Synthesis of a Pondaplin Dimer and Trimer. Aromatic Interactions in Novel Macrocycles

Article abstract of DOI:10.1021/jo0356006

Synthetic challenges in the use of an oxabicyclo[2.2.2]octenone moiety as a masked arene for the synthesis of pondaplin are disclosed. During the course of a study of the Heck reaction as a tool for macrocyclization to provide strained paracyclophanes, no

Full text of DOI:10.1021/jo0356006

Syn th esis of a P on d a p lin Dim er a n d Tr im er . Ar om a tic
In ter a ction s in Novel Ma cr ocycles
Michael S. Leonard,† Patrick J . Carroll,‡ and Madeleine M. J oullie´*,‡
Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323, and Department of Chemistry,
Washington & J efferson College, 60 South Lincoln Street, Washington, Pennsylvania 15301
mjoullie@sas.upenn.edu
Received October 30, 2003
Synthetic challenges in the use of an oxabicyclo[2.2.2]octenone moiety as a masked arene for the
synthesis of pondaplin are disclosed. During the course of a study of the Heck reaction as a tool for
macrocyclization to provide strained paracyclophanes, novel macrocycles displaying intra- and
intermolecular aromatic interactions have been synthesized. The geometry of these interactions is
compared to recent computational literature data.
In tr od u ction
Pondaplin1 (1) is a cyclic prenylated phenylpropanoid
isolated from Annona glabra, which is commonly referred
to as pond apple. Pond apple has been used in traditional
medicine as an insecticide and parasiticide.2,3 In 1999,
McLaughlin and co-workers isolated the compound from
the ethanol extracts of its leaves.1 Pondaplin was found
to have moderate and somewhat selective antitumor
activity when screened across six human tumor cell lines
in a seven-day MTT human solid tumor cytotoxicity test.1
Pondaplin is a structurally unique molecule as it appears
to be the only example of a [9]paracyclophane natural
product. Closely related are some members of the cyclo-
peptide alkaloid family of natural products, notably the
14-membered [10]paracyclophane pandamine4,5 and the
13-membered [10]metacyclophane zizyphine A.6-10 In
comparison with these compounds, pondaplin contains
a shorter tether that bears five sp2 centers, imparting a
high degree of strain energy and a potentially significant
deformation of the aromatic ring from planarity.11,12
F IGURE 1. Retrosynthetic analysis of pondaplin (1).
Resu lts a n d Discu ssion
Results from our laboratories,13 as well as a recent
communication by Bressy and Piva,14 have shown that a
ring-closing metathesis approach to the synthesis of
pondaplin, while attractive based upon its simplicity, is
unsuitable due to the highly strained structure and the
greater stability of the undesired E geometry of the
trisubstituted olefin. Because of these findings, we de-
vised a strategy that would construct a macrocycle
containing a core that would serve as a masked aromatic
ring and would not impose the same degree of strain on
the molecule during the cyclization events (Figure 1). To
this end, we selected an oxabicyclo[2.2.2]octenone core
structure. Following ring closure, extrusion of carbon
dioxide and subsequent oxidation would provide the
aromatic ring.
* To whom correspondence should be addressed. Phone: (215) 898-
3158. Fax: (215) 573-2112.
† Washington & J efferson College.
‡ University of Pennsylvania.
(1) Liu, X. X.; Pilarinou, E.; McLaughlin, J . L. Tetrahedron Lett.
1999, 40, 399.
(2) Ohsawa, K.; Atsuzawa, S.; Mitsui, T.; Yamamoto, I. J . Pesticide
Sci. 1991, 16, 93.
(3) Padmaja, V.; Thankamany, K.; Hara, N.; Fujimoto, Y.; Hisham,
A. J . Ethnopharmacol. 1995, 48, 21.
(4) Pa¨ıs, M.; Lusinchi, X.; Goutarel, R.; Monseur, X. Bull. Soc. Chim.
Fr. 1964, 817.
We believed the requisite bicyclooctenone could be
obtained by a Diels-Alder reaction of 5-bromo-2-py-
rone15,16 (4) and the tert-butyldimethylsilyl enol ether17,18
of acetaldehyde (5). The compounds were prepared ac-
cording to literature precedent, and cycloaddition pro-
(5) Pa¨ıs, M.; J arreau, F.-X.; Lusinchi, X.; Goutarel, R. Ann. Chim.
France 1966, 1, 83.
(6) Tschesche, R.; Kaussmann, E. U.; Eckhardt, G. Tetrahedron Lett.
1973, 2577.
(7) Schmidt, U.; Bokens, H.; Lieberknecht, A.; Griesser, H. Tetra-
hedron Lett. 1981, 22, 4949.
(8) Schmidt, U.; Lieberknecht, A.; Bokens, H.; Griesser, H. J . Org.
Chem. 1983, 48, 2680.
(9) Lin, H. Y.; Chen, C. H.; You, B. J .; Lin, K. C. S. C.; Lee, S. S. J .
Nat. Prod. 2000, 63, 1338.
(11) Tobe, Y. Top. Curr. Chem. 1994, 172, 1.
(12) Rosenfeld, S. M.; Choe, K. A. In Cyclophanes; Keehn, P. M.,
Rosenfeld, S. M., Eds.; Academic Press: New York, 1983; Vol. 45-I, p
311.
(13) (a) Leonard, M. S.; Chen, W.-C.; J oullie´, M. M. Abstracts of
Papers, 224th ACS National Meeting, Boston, MA, August 18-22; 2002;
ORGN-780. (b) Leonard, M. S., Ph.D. Thesis, University of Pennsyl-
vania, Philadelphia, PA, 2003.
(10) Tripathi, M.; Pandey, M. B.; J ha, R. N.; Pandey, V. B.; Tripathi,
P. N.; Singh, J . P. Fitoterapia 2001, 72, 507.
(14) Bressy, C.; Piva, O. Synlett 2003, 87.
10.1021/jo0356006 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/25/2004
2526
J . Org. Chem. 2004, 69, 2526-2531

Synthesis of a Pondaplin Dimer and Trimer
SCHEME 1a
unsuccessful under a variety of conditions, including the
use of highly active ligands such as tri-2-furylphosphine.
An alternate strategy involved installation of a vinyl
group via a Stille reaction followed by ring-closing
metathesis (Scheme 4). Disappointingly, vinyl bromide
12 proved to be totally inert to the Stille vinylation
conditions, despite the fact that a simple model (6) readily
underwent the reaction (Scheme 5). Consequently, this
approach to pondaplin was abandoned so that attention
could be focused on other synthetic strategies, some of
which are under investigation in our laboratory.
a
Reagents: (a) sealed tube, 95 °C, 2d or microwave irradiation,
6 h (73%; endo/exo 5:1).
SCHEME 2a
One of these alternate strategies, while unsuccessful
in generating the target molecule, provided extremely
interesting results. Heck macrocyclization of a simple
linear precursor was considered a potentially attractive
route to pondaplin. The linear precursor (21) was pre-
pared quickly and efficiently, in six steps and 62% overall
yield, from commercially available THP-protected pro-
pargyl alcohol (Scheme 6). The sequence began with
methoxycarbonylation of THP-propargyl alcohol. Subse-
quent conjugate addition and DIBAL reduction provided
allylic alcohol 18.21 Mitsunobu etherification, deprotec-
tion, and acylation afforded linear precursor 21.
Extensive investigation of the Heck macrocyclization
failed to develop conditions to provide pondaplin.13b
However, a pondaplin dimer (22) was successfully gener-
ated under several sets of reaction conditions. The
optimal yield of the dimer was 38% (Scheme 7). This
dimer has also been prepared in our laboratories by a
different method.21 A 10-fold increase in concentration
led to the formation of a trimeric structure (23) as well.
The availability of these novel macrocycles led us to
examine their X-ray structures and investigate the
existing aromatic interactions.
One of the salient features of the X-ray crystal struc-
ture of the pondaplin dimer (Figure 2) is the parallel-
displaced arrangement of the aromatic rings. This parallel-
displaced geometry is one of three main paradigms of
aromatic interaction.22 Aromatic interactions are likely
to influence crystal packing and supramolecular struc-
ture.22-26 Recently, high level ab initio calculations have
been used to assess the optimal parallel-displaced geom-
etry.27 This method using an estimated completed basis
set of MP2 binding energies found optimal values for R1,
the interplane distance, and R2, the center-to-center
distance, to be 3.4 and 1.6 Å, respectively. These values
were compared to the work of others in the field who have
calculated optimal R1/R2 values of 3.5/1.6,28 3.6/1.8,29 3.6/
1.8,30 and 3.4/ 1.631 using MP2, CCSD(T), MP2, and
ceeded smoothly to give the endo adduct 6 as the
predominant product (Scheme 1). This result is in agree-
ment with the work of Afarinkia and Posner.19 It is
possible that this type of cycloaddition is not a concerted
Diels-Alder reaction. Addition of the electron-rich olefin
to the pyrone followed by closure to provide the bridged
lactone has been suggested by some empirical findings.20
With the oxabicyclo[2.2.2]octenone core in hand, we
sought to liberate the secondary alcohol and append the
remainder of the tether (Scheme 2). The cleavage of the
silyl ether proceeded optimally with HF‚pyridine. This
reagent proved superior to TBAF, TBAF/HOAc, KF/18-
crown-6, LiBr/18-crown-6, and HOAc. The free alcohol 8
was treated with a model allylic mesylate (a cis-disub-
stituted olefin was used as a model for the Z-trisubsti-
tuted olefin present in the natural product) and mild
base, but instead of forming the expected product, the
alcohol fragmented to yield solely 4-bromohexa-2,4-(E,Z)-
dienal (10). Although other conditions were investigated,
these bicyclic lactones are known to be labile in acid and
base, and ether formation could not be achieved in
preference to fragmentation.
To circumvent this problematic rearrangement, the
cycloaddition was performed with a more elaborate
dienophile (11) prepared in two steps from acryloyl
chloride. Subsequent cycloaddition with 5-bromo-2-py-
rone did provide the desired linear precursor (12) with
good endo-to-exo selectivity, albeit in diminished yield
(Scheme 3). However, Heck macrocyclization proved
(21) Chen, W.-C., Ph.D. Thesis, University of Pennsylvania, Phila-
delphia, PA, 2000.
(22) J ennings, W. B.; Farrell, B. M.; Malone, J . F. Acc. Chem. Res.
2001, 34, 885.
(23) J aniak, C. J . Chem. Soc., Dalton Trans. 2000, 3885.
(24) Hunter, C. A.; Sanders, J . K. M. J . Am. Chem. Soc. 1990, 112,
5525.
(25) Garcia-Baez, E. V.; Martinez-Martinez, F. J .; Hoepfl, H.;
Padilla-Martinez, I. I. Cryst. Growth Des. 2003, 3, 35.
(26) Lin, C.-H.; Tour, J . J . Org. Chem. 2002, 67, 7761.
(27) Sinnokrot, M. O.; Valeev, E. F.; Sherrill, C. D. J . Am. Chem.
Soc. 2002, 124, 10887.
(15) Wiley, R. H.; Smith, N. R. Org. Synth. 1951, 31, 23.
(16) Cho, C. G.; Park, J . S.; J ung, I. H.; Lee, H. Tetrahedron Lett.
2001, 42, 1065.
(17) J ung, M. E.; Blum, R. B. Tetrahedron Lett. 1977, 3791.
(18) Srisiri, W.; Padias, A. B.; Hall, H. K., J r. J . Org. Chem. 1994,
59, 5424.
(19) Afarinkia, K.; Posner, G. H. Tetrahedron Lett. 1992, 33, 7839.
(20) J ung, M. E.; Street, L. J .; Usui, Y. J . Am. Chem. Soc. 1986,
108, 6810.
(28) Hobza, P.; Selzle, H. L.; Schlag, E. W. J . Am. Chem. Soc. 1994,
116, 3500.
(29) Hobza, P.; Selzle, H. L.; Schlag, E. W. J . Phys. Chem. 1996,
100, 18790.
(30) J affe, R. L.; Smith, G. D. J . Chem. Phys. 1996, 105, 2780.
(31) Arunan, E.; Gutowsky, H. S. J . Chem. Phys. 1993, 98, 4294.
J . Org. Chem, Vol. 69, No. 7, 2004 2527

Leonard et al.
SCHEME 3a
a
Reagents: (a) 5-bromo-2-pyrone, CH2Cl2, sealed tube, 100 °C, 16 h or microwave irradiation, 150 °C, 2 h (25%; endo/exo 5:1); (b) Heck
macrocyclization conditions.
SCHEME 4a
a
Reagents: (a) vinyl tri-n-butyltin, Pd(PPh3)4, BHT, THF,
F IGURE 2. ORTEP drawing of 22.
reflux or vinyl tri-n-butyl tin, PdCl2(PPh3)2, CH3CN, reflux; (b)
ring-closing metathesis (RCM).
reveals an association between the aromatic rings of
adjacent molecules (Figure 3). The average R1 value is
SCHEME 5a
3.6 Å, and the average R2 value is only 1.5 Å.
The aromatic interaction in this case appears to be of
the parallel-displaced variety as well. The implication of
intermolecular π stacking in this example is all the more
intriguing due to the lattice structure. The series of offset
trimer molecules form a helix in the crystal lattice
(Figure 4). Six molecules of the trimer serve to carry the
helix through one turn, which is approximately 19.9 Å
in length. Observation of the lattice in a broader scope
a
Reagents: (a) vinyl tri-n-butyltin, Pd(PPh3)4, THF, reflux
(52%).
reveals that individual helices interlock in the crystal.
experimental estimation, respectively. If the arrangement
of the aromatic rings in the pondaplin dimer is described
according to this method, the interplane distance, R1, is
3.4 Å, and the offset, R2, is 1.7 Å. These values were
obtained using the CrystMol program to analyze the
crystal structure and are in excellent agreement with the
literature data for optimal orientation.
The X-ray structure of the pondaplin trimer shows it
to be relatively flat in shape, with adjacent molecules in
the lattice offset relative to one another. Closer inspection
Con clu sion
While the methods presented herein have not yet found
utility in the total synthesis of the highly unusual natural
product pondaplin, large macrocycles with interesting
properties have resulted from this work. The dimeric
structure appears to display intramolecular parallel-
displaced π stacking. While pondaplin itself is exceed-
SCHEME 6a
a
Reagents: (a) n-BuLi, THF, -78 °C, 1 h then MeOC(O)Cl, -78 oC f 10 °C, 2 h (quant.); (b) Me2CuLi, THF, -78 °C, 4 h (90%); (c)
DIBAL, PhCH3, 0 °C, 1 h (84%); (d) p-iodophenol, DEAD, PPh3, PhMe (90%); (e) 50% aq. HOAc, 40 °C, 5 h (quant.); (f) acryloyl chloride,
TEA, CH2Cl2, 12 h (91%).
2528 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of a Pondaplin Dimer and Trimer
SCHEME 7a
a
Reagents: (a) Pd(OAc)2, PPh3, CF3CO2Ag, DMF (1 mM), 100
F IGURE 3. View of X-ray structure of 23 indicating adjacent
trimer molecules.
°C, 20 h (38%); (b) Pd(OAc)2, P(2-furyl)3, CF3CO2Ag, DMF (10 mM),
90 °C, 21 h (22, 7%; 23, 7%).
ingly rigid, the dimer possesses a larger number of
degrees of freedom. Consequently, it appears that the
solid-state conformation is not, in fact, imposed by
rigidity but is the result of the energetic benefit of this
interaction. Furthermore, the geometry of the π array is
in good agreement with the computational predictions
that have appeared in the literature. The intermolecular
π stacking observed in the crystal structure of the trimer
is also in close agreement with the computational predic-
tions. This association appears to be responsible for the
helical supramolecular structure displayed in the unit
cell.
°C for 2 days or was irradiated in a monomode microwave
reactor at 300 W (temperature controlled cycle: 100 °C) for 6
h. The crude reaction mixture was subjected to column
chromatography (5% ethyl acetate/petroleum ether) to afford
6 as a white solid (908 mg, 62%). The exo product 7 was
obtained as a white solid (78.6 mg, 6%). Endo: Rf 0.79 (25%
1
ethyl acetate/hexanes); H NMR (500 MHz, CDCl3) δ 0.04 (s,
3 H), 0.05 (s, 3 H), 0.83 (s, 9 H), 1.65 (d, J ) 14.0 Hz, 1 H),
2.52 (ddd, J 1 ) 14.0 Hz, J 2 ) 7.5 Hz, J 3 ) 3.9 Hz, 1 H), 3.63
(dd, J 1 ) 6.5 Hz, J 2 ) 3.5 Hz, 1 H), 4.29-4.31 (m, 1 H), 5.05
(dd, J 1 ) 3.8 Hz, J 2 ) 1.7 Hz, 1 H), 6.43 (dd, J 1 ) 6.4 Hz, J 2
) 2.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ -4.8, -4.8, 17.8,
25.5, 37.8, 52.0, 64.2, 80.6, 119.7, 128.0, 170.3; IR (KBr plate)
2954, 2929, 2887, 2856, 1769, 1617, 1104 cm-1; HRMS (ESI)
m/z 355.0342 (M+ calcd. for C13H21BrO3Si + Na, 355.0341).
Exo: Rf 0.70 (25% ethyl acetate/hexanes); 1H NMR (500 MHz,
CDCl3) δ 0.05 (s, 3 H), 0.07 (s, 3 H), 0.83 (s, 9 H), 1.90 (dt, J 1
) 13.7 Hz, J 2 ) 3.5 Hz, 1 H), 2.27 (ddd, J 1 ) 13.8 Hz, J 2 ) 8.5
Hz, J 3 ) 1.5 Hz, 1 H), 3.48 (dd, J 1 ) 6.9 Hz, J 2 ) 3.3 Hz, 1 H),
4.15 (dt, J 1 ) 8.6 Hz, J 2 ) 3.1 Hz, 1 H), 5.01 (m, 1 H), 6.43
Exp er im en ta l Section
7-Br om o-5-en d o-(ter t-bu tyld im eth ylsila n yloxy)-2-oxa -
bicyclo[2.2.2]oct-7-en -3-on e (6) a n d 7-Br om o-5-exo-(ter t-
bu tyld im eth ylsila n yloxy)-2-oxa bicyclo[2.2.2]oct-7-en -3-
on e (7). A mixture of tert-butyldimethylsilyl vinyl ether 5
(691.8 mg, 4.38 mmol) and 5-bromo-2-pyrone (4, 766.2 mg, 4.38
mmol) in CH2Cl2 (0.5 mL) was heated in a sealed tube at 95
F IGURE 4. Side and top views of the X-ray structure of 23 indicating the helix formed by six trimer molecules.
J . Org. Chem, Vol. 69, No. 7, 2004 2529

Leonard et al.
(dd, J 1 ) 6.9 Hz, J 2 ) 2.5 Hz, 1 H); 13C NMR (125 MHz, CDCl3)
δ -4.4, -4.5, 18.3, 26.0, 36.4, 52.6, 66.4, 81.0, 123.6, 128.3,
169.5.
14.0 Hz, 1 H), 2.58 (ddd, J 1 ) 14.2 Hz, J 2 ) 7.7 Hz, J 3 ) 3.9
Hz, 1 H), 3.93 (dd, J 1 ) 6.4 Hz, J 2 ) 3.2 Hz, 1 H), 4.04 (dt, J 1
) 7.7 Hz, J 2 ) 2.5 Hz, 1 H), 4.08-4.20 (m, 2 H), 4.66-4.74
(m, 2 H), 5.10 (m, 1 H), 5.69-5.78 (m, 2 H), 5.85 (dd, J 1
)
7-Br om o-5-en d o-h yd r oxy-2-oxa b icyclo[2.2.2]oct -7-en -
3-on e (8). Silyl ether 6 (50 mg, 0.15 mmol) was dissolved in
dry THF (3 mL) and cooled to 0 °C. HF‚pyridine (0.18 mL,
0.15 mmol) was added, and the reaction mixture was stirred
at room temperature for 30 min. Additional aliquots of HF‚
pyridine were added every 30 min until the reaction had gone
to completion. The mixture was then diluted with Et2O and
neutralized with saturated aqueous NaHCO3. The organic
layer was separated, washed with brine, dried (MgSO4),
filtered, and concentrated. The crude product was purified by
silica gel chromatography (gradient 20-30% acetone/hexanes)
to give 8 as a white solid (25 mg, 77%). Rf 0.22 (30% acetone/
hexanes); 1H NMR (500 MHz, CDCl3) δ 1.72 (dt, J 1 ) 14.4 Hz,
10.5 Hz, J 2 ) 1.2 Hz, 1 H), 6.13 (dd, J 1 ) 17.3 Hz, J 2 ) 10.4
Hz, 1 H), 6.42 (dd, J 1 ) 17.3 Hz, J 2 ) 1.3 Hz, 1 H), 6.48 (dd,
J 1 ) 6.4 Hz, J 2 ) 2.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
35.4, 48.9, 60.3, 65.2, 71.0, 80.8, 120.7, 127.6, 128.0, 128.4,
130.4, 131.7, 166.2, 170.3; IR (KBr plate) 2916, 2852, 1764,
1723, 1618, 1181 cm-1; HRMS (ESI) m/z 365.0023 (M+ calcd.
for C14H15BrO5 + Na, 365.0001).
5-en do-(ter t-Bu tyldim eth ylsilan yloxy)-7-vin yl-2-oxabicy-
clo[2.2.2]oct-7-en -3 -on e (15). To a solution of bicyclic vinyl
bromide 6 (100 mg, 0.30 mmol), Pd(PPh3)4 (17.3 mg, 0.02
mmol), and di-tert-butylphenol (3.1 mg, 0.02 mmol) in THF
(3.2 mL) was added vinyltri-n-butyltin (105.2 µL, 0.36 mmol).
The reaction mixture was stirred at ambient temperature for
2 days. The crude reaction mixture was concentrated in vacuo
and was loaded directly onto a silica gel column. Chromatog-
raphy (gradient 5-20% ether/hexanes) afforded 15 as a yellow
oil (40.6 mg, 48%). Rf 0.50 (30% acetone/hexanes); 1H NMR
(500 MHz, CDCl3) δ 0.04 (s, 3 H), 0.07 (s, 3 H), 0.82 (s, 9 H),
1.57-1.65 (m, 1 H), 1.93-2.06 (m, 1 H), 3.47 (dd, J 1 ) 6.5 Hz,
J 2 ) 3.4 Hz, 1 H), 4.11 (dt, J 1 ) 8.5 Hz, J 2 ) 3.1 Hz, 1 H), 5.19
(d, J ) 10.9 Hz, 1 H), 5.31 (d, J ) 17.7 Hz, 1 H), 5.37 (m, 1 H),
6.11 (dd, J 1 ) 6.5 Hz, J 2 ) 2.1 Hz, 1 H), 6.30 (dd, J 1 ) 17.6
Hz, J 2 ) 10.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ -4.9,
-4.8, 17.5, 25.6, 36.2, 50.5, 67.2, 72.7, 115.2, 124.2, 130.9,
144.0, 171.1; IR (KBr plate) 2955, 2929, 2856, 1765, 1640, 1103
cm-1; HRMS (ESI) m/z 281.1634 (M+ calcd. for C15H24O3Si +
H, 281.1573).
J 2 ) 1.6 Hz, 1 H), 2.67 (ddd, J 1 ) 14.4 Hz, J 2 ) 7.8 Hz, J 3
3.8 Hz, 1 H), 3.80 (dd, J 1 ) 6.4 Hz, J 2 ) 3.3 Hz, 1 H), 4.42 (m,
)
1 H), 5.12 (dd, J 1 ) 3.8 Hz, J 2 ) 2.1 Hz, 1 H), 6.43 (dd, J 1
)
6.4 Hz, J 2 ) 2.4 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ 35.6,
52.4, 66.0, 81.2, 120.7, 128.0, 170.6; IR (KBr plate) 3404, 2923,
2849, 1756 cm-1; HRMS (ESI) m/z 217.9583 (M+ calcd. for
C7H7BrO3, 217.9579).
4-Br om oh exa -2,4-(E,Z)-d ien a l (10). To a solution of mono-
TBS-protected cis-2-buten-1,4-diol (175.5 mg, 0.87 mmol) in
CH2Cl2 at 0 °C was added TEA (275.3 µL, 1.98 mmol).
Methanesulfonyl chloride (67.3 µL, 0.87 mmol) was then
added. Once the starting material had been quantitatively
converted to the mesylate (as monitored by TLC), the bicyclic
alcohol 8 (172.7 mg, 0.79 mmol) in CH2Cl2 (2 mL) was added.
The mixture was stirred at ambient temperature overnight.
The crude reaction mixture was diluted with CH2Cl2 and
washed with 10% HCl, saturated aqueous NaHCO3, and brine.
The organic layer was dried (MgSO4), filtered, and concen-
trated. Silica gel chromatography (10% acetone/hexanes) af-
forded none of the expected product; however, 4-bromosorbal-
dehyde, 10, was isolated. This compound was also isolated
when using preformed mesylate and when attempting to
remove the TBS ether from 6 using TBAF/HOAc (average yield
50%). Rf 0.50 (30% acetone/hexanes); 1H NMR (500 MHz,
CDCl3) δ 1.99 (d, J ) 6.9 Hz, 3 H), 6.44 (dd, J 1 ) 14.8 Hz, J 2
) 7.7 Hz, 1 H), 6.56 (q, J ) 6.8 Hz, 1 H), 7.07 (d, J ) 14.8 Hz,
1 H), 9.64 (d, J ) 7.7 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
18.2, 124.3, 131.4, 140.2, 150.5, 192.5.
Meth yl-4-(tetr a h yd r op yr a n -2-yloxy)bu t-2-yn oa te (16).
A solution of THP-protected propargyl alcohol (10 mL, 71.12
mmol) in THF (175 mL) was cooled to -78 °C. n-Butyllithium
(50 mL, 1.6 M in hexanes, 78.23 mmol) was added dropwise,
and the resultant mixture was stirred at -78 °C for 1 h.
Methyl chloroformate (6.1 mL, 78.23 mmol) was then added
dropwise, and the solution was allowed to warm to -10 °C
over a period of 2 h. The reaction was then quenched with
saturated aqueous NH4Cl and warmed to room temperature.
The mixture was concentrated, and the residue was redis-
solved in Et2O. The organic layer was washed with 10% aq.
HCl, sat. NaHCO3, and brine. Drying (MgSO4) was followed
by filtration and concentration to give a quantitative yield of
the product as an orange oil. Purification was accomplished
with silica gel chromatography (5-20% acetone/hexanes) to
4-Vin yloxybu t-2-(Z)-en yl Acr yla te (11). A mixture of the
allylic alcohol (1.00 g, 7.04 mmol) [prepared from cis-2-buten-
1,4-diol and acryloyl chloride] and Hg(OAc)2 (673 mg, 2.11
mmol) in ethyl vinyl ether (6.75 mL) was heated at reflux for
14 h. The mixture was then diluted with CH2Cl2 and washed
with 5% aqueous KOH. The aqueous layers were back ex-
tracted with CH2Cl2, and the combined organic layers were
dried (Na2SO4). The organic layer was filtered and concen-
trated. The crude product was passed through a silica gel plug
(20% acetone/ hexanes) to afford 11 as a clear, colorless oil
1
give 16 as a colorless oil. Rf 0.52 (30% acetone/hexanes); H
NMR (500 MHz, CDCl3) δ, 1.49-1.81 (m, 6 H), 3.51-3.54 (m,
1 H), 3.75 (s, 3 H), 3.77-3.82 (m, 1 H), 4.35 (s, 2 H), 4.78
(apparent t, J ) 3.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
18.7, 25.2, 30.0, 52.7, 53.5, 61.9, 83.9, 97.1, 153.5; IR (KBr
plate) 2949, 2872, 1719, 1256 cm-1; HRMS (ESI) m/z 197.0823
(M+ calcd. for C10H14O4 + H, 197.0814).
Meth yl (Z)-3-Meth yl-4-(tetr a h yd r op yr a n -2-yloxy)bu t-
2-en oa te (17). A solution of methyllithium (35.6 mL, 1.4 M
in Et2O, 49.81 mmol) was added dropwise to a suspension of
cuprous iodide (4.83 g, 25.36 mmol) in THF (80 mL) at 0 °C.
A distinct color change occurred during the course of the
addition from brown to yellow to green to black. This mixture
was stirred at 0 °C for an additional 0.5 h, after which the
temperature was lowered to -78 °C. A solution of alkyne 16
(4.48 g, 22.64 mmol) in THF (45 mL) was then added dropwise
1
(438 mg, 37%). Rf 0.69 (30% acetone/hexanes); H NMR (500
MHz, CDCl3) δ 4.06 (dd, J 1 ) 6.8 Hz, J 2 ) 2.3 Hz, 1 H), 4.22
(dd, J 1 ) 14.3 Hz, J 2 ) 2.2 Hz, 1 H), 4.38 (d, J ) 5.9 Hz, 2 H),
4.75 (d, J ) 6.4 Hz, 2 H), 5.72-5.89 (m, 3 H), 6.13 (dd, J 1
)
17.3 Hz, J 2 ) 10.5 Hz, 1 H), 6.39-6.60 (m, 2 H); 13C NMR
(125 MHz, CDCl3) δ 60.2, 63.7, 87.2, 126.7, 128.1, 129.4, 131.0,
151.1; IR (KBr plate) 2934, 1726, 1636, 1617, 1186 cm-1
;
HRMS (ESI) m/z 169.0868 (M+ calcd. for C9H12O3 + H,
169.0865).
to the dialkyl cuprate via
a cannula. The mixture was
maintained at -78 °C with stirring for 4 h and was subse-
quently quenched with one reaction volume of sat. NH4Cl. The
mixture was then allowed to warm to room temperature, and
the precipitate was removed. The organic layer was then
separated from the blue aqueous layer, and the aqueous layer
was extracted with Et2O. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concen-
trated. The crude reaction mixture was immediately loaded
onto a silica gel column, and the product eluted with 30%
4-(7-Br om o-2-oxa bicyclo[2.2.2]oct-7-en -5-yloxy)-bu t-2-
(Z)-en yl Acr yla te (12). A mixture of 5-bromo-2-pyrone (4,
52.5 mg, 0.30 mmol) and vinyl ether 11 (50.0 mg, 0.30 mmol)
in CH2Cl2 (0.6 mL) was heated at 100 °C in a sealed tube for
30 h. The crude reaction mixture was loaded directly onto a
silica gel column. Chromatography (gradient 20-30% ethyl
acetate/petroleum ether) provided 12 in 25% yield (25.5 mg)
as a white solid. Rf 0.61 (gradient 20-30% ethyl acetate/
1
petroleum ether); H NMR (500 MHz, CDCl3) δ 1.78 (d, J )
2530 J . Org. Chem., Vol. 69, No. 7, 2004

Synthesis of a Pondaplin Dimer and Trimer
acetone/hexanes. The product, 17, was obtained as a yellow
oil (3.80 g, 17.76 mmol) in 79% yield. Rf 0.40 (10% ethyl
acetate/petroleum ether); 1H NMR (500 MHz, CDCl3) δ 1.46-
1.55 (m, 4 H), 1.55-1.60 (m, 1 H), 1.60-1.80 (m, 1 H), 1.95 (s,
3H), 3.46-3.50 (m, 1 H), 3.63 (s, 3 H), 3.80-3.85 (m, 1 H),
4.58 (apparent t, J ) 3.6 Hz, 1 H), 4.67 (AB, J ) 13.7 Hz, 2
H), 5.69 (apparent t, J ) 1.5 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 19.4, 21.8, 25.3, 30.5, 50.9, 62.2, 66.4, 98.6, 116.4,
CH2Cl2 (40 mL) at 0 °C was added TEA (2.55 mL, 18.27 mmol).
Acryloyl chloride (1.1 mL, 13.40 mmol) was then added
dropwise, and the reaction was allowed to warm to room
temperature overnight. The reaction mixture was then diluted
with EtOAc (40 mL), and the organic layer was washed with
10% HCl, sat. NaHCO3, and brine. The organic phase was
dried (MgSO4), filtered, and concentrated to give the crude
product as a brown oil. Purification by silica gel chromatog-
raphy (10-30% acetone/hexanes) gave the product, a mild
lachrymator, as a yellow oil (3.38 g, 9.44 mmol) in 78% yield.
157.1, 166.2; IR (KBr plate) 2947, 2870, 1718, 1648, 1154 cm-1
;
HRMS (ESI) m/z 215.1285 (M+ calcd. for C11H18O4 + H,
215.1283).
1
Rf 0.66 (30% acetone/hexanes); H NMR (500 MHz, CDCl3) δ
(Z)-3-Met h yl-4-(t et r a h yd r op yr a n -2-yloxy)b u t -2-en -1-
ol (18). A solution of R,â-unsaturated ester 17 (3.80 g, 17.75
mmol) in PhCH3 (40 mL) was cooled to 0 °C. DIBAL (39 mL,
1 M in hexanes, 39.05 mmol) was added dropwise via cannula.
After the addition was completed, the reaction was allowed to
warm to room temperature. After 1 h, the reaction was
quenched at 0 °C by the addition of one-half reaction volume
of water. The white precipitate was removed by filtration, and
the biphasic solution was diluted with Et2O. The layers were
separated, and the organic layer was washed with 10% aq.
HCl, sat. NaHCO3, and brine. The organic layer was then dried
over MgSO4, filtered, and concentrated to yield a clear,
colorless oil (2.77 g, 84% yield) that was suitable for use
without purification. Rf 0.40 (30% acetone/hexanes); 1H NMR
(500 MHz, CDCl3) δ 1.47-1.58 (m, 4 H), 1.63-1.69 (m, 2 H),
1.76 (s, 3 H), 2.36 (br s, 1 H), 3.47-3.52 (m, 1 H), 3.78-3.82
(m, 1 H), 4.01-4.14 (m, 4 H), 4.59 (apparent t, J ) 3.4 Hz, 1
H), 5.63 (t, J ) 6.9 Hz, 1 H); 13C NMR (125 MHz, CDCl3) δ
19.0, 21.7, 25.3, 30.3, 58.1, 61.8, 65.1, 96.8, 128.5, 135.7; IR
(KBr plate) 3406, 2942, 2871, 1671, 1020 cm-1; HRMS (ESI)
m/z 209.1144 (M+ calcd. for C10H18O3 + Na, 209.1154).
2-[4-(4-Iod op h en oxy)-2-m eth ylbu t-2-en yloxy]tetr a h y-
d r op yr a n (19). To a solution of allylic alcohol 18 (2.72 g, 13.30
mmol), p-iodophenol (2.92 g, 13.30 mmol), and PPh3 (3.66 g,
13.97 mmol) in THF (130 mL) at 0 °C, DEAD (2.20 mL, 13.97
mmol) was added dropwise. The mixture was warmed to room
temperature and stirred for 12 h. The solvent was then
removed in vacuo, and the residue was purified by silica gel
column chromatography (20% acetone/hexanes). The product
was obtained as a yellow oil (4.65 g, 90%). Rf 0.69 (30% acetone/
1.89 (s, 3 H), 4.62 (d, J ) 6.5 Hz, 2 H), 4.76 (s, 2 H), 5.72 (t, J
) 6.5 Hz, 1 H), 5.88 (dd, J 1 ) 10.4 Hz, J 2 ) 1.4 Hz, 1 H), 6.16
(dd, J 1 ) 17.3 Hz, J 2 ) 10.4 Hz, 1H), 6.45 (dd, J 1 ) 17.3 Hz,
J 2 ) 1.4 Hz, 1 H), 6.71 (d, J ) 8.9 Hz, 2 H), 7.57 (d, J ) 8.9
Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 21.3, 62.8, 64.0, 82.9,
117.0, 124.8, 128.0, 131.0, 135.4, 138.1, 158.3, 165.8; IR (KBr
plate) 2940, 1724, 1484, 1237, 1176 cm-1; HRMS (ESI) m/z
358.0057 (M+ calcd. for C14H15O3I, 358.0066).
3-[4-(4-H yd r oxy-3-m et h ylb u t -(Z)-2-en yloxy)p h en yl]-
(E)-a cr yla te Dim er (22). A mixture of 21 (100 mg, 0.28
mmol), Pd(OAc)2 (6.3 mg, 0.028 mmol), triphenylphosphine (7.3
mg, 0.028 mmol), and silver trifluoroacetate (68 mg, 0.31
mmol) in DMF (280 mL) was heated at 100 °C for 20 h. The
reaction mixture was then concentrated to dryness and im-
mediately loaded onto a silica column (20% acetone/hexanes).
The dimer 22 was isolated as a white solid (24.5 mg, 38%). Rf
0.37 (30% acetone/hexanes); 1H NMR (500 MHz, CDCl3) δ 1.87
(s, 3H), 4.68 (d, J ) 7.3 Hz, 2 H), 4.74 (s, 2 H), 5.68 (t, J ) 7.1
Hz, 1 H), 5.95 (d, J ) 16 Hz, 1 H), 6.84 (d, J ) 9.0 Hz, 2 H),
7.21 (d, J ) 9.0 Hz, 2 H), 7.40 (d, J ) 16 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 22.8, 63.3, 64.3, 115.0, 115.6, 124.0, 126.8,
129.6, 136.8, 144.6, 160.3, 166.6; IR (KBr plate) 2923, 1707,
1628, 1601 cm-1; HRMS (ESI) m/z 461.1944 (M+ calcd. for
C
28H28O6 + H, 461.1964); X-ray crystallography confirmed this
structure.
3-[4-(4-H yd r oxy-3-m et h ylb u t -(Z)-2-en yloxy)p h en yl]-
(E)-a cr yla te Tr im er (23). A mixture of 21 (536 mg, 1.50
mmol), Pd(OAc)2 (33.6 mg, 0.15 mmol), tri-2-furylphosphine
(34.8 mg, 0.15 mmol), and silver trifluoroacetate (363.7 mg,
1.65 mmol) in DMF (150 mL) was heated at 90 °C for 21 h.
The reaction mixture was then concentrated and loaded
directly onto a silica gel column. Chromatography (20%
acetone/hexanes) afforded the trimer 23 as a white solid (23
mg, 7%), as well as dimer 22 (23 mg, 7%). Rf 0.61 (30% acetone/
hexanes); 1H NMR (500 MHz, CDCl3) δ 1.88 (s, 3H), 4.74 (s, 2
H), 4.78 (d, J ) 5.9 Hz, 2 H), 5.64 (t, J ) 5.7 Hz, 1 H), 6.33 (d,
J ) 15.9 Hz, 1 H), 6.96 (d, J ) 8.7 Hz, 2 H), 7.48 (d, J ) 8.7
Hz, 2 H), 7.68 (d, J ) 15.9 Hz, 1 H); 13C NMR (125 MHz,
CDCl3) δ 22.0, 63.0, 64.6, 114.8, 115.3, 125.8, 127.0, 129.9,
135.0, 145.3, 160.6, 167.1; IR (KBr plate) 2930, 1708, 1631,
1602 cm-1; HRMS (ESI) m/z 713.2695 (M+ calcd. for C42H42O9
+ Na, 713.2727); X-ray crystallography confirmed this struc-
ture.
1
hexanes); H NMR (500 MHz, CDCl3) δ 1.48-1.60 (m, 4 H),
1.67-1.73 (m, 2H), 1.83 (s, 3H), 3.47-3.51 (m, 1 H), 3.81-
3.86 (m, 1 H), 4.08 (AB, J ) 12.1 Hz, 1 H), 4.19 (AB, J ) 12.1
Hz, 1 H), 4.52-4.59 (m, 3 H), 5.60-5.63 (t, J ) 6.9 Hz, 1 H),
6.66 (d, J ) 9.1 Hz, 2 H), 7.51 (d, J ) 9.1 Hz, 2 H); 13C NMR
(125 MHz, CDCl3) δ 19.3, 21.7, 25.4, 30.5, 62.2, 64.2, 65.5, 82.7,
97.7, 117.1, 123.5, 137.6, 138.3, 158.5; IR (KBr plate) 2940,
2868, 1484, 1236, 1019 cm-1; HRMS (ESI) m/z 411.0442 (M+
calcd. for C16H21O3I + Na, 411.0433).
4-(4-Iod op h en oxy)-2-m eth ylbu t-2-en -1-ol (20). A solu-
tion of THP-protected allylic alcohol 19 (4.39 g, 11.32 mmol)
in 50% aq. HOAc (75 mL) was heated at 40 °C for 5 h. The
reaction mixture was then concentrated and extracted with
CH2Cl2. The organic layer was then dried over MgSO4, filtered,
and concentrated to give the free allylic alcohol as an orange
oil. The crude product was purified by silica gel chromatog-
raphy (30% acetone/hexane) to give a nearly quantitative yield
of a white solid. Rf 0.49 (30% acetone/hexanes); 1H NMR (500
MHz, CDCl3) δ 1.86 (s, 3 H), 4.18 (s, 2 H), 4.53 (d, J ) 6.6 Hz,
2 H), 5.60 (t, J ) 6.6 Hz, 1 H), 6.66 (d, J ) 8.7 Hz, 2 H), 7.53
(d, J ) 8.7 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 21.4, 61.9,
64.0, 117.1, 122.2, 138.2; IR (KBr pellet) 3334, 2935, 1486,
1241, 1004 cm-1; HRMS (ESI) m/z 326.9869 (M+ calcd. for
Ack n ow led gm en t. The authors would like to thank
Prof. Edward R. Thornton for helpful discussions. This
work was supported by grants from the National Science
Foundation (CHE 99-01449) and the National Institutes
of Health (CA-40081).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds and X-ray data for compounds
22 and 23. This material is available free of charge via the
Internet at http:// pubs.acs.org.
C
11H13O2I + Na, 326.9858).
4-(4-Iod op h en oxy)-2-m eth ylbu t-2-en yl Acr yla te (21).
To a solution of the free alcohol 20 (3.70 g, 12.18 mmol) in
J O0356006
J . Org. Chem, Vol. 69, No. 7, 2004 2531