A Heck-Based Strategy To Generate Anacardic Acids and Related

Letter Cite This: Org. Lett. 2018, 20, 6234−6238

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A Heck-Based Strategy To Generate Anacardic Acids and Related Phenolic Lipids for Isoform-Specific Bioactivity Profiling William K. Weigel, III,† Taylor N. Dennis,‡ Amrik S. Kang,‡ J. Jefferson P. Perry,*,‡ and David B. C. Martin*,† †

Department of Chemistry and ‡Department of Biochemistry, University of California Riverside, Riverside, California 92521, United States

Org. Lett. 2018.20:6234-6238. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/05/18. For personal use only.

S Supporting Information *

ABSTRACT: A synthetic strategy for phenolic lipids such as anacardic acid and ginkgolic acid derivatives using an efficient and selective redox-relay Heck reaction followed by a stereoselective olefination is reported. This approach controls both the alkene position and stereochemistry, allowing the synthesis of natural and unnatural unsaturated lipids as single isomers. By this strategy, the activities of different anacardic acid and ginkgolic acid derivatives have been examined in a matrix metalloproteinase inhibition assay.

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inhibition activities,5 among others.6 Despite abundant phytochemical feedstocks such as cashew nutshell oil,7 these lipids are generally obtained as mixtures of fully saturated, monounsaturated, and polyunsaturated species that can be difficult to isolate in pure form.2,8 Access to individual members of these families would facilitate the determination of their unique biological activity profiles. While hydrogenation of a mixture of unsaturated lipids can provide the fully saturated species, chemical synthesis provides the most straightforward way to access individual unsaturated species and could be used to access unnatural constitutional isomers and E stereoisomers.9 Herein we report an efficient and general solution to this challenge with complete control over the alkene position and stereochemistry using a redox-relay Heck reaction that proceeds with high efficiency. We also report inhibition data for individual natural and unnatural isomers of anacardic and ginkgolic acids with matrix metalloproteinase MMP-2. Previous syntheses of phenolic lipids have frequently relied on Grignard or another organometallic addition to an aldehyde to join the aromatic head and nonpolar tail sections.1,10 Reductive removal of the resulting benzylic alcohol and deprotection of any protected phenols give the final lipid product. Unsaturation is typically introduced by partial reduction of an alkyne to the (Z)-olefin. Gerlach’s unique Diels−Alder approach and Satoh’s condensation approach to construct the aromatic ring are creative alternatives.11 We wondered whether a modern cross-coupling strategy could be

henolic lipids are a subset of lipid molecules that are characterized by a long, nonpolar alkyl chain appended to a hydroxylated aromatic headgroup (Figure 1).1 While many of

Figure 1. Naturally occurring phenolic lipids.

them, such as α-tocopherol, are terpene-derived, the majority have an unbranched alkyl chain that can be saturated, monounsaturated, or polyunsaturated, similar to the related fatty acids. The natural sources of many phenolic lipids are used in traditional medicine, and therefore, the biological activities of these compounds have been explored. In particular, the anacardic and ginkgolic acids (2−4) possess antibacterial,2 histone acetyltransferase inhibition,3 SUMOylation inhibition,4 and matrix metalloproteinase (MMP) © 2018 American Chemical Society

Received: August 23, 2018 Published: September 25, 2018 6234

DOI: 10.1021/acs.orglett.8b02705 Org. Lett. 2018, 20, 6234−6238

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Organic Letters employed to introduce the alkyl chain to a suitable aromatic precursor.12 In particular, we were attracted to the idea of a redox-relay Heck strategy that would take advantage of commercially available unsaturated alcohols to give an aldehyde product for subsequent stereoselective olefination (Scheme 1).13 This strategy would allow the introduction of

Acetonide-protected triflate 11 was synthesized from 2,6dihydroxybenzoic acid in two efficient, scalable reactions.14 We examined the Heck reaction with 4-penten-1-ol (12) using a range of catalysts and conditions. Previous redox-relay Heck reactions have often employed phosphine ligands and elevated temperatures. We quickly found that catalytic Pd(OAc)2 in the presence of inorganic base and tetrabutylammonium salts in amide solvent, phosphine-free conditions often called Jeffery’s conditions, are effective at producing the 5-aryl aldehyde product in 91% yield, strongly favoring the linear regioisomer (r.r. = 94:6).19 The regioselectivity favoring the linear product is uniformly high across all of the unsaturated alcohols tested (see below), and the excellent yield is maintained across a range of non-amide solvents (acetonitrile, THF, 2-Me-THF, and DCE). The remarkable efficiency and selectivity are much higher than those in many previous reports, including Larock’s reaction of aryl iodides under similar Jeffery’s conditions (r.r. = 84:16 at rt).15b We wondered whether this is a result of the use of triflate starting materials or the particular substituents on the aryl triflate such as the o-carboxylate. We compared phenyl iodide, phenyl bromide, and phenyl triflate directly using 4penten-1-ol (Scheme 2, center) and found that although phenyl triflate gave the highest efficiency, the regioselectivities between linear and branched isomers were essentially identical (r.r. = 83:17). We also compared two o-carbomethoxy derivatives 16 (Scheme 2, bottom), both of which participate with high efficiency and regioselectivity (r.r. = 92:8). These results indicate that the high selectivity with triflate 11 is due to the presence of the o-carboxylate during the alkene insertion step, an unexpected benefit of the anacardic acid synthesis strategy described here.20 With these optimized conditions in hand, we examined the scope of this reaction with various unsaturated alcohols having different chain lengths (Scheme 3). Interestingly, the reactions with allyl alcohol and 4-penten-1-ol proceed at room temperature and give excellent yields and selectivity at 50 °C (97% and 96% yield, respectively, >20:1 r.r.). The reaction with 3-buten-1-ol is a little more sluggish, perhaps because of a more stable chelate of the substrate with Pd(II), but aldehyde

Scheme 1. Retrosynthesis of Anacardic and Ginkgolic Acids 4 via Olefination and Heck Coupling

either (E)- or (Z)-alkenes at any position along the chain, providing a general method to access a wide range of natural and unnatural phenolic lipids to investigate their individual activities. We settled on acetonide-protected triflate 11 (Scheme 2, top) as the most readily available aromatic substrate because of the ease of synthesis from inexpensive 2,6-dihydroxybenzoic acid.12,14 Surprisingly, while the Heck reactions of aryl halides with myriad unsaturated alcohols to give aldehyde or ketone products by successive alkene insertion/β-hydride elimination have been widely reported,15 few examples with aryl trif lates are known. A handful of examples with allylic alcohols to give aldehydes have been documented, along with a couple of unusual examples that give styrene products preferentially.16,17 We were intrigued by this gap in the literature and recognized that the ease of access of many aryl triflates could greatly expand the utility of this redox-relay approach.18

Scheme 2. Synthesis of Triflate 11 and Investigation of the Heck Reaction; Triflate, Iodide, and Bromide Show Similar Selectivity

a

Isolated yield. bYield determined by 1H NMR spectroscopy with an internal standard. 6235

DOI: 10.1021/acs.orglett.8b02705 Org. Lett. 2018, 20, 6234−6238

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product 20 is obtained in 88% yield at 50 °C. Longer-chain alcohols with six and eight carbons also react efficiently to deliver aldehydes 21 and 22 in good yields. In all cases, the linear to branched selectivity is extremely high (≥20:1 r.r. by 1 H NMR spectroscopy). The power of the Heck reaction to migrate the unsaturation to the end of the eight-carbon chain, involving at least six successive alkene insertion and β-hydride elimination steps to generate key anacardic acid intermediate 22, is quite remarkable.21 We also applied this strategy to a resorcinol derivative to generate aldehydes 23 and 24 as representative substrates, with aldehyde 24 serving as a precursor to the related cardanol natural products 5 (Figure 1). The yields and selectivities were in line with those for phenyl triflate (r.r. ≈ 87:13 for 23), again highlighting the improved selectivity of triflate 11 under these conditions. With the aldehyde in hand, we turned our attention to the synthesis of natural phenolic lipids (Scheme 4). In order to obtain ginkgolic acid (Z)-3, a Wittig olefination between aldehyde 22 and a heptylphosphonium salt was performed in 94% yield with excellent Z selectivity (97:3 Z/E by analysis of the corresponding epoxides).22 Removal of the acetonide protecting group with aqueous hydroxide in dioxane provided (Z)-3 in 84% yield. A representative unnatural trans-lipid was synthesized from the same intermediate using a Julia− Kocienski olefination (66% yield, 4:96 Z/E by analysis of the corresponding epoxides) and deprotection (95% yield).23 In this way, both cis and trans forms can be accessed in just five steps from 2,6-dihydroxybenzoic acid through a common intermediate. Anacardic acid 4a with two (Z)-alkenes was synthesized from commercially available (Z)-3-hepten-1-ol (26). Activation of the alcohol as a mesylate followed by substitution with lithium bromide and reaction with triphenylphosphine gave the known phosphonium salt 27.24 Wittig olefination (96% yield, 90:10 Z/E) and deprotection (86% yield) gave di-unsaturated lipid (Z,Z)-4a in excellent overall yield. By means of this strategy, access to natural or unnatural derivatives is achieved simply by proper selection of the unsaturated alcohol and olefination reagent. Because of the efficiency of the redox-relay Heck reaction and the flexibility of the complementary olefination reactions, this approach greatly simplifies the synthesis of many lipid analogues through common intermediates and robust protocols. To demonstrate the success of these strategies in generating natural and unnatural analogues of anacardic and ginkgolic acids, we conducted an inhibition study using matrix

Scheme 3. Scope of Redox-Relay Heck Coupling with Triflate 11a

a

Reaction conditions: 1 equiv of 11, 1.2 equiv of alkene, 5 mol % Pd(OAc)2, 2.5 equiv of LiOAc, 1 equiv of LiCl, 2 equiv of TBACl, 0.13 M in DMA, 50 °C, 2−3 h. All yields are isolated yields. b70 °C. c 1 equiv of 3-methoxyphenyl triflate, 1.75 equiv of alkene, 10 mol % Pd(OAc)2, 0.13 M in DMA, 70 °C, 3 h. dLinear:branched = 87:13. e Linear:branched = 82:18.

Scheme 4. Synthesis of Natural and Unnatural Anacardic Acid Analogues Using Olefination Methods

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metalloproteinase MMP-2, a protein known to be inhibited by anacardic acid.5 In our assay, recombinant MMP-2 catalytic domain protein (ENZO Life Sciences) was preincubated with each of the phenolic lipids, including a fully saturated anacardic acid control (2), and the enzymatic activities were quantified using fluorescently conjugated gelatin (Thermo Fisher Scientific) as the substrate. The MMP-2 enzymatic activity was measured in the presence of each phenolic lipid at concentrations of 1, 5, 10, 25, and 50 μM, and the percent inhibition of activity across this range of concentrations is shown in Figure 2. Inhibition was observed for all of the

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02705.

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Experimental procedures, characterization data, and 1H and 13C NMR spectra of all new compounds (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: jeff[email protected]. *E-mail: [email protected]. ORCID

David B. C. Martin: 0000-0002-8084-8225 Notes

The authors declare no competing financial interest.

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Table 1. IC50 Values for Compounds Tested in the MMP-2 Gelatinase Assay

ACKNOWLEDGMENTS The University of California, Riverside and the UC Cancer Research Coordinating Committee (CRN-18-526258 to D.B.C.M. and CRN-18-524906 to J.J.P.P.) are gratefully acknowledged for financial support. NMR instrumentation for this research was supported by funding from the NSF (CHE-1626673) and the U.S. Army (W911NF-16-1-0523). Mass spectrometry instrumentation for this research was supported by funding from the NSF (CHE-0541848). D.B.C.M. is a member of the UC Riverside Center for Catalysis.

between the alkyl and alkenyl chains does not have a significant effect on the levels of inhibition of MMP-2 activity. Interestingly, this observation is distinct from the previously reported antibacterial activity of natural anacardic acids, where a large effect on minimum inhibitory concentration was reported.2b,c,e,f Other enzyme inhibition activities may show greater or lesser dependence on the shape and rigidity of the tail. In summary, we have outlined a strategy for the synthesis of phenolic lipid natural products using a palladium-catalyzed redox-relay Heck reaction. This efficient method proceeds in high yield with high regioselectivity from a readily available triflate starting material. Olefination of the resulting aldehyde gives either (Z)- or (E)-alkene products selectively, allowing access to both natural and unnatural isomers with complete control of the alkene position and stereochemistry. Using this strategy, we synthesized and tested a number of phenolic lipids in an MMP-2 assay to demonstrate the applicability of the current work to the assessment of individual lipid components. The versatility of aldehydes as synthetic intermediates suggests that this Heck strategy could also be useful for a variety of unnatural lipid isomers beyond simple alkene analogues.

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Figure 2. Percent inhibition of MMP-2 activity by phenolic lipids.

compounds, with similar levels of inhibition compared to each other and to commercially available anacardic acid 2. The IC50 values in this assay for each of the compounds tested were similar, as shown in Table 1. This suggests that the difference

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DOI: 10.1021/acs.orglett.8b02705 Org. Lett. 2018, 20, 6234−6238

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