of the aromatic ring by the hydroxyl group. Several Brønsted and Lewis acids were assayed, and (+)-camphorsulfonic acid was found to provide the best results [32].
Taking into account these antecedents, seco-abietane dialdehyde 5 was synthesized and its behavior under the previously reported acidic conditions was investigated. First, the reaction with camphorsulfonic acid (1.1 equiv.) was assayed at room temperature for 14 h, following the procedure of Node et al. [32]. Surprisingly, standishinal (8) (5%), which was described by Node et al. as the sole product of this reaction, was obtained as the minor product, together with phenol 6 (80%), and aldehyde 7 (7%). Compound 7, which is the dehydration product of standishinal (8), has the characteristic 4a-methyltetrahydrofluorene skeleton of C20 taiwaniaquinoids, such as taiwaniaquinone H. This interesting result encouraged us to investigate the behavior of dialdehyde 5 under different acid conditions (Table 1). Some conclusions can be obtained from these results. Thus, the use of trifluoroacetic acid (entry two) favored the formation of C20 compound 7, resulting from a Friedel-Crafts cyclization. The C19 compound 6 is the major product when camphorsulfonic acid, which is a less strong acid, is used (entry one). Under weaker acid conditions (entries three and four), compound 6 was the only product. Treatment with BF3·Et2O afforded a 1:1 mixture of C19 and C20 compounds 6 and 7 (entry five). Moreover, a mixture of these compounds, in which C20 terpenes were predominant, was obtained when metal triflates were used (entries six to eight). To establish the scope and the limitations of this procedure, the behavior of a series of seco-abietane dialdehydes [36] with different functionalities in the gem-dimethyl group and in the aromatic ring was investigated ( Table 2).                 A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid.  A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid.  A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid.   A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid.   A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid.  A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid.  A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid. Some conclusions can be drawn from the results that are depicted in Table 2. Phenol dialdehydes, such as compound 5 (Table 1), produced significant amounts of C 20 compounds, such as compounds 7 and 8, due to the activation of the aromatic ring in the Friedel-Crafts cyclization (Scheme 2). The less activated substrates, such as dialdehyde 9 (entry one) or aromatic ethers, only gave the corresponding C 19 compound (entries one to six). Dialdehyde 18, with an ester group in the cyclohexane ring, yielded, in the presence of camphorsulfonic acid, the unsaturated lactone 19, resulting from the intramolecular attack of the enol aldehyde on the ester group (entry seven). When milder acidic conditions were used, the corresponding C 19 compound 20, with lactone 19, was obtained (entry eight). On the other hand, dialdehyde 21 showed a different behavior, due to the tendency of the acetyloxymethyl group to undergo the intramolecular attack of the enol aldehyde, leading to a dihydrofuran derivative (entries 10 and 11). When camphorsulfonic acid was used, the starting material 21 remained unaltered, which was probably due to the reversion of aldolic condensation (entry nine). To establish the scope and the limitations of this procedure, the behavior of a series of seco-abietane dialdehydes [36] with different functionalities in the gem-dimethyl group and in the aromatic ring was investigated ( Table 2). Some conclusions can be drawn from the results that are depicted in Table 2. Phenol dialdehydes, such as compound 5 (Table 1), produced significant amounts of C20 compounds, such as compounds 7 and 8, due to the activation of the aromatic ring in the Friedel-Crafts cyclization (Scheme 2). The less activated substrates, such as dialdehyde 9 (entry one) or aromatic ethers, only gave the corresponding C19 compound (entries one to six). Dialdehyde 18, with an ester group in the cyclohexane ring, yielded, in the presence of camphorsulfonic acid, the unsaturated lactone 19, resulting from the intramolecular attack of the enol aldehyde on the ester group (entry seven). When milder acidic conditions were used, the corresponding C19 compound 20, with lactone 19, was obtained (entry eight). On the other hand, dialdehyde 21 showed a different behavior, due to the tendency of the acetyloxymethyl group to undergo the intramolecular attack of the enol aldehyde, leading to a dihydrofuran derivative (entries 10 and 11). When camphorsulfonic acid was used, the starting material 21 remained unaltered, which was probably due to the reversion of aldolic condensation (entry nine).   9, 11, 13, 14, 16, 18, and 21  A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid. A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid. The results of the further experiments were consistent with the above proposal. Thus, the treatment of aldol 24, which was easily obtained from dialdehyde 11, with amberlyst A-15, gave compound 12 in high yield (Scheme 4). Another experiment that confirms the proposed mechanism that is depicted in Scheme 5. The O-methyl aldol 26 was obtained when dialdehyde 11 was treated with sodium methoxide in methanol, until the disappearance of the starting material, and then with 2N hydrochloric acid.  The results of the further experiments were consistent with the above proposal. Thus, the treatment of aldol 24, which was easily obtained from dialdehyde 11, with amberlyst A-15, gave compound 12 in high yield (Scheme 4).

12
Resin 3 CH2Cl2, rt, 19 h A possible mechanism is shown in Scheme 3. The cyclopentane ring is formed after the attack of the aliphatic aldehyde enol on the aromatic aldehyde. The dehydration of the protonated resulting aldol (I) leads to benzylic cation II, which is finally converted into the tricyclic cyclopentene derivative 6 after losing formic acid. The results of the further experiments were consistent with the above proposal. Thus, the treatment of aldol 24, which was easily obtained from dialdehyde 11, with amberlyst A-15, gave compound 12 in high yield (Scheme 4). Another experiment that confirms the proposed mechanism that is depicted in Scheme 5. The O-methyl aldol 26 was obtained when dialdehyde 11 was treated with sodium methoxide in methanol, until the disappearance of the starting material, and then with 2N hydrochloric acid.  Another experiment that confirms the proposed mechanism that is depicted in Scheme 5. The O-methyl aldol 26 was obtained when dialdehyde 11 was treated with sodium methoxide in methanol, until the disappearance of the starting material, and then with 2N hydrochloric acid. In accordance with the proposed mechanism, the acid was not consumed during the reaction. This outcome led us to believe that cyclization could occur using a substoichiometric quantity of acid. Compound 12 was effectively obtained in a 90% yield after the In accordance with the proposed mechanism, the acid was not consumed during the reaction. This outcome led us to believe that cyclization could occur using a substoichiometric quantity of acid. Compound 12 was effectively obtained in a 90% yield after the treatment of dialdehyde 11 with 30 mol % of camphorsulfonic acid (Scheme 6).

Scheme 5. Synthesis of compound 12 from dialdehyde 11, via O-methyl aldol 26.
In accordance with the proposed mechanism, the acid was not consumed during the reaction. This outcome led us to believe that cyclization could occur using a substoichiometric quantity of acid. Compound 12 was effectively obtained in a 90% yield after the treatment of dialdehyde 11 with 30 mol % of camphorsulfonic acid (Scheme 6). Scheme 6. Cyclization of dialdehyde 11 using a substoichiometric quantity of acid.
In view of the above results, the transformation of the abietane skeleton into the 4amethyltetrahydrofluorene skeleton, which is typical of some taiwaniaquinoids, in only two steps, is feasible. Therefore, this process could be proposed as a new biogenetic pathway from abietane diterpenes to taiwaniaquinoids. The scope and the limitations of this unprecedented cyclization are currently under study in order to apply it in organic synthesis.
In view of the above results, the transformation of the abietane skeleton into the 4a-methyltetrahydrofluorene skeleton, which is typical of some taiwaniaquinoids, in only two steps, is feasible. Therefore, this process could be proposed as a new biogenetic pathway from abietane diterpenes to taiwaniaquinoids. The scope and the limitations of this unprecedented cyclization are currently under study in order to apply it in organic synthesis.
This rearrangement of seco-abietane dialdehydes has been employed in order to achieve the first enantiospecific synthesis of bioactive taxodal (28) and cupresol (30) from methyl ether 12, which is easily obtained from (-)-abietic acid (Scheme 7) [37]. In accordance with the proposed mechanism, the acid was not consumed during the reaction. This outcome led us to believe that cyclization could occur using a substoichiometric quantity of acid. Compound 12 was effectively obtained in a 90% yield after the treatment of dialdehyde 11 with 30 mol % of camphorsulfonic acid (Scheme 6). Scheme 6. Cyclization of dialdehyde 11 using a substoichiometric quantity of acid.
In view of the above results, the transformation of the abietane skeleton into the 4amethyltetrahydrofluorene skeleton, which is typical of some taiwaniaquinoids, in only two steps, is feasible. Therefore, this process could be proposed as a new biogenetic pathway from abietane diterpenes to taiwaniaquinoids. The scope and the limitations of this unprecedented cyclization are currently under study in order to apply it in organic synthesis.

Materials
Unless otherwise stated, the reactions were performed in oven-dried glassware under an argon atmosphere using dry solvents. The solvents were dried as follows: THF over Na-benzophenone and CH 2 Cl 2 and MeOH over CaH 2 .
Thin-layer chromatography (TLC) was performed using Merck silica gel 60-F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching and phosphomolybdic acid solution staining. Flash chromatography was performed on silica gel (Merck Kieselgel 60, 230-400 mesh). Chromatography separations were carried out with a conventional column on silica gel 60 (230-400 Mesh), using Hexane-t-BuOMe (H-E) mixtures of increasing polarity. 1 H and 13 C NMR spectra were recorded on a Varian instrument (at 500 MHz and 125 MHz, respectively). CDCl 3 was treated with K 2 CO 3. The data for 1 H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), and integration), with the abbreviations s, br s, d, br d, dd, ddd, dd br t, q, and m denoting singlet, broad singlet, doublet, broad doublet, double doublet, double double doublet, broaddouble doublet, triplet, quartet, and multiplet, respectively. J = coupling constant in Hertz (Hz).
Infrared spectra (IR) were recorded as thin films or as solids on a Perkin Elmer model One FTIR spectrophotometer with samples between sodium chloride plates or as potassium bromide pellets and are reported in frequency of absorption (cm −1 ). The ([α] D ) measurements were carried out in a Perkin Elmer 341 polarimeter, using a 1 dm length cell and CHCl 3 as a solvent. The concentration is expressed in mg/mL. HRMS were recorded on an AutoSpecQ VG-Analytical (Fisons) spectrometer, using FAB with thioglicerol or glycerol matrix doped in NaI 1%.

General Procedure for the Obtention of Seco-Abietane Dialdehydes
Seco-abietane dialdehydes were obtained after the reductive ozonolysis of the corresponding 6,7-dehydro-8,11,13-abietatriene diterpenes, using the following procedure: An O 3 /O 2 mixture was slowly bubbled through a solution of the selected 6,7-dehydro-8,11,13-abietatriene derivative (1.0 mmol) in dry CH 2 Cl 2 (15 mL) at −78 • C, and the course of the reaction was monitored by TLC. When the TLC showed no starting material, the solution was flushed with argon, triphenylphosphine (1.1 mmol) was added, and the mixture was stirred at room temperature for 4 h. Then, the solvent was removed, affording a crude product, which was directly purified with a flash chromatography column on silica gel (t-BuOMe -Hexane mixtures) to produce the expected dialdehyde.

General
Procedure for the Reaction of Seco-Abietane Dialdehydes with (+)-CSA, Amberlyst A-15, Bi(OTf) 3 , Sc(OTf) 3 , or Gd(OTf) 3 The selected acid (0.12 mmol) was added to a solution of the corresponding dialdehyde (0.1 mmol) in dry CH 2 Cl 2 (10 mL), the mixture was stirred at room temperature for the specified time (see Table 1), and the course of the reaction was monitored by TLC. When the starting material was consumed, the solvent was removed under vacuum conditions, and the crude product was directly purified with a flash chromatography column on silica gel (Hexane-t-BuOMe mixtures) to produce the corresponding final product(s). The indicated acid (0.12 mmol) was added to a solution of the corresponding dialdehyde (0.1 mmol) in dry CH 2 Cl 2 (10 mL) and the mixture was stirred at the specified temperature for the indicated time (see Table 2). The course of the reaction was monitored by TLC. When the starting material was consumed, the reaction mixture was diluted with CH 2 Cl 2 (30 mL) and washed with a sat. aqueous solution of NaHCO 3 (2 × 10 mL) and brine (2 × 10 mL), and the organic phase was dried over anhydrous Na 2 SO 4 . Removal of the solvent under vacuum conditions afforded a crude product, which was purified with a flash chromatography column on silica gel (Hexane-t-BuOMe mixtures) to produce the corresponding final product(s).
O-methyl taxodal (27). An O 3 /O 2 mixture was slowly bubbled through a solution of 12 (243 mg, 0.86 mmol) in dry CH 2 Cl 2 (15 mL) at −78 • C, and the course of the reaction was monitored by TLC. When the TLC showed no starting material, the solution was flushed with argon, triphenylphosphine (293 mg, 1.11 mmol) was added, and the mixture