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

Article abstract of DOI:10.1021/jm060011o

Diacylglycerol lactones (DAG-lactones) are known to operate as effective agonists of protein kinase C (PKC), surpassing in potency the activity of natural diacylglycerol (DAG). Localization of activated PKC isozymes in the cell is determined in part by th

Full text of DOI:10.1021/jm060011o

J. Med. Chem. 2006, 49, 3185-3203
3185
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
Ji-Hye Kang,† Samira Benzaria,†,‡ Dina M. Sigano,† Nancy E. Lewin,§ Yongmei Pu,§ Megan L. Peach,|
Peter M. Blumberg,§ and Victor E. Marquez*,†
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer InstitutesFrederick, National Institutes of Health,
Frederick, Maryland 21702, Laboratory of Cellular Carcinogenesis & Tumor Promotion, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and Basic Research Program,
SAIC-Frederick, Inc., Frederick, Maryland 21702
ReceiVed January 5, 2006
Diacylglycerol lactones (DAG-lactones) are known to operate as effective agonists of protein kinase C
(PKC), surpassing in potency the activity of natural diacylglycerol (DAG). Localization of activated PKC
isozymes in the cell is determined in part by the different cellular scaffolds, the lipid composition of the
specific membranes, and the targeting information intrinsic to the individual isoforms bound to DAG. This
multifaceted control of diversity suggests that, to develop effective DAG-lactones capable of honing in on
a specific cellular target, we need to gain a better understanding of the chemical space surrounding its
binding site. Seeking to augment the chemical repertoire of DAG-lactone side chains that could steer the
translocation of PKC to specific cellular domains, we report herein the effects of incorporating simple or
substituted phenyl residues. A combined series of n-alkyl and phenyl substitutions were used to explore the
optimal location of the phenyl group on the side chains. The substantial differences in binding affinity
between DAG-lactones with identical functionalized phenyl groups at either the sn-1 or sn-2 position are
consistent with the proposed binding model in which the DAG-lactone binds to the C1 domain of PKC with
the acyl chain oriented toward the interior of the membrane and the R-alkylidene or R-arylalkylidene chains
directed to the surface of the C1 domain adjacent to the lipid interface. We conclude that DAG-lactones
containing R-phenylalkylidene side chains at the sn-2 position represent excellent scaffolds upon which to
explore further chemical diversity.
Introduction
to PLC-mediated hydrolysis of inositol lipids, such as phos-
phatidylinositol (4,5)-biphosphate.2 PKC action can be localized
to multiple compartments, which aside from the plasma
membrane include the endoplasmic reticulum, the Golgi ap-
paratus, and the nucleus.12 Localization is determined in part
by the different cellular scaffolds, the lipid composition of the
specific membranes,13 and the targeting information intrinsic
to the individual isoform bound to DAG.14 This multifaceted
control of diversity suggests that, to improve the likelihood of
developing DAG-like molecules capable of translocating
PKCs to specific cellular targets, we need to gain a better
understanding of the chemical space surrounding the DAG
binding site.
Previously, we have discovered potent DAG-like molecules,
referred to as DAG-lactones, that strongly activate PKC
isozymes.15 Diverse alkyl chains incorporated on these templates
at both their acyl and R-alkylidene positions have helped us
explore the surrounding binding sites of various isozymes with
some degree of success in achieving selective translocation of
some isozymes to specific cellular sites.15 In a recent paper
describing a solid-phase method for the synthesis of DAG-
lactones, we briefly described a few compounds containing aryl
moieties which showed potentially interesting properties.16
However, no attempt was made to find the optimal location of
the aryl group at either the acyl or R-alkylidene positions. Since
aryl groups provide the opportunity to add additional diversity
through the various substitution patterns on the aromatic
moieties, allowing us to probe further into the surrounding
chemical space of the binding sites, we set out to investigate in
a systematic fashion the effects of incorporating aryl residues
Diacylglycerol (DAG) is the principal physiological activator
for the majority of protein kinase C (PKC) isozymes.1-4 As
such, it is an important second messenger involved in the
regulation of cellular proliferation, survival, and differentiation.
Adding to this complex set of responses, oftentimes redundant
and even antagonistic, are some additional DAG responsive
targets that do not belong to the PKC family. These include
PKDs, RasGRP, chimaerins, Munc-13, and DAG kinases, whose
activation increases the level of complexity and multiplicity of
responses from DAG.5-7 Gaining knowledge about how the
regulation of PKC isozymes, PKD, and the non-kinase protein
targets control important intracellular events represents an
important field of study, particularly considering the high degree
of cross-talk between these differently DAG activated pathways
and their implications on cancer, immune responses, and
neurobiology.8,9
Activation of conventional (cPKC ) R, âI, âII, and γ) and
novel (nPKC ) δ, ꢀ, η, and θ) isoforms typically involves
recruitment of the enzyme to the membrane via an allosteric
interaction with DAG.10,11 Although there are many distinct
species of DAG, the DAG that activates these isozymes is
proposed to be a polyunsaturated form generated in response
* To whom correspondence should be addressed. Phone: (301) 846-
5954. Fax: (301) 846-6033. E-mail: marquezv@mail.nih.gov.
† National Cancer InstitutesFrederick, National Institutes of Health.
‡ Current address: Idenix Pharmaceuticals SARL, 170 Rue Leon Blum,
34000 Montpellier, France.
§ National Cancer Institute, National Institutes of Health.
| SAIC-Frederick, Inc.
10.1021/jm060011o CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/03/2006

3186 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
Table 2. Functionalization of the Phenyl Ring at the Optimal Position
on the R1 Arma
Ki(E-isomer) Ki(Z-isomer)
R1
R2
log P
(nM)
(nM)
8
9
(2-OMe)Ph (i-Pr)2CHCH2 3.77
(3-OMe)Ph (i-Pr)2CHCH2 3.77
73 ( 2
39 ( 2
23 ( 1
24 ( 1
10 (4-OMe)Ph (i-Pr)2CHCH2 3.77
36 ( 2
18 ( 1
11 (2-OH)Ph
12 (3-OH)Ph
13 (4-OH)Ph
(i-Pr)2CHCH2 3.47
(i-Pr)2CHCH2 3.47
(i-Pr)2CHCH2 3.47
67 ( 3
670 ( 15
2400 ( 530
30 ( 4
406 ( 11
983 ( 88
Figure 1. Design of aryl-substituted DAG-lactones to locate the
optimal location of the phenyl ring.
a See the general structure in Figure 2.
C1 domain of the kinase, the assays are routinely conducted in
the presence of 100 µg/mL phosphatidylserine (PS), which
fulfills this phospholipid requirement. Analysis of binding to
the intact PKC has the advantage that it is most appropriate for
evaluating ligand interactions with PKC as a therapeutic target.
Among PKC isoforms, we examined PKC-R for comparison
with our extensive knowledge of structure-activity relationships
for other DAG-lactones with this isoform15 and because of its
important role as a therapeutic target in cancer.22,23 Because
multiple structural elements within PKC contribute to membrane
interactions, e.g., the calcium responsive C2 domain in
PKC-R, and because the ligand-membrane-PKC interactions
are coupled to PKC activation,11,14 in select cases for which
we wished most closely to understand the mechanistic basis
underlying differences in measured binding affinities, we have
also extended our analysis to the individual C1 domain (vide
infra). For these latter studies, we used the C1b domain of
PKC-δ both because of the availability for this domain of the
X-ray structure of its interaction with a ligand24 and for the
technical considerations of stability and solubility.
Guided by the Ki values of the typically more potent
Z-isomers, the most favorable location for the phenyl ring was
found to be closest to the sn-1-carbonyl (compound 4, Table
1). We then compared the effects of exchanging the phenyl ring
of 4 for a cyclohexane ring (compound 5). We found that even
though the Ki value was 1.78-fold lower (higher affinity) the
log P value was 0.73 log unit higher, thus resulting in no
significant net gain. Because branched R-alkylidene chains lower
the log P value relative to that of their comparable linear
counterparts and also have been shown to be more effective in
selectively translocating PKC isozymes R and δ to different
cellular sites,25,26 compound 6 was synthesized. In relation to
4, this compound showed a slight 1.76-fold increase in Ki (lower
affinity), perhaps due to its 0.36 unit drop in log P value.
Although this reduction in binding affinity was recovered in
compound 7, which combines a cyclohexylacyl group with the
same branched R-alkylidene chain, compound 6 was still
considered to be the best candidate for further studies not only
because it had the lowest log P value (3.76), but also because
of the ease with which the phenyl ring could be further
functionalized without generating new asymmetric centers.
Starting with the selected parent compound 6 (Table 1), we
then studied the effects of adding polar methoxy (8-10) and
hydroxyl (11-13) groups at various positions on the phenyl
ring (Table 2). Relative to 6, the addition of a methoxy group
did not seem to have a significant effect on the calculated log
P value. Therefore, because compounds 8-10 have the same
capacity as 6 to partition into a lipid environment, they were
expected to provide information about the possible presence of
polar binding sites in their vicinity. Surprisingly, the methoxy
groups induced only a minimal effect on PKC binding, showing
a slight decrease in affinity relative to that of 6.
Figure 2. Generic structure of a DAG-lactone (the numbers correspond
to the glycerol backbone).
Table 1. Determination of the Optimal Location of the Phenyl Ring on
the R1 Arma
Ki(E-isomer) Ki(Z-isomer)
R1
R2
log P
(nM)
(nM)
1
2
3
4
5
6
7
Ph(CH2)3
Ph(CH2)2
PhCH2
Ph
cyclohexyl n-C9H19
Ph
n-C6H13
n-C7H15
n-C8H17
n-C9H19
4.13
4.13
4.13
4.13
4.86
27 ( 3
18 ( <1
44 ( 2
14 ( 1
9 ( 1
28 ( 3
10 ( <1
17 ( 1
14 ( 1
45 ( 3
9 ( 1
5 ( <1
16 ( 1
8 ( 1
(i-Pr)2CHCH2 3.76
cyclohexyl (i-Pr)2CHCH2 4.03
a See the general structure in Figure 2.
on DAG-lactones. From the data presented herein, we conclude
that aryl substituents represent useful scaffolds upon which to
explore chemical diversity on the DAG-lactones.
DAG-Lactone Design and PKC Binding Affinity
In previous studies with DAG and DAG-lactones having
different arrays of branched alkyl chains at the acyl and the
R-alkylidene positions, we have identified compounds that
display high binding affinity with reduced lipophilicity (log P).
Among DAG analogues, we identified a compound with a 40
nM binding affinity and a log P of 3.8,17 whereas for DAG-
lactones the log P could be as low as 3.2 for a compound
displaying a 30 nM binding affinity.18 Even with potent PKC
ligands, such as phorbol 12,13-dibutyrate (PDBU) and prostratin,
the log P values could be as low as 3.4 and 1.9, respectively.17
Therefore, the same principle of achieving the lowest possible
log P value to minimize nonselective lipid binding was also
applied once the optimal location of the aromatic ring on the
side chains of the DAG-lactones was identified. For the initial
phase of this investigation, a simple phenyl ring (Ph) was used
as a probe along both the sn-1 (acyl) and sn-2 (R-alkylidene)
chains as illustrated in Figure 1, and on the basis of the work
cited above and other studies,18,19 an initial target value of log
P around 4 was selected.
We started by investigating the optimal location for the phenyl
ring on the sn-1 acyl chain (R1) using a combination of variable-
length n-alkyl chains at the R-alkylidene position (R2) to
maintain a constant calculated log P20 of 4.13 (Figure 2, Table
1, compounds 1-4). For these studies PKC-R was used as the
target enzyme. The binding affinities of the DAG-lactones, as
reflected by their Ki values, were measured using a competition
assay with phorbol 12,13-dibutyrate. The assay has been
described in detail previously.21 Because the phospholipid
bilayer contributes to the binding interaction, along with the
In contrast, the hydroxyl group, which caused a small
reduction in the log P value, had a significant negative effect

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3187
Table 3. Optimal Location of the Phenyl Ring on the R2 Arma
Table 5. Comparison of p-Hydroxyl Ligands in Binding to PKC-δ-C1b
in the Presence or Absence of PS
Ki(E-isomer)
R1
R2
log P
(nM)
14
15
16
(i-Pr)2CHCH2
(i-Pr)2CHCH2
(i-Pr)2CHCH2
Ph
PhCH2
Ph(CH2)2
3.61
3.69
4.09
12 ( 3
14 ( 2
9 ( <1
a See the general structure in Figure 2.
Table 4. Functionalization of the Phenyl Ring at the Optimal Position
on the R2 Arma
Ki(E-isomer)
R1
R2
log P
(nM)
17
18
19
20
21
22
(i-Pr)2CHCH2
(i-Pr)2CHCH2
(i-Pr)2CHCH2
(i-Pr)2CHCH2
(i-Pr)2CHCH2
(i-Pr)2CHCH2
(2-OMe)Ph
(3-OMe)Ph
(4-OMe)Ph
(2-OH)Ph
(3-OH)Ph
(4-OH)Ph
3.62
3.62
3.62
3.32
3.32
3.32
16 ( 2
12 ( 1
7 ( <1
22 ( 1
17 ( <1
19 ( 3
a See the general structure in Figure 2.
on both E- and Z-isomers as the binding affinity plummeted
ca. 25-fold and ca. 70-fold, respectively, for the meta- and para-
isomers (compounds 12 and 13, Table 2). Remarkably, the
decrease in binding affinity for the ortho-isomer (11) in relation
to 6 (Table 1) was only ca. 2-fold for both E- and Z-isomers.
These combined results agree with a binding model in which
the acyl aryl ring is projected outside the C1 domain and into
the lipid milieu where a substantial desolvation penalty is
incurred for the free hydroxyl group. In compound 11, the
intramolecular H-bonding of the o-hydroxyl and the acyl
carbonyl forms a stable six-membered cyclic structure, thus
explaining why this ortho-isomer pays a lesser penalty of
dehydration.
accessible H-bond donors at the active site that can bind
effectively. The hydroxyl groups probably bind in a similar
fashion albeit a little less effectively.
Taken together, the combined results from Tables 2-4 point
to the existence of important differences between compounds
with identically functionalized phenyl groups at both ends of
the DAG-lactone. These results are consistent with the proposed
binding model in which the DAG-lactone binds to the C1
domain with the acyl chain oriented toward the lipid and its
R-alkylidene chain possibly interacting with the surrounding
space on the surface of the C1 domain. This binding model is
further supported by the observed 128-fold difference between
isomers (E)-13 (Ki ) 2400 nM) and (E)-22 (Ki ) 19 nM).
To study in more detail the contrast between (E)-13 and
(E)-22 in a simpler system than the intact PKC-R isozyme, we
decided to compare their binding affinities for the isolated δ-C1b
domain (Table 5). This specific C1 domain was chosen both
because the X-ray structure of its interaction with a ligand is
known24 and for technical considerations of stability and
solubility. Using the C1 domain, we have a strong basis for
relating our experimental Ki values to insights generated from
computer modeling.17,18 For the full PKC molecule, other
structural features contributing to membrane interaction, e.g.,
the pseudosubstrate domain or the C2 domain, the presence of
two functional C1 domains with distinct behavior, and the
coupling of ligand binding and membrane interaction to a
conformational change in the enzyme, with a resultant effect
of this conformational change on the energetics of binding, all
complicate interpretation.
The results from Table 2 prompted us to search for specific
interactions with the phenyl ring located at the alternative,
R-alkylidene position. As before, this also required determining
the best position for the phenyl ring on the R-alkylidene chain.
To rationally evaluate the two possible alternative locations of
the phenyl ring, the reverse isomer of compound 6 (Table 3,
compound 14) was synthesized along with two elongated
analogues containing one (15) and two (16) additional methylene
groups to increase the separation between the double bond and
the phenyl ring (Table 3). As can be appreciated, 14 (the reverse
isomer of 6), of which only the E-isomer was isolated, as
explained in Chemistry, had a slightly better binding affinity
than 6 and a similar calculated log P value. While distancing
the phenyl moiety from the double bond produced essentially
no change in binding affinity, the log P value increased steadily.
Therefore, compound 14 was selected for further studies.
Compounds 17-22 (Table 4) were synthesized with the
intention of probing for complementary H-bond donors or
acceptors around the C1 domain. In contrast to those of
compounds 8-13 (Table 2), where the functionalized phenyl
ring was part of the acyl moiety and large differences were
observed between the methoxy- and hydroxy-substituted com-
pounds, the differences in Ki values between the methoxy and
hydroxyl groups for compounds 17-22 were found to be
smaller, suggesting that these groups are indeed able to find
H-bonding partners. Although the increases in binding affinity
are modest relative to that of the parent compound 14, they
reach a value of 7 nM for the p-methoxy isomer, showing that
affinity increases in the order ortho < meta < para. Remark-
ably, the presence of a hydroxyl group does not lead to great
loss in binding affinity as with the reverse isomers (Table 2),
and only small changes of <2.5-fold are seen. The slightly better
performance of the methoxy isomers points to the presence of
Using the C1b domain, we further analyzed Ki for ligand
binding both under normal conditions, in which anionic phos-
pholipid (PS) is present to fulfill the complementary binding
half-site along with the C1 domain, and in the absence of
phospholipid. This latter condition, although nonphysiological,
helps dissect the contributions to the binding complex of the
C1 domain and of the lipid bilayer. This is important, because
the only crystal structure available is that of the binary complex
of the ligand and C1 domain,24 whereas the experimental
measurements under standard conditions represent the binding

3188 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
Figure 3. Model of the PKC-δ-C1b domain with bound DAG-lactones displaying the same hydrogen-bonding pattern as observed in the crystal
structure of the same domain bound to phorbol (yellow lines). Although the exact depth of penetration and orientation of the PKC-δ-C1b domain
relative to that of the membrane bilayer is not known experimentally, we can develop a reasonable estimate based on the location of hydrophobic
residues in the binding site loops. The bilayer interfacial region, which consists of the lipid headgroups and ordered water, is colored pale blue, and
the hydrophobic core of the lipid acyl chains is colored yellow. The left-hand structure shows the docked configuration of compound (E)-13, with
the polar hydroxyl group on the acyl side chain projected into the hydrophobic core of the bilayer. The right-hand structure shows the docked
configuration of compound (E)-22, with the R-phenylalkylidene side chain projected parallel to the membrane surface in the interfacial region,
where the hydroxyl group could form hydrogen bonds to water or lipid headgroups.
Scheme 1a
a Conditions and reagents: (a) LDA, ZnCl2, R2CHO, THF, -78 °C; (b) Et3N, MsCl, DBU, CH2Cl2, 0 °C f rt; (c) 70% HF/pyridine, pyridine, 0 °C f
rt, or Et3N‚3HF, CH3CN, ∆; (d) Bu2SnO, 4 Å molecular sieves, PhMe, ∆, then R1COCl, 0 °C.
affinity for the ternary complex of ligand-C1 domain-
phospholipid. The details of the assays were as described
previously.27,28
the sn-1 acyl group oriented toward the hydrophobic lipid
domain and the R-phenylalkylidene side chain projected parallel
to the membrane surface in the interfacial region (Figure 3).
The 128-fold difference in favor of (E)-22 over its isomer
(E)-13 with PKC-R (Tables 2 and 4) was magnified to 700-
fold when we switched to the isolated PKC-δ-C1b domain in
the presence of PS (Table 5). In the absence of PS, on the other
hand, this difference dropped to only 99-fold. Because the
lipophilicities of both isomers (E)-13 and (E)-22 are the same,
and the expected desolvation penalties when PS is present should
also be similar, removal of the lipid will impact more signifi-
cantly the isomer where the OH is engaged in polar interactions
with the charged PS headgroups. Hence, in the absence of PS,
(E)-13 experienced only a 17-fold drop in binding affinity,
whereas the stronger ligand (E)-22 experienced a 121-fold drop.
As before, these data further support the model already
proposed, where the DAG-lactone binds to the C1 domain with
Chemistry
The DAG-lactones 1-10 (E and Z), (E)-11, (E)-12, (E)-14,
and (E)-15 were synthesized as racemates according to published
methodology established in our laboratories as exemplified in
Scheme 1.25 Treatment of the previously reported protected
lactone I25 with LDA and ZnCl2 followed by aldehyde gave
the aldol adduct II. Subsequent mesylation followed by elimina-
tion with diazabicyclo[5.4.0]undec-7-ene (DBU) gave the
R-alkylidene DAG-lactone III as a mixture of E- and Z-isomers,
which were separated by silica gel chromatography. Consistent
with previously synthesized DAG-lactones, the vinyl proton of
the Z-isomer displayed a characteristic multiplet at δ ) 6.12-
1
6.18 in its H NMR spectrum, while the corresponding signal

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3189
Scheme 2
respectively, for the aldol condensation step. For DAG-lactones
(Z)-11, (Z)-12, (E)-13, and (Z)-13, the requisite isomeric
(benzyloxy)benzoic acid chlorides were synthesized from the
corresponding commercially available aldehydes according to
published methods (see the Experimental Section). Unlike the
method in Scheme 1, (Z)-11, (Z)-12, (E)-13, and (Z)-13 were
easily obtained by this approach without any evidence of E/Z-
isomerization. Using the benzyl-protected aromatic aldehyde,
or acid chloride, also offered the advantage of avoiding the
hydrolysis challenges that were encountered with the method
used in Scheme 2 and simplicity in simultaneously cleaving
both benzyl protecting groups in the last step.
Scheme 3a
Discussion
As a starting point, the phenyl ring was selected as the
simplest aryl group. To find the optimal placement of the phenyl
ring at the acyl position, several analogues were constructed
with the phenyl ring tethered to an alkyl chain at a predetermined
distance away from the lactone moiety and successively brought
closer until it was directly bonded to the carbonyl, giving the
benzoate ester. Methylene bridges from 3 down to 0 units were
employed, and for each methylene unit that was removed to
bring the phenyl ring closer to the lactone ring, one was added
to the R-alkylidene position to maintain a constant, optimal
calculated log P value of approximately 4 (Table 1, compounds
1-4). All of the compounds were separated into their geometric
isomers, and typically the more effective Z-isomers were about
1.2-1.5-fold more potent than the E-isomers. The combination
of the benzoate ester with a previously discovered highly
effective branched R-alkylidene moiety25 gave a set of com-
pounds ((E)-6 and (Z)-6) with a log P value below 4 and with
just a slight 1.7-fold drop in binding affinity relative to that of
compounds (E)-4 and (Z)-4 (Table 1). Two cyclohexyl variants
of 4 and 6 were synthesized to investigate the changes resulting
from the removal of the π-system (Table 1, compounds 5 and
7). However, the meager increase in affinity accrued at the
expense of a higher log P value and the expected difficulty in
obtaining simple substituted analogues on the cyclohexyl ring
convinced us that compound 6 provided the best combination
of substituents. This compound allowed us to explore the effects
of ortho-, meta- and para-substitutions on the phenyl ring (Table
2, compounds 8-13). In keeping with the notion that the
benzoate ester moiety at sn-1 appears to be projected into the
lipid environment of the membrane, no advantage was derived
by adding a methoxy group on the phenyl ring at various posi-
tions, as demonstrated by compounds 8-10. In a similar manner,
the conversion of methoxy groups into phenols (11-13) carried
the corresponding penalty of having these hydrophilic groups
projected into a hydrophobic lipid milieu. It is interesting that
the ortho-substituted compounds (E)-11 and (Z)-11 were
10-15 times more potent than the corresponding m-isomers
(E)-12 and (Z)-12 and ca. 35 times more potent than the
p-isomers (E)-13 and (Z)-13). This is probably due to the lower
desolvation penalty of compound 11 when moving into the lipid
medium due to the intramolecular hydrogen bonding of the
phenol with the sn-1-carbonyl of the lactone.
a Conditions and reagents: (a) LiHMDS, R2CHO, THF, -78 °C; (b)
Et3N, MsCl, DBU, CH2Cl2, 0 °C f rt; (c) CAN, CH3CN, 0 °C; (d) Et3N,
DMAP, R1COCl; (e) BCl3, CH2Cl2, -78 °C.
of the E-isomer appeared more downfield at δ ) 6.72-6.77.
Deprotection of III was accomplished using either HF/pyridine
or Et3N‚3HF. Monoacylation of the resulting diol was ac-
complished using Bu2SnO29 and acyl chloride to give the E-
and Z-isomers of DAG-lactones 1-10 and 14-15. The o- and
m-methoxy groups of DAG-lactones (E)-8 and (E)-9 (V) were
successfully removed with BBr3 to give (E)-11 and (E)-12 (VI),
respectively (Scheme 2). However, under the same reaction
conditions, the corresponding Z-isomers of 8 and 9 gave
inseparable E/Z-mixtures of 11 and 12, while the para-isomer
was completely cleaved to give diol IV (R2 ) CH2CH(i-Pr)2)
instead of 13. In this case, cleavage of the O-B bond occurred
preferentially via formation of p-quinone rather than by simple
aqueous hydrolysis during workup. These compounds ((Z)-11,
(Z)-12, (E)-13, and (Z)-13) were obtained by an alternative route
(vide infra).
An alternative strategy, which takes advantage of the lability
of the benzyl protecting group, was employed for the phenol-
substituted DAG-lactones ((Z)-11, (Z)-12, (E)-13, (Z)-13, and
(E)-20-(E)-22) (Scheme 3). This improved method was then
adapted as a general method for the synthesis of the remaining
DAG-lactones (16-22) selected for this study. Starting from
the previously reported asymmetrically protected DAG-lac-
tone VII,30,31 treatment with lithium bis(trimethylsilyl)amide
(LHMDS) followed by the designated aldehyde gave the aldol
adduct VIII. In a manner similar to the method described above,
subsequent mesylation followed by elimination with DBU gave
the diprotected R-alkylidene DAG-lactones IX as mixtures of
E- and Z-isomers, except for the precursors of compounds
17-22 (Table 4), which gave exclusively the E-isomer. Selective
deprotection of IX to remove the PMP group was accomplished
using ceric ammonium nitrate (CAN) in acetonitrile to give X.
Acylation with the selected acyl chloride, followed by deben-
zylation, gave the desired DAG-lactones XII. For DAG-lactones
(E)-17-(E)-19 and (E)-20-(E)-22, commercially available
anisaldehyde and (benzyloxy)benzaldehyde isomers were used,
Moving the aromatic moiety to an R-phenylalkylidene posi-
tion while maintaining the esterase stable [COCH2CH(i-Pr)2]
acyl group was also explored, commencing at the position
closest to the lactone and increasing the distance of the phenyl
ring by one or two methylene units (Table 3, compounds
14-16). In the case of 14, only the more thermodynamically
stable E-isomer was obtained. Since the Ki values for these
compounds were all in the same range, the compound with the

3190 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
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.
Molecular Modeling. Structures for compounds (E)-13 and
(E)-22 were built in Sybyl36 and minimized with the MMFF94 force
field and partial charges.37 These compounds were then docked
into the crystal structure of the C1b domain of PKC-δ,24 using the
program GOLD 2.2.38 We used standard default genetic algorithm
settings, with the binding site defined by atoms within a 10.0 Å
radius of the Nꢀ atom of residue Q257. The stochastic nature of
the GOLD docking algorithm gives a mixture of two binding modes.
We know, however, from detailed energetic analysis that the sn-2
binding mode is preferred for the lactone template,18 and we
therefore included H-bonding constraints to bias the docking toward
this mode. This allowed us to focus on exploring the conformational
space available to the aryl side chains.
(Benzyloxy)benzoic Acids and (Benzyloxy)benzoyl Chlorides.
4-(Benzyloxy)benzoic acid is commercially available. The other
isomers were obtained according to the method of Heaney and
Newbold39 from the corresponding aldehydes.40,41 The acid chlorides
were obtained after treatment with neat thionyl chloride at 50 °C.
Azeotropic removal of the excess reagent with benzene afforded
the crude acid chlorides, which were used immediately.
General Procedure for the Synthesis of II. Procedure A.
According to a literature procedure,32 a solution of I (1 equiv) in
THF (7 mL/mmol) at -78 °C was treated dropwise with LDA (2.5
equiv) and stirred at the same temperature for 1 h. ZnCl2 (1.1 equiv)
was added followed by dropwise addition of R1CHO (1.5 equiv),
and the reaction was stirred at -78 °C for 1 h and then -40 °C for
1 h. The reaction mixture was then quenched with a saturated
aqueous solution of NH4Cl and allowed to warm to room temper-
ature. The layers were separated, and the aqueous layer was
extracted with Et2O (3×). The combined organics were washed
with H2O (1×) and brine (1×), dried over MgSO4, and concentrated
in vacuo. Purification by silica gel flash column chromatography
gave II as an oil which was used directly without further
purification.
Procedure B. According to the literature procedure,32 a solution
of I (1 equiv) in THF (5 mL/mmol) at -78 °C was treated dropwise
with LDA (1.5 equiv) and stirred at the same temperature for 2 h.
A solution of R1CHO (2 equiv) was added dropwise, and the
reaction was stirred at -78 °C overnight. 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 over
MgSO4, and concentrated in vacuo. Purification by silica gel flash
column chromatography gave II as a mixture of diastereomers
which were used directly in the next step.
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
(hydroxyheptyl)-3,4,5-trihydrofuran-2-one (II, R2 ) C6H13).
According to general procedure A, I and heptyl aldehyde (1.14 g,
10.0 mmol) were reacted to give II (R2 ) C6H13; 5.15 g, 100%
yield).
phenyl ring closest to the lactone ((E)-14) was selected because
it had the lowest calculated log P value. This compound is the
reverse isomer of 6, and with a comparable calculated log P
value it showed better binding affinity than either (E)-6 or
(Z)-6.
In contrast to the case in which the functionalized phenyl
ring was part of the acyl moiety, the comparable Ki values
observed for both sets of methoxy- and hydroxyphenyl-
substituted compounds in Table 4 ((E)-17-(E)-22) suggest that
these groups are able to find H-bonding partners. Remarkably,
the presence of the OH in (E)-20-(E)-22 does not lead to a
significant loss in binding affinity as with the reverse isomers
in Table 2. Since only E-isomers were obtained in this series,
we cannot determine whether the same trend of “Z better than
E” observed for the R-alkylidene isomers will hold.
The contrasting results in Tables 2-4 point to the existence
of notable differences between compounds with identical
functionalized phenyl groups at both ends of the DAG-lactone.
These results are consistent with a model in which the DAG-
lactone occupies the C1 domain with its acyl chain oriented
toward the inner lipid core and where the polar groups on the
R-phenylalkylidene chain could bind beyond the C1 domain at
the lipid interface (Figure 3). The observed 128- and 700-fold
differences in binding affinities between isomers (E)-13 and (E)-
22 for PKC-R and the isolated δ-C1b domain support this
binding model. Because molecular docking of these isomers
into the empty δ-C1b domain did not reveal any critical
H-bonding contacts with amino acids on the surface of the C1
domain, we consider it likely that the contrasting behaviors
displayed by these isomers point to important polar interactions
at the lipid interface in the ternary complex (Figure 3).
We conclude from the present study that both DAG templates
containing the aryl ring closest to the lactone represent useful
scaffolds upon which to explore future chemical diversity. In
the case of the benzoate ester 4, compounds bearing additional
alkyl groups (Me, Et, i-Pr, and t-Bu) designed to seek additional
interactions with the membrane will be investigated. In the case
of the R-phenylalkylidene analogues, where the substituents are
expected to engage in polar interactions, additional polar groups
will be used to explore chemical diversity. We anticipate that a
combination of substituents balancing the properties of lipo-
philicity at the sn-1 position and chemical specificity at the sn-2
position of DAG-lactones will provide efficient tools with which
to explore specific translocation patterns of PKC to subcellular
spaces.
Experimental Section
Biological Activity. Enzyme-ligand interactions were assessed
in terms of the ability of the ligand to displace bound [20-3H]phor-
bol 12,13-dibutyrate (PDBU) from a recombinant single isozyme
(PKC-R) in the presence of phosphatidylserine.21,32-35 The partition
coefficients (log P) were calculated according to the atom-based
program MOE SLog P.20
General Procedures. All chemical reagents were commercially
available. Melting points were determined on a MelTemp II
apparatus, Laboratory Devices, and are uncorrected. Column
chromatography was performed on silica gel 60, 230-400 mesh
(E. Merck or Bodman Industries), and analytical TLC was
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
(hydroxyoctyl)-3,4,5-trihydrofuran-2-one (II, R2 ) C7H15). Ac-
cording to general procedure A, I and octyl aldehyde (1.31 g, 10.2
mmol) were reacted to give II (R2 ) C7H15; 4.04 g, 78% yield).
1
performed on Analtech Uniplates silica gel GF. H and 13C NMR
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
(hydroxynonyl)-3,4,5-trihydrofuran-2-one (II, R2 ) C8H17).
According to general procedure A, I and nonyl aldehyde (1.16 g,
8.14 mmol) were reacted to give II (R2 ) C8H17; 3.47 g, 66% yield).
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
(hydroxydecyl)-3,4,5-trihydrofuran-2-one (II, R2 ) C9H19).
According to general procedure A, I and decyl aldehyde (3.82 g,
spectra were recorded either on a Bruker AC-250 instrument at
250 and 62.9 MHz, respectively; or 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 (FABMS) were
obtained on a VG 7070E-HF double-focusing mass spectrometer
operated at an accelerating voltage of 6 kV under the control of a

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3191
24.4 mmol) were reacted to give II (R2 ) C9H19; 13.63 g, 100%
yield).
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
[1-hydroxy-4-methyl-3-(methylethyl)pentyl]-3,4,5-trihydrofuran-
2-one (II, R2 ) CH2CH(i-Pr)2). This compound was prepared as
previously reported.25
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
nonylidene-4,5-dihydrofuran-2-one (III, R2 ) C8H17). According
to general procedure C, II (R2 ) C8H17; 5.39 g, 7.04 mmol) was
reacted to give (E)-III (R2 ) C8H17; 3.80 g, 72% yield) and
(Z)-III (R2 ) C8H17; 542 mg, 10% yield).
Data for (E)-III (R2 ) C8H17): oil; 1H NMR (250 MHz, CDCl3)
δ 0.86 (app t, 3 H, CdCHCH2CH2(CH2)5CH3), 0.97 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.25-1.40 (m, 10 H, CdCHCH2CH2(CH2)5CH3),
1.40-1.55 (m, 2 H, CdCHCH2CH2(CH2)5CH3), 2.10-2.18 (m, 2
H, CdCHCH2CH2(CH2)5CH3), 2.72 (br s, 2 H, H-4ab), 3.68 (AB
q, J ) 10.7 Hz, 4 H, CCH2OSiPh2C(CH3)3), 6.60-6.73 (m, 1 H,
CdCHCH2CH2(CH2)5CH3), 7.30-7.45 and 7.58-7.65 (m, 20 H,
CCH2OSiPh2C(CH3)3). Anal. (C47H62O4Si2) C, H.
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
(hydroxyphenylmethyl)-3,4,5-trihydrofuran-2-one (II, R2 ) Ph).
According to general procedure B, I and benzaldehyde (2.09 g,
19.7 mmol) were reacted to give II (R2 ) Ph; 6.32 g, 90% yield).
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
(1-hydroxy-2-phenylethyl)-3,4,5-trihydrofuran-2-one (II, R2 )
CH2Ph). According to general procedure B, I and phenylacetal-
dehyde (2.26 g, 18.8 mmol) were reacted to give II (R2 ) CH2Ph;
6.32 g, 90% yield).
General Procedure for the Synthesis of III. Procedure C.
According to the literature procedure,32 a solution of II (1 equiv)
and triethylamine (4 equiv) in CH2Cl2 (10 mL/mmol) was treated
dropwise with 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, DBU (5 equiv) was added dropwise at 0 °C, and the
reaction mixture was allowed to reach room temperature over-
night. 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 over MgSO4, and concentrated in vacuo. Purification by silica
gel flash column chromatography gave III as a mixture of E- and
Z-isomers.
Data for (Z)-III (R2 ) C8H17): oil; 1H NMR (250 MHz, CDCl3)
δ 0.86 (app t, 3 H, CdCHCH2CH2(CH2)5CH3), 0.96 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.25-1.48 (m, 12 H, CdCHCH2CH2(CH2)5CH3),
2.60-2.76 (m, 2 H, CdCHCH2CH2(CH2)5CH3), 2.88 (br d, J )
2.0 Hz, 2 H, H-4ab), 3.66 (AB q, J ) 10.7 Hz, 4 H, CCH2OSiPh2C-
(CH3)3), 6.05-6.15 (m, 1 H, CdCHCH2CH2(CH2)5CH3), 7.23-
7.45 and 7.56-7.60 (m, 20 H, CCH2OSiPh2C(CH3)3). Anal.
(C47H62O4Si2) C, H.
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
decylidene-4,5-dihydrofuran-2-one (III, R2 ) C9H19). According
to general procedure C, II (R2 ) C9H19; 12.51 g, 16.05 mmol) was
reacted to give (E)-III (R2 ) C9H19; 7.67 g, 63% yield) and
(Z)-III (R2 ) C9H19; 2.57 g, 21% yield).
Data for (E)-III (R2 ) C9H19): oil; 1H NMR (250 MHz, CDCl3)
δ 0.97 (app t, 3 H, CdCHCH2CH2(CH2)6CH3), 1.08 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.35 (s, 12 H, CdCHCH2CH2(CH2)6CH3), 1.49-
1.52 (m, 2 H, CdCHCH2CH2(CH2)6CH3), 2.19-2.27 (q, J ) 7. 1
Hz, 2 H, CdCHCH2CH2(CH2)6CH3), 2.83 (s, 2 H, H-4ab), 3.79
(AB q, J ) 10.7 Hz, 4 H, CCH2OSiPh2C(CH3)3), 6.74-6.85 (m, 1
H, CdCHCH2CH2(CH2)6CH3), 7.41-7.51 and 7.68-7.71 (m, 20
H, CCH2OSiPh2C(CH3)3). Anal. (C48H64O4Si2).
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
heptylidene-4,5-dihydrofuran-2-one (III, R2 ) C6H13). According
to the general procedure C, II (R2 ) C6H13; 4.39 g, 5.95 mmol)
was reacted to give (E)-III (R2 ) C6H13; 2.26 g, 53% yield) and
(Z)-III (R2 ) C6H13; 941 mg, 22% yield).
Data for (Z)-III (R2 ) C9H19): oil; 1H NMR (250 MHz, CDCl3)
δ 0.97 (app t, 3 H, CdCHCH2CH2(CH2)6CH3), 1.09 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.35-1.55 (m, 14 H, CdCHCH2CH2(CH2)6CH3),
2.74-2.85 (m, 2 H, CdCHCH2CH2(CH2)6CH3), 2.91 (d, J ) 1.7
Hz, 2 H, H-4ab), 3.78 (AB q, J ) 10.7 Hz, 4 H, CCH2OSiPh2C-
(CH3)3), 6.20 (t, J ) 7.6 Hz, 1 H, CdCHCH2CH2(CH2)6CH3),
7.41-7.51 and 7.68-7.71 (m, 20 H, CCH2OSiPh2C(CH3)3). Anal.
(C48H64O4Si2) C, H.
(E)-5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)meth-
yl]-3-[4-methyl-3 -(methylethyl)pentylidene]-4,5-dihydrofuran-
2-one (III, R2 ) CH2CH(i-Pr)2) and (Z)-5,5-Bis[(2,2-dimethyl-
1,1-diphenyl-1-silapropoxy)methyl]-3-[4-methyl-3-(methylethyl)-
pentylidene]-4,5-dihydrofuran-2-one (III, R2 ) CH2CH(i-Pr)2).
These compounds are known and were prepared as previously
reported.25
Data for (E)-III (R2 ) C6H13): oil; 1H NMR (250 MHz, CDCl3)
δ 0.87 (app t, 3 H, CdCHCH2CH2(CH2)3CH3), 0.97 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.20-1.35 (m, 6 H, CdCHCH2CH2(CH2)3CH3),
1.35-1.50 (m, 2 H, CdCHCH2CH2(CH2)3CH3), 2.13-2.20 (m, 2
H, CdCHCH2CH2(CH2)4CH3), 2.70-2.75 (m, 2 H, H-4ab), 3.68
(AB q, J ) 10.8 Hz, 4 H, CCH2OSiPh2C(CH3)3), 6.68 (tt, J ) 7.5,
2.9 Hz, 1 H, CdCHCH2CH2(CH2)3CH3), 7.29-7.60 (m, 20 H,
CCH2OSiPh2C(CH3)3). Anal. (C45H58O4Si2‚0.5H2O) C, H.
Data for (Z)-III (R2 ) C6H13): oil; 1H NMR (250 MHz, CDCl3)
δ 0.86 (app t, 3 H, CdCHCH2CH2(CH2)3CH3), 0.98 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.20-1.43 (m, 8 H, CdCHCH2CH2(CH2)3CH3),
2.60-2.75 (m, 2 H, CdCHCH2CH2(CH2)3CH3), 2.80 (br d, J )
2.1 Hz, 2 H, H-4ab), 3.66 (AB q, J ) 10.7 Hz, 4 H, CCH2OSiPh2C-
(CH3)3), 6.09 (tt, J ) 7.6, 2.1 Hz, 1 H, CdCHCH2CH2(CH2)3CH3),
7.32-7.61 (m, 20 H, CCH2OSiPh2C(CH3)3). Anal. (C46H60O4Si2)
C, H.
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
(phenylmethylene)-4,5-dihydrofuran-2-one (III, R2 ) Ph). Ac-
cording to general procedure C, II (R2 ) Ph; 6.27 g, 8.60 mmol)
was reacted to give (E)-III (R2 ) Ph; 5.11 g, 84% yield) as the
major product and (Z)-III (R2 ) Ph; 218 mg, 3% yield), which
was only isolated as a crude oil.
5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-3-
octylidene-4,5-dihydrofuran-2-one (III, R2 ) C7H15). According
to general procedure C, II (R2 ) C7H15; 3.71 g, 4.94 mmol) was
reacted to give (E)-III (R2 ) C7H15; 1.85 g, 51% yield) and
(Z)-III (R2 ) C7H15; 782 mg, 22% yield).
1
Data for (E)-III (R2 ) Ph): oil; H NMR (250 MHz, CDCl3)
Data for (E)-III (R2 ) C7H15): oil; 1H NMR (250 MHz, CDCl3)
δ 0.86 (app t, 3 H, CdCHCH2CH2(CH2)4CH3), 0.97 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.15-1.35 (m, 8 H, CdCHCH2CH2(CH2)4CH3),
1.35-1.51 (m, 2 H, CdCHCH2CH2(CH2)4CH3), 2.10-2.20 (m, 2
H, CdCHCH2CH2(CH2)4CH3), 2.80 (br d, J ) 2.0 Hz, 2 H, H-4ab),
3.68 (AB q, J ) 10.7 Hz, 4 H, CCH2OSiPh2C(CH3)3), 6.68 (tt, J
) 7.5, 2.9 Hz, 1 H, CdCHCH2CH2(CH2)4CH3), 7.32-7.60 (m, 20
H, CCH2OSiPh2C(CH3)3). Anal. (C46H60O4Si2) C, H.
δ 1.06 (s, 18 H, CCH2OSiPh2C(CH3)3), 3.15 (d, J ) 2.7 Hz,
2 H, H-4ab), 3.85 (AB q, J ) 10.9 Hz, 4 H, CCH2OSiPh2C(CH3)3),
7.35-7.53 and 7.60-7.68 (m, 26 H, CCH2OSiPh2C(CH3)3 and
CdCHPh). Anal. (C45H50O4Si2) C, H.
(Z)-III (R2 ) Ph). Although this product was only obtained as
a crude oil, it helped establish the stereochemistry of the double
bond, relative to that of the major isomer (E)-III, on the basis of
the chemical shift of the CdCHPh signal: 1H NMR (250 MHz,
CDCl3) δ 1.08 (s, 18 H, CCH2OSiPh2C(CH3)3), 3.14 (d, J ) 2.2
Hz, 2 H, H-4ab), 3.83 (AB q, J ) 10.5 Hz, 4 H, CCH2OSiPh2C-
(CH3)3), 6.98 (br s, 1 H, CdCHPh), 7.38-7.50, 7.69-7.72, and
7.88-7.91 (m, 25 H, CCH2OSiPh2C(CH3)3 and CdCHPh).
(E)-5,5-Bis[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-
3-(2-phenylethylidene)-4,5-dihydrofuran-2-one (III, R2 ) CH2Ph).
According to general procedure C, II (R2 ) CH2Ph; 5.60 g, 7.54
Data for (Z)-III (R2 ) C7H15): oil; 1H NMR (250 MHz, CDCl3)
δ 0.86 (app t, 3 H, CdCHCH2CH2(CH2)4CH3), 0.98 (s, 18 H, CCH2-
OSiPh2C(CH3)3), 1.20-1.48 (m, 10 H, CdCHCH2CH2(CH2)4CH3),
2.62-2.74 (m, 2 H, CdCHCH2CH2(CH2)4CH3), 2.80 (br d, 2 H,
H-4ab), 3.66 (AB q, J ) 10.7 Hz, 4 H, CCH2OSiPh2C(CH3)3), 6.09
(tt, J ) 7.6, 2.1 Hz, 1 H, CdCHCH2CH2(CH2)4CH3), 7.32-7.60
(m, 20 H, (CH3)3CSiPh2OCH2C). Anal. (C46H60O4Si2) C, H.

3192 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
mmol) was reacted to give (E)-III (R2 ) CH2Ph; 2.85 g, 52% yield)
and a mixture of byproducts. A characteristic pattern consisting of
NMR signals at δ 6.56 (d, J ) 16 Hz, 1 H) and δ 6.28 (dd, J ) 16,
6.8 Hz, 1 H) confirmed that the double bond in the byproducts had
rearranged and that it was no longer conjugated to the lactone
carbonyl.
0.93-0.96 (m, 3 H, CdCHCH2CH2(CH2)4CH3), 1.33 (s, 8 H,
CdCHCH2CH2(CH2)4CH3), 1.45-1.53 (m, 2 H, CdCHCH2CH2-
(CH2)4CH3), 2.33 (br s, 2 H, CCH2OH), 2.73-2.82 (m, 2 H,
CdCHCH2CH2(CH2)4CH3), 2.87 (d, J ) 2.0 Hz, 2 H, H-4ab), 3.81
(distorted AB q, J ) 12.1 Hz, 4 H, CCH2OH), 6.32 (tt, J ) 7.7,
2.2 Hz, 1 H, CdCHCH2CH2(CH2)4CH3); 13C NMR (62.9 MHz,
CDCl3) δ 14.02, 22.56, 27.71, 28.98, 29.03, 29.17, 31.69, 32.62,
64.69, 84.57, 124.07, 145.58, 169.62; FAB-MS (m/z, relative
intensity) 257 (MH+, 100). Anal. (C14H24O4) C, H.
(E)-5,5-Bis(hydroxymethyl)-3-nonylidene-4,5-dihydrofuran-
2-one (IV, R2 ) C8H17). According to general procedure E,
(E)-III (R2 ) C8H17; 760 mg, 1.02 mmol) was reacted to give
(E)-IV (R2 ) C8H17; 255 mg, 92% yield): oil; 1H NMR (250 MHz,
CDCl3) δ 0.86 (app t, 3 H, CdCHCH2CH2(CH2)5CH3), 1.5 (s, 10
H, CdCHCH2CH2(CH2)5CH3), 1.43-1.48 (m, 2 H, CdCHCH2CH2-
(CH2)5CH3), 1.97 (br s, 2 H, CCH2OH), 2.12-2.20 (m, 2 H,
CdCHCH2CH2(CH2)5CH3), 2.70-2.72 (m, 2 H, H-4ab), 3.73 (AB
q, J ) 12.0 Hz, 4 H, CCH2OH), 6.74 (tt, J ) 7.6 2.9 Hz, 1 H,
CdCHCH2CH2(CH2)5CH3); 13C NMR (62.9 MHz, CDCl3) δ 14.05,
22.62, 28.03, 29.15, 29.31, 30.27, 31.79, 65.21, 84.90, 126.10,
142.26, 170.33; FAB-MS (m/z, relative intensity) 271 (MH+, 100).
Anal. (C15H26O4).
Data for II (R2 ) CH2Ph): oil; 1H NMR (250 MHz, CDCl3) δ
1.08 (s, 18 H, CCH2OSiPh2C(CH3)3), 2.88 (s, 2 H, H-4ab), 3.58 (d,
J ) 7.3 Hz, 2 H, CdCHCH2Ph), 3.79 (AB q, J ) 10.8 Hz, 4 H,
CCH2OSiPh2C(CH3)3), 6.94-7.02 (m, 1 H, CdCHCH2Ph), 7.22-
7.51 and 7.67-7.70 (m, 25 H, CCH2OSiPh2C(CH3)3 and
CdCHCH2Ph). Anal. (C46H52O4Si2‚0.25H2O) C, H.
General Procedure for the Synthesis of IV. Procedure D. A
solution of III (1 equiv) in pyridine (7 mL/mmol) was treated
dropwise with HF/pyridine (70%, 5 equiv) at 0 °C and allowed to
reach room temperature overnight. The reaction mixture was then
quenched with solid NaHCO3 and filtered. The filtrate was
concentrated in vacuo and azeotroped with toluene and chloroform.
Purification by silica gel flash column chromatography gave IV.
Procedure E. According to the literature procedure,42 a suspen-
sion of III (1 equiv) in CH3CN (29 mL/mmol) was treated with
Et3N‚3HF (6 equiv) and heated to reflux for 5 h. The reaction mix-
ture was then cooled to room temperature, pH 7.0 potassium phos-
phate buffer (1 mL/mL CH3CN) was added, and the mixture was
stirred for 30 min. The reaction mixture was then diluted with
EtOAc, the layers were separated, and the aqueous layer was ex-
tracted with EtOAc (2×). The combined organic layers were washed
with brine (1×), dried over MgSO4, and concentrated in vacuo.
Purification by silica gel flash column chromatography gave IV.
(E)-5,5-Bis(hydroxymethyl)-3-heptylidene-4,5-dihydrofuran-
2-one (IV, R2 ) C6H13). According to general procedure E,
(E)-III (R2 ) C6H13; 820 mg, 1.14 mmol) was reacted to give
(E)-IV (R2 ) C6H13; 206 mg, 75% yield): oil; 1H NMR (250 MHz,
CDCl3) δ 0.97 (app t, 3 H, CdCHCH2CH2(CH2)3CH3), 1.37
(br s, 6 H, CdCHCH2CH2(CH2)3CH3), 1.50-1.65 (m, 2 H,
CdCHCH2CH2(CH2)3CH3), 2.22-2.30 (m, 2 H, CdCHCH2-
CH2(CH2)3CH3), 2.42 (t, J ) 5.9 Hz, 2 H, CCH2OH), 2.81 (br s,
2 H, H-4ab), 3.74-3.91 (overlapping AB quartets, 4 H, CCH2OH),
6.80-6.88 (m, 1 H, CdCHCH2CH2(CH2)3CH3); 13C NMR (62.9
MHz, CDCl3) δ 14.08, 22.57, 28.04, 29.03, 29.39, 30.32, 31.59,
65.17, 85.09, 126.12, 142.19, 170.47; FAB-MS (m/z, relative
intensity) 243 (MH+, 100). Anal. (C13H22O4).
(Z)-5,5-Bis(hydroxymethyl)-3-heptylidene-4,5-dihydrofuran-
2-one (IV, R2 ) C6H13). According to general procedure D, (Z)-
III (R2 ) C6H13; 976 mg, 1.36 mmol) was reacted to give (Z)-IV
(R2 ) C6H13; 257 mg, 78% yield): oil; 1H NMR (250 MHz, CDCl3)
δ 0.96 (app t, 3 H, CdCHCH2CH2(CH2)3CH3), 1.36-1.53 (m, 8
H, CdCHCH2CH2(CH2)3CH3), 2.46 (br s, 2 H, CCH2OH), 2.74-
2.81 (m, 2 H, CdCHCH2CH2(CH2)3CH3), 2.86 (br d, J ) 2.2 Hz,
2 H, H-4ab), 3.81 (AB q, J ) 12.0 Hz, 4 H, CCH2OH), 6.33 (tt, J
) 7.7, 2.2 Hz, 1 H, CdCHCH2CH2(CH2)3CH3); 13C NMR (62.9
MHz, CDCl3) δ 14.00, 22.50, 27.71, 28.86, 28.94, 31.55, 32.59,
64.98, 84.18, 123.92, 145.70, 169.14; FAB-MS (m/z, relative
intensity) 243 (MH+, 100). Anal. (C13H22O4‚0.2H2O) C, H.
(E)-5,5-Bis(hydroxymethyl)-3-octylidene-4,5-dihydrofuran-2-
one (IV, R2 ) C7H15). According to general procedure E, (E)-III
(R2 ) C7H15; 3.71 g, 4.94 mmol) was reacted to give (E)-IV (R2
) C7H15; 227 mg, 80% yield): oil; 1H NMR (250 MHz, CDCl3) δ
0.83-0.89 (m, 3 H, CdCHCH2CH2(CH2)4CH3), 1.26 (s, 8 H,
CdCHCH2CH2(CH2)4CH3), 1.43-1.48 (m, 2 H, CdCHCH2CH2-
(CH2)4CH3), 2.02 (br s, 2 H, CCH2OH), 2.11-2.20 (m, 2 H,
CdCHCH2CH2(CH2)4CH3), 2.71 (m, 2 H, H-4ab), 3.73 (AB q,
J ) 12.0 Hz, 4 H, CCH2OH), 6.74 (tt, J ) 7.6, 2.9 Hz, 1 H,
CdCHCH2CH2(CH2)4CH3); 13C NMR (62.9 MHz, CDCl3) δ 14.04,
22.58, 28.03, 29.01, 29.27, 29.34, 30.27, 31.69, 65.20, 84.96,
126.11, 142.26, 170.41; FAB-MS (m/z, relative intensity) 257
(MH+, 100). Anal. (C14H24O4) C, H.
(Z)-5,5-Bis(hydroxymethyl)-3-nonylidene-4,5-dihydrofuran-
2-one (IV, R2 ) C8H17). According to general procedure E,
(Z)-III (R2 ) C8H17; 390 mg, 0.52 mmol) was reacted to give
(Z)-IV (R2 ) C8H17; 130 mg, 93% yield): oil; 1H NMR (250 MHz,
CDCl3) δ 0.83-0.88 (m, 3 H, CdCHCH2CH2(CH2)5CH3), 1.24-
1.40 (m, 12 H, CdCHCH2CH2(CH2)5CH3), 2.06 (br s, 2 H,
CCH2OH), 2.66-2.69 (m, 2 H, CdCHCH2CH2(CH2)5CH3), 2.75-
2.78 (m, 2 H, H-4ab), 3.71 (AB q, J ) 12.0 Hz, 4 H, CCH2OH),
6.23 (tt, J ) 7.7, 2.3 Hz, 1 H, CdCHCH2CH2(CH2)5CH3); 13C NMR
(62.9 MHz, CDCl3) δ 14.07, 22.63, 27.75, 29.03, 29.19, 29.24,
29.36, 31.82, 32.63, 65.11, 84.07, 124.41, 145.86, 169.13; FAB-
MS (m/z, relative intensity) 271 (MH+, 100). Anal. (C15H26O4).
(E)-5,5-Bis(hydroxymethyl)-3-decylidene-4,5-dihydrofuran-
2-one (IV, R2 ) C9H19). According to general procedure E,
(E)-III (R2 ) C9H19; 790 mg, 1.04 mmol) was reacted to give
1
(E)-IV (R2 ) C9H19; 271 mg, 92% yield): oil; H NMR (250
MHz, CDCl3) δ 0.81-0.91 (m, 3 H, CdCHCH2CH2(CH2)6CH3),
1.25 (s, 12 H, CdCHCH2CH2(CH2)6CH3), 1.38-1.54 (m, 2H,
CdCHCH2CH2(CH2)6CH3), 1.97 (br s, 2 H, CCH2OH), 2.08-2.24
(m, 2 H, CdCHCH2CH2(CH2)6CH3), 2.65-2.75 (m, 2 H, H-4ab),
3.73 (AB q, J ) 12.1 Hz, 4 H, CCH2OH), 6.74 (tt, J ) 7.6, 2.8
Hz, 1 H, CdCHCH2CH2(CH2)6CH3); 13C NMR (62.9 MHz, CDCl3)
δ 14.06, 22.64, 28.03, 29.24, 29.34, 29.45, 30.27, 31.82, 65.22,
84.85, 126.11, 142.26, 170.34; FAB-MS (m/z, relative intensity)
285 (MH+, 100). Anal. (C16H28O4) C, H.
(Z)-5,5-Bis(hydroxymethyl)-3-decylidene-4,5-dihydrofuran-2-
one (IV, R2 ) C9H19). According to general procedure D, (Z)-III
(R2 ) C9H19; 997 mg, 1.31 mmol) was reacted to give (Z)-IV (R2
) C9H19; 334 mg, 90% yield): oil; 1H NMR (250 MHz, CDCl3) δ
0.93-0.96 (m, 3 H, CdCHCH2CH2(CH2)6CH3), 1.34-1.70 (m, 14
H, CdCHCH2CH2(CH2)6CH3), 2.12 (t, J ) 6.4 Hz, 2 H, CCH2OH),
2.74-2.87 (m, 2 H, CdCHCH2CH2(CH2)6CH3), 2.88 (d, J )
2.2 Hz, 2 H, H-4ab), 3.74-3.90 (overlapping AB quartets, 4 H,
CCH2OH), 6.33 (tt, J ) 7.7, 2.2 Hz, 1 H, CdCHCH2CH2(CH2)6-
CH3); 13C NMR (62.9 MHz, CDCl3) δ 14.05, 22.61, 27.72, 28.99,
29.22, 29.38, 29.45, 29.63, 31.81, 32.60, 64.96, 84.22, 123.89,
145.86, 169.20; FAB-MS (m/z, relative intensity) 285 (MH+, 100).
Anal. (C16H28O4) C, H.
(E)-5,5-Bis(hydroxymethyl)-3-[4-methyl-3-(methylethyl)pen-
tylidene]-4,5-dihydrofuran-2-one (IV, R2 ) CH2CH(i-Pr)2). This
compound is known and was prepared as previously reported.25
(Z)-5,5-Bis(hydroxymethyl)-3-[4-methyl-3-(methylethyl)pen-
tylidene]-4,5-dihydrofuran-2-one (IV, R2 ) CH2CH(i-Pr)2). This
compound is known and was prepared as previously reported.25
(E)-5,5-Bis(hydroxymethyl)-3-(phenylmethylene)-4,5-dihydro-
furan-2-one (IV, R2 ) Ph). According to general procedure D,
(E)-III (R2 ) Ph; 2.08 g, 2.92 mmol) was reacted to give (E)-IV
(R2 ) Ph; 672 mg, 98% yield): 1H NMR (250 MHz, d4-MeOH) δ
3.22 (d, J ) 2.7 Hz, 2 H, H-4ab), 3.74 (AB q, J ) 12.1 Hz, 4 H,
(Z)-5,5-Bis(hydroxymethyl)-3-octylidene-4,5-dihydrofuran-2-
one (IV, R2 ) C7H15). According to general procedure D, (Z)-III
(R2 ) C7H15; 1.08 g, 1.47 mmol) was reacted to give (Z)-IV (R2 )
1
C7H15; 317 mg, 84% yield): oil; H NMR (250 MHz, CDCl3) δ

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3193
CCH2OH), 7.47-7.68 (m, 6 H CdCHPh); 13C NMR (62.9 MHz,
d4-MeOH) δ 32.61, 65.29, 87.91, 127.79, 130.04, 130.92, 131.26,
136.24, 136.78, 174.04; FAB-MS (m/z, relative intensity) 235
(MH+, 100). Anal. (C13H14O4) C, H.
CDCl3) δ 14.01, 22.50, 26.23, 27.68, 28.87, 28.96, 31.55, 33.01,
33.25, 34.97, 64.51, 65.10, 82.12, 123.43, 125.93, 128.29, 128.30,
140.88, 145.64, 168.41, 173.08; FAB-MS (m/z, relative intensity)
389 (MH+, 23), 147 (100). Anal. (C23H32O5‚0.5H2O) C, H.
(E)-[2-(Hydroxymethyl)-4-octylidene-5-oxo-2,3-dihydrofur-2-
yl]methyl 3-Phenylpropanoate ((E)-2, (E)-V, R1 ) Ph(CH2)2,
R2 ) C7H15). According to general procedure F, (E)-IV (R2 )
C7H15; 170 mg, 0.66 mmol) and Ph(CH2)2COCl (122.6 mg, 0.73
mmol) were reacted to give (E)-2 ((E)-V, R1 ) Ph(CH2)2, R2 )
(E)-5,5-Bis(hydroxymethyl)-3-(2-phenylethylidene)-4,5-dihy-
drofuran-2-one (IV, R2 ) CH2Ph). According to general proce-
dure D, (E)-III (R2 ) CH2Ph; 1.36 g, 1.87 mmol) was reacted to
give (E)-IV (R2 ) CH2Ph; 411 mg, 88% yield): 1H NMR (250
MHz, CDCl3) δ 2.70 (s, 2 H, H-4ab), 2.88 (s, 2 H, CdCHCH2Ph),
3.60 (d, J ) 1.5 Hz, 2 H, CCH2OH), 3.82 (AB q, J ) 12.1 Hz, 4
H, CCH2OH), 6.98 (tt, J ) 7.6, 2.7 Hz, 1 H, CdCHCH2Ph), 7.27-
7.42 (m, 5 H CdCHCH2Ph); 13C NMR (62.9 MHz, CDCl3) δ 29.37,
36.21, 64.90, 85.6, 126.65, 127.23, 128.31, 128.67, 137.33, 139.25,
170.5; FAB-MS (m/z, relative intensity) 249 (MH+, 100). Anal.
(C14H16O4‚0.25H2O) C, H.
General Procedure for the Synthesis of V. Procedure F.
According to the literature procedure,43 a mixture of IV (1 equiv),
4 Å molecular sieves (800 mg/mmol), and Bu2SnO (1.5 equiv) in
anhydrous toluene (14 mL/mmol) was heated to reflux for 2.5 h.
The reaction mixture was then cooled to 0 °C, treated dropwise
with the corresponding acid chloride (1.1 equiv), and stirred at 0
°C for 1 h. The reaction mixture was then quenched with pH 7.0
potassium phosphate buffer (1 mL/mL of toluene) and filtered
through a pad of Celite. The filtrate was then extracted with CHCl3
(1×), and the organic layer was dried over MgSO4 and concentrated
in vacuo. Purification by silica gel flash column chromatography
gave V and variable amounts of the diacylated product, which was
not characterized.
Procedure G. A solution of IV (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 (1.5 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 as determined by TLC. The crude solution was then
concentrated in vacuo and the residue purified by silica gel flash
column chromatography to give V and variable amounts of the
diacylated product, which was not characterized.
1
C7H15, 203 mg, 79% yield): oil; H NMR (250 MHz, CDCl3) δ
0.94-0.99 (m, 3 H, CdCHCH2CH2(CH2)4CH3), 1.36 (br s, 8 H,
CdCHCH2CH2(CH2)4CH3), 1.52-1.58 (m, 2 H, CdCHCH2CH2-
(CH2)4CH3), 2.14-2.28 (m, 3 H, CdCHCH2CH2(CH2)4CH3 and
CCH2OH), 2.59-2.88 (m
4 H, H-3ab and CCH2OC(O)-
CH2CH2Ph), 3.03 (t, J ) 7.6 Hz, 2 H, CCH2OC(O)CH2CH2Ph),
3.59-3.76 (m, 2 H, CCH2OH), 4.30 (AB q, J ) 12.0 Hz, 2 H,
CCH2OC(O)CH2CH2Ph), 6.80-6.89 (m, 1 H, CdCHCH2CH2(CH2)4-
CH3), 7.25-7.41 (m, 5 H, CCH2OC(O)CH2CH2Ph); 13C NMR (62.9
MHz, CDCl3) δ 13.52, 22.06, 27.51, 28.48, 28.74, 29.23, 29.74,
30.21, 31.15, 34.97, 64.05, 64.76, 82.17, 124.90, 125.79, 127.58,
127.93, 139.35, 141.65, 169.09, 171.95; FAB-MS (m/z, relative
intensity) 389 (MH+, 100). Anal. (C23H32O5).
(Z)-[2-(Hydroxymethyl)-4-octylidene-5-oxo-2,3-dihydrofur-2-
yl]methyl 3-Phenylpropanoate ((Z)-2, (Z)-V, R1 ) Ph(CH2)2, R2
) C7H15). According to general procedure F, (Z)-IV (R2
)
C7H15; 159 mg, 0.62 mmol) and Ph(CH2)2COCl (114.9 mg,
0.68 mmol) were reacted to give (Z)-2 ((E)-V, R1 ) Ph(CH2)2,
R2 ) C7H15; 188 mg, 78% yield): oil, 1H NMR (250 MHz,
CDCl3) δ 0.93-0.98 (m, 3 H, CdCHCH2CH2(CH2)4CH3), 1.35-
1.52 (m, 10 H, CdCHCH2CH2(CH2)4CH3), 2.63-2.93 (m, 6 H,
CdCHCH2CH2(CH2)4CH3, CCH2OC(O)CH2CH2Ph, and H-3ab),
3.03 (t, J ) 7.7 Hz, 2 H, CCH2OC(O)CH2CH2Ph), 3.65 (AB
q, J ) 12.2 Hz, 2 H, HOCH2C), 4.28 (AB q, J ) 11.7 Hz,
2 H, CCH2OC(O)CH2CH2Ph), 6.29 (tt, J ) 7.7, 2.1 Hz, 1 H,
CdCHCH2CH2(CH2)4CH3), 7.25-7.41 (m, 5 H, CCH2OC(O)-
CH2CH2Ph); 13C NMR (62.9 MHz, CDCl3) δ 14.03, 22.57, 27.69,
29.01, 29.17, 30.74, 31.68, 32.94, 35.51, 64.39, 65.13, 82.02,
123.38, 126.27, 128.10, 128.42, 139.87, 145.67, 168.36, 172.47;
FAB-MS (m/z, relative intensity) 389 (MH+, 100). Anal. (C23H32O5)
C, H.
(E)-[4-Heptylidene-2-(hydroxymethyl)-5-oxo-2,3-dihydrofur-
2-yl]methyl 4-Phenylbutanoate ((E)-1, (E)-V, R1 ) Ph(CH2)3,
R2 ) C6H13). According to general procedure F, (E)-IV (R2 )
C6H13; 160 mg, 0.66 mmol) and Ph(CH2)3COCl (132 mg, 0.72
mmol) were reacted to give (E)-1 ((E)-V, R1 ) Ph(CH2)3, R2 )
(E)-[2-(Hydroxymethyl)-4-nonylidene-5-oxo-2,3-dihydrofur-
2-yl]methyl 2-Phenylacetate ((E)-3, (E)-V, R1 ) PhCH2, R2 )
C8H17). According to general procedure F, (E)-IV (R2 ) C8H17;
133 mg, 0.49 mmol) and PhCH2COCl (83 mg, 0.54 mmol) were
reacted to give (E)-3 ((E)-V, R1 ) PhCH2, R2 ) C8H17; 119 mg,
1
C6H13; 196 mg, 76% yield): oil; H NMR (250 MHz, CDCl3) δ
0.94-0.99 (m, 3 H, CdCHCH2CH2(CH2)3CH3), 1.36 (br s, 6 H,
CdCHCH2CH2(CH2)3CH3), 1.48-1.57 (m, 2 H, CdCHCH2CH2-
(CH2)3CH3), 1.97-2.09 (m, 2 H, CCH2OC(O)CH2CH2CH2Ph),
2.19-2.27 (m, 2 H, CdCHCH2CH2(CH2)3CH3), 2.44 (t, J ) 7.6
Hz, 2 H, CCH2OC(O)CH2CH2CH2Ph), 2.70-2.94 (m, 4 H, H-3a,b
and CCH2OC(O)CH2CH2CH2Ph), 3.68-3.83 (m, 2 H, HOCH2C),
4.31 (AB q, J ) 11.8 Hz, 2 H, CCH2OC(O)CH2CH2CH2Ph), 6.80-
6.89 (m, 1 H, CdCHCH2CH2(CH2)3CH3), 7.23-7.40 (m, 5 H,
CCH2OC(O)CH2CH2CH2Ph); 13C NMR (62.9 MHz, CDCl3) δ
14.10, 22.59, 26.34, 28.05, 29.04, 29.88, 30.34, 31.60, 33.35, 35.08,
64.78, 65.35, 82.88, 125.57, 126.05, 128.41, 140.98, 142.21, 169.71,
173.15; FAB-MS (m/z, relative intensity) 389 (MH+, 92), 147 (100).
Anal. (C23H32O5).
1
63% yield): oil; H NMR (250 MHz, CDCl3) δ 0.94-0.99 (m, 3
H, CdCHCH2CH2(CH2)5CH3), 1.36 (br s, 10 H, CdCHCH2CH2-
(CH2)5CH3), 1.51-1.57 (m, 2 H, CdCHCH2CH2(CH2)5CH3), 2.12-
2.24 (m, 3 H, CdCHCH2CH2(CH2)5CH3 and HOCH2C), 2.63 (dt,
1 H, J ) 17.1, 1.2 Hz, H-3a), 2.81 (dt, 1 H, J ) 17.1, 1.2 Hz,
H-3b), 3.62-3.78 (m, 2 H, HOCH2C), 3.73 (s, 2 H, PhCH2C(O)-
OCH2C), 4.33 (AB q, J ) 11.8 Hz, 2 H, PhCH2C(O)OCH2C),
6.78-6.86 (m, 1 H, CdCHCH2CH2(CH2)5CH3), 7.31-7.41 (m, 5
H, PhCH2C(O)OCH2C); 13C NMR (62.9 MHz, CDCl3) δ 13.54,
22.08, 27.49, 28.62, 28.78, 28.80, 29.12, 29.71, 31.26, 40.58, 64.22,
65.07, 82.20, 124.85, 126.69, 128.05, 128.56, 132.69, 141.65,
169.04, 170.60; FAB-MS (m/z, relative intensity) 389 (MH+, 88),
91 (100). Anal. (C23H32O5) C, H.
(Z)-[4-Heptylidene-2-(hydroxymethyl)-5-oxo-2,3-dihydrofur-
2-yl]methyl 4-Phenylbutanoate ((Z)-1, (Z)-V, R1 ) Ph(CH2)3,
R2 ) C6H13). According to general procedure F, (Z)-IV (R2 )
C6H13; 103 mg, 0.42 mmol) and Ph(CH2)3COCl (84.4 mg, 0.46
mmol) were reacted to give (Z)-1 ((Z)-V, R1 ) Ph(CH2)3, R2 )
(Z)-[2-(Hydroxymethyl)-4-nonylidene-5-oxo-2,3-dihydrofur-
2-yl]methyl 2-Phenylacetate ((Z)-3, (Z)-V-Z, R1 ) PhCH2, R2
) C8H17). According to general procedure F, (Z)-IV (R2 ) C8H17;
101 mg, 0.37 mmol) and PhCH2COCl (63.1 mg, 0.41 mmol) were
reacted to give (Z)-3 ((Z)-V, R1 ) PhCH2, R2 ) C8H17; 117 mg,
1
C6H13; 74 mg, 45% yield): oil; H NMR (250 MHz, CDCl3) δ
1
0.94-0.96 (m, 3 H, CdCHCH2CH2(CH2)3CH3), 1.34-1.52 (m, 8
H, CdCHCH2CH2(CH2)3CH3), 1.97-2.09 (m, 3 H, CCH2OH and
CCH2OC(O)CH2CH2CH2Ph), 2.44 (t, J ) 7.4 Hz, 2 H, CCH2OC-
(O)CH2CH2CH2Ph), 2.70-3.00 (m, 6 H, CdCHCH2CH2(CH2)3-
CH3, CCH2OC(O)CH2CH2CH2Ph, and H-3ab), 3.73 (AB q, J ) 12.2
Hz, 2 H, CCH2OH), 4.29 (AB q, J ) 12.0 Hz, 2 H, CCH2OC(O)-
CH2CH2CH2Ph), 6.31 (m, 1 H, CdCHCH2CH2(CH2)3CH3), 7.23-
7.40 (m, 5 H, CCH2OC(O)CH2CH2CH2Ph); 13C NMR (62.9 MHz,
82% yield): oil; H NMR (250 MHz, CDCl3) δ 0.93-0.98 (m, 3
H, CdCHCH2CH2(CH2)5CH3), 1.35-1.61 (m, 12 H, CdCHCH2CH2-
(CH2)5CH3), 2.15 (br s, 1 H, CCH2OH), 2.66-2.93 (m, 4 H,
CdCHCH2CH2(CH2)5CH3 and H-3ab), 3.61-3.68 (m, 2 H, CCH2-
OH), 3.73 (s, 2 H, CCH2OC(O)CH2Ph), 4.31 (AB q, J ) 11.8 Hz,
2 H, CCH2OC(O)CH2Ph), 6.26-6.32 (m, 1 H, CdCHCH2-
CH2(CH2)5CH3), 7.32-7.44 (m, 5 H, CCH2OC(O)CH2Ph); 13C
NMR (62.9 MHz, CDCl3) δ 13.55, 22.09, 27.22, 28.51, 28.66,

3194 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
(O)OCH2C), 6.30-6.36 (m, 1 H, CdCHCH2CH2(CH2)6CH3); 13
28.73, 28.83, 31.28, 32.37, 40.57, 64.04, 64.93, 81.56, 122.82,
126.69, 128.03, 128.56, 132.71, 145.23, 167.84, 170.65; FAB-MS
(m/z, relative intensity) 389 (MH+, 22), 91 (100). Anal. (C23H32O5‚
0.25H2O) C, H.
C
NMR (62.9 MHz, CDCl3) δ 14.05, 22.60, 25.28, 27.71, 28.84,
29.01, 29.12, 29.23, 29.38, 29.43, 31.81, 33.03, 42.96, 64.53, 64.97,
82.24, 123.54, 145.50, 168.41, 175.64; FAB-MS (m/z, relative
intensity) 395 (MH+, 51), 83 (100). Anal. (C23H38O5) C, H.
(E)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl Benzoate ((E)-6, (E)-
V, R1 ) Ph, R2 ) CH2CH(i-Pr)2). According to general procedure
F, (E)-IV (R2 ) CH2CH(i-Pr)2; 110 mg, 0.41 mmol) and benzoyl
chloride (63.0 mg, 0.45 mmol) were reacted to give (E)-6 ((E)-V,
R1 ) Ph, R2 ) CH2CH(i-Pr)2; 129 mg, 84% yield): oil; 1H NMR
(250 MHz, CDCl3) δ 0.85-0.98 (m, 12 H, CdCHCH2CH(CH-
(CH3)2)2), 1.21-1.30 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.75-
1.91 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.11-2.26 (m, 3 H,
CdCHCH2CH(CH(CH3)2)2 and HOCH2C), 2.85 (dd, J ) 17.1, 2.2
Hz, 1 H, H-3a), 2.95-3.03 (m, 1 H, H-3b), 3.87 (AB q, J ) 12.0
Hz, 2 H, HOCH2C), 4.58 (AB q, J ) 12.0 Hz, 2 H, PhC(O)OCH2C),
6.88-6.97 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 7.49-7.55, 7.64-
7.69, 8.05-8.08 (m, 5 H, PhC(O)OCH2C); 13C NMR (62.9 MHz,
CDCl3) δ 19.26, 21.38, 29.06, 29.14, 50.20, 64.81, 66.00, 83.11,
124.69, 128.37, 128.96, 129.63, 133.36, 143.92, 166.11, 169.76;
FAB-MS (m/z, relative intensity) 375 (MH+, 83), 105 (100). Anal.
(C22H30O5) C, H.
(E)-[4-Decylidene-2-(hydroxymethyl)-5-oxo-2,3-dihydrofur-
2-yl]methyl Benzoate ((E)-4, (E)-V, R1 ) Ph, R2 ) C9H19).
According to general procedure F, (E)-IV (R2 ) C9H19; 168 mg,
0.59 mmol) and benzoyl chloride (90.8 mg, 0.65 mmol) were
reacted to give (E)-4 ((E)-V, R1 ) Ph, R2 ) C9H19; 215 mg,
94% yield): 1H NMR (250 MHz, CDCl3) δ 0.93-0.99 (m, 3 H,
CdCHCH2CH2(CH2)6CH3), 1.32 (br s, 12 H, CdCHCH2CH2-
(CH2)6CH3), 1.48-1.53 (m, 2 H, CdCHCH2CH2(CH2)6CH3), 2.24
(q, J ) 7.40 Hz, CdCHCH2CH2(CH2)6CH3), 2.34 (br s, 1 H,
HOCH2C), 2.85 (dm, J ) 17 Hz, 1 H, H-3a), 2.98 (dm, J ) 17 Hz,
1 H, H-3a), 3.86 (br AB q, J ) 12.0 Hz, 2 H, HOCH2C), 4.57 (AB
q, J ) 11.8 Hz, 2 H, PhC(O)OCH2C), 6.33 (m, 1 H, CdCHCH2-
CH2(CH2)6CH3), 7.49-7.55 (m 2 H, PhC(O)OCH2C), 7.67 (t, J )
7.3 Hz, 1 H, PhC(O)OCH2C), 8.07 (d, J ) 7.1 Hz, 2 H, PhC(O)-
OCH2C); 13C NMR (62.9 MHz, CDCl3) δ 13.55, 22.09, 27.47,
28.70, 28.74, 28.80, 28.86, 29.39, 29.74, 31.27, 64.24, 65.49, 82.62,
125.10, 127.87, 128.45, 129.14, 132.88, 141.57, 165.62, 169.22;
FAB-MS (m/z, relative intensity) 389 (MH+, 65), 105 (100). Anal.
(C23H32O5).
(Z)-[4-Decylidene-2-(hydroxymethyl)-5-oxo-2,3-dihydrofur-2-
yl]methyl Benzoate ((Z)-4, (Z)-V, R1 ) Ph, R2 ) C9H19).
According to general procedure F, (Z)-IV (R2 ) C9H19; 161 mg,
0.57 mmol) and benzoyl chloride (88.4 mg, 0.63 mmol) were
reacted to give (Z)-4 ((Z)-V, R1 ) Ph, R2 ) C9H19; 197 mg, 89%
yield): white solid; mp 58-60 °C; 1H NMR (250 MHz, CDCl3) δ
0.94-0.99 (m, 3 H, CdCHCH2CH2(CH2)6CH3), 1.34-1.46 (m, 14
H, CdCHCH2CH2(CH2)6CH3), 2.31 (br s, 1 H, HOCH2C), 2.74-
2.85 (m, 2 H, CdCHCH2CH2(CH2)6CH3), 2.90 (dm, J ) 17 Hz, 1
H, H-3a), 3.07 (dm, J ) 17 Hz, 1 H, H-3b), 3.84 (AB q, J ) 12.1
Hz, 2 H, HOCH2C), 4.56 (AB q, J ) 11.7 Hz, 2 H, PhC(O)OCH2C),
6.33 (tt, J ) 7.7, 2.1 Hz, 1 H, CdCHCH2CH2(CH2)6CH3), 7.49-
7.55, 7.64-7.70, and 8.06-8.10 (m, 5 H, PhC(O)OCH2C); 13C
NMR (62.9 MHz, CDCl3) δ 13.56, 22.11, 27.23, 28.47, 28.73,
28.80, 28.86, 28.94, 31.32, 32.67, 64.12, 65.38, 81.97, 123.05,
127.86, 128.52, 129.15, 132.85, 145.06, 165.62, 168.00; FAB-MS
(m/z, relative intensity) 389 (MH+, 22), 105 (100). Anal. (C23H32O5)
C, H.
(Z)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl Benzoate ((E)-6,
(Z)-V, R1 ) Ph, R2 ) CH2CH(i-Pr)2). According to general
procedure G, (Z)-IV (R2 ) CH2CH(i-Pr)2; 75 mg, 0.28 mmol) and
benzoyl chloride (47.2 mg, 0.33 mmol) were reacted to give (Z)-6
((Z)-V, R1 ) Ph, R2 ) CH2CH(i-Pr)2; 60 mg, 57% yield): oil; 1H
NMR (250 MHz, CDCl3) δ 0.91-1.00 (m, 12 H, CdCHCH2CH-
(CH(CH3)2)2), 1.13-1.22 (m, 1 H, CdCHCH2CH(CH(CH3)2)2),
1.65 (br s, 1 H, HOCH2C), 1.76-1.92 (m, 2 H, CdCHCH2CH-
(CH(CH3)2)2), 2.71-2.85 (m, 2 H, CdCHCH2CH(CH(CH3)2)2),
2.89 (dd, J ) 16.6, 2.2 Hz, 1 H, H-3a), 3.09 (dd, J ) 16.4, 2.7 Hz,
1 H, H-3b), 3.83 (AB q, 2 H, HOCH2C), 4.56 (AB q, 2 H, PhC-
(O)OCH2C), 6.32-6.38 (m, 1 H, CdCHCH2CH(CH(CH3)2)2),
7.50-7.53, 7.64-7.70, 8.07-8.11 (m, 5 H, PhC(O)OCH2C); 13C
NMR (62.9 MHz, CDCl3) δ 19.19, 21.41, 26.29, 29.24, 29.32,
51.08, 64.65, 65.74, 82.31, 122.41, 128.36, 129.02, 129.65, 133.35,
147.79, 165.10, 168.35; FAB-MS (m/z, relative intensity) 375
(MH+, 47), 105 (100). Anal. (C22H30O5).
(E)-[4-Decylidene-2-(hydroxymethyl)-5-oxo-2,3-dihydrofur-
2-yl]methyl Cyclohexanecarboxylate ((E)-5, (E)-V, R1 ) Cy-
clohexyl, R2 ) C9H19). According to general procedure F, (E)-IV
((E)-V, R2 ) C9H19; 80 mg, 0.28 mmol) and cyclohexanecarbonyl
chloride (44.9 mg, 0.31 mmol) were reacted to give (E)-5 (R1 )
cyclohexyl, R2 ) C9H19; 99.8 mg, 90% yield): 1H NMR (250 MHz,
CDCl3) δ 0.94-0.99 (m, 3 H, CdCHCH2CH2(CH2)6CH3), 1.25-
1.45 (br s, 14 H, CdCHCH2CH2(CH2)6CH3), 1.45-2.05 (m, 10
H, c-HexC(O)OCH2C), 2.21-2.30 (m, 2 H, CdCHCH2CH2(CH2)6-
CH3), 2.41 (tt, J ) 11.0, 3.5 Hz, 1 H, c-HexC(O)OCH2C), 2.72 (br
d, J ) 17.3 Hz, 1 H, H-3a), 2.90 (br d, J ) 17.1 Hz, 1 H, H-3b),
3.75 (AB q, J ) 17.2 Hz, 2 H, HOCH2C), 4.31 (AB q, J ) 11.8
Hz, 2 H, c-HexC(O)OCH2C), 6.81-6.90 (m, 1 H, CdCHCH2-
CH2(CH2)6CH3); 13C NMR (62.9 MHz, CDCl3) δ 14.04, 22.59,
25.25, 25.57, 28.00, 28.83, 29.21, 29.28, 29.33, 29.40, 29.74, 30.24,
31.78, 42.93, 64.66, 65.10, 82.98, 125.62, 141.96, 169.69, 175.63;
FAB-MS (m/z, relative intensity) 395 (MH+, 64), 83 (100). Anal.
(C23H38O5) C, H.
(E)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl Cyclohexanecarboxy-
late ((E)-7, (E)-V, R1 ) Cyclohexyl, R2 ) CH2CH(i-Pr)2).
According to general procedure F, (E)-IV (R2 ) CH2CH(i-Pr)2;
100 mg, 0.37 mmol) and cyclohexanecarbonyl chloride (65.8 mg,
0.45 mmol) were reacted to give (E)-7 ((E)-V, R1 ) cyclohexyl,
R2 ) CH2CH(i-Pr)2; 112 mg, 79% yield): oil; 1H NMR (250 MHz,
CDCl3) δ 0.94 and 0.99 (br d, J ≈ 7 Hz, 12 H, CdCHCH2CH-
(CH(CH3)2)2), 1.25-1.52 and 1.71-1.98 (m, 10 H, c-HexC(O)-
OCH2C, HOCH2C, and CdCHCH2CH(CH(CH3)2)2), 2.18-2.23 (m,
2 H, CdCHCH2CH(CH(CH3)2)2), 2.35-2.45 (m, 1 H, c-HexC-
(O)OCH2C), 2.74 (dd, J ) 17.3, 2.2 Hz, 1 H, H-3a), 2.91 (dd, J )
17.1, 2.4 Hz, 1 H, H-3b), 3.76 (AB q, J ) 12.0 Hz, 2 H, HOCH2C),
4.31 (AB q, J ) 12.0 Hz, 2 H, c-HexC(O)CH2C), 6.87-6.95 (m,
1 H, CdCHCH2CH(CH(CH3)2)2); 13C NMR (62.9 MHz, CDCl3)
δ 19.29, 21.54, 25.56, 28.65, 28.84, 28.96, 29.14, 29.17, 29.91,
42.93, 50.24, 64.74, 65.08, 82.89, 124.64, 143.84, 169.67, 175.62;
FAB-MS (m/z, relative intensity) 381 (MH+, 91), 83 (100). Anal.
(C22H36O5) C, H.
(Z)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl Cyclohexanecarboxy-
late ((Z)-7, (Z)-V, R1 ) Cyclohexyl, R2 ) CH2CH(i-Pr)2).
According to general procedure G, (Z)-IV (R2 ) CH2CH(i-Pr)2;
94 mg, 0.35 mmol) and cyclohexanecarbonyl chloride (61.4 mg,
0.42 mmol) were reacted to give (Z)-7 ((Z)-V, R1 ) cyclohexyl,
R2 ) CH2CH(i-Pr)2; 78 mg, 58% yield): oil; 1H NMR (250 MHz,
CDCl3) δ 0.94 and 0.99 (br d, J ≈ 7 Hz, 12 H, CdCHCH2CH-
(CH(CH3)2)2), 1.15-2.10 (m, 13 H, c-HexC(O)OCH2C and
CdCHCH2CH(CH(CH3)2)2), 2.36-2.46 (m, 1 H, c-HexC(O)-
OCH2C), 2.74-2.81 (m, 3 H, CdCHCH2CH(CH(CH3)2)2 and
(Z)-[4-Decylidene-2-(hydroxymethyl)-5-oxo-2,3-dihydrofur-2-
yl]methyl Cyclohexanecarboxylate ((Z)-5, (Z)-V, R1 ) Cyclo-
hexyl, R2 ) C9H19). According to general procedure G, (Z)-IV
((Z)-V, R2 ) C9H19; 128 mg, 0.45 mmol) and cyclohexanecarbonyl
chloride (65.8 mg, 0.45 mmol) were reacted to give (Z)-5 ((Z)-V,
1
R1 ) cyclohexyl, R2 ) C9H19; 90 mg, 50% yield): oil; H NMR
(250 MHz, CDCl3) δ 0.93-0.99 (m, 3 H, CdCHCH2CH2-
(CH2)6CH3), 1.34-1.52 and 1.73-1.99 (m’s, 24 H, CdCHCH2CH2-
(CH2)6CH3) and c-HexC(O)OCH2C), 2.25 (br s, 1 H, HOCH2C),
2.41 (tt, J ) 10.9, 3.5 Hz, 1 H, c-HexC(O)OCH2C), 2.74-3.01
(m, 4 H, H-3ab and CdCHCH2CH2(CH2)6CH3), 3.73 (AB q, J )
12.1 Hz, 2 H, HOCH2C), 4.29 (AB q, J ) 12.0 Hz, 2 H, c-HexC-

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3195
H-3a), 2.92-2.99 (m, 1 H, H-3b), 3.72 (AB q, J ) 12.2 Hz, 2 H,
HOCH2C), 4.29 (AB q, J ) 11.8 Hz, 2 H, c-HexC(O)CH2C), 6.31-
6.38 (m, 1 H, CdCHCH2CH(CH(CH3)2)2); 13C NMR (62.9
MHz, CDCl3) δ 25.28, 26.28, 28.85, 28.88, 29.29, 29.32, 33.13,
42.93, 51.12, 64.58, 64.91, 82.17, 122.47, 147.69, 168.48, 175.69;
FAB-MS (m/z, relative intensity) 381 (MH+, 61), 83 (100). Anal.
(C22H36O5) C, H.
ing to general procedure G, (Z)-IV (R2 ) CH2CH(i-Pr)2, 195 mg,
0.72 mmol) and 3-methoxybenzoyl chloride (148.1 mg, 0.87
mmol) were reacted to give (Z)-9 ((Z)-V, R1 ) 3-(OMe)C6H4, R2
) CH2CH(i-Pr)2; 167 mg, 57% yield) as a colorless oil: 1H NMR
(250 MHz, CDCl3) δ 0.90-0.99 (m, 12 H, CdCHCH2CH(CH-
(CH3)2)2), 1.12-1.21 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.78-
1.91 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.62-2.72 and 2.83-
3.07 (m, 4 H, CdCHCH2CH(CH(CH3)2)2 and H-3ab), 3.82 (AB q,
J ) 12.2 Hz, 2 H, HOCH2C), 3.93 (s, 3 H, CH3OC6H4C(CO)-
CH2C), 4.55 (AB q, J ) 12.2 Hz, 2 H, CH3OC6H4C(CO)CH2C),
6.31-6.37 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 7.18-7.22, 7.39-
7.46, and 7.60-7.69 (m, 4 H, CH3OC6H4C(CO)CH2C); 13C NMR
(62.9 MHz, CDCl3) δ 19.44, 21.60, 26.27, 29.21, 29.34, 33.29,
51.05, 55.38, 64.64, 65.85, 82.34, 114.23, 119.75, 122.01, 122.43,
129.39, 130.28, 147.76, 159.45, 166.05, 168.55; FAB-MS (m/z,
relative intensity) 405 (MH+, 26), 135 (100). Anal. (C23H32O6)
C, H.
(E)-[{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3 -dihydrofuryl}methyl 4-Methoxybenzoate ((E)-
10, (E)-V, R1 ) 4-(OMe)C6H4, R2 ) CH2CH(i-Pr)2). According
to general procedure G, (E)-IV (R2 ) CH2CH(i-Pr)2; 200 mg, 0.74
mmol) and 4-methoxybenzoyl chloride (189 mg, 1.11 mmol) were
reacted to give (E)-10 ((E)-V, R1 ) 4-(OMe)C6H4, R2 ) CH2CH-
(i-Pr)2; 173 mg, 58% yield) as a colorless oil: 1H NMR (250 MHz,
CDCl3) δ 0.86-0.98 (m, 12 H, CdCHCH2CH(CH(CH3)2)2), 1.21-
1.28 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.75-1.91 (m, 2 H,
CdCHCH2CH(CH(CH3)2)2), 2.11-2.25 (m, 2 H, CdCHCH2CH-
(CH(CH3)2)2), 2.83 (dd, J ) 17.3, 2.2 Hz, 1 H, H-3a), 2.98 (dd, J
) 17.1, 2.4 Hz, 1 H, H-3b), 3.84 (AB q, J ≈ 12 Hz, H, HOCH2C),
3.94 (s, 3 H, CH3OC6H4C(CO)CH2C), 4.54 (AB q, J ) 12.0 Hz, 2
H, CH3OC6H4C(CO)CH2C), 6.87-7.01 (m, 1 H, CdCHCH2CH-
(CH(CH3)2)2), 7.17 (d, J ) 9.0 Hz, 2 H, CH3OC6H4C(CO)CH2C),
8.02 (d, J ) 8.8 Hz, 2 H, CH3OC6H4C(CO)CH2C); 13C NMR (62.9
MHz, CDCl3) δ 19.28, 21.57, 28.63, 29.07, 29.13, 30.04, 50.20,
55.39, 64.72, 65.68, 83.21, 113.65, 121.26, 124.75, 131.76, 143.83,
163.65, 165.90, 169.81; FAB-MS (m/z, relative intensity) 405
(MH+, 26), 135 (100). Anal. (C23H32O6‚0.2H2O) C, H.
(Z)-[{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl 4-Methoxybenzoate ((Z)-
10, (Z)-V, R1 ) 4-(OMe)C6H4, R2 ) CH2CH(i-Pr)2). According
to general procedure G, (Z)-IV (R2 ) CH2CH(i-Pr)2; 201 mg, 0.74
mmol) and 4-methoxybenzoyl chloride (151.2 mg, 0.89 mmol) were
reacted to give (Z)-10 ((Z)-V, R1 ) 4-(OMe)C6H4, R2 ) CH2CH-
(i-Pr)2; 167 mg, 56% yield) as a colorless oil: 1H NMR (250 MHz,
CDCl3) δ 0.92, 0.93, 0.97, and 0.98 (d, J ) 6.8 Hz, 12 H,
CdCHCH2CH(CH(CH3)2)2), 1.13-1.21 (m, 1 H, CdCHCH2CH(CH-
(CH3)2)2), 1.78-1.91 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.18
(br s, 1 H, HOCH2C), 2.65-3.07 (m, 4 H, CdCHCH2CH(CH-
(CH3)2)2 and H-3ab), 3.81 (AB q, J ) 12.2 Hz, 2 H, HOCH2C),
3.94 (s, 3 H, CH3OC6H4C(CO)CH2C), 4.52 (AB q, J ) 12.0 Hz, 2
H, CH3OC6H4C(CO)CH2C), 6.31-6.37 (m, 1 H, CdCHCH2CH-
(CH(CH3)2)2), 6.99 (d, J ) 9.0 Hz, 2 H, CH3OC6H4C(CO)CH2C),
8.04 (d, J ) 8.8 Hz, 2 H, CH3OC6H4C(CO)CH2C); 13C NMR (62.9
MHz, CDCl3) δ 19.43, 21.61, 26.27, 29.22, 29.32, 33.27, 51.05,
55.38, 64.54, 65.48, 82.49, 113.64, 121.34, 122.53, 131.76, 147.64,
163.62, 165.94, 168.63; FAB-MS (m/z, relative intensity) 405
(MH+, 25), 135 (100). Anal. (C23H32O6) C, H.
(E)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl 2-Hydroxybenzoate ((E)-
11, (E)-VI, R1 ) 2-(OH)Ph, R2 ) CH2CH(i-Pr)2). A solution of
(E)-V ((E)-8, R1 ) 2-(OMe)C6H4, R2 ) CH2CH(i-Pr)2; 118 mg,
0.29 mmol) in CH2Cl2 (10 mL) was treated at -78 °C with
dropwise addition of BBr3 (1.2 mL, 1 M in CH2Cl2) and stirred at
the same temperature for 2 h. The reaction was quenched with
saturated aqueous NaHCO3 (1.3 mL), and the mixture was extracted
with Et2O (1 × 30 mL). The organic layer was then washed with
potassium phosphate buffer (pH 7, 1 × 10 mL) and brine (1 × 10
mL), dried over MgSO4, and concentrated in vacuo. Purification
by silica gel flash column chromatography gave (E)-11 ((E)-VI,
R1 ) 2-(OH)C6H4, R2 ) CH2CH(i-Pr)2; 97 mg, 85% yield): oil;
1H NMR (250 MHz, CDCl3) δ 0.87-1.99 (m, 12 H, CdCHCH2-
(E)-[{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3 -dihydrofur-2-yl}methyl 2-Methoxybenzoate
((E)-8, (E)-V, R1 ) 2-(OMe)C6H4, R2 ) CH2CH(i-Pr)2). Ac-
cording to general procedure G, (E)-IV (R2 ) CH2CH(i-Pr)2; 213
mg, 0.79 mmol) and 2-methoxybenzoyl chloride (201.7 mg, 1.18
mmol) were reacted to give (E)-8 ((E)-V, R1 ) 2-(OMe)C6H4, R2
) CH2CH(i-Pr)2; 182 mg, 57% yield) as an oily paste: 1H NMR
(250 MHz, CDCl3) δ 0.85-0.98 (m, 12 H, CdCHCH2CH(CH-
(CH3)2)2), 1.22-1.33 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.75-
1.88 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.16-2.22 (m, 2 H,
CdCHCH2CH(CH(CH3)2)2), 2.85 (dd, J ) 17.3, 2.2 Hz, 1 H, H-3a),
2.96 (dd, J ) 16.8, 2.2 Hz, 1 H, H-3b), 3.86 (AB q, J ≈ 12 Hz,
2 H, HOCH2C), 3.97 (s, 3 H, CH3OC6H4C(CO)CH2C), 4.53
(AB q, J ) 12.0 Hz, 2 H, CH3OC6H4C(CO)CH2C), 6.87-6.94
(m, 1 H, CdCHCH2CH(CH(CH3)2)2), 7.03-7.09 and 7.55-7.62
(m, 3 H, CH3OC6H4C(CO)CH2C), 7.88 (dd, J ) 7.8, 1.7 Hz, 1 H,
CH3OC6H4C(CO)CH2C); 13C NMR (62.9 MHz, CDCl3) δ 19.26,
21.57, 28.65, 29.07, 29.14, 30.15, 50.20, 55.77, 65.18, 66.05, 82.85,
111.85, 118.52, 120.11, 124.72, 132.03, 134.12, 143.83, 159.28,
165.75, 169.77; FAB-MS (m/z, relative intensity) 405 (MH+, 14),
135 (100). Anal. (C23H32O6‚0.3H2O) C, H.
(Z)-[{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3 -dihydrofur-2-yl}methyl 2-Methoxybenzoate
((Z)-8, (Z)-V, R1 ) 2-(OMe)C6H4, R2 ) CH2CH(i-Pr)2). Accord-
ing to general procedure G, (Z)-IV (R2 ) CH2CH(i-Pr)2; 196 mg,
0.72 mmol) and 2-methoxybenzoyl chloride (149 mg, 0.87 mmol)
were reacted to give (Z)-8 ((Z)-V, R1 ) 2-(OMe)C6H4, R2
)
CH2CH(i-Pr)2; 143 mg, 49% yield) as a white solid: mp 96.4-
1
97.5 °C; H NMR (250 MHz, CDCl3) δ 0.90-0.99 (m, 12 H,
CdCHCH2CH(CH(CH3)2)2), 1.13-1.22 (m, 1 H, CdCHCH2CH(CH-
(CH3)2)2), 1.75-1.91 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.65-
3.10 (m, 4 H, H-3ab and CdCHCH2CH(CH(CH3)2)2), 3.84 (s,
2 H, HOCH2C), 3.98 (s, 3 H, CH3OC6H4C(CO)CH2C), 4.51
(AB q, J ≈ 12 Hz, 2 H, CH3OC6H4C(CO)CH2C), 6.31-6.38 (m,
1 H, CdCHCH2CH(CH(CH3)2)2), 70.4-7.09 and 7.55-7.62 (m,
3 H, CH3OC6H4C(CO)CH2C), 7.89 (dd, J ) 7.8, 1.7 Hz, 1 H,
CH3OC6H4C(CO)CH2C); 13C NMR (62.9 MHz, CDCl3) δ 19.30,
19.41, 21.53, 21.60, 26.27, 29.24, 29.31, 33.44, 51.07, 55.84, 65.05,
65.86, 82.09, 111.88, 118.63, 120.14, 122.47, 132.00, 134.09,
147.73, 159.22, 165.74, 168.54; FAB-MS (m/z, relative intensity)
405 (MH+, 18), 135 (100). Anal. (C23H32O6) C, H.
(E)-[{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3 -dihydrofur-2-yl}methyl 3-Methoxybenzoate
((E)-9, (E)-V, R1 ) 3-(OMe)C6H4, R2 ) CH2CH(i-Pr)2). Ac-
cording to general procedure G, (E)-IV (R2 ) CH2CH(i-Pr)2; 197
mg, 0.73 mmol) and 3-methoxybenzoyl chloride (187 mg, 1.10
mmol) were reacted to give (E)-9 ((E)-V, R1 ) 3-(OMe)C6H4, R2
1
) CH2CH(i-Pr)2; 182 mg, 61% yield): oil; H NMR (250 MHz,
CDCl3) δ 0.85-0.98 (m, 12 H, CdCHCH2CH(CH(CH3)2)2), 1.20-
1.29 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.74-1.90 (m, 2 H,
CdCHCH2CH(CH(CH3)2)2), 2.13-2.21 (m, 2 H, CdCHCH2CH-
(CH(CH3)2)2), 2.84 (dd, J ) 17.1, 2.2 Hz, 1 H, H-3a), 2.98 (dd, J
) 17.1, 2.4 Hz, 1 H, H-3b), 3.80-3.92 (m, 2 H, HOCH2C), 3.92
(s, 3 H, CH3OC6H4C(CO)CH2C), 4.57 (s, 2 H, CH3OC6H4C(CO)-
CH2C), 6.87-6.96 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 7.18-
7.22, 7.34-7.45, and 7.56-7.66 (m, 4 H, CH3OC6H4C(CO)CH2C);
13C NMR (62.9 MHz, CDCl3) δ 19.28, 21.56, 28.65, 29.07, 29.12,
30.05, 50.19, 55.35, 64.78, 66.12, 83.12, 114.06, 119.90, 122.01,
124.73, 129.39, 130.20, 143.87, 159.44, 165.99, 169.78; FAB-MS
(m/z, relative intensity) 405 (MH+, 38), 135 (100). Anal. (C23H32O6‚
0.2H2O) C, H.
(Z)-[{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3 -dihydrofur-2-yl}methyl 3-Methoxybenzoate
((Z)-9, (Z)-V, R1 ) 3-(OMe)C6H4, R2 ) CH2CH(i-Pr)2). Accord-

3196 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
CH(CH(CH3)2)2), 1.23-1.37 (m, 1 H, CdCHCH2CH(CH(CH3)2)2),
1.74-1.92 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.17-2.23 (m,
2 H, CdCHCH2CH(CH(CH3)2)2), 2.85 (dm, J ) 17.3 Hz, 1 H,
H-3a), 3.00 (dm, J ) 17.3 Hz, 1 H, H-3b), 3.89 (AB q, J ) 12.0
Hz, 2 H, HOCH2C), 4.60 (s, 2 H, HOC6H4C(CO)CH2C), 6.92-
6.98 (m, 2 H, CdCHCH2CH(CH(CH3)2)2 and HOC6H4C(CO)-
CH2C), 7.07 (br d, J ) 8.1 Hz, 1 H, HOC6H4C(CO)CH2C), 7.53-
7.60 and 7.78-7.81 (m, 2 H, HOC6H4C(CO)CH2C); 13C NMR (62.9
MHz, CDCl3) δ 19.27, 21.58, 28.71, 29.07, 29.15, 30.00, 50.23,
64.91, 66.09, 82.75, 111.42, 117.62, 119.29, 124.41, 129.70, 136.17,
144.25, 161.64, 169.44, 169.52; FAB-MS (m/z, relative intensity)
391 (MH+, 73), 121 (100). Anal. (C22H30O6) C, H.
1 H, HOCH2C), 2.28 (d, 2 H, J ) 5.6, ((CH3)2CH)2CHCH2C(O)-
OCH2C), 3.12 (dd, J ) 17.8, 2.7 Hz, 1 H, H-3a), 3.31 (dd, J )
17.6, 2.9 Hz, 1 H, H-3b), 3.84 (AB q, J ) 12.2 Hz, 2 H, HOCH2C),
4.36 (AB q, J ) 12.0 Hz, 2 H ((CH3)2CH)2CHCH2C(O)OCH2C),
7.50-7.67 (m, 6 H, CdCHPh); 13C NMR (62.9 MHz, CDCl3) δ
18.63, 18.66, 18.70, 18.74, 21.28, 29.28, 29.34, 29.85, 32.69, 36.22,
46.85, 64.73, 65.33, 82.98, 126.63, 126.72, 128.25, 128.70, 128.77,
137.17, 139.21, 169.37, 174.47; FAB-MS (m/z, relative intensity)
389 (MH+, 59), 57 (100). Anal. (C23H32O5‚0.2H2O) C, H.
General Procedure for the Synthesis of VIII. Procedure H.
A solution of VII30,31 (1 equiv) in THF (3-5 mL/mmol) at -78
°C was treated dropwise with LHMDS (2 equiv, 1 M in THF).
After the solution was stirred at -78 °C for 15 min, R2CHO (1.5
equiv) was added and stirring continued for 30 min more at -78
°C. The reaction was monitored by TLC, quenched by slow addition
of 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 (1× ) and brine (1×), dried over MgSO4, and concen-
trated in vacuo. Purification by silica gel flash column chromatog-
raphy gave VIII as a mixture of diastereomers, which were used
directly in the next step.
(E)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl 3-Hydroxybenzoate ((E)-
12, (E)-VI, R1 ) 3-(OH)C6H4, R2 ) CH2CH(i-Pr)2). A solution
of (E)-V ((E)-9, R1 ) 3-(OMe)C6H4, R2 ) CH2CH(i-Pr)2; 132 mg,
0.33 mmol) in CH2Cl2 (10 mL) was treated at -78 °C with
dropwise addition of BBr3 (1.3 mL, 1.3 mmol, 1 M in CH2Cl2),
stirred at the same temperature for 2 h, and then warmed to -10
°C for 1.5 h. The reaction was then quenched with saturated aqueous
NaHCO3 (1.5 mL), and the mixture was extracted with Et2O (1 ×
30 mL). The organic layer was then washed with potassium
phosphate buffer (pH 7, 2 × 10 mL) and brine (1 × 10 mL), dried
over MgSO4, and concentrated in vacuo. Purification by silica gel
flash column chromatography gave (E)-12 ((E)-VI, R1 ) 3-(OH)-
C6H4, R2 ) CH2CH(i-Pr)2; 82 mg, 64% yield) as a semisolid
paste: IR (CHCl3) 3385 (OH), 2964 (CH), 2886 (CH), 1728
3-[1-Hydroxy-4-methyl-3-(methylethyl)pentyl]-5-[(4-meth-
oxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydro-
furan-2-one (VIII, R2 ) CH2CH(i-Pr)2). According to general
procedure H, VII (800 mg, 2.3 mmol) and 4-methyl-3-(methyl-
ethyl)pentan-1-one25 (399 mg, 2.8 mmol) were reacted to give VIII
(R2 ) CH2CH(i-Pr)2; 692 mg, 61% yield).
1
(CdO), 1672 (CdC) cm-1; H NMR (250 MHz, CDCl3) δ 0.84,
0.88, 0.89, and 0.95 (d, J ) 6.8 Hz, 12 H, CdCHCH2CH(CH-
(CH3)2)2), 1.19-1.28 (m, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.68-
1.89 (m, 3 H, CdCHCH2CH(CH(CH3)2)2 and HOC6H4C(CO)-
CH2C), 2.15-2.17 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.83 (dd,
J ) 17.1, 2.2 Hz, 2 H, H-3a), 2.99 (dd, J ) 17.1, 2.4 Hz, 2 H,
H-3b), 3.89 (AB q, J ) 12.2 Hz, 2 H, HOCH2C), 4.56 (AB q, J )
11.7 Hz, 2 H, HOC6H4C(CO)CH2C), 6.30 (br s, 1 H, HOC6H4C-
(CO)CH2C), 6.90-6.96 (m, 1 H, CdCHCH2CH(CH(CH3)2)2),
7.13-7.17, 7.38-7.41, and 7.47-7.49 (m, 3 H, HOC6H4C(CO)-
CH2C), 7.62 (br d, J ) 7.82 Hz, 1 H, HOC6H4C(CO)CH2C); 13C
NMR (62.9 MHz, CDCl3) δ 19.35, 21.68, 28.80, 29.13, 29.23,
30.16, 50.28, 64.84, 66.25, 83.59, 116.20, 120.83, 122.04, 124.82,
129.80, 130.32, 144.39, 155.89, 165.90, 170.44; FAB-MS (m/z,
relative intensity) 391 (MH+, 75), 121 (100). Anal. (C22H30O6‚
0.5H2O) C, H.
3-(1-Hydroxy-3-phenoxypropyl)-5-[(4-methoxyphenoxy)-
methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydrofuran-2-one
(VIII, R2 ) PhCH2CH2). According to general procedure H, VII
(600 mg, 1.8 mmol) and hydrocinnamaldehyde (0.28 mL, 2.1 mmol)
were reacted to give VIII (R2 ) PhCH2CH2; 1.35 g, 83% yield) as
a colorless oil.
3-[Hydroxy-(2-methoxyphenyl)methyl]-5-[(4-methoxyphenoxy)-
methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydrofuran-2-one
(VIII, R2 ) 2-(OMe)C6H4). According to general procedure H,
VII (1.0 g, 2.9 mmol) and o-anisaldehyde (473 mg, 3.5 mmol)
were reacted to give VIII (R2 ) 2-(OMe)C6H4; 1.38 g, 100% yield)
as a colorless oil.
3-[Hydroxy-(3-methoxyphenyl)methyl]-5-[(4-methoxyphenoxy)-
methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydrofuran-2-one
(VIII, R2 ) 3-(OMe)C6H4). According to general procedure H,
VII (1.0 g, 2.9 mmol) and m-anisaldehyde (0.42 mL, 3.5 mmol)
were reacted to give VIII (R2 ) 3-(OMe)C6H4; 1.25 g, 89% yield)
as a colorless oil.
3-[Hydroxy-(4-methoxyphenyl)methyl]-5-[(4-methoxyphenoxy)-
methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydrofuran-2-one
(VIII, R2 ) (4-(OMe)C6H4). According to general procedure H,
VII (1.0 g, 2.9 mmol) and p-anisaldehyde (0.42 mL, 3.5 mmol)
were reacted to give VIII (R2 ) 4-(OMe)C6H4; 1.15 g, 82% yield)
as a colorless oil.
3-{Hydroxy-[2-(phenylmethoxy)phenyl]methyl}-5-[(4-meth-
oxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydro-
furan-2-one (VIII, R2 ) 2-(PhCH2O)C6H4). According to general
procedure H, VII (1.0 g, 2.9 mmol) and 2-(benzyloxy)benzaldehyde
(742 mg, 3.5 mmol) were reacted to give VIII (R2 ) 2-(PhCH2O)-
C6H4; 1.35 g, 83% yield) as a colorless oil.
3-{Hydroxy-[3-(phenylmethoxy)phenyl]methyl}-5-[(4-meth-
oxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydro-
furan-2-one (VIII, R2 ) 3-(PhCH2O)C6H4. According to general
procedure H, VII (1.0 g, 2.9 mmol) and 3-(benzyloxy)benzaldehyde
(742 mg, 3.5 mmol) were reacted to give VIII (R2 ) 3-(PhCH2O)-
C6H4; 1.24 g, 76% yield) as a colorless oil.
3-{Hydroxy-[4-(phenylmethoxy)phenyl]methyl}-5-[(4-meth-
oxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydro-
furan-2-one (VIII, R2 ) 4-(PhCH2O)C6H4. According to general
procedure H, VII (1.0 g, 2.9 mmol) and 4-(benzyloxy)benzaldehyde
(742 mg, 3.5 mmol) were reacted to give VIII (R2 ) 4-(PhCH2O)-
C6H4; 1.25 g, 79% yield) as a colorless oil.
(E)-[2-(Hydroxymethyl)-5-oxo-4-(phenylmethylene)-2,3-dihy-
drofur-2-yl]methyl 4-Methyl-3-(methylethyl)pentanoate ((E)-14,
(E)-V, R1 ) CH2CH(i-Pr)2, R2 ) Ph). According to general
procedure G, (E)-IV (R2 ) Ph; 114 mg, 0.49 mmol) and 4-methyl-
3-(methylethyl)pentanoyl chloride25 (130.9 mg, 0.74 mmol) were
reacted to give (E)-14 ((E)-V, R1 ) CH2CH(i-Pr)2, R2 ) Ph; 53
1
mg, 29% yield): oil; H NMR (250 MHz, CDCl3) δ 0.80-1.02
(m, 12 H, ((CH3)2CH)2CHCH2C(O)OCH2C), 1.60-1.66 (m, 1 H,
((CH3)2CH)2CHCH2C(O)OCH2C), 1.70-1.82 (m, 2 H, ((CH3)2CH)2-
CHCH2C(O)OCH2C), 2.28 (d, 2 H, J ) 5.6 Hz ((CH3)2-
CH)2CHCH2C(O)OCH2C), 3.12 (dd, J ) 17.8, 2.7 Hz, 1 H, H-3a),
3.31 (dd, J ) 17.6, 2.9 Hz, 1 H, H-3b), 3.84 (AB q, J ) 12.2 Hz,
2 H, HOCH2C), 4.36 (AB q, J ) 12.0 Hz, 2 H, ((CH3)2-
CH)2CHCH2C(O)OCH2C), 7.50-7.67 (m, 6 H, CdCHPh); 13C
NMR (62.9 MHz, CDCl3) δ 18.59, 18.66, 21.21, 29.26, 32.21,
46.81, 64.75, 65.36, 83.16, 123.86, 128.82, 129.95, 134.21, 137.20,
170.84, 174.51; FAB-MS (m/z, relative intensity) 375 (MH+, 64),
57 (100). Anal. (C22H30O5‚0.07H2O) C, H.
(E)-[2-(Hydroxymethyl)-5-oxo-4-(2-phenylethylidene)-2,3-di-
hydrofur-2-yl]methyl 4-Methyl-3-(methylethyl)pentanoate ((E)-
15, (E)-V, R1 ) CH2CH(i-Pr)2, R2 ) CH2Ph). According to
general procedure G, (E)-IV (R2 ) CH2Ph; 116 mg, 0.47 mmol)
and 4-methyl-3-(methylethyl)pentanoyl chloride25 (125.1 mg, 0.71
mmol) were reacted to give (E)-15 ((E)-V, R1 ) CH2CH(i-Pr)2, R2
) CH2Ph; 77 mg, 42% yield): oil; 1H NMR (250 MHz, CDCl3) δ
0.88 and 0.97 (br d, J ≈ 6.8 Hz, 12 H, ((CH3)2CH)2CHCH2C(O)-
OCH2C), 1.60-1.66 (m, 1 H, ((CH3)2CH)2CHCH2C(O)OCH2C),
1.70-1.82 (m, 2 H, ((CH3)2CH)2CHCH2C(O)OCH2C), 2.04 (br s,

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3197
General Procedure for the Synthesis of IX. Procedure I.
Intermediate VIII was then taken up in dichloromethane (3-5
mL/mmol) and treated with triethylamine (1.7 equiv) and meth-
anesulfonyl chloride (1 equiv). After the solution was stirred for
30 min at room temperature, DBU (2.5 equiv) was added, and the
reaction was monitored by TLC. Concentration in vacuo and
purification by silica gel flash column chromatography gave IX.
In most cases only the E-isomer was formed; when the Z-isomer
was detected in small amounts, it was not characterized.
Data for (Z)-IX (R2 ) PhCH2CH2): 1H NMR (400 MHz,
CDCl3) δ 2.75 (irregular t, J ≈ 7.5 Hz, 2 H, CdCHCH2CH2C6H5),
2.84 (dm, J ) 16.5 Hz, 1 H, H-4a), 2.90 (dm, J ) 16.5 Hz, 1 H,
H-4b), 3.05 (dm, J ≈ 7.5 Hz, 1 H, CdCHCH2CHHC6H5), 3.07
(dm, J ≈ 7.5 Hz, 1 H, CdCHCH2CHHC6H5), 3.62 (AB q, J )
10.3 Hz, 2 H, CCH2OCH2C6H5), 3.74 (s, 3 H, CCH2OC6H4OCH3),
3.97 (AB q, J ) 9.7 Hz, CCH2OC6H4OCH3), 4.55 (AB q, J )
12.1 Hz, 2 H, CCH2OCH2C6H5), 6.18 (tt, J ) 7.6, 2.3 Hz, 1 H,
CdCHCH2CH2C6H5), 6.76-6.82 (m, 4 H, CCH2OC6H4OCH3),
7.14-7.34 (m, 10 H, CCH2OCH2C6H5 and CCH2OCH2C6H5); 13
C
(E)-5-[(4-Methoxyphenoxy)methyl]-3-[4-methyl-3-(methyl-
ethyl)pentylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydro-
furan-2-one ((E)-IX, R2 ) CH2CH(i-Pr)2) and (Z)-5-[(4-Meth-
oxyphenoxy)methyl]-3-[4-methyl-3-(methylethyl)pentylidene]-
5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one ((Z)-IX, R2
) CH2CH(i-Pr)2). According to general procedure I, VIII (R2 )
CH2CH(i-Pr)2; 692 mg, 1.43 mmol) was reacted to give (E)-IX
NMR (100 MHz, CDCl3) δ 28.89, 33.71, 35.05, 55.69, 70.39, 71.84,
73.62, 82.34, 114.62, 115.70, 125.14, 126.02, 127.59, 127.78,
128.37, 128.41, 128.49, 137.65, 140.95, 142.93, 152.53, 154.28,
168.76; FAB-MS (m/z, relative intensity) 459 (MH+, 22), 458 (M•+,
37), 91 (100). Anal. (C29H30O5) C, H.
(E)-3-[(2-Methoxyphenyl)methylene]-5-[(4-methoxyphenoxy)-
methyl]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one
((E)-IX, R2 ) 2-(MeO)C6H4). According to general procedure I,
VIII (R2 ) 2-(MeO)C6H4; 1.38 g, 2.88 mmol) was reacted to give
(E)-IX (R2 ) 2-(MeO)C6H4; 921 mg, 71% yield) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 3.12 (dd, J ) 17.7, 2.9 Hz, 1
H, H-4a), 3.20 (dd, J ) 17.7, 2.9 Hz, 1 H, H-4b), 3.64-3.74 (AB
q, J ) 10.2 Hz, 2 H, CCH2OCH2C6H5 containing δ 3.71 (s, 3 H,
CCH2OC6H4OCH3)), 3.81 (s, 3 H, CdCHC6H4OCH3), 4.04 (AB
q, 2 H, J ) 9.8 Hz, 2 H, CCH2OC6H4OCH3), 4.56 (s, 2 H, CCH2-
OCH2C6H5), 6.75-6.80 (m, 4 H, CCH2OC6H4OCH3), 6.90 (d, J
) 8.3 Hz, 1 H, CdCHC6H4OCH3), 6.96 (t, J ) 7.5 Hz, 1 H,
CdCHC6H4OCH3), 7.23-7.28 (m, 5 H, CCH2OCH2C6H5), 7.31-
7.36 (m, 1 H, CdCHC6H4OCH3), 7.42 (dd, J ) 7.7, 1.3 Hz, 1 H,
CdCHC6H4OCH3), 8.02 (t, J ) 2.8 Hz, 1 H, CdCHC6H4OCH3);
13C NMR (100 MHz, CDCl3) δ 32.69, 55.37, 55.49, 70.40, 71.78,
73.49, 82.80, 110.88, 114.45, 115.57, 120.25, 123.52, 129.34,
127.46, 127.60, 128.25, 128.90, 131.20, 137.44, 152.34, 154.12,
158.29, 171.22; FAB-MS (m/z, relative intensity) 461 (MH+, 60),
460 (M•+, 51), 91 (100). Anal. (C28H28O6‚0.8H2O) C, H.
(E)-3-[(3-Methoxyphenyl)methylene]-5-[(4-methoxyphenoxy)-
methyl]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one
((E)-IX, R2 ) 3-(MeO)C6H4). According to general procedure I,
VIII (R2 ) 3-(MeO)C6H4; 1.25 g, 2.6 mmol) was reacted to give
(E)-IX (R2 ) 3-(MeO)Ph; 460 mg, 38% yield) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 3.17 (dd, J ) 17.6, 2.9 Hz, 1 H,
H-4a), 3.25 (dd, J ) 17.6, 2.9 Hz, 1 H, H-4b), 3.68-3.74 (m, 2 H,
CCH2OCH2C6H5 containing δ 3.72 s, 3 H, CdCHC6H4OCH3), 3.81
(s, 3 H, CCH2OC6H4OCH3), 4.06 (AB q, 2 H, J ) 9.8 Hz, 2 H,
CCH2OC6H4OCH3), 4.57 (s, 2 H, CCH2OCH2C6H5), 6.75-6.80
(m, 4 H, CCH2OC6H4OCH3), 6.93 (dd, J ) 8.1, 2.2 Hz, 1 H,
CdCHC6H4OCH3), 7.00 (br s, 1 H, CdCHC6H4OCH3), 7.08 (d,
J ) 7.8 Hz, 1 H, CdCHC6H4OCH3), 7.20-7.35 (m, 6 H,
CCH2OCH2C6H5 and CdCHC6H4OCH3), 7.52 (t, J ) 2.8 Hz, 1
H, CdCHC6H4OCH3); 13C NMR (100 MHz, CDCl3) δ 32.75,
55.24, 55.58, 70.56, 71.85, 73.61, 83.07, 112.00, 114.54, 115.18,
115.66, 121.08, 124.97, 127.56, 128.36, 129.80, 135.85, 136.32,
136.50, 137.40, 152.36, 154.25, 159.70, 171.11; FAB-MS (m/z,
relative intensity) 461 (MH+, 58), 460 (M•+, 58), 91 (100). Anal.
(C28H28O6) C, H.
(R2 ) CH2CH(i-Pr)2; 240 mg, 36% yield) and (Z)-IX (R2
CH2CH(i-Pr)2; 257 mg, 39% yield).
)
Data for (E)-IX (R2 ) CH2CH(i-Pr)2): 1H NMR (400 MHz,
CDCl3) δ 0.85 and 0.86 (s, 6 H,CdCHCH2CH(CH(CH3)2)2), 0.90
and 0.92 (d, J ) 1.5 Hz, 6 H, CdCHCH2CH(CH(CH3)2)2), 1.22
(p, J ) 5.5 Hz, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.74-1.85 (m,
2 H, CdCHCH2CH(CH(CH3)2)2), 2.14 (dd, J ) 7.4, 5.8 Hz, 2 H,
CdCHCH2CH(CH(CH3)2)2), 2.88 (dq, J ) 17.1, 2.5 Hz, 2 H,
H-4ab), 3.68 (dd, J ) 22.7, 10.2 Hz, 2 H, CCH2OCH2C6H5), 3.76
(s, 3 H, CCH2OC6H4OCH3), 4.05 (dd, 1 H, J ) 23.1, 9.8 Hz, 2 H,
CCH2OC6H4OCH3) 4.59 (m, 2 H, CCH2OCH2C6H5), 6.82 (s, 5 H,
CCH2OC6H4OCH3 and CdCHCH2CH(CH(CH3)2)2), 7.27-7.36 (m,
5 H, CCH2OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ 19.23,
19.30, 21.51, 21.53, 28.58, 29.09, 29.14, 30.56, 50.20, 55.59, 70.65,
72.02, 73.61, 82.76, 114.53, 115.60, 125.28, 127.52, 127.70, 128.33,
137.50, 142.81, 152.45, 154.20, 170.05; FAB-MS (m/z, relative
intensity) 466 (MH+, 36), 91 (100). Anal. (C29H38O5) C, H.
Data for (Z)-IX (R2 ) CH2CH(i-Pr)2): 1H NMR (400 MHz,
CDCl3) δ 0.87 (d, J ) 2.8 Hz, 3 H, CdCHCH2CH(CH(CH3)2)2),
0.89 (d, J ) 2.7 Hz, 3 H, CdCHCH2CH(CH(CH3)2)2), 0.92 (d, J
) 1.6 Hz, 3 H, CdCCH2CH(CH(CH3)2)2), 0.93 (d, J ) 1.5 Hz, 3
H, CdCHCH2CH(CH(CH3)2)2), 1.13 (m, 1 H, CdCHCH2CH(CH-
(CH3)2)2), 1.76-1.84 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.75-
2.76 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.91 (dq, J ) 16.4, 2.0
Hz, 2 H, H-4ab), 3.66 (dd, J ) 21.5, 10.2 Hz, 2 H, CCH2-
OCH2C6H5), 3.77 (s, 3 H, CCH2OC6H4OCH3), 4.02 (dd, 1 H, J )
26.8, 9.7 Hz, 2 H, CCH2OC6H4OCH3) 4.59 (m, 1 H, CCH2-
OCH2C6H5), 6.23 (t, J ) 7.4 Hz, 1 H, CdCHCH2CH(CH(CH3)2)2),
6.82 (s, 4 H, CCH2OC6H4OCH3), 7.27-7.36 (m, 5 H, CCH2-
OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ 19.36, 19.42, 21.57,
21.61, 26.18, 29.26, 29.31, 33.86, 51.12, 55.61, 70.50, 71.88, 73.59,
82.10, 114.54, 115.64, 123.16, 127.54, 127.69, 128.34, 159, 146.66,
152.52, 154.19, 168.90; FAB-MS (m/z, relative intensity) 466
(MH+, 58), 91 (100). Anal. (C29H38O5) C, H.
(E)-5-[(4-Methoxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-
3-(phenylpropylidene)-4,5-dihydrofuran-2-one ((E)-IX, R2
)
PhCH2CH2) and (Z)-5-[(4-Methoxyphenoxy)methyl]-5-[(phen-
ylmethoxy)methyl]-3-(phenylpropylidene)-4,5-dihydrofuran-2-
one ((Z)-IX, R2 ) PhCH2CH2). According to general procedure
I, VIII (R2 ) PhCH2CH2; 747 mg, 1.63 mmol) was reacted to give
(E)-IX (R2 ) PhCH2CH2; 224 mg, 30% yield) and (Z)-IX (R2 )
PhCH2CH2; 201 mg, 27% yield) as colorless oils.
(E)-3-[(4-Methoxyphenyl)methylene]-5-[(4-methoxyphenoxy)-
methyl]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one
((E)-IX, R2 ) 4-(MeO)C6H4). According to general procedure I,
VIII (R2 ) 4-(MeO)C6H4; 1.15 g, 2.4 mmol) was reacted to give
(E)-IX (R2 ) 4-(MeO)Ph; 716 mg, 85% yield) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 3.12 (dd, J ) 17.5, 2.6 Hz, 1H,
H-4a), 3.19 (dd, J ) 17.5, 2.6 Hz, 1H, H-4b), 3.66-3.76 (m, 2 H,
CCH2OCH2C6H5 containing s, 3 H, CCH2OC6H4OCH3), 3.78 (s, 3
H, CdCHC6H4OCH3), 4.05 (AB q, 2 H, J ) 9.8 Hz, 2 H, CCH2-
OC6H4OCH3), 4.55 (s, 2 H, CCH2OCH2C6H5), 6.75-6.80 (m, 4
H, CCH2OC6H4OCH3), 6.92 (d, 2 H, CdCHC6H4OCH3), 7.22-
7.29 (m, 5 H, CCH2OCH2C6H5), 7.43 (d, 2 H, CdCHC6H4OCH3),
7.51 (br t, J ≈ 2.3 Hz, 1 H, 2 H, CdCHC6H4OCH3); 13C NMR
(100 MHz, CDCl3) δ 32.57, 55.12, 55.38, 70.44, 71.77, 73.40,
82.69, 114.18, 114.38, 115.53, 121.52, 127.13, 127.39, 127.54,
128.18, 131.66, 136.10, 137.36, 152.27, 154.06, 160.65, 171.35;
Data for (E)-IX (R2 ) PhCH2CH2): 1H NMR (400 MHz,
CDCl3) δ 2.47 (irregular q, 2 H, CdCHCH2CH2C6H5), 2.61 (dm,
J ) 17.1 Hz, 1 H, H-4a), 2.67 (dm, J ) 17.1 Hz, 1 H, H-4b), 2.77
(t, J ≈ 7.3 Hz, 2 H, CdCHCH2CH2C6H5), 3.56 (AB q, J ) 10.3
Hz, 2 H, CCH2OCH2C6H5), 3.74 (s, 3 H, CCH2OC6H4OCH3), 3.92
(AB q, J ) 9.7 Hz, CCH2OC6H4OCH3), 4.54 (br s, 2 H, CCH2-
OCH2C6H5), 6.73-6.82 (m, 6 H, CdCHCH2CH2C6H5), 7.10-7.34
(m, 9 H, CCH2OC6H4OCH3 and CCH2OCH2C6H5); 13C NMR (100
MHz, CDCl3) δ 30.32, 32.09, 34.19,55.69, 70.48, 71.89, 73.64,
82.23, 114.62, 115.70, 126.24, 127.30, 127.59, 127.80, 128.43,
128.48, 137.61, 139.45, 140.61, 152.51, 154.30, 169.84; FAB-MS
(m/z, relative intensity) 459 (MH+, 17), 458 (M•+, 28), 91 (100).
Anal. (C29H30O5‚0.2H2O) C, H.

3198 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
FAB-MS (m/z, relative intensity) 461 (MH+, 57), 91 (100). Anal.
(C28H28O6) C, H.
) CH2CH(i-Pr)2; 660 mg, 1.4 mmol) was reacted to give (E)-X
(R2 ) CH2CH(i-Pr)2; 381 mg, 78% yield) as a colorless oil.
(Z)-5-(Hydroxymethyl)-3-[4-methyl-3-(methylethyl)pentylidene]-
5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one ((Z)-X, R2
) CH2CH(i-Pr)2). According to general procedure J, (Z)-IX (R2
) CH2CH(i-Pr)2; 1.0 g, 2.1 mmol) was reacted to give (Z)-X (R2
) CH2CH(i-Pr)2; 370 mg, 49% yield) as a colorless oil.
(E)-5-[(4-Methoxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-
3-{[2-(phenylmethoxy)phenyl]methylene}-4,5-dihydrofuran-2-
one ((E)-IX, R2 ) 2-(PhCH2O)C6H4). According to general
procedure I, VIII (R2 ) 2-(PhCH2O)C6H4; 1.35 g, 2.43 mmol) was
reacted to give (E)-IX (R2 ) 2-(PhCH2O)C6H4; 906 mg, 71% yield)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 3.12 (dd, J )
17.7, 2.9 Hz, 1 H, H-4a), 3.20 (dd, J ) 17.7, 2.9 Hz, 1 H, H-4b),
3.70 (AB q, J ) 10.3 Hz, 2 H, CCH2OCH2C6H5), 3.76 (s, 3 H,
CCH2OC6H4OCH3), 4.06 (AB q, J ) 9.7 Hz, 2 H, CCH2OC6H4-
OCH3), 4.59 (s, 2 H, CCH2OCH2C6H5), 5.16 (s, 2 H, CdCHC6H4-
OCH2C6H5), 6.81 (s, 4 H, CCH2OC6H4OCH3), 6.97-7.02 (m, 2
H, CdCHC6H4OCH2C6H5), 7.27-7.48 (m, 12 H, CdCHC6H4-
OCH2C6H5 and CCH2OCH2C6H5), 8.09 (t, J ) 2.8 Hz, 1 H,
CdCHC6H4OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ 32.98,
55.69, 70.41, 70.44, 70.47, 71.89, 73.68, 82.86, 112.66, 114.58,
115.67, 120.69, 124.19, 124.37, 127.15, 127.61, 127.75, 127.99,
128.39, 128.65, 129.32, 131.15, 131.58, 136.43, 137.54, 152.48,
154.25, 157.48, 171.22; FAB-MS (m/z, relative intensity) 537
(MH+, 15), 536 (M•+, 15), 91 (100). Anal. (C34H32O6) C, H.
(E)-5-[(4-Methoxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-
3-{[3-(phenylmethoxy)phenyl]methylene}-4,5-dihydrofuran-2-
one ((E)-IX, R2 ) 3-(PhCH2O)C6H4). According to general
procedure I, VIII (R2 ) 3-(PhCH2O)C6H4; 1.24 g, 2.24 mmol) was
reacted to give (E)-IX (R2 ) 3-(PhCH2O)C6H4; 911 mg, 77% yield)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 3.09 (dd, J )
17.9, 2.8 Hz, 1 H, H-4a), 3.18 (dd, J ) 17.9, 2.8 Hz, 1 H, H-4b),
3.68-3.73 (m, 2 H, CCH2OCH2C6H5), 3.73 (s, 3 H, CCH2OC6H4-
OCH3), 4.05 (AB q, 2 H, J ) 9.9 Hz, 2 H, CCH2OC6H4OCH3),
4.58 (s, 2 H, CCH2OCH2C6H5), 5.08 (s, 2 H, CdCHC6H4OCH2-
C6H5), 6.80 (s, 4 H, CCH2OC6H4OCH3), 7.01-7.11 and 7.27-
7.43 (m, 14 H, CdCHC6H4OCH2C6H5 and CCH2OCH2C6H5), 7.53
(br t, 1 H, CdCHC6H4OCH2C6H5); 13C NMR (100 MHz, CDCl3)
δ 32.62, 55.48, 69.97, 70.45, 71.76, 73.50, 83.00, 114.47, 115.59,
116.09, 116.24, 122.85, 124.99, 127.22, 127.50, 127.67, 127.92,
128.28, 128.51 129.76, 135.78, 136.18, 136.50, 137.36, 152.29,
154.17, 158.76; FAB-MS (m/z, relative intensity) 537 (MH+, 23),
536 (M•+, 24), 91 (100). Anal. (C34H32O6‚0.2H2O) C, H.
(E)-5-[(4-Methoxyphenoxy)methyl]-5-[(phenylmethoxy)methyl]-
3-{[4-(phenylmethoxy)phenyl]methylene}-4,5-dihydrofuran-2-
one ((E)-IX, R2 ) 4-(PhCH2O)C6H4). According to general
procedure I, VIII (R2 ) 4-(PhCH2O)C6H4; 1.25 g, 2.25 mmol) was
reacted to give (E)-IX (R2 ) 4-(PhCH2O)C6H4; 503 mg, 41% yield)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 3.14 (dd, J )
17.7, 2.8 Hz, 1 H, H-4a), 3.22 (dd, J ) 17.7, 2.8 Hz, 1 H, H-4b),
3.70-3.77 (m, 2 H, CCH2OCH2C6H5 containing δ 3.72 s, 3 H,
CCH2OC6H4OCH3), 4.05-4.17 (m, 2 H, CCH2OC6H4OCH3), 4.61
(s, 2 H, CCH2OCH2C6H5), 5.12 (s, 2 H, CdCHC6H4OCH2C6H5),
6.83 (s, 4 H, CCH2OC6H4OCH3), 7.05 (d, J ) 8.8 Hz, 2 H,
CdCHC6H4OCH2C6H5), 7.28-7.50 (m, 12 H, CdCHC6H4-
OCH2C6H5 and CCH2OCH2C6H5), 7.56 (br t, J ) 2.6 Hz, 1 H,
CdCHC6H4OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ 32.76,
55.60, 710.01, 70.57, 71.91, 73.63, 82.84, 114.55, 115.21 115.68,
121.75, 127.37, 127.58, 127.74, 128.11, 128.36, 128.60, 131.83,
136.28, 136.34, 137.48, 152.43, 154.24 159.96, 171.52; FAB-MS
(m/z, relative intensity) 537 (MH+, 13), 536 (M•+, 10), 91 (100).
Anal. (C34H32O6) C, H.
(E)-5-(Hydroxymethyl)-5-[(phenylmethoxy)methyl]-3-
(phenylpropylidene)-4,5-dihydrofuran-2-one ((E)-X, R2
PhCH2CH2). According to general procedure J, (E)-IX (R2
)
)
PhCH2CH2; 224 mg, 0.49 mmol) was reacted to give (E)-X (R2 )
PhCH2CH2; 100 mg, 57% yield) as a colorless oil.
(E)-5-(Hydroxymethyl)-3-[(2-methoxyphenyl)methylene]-5-
[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one ((E)-X, R2 )
2-(MeO)C6H4). According to general procedure J, (E)-IX (R2 )
2-(MeO)Ph; 921 mg, 2.0 mmol) was reacted to give (E)-X (R2 )2-
(MeO)C6H4; 560 mg, 80% yield) as a colorless oil.
(E)-5-(Hydroxymethyl)-3-[(3-methoxyphenyl)methylene]-5-
[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one ((E)-X, R2 )
3-(MeO)C6H4). According to general procedure J, (E)-IX (R2 )
3-(MeO)C6H4; 460 mg, 1.0 mmol) was reacted to give (E)-X (R2
) 3-(MeO)C6H4; 232 mg, 66% yield) as a colorless oil.
(E)-5-(Hydroxymethyl)-3-[(4-methoxyphenyl)methylene]-5-
[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one ((E)-X, R2 )
4-(MeO)C6H4). According to general procedure J, (E)-IX (R2 )
4-(MeO)C6H4; 480 mg, 1.0 mmol) was reacted to give (E)-X (R2
) 4-(MeO)C6H4; 122 mg, 34% yield) as a colorless oil.
(E)-5-(Hydroxymethyl)-5-[(phenylmethoxy)methyl]-3-{[2-
(phenylmethoxy)phenyl]methylene}-4,5-dihydrofuran-2-one
((E)-X, R2 ) 2-(PhCH2O)C6H4). According to general procedure
J, (E)-IX (R2 ) 2-(PhCH2O)C6H4; 906 mg, 1.7 mmol) was reacted
to give (E)-X (R2 ) 2-(PhCH2O)C6H4; 631 mg, 88% yield) as a
colorless oil.
(E)-5-(Hydroxymethyl)-5-[(phenylmethoxy)methyl]-3-{[3-
(phenylmethoxy)phenyl]methylene}-4,5-dihydrofuran-2-one
((E)-X, R2 ) 3-(PhCH2O)C6H4). According to general procedure
J, (E)-IX (R2 ) 3-(PhCH2O)C6H4; 900 mg, 1.7 mmol) was reacted
to give (E)-X (R2 ) 3-(PhCH2O)C6H4; 631 mg, 88% yield) as a
colorless oil.
(E)-5-(Hydroxymethyl)-5-[(phenylmethoxy)methyl]-3-{[4-
(phenylmethoxy)phenyl]methylene}-4,5-dihydrofuran-2-one
((E)-X, R2 ) 4-(PhCH2O)C6H4). According to general procedure
J, (E)-IX (R2 ) 4-(PhCH2O)C6H4; 503 mg, 0.94 mmol) was reacted
to give (E)-X (R2 ) 4-(PhCH2O)C6H4; 242 mg, 60% yield) as a
colorless oil.
General Procedure for the Synthesis of XI. Procedure K. A
solution of (E)-X (1 equiv) in dichloromethane (12 mL/mmol) was
treated with Et3N (3 equiv), acid chloride (1.5 equiv), and a catalytic
amount of DMAP (0.1 equiv). The reaction was stirred at room
temperature and monitored by TLC, and upon completion it was
concentrated in vacuo. Purification by silica gel flash column
chromatography gave (E)-XI.
(Z)-{4-[4-Methyl-3-(methylethyl)pentylidene]-5-oxo-2-
[(phenylmethoxy)methyl]-2,3-dihydrofur-2-yl}methyl 2-(Phen-
ylmethoxy)benzoate ((Z)-XI, R1 ) 2-(PhCH2O)C6H4, R2
)
CH2CH(i-Pr)2). According to general procedure K, (Z)-X (R2 )
CH2CH(i-Pr)2; 100 mg, 0.28 mmol) and 2-(PhCH2O)PhCOCl (103
mg, 0.42 mmol) were reacted in CH2Cl2 (4 mL) to give (Z)-XI (R1
) 2-(PhCH2O)C6H4, R2 ) CH2CH(i-Pr)2; 109 mg, 68% yield) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.82, 0.83, 0.87,
and 0.88 (d, J ) 6.8 Hz, 12 H, CdCHCH2CH(CH(CH3)2)2), 1.05
(p, J ≈ 5.5 Hz, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.70-1.80 (m,
2 H, CdCHCH2CH(CH(CH3)2)2), 2.51-2.60 (m, 1 H, CdCHCH2-
CH(CH(CH3)2)2), 2.69-2.80 (m, 3 H, CdCHCH2CH(CH(CH3)2)2
and H-3a,b), 3.50 (AB q, J ) 10.1 Hz, 2 H, CCH2OCH2C6H5), 4.41
(AB q, J ) 11.7 Hz, 2 H, CCH2OC(O)C6H4OCH2C6H5), 4.50 (d,
J ) 2.9 Hz, 2 H, CCH2OCH2C6H5), 5.12 (s, 2 H, CCH2OC(O)-
C6H4OCH2C6H5), 6.08-6.13 (m, 1 H, CdCHCH2CH(CH(CH3)2)2),
6.94-6.99 (m, 2 H, CCH2OC(O)C6H4OCH2C6H5), 7.25-7.45 (m,
11 H, CCH2OC(O)C6H4OCH2C6H5 and CCH2OCH2C6H5), 7.77 (dd,
J ) 7.7, 1.8 Hz, 1 H, CCH2OC(O)C6H4OCH2C6H5); 13C NMR (100
General Procedure for the Synthesis of X. Procedure J. CAN
(3 equiv) was added to a stirring solution of IX (1 equiv) in
acetonitrile (8 mL/mmol of IX) and water (2 mL/mmol of IX) at
0 °C. The reaction was monitored by TLC and, after being stirred
for 30 min, quenched with a saturated aqueous NaHCO3 solution
and warmed to room temperature. The resulting aqueous solution
was extracted with EtOAc (3×), dried over MgSO4, and concen-
trated in vacuo. Purification by silica gel flash column chromatog-
raphy gave intermediate X as an oil which was used directly without
further purification.
(E)-5-(Hydroxymethyl)-3-[4-methyl-3-(methylethyl)pentylidene]-
5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one ((E)-X, R2
) CH2CH(i-Pr)2). According to general procedure J, (E)-IX (R2

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3199
MHz, CDCl3) δ 19.31, 19.47, 21.58, 21.65, 26.19, 29.27, 29.36,
33.90, 51.13, 65.93, 70.54, 71.70, 73.58, 81.51, 113.56, 119.70,
120.48, 122.90, 127.24, 127.56, 127.73, 127.91, 128.37, 128.58,
132.12, 133.81, 136.49, 137.57, 146.94, 158.39, 165.60, 168.77;
FAB-MS (m/z, relative intensity) 571 (MH+, 5), 91 (100). Anal.
(C36H42O6‚0.5H2O) C, H.
CCH2OC(O)C6H4OCH2C6H5), 4.59 (s, 2 H, CCH2OCH2C6H5),
5.12 (s, 2 H, CCH2OC(O)C6H4OCH2C6H5), 6.19-6.23 (m, 1 H,
CdCHCH2CH(CH(CH3)2)2), 6.97 (d, J ) 8.9 Hz, 2 H, CCH2OC-
(O)C6H4OCH2C6H5), 7.27-7.45 (m, 10 H, CCH2OC(O)C6H4-
OCH2C6H5 and CCH2OCH2C6H5), 7.92 (d, J ) 8.9 Hz, 2 H,
CCH2OC(O)C6H4OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ
19.29, 19.45, 21.55, 21.66, 26.19, 29.25, 29.34, 34.03, 51.09, 66.07,
70.08, 71.71, 73.66, 81.58, 114.51, 121.97, 122.85, 127.40, 127.64,
127.80, 128.19, 128.40, 128.64, 131.78, 132.78, 136.10, 137.37,
146.93, 162.71, 165.60, 168.74; FAB-MS (m/z, relative intensity)
571 (MH+, 6), 91 (100). Anal. (C36H42O6) C, H.
(E)-{5-Oxo-2-[(phenylmethoxy)methyl]-4-(3-phenylpro-
pylidene)-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-(methylethyl)-
pentanoate ((E)-XI, R1 ) CH2CH(i-Pr)2, R2 ) PhCH2CH2).
According to general procedure K, (E)-X (R2 ) PhCH2CH2; 100
mg, 0.28 mmol) and 4-methyl-3-(methylethyl)pentanoyl chloride25
(74 mg, 0.42 mmol) were reacted in CH2Cl2 (4 mL) to give (E)-XI
(R1 ) CH2CH(i-Pr)2, R2 ) PhCH2CH2; 108 mg, 78% yield) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.79 and 0.88 (d,
J ) 6.64 Hz, 12 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.55 (p, J
≈ 5.70 Hz, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.73 (m, 2 H,
CCH2OC(O)CH2CH(CH(CH3)2)2), 2.14 (d, J ) 5.6 Hz, CCH2OC-
(O)CH2CH(CH(CH3)2)2), 2.42-2.52 (m, 3 H, CdCHCH2CH2C6H5
and H-3a), 2.62 (d, J ) 16.6 Hz, 1 H, H-3b), 2.78 (t, J ≈
7 Hz, CdCHCH2CH2C6H5), 3.48 (AB q, J ) 9.76 Hz, 2 H,
CCH2OCH2C6H5), 4.14 (AB q, J ) 12.3 Hz, 2 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 4.52 (s, 2 H, CCH2OCH2C6H5), 6.76 (br t, 1
H, CdCHCH2CH2C6H5), 7.12-7.38 (m, 10 H, CdCHCH2CH2C6H5
and CCH2OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ 18.70,
21.32, 29.31, 29.35, 30.41, 32.11, 32.76, 34.17, 46.85, 65.83, 71.75,
73.70, 76.71, 77.04, 77.35, 81.93, 126.29, 126.99, 127.63, 127.88,
128.45, 128.51, 137.35, 139.62, 140.49, 169.54, 174.24; FAB-MS
(m/z, relative intensity) 493 (MH+, 27), 91 (100). Anal. (C31H40O5)
C, H.
(Z)-{4-[4-Methyl-3-(methylethyl)pentylidene]-5-oxo-2-
[(phenylmethoxy)methyl]-2,3-dihydrofur-2-yl}methyl 3-(Phen-
ylmethoxy)benzoate ((Z)-XI, R1 ) 3-(PhCH2O)C6H4, R2
)
CH2CH(i-Pr)2). According to general procedure K, (Z)-X (R2 )
CH2CH(i-Pr)2; 110 mg, 0.31 mmol) and 3-(PhCH2O)PhCOCl (162
mg, 0.66 mmol) were reacted in CH2Cl2 (6 mL) to give (Z)-XI (R1
) 3-(PhCH2O)C6H4, R2 ) CH2CH(i-Pr)2; 149 mg, 84% yield) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.82 and 0.87 (t, J
) 6.8 Hz, 12 H, CdCHCH2CH(CH(CH3)2)2), 1.08 (p, J ) 5.5 Hz,
1 H, CdCHCH2CH(CH(CH3)2)2), 1.70-1.80 (m, 2 H, CdCHCH2-
CH(CH(CH3)2)2), 2.54-2.61 (m, 1 H, CdCHCHHCH(CH(CH3)2)2),
2.79-2.86 (m, 2 H, CdCHCHHCH(CH(CH3)2)2 and H-3a), 2.94
(dd, J ) 16.6, 2.4 Hz, 1 H, H-3b), 3.62 (AB q, J ) 10.0 Hz, 2 H,
CCH2OCH2C6H5), 4.46 (AB q, J ) 11.8 Hz, 2 H, CCH2OC(O)-
C6H4OCH2C6H5), 4.58 (s, 2 H, CCH2OCH2C6H5), 5.09 (s, 2 H,
CCH2OC(O)C6H4OCH2C6H5), 6.18-6.24 (m, 1 H, CdCHCH2CH-
(CH(CH3)2)2), 7.18 (dd, J ) 8.2, 2.6 Hz, 1 H, CCH2OC(O)C6H4-
OCH2C6H5), 7.27-7.46 (m, 10 H, CCH2OC(O)C6H4OCH2C6H5 and
CCH2OCH2C6H5), 7.56-7.60 (m, 2 H, CCH2OC(O)C6H4OCH2C6H5),
7.73-7-75 (m, 1 H, CCH2OC(O)C6H4OCH2C6H5); 13C NMR (100
MHz, CDCl3) δ 19.29, 21.65, 26.23, 29.26, 29.36, 34.11, 51.12,
66.39, 70.16, 71.65, 73.69, 81.46, 115.26, 116.01, 120.50, 121.75,
122.35, 122.72, 123.15, 127.54, 127.65, 127.85, 128.08, 128.20,
128.43, 128.66, 129.92, 130.68, 136.44, 147.16, 158.71, 165.78,
168.71; FAB-MS (m/z, relative intensity) 571 (MH+, 7), 91 (100).
Anal. (C36H42O6‚0.1H2O) C, H.
(E)-{4-[4-Methyl-3-(methylethyl)pentylidene]-5-oxo-2-
[(phenylmethoxy)methyl]-2,3-dihydrofur-2-yl}methyl 4-(Phen-
ylmethoxy)benzoate ((E)-XI, R1 ) 4-(PhCH2O)C6H4, R2
)
(E)-{4-[(2-Methoxyphenyl)methylene]-5-oxo-2-[(phen-
ylmethoxy)methyl]-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-
CH2CH(i-Pr)2). According to general procedure K, (E)-X (R2 )
CH2CH(i-Pr)2; 150 mg, 0.41 mmol) and 4-(PhCH2O)PhCOCl (151
mg, 0.61 mmol) were reacted to give (E)-XI (R1 ) 4-(PhCH2O)-
C6H4, R2 ) CH2CH(i-Pr)2; 240 mg, 100% yield) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 0.76, 0.79, 0.82, and 0.85 (d, 6.8
Hz, 12 H, CdCHCH2CH(CH(CH3)2)2), 1.15 (p, J ) 5.6 Hz, 1 H,
(methylethyl)pentanoate ((E)-XI, R1 ) CH2CH(i-Pr)2, R2
)
2-(MeO)C6H4). According to general procedure K, (E)-X (R2 )
2-(MeO)C6H4; 560 mg, 1.6 mmol) and 4-methyl-3-(methylethyl)-
pentanoyl chloride25 (424 mg, 2.4 mmol) were reacted to give
(E)-XI (R1 ) CH2CH(i-Pr)2, R2 ) 2-(MeO)C6H4; 790 mg, 100%
yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.73,
0.76, 0.83, 0.85 (d, J ) 6.8 Hz, 12 H, CCH2OC(O)CH2CH-
(CH(CH3)2)2), 1.53 (p, J ) 5.8 Hz, 1 H, CCH2OC(O)CH2CH-
(CH(CH3)2)2), 1.68 (septet, J ) 6.8 Hz, 2 H, CCH2OC(O)CH2CH-
(CH(CH3)2)2), 2.14 (d, J ) 5.8 Hz, 2 H, CCH2OC(O)CH2CH-
(CH(CH3)2)2), 2.99 (dd, J ) 17.6, 2.9 Hz, 1 H, H-3a), 3.15 (dd,
J ) 17.6, 2.9 Hz, 1 H, H-3b), 3.61 (AB q, J ) 10.9 Hz, 2 H,
CCH2OCH2C6H5), 3.87 (s, 1 H, CdCHC6H4OCH3), 4.27 (AB q, J
) 11.9 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 4.57 (s, 2 H,
CCH2OCH2C6H5), 6.94 (d, J ) 8.3 Hz, 1 H, CdCHC6H4OCH3),
6.99 (t, J ) 2.9 Hz, 1 H, CdCHC6H4OCH3), 7.26-7.40 (m, 7 H,
CCH2OCH2C6H5 and CdCHC6H4OCH3), 8.01 (t, J ) 2.9 Hz, 1
H, CdCHC6H4OCH3); 13C NMR (100 MHz, CDCl3) δ 18.58,
21.21, 29.21, 32.68, 32.90, 34.03, 46.71, 55.36, 65.90, 71.73, 73.62,
82.08, 110.89, 120.28, 123.42, 123.61, 127.57, 127.77, 128.34,
128.89, 131.32, 131.37, 137.22, 158.36, 170.38, 171.11, 174.23;
FAB-MS (m/z, relative intensity) 495 (MH+, 34), 91 (100). Anal.
(C30H38O6) C, H.
CdCHCH2CH(CH(CH3)2)2), 1.73 (m,
2 H, CdCHCH2CH-
(CH(CH3)2)2), 2.07 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.74 (dd,
J ) 17.1, 2.5 Hz, 1 H, H-3a), 2.87 (dd, J ) 17.1, 2.5 Hz, 1 H,
H-3b), 3.64 (AB q, J ) 10.0 Hz, 2 H, CCH2OCH2C6H5), 4.44
(AB q, J ) 11.8 Hz, 2 H, CCH2OC(O)C6H4OCH2C6H5), 4.58 (s,
2 H, CCH2OCH2C6H5), 5.10 (s, 2 H, CCH2OC(O)C6H4OCH2C6H5),
6.80 (tt, J ) 7.3, 2.7 Hz, 1 H, CdCHCH2CH(CH(CH3)2)2), 6.95
(d, J ) 8.9 Hz, 2 H, CCH2OC(O)C6H4OCH2C6H5), 7.24-7.43 (m,
10 H, CCH2OC(O)C6H4OCH2C6H5 and CCH2OCH2C6H5), 7.89 (d,
J ) 8.9 Hz, 2 H, CCH2OC(O)C6H4OCH2C6H5); 13C NMR (100
MHz, CDCl3) δ 19.21, 19.26, 21.38, 21.52, 28.54, 29.02, 29.07,
30.72, 50.14, 66.24, 70.16, 71.80, 73.65, 82.24, 114.48, 121.81,
125.04, 127.35, 127.60, 127.79, 128.13, 128.37, 128.59, 131.73,
136.05, 137.26, 143.07, 162.69, 165.53, 169.87; FAB-MS (m/z,
relative intensity) 571 (MH+, 11), 91 (100). Anal. (C36H42O6)
C, H.
(Z)-{4-[4-Methyl-3-(methylethyl)pentylidene]-5-oxo-2-
[(phenylmethoxy)methyl]-2,3-dihydrofur-2-yl}methyl 4-(Phen-
ylmethoxy)benzoate ((Z)-XI, R1 ) 4-(PhCH2O)C6H4, R2
)
(E)-{4-[(3-Methoxyphenyl)methylene]-5-oxo-2-[(phen-
ylmethoxy)methyl]-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-
CH2CH(i-Pr)2). According to general procedure K, (Z)-X (R2 )
CH2CH(i-Pr)2; 160 mg, 0.44 mmol) and 4-(PhCH2O)PhCOCl (162
mg, 0.66 mmol) were reacted in CH2Cl2 (6 mL) to give (Z)-XI (R1
) 4-(PhCH2O)C6H4, R2 ) CH2CH(i-Pr)2; 152 mg, 61% yield) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.83, 0.84, 0.88,
and 0.89 (d, J ) 6.8 Hz, 12 H, CdCHCH2CH(CH(CH3)2)2), 1.09
(p, J ) 5.5 Hz, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.74 (m, 2 H,
CdCHCH2CH(CH(CH3)2)2), 2.54-2.64 (m, 1 H, CdCHCHHCH-
(CH(CH3)2)2), 2.74-2.84 (m, 2 H, CdCHCHHCH(CH(CH3)2)2 and
H-3a), 2.92 (dd, J ) 16.2, 2.5 Hz, 1 H, H-3b), 3.62 (AB q, J )
10.0 Hz, 2 H, CCH2OCH2C6H5), 4.44 (AB q, J ) 11.8 Hz, 2 H,
(methylethyl)pentanoate ((E)-XI, R1 ) CH2CH(i-Pr)2, R2
)
3-(MeO)C6H4). According to general procedure K, (E)-X (R2 )
3-(MeO)C6H4; 232 mg, 0.66 mmol) and 4-methyl-3-(methylethyl)-
pentanoyl chloride25 (174 mg, 0.99 mmol) were reacted to give
(E)-XI (R1 ) CH2CH(i-Pr)2, R2 ) 3-(MeO)C6H4; 230 mg, 70%
yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.73, 0.76,
0.82, 0.83 (d, J ) 6.8 Hz, 12 H, CCH2OC(O)CH2CH(CH(CH3)2)2),
1.48-1.55 (m, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.68 (septet,
J ) 6.3 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.14 (d,
J ) 5.8 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 3.01 (dd, J )

3200 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
17.6, 2.9 Hz, 1 H, H-3a), 3.16 (dd, J ) 17.6, 2.9 Hz, 1 H, H-3b),
3.58 (AB q, J ) 10.2 Hz, 2 H, CCH2OCH2C6H5), 3.83 (s, 1 H,
CdCHC6H4OCH3), 4.24 (AB q, J ) 12.1 Hz, 2 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 4.57 (s, 2 H, CCH2OCH2C6H5), 6.96 (dd, J
) 8.1, 2.4 Hz, 1 H, CdCHC6H4OCH3), 6.99 (br t, 1 H, CdCHC6H4-
OCH3), 7.07 (br d, J ) 7.8 Hz, 1 H, CdCHC6H4OCH3), 7.26-
7.38 (m, 6 H, CCH2OCH2C6H5 and CdCHC6H4OCH3), 7.49 (t, J
) 2.8 Hz, 1 H, CdCHC6H4OCH3); 13C NMR (100 MHz, CDCl3)
δ 21.15, 21.27, 29.32, 32.74, 46.82, 55.28, 65.90, 71.74, 73.71,
82.31, 115.27, 115.62, 122.40, 124.66, 127.48, 127.83, 128.43,
135.74, 136.39, 136.70, 137.20, 159.77, 170.89, 174.23; FAB-MS
(m/z, relative intensity) 495 (MH+, 34), 91 (100). Anal. (C30H38O6)
C, H.
1.53 (p, J ) 5.8 Hz, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.62-
1.74 (m, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.15 (d, J ) 5.7
Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.93 (dd, J ) 17.8,
2.8 Hz, 1 H, H-3a), 3.10 (dd, J ) 17.8, 2.9 Hz, 1 H, H-3b), 3.60
(AB q, J ) 10.0 Hz, 2 H, CCH2OCH2C6H5), 4.26 (s, 2 H, CCH2-
OC(O)CH2CH(CH(CH3)2)2), 4.58 (s, 2 H, CCH2OCH2C6H5), 5.11
(s, 2 H, CdCHC6H4OCH2C6H5), 7.04-7.09 (m, 3 H, CdCHC6H4-
OCH2C6H5), 7.28-7.44 (m, 11 H, CdCHC6H4OCH2C6H5 and
CCH2OCH2C6H5), 7.51 (t, J ) 2.8 Hz, 1 H, CdCHC6H4-
OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ 18.56, 21.17, 21.20,
21.26, 29.24, 32.72, 46.78, 65.87, 70.08, 71.69, 73.67, 82.29,
116.18, 116.42, 122.90,124.68, 127.25, 127.65, 127.87, 128.03,
128.41 128.61, 129.86, 135.72, 136.40, 136.53, 137.18, 158.86,
170.87, 174.20, 180.30; FAB-MS (m/z, relative intensity) 571
(MH+, 9), 91 (100). Anal. (C36H42O6‚0.3H2O) C, H.
(E)-{4-[(4-Methoxyphenyl)methylene]-5-oxo-2-[(phen-
ylmethoxy)methyl]-2,3-dihydrofur-2-yl}methyl
4-Methyl-3-
(methylethyl)pentanoate ((E)-XI, R1 ) CH2CH(i-Pr)2, R2
)
(E)-(5-Oxo-2-[(phenylmethoxy)methyl]-4-{[4-(phenylmeth-
oxy)phenyl]methylene}-2,3-dihydrofur-2-yl)methyl 4-Methyl-3-
4-(MeO)C6H4). According to general procedure K, (E)-X (R2 )
4-(MeO)C6H4; 122 mg, 0.34 mmol) and 4-methyl-3-(methylethyl)-
pentanoyl chloride25 (90 mg, 0.51 mmol) were reacted to give (E)-
XI (R1 ) CH2CH(i-Pr)2, R2 ) 4-(MeO)C6H4; 110 mg, 64% yield)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.72 and 0.76
(d, J ) 6.7 Hz, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 0.81-0.85
(m, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.52 (p, J ) 5.8 Hz, 1
H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.68 (irregular septet, 2 H,
CCH2OC(O)CH2CH(CH(CH3)2)2), 2.14 (d, J ) 5.8 Hz, 2 H, CCH2-
OC(O)CH2CH(CH(CH3)2)2), 3.00 (dd, J ) 17.5, 2.8 Hz, 1 H, H-3a),
3.16 (dd, J ) 17.5, 2.8 Hz, 1 H, H-3b), 3.62 (AB q, J ) 10.0 Hz,
2 H, CCH2OCH2C6H5), 3.85 (s, 3 H, CdCHC6H4OCH3), 4.28 (AB
q, J ) 12.0 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 4.57 (s, 2
H, CCH2OCH2C6H5), 6.96 (d, J ≈ 12 Hz, 2 H, CdCHC6H4OCH3),
7.25-7.35 (m, 5 H, CCH2OCH2C6H5), 7.45 (d, J ≈ 12 Hz, 2 H,
CdCHC6H4OCH3), 7.51 (t, 1 H, J ) 2.7 Hz, CdCHC6H4OCH3);
13C NMR (100 MHz, CDCl3) δ 18.66, 21.27, 29.29, 32.78, 46.84,
55.45, 66.00, 71.86, 73.76, 82.07, 114.38, 121.29, 127.27, 127.76,
128.45, 031.92, 136.46, 136.59, 137.28, 160.94, 171.35, 174.33;
FAB-MS (m/z, relative intensity) 495 (MH+, 21), 91 (100). Anal.
(C30H38O6‚0.2H2O) C, H.
(methylethyl)pentanoate ((E)-XI, R1 ) CH2CH(i-Pr)2, R2
)
4-(PhCH2O)C6H4). According to general procedure K, (E)-X (R2
) 4-(PhCH2O)C6H4; 242 mg, 0.56 mmol) and 4-methyl-3-(meth-
ylethyl)pentanoyl chloride25 (148 mg, 0.84 mmol) were reacted to
give (E)-XI (R1 ) CH2CH(i-Pr)2, R2 ) 4-(PhCH2O)C6H4; 213 mg,
66% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.74
and 0.77 (d, J ) 6.8 Hz, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2),
0.83 (d, J ) 6.0 Hz, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.54
(p, J ) 5.8 Hz, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.69
(irregular septet, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.15 (d,
J ) 5.8 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 3.01 (dd, J )
17.6, 2.7 Hz, 2 H, H-3a), 3.16 (dd, J ) 17.6, 2.8 Hz, 2 H, H-3b),
3.62 (AB q, J ) 9.9 Hz, 2 H, CCH2OCH2C6H5), 4.29 (AB q,
J ) 11.9 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 4.58 (s,
2 H, CdCHC6H4OCH2C6H5), 5.11 (s, 2 H, CCH2OCH2C6H5), 7.03
(d, J ) 8.8 Hz, 2 H, CdCHC6H4OCH2C6H5), 7.27-7.45 (m,
12 H, CdCHC6H4OCH2C6H5 and CCH2OCH2C6H5), 7.52 (t,
J ) 2.6 Hz, 1 H, CdCHC6H4OCH2C6H5); 13C NMR (100 MHz,
CDCl3) δ 18.55, 18.63, 21.16, 21.19, 29.23, 29.31, 32.72, 32.86,
46.76, 65.94, 70.00, 71.79, 73.67, 82.04, 115.24, 121.41, 127.34,
127.42, 127.63, 127.83, 128.10, 128.39, 128.59, 131.81, 136.23,
136.37, 137.22, 160.01, 171.28, 174.25; FAB-MS (m/z, rela-
tive intensity) 571 (MH+, 9), 91 (100). Anal. (C36H42O6‚0.3H2O6)
C, H.
(E)-(5-Oxo-2-[(phenylmethoxy)methyl]-4-{[2-(phenylmeth-
oxy)phenyl]methylene}-2,3-dihydrofur-2-yl)methyl 4-Methyl-3-
(methylethyl)pentanoate ((E)-XI, R1 ) CH2CH(i-Pr)2, R2
)
2-(PhCH2O)C6H4). According to general procedure K, (E)-X (R2
) 2-(PhCH2O)C6H4; 496 mg, 1.1 mmol) and 4-methyl-3-(meth-
ylethyl)pentanoyl chloride25 (240 mg, 1.3 mmol) were reacted to
give (E)-XI (R1 ) CH2CH(i-Pr)2, R2 ) 2-(PhCH2O)Ph; 439 mg,
70% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.71
and 0.73 (d, J ) 6.8 Hz, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2),
0.81 (t, J ) 6.8 Hz, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.55
(p, J ) 5.8 Hz, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.61-1.74
(m, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.16 (d, J ) 5.7 Hz, 2
H, CCH2OC(O)CH2CH(CH(CH3)2)2), 3.00 (dd, J ) 17.7, 2.9 Hz,
1 H, H-3a), 3.15 (dd, J ) 17.7, 3.0 Hz, 2 H, H-3b), 3.60 (AB q, J
) 10.0 Hz, 2 H, CCH2OCH2C6H5), 4.27 (s, 2 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 4.57 (s, 2 H, CCH2OCH2C6H5), 5.15 (s, 2
H, CdCHC6H4OCH2C6H5), 6.98-7.03 (m, 2 H, CdCHC6H4-
OCH2C6H5), 7.26-7.45 (m, 12 H, CdCHC6H4OCH2C6H5 and
CCH2OCH2C6H5), 8.09 (t, J ) 2.8 Hz, 1 H, CdCHC6H4-
OCH2C6H5); 13C NMR (100 MHz, CDCl3) δ 18.62, 21.15, 21.17,
29.23, 32.71, 33.05, 46.75, 65.88, 70.32, 71.75, 73.65, 81.98,
112.60, 120.64, 123.92, 127.06, 127.59, 127.79, 127.94, 128.36,
128.57, 129.16, 131.22, 131.42, 136.31, 137.25, 157.46, 170.93,
174.24; FAB-MS (m/z, relative intensity) 571 (MH+, 4), 91 (100).
Anal. (C36H42O6‚0.8H2O) C, H.
General Procedure for the Synthesis of XII. Procedure L.
Boron trichloride (3 equiv) was added slowly to a stirring solution
of XI (1 equiv) in dichloromethane (20 mL/mmol of XI) at -78
°C. The reaction was monitored by TLC, and upon completion,
the reaction mixture was slowly quenched with a saturated aqueous
NaHCO3 solution, diluted with dichloromethane (20 mL/mmol of
XI), and warmed to room temperature. The layers were separated,
and the aqueous layer was further extracted with dichloromethane
(2×). The combined organics were dried over MgSO4 and
concentrated in vacuo. Purification by silica gel flash column
chromatography gave XII.
(Z)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl 2-Hydroxybenzoate
((Z)-11, (Z)-XII, R1 ) 2-(OH)C6H4, R2 ) CH2CH(i-Pr)2). Ac-
cording to general procedure L, (Z)-XI (R1 ) 2-(PhCH2O)C6H4,
R2 ) CH2CH(i-Pr)2; 109 mg, 0.40 mmol) was reacted to give
(Z)-11 ((Z)-XII, R1 ) 2-(HO)C6H4, R2 ) CH2CH(i-Pr)2; 32 mg,
43% yield) as a white solid: mp 60 °C; 1H NMR (400 MHz, CDCl3)
δ 0.85, 0.86, 0.89, and 0.90 (d, J ) 6.8 Hz, 12 H, CdCHCH2CH-
(CH(CH3)2)2), 1.10 (p, J ) 5.6 Hz, 1 H, CdCHCH2CH(CH-
(CH3)2)2), 1.77 irregular septet, 2 H, CdCHCH2CH(CH(CH3)2)2),
2.25 (t, J ) 6.1 Hz, 1 H, CCH2OH), 2.59-2.67 (m, 1 H,
CdCHCHHCH(CH(CH3)2)2), 2.74-2.85 (m, 2 H, H-3a and
CdCHCHHCH(CH(CH3)2)2), 2.95 (ddd, J ) 16.6, 5.0, 2.5 Hz, 1
H, H-3b), 3.72 (br dd, J ) 12.1, 5.8 Hz, 1 H, CCHHOH), 3.80 (br
dd, J ) 12.1, 5.8 Hz, 1 H, CCHHOH), 4.49 (AB m, 2 H, CCH2-
OC(O)C6H4OH), 6.29 (tt, J ) 7.4, 2.2 Hz, 1 H, CdCHCH2CH-
(CH(CH3)2)2), 6.85-6.89 (m, 1 H, CCH2OC(O)C6H4OH), 6.98 (dd,
J ) 8.7, < 1 Hz, 1 H, CCH2OC(O)C6H4OH), 7.45-7.49 (m, 1 H,
CCH2OC(O)C6H4OH), 7.74 (dd, J ) 8.0, 1.7 Hz, 1 H, CCH2OC-
(E)-(5-Oxo-2-[(phenylmethoxy)methyl]-4-{[3-(phenylmeth-
oxy)phenyl]methylene}-2,3-dihydrofur-2-yl)methyl 4-methyl-3-
(methylethyl)pentanoate ((E)-XI, R1 ) CH2CH(i-Pr)2, R2
)
3-(PhCH2O)C6H4). According to general procedure K, (E)-X (R2
) 4-(PhCH2O)C6H4; 359 mg, 0.83 mmol) and 4-methyl-3-(meth-
ylethyl)pentanoyl chloride25 (219 mg, 1.2 mmol) were reacted to
give (E)-XI (R1 ) CH2CH(i-Pr)2, R2 ) 3-(PhCH2O)Ph; 366 mg,
77% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.74,
0.77, 0.83 (d, J ) 6.8 Hz, 12 H, CCH2OC(O)CH2CH(CH(CH3)2)2),

Conformationally Strained Analogues of DAG
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3201
(O)C6H4OH); 13C NMR (100 MHz, CDCl3) δ 19.33, 19.46, 21.57,
21.65, 26.36, 29.29, 29.37, 33.25, 51.13, 64.83, 65.98, 82.18,
111.62, 117.74, 119.38, 122.38,129.87, 136.27, 148.18, 161.79
168.59,169.62; FAB-MS (m/z, relative intensity) 391 (MH+, 30),
121 (100). Anal. (C22H30O6) C, H.
(E)-[2-(Hydroxymethyl)-5-oxo-4-(3-phenylpropylidene)-2,3-
dihydrofur-2-yl]methyl 4-Methyl-3-(methylethyl)pentanoate
((E)-16, (E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) PhCH2CH2). Ac-
cording to general procedure L, (E)-XI (R1 ) CH2CH(i-Pr)2, R2 )
PhCH2CH2; 104 mg, 0.22 mmol) was reacted to give (E)-14
((E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) PhCH2CH2; 61 mg, 68% yield)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.80 and 0.89
(d, J ) 6.64 Hz, 12 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.57 (p,
J ) 5.80 Hz, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.73 (m, 2
H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.18 (d, J ) 5.8 Hz, CCH2-
OC(O)CH2CH(CH(CH3)2)2), 2.42-2.53 (m, 3 H, CdCHCH2-
CH2C6H5 and H-3a), 2.61 (dm, J ≈ 16 Hz, 1 H, H-3b), 2.80 (t, J )
7.4 Hz, CdCHCH2CH2C6H5), 3.58 (AB q, J ) 12.3 Hz, 2 H, CCH2-
OH), 4.13 (AB q, J ) 11.9 Hz, 2 H, CCH2OC(O)CH2CH(CH-
(CH3)2)2), 6.74 (m, 1 H, CdCHCH2CH2C6H5), 7.14-7.32 (m, 5
H, CdCHCH2CH2C6H5); 13C NMR (100 MHz, CDCl3) δ 18.64,
18.69, 21.28, 21.30, 29.29, 29.34, 29.63, 32.13, 32.73, 34.12, 46.85,
64.10, 65.28, 83.06, 126.29, 126.92, 128.40, 128.50, 140.19, 140.48,
169.70, 174.62; FAB-MS (m/z, relative intensity) 403 (MH+, 100).
Anal. (C24H34O5) C, H.
(E)-{2-(Hydroxymethyl)-4-[(2-methoxyphenyl)methylene]-5-
oxo-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-(methylethyl)pen-
tanoate ((E)-17, (E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 2-(MeO)-
C6H4). According to general procedure L, (E)-XI (R1 ) CH2CH-
(i-Pr)2, R2 ) 2-(MeO)C6H4; 790 mg, 1.6 mmol) was reacted to
give (E)-17 ((E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 2-(MeO)C6H4; 474
mg, 75% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
0.74, 0.77, 0.84, and 0.85 (d, J ) 6.8 Hz, 12 H, CCH2OC(O)CH2-
CH(CH(CH3)2)2), 1.54 (p, J ≈ 5.7 Hz, 1 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 1.69 (septet, J ≈ 6.5 Hz, 2 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 2.17 (dd, J ) 5.8, 1.3 Hz, 2 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 2.34 (br s,1 H, CCH2OH), 2.97 (dd, J ) 17.6,
2.8 Hz, 1 H, H-3a), 3.12 (dd, J ) 17.6, 3.0 Hz, 1 H, H-3b), 3.70 (br
dd, J ) 12.9, 4.7 Hz, 1 H, CCHHOH), 3.78 (br dd, J ) 12.9, 4.7
Hz, 1 H, CCHHOH), 3.87 (s, 1 H, CdCHC6H4OCH3), 4.26 (AB
q, J ) 11.9 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 6.93 (d, J
) 8.3 Hz, 1 H, CdCHC6H4OCH3), 6.99 (t, J ) 7.9 Hz, 1 H,
CdCHC6H4OCH3), 7.35-7.43 (m, 2 H, CdCHC6H4OCH3), 8.02
(t, J ) 2.9 Hz, 1 H, CdCHC6H4OCH3); 13C NMR (100 MHz,
CDCl3) δ 18.65, 21.22, 29.32 32.29, 32.78, 46.83, 55.50, 64.81,
65.48, 83.14, 111.01, 120.39, 123.43, 123.45, 129.02, 131.56,
132.10, 158.50, 171.21, 174.74; FAB-MS (m/z, relative intensity)
405 (MH+, 100), 57 (23). Anal. (C30H38O6) C, H.
(E)-{2-(Hydroxymethyl)-4-[(3-methoxyphenyl)methylene]-5-
oxo-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-(methylethyl)pen-
tanoate ((E)-18, (E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 3-(MeO)-
C6H4). According to general procedure L, (E)-18 ((E)-XII R1 )
CH2CH(i-Pr)2, R2 ) 3-(MeO)C6H4; 222 mg, 0.45 mmol) was
reacted to give (E)-XII ((E)-18, R1 ) CH2CH(i-Pr)2, R2 ) 3-(MeO)-
C6H4; 140 mg, 77% yield) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 0.72, 0.75, (d, J ) 6.8 Hz, 6 H, CCH2OC(O)CH2CH-
(CH(CH3)2)2), 0.81, 0.83 (s, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2),
1.51 (p, J ≈ 5.7 Hz, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.67
(septet, J ≈ 6.5 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.15
(d, J ) 5.7 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.80 (s, 1
H, CCH2OH), 3.03 (dd, J ) 17.7, 2.6 Hz, 1 H, H-3a), 3.23 (dd, J
) 17.7, 2.6 Hz, 1 H, H-3b), 3.72 (br t, 2 H, CCH2OH), 3.82 (s, 1
H, CdCHC6H4OCH3), 4.25 (AB q, J ) 12.0 Hz, 2 H, CCH2OC-
(O)CH2CH(CH(CH3)2)2), 6.94 (dd, J ) 8.2, 1.9 Hz, 1 H,
CdCHC6H4OCH3), 6.99 (s, 1 H, CdCHC6H4OCH3), 7.07 (d, J )
6.8 Hz, 1 H, CdCHC6H4OCH3), 7.34 (t, J ) 7.9 Hz, 1 H,
CdCHC6H4OCH3), 7.53 (br t, 1 H, CdCHC6H4OCH3); 13C NMR
(100 MHz, CDCl3) δ 18.63, 21.20, 29.27, 32.12, 32.74, 46.84,
55.30, 64.69, 65.50, 83.54, 115.48, 115.59, 122.49, 124.53, 129.87,
135.60, 137.03, 159.76, 171.20, 174.61; FAB-MS (m/z, relative
intensity) 405 (MH+, 100), 57 (76). Anal. (C30H38O6) C, H.
(E)-{2-(Hydroxymethyl)-4-[(4-methoxyphenyl)methylene]-5-
oxo-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-(methylethyl)pen-
tanoate ((E)-19, (E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 4-(MeO)-
C6H4). According to general procedure L, (E)-XI (R1 ) CH2CH-
(i-Pr)2, R2 ) 4-(MeO)C6H4; 100 mg, 0.2 mmol) was reacted to
(Z)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl 3-Hydroxybenzoate
((Z)-12, (Z)-XII, R1 ) 3-(OH)C6H4, R2 ) CH2CH(i-Pr)2).
According to general procedure L, (Z)-XI (R1 ) 3-(PhCH2O)C6H4,
R2 ) CH2CH(i-Pr)2; 140 mg, 0.25 mmol) was reacted to give
(Z)-12 ((Z)-XII, R1 ) 3-(OH)C6H4, R2 ) CH2CH(i-Pr)2; 40 mg,
40% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.81
and 0.83 (d, J ) 6.8 Hz, 6 H, CdCHCH2CH(CH(CH3)2)2), 0.87 (t,
J ) 6.8 Hz, 6 H, CdCHCH2CH(CH(CH3)2)2), 1.10 (p, J ) 5.5
Hz, 1 H, CdCHCH2CH(CH(CH3)2)2), 1.75 (m, 2 H, CdCHCH2-
CH(CH(CH3)2)2), 2.59-2.65 (m, 1 H, CdCHCHHCH(CH(CH3)2)2),
2.70-2.82 (m, 2 H, CdCHCHHCH(CH(CH3)2)2 and H-3a), 2.96
(dm, J ) 16.4 Hz, 1 H, H-3b), 3.09 (br s, 1 H CCH2OH), 3.75 (br
dd, J ) 12.1, 4.3 Hz, 1 H, CCHHOH), 3.82 (br dd, J ) 12.1, 4.3
Hz, 1 H, CCHHOH), 4.45 (AB q, J ) 11.9 Hz, 2 H, CCH2OC-
(O)C6H4OH), 6.27 (irregular tt, 1 H, CdCHCH2CH(CH(CH3)2)2),
6.69 (s, 1 H, CCH2OC(O)C6H4OH), 7.09 (ddd, 1 H, J ) 8.1, 2.5,
0.9 Hz, CCH2OC(O)C6H4OH), 7.29 (dd, J ) 8.4, 7.4 Hz, 1 H,
CCH2OC(O)C6H4OH), 7.49-7.54 (m, 2 H, CCH2OC(O)C6H4OH);
13C NMR (100 MHz, CDCl3) δ 19.27, 19.44, 21.53, 21.62, 26.38,
29.24, 29.35, 33.32, 51.09, 64.60, 65.98, 82.98, 116.32, 120.92,
121.87, 122.53, 129.78, 130.30, 148.42, 156.12, 166.23, 169.58;
FAB-MS (m/z, relative intensity) 391 (MH+, 63), 121 (100). Anal.
(C22H30O6) C, H.
(E)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl 4-Hydroxybenzoate
((E)-13, (E)-XII, R1 ) 4-(OH)C6H4, R2 ) CH2CH(i-Pr)2).
According to general procedure L, (E)-XI (R1 ) 4-(PhCH2O)C6H4,
R2 ) CH2CH(i-Pr)2; 230 mg, 0.40 mmol) was reacted to give
(E)-13 ((E)-XII, R1 ) 4-(HO)C6H4, R2 ) CH2CH(i-Pr)2; 93 mg,
1
60% yield) as a white solid: mp 117-118 °C; H NMR (400
MHz, CDCl3) δ 0.78, 0.81, 0.84, and 0.87 (d, J ) 6.8 Hz, 12
H, CdCHCH2CH(CH(CH3)2)2), 1.16 (p, J ) 5.6 Hz, 1 H,
CdCHCH2CH(CH(CH3)2)2), 1.73 (m,
2 H, CdCHCH2CH-
(CH(CH3)2)2), 2.05-2.15 (m, 2 H, CdCHCH2CH(CH(CH3)2)2),
2.76 (dd, J ) 17.3, 2.4 Hz, 1 H, H-3a), 2.92 (dd, J ) 17.3, 2.4 Hz,
1 H, H-3b), 3.07 (br s, 1 H, CCH2OH), 3.79 (AB q, J ) 12.2 Hz,
2 H, CCH2OH), 4.45 (AB q, J ) 12.0 Hz, 2 H, CCH2OC(O)C6H4-
OH), 6.81-6.87 (m, 3 H, CCH2OC(O)C6H4OH and CdCHCH2-
CH(CH(CH3)2)2), 7.50 (br s, 1 H, CCH2OC(O)C6H4OH), 7.80 (d,
J ) 8.8 Hz, 2 H, CCH2OC(O)C6H4OH); 13C NMR (100 MHz,
CDCl3) δ 19.27, 21.42, 21.60, 28.76, 29.08, 29.18, 30.08, 50.25,
64.57, 65.76, 84.05, 115.45, 120.75, 124.82, 132.05, 144.81, 161.15,
166.22, 171.05; FAB-MS (m/z, relative intensity) 391 (MH+, 60),
121 (100). Anal. (C22H30O6‚0.5H2O) C, H.
(Z)-{2-(Hydroxymethyl)-4-[4-methyl-3-(methylethyl)pentyl-
idene]-5-oxo-2,3-dihydrofur-2-yl}methyl 4-Hydroxybenzoate
((Z)-13, (Z)-XII, R1 ) 4-(OH)C6H4, R2 ) CH2CH(i-Pr)2).
According to general procedure L, (Z)-XI (R1 ) 4-(PhCH2O)C6H4,
R2 ) CH2CH(i-Pr)2; 148 mg, 0.26 mmol) was reacted to give
(Z)-13 ((Z)-XII, R1 ) 4-(HO)C6H4, R2 ) CH2CH(i-Pr)2; 60 mg,
58% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.84,
0.85, 0.88, and 0.89 (d, J ) 6.8 Hz, 12 H, CdCHCH2CH(CH-
(CH3)2)2), 1.10 (p, J ) 5.5 Hz, 1 H, CdCHCH2CH(CH(CH3)2)2),
1.76 (m, 2 H, CdCHCH2CH(CH(CH3)2)2), 2.59-2.68 (m, 1 H,
H-3a), 2.72-2.82 (m, 2 H, H-3b and CdCHCHHCH(CH(CH3)2)2),
2.97 (ddd, J ) 16.6, 4.8, 2.4 Hz, 1 H, CdCHCHHCH(CH(CH3)2)2),
3.74 (AB q, J ) 12.2 Hz, 2 H, CCH2OH), 4.43 (AB q, J ) 12.0
Hz, 2 H, CCH2OC(O)C6H4OH), 6.30 (tt, J ) 7.5, 2.2 Hz, 1 H,
CdCHCH2CH(CH(CH3)2)2), 6.84 (m, 2 H, CCH2OC(O)C6H4OH),
7.01 (br s, 1 H, CCH2OC(O)C6H4OH), 7.84 (m, 2 H, CCH2OC-
(O)C6H4OH); 13C NMR (100 MHz, CDCl3) δ 19.32, 19.43, 21.56,
21.62, 26.42, 29.27, 29.33, 33.32, 51.09, 64.40, 65.50, 83.06,
115.44, 120.92, 122.48, 132.09, 148.61, 161.02, 166.28, 169.66;
FAB-MS (m/z, relative intensity) 391 (MH+, 53), 121 (100). Anal.
(C22H30O6) C, H.

3202 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Kang et al.
give (E)-19 ((E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 4-(MeO)C6H4; 50
mg, 60%) as a white powder: mp 97-99 °C; 1H NMR (400 MHz,
CDCl3) δ 0.75, 0.77, 0.84, 0.85 (d, J ) 6.8 Hz, 12 H, CCH2OC-
(O)CH2CH(CH(CH3)2)2), 1.55 (p, J ) 5.8 Hz, 1 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 1.70 (sept, J ≈ 6.6 Hz, 2 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 2.18 (d, J ) 5.8 Hz, 2 H, CCH2OC(O)CH2CH-
(CH(CH3)2)2), 2.21 (t, J ) 6.9 Hz, 1 H, CCH2OH), 3.01 (dd, J )
17.5, 2.8 Hz, 1 H, H-3a), 3.18 (dd, J ) 17.5, 2.8 Hz, 1 H, H-3b),
3.72 (dd, J ) 12.1, 6.8 Hz, 2 H, CCHHOH), 3.78 (dd, J ) 12.1,
6.8 Hz, 2 H, CCHHOH), 3.86 (s, 1 H, CdCHC6H4OCH3), 4.27
(AB q, J ) 11.9 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 6.94-
6.98 (m, 2 H, CdCHC6H4OCH3), 7.44-7.48 (m, 2 H, CdCHC6H4-
OCH3), 7.53 (t, J ) 2.8 Hz, 1 H, CdCHC6H4OCH3); 13C NMR
(100 MHz, CDCl3) δ 18.68, 21.26, 29.33, 32.26, 32.79, 46.87,
61.11, 64.90, 65.48, 83.05, 114.47, 120.93, 127.15, 131.97, 137.18,
161.10, 161.76, 174.76; FAB-MS (m/z, relative intensity) 405
(MH+, 41), 57 (100). Anal. (C30H38O6‚0.1H2O) C, H.
(E)-{2-(Hydroxymethyl)-4-[(2-hydroxyphenyl)methylene]-5-
oxo-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-(methylethyl)pen-
tanoate ((E)-20, (E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 2-(OH)C6H4).
According to general procedure L, (E)-XI (R1 ) CH2CH(i-Pr)2,
R2 ) 2-(PhCH2O)C6H4; 430 mg, 0.75 mmol) was reacted to give
(E)-20 ((E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 2-(HO)C6H4; 130 mg,
44% yield) as a yellow foam: 1H NMR (400 MHz, CDCl3) δ 0.74,
0.76, 0.83, and 0.84 (d, J ) 6.8 Hz, 12 H, CCH2OC(O)CH2CH-
(CH(CH3)2)2), 1.54 (p, J ) 5.8 Hz, 1 H, CCH2OC(O)CH2CH(CH-
(CH3)2)2), 1.69 (m, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.94
(br s, 1 H, CCH2OH), 2.18 (d, J ) 5.8 Hz, 2 H, CCH2OC(O)CH2-
CH(CH(CH3)2)2), 2.93 (br s, 1 H, CdCHC6H4OH), 3.00 (dd, J )
17.6, 2.8 Hz, 2 H, H-3a), 3.19 (dd, J ) 17.6, 2.9 Hz, 2 H, H-3b),
3.75 (AB q, J ) 12.1 Hz, 2 H, CCH2OH), 4.26 (AB q, J ) 12.0
Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 6.89-6.92 (m, 2 H,
CdCHC6H4OH), 7.22-7.28 (m, 1 H, CdCHC6H4OH), 7.36 (m, 1
H, CdCHC6H4OH), 8.11 (t, J ) 2.8 Hz, 1 H, CdCHC6H4OH);
13C NMR (100 MHz, CDCl3) δ 18.62, 18.68, 21.22, 21.24, 29.31,
32.23, 32.78, 46.90, 64.76, 65.44, 83.90, 116.45, 120.32, 121.67,
122.89, 129.01, 131.77, 132.84, 155.98, 172.61, 174.91; FAB-MS
(m/z, relative intensity) 391 (MH+, 66), 57 (100). Anal. (C22H30O6)
C, H.
(p, J ) 5.8 Hz, 1 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.70
(irregular septet, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.20 (d,
J ) 5.8 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 2.98 (dd, J )
17.5, 2.6 Hz, 1 H, H-3a), 3.19 (dd, J ) 17.5, 2.6 Hz, 1 H, H-3b),
3.45 (br t, J ) 5.7 H, 1 H, CCH2OH), 3.74 (dd, J ) 12.2, 6.0 Hz,
1 H, CCHHOH), 3.86 (dd, J ) 12.2, 6.0 Hz, 1 H, CCHHOH),
4.29 (AB q, J ) 11.9 Hz, 2 H, CCH2OC(O)CH2CH(CH(CH3)2)2),
6.87 (d, J ) 8.7 Hz, 2 H, CdCHC6H4OH), 7.27 (d, J ) 8.9 Hz, 2
H, CdCHC6H4OH), 7.43 (t, J ) 2.6 Hz, 1 H, CdCHC6H4OH);
13C NMR (100 MHz, CDCl3) δ 18.62, 18.68, 21.22, 21.25, 29.29,
31.17, 32.80, 46.92, 64.78, 65.56, 83.66, 116.08, 120.39, 126.59,
132.29, 137.58, 158.22, 172.37, 175.00; FAB-MS (m/z, rela-
tive intensity) 391 (MH+, 100), 57 (73). Anal. (C22H30O6‚0.2H2O)
C, H.
Acknowledgment. This research was supported by the
Intramural Research Program of the NIH, National Cancer
Institute, Center for Cancer Research. We thank Christina Torres
for technical assistance in the biological analysis. This research
has been funded in part with federal funds from the National
Cancer Institute, National Institutes of Health, under Contract
N01-CO-12400. The content of this paper does not necessarily
reflect the views or policies of the Department of Health and
Human Services, nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S.
Government.
Supporting Information Available: Combustion analysis
1
results for compounds III-VI, and IX, XI-XII and H and 13C
NMR spectra of compounds 1-22. This material is available free
of charge via the Internet at http://pubs.acs.org.
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(400 MHz, CDCl3) δ 0.72 and 0.74 (d, J ) 6.8 Hz, 6 H, CCH2-
OC(O)CH2CH(CH(CH3)2)2), 0.81 (d, J ) 6.8 Hz, 6 H, CCH2OC-
(O)CH2CH(CH(CH3)2)2), 1.53 (p, J ) 5.8 Hz, 1 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2),1.67(septet,J)6.7Hz,2H,CCH2OC(O)CH2CH-
(CH(CH3)2)2), 2.18 (d, J ) 5.7 Hz, 2 H, CCH2OC(O)CH2CH(CH-
(CH3)2)2), 3.00 (dd, J ) 17.9, 2.7 Hz, 1 H, H-3a), 3.25 (dd, J )
17.9, 2.7 Hz, 1 H, H-3b), 3.50 (br t, 1 H, CCH2OH), 3.72 (br dd,
J ≈ 11.6, 4.0 Hz, 1 H, CCHHOH), 3.82 (br dd, J ≈ 11.6, 4.0 Hz,
1 H, CCHHOH), 4.25 (AB q, J ) 12.0 Hz, 2 H, CCH2OC(O)-
CH2CH(CH(CH3)2)2), 6.88-7.00 (m, 3 H, CdCHC6H4OH), 7.22-
7.28 (m, 4 H, CdCHC6H4OH), 7.47 (t, J ) 2.6 Hz, 1 H,
CdCHC6H4OH); 13C NMR (100 MHz, CDCl3) δ 18.59, 18.66,
21.20, 21.22, 29.28 32.12, 32.79, 46.93, 64.59, 65.58, 83.97, 116.74,
117.55, 122.47, 124.12, 130.06, 135.48, 137.44, 156.38, 172.01,
175.02; FAB-MS (m/z, relative intensity) 391 (MH+, 100), 57 (100).
Anal. (C22H30O6) C, H.
(E)-{2-(Hydroxymethyl)-4-[(4-hydroxyphenyl)methylene]-5-
oxo-2,3-dihydrofur-2-yl}methyl 4-Methyl-3-(methylethyl)pen-
tanoate ((E)-22, (E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 4-(OH)C6H4).
According to general procedure L, (E)-XI (R1 ) CH2CH(i-Pr)2,
R2 ) 4-(PhCH2O)C6H4; 200 mg, 0.35 mmol) was reacted to give
(E)-22 ((E)-XII, R1 ) CH2CH(i-Pr)2, R2 ) 4-(HO)C6H4; 81 mg,
60% yield) as a white foam: 1H NMR (400 MHz, CDCl3) δ 0.74
and 0.76 (d, J ) 6.8 Hz, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2),
0.83 (d, J ) 6.8 Hz, 6 H, CCH2OC(O)CH2CH(CH(CH3)2)2), 1.55

Conformationally Strained Analogues of DAG
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