The synthesis of tethered ligand dimers for PPARγ-RXR protein heterodimers

Article abstract of DOI:10.1039/b600848h

The synthesis of heterodimeric compounds based on tethering the peroxisome proliferator-activated receptors (PPAR)γ agonist, Rosiglitazone and the RXR ligand Targetin is investigated. The synthesis of these compounds was accomplished via a convergent strategy, employed for preparing the appropriately-functionalized subunits of Rosiglitazone and Targetin and then attaching them to opposite ends of the tether. It was observed that a Mitsunobu reaction between the alcohol 5 and 4-hydroxy-benzaldehyde produced the ether 6 in a yield of 80%. It was concluded that the convergent strategy for the synthesis of these compounds could be easily adaptable to a larger and more diverse set of compounds as ligands for the PPARγ-RXR protein heterodimer.

Full text of DOI:10.1039/b600848h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
The synthesis of tethered ligand dimers for PPARc–RXR protein heterodimers
Debra L. Mohler*a,b and Gang Shena
Received (in Pittsburgh, PA, USA) 19 January 2006, Accepted 24th April 2006
First published as an Advance Article on the web 4th May 2006
DOI: 10.1039/b600848h
Heterodimeric compounds based on tethering the PPARc
agonist Rosiglitazone to the RXR ligand Targretin have been
prepared.
two enzymes lie at approximately this distance,9 the compounds
with shorter tethers may function as antagonists, by preventing
the alignment of the proteins required for heterodimerization. The
choice of tether attachment site was dictated by prior structure–
activity studies on the glitazones10,11 and Targretin analogs.8,12
The peroxisome proliferator-activated receptors (PPARs) are
transcription factors that play key roles in the body’s utilization
and storage of dietary fats.1 When these nuclear hormone recep-
tors are activated by ligand binding, they heterodimerize with
retinoic acid X receptors (RXRs)2 to induce the transcription of
genes encoding enzymes involved in fatty acid synthesis, storage,
and metabolism (including b- and x-oxidation, transport, and
intracellular binding).3 Because either PPAR or RXR ligands can
initiate this process,4 the simultaneous administration of agonists
for both PPAR and RXR results in greater activity than expected
based on a simple summation of the effects of the two individual
compounds.5 In addition, designed molecules combining the 2,4-
thiazolidinedione ring of PPARc ligands with the hydrophobic
moiety of RXR agonists have demonstrated a similar synergism
in effectiveness in biological assays.6
Therefore, we now report the synthesis of heterodimeric com-
pounds 1a–f, which are based on the PPARcagonist, Rosiglitazone
(2) and the RXR ligand Targretin (3). Rosiglitazone is an agent
used in the treatment of non-insulin dependent diabetes mellitus
(NIDDM, or type II diabetes), and Targretin has also shown anti-
NIDDM activity.7,8 For the tethers, polyethylene glycol chains of
various lengths are used, because they are commercially available,
stable, and soluble in water. Oligomers containing up to six
The synthesis of 1a–f was accomplished via a convergent
strategy, in which the appropriately-functionalized subunits of
Rosiglitazone and Targretin were prepared and then attached to
opposite ends of the tether. While the desired Targretin analog had
been previously reported, the substituted Rosiglitazone derivative
had not; and its preparation (Scheme 1) was based on a recent
modification13 of an earlier route.11 Thus, the synthesis began
with the protection of the amine in commercially available 2-
methylaminoethanol (4) to give compound 514 in a 92% yield.
A Mitsunobu reaction between the alcohol 5 and 4-hydroxy-
benzaldehyde produced the ether 615 in a yield of 80%, and a Kno-
evenagel condensation of this aldehyde with 2,4-thiazolidinedione
provided the benzylidene 2,4-thiazolidinedione 715 in a yield of
84%. The comparison of the chemical shift of the olefinic proton
in 7 to that of a calculated value16 suggested that (z)-isomer of
the alkene was formed, as has been reported previously for similar
systems.11
˚
glycol units provide a total length of approximately 21 A when fully
extended, a length beyond which the effects of increased local con-
centration are minimized. Because the ligand binding sites of the
aDepartment of Chemistry, Emory University, 1515 Dickey Drive, Atlanta,
Georgia, 30322, USA
bDepartment of Chemistry, James Madison University, MSC 4501, Har-
risonburg, Virginia, 22807, USA. E-mail: mohlerdl@jmu.edu; Fax: 540-
568-7938; Tel: 540-568-8803
Scheme 1 Synthesis of hydroxy-substituted Rosiglitazone derivative 10.
2082 | Org. Biomol. Chem., 2006, 4, 2082–2087 This journal is The Royal Society of Chemistry 2006
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Unfortunately, a number of subsequent attempts to remove the
Cbz group and reduce the olefin in one step were unsuccessful.
The alkene could be hydrogenated quantitatively with hydrogen
and Pd/C, but the nitrogen was not deprotected under these con-
ditions, even with the use of excess catalyst. Other heterogeneous
and homogeneous catalysts also failed, as did hydrogen transfer
reactions.17 Therefore, a variety of other conditions to remove
the Cbz group were examined; and the combination of PTSA
with trifluoroacetic acid18 was the most effective, removing the
Cbz group in high yield to afford 8,15 which was converted to
919 by hydrogenation. The yield of the subsequent nucleophilic
substitution reaction to produce 10 was disappointing, due to
the thermal decomposition of 9, which occurred faster than
nucleophilic attack on the pyridine functionalized with an electron
donating group.
In summary, a library of tethered Rosiglitazone–Targretin
heterodimers has been prepared by a highly convergent route that
should be easily adaptable to a larger and more diverse set of
compounds as ligands for the PPARc–RXR protein heterodimer.
Experimental
Unless otherwise noted, materials were obtained from commercial
suppliers and were used without further purification. The reactions
requiring anhydrous conditions were performed in oven-dried
glassware which was cooled under argon or nitrogen. Triethy-
lamine was distilled from CaH2 and THF was distilled from
sodium benzophenone ketyl. Ethanol was distilled from Mg, and
˚
acetone was dried over 3 A molecule sieves. NMR data were
collected at room temperature in CDCl3, DMSO-d6, or CD3OD
referenced to internal nondeuterated solvent.
The assembly of the target compounds is shown in Scheme 2.
First, the hydroxy groups in the oligoethylene glycols 11a–f were
converted into good leaving groups, tosylates, to give 12a–f20 in
high yield. The Targretin derivative was then connected to one end
of the tether by nucleophilic substitution with the deprotonated
oxime 1321 to afford the 14a–f. A second nucleophilic substitution
with the alkoxide derived from 10 produced all six of the target
compounds as their methyl esters 15a–f. However, a series of
attempts to hydrolyze these esters by well documented conditions
did not provide the desired acids. While lithium or potassium
hydroxide22 destroyed the molecules, gentler reagents like lithium
iodide23 and potassium carbonate had no effect on the methyl
ester 1a. Fortunately, acceptable deprotection conditions were
discovered after screening several less well established methods.
With sodium hydride (NaH) in dry, distilled THF, the ester
groups were converted to the corresponding acids 1a–f. While the
mechanism of this reaction has not been determined, it appears not
to involve hydroxide generated from NaH and adventitious water,
because NaH in wet THF also led to decomposition, a finding
that was in line with our previous observation of the sensitivity of
these molecules towards hydroxide.
2-[(N-benzyloxycarbonyl)methylamino]ethanol (5)
To a solution of 2-(methylamino)ethanol (4.4 mL, 54.0 mmol)
in CH2Cl2 (180 mL) were added benzylchloroformate (8.4 mL,
55.9 mmol) and Et3N (9.6 mL, 68.8 mmol) at 0 ◦C. The ice bath
was removed and the reaction mixture was then stirred under
nitrogen for 24 h. The solution was then washed with 10% citric
acid (120 mL) and H2O (2 × 120 mL). The organic phase was dried
with MgSO4, concentrated, and purified by chromatography with
40% EtOAc–hexanes to give 5 as a yellow oil (10.4 g, 92%). H
NMR (300 MHz, CDCl3) d 7.37–7.27 (m, 5H), 5.14 (s, 2H), 3.79
(br s, 2H), 3.47 (br s, 2H), 3.00 (s, 3H).
1
Aldehyde 6
Triphenylphosphine (8.29 g, 31.6 mmol), 5 (5.31 g, 25.4 mmol),
4-hydroxybenzaldehyde (3.77 g, 30.8 mmol), DEAD (5.2 mL,
32.0 mmol), and THF (250 mL) were placed in a 500 mL round-
bottom flask, which was then flushed with N2. After stirring at
room temperature for 24 h, the solvent was removed; and Et2O
Scheme 2 Synthesis of PEG-tethered Rosiglitazone–Targetrin derivatives.
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(250 mL) was added to the residue. After filtration, the ethereal
filtrate was washed with saturated NaHCO3 (2 × 250 mL) and
brine 2 × 250 mL), dried over MgSO4 and filtered. After removal
of the ether, the residue was subjected to chromatography on silica
with 25% EtOAc–hexanes to give compound 6 as a yellow oil
(6.36 g, 80%). 1H NMR (400 MHz, CDCl3) d 9.88 (s, 1H), 7.83–
7.78 (m, 2H), 7.36–7.30 (m, 5H), 7.00–6.90 (m, 2H), 6.91 (d, J =
6.6, 1H), 5.14 (s, 2H), 4.24–4.12 (m, 2H), 3.73–3.68 (m, 2H), 3.08
(s, 3H).
followed by the addition of 6-chloro-2-pyridinol (86.3 mg,
0.666 mmol). The mixture was heated at reflux under N2 for 24 h.
The solvent was removed, and the yellow residue was dissolved in
CHCl3 (25 mL). The organic phase was washed with H2O (15 mL),
dried over MgSO4, concentrated, and purified by chromatography
on silica with 5% MeOH–EtOAc to give 10 as a yellow solid
1
(0.240 g, 15%). H NMR (400 MHz, CDCl3) d 7.33 (t, J = 8.0,
1H), 7.09 (d, J = 8.8, 2H), 6.80 (d, J = 8.8, 2H), 5.89 (d, J = 8.0,
1H), 5.48 (d, J = 8.0, 1H), 4.34 (dd, J = 8.8, 4.0, 1H), 4.18–4.09 (m,
2H), 3.85–3.64 (m, 2H), 3.31 (dd, J = 14.0, 4.0, 1H), 3.08 (dd, J =
14.0, 8.8, 1H), 3.03 (s, 3H). 13C NMR (100 MHz, CDCl3) d 175.8,
172.4, 164.3, 157.7, 151.7, 143.7, 130.8, 128.8, 114.8, 103.8, 88.7,
65.9, 53.8, 51.3, 38.5, 37.8. MS (FAB+, 3−NBA/Li) m/z (relative
intensity) 397.7 (M+H2O+Li+, 100%) 380.5 (M+Li+, 9%), 378.6
(M+Li−2H+, 16%).
Substituted 2,4-thiazolidinedione 7
In an oven-dried 250 mL round bottom flask, benzaldehyde 6
(6.02 g, 19.2 mmol) and 2,4-thiazolidinedione (3.99 g, 34.0 mmol)
were dissolved in absolute ethanol (70 mL) and anhydrous toluene
(70 mL). Under nitrogen, piperidine (0.5 mL, 5.0 mmol) was
added, and a Dean–Stark trap filled with toluene was fitted on
the flask. The reaction was heated at reflux for 22 h to give a
bright yellow solution. The solvent was removed, and the residue
was dissolved in EtOAc (100 mL). This solution was washed with
brine (2 × 60 mL), dried with MgSO4, concentrated, and purified
by chromatography on silica with 25% EtOAc–hexanes to give 7
Oligo(ethylene glycol) ditosylates, general procedure
Tosyl chloride (1.05 equiv.) was dissolved in THF to make a
0.1 M solution. The ethylene glycol oligomer (1.00 equiv.) and
triethylamine (1.00 equiv.) were added and the mixture was stirred
under N2 for 24 h. After removal of the solvent, the reside was
dissolved in EtOAc and washed with an equal amount of water.
After drying the organic solution over MgSO4, the solvent was
removed and the residue subjected to chromatography on silica
with 25% (12a–b) 50% (12c–e) or 70% (12e) EtOAc–hexanes.
1
as a yellow solid (6.64 g, 84%). H NMR (300 MHz, CDCl3) d
8.11 (br s, 1H), 7.79 (s, 1H), 7.47–7.39 (m, 2H), 7.38–7.33 (m, 5H),
7.01–6.87 (m, 2H), 5.14 (s, 2H), 4.26–4.10 (m, 2H), 3.72–3.65 (m,
2H), 3.07 (s, 3H).
Ditosylate 12a. White solid (89%). 1H NMR (400 MHz,
CDCl3) d 7.79 (d, J = 8.0, 4H), 7.35 (d, J = 8.0, 4H), 3.53 (s,
4H), 2.44 (s, 6H).
p-Toluenesulfonic acid salt 8
A solution of 7 (6.64 g, 16.1 mmol) and PTSA·H2O (4.66 g,
24.5 mmol) in CH2Cl2 (75 mL) and trifluoroacetic acid (61 mL)
was stirred at room temperature for 28 h. The solvent was removed,
and the residue was kept under vacuum for 40 h. This solid can be
used in next step without further purification. Chromatography
on silica with 25% MeOH–CHCl3 provided 8 as a yellow solid
(6.34 g, 88%). 1H NMR (400 MHz, CD3OD) d 7.77 (s, 1H), 7.71
(d, J = 8.4, 2H), 7.56 (d, J = 8.4, 2H), 7.24 (d, J = 8.4, 2H), 7.15
(dd, J = 6.7, 2.0, 2H), 4.34 (t, J = 5.2, 2H), 3.48 (t, J = 5.2, 2H),
2.80 (s, 3H), 2.37 (s, 3H).
Ditosylate 12b. White solid (100%). 1H NMR (400 MHz,
CDCl3) d 7.78 (d, J = 8.0, 4H), 7.35 (d, J = 8.0, 4H), 4.09 (t,
J = 4.8, 4H), 3.61 (t, J = 4.8, 4H), 2.45 (s, 6H)
Ditosylate 12c. Yellow oil (100%). 1H NMR (400 MHz,
CDCl3) 7.79 (d, J = 11.2, 4H), 7.34 (d, J = 11.2, 4H), 4.14 (t,
J = 6.4, 4H), 3.65 (t, J = 6.4, 4H), 3.53 (s, 4H), 2.44 (s, 6H).
Ditosylate 12d. Yellow oil (80%). 1H NMR (400 MHz, CDCl3)
d 7.79 (d, J = 11.2, 4H), 7.34 (d, J = 11.2, 4H), 4.15 (t, J = 8.0,
4H), 3.68 (t, J = 6.4, 4H), 3.59–3.563 (br s, 8H), 2.44 (s, 6H).
5-(4-(2-methylaminoethoxy)benzyl)-2,4-thiazolidinedione
Ditosylate 12e. Yellow oil (83%). 1H NMR (400 MHz, CDCl3)
d 7.79 (d, J = 11.2, 4H), 7.34 (d, J = 11.2, 4H), 4.15 (t, J = 6.4,
4H), 3.68 (t, J = 6.4, 4H), 3.60 (br s, 4H) 3.58 (br s, 8H), 2.44 (s,
6H).
p-toluenesulfonic acid salt (9)
Compound 8 (6.34 g, 14.1 mmol) was dissolved in MeOH (160 mL)
in a medium pressure reaction flask, to which was added 10% Pd/C
(3.48 g, 3.27 mmol). The flask was shaken in a Parr apparatus at
room temperature under 50 psi hydrogen pressure for 4 d. the
mixture was filtered through celite, and the celite was washed with
large amount of MeOH. The filtrate was collected, concentrated,
and purified by chromatography with 25% MeOH–CHCl3 to give
Ditosylate 12f. Yellow oil (81%). 1H NMR (400 MHz, CDCl3)
d 7.79 (d, J = 11.2, 4H), 7.34 (d, J = 11.2, 4H), 4.15 (t, J = 6.4,
4H), 3.68 (t, J = 6.4, 4H), 3.61 (br s, 4H) 3.57 (br s, 12H), 2.44 (s,
6H).
1
9 as a pale yellow solid (6.37 g, 100%), H NMR (400 MHz,
Alkylation of oxime 13. To a solution of oxime 13 (0.04 M
in THF) was added 60% NaH in oil (2 equiv. vs. 13) under
nitrogen. The mixture was stirred at room temperature for 1 h,
and the oligo(ethylene glycol) ditosylate 12 (2 equiv. vs. 13) was
then added. A condenser was fitted on the flask, which was heated
at reflux for 24 h. The yellow solution was diluted with CHCl3 and
washed twice with H2O. The organic layer was dried over MgSO4,
concentrated, and purified by chromatography with 25% (14a–c)
or 50% (14d–f) EtOAc–hexanes.
CD3OD) d 7.71 (d, J = 8.0, 2H), 7.24 (d, J = 8.0, 2H), 7.22 (d,
J = 8.8, 2H), 6.96 (d, J = 8.8, 2H), 4.71 (dd, J = 9.2, 8.4, 1H),
4.24 (t, J = 5.2, 2H), 3.43 (t, J = 5.2, 2H), 3.36 (dd, J = 14.4, 8.4,
1H), 3.14 (dd, J = 14.4, 9.2, 1H), 2.78 (s, 3H), 2.37 (s, 3H).
Hydroxy-substituted Rosiglitazone 10
In an oven-dried 25 mL round bottom flask, 9 (0.297 g,
0.643 mmol) was mixed with diispropylethylamine (6 mL),
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Alkylated oxime 14a. Off-white solid (61%). Mp: 45–48◦ C 1H
NMR (300 MHz, CDCl3) d 7.99 (d, J = 8.4, 2H), 7.79 (d, J = 8.4,
2H), 7.49 (d, J = 8.4, 2H), 7.29 (d, J = 8.4, 2H), 7.19 (s, 1H), 6.94
(s, 1H), 4.37 (br s, 4H), 3.95 (s, 3H), 2.42 (s, 3H), 2.04 (s, 3H), 1.73
(br s, 4H), 1.35 (s, 6H), 1.25 (s, 6H).
1H), 4.58–4.51 (m, 4H), 4.48 (dd, J = 9.2, 4.0, 1H), 4.16–4.11 (m,
2H), 3.95–3.92 (m, 2H), 3.92 (s, 3H), 3.41 (dd, J = 14.4, 4.0, 1H),
3.12–3.07 (m, 1H), 3.10 (s, 3H), 2.06 (s, 3H), 1.68 (br s, 4H), 1.31
(s, 6H), 1.19 (s, 6H). 13C NMR (100 MHz, CDCl3) d 174.2, 170.5,
167.2, 162.6, 158.5, 157.3, 156.7, 145.5, 142.3, 141.0, 140.3, 133.0,
130.6, 130.5, 130.3, 129.7, 128.1, 127.8, 127.3, 126.7, 114.9, 97.3,
97.2, 73.2, 66.6, 63.9, 53.9, 52.5, 49.7, 38.1, 38.0, 37.9, 35.3, 35.2,
34.3, 34.1, 32.1, 19.6.
Alkylated oxime 14b. Off white solid (53%). Mp: 36–39◦ C 1H
NMR (300 MHz, CDCl3) d 7.99 (d, J = 8.4, 2H), 7.76 (d, J = 8.4,
2H), 7.54 (d, J = 8.4, 2H), 7.28 (d, J = 8.4, 2H), 7.17 (s, 1H), 6.93
(s, 1H), 4.24 (t, J = 4.8, 2H), 4.09 (t, J = 4.8, 2H), 3.92 (s, 3H),
3.68 (t, J = 4.8, 2H), 3.56 (t, J = 4.8, 2H), 2.41 (s, 3H), 2.05 (s,
3H), 1.68 (s, 4H), 1.29 (s, 6H), 1.20 (s, 6H).
Methyl ester 15b. Yellow oil (33%). 1H NMR (400 MHz,
CDCl3) d 7.96 (d, J = 8.4, 2H), 7.54 (d, J = 8.4, 2H), 7.36 (t,
J = 8.0, 1H), 7.14 (s, 1H), 7.11 (d, J = 8.8, 2H), 6.95 (s, 1H), 6.82
(d, J = 8.8, 2H), 6.03 (d, J = 8.0, 1H), 6.01 (d, J = 8.0, 1H), 4.48
(dd, J = 9.2, 4.0, 1H), 4.38–4.32 (m, 4H), 4.14 (t, J = 5.2, 2H),
3.94–3.90 (m, 2H), 3.92 (s, 3H), 3.83 (t, J = 5.2, 2H), 3.75 (t, J =
5.2, 2H), 3.39 (dd, J = 14.4, 4.0, 1H), 3.13 (dd, J = 14.4, 9.2, 1H),
3.09 (s, 3H), 2.07 (s, 3H), 1.68 (br s, 4H), 1.30 (s, 6H), 1.20 (s, 6H).
Alkylated oxime 14c. Colorless liquid (61%). 1H NMR
(400 MHz, CDCl3) d 7.96 (d, J = 8.8, 2H), 7.78 (d, J = 8.8,
2H), 7.53 (d, J = 8.8, 2H), 7.31 (d, J = 8.8, 2H), 7.15 (s, 1H), 6.93
(s, 1H), 4.31 (t, J = 4.8, 2H), 4.11 (t, J = 4.8, 2H), 3.91 (s, 3H),
3.73 (t, J = 4.8, 2H), 3.63 (t, J = 4.8, 2H), 3.50 (br s, 4H), 2.42 (s,
3H), 2.06 (s, 3H), 1.67 (s, 4H), 1.30 (s, 6H), 1.19 (s, 6H).
Methyl ester 15c. Yellow oil (25%). 1H NMR (400 MHz,
CDCl3) d 8.42 (br s, 1H), 7.95 (d, J = 8.4, 2H), 7.53 (d, J =
8.4, 2H), 7.35 (t, J = 8.0, 1H), 7.14 (s, 1H), 7.10 (d, J = 8.8, 2H),
6.93 (s, 1H), 6.82 (d, J = 8.8, 2H), 6.03 (d, J = 8.0, 1H), 6.01
(d, J = 8.0, 1H), 4.46 (dd, J = 8.8, 4.0, 1H), 4.38–4.31 (m, 4H),
4.16–4.11 (m, 2H), 3.96–3.82 (m, 3H), 3.90 (s, 3H), 3.82–3.574 (m,
4H), 3.63–3.56 (m, 4H), 3.35 (dd, J = 14.4, 4.0, 1H), 3.13 (dd, J =
14.4, 8.8, 1H), 3.08 (s, 3H)), 2.06 (s, 3H), 1.67 (s, 4H), 1.30 (s, 6H),
1.19. (s, 6H).
Alkylated oxime 14d. Colorless liquid (39%). 1H NMR
(400 MHz, CDCl3) d 7.96 (d, J = 8.4, 2H), 7.79 (d, J = 8.4,
2H), 7.53 (d, J = 8.4, 2H), 7.32 (d, J = 8.4, 2H), 7.14 (s, 1H), 6.93
(s, 1H), 4.33 (t, J = 5.2, 2H), 4.13 (t, J = 4.8, 2H), 3.91 (s, 3H),
3.76 (t, J = 5.2, 2H), 3.65 (t, J = 4.8, 2H), 3.54 (br s, 8H), 2.43 (s,
3H), 2.06 (s, 3H), 1.68 (s, 4H), 1.30 (s, 6H), 1.19 (s, 6H).
Alkylated oxime 14e. Colorless liquid (37%). 1H NMR
(300 MHz, CDCl3) d 7.96 (d, J = 8.4, 2H), 7.79 (d, J = 8.4,
2H), 7.53 (d, J = 8.4, 2H), 7.33 (d, J = 8.4, 2H), 7.14 (s, 1H), 6.93
(s, 1H), 4.33 (t, J = 5.1, 2H), 4.14 (t, J = 4.8, 2H), 3.90 (s, 3H),
3.76 (t, J = 5.1, 2H), 3.68 (t, J = 4.8, 2H), 3.58–3.52 (m, 12H),
2.43 (s, 3H), 2.06 (s, 3H), 1.67 (s, 4H), 1.30 (s, 6H), 1.19 (s, 6H).
Methyl ester 15d. Yellow oil (25%). 1H NMR (400 MHz,
CDCl3) d 8.56 (br s, 1H), 7.96 (d, J = 8.4, 2H), 7.53 (d, J =
8.4, 2H), 7.35 (t, J = 8.0, 1H), 7.14 (s, 1H), 7.10 (d, J = 8.8, 2H),
6.93 (s, 1H), 6.82 (d, J = 8.8, 2H), 6.03 (d, J = 8.0, 1H), 6.01 (d,
J = 8.0, 1H), 4.46 (dd, J = 8.8, 4.0, 1H), 4.37 (t, J = 4.8, 2H), 4.33
(t, J = 5.2, 2H), 4.13 (t, J = 6.8, 2H), 3.96–3.88 (m, 2H), 3.90 (s,
3H), 3.80–3.73 (m, 4H), 3.68–3.60 (m, 4H), 3.57 (br s, 4H), 3.33
(dd, J = 14.0, 4.0, 1H), 3.14 (dd, J = 14.0, 8.8, 1H), 3.08 (s, 3H),
2.06 (s, 3H), 1.67 (br s, 4H), 1.30 (s, 6H), 1.19 (s, 6H).
Alkylated oxime 14f. Colorless liquid (45%). 1H NMR
(300 MHz, CDCl3) d 7.96 (d, J = 8.7, 2H), 7.79 (d, J = 8.4,
2H), 7.53 (d, J = 8.7, 2H), 7.33 (d, J = 8.4, 2H), 7.14 (s, 1H), 6.93
(s, 1H), 4.34 (t, J = 5.1, 2H), 4.15 (t, J = 4.8, 2H), 3.91 (s, 3H),
3.77 (t, J = 5.1, 2H), 3.67 (t, J = 4.8, 2H), 3.60 (br s, 8H), 3.57
(br s, 8H), 2.44 (s, 3H), 2.06 (s, 3H), 1.68 (s, 4H), 1.30 (s, 6H), 1.20
(s, 6H).
Methyl ester 15e. Yellow oil (28%). 1H NMR (300 MHz,
CDCl3) d 8.93 (br s, 1H), 7.96 (d, J = 8.4, 2H), 7.53 (d, J =
8.4, 2H), 7.35 (t, J = 8.1, 1H), 7.14 (s, 1H), 7.10 (d, J = 8.7, 2H),
6.93 (s, 1H), 6.82 (d, J = 8.7, 2H), 6.03 (d, J = 8.1, 1H), 6.00
(d, J = 8.1, 1H), 4.45 (dd, J = 8.7, 3.9, 1H), 4.39–4.30 (m, 4H),
4.18–4.10 (m, 2H), 3.94–3.86 (m, 2H), 3.90 (s, 3H), 3.81–3.74 (m,
4H), 3.66–3.60 (m, 8H), 3.56 (br s, 4H), 3.34 (dd, J = 14.1, 3.9,
1H), 3.15–3.08 (m, 1H), 3.07 (s, 3H), 2.06 (s, 3H), 1.67 (s, 4H), 1.30
(s, 6H), 1.20 (s, 6H). 13C NMR (100 MHz, CDCl3) d 179.8, 174.4,
170.5, 167.1, 162.7, 158.5, 157.3, 156.6, 145.5, 142.4, 140.9, 140.3,
133.0, 130.7 130.6, 130.5, 130.2, 129.8, 128.1, 127.9, 127.3, 126. 6,
115.0, 97.4, 97.2, 74.2, 70.8 (br), 70.1, 69.9, 69.2, 67.3, 66.3, 64.7,
55.0, 53.7, 52.4, 49.7, 37.9, 37.7, 35.4, 35.3, 34.4, 34.2, 32.1 (br),
19.7.
Formation of protected heterodimer 15. To a solution of com-
pound 10 (0.07 M in MeOH) was added Cs2CO3 (1.25 equiv.)
◦
under nitrogen. The mixture was gently heated (at about 40 C),
and was stirred for 3 h. The solvent was removed first via
rotary evaporation and then under high vacuum. The residue was
dissolved in DMF to make a 0.09 M solution and compound 14 (1
equiv., 0.05 M in DMF) was added under nitrogen. The solution
was heated at 80–85 ◦C for 18 h. The resulting suspension was
diluted with 3 volumes of CHCl3 and was washed with H2O. The
aqueous layer was separated and was extracted with CHCl3,
and the combined organic layers were dried over MgSO4. The
mixture was filtered, and the filtrate was concentrated via rotary
evaporation; and the DMF was removed via vacuum transfer.
Chromatography of the residue on silica was accomplished with
25% (15a–b), 50% (15c–e), or 70% (15f) EtOAc–hexanes.
Methyl ester 15f. Yellow oil (19%). 1H NMR (400 MHz,
CDCl3) d 8.86 (br s, 1H), 7.96 (d, J = 8.4, 2H), 7.53 (d, J =
8.4, 2H), 7.36 (t, J = 8.0, 1H), 7.14 (s, 1H), 7.10 (d, J = 8.8, 2H),
6.93 (s, 1H), 6.82 (d, J = 8.8, 2H), 6.03 (d, J = 8.0, 1H), 6.01
(d, J = 8.0, 1H), 4.47 (dd, J = 9.0, 4.0, 1H), 4.38–4.31 (m, 4H),
4.17–4.11 (m, 2H), 3.97–3.90 (m, 2H), 3.90 (s, 3H), 3.80–3.74 (m,
4H), 3.70–3.59 (m, 12H), 3.57 (br s, 4H), 3.33 (dd, J = 14.0, 4.0,
Methyl ester 15a. Yellow oil (27%). 1H NMR (400 MHz,
CDCl3) d 7.97 (d, J = 8.4, 2H), 7.54 (d, J = 8.4, 2H), 7.37 (t,
J = 8.0, 1H), 7.15 (s, 1H), 7.09 (d, J = 8.8, 2H), 6.96 (s, 1H),
6.80 (d, J = 8.8, 2H), 6.02 (d, J = 8.0, 1H), 6.01 (d, J = 8.0,
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1H), 3.13 (dd, J = 14.0, 9.0, 1H), 3.07 (s, 3H), 2.06 (s, 3H), 1.67
142.1, 141.8, 140.3, 132.8, 130.2 (br), 127.9, 126.8 (br), 126.4 (br),
114.9, 97.4, 97.1, 74.2, 70.8 (br), 69.8 (br), 66.2, 64.4, 60.6, 54.4,
49.8, 38.0 (br), 35.4 (br), 34.3, 34.0, 32.1 (br), 19.6. MS (FAB−,
glycerol) m/z (relative intensity): 852.1 (M−, 61%), 851.1 ([M–H]−
90%), 496.2 (93%), 348.1 (100%). HRMS (FAB−, glycerol): calcd
for C47H55O9N4S1 ([M–H]−): 851.3690. Found: 851.3726.
(s, 4H), 1.30 (s, 6H), 1.19 (s, 6H).
Deprotection of the methyl esters to give the final acids
To a solution of methyl ester 15 (0.04 M in THF), was added
60% NaH in oil (10 equiv.) under nitrogen in one portion. The
suspension was stirred at room temperature for 8 h. The reaction
mixture was quenched with an equal volume of saturated NH4Cl,
and the aqueous layer was adjusted to pH 2 with 1 N HCl.
The mixture was extracted twice with CHCl3, and the combined
organic layers were dried over MgSO4, and concentrated. The
residue was purified by chromatography with 50% (1a–b), 60%
(1c–d), or 70% (1e–f) EtOAc–hexanes.
Heterodimeric ligand 1d. Yellow oil (66%). IR (neat): 3543,
2959, 1750, 1703, 1596, 1575, 1549, 1501, 1414, 1260, 1112, 1058,
1
1031, 957, 836, 796, 722 cm−1. H NMR (400 MHz, CD3OD): d
7.94 (d, J = 8.8, 2H), 7.50 (d, J = 8.8, 2H), 7.36 (t, J = 8.0, 1H),
7.22 (s, 1H), 7.13 (d, J = 8.4, 2H), 6.94 (s, 1H), 6.83 (d, J = 8.4,
2H), 6.08 (d, J = 8.0, 1H), 5.96 (d, J = 8.0, 1H), 4.66 (dd, J = 8.8,
4.0, 1H), 4.33 (t, J = 4.8, 2H), 4.29 (t, J = 4.8, 2H), 4.16 (t, J = 5.6,
2H), 3.92 (t, J = 5.6, 2H), 3.75 (t, J = 4.8, 2H), 3.74 (t, J = 4.8, 2H),
3.612–3.55 (m, 4H), 3.53 (br s, 4H), 3.39–3.32 (m, 1H), 3.09–3.05
(m, 1H), 3.07 (s, 3H), 2.06 (s, 3H), 1.70 (br s, 4H), 1.30 (s, 6H), 1.20
(s, 6H). 13C NMR (100 MHz, CDCl3) d 178.8, 176.7, 168.4, 162.6,
158.2, 157.4, 157.2, 145.0 (br), 142.1, 140.2, 132.7, 130.7, 130.2
(br), 127.8, 126.6 (br), 114.8, 97.3, 97.1, 74.1 (br), 70.8 (br), 69.9
(br), 66.4, 49.7, 38.0 (br), 35.5, 35.3, 34.3, 34.0, 32.1 (br), 19.6. MS
(FAB−, glycerol) m/z (relative intensity): 896.4 (M−, 16%), 895.4
([M–H]−, 24%), 540.3 (100%). HRMS (FAB−, glycerol) calcd for
C49H59O10N4S1 ([M–H]−): 895.3952. Found: 895.3934.
Heterodimeric ligand 1a. Yellow oil (29%). IR (neat): 3563,
3113, 2959, 1750, 1696, 1596, 1542, 1501, 1300, 1253, 1112, 1065,
1031, 944, 796, 783, 722 cm−1. 1H NMR (400 MHz CDCl3) d 8.01
(d, J = 8.4, 2H), 7.55 (d, J = 8.4, 2H), 7.36 (t, J = 8.0, 1H),
7.14 (s, 1H), 7.06 (d, J = 8.4, 2H), 6.95 (s, 1H), 6.76 (d, J = 8.4,
2H), 6.00 (d, J = 8.0, 2H), 4.56 (t, J = 5.0, 2H), 4.50 (t, J =
5.0, 2H), 4.47 (dd, J = 9.2, 4.0, 1H), 4.13–4.06 (m, 2H), 3.97–3.86
(m, 2H), 3.39 (dd, J = 14.0, 4.0, 1H), 3.11–3.03 (m, 1H), 3.08
(s, 3H), 2.05 (s, 3H), 1.670 (br s, 4H), 1.30 (s, 6H), 1.18 (s, 6H).
13C NMR (100 MHz, CDCl3) d 174.6, 170.8, 170.4, 162.6, 158.5,
157.3, 156.6, 145.5, 142.4, 141.7, 140.3, 132.9, 130.6, 130.3, 130.2,
128.1, 127.7, 127.3, 126.7, 114.9, 97.3, 97.1, 73.2, 66.6, 63.7, 53.9,
49.6, 37.9 (br), 35.3 (br), 34.4, 34.1, 32.1 (br), 19.6. MS (FAB−,
glycerol) m/z (relative intensity): 763.4 (M−H−, 18%), 720.4 (6%),
408.4 (55%), 348.2 (21%), 222.9 (100%). HRMS (FAB−, glycerol)
calcd. for C43H47O7N4S1 ([M−H]−): 763.3165. Found: 763.3192.
Heterodimeric ligand 1e. Yellow oil (72%). IR (neat): 3543,
3093, 2939, 1750, 1696, 1602, 1542, 1501, 1407, 1360, 1260, 1105,
1
1025, 944, 796, 722 cm−1. H NMR (400 MHz, CDCl3) d 8.02
(d, J = 8.8, 2H), 7.57 (d, J = 8.8, 2H), 7.36 (t, J = 8.0, 1H),
7.16 (s, 1H), 7.11 (d, J = 8.8, 2H), 6.95 (s, 1H), 6.83 (d, J = 8.8,
2H), 6.04 (d, J = 8.0, 1H), 6.01 (d, J = 8.0, 1H), 4.50 (dd, J =
8.4, 4.0, 1H), 4.38 (t, J = 4.8, 2H), 4.35 (t, J = 4.8, 2H), 4.16–
4.11 (m, 2H), 3.98–3.88 (m, 2H), 3.81–3.70 (m, 4H), 3.68–3.63 (m,
4H), 3.61 (br s, 4H), 3.58 (br s, 4H), 3.32 (dd, J = 14.0, 4.0, 1H),
3.18 (dd, J = 14.0, 8.4, 1H), 3.08 (s, 3H), 2.07 (s, 3H), 1.69 (br s,
4H), 1.31 (s, 6H), 1.21 (s, 6H). 13C NMR (100 MHz, CDCl3) d
179.4, 178.2, 174.7, 162.6, 158.4, 157.4, 157.2, 156.6, 147.4, 145.3,
142.2, 140.2 (br), 132.8, 130.6, 130.5, 130.1 (br), 127.9 (br), 127.0,
126.4, 115.0, 97.3, 97.2, 74.1 (br), 70.7 (br), 70.0, 69.8, 66.3, 64.7,
49.6, 37.9, 37.6, 35.4, 35.3, 34.3, 34.1, 32.1 (br), 19.6. MS (FAB−,
glyerol) m/z (relative intensity): 940.6 (M−, 64%), 939. ([M–H]−,
100%). HRMS (FAB−, glycerol) calcd for C51H63O11N4S1 ([M–
H]−): 939.4214. Found: 939.4205.
Heterodimeric ligand 1b. Yellow oil (42%). IR (neat): 3543,
3194, 2972, 1743, 1690, 1643, 1542, 1508, 1421, 1260, 1119, 1065,
1
736 cm−1. H NMR (400 MHz, CDCl3) d 8.02 (d, J = 8.4, 2H),
7.57 (d, J = 8.8, 2H), 7.36 (t, J = 8.0, 1H), 7.15 (s, 1H), 7.10 (d, J =
8.4, 2H), 6.96 (s, 1H), 6.81 (d, J = 8.4, 2H), 6.03 (d, J = 8.0, 1H),
6.01 (d, J = 8.0, 1H), 4.47 (dd, J = 9.2, 4.0, 1H), 4.38 (t, J = 5.2,
2H), 4.35 (t, J = 5.2, 2H), 4.16–4.10 (m, 2H), 3.94–3.90 (m, 2H),
3.84 (t, J = 5.2, 2H), 3.77 (t, J = 5.2, 2H), 3.40 (dd, J = 14.4, 4.0,
1H), 3.12–3.06 (m,1H), 3.08 (s, 3H)), 2.07 (s, 3H), 1.68 (br s, 4H),
1.31 (s, 6H), 1.20 (s, 6H). 13C NMR (75 MHz, CDCl3) d 174.6,
170.8 170.7, 162.6, 158.5, 157.3, 156.5, 145.5, 142.4, 141.6, 140.2,
132.9, 130.6, 130.3, 129.6, 128.1, 127.8, 127.3, 126.5, 115.0, 97.4,
97.2, 74.2, 70.0, 69.9, 66.4, 64.7, 53.8, 49.6, 37.9, 37.8, 35.3, 35.2,
34.3, 34.1, 32.1 (br), 19.6. MS (FAB−, 3-NBA/Li) m/z (relative
intensity): 815.9 (MLi+, 8%), 809.9 (MH+, 3%), 459.4 (25%), 401.4
(41%), 397.56 (75%), 327.3 (100%). HRMS (FAB+, 3-NBA/Li):
calcd. for C45H53O8N4S1(MH+): 809.3584. Found: 809.3613.
Heterodimeric ligand 1f. Yellow oil (37%). IR (neat): 3543,
3100, 2946, 1750, 1703, 1602, 1542, 1495, 1407, 1260, 1105, 1025,
1
951, 796, 736 cm−1. H NMR (400 MHz, CDCl3) d 8.01 (d, J =
8.8, 2H), 7.55 (d, J = 8.8, 2H), 7.35 (t, J = 8.0, 1H), 7.15 (s, 1H),
7.10 (d, J = 8.8, 2H), 6.94 (s, 1H), 6.82 (d, J = 8.8, 2H), 6.03
(d, J = 8.0, 1H), 6.00 (d, J = 8.0, 1H), 4.48 (dd, J = 8.8, 4.0,
1H), 4.37 (t, J = 4.8, 2H), 4.34 (t, J = 5.6, 2H), 4.16–4.10 (m,
2H), 3.97–3.87 (m, 2H), 3.80–3.75 (m, 4H), 3.68–3.61 (m, 8H),
3.61 (br s, 4H), 3.57 (br s, 4H), 3.33 (dd, J = 14.4, 4.0, 1H),
3.14 (dd, J = 14.4, 8.8, 1H), 3.07 (s, 3H), 2.06 (s, 3H), 1.68 (br s,
4H), 1.30 (s, 6H), 1.20 (s, 6H). 13C NMR (100 MHz, CD3OD): d
177.5, 173.3, 172.1, 163.9, 159.8, 158.8, 158.1, 146.6, 143.5, 141.4,
141.0, 134.2, 132.4, 131.7, 130.9, 130.8, 130.7, 130.0, 129.1, 127.9,
127.3, 115.8, 98.4, 97.8, 87.8, 75.3, 71.7 (br), 71.1, 70.9, 70.6, 67.3,
65.7, 55.4, 50.5, 38.2, 37.9, 36.5, 36.3, 36.2, 36.1, 35.2, 35.0, 32.5
(br), 32.2, 32.1, 19.8. MS (FAB−, glyerol) m/z (relative intensity):
Heterodimeric ligand 1c. Yellow oil (75%). IR (neat): 3543,
3070, 1757, 1703, 1596, 1569, 1542, 1508, 1407, 1253, 1125, 1072,
1025, 836, 790, 769, 722 cm−1. 1H NMR (400 MHz, CD3OD) d 7.91
(d, J = 8.8, 2H), 7.44 (d, J = 8.8, 2H), 7.36 (t, J = 8.0, 1H), 7.19 (s,
1H), 7.11 (d, J = 8.8, 2H), 6.92 (s, 1H), 6.82 (d, J = 8.8, 2H), 6.08
(d, J = 8.0, 1H), 5.96 (d, J = 8.0, 1H), 4.62 (dd, J = 9.2, 4.0, 1H),
4.31 (t, J = 4.8, 2H), 4.28 (t, J = 4.8, 2H), 4.15 (t, J = 6.0, 2H), 3.92
(t, J = 6.0, 2H), 3.74 (t, J = 5.2, 2H), 3.65 (m, 2H), 3.60–3.52 (m,
4H), 3.37–3.35 (m, 1H), 3.070 (s, 3H), 3.06–3.00 (m, 1H), 2.18 (s,
3H), 1.68 (br s, 4H), 1.28 (s, 6H), 1.18 (s, 6H). 13C NMR (75 MHz,
CDCl3) d 177.3, 176.7, 171.4, 162.6, 158.4, 157.3, 156.8, 145.1,
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983.8 (M−, 11%), 349.3 (100%). HRMS (FAB−, glycerol) calcd for
C53H67O12N4S1 ([M–H]−): 983.4476. Found: 983.4446
9 R. T. J. Gampe, V. G. Montana, M. H. Lambert, A. B. Miller, R. K.
Bledsoe, M. V. Milburn, S. A. Kliewer, T. M. Willson and H. E. Xu,
Mol. Cell., 2000, 5, 545–555.
10 T. M. Willson, J. E. Cobb, D. J. Cowan, R. W. Wiethe, I. D. Correa,
S. R. Prakash, K. D. Beck, L. B. Moore, S. A. Kliewer and J. M.
Lehmann, J. Med. Chem., 1996, 39, 665–668; S. P. Tanis, T. T. Parker,
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Reddy, P. R. Reddy, T. H. Krishna, I. N. Rao, H. K. Jajoo, N. V. S. M.
Rao, R. Chakrabarti, T. Dileepkumar and R. Rajagopalan, J. Med.
Chem., 1999, 42, 1927–1940.
Acknowledgements
We gratefully ackowledge funding from the Emory/Georgia Tech
Biomedical Technology Center and useful discussions with Dr
Tony Shuker (Metastatix, Inc.) and Chris Rito (Eli Lilly and Co.).
11 B. C. C. Cantello, M. A. Cawthorne, G. P. Cottam, P. T. Duff, D. Haigh,
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