Total Synthesis of (+)-Isoschizandrin Utilizing a Samarium(II) Iodide-Promoted 8-Endo Ketyl-Olefin Cyclization

Article abstract of DOI:10.1021/jo0347361

The 13-step synthesis of (+)-isoschizandrin reported herein features a samarium(II) iodide-promoted 8-endo ketyl-olefin coupling to assemble the eight-membered ring present in the target concomitantly with the required functionality and stereochemistry. In constructing (+)-isoschizandrin as a single atropisomer, the synthesis utilizes a kinetic resolution of a seven-membered lactone using a CBS-oxazaborolidine.

Full text of DOI:10.1021/jo0347361

VOLUME 68, NUMBER 25
DECEMBER 12, 2003
© Copyright 2003 by the American Chemical Society
Tota l Syn th esis of (+)-Isosch iza n d r in Utilizin g a Sa m a r iu m (II)
Iod id e-P r om oted 8-En d o Ketyl-Olefin Cycliza tion
Gary A. Molander,* Kelly M. George, and Lauren G. Monovich
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, and Department of Chemistry and Biochemistry,
University of Colorado, Boulder, Colorado 80309-0215
gmolandr@sas.upenn.edu
Received May 30, 2003
The 13-step synthesis of (+)-isoschizandrin reported herein features a samarium(II) iodide-promoted
8-endo ketyl-olefin coupling to assemble the eight-membered ring present in the target concomi-
tantly with the required functionality and stereochemistry. In constructing (+)-isoschizandrin as
a single atropisomer, the synthesis utilizes a kinetic resolution of a seven-membered lactone using
a CBS-oxazaborolidine.
In tr od u ction
(+)-Isoschizandrin (1) and (+)-schizandrin (2) repre-
sent two of nearly forty dibenzocyclooctadiene lignans
isolated from the fruit of Schizandra chinesis, a creeping
vine native to northern China (Figure 1).1 The extracts
from this lignan-rich plant have been used in Chinese
and J apanese traditional medicine as an antitussive and
a tonic. Several lignans isolated from these extracts are
thought to exhibit antirheumatic and antihepatotoxic
activity. (+)-Isoschizandrin, a minor component of the
extract, displays antiulcer activity in rats.2 Although
these lignans exhibit significant biological activity, the
principal synthetic interest in this family of natural
products lies within the unique dibenzocyclooctadiene
structure.
F IGURE 1. Cyclooctadiene lignans isoschizandrin and schi-
zandrin.
More recently, Tanaka and co-workers1d reported the first
asymmetric total synthesis of (+)-isoschizandrin.
In the current synthetic approach, we sought to
demonstrate a samarium(II) iodide-promoted 8-endo
ketyl-olefin radical cyclization as a means to provide the
eight-membered ring, the required functionality, and the
correct stereochemistry present in (+)-isoschizandrin in
a single transformation.5 This general approach to diben-
zocyclooctadiene lignan synthesis was first demonstrated
in a reported synthesis of (-)-steganone.6 In that study,
a samarium(II) iodide-promoted coupling between an
aromatic aldehyde and a butenolide proceeded in good
yields and with moderate selectivity.
To date, three research groups have communicated
syntheses of isoschizandrin. The Meyers group3 first
reported the total synthesis of (-)-isoschizandrin, thereby
establishing the absolute stereochemistry of the natural
product. This was soon followed by a racemic synthesis
of (()-isoschizandrin from the laboratories of Tobinaga.4
* To whom correspondence should be addressed at the University
of Pennsylvania.
(1) (a) Ayres, D. C.; Loike, J . D. Chemistry & Pharmocology of
Natural Products: Lignans; Chemical, Biological, and Chemical
Properties; Cambridge University Press: Cambridge, U.K., 1990. (b)
Whiting, D. A. Nat. Prod. Rep. 1985, 2, 191. (c) Whiting, D. A. Nat.
Prod. Rep. 1987, 4, 499. (d)Tanaka, M.; Mukaiyama, C.; Mitsuhashi,
H.; Maruno, M.; Wakamatsu, T. J . Org. Chem. 1995, 60, 4339.
(2) (a) Ikeya, Y.; Taguchi, H.; Mitsuhashi, H.; Takeda, S.; Kase, Y.;
Aburada, M. Phytochemistry 1988, 27, 569. (b) Ikeya, Y.; Sugama, K.;
Okada, M.; Mitsuhashi, H. Phytochemistry 1991, 30, 975.
(3) Warshawsky, A. M.; Meyers, A. I. J . Am. Chem. Soc. 1990, 112,
8090.
To obtain a single atropisomer of (+)-isoschizandrin,
the synthesis described herein utilizes the method of
(4) Takeya, T.; Ohguchi, A.; Tobinaga, S. Chem. Pharm. Bull. 1994,
42, 438.
(5) Molander, G. A.; McKie, J . A. J . Org. Chem. 1994, 59, 3186.
(6) Monovich, L. G.; Hue´rou, Y. L.; Ro¨nn, M.; Molander, G. A. J .
Am. Chem. Soc. 2000, 122, 52.
10.1021/jo0347361 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/20/2003
J . Org. Chem. 2003, 68, 9533-9540
9533

Molander et al.
SCHEME 1
Bringmann7 that allows for configurationally stable
seven-membered lactones to be kinetically resolved by
utilizing a chiral oxazaborolidine.8 Applying this method
provides the desired lactone intermediate with excellent
enantioselectivity.
yields in the 60-90% range with good to excellent levels
of diastereoselection (up to 96% de) and has been used
successfully in several total syntheses.11 This protocol has
the advantage of forming the biaryl and establishing the
stereochemistry in a single step.
By contrast, novel methods developed by Bringmann
and co-workers7 control the formation of the biaryl
juncture and atropisomerism separately, a strategy
nevertheless competitive because construction and de-
construction of a chiral auxiliary are excluded from the
linear sequence. Our initial interest lay in the application
of dynamic kinetic resolution7c,d to set the biaryl stereo-
chemistry en route to an asymmetric isoschizandrin
synthesis. In principle, the key diol (+)-5 could be
generated as a single atropisomer from benzocoumarin
lactone (()-6 via borane reduction in the presence of the
CBS ligand.
The synthesis of the key benzocoumarin lactone 6
(Scheme 2) was achieved by iodination of 3,4,5-tri-
methoxybenzoic acid, followed by DCC coupling with
3,4,5-trimethoxyphenol (9), which provided phenyl ha-
lobenzoate ester 7. Mizoroki-Heck coupling of 7 afforded
lactone 6, which was used to generate racemic diol 5 by
LAH reduction. Alternatively, lactone 6 provided entry
to an asymmetric synthesis of the target via dynamic
kinetic resolution by analogy to Bringmann’s method.7c,d
Atropoenantioselective reduction of benzocoumarin lac-
tone (()-6 with 4 equiv of BH3‚THF in the presence of
excess (R)-2-methyl-CBS-oxazaborolidine (3 equiv) pro-
vided the nonracemic diol (+)-5 in 95% yield and 95.6%
ee by chiral HPLC.12 Notably, the scale of this reaction
was 10-fold higher than that reported by Bringmann,
demonstrating its viability in total synthesis. Neverthe-
Resu lts a n d Discu ssion
Retrosynthetic analysis utilizing a samarium(II) iodide-
promoted 8-endo ketyl-olefin coupling suggests structure
(+)-3 as a direct precursor to isoschizandrin 1 (Scheme
1). Samarium(II)-promoted 8-endo ketyl-olefin cycliza-
tions are greatly enhanced by placing an electron-
withdrawing or π-conjugating substituent directly on the
olefin, thereby increasing the radical SOMO/alkene
LUMO interactions in the transition state leading to the
product.5,6 In the present synthesis, the aryl group thus
provides a useful structural element in facilitating this
type of cyclization.
To obtain the penultimate ketoolefin (+)-3, we initially
envisioned a Pd-mediated coupling reaction between a
(Z)-propenyl moiety and ketotriflate (+)-4 to install the
necessary carbon functionality in the ortho position.
Construction of the tetra-ortho-substituted biaryl moiety
must proceed with special regard to its atropisomerism,
because the 8-endo cyclization sets the remaining ste-
reocenters relative to the biaryl geometry. Generally,
three or four ortho substituents are required to make
asymmetric biaryl synthesis a viable consideration. Few
biaryl couplings succeed when three or four ortho sub-
stituents are present,9 and fewer still control the result-
ant biaryl geometry.10 Meyers’ pioneering method, which
utilizes a chiral oxazoline auxiliary to facilitate nucleo-
philic aromatic substitution of a methoxy group, provides
(10) (a) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int.
Ed. Engl. 1990, 29, 977. (b) Kamikawa, T.; Uozumi, Y.; Hayashi, T.
Tetrahedron Lett. 1996, 37, 3161. (c) Hayashi, T.; Niizuma, S.;
Kamikawa, T.; Suzuki, N.; Uozumi, Y. J . Am. Chem. Soc. 1995, 117,
9101.
(11) (a) Meyers, A. I.; Himmelsbach, R. J . J . Am. Chem. Soc. 1985,
107, 682. (b) Moorlag, H.; Meyers, A. I. Tetrahedron Lett. 1993, 34,
6989. (c) Moorlag, H.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 6993.
(12) Monovich, L. G. Ph.D. Thesis, University of Colorado at Boulder,
1998.
(7) Kinetic resolution: (a) Bringmann, G.; Hinrichs, J . Tetrahe-
dron: Asymmetry 1997, 8, 4121. (b) Bringmann, G.; Hinrichs, J .; Pabst,
T.; Henschel, P.; Peters, K.; Peters, E.-M. Synthesis 2001, 155. Dynamic
kinetic resolution: (c) Bringmann, G.; Hartung, T. Angew. Chem., Int.
Ed. Engl. 1992, 31, 761. (d) Bringmann, G.; Hartung, T. Tetrahedron
1993, 49, 7891.
(8) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc. 1987,
109, 7925.
(9) Stanforth, S. P. Tetrahedron 1998, 54, 263.
9534 J . Org. Chem., Vol. 68, No. 25, 2003

Total Synthesis of (+)-Isoschizandrin
SCHEME 2a
F IGURE 2. X-ray crystal structure of ketononaflate 13.
in this reaction provided the desired phenolic ketone 12
but required high dilution (0.007 M). Treatment of
ketophenol 12 with Tf2O afforded the desired coupling
precursor 4.
a
Reagents and conditions: (a) AgO2CCF3, I2, CHCl3, 99%; (b)
9, DCC, DMAP, CH2Cl2, 99%; (c) PdCl2(PPh3)2, NaOAc, DMA, 120
°C, 3 h, 87%; (d) LAH, THF, 80%; (e) SOCl2, CH2Cl2, imidazole,
99%.
Transition-metal-catalyzed carbon-carbon bond for-
mations are extraordinarily difficult with sterically hin-
dered, electron-rich aryl triflates.15 However, just such
a transformation was required to install the (Z)-propenyl
fragment necessary for the samarium-mediated cycliza-
tion. Consequently, numerous cross-coupling strategies
were tested (utilizing both cis-propenyl and 1-propynyl
organometallics) to convert 4 to 3 or a suitable precursor.
After an exhaustive number of protocols were investi-
gated, the desired product unfortunately could not be
obtained reproducibly, yielding instead detriflated mate-
rial as the major product. The analogous nonafluorobu-
tanesulfonate (nonaflate) 13, a pseudohalide generally
known to be less prone to oxygen-sulfur cleavage than
the triflate, also proved to be an unsuccessful coupling
partner in transition-metal couplings.16 The X-ray crystal
structure of ketononaflate 13 provides evidence of the
steric hindrance in this system, and this, combined with
the electron-rich nature of the electrophile, explains the
lack of successful coupling (Figure 2). Clearly, a new
approach was needed to arrive at the desired samarium
precursor 3.
SCHEME 3a
Because the atropoenantioselective reduction of ben-
zocoumarin lactone (()-6 provided an excellent pathway
to a single atropisomer, we sought to apply a related
strategy to the synthesis of a seven-membered lactone.
By altering our approach, both carbon ortho substituents
would now be poised for further chemistry without the
need to couple a carbon unit into a sterically hindered,
electron-rich position. Bringmann and co-workers have
a
Reagents and conditions: (a) AcCl, CH2Cl2, pyridine, 89%; (b)
SmI2, NiI2, THF, 81%; (c) Tf2O, DMAP, CH2Cl2, triethylamine,
71%.
less, the more facile LAH reduction was employed to
provide diol 5, which was then used to explore the success
of the subsequent transformations.
Utilizing racemic material, benzyl chloride (()-10 was
prepared using SOCl2 (Scheme 2). Acylation of the
corresponding phenol (Scheme 3) provided a substrate
capable of undergoing a samarium(II) iodide-promoted
(14) Machrouhi, F.; Hamann, B.; Namy, J . L.; Kagan, H. Synlett
1996, 7, 633.
(15) (a) Ritter, K. Synthesis 1993, 735. (b) Stang, P. J .; Hanack, M.;
Subramanian, L. R. Synthesis 1982, 85.
(16) (a) Rottla¨nder, M.; Knochel, P. J . Org. Chem. 1998, 63, 203.
(b) Han, X.; Stoltz, B. M.; Corey, E. J . J . Am. Chem. Soc. 1999, 121,
7600.
acyl-transfer reaction.13 The use of NiI2 as an additive
14
(13) Molander, G. A.; McKie, J . A. J . Org. Chem. 1993, 58, 7216.
J . Org. Chem, Vol. 68, No. 25, 2003 9535

Molander et al.
SCHEME 4
SCHEME 5a
a
Reagents and conditions: (a) NBS, CHCl3, reflux, 3 h, 96%;
(b) Cu, DMF, reflux, 18 h, 74%; (c) (i) KOH, EtOH, reflux, 1.5 h;
(ii) DCC, DMAP, CH2Cl2, rt, 63%; (d) (R)-2-methyl-CBS-ox-
azaborolidine, BH3‚THF, THF, -20 °C, 61% overall (after recy-
cling), 98% ee; (e) DIBALH, CH2Cl2, toluene, -78 °C, 70%.
recently developed such chemistry to obtain enantiomeri-
cally enriched biaryls via the kinetic resolution of con-
formationally stable biaryl lactones using a chiral
oxazaborolidine.7a,b We sought to apply this chemistry to
our synthesis.
With this new approach in mind, our revised retrosyn-
thetic analysis would utilize two different Wittig reac-
tions to homologate the carbon side chains, providing
ketoolefin (+)-3 (Scheme 4). Further disconnection re-
veals hydroxy aldehyde (+)-14 which could arise from a
selective DIBALH reaction of lactone (+)-15. Applying
Bringmann’s method,7a,b lactone (+)-15 would be enan-
tiomerically enriched via a kinetic resolution of a racemic
lactone mixture. Racemic lactone (()-15 could arise from
a Cannizzaro reaction of 16 followed by DCC coupling.
Finally, this dialdehyde can be accessed by an Ullmann
coupling of the corresponding haloaldehyde 17.
the desired racemic seven-membered lactone (()-15. This
lactone underwent kinetic resolution using Bringmann’s
method7a,b to provide the desired lactone (+)-15 in a 45%
yield (out of a possible 50%) with 98% ee as determined
by chiral HPLC.
The undesired diol (-)-19 was recycled by first oxidiz-
ing to the dialdehyde with Dess-Martin’s reagent19 (eq
1). After the dialdehyde was heated in acid to racemize
the material, (()-16 was again subjected to the Can-
nizarro/DCC conditions, providing racemic lactone (()-
15 in a 60% yield. Repeating this process increased the
overall yield of enantiomerically enriched lactone to 61%
(98% ee).
Our revised approach began with the bromination of
3,4,5-trimethoxybenzaldehyde (18) to provide the corre-
sponding bromoaldehyde 1717a (Scheme 5). Using a
standard Ullmann coupling protocol, bromoaldehyde 17
was heated with activated Cu in DMF to provide the
desired biaryl dialdehyde in good yields.10a,17 Treatment
of 16 with KOH in boiling ethanol18 afforded the hydroxy
acid, which was directly lactonized with DCC to produce
(17) (a) Ziegler, F. E.; Chliwner, I.; Fowler, K.; Kanfer, S. J .; Kuo,
S. J .; Sinha, N. D. J . Am. Chem. Soc. 1980, 102, 790. (b) Fanta, P. E.
Synthesis 1974, 9. (c) Degnan, A. P.; Meyers, A. I. J . Am. Chem. Soc.
1999, 121, 2762.
(18) (a) Abbaszadeh, M. R.; Bowden, K. J . Chem. Soc., Perkin Trans.
2 1990, 2081. (b) Kobayashi, S.; Kihara, M.; Hashimoto, T.; Shingu,
T. Chem. Pharm. Bull. 1976, 24, 716. (c) Kobayashi, S.; Mineo, S.;
Kihara, M.; Tagashira, S. Chem. Pharm. Bull. 1976, 24, 2191. (d)
Kobayashi, S.; Senoo, F.; Kihara, M.; Sakata, K.; Miura, A. Chem.
Pharm. Bull. 1971, 19, 1262.
DIBALH reduction of the enantiomerically enriched
lactone at -78 °C revealed aldehyde (+)-14 (Scheme 5).
Using ethyltriphenylphosphonium bromide, aldehyde
(+)-14 was then converted to the desired (Z)-propenyl
(19) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
9536 J . Org. Chem., Vol. 68, No. 25, 2003

Total Synthesis of (+)-Isoschizandrin
SCHEME 6a
engendered by an aryl unit on the olefin. Additionally,
the biaryl motif likely enhances the rate of 8-endo
cyclization by partially ordering at least four of the ring’s
eight carbons, thereby reducing the entropic demand on
the reaction and further enhancing ring closure.
Access to the correct relative stereochemistry of isos-
chizandrin is realized through three separate stereo-
chemical control elements (Scheme 7). First, the stereo-
SCHEME 7
a
Reagents and conditions: (a) TIPSCl, CH2Cl2, DMAP, imida-
zole, 98%; (b) ethyltriphenylphosphonium bromide, KHMDS, THF,
-78 °C, 85% (4:1 Z/E); (c) TBAF, THF, 91%; (d) Dess-Martin
periodinane, CH2Cl2, 90%; (e) (i) (R-methoxyethyl)triphenylphos-
phonium chloride, n-BuLi, THF; (ii) p-TsOH, THF, 0 °C, 54%.
fragment via a Wittig reaction in a 2:1 Z/E ratio (Scheme
6). After several protecting group strategies were tested,
the TIPS ether improved the Z/E selectivity to 4:1 (85%
yield), and also enabled the geometric isomer ratio to be
more easily enriched to >10:1 (35% yield) via MPLC. The
enriched material was then carried through to the end
of the synthesis. After the TIPS group was removed using
TBAF, benzyl alcohol (+)-21 was then oxidized using
Dess-Martin periodinane to provide unsaturated alde-
hyde (+)-22. Treatment of aldehyde (+)-22 with the ylide
derived from (R-methoxyethyl)triphenylphosphonium chlo-
ride20 afforded an enol ether that was carefully hydro-
lyzed to alkenyl ketone (+)-3.
With the desired substrate in hand, ketoolefin 3 was
treated with 2.2 equiv of samarium(II) iodide and
HMPA21 in THF along with 2 equiv of t-BuOH (eq 2).
The natural product was obtained with a dr >18:1 and
with no loss of ee (98%). The identity of the target
compound was confirmed by comparison with reported
analytical data.1d
chemistry at C-8 is set by the (Z)-olefin geometry, which
was obtained via a standard Wittig reaction. Conforma-
tional restrictions placed on dibenzocyclooctadiene ring
systems are generally restricted to the twist-boat-chair
(TBC) and the twist-boat (TB) limiting conformations.22
The stereodefined (Z)-alkene excludes the TB structure.
We therefore expected carbons 6-9 to assume the chair-
like transition-state geometry of the TBC conformation.
The second source of stereochemical control is a result
of the alkoxysamarium moiety assuming a pseudoequa-
torial orientation. Scheme 7 depicts how the alkoxysa-
marium(III) substituent of the slightly pyramidalized23
ketyl radical anion at C-7 may take on either a pseudo-
axial or a pseudoequatorial orientation. Tight coordina-
tion of the ketyl oxygen to the Sm(III) species, adorned
with up to four HMPA ligands in its coordination
sphere,24 is more sterically imposing than that of the
There are several important factors that contribute to
the high yield and selectivity of the samarium(II) iodide-
promoted coupling. In terms of the yield, we have alluded
previously to the favorable SOMO/LUMO interactions
(22) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley-Interscience: New York, 1994.
(23) (a) Davies, A. G.; Neville, A. G. J . Chem. Soc., Perkin Trans. 1
1992, 163. (b) Russell, G. A.; Stevenson, G. R. J . Am. Chem. Soc. 1971,
93, 2432. (c) Bennett, J . E.; Mile, B. J . Chem. Soc. A 1968, 298. (d)
Wu, Y. D.; Houk, K. N. J . Am. Chem. Soc. 1986, 114, 1656. (e) Novoa,
J . Can. J . Chem. 1986, 64, 2359.
(20) Coulson, D. R. Tetrahedron Lett. 1964, 45, 3323.
(21) (a) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485. (b) Otsubo, K.; Kawamura, K.; Inanaga, J .; Yamaguchi, M. Chem.
Lett. 1987, 1487.
J . Org. Chem, Vol. 68, No. 25, 2003 9537

Molander et al.
hexanes) to give 9.01 g (74%) of a white solid: Rf ) 0.3 (30%
EtOAc in hexanes); mp 124-126 °C (lit.28 mp 128 °C); IR (film)
3080, 2976, 2943, 2868, 1694, 1578, 1471 cm-1; 1H NMR (500
MHz, CDCl3) δ 9.57 (s, 2H), 7.38 (s, 2H), 3.96 (s, 6H), 3.96 (s,
6H), 3.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 190.0, 153.8,
151.5, 147.2, 130.4, 124.3, 105.6, 61.0, 60.6, 56.0; HRMS m/z
calcd for (C20H22O8 + Na)+ 413.1212, found 413.1222. Anal.
Calcd for C20H22O8: C, 61.53; H, 5.68. Found: C, 61.38; H,
5.52.
methyl group to the pseudoaxial hydrogen at C-9 and to
the pendant aromatic ring.
Third, the diastereotopic facial selectivity between the
olefin and the ketyl is determined by the biaryl stereo-
chemistry. This stereocontrol element, set earlier via a
kinetic resolution of racemic lactone (()-15, provided an
enantiomerically enriched atropisomer (98% ee) that was
carried throughout the synthesis without loss of stereo-
chemical integrity.
(()-1,2,3,9,10,11-Hexa m eth oxy-7H-d iben zo[c,e]oxep in -
5-on e [(()-15]. A solution of dialdehyde 16 (1.00 g, 2.62 mmol)
in EtOH (131 mL, 0.020 M) was treated with KOH (4.86 g,
86.7 mmol) and heated at reflux for 1.5 h. The solvent was
removed in vacuo, H2O was added, and the mixture was
acidified with 2 N HCl. Extraction with CH2Cl2, drying with
Na2SO4, and concentrating the material afforded the corre-
sponding hydroxy acid as a white solid, which was used
without purification for the next step. The hydroxy acid was
dissolved in CH2Cl2 (200 mL) together with DMAP (0.64 g,
5.2 mmol) and DCC (0.81 g, 3.9 mmol) and was stirred for 6 h
at rt under N2. The solution was then washed with H2O and
then brine and was subsequently dried and concentrated. The
residue was purified via flash chromatography (40% EtOAc
in hexanes) to yield racemic lactone (0.649 g, 63%) as a yellow
solid: Rf ) 0.35 (50% EtOAc in hexanes); mp 155-157 °C; IR
(film) 2942, 2837, 2251, 1716, 1593, 1487 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.14 (s, 1H), 6.74 (s, 1H), 4.94-4.76 (AB, J )
11.9 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.88 (s,
3H), 3.71 (s, 3H), 3.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
169.7, 153.3, 153.2, 152.9, 151.3, 144.9, 142.9, 131.3, 126.6,
121.3, 120.8, 108.5, 106.9, 69.7, 61.1, 61.0, 60.8, 60.8, 56.0;
HRMS m/z calcd for (C20H22O8 + Na)+ 413.1212, found
413.1209. Anal. Calcd for C20H22O8: C, 61.53; H, 5.68. Found:
C, 61.35; H, 5.52.
Con clu sion
The present synthesis illustrates in another format the
potential for the samarium(II) iodide-promoted reductive
coupling to achieve rapid and efficient access to the
dibenzocyclooctadiene lignans. Specifically, a stereocon-
trolled 8-endo ketyl-olefin coupling produced (+)-iso-
schizandrin (1) in good yield with excellent stereo- and
regioselectivity. Samarium diiodide is often featured as
a mild, chemoselective reagent for simple functional
group transformations employing complex substrates.25
Therefore, the flexibility in the 8-endo cyclization intro-
duced by varying the olefin substitution can be applied
to the construction of many eight-membered ring-
containing natural products, creating the rings and
installing the attendant functionality stereoselectively in
a single synthetic operation.
Exp er im en ta l Section
Kin etic Resolu tion of r a c-1,2,3,9,10,11-Hexa m eth oxy-
7H-d iben zo[c,e]oxep in -5-on e [(+)-15]. To a solution of (R)-
2-methyl-CBS-oxazaborolidine (4.5 mL of a 1 M solution in
toluene, 4.5 mmol) in THF (45 mL) at 0 °C under argon was
added BH3‚THF (6.0 mL of a 1 M solution, 6.0 mmol). After
being stirred for 30 min at rt, the solution was cooled to -20
°C and added dropwise over 5-10 min to a solution of lactone
(()-15 (0.585 g, 1.5 mmol) in THF (40 mL) at -20 °C. After 3
h, the mixture was hydrolyzed by careful addition of H2O and
acidified with 2 N HCl. After removal of the organic solvent
in vacuo, the mixture was extracted with CH2Cl2. The organic
phase was dried with Na2SO4, the solvent was removed in
vacuo, and the residue was purified via column chromatogra-
phy to afford lactone (R)-(+)-15 (0.250 g, 43%, 98% ee) and
diol (S)-(-)-19 (0.280 g, 47%, 88% ee). The diol could be
recycled by a two-step procedure involving oxidation with
Dess-Martin’s reagent to the dialdehyde and heating at reflux
in acetic acid for 24 h. The resulting dialdehyde was then
treated again in the Cannizzaro and DCC coupling conditions
to provide racemic lactone (0.080 g, 46%) and diol (0.091 g,
53%). Repeating this process provided a combined total of 0.357
Syn th esis of (+)-Isosch iza n d r in .
2-Br om o-3,4,5-tr im eth oxyben za ld eh yd e (17). To a solu-
tion of 3,4,5-trimethoxybenzaldehyde (50.0 g, 254 mmol) in
CHCl3 (500 mL) was added N-bromosuccinimide (54.43 g,
305.8 mmol). The solution was heated at reflux for 3 h. After
the reaction was complete by TLC and cooled to rt, the solution
was washed with water and extracted with Et2O. The com-
bined extracts were dried with MgSO4 and concentrated. The
bromoaldehyde was recrystallized in two crops from hexanes
and Et2O to give 67 g (96%) of the white solid: Rf ) 0.6 (30%
EtOAc in hexanes); mp 70-71 °C (lit.26 mp 70.5-71.5 °C); IR
(film) 2940, 2844, 2750, 1688, 1586, 1481, 672 cm-1; 1H NMR
(500 MHz, CDCl3) δ 10.15 (s, 1H), 7.18 (s, 1H), 3.88 (s, 3H),
3.81 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 190.4, 152.7, 150.5,
148.4, 128.5, 115.2, 107.2, 60.9, 60.8, 55.9; HRMS m/z calcd
for (C10H11BrO4 + Na)+ 296.9738, found 296.9769. Anal. Calcd
for C10H11BrO4: C, 43.66; H, 4.03. Found: C, 43.80, H, 4.15.
(()-4,4′,5,5′,6,6′-Hexa m eth oxy-1,1′-bip h en yl-2,2′-d ica r -
ba ld eh yd e (16). Bromoaldehyde 17 (17.1 g, 62.1 mmol) was
dissolved in degassed DMF (50 mL) and treated with activated
copper27 (15.78 g, 248.6 mmol) under N2 at 100 °C for 3 h and
then heated at reflux for 18 h. After the mixture had cooled to
rt, the copper was filtered off and water was added. The
products were extracted with Et2O, and the combined ether
extracts were washed with water and then a saturated NaCl
solution, dried with Na2SO4, and concentrated. The resulting
solid was purified via flash chromatography (30% EtOAc in
g (61%) of the enriched lactone: [R]25 +3.39 (c 6.44, CHCl3).
D
The physical3 and HPLC29 data for diol (S)-(-)-19 have been
reported.
(+)-(R)-6′-Hyd r oxym eth yl-4,5,6,2′,3′,4′-h exa m eth oxybi-
p h en yl-2-ca r ba ld eh yd e [(+)-14]. The enantio-enriched lac-
tone (+)-15 (0.728 g, 1.86 mmol) was dissolved in CH2Cl2 (3
mL) and toluene (9 mL) and cooled to -78 °C. A 1.36 mL
sample of a 1.5 M solution of DIBALH in toluene (2.05 mmol)
was then added to the solution in one swift addition. The
mixture was stirred for 20 min at -78 °C, then quenched with
(24) (a) Shabangi, M.; Flowers, R. A., II Tetrahedron Lett. 1997, 38,
1137. (b) Hou, Z.; Zhang, Y.; Wakatsuki, Y. Bull. Chem. Soc. J pn. 1997,
70, 149.
(25) (a) Girard, P.; Namy, J . L.; Kagan, H. J . Am. Chem. Soc. 1980,
102, 2693. (b) Molander, G. A. Chem. Rev. 1996, 96, 307. (c) Molander,
G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321. (d) Krief, A.; Laval,
A. M. Chem. Rev. 1999, 99, 745.
(26) Gutsche, C. D.; J ason, E. F.; Coffey, R. S.; J ohnson, H. E. J .
Am. Chem. Soc. 1958, 80, 5756.
(28) Hanaoka, M.; Sussa, H.; Shimezawa, C.; Arata, Y. Chem.
Pharm. Bull. 1974, 22, 1216.
(29) Nelson, T. D.; Meyers, A. I. J . Org. Chem. 1994, 59, 2577.
(30) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.
(27) Fuson, R. C.; Cleveland, E. A. Organic Syntheses; Wiley: New
York, 1955; Vol. III.
(31) Bengelmans, R.; Chastanet, J .; Ginsburg, H.; Quintero-Cortes,
L.; Roussi, G. J . Org. Chem. 1985, 50, 4933.
9538 J . Org. Chem., Vol. 68, No. 25, 2003

Total Synthesis of (+)-Isoschizandrin
MeOH (10 mL), and allowed to warm to rt. The material was
filtered, concentrated and purified via chromatography (40%
EtOAc in hexanes) to give 0.513 g (70%) of material: Rf ) 0.3
(50% EtOAc in hexanes); [R]28D +21.9 (c 4.54, CHCl3); IR (film)
3500, 2938, 2847, 2751, 2250, 1685, 1588, 1482 cm-1; 1H NMR
(500 MHz, CDCl3) δ 9.52 (s, 1H), 7.35 (s 1H), 6.90 (s, 1H), 4.23-
4.21 (m, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 3.85 (s,
3H), 3.63 (s, 3H), 3.60 (s, 3H), 2.55 (bs, 1H); 13C NMR (125
MHz, CDCl3) δ 190.8, 153.8, 153.2, 151.5, 150.9, 147.5, 141.1,
135.8, 129.9, 127.8, 117.8, 107.7, 105.5, 63.5, 61.0, 60.9, 60.7,
60.5, 56.0, 55.8; HRMS m/z calcd for (C20H24O8 + Na)+
415.1369, found 415.1361.
6.82 (s, 1H), 6.69 (s, 1H), 5.88-5.85 (dq, J ) 11.5, 1.69 Hz,
1H), 5.49-5.48 (dq, J ) 11.7, 6.98 Hz, 1H), 4.10 (s, 2H), 3.83
(s, 9H), 3.79 (s, 3H), 3.61 (s, 3H), 3.57 (s, 3H), 2.57 (br s, 1H),
1.77-1.76 (d, J ) 7.08, 1.72 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 152.8, 151.9, 151.08, 151.03, 141.0, 140.7, 135.1,
132.2, 128.8, 125.9, 122.5, 121.5, 108.6, 106.8, 63.2, 60.6, 60.49,
60.40, 60.1, 55.7, 55.5, 14.2; HRMS m/z calcd for (C22H28O7 +
Na)+ 427.1733, found 427.1733.
(+)-(R)-4,5,6,2′,3′,4′-H exa m et h oxy-6′-[(Z)-p r op en yl]b i-
p h en yl-2-ca r ba ld eh yd e [(+)-22]. To a solution of the benzyl
alcohol (+)-21 (0.1058 g, 0.261 mmol) in CH2Cl2 (3 mL) was
added 0.166 g (0.391 mmol) of Dess-Martin reagent at 0 °C
under N2. The mixture was warmed to rt and was monitored
for completion via TLC. After 2 h, the mixture was diluted
with Et2O and poured into a 1:1 mixture of saturated aqueous
NaHCO3 and Na2S2O3 (1.5 M). The mixture was stirred until
the ether layer was clear. The organic layer was then sepa-
rated, washed with brine, dried with Na2SO4, and concentrated
to give 0.0945 g (90%) of the desired aldehyde: Rf ) 0.3 (EtOAc
(+)-(R)-4,5,6,2′,3′,4′-Hexa m eth oxy-6′-(tr iisop r op ylsila -
n yloxym eth yl)bip h en yl-2-ca r ba ld eh yd e [(+)-18]. To a
solution of hydroxy aldehyde (+)-14 (0.504 g, 1.28 mmol) in
CH2Cl2 (13 mL, 0.10 M) were added DMAP (0.023 g, 0.15
mmol), imidazole (0.130 g, 0.192 mmol), and TIPSCl (0.271 g,
1.41 mmol) at 0 °C. The mixture was allowed to warm to rt
and stirred under N2 for 2 h. The reaction was quenched with
H2O, washed with brine, dried with Na2SO4, and concentrated.
After purification via radial chromatography (20% EtOAc in
hexanes), 0.609 g (98%) of the silyl ether was obtained as an
in hexanes); mp 116-119 °C; [R]26 +66.86 (c 1.895, CHCl3);
D
IR (film) 2938, 2844, 1733, 1635, 1588, 1483 cm-1; H NMR
1
(500 MHz, CDCl3) δ 9.41 (s, 1H), 7.24 (s, 1H), 6.64 (s, 1H),
5.81-5.79 (dq, J ) 11.5, 1.7 Hz, 1H), 5.50-5.46 (dq, J ) 11.4,
6.99 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.83 (s,
3H), 3.59 (s, 3H), 3.57 (s, 3H), 1.70-1.69 (d, J ) 6.96, 1.7 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 190.9, 152.9, 152.7, 151.8,
151.2, 147.3, 140.6, 132.9, 129.6, 129.0, 128.6, 126.8, 119.0,
108.2, 104.5, 60.69, 60.66, 60.38, 60.35, 55.78, 55.76, 14.19;
HRMS m/z calcd for (C22H26O7 + Na)+ 425.1576, found
425.1583. Anal. Calcd for C22H26O7: C, 65.66; H, 6.51. Found:
C, 65.44; H, 6.43.
oil: Rf ) 0.3 (20% EtOAc in hexanes); [R]27 +16.2 (c 4.66,
D
CHCl3); IR (film) 2941, 2892, 2865, 2748, 2604, 1964, 1681,
1
1588, 1481 cm-1; H NMR (500 MHz, CDCl3) δ 9.48 (s, 1H),
7.31 (s, 1H), 7.05 (s, 1H), 4.46 (d, J ) 13.5 Hz, 1H)), 4.24 (d, J
) 13.5 Hz, 1H), 3.90 (s, 6H), 3.87 (s, 3H), 3.81 (s, 3H), 3.60 (s,
3H), 3.57 (s, 3H), 0.99 (s, 18H), 0.97 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 190.0, 153.4, 153.0, 151.2, 151.1, 147.4, 140.1,
136.3, 129.6, 127.7, 116.1, 105.1, 104.8, 62.8, 60.7, 60.6, 60.5,
60.3, 55.8, 55.5, 17.7, 12.1, 11.7; HRMS m/z calcd for (C29H44O8-
Si + Na)+ 571.2703, found 571.2687.
(+)-(R)-2-(2′-Oxop r op yl-4,5,6-tr im eth oxy-2′-[(Z)-p r op e-
n yl]-3′,4′,5′-tr im eth oxybip h en yl [(+)-3]. A suspension of
0.58 g (1.4 mmol) of (R-methoxyethyl)triphenylphosphonium
chloride in 2.5 mL of THF was cooled to -78 °C under argon,
and n-BuLi (0.90 mL of a 1.6 M solution in hexanes, 1.44
mmol) was added dropwise, giving a characteristic red color
that persisted after 30 min of stirring at -78 °C. Aldehyde
(+)-22 (0.058 g, 0.14 mmol) in THF (2.0 mL) was then added
at -78 °C to the ylide mixture, and the resulting suspension
was stirred for 3 h at -78 °C. The reaction was quenched with
H2O and extracted with Et2O. The combined organic extracts
were concentrated to give the crude enol ether. A catalytic
amount of p-TsOH (1 crystal) was added to the crude enol ether
in THF (2 mL) at 0 °C, and the mixture was stirred for 30
min. The reaction was then quenched with water and extracted
with Et2O. The organic extracts were dried with Na2SO4,
concentrated, and purified via radial chromatography (40%
EtOAc in hexanes) to give 0.033 g (54%) of ketoolefin: Rf )
0.2 (30% EtOAc in hexanes); IR (film) 2937, 2847, 1712, 1592,
1483 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.72 (s, 1H), 6.53 (s,
1H), 5.88 (dq, J ) 11.7, 1.8 Hz, 1H), 5.55 (dq, J ) 11.7, 7.1
Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H),
3.67 (s, 3H), 3.62 (s, 3H), 3.28 (AB, J ) 10.3 Hz, 2H), 1.91 (s,
3H), 1.84 (dd, J ) 7.1, 1.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 206.7, 152.7, 152.2, 151.6, 132.4, 129.4, 128.9, 128.8, 126.6,
126.1, 123.6, 122.9, 108.5, 108.3, 60.8, 60.7, 60.6, 60.4, 55.9,
55.8, 47.9, 29.5, 14.5; HRMS m/z calcd for (C24H30O7 + Na)+
453.1889, found 453.1875.
(+)-(R)-(4,5,6,2′,3′,4′-Hexa m eth oxy-6′-[(Z)-p r op en yl]bi-
p h en yl-2-ylm eth oxy)tr iisop r op ylsila n e [(+)-20]. To a sus-
pension of ethyltriphenylphosphonium bromide (1.21 g, 3.23
mmol) in 30 mL of freshly distilled THF at 0 °C under N2 was
added via syringe KHMDS (6.56 mL of a 0.5 M solution in
toluene, 3.23 mmol). The resulting orange solution was allowed
to stir at 0 °C for 30 min. The ylide solution was then cooled
to -78 °C, and a solution of the aldehyde (+)-18 (0.600 g, 1.09
mmol) in 30 mL of THF was added dropwise. The reaction was
stirred at -78 °C and then slowly warmed to rt. The reaction
was then quenched with cold MeOH, extracted with EtOAc,
dried with Na2SO4, and concentrated. The crude reaction
provided 0.520 g (85%) of a 4:1 mixture of Z/E olefins. After
column chromatography via flash MPLC, 0.327 g (54%) of a
>10:1 Z/E mixture was obtained. This sample was carried
through the rest of the synthesis: Rf ) 0.3 (20% EtOAc in
hexanes); [R]26 +39.9 (c 4.07, CHCl3); IR (film) 2940, 2892,
D
2865, 2716, 1593, 1562, 1483 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.09 (s, 1H), 6.71 (s, 1H), 5.93 (d, J ) 11.6 Hz, 1H), 5.55 (dq,
J ) 11.5, 6.9 Hz, 1H), 4.36-4.25 (AB, J ) 14.0 Hz, 2H), 3.89
(s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H),
3.62 (s, 3H), 1.83 (d, J ) 6.6 Hz, 3H), 1.00 (s, 18H), 0.99 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 152.7, 151.9, 151.3, 150.8,
140.9, 140.0, 135.9, 132.0, 128.8, 125.7, 122.2, 119.7, 108.4,
104.3, 62.5, 60.7, 60.6, 60.3, 60.2, 55.8, 55.5, 17.8, 14.4, 11.8;
HRMS m/z calcd for (C31H48O7Si + Na)+ 583.3067, found
583.3096.
(+)-(R)-(4,5,6,2′,3′,4′-Hexa m eth oxy-6′-[(Z)-p r op en yl]bi-
p h en yl-2-yl)m eth a n ol [(+)-21]. To a solution of the silyl
ether (+)-20 (0.117 g, 0.208 mmol) in THF (2 mL) at 0 °C was
added TBAF (0.260 mL of a 1 M solution in THF, 0.260 mmol).
The reaction was stirred under N2 and was warmed to rt over
1-2 h. The reaction was quenched with H2O and extracted
with Et2O. The combined organic extracts were washed with
brine, dried with Na2SO4, and concentrated. After purification
via column chromatography (30% EtOAc in hexanes), 0.076 g
(91%) of benzyl alcohol was obtained as an oil: Rf ) 0.2 (40%
EtOAc in hexanes); [R]26D +20.0 (c 3.92, CHCl3); IR (film) 3494,
(+)-Isosch iza n d r in (1). A solution of samarium(II) iodide
was generated by adding CH2I2 (0.084 g, 0.31 mmol) to a slurry
of samarium metal (0.048 g, 0.32 mmol) in THF (3 mL). After
the solution was stirred overnight, HMPA (0.500 mL) was
added followed by the dropwise addition of ketoolefin (+)-3
(0.027 g, 0.063 mmol) and t-BuOH (9 mg, 0.125 mmol) in THF
(12 mL) via syringe pump over 2 h. Two hours after the
addition was complete, the reaction was quenched with aque-
ous NaHCO3, concentrated, and extracted with EtOAc. The
combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified via radial chromatog-
raphy (40% EtOAc in hexanes) to give the natural product as
2937, 2838, 1540, 1483 cm-1 1H NMR (500 MHz, CDCl3) δ
;
J . Org. Chem, Vol. 68, No. 25, 2003 9539

Molander et al.
a white foam (0.023 g, 85%) contaminated with <5% of
diastereomers. Purification by preparative HPLC [hexane/i-
PrOH (97:3, 10.0 mL/min)] was used to remove the minor
diastereomers. This revealed that the natural product was
formed with 98% enantiomeric excess by chiral HPLC: Rf )
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (Grant GM35249) for the
generous support of this work. We also thank Dr. Pat
Carroll for performing the X-ray crystal structure de-
termination and Dr. Rakesh Kohli for performing the
HRMS. Finally, we thank Northwoods Nursery, Inc., in
Molalla, OR, for the picture used in the cover art.
0.2 (50% EtOAc in hexanes); [R]25 +112.0 (c 0.400, CHCl3),
D
{lit.1d [R]24 +110.5 (c 0.405, CHCl3)}; IR (film) 3476, 2934,
D
1596, 1489 cm-1; H NMR (500 MHz, CDCl3) δ 6.59 (s, 1H),
1
6.52 (s, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.86 (s,
3H), 3.54 (s, 3H), 3.53 (s, 3H), 2.81 (d, J ) 13 Hz, 1H), 2.54-
2.47 (m, 2H), 2.31 (d, J ) 13 Hz, 1H), 1.88-1.86 (m, 1H), 1.53
(bs, 1H, OH), 1.17 (s, 3H), 0.87 (d, J ) 7.5, 3H); 13C NMR (125
MHz, CDCl3) δ 152.0, 151.79, 151.73, 151.6, 140.4, 140.3, 133.5,
123.3, 122.8, 110.5, 110.3, 74.0, 60.95, 60.92, 60.58, 60.55, 60.3,
55.9, 42.1, 40.7, 35.3, 29.2, 13.5; HRMS m/z calcd for (C24H32O7
+ Na)+ 455.2045, found 455.2029.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and structural data for all new compounds not described
within the text, as well as X-ray structure data for compound
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0347361
9540 J . Org. Chem., Vol. 68, No. 25, 2003