Total Synthesis of Natural Products Containing the Tetralone Subunit

Tetralone and its derivatives are unique structural motifs found in a wide range of natural products and serve as key scaffolds for the development of new drugs that target various biological end points. The tetralones have received a lot of interest because of their chemical features and their potential as lead molecules in the pharmaceutical sector. The goal of this review is to present the total synthesis of natural products bearing the 1-tetralone subunit, as well as to highlight key transformations for the synthesis of 1-tetralone. It summarizes the total syntheses of several natural products containing the tetralone subunit, such as 10-norparvulenone, catalponol, aristelegone-A, perenniporide A, and actinoranone

Some creative methods and more conventional approaches for the preparation of this valuable bicyclic nucleus have been developed.However, although few excellent reviews devoted to the related tetralones have been published [7][8][9][10][11] the chemistry of natural products containing α-tetralones has not been reviewed to date.
This review article focuses on the total synthesis of several natural products, namely 10-norparvulenone, O-methylasparvenone, aristelegone-A, aristelegone-B, catalponol, perenniporide A, and actinoranone.We have excluded discussing the remaining molecules in Figure 2 due to either the absence of any synthesis reports or previous reviews in the literature. 12The content of this review is intended to be informative for organic chemists as well as a contribution to the current body of literature in this field.

O-Methylasparvenone and 10-Norparvulenone
The natural products O-methylasparvenone and 10-norparvulenone both possess an α-tetralone subunit.O-Methylasparvenone is a rare type of serotonin receptor antagonist that lacks nitrogen and was discovered as a 5-HT2c antagonist 13 during a microbial screening for 5-HT2c ligands from the endophytic fungus Aspergillus parvulus Smith broth.On the other hand, 10-norparvulenone was first isolated in 2000 by Fukami et al. in the laboratory from Microsphaeropsis sp. 14 There is promising preliminary data from in vitro assays that suggest 10-norparvulenone may become a significant antiviral drug in the future.Both natural products contain a bicyclic carbon framework with a carbonyl function (1-tetralone), one methoxy group, and 2 or 3 hydroxyl groups as part of their structures.
To date, four total syntheses of O-methylasparvenone have been reported, while only one total synthesis of 10-norparvulenone has been documented.
Treatment of 20 with freshly distilled trifluoroacetic anhydride unusually resulted in an excellent yield of tetralone 21.Selective demethylation of the methoxy ether ortho to the carbonyl, followed by silyl deprotection using TBAF, produced the desired natural product (+)-O-methylasparvenone 1 in 83% yield. 17

Zard's total synthesis of (±)-10-norparvulenone and (±)-O-methylasparvenone (2003)
Zard and coworkers achieved the total synthesis of (±)-10-norparvulenone 2 and (±)-O-methylasparvenone 1 in 2003 by utilizing a xanthate-mediated free radical addition-cyclization sequence to construct the challenging tetralone component of these compounds (Scheme 4).The synthesis of (±)-10-norparvulenone 2 began with the preparation of tetralone subunit 27.Commercially available m-methoxyphenol 23 was acylated with bromoacetyl bromide to produce bromoacetophenone 24.Treatment of 24 with potassium ethyl xanthate in acetone at 0 °C, followed by addition of acetic anhydride, afforded the desired radical precursor 26 in quantitative yield.Next, 26 underwent a three-step, one-pot reaction sequence involving radical addition of the xanthate onto vinyl pivalate using dilauroyl peroxide (DLP) as the initiator under acetic anhydride medium (26 to A), followed by refluxing with DLP in DCE (A to B), and finally, treatment with ammonium hydroxide, resulting in the bicyclic tetralone intermediate 27 in an overall 36% yield (B to 27).After optimizing reaction conditions, the formyl group on the aromatic ring of 28 was introduced by treating a cold solution of 27 with TiCl4 and dichloromethyl methyl ether in 96% yield.Finally, chemoselective reduction of the aldehyde, followed by saponification of the trimethylacetyl ester group, produced (±)-10-norparvulenone 2 in 68% yield.Due to the close relationship between (±)-10-norparvulenone 2 and (±)-O-methylasparvenone 1, Zard opted to synthesize 1 using the common intermediate aldehyde 28.Aldehyde 28 was subjected to Wittig olefination to afford olefin 29 in a moderate yield.The olefin was then hydrogenated, followed by saponification to complete the synthesis of O-methylasparvenone 1. 18

Catalponol
Catalponol was first extracted from the wood of Catalpa ovata (also known as Kisasage in Japanese) by Inouye et al. in 1971. 19McDaniel has shown that this natural substance possesses significant antitermitic properties. 20urthermore, Lee has also demonstrated that catalponol has the ability to promote dopamine biosynthesis and protect a variety of PC12 cells against the cytotoxicity caused by L-DOPA. 21To date, the groups of Kündig and Sasai have each reported a total synthesis of catalponol.
Scheme 5 outlines the synthetic approach to catalponol.Initially, catalytic enantioselective asymmetric monoreduction of tetralin-1,4-dione using (R)-32 as the catalyst and catecholborane gave 4-hydroxy tetralone (S)-33 with excellent enantioselectivity.Compound 33 was then subjected to silyl protection to furnish 34.Compound 34 was transformed to its mono-prenylated derivative, resulting in the formation of cis 36 and trans 37 diastereoisomers in 83% yield with a 52:48 diastereomeric ratio, along with a minor diprenylated product.Treatment of the mixture of diastereoisomers 36 and 37 with TBAF afforded catalponol (30) and 2epi-catalponol (30a).However, this route failed to demonstrate higher selectivity for catalponol as anticipated. 22ündig's second approach is based on a more diastereoselective strategy, utilizing chromium complexes [Cr(arene)(CO)3].In this approach, the author prepared the chromium complex 40 of the widely available 1,4dihydroxynaphthalene precursor 38 through tautomer 39.Next, complex 40 was subjected to enantioselective © AUTHOR(S) reduction to install the appropriate chiral benzylic hydroxyl group, which was then protected as a TMS to afford 42.The LDA-mediated enolate formation and prenylation of the Cr(CO)3 complex resulted in the formation of a single diastereomer of exo-complex 43.This exo-complex was transformed into endo-complex 44 by enolate formation and exo-protonation with citric acid.Finally, ether hydrolysis and decomplexation yielded enantiomerically pure catalponol.

Suzuki's total synthesis of catalponol (2015)
Suzuki and colleagues developed a straightforward one-pot method for synthesizing benzylidenehydroxytetralones from meso-diols using chiral iridium-catalyzed tandem asymmetric hydrogen transfer oxidation/aldol condensation (Scheme 6).When meso-1,4-tetralinediol (46) was treated with 3-methyl-2butenal (47) in the presence of catalyst (R,R)-cat, followed by the addition of KOH, the desired dienone 48 was obtained in an 87% yield with 99% ee.After multiple experiments on the achiral conjugate reduction of unsaturated carbonyl compounds, the authors were able to complete the total synthesis of catalponol 30 in a 78% yield by utilizing PdCl2, dppf, and catecholborane, along with an undesired minor isomer 30a in 8%. 23heme 6. Suzuki's total synthesis of catalponol.

Perenniporides
Perenniporides A-D are a class of natural products that were isolated by Liu and Che in 2012 from the fungus Perenniporia sp.found in the larva of the phytophagous weevil, Euops chinesis. 24Among these compounds, Perenniporide A (49) has been found to exhibit a strong inhibitory effect on various plant pathogens.Its structure features α-tetralone skeleton with a 2-hydroxypropanoic acid appendage.So far, only one total synthesis of 49 has been reported in the literature.In 2015, Ohmori and Suzuki achieved the first total synthesis of perenniporide A (49), utilizing a remarkable high-pressure cycloaddition reaction to efficiently build the tetralone core of the molecule.
The synthesis began with the preparation of the crucial cycloaddition precursor, difluorodienone (56), starting from 1,3,5-trifluorobenzene (50) (Scheme 7).Compound 50 underwent a SNAr reaction with benzyl alkoxide, resulting in the formation of the single-substituted difluoride 51.This compound was then lithiated regioselectively using PhLi and added to epoxide 52 in the presence of BF3.OEt2, providing compound 53.TIPS protection of the secondary alcohol and selective removal of the TBS group under specified conditions gave primary alcohol 54 in 84% yield over two steps.The primary alcohol was transformed into carboxylic acid functionality by IBX oxidation, which was then followed by Kraus-Pinnick oxidation, yielding acid 55 in 88% yield (two steps).Compound 55 underwent H2, Pd/C-promoted removal of the benzyl ether, followed by © AUTHOR(S) oxidative dearomatization of the resulting labile phenol using PhI(OCOCF3)2, giving difluorodienone 56 in 68% yield.
After obtaining the key intermediate 56, the Diels-Alder reaction with siloxy diene 57 was investigated.After extensive optimization of reaction conditions, the siloxy diene 57 and difluorodienone 56 were subjected to ultra-high-pressure conditions (10 Kbar, DCM, rt, 24 h) to yield the Diels-Alder adduct (α-tetralone) 58 in a 68% yield as a 3/2 inseparable mixture (simple chromatography conditions).This mixture was separated using gel permeation chromatography (YMC-GPC T4000+T2000, AcOEt) to afford 58a and 58b in 40% and 26% yield, respectively.The relative stereochemistry was assigned using 2D NMR analysis.Next, the fluorine atom in 58a was replaced by a methoxy group, yielding compounds 59 and 60, which, upon treatment with tetrabutylammonium fluoride, afforded the natural product perenniporide A. Similarly, 58b was transformed into 4-epi-perenniporide A 61. 25

Actinoranone
Actinoranone is a meroterpene natural compound that was isolated from a marine-derived actinomycete by Fenical and colleagues in 2013. 26This natural product possesses an unusual scaffold composed of diterpene and polyketide (containing tetralone functionality) and has been demonstrated to exhibit significant in vitro cytotoxicity against HCT-116 human colon cancer cells, with an LD50 value of 2.0 µg/mL.
To date, the research teams of Xu/Ye, has completed a total synthesis.Pastre, and Christmann have secured formal syntheses of actinoranone.

Xu/Ye's total synthesis of actinoranone (2017)
In 2017, the Xu/Ye research group accomplished the first total synthesis of actinoranone 62 and successfully assigned its stereochemistry.The construction of the core skeleton was achieved through the use of an intramolecular Friedel-Crafts reaction and a benzylic C-H oxidation reaction (Scheme 8).

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To synthesize actinoranone, aldehyde 70 was prepared from (R)-oxazolidinone imide 63.Allylation of 63 with allyl bromide gave allylated amide 64, which was reduced using LiBH4 to afford primary alcohol 65.TIPS protection of the primary alcohol followed by hydroboration of the terminal olefin to obtain the monosilylated diol 66. Oxidation of alcohol 66 under Parikh-Doering conditions led to the aldehyde, which was then subjected to a Friedel-Crafts reaction and dehydration with catalytic p-toluenesulfonic acid to produce bicycle 68.This was hydrogenated, and the primary alcohol was desilylated to produce aldehyde 70 through Dess-Martin oxidation.The vinyl iodide coupling partner 72 was prepared from commercial (+)-sclareolide 71 in 15 steps, allowing for efficient synthesis of actinoranone.
The n-BuLi-mediated coupling of 72 and 70 proceeded smoothly, producing secondary alcohol 73 in a 78% yield with reasonable selectivity (Felkin/anti-Felkin = 5:1).The resulting diastereomers were separated using column chromatography, and the stereochemistry at the secondary hydroxyl group was determined using Mosher's ester.
The required major isomer was protected as a PNB ester, and benzylic C-H oxidation of 74 using DDQ gave tetralone 75.Hydrolysis of ester 75 ultimately yielded actinoranone (76).However, upon comparison of the spectral data with natural actinoranone, considerable differences were observed.To determine the exact structure of actinoranone, the ent-70 isomer of the aldehyde was prepared and coupled with vinyl iodide to form 77. The Mitsunobu inversion of alcohol 77, benzylic C-H activation, and ester hydrolysis were used to deliver the desired natural product, actinoranone 62, in a 29% yield over 3 steps.All analytical data agreed with known data. 27

Pastre's formal synthesis of actinoranone (2017/2018)
In 2017, Pastre and coworkers reported a formal synthesis of actinoranone (62) that utilized similar chemistry to Xu's approach in constructing the tetralene scaffold.The synthesis of actinoranone began with the preparation of aldehyde ent-70 and vinyl iodide 72.Initially, vinyl iodide 72 was obtained from commercial (+)sclareolide (71) in approximately 8 steps, using a sequence previously reported procedure.
The synthesis of the aldehyde fragment began with the enantioselective hydroxymethylation of allylic acetate 80 under an iridium catalyst, which provided a straightforward way of obtaining alcohol 81 (Scheme 9).The primary alcohol was protected as silyl ether, and the terminal olefin was converted into unsaturated aldehyde 83 using Grubbs cross metathesis with (E)-crotonaldehyde.Next, catalytic hydrogenation of the olefin, followed by Friedel-Crafts cyclization and dehydration, produced the bicycle with a new olefin 84.Compound 84 was subjected to a second hydrogenation, followed by silyl deprotection and DMP oxidation, which delivered the required aldehyde fragment ent-70.
Finally, the coupling of fragments 72 and ent-70 was carried out using lithium halogen exchange to give alcohol 77, which was an advanced intermediate in Xu/Ye's total synthesis, thus completing the formal synthesis of actinoranone (62). 28bout a year later, the same group reported a full account of their efforts towards the formal synthesis of actinoranone (62) (Scheme 10). 29The polyketide fragment was prepared using protecting group-free synthetic methods.The primary alcohol 81 was first transformed into an acrylate 86, which was then metathesized and hydrogenated to yield the δ-valerolactone derivative 88.DIBAL-H reduction of the lactone, followed by a subsequent Friedel-Crafts reaction of the resulting lactol, and hydrogenation produced compound 90.The desired aldehyde fragment ent-70 was obtained by oxidizing primary alcohol 90.Finally, the coupling of ent-70 and 72 using butyl lithium provided 77, an intermediate in previous syntheses of actinoranone, thus accomplishing the formal synthesis of actinoranone (62).

Menger and Christmann's formal synthesis of actinoranone (2019)
In 2019, Menger and Christmann reported an approach to the synthesis of actinoranone (62) through intermediate 77 (Scheme 11). 30The synthesis of 77 utilized a semipinacol rearrangement/Wittig reaction sequence and a chiral pool approach for the syntheses of the tetralone and octalin fragments, respectively.The epoxide 92 was synthesized from allylic alcohol 91 via catalytic Sharpless epoxidation, followed by silyl protection.The Yamamoto rearrangement of 92, using stoichiometric quantities of (methylaluminum bis-(4bromo-2,6-di-tert-butylphenoxide)), followed by direct addition of freshly produced Wittig reagent, resulted in the formation of unsaturated ester 93.Olefin hydrogenation followed by ester reduction led to the formation of aldehyde 95.Using p-TsOH as a catalyst, cyclization, silyl ether cleavage, and hydrogenation of the olefin provided the bicyclic alcohol 90.The oxidation of alcohol 90 by Dess Martin periodinane yielded aldehyde fragment ent-70.
When aldehyde ent-70 was combined with in-situ lithiated vinyl iodide 72, the allylic alcohol 77 was obtained, completing the formal synthesis of actinoranone.Scheme 11.Menger and Christmann's formal synthesis of actinoranone.

Aristelegone-A, B and Schiffnerone B
Aristelegone-A and B are natural metabolites that were isolated by the Wu research group in 2002 from the root and stem of Aristolochia elegans. 31Schiffnerone-B was isolated from the wood of Dysoxylum schiffneri. 32o date, four total syntheses of aristelegone-A and B and one synthesis of schiffnerone-B have been reported.
The concise total synthesis of aristelegone-A was accomplished by Friedel-Crafts reaction of chiral butanoic acid (101) and subsequent demethylation with Et2NCH2CH2SNa (Scheme 12). 33heme 12. Zhou's total synthesis of aristelegone-A.

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© AUTHOR(S) Scheme 13.Serra's total synthesis of aristelegone-A, B and schiffnerone B.

Argade's total synthesis of aristelegone B and methylaristelegone A (2015)
In 2015, Batwal and Argade reported a chemoenzymatic total synthesis of various optically active terpenoids based on a tetralone scaffold.Their approach employed late-stage efficient enzymatic resolution, providing access to both enantiomers.

Hong/Lu's total synthesis of aristelegone A and B (2022)
The research groups of Hong and Lu have developed an efficient cobalt-catalyzed enantioconvergent hydrogenation technique, which utilizes easily available, minimally functionalized E/Z-olefin mixtures.This technique was used for the formal total synthesis of aristelegone A and B. The synthesis began with the enantioselective hydrogenation of trisubstituted olefin 116, which delivered the chiral compound 118 in quantitative yield and 98% ee.Compound 118 was subsequently transformed into known intermediate methylaristelegone A (115b) in two stages via 119.This completed the formal synthesis of 96 and 97 (Scheme 15). 36© AUTHOR(S) Scheme 15.Hong/Lu's total synthesis of aristelegone A and B.

Conclusions
The α-tetralone skeleton is a unique structural feature found in natural products with diverse biological activities, making them a subject of increasing interest in the organic synthetic community.This review provides a summary of the total syntheses of various natural products containing this scaffold, such as 10norparvulenone, O-methylasparvenone, aristelegone-B, catalponol, perenniporide A, and actinoranone, achieved since 1991.To construct this tetralone framework, several general and concise synthetic strategies have been employed, including ring-formation reactions such as Diels-Alder and Friedel-Crafts acylation-cyclization, as well as radical cyclization reactions.Although several other natural products with this motif have been isolated, their syntheses have not yet been reported.The unique challenges associated with tetralones have spurred innovative solutions and novel chemical techniques.As new bioactive tetralones are discovered every year, the synthetic interest in this class of natural products is expected to grow.Therefore, it will be intriguing to witness the emergence of new strategies, alternative disconnections, and useful synthetic methods in the future.