Benzyne Insertion onto β-Keto Esters of Polycyclic Natural Products

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Letter Cite This: Org. Lett. 2018, 20, 7121−7124

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Benzyne Insertion onto β‑Keto Esters of Polycyclic Natural Products: Synthesis of Benzo Octacyclo Scaffolds Shivakrishna Kallepu,† Karekar Sanjeev,†,‡ Rambabu Chegondi,†,‡ Prathama S. Mainkar,†,‡ and Srivari Chandrasekhar*,†,‡ †

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Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500007, India ‡ Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India S Supporting Information *

ABSTRACT: Benzyne insertion to build the privileged scaffold of a [6.8.6]-tricyclic framework on polycyclic and sp3-rich natural products has been developed. The formation of the [6.8.6]-tricyclic ring system is solvent dependent.

N

atural products account for a major number of therapeutic molecules identified for treatment of various ailments.1 The extensive effort involved in the isolation of miniscule quantities of new scaffolds is a deterrent in evaluating their therapeutic indices. In addition, due to the limited biochemical pathways preserved in nature, the structures are limited to a select few skeletons. For example, terpenoids and steroids, two major classes of compounds, originate from the same building block, the five-carbon unit isoprene. Thus, any addition to the existing structure by biochemical pathways is always by five carbons, thereby reducing flexibility. Synthetic organic chemists can, however, introduce any number of carbons into the molecule by carrying out transformations such as Wittig, Grignard, aldol, C−H activation, cycloaddition reactions, etc. A prudent scaffold [6.8.6]-tricyclic framework has been embodied into the taxane (1) class of natural products.2 The most important compound in the series is paclitaxel, which has been used since 1992 for the treatment of ovarian cancer and metastatic breast cancer.3 A semisynthetic analogue, docetaxel, was approved in 1996 for the treatment of advanced breast cancer. The molecule stabilizes microtubules, which blocks the progression of mitosis. Glycyrrhetinic acid (2, Figure 1) and malabaricol (3) are abundantly isolable triterpenoids, available commercially at throwaway prices, and reported to be used in traditional medicine.4 Screening for anticancer activity of glycyrrhetinic acid or its glycosylated molecule (glycyrrhizin) indicated mild inhibitory activity.5 This has prompted synthetic organic chemists to prepare derivatives of glycyrrhetinic acid and screen them for identifying molecules with better activity, but most of them have resulted in a very slight improvement in the activity.6 Similarly, malabaricol (3) and its derivatives have been screened for their cytotoxic activity and © 2018 American Chemical Society

Figure 1. Structures of taxane (1), glycyrrhetinic acid (2), and malabaricol (3).

potential toward the diagnoses of metabolic disorder, insulin resistance, and diabetes, but without much success.7 We were intrigued by the work of Stoltz et al. (Scheme 1)8 on the application of benzyne to β-keto ester9,10 and thought Scheme 1. Stoltz’s Aryne Insertion Reaction

that simple manipulation of commercially available natural products11 with this chemistry may result in [6.8.6]-tricyclic skeletons. We reasoned that expanding the skeletal diversity of abundantly available polycyclic and strained natural products would be a new avenue to explore biochemical pathways and drug discovery.12 Received: September 25, 2018 Published: November 5, 2018 7121

DOI: 10.1021/acs.orglett.8b03070 Org. Lett. 2018, 20, 7121−7124

Letter

Organic Letters This paper describes our findings on novel expansion of Aring of glycyrrhetinic acid and malabaricol through an aryne insertion reaction. The β-keto ester required for the reaction was synthesized by oxidation to 4 using Jones’ conditions on 2. Installation of the ester group at C-2 was carried out using sodium hydride and dimethyl carbonate in 75% yield.13 Treatment of β-keto ester (5) with benzyne, generated from osilyl aryltriflate 6a,14 gave us a mixture of two compounds. To our dismay, 7a was isolated as the major product where we anticipated 8a as the main product (Scheme 2).

Scheme 3. Substrate Scope for Arynes

Scheme 2. Initial Attempt of Benzyne Insertion on Complex β-Keto Ester

Table 1a,b entry c

1 2 3 4 5 6 7 8

aryne precursor

solvent

7, yield (%)

8, yield (%)

6a 6a 6b 6b 6c 6c 6d 6d

CH3CN THF CH3CN THF CH3CN THF CH3CN THF

7a, 57 7a, 13 7b, 64 7b, 26 7c, 58 7c, 22 7d, 52 7d, 10

8a, 15 8a, 55 8b, 12 8b, 40 8c, traces 8c, 45 8d, 5 8d, 45

a

Reaction conditions: The reaction was carried out with 5 (1.0 equiv), 6 (1.5 equiv), and CsF (3.0 equiv) in solvent (0.2 M). bYields of products isolated after column chromatography. cReaction at 65 °C gave 7a in 45% yield and 8a in 13% yield.

On the basis of the account of Stoltz et al., the desired compound should have been ring-expansion product 8a, but to our surprise, the reaction conditions yielded a major quantity of C-arylated product 7a and minor quantities of ring expansion product 8a (Scheme 2). The structures of 7a and 8a were fully characterized using NMR, HRMS, and IR data. On the basis of our previous approach,15 it was hypothesized that the reaction proceeded through α-arylation and subsequent protonation with CH3CN to give 7a as the major product. Formation of the minor product 8a was due to the expected [2 + 2] cycloaddition through the benzocyclobutene intermediate. Both of the products were formed as single diastereomers, presumably due to their steric congestion. This result prompted us to study the reasons for the unexpected outcome. As a first change, we substituted acetonitrile solvent with THF to decide if solvent played any role in the reversal of the results. A reaction in THF, as a solvent, gave us opposite results; i.e., ring expansion product 8a was formed in major quantities. To substantiate these observations, the insertion reaction of β-keto ester 5 was carried out with various substituted arynes 6 (Scheme 3) in both THF and acetonitrile solvents, and the results are summarized in Table 1. The reactions afforded the corresponding products 7a−d and 8a−d with varying yields in two different solvents (Table 1). It is noted that the reaction in CH3CN solvent gave C-arylation product 7 and in THF solvent afforded ring-expansion product 8 as major products, which is consistent with our previous observation as in Scheme 2. In addition, the insertion of both symmetrical arynes 6a−c and unsymmetrical aryne 6d with β-keto ester 5 furnished corresponding products 7 and 8 in a regio- and stereoselective manner (Table 1). The C-2 stereochemistry of compound 7b was confirmed by NOESY studies (see the Supporting

Information). The structure of ring-expansion product 8b is confirmed by X-ray crystallography (Figure 2).

Figure 2. ORTEP of compound 8b.

Enticed by these results, we expanded our study on other natural products with easy access and similar structural skeletons. Malabaricol (3) is another triterpene which has a [6.6.5]-tricyclic ring structure.16 The desired β-keto ester 9 was prepared following a known procedure13 from 3, and subsequent oxidative cleavage of 9 with PCC resulted in required lactone 10 (Scheme 4). Aryne insertion reactions on 10 using various o-silyl aryltriflates 6 with THF and acetonitrile as solvents independently gave similar results. Thus, acetonitrile as a solvent gave more of C-arylation product 11 and THF as solvent resulted in ring-expansion product 12, thereby resulting in [6.8.6]-tricyclic skeletons (Table 2). Moreover, we also extended the aryne insertion studies on simple bicyclic β-keto ester 14, which was synthesized from glycyrrhetinic acid 2 using a literature procedure in three steps.17 These results are also consistent with our previous observation in both solvents (Scheme 5). 7122

DOI: 10.1021/acs.orglett.8b03070 Org. Lett. 2018, 20, 7121−7124

Letter

Organic Letters Scheme 4. Aryne Insertion on Complex β-Keto Ester 9

Scheme 7. Plausible Mechanism for Aryne Insertion Reaction

Table 2a entry

aryne precursor

solvent

11, yieldb (%)

12, yield (%)

1 2 3 4 5 6

6a 6a 6b 6b 6c 6c

CH3CN THF CH3CN THF CH3CN THF

11a, 55 11a, 15 11b, 52 11b, 10 11c, 46 11c, 6

12a, 20 12a, 62 12b, 25 12b, 60 12c, traces 12c, 41

subsequent protonation to deliver α-arylation product 7a. The same intermediate A proceeds through a formal [2 + 2] cycloaddition via benzocyclobutene intermediate B to furnish the benzo octocyclic product 8a (Scheme 7). We believe that addition of the aryl carbanion to the keto group leading to the requisite cyclobutene intermediates is likely hampered in the congested steric environment. As a result, the protonation pathway becomes competitive. This might force the protonation before the cyclization resulting in arylation over ring expansion. However, in THF, the nonavailability of the proton source results in formation of the ring-expansion product predominantly. In summary, the present work opens up syntheses of new skeletons for medicinal chemists. Thus, in the case of aliphatic β-keto esters, the major product on the arylation is the ringexpansion product, whereas in the case of polycyclic compounds C-arylation is the major product in acetonitrile. The resulting [6.8.6]-tricyclic compounds are akin to the taxane skeleton, and their biological activity is being explored, the results of which will be presented elsewhere.

a

Reaction conditions: The reaction was carried out with 10 (1.0 equiv), 6 (1.5 equiv), and CsF (3.0 equiv) in solvent (0.2 M). bYields of products isolated after column chromatography.

Scheme 5. Aryne Insertion on Simple β-Keto Ester 14



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03070. Experimental procedures, characterization details and 1H and 13C NMR spectra of new compounds (PDF)

To gain further insight into the mechanism of the insertion reaction, the reaction was conducted between 5 and 6a in the presence of CsF in CD3CN solvent to afford monodeuterated product 7a-d1 at the ortho-position of the phenyl ring (Scheme 6). This experiment confirmed that the formation of 7a-d1 progressed through the protonation from solvent. A plausible mechanism is proposed in Scheme 7 based on the reaction outcome and previous reports.8,15 The mechanism involves the insertion of benzyne 6a on to β-keto ester 5 to generate α-aryl carbanion A. The α-aryl carbanion undergoes

Accession Codes

CCDC 1847016 contains 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.



Scheme 6. Mechanistic Study

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Rambabu Chegondi: 0000-0003-2072-7429 Srivari Chandrasekhar: 0000-0003-3695-4343 7123

DOI: 10.1021/acs.orglett.8b03070 Org. Lett. 2018, 20, 7121−7124

Letter

Organic Letters Notes

(14) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12, 1211. (15) Kranthikumar, R.; Chegondi, R.; Chandrasekhar, S. J. Org. Chem. 2016, 81, 2451. (16) (a) Chawla, A.; Dev, S. Tetrahedron Lett. 1967, 8, 4837. (b) Srinivas, P. V.; Rao, R. R.; Rao, J. M. Chem. Biodiversity 2006, 3, 930. (17) (a) Falck, J. R.; Chandrasekhar, S.; Manna, S.; Chiu, C.-C. S.; Mioskowski, C.; Wetzel, I. J. Am. Chem. Soc. 1993, 115, 11606. (b) Falck, J. R.; Manna, S.; Chandrasekhar, S.; Alcaraz, L.; Mioskowski, C. Tetrahedron Lett. 1994, 35, 2013.

The authors declare no competing financial interest. CSIR-IICT manuscript communication no. IICT/Pubs./2018/ 298.



ACKNOWLEDGMENTS S.C. thanks DST for a J. C. Bose fellowship (SB/S2/JCB-002/ 2015). We gratefully acknowledge Dr. Balasubramanian Sridhar, Laboratory of X-ray Crystallography, CSIR-IICT, for X-ray analysis. We also thank Dr. Nagaiah, Chief Scientist, CSIR-IICT, and Dr. B.S. Sastry, Senior Technical Officer, CSIR-IICT, for providing malabaricol and Mr. Kranthikumar, Senior Research Fellow, CSIR-IICT, for fruitful discussions.



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DOI: 10.1021/acs.orglett.8b03070 Org. Lett. 2018, 20, 7121−7124