Cyclopropylmethyl Protection of Phenols: Total Synthesis of the Resveratrol Dimers Anigopreissin A and Resveratrol–Piceatannol Hybrid

Article abstract of DOI:10.1002/open.201800214

We demonstrate the versatile use of the cyclopropylmethyl group to protect phenols through the total synthesis of two benzofuran-based natural products, that is, anigopreissin A and the resveratrol–piceatannol hybrid. This protecting group is a good alter

Full text of DOI:10.1002/open.201800214

DOI: 10.1002/open.201800214
Cyclopropylmethyl Protection of Phenols: Total Synthesis
of the Resveratrol Dimers Anigopreissin A and
Resveratrol–Piceatannol Hybrid
Arvind Kumar+, Michael Saleeb+, Dominik Werz, and Mikael Elofsson*[a]
We demonstrate the versatile use of the cyclopropylmethyl
group to protect phenols through the total synthesis of two
benzofuran-based natural products, that is, anigopreissin A
and the resveratrol–piceatannol hybrid. This protecting group
is a good alternative to the conventional methyl group, owing
to the feasibility of introduction, stability under a variety of
conditions, and its relative ease of removal under different
acidic conditions.
HIV-1 reverse transcriptase (IC50 =8 mM) and two mutant en-
zymes which are resistant to the clinical drug nevirapine.[14] Re-
sveratrol-piceatannol hybrid was isolated in 2015 from a grape
extract (vitis vinifera), which was first fractionated using a hepa-
titis C virus replication inhibition assay.[15] These natural prod-
ucts have previously been synthesized using methyl protecting
groups, which are removed under harsh acidic conditions such
as BBr3 or BCl3/TBAI. These conditions are frequently not com-
patible with the target compound and result in formation of
undesired products and low yields.[16] For example, BBr3 failed
to give anigopreissin A[11] or shoreaphenol[17] from their corre-
sponding permethylated analogues, whereas anigopreissin A
was only obtained in 23% yield when using BCl3/TBAI.[11] Thus,
the unpredictability of the demethylation step for many of
these polyphenolic natural products indicate a need for alter-
native protecting groups.
Heterocyclic compounds are of vital importance in medicinal
chemistry and appear in a variety of approved drugs and bio-
logically active compounds.[1] Among those heterocyclic com-
pounds, the benzofuran scaffold exists widely in natural and
synthetic compounds with an enormous range of pharmaco-
logical activities, such as antibacterial,[2] antifungal,[3] anti-in-
flammatory,[4] antioxidative,[5] antiviral[6] and antineoplastic.[7]
Furthermore, benzofuran derivatives are used as fluorescent
sensors in organic chemistry.[8] Our interest in these scaffolds
originates from our finding of the resveratrol tetramer,
(À)-hopeaphenol—a complex plant stilbenoid isolated from
the Papua Guinean tree species Anisoptera thurifera and Ani-
soptera polyandra—as an irreversible inhibitor of the type III
secretion in gram-negative pathogens Yersinia pseudotubercu-
losis and Pseudomonas aeruginosa.[9] Based on this finding, we
initiated studies to expand our knowledge on the chemistry
and biology of these scaffolds and recently published total
syntheses of benzofuran based natural products (Æ)-ampelop-
sin B and (Æ)-e-viniferin.[10] Subsequently, we reported the total
synthesis of other benzofuran based natural products viz. vini-
ferifuran, anigopreissin A and resveratrol–piceatannol hybrid;[11]
as well as natural product inspired libraries based on the ben-
zofuran scaffold.[12] Anigopreissin A, a naturally occurring dimer
of resveratrol, shows low antimicrobial activity against S.
aureus and S. pyogene.[13] It is also a potent inhibitor of the
In this work, we explored the use of cyclopropylmethyl
(cPrMe) ether inspired by a report from Nagata et al., in which
the cPrMe ethers were selectively cleaved under acidic condi-
tions and yet stable to a wide range of reaction conditions.[18]
Our group has applied the cPrMe protection during the total
synthesis of the resveratrol oligomer (Æ)-ampelopsin B that al-
lowed an ultimate three-step one-pot deprotection, epimeriza-
tion and cyclization to form the target compound.[10] Given the
lability of the cPrMe ethers to acids and the feasibility to
cleave it off under variety of conditions, and in continuation of
our efforts on the polyphenol natural products,[12] we herein
described the successful use of cPrMe as a protecting group in
the total synthesis of anigopreissin A and resveratrol–piceatan-
nol hybrid.
To date, three synthetic strategies for preparation of anigo-
preissin A have been published.[11,19] The earlier two synthesis
were reported with the constraint that only permethylated ani-
gopreissin A was obtained.[19] Despite several attempts to de-
protect the methyl ether groups using for example, BBr3,
BBr3·SMe2 and L-Selectride, the authors observed either decom-
position or partial deprotection.[19a] The third and successful
total synthesis of this natural product was published by our
group in 2016 in which the permethylated anigopreissin A was
deprotected in 23% yield using BCl3/TBAI.[11] Based on these re-
sults we moved on and explored the cPrMe group as an alter-
native phenolic protecting group.
[a] Dr. A. Kumar,+ Dr. M. Saleeb,+ D. Werz, Prof. M. Elofsson
Department of Chemistry, Umeꢀ University
90187, Umeꢀ (Sweden)
E-mail: mikael.elofsson@umu.se
[+] These authors contributed equally to this work
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/open.201800214.
The synthesis of anigopreissin A using cPrMe protection
commenced with preparation of the key intermediates 4, 8
and 10 (Scheme 1). The terminal alkyne 4 was synthesized in
three steps from 4-hydroxybenzaldehyde 1, starting with the
protection of the free phenolic group with the cyclopropyl-
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Scheme 1. Construction of key intermediates. Reagents and conditions: a) bromomethyl-cyclopropane, K2CO3, acetone, 808C, 12 h, 92% for 2 and 89% for 8;
b) CBr4, PPh3, DCM, 08C, 0.5 h, 81%; c) LDA, THF, À788C to rt, 16 h, 87%; d) BBr3, CH2Cl2, 08C to rt, 4 h, 90%; e) bis(pinacolaton)diboron, potassium acetate,
Pd2(dba)3·CHCl3, X-Phos, dioxane, 1108C, 18 h, 74%; f) NaBH4, MeOH, 08C to rt, 1 h; then SOCl2, Et2O, rt, 2 h, 83% over two steps; g) triethylphosphite, 1308C,
15 h, 81%.
methyl bromide to afford protected 4-hydroxybenzaldehyde 2.
The desired terminal alkyne 4 was then synthesized from com-
pound 2 via Corey–Fuchs reaction over two steps going
through the dibromoalkene intermediate 3 as shown in
Scheme 1.
I2 and used for the tandem Pd-Cu mediated domino Sonoga-
shira-hetero-annulation reaction with alkyne 4 to give inter-
mediate 13 (Scheme 2). O-alkylation of the free hydroxyl group
with the cyclopropylmethyl bromide gave the protected inter-
mediate 14, which was converted to aryl iodide 15 upon iodi-
nation with NIS/TFA. Next, the C-3-aryl-group was introduced
through microwave-assisted Suzuki-cross-coupling of inter-
mediate 15 with boronate ester 8 to provide compound 16.
The microwave-assisted Wittig–Horner olefination of aldehyde
16 with the phosphonate ester 10 afforded only trans-isomer
of penta-protected anigopreissin A 17, which was subjected to
deprotection under various conditions. Firstly, we started to
study the acid lability of this protecting group using HCl/THF
under microwave irradiation. Under these conditions anigo-
preissin A was fully deprotected at 1008C under microwave in
43% yield.
The boronate ester 8 was synthesized over three steps start-
ing with the demethylation of the commercially available 1-
bromo-3,5-dimethoxybenzene 5 using BBr3 to give intermedi-
ate 6. Subsequently, pinacol boronate 8 was prepared via Pd-
catalyzed coupling of arylbromide 6 and diboronyl reagent to
give boronic ester 7, which was protected with cPrMe groups
to afford the key intermediate 8. The phosphonate ester 10
was synthesized using our previously reported route[10] from
cPrMe-protected 4-hydroxybenzaldehyde 2, which was trans-
formed to the corresponding benzyl chloride 9 upon reduction
with NaBH4 and treatment with thionyl chloride. The resultant
benzyl chloride 9 was reacted with triethylphosphite to yield
the required phosphonate ester 10.
With this promising result, we went forward to confirm the
feasibility of cleaving cPrMe ethers with other reagents that
are typically used for the methyl ether cleavage such as BBr3
and BCl3. To our delight, both BBr3 and BCl3/TBAI were success-
To construct the benzofuran ring, 3,5-dihydroxy-4-iodoben-
zaldehyde 12 was prepared via iodination of aldehyde 11 with
Scheme 2. Synthesis of anigopreissin A. Reagents and conditions: a) I2, H2O2, H2O, 508C, 12 h, 61%; b) Pd(PPh3)2Cl2, CuI, 4, DMF, TEA, 508C, 12 h, 61%; c) bro-
momethyl-cyclopropane, K2CO3, DMF, 808C, 12 h, 82%; d) NIS, TFA, DCM, 08C to rt, 4 h, 61%; e) Pd(dppf)Cl2·CH2Cl2, K2CO3, 8, THF:H2O (2:1), MWI, 708C, 1 h,
0
70%; f) 10, NaH, THF, MWI, 1408C, 110 min, 52%; g) 12m HCl, THF, MWI, 1008C, 0.5 h, 43%; h) BBr3, DCM, À78 C to rt, 16 h, 38%; i) BCl3/TBAI, THF, 08C to rt,
4 h, 34%.
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ful to yield anigopreissin A 18 in 38% and 34% respectively
compared to the methyl ether protecting group in which BBr3
failed to give the desired polyphenol.[11] In terms of yield, the
cPrMe group is superior to the methyl ether, which resulted
only in 23% yield using BCl3/TBAI.[11]
which was subjected to microwave-assisted Suzuki reaction
with previously synthesized boronic ester 8 to furnish the
cross-coupled product 26. The phosphonate ester for the
Wittig–Horner olefination (31) was synthesized in four steps
from 3,5-dihydroxybenzaldehyde (Scheme 4). The free hydroxyl
groups of 3,5-dihydroxybenzaldehyde 27 were protected as
cPrMe-ethers 28 and aldehyde was reduced to the correspond-
ing alcohol using NaBH4. This alcohol intermediate 29 was
then transformed into bromide 30 under Appel reaction condi-
tions. Subsequently, treatment of benzyl bromide with triethyl-
phosphite provided the required phosphonate ester 31. Even-
tually, Wittig–Horner olefination of aldehyde 26 and phospho-
nate ester 31 using NaH as a base under microwave irradiation
gave the desired penta-protected resveratrol–piceatannol
hybrid 32. To deprotect the resveratrol–piceatannol hybrid, we
first applied HCl/THF that was successfully applied for anigo-
preissin A (Scheme 2). However, to our surprise this reagent
failed to remove all cyclopropylmethyl groups even at elevated
temperatures (Table 1, entry 1–3) and mixtures of inseparable
products were formed. We also investigated the effect of other
protic acids such as HBr or TFA, that also failed to produce the
desired product (Table 1, entry 4–5). We then turned to BBr3
and BCl3/TBAI systems and we found that BBr3 produced the
desired polyphenol 33 in 69% yield (Table 1, entry 6), while
BCl3/TBAI gave the desired resveratrol–piceatannol hybrid 33
in 34% yield (Table 1, entry 7).
Encouraged by these results, we turned our attention to-
wards the synthesis of resveratrol–piceatannol hybrid using
cPrMe protection. Although resveratrol–piceatannol hybrid was
successfully prepared using methyl ether protecting group, the
final deprotection step resulted in low yield (13%) when using
BCl3/TBAI.[11] The synthetic strategy for resveratrol–piceatannol
hybrid utilizing cPrMe protection is outlined in Scheme 3. Ini-
tially, we attempted to start from the commercially available 3-
hydroxy-2-iodo-4-methoxybenzaldehyde 19 and 4-ethynylani-
sole to construct the benzofuran ring 20 via microwave-assist-
ed Sonogashira-hetero-annulation reaction. However, all at-
tempts to switch protecting groups from methyl ethers of 20
to reach the cPrMe-protected intermediate 24 were not suc-
cessful and typically resulted in either mono-deprotection or
decomposition. This result also further highlights the need for
alternative protecting groups for this class of compounds. In-
stead, we prepared the dihydroxylated iodobenzaldehyde 22
by treating 19 with BBr3, and used it directly for the construc-
tion of the benzofuran ring 23 followed by alkylation with cy-
clopropylmethyl bromide under basic condition to afford pro-
tected 2-aryl-benzofuran 24. The resulting product was bromi-
nated with N-bromosuccinimide to give aryl bromide 25,
Scheme 3. Synthesis of the resveratrol–piceatannol hybrid. Reagents and conditions: a) BBr3, DCM, À788C to rt, 12 h, 77% for 22 and 0% for 21;
b) Pd(PPh3)2Cl2, CuI, 4-ethynylanisole for 20 and alkyne 4 for 23, THF, TEA, MWI, 0.5 h, 408C (i); CH3CN, MWI, 0.5 h, 1008C, 82% for 20 and 23 (ii); c) K2CO3, bro-
momethyl-cyclopropane, acetone, 808C, 16 h, 75%; d) NBS, DCM, rt, 4 h, 75%; e) Pd(dppf)Cl2·CH2Cl2, 8, K2CO3, THF:H2O (2:1), MWI, 708C, 1 h, 81%; f) THF, NaH,
31, MWI, 1408C, 110 min, 56%.
Scheme 4. Construction of phosphonate ester. Reagents and conditions: a) DMF, K2CO3, bromomethyl-cyclopropane, 808C, 12 h, 90%; b) MeOH, NaBH4, 08C
to rt, 1 h, 93%; c) CBr4, PPh3, DCM, 08C, 0.5 h, 92%; d) triethylphosphite, 1308C, 15 h, 71%.
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Table 1. Summary of reagents and conditions tested to deprotect the
penta-protected resveratrol–piceatannol hybrid.
Entry
Reagent
Condition[a]
Time[h]
Yield [%]
1.
2
3
4
5
HCl/THF
HCl/THF
HCl/THF
HBr/EtOH
TFA/DCM
BBr3/DCM
BCl3/TBAI/DCM
MWI 1008C
MWI 1308C
rt
MWI 1008C
rt
1
0[b]
0[b]
0.5
24
0.5
12
16
6
0[b]
0[b]
0[b]
69[c]
34[c]
6
7.
À788C to rt
08C to rt
[a] MWI=microwave irradiation, rt=room temperature. Yields are based
on [b] TLC and LCMS, [c] isolated yield
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In summary, we have explored the use of the cPrMe protect-
ing group in synthesis of resveratrol-based polyphenolic natu-
ral products. Generally, the cPrMe group offers more choices
for removal compared to the conventional methyl ether, which
typically requires harsh conditions and often resulting in un-
predictable outcomes and low yields. We successfully applied
the cPrMe protecting group in the total synthesis of anigo-
preissin A and resveratrol–piceatannol hybrid. The cPrMe
group can readily incorporated in the synthetic sequences and
is stable to a wide variety of chemistries. Finally, it can be re-
moved using a variety of acidic conditions and proved to be
more versatile than the methyl group that is typically used in
syntheses of polyphenolic compounds. Given the chemostabili-
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cPrMe group can be applied as a general protecting group for
polyphenols.
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Acknowledgements
This work was supported by the Swedish Research Council (VR,
621–2014–4670) and Umeꢀ Centre for Microbial Research
(UCMR), Umeꢀ, Sweden.
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Conflict of Interest
[14] a) C. Tancharoen, Master Thesis, Kasetsart University, 2012; b) P. Conver-
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The authors declare no conflict of interest.
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Keywords: anigopreissin A
group · deprotection · resveratrol–piceatannol hybrid · total
synthesis
·
cyclopropylmethyl protecting
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Received: October 13, 2018
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COMMUNICATIONS
A. Kumar, M. Saleeb, D. Werz,
M. Elofsson*
&& – &&
Cyclopropylmethyl Protection of
Phenols: Total Synthesis of the
Resveratrol Dimers Anigopreissin A
and Resveratrol–Piceatannol Hybrid
Don’t be overprotective: The cyclopro-
pylmethyl protecting group is success-
fully used as an alternative to methyl
ethers in the total synthesis of anigo-
preissin A and resveratrol–piceatannol
hybrid.
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