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Feb 9, 2018 - ABSTRACT: An enantioselective total synthesis of blennolide D and the enantiomers of blennolide E and F is described using ... present in a vast amount of natural products predom- .... for the synthesized compounds (PDF).

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Enantioselective Total Synthesis of the Fungal Metabolite Blennolide D and the Enantiomers of Blennolide E and F Soundararasu Senthilkumar, Guillermo Valdomir, Dhandapani Ganapathy, Yun Zhang, and Lutz F. Tietze* Institute of Organic and Biomolecular Chemistry, Georg-August University Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany S Supporting Information *

ABSTRACT: An enantioselective total synthesis of blennolide D and the enantiomers of blennolide E and F is described using an enantioselective Wacker-type oxidation followed by the formation of the lactone moiety. For the introduction of the hydroxyl group in the γ-lactone, a TEMPO-mediated α-oxygenation was used which was followed by a benzylic oxidation and deprotection to give the desired compounds. In addition, an unknown diastereomer was synthesized. first enantioselective total synthesis of secalonic acid E (2) via a Suzuki-type dimerization with 99% enantioselectivity. In 2017, the Tietze group then published the first enantioselective total synthesis of the dimeric tetrahydroxanthone dicerandrol C (3c) (Figure 1).6 Another group of natural dimeric compounds with a biaryl moiety are blennolide H7 (4), phomopsis-H76 A,8 and gonytolide A9 as well as gonytolide B,9 which contain a chromanone core bearing a lactone ring. All four compounds have not yet been synthesized, but the monomeric precursor 5 of gonytolide A has recently been prepared by Sudhakar et al.,10 Brimble et al.,11 and Tietze et al.12 Recently, another group of interesting chromanones 6−8 (Figure 2) possessing a hydroxyl γ-lactone moiety have been isolated from Blennoria sp., an endophytic fungus from the succulent Carpobrotus edulis growing on La Gomera;13 biogenetically, they seem to be derived from blennolides A14 and B. They show some interesting biological activities such as the inhibition of Microbotryum violaceum and Chlorella f usca.13 These compounds have not yet been synthesized and their dimeric counterparts are unknown. Here, we describe the first total synthesis of blennolide D (6) and the enantiomers of blennolide E (7) and F (8). In addition, we have also prepared a so far unknown diastereomer of 6. As starting material for the synthesis of these compounds we used the chromane 11, which is easily accessible through an enantioselective Wacker type cyclization using (S,S)-i-PrBOXAX 1014 with 99% ee (Scheme 1).5,15 Compound 11


anthones and chromanones are common skeletons present in a vast amount of natural products predominantly isolated from different types of fungi, and many of them show a pronounced bioactivity.1 The most complex compounds of this type are dimeric tetrahydroxanthones as evidenced by secalonic acids 1 and 2 as well as the dicerandrols 3 (Figure 1).

Figure 1. Secalonic acid D (1), secalonic acid E (2), dicerandrols A−C (3a−c), and blennolide H (4).

In 1971, Whalley2 and in 2004 Bräse3 did some studies on the formation of the biaryl linkage in this type of compounds. The secalonic acids have been known for a long time; however, the first high-yielding access to secalonic acid A and D (1) was published by Porco et al.4 in 2014 using a Stille-type dimerization, and one year later, Tietze et al.5 described the © XXXX American Chemical Society

Received: February 9, 2018


DOI: 10.1021/acs.orglett.8b00487 Org. Lett. XXXX, XXX, XXX−XXX


Organic Letters

protected α-oxygenated diastereomers 18 and 19 in a 1.5:1 ratio with 60% yield (71% based on recovered starting material) (Scheme 1). However, all attempts to improve the yield by changing the amount of base and increasing the reaction time and the reaction temperature were unsuccessful. After some time the reaction stopped and did not go for completion. On the other hand, with oxodiperoxymolybdenum(pyridine) (hexamethylphosphoric triamide) (MoOPH)17 only traces of the desired hydroxylated compounds were obtained. The two diastereomers could easily be separated by column chromatography. Extensive 2D-NMR spectroscopic investigations revealed that the major diastereomer is the all-syn substituted chromane−lactone 18. For the necessary introduction of the keto moiety in 18 on the way to 6, a direct one-step oxidation procedure was not suitable. As will be shown later, a selective cleavage of the TMP group in the presence of a keto moiety could not be achieved. Therefore, first we removed the TMP group in 18 using Zn in acetic acid to give 20 and then protected the obtained free hydroxyl group as an acetate 22 (Scheme 2). With this

Figure 2. Structures of gonytolide C (5) and blennolides D−F (6−8).

Scheme 1. Synthesis of the Chromane−Lactone−TEMPO Adducts 13 and 14

Scheme 2. Synthesis of Blennolide D (6) and an Unknown Diastereomer

compound, an oxidation employing potassium permanganate in the presence of magnesium sulfate18 to give the desired ketone 24 was possible but the obtained yield of 35% (brsm) was less satisfying. To improve the yield we investigated the use of other reagents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),12 KBr/Oxone,19 and t-BuOOH/dirhodium tetracaprolactamate (Rh2(Cap)4).15,20 Whereas the first two reagents gave bad results, the rhodium-catalyzed oxidation allowed a remarkable improvement. Thus, exposure of acetate 22 to catalytic amounts of Rh2(Cap)4 in the presence of t-BuOOH and NaHCO3 afforded the chromanone 24 along with some benzylic alcohol which was readily oxidized using tetrapropylammonium perruthenate (TPAP) and 4-methylmorpholine Noxide (NMO)11,21 in an overall yield of 68% yield (brsm) over two steps. A longer reaction time and an increase of the temperature led to a slow decomposition of substrate and the product. Solvolysis of the acetate moiety with sodium methoxide22 in methanol and cleavage of the methyl ether with BBr3 led to blennolide D (6) in 85% yield over two steps

was transformed into the two aldehydes 12 and 13 as 1:7.6 mixture, which can be separated. However, in order to facilitate the synthesis of the desired blennolides, we used the mixture of 12 and 13 without separation to proceed with the sequence to obtain the desired lactones 14 and 15, which could be purified by column chromatography to yield the enantio- and diastereomeric pure chromane−lactones.15 These were then employed for the next steps. For the introduction of the hydroxyl group into the lactone moiety, the best results were obtained using 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO).16 Thus, treatment of 14 with LDA to give the enolate was followed by addition of TEMPO 16 in the presence of ferrocenium hexafluorophosphate 17 to yield the 2,2,6,6-tetramethylpiperidyl (TMP)B

DOI: 10.1021/acs.orglett.8b00487 Org. Lett. XXXX, XXX, XXX−XXX


Organic Letters

Reductive cleavage of the N−O bond in 27 and 28 using Zn and acetic acid followed by protection as acetate gave 32 and 33, respectively, via 30 and 31 in good yield (Scheme 3). The benzylic oxidation was again performed in a two-step process using t-BuOOH/dirhodium tetracaprolactamate (Rh2(Cap)4) and TPAP/NMO to give 34 in 71% (brsm) yield and 35 in 68% (brsm) yield. We have also investigated the oxidation of 27 using KMnO4 to give the ketone 29 in 42% (brsm). However, all attempts to remove the TMP group in 29 without reducing the carbonyl moiety were unsuccessful; in this reaction, only compound 30 was obtained (Scheme 3). The final steps in the synthesis of ent-blennolide E (ent-7) and ent-blennolide F (ent-8) were the solvolysis of the acetyl group and the cleavage of the methly ether in 34 and 35, which could be performed in good yield using NaOMe in methanol and BBr3 in dichloromethane (Scheme 3). Comparison of the NMR data of the synthetic and the natural compounds showed complete agreement. Moreover, the measured CD spectra of the synthetic compounds (ent-7 and ent-8) exhibited complete agreement with those of the natural products reported by Krohn et al.13 but as expected displayed the opposite sign. The optical rotation value for ent-7 again showed the opposite sign but with almost the same absolute value as found for natural blennolide E (7). Similarly, the opposite sign of the optical rotation was found for synthetic ent-8 compared to natural blennoide F (8); however, in this case the absolute value of the synthetic material was much higher (see the SI). In summary, the first enantioselective total syntheses of blennolide D (6) and the enantiomers of blennolide E and F (ent-7 and ent-8) have been achieved using a TEMPO oxidation as key step for the introduction of a hydroxyl group onto the γlactone.

(Scheme 2). Comparison of the spectroscopic information on synthetic blennolide D (6) showed complete agreement with the data reported for the natural product.13 In a similar sequence, consisting of the cleavage of the N−O bond, protection of the obtained hydroxyl group as acetate, oxidation of the benzylic position using Rh2(Cap)4 in the presence of t-BuOOH and double deprotection, chromane 19 was transformed into 26 in good overall yield via 21, 23, and 25. Compound 26 is a diastereomer of 6 with the opposite configuration at C-11 which has not yet been identified as a natural product (Scheme 2). In contrast to blennolide D (6) with the S-configuration at C-2, blennolides E (7) and F (8) have the R-configuration at this stereogenic center. To synthesize the natural compounds it would have been necessary to use the enantiomer of 15, which can easily be obtained using the (R,R)-i-Pr-BOXAX ligand for the enantioselective Wacker oxidation of 9. However, since we had large amounts of 15 in our hands, we aimed at the synthesis of the enantiomers of blennolide E (ent-7) and F (ent-8). For the synthesis of these compounds, 15 was treated with TEMPO in the presence of the ferrocenium complex 17 to give the two separable diastereomers 27 and 28 in a ratio of 1.6:1, respectively in 75% yield (82% brsm) (Scheme 3). Extensive 2D-NMR techniques, mainly the NOESY studies, were utilized to determine the configuration of the newly formed stereogenic center in the TEMPO reaction. As found for the reaction of 14, the major product is the all-syn derivative 27. For the synthesis of ent-7 and ent-8 we followed the same sequence as described for the preparation of blennolide D (6). Scheme 3. Stereoselective Synthesis of ent-Blennolide E (ent7) and ent-Blennolide F (ent-8)


S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00487. Complete experimental details and characterization data for the synthesized compounds (PDF)


Corresponding Author

*E-mail: [email protected] ORCID

Guillermo Valdomir: 0000-0002-5399-3662 Lutz F. Tietze: 0000-0003-3847-0756 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS We thank the Deutsche Forschungsgemeinschaft (DFG), the State of Lower Saxony, the VW-foundation, and the Humboldt Foundation for their generous support. D.G., S.S., and Y.Z. thank Georg-August-University Göttingen and G.V. thanks the Humboldt Foundation for a postdoctoral fellowship.


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DOI: 10.1021/acs.orglett.8b00487 Org. Lett. XXXX, XXX, XXX−XXX


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DOI: 10.1021/acs.orglett.8b00487 Org. Lett. XXXX, XXX, XXX−XXX

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