Diastereoselective synthesis of polycyclic acetal-fused pyrano[3,2-c]pyran-5(2H)-one derivatives

Article abstract of DOI:10.1021/jo8023889

A facile and efficient diastereoselective one-pot synthesis of polycyclic acetal-fused pyrano[3,2-c]pyrane-5(2H)-one was achieved through the annulation reaction of 2-C-formyl glycals with various 4-hydroxycoumarins and 4-hydroxy-6methyl-2//-pyran-2-one.

Full text of DOI:10.1021/jo8023889

becomes imperative.5 Coumarin or fused-pyrone derivatives are
found in various natural bioactive and synthetic products as well
as pharmaceutical agents (A-D, Figure 1).6 They exhibit
Diastereoselective Synthesis of Polycyclic
Acetal-Fused Pyrano[3,2-c]pyran-5(2H)-one
Derivatives
Ram Sagar, Jongmin Park, Minseob Koh, and
Seung Bum Park*
Department of Chemistry, Seoul National UniVersity,
Seoul 151-747, Korea
sbpark@snu.ac.kr
ReceiVed October 24, 2008
FIGURE 1. Bioactive small molecules with the pyranopyrone skeleton
(A-D) and antibiotics with acetal-fused rings (E and F): (A) arisugacin
A, a selective inhibitor of acetylcholinesterase; (B) cyathuscavins A,
an antioxidant; (C) calanolide A, anti-HIV drug; (D) pterophyllin; (E,
F) spectinomycin and acmimycin, antibiotics; and (G) our designed
novel acetal-fused pyranopyrones.
antidiabetic, anti-Alzheimer, antitumor, anticoagulant, insecti-
cidal, hypnotic, and antifungal properties, and inhibit the HIV
protease.6,7 Fused-acetal moieties are also present in a variety
of biologically active natural products, i.e,. spectinomycin (E)
and acmimycin (F).8 Numerous literature reports regarding
bioactivities of the fused acetal motif and coumarin/pyrone
derivatives strongly support their values as privileged substruc-
tural moieties. In continuation of our research on DOS,9 we
designed and synthesized polycyclic acetal-fused pyrano[3,2-
c]pyrane-5-(2H)-ones (pyranopyrones, G) derived from the
hybrid structure of 4-hydroxycoumarin and 2-C-formylglycals
for the discovery of novel therapeutic agents.
For the synthesis of polycyclic acetal-fused pyranopyrones,
we identified 2-C-formyl galactal 1 as a key intermediate in
the s-cis enal system that can be transformed to the desired
acetal-fused pyranopyrone via an annulation reaction with
4-hydroxycoumarin 8.10 This annulation reaction involving
4-hydroxycoumarin and R,ꢀ-unsaturated ketone was first cited
by Link in 194411 and studied in detail later by Moreno-Man˜as
A facile and efficient diastereoselective one-pot synthesis of
polycyclic acetal-fused pyrano[3,2-c]pyrane-5(2H)-one was
achieved through the annulation reaction of 2-C-formyl
glycals with various 4-hydroxycoumarins and 4-hydroxy-6-
methyl-2H-pyran-2-one. The asymmetric induction was
significantly influenced by the C-4 stereogenic center of 2-C-
formyl glycals. The resulting polycyclic acetal-fused pyra-
nopyrones demonstrated anticancer activities.
The syntheses of drug-like small molecules that specifically
perturb the individual functions of gene products, enable the
exploration of biological pathways in cells or organisms.1
Further, bioactive compounds are widely used to modulate
protein function and can serve as important leads for drug
development.2 Therefore, the development of an efficient route
for the synthesis of a drug-like bioactive small molecule has
been the research focus of medicinal/bioorganic chemists and
chemical biologists.3 Diversity-oriented synthesis (DOS) aims
to populate the chemical space with skeletally and stereochemi-
cally diverse small molecules with high appending potentials
and has been proven to be an essential tool for the discovery of
bioactive small molecules.4 In the DOS pathway, the incorpora-
tion of privileged substructures into novel core skeletons
(5) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga,
S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939.
(6) (a) Ma, T.; Liu, L.; Xue, H.; Li, L.; Han, C.; Wang, L.; Chen, Z.; Liu,
G. J. Med. Chem. 2008, 51, 1432. (b) Kang, H.-S.; Kim, K.-R.; Jun, E.-M.;
Park, S.-H.; Lee, T.-S.; Suh, J.-W.; Kim, J.-P. Bioorg. Med. Chem. Lett. 2008,
18, 4047. (c) Mo, S.; Wang, S.; Zhou, G.; Yang, Y.; Li, Y.; Chem, X.; Shi, J.
J. Nat. Prod. 2004, 67, 823. (d) Sunazuka, T.; Handa, M.; Nagai, K.; Shirahata,
T.; Harigaya, Y.; Otoguro, K.; Kuwajima, I.; Omura, S. Org. Lett. 2002, 4, 367.
(7) (a) McGlacken, G. P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22, 369.
(b) Jin, L.-W.; Hua, D. H.; Shie, F.-S.; Maezawa, I.; Sopher, B.; Martin, G. M.
J. Mol. Neurosci. 2002, 19, 57.
(8) McAlpine, J. B.; Brill, G. M.; Spanton, S. G.; Mueller, S. L.; Stanaszek,
R. S. J. Antibiot. 1984, 37, 1519.
(9) (a) Kim, E.; Koh, M.; Rhu, J.; Park, S. B. J. Am. Chem. Soc. 2008, 130,
12206. (b) Sagar, R.; Park, S. B. J. Org. Chem. 2008, 73, 3270. (c) An, H.;
Eum, S-J.; Lee, S. K.; Park, S. B. J. Org. Chem. 2008, 73, 1752. (d) Lee, S.-C.;
Park, S. B. Chem. Commun. 2007, 3714. (e) Ko, S. K.; Jang, H. J.; Kim, E.;
Park, S. B. Chem. Commun. 2006, 28, 2962.
(10) (a) Ramesh, N. G.; Balasubramanian, K. K. Tetrahedron Lett. 1991,
32, 3875. (b) Ramesh, N. G.; Balasubramanian, K. K. Eur. J. Org. Chem. 2003,
4477.
(1) Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127.
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E.; Proctor, M.; Shokat, K. M.; Zhang, C.; Davis, R. W.; Giaever, G.; StOnge,
R. P.; Nislow, C. Nat. Chem. Biol. 2008, 4, 498.
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(4) (a) Koehler, A. N.; Shamji, A. F.; Schreiber, S. L. J. Am. Chem. Soc.
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2004, 43, 46. (c) Tan, D. S. Nature Chem. Biol. 2005, 1, 74. (d) Spandl, R. J.;
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66, 902. (b) Seidman, M.; Robertson, D. N.; Link, K. P. J. Am. Chem. Soc.
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10.1021/jo8023889 CCC: $40.75
Published on Web 02/04/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2171–2174 2171

TABLE 1. Reaction Optimization for the Synthesis of 13
FIGURE 2. Organocatalysts.
reaction conditionsa
dr (R:ꢀ)b yield (%)
found that the annulation of 1 with 8 in the presence of 2a (0.5
equiv) in EtOAc at 77 °C affords 13 in good yield with excellent
diastereoselectivity, though the reaction requires extended time
for completion. When we tested the same transformation with
D-proline (2b), we obtained the identical result of L-proline
without the reduction of diastereoselectivity (Table 1, entry 3).
In the case of more acidic tetrazole-based L-proline derivatives
(2c), we did not observe any significant difference in the reaction
rate (Table 1, entry 4).
Then, we turned our attention to simple achiral secondary
amines as organocatalysts, but we observed that the annulation
of 1 and 8 in the presence of pyrrolidine (2d) was halted at the
imine formation of 1 and 2d without forming any desired
product after 6 h refluxing at 77 °C in EtOAc. At this juncture,
we presumed that organocatalysts 2a-c have an inherent proton
source that helps accelerate the annulation reaction; however,
2d requires an external proton source, i.e., acetic acid, for this
transformation.13f To our pleasant surprise, 2d can serve as an
organocatalyst in the presence of 1% acetic acid to afford a
single diastereomer 13 in fairly good yield (79%) with significant
reduction of reaction time (Table 1, entry 5). Therefore, we
concluded that the diastereoselectivity of the reaction leading
to 13 is caused by substrate-control, not by reagent-control,
because four different organocatalysts (2a-d) yield 13 with the
same diastereoselectivity irrespective of chirality and acidity
of organocatalysts (Table 1, entries 2-5). In our further
optimization, piperidine (2e) and morpholine (2f) were found
inferior compared to 2d in terms of reaction time (Table 1,
entries 6 and 7).
To study solvent effects, we screened toluene, acetonitrile,
chloroform, methanol, and acetic acid in the presence of 2d
(Table 1, entries 9-12) and 1% acetic acid. In general, polar
solvents, i.e., acetonitrile, acetic acid, and methanol, were not
favorable because of the following reasons: acetonitrile and
methanol provide poor yield of 13 (50% and 30%, respectively)
and acetic acid causes an incomplete reaction even after a long
time. In comparison, nonpolar solvents were generally better,
and toluene was found to be the best solvent for this transforma-
tion (Table 1, entry 12).
The mechanism of this transformation can be postulated as
shown in Figure 3: 2d attacks the 2-C-formyl galactal 1 to form
a carbinolamine (I), which undergoes the dehydration in the
presence of a proton source (AcOH). The resulting iminium
ion (II) is a better electrophile than 1 and undergoes nucleophilic
C-1,2-addition with 4-hydroxycoumarin to afford III. Intermedi-
ate III rearranges to IV, which transforms into a conjugate
intermediate V (1-oxatriene) with the regeneration of 2d via
ꢀ-elimination. Finally, V undergoes 6π-electron cyclization to
afford the corresponding polycyclic acetal-fused pyranopyrone
with excellent diastereoselectivity.13d
entry
1c EtOAc, 77 °C, 48 h
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
29
83
82
78
79
77
76
73
50
80
50
82
2
3
2a, EtOAc, 77 °C, 20 h
2b, EtOAc, 77 °C, 19 h
4
2c, EtOAc, 77 °C, 19 h
5
6
7
8
9
10
2d, EtOAc/AcOH (1:0.01), 77 °C, 3 h
2e, EtOAc/AcOH (1:0.01), 77 °C, 6 h
2f, EtOAc/AcOH (1:0.01), 77 °C, 7 h
2a, EtOAc/AcOH (1:0.01), 77 °C, 17 h
2d, CH3CN/AcOH (1:0.01), 77 °C, 3 h
2d, CHCl3/AcOH (1:0.01), 77 °C, 4 h
11c 2d, AcOH, 80 °C, 24 h
12
2d, Toluene/AcOH (1:0.01), 80 °C, 3 h
a 0.5 equiv of organocatalyst was used in each case. b Diastereomeric
ratio (dr) was determined by crude 1H NMR. c Reaction was not
completed.
using 4-hydroxy-6-methylpyrane-2-one and (E)-2-butenal.12
Since then, many research groups have explored and utilized
this reaction for the synthesis of natural products and biologi-
cally relevant molecules.13
The annulation reaction of 1 with 8 was initially performed
under simple refluxing condition in EtOAc without any additives
or catalysts. As depicted in Table 1 (entry 1), polycyclic acetal-
fused pyranopyrone 13 was obtained as a 29% yield with high
diastereoselectivity along with the recovery of the starting
material. The molecular structure of compound 13 was unam-
biguously established by 1D and 2D NMR (HMQC, HMBC,
COSY, and NOE) experiments. The stereochemistry of newly
generated chiral center was assigned by a strong NOE correla-
tion between the acetal-fused methine proton (new chiral center)
and predefined chiral protons (especially H-2′ and H-3′) of the
sugar part in compound 13. This suggested that the proton at
the newly generated chiral center is in the same face as the
methine proton at the sugar part in compound 13. To optimize
this reaction, we designed and tested a series of annulation
conditions using various catalysts and solvent systems. The
treatment of 1 with 8 in CH2Cl2 in the presence of Lewis acid
(TiCl4 or InCl3) at 0 and 40 °C leads to the decomposition of 1
without yielding any desired product 13. To enhance the
reactivity of 1 through imine formation, secondary-amine-based
organocatalysts were introduced (Figure 2).14 After screening
a set of reactions by using different concentrations of L-proline
(2a) either at room temperature or reflux temperature, it was
(12) (a) March, P. de; Moreno-Man˜as, M.; Casado, J.; Pleixats, R.; Roca, J. L.;
Trius, A. J. Heterocycl. Chem. 1984, 21, 85. (b) March, P. de; Moreno-Man˜as, M.;
Casado, J.; Pleixats, R.; Roca, J. L.; Trius, A. J. Heterocycl. Chem. 1984, 21, 1369.
(13) (a) Hsung, R. P.; Kurdyumor, A. V.; Sydorenko, N. Eur. J. Org. Chem.
2005, 1, 23, and references cited therein. (b) Sagar, R.; Singh, P.; Kumar, R.;
Maulik, P. R.; Shaw, A. K. Carbohydr. Res. 2005, 340, 1287. (c) Sunazuka, T.;
Handa, M.; Nagai, K.; Shirahata, T.; Harigaya, Y.; Otoguro, K.; Kuwajima, I.;
Omura, S. Tetrahedron 2004, 60, 7845. (d) Shen, H. C.; Wang, J.; Cole, K. P.;
McLaughlin, M. J.; Morgan, C. D.; Douglas, C. P.; Hsung, R. P.; Coverdale,
H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Sklenicka, H. M.; Wei, L. L.;
Zehnder, L. R.; Zificsak, C. A. J. Org. Chem. 2003, 68, 1729. (e) Cravotto, G.;
Nano, G. M.; Palmisano, G.; Tagliapietra, S. Synthesis 2003, 1286. (f) Hua,
D. H.; Chen, Y.; Sin, H.-S.; Maroto, M. J.; Robinson, P. D.; Newell, S. W.;
Perchellet, E. M.; Ladesich, J. B.; Freeman, J. A.; Perchellet, J.-P.; Chiang, P. K.
J. Org. Chem. 1997, 62, 6888.
Having optimized reaction conditions, we investigated the
scope of this transformation. As shown in Table 2 (entries 1-5),
1 was successfully coupled with various substituted 4-hydroxy-
(15) (a) Booma, C.; Balasubramanian, K. J. Chem. Soc., Perkin Trans. I
1993, 393. (b) See the Supporting Information and: Sklenicka, H. M.; Hsung,
R. P.; McLaughlin, M. J.; Wei, L.-I.; Gerasyuto, A. I.; Brennessel, W. B. J. Am.
Chem. Soc. 2002, 124, 10435.
(14) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
580.
2172 J. Org. Chem. Vol. 74, No. 5, 2009

TABLE 2. Synthesis of Pyranopyrones
time/
yield (%)
entry
enals
coumarin
R1
R2
R3
R4
dra (R:ꢀ)
product
1
2
3
1
1
1
1
1
3
3
3
3
3
3
8
OBn
OBn
OBn
OBn
OBn
H
H
H
H
H
H
H
H
H
H
Cl
Me
Me
NO2
H
H
Cl
Me
Me
NO2
H
H
H
Me
H
H
H
H
H
>99:1
>99:1
>99:1
>99:1
>99:1
55:45
55:45
57:43
54:46
51:49
60:40
13
3 h/82
5 h/82
4 h/82
4 h/80
6 h/83
18 h/87
4 h/84
6 h/85
5 h/83
5 h/86
6 h/80
9
14
10
11
12
8
8
9
10
11
12
15
4
16
5
H
17
6b
7
OBn
OBn
OBn
OBn
OBn
OBn
18a/18b
18a/18b
19a/19b
20a/20b
21a/21b
22a/22b
8
9
10
11
Me
H
H
a
Diastereomeric ratio (dr) was determined by crude H NMR. b Reaction conditions: L-proline (0.5 equiv), EtOAc, 75 °C, 18 h.
1
TABLE 3.
Reaction of Different Enals (1, 3-7) with 8
time/
yield (%)
entry
enals
R
R1
R2
R′
Bn
Bn
dra (R:ꢀ)
product
1
2
3
4
5
6
1
3
4
5
6
7
Bn
Bn
Me
Me
PMB
PMB
OBn
H
OMe
H
OPMB
H
H
>99:1
55:45
>99:1
49:51
>99:1
51:49
13
18a/18b
23
24a/24b
25
26a/26b
3 h/82
4 h/84
4 h/50
4 h/60
3 h/85
3 h/88
OBn
H
OMe
H
Me
CPh3
PMB
PMB
OPMB
a
1
Diastereomeric ratio (dr) was determined by crude H NMR.
On the basis of these observations, we confirmed that diaste-
reoselectivity is substrate-controlled and not reagent-controlled.
Therefore, the drastic difference in the diastereoselectivity of the
reactions might be caused by the structural difference between the
C-4 stereogenic centers of 1 and 3; the C-4 OBn group in the
1-oxatriene intermediate of 1 might interact sterically with the
aromatic ring of 4-hydroxycoumarin, which results in conforma-
tional changes and a drastic difference in its diastereoselectivity.
To confirm this hypothesis, tri-O-methyl-substituted 2-C-formyl
galactal 4 was treated with 8 under the identical reaction conditions,
and polycyclic acetal-fused pyranopyrone 23 was obtained as a
single diastereomer. In contrast, the annulation of its glucal
derivative 5 with 8 afforded an epimeric mixture of the corre-
sponding products 24a/24b (Table 3, entries 3 and 4). Similar
diastereoselectivity patterns were observed in tri-O-p-methoxy-
benzyl (PMB)-protected 6 and its glucal derivative 7 with 8 (Table
3, entries 5 and 6). This pattern indicates that the C-4 stereogenic
center itself plays a striking role in the stabilization of different
conformers of 1 and 3, which might lead to the difference in
diastereoselectivity.15a On the basis of our calculations, the energy
difference between galactal-derived pyranopyrones was ∆E ) 3.97
kcal/mol, whereas that of glucal-derived pyranopyrones was ∆E
) 1.24 kcal/mol,15b which can suggest a potential rationalization
of the observed diastereoselectivity via thermodynamic
equilibrium.15b
FIGURE 3. Plausible reaction mechanism.
coumarines (8-12) to afford respective products (13-17) in
good yields with excellent diastereoselectivity. The substituents
at the R3 and R4 positions on 4-hydroxycoumarin influenced
neither the yield nor the reaction completion time. However,
similar annulation reactions of 2-C-formyl glucal 3 afforded,
unexpectedly, an epimeric mixture of polycyclic acetal-fused
pyranopyrones 18a/18b in good yields. The complete loss of
asymmetric induction cannot be restored by using various
solvents and chiral organocatalysts. In fact, the diastereoselec-
tivity pattern in the annulations of 3 with 8 was identical when
the organocatalyst used was L-proline 2a or pyrrolidine 2d
(Table 2, entries 6 and 7). Similarly, different 4-hydroxycou-
marines (9-12) were coupled with 3, and their respective
products (19a/19b-22a/22b) were obtained in good yields in
the form of inseparable epimeric mixtures.
After the synthesis of tetracyclic acetal-fused pyranopyrones,
we turned our attention to the synthesis of tricyclic acetal-fused
pyranopyrones.13f In fact, it requires extended reaction time
J. Org. Chem. Vol. 74, No. 5, 2009 2173

TABLE 4.
Reaction of Different Enals with 27
entry
enals
R1
R2
R
reaction conditions
2a, EtOAc 77 °C, 20 h
2d, toluene/AcOH (1:0.01), 80 °C, 21 h
2d, EtOAc/AcOH (1:0.01) 77 °C, 22 h
2a, EtOAc 77 °C, 22 h
2d, EtOAc/AcOH (1:0.01) 77 °C, 22 h
2a, EtOAc 77 °C, 21 h
2a, EtOAc 77 °C, 20 h
product
dra (R:ꢀ)
yield (%)
1
2
3
4
5
6
7
1
1
1
3
3
6
7
OBn
OBn
OBn
H
H
H
H
Bn
Bn
Bn
Bn
Bn
PMB
PMB
28
28
28
29a/29b
29a/29b
30
>99:1
>99:1
>99:1
51:49
51:49
>99:1
52:48
77
37
80
80
77
88
87
OBn
OBn
H
H
OPMB
H
OPMB
31a/31b
a
1
Diastereomeric ratio (dr) was determined by crude H NMR.
1H), 4.40 (d, J ) 11.5 Hz, 1H), 4.14 (t, J ) 2.0 Hz, 1H), 3.98 (d,
J ) 1.5 Hz, 1H), 3.85 (t, J ) 6.5 Hz, 1H), 3.61 (dd, J ) 9.5 and
6.0 Hz, 1H), 3.51 (dd, J ) 9.5 and 6.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 160.8, 156.4, 152.9, 138.3, 137.9, 137.7, 132.4,
128.9, 128.8, 128.7, 128.4, 128.2, 128.1, 127.9, 127.6, 126.9, 124.4,
123.0, 116.9, 114.8, 112.8, 99.8, 97.1, 79.6, 76.6, 75.4, 74.6, 73.8,
71.9, 68.9; FAB HRMS m/z calcd for C37H32O7 [M + H]+
589.2226, found 589.2225.
when 4-hydroxy-6-methylpyran-2H-one 27 was subjected to the
annulation with 2-C-formyl glycals (1 and 3) and EtOAc was
a better solvent than toluene for these substrates (Table 4, entries
2 and 3). In the case of 1, both L-proline 2a and pyrrolidine 2d
served as good organocatalysts with similar reaction rates and
afforded the desired tricyclic product 28 in good yields with
excellent diastereoselectivity (Table 4, entries 1 and 3). How-
ever, of all the reaction conditions examined in our study, the
treatment of 3 with 27 only afforded a diastereomeric mixture
of tricyclic products 29a/29b in an almost 1:1 ratio.
The resulting tetra- and tricyclic acetal-fused pyranopyrones
were screened for their anticancer activities against three
different cancer cell lines. As shown in SI Table 2, tetracyclic
compounds 13-15 and 17 showed antiproliferative activity
(IC50) at micromolar concentrations. Further lead optimization
of active compounds is currently in progress.
In summary, we have developed an efficient one-step
synthetic protocol for the synthesis of polycyclic acetal-fused
pyranopyrones. The acetal-fused pyranopyrones were designed
to encompass stereochemically enriched carbohydrate skeletons.
This sugar part can also be further modified and diversified to
enhance their biological activities. Subsequently, we demon-
strated that some of these pyranopyrones possess anticancer
activities at micromolar levels. The complete library realization
of these polycyclic acetal-fused pyranopyrones with DOS and
their further biological evaluation will be reported in due course.
Synthesis of Compound 28. To a stirred solution of 2-C-formyl
galactal 1 (110 mg, 0.250 mmol) in 5 mL of dry EtOAc with 3 Å
molecular sieves was added L-proline (0.5 equiv) or pyrrolidine
(0.5 equiv) with 50 µL of AcOH, followed by the addition of
4-hydroxy-6-methyl-2H-pyrane-2-one 27 (63 mg, 0.50 mmol). The
resulting mixture was heated at 77 °C, and the reaction completion
was monitored by the consumption of 2-C-formyl galactal 1.
Compound 27 was added in four installments. The product mixture
was cooled to room temperature, and the reaction was quenched
by adding NaHCO3 (8 mL). The organic layer was separated, and
the aqueous layer was extracted by EtOAc (3 × 5 mL). The
combined organic layer was washed with brine and dried over
anhydrous Na2SO4. The crude product was purified by silica gel
flash column chromatography to obtain the desired product 28 (110
mg) in 80% yield as an amorphous solid. Rf 0.45 (2:3 ) acetone:
hexanes, v/v); [R]28D -42.87 (c 0.333, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.37-7.23 (m, 15H), 6.87 (d, J ) 2.0 Hz, 1H), 5.90 (s,
1H), 5.87 (s, 1H), 4.92 (d, J ) 12.0 Hz, 1H), 4.77 (d, J ) 12.0 Hz,
1H), 4.65 (d, J ) 12.0 Hz, 1H), 4.57 (d, J ) 12.0 Hz, 1H), 4.46
(d, J ) 12.0 Hz, 1H), 4.38 (d, J ) 12.0 Hz, 1H), 4.06 (br s, 1H),
3.94 (d, J ) 2.0 Hz, 1H), 3.76 (t, J ) 6.0 Hz, 1H), 3.58 (dd, J )
9.5 and 5.5 Hz, 1H), 3.50 (dd, J ) 9.5 and 6.5 Hz, 1H), 2.21 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 162.4, 162.3, 161.5, 138.4,
137.9, 137.8, 128.8, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.5,
125.3, 112.4, 99.7, 97.6, 97.0, 79.6, 76.3, 75.3, 74.5, 73.8, 71.9,
68.8, 20.3; FAB HRMS m/z calcd for C34H32O7 [M + H]+
553.2226, found 553.2222.
Experimental Section
Synthesis of Compound 13. To a stirred solution of 2-C-formyl
galactal 1 (110 mg, 0.250 mmol) in 5 mL of toluene with 3 Å
molecular sieves were added 8.9 mg of pyrrolidine (0.5 equiv) and
50 µL of AcOH, followed by the addition of 4-hydroxycoumarin
8 (48.6 mg, 0.30 mmol). The resulting mixture was heated at 80
°C, and the reaction completion was monitored by the consumption
of 2-C-formyl galactal 1. The product mixture was cooled to room
temperature, and the reaction was quenched by the addition of
NaHCO3 (8 mL). The organic layer was separated, and the aqueous
layer was extracted by EtOAc (3 × 5 mL). The combined organic
layer was washed with brine and dried over anhydrous Na2SO4.
The crude product was purified by silica gel flash column
chromatography to obtain the desired product 13 (120 mg) in 82%
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (KOSEF); the MarineBio
Technology Program funded by Ministry of Land, Transport,
and Maritime Affairs, Korea; and the Research Program for New
Drug Target Discovery grant from the Ministry of Education,
Science & Technology (MEST). R.S., J.P., and M.K. are grateful
for the fellowship award by the BK21 Program.
yield as an amorphous solid. Rf 0.40 (3:7 ) acetone:hexanes, v/v);
Supporting Information Available: Experimental procedures,
complete spectroscopic data, and NOE experiments along with
copies of 1H and 13C NMR spectra of all compounds 13-31. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
1
[R]28 -285.05 (c 0.453, CHCl3); H NMR (500 MHz, CDCl3) δ
D
7.84 (dd, J ) 8.0 and 1.5 Hz, 1H), 7.48 (dt, J ) 8.0 and 1.5 Hz,
1H), 7.38-7.23 (m, 17H), 7.01 (d, J ) 1.5 Hz, 1H), 6.08 (s, 1H),
4.93 (d, J ) 11.5 Hz, 1H), 4.81 (d, J ) 12.0 Hz, 1H), 4.66 (d, J )
12.0 Hz, 1H), 4.61 (d, J ) 13.0 Hz, 1H), 4.47 (d, J ) 11.5 Hz,
JO8023889
2174 J. Org. Chem. Vol. 74, No. 5, 2009