Selective Prenylation of Protected Phenols for Synthesis of Pawhuskin A Analogues

Article abstract of DOI:10.1021/acs.joc.5b02756

(Figure Presented) Pawhuskin A is a prenylated stilbene that functions as an antagonist of the kappa opioid receptor. Analogues of this natural product bearing different placements of the prenyl group in the A-ring have shown selectivity for either the ka

Full text of DOI:10.1021/acs.joc.5b02756

Article
pubs.acs.org/joc
Selective Prenylation of Protected Phenols for Synthesis of
Pawhuskin A Analogues
Kevyn D. Gardner and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States
S
* Supporting Information
ABSTRACT: Pawhuskin A is a prenylated stilbene that functions as an antagonist of the kappa opioid receptor. Analogues of
this natural product bearing different placements of the prenyl group in the A-ring have shown selectivity for either the kappa or
the delta receptors subtypes. This differential activity has drawn attention to regiospecific preparation of the C-2, C-5, and C-6
prenylated A-ring regioisomers. Through halogen metal exchange, advanced intermediates representing each of these
regioisomers have been prepared, and the new C-6 intermediate has been converted to a new analogue of the natural stilbene.
INTRODUCTION
■
The linear intermediates of isoprenoid metabolism often are
appended to aromatic compounds to generate meroterpe-
noids,1 products of mixed biogenetic origin. Various enzymes
mediate these additions, but in general they display exquisite
regiocontrol. As just one example, biosynthetic studies have
indicated that farnesylation of 3,4-dihydroxybenzoic acid occurs
at C-5 in the basidiomycete Chroogomphus rutilus to afford
compound 1, while geranylgeranylation occurs at C-2 in Suillus
bovines to give compound 2 (Figure 1).2 It can be challenging
for the synthetic chemist to accomplish this regiocontrol, and
with unsymmetrical stilbenes where both aromatic rings can be
viewed as C-prenylated phenols the challenges only grow. Of
particular interest to us, both the schweinfurthins3 (e.g., 3 and
4) and the pawhuskins4 (e.g., 5) display different oxygenation
patterns on the aromatic core and both rings bear isoprenoid
substituents.
The prominence of prenylated compounds in nature,
together with the significant biological activity that they often
display, has generated substantial interest in development of
applicable synthetic methodology. Even so, selective addition of
a prenyl chain in a complicated system still can prove to be
difficult.5 Approaches that have been explored include Claisen
rearrangements,6−8 olefin cross metathesis,8,9 and Suzuki
reactions.10,11 All of these strategies have limitations and may
require a specific adjacent functional group, regiocontrolled
installation of a precursor such as an allyl group, and/or a
particular skeletal motif.
Figure 1. Selected examples of C-prenylated phenols.
ring.14 More recently, we have become interested in the
pawhuskins, which have different placements of the isoprenoid
substituent in both the catechol and the resorcinol rings and
which were reported to demonstrate activity toward an opioid
During the course of our syntheses of schweinfurthin A12 and
B,13 we relied upon a halogen metal exchange reaction for
introduction of the geranyl chain used to generate the A- and B-
rings, while directed ortho metalation (DoM) was employed to
introduce the isoprenoid substituent on a precursor to the D-
Received: December 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
receptor in an ex vivo tissue preparation.4 The synthesis of
pawhuskin A15 and some methylated analogues16,17 allowed
more detailed bioassays and identified these compounds as
functional antagonists in cell lines transfected with individual
human receptor subtypes. However, while both the natural
product 5 and the analogue 6 (Figure 2) have greater affinity
phosphite,22,23 which gave phosphonate 12 in a single step with
a yield comparable to the more traditional Arbuzov sequence24
(Scheme 2). Upon exposure of phosphonate 12 to NaH,
Scheme 2. Synthesis and Prenylation of Phosphonate 12
Figure 2. Pawhuskin analogues with apparent affinity as antagonists at
the opioid receptors (μM).16,17
for the kappa opioid receptor, the isomeric compound 7
recently has been found to be a selective antagonist of the delta
opioid receptor.17 Given the growing interest in non-nitro-
genous compounds as opioid receptor ligands18−20 and the
observation that simple modification of the prenyl group
placement in compounds 6 and 7 significantly altered the
opioid receptor selectivity, strategies that could deliver
prenylated aromatic compounds with regiospecificity became
a priority.
followed by treatment with n-BuLi,25 reaction with prenyl
bromide provided the undesired isomer 13 as the major
product (31%), along with small amounts of both the C-2 and
the C-5 prenylated compounds. Use of LiHMDS instead of
NaH did not provide a better outcome. Instead, based on the
31P NMR spectrum of the reaction mixture it was clear that the
major product again was the result of prenylation at the α-
position.
Numerous aromatic alkylations have been accomplished
through halogenated precursors,26−28 and so the next approach
was to consider formation of the three prenylated regiosomers
through the corresponding bromide intermediates. While cross-
coupling reactions might allow introduction of the prenyl
substituent,29−31 an sp2−sp3 coupling can be challenging and a
set of conditions more parallel to the DoM route could be
based on halogen metal exchange reactions. From either
perspective, a retrosynthetic analysis of the three alcohols 10,
11, and 14 suggested that they could arise from protected
intermediates 15−17, which in turn might be derived from the
three commercially available bromobenzaldehydes (18−20,
Scheme 3). All three of the bromides 18,32,33 19,26,34 and
2035,36 also can be readily prepared.
Analogues 6 and 7 originally were synthesized from MOM-
protected 3,4-dihydroxybenzaldehyde (8) utilizing a DoM
approach (Scheme 1). After reduction of the aldehyde to the
Scheme 1. Prenylation of a Benzyl Alcohol via Directed
Ortho Metalation17,21
In the synthetic direction, the bromides 18−20 were treated
with MOMCl, followed by aldehyde reduction under standard
conditions (Scheme 4) to provide the desired benzylic alcohol
intermediates 21−23 in high yields.
benzyl alcohol, metalation and reaction with prenyl bromide
gave both the 2- and the 5-substituted isomers (10 and 11) in
low to modest yields under all of the conditions examined.17,21
While this strategy allowed synthesis of several target
compounds, formation of both isomers limits the yield of
either and complete separation of the alcohols 10 and 11 has
become more critical given the different biological activity of
the stilbenes prepared from them. Furthermore, observation of
significant activity in both the 2- and the 5-substituted
compounds piqued our interest in preparation of compounds
in the C-6 prenylated series, the remaining A-ring regioisomer.
Herein is described the exploration of alternative methods to
the C-2 and C-5 isomers as well as a parallel approach for
preparation of the C-6-substituted compounds. Synthesis of the
C-6 alcohol ultimately allowed preparation of a new pawhuskin
regioisomer which will be examined for its opioid-like activity.
Scheme 3. Alternative Strategy Parallel to a DoM Sequence
RESULTS AND DISCUSSION
■
Because a DoM approach with alcohol 9 did allow prenylation,
albeit affording a mixture of regioisomers, the feasibility of a
dianion strategy with a different substrate was examined. First,
the benzylic alcohol 9 was treated with zinc iodide and triethyl
B
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Synthesis of Aryl Bromide Isomers 21−23
Scheme 6. Halogen Metal Exchange Sequence with TBS
Ethers 27−29
Compound 22 was readily available from the relatively
inexpensive 5-bromovanillin, and therefore, this isomer was
used to explore halogen metal exchange conditions37 in the
presence of different alcohol protecting groups. A benzyl
methyl ether (24) was utilized first because that group has
proven so useful in syntheses of schweinfurthins13,38 and other
hexahydroxanthenes39 (Scheme 5). With the methyl ether 24 it
Scheme 5. Solvent Impact on Prenylation of the 5-Bromo
Isomer
and 14 in overall yields of 38%, 58%, and 14%, respectively,
over 5 steps. Thus, this reaction sequence gave the known
products 10 and 11 in yields higher than those obtained from
the DoM sequence (vide supra),15,17,21 avoids the need for
purification of the isomers, and also gives access to the new C-6
isomer 14 in a modest overall yield.
In the series of TBS ethers, there may be several reasons why
the C-2 and C-6 isomers are lower yielding in the alkylation
reaction than the corresponding C-5 isomer, including steric
effects and the possibility of a retro-Brook rearrangement as a
competing side reaction.42 To avoid the possibility of a silyl
rearrangement, use of a parallel sequence with THP ethers was
examined (Scheme 7). Protection to the corresponding THP
intermediates 33−35 proved to be straightforward. Treatment
of the C-2, C-5, and C-6 isomers with n-BuLi and prenyl
bromide gave the desired products 36−38 in reasonable yields.
Selective hydrolysis of the THP acetal in the presence of two
MOM acetals proved somewhat challenging. Attempted
was determined that treatment with n-BuLi followed by prenyl
bromide in Et2O provided the desired prenyl compound 25 but
in only modest yield, while the debrominated starting material
26 was the major product. Fortunately simple modification of
the reaction conditions to use of THF as the solvent gave
compound 25 in 67% yield and the undesired 26 in only 15%
yield.
Scheme 7. Halogen Metal Exchange Reactions with THP
It would be attractive to take advantage of the small methyl
group as the protecting group, and this strategy was successful
in our earlier work when there were no prenyl groups present at
the time of deprotection.13,38,39 However, in this case,
attempted use of DDQ to cleave the benzyl methyl ether did
not give any significant amount of the desired aldehyde under
standard conditions.13,40,41 Therefore, other protecting groups
were explored.
Ethers 33−35
The halogen metal exchange protocol was successfully
conducted on a TBS-protected 5-bromovanillin derivative,
followed by alkylation with geranyl bromide, during synthesis of
schweinfurthin intermediates.26 Therefore, one might assume
that it would be reasonable to employ a TBS group with all
three isomeric aryl bromides (Scheme 6). Introduction of the
TBS group was accomplished under standard conditions in all
three cases, providing the desired silyl compounds 27−29 in
acceptable yields. Upon treatment with n-BuLi and prenyl
bromide, the C-5 isomer was alkylated smoothly while the C-2
and C-6 isomers gave more modest yields. Nevertheless, all
three isomers were prenylated regiospecifically, and depro-
tection of the silyl compounds was possible in high yield. The
overall sequence provided the desired alcohol isomers 10, 11,
C
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
hydrolysis by treatment with TsOH in methanol gave the
desired products 10 and 14 in low yields, accompanied by
products of MOM hydrolysis. Fortunately, reaction with
collidine and TESOTf cleanly afforded the benzylic alcohols
10 (83%) and 14 (79%) while preserving the MOM-protected
phenols.43 Thus, the overall yields of the known C-2 compound
10 and new C-6 isomer 14 were 55% and 35%, respectively, for
the 5-step sequences from the corresponding benzaldehydes 18
and 20. The C-5 isomer already had been obtained in a
comparable yield (58%) via the TBS-protected sequence, so the
THP derivative was not carried through the hydrolysis step.
Through the halogen metal exchange approach, the
formation of the desired alcohol 14 was accomplished in a
reasonable yield and in sufficient quantity to complete the
synthesis of the new pawhuskin analogue 42 (Scheme 8).
ether works best for preparation of the C-5 isomer, whereas the
C-2 and C-6 isomers are best prepared via intermediates with a
THP protecting group. The C-6 regioisomer has been prepared
for the first time and used to generate the new pawhuskin
analogue 42. This stilbene has been synthesized as a single
isomer in 13% yield over 8 steps through the halogen metal
exchange approach. With the new C-6 analogue 42 now in
hand, additional bioassays with the various opioid receptors will
be pursued and results of those assays will be reported in due
course.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Both tetrahydrofuran
(THF) and diethyl ether (Et2O) were freshly distilled from sodium
and benzophenone, whereas methylene chloride (CH2Cl2) was
distilled from calcium hydride prior to use. The ZnI2 was oven dried
overnight, and solutions of n-BuLi were purchased from a commercial
source and titrated with diphenylacetic acid prior to use. All other
reagents and solvents were purchased from commercial sources and
used without further purification. All reactions in nonaqueous solvents
were conducted in flame-dried glassware under a positive pressure of
argon and with a magnetic stir bar. NMR spectra were obtained at 300
Scheme 8. Preparation of a C-6 Analogue of Pawhuskin A
1
or 500 MHz for H, 75 or 125 MHz for 13C NMR, and 121 or 202
MHz for 31P in CDCl3 with (CH3)4Si (1H, 0.00 ppm) or CDCl3 (1H,
7.26 ppm; 13C NMR; 77.0 ppm) as the internal standard. High-
resolution mass spectra were obtained by GC-TOF. Silica gel (60 Å,
0.040−0.063 mm) was used for flash column chromatography.
Diethyl 3,4-bis(methoxymethoxy)benzylphosphonate (12).
Treatment of benzylic alcohol 9 (165 mg, 0.72 mmol) in THF (15
mL) with ZnI2 (374 mg, 1.2 mmol) was followed by P(OEt)3 (0.3 mL,
1.7 mmol). The reaction was heated at reflux overnight before the heat
source was removed, and the reaction mixture was concentrated in
vacuo. The residual oil was diluted with EtOAc and washed with 2 M
NaOH, and the aqueous layer was extracted with Et2O. The combined
organic layers were dried (MgSO4) and filtered, and the filtrate was
concentrated in vacuo to provide phosphonate 12 (221 mg, 88%) as a
1
clear oil, with a H NMR spectrum that matched closely to known
data.24
Diethyl (1-(3,4-bis(methoxymethoxy)phenyl)-4-methylpent-3-en-
1-yl)phosphonate (13). To a stirred suspension of NaH (60%
dispersion in mineral oil, washed with hexanes, 38 mg, 0.94 mmol) in
THF (0.34 mL), phosphonate 12 (322 mg, 0.92 mmol) in THF was
added at room temperature. After 1 h, the reaction mixture was placed
in an ice bath, followed by dropwise addition of n-BuLi (2.44 M in
hexanes, 0.42 mL, 1.03 mmol). After 20 min, prenyl bromide (0.13
mL, 1.13 mmol) was added and the ice bath was removed. After an
additional hour, the reaction mixture was quenched by addition of 2 N
HCl. The aqueous layer was extracted with CHCl3, dried (MgSO4),
and filtered, and the filtrate was concentrated in vacuo. Final
purification via flash column chromatography (0.25−1% EtOH in
CH2Cl2) afforded the new prenyl compound 13 (119 mg, 31%) as a
Treatment of alcohol 14 with triethyl phosphite and zinc
iodide22,23 gave the desired phosphonate 39 in excellent yield.
Condensation of phosphonate 38 with the known aldehyde
4015−17,21 under standard HWE conditions provided the
stilbene 41 in 75% yield, with no apparent steric impact of
the prenyl group ortho to the phosphonate. Final hydrolysis of
the MOM protecting groups afforded the new pawhuskin
analogue 42.
Full characterization of the biological activity of compound
42 has not yet been completed. However, preliminary studies
with a FLIPR assay of Ca2+ mobilization44 in kappa opioid
receptor expressing CHO cells suggest that this compound has
modest activity as either an antagonist or a negative allosteric
modulator when compared to the known kappa agonist
U50,488.45 A more thorough profile of its activity and
selectivity for the various opioid receptors is underway and
will be reported in due course.
1
pale green oil: H NMR (300 MHz, CDCl3) δ 7.12−7.08 (m, 2H),
6.92 (dt, J = 8.5, 2.2 Hz, 1H), 5.25−5.20 (m, 4H), 4.96 (t, J = 6.6 Hz,
1H), 4.13−3.74 (m, 4H), 3.52 (s, 3H), 3.51 (s, 3H), 2.94 (ddd, JHP
=
21.3 Hz, J = 11.0, 4.0 Hz, 1H), 2.77 (m, 1H), 2.59 (m, 1H), 1.60 (s,
3H), 1.56 (d, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 146.8 (d, JCP = 2.6 Hz), 146.3 (d, JCP
=
3.4 Hz), 133.2 (d, JCP = 1.6 Hz), 130.3 (d, JCP = 6.7 Hz), 123.3 (d, JCP
= 7.1 Hz), 121.3 (d, JCP = 15.6 Hz), 118.0 (d, JCP = 6.8 Hz), 116.4 (d,
JCP = 2.6 Hz), 95.5, 95.4, 62.2 (d, JCP = 6.9 Hz), 61.6 (d, JCP = 7.2 Hz),
56.1, 56.0, 44.2 (d, JCP = 135.5 Hz), 28.4 (d, JCP = 2.6 Hz), 25.5, 17.7,
16.3 (d, JCP = 5.9 Hz), 16.2 (d, JCP = 5.9 Hz); 31P NMR (121 MHz,
CDCl3) δ 28.7; and HRMS (EI+) m/z calcd for C20H33O7P (M+)
416.1964, found 416.1967.
General Procedure for MOM Protection. Treatment of the
diphenol in THF with DIPEA at 0 °C was followed by addition of
MOMCl in small portions. The reaction was allowed to warm over
time, and the resulting solution was quenched by addition of saturated
In conclusion, all three prenylated regioisomers of the 3,4-
dihydroxybenzaldehyde derivatives were synthesized through a
halogen metal exchange sequence. Both the C-2 and the C-5
regioisomers now have been formed selectively and in higher
yields than the original DoM route, despite the additional steps.
The halogen metal exchange strategy in the presence of a TBS
D
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NH4Cl and extracted with EtOAc.26,46 The combined organic layers
were washed with 1 M NaOH and brine, dried (MgSO4), and filtered,
and the filtrate was concentrated in vacuo to give the desired
bis(methoxymethoxy) compound.
provided the desired methyl ether 24 (0.88 g, 83%) as a clear oil with
an NMR spectrum that closely matches the reported literature.38
1,2-Bis(methoxymethoxy)-5-(methoxymethyl)-3-(3-methylbut-2-
en-1-yl)benzene (25) and 1,2-bis(methoxymethoxy)-4-
(methoxymethyl)benzene (26). To a solution of methyl ether 24
(313 mg, 0.97 mmol) in THF (1 mL) in a dry ice/acetone bath was
added n-BuLi (2.50 M in hexanes, 0.4 mL, 1.0 mmol). After 8 min,
prenyl bromide (0.15 mL, 1.1 mmol) in THF (1.5 mL) was slowly
added. The bath was allowed to warm to just above 0 °C over 2 h,
before the reaction was quenched by addition of H2O and extracted
with EtOAc. The combined organic layers were washed with brine,
dried (MgSO4), and filtered, and the filtrate was concentrated in
vacuo. Further purification via flash column chromatography (5%
EtOAc in hexanes) afforded the prenyl compound 25 (202 mg, 67%)
as a clear oil and compound 26 (36 mg, 15%) as a clear oil. For
(2-Bromo-3,4-bis(methoxymethoxy)phenyl)methanol (21). Di-
phenol 18 (2.12 g, 9.8 mmol) in THF (40 mL) and CH2Cl2 was
treated with DIPEA (5.6 mL, 32.2 mmol) and MOMCl (2.8 mL, 36.9
mmol) under standard MOM protection conditions. After the reaction
was stirred for 5 h, standard workup gave 2-bromo-3,4-bis-
(methoxymethoxy)benzaldehyde as a white solid: 1H NMR (500
MHz, CDCl3) δ 10.14 (d, J = 0.6 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H),
7.09 (d, J = 5.1 Hz, 1H), 5.10 (s, 2H), 5.19 (s, 2H), 3.57 (s, 3H), 3.39
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 190.5, 155.6, 143.6, 128.0,
126.0, 122.9, 114.1, 98.6, 94.6, 57.8, 56.3; HRMS (EI+) m/z calcd for
C11H13BrO5 (M+) 303.9946, found 303.9959.
1
Under standard aldehyde reduction conditions,26,46 2-bromo-3,4-
bis(methoxymethoxy)benzaldehyde in MeOH (100 mL) was treated
with NaBH4 (0.419 g, 11.1 mmol) and the reaction was allowed to
warm overnight. Standard workup provided benzyl alcohol 21 (2.84 g,
compound 25: H NMR (500 MHz, CDCl3) δ 6.97 (d, J = 1.5 Hz,
1H), 6.80 (d, J = 1.0 Hz, 1H), 5.26 (m, 1H), 5.19 (s, 2H), 5.10 (s,
2H), 4.35 (s, 2H), 3.59 (s, 3H), 3.50 (s, 3H), 3.41 (d, J = 7.0 Hz, 2H),
3.38 (s, 3H), 1.74 (s, 3H), 1.71 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 149.7, 144.2, 135.9, 134.2, 132.5, 122.6, 122.4, 113.6, 99.0, 95.1, 74.5,
58.1, 57.4, 56.2, 28.5, 25.7, 17.8; HRMS (EI+) m/z calcd for C17H26O5
1
95% over 2 steps) as a white solid: mp 57−60 °C; H NMR (300
MHz, CDCl3) δ 7.15 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H),
5.19 (s, 2H), 5.18 (s, 2H), 4.66 (br s, 2H), 3.67 (s, 3H), 3.49 (s, 3H),
2.50 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 150.0, 144.0, 134.5,
124.1, 118.2, 115.3, 98.8, 95.2, 64.8, 57.9, 56.2; HRMS (EI+) m/z calcd
for C11H15BrO5 (M+) 306.0103, found 306.0091.
1
(M+) 310.1780, found 310.1776. For compound 26: H NMR (500
MHz, CDCl3) δ 7.15 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H),
6.92 (dd, J = 8.3, 1.8 Hz, 1H), 5.23 (s, 2H), 5.21 (s, 2H), 4.36 (s, 2H),
3.51 (s, 3H), 3.50 (s, 3H), 3.36 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 147.1, 146.6, 132.5, 121.7, 116.5, 116.2, 95.3, 95.2, 74.1, 57.7, 55.9,
55.9.47
((2-Bromo-3,4-bis(methoxymethoxy)benzyl)oxy)(tert-butyl)-
dimethylsilane (27). Treatment of benzyl alcohol 21 (1.42 g, 4.6
mmol) in CH2Cl2 (19 mL) with TBSCl (0.927 g, 6.2 mmol) and
imidazole (0.964 g, 14.2 mmol) under standard conditions26 for 2 h
followed by workup gave the silyl compound 27 (1.74 g, 89%) as a
clear oil: 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J = 8.4 Hz, 1H), 7.13
(d, J = 8.7 Hz, 1H), 5.19 (s, 2H), 5.18 (s, 2H), 4.69 (s, 2H), 3.67 (s,
3H), 3.50 (s, 3H), 0.96 (s, 9H), 0.12 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 149.4, 143.7, 135.0, 122.7, 116.6, 115.5, 98.9, 95.4, 64.5,
58.0, 56.2, 25.9 (3C), 18.4, −5.4 (2C); HRMS (EI+) m/z calcd for
C13H20BrO5Si (M+) 363.0263, found 363.0253.
(3-Bromo-4,5-bis(methoxymethoxy)phenyl)methanol (22). Com-
pound 19 (2.51 g, 11.6 mmol) in THF (50 mL) was treated with
DIPEA (6.8 mL, 39.0 mmol) and MOMCl (2.7 mL, 35.6 mmol)
under standard conditions. Following the usual workup, the resulting
orange oil was diluted with MeOH (115 mL) and treated with NaBH4
(0.497 g, 13.1 mmol) under standard conditions. The reaction was
allowed to warm to rt over 1 day, and standard workup gave benzyl
1
alcohol 22 (3.50 g, 99% over 2 steps) as an orange oil. The H NMR
spectrum closely matches the reported literature.14,46
(2-Bromo-4,5-bis(methoxymethoxy)phenyl)methanol (23). Di-
phenol 20 (2.37 g, 10.9 mmol) in THF (44 mL) was treated with
DIPEA (6.4 mL, 36.7 mmol) and MOMCl (2.5 mL, 32.9 mmol)
under standard conditions. After warming to rt overnight, the usual
workup gave 2-bromo-4,5-bis(methoxymethoxy)benzaldehyde as an
((3-Bromo-4,5-bis(methoxymethoxy)benzyl)oxy)(tert-butyl)-
dimethylsilane (28). Under standard conditions benzyl alcohol 22
(1.05 g, 3.4 mmol) in CH2Cl2 (14 mL) was treated with TBSCl (0.729
g, 4.8 mmol) and imidazole (0.712 g, 10.5 mmol). After 2 h, the usual
workup provided silyl compound 28 (1.23 g, 85%) as a clear oil, and
1
orange solid: H NMR (300 MHz, CDCl3) δ 10.19 (s, 1H), 7.69 (s,
1H), 7.41 (s, 1H), 5.32 (s, 2H), 5.27 (s, 2H), 3.53 (s, 3H), 3.51 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 190.6, 152.7, 146.6, 127.6, 120.9,
119.8, 116.2, 95.3, 95.1, 56.6, 56.4; HRMS (EI+) m/z calcd for C11H13
BrO5 (M+) 303.9946, found 303.9950.
46,48
1
the H NMR spectrum matched known data.
((2-Bromo-4,5-bis(methoxymethoxy)benzyl)oxy)(tert-butyl)-
dimethylsilane (29). Under standard conditions, benzyl alcohol 23
(427 mg, 1.4 mmol) in CH2Cl2 (6 mL) was treated with TBSCl (280
mg, 1.9 mmol) and imidazole (292 mg, 4.3 mmol). After 1 h, workup
Under standard conditions aldehyde 2-bromo-4,5-bis-
(methoxymethoxy)benzaldehyde in MeOH (110 mL) was treated
with NaBH4 (0.47 g, 12.3 mmol), and the reaction was allowed to
warm to rt over 1 day. The resulting solution was quenched by
addition of H2O and brine and concentrated in vacuo. The aqueous
layer was extracted with EtOAc, and the combined organic phases
were washed with brine, dried (MgSO4), and filtered, and the filtrate
was concentrated in vacuo to afford benzylic alcohol 23 (3.10 g, 92%
1
afforded silyl ether 29 (369 mg, 63%) as a clear oil: H NMR (300
MHz, CDCl3) δ 7.41 (s, 1H), 7.31 (s, 1H), 5.21 (s, 2H), 5.19 (s, 2H),
4.66 (d, J = 0.9 Hz, 2H), 3.50 (s, 3H), 3.49 (s, 3H), 0.97 (s, 9H), 0.13
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 146.6, 146.4, 134.3, 120.2,
116.0, 112.2, 95.5, 95.4, 64.0, 56.0, 55.9, 25.7 (3C), 18.1, −5.5 (2C);
HRMS (EI+) m/z calcd for C17H29BrO5Si (M+) 420.0968, found
420.0950.
1
over 2 steps) as a tan solid: mp 51−55 °C; H NMR (300 MHz,
CDCl3) δ 7.36 (s, 1H), 7.29 (s, 1H), 5.23 (s, 2H), 5.22 (s, 2H), 4.67
(d, J = 6.3 Hz, 2H), 3.51 (s, 6H), 1.93 (t, J = 6.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 147.1, 146.7, 133.7, 120.6, 117.0, 114.3, 95.5,
95.4, 64.7, 56.3 (2C); HRMS (EI+) m/z calcd for C11H15BrO5 (M+)
306.0103, found 306.0114.
((3,4-Bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)benzyl)oxy)
tert-butyl)dimethylsilane (30). To a stirred solution of silyl
compound 27 (1.65 g, 3.9 mmol) in THF (8 mL) in a dry ice/
acetone bath, n-BuLi (2.5 M in hexanes, 1.6 mL, 4.0 mmol) was added
slowly. After 14 min, prenyl bromide (0.6 mL, 5.0 mmol) in THF (2
mL) was added slowly. The bath was allowed to warm to 5 °C over 3 h
before the reaction was quenched by addition of H2O and extracted
with EtOAc, and the organic layer was washed with brine. The
combined organic phases were dried (MgSO4) and filtered, and the
filtrate was concentrated in vacuo. Further purification via flash column
chromatography (2% EtOAc in hexanes) gave prenyl compound 30
1-Bromo-2,3-bis(methoxymethoxy)-5-(methoxymethyl)benzene
(24). Treatment of benzylic alcohol 22 (1.01 g, 3.3 mmol) in THF (12
mL) with NaH (60% dispersion in mineral oil, 162 mg, 4.0 mmol) at 0
°C was followed by addition of CH3I (0.3 mL, 4.8 mmol). After
stirring for 5 h, NaH (60% dispersion in mineral oil, 84 mg, 2.1 mmol)
and CH3I (0.2 mL, 3.2 mmol) were added and the reaction was
allowed to continue stirring while it warmed to rt overnight. The
reaction was quenched by addition of saturated NH4Cl and extracted
with EtOAc. The combined organic layers were washed with brine,
dried (MgSO4), and filtered, and the filtrate was concentrated in
vacuo. The resulting oil was diluted with EtOAc and filtered. Final
purification via flash column chromatography (15% EtOAc in hexanes)
1
(0.831 g, 52%) as a pale yellow oil: H NMR (500 MHz, CDCl3) δ
7.15 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 5.17 (s, 2H), 5.09−
5.06 (m, 3H), 4.64 (s, 2H), 3.58 (s, 3H), 3.49 (s, 3H), 3.42 (d, J = 6.5
Hz, 2H), 1.76 (s, 3H), 1.67 (d, J = 1.0 Hz, 3H), 0.93 (s, 9H), 0.07 (s,
E
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6H); 13C NMR (125 MHz, CDCl3) δ 148.8, 144.6, 134.1, 133.0,
131.3, 122.9, 122.7, 113.8, 99.2, 95.2, 62.5, 57.4, 56.1, 25.9 (3C), 25.6,
25.1, 18.4, 17.9, −5.3 (2C); HRMS (EI+) m/z calcd for C22H38O5Si
(M+) 410.2489, found 410.2486.
h. The usual workup was followed by final purification via flash column
chromatography (4−5% EtOAc in hexanes) to provide acetal 33 (1.74
g, 96%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.21 (d, J = 8.7
Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 5.19 (s, 2H), 5.18 (s, 2H), 4.80−
4.74 (m, 2H), 4.54 (d, J = 12.9 Hz, 1H), 3.92 (m, 1H), 3.67 (s, 3H),
3.56 (m, 1H), 3.48 (s, 3H), 1.95−1.48 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 149.9, 144.0, 132.3, 124.4, 118.6, 115.1, 98.7, 98.1, 95.1,
68.4, 62.0, 57.8, 56.1, 30.4, 25.3, 19.2; HRMS (EI+) m/z calcd for
C16H23BrO6 (M+) 390.0678, found 390.0701.
2-((3-Bromo-4,5-bis(methoxymethoxy)benzyl)oxy)tetrahydro-
2H-pyran (34). Treatment of benzyl alcohol 22 (1.05 g, 3.4 mmol) in
CH2Cl2 (12 mL) with DHP (0.6 mL, 6.6 mmol) and PPTS (92 mg,
0.4 mmol) under standard conditions was allowed to proceed for 6 h.
After workup, final purification via flash column chromatography (4%
EtOAc in hexanes) gave the desired acetal 34 (1.13 g, 84%) as a clear
oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J = 1.8 Hz, 1H), 7.09 (d, J
= 2.1 Hz, 1H), 5.19 (s, 2H), 5.17 (s, 2H), 4.70−4.66 (m, 2H), 4.40 (d,
J = 12.3 Hz, 1H), 3.89 (m, 1H), 3.66 (s, 3H), 3.54 (m, 1H), 3.49 (s,
3H), 1.90−1.52 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 150.8, 143.3,
135.7, 125.5, 117.6, 115.2, 98.7, 97.7, 95.2, 67.7, 62.1, 57.8, 56.3, 30.4,
25.3, 19.2; HRMS (EI+) m/z calcd for C16H23BrO6 (M+) 390.0678,
found 390.0687.
((3,4-Bis(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)benzyl)-
oxy)(tert-butyl)dimethysilane (31). To a solution of bromide 28 (2.41
g, 5.7 mmol) in THF (10 mL) in a dry ice/acetone bath was slowly
added n-BuLi (2.50 M in hexanes, 2.5 mL, 6.3 mmol). After 12 min,
prenyl bromide (0.87 mL, 7.5 mmol) in THF (4 mL) was added over
5 min. The bath was allowed to warm to 13 °C over 4 h before the
reaction was quenched by addition of H2O. The resulting solution was
extracted with EtOAc, and the combined organic phases were washed
with brine, dried (MgSO4), and filtered, and the filtrate was
concentrated in vacuo. Final purification via flash column chromatog-
raphy (0.5% to 2% EtOAc in hexanes) afforded prenyl compound 31
(1.86 g, 79%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 6.97 (d, J
= 1.8 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 5.31 (m, 1H), 5.17 (s, 2H),
5.09 (s, 2H), 4.65 (s, 2H), 3.59 (s, 3H), 3.49 (s, 3H), 3.40 (d, J = 7.5
Hz, 2H), 1.74 (d, J = 0.9 Hz, 3H), 1.71 (s, 3H), 0.94 (s, 9H), 0.09 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 149.6, 143.4, 137.4, 135.6, 132.5,
122.7, 120.4, 112.0, 99.1, 95.2, 64.6, 57.4, 56.0, 28.5, 25.9 (3C), 25.7,
18.3, 17.8, −5.3 (2C); HRMS (EI+) m/z calcd for C22H38O5Si (M+)
410.2489, found 410.2488.
2-((2-Bromo-4,5-bis(methoxymethoxy)benzyl)oxy)tetrahydro-
2H-pyran (35). Treatment of benzyl alcohol 23 (1.13 g, 3.7 mmol) in
CH2Cl2 (15 mL) with DHP (0.70 mL, 7.7 mmol) and PPTS (95 mg,
0.38 mmol) under standard conditions was allowed to proceed for 5 h.
The usual workup was followed by final purification via flash column
chromatography (5% EtOAc in hexanes) to afford the new acetal 35
((4,5-Bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)benzyl)-
oxy)(tert-butyl)dimethylsilane (32). To a stirred solution of bromide
29 (350 mg, 0.83 mmol) in THF (1 mL) in a dry ice/acetone bath, n-
BuLi (2.5 M in hexanes, 0.34 mL, 0.85 mmol) was added slowly. After
11 min, prenyl bromide (0.14 mL, 1.2 mmol) in THF (1.1 mL) was
added slowly. The bath was allowed to warm to 6 °C over 4 h before
the reaction was quenched by addition of H2O and extracted with
EtOAc. The combined organic layers were washed with brine, dried
(MgSO4), and filtered, and the filtrate was concentrated in vacuo. Final
purification via flash column chromatography (1−2% EtOAc in
hexanes) provided the desired prenyl compound 32 (97 mg, 29%) as a
1
(1.10 g, 77%) as a clear oil: H NMR (300 MHz, CDCl3) δ 7.25 (s,
1H), 7.22 (s, 1H), 5.12 (s, 2H), 5.10 (s, 2H), 4.66−4.61 (m, 2H), 4.40
(d, J = 12.9 Hz, 1H), 3.83 (m, 1H), 3.49−3.40 (m, 7H), 1.86−1.42
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 146.9, 146.3, 131.4, 120.4,
117.5, 114.5, 98.0, 95.3, 95.3, 68.0, 61.9, 56.0, 55.9, 30.2, 25.2, 19.1;
HRMS (EI+) m/z calcd for C16H23BrO6 (M+) 390.0678, found
390.0680.
1
clear oil: H NMR (500 MHz, CDCl3) δ 7.31 (s, 1H), 6.97 (s, 1H),
2-((3,4-Bis(methoxymethoxy)-2-(3-methylbuten-2-en-1-yl)-
benzyl)oxy)tetrahydro-2H-pyran (36). n-BuLi (2.5 M in hexanes, 3.8
mL, 9.5 mmol) was added slowly to a stirred solution of bromide 33
(3.53 g, 9.0 mmol) in THF (20 mL) in a dry ice/acetone bath. After 9
min, prenyl bromide (1.5 mL, 13.0 mmol) in THF (3.5 mL) was
added and the bath was allowed to warm to 4 °C over 3 h before the
reaction was quenched by addition of H2O. The resulting solution was
extracted with EtOAc, and the organic layer was washed with brine.
The aqueous layer was extracted with EtOAc, and the combined
organic extracts were dried (MgSO4) and filtered. The filtrate was
concentrated in vacuo followed by purification of the resulting oil via
flash column chromatography (5% EtOAc in hexanes) to give the
prenyl compound 36 (2.47 g, 72%) as a pale yellow oil: 1H NMR (500
MHz, CDCl3) δ 7.09 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H),
5.18 (s, 2H), 5.11 (m, 1H), 5.09 (s, 2H), 4.71 (d, J = 12.0 Hz, 1H),
4.67 (t, J = 3.5 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 3.91 (m, 1H), 3.59
(s, 3H), 3.56−3.49 (m, 6H), 1.85 (m, 1H), 1.77 (s, 3H), 1.74−1.58
(m, 6H), 1.55−1.49 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 149.5,
144.9, 135.2, 131.2, 130.9, 125.4, 123.2, 113.7, 99.1, 97.8, 95.1, 66.7,
62.0, 57.4, 56.1, 30.6, 25.6, 25.5 (2C), 19.3, 18.0; HRMS (EI+) m/z
calcd for C21H32O6 (M+) 380.2199, found 380.2175.
2-((3,4-Bis(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)benzyl)-
oxy)tetrahydro-2H-pyran (37). To a solution of bromide 34 (1.12 g,
2.9 mmol) in THF (5 mL) in a dry ice/acetone bath was slowly added
n-BuLi (2.34 M in hexanes, 1.3 mL, 3.0 mmol). After 10 min, prenyl
bromide (0.45 mL, 3.9 mmol) in THF (2 mL) was added over 2 min.
The bath was allowed to warm to 12 °C over 4 h before the reaction
was quenched by addition of H2O. The resulting solution was
extracted with EtOAc, and the combined organic phases were washed
with brine, dried (MgSO4), and filtered, and the filtrate was
concentrated in vacuo. Final purification via flash column chromatog-
raphy (5% EtOAc in hexanes) afforded prenyl compound 37 (0.74 g,
69%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 7.00 (d, J = 2.0 Hz,
1H), 6.84 (d, J = 1.5 Hz, 1H), 5.31 (m, 1H), 5.18 (d, J = 0.5 Hz, 2H),
5.09 (s, 2H), 4.70−4.68 (m, 2H), 4.41 (d, J = 12.0 Hz, 1H), 3.92 (m,
5.25−5.22 (m, 5H), 4.68 (s, 2H), 3.54 (s, 3H), 3.53 (s, 3H), 3.25 (d, J
= 7.0 Hz, 2H), 1.75 (s, 3H), 1.74 (s, 3H), 0.97 (s, 9H), 0.12 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 145.9, 145.4, 133.4, 132.6, 132.3,
122.7, 117.9, 116.1, 95.7, 95.7, 62.3, 56.1, 55.9, 30.7, 25.9 (3C), 25.6,
18.3, 17.8, −5.4 (2C); HRMS (EI+) m/z calcd for C22H38O5Si (M+)
410.2489, found 410.2467.
(3,4-Bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)phenyl)-
methanol (10). Silyl compound 30 (0.824 g, 2.0 mmol) in THF (68
mL) was treated with TBAF (1.0 M in THF, 2.2 mL, 2.2 mmol) under
standard conditions.26 After 3 h, the usual workup followed by flash
column chromatography (10−12% EtOAc in hexanes) afforded benzyl
alcohol 10 (0.517 g, 87%) as a cloudy white oil.15,17,21
(3,4-Bis(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)phenyl)-
methanol (11). Silyl compound 31 (897 mg, 2.2 mmol) in THF (70
mL) was treated with TBAF (1.0 M in THF, 2.4 mL, 2.4 mmol) under
standard conditions for 1 h. The usual workup followed by further
purification via flash column chromatography (10−15% EtOAc in
hexanes) afforded benzylic alcohol 11 (565 mg, 87%) as a yellow
oil.16,21
(4,5-Bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)phenyl)-
methanol (14). Silyl compound 32 (95 mg, 0.23 mmol) in THF (7.8
mL) was treated with TBAF (1.0 M in THF, 0.26 mL, 0.26 mmol)
under standard conditions. After 2 h, standard workup followed by
purification via flash column chromatography (12% EtOAc in hexanes)
1
provided benzyl alcohol 14 (56 mg, 82%) as a cloudy white oil: H
NMR (300 MHz, CDCl3) δ 7.17 (s, 1H), 6.99 (s, 1H), 5.24−5.19 (m,
5H), 4.60 (s, 2H), 3.51 (s, 3H), 3.51 (s, 3H), 3.33 (d, J = 6.9 Hz, 2H),
1.83−1.72 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 146.6, 145.3,
134.2, 132.8, 132.6, 123.2, 118.2, 117.3, 95.5 (2C), 62.8, 56.1 (2C),
31.0, 25.6, 17.9; HRMS (EI+) m/z calcd for C16H24O5 (M+) 296.1624,
found 296.1622.
2-((2-Bromo-3,4-bis(methoxymethoxy)benzyl)oxy)tetrahydro-
2H-pyran (33). Treatment of benzyl alcohol 21 (1.42 g, 4.6 mmol) in
CH2Cl2 (19 mL) with DHP (0.65 mL, 7.2 mmol) and PPTS (121 mg,
0.48 mmol) under standard conditions49 was allowed to proceed for 6
F
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 3.59 (s, 3H), 3.54 (m, 1H), 3.50 (s, 3H), 3.40 (d, J = 7.5 Hz,
2H), 1.86 (m, 1H), 1.77−1.71 (m, 7H), 1.66−1.51 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ 149.6, 144.1, 135.8, 134.2, 132.5, 122.6,
122.5, 113.8, 99.0, 97.7, 95.2, 68.7, 62.2, 57.4, 56.1, 30.5, 28.5, 25.7,
25.4, 19.4, 17.8; HRMS (EI+) m/z calcd for C21H32O6 (M+) 380.2199,
found 380.2182.
(19 mg, 0.06 mmol) in THF (1.3 mL). The reaction was allowed to
warm to rt overnight before it was quenched by addition of saturated
NH4Cl and the organic layer was extracted with EtOAc. The
combined organic phases were washed with brine, dried (MgSO4),
and filtered, and the filtrate was concentrated in vacuo. Further
purification via flash column chromatography (2% EtOAc in hexanes)
1
afforded stilbene 41 (27 mg, 75%) as a cloudy white oil: H NMR
2-((4,5-Bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)benzyl)-
oxy)tetrahydro-2H-pyran (38). To a stirred solution of bromide 35
(1.10 g, 2.8 mmol) in THF (5.0 mL) in a dry ice/acetone bath was
slowly added n-BuLi (2.5 M in hexanes, 1.2 mL, 3.0 mmol). After 11
min, prenyl bromide (0.5 mL, 4.3 mmol) in THF (2.0 mL) was added
over 1 min. The bath was allowed to warm to 11 °C for 5 h before the
reaction was quenched by addition of H2O. The resulting solution was
extracted with EtOAc, and the organic layer was washed with brine.
The combined organic extracts were dried (MgSO4) and filtered, and
the filtrate was concentrated in vacuo. Final purification via flash
column chromatography (5% EtOAc in hexanes) gave the new prenyl
(500 MHz, CDCl3) δ 7.38 (s, 1H), 7.11 (s, 2H), 6.97 (s, 1H), 6.69 (d,
J = 2.5 Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H), 5.23 (s, 5H), 5.12 (m, 1H),
5.05 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.53 (s, 6H), 3.42 (d, J = 6.5
Hz, 2H), 3.38 (d, J = 7.0 Hz, 2H), 2.03 (m, 2H), 1.95 (m, 2H), 1.78
(s, 3H), 1.74 (s, 3H), 1.72 (s, 3H), 1.61 (s, 3H), 1.54 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 158.5, 158.4, 147.0, 145.7, 138.3, 134.4,
134.3, 132.1, 121.2, 130.7, 127.7, 127.3, 124.4, 123.4, 123.2, 121.3,
117.8, 114.5, 101.9, 98.0, 95.8, 95.5, 56.2, 56.2, 55.7, 55.3, 39.7, 32.0,
26.8, 25.7, 25.6, 24.4, 18.0, 17.6, 16.3; HRMS (EI+) m/z calcd for
C35H48O6 (M+) 564.3451, found 564.3427.
1
4-((E)-2-((E)-3,7-Dimethylocta-2,6-dien-1-yl)-3,5-dimethoxystyr-
yl)-5-(3-methylbut-2-en-1-yl)benzene-1,2-diol (42). Bis-
(methoxymethoxy) acetal 41 (27 mg, 0.05 mmol) in MeOH (4
mL) and THF (0.8 mL) was treated with TsOH (40 mg, 0.21 mmol)
at rt, and the reaction was allowed to stir overnight before it was
quenched by addition of saturated NaHCO3. The organic layer was
extracted with EtOAc, dried (MgSO4), and filtered, and the filtrate was
concentrated in vacuo. Final purification via preparative TLC (25%
EtOAc in hexanes, run twice) provided the desired analogue 42 (11
compound 38 (0.67 g, 62%) as a clear oil: H NMR (300 MHz,
CDCl3) δ 7.18 (s, 1H), 6.98 (s, 1H), 5.26−5.18 (m, 5H), 4.74−4.67
(m, 2H), 4.42 (d, J = 11.4 Hz, 1H), 3.92 (m, 1H), 3.58−3.50 (m, 7H),
3.32 (d, J = 6.9 Hz, 2H), 1.93−1.50 (m, 12H); 13C NMR (75 MHz,
CDCl3) δ 146.6, 145.0, 134.7, 132.0, 129.9, 122.9, 118.1, 117.8, 97.7,
95.5, 95.4, 66.4, 61.9, 55.9, 55.9, 30.7, 30.4, 25.5, 25.3, 19.2, 17.7;
HRMS (EI+) m/z calcd for C21H32O6 (M+) 380.2199, found 380.2177.
General Procedure for Deprotection of THP acetals with
2,4,6-collidine and TESOTf. Treatment of the acetal in CH2Cl2 at 0
°C with 2,4,6-collidine was followed by addition of TESOTf. After 30
min the clear reaction solution was quenched by addition of H2O, and
the reaction was allowed to stir for 10 min, resulting in a cloudy white
mixture. The organic layer was extracted with CH2Cl2, and the
combined organic layers were washed with brine, dried (MgSO4), and
filtered, the filtrate was concentrated in vacuo, and the resulting oil was
purified by flash column chromatography.43
(3,4-Bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)phenyl)-
methanol (10). Acetal 36 (0.50 g, 1.3 mmol) in CH2Cl2 (13.2 mL)
was treated with 2,4,6-collidine (0.54 mL, 4.1 mmol) and TESOTf
(0.60 mL, 2.7 mmol) under standard conditions. Further purification
via flash column chromatography (15% EtOAc and 1% TEA in
hexanes) provided the desired benzylic alcohol 10 (325 mg, 83%) as a
yellow oil.
1
mg, 51%) as a gel-like orange oil: H NMR (500 MHz, CDCl3) δ
7.12−7.09 (m, 2H), 7.06 (d, J = 16.0 Hz, 1H), 6.71−6.69 (m, 2H),
6.41 (d, J = 2.5 Hz, 1H), 5.25−5.20 (m, 2H), 5.12 (m, 1H), 5.07−5.05
(m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.42 (d, J = 7.0 Hz, 2H), 3.34 (d, J
= 6.5 Hz, 2H), 2.05 (m, 2H), 1.97 (m, 2H), 1.78 (s, 3H), 1.73 (s, 6H),
1.62 (d, J = 0.5 Hz, 3H), 1.55 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
158.6, 158.5, 143.3, 141.7, 138.4, 134.6, 133.0, 132.2, 131.3, 129.4,
127.5, 126.7, 124.4, 123.5, 123.2, 121.2, 116.2, 112.7, 101.9, 97.9, 55.7,
55.3, 39.7, 31.4, 26.8, 25.7, 25.6, 24.4, 17.9, 17.6, 16.3; HRMS (EI+)
m/z calcd for C31H40O4 (M+) 476.2927, found 476.2917.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02756.
(4,5-Bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)phenyl)-
methanol (14). Acetal 38 (270 mg, 0.71 mmol) in CH2Cl2 (7.0 mL)
was treated with 2,4,6-collidine (0.29 mL, 2.2 mmol) and TESOTf
(0.32 mL, 1.4 mmol) under standard conditions. Final purification via
flash column chromatography (15−18% EtOAc in hexanes) afforded
benzylic alcohol 14 (166 mg, 79%) as a pale yellow oil.
1H and 13C NMR spectra of compounds 13, 14, 21, 23,
1
25−27, 29−39, 41, and 42, and the H NMR spectra of
compounds 10 and 11 (PDF)
Diethyl 4,5-bis(methoxymethoxy)-2-(3-methylbut-2-en-1-yl)-
benzylphosphonate (39). To a stirred mixture of oven-dried ZnI2
(84 mg, 0.26 mmol) and P(OEt)3 (0.06 mL, 0.34 mmol) was added
benzylic alcohol 14 (41 mg, 0.14 mmol) in THF (3 mL). The reaction
was heated at reflux overnight before the heat source was removed,
and the solution was concentrated in vacuo. The resulting oil was
washed with 2 M NaOH, and the organic layer was extracted with
Et2O. The combined organic layers were dried (MgSO4) and filtered,
and the filtrate was concentrated in vacuo to provide phosphonate 39
AUTHOR INFORMATION
Corresponding Author
*E-mail: david-wiemer@uiowa.edu
Notes
■
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
1
■
(57 mg, 98%) as a pale orange oil: H NMR (500 MHz, CDCl3) δ
We thank Prof. Jeffrey D. Neighbors (Pennsylvania State
University) for providing the bioassay data on compound 42
and Mr. Vic Parcell (University of Iowa) for providing the
HRMS data. Financial support from the Roy J. Carver
Charitable Trust (no. 01-224) is greatly appreciated.
7.07 (d, J = 3.0 Hz, 1H), 7.00 (s, 1H), 5.19 (s, 5H), 4.05−4.00 (m,
4H), 3.51−3.50 (m, 6H), 3.36 (d, J = 7.0 Hz, 2H), 3.10 (d, JHP = 21.0
Hz, 2H), 1.73, (s, 6H), 1.26 (t, J = 7.0 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 146.2 (d, JCP = 4.0 Hz), 145.2 (d, JCP = 3.8 Hz), 134.9 (d,
JCP = 7.3 Hz), 132.6, 123.7 (d, JCP = 9.4 Hz), 122.7 (d, JCP = 0.9 Hz),
119.5 (d, JCP = 5.1 Hz), 118.1 (d, JCP = 3.3 Hz), 95.6 (2C), 61.8 (d, JCP
= 6.8 Hz, 2C), 56.1, 56.1, 31.5 (d, JCP = 1.3 Hz), 30.0 (d, JCP = 138.1
Hz), 25.6, 17.9, 16.4, 16.3; 31P NMR (202 MHz, CDCl3) δ 26.8;
HRMS (EI+) m/z calcd for C20H33O7P (M+) 416.1964, found
416.1988.
REFERENCES
■
(1) Itoh, T.; Tokunaga, K.; Matsuda, Y.; Fujii, I.; Abe, I.; Ebizuka, Y.;
Kushiro, T. Nat. Chem. 2010, 2, 858.
(2) Muhlbauer, A.; Beyer, J.; Steglich, W. Tetrahedron Lett. 1998, 39,
1-((E)-4,5-Bis(methoxymethoxy-2-(3-methylbut-2-en-1-yl)styryl)-
2-(E)-3,7-dimethylocta-2,6-dien-1-yl)-3,5-dimethoxybenzene (41).
To a solution of KHMDS (1.0 M in THF, 0.32 mL, 0.32 mmol) at
0 °C was added phosphonate 39 (41 mg, 0.10 mmol) and aldehyde 40
5167.
(3) Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. J. Nat.
Prod. 1998, 61, 1509.
G
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(4) Belofsky, G.; French, A. N.; Wallace, D. R.; Dodson, S. L. J. Nat.
Prod. 2004, 67, 26.
(5) Hoarau, C.; Pettus, T. R. R. Synlett 2003, 127.
(6) Crombie, L.; Jamieson, S. V. J. Chem. Soc., Perkin Trans. 1 1982,
1467.
(41) Tso, H.-H.; Hwang, T.-K.; Chen, Y.-J. Bull. Inst. Chem., Acad.
Sin. 1994, 41, 25.
(42) Bariak, V.; Malastova, A.; Almassy, A.; Sebesta, R. Chem. - Eur. J.
2015, 21, 13445.
(43) Fujioka, H.; Okitsu, T.; Ohnaka, T.; Sawama, Y.; Kubo, O.;
Okamoto, K.; Kita, Y. Adv. Synth. Catal. 2007, 349, 636.
(44) Coward, P.; Chan, S. D. H.; Wada, H. G.; Humphries, G. M.;
Conklin, B. R. Anal. Biochem. 1999, 270, 242.
(45) Szmuszkovicz, J.; Vonvoigtlander, P. F.; Kane, M. P. J. Med.
Chem. 1981, 24, 1230.
(7) Iikubo, K.; Ishikawa, Y.; Ando, N.; Umezawa, K.; Nishiyama, S.
Tetrahedron Lett. 2002, 43, 291.
(8) Escobar, Z.; Solano, C.; Larsson, R.; Johansson, M.; Salamanca,
E.; Gimenez, A.; Munoz, E.; Sterner, O. Tetrahedron 2014, 70, 9052.
(9) Horeischi, F.; Biber, N.; Plietker, B. J. Am. Chem. Soc. 2014, 136,
4026.
(10) Kapdi, A. R.; Prajapati, D. RSC Adv. 2014, 4, 41245.
(11) Wang, H.-M.; Zhang, L.; Liu, J.; Yang, Z.-L.; Zhao, H.-Y.; Yang,
Y.; Shen, D.; Lu, K.; Fan, Z.-C.; Yao, Q.-W.; Zhang, Y.-M.; Teng, Y.-
O.; Peng, Y. Eur. J. Med. Chem. 2015, 92, 439.
(12) Topczewski, J. J.; Kodet, J. G.; Wiemer, D. F. J. Org. Chem.
2011, 76, 909.
(46) Chakrapani, L.; Jung, E. M.; Lee, Y. R. Helv. Chim. Acta 2010,
93, 829.
(47) Taniguchi, S.; Miyashita, Y.; Ueyama, T.; Tanaka, H.;
Matsumoto, K.; Hirase, J.; Ueda, A.; Sogawa, T.; Oshima, H.;
Nishino, M.; Okui, Y. Preparation of 1,3-benzodioxole-2-thione
derivatives for treatment of liver diseases; Shin Nippon Yakuhin Co.,
Ltd.: Japan, 1993; p 16.
(48) Jung, E. M.; Lee, Y. R. Bull. Korean Chem. Soc. 2009, 30, 2563.
(49) Tan, Y.-L.; White, A. J. P.; Widdowson, D. A.; Wilhelm, R.;
Williams, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 3269.
(13) Topczewski, J. J.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem.
2009, 74, 6965.
(14) Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F. J. Org. Chem.
1999, 64, 8718.
(15) Neighbors, J. D.; Buller, M. J.; Boss, K. D.; Wiemer, D. F. J. Nat.
Prod. 2008, 71, 1949.
(16) Hartung, A. M.; Beutler, J. A.; Navarro, H. A.; Wiemer, D. F.;
Neighbors, J. D. J. Nat. Prod. 2014, 77, 311.
(17) Hartung, A. M.; Navarro, H. A.; Wiemer, D. F.; Neighbors, J. D.
Bioorg. Med. Chem. Lett. 2015, 25, 5532.
(18) Prisinzano, T. E. J. Med. Chem. 2013, 56, 3435.
(19) Riley, A. P.; Groer, C. E.; Young, D.; Ewald, A. W.; Kivell, B. M.;
Prisinzano, T. E. J. Med. Chem. 2014, 57, 10464.
(20) Simonson, B.; Morani, A. S.; Ewald, A. W. M.; Walker, L.;
Kumar, N.; Simpson, D.; Miller, J. H.; Prisinzano, T. E.; Kivell, B. M.
Br. J. Pharmacol. 2015, 172, 515.
(21) Hartung, A. M. Ph. D. Thesis, University of Iowa, 2014.
(22) Richardson, R. M.; Barney, R. J.; Wiemer, D. F. Tetrahedron Lett.
2012, 53, 6682.
(23) Barney, R. J.; Richardson, R. M.; Wiemer, D. F. J. Org. Chem.
2011, 76, 2875.
(24) Wang, Y. M.; Mathis, C. A.; Huang, G. F.; Holt, D. P.; Debnath,
M. L.; Klunk, W. E. J. Labelled Compd. Radiopharm. 2002, 45, 647.
(25) Grieco, P. A.; Pogonowski, C. S. J. Am. Chem. Soc. 1973, 95,
3071.
(26) Mente, N. R.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem.
2008, 73, 7963.
(27) Takaoka, S.; Nakade, K.; Fukuyama, Y. Tetrahedron Lett. 2002,
43, 6919.
(28) Paz, J. L.; Rodrigues, J. A. R. J. Braz. Chem. Soc. 2003, 14, 975.
(29) Farmer, J. L.; Hunter, H. N.; Organ, M. G. J. Am. Chem. Soc.
2012, 134, 17470.
(30) Yang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 10642.
(31) Yang, Y.; Mustard, T. J. L.; Cheong, P. H. Y.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2013, 52, 14098.
(32) Pilger, C.; Westermann, B.; Florke, U.; Fels, G. Synlett 2000,
1163.
(33) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem. 1967,
32, 2358.
(34) Lange, R. G. J. Org. Chem. 1962, 27, 2037.
(35) Liu, T.; Qian, C.; Chen, X.-z. Zhejiang Daxue Xuebao,
Gongxueban 2006, 40, 520.
(36) Li, Z.-k.; Wang, L.-s.; Li, X.; Guo, D.-t.; Huang, X.-s. Guangxi
Daxue Xuebao, Ziran Kexueban 2010, 35, 467.
(37) Bridges, A. J.; Patt, W. C.; Stickney, T. M. J. Org. Chem. 1990,
55, 773.
(38) Topczewski, J. J.; Wiemer, D. F. Tetrahedron Lett. 2011, 52,
1628.
(39) Topczewski, J. J.; Callahan, M. P.; Neighbors, J. D.; Wiemer, D.
F. J. Am. Chem. Soc. 2009, 131, 14630.
(40) Feng, H.-X.; Wang, Y.-Y.; Chen, J.; Zhou, L. Adv. Synth. Catal.
2015, 357, 940.
H
DOI: 10.1021/acs.joc.5b02756
J. Org. Chem. XXXX, XXX, XXX−XXX