Conformationally constrained analogues of diacylglycerol. 30. An investigation of diacylglycerol-lactones containing heteroaryl groups reveals compounds with high selectivity for ras guanyl nucleotide-releasing proteins

Article abstract of DOI:10.1021/jm800380b

Using a diacylglycerol-lactone (DAG-lactone) template previously developed in our laboratory as a scaffold with high binding affinity for C1 domains, we describe herein a series of novel DAG-lactones containing heterocyclic moieties (pyridines, quinolines, and indoles) as α-arylidene fragments. Some of the DAG-lactones obtained show selective binding to RasGRP3 as compared to PKCα by more than 2 orders of magnitude and possess subnanomolar affinities. Because activated C1 domains bound to their ligands (DAG or DAG-lactones) insert into membranes, the lipid composition of membranes (cellular, nuclear, and those of internal organelles) is an important determinant for specificity. Therefore, reaching a proper hydrophilic/lipophilic balance for these molecules is critical. This was achieved by carefully selecting partnering acyl fragments for the DAG-lactones with the appropriate lipophilicity. The results clearly show that the combination of chemical and physical properties in these molecules needs to be perfectly balanced to achieve the desired specificity.

Full text of DOI:10.1021/jm800380b

J. Med. Chem. 2008, 51, 5371–5386
5371
Conformationally Constrained Analogues of Diacylglycerol. 30. An Investigation of
Diacylglycerol-lactones Containing Heteroaryl Groups Reveals Compounds with High
Selectivity for Ras Guanyl Nucleotide-Releasing Proteins
Sa¨ıd El Kazzouli,† Nancy E. Lewin,‡ Peter M. Blumberg,‡ and Victor E. Marquez*,†
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health,
376 Boyles Street, Frederick, Maryland 21702, and Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20892
ReceiVed April 2, 2008
Using a diacylglycerol-lactone (DAG-lactone) template previously developed in our laboratory as a scaffold
with high binding affinity for C1 domains, we describe herein a series of novel DAG-lactones containing
heterocyclic moieties (pyridines, quinolines, and indoles) as R-arylidene fragments. Some of the DAG-
lactones obtained show selective binding to RasGRP3 as compared to PKCR by more than 2 orders of
magnitude and possess subnanomolar affinities. Because activated C1 domains bound to their ligands (DAG
or DAG-lactones) insert into membranes, the lipid composition of membranes (cellular, nuclear, and those
of internal organelles) is an important determinant for specificity. Therefore, reaching a proper hydrophilic/
lipophilic balance for these molecules is critical. This was achieved by carefully selecting partnering acyl
fragments for the DAG-lactones with the appropriate lipophilicity. The results clearly show that the
combination of chemical and physical properties in these molecules needs to be perfectly balanced to achieve
the desired specificity.
Introduction
Interposed between the tandem C1/C2 domains and the catalytic
domain of PKD is a PH domain present in many signal
transduction proteins which is capable of binding to membrane
lipids and other proteins.7 The Ras guanyl nucleotide-releasing
protein family members (RasGRP1-4) function as guanine
nucleotide exchange factors for Ras or Rap, leading to their
activation, and are also substrates for PKC.8,9 The chimaerins
are GTPase-activating proteins for Rac, leading to Rac inhibi-
tion.10 The Munc13 proteins are involved in the priming of
vesicle fusion,11 and the MRCKs (myotonic dystrophy kinase-
related Cdc42-binding kinase) are downstream effectors of
Cdc42, which are structurally related to the dystrophia myo-
tonica kinase (DMPK) family, and are involved in actin
cytoskeletal reorganization.12 Finally, the DAGKs (DAG ki-
nases) function to abrogate DAG signaling, thus providing a
negative feedback regulatory loop for the DAG signaling
pathway.13
Protein kinase C (PKC) was the first enzyme identified as a
receptor for the lipophilic second messenger diacylclycerol
(DAGa).1 DAG is generated from the hydrolysis of phosphati-
dylinositol 4,5-bisphosphate catalyzed by phospholipase C
isoforms, which become activated by G-protein-coupled recep-
tors and by receptor tyrosine kinases.2 DAG can also be
generated indirectly from phosphatidylcholine via phospholipase
D.3 PKCs have always been considered major players in cellular
signal transduction involving numerous physiological and
pathological processes, including proliferation, differentiation,
apoptosis, angiogenesis, and drug resistance.4 However, the
complexity of the different PKCs that are responsive to DAG,
which include the conventional (R, ꢀI, ꢀII, and γ) and novel
(δ, ꢀ, η, and θ) isoforms, and their level of differential
expression under physiological conditions make it difficult to
assign a particular role to each isozyme. Furthermore, the
discovery of other DAG-responsive proteins, such as the PKDs,
RasGRPs, chimaerins, Munc13s, MRCKs, and DAGKs further
complicates our understanding of the downstream roles of this
widespread second messenger.5,6 The protein kinase D (PKD/
PKCµ) family represents kinases superficially similar to PKC.
The major recognition motifs for DAG in PKC and other
DAG-responsive proteins are zinc finger structures called C1
domains.14 These highly conserved structures of ∼50 amino
acids, which bind DAG or the DAG-mimicking phorbol es-
ters, appear in tandem in the novel/classical PKCs and in the
PKDs and as single domains in the chimaerins, RasGRPs,
Munc13, and MRCK. X-ray crystallography and NMR analyses,
together with molecular modeling, have provided a detailed
understanding of the interaction of phorbol esters and DAG with
C1 domains.15-19 The phorbol esters and DAG bind in a
hydrophilic cleft in an otherwise hydrophobic surface atop the
C1 domain, resulting in membrane translocation and a confor-
mational change that in PKCs remove the pseudosubstrate
domain from the catalytic site, thereby activating the enzyme.15
Strikingly, the affinity of C1 domains for DAG is approximately
3 orders of magnitude lower than that of the phorbol esters.20
To help overcome this deficiency, we have developed a
conformationally rigid DAG scaffold in the form of a DAG-
lactone which, when substituted with an array of side chains
* To whom correspondence should be addressed. Phone: 301-846-5954.
Fax: 301-846-6033. E-mail: marquezv@mail.nih.gov.
†
Laboratory of Medicinal Chemistry.
Laboratory of Cancer Biology and Genetics.
‡
a Abbreviations: CAN, ceric ammonium nitrate; DAG, diacylglycerol;
DAGK, diacylglycerol kinase; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene;
DMAP, 4-dimethylaminopyridine; DMPK, dystrophia myotonica protein
kinase; FAB-MS, fast atom bombardment mass spectrometry; GTP,
guanosine triphosphate; IC50, half maximal (50%) inhibitory concentration;
LiHMDS, lithium hexamethyldisilazide; MRCK, myotonic dystrophy ki-
nase-related Cdc42-binding kinase; MsCl, methanesulfonyl chloride; NMR,
nuclear magnetic resonance; PDBu, [20-3H]phorbol 12,13-dibutyrate; PH,
pleckstrin homology; PKC, protein kinase C; PKD, protein kinase D;
RasGRP, Ras guanyl nucleotide-releasing protein; SAR, structure-activity
relationship; TBAF, tetra-n-butylammonium fluoride; THF, tetrahydrofuran;
TLC, thin layer chromatography.
10.1021/jm800380b This article not subject to U.S. Copyright. Published 2008 by the American Chemical Society
Published on Web 08/16/2008

5372 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
Table 1. Binding Affinities (Ki, nM) for PKCR and RasGRP3 for Compounds 12a-l
designed to achieve an appropriate hydrophobic/hydrophilic
balance, provides ligands with strong binding affinities for
PKCs.19 With this strategy, we have generated combinatorial
libraries of DAG-lactones that function as potent surrogates of
DAG. In these libraries, the nature of the R1 and R2 substituents
on the DAG-lactone template emerged as the principal deter-
minant in controlling biological activity (see general structures
in Tables 1 and 2). For example, switching from simple n-alkyl
chains to branched alkyl chains or incorporating aromatic
moieties at R1 and/or R2 produced compounds that in some cases

Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5373
Table 2. Binding Affinities (Ki, nm) for PKCR and RasGRP3 for
Compounds 12m-r
Figure 1. Chemical structures of DAG-lactones 1 and 2, Ki values
for PKCR and RasGRP3, and Ki(PKCR)/Ki(RasGRP3) ratios.
Scheme 1a
a Conditions and reagents: (a) LiHMDS, R2CHO, THF, -78 °C; (b) Et3N,
MsCl, DBU, CH2Cl2, 0°C f room temp; (c) (7) CAN, CH3CN, 0 °C; or
(8) TBAF, THF; (d) (9) Et3N, DMAP, R1COCl; or (10) pyridine, CH2Cl2,
then R1COCl, 0 °C; (e) BCl3, CH2Cl2, -78 °C.
constant as the p-dimethylaminophenyl and p-methoxyphenyl
moieties, respectively (Table 1). Then, the R-heteroarylidene
moieties were combined with lipophilic, branched acyl chains
to replace the aromatic acyl moieties for optimal activity (Table
2).
displayed significant degrees of specificity for PKC isozymes
and other proteins containing DAG-responsive C1 domains.21
After the DAG-lactones bind to the C1 domain, these sets of
side chains (R1 and R2) function as “chemical zip codes”, which
are capable of interacting with the membrane in the chemical
space outside the C1 domain of PKC and other C1-domain
containing proteins.21 Owing to the different lipid compositions
of plasma membranes, nuclear membranes and membranes of
cellular organelles, such as lysosomes, peroxysomes, mitochon-
dria, endoplastic reticulum, lipid bodies, and Golgi, the interac-
tions between the “chemical zip codes” and the characteristic
lipid-water-protein microenvironment outside the C1-domain
appear to direct the DAG-lactone-C1-domain complexes to
distinct membrane locations producing unique biological re-
sponses.21 This sorting ability of the “chemical zip codes” was
demonstrated with {2-(hydroxymethyl)-4-[(4-nitrophenyl)meth-
yene]-5-oxo-2-(2,3-dihydrofurfuryl)}methyl 4-(dimethylami-
no)benzoate (1, aka 130C032) and {2-(hydroxymethyl)-4-[(4-
nitrophenyl)methyene]-5-oxo-2-(2,3-dihydrofurfuryl)}methyl
4-methoxybenzoate (2, aka 130C037), which efficiently dis-
criminated between PKCR and RasGRP (both isoforms Ras-
GRP1 and RasGRP3).22 The selectivity for RasGRP3 over
PKCR was 20-fold for 1 and 90-fold for 2 (Figure 1).22 Since
according to the proposed binding mode for DAG-lactones23
the R-arylidene moiety is oriented toward the C1 domain/lipid
interface, we decided to explore changes in the p-nitrophenyl
groups of 1 and 2, beyond the o- and p-isomers already
explored,21 to enhance even further the discrimination between
PKCR and RasGRP. In order to search for different types of
interactions, we decided to incorporate for the first time a set
of R-heteroarylidene moieties while leaving the two acyl groups
Chemistry
As illustrated in Scheme 1, the syntheses of DAG-lactone
analogues 12 were completed from racemic lactones (3 and
4)24-26 employing a well-established methodology developed
in our laboratory.26 This involves formation of the aldol
intermediates (5 and 6) with different aldehydes, followed by
elimination of the ꢀ-hydroxylactone intermediate to the corre-
sponding olefin (7 and 8), which in most cases generated
mixtures of E- and Z-isomers. Consistent with previously
synthesized DAG-lactones, the E/Z geometry around the double
bond was assigned by 1H NMR; the vinyl proton for the
E-isomers displayed a characteristic multiplet that was farther
downfield from that of the corresponding Z-isomers. After
separation of the geometric E/Z-isomers, the compounds were
individually converted to the corresponding DAG-lactones with
different R1 acyl groups by conventional methods. When the
protecting group was the benzyl ether (PG2 ) Bn), debenzy-
lation of intermediates 11 afforded the desired compounds 12.
Because the methylindole moiety was labile to CAN, the
syntheses of DAG-lactones where R2 ) methylindole were
accomplished starting with 426 with identical twin protecting
groups (PG1 ) PG2 ) TBDPS). In this case, olefination of the
aldol product (6) resulting from the reaction with 1-methylin-
dole-3-carboxaldehyde afforded exclusively the E-isomer (8).
The deprotection of the hydroxyl groups with TBAF (10) was
followed by selective monoacylation to give directly the
expected compounds 12.

5374 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
Table 3. Affinity Ratios of PKCR to RasGRP3 for Compounds 12a-r
E-isomer Ki ratio PKCR/RasGRP-3 Z-isomer Ki ratio PKCR/RasGRP-3
Because most of the compounds in Table 1 have log P values
in the lower range of 2.0-3.5, we decided to replace the
aromatic acyl moieties with the more lipophilic branched chain
of valproic acid to improve membrane localization (Table 2).
The preferred use of branched acyl chains, as opposed to linear
n-alky chains, has been discussed previously.19 The changes
resulting from the incorporation of valproic acid were very
impressive, particularly for RasGRP3. Although affinity for
PKCR improved somewhat for all the compounds relative to
the values shown in Table 1, the changes were not as dramatic
as those observed for RasGRP3 (Table 2) where the affinities
were in the low nanomolar range and even reached subnano-
molar values for compounds 12m-E, 12q-E, and 12r-E. For
PKCR, the preferred active isomers were again the E-isomers,
but the differences were in general not as large as those observed
in Table 1. On the contrary, for RasGRP3 the differences
between geometrical isomers were equal to or even higher than
those observed in Table 1, with the exception of two compounds
(12o and 12p) where the differences were only 3-fold.
12a-E
12b-E
12c-E
12d-E
12e-E
12f-E
12g-E
12h-E
12i-E
12j-E
12k-E
12l-E
12m-E
12n-E
12o-E
12p-E
12q-E
12r-E
43
13
19
14
6
47
32
10
27
16
8
64
119
47
45
31
27
165
12b-Z
12c-Z
12d-Z
12e-Z
20
14
8
3
12g-Z
12h-Z
12i-Z
12j-Z
12k-Z
11
4
7
2
6
12m-Z
12n-Z
12o-Z
12p-Z
12q-Z
16
5
20
17
5
The decision to prepare racemic DAG-lactones was mainly
practical, especially when synthesizing a large number of
compounds. These compounds are easier to synthesize, and in
the case of the more potent analogues, which display subna-
nomolar binding affinities, the differences between enantiomers
is minimal as we have shown peviously.27
To select the compounds with the highest selectivity for
RasGRP3, the Ki ratios for PKCR/RasGRP3 were calculated
for all the compounds in Tables 1 and 2. The results in Table
3 show that the two compounds with the highest selectivities
for RasGRP3 are compounds 12m-E and 12r-E with ratios of
119 and 165, respectively. Both compounds were more selective
for RasGRP3 than either 1 and 2.
Biological Results
The interaction of the target DAG-lactones with PKCR and
RasGRP3 was assessed in terms of the ability of the ligands to
displace bound [20-3H]phorbol 12,13-dibutyrate (PDBu) from
recombinant PKCR and RasGRP3, respectively, in the presence
of phosphatidylserine as previously described.22 The IC50 values
were determined by fitting the data points to the theoretical
competition curve, and the Ki values for inhibition of binding
were calculated from the corresponding IC50 values (Tables 1,
2, and 4). For the biological studies, we selected PKCR as
representative of the classical PKCs, which had previously
shown the larger difference in SAR relative to the RasGRP
isoforms.22 PKCR has the further advantage that it has been
the standard PKC isoform against which all the DAG-latones
have routinely been characterized.19 RasGRP3 and RasGRP1
in previous studies have shown similar SAR.22 We picked
RasGRP3 for the present comparisons because of its emerging
role in solid tumors.
Table 1 displays DAG-lactones containing six different types
of R-heteroarylidene moieties with either the p-dimethylami-
nophenyl (12a-f) or the p-methoxyphenyl (12g-l) acyl groups
characteristic of 2 or 1, respectively. In the majority of the cases,
the geometric isomers were separated and studied individually
except when only one isomer was obtained exclusively (com-
pounds 12a-E, 12f-E, and 12l-E). The Ki values in Table 1 for
PKCR and RasGRP3 demonstrate, as expected, that none of
the compounds had a very good affinity for PKCR whereas
affinity for RasGRP3 was very good, particularly for compounds
12f-E and 12l-E. Another important observation was the large
disparities in affinities shown by the two geometrical isomers
for both enzymes. In previous studies with DAG-lactones having
an R-alkylidene moiety the trend was different, almost always
favoring the Z-isomer;19 however, the differences in binding
affinities were small, less than 2-fold. Here, for the R-het-
eroarylidene moieties, not only was the trend reversed but the
differences between geometrical isomers appeared as large as
100-fold (for PKCR) and 185-fold (for RasGRP3), always in
favor of the E-isomer.
In earlier studies we have shown that a highly branched acyl
chain endows the DAG-lactones with more stability and
membrane affinity.19 Therefore, in an effort to expand even more
the difference in affinities between PKCR and RasGRP3, the
highly branched chain of 5-methyl-3-(2-methylpropyl)hexanoic
acid was employed to modify compounds 12m-E and 12r-E.
Unfortunately, despite the fact that the affinity for RasGRP3
remained in the subnanomolar range, the affinity for PKCR was
also augmented. Thus, the ratio of 119 displayed by compound
12m-E dropped to 23 for compound 12s-E and the ratio of 165
for 12r-E plummeted to 21 for compound 12t-E (Table 4).
In conclusion, this work demonstrates that R-heteroarylidene
moieties are novel DAG-lactone constituents with the distinct
ability to significantly discriminate between a conventional PKC
isozyme, represented by the R-isozyme, and another C1 domain-
containing protein, RasGRP3. Since this work describes only a
minor fraction of a potentially sizable chemical space that could
be explored further with larger sets of DAG-lactones, our
findings bode well for the future discovery of compounds
capable of differentiating between PKC isozymes and other C1
domain-containing proteins besides RasGRPs. The other sig-
nificant finding of this work is the importance of the appropriate
hydrophilic/lipophilic balance to achieve selectivity. Because
the lipid composition of the cellular and nuclear membranes as
well as membranes in other intracellular organelles is different,
reaching a proper hydrophilic/lipophilic balance seems to be
of paramount importance for achieving selectivity. Therefore,
the combination of chemical and physical properties in these
molecules has to be perfectly balanced. This was demonstrated
by the loss of selectivity observed between compounds 12m-E
and 12s-E and between compounds 12r-E and 12t-E, where an
increase in 0.88 log P units brought about by enlarging the acyl
group from valproate to 5-methyl-3-(2-methylpropyl)hexanoate
abolished all selectivity. Presently, our laboratory is engaged
in expanding the chemical and physical domains of novel DAG-

Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5375
Table 4. Affinity Ratios of PKCR to RasGRP3 for Compounds 12m-E versus 12s-E and Compound 12r-E versus 12t-E
Aldol Condensation (Procedure A). A solution of 324,25 (1
lactones with the intent of controlling the makeup of novel
DAG-lactones that will show specificity and unique biology.
equiv) in THF (5 mL/mmol) at -78 °C was treated dropwise with
[(CH3)3Si]2NLi (LiHMDS, 1.5 equiv) and stirred at the same
temperature for 2 h. A solution of R2CHO (1.5 equiv) was added
dropwise, and the mixture was stirred at -78 °C (3-6 h). The
reaction mixture was then quenched with a saturated aqueous
solution of NH4Cl and allowed to warm to room temperature. The
layers were separated, and the aqueous layer was extracted with
Et2O (3×). The combined organics were washed with H2O (2×)
and brine (1×), dried (MgSO4), and concentrated in vacuo.
Purification by silica gel flash column chromatography [hexanes
and EtOAc (0% f 75%)] gave 5 as a mixture of diastereomers,
which was used directly in the next step.
Olefination (Procedure B). A solution of 5 (1 equiv) and Et3N
(4 equiv) in CH2Cl2 (10 mL/mmol) was treated dropwise with
CH3SO2Cl (MsCl, 2 equiv) at 0 °C and then stirred at room
temperature for 1 h. The reaction mixture was then cooled again
to 0 °C and treated dropwise with 1,8-diazabicyclo[5.4.0]non-5-
ene (DBU, 5 equiv). When the addition of DBU was completed,
the reaction mixture was allowed to reach room temperature
overnight. The volatiles were removed in vacuo, and the residue
was treated with EtOAc followed by 1 N HCl. The layers were
separated, and the aqueous layer was extracted with EtOAc (1×).
The combined organics were washed with H2O (2×) and brine (1×),
dried (MgSO4), and concentrated in vacuo. Purification by silica
Experimental Section
General Procedures. All chemical reagents were commercially
available. [20-3H]phorbol 12,13-dibutyrate (PDBu) was obtained
from Perkin-Elmer, Waltham, MA. Melting points were determined
on a MelTemp II apparatus, Laboratory Devices, and are uncor-
rected. Combi-flash column chromatography was performed on
silica gel 60 (230-240 mesh) employing a Teledyne Isco instru-
ment, and analytical TLC was performed on Analtech Uniplates
silica gel GF. 1H and 13C NMR spectra were recorded on a Varian
Unity Inova instrument at 400 and 100 MHz, respectively. Spectra
are referenced to the solvent in which they were run (7.26 ppm for
CDCl3). Positive-ion fast atom bombardment mass spectra were
obtained on a VG 7070E-HF double-focusing mass spectrometer
operating at an accelerating voltage of 6 kV under the control of a
MASPEC-II data system for Windows (Mass Spectrometry Ser-
vices, Ltd.). Either glycerol or 3-nitrobenzyl alcohol was used as
the sample matrix, and ionization was effected by a beam of xenon
atoms generated in a saddle-field ion gun at 8.0 ( 0.5 kV. Nominal
mass spectra were obtained at a resolution of 1200, and matrix-
derived ions were background-subtracted during data system
processing. Elemental analyses were performed by Atlantic Mi-
crolab, Inc., Norcross, GA.

5376 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
gel flash column chromatography [hexanes and EtOAc (0% f
75%)] gave 7 as a mixture of E- and Z-isomers.
1751 (CO) cm-1; FAB-MS (m/z, relative intensity) 432.2 (MH+,
100). Anal. (C26H25NO5 ·0.3H2O) C, H, N.
7-E (R2 ) 2-pyridyl): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 8.70 (dm, 1H, J ) 3.9 Hz, H6-pyridine), 7.72 (irregular td, 1H,
J ≈ 8.0, 2.0 Hz, H3-pyridine), 7.51 (t, 2H, J ) 2.9 Hz, CH)C),
7.43 (d, 1H, J ) 7.7 Hz, H4-pyridine), 7.21-7.31 (m, 6H, Ph, H5-
pyridine), 6.78-6.83 (m, 4H, CH3OC6H4), 4.57-4.63 (AB m, 2H,
PhC H2OCH2), 4.03-4.15 (AB m, 2H, CH3OC6H4OCH2), 3.68-3.77
(m, 5H, CH3OC6H4, PhCH2OC H2), 3.58 (dd, 1H, J ) 19.6, 2.8
Hz, CHH-lactone), 3.48 (dd, 1H, J ) 19.6, 3.0 Hz, CHH-lactone);
13C NMR (100 MHz, CDCl3) δ 171.45, 154.38, 154.06, 152.71,
150.08, 137.75, 136.59, 133.74, 130.02, 128.52, 127.86, 127.73,
126.95, 123.32, 115.90, 114.71, 84.14, 73.82, 72.29, 70.93, 55.82,
34.23; IR (neat) 1757 (CO) cm-1; FAB-MS (m/z, relative intensity)
432.3 (MH+, 58%), 91.1 (100%). Anal. (C26H25NO5) C, H, N.
7-Z (R2 ) 2-pyridyl): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 8.53 (dm, 1H, J ) 4.9 Hz, H6-pyridine), 7.58 (dt, 1H, J ) 7.6,
1.8 Hz, H3 and H5-pyridine), 7.23-7.33 (m, 6H, Ph, H5-pyridine),
7.21 (t, 1H, J ) 1.5 Hz, CHdC), 7.15 (dd, 1H, J ) 4.9, 1.1 Hz,
H4-pyridine), 6.74-6.81 (m, 4H, CH3OC6H4), 4.54 (AB q, 2H, J
) 12.0 Hz, PhCH2OCH2), 4.21 (AB d, 1H, J ) 10.4 Hz,
CH3OC6H4OCHH), 4.05 (AB d, 1H, J ) 10.4 Hz, CH3OC6H4OCH
H), 3.82 (AB d, 1 H, J ) 1.4 Hz, PhCH2OCH2), 3.78 (d, 1H, J )
10 Hz, CHH-lactone), 3.75 (s, 3H, CH3OC6H4), 3.72 (d, 1H, J )
10 Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3) δ 172.37,
157.26, 154.49, 152.45, 149.22, 137.52, 136.92, 134.04, 128.55,
127.95, 127.75, 123.46, 121.98, 115.92, 114.74, 87.25, 73.91, 70.61,
69.32, 55.81, 34.40; IR (neat) 1760 (CO) cm-1; FAB-MS (m/z,
relative intensity) 432.3 (MH+, 81%), 91.1 (100%). This material
was used in the next step without further attempts to obtain an
analytically pure sample.
7-Z (R2 ) 4-pyridyl): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 8.41 (m, 2H, H2 and H6-pyridine), 7.18-7.28 (m, 5H, Ph), 7.10
(m, 2H, H3 and H5-pyridine), 7.05 (t, 1H, J ) 1.4 Hz, CHdC),
6.68-6.76 (m, 4H, CH3OC6H4), 4.49 (AB q, 2H, J ) 12.0 Hz,
PhCH2OCH2), 4.16 (AB d, 1H, J ) 9.9 Hz, CH3OC6H4OCHH),
4.00 (AB d, 1H, J ) 9.9 Hz, CH3OC6H4OCH H), 3.76 (AB d, 1H,
J ) 9.9 Hz, PhCH2OCHH), 3.70 (s, 3H, CH3OC6H4), 3.66 (d, 1H,
J ) 9.9 Hz, PhCH2OCH H), 3.58 (br s, 2H, CH2-lactone); 13C
NMR (100 MHz, CDCl3) δ 171.88, 154.58, 152.25, 150.56, 149.50,
146.73, 137.26, 133.79, 128.61, 128.58, 128.12, 127.80, 127.77,
124.19, 123.56, 115.82, 114.79, 114.76, 113.58, 87.35, 73.98, 70.54,
69.26, 55.78, 31.17; IR (neat) 1758 (CO) cm-1; FAB-MS (m/z,
relative intensity) 432.1 (MH+, 100). Anal. (C26H25NO5) C, H, N.
7-E (R2 ) 2-quinolyl): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 8.18 (d, 1H, J ) 8.4 Hz, H4-quinoline), 8.12 (d, 1H, J )
8.4 Hz, H5-quinoline), 7.82 (dm, 1H, J ) 8.2 Hz, H8-quinoline),
7.73 (m, 2H, H7-quinoline), 7.68 (t, 1H, J ) 3.1 Hz, CHdC), 7.56
(dm, 1H, H6-quinoline), 7.53 (d, 1H, J ) 8.4 Hz, H3-quinoline),
7.25-7.31 (m, 5H, Ph), 6.78-6.85 (m, 4H, CH3OC6H4), 4.62 (AB
m, 2H, PhCH2OCH2), 4.15 (AB m, 2H, CH3OC6H4OCH2), 3.78
(s, 2H, PhCH2OCH2), 3.69-3.74 (m, 4H, CH3OC6H4, CHH-
lactone), 3.66 (dd, 1H, J ) 19.9, 3.1, Hz, CHH-lactone); 13C NMR
(100 MHz, CDCl3) δ 171.34, 154.40, 154.02, 152.75, 148.46,
137.75, 136.58, 133.73, 131.58, 130.09, 130.00, 128.54, 127.88,
127.76, 127.67, 127.47, 127.35, 123.96, 115.96, 114.73, 84.31,
73.85, 72.31, 71.01, 55.82, 34.55; IR (neat) 1755 (CO) cm-1; FAB-
MS (m/z, relative intensity) 482.5 (MH+, 100%). Anal. (C30H27NO5)
C, H, N.
7-Z (R2 ) 2-quinolinyl): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 8.06 (d, 1H, J ) 8.5 Hz, H4-quinoline), 8.03 (d, 1H, J )
8.5 Hz, H5-quinoline), 7.80 (d, 1H, J ) 8.0 Hz, H8-quinoline), 7.71
(m, 1H, Hz, H7-quinoline), 7.52 (m, 1H, H6-quinoline), 7.36 (d,
1H, J ) 8.5 Hz, H3-quinoline), 7.21-7.28 (m, 6H, Ph, CHdC),
6.72-6.78 (m, 4H, CH3OC6H4), 4.54 (AB q, 2H, J ) 12.0 Hz,
PhCH2OCH2), 4.22 (dm, 1H, J ) 9.8 Hz, CH3OC6H4OCHH), 4.06
(dm, 1H, J ) 9.8 Hz, CH3OC6H4OCHH), 4.02 (br s, 2H,
PhCH2OCH2), 3.79 (dm, 1H, J ) 10.2 Hz, CHH-lactone), 3.74 (s,
3H, CH3OC6H4), 3.72 (dm, 1H, J ) 10.2 Hz, CHH-lactone); 13C
NMR (100 MHz, CDCl3) δ 172.26, 157.55, 154.32, 152.27, 149.44,
137.31, 136.96, 133.72, 129.67, 128.83, 128.37, 127.79, 127.59,
127.55, 126.94, 126.30, 121.40, 115.77, 114.56, 87.23, 73.75, 70.44,
69.18, 55.64, 34.88; IR (neat) 1758 (CO) cm-1; FAB-MS (m/z,
relative intensity) 482.7 (MH+, 100%). Anal. (C30H27NO5) C, H,
N.
7-E (R2 ) 3-pyridyl): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 8.78 (d, 1H, J ) 1.6 Hz, H2-pyridine), 8.62 (dd, 1H, J ) 1.2, 4.8
Hz, H6-pyridine), 7.83 (dm, 1H, J ) 8.0 Hz, H4-pyridine), 7.53
(irregular t, 1H, J ≈ 2.8 Hz CHdC), 7.42 (dd, 1H, J ) 7.9, 4.8
Hz, H5-pyridine), 7.28-7.33 (m, 5H, Ph), 6.80 (s, 4H, CH3OC6H4),
4.60 (s, 2H, PhCH2OCH2), 4.12 (AB d, 1H, J ) 10.1 Hz,
CH3OC6H4OCHH), 4.06 (AB d, 1H, J ) 10.1 Hz, CH3OC6H4OCH
H), 3.69-3.76 (m, 5H, CH3OC6H4, PhCH2OCH2), 3.28 (dd, 1H,
17.9, 2.9 Hz, CHH-lactone), 3.21 (dd, 1H, 17.9, 2.9 Hz, CH
H-lactone); 13C NMR (100 MHz, CDCl3) δ 169.54, 153.58, 151.44,
149.28, 148.58, 136.44, 136.22, 131.36, 127.62, 127.15, 127.08,
126.82, 123.12, 114.88, 113.80, 82.52, 72.91, 70.97, 69.80, 54.84,
31.94; IR (neat) 1752 (CO) cm-1; FAB-MS (m/z, relative intensity)
432.3 (MH+, 42%), 91.1 (100%). Anal. (C26H25NO5 ·0.6H2O) C,
H, N.
7-Z (R2 ) 3-pyridyl): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 8.50 (m, 2H, H2 and H6-pyridine), 7.55 (dt, 1H, J ) 7.8, 2.1 Hz,
H4-pyridine), 7.18-7.34 (m, 6H, Ph, H5-pyridine), 7.04 (t, 1H, J
) 1.5 Hz, CHdC), 6.73-6.81 (m, 4H, CH3OC6H4), 4.53 (AB q,
2H, J ) 12.0 Hz, PhCH2OCH2), 4.19 (AB d, 1H, J ) 11.8 Hz,
CH3OC6H4OCHH), 4.04 (AB d, 1H, J ) 11.8 Hz, CH3O-
C6H4OCHH), 3.77 (AB d, 1H, J ) 12.2 Hz, PhCH2OCHH), 3.75
(s, 3H, OCH3), 3.68 (AB d, 1H, J ) 12.2 Hz, PhCH2OCH H),
3.63 (br s, 2H, CH2-lactone); 13C NMR (100 MHz, CDCl3) δ
171.93, 154.53, 152.29, 150.03, 148.93, 137.32, 136.53, 134.86,
132.91, 128.57, 128.03, 127.74, 123.71, 115.85, 114.76, 87.24,
73.90, 70.52, 69.22, 55.77, 29.15; IR (neat) 1758 (CO) cm-1; FAB-
MS (m/z, relative intensity) 432.3 (MH+, 100%). Anal.
(C26H25NO5 ·0.3H2O) C, H, N.
7-E (R2 ) 3-quinolyl): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 9.04 (d, 1H, J ) 2.2 Hz, H2-quinoline), 8.23 (br d, 1H, J ) 1.9
Hz, H4-quinoline), 8.13 (d, 1H, J ) 8.4 Hz, H5-quinoline), 7.88
(dm, 1H, J ) 8.4 Hz, H8-quinoline), 7.77 (m, 1H, H7-quinoline),
7.71 (t, 1H, J ) 2.9 Hz, CHdC), 7.60 (m, 1H, H6-quinoline),
7.24-7.32 (m, 5H, Ph), 6.78-6.83 (m, 4H, CH3OC6H4), 4.60 (s,
2H, PhCH2OCH2), 4.11 (AB q, 2H, J ) 9.9 Hz, CH3OC6H4OCH2),
3.75 (AB q, 2H, J ) 10.2 Hz, CH3OC6H4OCH2), 3.74 (s, 3H,
CH3OC6H4), 3.39 (dd, 1H, J ) 17.8, 2.9 Hz, CHH-lactone), 3.31
(dd, 1H, J ) 2.9, 17.8 Hz, CHH-lactone); 13C NMR (100 MHz,
CDCl3) δ 170.74, 154.52, 152.46, 151.14, 147.96, 137.44, 136.83,
132.90, 131.01, 129.45, 128.59, 128.51, 128.03, 127.28, 127.80,
127.64, 127.47,115.87, 114.77, 83.47, 73.89, 71.99, 70.81, 55.79,
33.07, 31.63; IR (neat) 1751 (CO) cm-1; FAB-MS (m/z, relative
intensity) 482.1 (MH+, 100%). This material was used in the next
step without further attempts to obtain an analytically pure sample.
7-Z (R2 ) 3-quinolyl): yellow oil; 1H NMR (400 MHz, CDCl3)
δ 9.00 (s, 2H, H2 and H4-quinoline), 8.08 (d, 1H, J ) 8.4 Hz, H5-
quinoline), 7.89 (dd, 1H, J ) 8.4, 1.1 Hz, H8-quinoline), 7.74 (m,
1H, H7-quinoline), 7.56 (m, 1H, H6-quinoline), 7.27-7.32 (m, 5H,
Ph), 7.09 (t, 1H, J ) 2.4 Hz, CHdC), 6.75-6.82 (m, 4H,
CH3OC6H4), 4.62 (AB m, 2H, PhCH2OCH2), 4.11 (AB q, 2H, J )
9.9 Hz, CH3OC6H4OCH2), 3.70-3.83 (m, 5H, CH3OC6H4OCH2,
CH3OC6H4), 3.27 (dd, 1H, J ) 17.2, 2.4 Hz, CHH-lactone), 3.21
(dd, 1H, J ) 17.2, 2.4 Hz, CHH-lactone); 13C NMR (100 MHz,
1
7-E (R2 ) 4-pyridyl): Solid; mp 105-106 °C; H NMR (400
MHz, CDCl3) 8.66 (m, 2H, H2 and H6-pyridine), 7.43 (t, 1H, J )
2.9 Hz, CHdC), 7.29-7.31 (m, 2H, H3 and H5-pyridine), 7.22-7.28
(m, 5H, Ph), 6.76 (s, 4H, CH3OC6H4), 4.55 (s, 2H, PhCH2OCH2),
4.07 (AB q, 2H, J ) 9.9 Hz, CH3OC6H4OCH2), 3.70 (s, 3H,
CH3OC6H4), 3.71 (AB d, 1H, J ) 10.2 Hz, PhCH2OCHH), 3.67
(AB d, 1H, J ) 10.2 Hz, PhCH2OCH H), 3.27 (dd, 1H, J ) 18.1,
2.9 Hz, CHH-lactone), 3.19 (dd, 1H, J ) 18.1, 2.9 Hz, CH
H-lactone); 13C NMR (100 MHz, CDCl3) 170.24, 154.47, 152.30,
150.43, 141.79, 137.33, 133.13, 130.48, 128.51, 127.97, 127.70,
123.52, 115.77, 114.70, 73.76, 71.85, 70.68, 55.70, 32.85; IR (neat)

Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5377
CDCl3) δ 167.84, 154.54, 152.58, 152.21, 147.93, 137.77, 137.62,
135.56, 130.59, 129.27, 129.00, 128.63, 128.05, 127.82, 127.80,
127.53, 127.07, 126.85, 115.86, 114.84, 82.87, 73.96, 72.13, 70.77,
55.87, 36.11; IR (neat) 1755 (CO) cm-1; FAB-MS (m/z, relative
intensity) 482.4 (MH+, 100%). Anal. (C30H27NO5) C, H, N.
General Procedure for the Synthesis of 9. Ceric ammonium
nitrate (CAN, 3 equiv) was added to a stirring solution of 7 (1
equiv) in acetonitrile (8 mL/mmol of 7) and water (2 mL/mmol of
7) at 0 °C. The reaction was monitored by TLC and quenched after
30 min with a saturated aqueous NaHCO3 solution, and the mixture
was warmed to room temperature. The resulting aqueous solution
was extracted with EtOAc (3×), dried (MgSO4), and concentrated
in vacuo. Purification by silica gel flash column chromatography
[CH2Cl2-MeOH (0% f 10%)] gave intermediate 9.
IR (neat) 3144 (OH), 1745 (CO) cm-1; FAB-MS (m/z, relative
intensity) 326.2 (MH+, 100%). Anal. (C19H19NO4 ·0.3H2O) C, H,
N.
9-Z (R2 ) 4-pyridyl): colorless oil; 1H NMR (400 MHz, CDCl3)
δ 8.40 (m, 2H, H2 and H6-pyridine), 7.23-7.34 (m, 5H, Ph), 7.14
(m, 2H, H3 and H5-pyridine), 7.04 (t, 1H, J ) 1.4 Hz, CHdC),
4.51 (AB q, 2H, J ) 11.9 Hz, PhCH2OCH2), 3.82 (AB q, 2H, J )
12.0 Hz, HOCH2), 3.74 (d, 1H, J ) 10.0 Hz, PhCH2OCHH),
3.60-3.63 (overlapped d and br s, 3H, PhCH2OCHH, CH2-lactone);
13C NMR (100 MHz, CDCl3) δ 172.36, 150.22, 149.54, 147.06,
137.34, 133.50, 128.61, 128.11, 127.78, 124.32, 89.23, 73.96, 70.48,
63.63, 31.17; IR (neat) 3316 (OH), 1754 (CO) cm-1; FAB-MS
(m/z, relative intensity) 326.1 (MH+, 100%). Anal. (C19H19NO4 ·
0.2H2O) C, H, N.
9-E (R2 ) 2-pyridyl): colorless oil; 1H NMR (400 MHz, CDCl3)
δ 8.67 (dm, 1H, J ) 4.3 Hz, H6-pyridine), 7.70 (td, 1H, J ) 7.7,
1.8 Hz, H4-pyridine), 7.46 (t, 1H, J ) 3.0 Hz, CHdC), 7.40 (d,
1H, J ) 7.8 Hz, H5-pyridine), 7.20-7.31 (m, 6H, Ph, H3-pyridine),
4.55 (s, 2H, PhCH2OCH2), 3.84 (AB d, 1H, J ) 12.1 Hz, HOCHH),
3.72 (AB d, 1H, J ) 12.1 Hz, HOCHH), 3.63 (s, 2H, PhCH2OCH2),
3.40 (dd, 1H, J ) 19.6, 3.0 Hz, CHH-lactone), 3.36 (dd, 1H, J )
19.6, 3.0 Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3) δ 171.70,
153.95, 150.02, 137.69, 136.58, 133.85, 130.22, 128.49, 127.85,
127.69, 126.85, 123.33, 85.56, 73.77, 72.17, 65.65, 33.57; IR (neat)
3412 (OH), 1746 (CO) cm-1; FAB-MS (m/z, relative intensity)
326.2 (MH+, 97%), 91.1 (100%). Anal. (C19H19NO4) C, H, N.
9-Z (R2 ) 2-pyridyl): colorless oil; 1H NMR (400 MHz, CDCl3/
CD3OD) δ 8.55 (d, 1H, J ) 4.8 Hz, H6-pyridine), 7.88 (t, 1H, J )
7.8, Hz, H4-pyridine), 7.56 (d, 1H, J ) 7.8 Hz, H3-pyridine), 7.50
(irregular t, 1H, J ≈ 6.3 Hz, H5-pyridine), 7.34 (s, 1H, CHdC),
7.16-7.26 (m, 5H, Ph), 4.42 (AB s, 2H, PhCH2OCH2), 3.95 (s,
2H, CH2OH), 3.74 (AB q, 2H, J ) 12.0 Hz, PhCH2OCH2), 3.66
(AB q, 2H, J ) 10.4 Hz, CH2-lactone); 13C NMR (100 MHz,
CDCl3/CD3OD) δ 172.58, 153.98, 152.61, 144.12, 143.44, 137.33,
130.40, 128.43, 127.88, 127.76, 126.39, 124.23, 90.29, 73.80, 70.06,
62.64, 30.81; IR (neat) 3420 (OH), 1751 (CO) cm-1; FAB-MS
(m/z, relative intensity) 326.1 (MH+, 100%). Anal. (C19H19NO4)
C, H, N.
9-E (R2 ) 2-quinolyl): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 8.18 (d, 1H, J ) 8.4 Hz, H4-quinoline), 8.11 (d, 1H, J )
8.4 Hz, H5-quinoline), 7.82 (dm, 1H, J ) 8.4 Hz, H8-quinoline),
7.73 (m, 1H, H7-quinoline), 7.65 (t, 1H, J ) 3.1 Hz, CHdC), 7.55
(m, 1H, H6-quinoline), 7.51 (d, 1H, J ) 8.4 Hz, H3-quinoline),
7.25-7.30 (m, 5H, Ph), 4.59 (s, 2H, PhCH2OCH2), 3.90 (AB d,
1H, J ) 12.2 Hz, HOCHH), 3.79 (AB d, 1H, J ) 12.2 Hz,
HOCHH), 3.67 (s, 2H, PhCH2OCH2), 3.65 (dd, 1H, J ) 19.8, 3.1
Hz, CHH-lactone), 3.55 (dd, 1H, J ) 19.8, 3.1 Hz, CHH-lactone);
13C NMR (100 MHz, CDCl3) δ 171.39, 153.81, 137.68, 137.42,
130.27, 129.80, 128.61, 128.57, 127.95, 127.83, 127.78, 127.70,
127.65, 127.40, 123.86, 85.66, 73.97, 73.86, 72.17, 65.83, 33.07;
13C NMR (100 MHz, CDCl3) δ 171.39, 153.81, 137.68, 137.42,
130.27, 129.80, 128.61, 128.57, 127.95, 127.83, 127.78, 127.70,
127.65, 127.40, 123.86, 85.66, 73.97, 73.86, 72.17, 65.83, 33.95;
IR (neat) 3348 (OH), 1754 (CO) cm-1; FAB-MS (m/z, relative
intensity) 376.1 (MH+, 100%). This material was used in the next
step without further attempts to obtain an analytically pure sample.
9-Z (R2 ) 2-quinolyl): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 8.47 (d, 1H, J ) 8.4 Hz, H4-quinoline), 8.36 (d, 1H, J )
8.4 Hz, H5-quinoline), 7.96 (d, 1H, J ) 8.3 Hz, H8-quinoline), 7.92
(irregular t. 1H, J ≈ 7.7 Hz, H7-quinoline), 7.81 (d, 1H, J ) 8.4
Hz, H6-quinoline), 7.74 (t, 1H, J ) 7.6 Hz, H3-quinoline), 7.61 (br
s, 1H, CHdC), 7.19-7.27 (m, 5H, Ph), 4.45 (s, 2H, PhCH2OCH2),
4.32 (AB q, 2H, J ) 15.8 Hz, HOCH2), 3.83 (AB q, 2H, J ) 12.0
Hz, PhCH2OCH2), 3.73 (AB q, 2H, J ) 10.5 Hz, CH2-lactone);
13C NMR (100 MHz, CDCl3) δ 172.26, 155.98, 154.00, 146.01,
138.58, 137.51, 134.81, 129.26, 128.57, 128.55, 128.53, 127.92,
127.90, 127.51, 122.93, 121.51, 90.66, 73.89, 70.21, 62.96, 30.69;
FAB-MS (m/z, relative intensity) 376.1 (MH+, 100%). This material
decomposed on standing and was not analyzed.
9-E (R2 ) 3-pyridyl): colorless oil; 1H NMR (400 MHz, CDCl3)
δ 8.71 (d, 1H, J ) 1.7 Hz, H2-pyridine), 8.56 (dd, 1H, J ) 4.8, 1.3
Hz, H6-pyridine), 7.77 (dt, 1H, J ) 8.0, 1.8 Hz, H4-pyridine), 7.44
(t, 1H, J ) 2.9 Hz, CHdC), 7.34 (dd, 1H, J ) 8.0, 4.8 Hz, H5-
pyridine), 7.21-7.30 (m, 5H, Ph), 4.53 (s, 2H, PhCH2OCH2), 3.84
(AB d, 1H, J ) 12.2 Hz, HOCHH), 3.72 (AB d, 1H, J ) 12.2 Hz,
HOCHH), 3.60 (s, 2H, PhCH2OCH2), 3.20 (dd, 1H, J ) 17.8, 2.9
Hz, CHH-lactone), 3.12 (dd, 1H, J ) 17.8, 2.9 Hz, CHH-lactone);
13C NMR (100 MHz, CDCl3) δ 171.10, 150.81, 150.02, 137.47,
136.75, 132.47, 130.82, 128.54, 128.27, 127.97, 127.70, 123.88,
85.22, 73.77, 71.89, 65.09, 32.27; IR (neat) 3060 (OH), 1745 (CO)
cm-1; FAB-MS (m/z, relative intensity) 326.2 (MH+, 100%). Anal.
(C19H19NO4) C, H, N.
1
9-E (R2 ) 3-quinolyl): with solid; mp 138-139 °C; H NMR
(400 MHz, CDCl3) δ 9.02 (d, 1H, J ) 2.2 Hz, H2-quinoline), 8.23
(d, 1H, J ) 2.0 Hz, H4-quinoline), 8.11 (d, 1H, J ) 8.4 Hz, H5-
quinoline), 7.85 (dm, 1H, J ) 8.2 Hz, H8-quinoline), 7.76 (m, 1H,
H7-quinoline), 7.64 (t, 1H, J ) 2.9 Hz, CHdC), 7.59 (m, 1H, H6-
quinoline), 7.22-7.31 (m, 5H, Ph), 4.56 (s, 2H, PhCH2OCH2), 3.91
(AB d, 1H, J ) 12.2 Hz, HOCHH), 3.81 (AB d, 1H, J ) 12.2 Hz,
HOCHH), 3.68 (AB q, 2H, J ) 10.2 Hz, PhCH2OCH2), 3.33 (dd,
1H, J ) 17.8, 2.9 Hz, CHH-lactone), 3.33 (dd, 1H, J ) 17.8, 2.9
Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3) δ 171.18, 151.08,
147.76, 137.46, 137.00, 132.84, 132.85, 131.06, 129.25, 128.58,
128.50, 128.02, 127.94, 127.78, 127.66, 85.15, 73.85, 71.96, 65.26,
32.49; IR (neat) 3420 (OH), 1745 (CO) cm-1; FAB-MS (m/z,
relative intensity) 376.4 (MH+, 100%). Anal. (C23H21NO4 ·0.3H2O)
C, H, N.
1
9-Z (R2 ) 3-pyridyl): white solid; mp 146-147 °C; H NMR
(400 MHz, CDCl3/CD3OD) δ 8.54-8.66 (br doublets, 2H, H2 and
H6-pyridine), 8.02 (d, 1H, J ) 7.9 Hz, H4-pyridine), 7.50 (br s,
1H, H5-pyridine), 7.20-7.31 (m, 6H, Ph, CHdC), 4.48 (AB q, J
) 12.0 Hz, 1H, PhCH2OCH2), 3.71-3.81 (m, 4H, HOCH2,
PhCH2OCH2), 3.66 (AB q, 2 H, J ) 10.3 Hz, CH2-lactone); 13C
NMR (100 MHz, CDCl3/CD3OD) δ 172.71, 151.89, 145.06, 142.77,
141.00, 137.30, 131.90, 128.42, 127.88, 127.68, 126.50, 126.48,
90.21, 73.74, 70.17, 62.46, 28.49; IR (neat) 3376 (OH), 1752 (CO)
cm-1; FAB-MS (m/z, relative intensity) 326.1 (MH+, 100%). Anal.
(C19H19NO4 ·0.2H2O) C, H, N.
9-Z (R2 ) 3-quinolyl): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 8.82 (d, 1H, J ) 1.7 Hz, H2-quinoline), 8.12 (d, 1 H, J
) 8.4 Hz, H5-quinoline), 8.08 (d, 1H, J ) 1.7 Hz, H4-quinoline),
7.68-7.74 (m, 2H, H7 and H8-quinoline), 7.54 (m, 1H, H6-
quinoline), 7.22-7.31 (m, 5H, Ph), 7.07 (t, 1H, J ) 1.4 Hz, CHdC),
4.52 (AB q, 2H, J ) 12.0 Hz, PhCH2OCH2), 3.83 (AB q, 2H, J )
12.0 Hz, HOCH2), 3.80 (br s, 2 H, PhCH2OCH2), 3.73 (AB d, 1H,
J ) 10.0 Hz, CH2-lactone); 13C NMR (100 MHz, CDCl3) δ 172.37,
150.56, 150.04, 145.70, 137.35, 137.02, 134.33, 130.41, 130.20,
130.16, 128.63, 128.22, 128.10, 127.81, 127.77, 127.54, 89.11,
1
9-E (R2 ) 4-pyridyl): white solid; mp 144-145 °C; H NMR
(400 MHz, DMSO-d6) δ 8.67 (m, 2H, H2 and H6-pyridine), 7.56
(m, 2H, H3 and H5-pyridine), 7.34 (t, 1H, J ) 2.9 Hz, CHdC),
7.23-7.31 (m, 5H, Ph), 5.25 (t, 1H, J ) 5.8 Hz, HOCH2), 4.52 (s,
2H, PhCH2OCH2), 3.52-3.66 (m, 4H, PhCH2OCH2, HOCH2), 3.20
(dd, 1H, J ) 18.4, 2.9 Hz, CHH-lactone), 3.12 (dd, 1H, J ) 18.4,
2.9 Hz, CHH-lactone); 13C NMR (100 MHz, DMSO-d6) δ 170.33,
150.29, 150.26, 141.52, 137.97, 132.34, 130.91, 130.85, 128.24,
127.48, 127.25, 123.58, 123.55, 85.73, 72.53, 71.75, 63.43, 31.90;
73.97, 70.53, 63.78, 29.39; IR (neat) 3450 (OH), 1738 (CO) cm-1
;

5378 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
FAB-MS (m/z, relative intensity) 376.1 (MH+, 100%). Anal.
(C23H21NO4 ·0.8H2O) C, H, N.
1762 (CO), 1703 (CO) cm-1; FAB-MS (m/z, relative intensity)
473.2 (MH+, 73%), 148.1 (MH+, 100%). Anal. (C28H28N2O5 ·
0.5H2O).
General Procedure for the Synthesis of 11. A solution of 9 (1
equiv) in CH2Cl2 (12 mL/mmol) was treated with Et3N (3 equiv),
R1COCl (1.5 equiv), and a catalytic amount of DMAP (0.1 equiv).
The mixture was stirred at room temperature and monitored by
TLC. Upon completion, the mixture was concentrated in vacuo and
purified by silica gel flash column chromatography [hexanes-EtOAc
(0% f 75%)] to give 11.
11-E (R1 ) 4-(CH3)2NC6H4, R2 ) 2-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.68 (dm, 1H, J ) 4.8 Hz, H6-
pyridine), 7.79 (m, 2H, (CH3)2NC6H4CO2), 7.70 (td, 1H, J ) 7.7,
1.9 Hz, H4-pyridine), 7.50 (t, 1H, J ) 3.0 Hz, CHdC), 7.40 (d,
1H, J ) 7.8 Hz, H3-pyridine), 7.20-7.30 (m, 6H, Ph, H5-pyridine),
6.57 (m, 2H, (CH3)2N C6H4CO2), 4.62 (s, 2H, PhCH2O), 4.48 (AB
m, 2H, CO2CH2), 3.72 (AB m, 2H, PhCH2OCH2), 3.56 (dd, 1H, J
) 19.6, 3.0 Hz, CHH-lactone), 3.52 (dd, 1H, J ) 19.6, 3.0 Hz,
CHH-lactone), 3.01 (s, 6H, (CH3)2NC6H4); 13C NMR (100 MHz,
CDCl3) δ 171.43, 166.39, 153.95, 153.55, 150.11, 137.63, 136.53,
133.70, 131.58, 129.95, 128.52, 127.87, 127.73, 126.87, 123.32,
116.11, 110.77, 83.87, 73.85, 72.23, 66.00, 40.13, 34.29; IR (neat)
1754 (CO), 1701 (CO) cm-1; FAB-MS (m/z, relative intensity)
473.2 (MH+, 41%), 148.1 (MH+, 100%). Anal. (C28H28N2O5) C,
H, N.
11-E (R1 ) 4-(CH3)2NC6H4, R2 ) 3-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.70 (d, 1H, J ) 2.0 Hz,
H2-pyridine), 8.58 (dd, 1H, J ) 4.8. 1.4 Hz, H6-pyridine), 7.72-7.77
(m, 3H, H4-pyridine, (CH3)2NC6H4CO2), 7.51 (t, 1H, J ) 2.9 Hz,
CHdC), 7.34 (dd, 1H, J ) 8.0, 4.8 Hz, H5-pyridine), 7.26-7.30
(m, 5H, Ph), 6.56 (m, 2H, (CH3)2NC6H4CO2), 4.59 (AB q, 2H, J
) 12.1 Hz, PhCH2O), 4.52 (AB d, J ) 12.1 Hz, 1H, CO2CHH),
4.42 (AB d, J ) 12.1 Hz, 1H, CO2CHH), 3.73 (AB d, 1H, J )
10.2 Hz, PhCH2OCHH), 3.71 (AB q, 2H, J ) 10.2 Hz,
PhCH2OCH2), 3.24 (dd, 1H, J ) 17.8, 2.9, Hz, CHH-lactone), 3.14
(dd, 1H, J ) 17.8, 2.9 Hz, CHH-lactone), 3.01 (s, 6H,
(CH3)2NC6H4); 13C NMR (100 MHz, CDCl3) δ 170.56, 166.24,
153.63, 151.15, 150.33, 137.32, 136.23, 132.62, 131.54, 130.56,
128.58, 128.04, 127.79, 127.63, 123.78, 115.64, 110.75, 83.26,
73.88, 71.83, 65.75, 40.09, 33.03; IR (neat) 1753 (CO), 1700 (CO)
cm-1; FAB-MS (m/z, relative intensity) 473.3 (MH+, 36%), 148.1
(MH+, 100%). Anal. (C28H28N2O5 ·0.3H2O) C, H, N.
11-Z (R1 ) 4-(CH3)2NC6H4, R2 ) 4-pyridyl): colorless oil; 1H
NMR (400 MHz, CDCl3) δ 8.32 (br d, J ) 6.0 Hz, 2H, H2 and
H6-pyridine), 7.74 (m, 2H, (CH3)2NC6H4CO2), 7.27-7.36 (m, 5H,
Ph), 7.07 (br d, 2H, J ) 6.0 Hz, H3 and H5-pyridine), 7.05 (t, 1H,
J ) 1.4 Hz, CHdC), 6.59 (m, 2H, (CH3)2NC6H4CO2), 4.78 (AB
d, 1H, J ) 11.9 Hz, CO2CHH), 4.55 (AB q, 2H, J ) 11.9 Hz,
PhCH2O), 4.38 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.77 (AB d,
1H, J ) 10.1 Hz, PhCH2OCHH), 3.67 (AB d, 1H, J ) 10.1 Hz,
PhCH2OCHH), 3.58 (br s, 2H, CH2-lactone), 2.98 (s, 6H,
(CH3)2NC6H4); 13C NMR (100 MHz, CDCl3) δ 171.85, 166.21,
153.81, 149.17, 148.66, 137.15, 133.54, 131.58, 128.70, 128.24,
127.91, 124.43, 115.40, 110.91, 110.85, 87.76, 74.11, 70.79, 62.88,
40.20, 31.29; IR (neat) 1759 (CO), 1698 (CO) cm-1; FAB-MS
(m/z, relative intensity) 473.2 (MH+, 100%). Anal. (C28H28N2O5)
C, H, N.
11-E (R1 ) 4-(CH3)2NC6H4, R2 ) 2-quinolyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.13 (d, 1H, J ) 8.4 Hz,
H4-quinoline), 8.07 (d, 1H, J ) 8.4 Hz, H5-quinoline), 7.80 (m,
3H, (CH3)2NC6H4CO2, H8-quinoline), 7.69 (m, 1H, H7-quinoline),
7.64 (t, 1H, J ) 3.0 Hz, CHdC), 7.52 (m, 1H, H6-quinoline), 7.47
(d, 1H, J ) 8.4 Hz, H3-quinoline), 7.20-7.28 (m, 5H, Ph), 6.53
(m, 2H, (CH3)2NC6H4CO2), 4.58 (s, 2H, PhCH2O), 4.49(AB q, 2H,
J ) 12.00 Hz, CO2CH2), 3.61-3.78 (overlapping AB q and dd,
3H, J ) 10.2 and 19.8, 3.0 Hz, PhCH2OCH2 and CHH-lactone),
3.60 (dd, 1 H, J ) 19.8, 3.0 Hz, CHH-lactone), 3.01 (s, 6H,
(CH3)2NC6H4); 13C NMR (100 MHz, CDCl3) δ 171.35, 166.45,
153.93, 153.59, 148.48, 137.64, 136.55, 133.70, 131.62, 131.53,
130.17, 130.03, 128.56, 127.91, 127.79, 127.63, 127.49, 127.35,
123.86, 116.12, 110.80, 84.08, 73.89, 72.23, 66.08, 40.15, 34.62;
IR (neat) 1759 (CO), 1701 (CO) cm-1; FAB-MS (m/z, relative
intensity) 523.3 (MH+, 40%), 148.1 (MH+, 100%). Anal. (C32H30-
N2O5 ·0.1H2O) C, H, N.
11-Z (R1 ) 4-(CH3)2NC6H4, R2 ) 2-quinolyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.02 (br d, 1H, J ) 8.4 Hz, H4-
quinoline), 7.94 (d, 1H, J ) 8.4 Hz, H5-quinoline), 7.73-7.77 (m,
4H, (CH3)2NC6H4CO2, H7 and H8-quinoline), 7.51 (m, 1H, J )
H6-quinoline), 7.20-7.31 (m, 7H, Ph, H3-quinoline, CHdC), 6.50
(m, 2H, (CH3)2NC6H4CO2), 4.66 (AB d, 1H, J ) 11.8 Hz,
CO2CHH), 4.56 (AB q, 2H, J ) 12.0 Hz, PhCH2O), 4.45 (AB d,
1H, J ) 11.8 Hz, CO2CHH), 3.98 (br s, 2H, PhCH2OCH2), 3.77
(AB d, 1H, J ) 10.1 Hz, C6H5CH2OCHH), 3.66 (AB d, 1H, J )
10.1 Hz, C6H5CH2OCHH) 3.02 (s, 6H, N(CH3)2); 13C NMR (100
MHz, CDCl3) δ 172.39, 166.09, 157.44, 153.57, 149.35, 149.33,
137.30, 133.74, 131.50, 130.02, 128.62, 128.57, 128.00, 127.84,
127.80, 127.66, 127.07, 126.57, 121.50, 115.81, 110.74, 87.50,
73.78, 70.86, 63.18, 40.14, 34.69; IR (neat) 1762 (CO), 1703 (CO)
cm-1; FAB-MS (m/z, relative intensity) 523.2 (MH+, 87%), 148.1
(MH+, 100%). This material was used in the next step without
further attempts to obtain an analytically pure sample.
11-Z (R1 ) 4-(CH3)2NC6H4, R2 ) 3-pyridyl): colorless oil; 1H
NMR (400 MHz, CDCl3) δ 8.40-8.42 (m, 2H, H2 and H6-pyridine),
7.71 (m, 2H, (CH3)2NC6H4CO2), 7.37 (dt, 1H, J ) 6.1, ∼1.9 Hz,
H4-pyridine), 7.21-7.31(m, 5H, Ph), 7.04 (ddd, 1H, J ) 4.9, 3.0,
∼0.7 Hz, H5-pyridine), 6.90 (t, 1H, J ) 1.5 Hz, CHdC), 6.56 (m,
2H, (CH3)2NC6H4CO2), 4.65 (AB d, 1H, J ) 11.8 Hz, CO2CHH)
4.51 (AB q, 2H, J ) 12.0 Hz, PhCH2O), 4.36 (AB d, 1H, J ) 11.8
Hz, CO2CHH), 3.71 (AB d, 1H, J ) 10.1 Hz, PhCH2OCHH), 3.60
(AB d, 1H, J ) 10.1 Hz, PhCH2OCHH), 3.51 (br s, 2H, CCH2-
lactone), 3.01 (s, 3H, (CH3)2NC6H4); 13C NMR (100 MHz, CDCl3)
δ 171.93, 166.12, 153.69, 149.89, 148.27, 148.13, 137.19, 136.54,
135.00, 132.77, 131.51, 128.62, 128.09, 127.81, 123.72, 115.63,
110.85, 87.45, 73.97, 70.69, 63.01, 40.13, 29.11; IR (neat) 1755
(CO), 1702 (CO) cm-1; FAB-MS (m/z, relative intensity) 473.2
(MH+, 95%), 148.1 (MH+, 100%). Anal. (C28H28N2O5 ·0.1H2O)
C, H, N.
11-E (R1 ) 4-(CH3)2NC6H4, R2 ) 4-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.62 (br d, 2H, J ) 6.0 Hz, H2 and
H6-pyridine), 7.70 (m, 2H, (CH3)2NC6H4CO2), 7.38 (t, 1H, J )
2.9 Hz, CHdC), 7.22-7.25 (m, 7H, Ph, H3 and H5-pyridine), 6.52
(m, 2H, (CH3)2NC6H4CO2), 4.53 (AB q, 2H, J ) 11.8 Hz,
PhCH2O), 4.50 (AB d, 1H, J ) 12.0 Hz, CO2CHH), 4.37 (AB d,
1H, J ) 12.0 Hz, CO2CHH), 3.67 (AB m, 2H, J ) PhCH2OCH2),
3.21 (dd, 1H, J ) 18.0, 2.9 Hz, CHH-lactone), 3.12 (dd, 1H, J )
18.0, 2.9 Hz, CHH-lactone), 2.98 (s, 6H, (CH3)2NC6H4); 13C NMR
(100 MHz, CDCl3) δ 170.17, 166.19, 153.65, 149.90, 142.31,
137.24, 132.88, 131.55, 130.90, 128.59, 128.07, 127.80, 123.65,
115.52, 110.74, 83.59, 73.89, 71.72, 65.62, 40.09, 33.03; IR (neat)
11-E (R1 ) 4-(CH3)2NC6H4, R2 ) 3-quinolyl): yellow solid;
mp 146-147 °C; 1H NMR (400 MHz, CDCl3) δ 8.94 (br d, 1H, J
) 1.7 Hz, H2-quinoline), 8.14 (br d, 1H, J ) 1.8 Hz, H4-quinoline),
8.07 (d, 1H, J ) 8.4 Hz, H5-quinoline), 7.82 (dm, 1H, J ) 8.4 Hz,
H8-quinoline), 7.71-7.75 (m, 3H, H7-quinoline, (CH3)2NC6H4CO2),
7.64 (br t, 1H, J ) 2.9 Hz, CHdC), 7.56 (m, 1H, H6-quinoline),
7.20-7.29 (m, 5H, Ph), 6.51 (m, 2H, (CH3)2NC6H4CO2), 4.57 (AB
m, 2H, PhCH2OCH2), 4.53 (AB d, 1H, J ) 11.9 Hz, CO2CHH),
4.41 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.78 (AB q, 2H, J )
10.1 Hz, C6H5CH2OCH2), 3.32 (dd, 1H, J ) 17.8, 2.9 Hz, CHH-
lactone), 3.22 (dd, 1H, J ) 17.8, 2.9 Hz, CHH-lactone), 2.96 (s,
3H, (CH3)2NC6H4); 13C NMR (100 MHz, CDCl3) δ 170.68, 166.26,
153.60, 151.19, 147.98, 137.32, 136.58, 132.74, 131.53, 130.95,
129.43, 128.59, 128.50, 128.03, 127.82, 127.58, 127.49, 115.63,
110.73, 83.33, 73.91, 71.86, 65.79, 40.07, 33.20; IR (neat) 1752
(CO), 1699 (CO) cm-1; FAB-MS (m/z, relative intensity) 523.5
(MH+
C, H, N.
, 75%), 148.2 (MH+, 100%). Anal. (C32H30N2O5 ·0.5H2O)

Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5379
11-Z (R1 ) 4-(CH3)2NC6H4, R2 ) 3-quinolyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.75 (d, 1H, J ) 2.2 Hz,
H2-quinoline), 8.07 (d, 1H, J ) 8.4 Hz, H8-quinoline), 7.92 (br d,
1H, J ) 1.8 Hz, H4-quinoline), 7.64-7.70 (m, 3H, (CH3)2-
NC6H4CO2, H5-quinoline), 7.49 (br dm, 1H, J ) 8.0 Hz, H7-
quinoline), 7.48 (m, 1H, H6-quinoline), 7.24-7.32 (m, 5H, Ph),
7.03 (t, 1H, J ) 1.4 Hz, CHdC), 6.46 (m, 2H, (CH3)2NC6H4CO2),
4.69 (AB d, 1H, J ) 11.8 Hz, CO2CHH), 4.54 (AB q, 2H, J )
12.0 Hz, PhCH2OCH2), 4.41 (AB d, 1H, J ) 11.8 Hz, CO2CHH),
3.74-3.76 (m, 3H, C6H5CH2OCH2, CHH-lactone), 3.64 (AB d, 1H,
J ) 10.1 Hz, CHH-lactone), 2.99 (s, 6H, N(CH3)2); 13C NMR (100
MHz, CDCl3) δ 172.00, 166.14, 153.56, 151.23, 148.43, 137.18,
135.74, 134.90, 131.40, 129.93, 129.41, 129.00, 128.98, 128.62,
128.09, 128.06, 127.80, 127.77, 126.93, 115.51, 110.74, 87.48,
74.00, 70.75, 63.01, 40.09, 29.32; IR (neat) 1762 (CO), 1702 (CO)
cm-1; FAB-MS (m/z, relative intensity) 523.2 (MH+, 100%). This
material was used in the next step without further attempts to obtain
an analytically pure sample.
11.8 Hz, CO2CHH), 3.86 (s, 3H, CH3OC6H4), 3.75 (AB d, 1H, J
) 10 Hz, C6H5CH2OCHH), 3.61 (AB d, 1H, J ) 10 Hz,
PhCH2OCHH-), 3.56 (AB m, 2H, CH2-lactone); 13C NMR (100
MHz, CDCl3) δ 171.79, 165.56, 163.89, 149.80, 148.13, 137.10,
136.61, 135.18, 132.92, 131.83, 128.67, 128.18, 127.87, 123.80,
121.50, 114.26, 113.95, 87.14, 74.01, 70.66, 63.49, 55.62, 29.16;
IR (neat) 1763 (CO), 1716 (CO) cm-1; FAB-MS (m/z, relative
intensity) 460.2 (MH+, 100%). Anal. (C27H25NO6 ·0.5H2O) C, H,
N.
1
11-E (R1 ) 4CH3OC6H4, R2 ) 4-pyridyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.69 (irregular d, 2H, J ≈ 6.0 Hz, H2
and H6-pyridine), 7.83 (m, 2H, CH3OC6H4CO2), 7.45 (br t, 1H, J
) 3.0 Hz, CHdC), 7.34 (br d, 2H, J ≈ 6.0 Hz, H3 and H5-pyridine),
7.26-7.30 (m, 5H, Ph), 6.86 (m, 2H, CH3OC6H4CO2), 4.58 (AB
q, 2H, J ) 12.0 Hz, C6H5CH2O), 4.55 (AB d, 1H, J ) 12.0 Hz,
CO2CHH), 4.46 (AB d, 1H, J ) 12.0 Hz, CO2CHH), 3.81 (s, 3H,
CH3OC6H4), 3.74 (AB q, 2H, J ) 10.1 Hz, C6H5CH2OCH2), 3.69
(AB d, 1H, J ) 10.1 Hz, C6H5CH2OCHH), 3.28 (dd, 1H, J ) 18.1,
3.0 Hz, CHH-lactone), 3.15 (dd, 1H, J ) 18.1, 3.0 Hz, CHH-
lactone); 13C NMR (100 MHz, CDCl3) δ 170.04, 165.66, 163.91,
149.89, 149.87, 137.17, 133.11, 131.90, 128.67, 128.20, 127.90,
123.71, 121.46, 113.89, 83.34, 73.97, 71.61, 66.12, 55.61, 33.15,
31.71, 22.78; IR (neat) 1760 (CO), 1715 (CO) cm-1; FAB-MS
(m/z, relative intensity) 460.2 (MH+, 100%). Anal. (C27H25NO6)
C, H, N.
1
11-E (R1 ) 4-CH3OC6H4, R2 ) 2-pyridyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.69 (dm, 2H, J ) 4.8 Hz, H6-pyridine),
7.87 (m, 2H, CH3OC6H4CO2), 7.72 (td, 1H, J ) 7.7, 1.8 Hz, H4-
pyridine), 7.51 (t, 1H, J ) 3.0 Hz, CHdC), 7.40 (d, 1H, J ) 7.7
Hz, H3-pyridine), 7.21-7.30 (m, 6H, Ph, H5-pyridine), 6.85 (m,
2H, CH3OC6H4CO2), 4.60 (AB m, 2H, CO2CH2), 4.51 (AB q, 2H,
J ) 11.9 Hz, C6H5CH2OCH2), 3.83 (s, 3H, CH3OC6H4), 3.71 (AB
q, 2H, J ) 10.1 Hz, C6H5CH2OCH2), 3.54 (dd, H, J ) 19.6, 3.0
Hz, CHH-lactone), 3.47 (dd, 1H, J ) 19.6, 3.0 Hz, CHH-lactone);
13C NMR (100 MHz, CDCl3) δ 171.31, 165.79, 163.69, 153.84,
150.09, 137.54, 136.65, 133.79, 131.90, 129.77, 128.55, 127.94,
127.79, 126.97, 123.43, 121.89, 113.77, 83.64, 73.87, 72.10, 66.46,
55.55, 34.35; IR (neat) 1755 (CO), 1714 (CO) cm-1; FAB-MS
(m/z, relative intensity) 460.2 (MH+, 95%), 135.1 (MH+, 100%).
Anal. (C27H25NO6) C, H, N.
1
11-Z (R1 ) 4-CH3OC6H4, R2 ) 4-pyridyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.35 (br d, 2H, J ) 6.0 Hz, H2 and
H6-pyridine), 7.82 (m, 2H, CH3OC6H4CO2), 7.26-7.34 (m, 5H,
Ph), 7.07 (m, 2H, H3 and H5-pyridine), 7.05 (br t, 1H, J ) 1.4 Hz,
CHdC), 6.88 (m, 2H, CH3OC6H4CO2), 4.74 (AB d, 1H, J ) 11.9
Hz, CO2CHH), 4.55 (AB q, J ) 12.0 Hz, C6H5CH2O), 4.45 (AB
d, 1H, J ) 11.9 Hz, CO2CHH), 3.88 (s, 3H, CH3OC6H4), 3.79 (AB
d, 1H, J ) 10.0 Hz, C6H5CH2OCHH), 3.65 (AB d, 1H, J ) 10 Hz,
PhCH2OCHH), 3.58 (br s, 2H CH2-lactone); 13C NMR (100 MHz,
CDCl3) δ 171.71, 165.62, 164.04, 149.07, 148.85, 147.25, 137.06,
133.92, 131.86, 128.73, 128.31, 127.95, 124.32, 121.39, 114.02,
87.36, 74.13, 70.71, 63.43, 55.70, 31.27; IR (neat) 1761 (CO), 1702
(CO) cm-1; FAB-MS (m/z, relative intensity) 460.3 (MH+, 100%).
Anal. (C27H25NO6) C, H, N.
1
11-Z (R1 ) 4-CH3OC6H4, R2 ) 2-pyridyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.44 (d, J ) 4.6 Hz, 1H, H6-pyridine),
7.78 (m, 2H, CH3OC6H4CO2), 7.49 (td, 1H, J ) 7.7, 1.8, Hz, H4-
pyridine), 7.24-7.31 (m, 5H, Ph), 7.17 (irregular br t, 1H, CHdC),
7.13 (d, 1H, J ) 7.7 Hz, H3-pyridine), 7.11 (br dd, 1 H, J ≈ 7.6,
5.1, H5-pyridine), 6.85 (m, 2H, CH3OC6H4CO2), 4.63 (AB d, 1H,
J ) 11.8 Hz, CO2CHH), 4.56 (AB q, 2H, J ) 12.0 Hz, PhCH2O),
4.48 (AB d, 1H, J ) 11.8 Hz, CO2CHH), 3.84 (s, 3H, CH3OC6H4),
3.74-377 (m, 3H, PhCH2OCH2, CHH-lactone), 6.63 (AB d, 1H, J
) 10 Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3) δ 172.19,
165.52, 163.75, 156.05, 149.05, 148.82, 137.37, 137.24, 134.02,
131.86, 128.59, 128.05, 127.82, 123.60, 122.12, 121.71, 113.82,
87.05, 73.96, 70.78, 63.65, 55.58, 33.94; IR (neat) 1769 (CO), 1709
(CO) cm-1; FAB-MS (m/z, relative intensity) 460.2 (MH+, 100%).
Anal. (C27H25NO6 ·0.5H2O) C, H, N.
1
11-E (R1 ) 4-CH3OC6H4, R2 ) 2-quinolyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.17 (d, 1H, J ) 8.4 Hz, H4-quinoline),
8.17 (d, 1H,
J ) 8.4 Hz, H5-quinoline), 7.87 (m, 2H,
CH3OC6H4CO2), 7.80 (br d, 1H, J ) 8.4 Hz, H8-quinoline), 7.73
(m, 1H, H6-quinoline), 7.68 (t, 1H, J ) 3.0 Hz, CHdC), 7.56 (m,
1H, H7-quinoline), 7.49 (d, 1H, J ) 8.4 Hz, H3-quinoline),
7.24-7.32 (m, 5H, Ph), 6.84 (m, 2H, CH3OC6H4CO2), 4.62 (s, 2H,
C6H5CH2OCH2), 4.55 (AB q, 2H, J ) 11.9 Hz, CO2CH2), 3.81 (s,
3H, CH3OC6H4), 3.71-3.79 (m, 3H, C6H5CH2OCH2, CHH-
lactone), 3.66 (dd, 1H, J ) 19.8, 3.0 Hz, CHH-lactone); 13C NMR
(100 MHz, CDCl3) δ 171.18, 165.78, 163.64, 153.78, 148.41,
137.51, 136.57, 133.79, 131.86, 131.22, 130.07, 130.03, 128.54,
127.92, 127.78, 127.63, 127.51, 127.32, 123.89, 121.84, 113.75,
83.78, 73.84, 72.05, 66.47, 55.51, 34.63; IR (neat) 1761 (CO), 1715
(CO) cm-1; FAB-MS (m/z, relative intensity) 510.3 (MH+, 81%),
135.1 (MH+, 100%). Anal. (C31H27NO6 ·0.1H2O) C, H, N.
1
11-E (R1 ) 4-CH3OC6H4, R2 ) 3-pyridyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.70 (d, 1H, J ) 2.1 Hz, H2-pyridine),
8.59 (dd, 1H, J ) 4.8, 1.6 Hz, H6-pyridine), 7.84 (m, 2H,
CH3OC6H4CO2), 7.73 (br dt, 1H, J ) 8.0 Hz, H4-pyridine), 7.51
(t, 1H, J ) 2.9 Hz, CHdC), 7.34 (br dd, 1H, J ≈ 8.0, 4.5 Hz,
H5-pyridine), 7.23-7.31 (m, 5H, Ph), 6.84 (m, 2H, CH3OC6H4CO2),
4.58 (AB q, J ) 12.1 Hz, PhCH2O), 4.53 (AB d, 1H, J ) 11.9 Hz,
CO2CHH), 4.46 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.82 (s, 3H,
CH3OC6H4), 3.69 (AB q, 2H, J ) 10.0 Hz, PhCH2O), 3.26 (dd,
1H, J ) 17.8, 2.9 Hz, CHH-lactone), 3.12 (dd, 1H, J ) 17.8, 2.9
Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3) δ 170.40, 165.61,
163.78, 150.98, 150.36, 137.21, 136.35, 132.83, 131.82, 130.46,
128.58, 128.06, 127.80, 127.31, 123.81, 121.50, 113.81, 82.94,
73.86, 71.64, 66.18, 55.53, 33.08; IR (neat) 1757 (CO), 1715 (CO)
cm-1; FAB-MS (m/z, relative intensity) 135.1 (100%), 460.2 (MH+,
96%). Anal. (C27H25NO6) C, H, N.
1
11-Z (R1 ) 4-CH3OC6H4, R2 ) 2-quinolyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.00 (br d, 1H, J ) 8.5 Hz,
H4-quinoline), 7.95 (d, 1H, J ) 8.3 Hz, H5-quinoline), 7.73-7.77
(m, 3H, CH3OC6H4CO2, H8-quinoline), 7.68 (m, 1H, Hz, H7-
quinoline), 7.51 (m, 1H, H6-quinoline), 7.24-7.29 (m, 7H, Ph, H3-
quinoline, CHdC), 6.74 (m, 2H, CH3OC6H4CO2), 4.66 (AB d, 1H,
J ) 11.8 Hz, CO2CHH), 4.55 (AB q, 2H, J ) 12.0 Hz, C6H5CH2O),
4.53 (AB d, 1H, J ) 11.8 Hz, C6H5CHHO), 4.50 (AB d, 1H, J )
11.8 Hz, CO2CHH), 3.98 (br AB d, 2H, J ) 1.4 Hz,
C6H5CH2OCH2), 3.81 (s, 3H, CH3OC6H4), 3.78 (AB d, 1H, J )
10.0 Hz, CHH-lactone), 3.64 (AB d, 1H, J ) 10.0 Hz, CHH-
lactone); 13C NMR (100 MHz, CDCl3) δ 172.27, 165.47, 163.65,
157.39, 148.99, 137.19, 133.99, 131.72, 129.85, 128.84, 128.56,
128.03, 127.79, 127.64, 127.01, 126.47, 121.56, 121.43, 113.71,
87.14, 73.94, 70.80, 63.57, 55.52, 34.82; IR (neat) 1762 (CO), 1715
1
11-Z (R1 ) 4-CH3OC6H4, R2 ) 3-pyridyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.45 (br s, 2H, H2 and H6-pyridine),
7.81 (m, 2H, CH3OC6H4CO2), 7.43 (br dt, 1H, J ) 8.0 Hz, H4-
pyridine), 7.24-7.35 (m, 5H, Ph), 7.10 (br dd, 1H, J ≈ 7.8, 4.8
Hz, H5-pyridine), 6.96 (br t, 1H, J ≈ 1.5 Hz, CHdC), 6.87 (m,
2H, CH3OC6H4CO2), 4.68 (AB d, 1H, J ) 11.8 Hz, CO2CHH),
4.54 (AB q, 2H, J ) 12.0 Hz, C6H5CH2O), 4.45 (AB d, 1H, J )

5380 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
(CO) cm-1; FAB-MS (m/z, relative intensity) 510.1 (MH+, 100%).
Anal. (C31H27NO5) C, H, N.
MS (m/z, relative intensity) 452.2 (MH+, 100%). Anal. (C27H33NO5 ·
0.6H2O) C, H, N.
11-E (R1 ) CH(CH2CH2CH3)2, R2 ) 3-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H, H2-pyridine), 8.61 (br
d, 1H, J ) 4.0 Hz, H6-pyridine), 7.75 (dm, 1H, J ) 8.0 Hz, H4-
pyridine), 7.75 (t, 1H, J ) 2.9 Hz, CdCH), 7.37 (dd, 1H, J ) 8.0,
4.8 Hz, H5-pyridine), 7.25-7.33 (m, 5H, Ph), 4.56 (s, 2H,
C6H5CH2O), 4.28 (AB q, 2H, J ) 11.9 Hz, CH2CO2CH2), 3.61
(AB q, 2H, J ) 10 Hz, C6H5CH2OCH2), 3.20 (dd, 1H, J ) 17.9,
2.9 Hz, CHH-lactone), 3.02 (dd, 1H, J ) 17.9, 2.9 Hz, CHH-
lactone), 2.29-3.36 (m, 1H, (CH3CH2CH2)2CHCO2CH2), 1.43-1.52
(m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.29-1.38 (m, 2H, (CH3CH2-
CH2)2CHCO2CH2), 1.10-1.24 (m, 4H, (CH3CH2CH2)2CHCO2CH2),
0.73-0.80 (overlapping t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2-
CHCO2CH2); 13C NMR (100 MHz, CDCl3) δ 175.85, 170.30,
151.08, 150.45, 137.19, 136.37, 132.76, 130.52, 128.61, 128.12,
127.81, 127.26, 123.83, 82.61, 73.90, 71.79, 65.72, 45.25, 34.52,
34.48, 33.02, 20.69, 20.64, 13.98, 13.94; IR (neat) 1757 (CO), 1734
(CO) cm-1; FAB-MS (m/z, relative intensity) 452.3 (MH+, 91%),
91.1 (100%). Anal. (C27H33NO5) C, H, N.
11-Z (R1 ) CH(CH2CH2CH3)2, R2 ) 3-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.52 (s, 2H, H2 and H6-pyridine),
7.60 (dm, 1H, J ) 7.8 Hz, H5-pyridine), 7.23-7.34 (m, 6H, Ph,
H4-pyridine), 6.92 (t, 1H, J ) 1.5 Hz, CdCH), 4.51 (AB q, 2H, J
) 11.9 Hz, CO2CH2), 4.32 (s, 2H, C6H5CH2OCH2), 3.68 (AB d,
1H, J ) 10.0 Hz, CHH-lactone), 3.62 (br s, 2H, C6H5CH2OCH2),
3.53 (AB d, 1H, J ) 10.0 Hz, CHH-lactone), 2.26-3.33 (m, 1H,
(CH3CH2CH2)2CHCO2CH2), 1.44-1.54 (m, 2H, (CH3CH2CH2)2-
CHCO2CH2), 1.30-1.39 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.17-1.26 (m, 4H, (CH3CH2CH2)2CHCO2CH2), 0.83-0.87 (over-
lapping t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2CHCO2CH2); 13C NMR
(100 MHz, CDCl3) δ 175.76, 171.63, 149.43, 148.33, 147.78,
137.18, 137.09, 135.00, 128.66, 128.19, 127.83, 86.62, 74.02, 70.71,
63.20, 45.16, 34.50, 34.48, 29.18, 20.70, 20.65, 14.09, 14.07; IR
(neat) 1768 (CO), 1734 (CO) cm-1; 452.3 (MH+, 100%); FAB-
MS (m/z, relative intensity). Anal. (C27H33NO5) C, H, N.
11-E (R1 ) CH(CH2CH2CH3)2, R2 ) 4-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.71 (d, 2H, J ) 6.1 Hz, H2 and
H6-pyridine), 7.46 (t, 1H, J ) 2.9 Hz, CHdC), 7.35 (br d, 2H, J )
6.1 Hz, H3 and H5-pyridine), 7.24-7.34 (m, 4H, Ph), 4.56 (s, 2H,
C6H5CH2OCH2), 4.29 (s, 2H, CO2CH2), 3.62 (AB q, 2H, J ) 10.1
Hz, C6H5CH2OCH2), 3.22 (dd, 1H, J ) 18.2, 2.9 Hz, CHH-lactone),
3.05 (dd, 1H, J ) 18.2, 2.9 Hz, CHH-lactone), 2.30-3.33 (m, 1H,
(CH3CH2CH2)2CHCO2CH2), 1.46-1.52 (m, 2H, (CH3CH2CH2)2-
CHCO2CH2), 1.32-1.37 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.15-1.25 (m, 4H, (CH3CH2CH2)2CHCO2CH2), 0.75-0.82 (over-
lapping t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2CHCO2CH2); 13C NMR
(100 MHz, CDCl3) δ 174.87, 168.87, 148.75, 136.13, 131.92,
127.68, 127.24, 126.89, 122.81, 81.97, 72.99, 70.73, 64.65, 52.56,
44.29, 33.57, 33.52, 32.08, 19.74, 19.69, 13.03, 12.99; IR (neat)
1765 (CO), 1735 (CO) cm-1; FAB-MS (m/z, relative intensity)
452.3 (MH+, 100%). Anal. (C27H33NO5 ·H2O) C, H, N.
11-E (R1 ) 4-CH3OC6H4, R2 ) 3-quinolyl): This intermediate
was used directly in the next step without further purification or
characterization.
1
11-Z (R1 ) 4-CH3OC6H4, R2 ) 3-quinolyl): colorless oil; H
NMR (400 MHz, CDCl3) δ 8.75 (d, 1H, J ) 2.0 Hz, H2-quinoline),
8.07 (d, 1H, J ) 8.4 Hz, H8-quinoline), 7.93 (d, 1H, J ) 2.0 Hz,
H4-quinoline), 7.74 (m, 2H, CH3OC6H4CO2), 7.66 (m, 1H, H7-
quinoline), 7.62 (br dd, 1H, J ≈ 8.0, 1.5 Hz, H5-quinoline), 7.51
(m, 1H, H6-quinoline), 7.24-7.32 (m, 5H, Ph), 7.04 (t, 1H, J )
1.4 Hz, CHdC), 6.72 (m, 2H, CH3OC6H4CO2), 4.68 (AB d, 1H, J
) 11.8 Hz, CO2CHH), 4.57 (AB q, 2H, J ) 12.0 Hz, C6H5CH2O),
4.45 (AB d, 1H, J ) 11.8 Hz, CO2CHH), 3.79 (s, 3H, OCH3),
3.71-3.74 (m, 3H, C6H5CH2OCH2, CHH-lactone), 3.62 (AB d, 1H,
J ) 10.0 Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3) δ
171.85, 165.54, 163.72, 151.19, 148.19, 146.95, 137.07, 135.63,
135.12, 131.65, 129.87, 129.47, 129.06, 128.64, 128.15, 128.00,
127.83, 127.70, 127.01, 121.33, 113.80, 87.14, 74.00, 70.69, 63.45,
55.51, 29.32; IR (neat) 1763 (CO), 1714 (CO) cm-1; FAB-MS
(m/z, relative intensity) 510.2 (MH+, 100%). Anal. (C31H27NO6 ·
0.5H2O) C, H, N.
11-E (R1 ) CH(CH2CH2CH3)2, R2 ) 2-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.69 (dm, 1H, J ) 4.7 Hz, H6-
pyridine), 7.72 (td, 1H, J ) 7.7, 1.8 Hz, H4-pyridine), 7.48 (t, 1H,
J ) 3.0 Hz,CdCH), 7.42 (d, 1H, J ) 7.7 Hz, H3-pyridine),
7.21-7.34 (m, 6H, Ph, H5-pyridine), 4.58 (s, 2H, PhCH2OCH2),
4.30 (s, 2H, CO2CH2), 3.65 (AB q, 2H, J ) 10.1 Hz, PhCH2OCH2),
3.41 (m, 2H, CH2-lactone), 2.29-3.36 (m, 1H, (CH3CH2CH2)2-
CHCO2CH2), 1.46-1.52 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.29-1.35 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.11-1.23 (m, 4H,
(CH3CH2CH2)2CHCO2CH2), 0.74 and 0.78 (t, 6H, J ) 7.3 Hz,
(CH3CH2CH2)2CHCO2CH2); 13C NMR (100 MHz, CDCl3) δ
176.02, 171.24, 153.95, 150.09, 137.55, 136.63, 133.57, 129.88,
128.58, 127.98 127.78, 127.01, 123.37, 83.44, 73.91, 72.30, 65.98,
45.37, 34.95, 34.57, 34.30, 20.69, 14.02, 13.98; IR (neat) 1733
(CO), 1756 (CO) cm-1; FAB-MS (m/z, relative intensity) 452.3
(MH+, 93%), 91.1 (100%). Anal. (C27H33NO5) C, H, N.
11-E (R1 ) CH2CH[CH2CH(CH3)2]2, R2 ) 2-pyridyl): color-
less oil; 1H NMR (400 MHz, CDCl3) δ 8.69 (dm, 1H, J ) 4.8 Hz,
H6-pyridine), 7.72 (td, 1H, J ) 7.7, 1.8, Hz, H4-pyridine), 7.47 (t,
1H, J ) 3.0 Hz, CdCH), 7.41 (dm, 1H, J ) 7.7 Hz, H3-pyridine),
7.21-7.34 (m, 6H, Ph, H5-pyridine), 4.54 (s, 2H, C6H5CH2OCH2),
4.25 (s, 2H, CO2CH2), 3.59 (AB q, 2H, J ) 10.0 Hz,
C6H5CH2OCH2), 3.46 (dd, 1H, J ) 19.7, 3.0 Hz, CHH-lactone),
3.33 (dd, 1H, J ) 19.7, 3.0 Hz, CHH-lactone), 2.18 (d, 2H, J )
6.5Hz,CH2CH[CH2CH(CH3)2]2),1.84-1.91(m,1H,CH2CH[CH2CH-
(CH3)2]2), 1.51-1.57 (m, 2H, CH2CH[CH2CH(CH3)2]2), 0.99-1.12
(m, 4H, CH2CH[CH2CH(CH3)2]2), 0.77-0.82 (m, 12H, CH2CH-
[CH2CH(CH3)2]2); 13C NMR (100 MHz, CDCl3) δ 186.59, 173.03,
171.17, 153.92, 150.09, 137.56, 136.62, 133.71, 129.74, 128.55
127.94, 127.75, 127.01, 123.37, 83.28, 73.85, 72.20, 65.98, 44.11,
39.46, 34.23, 30.68, 25.20, 22.65, 22.92, 22.67, 22.63; IR (neat)
1758 (CO), 1741 (CO) cm-1; FAB-MS (m/z, relative intensity)
494.2 (MH+, 88%), 91.1 (100%). Anal. (C30H39NO5) C, H, N.
11-Z (R1 ) CH(CH2CH2CH3)2, R2 ) 2-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.53 (dm, 1H, J ) 4.9 Hz, H6-
pyridine), 7.60 (td, 1H, J ) 7.7, 1.8 Hz, H4-pyridine), 7.23-7.34
(m, 6H, Ph, H3-pyridine), 7.17 (m, 1H, H5-pyridine), 7.12 (t, 1H,
J ) 1.4 Hz, CdCH), 4.53 (AB q, 2H, J ) 12.0 Hz, CO2CH2),
4.33 (s, 2H, C6H5CH2OCH2), 3.81 (s, 2H, C6H5CH2OCH2), 3.70
(AB d, 1H, J ) 10.0 Hz, CH-lactone), 3.57 (AB d, 1H, J ) 10.0
Hz, CH-lactone), 2.26-3.33 (m, 1H, (CH3CH2CH2)2CHCO2CH2),
1.44-1.54 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.30-1.39 (m, 2H,
(CH3CH2CH2)2CHCO2CH2), 1.17-1.26 (m, 4H, (CH3CH2CH2)2-
CHCO2CH2), 0.83-0.87 (2 t, 6H, J ) 7.2 Hz, (CH3CH2CH2)2-
CHCO2CH2); 13C NMR (100 MHz, CDCl3) δ 175.77, 172.14,
148.73, 137.29, 128.61, 128.07, 127.78, 123.71, 123.70, 123.67,
122.17, 86.63, 73.99, 70.89, 63.31, 45.18, 34.50, 34.46, 20.68,
20.65, 14.11, 14.09; IR (neat) 1764 (CO), 1765 (CO) cm-1; FAB-
11-Z (R1 ) CH(CH2CH2CH3)2, R2 ) 4-pyridyl): colorless oil;
1H NMR (400 MHz, CDCl3) δ 8.48 (d, 2H, J ) 6.0 Hz, H2 and
H6-pyridine), 7.23-7.36 (m, 5H, Ph), 7.16 (d, 2H, J ) 6.0 Hz, H3
and H5-pyridine), 6.97 (t, 1H, J ) 1.4 Hz, CHdC), 4.51 (AB q,
2H, J ) 11.8 Hz, CO2CH2), 4.33 (s, 2H, C6H5CH2OCH2), 3.72
(AB d, 1H, J ) 10.0 Hz, CHH-lactone), 3.62 (s, 2H, C6H5-
CH2OCH2), 3.57 (AB d, 1H, J ) 10.0 Hz, CHH-lactone), 2.27-3.34
(m, 1H, (CH3CH2CH2)2CHCO2CH2), 1.45-1.54 (m, 2H, (CH3CH2-
CH2)2CHCO2CH2), 1.32-1.41(m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.16-1.27 (m, 4H, (CH3CH2CH2)2CHCO2CH2), 0.84-0.88 (over-
lapping t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2CHCO2CH2); 13C NMR
(100 MHz, CDCl3) δ 175.80, 171.61, 149.62, 148.77, 137.06,
134.10, 128.72, 128.32, 127.90, 124.29, 86.72, 74.12, 70.70, 63.23,
45.22, 34.54, 34.50, 31.27, 20.74, 20.68, 14.12, 14.10; IR (neat)
1764 (CO), 1718 (CO) cm-1; FAB-MS (m/z, relative intensity)
452.3 (MH+, 100%). Anal. (C27H33NO5 ·0.6H2O) C, H, N.
11-E (R1 ) CH(CH2CH2CH3)2, R2 ) 2-quinolyl): colorless
oil;
1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J ) 8.4 Hz, H4-
quinoline), 8.09 (d, 1H, J ) 8.4 Hz, H5-quinoline), 7.81 (d, 1H, J

Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5381
) 8.4 Hz, H8-quinoline), 7.73 (m, 1H, H6-quinoline), 7.65 (t, 1H,
J ) 3.0, Hz, CHdC), 7.57 (m, 1H, H7-quinoline), 7.51 (d, 1H, J
) 8.4 Hz, H3-quinoline), 7.24-7.31 (m, 5H, Ph), 4.60 (s, 2H,
PhCH2OCH2), 4.35 (s, 2H, CO2CH2), 3.67 (AB q, 2H, J ) 10.0
Hz, PhCH2OCH2), 3.54-3.61 (m, 2H, CH2-lactone), 2.30-3.37 (m,
1H, (CH3CH2CH2)2CHCO2CH2), 1.45-1.55 (m, 2H, (CH3CH2CH2)2-
CHCO2CH2), 1.28-1.36 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.11-1.23 (m, 4H, (CH3CH2CH2)2CHCO2CH2), 0.68 and 0.76 (t,
6H, J ) 7.3 Hz, (CH3CH2CH2)2CHCO2CH2); 13C NMR (100 MHz,
CDCl3) δ 176.05, 171.13, 153.88, 148.48, 137.55, 136.59, 133.60,
131.36, 130.09, 130.05, 128.59, 127.98, 127.80, 127.67, 127.54,
127.33, 124.00, 83.61, 73.91, 72.29, 65.96, 45.36, 34.60, 34.56,
20.69, 14.00, 13.94; IR (neat) 1763 (CO), 1735 (CO) cm-1; FAB-
MS (m/z, relative intensity) 502.3 (MH+, 100%). Anal. (C31H35NO5 ·
0.5H2O) C, H, N.
34.28, 34.26, 29.20, 20.49, 20.20, 13.93, 13.88; IR (neat) 1764
(CO), 1735 (CO) cm-1; FAB-MS (m/z, relative intensity) 91.1
(MH+, 100%), 502.2 (MH+, 82%). Anal. (C31H35NO5 ·0.2H2O) C,
H, N.
General Procedure for the Synthesis of 12 (R2 * 1-Meth-
ylindole). BCl3 (3 equiv) was added slowly to a stirring solution
of 11 (1 equiv) in CH2Cl2 (20 mL/mmol of 11) at -78 °C. The
reaction was monitored by TLC and quenched upon completion
by the slow addition of a saturated aqueous NaHCO3 solution,
diluted with CH2Cl2 (20 mL/mmol of 11), and warmed to room
temperature. The layers were separated, and the aqueous layer was
further extracted with CH2Cl2 (2×). The combined organics were
dried (MgSO4) and concentrated in vacuo. Purification by silica
gel flash column chromatography [CH2Cl2-MeOH (0% f 10%)]
gave 12.
12a-E: colorless oil; 1H NMR (400 MHz, CDCl3/CD3OD) δ 8.67
(br d, 1H, J ) 3.8 Hz, H6-pyridine), 7.80 (d, 2H, J ) 9.0 Hz,
(CH3)2NC6H4CO2), 7.72 (br t, 1H, J ) 7.3, 7.6 Hz, H4-pyridine),
7.50 (irregular t, 1H, J ≈ 2.9 Hz, CHdC), 7.41 (d, 1H, J ) 7.6
Hz, H3-pyridine), 7.22 (m, 1H, H5-pyridine), 6.57 (d, 2H, J ) 9.0
Hz, (CH3)2NC 6H4CO2), 4.51 (AB d, 1H, J ) 12.0 Hz, CO2C HH),
4.39 (AB d, 1H, J ) 12.0 Hz, CO2CHH), 3.82 (AB d, 1H, J )
12.3 Hz, HOCHH), 3.75 (AB d, 1H, J ) 12.3 Hz, HOCHH), 3.52
(dd, 1H, J ) 19.8, 2.9 Hz, CHH-lactone), 3.40 (dd, 1H, J ) 19.8,
2.9 Hz, CHH-lactone), 3.00 (s, 6H, (CH3)2NC6H4); 13C NMR (100
MHz, CDCl3/CD3OD) δ 171.76, 166.88, 153.70, 153.68, 150.03,
136.77, 134.11, 131.67, 129.90, 126.95, 123.55, 115.75, 110.83,
85.06, 65.56, 64.83, 40.13, 33.54; IR (neat) 3370 (OH), 1719 (CO),
1626 (CO) cm-1; FAB-MS (m/z, relative intensity) 383.1 (MH+,
84%), 148.1 (100%); HRMS (FAB) calc for C21H22N2O5, 383.1607;
found, 383.1640.
11-Z (R1 ) CH(CH2CH2CH3)2, R2 ) 2-quinolyl): colorless
1
oil; H NMR (400 MHz, CDCl3) δ 8.03-8.07 (irregular t, 2H, J
≈ 9 Hz, H4 and H5-quinoline), 7.79 (dm, 1H, J ) 8.2 Hz, H8-
quinoline), 7.70 (m, 1H, H6-quinoline), 7.52 (m, 1H, H7-quinoline),
7.36 (d, 1H, J ) 8.4 Hz, H3-quinoline), 7.20-7.23 (m, 5H, Ph),
7.17 (br t, 1H, J ) 1.4 Hz, CHdC), 4.50 (AB q, 2H, J ) 12.0 Hz,
CO2CH2), 4.33 (s, 2H, C6H5CH2OCH2), 4.00 (s, 2H, C6H5CH2O-
CH2), 3.69 (AB d, 1H, J ) 10.0 Hz, CHH-lactone), 3.56 (AB d,
1H, J ) 10.0 Hz, CHH-lactone), 2.22-3.29 (m, 1H, (CH3CH2CH2)2-
CHCO2CH2), 1.40-1.50 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.24-1.34 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.13-1.22 (m, 4H,
(CH3CH2CH2)2CHCO2CH2), 0.81 (t, 6H, J ) 7.2 Hz, (CH3-
CH2CH2)2CHCO2CH2); 13C NMR (100 MHz, CDCl3) δ 175.68,
172.16, 157.46, 148.92, 137.20, 137.16, 133.99, 129.87, 128.88,
128.86, 128.53, 128.00, 127.71, 127.66, 127.06, 126.50, 121.54,
121.52, 86.65, 73.91, 70.82, 63.26, 45.11, 34.80, 34.65, 34.42,
34.39, 20.60, 20.57, 14.02, 14.00; IR (neat) 1766 (CO), 1735 (CO)
cm-1; FAB-MS (m/z, relative intensity) 502.2 (MH+, 82%), 91.1
(MH+, 100%). Anal. (C31H35NO5 ·0.2H2O) C, H, N.
12b-E: white solid; mp 158-159 °C; 1H NMR (400 MHz,
CDCl3/CD3OD) δ 8.63 (s, 1H, H2-pyridine), 8.50 (d, 1H, J ) 4.2
Hz, H6-pyridine), 7.78 (d, 1H, J ) 8.0 Hz, H4-pyridine), 7.69 (m,
2H, (CH3)2NC6H4CO2), 7.45 (t, 1H, J ) 2.8 Hz, CHdC), 7.35 (dd,
1H, J ) 8.0, 4.8 Hz, H5-pyridine), 6.52 (m, 2H, (CH3)2NC6H4CO
2), 4.39 (AB q, 2H, J ) 12.0 Hz, CO2CH2), 3.80 (AB d, 1H, J )
12.2 Hz, HOCHH), 3.70 (AB d, 1H, J ) 12.2 Hz, HOCHH), 3.27
(dd, 1H, J ) 17.8, 2.8 Hz, CHH-lactone), 3.08 (dd, 1H, J ) 17.8,
2.8 Hz, CHH-lactone), 2.97 (s, 6H, (CH3)2NC6H4); 13C NMR (100
MHz, CDCl3/CD3OD) δ 171.19, 166.70, 153.73, 150.66, 149.88,
136.75, 132.63, 131.53, 130.75, 128.06, 124.04, 115.27, 110.74,
84.78, 65.48, 64.31, 40.02, 32.20; IR (neat) 3402 (OH), 1702 (CO),
1654 (CO) cm-1; FAB-MS (m/z, relative intensity) 383.2 (MH+,
57%), 148.1 (100%). Anal. (C21H22N2O5 ·0.1H2O) C, H, N.
11-E (R1 ) CH(CH2CH2CH3)2, R2 ) 3-quinolyl): colorless
1
oil; H NMR (400 MHz, CDCl3) δ 9.03 (d, 1H, J ) 2.1 Hz, H2-
quinoline), 8.22 (d, 1H, J ) 1.8 Hz, H4-quinoline), 8.13 (d, 1H, J
) 8.4 Hz, H5-quinoline), 7.87 (d, 1H, J ) 8.4 Hz, H8-quinoline),
7.79 (m, 1H, H7-quinoline), 7.70 (t, 1H, J ) 2.9 Hz, CHdC), 7.62
(m, 1H, H6-quinoline), 7.26-7.33 (m, 5H, Ph), 4.58 (s, 2H,
C6H5CH2OCH2), 4.33 (AB q, 2H, J ) 12.0 Hz, CO2CH2), 3.60
(AB q, 2H, J ) 10.0 Hz, C6H5CH2OCH2), 3.32 (dd, 1H, J ) 17.9,
2.9 Hz, CHH-lactone), 3.14 (dd, 1H, J ) 17.9, 2.9 Hz, CHH-
lactone), 2.32-3.36 (m, 1H, (CH3CH2CH2)2CHCO2CH2-), 1.39-
1.52 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.31-1.39 (m, 2H,
(CH3CH2CH2)2CHCO2CH2), 1.10-1.25 (m, 4H, (CH3CH2CH2)2-
CHCO2CH2), 0.73 and 0.78 (t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2-
CHCO2CH2); 13C NMR (100 MHz, CDCl3) δ 175.94, 170.45,
151.05, 148.02, 137.22, 136.86, 132.98, 131.16, 129.50, 128.66,
128.50, 128.17, 127.89, 127.86, 127.77, 127.65, 127.15, 82.69,
73.99, 71.86, 65.78, 45.29, 34.57, 34.52, 33.21, 20.74, 20.69, 14.02,
13.97; IR (neat) 1752 (CO), 1735 (CO) cm-1; FAB-MS (m/z,
relative intensity) 502.5 (MH+, 100%). This material was used in
the next step without further attempts to obtain an analytically pure
sample.
1
12b-Z. colorless oil; H NMR (400 MHz, CDCl3) δ 9.19 (m,
1H, H2-pyridine), 9.10 (m, 1H, H6-pyridine), 8.00 (br d, 1H, J )
8.0 Hz, H4-pyridine), 7.74 (m, 2H, (CH3)2NC6H4CO2), 7.46 (dd,
1H, J ) 8.0, 6.1 Hz, H5-pyridine), 7.05 (t, 1H, J ) 1.2 Hz, CHdC),
6.62 (m, 2H, (CH3)2NC6H4CO2), 4.72 (AB d, 1H, J ) 11.9 Hz,
CO2CHH), 4.46 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.88 (s, 2H,
HOCH2), 3.79 (AB q, 2H, J ) 16.0 Hz, CH2-lactone), 3.07 (s, 6H,
(CH3)2NC6H4); 13C NMR (100 MHz, CDCl3) δ 171.61, 166.50,
150.00, 144.63, 144.05, 143.19, 132.65, 131.68, 125.91, 125.89,
111.30, 111.28, 89.28, 63.48, 62.43, 40.41, 29.17; IR (neat) 3412
(OH), 1715 (CO), 1637 (CO) cm-1; FAB-MS (m/z, relative
intensity) 383.1 (MH+, 60%), 148.1 (100%); HRMS (FAB) calc
for C21H22N2O5, 383.1607; found, 383.1590.
11-Z (R1 ) CH(CH2CH2CH3)2, R2 ) 3-quinolyl): colorless
1
oil; H NMR (400 MHz, CDCl3) δ 8.77 (d, 1H, J ) 2.2 Hz, H2-
quinoline), 8.07 (d, 1H, J ) 8.4 Hz, H5-quinoline), 7.98 (d, 1H, J
) 1.9 Hz, H4-quinoline), 7.64-7.70 (m, 2H, H7 and H8-quinoline),
7.50 (m, 1H, J ) 1.2, 8.1, 8.4 Hz, H6-quinoline), 7.18-7.29 (m,
5H, Ph), 6.94 (t, 1H, J ) 1.5 Hz, CHdC), 4.47 (AB q, 2H, J )
12.0 Hz, C6H5CH2OCH2), 4.30 (AB q, 2H, J ) 11.8 Hz, CO2CH2),
3.80 (br s, 2H, C6H5CH2OCH2), 3.65 (AB d, 1H, J ) 10.0 Hz,
CHH-lactone), 3.52 (AB d, 1H, J ) 10.0 Hz, CHH-lactone),
2.20-3.27 (m, 1H, (CH3CH2CH2)2CHCO2CH2), 1.37-1.47 (m, 2H,
(CH3CH2CH2)2CHCO2CH2), 1.23-1.31 (m, 2H, (CH3CH2CH2)2-
CHCO2CH2), 1.10-1.20 (m, 4H, (CH3CH2CH2)2CHCO2CH2), 0.78
and 0.81 (t, 6H, J ) 7.2 Hz, (CH3CH2CH2)2CHCO2CH2); 13C NMR
(100 MHz, CDCl3) δ 175.50, 171.55, 151.25, 148.10, 147.09,
136.96, 135.34, 135.07, 129.81, 129.31, 129.11, 128.45, 127.96,
127.91, 127.58, 127.50, 126.93, 86.47, 73.79, 70.55, 63.02, 44.97,
12c-E: yellow solid; mp 130-133 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.75 (d, J ) 6.2 Hz, 2H, H2 and H6-pyridine), 7.72
(d, 2H, J ) 6.2 Hz, H3 and H5-pyridine), 7.63 (m, 2H,
(CH3)2NC6H4CO2), 7.46 (t, 1H, J ) 2.9 Hz, CHdC), 6.67 (m, 2H,
(CH3)2NC6H4CO2), 4.40 (AB q, 2H, J ) 11.9 Hz, CO2CH2), 3.69
(AB q, 2H, J ) 11.9 Hz, HOCH2), 3.32 (dd, 1H, J ) 18.7, 2.9,
Hz, CHH-lactone), 3.26 (dd, 1H, J ) 18.7, 2.9 Hz, CHH-lactone),
2.99 (s, 6H, (CH3)2NC6H ); 13C NMR (100 MHz, DMSO-d6) δ
4
170.00, 165.29, 153.38, 148.38, 133.31, 130.80, 130.73, 124.36,
124.35, 124.33, 124.32, 114.89, 110.82, 110.78, 84.95, 65.56, 63.20,
32.01; IR (neat) 3176 (OH), 1750 (CO), 1713 (CO) cm-1; FAB-
MS (m/z, relative intensity) 383.2 (MH+, 100%). Anal. (C21H22-
N2O5 ·0.9H2O) C, H, N.

5382 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
12c-Z. white solid; mp 142-143 °C; 1H NMR (400 MHz,
CDCl3) δ 8.39 (v br d, J ) 4.7 Hz, 2H, H2 and H6-pyridine), 7.78
(m, 2H, (CH3)2NC6H4CO2), 7.19 (br d, 2H, J ) 5.6 Hz, H3 and
H5-pyridine), 7.09 (br s, 1H, CHdC), 6.61 (m, 2H, (CH3)2NC6H
4CO2), 4.67 (AB d, 1H, J ) 12.0 Hz, CO2CHH), 4.48 (AB d, 1H,
J ) 12.0 Hz, CO2CHH), 3.81-3.88 (AB m, 2H, HOCH2), 3.63 (s,
7.52 (t, 1H, J ) 3.0 Hz, CHdC), 7.42 (d, 1H, J ) 7.7 Hz, H3-
pyridine), 7.24 (ddd, J ) 7.7, 4.7, 1.1 Hz, H5-pyridine), 6.87 (m,
2H, CH3OC6 H4CO2), 4.59 (AB d, 1H, J ) 12.0 Hz, CO2CHH),
4.44 (AB d, 1H, J ) 12.0 Hz, CO2CHH), 3.84-3.88 (m, 4H,
CH3OC6H4, HOCHH), 3.79 (AB d, 1H, J ) 12.2 Hz, HOCHH),
3.55 (dd, 1H, J ) 19.7, 3.0 Hz, CHH-lactone), 3.47 (dd, 1H, J )
19.7, 3.0 Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3) δ 171.32,
166.21, 163.88, 153.71, 150.13, 136.74, 134.37, 132.04, 129.46,
127.13, 123.59, 121.66, 113.88, 84.54, 65.98, 65.11, 55.61, 33.71;
IR (neat) 3421 (OH), 1751 (CO), 1714 (CO) cm-1; FAB-MS (m/
z, relative intensity) 370.1 (MH+, 75%), 135.1 (MH+, 100%). Anal.
(C20H19NO6 ·0.1H2O) C, H, N.
2H, CH2-lactone), 3.08 (s, 6H, (CH3)2NC6H ); 13C NMR (100
4
MHz, CDCl3) δ 171.81, 166.52, 153.97, 150.24, 144.76, 132.75,
131.68, 129.34, 126.04, 118.84, 114.93, 110.87, 89.37, 63.43, 62.48,
43.21, 40.26, 31.70; IR (neat) 3175 (OH), 1755 (CO), 1715.41 (CO)
cm-1; FAB-MS (m/z, relative intensity) 383.1 (MH+, 40%), 176
(MH+, 100%). Anal. (C21H22N2O5 ·0.4H O) C, H, N.
2
12d-E: yellow solid; mp 120-122 °C; 1H NMR (400 MHz,
CDCl3) δ 8.17 (d, 1H, J ) 8.4 Hz, H4-quinoline), 8.05 (d, 1H, J )
8.4 Hz, H5-quinoline), 7.66 (dm, 1H, J ) 8.4 Hz, H8-quinoline),
7.65-7.69 (m, 3H, (CH3)2NC6H4CO2, H7-quinoline), 7.61 (t, 1H,
12g-Z: colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.47 (br d,
1H, J ) 3.7 Hz, H6-pyridine), 7.89 (m, 2H, CH3OC6H4CO2), 7.59
(td, 1H, J ) 7.7, 1.7 Hz, H4-pyridine), 7.14-7.23 (m, 3H, CHdC,
H3 and H5-pyridine), 6.89 (m, 2H, CH3O C6H4CO2), 3.57 (AB q,
2 H, J ) 12.0 Hz, CO2CH2), 2.81-2.89 (m, 5H, HOCH2, CH
3OC6H4) 2.81 (br s, 2H, CH2-lactone); 13C NMR (100 MHz, CDCl3)
δ 172.25, 165.98, 163.94, 149.04, 148.81, 137.74, 134.20, 132.01,
124.00, 122.39, 121.51, 113.93, 110.18, 88.30, 63.61, 63.44, 55.63,
33.91; IR (neat) 3343 (OH), 1760 (CO), 1714 (CO) cm-1; FAB-
MS (m/z, relative intensity) 370.1 (MH+, 100%). Anal. (C20H19NO6 ·
0.1H2O) C, H, N.
J ) 3.0 Hz, CHdC), 7.48-7.53 (m, 2H, H3, and H -quinoline),
6
6.49 (m, 2H, (CH3) NC6H4CO2), 4.40 (AB q, 2H, J ) 12.00 Hz,
2
CO2CH2), 3.80 (AB d, 1H, J ) 12.2 Hz, HOCHH), 3.72 (AB d,
1H, J ) 12.2 Hz, HOCHH), 3.61 (dd, 1H, J ) 19.6, 3.0 Hz, CHH-
lactone), 3.50 (dd, 1H, J ) 19.6, 3.0 Hz, CHH-lactone), 2.92 (s,
6H, (CH3)2NC6H4); 13C NMR (100 MHz, CDCl3) δ 172.10, 167.40,
154.21, 153.39, 139.00, 132.79, 132.76, 131.85, 131.58, 128.60,
128.37, 128.12, 123.43, 115.87, 111.26, 110.62, 86.14, 66.25, 64.75,
43.29, 40.17, 33.88; IR (neat) 3378 (OH), 1752 (CO), 1698 (CO)
cm-1; FAB-MS (m/z, relative intensity) 433.3 (MH+, 61%), 148.1
12h-E: white solid; mp 139-140 °C; 1H NMR (400 MHz,
CDCl3/CD3OD) δ 8.67 (br d, 1H, J ) 1.2 Hz, H2-pyridine), 8.53
(dd, 1H, J ) 4.8, 1.4 Hz, H6-pyridine), 7.80-7.83 (m, 2H,
CH3OC6H4CO2), 7.77 (dm, 1H, J ) 8.0 Hz, H4-pyridine), 7.47 (t,
1H, J ) 2.9 Hz, CHdC), 7.38 (dd, 1H, J ) 8.0, 4.8 Hz,
H5-pyridine), 6.83 (m, 2H, CH3OC6H4CO2), 4.44 (s, 2H, CO2CH
2), 3.83 (AB d, J ) 12.2 Hz, HOCHH), 3.80 (s, 2H, CH3OC6H4),
3.74 (AB d, J ) 12.2 Hz, HOCHH), 3.30 (dd, 1H, J ) 17.9, 2.9
Hz, CHH-lactone), 3.09 (dd, 1H, J ) 17.9, 2.9 Hz, CHH-lactone);
13C NMR (100 MHz, CDCl3) δ 171.10, 165.94, 163.82, 150.02,
149.39, 137.18, 132.27, 131.67, 130.84, 128.24, 124.22, 121.21,
113.75, 84.59, 65.93, 64.04, 55.38, 32.08; IR (neat) 3401 (OH),
1709 (CO), 1652 (CO) cm-1; FAB-MS (m/z, relative intensity)
370.1 (100%). Anal. (C20H19NO6 ·0.1H2O) C, H, N.
(MH+, 100%). Anal. (C25H24N2O5 ·0.1H O) C, H, N.
2
1
12d-Z. colorless oil; H NMR (400 MHz, CDCl3) δ 7.96 (v br
d, 2H, J ) 8.4 Hz, H4 and H5-quinoline), 7.66-7.70 (m, 3H,
(CH3)2NC6H4CO2, H8-quinoline), 7.60 (m, 1H, H7-quinoline), 7.42
(m, 1H, H6-quinoline), 7.23 (d, 1H, J ) 8.4 Hz, H3-quinoline),
7.15 (br s, 1H, CHdC), 6.44 (m, 2H, (CH3)2NC6H4CO2), 4.45 (s,
2H, CO2C H2), 3.92 (AB d, 2H, J ) 1.3 Hz, HOCH2), 3.75 (AB q,
2H, J ) 12.0 Hz, CH 2-lactone), 2.93 (s, 6H, N(CH3) 2); 13C NMR
(100 MHz, CDCl3) δ 172.41, 166.67, 157.21, 153.75, 149.38,
137.85, 133.88, 131.69, 130.27, 128.39, 127.71, 127.16, 126.76,
121.75, 115.48, 110.79, 110.17, 88.63, 63.52, 62.99, 40.16, 34.56;
IR (neat) 3392 (OH), 1760 (CO), 1703 (CO) cm-1; FAB-MS (m/
z, relative intensity) 433.2 (MH+, 100%). Anal. (C25H24N2O5 ·
0.1H2O) C, H, N.
12h-Z: yellow solid; mp 155-157 °C; 1H NMR (400 MHz,
CDCl3) δ 8.49 br (s, 1H, H2-pyridine), 8.43 (br d, 1H, J ) 4.9 Hz,
H6-pyridine), 7.84 (m, 2H, CH3OC6H4CO2), 7.55 (br d, 1H, J )
7.8 Hz, H4-pyridine), 7.18 (dd, 1H, J ) 7.7, 5.0 Hz, H5-pyridine),
7.02 (br s, 1H, CHdC), 6.87 (m, 2H, CH3O C6H4CO2), 4.53 (AB
d, 1H, J ) 12.0 Hz, CO2CHH), 4.49 (AB d, 1H, J ) 12.0 Hz,
CO2CHH), 3.84 (s, 3H, CH3OC6H4), 3.80 (AB q, 2H, J ) 12.0
Hz, HOCH2), 3.59 (br s, 2H, CH 2-lactone); 13C NMR (100 MHz,
CDCl3) δ 171.89, 165.98, 164.07, 148.89, 148.41, 147.06, 137.96,
135.08, 133.47, 131.98, 124.20, 121.30, 114.05, 88.47, 63.59, 63.25,
12e-E: white solid; mp 135-137 °C; 1H NMR (400 MHz,
DMSO-d6) δ 9.12 (d, 1H, J ) 2.2 Hz, H2-quinoline), 8.65 (br d,
1H, J ) 1.7 Hz, H4-quinoline), 8.10 (dm, 1H, J ) 8.4 Hz, H5-
quinoline), 8.04 (d, 1H, J ) 8.4 Hz, H8-quinoline), 7.82 (m, 1H,
H7-quinoline), 7.62-7.69 (m, 4H, H6-quinoline, (CH3)2NC6H4CO2,
CHdC), 6.65 (m, (CH3)2NC6H4CO2), 4.41 (AB q, 2H, J ) 11.9
Hz, CO2CH2), 3.71 (AB q, 2H, J ) 11.9 Hz,, HOCH 2), 3.37-3.39
(m, 2H, CH2-lactone), 2.97 (s, 6H, (CH3) 2NC6H4); 13C NMR (100
MHz, DMSO-d6) δ 170.48, 165.35, 153.35, 151.67, 147.18, 136.28,
130.80, 130.77, 129.27, 128.81, 128.71, 127.82, 127.37, 127.23,
114.95, 110.77, 84.62, 65.76, 63.36, 32.04; IR (neat) 3424 (OH),
1749 (CO), 1677 (CO) cm-1; FAB-MS (m/z, relative intensity)
433.2 (MH+, 89%), 148.1 (MH+, 100%). Anal. (C25H24N2O5 ·0.8H2O)
C, H, N.
55.68, 29.26; IR (neat) 3094 (OH), 1756 (CO), 1607 (CO) cm-1
;
FAB-MS (m/z, relative intensity) 370.1 (MH+, 100%). Anal.
(C20H19NO6) C, H, N.
12i-E: white solid; mp 164-166 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.68 (m, 2H, H2 and H6-pyridine), 7.78 (m, 2H,
CH3OC6H4CO2), 7.57 (m, 2H, H3 and H5-pyridine), 7.42 (t, 1H, J
) 2.9 Hz, CHdC), 7.00 (m, 2H, CH3OC6 H4CO2), 5.40 (br s, 1H,
HOCH2), 4.44 (AB q, 2H, J ) 11.9, Hz, CO2CH2), 3.82 (s, 3H,
CH3OC6H4), 3.68-3.70 (m, 2H, HOCH2), 3.28-3.29 (m, 2H, CH2-
lactone); 13C NMR (100 MHz, DMSO-d6) δ 170.14, 164.84,
163.34, 150.27, 150.22, 141.45, 131.82, 131.47, 131.37, 131.27,
131.20, 123.65, 123.56, 121.21, 114.12, 114.08, 84.65, 66.14, 63.24,
31.94; IR (neat) 3164 (OH), 1750 (CO), 1710 (CO) cm-1; FAB-
MS (m/z, relative intensity) 370.1 (MH+, 100%). Anal. (C20H19NO6 ·
0.4H2O) C, H, N.
12e-Z: colorless oil; 1H NMR (400 MHz, CDCl3/CD3OD) δ 8.68
(d, 1H, J ) 1.9 Hz, H2-quinoline), 7.96 (d, 1H, J ) 8.4 Hz, H8-
quinoline), 7.94 (d, 1H, J ) 1.9 Hz, H4-quinoline), 7.57-7.63 (m,
4H, (CH3)2NC6H4CO2, H5 and H7-quinoline), 7.49 (m, 1H, H6-
quinoline), 7.07 (t, 1H, J ) 1.3 Hz, CHdC), 6.38 (m, 2H,
(CH3)2NC6H4CO 2), 4.59 (AB d, 1H, J ) 11.8 Hz, CO2CHH), 4.38
(AB d, 1H, J ) 11.8 Hz, CO2CHH), 3.77 (AB q, 2H, J ) 12.0 Hz,
HOCH2), 3.71 (br s, 2H, CH2-lactone), 2.92 (s, 6H, N(CH3)2); 13
C
NMR (100 MHz, CDCl3/CD3OD) δ 172.66, 166.48, 153.50, 150.66,
148.95, 145.93, 136.20, 134.46, 131.12, 130.07, 129.65, 127.99,
127.75, 127.71, 127.01, 114.90, 110.52, 89.00, 63.01, 62.54, 39.75,
28.96; IR (neat) 3428 (OH), 1759 (CO), 1684 (CO) cm-1; FAB-
MS (m/z, relative intensity) 433.2 (MH+, 100%). Anal. (C25H24N2O5 ·
0.6H2O) C, H, N.
12i-Z: yellow solid; mp 156-158 °C; 1H NMR (400 MHz,
CDCl3) δ 8.38 (br d, 2H, J ) 6.0 Hz, H2 and H6-pyridine), 7.86
(m, 2H, CH3OC6H4CO2), 7.09 (m, 2H, H3 and H5-pyridine), 7.05
(t, 1H, J ) 1.4 Hz, CHdC), 6.89 (m, 2H, CH3OC H4CO2), 4.67
6
(AB d, 1H, J ) 11.9 Hz, CO2CHH), 4.51 (AB d, 1H, J ) 11.9 Hz,
CO2CH), 3.86 (overlapping s and AB q, 5H, J ≈ 12 Hz, CH3OC6H4,
HOCH2), 3.58 (br s, 2H, CH2-lactone); 13C NMR (100 MHz,
CDCl3) δ 171.93, 165.94, 164.09, 149.64, 148.64, 146.64, 134.40,
131.92, 124.30, 121.28, 114.04, 88.62, 63.63, 63.20, 55.67, 31.30;
12g-E: white solid; mp 92-94 °C; 1H NMR (400 MHz, CDCl3)
δ 8.70 (dm, 1H, J ) 4.8 Hz, H6-pyridine), 7.92 (m, 2H, J ) 2.1,
9.0 Hz, CH3OC6H4CO2), 7.73 (td, 1H, J ) 7.7, 1.8 Hz, H4-pyridine),

Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5383
IR (neat) 3095 (OH), 1758 (CO), 1705 (CO) cm-1; FAB-MS (m/
z, relative intensity) 370.1 (MH+, 100%). Anal. (C20H19NO6) C,
H, N.
CHCO2CH2), 1.32-1.37 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.15-1.24 (m, 4H, (CH3CH2CH ) CHCO2CH2-), 0.79 and 0.75
2 2
(t, 3H, J ) 7..3 Hz, (CH 3CH2CH2)2CHCO 2CH2); 13C NMR (100
MHz, CDCl3) δ 176.33, 171.32, 153.79, 150.09, 136.65, 134.09,
129.61, 127.10, 123.48, 84.42, 65.47, 65.23, 45.34, 34.55, 33.55,
20.69, 14.01, 13.97; IR (neat) 3458 (OH), 1752 (CO), 1734 (CO)
cm-1; FAB-MS (m/z, relative intensity) 362.2 (MH+, 100%). Anal.
(C20H27NO5 ·0.2H2O) C, H, N.
12j-E: white solid; mp 90-91 °C; 1H NMR (400 MHz, CDCl3)
δ 8.13 (d, 1H, J ) 8.4 Hz, H4-quinoline), 8.17 (d, 1H, J ) 8.5 Hz,
H5-quinoline), 7.72-7.78 (m, 3H, H8-quinoline, CH3OC6H4CO2),
7.65 (m, 1H, H7-quinoline), 7.59 (t, 1H, J ) 3.0 Hz, CHdC), 7.49
(m, 1 H, H6-quinoline), 7.47 (d, 1H, J ) 8.4 Hz, H3-quinoline),
6.75 (m, 2H, CH3OC6H4CO2), 4.46 (AB d, 1H, J ) 12.0 Hz,
CO2CHH), 4.40 (AB d, 1H, J ) 12.0 Hz, CO2CHH), 3.80 (AB d,
1H, J ) 12.2 Hz, HOCHH), 3.73 (AB d, 1H, J ) 12.2 Hz,
HOCHH), 3.72 (s, 3H, OCH3C6H4), 3.67 (br s, 1H, HOCH2), 3.60
(dd, 1H, J ) 19.7, 3.0, Hz, CHH-lactone), 3.53 (dd, 1H, J ) 19.7,
3.0 Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3/CD3OD) δ
171.75, 166.07, 163.68, 153.33, 147.79, 137.07, 133.63, 131.68,
130.29, 129.29, 127.64, 127.57, 127.32, 123.39, 121.41, 113.69,
85.24, 66.13, 64.45, 55.34, 33.47; IR (neat) 3381 (OH), 1731 (CO),
1715 (CO) cm-1; FAB-MS (m/z, relative intensity) 420.2 (MH+,
73%), 135.1 (MH+, 100%). Anal. (C24H21NO6 ·H2O) C, H, N.
12j-Z: colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.99
(irregular t, 2H, J ≈ 8 Hz, H4 and H5-quinoline), 7.79 (m, 2H,
CH3OC6H4CO2), 7.74 (dd, 1H, J ) 8.4, 1.3 Hz, H8-quinoline), 7.66
(m, 1H, H7-quinoline), 7.49 (m, 1H, H6-quinoline), 7.29 (d, 1H, J
) 8.4 Hz, H3-quinoline), 7.24 (t, 1H,, J ) 1.3 Hz, CHdC), 6.76
(m, 2H, CH3OC6 H4CO2), 4.62 (AB d, 1H, J ) 11.9 Hz, CO2CHH),
4.54 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.98 (br AB d, 2H,
HOCH2), 3.89 (br AB q, 2H, CH2-lactone), 3.81 (s, 3H, OCH3);
13C NMR (100 MHz, CDCl3) δ 172.45, 165.86, 163.79, 157.32,
148.94, 147.56, 137.39, 134.17, 131.83, 130.00, 128.61, 127.68,
127.06, 126.56, 121.60, 121.38, 113.76, 88.49, 63.51, 63.33, 55.55,
34.70; IR (neat) 3354 (OH), 1759 (CO), 1713 (CO) cm-1; FAB-
MS (m/z, relative intensity) 420.1 (MH+, 100%). Anal. (C21H21NO6 ·
0.5H2O) C, H, N.
1
12m-Z: colorless oil; H NMR (400 MHz, CDCl3) δ 8.53 (d,
1H J ) 4.1 Hz, H6-pyridine), 7.69 (td, 1H, J ) 7.6, 1.0 Hz, H4-
pyridine), 7.32 (d, 1H, J ) 7.6 Hz, H3-pyridine), 7.22 (m, 1H, H5-
pyridine), 7.12 (d, 1H, J ) 1.1 Hz, CdCH), 4.33 (AB q, 2H, J )
11.6 Hz, CO2CH2), 3.77 (s, 2H, HOCH2), 3.82 (s, 2H, CH2-lactone),
3.18 (br s, 1 H, HOCH2), 2.31-3.38 (m, 1H, (CH3CH2CH2)2CHCO2-
CH2), 1.47-1.57 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.33-1.42
(m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.22 (sextuplet, 4 H, J ≈ 7.4
Hz, 4H, (CH3CH2CH2)2CHCO2CH2), 0.86 (overlapping t, 6H, J )
7.3 Hz, (CH3CH2CH2)2CHCO2CH2); 13C NMR (100 MHz, CDCl3)
δ 176.22, 172.10, 156.39, 148.84, 137.98, 134.05, 124.24, 122.52,
87.94, 63.56, 63.00, 45.20, 34.52, 33.84, 20.72, 20.70, 14.11; IR
(neat) 3357 (OH), 1761 (CO), 1735 (CO) cm-1; FAB-MS (m/z,
relative intensity) 362.2 (MH+, 100%). Anal. (C20H27NO5 ·0.5H2O)
C, H, N.
12n-E: colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.77 (br s,
1H, H2-pyridine), 8.61 (br s, 1H, H6-pyridine), 7.47 (d, 1H, J )
7.6 Hz, H4-pyridine), 7.53 (br irregular t, 1H, CHdC), 7.40 (br
dd, 1H, J ) 7.6, 4.7 Hz, H5-pyridine), 4.28 (AB q, 2H, J ) 12.0
Hz, CO2CH2), 3.82 (AB d, 1H, J ) 12.1 Hz, HOCHH), 3.73 (AB
d, 1H, J ) 12.1 Hz, HOCHH), 3.29 (dd, 1H, J ) 17.9, 2.9 Hz,
CHH-lactone), 3.03 (dd, 1H, J ) 17.9, 2.9 Hz, CHH-lactone),
2.32-2.38 (m, 1H, (CH3CH2CH2)2CHCO2CH2), 1.46-1.56 (m, 2H,
(CH3CH2CH2)2CHCO2CH2), 1.32-1.41 (m, 2H, (CH3CH2CH2)2CH-
CO2CH2), 1.14-1.26 (m, 4H, (CH3CH2CH ) CHCO2CH2), 0.77
2 2
12k-E: white solid; mp 161-162 °C; 1H NMR (400 MHz,
CDCl3/CD3OD) δ 9.00 (v br s, 1H, H2-quinoline), 8.22 (s, 1H, H4-
quinoline), 8.06 (m, 1H, H8-quinoline), 7.88 (br d, 1H, J ) 7.7
Hz, H5-quinoline), 7.80 (m, 2H, CH3OC6H4CO2), 7.74 (br t, 1H, J
) 6.8 Hz, H6-quinoline), 7.64 (t, 1H, J ) 2.5 Hz, CHdC), 7.57
(dd, 1H, J ) 8.1, 6.9 H7-quinoline), 6.83 (m, 2H, CH3OC6H4CO2),
4.45 (s, 2H, CO2CH2), 3.84 (AB d, 1 H, J ) 12.2 Hz, HOCHH),
3.73-3.77 (overlapping s and AB d, 4H, HOCHH, OCH3), 3.41
(AB d, J ) 17.8, 2.5 Hz, CHH-lactone), 3.18 (AB d, J ) 17.8, 2.5
Hz, CHH-lactone); 13C NMR (100 MHz, CDCl3/CD3OD) δ 171.15,
166.03, 163.94, 163.91, 137.60, 132.89, 131.87, 131.56, 128.79,
128.77, 128.75, 128.71, 128.66, 128.03, 127.78, 121.35, 113.88,
84.60, 66.00, 64.38, 55.55, 32.45; IR (neat) 3393 (OH), 1748 (CO),
1714 (CO) cm-1; FAB-MS (m/z, relative intensity) 420.1 (MH+,
100%). Anal. (C24H21NO6) C, H, N.
and 0.81 (t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2CHCO CH2); 13C
2
NMR (100 MHz, CDCl3) δ 176.26, 170.54, 150.89, 150.39, 136.77,
133.18, 127.35, 124.01, 83.88, 65.37, 64.77, 45.31, 34.55, 34.53,
32.33, 20.76, 20.72, 14.03, 14.00; IR (neat) 3459 (OH), 1735 (CO),
1655 (CO) cm-1; FAB-MS (m/z, relative intensity) 362.3 (MH+,
100%). Anal. (C20H27NO5) C, H, N.
12n-Z: colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.84 (br s,
1H, H2-pyridine), 8.56 (br s, 1H, H6-pyridine), 7.97 (d, 1H, J )
7.9 Hz, H4-pyridine), 7.53 (dm, 1H, J ) 7.9 Hz, H5-pyridine), 7.19
(s, 1H, CdCH-), 4.35 (AB q, 2H, J ) 11.9, CO2CH2), 3.82 (AB
d, 1H, J ) 11.8 Hz, HOCHH), 3.70-3.79 (m, 3H, HOCHH, CH2-
lactone), 2.32-3.39 (m, 1H, (CH3CH2CH2)2CHCO2CH2), 1.49-1.58
(m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.35-1.43 (m, 2H, (CH3CH2-
CH2)2CHCO2CH2), 1.19-1.29 (m, 4H, (CH3CH2CH2)2CHCO2CH2),
0.87 and 0.88 (t, 3H, J ) 7.2 Hz, (CH3CH2CH2)2CHCO2CH2); 13
C
1
12k-Z: colorless oil; H NMR (400 MHz, CDCl3) δ 8.76 (d,
NMR (100 MHz, CDCl3) δ 176.13, 171.76, 149.74, 146.47, 144.04,
141.38, 133.66, 110.19, 88.34, 63.22, 62.94, 45.20, 34.54, 29.30,
20.75, 20.72, 14.12; IR (neat) 3495 (OH), 1735 (CO), 1662 (CO)
cm-1; FAB-MS (m/z, relative intensity) 362.3 (MH+, 100%). Anal.
(C20H27NO5) C, H, N.
1H, J ) 1.7 Hz, H2-quinoline), 8.04 (d, 1H, J ) 8.4 Hz,
H5-quinoline), 7.97 (s, 1H, H4-quinoline), 7.74 (d, 2H, J ) 9.1 Hz,
CH3OC6H4CO2), 7.63-7.67 (m, 2H, H8-quinoline, H7-quinoline),
7.48 (irregular t, 1H, J ≈ 7 Hz, H6-quinoline), 7.12 (s, 1H, CHdC),
6.71 (d, 2H, J ) 9.1 Hz, CH3OC H4CO2), 4.63 (AB d, 1H, J )
12o-E: yellow solid; mp 83-86 °C; 1H NMR (400 MHz,
CD3OD) δ 8.67 (m, 2H, H2 and H6-pyridine), 7.66 (m, 2H, H3 and
H5-pyridine), 7.47 (t, 1H, J ) 3.0 Hz, CHdC), 4.31 (AB q, 2H, J
) 12.0 Hz, CO2CH2), 3.80 (AB d, 1H, J ) 12.0 Hz, HOCHH),
3.72 (AB d, 1H, J ) 12.0 Hz, HOCHH), 3.34 (AB dd, 1H, J )
18.6, 3.0 Hz, CHH-lactone), 3.18 (AB d, 1H, J ) 18.6, 3.0 Hz,
CHH-lactone), 2.29-2.36 (m, 1H, (CH3CH2CH2)2CHCO2CH2),
1.43-1.50 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.30-1.41 (m, 2H,
(CH3CH2CH2)2CHCO2CH2), 1.14-1.24 (m, 4H, (CH3CH2CH 2)2-
CHCO2CH2), 0.77 and 0.79 (overlapping t, 6H, J ) 7.2 Hz, (CH
3CH2CH2)2CHCO 2CH2); 13C NMR (100 MHz, CD3OD) δ 177.05,
172.01, 150.19, 145.06, 134.12, 132.78, 132.71, 125.65, 125.61,
86.08, 66.85, 65.03, 46.62, 35.73, 35.70, 33.25, 21.66, 21.58, 14.20,
14.19; IR (neat) 3164 (OH), 1759 (CO), 1722 (CO) cm-1; FAB-
MS (m/z, relative intensity) 362.2 (MH+, 100%). Anal. (C20H27NO5 ·
0.7H2O) C, H, N.
6
11.9 Hz, CO2CHH), 4.49 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.88
(br s, 2H, HOC H2), 3.78 (s, 3H, CH3OC6H ), 3.74 (br s, 2H,
4
CH2-lactone); 13C NMR (100 MHz, CDCl ) δ 172.54, 165.77,
3
163.65, 150.58, 148.76, 145.90, 136.40, 134.65, 131.42, 130.09,
129.81, 127.98, 127.82, 127.68, 127.18, 121.00, 113.66, 88.79,
63.05, 63.00, 55.31, 28.99; IR (neat) 3396 (OH), 1758 (CO), 1715
(CO) cm-1; FAB-MS (m/z, relative intensity) 420.1 (MH+, 100%).
Anal. (C24H21NO6) C, H, N.
12m-E: colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.67 (dm,
1H, J ) 4.8 Hz, H6-pyridine), 7.72 (td, 1H, J ) 7.7, 1.9 Hz, H4-
pyridine), 7.48 (t, 1H, J ) 3.0 Hz, CHdC), 7.42 (br d, 1H, J )
7.7 Hz, H3-pyridine), 7.23 (ddd, 1H, J ) 7.7, 4.8, 1.0 Hz, H5-
pyridine), 4.29 (AB q, 2H, J ) 11.9, Hz, CO2CH2), 3.80 (AB d,
1H, J ) 12.2 Hz, HOCHH), 3.72 (AB d, 1H, J ) 12.2 Hz,
HOCHH), 3.44 (dd, 1H, J ) 19.7, 3.0 Hz, CHH-lactone), 3.38 (dd,
1H, J ) 19.7, 3.0 Hz, CHH-lactone), 2.31-2.38 (m, 1H,
(CH3CH2CH2)2CHCO2CH2), 1.46-1.55 (m, 2H, (CH3CH2CH2)2-
12o-Z: colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.52 (d,
2H, J ≈ 6.0 Hz, H2 and H6-pyridine), 7.23 (d, 2H, J ≈ 6.0 Hz, H3

5384 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
and H5-pyridine), 6.99 (irregular t, 1H, J < 1 Hz, CHdC), 4.38
(AB d, 1H, J ) 11.9 Hz, CO2CHH), 4.30 (AB d, 1H, J ) 11.9 Hz,
CO2CHH), 3.79 (s, 2H, HOCH2), 3.64 (s, 2H, CH2-lactone), 2.78
(br s, 1H, HOCH2), 2.31-3.38 (m, 1H, (CH3CH2CH2)2CHCO2CH2),
1.47-1.55 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.34-1.43 (m, 2H,
(CH3CH2CH2)2CHCO2CH2), 1.19-1.28 (m, 4H, (CH3CH2CH 2)2-
CHCO2CH2), 0.87 and 0.88 (t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2-
CHCO2CH2); 13C NMR (100 MHz, CDCl3) δ 176.21, 171.72,
149.27, 148.74, 147.34, 134.32, 124.58, 110.18, 87.99, 63.56, 62.96,
45.22, 34.52, 31.40, 20.75, 20.72, 14.11, 14.10; IR (neat) 3179
(OH), 1761 (CO), 1735 (CO) cm-1; FAB-MS (m/z, relative
intensity) 362.2 (MH+, 100%). Anal. (C20H27NO5 ·0.2H2O) C, H,
N.
(m, H6-quinoline), 7.56 (m, 1H, H7-quinoline), 7.02 (t, 1H, J )
1.5 Hz, CHdC), 4.37 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 4.29
(AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.81 (br s, 2H, CH2-lactone),
3.78(s,2H,HOCH2),2.27-3.34(m,1H,(CH3CH2CH2)2CHCO2CH2),
1.44-1.54 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.29-1.38 (m, 2H,
(CH3CH2CH2)2CHCO2CH2), 1.14-1.25 (m, 4H, (CH3CH2CH 2)2-
CHCO2CH2), 0.83 and 0.84 (overlapping t, 6H, J ) 7.3 Hz, (CH
3CH2CH2)2CHCO 2CH2); 13C NMR (100 MHz, CDCl3) δ 176.16,
171.94, 150.78, 148.52, 146.19, 136.71, 135.20, 130.08, 128.39,
128.16, 127.76, 127.51, 88.07, 63.51, 62.96, 45.18, 34.47, 29.46,
20.71, 20.67, 14.09, 14.06; IR (neat) 3298 (OH), 1757 (CO), 1735
(CO) cm-1; FAB-MS (m/z, relative intensity) 412.2 (MH+, 100%).
Anal. (C24H29NO5 ·0.3H2O) C, H, N.
1
12s-E: colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.68 (br d,
1H, J ) 4.6 Hz, H6-pyridine), 7.72 (m, 1H, H4-pyridine), 7.47
(irregular t, 1H, J ≈ 3.0 Hz, CdCH-), 7.41 (br d, 1H, J ) 7.8 Hz,
H3-pyridine), 7.22-7.25 (m, 1H, H5-pyridine), 4.32 (dd, 1H, J )
11.9, <1.0 Hz, CO2CHH), 4.23 (dd, 1H, J ) 11.9, <1.0 Hz,
CO2CHH), 3.80 (AB d, 1H, J ) 12.2 Hz, HOCHH), 3.72 (AB d,
1H, J ) 12.2 Hz, HOCHH), 3.47 (dd, 1H, J ) 19.8, 3.0 Hz, CHH-
lactone), 2.84 (dd, 1H, J ) 19.8, 3.0 Hz, CHH-lactone), 2.20
(irregular d, 2H, J ≈ 6.4 Hz, CH2CH[CH2CH(CH3)2]2), 1.85-1.92
(septuplet, 1H, J ≈ 6.7 Hz, CH2CH[CH2CH(CH3)2]2), 1.51-1.58
(m, 2H, CH2CH[CH2CH(CH3)2]2), 0.98-1.13 (m, 4H, CH2CH-
[CH2CH(CH3)2]2), 0.79-0.83 (m, 12H, CH2CH[CH2CH(CH3)2]2);
13C NMR (100 MHz, CDCl3) δ 173.36, 171.21, 153.69, 149.98,
136.82, 134.07, 129.59, 127.14, 123.56, 84.28, 65.48, 65.19, 44.13,
39.47, 33.54, 30.73, 25.23, 22.95, 22.93, 22.68, 22.64; IR (neat)
3450 (OH), 1737 (CO), 1663 (CO) cm-1; FAB-MS (m/z, relative
intensity) 404.2 (MH+, 100%). Anal. (C23H33NO5) C, H, N.
12t-E: yellow solid; mp 111-112 °C; 1H NMR (400 MHz,
CDCl3) δ 7.94 (t, 1H, J ) 2.6 Hz, CHdC), 7.82 (dm, 1H, J ) 7.8
12p-E: colorless oil; H NMR (400 MHz, CDCl3) δ 8.17 (d,
1H, J ) 8.2 Hz, H4-quinoline), 8.09 (d, 1H, J ) 8.4 Hz,
H5-quinoline), 7.81 (dd, 1H, J ) 8.4, 1.2 Hz, H8-quinoline), 7.73
(m, 1H, H7-quinoline), 7.65 (t, 1H, J ) 3.1 Hz, CHdC), 7.56 (m,
1H, H6-quinoline), 7.51 (d, 1H, J ) 8.4 Hz, H3-quinoline), 4.34
(AB q, 2H, J ) 12.0 Hz, CO2CH2), 3.86 (AB d, 1H, J ) 12.2 Hz,
HOCHH), 3.77 (AB d, 1H, J ) 12.2 Hz, HOCHH), 3.64 (dd, 1H,
J ) 20.0, 3.1 Hz, CHH-lactone), 3.03 (dd, 1H, J ) 20.0, 3.1 Hz,
CHH-lactone), 2.50 (br s, 1 H, HOCH2), 2.32-3.39 (m, 1H,
(CH3CH2CH2)2CHCO2CH2), 1.47-1.56 (m, 2H, (CH3CH2CH2)2CH-
CO2CH2), 1.29-1.39 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.09-1.26
(m, 4H, (CH3CH2CH ) CHCO2CH2), 0.71 and 0.77 (t, 6H, J )
2 2
7.3 Hz, (CH3CH2CH2)2CHCO 2CH2); 13C NMR (100 MHz, CDCl3)
δ 176.37, 171.19, 153.68, 148.39, 136.69, 134.06, 131.12, 130.13,
130.00, 127.67, 127.63, 127.36, 124.00, 84.59, 65.48, 65.27, 45.53,
34.58, 34.55, 33.87, 20.70, 14.00, 13.94; IR (neat) 3364 (OH), 1757
(CO), 1734 (CO) cm-1; FAB-MS (m/z, relative intensity) 412.3
(MH+, 98%), 57.1(MH+, 100%). Anal. (C24H29NO5 ·0.2H2O) C,
H, N.
1
12p-Z: colorless oil; H NMR (400 MHz, CDCl3) δ 8.12 (d,
Hz, H4-indole), 7.24-7.37 (m, 4H, H2, H , H6, and H7-indole),
5
1H, J ) 8.4 Hz, H4-quinoline,), 8.02 (d, 2H, J ) 8.4 Hz,
H5-quinoline), 7.80 (dd, 1H, J ) 8.4, 1.3 Hz, H8-quinoline), 7.70
(m, 1H, H7-quinoline), 7.52 (m, 1H, H6-quinoline), 7.39 (d, 1H, J
) 8.4 Hz, H3-quinoline), 7.15 (irregular t, 1H, J ≈ 1.5 Hz, CHdC),
4.34 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 4.28 (AB d, 1H, J )
11.9 Hz, CO2CHH), 3.85 (s, 3H, CH3N), 3.77 (AB d, 1H, J )
12.1 Hz, HOCHH), 3.74 (AB d, 1H, J ) 12.1 Hz, HOCHH), 3.05
(dd, 1H, J ) 17.2, 2.6 Hz, CHH-lactone), 2.84 (dd, 1H, J ) 17.2,
2.6 Hz, CHH-lactone), 2.22 (irregular d, 2H, J ) 6.5 Hz,
CH2CH[CH2CH(CH3)2]2), 1.87-1.93 (septuplet, 1H, J ≈ 6.8 Hz,
4.34 (AB q, 1H, J ) 12.1 Hz, CO2CH ), 4.03 (dd, 1H, J ) 16.3,
2
1.5 Hz, C HH-lactone), 3.98 (dd, 1H, J ) 16.3, 1.5 Hz, CHH-
lactone), 3.80 (s, 2H, HOCH 2), 2.28-3.35 (m, 1H, (CH3CH2CH2)2-
CHCO2CH2), 1.44-1.54 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.29-1.38 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.15-1.25 (m, 4H,
CH2CH[CH CH(CH3)2]2), 1.50-1.59 (m, 2H, CH2CH[CH2CH-
2
(CH3) 2]2), 1.00-1.11 (m, 4H, CH2CH[CH2CH(CH 3)2]2), 0.77-0.83
(m, 12H, CH2CH[CH2CH(CH3)2]2); 13C NMR (100 MHz, CDCl3)
δ 173.68, 171.73, 136.89, 130.66, 128.84, 128.04, 123.44, 121.44,
119.06, 119.00, 117.00, 111.95, 109.86, 82.85, 65.63, 65.09, 44.15,
44.12, 39.44, 33.55, 33.32, 30.71, 25.24, 25.21, 22.96, 22.70, 22.62;
IR (neat) 3449 (OH), 1737 (CO), 1635 (CO) cm-1; FAB-MS (m/
z, relative intensity) 456.3 (MH+, 97%), 455.2 (M+•, 100). Anal.
(C27H37NO5 ·0.1H2O) C, H, N.
(CH3CH2CH ) CHCO2CH2), 0.83 and 0.85 (t, 6H, J ) 7.3 Hz,
2 2
(CH3CH2CH2)2CHCO 2CH2); 13C NMR (100 MHz, CDCl3) δ
176.20, 172.24, 157.22, 148.80, 137.53, 134.20, 130.15, 128.60,
127.73, 127.16, 126.71, 121.74, 88.00, 63.52, 62.97, 45.18, 34.61,
34.47, 20.67, 14.06, 14.05; IR (neat) 3460 (CO), 1762 (CO), 1736
(CO) cm-1; FAB-MS (m/z, relative intensity) 412.2 (MH+, 100%).
Anal. (C24H29NO5 ·0.4H2O) C, H, N.
General Procedure for the Synthesis of 8 (R2 ) 1-Methylin-
dole). This compound was prepared from 426 following a similar
protocol described in procedures A and B.
12q-E: yellow solid; mp 113-114 °C; 1H NMR (400 MHz,
CDCl3) δ 9.04 (br s, 1H, H2-quinoline), 8.24 (br d, 1H, J ) 1.6
Hz, H4-quinoline), 8.12 (d, 1H, J ) 8.4 Hz, H5-quinoline), 7.86
(br d, 1H, J ) 8.4 Hz, H8-quinoline), 7.78 (m, 1H, H7-quinoline),
7.70 (t, 1H, J ) 3.0 Hz, CHdC), 7.61 (m, 1H, H6-quinoline), 4.36
(AB d, 1H, J ) 12.0 Hz, CO2CHH), 4.30 (AB d, 1H, J ) 12.0 Hz,
CO2CHH), 3.88 (AB d, 1H, J ) 12.2 Hz, HOCHH), 3.78 (AB d,
1H, J ) 12.2 Hz, HOCHH), 3.42 (dd, 1H, J ) 17.8, 3.0 Hz, CHH-
lactone), 3.15 (dd, 1H, J ) 17.8, 3.0 Hz, CHH-lactone), 2.32-3.39
(m, 1H, (CH3CH2CH2)2CHCO2CH2), 1.46-1.56 (m, 2H, (CH3-
CH2CH2)2CHCO2CH2), 1.31-1.40 (m, 2H, (CH3CH2CH2)2CH-
8-E: white solid; mp 196-197 °C; 1H NMR (400 MHz, CDCl3)
δ 7.91 (t, 1H, J ) 2.5 Hz, CHdC), 7.86 (d, 1H, J ) 7.9 Hz, H5-
indole), 7.59-7.62 (m, 8H, H6-H 8-indole, Ph), 7.27-7.42 (m, 15H,
Ph), 7.14 (s, 1H, H2 -indole), 3.87 (s, 3 H, NCH3), 3.83 (AB q,
4H, 2 × SiOCH2), 2.89 (AB m, 2H, CH2-lactone), 0.99 (s, 18H, 2
× SiC (C H3)3); 13C NMR (100 MHz, CDCl3) δ 172.31, 136.85,
135.77, 135.74, 133.12, 132.96, 130.09, 129.89, 129.88, 128.14,
127.85, 127.05, 123.23, 121.15, 119.46, 119.22, 112.31, 109.73,
85.05, 66.41, 33.58, 33.26, 26.84, 19.38; IR (neat) 1747 (CO) cm-1
FAB-MS (m/z, relative intensity) 764.5 (MH+, 37%), 763 (M+•
;
,
CO2CH2), 1.12-1.26 (m, 4H, (CH3CH2CH ) CHCO2CH2), 0.74
2 2
and 0.79 (t, 6H, J ) 7.3 Hz, (CH3CH2CH2)2CHCO CH2); 13C
2
15%), 135.1 (100%). This material was used in the next step without
further attempts to obtain an analytically pure sample.
NMR (100 MHz, CDCl3) δ 176.30, 170.71, 150.92, 150.89, 147.92,
137.20, 133.39, 131.29, 129.35, 128.53, 127.84, 127.65, 127.09,
83.93, 65.41, 64.79, 45.29, 34.55, 34.51, 32.50, 20.75, 20.71, 14.03,
13.97; IR (neat) 3367 (OH), 1734 (CO), 1655 (CO) cm-1; FAB-
MS (m/z, relative intensity) 412.2 (MH+, 100%). Anal.
(C24H29NO5 ·0.8H2O) C, H, N.
General Procedure for the Synthesis of 10 (R2 ) 1-Meth-
ylindole). A solution of 8 (1 equiv) in tetrahydrofuran (THF, 10
mL/mmol) was treated with [(CH3(CH2)3]4F (TBAF, 3 equiv). The
mixture was stirred at room temperature for 1 h and concentrated
in vacuo. Purification by silica gel flash column chromatography
[CH2Cl2-MeOH (0% f 10%)] gave 10 as a yellow solid in 62%
yield.
12q-Z: colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.84 (br d,
1H, J ) 2.0 Hz, H2-quinoline), 8.10-8.12 (m, 2H, H5 and H4-
quinoline), 7.79 (br dd, 1H, J ) 8.2, 1.2 Hz, H8-quinoline), 7.71

Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5385
10-E: white solid; mp 211-212 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.84 (d, 1H, J ) 7.9 Hz, H5-indole), 7.81 (s, 1H,
H2-indole), 7.64 (t, 1H, J ) 2.7 Hz, CHdC), 7.53 (d, 1H, J ) 8.0
Hz, H8-indole), 7.28 (m, 1H, H6-indole), 7.20 (m, 1H, H7-indole),
5.10 (t, 2H, J ) 5.7 Hz, 2 × HOCH2), 3.90 (s, 3H, CH3N),
3.48-3.57 (m, 4H, 2 × HOCH2), 2.91 (br AB d, J ) 2.7 Hz, 2H,
CH2-lactone); 13C NMR (100 MHz, CDCl3) δ 171.49, 136.48,
131.73, 127.30, 125.26, 122.55, 120.66, 120.10, 118.28, 110.53,
110.41, 85.53, 63.63, 32.98, 31.94; IR (neat) 3259 (OH), 1724 (CO)
cm-1, FAB-MS (m/z, relative intensity) 288.2 (MH+, 10%). This
material was used in the next step without further attempt to obtain
an analytically pure sample.
Institute, Center for Cancer Research. The authors thank Dr.
Dina M. Sigano for her help during the prearation of this
manuscript.
Supporting Information Available: Combustion analysis results
1
and H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Takai, Y.; Kishimoto, A.; Kikkawa, U.; Mori, T.; Nishizuka, Y.
Unsaturated diacylglycerol as a possible messenger for the activation
of calcium-activated, phospholipid-dependent protein kinase system.
Biochem. Biophys. Res. Commun. 1979, 91, 1218–1224.
(2) Rhee, S. G. Regulation of phosphoinositide-specific phorpholipase C.
Annu. ReV. Biochem. 2001, 70, 281–312.
(3) Nishizuka, Y. Intracellular signalin by hydrolysis of phospholipids
and activation of protein kinase C. Science 1992, 258, 607–614.
(4) Hofmann, J. Protein kinase C isozymes as potential targets for
anticancer therapy. Curr. Cancer Drug Targets 2004, 4, 125–146.
(5) Ron, D.; Kazanietz, M. G. New insights into the regulation of protein
kinase C and novel phorbol ester receptors. FASEB J. 1999, 13, 1658–
1676.
(6) Brose, N.; Rosenmund, C. Move over protein kinase C, you’ve got
company: alternative cellular effectors of diacylglycerol and phorbol
esters. J. Cell Sci. 2002, 115, 4399–4411.
(7) Rozengurt, E.; Sinnett-Smith, J.; Zugaza, J. Protein kinase D: a novel
target for diacylglycerol and phorbol esters. Biochem. Soc. Trans. 1997,
25, 565–571.
(8) Ebinu, J. O.; Bottorff, D. A.; Chan, E. Y. W.; Stang, S. L.; Dunn,
R. J.; Stone, J. C. RasGRP, a Ras guanyl nucleotide-releasing protein
with calcium and diacylglycerol-binding motifs. Science 1998, 280,
1082–1086.
(9) Kawasaki, H.; Sprihtgett, G. M.; Toki, S.; Canales, J. J.; Harlan, P.;
Blumenstiel, J. P.; Chen, E. J.; Bany, I. A.; Mochizuki, N.; Ashbacher,
A.; Matsuda, M.; Housman, D. E.; Graybiel, A. M. A Rap guanine
nucleotide exchange factor enriched highly in the basal ganglia. Proc.
Natl. Acad. Sci. U.S.A. 1998, 95, 13278–13283.
(10) Ahmed, S.; Lee, J.; Kozma, R.; Best, A.; Monfries, C.; Lim, L. A
novel functional target for tumor-promoting phorbol esters and
lysophosphatidic acidsthe P21rac-Gtpase activating protein n-Chi-
maerin. J. Biol. Chem. 1993, 268, 10709–10712.
(11) Brose, N.; Rosenmund, C.; Rettig, J. Regulation of transmitter release
by Unc-13 and its homologues. Curr. Opin Neurobiol. 2000, 10, 303–
311.
General Procedure for the Synthesis of 12 (R2
)
1-Methylindole). A solution of 10 (1 equiv) in CH2Cl2 (16 mL/
mmol) was treated with anhydrous pyridine (2 equiv) at room
temperature and stirred for 2 h. The reaction temperature was then
lowered to 0 °C, and the acid chloride (R1COCl, 1.1 equiv) was
added dropwise. The resulting solution was stirred at 0 °C for 30
min to 1 h and then at room temperature until the reaction was
considered complete by TLC. The crude solution was then
concentrated in vacuo and purified by silica gel flash column
chromatography [CH2Cl2-MeOH (0% f 10%)] to give 12 and
variable amounts of the diacylated product, which was not
characterized.
12f-E: yellow solid; mp 160-162 °C; 1H NMR (400 MHz,
CDCl3) δ 7.98 (br t, 1H, J ) 2.6 Hz, CHdC), 7.83 (m, 2H,
(CH3)2NC 6H4CO2), 7.27-7.35 (m, 5H, indole), 6.55 (m, 2H,
(CH3)2NC H4CO2), 4.63 (AB d, 1H, J ) 12.0, Hz, CO2C HH),
6
4.39 (AB d, 1H, J ) 12.0, Hz, CO2CHH), 3.86 (s, 3H, NCH ),
3
3.80 (s, 2H, HOCH2), 2.87-3.17 (m, 8H, (CH3)2NC H4, CH2-
6
lactone); 13C NMR (100 MHz, CDCl3) δ 171.92, 167.31, 153.71,
136.91, 131.80, 130.74, 128.87, 128.10, 123.38, 121.37, 119.06,
117.27, 115.67, 111.95, 110.87, 110.17, 109.89, 83.35, 65.67, 64.91,
40.16, 33.62, 33.51; IR (neat) 3396 (OH), 1738 (CO), 1698 (CO)
cm-1; FAB-MS (m/z, relative intensity) 435.2 (MH+, 15%), 148.1
(100%). Anal. (C25H26N2O5 ·0.9H2O) C, H, N.
12l-E: white solid; mp 120-122 °C; 1H NMR (400 MHz,
CDCl3) δ 7.91 (t, J ) 2.6 Hz, 1H, CHdC), 7.81 (m, 2H, CH3OC
6H4CO2), 7.78 (dm, 1H, J ) 8.0 Hz, H4-indole), 7.19-7.32 (m,
4H, indole), 6.75 (m, 2H, CH3OC6H4CO2), 4.59 (AB d, 1H, J )
11.9 Hz, CO2CHH), 4.41 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 3.81
(s, 3H, NCH3), 3.77 (AB q, 2H, J ) 11.9 Hz, HOCH2), 3.73 (s, 3
H, CH3OC6H4), 3.05 (dd, 1H, J ) 17.1, 2.6 Hz, CHH-lactone),
2.93 (dd, J ) 17.1, 2.6 Hz, CHH-lactone); 13C NMR (100 MHz,
CDCl3) δ 172.76, 166.31, 163.73, 136.84, 131.80, 130.90, 128.70,
127.96, 123.31, 121.49, 121.29, 118.81, 117.36, 113.78, 111.71,
109.85, 83.80, 66.36, 64.68, 55.43, 33.46, 33.17; IR (neat) 3366
(OH), 1706 (CO), 1636 (CO) cm-1; FAB-MS (m/z, relative
intensity) 422.2 (MH+, 91%), 135.1 (100%). Anal. (C24H23NO6)
C, H, N.
(12) Choi, S. H.; Czifra, G.; Kedei, N.; Lewin, N. E.; Lazar, J.; Pu, Y.;
Marquez, V. E.; Blumberg, P. M. Characterization of the interaction
of phorbol esters with the C1 domain of MRCK (myotonic dystrophy
kinase-related CdC42-binding kinase) alpha/beta. J. Biol. Chem. 2008,
283, 10543–10549.
(13) Luo, B.; Regier, D. S.; Prescott, S. M.; Topham, M. K. Diacylglycerol
kinases. Cell. Signalling 2004, 16, 983–989.
(14) Geiger, M.; Wrulich, O. A.; Jenny, M.; Schwaiger, W.; Grunicke,
H. H.; Uberall, F. Defining the human targets of phorbol ester and
diacylglycerol. Curr. Opin. Mol. Ther. 2003, 5, 631–641.
(15) Zhang, G. G.; Kazanietz, M. G.; Blumberg, P. M.; Hurley, J. H.
Crystal-structure of the Cys2 activator-binding domain of protein-
kinase C-delta in complex with phorbol ester. Cell 1995, 81, 917–
924.
(16) Hommel, U.; Zurini, M.; Luyten, M. Solution structure of a cysteine
rich domain of rat protein kinase C. Nat. Struct. Biol. 1994, 1, 383–
387.
(17) Xu, R. X.; Pawelczyk, T.; Xia, T. H.; Brown, S. C. NMR structure of
a protein kinase C-γ phorbol-binding domain and study of protein-
lipid micelle interactions. Biochemistry 1997, 36, 10709–10717.
(18) Shen, N.; Guryev, O.; Rizo, J. Intramolecular occlusion of the
diacylglycerol-binding site in the C1 domain of Munc13-1. Biochem-
istry 2005, 44, 1089–1096.
(19) Marquez, V. E.; Blumberg, P. M. Synthetic diacylglycerols (DAG)
and DAG-lactones as activators of protein kinase C (PK-C). Acc.
Chem. Res. 2003, 36, 434–443.
(20) Sharkey, N. A.; Blumberg, P. M. Comparison of the activity of phorbol
12-myristate 13-acetate and the diglyceride glycerol 1-myristate
2-acetate. Carcinogenesis 1986, 7, 677–679.
(21) Duan, D.; Sigano, D. M.; Kelley, J. A.; Lai, C.; Lewin, N. E.; Kedei,
N.; Peach, M. L.; Lee, J.; Abeyweera, T. P.; Rotenberg, S. A.; Kim,
H.; Kim, Y. H.; El Kazzouli, S.; Chung, J.-U.; Young, H. A.; Young,
M.; Baker, A.; Colburn, N. H.; Haimovitz-Friedman, A.; Truman, J.-
P.; Parrish, D. A.; Deschamps, J. R.; Perry, N. A.; Surawski, R. J;
Blumberg, P. M.; Marquez, V. E. Conformationally constrained
12r-E: yellow solid; mp 125-127 °C; 1H NMR (400 MHz,
CDCl3) δ 7.96 (t, J ) 2.7 Hz, 1H, CHdC), 7.84 (irregular d, J ≈
7.9 Hz, 2H, H4-indole), 7.27-7.37 (m, 4H, H2, H5, H6, and H7-
indole), 4.39 (AB d, 1H, J ) 11.9 Hz, CO2CHH), 4.27 (AB d, 1H,
J ) 11.9 Hz, CO2CHH), 3.87 (s, 3H, NCH3), 3.79 (AB d, 1H, J )
12.1 Hz, HOCHH), 3.73 (AB d, 1H, J ) 12.1 Hz, HOCHH), 3.05
(dd, 1H, J ) 17.1, 2.7 Hz, CHH-lactone), 2.84 (dd, 1H, J ) 17.1,
2.7 Hz, CHH-lactone), 2.35-2.42 (m, 1H, (CH3CH2CH2)2-
CHCO2CH2), 1.49-1.57 (m, 2H, (CH3CH2CH2)2CHCO2CH2),
1.36-1.40 (m, 2H, (CH3CH2CH2)2CHCO2CH2), 1.19-1.27 (m, 4H,
(CH3CH2CH2)2CHCO2CH2), 0.78 and 0.83 (t, 6H, J ) 7.3 Hz,
(CH3CH2CH2)2CHCO2CH2); 13C NMR (100 MHz, CDCl3) δ
176.73, 171.68, 136.92, 130.57, 128.89, 128.06, 123.49, 121.48,
119.80, 117.04, 112.04, 109.88, 82.87, 65.50, 65.18, 45.37, 34.56,
33.63, 33.37, 20.76, 14.07, 14.02; IR (neat) 3437 (OH), 1735 (CO),
1637 (CO) cm-1; FAB-MS (m/z, relative intensity) 414.3 (MH+,
100%) 413.3 (M+•, 94.5). Anal. (C24H31NO5 ·0.6H2O) C, H, N.
Acknowledgment. This research was supported by the
Intramural Research Program of the NIH, National Cancer

5386 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
El Kazzouli et al.
analogues of diacylglycerol (DAG). 29. Cells sort DAG-lactone
chemical zip codes to produce diverse and selective biological
activities. J. Med. Chem. 2008, 51, 5198–5220.
(25) Choi, Y.; Kang, J. H.; Lewin, N. E.; Blumberg, P. M.; Lee, J.; Marquez,
V. E. Conformationally constrained analogues of diacylglycerol. 19.
Synthesis and protein kinase C binding affinity of diacylglycerol
lactones bearing an N-hydroxylamide side chain. J. Med. Chem. 2003,
46, 2790–2793.
(22) Pu, Y.; Perry, N. A.; Yang, D.; Lewin, N. E.; Kedei, N.; Braun, D. C.;
Choi, S. H.; Blumberg, P. M.; Garfield, S. H.; Stone, J. C.; Duan, D.;
Marquez, V. E. A novel diacylglycerol-lactone shows marked selectiv-
ity in vitro among C1 domains of protein kinase C (PKC) isoforms R
and δ as well as selectivity for RasGRP compared with PKCR. J. Biol.
Chem. 2005, 280, 27329–27338.
(23) Kang, J. H.; Benzaria, S.; Sigano, D. M.; Lewin, N. E.; Pu, Y. M.;
Peach, M. L.; Blumberg, P. M.; Marquez, V. E. Conformationally
constrained analogues of diacylglycerol. 26. Exploring the chemical
space surrounding the C1 domain of protein kinase C with DAG-
lactones containing aryl groups at the sn-1 and sn-2 positions. J. Med.
Chem. 2006, 49, 3185–3203.
(26) Nacro, K.; Bienfait, B.; Lee, J.; Han, K. C.; Kang, J. H.; Benzaria, S.;
Lewin, N. E.; Bhattacharyya, D. K.; Blumberg, P. M.; Marquez, V. E.
Conformationally constrained analogues of diacylglycerol (DAG). 16.
How much structural complexity is necessary for recognition and high
binding affinity to protein kinase C? J. Med. Chem. 2000, 43, 921–944.
(27) Kang, J.-H.; Siddiqui, M. A.; Lewin, N. E.; Sigano, D. M.; Blumberg,
P. M.; Lee, J.; Marquez, V. E. Conformationally constrained analogues
of diacylglycerol. 24. Asymmetric synthesis of a chiral R-DAG-lactone
template as a versatile precursor for highly functionalized DAG-
lactones. Org. Lett. 2004, 6, 2413–2416.
(24) Lee, J. Design and synthesis of bioisosteres of ultrapotent protein kinase
C (PKC) ligand, 5-acetoxymethyl-5-hydroxymethyl-3-alkylidene tet-
rahydro-2-furanone. Arch. Pharmacal Res. 1998, 21, 452–457.
JM800380B