Domino heck/lactonization-catalyzed synthesis of 3-C-linked mannopyranosyl coumarins

Article abstract of DOI:10.1021/jo901855p

(Chemical Equation Presented). Selective syntheses of methyl α- (8) and β-C-mannopyranosyl acrylates (9) were obtained from α-C-allyl mannopyranoside (3) by ozonolysis to 4 followed by α-methylenation to provide intermediate aldehydes 5 and 6. The β-anomer 6 was obtained by in situ anomeric epimerization. The acrylates and the homologous α-anomer 16, obtained by oxidative hydroboration, oxidation, and α-methylenation, were converted into 3-C-linked mannopyranosyl coumarins 11, 12, and 19 in good yields under one-pot Heck/lactonization conditions. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901855p

pubs.acs.org/joc
biological activities.3 When coupled to carbohydrate residues,
Domino Heck/Lactonization-Catalyzed Synthesis of
3-C-Linked Mannopyranosyl Coumarins
coumarins have shown application as antibacterial (inhibitors
of gyrase B),4 anticoagulant,5 anticancer agents,6 or even as
fluorescent probes for ultrafast DNA dynamics.7 From a
synthetic point of view, coumarins can be classically synthesized
by the Perkin,3d,8 Pechmann,3d,9 Knoevenagel,10 Wittig,11
Kostanecki-Robinson,12 Reformatsky,13 and more recently
cross-metathesis14 and palladium coupling reactions.15
Most methods lack generality and efficiency; therefore, the
use of a mild catalytic methodology to create the coumarin
backbone in the presence of sensitive functional groups is thus
required.
ꢀ
Denis Giguere, Philipe Cloutier, and Rene Roy*
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Department of Chemistry, Universite du Quebec a Montreal,
P.O. Box 8888, Succ. Centre-Ville Montreꢁal, QC, Canada
H3C 3P8
roy.rene@uqam.ca
Received August 27, 2009
A large number of glycosyl coumarin derivatives, includ-
ing some with O- or C-glycosidic linkages, occur naturally.16
The first synthesis of C-glycosyl coumarin derivatives was
made by Mahling et al.,17 and since then, most reports
described the synthesis of glycosyl coumarins having the aryl
function attached at the anomeric position of the carbohy-
drate residues.18 However, to the best of our knowledge, no
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see: (a) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins.
Ocurrence, Chemistry and Biochemistry; John Wiley and Sons: Chichester, UK,
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Nat. Prod. Rep. 1995, 12, 477–505. (e) O'Kennedy, R.; Thornes, R. D.
Coumarins. Biology, Applications and Mode of Action; John Wiley and Sons:
Chichester, UK, 1997. (f) Sardari, S.; Nishibe, S.; Daneshtalab, M. Stud. Nat.
Prod. Chem. 2000, 23, 335–393. (g) Garazd, M. M.; Garadz, Y. L.; Khilya, V. P.
Chem. Nat. Compd. 2003, 39, 54–121.
(4) (a) Scatigno, A. C.; Garrido, S. S.; Marchetto, R. J. Peptide Sci. 2004,
10, 566–577. (b) Musicki, B.; Periers, A.-M.; Piombo, L.; Laurin, P.; Klich,
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2003, 44, 9259–9262.
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Khilya, V. P. Chem. Nat. Compd. 2005, 5, 508–512.
Selective syntheses of methyl R- (8) and β-C-mannopyra-
nosyl acrylates (9) were obtained from R-C-allyl mannopyr-
anoside (3) by ozonolysis to 4 followed by R-methylenation
to provide intermediate aldehydes 5 and 6. The β-anomer 6
was obtained by in situ anomeric epimerization. The acry-
lates and the homologous R-anomer 16, obtained by oxida-
tive hydroboration, oxidation, and R-methylenation, were
converted into 3-C-linked mannopyranosyl coumarins 11,
12, and 19 in good yields under one-pot Heck/lactonization
conditions.
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The syntheses of glycoconjugate mimics in which robust
linkers hold together the carbohydrate and aglycone moieties
have been actively investigated in modern glycochemistry.
When the aglycones possess well-established pharmacophores,
this could lead to new carbohydrate-based drugs.1 The intro-
duction of carbohydrate fragments onto small, biologically
active molecules is envisaged to improve their pharmacokinetic
and -dynamic profiles without altering their activity and selec-
tivity. Additionally, this transformation could give rise to a
novel class of stable molecules with modified and/or unex-
pected biological properties due to the unique functions of
carbohydrates at the molecular level.2 In this context, we
believed that joining carbohydrates to coumarins via C-C
bond could provide more valuable and glycosidically stable
analogues for various biological investigations. Coumarins
represent such privileged pharmacophores including varied
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8480 J. Org. Chem. 2009, 74, 8480–8483
Published on Web 10/09/2009
DOI: 10.1021/jo901855p
r
2009 American Chemical Society

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Giguere et al.
JOCNote
SCHEME 1. Synthesis of (a) 4-C-Linked Glycosyl Coumar-
ins15f and (b) 3-C-Linked Mannosyl Coumarins (This Work)
SCHEME 2. Selective Synthesis of R- and β-Substituted Acro-
leins 5 and 6 from Commercialy Avalaible Methyl R-D-Manno-
pyranoside (1)
report on anomerically 3-C-linked glycocoumarins is
known. To this end, we used a domino Heck reaction/
lactonization process. Scheme 1 shows (a) our previous
synthesis of 4-C-linked glycosyl coumarins15f originating
from cross-metathesis followed by a Heck coupling and (b) the
family presented herein includes an alternative R-methylenation
strategy.
Transition-metal-catalyzed cross-couplings have proven
to be powerful tools for mild and highly efficient car-
bon-carbon bond formations. Among these processes,
those involving palladium (Heck) catalysis are particularly
efficient for the synthesis of complex molecules, owing to
their excellent level of selectivity and high functional group
tolerance.19 Consequently, and on the basis of previous
expertise in our group,20 the palladium(0)-catalyzed Heck
reaction was used to synthesize 3-C-linked coumarins from
methyl C-glycosyl acrylates. When carbohydrates are con-
nected with such varied decorations, a large number of
diverse and novel biologically useful glycoconjugates can
be generated.
The syntheses were initiated from the known R-C-allyl
mannopyranoside 321 (Scheme 2). Reductive ozonolysis of
R-C-allyl glycoside 3 afforded aldehyde 4 in 95% yield.
A mild organocatalytic R-methylenation of aldehyde 4 using
aqueous formaldehyde and pyrrolidine afforded a 1:1 mix-
ture of both conjugated R-aldehyde 5 and its epimeric
β-anomer 6, respectively, in 69% yield.22 The β-anomeric
configuration of 6 was determined by NOE experiments. It is
important to note that all of these interactions were absent
on the R-anomer 5. With the aim of isolating both pure
substituted acroleins, a method developed by the group of
Hon was used.23 The ozonide from 3 was quenched by a
preheated mixture of dibromomethane and dimethylamine.
This method permitted the formation of only one R-isomer
5 in 63% yield over two steps. Alternatively, the selective
synthesis of the β-anomer 6 was initiated by the microwave-
assisted organocatalytic anomerization of R-C-glycosyl
ethanal 4 as previously described.24 Hence, L-proline and
MW irradiation promoted complete anomerization of 4 into
β-anomer 7 in 85% yield. Aldehyde 7 was then easily
converted to the single β-anomer 6 in 71% yield using the
same organocatalytic R-methylenation strategy described
above. Interestingly, this is the first anomeric R-methylena-
tion reaction of this type in carbohydrate chemistry allowing
the synthesis of β-C-mannopyranosyl derivatives.25
With a selective access to both anomeric aldehydes in
hand, our attention was turned to the oxidation26 of 5 and
6 to their corresponding carboxylic acids under mild condi-
tions, followed by methyl ester formation (Scheme 3). Thus,
acrylates 8 and 9 were, respectively, isolated in 78 and 79%
yields over two steps from conjugated aldehydes 5 and 6. The
next step involved Heck couplings onto methyl acrylates
8 and 9 using the same optimized reaction conditions pre-
viously described.15f When the R-anomer 8 was coupled to
2-iodophenol, two products were obtained in 77% yield: the
expected Heck adduct 1027 and the coumarin 11 in a 1:5
ratio, respectively. The Heck product 10 was easily converted
into coumarin 11 under basic conditions in 83% yield
(NaOMe, MeOH). The C-mannosyl coumarin 11 likely
resulted from the standard Heck reaction with the usual
syn β-elimination of the palladium to get the E-isomer,
(19) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518–5526. (b) Heck,
R. F.; Nolley, J. P. Jr. J. Org. Chem. 1972, 37, 2320–2322. (c) Heck, R. F.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, NY, 1991; Vol. 4, Chapter 4.3. (d) Heck, R. F. Org. React. 1982, 27, 345–
390. (e) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7. (f) Beletskaya,
I. P.; Chaprakov, A. V. Chem. Rev. 2000, 100, 3009–3066.
(24) Massi, A.; Nuzzi, A.; Dononi, A. J. Org. Chem. 2007, 72, 10279–
10282.
(20) (a) Roy, R.; Das, S. K.; Dominique, R.; Trono, M. C.; Hernandez-
Mateo, F.; Santoyo-Gonzalez, F. Pure Appl. Chem. 1999, 71, 565–572.
(b) Roy, R.; Dominique, R.; Das, S. K. J. Org. Chem. 1999, 64, 5408–
5412. (c) Hu, Y.-J.; Roy, R. Tetrahedron Lett. 1999, 40, 3305–3308.
(d) Dominique, R.; Liu, B.; Das, S. K.; Roy, R. Synthesis 2000, 862–868.
(e) Roy, R.; Das, S. K. Chem. Commun. 2000, 7, 519–529. (f) Liu, B.; Das,
S. K.; Roy, R. Org. Lett. 2002, 4, 2723–2726.
(21) (a) Koto, S.; Morishima, N.; Miyata, Y.; Zen, S. Bull. Chem. Soc.
Jpn. 1976, 49, 2639–2640. (b) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetra-
hedron Lett. 1984, 25, 2383–2386.
(25) This method is more efficient than the one described previously:
Lichtenthaler, F. W.; Lergenmuller, M.; Schwidetzky, S. Eur. J. Org. 2003,
3094–3103.
(26) Douelle, F.; Capes, A. S.; Greaney, M. F. Org. Lett. 2007, 9, 1931–
1934.
(27) Cinnamyl glycosides are biologically active: (a) Rojas-Melgarejo, F.;
Marin-Iniesta, F.; Rodriguez-Lopez, J. N.; Garcia-Canovas, F.; Garcia-
Ruiz, P. A. Enzyme Microb. Technol. 2006, 38, 748–755. (b) Marin-Zamor,
M. E.; Rojas-Melgarejo, F.; Garcia-Canovas, F.; Garcia-Ruiz, P. A.
J. Chem. Technol. Biotechnol. 2005, 80, 1356–1364. (c) Rojas-Melgarejo,
F.; Rodriguez-Lopez, J. N.; Garcia-Canovas, F.; Garcia-Ruiz, P. A. Carbo-
hydr. Polym. 2004, 58, 79–88. (d) Jarrahpour, A. A.; Shekarriz, M.; Taslimi,
A. Molecules 2004, 9, 29–38.
€
(22) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538–2541.
(23) Hon, Y.-S.; Liu, Y.-W.; Hsieh, C.-H. Tetrahedron 2004, 60, 4837–
4860.
J. Org. Chem. Vol. 74, No. 21, 2009 8481

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SCHEME 3. Synthesis of 3-C-Linked Mannopyranosyl Coumar-
ins 11 and 12 Using a Domino Heck/Lactonization Process
SCHEME 4. Synthesis of Unprotected 3-C-Linked R-Manno-
pyranosyl Coumarin 19 Using a Domino Heck/Lactonization
Process
followed by isomerization of the double bond under the basic
reaction conditions or by the epimerization of the σ-palla-
dium complex.28 Similarly, conjugated β-methyl ester 9 was
also submitted to the Heck conditions, and only coumarin
12 was isolated. These results could be explained by the easier
trans to cis isomerization of the glycosyl cinnamate under the
Heck conditions when the β-aglycone is less hindered, favor-
ing formation of coumarin 12.
in DCM (0.4 M, 5 mL) and subjected to ozonolysis at -78 °C.
To this solution was added a preheated mixture of Et2NH
(0.245 mL, 2.364 mmol) and CH2Br2 (0.494 mL, 7.092 mmol)
(heated at 55 °C for 1.5 h and cooled to rt) at -78 °C. After the
addition, the cooling bath was removed and the reaction was
warmed to room temperature and stirred for 1.5 h at room
temperature. The mixture was concentrated and chromato-
graphed using 10% Et2O in toluene, affording exclusively
R-acrolein 5 (172 mg) in 63% yield isolated as a yellow oil:
The same synthetic strategy was next used to create the
homologuous mannopyranosyl coumarin 19 (Scheme 4).
The synthesis was initiated by hydroboration of R-C-allyl
mannoside 3 using 9-BBN in 81% yield (13), followed by
oxidation under Swern conditions to provide aldehyde 14 in
92% yield.29 Under R-methylenation conditions,22 aldehyde
14 was converted into conjugated aldehyde 15 in 69% yield.
Oxidation of the aldehyde to carboxylic acid followed by
methyl ester formation gave 16 in 84% yield over two steps.
Under the above Heck conditions, 16 was converted into
C-mannopyranosyl coumarin 18 along with the expected
Heck adduct 17 in 71% yield (2:1 ratio, respectively). Inter-
mediate mannosyl cinnamate 17 was converted into coumar-
in 18 under basic reaction conditions without the palladium
catalyst (38%). Finally, benzyl ether deprotection was
achieved using palladium-catalyzed hydrogenolysis as described
for the synthesis of mannopyranosyl coumarin 19 in 67% yield.
In conclusion, we described a convenient regioselective
catalytic synthesis of 3-C-mannopyranosyl coumarin deri-
vatives using a domino Heck reaction/lactonization process.
Moreover, mannosyl cinnamates were isolated and trans-
formed under basic conditions into their coumarin counter-
parts. Finally, efficient deprotection allowed formation of
unprotected glycosyl coumarins.
[R]25 þ24.9 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3,
D
δ ppm) 3.81-3.71 (m, 2H, H6), 3.58 (dd, J=2.5, 7.1 Hz, 1H,
H5), 3.88-3.84 (m, 1H, H4), 4.01-3.95 (m, 1H, H3), 4.21-4.18
(m, 1H, H2), 4.70-4.41 (m, 8H, OCH2Ph), 4.91 (d, J=4.9 Hz,
1H, H1), 6.18 (s, 1H, CdCH2), 6.54 (s, 1H, CdCH2),
7.36-7.12 (m, 20H, OCH2Ph), 9.52 (s, 1H, CHO); 13C NMR
(75.5 MHz, CDCl3, δ ppm) 193.4, 147.1, 138.4, 136.5, 128.6,
128.5, 128.2, 128.0, 127.9, 127.8, 76.8, 75.5, 75.1, 73.9, 72.2,
71.9, 70.3, 69.3; IR (neat NaCl) cm-1 2865, 1695, 1454, 1101,
739; HRMS m/z calcd for C37H38O6 [M þNa]þ 601.2566,
found 601.2557.
2-(2,3,4,6-Tetra-O-benzyl-β-D-mannopyranosyl)prop-2-enal (6).
Formaldehyde (39% in water, 31 mg, 0.3837 mmol), propionic
acid (2.86 μL, 0.0384 mmol), and pyrrolidine (3.20 μL, 0.0384 mmol)
were added to a solution of aldehyde 7 (217 mg, 0.3837 mmol)
dissolved in i-PrOH (0.1 mL). The mixture was stirred at 50 °C
for 45 min, then cooled to rt. Saturated NaHCO3 solution was
added to the mixture, and the aqueous solution was extracted
with DCM (3 ꢀ 5 mL). The combined organic extracts were
washed with brine (1ꢀ5 mL), dried over Na2SO4, filtered, and
concentrated. Silica gel chromatography using 5% Et2O in
toluene afforded pure β-acrolein 6 in 71% yield. β-Acrolein 6
was isolated as a yellow oil: [R]25D 2.6 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3, δ ppm) 3.60-3.54 (m, 1H, H5), 3.82-3.75
(m, 3H, H3, H6), 3.95 (dd, J=9.6 Hz, 1H, H4), 3.95 (dd, J=9.6
Hz, 1H, H4), 4.11 (dd, J=1.9 Hz, 1H, H2), 4.29 (m, 1H, H1),
4.95-4.43 (m, 8H, OCH2Ph), 6.15 (s, 1H, CdCH2), 6.72 (s, 1H,
CdCH2), 7.43-7.20 (m, 20H, OCH2Ph), 9.30 (s, 1H, CHO);
13C NMR (75.5 MHz, CDCl3, δ ppm) 193.1, 146.5, 138.7,
138.6, 138.6, 138.5, 137.5, 128.7, 128.7, 128.6, 128.4, 128.3,
128.1, 127.9, 127.9, 127.8, 127.8, 84.9, 80.0, 75.5, 75.2, 74.7,
74.7, 73.9, 73.7, 72.6, 69.9; IR (neat NaCl) cm-1 3063, 3030,
2901, 2862, 1685, 1104; HRMS m/z calcd for C37H38O6 [M þ
Na]þ 601.2566, found 601.2557.
Experimental Section
2-(2,3,4,6-Tetra-O-benzyl-r-D-mannopyranosyl)prop-2-enal
(5). R-C-Allyl mannoside 321 (267 mg, 0.473 mmol) was dissolved
(28) Isomerization of trans to cis cinnamate toward coumarins using
palladium has already been proposed: refs 15a,15b. See also: Ikeda, M.;
El Bialy, S. A. A.; Yakura, T. Heterocycles 1999, 51, 1957–1970.
(29) Palomo, C.; Oiarbide, M.; Landa, A.; Gonzalez-Rego, M. C.;
Garcia, J. M.; Gonzalez, A.; Odriozola, J. M.; Martin-Pastor, M.; Linden,
A. J. Am. Chem. Soc. 2002, 124, 8637–8643.
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Giguere et al.
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Methyl 2-(2,3,4,6-tetra-O-benzyl-r-D-mannopyranosyl)prop-
2-enoate (8). Step 1: A solution of NaClO2 (62 mg, 0.687 mmol)
and NaH2PO4 (71 mg, 0.598 mmol) in H2O (0.5 M, 0.6 mL) was
added to a mixture of aldehyde 5 (172 mg, 0.299 mmol) and
2-methyl butene (0.897 mmol) in t-BuOH (0.2 M, 1.5 mL). The
mixture was stirred 2.5 h and concentrated under reduced
pressure. The yellow residue was dissolved in water (5 mL),
and 1 M HCl was added until pH=2. The mixture was extracted
with EtOAc (3ꢀ10 mL) and DCM (3ꢀ10 mL), and the combined
organic extracts were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude residue was used for
the next step without further purification. Step 2: K2CO3 (62 mg,
0.448 mmol) and MeI (0.744 mL, 0.448 mmol) were added to the
crude acid dissolved in CH3CN (6 mL). The mixture was stirred
overnight, filtered, concentrated, and chromatographed using
5% Et2O in toluene, affording pure unsaturated ester 8 (141 mg,
78% over two steps) isolated as a yellow oil: [R]25D þ18.2 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3, δ ppm) 3.66 (s, 3H), 3.70
(dd, J=2.5, 3.8 Hz, 1H), 3.70 (dd, J=2.5, 3.8 Hz, 1H), 3.84-3.73
(m, 2H), 3.93-3.86 (m, 1H), 4.06-3.99 (m, 2H), 4.74-4.49 (m,
8H), 4.94 (d, J=5.2 Hz, 1H), 5.86 (s, 1H), 6.27 (s, 1H), 7.33-7.16
(m, 20H); 13C NMR (75.5 MHz, CDCl3, δ ppm) 166.6, 138.6,
138.3, 138.2, 138.2, 128.3, 128.2, 127.8, 127.6, 127.4, 126.5, 76.5,
76.3, 75.0, 74.9, 73.2, 72.3, 71.6, 70.8, 68.9, 51.8; IR (neat NaCl)
cm-1 2926, 2866, 1723, 1454, 1100, 738; HRMS m/z calcd for
C38H40O7 [M þ H]þ 609.2853, found 609.2844.
3-(2,3,4,6-Tetra-O-benzyl-r-D-mannopyranosyl)-2H-chromen-2-
one (11). Ιsolated as a colorless oil: [R]25D þ3.1 (c 1.2, CHCl3);
1H NMR (300 MHz, CDCl3, δ ppm) 3.71 (dd, J=2.7, 6.6 Hz,
1H), 3.78 (dd, J = 4.4, 10.4 Hz, 1H), 3.91-3.86 (m, 2H),
4.48-4.12 (m, 1H), 4.57-4.53 (m, 1H), 4.69-4.58 (m, 8H),
5.17 (d, J=5.2 Hz, 1H), 7.33-7.18 (m, 23H), 7.48 (t, J=6.7 Hz,
1H), 7.77 (s, 1H); 13C NMR (75.5 MHz, CDCl3, δ ppm) 160.2,
153.3, 140.5, 138.2, 138.1, 138.0, 131.4, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 126.2, 124.3, 118.9,
116.3, 76.5, 75.9, 75.3, 75.0, 73.3, 72.1, 71.5, 70.3, 68.9; IR (neat
NaCl) cm-1 2922, 2861, 1718, 1456, 1093, 737, 697; HRMS m/z
calcd for C43H40O7 [M þ H]þ 669.2853, found 669.2839.
3-(2,3,4,6-Tetra-O-benzyl-r-D-mannopyranosylmethyl)-2H-
chromen-2-one (18). Isolated as a yellow oil: [R]25D þ 7.6 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3, δ ppm) 2.68 (dd, J=9.1,
14.6 Hz, 1H), 2.87 (dd, J=4.1, 15.1 Hz, 1H), 3.71-3.64 (m, 2H),
3.82-3.74 (m, 2H), 3.93-3.85 (m, 2H), 4.35-4.29 (m, 1H),
4.63-4.44 (m, 7H), 4.71 (d, J=11.2 Hz, 1H), 7.00 (t, J=7.9 Hz,
1H), 7.31-7.09 (m, 22H), 7.51-7.38 (m, 1H), 7.61 (s, 1H); 13
C
NMR (75.5 MHz, CDCl3, δ ppm) 161.9, 153.1, 140.9, 138.1,
137.4, 131.4, 130.7, 129.7, 128.4, 128.3, 128.1, 127.9, 127.9,
127.8, 127.7, 127.6, 127.5, 125.6, 124.2, 121.4, 119.5, 116.7,
116.3, 77.1, 75.4, 75.1, 73.9, 73.7, 73.3, 72.1, 71.6, 69.4, 30.2;
IR (neat NaCl) cm-1 2924, 2868, 1717, 1456, 1096, 1028, 752;
HRMS m/z calcd for C44H42O7 [M þ H]þ 683.3009, found
683.2994.
3-(r-D-mannopyranosylmethyl)-2H-chromen-2-one (19). To a
solution of coumarin 18 (60 mg, 0.088 mmol) in MeOH
were added two drops of AcOH and 10% Pd/C (6 mg). H2 gas
was bubbled for 6 h into the mixture. The solution was filtered
over Celite, concentrated, and chromatographed using 20%
MeOH in DCM. Unprotected mannosyl coumarin 19 was
Methyl (E)-3-(2-hydroxyphenyl)-2-(2,3,4,6-tetra-O-benzyl-r-
D-mannopyranosyl)prop-2-enoate (10) and 3-(2,3,4,6-Tetra-O-
benzyl-R-D-mannopyranosyl)-2H-chromen-2-one (11). To a 0.16
M solution of unsaturated ester 8 (89.7 mg, 0.147 mmol) in dry
DMF (9 mL) were added 2-iodophenol (66.0 mg, 0.295 mmol),
palladium(II) acetate (3.3 mg, 0.015 mmol), tetrabutylammo-
nium bromide (47.0 mg, 0.147 mmol), and sodium bicarbonate
(37.0 mg, 0.442 mmol). The reaction mixture was heated at 85 °C
under a nitrogen atmosphere for 30 h. The solution was cooled
to rt, dissolved in EtOAc (20 mL), washed with water (5 ꢀ
10 mL), dried over Na2SO4, filtered, concentrated under re-
duced pressure, and purified by flash column chromatography
on silica gel (50% EtOAc in hexanes) to a mixture of cinnamate
10 and coumarin 11 (77%, 1:5 ratio, respectively).
isolated as a white solid (67%, 18.9 mg, 0.059 mmol):
1
mp=151-152 °C (MeOH); [R]25 þ36.3 (c 0.8, CH3OH); H
D
NMR (300 MHz, CD3OD, δ ppm) 2.90-2.70 (m, 2H),
3.46-3.43 (m, 1H), 3.60-3.54 (m, 2H), 3.63 (br s, 1H),
3.73-3.69 (m, 2H), 4.16-4.11 (m, 1), 7.24-7.19 (m, 2H),
7.51-7.41 (m, 2H), 7.83 (s, 1H); 13C NMR (75.5 MHz, CD3OD,
δ ppm) 163.7, 154.5, 143.0, 132.2, 129.0, 126.8, 125.7, 121.0,
117.1, 76.9, 76.4, 72.6, 72.6, 69.4, 62.8, 31.1; IR (KBr) cm-1
3370, 2923, 1717, 1559, 1097; HRMS m/z calcd for C16H18O7
[M þ Na]þ 345.0945, found 345.0943.
Methyl (E)-3-(2-hydroxyphenyl)-2-(2,3,4,6-tetra-O-benzyl-r-
D-mannopyranosyl)prop-2-enoate (10). Isolated as a yellow oil:
[R]25 -56.4 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3,
D
δ ppm) 3.41-3.35 (m, 1H), 3.62-3.55 (m, 2H), 3.74 (s, 3H),
3.76-3.75 (m, 1H), 4.07-4.03 (m, 1H), 4.18-4.13 (m, 1H),
4.37-4.29 (m, 3H), 4.41 (m, 2H), 4.54-4.48 (m, 2H), 4.60 (dd,
J=2.5, 9.9 Hz, 1H), 4.95-4.91 (m, 1H), 6.86-6.77 (m, 3H), 6.95
(s, 1H), 7.28-7.08 (m, 20H), 7.84 (s, 1H); 13C NMR (75.5 MHz,
CDCl3, δ ppm) 166.7, 153.1, 141.5, 138.3, 137.6, 131.9, 130.0,
129.6, 128.4, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5, 127.4,
122.2, 120.2, 117.9, 75.6, 74.8, 74.1, 74.0, 73.3, 72.7, 71.8, 71.4,
67.7, 66.1, 51.9, 29.7; IR (neat NaCl) cm-1 3359, 2924, 2857,
1717, 1456, 1097, 1027, 771; HRMS m/z calcd for C44H44O8
[M þ H]þ 701.3116, found 701.3112.
Acknowledgment. This work was supported from Natural
Sciences and Engineering Research Council of Canada
(NSERC) for a Canadian Research Chair in Therapeutic
ꢁ
Chemistry to R.R. D.G. thanks FQRNT (Quebec) for a
postgraduate fellowship.
Supporting Information Available: Experimental details for
all new compounds. 1H and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 21, 2009 8483