Evidence for π-stacking as a source of stereocontrol in the synthesis of the core pyranochromene ring system common to calyxin I, calyxin J, and epicalyxin J

Article abstract of DOI:10.1021/jo901436u

(Chemical Equation Presented) A diastereoselective synthesis of the tetrahydropyranochromene ring system common to several natural product isolates of Alpinia blepharocalyx is reported. We have shown that a stereochemical preference exists for a syn confi

Full text of DOI:10.1021/jo901436u

pubs.acs.org/joc
synthetic work in this area has been sparse. Li and co-
Evidence for π-Stacking as a Source of Stereocontrol
in the Synthesis of the Core Pyranochromene Ring
System common to Calyxin I, Calyxin J, and
Epicalyxin J
workers have reported stereoselective syntheses of com-
pounds 4 and 5 using the Prins cyclization,4 but they did
not report the formation of bis-aryl derivatives by their
route. We therefore chose compound 6 as a model synthetic
target to see if a stereochemical preference exists for the aryl
substituents to be syn to each other as indicated, analogous
to the C-7 and C-70 positions in the natural products. The
nature of the interaction between the two aromatic rings at
these positions would be important, and the possibility of a
favorable π-stacking effect was not ruled out as a controlling
factor.5
Sidika Polat Cakir, Sean Stokes, Andrzej Sygula, and
Keith T. Mead*
Department of Chemistry, Mississippi State University,
Mississippi State, Mississippi 39762
kmead@ra.msstate.edu
Received July 6, 2009
A diastereoselective synthesis of the tetrahydropyrano-
chromene ring system common to several natural product
isolates of Alpinia blepharocalyx is reported. We have
shown that a stereochemical preference exists for a syn
configuration between the anomeric aryl substituents,
representative of the C-7 and C-70 substituents in the
natural products. Further, our results show that stereo-
control is under kinetic control, and calculations suggest
that a favorable π-stacking interaction may be the source
of this stereocontrol.
Our route began with the racemic lactone 8, which was
prepared in 56% yield by a palladium-catalyzed addition of
2-benzyloxyiodobenzene 76 to 5,6-dihydro-2H-pyran-2-one
(Scheme 1). A directed aldol reaction of lactone 8 with
p-methoxybenzaldehyde, via its boron enolate, then gave
alcohol 9 in a 91% yield as a single isomer,7 which was
cleanly converted to the diol 10 in 94% yield under standard
hydrogenation conditions. Exposure of diol 10 to Lewis acid
then provided compound 11 diastereomerically pure (79%
from compound 9). The stereochemistry of compound 11
was easily assignable based on proton NMR coupling con-
stants. A doublet at δ 5.22 (J=10 Hz) established the trans-
diaxial relationship between Ha and Hb, while a doublet of
doublets at δ 3.08 (J=10, 13 Hz) confirmed the same rela-
tionship between Ha and Hc. Although the formation of 11
from diol 10 proceeded with complete inversion of config-
uration, establishment of the newly formed ring stereocenter
in this reaction, with a pseudoequatorial aryl substituent,
is most likely the result of an SN1 mechanism involving
More than 50 polyphenolic constituents of the seeds of
Alpinia blepharocalyx have been isolated by Kadota and co-
workers,1 and several of them have been shown to possess
significant antiproliferative activity against colon 26-L5
carcinoma and HT-1080 fibrosarcoma cells. Not surpris-
ingly, these compounds have attracted the attention of
several groups, resulting in both partial2 and total3 syntheses
of a number of analogues. Calyxin I (1) along with the
epimeric analogues calyxin J (2) and epicalyxin J (3) com-
prise a subset of isolates that are characterized by the
presence of a novel bis-C-arylpyranoside moiety embedded
in a tetrahydropyranochromene framework. To date,
(1) (a) Ali, M. S.; Bankskota, A. H.; Tezuka, Y.; Saiki, I.; Kadota, S. Biol.
Pharm. Bull. 2001, 24, 525–528. (b) Gewali, M. B.; Tezuka, Y.; Banskota,
A. H; Ali, M. S.; Saiki, I.; Dong, H.; Kadota, S. Org. Lett. 1999, 1, 1733–
1736. (c) Tezuka, Y.; Gewali, M. B.; Ali, M. S.; Banskota, A. H; Kadota, S.
J. Nat. Prod. 2001, 64, 208–213.
(2) (a) Polat Cakir, S.; Mead, K. T. Tetrahedron Lett. 2006, 47, 2451–
2454. (b) Washio, T.; Nambu, H.; Anada, M.; Hashimoto, S. Tetrahedron:
Asymmetry 2007, 2606–2612.
(4) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J. Synlett 2005, 1912–1916.
(5) For a recent example, see: Fustero, S.; Navarro, A.; Pina, B.; Soler,
J. G.; Bartolome, A.; Asensio, A.; Simon, A.; Bravo, P.; Fronza, G.;
Volonterio, A.; Zanda, M. Org. Lett. 2001, 3, 2621–2624.
(6) Portscheller, J. L.; Malinakova, H. C. Org. Lett. 2002, 4 (21), 3679–
3681.
(7) The stereochemistry assigned to compound 9 was based on literature
precedent. See: Ito, H.; Momose, T.; Konishi, M.; Yamada, E.; Watanabe,
K.; Iguchi, K. Tetrahedron 2006, 62, 10425–10433.
(3) (a) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem. 2006, 71,
3176–3183. (b) Tian, X.; Rychnovsky, S. D. Org. Lett. 2007, 9, 4955–4958.
DOI: 10.1021/jo901436u
r
Published on Web 09/02/2009
J. Org. Chem. 2009, 74, 7529–7532 7529
2009 American Chemical Society

Cakir et al.
JOCNote
SCHEME 1
SCHEME 2
mixture of diols 13 was converted to an equal mixture of 6
and its anomer 16 via the primary tosylate 15 (Scheme 2), and
the two diastereomers were separated by column chroma-
tography. However, treatment of compound 16 with
p-TsOH, TiCl4, or BF3 OEt2 failed to yield any of the syn
3
isomer 6, suggesting that its formation from intermediate 14
is most likely under kinetic control.
In an attempt to determine the origin of the stereocontrol
in the formation of 6 from 14, we decided to calculate the
relative energies of the syn and anti conformers of carboca-
tion 14, leading to the formation of 6a and 16a, respectively
(see Figure 1). These two conformations have been labeled
14-syn and 14-anti to designate the syn and anti relationship,
respectively, between the two 4-methoxyphenyl groups.
Calculations were carried out using the MP2/cc-pVDZ
approach, as this method takes into account the possibility
of weak interactions such as π-stacking effects.9 We felt that
this could be a significant factor in carbocation 14, as there is
the potential for a donor-acceptor interaction, given that
one aromatic ring is electron deficient by virtue of the
benzylic cationic center. Indeed, our calculations show that
conformer 14-syn is 5.7 kcal/mol lower in energy than
conformer 14-anti and that the corresponding ring-closed
product, 6a, is 5.0 kcal/mol more stable than 16a. Interest-
ingly, the smaller distances separating the two 4-methoxy-
phenyl rings in 14-syn indicate that attractive forces are
involve0d. The interatomic separation between carbon atoms
formation of a stabilized benzyl carbocation. Unfortunately,
attempts to open the lactone ring of 11 by reaction with
commercially available p-methoxyphenylmagnesium bro-
mide gave only starting material. However, use of the
corresponding aryllithium reagent provided 12 in 72% yield.
The final ring closure was accomplished in two steps (81%)
by treatment of 12 with NaBH4 followed by exposure of the
crude mixture of diols 13 to p-TsOH. To our surprise,
compound 6 was formed diastereomerically pure by NMR
analysis. The stereochemistry was confirmed by assignments
of the alicyclic ring protons, which were supported by GIAO
calculations of the chemical shifts. Both anomeric protons
Hb and Hd appeared as doublets with coupling constants of
9.7 Hz, thereby confirming the trans-diaxial relationship
between Ha and Hd. A final verification of the stereochemi-
stry was provided by the NOESY spectrum, which showed
the expected cross peaks for Hb-Hc, Hb-Hd, and Hc-Hd,
but not for Ha (see the Supporting Information).
We considered the possibility that both anomeric stereo-
centers in 6 were formed under equilibrating conditions,
given their potential acid lability.8 Formation of benzyl
carbocation 14 from the diol mixture 13 would be expected
to be facile by virtue of the stabilizing effect of the p-methoxy
group. However, the question of whether this effect was
sufficient to allow its formation reversibly from the pyrano-
chromene product remained to be addressed. To test for
thermodynamic control in the formation of compound 6, the
0
˚
1 and 1 , for example, is 3.07 A, while carbon atoms 4 and 4
˚
are separated by a distance of 3.30 A. This suggests that the
stabilization calculated for this conformer might be due to a
favorable π-stacking interaction that is obviously absent in
14-anti. On the basis of these calculations, stereocontrol in
the formation of compound 6 (see Scheme 1) can be ex-
plained by making the reasonable assumptions that carboca-
tion conformer 14-syn is formed from both diastereomers of
(9) (a) Hobza, P.; Sezle, H. L.; Schlag, E. W. J. Phys. Chem. 1996, 100,
ꢀ
18790–18794. (b) Spirko, V.; Enqvist, O.; Soldan, P.; Sezle, H. L.; Schlag,
ꢀ
E. W; Hobza, P. J. Chem. Phys. 1999, 111, 572–582.
(8) For evidence of this, see: Polat Cakir, S.; Mead, K. T. J. Org. Chem.
2004, 69, 2203–2205.
7530 J. Org. Chem. Vol. 74, No. 19, 2009

Cakir et al.
JOCNote
FIGURE 1. MP2/cc-pVDZ-optimized structures and energies (in Hartrees) of syn (top) and anti (bottom) conformers of carbocation 14 (left),
as well as initial ring-closed products 6a and 16a (right). Relative energies (kcal/mol) of the syn-anti pairs are given in parentheses.
1
diol 13 at a faster rate than 14-anti and that ring closure from
14-syn is fast relative to conformational interchange. Efforts
are currently underway to apply these results to the enantio-
selective syntheses of both calyxin J and epicaylyxin J.
crystalline white solid: mp 122-124 °C; H NMR (600 MHz,
CDCl3) δ 7.43-7.36 (m, 5H), 7.33 (dt, J=1.6 and 8.3 Hz, 1H),
7.11 (d, J = 8.5 Hz, 3H), 6.95 (d, J=8.6 Hz, 1H), 6.91 (d, J=7.5
Hz, 1H), 6.75 (d, J = 8.7 Hz, 2H), 5.07 (d, J = 11.2 Hz, 1H),
5.04 (d, J=11.2 Hz, 1H), 4.72 (s (broad), 1H), 4.24-4.19 (m,
1H), 4.08-4.04 (m, 1H), 3.81-3.80 (m, 1H), 3.76 (s, 3H),
3.56-3.49 (m, 2H), 2.18-2.11 (m, 1H), 2.05-1.99 (m, 1H);
13C NMR (150 MHz, CDCl3) δ 174.2, 158.7, 155.8, 136.3, 133.8,
130.7, 129.7, 128.7, 128.3, 128.2, 127.7, 127.3, 121.1, 113.4,
112.0, 72.6, 70.2, 67.0, 55.1, 50.3, 36.0, 29.1; FT-IR (CHCl3)
3445 (broad), 2935, 1716, 1512, 1248, 752 cm-1
Experimental Section
4-(2-Benzyloxyphenyl)tetrahydropyran-2-one ((()-8). A mix-
ture of 1-benzyloxy-2-iodobenzene 76 (174 mg, 0.56 mmol), 5,6-
dihydro-2H-pyran-2-one (50 mg, 0.51 mmol), tetrakis-
(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), and
triethylamine (57 mg, 0.56 mmol) was purged with N2 gas and
heated to 80 °C for 10 h. The solution was quenched with 10%
HCl and extracted with EtOAc. The organic layer was washed
with water and then dried over anhydrous MgSO4. The crude oil
was subjected to column chromatography using an ethyl acet-
ate/hexane mixture as the eluting solvent to afford the product
3-[Hydroxy(4-methoxyphenyl)methyl]-4-(2-hydroxyphenyl)tetra-
hydropyran-2-one (10). Lactone 9 (700 mg, 1.7 mmol) was dissolved
in 15 mL of EtOAc/EtOH (2:1), and 10 mol % of Pd/C was added
to the solution. The resultant mixture was stirred overnight at room
temperature under H2 gas atmosphere. The reaction mixture was
filtered, and the solvent was removed in vacuo. The crude product
was purified by flash column chromatography using ethyl acetate/
hexane mixture as eluting solvent to provide the product (515 mg,
1
(81 mg, 56%) as a crystalline white solid (mp 82-84 °C): H
NMR (600 MHz, CDCl3) δ 7.42-7.36 (m, 5H), 7.24 (t, J=7.3
Hz, 1H), 7.15 (d, J=7.1 Hz, 1H), 7.00-6.96 (m, 2H), 5.09 (s,
2H), 4.43-4.25 (m, 2H), 3.65-3.55 (m, 1H), 2.90 (dd, J = 5.9
and 17.3 Hz, 1H), 2.67 (dd, J = 10.2, 17.3 Hz, 1H), 2.10-2.00
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 171.4, 155.9, 136.7,
131.1, 128.6, 128.0, 127.2, 126.8, 121.1, 112.0, 70.1, 68.4, 35.8,
1
94%) as a crystalline white solid: mp 48-50 °C; H NMR (600
MHz, CDCl3) δ 7.15 (d, J = 8.7 Hz, 2H), 7.08-7.02 (m, 2H),
7.00-6.97 (m, 1H), 6.79 (t, J=7.0 Hz, 1H), 6.76 (d, J=8.7 Hz, 2H),
4.80 (s (broad), 1H), 4.41 (ddd, J= 4.2, 7.2, and 11.3 Hz, 1H),
4.07-4.02 (m, 1H), 3.73 (s, 3H), 3.53 (dd, J = 4.2 and 9.1 Hz, 1H),
3.47-3.40 (m, 1H), 2.11-2.05 (m, 2H); 13C NMR (150 MHz,
CDCl3) δ 174.5, 158.8, 153.7, 133.4, 129.3, 128.2, 127.2, 120.7,
116.4, 114.2, 113.5, 72.9, 67.6, 55.2, 51.4, 35.6, 29.1; FT-IR (CHCl3)
3362 (broad), 2933, 1705, 1513, 1249, 755 cm-1; HRMS: calcd for
C19H20O5 328.1305, found 328.1311.
31.8, 28.5; FT-IR (CHCl3) 3033, 2904, 1736, 1234, 752 cm-1
HRMS calcd for C18H18O3 282.1255, found 282.1256.
;
4-(2-Benzyloxyphenyl)-3-[hydroxy(4-methoxyphenyl)methyl]-
tetrahydropyran-2-one (9). Dibutylboron trifluoromethanesul-
fonate (1 M solution in dichloromethane, 6.6 mL, 6.6 mmol)
and N,N-diisopropylethylamine (1.4 mL, 8.25 mmol) were
added to a solution of lactone 8 (930 mg, 3.3 mmol) in
dichloromethane (20 mL) at -78 °C. The resultant mixture
was stirred at the same temperature for 2 h, and then p-methoxy
benzaldehyde (0.8 mL, 6.6 mmol) was added to the mixture and
stirred for another 2 h. After the mixture was stirred for an
additional 2 h at 0 °C, phosphate buffer solution (pH=7.0, 8
mL), methanol (15 mL), and H2O2 (30 wt. % solution in water, 8
mL) were added and the mixture stirred overnight at room
temperature. The solvent was removed in vacuo, and the residue
was extracted with dichloromethane. The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
column chromatography using ethyl acetate/hexane mixture
as eluting solvent to give the product (1.25 g, 91%) as a
5-(4-Methoxyphenyl)-1,4a,5,10b-tetrahydro-2H-pyrano[3,4-c]-
chromen-4-one (11). To a solution of diol 10 (130 mg, 0.39 mmol)
˚
in dichloromethane (10 mL) were added crushed 4 A molecular
sieves and BF3 OEt2 (24 μL, 0.2 mmol, 0.5 equiv) at 0 °C. The
3
resulting mixture was stirred at the same temperature for 1 h and
then quenched with water and extracted with dichloromethane.
The organic layer was dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography using ethyl acetate/hexane mix-
tures as eluting solvent to give the product (102 mg, 84%) as a
1
crystalline white solid: mp 218-220 °C; H NMR (600 MHz,
CDCl3) δ 7.43 (d, J=8.6 Hz, 2H), 7.20-7.14 (m, 2H), 6.98 (t, J=
7.1 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.1 Hz, 1H), 5.22
(d, J = 10.0 Hz, 1H), 4.50 (ddd, J = 3.6, 7.5, and 11.4 Hz, 1H),
4.40(ddd, J =6.3, 9.5, and 11.9 Hz), 3.82(s,3H), 3.37 (td, J = 8.9
J. Org. Chem. Vol. 74, No. 19, 2009 7531

Cakir et al.
JOCNote
and 13.0 Hz, 1H), 3.08 (dd, J = 10.0 and 13.0 Hz, 1H), 2.82-2.74
(m, 1H), 2.14-2.08 (m, 1H); 13C NMR (150 MHz, CDCl3) δ
170.8, 159.7, 153.9, 132.0, 129.0, 128.3, 126.1, 123.9, 121.1, 117.1,
113.7, 77.3, 65.4, 55.2, 44.4, 33.2, 27.0; FT-IR (CHCl3) 2910,
1737, 1230, 754 cm-1; HRMS calcd for C19H18O4 310.1199,
found 310.1196.
ethanol was evaporated under reduced pressure. The residue was
extracted twice with EtOAc, and the combined organic layers were
dried over MgSO4 and concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (2mL), andacatalyticamountofp-
TsOH was added at room temperature. The reaction mixture was
stirred until the disappearance of the diol was indicated by TLC. The
mixture was filtered and concentrated under reduced pressure, and
the crude product was purified by flash column chromatography
using ethyl acetate/hexane mixtures as eluting solvent to give the
product as an oil (13 mg, 81%): 1H NMR (600 MHz, CDCl3) δ 7.23
(d, J=7.6 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H),
6.78 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.5
Hz, 2H), 6.45 (d, J = 8.5 Hz, 2H), 6.42 (d, J = 8.5 Hz, 2H), 4.83 (d,
J= 9.7 Hz, 1H), 4.29 (dd, J= 3.5 and 11.4 Hz, 1H), 4.18 (d, J=9.6
Hz, 1H), 3.82 (dt, J=1.9 and 11.9 Hz, 1H), 3.67 (s, 6H), 3.06 (dt,
J = 2.8 and 11.3 Hz, 1H), 2.39 (d (broad), J=12.9 Hz, 1H), 2.34 (q,
J = 9.9 Hz, 1H), 1.91 (dq, J= 4.5 and 12.5 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 158.7, 154.4, 132.6, 132.1129.0, 128.9, 127.7, 126.7,
124.4, 120.6, 116.7, 113.3, 113.2, 83.0, 81.6, 68.1, 55.1, 47.9, 38.1,
28.9; FT-IR (CHCl3) 2952, 2835, 1515, 1246 cm-1; HRMS calcd for
C26H26O4 402.1825, found 402.1822.
[4-(2-Hydroxyethyl)-2-(4-methoxyphenyl)chroman-3-yl](4-metho-
xyphenyl)methanone (12). To a solution of lactone 11 (32 mg, 0.10
mmol) in anhydrous THF (2 mL) and HMPA (0.1 mL) was added
freshly prepared p-MeOPhLi in a dropwise manner at -78 °C until
the disappearance of the lactone was indicated by TLC, and the
resulting solution was stirred at the same temperature for 6 h. The
reaction was quenched by the addition of water and warmed to room
temperature. The mixture was extracted twice with EtOAc, and the
combined organic layers were dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel to give the product as an oil (31 mg,
72%): 1H NMR (600 MHz, CDCl3) δ7.66 (d, J = 8.7 Hz, 2H), 7.33
(d, J=7.6 Hz, 1H), 7.23 (d, J= 8.4 Hz, 2H), 7.15 (t, J=7.4Hz, 1H),
6.99-6.94 (m, 2H), 6.73 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.4 Hz,
2H), 4.95 ((d, J = 9.6 Hz, 1H), 4.09 (t, J = 10.1 Hz, 1H), 3.85-3.78
(m,1H),3.78(s,3H),3.66(s,3H),3.58-3.50 (m, 2H), 2.03-2.00 (m,
1H), 1.98-1.92 (m,1H); 13C NMR (150 MHz, CDCl3) δ 200.6,
163.5, 159.4, 155.0, 130.7, 128.2, 127.5, 127.3, 125.0, 121.2, 117.2,
113.7, 113.5, 80.5, 60.0, 55.4, 55.2, 52.0, 36.6, 35.5; FT-IR (CHCl3)
3471, 2935, 1660, 1598, 1514, 1251, 1174 cm-1. HRMS calcd for
C26H26O5 418.1774, found 418.1782.
Acknowledgment. We thank the National Institutes of
Health, through NCI Grant No. R15 CA122083-01, for
financial support of this research. Helpful suggestions from
Professor Bruce Ganem are appreciated.
4,5-Bis(4-methoxyphenyl)-1,4a,5,10b-tetrahydro-2H,4H-py-
rano[3,4-c]chromene (6). To a solution of compound 12 (18.2 mg,
0.04 mmol) in EtOH (2 mL) was added NaBH4 (1.7 mg, 0.044
mmol) at 0 °C, and the reaction mixture was stirred for 2 h at the
same temperature. The reaction was quenched with water, and the
Supporting Information Available: 1H and 13C spectra for
new compounds and details of the computational studies. This
material is available free of charge via the Internet at http://
pubs.acs.org
7532 J. Org. Chem. Vol. 74, No. 19, 2009