2.3.1. Marcos's Synthesis of (−)-Aureol

Marcos and colleagues [28] reported the total synthesis of the (−) enantiomer of aureol (*ent*-**1**) from the methyl ester of natural *ent*-halimic acid (Scheme 7a). Their approach was based on: (a) the acid-induced cyclization of sesquiterpene hydroquinone *ent*-**11**, (b) the Barton decarboxylation reaction/*p*-benzoquinone addition sequence and the subsequent reduction with Raney® nickel (*ent*-**11** from **29**), and (c) the side-chain degradation of *ent*halimic acid methyl ester **30** and the subsequent reduction of C-18 methyl ester.

As shown in Scheme 7b the synthesis of (−)-aureol (*ent*-**1**) used *ent*-halimic acid methyl ester **30** as the starting material. The degradation of the side chain of **30** was achieved [29,30] by oxidation with OsO<sup>4</sup> followed by Pb(OAc)4, which gave ketone **31** (94% yield, two steps). The synthesis of the *endo*-olefin **33** required the Wittig methylenation of **31** (87% yield) and subsequent acid isomerization of **32** (99% yield). In order to remove the C-18 methyl ester, a three steps sequence from **33** to **36** was used, a process which gave a very good global yield. The synthesis of product **39** was achieved in four steps: a) the chemoselective epoxidation of the side-chain double bond in **36** (98% yield), b) the oxidative cleavage with H5IO<sup>6</sup> in H2O/THF to afford **37** (94% yield); c) reduction with LiAlH<sup>4</sup> (99% yield) to give **38** (99% yield), and d) the acetylation of the hydroxy group in **38** to afford **39** (99% yield). The isomerization of the olefin double bond present in acetate **39** with HI (97% yield) followed by the saponification of the acetoxy group (98% yield) gave the rearranged product *ent*-**40**. Finally, the oxidation of *ent*-**40** to acid **29** via aldehyde **41** was achieved with pyridinium dichromate (PDC) in a moderate yield. Once intermediate **29** was available, the key precursor *ent*-**11** of (−)-aureol (*ent*-**1**) could be readily prepared by Barton decarboxylation reaction in the presence of *p*-benzoquinone, a methodology reported by Theodorakis and colleagues [31,32] for the synthesis of ilimaquinone. In this way, when **29** was treated with 2-mercaptopyridine *N*-oxide in the presence of *N,N*0 dicyclohexylcarbodiimide (DCC) a photo labile thio-hydroxamic ester (**42**) was obtained. Then, **43** was prepared by light-induced decarboxylation (halogen lamp 500W) of **42** in the presence of benzoquinone in a 65% yield from **29**. The subsequent reduction of **43** with Raney® nickel gave *ent*-**11** in a 99% yield. With the key precursor *ent*-**11** in their hands, the treatment of this compound with BF<sup>3</sup> .Et2O at low temperature exclusively afforded (−)-aureol (*ent*-**1**) with complete stereoselectivity (60% yield). This total synthesis was

achieved in 19 steps (10.3% overall yield) from *ent*-halimic acid methyl ester **30** as the chiral pool starting material. achieved in 19 steps (10.3% overall yield) from *ent*-halimic acid methyl ester **30** as the chiral pool starting material.

**Scheme 7.** Strategy for the synthesis of (−)-aureol (*ent*-**1**) according to Marcos and colleagues [26]. (**a**): Retrosynthetic plan. (**b**): Synthesis of (−)-aureol (*ent*-**1**). NMO = *N*-methylmorpholine-*N*-oxide; TPAP = tetra-*n*-propylammonium perruthenate; *m*CPBA = *m*-chloroperoxybenzoic acid; PDC = pyridinium dichromate; DCC = *N,N*′-dicyclohexylcarbodiimide. **Scheme 7.** Strategy for the synthesis of (−)-aureol (*ent*-**1**) according to Marcos and colleagues [26]. (**a**): Retrosynthetic plan. (**b**): Synthesis of (−)-aureol (*ent*-**1**). NMO = *N*-methylmorpholine-*N*-oxide; TPAP = tetra-*n*-propylammonium perruthenate; *m*CPBA = *m*-chloroperoxybenzoic acid; PDC = pyridinium dichromate; DCC = *N,N*0 -dicyclohexylcarbodiimide.

#### 2.3.2. George´s Synthesis of (+)-Aureol 2.3.2. George's Synthesis of (+)-Aureol

George´s group [33] published in 2012 the second total synthesis of (+)-aureol (**1**). Their biosynthetically inspired retrosynthesis of (+)-aureol (**1**) (Scheme 8a) rests upon the biomimetic acid-mediated cyclization of the key tetrasubstituted olefin intermediate **11**, which could be prepared through a process involving the addition of an aryllithium derivative to aldehyde **44**. This aldehyde could be formed using a one-carbon dehomologation sequence from **45**. Another key step in the process is the biomimetic sequence of 1,2 hydride and 1,2-methyl shifts, which converts alcohol **46** into **45**. Finally, the reduction and selective protection of the commercially available enantiopure starting material George's group [33] published in 2012 the second total synthesis of (+)-aureol (**1**). Their biosynthetically inspired retrosynthesis of (+)-aureol (**1**) (Scheme 8a) rests upon the biomimetic acid-mediated cyclization of the key tetrasubstituted olefin intermediate **11**, which could be prepared through a process involving the addition of an aryllithium derivative to aldehyde **44**. This aldehyde could be formed using a one-carbon dehomologation sequence from **45**. Another key step in the process is the biomimetic sequence of 1,2-hydride and 1,2-methyl shifts, which converts alcohol **46** into **45**. Finally, the reduc-

(+)-sclareolide (**47**) would form the intermediate **46**.

tion and selective protection of the commercially available enantiopure starting material (+)-sclareolide (**47**) would form the intermediate **46**. *Mar. Drugs* **2021**, *19*, x FOR PEER REVIEW 9 of 16

**Scheme 8.** Strategy for the synthesis of (+)-aureol (**1**) according to George and colleagues [33]. (**a**) Retrosynthetic plan. (**b**) Synthesis of (+)-aureol (**1**). DMAP = 4-(dimethylamino)pyridine; NMO= *N*-methylmorpholine-*N*-oxide; TBAF = tetrabutylammonium fluoride. **Scheme 8.** Strategy for the synthesis of (+)-aureol (**1**) according to George and colleagues [33]. (**a**) Retrosynthetic plan. (**b**) Synthesis of (+)-aureol (**1**). DMAP = 4-(dimethylamino)pyridine; NMO= *N*-methylmorpholine-*N*-oxide; TBAF = tetrabutylammonium fluoride.

As shown in Scheme 8b, George´s synthesis of (+)-aureol (1) used **11** as the key intermediate, which was prepared from natural (+)-sclareolide (**47**). Its reduction with LiAlH4 gave a diol, which was selectively protected at the primary hydroxy group with Ac2O in pyridine to afford the acetate **46** in an 84% yield (two steps). Monoacetate **46** was stereoselectively converted to the single stereoisomer olefin **45** (70% yield) in a rearrangement induced by BF3. Et2O, which occurred via stereospecific sequential 1,2-hydride and 1,2-methyl shifts. Saponification of the acetate in **45** gave alcohol **40** (83% yield), which was readily converted into aldehyde **44** through a one-carbon dehomologation sequence using the Grieco–Sharples elimination protocol [34,35] (67% yield in two steps) followed by oxidative cleavage of the resulting terminal alkene **48** (45% yield in two steps). With aldehyde **44** in their hands, the coupling between **44** and an aryllithium species gave the mixture of diastereomeric benzylic alcohols **49**. In order to remove the OH group, this mixture of alcohols (**49**) was treated with lithium in liquid ammonia followed by NH4Cl aqueous solution to afford deoxygenated compound **50** in a 78% yield (two steps). Removal of the TBS protecting groups in **50** with tetrabutylammonium fluoride provided the key inter-As shown in Scheme 8b, George's synthesis of (+)-aureol (1) used **11** as the key intermediate, which was prepared from natural (+)-sclareolide (**47**). Its reduction with LiAlH<sup>4</sup> gave a diol, which was selectively protected at the primary hydroxy group with Ac2O in pyridine to afford the acetate **46** in an 84% yield (two steps). Monoacetate **46** was stereoselectively converted to the single stereoisomer olefin **45** (70% yield) in a rearrangement induced by BF<sup>3</sup> .Et2O, which occurred via stereospecific sequential 1,2-hydride and 1,2-methyl shifts. Saponification of the acetate in **45** gave alcohol **40** (83% yield), which was readily converted into aldehyde **44** through a one-carbon dehomologation sequence using the Grieco–Sharples elimination protocol [34,35] (67% yield in two steps) followed by oxidative cleavage of the resulting terminal alkene **48** (45% yield in two steps). With aldehyde **44** in their hands, the coupling between **44** and an aryllithium species gave the mixture of diastereomeric benzylic alcohols **49**. In order to remove the OH group, this mixture of alcohols (**49**) was treated with lithium in liquid ammonia followed by NH4Cl aqueous solution to afford deoxygenated compound **50** in a 78% yield (two steps). Removal of the TBS protecting groups in **50** with tetrabutylammonium fluoride provided

the key intermediate **11** in an 86% yield. To complete the synthesis of (+)-aureol (**1**), the intermediate **11** was treated with BF<sup>3</sup> .Et2O to afford (+)-aureol (**1**) in a 66% yield. This total synthesis was achieved in 12 steps (6% overall yield) from (+)-sclareolide (**47**). **11** was treated with BF3. Et2O to afford (+)-aureol (**1**) in a 66% yield. This total synthesis was achieved in 12 steps (6% overall yield) from (+)-sclareolide (**47**).

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#### 2.3.3. Wu's Synthesis of (+)-Aureol 2.3.3. Wu´s Synthesis of (+)-Aureol

In 2018, Wu and colleagues [36] published the formal synthesis of (+)-aureol (**1**). Their retrosynthesis of (+)-aureol is outlined in Scheme 9a. This retrosynthetic analysis is based on: (a) the biomimetic acid-mediated cyclization of the hydroquinone **11** to generate (+)-aureol (**1**), (b) the removal of the two O-Me protecting groups of **51** to afford the key intermediate **11**, (c) the cross-coupling reaction between alkyl iodide **52** and Grignard reagent **53** to give the intermediate **51**, (d) the rearrangement reaction of **54** to afford **52**, and (e) the reduction of (+)-sclareolide (**47**) and subsequent C-C bond cleavage to give **54**. In 2018, Wu and colleagues [36] published the formal synthesis of (+)-aureol (**1**). Their retrosynthesis of (+)-aureol is outlined in Scheme 9a. This retrosynthetic analysis is based on: (a) the biomimetic acid-mediated cyclization of the hydroquinone **11** to generate (+) aureol (**1**), (b) the removal of the two O-Me protecting groups of **51** to afford the key intermediate **11**, (c) the cross-coupling reaction between alkyl iodide **52** and Grignard reagent **53** to give the intermediate **51**, (d) the rearrangement reaction of **54** to afford **52**, and (e) the reduction of (+)-sclareolide (**47**) and subsequent C-C bond cleavage to give **54**.

**Scheme 9.** Strategy for the synthesis of (+)-aureol (**1**) according to Wu and colleagues [36]. (**a**): Retrosynthetic plan. (**b**): Synthesis of (+)-aureol (**1**). DIBAL-H = diisobutylaluminium hydride; PIDA = (diacetoxyiodo)benzene. **Scheme 9.** Strategy for the synthesis of (+)-aureol (**1**) according to Wu and colleagues [36]. (**a**): Retrosynthetic plan. (**b**): Synthesis of (+)-aureol (**1**). DIBAL-H = diisobutylaluminium hydride; PIDA = (diacetoxyiodo)benzene.

As shown in Scheme 9b, the synthesis of intermediate **11** was carried out starting from commercially available (+)-sclareolide (**47**). Reduction of **47** using diisobutylaluminium hydride (DIBAL-H) generated sclareal **55** in a 98% yield. The treatment of **55** under the C-C bond cleavage conditions described by Suárez and colleagues [37] gave drimanal As shown in Scheme 9b, the synthesis of intermediate **11** was carried out starting from commercially available (+)-sclareolide (**47**). Reduction of **47** using diisobutylaluminium hydride (DIBAL-H) generated sclareal **55** in a 98% yield. The treatment of **55** under the C-C bond cleavage conditions described by Suárez and colleagues [37] gave drimanal

iodoformate (**54**) in a 78% yield. The crucial step was the BF<sup>3</sup> .Et2O-mediated rearrangement of **54**, which occurred via stereospecific sequential 1,2-hydride and 1,2-methyl shifts to generate the desired alkyl iodide **52** (63%), together with a minor amount of by-product **56** (20%). In this reaction, the intermediate carbocations **V**-**VII** could be involved. With alkyl iodide **52** in their hands, the cross-coupling reaction between Grignard reagent **53** and alkyl iodide **52** generated the key intermediate **51** in a 56% yield. As olefin **51** was an advanced intermediate in the Rosales's synthesis [38,39] of (±)-aureol (**1**), their strategy constituted a formal synthesis of (+)-aureol (**1**). This formal synthesis was completed in four steps (27% overall yield) from starting material (+)-sclareolide (**47**). iodoformate (**54**) in a 78% yield. The crucial step was the BF3. Et2O-mediated rearrangement of **54**, which occurred via stereospecific sequential 1,2-hydride and 1,2-methyl shifts to generate the desired alkyl iodide **52** (63%), together with a minor amount of by-product **56** (20%). In this reaction, the intermediate carbocations **V**-**VII** could be involved. With alkyl iodide **52** in their hands, the cross-coupling reaction between Grignard reagent **53** and alkyl iodide **52** generated the key intermediate **51** in a 56% yield. As olefin **51** was an advanced intermediate in the Rosales´s synthesis [38,39] of (±)-aureol (**1**), their strategy constituted a formal synthesis of (+)-aureol (**1**). This formal synthesis was completed in four steps (27% overall yield) from starting material (+)-sclareolide (**47**).

#### 2.3.4. Rosales Martínez's Synthesis of (±)-Aureol 2.3.4. Rosales Martínez´s Synthesis of (±)-Aureol

As a part of our efforts directed towards the synthesis of marine terpenoids [40], we embarked on a project aimed at the divergent synthesis of tetracyclic meroterpenoids. Our endeavors started with the racemic preparation of (±)-aureol (**1**) in 2015 [38], a process we latter improved in 2020 [39]. This effort continues with the divergent synthesis of other tetracyclic meroterpenoids using aureol (**1**) as a common synthetic intermediate. The retrosynthetic plan for each synthesis is shown in Scheme 10. Our strategy is based on the preparation of (±)-aureol (**1**) through the biomimetic acid cyclization of hydroquinone **11**, an intermediate that could be generated from **57** through a sequence of 1,2-hydride and 1,2-methyl shifts and the subsequent deprotection of both O-Me groups. **57** is an intermediate common to both synthetic approaches. In one of them, **57** is prepared through Cp2TiCl-catalyzed reductive epoxide cyclization cascade of epoxyfarnesol derivative **58** and the subsequent deoxygenation of the OH-group. In the other, a cross-coupling reaction between albicanal (**59**) and 2-lithiohydroquinone is used. As a part of our efforts directed towards the synthesis of marine terpenoids [40], we embarked on a project aimed at the divergent synthesis of tetracyclic meroterpenoids. Our endeavors started with the racemic preparation of (±)-aureol (**1**) in 2015 [38], a process we latter improved in 2020 [39]. This effort continues with the divergent synthesis of other tetracyclic meroterpenoids using aureol (**1**) as a common synthetic intermediate. The retrosynthetic plan for each synthesis is shown in Scheme 10. Our strategy is based on the preparation of (±)-aureol (**1**) through the biomimetic acid cyclization of hydroquinone **11**, an intermediate that could be generated from **57** through a sequence of 1,2-hydride and 1,2-methyl shifts and the subsequent deprotection of both O-Me groups. **57** is an intermediate common to both synthetic approaches. In one of them, **57** is prepared through Cp2TiCl-catalyzed reductive epoxide cyclization cascade of epoxyfarnesol derivative **58** and the subsequent deoxygenation of the OH-group. In the other, a cross-coupling reaction between albicanal (**59**) and 2-lithiohydroquinone is used.

**Scheme 10.** Retrosynthetic plan of (±)-aureol (**1**) according to Rosales Martínez et al. [38,39]. **Scheme 10.** Retrosynthetic plan of (±)-aureol (**1**) according to Rosales Martínez et al. [38,39].

Initially [38], we pursued the synthesis of the key intermediate **57** using epoxyfarnesol **60** as the starting material (Scheme 11). The one-pot mesylation of product **60** with MsCl, and the subsequent addition of LiBr quantitatively gave a yield of bromide **61**. The cross-coupling reaction between **61** and 2,5-dimethoxyphenylmagnesium bromide afforded the epoxyfarnesol derivative **58** (97% yield). A very elegant Cp2TiCl-catalyzed [40] radical cascade cyclization of **58** gave **62** in a moderate 48% yield. The subsequent deoxygenation of alcohol **62** was carried out using the Barton–McCombie procedure, which afforded **57** in an 86% overall yield (two steps). Later [39], the key intermediate **57** was also prepared through a C-C bond-forming reaction between 2-lithiohydroquinone dimethyl ether and (±)-albicanal (**59**) as starting material, which was previously obtained by oxida-Initially [38], we pursued the synthesis of the key intermediate **57** using epoxyfarnesol **60** as the starting material (Scheme 11). The one-pot mesylation of product **60** with MsCl, and the subsequent addition of LiBr quantitatively gave a yield of bromide **61**. The crosscoupling reaction between **61** and 2,5-dimethoxyphenylmagnesium bromide afforded the epoxyfarnesol derivative **58** (97% yield). A very elegant Cp2TiCl-catalyzed [40] radical cascade cyclization of **58** gave **62** in a moderate 48% yield. The subsequent deoxygenation of alcohol **62** was carried out using the Barton–McCombie procedure, which afforded **57** in an 86% overall yield (two steps). Later [39], the key intermediate **57** was also prepared through a C-C bond-forming reaction between 2-lithiohydroquinone dimethyl ether and (±)-albicanal (**59**) as starting material, which was previously obtained by oxidation of (±)-albicanol (**63**) with the Dess–Martin reagent (99.7% yield). In this way, the coupling of **59** with 2-lithiohydroquinone dimethyl ether gave a mixture of diastereomeric benzylic

alcohols which, without separation, was treated with lithium in liquid NH3/THF followed by aqueous NH4Cl to give the deoxygenated product **57** in a 90% yield (two steps). With **57** in our hands, tetrasubstituted olefin **51** was synthesized by biomimetic-type rearrangement of **57** mediated by BF<sup>3</sup> .Et2O. benzylic alcohols which, without separation, was treated with lithium in liquid NH3/THF followed by aqueous NH4Cl to give the deoxygenated product **57** in a 90% yield (two steps). With **57** in our hands, tetrasubstituted olefin **51** was synthesized by biomimetictype rearrangement of **57** mediated by BF3. Et2O.

tion of (±)-albicanol (**63**) with the Dess–Martin reagent (99.7% yield). In this way, the coupling of **59** with 2-lithiohydroquinone dimethyl ether gave a mixture of diastereomeric

*Mar. Drugs* **2021**, *19*, x FOR PEER REVIEW 12 of 16

**Scheme 11.** Synthesis of (±)-aureol (**1**) according to Rosales Martínez et al. [38,39]. DMAP = 4-(dimethylamino)pyridine; AIBN = 2,2′-azobis(2-methylpropionitrile). **Scheme 11.** Synthesis of (±)-aureol (**1**) according to Rosales Martínez et al. [38,39]. DMAP = 4- (dimethylamino)pyridine; AIBN = 2,20 -azobis(2-methylpropionitrile).

Under these conditions, **51** was obtained in a 63% yield, together with the by-product **64** in a 30% yield. In this reaction, the intermediate carbocations **IX**-**XI** could be involved [39]. The cationic rearrangement might be initiated by a proton from HF, which could be formed through hydrolysis of BF3, since is known that BF<sup>3</sup> .Et2O is very moisture sensitive. The demethylation of **51** gave **11** in an 82% yield over the two steps. Finally, the treatment of the hydroquinone **11** with BF<sup>3</sup> .Et2O afforded aureol (**1**) (62%). This cyclization was originally explored by Marcos et al. [28] This synthesis of racemic (±)-aureol (**1**) was completed in eight steps (14% overall yield) from the starting material epoxyfarnesol (**60**) or in seven steps (28% yield overall yield) from the starting material (±)-albicanal (**59**). [39]. The cationic rearrangement might be initiated by a proton from HF, which could be formed through hydrolysis of BF3, since is known that BF3. Et2O is very moisture sensitive. The demethylation of **51** gave **11** in an 82% yield over the two steps. Finally, the treatment of the hydroquinone **11** with BF3. Et2O afforded aureol (**1**) (62%). This cyclization was originally explored by Marcos et al. [28] This synthesis of racemic (±)-aureol (**1**) was completed in eight steps (14% overall yield) from the starting material epoxyfarnesol (**60**) or in seven steps (28% yield overall yield) from the starting material (±)-albicanal (**59**).

Under these conditions, **51** was obtained in a 63% yield, together with the by-product **64** in a 30% yield. In this reaction, the intermediate carbocations **IX**-**XI** could be involved

#### **3. Aureol as Pluripotent Late-Stage Intermediate for the Synthesis of Tetracyclic Meroterpenoids 3. Aureol as Pluripotent Late-Stage Intermediate for the Synthesis of Tetracyclic Meroterpenoids**

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The possibility of using aureol (**1**) as a late-intermediate for the divergent synthesis of other tetracyclic terpenoids stems from the fact that these compounds have differences mostly on the aromatic moiety. Furthermore, the easy epimerization of aureol (**1**) into 5-*ep*i-aureol (**5**) previously described by Magauer and colleagues [8] opens the door to the preparation of *trans*-decaline. From both *cis*- or *trans*-decaline frameworks, it should be quite straightforward the access to a library of natural or non-natural tetracyclic meroterpenoid analogues, just by simple variation of the arene moiety. The examples represented in Scheme 12 illustrate how other compounds can be obtained from aureol (**1**). The nonnatural 5-*epi*-aureol (**5**) was synthesized by thermal isomerization of (+)-aureol (**1**) using hydroiodic acid in benzene at 90 ◦C (87% yield) [8]. From 5-*epi*-aureol (**5**), the compounds (−)-cyclosmenospongine (**4**) and 5-*epi*-smenoqualone (**6**) were prepared by sequential functionalization of their aromatic core. In this way, selective bromination of **5** with Br2, and the subsequent methylation gave the compound **65** in an excellent yield. The non-natural 5-*epi*-smenoqualone (**6**) was prepared from **65** via a boronation-oxidation sequence in a 58% yield (two steps). Eventually, non-natural **6** was converted to (−)-cyclomenospongine (**4**) via aminolysis (60% yield). In addition, the application of this sequential functionalization of the aromatic core to (+)-aureol (**1**) could be used to prepare natural (+)-smenoqualone (**4**). The possibility of using aureol (**1**) as a late-intermediate for the divergent synthesis of other tetracyclic terpenoids stems from the fact that these compounds have differences mostly on the aromatic moiety. Furthermore, the easy epimerization of aureol (**1**) into 5 *ep*i-aureol (**5**) previously described by Magauer and colleagues [8] opens the door to the preparation of *trans*-decaline. From both *cis*- or *trans*-decaline frameworks, it should be quite straightforward the access to a library of natural or non-natural tetracyclic meroterpenoid analogues, just by simple variation of the arene moiety. The examples represented in Scheme 12 illustrate how other compounds can be obtained from aureol (**1**). The non-natural 5-*epi*-aureol (**5**) was synthesized by thermal isomerization of (+)-aureol (**1**) using hydroiodic acid in benzene at 90 °C (87% yield) [8]. From 5-*epi*-aureol (**5**), the compounds (−)-cyclosmenospongine (**4**) and 5-*epi*-smenoqualone (**6**) were prepared by sequential functionalization of their aromatic core. In this way, selective bromination of **5** with Br2, and the subsequent methylation gave the compound **65** in an excellent yield. The non-natural 5-*epi*-smenoqualone (**6**) was prepared from **65** via a boronation-oxidation sequence in a 58% yield (two steps). Eventually, non-natural **6** was converted to (−)-cyclomenospongine (**4**) via aminolysis (60% yield). In addition, the application of this sequential functionalization of the aromatic core to (+)-aureol (**1**) could be used to prepare natural (+)-smenoqualone (**4**).

**Scheme 12.** Synthesis of (-)-cyclomenospongine (**4**) and 5-*epi*-smenoquealone (**6**) from (+)-aureol (**1**). DMF = *N,N*′-dimethylformamide. **Scheme 12.** Synthesis of (-)-cyclomenospongine (**4**) and 5-*epi*-smenoquealone (**6**) from (+)-aureol (**1**). DMF = *N,N*0 -dimethylformamide.

#### **4. Conclusions**

The divergent synthesis is a valuable tool in the design of efficient routes for the synthesis of natural products using a common intermediate. Although several unified strategies have been reported for some families of natural products, it is desirable to extrapolate this methodology to the synthesis of tetracyclic meroterpenoids. In this context, this article reviews the synthesis of the marine natural product aureol (**1**), with special emphasis on their strategies and methodologies. In addition, this natural tetracyclic meroterpenoid can be used as pluripotent late-stage intermediate for the synthesis of other natural and non-natural tetracyclic meroterpenoids. In this article, we proposed a methodology based on a diversification strategy that we believe will be useful in future research for the preparation of other tetracyclic meroterpenoids as substances that could be used as new drugs or in structure–activity relationship studies.

**Author Contributions:** A.R.M.: design and coordination of the project, writing—original draft, writing—review and editing. I.R.-G.: writing—review and editing. J.L.L.-M.: writing—review. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the Vicerrectorado de Investigación (Project 2020/00001014) of University of Sevilla (Spain) and by the Vicerrectorado de Investigación e Innovación of University of Almería (Project PPUENTE2020/010).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** A. Rosales Martínez acknowledges University of the Sevilla for his position as professor and for financial support (Project 2020/00001014).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

