Total synthesis of (+)-schweinfurthins B and E

Article abstract of DOI:10.1021/jo901161m

(Chemical Equation Presented) The first total synthesis of (+)-schweinfurthin B, a potent and differentially active cytotoxic agent, has been accomplished. Completion of the synthesis required just 16 steps in the longest linear sequence from commercially

Full text of DOI:10.1021/jo901161m

pubs.acs.org/joc
Total Synthesis of (þ)-Schweinfurthins B and E
Joseph J. Topczewski, Jeffrey D. Neighbors, and David F. Wiemer*
Department of Chemistry University of Iowa, Iowa City, Iowa 52242-1294
david-wiemer@uiowa.edu
Received June 1, 2009
The first total synthesis of (þ)-schweinfurthin B, a potent and differentially active cytotoxic agent,
has been accomplished. Completion of the synthesis required just 16 steps in the longest linear
sequence from commercially available vanillin. Key synthetic transformations included a Shi
epoxidation and an efficient cascade cyclization initiated by treatment of the resulting epoxide with
BF3 OEt2. Furthermore, use of a methyl ether as a stable protecting group for benzylic alcohols
3
dramatically increased the efficiency of the overall sequence. The benzylic ether can be removed from
this electron-rich aromatic system through oxidation with DDQ that provided the desired aldehyde
intermediate in quantitative yield and shortened the synthetic sequence. Introduction of the A-ring
diol in the required cis stereochemistry then became viable through a short sequence highlighted by
an aldol condensation with benzaldehyde to introduce an olefin as a latent carbonyl group at the C-3
position. This synthesis established for the first time the absolute stereochemistry of the natural
product, and provides access to material on a scale that will advance biological studies. The total
synthesis of the closely related compound (þ)-schweinfurthin E also is reported.
Introduction
Institutes’s (NCI) 60-cell line assay.1 Although compounds
are known with greater potency, only the stellettins,5-7
cephalostatins,8-11 and OSW-112 display a similar pattern
of activity in the 60-cell line assay. Furthermore the schwein-
furthins do not correlate through the COMPARE statistical
analysis13 to any clinical agent in NCI’s standard agent
database, which suggests that they attack a new target or
have a novel mode of action. At present no mechanism has
been determined to account for their biological activity. The
For some years, our research group has been interested
in the schweinfurthins and the closely related compound
vedelianin, a small family of isoprene substituted stilbenes
(1-9, Figure 1).1-4 These natural products have been iso-
lated from various Macaranga species in small and in some
cases not easily reproducible quantities. We became inter-
ested in the schweinfurthins because they display significant
and differential cytotoxicity based on the National Cancer
(7) McKee, T. C.; Bokesch, H. R.; McCormick, J. L.; Rashid, M. A.;
Spielvogel, D.; Gustafson, K. R.; Alavanja, M. M.; Cardellina, J. H.; Boyd,
M. R. J. Nat. Prod. 1997, 60, 431–438.
(8) Cragg, G. M.; Powell, R. G.; Singh, S. B. J. Nat. Prod. 2008, 71, 297–
299.
(9) Moser, B. R. J. Nat. Prod. 2008, 71, 487–491.
*To whom correspondence should be addressed. Phone: 319-335-1365.
Fax: 319-335-1270.
(1) Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. J. Nat.
Prod. 1998, 61, 1509–1512.
ꢀ
ꢀ
(10) Rudy, A.; Lopez-Anton, N.; Dirsch, V. M.; Vollmar, A. M. J. Nat.
(2) Yoder, B. J.; Cao, S.; Norris, A.; Miller, J. S.; Ratovoson, F.;
Razafitsalama, J.; Andriantsiferana, R.; Rasamison, V. E.; Kingston, D.
G. I. J. Nat. Prod. 2007, 70, 342–346.
(3) Thoison, O.; Hnawia, E.; Gueritte-Voegelein, F.; Sevenet, T. Phyto-
chemistry 1992, 31, 1439–1442.
Prod. 2008, 71, 482–486.
(11) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.;
Dufresne, C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.; Krupa, T. S.
J. Am. Chem. Soc. 1988, 110, 2006–2007.
(4) Beutler, J. A.; Jato, J.; Cragg, G. M.; Boyd, M. R. Nat. Prod. Lett.
2000, 14, 399–404.
(5) Su, J. Y.; Meng, Y. H.; Zeng, L. M.; Fu, X.; Schmitz, F. J. J. Nat. Prod.
1994, 57, 1450–1451.
(6) McCormick, J. L.; McKee, T. C.; Cardellina, J. H.; Leid, M.; Boyd,
M. R. J. Nat. Prod. 1996, 59, 1047–1050.
(12) Mimaki, Y.; Kuroda, M.; Kameyama, A.; Sashida, Y.; Hirano, T.;
Oka, K.; Maekawa, E.; Wada, T.; Sugita, K.; Beutler, J. A. Biorg. Med.
Chem. Lett. 1997, 7, 633–636.
(13) Paull, K. D.; Shoemaker, R. H.; Hodes, L.; Monks, A.; Scudiero, D.
A.; Rubinstein, L.; Plowman, J.; Boyd, M. R. J. Nat. Cancer Inst. 1989, 81,
1088–1092.
DOI: 10.1021/jo901161m
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Published on Web 08/21/2009
J. Org. Chem. 2009, 74, 6965–6972 6965
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FIGURE 1. The schweinfurthins.
SCHEME 1. Oxidations of Hexahydroxanthenes
schweinfurthins, which may be the most synthetically acces-
sible of these families, show special potency toward central
nervous system-derived cell lines including those from glio-
blastoma multiforme (e.g., SF-295, <10 nM GI50) for which
there is no effective clinical treatment. It is this pattern of
selective activity, together with the scarcity of the natural
materials, that drove us to initiate studies aimed at the
synthesis of the schweinfurthins.
Our group’s initial efforts resulted in the synthesis of
schweinfurthin C (3), the simplest member of the family.14
This effort demonstrated the utility of a Horner-Wads-
worth-Emmons (HWE) condensation for assembly of the
central stilbene olefin, and provided intermediates represent-
ing the D-ring that have been useful in the preparation of
subsequent targets. Expanding on this work, we were able to
synthesize the hexahydroxanthene skeleton of the tetracyclic
schweinfurthins, initially via an acid-mediated cascade cycli-
zation of a phenylselenide.15 Unfortunately, while the result-
ing tricyclic intermediate was obtained as
a single
diastereomer, it was not easily elaborated to the A-ring diol
of a natural product.15 Further investigation led to use of a
similar cascade on an epoxide, mediated first by a Bronsted
acid16 and then by Lewis acid catalysts.17 These advances
provided reasonable quantities of the A-ring alcohol found
in 3-deoxyschweinfurthin B (3dSB, 10) prior to the isolation
of schweinfurthins F (7) and G (8),16 and thus 3dSB became
the lead compound for our biological investigations.18 Im-
provements to the original sequence have allowed the pre-
paration of numerous schweinfurthin analogues19 as well as
schweinfurthin G (8) and both enantiomers of schwein-
furthin F (7).17,20 Although this work has allowed mean-
ingful SAR studies, the natural schweinfurthins that contain
an A-ring diol have as yet eluded total synthesis. Presented
here is a detailed description of the first total synthesis of
schweinfurthins B (2) and E (6), which both contain the key
A-ring diol. Apart from providing access to material on a
scale that the natural source of schweinfurthin B has not been
able to deliver, the present studies establish the absolute
stereochemistry of these intriguing natural products.
(14) Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F. J. Org. Chem. 1999,
64, 8718–8723.
(15) Treadwell, E. M.; Neighbors, J. D.; Wiemer, D. F. Org. Lett. 2002, 4,
3639–3642.
(16) Neighbors, J. D.; Beutler, J. A.; Wiemer, D. F. J. Org. Chem. 2005,
70, 925–931.
(17) Mente, N. R.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2008,
73, 7963–7970.
(18) Wiemer, D. F.; Neighbors, J. D.; Beutler, J. A. In PCT Int. Appl.
Preparation of Schweinfurthin analogues, pp CODEN: PIXXD2 WO
2005092878 A2 20051006 CAN 143:347317 AN 2005:1075787, 2005.
(19) Neighbors, J. D.; Salnikova, M. S.; Beutler, J. A.; Wiemer, D. F.
Biorg. Med. Chem. 2006, 14, 1771–1784.
Results and Discussion
Once the hexahydroxanthene core of the schweinfurthins
was obtained via cascade cyclization,17 access to the natural
(20) 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.
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SCHEME 2. Revised Synthesis of 3-Deoxyschweinfurthin B (3dSB)
SCHEME 3. Oxidations of Ketone 24
A-ring diols could have been pursued either through oxida-
tion of a tricyclic intermediate or via a parallel cascade
process that employed a more oxidized substrate. Because
the trans ring fusion and absolute stereochemistry of the
hexahydroxanthenes had been verified by our earlier synth-
eses, we chose to pursue oxidation of the tricyclic compounds
and began with studies of the key intermediate 11 (Scheme 1).
At the outset of these studies, this compound was available
via our previous work in 12 total steps from vanillin.16,17,21
Treatment of aldehyde 11 with TPAP22 gave the crystal-
line ketone 12 in excellent yield, and once suitable crystals
were obtained a diffraction analysis was secured. Oxidation
of the C-3 position of keto aldehyde 12 was attempted under
conditions developed by Davis,23,24 but in all cases (with
LDA, LiHMDS, or NaHMDS as the base) there was no
evidence for formation of an acyloin product and significant
quantities of starting material were recovered. To avoid the
possibility of competitive aldol processes, the aldehyde
group of compound 12 was protected under Luche condi-
tions25 as its dimethyl acetal 13, and this product then was
subjected to Rubottom26-28 and Davis conditions. Again,
no evidence for acyloin 14 was observed. At this stage it
became evident that a more efficient synthesis of the hex-
ahydoxanthene core would be desirable to support further
attempts at oxidation of the C-3 position, and this became
the immediate goal.
suggested use of a benzyl methyl ether as a masked benzalde-
hydein place of the TBSether employed as a protecting group
in our previous work.17 This modification dramatically im-
proved material throughput, cost effectiveness, and atom
economy. The new sequence (Scheme 2) began with benzyl
alcohol 15, which itself was available in 3 steps and 94%
overall yield from vanillin.15,16 Methylation via a Williamson
ether synthesis provided compound 16, which was then
exposed to n-BuLi to induce halogen-metal exchange. Reac-
tion of the resulting aryl anion with geranyl bromide (17)
furnished intermediate 18 in excellent overall yield. The
methyl ether 18 was much more easily purified by column
chromatography than the corresponding TBS analogues,
which allowed preparation of this intermediate on a 5- to
10-g scale.
An apparently trivial change in the protecting group
strategy had a dramatic impact on the efficiency of the central
reaction sequence. The elegant work of Danishefsky29,30
Compound 18 was epoxidized under Shi’s conditions with
the sugar derivative 19.21,31 This protocol consistently pro-
duced epoxide 20 in greater than 90% ee as determined by
HPLC. Although the yield for this step was modest, signifi-
cant quantities of starting material were recovered and could
be recycled, which makes the yield based on recovered
starting material more attractive (85%). As anticipated,17
cyclization of epoxide 20 occurred upon brief exposure to
(21) Neighbors, J. D.; Mente, N. R.; Boss, K. D.; Zehnder, D. W. II;
Wiemer, D. F. Tetrahedron Lett. 2008, 49, 516–519.
(22) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639–666.
(23) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919–934.
(24) Davis, F. A.; Haque, M. S. J. Org. Chem. 1986, 51, 4083–4085.
(25) Luche, J. L.; Gemal, A. L. J. Chem. Soc., Chem. Commun. 1978, 976–
977.
(26) Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599–1602.
(27) Rubottom, G. M.; Marrero, R. J. Org. Chem. 1975, 40, 3783–3784.
(28) Rubottom, G. M.; Mott, R. C.; Juve, H. D. J. Org. Chem. 1981, 46,
2717–2721.
(29) Cook, S. P.; Danishefsky, S. J. Org. Lett. 2006, 8, 5693–5695.
(30) Cook, S. P.; Gaul, C.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46,
843–847.
BF3 OEt2 and produced a mixture of compounds 21 and 22
3
in excellent overall yield. The formation of this mixture was
(31) Shi, Y. Acc. Chem. Res. 2004, 37, 488–496.
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SCHEME 4. Formation of an A-Ring Diol and Synthesis of Schweinfurthin B
of little consequence because compounds 21 and 22 could be
interconverted in excellent yield and both are useful inter-
mediates.17 A final DDQ oxidation of compound 21 pro-
ceeded in quantitative yield to produce aldehyde 23,
simplifying the previously established desilyation/oxidation
sequence into a single step. Preparation of intermediate 23,
now available in much improved yield and in just 8 total steps
from commercial vanillin,19,20 intersected our previous ef-
forts and thus constituted a formal synthesis of both 3-
deoxyschweinfurthin B (10)16 and schweinfurthin F (7).17
To continue efforts aimed at schweinfurthin B, hexahy-
droxanthene 21 was oxidized under Ley’s conditions22 to
afford ketone 24 in excellent yield (Scheme 3). Ketone 24 then
served as a platform for numerous oxidations. The Rubottom
approach was explored by using the more reactive silyl
triflates to encourage enol ether formation.32,33 Even so,
conversion to the silyl enol ether was incomplete (∼60%), as
our model systems. When more forcing conditions were
attempted with this oxidation, only decomposition was ob-
served. In hindsight, the intransigence of this ketone to
oxidation is consistent with the difficulty observed upon
attempted oxidation of an A-ring olefin.15 Ketone 24 proved
to be more reactive to oxidation by O2 under basic condi-
tions,35 but in this case the only isolated product had under-
gone rearrangement to an acid tentatively assigned structure
26, a product similar to one observed by Danishefsky.36
The limited success of direct methods for oxidation of
ketone 24 drove us to consider less straightforward strategies
for preparation of the cis A-ring diol. Furthermore, even if
the yield to compound 25 could be improved, obtaining the
desired diol stereoisomer from this compound might require
a lengthy reaction sequence. Reduction of a C-2 ketone
favored the equatorial alcohol in the 3dSB series, and the
diffraction analysis of compound 12 suggested that reduc-
tion also would occur cleanly from the less hindered face.
Therefore, a stepwise approach where reduction of a C-2
ketone was followed by reduction of a C-3 ketone to intro-
duce that axial alcohol appeared to be promising. Indeed, a
literature precedent involving reduction of a triterpene with
an A-ring R-diketone was very encouraging.37 However,
given that attempted oxidation of ketone 24 to an A-ring
diketone was not straightforward, an approach based on use
of an aldol condensation to generate a latent carbonyl group
in the form of an exocyclic olefin at C-3 was examined.38,39
After some experimentation, it was discovered that brief
1
observed by H NMR analysis of a reaction conducted in
CD2Cl2 or by analysis of the initial product mixture. When
this mixture was treated withmCPBA, the best result obtained
was a 9% isolated yield of acyloin 25. Attempted MoOPH
oxidation34 of ketone 24 afforded only recovered starting
material. Attempted use of the recent procedure of Tomkin-
son,35 based on treatment of a ketone with N-methyl-O-
benzoylhydroxylamine and rearrangement to the R-benzy-
loxy compound, also failed even though it worked superbly on
(32) Deng, Y.; Snyder, J. K. J. Org. Chem. 2002, 67, 2864–2873.
(33) Zhu, C.; Tang, P.; Yu, B. J. Am. Chem. Soc. 2008, 130, 5872–5873.
(34) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43,
188–196.
(35) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, K. L.; Jones, T. C.;
Killeen, N. M.; Taylor, P. H.; Thomas, S. P.; Tomkinson, N. C. O. Org. Lett.
2005, 7, 5729–5732.
(36) Liu, H.; Siegel, D. R.; Danishefsky, S. J. Org. Lett. 2006, 8, 423–425.
(37) 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.
(38) Wasserman, H. H.; Kuo, G. Tetrahedron 1992, 48, 7071–7082.
(39) Wasserman, H. H.; Parr, J. Acc. Chem. Res. 2004, 37, 687–701.
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FIGURE 3. Intermediate diol 32.
FIGURE 2. Key NOE correlations for alcohol 29.
exposure of ketone 24 to benzaldehyde and base in ethanol
produced enone 27 in quantitative yield. The availability of
this enone allowed exploration of a variety of strategies for
formation of a 3-keto compound.
SCHEME 5. Synthesis of Schweinfurthin E
One might reasonably assume that the limited function-
ality of enone 27 would enable straightforward oxidation of
the exocyclic olefin (Scheme 4). However, direct treatment of
40
compound 27 with OsO4/NaIO4 gave the complex acetal
28 as the sole product. Compound 28 may result from
formation of the desired R-diketone followed by overoxida-
tion of the corresponding enol form, similar to observations
by Sejbal41 and Hanson.42 To circumvent this problem, a
more stepwise approach was pursued. Reduction of the R,β-
unsaturated ketone 27 under Luche conditions43,44 afforded
alcohol 29 with the desired configuration at the C-2 position
as evidenced by key NOESY correlations (Figure 2). To stay
any potential side reactions, the hindered alcohol 29 was
protected as a MOM acetal under forcing conditions to
afford compound 30 in moderate yield, albeit a significant
amount of starting material also could be recovered. Initial
attempts at oxidative cleavage of the olefin via reaction with
provided schweinfurthin B (2) in moderate yield. Synthetic
schweinfurthin B proved to be identical with an authentic
sample of the natural material in all respects,1 including
specific rotation after correction for the known ee of the
synthetic material.
40
OsO4/NaIO4 did provide a modest yield of ketone 31
(32%) along with a significant amount of diol 32 (26%,
Figure 3). Addition of excess NaIO4, use of longer reaction
time, and application of a higher reaction temperature all
failed to effect a complete conversion. However, the use of a
more active oxidant in excess (KMnO4, 10 equiv)45 did
provide a satisfactory yield of the desired ketone 31 along
with significant quantities of recovered staring material even
after prolonged exposure. It is worth noting that attempted
ozonolysis of intermediates 27, 29, and 30 under both
standard and modified46 conditions produced only complex
mixtures.
With ketone 31 in hand, the remainder of the synthesis
proceeded smoothly. Ketone 31 was reduced upon treatment
with NaBH4 in quantitative yield to afford alcohol 33 as
the only observed diastereomer.37 The relative stereochem-
istry of the C-3 center was assigned based on coupling
constants: H-3 appears as an apparent quartet with J =
3.2 Hz. Exposure of compound 33 to DDQ afforded alde-
hyde 34 directly from the methyl ether. Aldehyde 34 then was
coupled to known phosphonate 3514 under standard HWE
conditions to yield stilbene 36. Finally, acidic hydrolysis
of the three MOM acetals under standard conditions20
One key advantage of the convergent approach to the
schweinfurthins we have developed is that both the left and
right half subunits can be employed in a divergent fashion to
afford multiple products efficiently. In this vein, aldehyde 34
also was coupled with phosphonate 3720 (Scheme 5) to
produce stilbene 38. Deprotection of compound 38 afforded
schweinfurthin E (6) in excellent yield. Synthetic schwein-
1
furthin E prepared in this fashion displayed identical H
NMR and 13C NMR data, and a specific rotation very
similar to that reported for the natural material.2
In conclusion, we have successfully synthesized the natural
antipode of schweinfurthins B and E via a Shi epoxidation/
cascade cyclization sequence. Although attempts at direct R-
oxidation of some hexahydroxanthene intermediates were
not productive, it was possible to develop a reaction se-
quence based on a classic aldol condensation. A subsequent
oxidation/reduction sequence furnished the desired cis 2,3-
dihydroxyhexahydroxanthene. This synthesis has deter-
mined the absolute stereochemistry of both schweinfurthin
B and E for the first time. Now that this route to the natural
A-ring diols has been established, future efforts can focus on
the synthesis of schweinfurthin A (1) and should be straight-
forward given our past synthesis of schweinfurthin G (8).10
In addition, aldehyde 34 can be used as a point of divergence
to continue exploration of the schweinfurthins’ essential
pharmacophore as well as the mechanism(s) responsible
for their biological activity. Our efforts along these lines will
be reported in due course.
(40) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–
3219.
(41) Sejbal, J.; Homolova, M.; Tislerova, I.; Krecek, V. Collect. Czech.
Chem. C 2000, 65, 1339–1356.
(42) Hanson, J. R. Tetrahedron 1966, 22, 1453–1460.
(43) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(44) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459.
(45) Cope, A. C.; Berchtold, G. A.; Peterson, P. E.; Sharman, S. H. J. Am.
Chem. Soc. 1960, 82, 6366–6369.
(46) Schiaffo, C. E.; Dussault, P. H. J. Org. Chem. 2008, 73, 4688–4690.
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Experimental Section
320.1991. The MOM acetal 22 (140 mg, 17%) also was isolated
from this reaction mixture: [R]26.4D þ34.8 (c 1.56, CH3OH, 92%
ee by HPLC); 1H NMR (CDCl3) δ 6.67 (s, 1H), 6.66 (s, 1H), 4.74
(d, J = 6.8 Hz, 1H), 4.61 (d, J = 6.9 Hz, 1H), 4.31 (s, 2H), 3.82
(s, 3H), 3.40 (s, 3H), 3.36 (s, 3H), 3.24 (dd, J = 11.5, 4.2 Hz, 1H),
2.68-2.65 (m, 2H), 2.12-2.07 (m, 1H), 1.98-1.93 (m, 1H),
Methyl Ether 16. To a solution of the known benzyl alcohol
1521 (4.42 g, 15.9 mmol) in THF at 0 °C was added NaH (1.2 g,
60% in oil, 30 mmol) followed by CH3I (1.5 mL, 24 mmol). After
3 h the reaction was quenched by addition of water. The
resulting solution was extracted with ethyl acetate, and the
organic extract was washed with brine. After the organic phase
was dried (MgSO4) and concentrated in vacuo, final purification
by column chromatography (3:1 hexanes/ethyl acetate) af-
forded methyl ether 16 (4.84 g, 96%) as a yellow oil: 1H NMR
(CDCl3) δ 7.06 (s, 1H), 6.82 (s, 1H), 5.12 (s, 2H), 4.31 (s, 2H),
3.80 (s, 3H), 3.60 (s, 3H), 3.33 (s, 3H); 13C NMR (CDCl3) δ
153.6, 142.8, 135.8, 124.1, 117.7, 111.0, 98.8, 73.9, 58.4, 58.1,
56.2; HRMS (ESI) m/z calcd for C11H15O4Br (Mþ) 290.0154,
found 290.0157.
Genanyl Arene 18. To a solution of methyl ether 16 (2.0 g,
6.9 mmol) in THF at -78 °C was added n-BuLi (3.0 mL, 2.5 M in
hexanes) over 5 min. After ∼30 min geranyl bromide (17, 1.5 mL,
7.9 mmol) was added dropwise. The solution was kept cold for
50 min and quenched by addition of water. The resulting solution
was extracted with ethyl acetate, and the combined organic
phases were washed with brine. The organic phase was dried
(MgSO4) and concentrated in vacuo. Final purification by
column chromatography (9:1 hexanes/ethyl acetate) afforded
arene 18 (2.2 g, 91%) as a yellow oil: 1H NMR (CDCl3) δ 6.78
(s, 1H), 6.73 (s, 1H), 5.32 (t, J=7.2 Hz, 1H), 5.13-5.10 (m, 1H),
5.07 (s, 2H), 4.37 (s, 2H), 3.84 (s, 3H), 3.59 (s, 3H), 3.43 (d, J =
7.2 Hz, 2H), 3.38 (s, 3H), 2.12-2.02 (m, 4H), 1.71 (s, 3H), 1.69 (s,
3H), 1.60 (s, 3H); 13C NMR (CDCl3) δ 152.1, 143.3, 136.0, 135.5,
134.0, 131.2, 124.2, 122.6, 121.0, 109.3, 98.8, 74.6, 58.0, 57.3,
55.6, 39.6, 28.2, 26.5, 25.6, 17.6, 16.0; HRMS (ESI) m/z calcd for
C21H32O4 (Mþ) 348.2301, found 348.2309.
1.78-1.53 (m, 3H), 1.21 (s, 3H), 1.05 (s, 3H), 0.87 (s, 3H); 13
C
NMR (CDCl3) δ 148.6, 142.0, 128.9, 122.2, 121.1, 108.9, 96.0,
83.9, 76.6, 74.8, 57.8, 55.8, 55.5, 46.8, 38.1, 37.4, 27.2, 25.1, 22.9,
19.6, 15.0; HRMS (ESI) m/z calcd for C21H32O5 (Mþ) 364.2250,
found 364.2256.
Aldehyde 23.16. To a solution of tricyclic ether 21 (36 mg, 0.11
mmol) in CH2Cl2/water (10:1) at rt was added DDQ (67 mg,
0.30 mmol), and after 75 min the reaction was quenched by
addition of NaHCO3. The resulting solution was extracted with
CH2Cl2, and the combined organic phases were washed with
brine, dried (MgSO4), and concentrated in vacuo. Final purifi-
cation by column chromatography (1:1 hexanes/ethyl acetate)
afforded tricyclic aldehyde 23 (34 mg, 100%) as a yellow wax.
The spectroscopic data and reactivity of this material were
identical with those of aldehyde 23 prepared via different
methods.16
Ketone 24. To a solution of tricycle 21 (119 mg, 0.28 mmol) in
CH2Cl2 at rt was added TPAP (9 mg, 0.03 mmol) and NMO (49
mg, 0.41 mmol). After 18.5 h the reaction mixture was diluted
with ethyl acetate, filtered through Celite, and concentrated in
vacuo. Final purification by column chromatography (2:3 hex-
anes/ethyl acetate) afforded ketone 24 (117 mg, 99%) as a
colorless oil: [R]26.4 91.8 (c 1.1, CH3OH, 92% ee by HPLC);
D
1H NMR (CDCl3) δ 6.72 (s, 1H), 6.70 (s, 1H), 4.34 (s, 2H), 3.85
(s, 3H), 3.39 (s, 3H), 2.81 (dd, J = 16.0, 13.6 Hz, 1H), 2.73-2.63
(m, 2H), 2.48 (ddd, J = 18.5, 4.7, 3.2 Hz, 1H), 2.37 (ddd, J =
13.1, 5.7, 3.2 Hz, 1H), 2.16 (dd, J = 14.4, 4.7 Hz, 1H), 2.07 (dd,
Epoxide 20. To a solution of arene 18 (2.8 g, 8.0 mmol) and
Shi’s catalyst (19, 590 mg, 2.1 mmol) in aq buffer (30 mL, 2 M
K2CO3 and 4 mM EDTA) and organic phase (50 mL, 1:1:1
CH2Cl2/MeCN/EtOH) at 0 °C was added hydrogen peroxide
(7 mL, 30%) over 7 h. After an additional 2 h the reaction was
quenched by addition of aq Na2SO3. The resulting solution was
extracted with ethyl acetate, and the combined organic phases
were washed with brine. The organic phase was dried (MgSO4)
and concentrated in vacuo. Final purification by column chro-
matography (4:1 hexanes/ethyl acetate) afforded recovered
starting material (0.62 g, 22%) and epoxide 20 (1.84 g, 63%)
as a colorless oil: 1H NMR (CDCl3) δ 6.75 (s, 1H), 6.69 (s, 1H),
5.34 (t, J = 7.1 Hz, 1H), 5.04 (s, 2H), 4.34 (s, 2H), 3.81 (s, 3H),
3.55 (s, 3H), 3.40 (d, J = 7.1 Hz, 2H), 3.35 (s, 3H), 2.68 (t, J =
6.3 Hz, 1H), 2.31-2.08 (m, 2H), 1.71 (s, 3H), 1.68-1.63 (m, 2H),
1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (CDCl3) δ 152.0, 143.2,
135.2, 135.0, 134.0, 123.1, 120.8, 109.3, 98.7, 74.5, 64.0, 58.2,
58.0, 57.3, 55.5, 36.2, 28.2, 27.2, 24.7, 18.6, 16.0; HRMS (ESI)
m/z calcd for C21H32O5 (Mþ) 364.2250, found 364.2262.
Tricyclic Ether 21. To a solution of epoxide 20 (958 mg,
J = 13.0, 4.9 Hz, 1H), 1.43 (s, 3H), 1.20 (s, 3H), 1.11 (s, 3H); 13
C
NMR (CDCl3) δ 213.6, 148.8, 141.8, 129.6, 121.5, 121.0, 109.2,
75.6, 74.8, 58.0, 55.9, 47.4, 46.4, 38.0, 35.2, 24.5, 23.7, 20.8, 19.0;
HRMS (ESI) m/z calcd for C19H26O4 (Mþ) 318.1831, found
318.1812.
Enone 27. To a solution of ketone 24 (152 mg, 0.48 mmol) in
ethanol at rt was added benzaldehyde (0.2 mL, 1.7 mmol)
followed by KOH (209 mg, 3.7 mmol). After 2 h the reaction
was quenched by addition of NH4Cl, the resulting solution was
extracted with ethyl acetate, and the combined organic extract
was washed with brine. The organic phase was dried (MgSO4)
and concentrated in vacuo. Final purification of the residue by
column chromatography (3:1 hexanes/ethyl acetate) afforded
enone 27 (194 mg, 100%) as a colorless oil: [R]26.4D 201 (c 1.0,
CHCl3, 92% ee by HPLC); 1H NMR (CDCl3) δ 7.63 (d, J = 3.2
Hz, 1H), 7.45-7.33 (m, 5H), 6.74 (d, J = 1.2 Hz, 1H), 6.71 (m,
1H), 4.35 (s, 2H), 3.86 (s, 3H), 3.55 (d, J = 15.6 Hz, 1H), 3.39 (s,
3H), 3.00 (dd, J = 15.6, 2.8 Hz, 1H), 2.81-2.71 (m, 2H), 2.35
(dd, J = 12.4, 5.2 Hz, 1H), 1.32 (s, 3H), 1.21 (s, 3H), 1.17 (s, 3H);
13C NMR (CDCl3) δ 205.0, 148.5, 141.5, 138.6, 135.0, 132.3,
130.0 (2C), 129.5, 128.6, 128.3 (2C), 121.2, 120.8, 109.3, 75.4,
74.6, 57.8, 55.9, 45.9, 45.3, 41.7, 28.7, 24.2, 22.3, 19.0; HRMS
(ESI) m/z calcd for C26H30O4 (Mþ) 406.2144, found 406.2135.
Alcohol 29. To a solution of ketone 27 (1.75 g, 4.3 mmol) in
2.6 mmol) in CH2Cl2 (350 mL) at -78 °C was added BF3 OEt2
3
(2.0 mL, 16 mmol). After 7 min the reaction was quenched by
addition of TEA (4.1 mL, 29 mmol). The resulting solution was
concentrated in vacuo, dissolved in CH2Cl2, and washed with
water then brine. The organic phase was dried (MgSO4) and
concentrated in vacuo. Final purification by column chroma-
tography (1:1 hexanes/ethyl acetate) afforded desired tricyclic
CH3OH at rt was added CeCl3 7H2O (1.81 g, 4.9 mmol)
3
followed by NaBH4 (300 mg, 7.9 mmol). After 20 min, the
reaction was quenched by addition of water and concentrated in
vacuo. The resulting solution was extracted with ethyl acetate,
and the combined extracts were washed with brine, dried
(MgSO4), and concentrated in vacuo, to afford alcohol 29
(1.75 g, 100%) as white crystals. This material was used in the
ether 21 (583 mg, 69%) as a yellow oil: [R]26.4 þ122 (c 1.3,
D
CH3OH, 92% ee by HPLC); 1H NMR (CDCl3) δ 6.69 (s, 1H),
6.67 (s, 1H), 4.33 (s, 2H), 3.83 (s, 3H), 3.38 (s, 3H), 3.38-3.33 (m,
1H), 2.70-2.67 (m, 2H), 2.13-2.04 (m, 1H), 1.87-1.76 (m, 3H),
1.68-1.57 (m, 2H), 1.24 (s, 3H), 1.06 (s, 3H), 0.85 (s, 3H); 13
C
next step without further purification: [R]26.4 45.3 (c 1.0,
D
NMR (CDCl3) δ 148.7, 142.1, 129.0, 122.3, 121.3, 109.0, 77.8,
76.7, 74.9, 58.0, 55.9, 46.6, 38.3, 37.6, 28.2, 27.3, 23.0, 19.7, 14.2;
HRMS (ESI) m/z calcd for C19H28O4 (Mþ) 320.1988, found
CHCl3, 92% ee by HPLC); 1H NMR (CDCl3) δ 7.33-7.21
(m, 5H), 6.77 (s, 1H), 6.68-6.67 (m, 2H), 4.32 (s, 2H), 3.91
(s, 1H), 3.81 (s, 3H), 3.39 (s, 3H), 3.36 (d, J=7.2Hz,1H),2.72-2.60
6970 J. Org. Chem. Vol. 74, No. 18, 2009

Topczewski et al.
JOCArticle
(m, 2H), 2.29 (d, J = 12.8 Hz, 1H), 1.90 (dd, J = 11.6, 5.6 Hz,
1H), 1.19 (s, 3H), 1.04 (s, 3H), 0.83 (s, 3H); 13C NMR (CDCl3) δ
148.7, 142.2, 138.2, 137.4, 129.2, 128.8 (2C), 128.2 (2C), 126.4,
124.0, 122.2, 121.3, 109.1, 80.0, 78.1, 74.9, 58.0, 55.9, 47.2, 41.2,
39.7, 27.3, 23.2, 19.8, 14.2; HRMS (ESI) m/z calcd for C26H32O4
(Mþ) 408.2301, found 408.2295. Images of the NOSEY and
COSEY spectra are included in the SI.
small amount of water followed by brine. The organic phase was
dried (MgSO4) and concentrated in vacuo. Aldehyde 34 (48 mg,
100%) was obtained as a faintly yellow wax that was used
without further purification: [R]26.4D 41.6 (c 1.0, CH3OH, 92%
ee by HPLC); 1H NMR (CDCl3) δ 9.80 (s, 1H), 7.25 (s, 1H), 7.24
(s, 1H), 4.83 (d, J = 6.6 Hz, 1H), 4.73 (d, J = 6.6 Hz, 1H), 4.32
(ddd, J = 3.6, 3.6, 3.6 Hz, 1H), 3.90 (s, 3H), 3.47 (s, 3H), 3.27 (d,
J = 3.6 Hz, 1H), 2.86-2.79 (m, 2H), 2.59 (dd, J = 14.4, 3.6 Hz,
1H), 2.39 (br d, 1H), 1.98 (dd, J = 14.4, 3.6 Hz, 1H), 1.79 (dd,
Arene 30. To a solution of alcohol 29 (236 mg, 0.58 mmol) in
CH2Cl2 at rt was added DIPEA (0.4 mL, 2.3 mmol) followed by
MOMCl (0.1 mL, 1.3 mmol). After 15 h, the reaction was
quenched by addition of water. The resulting solution was
extracted with CH2Cl2, and the combined 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 (4:1 hexanes/ethyl acetate) afforded
recovered starting material (42 mg, 18%) and the MOM acetal
30 (262 mg, 68%) as a colorless oil: [R]26.4D 21.7 (c 1.1, CHCl3,
J = 13.2, 5.4 Hz, 1H), 1.49 (s, 3H), 1.13 (s, 3H), 1.11 (s, 3H); 13
C
NMR (CDCl3) δ 191.0, 149.7, 148.5, 128.8, 127.2, 122.7, 107.5,
97.0, 84.7, 78.0, 68.6, 56.2, 56.1, 46.9, 42.1, 38.0, 28.8, 22.9, 21.8,
16.7; HRMS (ESI) m/z calcd for C20H28O6 (Mþ) 364.1886,
found 364.1896.
Stilbene 36. To a solution of aldehyde 34 (23 mg, 0.063 mmol)
and phosphonate 3514 (50 mg, 0.1 mmol) in THF at rt was added
15-crown-5 (0.01 mL) followed by NaH (44 mg, 60% in oil,
1.1 mmol). After 3.5 h the reaction was quenched by addition of
water, the resulting solution was extracted with ethyl acetate,
and the combined organic phases were washed with brine. The
organic phase was dried (MgSO4) and concentrated in vacuo.
Final purification by preparative thin layer chromatography
(2:8 hexanes/ethyl acetate) afforded stilbene 36 (31 mg, 71%) as
a yellow wax: 1H NMR (CDCl3) δ 6.97-6.86 (m, 6H), 5.22 (s,
4H), 5.23-5.22 (m, 1H), 5.07-5.06 (m, 1H), 4.83 (d, J = 6.4 Hz,
1H), 4.72 (d, J = 6.8 Hz, 1H), 4.32 (ddd, J = 3.2, 3.2, 3.2 Hz,
1H), 3.90 (s, 3H), 3.50 (s, 6H), 2.46 (s, 3H), 3.40 (d, J = 7.2 Hz,
2H), 3.27 (d, J = 2.8 Hz, 1H), 2.79-2.74 (m, 2H), 2.56 (dd, J =
14.4, 3.2 Hz, 1H), 2.36 (br d, 1H), 2.06-1.94 (m, 5H), 1.79 (s,
3H), 1.81-1.77 (m, 1H), 1.65 (s, 3H), 1.57 (s, 3H), 1.47 (s, 3H),
1.12 (s, 3H), 1.09 (s, 3H); 13C NMR (CDCl3) δ 155.9 (2C), 149.0,
142.3, 136.7, 134.6, 131.2, 128.9, 128.3, 126.4, 124.4, 122.8,
122.6, 120.5, 119.5, 107.0 (2C), 106.0, 96.9, 94.5 (2C), 84.9,
76.5, 68.7, 56.1 (2C), 56.0, 55.9, 47.2, 42.3, 39.8, 37.9, 28.8, 26.7,
25.6, 23.0, 22.7, 21.5, 17.6, 16.7, 16.1; HRMS (ESI) m/z calcd for
C41H58O9 (Mþ) 694.4081, found 694.4077.
1
92% ee by HPLC); H NMR (CDCl3) δ 7.34-7.19 (m, 5H),
6.68-6.67 (m, 3H), 4.78 (d, J = 6.8 Hz, 1H), 4.70 (d, J = 7.2 Hz,
1H), 4.33 (s, 2H), 3.99 (d, J = 1.2 Hz, 1H), 3.82 (s, 3H), 3.45 (s,
3H), 3.40 (d, J = 10.8 Hz, 1H), 3.38 (s, 3H), 2.73-2.67 (m, 2H),
2.29 (d, J = 12.4 Hz, 1H), 1.95 (dd, J = 12.4, 5.6 Hz, 1H), 1.21
(s, 3H), 1.01 (s, 3H), 0.88 (s, 3H); 13C NMR (CDCl3) δ 148.7,
142.2, 137.3, 135.1, 129.3, 128.8 (2C), 128.2 (2C), 126.4, 124.9,
122.3, 121.2, 109.0; 96.2, 85.6, 78.2, 74.8, 58.0, 56.4, 55.9, 47.4,
41.4, 39.6, 27.3, 23.2, 19.6, 15.0; HRMS (ESI) m/z calcd for
C28H36O5 (Mþ) 452.2563, found 452.2561.
Ketone 31. To a solution of compound 30 (35 mg, 0.08 mmol)
in acetone was added NaHCO3 (14 mg, 0.17 mmol) followed by
KMnO4 (23 mg, 0.15 mmol). After 20 h at rt, additional
NaHCO3 (70 mg, 0.83 mmol) and KMnO4 (20 mg, 0.13 mmol)
were added. After an additional 24 h at rt, the reaction mixture
was filtered through Celite, washed with acetone, and concen-
trated in vacuo. Final purification by column chromatography
(3:1 hexanes/ethyl acetate) afforded recovered starting material
(8 mg, 23%) and ketone 31 (19 mg, 65%) as a colorless oil: 1H
NMR (CDCl3) δ 6.73 (s, 1H), 6.71 (s, 1H), 4.73 (d, J = 7.2 Hz,
1H), 4.70 (d, J = 7.2 Hz, 1H), 4.36 (s, 2H), 4.14 (s, 1H), 3.86 (s,
3H), 3.44 (s, 3H), 3.40 (s, 3H), 3.00-2.78 (m, 4H), 2.34 (dd, J =
12.4, 5.6 Hz, 1H), 1.26 (s, 3H), 1.21 (s, 3H), 0.88 (s, 3H); 13C
NMR (CDCl3) δ 206.4, 150.0, 142.8, 131.2, 122.9, 122.2, 110.5,
97.4, 87.4, 79.6, 75.9, 59.2, 57.8, 57.4, 55.0, 48.4, 42.0, 28.3, 24.4,
21.8, 16.8; HRMS (ESI) m/z calcd for C21H30O6 (Mþ) 378.2049,
found 378.2042.
Schweinfurthin B (2). To a solution of compound 36 (12 mg,
0.017 mmol) in CH3OH was added TsOH (24 mg, 0.13 mmol)
and the resulting solution was stirred at rt. After 46 h, the reaction
was quenched by addition of NaHCO3 and concentrated in
vacuo. The resulting solution was extracted with ethyl acetate,
and the combined organic phases were washed with brine, dried
(MgSO4), and concentrated in vacuo. After final purification by
preparative thin layer chromatography (1:9 hexanes/ethyl
acetate), schweinfurthin B (2, 5.3 mg, 55%) was obtained as
Alcohol 33. To a solution of ketone 31 (18 mg, 0.05 mmol)
in CH3OH at rt was added NaBH4 (24 mg, 0.66 mmol). After
10 min, the reaction was quenched by addition of water and
concentrated in vacuo. The resulting solution was extracted
with ethyl acetate, and the combined organic phases were
washed with brine, dried (MgSO4), and concentrated in vacuo.
This afforded alcohol 33 (18 mg, 100%) as a white solid, which
was used in the subsequent step without further purification:
colorless wax: [R]26.4D þ40.2 (c 0.41, EtOH, 92% ee by HPLC);
1
lit.1 [R]26.4 þ44.7 (c 1.0, EtOH); the H and 13C NMRs were
D
found to be identical with the literature spectra.1 HRMS (ESI)
m/z calcd for C35H46O6 (Mþ) 562.3294, found 562.3287.
Stilbene 38. To a solution of aldehyde 34 (21 mg, 0.058 mmol)
and phosphonate 3914 (38 mg, 0.09 mmol) in THF (5 mL) at rt
was added 15-crown-5 (0.01 mL) followed by NaH (60 mg, 60%
in oil, 1.5 mmol), and after 4 h the reaction was quenched by
addition of water. The resulting solution was extracted with
ethyl acetate, and the combined organic phases were washed
with brine, dried (MgSO4), and concentrated in vacuo. Final
purification by column chromatography (3:7 hexanes/ethyl
[R]26.4 22.2 (c 1.1, CH3OH, 92% ee by HPLC); 1H NMR
D
(CDCl3) δ 6.70 (s, 1H), 6.68 (s, 1H), 4.82 (d, J = 6.4 Hz, 1H),
4.70 (d, J = 7.2 Hz, 1H), 4.34 (s, 2H), 4.31 (ddd, J = 3.2, 3.2, 3.2
Hz, 1H), 3.85 (s, 3H), 3.45 (s, 3H), 3.38 (s, 3H), 3.26 (d, J = 3.2
Hz, 1H), 2.77-2.60 (m, 2H), 2.54 (dd, J = 14.0, 3.6 Hz, 1H),
2.36 (br d, 1H), 1.96 (dd, J = 14.4, 3.6 Hz, 1H), 1.77 (dd, J =
12.8, 5.2 Hz, 1H), 1.45 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H); 13C
NMR (CDCl3) δ 148.9, 141.8, 129.1, 122.6, 121.2, 109.2, 96.9,
84.9, 76.2, 74.9, 68.7, 57.9, 56.1, 56.0, 47.1, 42.3, 37.8, 28.7, 22.9,
21.4, 16.6; HRMS (ESI) m/z calcd for C21H32O6 (Mþ) 380.2199,
found 380.2183.
1
acetate) afforded stilbene 38 (26 mg, 72%) as a white wax: H
NMR (CDCl3) δ 6.97-6.87 (m, 6H), 5.21 (s, 4H), 5.24-5.19 (m,
1H), 4.83 (d, J = 6.8 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.31
(ddd, J = 3.2, 3.2, 3.2 Hz, 1H), 3.90 (s, 3H), 3.50 (s, 6H), 3.46 (s,
3H), 3.39 (d, J = 7.2 Hz, 2H), 3.27 (d, J = 3.2 Hz, 1H), 2.80-
2.74 (m, 2H), 2.56 (dd, J = 14.4, 3.2 Hz, 1H), 2.36 (br d, 1H),
1.98 (dd, J = 14.4, 3.2 Hz, 1H), 1.81-1.77 (m, 1H), 1.79 (s, 3H),
1.66 (s, 3H), 1.48 (s, 3H), 1.12 (s, 3H), 1.09 (s, 3H); 13C NMR
(CDCl3) δ 158.5, 155.8 (2C), 149.0, 142.3, 136.7, 131.0, 128.9,
128.3, 126.4, 122.8, 120.4, 119.4, 107.0, 105.9 (2C), 96.9, 94.5
(2C), 84.9, 76.5, 68.7, 56.1, 56.0, 56.0 (2C), 47.2, 42.3, 37.9, 28.8,
Aldehyde 34. To a solution of methyl ether 33 (50 mg,
0.13 mmol) in CH2Cl2/water (4:1) at rt was added DDQ (34 mg,
0.15 mmol). After 80 min the reaction was quenched by addition
of brine and NaHCO3. The resulting solution was extracted with
CH2Cl2, and the combined organic phases were washed with a
J. Org. Chem. Vol. 74, No. 18, 2009 6971

Topczewski et al.
JOCArticle
25.8, 22.9, 22.8, 21.5, 17.7, 16.6; HRMS (ESI) m/z calcd for
Dr. Dale C. Swenson for his assistance with the diffraction
analysis of compound 12, and the University of Iowa Mass
Spectrometry Facility for providing the high-resolution mass
spectra. Financial support from the Roy J. Carver Charita-
ble Trust and the Children’s Tumor Foundation is gratefully
acknowledged.
C36H50O9 (Mþ) 626.3455, found 626.3466.
Schweinfurthin E (6). Stilbene 38 (12 mg, 0.02 mmol) was
treated with TsOH (24 mg, 0.13 mmol) in CH3OH as described
for compound 36. After standard workup and final purification
by preparative thin layer chromatography (1:9 hexanes/ethyl
acetate), schweinfurthin E (6, 7.6 mg, 81%) was obtained as a
colorless oil: [R]26.4D þ40.5 (c 0.67, CH3OH; 92% ee by HPLC);
Supporting Information Available: General experimental
procedures, experimental paragraphs for compounds 12, 21, 22,
25, 26, 28, and 32, 1H and 13C NMR spectra for compounds 2, 6,
12, 16, 18, and 20-34, details of the diffraction analysis of
compound 12, along with NOESY and COSEY spectra of
compound 29. This material is available free of charge via the
Internet at http://pubs.acs.org.
lit.2 [R]26.4 þ49.2 (c 0.13, CH3OH); the 1H and 13C NMR
D
spectra were identical with literature data.2 HRMS (ESI) m/z
calcd for C30H38O6 (Mþ) 494.2668, found 494.2670.
Acknowledgment. We thank Dr. Nolan Mente for provid-
ing phosphonates 35 and 37 as well as for helpful discussions,
6972 J. Org. Chem. Vol. 74, No. 18, 2009