Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.

Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia¹ from the Pacific Ocean. (+)-Halenaquinone (1),^2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)^4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)^6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)^8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua² and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.^4a and the Truk Lagoon sponge Adocia sp.,^4b and they show cardiotonic,^4a,c cytotoxic,^4b,i antifungal,⁴ⁱ antimalarial,^4j and antitumor^4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,^4d topoisomerases I^4e and II,^4f myosin Ca²⁺ ATPase,^4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.^4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,^{3a,d,e,5a–c,e,g} furan ring transfer,^5b Heck,^{3b,c,5f,7,9b,d} palladium-catalyzed polyene cyclization,^5d Pd-catalyzed oxidative cyclization,^3f and hydrogen atom transfer (HAT) radical cyclization^9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.^10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction^12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)^4b,5c and our previous studies,⁷ the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.^10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,^11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.^11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (†).Attempts of organocatalytic desymmetric intramolecular Michael addition^a

Entry	Cat. (equiv.)	Additive (equiv.)	Solvent	Time	Yield/d.r. at C2b	e.e.c
1	(R)-cat.I (0.5)	—	Toluene	10.0 h	52%/10.3 : 1	14a: 96%; 14b: 75%
2	(R)-cat.I (1.0)	—	Toluene	4.0 h	60%/10.0 : 1	14a: 93%; 14b: 75%
3	(R)-cat.I (1.0)	—	MeOH	4.0 h	47%/5.5 : 1	14a: 86%; 14b: −3%
4	(R)-cat.I (1.0)	—	DCM	10.0 h	28%/24.0 : 1	14a: 91%; 14b: 7%
5	(R)-cat.I (1.0)	—	Et2O	10.0 h	22%/22.0 : 1	14a: 91%; 14b: 65%
6	(R)-cat.I (1.0)	—	MeCN	10.0 h	12%/2.6 : 1	14a: 90%; 14b: 62%
7	(R)-cat.I (1.0)	—	Toluene/MeOH (2 : 1)	4.0 h	47%/10.0 : 1	14a: 87%; 14b: −38%
8d	(R)-cat.I (1.0)	AcOH (5.0)	Toluene	4.0 h	60%e/2.1 : 1	14a: 96%; 14b: 95%
9d	(R)-cat.I (0.5)	AcOH (2.0)	Toluene	6.0 h	75%e/4.0 : 1	14a: 97%; 14b: 91%
10d	(R)-cat.I (0.5)	AcOH (0.2)	Toluene	6.0 h	73%e/4.3 : 1	14a: 96%; 14b: 92%
11f	(R)-cat.I (0.5)	AcOH (0.2)	Toluene	6.0 h	75%e/8.0 : 1g	14a: 95%; 14b: 93%
12h	(R)-cat.I (0.2)	AcOH (0.2)	Toluene	9.0 h	80%i/6.0 : 1j	14a: 97%; 14b: 91%

Open in a separate window^aAll reactions were performed using 13 (5.8 mg, 0.03 mmol, 1.0 equiv., and 0.1 M) and a catalyst at room temperature in analytical-grade solvents, unless otherwise noted.^bThe yields and diastereoisomeric ratios (d.r.) were determined from the crude ¹H NMR spectrum of 14 using CH₂Br₂ as an internal standard, unless otherwise noted.^cThe enantiomeric excess (e.e.) values were determined by chiral high-performance liquid chromatography (Chiralpak IG-H).^dCompound 13: 9.6 mg, 0.05 mmol, and 0.1 M.^eIsolated combined yield of 14a + 14b.^fCompound 13: 192 mg, 1.0 mmol, and 0.1 M.^gThe d.r. values decreased to 1 : 1 after purification by silica gel column chromatography.^hCompound 13: 1.31 g, 6.82 mmol, and 0.1 M.ⁱIsolated combined yield of 12a + 12b.^jThe d.r. values were determined from the crude ¹H NMR spectrum of 12 obtained from the one-pot process.We initially investigated the desymmetric intramolecular Michael addition of 13 using (S)-Hayashi–Jørgensen catalysts,¹⁷ and found that the absolute configuration of the obtained cis-decalin was opposite to the required stereochemistry of the natural products (see Table S1 in the ESI^†). In order to achieve the desired absolute configuration of the angular methyl group at C-6, (R)-cat.I was used for further screening. In the presence of this catalyst, the intramolecular Michael addition afforded 14a (96% e.e.) and 14b (75% e.e.) in a ratio of 10.3 : 1 and 52% combined yield (entry 1, 11d,e we added 5.0 equivalents of acetic acid (AcOH) to a solution of compound 13 and (R)-cat.I in toluene, which improved the enantiomeric excess of 14b to 95% with a 60% combined yield (entry 8, †). Further adjustment of the (R)-cat.I and AcOH amount and ratio (entries 9–12, †) as the dienophiles to prepare the tetracyclic naphthalene framework 10 through a sequence of Ti(Oi-Pr)₄-promoted PEDA, dehydration, and aromatization reactions (Scheme 2). When using 3,6-dimethoxy-2-methylbenzaldehyde (11) as the precursor of diene, no reaction occurred between 12a/12a′ and 11 under UV irradiation at 366 nm in the absence of Ti(Oi-Pr)₄ (Scheme 2A). In contrast, the 1,2-dihydronaphthalene compounds 16a and 16a′ were successfully synthesized when 3.0 equivalents of Ti(Oi-Pr)₄ were used. Based on our previous studies,^13a,e the desired hydroanthracenol 15a was probably generated through the chelated intermediate TS-B and the cycloaddition occurred through an endo direction (Scheme 2B).¹⁸ The newly formed β-hydroxyl ketone groups in 15a and 15a′ could then be dehydrated with excess Ti(Oi-Pr)₄ to form enones 16a and 16a′. These results confirmed the pivotal role of Ti(Oi-Pr)₄ in this PEDA reaction: it stabilized the photoenolized hydroxy-o-quinodimethanes and controlled the diastereoselectivity of the reaction.Open in a separate windowScheme 2PEDA reaction of 11 and enone 12.Subsequent aromatization of compounds 16a and 16a′ with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) at 80 °C afforded compounds 10a and 10a′ bearing a fused tetracyclic B–C–D–E skeleton. The stereochemistry and absolute configuration of 10a were confirmed by X-ray diffraction analysis of single crystals (Scheme 3). The synthesis of (+)-xestoquinone (2) and (+)-adociaquinones A (3) and B (4) was completed by forming the furan A ring. Compound 10 was oxidized using bubbling oxygen gas in the presence of t-BuOK to give the unstable diosphenol 17a, which was used without purification in the next step. The subsequent acid-promoted deprotection of the acetal group led to the formation of an aldehyde group, which reacted in situ with enol to furnish the pentacyclic compound 18 bearing the furan A ring. The stereochemistry and absolute configuration of 18 were confirmed by X-ray diffraction analysis of single crystals (Scheme 3). Further oxidation of 18 with ceric ammonium nitrate afforded (+)-xestoquinone (2) in 82% yield. Following the same reaction process, (−)-xestoquinone (2′) was also synthesized from 10a′ in order to determine in the future whether xestoquinone enantiomers differ in biological activity. Further heating of a solution of (+)-xestoquinone (2) with hypotaurine (9) at 50 °C afforded a mixture of (+)-adociaquinones A (3) (21% yield) and B (4) (63% yield). We also tried to optimize the selectivity of this condensation by tuning the reaction temperature and pH of reaction mixtures (see Table S3 in the ESI^†). The ¹H and ¹³C NMR spectra, high-resolution mass spectrum, and optical rotation of synthetic (+)-xestoquinone (2), (+)-adociaquinones A (3) and B (4) were consistent with those data reported by Nakamura,^4a,g Laurent,^4j Schmitz,^4b Harada^5a,c and Keay.^5dOpen in a separate windowScheme 3Total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B.