Total synthesis of plagiochin D by an intramolecular SNAr reaction

Article abstract of DOI:10.1002/ejoc.201001412

The total synthesis of plagiochin D, a macrocyclic bis(bibenzyl) compound isolated from the liverwort plagiochila acanthophylla, has been accomplished. Closure of the key 16-membered ring, which contained biphenyl ether and biaryl units, was achieved in good yield by an intramolecular S_NAr reaction. The Suzuki and Wittig protocols proved to be powerful tools for the construction of a linear precursor that was crucial for ring cyclization. Copyright

Full text of DOI:10.1002/ejoc.201001412

FULL PAPER
DOI: 10.1002/ejoc.201001412
Total Synthesis of Plagiochin D by an Intramolecular SNAr Reaction
Julio Cesar Cortes Morales,[a] Alejandro Guillen Torres,[a] and
Eduardo González-Zamora*[a]
Keywords: Natural products / Cyclization / Nucleophilic substitution / Total synthesis
The total synthesis of plagiochin D, a macrocyclic bis(bibenz-
yl) compound isolated from the liverwort plagiochila acan-
thophylla, has been accomplished. Closure of the key 16-
membered ring, which contained biphenyl ether and biaryl
units, was achieved in good yield by an intramolecular SNAr
reaction. The Suzuki and Wittig protocols proved to be
powerful tools for the construction of a linear precursor that
was crucial for ring cyclization.
Recently, a novel bis(bibenzyl) compound, plagiochin E
(5), was isolated from the liverwort plant Marchantia poly-
morpha L.[7] and shown to have significant antifungal ac-
tivity towards Candida albicans[8] with a minimum inhibi-
tory concentration of MIC = 16.0 μgmL–1, which is con-
Introduction
Bis(bibenzyl) systems (riccardins, plagiochins, and
marchantins) are structurally simple phenolic natural prod-
ucts that are found exclusively in bryophytes (liverworts)
and exhibit remarkable biological activity.[1–3] Cyclic bis(bi-
benzyl) compounds are categorized into three structural
types (1, 2, or 3) that comprise macrocyclic rings linked
through two biphenyl ether C–O bonds, biphenyl ether C–
O and biaryl C–C bonds, or two biaryl C–C bonds, respec-
tively. Plagiochins A–D (1–4), isolated in 1984 from Plagi-
ochila acanthophylla[4] (Figure 1), are of structural type 2
and feature a highly strained 16-membered ring system[5]
made up of biphenyl ether C–O and biaryl C–C bonds. Of
these plagiochins, plagiochin A (1), in particular, exhibits
significant neurotrophic properties.[6]
siderably lower than that of fluconazole (MIC
=
128.0 μgmL–1). Moreover, an additive effect was observed
when C. albicans was simultaneously treated with plagi-
ochin E and fluconazole.[9] Remarkable antitumor activity
has been observed, and the compound may be a potential
candidate for reversing drug resistance in cancer chemo-
therapy.[10] In 1992, Nógrádi and co-workers reported the
synthesis of plagiochin D (4), the simplest member of the
plagiochins,[11] using a Wurtz-type radical coupling at posi-
tion a to form the macrocycle (Figure 2). In 1999, Fukuy-
ama et al.[12] reported the synthesis of the same plagiochin
Figure 1. Plagiochins A–E.
[a] Departamento de Química, Universidad Autónoma
Metropolitana-Iztapalapa,
San Rafael Atlixco 186, Col. Vicentina, Iztapalapa, C.P. 09340
México, D.F
Fax: +52-55-5804-4666
E-mail: egz@xanum.uam.mx
Figure 2. Retrosynthetic analysis of plagiochin D, fragments A–D.
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J. C. Cortes Morales, A. Guillen Torres, E. González-Zamora
FULL PAPER
by an intramolecular Still–Kelly reaction at position b to
achieve the key 16-membered ring closure. Both methods
gave poor yields of 17 and 20%, respectively.
In 2001, Fukuyama et al.[13] extended the intramolecular
Still–Kelly reaction approach to the crucial 16-membered
ring cyclization to synthesize plagiochin A (1) in 31% yield.
In 2009, the total synthesis of the proposed structure of
plagiochin E (5) was achieved by Speicher and co-
workers[14] using the McMurry protocols for the key 16-
membered macrocyclization at position a, with a similar
yield (23%; Figure 2).
As part of our ongoing program to develop efficient and
robust methods, and considering the biological activities of
the bis(bibenzyl) compounds, we turned our attention to
biaryl ether formation at position c (Figure 2). Herein, we
describe a novel, efficient, and general methodology for the
total synthesis of this class of bis(bibenzyl) system using an
extension of the SNAr reaction[15] to achieve the key 16-
membered ring closure.
Scheme 2. Synthesis of fragment B. Reagents and conditions:
(a) Br2, CH2Cl2; (b) HOCH2CH2OH, APTS, benzene;
(c) (i) nBuLi, THF; (ii) B(iPrO)3; (iii) HCl, H2O.
corresponding alcohol and then bromination with PBr3 to
give the bromo derivative, which, upon treatment with
PPh3, led to the phosphonium salt (Scheme 3).
Results and Discussion
The synthesis began with the construction of the linear
precursor 6, which includes a nucleophilic phenol function
ortho to the isopropoxy group (ring C) and an electrophilic
ring A for carrying out the ring closure. This precursor was
formed by coupling four fragments, two phosphonium salts
7 and 8, a boronic acid 9, and a bromo derivative 10. The
fragments containing the corresponding protected phenol
moieties, the nucleophilic and the electrophilic functionali-
ties, are indicated in Figure 2.
The phosphonium salt 7 (fragment A), was prepared in
74% overall yield from 4-fluorobenzaldehyde (11) by a four-
step sequence involving nitration, hydride reduction, bromi-
nation, and PPh3 addition[16] (Scheme 1).
Scheme 3. Synthesis of fragment C. Reagents and conditions:
(a) iPrBr, K2CO3, DMF, 40 °C; (b) BrBn, K2CO3, DMF, 40 °C;
(c) LiAlH4, diethyl ether; (d) (i) PBr3, toluene; (ii) P(Ph)3, toluene.
Fragment D, 2-bromo-5-isopropoxybenzaldehyde (10),
was prepared in 90% overall yield by protecting the phenol
moiety of 3-hydroxybenzaldehyde (21) with isopropyl bro-
mide and subsequent bromination with bromine by the
Lian-Yun protocol[18] (Scheme 4).
Scheme 1. Synthesis of fragment A. Reagents and conditions:
(a) HNO3, H2SO4; (b) NaBH4, MeOH; (c) PBr3, toluene; (d) P-
(Ph)3, toluene.
Boronic acid 9 (fragment B) was prepared in 74% overall
yield starting from 3-methoxybenzaldehyde (14) by a three-
step sequence involving bromination, protection of the alde-
hyde moiety with ethane-1,2-diol, then treatment with
Scheme 4. Synthesis of fragment D. Reagents and conditions:
(a) iPrBr, K2CO3, DMF; (b) Br2, CH2Cl2.
Coupling of the units 8 and 10 by using the Wittig reac-
nBuLi and B(OiPr)3, and then hydrolysis under hydrochlo- tion under optimized conditions [Na2CO3(aq.), CH2Cl2]
ric acid[17] (Scheme 2).
furnished the D–C segment 22 as an (E)/(Z) mixture in a
The phosphonium salt 8 (fragment C) was prepared in ratio of 3:7 in 98% yield, and the pure forms (22E and
70% overall yield from the commercially available 3,4-di- 22Z) were obtained by silica gel column chromatography
hydroxybenzaldehyde (17) by selective protection of the (Scheme 5). The double bond of each isomer was then re-
phenol moieties with isopropyl and benzyl bromide, respec- duced quantitatively by using Wilkinson’s catalyst[19] to give
tively, followed by reduction with lithium hydride to the a single compound 23. The benzyl ether and even the aryl
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Total Synthesis of Plagiochin D
bromide were tolerated under these mild hydrogenation
conditions. Compound 23 was prepared on a larger scale
for use in the next steps by reduction of the (E)/(Z) mixture
of the crude product of the Wittig reaction. The biaryl com-
pound 24, segment B–D–C, was obtained in 86% yield by
Suzuki reaction between segment 23 and the boronic acid
9.
Scheme 6. Preparation of the precursor 6. Reagents and conditions:
(a) Na2CO3(aq.), CH2Cl2; (b) Wilkinson’s cat., THF/tBuOH;
(c) AcOH, HCl (concd.).
Scheme 5. Preparation of the precursor 24. Reagents and condi-
tions: (a) Na2CO3(aq.), CH2Cl2; (b) Wilkinson’s cat., THF/tBuOH;
(c) [Pd(PPh3)4], K2CO3, DME.
Wittig reaction between unit 24 and the phosphonium
salt 7 gave the stilbene 25 as a 1:10 (E)/(Z) mixture in 98%
yield. The (E)/(Z) mixture was reduced to compound 26 by
catalytic hydrogenation[19] in 96% yield. Selective removal
of the benzyloxy group was realized under carefully con-
trolled conditions using a solution of concentrated HCl in
AcOH to afford the precursor 6, with a free hydroxy group
for the crucial C–O ring-closure step, in 88% yield
(Scheme 6).
Macrocyclization was achieved in 86% yield through an
intramolecular SNAr reaction using K2CO3 in DMF. A dia-
stereomeric mixture was expected as a consequence of two
distinct processes: (i) Creation of an axial chiral center at
the biaryl axis (segment B–D–C) and (ii) creation of a chiral
planar center on biaryl ether bond formation (segment A–
O–C). However, the desired compound 27 was obtained as
Scheme 7. Key 16-membered ring closure and synthesis of plagi-
ochin D (4). Reagents and conditions: (a) K2CO3, DMF; (b) Pd/C
(10%), H2, THF; (c) AcOH, NaNO2, EtOH, NaHSO3, H2O;
(d) BCl3, CH2Cl2.
a
mixture of two inseparable atropisomers (Sp)/(Rp)
(Scheme 7) in a ratio of 1:1.[20]
ductive deamination[22] to afford a common product (29)
Intramolecular SNAr-based cyclization reactions were ex- devoid of the chiral planar center. Finally, removal of the
pected to produce atropisomeric mixtures of 14-, 15-, 16-, isopropyl groups by using BCl3 afforded the natural com-
and 17-membered cyclic macropolypeptides as a conse- pound plagiochin D (4; Scheme 7). The spectroscopic data
quence of the creation of a chiral planar center[21] that for compound 4 are identical to those of plagiochin D re-
could be destroyed by removal of the activating nitro group ported in the literature.[4,11,23]
in the next stages of the synthesis. Reduction (H2, Pd/C in
Thus, the bis(bibenzyl) system has been prepared by bi-
THF) gave the amine 28 as a mixture of separable atropiso- aryl ether formation (SNAr) in a critical key 16-membered
mers in quantitative yield, and the diastereomerically pure ring-closing step in 50% overall yield starting from four
forms (28a and 28b) were obtained by silica gel column simple and readily available aromatic subunits (fragments
chromatography. These compounds were submitted to re- A–D). This compares with the previously described Wurtz-
Eur. J. Org. Chem. 2011, 3165–3170
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J. C. Cortes Morales, A. Guillen Torres, E. González-Zamora
FULL PAPER
= 8.8, 3.0, 0.5 Hz, 1 H), 6.54 (d, J = 12.0 Hz, 1 H, CH=CH), 6.46
(d, J = 12.0 Hz, 1 H, CH=CH), 4.82 (s, 2 H, CH2Ph), 4.46 [sept,
J = 6.1 Hz, 1 H, OCH(CH3)2], 4.24 [sept, J = 6.1 Hz, 1 H,
OCH(CH3)2], 1.31 [d, J = 6.1 Hz, 6 H, OCH(CH3)2], 1.14 [d, J =
6.1 Hz, 6 H, OCH(CH3)2] ppm. 13C NMR (126 MHz, CDCl3,
25 °C): δ = 156.85, 149.36, 147.45, 138.98, 137.25, 133.27, 130.95,
129.82, 128.36, 128.15, 127.64, 127.17, 122.77, 117.42, 117.38,
117.01, 115.65, 114.05, 72.01 [OCH(CH3)2], 70.94 (CH2Ph), 70.07
[OCH(CH3)2], 22.16 [OCH(CH3)2], 21.77 [OCH(CH3)2] ppm. MS
(FAB): m/z = 480, 482 [M]+.
type cyclization of an ethylene bridge (Nógrádi and co-
workers, 7.4%),[11] the Still–Kelly reaction to form the bi-
aryl (Fukuyama and co-workers, 8.6 and 9.0%),[12,13] and
the McMurry protocol to form a stilbene bridge (Speicher
and co-workers, 11.9%),[14] all of which start from elabo-
rated precursors.
Conclusions
We have developed an efficient synthesis of plagiochin D
(4). An intramolecular SNAr reaction was useful for the key
16-membered ring-closing procedure and gave excellent and
reproducible yields compared with other methodologies,
which demonstrates the usefulness of intramolecular SNAr-
based methodologies for the construction of bis(bibenzyl)
systems containing biaryl ether bonds. The synthesis of the
other plagiochins by this methodology is currently un-
derway, and the method may be extended to the synthesis
of a small library by transformation of the nitro group into
amino, amido, hydroxy, or halogenated derivatives.
2-(Benzyloxy)-4-(2-bromo-5-isopropoxyphenethyl)-1-isopropoxyben-
zene (23): Wilkinson’s catalyst (4%, 20 mg) was added to a solution
of compound 22 (457 mg, 0.94 mmol) in degassed solvent (THF/
tBuOH, 1:1, 0.14 m) saturated by hydrogen. The solution was
stirred under hydrogen at room temperature. When the hydrogena-
tion was deemed complete by TLC, the reaction mixture was fil-
tered through a short Celite pad and washed thoroughly with THF.
The solvent was removed to afford 13 in quantitative yield. FTIR:
ν = 2975, 2908, 2338, 2117, 1604, 1507, 1477, 1383, 1254, 1222,
˜
1162, 1115, 1048, 985, 940, 854, 810, 732 cm–1 1H NMR
.
(500 MHz, CDCl3, 25 °C): δ = 7.47–7.45 (m, 2 H), 7.41–7.36 (m, 3
H), 7.32–7.31 (m, 1 H), 6.86 (d, J = 8.1 Hz, 1 H), 6.78 (d, J =
2.1 Hz, 1 H), 6.74 (dd, J = 8.1, 2.1 Hz, 1 H), 6.65 (d, J = 3.0 Hz,
1 H), 6.62 (dd, J = 8.7, 3.0 Hz, 1 H), 5.09 (s, 2 H, CH2Ph), 4.47
[sept, J = 6.1 Hz, 1 H, OCH(CH3)2], 4.43 [sept, J = 6.1 Hz, 1 H,
OCH(CH3)2], 2.93–2.89 (m, 2 H, CH2CH2), 2.81–2.77 (m, 2 H,
CH2CH2), 1.34 [d, J = 6.1 Hz, 6 H, OCH(CH3)2], 1.28 [d, J =
6.1 Hz, 6 H, OCH(CH3)2] ppm. 13C NMR (126 MHz, CDCl3,
25 °C): δ = 157.11, 149.88, 146.43, 141.85, 137.59, 136.15, 135.09,
133.20, 128.39, 127.67, 127.31, 121.39, 118.23, 118.08, 116.11,
115.19, 114.58, 72.33 [OCH(CH3)2], 71.38 (CH2Ph), 70.10
[OCH(CH3)2], 38.63 (CH2CH2), 35.61 (CH2 CH2), 22.30
[OCH(CH3)2], 21.93 [OCH(CH3)2] ppm. MS (FAB): m/z = 482, 484
[M]+.
Experimental Section
General: Commercially available reagents were used without further
purification. Column chromatography (CC) was carried out on sil-
ica gel 60 from Merck with particle size 0.040–0.063 mm for nor-
mal-pressure and flash chromatography. IR spectra were deter-
mined with a Perkin-Elmer Spectrum GX instrument, and mass
1
spectra were recorded with a JEOL JMS-700 instrument. H (500
MHz) and 13C (125 MHz) NMR spectra were recorded with a
Bruker AVANCE-III 500 instrument; the spectra were measured at
298 K in CDCl3 solution with TMS as internal reference.
(E/Z)-2-(Benzyloxy)-4-(2-bromo-5-isopropoxystyryl)-1-isopropoxy- 2Ј-[3-(Benzyloxy)-4-isopropoxyphenethyl]-4Ј-isopropoxy-4-meth-
benzene (22): Aq. Na2CO3 (25 mL of a 1 m solution) was added to
a solution of aldehyde 10 (2.3 g, 9.46 mmol) and phosphorus salt 8
(7.36 g, 12.29 mmol) in CH2Cl2 (50 mL). After stirring the reaction
mixture at 40 °C for 24 h, the mixture was cooled, and water was
added and then extracted with CH2Cl2. The combined organic lay-
ers were dried (Na2SO4) and concentrated under vacuum to afford
22E and 22Z as a mixture of separable isomers [(E)/(Z) = 3:7;
4.48 g, 98 % yield], which were separated by flash column
oxybiphenyl-2-carbaldehyde (24): The boronic acid 9 (244 mg,
1.35 mmol) in ethanol (5 mL) was added to a mixture of compound
23 (437 mg, 0.90 mmol), 1,2-dimethoxyethane (25 mL), [Pd-
(PPh3)4] (104 mg, 0.09 mmol), and 2 m aq. Na2CO3 (4.6 mL). After
heating at reflux for 24 h, the mixture was cooled, water was added,
and then the mixture was extracted with CH2Cl2. The combined
organic layers were dried (NaSO4) and concentrated. The product
was isolated by flash chromatography on silica gel (hexane/ethyl
chromatography (hexane/ethyl acetate, 200:1). 22E: FTIR: ν =
acetate, 20:1) in 86% yield. FTIR: ν = 2973, 2915, 2338, 2117,
˜
˜
2975, 2901, 2338, 2116, 1586, 1506, 1462, 1371, 1262, 1224, 1178,
1685, 1604, 1507, 1479, 1383, 1253, 1222, 1162, 1115, 1045, 986,
1
1164, 1108, 1026, 997, 955, 856, 801, 735 cm–1
.
1H NMR 939, 854, 813, 732 cm–1. H NMR (500 MHz, CDCl3, 25 °C): δ =
(500 MHz, CDCl3, 25 °C): δ = 7.49–7.47 (m, 2 H), 7.42 (d, J = 9.68 (s, 1 H, CHO), 7.48 (d, J = 2.7 Hz, 1 H), 7.42–7.40 (m, 2 H),
8.8 Hz, 1 H), 7.39–7.36 (m, 2 H), 7.32–7.30 (m, 1 H), 7.20 (d, J = 7.37–7.34 (m, 2 H), 7.31–7.29 (m, 1 H), 7.15 (dd, J = 8.4, 2.8 Hz,
16.1 Hz, 1 H, CH=CH), 7.14–7.12 (m, 2 H), 7.07 (ddd, J = 8.3,
1 H), 7.09 (dd, J = 8.4, 0.4 Hz, 1 H), 7.03 (d, J = 8.3 Hz, 1 H),
2.1, 0.3 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 16.1 Hz, 6.81 (d, J = 2.6 Hz, 1 H), 6.77 (dd, J = 8.3, 2.6 Hz, 1 H), 6.74 (d,
1 H, CH=CH), 6.66 (dd, J = 8.8, 3.0 Hz, 1 H), 5.17 (s, 2 H, J = 7.9 Hz, 1 H), 6.44–6.41 (m, 2 H), 4.93 (s, 2 H, CH2Ph), 4.56
CH2Ph), 4.57–4.53 [m, 2 H, OCH(CH3)2], 1.37 [d, J = 6.1 Hz, 6 [sept, J = 6.1 Hz, 1 H, OCH(CH3)2], 4.41 [sept, J = 6.1 Hz, 1 H,
H, OCH(CH3)2], 1.34 [d, J = 6.1 Hz, 6 H, OCH(CH3)2] ppm. 13C OCH(CH3)2], 3.85 (s, 3 H, OCH3), 2.70–2.56 (m, 4 H, CH2CH2),
NMR (126 MHz, CDCl3, 25 °C): δ = 157.24, 149.88, 148.53,
1.36 [dd, J = 6.1, 0.9 Hz, 6 H, OCH(CH3)2], 1.30 [dd, J = 6.1,
138.02, 137.37, 133.47, 131.01, 130.69, 128.48, 127.77, 127.32, 0.9 Hz, 6 H, OCH(CH3)2] ppm. 13C NMR (126 MHz, CDCl3,
125.77, 120.91, 117.14, 116.34, 114.53, 113.95, 113.68, 72.03 25 °C): δ = 192.32 (CHO), 158.92, 157.75, 149.79, 146.30, 141.71,
[OCH(CH3)2], 71.48 (CH2Ph), 70.27 [OCH(CH3)2], 22.21
[OCH(CH3)2], 21.99 [OCH(CH3)2] ppm. MS (FAB): m/z = 480, 482 127.64, 127.26, 121.21, 121.09, 117.96, 116.71, 115.55, 112.78,
[M]+. 22Z: FTIR: ν = 2974, 2908, 2338, 2112, 1604, 1507, 1472,
109.18, 72.32 [OCH(CH3)2], 71.12 (CH2Ph), 69.81 [OCH(CH3)2],
138.14, 137.46, 135.13, 134.85, 132.71, 132.06, 128.91, 128.31,
˜
1371, 1254, 1222, 1196, 1164, 1115, 1048, 985, 940, 855, 810, 55.50 (OCH3), 36.65 (CH2CH2), 35.67 (CH2CH2), 22.26
740 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.45 (d, J = [OCH(CH3)2], 22.09 [OCH(CH3)2] ppm. MS (FAB): m/z = 538
8.8 Hz, 1 H), 7.34–7.27 (m, 5 H), 6.78–6.74 (m, 4 H), 6.65 (ddd, J [M]+.
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Total Synthesis of Plagiochin D
(E/Z)-2-[3-(Benzyloxy)-4-isopropoxyphenethyl]-2Ј-(4-fluoro-3- 133.12, 132.34, 131.53, 131.06, 125.45, 119.54, 117.95 (d, J =
nitrostyryl)-4-isopropoxy-4Ј-methoxybiphenyl (25): Aq. Na2CO3
(1.0 mL of a 1 m solution) was added to a solution of aldehyde 24
(210 mg, 0.390 mmol) and phosphorus salt 7 (292 mg, 0.585 mmol)
in CH2Cl2 (10 mL). After stirring the reaction mixture at 40 °C for
24 h, the mixture was cooled, water was added, and the mixture
was extracted with CH2Cl2. The combined organic layers were
dried (Na2SO4) and concentrated under vacuum to afford 25 as an
(E)/(Z) mixture (1:10; 258 mg, 98%), which was purified by flash
column chromatography (hexane/ethyl acetate, 10:1) to eliminate
the triphenylphosphane oxide. Complex NMR spectroscopic data.
MS (FAB): m/z = 675 [M]+.
20.89 Hz, CHCHCF), 116.56, 114.53, 113.31, 112.70, 111.27, 71.77
[OCH(CH3)2], 69.82 [OCH(CH3)2], 55.24 (OCH3), 36.61
(CH2CH2), 36.00 (CH2CH2), 35.75 (CH2CH2), 35.41 (CH2CH2),
22.17 [OCH(CH3)2], 22.12 [OCH(CH3)2], 22.08 [OCH(CH3)2] ppm.
MS (FAB): m/z = 587 [M]+.
Macrocycle 27: A solution of 6 (160 mg, 0.27 mmol) and anhydrous
K2CO3 (113 mg, 0.82 mmol) in dry DMF (27 mL) was stirred at
room temperature for 24 h. Then the reaction mixture was diluted
with H2O and extracted with EtOAc. The combined organic layers
were washed with H2O (5ϫ100 mL), dried with Na2SO4, and con-
centrated under vacuum. The residue was purified by flash column
chromatography to afford 27 as a mixture of inseparable atropiso-
mers in a ratio of 1:1 (132 mg, 86%). 1H NMR (500 MHz, CDCl3,
25 °C): δ = 7.64 (d, J = 2.1 Hz, 1 H), 7.56 (d, J = 2.1 Hz, 1 H),
7.17–7.10 (m, 5 H), 7.05 (d, J = 8.5 Hz, 1 H), 6.94 (d, J = 8.4 Hz,
2-[3-(Benzyloxy)-4-isopropoxyphenethyl]-2Ј-(4-fluoro-3-nitrophen-
ethyl)-4-isopropoxy-4Ј-methoxybiphenyl (26): Wilkinson’s catalyst
(4%, 10 mg) was added to a solution of compound 25 (245 mg,
0.362 mmol) in degassed solvent (THF/tBuOH, 1:1, 0.14 m) satu-
rated by hydrogen. The solution was stirred under hydrogen at 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.87–6.77 (m, 5 H), 6.75–6.67 (m,
room temperature. When the hydrogenation was deemed complete
by TLC, the reaction mixture was filtered through a short pad of
Celite and washed thoroughly with THF. The solvent was removed
5 H), 6.61 (d, J = 2.2 Hz, 1 H), 6.55 (d, J = 2.2 Hz, 1 H), 5.26 (d,
J = 1.7 Hz, 1 H), 5.21 (d, J = 1.7 Hz, 1 H), 4.58 [sept, J = 6.1 Hz,
2 H, OCH(CH3)2], 4.46–4.36 [m, 2 H, OCH(CH3)2], 3.89 (s, 3 H,
OCH3), 3.87 (s, 3 H, OCH3), 3.19–2.83 (m, 14 H, CH2CH2), 2.24–
2.18 (m, 1 H, CH2CH2), 2.11–2.03 (m, 1 H, CH2CH2), 1.40 [dd, J
= 6.1, 3.1 Hz, 6 H, OCH(CH3)2], 1.37 [d, J = 6.1 Hz, 6 H,
to afford 26 (236 mg, 96% yield). FTIR: ν = 2973, 2915, 2338,
˜
2117, 1685, 1604, 1507, 1479, 1383, 1253, 1222, 1162, 1115, 1045,
1
986, 939, 854, 813, 732 cm–1. H NMR (500 MHz, CDCl3, 25 °C):
δ = 7.56–7.54 (m, 1 H), 7.43–7.41 (m, 2 H), 7.38–7.34 (m, 2 H), OCH(CH3)2], 1.30 [dd, J = 7.6, 6.1 Hz, 6 H, OCH(CH3)2], 1.23 [d,
7.31–7.28 (m, 1 H), 7.05–7.04 (m, 2 H), 6.98–6.96 (m, 1 H), 6.87
J = 6.1 Hz, 3 H, OCH(CH3)2], 1.16 [d, J = 6.1 Hz, 3 H, OCH-
(d, J = 8.3 Hz, 1 H), 6.81–6.78 (m, 3 H), 6.75 (dd, J = 8.2, 2.9 Hz, (CH3)2] ppm. MS (FAB): m/z = 567 [M]+.
2 H), 6.46 (dd, J = 8.1, 2.1 Hz, 1 H), 6.41 (d, J = 2.0 Hz, 1 H),
Macrocycle 28: Pd/C catalyst (10%, 13 mg) was added to a stirred
4.93 (d, J = 1.7 Hz, 2 H, CH2Ph), 4.57 [sept, J = 6.1 Hz, 1 H,
OCH(CH3)2], 4.40 [sept, J = 6.1 Hz, 1 H, OCH(CH3)2], 3.79 (s, 3
H, OCH3), 2.72–2.48 (m, 8 H, CH2CH2), 1.37 [dd, J = 6.1, 3.4 Hz,
solution of compound 27 (130 mg, 0.23 mmol) in THF (10 mL).
The mixture was then hydrogenated under H2 (balloon) at room
temperature for 5 h. Then the mixture was filtered through a short
pad of Celite. The solvent was removed to afford 28a and 28b as a
mixture of atropisomers (122 mg, quantitative yield), which were
6 H, OCH(CH3)2], 1.30 [d, J = 6.1 Hz, 6 H, OCH(CH3)2] ppm. 13
C
NMR (126 MHz, CDCl3, 25 °C): δ = 158.75, 157.17, 153.83 (d, J
= 262.83 Hz, CF), 149.83, 146.19, 141.33, 139.97, 138.66 (d, J =
4.33 Hz, CH2CCH), 137.49, 136.97 (d, J = 7.53 Hz, CNO2), 135.42
(d, J = 7.59 Hz, CCHCHCF), 135.33, 133.15, 132.34, 131.65,
131.07, 128.33, 127.62, 127.25, 125.45, 121.07, 117.94 (d, J =
18.67 Hz, CHCHCF), 116.66, 115.50, 114.46, 112.67, 111.17, 72.35
[OCH(CH3)2], 71.08 (CH2Ph), 69.79 [OCH(CH3)2], 55.20 (OCH3),
36.92 (CH2CH2), 36.03 (CH2CH2), 35.41 (CH2CH2), 22.25
[OCH(CH3)2], 22.13 [OCH(CH3)2], 22.09 [OCH(CH3)2] ppm. MS
(FAB): m/z = 677 [M]+.
separated by flash column chromatography. 28a: FTIR: ν = 3474,
˜
3376, 2977, 2926, 1723, 1605, 1507, 1479, 1439, 1371, 1341, 1283,
1255, 1222, 1164, 1116, 1048, 986, 939, 854, 811, 719 cm–1. 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 7.17 (d, J = 2.3 Hz, 1 H),
7.01 (d, J = 8.5 Hz, 1 H), 6.91 (d, J = 8.3 Hz, 1 H), 6.81 (d, J =
8.2 Hz, 1 H), 6.72 (dd, J = 8.1, 2.2 Hz, 1 H), 6.69 (t, J = 2.7 Hz, 1
H), 6.67 (t, J = 2.6 Hz, 1 H), 6.64 (d, J = 2.5 Hz, 1 H), 6.54 (d, J
= 8.0 Hz, 1 H), 6.35 (d, J = 2.0 Hz, 1 H), 6.31 (dd, J = 8.0, 2.1 Hz,
1 H), 5.57 (d, J = 2.1 Hz, 1 H), 4.55 [sept, J = 6.1 Hz, 1 H,
OCH(CH3)2], 4.45 [sept, J = 6.1 Hz, 1 H, OCH(CH3)2], 3.87 (s, 3
H, OCH3), 3.41 (br. s, 2 H, NH2), 2.88 (s, 7 H, CH2CH2), 2.17 (m,
1 H, CH2CH2), 1.38 [dd, J = 9.1, 6.1 Hz, 6 H, OCH(CH3)2], 1.32
[d, J = 6.1 Hz, 3 H, OCH(CH3)2], 1.21 [d, J = 6.1 Hz, 3 H,
OCH(CH3)2] ppm. 13C NMR (126 MHz, CDCl3, 25 °C): δ =
158.06, 156.50, 150.61, 144.59, 142.07, 140.53, 140.19, 140.13,
139.89, 134.59, 132.94, 132.09, 132.04, 131.80, 122.84, 121.20,
120.08, 116.90, 116.40, 115.39, 114.92, 114.76, 111.18, 110.11,
72.35 [OCH(CH3)2], 69.55 [OCH(CH3)2], 55.25 (OCH3), 34.78
5-{2-[2Ј-(4-Fluoro-3-nitrophenethyl)-4-isopropoxy-4Ј-methoxybi-
phenyl-2-yl]ethyl}-2-isopropoxyphenol (6): Concd. HCl was added
drop by drop (4 mL) to a solution of compound 26 (65 mg,
0.09 mmol) in acetic acid (4 mL). After heating at 70 °C for 4 h,
the reaction mixture was cooled and then extracted with ethyl acet-
ate. The organic phase was washed with brine, dried with Na2SO4,
and concentrated under vacuum. The pure product was isolated by
flash column chromatography on silica gel (hexane/ethyl acetate,
10:1) in 88% yield. FTIR: ν = 3520, 2976, 2921, 2098, 1604, 1535,
˜
1504, 1480, 1349, 1272, 1231, 1162, 1113, 1047, 970, 943, 862, 816, (CH2CH2), 34.69 (CH2CH2), 32.05 (CH2CH2), 30.66 (CH2CH2),
745 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.55 (d, J = 22.29 [OCH(CH3)2], 22.26 [OCH(CH3)2], 21.92 [OCH(CH3)2] ppm.
7.0 Hz, 1 H), 7.04 (dd, J = 16.8, 8.0 Hz, 3 H), 6.88 (d, J = 8.3 Hz,
MS (FAB): m/z = 537 [M]+. 28b: FTIR: ν = 3469, 3374, 2973, 2915,
˜
1 H), 6.83 (d, J = 2.3 Hz, 1 H), 6.81–6.79 (m, 2 H), 6.74 (dd, J = 1723, 1605, 1507, 1478, 1439, 1371, 1341, 1286, 1255, 1222, 1195,
8.3, 2.4 Hz, 1 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.51 (d, J = 1.7 Hz, 1 1116, 1048, 986, 940, 854, 811, 719 cm–1. 1H NMR (500 MHz,
H), 6.38 (dd, J = 8.1, 1.7 Hz, 1 H), 5.61 (s, 1 H, OH), 4.57 [sept, J CDCl3, 25 °C): δ = 7.15 (d, J = 2.7 Hz, 1 H), 7.06 (d, J = 8.5 Hz,
= 6.1 Hz, 1 H, OCH(CH3)2], 4.47 [sept, J = 6.1 Hz, 1 H,
1 H), 6.91 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 8.2 Hz, 1 H), 6.73 (dd,
OCH(CH3)2], 3.84 (s, 3 H, OCH3), 2.72–2.50 (m, 8 H, CH2CH2), J = 8.1, 2.2 Hz, 1 H), 6.69 (dd, J = 8.4, 2.7 Hz, 1 H), 6.67 (dd, J
1.37 [dd, J = 5.9, 3.3 Hz, 6 H, OCH(CH3)2], 1.31 [d, J = 6.1 Hz, 6
H, OCH(CH3)2] ppm. 13C NMR (126 MHz, CDCl3, 25 °C): δ =
= 8.0, 2.7 Hz, 1 H), 6.60 (d, J = 2.5 Hz, 1 H), 6.56 (d, J = 8.1 Hz,
1 H), 6.35 (d, J = 2.0 Hz, 1 H), 6.29 (dd, J = 8.2, 2.0 Hz, 1 H),
158.77, 157.15, 153.82 (d, J = 262.83 Hz, CF), 146.36, 142.70, 5.57 (d, J = 2.1 Hz, 1 H), 4.55 [sept, J = 6.1 Hz, 1 H, OCH-
141.35, 139.88, 138.71 (d, J = 3.61 Hz, CH2CCH), 136.96 (d, J =
7.40 Hz, CNO2), 135.38 (d, J = 8.03 Hz, CCHCHCF), 135.09,
(CH3)2], 4.41 [sept, J = 6.1 Hz, 1 H, OCH(CH3)2], 3.87 (s, 3 H,
OCH3), 3.43 (br. s, 2 H, NH2), 3.02–2.93 (m, 7 H, CH2CH2), 2.25–
Eur. J. Org. Chem. 2011, 3165–3170
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3169

J. C. Cortes Morales, A. Guillen Torres, E. González-Zamora
FULL PAPER
2.18 (m, 1 H, CH2CH2), 1.38 [dd, J = 13.7, 6.1 Hz, 6 H, OCH-
(CH3)2], 1.30 [d, J = 6.1 Hz, 3 H, OCH(CH3)2], 1.18 [d, J = 6.0 Hz,
3 H, OCH(CH3)2] ppm. 13C NMR (126 MHz, CDCl3, 25 °C): δ =
158.06, 156.49, 150.64, 144.52, 141.49, 140.27, 140.19, 139.99,
138.73, 134.28, 132.88, 132.25, 132.01, 131.55, 124.09, 121.32,
119.03, 117.35, 117.03, 114.97, 114.88, 111.61, 110.01, 72.31
[OCH(CH3)2], 69.72 [OCH(CH3)2], 55.25 (OCH3), 35.21
(CH2CH2), 34.68 (CH2CH2), 31.26 (CH2CH2), 30.13 (CH2CH2),
22.30 [OCH(CH3)2], 22.26 [OCH(CH3)2], 22.24 [OCH(CH3)2],
21.73 [OCH(CH3)2] ppm. MS (FAB): m/z = 537 [M]+.
(CH2CH2), 30.57 (CH2CH2), 29.14 (CH2CH2) ppm. HRMS: calcd.
for [MH]+ 438.18; found 438.18.
Acknowledgments
The authors thank the Consejo Nacional de Ciencia y Tecnología
(CONACYT) for financial support (project 51346-Q) and for the
scholarship awarded to J. C. C. M. We thank A. Gutiérrez-Carrillo
for NMR spectra. We also thank V. Labastida for her valuable
technical help in obtaining mass spectra.
Macrocycle 29: Macrocycle 28 (70 mg, 0.13 mmol) was dissolved in
ethanol (5 mL) and acetic acid (3 mL) at room temperature. Solu-
tions of sodium nitrite (1.30 mmol in 3 mL water) and sodium bi-
sulfite (1.30 mmol in 4 mL of water) were added sequentially to
the stirred solution. The reaction was monitored by TLC. Upon
completion (12 h), the reaction mixture was extracted with ethyl
acetate, and the organic phase was washed with water. The com-
bined organic layers were dried (Na2SO4) and concentrated under
vacuum. The pure product was isolated by flash chromatography
[1] H. D. Zinsmeister, H. Becker, T. Eicher, Angew. Chem. 1991,
103, 134–151; Angew. Chem. Int. Ed. Engl. 1991, 30, 130–147.
[2] H. D. Zinsmeister, H. Becker, T. Eicher, R. Mues, Naturwiss.
Rundschau 1994, 47, 131–136.
[3] a) Y. Asakawa, Progress in the Chemistry of Organic Natural
Products (Eds.: E. Herz, G. W. Kirby, R. E. Moore, W. Steglich,
C. Tamm), Springer, Vienna, New York, 1995, p. 5; b) Y. Asak-
awa, M. Toyota, M. Tori, T. Hashimoto, Spectroscopy 2000,
14, 149–175; c) Y. Asakawa, A. Ludwiczuk, F. Nagashima, M.
Toyota, T. Hashimoto, M. Tori, Y. Fukuyama, L. Harinan-
tenaina, Heterocycles 2009, 77, 99–150.
on silica gel (hexane/ethyl acetate, 12:1) in 84% yield. FTIR: ν =
˜
2928, 2522, 2159, 1733, 1605, 1505, 1476, 1371, 1259, 1220, 1163,
1115, 1049, 985, 938, 906, 808, 729, 598 cm–1. 1H NMR (500 MHz,
CDCl3, 25 °C): δ = 7.19 (d, J = 2.7 Hz, 1 H), 7.05 (d, J = 8.5 Hz,
1 H), 6.94–6.90 (m, 3 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.74–6.67 (m,
5 H), 6.61 (d, J = 2.5 Hz, 1 H), 5.29 (d, J = 2.1 Hz, 1 H), 4.55
[sept, J = 6.1 Hz, 1 H, OCH(CH3)2], 4.43 [sept, J = 6.1 Hz, 1 H,
OCH(CH3)2], 3.88 (s, 3 H, OCH3), 3.10–2.83 (m, 7 H, CH2CH2),
2.19–2.12 (m, 1 H, CH2CH2), 1.38 [d, J = 6.1 Hz, 3 H, OCH-
(CH3)2], 1.37 [d, J = 6.1 Hz, 3 H, OCH(CH3)2], 1.31 [d, J = 6.1 Hz,
[4] T. Hashimoto, M. Tori, Y. Asakawa, Y. Fukazawa, Tetrahedron
Lett. 1987, 28, 6295–6298.
[5] G. M. Keserü, M. Nógrádi, Phytochemistry 1992, 31, 1573–
1576.
[6] Y. Fukuyama, K. Nakamura, M. Kodama, 111th Annual Meet-
ing of the Pharmaceutical Society of Japan, Tokyo, Japan, 1991,
Abstracts 2, p. 4.
[7] C. Niu, J.-B. Qu, H.-X. Lou, Chem. Biodivers. 2006, 3, 34–40.
[8] a) X.-Z. Wu, W.-Q. Chang, A.-X. Chen, L.-M. Sun, H.-X. Lou,
Biochim. Biophys. Acta 2010, 439–447; b) X.-Z. Wu, A.-X.
Chen, L.-M. Sun, S.-J. Sun, H.-X. Lou, Biochim. Biophys. Acta
2009, 770–777.
[9] X.-L. Guo, P. Leng, Y. Yang, L.-G. Yu, H.-X. Lou, J. Appl.
Microbiol. 2008, 104, 831–838.
[10] Y.-Q. Shi, X.-J. Qu, Y.-X. Liao, C.-F. Xie, Y.-N. Cheng, S. Li,
H.-X. Lou, Eur. J. Pharmacol. 2008, 66–71.
[11] G. M. Keserü, G. Mezey-Vandor, M. Nógrádi, B. Vermes, M.
Kajtar-Peredy, Tetrahedron 1992, 48, 913–922.
[12] Y. Fukuyama, H. Yaso, K. Nakamura, M. Kodama, M.
Kajtar-Peredy, Tetrahedron Lett. 1999, 40, 105–108.
[13] Y. Fukuyama, H. Yaso, T. Mori, H. Takahashi, H. Minami,
M. Kodama, Heterocycles 2001, 54, 259–274.
3 H, OCH(CH3)2], 1.20 [d, J = 6.1 Hz, 3 H, OCH(CH3)2] ppm. 13
C
NMR (126 MHz, CDCl3, 25 °C): δ = 158.08, 156.51, 155.10,
152.98, 144.27, 140.13, 139.72, 139.00, 134.01, 132.27, 132.04,
131.39, 130.10, 129.68, 123.89, 122.57, 120.74, 117.13, 115.99,
115.01, 114.87, 111.47, 110.05, 72.43 [OCH(CH3)2], 69.67
[OCH(CH3)2], 55.23 (OCH3), 34.83 (CH2CH2), 34.80 (CH2CH2),
31.41 (CH2CH2), 30.21 (CH2CH2), 22.25 [OCH(CH3)2], 22.21
[OCH(CH3)2], 21.76 [OCH(CH3)2] ppm. MS (FAB): m/z = 522
[M]+.
Plagiochin D (4): A solution of 29 (45 mg, 0.08 mmol) in dichloro-
methane (5 mL) was treated at 0 °C with BCl3 (0.51 mL, 1 m in
CH2Cl2). After 30 min, dry methanol (10 mL) was added. The mix-
ture was stirred at 0 °C for 5 min, and then the solvent was removed
under reduced pressure, and the residue was purified by column
chromatography on silica gel (hexane/ethyl acetate, 3:1) to afford
[14] a) A. Speicher, M. Groh, J. Zapp, A. Schaumlöffel, M. Knauer,
G. Bringmann, Synlett 2009, 11, 1852–1858; b) A. Speicher, M.
Groh, M. Hennrich, A.-M. Huynh, Eur. J. Org. Chem. 2010,
6770–6778.
[15] J. Zhu, Synlett 1997, 133–144.
[16] R. Beugelmans, P. S. Girij, M. Bois-Choussy, J. Chastanet, J.
Zhu, J. Org. Chem. 1994, 59, 5535–5542.
plagiochin D (4) in quantitative yield. FTIR: ν = 3902, 3177, 2927,
˜
2533, 2159, 2023, 1741, 1668, 1604, 1504, 1445, 1347, 1285, 1218,
1162, 1112, 1021, 996, 817, 760 cm–1. 1H NMR (500 MHz, CDCl3,
25 °C): δ = 8.59 (s, 1 H, OH), 7.97 (s, 1 H, OH), 7.17 (d, J = 2.6 Hz,
1 H), 7.06 (d, J = 8.5 Hz, 1 H), 6.96 (dd, J = 8.2, 2.1 Hz, 1 H),
6.90 (dd, J = 8.2, 2.1 Hz, 1 H), 6.82 (d, J = 8.2 Hz, 1 H), 6.77 (d,
J = 8.2 Hz, 1 H), 6.72 (dd, J = 8.3, 2.4 Hz, 1 H), 6.70 (dd, J = 8.3,
2.4 Hz, 2 H), 6.65 (dd, J = 8.1, 2.5 Hz, 1 H), 6.62 (dd, J = 8.1,
2.5 Hz, 1 H), 6.58 (d, J = 2.4 Hz, 1 H), 5.26 (d, J = 2.0 Hz, 1 H),
3.88 (s, 3 H, OCH3), 3.09–2.81 (m, 7 H, CH2CH2), 2.19 (m, 1 H,
CH2CH2) ppm. 13C NMR (126 MHz, CDCl3, 25 °C): δ = 157.44,
155.42, 154.15, 149.31, 142.70, 139.32, 139.17, 138.96, 132.51,
131.97, 131.59, 129.50, 129.43, 129.35, 123.22, 121.96, 120.83,
115.22, 114.49, 114.37, 113.42, 111.02, 109.54, 54.76 (OCH3), 34.17
[17] M. Lautens, T. Marquardt, J. Org. Chem. 2004, 69, 4607–4614.
[18] Z. Lian-Yun, L. Quiao, R. Suo-Bao, Bioorg. Med. Chem. Lett.
2001, 11, 955–959.
[19] A. Jourdan, E. González-Zamora, J. Zhu, J. Org. Chem. 2002,
67, 3163–3164.
[20] Identified by NMR spectroscopy. See the NMR spectroscopic
data for macrocycle 27 in the Exp. Sect.
[21] R. Beugelmans, G. Roussi, E. González-Zamora, A.-C. Car-
bonnelle, Tetrahedron 1999, 55, 5089–5112.
[22] O. J. Geoffroy, T. A. Morinellib, G. P. Meier, Tetrahedron Lett.
2001, 42, 5367–5369.
[23] Y. Fukuyama, H. Yaso, T. Mori, H. Takahashi, H. Minami,
M. Kodama, Heterocycles 2001, 54, 259–274.
Received: October 15, 2010
Published Online: April 21, 2011
3170
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3165–3170