Exploration of Cascade Cyclizations Terminated by Tandem Aromatic Substitution: Total Synthesis of (+)-Schweinfurthin A

Article abstract of DOI:10.1021/jo1022102

The termination of epoxide-initiated cascade cyclizations with a range of "protected" phenols is described. When the protecting group can be lost as a stabilized electrophile, the cascade process continues beyond ring closure to afford products which have undergone a tandemelectrophilic aromatic substitution. A number of groups have proven viable in this process and the regiochemistry of their substitution reactions has been studied. Application of this methodology in the first total synthesis of (+)-schweinfurthin A, a potent antiproliferative agent, has been achieved.

Full text of DOI:10.1021/jo1022102

pubs.acs.org/joc
Exploration of Cascade Cyclizations Terminated by Tandem Aromatic
Substitution: Total Synthesis of (þ)-Schweinfurthin A
Joseph J. Topczewski, John G. Kodet, and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States
david-wiemer@uiowa.edu
Received November 10, 2010
The termination of epoxide-initiated cascade cyclizations with a range of “protected” phenols is
described. When the protecting group can be lost as a stabilized electrophile, the cascade process
continues beyond ring closure to afford products which have undergone a tandem electrophilic aromatic
substitution. A number of groups have proven viable in this process and the regiochemistry of their
substitution reactions has been studied. Application of this methodology in the first total synthesis of
(þ)-schweinfurthin A, a potent antiproliferative agent, has been achieved.
Introduction
polyene cyclizations and recent studies have led to many
significant advances in novel modes of cascade initiation.13-25
In contrast, very little has been done to extend cationic cascade
cyclizations beyond terminal ring closure.
Our group has been interested in epoxide initiated cascade
cyclizations as they pertain to the formation of hexahydro-
xanthene and particularly as they apply to synthesis of the
schweinfurthins.26-31 Previous studies have shown that
“MOM-protected” phenols are sufficiently nucleophilic to
terminate a cascade sequence (e.g., conversion of epoxide 1
As the field of organic synthesis has evolved, the laboratory
synthesis of ever more complex natural products has become
feasible.1-3 For such syntheses to be practical, however, it is
very helpful to assemble multiple bonds in a single transforma-
tion, and in this context catalytically driven tandem4 or
cascade reactions can be particularly appealing.5-10 Epoxides
have proven their utility as cascade components6-9 and argu-
ably one of the most powerful cascade classes is based upon
epoxide initiated, cationic polyene cyclizations.10-12 Although
pioneering descriptions of such cascade cyclizations were set
forth in the 19500s,10-12 modern chemists continue to explore
(13) Nelsen, D. L.; Gagne, M. R. Organometallics 2009, 28, 950–952.
(14) Mullen, C. A.; Campbell, A. N.; Gagne, M. R. Angew. Chem., Int.
Ed. 2008, 47, 6011–6014.
(15) Mullen, C. A.; Gagne, M. R. J. Am. Chem. Soc. 2007, 129, 11880–
11881.
(16) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
5027–5029.
(17) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48, 7899–
7903.
(18) Zhao, Y.; Serena, L.; Li, B.; Li, S.; Loh, T. Chem. Commun. 2009,
3738–3740.
(1) Nicolaou, K. C.; Sorensen, E. J. In Classics in Total Synthesis:
Targets, Strategies, Methods; Wiley-VCH: New York, 1996; Vol. 1, p 821.
(2) Nicolaou, K. C.; Snyder, S. A. In Classics in Total Synthesis II: More
Targets, Strategies, Methods; Wiley-VCH: New York, 2003; Vol. 1, p 658.
(3) Corey, E. J.; Cheng, X. In The Logic of Chemical Synthesis; Wiley-
Interscience: New York, 1995; Vol. 1, p 436.
(4) Many reaction sequences have been combined in tandem or domino
processes, cf.: Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
(5) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134–7186. (b) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A.
Chem. Commun. 2003, 551–564.
(19) Zhao, Y.; Loh, T. Chem. Commun. 2008, 1434–1436.
(20) Zhao, Y.; Loh, T. J. Am. Chem. Soc. 2008, 130, 10024–10029.
(21) Zhao, Y.; Chng, S.; Loh, T. J. Am. Chem. Soc. 2007, 129, 492–493.
€
(22) Gansauer, A.; Justicia, J.; Rosales, A.; Worgull, D.; Rinker, B.;
(6) Rolfe, A.; Samarakoon, T. B.; Hanson, P. R. Org. Lett. 2010, 12,
1216–1219.
(7) Smith, A. B.; Kim, W.; Tong, R. Org. Lett. 2010, 12, 588–591.
(8) Smith, A. B.; Tong, R. Org. Lett. 2010, 12, 1260–1263.
(9) Smith, A. B.; Xian, M. J. Am. Chem. Soc. 2006, 128, 66–67.
(10) Johnson, W. S. Acc. Chem. Res. 1968, 1, 1–8.
Cuerva, J. M.; Oltra, J. E. Eur. J. Org. Chem. 2006, 2006, 4115–4127.
(23) Kumazawa, K.; Ishihara, K.; Yamamoto, H. Org. Lett. 2004, 6,
2551–2554.
(24) Franck-Neumann, M.; Geoffroy, P.; Hanss, D. Tetrahedron Lett.
2002, 43, 2277–2280.
(25) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900–903.
(26) Treadwell, E. M.; Neighbors, J. D.; Wiemer, D. F. Org. Lett. 2002, 4,
3639–3642.
(11) Johnson, W. S. Tetrahedron 1991, 47, xi–l.
(12) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730–4756.
DOI: 10.1021/jo1022102
r
Published on Web 01/12/2011
J. Org. Chem. 2011, 76, 909–919 909
2011 American Chemical Society

Topczewski et al.
SCHEME 1. Cascade Cyclization Routes to Hexahydrox-
anthenes
JOCArticle
to hexahydroxanthene 2, Scheme 1), and also have discovered
that the MOM group could be transferred to the A-ring
hydroxyl group during the cyclization (e.g., yielding com-
pound 3).29 If transfer of the MOM group is the result of a
transient electrophilic species, then one might envision other
applications of this electrophile.32 In an initial report on the
extension of this cascade process,33 our lab demonstrated that
a MOM group can be transferred to an adjacent aromatic ring
with high efficiency. This represents a cationic cascade ulti-
mately terminated with a tandem electrophilic aromatic sub-
stitution reaction (e.g., cyclization of epoxide 4 to compound 5).
In this initial example, the reaction sequence continues beyond
ring closure to electrophilic aromatic substitution, and a new
carbon-carbon bond is the result. That tandem process
allowed a highly efficient synthesis of (þ)-angelichalcone.33
The genesis of the present work resides in the concept that a
new tandem cascade sequence might be used in the synthesis of
several schweinfurthins via a single late stage intermediate.
This report describes (1) issues of regioselectivity that arise
during application of the MOM-based cascade cyclization/
aromatic substitution process, (2) exploration of tandem
cascade cyclization/aromatic substitution with other “protect-
ing” groups, and (3) application of a new tandem cascade
cyclization/aromatic substitution sequence to the formal
synthesis of schweinfurthins B, E, F, and G, and the first total
synthesis of (þ)-schweinfurthin A.29,30,34,35
this starting material would require demethylation early in the
sequence. In an effort to develop a more versatile late-stage
intermediate, a tantalizing synthetic proposal exploiting cas-
cade cyclization terminated by electrophilic aromatic substi-
tution33 was envisioned to allow a diversity oriented synthesis
(Scheme 2). This approach would be based upon a tandem
cascade cyclization/aromatic substitution of the “MOM-
protected” epoxide 6 to obtain the hexahydroxanthene 7
followed by elaboration of the benzylic position at C-5 to
phenolic functionality via standard oxidation protocols. If an
efficient route could be developed, the intermediate 8 would
represent a single keystone intermediate that could be con-
verted into both C-5 hydroxy- and methoxy-substituted
schweinfurthins (Scheme 2) as well as new analogues.
Results and Discussion
Several schweinfurthins and numerous analogues have been
prepared through synthesis,27,29,30 but one of the most potent
congeners34,35 of the natural family (schweinfurthin A, 9) has
remained elusive until now. As part of an ongoing program to
determine their mode of action as antiproliferative agents,36-38
we have attempted to optimize access to a key intermediate en
route to schweinfurthin A. Previous work has utilized vanillin
as an inexpensive, commercial starting material.26,27,30 This
reagent fits especially well into syntheses of schweinfurthin B,
E, and F (10-12), where the methoxy group derived from
vanillin remains on the C-5 position of the natural products,
but for synthesis of schweinfurthin A or G (9 and 13) the use of
To explore this possibility, methyl 4-hydroxybenzoate (14)
was elaborated rapidly to the requisite R epoxide 15 by
standard methods (Scheme 3).39,40 To our delight, when
compound 15 was treated with BF3 OEt2 under standard
3
cyclization conditions, the major product obtained had under-
gone both cyclization and electrophilic aromatic substitution.
Unfortunately, even though the hexahydroxanthene 16 was
obtained in reasonable yield as a single stereo- and regioi-
somer, efforts directed at further elaboration met with limited
success. While oxidation, hydrolysis, and substitution reac-
tions demonstrated high regioselectivity, they uniformly fa-
vored the benzylic position para to the hexahydroxanthene
oxygen, rather than the position ortho. Thus, for example,
treatment of compound 16 with excess DDQ afforded the
single aldehyde 17 in nearly quantitative yield.
(27) Neighbors, J. D.; Beutler, J. A.; Wiemer, D. F. J. Org. Chem. 2005,
70, 925–931.
(28) Neighbors, J. D.; Mente, N. R.; Boss, K. D.; Zehnder, D. W., II;
Wiemer, D. F. Tetrahedron Lett. 2008, 49, 516–519.
(29) Mente, N. R.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2008,
73, 7963–7970.
(30) Topczewski, J. J.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem.
2009, 74, 6965–6972.
(31) Neighbors, J. D.; Topczewski, J. J.; Swenson, D. C.; Wiemer, D. F.
Tetrahedron Lett. 2009, 50, 3881–3884.
(32) Kartika, R.; Frein, J. D.; Taylor, R. E. J. Org. Chem. 2008, 73, 5592–
5594.
(33) Topczewski, J. J.; Callahan, M. P.; Neighbors, J. D.; Wiemer, D. F.
J. Am. Chem. Soc. 2009, 131, 14630–14631.
(34) Beutler, J. A.; Jato, J. l. C., G.; Wiemer, D. F.; Neighbors, J. D.;
Salnikova, M. S.; Hollingshead, M.; Scudiero, D. A.; McCloud, T. G.
Medicinal and Aromatic Plants. In The Schweinfurthins: Issues in Develop-
ment of a Plant-Derived Anticancer Lead; Bogers, R. J., Ed.; Springer:
New York, 2006; pp 301-309.
In an effort to sway this natural selectivity through mod-
ification of steric or electronic factors, a more extended
sequence was pursued. Reduction of aldehyde 17 and protec-
tion of the resulting alcohol was readily accomplished and
allowed preparation of a variety of protected alcohols. Of
those prepared, including the Boc derivative, the p-nitrobenzo-
ate ester, the MOM acetal, and the TBS ether, only derivatives
with acyl groups were found to allow preparation of the
desired C-5 aldehyde. For example, after preparation of the
Boc derivative 18 or the p-nitrobenzoate 19, subsequent reac-
tion with DDQ gave the desired aldehydes 20 and 21 in ∼75%
yield. While this longer sequence allowed preparation of the
desired aldehyde regioisomer, the incompatibility of carbonyl-
containing substituents with the organolithium intermediate
(35) Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. J. Nat.
Prod. 1998, 61, 1509–1512.
(36) Topczewski, J. J.; Kuder, C. H.; Neighbors, J. D.; Hohl, R. J.;
Wiemer, D. F. Bioorg. Med. Chem. 2010, 18, 6734–6741.
(37) Ulrich, N. C.; Kuder, C. H.; Hohl, R. J.; Wiemer, D. F. Bioorg. Med.
Chem. Lett. 2010, 20, 6716–6720.
(39) Basabe, P.; Diego, A.; Delgado, S.; Dıez, D.; Marcos, I. S.; Urones,
´
J. G. Tetrahedron 2003, 59, 9173–9177.
(40) See the Supporting Information.
(38) Kuder, C. H.; Neighbors, J. D.; Hohl, R. J.; Wiemer, D. F. Bioorg.
Med. Chem. 2009, 17, 4718–4723.
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SCHEME 2. Synthetic Plan for a Divergent Route to the Schweinfurthins
SCHEME 3. Synthesis and Regioselective Oxidation of Compound 16
necessary for the synthesis of epoxide 15 rules out early
introduction of these protecting groups. Given the inherent
impracticality and nonideality41-43 of the oxidation/reduction
and protection/deprotection sequences described above, it
became prudent to explore alternative approaches. On the
basis of the hypothesis that an ortho-selective differentiation of
the benzylic positions could be accomplished if a group other
than the MOM acetal were induced to undergo a cascade
cyclization/electrophilic aromatic substitution, this process
was examined with other phenolic substituents.
groups undergo parallel cascade cyclization/aromatic substi-
tution reactions. The BOM (23), SEM (24), and MEM (25)
derivatives all favored formation of the substituted products
29a-31a in yields comparable to that observed in the MOM
case (28a).33 All of these products were obtained as single
diastereo- and regioisomers. Furthermore, when a competition
reaction was conducted with a 1:1 mixture of compounds 23
and 24, the major products were compounds 29a and 30a, both
were found in yields comparable to those for the individual
experiments, and no evidence for a crossed product was
detected. The pivaloyloxymethyl (or POM) group, which
features an acyloxy rather than an alkoxy substituent, was
resistant to a complete cascade cyclization and the reaction of
compound 26 instead gave the bridged ether 32c as the only
major product.44-49 The surprising case in this series was the
cyclization involving the 4-chlorophenoxymethyl group (27),
which arose from commercially available R,4-dichloroanisole.
Exploration of Cascade Cyclizations Terminated with Aro-
matic Substitution. Because it contains unsubstituted ortho
and para positions and because it is readily available,33
4-geranylresorcinol was used as the starting point to explore
the viability of different phenolic substituents in cascade
cyclization/aromatic substitution reactions. Numerous race-
mic epoxides bearing different groups at the phenolic oxygens
(22-27) were prepared by standard methods and then treated
with BF3 OEt2 under typical cyclization conditions.33 Because
3
(44) Tsangarakis, C.; Arkoudis, E.; Raptis, C.; Stratakis, M. Org. Lett.
2007, 9, 583–586.
the electrophilic species generated from the previously employed
MOM acetal would be stabilized by the adjacent heteroatom,
other acetals of similar structures were explored first (Table 1).
As one might predict, other common alkoxymethyl protecting
(45) Janusz, J. M.; Gardlik, J. M.; Young, P. A.; Burkes, R. V.; Stoll, S. J.;
Estelle, A. F.; Riley, C. M. J. Med. Chem. 1990, 33, 1052–1061.
(46) Aziz, M.; Rouessac, F. Tetrahedron 1988, 44, 101–110.
(47) Yamada, Y.; Sanjoh, H.; Iguchi, K. J. Chem. Soc., Chem. Commun.
1976, 997–998.
(48) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Mar Herrador, M.;
Alvarez-Manzaneda, R.; Quilez, J.; Chahboun, R.; Linares, P.; Rivas, A.
Tetrahedron Lett. 1999, 40, 8273–8276.
(49) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Palomino, P. L. Tetra-
hedron 1994, 50, 13239–13250.
(41) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657–4673.
(42) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009, 42,
530–541.
(43) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193–205.
J. Org. Chem. Vol. 76, No. 3, 2011 911

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TABLE 1. Cyclizations of Alkoxymethyl-Substituted Phenolsa
entry
substrate (R =)
common abbreviation
% yield of ab
% yield of bb
30 (28b)
% yield of cb
133
2
3
4
5
6
CH3 (22)
Bn (23)
CH2CH2TMS (24)
CH2CH2OCH3 (25)
C(O)C(CH3)3 (26)
4-ClC6H4 (27)
MOM
BOM
SEM
MEM
POM
52 (28a)
62 (29a)
57 (30a)
53 (31a)
28 (31b)
56 (33b)
47 (32c)
37 (33c)
aSee the Supporting Information for experimental details. bIsolated yields.
This reaction provided compound 33b as the major product
and none of compound 33a was isolated. Because all of the
other substrates in Table 1 favored formation of either the a- or
c-type products, this is unique among the groups surveyed. The
use of secondary acetals was less productive under standard
conditions,40 and the modest mass balance reflected in the
isolated yields for some of these cyclizations may result from
formation of trace amounts of the b-type structure as well as
any of several epoxide rearrangement pathways.12,31,50
Other common protecting groups also were explored, includ-
ing the acetate (34), benzoate, and Boc protected compounds.
In all of these cases, however, the major products were the
bridged A-ring ethers as shown for the acetate 35 (Figure 1).40
This type of structure has been observed in several earlier studies
and in some natural products.44-49,51,52 A crystalline sample of
the product 35 was subjected to X-ray diffraction analysis to
assign the relative configuration unambiguously, and acetate 35
was found to have an exo (trans) structure. On this basis, the
structures of the parallel products from cyclization of the
benzoate and Boc derivatives were assigned analogous
stereochemistry.20,40,53
FIGURE 1. ORTEP of compound 35.
expect, addition of withdrawing or donating groups to modify
electron density at the benzylic position leads to stark differ-
ences in the product distribution (Table 2). With the parent
system, benzyl ether 39, standard reaction conditions afforded
the product of the tandem process as the major product (47a),
along with a significant amount of the cascade-only product
47b. A trace of the para-substituted product 47d was found in
this reaction, which marks the first observation of electrophilic
aromatic substitution at the para position during the cascade
process. Addition of an electron-withdrawing 4-nitro substi-
tuent to the phenyl ring (38) resulted in an unusually compli-
cated reaction mixture, and the bridged ether 46c was the only
significant product found. While reaction of the 2-bromophe-
nyl derivative 40 gave a much less complicated reaction
mixture, again only the bridged product (48c) was observed.
In contrast, addition of an electron-donating 4-methoxy sub-
stituent (41) resulted in cascade cyclization/aromatic substitu-
tion to afford the ortho product 49a, but a significant amount
of the para regioisomer 49d also was observed. Further
increasing the electron density of the aromatic system with the
trimethoxybenzyl group (42) completely reversed the ortho
regioselectivity, and only substitution at the para position was
observed (50d) along with the cascade-only product (50b).
Finally, the 3-furyl group was examined as a representative
case of a heteroaryl system because it is found as a component
of numerous natural terpenoids.54-57 The furan derivative 43
The tandem cascade cyclization/aromatic substitution pro-
cess then was explored with various alkyl groups as the phenol
substituents (36-43, Table 2). Not surprisingly, the methyl
compound 36 gave bridged ether 44c as the major product. The
allyl derivative 37, which would add stabilization to the pre-
sumed intermediate through π delocalization, proved more
interesting. Exposure of the diallyl epoxide 37 to BF3 OEt2
3
resulted in a mixture of products, with the bridged ether 45c
predominating, and the cyclization/aromatic substitution pro-
duct (45a) isolated as a minor component. This suggests that a
group that could provide at least some stabilization to a formal
cation is required for a tandem cascade cyclization/aromatic
substitution process to occur.
To strengthen a hypothesis regarding the impact of the
displaced electrophile’s stability on the results of cascade
cyclization/aromatic substitution reactions, several benzyl
groups with varied substituents were examined. As one might
(50) Fish, P. V.; Sudhakar, A. R.; Johnson, W. S. Tetrahedron Lett. 1993,
34, 7849–7852.
(51) Marco, J. A.; Sanz, J. F.; Yuste, A.; Carda, M.; Jakupovic, J.
Phytochemistry 1991, 30, 3661–3668.
(52) Xu, Y.; Lai, Y.; Imiyabir, Z.; Goh, S. J. Nat. Prod. 2001, 64, 1191–
1195.
(53) Zhao, Y.; Loh, T. Org. Lett. 2008, 10, 2143–2145.
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TABLE 2. Cascade Cyclization/Aromatic Substitution of Alkyl-Substituted Phenolsa
entry
substrate (R =)
H (36)
CHdCH2 (37)
4-NO2C6H4 (38)
C6H5 (39)
2-BrC6H4 (40)
4-CH3OC6H4 (41)
3,4,5-trimethoxyphenyl (42)
3-furyl (43)
% yield of ab
% yield of bb
18 (47b)
% yield of cb
% yield of db
1
2
3
4
5
6
7
8
72 (44c)
32 (45c)
20 (46c)
8 (45a)
43 (47a)
33 (49a)
49 (51a)
2 (47d)
49 (48c)
12 (49b)c
41 (50b)d
19 (49d)
28 (50d)
aSee the Supporting Information for experimental details. bIsolated yields. cIsolated as the A-ring PMB ether. dIsolated as the A-ring alcohol (32%)
and A-ring ether (9%).
was found to undergo cascade cyclization/aromatic substitu-
tion and afford compound 51a as the major product. Thus it
appears that a variety of neutral or electron-rich arenes will
afford a major product that has undergone cascade cycliza-
tion/aromatic substitution, but as the ability of the arene to
stabilize a benzylic cation increases, less regioselectivity is
observed. Ultimately, if there is minimal stabilization for a
benzylic cation, the cascade process stops at the A-ring bridged
ethers.
SCHEME 4. A Possible Mechanistic Picture
On the basis of the observations described above, at least a
partial mechanistic picture of this process can be offered
(Scheme 4). Initial complexation of BF3 to the epoxide oxygen,
generalized as structure 52, could be followed by a cascade
cyclization to the oxonium ion 53.58,59 If loss of the primary
alkyl group from the oxonium ion would afford an unstabi-
lized carbocation (e.g., a methyl group), then the reaction may
continue through the tertiary carbocation 54 instead. In this
case, attack of the A-ring oxygen on the tertiary cation would
explain formation of ether 55. The bridged ether 55 would have
the stereochemistry shown, as found in the diffraction analysis
of compound 35, because the C-60 stereochemistry is set in the
original epoxide and the C-20 stereochemistry would be estab-
lished through the chair-chair transition state11,12,27 that leads
to oxonium ion 53. If oxonium ion 53 instead undergoes loss of
a semistabilized or highly stabilized carbocation, the adjacent
arene may serve as a Lewis base and quickly trap this electro-
phile. This sequence would rapidly afford a π complex such as
structure 56. This branch of the reaction manifold would be
consistent with the lack of crossover products observed in
earlier studies with isotopically labeled MOM groups,33 as well
as the fidelity observed in the competition experiment with
compounds 23 and 24. Rapid formation of an ipso complex
would be expected for any relatively short-lived cationic
species (e.g., allyl or BOM), which would lead to the proximal
substitution product at C-2. In the case of longer-lived cationic
species, partial diffusion would lead to formation of the distal
ipso complex and subsequently substitution at C-6. Finally, in
those cases where dissociation of the oxonium ion 53 gives the
longest lived cations (e.g., trimethoxybenzyl) a greater percen-
tage of the unsubstituted hexahydroxanthene product would
be more likely.
(54) Savona, G.; Bruno, M.; Piozzi, F.; Barbagallo, C. Phytochemistry
1982, 21, 2132–2133.
(55) Ono, M.; Sawamura, H.; Ito, Y.; Mizuki, K.; Nohara, T. Phyto-
chemistry 2000, 55, 873–877.
(56) Prisinzano, T. E. J. Nat. Prod. 2009, 72, 581–587.
(57) Shults, E. E.; Velder, J.; Schmalz, H.-G.; Chernov, S. V.; Rubalova,
T. V.; Gatilov, Y. V.; Henze, G.; Tolstikov, G. A.; Prokop, A. Bioorg. Med.
Chem. Lett. 2006, 16, 4228–4232.
(58) Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc.
2008, 130, 16864–16866.
(59) Mascal, M.; Hafezi, N.; Toney, M. D. J. Am. Chem. Soc. 2010, 132,
10662–10664.
Taken together, these results indicate that the cascade
cyclization/aromatic substitution is a general process for those
cases where the phenolic substituent can form a reasonably
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SCHEME 5. Formal Synthesis of Schweinfurthins B, E, F, and G
stabilized carbocation. With a touch of reflection, it should be
clear that this process is a powerful strategy: this tandem
reaction sequence closed two rings, generated two additional
stereogenic centers with complete control of the relative ster-
eochemistry, and forged a new functionalized carbon-carbon
bond in a single operation. In addition, this cascade sequence
has proven its viability in forming new benzylic positions with a
range of substituent groups. With this improved understanding
of the scope of this process, application of a tandem cascade
cyclization/aromatic substitution sequence to a schweinfurthin
synthesis was reexamined.
Baeyer-Villiger oxidation60 with m-CPBA and hydrolysis of
the resultant formate provided phenol 65 in excellent yield.
This reaction sequence extends cascade cyclization/aromatic
substitution strategy to allow the introduction of the C-5
phenol central to the schweinfurthins. In fact, phenol 65 serves
as the keystone divergent intermediate which intersects most of
the previously synthesized schweinfurthins. Alkylation of
phenol 65 with either methyl iodide or MOMCl proceeded
with excellent selectivity to afford intermediates 66 and 67,
respectively. The synthesis of compound 66 constitutes a for-
mal synthesis of schweinfurthins B, E, and F as well as most of
the presently known schweinfurthin analogues.27,29,30,36,38,61-63
In a similar sense, preparation of compound 67 accomplishes a
formal synthesis of schweinfurthin G.29 More importantly, the
ready availability of compound 67 has provided the means to
pursue the synthesis of the parent compound in this family,
(þ)-schweinfurthin A.
Application to the Synthesis of Schweinfurthins A, B, E, F,
and G. Application of the cascade cyclization/aromatic sub-
stitution strategy to the synthesis of key intermediates en route
to schweinfurthins now could proceed as shown in Scheme 5.
The expanded scope of the tandem reaction sequence was
exploited to differentiate the newly generated benzylic position
at C-5 from the original benzyl methyl ether at an early stage in
the synthesis (vide supra). To accomplish this objective, a BOM
acetal was chosen as the phenolic substituent, because of both
its commercial availability and the assumption that the benzyl
ether could be selectively cleaved by hydrogenolysis late in the
synthesis. The synthetic sequence was initiated with bromina-
tion of 4-hydroxybenzoate (58) followed by BOM protection.
Reduction of the intermediate ester and methylation all pro-
ceeded smoothly to afford arene 59 in high overall yield on a
50 g scale. Halogen metal exchange, transmetalation, and
addition of (R)-6,7-epoxygeranyl bromide (up to 93% ee)28,29
afforded epoxide 60 in excellent yield, again on a multigram
scale. The crucial cascade cyclization/aromatic substitution
proceeded smoothly to afford the desired tricycle 62 along with
the unsubstituted analogue 61 (which had been obtained earlier
from reaction of the corresponding MOM compound).
Although compounds 61 and 62 were obtained as an insepar-
able mixture, each was a single regio- and diastereoisomer.
Separation of these products was readily accomplished after
selective hydrogenolysis, which afforded the benzylic alcohol
63 and recovered hexahydroxanthene 61, provided the reaction
was monitored frequently. With excessive hydrogen pressure
or extended reaction duration, over reduction was observed.
Once alcohol 63 was in hand, installation of the requisite C-5
phenol proceeded smoothly (Scheme 5). Chemoselective oxi-
dation of benzyl alcohol 63 to the corresponding aldehyde 64
was accomplished upon treatment with MnO2. Subsequent
With gram amounts of intermediate 67 now in hand, the
total synthesis of (þ)-schweinfurthin A was pursued (Scheme
6).30 Intermediate 67 was oxidized with TPAP/NMO64 to
provide the new ketone 68. Condensation of ketone 68 with
benzaldehyde provided enone 69, which was to be utilized as a
latent carbonyl group.65,66 Reduction proceeded smoothly
under Luche conditions67 to afford alcohol 70 in excellent
yield. The relative stereochemistry was assigned based on
consideration of models and precedence,30 and ultimately
was confirmed by comparison of the final product to natural
material. Alcohol 70 was subjected to Upjohn dihydroxy-
lation68 to provide triol 71. Subsequent glycolytic cleavage
was accomplished in a separate step upon reaction with
NaIO4. This reaction was highly selective for cleavage of the
exocyclic diol, and provided ketone 72 in very good yield. In
(60) Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625–3633.
(61) Mente, N. R.; Wiemer, A. J.; Neighbors, J. D.; Beutler, J. A.; Hohl,
R. J.; Wiemer, D. F. Biorg. Med. Chem. Lett. 2007, 17, 911–915.
(62) Ulrich, N. C.; Kodet, J. G.; Mente, N. R.; Kuder, C. H.; Beutler,
J. A.; Hohl, R. J.; Wiemer, D. F. Bioorg. Med. Chem. 2010, 18, 1676–1683.
(63) Neighbors, J. D.; Salnikova, M. S.; Beutler, J. A.; Wiemer, D. F.
Biorg. Med. Chem. 2006, 14, 1771–1784.
(64) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639–666.
(65) Wasserman, H. H.; Parr, J. Acc. Chem. Res. 2004, 37, 687–701.
(66) Wasserman, H. H.; Kuo, G. Tetrahedron 1992, 48, 7071–7082.
(67) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(68) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17,
1973–1976.
914 J. Org. Chem. Vol. 76, No. 3, 2011

Topczewski et al.
JOCArticle
SCHEME 6. Total Synthesis of (þ)-Schweinfurthin A
comparison to the earlier synthesis of schweinfurthin B, where
attempted oxidation in the presence of a C-2 MOM group was
too sluggish to be useful,30 the C-2 hydroxyl group in this series
greatly accelerated the desired oxidation. Diastereoselective
reduction of ketone 72 provided diol 73, where the C-2
stereochemistry could be assigned based on precedents30,69
and a straightforward analysis of the relevant coupling con-
stants in the 1H NMR spectrum. Treatment of benzyl ether 73
with DDQ provided aldehyde 74, demonstrating once again
the value of a benzyl methyl ether as a latent benzal-
dehyde.30,70,71 Unfortunately, ensuing attempts at a direct
HWE condensation of aldehyde 74 with phosphonate 76
proved troublesome. To circumvent this problem, the A-ring
diol of aldehyde 74 was protected by treatment with excess
MOMCl and base to afford aldehyde 75. Subsequent attempts
at the HWE condensation of aldehyde 75 with phosphonate
7672,73 in the presence of KHMDS afforded stilbene 77 in
moderate yield. Global hydrolysis of the MOM acetals pro-
vided schweinfurthin A in an acceptable yield. In direct NMR
analyses, synthetic (þ)-schweinfurthin A proved identical to
an authentic sample of the natural material and displayed a
specific rotation of the same sign and magnitude as that
include an array of substituents that ultimately become in-
corporated on the arene. This tandem process appears to be
general as long as the original protecting group affords an
electrophile that can be viewed as a stabilized cation. The
diether 16 was found to undergo a highly regioselective para
oxidation upon treatment with DDQ, but migration of other
stabilized motifs has allowed rapid generation of complex
polycycles that lead to the ortho oxidized products. To de-
monstrate the potential of this approach, a cascade cyclization/
aromatic substitution strategy has been used to provide a late
stage schweinfurthin intermediate that represents a formal
synthesis of four natural products. Furthermore, this inter-
mediate has been elaborated to complete the first synthesis of
natural (þ)-schweinfurthin A, which makes the rare natural
product available by synthesis. Efforts to exploit the utility of
this reaction manifold in other natural product syntheses are in
progress and will be reported in due course.74-76
Experimental Section
Epoxide 15. To a solution of the corresponding olefin40 (6.2 g,
19 mmol) and Shi’s catalyst (1.4 g, 5.0 mmol) in aq buffer (80 mL,
2 M K2CO3 and 4 mM EDTA) and organic phase (100 mL, 1:1:1
CH2Cl2/MeCN/EtOH) at 0 °C was added hydrogen peroxide
(7 mL, 30%) via syringe pump over 20 h. The reaction was then
quenched by addition of aq Na2SO3. The resulting solution was
extracted with ethyl acetate, and the organic phase was washed
with brine. After the organic phase was dried (MgSO4), and
concentrated in vacuo, final purification by column chromatog-
raphy (20% ethyl acetate in hexanes) afforded recovered starting
material (2.8 g, 44%) and epoxide 15 (2.9 g, 44%, ee ranged from
88-92%) as a colorless oil: 1H NMR (CDCl3) δ 7.11-7.08
reported for the natural product ([R]25 þ47 (c 1.0, EtOH,
D
from epoxide of 90% ee); lit.35 [R]25D þ51.8 (c 2.0, EtOH)).35
Therefore, the natural antipode of schweinfurthin A now can
be assigned as (þ)-(2S,3R,4aR,9aR)-schweinfurthin A.
Conclusions
In conclusion, the scope of cascade cyclizations terminated
by electrophilic aromatic substitution has been expanded to
(69) Wen, X.; Xia, J.; Cheng, K.; Zhang, L.; Zhang, P.; Liu, J.; Zhang, L.;
Ni, P.; Sun, H. Biorg. Med. Chem. Lett. 2007, 17, 5777–5782.
(70) Cook, S. P.; Danishefsky, S. J. Org. Lett. 2006, 8, 5693–5695.
(71) Liu, H.; Siegel, D. R.; Danishefsky, S. J. Org. Lett. 2006, 8, 423–425.
(72) Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F. J. Org. Chem. 1999,
64, 8718–8723.
(74) Singh, S. B.; Zink, D. L.; Williams, M.; Polishook, J. D.; Sanchez,
M.; Silverman, K. C.; Lingham, R. B. Bioorg. Med. Chem. Lett. 1998, 8,
2071–2076.
(75) Hinkley, S. F.; Fettinger, J. C.; Dudley, K.; Jarvis, B. B. J. Antibiot.
1999, 52, 988–997.
(76) Pecchio, M.; Solis, P. N.; Lopez-Perez, J.; Vasquez, Y.; Rodriguez,
N.; Olmedo, D.; Correa, M.; San Feliciano, A.; Gupta, M. P. J. Nat. Prod.
2006, 69, 410–413.
(73) Neighbors, J. D.; Salnikova, M. S.; Wiemer, D. F. Tetrahedron Lett.
2005, 46, 1321–1324.
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(m, 2H), 7.01 (d, J=8.0 Hz, 1H), 5.35 (m, 1H), 5.19 (s, 2H), 4.35 (s,
2H), 3.45 (s, 3H), 3.34 (s, 3H), 3.35 (m, 2H), 2.69 (t, J=6.4 Hz,
1H), 2.19-2.11 (m, 2H), 1.73 (s, 3H), 1.68-1.60 (m, 2H), 1.25 (s,
3H), 1.23 (s, 3H); 13C NMR (CDCl3) δ 154.4, 134.8, 131.1, 130.4,
129.3, 126.6, 123.0, 113.6, 94.2, 74.3, 64.0, 58.2, 57.8, 55.8, 36.3,
28.5, 27.3, 24.7, 18.6, 16.0; HRMS (EI) m/z calcd for C20H30O4
(Mþ) 334.2144, found 334.2135.
NMR (CDCl3) δ 8.20-8.05 (m, 4 H), 7.19 (d, J=1.6 Hz, 1H), 7.06
(d, J=2.0 Hz, 1H), 5.20 (s, 2H), 4.35 (d, J=12.4 Hz, 1H), 4.30 (d,
J=12.4 Hz, 1H), 3.34 (s, 3H), 3.30-3.27 (m, 1H), 2.65-2.62 (m,
2H), 1.94-1.91 (m, 1H), 1.78-1.50 (m, 4H), 1.11 (s, 3H), 1.02 (s,
3H), 0.80 (s, 3H); 13C NMR (CDCl3) δ 165.6, 152.0, 151.5, 136.5,
131.6 (2C), 130.8, 128.2, 127.4, 127.1, 124.3 (2C), 123.0, 78.3, 77.7,
70.0, 68.6, 58.7, 47.7, 39.2, 38.7, 28.7, 27.8, 23.9, 20.4, 14.8; HRMS
(EI) m/z calcd for C26H31NO7 (Mþ) 469.2101, found 469.2096.
Aldehyde 20. To a solution of carbonate 18 (95 mg, 0.23 mmol)
in CH2Cl2 (5 mL) and water (0.5 mL) at rt was added DDQ (110
mg, 0.48 mmol). After 2 h, the reaction was quenched by addition
of NaHCO3, and the resulting mixture was extracted with CH2Cl2.
The organic phases were washed with brine, dried (MgSO4), and
concentrated in vacuo to afford aldehyde 20 (71 mg, 78%) as an
orange oil:[R]25D þ42 (c 0.7, CHCl3, 82% ee by HPLC); 1H NMR
(CDCl3) δ 10.37 (s, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.34 (d, J=2.0
Hz, 1H), 4.98 (s, 2H,), 3.44 (dd, J=11.2, 4.4 Hz, 1H), 2.75-2.71
(m, 2H), 2.07-2.04 (m, 1H), 1.48 (s, 9H), 1.25 (s, 3H), 1.07 (s, 3H),
0.88 (s, 3H); 13C NMR (CDCl3) δ189.8, 156.2, 153.3, 136.3, 126.8,
126.3, 124.2, 123.8, 82.4, 80.0, 77.7, 68.0, 46.3, 38.3, 37.4, 28.1, 27.7
(3C), 27.2, 22.8, 20.1, 14.2; HRMS (EI) m/z calcd for C23H32O6
(Mþ) 404.2199, found 404.2192.
Aldehyde 21. According to the procedure described above,
compound 19 was treated with DDQ followed by standard
workup. Concentration of the resulting solution afforded alde-
hyde 21 (140 mg, 71%) as an orange oil: 1HNMR (CDCl3) δ10.38
(s, 1H), 8.24 (d, J = 8.6 Hz, 2H), 8.18 (d, J=8.6 Hz, 2H), 7.71 (d,
J=2.4 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 5.28 (s, 2H), 3.42 (dd, J=
11.6, 4.4 Hz, 1H), 2.77-2.74 (m, 2H), 2.05 (dt, J=12.8, 3.2 Hz,
1H), 2.04 (br, 1H), 1.89 (dq, J=12.8, 3.2 Hz, 1H), 1.78 (dd, J=
13.2, 3.6Hz, 1H), 1.70 (dd, J=11.6Hz, 6.4Hz, 1H), 1.64-1.60 (m,
1H), 1.23 (s, 3H), 1.10 (s, 3H), 0.87 (s, 3H); 13C NMR (CDCl3) δ
189.7, 164.4, 156.3, 150.4, 136.4, 135.3, 130.7 (2C), 126.4, 126.4,
124.2, 124.0, 123.4 (2C), 78.1, 77.5, 66.9, 46.2, 38.3, 37.4, 28.0,
27.1, 22.8, 20.1, 14.2; HRMS (EI) m/z calcd for C25H27NO7 (Mþ)
453.1788, found 453.1782.
Ether 16. To a solution of epoxide 15 (1.15 g, 3.4 mmol) in
CH2Cl2 (350 mL) at -78 °C was added BF3 OEt2 (2.2 mL, 20
3
mmol). After 9 min, the reaction was quenched by addition of
excess Et3N (5 mL). The resulting solution was concentrated in
vacuo and the resulting oil was dissolved in ethyl acetate, which
was washed with 1 N HCl followed by brine. The organic phase
was dried (MgSO4) and concentrated in vacuo. Final purification
by column chromatography (30% ethyl acetate in hexanes)
afforded the cyclized product without a C-5 substituent40 (229
mg, 23%) along with ether 16 (620 mg, 54%) as a yellow oil:
[R]25D þ39 (c 0.9, CHCl3, 82% ee by HPLC); 1H NMR (CDCl3) δ
7.12 (s, 1H), 6.97 (s, 1H), 4.40 (s, 2H), 4.30 (s, 2H), 3.38 (s, 3H),
3.34 (s, 3H), 3.09 (dd, J = 11.2, 4.0 Hz, 1H), 2.85 (br, 1H),
2.66-2.62 (m, 2H), 1.93-1.89 (m, 1H), 1.72-1.52 (m, 4H), 1.13
(s, 3H), 0.97 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3) δ 150.0,
128.7, 128.5, 126.3, 125.7, 121.2, 77.1, 76.2, 74.5, 68.9, 58.1, 57.7,
46.5, 37.9, 37.5, 27.9, 27.0, 22.8, 19.8, 14.0; HRMS (EI) m/z calcd
for C20H30O4 (Mþ) 334.2144, found 334.2134.
Aldehyde 17. To a solution of benzyl ether 16 (400 mg, 1.2
mmol) in CH2Cl2 (10 mL) and water (1.0 mL) at rt was added
DDQ (308 mg, 1.4 mmol). After 2 h, the reaction was quenched by
addition of NaHCO3. The resulting mixture was extracted with
CH2Cl2. The organic phases were washed with brine, dried
(MgSO4), and concentrated in vacuo to afford aldehyde 17 as
an orange oil, which was advanced to the next step without further
purification: 1H NMR (CDCl3) δ 9.79 (s, 1H), 7.70 (d, J=1.2 Hz,
1H), 7.56 (d, J=1.2 Hz, 1H), 4.46 (s, 2H), 3.41 (s, 3H), 3.40 (m,
1H), 2.76-2.71 (m, 2H), 2.25 (br, 1H), 2.01 (ddd, J=12.4, 3.6, 3.6
Hz, 1H), 1.84 (dq, J=12.8, 3.6 Hz, 1H), 1.73 (dd, J=13.0, 3.8 Hz,
1H), 1.65 (dd, J=11.8, 5.8 Hz, 1H), 1.59 (m, 1H), 1.19 (s, 3H), 1.07
(s, 3H), 0.85 (s, 3H); 13C NMR (CDCl3) δ 191.3, 156.1, 130.7,
128.5, 128.4, 127.0, 122.1, 78.0, 77.5, 68.7, 58.5, 46.3, 38.3, 37.4,
27.9, 27.1, 22.8, 20.2, 14.2; HRMS (EI) m/z calcd for C19H26O4
(Mþ) 318.1831, found 318.1813.
BOM Epoxide 23. To the parent geranyl arene40 (411 mg, 0.88
mmol) in CH2Cl2 (15 mL) at-20 °Cwas addedm-CPBA (200 mg,
0.89 mmol) slowly. The reaction was allowed to stir for 1 h and
then quenched by addition of Na2SO3 (sat.) and extracted with
CH2Cl2. The organic extracts were washed with 0.5 M NaOH and
brine, dried (MgSO4), filtered, and concentrated in vacuo. Final
purification by flash column chromatography (4% to 5% ethyl
acetate in hexanes) afforded the external epoxide 23 (131 mg,
31%) as a colorless oil: 1H NMR (CDCl3) δ 7.33-7.27 (m, 10H),
7.04 (d, J=8.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.71 (dd, J=8.3,
2.3 Hz, 1H), 5.36 (t, J=7.3 Hz, 1H), 5.29 (s, 2H), 5.24 (s, 2H), 4.72
(s, 2H), 4.71 (s, 2H), 3.32 (d, J=7.3 Hz, 2H), 2.71 (t, J=6.3 Hz,
1H), 2.22-2.12 (m, 2H), 1.74 (s, 3H), 1.74-1.61 (m, 2H), 1.27 (s,
3H), 1.24 (s, 3H); 13C NMR (CDCl3) δ 156.5, 155.5, 137.2, 137.2,
134.7, 129.7, 128.4 (2C), 128.4 (2C), 127.9 (2C), 127.9 (2C), 127.8,
127.7, 123.9, 123.3, 108.8, 103.5, 92.4, 92.2, 69.9, 69.7, 64.2, 58.4,
36.3, 27.9, 27.3, 24.8, 18.7, 16.1; HRMS (EI) m/z calcd for
C32H38O5 (Mþ) 502.2719, found 502.2716.
Boc Carbonate 18. To a solution of the parent alcohol40 (179
mg, 0.56 mmol) in THF in an ice bath was added NaH (190 mg,
60% in oil, 4.8 mmol) followed by Boc2O (153 mg, 0.70 mmol).
After 12 h, the reaction was quenched by addition of water, the
resulting solution was extracted with ethyl acetate, and the organic
phases were washed with brine. The organic phase was dried
(MgSO4) and concentrated in vacuo. Final purification by column
chromatography (40% ethyl acetate in hexanes) afforded Boc
carbonate 18 (102 mg, 43%) as a colorless oil: 1H NMR(CDCl3) δ
7.17 (d, J=2.0 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 4.97 (s, 2H), 4.39
(s, 2H), 3.39 (s, 3H), 3.39-3.33 (m, 1H), 2.69-2.65 (m, 2H), 2.09
(br, 1H), 1.96 (dt, J=12.8, 3.4 Hz, 1H), 1.81 (dq, J=8.8, 3.6 Hz,
1H), 1.72 (dd, J=14.0, 4.0 Hz, 1H), 1.63 (dd, J=12.0, 6.4 Hz, 1H),
1.58-1.50 (m, 1H), 1.46 (s, 9H), 1.15 (s, 3H), 1.04 (s, 3H), 0.83 (s,
3H); 13C NMR (CDCl3) δ 156.4, 153.4, 150.7, 129.4, 127.0, 126.2,
121.6, 81.9, 77.7, 76.4, 69.0, 68.8, 58.3, 46.5, 38.2, 37.6, 28.0, 27.7
(3C), 27.2, 22.9, 19.9, 14.1; HRMS (EI) m/z calcd for C24H36O6
(Mþ) 420.2512, found 420.2507.
Benzyl Ether 29a. To epoxide 23 (121 mg, 0.24 mmol) in
CH2Cl2 (50 mL) at -78 °C was added BF3 OEt2 (0.15 mL, 1.19
3
mmol). After 8 min the reaction was quenched by addition of
Et3N, diluted with water, and extracted with CH2Cl2. The organic
layers were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo. Final purification by flash column chro-
matography (30% ethyl acetate in hexanes) afforded ether 29a (75
mg, 62%) as a colorless oil: 1H NMR (CDCl3) δ 7.39-7.21 (m,
10H), 6.98 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 5.28 (s, 2H),
4.70 (s, 2H), 4.65 (d, J=10.0 Hz, 1H), 4.61 (d, J=9.9 Hz, 1H), 4.58
(s, 2H), 3.41 (dd, J = 11.5, 4.1 Hz, 1H), 2.67-2.64 (m, 2H),
2.04-1.97 (m, 1H), 1.85-1.75 (m, 2H), 1.70-1.56 (m, 3H), 1.20
(s, 3H), 1.08 (s, 3H), 0.86 (s, 3H); 13C NMR (CDCl3) δ 155.4,
152.6, 139.3, 137.4, 129.8, 128.4 (2C), 128.1 (2C), 127.9 (2C),
p-Nitrobenzoate 19. To a solution of the parent alcohol40 (222
mg, 0.69 mmol) in THF (10 mL) at rt was added 4-nitrobenzoyl
chloride (160 mg, 0.86 mmol) followed by py (0.12 mL, 1.5 mmol).
After 3.5 h, the reaction was quenched by addition of water and
the resulting mixture was extracted with ethyl acetate. The organic
phases were washed with brine, dried (MgSO4), and concentrated
in vacuo. Final purification by column chromatography (30% to
50% ethyl acetate in hexanes) afforded ester 19 (209 mg, 64%) as a
1
colorless oil: [R]25 þ41 (c 0.6, CHCl3, 82% ee by HPLC); H
D
916 J. Org. Chem. Vol. 76, No. 3, 2011

Topczewski et al.
JOCArticle
127.7, 127.2 (2C), 127.2, 115.6, 115.0, 106.6, 92.7, 78.1, 76.4, 72.0,
69.9, 60.8, 46.7, 38.3, 37.7, 28.2, 27.3, 22.7, 20.0, 14.2; HRMS (EI)
m/z calcd for C32H38O5 (Mþ) 502.2719, found 502.2721.
Competition Experiment. To a solution of epoxide 23 (77 mg,
0.15 mmol) and epoxide 24 (85 mg, 0.16 mmol) in CH2Cl2 (40 mL)
bromide, prepared from the corresponding alcohol (3.74 g, 22
mmol, 93%ee), was addedviacanulaas a solutioninether (5 mL).
The reaction was allowed to warm slowly to rt and then was
quenched by addition of NH4Cl after an additional 4 h. The
resulting mixture was extracted with ethyl acetate, and the organic
phases were washed with brine, dried (MgSO4), and concentrated
in vacuo. Final purification by column chromatography (18%
ethyl acetate in hexanes) afforded epoxide 60 (4.2 g, 71%) as a
colorless oil: 1H NMR (CDCl3) δ 7.31-7.22 (m, 5H), 7.13 (s, 1H),
7.09 (m, 2H), 5.38 (t, J=7.2Hz, 1H), 5.26 (s, 2H), 4.67(s, 2H), 4.33
(s, 2H), 3.37 (d, J=7.2 Hz, 2H), 3.32 (s, 3H), 2.66 (t, J=6.2 Hz,
1H), 2.20-2.12 (m, 2H), 1.74 (s, 3H), 1.67-1.60 (m, 2H), 1.23 (s,
3H), 1.21 (s, 3H); 13C NMR (CDCl3) δ 154.3, 137.0, 134.6, 131.0,
130.1, 129.0, 128.1 (2C), 127.6 (2C), 127.4, 126.4, 122.9, 113.5,
92.0, 74.1, 69.6, 63.6, 57.8, 57.5, 36.1, 28.4, 27.1, 24.5, 18.4, 15.8;
HRMS (EI) m/z calcd for C26H34O4 (Mþ) 410.2457, found
410.2462.
at -78 °C was added BF3 OEt2 (0.20mL, 1.6mmol). After10min,
3
the reaction was quenched by addition of Et3N (0.4 mL), allowed
to warm to rt, and then extracted with CH2Cl2. The organic
extracts were washed with water, dried (MgSO4), and filtered, and
then the filtrate was concentrated in vacuo. Final purification by
flash column chromatography (7.5% to 20% ethyl acetate in
hexanes) afforded compound 29a as a colorless oil (52 mg, 68%)
and compound 30a (58 mg, 68%) as a colorless oil.
Epoxide 34. To a solution of the geranyl arene40 (304 mg, 0.92
mmol) in CH2Cl2 (40 mL) at -30 °C was added m-CPBA(228mg,
77% maximum by mass, 1.0 mmol). After 1 h the reaction was
quenched by addition of NaHCO3 and the resulting solution was
extracted with CH2Cl2. The organic phases were washed with
brine, dried (MgSO4), and concentrated in vacuo. Final purifica-
tion by column chromatography (8% to 25% ethyl acetate in
hexanes) afforded epoxide 34 (226 mg, 71%) as a colorless oil: 1H
NMR (CDCl3) δ7.17 (d, J = 8.4 Hz, 1H), 6.89 (dd, J=8.4, 2.4 Hz,
1H), 6.83 (d, J=2.4 Hz, 1H), 5.24 (td, J=7.2, 1.2 Hz, 1H), 3.20 (d,
J=7.2 Hz, 2H), 2.67 (t, J = 6.2 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H),
2.20-2.09 (m, 2H), 1.68 (s, 3H), 1.65-1.59 (m, 2H), 1.24 (s, 3H),
1.22 (s, 3H); 13C NMR (CDCl3) δ 170.1, 169.9, 150.2, 150.0, 137.2,
131.8, 131.2, 122.9, 120.2, 117.0, 65.0, 59.3, 37.4, 29.3, 28.4, 25.9,
22.1, 21.8, 19.8, 17.2; HRMS (EI) m/z calcd for C20H26O5 (Mþ)
346.1780, found 346.1772.
Hexahydroxanthene 62. To a solution of epoxide 60 (774 mg,
1.89 mmol) in CH2Cl2 (200 mL) at -78 °C was added BF3 OEt2
3
(1.0 mL, 8.0 mmol). After 8 min, the reaction was quenched by
addition of Et3N (2 mL), allowed to warm to rt, and concentrated
in vacuo. Purification of the initial oil by column chromatography
(30% ethyl acetate in hexanes) afforded compounds 61 and 62 as
an inseparable mixture (520 mg, 1:2 61:62 corresponding to
compound 62 (384 mg, 50%) and compound 61 (136 mg, 25%))
as a colorless oil: for compound 62, HRMS (EI) m/z calcd for
C26H34O4 (Mþ) 410.2457, found 410.2450.
Benzyl Alcohol 63. A mixture of compound 61 and compound
62 (185 mg, 2:1 62 to 61) was dissolved in CH3OH (0.5 mL) and
10% Pd/C (30 mg) was added. The reaction vessel was sealed and
purged with H2 at rt. A stream of H2 then was provided to
maintain 1 atm of H2, which resulted in the slow concentration
of the solution to near dryness. After 23 h, the resulting mixture
was diluted with CH3OH, filtered through Celite, and concen-
trated in vacuo. Final purification by column chromatography
(50% ethyl acetate in hexanes) afforded alcohol 63 (81 mg, 76%)
Bridged Ether 35. To a solution of epoxide 34 (95 mg, 0.27
mmol) in CH2Cl2 (50 mL) at -78 °C was added BF3 OEt2 (0.18
3
mL, 1.4 mmol). After 7 min the reaction was quenched by addition
of Et3N (0.35 mL, 2.5 mmol) and concentrated in vacuo. The
residue was dissolved in ethyl acetate and washed with water, 1 N
HCl, and brine. The organic phase was then dried (MgSO4), and
concentrated in vacuo. Final purification by column chromatog-
raphy (20% to 50% ethyl acetate in hexanes) afforded tricyclic
ether 35 (44 mg, 46%) as a colorless oil: 1H NMR (CDCl3) δ 7.20
(d, J=8.4 Hz, 1H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J=2.4
Hz, 1H), 3.68 (d, J = 5.2 Hz, 1H), 2.45 (d, J=7.6 Hz, 2H), 2.23 (s,
3H), 2.18 (s, 3H), 1.88-1.84 (m, 1H), 1.81 (t, J=7.6 Hz, 1H),
1.66-1.59 (m, 1H), 1.51-1.45 (m, 1H), 1.39 (dd, J = 12.2, 4.8 Hz,
1H), 1.20 (s, 3H), 0.90 (s, 3H), 0.90 (s, 3H); 13C NMR (CDCl3) δ
168.8, 168.6, 148.8, 148.7, 131.0, 129.7, 118.6, 115.9, 86.6, 86.0,
54.2, 45.4, 38.8, 26.8, 25.8, 25.8, 23.6, 21.0, 20.8, 19.0; HRMS (EI)
m/z calcd for C20H26O5 (Mþ) 346.1780, found 346.1790.
1
as a colorless oil: H NMR (CDCl3) δ 7.03 (m, 2H), 4.63 (d,
J=12.8 Hz, 1H), 4.57 (d, J=12.8, 1H), 4.34 (s, 2H), 3.41 (dd, J=
11.6, 4.0 Hz, 1H), 3.37 (s, 3H), 2.73-2.68 (m, 2H), 2.02 (dt, J=
12.8, 3.4 Hz, 1H), 1.88-1.60 (m, 4 H), 1.22 (s, 3H), 1.09 (s, 3H),
0.90 (s, 3H); 13C NMR (CDCl3) δ150.7, 129.4, 129.0, 128.5, 126.4,
121.8, 77.9, 74.5, 62.4, 58.0, 46.8, 38.4, 37.8, 28.2, 27.3, 22.9, 20.1,
14.2; 13C NMR (MeOD) δ 151.3, 130.1, 130.0, 129.8, 126.8, 122.8,
78.8, 77.7, 75.8, 60.3, 57.9, 39.4, 39.0, 29.0, 27.9, 24.0, 20.3, 14.8;
HRMS (EI) m/z calcd for C19H28O4 (Mþ) 320.1988, found
320.1990.
Methyl Ether 59. To a solution of the parent alcohol40 (ca. 210
mmol from above) in THF (250 mL) cooled to 0 °C was added
NaH (18 g, 60% in oil, 600 mmol) in small portions. After
evolution of hydrogen ceased (ca. 10 min), CH3I (17 mL, 272
mmol) was added slowly. After an additional 5 h, the reaction was
slowly quenched by addition of water. The resulting solution was
extracted with ethyl acetate. The organic phases were washed with
brine, dried (MgSO4), and concentrated in vacuo. Final purifica-
tion by column chromatography (25% ethyl acetate in hexanes)
afforded compound 59 (51 g, 73% over 4 steps) as a colorless oil:
1H NMR (CDCl3) δ 7.61 (s, 1H), 7.38-7.37 (m, 5H), 7.24-7.23
(m, 2H), 5.37 (s, 2H), 4.79 (s, 2H), 4.39 (s, 2H), 3.39 (s, 3H); 13C
NMR (CDCl3) δ 152.95, 136.7, 133.1, 132.5, 128.2, (2C), 127.8
(2C), 127.7, 127.7, 115.7, 112.5, 92.6, 73.1, 70.0, 57.7; HRMS (EI)
m/z calcd for C16H17O3Br (Mþ) 336.0361, found 336.0362.
Epoxide 60. To a solution of TMEDA (3 mL, 20 mmol) inether
(40 mL) cooled in a brine bath was added BuLi (7.5 mL, 2.3 M in
hexanes, 17.3 mmol). After 5 min, bromide 59 (4.86 g, 14.4 mmol)
was added in ether (20 mL) via canula. After an additional 15 min,
CuI (3.0 g, 16 mmol) was added as a solid in one portion, resulting
in a slow blackening of the solution. After an additional 15 min at
the same temperature, freshly prepared (R)-6,7-epoxy geranyl
Aldehyde 64. To a solution of alcohol 63 (13 mg, 0.04 mmol) in
CH2Cl2 atrtwas addedactivatedMnO2 (95 mg, 0.87 mmol). After
20 h at rt, the solution was diluted with ethyl acetate, filtered
through Celite, and concentrated in vacuo, which afforded alde-
hyde 64 (13 mg, 96%) as a yellow oil: 1H NMR (CDCl3) δ 10.40 (s,
1H), 7.58 (d, J=2.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 4.35 (s, 2H),
3.42 (dd, J=11.6, 3.6 Hz, 1H), 3.37 (s, 3H), 2.76-2.73 (m, 2H),
2.05 (dt, J=12.6, 3.2 Hz, 1H), 1.90-1.60 (m, 5H), 1.26 (s, 3H),
1.10 (s, 3H), 0.88 (s, 3H); 13C NMR (CDCl3) δ 190.0, 155.8, 135.7,
129.5, 125.6, 125.1, 123.7, 77.8, 77.8, 74.0, 58.1, 46.4, 38.4, 37.5,
28.2, 27.2, 22.9, 20.1, 14.2; HRMS (EI) m/z calcd for C19H26O4
(Mþ) 318.1831, found 318.1839.
Phenol 65. To a solution of aldehyde 64 (18 mg, 0.056 mmol) in
CH2Cl2 (2 mL) was added m-CPBA (35 mg, 77% maximum, 0.14
mmol) at rt. After 2 h, the reaction was diluted with CH3OH (3
mL) and solid K2CO3 (65 mg, 0.47 mmol) was added. After an
additional 20 h, the reaction was quenched by addition of 1 N HCl
and Na2SO3. The resulting mixture was neutralized by addition of
NaHCO3 and extracted with CH2Cl2. After the organic phases
were washed with brine, dried (MgSO4), and concentrated in
vacuo, final purification by column chromatography (30% to
50% ethyl acetate in hexanes) afforded phenol 65 (17 mg, 98%) as
J. Org. Chem. Vol. 76, No. 3, 2011 917

Topczewski et al.
JOCArticle
a colorless oil: 1H NMR (CDCl3) δ 6.73 (d, J=1.6 Hz, 1H), 6.63
(d, J = 1.6, 1H), 5.46 (s, 1H), 4.31 (s, 2H), 3.40 (dd, J=11.2, 3.6
Hz, 1H), 3.36 (s, 3H), 2.71-2.66 (m, 2H), 2.01 (dt, J=12.8, 3.6 Hz,
as white crystals: [R]25D þ62 (c 0.9, CHCl3, 90% ee by HPLC); 1H
NMR (CDCl3) δ 7.37-7.22 (m, 5H), 6.94 (d, J=2.0 Hz, 1H), 6.80
(m, 2H), 5.19 (d, J=6.6 Hz, 1H), 5.14 (d, J=6.6 Hz, 1H), 4.33 (s,
2H), 3.91 (s, 1H), 3.41 (s, 3H), 3.39 (s, 3H), 2.75-2.70 (m, 2H),
2.29 (m, 2H), 1.92 (dd, J = 12.2, 5.8 Hz, 1H), 1.20 (s, 3H), 1.06 (s,
3H), 0.85 (s, 3H); 13C NMR (CDCl3) δ 145.8, 143.5, 138.0, 137.4,
129.2, 128.8 (2C), 128.2 (2C), 126.3, 123.9, 123.2, 122.8, 115.3,
95.6, 79.8, 78.0, 74.6, 58.0, 56.0, 47.1, 41.2, 39.7, 27.2, 23.2, 19.8,
14.2; HRMS (EI) m/z calcd for C27H34O5 (Mþ) 438.2406, found
438.2408.
Triol 71. To a solution of alcohol 70 (115 mg, 0.26 mmol) in
dioxane (2 mL) and water (0.1 mL) at rt was added OsO4 (0.2 mL,
0.002 M in t-BuOH, 0.004 mmol) followed by NMO (68 mg, 0.58
mmol). After 17 h, the reaction was diluted with water and
extracted with ethyl acetate. The extracts were washed with brine,
dried (MgSO4), and concentrated in vacuo, which afforded triol
71 as a crystalline solid: 1H NMR (CDCl3) δ 7.50-7.48 (m, 2H),
7.34-7.26 (m, 3H), 6.86 (s, 1H), 6.75 (s, 1H), 5.07 (s, 1H), 5.03 (s,
2H), 4.64 (br s, 1H), 4.36 (br s, 1H), 4.28 (s, 2H), 3.61 (br s, 1H),
3.40 (s, 3H), 3.36-3.30 (m, 1H), 3.33 (s, 3H), 2.69-2.66 (m, 2H),
2.14(d, J=14.4Hz, 1H), 1.94 (dd, J=10.8, 7.2 Hz, 1H), 1.72 (d, J=
14.4 Hz, 1H), 1.26 (s, 3H), 1.12 (s, 3H), 1.06 (s, 3H); 13C NMR
(CDCl3) δ 145.8, 143.2, 139.4, 129.1 (2C), 129.1, 128.2 (2C), 128.1,
123.2, 123.0, 115.8, 95.8, 84.8, 77.8, 76.7, 75.1, 74.5, 57.9, 56.0,
46.0, 45.5, 37.8, 30.1, 23.2, 21.7, 16.5; HRMS (EI) m/z calcd for
C27H36O7 (Mþ) 472.2461, found 472.2467.
Ketone 72. To a solution of partially purified triol 71 (ca. 0.26
mmol) in CH2Cl2 (5 mL) and water (0.1 mL) at rt was added
NaIO4 (720 mg, 3.3 mmol) and the resulting mixture was vigor-
ously stirred. After 24 h, the reaction was diluted with water and
extracted with CH2Cl2 and the extracts were washed with brine,
dried (MgSO4), and concentrated in vacuo. Final purification by
column chromatography (30% ethyl acetate in hexanes) afforded
ketone 72 (81 mg, 84% over 2 steps) as a colorless oil: 1H NMR
(CDCl3) δ 6.95 (d, J=1.6 Hz, 1H), 6.80 (s, 1H), 5.18 (d, J=6.4 Hz,
1H), 5.15 (d, J=6.4 Hz, 1H), 4.33 (s, 2H), 4.05 (d, J=3.6 Hz, 1H),
3.50 (s, 3H), 3.46 (d, J = 4.4 Hz, 1H), 3.38 (s, 3H), 3.03-2.99 (m,
2H), 2.85 (dd, J=16.4, 3.6 Hz, 1H), 2.77 (m, 1H), 2.34 (dd, J=
12.8, 5.2 Hz, 1H), 1.25 (s, 3H), 1.20 (s, 3H), 0.74 (s, 3H); 13C NMR
(CDCl3) δ 207.5, 146.0, 142.8, 130.2, 122.9, 122.5, 115.4, 95.8,
82.6, 78.8, 74.5, 58.1, 56.2, 52.5, 46.3, 41.5, 27.3, 23.2, 21.0, 15.1;
HRMS (EI) m/z calcd for C20H28O6 (Mþ) 364.1886, found
364.1883.
Diol 73. To a solution of ketone 72 (81 mg, 0.22 mmol) in
CH3OH (0.3 mL) and THF (3 mL) at rt was added NaBH4 (18
mg, 0.47 mmol). After 15 min, the reaction was quenched by
addition of 1 N HCl. The resulting solution was extracted with
ethyl acetate, and the organic phases were washed with brine,
dried (MgSO4), and concentrated in vacuo. Immediate purifica-
tion by column chromatography (80% ethyl acetate in hexanes)
afforded diol 73 (78mg, 96%) as a colorless oil:1H NMR (CDCl3)
δ6.92 (d, J=1.6Hz, 1H), 6.77 (s, 1H), 5.18(d, J=6.0 Hz, 1H), 5.14
(d, J=6.4 Hz, 1H), 4.31 (s, 2H), 4.15 (q, J=3.2 Hz, 1H), 3.51 (s,
3H), 3.38 (s, 3H), 3.39-3.36 (m, 1H), 3.16 (brd, 1H), 2.77-2.69
(m, 3H), 2.42 (dd, J=14.2, 3.0 Hz, 1H), 1.93 (dd, J=14.4, 3.6 Hz,
1H), 1.70 (dd, J=12.2, 5.4 Hz, 1H), 1.41 (s, 3H), 1.05 (s, 3H), 1.04
(s, 3H); 13C NMR (CDCl3) δ 145.9, 143.3, 129.1, 123.4, 123.2,
115.9, 95.9, 77.3, 76.3, 74.7, 70.8, 58.0, 56.2, 46.9, 43.3, 37.9, 28.8,
23.0, 21.5, 15.9; HRMS (EI) m/z calcd for C20H30O6 (Mþ)
366.2042, found 366.2041.
1H), 1.89-1.59 (m, 5H), 1.22 (s, 3H), 1.09 (s, 3H), 0.87 (s, 3H); 13
C
NMR (CDCl3) δ 145.0, 139.6, 130.0, 121.9, 120.1, 112.0, 77.9,
77.7, 74.7, 57.9, 47.2, 38.4, 37.7, 28.2, 27.3, 22.7, 20.1, 14.3; HRMS
(EI) m/z calcd for C18H26O4 (Mþ) 306.1831, found 306.1837.
Schweinfurthin B Intermediate 66. To a solution of phenol 65 (9
mg, 0.03 mmol) in acetone (2 mL) was added K2CO3 (60 mg, 0.43
mmol) followed by CH3I (0.06 mL, 0.96 mmol) and this solution
was heated to reflux. After 2 h, the solution was allowed to cool to
rt, quenchedbyadditionofwater, andextractedwithCH2Cl2. The
organic phases were washed with brine, dried (MgSO4), and
concentrated in vacuo to afford compound 66 (9 mg, 94%) as a
1
colorless oil in sufficient purity for further use. The H MNR
spectrum of this material was identical to that prepared via
different methods.30
Schweinfurthin G Intermediate 67. To a solution of phenol 65
(13 mg, 0.04 mmol) in CH2Cl2 (2 mL) was added DIPEA (0.1 mL,
0.57 mmol) followed by MOMCl (0.02 mL, 0.26 mmol). After 2 h
at rt, the reaction was quenched by addition of water and extracted
with CH2Cl2. The resulting solution was washed with 1 N HCl.
The organic phase was dried (MgSO4) and concentrated in vacuo
1
to afford compound 67 (13 mg, 89%) as a yellow oil. The H
NMR spectrum of this material was identical to that prepared via
different methods;29 [R]25D þ34 (c 1.6, CHCl3, 90% ee by HPLC).
Ketone 68. To a solution of hexahydroxanthene 67 (680 mg, 1.9
mmol) in CH2Cl2 at rt was added catalytic TPAP (73 mg, 0.21
mmol) and NMO (284 mg, 2.4 mmol). After 26 h, the reaction
mixture was diluted with ethyl acetate, filtered through Celite and
silica, and concentrated in vacuo. Final purification by column
chromatography (50% ethyl acetate in hexanes) afforded ketone
68 (675 mg, 100%) as a colorless oil: [R]25 þ88 (c 1.1, CHCl3,
D
90% ee by HPLC); 1H NMR (CDCl3) δ 6.81 (s, 1H), 6.66 (s, 1H),
5.04 (d, J=6.4 Hz, 1H), 5.02 (d, J=6.8 Hz, 1H), 4.18 (s, 2H), 3.36
(s, 3H), 3.22 (s, 3H), 2.73-2.65 (m, 1H), 2.60-2.52 (m, 2H),
2.33-2.28 (m, 1H), 2.22-2.17 (m, 1H), 2.01-1.90 (m, 2H), 1.29
(s, 3H), 1.02 (s, 3H), 0.96 (s, 3H); 13C NMR (CDCl3) δ 212.5,
145.3, 142.7, 129.2, 122.4, 121.5, 115.2, 95.2, 74.9, 73.8, 57.3, 55.5,
46.9, 45.8, 37.5, 34.5, 23.9, 23.1, 20.2, 18.5; HRMS (EI) m/z calcd
for C20H28O5 (Mþ) 348.1937, found 348.1940.
Enone 69. To a solution of ketone 68 (140 mg, 0.40 mmol) in
ethanol at rt was added benzaldehyde (0.2 mL, 1.7 mmol)
followed by KOH (177 mg, 3.2 mmol). After 25 min, the reaction
was quenched by addition of NH4Cl, the resulting solution was
extracted with ethyl acetate, and the organic extracts were washed
with brine. After the organic phase was dried (MgSO4) and
concentrated in vacuo, final purification of the residue by column
chromatography (25% ethyl acetate in hexanes) afforded enone
69 (148 mg, 86%) as a colorless oil: [R]25D þ157 (c 1.0, CH3OH,
90% ee by HPLC); 1H NMR (CDCl3) δ 7.63 (d, J=2.4 Hz, 1H),
7.45-7.32 (m, 5H), 6.96 (d, J = 2.0 Hz, 1H), 6.79 (d, J=1.6 Hz,
1H), 5.20 (d, J = 6.8 Hz, 1H), 5.15 (d, J = 6.8 Hz, 1H), 4.32 (s,
2H), 3.49 (s, 3H), 3.50-3.40 (m, 1H), 3.36 (s, 3H), 2.98 (dd, J=
15.2, 2.8 Hz, 1H), 2.84-2.70 (m, 2H), 2.34 (dd, J=12.6, 5.6, 1H),
1.31 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H); 13C NMR (CDCl3) δ 205.0,
145.5, 142.8, 138.6, 135.0, 132.2, 130.0 (2C), 129.5, 128.7, 128.3
(2C), 122.6, 121.8, 115.4, 95.6, 75.4, 74.3, 57.8, 56.0, 45.7, 45.3,
41.7, 28.6, 24.2, 22.1, 19.1; HRMS (EI) m/z calcd for C27H32O5
(Mþ) 436.2250, found 436.2257.
Alcohol 70. To a solution of ketone 69 (115 mg, 0.26 mmol) in
CH3OH at rt was added CeCl3 7H2O (108 mg, 0.27 mmol)
Aldehyde 74. To a solution of methyl ether 73 (116 mg, 0.32
mmol) in CH2Cl2/water (15:1) at rt was added DDQ (90 mg, 0.40
mmol). After 15 min, the reaction was quenched by addition of
brine and NaHCO3. The resulting solution was extracted with
CH2Cl2, and the organic extracts were washed with a small
amount of water followed by brine. After the organic phase was
dried (MgSO4) and concentrated in vacuo, aldehyde 74 (109 mg,
98%) was obtained as a faintly yellow wax that was used without
3
followed by NaBH4 (12 mg, 0.32 mmol). After 2 h, the reaction
was quenched by addition of water and concentrated in vacuo.
The resulting solution was extracted with ethyl acetate, and the
extracts were washed with brine, dried (MgSO4), and concen-
trated in vacuo. Final purification by column chromatography
(20% ethyl acetate in hexanes) afforded alcohol 70 (110 mg, 96%)
918 J. Org. Chem. Vol. 76, No. 3, 2011

Topczewski et al.
JOCArticle
further purification: 1H NMR (CDCl3) δ 9.79 (s, 1H), 7.46 (d, J=
1.6 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 5.23 (d, J=6.4 Hz, 1H), 5.21
(d, J=6.4 Hz,1 H), 4.26 (q, J=3.2 Hz, 1H), 3.56 (s, 3H), 3.40 (m,
1H), 2.86-2.82 (m, 2H), 2.51 (dd, J=14.2, 3.0 Hz, 1H), 2.25 (m,
2H), 2.03 (dd, J=14.8, 3.4, Hz, 1H), 1.78 (dd, J=11.8, 5.8 Hz, 1H),
1.47 (s, 3H), 1.13 (s, 3H), 1.09 (s, 3H); 13C NMR (CDCl3) δ 190.9,
149.6, 146.6, 128.8, 127.1, 123.5, 115.3, 95.7, 78.0, 77.4, 70.7, 56.3,
46.6, 43.2, 38.1, 28.9, 23.0, 21.8, 16.0; HRMS (EI) m/z calcd for
C19H26O6 (Mþ) 350.1729, found 350.1736.
Hz, 2H), 3.35 (d, J=3.6 Hz, 1H), 2.78-2.75 (m, 2H), 2.51 (dd, J=
14.0, 2.8 Hz, 1H), 2.06-1.88 (m, 6H), 1.78 (s, 3H), 1.64 (s, 3H),
1.56 (s, 3H), 1.43 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H); 13C NMR
(CDCl3) δ 155.4 (2C), 146.1, 142.9, 136.3, 134.7, 131.4, 128.7,
127.6, 126.2, 124.1, 123.2, 122.1, 121.7, 118.9, 112.3, 105.3 (2C),
95.9, 95.4, 95.3, 93.9 (2C), 82.3, 77.2, 72.9, 56.2, 56.2, 55.9 (2C),
55.6, 46.9, 41.2, 39.7, 38.1, 28.6, 26.5, 25.7, 22.9, 22.4, 21.0, 17.6,
16.2, 16.0; HRMS (EI) m/z calcd for C44H64O11 (Mþ) 768.4449,
found 768.4452.
Tris-MOM Aldehyde 75. To a solution of diol 74 (40 mg, 0.11
mmol) in CH2Cl2 (0.5 mL) at rt was added DIPEA (0.8 mL, 7.3
mmol) followed by slow addition of MOMCl (0.2 mL, 2.6 mmol)
over 20 min. After 5 h, the reaction was quenched by addition of
water, the resulting solution was extracted with CH2Cl2, and the
organic phases were washed with 1 N HCl followed by brine. The
organic phase was dried (MgSO4) and concentrated in vacuo.
Final purification by column chromatography (45% ethyl acetate
in hexanes) afforded aldehyde 75 (37 mg, 74%) as a colorless oil:
1H NMR (CDCl3) δ 9.78 (s, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.35 (d,
J = 1.2 Hz, 1H), 5.24 (d, J = 6.4 Hz, 1H), 5.20 (d, J=6.8 Hz, 1H),
4.85 (d, J=6.8 Hz, 1H), 4.70 (s, 2H), 4.64 (d, J=6.8 Hz, 1H), 4.21
(q, J=3.4 Hz, 1H), 3.50 (s, 3H), 3.45 (s, 3H), 3.40 (s, 3H), 3.32 (d,
J=3.2 Hz, 1H), 2.84-2.81 (m, 2H), 2.50 (dd, J=14.4, 3.6 Hz, 1H),
1.91 (dd, J=14.0, 3.2 Hz, 1H), 1.78 (dd, J=11.2, 6.8 Hz, 1H), 1.44
(s, 3H), 1.12 (s, 3H), 1.11 (s, 3H); 13C NMR (CDCl3) δ 190.9,
149.5, 146.6, 128.7, 127.1, 123.6, 115.0, 96.2, 95.9, 95.5, 82.7, 78.1,
72.9, 56.3, 56.2, 55.6, 47.1, 41.5, 38.3, 28.7, 22.9, 21.3, 16.2; HRMS
(EI) m/z calcd for C23H34O8 (Mþ) 438.2254, found 438.2250.
Stilbene 77. To a solution of diisopropyl amine (0.05 mL, 0.36
mmol) in THF (0.3 mL) in an ice bath was added BuLi (2.4 M in
hexanes, 0.05 mL, 0.12 mmol). To this solution was added
phosphonate 76 (68 mg, 0.14 mmol) in THF (0.5 mL) via canula.
After 5 min, aldehyde 75 (21 mg, 0.05 mmol) in THF (0.5 mL) was
added via canula. After 2 h, TLC analysis showed little reaction
progress and additional base was added (KHMDS, 0.5 M in
toluene, 0.3 mL, 0.15 mmol). After an additional 2 h, the reaction
was complete by TLC and the reaction was quenched by addition
of NH4Cl. The resulting solution was extracted with ethyl acetate,
and the organic phases were washed with 1 N HCl followed by
brine. After the organic phase was dried (MgSO4) and concen-
trated in vacuo, final purification by column chromatography
(50% ethyl acetate in hexanes) afforded stilbene 77 (25 mg, 68%)
as a colorless oil: 1H NMR (CDCl3) δ 7.16 (d, J=1.6 Hz, 1H), 6.96
(s, 1H), 6.94-6.89 (m, 4H), 5.27 (d, J=6.8 Hz, 1H), 5.25 (s, 4H),
5.23 (d, J=7.2 Hz, 1H), 5.20 (t, J = 5.2 Hz, 1H), 5.05 (t, J = 5.2
Hz, 1H), 4.87 (d, J=6.8 Hz, 1H), 4.73 (d, J=6.8 Hz, 1H), 4.68 (d,
J=7.2 Hz, 1H), 4.66 (d, J=7.2 Hz, 1H), 4.20 (q, J=3.2 Hz, 1H),
3.54 (s, 3H), 3.49 (s, 6H), 3.46 (s, 3H), 3.41 (s, 3H), 3.37 (d, J=6.4
Schweinfurthin A (9). To a solution of stilbene 77 (12 mg, 0.016
mmol) in methanol (1 mL) at rt was added TsOH (16 mg, 0.08
mmol). After 48 h, the reaction was quenched by addition of
NaHCO3 and the resulting solution was extracted with ethyl
acetate. The organic phase was dried (MgSO4) and concentrated
in vacuo. Final purification by preparative thin layer chromatog-
raphy (70% ethyl acetate in hexanes) afforded schweinfurthin A
(9, 5 mg, 58%) as a yellow wax: [R]25D þ47 (c 1.0, EtOH, 90% ee
by HPLC); 1H NMR (MeOD) δ 6.79 (s, 1H), 6.77 (d, J=16.4 Hz,
1H), 6.72 (s, 1H), 6.72 (d, J=16.4 Hz, 1H), 6.44 (s, 2H), 5.24 (t, J=
7.2 Hz, 1H), 5.07 (t, J=7.2 Hz, 1H), 4.14 (q, J = 3.6 Hz, 1H), 3.30
(m, 3H), 2.75 (m, 2H), 2.36 (dd, J=13.8, 3.0 Hz, 1H), 2.06-2.02
(m, 2H), 1.96-1.93 (m, 3H), 1.76 (s, 3H), 1.77-1.73 (m, 1H), 1.62
(s, 3H), 1.56 (s, 3H), 1.41 (s, 3H), 1.10 (s, 3H), 1.08 (s, 3H); 13
C
NMR (MeOD) δ 157.3 (2C), 147.1, 141.9, 137.5, 134.8, 132.0,
130.9, 128.6, 127.4, 125.5, 124.6, 124.2, 120.4, 115.8, 111.0, 105.6
(2C), 78.8, 78.1, 71.8, 48.9, 44.7, 41.0, 39.2, 29.4, 27.8, 25.9, 23.9,
23.2, 22.0, 17.7, 16.6, 16.3; HRMS (EI) m/z calcd for C34H44O6
(Mþ) 548.3138, found 548.3145.
Acknowledgment. We thank Dr. Nolan R. Mente for
providing phosphonate 76, Dr. Dale C. Swenson for his
assistance with the diffraction analysis of compound 12, and
Dr. John A. Beutler (National Cancer Institute-Frederick)
for an authentic sample of schweinfurthin A. Financial
support from the ACS Division of Medicinal Chemistry (in the
form of a predoctoral fellowship to J.J.T.), the University
of Iowa Graduate College (in the form of a Presidential
Fellowship to J.G.K.), and the National Cancer Institute
(R41CA126020 via Terpenoid Therapeutics, Inc.) is gratefully
acknowledged.
Supporting Information Available: Experimental details for
1
all other compounds, and the H and 13C NMR spectra for
compounds 15-21, 23-27, 29-51, 59-75, 77, and 9. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 76, No. 3, 2011 919