Open access peer-reviewed chapter

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

By Yan-Chao Wu, Yun-Fei Cheng and Hui-Jing Li

Submitted: April 19th 2019Reviewed: June 7th 2019Published: July 3rd 2019

DOI: 10.5772/intechopen.87927

Downloaded: 459

Abstract

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.

Keywords

  • total synthesis
  • marine natural product
  • puupehenones
  • convergent synthesis
  • linear synthesis

1. 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.

Figure 1.

Representatives of puupehenone-type natural products.

Advertisement

2. Isolation and biological activities

The natural product puupehenone was first isolated from the Hawaiian sponge Chondrosia chucallaby Schauer group in 1979 [15]. Subsequently, it was obtained from sponges such as Heteronema, Hyrtios, and Strongylophorasp. [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 (−)-drimenol (14), and since then the absolute configuration of puupehenone has been determined.

Figure 2.

The confirmation of the absolute configuration of puupehenone by chemical decomposition [18].

Studies show that puupehenone-type marine natural products have antitumor [5, 6, 7, 8], anti-HIV [9], anticancer [10], antiviral [11], antimalaria [12], antimite [9, 13], immunomodulation [14], and other important physiological activities. In view of their important biological activities, such natural products have been favored by organic synthetic chemists since their separation.

3. 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.

3.1 Convergent synthesis route

Barrero group has been working on the study of total synthesis of puupehenone-type 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 17and aromatic synthon 18were prepared from commercially available sclareol 15and veratraldehyde 16in high yields through a series of transformations. The acetoxy alcohol 19was completed by condensation of 17with the aryllithium derived from 16, and after three steps compound 19gave the phenolic derivatives 20. Finally, complete diastereoselectivity was achieved by organoselenium-induced cyclization. The treatment of 20with NPSP(N-phenylselenophthalimide) and SnCl4 obtained a mixture of the selenium derivatives 21and 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).

Figure 3.

Barrero’s stereoselective synthesis of puupehenol and puupehenone [33].

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 15and veratraldehyde 16were employed as the starting materials to obtain synthons 23and 18, which were accordingly converted to the key skeleton 24in two steps. The treatment of 24in the presence of mCPBA gave epoxydes 25, and finally alcohol 26was obtained in high yield when 8a, 9a-epoxyde 25was treated with KOH in methanol. The subsequent two-step routine transformations, involving dehydration of alcohol 26and oxidation, gave the target compound puupehedione.

Figure 4.

Barrero’s asymmetric synthesis of puupehedione [35].

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 29and aromatic synthon 30in eight and three steps, respectively. Exposure of the vinyl lithium species, produced by the addition of tosylhydrazone 29to an excess of n-BuLi, to 30afforded the diene 31. Then, the cleavage of the O-allyl ether of compound 31with a catalytic amount of RhCl3·3H2O in refluxing EtOH resulted in spontaneous cyclization [37], affording a mixture of the puupehedione (4) and 8-epi-puupehedione (32).

Figure 5.

Maiti’s RhCl3 catalyzed cyclization synthesis of 8-epi-puupehedione [36].

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-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)2Mg and MoOPH afforded 35and 36, which were converted into 39after hydride reduction with DIBAL and oxidation with NaIO4. Then, coupling of aldehyde 15with bromide 40was achieved via a standard halogen-metal exchange protocol. Then, the key skeleton catechol 41was 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.

Figure 6.

Quideau’s asymmetric synthesis of puupehenone [38].

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, the drimane synthon 44is easily prepared from sclareol (15) in seven steps. According to the procedure reported by Barrero [40], the drimane precursor 43was prepared over three steps from 15in 75% overall yield. Treating 43with t-BuOK in a mixed solvent of DMSO-H2O, followed by oxidative hydroboration, dehydration, and oxidation, afforded synthon 44in 52% yield over four steps. The new synthon 47from the 3,4-bis(benzyloxybenzyloxy)phenol (45), in a two-step sequence in 83% overall yield. Then, the key skeleton 48was obtained by the coupling of 44and 47. Alvarez-Manzaneda and coworkers realized that catalytic PdCl2 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.

Figure 7.

Synthesis of several puupehenone-type natural products by palladium-catalyzed cyclization [39].

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 53was constructed by the coupling of two synthons 51and 52, based on a Diels-Alder cycloaddition approach. They employed sclareol oxide (50) as starting material to afford 51over four steps which was treated with dienophile R-chloroacrylonitrile to afford compound 53utilizing Diels-Alder cycloaddition. Treatment of 53with 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 55to the appropriate ortho-quinone precursor of target compound 32was then addressed.

Figure 8.

Synthesis of 8-epi-puupehenone-type compound by Diels-Alder cyclization [41].

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 57which is a key synthon employed in the total synthesis of puupehenones, starting from commercially available sclareol (15) in 60% yield. Then, the key intermediate ketone 59was obtained in high yield and with complete diastereoselectivity by treatment of 57with protected phenol 58under the condition of Amberlyst A-15. Alternatively, treatment of ketone 59with MeMgBr, further cleavage of the benzyl ether and protection of hydroxyl gave triflate 60in 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 60with Pd(OAc)2, DPPF (1,1-bis(diphenylphosphanyl) ferrocene), and sodium tertbutoxide in toluene.

Figure 9.

Synthesis of puupehenol by Friedel-Crafts coupling reaction [42].

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 33and incorporation of BOH in its place (Figure 10). Thus, compound 63was accessed from 33in 59% yield over five steps including DIBAL-mediated reduction of 33, PIDA/I2-mediated C▬C bond cleavage, dehydroiodination, hydrolysis (AgF in pyridine followed by K2CO3 in methanol), and hydroboration with BH3. This strategy constitutes the most efficient synthesis and highest yielding of 63by far. Then, the key skeleton 55was synthesized by treating 63with an excess of 1,4-benzoquinone under the condition of K2S2O8 and AgNO3 in PhCF3/H2O at 60°C. By following an oxidation-reduction-oxidation procedure, compound 55was converted into 8-epi-puupehedione (32) in 24% yield.

Figure 10.

Baran’s synthesis of puupehenone-type natural products [43].

The generation of boron-sclareolide 63in 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 39was accomplished starting from commercially available sclareolide (33) over four steps with an markedly higher overall yield (66%) including the stereospecific 8-episclareolide with H2SO4 in HCO2H, α-hydroxylation, reduction with LiH4Al, and in situ lactol-oxidation/ester-hydrolysis. The key skeleton 67was constructed by the coupling of aldehyde 39and ketone 66. Treatment of 66with LDA in THF at −78°C in the presence of 39gave 67in 67% yield. The following hemiacetalization/dehydroxylation/hydroxylation/retro-hemi-acetalization of 67permitted to produce enone 68as the only product in 92% yield, which can be converted into α-hydroxylated product 69in 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 NaBH4 gave puupehenol (5) in 92% yield and oxidation of 5with DDQ afforded puupehedione (4) in 71% yield.

Figure 11.

Wu’s synthesis of puupehenone-type natural products [44].

It is worth mentioning that the preparation strategy of the key intermediates 67can be employed for the total synthesis of haterumadienone- and puupehenone-type natural products without using protecting groups.

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 71and 72were 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 70and aryl iodine in the presence of Pd(PPh3)4 and K2CO3 in toluene at 110°C afforded key skeletons 71and 72in 40 and 45% yields, respectively. Exposure of the mixture of drimanal trimethoxystyrenes 71and 72with Pb/C produced compound 73in 62% yield. Then, the p-benzoquinone (74) can be prepared by treating 73with CAN (ceric ammonium nitrate) in 84% yield. Treatment of 74with pTsOH at room temperature produced compound 75by intramolecular oxa-Stork-Danheiser transposition. Finally, puupehenone (1) was achieved over nine steps in 26% overall yield by exposing the resulting product 75with K2CO3 in an enolization process. Besides, natural product puupehenol (5) can be obtained by reduction of 75in presence of NaBH4 in EtOH at room temperature (Figure 12).

Figure 12.

Wu’s synthesis of puupehenone-type natural products [45].

Interestingly, natural product puupehedione (4) can be accomplished as the sole diastereoisomer in 47% yield when the mixture of 71and 72was treated with CAN at room temperature.

In 2018, Wu and his coworkers reported the divergent synthesis of (+)-8-epi-puupehedione [46].

Figure 13 shows the synthesis of 8-epi-puupehedione based on the Lewis acid catalyzed cyclization with sclareolide as starting material. Drimanal hydrazone 75was obtained over four steps, as mentioned above. Then, the key skeleton was obtained by cross-coupling reaction of aryl iodide and drimanal hydrazone 75, yielding intermediates 76and 77in 32 and 54% yields, respectively. Allylic product 78was prepared in 91% yield by reduction of compounds 76and 77with TFA (trifluoroacetic acid) in the presence of Et3SiH. Exposure of product 78to CAN produced compound 80as the major product in 48% yield, together with byproduct 79in 9% yield. Then, the cyclization product 8-epi-19-methoxy puupehenol (82) was synthesized in 87% yield from compound 80over two steps including treating 80with Na2S2O4 in the presence of tetrabutylammonium bromide (TBAB) and treating 81with BF3·Et2O. Exposure of 82to CAN afforded 83in 77% yield. Finally, 8-epi-puupehedione (32) was completed in 48% overall yield by reducing 83with NaBH4 and subsequent treatment with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone).

Figure 13.

Wu’s synthesis of 8-epi-puupehedione based on the Lewis acid catalyzed cyclization [46].

Figure 14 shows another synthesis route of 8-epi-puupehedione (32) based on the tandem cyclization. Compound 84was prepared in 62% yield by a ring opening reaction starting from 8-epi-19-methoxy puupehenol (82) by treatment with DDQ. Then, compound 84was converted into 83in 92% yield via an intramolecular oxa-Stork-Danheiser transposition reaction when it was treated with pTsOH. Reduction of 83with NaBH4 gave 8-epi-puupehenol (56), which can be transformed into 8-epi-puupehedione (32) by oxidation in the presence of DDQ.

Figure 14.

Wu’s synthesis of 8-epi-puupehedione based on the tandem cyclization [46].

Figure 15 shows an alternative synthesis of (+)-8-epi-puupehedione (32) based on the 6π electrocyclic reaction. Compound 87was achieved in 86% yield when 80was reacted with base in MeOH. Then, treatment of 87with DDQ in a mixed solvent of CH2Cl2 and H2O (10:1, v/v) obtained 8-epi-puupehedione (32) in 65% yield.

Figure 15.

Wu’s synthesis of 8-epi-puupehedione based on 6π-electrocyclic reaction [46].

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.

As shown in Figure 16, the 8-O-acetylhomodrimanic acid (89) was obtained by oxidative degradation of sclareol (15) with potassium permanganate and Ac2O, and then the key intermediate thiohydroxamic ester 90was achieved from the coupling of 8-O-acetylhomodrimanic acid (89) with 2-mercaptopyridine N-oxide under Steglichesterification conditions. Treatment of Barton ester [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 92in 91% yield when it was treated with Raney-nickel in EtOH at room temperature. To a solution of compound 92in anhydrous THF added LiAlH4 gave 93in 93% yield which was treated with TFA (trifluoroacetic acid) to obtain 94in 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].

Figure 16.

Li’s formal synthesis of 8-epi-puupehenol and 8-epi-puupehedione [47].

3.2 Linear synthesis route

In 2004, Yamamoto group [50] developed a liner synthesis route of 8-epi-puupehenone (32) employing a new artificial cyclase 97. Utilizing this cyclase, polycyclic terpenoids bearing a chroman skeleton can be obtained effectively.

8-epi-puupehenone 32was achieved in 57% overall yield from 95over four steps. Firstly, treatment of 95with (R)-catalyst 97through the enantio- and diastereoselective cyclization gave compound 96in 62% yield. Then, 96was transformed into 8-epi-puupehenone 32through treatment of 96with DDQ in 1,4-dioxane followed by hydrosilylative acetal cleavage employing Et3SiH and B(C6F5)3 and DDQ oxidation (Figure 17).

Figure 17.

Yamamoto’s synthesis of 8-epi-puupehenone by new type LBA [50].

In 2006, Gansäuer and coworkers reported a highly stereoselective and catalytic synthesis strategy for the marine natural product puupehedione (8) [51].

As shown in Figure 18, compound 98was converted into cyclization precursor 101over two steps in 42% yield. Bromination of 98with NBS (N-bromosuccinimide) gave compound 99in 70% yield and treatment of 100with Grignard reagent derived from 99in the presence of Li2CuCl4 via copper-catalyzed allylic substitution reaction. Then, the bicyclic alcohol 102was obtained in 41% yield by Cp2TiCl-catalyzed epoxypolyene cyclization of 101. The desired building unit 103was achieved over three steps from compound 102including deoxygenation of 102by a Barton-McCombie reaction and high yielding cleavage of protecting group. Treating 103with N-(phenylseleno) phthalimide and reduction with Bu3SnH obtained compound 104. Then, puupehedione (8) was completed according to the literature published by Barrero [35].

Figure 18.

Gansäuer’s formal synthesis of puupehedione [51].

4. 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/retro-hemiacetalization tandem reaction, and linear synthesis routes. Advances in total synthesis above offer new strategies for the chemical optimization of biologically active puupehenones.

Acknowledgments

This work was supported by the Natural Science Foundation of Shandong (ZR2019MB009), the Fundamental Research Funds for the Central Universities (HIT.NSRIF.201701), the Science and Technology Development Project of Weihai (2012DXGJ02, 2015DXGJ04), the Natural Science Foundation of China (21672046, 21372054), and the Found from the Huancui District of Weihai City.

Advertisement

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite and reference

Link to this chapter Copy to clipboard

Cite this chapter Copy to clipboard

Yan-Chao Wu, Yun-Fei Cheng and Hui-Jing Li (July 3rd 2019). Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products, Organic Synthesis - A Nascent Relook, Belakatte Parameshwarappa Nandeshwarappa, IntechOpen, DOI: 10.5772/intechopen.87927. Available from:

chapter statistics

459total chapter downloads

More statistics for editors and authors

Login to your personal dashboard for more detailed statistics on your publications.

Access personal reporting

Related Content

This Book

Next chapter

N,N-Dialkyl Amides as Versatile Synthons for Synthesis of Heterocycles and Acyclic Systems

By Andivelu Ilangovan, Sakthivel Pandaram and Tamilselvan Duraisamy

Related Book

First chapter

Introductory Chapter: Synthesis and Antimicrobial Activities of Dihydroazeto[2′,3′:4,5]seleno[2,3-b]quinolines

By B.P. Nandeshwarappa, G.K. Prakash and S.O. Sadashiv

We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists. Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. We share our knowledge and peer-reveiwed research papers with libraries, scientific and engineering societies, and also work with corporate R&D departments and government entities.

More About Us