Total synthesis of the marine metabolite (±)-Polysiphenol via highly regioselective intramolecular oxidative coupling

Article abstract of DOI:10.1021/np200596q

(±)-Polysiphenol (1), an atropisomerically stable 4,5-dibrominated 9,10-dihydrophenanthrene from Polysiphonia ferulacea, was prepared by a biomimetically inspired highly regioselective intramolecular oxidative coupling of a dibrominated dihydrostilbene. T

Full text of DOI:10.1021/np200596q

ARTICLE
pubs.acs.org/jnp
Total Synthesis of the Marine Metabolite (()-Polysiphenol via Highly
Regioselective Intramolecular Oxidative Coupling
Tim N. Barrett,† D. Christopher Braddock,*,† Anna Monta,† Michael R. Webb,‡ and Andrew J. P. White†
†Department of Chemistry, Imperial College London, London, South Kensington SW7 2AZ, U.K.
‡GlaxoSmithKline Research and Development Ltd, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
S Supporting Information
b
ABSTRACT: (()-Polysiphenol (1), an atropisomerically stable
4,5-dibrominated 9,10-dihydrophenanthrene from Polysiphonia
ferulacea, was prepared by a biomimetically inspired highly regio-
selective intramolecular oxidative coupling of a dibrominated
dihydrostilbene. The installation of the two bromine atoms prior
to oxidative coupling prevents further oxidation to a planar
aromatized phenanthrene. By this strategy, the synthesis of
(()-polysiphenol was achieved in four steps in 70% overall yield.
Synthesis of the naturally occurring 5,50-(ethane-1,2-diyl)bis(3-bromobenzene-1,2-diol) (2) (the likely biogenetic precursor of
polysiphenol) and 5,50-(ethane-1,2-diyl)bis(3,4,6-tribromobenzene-1,2-diol) (9) are also reported. The origins of the regioselectivity
in the oxidative coupling are explored.
olysiphenol (1)1 is one of a number of naturally occurring
bromophenols isolated from red marine algae Rhodomel-
Moreover, we also recognized the need to control the regiochem-
istry of the proposed oxidative coupling, such that CꢀC biaryl
bond formation occurs to form a 4,5-dibromodihydrophenan-
threne (Figure 2, mode a) rather than a 2,7-dibromo- (mode b)
or 2,5-dibromodihydrophenanthrene (mode c). We posited that
such control could be gained by exploiting the well-known
coplanarconformational preference of ortho-dimethoxybenzenes12
to sterically shield the undesired sites of modes b and c coupling
(Figure 2). This interaction was expected to be particularly severe
in mode b, where two methoxy groups must approach each other.
Further, we also recognized the need for an oxidative coupling that
was compatible with aryl bromides.
P
aceae,2ꢀ4 with members of this family showing assorted biologi-
cal activities and other properties.5 Polysiphenol, the first 9,10-
dihydrophenanthrene6 to be isolated from a marine source, was
obtained from the red alga Polysiphonia ferulacea collected at Joal,
Senegal, in 1990.1 It was found to exist as a stable atropisomer at
room temperature, and its R configuration was established from its
CD spectrum.1 Two more axially chiral bromophenol-9,10-dihy-
drophenanthrenes have recently been isolated from Polysiphonia
urceolata.3b Biogenetically, it seems reasonable to propose that these
bromophenolic 9,10-phenanthrenes could arise from dihydrostil-
bene derivatives by oxidative phenolic coupling.7,8 Indeed, dihy-
drostilbene 2, which could serve as the biogenetic precursor for 1 in
this fashion, has been isolated from P. urceolata.9 Such a coupling
would present a direct and attractive synthetic route to these
compounds (Figure 1). However, there are only a few reports on
the synthesis10 of naturally occurring bromophenols, and no
syntheses of polysiphenol (1) or of the other phenanthrenes have
been reported to date. Herein, we report on the first synthesis of
(()-polysiphenol (1) via a highly regioselective intramolecular
oxidative coupling. We also report on the synthesis of dihydrostil-
bene 2 and a naturally occurring hexabromide (vide infra). Finally,
the origins of the high regioselectivity of the oxidative coupling step
are explored.
’ RESULTS AND DISCUSSION
To test the validity of these propositions, we initially
explored the chemistry of some model compounds. Thus
stilbene 511c was prepared in a novel one-pot procedure from
commercially available 3,4-dimethoxybenzyl alcohol (3) involv-
ing Appel bromination and in situ phosphonium salt formation
with excess triphenyl phosphine, ylid formation by subsequent
addition of base, and finally Wittig reaction with commercially
available aldehyde 4 (Scheme 1). Subsequent hydrogenation
of alkene 511c gave tetramethoxydihydrostilbene 6. The X-ray
crystal structure of dihydrostilbene 6 clearly shows the coplanar
conformation in each of the ortho-dimethoxybenzene subunits
(Figure 3).13
At the outset of our investigations we considered that successful
oxidative coupling would require a substrate with the two bromine
atoms already installed, leading necessarily (because of the bulky
bromine substituents)1 to a nonplanar atropisomeric dihydrophe-
nanthrene framework, where further undesirable oxidation to
a planar fully aromatized phenanthrene could not occur.11
Dihydrostilbene 6 is known to undergo highly regioselec-
tive oxidative biaryl coupling with hypervalent iodine reagent
Received: July 15, 2011
Published: August 29, 2011
r
Copyright
2011 American Chemical Society and
1980
dx.doi.org/10.1021/np200596q J. Nat. Prod. 2011, 74, 1980–1984
American Society of Pharmacognosy
|

Journal of Natural Products
ARTICLE
Figure 3. Molecular structure of 6.
Scheme 2. Proposed PIFA-Mediated Oxidative
CouplingꢀAromatization Mechanism
Figure 1. Proposed biogenesis of polysiphenol.
Figure 2. Considerations for regioselective biaryl bond formation: (i)
possible modes of coupling; (ii) possible influence of coplanar di-
methoxy benzene motif.
Scheme 1. Preparation of Model Compound 6
Scheme 3. Synthesis of Naturally Occurring Hexabromide 9
phenyliodine bis(trifluoroacetate) (PIFA) in conjunction with
BF3 OEt2 with unavoidable aromatization to give phenan-
3
threne 7 in excellent yield (Scheme 2).11 Two aspects of this
reaction deserve further comment. Although there has been
no speculation in the literature, the observed regioselectivity
may, in part, be controlled by the conformation of the
methoxy groups in each dimethoxybenzene subunit, with their
preferred coplanar ortho-dimethoxybenzene conformations
disfavoring coupling by modes b or c (cf. Figure 2). Second,
the dihydrophenanthrene (intemediate A, Scheme 2) that
must be initially formed is subject to further oxidation. The
coplanar nature of this initial biaryl adduct A evidently leads to
extended conjugation of the π-system and a higher energy
HOMO, thus facilitating competitive oxidation.14 In our
hands the oxidative cyclizationꢀaromatization of 6 with PIFA
proceeded as previously reported to give aromatic 7 in good
isolated yield (81%).
1981
dx.doi.org/10.1021/np200596q |J. Nat. Prod. 2011, 74, 1980–1984

Journal of Natural Products
ARTICLE
Scheme 4. Regioselective Dibromination
Figure 5. Molecular structure of E-13 showing the now out-of-plane
arrangement of the 4-methoxy groups.
Scheme 6. Regioselectivity Experiments
Figure 4. Molecular structure of 10.
Scheme 5. Total Synthesis of (()-Polysiphenol 1 and
Dibromodihydrostilbene 2
aromatic bromides survive the PIFA oxidative-coupling condi-
tions? Second, with the two bromines now blocking the pre-
viously preferred positions of coupling (cf. compound 6,
Scheme 2), would coupling occur instead between the other
two free ortho positions? An X-ray crystal structure of compound
10 (Figure 4) clearly shows the coplanar arrangement of the two
pairs of methoxy groups,19 which may be a factor in controlling
regioselective coupling.
In the event, subjecting compound 10 to identical oxidative-
coupling conditions as used for 6 gave complete return of
unreacted starting material upon workup. This experiment thus
demonstrates that (a) the aromatic bromide functionality is
tolerant of these conditions and (b) that the oxidative coupling
does not proceed when this position is blocked.
Having established the above, attention now turned to a
synthesis of polysiphenol (1). Commercially available 5-bromo-
veratraldehyde 11 was reduced to the corresponding alcohol
1220 (Scheme 5). Alcohol 12 was converted into olefin 1321 in a
telescoped one-pot reaction sequence via the bromide, phospho-
nium salt, ylid, and Wittig reaction with 11. E-13 proved to be
crystalline, and an X-ray crystal structure was obtained
(Figure 5). Although the bromine atoms buttress their adjacent
methoxy groups, the remote methoxy groups maintain their
preferred planar arrangement with the aromatic ring.22
Subsequent hydrogenation of olefin 13 afforded dibromide
1423 as the substrate for oxidative coupling. To our delight,
oxidative coupling proceeded smoothly to dibromodihydro-
phenanthrene 15 in excellent yield (90%) and with perfect
regioselectivity. Evidently, this dihydrophenanthrene, with the
two bromine atoms preinstalled at the 4- and 5-positions
(phenanthrene numbering), cannot aromatize to a planar
phenanthrene. Finally, the methoxy groups were removed from
Tetramethoxydihydrostilbene 6 could also be deprotected
to tetrol 8 (Scheme 3).15 Electrophilic bromination at all the
available aromatic positions gave the naturally occurring
hexabromide 9.16 This constitutes the first synthesis of this
metabolite.
Tetramethoxydihydrostilbene 6 was dibrominated using NBS
in DMF with the expected selectivity17 to give dibromide 1018 in
excellent yield (Scheme 4).
In compound 10, the two bromine substituents are incorrectly
positioned on the aromatic rings to lead to polysiphenol (1) by
oxidative coupling. However, this substrate was purposefully
prepared for a 2-fold test of the oxidative coupling. First, would
1982
dx.doi.org/10.1021/np200596q |J. Nat. Prod. 2011, 74, 1980–1984

Journal of Natural Products
ARTICLE
(petroleum spirit/EtOAc, 2:1) to provide the title compound, 15
(0.18 g, 90%), as a white solid: mp 215 °C; IR (neat) 2939, 2837,
1594, 1464, 1401, 1257, 1059, 996 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 6.84 (2H, s, ArH), 3.94 (6H, s, ArOCH3), 3.92 (6H, s, ArOCH3),
2.75ꢀ2.57 (4H, m, ArC2H4Ar); 13C NMR (125 MHz, CDCl3) δ 152.1,
145.7, 137.9, 128.8, 119.1, 110.2, 60.7, 56.2, 31.6; MS (CI+, NH3) m/z
474, 476, 478 [M + NH4]+; HRCIMS (NH3) m/z 473.9931 [M +
NH4]+ (calcd for C18H2279Br2NO4, 473.9916).
(()-Polysiphenol (1).1 To a stirred solution of tetramethoxyphe-
nanthrene 15 (0.20 g, 0.51 mmol) in CH2Cl2 (5 mL) at ꢀ78 °C was
added a solution of BBr3 in CH2Cl2 (1 M, 3.06 mL, 3.06 mmol)
dropwise. The mixture was allowed to warm to rt and was stirred for
16 h. The reaction mixture was quenched by the addition of MeOH
(25 mL), and the solvent evaporated in vacuo. The solid was placed
under high vacuum at 60 °C for 16 h to give the title compound, 1
(0.18 g, 100%), as an off-white solid: mp 133 °C;29 IR (neat)
3550ꢀ2800, 2942, 1608, 1578, 1520, 1471, 1421, 1261, 1232, 1199,
Figure 6. Intermediates X, Y, and Z with decreasing amounts of cross-
conjugation.
15 to give (()-polysiphenol (1).1,24 Dibromide 14 could also
be deprotected to provide naturally occurring dibromodihy-
drostilbene 2.9,25
To further probe the regioselectivity of the oxidative coupling,
we examined the PIFA-mediated reaction of methylenedioxy
compounds 16 and 17. Dihydrostilbene 1626 was prepared from
tetrol 8, and dibromide 17 was prepared by regioselective
bromination of 16 (Scheme 6). While 16 underwent efficient
cyclization (and aromatization) to 18,27 dibromide 17 returned
only starting material under these conditions. These experiments
prove that the regioselectivity of the oxidative coupling is not
controlled by steric effects due to enforced coplanar dimethox-
ybenzene conformations in compounds 6, 10, and 14 and must
instead be under electronic control. We suggest that the observed
regioselectivity of coupling is such that cross-conjugation28 is
maximized in the transition state leading to intermediate X (via
mode a, cf., Figure 2) rather than intermediates Y (mode c) or Z
(mode b) (Figure 6).
In conclusion, we have reported the first total syntheses of
naturally occurring (()-polysiphenol 1, dibromodihydrostil-
bene 2, and hexabromide 9. The synthesis of (()-polysiphenol
1 is brought about in four steps with an overall yield of 70%.
The key step involves highly regioselective oxidative coupling
of a dibrominated dihydrostilbene, as inspired by the probable
biogenesis of polysiphenol.
1
1152 cmꢀ1; H NMR (400 MHz, CDCl3) δ 6.85 (2H, s, ArH), 5.58
(2H, s, ArOH), 5.49 (2H, s, ArOH), 2.69ꢀ2.47 (4H, m, ArC2H4Ar);
13C NMR (125 MHz, CDCl3) δ 143.2, 139.3, 135.6, 127.1, 113.5, 110.1,
31.2; MS (CI+, NH3) m/z 400, 402, 404 [M]+; HRCIMS (NH3) m/z
399.8944 [M]+ (calcd for C14H1079Br2O4, 399.8946).
5,50-(Ethane-1,2-diyl)bis(3-bromobenzene-1,2-diol) (2).9
To a stirred solution of dihydrostilbene 14 (0.10 g, 0.22 mmol) in
CH2Cl2 (2 mL) at ꢀ78 °C was added a solution of BBr3 in CH2Cl2 (1 M,
1.30 mL, 1.30 mmol) dropwise. The reaction mixture was allowed to
warm to rt and was stirred for 16 h. The reaction mixture was quenched
by the addition of MeOH (10 mL), and the solvent evaporated in vacuo.
The solid was placed under high vacuum at 60 °C overnight to remove
volatile impurities, giving the title compound, 2 (0.18 g, 100%), as an off-
white solid: mp 198 °C, lit.9 205ꢀ206 °C; IR (neat) 3529, 3448, 3240,
1
2925, 2852 cmꢀ1; H NMR (400 MHz, DMSO-d6) δ 9.49 (2H, s,
ArOH), 8.72 (2H, s, ArOH), 6.73 (2H, d, J = 2 Hz, ArH), 6.54 (2H, d, J =
2 Hz, ArH), 2.58 (4H, s, ArC2H4Ar); 13C NMR (100 MHz, DMSO-d6)
δ 146.0, 140.8, 133.5, 122.2, 114.8, 109.6, 36.1; MS (EI+) m/z 402, 404,
406 [M]+; HRCIMS (NH3) m/z 419.9426 [M + NH4]+ (calcd for
C14H1679Br2NO4, 419.9946).
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental proce-
b
’ EXPERIMENTAL SECTION
dures and characterization data for 5ꢀ8, 10, 12ꢀ14, and 16ꢀ18,
copies of 1H and 13C NMR spectra for 15, 1, 2, 9, 17, and 18, a
comparison of the spectroscopic data of synthetic (()-1 and the
published data, and X-ray crystallographic details for 6, 10, and
E-13. This material is available free of charge via the Internet at
http://pubs.acs.org.
General Experimental Procedures. See Supporting Information.
5,50-(Ethane-1,2-diyl)bis(3,4,6-tribromobenzene-1,2-diol)
(9).16 To a stirred solution of tetrol 8 (0.10 g, 0.41 mmol) in acetic acid
(5 mL) was added bromine (2.1 mL, 4.1 mmol, 10 equiv), and the
mixture was stirred for 48 h. The mixture was diluted with CH2Cl2
(10 mL), quenched with saturated aqueous sodium sulfite solution
(25 mL), and extracted with CH2Cl2 (3 ꢁ 25 mL). The combined
organic layers were washed with H2O (2 ꢁ 25 mL) and brine (20 mL),
dried over MgSO4, and concentrated, affording title compound, 9
(0.19 g, 65%), as a yellow solid: mp 228 °C; lit.16 230ꢀ232 °C; IR
(neat) 3550ꢀ2700 cmꢀ1; 1H NMR (400 MHz, acetone-d6) δ 8.69 (2H,
br s, ArOH), 8.56 (2H, br s, ArOH), 3.45 (4H, s, ArC2H4Ar); 13C NMR
(100 MHz, acetone-d6) δ 144.0, 143.9, 132.5, 118.0, 113.9, 37.3; MS (EI+)
m/z 714, 716, 718, 720, 722, 724, 726 [M]+; HREIMS m/z 713.5522
[M]+ (calcd for C14H8O479Br6, 713.5523).
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: c.braddock@imperial.ac.uk.
’ ACKNOWLEDGMENT
We thank the EPSRC and GSK for a DTA-CASE award (to A.M.)
(()-4,5-Dibromo-2,3,6,7-tetramethoxy-9,10-dihydrophe-
nanthrene (15). To a stirred solution of diarylethane 14 (0.20 g, 0.43
mmol) in CH2Cl2 (10 mL) at ꢀ40 °C were added PIFA (0.24 g, 0.52
’ REFERENCES
(1) Aknin, M.; Samb, A.; Mirailles, J.; Constantino, V.; Fattorusso,
E.; Mangoni, A. Tetrahedron Lett. 1992, 33, 555–558.
(2) Reviews: (a) Gribble, G. W. Chem. Soc. Rev. 1999, 28, 335–346.
(b) de Carvalho, L. R.; Roque, N. F. Quim. Nova 2000, 23, 757–764.
(3) For recent representative examples see: (a) Liu, Q.-W.; Qiao,
Q.-A.; Zhang, T.; Sun, L.-X.; Wang, M.-S. J. Mol. Struct. 2009, 929, 1–5.
mmol) and BF3 OEt2 (0.13 mL, 1.04 mmol), and the mixture was
3
allowed to warm to room temperature (rt) and stirred for 24 h. The
solution was filtered through a silica plug, and the solvent evaporated
in vacuo. The residue was subjected to column chromatography
1983
dx.doi.org/10.1021/np200596q |J. Nat. Prod. 2011, 74, 1980–1984

Journal of Natural Products
ARTICLE
(b) Li, K.; Li, X.-M.; Ji, N.-Y.; Wang, B.-G. J. Nat. Prod. 2008, 71, 28–30.
(c) Li, K.; Li, X.-M.; Ji, N.-Y.; Gloer, J. B.; Wang, B.-G. Org. Lett. 2008,
10, 1429–1432. (d) Ma, M.; Zhao, J.; Wang, S.; Li, S.; Yang, Y.; Shi, J.;
Fan, X.; He, L. J. Nat. Prod. 2007, 70, 337–341. (e) Li, K.; Li, X.-M.; Ji,
N.-Y.; Wang, B.-G. Bioorg. Med. Chem. 2007, 15, 6627–6631. (f) Liu,
Q.-W.; Tan, C.-H.; Zhang, T.; Zhang, S.-J.; Han, L.-J.; Fan, X.; Zhu, D.-Y.
J. Asian Nat. Prod. Res. 2006, 8, 379–383. (g) Ma, M.; Zhao, J.; Wang, S.;
Li, S.; Yang, Y.; Shi, J.; Fan, X.; He, L. J. Nat. Prod. 2006, 69, 206–210.
(h) Zhao, J.; Ma, M.; Wang, S.; Li, S.; Cao, P.; Yang, Y.; L€u, Y.; Shi, J.; Xu,
N.; Fan, X.; He, L. J. Nat. Prod. 2005, 68, 691–694. (i) Zhao, J.; Fan, X.;
Wang, S.; Li, S.; Yang, Y.; Xu, N.; L€u, Y.; Shi, J. J. Nat. Prod. 2004,
67, 1032–1035. (j) Fan, X.; Xu, N.-J.; Shi, J.-G. J. Nat. Prod. 2003,
66, 455–458. (k) Fan, X.; Xu, N. J.; Shi, J. G. Chin. Chem. Lett. 2003,
14, 1045–1047. (l) Xu, N. J.; Fan, X.; Yang, Y. C.; Shi, J. G. Chin. Chem.
Lett. 2003, 14, 807–809. (m) Fan, X.; Xu, N. J.; Shi, J. G. Chin. Chem.
Lett. 2003, 14, 939–941, and references therein.
(4) Assorted bromophenols have been isolated from brown algae
also. See: (a) Popplewell, W. L.; Northcote, P. T. Tetrahedron Lett. 2009,
50, 6814–6817. (b) Xu, X.; Song, F.; Wang, S.; Li, S.; Xiao, F.; Zhao, J.;
Yang, Y.; Shang, S.; Yang, L.; Shi, J. J. Nat. Prod. 2004, 67, 1661–1666.
(c) Xu, X. L.; Fan, X.; Song, F. H.; Zhao, J. L.; Han, L. J.; Shi, J. G. Chin.
Chem. Lett. 2004, 15, 661–663, and references therein.
(5) For example: (a) α-glucosidase inhibitors: Kim, K. Y.; Nam,
K. A.; Kurihara, H.; Kim, S. M. Phytochemistry 2008, 69, 2820–2825.
(b) Cytotoxicity: refs 4b and 3g. (c) DPPH-radical scavenging ability:
refs 3b, 3c, and 3e. (d) Isocitrate lyase inhibitor: Lee, H.-S.; Lee, T.-H.;
Lee, J.-H.; Chae, C.-S.; Chung, S.-C.; Shin, D.-S.; Shin, J.; Oh, K.-B.
J. Agric. Food Chem. 2007, 55, 6923–6928.
equivalents of PIFA to effect. In our work and other previous work (see
ref 11) only 1.2 equivalents of PIFA are used. The referee suggested that in
all likelihood aerial oxidation is involved in the final aromatization.
(15) Nishimura, N.; Kobayashi, K. Angew. Chem., Int. Ed. 2008, 47,
6255–6258.
(16) Duan, X.-J.; Li, X.-M.; Wang, B.-G. J. Nat. Prod. 2007, 70,
1210–1213.
(17) 3,4-Dimethoxytoluene is regioselectively monobrominated at
the 2-position using NBS in DMF: Fukuda, T.; Iwao, M. Heterocycles
2007, 74, 701–720.
(18) Erdtman, H. Ann. Chem. 1933, 195–202.
(19) CCDC 789908. The two methoxy units are essentially coplanar
with their parent aromatic ring, the ArꢀOMe twist angles being ca. 2°
and 8° for the 4- and 5-methoxy groups, respectively.
(20) Srikrishna, A.; Satyanarayana, G.Tetrahedron 2006, 62, 2892–2900.
(21) Ueda, S. Yakugaku Zasshi 1962, 82, 714–718.
(22) CCDC 831197. The 4-methoxy groups (adjacent to the bromine
substituent) are twistedout of the arylringplane, theArꢀOMe twist angle
being ca. 88° (the twist angles for the 5-methoxy groups are ca. 5°).
(23) Iyoda, M.; Sakaitani, M.; Otsuka, Hi.; Oda, M. Chem. Lett.
1985, 127–130.
(24) The spectroscopic data of synthetic 1 matched the published
data in ref 1 (see Supporting Information).
(25) Attempted PIFA cyclization of 2 into 1 using PIFA/BF3 OEt2
3
in CH2Cl2 failed.
(26) Oh, K.-B.; Jeon, H. B.; Han, Y.-R.; Lee, T.-J.; Park, J.; Lee, S.-H.;
Yang, D.; Kwon, M.; Shin, J.; Lee, H.-S. Bioorg. Med. Chem. Lett. 2010,
20, 6644–6648.
(6) For a review of naturally occurring phenanthrenes see: Kovꢀacs,
A.; Vasas, A.; Hohmann, J. Phytochemistry 2008, 69, 1084–1110.
(7) Whiting, D. A. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press, 1991; Vol. 3, pp 659ꢀ703, and
references therein.
(27) The moderate isolated yield of 18 is a reflection of its instability
on silica gel on purification.
(28) Phelan, N. F. J. Chem. Educ. 1968, 45, 633–637.
(29) A melting point for polysiphenol was not reported in the
original isolation paper (ref 1).
(8) An intramolecular free-radical dimerization of two phenyl radicals
(as opposed to oxidative coupling) has been proposed as the key
carbonꢀcarbon bond forming step in the biogenesis of urceolatin (ref 3c).
(9) Kurata, K.; Amiya, T. Bull. Chem. Soc. Jpn. 1980, 53, 2020–2022.
(10) For thesynthesisof halogenatedbis(hydroxyphenyl)methanessee:
(a) Akbaba, K.; Balaydin, H. T.; Goksu, S.; Sahin, E.; Menzek, A. Helv. Chim.
Acta 2010, 93, 1127–1135. (b) Oh, K.-B.; Lee, J. H.; Lee, J. W.; Yoon, K.-M.;
Chung, S.-C.; Jeon, H. B.; Shin, J.; Lee, H.-S. Bioorg. Med. Chem. Lett. 2009,
19, 945–948. (c) Li, J.; Guo, S. J.; Su, H.; Han, L. J.; Shi, D. Y. Chin. Chem.
Lett. 2008, 19, 1290–1292.
(11) Biveratryl (compound 6 in this work) is known to readily
aromatize during oxidative coupling using PIFA: (a) Rossiter, L. M.;
Slater, L. M.; Giessert, R. E.; Sakwa, S. A.; Herr, R. J. J. Org. Chem. 2009,
74, 9554–9557. (b) Zeng, W.; Chemler, S. R. J. Org. Chem. 2008,
73, 6045–6047. (c) Moreno, I.; Tellitu, I.; Dominguez, E.; SanMartin, R.
Eur. J. Org. Chem. 2002, 2126–2135, and references therein.
(12) For solution studies see: (a) Schaefer, T.; Laatikainen, R. Can.
J. Chem. 1983, 61, 224–229. For a discussion of 32 X-ray crystal structures
with this motif see:(b) Caillet, J. Acta Crystallogr. 1982, B38, 1786–1791. For
computational studies see:(c) Chein, R.-J.; Corey, E. J. Org. Lett. 2010,
12, 132–135. (d) Vande Velde, C.; Bultinck, E.; Tersago, K.; Van Alsenoy, C.;
Blockhuys, F. Int. J. Quant. Chem. 2007, 107, 670–679, and references therein.
(13) CCDC 831106. The two methoxy groups are coplanar with
their parent aromatic ring, the ArꢀOMe twist angles being ca. 3° and 8°
for the 3- and 4-methoxy groups, respectively. Given that the coplanar
conformational preference of 1,2-dimethoxybenzene has also been
established in solution (ref 12a), we consider that the solid-state
conformation observed here should translate to solution also. Crystal-
lographic data for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre. Copies
of the data can be obtained, free of charge, on application to the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
(14) One referee noted that the overall conversion of dihydrostilbene 6
to phenanthrene 7 is a four-electron oxidation, theoretically requiring 2
1984
dx.doi.org/10.1021/np200596q |J. Nat. Prod. 2011, 74, 1980–1984