Synthesis of nonracemic 3-deoxyschweinfurthin B

Article abstract of DOI:10.1021/jo048444r

(Chemical Equation Presented) Synthesis of nonracemic 3-deoxyschweinfurthin B has been accomplished through a synthetic sequence including a key cascade cyclization of an epoxy olefin. The intermediate epoxide could be prepared as a single enantiomer thro

Full text of DOI:10.1021/jo048444r

Synthesis of Nonracemic 3-Deoxyschweinfurthin B
Jeffrey D. Neighbors,† John A. Beutler,‡ and David F. Wiemer*,†
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, and Molecular Targets
Development Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702
david-wiemer@uiowa.edu
Received September 3, 2004
Synthesis of nonracemic 3-deoxyschweinfurthin B has been accomplished through a synthetic
sequence including a key cascade cyclization of an epoxy olefin. The intermediate epoxide could be
prepared as a single enantiomer through an AD-mix-R (or AD-mix-â) oxidation, and the stereo-
chemistry of the epoxide has been shown to control formation of the two additional stereogenic
centers created through the cyclization. Synthetic 3-deoxyschweinfurthin B was found to have potent
differential activity in the National Cancer Institute’s 60 cell line anticancer assay. This represents
the first synthesis of the tetracyclic schweinfurthin skeleton, validating our overall synthetic strategy
and providing the first schweinfurthin analogue with activity slightly greater than those of the
natural products.
At this time, the small family of natural products
known as the schweinfurthins is composed of four
compounds (Figure 1, 1-4) isolated from the African
plant Macaranga schweinfurthii Pax at the National
Cancer Institute.1,2 Schweinfurthins A (1), B (2), and D
(4) display significant activity in the National Cancer
Institute’s (NCI’s) 60 cell line anticancer assay with mean
GI50 values <1 µM. Their biological activity has attracted
interest because some central nervous system, renal, and
breast cancer cell lines are among the types most
sensitive to these compounds. Furthermore, the spectrum
of their anticancer activity shows no correlation with any
currently used agent and suggests that these compounds
may be acting at a previously unrecognized target or
through a novel mechanism. Repeated attempts to isolate
larger samples of the schweinfurthins from the natural
source have met with limited success, and the absolute
stereochemistry of these natural products has yet to be
determined. For these reasons, as well as their interest-
FIGURE 1. Natural schweinfurthins.
ing biological activity, we have undertaken an effort
directed at total synthesis of the schweinfurthins. An
asymmetric synthesis would be particularly attractive
because it would allow assignment of the absolute stereo-
chemistry of the natural products and could provide a
reliable source of natural schweinfurthins and synthetic
analogues for further biological testing.
Our retrosynthetic analysis of schweinfurthin B (Fig-
ure 2) calls for an approach where the central stilbene
olefin would be constructed in the penultimate step. This
* To whom correspondence should be addressed. Phone: (319) 335-
1365. Fax: (319) 335-1270.
† University of Iowa.
‡ National Cancer Institute.
(1) Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. J.
Nat. Prod. 1998, 61, 1509-1512.
(2) Beutler, J. A.; Jato, J.; Cragg, G. M.; Boyd, M. R. Nat. Prod. Lett.
2000, 14, 349-404.
10.1021/jo048444r CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/11/2005
J. Org. Chem. 2005, 70, 925-931
925

Neighbors et al.
SCHEME 2
paper.4 Schweinfurthin B (2) was chosen as the initial
target so recourse could be made to commercial vanillin
as a starting material. This would forego the need for an
orthogonal protection of the aryl oxygens because the
regiochemistry of the required methyl ether is secured.
Our initial route to racemic hexahydroxanthene 7
involved epoxidation of the geranyl arene 9, available
from vanillin in 60% yield over seven steps.4 The epoxide
10 was opened to phenyl selenide 11, which, after
deprotection and acid-catalyzed cationic cascade cycliza-
tion, afforded a single racemic diastereomer of the trans-
fused tricyle 7. Completion of the natural product from
this point would require selenoxide elimination, dihy-
droxylation of the resulting olefin, and an HWE conden-
sation of the aldehyde with the phosphonate encompass-
ing schweinfurthin’s right half (vide supra). In the event,
oxidation of racemic phenyl selenide 7 with m-CPBA and
thermal elimination of the resulting selenoxide gave the
olefin 13 (Scheme 2) in moderate yield.5 Despite some
literature precedent for similar oxidation/elimination
reactions under mild reaction conditions, it was necessary
to subject this system to a more forceful protocol.6,7 In
this case, the decreased flexibility of the tricyclic system
may make it difficult to achieve the syn conformation of
the selenoxide and the adjacent hydrogen necessary for
elimination.
FIGURE 2. Retrosynthetic analysis.
SCHEME 1
With olefin 13 in hand, introduction of the diol moiety
through an osmium-mediated dihydroxylation reaction
was examined. Inspection of a molecular model of olefin
13 showed that both faces might be somewhat inacces-
sible, and that if reaction occurred it would most likely
take place from the undesired face of the olefin trans to
the angular methyl group. Despite this analysis, there
is literature precedent for dihydroxylation in similar
systems,8 and both diastereomers of the cis-diol would
be of use from a structure-activity standpoint. Unfor-
tunately, treatment of olefin 13 with catalytic or sto-
ichiometric osmium tetroxide or potassium osmate failed
to give any detectable dihydroxylation products in our
hands.9
approach is highly convergent and should allow facile
access to analogues for structure-activity studies. We
already have demonstrated that a Horner-Wadsworth-
Emmons (HWE) condensation can be used to introduce
the stilbene olefin through synthesis of the simplest
member of the family, schweinfurthin C (3),3 and the
“right-half” phosphonate (5) employed in that endeavor
can be conserved for synthesis of schweinfurthins A and/
or B. All of the tetracyclic schweinfurthins require a
dihydroxylated “left-half” core represented in the alde-
hyde 6. A synthetic approach to phenyl selenide 7
(Scheme 1), which can be viewed as an advanced precur-
sor to this aldehyde, has been reported in a previous
(4) Treadwell, E. M.; Neighbors, J. D.; Wiemer, D. F. Org. Lett. 2002,
4, 3639-3642.
(5) Reich, H. J.; Wollowitz, S.; Trend, J. E.; Chow, F.; Wendelburn,
D. F. J. Org. Chem. 1978, 43, 1697-1705.
(6) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975,
97, 5434-5447.
(7) It was found that yields increased for the elimination when going
from the original conditions of Reich (refluxing dichloromethane) to
benzene and finally toluene.
(8) (a) McMurray, J. E.; Erion, M. D. J. Am. Chem. Soc. 1985, 107,
2712-2720. (b) Mori, K.; Komatsu, M. Liebigs Ann. Chem. 1988, 107-
119.
(9) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K.
B. Adv. Synth. Catal. 2002, 344, 421-433.
(3) Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F. J. Org. Chem.
1999, 64, 8718-8723.
926 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of Nonracemic 3-Deoxyschweinfurthin B
SCHEME 3
FIGURE 3. Proposed path of epoxide cyclization.
The risk of an adverse stereochemical outcome of the
dihydroxylation and the difficult oxidation observed in
practice made it necessary to seek alternative methodol-
ogy for introduction of functionality in the A ring of the
tricycle. The pioneering work of van Tamelen10 and
Corey11 on biogenic cyclization of oxidosqualene, and
subsequently on acid-catalyzed cyclization of synthetic
equivalents, suggested that a nonracemic epoxide (Figure
3) could serve as a viable substrate for cyclization.
Perusal of the literature shows numerous examples of
protic and Lewis acid-catalyzed epoxyolefin cyclizations.12
In this system, a pseudo-chair-chair-like transition state
terminated through capture of the tertiary cation by the
phenolic oxygen would afford the desired trans-fused
xanthene. If a pseudoequatorial disposition of the epoxide
moiety were favored, then cyclization of the (R)-epoxide
could be predicted to favor the (2R,5R,7R)-diastereomer
of the resulting tricycle, as shown. This strategy could
lead directly to 3-deoxyschweinfurthin B, and in principle
further elaboration of the A-ring could lead to the natural
product.
to the epoxide via the secondary mesylate,14 to intersect
the route already developed4 or bring new functionality
into the tricyclic system. To our delight, treatment of
diene 9 with AD-mix-R in the presence of methane-
sulfonamide gave the desired diol 14 in 68% yield and
83% ee (Scheme 3). Use of the pictorial device suggested
by Sharpless et al.15 for the facial selectivity of the attack
indicated that an (S)-alcohol should be expected at the
newly created asymmetric center.
While the stereochemistry at the new stereogenic
center was assigned tentatively as S, a spectroscopic
method to support an assignment was pursued.16 In this
case, separate samples of the enantioenriched diol 14
were treated with the (S)- and (R)-enantiomers of O-
methylmandelic acid under standard mixed anhydride
coupling conditions. After isolation of the major diaste-
reomer from each reaction, compounds 15 and 16,
respectively, the 1H NMR spectra were examined for
chemical shift differences in accordance with the model
of Trost et al.16b Significant shifts were noted for two sets
of easily identifiable hydrogens in the two diastereomers
(Figure 4). The terminal methyl groups are found as a
singlet with a chemical shift of 1.16 ppm in ester 16 and
are shifted to 0.94 ppm in isomer 15. In contrast, the
olefinic hydrogen is shifted from 5.27 ppm in compound
15 to a more upfield 5.00 ppm in the isomer 16. Both of
these changes are consistent with expectations based on
placing the more upfield hydrogens in the shielding
region of the phenyl ring when viewed in an extended
Newman projection format as required by the Trost
model.16b On this basis, the new asymmetric center in
diol 14 was assigned the S configuration.
There is considerable literature precedent for regio-
selective dihydroxylation of the terminal olefin in geraniol
itself,13 and it appeared that the steric encumbrance and
electronic effects in a geranyl arene would favor parallel
regiocontrol. The resulting diol might then be converted
(10) (a) van Tamelen, E. E.; Willet, J. D.; Clayton, R. B.; Lord, K.
E. J. Am. Chem. Soc. 1966, 88, 4752-4754. (b) Willet, J. D.; Sharpless,
K. B.; Lord, K. E.; van Tamelen, E. E.; Clayton, R. B. J. Biol. Chem.
1967, 242, 4181-4191.
(11) Corey, E. J.; Russey, W. E.; Ortiz de Motellano, P. R. J. Am.
Chem. Soc. 1966, 88, 4750-4751.
(12) (a) Sharpless, K. B. J. Am. Chem. Soc. 1970, 92, 6999-7001.
(b) van Tamelen, E. E.; Holton, R. A.; Hopla, R. E.; Kouz, W. E. J. Am.
Chem. Soc. 1972, 94, 8228-8229. (c) van Tamelen, E. E.; Anderson,
R. J. J. Am. Chem. Soc. 1972, 94, 8225-8228. (d) van Tamelen, E. E.;
Seiler, M. P.; Wierenga, W. J. Am. Chem. Soc. 1972, 94, 8229-8231.
(e) Tanis, S. P.; Herrington, P. M. J. Org. Chem. 1983, 48, 4572-4580.
(f) Corey, E. J.; Sodeoka, M. Tetrahedron Lett. 1991, 32, 7005-7008.
(g) Fish, P. V.; Sudhakar, A. R.; Johnson, W. S. Tetrahedron Lett. 1993,
34, 7849-7852. (h) Sen, S. E.; Zhang, Y. Z.; Smith, S. M.; Huffman, J.
C. J. Org. Chem. 1998, 63, 4459-4465. (i) Corey, E. J.; Staas, D. D. J.
Am. Chem. Soc. 1998, 120, 3526-2527. (j) Sen, S. E.; Roach, S. L.;
Smith, S. M.; Zhang, Y. Z. Tetrahedron Lett. 1998, 39, 3969-3972.
(13) (a) Corey, E. J.; Zhang, J. Org. Lett. 2001, 3, 3211-3214. (b)
Vidari, G.; Dapiaggi, A.; Zanoni, G.; Garlaschelli, L. Tetrahedron Lett.
1993, 34, 6485-6488. (c) Zhang, X.; Archelas, A.; Meou, A.; Furstoss,
R. Tetrahedron: Asymmetry 1991, 2, 247-250.
(14) For examples, see: (a) Rickards, R. W.; Thomas, R. D. Tetra-
hedron Lett. 1993, 34, 8369-8372. (b) McMurray, J. E.; Dushin, R. G.
J. Am. Chem. Soc. 1990, 112, 6942-6949. (c) Huang, A. X.; Xiong, Z.;
Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999-10003.
(15) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, X.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768-2771.
(16) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-
519. (b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370-2374. (c) For
application to an extended alicyclic system, see, for example: Gallinis,
D. L.; Wiemer, D. F. J. Org. Chem. 1993, 58, 7804-7807.
J. Org. Chem, Vol. 70, No. 3, 2005 927

Neighbors et al.
Wadsworth-Emmons conditions17 gave the protected
stilbene 21 in high yield, all without recourse to protec-
tion of the secondary alcohol. Final deprotection of the
MOM ethers upon treatment with camphorsulfonic acid
gave enantioenriched 3-deoxyschweinfurthin B (22) in
good yield.18
After the viability of this strategy had been demon-
strated with enantioenriched epoxide 17, application of
this approach to enantiopure material was pursued. The
initial studies with a phenyl selenide cyclization precur-
sor had been made with the assumption that this large
substituent could ultimately be used to transfer absolute
stereocontrol through a cationic cyclization manifold.
There was some reason, however, to question this hy-
pothesis. It had been noted in reactions of episulfonium
ions that there is potential for the positive charge to be
carried by either center of the three-membered ring
intermediate.19 In contrast there is literature precedent
for faithful transmission of stereochemical information
through the epoxide cyclization transition state,20 but to
determine the stereointegrity of this specific case, a
resolution of the enantioenriched material was required.
Our experience with the Trost-Mosher esters 15 and 16
indicated this should be straightforward. To this end a
large-scale esterification was conducted (Scheme 5), and
the resulting material was readily partitioned into major
(15) and minor diastereomers by flash chromatography.
Hydrolysis of the major ester 15 was accomplished upon
treatment with sodium hydroxide in ethanol to afford diol
(S)-14 as a single enantiomer.21
FIGURE 4. Mosher-Trost analysis of O-methylmandelate
esters.
SCHEME 4
The diol (S)-14 then was subjected to the same proto-
cols developed for the epoxide cyclization which led to
tricylic material in the enantioenriched series. Treatment
with mesyl chloride followed by internal displacement
mediated by potassium carbonate gave the epoxide (R)-
17 in moderate yield. Removal of the silyl ether protect-
ing groups and subsequent cyclization with trifluoracetic
acid gave, as expected, the tricyclic diol (R,R,R)-19 in
reasonable yield. This diol could be subjected to benzylic
oxidation with manganese dioxide to afford the aldehyde
(R,R,R)-20.
The aldehyde (R,R,R)-20 displayed a specific rotation
of +159°. Two other samples of optically active compound
20 also were available: one with a rotation of +97.8° for
material synthesized from diol 14 with an enantiomeric
excess of 64% ([R]D ) -6.1°), and another with a rotation
of +112° from diol 14 with an enantiomeric excess of 74%
([R]D ) -7.0°). On the basis of the rotation of the
enantiopure aldehyde (R,R,R)-20, these values would
correspond to ee’s of 63% and 72%, respectively, indicat-
ing that this cascade cyclization is stereospecific within
Treatment of diol 14 with mesyl chloride and base,
followed by in situ nucleophilic displacement of the
resulting mesylate by the tertiary alkoxide, did in fact
deliver the nonracemic epoxide 17 in good yield (Scheme
4). Deprotection of epoxide 17 to the diol 18 followed by
treatment with trifluoroacetic acid to induce cyclization
gave the expected tricycle as the trifluoroacetate ester,
and subsequent hydrolysis gave the benzyl alcohol 19 as
a single diastereomer. That the secondary alcohol of
compound 19 is indeed in an equatorial disposition is
(17) Baker, R.; Sims, R. J. Synthesis 1981, 117.
(18) Iikubo, K.; Ishikawa, Y.; Ando, N.; Umezawa, K.; Nishiyama,
S. Tetrahedron Lett. 2002, 43, 291-293.
(19) (a) Branchaud, B. P.; Blanchette, H. S. Tetrahedron Lett. 2002,
43, 351-353. (b) Toshimitsu, A.; Hirosawa, C., Tamao, K. Synlett 1996,
465-467.
(20) (a) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-
8874. (b) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765-
8766. (c) Corey, E. J.; Lou, G.; Lin, S. J. Am. Chem. Soc. 1997, 119,
9927-9928. (d) Corey, E. J.; Lou, G.; Lin, L. S. Angew. Chem., Int.
Ed. 1998, 37, 1126-1128. (e) Haung, A. X.; Xiong, Z.; Corey, E. J. J.
Am. Chem. Soc. 1999, 121, 9999-10003. (f) Zhang, J.; Corey, E. J. Org.
Lett. 2001, 3, 3215-3216 and references therein.
evidenced by the large coupling constant (J(H2
)
ax-H3ax
)
11.9 Hz) observed in the 1H NMR spectrum. Manganese
dioxide oxidation cleanly affords aldehyde 20, and con-
densation with phosphonate 5 under modified Horner-
(21) Schneider, J. P.; Kelly, J. W. J. Am. Chem. Soc. 1995, 117,
2533-2546.
928 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of Nonracemic 3-Deoxyschweinfurthin B
SCHEME 5
SCHEME 6
the error of these measurements. It should be noted that
oxidation of compound 9 with the AD-mix-â reagent
affords the diol (R)-14 in similar yield and enantiopurity
(Scheme 6). The tricyclic aldehyde (S,S,S)-20 has been
synthesized from diol (R)-14 via this route as well, thus
providing access to either enantiomer of compound 22.
Enantioenriched compound 22 was tested at the NCI
in the 60 cell line anticancer assay, and was found to have
a mean GI50 of 0.21 µM, slightly lower than those of any
of the natural schweinfurthins. The finding of more
potent activity in this analogue is significant and makes
this compound an interesting addition to a family which
warrants further study. Furthermore, the viability of the
epoxide cyclization suggests that the biosynthesis of the
natural schweinfurthins may follow a similar reaction
manifold. In that context, the very recent report of the
natural product 23,22 identical to 3-deoxyschweinfurthin
B except for the D-ring prenyl substituent that replaces
the geranyl group of schweinfurthin B, is intriguing and
strongly suggests that 3-deoxyschweinfurthin B may
someday be found as a natural product.
In conclusion, a cascade cyclization of an epoxy olefin
has been used to prepare the carbon skeleton of the
hexahydroxanthene unit found in schweinfurthins A, B,
and D. Furthermore, an aldehyde derived from this
tricyclic compound has been condensed with the right-
half synthon reported earlier to afford the complete
schweinfurthin skeleton in a product that can be viewed
as 3-deoxyschweinfurthin B. This work represents the
first synthesis of a tetracyclic schweinfurthin analogue
and, with absolute stereochemistry derived from an AD-
mix reagent, can afford the final product as a single
enantiomer. These efforts validate the strategies we have
developed for the synthesis of this family of natural
products. Application of these strategies to preparation
of the natural compounds, as well as the results of
bioassays conducted on various synthetic materials, will
be reported in due course.
Experimental Section
Olefin 13. To a solution of the alcohol 7 (32 mg, 0.07 mmol)
in THF (5 mL) at -10 °C was added m-CPBA (24 mg, 0.1
mmol, 70% technical grade). The resulting solution was stirred
for 40 min and transferred into a solution of diisopropylamine
(22) Yoder, B. J.; Schilling, J. K.; Norris, A.; Miller, J. S.; Andrian-
tsiferana, R.; Rasamison, V. E.; Kingston, D. G. I. International
Congress on Natural Products Research, Phoenix, AZ, August 2004;
Paper O-16.
J. Org. Chem, Vol. 70, No. 3, 2005 929

Neighbors et al.
(30 µL, 0.22 mmol) in toluene (30 mL) at reflux. After 3 h the
mixture was allowed to cool to rt and quenched by addition of
10% aqueous sodium sulfite. The mixture was extracted with
EtOAc, and the organic phase was washed with brine, dried
(MgSO4), and then concentrated in vacuo. The resulting yellow
oil was subjected to final purification by column chromatog-
raphy (10:1, 4:1, and 3:2 hexanes/ethyl acetate) to afford the
olefin 13 (13 mg, 62%) as a clear oil: 1H NMR δ 6.75 (s, 1H),
6.71 (s, 1H), 5.55 (dt, J ) 10.3, 4.0 Hz, 1H), 5.42 (dt, J ) 10.1,
1.9 Hz, 1H), 4.59 (s, 2H), 3.86 (s, 3H), 2.74 (m, 2H), 2.46 (dd,
J ) 11.9, 6.15 Hz, 1H), 2.01 (dd, J ) 3.9, 1.9 Hz, 2H), 1.28 (s,
3H), 1.10 (s, 3H), 0.99 (s, 3H); 13C NMR δ 148.6, 142.2, 137.7,
131.7, 122.5, 120.6, 120.3, 108.6, 76.6, 65.6, 56.1, 44.5, 39.5,
35.9, 31.3,23.3, 23.1, 20.1; HRMS (EI) m/z calcd for C18H24O3
288.1725, found 288.1727.
3-(3′,7′-Dimethyl-2-octen-6′(S),7′-diol)-4-(tert-butyldim-
ethylsiloxy)-5-methoxybenzyloxy]-tert-butyldimethylsi-
lane (14). To a solution of AD-mix-R (15.13 g) in water/t-BuOH
(150 mL, 1:1) was added methanesulfonamide (1.13 g), and
the solution was cooled to 6 °C. The geranylated arene 94 (5.29
g, 10.2 mmol) was added via syringe as a neat oil, and the
solution was kept at 6 °C for 15 h. Solid Na2SO3 was added,
and the solution was stirred for 1 h. The solution was extracted
with EtOAc, and the resulting organic layer was washed with
2 N NaOH and brine, then dried (MgSO4), and concentrated
in vacuo to afford a clear oil. Final purification by column
chromatography (1:1 hexanes/ethyl acetate) gave the diol 14
(3.86 g, 68%) as a clear oil: [R]26.4D ) -7.9 (c 0.10, CHCl3); 1H
NMR δ 6.72 (d, J ) 2.0 Hz, 1H), 6.65 (d, J ) 2.0 Hz, 1H), 5.38
(t, J ) 7.1 Hz, 1H), 4.64 (s, 2H), 3.77 (s, 3H), 3.35 (d, J ) 7.3
Hz, 2H), 3.35 (m, 1H), 2.33-2.23 (m, 2H), 2.17-2.00 (m, 2H),
1.70 (s, 3H), 1.66-1.56 (m, 1H), 1.50-1.36 (m, 1H), 1.19 (s,
3H), 1.15 (s, 3H), 1.00 (s, 9H), 0.93 (s, 9H), 0.17 (s, 6H), 0.08
(s, 6H); 13C NMR δ 149.7, 141.3, 135.7, 133.7, 132.1, 123.3,
119.0, 107.3, 78.2, 73.0, 65.0, 54.7, 36.7, 29.7, 28.5, 26.4, 26.1
(3C), 25.9 (3C), 23.2, 21.0, 18.9, 16.2, -3.9 (2C), -5.2 (2C).
Anal. Calcd for C30H56O5Si2: C, 65.17; H, 10.21. Found: C,
65.11, H, 10.22.
(t, J ) 6.6 Hz, 1H), 4.80 (m, 2H), 4.65 (s, 2H), 3.78 (s, 3H),
3.43 (s, 3H), 3.24 (d, J ) 6.9 Hz, 2H), 1.60 (m, 5H, 1H
exchanges with D2O), 1.45 (s, 3H), 1.16 (s, 6H), 0.99 (s, 9H),
0.93 (s, 9H), 0.17 (s, 6H), 0.09 (s, 6H); 13C NMR δ 170.9, 149.7,
141.3, 136.3, 134.9, 133.6, 132.1, 128.8, 128.6 (2C), 127.1 (2C),
123.0, 119.0, 107.3, 82.7, 80.7, 72.4, 65.1, 57.3, 54.7, 35.4, 28.3,
28.2, 26.6, 26.1 (3C), 26.0 (3C), 24.7, 18.9, 18.4, 16.1, -3.9 (2C),
-5.1 (2C); HRFABMS m/z calcd for C39H64O7NaSi2 (M + Na)+
723.4088, found 723.4101.
[4-(tert-Butyldimethylsilyloxy)-5-methoxy-3-(3′,7′-di-
methyl-6′-epoxy-2′-octenyl)benzyloxy-tert-butyldimeth-
ylsilane (17). To a solution of diol 14 (2.03 g, 3.7 mmol), in
CH2Cl2 (20 mL) at 0 °C, was added TEA (1.35 mL, 9.69 mmol)
followed 30 min later by MsCl (0.43 mL, 5.58 mmol). After 35
min, the reaction was allowed to warm to rt, and after a total
of 2 h, a second aliquot of TEA (0.80 mL, 5.74 mmol) was added
and the reaction was stirred for 30 min. A solution of K2CO3
(2.31 g, 16.7 mmol) in MeOH (70 mL) was poured into the
vessel, and the solution was allowed to react for 20 h. After
filtration and extraction of the resulting filtrate with ethyl
acetate, the combined organic phase was washed with brine,
dried (MgSO4), and concentrated under vacuum to afford a
white oil. Final purification by flash chromatography (12:1
hexanes/ethyl acetate) yielded the target epoxide 17 as a
viscous clear oil (1.48 g, 75%): 1H NMR δ 6.72 (d, J ) 1.7 Hz,
1H), 6.65 (d, J ) 1.6 Hz, 1H), 5.36 (tm, J ) 7.2 Hz, 1H), 4.64
(s, 2H), 3.77 (s, 3H), 3.34 (d, J ) 7.1 Hz, 2H), 2.72 (t, J ) 6.3
Hz, 1H), 2.30-2.10 (m, 2H), 1.70 (s, 3H), 1.75-1.60 (m, 2H),
1.28 (s, 3H), 1.25 (s, 3H), 0.99 (s, 9H), 0.93 (s, 9H), 0.17 (s,
6H), 0.08 (s, 6H); 13C NMR δ 149.7, 141.3, 135.0, 133.7, 132.1,
123.3, 119.0, 107.3, 65.0, 64.2, 58.3, 54.7, 36.3, 28.5, 27.4, 26.1
(3C), 26.0 (3C), 24.9, 18.9, 18.7, 18.4, 16.2, -3.9 (2C), -5.2 (2C).
Anal. Calcd for C30H54O4Si2: C, 67.36; H, 10.17. Found: C,
67.12; H, 10.28.
(6′R)-4-Hydroxy-3-methoxy-5-(3′,7′-dimethyl-6′-epoxy-
2′-octenyl)benzyl Alcohol (18). Silyl ether 17 (840 mg, 1.57
mmol) was dissolved in THF (70 mL), and the solution was
cooled to 0 °C. To this solution was added TBAF (4.6 mL, 1.00
M in THF), and the reaction was allowed to warm to rt and
after 1.5 h was quenched with satd NH4Cl. After extraction
with ethyl acetate, the combined organic extract was washed
with water and brine, dried over MgSO4, and concentrated in
vacuo to give a yellow oil. Final purification by flash chroma-
tography (4:1 hexanes/ethyl acetate) gave the diol 18 (352 mg,
96%): 1H NMR (CDCl3) δ 6.77 (s, 1H), 6.74 (s, 1H), 5.70 (s,
1H), 5.37 (t, J ) 7.3 Hz, 1H), 4.57 (d, J ) 5.5 Hz, 2H), 3.89, (s,
3H), 3.36 (d, J ) 7.3 Hz, 2H), 2.71 (t, J ) 6.2 Hz, 1H), 2.24-
2.12 (m, 2H), 1.74 (s, 3H), 1.68-1.62 (m, 3H), 1.27 (s, 3H), 1.25
(s, 3H); 13C NMR (CDCl3) δ 146.3, 142.8, 135.3, 132.1, 127.0,
122.7, 120.7, 107.5, 65.6, 64.3, 58.4, 56.0, 36.4, 27.8, 27.3, 24.8,
18.7, 16.1. Anal. Calcd for C18H26O4‚0.5H2O: C, 68.55; H, 8.63.
Found: C, 68.23; H, 8.53.
Diol 19. To a solution of epoxyphenol 18 (352 mg, 1.2 mmol)
in CH2Cl2 (40 mL) at 0 °C was added trifluoroacetic acid (0.26
mL, 3.4 mmol). The resulting solution was allowed to stir for
2 h, and Et3N (1.4 mL, 10.0 mmol) was added. After an
additional 30 min, water (75 mL) was added, the phases were
separated, and the aqueous phase was extracted with ethyl
acetate. The combined organic phase was washed with water
and brine, then dried (MgSO4), and concentrated. Final
purification by flash chromatography (2:1 to 1:1 hexanes/ethyl
acetate) afforded the tricyclic diol 19 (135 mg, 38%) as a light
yellow oil: 1H NMR (CDCl3) δ 6.73 (s, 1H), 6.70 (s, 1H), 4.57
(s, 2H), 3.86 (s, 3H), 3.39 (dd, J ) 11.6, 3.8 Hz, 1H), 2.69 (d, J
) 8.9 Hz, 2H), 2.15-2.04 (m, 2H), 1.88-1.59 (m, 6H, 2H
exchange with D2O), 1.23 (s, 3H), 1.08 (s, 3H), 0.87 (s, 3H);
13C NMR (CDCl3) δ 148.9, 142.1, 132.0, 122.5, 120.4, 108.5,
78.0, 76.8, 65.5, 56.0, 46.7, 38.3, 37.6, 28.3, 27.3, 23.1, 19.7,
14.2; HRMS (ESI) m/z calcd for C18H26O4 (M+) 306.1831, found
306.1823.
(S)-O-Methylmandelate 15. To a solution of diol 14 (3.65
g, 6.60 mmol), EDC (1.64 g, 8.60 mmol), and DMAP (0.83 g,
6.76 mmol) in CH2Cl2 (25 mL) was added (S)-(+)-O-methyl-
mandelic acid (1.15 g, 6.93 mmol). After 1 h at rt, water was
added and the resulting solution was extracted with CH2Cl2.
The combined organic phase was dried (MgSO4) and concen-
trated. Further purification by flash chromatography (4:1 to
3:1 hexanes/ethyl acetate) afforded the mandelate ester 15
(3.77 g, 82%) as a clear oil, along with a small amount of the
diastereomeric ester (not isolated): [R]26.4 ) +14.6 (c 0.10,
D
CHCl3); 1H NMR (CDCl3) δ 7.46 (dd, J ) 7.9, 1.8 Hz, 2H),
7.40-7.32 (m, 3H), 6.72 (s, 1H), 6.64 (s, 1H), 5.27 (t, J ) 8.0
Hz, 1H), 4.79 (s, 1H), 4.65 (s, 2H), 3.77 (s, 3H), 3.43 (s, 3H),
3.33 (d, J ) 7.9 Hz, 2H), 1.96 (t, J ) 8.0 Hz, 2H), 1.78-1.61
(m, 3H), 1.64 (s, 3H), 1.00 (s, 9H), 0.94 (s, 15H), 0.18 (s, 6H),
0.09 (s, 6H); 13C NMR δ 170.4, 149.7, 141.3, 136.5, 135.0, 133.7,
132.1, 129.0, 128.7 (2C), 127.2 (2C), 123.1, 119.0, 107.3, 82.6,
80.7, 72.3, 65.0, 57.3, 54.7, 35.0, 28.5, 28.1, 26.1 (3C), 26.0 (3C),
25.9, 24.6, 18.9, 18.4, 16.3, -3.9 (2C), -5.1 (2C); HRMS (ESI)
m/z calcd for C39H64O7Si2Na (M + Na)+ 723.4088, found
723.4090.
(R)-O-Methylmandelate 16. In a manner identical to that
described above for the preparation of ester 15, the diol 14
(38 mg, 0.07 mmol), EDC (20 mg, 0.1 mmol), and DMAP (10
mg, 0.08 mmol) were allowed to react with (R)-(-)-O-methyl
mandelic acid (12 mg, 0.07 mmol). Standard workup and final
purification by column chromatography (5:1 hexanes/ethyl
acetate) afforded the target ester 16 (41.5 mg, 82%) as a clear
oil along with the (R,R)-diastereomer (total yield of 100%). A
diastereomeric ratio of 84:16, corresponding to an initial ee of
68% for compound 14, was determined by integration of signals
1
at 5.00 and 5.27 ppm in the H NMR spectrum of the initial
mixture. Data for diastereomer 16: 1H NMR δ 7.46 (d, J )
8.7 Hz, 2H), 7.36-7.28 (m, 3H), 6.73 (s, 1H), 6.57 (s, 1H), 5.00
Aldehyde 20. To a solution of benzylic alcohol 19 (251 mg,
0.82 mmol) in CH2Cl2 (30 mL) was added MnO2 (1.71 g, 19.6
930 J. Org. Chem., Vol. 70, No. 3, 2005

Synthesis of Nonracemic 3-Deoxyschweinfurthin B
mmol) as a single aliquot. The resulting suspension was
allowed to stir for 26 h and then filtered through Celite, and
the residue was concentrated in vacuo to afford the aldehyde
allowed to warm to rt, a second aliquot of TEA (0.60 mL,
4.36 mmol) was added, and the reaction was stirred for
4 h. This solution was transferred via cannula into a
suspension of K2CO3 (2.35 g, 17.0 mmol) in MeOH (40
mL), and the resulting suspension was allowed to react
for 20 h. After filtration and extraction of the resulting
filtrate with ethyl acetate, the combined organic phase was
washed with brine, dried (MgSO4), and concentrated under
vacuum to afford a colorless oil. Final purification by flash
chromatography (12:1 hexanes/EtOAc) yielded the target
epoxide (R)-17 as a single enantiomer (0.91 g, 67%) as
20 as a white solid (249 mg, 100%): mp 160.5-162.0 °C; [R]25.0
D
) +97.8 (c 0.126, CHCl3); 1H NMR (CDCl3) δ 9.80 (s, 1H), 7.25
(s, 1H), 7.24 (s, 1H), 3.90 (s, 3H), 3.45 (dd, J ) 11.4, 3.8 Hz,
1H), 2.80-2.77 (m, 2H), 2.22-2.15 (m, 1H), 1.94-1.82 (m, 2H),
1.74-1.61 (m, 2H), 1.28 (s, 3H), 1.13 (s, 3H), 0.91 (s, 3H); 13
C
NMR δ 191.1, 149.5, 148.7, 128.7, 127.3, 122.5, 107.3, 78.4,
77.8, 56.0, 46.5, 38.4, 37.5, 28.2, 27.3, 23.0, 20.0, 14.3. HRMS
m/z calcd for C18H25O4 (M + H)+ 305.1753, found 305.1743.
Anal. Calcd for C18H24O4‚H2O: C, 67.06; H, 8.13. Found: C,
66.98; H, 8.17.
a viscous colorless oil: [R]26.4 ) +0.83 (c 0.18, CHCl3);
D
1
both H and 13C spectra were identical to those of racemate
3-Deoxydimethoxymethylschweinfurthin B (21). A
suspension of NaH (29 mg, 1.2 mmol) and 15-crown-5 (4 µL,
0.02 mmol) in THF (1.5 mL) was cooled to 5 °C. To this were
added aldehyde 20 (10 mg, 0.03 mmol) and phosphonate 5 (22
mg, 0.05 mmol) in THF (2 mL). The mixture was allowed to
warm to rt and stirred for a total of 18 h. Water was added
dropwise, and the solution was extracted with ether. The
resulting organic phase was washed with brine, dried over
MgSO4, and concentrated in vacuo. Final purification by
column chromatography (3.5:1 to 1:1 hexanes/ethyl acetate)
gave the stilbene 21 (15.2 mg, 80%) as a straw-colored oil: 1H
NMR (CDCl3) δ 6.95-6.85 (m, 6H), 5.24 (s, 4H), 5.24 (t, 1H,),
5.07 (t, J ) 11.7 Hz, 1H), 3.89 (s, 3H), 3.50 (s, 6H), 3.40 (m,
3H), 2.72 (d, J ) 8.7 Hz, 2H), 2.16-1.85 (m, 7H), 1.79 (s, 3H),
1.70-1.65 (m, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.26 (s, 3H), 1.10
(s, 3H), 0.89 (s, 3H); 13C NMR (CDCl3) δ 155.9 (2C), 148.9,
142.5, 136.7, 134.6, 131.2, 128.9, 128.2, 126.4, 124.3, 122.6,
122.5, 120.5, 119.5, 106.8, 105.9 (2C), 94.5 (2C), 78.1, 77.0, 55.9
(2C), 55.9, 46.7, 39.8, 38.4, 37.7, 28.3, 27.3, 26.7, 25.6, 23.1,
22.7, 19.8, 17.6, 16.0, 14.3; HRMS (ESI) m/z calcd for C39H54O7
(M+) 634.3870, found 634.3871.
10 and enantioenriched compound 17.
Tricyclic Diol (R,R,R)-19. Silyl ether (R)-17 (936 mg, 1.75
mmol) was dissolved in THF (15 mL), and the solution was
cooled to 0 °C. To this solution was added TBAF (5.4 mL, 1.0
M in THF), and the reaction was allowed to warm to rt and
after 2.5 h was quenched with satd NH4Cl. After extraction
with ethyl acetate, the combined organic extract was washed
with brine, dried (MgSO4), and concentrated in vacuo to give
a yellow oil. This oil (430 mg, 1.4 mmol) was dissolved in
CH2Cl2 (60 mL) at 0 °C, and trifluoroacetic acid (0.3 mL, 3.89
mmol) was added. The resulting solution was allowed to stir
5 h, and then Et3N (0.7 mL, 5.09 mmol) was added. After an
additional 1 h, water (20 mL) was added, the phases were
separated, and the aqueous phase was extracted with CHCl3.
The combined organic phase was washed with brine, then
dried (MgSO4), and concentrated. Final purification by flash
chromatography (2:1 to 1:1 hexanes/EtOAc) afforded the
tricyclic diol (R,R,R)-19 (177 mg, 33% from epoxide (R)-17) as
a light yellow oil: [R]26.4 ) +38.8 (c 0.03, CHCl3); spectral
D
data were identical to those of the enantioenriched diol 19.
Aldehyde (R,R,R)-20. To a solution of benzylic alcohol
(R,R,R)-19 (118 mg, 0.4 mmol) in CH2Cl2 (15 mL) was added
MnO2 (954 mg, 11.0 mmol) as a single aliquot. The resulting
suspension was allowed to stir for 19 h and then filtered
through Celite, and the residue was concentrated in vacuo to
give a yellow solid. Final purification by flash chromatography
(3:1 hexane/EtOAc) gave the aldehyde (R,R,R)-20 as a white
solid (74 mg, 62%): [R]D ) +159 (c 0.012, CHCl3); the spectral
data were identical to those of the enantioenriched aldehyde
20.
3-Deoxyschweinfurthin B (22). To a solution of stilbene
21 (24 mg, 0.04 mmol) in MeOH (2 mL) was added camphor-
sulfonic acid (10 mg, 0.04 mmol). The resulting solution was
stirred at rt for 20 h and then heated to 60 °C for an additional
5 h. The reaction was quenched by addition of satd NaHCO3
and extracted with ethyl acetate, and the organic phase was
washed with brine and dried over MgSO4. Concentration in
vacuo, followed by final purification by column chromatogra-
phy (1:1 hexanes/ethyl acetate), afforded 22 (16 mg, 79%) as
a clear oil: 1H NMR (CDCl3) δ 6.83 (m, 4H), 6.55 (s, 2H), 5.31
(s, 1H), 5.28 (t, J ) 6.9 Hz, 1H), 5.06 (m, 1H), 3.88 (s, 3H),
3.43 (m, 3H), 2.72 (d, J ) 9.1 Hz, 2H), 2.15-2.06 (m, 5H),
1.90-1.82 (m, 3H), 1.82 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.25
(s, 3H), 1.10 (s, 3H),0.88 (s, 3H); 13C NMR (CDCl3) δ 155.2 (2C),
148.9, 142.7, 139.2, 137.1, 132.1, 128.8, 128.6, 125.7, 124.2,
122.6, 121.4, 120.6, 112.8, 107.0, 106.2 (2C), 78.0, 77.1, 55.0,
46.8, 39.7, 38.4, 37.6, 28.3, 27.3, 26.4, 25.7, 23.1, 22.5, 19.8,
17.7, 16.2, 14.3; HRMS (ESI) m/z calcd for C35H46O5 (M+)
546.3345, found 546.3342.
(-)-3-(3′,7′-Dimethyl-2-octen-6′(S),7′-diol)-4-(tert-bu-
tyl-dimethylsiloxy)-5-methoxybenzyloxy]-tert-butyldi-
methylsilane ((S)-14). To a solution of mandelate ester 15
(203 mg, 0.29 mmol) in EtOH (10 mL) was added NaOH (0.63
mL, 0.63 mmol, aq, 1 M). After 5 h at rt, HCl (0.63 mL, 0.063
mmol, aq, 1 M) was added and the mixture was extracted with
ethyl acetate. The combined organic phase was washed with
water and brine, then dried (MgSO4), and concentrated in
vacuo to give a slightly yellow oil. Purification by column
chromatography (1:1 hexanes/EtOAc) afforded the diol (S)-14
(132 mg, 83%) as a colorless oil: [R]26.4D ) -9.6 (c 0.03, CHCl3);
spectral data were identical to those of the enantioenriched
diol 14.
3-(3′,7′-Dimethyl-2-octen-6′(R),7′-diol)-4-(tert-butyldi-
methylsiloxy)-5-methoxybenzyloxy]-tert-butyldimethyl-
silane ((R)-14). To a solution of AD-mix-â (8.57 g) in water/
t-BuOH (100 mL, 1:1) was added methanesulfonamide (0.62
g), and the solution was cooled to 0 °C. The geranylated arene
9 (3.19 g, 6.15 mmol) was added via syringe as a neat oil, and
the solution was kept at 0 °C for 20 h. Solid Na2SO3 was added,
and the solution was stirred for 1 h. The solution was extracted
with EtOAc, and the resulting organic layer was washed with
2 N NaOH and brine, then dried (MgSO4), and concentrated
in vacuo to afford a clear oil. Final purification by column
chromatography (1:1 hexanes/EtOAc) gave the diol (R)-14 (1.97
g, 58%) as a clear oil: [R]25.0D ) +8.5 (86% ee) (c 0.223, CHCl3);
1
both H and 13C NMR spectra were identical to those of diol
(S)-14.
Acknowledgment. Financial support from the Breast
Cancer Research Program (Grants DAMD17-01-1-0276
and DAMD17-02-1-0423) and the University of Iowa
Graduate College is gratefully acknowledged.
(+)-[4-(tert-Butyldimethylsilyloxy)-5-methoxy-3-(3′,7′-
dimethyl-6(R′)-epoxy-2′-octenyl)benzyloxy-tert-butyl-
dimethylsilane ((R)-17). To a solution of diol (S)-14 (1.41
g, 2.56 mmol), in CH2Cl2 (20 mL) at 0 °C, was added
TEA (1.05 mL, 7.64 mmol) followed 50 min later by MsCl
(0.27 mL, 3.50 mmol). After 45 min, the reaction was
Supporting Information Available: General experimen-
tal procedures and 1H and 13C NMR spectra for compounds
13, 15, 16, and 18-22 (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JO048444R
J. Org. Chem, Vol. 70, No. 3, 2005 931