Marine Puupehenone and Puupehedione: Synthesis and Future Perspectives

Puupehenone and puupehedione are natural products isolated from marine organisms. These compounds display a broad spectrum of biological activities, the in vitro antitubercular activity of puupehenone being a stand out, and are equipped with an interesting structural complexity. These products have served to stimulate the continual interest of the synthetic community. The first part of this article is a review of their total synthesis, using natural compounds which have the potential to be transformed into these marine compounds as starting materials; the synthetic routes employed to generate the basic skeleton; and the advances made to synthesize the pyran C ring with the required diastereoselectivity to obtain the natural products. Finally, this perspective shows a personal reflection of the authors on a possible unified and efficient retrosynthetic route that could allow easy access to these natural products, as well as their epimers at the C8 carbon and which could be used to address future biological issues in the production of pharmacologically active compounds.

Structurally, puupehenone-type natural compounds are tetracyclic products which consist of a trans-decalin system (A-and B-rings) and a shikimic acid/O-phenol/Obenzoquinone (D-ring) linked by a tetrahydropyran/dihydropyran (C-ring). The stereochemistry at carbon 8 in this class of natural products is "S", the orientation of the C 8 -Me group being backwards when represented as in Figure 1. This orientation is usually denoted in literature as "α" or C 8 -Me α . The opposite orientation, present in some unnatural derivatives, is denoted as "β" or C 8 -Me β . The full stereochemistry of (+)-puupehenone (1) has been well-established using chemical correlation methods from this compound to finally obtain the known structure of (-)-drimenol [9]. These compounds have great interest for the synthetic and pharmaceutical community due to their unusual fused ring system and their wide variety of biological activities. Natural puupehenones and their C-8 epimers show relevant bioactive properties, exhibiting antitumor, immunomodulatory, antimalarial, antiviral, antibiotic, antiatherosclerotic, and, most remarkably, in vitro antitubercular activity in the case of puupehenone (1). Medina and coworkers [10] have published an excellent and complete review of the biological activity of these compounds. antimalarial, antiviral, antibiotic, antiatherosclerotic, and, most remarkably, in vitro antitubercular activity in the case of puupehenone (1). Medina and coworkers [10] have published an excellent and complete review of the biological activity of these compounds. Among all the products that belong to this family, the most representative members are puupehenone (1) and puupehedione (2), these being the most intensively researched. For this reason, this article highlights the main synthetic efforts toward these marine compounds. Finally, a unified retrosynthesis for the future synthesis of both natural puupehenone-type and non-natural (C8-Meβ) products will be discussed.

Results
The total synthesis of complex natural compounds remains among the most dynamic areas in organic and pharmaceutical chemistry, and it is an excellent indicator for the validation of new synthetic methodologies. Usually, the starting materials in a total synthesis are commercially available precursors, which are transformed into the natural product of interest through either a convergent synthetic route or a linear synthetic route. In the first case, two fragments are coupled at a late stage to generate the desired natural product, normally through either a nucleophilic or an electrophilic reaction. In a linear synthesis, a series of consecutive transformations (reactions) are employed to transform a reactant or some reactants into a natural product. Normally, this synthetic process entails a longer route to produce the target product.
Scheme 1 summarizes the pool of chiral starting materials that have been used in the syntheses of puupehenone (1) and puupehedione (2) through convergent synthetic routes (solid arrows) and the non-chiral starting materials used in the synthesis of 1 and 2 by linear synthetic routes (dashed arrows). Among all the products that belong to this family, the most representative members are puupehenone (1) and puupehedione (2), these being the most intensively researched. For this reason, this article highlights the main synthetic efforts toward these marine compounds. Finally, a unified retrosynthesis for the future synthesis of both natural puupehenone-type and non-natural (C 8 -Me β ) products will be discussed.

Results
The total synthesis of complex natural compounds remains among the most dynamic areas in organic and pharmaceutical chemistry, and it is an excellent indicator for the validation of new synthetic methodologies. Usually, the starting materials in a total synthesis are commercially available precursors, which are transformed into the natural product of interest through either a convergent synthetic route or a linear synthetic route. In the first case, two fragments are coupled at a late stage to generate the desired natural product, normally through either a nucleophilic or an electrophilic reaction. In a linear synthesis, a series of consecutive transformations (reactions) are employed to transform a reactant or some reactants into a natural product. Normally, this synthetic process entails a longer route to produce the target product. Scheme 1 summarizes the pool of chiral starting materials that have been used in the syntheses of puupehenone (1) and puupehedione (2) through convergent synthetic routes (solid arrows) and the non-chiral starting materials used in the synthesis of 1 and 2 by linear synthetic routes (dashed arrows). (1) and Puupehedione (2) from Chiral Starting Materials 2.1.1. Synthesis of Puupehenone (1) and Puupehedione (2) from (-)-Sclareol (8) (-)-Sclareol (8) is a natural bicyclic diterpene alcohol with five stereogenic centers isolated from the herbaceous aromatic plant clary sage (Salvia sclarea) [24], a member of the Lamiaceae family [25] native to the Mediterranean basin, Southern Europe, and Iran. The isolation of (-)-sclareol (8) requires hydro-distillation of the aerial parts of the plant and is a starting material commercially available, making it an attractive chiral synthon for the asymmetric total synthesis of natural compounds [26].
In 1997, Barrero's group reported the first enantioselective synthesis of marine (+)-puupehenone (1) from (-)-sclareol (8) and protocatechualdehyde [11] (Scheme 2) via an organoselenium-induced cyclization of a mixture of endo/exo decalins 17a-b and the simultaneous removal of selenyl groups 18 and 19 using Raney Ni. The oxidative degradation of commercially available (-)-sclareol (8) provided the acetoxy aldehyde 14 (73% yield) in three steps [27]. The nucleophilic addition of the organolithium derived from 15 to the acetoxy aldehyde 14 gave the compound 16 (88% yield) with complete diastereoseletivity. The aromatic bromide ring 15 was obtained from protocatechualdehyde in five steps, with an overall yield of 75%. The compound 16, after three steps, was converted to phenolic derivatives 17a-b (69% overall yield). Electrophilic cyclization of compounds 17a-b with SnCl4 and N-phenylselenophtalimide afforded a mixture of selenyl derivatives 18 and 19 (91% yield). Finally, the treatment of 18 and 19 with Raney Ni and subsequent oxidation with pyridinium dichromate gave natural (+)puupehenone (1) (52% yield, two steps). The use of organoselenium-mediated cyclization of the mixture of endocyclic and exocyclic alkenes 17a and 17b followed by reduction is an excellent methodology for the synthesis of natural puupehenone-type compounds since, under acid conditions, the hydroxyl group of the aromatic ring in both 17a and 17b attacks the double bond of the decalin through the less hindered α side, generating the unnatural epimer C8-Meβ as the main product.
Later, the same research group reported the first enantioselective synthesis of marine puupehedione (2) from (-)-sclareol (8), using different strategies [12] (Scheme 3). Among the different methodologies investigated, the methodology shown in Scheme 3 gave the highest levels of stereoselectivity. In this strategy, the key step involves a base-mediated cyclization of epoxide 23. The key merosesquiterpenic intermediate 21 was generated by condensation of the aldehyde 20 with the aromatic compound 15, subsequent cationic deoxygenation of the resulting alcohol, and final removal of the silyl protecting group. The preparation of the drimanic aldehyde 20 had been previously reported by the same research group from (-)-sclareol (8) [28]. As in the method described in Scheme 2, the aromatic derivative 15 was obtained here from protocatechualdehyde. Acetylation of the phenolic product 21 with Ac2O and subsequent treatment with m-chloroperbenzoic acid gave a mixture of epoxides 22 and 23 (98% yield, 1:1 mixture). After separation of 23 by column chromatography, this compound was treated with KOH in methanol, generating a tetracyclic compound, which, after deprotection of the benzylether groups with palladium on carbon, afforded the diphenol 24 (86% two steps). Finally, the dehydration of 24 and oxidation of the aromatic ring yielded the desired marine puupehedione (2). The oxidative degradation of commercially available (-)-sclareol (8) provided the acetoxy aldehyde 14 (73% yield) in three steps [27]. The nucleophilic addition of the organolithium derived from 15 to the acetoxy aldehyde 14 gave the compound 16 (88% yield) with complete diastereoseletivity. The aromatic bromide ring 15 was obtained from protocatechualdehyde in five steps, with an overall yield of 75%. The compound 16, after three steps, was converted to phenolic derivatives 17a-b (69% overall yield). Electrophilic cyclization of compounds 17a-b with SnCl 4 and N-phenylselenophtalimide afforded a mixture of selenyl derivatives 18 and 19 (91% yield). Finally, the treatment of 18 and 19 with Raney Ni and subsequent oxidation with pyridinium dichromate gave natural (+)-puupehenone (1) (52% yield, two steps). The use of organoselenium-mediated cyclization of the mixture of endocyclic and exocyclic alkenes 17a and 17b followed by reduction is an excellent methodology for the synthesis of natural puupehenone-type compounds since, under acid conditions, the hydroxyl group of the aromatic ring in both 17a and 17b attacks the double bond of the decalin through the less hindered α side, generating the unnatural epimer C 8 -Me β as the main product.
Later, the same research group reported the first enantioselective synthesis of marine puupehedione (2) from (-)-sclareol (8), using different strategies [12] (Scheme 3). Among the different methodologies investigated, the methodology shown in Scheme 3 gave the highest levels of stereoselectivity. In this strategy, the key step involves a base-mediated cyclization of epoxide 23. The key merosesquiterpenic intermediate 21 was generated by condensation of the aldehyde 20 with the aromatic compound 15, subsequent cationic deoxygenation of the resulting alcohol, and final removal of the silyl protecting group. The preparation of the drimanic aldehyde 20 had been previously reported by the same research group from (-)-sclareol (8) [28]. As in the method described in Scheme 2, the aromatic derivative 15 was obtained here from protocatechualdehyde. Acetylation of the phenolic product 21 with Ac 2 O and subsequent treatment with m-chloroperbenzoic acid gave a mixture of epoxides 22 and 23 (98% yield, 1:1 mixture). After separation of 23 by column chromatography, this compound was treated with KOH in methanol, generating a tetracyclic compound, which, after deprotection of the benzylether groups with palladium In 2005, Álvarez-Manzaneda and co-workers reported a new route toward puupehenone-type marine compounds from (-)-sclareol (8) [13] (Scheme 4). The key step was based on the palladium(II)-promoted diastereoselective cyclization of a drimenyl phenol 28. The drimane skeleton 25 was obtained in seven steps from (-)-sclareol (8). The nucleophilic addition of the organolithium derived from 26 to drimenol 25 resulted in a C-C bond formation reaction with concomitant carbamate elimination giving the compound 27. Bromide aromatic ring 26 was synthesized from 3,4-bis(benzyloxy)phenol in two steps (83% overall yield). Reduction of 27 with Raney Ni afforded 28. Subsequent cyclization of the drimenyl phenol 28 with catalytic PdCl2 and Pd(OAc)2 gave the desired compound 29 with complete diastereoselectivity. The catalytic hydrogenation of 29 gave puupehenol (5), which is the key compound for the synthesis of puupehenone-type natural products, such as (+)-puupehenone (1) and (+)-puupehedione (2). Again, to avoid the formation of an unnatural epimer C8-Meβ, the palladium-promoted cycloisomerization strategy turned out to be satisfactory. In 2005, Álvarez-Manzaneda and co-workers reported a new route toward puupehenonetype marine compounds from (-)-sclareol (8) [13] (Scheme 4). The key step was based on the palladium(II)-promoted diastereoselective cyclization of a drimenyl phenol 28. The drimane skeleton 25 was obtained in seven steps from (-)-sclareol (8). The nucleophilic addition of the organolithium derived from 26 to drimenol 25 resulted in a C-C bond formation reaction with concomitant carbamate elimination giving the compound 27. Bromide aromatic ring 26 was synthesized from 3,4-bis(benzyloxy)phenol in two steps (83% overall yield). Reduction of 27 with Raney Ni afforded 28. Subsequent cyclization of the drimenyl phenol 28 with catalytic PdCl 2 and Pd(OAc) 2 gave the desired compound 29 with complete diastereoselectivity. The catalytic hydrogenation of 29 gave puupehenol (5), which is the key compound for the synthesis of puupehenone-type natural products, such as (+)-puupehenone (1) and (+)-puupehedione (2). Again, to avoid the formation of an unnatural epimer C 8 -Me β , the palladium-promoted cycloisomerization strategy turned out to be satisfactory.
A different strategy towards puupehenone-type natural products, also using (-)-sclareol (8) as a starting material, was reported by the same group [14] (Scheme 5). Here, the key step was based on the cationic-resin-mediated Friedel-Crafts alkylation of the alkoxyarene 31 with the α,β-unsaturated ketone 30. In turn, the compound 30 had been previously prepared from (-)-sclareol (8)  A different strategy towards puupehenone-type natural products, also using (-)sclareol (8) as a starting material, was reported by the same group [14] (Scheme 5). Here, the key step was based on the cationic-resin-mediated Friedel-Crafts alkylation of the alkoxyarene 31 with the α,β-unsaturated ketone 30. In turn, the compound 30 had been previously prepared from (-)-sclareol (8) in four steps. Treatment of enone 30 with the aromatic ring 31 under a cationic resin Amberslyst A-15 gave the key ketone 32 with complete diastereoselectivity (94% yield).
Quideau and co-workers were the first research group to describe the use of (+)-sclareolide (9) as a starting material for the synthesis of (+)-puupehenone (1) [15] (Scheme 6). The key step of this synthesis was based on the nucleophilic character of the terpenoid C8-oxygen of 37 to promote heterocyclization by attacking an oxidatively activated 1,2-dihydroxyphenyl unit. The drimane β-hydroxy aldehyde 35 was synthesized in four steps from (+)-sclareolide (9) through a degradative sequence of reactions which included the inversion of the configuration at C8. Then, the C-C bond formation reaction between 35 and the organolithium derived from 36 gave, after deoxygenation and benzyl ether deprotection, the key compound 37. The aromatic derivative 36 was prepared from cathecol in two steps in a 78% overall yield. Finally, in two reaction steps, (+)-puupehenone (1) was obtained from 37. In this way, BTI oxidation with concomitant cyclization led to the spirocycle 38, which was rearranged under basic conditions into (+)-puupehenone (1).

Synthesis of Puupehenone
Quideau and co-workers were the first research group to describe the use of (+)sclareolide (9) as a starting material for the synthesis of (+)-puupehenone (1) [15] (Scheme 6). The key step of this synthesis was based on the nucleophilic character of the terpenoid C8-oxygen of 37 to promote heterocyclization by attacking an oxidatively activated 1,2dihydroxyphenyl unit. The drimane β-hydroxy aldehyde 35 was synthesized in four steps from (+)-sclareolide (9) through a degradative sequence of reactions which included the inversion of the configuration at C8. Then, the C-C bond formation reaction between 35 and the organolithium derived from 36 gave, after deoxygenation and benzyl ether deprotection, the key compound 37. The aromatic derivative 36 was prepared from cathecol in two steps in a 78% overall yield. Finally, in two reaction steps, (+)-puupehenone (1) was obtained from 37. In this way, BTI oxidation with concomitant cyclization led to the spirocycle 38, which was rearranged under basic conditions into (+)-puupehenone (1).

I (4 steps)
H H
tions, 40 underwent a series of one-pot transformations-hemiacetalization, dihydroxylation, hydroxylation, and retro-hemiacetalization-which led to the formation of enone 41 without C8 epimerization (92% yield). The reaction of enone 41 with KHDMS and subsequent oxidation with O2 in the presence of P(OMe)3 gave puupehenone (1) (38% yield) and the α-hydroxylated compound 42 in a 19% yield. Compound 42 was converted in 1 via treatment with t-BuOK (86% yield). Finally, reduction of puupehenone (1) and subsequent oxidation with DDQ provided puupehedione (2) in a 71% yield. In connection with the previously mentioned synthetic route, the same research group reported an enantiospecific and concise semisynthesis of puupehenone (1) and puupehedione (2) using (+)-sclareolide (9) as a starting material in only seven steps while also avoiding the use of protecting groups [17] (Scheme 8). The main features of this synthetic route were the development of a palladium-catalyzed C-C bond formation reaction between drimanal hydrazone 43 and the aryliodine 44 for the synthesis of the key intermediate drimanal trimethoxystyrene skeleton 45 and 46 and the development of a CANoxidation/intramolecular oxa-Stork-Danheiser transposition tandem reaction of 48 to form the C and D rings of puupehenone (1). Again, the β-hydroxyaldehyde 35 was prepared from (+)-sclareolide (9) using the procedure previously reported [15].  In connection with the previously mentioned synthetic route, the same research group reported an enantiospecific and concise semisynthesis of puupehenone (1) and puupehedione (2) using (+)-sclareolide (9) as a starting material in only seven steps while also avoiding the use of protecting groups [17] (Scheme 8). The main features of this synthetic route were the development of a palladium-catalyzed C-C bond formation reaction between drimanal hydrazone 43 and the aryliodine 44 for the synthesis of the key intermediate drimanal trimethoxystyrene skeleton 45 and 46 and the development of a CAN-oxidation/intramolecular oxa-Stork-Danheiser transposition tandem reaction of 48 to form the C and D rings of puupehenone (1). Again, the β-hydroxyaldehyde 35 was prepared from (+)-sclareolide (9) using the procedure previously reported [15]. The condensation of 35 with p-toluensulfonyl hydrazide afforded the intermediate 43. The cross-coupling reaction between hydrazone 43 and aryl iodide 44 using catalytic Pd(PPh 3 ) 4 and K 2 CO 3 gave the key intermediate drimanal-trimethoxystyrene as a mixture of isomers 45 (40% yield) and 46 (45% yield). Finally, the chemoselective oxidation of both isomers 45 and 46 with CAN provided puupehedione (2) (47% yield). In addition, hydrogenolysis of this 45-46 mixture with Pd/C produced compound 47 in 62% yield, which was transformed into the p-benzoquinone 48 by treatment with ceric ammonium nitrate (84% yield). The intramolecular oxa-Stork-Danheiser reaction of 48 with pTsOH gave 49. Finally, puupehenone (1) was obtained by the enolization of 49 with K 2 CO 3 (92% yield).
In 2001, Banaerjee and coworkers reported an enantiospecific synthesis of puupehedione (2) from commercially available (-)-carvone (10) [18] (Scheme 9). The key steps were a cross-coupling reaction between a vinyl anion formed from bicyclic tosylhydrazone 50 and the aromatic synthon 51. Tosylhydrazone 50 was synthesized from natural (-)-carvone (10) in eight steps [18], and the aromatic synthon 51 was prepared in three steps with high yield from sesamol [18]. The exposure of the tosylhydrazone 50 to n-BuLi formed a vinyl anion, which reacted with 51 to give a mixture of an unstable allyl alcohol 52 and the diene 53. In fact, 52 suffers dehydration when treated with silica, leading to the diene 53. Finally, when 53 was treated with RhCl 3 ·3H 2 O for O-allyl deprotection, an immediate cyclization took place, leading to a mixture of puupehedione (2) and its epimer 8-epipuupehedione (C 8 -Me β ) (54) in a ratio 1:4 and in quantitative yield. 8-Epipuupehedione (54) was the main compound generated because it is more stable [35] than its natural epimer C 8 -Me α 2.
In 2001, Banaerjee and coworkers reported an enantiospecific synthesis of puupehedione (2) from commercially available (-)-carvone (10) [18] (Scheme 9). The key steps were a cross-coupling reaction between a vinyl anion formed from bicyclic tosylhydrazone 50 and the aromatic synthon 51. Tosylhydrazone 50 was synthesized from natural (-)-carvone (10) in eight steps [18], and the aromatic synthon 51 was prepared in three steps with high yield from sesamol [18]. The exposure of the tosylhydrazone 50 to n-BuLi formed a vinyl anion, which reacted with 51 to give a mixture of an unstable allyl alcohol 52 and the diene 53. In fact, 52 suffers dehydration when treated with silica, leading to the diene 53. Finally, when 53 was treated with RhCl3 . 3H2O for O-allyl deprotection, an immediate cyclization took place, leading to a mixture of puupehedione (2) and its epimer 8-epipuupehedione (C8-Meβ) (54) in a ratio 1:4 and in quantitative yield. 8-Epipuupehedione (54) was the main compound generated because it is more stable [35] than its natural epimer C8-Meα 2. Using a different approach, but also starting from (-)-carvone (10), Xie and coworkers recently reported the total synthesis of (+)-puupehenone (1) and (+)-puupehedione (2) [19] (Scheme 10). The key steps were a Suzuki carbonylative cross-coupling reaction to combine the bicyclic unit 55 and an aromatic derivative 56 and an intramolecular cyclization Using a different approach, but also starting from (-)-carvone (10), Xie and coworkers recently reported the total synthesis of (+)-puupehenone (1) and (+)-puupehedione (2) [19] (Scheme 10). The key steps were a Suzuki carbonylative cross-coupling reaction to combine the bicyclic unit 55 and an aromatic derivative 56 and an intramolecular cyclization reaction to generate the key chromanone core of 59. The bicyclic vinyl triflate 55 was prepared starting from (-)-carvone (10) through a four-step synthetic route [19]. The aromatic derivative 56 was synthesized from commercially available 1,2,4-trimethoxybenzene in two steps following a previously reported procedure [36]. A Suzuki carbonylation cross-coupling reaction between those two segments, 55 and 56, under CO atmosphere gave the intermediate 57 (73% yield). A subsequent selective demethylation reaction of 57 with AlCl 3 gave the corresponding demethylated compounds as a 4:1 mixture of tautomers, 58 and 58a (90% yield). Treatment of this mixture with KOH promoted an intramolecular cyclization, leading to the formation of the compound 59 with the desired stereochemistry at C8 (C 8 -Me α ) (86% yield). From 59, the formal synthesis of puupehedione (2) and total synthesis of puupehenone (1) were completed. Thus, when compound 59 was sequentially treated with LiAlH 4 and trifluoroacetic acid, the tetracyclic compound 60 was formed (86% yield). As the tetracyclic chromone 60 is an advanced intermediate key in Armstrong et al.'s [20] total synthesis of (+)-puupehedione (2), this work constituted a formal synthesis of 2. On the other hand, the demethylation reaction of compound 59 with BBr 3 gave (-)-15-oxopuupehenol (7). Since a direct reduction of 7 was not successful, the two phenolic groups in 7 had to be protected as the corresponding MOM ethers. Finally, reduction of the C-15 ketone group followed by p-TsOH mediated one-pot MOM ether deprotection/dehydration elimination of the C-15 hydroxyl group gave (+)-puupehenone (1) in a 56% yield based on the recycled starting material. (-)-Drimenol (11) is a sesquiterpene alcohol which was first isolated from the bark of Drimys winteri Forst [37]. This natural compound, which has been employed as a chiral synthon for a large number of natural drimane-type products [38], is typically isolated in a 13% yield from the petroleum ether extract of the bark of the above-mentioned tree.  (11) (-)-Drimenol (11) is a sesquiterpene alcohol which was first isolated from the bark of Drimys winteri Forst [37]. This natural compound, which has been employed as a chiral synthon for a large number of natural drimane-type products [38], is typically isolated in a 13% yield from the petroleum ether extract of the bark of the above-mentioned tree.

Synthesis of Puupehedione (2) from (-)-Drimenol
In 2003, Armstrong and co-workers [20] reported the synthesis of puupehedione (2) from (-)-drimenol (11) (Scheme 11). The key step in this synthetic route was the coupling of drimanal 25 with the aromatic synthon 61. Drimanal was synthesized from (-)-drimenol (11) via oxidation with pyridinium chlorochromate, and the aromatic synthon 61 was prepared from 3,4-dimethoxybenzaldehyde in four steps with a high yield [20]. The addition of drimanal 25 to the aryllithium derived from 61 and subsequent deprotection of the tert-butyldimethylsilyl ether gave a mixture of 62 and 63 in a ratio 3:1. The treatment of this mixture with p-toluenesulfonic acid gave the cyclization products 60 and 60a in a 1:3 ratio. Finally, the simultaneous demethylation and oxidation of 60 and 60a with AgO/HNO 3 afforded a mixture of puupehedione (2) and 8-epipuupehedione (54) in the same 1:3 ratio. 8-Epipuupehedione (54) was the main compound due to its higher stability. An alternative procedure by direct treatment of the condensation compound with acid, without previous deprotection of the silyl ether (step V, Scheme 11), gave 60 and 60a in a 1:8 ratio. Simultaneous demethylation and oxidation of 60 and 60a with AgO/HNO 3 afforded natural puupehedione (2) and its epimer (54) in a ratio 1:8. Therefore, this second procedure generated a lower yield of the natural puupehedione (2), as it was much more selective towards its unnatural β-epimer.

Synthesis of Puupehenone (1) and Puupehedione (2) from Non-Chiral Starting Material
2.2.1. Synthesis of (±)-Puupehenone (2) from Farnesyl Bromide (E,E)-Farnesyl bromide, a derivative of natural farnesol, is a commercially available product which has been used in the total synthesis of several natural products [39]. In 1978, Trammell reported the first total synthesis of (±)-puupehenone (1) using farnesyl bromide as starting material [21] (Scheme 12). In this procedure a linear synthetic route was used. The key step was an acid-mediated cyclization of the polyene 12, prepared by alkylation of the lithium salt of sesamol with farnesyl bromide. Cyclization of 12 with boron trifluoride etherate afforded an incompletely cyclized product. For this reason, 12 was  (1) and Puupehedione (2) from Non-Chiral Starting Material 2.2.1. Synthesis of (±)-Puupehenone (2) from Farnesyl Bromide (E,E)-Farnesyl bromide, a derivative of natural farnesol, is a commercially available product which has been used in the total synthesis of several natural products [39]. In 1978, Trammell reported the first total synthesis of (±)-puupehenone (1) using farnesyl bromide as starting material [21] (Scheme 12). In this procedure a linear synthetic route was used. The key step was an acid-mediated cyclization of the polyene 12, prepared by alkylation of the lithium salt of sesamol with farnesyl bromide. Cyclization of 12 with boron trifluoride etherate afforded an incompletely cyclized product. For this reason, 12 was acetylated. Cyclization of acetate 64 with BF 3 ·Et 2 O followed by alkaline hydrolysis gave phenol 65 (40% overall yield). Subsequent treatment of compound 65 with a catalytic amount of β-naphthalenesulfonic acid afforded a mixture of two isomers, 66 and 67, in a ratio 1/2.4. The yield of this cyclization was not reported in the original paper. Cleavage of the methylenedioxy protecting group in 67 with phosphorus pentachloride, and subsequent hydrolysis gave (±)-puupehenol 5. The yield of this deprotection was not reported in the original publication. Finally, aerobic oxidation of phenol 5 in the presence of KOH yielded (±)-puupehenone ((±)-1) in an almost quantitative yield. Although Barrero and coworkers later observed the lack of reproducibility of this synthesis [11], the electrophilic addition approach to the oxygen heterocycle probably inspired these researchers, who later reported a second synthesis of puuphenone via an organoselenium-mediated heterocyclization step [11].
In 2006, Gansäuer et al. [22,43] reported an efficient synthetic approach to (±)-puupehedione ((±)-2) from commercially available farnesol (68). Some of us collaborated in this synthesis. Key steps in this synthetic linear route were an allylic substitution reaction between 13 and 69, and the titanocene(III)-catalyzed radical cascade cyclization of a suitable epoxy-polyprene 70 (Scheme 13). The arylepoxypolyene 70 was prepared via the coupling of the epoxyfarnesyl acetate 13 with the benzyl Grignard reagent 69 through an allylic substitution reaction catalyzed by Li2CuCl4 in a 60% yield. Epoxyfarnesyl acetate 13 was synthesized from farnesol 68, while benzyl Grignard reagent 69 was obtained using its bromide aromatic ring derivative and magnesium. The trans-decaline 71 was prepared by Cp2TiCl-catalyzed epoxypolyene diastereoselective cyclization of 70 in 41% yield. The key intermediate 72 was obtained in a sequence of three steps, including deoxygenation of hydroxyl group at C3 via a Barton-McCombie deoxygenation reaction and cleavage of the methoxymethyl ether group of 71 in a 74% overall yield. The reaction of 72 with N-(phenylseleno)phthalimide and subsequent reduction with Bu3SnH yielded 73 in good overall yield (69%), completing the formal synthesis of marine (±)-puupehedione ((±)-2) [12].
In 2006, Gansäuer et al. [22,43] reported an efficient synthetic approach to (±)-puupehedione ((±)-2) from commercially available farnesol (68). Some of us collaborated in this synthesis. Key steps in this synthetic linear route were an allylic substitution reaction between 13 and 69, and the titanocene(III)-catalyzed radical cascade cyclization of a suitable epoxy-polyprene 70 (Scheme 13). The arylepoxypolyene 70 was prepared via the coupling of the epoxyfarnesyl acetate 13 with the benzyl Grignard reagent 69 through an allylic substitution reaction catalyzed by Li 2 CuCl 4 in a 60% yield. Epoxyfarnesyl acetate 13 was synthesized from farnesol 68, while benzyl Grignard reagent 69 was obtained using its bromide aromatic ring derivative and magnesium. The trans-decaline 71 was prepared by Cp 2 TiCl-catalyzed epoxypolyene diastereoselective cyclization of 70 in 41% yield. The key intermediate 72 was obtained in a sequence of three steps, including deoxygenation of hydroxyl group at C3 via a Barton-McCombie deoxygenation reaction and cleavage of the methoxymethyl ether group of 71 in a 74% overall yield. The reac-tion of 72 with N-(phenylseleno)phthalimide and subsequent reduction with Bu 3 SnH yielded 73 in good overall yield (69%), completing the formal synthesis of marine (±)-puupehedione ((±)-2) [12]. Finally, to conclude this section, it is worth indicating that some of the synthetic procedures reported here have enabled the synthesis of other derivatives of puupehenonetype products [23], mainly their epimers at carbon-8, which also turn out to be interesting due to their important biological properties [10].

Future Perspectives
In light of the exhaustive review of the different syntheses of the marine puupehenone (1) and puupehedione (2) from accessible natural synthons presented in Section 2, it is obvious that the development of new synthetic methodologies has allowed the efficient construction of the carbon skeletons of these types of compounds. In this way, different synthetic routes to prepare puupehenone (1) and puupehedidone (2) have been described, including the coupling of the aldehydes with aromatic synthons, the Suzuki carbonylative coupling reaction, the hemiacetalization/dehydroxylation/hydroxylation/retrohemiacetalization tandem reaction, the Friedel-Crafts coupling reaction, and linear synthetic routes. Another important aspect to highlight is the efforts made to achieve high levels of diastereoselection in the formation of the pyran ring of these compounds (C ring) since natural products with their methyl group on C8 with α orientation (C8-Meα) are less stable than their C8-epimers (C8-Meβ). For this purpose, important advances have been made: the use of organoselenium reagents, although with an increase in the number of synthetic operations that must be performed; the palladium(II)-mediated diastereoselective cyclization; the hemiacetalization/dehydroxylation/hydroxylation/retro-hemiacetalization; the diastereoselective intramolecular cyclization, in basic medium, of a skeleton having an oxygen atom attached to C-15 to obtain the desired natural products (C8-Meα), avoiding the use of protecting groups and transition metals. However, despite all the advances made, we consider that a unified synthesis for the preparation of puupehenone-type compounds is desirable.
Finally, to conclude this section, it is worth indicating that some of the synthetic procedures reported here have enabled the synthesis of other derivatives of puupehenonetype products [23], mainly their epimers at carbon-8, which also turn out to be interesting due to their important biological properties [10].

Future Perspectives
In light of the exhaustive review of the different syntheses of the marine puupehenone (1) and puupehedione (2) from accessible natural synthons presented in Section 2, it is obvious that the development of new synthetic methodologies has allowed the efficient construction of the carbon skeletons of these types of compounds. In this way, different synthetic routes to prepare puupehenone (1) and puupehedidone (2) have been described, including the coupling of the aldehydes with aromatic synthons, the Suzuki carbonylative coupling reaction, the hemiacetalization/dehydroxylation/hydroxylation/retrohemiacetalization tandem reaction, the Friedel-Crafts coupling reaction, and linear synthetic routes. Another important aspect to highlight is the efforts made to achieve high levels of diastereoselection in the formation of the pyran ring of these compounds (C ring) since natural products with their methyl group on C8 with α orientation (C 8 -Me α ) are less stable than their C 8 -epimers (C 8 -Me β ). For this purpose, important advances have been made: the use of organoselenium reagents, although with an increase in the number of synthetic operations that must be performed; the palladium(II)-mediated diastereoselective cyclization; the hemiacetalization/dehydroxylation/hydroxylation/retro-hemiacetalization; the diastereoselective intramolecular cyclization, in basic medium, of a skeleton having an oxygen atom attached to C-15 to obtain the desired natural products (C 8 -Me α ), avoiding the use of protecting groups and transition metals. However, despite all the advances made, we consider that a unified synthesis for the preparation of puupehenone-type compounds is desirable.
In this section, based on the antecedents discussed, and in our personal experience in the total synthesis of marine natural products [22,[45][46][47][48][49][50][51][52], we propose a retrosynthetic analysis towards a common intermediate 74 in which the carbon 15 is functionalized with a hydroxy group (Scheme 14). Our proposal should allow the preparation of either the natural puupehenone-type compound with total diastereoselectivity or, alternatively, their nonnatural epimers (C 8 -Me β ) by previous hydrogenolysis of the hydroxy group on the carbon 15 of 74 (Scheme 14). We consider that a convergent synthesis toward intermediate 74 is the best strategy for the synthesis of puupehenone-type products since it improves the efficiency of the multistep synthesis. Therefore, the key endocyclic compound 74 could be synthesized via a C-C bond coupling reaction between an electrophilic drimenal 25 with the aryllithium derivative 75. Drimenal 25 can be obtained in optically pure form from E,E-farnesol by cationic cyclization followed by resolution of the racemic mixture via chromatographic separation of the diasteromeric camphanoate derivatives [53,54]. The aryllithium 75 would be formed by the lithiation of 76. We propose the aromatic ring 76 as the second fragment in the coupling process with 25, since it has been shown that it can be selectively demethylated [19], a step which is necessary for the completion of the synthetic route. Deoxygenation of the C15-OH group in 74 and subsequent total demethylation would afford the first key intermediate 77. Acid-mediated cyclization of 77 would give 8-epipuupehenol, from which puupehenone-type unnatural products (C8-Meβ) would be Scheme 14. Unified retrosynthetic analysis of puupehenone-type natural and unnatural products.
We consider that a convergent synthesis toward intermediate 74 is the best strategy for the synthesis of puupehenone-type products since it improves the efficiency of the multistep synthesis. Therefore, the key endocyclic compound 74 could be synthesized via a C-C bond coupling reaction between an electrophilic drimenal 25 with the aryllithium derivative 75. Drimenal 25 can be obtained in optically pure form from E,E-farnesol by cationic cyclization followed by resolution of the racemic mixture via chromatographic separation of the diasteromeric camphanoate derivatives [53,54]. The aryllithium 75 would be formed by the lithiation of 76. We propose the aromatic ring 76 as the second fragment in the coupling process with 25, since it has been shown that it can be selectively demethylated [19], a step which is necessary for the completion of the synthetic route. Deoxygenation of the C15-OH group in 74 and subsequent total demethylation would afford the first key intermediate 77.
Acid-mediated cyclization of 77 would give 8-epi-puupehenol, from which puupehenonetype unnatural products (C 8 -Me β ) would be obtained via the modification of its functional groups. On the other hand, for the synthesis of puupehenone-type natural compounds (C 8 -Me α ), intermediate 74 should be oxidized, generating the ketone 78, which would be the second key intermediate. The isomerization of the trisubstituted double bond in 78 would form the aryl vinyl ketone 58. Selective demethylation and diastereoselective cyclization of 58 with KOH should lead to the tetracyclic compound 59 with the correct stereochemistry at C8, the one present in the puupehenone-type natural products, as we have previously commented [31]. Finally, there is a selection of different experimental conditions which could convert the tetracyclic compound 59 into puupehenones-type natural products. This general retrosynthetic analysis shown in Scheme 14 represents a unified, low-cost, and powerful tool for the construction of puupehenone-type natural products and their C8-epimers, both of which could be used to address relevant biological and pharmaceutical studies.

Conclusions
A review of the synthesis of marine puupehenone (1) and puupehedione (2) has been presented in terms of the starting material and synthetic strategy employed. Being complex structures, their synthesis often requires a reasonable number of synthetic operations. Taking into consideration the best results from each approach, we have described in this perspective article a new unified retrosynthetic analysis for the preparation of puupehenone-type natural and unnatural products. The proposal is designed to require the minimum synthetic operations and demonstrates its versatility and power for the preparation of these fascinating compounds, which could be used to address future biological and pharmaceutical issues.