A library of noviosylated coumarin analogues

Article abstract of DOI:10.1021/jo062083t

(Chemical Equation Presented) The DNA gyrase inhibitor, novobiocin, was recently shown to inhibit Hsp90 via a previously unrecognized C-terminal ATP-binding site. Previous structure-activity relationship studies identified key moieties that appear importa

Full text of DOI:10.1021/jo062083t

VOLUME 72, NUMBER 10
MAY 11, 2007
© Copyright 2007 by the American Chemical Society
A Library of Noviosylated Coumarin Analogues
Yung-Tzung Huang and Brian S. J. Blagg*
Department of Medicinal Chemistry and The Center for Chemical Methodologies and
Library DeVelopment, The UniVersity of Kansas, 1251 Wescoe Hall DriVe, Malott Hall 4070,
Lawrence, Kansas 66045-7563
bblagg@ku.edu
ReceiVed October 7, 2006
The DNA gyrase inhibitor, novobiocin, was recently shown to inhibit Hsp90 via a previously unrecognized
C-terminal ATP-binding site. Previous structure-activity relationship studies identified key moieties that
appear important for Hsp90 inhibitory activity. In an effort to provide a more efficacious lead compound,
a parallel library of noviosylated coumarin analogues was prepared.
Introduction
exerts its antimicrobial activity has been described by its ability
to inhibit bacterial DNA gyrase.10-13 DNA gyrase mediates the
topology of double stranded DNA similar to the process utilized
by the 90 kDa heat shock proteins (Hsp90) to fold nascent
polypeptides into biologically active three-dimensional struc-
tures.14 Both proteins require ATP as a requisite source of energy
for the reorientation of topological substrates and they both bind
ATP in a similar manner. In contrast to most ATP-utilizing
proteins that bind nucleotide substrates in an extended confor-
mation, DNA gyrase15-17 and Hsp9018 bind ATP in an unusual
bent conformation. On the basis of similarities of binding and
previously recognized antitumor activity, Neckers and co-
Novobiocin is a natural product isolated from soil samples
containing Streptomyces spheroids1 and has clinical use for the
treatment of bacterial infection2-5 and more recently some forms
of cancer.6-9 The mechanism of action by which novobiocin
* To whom correspondence should be addressed. Phone: 785-864-2288. Fax,
785-864-5326.
(1) Hengeller, C.; Licciardelo, G.; Tudino, V.; Marcelli, E.; Virgilio, A.
Nature 1965, 205, 418-419.
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Swartz, M. N. Antimicrob. Agents Chemother. 1982, 22, 662.
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Hiyama, Y.; Suzuki, K.; Ito, H.; Terauchi, H.; Kawasaki, M.; Nagai, K.;
Wachi, M.; Yamagishi, J. J. Med. Chem. 2004, 47, 3693.
(5) Albernamm, C.; Soriano, A.; Jiang, J.; Vollmer, H.; Biggins, J. B.;
Barton, W. A.; Lesniak, J.; Nikolov, D. B.; Thorson, J. S. Org. Lett. 2003,
5, 933.
(10) Lewis, R. J.; Tsai, F. T.; Wigley, D. B. BioEssays 1996, 18, 661.
(11) Reece, R. J.; Maxwell, A. Crit. ReV. Biochem. Mol. Biol. 1991, 26,
335.
(12) 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.
(13) Ali, J. A.; Jackson, A. P.; Howells, A. J.; Maxwell, A. Biochemistry
1993, 32, 2717.
(14) Blagg, B. S. J.; Kerr, T. D. Med. Res. ReV. 2006, 26, 310-338.
(15) Jackson, A. P.; Maxwell, A.; Wigley, D. B. J. Mol. Biol. 1991,
217, 15.
(6) Gobernado, M.; Canton, E.; Santos, M. Eur. J. Clin. Microbiol. 1984,
3, 371.
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S. A.; Ara, G.; Herman, T. S. Cancer Chemother. Pharmacol. 1993, 32,
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Novogrodsky, A.; Sidi, Y. Br. J. Cancer 1992, 65, 183.
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Weston, S.; Tucker, A.; Pauptit, R. A.; Breeze, A. L.; Poyser, J. P.; O’Brien,
R.; Ladbury, J. E.; Wigley, D. B. Proteins 1997, 28, 41.
10.1021/jo062083t CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/01/2007
J. Org. Chem. 2007, 72, 3609-3613
3609

Huang et al.
FIGURE 3. Rationale for noviosylated coumarin analogues.
FIGURE 1. Hsp90 C-terminal inhibitors, novobiocin and A4.
was designed so that both the 4-hydroxyl and 3′-carbamate were
omitted. However, additional hydrophobic and hydrogen bond-
ing interactions could be provided by incorporation of additional
functionalities as shown in Figure 3. Specifically, the 2-aryl
was designed for incorporation of additional H-bond donors/
acceptors, whereas the benzamide allowed for inclusion of
various aromatics that were expected to occupy the hydrophobic
cavity to which the prenylated benzamide side chain of
novobiocin resides. Consistent with data obtained from prior
studies, the 7-noviosyl linkage was maintained as well as the
requisite 2′,3′-diol. In this paper we report the parallel synthesis
of a library containing 56 noviosylated coumarin anlogues that
exhibit these attributes.
workers proposed that novobiocin may be exerting its antitumor
activity through inhibition of the Hsp90-mediated protein folding
process.19,20 Results from their studies proved that novobiocin
did inhibit Hsp90, but at a much higher concentration than that
needed to inhibit DNA gyrase (0.9 µM). Furthermore, their
studies concluded that novobiocin did not bind to the analogous
ATP-binding pocket located at the N-terminus of Hsp90, but
instead bound to a previously unidentified C-terminal nucleotide
binding pocket. In Hsp90 assays, novobiocin was found to
manifest an IC50 value of ∼700 µM, suggesting the need for
improved analogues that exhibit increased efficacy.
In an effort to identify more potent inhibitors of Hsp90, a
small library of novobiocin analogues was prepared and initial
structure-activity relationships (SAR) revealed.21 The most
potent compound identified from this library was A4, which is
structurally related to novobiocin, but lacks the 4-hydroxyl, the
benzamide side chain, and the 3′-carbamate. Those studies
clearly demonstrated that the 3′-carbamate was detrimental to
anti-Hsp90 activity, suggesting an important role for the 2′,3′-
diol of the noviose appendage. A summary of the observed SAR
trends elucidated by this initial investigation is presented in
Figure 2.
Results and Discussion
Retrosynthetically, the scaffold chosen for elucidation of
structure-activity relationships was envisioned for construction
from four components: an o-iodobenzoic ester (1),22 a variety
of commercially available boronic acids (2a-f), noviose (3),23
and a series of amines (4a-c, Scheme 1). Previous work from
our laboratory demonstrated that the trichloroacetimidate of
noviose carbonate couples readily with coumarin phenols to give
the desired R-anomer in high yield.24 However, the â-anomers
have not been prepared nor have their activities been evaluated.
Therefore, we elected to synthesize both the R- and â-anomers
in an effort to further diversify this library. The boronic acids
were chosen to contain both electronic and steric moieties that
could aid in elucidation of additional SAR and reveal crucial
interactions with the surrounding pocket to which the benzamide
side chain of novobiocin binds Hsp90 and gyrase.
The Suzuki precursor, tert-butyl 4-benzyloxy-2-iodobenzoate
(1), was prepared from 2-amino-5-hydroxybenzoic acid, 5
(Scheme 2).25 Treatment of the 2-amino group with sodium
nitrate under acidic conditions resulted in formation of the
corresponding diazonium salt, which underwent nucleophilic
aromatic substitution with potassium iodide to give the iodinated
product, 6. Conversion of the acid to the tert-butyl ester (7)
was accomplished upon reflux with N,N-dimethylformamide di-
tert-butyl acetal.26 The phenol was then protected as the benzyl
FIGURE 2. Previously observed SAR between A4 and Hsp90.
On the basis of these observations and previously elucidated
SAR’s for novobiocin and DNA gyrase, a parallel library of
noviosylated coumarin analogues was envisioned to provide a
succinct method for continued exploration of SAR. The library
(22) Mulbarier, M.; Giannis, A. Angew. Chem., Int. Ed. 2001, 40, 4393-
4394.
(23) Yu, X. M.; Shen, G.; Blagg, B. S. J. J. Org. Chem. 2004, 69, 7375-
7378.
(17) Holdgate, G. A.; Tunnicliffe, A.; Ward, W. H. J.; Weston, S. A.;
Rosenbrock, G.; Barth, P. T.; Taylor, I. W. F.; Pauptit, R. A.; Timms, D.
Biochemistry 1997, 36, 9663.
(18) Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.; Piper, P.
W.; Pearl, L. H. J. Med. Chem. 1999, 42, 260.
(19) Marcu, M. G.; Schulte, T. W; Neckers, L. J. Natl. Cancer Inst.
2000, 92, 242.
(20) Marcu, M. G.; Chadli, A.; Bouhouche, I.; Catelli, B.; Neckers, L.
M. J. Biol. Chem. 2000, 276, 37181.
(21) 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.
(24) Shen, G.; Yu, X. M.; Blagg, B. S. J. Bioorg. Med. Chem. Lett. 2004,
14, 5903-5906.
(25) (a) Moss, R. A.; Alwis, K. W.; Shin, J. S. J. Am. Chem. Soc. 1984,
106, 2651-2655. (b) Reed, N. N.; Delgado, M.; Hereford, K.; Clapham,
B.; Janda, K. D. Bioorg. Med. Chem. Lett. 2002, 12, 2047-2049. (c)
Patterson, S.; Lorenz, C.; Slawin, A. M. Z.; Westwood, N. J. QSAR Comb.
Sci. 2004, 23, 883-890.
(26) Widmer, U. Synthesis 1983, 135-136.
3610 J. Org. Chem., Vol. 72, No. 10, 2007

A Library of NoViosylated Coumarin Analogues
SCHEME 1. Retrosynthetic Analysis of Coumarin
Analogue Scaffold
SCHEME 3. Preparation of the Noviosylated Coumarin
Analogue Library
SCHEME 2. Preparation of tert-Butyl
4-Benzyloxy-2-iodobenzoate
ic acids were coupled to the o-iodo benzoate (1) via the use of
Buchwald’s ligand,28 8, which proved essential to this reaction
(Scheme 3). Although other ligands were probed, none were
capable of producing the diaryl compounds in yields greater
than 10%. With the desired compounds in hand (9), the tert-
butyl esters were removed upon exposure to trifluoroacetic acid
to furnish the corresponding acids. The resulting acids were
subjected to a wide array of coupling conditions, but the pres-
ence of the o-aryl substituent significantly encumbered the reac-
tivity of this moiety, which resulted in little or no coupled prod-
ucts. Consequently, we chose to convert the acid into the acid
chloride and then treat those products directly with the requisite
amines to form the corresponding amides, 12. This latter reaction
worked well for all three amino substrates investigated, including
benzylamine, phenethylamine, and phenpropylamine substrates.
Upon construction of the amides, the benzyl ethers were
removed by hydrogenolysis to afford the free phenols, which
were then noviosylated using our standard protocol24 to give a
mixture of anomers, 14. The cyclic carbonates were then
solvolyzed with triethylamine in methanol to give the requisite
diols, 15, which were purified via silica chromatography.
In total, 56 members of the library were prepared including
an equal number of R- and â-anomers as shown in Figures 5
and 6, respectively. The compounds obtained were individually
characterized and their identity confirmed by normal spectral
methods. The compounds reported herein represent the first set
of coumarin analogues prepared for elucidation of DNA gyrase
ether under standard conditions27 to provide the Suzuki precursor
1, for use in construction of the library.
Substrates for the Suzuki reaction were selected based on
previously reported SAR. It was clear from the structure of
novobiocin that there was a hydrophobic pocket into which the
benzamide side chain projected.21 Furthermore, there appeared
to be interactions between the amide itself and the binding
pocket, suggesting the potential for key hydrogen-bonding
interactions. Therefore, we carefully selected 10 boronic acids
(2a-f) for coupling to aryl iodide 1 (Figure 4). These molecules
contained variously substituted H-bond donors/acceptors as well
as hydrophobic moieties that would allow for exploration of
the Hsp90 C-terminal binding pocket as described previously
in Figures 2 and 3.
FIGURE 4. Boronic acid/esters used for elucidation of SAR.
(27) Kim, S.; Wu, J. Y.; Zhang, Z.; Tang, W.; Doss, G. A.; Dean, B. J.;
DiNinno, F.; Hammond, M. L. Org. Lett. 2005, 7, 411-414.
(28) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685-4696.
Upon selection of the boronic acid/ester library, our attention
turned toward assembly of the novobiocin-like library. The boron-
J. Org. Chem, Vol. 72, No. 10, 2007 3611

Huang et al.
results from such studies will be disclosed in due course along
with optimized derivatives.
Experimental Procedures
tert-Butyl 5-(Benzyloxy)-2-iodobenzoate (1). tert-Butyl 5-hy-
droxy-2-iodobenzoate 7 (0.6507 g, 2.0 mmol) was dissolved in
anhydrous DMF (25 mL) before K2CO3 (0.46 g, 3.3 mmol) and
benzyl bromide (0.3 mL, 2.6 mmol) were added to the solution.
The resulting mixture was stirred for 14 h at room temperature.
The reaction was quenched by the addition of H2O (30 mL) and
the aqueous phase extracted with EtOAc (4 × 40 mL). The
combined organic layers were washed with saturated aqueous NaCl
(20 mL), dried over anhydrous Na2SO4, filtered, and concentrated.
The product was purified via chromatography (SiO2, 8:1, hexanes:
EtOAc) to afford 1 (0.7512 g, 90%) as a light yellow oil: 1H NMR
(CDCl3/400 MHz, ppm) δ 7.80 (d, J ) 8.7 Hz, 1H), 7.47-7.30
(m, 6H), 6.78 (dd, J ) 8.7, 3.1 Hz, 1H), 5.07 (s, 2H), 1.65 (s, 9H);
13C NMR (CDCl3/400 MHz, ppm) δ 165.9, 158.7, 141.7, 138.2,
136.2, 128.8 (2C), 128.3, 127.6 (2C), 119.2, 117.5, 82.8, 82.3, 70.3,
28.2 (3C); IR (neat) 3088, 3065, 3032, 3001, 2978, 2930, 2874,
1728, 1589, 1562, 1454, 1393, 1300, 1254, 1165, 1026, 845, 779,
696, 642 cm-1; HRMS (ESI) m/z calcd for C18H23IO3N [M + NH4]+
428.0723, found 428.0745.
tert-Butyl 5-(Benzyloxy)-2-(dibenzo[b,d]furan-4-yl)benzoate
(9f). tert-Butyl 5-(benzyloxy)-2-iodobenzoate 1 (0.3509 g, 0.86
mmol, 1.0 equiv), 4-dibenzofuranboronic acid 2f (0.2731 g, 1.29
mmol, 1.5 equiv), Pd2(dba)3 (0.0164 g, 0.02 mmol, 4.0 mol %),
K3PO4 (0.5623 g, 2.57 mmol, 3.0 equiv), and 2-dicyclohexylphos-
phino-2′,6′-dimethoxy-1,1′-byphenyl 8 (0.029 g, 0.07 mmol, 8.0
mol %) were dissolved in toluene (30 mL). The resulting solution
was stirred for 15 min at room temperature and then heated at reflux
for 14 h. The product was filtered through a pad of silica gel and
eluted with EtOAc. The eluent was concentrated and the product
purified via chromatography (SiO2, 20:1, hexane/EtOAc) to afford
9f (0.3512 g, 0.78 mmol, 91%) as a colorless solid: 1H NMR
(CDCl3/400 MHz, ppm) δ 7.96-7.83 (m, 2H), 7.67-7.58 (m 1H),
7.51-7.22 (m, 11H), 7.20-7.12 (m, 1H), 5.13 (s, 2H), 0.96 (s,
9H); 13C NMR (CDCl3/400 MHz, ppm) δ 167.1, 158.6, 156.1,
153.9, 136.7, 134.3, 132.7, 129.3, 128.8 (2C), 128.3, 127.8 (2C),
127.4, 127.2, 126.8, 124.4, 123.8, 123.0, 122.8, 120.8, 119.4, 118.4,
116.1, 112.1, 81.1, 70.4, 27.5 (3C); IR (neat) 3398, 3063, 3036,
2978, 2932, 2874, 1713, 1604, 1566, 1508, 1450, 1369, 1296, 1169,
1080, 1026, 910, 845, 752 cm-1; HRMS (ESI) m/z calcd for
C30H26O4Na1 [M + Na]+ 473.1729, found 473.1717.
FIGURE 5. R-Anomeric members of the library prepared.
4-(Benzyloxy)-2′-chlorobiphenyl-2-carboxic acid (10b-oCl).
tert-Butyl ester 9b-oCl (0.3946 g, 1.0 mmol) and trifluoroacetic
acid (TFA, 5 mL) were dissolved in CH2Cl2 (30 mL) and stirred
for 6 h at room temperature. The solvent was removed and the
product purified via chromatography (SiO2, 1:1 to 2:1, hexanes:
EtOAc) to afford 10b-oCl (0.2691 g, 0.8 mmol, 80%) as a colorless
solid: 1H NMR (CDCl3/400 MHz, ppm) δ 7.73 (d, J ) 2.4 Hz),
7.52-7.36 (m 6H), 7.33-7.19 (m, 5H), 5.17 (s, 2H); 13C NMR
(CDCl3/400 MHz, ppm) δ 171.9, 158.4, 140.2, 136.6, 133.9, 133.3,
132.8, 130.6, 130.4, 129.2, 128.9 (2C), 128.6, 128.4, 127.8 (2C),
126.7, 119.8, 116.5, 70.5; IR (neat) 3063, 3009, 2964, 2918, 2872,
2860, 2818, 1693, 1682, 1603, 1504, 1418, 1277, 1227, 1026, 999,
824, 733, 696 cm-1; HRMS (ESI) m/z calcd for C20H16Cl1O3 [M
+ H]+ 339.0788, found 339.0795.
General Procedure for Amide Formation. Carboxylic acid 10d
(0.1964 g, 0.52 mmol, 1.0 equiv), oxalyl chloride (0.18 mL, 2.1
mmol, 4.0 equiv), and one drop of DMF were dissolved in CH2Cl2
(15 mL), and the solution was stirred for 5 h at room temperature.
The solvent was removed and the acid chloride product 11d was
used in the next step without further purification. The freshly made
acid chloride 11d (0.0719 g, 0.18 mmol, 1.0 equiv), 3-phenyl-1-
propylamine (0.11 mL, 0.78 mmol, 4.0 equiv), and Et3N (0.26 mL,
1.8 mmol, 10.0 equiv) were dissolved in CH2Cl2 (12 mL) and stirred
for 14 h at room temperature. After the solvent was removed, the
FIGURE 6. â-Anomers of the library prepared.
and Hsp90 structure-activity relationships. Biological studies
with these compounds are currently under investigation and the
3612 J. Org. Chem., Vol. 72, No. 10, 2007

A Library of NoViosylated Coumarin Analogues
product was purified via chromatography (SiO2, 5:1, hexanes:
EtOAc) to afford 12d (n ) 3) (0.0712 g, 0.14 mmol, 79%) as a
colorless solid: 1H NMR (CDCl3/400 MHz, ppm) δ 7.67-7.62
(m, 2H), 7.57-7.53 (m, 2H), 7.52-7.33 (m, 12H), 7.21-7.10 (m,
4H), 7.03-6.99 (m, 2H), 5.33 (t, J ) 5.8 Hz, 1H), 5.16 (s, 2H),
3.27-3.20 (m, 2H), 2.37 (t, J ) 7.8 Hz, 2H), 1.60-1.50 (m 2H);
13C NMR (CDCl3/400 MHz, ppm) δ 169.4, 158.5, 141.3, 140.5
(2C), 139.1, 137.1, 136.7, 131.8, 131.7, 129.4 (2C), 129.0 (2C),
128.9 (2C), 128.5 (2C), 128.4 (2C), 128.3, 127.7 (2C), 127.7, 127.5
(2C), 127.2 (2C), 126.1, 117.6, 114.5, 70.4, 39.6, 33.1, 30.7; IR
(neat) 3279, 3082, 3061, 3028, 2962, 2924, 2895, 2856, 1632, 1607,
1539, 1479, 1454, 1313, 1049, 1003, 690 cm-1; HRMS (ESI) m/z
calcd for C35H31N1O2Na1 [M + Na]+ 520.2253, found 520.2225.
General Procedure for Removal of Benzyl Protecting Group.
The benzyl protected phenol 12c-oOMe (n ) 2) (0.0477 g, 0.11
mmol, 1.0 equiv) and 10% palladium on carbon (0.011 g, 20%
g/g) were stirred in EtOAc (12 mL). The slurry was stirred under
hydrogen gas (1 atm) for 14 h before the mixture was filtered
through a pad of silica gel and eluted with EtOAc. The eluent was
concentrated and the product purified via chromatography (SiO2,
1:1, hexanes:EtOAc) to afford 13c-oOMe (n ) 2) (0.0378 g, 0.11
mmol, 99%) as a colorless solid: 1H NMR (CDCl3/400 MHz, ppm)
δ 8.81 (s, 1H), 7.75 (d, J ) 2.6 Hz, 1H), 7.41-7.34 (m, 1H), 7.30-
7.12 (m, 5H), 7.08-6.90 (m, 5H), 5.74 (t, J ) 5.5 Hz, 1H), 3.74
(s, 3H), 3.48-3.40 (m, 2H), 2.50 (t, J ) 6.9 Hz, 2H); 13C NMR
(CDCl3/400 MHz, ppm) δ 170.1, 157.0, 156.7, 138.5, 136.2, 132.6,
131.1, 129.4, 129.2, 128.8 (2C), 128.7 (2C), 126.8, 126.7, 121.3,
118.4, 116.4, 110.8, 55.5, 41.2, 35.2; IR (neat1) 3409, 3269, 3244,
3232, 3217, 3086, 3063, 3026, 2928, 2874, 2854, 2835, 1639, 1601,
room temperature. The reaction was quenched by the addition of
Et3N (250 µL) and stirred for 5 min. After the solvent was removed,
the product was purified via chromatography (SiO2, 1:20, acetone:
CH2Cl2) to afford a mixture of R- and â-14c-pOMe (n ) 2), which
was used without further purification.
General Procedure for Solvolysis the Cyclic Carbonate. The
noviosylated coumarin mimic 14a (n ) 1) (∼0.05 g, ∼0.1 mmol)
was dissolved in methanolic Et3N (10 mL, 10% solution) and stirred
for 14 h at room temperature. The solvent was removed and the
product purified via chromatography (SiO2, 1:4, acetone:CH2Cl2)
to afford R- and â-15a (n ) 1) as colorless solids. R-15a (n ) 1):
1H NMR (CDCl3/400 MHz, ppm) δ 7.40-7.33 (m 6H), 7.29-
7.13 (m, 5H), 6.90-6.85 (m, 2H), 5.56 (d, J ) 2.0 Hz, 1H), 4.33
(d, J ) 5.4 Hz, 2H), 4.25-4.18 (m, 1H), 4.18-4.15 (m, 1H), 3.62
(s, 3H), 3.39 (m, 2H), 2.97 (d, J ) 4.4 Hz, 1H), 1.82 (br s, 1H),
1.39 (s, 3H), 1.22 (s, 3H); 13C NMR (CDCl3/400 MHz, ppm) δ
169.3, 156.3, 140.0, 137.4, 136.6, 133.2, 131.8, 129.0 (2C), 128.9
(2C), 128.8 (2C), 128.0 (2C), 127.7, 127.6, 117.8, 116.7, 98.1, 84.5,
78.6, 71.4, 68.7, 62.1, 44.5, 29.2, 23.1; IR (neat) 3418, 3323, 3107,
3061, 3030, 2982, 2932, 2854, 2931, 1643, 1634, 1607, 1480, 1304,
1223, 1130, 1040, 993, 808, 734, 700 cm-1; HRMS (ESI) m/z calcd
for C28H32N1O6 [M + H]+ 478.2230, found 478.2232. â-15a (n )
1
1): H NMR (CDCl3/400 MHz, ppm) δ 7.46-7.14 (m, 11H), 6.92-
6.87 (m, 2H), 5.52 (t, J ) 4.7 Hz, 1H), 5.41 (br s, 1H), 4.34 (d, J
) 5.4 Hz, 2H), 4.22 (s, 1H), 3.87-3.80 (m, 1H), 3.65 (s, 3H),
3.32 (d, J ) 9.4 Hz, 1H), 2.77 (s, 1H), 2.71 (d, J ) 7.6 Hz, 1H),
1.43 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3/400 MHz, ppm) δ
168.8, 156.3, 139.9, 137.5, 136.7, 134.1, 131.9, 129.0 (2C), 129.9
(2C), 128.8 (2C), 127.9 (2C), 127.8, 127.6, 118.5, 116.4, 94.2, 84.4,
76.3, 71.5, 71.3, 62.2, 44.4, 28.8, 18.8; IR (neat) 3348, 3107, 3063,
3030, 2980, 2928, 2903, 2853, 2833, 1645, 1599, 1520, 1479, 1383,
1227, 1107, 1030, 883, 769, 698 cm-1; HRMS (ESI) m/z calcd for
C28H32N1O6 [M + H]+ 478.2230, found 478.2228.
1568, 1531, 1483, 1454, 1308, 1263, 1238, 1028, 752, 700 cm-1
;
HRMS (ESI) m/z calcd for C22H22N1O3 [M + H]+ 348.1600, found
348.1598.
General Procedure of the Noviose Coupling Reaction. Noviose
carbonate (0.1428 g, 0.65 mmol, 1.0 equiv) was dissolved in CH2-
Cl2 (10 mL) before Cs2CO3 (0.0431 g, 0.13 mmol, 0.2 equiv) and
trichloroacetonitrile (0.14 mL, 1.37 mmol, 2.0 equiv) were added
to the solution. The resulting mixture was stirred for 14 h at room
temperature. The slurry was filtered through a cotton-packed pipet
and the solvent removed. The product was used in the next step
without further purification. The freshly prepared noviose carbonate
trichloroacetimidate (∼0.090 g, ∼0.25 mmol, 1.0 equiv) in CH2-
Cl2 (10 mL) was added to a solution of 13c-pOMe (n ) 2) (0.0861
g, 0.25 mmol, 1.0 equiv) in CH2Cl2 (20 mL) and the mixture was
stirred for 10 min before BF3-OEt2 (0.010 mL, 0.08 mmol, 0.3
equiv) was added. The resulting mixture was stirred for 14 h at
Acknowledgment. The authors gratefully acknowledge the
Department of Defense Prostate Cancer Research Program
(PC050269) and the NIH Center of Excellence in Combinatorial
Methods and Library Development (5 P50 GM069663) for
financial support of this project.
Supporting Information Available: General experimental
conditions and spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO062083T
J. Org. Chem, Vol. 72, No. 10, 2007 3613