Asymmetric total synthesis of dibenzocyclooctadiene lignan natural products

Article abstract of DOI:10.1021/jo051525i

Full details of the asymmetric total syntheses of the dibenzocyclooctadiene lignans interiotherin A, angeloylgomisin R, gomisin O, and gomisin E (epigomisin O) are presented. The syntheses were based on a unified synthetic strategy involving a novel crotylation using the Leighton auxiliary that occurred with excellent asymmetric induction (>98:2 enantiomeric ratio), a diastereoselective hydroboration/Suzuki-Miyaura coupling reaction sequence, and an atropdiastereoselective biarylcuprate coupling, both of which occurred with total (>20:1) stereocontrol. The syntheses were achieved in six to eight steps from simple aromatic precursors.

Full text of DOI:10.1021/jo051525i

Asymmetric Total Synthesis of Dibenzocyclooctadiene Lignan
Natural Products
Robert S. Coleman,* Srinivas Reddy Gurrala, Soumya Mitra, and Amresh Raao
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210
coleman@chemistry.ohio-state.edu
Received July 21, 2005
Full details of the asymmetric total syntheses of the dibenzocyclooctadiene lignans interiotherin
A, angeloylgomisin R, gomisin O, and gomisin E (epigomisin O) are presented. The syntheses were
based on a unified synthetic strategy involving a novel crotylation using the Leighton auxiliary
that occurred with excellent asymmetric induction (>98:2 enantiomeric ratio), a diastereoselective
hydroboration/Suzuki-Miyaura coupling reaction sequence, and an atropdiastereoselective biaryl-
cuprate coupling, both of which occurred with total (>20:1) stereocontrol. The syntheses were
achieved in six to eight steps from simple aromatic precursors.
Introduction
Lignans are a class of naturally occurring plant phe-
nols that formally arise biosynthetically from two cin-
namic acid (phenylpropanoid) residues,1 as defined orig-
inally by Howarth in 1936.2 Typically, the aromatic rings
are highly oxygenated and often fused to additional
carbocyclic or oxygen heterocyclic rings. Lignans are
found in all parts of producing plants, including the roots,
stems, leaves, fruit, and seeds, and they exhibit a wide
range of biological activities. These natural products have
been used medicinally for thousands of years. In many
cases, the active principle of lignan-based traditional
medicines is not known, and a detailed study of the active
principles may provide useful leads in the development
of new pharmaceutical agents.
FIGURE 1. Biosynthetic considerations in the lignan family
of plant natural products.
A typical lignan carbon framework is formed by the
â,â-union of two cinnamic acids (Figure 1). Further
modification by biaryl bond formation gives the diben-
zocyclooctadiene framework by a free-radical process first
proposed by Erdtmann in 1933.3 The biosynthetic path-
ways are well established1 and give rise to a remarkably
diverse set of structures. Many highly modified systems
are known. Lignans of the dibenzocyclooctadiene family
are widely occurring, and the first examples were isolated
from the seeds of Schizandra chinensis in 1961.4 This and
a related species, Kadsura coccinea, produce a variety of
biologically active dibenzocyclooctadienes such as schi-
zandrol. Both of these plants are used in traditional
(1) Lignans: Chemical, Biological and Clinical Properties; Ayers,
D. C., Loike, J. D., Ed.; University Press: Cambridge, 1990.
(2) Howarth, R. D. Ann. Rep. Prog. Chem. 1936, 33, 266.
(3) Erdtmann, H. Leibigs Ann. Chem. 1933, 503, 283.
(4) Kochetkov, N. K.; Khorlin, A.; Chizhov, O. S.; Sheichenko, V. I.
Tetrahedron Lett. 1961, 2, 730.
10.1021/jo051525i CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/05/2005
8932
J. Org. Chem. 2005, 70, 8932-8941

Synthesis of Dibenzocyclooctadiene Lignan Natural Products
Chinese medicine and are listed in the Pharmacopoeia
of the Peoples Republic of China. Dibenzocyclooctadiene
lignans exhibit a wide variety of interesting biological
activities,5 including antiviral,6 anticancer,7 antiinflam-
matory,8 and hepatoprotective effects.9
In Meyers’ synthesis of (-)-schizandrin,18 the stereogenic
axis was set with 6.2:1 diastereoselection using their
oxazoline/Grignard strategy, an auxiliary-based diaste-
reoselective reaction. The absolute configuration of the
axis was subsequently used to control introduction of the
remaining stereogenic centers. In a report by Motherwell
and co-workers on the synthesis of steganone-like sys-
tems,19 substrate control was used with side-chain ste-
reogenic centers controlling the sense of induction in the
stereogenic axis. The level of diastereoinduction was not
reported, but the correct stereoisomer was isolated in low
yield. In a contribution to this area on the synthesis of
(-)-steganone by Molander and co-workers,20 diastereo-
selective Suzuki coupling of an arylboronic acid and
Uemura’s bromoaryl chromium tricarbonyl complex ini-
tially afforded the wrong atropdiastereomer, which epimer-
ized during the reaction to the correct atropisomer, but
a late-stage epimerization of the side-chain stereogenic
center re-epimerized the stereogenic axis. In a more
recent contribution by this group,21 (+)-isoschizandrin
was constructed in 12 steps using a diastereoselective
SmI2-promoted 8-endo closure of the cyclooctadiene ring;
the stereogenic biaryl axis was introduced using the
kinetic resolution method of Bringmann.22
A recent report described the isolation of interiotherin
A from the stems of Kadsura interior,23 a vine of the
Schisandraceae family native to southern China. This
group subsequently reported the isolation of the more
highly modified lignans interiotherins C and D.24 The
interiotherins inhibit the replication of HIV at µg/mL
levels. Interiotherin A is closely related to angeloylgo-
misin R (2).25 Gomisin O, a prototypical dibenzocyclooc-
tadiene lignan, was isolated from Schizandra chinensis
along with a number of congeners, including the epimeric
gomisin E (epigomisin O).26 Herein, we report full details
of the total synthesis of the dibenzocyclooctadiene lignans
interiotherin A (1) and angeloylgomisin R (2)27 and the
total syntheses of gomisin O (3) and gomisin E (epigo-
misin O) (4) (Figure 2). The three stereogenic centers
present on the eight-membered ring and the stereogenic
biaryl axis are introduced with complete control of
absolute and relative stereochemistry.
The best-studied lignan is podophylotoxin, and many
of its derivatives exhibit strong antiviral activity against
herpes simplex virus (nM MIC values).10 Gomisin J and
derived dibenzocyclooctadiene lignans are reported to
have effective anti-HIV activity at sub-micromolar levels
via inhibition of reverse transcriptase,11 and schisan-
therin D and kadsuranin showed similarly effective anti-
HIV activity.12 Etoposide and teniposide are semisyn-
thetic derivatives of podophylotoxin that are used for the
treatment of small-cell lung cancer, testicular cancer,
lymphoma, and lymphocytic leukemia. These compounds
are good examples of the value of exploring traditional
medicines for lead compounds and of the successful
development of effective anticancer agents from plant
natural products.
The first total syntheses of the dibenzocyclooctadienes
steganone and steganacin were reported almost 30 years
ago by Kende13 and Raphael,14 respectively, and Koga and
co-workers more recently reported the asymmetric total
synthesis of steganacin15 and reported on structure-
cytotoxicity relationships for this natural product.16,17 An
important step in the construction of the dibenzocyclooc-
tadiene ring system is installation of the stereogenic axis.
(5) Charlton, J. L. J. Nat. Prod. 1998, 61, 1447.
(6) (a) Fujihashi, T.; Hara, H.; Sakata, T.; Mori, K.; Higuchi, H.;
Tanaka, A.; Kaji, H.; Kaji, A. Antimicrob. Agents Chemother. 1995,
39, 2000. (b) Chen, D.-F.; Zhang, S.-X.; Chen, K.; Zhou, B.-N.; Wang,
P.; Cosentino, L. M.; Lee, K.-H. J. Nat. Prod. 1996, 59, 1066. (c) Chen,
D.-F.; Zhang, S.-X.; Xie, L.; Xie, J.-X.; Chen, K.; Kashiwada, Y.; Zhou,
B.-N.; Wang, P.; Cosentino, L. M.; Lee, K.-H. Bioorg. Med. Chem. 1997,
5, 1715. (d) Lee, K.-H. J. Nat. Prod. 2004, 67, 273.
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Aburada, M.; Nakagawa, S.; Takeuchi, M.; Takido, M. Oncology 1992,
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62, 3242. (c) Kuo, Y.-H.; Huang, H.-C.; Kuo, L.-M. Y.; Chen, C.-F. J.
Org. Chem. 1999, 64, 7023.
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Pharmacol. 1994, 113, 945.
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50, 213. (b) Kiso, Y.; Tohkin, M.; Hikino, H.; Ikeya, Y.; Taguchi, H.
Planta Med. 1985, 51, 331. (c) Yamada, S.; Murawaki, Y.; Kawasaki,
H. Biochem. Pharmacol. 1993, 46, 1081. (d) Ko, K. M.; Ip, S. P.; Poon,
M. K. T.; Wu, S. S.; Che, C. T.; Ng, K. H.; Kong, T. C. Planta Med.
1995, 61, 134.
(10) Markkanen, T.; Makinen, M. L.; Maunuksela, E.; Himanen, P.
Drugs Exptl. Clin. Res. 1981, 7, 711.
(11) Fujihashi, T.; Hara, H.; Sakata, T.; Mori, K.; Higuchi, H.;
Tanaka, A.; Kaji, H.; Kaji, A. Antimicrob. Agents Chemother. 1995,
39, 2000.
(12) Chen, D.-F.; Zhang, S.-X.; Xie, L.; Xie, J.-X.; Chen, K.; Kashi-
wada, Y.; Zhou, B.-N.; Wang, P.; Cosentino, L. M.; Lee, K.-H. Bioorg.
Med. Chem. 1997, 5, 1715.
(13) Kende, A. S.; Liebeskind, L. S. J. Am. Chem. Soc. 1976, 98,
267.
Results and Discussion
In our retrosynthetic analysis (Scheme 1), three critical
bond construction events must be developed for the
(18) Warshawsky, A. M.; Meyers, A. I. J. Am. Chem. Soc. 1990, 112,
8090.
(19) Bradley, A.; Motherwell, W. B.; Ujjainwalla, F. Chem. Commun.
1999, 10, 917.
(20) Monovich, L. G.; Hue´rou, Y. L.; Ro¨nn, M.; Molander, G. A. J.
Am. Chem. Soc. 2000, 122, 52.
(21) Molander, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem.
2003, 68, 9533.
(14) Hughes, L. R.; Raphael, R. A. Tetrahedron Lett. 1976, 17, 1543.
(15) Tomioka, K.; Ishiguro, T.; Iitaka, Y.; Koga, K. Tetrahedron 1984,
40, 1303.
(16) Tomioka, K.; Ishiguro, T.; Mizuguchi, H.; Komeshima, N.; Koga,
K.; Tsukagoshi, S.; Tsuruo, T.; Tashiro, T.; Tanida, S.; Kishi, T. J. Med.
Chem. 1991, 34, 54.
(22) (a) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615.
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Kamikawa, K.; Uemura, M. J. Organomet. Chem. 2002, 661, 31. (c)
Bringmann, G.; Tasler, S.; Pfeifer, R.-M.; Breuning, M. J. Organomet.
Chem. 2002, 661, 49.
(17) For other work in this area, see: (a) Takeya, T.; Yamaki, S.;
Itoh, T.; Hosogai, H.; Tobinaga, S. Chem. Pharm. Bull. 1996, 44, 909.
(b) Tanaka, M.; Mukaiyama, C.; Mitsuhashi, H.; Maruno, M.; Waka-
matsu, T. J. Org. Chem. 1995, 60, 4339. (c) Takeya, T.; Ohguchi, A.;
Tobinaga, S. Chem. Pharm. Bull. 1994, 42, 438. (d) Takeya, T.;
Ohguchi, A.; Ara, Y.; Tobinaga, S. Chem. Pharm. Bull. 1994, 42, 430.
(e) Takeya, T.; Ohguchi, A.; Ikeya, T.; Tobinaga, S. Chem. Pharm. Bull.
1994, 42, 677. (f) Ishiguro, T.; Mizuguchi, H.; Tomioka, K.; Koga, K.
Chem. Pharm. Bull. 1985, 33, 609. (g) Tomioka, K.; Mizuguchi, H.;
Koga, K. Tetrahedron Lett. 1979, 20, 1409.
(23) Chen, D.-F.; Zhang, S.-X.; Chen, K.; Zhou, B.-N.; Wang, P.;
Consentino, L. M.; Lee, K.-H. J. Nat. Prod. 1996, 59, 1066.
(24) Chen, D.-F.; Zhang, S.-X.; Kozuka, M.; Sun, Q.-Z.; Feng, J.;
Wang, Q.; Mukainaka, T.; Nobukuni, Y.; Tokuda, H.; Nishino, H.;
Wang, H.-K.; Morris-Natschke, S. L.; Lee, K.-H. J. Nat. Prod. 2002,
65, 1242.
(25) Tan, R.; Li, L. N.; Fang, Q. Planta Med. 1984, 50, 414.
(26) Ikeya, Y.; Taguchi, H.; Yosioka, I.; Kobayashi, H. Chem. Pharm.
Bull. 1979, 27, 2695.
(27) Coleman, R. S.; Gurrala, S. R. Org. Lett. 2005, 7, 1849.
J. Org. Chem, Vol. 70, No. 22, 2005 8933

Coleman et al.
SCHEME 2
cis and is introduced in a straightforward manner by use
of the Mitsunobu inversion at C6. The C9-C10 bond of
6 is introduced concomitant with formation of the C8-
stereogenic center using an A1,3-controlled hydrobora-
tion29 and in situ B-alkyl Suzuki-Miyaura reaction30
sequence starting from alkene 9, via trialkylborane 7,
which is coupled in situ with aryl bromide 8. The key
C6/C7 bond construction event is the enantioselective and
diastereoselective production of alkene 9 by an asym-
metric crotylation of aryl aldehyde 10 using chiral
organometallic reagent 11.
FIGURE 2. Dibenzocyclooctadiene natural product targets.
SCHEME 1
Successful implementation of this plan required solu-
tions to three key synthetic objectives. First, methodology
for asymmetric crotylation was required. There were no
examples of the necessary substitution pattern of the
tiglyl [(E)-2-methyl-2-buten-1-yl] organometallic reagent
known. Second, diastereoselection in the hydroboration
of the crotylated product needed to be established as this
step sets the relative stereochemistry of the two methyl
groups of the targets. We proposed that A1,3 strain would
control the facial selectivity of this reaction. Third, the
ability to control the sense of atropisomerism about the
stereogenic biaryl axis that is formed in the biaryl
coupling reaction was difficult to predict a priori, al-
though we had previously found that existing stereogenic
centers exert a strong influence on this reaction.31 In the
end, we found solutions to all these problems, and the
asymmetric synthesis of the targeted dibenzocycloocta-
diene natural products was achieved with complete
control of stereochemistry.
Diastereoselective Methylcrotylation of Aryl Al-
dehydes. The proposed asymmetric synthesis of diben-
zocyclooctadiene lignans relied on the enantio- and
diastereoselective crotylation of an oxygenated electron-
rich aryl aldehyde (Scheme 2).32 Given stereodefined
allylic organometallic systems 12 [(E)-2-methyl-2-buten-
1-yl (tiglyl)] and 13 [(Z)-2-methyl-2-buten-1-yl (angelyl)],
synthesis of the anti-adduct 14 and syn-adduct 15 adduct
success of a stereocontrolled and synthetically efficient
approach to this family of lignans. The C15/C16 stereo-
genic biaryl axis of prototype dibenzocyclooctadiene 5 is
introduced with complete control of atropdiastereoselec-
tion using oxidative cuprate chemistry developed by
Lipshutz.28 The sense of stereoinduction in this reaction
was dependent solely upon the configuration of the C6-
stereogenic center of 6, such that C6/C7-anti stereochem-
istry allows for complete stereocontrol of the newly
formed axis. With respect to interiotherin A and gomisin
R and O systems, typified by 5, the relative configuration
about the eight-membered ring is C6/C7-trans, C7/C8-
(29) (a) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis
1994, 629. (b) Coutts, L. D.; Cywin, C. L.; Kallmerten, J. Synlett 1993,
696. (c) Bernsmann, H.; Fro¨hlich, R.; Metz, P. Tetrahedron Lett. 2000,
41, 4347. (d) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D.
Tetrahedron 2002, 58, 1983. (e) Herb, C.; Maier, M. E. J. Org. Chem.
2003, 68, 8129.
(30) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4544.
(31) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1994, 116, 8795.
Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889.
(32) Roush, W. R. Allylic Organometallics. In Comprehensive Or-
ganic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; pp 1-53.
(28) (a) Lipshutz, B. H.; Siegmann, K.; Garcia, E. J. Am. Chem. Soc.
1991, 113, 8161. (b) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser,
F. J. Am. Chem. Soc. 1993, 115, 9276. (c) Lipshutz, B. H.; Kayser, F.;
Maullin, N. Tetrahedron Lett. 1994, 35, 815. (d) Lipshutz, B. H.; Liu,
Z.-P.; Kayser, F. Tetrahedron Lett. 1994, 35, 5567. (e) Lipshutz, B. H.;
Kayser, F.; Liu, Z.-P. Angew. Chem., Int. Ed. Engl. 1994, 33, 1842.
8934 J. Org. Chem., Vol. 70, No. 22, 2005

Synthesis of Dibenzocyclooctadiene Lignan Natural Products
SCHEME 3
SCHEME 4
SCHEME 5
in diastereomerically and enantiomerically pure form
should be possible.33
A nonobvious but precedented pitfall to this strategy
is that precursor allylic organometallic reagents 12 and
13 (M ) Mg, Li) undergo allylic equilibration,34 giving
rise to stereochemically scrambled crotylation reagents
upon transmetalation (e.g., M ) B, Sn, Si). This problem
was patently obvious upon formation of the Grignard
reagent 12 (M ) MgBr) from the corresponding bromide
(Scheme 2). This reagent failed to effect useful diaste-
reoselection in the addition to aldehyde 10 owing to the
rapidly equilibrating mixture of regioisomeric allylic
isomers (eq 1).
to afford a 13:87 ratio of syn/anti adducts 20 and 21,
respectively. Attempts to increase diastereoselectivity
with lower reaction temperatures were unsuccessful
because the tiglylchromium reagent was unreactive
below -30 °C. Addition of stoichiometric menthol as a
chiral auxiliary41 provided no asymmetric induction and
resulted in lowered yields, and this metal was not
pursued.
Halogen-metal exchange of tiglyl bromide with indium
in DMF afforded the tiglylindium reagent,42 which proved
highly effective in diastereoselective crotylation of aryl
aldehydes (Scheme 4). At room temperature in DMF,
reaction of this reagent with 16 afforded an 82% com-
bined yield of products in a 2.5:1 ratio of syn- and anti-
adducts 20 and 21, respectively, which could be improved
to 11:1 at -45 °C (85% combined yield) and to >19:1 in
5:1 DMF/THF at -78 °C (98%). The indium reagent
generated in THF provided no diastereoselectivity in this
addition reaction. Addition of a stoichiometric amount
of (+)-cinchonidine43 or (S)-BINAP (DMF/THF 5:1, -78
°C, 2 h) resulted only in decreased yield without effecting
detectable asymmetric induction. Attempts at transmeta-
lation from indium to boron using Ipc2BX (X ) Cl, OMe)
were unsuccessful.
In efforts to surmount this equilibration problem, we
examined silicon and tin (Scheme 3), which provide
configurationally stable species.35 Using 2-bromo-3,4,5-
trimethoxybenzaldehyde (16),36 Yamamoto CAB-cata-
lyzed crotylsilylation37 with tiglyltrimethylsilane (17)
(CH3CH2CN, -10 °C, 3 h, 56%) afforded poor diastereo-
selectivity (1.5:1 syn/anti 20/21) and the reaction of
tiglyltributylstannane (18) in the presence of AgOTf/(S)-
BINAP38 (CH2Cl2, 25 °C, 24 h) or Ti/BINOL39 (CH2Cl2,
25 °C, 18 h) failed to provide product.
The tiglylchromium reagent 19 (Scheme 3) prepared
from tiglyl bromide and CrCl2 in THF40 underwent
addition to aldehyde 16 (THF, -30 to +25 °C, 2 h, 69%)
Enantioselective Methylcrotylation of Aryl Alde-
hydes. Starting from stereodefined tiglyl bromide, for-
mation of the Grignard reagent and transmetalation from
magnesium to boron occurred by treatment with (-)-Ipc2-
BCl to form the Brown diisopinocampheylborane reagent
23 (Scheme 5).44 This reagent underwent quantitative
addition to aldehyde 22, although with little diastereo-
selectivity, to form a separable 4:3 mixture of (6S,7R)-
syn-adduct 24 and (6S,7S)-anti-adduct 25 in 97% com-
bined yield. These products were produced with good
enantiomeric purity (90% ee), but with unacceptable
(33) (a) Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243. (b) Hoffmann,
R. W. Angew. Chem., Int. Ed. Engl. 1982, 21, 555. (c) Courtois, G.;
Miginiac, L. J. Organomet. Chem. 1974, 69, 1.
(34) (a) Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13, 701.
(b) Schlosser, M.; Hartman, J.; David, V. Helv. Chim. Acta 1974, 57,
1567. (c) Schlosser, M.; Hartman, J. J. Am. Chem. Soc. 1976, 98, 4674.
(d) Sta¨hle, M.; Hartmann, J.; Schlosser, M. Helv. Chim. Acta. 1977,
60, 1730. (e) Fuzita, K.; Schlosser, M. Helv. Chim. Acta 1982, 65, 1258.
(f) Hoffmann, R. W.; Polachowski, A. Chem. Eur. J. 1998, 4, 1724.
(35) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(36) (a) Molander, G. A.; George, K. M.; Monovich, L. G. J. Org.
Chem. 2003, 68, 9533. (b) Yamada, K.; Kurokawa, T.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630.
(37) (a) Furuta, K.; Mouri, M.; Yamamoto, H. Synlett 1991, 561. (b)
Ishihara, K.; Mouri, M.; Gao, Q.; Maruyama, T.; Furuta, K.; Yamamoto,
H. J. Am. Chem. Soc. 1993, 115, 11490.
(38) Yanagisawa, A.; Nakatsuka, Y.; Nakashima, H.; Yamamoto, H.
Synlett 1997, 933.
(39) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467. (b) Hanawa, H.; Kii, S.; Maruoka, K. Adv. Synth.
Catal. 2001, 343, 57. (c) Hanawa, H.; Hashimoto, T.; Maruoka, K. J.
Am. Chem. Soc. 2003, 125, 1708. (d) Kii, S.; Maruoka, K. Chirality
2003, 15, 68.
(40) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179.
(41) Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1997,
62, 2322.
(42) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
(43) (a) Loh, T.-P.; Zhou, J.-R.; Li, X.-R. Tetrahedron Lett. 1999, 40,
9333. (b) Loh, T.-P.; Zhou, J.-R.; Yin, Z. Org. Lett. 1999, 1, 1855.
(44) (a) Brown, H. C.; Jadhav, P. J. Am. Chem. Soc. 1983, 105, 2092.
(b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293. (c)
Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919. (d)
Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401. (e)
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J. Org. Chem, Vol. 70, No. 22, 2005 8935

Coleman et al.
SCHEME 6
SCHEME 8
SCHEME 9
SCHEME 7
which underwent addition to aldehyde 22 to afford
(6S,7S)-anti-adduct 25 (78%) with complete diastereose-
lectivity and excellent enantioselection (96% ee).
Using this protocol, adduct (6S,7S)-anti-21 was ob-
tained from aldehyde 16 in 75% yield (97% ee) through
reaction with tiglylsilane 29 (Scheme 8).
diastereoselection. Efforts to synthesize the diisopi-
nocampheylborane reagent 23 from the configurationally
stable tiglylpotassium34 were unsuccessful.
Leighton’s chiral diamine protocol45 was successfully
employed in a diastereoselective and enantioselective
protocol for the formation of syn- and anti-adducts.
Angelyltrichlorosilane (26) was formed stereoselectively
by palladium-catalyzed hydrosilylation of isoprene,46 and
the complementary tiglyltrichlorosilane (27) was formed
by base-promoted displacement of tiglyl chloride with
trichlorosilane (Scheme 6).47
Hydroboration/Suzuki-Miyaura Coupling: 1,4-
Diarylbutane Construction. Protection of the benzylic
hydroxyl group of 25 as the tert-butyldimethylsilyl ether
afforded 30 (98%). Hydroboration of the alkene of 30 with
9-borabicyclononane (9-BBN) occurred with complete
diastereofacial selectivity to afford the intermediate
trialkylborane 31, which was coupled in situ with aryl
bromides 32 or 33 under standard Suzuki-Miyaura
coupling conditions30 to afford 1,4-diarylbutanes 34 (72%)
and 35 (77%) overall yield (Scheme 9). These compounds
contain three of the four necessary stereogenic elements
of interiotherin and gomisin R in the correct absolute and
relative configuration, and which were introduced via two
highly stereoselective transformations.
Initially, it was unclear whether bromination of the
newly installed aromatic ring of 34 could be achieved
regioselectively (i.e., ortho to the methoxy group). Con-
sequently, the benzyloxy compound 35 was used to take
advantage of the established ortho-directing effect of a
phenolic hydroxyl group (Scheme 10).48 Hydrogenolysis
of the benzyl ether of 35 (EtOAc, 25 °C, 6 h, 98%) afforded
the corresponding phenol 36, which underwent facile
bromination with complete regioselectivity (dioxane, 15
°C, 12 h, 90%) to afford 37. Methylation of 37 (acetone,
K2CO3, 56 °C, 2 h, 95%) provided 38. It was subsequently
established that bromination could be achieved with
complete regioselectivity (CHCl3, 25 °C, 6 h), ortho to the
Reaction of angelyltrichlorosilane (26) with the (1S,2S)-
1,2-diaminocyclohexane-based auxiliary (DBU, CH2Cl2,
25 °C, 14 h) afforded chiral angelylsilane 28 (Scheme 7).
This reagent underwent addition to aldehyde 22 to afford
(6R,7S)-syn-adduct 24 (78%) with complete diastereose-
lection (>50:1 syn/anti) and excellent enantioselectivity
(96% ee). The reagent 28 could not be crystallized,
whereas allyl and crotyl reagents are reported to be
stable crystalline solids.45 Consequently, it was critical
to use a trichlorosilane/auxiliary ratio of exactly 1:1; with
a 1.1:1 or 1.2:1 ratio, the resulting reagent systems
afforded adduct 24 in 80% ee and 60% ee, respectively.
Reaction of tiglyltrichlorosilane (27) with the (1R,2R)-
1,2-diaminocyclohexane-based auxiliary (DBU, CH2Cl2,
25 °C, 14 h) afforded chiral tiglylsilane 29 (Scheme 7),
(45) (a) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett.
2004, 6, 4375. (b) Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed.
2003, 42, 946.
(46) (a) Tsuji, J.; Hara, M.; Ohno, K. Tetrahedron 1974, 30, 2143.
(b) Takahashi, S.; Shibano, T.; Hagihara, N. J. Chem. Soc., Chem.
Commun. 1969, 161. (c) Kira, M.; Kobayashi, M.; Sakurai, H. Tetra-
hedron Lett. 1987, 28, 4081. (d) Kira, M.; Hino, T.; Sakurai, H.
Tetrahedron Lett. 1989, 30, 1099.
(48) (a) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida,
A. Bull. Chem. Soc. Jpn. 1993, 66, 1576. (b) Pearson, D. E.; Wysong,
R. D.; Breder, C. V. J. Org. Chem. 1967, 32, 2358.
(47) Furuya, N.; Sukawa, T. J. Organomet. Chem. 1975, 96, C1.
8936 J. Org. Chem., Vol. 70, No. 22, 2005

Synthesis of Dibenzocyclooctadiene Lignan Natural Products
SCHEME 12
SCHEME 13
FIGURE 3. A1,3-strain model for diastereofacial selectivity.
SCHEME 10
SCHEME 11
with 9-BBN in EtOH and subsequent oxidation with
basic hydrogen peroxide afforded primary alcohol 44
(91%), as a 94:6 ratio of diastereomers (Scheme 12).
Crystals of purified 44 were obtained from hexane, and
the resulting structure showed that the model proposed
above was determinant with respect to diastereofacial
selectivity. The C7/C8 methyl groups in product 44 are
anti.
The relative configuration of the benzylic alcohol
stereocenter had no effect on the diastereofacial selectiv-
ity of the approach of the borane (Scheme 13). Hydrobo-
ration of 4549 followed by in situ Suzuki-Miyaura
coupling (THF, Pd(Ph3P)4, aq NaOH, 70 °C, 12 h) with
aryl bromide 46 afforded 1,4-diarylbutane 47 as a single
stereoisomer (70%). Crystals of 47 were obtained from
hexane, and the resulting X-ray structure possessed 6,7-
syn/7,8-anti stereochemistry, with the key methyl groups
anti (see the Supporting Information). Thus, it appeared
that the A1,3-based model was the controlling factor with
respect to diastereofacial selectivity.
This straightforward protocol of hydroboration/Su-
zuki-Miyaura coupling effectively complemented the
asymmetric crotylation methodology and, when coupled
with the high-yielding and regioselective bromination
reaction, provided for an efficient, four-step conversion
of aryl aldehydes 22 and 16 to 1,4-diarylbutanes 38 (41%
overall) and 42 (38% overall), respectively, with complete
control of absolute and relative stereochemistry (Scheme
14). These compounds possess all necessary functionality
for conversion to the target dibenzocyclooctadiene natural
products.
methoxy group of 34, which significantly shortened the
route to dibromide 38.
The syn-stereoisomer 20 similarly provided excellent
diastereoselection upon hydroboration/Suzuki-Miyaura
coupling (Scheme 11). Protection as the tert-butyldim-
ethylsilyl ether (95%) and hydroboration of 39 provided
the intermediate trialkylborane 40. This species was
mixed with the preformed reagent obtained upon reaction
of aryl bromide 32 with Pd(0). Coupling of borane 40 with
aryl bromide 32 under standard Suzuki-Miyaura condi-
tions afforded a good yield of 1,4-diarylbutane 42. Bro-
mination occurred selectively ortho to the methoxy group
of 41 (CHCl3, 22 °C, 7 h) to afford dibromide 42 (85%) in
excellent yield.
The origin of the diastereoselection in the hydrobora-
tion of 30 and 39 is explained by examination of the
lowest energy conformation (MM3) about the sp2-sp3
bond, wherein the allylic hydrogen is eclipsed with the
alkene in order to minimize A1,3 strain (Figure 3). The
least sterically congested approach by 9-BBN is from the
side of the allylic methyl group, giving a new stereogenic
center wherein the methyl groups are anti. This model
has precedent in a number of related contexts.29
The sense of diastereoselection in the hydroboration
was confirmed by single-crystal X-ray structural analysis
of 44 (see the Supporting Information). Treatment of 4349
Oxidative Cuprate Biaryl Coupling. Of particular
concern in the present case was the issue of atropdias-
tereoselection in the key intramolecular biaryl coupling.
Tobinaga and co-workers50 have reported that oxidative
aryl-aryl coupling of 1,4-diarylbutanes bearing stereo-
genic centers in the aliphatic tether results in significant
(49) Racemic 43 and 45 were obtained from addition of Grignard
reagent 12 (Scheme 2, M ) MgBr) to 3,4,5-trimethoxybenzaldehyde.
(50) Takeya, T.; Ohbuchi, A.; Tobinaga, S. Chem. Pharm. Bull. 1994,
42, 438-442.
J. Org. Chem, Vol. 70, No. 22, 2005 8937

Coleman et al.
SCHEME 14
FIGURE 4. Relative configuration of biaryl coupled product
51.
cuprous cyanide at -40 °C to form an intermediate cyclic,
higher-order biarylcuprate. Oxidation occurred smoothly
using oxygen, as originally described, or more effectively
using 1,3-dinitrobenzene,54 and dibenzocyclooctadiene 49
was isolated in 69% yield as the sole diastereomer
present. Removal of the silyl ether of 49 (THF, 55 °C, 12
h) afforded the corresponding alcohol 50 (89%).
SCHEME 15
Assignment of configuration about the biaryl axis of
49 was obtained by correlation of key 1H NMR chemical
shifts with those of the related system 51, obtained by
biaryl coupling as a 15:1 mixture of separable diastere-
omers (Figure 4). The relative configuration of the major
diastereomer 51 was determined by single-crystal X-ray
analysis (see the Supporting Information). In this struc-
ture, the Pax configuration about the stereogenic biaryl
bond correlates with the S configuration at the C6
benzylic stereogenic center of the four-carbon bridge. The
chemical shifts of the C4-H and C11-H protons of 51 were
diagnostic of the relative configuration between the C6-
stereogenic center and the stereogenic biaryl axis. When
the absolute configuration of C6 is S, as in 51, the C4-H
and C11-H protons resonated with a chemical shift
difference of ∆δ ) 0.52 ppm in the Pax diastereomer,
whereas this difference was ∆δ ) 0.11 ppm in the minor
Max diastereomer. Since ∆δ ) 0.44 for C4-H/C11-H of 49,
the axial configuration must be Pax. Correlation of other
1H NMR resonances of 49 and 51 was observed,55 further
strengthening the stereochemical assignment.
diastereoselection, but in extremely low yields (5-36%
with 85:15 diastereoselection). In a later study, this same
group51 reported a similar oxidation, mediated by Fe(III)
salts, to proceed with 4:1 diastereoselection in 36% yield.
In our own work, we observed 8:1 atropdiastereoselection
in the formation of a key biaryl bond during the course
of the total synthesis of calphostin A.31,52
In the present case the conformation about the carbon-
metal-carbon bond of an intermediate biaryl cuprate will
depend most importantly on the conformational biases
of the four-carbon tether, and it was presumed that the
relative configuration of the stereogenic center(s) in the
butane tether would control the sense of stereoinduction
during biaryl bond formation.
Alcohol 50 underwent a Mitsunobu inversion with
benzoic acid to afford interiotherin A (1) (Scheme 16). In
a similar manner, reaction of alcohol 50 with angelic acid
under Mitsunobu reaction conditions afforded angeloylgo-
1
misin R (2). The H and 13C NMR data for synthetic 1
Implementation of the Lipshutz methodology27 for
biaryl coupling proved exceptionally effective in these
systems. This protocol involves low temperature forma-
tion of a mixed diarylcuprate and oxidation of this species
to form the carbon-carbon biaryl bond. This reaction is
relatively insensitive to steric or electronic features of
the aromatic systems when compared to palladium-
mediated processes. We have previously used this chem-
istry in the total syntheses of eupomatilones 4 and 6.53
Remarkably, complete diastereoselectivity was ob-
served in the Lipshutz coupling of 6,7-anti/7,8-anti dia-
rylbutane 38 (Scheme 15). In this case, halogen-lithium
exchange with tert-butyllithium afforded the intermedi-
ate bis-lithiated system, which was reacted directly with
and 2 were identical with those reported for the naturally
occurring compounds.
In the case of the 6,7-syn/7,8-anti stereoisomer of the
diarylbutane (42), treatment with four equivalents of tert-
butyllithium in 2-methyltetrahydrofuran (MeTHF) af-
forded the dilithio species, which was treated with copper
cyanide at -40 °C to form the higher order biarylcuprate
(Scheme 17). Even though exchange of the aryl ligands
on copper is not possible because of the cyclic nature of
the cuprate, it was important to perform the subsequent
oxidation at low temperature in order to avoid protode-
(54) (a) Spring, D. R.; Krishnan, S.; Schreiber, S. L. J. Am. Chem.
Soc. 2000. 122, 5656. (b) Reference 28b.
(55) Characteristic chemical shifts for (P)-51: C4-H/C10-H δ 7.02/
6.50; C6-H δ 4.42; C7-CH3/C8-CH3 δ 1.03/0.66. For (M)-51: C4-H/
C10-H δ 6.47/6.36; C6-H δ 4.73; C7-CH3/C8-CH3 δ 1.17/0.97. For
compound 49: C4-H/C10-H δ 6.87/6.43; C6-H δ 4.37; C7-CH3/C8-CH3
δ 0.98/0.65.
(51) Takeya, T.; Yamaki, S.; Itoh, T.; Hosogai, H.; Tobinaga, S.
Chem. Pharm. Bull. 1996, 44, 909-918.
(52) Coleman, R. S.; Grant, E. B. Tetrahedron Lett. 1993, 34, 2225.
(53) Coleman, R. S.; Gurrala, S. R. Org. Lett. 2004, 6, 4025.
8938 J. Org. Chem., Vol. 70, No. 22, 2005

Synthesis of Dibenzocyclooctadiene Lignan Natural Products
SCHEME 16
SCHEME 18
provided 1H NMR spectral data identical with that
reported for gomisin E (epigomisin O). Mitsunobu inver-
sion using p-nitrobenzoic acid56 (THF, 0-25 °C, 12 h)
with subsequent saponification of the inverted ester (25
°C, 10 h) provided gomisin O (3) in excellent yield for
the two-step conversion. By this route, gomisin E and
gomisin O were synthesized in six and eight steps,
respectively, from aromatic precursors 16 and 41.
In this key biaryl coupling, the C6-stereogenic center
seemed to be the determining element in controlling the
relative configuration of the incipient biaryl axis. With
the 6S configuration, as in 38 and 56, the emergent
stereogenic axis is P and the coupling reaction occurs
with complete atropdiastereoselectivity. When this center
is 6R, as in 43, the emergent axis is formed with
essentially no diastereoselectivity and the major diaste-
reomer possesses the M configuration (1:2 P/M). However,
we have not performed biaryl coupling reactions on the
complete series of diastereomeric 1,4-diarylbutanes, so
more subtle effects may be evident when the other
stereogenic centers are altered in relative configuration.
It is assumed that this stereogenic center effects the
chirality of the intermediate diarylcuprate prior to reduc-
tive elimination, but lacking detailed knowledge of the
structure of this intermediate, it is difficult to provide
detailed speculation about the origin of the diastereose-
lection at this point.
SCHEME 17
cupration after workup. Oxygen proved to be the best
oxidant in this system, and a 1:2 mixture of two atropi-
somers 52 and 53 were isolated from the reaction in
modest yield. 1,3-Dinitrobenzene was not effective in this
case.
Upon deprotection of the silyl ethers of 52 and 53
(THF, 55 °C, 5 h), the minor stereoisomeric product 54
gave identical H and 13C NMR spectral data with that
1
Conclusion
reported for gomisin O and thus must possess P absolute
configuration about the stereogenic axis. Again, the C4-H
and C11-H protons were diagnostic of the relationship
between the C6-stereogenic center and the biaryl stereo-
genic axis. When the absolute configuration of C6 is R,
as in 54 and 55, the C4-H and C11-H protons resonated
with chemical shifts ∆δ ) 0.14 ppm in the Pax diastere-
omer 54 and by ∆δ ) 0.50 ppm in the Max diastereomer
55, or opposite to the system with the C6 stereogenic
center in the S configuration.
In contrast, Lipshutz coupling of the 6,7-anti/7,8-anti
diarylbutane 56 provided a single atropdiastereoisomer
in 35% yield (Scheme 18). Upon deprotection of the silyl
ether of product 57 (THF, 55 °C, 3 h), the product 4
The total syntheses of the dibenzocyclooctadiene natu-
ral products interiotherin A, angeloylgomisin R, gomisin
O, and gomisin E (epigomisin O) were achieved in a
convergent and efficient fashion.27 Starting from known
aromatic systems 16, 22, and 32, the natural products
were produced in six to eight steps with complete control
of absolute and relative stereochemistry. Key steps
included a novel asymmetric crotylation reaction using
the Leighton auxiliary that provided adducts with 96-
97% ee, a diastereoselective hydroboration reaction coupled
with an in situ Suzuki-Miyaura alkylborane coupling
(56) (a) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994,
59, 234. (b) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
J. Org. Chem, Vol. 70, No. 22, 2005 8939

Coleman et al.
and washed with saturated aqueous Na2S2O3, water, and
saturated aqueous NaCl. The organic layer was dried (Na2-
SO4) and concentrated, and the residue was purified by flash
chromatography (silica, 15% EtOAc/hexane) to afford 38 (83
mg, 82%) as colorless solid.
that occurred with >20:1 diastereoselectivity, and an
oxidative biarylcuprate coupling that occurred with
complete atropdiastereoselection.
Experimental Section
(6S,7S,8S,Pax)-Dibenzocyclooctadiene 49. A solution of
38 (0.05 g, 0.074 mmol) in MeTHF (2 mL) was treated with
t-BuLi (2.3 M, 0.13 mL, 0.29 mmol) at -78 °C under argon.
After 15 min, the pale yellow reaction mixture was transferred
via cannula to a flask containing CuCN (7.0 mg, 0.074 mmol)
in MeTHF (2 mL) at -78 °C under argon. The heterogeneous
mixture was allowed to warm to -40 °C over 1 h and was
stirred at this temperature until homogeneous (ca. 1.5 h). The
reaction mixture was treated with a freshly prepared solution
of 1,3-dinitrobenzene (0.5 M, 0.59 mL, 0.29 mmol) at -40 °C
and was allowed to warm to 25 °C. The reaction mixture was
stirred at this temperature for 10 h and was quenched by the
addition of 10% NH4OH in saturated aqueous NH4Cl. The
resulting two-phase mixture was stirred for 30 min and the
phases were separated. The aqueous phase was extracted two
times with EtOAc (20 mL), and the combined organic layers
were washed with water and saturated aqueous NaCl. The
organic layer was dried (Na2SO4), concentrated, and the
residue was purified by flash chromatography (5% EtOAc/
hexane) to afford 49 (26 mg, 69%) as colorless solid: 1H NMR
(CDCl3, 500 MHz) δ 6.87 (s, 1H), 6.43 (s, 1H), 5.96 (app t, 2H,
J ) 1.2 Hz), 5.95 (ABq, 2H, J ) 1.5 Hz, ∆ν ) 27.9 Hz), 4.37
(d, 1H, J ) 1.3 Hz), 3.84 (s, 3H), 3.82 (s, 3H), 2.12 (dd, 1H, J
) 13.3, 9.2 Hz), 1.93 (d, 1H, J ) 13.3 Hz), 1.90-1.80 (m, 2H),
0.97 (d, 3H, J ) 6.9 Hz), 0.83 (s, 9H), 0.65 (d, 3H, J ) 6.9 Hz),
-0.14 (s, 3H), -0.19 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
148.9, 147.8, 140.8, 140.3, 138.2, 136.2, 134.8, 134.0, 120.0,
119.5, 103.2, 102.6, 100.7, 100.6, 73.6, 59.6, 59.4, 44.4, 39.3,
34.7, 25.9, 22.0, 18.1, 7.8, -4.8, -5.2; IR (film) νmax 2954, 2885,
1632, 1607, 1506, 1474, 1400, 1277, 1252, 1134, 1087, 1046,
960, 936, 857, 776, 736, 678 cm-1; HRMS (ESI) m/z calcd for
C28H38O7SiNa 537.2285, found 537.2279.
Interiotherin A (1). A solution of 50 (12.0 mg, 0.03 mmol),
Ph3P (32.0 mg, 0.12 mmol), and benzoic acid (14.0 mg, 0.12
mmol) in THF (1 mL) was vigorously stirred at 0 °C for 10
min. Diisopropyl azodicarboxylate (24.0 µmL, 0.13 mmol) was
added dropwise over a period of 5 min, and the reaction
mixture was allowed to warm to 25 °C and was stirred at this
temperature for 10 h. The reaction mixture was diluted with
EtOAc (10 mL) and was washed with water and saturated
aqueous NaCl. The organic layer was dried (Na2SO4) and
concentrated, and the residue was purified by flash chroma-
tography (5% EtOAc/hexane) to afford interiotherin A (1) (9.0
mg, 62%) as a solid: 1H NMR (CDCl3, 500 MHz) δ 7.64 (d,
2H, J ) 7.3 Hz), 7.50-7.40 (m, 1H), 7.35-7.30 (m, 2H), 6.69
(s, 1H), 6.49 (s, 1H), 5.98 (ABq, 2H, J ) 1.5 Hz, ∆ν ) 21.8
Hz), 5.88 (ABq, 2H, J ) 1.5 Hz, ∆ν ) 10.2 Hz), 5.86
(overlapping d, 1H, J ) 6.0 Hz), 3.79 (s, 3H), 3.58 (s, 3H), 2.26
(d, 2H, J ) 6.5 Hz), 2.15-2.00 (m, 2H), 1.02 (d, 3H, J ) 7.0
Hz), 0.86 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3, 125 MHz) δ
165.3, 148.8, 141.6, 141.2, 136.8, 134.2, 132.6, 131.1, 129.7
(2C), 127.9 (2C), 122.4, 121.5, 106.3, 102.5, 101.2, 100.6, 81.4,
59.7, 59.0, 37.6, 36.6 (2C), 19.3, 14.1; IR (film) νmax 2924, 2358,
1713, 1616, 1475, 1450, 1372, 1269, 1211, 1101, 1070, 1049,
936, 711 cm-1; HRMS (ESI) m/z calcd for C29H28O8Na 527.1682,
found 527.1641.
(1R,2S)-1-(6-Bromo-7-methoxybenzo[d][1,3]dioxol-5-
yl)-2,3-dimethylbut-3-en-1-ol (24). A solution of aryl alde-
hyde 22 (50 mg, 0.19 mmol) in CH2Cl2 (1.0 mL) was added
dropwise to a solution of reagent 28 (0.125 g, 0.2 mmol) in
CH2Cl2 (1.5 mL) at -78 °C over 10 min. The reaction mixture
was gradually allowed to warm to 0 °C and was stirred for 12
h at this temperature. The reaction mixture was acidified with
1 N hydrochloric acid (3 mL) and was stirred for 15 min. The
reaction mixture was diluted with CH2Cl2 (30 mL) and water
(10 mL), and the organic layer was separated. The organic
layer was washed with water, saturated aqueous NaCl, and
water, and was dried and concentrated. The residue was
purified by flash chromatography (silica, 15% EtOAc/hexane)
to afford 24 (47 mg, 75%) as a colorless oil: 98:2 enantiomeric
ratio.
(1S,2S)-1-(6-Bromo-7-methoxybenzo[d][1,3]dioxol-5-
yl)-2,3-dimethylbut-3-en-1-ol (25). Following the procedure
for the preparation of 24, a solution of aryl aldehyde 22 (0.10
g, 0.38 mmol) in CH2Cl2 (2.0 mL) was added to a solution of
reagent 29 (0.22 g, 0.37 mmol) in CH2Cl2 (2 mL) at -50 °C.
The reaction mixture was gradually allowed to warm to 0 °C
and was stirred for 24 h at this temperature. Purification
afforded 25 (95 mg, 75%) as a colorless oil: 98:2 enantiomeric
ratio.
(1S,2S)-1-(2-Bromo-3,4,5-trimethoxyphenyl)-2,3-dime-
thylbut-3-en-1-ol (21). Following the procedure for the
preparation of 24, a solution of aryl aldehyde 16 (72 mg, 0.31
mmol) in CH2Cl2 (2.0 mL) was added to a solution of reagent
29 (0.27 g, 0.46 mmol) in CH2Cl2 (1.5 mL) at -50 °C. The
reaction mixture was gradually allowed to warm to 0 °C and
was stirred for 24 h at this temperature. Purification afforded
21 (70 mg, 78%) as a colorless oil: 97:3 enantiomeric ratio.
((1S,2S,3S)-1-(5-Bromo-4-methoxybenzo[d][1,3]dioxol-
6-yl)-4-(4-methoxybenzo[d][1,3]dioxol-6-yl)-2,3-dimethyl-
butoxy)(tert-butyl)dimethylsilane (34). Following the pro-
cedure for the preparation of 1,4-diarylbutane 35, a solution
of 9-BBN in THF (0.5 M, 0.65 mL, 0.32 mmol) was added to a
solution of 30 (0.10 g, 0.22 mmol) in THF (1 mL), which was
transferred to a flask containing 6-bromo-4-methoxybenzo[d]-
[1,3]dioxole (32) (0.10 g, 0.44 mmol), Pd(PPh3)4 (0.016 g, 0.014
mmol), and aqueous NaOH (3 M, 0.25 mL, 0.73 mmol, NaOH
dissolved in 0.2 mL water) in THF (2 mL) at 0 °C. The reaction
mixture was warmed at 70 °C for 16 h to afford 34 (96 mg,
72%) as a syrup: 1H NMR (CDCl3, 500 MHz) δ 6.78 (s, 1H),
6.39 (d, 1H, J ) 1.1 Hz), 6.37 (app s, 1H), 5.98 (ABq, 2H, J )
1.4 Hz, ∆ν ) 16.5 Hz), 5.93 (s, 2H), 5.10 (d, 1H, J ) 7.8 Hz),
4.04 (s, 3H), 3.90 (s, 3H), 2.99 (dd, 1H, J ) 13.2, 3.2 Hz), 2.30-
2.15 (m, 1H), 2.11 (dd, 1H, J ) 13.1, 11.7 Hz), 1.80 (qd, 1H, J
) 7.4, 1.7 Hz), 0.91 (s, 9H), 0.79 (d, 3H, J ) 6.8 Hz), 0.73 (d,
3H, J ) 7.2 Hz), 0.13 (s, 3H) -0.25 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 148.7, 148.6, 143.3, 139.4, 138.7, 136.8, 136.3,
133.0, 107.9, 107.7, 103.1, 102.8, 101.5, 101.1, 75.9, 60.1, 56.4,
46.3, 37.2, 33.9, 25.9, 18.3, 18.0, 10.5, -4.5, -4.8; IR (film)
νmax 2954, 2884, 2856, 1632, 1608, 1508, 1472, 1400, 1374,
1277, 1252, 1132, 1087, 1046, 960, 934, 857, 837, 776, 736,
678 cm-1; HRMS (ESI) m/z calcd for C28H39BrO7SiNa 617.1546,
found 617.1541.
Angeloylgomisin R (2). Following the procedure for the
preparation of interiotherin A, diisopropyl azodicarboxylate (16
µL, 0.08 mmol), 50 (8.0 mg, 0.02 mmol), PPh3 (21.0 mg, 0.08
mmol), and angelic acid (8.0 mg, 0.08 mmol) in THF (1 mL)
afforded angeloylgomisin R (2) (5.0 mg, 51%) as a syrup: 1H
NMR (CDCl3, 500 MHz) δ 6.70 (s, 1H), 6.41 (s, 1H), 5.98 (ABq,
2H, J ) 1.5 Hz, ∆ν ) 15.0 Hz), 5.95-5.90 (m, 3H), 5.68 (d,
1H, J ) 8.5 Hz), 3.83 (s, 3H), 3.79 (s, 3H), 2.45-2.25 (m, 3H),
2.20-1.95 (m, 1H), 1.85 (dq, 3H, J ) 7.2, 1.4 Hz), 1.59 (q, 3H,
J ) 1.4 Hz), 0.94 (d, 3H, J ) 7.0 Hz), 0.84 (d, 3H, J ) 6.8 Hz);
IR (film) νmax 2924, 2358, 1710, 1638, 1611, 1450, 1374, 1250,
((1S,2S,3S)-1,4-Bis(5-bromo-4-methoxybenzo[d][1,3]-
dioxol-6-yl)-2,3-dimethylbutoxy)(tert-butyl)dimethylsi-
lane (38). A solution of 34 (90 mg, 0.15 mmol) in CHCl3 (2
mL) was cooled to 15 °C, and a solution of N-bromosuccinimide
(30 mg, 0.16 mmol) in CHCl3 (6 mL) was added dropwise by
syringe over 1 h at this temperature. The reaction mixture
was stirred for 6 h at 25 °C and was quenched by the addition
of saturated aqueous Na2S2O3 (1 mL). The mixture was
concentrated, and the residue was dissolved in EtOAc (25 mL)
8940 J. Org. Chem., Vol. 70, No. 22, 2005

Synthesis of Dibenzocyclooctadiene Lignan Natural Products
1211, 1100, 1070, 1049, 936 cm-1; HRMS (ESI) m/z calcd for
C27H30O8Na 505.1838, found 505.1827.
kept under high vacuum for 1 min to remove dissolved oxygen.
The reaction mixture was warmed to -30 °C and was
quenched by the addition of 10% NH4OH in saturated aqueous
NH4Cl (4 mL). The two-phase mixture was stirred for 30 min
as it was allowed to warm to room temperature. The aqueous
layer was extracted with EtOAc (2 × 20 mL), and the combined
organics were washed with saturated aqueous NH4Cl (10 mL)
and saturated aqueous NaCl (2 × 10 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated, and the residue
was purified by flash chromatography (silica gel, 5% EtOAc/
hexane) to afford 57 (14 mg, 35%) as a colorless solid: 1H NMR
(CDCl3, 500 MHz) δ 6.99 (s, 1H), 6.43 (s, 1H), 5.95 (ABq, 2H,
J ) 1.5 Hz, ∆ν ) 17.6 Hz), 4.42 (d, 1H, J ) 1.4 Hz), 3.91 (s,
3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.57 (s, 3H), 2.12 (dd, 1H, J )
13.3, 9.1 Hz), 1.93 (d, 1H, J ) 13.3 Hz), 1.88 (m, 2H), 0.99 (d,
3H, J ) 7.0 Hz), 0.86 (s, 9H), 0.65 (d, 3H, J ) 6.9 Hz), -0.13
(s, 3H), -0.19 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 151.6,
150.7, 148.9, 140.9, 140.5, 140.1, 137.9, 137.0, 120.6, 119.8,
107.2, 102.5, 100.7, 73.7, 60.9, 60.6, 59.9, 55.7, 44.5, 39.3, 34.7,
26.0, 25.8, 22.1, 18.1, 7.8, -4.6, -5.3; IR (film) νmax 2954, 1597,
1471, 1268, 1200, 1107, 1053 cm-1; HRMS (ESI) m/z calcd
for C29H42O7SiNa 553.2598, found 553.2574.
Gomisin O (3). A solution of n-Bu4NF (1.0 M, 20 µL, 0.015
mmol) in THF was added to a solution of 52 (8.0 mg, 0.015
mmol) in THF (0.80 mL) at room temperature, and the reaction
mixture was warmed at 55 °C for 6 h. The volatiles were
removed, and the residue was dissolved in EtOAc (5 mL) and
was washed with saturated aqueous NH4Cl (5 mL) and
saturated aqueous NaCl solution (2 × 5 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated, and the residue
was purified by flash chromatography (silica gel, 30% EtOAc/
hexane) to afford 3 (6.0 mg, 95%) as a colorless oil: 1H NMR
(CDCl3, 500 MHz) δ 6.57 (s, 1H), 6.43 (s, 1H), 5.97 (ABq, 2H,
J ) 1.4 Hz, ∆ν ) 8.6 Hz), 4.35 (dd, 1H, J ) 8.0 Hz), 3.90 (s,
3H), 3.91 (s, 3H), 3.92 (s, 3H), 3.54 (s, 3H), 2.32 (dd, 1H, J )
13.0, 5.6 Hz), 2.03 (dd, 1H, J ) 12.9, 9.8 Hz), 1.86 (m, 1H),
1.67 (br s, 1H), 0.94 (d, 3H, J ) 7.4 Hz), 0.92 (d, 3H, J ) 6.9
Hz); 13C NMR (CDCl3, 125 MHz) δ 152.1, 152.0, 149.3, 141.6,
141.5, 137.0, 135.5, 134.6, 122.2, 120.6, 110.1, 102.6, 100.8,
81.4, 60.9, 60.4, 59.5, 56.0, 40.0, 37.1, 31.6, 22.7, 14.1; IR (film)
νmax 3482, 2937, 2361, 1723, 1617, 1474, 1327, 1105, 1050 cm-
1; HRMS (ESI) m/z calcd for C23H28O7Na 439.1733, found
439.1740.
Gomisin E (6-epi-Gomisin O) (4). A solution of n-Bu4NF
(1.0 M, 25 µL, 0.024 mmol) in THF was added to a solution of
57 (9.0 mg, 0.02 mmol) in THF (0.80 mL) at room temperature,
and the reaction mixture was warmed at 55 °C for 6 h. The
volatiles were removed, and the residue was dissolved in
EtOAc (5 mL) and washed with saturated aqueous NH4Cl (5
mL) and saturated aqueous NaCl solution (2 × 5 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated,
and the residue was purified by flash chromatography (silica
gel, 30% EtOAc/hexane) to afford 4 (5.5 mg, 79%) as a colorless
liquid: 1H NMR (CDCl3, 500 MHz) δ 7.02 (s, 1H), 6.45 (s, 1H),
5.95 (s, 2H), 4.58 (d, 1H, J ) 1.4 Hz), 3.93 (s, 3H), 3.92 (s,
1H), 3.86 (s, 1H), 3.55 (s, 3H), 2.12 (dd, 1H, J ) 13.4, 9.4 Hz),
2.02 (m, 1H), 1.97 (d, 1H, J ) 13.2 Hz), 1.93 (m, 1H), 1.65 (br
s, 1H), 1.02 (d, 3H, J ) 7.2 Hz), 0.71 (d, 3H, J ) 7.0 Hz); 13C
NMR (CDCl3, 100 MHz) δ 152.2, 151.1, 149.1, 140.8, 140.6,
137.9, 136.4, 134.5, 121.2, 119.4, 106.2, 102.8, 100.8, 73.4, 61.0,
60.6, 59.6, 55.9, 42.4, 39.2, 34.6, 22.0, 7.8; IR (film) νmax 3437,
2934, 1618, 1463, 1402, 1269, 1203, 1106, 1050 cm-1; HRMS
(ESI) m/z calcd for C23H28O7Na 439.1733, found 439.1753.
epi-Gomisin O (M)-55. A solution of n-Bu4NF (1.0 M, 50
µL, 0.05 mmol) in THF was added to a solution of 53 (18.0
mg, 0.034 mmol) in THF (1.0 mL) at room temperature, and
the reaction mixture was warmed at 55 °C for 6 h. The volatiles
were removed and the residue was dissolved in EtOAc (5 mL)
and washed with saturated aqueous NH4Cl (5 mL) and
saturated aqueous NaCl solution (2 × 5 mL). The organic layer
was dried (Na2SO4), filtered, concentrated, and the residue was
purified by flash chromatography (silica gel, 30% EtOAc/
hexane) to afford 55 (12 mg, 86%) as a colorless solid: 1H NMR
(CDCl3, 400 MHz) δ 6.93, 6.42, 5.95 (ABq, 2H, J ) 1.2 Hz, ∆ν
) 6.3 Hz), 4.32 (dd, 1H, J ) 8.0, 2.4 Hz), 3.93 (s, 3H), 3.92 (s,
3H), 3.84 (s, 3H), 3.64 (s, 3H), 2.61 (dd, 1H, J ) 15.6, 4.8 Hz),
2.37 (dd, 1H, J ) 16.0, 10.4 Hz), 1.72 (d, 1H, J ) 2.8 Hz), 1.61
(m, 2H), 1.02 (d, 3H, J ) 6.8 Hz), 0.82 (d, 3H, J ) 6.8 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 153.5, 151.5, 148.3, 140.9, 140.4,
140.0, 135.1, 134.6, 120.9, 120.4, 105.1, 102.2, 100.9, 74.2, 61.0,
60.9, 59.6, 55.9, 46.9, 40.2, 33.5, 19.4, 12.3; IR (film) νmax 3410,
2958, 1597, 1463, 1404, 1107, 1050 cm-1; HRMS (ESI) m/z
calcd for C23H28O7Na 439.1733, found 439.1753.
O-tert-Butyldimethylsilyl 6-epi-Gomisin O (57). A solu-
tion of anti-anti dibromosilyl ether 56 (0.052 mg, 0.075 mmol)
in MeTHF (4 mL) was treated with a solution of t-BuLi (2.5
M, 0.12 mL, 0.30 mmol) at -78 °C under argon. After 30 min,
the pale yellow mixture was transferred via cannula to a flask
containing CuCN (7.0 mg, 0.075 mmol) in MeTHF (7 mL) at
-78 °C under argon. The heterogeneous reaction mixture was
allowed to warm to -40 °C over 1.5 h and was stirred
vigorously until homogeneous at this temperature. The result-
ing solution was cooled to -125 °C (liquid N2/n-pentane), and
oxygen gas was bubbled into the reaction for 4 h using a fritted
glass tube. The reaction mixture was purged with argon and
Acknowledgment. This work was supported by a
grant from the National Cancer Institute (NIH R01
CA91904).
Supporting Information Available: Full experimental
procedures and spectral characterization of intermediates and
products and CIF files for reported crystal structures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051525I
J. Org. Chem, Vol. 70, No. 22, 2005 8941