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.
- total synthesis
- marine natural product
- convergent synthesis
- linear synthesis
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.
2. Isolation and biological activities
The natural product puupehenone was first isolated from the Hawaiian sponge
Studies show that puupehenone-type marine natural products have antitumor [5, 6, 7, 8], anti-HIV , anticancer , antiviral , antimalaria , antimite [9, 13], immunomodulation , 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 . 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 . As shown in Figure 3, acetoxyaldehyde
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 . As shown in Figure 4, Sclareol
In 2001, Maiti group reported the total synthesis of 8-epi-puupehedione with angiogenesis inhibitory activity . As shown in Figure 5, commercially available carvone (
In 2002, Quideau and coworkers completed asymmetric total synthesis of puupehenone in 10 steps starting from commercially available (+)-sclareolide . 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
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  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
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 (
In 2009, Manzaneda group  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
In 2012, Baran group  described a scalable, divergent synthesis of bioactive meroterpenoids via borono-sclareolide (
The generation of boron-sclareolide
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 , 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
It is worth mentioning that the preparation strategy of the key intermediates
In the same year, Wu’s group reported an enantiospecific semisynthesis of puupehedione commencing from sclareolide (
The key drimanal trimethoxystyrene skeleton
Interestingly, natural product puupehedione (
In 2018, Wu and his coworkers reported the divergent synthesis of (+)-8-epi-puupehedione .
Figure 13 shows the synthesis of 8-epi-puupehedione based on the Lewis acid catalyzed cyclization with sclareolide as starting material. Drimanal hydrazone
Figure 14 shows another synthesis route of 8-epi-puupehedione (
Figure 15 shows an alternative synthesis of (+)-8-epi-puupehedione (
In 2018, Li’s group developed an efficient synthesis of 8-epi-puupehenol  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 (
3.2 Linear synthesis route
In 2004, Yamamoto group  developed a liner synthesis route of 8-epi-puupehenone (
In 2006, Gansäuer and coworkers reported a highly stereoselective and catalytic synthesis strategy for the marine natural product puupehedione (
As shown in Figure 18, compound
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 .
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.
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.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.