Marine Puupehenone and Puupehedione. Synthesis and Future Perspectives

Citation: Rosales Martínez, A.; Rodríguez-García, I. Marine Puupehenone and Puupehedione: Synthesis and Future Perspectives. Mar. Drugs 2023,21, 322. https://doi.org/10.3390/md21060322 Academic Editors: Francisco Sarabia and Ivan Cheng-Sanchez Received: 8 May 2023 Revised: 21 May 2023 Accepted: 24 May 2023 Published: 26 May 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). marine drugs Perspective Marine Puupehenone and Puupehedione: Synthesis and Future Perspectives Antonio Rosales Martínez 1,* and Ignacio Rodríguez-García2 1 Department of Chemical Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain 2Organic Chemistry, ceiA3, CIAIMBITAL, University of Almería, 04120 Almería, Spain; ir[email protected] *Correspondence: ar[email protected] Abstract: 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. Keywords: marine natural products; meroterpenoids; puupehenone; puupehedione 1. Introduction Quinone/hydroquinone meroterpenoids are constituents of the secondary metabolite extracts of many marine organisms [ 1 ]. As a common structural feature, these compounds are constituted by two biogenetically diverse sub-units: a sesquiterpene portion and a quinone or phenolic moiety [ 2 ]. Within the meroterpenoid family, there is a remarkable group: the puupehenones. These natural marine compounds have been isolated from sponges, mainly from the orders Dictyoceratida and Verongida, although some products from this family have been isolated as well from the orders Haplosclerida and Dendroceratida [ 3 – 8 ]. The most representative compoundsofthisgroupofmarinenaturalproductsare(+)-puupehenone( 1 ),(+)-puupehedione ( 2 ), the halopuupehenones ( 3 ) and ( 4 ), (-)-puupehenol ( 5 ), (+)-cyanopuupehenol ( 6 ), and (-)-15- oxo-puupehenol (7) (Figure 1). 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/O- benzoquinone (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. Mar. Drugs 2023,21, 322. https://doi.org/10.3390/md21060322 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2023,21, 322 2 of 17 Mar. Drugs 2023, 21, x FOR PEER REVIEW 2 of 18 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. Figure 1. Selected members of puupehenone-type natural compounds (C8-Meα). (Rings and atoms labels drawn only in 1). 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. 2. 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). Figure 1. Selected members of puupehenone-type natural compounds (C 8 -Me α ). (Rings and atoms labels drawn only in 1). 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. 2. 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 1summarizes 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). Mar. Drugs 2023,21, 322 3 of 17 Mar. Drugs 2023, 21, x FOR PEER REVIEW 3 of 18 Scheme 1. Starting materials employed in the previous synthesis of puupehenone (1) and puupehedione (2) [11–23]. 2.1. Synthesis of Puupehenone (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. Scheme 1. Starting materials employed in the previous synthesis of puupehenone ( 1 ) and puupehedione (2) [11–23]. 2.1. Synthesis of Puupehenone (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. Mar. Drugs 2023,21, 322 4 of 17 Mar. Drugs 2023, 21, x FOR PEER REVIEW 4 of 18 Scheme 2. Barreros enantioselective synthesis of (+)-puupenhenone (1) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [27]; (II) 15, t-BuLi, Et2O, −78 °C, 88%; (III) (i) Cl2SO, Py, rt, 1 h, 94%; (ii) TBAF, THF, rt, 15 min, 81%; (iii) NaBH4, EtOH, rt, 20 min, 91%; (IV) NPSP, SnCl4, CH2Cl2, −78 °C, 2 h, 91%; (V) (i) Raney Ni, THF, rt, 20 h, 75%; (ii) PDC, CH2Cl2, rt, 3 h, 70%. TBAF = tetrabutylammonium fluoride; NPSP = N-phenylselenophtalimide; PDC = pyridinium dichromate. 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). Scheme 2. Barrero’s enantioselective synthesis of (+)-puupenhenone ( 1 ) from (-)-sclareol ( 8 ). Reagents and conditions: (I) Ref. [ 27 ]; (II) 15 ,t-BuLi, Et 2 O, − 78 ◦ C, 88%; (III) (i) Cl 2 SO, Py, rt, 1 h, 94%; (ii) TBAF, THF, rt, 15 min, 81%; (iii) NaBH 4 , EtOH, rt, 20 min, 91%; (IV) NPSP, SnCl 4 , CH 2 Cl 2 , − 78 ◦ C, 2 h, 91%; (V) (i) Raney Ni, THF, rt, 20 h, 75%; (ii) PDC, CH 2 Cl 2 , rt, 3 h, 70%. TBAF = tetrabutylammonium fluoride; NPSP = N-phenylselenophtalimide; PDC = pyridinium dichromate. 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 C8-Meβas 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 3gave 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 Mar. Drugs 2023,21, 322 5 of 17 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). Mar. Drugs 2023, 21, x FOR PEER REVIEW 5 of 18 Scheme 3. Barreros enantioselective synthesis of puupehedione (2) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [28]; (II) (i) t-BuLi, 15, Et2O, −78 °C, 50 min, Ar; 20 Et2O, −78 °C, 40 min; (ii) Et3SiH, TFA, CH2Cl2, −78 °C, 45 min, 79%, two steps; (iii) TBAF, THF, rt, 15 min, 95%; (III) (i) Ac2O, NaAcO, reflux, 2 h, 98%; (ii) mCPBA, NaHCO3, CH2Cl2, −20 °C, 2 h, 98%; (IV) (i) 2N KOH-MeOH, rt, 48 h, 95%; (ii) H2, 10% Pd/C, MeOH, rt, 1 h, 91%; (V) (i) silica gel, 45%; (ii) NaIO4, EtOH-H2O, rt, 15 min, 80%. TFA = trifluoroacetic acid; TBAF = tetrabutylammonium fluoride; mCPBA = meta-chlo- roperbenzoic acid. 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. Scheme 3. Barrero’s enantioselective synthesis of puupehedione ( 2 ) from (-)-sclareol ( 8 ). Reagents and conditions: (I) Ref. [ 28 ]; (II) (i) t-BuLi, 15 , Et 2 O, − 78 ◦ C, 50 min, Ar; 20 Et 2 O, − 78 ◦ C, 40 min; (ii) Et 3 SiH, TFA, CH 2 Cl 2 , − 78 ◦ C, 45 min, 79%, two steps; (iii) TBAF, THF, rt, 15 min, 95%; (III) (i) Ac 2 O, NaAcO, reflux, 2 h, 98%; (ii) mCPBA, NaHCO 3 , CH 2 Cl 2 , − 20 ◦ C, 2 h, 98%; (IV) (i) 2N KOH-MeOH, rt, 48 h, 95%; (ii) H 2 , 10% Pd/C, MeOH, rt, 1 h, 91%; (V) (i) silica gel, 45%; (ii) NaIO 4 , EtOH-H 2 O, rt, 15 min, 80%. TFA = trifluoroacetic acid; TBAF = tetrabutylammonium fluoride; mCPBA = meta-chloroperbenzoic acid. 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 ) 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). Mar. Drugs 2023,21, 322 6 of 17 Mar. Drugs 2023, 21, x FOR PEER REVIEW 6 of 18 Scheme 4. Álvarez-Manzanedas enantioselective synthesis of (+)-puupehenone (1) and (+)- puupehedione (2) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [13]; (II) t-BuLi, 26, THF, −80 °C, 30 min, Ar; 25, THF, −80 °C, 30 min, 87%; (III) Raney Ni, THF, rt, 30 min, 98%; (IV) PdCl2, Pd(OAc)2 (cat), MeOH-H2O (99:1), 40 °C, 48 h, 91%, (V) H2, Pd/C, EtOH, rt, 48%, 99%; (VI) Ag2O, THF, rt, 90 min, 95%; (VII) DDQ, dioxane, reflux, 2 h, 80%. DDQ = 2,3-Dichloro-5,6-dicyano-1,4- benzoquinone. 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). Scheme 5. Álvarez-Manzanedas enantioselective formal synthesis of (+)-puupehenone (1) from (-)- sclareol (8). Reagents and conditions: (I) Ref. [14]; (II) Amberlyst A-15, 4 Å molecular sieves, CH2Cl2, reflux, 12 h, 94%; (III) (i) MeMgBr, Et2O, 0 °C, 30 min, 94%; (ii) H2, Pd/C, MeOH, rt, 1 h, 93%; (IV) (i) (TfO)2O, CH2Cl2, iPrNEt2, 0 °C, 5 min, 83%; (ii) Pd(OAc)2 (cat), DPPF, NaOtBu, toluene, 100 °C, 14 h, 76%; (V) (i) BBr3, CH2Cl2, 0 °C, 80 min, 82%; (ii) Ref. [13]. DPPF = 1,1′-bis(diphenylphosphanyl)ferrocene. Scheme 4. Álvarez-Manzaneda’s enantioselective synthesis of (+)-puupehenone ( 1 ) and (+)-puupehedione ( 2 ) from (-)-sclareol ( 8 ). Reagents and conditions: (I) Ref. [ 13 ]; (II) t-BuLi, 26 , THF, − 80 ◦ C, 30 min, Ar; 25 , THF, − 80 ◦ C, 30 min, 87%; (III) Raney Ni, THF, rt, 30 min, 98%; (IV) PdCl 2 , Pd(OAc) 2 (cat), MeOH-H 2 O (99:1), 40 ◦ C, 48 h, 91%, (V) H 2 , Pd/C, EtOH, rt, 48%, 99%; (VI) Ag 2 O, THF, rt, 90 min, 95%; (VII) DDQ, dioxane, reflux, 2 h, 80%. DDQ = 2,3-Dichloro-5,6-dicyano- 1,4-benzoquinone. Mar. Drugs 2023, 21, x FOR PEER REVIEW 6 of 18 Scheme 4. Álvarez-Manzanedas enantioselective synthesis of (+)-puupehenone (1) and (+)- puupehedione (2) from (-)-sclareol (8). Reagents and conditions: (I) Ref. [13]; (II) t-BuLi, 26, THF, −80 °C, 30 min, Ar; 25, THF, −80 °C, 30 min, 87%; (III) Raney Ni, THF, rt, 30 min, 98%; (IV) PdCl2, Pd(OAc)2 (cat), MeOH-H2O (99:1), 40 °C, 48 h, 91%, (V) H2, Pd/C, EtOH, rt, 48%, 99%; (VI) Ag2O, THF, rt, 90 min, 95%; (VII) DDQ, dioxane, reflux, 2 h, 80%. DDQ = 2,3-Dichloro-5,6-dicyano-1,4- benzoquinone. 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). Scheme 5. Álvarez-Manzanedas enantioselective formal synthesis of (+)-puupehenone (1) from (-)- sclareol (8). Reagents and conditions: (I) Ref. [14]; (II) Amberlyst A-15, 4 Å molecular sieves, CH2Cl2, reflux, 12 h, 94%; (III) (i) MeMgBr, Et2O, 0 °C, 30 min, 94%; (ii) H2, Pd/C, MeOH, rt, 1 h, 93%; (IV) (i) (TfO)2O, CH2Cl2, iPrNEt2, 0 °C, 5 min, 83%; (ii) Pd(OAc)2 (cat), DPPF, NaOtBu, toluene, 100 °C, 14 h, 76%; (V) (i) BBr3, CH2Cl2, 0 °C, 80 min, 82%; (ii) Ref. [13]. DPPF = 1,1′-bis(diphenylphosphanyl)ferrocene. Scheme 5. Álvarez-Manzaneda’s enantioselective formal synthesis of (+)-puupehenone ( 1 ) from (-)-sclareol ( 8 ). Reagents and conditions: (I) Ref. [ 14 ]; (II) Amberlyst A-15, 4 Å molecular sieves, CH 2 Cl 2 , reflux, 12 h, 94%; (III) (i) MeMgBr, Et 2 O, 0 ◦ C, 30 min, 94%; (ii) H 2 , Pd/C, MeOH, rt, 1 h , 93%; (IV) (i) (TfO) 2 O, CH 2 Cl 2 ,iPrNEt 2 , 0 ◦ C, 5 min, 83%; (ii) Pd(OAc) 2 (cat), DPPF, NaOtBu, toluene, 100 ◦ C, 14 h, 76%; (V) (i) BBr 3 , CH 2 Cl 2 , 0 ◦ C, 80 min, 82%; (ii) Ref. [ 13 ]. DPPF = 1,1 0 - bis(diphenylphosphanyl)ferrocene. Treatment of ketone 32 with MeMgBr and further cleavage of the benzyl ether afforded hydroxyphenol 33 . Triflate derivatization of the phenol group in 33 followed by cyclization in the presence of Pd(OAc) 2 , 1,1 0 -bis(diphenylphosphanyl)ferrocene and sodium tert-butoxide, led to the formation of the tetracyclic compound 34 . Finally, deprotection of both methoxy groups resulted in diphenol 5 , previously presented in Scheme 4, which is an advanced intermediate in the Álvarez-Manzaneda’s synthesis of (+)-puupehenone ( 1 ) [ 13 ]. Mar. Drugs 2023,21, 322 7 of 17 2.1.2. Synthesis of Puupehenone (1) and/or Puupehedione (2) from (+)-Sclareolide (9) (+)-Sclareolide ( 9 ) is a sesquiterpene lactone isolated from different plant sources including Salvia sclarea,Salvia yosgadensis, and cigar tobacco [ 29 , 30 ]. Due to its commercial availability, as well as the correct chirality for three of the four (+)-puupehenone stereogenic centers, this natural compound has been employed as a starting material for the total synthesis of many terpenoids and their derivatives [26,31,32]. 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). Mar. Drugs 2023, 21, x FOR PEER REVIEW 7 of 18 Treatment of ketone 32 with MeMgBr and further cleavage of the benzyl ether afforded hydroxyphenol 33. Triflate derivatization of the phenol group in 33 followed by cyclization in the presence of Pd(OAc)2, 1,1′-bis(diphenylphosphanyl)ferrocene and sodium tert-butoxide, led to the formation of the tetracyclic compound 34. Finally, deprotection of both methoxy groups resulted in diphenol 5, previously presented in Scheme 4, which is an advanced intermediate in the Álvarez-Manzanedas synthesis of (+)-puupehe- none (1) [13]. 2.1.2. Synthesis of Puupehenone (1) and/or Puupehedione (2) from (+)-Sclareolide (9) (+)-Sclareolide (9) is a sesquiterpene lactone isolated from different plant sources including Salvia sclarea, Salvia yosgadensis, and cigar tobacco [29,30]. Due to its commercial availability, as well as the correct chirality for three of the four (+)-puupehenone stereogenic centers, this natural compound has been employed as a starting material for the total synthesis of many terpenoids and their derivatives [26,31,32]. 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). I (4 steps) H H 35 37 OBn OBn 36 II (2 steps) 1: (+)-Puupehenone O O H OH OH OH H 9: (+)-Sclareolide O O CHO OH Br OH H 38 O HO O IV 8III Scheme 6. Quideaus enantiospecific synthesis of (+)-puupehenone (1) from (+)-sclareolide (9). Reagents and conditions: (I) Ref. [15]; (II) (i) 36, t-BuLi, THF, −78 °C, 20 min; then 35 THF, −78 °C, 15 min, 73%; (ii) H2, Pd/C (10%), THF, rt, overnight, 87%; (III) BTI, CH2Cl2, 45 min, −25 °C, 67%; (IV) KH, dioxane, rt, 1h; then 20 min at 45 °C, 27%. BTI = [bis(trifluoroacetoxy)-iodo]benzene. More recently, in 2017, Wu et al. [16] reported a green synthesis of puupehenone (1) and puupehedione (2) which avoided the use of protecting groups and also started from (+)-sclareolide (9). In this strategy, the key step is a hemiacetalization/dehydroxylation/hydroxylation/retro-hemiacetalization tandem reaction of 40 (Scheme 7). The drimanic βhydroxyaldehyde 35 was prepared following Quideaus procedure from commercially available (+)-sclareolide (9) [15]. With the compound 35 in their hands, the key intermediate 40 was obtained in a 67% yield via the treatment of ketone 39 with LDA and a Scheme 6. Quideau’s enantiospecific synthesis of (+)-puupehenone ( 1 ) from (+)-sclareolide ( 9 ). Reagents and conditions: (I) Ref. [ 15 ]; (II) (i) 36 ,t-BuLi, THF, − 78 ◦ C, 20 min; then 35 THF, − 78 ◦ C, 15 min, 73%; (ii) H 2 , Pd/C (10%), THF, rt, overnight, 87%; (III) BTI, CH 2 Cl 2 , 45 min, − 25 ◦ C, 67%; (IV) KH, dioxane, rt, 1h; then 20 min at 45 ◦C, 27%. BTI = [bis(trifluoroacetoxy)-iodo]benzene. More recently, in 2017, Wu et al. [ 16 ] reported a green synthesis of puupehenone ( 1 ) and puupehedione ( 2 ) which avoided the use of protecting groups and also started from (+)-sclareolide ( 9 ). In this strategy, the key step is a hemiacetalization/dehydroxylation/ hydroxylation/retro-hemiacetalization tandem reaction of 40 (Scheme 7). The drimanic β -hydroxyaldehyde 35 was prepared following Quideau’s procedure from commercially available (+)-sclareolide ( 9 ) [ 15 ]. With the compound 35 in their hands, the key intermediate 40 was obtained in a 67% yield via the treatment of ketone 39 with LDA and a subsequent C–C bond forming reaction with aldehyde 35 . Under controlled acidic conditions, 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 O 2 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. Mar. Drugs 2023,21, 322 8 of 17 Mar. Drugs 2023, 21, x FOR PEER REVIEW 8 of 18 subsequent C–C bond forming reaction with aldehyde 35. Under controlled acidic conditions, 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. Scheme 7. Wus enantiospecific synthesis of puupehenone (1) and puupehedione (2) from (+)- sclareolide (9). Reagents and conditions: (I) Ref. [15]; (II) 39, LDA, THF, −78 °C, 30 min; then 35, 1h, 67%; (III) HCl, MeOH, rt, 30 min, 92%; (IV) (i) KHDMS, THF, −78 °C, 30 min; (ii) then P(OMe)3, O2, −78 °C, 1 h, 42 (19%), 1 (38%); (V) tBuOK, tBuOH rt, 1 h, 86%; (VI) (i) NaBH4, EtOH, rt, 20 min, 92%; (ii) DDQ, 1,4-dioxane, reflux, 2h, 71%. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. 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-cou- pling reaction between hydrazone 43 and aryl iodide 44 using catalytic Pd(PPh3)4 and K2CO3 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 K2CO3 (92% yield). Scheme 7. Wu’s enantiospecific synthesis of puupehenone ( 1 ) and puupehedione ( 2 ) from (+)- sclareolide ( 9 ). Reagents and conditions: (I) Ref. [ 15 ]; (II) 39 , LDA, THF, − 78 ◦ C, 30 min; then 35 , 1 h, 67%; (III) HCl, MeOH, rt, 30 min, 92%; (IV) (i) KHDMS, THF, − 78 ◦ C, 30 min; (ii) then P(OMe) 3 , O 2 , − 78 ◦ C, 1 h, 42 (19%), 1 (38%); (V) tBuOK, tBuOH rt, 1 h, 86%; (VI) (i) NaBH 4 , EtOH, rt, 20 min, 92%; (ii) DDQ, 1,4-dioxane, reflux, 2h, 71%. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. 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 K2CO3(92% yield). 2.1.3. Synthesis of (+)-Puupehenone ( 1 ) and/or (+)-Puupehedione ( 2 ) from (-)-Carvone ( 10 ) (-)-Carvone ( 10 ) is a monoterpene that occurs at high concentrations (70–80%) in spearmint oil [ 33 ]. This natural product is economically available, making it an attractive chiral synthon for the enantiospecific total synthesis of natural compounds [34]. 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 Mar. Drugs 2023,21, 322 9 of 17 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 C8-Meα2. Mar. Drugs 2023, 21, x FOR PEER REVIEW 9 of 18 Scheme 8. Wus enantiospecific synthesis of puupehenone (1) and puupehedione (2) from (+)- sclareolide (9). Reagents and conditions: (I) Ref. [15]; (II) pTsNHNH2, MeOH, rt, 12 h, 88%; (III) 44, Pd(PPh3)4 (cat), K2CO3, toluene, 110 °C, 8 h, 85%; (IV) CAN, MeCN-H2O, rt, 47%; (V) Pd/C, H2, MeOH, 40 °C, 62%; (VI) CAN, MeCN-H2O, −5 °C to rt, 84%; (VII) pTsOH, CH2Cl2, rt; (VIII) K2CO3, CH3CN, rt, 92% from 48. CAN = ceric ammonium nitrate. 2.1.3. Synthesis of (+)-Puupehenone (1) and/or (+)-Puupehedione (2) from (-)-Carvone (10) (-)-Carvone (10) is a monoterpene that occurs at high concentrations (70–80%) in spearmint oil [33]. This natural product is economically available, making it an attractive chiral synthon for the enantiospecific total synthesis of natural compounds [34]. 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. Scheme 8. Wu’s enantiospecific synthesis of puupehenone ( 1 ) and puupehedione ( 2 ) from (+)-sclareolide ( 9 ). Reagents and conditions: (I) Ref. [ 15 ]; (II) pTsNHNH 2 , MeOH, rt, 12 h, 88%; (III) 44 , Pd(PPh 3 ) 4 (cat), K 2 CO 3 , toluene, 110 ◦ C, 8 h, 85%; (IV) CAN, MeCN-H 2 O, rt, 47%; (V) Pd/C, H 2 , MeOH, 40 ◦ C, 62%; (VI) CAN, MeCN-H 2 O, − 5 ◦ C to rt, 84%; (VII) pTsOH, CH 2 Cl 2 , rt; (VIII) K2CO3, CH3CN, rt, 92% from 48. CAN = ceric ammonium nitrate. Mar. Drugs 2023, 21, x FOR PEER REVIEW 10 of 18 Scheme 9. Banerjees enantiospecific synthesis of puupehedione (2) from (-)-carvone (10). Reagents and conditions: (I) Ref. [18]; (II) n-BuLi, −78 °C (3 h) to −5 °C (6 h), to rt (2 h); then 50, −78 °C, 5 h, 59%; (III) silica gel, CH2Cl2, rt, 3–4 h; (IV) RhCl3.3H2O, EtOH, reflux, 7 h, quantitative. 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 crosscoupling 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 AlCl3 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 (C8-Meα) (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 LiAlH4 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 BBr3 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. Scheme 9. Banerjee’s enantiospecific synthesis of puupehedione ( 2 ) from (-)-carvone ( 10 ). Reagents and conditions: (I) Ref. [ 18 ]; (II) n-BuLi, − 78 ◦ C (3 h) to − 5 ◦ C (6 h), to rt (2 h); then 50 , − 78 ◦ C, 5 h, 59%; (III) silica gel, CH2Cl2, rt, 3–4 h; (IV) RhCl3·3H2O, EtOH, reflux, 7 h, quantitative. Mar. Drugs 2023,21, 322 16 of 17 6. Hamann, M.T.; Scheuer, P.J. Cyanopuupehenol, an antiviral metabolite of a sponge of the order Verongida. Tetrahedron Lett. 1991 , 32, 5671–5672. [CrossRef] 7. 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