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

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

## **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 [1–4]. The puupehenone-type marine natural products obtained from deep sea sponge have played a very important role in health care and prevention of diseases [5–14].

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.

Studies show that puupehenone-type marine natural products have antitumor

Compound supply and appropriate structural analysis are two main barriers to develop a natural product into drug [19–31]. 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

In the present chapter, approaches to the total synthesis of puupehenone-type marine natural products have been reviewed. In general, the strategies employed in

• Convergent synthesis route with two synthons coupled by nucleophilic or

• Linear synthesis route with polyene series cyclization as a key reaction.

type natural products, and has obtained great achievements [32–35]. 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 group has been working on the study of total synthesis of puupehenone-

[5–8], 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

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

**3. Total synthesis of puupehenone-type marine natural products**

favored by organic synthetic chemists since their separation.

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

been widely researched and published in excellent literature.

the total synthesis of puupehenones are as follows:

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

electrophilic reaction.

**3.1 Convergent synthesis route**

**Figure 3.**

**53**

#### **Figure 1.**

*Representatives of puupehenone-type natural products.*

**Figure 2.** *The confirmation of the absolute configuration of puupehenone by chemical decomposition [18].*

## **2. 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 ()-drimenol (**14**), and since then the absolute configuration of puupehenone has been determined.

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

Studies show that puupehenone-type marine natural products have antitumor [5–8], 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 [19–31]. 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:


#### **3.1 Convergent synthesis route**

Barrero group has been working on the study of total synthesis of puupehenonetype natural products, and has obtained great achievements [32–35]. 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

**Figure 3.** *Barrero's stereoselective synthesis of puupehenol and puupehenone [33].*

**2. Isolation and biological activities**

*Representatives of puupehenone-type natural products.*

*Organic Synthesis - A Nascent Relook*

has been determined.

**52**

**Figure 1.**

**Figure 2.**

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 ()-drimenol (**14**), and since then the absolute configuration of puupehenone

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

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 SnCl4 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 RhCl33H2O 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-

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 **35** and **36**, which were converted into **39** after hydride reduction with DIBAL and oxidation with NaIO4. 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

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**,

synthesis of puupehenone.

*Quideau's asymmetric synthesis of puupehenone [38].*

**Figure 5.**

**Figure 6.**

**55**

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

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

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

**Figure 4.** *Barrero's asymmetric synthesis of puupehedione [35].*

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

**Figure 5.** *Maiti's RhCl3 catalyzed cyclization synthesis of 8-epi-puupehedione [36].*

**Figure 6.** *Quideau's asymmetric synthesis of puupehenone [38].*

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 **35** and **36**, which were converted into **39** after hydride reduction with DIBAL and oxidation with NaIO4. 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**,

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(N-

phenylselenophthalimide) and SnCl4 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

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

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

**15** and veratraldehyde **16** were employed as the starting materials to obtain

catalytic amount of RhCl33H2O in refluxing EtOH resulted in spontaneous cyclization [37], affording a mixture of the puupehedione (**4**) and 8-epi-

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-

pyridinium dichromate (PDC).

*Organic Synthesis - A Nascent Relook*

puupehedione (**32**).

**Figure 4.**

**54**

*Barrero's asymmetric synthesis of puupehedione [35].*

#### **Figure 7.**

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

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-H2O, 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 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.

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.

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

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

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

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

*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 **33** and incorporation of BOH in its place

toluene.

**57**

**Figure 9.**

**Figure 8.**

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.

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

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

**Figure 9.** *Synthesis of puupehenol by Friedel-Crafts coupling reaction [42].*

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

the drimane synthon **44** is easily prepared from sclareol (**15**) in seven steps.

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

via palladium(II) catalysis of compound **48**. Finally, puupehenol (**5**) can be

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 appropri-

ate ortho-quinone precursor of target compound **32** was then addressed.

of compound **57** which is a key synthon employed in the total synthesis of puupehenones, starting from commercially available sclareol (**15**) in 60% yield.

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

products.

**56**

**Figure 7.**

*Organic Synthesis - A Nascent Relook*

transformed into 15-oxopuupehenol (**7**) and the other puupehenone-related natural

Continuing their research into the total synthesis of this type of natural product,

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-H2O, 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 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

**Figure 10.**

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

(**Figure 10**). Thus, compound **63** was accessed from **33** in 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 **63** by far. Then, the key skeleton **55** was synthesized by treating **63** with an excess of 1,4-benzoquinone under the condition of K2S2O8 and AgNO3 in PhCF3/H2O 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 the same year, Wu's group reported an enantiospecific semisynthesis of puupehedione commencing from sclareolide (**33**) in only seven steps with an over-

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

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

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(PPh3)4 and K2CO3 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 K2CO3 in an enolization process. Besides, natural product puupehenol (**5**) can be obtained by reduction of **75** in presence of NaBH4 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

In 2018, Wu and his coworkers reported the divergent synthesis of (+)-8-epi-

**Figure 13** shows the synthesis of 8-epi-puupehedione based on the Lewis acid catalyzed cyclization with sclareolide as starting material. Drimanal hydrazone **75** was 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 **76** and **77** in 32 and 54% yields, respectively. Allylic product **78** was

all yield of 25% [45].

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

**Figure 11.**

at room temperature.

puupehedione [46].

**59**

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 H2SO4 in HCO2H, α-hydroxylation, reduction with LiH4Al, 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 78°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 NaBH4 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.

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

**Figure 11.** *Wu's synthesis of puupehenone-type natural products [44].*

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(PPh3)4 and K2CO3 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 K2CO3 in an enolization process. Besides, natural product puupehenol (**5**) can be obtained by reduction of **75** in presence of NaBH4 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, Wu and his coworkers reported the divergent synthesis of (+)-8-epipuupehedione [46].

**Figure 13** shows the synthesis of 8-epi-puupehedione based on the Lewis acid catalyzed cyclization with sclareolide as starting material. Drimanal hydrazone **75** was 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 **76** and **77** in 32 and 54% yields, respectively. Allylic product **78** was

(**Figure 10**). Thus, compound **63** was accessed from **33** in 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 **63** by far. Then, the key skeleton **55** was synthesized by treating **63** with an excess of 1,4-benzoquinone under the condition of K2S2O8 and AgNO3 in PhCF3/H2O at 60°C. By following an oxidationreduction-oxidation procedure, compound **55** was converted into 8-epi-

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 problem-

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

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

It is worth mentioning that the preparation strategy of the key intermediates **67** can be employed for the total synthesis of haterumadienone- and puupehenone-

with H2SO4 in HCO2H, α-hydroxylation, reduction with LiH4Al, 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 78°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 NaBH4 gave puupehenol (**5**) in 92% yield and oxida-

atic, probably due to its lower stability than its C8α-Me epimer.

tion of **5** with DDQ afforded puupehedione (**4**) in 71% yield.

type natural products without using protecting groups.

puupehedione (**32**) in 24% yield.

*Organic Synthesis - A Nascent Relook*

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

**Figure 10.**

**58**

of the intermediates, and overall yield.

**Figure 12.** *Wu's synthesis of puupehenone-type natural products [45].*

prepared in 91% yield by reduction of compounds **76** and **77** with TFA (trifluoroacetic acid) in the presence of Et3SiH. Exposure of product **78** to CAN produced compound **80** as the major product in 48% yield, together with byproduct **79** in 9% yield. Then, the cyclization product 8-epi-19-methoxy puupehenol (**82**) was synthesized in 87% yield from compound **80** over two steps including treating **80** with Na2S2O4 in the presence of tetrabutylammonium bromide (TBAB) and treating **81** with BF3Et2O. Exposure of **82** to CAN afforded **83** in 77% yield. Finally, 8-epipuupehedione (**32**) was completed in 48% overall yield by reducing **83** with NaBH4 and subsequent treatment with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone).

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

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

> 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 **90** was achieved from the coupling of

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

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

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

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

**Figure 13.**

**Figure 14.**

**61**

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.

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

**Figure 13.** *Wu's synthesis of 8-epi-puupehedione based on the Lewis acid catalyzed cyclization [46].*

**Figure 14.**

prepared in 91% yield by reduction of compounds **76** and **77** with TFA

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

*Organic Synthesis - A Nascent Relook*

**Figure 12.**

**60**

8-epi-puupehedione (**32**) by oxidation in the presence of DDQ.

one-pot radical decarboxylation and quinone.

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

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

(trifluoroacetic acid) in the presence of Et3SiH. Exposure of product **78** to CAN produced compound **80** as the major product in 48% yield, together with byproduct **79** in 9% yield. Then, the cyclization product 8-epi-19-methoxy puupehenol (**82**) was synthesized in 87% yield from compound **80** over two steps including treating **80** with Na2S2O4 in the presence of tetrabutylammonium bromide (TBAB) and treating **81** with BF3Et2O. Exposure of **82** to CAN afforded **83** in 77% yield. Finally, 8-epipuupehedione (**32**) was completed in 48% overall yield by reducing **83** with NaBH4 and subsequent treatment with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). **Figure 14** shows another synthesis route of 8-epi-puupehedione (**32**) based on the tandem cyclization. Compound **84** was prepared in 62% yield by a ring opening reaction starting from 8-epi-19-methoxy puupehenol (**82**) by treatment with DDQ. Then, compound **84** was converted into **83** in 92% yield via an intramolecular oxa-Stork-Danheiser transposition reaction when it was treated with pTsOH. Reduction of **83** with NaBH4 gave 8-epi-puupehenol (**56**), which can be transformed into

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

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 **90** was achieved from the coupling 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].

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

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

**3.2 Linear synthesis route**

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

and DDQ oxidation (**Figure 17**).

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

**Figure 17.**

**Figure 18.**

**63**

*Gansäuer's formal synthesis of puupehedione [51].*

**Figure 16.** *Li's formal synthesis of 8-epi-puupehenol and 8-epi-puupehedione [47].*

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 **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 LiAlH4 gave **93** in 93% yield which was treated with TFA (trifluoroacetic acid) to obtain **94** in excellent yield. Finally, synthesis of

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

8-epi-puupehenol (**56**) and 8-epi-puupehedione (**32**) was accomplished via IBX oxidation, followed by redox manipulation, according to the published literature [43].

## **3.2 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.

8-epi-puupehenone **32** was achieved in 57% overall yield from **95** over four steps. Firstly, treatment of **95** with (R)-catalyst **97** through the enantio- and diastereoselective cyclization gave compound **96** in 62% yield. Then, **96** was transformed into 8-epi-puupehenone **32** through treatment of **96** with 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].*

**Figure 18.** *Gansäuer's formal synthesis of puupehedione [51].*

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 **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 LiAlH4 gave **93** in 93% yield which was treated with TFA (trifluoroacetic acid) to obtain **94** in excellent yield. Finally, synthesis of

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

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

**Figure 15.**

*Organic Synthesis - A Nascent Relook*

**Figure 16.**

**62**

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 **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 Li2CuCl4 via coppercatalyzed allylic substitution reaction. Then, the bicyclic alcohol **102** was obtained in 41% yield by Cp2TiCl-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 Bu3SnH obtained compound **104**. Then, puupehedione (**8**) was completed according to the literature published by Barrero [35].

## **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/retrohemiacetalization tandem reaction, and linear synthesis routes. Advances in total synthesis above offer new strategies for the chemical optimization of biologically active puupehenones.

## **Acknowledgements**

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.

**Author details**

P. R. China

**65**

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

\*Address all correspondence to: ycwu@iccas.ac.cn

provided the original work is properly cited.

School of Marine Science and Technology, Harbin Institute of Technology, Weihai,

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

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

### **Conflict of interest**

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

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

## **Author details**

In 2006, Gansäuer and coworkers reported a highly stereoselective and catalytic

obtained in 41% yield by Cp2TiCl-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 yield-

Undoubtedly, puupehenone-type marine natural products play a vital role in new drug development. Thus, the total synthesis of puupehenones has become a

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

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,

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

21372054), and the Found from the Huancui District of Weihai City.

synthesis strategy for the marine natural product puupehedione (**8**) [51]. 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 Li2CuCl4 via coppercatalyzed allylic substitution reaction. Then, the bicyclic alcohol **102** was

ing cleavage of protecting group. Treating **103** with N-(phenylseleno) phthalimide and reduction with Bu3SnH obtained compound **104**. Then, puupehedione (**8**) was completed according to the literature published by

Barrero [35].

*Organic Synthesis - A Nascent Relook*

**4. Conclusions**

active puupehenones.

**Acknowledgements**

**Conflict of interest**

of interest.

**64**

research hotspot for organic chemists [52].

Yan-Chao Wu\*, Yun-Fei Cheng and Hui-Jing Li School of Marine Science and Technology, Harbin Institute of Technology, Weihai, P. R. China

\*Address all correspondence to: ycwu@iccas.ac.cn

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

## **References**

[1] Butler MS. Natural products to drugs: Natural product-derived compounds in clinical trials. Natural Product Reports. 2008;**25**:475-516. DOI: 10.1039/ B514294F

[2] Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 19812002. Journal of Natural Products. 2003;**66**: 1022-1037. DOI: 10.1021/np030096l

[3] Gerwick WH, Fenner AM. Drug discovery from marine microbes. Microbial Ecology. 2013;**65**:800-806. DOI: 10.1007/s00248-012-0169-9

[4] Jin L, Quan C, Hou X. Potential pharmacological resources: Natural bioactive compounds from marinederived fungi. Marine Drugs. 2016;**14**: 76. DOI: 10.3390/md14040076

[5] Kohmoto S, McConnell OJ, Wright A. Puupehenone, a cytotoxic metabolite from a deep water marine sponge, *Stronglyophora hartman*. Journal of Natural Products. 1987;**50**:336-336. DOI: 10.1021/np50050a064

[6] Pina IC, Sanders ML, Crews P. Puupehenone congeners from an indo-Pacific *Hyrtios* sponge. Journal of Natural Products. 2003;**66**:2-6. DOI: 10.1021/np020279s

[7] Longley RE, McConnell OJ, Essich E. Evaluation of marine sponge metabolites for cytotoxicity and signaltransduction activity. Journal of Natural Products. 1993;**56**:915-920. DOI: 10.1021/np50096a015

[8] Sova VV, Fedoreev SA. Metabolites from sponges as beta-1,3-gluconase inhibitors. Khimiya Prirodnykh Soedinenii. 1990;**4**:497-500

[9] El Sayed KA, Bartyzel P, Shen XY. Marine natural products as antituberculosis agents. Tetrahedron.

2000;**56**:949-953. DOI: 10.1016/ S0040-4020(99)01093-5

[10] Castro ME, González-Iriarte M, Barrero AF. Study of puupehenone and related compounds as inhibitors of angiogenesis. International Journal of Cancer. 2004;**110**:31-38. DOI: 10.1002/ ijc.20068

*Hyrtios* species. Journal of Natural Products. 1999;**62**:1304-1305. DOI:

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

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

structural complementarity of natural products and synthetic compounds. Angewandte Chemie (International Ed. in English). 1999;**38**:643-647. DOI: 10.1002/(SICI)1521-3773(19990301)38: 5<643::AID-ANIE643>3.0.CO;2-G

[27] Capon RJ. Marine natural products chemistry: Past, present, and future. Australian Journal of Chemistry. 2010; **63**:851-854. DOI: 10.1071/ch10204

[28] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2009;**26**:

[29] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2008;**25**: 95-117. DOI: 10.1039/B701533J

[30] Morris JC, Nicholas GM, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2007; **24**:87-108. DOI: 10.1039/B602832M

[31] Nicholas GM, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2006;**23**:79-99.

DOI: 10.1039/B501014B

(95)00370-N

(98)00235-X

[32] Barrero AF, Manzaneda EA, Altarejos J. Synthesis of biologically active drimanes and homodrimanes from ()-sclareol. Tetrahedron. 1995;**51**: 7435-7450. DOI: 10.1016/0040-4020

[33] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. Enantiospecific synthesis of (+)-puupehenone from ()-sclareol and protocatechualdehyde. Tetrahedron

[34] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. Synthesis of wiedendiol-A

Letters. 1997;**38**:2325-2328. DOI: 10.1016/S0040-4039(97)00305-5

and wiedendiol-B from labdane diterpenes. Tetrahedron. 1998;**54**: 5635-5650. DOI: 10.1016/S0040-4020

245-265

[18] Urban S, Capon RJ. Absolute stereochemistry of puupehenone and related metabolites. Journal of Natural Products. 1996;**59**:900-901. DOI:

[19] Suyama TL, Gerwick WH, McPhail KL. Survey of marine nature product structure revisions: A synergy of spectroscopy and chemical synthesis. Bioorganic & Medicinal Chemistry. 2011;**19**:6675-6701. DOI: 10.1016/j.

[20] Baran PS, Maimone TJ, Richter JM. Total synthesis of marine natural products without using protecting groups. Nature. 2007;**446**:404-408.

10.1021/np9900829

10.1021/np9603838

bmc.2011.07.017

DOI: 10.1038/nature05569

10.1351/PAC-CON-08-07-12

DOI: 10.1038/ja.2011.74

[21] Hanessian S. Structure-based synthesis: From natural products to drug prototypes. Pure and Applied Chemistry. 2009;**81**:1085-1091. DOI:

[22] Hashimoto S. Natural product chemistry for drug discovery. The Journal of Anibiotics. 2011;**64**:697-701.

[23] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2011;**28**: 269-289. DOI: 10.1039/C0NP00066C

[24] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2010;**27**: 1186-1203. DOI: 10.1039/B919366A

[25] Carter GT. Natural products and pharma 2011: Strategic changes spur new opportunities. Natural Product Reports. 2011;**28**:1783-1789. DOI:

[26] Henkel T, Brunne RM, Reichel F. Statistical investigation into the

10.1039/C1NP00033K

**67**

[11] John FD. Marine natural products. Natural Product Reports. 1998;**15**: 113-158. DOI: 10.1039/A815113Y

[12] Hamann MT, Scheuer PJ. Cyanopuupehenol, an antiviral metabolite of a sponge of the order Verongida. Tetrahedron Letters. 1991; **32**:5671-5672. DOI: 10.1016/S0040-4039 (00)93525-1

[13] Kraus GA, Nguyen T, Bae J. Synthesis and antitubercular activity of tricyclic analogs of puupehenone. Tetrahedron. 2004;**60**:4223-4225. DOI: 10.1016/j.tet.2004.03.043

[14] Nasu SS, Yeung BK, Hamann MT. Puupehenone-related metabolites from two Hawaiian sponges, *Hyrtios* spp. The Journal of Organic Chemistry. 1995;**60**: 7290-7292. DOI: 10.1021/jo00127a039

[15] Ravi BN, Perzanowski HP, Ross RA. Recent research in marine natural products: The puupehenones. Pure and Applied Chemistry. 1979;**51**:1893-1900. DOI: 10.1351/pac197951091893

[16] Bourguet-Kondracki M-L, Debitus C, Guyot M. Dipuupehedione, a cytotoxic new red dimer from a new Caledonian marine sponge *Hyrtios* sp. Tetrahedron Letters. 1996;**37**:3861-3864. DOI: 10.1016/0040-4039(96)00700-9

[17] Bourguet-Kondracki M-L, Lacombe F, Guyot M. Methanol adduct of puupehenone, a biologically active derivative from the marine sponge

*Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

*Hyrtios* species. Journal of Natural Products. 1999;**62**:1304-1305. DOI: 10.1021/np9900829

**References**

B514294F

[1] Butler MS. Natural products to drugs: Natural product-derived compounds in clinical trials. Natural Product Reports.

2000;**56**:949-953. DOI: 10.1016/ S0040-4020(99)01093-5

ijc.20068

(00)93525-1

[10] Castro ME, González-Iriarte M, Barrero AF. Study of puupehenone and related compounds as inhibitors of angiogenesis. International Journal of Cancer. 2004;**110**:31-38. DOI: 10.1002/

[11] John FD. Marine natural products. Natural Product Reports. 1998;**15**: 113-158. DOI: 10.1039/A815113Y

[12] Hamann MT, Scheuer PJ. Cyanopuupehenol, an antiviral metabolite of a sponge of the order Verongida. Tetrahedron Letters. 1991; **32**:5671-5672. DOI: 10.1016/S0040-4039

[13] Kraus GA, Nguyen T, Bae J.

10.1016/j.tet.2004.03.043

Synthesis and antitubercular activity of tricyclic analogs of puupehenone. Tetrahedron. 2004;**60**:4223-4225. DOI:

[14] Nasu SS, Yeung BK, Hamann MT. Puupehenone-related metabolites from two Hawaiian sponges, *Hyrtios* spp. The Journal of Organic Chemistry. 1995;**60**: 7290-7292. DOI: 10.1021/jo00127a039

[15] Ravi BN, Perzanowski HP, Ross RA. Recent research in marine natural products: The puupehenones. Pure and Applied Chemistry. 1979;**51**:1893-1900.

[16] Bourguet-Kondracki M-L, Debitus C, Guyot M. Dipuupehedione, a cytotoxic new red dimer from a new Caledonian marine sponge *Hyrtios* sp. Tetrahedron Letters. 1996;**37**:3861-3864. DOI: 10.1016/0040-4039(96)00700-9

[17] Bourguet-Kondracki M-L, Lacombe F, Guyot M. Methanol adduct of puupehenone, a biologically active derivative from the marine sponge

DOI: 10.1351/pac197951091893

[2] Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 19812002. Journal of Natural Products. 2003;**66**: 1022-1037. DOI: 10.1021/np030096l

[3] Gerwick WH, Fenner AM. Drug discovery from marine microbes. Microbial Ecology. 2013;**65**:800-806. DOI: 10.1007/s00248-012-0169-9

[4] Jin L, Quan C, Hou X. Potential pharmacological resources: Natural bioactive compounds from marinederived fungi. Marine Drugs. 2016;**14**: 76. DOI: 10.3390/md14040076

[5] Kohmoto S, McConnell OJ, Wright A. Puupehenone, a cytotoxic metabolite from a deep water marine sponge, *Stronglyophora hartman*. Journal of Natural Products. 1987;**50**:336-336. DOI:

10.1021/np50050a064

10.1021/np020279s

10.1021/np50096a015

[6] Pina IC, Sanders ML, Crews P. Puupehenone congeners from an indo-Pacific *Hyrtios* sponge. Journal of Natural Products. 2003;**66**:2-6. DOI:

[7] Longley RE, McConnell OJ, Essich E.

metabolites for cytotoxicity and signaltransduction activity. Journal of Natural

[8] Sova VV, Fedoreev SA. Metabolites from sponges as beta-1,3-gluconase inhibitors. Khimiya Prirodnykh Soedinenii. 1990;**4**:497-500

[9] El Sayed KA, Bartyzel P, Shen XY.

antituberculosis agents. Tetrahedron.

Marine natural products as

**66**

Evaluation of marine sponge

Products. 1993;**56**:915-920. DOI:

2008;**25**:475-516. DOI: 10.1039/

*Organic Synthesis - A Nascent Relook*

[18] Urban S, Capon RJ. Absolute stereochemistry of puupehenone and related metabolites. Journal of Natural Products. 1996;**59**:900-901. DOI: 10.1021/np9603838

[19] Suyama TL, Gerwick WH, McPhail KL. Survey of marine nature product structure revisions: A synergy of spectroscopy and chemical synthesis. Bioorganic & Medicinal Chemistry. 2011;**19**:6675-6701. DOI: 10.1016/j. bmc.2011.07.017

[20] Baran PS, Maimone TJ, Richter JM. Total synthesis of marine natural products without using protecting groups. Nature. 2007;**446**:404-408. DOI: 10.1038/nature05569

[21] Hanessian S. Structure-based synthesis: From natural products to drug prototypes. Pure and Applied Chemistry. 2009;**81**:1085-1091. DOI: 10.1351/PAC-CON-08-07-12

[22] Hashimoto S. Natural product chemistry for drug discovery. The Journal of Anibiotics. 2011;**64**:697-701. DOI: 10.1038/ja.2011.74

[23] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2011;**28**: 269-289. DOI: 10.1039/C0NP00066C

[24] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2010;**27**: 1186-1203. DOI: 10.1039/B919366A

[25] Carter GT. Natural products and pharma 2011: Strategic changes spur new opportunities. Natural Product Reports. 2011;**28**:1783-1789. DOI: 10.1039/C1NP00033K

[26] Henkel T, Brunne RM, Reichel F. Statistical investigation into the

structural complementarity of natural products and synthetic compounds. Angewandte Chemie (International Ed. in English). 1999;**38**:643-647. DOI: 10.1002/(SICI)1521-3773(19990301)38: 5<643::AID-ANIE643>3.0.CO;2-G

[27] Capon RJ. Marine natural products chemistry: Past, present, and future. Australian Journal of Chemistry. 2010; **63**:851-854. DOI: 10.1071/ch10204

[28] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2009;**26**: 245-265

[29] Morris JC, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2008;**25**: 95-117. DOI: 10.1039/B701533J

[30] Morris JC, Nicholas GM, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2007; **24**:87-108. DOI: 10.1039/B602832M

[31] Nicholas GM, Phillips AJ. Marine natural products: Synthetic aspects. Natural Product Reports. 2006;**23**:79-99. DOI: 10.1039/B501014B

[32] Barrero AF, Manzaneda EA, Altarejos J. Synthesis of biologically active drimanes and homodrimanes from ()-sclareol. Tetrahedron. 1995;**51**: 7435-7450. DOI: 10.1016/0040-4020 (95)00370-N

[33] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. Enantiospecific synthesis of (+)-puupehenone from ()-sclareol and protocatechualdehyde. Tetrahedron Letters. 1997;**38**:2325-2328. DOI: 10.1016/S0040-4039(97)00305-5

[34] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. Synthesis of wiedendiol-A and wiedendiol-B from labdane diterpenes. Tetrahedron. 1998;**54**: 5635-5650. DOI: 10.1016/S0040-4020 (98)00235-X

[35] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. Synthesis and antitumor activity of puupehedione and related compounds. Tetrahedron. 1999;**55**: 15181-15208. DOI: 10.1016/S0040-4020 (99)00992-8

[36] Maiti S, Sengupta S, Giri C. Enantiospecific synthesis of 8 epipuupehedione from (R)-() carvone. Tetrahedron Letters. 2001;**42**: 2389-2391. DOI: 10.1016/S0040-4039 (01)00153-8

[37] Martin SF, Garrison PJ. General methods for alkaloid synthesis. Total synthesis of racemic lycoramine. The Journal of Organic Chemistry. 1982;**47**: 1513-1518. DOI: 10.1021/jo00347a029

[38] Quideau S, Lebon M, Lamidey A-M. Enantiospecific synthesis of the antituberculosis marine sponge metabolite (+)-puupehenone. The arenol oxidative activation route. Organic Letters. 2002;**4**:3975-3978. DOI: 10.1021/ol026855t

[39] Alvarez-Manzaneda EJ, Chahboun R, Barranco Pérez I, et al. First enantiospecific synthesis of the antitumor marine sponge metabolite ()-15-oxopuupehenol from () sclareol. Organic Letters. 2005;**7**: 1477-1480. DOI: 10.1021/ol047332j

[40] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. New routes toward drimanes and nor-drimanes from () sclareol. Synlett. 2000;**2000**:1561-1564. DOI: 10.1055/s-2000-7924

[41] Alvarez-Manzaneda EJ, Chahboun R, Cabrera E. Diels–Alder cycloaddition approach to puupehenone-related metabolites: Synthesis of the potent angiogenesis inhibitor 8 epipuupehedione. The Journal of Organic Chemistry. 2007;**72**:3332-3339. DOI: 10.1021/jo0626663

[42] Alvarez-Manzaneda E, Chahboun R, Cabrera E. A convenient

enantiospecific route towards bioactive merosesquiterpenes by cationic-resinpromoted Friedel–Crafts alkylation with A,B-enones. European Journal of Organic Chemistry. 2009;**2009**: 1139-1143. DOI: 10.1002/ ejoc.200801174

sesquiterpenes. Tetrahedron. 2010;**66**:

*DOI: http://dx.doi.org/10.5772/intechopen.87927*

[50] Ishibashi H, Ishihara K, Yamamoto

deoxytaondiol methyl ether. Journal of the American Chemical Society. 2004;

[51] Gansäuer A, Rosales A, Justicia J. Catalytic epoxypolyene cyclization via radicals: Highly diastereoselective formal synthesis of puupehedione and 8-epi-puupehedione. Synlett. 2006; **2006**:927-929. DOI: 10.1055/s-2006-

[52] Shen B. A new golden age of natural products drug discovery. Cell. 2015;**163**:

1297-1300. DOI: 10.1016/j.cell.


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

8280-8290. DOI: 10.1016/j.tet.

H. A new artificial cyclase for polyprenoids: enantioselective total synthesis of (�)-chromazonarol, (+)- 8-epi-puupehedione, and (�)-11<sup>0</sup>

**126**:11122-11123. DOI: 10.1021/

2010.08.038

ja0472026

933139

2015.11.031

**69**

[43] Dixon DD, Lockner JW, Zhou Q. Scalable, divergent synthesis of meroterpenoids via "boronosclareolide". Journal of the American Chemical Society. 2012;**134**:8432-8435. DOI: 10.1021/ja303937y

[44] Wang HS, Li HJ, Wu YC. Protecting-group-free synthesis of haterumadienone- and puupehenonetype marine natural products. Green Chemistry. 2017;**19**:2140-2144. DOI: 10.1039/c7gc00704c

[45] Wang HS, Li HJ, Wu YC. Enantiospecific semisynthesis of puupehedione-type marine natural products. The Journal of Organic Chemistry. 2017;**82**:12914-12919. DOI: 10.1021/acs.joc.7b02413

[46] Wang HS, Li HJ, Wu YC. Divergent synthesis of bioactive meroterpenoids via palladium-catalyzed tandem carbene migratory insertion. European Journal of Organic Chemistry. 2018;**2018**: 915-925. DOI: 10.1002/ejoc.201800026

[47] Li SK, Zhang SS, Wang X. Expediently scalable synthesis and antifungal exploration of (+)-yahazunol and related meroterpenoids. Journal of Natural Products. 2018;**81**:2010-2017. DOI: 10.1021/acs.jnatprod.8b00310

[48] Ling T, Xiang AX, Theodorakis EA. Enantioselective total synthesis of avarol and avarone. Angewandte Chemie (International Ed. in English). 1999;**38**: 3089-3091. DOI: 10.1002/(SICI) 1521-3773(19991018)38:20<3089::AID-ANIE3089>3.0.CO;2-W

[49] Marcos IS, Conde A, Moro RF. Synthesis of quinone/hydroquinone *Approaches to the Total Synthesis of Puupehenone-Type Marine Natural Products DOI: http://dx.doi.org/10.5772/intechopen.87927*

sesquiterpenes. Tetrahedron. 2010;**66**: 8280-8290. DOI: 10.1016/j.tet. 2010.08.038

[35] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. Synthesis and antitumor activity of puupehedione and related compounds. Tetrahedron. 1999;**55**: 15181-15208. DOI: 10.1016/S0040-4020 enantiospecific route towards bioactive merosesquiterpenes by cationic-resinpromoted Friedel–Crafts alkylation with

A,B-enones. European Journal of Organic Chemistry. 2009;**2009**: 1139-1143. DOI: 10.1002/

[43] Dixon DD, Lockner JW, Zhou Q. Scalable, divergent synthesis of meroterpenoids via "borono-

sclareolide". Journal of the American Chemical Society. 2012;**134**:8432-8435.

DOI: 10.1021/ja303937y

10.1039/c7gc00704c

10.1021/acs.joc.7b02413

[44] Wang HS, Li HJ, Wu YC. Protecting-group-free synthesis of haterumadienone- and puupehenonetype marine natural products. Green Chemistry. 2017;**19**:2140-2144. DOI:

[45] Wang HS, Li HJ, Wu YC. Enantiospecific semisynthesis of puupehedione-type marine natural products. The Journal of Organic Chemistry. 2017;**82**:12914-12919. DOI:

[47] Li SK, Zhang SS, Wang X. Expediently scalable synthesis and antifungal exploration of (+)-yahazunol and related meroterpenoids. Journal of Natural Products. 2018;**81**:2010-2017. DOI: 10.1021/acs.jnatprod.8b00310

ANIE3089>3.0.CO;2-W

[49] Marcos IS, Conde A, Moro RF. Synthesis of quinone/hydroquinone

[46] Wang HS, Li HJ, Wu YC. Divergent synthesis of bioactive meroterpenoids via palladium-catalyzed tandem carbene migratory insertion. European Journal of Organic Chemistry. 2018;**2018**: 915-925. DOI: 10.1002/ejoc.201800026

[48] Ling T, Xiang AX, Theodorakis EA. Enantioselective total synthesis of avarol and avarone. Angewandte Chemie (International Ed. in English). 1999;**38**: 3089-3091. DOI: 10.1002/(SICI) 1521-3773(19991018)38:20<3089::AID-

ejoc.200801174

[36] Maiti S, Sengupta S, Giri C. Enantiospecific synthesis of 8 epipuupehedione from (R)-() carvone. Tetrahedron Letters. 2001;**42**: 2389-2391. DOI: 10.1016/S0040-4039

*Organic Synthesis - A Nascent Relook*

[37] Martin SF, Garrison PJ. General methods for alkaloid synthesis. Total synthesis of racemic lycoramine. The Journal of Organic Chemistry. 1982;**47**: 1513-1518. DOI: 10.1021/jo00347a029

[38] Quideau S, Lebon M, Lamidey A-M.

[39] Alvarez-Manzaneda EJ, Chahboun

[40] Barrero AF, Alvarez-Manzaneda EJ, Chahboun R. New routes toward drimanes and nor-drimanes from () sclareol. Synlett. 2000;**2000**:1561-1564.

[41] Alvarez-Manzaneda EJ, Chahboun R, Cabrera E. Diels–Alder cycloaddition approach to puupehenone-related metabolites: Synthesis of the potent

R, Barranco Pérez I, et al. First enantiospecific synthesis of the antitumor marine sponge metabolite ()-15-oxopuupehenol from () sclareol. Organic Letters. 2005;**7**: 1477-1480. DOI: 10.1021/ol047332j

DOI: 10.1055/s-2000-7924

angiogenesis inhibitor 8-

DOI: 10.1021/jo0626663

R, Cabrera E. A convenient

**68**

epipuupehedione. The Journal of Organic Chemistry. 2007;**72**:3332-3339.

[42] Alvarez-Manzaneda E, Chahboun

Enantiospecific synthesis of the antituberculosis marine sponge metabolite (+)-puupehenone. The arenol oxidative activation route. Organic Letters. 2002;**4**:3975-3978. DOI:

10.1021/ol026855t

(99)00992-8

(01)00153-8

[50] Ishibashi H, Ishihara K, Yamamoto H. A new artificial cyclase for polyprenoids: enantioselective total synthesis of (�)-chromazonarol, (+)- 8-epi-puupehedione, and (�)-11<sup>0</sup> deoxytaondiol methyl ether. Journal of the American Chemical Society. 2004; **126**:11122-11123. DOI: 10.1021/ ja0472026

[51] Gansäuer A, Rosales A, Justicia J. Catalytic epoxypolyene cyclization via radicals: Highly diastereoselective formal synthesis of puupehedione and 8-epi-puupehedione. Synlett. 2006; **2006**:927-929. DOI: 10.1055/s-2006- 933139

[52] Shen B. A new golden age of natural products drug discovery. Cell. 2015;**163**: 1297-1300. DOI: 10.1016/j.cell. 2015.11.031

**Chapter 5**

**Abstract**

*N*,*N*-Dialkyl Amides as Versatile

Heterocycles and Acyclic Systems

*N*,*N*-dimethylacetamide (DMA), are common polar solvents, finds application as a multipurpose reagent in synthetic organic chemistry. They are cheap, readily available and versatile synthons that can be used in a variety of ways to generate different functional groups. In recent years, many publications showcasing, excellent and useful applications of *N*,*N*-dialkyl amides in amination (R-NMe2), formylation (R-CHO), as a single carbon source (R-C), methylene group (R-CH2), cyanation (R-CN), amidoalkylation (-R), aminocarbonylation (R-CONMe2), carbonylation (R-CO) and heterocycle synthesis appeared. This chapter highlights important developments in the employment of *N*,*N*-dialkyl amides in the synthesis of heterocycles and functionalization of acyclic systems. Although some review articles covered the application of DMF and/or DMA in organic functional group transformations, there is no specialized review on their application in the synthesis

Synthons for Synthesis of

*N*,*N*-Dialkyl amides such as *N*,*N*-dimethylformamide (DMF),

**Keywords:** amination, amidation, amidoalkylation, aminocarbonylation,

The great advantage of DMF, DMA and other *N*,*N*-dialkylamides are their versatility as reaction medium, polar and aprotic nature, high boiling point, cheap and ready availability. DMF can react as electrophile or a nucleophile and also act as a source of several key intermediates and take a role in reactions as a dehydrating agent, as a reducing agents [1] or as a catalyst [2–5], stabilizer [6–10]. For the synthesis of metallic compounds DMF can be an effective ligand. *N*,*N*-dialkylamides could be considered as a combination of several functional groups such as alkyl, amide, carbonyl, dialkyl amine, formyl, N-formyl and highly polar C-N, C〓O, and C-H bonds. Due to flexible reactivity of *N*,*N*-dialkylamides, during the past few years, chemists have succeeded in developing reactions, where DMF and DMA could be used to deliver different functional groups such as amino (R-NMe2), formyl (R-CHO), methylene (R-CH2), cyano (R-CN), amidoalkyl (CH2N(CH3)-C(〓O) CH3-R) aminocarbonyl(R-CONMe2), carbonyl(R-CO), methyl (-Me), a single atoms such as C, O, H etc. (**Figure 1**). Similarly, DMF and DMA could be used in the

cyanation, dialkyl amides, formylation, heterocycles

*Andivelu Ilangovan, Sakthivel Pandaram*

*and Tamilselvan Duraisamy*

of cyclic and acyclic systems.

**1. Introduction**

**71**

## **Chapter 5**
