# Stereodivergent Total Syntheses of (+)-Mycaperoxides C, D, G Methyl Ester and (-)-Mycaperoxide B

Mansour Kerim, Laurent Evanno, Laurent Ferrié

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Mansour Kerim, Laurent Evanno, Laurent Ferrié. Stereodivergent Total Syntheses of (+)-Mycaperoxides C, D, G Methyl Ester and (-)-Mycaperoxide B. Chemistry - A European Journal, 2023, 29 (6), 10.1002/chem.202203004. hal-04250595

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# Stereodivergent Total Syntheses of (+)-Mycaperoxides C, D, G Methyl Ester and (-)-Mycaperoxide B

Mansour D. Kerim, Laurent Evanno, and Laurent Ferrié*

[a] Dr. M. D. Kerim, Dr. L. Evanno, Dr. L. Ferrié
BioCIS
CNRS, Université Paris-Saclay,
Bâtiment Henri-Moissan, 17 avenue des Sciences, 91400 Orsay (France)
E-mail: laurent.ferrie@universite-paris-saclay.fr

Supporting information for this article is given via a link at the end of the document.

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**Abstract:** Mycaperoxides are natural endoperoxides isolated from different Mycale genus sponges, showing significant antiviral or antibacterial activities. We report herein the first total syntheses of representative congeners of this family from sclareol using a stereodivergent approach. Thus, an innovative oxidative ring expansion of cyclobutanol was used to bring the 1,2-dioxane subunit, and a Mukaiyama aldol reaction on peroxycarbenium species was utilized to install the propionic acid subunit. During the study toward (+)-mycaperoxide D methyl ester (2), the isolation of the eight possible diastereomers under their ethyl thioester form allowed to build a pertinent database for further NMR assignment studies. Thus, we completed the total syntheses of (+)-mycaperoxides D, C, G methyl ester, and (-)-mycaperoxide B in 11 to 15 steps, confirming their original assignment.

## Introduction

The endoperoxide motif is an uncommon chemical function in natural products. However, a relatively large group of marine norsesterterpene metabolites represent a significant class of natural endoperoxides.[1–3] Indeed, more than 70 members have been isolated from various sponges of the class Demospongiae, including the genera *Prianos*, *Sigmosceptrella*, *Lacuntrulia*, *Diacarnus* or *Mycale*. Structurally, these endoperoxides have a common backbone consisting of a 1,2-dioxane ring substituted by a propionic acid subunit on one side and a sesquiterpene subunit connected *via* a methylene bridge on the other side. The main difference between all members lies in the nature of the sesquiterpene side chain and, in particular, the degree of cyclization of the chain, the intervention of methyl transpositions, and the enantiomeric series of this chain. The absolute configuration of the stereogenic centers of this subclass of

natural products is not identical from one product to another, depending mainly on their origin. Despite many members, this subclass has been barely studied at the synthetic level. Indeed, Harwood reported several synthetic studies towards the total synthesis of mycaperoxide B, leading, with difficulty, to the obtention of four inseparable diastereomers, in a total of 16 steps, sharing the gross structure of the target. However, none of them corresponded to the natural product.[4–7] Later, Seifert reported the total synthesis of diacarnoxide C in about 20 steps but obtained as an inseparable mixture of *cis* and *trans*-1,2-dioxanes with epimerization at C₆ (Figure 1).[8] Lately, Wu and co-workers reported the enantioselective total synthesis of (+)-Muqubilin from seudenol, by adding hydrogen peroxide to a chiral epoxide. Still, a long synthetic sequence was necessary to reach this objective (29 linear steps).[9]

Recently, we have developed a synthetic method to construct 1,2-dioxanes from the oxidative expansion of cyclobutanols,[10] followed by the alkylation of the resulting peroxyacetals.[10–12] Thus, we felt it would be particularly well suited to the total synthesis of several members of this family of norsesterterpene endoperoxides. Mycaperoxides were targeted as some members have been reported to have significant antiviral activities ($IC_{50}$ = 0.25-1.0 µg/mL against vesicular stomatitis virus and herpes simplex virus type-1) and antibacterial properties (inhibition of the growth of gram-positive bacteria *Bacillus subtilis* and *Staphylococcus aureus*).[13]

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Mycaperoxides A-D and G, and diacarnoxide C.</figcaption></figure>

## Results and Discussion
In terms of synthetic access, these molecules, mainly mycaperoxides B, C, D, and G, would be strategically accessible from sclareol (Salvia sclarea) used as starting synthon. Concerning the chirality control strategy, mycaperoxide B (4) would be directly accessible from sclareol as the latter corresponds to the proper enantiomeric series of the decalin moiety. For the mycaperoxides C, D, and G, their antipodes (ent-mcaperoxides C, D, and G) would be accessible by total synthesis from sclareol. For these three compounds, methyl esters (1), (2), and (3) were targeted as the natural products were isolated and characterized in this form after derivatization with diazomethane.[14,15] Thus, a stereodivergent total synthesis was collectively designed for all these products. They could be obtained by a Mukaiyama aldol reaction performed on an acetoxy-endoperoxyketal.[10–12] The 1,2-dioxane ring of the latter could be constructed from a cyclobutanol by ring expansion with molecular oxygen mediated by Co(acac)₂.[10] The cyclobutanol could be easily obtained from a methyl ketone derived from sclareol. The four required decalins would thus be prepared from the same starting synthon via divergent functional arrangements.

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Stereodivergent strategy from sclareol to access ent-mcaperoxides C, D, and G, and mycaperoxide B</figcaption></figure>

The synthesis of the different targeted mycaperoxides consisted first of the functionalization of sclareol (5). The latter underwent an oxidative cleavage with KMnO₄ leading to methyl ketone 6.[16] A Wittig olefination then led to the formation of cyclopropylidene 7,[17] the precursor of mycaperoxide D. To obtain the other congeners, a hydroxyl elimination gave rise to a mixture of isomers 8 and 8' in an 85:15 ratio and thus gave access to the other required decalins. Epoxidation of the 8/8' mixture followed by Wittig olefination provided the three separable isomers **9a**, **9b**, and **9c** in a 61:30:9 ratio. Compounds **9a** and **9b** were subjected

to reduction with LiAlH₄. From **9a**, hydride attack led exclusively to **10a**, the precursor of mycaperoxide B and ent-mcaperoxide G. The same reaction performed on **9b** gave only **10b**, the precursor of ent-mcaperoxide C. The regioselectivity of hydride attack is in agreement with the Fürst-Plattner rule.[18–20] (Scheme 2)

<figure><img src="image_6.png" /><figcaption>**Scheme 2.** Divergent synthesis of sesquiterpene moiety of ent-mcaperoxides C, D, G and mycaperoxide B from sclareol.</figcaption></figure>

The synthesis of ent-mcaperoxide D was firstly studied for its better accessibility. Thus, after the protection of the hydroxyl in the form of a silyl ether (TES), the cyclopropylidene was epoxidized. *In situ* acid-catalyzed rearrangement led then directly to cyclobutanone **11**. After reduction with NaBH₄, the resulting cyclobutanol underwent a ring enlargement reaction in the presence of Co(acac)₂, affording 1,2-dioxanol **12** in good yield.[10] Although any initial stereochemistry at C3 and C6 was lost during the process due to hydroperoxyacetal equilibrium and radical mechanism of the reaction, we observed that the decalin slightly induced stereoselectivity during the cyclobutanol oxidative ring opening (see below for further discussion). The hydroxyl was acetylated in the presence of pyridine,[21] and the resulting acetoxy-endoperoxyacetal **13** reacted with silylketenethioketal **14**[22] as well as a catalytic amount of Sc(OTf)₃.[10] At this step, the first resolution of diastereomers [2,3-syn/2,3-anti and cis/trans-1,2-dioxanes] was thus performed by silica gel chromatography. Therefore, three fractions (F1, F2, and F3) were obtained in 8%, 32%, and 31% yield, respectively; each containing a mixture of defined diastereomers among the eight possible (Scheme 3, A). The stereoselectivity of the reaction was estimated to be 4:1 in favor of cis-1,2-dioxanes, but no selectivity was observed for the syn/anti relationship at C₂-C₃. After cleavage of the silyl ether by acid methanolysis performed independently on each fraction (F1, F2 and F3), a further separation of diastereomers was again done to deliver thioesters **16a-h**. All cis-1,2-dioxanes could be isolated as single stereoisomers but, trans-1,2-dioxanes, do not allow a separation of their 2,3,6-epimer and were thus obtained as a mixture of two diastereoisomers. For the trans-1,2-dioxanes mixtures, a selectivity about 55:45 in favor of one particular 2,3,6-isomer, allowed the differentiation of carbon for attribution.
The structures of the different diastereomers were attributed as
follow by using Capon's empirical rules[23] based on the ¹³C NMR
chemical shift. Firstly, *cis/trans*-1,2-dioxanes were assigned
thanks to ¹³C NMR and the characteristic chemical shifts of the
methyl groups at position C₆ (20.0 - 21.0 ppm for *trans*-dioxanes
vs. 23.5 - 23.7 ppm for *cis*-dioxanes) and of position C₇ (43.0 -
43.9 ppm for *trans*-dioxanes vs. 37.7 - 39.1 ppm for *cis-
dioxanes*). Secondly, the 2,3-*syn* or 2,3-*anti* configurations were
then attributed based on the characteristic chemical shifts of the
methyl groups at position C₂ (13.2 - 13.3 ppm for 2,3-*anti* vs.
14.4 - 14.9 ppm for 2,3-*syn* products) and of position C₄ (23.4 -
23.7 ppm for 2,3-*anti* vs. 22.6 - 22.8 ppm for 2,3-*syn* products).
Thirdly, 2,3,6-epimer pairs [2,3-*syn*, *trans*-dioxane **16a** vs. **16b**,
2,3-*syn*, *cis*-dioxane **16c** vs. **16d**, etc.] were the most difficult to
discriminate due to the slight chemical shift differences due to
the spacer between decalin and 1,2-dioxane units. Structure of
*cis*-dioxanes **16g** and **16h** were deduced from the similarities
observed on ¹³C NMR with natural (-)-mycaperoxide D.
Although tight chemical shift differences at C₇ and C₈, these
positions are characteristic (± 0.2 - 0.8 ppm difference for each
2,3,6-epimer pairs) and *cis*-dioxanes **16c** and **16d** were next
assigned. A more significant difference can be observed at C₁₁
for *cis*-dioxanes **16c** and **16g** versus *trans*-dioxanes **16d** and
**16h** (+1.6 ppm), which is indicative of a hydrogen bond of the
hydroxyl at C10. Indeed, DFT calculation at the B3LYP/6-
31G(d,p) showed that among the lowest energy conformers, an
evident hydrogen bond exists between this hydroxyl group and
carbonyl group at C1 with a distance of 2.18 Å (Scheme 2). This
particularity also explains the ability of *cis*-dioxanes **6c-d** and
**6g-h** to be isolatable as lone diastereomers compared to
protected compounds **15a-h** and *trans*-dioxanes where this
hydrogen bond is not possible. Thus, collectively taking into
account the ¹³C-NMR chemical shifts at positions C₇, C₈, and C₁₁,
2,3,6-epimers **16a**, **16b**, **16e**, and **16f** were assigned.

<figure><img src="image_7.png" /><figcaption>**Figure 2.** Evidence of a hydrogen bond on diastereoisomer **16h** between the carbonyl group of thioester at C<sub>1</sub> and hydroxy group at C<sub>10</sub>. DFT Energy minimization at the theoretical level B3LYP/6-31G(d,p).</figcaption></figure>

Among the eight diastereomers **16a-h**, thioester **16h** was
spectroscopically the best match with mycaperoxide D methyl
ester. Thus, in two steps, **16h** was transformed into methyl ester
**2** by transesterification. Spectral data of synthetic **2** were in
agreement with the description of the natural product and the
antipode sign of the optical rotation compared to those of natural
mycaperoxides D methyl ester [+68 (c 0.25, CHCl<sub>3</sub>); lit:[13] –52 (c

0.3, CHCl₃)] confirmed the original assignment of mycaperoxide
D (Scheme 3, A).

Afterward, the synthesis of (+)-mycaperoxide C methyl ester (1) was investigated. Thus, endoperoxycetal 19 was obtained in five steps from 10b, using a sequence of ring-expansion of cyclobutanone 17 producing endoperoxide 18, similar to those described for the total synthesis of 2. A notable difference between the two synthetic routes lies in using TMS as the protecting group for the hydroxy group at C10. The conformation of 10b did not allow the introduction of TES; consequently, only the use of TMS-triflate with Et3N succeeded in the protection step. However, the use of TMS led to an unexpected consequence. Upon Mukaiyama-type aldol reaction, in the presence of Sc(OTf)3 on 19, the hydroxyl at C10 was eliminated. The use of less active Y(OTf)3[11] allowed the aldolization to be carried out without significant side-reaction (Scheme 3, B). The selectivities were comparable for the stereocenters at C6 and C2 to that was obtained in the total synthesis of 2. Again, during this synthesis, the formation of the cis-dioxane rings (C3) was favored over the trans one, with a 2:1 cis:trans ratio. As described in the total synthesis of 2, we obtained a mixture of diastereomers distributed over three fractions. The fraction F3 was also containing the isomer corresponding to the natural product according to ¹³C NMR data. After deprotection of the alcohol function, the compound of interest 21h was separated from its isomer 21g. The final transesterification performed on 21h led to the synthesis of the (-)-mycaperoxide methyl ester C (1). Spectral data matched to the described natural product and, again, the optical rotation [+50 (c 0.198, CHCl3); lit:[13] –71 (c 1.1, CHCl3)] confirmed the synthesis of ent-mycaperoxide C methyl ester and the original assignment of mycaperoxide C (Scheme 3, B).

Regarding (+)-mycaperoxide methyl ester G (3) and (-)-mycaperoxide B (4), their total synthesis was planned from compound 10a. The same reaction sequence used to prepare intermediates 13 and 19 (Schemes 3A and 3B) led to the formation of 24 in five steps. However, here again, a particular reactivity of substrate 10a led us to some adaptations. Hydroxyl in position C9 was reluctant to protection and systematically underwent an elimination reaction during all attempts to form a silyl ether. It was thus chosen to leave it free for the rest of the synthesis, its tertiary position inducing a steric hindrance making it less accessible and therefore less reactive. Indeed, the acetylation of 23 was carried out chemoselectively on the 1,2-dioxane hydroxyl. To avoid further elimination reactions of the hydroxyl at the C9 position during the Mukaiyama aldol reaction, Y(OTf)3 was used again, which led to the obtention of two fractions, F1 and F2 in 87% yield (1,2-dioxane cis:trans = 3:2; 2,3-syn:2,3-anti = 1:1). The fraction of interest, F2, contained a mixture of three products, including isomers 25e and 25f, which corresponded to the relative stereochemistry of mycaperoxide B (4) and (+)-mycaperoxide G methyl ester (3) respectively. The utilization of preparative HPLC for fraction F2 led to the separation of isomer 25h[24] from the mixture of isomers 25e/25f. Thioesters 25e and 25f were saponified, providing mycaperoxide B (4) in an inseparable mixture with 26e isomer in about a 53:47 ratio. Assignment of isomers 25e and 25f (or 26e and 4) was tricky due to tenuous differences in the ¹³C NMR chemical shifts for those compounds [δ = 0.1 ppm only for three carbons (C₇, C₁₀-Me, and C₁₈)]. Data for synthetic 4 were slightly closer to the reported natural mycaperoxides B than isomer 26e, thus seeming to confirm the original statement. (Scheme 3, C)
<figure><img src="image_8.png" /><figcaption>**Scheme 3.** Stereodivergent total of mycaperoxides: A (+)-mycaperoxide D methyl ester; B (+)-mycaperoxide C methyl ester; C (+)-mycaperoxide G methyl ester and (-)-mycaperoxide B.</figcaption></figure>
From the fraction F2 containing isomers **25e-g**, elimination of hydroxyl group induced by the action of SOCl₂ led selectively to the tetrasubstituted olefin. Compound **27g** and a mixture of **27e** and **27f** were thus obtained. The combination of **27e/27f** was transesterified, finalizing the synthesis of the (+)-mycaperoxide methyl ester G (**3**) as a mixture with **28e**. As for **26e** and **4**, the ¹³C NMR data for products **3** and **28e** were very close. The most significant differences were observed for the ethylenic carbons at C₉ and C₁₀ [δ = 0.2 ppm]. The synthetic product with NMR signals matching the most with the natural product was attributed to structure **3** (Scheme 3, C).

## Conclusion

In summary, we were able to construct for the first time several members of the mycaperoxides, about thirty years after their discovery, employing an oxidative expansion of cyclobutanol to 1,2-dioxane followed by a Mukaiyama aldol reaction on a peroxycarbenium species as key steps. Thus, the methyl esters of (+)-mycaperoxides C (**1**) and D (**2**) were obtained in 15 and 11 steps, respectively. The methyl ester of (+)-mycaperoxide G (**3**) and (−)-mycaperoxide B (**4**) were obtained in 14 and 13 steps but combined with their respective 2,3,6-epimer. Original assignments were thus confirmed. We highlighted the utility of yttrium compared to scandium in the Lewis acid-catalyzed Mukaiyama aldol reaction, which allowed smoother conditions reducing elimination side reaction with tertiary alkoxides. Although our approach did not allow us to control all the stereogenic centers of the synthetic targets, the different mycaperoxides studied were obtained efficiently accordingly to literature precedents.[⁷,⁸] In addition, obtaining several well-identified diastereomers provides a valuable NMR database for the assignment of new natural endoperoxides of the same family. 2,3-syn/2,3-anti and cis/trans-1,2-dioxanes relationships are easily determined by this method. However, the assignment of the 2,3,6-epimers is more challenging, leading to small differences in NMR spectral data. Moreover, the affected positions are also a function of the nature of the decalin unit, which makes a general rule impossible for these pairs of diastereomers. This project also underlines the lack of enantiomeric methods to build organic peroxides, with few reported examples.[²⁵⁻²⁷] Therefore, significant work must be undertaken to overcome the actual limitations in the field.[²⁸] Such effort will be reported from our laboratory in due course.

## Experimental Section

General information, detailed experimental procedures, characterization data, cartesian coordinates of **16h**, tables of NMR data for each mycaperoxides and copies of ¹H and ¹³C NMR spectra of all compounds are in the Supporting Information.

## Acknowledgements

We thank the CNRS for financing the project MYCOXY through a call of project on natural substances. We thank Karine Leblanc and Somia Rharrabti (BioCIS, Châtenay-Malabry) for HRMS analysis and preparative HPLC support, and Jean-Christophe Jullian and Rémi Franco (BioCIS, Châtenay-Malabry) for NMR services.

**Keywords:** Endoperoxide • NMR analysis • Peroxycarbenium ions • Ring-expansion • Total synthesis

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