Total Synthesis of Propolisbenzofuran B - Organic Letters (ACS

Dec 4, 2017 - In 2000, Kadota and co-workers reported the isolation of propolisbenzofurans A and B (1) from the bioactivity guided fractionation of th...
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Letter Cite This: Org. Lett. 2017, 19, 6466−6469

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Total Synthesis of Propolisbenzofuran B Kolluru Srinivas and Chepuri V. Ramana* Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India S Supporting Information *

ABSTRACT: An efficient synthesis of propolisbenzofuran B, which possesses promising anticancer activity, is reported. The key cyclohexanone framework of this tricyclic natural product has been constructed employing a Rh-catalyzed intramolecular olefin hydroacylation. The requisite key olefin intermediate was synthesized by using gold-catalyzed allenyl ether [1,3] O → C rearrangement.

I

Scheme 1. Propolisbenzofuran B Retrosynthetic Scheme

n 2000, Kadota and co-workers reported the isolation of propolisbenzofurans A and B (1) from the bioactivity guided fractionation of the methanol extracts of Brazilian propolis.1 Both natural products exhibited moderate cytotoxicity to murine colon 26-L5 carcinoma (13.7 μg/L) and human HT1080 fibrosarcoma cells (43.7 μg/L). While the propolisbenzofuran A possesses a 2,3,5-trisubstituted dihydropyran skeleton, propolisbenzofuran B is characterized by an 1-aryl-2,3dihydrodibenzo[b,d]furan-4(1H)-one tricyclic core.2 Thus, the unique tricyclic core present in 1 and the unexplored origin of its biological activity warrant efficient methods for the construction of this central core. In this context, the first total synthesis of 1 was reported in 2014 by Thomson’s group, featuring a novel cascade reaction comprised of cyclocondensation of a dihydrobenzoquinone with a pendant cyclohexenone to construct the central benzofuran ring.3 Herein, we document our recent completed total synthesis of 1 that complements Thomson’s approach, wherein a cyclohexanone skeleton has been annulated to a benzofuran ring. As depicted in Scheme 1, we envisioned the construction of the central cyclohexanone core by a challenging intramolecular alkene hydroacylation reaction.4−6 The intramolecular hydroacylation has been widely used for the annulation of cyclohexanones on the benzene and other heterocyclic rings, and the reports are limited mainly to a monosubstituted olefin.5 In the present case, the control of the regioselectivity (5-exo vs 6-endo) and the diastereoselectivity seems to be the key challenge.6 The other important retrosynthetic disconnection was the placing of the C(6)-ethyl group as a surrogate for the C(6)-acyl group. This was to avoid the problematic late stage direct introduction of the C(6)-acyl group which was a key issue in the earlier synthesis.3 By following this, we envisioned the known penultimate intermediate 2 as the target for testing the intramolecular hydroacylation and identified the 2-formyl benzofuran 3 as the key intermediate. In our initial plan, we opted for direct formylation of the C(2)-carbanion or a C(2) methyl as a surrogate for the formyl group as an alternative, if problems arose in the former approach. To install the key prop-2-en-1-ol unit in 3, we decided to employ the gold(I)-catalyzed [1,3] O → C © 2017 American Chemical Society

rearrangement of the corresponding allenyl ether,7 which, in turn, was planned from the propargylic ether 4. The synthesis of corresponding ketone 5 was planned by following the established methods for the synthesis of 3-aroylbenzofurans that involve the condensation of 2-ethyl-1,4-benzoquinone (6)8 with a suitable enaminone.9−11 At the outset, starting with the benzoquinone 6, we realized that synthesis of a suitably functionalized benzofuran that can be advanced to 4 is associated with several challengesmainly, Received: September 21, 2017 Published: December 4, 2017 6466

DOI: 10.1021/acs.orglett.7b02732 Org. Lett. 2017, 19, 6466−6469

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Organic Letters the regioselectivity during the initial Michael addition. In this context, initially we examined the condensation of benzoquinone 6 with the 3-(dimethylamino)-1-arylprop-2-en-1-one 7 (Scheme 2).9 This reaction led to the isolation of a mixture of

Scheme 3. Initial Setbacks in the Synthesis

Scheme 2. Synthesis of Starting Benzofurans

solvents such as toluene, DMF, and DMSO for the KOtBumediated alkyne to allene isomerization. All these reactions met with undesired resultseither recovery of starting alkyne or formation of a complex mixture (see SI Table S1, entries 3−5). Next, other bases such as KOH and NaOMe were screened in DMSO solvent at room temperature or at 60 °C (see SI Table S1, entries 6−9).13 These too failed to deliver the required allene. Employing other bases such as LDA14 or a mixture of bases (NaH and KOtBu)15 in one pot was also not fruitful in allene formation at room temperature or at 50 °C (see SI Table S1, entries 10−13). Having synthesized a wide range of allenes during our method development, we took this step of allene synthesis for granted in our retrosynthetic design, and this failure is completely unanticipated and difficult to understandpresumably warranting a change in the retrosynthetic disconnections. However, we did not give up our original approach and opted for a detour at the beginning, considering the ready availability of another benzofuran precursor 13. The next approach for propolisbenzofuran B commenced with benzofuran 13 in which the phenolic functionality was protected as O-isopropyl ether resulting in 21 in 97% yield followed by SeO2-mediated oxidation in refluxing 1,4-dioxane for 28 h to obtain the aldehyde 22 in 89% yield (Scheme 4).16 Next, nBuLi-mediated addition of bromo compound 18 to the aldehyde 22 gave the intermediate alcohol 23 that was treated with propargyl bromide and sodium hydride in DMF to obtain the initially planned intermediate 4. Next, the propargyl ether 4 was subjected to the KOtBu-mediated isomerization under standard conditions, and the resulting allene was used directly for the [1,3] O → C rearrangement employing a combination of 1 mol % Au(PPh3)Cl and 5 mol % AgSbF6 in dichloromethane at −30 °C to obtain the requisite αsubstituted acryl aldehyde 24 in 78% yield.7a Reduction of the aldehyde 24 with DIBAL-H and protection of the resulting allyl alcohol 25 using TBDPSCl gave the intermediate 26 in excellent yield (Scheme 5). The attempted formylation at C2 of benzofuran 26, using nBuLi and DMF at −78 °C or at −40 °C, failed to provide the product. However, when conducted at 0 °C, the reaction proceeded smoothly and gave the key olefin

two regioisomers 8 and 9 in a 1:7 ratio. An examination of their NMR spectra and the single-crystal X-ray of the minor isomer 8 revealed that it was the desired 5-hydroxy-6-ethyl-3-aroylbenzofuran. Varying the reaction conditions such as solvent and/or temperature had no substantial effect on the outcome of the reaction. Next, we examined the condensation of benzoquinone 6 with ethyl acetoacetate10 and with the enamine of propionaldehyde 12.11 In both the cases, the required isomers 10 and 13 were obtained in equal proportion along with the undesired isomers 11 and 14. Despite having regioselectivity issues, with easy access to the two early intermediates 10 and 13, we proceeded further to examine the proposed approach for the synthesis of propolisbenzofuran B. Initially, the carboxylate 10 was selected as a starting point, considering the readily available ester unit that can be transformed to the intermediate propargyl ether for examining the feasibility of 1,3-rearrangement (Scheme 3). In this context, the free phenolic−OH in compound 10 was protected as its isopropyl ether by treating it with isopropyl bromide and Cs2CO3 at 60 °C in N-methylpyrrolidin-2-one resulting in compound 15 in 95% yield. Compound 15 was subjected to the carboxylate reduction using LAH, and the intermediate alcohol was oxidized with IBX in refluxing EtOAc to the corresponding aldehyde 17. Next, the nBuLi-mediated addition of bromo compound 18 to aldehyde 17 gave the desired alcohol 19 in 71% yield. The free −OH group in compound 19 was propargylated using propargyl bromide and sodium hydride in DMF to obtain the alkyne 20 in 85% yield. Having the alkyne 20 in hand, the next step was its isomerization to allene and the subsequent gold-catalyzed [1,3] O → C rearrangement. Surprisingly, when the alkyne 20 was treated for the KOtBu-mediated isomerization under previously optimized conditions,12 there was no formation of allene, and the starting alkyne 20 was recovered (see Supporting Information (SI) Table S1 for complete details). When the same reaction was heated at 60 °C for 1 h, a complex mixture was formed. In this context, we screened various 6467

DOI: 10.1021/acs.orglett.7b02732 Org. Lett. 2017, 19, 6466−6469

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Organic Letters

mixture of trans-29 and cis-29 (determined from the NMR of the crude reaction mixture). Both isomers were separated by preparative HPLC. The spectral data of trans-29 were comparable with the data reported by Thomson’s group.3 Next, following the sequence of reactions [benzylic C−H oxidation, TBDPS deprotection followed by acetylation and deprotection of isopropyl ethers using AlCl3] that have been reported by Thomson’s group, compound trans-29 was transformed to propolisbenzofuran B (1) in 58% overall yield over 4 steps (Scheme 6). The spectral data of synthetic 1 are in full agreement with the data reported by isolation and synthetic groups.1,3

Scheme 4. Synthesis of Key Intermediate by Gold-Catalyzed [1,3] O → C Rearrangement

Scheme 6. Completion of Total Synthesis

Scheme 5. Exploring the Key Intramolecular Hydroacylation

In conclusion, the total synthesis of propolisbenzofuran B has been completed. The adopted approach is highly modular and is characterized with the use of easily accessible building blocks and simple reagents. Rh-catalyzed intramolecular olefin hydroacylation was used for the key skeletal construct and is the first example of such a use for the construction of a 4,5-disubstituted cyclohexanone.



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02732. Experimental details and NMR spectra (PDF)

aldehyde 3 (68%) and a mixture of reduced alcohol 27 and amide 28 (1:1 ratio). The oxidation of this mixture with IBX in refluxing EtOAc led to the isolation of another 7% aldehyde 3 (with respect to the starting 26), and 7% of amide 28 was recovered. After having the aldehyde 3 in hand, the stage was set for another key reactionrhodium-catalyzed intramolecular olefin hydroacylation. This reaction required substantial exploration employing various conditions that have been documented in the literature. In this pursuit, we initially examined the Wilkinson’s catalyst along with the additives aniline, benzoic acid, and 2-amino-3-picoline in toluene.17 In all cases, the formation of an intractable complex mixture was noticed While performing the same reaction with Wilkinson’s catalyst in the presence of Cp2TiCl2 and 2-amino-3-picoline in THF at 100 °C,18 the reaction proceeded smoothly resulting in a 6:1

Accession Codes

CCDC 1588622−1588624 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chepuri V. Ramana: 0000-0001-5801-311X 6468

DOI: 10.1021/acs.orglett.7b02732 Org. Lett. 2017, 19, 6466−6469

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Organic Letters Notes

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The authors declare no competing financial interest.



ACKNOWLEDGMENTS We acknowledge CSIR (India) for funding this project under 12FYP ORIGIN program (CSC0108) and for a research fellowship to KS.



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DOI: 10.1021/acs.orglett.7b02732 Org. Lett. 2017, 19, 6466−6469