Synthesis and structure revision of calyxin natural products

Article abstract of DOI:10.1021/jo060094g

Tandem Prins cyclization and Friedel-Crafts reaction with an electron-rich aromatic ring were used to prepare the core structures of calyxin natural products. The proposed structure of epicalyxin F was prepared and shown to be incorrect. Several calyxin n

Full text of DOI:10.1021/jo060094g

Synthesis and Structure Revision of Calyxin Natural Products
Xia Tian, James J. Jaber, and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, IrVine, California 92697
srychnoV@uci.edu
ReceiVed January 17, 2006
Tandem Prins cyclization and Friedel-Crafts reaction with an electron-rich aromatic ring were used to
prepare the core structures of calyxin natural products. The proposed structure of epicalyxin F was prepared
and shown to be incorrect. Several calyxin natural products, including calyxin F and L, were synthesized,
and the structures were reassigned on the basis of NMR data and synthetic correlations.
Introduction
A new family of natural products was isolated recently from
the Alpinia blepharocalyx seeds, which are used for the
treatment of stomach disorders in Chinese medicine (Figure 1).1
Several of these natural products show interesting antiprolif-
erative activity against carcinoma cells. Epicalyxin F is the most
potent member of the class and showed ca. 1 µM activity against
human HT-1080 fibrosarcoma and murine 26-L5 carcinoma. It
is accompanied by calyxin F and a host of related diarylhep-
tanoid natural products. Described herein are a synthesis of the
reported structure of epicalyxin F using a tandem Prins
cyclization Friedel-Crafts arylation strategy and the synthesis
and structure revision of several calyxin natural products.
Prins cyclizations normally lead to tetrahydropyran rings with
a heteroatom at the C4 position. We found that under some
circumstances the electrophilic C4 position reacts with an
aromatic ring in a Friedel-Crafts alkylation reaction to introduce
an aryl group in the equatorial position.2 This carbon trapping
of the cyclized carbenium ion rapidly builds structural complex-
ity and could be a useful synthetic method. Very recently, Li’s
group reported a three-component Prins-Friedel-Crafts cy-
clization closely related to our work.3,4 The isolation of
(1) (a) Gewali, M. B.; Tezuka, Y.; Banskota, A. H.; Ali, M. S.; Saiki, I.;
Dong, H.; Kadota, S. Org. Lett. 1999, 1, 1733-1736. (b) Tezuka, Y.;
Gewali, M. B.; Ali, M. S.; Banskota, A. H.; Kadota, S. J. Nat. Prod. 2001,
64, 208-213. (c) Kadota, S.; Tezuka, Y.; Prasain, J. K.; Ali, M. S.;
Banskota, A. H. Curr. Top. Med. Chem. 2003, 3, 203-225. (d) Praisin, J.
K.; Li, J. X.; Tezuka, Y.; Tanaka, K.; Basnee, P.; Dong, H.; Namba, T.;
Kadota, S. J. Chem. Res. 1998, 265-279.
FIGURE 1. Proposed structures of epicalyxin F, calyxin F, and several
related natural products isolated from A. blepharocalyx seeds.
(2) Hu, Y.; Skalitzky, D. J.; Rychnovsky, S. D. Tetrahedron Lett. 1996,
37, 8679-8682.
epicalyxin F, whose structure is very well suited to a Prins
cyclization and Friedel-Crafts trapping strategy, led us to
(3) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J. Synlett 2005, 1912-
1916.
10.1021/jo060094g CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/16/2006
3176
J. Org. Chem. 2006, 71, 3176-3183

Synthesis of Calyxin Natural Products
SCHEME 1. Arene-Terminated Prins Cyclization To
Assemble a Partial Structure for Epicalyxin F
a more labile benzyl group replaced one of the methyl ethers.5
The optically pure R-acetoxy ether 8 was prepared from the
appropriately protected precursors 3 and 4 as illustrated in
Scheme 2. Prins cyclization and aryl substitution worked well
to produce the tetrahydropyran, but now as a mixture of two
isomers, 10a and 10b, in a 1:2 ratio. NMR analysis demonstrated
that both isomers had the expected stereochemical configuration,
and initially we attributed the structural difference to slow
rotation around the hindered aryl-THP bond.10 Ultimately, we
found that the major product resulted from ipso substitution and
bromine migration, leading to unexpected aryl regioisomer
10b.11 The bromine migration may be related to the reported
debromination of an electron-rich aromatic ring under acidic
conditions, using a bromonium ion scavenger.12 The isomeric
mixture of 10a and 10b was metalated with PhLi.13 Addition
of aldehyde 11 gave the allylic alcohol, which was oxidized
with DDQ to produce enones 12a and 12b. Deprotection of
12a/b required the removal of the more hindered methyl ether.
The deprotection was accomplished in very modest yield by
treatment with BCl3 to remove the benzyl ethers. Incomplete
deprotection of the methyl ethers from the two different starting
materials led to a mixture of monomethyl and dimethyl phenols.
Selective removal of the more hindered methyl ether was
expected on the basis of literature precedent and previous studies
with adduct 7, but it was not independently confirmed on the
mixture of products from 12a/b. Hydrolysis of the sulfonate
with KOH in MeOH/H2O resulted in less than 4% yield of a
FIGURE 2. Retrosynthetic analysis of epicalyxin F.
initiate a study of this reaction directed toward the synthesis of
epicalyxin F.5
The synthetic disconnections for epicalyxin F are shown in
Figure 2. The central Prins cyclization precursor, an R-acetoxy
ether, would be prepared from the ester of alcohol 3 and acid
4. Prins cyclization and in situ Friedel-Crafts arylation with
brominated phloroglucinol 1 would assemble the bulk of the
structure. The unsaturated ketone fragment would be added by
lithiation of an aryl bromide and addition to the unsaturated
aldehyde 2. The strategy used readily available starting materials
and was highly convergent. The implementation of this strategy
turned out to be more challenging than anticipated.5
Results and Discussion
The key Prins cyclization was successful. However, the
protecting group strategy was not. Initial studies ruled out the
use of a benzyl protecting group in component 3 because it led
to solvolysis rather than Prins cyclization, as previously observed
by Willis and co-workers.6 The use of chloride as an oxygen
surrogate led to cyclization precursor 5. Prins reaction in the
presence of 2 equiv of the aryl bromide 6 gave tetrahydropyran
7 as a single diastereomer in 60% yield (Scheme 1). Tri-
methoxybenzene could be used in place of 6, but it led to a
reduced yield of the product (42%) and more side products.7
The Prins cyclization and Friedel-Crafts trapping of acetoxy
ether 5 assemble most of the carbon skeleton for epicalyxin F
in a single step. The tetrahydropyran 7 was not a viable precursor
to epicalyxin F, however, because conversion of the chloride
to an alcohol using Buchwald-Hartwig8 chemistry worked
poorly with this substrate, and the three methyl ethers could
not be differentiated effectively.5
(7) The side products in the reaction were tentatively identified (LRMS)
as bis(trimethoxybenzene) adducts with the aldehyde components. These
adducts presumably arise from addition to the oxocarbenium ion intermedi-
ate, followed by solvolysis and addition of a second equivalent of
trimethoxybenzene. Use of the more electron-deficient bromotrimethoxy-
benezene 6 minimized this side reaction.
(8) (a) Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498-
2500. (b) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 3224-3225.
(9) Sulfonates have been used as phenol protecting groups. For example,
see: (a) Hibino, S.; Weinreb, S. M. J. Org. Chem. 1977, 42, 232-236. (b)
Basha, F. Z.; Hibino, S.; Kim, D.; Pye, W. E.; Wu, T.-T.; Weinreb, S. M.
J. Am. Chem. Soc. 1980, 102, 3962-3964.
(10) Debenzylation and methylation of 10a and 10b led to a single
compound, and therefore their structures must be closely related.
(11) Debromination of compound 10b led to a symmetrically substituted
aryl ring only consistent with the assigned structure.
(12) Choi, H. Y.; Chi, D. Y. J. Am. Chem. Soc. 2001, 123, 9202-9203.
(13) Metal-halogen exchange with n-BuLi, s-BuLi, or t-BuLi produced
only protonated product.
A second synthesis was developed with sulfonate protecting
groups to avoid the problematic Buchwald substitution,6b,c,9 and
(4) Hanessian’s group reported a related Azonia-Prins/Friedel-Crafts
reaction based on N-acyloxyiminium ion cyclizations: Hanessian, S.;
Tremblay, M. Org. Lett. 2004, 6, 4683-4686.
(5) Jaber, J. J. Ph.D. Thesis, University of California, Irvine, 2002.
(6) (a) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 3407-3410. (b) Crosby, S. R.; Harding, J. R.;
King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2002, 4, 577-580. (c)
Barry, C. S.; Bushby, N.; Harding, J. R.; Hughes, R. A.; Parker, G. D.;
Roe, R.; Willis, C. L. Chem. Commun. 2005, 3727-3729.
J. Org. Chem, Vol. 71, No. 8, 2006 3177

Tian et al.
SCHEME 2. Unexpected Synthesis of Calyxin F
product with the expected molecular weight. Comparison with
the reported spectroscopic data demonstrated that the material
was not epicalyxin F, but instead was the reported epimer,
calyxin F.5 The assembly of the carbon framework worked very
well, but the final deprotection was not at all practical.
Unfortunately, the isolation of calyxin F raised more questions
than it answered.
The isolation of calyxin F from the deprotection sequence
suggested that the structure reported for the natural product
might be erroneous or that the vigorous conditions used in the
deprotection might have isomerized the starting material, 12a/
b. The latter view received some support because the proton
NMR spectrum of synthetic calyxin F was significantly different
from that of the protected precursors 12a/b. The structure
assignments were also suspect because both calyxin F and
epicalyxin F had been assigned boat conformations based on
ROESY correlations, but extensive molecular modeling in our
hands provided no support for these conformations.14 Finally,
entering the deprotection with a mixture of regioisomers (12a/
b) just confused the situation.15 We decided to develop a new
synthesis with a very safe protecting group strategy that would
avoid any possibility of rearrangement. Hopefully such a strategy
would allow us to unambiguously determine the structure of
epicalyxin F.
diastereomer. Debromination produced the symmetric tribenzyl
compound 18 in 42% yield over two steps. Selective removal
of the least hindered benzyl ether, methylation, and hydrogena-
tion delivered the diphenol 19. The symmetry apparent in the
NMR spectra of 19 unambiguously established the position of
the methyl ether.
The completion of the synthesis was straightforward. Repro-
tection of the phenols in 19 with SEMCl,19 bromination, and
coupling with aldehyde 20 as previously described (Scheme 2)
gave the complete carbon skeleton of epicalyxin F, compound
21. Removal of the SEM groups with HF‚pyridine, followed
by hydrolysis of the sulfonate protecting groups with K2CO3 in
MeOH produced the proposed structure of epicalyxin F,
compound 22. Unfortunately, the spectral data did not match
that reported for the natural product. The C7 proton appeared
at 4.31 ppm (dd, 12.0, 2.0 Hz) rather than at 5.05 ppm (dd,
12.0, 2.0 Hz). Thus the structure of epicalyxin F is not 22. On
inspection, we found that the NMR data for our synthetic
material (22) did match another natural product isolated from
the same plant, calyxin L.20 The correct structure for calyxin L
is shown in Scheme 3.
How was calyxin F produced in Scheme 2? Presumably, the
harsh deprotection conditions led to an isomerization of 12a or
12b, perhaps through solvolysis to a stabilized C7 cation. With
an eye toward reproducing the earlier structural rearrangement,
calyxin L was exposed to acidic conditions. Synthetic calyxin
L produced a mixture of products when heated in neat acetic
acid at 90 °C (Scheme 4). Calyxin F21 and L were isolated as
The new synthesis of epicalyxin F is outlined in Scheme 3.
Protection and enantioselective allylation16 of 4-hydroxyben-
zaldehyde generated alcohol 14 with 93% ee. Esterification and
reductive acylation17 produced the Prins cyclization precursor
16. Prins cyclization in the presence of the tribenzyl aryl bromide
1718 and BF3‚OEt2 gave the expected adduct as a single
(17) (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
8317-8320. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191-198.
(14) Conformational searches with the proposed structures for calyxin
F and epicalyxin F did not identify any low energy twist boat conformations
and only led to low energy chair conformations. The searches were carried
out using Macromodel with the Monte Carlo algorithm.
(15) One possible explanation was that calyxin F arose from deprotection
of 12b, and that the actual structure of calyxin F was that reported for
epicalyxin F except with the methyl ether para to the ketone. More recently,
we have synthesized this compound and shown that it does not match the
data for any of the calyxin natural products. Spectroscopic data for this
compound is reported in the Supporting Information.
(16) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467-8468. (b) Costa, A. L.; Piazza, M. G.; Tagliavini, E.;
Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001-
7002.
(18) Kawamoto, H.; Nakatsubo, F.; Murakami, K. Synth. Commun. 1996,
26, 531-534.
(19) For an example of the SEM ether used as a phenol protecting group,
see: Fu¨rstner, A.; Gastner, T. Org. Lett. 2000, 2, 2467-2470.
(20) Natural calyxin L: [R]24D +77.1 (c 0.05, MeOH); synthetic calyxin
L: [R]25 -6 (c 0.08, MeOH). Measurements of the optical rotation of
D
calyxin L were completely unreliable, and we do not draw any conclusion
about the absolute configuration or optical purity of the samples based on
these data. We observed both positive and negative rotations of differing
magnitudes from the same sample. A systematic investigation of concentra-
tion versus rotation is presented in the Supporting Information.
(21) Natural calyxin F: [R]25D +5.7 (c 0.26, MeOH). Synthetic calyxin
F: [R]25 +16.3 (c 0.175, MeOH).
D
3178 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis of Calyxin Natural Products
SCHEME 3. New Protecting Group Strategy for the Synthesis of Epicalyxin F
SCHEME 4. Acid-Catalyzed Isomerization of Calyxin L Produces Calyxin F and Related Natural Products
well as mixtures of compounds tentatively assigned as calyxin
G & epicalyxin G and calyxin M & epicalyxin M.22 Unfortu-
nately, the structures proposed in the literature (Figure 1) did
not appear to be consistent with the NMR data for these
products.
below 4.5 ppm. The C7 proton shift for calyxins F, G, and epi-G
suggested an aryl ether rather than an aliphatic ether in the THP
ring. Solvolysis of the labile C7 oxygen and reclosure on one
of the adjacent phenols could account for the C7 proton shifts
above 5.0 ppm. Such a rearrangement would expose a C3
alcohol. Acetylation of calyxin F formed a tetraacetate (not
shown) that shifted the C3 proton from 3.79 to 5.06 ppm,
suggesting a free alcohol at that position. Calyxin F was oxidized
to the corresponding C3 ketone (Scheme 5).23 Ketone 23 showed
the expected spectral characteristics. Subsequent reduction with
NaBH4 returned calyxin F and 3-epicalyxin F (24). The spectral
The calyxins F, G, and epi-G all showed a C7 proton above
5.0 ppm, whereas calyxins L, M, and epi-M all had a C7 proton
(22) The NMR data for synthetic calyxin F and calyxin L match the
reported data very well. However, there are small deviations in the proton
and 13C data for calyxin G and epicalyxin G and calyxin M and epicalyxin
M. Most of the NMR data matches perfectly. The NMR data for these
compounds were collected on mixtures, and some of the discrepancies may
be due to the complexity of the mixtures or to concentration dependence
of the chemical shifts. Without the original compounds or original spectra,
we cannot resolve these discrepancies.
(23) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
J. Org. Chem, Vol. 71, No. 8, 2006 3179

Tian et al.
SCHEME 5. Oxidation and Reduction of Calyxin F
(18.5 g, kept in 120 °C oven for 2 days) followed by Ti(O-iPr)4
(1.86 mL, 6.21 mmol, 0.1 equiv), and the resultant dark red mixture
was refluxed for 1 h and then allowed to cool to room temperature.
A solution of benzenesulfonic acid 4-formylphenyl ester (16.3 g,
62.1 mmol, 1 equiv) in 12.3 mL of methylene chloride was added
to the mixture and stirred for 10 min. The solution was cooled to
-78 °C, and allyltributyltin (23.3 mL, 74.5 mmol, 1.2 equiv) was
added as a steady stream over 5 min. The flask was sealed with an
unpunctured septa and placed in a -20 °C freezer without stirring
for 108 h. The reaction was quenched with 50 mL of saturated
aqueous NaHCO3. The mixture was diluted with 50 mL of
methylene chloride, allowed to warm to room temperature, and
stirred for 2 h. Following filtration through Celite, the filter cake
was washed thoroughly with 3 × 30 mL methylene chloride, and
the combined filtrate was dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude residue was purified by flash chroma-
tography (10 to 25% EtOAc/hexanes) to yield 14 as a yellow oil
(16.8 g, 89%): [R]24D -31.4 (c 1.42, CHCl3); IR (neat/NaCl) 3350,
3412, 3073, 1504, 1372 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87
(dd, J ) 8.4, 1.2, 2H), 7.71 (tt, J ) 7.5, 1.2, 1H), 7.59-7.54 (m,
2H), 7.35-7.30 (m, 2H), 7.02-6.97 (m, 2H), 5.85-5.75 (m, 1H),
5.20-5.15 (m, 2H), 4.74 (dt, J ) 7.9, 3.4, 1H), 2.55-2.43 (m,
2H), 2.20 (d, J ) 3.4, 1H); 13C NMR (100 MHz, CDCl3) δ 148.7,
142.9, 135.3, 134.2, 133.9, 129.1, 128.4, 127.0, 122.2, 118.9, 72.4,
43.9; HRMS (CI/NH3) m/z calcd for C16H16O3S [M - OH]+
287.0742, found 287.0750. Anal. Calcd for C16H16O4S: C, 63.14;
H, 5.30. Found: C, 63.17; H, 5.49; the enantiomeric excess was
determined by chiral HPLC on a Chiracel OJ column with 82:18
hexanes/IPA as eluant. Retention time of the major S-isomer was
22.27 min, and the minor R-isomer had a retention time of 25.28
min.
data for alcohol 24 did not match that reported for the natural
product epicalyxin F.
The configuration of calyxin F is apparent on inspection of
the spectral data. All of the C7 protons for the calyxin natural
products in Scheme 4 showed a large coupling constant
consistent with a diaxial arrangement of vicinal protons in a
chair conformation. Calyxin F showed an NOE correlation
between the C7 proton and a C4 proton, indicating a trans
relationship between the C7 aryl substituent and the C4 carbon
chain. Treatment of the calyxin G and epicalyxin G mixture
with K2CO3 in MeOH produced calyxin F, which rules out the
regioisomeric aryl THP ring structure. Similarly, treatment of
calyxin M and epicalyxin M gave calyxin L. These data led to
the reassignment of these calyxins to the structures shown in
Scheme 4.
The Friedel-Crafts arylation of Prins intermediates is a viable
approach to highly substituted tetrahydropyran rings. We have
discovered a facile acid-catalyzed rearrangement of several
different calyxin natural products. This project has led to
syntheses and structural reassignments for calyxins F, G, L, and
M and epicalyxins G and M. The structure of the most active
member of the family, epicalyxin F, has yet to be determined.
4-Phenylsulfonylphenylpropionic Acid 15. 4-Hydroxyphenyl-
propionic acid (13.2 g, 79.2 mmol, 1 equiv) was dissolved in a 4:1
mixture of water and dioxane and cooled to 0 °C. KOH (8.87 g,
158 mmol, 2 equiv) was added slowly, and the homogeneous
solution was stirred at 0 °C for 1 h. Benzensulfonyl chloride (10.1
mL, 79.2 mmol, 1 equiv) was then added as a steady stream, and
the reaction was stirred overnight, allowing the bath to warm to
room temperature. The solution was acidified to pH 1 with 1 M
NaHSO4, at which point the product precipitated as a white solid.
The solid was collected by filtration and then dissolved in 150 mL
of ether and washed with 50 mL of brine, dried over MgSO4 and
concentrated under reduced pressure to give 15 as a white powder
(15.5 g, 64%): mp 118-119 °C; IR (neat/NaCl) 3046, 1709, 1507,
1
1448, 1442, 1369 cm-1; H NMR (500 MHz, CDCl3) δ 7.84 (dd,
J ) 7.3, 2H), 7.66 (t, J ) 7.5, 1H), 7.52 (t, J ) 7.9, 2H), 7.11 (d,
J ) 8.5, 2H), 6.90 (d, J ) 8.5, 2H), 2.93 (t, J ) 7.7, 2H), 2.65 (t,
J ) 7.7, 2H); 13C NMR (125 MHz, CDCl3) δ 177.8, 148.0, 139.2,
135.4, 134.2, 129.5, 129.1, 128.5, 122.4, 35.1, 29.8. Found: C,
63.07; H, 4.5; HRMS (ESI) m/z calcd for C15H14O5S [M + Na]+
329.0460, found 329.0458.
Experimental Section
Benzenesulfonic Acid 4-Formylphenyl Ester. To a 0 °C
solution of 4-hydroxybenzaldehyde (8.0 g, 65 mmol) in methylene
chloride (120 mL) was added benzenesulfonyl chloride (8.4 mL,
65 mmol) followed by dropwise addition of triethylamine (9.2 mL,
65 mmol). At the end of the addition, the homogeneous solution
was removed from the ice bath and stirred at room temperature for
2 h. The reaction was diluted with 1 M HCl (30 mL) and shaken
in a separatory funnel. The organic layer was further washed with
2 × 30 mL 1 M HCl followed by 2 × 30 mL saturated aqueous
NaHCO3 and finally with 40 mL of brine. The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. Chromatography of the residue in 20% EtOAc/
hexanes yielded the product (17 g, 98%) as a white solid: IR (neat/
Sulfonate Ester from 14 and 15. To a 0 °C solution of
homoallylic alcohol 14 (18.0 g, 59.0 mmol, 1 equiv), 4-phenyl-
sulfonylphenylpropionic acid (20.8 g, 67.8 mmol, 1.15 equiv), and
DMAP (1.40 g, 11.8 mmol, 0.2 equiv) in 200 mL of methylene
chloride was added DCC (14.6 g, 70.8 mmol, 1.2 equiv) in one
portion, and the reaction was stirred overnight, allowing the ice
bath to warm to room temperature. After 20 h, the DCU precipitate
was filtered, and the filter cake was washed with methylene chloride
(2 × 20 mL). The combined filtrate was concentrated and purified
by flash chromatography (60% hexanes/35% dichloromethane/5%
ether) to give the product as a yellow oil (33 g, 95%): [R]24D -11.0
(c 0.95, CHCl3); IR (neat/NaCl) 3078, 2938, 1737, 1504, 1374,
NaCl) 3070, 2360, 1704, 1377, 1201 cm-1; H NMR (400 MHz,
1
CDCl3) δ 9.98 (s, 1H), 7.87-7.83 (m, 4H), 7.71 (tt, J ) 7.5, 1.2
Hz, 1H), 7.56 (dt, J ) 7.6, 1.7, 2H), 7.18 (dd, J ) 6.8, 1.9, 2H);
13C NMR (100 MHz, CDCl3) δ 190.5, 153.8, 135.1, 134.9, 134.6,
131.3, 129.4, 128.4, 123.0; mp 82-84 °C, lit. 81-82 °C.24
Alcohol 14. A 250-mL round-bottom flask was charged with
(S)-BINOL (1.78 g, 6.21 mmol, 0.1 equiv) and 62 mL of methylene
chloride. To this solution was added powdered four molecular sieves
1
1200, 1180 cm-1; H NMR (500 MHz, CDCl3) δ 7.85-7.83 (m,
4H), 7.69-7.66 (m, 2H), 7.55-7.51 (m, 4H), 7.18 (d, J ) 8.6,
(24) (a) Palmieri, G.; Natile, G.; Gasparrini, F.; Giovannoli, M.; Misiti,
D. Synth. Commun. 1988, 18, 69-76. For 1H and 13C data, see: (b) Mori,
M.; Tonogaki, K.; Nishiguchi, N. J. Org. Chem. 2002, 67, 224-226.
3180 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis of Calyxin Natural Products
2H), 7.07 (d, J ) 8.4, 2H), 6.95 (d, J ) 8.5, 2H), 6.87 (d, J ) 8.4,
2H), 5.74 (t, J ) 6.1, 1H), 5.57 (dddd, J ) 17.3, 14.1, 10.5, 6.9,
1H), 5.02-4.98 (m, 2H), 2.89 (t, J ) 7.6, 2H), 2.66-2.43 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 171.6, 149.0, 147.9, 139.4, 138.9,
135.5, 135.4, 134.3, 134.2, 132.6, 129.4, 129.2, 129.1, 128.5, 128.4,
127.8 (2), 122.3, 118.5, 74.4, 40.6, 35.6, 30.1; HRMS (ESI) m/z
calcd for C31H28O8S2 [M + Na]+ 615.1123, found 615.1127. Anal.
Calcd for C31H28O8S2: C, 62.82; H, 4.76.
reduced pressure. Purification by flash chromatography (55%
hexanes/45% dichloromethane/5% diethyl ether) yielded the product
as a white foam (4.48 g, as a 2:1 inseparable mixture of brominated
and protonated compounds).
The mixture from the previous reaction was dissolved in 20 mL
of THF and cooled to -94 °C. t-BuLi (3 mL, 5.1 mmol, 1.2 equiv)
was added dropwise over 5 min, and the mixture was stirred for
an additional 5 min, at which point acetic acid (0.5 mL, 8.5 mmol,
2 equiv) was added slowly and the bath was removed. After the
mixture had warmed to 0 °C, it was diluted with EtOAc and washed
with saturated aqueous bicarbonate and brine. The combined organic
layers were dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by flash chromatography
(60% hexanes/35% dichloromethane/5% ether) to give 18 (3.2 g,
R-Acetoxy Ether 16. A two-necked 1000-mL round-bottom flask
was charged with sulfonate ester (above) (31.4 g, 53 mmol, 1 equiv),
diluted with 250 mL of methylene chloride, and cooled to -78
°C. The internal temperature was monitored with a low temperature
thermometer on one of the two necks. In a separate flask, DIBAL-H
(1 M solution in toluene, 74.3 mL, 74.3 mmol, 1.4 equiv) was
cooled to -78 °C and then cannulated into the 1 L flask slowly,
keeping the internal temperature less than -72 °C. After 30 min,
another 0.15 equiv of DIBAL-H was added in the same way, and
the mixture was stirred for an additional 45 min at which point no
more starting ester was observed by TLC. Pyridine (12.8 mL, 159
mmol, 3 equiv) was cooled to -78 °C and added via cannula. A
solution of DMAP (12.9 g, 106 mmol, 2 equiv) in 100 mL of
methylene chloride was then added down the side of the flask by
syringe, followed by addition of acetic anhydride (15 mL, 159
mmol, 3 equiv). Throughout the additions, the internal temperature
never rose above -72 °C. The solution was stirred at -78 °C for
3 h, and then the bath was removed. The solution was allowed to
warm in air to -10 °C over 30 min, then placed in an ice bath for
30 min. The reaction was quenched with addition of 150 mL
saturated aqueous ammonium chloride and 150 mL of saturated
aqueous sodium potassium tartrate. The resultant biphasic suspen-
sion was stirred vigorously at 0 °C for 2 h until phase separation
occurred. The milky white aqueous layer was extracted with 3 ×
75 mL of methylene chloride, and the combined organic layers were
washed with 3 × 100 mL of 1 M NaHSO4, followed by 3 × 100
mL of saturated aqueous NaHCO3, then 2 × 100 mL of brine. The
brine and NaHCO3 layers were back-extracted with 2 × 50 mL of
methylene chloride. The organic layers were dried over sodium
sulfate, filtered, and concentrated under reduced pressure to give
the crude R-acetoxy ether 16 (32.8 g, 97%), which was used without
purification: IR (neat/NaCl) 3072, 2935, 1734, 1729, 1502, 1374
42% over 2 steps) as a white foam: [R]24 -6.57 (c 0.7, CHCl3);
D
IR (neat/NaCl) 3064, 3033, 2921, 2858, 2361, 1603, 1586, 1501,
1
1373 cm-1; H NMR (500 MHz, CDCl3) δ 7.86-7.81 (m, 4H),
7.69-7.63 (m, 2H), 7.57-7.49 (m, 4H), 7.40-7.30 (m, 15H), 7.17
(d, J ) 8.6, 2H), 7.05 (d, J ) 8.6, 2H), 6.88 (d, J ) 8.5, 2H), 6.84
(d, J ) 8.5, 2H), 6.29 (s, 2H), 5.03 (s, 4H), 4.99 (s, 2H), 4.33 (dd,
J ) 11.7, 1.2, 1H), 3.65 (dddd, J ) 13, 13, 4, 4, 1H), 3.49-3.47
(m, 1H), 2.69-2.62 (m, 2H), 2.28 (q, J ) 11.9, 1H), 2.19 (q, J )
13, 1H), 1.80-1.70 (m, 2H), 1.61-1.58 (m, 1H), 1.46-1.43 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 158.5, 158.2, 148.4, 147.5,
142.9, 141.7, 137.0, 136.8, 135.6, 135.5, 134.09, 134.07, 129.5,
129.1, 129.0, 128.63, 128.55, 128.50, 128.50, 128.1, 127.9, 127.5,
127.3, 127.1, 114.6, 94.1, 79.1, 77.3, 77.0, 76.8, 70.8, 70.2, 37.6,
37.2, 34.4, 32.1, 30.9; ΗRMS (ESI) m/z calcd for C58H52O10S2 [M
+ Na]+ 995.2900, found 995.2855.
Phenol from 18. To a 0 °C solution of 18 (7.8 g, 7.4 mmol, 1
equiv) in 20 mL of dichloromethane was added 12 mL of PhSH
followed by dropwise addition of BF3‚OEt2 (5.6 mL, 44.5 mmol,
6 equiv). The mixture was stirred for 45 min, and then the bath
was removed. Stirring was continued for an additional 5 h. The
reaction was quenched at 0 °C with the addition of 6 mL of a 1:1
mixture of methanol/triethylamine. The solution was poured into a
separatory funnel and washed with 2 × 10 mL of 1 M NaHSO4
and dried over sodium sulfate. Concentration followed by flash
chromatography (80-70-60-50% hexanes/15-25-35-45% dichlo-
romethane/5% ether) yielded the monophenol (3 g, 46%, plus 1.6
g of recovered starting material): [R]24D -7.50 (c 0.4, CHCl3); IR
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.85-7.81 (m, 6H), 7.69-
(neat/NaCl) 3484, 2921, 2360, 2342, 1598, 1501, 1449, 1372 cm-1
;
7.65 (m, 3H), 7.54-7.49 (m, 6H), 7.20-7.17 (m, 3H), 7.08 (d, J
) 8.5, 2H), 6.97-6.94 (m, 4H), 6.89 (d, J ) 8.5, 2H), 6.84 (d, J
) 8.1, 1H), 5.97 (t, J ) 5.1, 1H), 5.69-5.58 (m, 2H), 5.04-4.98
(m, 3H), 4.53-4.48 (m, 1.5H), 2.69-2.31 (m, 6.3H), 2.03-1.85
(m, 3H), 2.04 (s, 1.8H), 1.46 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 170.7, 170.3, 149.2, 148.6, 147.8, 147.7, 141.4, 140.2, 140.1,
140.0, 135.6, 135.5, 135.4, 135.4, 134.2, 134.2, 134.1, 133.7, 133.5,
129.4, 129.3, 129.13, 129.11, 129.08, 128.5, 128.43, 128.41, 128.4,
128.3, 127.6, 122.4, 122.24, 122.19, 121.9, 118.0, 117.5, 97.4, 95.5,
81.6, 79.1, 42.6, 41.9, 35.9, 35.7, 29.6, 29.3, 21.1, 20.5; HRMS
(ESI) m/z calcd for C33H32O9S2 [M + Na]+ 659.1385, found
659.1380. Anal. Calcd for C33H32O9S2: C, 62.25; H, 5.07. Found:
C, 62.16; H, 4.96.
1H NMR (500 MHz, CDCl3) δ 7.84-7.80 (m, 4H), 7.66-7.62 (m,
2H), 7.52-7.48 (m, 4H), 7.40-7.26 (m, 10H), 7.14 (d, J ) 8.5,
2H), 7.03 (d, J ) 8.5, 2H), 6.87 (d, J ) 8.7, 2H), 6.83 (d, J ) 8.5,
2H), 6.14 (s, 2H), 5.02 (s, 4H), 4.76 (s, 1H), 4.31 (dd, J ) 11.5,
2.0, 1H), 3.62 (dddd, J ) 13, 13, 3.5, 3.5, 1H), 3.48-3.44 (m,
1H), 2.70-2.59 (m, 2H), 2.27 (q, J ) 12.5, 1H), 2.15 (q, J ) 12.5,
1H), 1.82-1.68 (m, 2H), 1.61-1.57 (m, 1H), 1.44 (d, J ) 13, 1H);
13C NMR (125 MHz, CDCl3) δ 158.3, 155.1, 148.3, 147.5, 142.9,
141.7, 136.9, 135.5, 135.4, 134.11, 134.10, 129.5, 129.09, 129.06,
128.6, 128.50, 128.49, 127.9, 127.2, 127.1, 122.1, 122.0, 121.9,
114.0, 94.2, 79.1, 70.7, 37.6, 37.2, 34.4, 32.0, 30.9; HRMS (ESI)
m/z calcd for C51H46O10S2 [M + Na]+ 905.2430, found 905.2442.
Anal. Calcd for C51H46O10S2: C, 69.37; H, 5.25. Found: C, 69.59;
H, 5.37.
Tetrahydropyran 18. To a solution of R-acetoxy ether 16 (5 g,
7.86 mmol, 1 equiv) and arene 17 (7.45 g, 15.7 mmol, 2 equiv) in
13 mL of methylene chloride was added 5 g of 3 D sieves (pellets,
activated in furnace at 270 °C overnight), and the mixture was
stirred for 1 h at room temperature. The solution was cannulated
into a fresh flask, and the sieves were rinsed with 3 × 2 mL of
methylene chloride, which was also transferred via cannula. The
solution was cooled to 0 °C, and BF3‚OEt2 (99.6 µL, 0.786 mmol,
0.1 equiv) was added dropwise. After 5 min, the bath was removed.
The reaction was stirred at room temperature for 5 h and then
quenched at 0 °C with 10 drops of triethylamine. Addition of 10
mL of saturated aqueous bicarbonate was followed by dilution with
20 mL of methylene chloride. The aqueous layer was extracted
with 2 × 20 mL of methylene chloride, and the combined organic
layers were dried over magnesium sulfate and concentrated under
Methyl Ether from Phenol. The phenol derived from 18 (200
mg, 0.22 mmol, 1 equiv) was dissolved in 2 mL of distilled acetone,
and dimethyl sulfate (44 µL, 0.44 mmol, 2 equiv) was added
followed by K2CO3 (60 mg, 0.44 mmol, 2 equiv). The mixture was
heated at reflux for 2 h. After the flask cooled to room temperature,
triethylamine (100 µL) was added, and the mixture was stirred for
1 h at room temperature. The solids were removed by filtration,
and the filtrate was concentrated. The residue was purified by flash
chromatography (60% hexanes/35% dichloromethane/5% ether) to
give the product (200 mg, 98%): [R]24 -7.80 (c 0.85, CHCl3);
D
IR (neat/NaCl) 3064, 3033, 2919, 2845, 1605, 1587, 1501, 1449,
1
1373 cm-1; H NMR (500 MHz, CDCl3) δ 7.84-7.81 (m, 4H),
7.66-7.62 (m, 2H), 7.52-7.48 (m, 4H), 7.41-7.30 (m, 10H), 7.15
J. Org. Chem, Vol. 71, No. 8, 2006 3181

Tian et al.
(d, J ) 8.6, 2H), 7.03 (d, J ) 8.5, 2H), 6.87 (d, J ) 8.6, 2H), 6.83
(d, J ) 8.5, 2H), 6.21 (s, 2H), 5.05 (s, 4H), 4.31 (dd, J ) 11.2,
1.8, 1H), 3.73 (s, 3H), 3.63 (dddd, J ) 12, 13, 4, 4, 1H), 3.48-
3.42 (m, 1H), 2.70-2.58 (m, 2H), 2.28 (q, J ) 12.4, 1H), 2.16 (q,
J ) 12.4, 1H), 1.84-1.69 (m, 2H), 1.60-1.57 (m, 1H), 1.44 (d, J
) 13, 1H); 13C NMR (125 MHz, CDCl3) δ 159.3, 158.3, 148.4,
147.6, 142.9, 141.7, 137.1, 135.60, 135.56, 134.08, 134.07, 129.5,
129.08, 129.06, 128.6, 128.51, 128.50, 127.91, 127.90, 127.3, 127.1,
122.0, 121.9, 114.3, 93.1, 79.2, 70.8, 55.3, 37.6, 37.2, 34.4, 32.2,
30.9; HRMS (ESI) m/z calcd for C52H48O10S2 [M + Na]+ 919.2587,
found 919.2559; Anal. Calcd for C52H48O10S2: C, 69.62; H, 5.39.
Found: C, 69.64; H, 5.20.
Stirring was continued for 30 min more at room temperature. The
solution was filtered, and the solids were washed with ether. The
mother liquor was concentrated and loaded directly onto a silica
column and chromatographed in 15-25% EtOAc/hexanes to give
the product (62 mg, 60%): [R]24D +0.46 (c 1.4, CHCl3); IR (neat/
NaCl) 3066, 2952, 2360, 1591, 1502, 1449, 1376, 1249, 1200, 1152;
1H NMR (500 MHz, CDCl3) δ 7.86-7.82 (m, 4H), 7.68-7.65 (m,
2H), 7.54-7.51 (m, 4H), 7.30 (d, J ) 8.7, 2H), 7.07 (d, J ) 8.5,
2H), 6.94 (d, J ) 8.6, 2H), 6.87 (d, J ) 8.5, 2H), 6.65 (s, 1H),
5.22 (s, 2H), 5.09 (s, 2H), 4.40 (dd, J ) 10, 1.2, 1H), 3.95-3.90
(m, 2H), 3.85 (s, 3H), 3.72-3.68 (m, 2H), 3.60-3.55 (m, 2H),
2.81-2.67 (m, 2H), 2.22 (q, J ) 12, 3, 1H), 2.12 (q, J ) 11.6,
1H), 1.96-1.88 (m, 1H), 1.82-1.72 (m, 2H), 1.58-1.56 (m, 1H),
1.01-0.91 (m, 4H), 0.026 (s, 9H), -0.049 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 156.9, 155.5, 153.8, 148.5, 147.6, 142.1, 141.4,
135.53, 135.49, 134.15, 134.12, 129.5, 129.13, 129.08, 128.5 (2),
126.9, 122.1, 122.0, 120.6, 99.5, 98.7, 96.3, 92.7, 78.8, 77.8, 68.0,
66.5, 56.4, 37.9, 36.7, 35.0, 34.3, 31.3, 18.3, 18.0, -1.36, -1.43;
LRMS (ESI) m/z calcd for C50H63BrO12S2Si2 [M + Na]+ 1079.24,
found 1079.19; Anal. Calcd for C50H63BrO12S2Si2: C, 56.86; H,
6.01. Found: C, 56.66; H, 5.98.
Enone 21. To a solution of bromide (200 mg, 0.19 mmol, 1
equiv) in 3 mL of THF at -78 °C was added PhLi (0.86 M, 664
µL, 0.57 mmol, 3 equiv) quickly, and the mixture was stirred for
5 min. Aldehyde 20 (156 mg, 0.57 mmol, 3 equiv) in 669 µL of
THF was then added quickly, and the mixture was stirred for 2 h
at -78 °C. The reaction was quenched with 5 mL of pH 7 buffer,
and the bath was removed. Once the mixture warmed to room
temperature, the aqueous layer was extracted with ethyl acetate (5
× 5 mL), and the combined organic layers were dried over sodium
sulfate. The sodium sulfate was removed by filtration, and the
filtrate was concentrated in vacuo to give the crude diastereomeric
alcohols.
Diphenol 19. A solution of methyl ether (490 mg, 0.55 mmol,
1 equiv) in THF was added to a slurry of Raney nickel (washed
with water, then ethanol, then THF) in THF. The mixture was
sonicated for 1 h and then filtered through Celite. The filtrate was
concentrated, then dissolved in 3 mL of THF, 10% Pd/C (40 mg)
was added, and the flask was placed in a Parr apparatus and filled
to 60 psi with hydrogen. After being stirred for 12 h at room
temperature, the solution was filtered through Celite and concen-
trated under reduced pressure. The residue was purified by flash
chromatography (40% hexanes/55% dichloromethane/5% ether) to
give 19 (320 mg, 82%): [R]24 -5.36 (c 1.1, CHCl3); IR (neat/
D
NaCl) 3479, 2922, 2845, 1622, 1602, 1527, 1467, 1449; 1H NMR
(500 MHz, CDCl3) δ 7.83-7.80 (m, 4H), 7.66-7.62 (m, 2H),
7.52-7.48 (m, 4H), 7.30 (d, J ) 8.6, 2H), 7.06 (d, J ) 8.5, 2H),
6.91 (d, J ) 8.7, 2H), 6.84 (d, J ) 8.6, 2H), 5.90 (s, 2H), 5.05 (s,
2H), 4.41 (dd, J ) 11.2, 1.2, 1H), 3.66 (s, 3H), 3.55-3.50 (m,
1H), 3.42 (dddd, J ) 12, 12, 4, 4, 1H), 2.80-2.64 (m, 2H), 2.27
(q, J ) 12.3, 1H), 2.17 (q, J ) 12.4, 1H), 1.92-1.89 (m, 1H),
1.78-1.76 (m, 2H), 1.55-1.52 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 158.8, 155.6, 148.4, 147.5, 142.3, 141.6, 135.4, 134.2,
129.6, 129.5, 129.13, 129.11, 128.5, 127.2, 127.1, 122.1, 122.0,
121.99, 110.1, 94.9, 79.0, 77.6, 55.2, 37.5, 36.6, 34.6, 32.2, 31.1;
HRMS (ESI) m/z calcd for C38H36O10S2 [M + Na]+ 739.1647, found
739.1647.
The crude alcohol was dissolved in 4 mL of dioxane and added
to a stirred suspension of NaHCO3 (200 mg) and DDQ (129 mg,
0.57 mmol, 3 equiv) in 1 mL of dioxane. The yellow suspension
immediately turned dark green upon addition of the alcohol. The
mixture was stirred at room temperature for 30 min. The mixture
was filtered and concentrated, and the residue was filtered through
a plug of neutral alumina eluting with dichloromethane. The filtrate
was concentrated and chromatographed in 20-50% EtOAc/hexanes
Bis SEM Ether from 19. To a solution of KH (washed with
hexanes, 12 mg, 0.28 mmol, 2 equiv) in 1 mL of THF was added
catalytic 18-crown-6 (spatula tip) then cooled to 0 °C. Diphenol
19 (100 mg, 0.14 mmol, 1 equiv) dissolved in 1.2 mL of THF was
added dropwise to the KH solution. The purplish mixture was stirred
for 5 min, then SEM-Cl (48 µL, 0.28 mmol, 2 equiv) was added
dropwise, and the bath was removed. After 2 h, the reaction was
cooled in an ice bath, and saturated aqueous ammonium chloride
(2 mL) was added slowly followed by brine (2 mL). The aqueous
layer was extracted with 5 × 5 mL of EtOAc, and the combined
organic layers were dried over sodium sulfate, filtered, and
concentrated. The crude residue was purified by flash chromatog-
raphy (15-25% EtOAc/hexanes) to give the bis SEM ether (88
over silica to give 140 mg of enone 21 (58% from bromide): [R]24
D
+650.6 (c 0.8, CHCl3); IR (neat/NaCl) 2952, 2927, 1597, 1502,
1
1449, 1376, 1199; H NMR (500 MHz, CDCl3) δ 7.86-7.83 (m,
6H), 7.70-7.65 (m, 3H), 7.55-7.51 (m, 6H), 7.44 (d, J ) 8.5,
2H), 7.34 (d, J ) 16, 1H), 7.31 (d, J ) 8.5, 2H), 7.08 (d, J ) 8.5,
2H), 7.00 (d, J ) 8.5, 2H), 6.95-6.93 (m, 2.5 H), 6.89-6.86 (m,
2.5H), 6.62 (s, 1H), 5.26 (s, 2H), 4.91 (s, 2H), 4.40 (dd, J ) 12.2,
2.1, 1H), 3.75 (s, 3H), 3.72-3.68 (m, 4H), 3.54-3.52 (m, 2H),
2.83-2.65 (m, 2H), 2.22 (q, J ) 12, 1H), 2.14 (q, J ) 12, 1H),
1.94-1.92 (m, 1H), 1.82-1.76 (m, 2H), 1.58-1.56 (m, 1H), 0.94
(t, J ) 8.5, 2H), 0.88 (t, J ) 8.5, 2H), -0.04 (s, 9H), -0.05 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 193.5, 159.0, 156.6, 154.1,
150.7, 148.5, 147.6, 142.1, 142.0, 141.4, 135.6, 135.5, 135.2, 134.4,
134.2, 134.1, 133.8, 129.6, 129.5, 129.4, 129.2, 129.1, 129.09,
128.48 (2), 128.47 (2), 122.9, 122.1, 122.06, 119.1, 117.8, 99.9,
95.3, 92.5, 78.8, 77.7, 67.8, 66.7, 55.9, 37.9, 36.8, 35.0, 33.5, 31.3,
18.2, 18.0, -1.41, -1.43; LRMS (ESI) calcd for C65H74O16S3Si2
[M + Na]+ 1285.36, found 1285.31.
mg, 65%): [R]24 -4.89 (c 0.45, CHCl3); IR (neat/NaCl) 2953,
D
2921, 1608, 1590, 1376, 1200, 1152; 1H NMR (500 MHz, CDCl3)
δ 7.86-7.84 (m, 4H), 7.69-7.66 (m, 2H), 7.55-7.52 (m, 4H), 7.32
(d, J ) 8.6, 2H), 7.09 (d, J ) 8.4, 2H), 6.94 (d, J ) 8.5, 2H), 6.88
(d, J ) 8.3, 2H), 6.41 (s, 2H), 5.19 (s, 4H), 4.42 (dd, J ) 11, 1.2,
1H), 3.80 (s, 3H), 3.73 (t, J ) 8.1, 4H), 3.61-3.50 (m, 2H), 2.80-
2.70 (m, 2H), 2.22 (q, J ) 12.3, 1H), 2.11 (q, J ) 10, 1H), 1.95-
1.88 (m, 1H), 1.79-1.72 (m, 2H), 1.52 (d, J ) 13, 1H), 0.95 (t, J
) 8.3, 4H), -0.02 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 159.2,
156.9, 148.4, 147.6, 142.4, 141.5, 135.6, 135.5, 134.1, 131.5, 129.6,
129.11, 129.08, 128.5, 127.0, 122.1, 122.0, 118.2, 114.3, 94.9, 93.0,
78.8, 77.5, 66.3, 55.3, 37.8, 36.7, 35.1, 32.4, 31.2, 18.0, -1.41;
HRMS (ESI) m/z calcd for C50H64O12S2Si2 [M + Na]+ 999.3276,
found 999.3289; Anal. Calcd for C50H64O12S2Si2: C, 61.45; H, 6.60.
Found: C, 61.61; H, 6.48.
Bisphenol from 21. Enone 21 (245 mg, 0.194 mmol) was
dissolved in 6 mL of THF and cooled to 0 °C. HF‚pyridine (6 mL)
was added dropwise, and the bath was removed. The reaction was
stirred at room temperature for 4 h. The reaction was cooled with
an ice bath and diluted with 10 mL of ether and washed with 1 M
NaHSO4 (3 × 3 mL). The organic extracts were dried over Na2-
SO4, filtered, and concentrated. The residue was purified by prep-
Bromination of SEM Protected 19. The bis SEM ether (95
mg, 0.097 mmol, 1 equiv) was dissolved in 2 mL of THF and cooled
to 0 °C. NBS (17 mg, 0.097 mmol, 1 equiv) dissolved in 1 mL of
THF was added dropwise. The reaction was stirred for 30 min at
0 °C and then quenched with addition of 100 mg of NaHCO3.
TLC to give 174 mg of bisphenol (89%): [R]24 +18.0 (c 0.25,
D
CHCl3); IR (neat/NaCl) 3436, 2923, 1613, 1502, 1373, 1199, 1150;
1H NMR (500 MHz, CDCl3) δ 14.57 (s, 1H), 7.86-7.82 (m, 6H),
3182 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis of Calyxin Natural Products
7.76 (d, J ) 16, 1H); 7.70-7.63 (m, 4H), 7.55-7.48 (m, 8H), 7.33
(d, J ) 8.5, 2H), 7.08 (d, J ) 8.5, 2H), 7.01 (d, J ) 8.5, 2H), 6.92
(d, J ) 8.5, 2H), 6.86 (d, J ) 8.5, 2H), 6.38 (s, 1H), 5.79 (s, 1H),
4.45 (dd, J ) 11.2, 1.1, 1H), 3.82 (s, 3H), 3.60-3.52 (m, 2H),
2.83-2.66 (m, 2H), 2.30 (q, J ) 12.4, 1H), 2.18 (q, J ) 12.3, 1H),
1.96-1.88 (m, 1H), 1.82-1.74 (m, 2H), 1.56-1.51 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 192.5, 165.9, 161.4, 161.0, 155.2, 150.4,
148.5, 147.5, 142.2, 141.5, 140.2, 135.3, 135.2, 134.6, 134.5, 134.2,
130.4, 129.6, 129.5, 129.3, 129.2, 129.1, 128.7, 128.5 (2), 127.2
(2), 122.8, 122.1, 122.0, 110.5, 106.1, 91.3, 78.9, 77.6, 55.8, 37.5,
35.9, 34.0, 31.6, 31.1; LRMS (ESI) m/z calcd for C53H46O14S3 [M
+ H]+ 1003.21, found 1003.18.
Calyxin L. The bisphenol derived from 21 (59 mg, 0.059 mmol,
1 equiv) was dissolved in 2.4 mL of a 1:1 mixture of methanol
and THF (degassed by sparging with Ar for 30 min) and ignited
K2CO3 (81 mg, 0.59 mmol, 10 equiv) was added. The mixture was
heated at 50 °C for 15 h, then another 5 equiv of K2CO3 was added,
and heating continued for 2 h. The orange-colored solution was
then cooled to room temperature and diluted with 10 mL of ether
and washed with 5 mL of saturated aqueous ammonium chloride.
Mixing was continued until the color of the solution changed from
orange to yellow. The organic layer was dried over sodium sulfate,
filtered, and concentrated under reduced pressure. Purification by
prep-TLC (10% 9:1 MeOH/AcOH, 90% dichloromethane) yielded
the title compound as a yellow film (12 mg, 35%) plus a mixture
of mono- and bis-sulfonates (8 mg). Total combined yield after
one recycling was 58%: [R]24D -6 (c 0.08, MeOH); IR (neat/NaCl)
1
3436, 2920, 1603, 1508, 1399, 1227; H NMR (500 MHz, CD3-
OD) δ 7.77 (d, J ) 15.5, 1H), 7.67 (d, J ) 15.5, 1H), 7.49 (d, J )
8.6, 2H), 7.24 (d, J ) 8.6, 2H), 7.01 (d, J ) 8.4, 2H), 6.82 (d, J )
8.6, 2H), 6.76 (d, J ) 8.6, 2H), 6.68 (d, J ) 8.4, 2H), 6.02 (s, 1H),
4.35 (dd, J ) 11.1, 1.2, 1H), 3.89 (s, 3H), 3.60-3.55 (m, 2H),
2.71-2.58 (m, 2H), 2.46 (q, J ) 12.3, 1H), 2.23 (q, J ) 12.3, 1H),
1.90-1.83 (m, 1H), 1.76-1.72 (m, 1H), 1.62 (d, J ) 13, 1H), 1.50
(d, J ) 13, 1H); 13C NMR (125 MHz, CD3OD) δ 194.2, 166.8,
164.4, 162.5, 161.1, 157.7, 156.2, 143.4, 135.6, 134.6, 131.3, 130.4,
128.7, 128.4, 125.9, 116.9, 116.1, 115.9, 111.9, 106.6, 92.1, 81.7,
79.5, 56.2, 39.7, 37.3, 35.6, 33.3, 32.0; HRMS (ESI) m/z calcd for
C35H34O8 [M + Na]+ 605.2151, found 605.2137.
Acknowledgment. This work was supported by the National
Cancer Institute (CA-081635). We thank Professor S. Kadota
for providing NMR spectra of calyxin F and epicalyxin F.
Supporting Information Available: Experimental procedures
and NMR spectra of the new compounds, including detailed
comparisons between the synthetic and isolated natural products
described herein. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060094G
J. Org. Chem, Vol. 71, No. 8, 2006 3183