A Synthetic View on Momilactones and Related 9β-H Pimarane Skeleton Diterpenoids

Allelochemicals are secondary metabolites produced from plants and used to prevent and control the invasion of other plants and microorganisms, with broad application prospects in crop protection. Structurally, momilactones belong to 9β-H pimarane diterpenoids, one of rice’s significant allelochemicals with anti-weeds and antibacterial activity. Rare studies have been reported with the synthesis challenges of the unique 9β-H pimarane skeleton. Hence, synthetic strategies of momilactones and related 9β-H pimarane skeleton are reviewed from 1984 to 2021.


INTRODUCTION
Modern genetic evidence and recent studies have shown that momilactones are among the most active allelochemicals (Lin et al., 2019) and play a key role in allelopathy and resistance induction in rice (Okada et al., 2016). In 1973, momilactone A (1) and momilactone B (2) were isolated from Oryza sativa L. by Kato (Kato et al., 1973), firstly identified as new growth inhibitors. They have significant bioactivities, including weeds elimination in paddy fields and antimicrobial activity, especially toward Pyricularia oryzae Cav. (Jiang et al., 2016). However, the natural content of momilactones could not meet further research needs. Synthetic approaches to yield these natural products seem to attract synthetic chemists (Mohan et al., 1996). Kato (Kato et al., 1977) determined the stereochemical configuration of momilactone A by X-ray single-crystal diffraction as 9β-H. Momilactone A has continuous chiral centers with a trans-syn-cis tricyclic skeleton named 9β-H pimaranes, as shown in Figure 1, characterized in the family compounds (Zhao et al., 2018). Moreover, the trans-syn-cis tricyclic ring and the stereochemistry at C-9 led to significant challenges in synthesizing these molecules. In the early stage , the construction of the 9β-H-pimarane skeleton commonly had drawn the attention of scientists devoted to the synthesis of momilactones and related diterpenoids.

SYNTHETIC STUDIES TOWARD 9β-H PIMARANE SKELETON DITERPENOIDS
A few synthetic strategies about 9β-H-pimarane skeleton molecules had been described for the challenging framework, especially the continuous chiral centers. It would be difficult to accomplish the trans-syn-cis tricyclic with stereoselectivity.
In 1984, Sicherer-Roetman (Sicherer-Roetman et al., 1984) described the synthesis of model compound (±)-4,4-dinor-(9β-H)pimara-7,15-diene 42, possessing the trans-syn-cis skeleton and αmethyl and β-vinyl groups at C-13. The transannular Diels-Alder strategy had been used to construct the core tricyclic system, as shown in Scheme 1. Product 36 was obtained by the Diels-Alder reaction of ketone formaldehyde 34 and o-diolefin 35 under the catalysis of ZnCl 2 ; the step provided that cis-adduct 36 was deformylated in the presence of triton B and then hydrogenated with LiAl(OtBu) 3 H to obtain sole reduction product 37. From this point on, compound 42 could be provided by two different strategies. First, compound 37 was dehydrated in POCl 3 and pyridine to yield dienolsilane 38. Then, dithioacetal 39 was obtained with 2-ethoxy-1,3-dithiolan, and cis-βhydroxyaldehyde 40 was afforded by reduction and hydrolysis. They got β-vinyl product 41 through a Wittig reaction of compound 40. Considerable epimerization occurred at C-12 and C-13, a handful of the α-vinyl product was detected. Finally, oxidation of 41 and Wolff-Kishner reduction of the carbonyl gave compound 42 at 47% yield. The second approach protected the hydroxyl group to afford acetyl ester 43. Alkene intermediate 45 was afforded through the alkylation, hydrolyzation, and dehydration, followed by reduction and hydrolyzation. With compound 46 in hand, epimerization also occurred, resulting in a single β-vinyl product. The target compound 42 is finally transformed under the same conditions as the first route.
Frontiers in Chemistry | www.frontiersin.org March 2022 | Volume 10 | Article 882404 5 shown in Scheme 4, the unsaturated compound 66 was obtained from 65 by isomerization to its Δ 8 isomer with HC1/CHC1 3 . Regioselective allylic oxidation of 66 provided ketene 67. It was refluxed with p-toluene sulfonyl hydrazine in ethanol to obtain tosylhydrazone 68 and treated with catechol borane and sodium acetate. Double bond isomerization rearrangement was used, and Δ7,8-olefin 69 was obtained. Subsequently, the 4α-ester group of compound 69 was reduced by lithium aluminum-hydrogen to yield primary alcohol, and hydroxyl was protected after removing the methyl sulfonyl and fulguration. Finally, the target product (−)-(9β-H)-pimara-7,15-diene (64) was obtained by desulphurization with liquid lithium ammonia.
Frontiers in Chemistry | www.frontiersin.org March 2022 | Volume 10 | Article 882404 6 ketone (±)−70, and 71 was gained via several transformations in good yield. Then, the hydroxyl group was oxidized. After the Witting olefination and deprotection, vinyl product 72 was obtained. The hydroxyl group of 72 was removed to get the desired derivative 73. It possesses β-vinyl groups at C-13. After reducing 74 by catechol borane, under the presence of sodium acetate, the desired 9,10-syn tricyclic compound (±)−3α-hydroxy-9β-pimara-7,15-diene (75) was provided, which was considered a putative intermediate of momilactones and other diterpene phytoalexins in rice. It can be converted into 76 and momillactone A (1). In these syntheses, it furnished the configuration of the C-13 quaternary center using a stereoselective approach, and 9,10-syn tricyclic skeleton was constructed via rearrangement. This methodology would also apply to the synthesis of 9β-H pimaranes.
Fusidane triterpenes are a relatively small family of natural steroidal antibiotics, including fusidine, helvolic acid, and fusidic acid. These compounds have a unique chair-boat-chair ABC tricyclic ring system seen as a sort of 9β-pimara skeleton (Caron and Deslongchamps, 2010). In 2014, the intermolecular/transannular Michael reaction was first applied to the synthesis of ABC-ring in fusidane triterpenes by Fujii and Nakada (Fujii and Nakada, 2014). In Scheme 7, they developed the stereoselective intramolecular Michael reaction of compound 87 with L-Selectride to provide compound 88 (Scheme 7).
Compound 88 was performed with benzyl thiol and potassium carbonate affording the benzyl thioester 89. It was then converted to aldehyde 90 by Fukuyama reduction. Enone 91 was prepared via HWE reaction of aldehyde 90 and keto phosphonate 92. The dimethyl acetal 93 was afforded from 91, followed by reduction, and Dess-Martin oxidation gave aldehyde 94. The intramolecular Cr-mediated reaction of compound 94 was optimized when the reaction was performed in THF/DMF mixture, offering sole product 95 (70%). After that, oxidation of compound 95 provided the bis-enone 96, the substrate for intermolecular/transannular Michael reaction cascade. Then, they carried out the reaction of compound 96 under several conditions. Annulation product 97 was formed when thiophenol and DBU were used in methanol at 0°C in a 73% yield.
Germain and Deslongchamps (Germain and Deslongchamps, 2002) accomplished the first total synthesis of (±)-momilactone A (1) via a Diels-Alder reaction . Scheme 8 shows that the condensation was accomplished from conjugated olefins 98 and vinylaldehydes 99 with 88% yield to give diethylisomers 100. Subsequently, MOM ether was obtained from 100 via the protection, followed by selective desilication of primary hydroxyl ether to obtain compound 102. Trans-syn-trans tricyclic compound 103 was offered by Diels-Alder reaction with stereoselectivity under reflux in cesium carbonate acetonitrile solution. In a word, a series of conversions of 100 provided the diastereoisomer 103 in the chairboat-chair configuration, which is consistent with (±)-momilactone A (1). The target product was obtained through linear strategy transformation starting from intermediate 103. Malonate compound 103 underwent partial hydrolysis and several functional group transformations to afford intermediate 104. Then, the double bond addition was performed under the action of NBS and silver acetate to obtain bromoacetate 109 with high stereoselectivity, followed by the Dess-Martin oxidation and Wittig reaction to obtain the alkenone. Under the condition of acetic acid-water, intramolecular esterification was performed. Moreover, the hydrolysis of acetyl ester was carried out to obtain hydroxylolactone 111. Then, the target product (±)-momilactone A (1) was obtained by the carbonyl αmethylation and dehydration of lactone.

SUMMARY AND FURTHER PROSPECTS
Some synthetic strategies have been reported about the construction of the 9β-H piamarane skeleton, such as Diels-Alder reaction, Michael addition, and catechol borane reduction. They carried out the syntheses of the skeleton and the intermediates in natural products using simple procedures. The asymmetric totals synthesis of 9β-H piamaranes has not been reported so far. A new approach must be applied to the natural products in 9β-H pimaranes.

AUTHOR CONTRIBUTIONS
YZ collected and organized all literature about 9β-H pimarane diterpenoids and reviewed for abstract, introduction, some 9β-H pimarane skeleton, and momilactones syntheses. ML prepared all the scheme and references, summary, and further prospects. QL reviewed Coates's synthesis of (9β-H)-pimara-7,15-diene and De Groot's first synthesis of 4,4-dinor-(9β-H)-pimara-7,15-diene. JH reviewed all literature and gave significant discussion. YC reviewed the synthetic efforts towards 9β-H pimarane diterpenoids in the past three decades. He summed up very beautiful reaction schemes.