Total Synthesis of Viniferifuran, Resveratrol-Piceatannol Hybrid, Anigopreissin A and Analogues – Investigation of Demethylation Strategies

Article abstract of DOI:10.1002/adsc.201601089

Resveratrol-based natural products constitute a valuable source of unique compounds with diverse biological activities. In this report we investigate demethylation strategies to minimize formation of cyclized and dimerized products during the synthesis of viniferifuran and analogues. We found that boron trichloride/tetra-n-butylammonium iodide (BCl₃/TBAI) is typically more effective than boron tribromide (BBr₃). Based on these findings we carried out the first syntheses of dehydro-δ-viniferin, resveratrol-piceatannol hybrid and anigopreissin A. In addition, we have developed a short and efficient route to viniferifuran that was obtained in 13% yield over six steps. (Figure presented.).

Full text of DOI:10.1002/adsc.201601089

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DOI: 10.1002/adsc.201601089
Total Synthesis of Viniferifuran, Resveratrol-Piceatannol Hybrid,
Anigopreissin A and Analogues – Investigation of Demethylation
Strategies
Duc Duy Voa and Mikael Elofssona,*
a
Department of Chemistry, Umeꢀ University, SE90187, Umeꢀ, Sweden
E-mail: Mikael.Elofsson@umu.se
Received: October 4, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601089.
Abstract: Resveratrol-based natural products consti- ried out the first syntheses of dehydro-d-viniferin, re-
tute a valuable source of unique compounds with di- sveratrol-piceatannol hybrid and anigopreissin A. In
verse biological activities. In this report we investi- addition, we have developed a short and efficient
gate demethylation strategies to minimize formation route to viniferifuran that was obtained in 13% yield
of cyclized and dimerized products during the syn- over six steps.
thesis of viniferifuran and analogues. We found that
boron trichloride/tetra-n-butylammonium iodide Keywords: demethylation; natural products; poly-
(BCl3/TBAI) is typically more effective than boron phenols; resveratrol oligomers; stilbenoids; total syn-
tribromide (BBr3). Based on these findings we car- thesis
Introduction
allow alteration of the core structures or substituent
patterns, for example, to determine structure–activity
Stilbenoids of plant origin constitute a rich source of relationships for bioactive stilbenoids. To address this
polyphenolic compounds with intriguing structures Snyder and co-workers developed de novo methods
and diverse biological activities.[1] To date the struc- allowing the preparation of a large number of resver-
tures and absolute stereochemistry for several hun- atrol dimers and higher order stilbenoids.[5] These im-
dred higher order stilbenoids have been determined. pressive studies spawned a number of syntheses ap-
Most of these often very complex natural products plying innovative approaches for the preparation of
are formed by oligomerization of the key building racemic compounds.[5,6] The first enantiototal synthe-
block resveratrol. The large number of reports de- sis of a stilbene dimer was the case of d-viniferin (3)
scribing the positive effects of stilbenoids on human where Shaw and co-workers elegantly applied a car-
health have instigated wide interest in the chemistry bene-insertion chemistry using a rhodium catalyst to
and biology of resveratrol and its oligomers. The construct the dihydrobenzofuran core asymmetrical-
mode of action on the molecular level is, however, ly.[7] Our interest in this intriguing family of natural
known for only a few stilbenoids, for example, dip- products stems from the finding that the resveratrol
toindonesin G (13, Figure 1) that was recently identi- tetramer (À)-hopeaphenol blocks type III secretion,
fied as an inhibitor of CHIP E3 ubiquitin ligase.[2] an indispensable virulence system, in the Gram-nega-
Due to scarce quantity of many higher order stilbe- tive pathogens Yersinia pseudotuberculosis and Pseu-
noids in nature, intense efforts have been made to de- domonas aeruginosa.[8] While (À)-hopeaphenol can be
velop synthetic methods employing both biomimetic obtained in gram quantities from natural sources[9] we
and de novo strategies. Biomimetic strategies usually focused on the de novo synthesis of partial structures
involve metal- or enzyme-catalyzed oxidative cou- and recently published total syntheses of (Æ)-ampe-
plings of stilbenes but these protocols typically result lopsin B (6)[10] and (Æ)-e-viniferin (1),[10] the key inter-
in product mixtures and poor yields.[1d,3] Recent im- mediate to form almost, if not all, higher order of stil-
provements resulted in protocols for the preparation bene structures (Figure 1).[1] To further advance our
of racemic pallidol and quadrangularin by dimeriza- understanding of structural features that affect inhibi-
tion of protected resveratrol derivatives in excellent tion of type III secretion, we have continued to pre-
yields.[4] However, biomimetic methods do not readily pare resveratrol dimers. In this study we describe
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Figure 1. Selected natural and non-natural resveratrol dimers and the stilbenoid diptoindonesin G.
total syntheses of viniferifuran (2),[11] its isomer anigo- high temperature (1708C) with excess of the strong
preissin A (11)[12] and the recently reported resvera- hindered phosphazene base P4-t-Bu[17] or by using
trol-piceatannol hybrid (12)[13] (Figure 1). Viniferifur- excess of the strong base LiTMP followed by dehy-
an is a competitive inhibitor of syk kinase (IC50 = dratation using pTsOH.[18] Kim and Choi[19] on the
62 nM)[14] and this mechanism is believed to be key other hand employed a more versatile and milder
for the anti-inflammatory activity of viniferifuran. procedure to construct a 3-arylbenzofuran by cycliza-
Anigopreissin A was recently discovered as an inhibi- tion of the corresponding b-aryloxy ketone using
tor of HIV-1 reverse transcriptase (IC50 =8 mM) in- Bi(OTf)3, followed by introduction of a 2-aryl sub-
cluding two mutant enzymes resistant to the clinical stituent by Pd(OAc)2-catalyzed direct arylation.
drug nevirapine.[12b] Viniferifuran (2) is a highly sub-
After generation of an aldehyde, the styryl moiety
stituted 7-hydroxy-5-styryl-2,3-diarylbenzofuran struc- was then introduced by a Wittig–Horner reaction.[19]
ture that can be prepared in four steps starting with However, when reinvestigating the strategy by Kim
biomimetic dimerization of resveratrol to form (Æ)-e- and Choi (Supporting Information, SI-2) the Wittig–
viniferin (1).[15] Subsequent transformations including Horner reaction in our hands only resulted in very
a key oxidative dehydrogenation by DDQ furnished low conversion of aldehyde 16a to the styryl moiety
viniferifuran (2).[11] In our hands viniferifuran could 17a. Using NaH instead of t-BuOK[20] under micro-
be obtained in gram quantity in 11% yield over four wave irradiation at 1208C during 30 min produced
steps (Supporting Information, SI-1). In addition, we permethylated viniferifuran 17a in 80% yield. We
prepared a number of viniferifuran analogues and in- then modified the route described by Kim and
vestigated conditions for demethylation of phenols, Choi[19] to conveniently prepare permethylated vini-
a critical transformation in the total synthesis of re- ferifuran 17a and analogues (Scheme 1). In this modi-
sveratrol oligomers.
fied route, the ester moiety in 14a was transformed to
the aldehyde 15a before harnessing the direct aryla-
tion[10] to prepare intermediate 16a that is now ready
for the Wittig–Horner olefination to give 17a. Inter-
estingly, we could exploit the direct arylation of 15a
Results and Discussion
Despite the number of methods available to construct with a low loading of 5% of PdCl(C3H5)(dppb),[21]
the 2,3-diarylbenzofuran core,[16] only a few attempts conditions that were found to be unsuccessful with
have been made towards the total synthesis of the ester substrate 14a. Kraus and Gupta[15] reported
viniferiACHTUNGTRENNUNG
furan. Kraus and Gupta[17] and Chen et al.[18] the final demethylation of 17a to form viniferifuran
applied strategies relying on cyclization and subse- (2) in 67% yield using 1M BBr3 in CH2Cl2 at 08C.
quent dehydration of keto benzyl ethers by heating at However, when applying these conditions we ob-
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tained the cyclized product dehydroampelopsin B (9,
Figure 1) as major product (46% yield after purifica-
tion by HPLC) with only minor amounts of viniferi-
furan (not isolated) and mixtures of its dimers that
were detected by LC-MS (Supporting Information,
SI-2). Alternative protocols for demethylation were
investigated and we found that BCl3/TBAI[22] gave 2
and 9 in a 1:1 ratio without formation of dimerized
products. HPLC purification furnished pure 2 and 9,
each isolated in 23% yield (Supporting Information,
SI-2, and Table 1). We realized that the final deme-
thylation would be a challenge when synthesizing ana-
logues with variation of substituents on the A–D rings
with the goal to allow elucidation of structure–activity
relationships. This prompted us to investigate if BCl3/
TBAI could be used as a general demethylation re-
agent. Interestingly, we also found that the Tf2O-cata-
lyzed cyclization of viniferifuran (2) gave racemic de-
hydroampelopsin B (9) in 50% yield (Supporting In-
formation, SI-1). We hypothesize that this compound
might exist in nature since it is the core of shoreake-
tone (7) and malibatol A (8), both natural products
(Figure 1).[1]
We applied the modified route and prepared
a number of permethylated compounds 17b–p with
different substituents on rings B, C and D (Scheme 2,
and Supporting Information, SI-3). The carboxylic
esters 14a–i were transformed to aldehydes 15a–i by
a sequence of LiAlH4 reduction followed by a Dess–
Martin oxidation. Direct arylation of 15a–i was then
carried out with a set of aryl bromides carrying differ-
ent electron-withdrawing and electron-donating sub-
stituents. The methylated products 16b–m were ob-
tained in 35–74% yield using 10 mol% (PdOAc)2 or
47–60% using 5 mol% PdCl(C3H5)(dppb). Next, ap-
plication of our improved conditions for the Wittig–
Horner reaction to install the styryl moiety afforded
Scheme 1. Modified synthetic route to viniferifuran. Re-
agents and conditions: a) LiAlH4 (3 equiv.), THF, 08C,
10 min. b) Dess–Martin periodinane (1.2 equiv.), DCM, 08C,
1 h, 80–90%,
2 steps. c) ArBr or ArI (1.5–2 equiv.),
Pd(OAc)2 (0.1 equiv.), PCy3·HBF4 (0.2 equiv.), K2CO3
(1.5 equiv.), PivOH (3 equiv.), 1008C, 20 h, 74%. d) ArBr
(1.5–2 equiv.),
PdCl(C3H5)dppb
(0.05 equiv.),
KOAc
(2 equiv.), DMA, 1508C, 20 h, 60%. e) Phosphonate deriva-
tives (1.5 equiv.), NaH (3 equiv.), THF, 1208C, MWI,
30 min, 80%. f) BCl3, TBAI, DCM, 08C to room tempera-
ture, 6 h, 23% (HPLC).
Scheme 2. Modified synthetic route to viniferifuran. Reagents and conditions: a) ArBr or ArI (1.5–2 equiv.), Pd(OAc)2
(0.1 equiv.), PCy3·HBF4 (0.2 equiv.), K2CO3 (1.5 equiv.), PivOH (3 equiv.), 1008C, 20 h, 35–74%. b) ArBr (1.5–2 equiv.),
PdCl(C3H5)(dppb) (0.05 equiv.), KOAc (2 equiv.), DMA, 1508C, 20 h, 47–60%. c) Phosphonate derivatives (1.5 equiv.), NaH
(3 equiv.), THF, 1208C, MWI, 30 min, 52–82%. d) BCl3, TBAI, DCM, 08C to room temperature, 6 h.
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Table 1. Demethylation with BCl3/TBAI to afford viniferifuran analogues.
Substrate
R1
R2
R3
Product
Product/cyclized form[d]
Yield [%][a]
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
17p
3,5-diOMe
3,5-diOMe
3,5-diOMe
3,5-diOMe
3,5-diOMe
3,5-diOMe
3,5-diOMe
3,5-diOMe
2,5-diOMe
3-OMe
4-OMe
4-CF3
4-F
3-F
3-Cl
H
OMe
F
OMe
OMe
OMe
H
F
NO2
Cl
2
1:1
<3:7
<3:7
>9:1
1:0
–
23[b]
18a
18b
18c
18d
18e
18f
18g
18h
18i
18j
18k
18l
18m
18n
18o
(<10)[e]
COOH
OMe
OMe
OMe
NO2
(<10)[e]
50
51[b] (11)[c]
–
–
–
NH2
Cl
1:0
1:0
7:3
1:0
1:0
1:0
1:0
1:0
1:0
18[b]
46
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
24[b]
19[b]
54
53 (16)[c]
55
55
53
[a]
Isolated yields.
Purified by HPLC.
Yield with BBr31as demethylation agent.
Ratio based on H NMR of crude product.
Estimated yield, not isolated.
[b]
[c]
[d]
[e]
the permethylated intermediates 17b–p in 52–82%
Our results indicate that BCl3/TBAI is superior to
yield. Finally, we investigated the impact of the differ- BBr3 for our purposes but for some compounds the
ent substituent patterns on demethylation and cycliza- yields are still low and in several cases HPLC was re-
tion of 17b–p using BCl3/TBAI in DCM at 08C to quired to purify the compounds and remove excess
room temperature for 6 h (Table 1).
TBAI. We therefore decided to explore alternative
Under these conditions all the starting materials routes based on demethylation early in the synthetic
were consumed and we anticipated that cyclization sequence.
would be suppressed in compounds with less nucleo-
First we applied an alternative route where a set of
philic C rings. Indeed, 18h (2,5-diOH) and 18i (3-OH) D ring moieties were attached by applying the
were obtained in higher yields than viniferifuran (2) Wittig–Horner reaction on the early aldehyde inter-
and minor amounts of the cyclized product was ob- mediate 15a to afford 20a–c in 60–80% yield
served only with starting material carrying the 3-OMe (Scheme 3). Interestingly, BBr3-mediated demethyla-
group. This pattern was observed for other C-ring tion could effectively occur in these cases and after
substituents (3-H, 3-F, 3-Cl, 4-F, 4-CF3, 4-OMe) that acetylation the protected derivatives 21a–c were iso-
furnished 18k–p in 19–55% yield. Modification of ring lated in 38–62% yield. Bromination with NBS and
B with substituents such as 4-F or 4-COOH increased subsequent deacetylation furnished the bromo poly-
formation of the cyclized dehydroampelopsin B ana- phenolic substrates 22a–c. As a final step substituted
logues 35 and 36, respectively (Supporting Informa- B rings were introduced by Suzuki couplings to give
tion, SI-4) and 18a and b was observed as minor prod- the target compounds 18d and 18p--s in 41–76% yield
ucts (not isolated). We also found that removal of the (Table 2). Next we exploited the strategy previously
4-OMe group or replacement with a fluorine atom on developed for the total synthesis of (Æ)-e-viniferin.[10]
ring D reduced the degree of cyclization and afforded Direct arylation of the bromo derivative 19, prepared
18c and 18d in 50 and 51% yields, respectively. Com- in three steps from 1-bromo-3,5-dimethoxybenzene in
pounds 18e and 18f could not be isolated due to de- 59% yield,[10] installed ring B to give 23 in 36% yield
composition of the NO2 group during the demethyla- and subsequent demethylation by BBr3 produced the
tion. However, 18g could be obtained when NO2 was bromo polyphenolic substrate 24 in 96% yield
replaced by NH2. Several substrates were also deme- (Scheme 3). A set of D rings was introduced by Heck
thylated with BBr3 that typically resulted in lower couplings of the corresponding styrene derivatives
yields than BCl3/TBAI. In several cases, decomposi- gave viniferifuran (2) in 64% yield and target com-
tion occurred or complex mixtures of dimerized prod- pounds 18t–x in 25–64% yield (Table 2). This synthe-
ucts formed (Supporting Information, SI-5). Acid-cat- sis of viniferifuran is the shortest achieved to date
alyzed dimerization of stilbenes has been described and provides the target compound in 13% yield over
using a variety of acids including BBr3.[3,23]
6 steps from 1-bromo-3,5-dimethoxybenzene. Impor-
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Scheme 3. Alternative routes for the synthesis of viniferifuran and analogues. Reagents and conditions: a) Phosphonate de-
rivatives (1.5 equiv.), NaH (3 equiv.), THF, 1208C, MWI, 30 min, 60–80%. b) BBr3 (9–12 equiv.), DCM, À788C to room tem-
perature, 6 h. c) Ac2O, THF, Et3N, room temperature, overnight, 38–62%, 2 steps. d) NBS (3 equiv.), pTsOH, room tempera-
ture, 24–48 h. e) KOH, MeOH, 08C, 30 min, 15–30%, 2 steps. f) PdCl2(dppf)·DCM (5% mol), boronic acid (1.5–2 equiv.),
Na2CO3, DME/H2O (1/1), 708C, MWI, 30 min, 41–76%. g) 4-Bromoanisole (2 equiv.), Pd(OAc)2 (0.1 equiv.), PCy3·HBF4
(0.2 equiv.), K2CO3 (1.5 equiv.), PivOH (3 equiv.), 1008C, 20 h, 25–36%. h) Styrene derivatives (1.2 equiv.), Pd(OAc)2
(0.1 equiv.), dppp (0.1 equiv.), Et3N, DMF, 1208C, 20 h, 25–64%.
Table 2. Obtained viniferifuran analogues by final Suzuki or
(Figure 1). The resveratrol-piceatannol hybrid was
Heck couplings.
isolated from a Vitis extract after a bioguided fractio-
Compound
R2
R3
Yield [%][a]
nation using a hepatitis C virus replication inhibition
assay.[13] Dehydro-d-viniferin was recently synthesized
by laccase-biocatalyzed dimerization of resveratrol to
form d-viniferin (3) followed by dehydrogenation,
a strategy limited to 4-hydroxystilbene starting mate-
rials.[24]
The final demethylations by BBr3 and BCl3/TBAI
were studied on permethylated intermediates 29, 31
and 34 (Scheme 4). In order to prepare these inter-
mediates, we constructed 2-arylbenzofuran derivatives
by a one pot two-step Sonogashira cyclization applied
to o-iodophenol derivatives containing a free CHO
group using a rapid and efficient protocol recently de-
scribed by Markina et al.[25] This procedure was ap-
plied to 25 and 26 to afford 28 and 30 in 74 and 90%
yields, respectively. In the case of 27, addition of 1-
18p
18d
18q
18r
18s
18t
18u
18v
NHAc
OH
F
OH
F
OH
OH
OH
OH
OH
OH
OH
F
F
Cl
76
50
55
41
41
25[b]
58
60
64
54
64
Cl
3-NO2, 4-OH
3-OH, 4-NO2
4-COOH
4-NH2
4-EtOCOCH2O
4-OH
18w
18x
viniferifuran 2
[a]
Isolated yield.
Purified by HPLC.
[b]
tantly this strategy avoids formation of dimers or cy- iodo-3,5-dimethoxybenzene during the cyclization
clized products and also allows introduction of, for ex- step partially resulted in a direct coupling to intro-
ample, nitro and carboxylic acid substituents (cf. 18t– duce the C-3 aryl on the benzofuran and 2,3-diaryl-
x) that are not compatible with a final demethylation.
ACHTUNGTRENbNGNU enzofuran 33 and 2-arylbenzofuran 32 were isolated
Having an understanding of the different reactivity in 25% and 60% yields, respectively. Intermediates 28
of BBr3 and BCl3/TBAI, we turned our attention to and 30 were then transformed by halogenation,
the total synthesis of the benzofuryl stilbene dimers Suzuki coupling to install the C-3 aryl followed by the
anigopreissin
A a resveratrol-piceatannol Wittig–Horner reaction to achieve the permethylated
(11),[12]
hybrid (12)[13] and dehydro-d-viniferin (4)[24] intermediates 29 and 31 in 31% (5 steps from 25) and
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Scheme 4. Total synthesis of anigopreissin A, resveratrol-piceatannol hybrid and dehydro-d-viniferin. Reagents and condi-
tions: a) PdCl2(PPh3)2 (5% mol), CuI (3% mol), ethynylanisole (1.2–1.5 equiv.), Et3N/THF (2/1), MWI, 408C, 30 min then
CH3CN, 1008C, MWI, 30 min, 74–90%. b) MeI, K2CO3, DMF, room temperature, overnight, 77%. c) NIS (1 equiv.), pTsOH
cat., CH3CN, room temperature, overnight, 59%. d) PdCl2(dppf)·DCM (5% mol), 3,5-dimethoxyphenylboronic acid
(1.5 equiv.), K2CO3, DME/H2O (4/1), 80–1008C, MWI, 30 min, 83–91%. e) Phosphonate derivatives (1.5 equiv.), NaH
(3 equiv.), THF, 1208C, MWI, 30 min, 58–84%. f) BBr3, DCM, À788C to room temperature, 6 h. g) BCl3, TBAI, DCM, 08C
to room temperature, 6 h. h) NBS (1.1 equiv.), DCM, room temperature, overnight, 50%. i) PdCl2(PPh3)2 (5% mol), CuI
(3% mol), 4-ethynylanisole (1.2–1.5 equiv.), Et3N/THF (2/1), MWI, 408C, 30 min then 1-iodo-3,5-dimethoxybenzene
(1.5 equiv.), CH3CN, 1008C, MWI, 30 min, 25% 33+60% 32. j) 1-Bromo-3,5-dimethoxybenzene (1.5 equiv.),
PdCl(C3H5)dppb (5% mol), KOAc (2 equiv.), DMA, 1508C, 20 h, 60%.
27% (4 steps from 26) yields, respectively. Interesting- sired products 12 and 4 in 61% and 62% yields, re-
ly, we could also apply direct arylation of 32 with 1- spectively. The use of BCl3/TBAI was less efficient
bromo-3,5-dimethoxybenzene in the presence of and in both cases HPLC was required for purification
5 mol% PdCl(C3H5)dppb to give 33 in 60% yield. providing pure 12 and 4 in low yields. In contrast,
This is the first reported C-3 arylation of a benzofuran BBr3 failed to produce anigopreissin A while BCl3/
when C-2 is blocked by an aryl group containing an TBAI gave the target compound in 23% yield after
electron-donating 4-methoxy substituent. In a recent purification by HPLC.
study this type of arylation was unsuccessful using
Pd(OAc)2 and Sphos as ligand.[26] A Wittig–Horner re-
action was then applied to 33 to afford 34 in overall Conclusions
43% yield (3 steps from 27). During demethylation,
we again observed different reactivity between BBr3 We have prepared a number of permethylated natural
and BCl3/TBAI. Surprisingly, BBr3-mediated deme- and non-natural stilbenoid compounds and studied
thylation of stilbenes 31 and 34 which both contain demethylations using BBr3 and BCl3/TBAI. The latter
a 3,5-dimethoxystyryl moiety afforded the pure de- was found to be superior in demethylation of viniferi-
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The organic phase was dried with Na2SO4 and concentrated
under reduced pressure. FC (DCM:MeOH 9:1) afforded
a mixture that was purified using HPLC method A to give
dehydroampelopsin B 9 as yellow solid; yield: 10 mg (46%).
furan analogues and produced the product in higher
yields and with less cyclized derivatives and higher
order oligomers. In addition, strategies based on early
demethylation were explored and viniferifuran (2)
could be obtained in 13% yield over six steps, the
shortest and most efficient synthesis reported so far.
Finally, we achieved the first total syntheses of dehy-
dro-d-viniferin (4, 4 steps, 27%), resveratrol-piceatan-
nol hybrid (12, 5 steps, 16%) and anigopreissin A (11,
6 steps, 4%). The synthesis of dehydro-d-viniferin also
included a successful benzofuran C-3 arylation with
C-2 blocked by an aryl group containing an electron-
donating substituent. The methods and strategies de-
scribed have the potential be applicable in syntheses
of other stilbenoid natural products and analogues to
establish structure–activity relationships.
Procedure B: Demethylation with BCl3/TBAI
[Exemplified with Dehydroampelopsin B (9) and
Viniferifuran (2)]
To a stirred solution of 17a (25 mg, 0.048 mmol, 1 equiv.),
TBAI (265 mg, 0.72 mmol, 15 equiv.) at 08C in DCM (3 mL)
under a nitrogen atmosphere was added 1M BCl3 solution
in DCM (0.72 mL, 0.72 mmol, 15 equiv.). The mixture was
stirred at room temperature for 6 h. The reaction was
quenched with H2O (1 mL) at 08C. The mixture was diluted
with EtOAc (25 mL), washed with 10% Na2S2O3 solution
(5 mL), H2O (5 mL) and brine (5 mL). The organic phase
was dried with Na2SO4 and concentrated under reduced
pressure. FC (DCM:MeOH 9:1) afforded a 1:1 mixture of 2
and 9 that was purified using HPLC method A to give vini-
ferifuran 2 (yield: 5 mg, 23%) and dehydroampelopsin B 9
(yield: 5 mg, 23%) as yellow solids.
Experimental Section
General
Anigopreissin A (11): Application of procedure B for de-
methylation of 29 (20 mg, 0.038 mmol FC (DCM:MeOH
9:1) followed by HPLC method A gave 11 as yellow solid;
LC-MS analysis was carried out on a Waters LC system
equipped with an Xterra MS C18 18.5 mm 4.6ꢂ50 mm
column and an eluent system consisting of MeCN in water,
both of which contained 0.2% formic acid. Detection was
performed at 214 and 254 nm. Mass spectra were obtained
by use of a Waters micromass ZG 2000, using both positive
and negative electrospray ionization (ESI). 1H NMR and
13C NMR spectra were recorded on a Bruker DRX-400
spectrometer in CDCl3 solution [residual CHCl3 (dH =
7.26 ppm, dC =77.16 ppm) as internal standard] or in
SO(CD3)2 solution [residual SO(CD3)(CD2H) (dH =
2.50 ppm, dC =39.52 ppm) as internal standard] or in
CO(CD3)2 solution [residual CO(CD3)(CD2H) (dH =
2.05 ppm, dC =29.84 ppm) as internal standard] or in
CD3OD solution [residual CD2HOH (dH =3.31 ppm, dC =
49.00 ppm) as internal standard]. A Biotage Initiator 400W
was used for microwave heating. TLC analysis was carried
out using TLC aluminum sheets from EMD/Merck KGaA
(mfr. no. Merck, 1.05554.0001). Product purification was
done using Biotage flash chromatography (FC) with car-
tridge or ultra cartridge of 10 g, 25 g, 50 g or 100 g of silica
gel. HPLC purification was carried out on a Gilson system
equipped with a Macherey–Nagel Nucleodur C18 HTEC
5 mm 21ꢂ250 mm column. All eluents contained 0.005%
formic acid and the flow rate was set to 20 mL/minute for
CH3CN and 15 mL/minute for MeOH (method A: H2O/
MeOH 80/20 to 0/100 over 30 min; method B: H2O/ CH3CN
80/20 to 0/100 over 30 min).
1
yield: 4 mg (23%). H NMR (400 MHz, CD3OD): d=7.44–
7.35 (m, 4H), 7.15 (d, J=0.9 Hz, 1H), 7.06 (d, J=16.2 Hz,
1H), 6.98 (d, J=16.2 Hz, 1H), 6.78 (d, J=8.6 Hz, 2H), 6.76
(d, J=0.9 Hz, 1H), 6.71 (d, J=8.8 Hz, 2H), 6.42 (d, J=
2.2 Hz, 2H), 6.31 (t, J=2.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=159.5, 158.7, 158.4, 157.2, 153.0, 151.2, 137.2,
136.8, 130.7, 129.3, 128.9, 128.8, 127.3, 123.7, 119.1, 116.8,
116.6, 116.2, 110.3, 107.2, 102.8, 101.7;: ESI-MS m/z=
451.02, calcd. for [MÀH]À: 451.12. Analytical data were in
agreement with those reported in the literature.[12]
Resveratrol-piceatannol hybrid (12): Application of pro-
cedure A for demethylation of 31 (50 mg, 0.09 mmol). FC
(DCM:MeOH 9:1) gave 12 as yellow solid; yield: 26 mg
(61%). Application of procedure B for demethylation of 31
(25 mg, 0.045 mmol). FC (DCM:MeOH 9:1) followed by
HPLC method A gave 12 as yellow solid; yield: 3 mg
(14%). 1H NMR (600 MHz, acetone-d6): d=9.12–8.04 (br,
OHs), 7.56 (d, J=8.9 Hz, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.08
(d, J=16.2 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.82 (d, J=
8.9 Hz, 2H), 6.76 (d, J=16.2 Hz, 1H), 6.58 (t, J=2.2 Hz,
1H), 6.49 (d, J=2.2 Hz, 2H), 6.22 (d, J=2.1 Hz, 2H).6.20
(t, J=2.1 Hz, 1H); 13C NMR (150 MHz, acetone-d6): d=
161.3, 160.3, 159.6, 152.5, 143.8, 143.6, 142.1, 138.3, 131.6,
129.8, 128.2, 126.7, 125.0, 124.1, 121.8, 118.6, 117.2, 113.0,
110.9, 106.8, 104.7, 103.4; ESI.MS: m/z=467.04, calcd. for
[MÀH]: 467.11. Analytical data for the resveratrol-piceatan-
nol have not been reported in the literature.[13]
Dehydro-d-viniferin (4): Application of procedure A for
demethylation of 34 (15 mg, 0.029 mmol). FC (DCM:MeOH
9:1) gave 4 as yellow solid; yield: 8 mg (62%). Application
Procedure A: Demethylation with BBr3 [Exemplified
with Dehydroampelopsin B (9)]
To a stirred solution of 17a (25 mg, 0.048 mmol, 1 equiv.) at
08C in DCM (3 mL) under a nitrogen atmosphere was
added 1M BBr3 solution in DCM (0.72 mL, 0.72 mmol,
15 equiv.). The mixture was allowed to warm up and stirred
at room temperature for 6 h. The reaction was quenched
with H2O (1 mL) at 08C. The mixture was diluted with
EtOAc (25 mL), washed with H2O (5 mL) and brine (5 mL).
of procedure
B
for demethylation of 34 (15 mg,
0.029 mmol). FC (DCM:MeOH 9:1) gave a mixture of 4
and partially deprotected products+excess of TBAI.
1H NMR (400 MHz, acetone-d6): d=8.76 (s, 1H, OH), 8.42
(s, 2H, OHs), 8.22 (s, 2H, OHs), 7.66–7.50 (m, 5H), 7.23 (d,
J=16.3 Hz, 1H), 7.06 (d, J=16.3 Hz, 1H), 6.60 (d, J=
2.1 Hz, 2H), 6.51 (d, J=2.2 Hz, 2H), 6.45 (t, J=2.2 Hz,
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asc.wiley-vch.de
1H), 6.30 (t, J=2.1 Hz, 1H); 13C NMR (100 MHz, acetone-
d6): d=161.1, 160.6, 159.9, 155.3, 153.4, 141.6, 136.4, 134.8,
132.6, 130.6, 130.5, 129.7, 124.9, 123.8, 119.5, 117.6, 117.3,
112.8, 109.9, 106.9, 104.1, 104.0; ESI-MS: m/z=451.02,
calcd, for [MÀH]À: 451.12. Analytical data are in agreement
with those reported in the literature.[24]
d) F. Klotter, A. Studer, Angew. Chem. 2014, 126, 2505;
Angew. Chem. Int. Ed. 2014, 53, 2473; e) G. Sudhakar,
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[7] C. Soldi, K. N. Lamb, R. A. Squitieri, M. Gonzalez-
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2014, 136, 15142.
[8] C. E. Zetterstrçm, J. Hasselgren, O. Salin, R. A. Davis,
R. J. Quinn, C. Sundin, M. Elofsson, PLoS ONE 2013,
8, e81969.
Acknowledgements
[9] R. A. Davis, K. D. Beattie, M. Xu, X. Yang, S. Yin, H.
Holla, P. C. Healy, M. Sykes, T. Shelper, V. M. Avery,
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This work was supported by the Swedish Research Council
(grant 2014-4670). We are grateful to Dr. Anders Lindgren
for helpful comments on the manuscript.
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FULL PAPERS
Total Synthesis of Viniferifuran, Resveratrol-Piceatannol
Hybrid, Anigopreissin A and Analogues – Investigation of
Demethylation Strategies
9
Adv. Synth. Catal. 2016, 358, 1 – 9
Duc Duy Vo, Mikael Elofsson*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!