A Heck-Based Strategy to Generate Anacardic Acids and Related Phenolic Lipids for Isoform-Specific Bioactivity Profiling

Article abstract of DOI:10.1021/acs.orglett.8b02705

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.

Full text of DOI:10.1021/acs.orglett.8b02705

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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
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.
henolic lipids are a subset of lipid molecules that are
characterized by a long, nonpolar alkyl chain appended to
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.
P
a hydroxylated aromatic headgroup (Figure 1).1 While many of
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
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 SUMOyla-
tion inhibition,4 and matrix metalloproteinase (MMP)
Received: August 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02705
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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 2,6-
dihydroxybenzoic 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 4-
penten-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
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 triflates
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
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 2. Synthesis of Triflate 11 and Investigation of the Heck Reaction; Triflate, Iodide, and Bromide Show Similar
Selectivity
a
b
1
Isolated yield. Yield determined by H NMR spectroscopy with an internal standard.
B
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Letter
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
1H 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.
Scheme 3. Scope of Redox-Relay Heck Coupling with
Triflate 11
a
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,
b
0.13 M in DMA, 50 °C, 2−3 h. All yields are isolated yields. 70 °C.
c
1 equiv of 3-methoxyphenyl triflate, 1.75 equiv of alkene, 10 mol %
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
d
Pd(OAc)2, 0.13 M in DMA, 70 °C, 3 h. Linear:branched = 87:13.
e
Linear:branched = 82:18.
Scheme 4. Synthesis of Natural and Unnatural Anacardic Acid Analogues Using Olefination Methods
C
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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
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02705.
■
S
1
Experimental procedures, characterization data, and H
and 13C NMR spectra of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jeff.perry@ucr.edu.
*E-mail: dave.martin@ucr.edu.
ORCID
David B. C. Martin: 0000-0002-8084-8225
Notes
The authors declare no competing financial interest.
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.
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
Table 1. IC50 Values for Compounds Tested in the MMP-2
Gelatinase Assay
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