Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products

Puupehenones have been isolated from the marine sponge Chondrosia chucalla , which belong to a growing family of natural products with more than 100 members. These marine natural products have attracted increasing attention mainly due to their wide variety of biological activities such as antitumor, antiviral, and anti-HIV, and thus offer promising opportunities for new drug development. This chapter covers the approaches to the total synthesis of puupehenone-type marine natural products including puupehenol, puupehenone, puupehedione, and halopuupehenones. The routes begin with the construction of their basic skeletons, followed by the modification of their C- and D-rings. The contents are divided into two sections in terms of the key strategies employed to construct the basic skeleton. One is the convergent synthesis route with two synthons coupled by nucleophilic or electrophilic reaction, and the other is the linear synthesis route with polyene series cyclization as a key reaction.


Introduction
In recent years, the synthesis and application of marine natural products have become the focus of a much greater research effort, which is due in large part to the increased recognition of marine organisms as a rich source of novel compounds with biological applications [1][2][3][4]. The puupehenone-type marine natural products obtained from deep sea sponge have played a very important role in health care and prevention of diseases [5][6][7][8][9][10][11][12][13][14].
As shown in Figure 1, the most representative of this natural product family includes puppehenone, halopuupehenones, puupehedione, puupehenol, 15-cyanopuupehenol, 15-oxopuupehenol, and bispuupehenonen. Structurally, puupehenones are tetracyclic compounds consisting of a bicyclic sesquiterpene A-and B-rings and a shikimic acid/O-benzoquinone/O-phenol D-ring connected by tetrahydropyran/dihydropyran C-ring. In addition, the chiral center of the C-8 of this series of natural products listed in the figure is 8S, which is also the structural specificity of them.

Isolation and biological activities
The natural product puupehenone was first isolated from the Hawaiian sponge Chondrosia chucalla by Schauer group in 1979 [15]. Subsequently, it was obtained from sponges such as Heteronema, Hyrtios, and Strongylophora sp. [14,16,17]. At that time, the assignment of an absolute stereochemistry to puupehenone was not permitted by spectroscopic analysis or degradative studies. As shown in Figure 2, it was not until 1996 that Capon group [18] used chemical decomposition, ozone oxidative decomposition, and lithium aluminum hydride reduction to finally decompose the natural product into the known structure (+)-drimenyl acetate (13) and (À)-drimenol (14), and since then the absolute configuration of puupehenone has been determined.  The confirmation of the absolute configuration of puupehenone by chemical decomposition [18].

Total synthesis of puupehenone-type marine natural products
Compound supply and appropriate structural analysis are two main barriers to develop a natural product into drug [19][20][21][22][23][24][25][26][27][28][29][30][31]. Chemical synthesis of marine natural products could provide the technological base for preparing enough materials for further research of bioactivity [19]. Thus, the total synthesis of puupehenones has been widely researched and published in excellent literature.
In the present chapter, approaches to the total synthesis of puupehenone-type marine natural products have been reviewed. In general, the strategies employed in the total synthesis of puupehenones are as follows: • Convergent synthesis route with two synthons coupled by nucleophilic or electrophilic reaction.
• Linear synthesis route with polyene series cyclization as a key reaction.

Convergent synthesis route
Barrero group has been working on the study of total synthesis of puupehenonetype natural products, and has obtained great achievements [32][33][34][35]. In 1997, Barrero and coworkers reported the first enantiospecific synthesis of puupehenol and puupehenone in 32 and 22% yield, respectively [33]. As shown in Figure 3, acetoxyaldehyde 17 and aromatic synthon 18 were prepared from commercially available sclareol 15 and veratraldehyde 16 in high yields through a series of Barrero's stereoselective synthesis of puupehenol and puupehenone [33].
transformations. The acetoxy alcohol 19 was completed by condensation of 17 with the aryllithium derived from 16, and after three steps compound 19 gave the phenolic derivatives 20. Finally, complete diastereoselectivity was achieved by organoselenium-induced cyclization. The treatment of 20 with NPSP(Nphenylselenophthalimide) and SnCl 4 obtained a mixture of the selenium derivatives 21 and 22. Treatment with Raney Ni allowed both deprotection of the phenylselenyl group and removal of the benzyl ethers, producing puupehenol (5) as the only product, which was easily oxidized to (+)-puupehenone (1) in the presence of pyridinium dichromate (PDC).
Besides the above-mentioned research work, in 1999, Barrero group applied a base-mediated cyclization via 8,9-epoxy derivative to achieve the first asymmetric synthesis of puupehedione in 17% overall yield [35]. As shown in Figure 4, Sclareol 15 and veratraldehyde 16 were employed as the starting materials to obtain synthons 23 and 18, which were accordingly converted to the key skeleton 24 in two steps. The treatment of 24 in the presence of mCPBA gave epoxydes 25, and finally alcohol 26 was obtained in high yield when 8a, 9a-epoxyde 25 was treated with KOH in methanol. The subsequent two-step routine transformations, involving dehydration of alcohol 26 and oxidation, gave the target compound puupehedione.
In 2001, Maiti group reported the total synthesis of 8-epi-puupehedione with angiogenesis inhibitory activity [36]. As shown in Figure 5, commercially available carvone (27) and sesamol (28) were converted into tosylhydrazone 29 and aromatic synthon 30 in eight and three steps, respectively. Exposure of the vinyl lithium species, produced by the addition of tosylhydrazone 29 to an excess of n-BuLi, to 30 afforded the diene 31. Then, the cleavage of the O-allyl ether of compound 31 with a catalytic amount of RhCl 3 Á3H 2 O in refluxing EtOH resulted in spontaneous cyclization [37], affording a mixture of the puupehedione (4) and 8-epipuupehedione (32).
In 2002, Quideau and coworkers completed asymmetric total synthesis of puupehenone in 10 steps starting from commercially available (+)-sclareolide [38]. The main feature of this synthesis strategy is an intramolecular attack of the terpenoid-derived C-8 oxygen function onto an oxidatively activated 1,2- Barrero's asymmetric synthesis of puupehedione [35]. dihydroxyphenyl unit to construct the heterocycle. As shown in Figure 6, the first step in their synthesis is inversion of the configuration at C-8 to construct a C-8 chiral center via simple acid treatment before coupling two key synthons. Subsequent treatment with (DA) 2 Mg and MoOPH afforded 35 and 36, which were converted into 39 after hydride reduction with DIBAL and oxidation with NaIO 4 . Then, coupling of aldehyde 15 with bromide 40 was achieved via a standard halogen-metal exchange protocol. Then, the key skeleton catechol 41 was obtained in good yield by a subsequent hydrogenolysis to remove both the benzyl protective groups. Finally, key oxidative activation of the catechol unit toward intramolecular attack by the drimane 8-oxygen and rearrangement with KH accomplished total synthesis of puupehenone.
In 2005, Alvarez-Manzaneda group reported a new strategy toward puupehenone-related natural products based on the palladium(II)-mediated diastereoselective cyclization of a drimenylphenol [39] to complete the first enantiospecific synthesis of 15-oxopuupehenol, together with improved syntheses of 15-cyanopuupehenone, puupehenone and puupehedione. As shown in Figure 7,  Quideau's asymmetric synthesis of puupehenone [38].
the drimane synthon 44 is easily prepared from sclareol (15) in seven steps. According to the procedure reported by Barrero [40], the drimane precursor 43 was prepared over three steps from 15 in 75% overall yield. Treating 43 with t-BuOK in a mixed solvent of DMSO-H 2 O, followed by oxidative hydroboration, dehydration, and oxidation, afforded synthon 44 in 52% yield over four steps. The new synthon 47 from the 3,4-bis(benzyloxybenzyloxy)phenol (45), in a two-step sequence in 83% overall yield. Then, the key skeleton 48 was obtained by the coupling of 44 and 47. Alvarez-Manzaneda and coworkers realized that catalytic PdCl 2 and Pd(OAc) 2 allowed to obtain the desired C8α-Me epimer with complete diastereoselectivity by inducing cyclization, yielding the most satisfactory compounds. Thus, puupehenol (5) was achieved by catalytic hydrogenation of 49, which was obtained in high yield via palladium(II) catalysis of compound 48. Finally, puupehenol (5) can be transformed into 15-oxopuupehenol (7) and the other puupehenone-related natural products.
Continuing their research into the total synthesis of this type of natural product, in 2007, Alvarez-Manzaneda group reported a new synthetic route toward puupehenone-related natural products starting from sclareol oxide (50) [41]. As shown in Figure 8, the key structure 53 was constructed by the coupling of two synthons 51 and 52, based on a Diels-Alder cycloaddition approach. They employed sclareol oxide (50) as starting material to afford 51 over four steps which was treated with dienophile R-chloroacrylonitrile to afford compound 53 utilizing Diels-Alder cycloaddition. Treatment of 53 with DBU in benzene and DDQ in dioxane at room temperature led to aromatic nitrile 54. Then, ent-chromazonarol (55) was obtained over three steps in 63% yield. The oxidation of phenol 55 to the appropriate ortho-quinone precursor of target compound 32 was then addressed.
In 2009, Manzaneda group [42] reported an enantiospecific route toward puupehenone and other related metabolites based on the cationic-resin-promoted Friedel-Crafts alkylation of alkoxyarenes with an α,β-unsaturated ketone 57. As shown in Figure 9, Manzaneda and coworkers developed a very efficient synthesis of compound 57 which is a key synthon employed in the total synthesis of puupehenones, starting from commercially available sclareol (15) in 60% yield. Synthesis of several puupehenone-type natural products by palladium-catalyzed cyclization [39].
Then, the key intermediate ketone 59 was obtained in high yield and with complete diastereoselectivity by treatment of 57 with protected phenol 58 under the condition of Amberlyst A-15. Alternatively, treatment of ketone 59 with MeMgBr, further cleavage of the benzyl ether and protection of hydroxyl gave triflate 60 in 72% yield, which was a perfect intermediate for synthesizing puupehenone-type derivatives. Finally, puupehenol (5) was achieved in 82% yield by the deprotection of tetracyclic compound 61 obtained by the cyclization of triflate 60 with Pd(OAc) 2 , DPPF (1,1-bis(diphenylphosphanyl) ferrocene), and sodium tertbutoxide in toluene.
In 2012, Baran group [43] described a scalable, divergent synthesis of bioactive meroterpenoids via borono-sclareolide (63) of which the preparation requires the excision of carbon monoxide from 33 and incorporation of BOH in its place  ( Figure 10). Thus, compound 63 was accessed from 33 in 59% yield over five steps including DIBAL-mediated reduction of 33, PIDA/I 2 -mediated C▬C bond cleavage, dehydroiodination, hydrolysis (AgF in pyridine followed by K 2 CO 3 in methanol), and hydroboration with BH 3 . This strategy constitutes the most efficient synthesis and highest yielding of 63 by far. Then, the key skeleton 55 was synthesized by treating 63 with an excess of 1,4-benzoquinone under the condition of K 2 S 2 O 8 and AgNO 3 in PhCF 3 /H 2 O at 60°C. By following an oxidationreduction-oxidation procedure, compound 55 was converted into 8-epipuupehedione (32) in 24% yield.
The generation of boron-sclareolide 63 in such a direct manner enables total synthesis of puupehenone-type compounds to be more succinct than those previously established. However, the synthesis of C8α-Me boron-sclareolide is problematic, probably due to its lower stability than its C8α-Me epimer.
In 2017, Wu and his coworkers developed a hemiacetalization/dehydroxylation/ hydroxylation/retro-hemiacetalization tandem reaction as the key step to synthesize puupehenone-type marine natural products [44], and this novel synthetic strategy is superior to other reported routes in terms of synthetic steps, purification of the intermediates, and overall yield.
As shown in Figure 11, the key synthon β-hydroxyl aldehyde 39 was accomplished starting from commercially available sclareolide (33) over four steps with an markedly higher overall yield (66%) including the stereospecific 8-episclareolide with H 2 SO 4 in HCO 2 H, α-hydroxylation, reduction with LiH 4 Al, and in situ lactol-oxidation/ester-hydrolysis. The key skeleton 67 was constructed by the coupling of aldehyde 39 and ketone 66. Treatment of 66 with LDA in THF at À78°C in the presence of 39 gave 67 in 67% yield. The following hemiacetalization/ dehydroxylation/hydroxylation/retro-hemi-acetalization of 67 permitted to produce enone 68 as the only product in 92% yield, which can be converted into αhydroxylated product 69 in 19% yield and natural product puupehenone (1) in 38% yield when treated with KHMDS and subsequent reaction with P(OMe) 3 . Besides, natural products puupehenol (5) and puupehedione (4) were also achieved in good yield. Reduction of one with NaBH 4 gave puupehenol (5) in 92% yield and oxidation of 5 with DDQ afforded puupehedione (4) in 71% yield.
It is worth mentioning that the preparation strategy of the key intermediates 67 can be employed for the total synthesis of haterumadienone-and puupehenonetype natural products without using protecting groups. Baran's synthesis of puupehenone-type natural products [43].
In the same year, Wu's group reported an enantiospecific semisynthesis of puupehedione commencing from sclareolide (33) in only seven steps with an overall yield of 25% [45].
The key drimanal trimethoxystyrene skeleton 71 and 72 were constructed by the palladium-catalyzed cross-coupling reaction of an aryl-iodine and a drimanal hydrazine (70) which was obtained from commercially available sclareolide over five steps. Treatment of compound 70 and aryl iodine in the presence of Pd(PPh 3 ) 4 and K 2 CO 3 in toluene at 110°C afforded key skeletons 71 and 72 in 40 and 45% yields, respectively. Exposure of the mixture of drimanal trimethoxystyrenes 71 and 72 with Pb/C produced compound 73 in 62% yield. Then, the p-benzoquinone (74) can be prepared by treating 73 with CAN (ceric ammonium nitrate) in 84% yield. Treatment of 74 with pTsOH at room temperature produced compound 75 by intramolecular oxa-Stork-Danheiser transposition. Finally, puupehenone (1) was achieved over nine steps in 26% overall yield by exposing the resulting product 75 with K 2 CO 3 in an enolization process. Besides, natural product puupehenol (5) can be obtained by reduction of 75 in presence of NaBH 4 in EtOH at room temperature (Figure 12).
Interestingly, natural product puupehedione (4) can be accomplished as the sole diastereoisomer in 47% yield when the mixture of 71 and 72 was treated with CAN at room temperature.
In 2018, Li's group developed an efficient synthesis of 8-epi-puupehenol [47] and central to this strategy is the Barton decarboxylative coupling, comprising a one-pot radical decarboxylation and quinone. Wu's synthesis of puupehenone-type natural products [45].
As shown in Figure 16, the 8-O-acetylhomodrimanic acid (89) was obtained by oxidative degradation of sclareol (15) with potassium permanganate and Ac 2 O, and then the key intermediate thiohydroxamic ester 90 was achieved from the coupling of   [48,49] 90 with 250 W light in the presence of the electron-deficient benzoquinone gave pyridylthioquinone meroterpenoid 91 in 85% yield which was converted into acetate 92 in 91% yield when it was treated with Raney-nickel in EtOH at room temperature. To a solution of compound 92 in anhydrous THF added LiAlH 4 gave 93 in 93% yield which was treated with TFA (trifluoroacetic acid) to obtain 94 in excellent yield. Finally, synthesis of  8-epi-puupehenol (56) and 8-epi-puupehedione (32) was accomplished via IBX oxidation, followed by redox manipulation, according to the published literature [43].

Linear synthesis route
In 2004, Yamamoto group [50] developed a liner synthesis route of 8-epipuupehenone (32) employing a new artificial cyclase 97. Utilizing this cyclase, polycyclic terpenoids bearing a chroman skeleton can be obtained effectively.
As shown in Figure 18, compound 98 was converted into cyclization precursor 101 over two steps in 42% yield. Bromination of 98 with NBS (N-bromosuccinimide) gave compound 99 in 70% yield and treatment of 100 with Grignard reagent derived from 99 in the presence of Li 2 CuCl 4 via coppercatalyzed allylic substitution reaction. Then, the bicyclic alcohol 102 was obtained in 41% yield by Cp 2 TiCl-catalyzed epoxypolyene cyclization of 101. The desired building unit 103 was achieved over three steps from compound 102 including deoxygenation of 102 by a Barton-McCombie reaction and high yielding cleavage of protecting group. Treating 103 with N-(phenylseleno) phthalimide and reduction with Bu 3 SnH obtained compound 104. Then, puupehedione (8) was completed according to the literature published by Barrero [35].

Conclusions
Undoubtedly, puupehenone-type marine natural products play a vital role in new drug development. Thus, the total synthesis of puupehenones has become a research hotspot for organic chemists [52].
Recent accomplishments made in total syntheses of puupehenone-type marine natural products are highlighted as above in terms of the employed synthetic strategy. The main routes to synthesize puupehenones include Diels-Alder cycloaddition reaction, coupling of the aldehydes with halogenated aromatic synthon, Friede-Crafts coupling reaction, hemiacetalization/dehydroxylation/hydroxylation/retrohemiacetalization tandem reaction, and linear synthesis routes. Advances in total synthesis above offer new strategies for the chemical optimization of biologically active puupehenones.