Synthesis of the Tetracyclic Spiro-naphthoquinone Chartspiroton

Chartspiroton is a recently discovered naphthoquinone natural product that features a spiro-fused benzofuran lactone. We report its first synthesis via an 11-step linear sequence. The sterically hindered tetra-ortho-substituted biaryl subunit was installed by base-induced ring expansion of a readily available 1,3-indandione. This step also liberated the fully substituted naphthalene core unit at the same time. The unique spiro-fused benzofuran lactone of the natural product was constructed via late-stage oxidation of an advanced naphthoquinone.

I n 2020, Hu and co-workers reported the isolation of chartspiroton (1) from the endophytic Streptomyces sp.SH-1.2-R-1 in Dendrobium off icinale (Figure 1A). 1 Dendrobium off icinale is well known in traditional Chinese medicine and has demonstrated various clinical benefits, such as hepatoprotective, anticancer, hypoglycemic, antifatigue, and gastric ulcer protection. 2,3From a structural perspective, chartspiroton displays a unique 6/6/5/6 tetracyclic polyketide scaffold with a spiro-fused benzofuran lactone moiety 1 and showcases structural elements that biosynthetically relate with elsamicin B (2) and its aglycon chartarin (3).Together with the gilvocarcins, as exemplified by defucogilvocarcin M (4), this natural product family stands out for its potent antibacterial and antitumor properties. 4,5−15 As part of our continuous effort to develop practical and scalable methods to synthesize polysubstituted, highly functionalized (hetero)arenes, we previously set out to investigate a variety of ring expansion reactions. 16,17While this ultimately enabled access to the polyketide natural products chartarin (3) 16 and defucogilvocarcin M (4), 17 we considered those strategies to be unsuited for reaching the more complex structure of chartspiroton (1).
As a result, we evaluated alternative ring expansion strategies for their potential to produce the desired molecular architecture.This guided us to 2-arylated 1,3-indandiones as valuable precursors to tetra-ortho-substituted biaryl subunits. 18,19In seminal work by Radulescu and Gheorgiu, it was shown that indanones undergo acid-and base-mediated ring expansion to tetrasubstituted naphthalenes. 18More recently, Zhang and co-workers extended this chemistry to the construction of 1,4-naphthoquinones via a copper(I)-mediated insertion of alkenes into 2-aryl-1,3-indandiones. 19The implementation of this ring expansion strategy to the retrosynthesis of chartspiroton (1) led to removal of the spiro-lactone and revealed biaryl 5a as our first key intermediate (Figure 1B).Ring contraction of the naphthalene component produced the 2,2-disubstituted 1,3-indandione 6, which was further traced back to 7. The 2-aryl substituent of 7 was envisioned to be derived from the base-mediated condensation of methoxyisobenzofuranone 8 and aldehyde 9.
We initiated our synthetic studies toward chartspiroton (1) by preparing known methoxyisobenzofuranone 8 and o,odisubstituted aldehyde 9 (Scheme 1).The former was accessible through a two-step sequence starting from inexpensive 3-hydroxybenzoic acid. 20,21The aldehyde 9 was synthesized in four steps from 2-bromo-4-fluorotoluene involving formylation 22 and benzyl protection of the corresponding phenol (for details, see the Supporting Information).Having acquired both components, the aldehyde 9 underwent basic condensation with 8 to furnish the corresponding 1,3-indandione 7 in 58% yield. 23As reported by Freedman and co-workers, the use of ethyl propionate as solvent effectively removed the generated water and led to improved yields. 24While both ortho-substituents of aldehyde 9 were tolerated in this reaction, we encountered difficulties when attempting the C2-functionalization of the 1,3indandione.We concluded that steric encumbrance arising from the Br-and OBn-substituent prevented any further Calkylation.Instead, we observed exclusive formation of the corresponding O-alkylated intermediates 10a and 10b in 90% overall yield when reacting 7 with allyl bromide under basic conditions (K 2 CO 3 ).The inconsequential mixture of regioisomers 10a and 10b were separated by flash column chromatography to allow for structure validation of 10b via single-crystal X-ray analysis.Both regioisomers underwent the subsequent [3,3]-Claisen rearrangement to give the Calkylated 1,3-indandione 11 in 76% yield.Ozonolysis of the terminal alkene followed by reductive workup employing dimethyl sulfide gave the corresponding aldehyde 12. Next, 12 was subjected to a two-step sequence involving Pinnick− Lindgren oxidation 25,26 and methylation to give the corresponding methyl ester 6.
With methyl ester 14 in hand, we found a suitable precursor to investigate the key biaryl formation through the envisioned ring expansion reaction.Gratifyingly, treatment of 6 with potassium hexamethyldisilazide (KHMDS) at −78 °C induced smooth ring expansion to reveal the tetra-ortho-substituted biaryl subunit.Other bases, such as sodium hydride, triethylamine, or potassium tert-butoxide, also in combination with Lewis acids (e.g., titanium tetrachloride), were screened as well, but turned out to be inferior.Mechanistically the reaction is assumed to proceed via an intramolecular cyclopropane formation resulting from the nucleophilic attack of the ester enolate I.The attack of I can occur at either of the carbonyl functionalities of the1,3-indandione (indicated as pathway A or B in Scheme 1).As indicated for II (pathway A), collapse of the cyclopropane entails regioselective ring expansion and aromatization to give 5a (42%) as the major product, together with its 1,4-naphthoquinone 5b (7%), which was validated via single-crystal X-ray analysis.Quantitative conversion of 5a to 5b was achieved upon exposure of 5a to ceric ammonium nitrate (CAN).For pathway B, attack of the enolate I occurred at the conjugated, and thus less reactive ketone.The obtained regiosimeric quinone 13 (24%) features an undesired orientation of the methoxy group with respect to the biaryl axis.The corresponding hydroquinone was also isolated in traces (for details, see the Supporting Information).It should be noted that attempts to construct the crucial biaryl unit employing a Heck reaction, conjugate addition, or Diels−Alder chemistry failed in our hands (see the Supporting Information for a graphical summary).
Having obtained the advanced biaryl 5b, we proceeded to replace the aromatic bromide substituent.To our surprise, all attempts to directly install the carboxylic acid function were met with failure.Therefore, we chose to couple a furan as a masked carboxylic acid.To this end, a Suzuki−Miyaura coupling reaction of 5b with potassium furan-2-trifluoroborate 14 provided furan 15 in 50% yield (Scheme 2).Analysis of the remaining material showed that the coupling reaction was Scheme 1. Installation of the tetra-ortho-substituted biaryl subunit through ring expansion of a 2,2-disubstituted 1,3indandione.

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accompanied by the formation of a naphtho[1,2-b]benzofuran byproduct in up to 10% yield (for details, see the Supporting Information).Despite screening different palladium catalysts, bases, and solvents, the formation of the byproduct could not be completely suppressed.
The ensuing oxidative cleavage of the furan with ruthenium tetroxide yielded the desired carboxylic acid 16 in up to 58% yield.In addition, an inseparable mixture of 16 and spirolactone 17a was obtained.Structure elucidation through singlecrystal X-ray analysis was crucial in revealing that 17a has the opposite relative stereochemistry at C7 compared with that of chartspiroton (1).In contrast, 17b, which possesses the desired stereochemistry at C7, was not obtained via the oxidative cleavage of the furan.Although it is possible that traces of 17b were also formed, we did not detect it in the crude NMR.While the isolation of 17a demonstrated the possibility of accessing the spiro-lactone moiety in a single step, the incorrect stereochemistry required further investigation of the oxidative spiro-lactonization.
Upon exposure of naphthoquinone 16 to epoxidation conditions (hydrogen peroxide, sodium carbonate), direct formation of the spiro-lactones 17a and 17b was observed (Scheme 3).The corresponding epoxides were not observed under these conditions.
Unfortunately, spiro-lactone 17a featuring the incorrect stereochemistry at C7 was favored over 17b (17a/17b = 2:1).Nonetheless, subjecting the minor spiro-lactone 17b to boron tribromide led to global deprotection of the methyl and the benzyl ether to give chartspiroton (1) as the sole product in 43% yield.In line with our expectations, exposure of spirolactone 17a to the same conditions produced 7-epichartspiroton (18).After purification, 18 underwent spontaneous conversion into chartspiroton (1) upon standing in deuterated dimethyl sulfoxide (DMSO-d 6 ).We assume that the free phenol assists in isomerization via reversible lactone opening to furnish ortho-quinone methide 19, which can reclose to form chartspiroton (1). 27Spectroscopic data for synthetic chartspiroton (1) were identical in all respects to those reported in the literature. 1 In summary, we have successfully achieved the first reported synthesis of the natural product chartspiroton through an 11step linear sequence.To establish the tetra-ortho-substituted biaryl unit, we employed a base-induced ring expansion reaction of a 2,2-disubstituted-1,3-indandione.The unique spiro-fused benzofuran lactone moiety of the natural product could be installed by a late-stage oxidative cyclization sequence.Additionally, we could demonstrate that the spirolactone with the incorrect relative stereochemistry spontaneously equilibrates at the stage of the phenol to give chartspiroton.Future studies will explore the ring expansion of related indandiones and their use for the synthesis of glycosylated congeners.