The design, synthesis, and evaluation of coumarin ring derivatives of the novobiocin scaffold that exhibit antiproliferative activity

Article abstract of DOI:10.1021/jo801312r

(Chemical Equation Presented) Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the Hsp90 C-terminus and induces degradation of Hsp90-dependent client proteins at ～700 μM in breast cancer cells (SKBr3). Although many analogues of novobiocin have been synthesized, it was only recently demonstrated that monomeric species exhibit antiproliferative activity against various cancer cell lines. To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives was synthesized and evaluated to elucidate structure-activity relationships for novobiocin as an anticancer agent. Results obtained from these studies have produced novobiocin analogues that manifest low micromolar activity against several cancer cell lines.

Full text of DOI:10.1021/jo801312r

The Design, Synthesis, and Evaluation of Coumarin Ring
Derivatives of the Novobiocin Scaffold that Exhibit Antiproliferative
Activity
Alison C. Donnelly,§,† Jared R. Mays,§,† Joseph A. Burlison,† John T. Nelson,‡
George Vielhauer,‡ Jeffrey Holzbeierlein,‡ and Brian S. J. Blagg*,†
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Malott 4070, The UniVersity of Kansas,
Lawrence, Kansas 66045-7563, and Department of Urology, The UniVersity of Kansas Medical Center,
3901 Rainbow BlVd., Mail Stop 3016, Kansas City, Kansas 66160
bblagg@ku.edu
ReceiVed June 18, 2008
Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the Hsp90
C-terminus and induces degradation of Hsp90-dependent client proteins at ∼700 µM in breast cancer
cells (SKBr3). Although many analogues of novobiocin have been synthesized, it was only recently
demonstrated that monomeric species exhibit antiproliferative activity against various cancer cell lines.
To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives
was synthesized and evaluated to elucidate structure-activity relationships for novobiocin as an anticancer
agent. Results obtained from these studies have produced novobiocin analogues that manifest low
micromolar activity against several cancer cell lines.
Introduction
represent individually pursued antitumor targets.4-9 Hsp90 plays
a unique role in regulating the function and stability of a growing
number of proteins upon which cancer cells depend for survival.
It is because of this role and its related regulation of many
mutated and overexpressed proteins that contribute to cancer
cell proliferation that Hsp90 has evolved into a promising drug
target.10
Increasing resistance to chemotherapeutics and knowledge
that cancers employ multiple abnormalities have resulted in an
increased interest in targeting the Hsp90 molecular chaperone
for the treatment of cancer.1 Hsp90 is a molecular chaperone
that is responsible for the folding and conformational mainte-
nance of more than 100 Hsp90-dependent client proteins.2,3 In
ViVo, Hsp90 substrates have been implicated in cellular signaling
networks, such as those mediated by steroid hormone receptors,
transcription factors, and protein kinases, many of which
Hsp90 inhibition results in the destabilization of a substrate-
bound heteroprotein complex, which leads to degradation of
(4) Terasawa, K.; Minami, M.; Minami, Y. J. Biochemistry 2005, 137, 443–
447.
(5) Buchner, J. Trends Biochem. Sci. 1999, 24, 136–141.
(6) Picard, D. Cell. Mol. Life Sci. 2002, 59, 1640–1648.
(7) Yonehara, M.; Minami, Y.; Kawata, Y.; Nagai, J.; Yahara, I. J. Biol.
Chem. 1996, 271, 2641–2645.
* Author to whom correspondence should be addressed. Phone: (785) 864-
2288. Fax: (785) 864-5326.
† The University of Kansas.
‡ The University of Kansas Medical Center.
(8) Xiao, L.; Lu, X.; Ruden, D. M. Mini-ReV. Med. Chem. 2006, 6, 1137–
§ Both authors contributed equally to this work.
(1) Powers, M. V.; Workman, P. Endocr.-Relat. Cancer 2006, 13, S125–
S135.
1143.
(9) Zhao, R.; Houry, W. A. Biochem. Cell Biol. 2005, 83, 703–710.
(10) Neckers, L.; Ivy, S. P. Curr. Opin. Oncol. 2003, 15, 419–424.
(11) Yu, X. M.; Shen, G.; Neckers, L.; Blake, H.; Holzbeierlein, J.; Cronk,
B.; Blagg, B. S. J. J. Am. Chem. Soc. 2005, 127, 12778–12779.
(2) Pratt, W. B.; Toft, D. O. Exp. Biol. Med. 2003, 228, 111–133.
(3) Issacs, J. S.; Xu, W.; Neckers, L. Cancer Cell 2003, 3, 213–217.
10.1021/jo801312r CCC: $40.75
Published on Web 10/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8901–8920 8901

Donnelly et al.
Neckers and co-workers demonstrated that novobiocin also
binds Hsp90 and exhibits antitumor activity (∼700 µM)
against SKBr3 human breast cancer cells. In testing their
hypothesis, Neckers and co-workers showed via Western blot
analyses that novobiocin induces degradation of Hsp90-
dependent clients in a concentration-dependent manner.
Related studies in which truncated variants of Hsp90 were
eluted from an immobilized novobiocin solid-support revealed
that only the C-terminus of Hsp90 was capable of binding
novobiocin, which is in contrast to other Hsp90 inhibitors
that bind solely to the well-established N-terminal ATP-
binding site.34
FIGURE 1. Structure of novobiocin.
Hsp90-dependent clients via ubiquitinylation of the unfolded
client followed by proteasome-mediated hydrolysis.11-16 As
such, small molecule inhibitors of Hsp90 transform the protein
folding machinery into a catalyst for protein degradation.17
Through Hsp90 inhibition, depletion of multiple oncogenic
proteins readily occurs and the outcome is similar to a
combinatorial attack on multiple signaling nodes that contribute
to oncogenic signaling and modulation of the malignant
phenotype.1,18,19 Hsp90 has been shown to be overexpressed
in a wide variety of human malignancies and provides an
opportunity for high differential selectivity.1,18,20 The ability to
simultaneously disrupt multiple signaling events through a single
target makes Hsp90 an attractive protein for the development
of chemotherapeutic agents.1,19,21
In addition, it was found that inhibitors bound to the Hsp90
N-terminus were readily displaced by occupation of the C-
terminus by novobiocin, which is not recipricol.34,35 It has been
proposed that novobiocin may antagonize Hsp90 function by
inducing a conformational change that results in separation of
the homodimeric C-terminal domains and subsequent release
of substrate;36 however, studies with improved analogues are
needed to confirm this hypothesis. It is proposed that the
synthesis of improved analogues will not only allow elucidation
of the Hsp90 C-terminal nucleotide-binding pocket, but will also
provide insight into the unique mechanism exhibited by Hsp90
during the complex protein folding process.36
3
Novobiocin (Figure 1), a member of the coumermycin
family of antibiotics, binds to the ATP-binding pocket of
DNA gyrase and elicits antimicrobial activity through inhibi-
tion of ATP-hydrolysis.22-25 Co-crystal structures of GyrB,
the B subunit of DNA gyrase, bound to novobiocin and ADP
revealed both molecules bind in a bent conformation,26-28
similar to the manner in which Hsp90 binds ADP.29 With
prior knowledge that novobiocin manifests cytotoxicity and
binds to a similarly shaped pocket in DNA Gyrase,25,30-33
(12) Zhang, H.; Burrows, F. J. Mol. Med. 2004, 82, 488–499.
(13) Chiosis, G.; Vilenchik, M.; Kim, J.; Solit, D. Drug Discuss. Today 2004,
9, 881–888.
(14) Burlison, J. A.; Neckers, L.; Smith, A. B.; Maxwell, A.; Blagg, B. S. J.
J. Am. Chem. Soc. 2006, 128, 15529–15536.
(15) Toft, D. O. Trends Endocrin. Metab. 1998, 9, 238–243.
(16) Walter, S.; Buchner, J. J. Angew. Chem., Int. Ed. 2002, 41, 1098–1113.
(17) Blagg, B. S. J.; Kerr, T. D. Med. Res. ReV. 2006, 26, 310–338.
(18) Maloney, A.; Workman, P. Expert Opin. Biol. Ther. 2002, 2, 3–24.
(19) Workman, P. Cancer Lett. 2004, 206, 149–157.
(20) Sreedhar, A. S.; Kalmar, E.; Csermely, P.; Shen, Y. F. FEBS Lett. 2004,
562, 11–15.
(21) Workman, P. Cold Spring Harbor Symp. Quant. Biol. 2005, 70, 499–
515.
(22) Lewis, R. J.; Tsai, F. T.; Wigley, D. B. BioEssays 1996, 18, 661–671.
(23) Reece, R. J.; Maxwell, A. Crit. ReV. Biochem. Mol. Biol. 1991, 26, 335–
375.
(24) Laurin, P.; Ferroud, D.; Schio, L.; Klich, M.; Dupuis-Hamelin, C.;
Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Bioorg. Med. Chem. Lett.
1999, 9, 2875–2880.
(25) Ali, J. A.; Jackson, A. P.; Howells, A. J.; Maxwell, A. Biochemistry
1993, 32, 2717–2724.
(26) Holdgate, G. A.; Tunnicliffe, A.; Ward, W. H. J.; Weston, S. A.;
Rosenbrock, G.; Barth, P. T.; Taylor, I. W. F.; Paupit, R. A.; Timms, D.
Biochemistry 1997, 36, 9663–9673.
FIGURE 2. Structures of A4, DHN1, DHN2, and A4-dimer.
(27) Lewis, R. J.; Singh, O. M. P.; Smith, C. V.; Skarzyknski, T.; Maxwell,
A.; Wonacott, A. J.; Wigley, D. B. EMBO J. 1996, 15, 1412–1420.
(28) Tsai, F. T. F.; Singh, O. M. P.; Skarzynski, T.; Wonacott, A. J.; Weston,
S.; Tucker, A.; Pauptit, R. A.; Breeze, A. L.; Poyser, J. P.; O’Brien, R.; Ladbury,
J. E.; Wigley, D. B. Proteins: Struct., Funct., Genet. 1997, 28, 41–52.
(29) Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.; Piper, P. W.;
Pearl, L. H. J. Med. Chem. 1999, 42, 260–266.
(30) Gobernado, M.; Canton, E.; Santos, M. Eur. J. Clin. Microbiol. 1984,
3, 371.
(31) Schwartz, G. N.; Teicher, B. A.; Eder, J. P., Jr.; Korbut, T.; Holden,
S. A.; Ara, G.; Herman, T. S. Cancer Chemother. Pharmacol. 1993, 32, 455–
462.
Several groups have attempted to develop improved analogues
of novobiocin to improve its comparatively poor Hsp90 inhibi-
tory activity.34 A library of novobiocin analogues disclosed in
(33) Hombrouck, C.; Capmau, M.; Moreau, N. Cell Mol. Biol. 1999, 45,
347–352.
(34) Marcu, M. G.; Schulte, T. W.; Neckers, L. J. Natl. Cancer Inst. 2000,
92, 242–248.
(35) Marcu, M. G.; Chadli, A.; Bohouche, I.; Catelli, B.; Neckers, L. M.
J. Biol. Chem. 2001, 276, 37181–37186.
(32) Nordenberg, J.; Albukrek, D.; Hadar, T.; Fux, A.; Wasserman, L.;
Novogrodsky, A.; Sidid, Y. Br. J. Cancer 1992, 65, 183–188.
(36) Allan, R. K.; Mok, D.; Ward, B. K.; Ratajczak, T. J. Biol. Chem. 2006,
281, 7161–7171.
8902 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
2005 demonstrated that A4 (Figure 2) induced degradation of
Hsp90-dependent client proteins at ∼70-fold lower concentration
than novobiocin.11 The structure of A4 included a shortened
N-acyl side chain, removal of the 4-hydroxy substituent, and
an absent carbamoyl group on the noviose appendage. More
importantly, this study highlighted that attachment of the noviose
moiety to the 7-position and an amide linker at the 3-position
of the coumarin ring are critical for anti-Hsp90 activity.11 To
confirm the observed SAR trends elucidated from this library,
two natural product analogues were prepared and evaluated,
DHN1 and DHN2 (Figure 2). Upon evaluation of these
molecules in several assays, it was confirmed that the 4-hydroxyl
and the 3′-carbamate are detrimental to Hsp90 inhibitory activity,
but critical for DNA gyrase inhibition.14
Compound A4 was found to exhibit unique activities. A4
induced Hsp90 at concentrations (103-104)-fold lower than that
required for client protein degradation and was thus evaluated
for neuroprotective activity. A4 exhibited an EC50 at 6 nM and
demonstrated no toxicity at any concentration tested in a model
for Alzheimer’s disease.11 In contrast to the monomeric species,
the A4-dimer, based on the structure of coumermycin A1, was
found to manifest antiproliferative activity. These results sug-
gested that modification of the amide side chain resulted in
conversion of a nontoxic molecule into an antiproliferative
agent.37 Consequently, a series of monomeric species based on
A4 was synthesized and evaluated for antitumor activity.38 This
later study described the synthesis and evaluation of biaryl and
heterocyclic amide derivatives that explore hydrogen bonding
interactions with the putative novobiocin binding pocket, which
typically binds the prenylated benzamide of the natural product.
These studies led to the first set of SAR for the amide side
chain.
FIGURE 3. Complementarity of GTP and coumarin analogues.
The coumarin scaffolds were designed to complement
interactions present on the purine nucleus, via probing the
importance of hydrogen bond donor and acceptors in positions
surrounding the aromatic ring system. Rationale for these
analogues is based on the identification of additional interactions
with the nucleotide-binding domain that typically binds the
corresponding purine substrate and may lead to enhanced
inhibitory affinity for these compounds. Minor perturbations
were made on each analogue; however, the addition of one
hydrogen bond can produce 1-2 kcal/mol of binding energy
and thus increase binding by 10-fold.40 Therefore, these
complementary interactions can exhibit a substantial impact on
binding and subsequent inhibition. While it has been demon-
strated that the N-terminal site is fairly specific for adenine
nucleotides, the C-terminal site has been shown to be more
promiscuous, and binds both purines and pyrimidines. While
adenine specifically binds to the N-terminus, GTP and UTP
are specific C-terminal substrates.41 On the basis of these
previous studies, mimics of the guanosine nucleus were chosen
to take advantage of this differential. Hydrogen bond acceptors
were placed at the 5-, 6-, and 8-positions of the coumarin ring
to mimic those at the 6-, 7-, and 3-positions of guanine,
respectively (Figure 3). Additionally, analogues bearing modi-
fication to the coumarin lactone were constructed to probe the
importance of hydrogen bond donors/acceptors at this position
as well as to potentially improve upon the solubility of the
novobiocin scaffold. The activity of such compound will provide
insight into the interactions that are essential or those that can
be further optimized.
Although the Hsp90 C-terminus does not exhibit ATPase
activity, it does play a critical role in conformational rearrange-
ment upon ATP binding.36 To further explore SAR, derivatives
of A4 with variations to the coumarin scaffold were designed
to probe the importance of interactions typically manifested by
the purine ring. These coumarin-derived motifs possess hydro-
gen bonding capabilities similar to those of the nucleotide bases,
adenine and guanine, and contain strategically placed hydrogen
bond acceptors and donors and alkyl groups of variable size to
probe the size and nature of the complementary binding pocket.
The design, synthesis, and evaluation of such compounds are
described in this article.
SCHEME 1. Retrosynthesis of Novobiocin Analogues
Results and Discussion
Design of New Novobiocin Analogues. To elucidate struc-
ture-activity relationships for the coumarin ring system of
novobiocin, we envisioned construction of novobiocin analogues
with modified coumarin cores. As shown in Scheme 1, the
derivatives were assembled in a modular fashion allowing
sequential coupling of noviose and a series of benzoic acids
with the modified coumarin cores. We previously demonstrated
that the trichloroacetimidate of noviose carbonate couples readily
to coumarin phenols in good yield, to afford the corresponding
R-anomer.39 The benzoic acids selected were based upon
previously obtained SAR for the amide side chain as described
by Burlison and co-workers.38
Since the discovery of the C-terminal binding site is a recent
achievement and no Hsp90 co-crystal structure bound to
C-terminal inhibitors exists, there is limited knowledge regarding
its shape and dimensions. Therefore, several analogues were
designed to probe the breadth of the pocket at positions that
(37) Burlison, J. A.; Blagg, B. S. J. Org. Lett. 2006, 8, 4855–4858.
(38) Burlison, J. A.; Avila, C.; Vielhauer, G.; Lubbers, D. J.; Holzbeierlein,
J.; Blagg, B. S. J. J. Org. Chem. 2008, 73, 2130–2137.
(39) Shen, G.; Yu, X. M.; Blagg, B. S. J. Bioorg. Med. Chem. Lett. 2004,
14, 5903–5906.
J. Org. Chem. Vol. 73, No. 22, 2008 8903

Donnelly et al.
SCHEME 3. Synthesis of 5-Substituted Resorcinol
potentially project into hydrophobic regions. Alkyl and aryl
groups of variable size were attached at the 5-, 6-, and
8-positions of the coumarin ring to maximize putative hydro-
phobic interactions and to optimize affinity. A methoxy group
was attached at the 5-poistion of the coumarin ring, while
methoxy, propoxy, and isopropoxy ethers were installed at the
6-position. Methyl, ethyl, methoxy, benzyl, and phenyl substit-
uents were placed at the 8-position, offering a variety of possible
interactions to fill the pocket that is occupied by the chlorine
of chlorobiocin and the methyl substituent of novobiocin. The
culmination of structure-activity relationships elucidated by
such compounds will provide a platform upon which improved
analogues can be sought.
Syntheses of 5-, 6-, and 8-Alkyl(oxy) Novobiocin
Analogues. To generate the resorcinol precursors with substitu-
tions at the 4-position, which result in coumarin ring systems
with appendages at the 6-position, the phenols of benzaldehyde
1 were protected as the corresponding ethers (Scheme 2). The
resulting benzaldehydes (2a,b)42 were converted to their formate
esters via Baeyer-Villiger oxidation, and then hydrolyzed to
afford phenols 3a,b.43,44 O-Alkylation with the requisite alkyl
iodide proceeded in good yield and generated a series of
protected 4-substituted resorcinolic ethers (4a-c). Ortho-
lithiation of 4a-c, followed by alkylation with methyl iodide
provided the 2-methyl protected resorcinols, 5a-c.45 Depro-
tection46 of the alkoxy ethers by exposure to acidic conditions
gave resorcinols 6a-c.
iodide, led to installation of a methyl group at the 2-position of
9.45 Acidic deprotection46 was employed to afford resorcinol
10.
To generate the resorcinol precursors with aryl substituents
at the 2-position, the phenols of resorcinol 11 were protected
as the corresponding alkoxy ethers, 12 (Scheme 4). Subsequent
ortho-lithiation of 12, followed by the addition of benzyl
bromide provided the benzyl derivative, 13.45 Removal of the
ether protecting groups46 gave diphenol 14.45 The anion of
resorcinol 12 was also employed to construct the corresponding
2-iodide via reaction with iodine to yield 15.47 A Suzuki
coupling in the presence of biaryl ligand S-Phos48 was used to
generate biaryl 16, which underwent deprotection46 to provide
17.
SCHEME 4. Syntheses of 2-Substituted Resorcinols
SCHEME 2. Syntheses of 4-Substituted Resorcinols (OEOM
) OCH2OEt)
To generate resorcinol precursors with substitutions at the
5-position, the phenols of 5-methoxy resorcinol 7 were once
again protected as the corresponding alkoxy ethers, 8 (Scheme
3). Ortho-lithiation of 8, followed by treatment with methyl
To generate resorcinol precursors with alkyl substitutions at
the 2-position, pyragallol (18) was O-alkylated with methyl
iodide to generate 2-methoxy resorcinol among an inseparable
mixture of regioisomers (Scheme 5). The mixture was subse-
quently subjected to coumarin formation and the correspond-
ing products isolated. Preparation of 2-ethyl resorcinol (21)
from 2,6-dihydroxyacetophenone (20) was accomplished ac-
cording to published procedures.49
(40) Klaholz, B. P.; Moras, D. Structure 2002, 10, 1197–1204.
(41) Soti, C.; Vermes, A.; Haystead, T. A. J.; Csermely, P. Eur. J. Biochem.
2003, 270, 2421–2428.
(42) Nabaei-Bidhendi, G.; Bannerjee, N. R. J. Indian Chem. Soc. 1990, 67,
43–45.
(43) Horvath, R. F.; Chan, T. H. J. Org. Chem. 1986, 52, 4489–4494.
(44) Miyake, M.; Hanaoka, Y.; Fujimoto, Y.; Sato, Y.; Taketomo, N.; Yokota,
I.; Yoshiyama, Y. Heterocycles 1996, 43, 665–674.
(45) Carreno, M. C.; Garcia Ruano, J. L.; Toledo, M. A.; Urbano, A.
Tetrahedron: Asymmetry 1997, 8, 913–921.
(46) Wang, Y.; Tan, W.; Li, W. Z.; Li, Y. J. Nat. Prod. 2001, 64, 196–199.
(47) Ruenitz, P. C.; Bagley, J. R.; Nanavati, N. T. J. Med. Chem. 1988, 31,
1471–1475.
(48) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028–
13032.
(49) Elliger, C. A. Synth. Commun. 1985, 15, 1315–1324.
8904 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
SCHEME 5. Synthesis of 2-Methoxy Resorcinol and 2-Ethyl
Resorcinol
SCHEME 7. Syntheses of 7-Hydroxyquinolines
Once resorcinols 6a-c, 10, 14, 17, 19, and 21 were obtained,
the corresponding coumarins 23a-h were synthesized through
a modified Pechmann condensation with eneamine 22 as
previously described.50,51 The resulting coumarin phenols were
noviosylated with the trichloroacetimidate of noviose carbonate
(24) in the presence of catalytic boron trifluoride etherate to
generate scaffolds 25a-h in good yield.39 The benzyl carbonate
was removed via hydrogenolysis to produce aminocoumarins,
which were readily coupled with preselected benzoic acids in
the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiim-
ide hydrochloride (EDCI) and pyridine. Benzoic acids were
chosen based on previously determined SAR trends reported
by Burlison and co-workers.38 The cyclic carbonates were
treated with triethylamine in methanol to give the solvolyzed
products 26a-p in moderate to good yield over three steps
(Scheme 6).
Syntheses of Quinoline- and Naphthalene-Containing No-
vobiocin Analogues. Novobiocin analogues containing a quino-
line or naphthalene ring in lieu of the 8-methylcoumarin of
novobiocin were synthesized to probe the importance of the
coumarin lactone moiety in binding the Hsp90 C-terminus, as
well as to potentially circumvent the limited solubility of
coumarin-containing analogues. Protection of the phenol in 27
as the tert-butyl-carbonate52 served two purposes (Scheme 7).
Not only did phenol protection remove the quinolone-like
properties of 27, but the sterically hindered tert-butyl-carbonate
also decreased the relative amount of 6- and 8-bromo regioi-
somers normally produced upon bromination of 28. Thus, the
isolable percentage of desired 3-bromo regioisomer was enriched
to 46% yield.53 One-pot tert-butyl-carbonate deprotection,
followed by immediate reprotection with benzyl bromide
afforded intermediate 30. N-Arylation of 30 was accomplished
with p-methoxybenzylamine under Ullman-like conditions
employing CuI and L-(-)-proline as a catalyst to provide 31.54
Acylation of the secondary aniline with the desired benzoyl
chloride,55 generated in situ from the appropriate benzoic acid,56
afforded PMB-protected amide 32. Interestingly, subjection of
32 to aluminum trichloride in anisole57 resulted solely in the
formation of 7-hydroxy 33; the PMB-protected amide remained
intact. Global removal of the PMB and benzyl groups was
ultimately accomplished with trifluoromethanesulfonic acid to
provide phenol 34.58
Construction of the corresponding naphthalene-containing
analogues began by benzyl protection of phenol 35 to provide
36 in high yield (Scheme 8).59 N-Arylation of 36 with
p-methoxybenzylamine provided 37,54 which was acylated with
the desired benzoyl chloride to afford 38.55,56 6-Benzyloxy
deprotection of 38 to 39 was performed with aluminum
trichloride in anisole,57 while concurrent benzyl- and PMB-
deprotection to intermediate 40 was accomplished with trifluo-
romethanesulfonic acid.58
Phenols 33, 34, 39, and 40 were noviosylated with the
trichloroacetimide of noviose carbonate (24) in the presence of
SCHEME 6. Preparation of 5-, 6-, and 8-Modified Novobiocin Analogues
J. Org. Chem. Vol. 73, No. 22, 2008 8905

Donnelly et al.
SCHEME 8. Syntheses of 6-Hydroxynaphthalenes
SCHEME 9. Preparation of Quinoline- and Naphthalene-Derived Novobiocin Analogues
TABLE 1. Anti-Proliferation Activities of Coumarin-Derived Novobiocin Analogues
compd no.
(IC50, µM)
R1
R2
R3
R4
MCF-7
SKBr3
PC-3
35.4
LnCaP
26a
26b
26c
26d
26e
26f
26g
26h
26i
26j
26k
26l
26m
26n
26o
26p
biaryl
biaryl
biaryl
biaryl
biaryl
biaryl
biaryl
biaryl
2-indole
2-indole
2-indole
2-indole
2-indole
2-indole
2-indole
2-indole
H
H
H
OMe
H
H
H
H
H
H
H
OMe
H
H
OMe
OPr
OiPr
H
H
H
H
H
OMe
OPr
OiPr
H
Me
Me
Me
Me
Bn
Ph
OMe
Et
Me
Me
Me
Me
Bn
Ph
OMe
Et
>100a
58.8 ( 1.3
>100
58.6 ( 5.4
55.7 ( 6.9
>100
17.3 ( 3.4
13.9 ( 1.2
28.6 ( 1.1
25.1 ( 7.7
2.1 ( 0.8
20.7 ( 0.4
9.0 ( 0.8
38.0 ( 3.0
38.8 ( 8.3
9.7 ( 1.0
4.3 ( 3.4
6.6
>100
5.6 ( 5.7
60.7 ( 9.1
11.3 ( 2.0
>100
3.0 ( 0.6
14.4 ( 4.2
2.0 ( 0.8
49.7 ( 25.0
1.0 ( 0.1
1.1 ( 0.1
1.6 ( 0.3
10.5 ( 0.3
1.8 ( 0.7
11.4
66.9 ( 3.1
82.8
>100
>100
>100
9.0 ( 5.4
41.7 ( 14.0
24.4 ( 1.2
2.1 ( 0.1
20.0 ( 1.0
6.1 ( 1.7
13.2 ( 0.6
22.9 ( 2.1
>100
2.3 ( 2.9
1.8 ( 0.6
20.2 ( 9.8
6.2 ( 1.8
11.9
11.8 ( 1.3
73.3 ( 3.7
28.0 ( 12.1
>100
12.9 ( 4.4
67.6 ( 6.3
27.6 ( 10.8
>100
H
H
H
H
H
H
4.3 ( 2.5
>100
>100
a Values represent mean ( standard deviation for at least two separate experiments performed in triplicate.
boron trifluoride etherate to provide noviose carbonate analogues
41a-d.39 In particular, analogues 33 and 34 containing the
quinoline nitrogen were both slow to react and low yielding,
even with greater than stoichiometric boron trifluoride etherate,
suggesting chelation of the quinoline nitrogen to boron was
problematic. Solvolysis of carbonates 41a-d with triethylamine
in methanol/dichloromethane afforded diols 42a-d in moderate
yields (Scheme 9).
more active against prostate cancer cells than breast cancer cells
versus the corresponding 6-H derivative. For reasons that remain
unclear, the putative binding pocket for biaryl-containing
analogues does not appear to tolerate incorporation of steric
bulk at the 6-position. Analogues containing the 2-indole side
chain (26i-k) were consistently more active than their corre-
sponding biaryl derivatives, which corresponds with previously
observed trends.38 Analogue 26j, containing a 6-propoxy-
Biological Evaluation of Novobiocin Analogues. Upon
construction of the library of novobiocin analogues, the
compounds were evaluated for antiproliferative activity against
SKBr3 (estrogen receptor negative, Her2 overexpressing breast
cancer cells), MCF-7 (estrogen receptor positive breast cancer
cells), LnCaP (androgen receptor sensitive prostate cancer cells),
and PC-3 (androgen receptor insensitive prostate cancer cells)
cell lines. As shown in Table 1, the 6-substituted analogues
containing the biaryl side chain (26a-c) were 3- to 7-fold less
active against the two breast cancer cells lines than analogues
containing hydrogen at this position.38 These analogues were
(50) Robinson, A. J.; Lim, C. Y.; He, L.; Ma, P.; Li, H.-Y. J. Org. Chem.
2001, 66, 4141–4147.
(51) Toplak, R.; Svete, J.; Stanovnik, B.; Grdadolnik, S. G. J. Heterocycl.
Chem. 1999, 36, 225–235.
(52) Hansen, M. M.; Riggs, J. R. Tetrahedron Lett. 1998, 39, 2705–2706.
(53) Zymalkowski, F.; Tinapp, P. Justus Liebigs Ann. Chem. 1966, 699, 98–
106.
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(55) Ulbrich, H. K.; Luxenburger, A.; Prech, P.; Eriksson, E. E.; Soehnlein,
O.; Rotzius, P.; Lindborn, L.; Dannhardt, G. J. Med. Chem. 2006, 49, 5988–
5999.
(56) Jin, Y.; Zhou, Z.-Y.; Tian, W.; Yu, Q.; Long, Y.-Q. Bioorg. Med. Chem.
Lett. 2006, 16, 5864–5869.
8906 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
TABLE 2. Anti-Proliferation Activities of Quinoline- and Naphthalene-Containing Novobiocin Analogues
compd no.
R1
R7
X
MCF-7
>100a
13.1 ( 4.1
>100
46.4 ( 5.3
SKBr3
>100
16.5 ( 6.2
>100
38.9 ( 2.4
PC-3
>100
17.6 ( 4.6
>100
10.9 ( 0.7
LnCaP
>100
14.2 ( 0.4
>100
19.6 ( 1.6
42a
42b
42c
42d
biaryl
biaryl
biaryl
biaryl
4-OMe-Bn
N
N
CH
CH
H
4-OMe-Bn
H
a Values represent mean ( standard deviation for at least two separate experiments performed in triplicate.
coumarin, was consistently the most potent derivative in this
library, exhibiting 2-fold enhanced potency relative to its 6-H
analogue in LnCaP cells.
as the 4-aryloxy substituted novobiocin analogues60,61 or, more
simply, the secondary amide is required for benzamide-
containing novobiocin analogues to manifest antiproliferative
activity, which is consistent with prior structure-activity
trends.38 It is plausible that the steric congestion of amides 42a
and 42c forces adoption of a more static conformation that
disallows cis/trans isomerization of the amide, a feature that
has been hypothesized to be essential for antiproliferative
activity of novobiocin analogues against bacteria. The lack of
reactivity for tertiary amides 42a and 42c to all but the harshest
conditions for p-MeOBn removal58,62,63 also suggests these
compoundsmayadoptahighlyorganizedandstableconformation.
Against breast cancer cells, analogue 42b exhibited similar
antiproliferative activities as the corresponding 8-methylcou-
marin analogue, while 42d was between 2- and 5-fold less
active.38 In contrast, both 42b and 42d were significantly more
active against PC-3 cells than the corresponding 8-methylcou-
marin; 42b and 42d exhibited between 7- and 9-fold reduced
activity against LnCaP cells. Given that both 42b and 42d lack
the 8-methyl feature that yields an increased activity of ∼10-
fold, it is reasonable to hypothesize that the quinoline- and
naphthalene-derived analogues that include an 8-methyl sub-
stituent could exhibit antiproliferative activities between 1-5
µM against breast cancer cells and 1-2 µM against prostate
cancer cells, approximately an order of magnitude less than the
novobiocin analogue containing a coumarin. These results
suggest that, while the lactone moiety may provide beneficial
hydrogen bonding interactions with the novobiocin binding
pocket, these interactions may not be required to manifest
antiproliferative activity. More importantly, these results im-
plicate that continued optimization of the coumarin scaffold
connecting the sugar and benzamide motifs is likely to produce
compounds with enhanced antiproliferative activity. A summary
of the observed trends for antiproliferative activities of cou-
marin-derived novobiocin analogues is depicted in Figure 4.
To provide additional support that the antiproliferative
activities exhibited by coumarin-derived novobiocin analogues
result from Hsp90 inhibition, analogues 26g, 26j, and 42d were
evaluated for their abilities to induce degradation of Hsp90-
dependent client proteins. As shown in Figure 5, the Hsp90
client proteins Her2 and Raf were degraded in MCF-7 cells in
a concentration-dependent manner upon treatment with cou-
By comparison, incorporation of a hydrogen bond acceptor
at the 5-position (26d, 26l) resulted in equivalent or decreased
activity versus corresponding 6-H analogues, especially against
both breast cancer cell lines.38 In general, 5-methoxy function-
alized coumarins do not appear beneficial for antiproliferative
activity.
It was previously demonstrated that 8-methyl analogues were
∼10-fold more active than the corresponding 8-hydrogen
derivatives.38 To further elaborate upon this trend, a larger
selection of 8-fuctionalized coumarins were evaluated. Incor-
poration of an 8-methoxy (26g) led to 2-fold improved activity
over its 8-methyl counterpart, and 5-fold increased activity over
the similarly sized 8-ethyl derivative 26h. Introduction of steric
bulk (26e, 26f) generally decreased antiproliferative activity,
especially against MCF-7 cells. It appears that while short
alkoxy side chains take advantage of putative interactions, steric
bulk appears detrimental to inhibitory activity at this location.
A similar trend was observed against prostate cancer cells, with
26g and 26h exhibiting 10-fold increased activity versus their
8-methyl counterparts.38 Surprisingly, 8-benzyl 26e was more
than twice as active as the 8-methyl derivative against LnCaP
cells. In contrast, 8-position analogues containing the 2-indole
side chain (26m-p) did not exhibit similar, consistent trends
against prostate and breast cancer cells. Against breast cancer
cells, compounds 26m, 26n, and 26p exhibited significantly
reduced activity versus the 8-methyl derivative. The 8-methoxy
26o was inactive against MCF-7 cells, while both 26o and 26p
were inactive against PC-3 and LnCaP cells. The selectivity of
26o and 26p for breast cancer cells versus prostate cancer cells
is intriguing and requires further investigation.
As shown in Table 2, compounds 42a and 42c containing
the p-MeOBn-alkylated amides did not exhibit antiproliferative
activity against the cell lines tested. This is in contrast to
analogues 42b and 42d lacking the p-MeOBn functionality,
which manifested modest antiproliferative activity. This stark
difference suggests one of two scenarios regarding the role of
the p-MeOBn functionality; either the p-MeOBn group of
tertiary amides 42a and 42c is unable to occupy the same pocket
(60) Radanyi, C.; La Bras, G.; Messaoudi, S.; Couclier, C.; Peyrat, J.-F.;
Brion, J.-D.; Marsaud, V.; Renoir, J.-M.; Alami, M. Bioorg. Med. Chem. Lett.
2008, 18, 2495–2498.
(61) Le Bras, G.; Radanyi, C.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.; Marsaud,
V.; Stella, B.; Renoir, J.-M. J. Med. Chem. 2007, 50, 6189–6200.
(62) Faraoni, R.; Blanzat, M.; Kubicek, S.; Braun, C.; Schweizer, W. B.;
Gramlich, V.; Diederich, F. Org. Biomol. Chem. 2004, 2, 1962–1964.
(63) Nadin, A.; Lopez, J. M. S.; Owens, A. P.; Howells, D. M.; Talbot, A. C.;
Harrison, T. J. Org. Chem. 2003, 68, 2844–2852.
(57) Akiyama, T.; Takesue, Y.; Kumegawa, M.; Nishimoto, H.; Ozaki, S.
Bull. Chem. Soc. Jpn. 1991, 64, 2266–2269.
(58) Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.; Moquin, R. V.;
Shen, Z.; Cook, L. S.; Doweyko, A. M.; Pitt, S.; Pang, S.; Shen, D. R.;
Fang, Q.; de Fex, H. F.; McIntyre, K. W.; Shuster, D. J.; Gillooly, K. M.;
Behnia, K.; Schieven, G. L.; Wityak, J.; Barrish, J. C. J. Med. Chem. 2006,
49, 6819–6832.
(59) Ling, K.-Q.; Sayre, L. M. J. Am. Chem. Soc. 2006, 127, 4777–4784.
J. Org. Chem. Vol. 73, No. 22, 2008 8907

Donnelly et al.
activity through inhibition of Hsp90. These analogues provide
sufficient evidence to continue the search for optimal ring
systems that bridge the benzamide and noviose functionalities.
Studies to construct analogues based upon these structure-activity
relationships are currently underway and will be reported in
due course.
Experimental Section
2,4-Bis(ethoxymethoxy)benzaldehyde (2a).42 N,N-Diisopropyl-
ethylamine (25.3 mL, 145 mmol) was slowly added to 2,4-
dihydroxybenzaldehyde (5.00 g, 36.2 mmol) in anhydrous N,N-
dimethylformamide (100 mL) over 5 min at rt. After 30 min, the
solution was cooled to 0 °C and chloromethyl ethyl ether (14.2
mL, 145 mmol) was added and the mixture warmed to rt over 12 h.
The reaction was quenched by the addition of saturated aqueous
NH4Cl solution and extracted with EtOAc (3 × 50 mL). The
combined organic fractions were washed with saturated aqueous
NaCl, dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 5:1 f 1:1 hexane:
EtOAc) to give 2a as a brown amorphous solid (9.10 g, 99%): 1H
NMR (CDCl3, 400 MHz) δ 10.34 (d, J ) 2.4 Hz, 1H), 7.81 (dd, J
) 8.7, 2.8 Hz, 1H), 6.89 (t, J ) 2.5 Hz, 1H), 6.74 (m, 1H), 5.34
(d, J ) 2.8, 2H), 5.28 (d, J ) 2.8, 2H), 3.81-3.71 (m, 4H),
1.28-1.22 (m, 6H).
FIGURE 4. Structure-activity relationships observed for the coumarin
scaffold of novobiocin analogues exhibiting antiproliferative activities.
2,4-Bis(ethoxymethoxy)phenol (3a). A solution of 2a (3.78 g,
12.0 mmol) in anhydrous CH2Cl2 (4.0 mL) was slowly added to
mCPBA (70% w/w, 3.26 g, 13.2 mmol) in anhydrous CH2Cl2 (16.3
mL) at 0 °C. The resulting solution was warmed to rt, then refluxed
for 12 h. After cooling to rt, the resulting solution was washed
with saturated aqueous NaHCO3 solution (3 × 20 mL) and 10%
aqueous Na2S2O3 (30 mL). Combined organic fractions were dried
(Na2SO4), filtered, and concentrated. The residue was redissolved
in MeOH (5 mL) and stirred with excess 10% aqueous NaOH for
3 h at rt. The pH was adjusted to 2 with 6 M HCl and the solution
was extracted with CH2Cl2 (3 × 10 mL). Combined organic
fractions were dried (Na2SO4), filtered, and concentrated to give
3a as an orange oil (8.21 g, 94%): 1H NMR (CDCl3, 500 MHz) δ
6.89-6.85 (m, 2H), 6.67 (dd, J ) 8.8, 2.7 Hz, 1H), 5.81 (d, J )
6.6 Hz, 1H), 5.23 (s, 2H), 5.15 (s, 2H), 3.80-3.73 (m, 4H),
1.29-1.24 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 151.0, 145.0,
141.5, 115.2, 110.6, 106.0, 94.9, 94.2, 64.8, 64.1, 15.1, 15.1; IR
(film) νmax 3362, 2887, 1460, 1286, 1162, 735 cm-1; HRMS (ESI+)
m/z [M + Na]+ calcd for C12H18O5 265.1052, found 265.1045.
2,4-Bis(methoxymethoxy)phenol (3b).44 Benzaldehyde 2b (700
mg, 3.11 mmol) in CHCl3 (1.80 mL) at 0 °C was treated with
mCPBA (70% w/w, 1.61 g, 9.33 mmol). After 10 min, the
solution was warmed to rt, then refluxed for 12 h. Upon cooling
to rt, the solution was washed with saturated aqueous NaHCO3
(3 × 10 mL), saturated aqueous Na2SO3 (20 mL), and saturated
aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The
residue was dissolved in MeOH (5 mL) and stirred with excess
triethylamine for 3 h at rt. The solvent was concentrated and
the residue was purified by column chromatography (SiO2, 4:1
f 3:1 hexane:EtOAc) to afford 3b as a yellow oil (320 mg,
FIGURE 5. Western blot analyses of Hsp90 client protein degradation
assays against MCF-7 breast cancer cells. Concentrations (in µM) of
26g (top), 26j (middle), and 42d (bottom) are indicated above each
lane. GDA (geldanamycin, 500 nM) and DMSO were respectively
employed as positive and negative controls.
marin-derived novobiocin analogues. Moreover, Hsp90 client
protein degradation correlates well with observed antiprolifera-
tive IC50s; 26g (IC50 ) 9.0 µM) and 26j (IC50 ) 2.1 µM)
induced client degradation at ∼10 µM, while 42d, with its more
modest antiproliferative activity (IC50 ) 46.4 µM), induced
client degradation at ∼50 µM. Since Actin, a non-Hsp90-
dependent protein, is not affected by these analogues, antipro-
liferative activities of these analogues correlate directly with
Hsp90-client protein degradation.
Conclusions
Compounds 26g and 26j demonstrated the most potent
antiproliferative activity against the cancer cell lines tested and
represent scaffolds that will be further probed to improve
activity. Derivatives 26f and 26o appear to represent compounds
that exhibit differential selectivity for one cancer cell line versus
another, for reasons that remain unclear. Since these compounds
demonstrated low micromolar activity against one cell line and
are inactive against others, they may provide a tool for further
exploration and perhaps unraveling of the complicated processes
involved. The activities of analogues 42b and 42d, the first
documented novobiocin analogues lacking the coumarin func-
tionality, implicate that, while the coumarin ring may participate
in hydrogen bonding interactions with Hsp90 that abrogate
activity, these interactions are not essential for antiproliferative
1
50%): H NMR (CDCl3, 400 MHz) δ 6.87 (d, J ) 8.9 Hz, 1H),
6.86 (s, 1H), 6.67 (dd, J ) 11.5, 2.8 Hz, 1H), 5.21 (s, 2H), 5.11
(s, 2H), 3.54 (s, 3H), 3.50 (s, 3H).
2,4-Bis(ethoxymethoxy)-1-methoxybenzene (4a). Potassium car-
bonate (14.3 g, 103 mmol) was added to 3a (2.50 g, 10.3 mmol) in
N,N-dimethylformamide (103 mL). After 10 min, methyl iodide
(6.43 mL, 103 mmol) was added and the solution was heated to
reflux for 12 h. Upon cooling to rt, the solution was extracted with
EtOAc (3 × 50 mL); combined organic fractions were washed with
saturated aqueous NaCl, dried (Na2SO4), and concentrated. The
residue was purified by column chromatography (SiO2, 4:1 hexane:
EtOAc) to afford 4a as a yellow oil (2.40 g, 91%): 1H NMR (CDCl3,
500 MHz) δ 6.87 (d, J ) 2.8 Hz, 1H), 6.72 (d, J ) 8.9 Hz, 1H),
6.60 (dd, J ) 13.3, 1.7 Hz, 1H), 5.18 (s, 2H), 5.07 (s, 2H), 3.76 (s,
8908 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
3H), 3.72-3.69 (m, 2H), 3.68-3.63 (m, 2H), 1.17-1.13 (m, 6H);
13C NMR (CDCl3, 125 MHz) δ 150.7, 146.2, 143.9, 111.2, 107.9,
105.8, 93.2, 93.0, 63.3, 63.0, 55.4, 14.1, 14.0; IR (film) νmax 2976,
2932, 2899, 2835, 1595, 1508, 1393, 1227, 1153, 1103, 1080, 1009,
847 cm-1; HRMS (ESI+) m/z [M + Na]+ calcd for C13H20O5
279.1208, found 279.1181.
aqueous NH4Cl. Water (5 mL) was added and the solution was
extracted with CH2Cl2 (3 × 10 mL). Combined organic fractions
were dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 6:1 hexane:EtOAc) to
1
afford 5b as a yellow oil (166 mg, 95%): H NMR (CDCl3, 500
MHz) δ 6.66 (d, J ) 9.0 Hz, 1H), 6.60 (d, J ) 9.0 Hz, 1H), 5.02
(s, 2H), 5.00 (s, 2H), 3.80-3.77 (m, 2H), 3.49 (s, 3H), 3.47 (s,
3H), 2.14 (d, J ) 7.1 Hz, 3H), 1.73-1.69 (m, 2H), 0.94 (t, J ) 7.5
Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 148.5, 148.5, 147.3, 145.6,
126.7, 123.0, 112.8, 110.8, 110.4, 99.2, 57.7, 57.6, 21.2, 10.9, 10.0;
IR (film) νmax 2957, 2924, 2853, 1738, 1597, 1487, 1468, 1391,
1335, 1231, 1157, 974, 798 cm-1; HRMS (ESI+) m/z [M + H]+
calcd for C14H22O5 271.1545, found 271.1558.
2,4-Bis(methoxymethoxy)-1-propoxybenzene (4b). Potassium
carbonate (322 mg, 2.33 mmol) was added to 3b (50 mg, 0.233
mmol) in N,N-dimethylformamide (2.33 mL) at rt. After 10 min,
iodopropane (226 µL, 2.33 mmol) was added and the solution was
heated to reflux for 12 h. Upon cooling to rt, the solution was
extracted with EtOAc (3 × 10 mL); combined organic fractions
were washed with saturated aqueous NaCl, dried (Na2SO4), filtered,
and concentrated. The residue was purified by column chromatog-
raphy (SiO2, 5:1 hexane:EtOAc) to afford 4b as a yellow oil (36.4
1,3-Bis(ethoxymethoxy)-4-isopropoxy-2-methylbenzene (5c). A
solution of 4c (190 mg, 0.67 mmol) in anhydrous THF (530 µL)
was added dropwise to a solution of nBuLi (2.5 M in hexanes, 410
µL, 1.00 mmol) in anhydrous THF (440 µL) at rt. After 1 h, the
solution was cooled to -78 °C and methyl iodide (170 µL, 2.67
mmol) was added. The resulting solution was warmed to rt over
12 h, and the reaction was quenched by the addition of saturated
aqueous NH4Cl. Water (5 mL) was added and the solution was
extracted with CH2Cl2 (3 × 10 mL). Combined organic fractions
were dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 6:1 hexane:EtOAc) to
1
mg, 61%): H NMR (CD2Cl2, 400 MHz) δ 6.87 (s, 1H), 6.84 (d,
J ) 2.9 Hz, 1H), 6.68 (dd, J ) 11.7, 2.8 Hz, 1H), 5.19 (s, 2H),
5.12 (s, 2H), 3.93 (t, J ) 6.6 Hz, 2H), 3.53 (s, 3H), 3.49 (s, 3H),
1.86-1.78 (m, 2H), 1.06 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 150.6, 146.5, 143.8, 113.7, 108.5, 106.6, 94.7, 94.2,
70.3, 55.2, 54.9, 21.6, 9.5; IR (film) νmax 2961, 2826, 1595, 1506,
1400, 1261, 1154, 1013, 1076, 924, 800 cm-1; HRMS (ESI+) m/z
[M + H]+ calcd for C13H20O5 257.1389, found 257.1410; [M +
Na]+ calcd for C13H20O5 279.1208, found 279.1165.
1
2,4-Bis(ethoxymethoxy)-1-isopropoxybenzene (4c). Potassium
carbonate (2.85 g, 20.7 mmol) was added to 3a (500 mg, 2.07
mmol) in N,N-dimethylformamide (4.10 mL) at rt. After 10 min,
2-iodopropane (2.06 mL, 20.7 mmol) was added and the solution
was heated to reflux for 12 h. Upon cooling to rt, the solution was
extracted with EtOAc (3 × 20 mL); combined organic fractions
were washed with saturated aqueous NaCl, dried (Na2SO4), filtered,
and concentrated. The residue was purified via column chroma-
tography (SiO2, 5:1 f 1:1 hexane:EtOAc) to afford 4c as a yellow
afford 5c as a yellow oil (157 mg, 79%): H NMR (CDCl3, 500
MHz) δ 6.70 (d, J ) 9.0 Hz, 1H), 6.61 (d, J ) 9.0 Hz, 1H), 5.10
(s, 2H), 5.08 (s, 2H), 4.34 (quintet, J ) 6.1 Hz, 1H), 3.78 (q, J )
7.1 Hz, 2H), 3.67 (q, J ) 7.1 Hz, 2H), 2.13 (s, 3H), 1.23 (d, J )
6.1 Hz, 6H), 1.24-1.15 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ
150.3, 146.6, 145.3, 122.7, 113.7, 110.1, 97.3, 94.0, 71.5, 65.4,
64.2, 29.4, 22.2, 15.2, 15.2, 9.9; IR (film) νmax 2924, 2853, 2359,
2339, 1591, 1483, 1113, 1057, 974 cm-1; HRMS (ESI+) m/z [M
+ H]+ calcd for C16H26O5 299.1858, found 299.1909.
1
oil (0.32 g, 55%): H NMR (CD2Cl2, 400 MHz) δ 6.87 (s, 1H),
4-Methoxy-2-methylbenzene-1,3-diol (6a). A solution of 5a (910
mg, 3.37 mmol) in MeOH (28.0 mL) at rt was treated dropwise
with 3 M HCl (9.00 mL, 26.9 mmol), then heated to reflux for 1 h.
Water (30 mL) was added and the solution was extracted with
EtOAc (3 × 30 mL). Combined organic fractions were washed
with saturated aqueous NaCl, dried (Na2SO4), filtered, and con-
centrated. The residue was purified via column chromatography
(SiO2, 6:1 hexane:EtOAc) to afford 6a as a red amorphous solid
(509 mg, 98%): 1H NMR (aAcetone-d6, 500 MHz) δ 7.68 (s, 1H),
7.24 (s, 1H), 6.60 (d, J ) 11 Hz, 1H), 6.29 (d, J ) 11 Hz, 1H),
3.74 (s, 3H), 2.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 144.7,
142.1, 139.7, 115.6, 110.2, 108.6, 55.6, 7.6; IR (film) νmax 3583,
6.86 (d, J ) 4.9 Hz, 1H), 6.66 (dd, J ) 11.6, 3.4 Hz, 1H), 5.23 (s,
2H), 5.17 (s, 2H), 4.44-4.38 (m, 1H), 3.83-3.72 (m, 4H), 1.33
(s, 3H), 1.31 (s, 3H), 1.27-1.23 (m, 6H); 13C NMR (CDCl3, 125
MHz) δ 152.4, 149.1, 143.2, 118.6, 109.5, 107.5, 94.4, 93.9, 72.8,
64.3, 64.1, 22.2 (2C), 15.1, 15.1; IR (film) νmax 2976, 1591, 1504,
1528, 1391, 1258, 1217, 1107, 1011, 847 cm-1; HRMS (ESI+) m/z
[M + H]+ calcd for C15H24O5 285.1702, found 285.1746; [M +
Na]+ calcd for C15H24O5 307.1522, found 307.1310.
1,3-Bis(ethoxymethoxy)-4-methoxy-2-methylbenzene (5a). A so-
lution of 4a (632 mg, 2.27 mmol) in anhydrous THF (1.94 mL)
was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.48
mL, 3.70 mmol) in anhydrous THF (1.62 mL) at rt. After 1 h, the
solution was cooled to -78 °C and methyl iodide (620 µL, 9.87
mmol) was added. The resulting solution was warmed to rt over
12 h, and the reaction was quenched by the addition of saturated
aqueous NH4Cl. Water (5 mL) was added and the solution was
extracted with CH2Cl2 (3 × 10 mL). Combined organic fractions
were dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 8:1 f 5:1 hexane:
2920, 2359, 1616, 1259, 1090, 1020, 798 cm-1
.
2-Methyl-4-propoxybenzene-1,3-diol (6b). A solution of 5b (580
mg, 2.15 mmol) in MeOH (17.9 mL) was treated dropwise with 3
M HCl (630 µL, 17.2 mmol), then heated to reflux for 1 h. Water
(20 mL) was added and the solution was extracted with EtOAc (3
× 20 mL). Combined organic fractions were washed with saturated
aqueous NaCl, dried (Na2SO4), and concentrated to afford 6b as a
red amorphous solid (387 mg, 99%). 1H NMR (CDCl3, 500 MHz)
δ 6.51 (d, J ) 8.7 Hz, 1H), 6.21 (d, J ) 8.6 Hz, 1H), 5.74 (s, 1H),
4.36 (s, 1H), 3.87-3.85 (m, 2H), 2.09 (s, 3H), 1.75-1.71 (m, 2H),
0.96 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 147.5,
143.8, 139.0, 109.8, 108.4, 103.8, 70.2, 21.6, 9.5, 7.3; IR (film)
νmax 3520, 3360, 2966, 2880, 2359, 2341, 1636, 1236, 1068, 785,
1
EtOAc) to afford 5a as a yellow oil (353 mg, 53%): H NMR
(CDCl3, 500 MHz) δ 6.74 (d, J ) 9.0 Hz, 1H), 6.60 (d, J ) 9.0
Hz, 1H), 5.10 (s, 2H), 5.05 (s, 2H), 3.78 (q, J ) 7.1 Hz, 2H), 3.72
(s, 3H), 3.67 (q, J ) 7.1 Hz, 2H), 2.14 (s, 3H), 1.18-1.15 (m,
6H); 13C NMR (CDCl3, 125 MHz) δ 149.1, 146.5, 121.7, 109.0,
108.4, 96.2, 93.0, 64.3, 63.1, 55.1, 28.7, 14.2, 14.1, 8.8; IR (film)
750 cm-1
.
νmax 2918, 2359, 1487, 1260, 1248, 1082, 1055, 945, 798 cm-1
;
4-Methoxybenzene-1,3-diol (6c). A solution of 5c (157 mg, 0.53
mmol) in MeOH (4.40 mL) at rt was treated dropwise with 3 M
HCl (1.40 mL, 4.21 mmol), then heated to reflux for 1 h. Water (5
mL) was added and the solution was extracted with EtOAc (3 ×
10 mL). Combined organic fractions were washed with saturated
aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford
6c as a red amorphous solid (95 mg, 99%): 1H NMR (CDCl3, 500
MHz) δ 6.54 (d, J ) 8.7 Hz, 1H), 6.21 (d, J ) 8.7 Hz, 1H), 5.78
(s, 1H), 4.37-4.32 (m, 1H), 2.09 (s, 3H), 1.25 (d, J ) 6.1 Hz,
6H); 13C NMR (CDCl3, 125 MHz) δ 147.7, 144.9, 137.5, 110.8,
HRMS (ESI+) m/z [M + Na]+ calcd for C14H22O5 293.1365, found
293.1357.
1,3-Bis(methoxymethoxy)-2-methyl-4-propoxybenzene (5b). A
solution of 4b (165 mg, 0.64 mmol) in anhydrous THF (520 µL)
was added dropwise to a solution of nBuLi (2.5 M in hexanes, 390
µL, 0.97 mmol) in anhydrous THF (420 µL) at rt. After 1 h, the
solution was cooled to -78 °C and methyl iodide (160 µL, 2.58
mmol) was added. The resulting solution was warmed to rt over
12 h, and the reaction was quenched by the addition of saturated
J. Org. Chem. Vol. 73, No. 22, 2008 8909

Donnelly et al.
109.8, 104.0, 71.7, 21.3 (2C); IR (film) νmax 3526, 2974, 2924,
2853, 1717, 1607, 1475, 1238, 1113, 1067, 928, 887, 791 cm-1
2-Benzyl-1,3-bis(methoxymethoxy)benzene (13). A solution of
12 (500 mg, 2.52 mmol) in anhydrous THF (2.02 mL) was added
dropwise to a solution of nBuLi (2.5 M in hexanes, 1.51 mL, 3.78
mmol) in anhydrous THF (1.65 mL) at rt. After 1 h, the solution
was cooled to -40 °C and benzyl bromide (1.22 mL, 10.10 mmol)
was added. The resulting solution was warmed to rt over 12 h, and
the reaction was quenched by the addition of saturated aqueous
NH4Cl. Water (5 mL) was added and the solution was extracted
with CH2Cl2 (3 × 10 mL). Combined organic fractions were dried
(Na2SO4), filtered, and concentrated. The residue was purified via
column chromatography (SiO2, 4:1; hexane:EtOAc) to afford 13
.
1-Methoxy-3,5-bis(methoxymethoxy)benzene (8). N,N-Diisopro-
pylethylamine (3.15 mL, 18.1 mmol) was added to 5-methoxyben-
zene-1,3-diol (634 mg, 4.52 mmol) in anhydrous N,N-dimethyl-
formamide (12.6 mL) over 5 min at rt. After 30 min, the solution
was cooled to 0 °C, methoxy methylchoride (3.02 mL, 18.1 mmol)
was added, and the solution was warmed to rt over 12 h. The
reaction was quenched by the addition of saturated aqueous
NaHCO3 at 0 °C and extracted with EtOAc (3 × 10 mL). Combined
organic fractions were washed with saturated aqueous NaCl, dried
(Na2SO4), filtered, and concentrated. The residue was purified via
column chromatography (SiO2, 6:1f 4:1 hexane:EtOAc) to afford
1
as a yellow oil (214 mg, 30%): H NMR (CDCl3, 500 MHz) δ
7.17 (d, J ) 7.9 Hz, 2H), 7.17-7.12 (m, 2H), 7.06-7.02 (m, 2H),
6.71 (d, J ) 8.3 Hz, 2H), 5.09 (s, 4H), 4.00 (s, 2H), 3.29 (s, 6H);
13C NMR (CDCl3, 125 MHz) δ 155.9 (2C), 141.6, 128.5 (2C), 128.0
(2C), 127.5, 125.4, 119.4, 107.7 (2C), 94.3 (2C), 56.0 (2C), 29.1;
IR (film) νmax 2953, 2930, 1595, 1470, 1452, 1254, 1153, 1097,
1043, 941, 922, 727, 698 cm-1; HRMS (ESI+) m/z [M + Na]+
calcd for C17H20O4 311.1259, found 311.1201.
1
8 as a yellow amorphous solid (441 mg, 43%): H NMR (CDCl3,
500 MHz) δ 6.29 (t, J ) 2.2 Hz, 1H), 6.21 (d, J ) 2.2 Hz, 2H),
5.07 (s, 4H), 3.69 (s, 3H), 3.40 (s, 6H); 13C NMR (CDCl3, 125
MHz) δ 161.394, 159.0 (2C), 97.2, 96.2 (2C), 94.5 (2C), 56.1, 55.4
(2C); IR (film) νmax 2997, 2955, 2903, 2827, 1601, 1475, 1400,
1215, 1194, 1146, 1032, 991, 924, 829, 685 cm-1; HRMS (ESI+)
m/z [M + Na]+ calcd for C11H16O5 251.0895, found 251.0910.
5-Methoxy-1,3-bis(methoxymethoxy)-2-methylbenzene (9). A
solution of 8 (441 mg, 1.93 mmol) in anhydrous THF (1.55 mL)
was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.16
mL, 2.90 mmol) in anhydrous THF (1.26 mL) at rt. After 1 h, the
solution was cooled to -78 °C and methyl iodide (480 µL, 7.73
mmol) was added. The resulting solution was warmed to rt over
12 h, and the reaction was quenched by the addition of saturated
aqueous NH4Cl. Water (5 mL) was added and the solution was
extracted with CH2Cl2 (3 × 10 mL). Combined organic fractions
were dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 6:1 f 4:1; hexane:
EtOAc) to afford 9 as a yellow oil (314 mg, 67%): 1H NMR
(CDCl3, 500 MHz) δ 6.38 (d, J ) 2.2 Hz, 1H), 6.24 (d, J ) 2.1
Hz, 1H), 5.08 (d, J ) 3.6 Hz, 2H), 5.06 (d, J ) 2.6 Hz, 2H), 3.72
(s, 3H), 3.40 (s, 6H), 1.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
160.3, 157.8, 155.4, 108.2, 93.9, 93.8, 93.7, 92.9, 55.0, 55.0, 54.6,
7.0; IR (film) νmax 2953, 2934, 2905, 1597, 1497, 1396, 1215, 1144,
1126, 1074, 1059, 1028, 922, 822 cm-1; HRMS (ESI+) m/z [M +
H]+ calcd for C12H18O5 243.1233, found 243.1223.
5-Methoxy-2-methylbenzene-1,3-diol (10). A solution of 9 (314
mg, 1.30 mmol) in MeOH (10.8 mL) at rt was treated dropwise
with 3 M HCl (3.46 mL, 10.3 mmol), then heated to reflux for 1 h.
Water (11 mL) was added and the solution was extracted with
EtOAc (3 × 15 mL). Combined organic fractions were washed
with saturated aqueous NaCl, dried (Na2SO4), filtered, and con-
centrated to afford 10 as a red amorphous solid (177 mg, 99%):
1H NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 6.09 (d, J ) 1.6 Hz,
1H), 6.04 (s, 1H), 3.67 (d, J ) 9.9 Hz, 3H), 2.08 (d, J ) 4.1 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 160.3, 157.8, 155.4, 108.4,
93.9, 93.8, 55.0, 7.0; IR (film) νmax 3445, 2924, 2853, 2359, 2332,
1653, 1636, 1456, 1080, 1022, 798, 669 cm-1; HRMS (ESI+) m/z
[2 M + H]+ calcd for C8H10O3 309.1338, found 309.1332.
1,3-Bis(methoxymethoxy)benzene (12).64 Sodium hydride (872
mg, 36.3 mmol) was added to resorcinol (1.00 g, 9.08 mmol) in
anhydrous N,N-dimethylformamide (25.4 mL) at 0 °C. After 30
min, methoxy methylchloride (2.76 mL, 36.3 mmol) was added
and the resulting solution was warmed to rt over 12 h. The reaction
was cooled to 0 °C, quenched by the addition of saturated aqueous
NaHCO3, and extracted with EtOAc (3 × 30 mL). Combined
organic fractions were washed with saturated aqueous NaCl, dried
(Na2SO4), filtered, and concentrated. The residue was purified via
column chromatography (SiO2, 4:1 hexane:EtOAc) to afford 12 as
a yellow oil (1.75 g, 97%): 1H NMR (CDCl3, 400 MHz) δ
7.25-7.20 (m, 1H), 6.80 (d, J ) 2.3 Hz, 1H), 6.75 (dd, J ) 8.2,
2.4 Hz, 2H), 5.20 (s, 4H), 3.51 (s, 6H).
2-Benzylbenzene-1,3-diol (14).65 A solution of 13(214 mg, 0.74
mmol) in MeOH (6.20 mL) was treated dropwise with 3 M HCl
(0.22 mL, 5.92 mmol), then heated to reflux for 1 h. Water (10
mL) was added and the solution was extracted with EtOAc (3 ×
15 mL). Combined organic fractions were washed with saturated
aqueous NaCl, dried (Na2SO4), and concentrated to afford 14 as a
red amorphous solid (149 mg, 99%). 1H NMR (CDCl3, 400 MHz)
δ 7.31 (d, J ) 6.6 Hz, 4H), 7.25-7.19 (m, 1H), 7.01 (t, J ) 8.1
Hz, 1H), 6.44 (d, J ) 8.1 Hz, 2H), 4.82 (s, 2H), 4.09 (s, 2H).
2-Iodo-1,3-bis(methoxymethoxy)benzene (15). n-Butyllithium
(2.5 M in hexanes, 0.22 mL, 0.56 mmol) was added to a solution
of 12 (100 mg, 0.50 mmol) in anhydrous THF (790 µL) at 0 °C.
After 5 min, iodine (141 mg, 0.56 mmol) in anhydrous THF (320
µL) was added. After 2 h at rt, the reaction was quenched via
dropwise addition of MeOH and the solvent was concentrated.
Water (5 mL) was added and the solution was extracted with EtOAc
(3 × 10 mL). Combined organic fractions were washed with
saturated aqueous Na2S2O3 and saturated aqueous NaCl, dried
(Na2SO4), filtered, and concentrated to afford 15 as a brown oil
(129 mg, 79%): 1H NMR (CDCl3, 100 MHz) δ 7.25-7.18 (m, 1H),
6.79-6.71 (m, 2H), 5.27 (s, 2H), 5.18 (s, 2H), 3.54 (s, 3H), 3.50
(s, 3H); IR (film) νmax 2953, 2924, 2853, 1458, 1377 cm-1
.
2,6-Bis(methoxymethoxy)biphenyl (16). Anhydrous toluene (2.0
mL) was added to a flask charged with Pd2(dba)3 (56.3 mg, 0.062
mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (50.5
mg, 0.12 mmol), phenylboronic acid (281 mg, 2.31 mmol), and
potassium phosphate (979 mg, 4.61 mmol) at rt. After 15 min, a
solution of 15 (500 mg, 1.54 mmol) in anhydrous toluene (1.0 mL)
was added and the resulting solution was heated to reflux for 12 h.
Upon cooling to rt, ether was added and the solution was filtered
through SiO2 and concentrated to give 16 as a colorless amorphous
1
solid (418 mg, 99%): H NMR (CDCl3, 500 MHz) δ 7.35-7.28
(m, 2H), 7.28-7.25 (m, 2H), 7.18-7.15 (m, 2H), 6.83 (d, J ) 8.3
Hz, 2H), 4.96 (s, 4H), 3.24 (s, 6H); 13C NMR (CDCl3, 125 MHz)
δ 155.3, 155.0, 134.3, 130.8, 129.5, 128.7, 128.0, 127.6, 126.8,
122.6, 109.4 (2C), 94.9 (2C), 56.0 (2C); IR (film) νmax 2955, 2928,
2901, 2359, 2341, 1587, 1466, 1439, 1400, 1244, 1153, 1099, 1080,
1041, 922, 764, 733, 700 cm-1; HRMS (ESI+) m/z [M + Na]+
calcd for C16H18O4 297.1103, found 297.1052.
Biphenyl-2,6-diol (17).66 A solution of 16(400 mg, 1.46 mmol)
in MeOH (12.0 mL) at rt was treated dropwise with 3 M HCl (430
µL, 11.7 mmol), then heated to reflux for 1 h. Water (15 mL) was
added and the solution was extracted with EtOAc (3 × 20 mL).
Combined organic fractions were washed with saturated aqueous
NaCl, dried (Na2SO4), filtered, and concentrated to afford 17 as an
1
orange amorphous solid (269 mg, 99%): H NMR (CDCl3, 400
(64) Akritopoulou-Zanze, I.; Patel, J. R.; Hartandi, K.; Brenneman, J.; Winn,
M.; Pratt, J. K.; Grynfarb, M.; Goos-Nisson, A.; von Geldern, T. W.; Kym,
P. R. Bioorg. Med. Chem. Lett. 2004, 14, 2079–2082.
(65) Klarmann, E. J. Am. Chem. Soc. 1926, 48, 791–794.
(66) Greig, L. M.; Slawin, A. M. Z.; Smith, M. H.; Philp, D. Tetrahedron
2007, 63, 2391–2403.
8910 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
MHz) δ 7.60 (d, J ) 7.6 Hz, 2H), 7.53-7.49 (m, 1H), 7.46-7.44
(m, 2H), 7.18 (t, J ) 8.2 Hz, 1H), 6.62 (d, J ) 8.2 Hz, 2H), 4.84
(s, 1H), 4.83 (s, 1H).
Benzyl 7-Hydroxy-5-methoxy-8-methyl-2-oxo-2H-chromen-3-
ylcarbamate (23d). A solution of 10 (251 mg, 1.63 mmol) and
eneamine 22 (680 mg, 2.44 mmol) in glacial acetic acid (10.2 mL)
was heated to reflux for 40 h. Upon cooling to rt, the solution was
extracted with EtOAc (3 × 15 mL); combined organic fractions
were dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 40:1 f 20:1; CH2Cl2:
acetone) to afford 23d as a yellow amorphous solid (204 mg, 35%):
1H NMR (CD2Cl2, 400 MHz) δ 8.48 (s, 1H), 7.46-7.38 (m, 6H),
6.38 (s, 1H), 5.25 (s, 2H), 5.15 (s, 1H), 3.87 (s, 3H), 2.23 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 159.1, 155.8, 154.3, 153.2, 149.8,
137.0, 128.7, 128.6, 128.6, 128.2, 128.2, 109.3, 109.0, 108.5, 105.6,
96.9, 70.8, 60.2, 7.3; IR (film) νmax 3406, 2935, 2837, 1713, 1670,
2-Methoxybenzene-1,3-diol (19).67 Lithium carbonate (281 mg,
1.98 mmol) was added to pyrogallol (100 mg, 0.79 mmol) in N,N-
dimethylformamide (3.0 mL) at rt. After 5 min, methyl iodide (130
µL, 1.98 mmol) was added and the resulting solution was heated
to 50 °C for 48 h. Upon cooling to rt, water (20 mL) was added
and the solution was extracted with EtOAc (3 × 20 mL). Combined
organic fractions were dried (Na2SO4), filtered, and concentrated.
The residue was purified via column chromatography (SiO2, 5:1
f 1:1 hexane:EtOAc) to afford 19 as a colorless amorphous solid
(44.2 mg, 34%): 1H NMR (CDCl3, 400 MHz) δ 6.89 (td, J ) 8.0,
0.9 Hz, 1H), 6.53 (dd, J ) 8.2, 0.8 Hz, 2H), 5.83 (br s, 2H), 3.90
(s, 3H).
1607, 1529, 1501, 1364, 1242, 1101, 1051, 991, 966, 735 cm-1
;
HRMS (ESI+) m/z [M + Na]+ calcd for C19H17NO6 378.0954,
found 378.0974.
Benzyl 7-Hydroxy-6-methoxy-8-methyl-2-oxo-2H-chromen-3-
ylcarbamate (23a). A solution of 6a (183 mg, 1.19 mmol) and
eneamine 22 (331 mg, 1.19 mmol) in glacial acetic acid (7.40 mL)
was heated to reflux for 40 h. Upon cooling to rt, the solution was
extracted with EtOAc (3 × 20 mL); combined organic fractions
were dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 100:1 CH2Cl2:acetone)
to afford 23a as a yellow amorphous solid (195 mg, 46%): 1H NMR
(CDCl3, 400 MHz) δ 8.27 (s, 1H), 7.54 (s, 1H), 7.43-7.37 (m,
4H), 6.77 (s, 1H), 6.07 (s, 1H), 5.25 (s, 2H), 3.96 (s, 3H), 2.37 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 159.0, 153.3 (2C), 145.7,
144.1, 144.0, 135.7, 128.7, 128.5, 128.2 (2C), 122.5, 121.6, 112.1,
111.6, 104.5, 67.4, 56.3, 8.2; IR (film) νmax 2910, 2359, 2339, 1693,
1537, 1354, 1209, 1078, 1024 cm-1; HRMS (ESI+) m/z [M + Na]+
calcd for C19H17NO6 378.0954, found 378.0936.
Benzyl 8-Benzyl-7-hydroxy-2-oxo-2H-chromen-3-ylcarbamate
(23e). A solution of 14 (115 mg, 0.57 mmol) and eneamine 22 (160
mg, 0.57 mmol) in glacial acetic acid (4.00 mL) was heated to
reflux for 40 h. Upon cooling to rt, the solution was extracted with
EtOAc (3 × 10 mL); combined organic fractions were dried
(Na2SO4), filtered, and concentrated. The residue was purified via
column chromatography (SiO2, 100:1; CH2Cl2:acetone), followed
by recrystallization from MeOH to afford 23e as an orange
1
amorphous solid (296 mg, 48%): H NMR (CD2Cl2, 400 MHz) δ
8.29 (s, 1H), 7.53 (s, 1H), 7.46-7.38 (m, 4H), 7.37-7.27 (m, 4H),
7.23-7.19 (m, 2H), 7.01 (t, J ) 8.1 Hz, 1H), 6.86 (d, J ) 8.4 Hz,
1H), 6.46 (d, J ) 8.1 Hz, 1H), 5.25 (s, 2H), 4.25 (s, 2H), 4.06 (s,
1H); 13C NMR (CDCl3, 125 MHz) δ 157.7, 154.3, 153.9, 152.2,
148.0, 137.9, 134.5, 127.6, 127.6, 127.6, 127.6, 127.5, 127.3, 127.2,
127.4, 126.6, 125.4, 125.3, 121.4, 120.4, 114.0, 112.6, 66.5, 27.5;
IR (film) νmax 3381, 2957, 2928, 2359, 2341, 1693, 1607, 1526,
1466, 1454, 1383, 1366, 1219, 1204, 1076, 1045, 764, 737, 700
cm-1; HRMS (ESI+) m/z [M + H]+ calcd for C24H19NO5 402.1341,
found 402.1341.
Benzyl 7-Hydroxy-8-methyl-2-oxo-6-propoxy-2H-chromen-3-
ylcarbamate (23b). A solution of 6b (390 mg, 2.14 mmol) and
eneamine 22 (596 mg, 2.14 mmol) in glacial acetic acid (13.4 mL)
was heated to reflux for 36 h. Upon cooling to rt, the precipitated
yellow solid was collected by filtration, washed with water,
recrystallized from MeOH/water, and extracted with EtOAc (3 ×
20 mL). Combined organic fractions were washed with saturated
aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The
residue was purified via column chromatography (SiO2, 100:1
CH2Cl2:acetone) and recrystallized from MeOH/water to afford 23b
Benzyl 7-Hydroxy-2-oxo-8-phenyl-2H-chromen-3-ylcarbamate
(23f). A solution of 17 (400 mg, 2.15 mmol) and eneamine 22 (598
mg, 2.15 mmol) in glacial acetic acid (14.3 mL) was heated to
reflux for 40 h. Upon cooling to rt, the solution was extracted with
EtOAc (3 × 30 mL); combined organic fractions were dried
(Na2SO4), filtered, and concentrated. The residue was purified via
column chromatography (SiO2, 100:1; CH2Cl2:acetone), then
recrystallized from MeOH to afford 23f as an orange amorphous
solid (264 mg, 27%): 1H NMR (CDCl3, 500 MHz) δ 8.25 (s, 1H),
7.51-7.48 (m, 2H), 7.43-7.40 (m, 2H), 7.35-7.29 (m, 8H), 6.94
(d, J ) 8.6 Hz, 1H), 5.16 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ
158.5 (2C), 154.3, 153.2, 147.7, 135.6, 130.9, 130.6, 130.5, 129.8,
129.4, 129.2 (2C), 128.7 (2C), 128.6, 128.3, 127.8, 122.2, 121.6,
113.3, 113.5, 67.5; IR (film) νmax 3398, 2957, 2926, 2854, 1815,
1699, 1601, 1524, 1383, 1366, 1308, 1215, 1045, 1009, 764, 750,
698 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for C23H17NO5
388.1185, found 388.1214.
1
as a yellow amorphous solid (278 mg, 34%): H NMR (CD2Cl2,
400 MHz) δ 8.26 (s, 1H), 7.56 (s, 1H), 7.47-7.38 (m, 5H), 6.84
(s, 1H), 6.28 (s, 1H), 5.25 (s, 2H), 4.09 (t, J ) 6.6 Hz, 2H), 2.36
(s, 3H), 1.93-1.88 (m, 2H), 1.10 (t, J ) 7.4 Hz, 3H); 13C NMR
(CDCl3, 125 MHz) δ 158.0, 152.2, 144.9, 142.9, 142.3, 134.6,
129.0, 127.6, 127.5 (2C), 127.2 (2C), 121.5, 120.5, 110.9, 110.5,
104.4, 69.8, 66.3, 21.4, 9.4, 7.1; IR (film) νmax 2957, 2920, 2851,
2359, 2341, 1693, 1537, 1358, 1277, 1080, 1024, 910 cm-1; HRMS
(ESI+) m/z [M + H]+ calcd for C21H21NO6 384.1447, found
384.1447.
Benzyl 7-Hydroxy-6-isopropoxy-8-methyl-2-oxo-2H-chromen-
3-ylcarbamate (23c). A solution of 6c (142 mg, 0.78 mmol) and
eneamine 22 (217 mg, 0.78 mmol) in glacial acetic acid (4.90 mL)
was heated to reflux for 40 h. Upon cooling to rt, the solution was
extracted with EtOAc (3 × 10 mL); combined organic fractions
were dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 40:1 CH2Cl2:acetone)
to afford 23c as a yellow amorphous solid (159 mg, 53%): 1H NMR
(CD2Cl2, 400 MHz) δ 8.26 (s, 1H), 7.56 (s, 1H), 7.44-7.38 (m,
5H), 6.85 (s, 1H), 6.31 (s, 1H), 5.25 (s, 2H), 4.66 (quintet, J ) 6.1
Hz, 1H), 2.35 (s, 3H), 1.42 (d, J ) 6.0 Hz, 6H); 13C NMR (CDCl3,
125 MHz) δ 159.1, 154.9, 146.7, 143.9 (2C), 142.0, 135.7, 128.7
(2C), 128.5 128.2 (2C), 122.6 (2C), 111.6, 107.0, 72.3, 67.4, 22.1
(2C), 8.2; IR (film) νmax 3400, 2924, 2853, 2359, 1817, 1699, 1524,
1412, 1354, 1300, 1221, 1204, 1113, 1076, 1022, 824 cm-1; HRMS
(ESI+) m/z [M + H]+ calcd for C21H21NO6 384.1447, found
384.1452.
Benzyl 7-Hydroxy-8-methoxy-2-oxo-2H-chromen-3-ylcarba-
mate (23g). A solution of 19 (1.10 g, 7.86 mmol) and eneamine 22
(2.18 g, 7.86 mmol) in glacial acetic acid (60.0 mL) was heated to
reflux for 90 h. Upon cooling to rt, the solution was extracted with
EtOAc (3 × 50 mL); combined organic fractions were washed with
saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated.
The residue was purified via column chromatography (SiO2, 11:1;
hexane:EtOAc f EtOAc) then recrystallized from MeOH/water
1
to afford 23g as a colorless amorphous solid (207 mg, 7.7%): H
NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 7.50 (s, 1H), 7.43-7.36
(m, 5H), 7.13 (d, J ) 8.6 Hz, 1H), 6.97 (d, J ) 7.9 Hz, 1H), 6.04
(s, 1H), 5.21 (s, 2H), 4.13 (s, 3H); 13C NMR (acetone-d6, 100 MHz)
δ 157.3, 153.3, 151.5 (2C), 144.1, 136.5, 134.4, 128.4 (2C), 128.1,
128.0 (2C), 122.7, 121.6, 113.6, 113.2, 66.7, 60.7; IR (film) νmax
2920, 2851, 2405, 2357, 1707, 1605, 1522, 1458, 1385, 1364, 1275,
1259, 1213, 1088, 1047, 750 cm-1; HRMS (ESI+) m/z [M + Na]+
calcd for C18H15NO6 364.0797, found 364.0776.
(67) Green, K. J. Org. Chem. 1991, 56, 4325–4326.
J. Org. Chem. Vol. 73, No. 22, 2008 8911

Donnelly et al.
Benzyl 8-Ethyl-7-hydroxy-2-oxo-2H-chromen-3-ylcarbamate
(23h). A solution of 21 (1.40 g, 10.1 mmol) and eneamine 22 (2.80
g, 10.1 mmol) in glacial acetic acid (50.0 mL) was heated to reflux
for 12 h. Upon cooling to rt, the solvent was concentrated. The
residue was purified via column chromatography (SiO2, 4:1 f 2:1;
hexane:EtOAc), then recrystallized from acetone/hexanes to afford
23h as a colorless amorphous solid (600 mg, 17%). 1H NMR
(DMSO-d6, 400 MHz) δ 9.07 (s, 1H), 8.12 (s, 1H), 7.46-7.32 (m,
6H), 6.86 (d, J ) 8.4 Hz, 1H), 5.18 (s, 2H), 2.72 (q, J ) 7.6 Hz,
2H), 1.11 (t, J ) 7.6 Hz, 3H); 13C NMR (DMSO-d6, 125 MHz) δ
158.0, 157.1, 153.8 (2C), 149.5, 136.4, 128.4 (2C), 127.9, 127.8,
127.2, 125.8, 120.4, 116.6, 112.8, 111.4, 66.1, 15.7, 13.5; IR (film)
1H), 7.35 (s, 1H), 7.34-7.33 (m, 4H), 6.74 (s, 1H), 5.54 (dd, J )
9.2, 1.2 Hz, 1H), 5.16 (s, 2H), 4.87-4.84 (m, 1H), 4.73 (dd, J )
7.9, 1.9 Hz, 1H), 4.51 (quintet, J ) 6.0 Hz, 1H), 3.52 (s, 3H), 3.28
(d, J ) 4.8 Hz, 1H), 2.33 (s, 3H), 1.80-1.77 (m, 6H), 1.30 (s,
3H), 1.27 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 161.6, 158.6,
153.2 153.1, 147.1, 146.8, 142.5, 135.5, 128.7, 128.6, 128.3, 123.3,
121.4, 121.1, 116.2, 108.6, 99.4, 83.1, 79.9, 76.1, 74.7, 72.2, 68.0,
60.5, 27.1, 25.6, 21.9, 21.6, 21.0, 10.1; IR (film) νmax 2955, 2922,
2853, 2359, 2339, 1819, 1711, 1520, 1464, 1375, 1171, 1111, 1034,
962, 822, 766 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for
C30H33NO11 584.2132, found 584.2111.
Benzyl 5-Methoxy-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-
2-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-
2-oxo-2H-chromen-3-ylcarbamate (25d). Boron trifluoride etherate
(18.5 µL, 0.15 mmol) was added to 23d (174 mg, 0.49 mmol) and
(3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-
[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (621 mg,
1.71 mmol) in anhydrous CH2Cl2 (11.0 mL). After stirring at rt for
14 h, triethylamine (150 µL) was added and the solvent was
concentrated. The residue was purified via column chromatography
(SiO2, 40:1 CH2Cl2:acetone) to give 25d as a colorless foam (200
mg, 74%): 1H NMR (CDCl3, 500 MHz) δ 8.49 (s, 1H), 7.34-7.27
(m, 5H), 6.67 (s, 1H), 6.60 (s, 1H), 5.69 (s, 2H), 5.16 (d, J ) 5.3
Hz, 1H), 4.89 (t, J ) 7.8 Hz, 1H), 4.63 (dd, J ) 7.9, 2.4 Hz, 1H),
3.83 (s, 3H), 3.37 (s, 3H), 3.15 (d, J ) 8.0 Hz, 1H), 2.16 (s, 3H),
2.16 (s, 3H), 2.12 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.9,
156.0, 155.2, 154.2, 153.1 (2C), 149.4, 135.7, 128.7 (2C), 128.5,
128.2 (2C), 120.8, 117.4, 106.6, 105.4, 94.6, 94.1, 82.9, 67.4, 60.6,
60.6, 56.1, 56.0, 22.2, 22.0, 7.9; IR (film) νmax 2955, 2924, 2853,
1817, 1713, 1526, 1209, 1105, 1072, 1034, 976, 808 cm-1; HRMS
(ESI+) m/z [M + H]+ calcd for C28H29NO11 556.1819, found
556.1826.
νmax 3391, 3339, 2964, 2870, 2357, 1732, 1682, 1620, 1524, 1506,
1454, 1364, 1277, 1188, 1097, 1024, 752, 698 cm-1; HRMS (ESI+)
m/z [M + H]+ calcd for C19H17NO5 340.1185, found 340.1181.
Benzyl 6-Methoxy-7-((3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-
2-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-
2-oxo-2H-chromen-3-ylcarbamate (25a). Boron trifluoride etherate
(5.30 µL, 0.042 mmol) was added to 23a (50.0 mg, 0.14 mmol)
and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-
3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (171
mg, 0.47 mmol) in anhydrous CH2Cl2 (3.00 mL). After stirring at
rt for 14 h, triethylamine (150 µL) was added and the solvent was
concentrated. The residue was purified via column chromatography
(SiO2, 40:1 CH2Cl2:acetone) to give 25a as a colorless foam (74.0
1
mg, 95%): H NMR (CD2Cl2, 400 MHz) δ 8.29 (s, 1H), 7.64 (s,
1H), 7.47-7.39 (m, 5H), 6.91 (s, 1H), 5.52 (d, J ) 3.4 Hz, 1H),
5.26 (s, 2H), 5.23 (dd, J ) 8.4, 3.5 Hz, 1H), 4.95 (t, J ) 8.2 Hz,
1H), 3.92 (s, 3H), 3.60 (s, 3H), 3.33 (d, J ) 8.0 Hz, 1H), 2.42 (s,
3H), 1.38 (s, 3H), 1.33 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
157.6, 152.7, 152.1, 148.1, 144.8, 141.8, 134.5, 127.8, 127.7, 127.5,
127.3, 122.3, 120.2, 119.8, 115.1. 109.6, 105.2, 98.3, 82.0, 77.1,
66.5, 65.5, 59.4, 57.4, 55.1, 26.0, 20.9, 8.9; IR (film) νmax 2957,
2928, 2854, 2359, 2341, 1817, 1709, 1522, 1464, 1389, 1371, 1205,
1174, 1111, 1072, 1034, 957, 800 cm-1; HRMS (ESI+) m/z [M +
H]+ calcd for C28H29NO11 556.1819, found 556.1822.
Benzyl 8-Benzyl-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-
2-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2-oxo-2H-
chromen-3-ylcarbamate (25e). Boron trifluoride etherate (7.80 µL,
0.062 mmol) was added to 23e (80.0 mg, 0.21 mmol) and
(3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-
[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (299 mg,
0.83 mmol) in anhydrous CH2Cl2 (5.20 mL). After stirring at rt for
48 h, triethylamine (150 µL) was added and the solvent was
concentrated. The residue was purified via column chromatography
(SiO2, 40:1 CH2Cl2:acetone) to give 25e as a colorless foam (47.0
Benzyl 7-((3aR,4S,7R,7aR)-7-Methoxy-6,6-dimethyl-2-oxotet-
rahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2-oxo-6-
propoxy-2H-chromen-3-ylcarbamate (25b). Boron trifluoride ether-
ate (16.7 µL, 0.13 mmol) was added to 23b (170 mg, 0.44 mmol)
and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-
3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (643
mg, 1.77 mmol) in anhydrous CH2Cl2 (11.1 mL). After stirring at
rt for 48 h, triethylamine (150 µL) was added and the solvent was
concentrated. The residue was purified via column chromatography
(SiO2, 100:1 f 40:1 CH2Cl2:acetone) to give 25b as a colorless
foam (246 mg, 95%): 1H NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H),
7.35-7.27 (m, 5H), 6.84 (s, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 4.99
(d, J ) 7.5 Hz, 1H), 4.59 (d, J ) 9.7 Hz, 1H), 4.23 (d, J ) 9.6 Hz,
1H), 3.97 (t, J ) 6.6 Hz, 1H), 3.82-3.75 (m, 2H), 3.37 (s, 3H),
1.84-1.79 (m, 2H), 1.51 (s, 3H), 1.41 (s, 3H), 1.18 (s, 3H), 1.00
(t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.8, 154.3,
152.2, 151.8, 146.7, 144.2, 142.9, 134.6, 127.8, 127.6, 127.5, 127.5,
127.2, 121.0, 120.9, 111.1, 105.3, 101.7, 91.6, 85.7, 82.8, 80.0,
69.8, 58.1, 54.8, 28.3, 28.2, 22.4, 21.3, 9.4; IR (film) νmax 2961,
2939, 2906, 2359, 2341, 1811, 1757, 1726, 1522, 1445, 1371, 1267,
1175, 1113, 1086, 825, 768 cm-1; HRMS (ESI+) m/z [M + Na]+
calcd for C30H33NO11 606.1952, found 606.1950.
1
mg, 39%): H NMR (CDCl3, 500 MHz) δ 8.22 (s, 1H), 7.46 (s,
1H), 7.35-7.27 (m, 5H), 7.17-7.06 (m, 5H), 6.86 (d, J ) 10 Hz,
1H), 6.01 (d, J ) 10 Hz, 1H), 5.65 (d, J ) 1.6 Hz, 1H), 5.23 (s,
2H), 5.16 (s, 2H), 4.77-4.70 (m, 1H), 4.10 (s, 1H), 3.50 (s, 3H),
3.28 (s, 1H), 3.16 (d, J ) 7.4 Hz, 1H), 1.25 (s, 3H), 1.18 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 155.1, 153.2 (2C), 153.1, 148.6
(2C), 139.6 (2C), 128.7, 128.6 (2C), 128.4 (2C), 128.3 (2C), 128.3
(2C), 126.5, 126.2, 123.1, 122.4, 121.7, 117.6, 114.9, 111.5, 94.7,
82.8, 67.6, 60.6 (2C), 29.7, 27.6, 21.9; IR (film) νmax 2926, 2854,
2359, 2341, 1811, 1709, 1607, 1522, 1456, 1381, 1366, 1259, 1209,
1171, 1078, 1049, 968, 766, 700 cm-1; HRMS (ESI+) m/z [M +
H]+ calcd for C33H31NO10 602.2026, found 602.2053.
Benzyl 7-((3aR,4R,7R,7aR)-7-Methoxy-6,6-dimethyl-2-oxotet-
rahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2-oxo-8-phenyl-2H-
chromen-3-ylcarbamate (25f). Boron trifluoride etherate (14.6 µL,
0.12mmol)wasaddedto23f(155mg,0.39mmol)and(3aR,4S,7R,7aR)-
7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-
c]pyran-4-yl 2,2,2-trichloroacetimidate (560 mg, 1.55 mmol) in
anhydrous CH2Cl2(9.70 mL). After stirring at rt for 48 h,
triethylamine (150 µL) was added and the solvent was concen-
trated. The residue was purified via column chromatography
(SiO2, 100:1 f 40:1 CH2Cl2:acetone) to give 25f as a colorless
Benzyl 6-Isopropoxy-7-((3aR,4S,7R,7aR)-7-methoxy-6,6-dimeth-
yl-2-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-meth-
yl-2-oxo-2H-chromen-3-ylcarbamate (25c). Boron trifluoride ether-
ate (1.30 µL, 0.010 mmol) was added to 23c (13.0 mg, 0.034 mmol)
and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-
3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (83.0
mg, 0.23 mmol) in anhydrous CH2Cl2 (1.30 mL). After stirring at
rt for 1.5 h, triethylamine (150 µL) was added and the solvent was
concentrated. The residue was purified via column chromatography
(SiO2, 40:1 CH2Cl2:acetone) to give 25c as a colorless foam (19.0
1
foam (225 mg, 99%): H NMR (CD2Cl2, 400 MHz) δ 8.37 (s,
1H), 7.75-7.73 (m, 2H), 7.60-7.36 (m, 10H), 7.32 (d, J ) 8.8
Hz, 1H), 5.77 (d, J ) 1.7 Hz, 1H), 5.26 (s, 2H), 4.76-4.68 (m,
1H), 4.36-4.28 (m, 1H), 3.56 (s, 3H), 3.28 (d, J ) 7.2 Hz,
1H), 1.37 (s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
1
mg, 95%): H NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 7.51 (s,
8912 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
157.2, 153.0 (2C), 152.1 (2C), 152.1, 134.4, 129.9, 129.8, 129.4,
127.7 (2C), 127.5, 127.2 (2C), 127.1 (2C), 127.0, 126.3, 121.5
(2C), 120.3, 111.2 (2C), 93.9, 81.9, 66.5, 59.4 (3C), 20.9 (2C);
IR (film) νmax 3400, 2959, 2926, 2853, 2359, 2341, 1819, 1715,
1601, 1522, 1381, 1366, 1261, 1215, 1173, 1111, 1059, 970,
800, 700 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for
C32H29NO10 588.1870, found 588.1846.
raphy (SiO2, 20:1; CH2Cl2:MeOH) to afford 26a as a colorless
amorphous solid (2.00 mg, 20%, 5% over 3 steps): 1H NMR
(CDCl3, 500 MHz) δ 8.73 (s, 1H), 8.70 (d, J ) 5.4 Hz, 1H), 7.84
(td, J ) 6.2, 2.4 Hz, 1H), 7.82 (s, 1H), 7.30 (t, J ) 8.0 Hz, 1H),
7.06 (d, J ) 7.8 Hz, 1H), 7.03-7.00 (m, 2H), 6.88-6.86 (m, 1H),
6.81 (s, 1H), 4.99 (d, J ) 6.6 Hz, 1H), 4.24 (t, J ) 4.2 Hz, 1H),
4.00 (dd, J ) 6.5, 3.7 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.83 (s,
3H), 3.80 (d, J ) 7.4 Hz, 1H), 3.45 (s, 3H), 3.08 (d, J ) 4.7 Hz,
1H), 2.67 (s, 1H), 2.42 (s, 3H), 1.28 (d, J ) 8.1 Hz, 3H), 1.18 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 164.6, 158.9, 158.3, 158.2,
148.2, 145.6, 142.5, 137.5, 130.1, 129.0, 128.2, 127.2, 124.9, 122.5,
122.2, 121.2, 121.0, 115.1, 144.2, 112.1, 110.0, 105.4, 101.3, 81.7,
76.8, 69.0, 68.0, 59.1, 55.3, 54.9, 54.3, 28.3, 28.2, 9.1; IR (film)
Benzyl 8-Methoxy-7-((3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-
2-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2-oxo-2H-
chromen-3-ylcarbamate (25g). Boron trifluoride etherate (17.3 µL,
0.14mmol)wasaddedto23g(157mg,0.46mmol)and(3aR,4S,7R,7aR)-
7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-
c]pyran-4-yl 2,2,2-trichloroacetimidate (665 mg, 1.83 mmol) in
anhydrous CH2Cl2 (11.5 mL). After stirring at rt for 24 h,
triethylamine (150 µL) was added and the solvent was concentrated.
The residue was purified via column chromatography (SiO2, 40:1
f 10:1 CH2Cl2:acetone) to give 25g as a colorless foam (237 mg,
ν
max 2961, 2928, 1713, 1670, 1601, 1464, 1383, 1261, 1094, 1022,
798, 700 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for C34H37NO11
636.2445, found 636.2477.
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-6-propoxy-2H-chromen-
3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26b). Palladium on
carbon (10%, 85.0 mg) was added to 25b (425 mg, 0.7283 mmol)
in anhydrous THF (4.90 mL) and the solution was placed under an
atmosphere of H2. After 6.5 h, the solution was filtered through
SiO2 (1:1 CH2Cl2:acetone) and the eluent was concentrated to afford
a yellow solid, which was used without further purification (325
mg, 99%).
EDCI (116 mg, 0.60 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (125 mg, 0.4821 mmol) were added to the amine
(108 mg, 0.2410 mmol) in 30% pyridine/CH2Cl2 (6.70 mL). After
12 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 3:1 hexane:ether f 20:1
CH2Cl2:acetone) to afford a colorless solid, which was used without
further purification (51.0 mg, 31%).
1
95%): H NMR (CDCl3, 500 MHz) δ 8.20 (s, 1H), 7.48 (s, 1H),
7.33-7.29 (m, 5H), 7.09 (dd, J ) 14.2, 8.8 Hz, 2H), 5.72 (d, J )
1.8 Hz, 1H), 5.16 (s, 2H), 5.02 (dd, J ) 7.8, 1.8 Hz, 1H), 4.89 (t,
J ) 7.8 Hz, 1H), 3.88 (s, 3H), 3.52 (s, 3H), 3.21 (d, J ) 7.8 Hz,
1H), 1.27 (s, 3H), 1.17 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
158.0, 153.3, 153.2, 153.1, 149.8, 143.8, 137.1, 135.5, 128.7 (2C),
128.6, 128.3 (2C), 122.7, 122.2, 121.4, 116.1, 113.7, 95.3, 74.7,
72.9, 67.6, 61.9, 60.7, 60.6, 29.7, 29.4; IR (film) νmax 3400, 3319,
2984, 2935, 2359, 1815, 1715, 1609, 1526, 1464, 1383, 1364, 1285,
1213, 1175, 1111, 1063, 968, 764, 737, 700 cm-1; HRMS (ESI+)
m/z [M + Na]+ calcd for C27H27NO11 564.1482, found 564.1455.
Benzyl 8-Ethyl-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-
2-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2-oxo-
2H-chromen-3-ylcarbamate (25h). Boron trifluoride etherate (19.0
µL, 0.15 mmol) was added to 23h (171 mg, 0.51 mmol) and
(3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-
[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (183 mg,
0.51 mmol) in anhydrous CH2Cl2 (11.0 mL). After stirring at rt for
24 h, triethylamine (150 µL) was added and the solvent was
concentrated. The residue was purified via column chromatography
(SiO2, 40:1 CH2Cl2:acetone) to give 25h as a colorless foam (138
Triethylamine (150 µL) was added to the carbonate (51.0 mg,
0.074 mmol) in MeOH (2.50 mL). After 48 h, the solvent was
concentrated and the residue was purified via column chromatog-
raphy (SiO2, 40:1 CH2Cl2:acetone) to afford 26b as a colorless
amorphous solid (22.8 mg, 47%, 14% over 3 steps): 1H NMR
(CD2Cl2, 400 MHz) δ 8.79 (s, 1H), 8.78 (s, 1H), 7.96 (dd, J ) 8.6,
2.4 Hz, 1H), 7.91 (d, J ) 2.4 Hz, 1H), 7.39 (t, J ) 7.9 Hz, 1H),
7.16-7.11 (m, 2H), 6.97-6.94 (m, 2H), 5.97 (s, 1H), 5.14 (d, J )
6.5 Hz, 1H), 4.31 (t, J ) 3.5 Hz, 1H), 4.12-4.06 (m, 2H), 4.03
(dd, J ) 6.8, 1.8 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.65 (s, 1H),
3.53 (s, 3H), 3.17 (d, J ) 4.8 Hz, 1H), 2.80 (s, 1H), 2.48 (s, 3H),
1.95-1.90 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.11 (t, J ) 7.4 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 165.0, 164.6, 158.8, 158.3,
147.7, 145.7, 142.3, 137.8, 137.5, 131.3, 129.0, 128.2, 127.2, 124.9,
122.3, 121.2, 121.0, 115.111, 114.2, 112.1, 110.0, 106.2, 101.1,
81.7, 70.0, 69.0, 68.0, 64.8, 59.1, 54.9, 54.3, 24.7, 24.0, 21.3, 9.5,
9.1; IR (film) νmax 3398, 3196, 2964, 2935, 2359, 2330, 1705, 1580,
1
mg, 51%): H NMR (CD2Cl2, 400 MHz) δ 8.29 (s, 1H), 7.62 (s,
1H), 7.47-7.38 (m, 5H), 7.36 (d, J ) 8.8 Hz, 1H), 7.19 (d, J )
8.4 Hz, 1H), 5.81 (d, J ) 2.4 Hz, 1H), 5.25 (s, 2H), 5.10 (dd, J )
8.0, 2.0 Hz, 1H), 5.02 (t, J ) 7.8 Hz, 1H), 3.55 (s, 3H), 3.41 (d, J
) 7.2 Hz, 1H), 2.87 (q, J ) 7.4 Hz, 2H), 1.42 (s. 3H), 1.28 (s,
3H), 1.21 (t, J ) 7.4 Hz, 3H); 13C NMR (CD2Cl2, 100 MHz) δ
158.5, 154.8, 153.2, 153.1, 148.4, 136.0, 128.6 (2C), 128.4, 128.1,
125.6, 122.4, 121.5, 120.7, 114.8, 111.4, 94.8, 82.7, 77.9, 77.2,
76.6, 67.3, 60.3, 27.3, 22.3, 16.4, 13.6; IR (film) νmax 3400, 2980,
2937, 2359, 2339, 1817, 1711, 1607, 1524, 1383, 1366, 1227, 1205,
1175, 1101, 1040, 906, 768, 737, 700 cm-1; [M + Na]+ calcd for
C28H29NO10 562.1689, found 562.1689.
1526, 1504, 1381, 1242, 1124, 1094, 939, 808, 760, 735 cm-1
;
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-
3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26a). Palladium on
carbon (10%, 20.0 mg) was added to 25a (100 mg, 0.18 mmol) in
anhydrous THF (5.00 mL) and the solution was placed under an
atmosphere of H2. After 6.5 h, the solution was filtered through
SiO2 (1:1 CH2Cl2:acetone) and the eluent was concentrated to afford
a yellow solid, which was used without further purification (56.0
mg, 75%).
EDCI (21.4 mg, 0.11 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (23.1 mg, 0.089 mmol) were added to the amine
(18.7 mg, 0.045 mmol) in 30% pyridine/CH2Cl2 (0.70 mL). After
12 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford
a colorless solid, which was used without further purification (10.5
mg, 36%).
HRMS (ESI+) m/z [M + H]+ calcd for C36H41NO11 664.2758, found
664.2754.
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-6-isopropoxy-8-methyl-2-oxo-2H-
chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26c). Pal-
ladium on carbon (10%, 11 mg) was added to 25c (54.5 mg, 0.093
mmol) in anhydrous THF (600 µL) and the solution was placed
under an atmosphere of H2. After 12 h, the solution was filtered
through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated
to afford a yellow solid, which was used without further purification
(42.0 mg, 99%).
EDCI (14.9 mg, 0.078 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (16 mg, 0.062 mmol) were added to the amine (14.0
mg, 0.031 mmol) in 30% pyridine/CH2Cl2 (900 µL). After 12 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 3:1 hexane:ether f 40:1 CH2Cl2:
acetone) to afford a colorless solid, which was used without further
purification (17.5 mg, 82%).
Triethylamine (150 µL) was added to the carbonate (10.4 mg,
0.016 mmol) in MeOH (2.50 mL). After 12 h, the solvent was
concentrated and the residue was purified via column chromatog-
J. Org. Chem. Vol. 73, No. 22, 2008 8913

Donnelly et al.
Triethylamine (150 µL) was added to the carbonate (17.5 mg,
0.025 mmol) in MeOH (2.50 mL) and CH2Cl2 (2.50 mL). After
12 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 10:1 CH2Cl2:acetone) to afford
26c as a colorless amorphous solid (6.0 mg, 35%, 28% over 3 steps):
1H NMR (CD2Cl2, 500 MHz) δ 8.69 (s, 1H), 8.67 (s, 1H), 7.84
(dd, J ) 8.6, 2.4 Hz, 1H), 7.80 (d, J ) 2.4 Hz, 1H), 7.29 (d, J )
8.0 Hz, 1H), 7.25 (t, J ) 7.9 Hz, 1H), 7.03-7.01 (m, 2H), 6.87 (s,
1H), 6.87-6.83 (m, 1H), 4.96 (d, J ) 6.8 Hz, 1H), 4.61-4.56 (m,
1H), 4.19 (t, J ) 4.0 Hz, 1H), 3.89 (dd, J ) 6.8, 3.7 Hz, 1H), 3.82
(s, 3H), 3.76 (s, 3H), 3.75 (s, 1H), 3.41 (s, 3H), 3.34 (s, 1H), 3.03
(d, J ) 4.5 Hz, 1H), 2.36 (s, 3H), 1.33 (t, J ) 6.2 Hz, 6H), 1.25
(s, 3H), 1.23 (s, 3H); 13C NMR (CD2Cl2, 125 MHz) δ 164.6, 159.1,
158.6, 158.3, 146.7, 146.3, 142.5, 138.1, 130.2, 129.1, 128.3, 127.4,
125.2, 122.8, 122.2, 121.2, 121.1, 115.5, 144.5, 112.1, 110.2, 108.4,
101.4, 81.9, 77.0, 71.1, 69.2, 68.3, 59.1, 55.1, 54.5, 28.7, 28.6, 20.8,
20.8, 9.1; IR (film) νmax 2924, 2854, 2359, 2341, 1734, 1684, 1653,
1558, 1541, 1522, 1506, 1458, 1387, 1339, 1286, 1244, 1113, 912,
797 cm-1; HRMS (ESI+) m/z [M + Na]+ calcd for C36H41NO11
686.2578, found 686.2610.
N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-5-methoxy-8-methyl-2-oxo-2H-chromen-
3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26d). Palladium on
carbon (10%, 40 mg) was added to 25d (200 mg, 0.36 mmol) in
anhydrous THF (2.40 mL) and the solution was placed under an
atmosphere of H2. After 12 h, the solution was filtered through
SiO2 (1:1 CH2Cl2:acetone) and the eluent was concentrated to afford
a yellow solid, which was used without further purification (150
mg, 99%).
Triethylamine (150 µL) was added to the carbonate (12.3 mg,
0.017 mmol) in MeOH (1.5 mL) and CH2Cl2 (1.5 mL). After 48 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford 26e
as a colorless amorphous solid (6.00 mg, 51%, 7.1% over 3 steps):
1H NMR (CD2Cl2, 400 MHz) δ 8.84 (s, 1H), 8.72 (s, 1H), 7.96
(dd, J ) 10, 2.4 Hz, 1H), 7.91 (d, J ) 2.4 Hz, 1H), 7.50 (d, J )
8.8 Hz, 1H), 7.39 (t, J ) 7.9 Hz, 1H), 7.31 (d, J ) 8.8 Hz, 1H),
7.28-7.25 (m, 5H), 7.21-7.18 (m, 1H), 7.15-7.11 (m, 2H),
6.97-6.94 (m, 1H), 5.54 (d, J ) 2.7 Hz, 1H), 4.25 (t, J ) 15.1
Hz, 2H), 4.17-4.11 (m, 1H), 4.05 (d, J ) 2.6 Hz, 1H), 3.93 (s,
3H), 3.88 (s, 3H), 3.58 (s, 3H), 3.31 (d, J ) 8.7 Hz, 1H), 2.64 (s,
1H), 2.04 (s, 1H), 1.40 (s, 3H), 1.03 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 165.5, 159.8, 159.3, 159.3, 156.4, 148.9, 140.0 (2C),
138.6, 131.1, 130.0, 129.2, 128.5, 128.3, 128.2, 127.0, 126.2 (2C),
126.0 (2C), 124.1, 122.2, 122.0, 117.2, 115.2, 114.4, 113.2, 111.7,
111.0, 98.0, 70.6 (2C), 68.6, 61.6, 55.9, 55.4, 29.3, 28.9, 28.3; IR
(film) νmax 3404, 2930, 2359, 2341, 1713, 1670, 1605, 1526, 1502,
1367, 1244, 1180, 1134, 1076, 1026, 960 cm-1; HRMS (ESI+) m/z
[M + H]+ calcd for C39H39NO10 682.2652, found 682.2653.
N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-2-oxo-8-phenyl-2H-chromen-3-yl)-3′,6-
dimethoxybiphenyl-3-carboxamide (26f). Palladium on carbon
(10%, 14 mg) was added to 25f (68.0 mg, 0.12 mmol) in anhydrous
THF (800 µL) and the solution was placed under an atmosphere
of H2. After 12 h, the solution was filtered through SiO2 (1:1
CH2Cl2:acetone) and the eluent was concentrated to afford a yellow
solid, which was used without further purification (52.0 mg, 99%).
EDCI (18.5 mg, 0.096 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (19.9 mg, 0.077 mmol) were added to the amine
(17.5 mg, 0.039 mmol) in 30% pyridine/CH2Cl2 (1.10 mL). After
12 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford
a colorless solid, which was used without further purification (14.0
mg, 52%).
Triethylamine (150 µL) was added to the carbonate (14.0 mg,
0.020 mmol) in MeOH (1.5 mL) and CH2Cl2 (1.5 mL). After 48 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford 26f
as a colorless amorphous solid (5.20 mg, 39%, 20% over 3 steps):
1H NMR (CD2Cl2, 500 MHz) δ 8.85 (s, 1H), 8.65 (s, 1H), 7.92 (d,
J ) 2.4 Hz, 1H), 7.90 (d, J ) 2.4 Hz, 1H), 7.86 (d, J ) 2.4 Hz,
1H), 7.57-7.43 (m, 3H), 7.36-7.33 (m, 4H), 7.11-7.06 (m, 3H),
6.92 (d, J ) 0.8 Hz, 1H), 5.52 (d, J ) 2.4 Hz, 1H), 4.08 (q, J )
7.2, Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.74 (dd, J ) 9.0, 3.5 Hz,
1H), 3.50 (s, 3H), 3.23 (d, J ) 9.0 Hz, 1H), 2.12 (s, 1H), 2.00 (s,
1H), 1.33 (s, 3H), 1.04 (s, 3H); 13C NMR (CD2Cl2, 125 MHz) δ
164.5, 159.0 (2C), 158.6, 158.1, 154.4, 147.2, 138.0 (2C), 130.7,
130.1, 129.7, 129.1, 128.7, 128.3, 127.4, 127.2, 127.0, 127.0, 125.2,
122.6, 121.6, 121.1, 118.6, 114.5, 113.8, 112.1, 111.3, 110.2, 97.5,
70.1 (2C), 67.4, 60.8, 55.0, 54.5, 21.9, 21.6; IR (film) νmax 3402,
2932, 2359, 2341, 1713, 1603, 1524, 1500, 1367, 1267, 1086, 1040,
964, 750 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for C38H37NO10
668.2496, found 668.2485.
EDCI (57.5 mg, 0.30 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (62 mg, 0.24 mmol) were added to the amine (50.6
mg, 0.12 mmol) in 30% pyridine/CH2Cl2 (3.30 mL). After 12 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 3:1 hexane:ether f 40:1 f 10:1
CH2Cl2:acetone) to afford a colorless solid, which was used without
further purification (25.2 mg, 32%).
Triethylamine (150 µL) was added to the carbonate (25.2 mg,
0.038 mmol) in MeOH (2.0 mL) and CH2Cl2 (2.0 mL). After 48 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford 26d
as a colorless amorphous solid (17.0 mg, 70%, 22% over 3 steps):
1H NMR (CD2Cl2, 400 MHz) δ 9.02 (s, 1H), 8.97 (s, 1H), 8.66 (s,
1H), 7.96 (dd, J ) 8.6, 2.4 Hz, 1H), 7.91-7.90 (m, 1H), 7.39 (t,
J ) 7.9 Hz, 1H), 7.16-7.11 (m, 2H), 6.96 (dd, J ) 8.3, 2.6 Hz),
6.85 (d, J ) 5.5 Hz, 1H), 5.70 (d, J ) 2.1 Hz, 1H), 4.36-4.33 (m,
1H), 4.27 (m, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.88 (s, 3H), 3.62 (s,
3H), 3.41-3.38 (m, 1H), 2.24 (s, 3H), 1.41 (s, 3H), 1.19 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 164.2, 158.7, 158.6, 158.3, 155.3,
153.5, 148.6, 137.6, 129.9, 128.9, 128.1, 127.1, 125.1, 121.0, 119.4,
118.9, 114.2, 114.2, 112.1, 110.0, 104.9, 103.7, 96.7, 92.9, 83.2,
70.1, 67.5, 60.9, 60.8, 54.8, 54.3, 21.9, 21.4, 6.8; IR (film) νmax
3405, 2986, 2934, 1713, 1609, 1528, 1383, 1250, 1213, 1053, 999,
914, 878, 737 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for
C34H37NO11 636.2445, found 636.2482.
N-(8-Benzyl-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-di-
methyltetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)-3′,6-
dimethoxybiphenyl-3-carboxamide (26e). Palladium on carbon
(10%, 46 mg) was added to 25e (230 mg, 0.38 mmol) in anhydrous
THF (2.50 mL) and the solution was placed under an atmosphere
of H2. After 12 h, the solution was filtered through SiO2 (1:1
CH2Cl2:acetone) and the eluent was concentrated to afford a yellow
solid, which was used without further purification (177 mg, 99%).
EDCI (61.5 mg, 0.32 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (66.3 mg, 0.26 mmol) were added to the amine
(60.0 mg, 0.13 mmol) in 30% pyridine/CH2Cl2 (3.50 mL). After
12 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 3:1 hexane:ether f 20:1
CH2Cl2:acetone) to afford a colorless solid, which was used without
further purification (12.3 mg, 14%).
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-8-methoxy-2-oxo-2H-chromen-3-yl)-
3′,6-dimethoxybiphenyl-3-carboxamide (26g). Palladium on carbon
(10%, 47 mg) was added to 25g (237 mg, 0.44 mmol) in anhydrous
THF (2.93 mL) and the solution was placed under an atmosphere
of H2. After 12 h, the solution was filtered through SiO2 (1:1
CH2Cl2:acetone) and the eluent was concentrated to afford a yellow
solid, which was used without further purification (177 mg, 99%).
EDCI (69.4 mg, 0.36 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (74.8 mg, 0.29 mmol) were added to the amine
(59.0 mg, 0.14 mmol) in 30% pyridine/CH2Cl2 (4.00 mL). After
12 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 3:1 hexane:ether f 40:1
CH2Cl2:acetone) to afford a colorless solid, which was used without
further purification (26.0 mg, 28%).
8914 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
Triethylamine (150 µL) was added to the carbonate (26.0 mg,
0.040 mmol) in MeOH (2.0 mL) and CH2Cl2 (2.0 mL). After 48 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford 26g
as a colorless amorphous solid (15.7 mg, 63%, 18% over 3 steps):
1H NMR (CD2Cl2, 400 MHz) δ 8.82 (s, 1H), 8.73 (s, 1H), 7.96
(dd, J ) 8.6, 2.4 Hz, 1H), 7.91 (d, J ) 2.4 Hz, 1H), 7.39 (t, J )
7.9 Hz, 1H), 7.30 (s, 2H), 7.14 (d, J ) 8.6 Hz, 2H), 7.12 (d, J )
2.2 Hz, 1H), 6.96 (dd, J ) 8.3, 2.5 Hz, 1H), 5.61 (d, J ) 2.4 Hz,
1H), 4.29 (t, J ) 4.0 Hz, 1H), 4.27-4.25 (m, 1H), 3.98 (s, 3H),
3.93 (s, 3H), 3.88 (s, 3H), 3.62 (s, 3H), 3.47 (s, 1H), 3.37 (d, J )
8.8 Hz, 1H), 2.62 (s, 1H), 1.30 (s, 3H), 1.24 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 164.5, 158.8, 158.3, 157.8, 150.2 (2C), 142.9,
137.5, 135.6, 130.0, 128.9, 128.2, 127.2, 127.2, 124.9, 122.8, 121.6,
121.0, 114.3, 114.2, 112.3, 112.1, 110.0, 97.7, 70.0 (2C), 67.5, 60.8
(2C), 54.9, 54.3, 28.7, 28.3; IR (film) νmax 3402, 2961, 2928, 2853,
1713, 1672, 1607, 1526, 1504, 1462, 1367, 1263, 1248, 1086, 1040,
953, 798, 735, 700 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for
C33H35NO11 622.2288, found 622.2307.
N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-8-ethyl-2-oxo-2H-chromen-3-yl)-3′,6-
dimethoxybiphenyl-3-carboxamide (26h). Palladium on carbon
(10%, 12 mg) was added to 25h (121 mg, 0.22 mmol) in anhydrous
THF (5.00 mL) and the solution was placed under an atmosphere
of H2. After 12 h, the solution was filtered through SiO2 (1:1
CH2Cl2:acetone) and the eluent was concentrated to afford a yellow
solid, which was used without further purification (90.0 mg, 99%).
Triethylamine (150 µL) was added to the carbonate (68.0 mg,
0.12 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.50 mL). After 12 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford 26i
as a colorless amorphous solid (12.6 mg, 19%, 16% over 3 steps):
1H NMR (CD2Cl2, 400 MHz) δ 8.29 (s, 1H), 7.63 (s, 1H),
7.45-7.39 (m, 3H), 6.92 (s, 1H), 6.85 (s, 1H), 6.19 (s, 1H), 5.09
(d, J ) 6.5 Hz, 1H), 4.31-4.28 (m, 1H), 4.01-3.97 (m, 1H), 3.94
(s, 3H), 3.62 (s, 1H), 3.56 (s, 3H), 3.15 (d, J ) 4.9 Hz, 1H), 2.46
(s, 3H), 2.36 (s, 1H), 1.38 (d, J ) 11.5 Hz, 3H), 1.32 (s, 3H); 13
C
NMR (CDCl3, 125 MHz) δ 157.6, 152.1, 148.2, 145.4, 142.2, 134.5,
129.9, 127.8, 127.7, 127.5, 127.3, 122.3, 121.2, 120.2, 115.0, 105.3,
105.1, 101.3, 81.7, 69.0, 68.0, 66.5, 59.1, 55.2, 28.7, 24.6, 24.1,
9.1; IR (film) νmax 2926, 1707, 1526, 1464, 1391, 1340, 1296, 1231,
1207, 1086, 1024, 943, 739, 700, 623 cm-1; HRMS (ESI+) m/z
[M + Na]+ calcd for C28H30N2O9 561.1849, found 561.1781.
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-6-propoxy-2H-chromen-
3-yl)-1H-indole-2-carboxamide (26j). Palladium on carbon (10%,
85 mg) was added to 25b (425 mg, 0.729 mmol) in anhydrous
THF (4.90 mL) and the solution was placed under an atmosphere
of H2. After 12 h, the solution was filtered through SiO2 (1:1
CH2Cl2:acetone) and the eluent was concentrated to afford a yellow
solid, which was used without further purification (325 mg, 99%).
EDCI (116 mg, 0.6026 mmol) and 1H-indole-2-carboxylic acid
(77.7 mg, 0.4821 mmol) were added to the amine (108 mg, 0.2410
mmol) in 30% pyridine/CH2Cl2 (6.70 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 3:1 hexane:ether f 40:1 CH2Cl2:acetone) to
afford a colorless solid, which was used without further purification
(91.0 mg, 64%).
EDCI (46.2 mg, 0.24 mmol) and 3′,6-dimethoxybiphenyl-3-
carboxylic acid (43.9 mg, 0.19 mmol) were added to the amine
(39.0 mg, 0.096 mmol) in 30% pyridine/CH2Cl2 (2.65 mL). After
12 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford
a colorless solid, which was used without further purification (39.1
mg, 66%).
Triethylamine (150 µL) was added to the carbonate (91.0 mg,
0.1536 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.50 mL). After
48 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford
26j as a colorless amorphous solid (17.5 mg, 20%, 13% over 3
Triethylamine (150 µL) was added to the carbonate (13.0 mg,
0.020 mmol) in MeOH (1.5 mL). After 12 h, the solvent was
concentrated and the residue was purified via column chromatog-
raphy (SiO2, 40:1 CH2Cl2:acetone) to afford 26h as a colorless
amorphous solid (4.10 mg, 33%, 22% over 3 steps): 1H NMR
(CD2Cl2, 500 MHz) δ 8.70 (s, 1H), 8.61 (s, 1H), 7.83 (dd, J ) 8.5,
2.5 Hz, 1H), 7.78 (d, J ) 2.5 Hz, 1H), 7.31 (d, J ) 9.0 Hz, 1H),
7.27 (t, J ) 7.8 Hz, 1H), 7.17 (d, J ) 8.5 Hz, 1H), 7.03-6.99 (m,
3H), 6.85-6.82 (m, 1H), 5.49 (d, J ) 1.5 Hz, 1H), 4.15 (t, J ) 8.5
Hz, 1H), 4.14 (d, J ) 8.5 Hz, 1H), 3.90 (s, 2H), 3.87 (s, 3H), 3.81
(s, 3H), 3.28 (s, 3H), 3.27 (d, J ) 8.5 Hz, 1H), 2.76 (q, J ) 4.5
Hz, 2H), 1.29 (s, 3H), 1.09 (t, J ) 7.4 Hz, 3H), 1.08 (s, 3H); 13C
NMR (CD2Cl2, 125 MHz) δ 164.5, 159.0, 158.6, 158.5, 155.1,
147.9, 138.1, 130.1, 129.1, 128.3, 127.4, 125.4, 125.2, 123.1, 121.4,
121.2, 119.4, 114.5, 113.5, 112.1, 110.8, 110.2, 97.6, 83.4, 77.7,
70.6, 67.8, 61.0, 55.1, 54.5, 28.2, 21.6, 15.6, 12.9; IR (film) νmax
3404, 2968, 2934, 2359, 2341, 1715, 1605, 1524, 1504, 1367, 1244,
1101, 1024, 995, 960, 800 cm-1; HRMS (ESI+) m/z [M + H]+
calcd for C34H37NO10 620.2496, found 620.2507.
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-
3-yl)-1H-indole-2-carboxamide (26i). Palladium on carbon (10%,
15 mg) was added to 25a (74.0 mg, 0.13 mmol) in anhydrous THF
(5.00 mL) and the solution was placed under an atmosphere of H2.
After 12 h, the solution was filtered through SiO2 (1:1 CH2Cl2:
acetone) and the eluent was concentrated to afford a yellow solid,
which was used without further purification (60.0 mg, 99%).
1
steps): H NMR (CD2Cl2, 400 MHz) δ 9.32 (s, 1H), 8.80 (s, 1H),
8.76 (s, 1H), 7.77 (d, J ) 8.0 Hz, 1H), 7.53 (d, J ) 7.5 Hz, 1H),
7.40-7.36 (m, 1H), 7.24-7.20 (m, 1H), 6.98 (s, 1H), 6.01 (s, 1H),
5.15 (d, J ) 6.5 Hz, 1H), 4.32-4.25 (m, 1H), 4.11-4.04 (m, 1H),
3.62-3.59 (m, 2H), 3.53 (s, 3H), 3.18-3.12 (m, 1H), 2.64 (s, 1H),
2.49 (s, 3H), 2.18 (s, 1H), 1.95-1.91 (m, 2H), 1.36 (d, J ) 9.6
Hz, 3H), 1.29 (d, J ) 9.8 Hz, 3H), 1.12 (t, J ) 7.4 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) δ 160.1, 159.0, 148.8, 146.9, 143.4, 136.9,
129.8, 127.6, 125.5, 123.5, 123.0, 122.6, 122.3, 121.2, 116.0, 112.0,
107.3, 104.3, 102.2, 82.8, 71.0, 70.1, 69.1, 60.2, 59.7, 25.7, 23.1,
23.4, 10.5, 10.2; IR (film) νmax 3630, 3304, 2926, 2854, 2359, 2332,
1713, 1705, 1539, 1387, 1240, 1103, 947, 930, 822, 739 cm-1
;
HRMS (ESI+) m/z [M + H]+ calcd for C30H34N2O9 567.2342, found
567.2367.
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-6-isopropoxy-8-methyl-2-oxo-2H-
chromen-3-yl)-1H-indole-2-carboxamide (26k). Palladium on car-
bon (10%, 4 mg) was added to 25c (19.0 mg, 0.033 mmol) in
anhydrous THF (220 µL) and the solution was placed under an
atmosphere of H2. After 12 h, the solution was filtered through
SiO2 (1:1 CH2Cl2:acetone) and the eluent was concentrated to afford
a yellow solid, which was used without further purification (14.5
mg, 99%).
EDCI (15.6 mg, 0.081 mmol) and 1H-indole-2-carboxylic acid
(10.5 mg, 0.065 mmol) were added to the amine (14.5 mg, 0.033
mmol) in 30% pyridine/CH2Cl2 (1.00 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 40:1 CH2Cl2:acetone) to afford a colorless solid,
which was used without further purification (10.0 mg, 50%).
Triethylamine (150 µL) was added to the carbonate (10.0 mg,
0.017 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.50 mL). After 12 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 10:1 CH2Cl2:acetone) to afford 26k
EDCI (69.0 mg, 0.36 mmol) and 1H-indole-2-carboxylic acid
(46.4 mg, 0.29 mmol) were added to the amine (60.0 mg, 0.14
mmol) in 30% pyridine/CH2Cl2 (3.50 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 3:1 hexane:ether f 40:1 CH2Cl2:acetone) to
afford a colorless solid, which was used without further purification
(68.0 mg, 85%).
J. Org. Chem. Vol. 73, No. 22, 2008 8915

Donnelly et al.
as a colorless amorphous solid (6.00 mg, 46%, 23% over 3 steps):
1H NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 7.52 (s, 1H), 7.34-7.30
(m, 5H), 6.75 (s, 1H), 4.93 (d, J ) 5.0 Hz, 1H), 4.56-4.51 (m,
1H), 4.23 (t, J ) 4.0 Hz, 1H), 3.98-3.96 (m, 1H), 3.76 (s, 1H),
3.43 (s, 3H), 3.06 (d, J ) 4.3 Hz, 1H), 2.65 (s, 1H), 2.38 (s, 3H),
1.33 (dd, J ) 11.2, 6.1 Hz, 6H), 1.29 (s, 3H), 1.27 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 157.6, 152.1, 146.6, 146.0, 142.1, 134.5,
127.7, 127.5, 127.2, 122.2, 121.3 (2C), 120.2 (2C), 115.0 (2C),
108.1 (2C), 101.2, 81.6, 71.2, 68.9, 68.1, 66.5, 59.0, 24.8, 23.6,
20.8 (2C), 9.1; IR (film) νmax 3406, 2930, 2375, 1705, 1522, 1394,
1229, 1205, 1111, 1078, 1049, 933, 793, 739, 698 cm-1; HRMS
(ESI+) m/z [M + Na]+ calcd for C30H34N2O9 589.2162, found
589.2111.
1H), 2.21 (s, 1H), 1.25 (s, 3H), 0.95 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 166.8, 155.4, 153.8, 140.2, 131.6, 130.2, 128.0, 127.6,
127.5 (2C), 127.4 (2C), 126.9, 125.1 (2C), 115.2, 108.3 (2C), 105.8
(2C), 97.1 (2C), 83.3 (2C), 77.2, 70.2, 67.9 (2C), 65.0, 60.6, 21.9,
13.1, 13.0; IR (film) νmax 3333, 2961, 2926, 2854, 1717, 1601, 1466,
1261, 1090, 1076, 1041, 800, 750 cm-1; HRMS (ESI+) m/z [M +
Na]+ calcd for C33H32N2O8 607.2056, found 607.2056.
N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-2-oxo-8-phenyl-2H-chromen-3-yl)-1H-
indole-2-carboxamide (26n). Palladium on carbon (10%, 14 mg)
was added to 25f (68.0 mg, 0.12 mmol) in anhydrous THF (800
µL) and the solution was placed under an atmosphere of H2. After
12 h, the solution was filtered through SiO2 (1:1 CH2Cl2:acetone)
and the eluent was concentrated to afford a yellow solid, which
was used without further purification (52.0 mg, 99%).
N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-5-methoxy-8-methyl-2-oxo-2H-chromen-
3-yl)-1H-indole-2-carboxamide (26l). Palladium on carbon (10%,
40 mg) was added to 25d (200 mg, 0.36 mmol) in anhydrous THF
(2.40 mL) and the solution was placed under an atmosphere of H2.
After 12 h, the solution was filtered through SiO2 (1:1 CH2Cl2:
acetone) and the eluent was concentrated to afford a yellow solid,
which was used without further purification (150 mg, 99%).
EDCI (57.5 mg, 0.30 mmol) and 1H-indole-2-carboxylic acid
(38.7 mg, 0.24 mmol) were added to the amine (50.6 mg, 0.12
mmol) in 30% pyridine/CH2Cl2 (3.30 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 40:1 CH2Cl2:acetone) to afford a colorless solid,
which was used without further purification (26.3 mg, 39%).
Triethylamine (150 µL) was added to the carbonate (26.3 mg,
0.047 mmol) in MeOH (2.00 mL) and CH2Cl2 (2.00 mL). After
48 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford
26l as a colorless amorphous solid (6.60 mg, 26%, 10% over 3
EDCI (18.5 mg, 0.096 mmol) and 1H-indole-2-carboxylic acid
(12.4 mg, 0.077 mmol) were added to the amine (17.5 mg, 0.039
mmol) in 30% pyridine/CH2Cl2 (1.10 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 40:1 CH2Cl2:acetone) to afford a colorless solid,
which was used without further purification (8.20 mg, 36%).
Triethylamine (150 µL) was added to the carbonate (8.2 mg,
0.014 mmol) in MeOH (1.00 mL) and CH2Cl2 (1.00 mL). After
48 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford
26n as a colorless amorphous solid (4.00 mg, 51%, 18% over 3
1
steps): H NMR (CD2Cl2, 500 MHz) δ 9.23 (s, 1H), 8.80 (s, 1H),
8.67 (s, 1H), 7.71 (dd, J ) 8.0, 0.7 Hz, 1H), 7.57 (d, J ) 8.8 Hz,
1H), 7.51-7.48 (m, 3H), 7.46-7.44 (m, 1H), 7.37-7.32 (m, 4H),
7.19-7.17 (m, 2H), 5.53 (d, J ) 2.4 Hz, 1H), 3.86 (s, 1H),
3.76-3.73 (m, 2H), 3.51 (s, 3H), 3.23 (d, J ) 9.1 Hz, 1H), 2.41
(s, 1H), 1.34 (s, 3H), 1.05 (s, 3H); 13C NMR (CD2Cl2, 125 MHz)
δ 159.1, 157.9, 154.5, 147.3, 136.0 (2C), 130.7 (2C), 129.8, 129.2,.
127.3, 127.1, 127.0, 126.9, 124.5, 122.8, 121.6, 121.2, 120.3, 113.7,
111.4, 111.1, 103.1 (2C), 97.5, 83.2, 77.7, 70.1, 67.5, 60.8, 21.9,
21.7; IR (film) νmax 3427, 2961, 2924, 2853, 2062, 1643, 1614,
1537, 1362, 1236, 1094, 1041, 962, 791, 739, 698 cm-1; HRMS
(ESI+) m/z [M + Na]+ calcd for C32H30N2O8 593.1900, found
593.1890.
1
steps): H NMR (CD2Cl2, 400 MHz) δ 9.26 (s, 1H), 8.96 (s, 1H),
8.68 (s, 1H), 7.74 (d, J ) 8.1 Hz, 1H), 7.52 (d, J ) 8.3 Hz, 1H),
7.38-7.34 (m, 1H), 7.22-7.16 (m, 1H), 6.84 (s, 1H), 6.00 (s, 1H),
5.65 (d, J ) 1.7 Hz, 1H), 4.26-4.21 (m, 2H), 3.96 (s, 3H), 3.59
(s, 3H), 3.35 (d, J ) 8.6 Hz, 1H), 2.25 (s, 3H), 1.53 (s, 3H), 1.20
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 165.1, 157.4, 156.5, 149.7,
136.7, 134.7, 127.7, 125.3, 122.5, 121.1, 120.0, 111.9, 104.6, 103.8,
97.7, 94.0, 84.3, 84.2, 82.6, 69.6, 69.1, 66.1, 62.2, 62.0, 59.7, 23.1,
22.7, 14.2; IR (film) νmax 3389, 2924, 2853, 1697, 1605, 1535, 1460,
1340, 1211, 1101, 1088, 962, 729 cm-1; HRMS (ESI+) m/z [M +
H]+ calcd for C28H30N2O9 539.2030, found 539.2056.
N-(7-((2S,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-8-methoxy-2-oxo-2H-chromen-3-yl)-
1H-indole-2-carboxamide (26o). Palladium on carbon (10%, 47 mg)
was added to 25g (237 mg, 0.44 mmol) in anhydrous THF (2.93
mL) and the solution was placed under an atmosphere of H2. After
12 h, the solution was filtered through SiO2 (1:1 CH2Cl2:acetone)
and the eluent was concentrated to afford a yellow solid, which
was used without further purification (177 mg, 99%).
EDCI (69.4 mg, 0.36 mmol) and 1H-indole-2-carboxylic acid
(46.7 mg, 0.29 mmol) were added to the amine (59.0 mg, 0.14
mmol) in 30% pyridine/CH2Cl2 (4.00 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 3:1 hexane:ether f 40:1 CH2Cl2:acetone) to
afford a colorless solid, which was used without further purification
(32.0 mg, 49%).
N-(8-Benzyl-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-di-
methyltetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)-1H-
indole-2-carboxamide (26m). Palladium on carbon (10%, 46 mg)
was added to 25e (230 mg, 0.38 mmol) in anhydrous THF (2.50
mL) and the solution was placed under an atmosphere of H2. After
12 h, the solution was filtered through SiO2 (1:1 CH2Cl2:acetone)
and the eluent was concentrated to afford a yellow solid, which
was used without further purification (177 mg, 99%).
EDCI (61.5 mg, 0.32 mmol) and 1H-indole-2-carboxylic acid
(41.4 mg, 0.26 mmol) were added to the amine (60.0 mg, 0.13
mmol) in 30% pyridine/CH2Cl2 (3.50 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 3:1 hexane:ether f 40:1 CH2Cl2:acetone) to
afford a yellow solid, which was used without further purification
(66.2 mg, 85%).
Triethylamine (150 µL) was added to the carbonate (66.2 mg,
0.11 mmol) in MeOH (2.50 mL) and CH2Cl2 (2.50 mL). After 12 h,
the solvent was concentrated and the residue was purified via
column chromatography (SiO2, 40:1 CH2Cl2:acetone) to afford 26m
as a colorless amorphous solid (6.50 mg, 10%, 8.4% over 3 steps):
1H NMR (CD2Cl2, 500 MHz) δ 8.68 (s, 1H), 8.62 (s, 1H),
7.63-7.61 (m, 1H), 7.47 (dd, J ) 5.7, 3.3 Hz, 1H), 7.16-7.10 (m,
4H), 7.10-7.04 (m, 4H), 6.99 (t, J ) 8.2 Hz, 1H), 6.74 (d, J ) 8.0
Hz, 1H), 6.43 (dd, J ) 8.1, 0.7 Hz, 1H), 5.31 (d, J ) 2.9 Hz, 1H),
4.17 (t, J ) 6.8 Hz, 1H), 4.01 (dd, J ) 8.5, 2.9 Hz, 1H), 3.90 (d,
J ) 13.1 Hz, 2H), 3.45 (s, 3H), 3.16 (d, J ) 8.6 Hz, 1H), 2.43 (s,
Triethylamine (150 µL) was added to the carbonate (32.0 mg,
0.071 mmol) in MeOH (2.00 mL) and CH2Cl2 (2.00 mL). After
48 h, the solvent was concentrated and the residue was purified
via column chromatography (SiO2, 3:1 CH2Cl2:acetone) to afford
26o as a colorless amorphous solid (22.1 mg, 73%, 35% over 3
1
steps): H NMR (CD2Cl2, 400 MHz) δ 9.28 (s, 1H), 8.78 (s, 1H),
7.77 (d, J ) 8.1 Hz, 1H), 7.53 (dd, J ) 8.3, 0.8 Hz, 1H), 7.38 (m,
1H), 7.31 (s, 2H), 7.24 (d, J ) 0.9 Hz, 1H), 7.22-7.20 (m, 1H),
6.02 (s, 1H), 5.62 (d, J ) 2.3 Hz, 1H), 4.25 (t, J ) 3.5 Hz, 1H),
3.99 (s, 3H), 3.75 (dd, J ) 9.0, 3.6 Hz, 1H), 3.62 (s, 3H), 3.13 (d,
J ) 3.6 Hz, 1H), 1.30 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 163.8, 159.1, 157.7, 150.6, 143.3, 136.0, 135.8, 129.2,
126.9, 124.6, 122.8, 121.8, 121.6, 121.4, 120.3, 114.4, 112.5, 111.2,
103.1, 98.0, 83.2, 77.9, 74.0, 60.9, 58.7, 22.3, 21.8; IR (film) νmax
3420, 2957, 2924, 2854, 2359, 1653, 1558, 1541, 1246, 1001, 798
8916 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
cm-1; HRMS (ESI+) m/z [M + H]+ calcd for C27H28N2O9 525.1873,
found 525.1875.
(997 mg, 24.93 mmol) was added. After 15 min, BnBr (1.20 mL,
1.73 g, 10.09 mmol) was added and the reaction was warmed to rt
over 18 h. Reaction contents were partitioned between saturated
aqueous NaHCO3 (500 mL) and EtOAc (500 mL), then extracted
with EtOAc (3 × 500 mL). The combined organic layers were
washed with water (3 × 1 L) and saturated aqueous NaCl solution
(1 L), dried (Na2SO4), filtered, and concentrated. The residue was
purified via column chromatography (SiO2, 9:1 hexanes:EtOAc)
to give 30 as a light orange solid containing >80% 3-bromo isomer
(1.70 g, 88%), which was used without further purification.
4-Methoxybenzylamine (1.77 mL, 1.87 g, 13.64 mmol) and
anhydrous DMSO (2.90 mL) were added to a high-pressure flask
charged with 30 (1.65 g, 5.26 mmol), K3PO4 (2.36 g, 11.10 mmol),
CuII (167 mg, 0.88 mmol), and L-(-)-proline (141 mg, 1.22 mmol);
the sealed flask was heated to 80 °C for 44 h. After cooling to rt,
reaction contents were partitioned between water (50 mL) and
EtOAc (100 mL), then were extracted with EtOAc (2 × 100 mL).
The combined organic layers were washed with saturated aqueous
NaCl solution (200 mL), dried (Na2SO4), filtered, and concentrated.
The residue was purified via column chromatography (SiO2, 1:1
hexanes:EtOAc) to give 31 as a light yellow amorphous solid (1.43
g, 73%): 1H NMR (CDCl3, 500 MHz) δ 8.44 (d, J ) 2.8 Hz, 1H),
7.52 (d, J ) 8.9 Hz, 1H), 7.50 (m, 2H), 7.43-7.38 (m, 3H),
7.36-7.32 (m, 3H), 7.20 (dd, J ) 8.9, 2.6 Hz, 1H), 7.06 (d, J )
2.7 Hz, 1H), 6.91 (m, 2H), 5.17 (s, 2H), 4.35 (d, J ) 4.8 Hz, 2H),
4.17 (br t, J ) 4.8 Hz, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 159.3, 156.9, 143.4, 143.3, 140.5, 137.0, 130.6, 129.1 (2C),
128.8 (2C), 128.2, 127.9 (2C), 127.3, 124.7, 120.4, 114.4 (2C),
112.0, 109.0, 70.3, 55.5, 48.0; IR (film) νmax 3279, 2953, 2833,
1609, 1510, 1377, 1354, 1302, 1225, 1175, 1124, 1028, 995, 868,
818, 762, 708 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for
C24H22N2O2 371.1759, found 371.1732.
N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)-8-ethyl-2-oxo-2H-chromen-3-yl)-1H-
indole-2-carboxamide (26p). Palladium on carbon (10%, 12 mg)
was added to 25h (121 mg, 0.22 mmol) in anhydrous THF (5.00
mL) and the solution was placed under an atmosphere of H2. After
12 h, the solution was filtered through SiO2 (1:1 CH2Cl2:acetone)
and the eluent was concentrated to afford a yellow solid, which
was used without further purification (90.0 mg, 99%).
EDCI (28.3 mg, 0.15 mmol) and 1H-indole-2-carboxylic acid
(19.0 mg, 0.12 mmol) were added to the amine (24.0 mg, 0.059
mmol) in 30% pyridine/CH2Cl2 (1.63 mL). After 12 h, the solvent
was concentrated and the residue was purified via column chro-
matography (SiO2, 40:1 CH2Cl2:acetone) to afford a colorless foam,
which was used without further purification (23.8 mg, 73%).
Triethylamine (150 µL) was added to the carbonate (14.1 mg,
0.026 mmol) in MeOH (1.50 mL). After 12 h, the solvent was
concentrated and the residue was purified via column chromatog-
raphy (SiO2, 40:1 CH2Cl2:acetone) to afford 26p as a yellow
amorphous solid (5.00 mg, 37%, 27% over 3 steps): 1H NMR
(CD2Cl2, 500 MHz) δ 8.65 (s, 1H), 7.62 (d, J ) 8.0 Hz, 1H), 7.41
(d, J ) 8.5 Hz, 1H), 7.33 (d, J ) 8.5 Hz, 1H), 7.23 (t, J ) 7.8 Hz,
1H), 7.20 (d, J ) 8.5 Hz, 2H), 7.13 (s, 2H), 7.07 (t, J ) 7.5 Hz,
1H), 5.46 (d, J ) 2.0 Hz, 1H), 4.07 (dd, J ) 9.3, 3.5 Hz, 1H), 4.04
(t, J ) 3.5 Hz, 1H), 3.51 (s, 3H), 3.25 (d, J ) 7.2 Hz, 1H), 2.78
(q, J ) 7.0 Hz, 2H), 1.27 (s, 3H), 1.10 (t, J ) 7.5 Hz, 3H), 1.06
(s, 3H); 13C NMR (CD2Cl2, 125 MHz) δ 158.4, 157.3, 154.2, 146.8,
135.3, 128.1, 125.5, 124.0, 123.0, 123.0, 122.8, 120.1, 119.5, 118.7,
118.2, 112.0, 110.1, 109.7, 102.4, 97.0, 82.1, 76.5, 69.3, 66.4, 26.7,
20.3, 14.3, 11.4; IR (film) νmax 3435, 3416, 2974, 2935, 2469, 2359,
2339, 1715, 1651, 1520, 1456, 1435, 1379, 1354, 1259, 1180, 1113,
1088, 1026, 997, 962, 798, 739 cm-1; HRMS (ESI+) m/z [M +
Na]+ calcd for C28H30N2O8 545.1900, found 545.1909.
tert-Butylquinolin-7-yl Carbonate (28). Di-tert-butyl dicarbonate
(7.40 g, 33.92 mmol) and 4-(dimethylamino)pyridine (222 mg, 1.81
mmol) were added in sequence to 7-hydroxyquinoline (2.00 g, 13.75
mmol) in anhydrous N,N-dimethylformamide (20.0 mL) at rt. After
18 h, the reaction was diluted with EtOAc (250 mL). The organic
layer was washed with 1.0 M NaOH (250 mL), water (3 × 250
mL), and saturated aqueous NaCl solution (250 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified via
column chromatography (SiO2, 1:1 hexanes:EtOAc) to give 28 as
a colorless amorphous solid (3.26 g, 97%): 1H NMR (CDCl3, 500
MHz) δ 8.93 (dd, J ) 4.2, 1.7 Hz, 1H), 8.17 (br d, J ) 8.4 Hz,
1H), 7.90 (d, J ) 2.2 Hz, 1H), 7.84 (d, J ) 8.9 Hz, 1H), 7.43 (dd,
J ) 8.8, 2.3 Hz, 1H), 7.40 (dd, J ) 8.3, 4.3 Hz, 1H), 1.60 (s, 9H);
13C NMR (CDCl3, 125 MHz) δ 151.7, 151.7, 148.9, 135.9, 129.0,
126.3, 122.0, 121.0, 120.2, 84.2, 27.8 (3C); IR (film) νmax 1759,
1277, 1240, 1142, 768, 750 cm-1; HRMS (ESI+) m/z [M + H]+
calcd for C14H15NO3 246.1130, found 246.1113.
N-(4-Methoxybenzyl)-N-(7-(benzyloxy)quinolin-3-yl)-4-methoxy-
3-(3-methoxyphenyl)benzamide (32). Thionyl chloride (395 µL, 644
mg, 5.42 mmol) was added to 4-methoxy-3-(3-methoxyphenyl)-
benzoic acid (464 mg, 1.80 mmol) in anhydrous THF (6.10 mL) at
rt and the resulting solution was heated at reflux for 4.5 h. The
solvent was removed and the resulting acid chloride was used
without further purification.
Sodium hydride (93 mg, 2.31 mmol) was added to 31 (508 mg,
1.37 mmol) in anhydrous THF (9.10 mL). After stirring for 2 h at
rt, a solution of the freshly prepared acid chloride (1.80 mmol) in
anhydrous THF (3.00 mL) was added and the reaction was heated
to reflux for 18 h. The reaction was cooled, partitioned between
saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (50 mL), then
extracted with CH2Cl2 (3 × 100 mL). Combined organic extracts
were washed with saturated aqueous NaCl solution (200 mL), dried
(Na2SO4), filtered, and concentrated. The residue was purified via
column chromatography (SiO2, 1:1 EtOAc:hexanes to 2:1 EtOAc:
hexanes) to give 32 as a pale yellow amorphous solid (684 mg,
1
82%): H NMR (CDCl3, 500 MHz) δ 8.35 (d, J ) 2.3 Hz, 1H),
N-(4-Methoxybenzyl)-7-(benzyloxy)quinolin-3-amine (31). Bro-
mine (790 µL, 2.48 g, 15.38 mmol) was added to 28 (3.26 g, 13.30
mmol) in CCl4 (30.0 mL) at rt. This solution was heated to reflux,
anhydrous pyridine (1.20 mL,1.17 g, 14.84 mmol) was added over
10 min, and the solution was stirred at reflux for 18 h. The cooled
reaction was diluted with EtOAc/MeOH (250 mL) and saturated
aqueous NaHCO3 (200 mL), then extracted with EtOAc (4 × 250
mL). Combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified via column chromatography
(SiO2, 4:1 hexanes:EtOAc) to give 29 as a light yellow solid
containing >80% 3-bromo isomer (2.00 g, 46%), which was used
without further purification.
Hydrogen chloride was bubbled through 29 (2.00 g, 6.16 mmol)
in anhydrous MeOH (44.0 mL) for 3 min at rt, then the solution
was stirred at 50 °C for 5 min. The solvent was concentrated and
the residue placed under high vacuum for 6 h to ensure complete
removal of MeOH. The yellow residue was dissolved in anhydrous
N,N-dimethylformamide (44.0 mL) and cooled to 0 °C, then NaH
7.67 (d, J ) 2.4 Hz, 1H), 7.57 (d, J ) 9.0 Hz, 1H), 7.48 (m, 2H),
7.44-7.34 (m, 5H), 7.29 (m, 2H), 7.23 (m, 2H), 7.13 (t, J ) 7.9
Hz, 1H), 6.81 (m, 2H), 6.78 (dd, J ) 2.5, 1.0 Hz, 1H), 6.74 (d, J
) 8.6 Hz, 1H), 6.64 (m,1H), 6.61 (m, 1H), 5.19 (s, 2H), 5.15 (s,
2H), 3.77 (s, 3H), 3.72 (s, 3H), 3.66 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 170.2, 160.2, 159.3, 159.3, 157.9, 150.9, 147.9, 138.9,
136.4, 136.0, 132.6, 132.4, 130.5, 130.2 (2C), 130.1, 129.4, 129.0,
129.0 (2C), 128.5, 127.9 (2C), 127.4, 123.1, 122.1, 121.2, 114.8,
114.2 (2C), 113.3, 110.6, 108.6, 70.5, 55.7, 55.4, 55.3, 53.8; IR
(film) νmax 3032, 3001, 2953, 2935, 2835, 1645, 1603, 1512, 1456,
1429, 1385, 1331, 1248, 1209, 1178, 1034, 1026, 818, 735, 698
cm-1; HRMS (ESI+) m/z [M + H]+ calcd for C39H34N2O5 611.2546,
found 611.2574.
N-(4-Methoxybenzyl)-N-(7-(hydroxy)quinolin-3-yl)-4-methoxy-
3-(3-methoxyphenyl)-benzamide (33). A solution of AlCl3 (44 mg,
0.33 mmol) in anhydrous anisole (150 µL) was added to 32 (43
mg, 0.07 mmol) in anhydrous anisole (150 µL) and the resulting
solution was stirred at rt for 18 h. The reaction was diluted with
J. Org. Chem. Vol. 73, No. 22, 2008 8917

Donnelly et al.
MeOH (150 µL) and the solvent was concentrated. The residue
was purified via column chromatography (SiO2, 80:20:1 EtOAc:
hexanes:MeOH) to give 33 as a yellow amorphous solid in
3H); 13C NMR (CDCl3, 125 MHz) δ 159.1, 154.6, 137.4, 130.7,
129.3 (2C), 128.8 (2C), 128.1, 128.0, 127.8 (2C), 119.4 (2C),
118.6, 114.3 (2C), 107.9, 70.3, 55.5; IR (film) νmax 3734, 1558,
1456, 1259, 1167, 847, 746, 702, 660 cm-1; HRMS (ESI+) m/z
[M + H]+ calcd for C25H23NO2 370.1807, found 370.1786.
N-(4-Methoxybenzyl)-N-(6-(benzyloxy)naphthalen-2-yl)-4-meth-
oxy-3-(3-methoxyphenyl)benzamide (38). Thionyl chloride (308 µL,
502 mg, 4.22 mmol) was added to 4-methoxy-3-(3-methoxyphe-
nyl)benzoic acid (365 mg, 1.41 mmol) in anhydrous THF (4.75
mL) at rt, and the resulting solution was heated at reflux for 4.5 h.
The solvent was removed and the resulting acid chloride was used
without further purification.
1
quantitative yield: H NMR (CDCl3, 500 MHz) δ 8.35 (s, 1H),
7.74 (s, 1H), 7.58 (d, J ) 8.9 Hz, 1H), 7.52 (br s, 1H), 7.37 (m,
1H), 7.31 (m, 1H), 7.25-7.11 (m, 5H), 6.84-6.77 (m, 3H), 6.74
(d, J ) 8.6 Hz, 1H), 6.67 (d, J ) 7.6 Hz, 1H), 6.64 (s, 1H), 5.16
(s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 170.3, 159.4, 159.3, 158.0, 138.8, 135.5, 132.3, 130.4,
130.3, 130.1 (2C), 129.6, 129.1 (2C), 127.1, 123.0, 122.0, 114.9,
114.3 (2C), 113.3, 110.7, 55.8, 55.4, 53.9; IR (film) νmax 2926,
1601, 1506, 1248, 1177, 1030, 818 cm-1; HRMS (ESI+) m/z [M
+ H]+ calcd for C32H28N2O5 521.2076, found 521.2030.
Sodium hydride (85 mg, 2.12 mmol) was added to 37 (378
mg, 1.02 mmol) in anhydrous THF (7.50 mL). After stirring for
2 h at rt, a solution of the freshly prepared acid chloride (1.41
mmol) in anhydrous THF (2.40 mL) was added and the reaction
was heated to reflux for 18 h. The reaction was cooled,
partitioned between saturated aqueous NaHCO3 (50 mL) and
CH2Cl2 (50 mL), then extracted with CH2Cl2 (3 × 100 mL).
Combined organic extracts were washed with saturated aqueous
NaCl solution (200 mL), dried (Na2SO4), filtered, and concen-
trated. The residue was purified via column chromatography
(SiO2, 4:1:1 hexanes:EtOAc:CH2Cl2) to give 38 as a brown-
N-(7-Hydroxyquinolin-3-yl)-4-methoxy-3-(3-methoxyphenyl)-
benzamide (34). Trifluoromethanesulfonic acid (120 µL, 204 mg,
1.36 mmol) was added to 32 (184 mg, 0.30 mmol) in 1:1 CH2Cl2:
TFA (1.36 mL) and the solution was stirred at rt for 2 h. The
resulting solution was diluted with CH2Cl2 (100 mL), washed with
saturated aqueous NaHCO3 (3 × 50 mL) and saturated aqueous
NaCl solution (2 × 50 mL), dried (Na2SO4), filtered, and concen-
trated. The residue was purified via column chromatography (SiO2,
100:1 EtOAc:MeOH to 4:1 EtOAc:MeOH) to give 34 as a yellow
oil (51 mg, 43%): 1H NMR (CD3OD, 500 MHz) δ 9.01 (br s, 1H),
8.61 (br s, 1H), 8.02 (dd, J ) 8.5, 1.7 Hz, 1H), 7.97 (d, J ) 1.9
Hz, 1H), 7.74 (d, J ) 8.9 Hz, 1H), 7.30 (t, J ) 8.2 Hz, 1H), 7.27
(d, J ) 1.9 Hz, 1H), 7.19 (dd, J ) 8.9, 2.1 Hz, 1H), 7.17 (d, J )
8.8 Hz, 1H), 7.11-7.08 (m, 2H), 6.89 (m, 1H), 3.88 (s, 3H), 3.81
(s, 3H); 13C NMR (CD3OD, 125 MHz) δ 168.7, 161.2, 160.9, 160.2,
147.1, 146.2, 140.5, 132.0, 132.0, 131.5, 130.4, 130.2, 130.1, 128.5,
127.6, 124.2, 123.2, 121.5, 116.5, 113.8, 112.4, 109.7, 56.5, 55.9;
IR (film) νmax 3281, 3203, 2930, 2835, 1605, 1545, 1499, 1371,
1252, 1036, 764, 735 cm-1; HRMS (ESI+) m/z [M + H]+ calcd
for C24H20N2O4 401.1501, found 401.1481.
1
yellow amorphous solid (515 mg, 83%): H NMR (CDCl3, 500
MHz) δ 7.58 (d, J ) 9.0 Hz, 1H), 7.55 (d, J ) 8.7 Hz, 1H),
7.50-7.45 (m, 3H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 2H),
7.29 (d, J ) 2.2 Hz, 1H), 7.25 (m, 2H), 7.21 (dd, J ) 8.9, 2.6
Hz, 1H), 7.15 (d, J ) 2.4 Hz, 1H), 7.09 (m, 1H), 7.01 (dd, J )
8.7, 2.1 Hz, 1H), 6.80 (m, 2H), 6.77 (ddd, J ) 8.2, 2.7, 0.9 Hz,
1H), 6.74 (d, J ) 8.7 Hz, 1H), 6.59-6.56 (m, 2H), 5.16 (s,
2H), 5.14 (s, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.62 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 170.0, 159.3, 159.0, 157.6, 157.3,
139.9, 139.1, 136.8, 133.0, 132.4, 130.5, 130.1, 130.1 (2C),
129.6, 129.5, 129.1, 128.9, 128.9 (2C), 128.4, 128.2, 127.9, 127.7
(2C), 127.3, 125.8, 122.1, 120.0, 114.7, 114.0 (2C), 113.2, 110.4,
107.1, 70.3, 55.7, 55.4, 55.2, 53.9; IR (film) νmax 3059, 3032,
2999, 2934, 2835, 1636, 1601, 1506, 1456, 1389, 1248, 1209,
1026, 854, 818, 735, 698 cm-1; HRMS (ESI+) m/z [M + H]+
calcd for C40H35NO5 610.2593, found 610.2567.
2-(Benzyloxy)-6-bromonaphthalene (36). Sodium hydride (1.16
g, 29.12 mmol) was added to 6-bromo-2-naphthol (5.00 g, 22.41
mmol) in anhydrous N,N-dimethylformamide (162 mL) at 0 °C.
After 15 min, benzyl bromide (2.40 mL, 3.45 g, 20.18 mmol) was
added and the reaction was warmed to rt over 18 h. The reaction
was diluted with EtOAc (500 mL), saturated aqueous NaHCO3 (200
mL) was added, and the solution was extracted with EtOAc (3 ×
500 mL). The combined organic layers were washed with water (3
× 1 L) and saturated aqueous NaCl solution (1 L), dried (Na2SO4),
filtered, and concentrated. The residue was purified via column
chromatography (SiO2, 5:1 hexanes:CH2Cl2) to give 36 as a
N-(4-Methoxybenzyl)-N-(6-hydroxynaphthalen-2-yl)-4-methoxy-
3-(3-methoxyphenyl)benzamide (39). A solution of AlCl3 (203 mg,
1.52 mmol) in anhydrous anisole (750 µL) was added to 38 (191
mg, 0.31 mmol) in anhydrous anisole (750 µL) and the resulting
solution was stirred at rt for 18 h. The reaction was diluted with
MeOH (750 µL) and the solvent was concentrated. The residue
was purified via column chromatography (SiO2, 1:1 EtOAc:
hexanes) to give 39 as a light yellow amorphous solid (126 mg,
1
colorless amorphous solid (5.71 g, 90%): H NMR (CDCl3, 500
MHz) δ 7.94 (d, J ) 1.9 Hz, 1H), 7.68 (d, J ) 9.0 Hz, 1H), 7.61
(d, J ) 8.7 Hz, 1H), 7.53-7.47 (m, 3H), 7.46-7.40 (m, 2H), 7.37
(m, 1H), 7.26 (dd, J ) 9.0, 2.5 Hz, 1H), 7.20 (d, J ) 2.5 Hz, 1H),
5.18 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 157.2, 136.8, 133.2,
130.3, 129.9, 129.9, 128.9 (2C), 128.8, 128.7, 128.4, 127.8 (2C),
120.3, 117.4, 107.3, 70.3; IR (film) νmax 1585, 1452, 1256, 1219,
1
77%): H NMR (CDCl3, 500 MHz) δ 7.56 (m, 1H), 7.50 (d, J
) 8.7 Hz, 1H), 7.47 (dd, J ) 8.6, 2.3 Hz, 1H), 7.36 (d, J ) 2.0
Hz, 1H), 7.29 (d, J ) 2.2 Hz, 1H), 7.25 (m, 2H), 7.12-7.06
(m, 3H), 7.00 (dd, J ) 8.7, 2.1 Hz, 1H), 6.80 (m, 2H), 6.77 (m,
1H), 6.73 (d, J ) 8.7 Hz, 1H), 6.59-6.55 (m, 2H), 5.43 (s,
1H), 5.15 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.62 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 170.2, 159.3, 159.0, 157.6, 154.2,
139.7, 139.0, 133.1, 132.4, 130.5, 130.1, 130.1 (2C), 130.0,
129.5, 128.9, 128.9, 128.0, 127.5, 127.3, 125.9, 122.1, 118.7,
114.7, 114.0 (2C), 113.2, 110.4, 109.5, 55.7, 55.4, 55.3, 54.0;
IR (film) νmax 3236, 2934, 2835, 1599, 1508, 1456, 1437, 1394,
1248, 1177, 1036 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for
C33H29NO5 520.2124, found 520.2120.
1204, 1165, 1065, 997, 924, 852, 820, 800, 733, 698, 476 cm-1
.
N-(4-Methoxybenzyl)-6-(benzyloxy)naphthalen-2-amine (37).
4-Methoxybenzylamine (3.40 mL, 3.59 g, 26.20 mmol) and
anhydrous DMSO (5.20 mL) were added to a high-pressure flask
charged with 36 (3.00 g, 9.58 mmol), K3PO4 (4.19 g, 19.73
mmol), CuII (290 mg, 1.52 mmol), and L-(-)-proline (255 mg,
2.21 mmol); the sealed flask was heated to 80 °C for 44 h. After
cooling to rt, reaction contents were partitioned between water
(100 mL) and EtOAc (200 mL), then were extracted with EtOAc
(2 × 200 mL). The combined organic layers were washed with
saturated aqueous NaCl solution (500 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified via column
chromatography (SiO2, 7:1:1 hexanes:CH2Cl2:EtOAc) to give 37
as a light orange amorphous solid (952 mg, 27%): 1H NMR
(CDCl3, 500 MHz) δ 7.55 (d, J ) 8.7 Hz, 2H), 7.49 (m, 2H),
7.41 (m, 2H), 7.37-7.32 (m, 3H), 7.15 (dd, J ) 8.8, 2.6 Hz,
1H), 7.13 (m, 1H), 6.92 (dd, J ) 8.8, 2.3 Hz, 1H), 6.90 (d, J )
8.7 Hz, 2H), 6.87 (m, 1H), 5.14 (s, 2H), 4.35 (s, 2H), 3.82 (s,
N-(4-Methoxybenzyl)-N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-meth-
oxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)quinolin-3-yl)-4-
methoxy-3-(3-methoxyphenyl)benzamide (42a). Boron trifluoride
etherate (45 µL, 52 mg, 0.36 mmol) was added to 33 (160 mg,
0.31 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-
tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimi-
date (181 mg, 0.50 mmol) in anhydrous CH2Cl2 (5.00 mL). After
stirring at rt for 40 h, triethylamine (30 µL) was added and the
solvent was concentrated. The residue was partially purified via
8918 J. Org. Chem. Vol. 73, No. 22, 2008

Synthesis of Coumarin Ring DeriVatiVes
column chromatography (SiO2, 1:1 EtOAc:hexanes) to provide 41a,
which was used without further purification.
2:1 EtOAc:hexanes to EtOAc) to give 42c as a colorless oil (27
mg, 66%, 42% over two steps): H NMR (CDCl3, 500 MHz) δ
1
7.58 (d, J ) 8.8 Hz, 1H), 7.55 (d, J ) 9.0 Hz, 1H), 7.48 (dd, J
) 8.7, 2.2 Hz, 1H), 7.37 (d, J ) 2.3 Hz, 1H), 7.35 (d, J ) 2.0
Hz, 1H), 7.28 (d, J ) 2.3 Hz, 1H), 7.25 (m, 2H), 7.14 (dd, J )
8.9, 2.4 Hz, 1H), 7.09 (t, J ) 7.9 Hz, 1H), 7.04 (dd, J ) 8.7,
2.1 Hz, 1H), 6.80 (m, 2H), 6.76 (ddd, J ) 8.2, 2.5, 0.9 Hz, 1H),
6.73 (d, J ) 8.7 Hz, 1H), 6.58 (m, 1H), 6.54 (br d, J ) 7.7 Hz,
1H), 5.66 (d, J ) 2.1 Hz, 1H), 5.14 (s, 2H), 4.25 (m, 1H), 4.22
(m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.63 (s, 3H), 3.61 (s, 3H),
3.38 (d, J ) 9.2 Hz, 1H), 2.84 (br s, 1H), 2.71 (br s, 1H), 1.39
(s, 3H), 1.20 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.2,
159.2, 159.0, 157.6, 155.1, 140.1, 139.0, 132.9, 132.4, 130.5,
130.1 (2C), 129.5, 129.5, 129.4, 128.9, 128.3, 128.1, 127.1,
125.8, 122.1, 119.5, 114.7, 114.0, 113.2 (2C), 110.4, 109.9, 97.9,
94.6, 78.6, 71.5, 68.7, 62.1, 55.7, 55.4, 55.3, 53.9, 29.4, 22.9;
IR (film) νmax 3420, 2932, 2835, 1601, 1506, 1394, 1387, 1248,
1178, 1117, 1026, 993, 910, 733 cm-1; HRMS (ESI+) m/z [M
+ H]+ calcd for C41H43NO9 694.3016, found 694.3010.
N-(6-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tet-
rahydro-2H-pyran-2-yloxy)naphthalen-2-yl)-4-methoxy-3-(3-meth-
oxyphenyl)benzamide (42d). Trifluoromethanesulfonic acid (130
µL, 221 mg, 1.47 mmol) was added to 38 (198 mg, 0.33 mmol) in
1:1 CH2Cl2:TFA (1.48 mL) and the solution was stirred at rt for
2 h. The resulting solution was diluted with CH2Cl2 (100 mL),
washed with saturated aqueous NaHCO3 (3 × 50 mL) and saturated
aqueous NaCl solution (2 × 50 mL), dried (Na2SO4), filtered, and
concentrated. The residue was partially purified via column
chromatography (SiO2, 1:1:1 hexanes:EtOAc:CH2Cl2) to give 40
as a purple solid, which was used without further purification (28
mg, 22%).
Carbonate 41a was added to MeOH (22.0 mL), CH2Cl2 (1.5 mL),
and triethylamine (2.2 mL) and the mixture was stirred for 18 h at
rt. The solvent was concentrated and the residue was purified via
column chromatography (SiO2, 50:1 EtOAc:MeOH) to give 42a
as a near-colorless amorphous solid (33 mg, 16% over two steps):
1H NMR (CDCl3, 500 MHz) δ 8.38 (d, J ) 2.4 Hz, 1H), 7.67 (d,
J ) 2.4 Hz, 1H), 7.65 (d, J ) 2.3 Hz, 1H), 7.54 (d, J ) 9.1 Hz,
1H), 7.41 (dd, J ) 8.6, 2.3 Hz, 1H), 7.26 (d, J ) 2.3 Hz, 1H), 7.22
(m, 2H), 7.17 (dd, J ) 8.9, 2.4 Hz, 1H), 7.10 (t, J ) 7.8 Hz, 1H),
6.80 (m, 2H), 6.75 (dd, J ) 8.4, 1.0 Hz, 1H), 6.74 (d, J ) 8.7 Hz,
1H), 6.62-6.57 (m, 2H), 5.69 (d, J ) 2.3 Hz, 1H), 5.15 (AB, JAB
) 14.6 Hz, 1H), 5.15 (AB, JAB ) 14.6 Hz, 1H), 4.23 (dd, J ) 9.1,
3.4 Hz, 1H), 4.15 (m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.64 (s, 3H),
3.59 (s, 3H), 3.38 (d, J ) 9.1 Hz, 1H), 1.39 (s, 3H), 1.17 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 170.3, 159.3, 159.2, 158.1, 157.9,
150.9, 147.4, 138.8, 136.1, 132.7, 132.4, 130.5, 130.1 (2C), 129.3,
129.0, 128.9, 127.3, 123.4, 122.0, 120.7, 114.8, 114.2 (2C), 113.2,
111.3, 110.7, 98.2, 84.5, 78.7, 71.1, 68.6, 62.0, 55.7, 55.4, 55.3,
53.8, 29.0, 23.0; IR (film) νmax 2937, 2833, 1601, 1246, 1209, 1117,
1033, 989, 964 cm-1; HRMS (ESI+) m/z [M + H]+ calcd for
C40H42N2O9 695.2969, found 695.2891.
N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltet-
rahydro-2H-pyran-2-yloxy)quinolin-3-yl)-4-methoxy-3-(3-methox-
yphenyl)benzamide (42b). Boron trifluoride etherate (46 µL, 53 mg,
0.37mmol)wasaddedto34(51mg,0.13mmol)and(3aR,4S,7R,7aR)-
7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-
c]pyran-4-yl 2,2,2-trichloroacetimidate (180 mg, 0.50 mmol) in
anhydrous CH2Cl2 (5.00 mL). After stirring at rt for 40 h,
triethylamine (30 µL) was added and the solvent was concentrated.
The residue was purified via column chromatography (SiO2, 1:1
EtOAc:hexanes) to give 41b (29 mg, 37%) in a 10:1 ratio of
anomers (R:ꢀ), which was used without further purification.
Carbonate 41b was added to MeOH (7.5 mL), CH2Cl2 (500
µL), and triethylamine (750 µL) and the mixture was stirred for
18 h at rt. The solvent was concentrated and the residue was
purified via column chromatography (SiO2, 40:1 EtOAc:MeOH)
to give 42b as a near-colorless amorphous solid (11 mg, 15%
Boron trifluoride etherate (4 µL, 5 mg, 0.03 mmol) was added
to 40 (28 mg, 0.07 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-
dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-
trichloroacetimidate (83 mg, 0.23 mmol) in anhydrous CH2Cl2 (1.85
mL). After stirring at rt for 40 h, triethylamine (10 µL) was added
and the solvent was concentrated. The residue was partially purified
via column chromatography (SiO2, 3:1:1 hexanes:EtOAc:CH2Cl2)
to provide 41d, which was used without further purification (30
mg).
1
over two steps): H NMR (CDCl3, 500 MHz) δ 8.81 (br s, 2H),
7.98 (dd, J ) 8.7, 2.4 Hz, 1H), 7.89 (d, J ) 2.3 Hz, 1H), 7.72
(d, J ) 9.0 Hz, 1H), 7.70 (d, J ) 1.9 Hz, 1H), 7.37 (t, J ) 8.0
Hz, 1H), 7.23 (dd, J ) 9.0, 2.3 Hz, 1H), 7.13 (dt, J ) 7.8, 1.2
Hz, 1H), 7.10 (m, 1H), 7.09 (d, J ) 8.6 Hz, 1H), 6.94 (ddd, J
) 8.2, 2.5, 0.8 Hz, 1H), 5.73 (d, J ) 2.0 Hz, 1H), 4.30-4.22
(m, 2H), 3.91 (s, 2H), 3.86 (s, 3H), 3.61 (s, 3H), 3.39 (d, J )
8.9 Hz, 1H), 1.40 (s, 3H), 1.21 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 165.8, 159.9, 159.6, 157.1, 146.7, 144.7, 138.9, 131.1,
130.6, 129.9, 129.4, 129.0, 128.7, 126.6, 125.0, 124.0, 122.2,
120.5, 115.6, 113.2, 111.5, 111.4, 98.0, 84.6, 78.6, 71.4, 68.8,
62.1, 56.1, 55.6, 29.2, 23.0; IR (film) νmax 3288, 2976, 2934,
2835, 1373, 1250, 1117, 731 cm-1; HRMS (ESI+) m/z [M +
H]+ calcd for C32H34N2O8 575.2393, found 575.2368.
N-(4-Methoxybenzyl)-N-(6-((2R,3R,4S,5R)-3,4-dihydroxy-5-meth-
oxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)naphthalen-2-yl)-4-
methoxy-3-(3-methoxyphenyl)benzamide (42c). Boron trifluoride
etherate (10 µL, 12 mg, 0.08 mmol) was added to 39 (77 mg,
0.15 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-
tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroace-
timidate (214 mg, 0.59 mmol) in anhydrous CH2Cl2 (5.00 mL).
After stirring at rt for 40 h, triethylamine (10 µL) was added
and the solvent was concentrated. The residue was partially
purified via column chromatography (SiO2, 1:1 EtOAc:hexanes)
to give 41c, which was used without further purification (69
mg, 64%).
Carbonate 41d was added to MeOH (10.0 mL), CH2Cl2 (1.0 mL),
and triethylamine (1.0 mL) and the solution was stirred for 18 h at
rt. The solvent was concentrated and the residue was purified via
column chromatography (SiO2, 2:1 EtOAc:hexanes, then EtOAc)
to give 42d as a colorless oil (12 mg, 6% in three steps): 1H NMR
(CDCl3, 500 MHz) δ 8.28 (d, J ) 1.9 Hz, 1H), 7.96 (dd, J ) 8.5,
2.4 Hz, 1H), 7.90 (br s, 1H), 7.86 (d, J ) 2.4 Hz, 1H), 7.75 (br s,
1H), 7.73 (br s, 1H), 7.55 (dd, J ) 8.9, 2.2 Hz, 1H), 7.42 (d, J )
2.3 Hz, 1H), 7.38 (t, J ) 8.0 Hz, 1H), 7.18 (dd, J ) 8.9, 2.5 Hz,
1H), 7.15 (m, 1H), 7.11 (m, 1H), 7.09 (d, J ) 8.7 Hz, 1H), 6.94
(ddd, J ) 8.2, 2.5, 0.8 Hz, 1H), 5.69 (d, J ) 2.1 Hz, 1H), 4.28 (dt,
J ) 9.2, 3.6 Hz, 1H), 4.25 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.62
(s, 3H), 3.39 (d, J ) 9.2 Hz, 1H), 2.61 (d, J ) 2.5 Hz, 1H), 2.56
(d, J ) 3.7 Hz, 1H), 1.41 (s, 3H), 1.22 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 165.4, 159.6 (2C), 154.2, 139.1, 134.2, 131.8, 131.0,
129.9, 129.7, 129.4, 129.4, 128.6, 128.2, 127.4, 122.2, 120.9, 119.5,
117.3, 115.5, 113.2, 111.3, 110.1, 97.9, 84.7, 78.5, 71.6, 68.8, 62.1,
56.1, 55.6, 29.4, 22.9; IR (film) νmax 3400, 2970, 2930, 2835, 1605,
1535, 1342, 1250, 1178, 1117, 1024, 995, 966, 908, 733 cm-1
;
HRMS (ESI+) m/z [M + H]+ calcd for C33H35NO8 574.2441, found
574.2461.
Anti-Proliferation Assays. Cells were maintained in a 1:1
mixture of Advanced DMEM/F12 (Gibco) supplemented with
nonessential amino acids, L-glutamine (2 mM), streptomycin (500
µg/mL), penicillin (100 units/mL), and 10% FBS. Cells were
grown to confluence in a humidified atmosphere (37 °C, 5%
CO2), seeded (2000/well, 100 µL) in 96-well plates, and allowed
to attach overnight. Compound or GDA at varying concentrations
in DMSO (1% DMSO final concentration) was added, and cells
Carbonate 41c (42 mg, 0.06 mmol) was added to MeOH (9.1
mL), CH2Cl2 (650 µL), and triethylamine (910 µL) and the
mixture was stirred for 18 h at rt. The solvent was concentrated
and the residue was purified via column chromatography (SiO2,
J. Org. Chem. Vol. 73, No. 22, 2008 8919

Donnelly et al.
were returned to the incubator for 72 h. At 72 h, the number of
viable cells was determined by using an MTS/PMS cell
proliferation kit (Promega) per the manufacturer’s instructions.
Cells incubated in 1% DMSO were used at 100% proliferation,
and values were adjusted accordingly. IC50 values were calcu-
lated from separate experiments performed in triplicate, using
GraphPad Prism.
Western Blot Analyses. MCF-7 cells were cultured as described
above and treated with various concentrations of drug, GDA in
DMSO (1% DMSO final concentration), or vehicle (DMSO) for
24 h. Cells were harvested in cold PBS and lysed in RIPA lysis
buffer containing 1 mM PMSF, 2 mM sodium orthovanadate,
and protease inhibitors on ice for 1 h. Lysates were clarified at
14000g for 10 min at 4 °C. Protein concentrations were
determined by using the Pierce BCA protein assay kit per the
manufacturer’s instructions. Equal amounts of protein (20 µg)
were electrophoresed under reducing conditions, transferred to
a nitrocellulose membrane, and immunoblotted with the corre-
sponding specific antibodies. Membranes were incubated with
an appropriate horseradish peroxidase-labeled secondary anti-
body, developed with a chemiluminescent substrate, and visualized.
Acknowledgment. The authors gratefully acknowledge sup-
port of this project by the NIH/NCI (CA120458) and the DOD
Prostate Cancer Research Program (QH815179). The authors
acknowledge Donna Lubbers for her preliminary studies toward
the preparation of 14, 17, and 21.
Supporting Information Available: Full experimental pro-
cedures and characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801312R
8920 J. Org. Chem. Vol. 73, No. 22, 2008