Conformationally constrained analogues of diacylglycerol. 10. Ultrapotent protein kinase C ligands based on a racemic 5-disubstituted tetrahydro-2-furanone template

Article abstract of DOI:10.1021/jm950276v

5,5-Bis(hydroxymethyl)tetrahydro-2-furanone and its isomer 4,4-bis(hydroxymethyl)tetrahydro-2-furanone were investigated as possible templates for the construction of conformationally constrained analogues of the biologically important second messenger, diacylglycerol (DAG). The former lactone contains embedded within its structure an exact glycerol moiety, while in the latter the ring oxygen has been transposed to the other side of the carbonyl group. All target compounds were synthesized as racemates from 1,3-dihydroxy-2-propanone. The 5,5-bis(hydroxymethyl)tetrahydro-2-furanone proved to be the better template for the construction of DAG surrogates that were demonstrated to have high binding affinities for the biological target, protein kinase C (PK-C). The simplest target compounds derived from this template (3e and 3f) have one of the hydroxyl moieties functionalized either as a myristate or as an oleate ester. The simplest target compound (9c) derived from the ineffective 4,4-bis-(hydroxymethyl)tetrahydro-2-furanone template was investigated only with a myristoyl acyl chain. Reducing the long acyl chain to an acetyl moiety and attaching a compensating lipophilic chain to the lactone ring as an α-alkylidene moiety produced compounds 10e and 10f (Z-isomers) and 11e and 11f (E-isomers), which were constructed on the more effective 5,5-bis(hydroxymethyl)tetrahydro-2-furanone template. Targets 14c (Z-isomer) and 15c (E-isomer) were derived, in turn, from 4,4-bis(hydroxymethyl)tetrahydro-2-furanone. The affinities of these ligands for PK-C were assessed in terms of their ability to displace bound [³H-20]phorbol 12,13-dibutyrate (PDBU) from the single isozyme PK-Cα. The biological data support the hypothesis that the increase in binding affinity for PK-C shown by some of these constrained DAG mimetics appears to be entropic in nature. Two of the designed ligands (10e and 10f) showed the highest affinities (34 and 24 nM, respectively) reported so far for a DAG analogue. Assuming that the interaction between these racemic compounds and PK-C is stereospecific, the potency of the active enantiomer is anticipated to double.

Full text of DOI:10.1021/jm950276v

J . Med. Chem. 1996, 39, 19-28
19
Con for m a tion a lly Con str a in ed An a logu es of Dia cylglycer ol. 10. Ultr a p oten t
P r otein Kin a se C Liga n d s Ba sed on a Ra cem ic 5-Disu bstitu ted
Tetr a h yd r o-2-fu r a n on e Tem p la te1
Rajiv Sharma,† J eewoo Lee,† Shaomeng Wang,† George W. A. Milne,† Nancy E. Lewin,‡ Peter M. Blumberg,‡ and
Victor E. Marquez*,†
Laboratory of Medicinal Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, and Molecular
Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20892
Received April 12, 1995X
5,5-Bis(hydroxymethyl)tetrahydro-2-furanone and its isomer 4,4-bis(hydroxymethyl)tetrahydro-
2-furanone were investigated as possible templates for the construction of conformationally
constrained analogues of the biologically important second messenger, diacylglycerol (DAG).
The former lactone contains embedded within its structure an exact glycerol moiety, while in
the latter the ring oxygen has been transposed to the other side of the carbonyl group. All
target compounds were synthesized as racemates from 1,3-dihydroxy-2-propanone. The 5,5-
bis(hydroxymethyl)tetrahydro-2-furanone proved to be the better template for the construction
of DAG surrogates that were demonstrated to have high binding affinities for the biological
target, protein kinase C (PK-C). The simplest target compounds derived from this template
(3e and 3f) have one of the hydroxyl moieties functionalized either as a myristate or as an
oleate ester. The simplest target compound (9c) derived from the ineffective 4,4-bis-
(hydroxymethyl)tetrahydro-2-furanone template was investigated only with a myristoyl acyl
chain. Reducing the long acyl chain to an acetyl moiety and attaching a compensating lipophilic
chain to the lactone ring as an R-alkylidene moiety produced compounds 10e and 10f (Z-isomers)
and 11e and 11f (E-isomers), which were constructed on the more effective 5,5-bis(hydroxym-
ethyl)tetrahydro-2-furanone template. Targets 14c (Z-isomer) and 15c (E-isomer) were derived,
in turn, from 4,4-bis(hydroxymethyl)tetrahydro-2-furanone. The affinities of these ligands for
PK-C were assessed in terms of their ability to displace bound [3H-20]phorbol 12,13-dibutyrate
(PDBU) from the single isozyme PK-CR. The biological data support the hypothesis that the
increase in binding affinity for PK-C shown by some of these constrained DAG mimetics appears
to be entropic in nature. Two of the designed ligands (10e and 10f) showed the highest affinities
(34 and 24 nM, respectively) reported so far for a DAG analogue. Assuming that the interaction
between these racemic compounds and PK-C is stereospecific, the potency of the active
enantiomer is anticipated to double.
In tr od u ction
of any DAG, we have attempted to increase the potency
of the latter by designing analogues which constrain the
glycerol backbone in order to reduce the entropy penalty
associated with binding. Although our original attempts
suggested that this concept was plausible, the first
conformationally constrained analoguessbuilt on a
2-deoxy-L-ribonolactone templateswere no more potent
than the parent DAG molecule with an equivalent
lipophilic acyl chain.11 We later concluded that minor
deviations in the orientation of important pharmacoph-
ore atoms, imposed by the structural constraints of the
2-deoxy-L-ribonolactone ring, canceled the entropic ad-
vantage.12 In this paper, we describe a new lactone
template which leads to compounds with a significant
increase in binding affinity for PK-C relative to the
equivalent linear DAG molecule. This new lactone
template can be envisaged as resulting from an idealized
intramolecular cyclization of DAG (path a, Chart 1) that
requires an additional carbon atom to complete the five-
membered ring structure (template I). Two additional
modifications of template I were also considered. First,
template I was transformed into template II (path b,
Chart 1) to study the effects of a reversed lactone
function. We have shown previously that a comparable
reversal of the ester function on the acyl chain of
2-deoxy-L-ribonolactone analogues of DAG did not re-
Protein kinase C (PK-C) plays a pivotal role in cell
signaling by functioning as a central signal transducing
element. These signals are generated by a broad range
of ligands which produce the lipid second messenger,
diacylglycerol (DAG).2,3 The identification of PK-C as
the primary receptor for the phorbol esters,4-7 and the
demonstration that these esters bind to PK-C with
extremely high affinities at a site used by DAG causing
the activation of the enzyme,8 has made the phorbol
esters valuable tools for studying the role of PK-C in
many cellular functions.2 However, the phorbol esters
may act supraphysiologically and activate responses
that are not normally elicited by the physiologically
relevant activator DAG.9 This, combined with evidence
for the existence of additional phorbol ester receptors
with different biological functions,10 suggests the utility
of more specific and potent DAG agonists.
Since the phorbol esters bind to PK-C with affinities
that are several orders of magnitude higher than those
† Laboratory of Medicinal Chemistry, Developmental Therapeutics
Program.
‡ Molecular Mechanisms of Tumor Promotion Section, Laboratory
of Cellular Carcinogenesis and Tumor Promotion.
X Abstract published in Advance ACS Abstracts, November 1, 1995.
This article not subject to U.S. Copyright. Published 1996 by the American Chemical Society

20 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Sharma et al.
Ch a r t 1
Sch em e 2
Sch em e 1
lactone was achieved by hydroboration of the double
bond in 2c and 2d followed immediately by oxidation
with pyridinium chlorochromate (PCC).16 Under these
reaction conditions, the ensuing cyclization to the lactol
proceeded with further oxidation to give, respectively,
the antepenultimate and penultimate intermediate lac-
tones 3c and 3d . Removal of the silyl ether protection
from 3d with tetrabutylammonium fluoride (TBAF)
afforded the target lactone 3e, while 3c was reacted
with NH4F17 to give the free lactone 3a . Monoacylation
of lactone 3a gave the oleate (3f).
Template II (Chart 1) required the same starting
material, but this time protection was achieved with the
less sterically demanding tert-butyldimethylsilyl chlo-
ride to give 4a (Scheme 2). Wadsworth-Emmons
reaction of 4a with the stabilized ylide methyl (triph-
enylphosphoranylidene)acetate gave 5a , which was
reduced to the allylic alcohol 6a with diisobutylalumi-
num hydride (DIBAL). Claisen rearrangement of the
intermediate enol ester, formed by reacting 6a with
triethyl orthoacetate, produced the pivotal intermediate
ester 7a which cyclized to lactone 8b under acidic
conditions. Acylation of the primary alcohol function
provided the myristate ester 8c, and oxidation of the
terminal olefin with OsO4/NaIO4 gave the corresponding
aldehyde which was readily converted to the desired
target lactone 9c after borohydride reduction.
duce PK-C binding affinity.13 Hence, placing the oxygen
at the other side of the carbonyl, as in template II,
maintains the carbonyl group in the same relative
disposition (Chart 1). The second modification consisted
of the abbreviation of the long acyl function in templates
I and II to a simple acetyl function and the extension
of the lipophilic chain from the lactone ring as an
R-alkylidene appendage (Chart 1). Implementation of
this change with the 2-deoxy-L-ribonolactone analogues
of DAG investigated earlier led to compounds with a
10-fold increase in binding affinity for PK-C.14 Initially,
all the compounds constructed on templates I and II
were investigated in racemic form.
Ch em istr y
Template I (Chart 1) was built from 1,3-dihydroxy-
acetone (1a ) according to Scheme 1 where only the
principal steps are shown. Two different approaches
were followed. Initially, the monoprotected tert-butyl-
diphenylsilyl ether 1b was treated with myristoyl
chloride to give 1d . Alternatively, 1a was fully pro-
tected as 1c. Conversion of 1c and 1d to the tertiary
homoallylic alcohols 2c and 2d was achieved, respec-
tively, with either allylmagnesium bromide or allyltri-
methylsilane/TiCl4.15 Following the methodology of
Mandal and Mahajan a “one-pot” synthesis of the
The abbreviation of the acyl function and extension
of the lipophilic chain from the lactone ring was
performed in a similar manner for templates I and II
(Chart 1). Following our reported methodology,14 lac-
tones 3c (Scheme 3) and 13 (Scheme 4) were treated
with the corresponding aldehydes (myristoyl or oleoyl
aldehyde) to give ca. 70% of the intermediate alcohol
which was readily dehydrated to a separable mixture
of the corresponding Z- (10a ,b and 14a ) and E-isomers
(11a ,b and 15a ). The geometry of the exocyclic double

Conformationally Constrained Analogues of Diacylglycerol. 10
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 21
Ch a r t 2
Sch em e 3
Ta ble 1. Apparent Ki (nM) Values for Ligands as Inhibitors of
PDBU Binding to PK-CR
Sch em e 4
favor of the new template I (Chart 2). On the other
hand, the equivalent isolactone 9c constructed with
template II displayed very poor affinity for PK-C (Table
1). For the active template I, changes in the constitu-
tion of the acyl chain were also accompanied by in-
creases in affinities consistent with the previously
observed trend with the 2-deoxy-L-ribonolactones.18
Hence, the oleate analogue (3f) was ca. 1.5 times more
potent than the myristate 3e (Table 1).
With either template I or II, where the acyl function
had been abbreviated to a simple acetyl and the lipo-
philic component incorporated in the form of an R-alky-
lidene chain (Chart 1), PK-C binding affinities increased
in each case (Table 1). However, the corresponding
increases observed for template II were minimal, sug-
gesting that it was indeed a poor template for a rigid
diacylglycerol backbone. On the other hand, the in-
creases observed for template I were quite impressive.
The simplest of the compounds with a CH3(CH2)12 alkyl
chain (10e) displayed unprecedented potency for a DAG
analogue (Ki ) 35 nM). This suggests that the spatial
disposition of pharmacophores achieved with this tem-
plate is probably very close to that present in PK-C-
bound DAG. Also, a 2-fold difference in affinity was
confirmed for the Z-isomer (10e) relative to the corre-
sponding E-isomer (11e). The magnitude of this differ-
ence was similar to that observed for the equivalent
R-alkylidene isomers built with our previous 2-deoxy-
1
bond in these isomers was assigned by H NMR spec-
troscopy which showed the â-cis vinyl protons ca. 0.5
ppm downfield from the corresponding â-trans protons.14
Removal of the protective ether groups from these
compounds, followed by formation of the corresponding
monoacetates, gave the desired targets 10e,f and 11e,f
(template I), and 14c and 15c (template II). Catalytic
hydrogenation of either 10e or 11e afforded compound
12 as a mixture of epimers.
Biologica l Resu lts
The affinity of these ligands for PK-C was assessed
in terms of their ability to displace bound [3H-20]phorbol
12,13-dibutyrate (PDBU) from a recombinant single
isozyme PK-CR. The inhibition curves obtained for
these ligands were of the type expected for competitive
inhibition, and the ID50 values were determined by fit
of the data points to the theoretical noncooperative
competition curve.11 The Ki’s for inhibition of binding
were calculated from the ID50 values. A comparison
between the simplest compound derived from template
I (3e) and the equivalent lactone derived from our
previous 2-deoxy-L-ribonolactone template (16)11 re-
vealed an order of magnitude difference in affinity in

22 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Sharma et al.
L-ribonolactone template14 and supports our view that
the orientation of the alkyl chain is a key factor for the
optimization of binding. The incorporation of an ad-
ditional midpoint unsaturation to mimic the oleate side
chain in compounds 10f and 11f resulted in a slight,
but definitive, increase in affinity. However, in these
compounds, the difference favoring the Z-isomer almost
disappeared. It is possible that for these compounds the
midpoint cis double bond further along the alkyl chain
compensates for the less favorable orientation of the
E-isomer. Ultimately, removal of the unsaturation gave
the corresponding R-alkyl analogue as an inseparable
mixture of epimers (12) which showed a reduced level
of affinity for PK-C (Ki ) 75 ( 2.5 nM) similar to that
shown by the less effective E-isomer 11e (78 ( 4.7 nM).
These investigations have produced a conformation-
ally restricted DAG molecule (10f) with the highest
affinity (Ki ) 24 nM) reported to date for a DAG
analogue. Structurally, 10f represents a constrained
form of the lipophilically equivalent 1-oleoyl-2-acetyl-
sn-glycerol (OAG), which under the same experimental
conditions was 10-fold less potent (Ki ) 230 nM)19 than
10f. It is proposed that the 10-fold increase in binding
affinity for 10f is derived from the highly complemen-
tary binding of this preorganized OAG analogue where
the conformational entropic penalty associated with the
binding of the linear and more flexible molecule is
reduced.20 Finally, assuming that the interaction be-
tween 10f and PK-C is stereospecific, as is the case with
DAGs,21 one can anticipate a two-fold increase in
binding affinity for the active enantiomer. The realiza-
tion of such a goal through the chiral synthesis of the
active enantiomer is the subject of the following paper.
F igu r e 1. Superposition of core template I and core template
II.
The reason for selecting this quaternary carbon as the
anchor point is that it allows the superposition of the
hydroxymethyl pharmacophore in both lactones. Al-
though we have no proof that this pharmacophore binds
first to the receptor, a recent X-ray study of the Cys2
domain of PK-Cδ complexed to phorbol 13-acetate
showed that hydrogen bonding of the equivalent hy-
droxymethyl pharmacophore in phorbol was the most
important interaction in the complex.23 Therefore, if in
this hypothetical model we assume that the spatial
disposition achieved with template I approximates the
ideal conformation of bound DAG, our comparison would
explain the inadequacy of template II (Figure 1). When
the same conformational analysis was extended to
compounds 10e and 10f (template I), which have the
additional R-alkylidene chain, the molecules superim-
posed nicely on 3e with a root mean square (rms)
deviation of 0.0580 Å for all non-hydrogen atoms on the
lactone rings. This means that introduction of an sp2
carbon adjacent to the carbonyl function did not have a
major conformational effect, and the ring puckering of
the potent ligands 3e, 10e, and 10f remained virtually
identical. Similarly, the lactone rings of the inactive
compounds 9c, 14c and 15c, superimposed nicely with
each other (rms ) 0.0510 Å).
Molecu la r Mod elin g
The dramatic difference in binding affinities between
the isosteric lactones 3e (138 nM) and 9c (9810 nM) was
at first intriguing since the only structural difference
between the two compounds was the transposed lactone
oxygen from one side of the carbonyl to the other. This
enormous variance, which was not observed when the
same transposition was performed on the acyl chain of
DAG analogues built with the 2-deoxy-L-ribonolactone
template,13 suggested that such an operation in the
cyclic system had caused a significant change in the
conformation of the lactone ring. Indeed, a search in
the Cambridge Structural Database22 for the uncon-
strained “Core Templates” identified four compounds
corresponding to template I (present in compound 3e,
Figure 1) and three compounds corresponding to tem-
plate II (present in compound 9c, Figure 1) which
showed significant differences in ring puckering. Not
surprisingly, the X-ray structures within each group
showed a virtually identical form of ring puckering.
When these isolated templates (I and II) were energy
minimized and compared, it could be seen that the
different forms of puckering could cause a severe
mistmach of pharmacophores, although the conforma-
tional barrier to force one conformation into the other
was not very large (3.0 kcal/mol) according to QUANTA
CHARMm. In order to visualize the displacement of
pharmacophores, template I and template II were
superimposed on each other using the quaternary
carbon on the ring as the anchor point. When this was
done, the ring carbonyl pharmacophores appeared se-
verely displaced from each other by 1.620 Å (Figure 1).
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All chemical reagents were com-
mercially available. Melting points were determined on a Mel-
Temp II apparatus, Laboratory Devices, USA, and are uncor-
rected. Silica gel column chromatography was performed on
silica gel 60, 230-400 mesh (E. Merck). Proton and 13C NMR
spectra were recorded on a Bruker AC-250 instrument at 250
and 62.9 MHz, respectively. Spectra were referenced to the
solvent in which they were run (7.24 ppm for CDCl3). Infrared
spectra were recorded on a Perkin-Elmer 1600 Series FTIR.
Elemental analyses were performed by Atlantic Microlab, Inc.,
Atlanta, GA.
An a lysis of In h ibition of [3H]P DBU Bin d in g by Non -
r a d ioa ctive Liga n d s. Enzyme-ligand interactions were
analyzed by competition with [3H]PDBU binding essentially
as described in our previous work,11 except that the PK-C
preparation used here was the single isozyme PK-CR. This
recombinant PK-CR was expressed in the baculovirus system
and was isolated as described in ref 19. The ID50 values were
determined from the competition curves, and the correspond-
ing Ki values for the ligands were calculated from the ID50
values as described before.11,19 Values represent the mean (
standard error (three determinations).
Molecu la r Mod elin g. All structures were modeled using
QUANTA 3.1 on a Silicon Graphics Indigo with CHARMm 2.2

Conformationally Constrained Analogues of Diacylglycerol. 10
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 23
1
force field parameters. Semi-empirical quantum mechanics
studies using AM1 Hamiltonian parameters within Mopac 6.0,
performed on a Convex mini-supercomputer, confirmed the
results obtained using CHARMm.
liquid: IR (neat) 3565, 1427 cm1; H NMR (CDCl3) δ 1.05 (s,
18 H, C(CH3)3), 2.35 (d, J ) 7.2 Hz, 2 H, CH2CHdCH2), 2.50
(s, 1 H, OH), 3.65 (AB q, J ) 9.8 Hz, 4 H, CH2OSi), 5.00 (m,
2 H, CHdCH2), 5.75 (m, 1 H, CHdCH2), 7.30-7.70 (m, 20 H,
Ph); 13C NMR (CDCl3) δ 19.28, 26.88, 38.40, 66.05, 74.39,
117.97, 127.70, 129.71, 133.08, 133.29, 135.62. Anal. (C38H48O3-
Si2) C, H.
1-O-(t er t -Bu t yld ip h e n ylsilyl)-1,3-d ih yd r oxy-2-p r o-
p a n on e (1b). tert-Butylchlorodiphenylsilane (0.76 g, 2.7
mmol) was added over a period of 10 min to a chilled (0 °C)
solution of 1,3-dihydroxyacetone (1a , 0.5 g, 2.7 mmol) and
(dimethylamino)pyridine (DMAP, 0.085 g, 0.7 mmol) in dry
pyridine (20 mL). The reaction mixture was allowed to reach
room temperature, and stirring was continued for a total of
16 h. After the addition of ice-cold water (100 mL), the mixture
was extracted with EtOAc (3 × 20 mL). The combined organic
extract was washed with 1 N HCl solution (3 × 10 mL) and
water (15 mL) and dried over Na2SO4. The residue obtained
after removing the organic solvent was purified by flash
column chromatography over silica gel with mixtures of
hexane/EtOAc (95:5 followed by 85:15) as eluants to give 1b
2-Hyd r oxy-2-[[(ter t-bu tyld ip h en ylsilyl)oxy]m eth yl]-1-
(tetr a d eca n oyloxy)-4-p en ten e (2d ). A solution of TiCl4 in
CH2Cl2 (1 M, 6.3 mL) was added to a stirred solution of 1d
(2.25 g, 4.2 mmol) in CH2Cl2 (50 mL) at room temperature.
After 5 min, neat allyltrimethylsilane (1.43 g, 12.5 mmol) was
rapidly added, and stirring was continued for 40 min. The
reaction was quenched with ice-cold water (50 mL) and
extracted with ether (3 × 50 mL). The combined ether extract
was washed with water (3 × 25 mL), dried (Na2SO4), and
evaporated under reduced pressure. The residue was chro-
matographed by flash column chromatography over silica gel.
The appropriate fractions, eluted with hexane containing
increasing proportions of EtOAc (3-4%), were combined and
evaporated under reduced pressure to give 2d (1.87 g, 77%)
as an oil: IR (neat) 3486, 1741 cm-1; 1H NMR (CDCl3) δ 0.85
(distorted t, 3 H, CH3), 1.10 (s, 9 H, C(CH3)3), 1.30 (m, 20 H,
CH3(CH2)10CH2CH2CO), 1.60 (m, 2 H, CH3(CH2)10CH2CH2CO),
2.25 (t, J ) 7.4 Hz, 2 H, CH3(CH2)10CH2CH2CO), 2.35 (br d, J
) 8.3 Hz, 2 H, CH2CHdCH2), 2.50 (s, 1 H, OH), 3.52 (s, 2 H,
CH2OSi), 4.10 (AB q, J ) 13.4 Hz, 2 H, CH2OCO), 5.00-5.10
(m, 2 H, CHdCH2), 5.70-5.90 (m, 1 H, CHdCH2), 7.30-7.70
(m, 10 H, Ph); 13C NMR (CDCl3) δ 14.10, 19.26, 22.67, 24.88,
26.84, 29.15, 29.25, 29.34, 29.45, 29.59, 29.63, 29.66, 31.90,
34.18, 38.88, 66.08, 66.12, 73.23, 118.91, 127.77, 129.87,
132.38, 135.58, 173.64. Anal. (C36H56O4Si) C, H.
(0.472 g, 52%) as an oil: IR (neat) 3444 and 1732 cm-1 1H
;
NMR (CDCl3) δ 1.10 (s, 9 H, C(CH3)3), 4.30 (s, 2 H, CH2OSi),
4.60 (s, 2 H, CH2OH), 7.30-7.70 (m, 10 H, Ph); 13C NMR
(CDCl3) δ 19.20, 26.71, 66.76, 68.30, 128.03, 130.23, 132.00,
135.44, 210.28. Anal. (C19H24O3Si) C, H.
1,3-Bis-O-(ter t-bu tyldiph en ylsilyl)-1,3-dih ydr oxy-2-pr o-
p a n on e (1c). tert-Butylchlorodiphenylsilane (50 g, 181.9
mmol) was added over a period of 30 min to a chilled (0 °C)
solution of 1,3-dihydroxyacetone (1a , 7.28 g, 0.42 mmol) and
DMAP (2.47 g, 20.2 mmol) in dry pyridine (100 mL). The
reaction mixture was allowed to reach room temperature, and
stirring was continued for a total of 4 days. The reaction
mixture was poured over crushed ice (500 g) and left overnight.
The precipitated solid was filtered and washed with water (ca.
500 mL). The filtrate was extracted with EtOAc (3 × 150 mL),
and the combined organic extract was washed with 1 N HCl
(3 × 100 mL) and water (2 × 100 mL), dried (Na2SO4), and
evaporated under reduced pressure to give a white solid. The
solid was recrystallized from EtOAc/hexane to a give 1c (41.7
5-Bis[[(ter t-bu tyldiph en ylsilyl)oxy]m eth yl]tetr a h yd r o-
2-fu r a n on e (3c). A stirred solution of 2c (1.92g, 3.15 mmol)
in dry THF (30 mL) at -78 °C was treated dropwise with a
THF solution of BH3‚SMe2 (2 M, 3.15 mL) while being
maintained under a blanket of argon. The reaction mixture
was allowed to reach room temperature during the course of
24 h, and then it was concentrated under reduced pressure.
The residue obtained was dissolved in dry CH2Cl2 (100 mL)
and treated with pyridinium chlorochromate (PCC,15 g, 69.5
mmol). The dark reaction mixture was stirred at room
temperature for 36 h and was diluted with dry ether (200 mL)
before being filtered through a short silica gel column. The
solution obtained was dried (Na2SO4) and evaporated, and the
residue was purified by flash column chromatography over
silica gel using hexane/EtOAc (94:6) as eluant to give the title
compound 3c (1.28 g, 65%) as a white solid: mp 125.5-126.5
g, 91%) as a white solid: mp 100-101 °C; IR (KBr) 1749 cm-1
;
1H NMR (CDCl3) δ 1.05 (s, 18 H, C(CH3)3), 4.40 (s, 4 H, CH2-
OSi), 7.30-7.60 (m, 20 H, Ph); 13C NMR (CDCl3) δ 19.17, 26.68,
68.53, 127.81, 129.91, 132.58, 135.46, 207.10. Anal. (C35H42O3-
Si2) C, H.
3-O-Tetr a d eca n oyl-1-O-(ter t-bu tyld ip h en ylsilyl)-1,3-d i-
h yd r oxy-2-p r op a n on e (1d ). A solution of 1b (0.170 g, 0.52
mmol), dry pyridine (0.204 g, 2.6 mmol), and DMAP (0.010 g,
0.08 mmol) in dry CH2Cl2 (12 mL) was treated with myristoyl
chloride (0.255 g, 1.03 mmol), and the resulting mixture was
stirred under argon for 24 h. After volatiles were removed,
the residue was partitioned in a mixture of ether (20 mL) and
1 N HCl (10 mL). The ether layer was washed consecutively
with 1 N HCl (10 mL) and water (10 mL) and dried (Na2SO4).
The solvent was removed, and the residue obtained was
purified by flash column chromatography over silica gel with
hexane/EtOAc (96:4) as eluant to provide 1d (0.215 g, 77%)
°C (EtOAc/hexane); IR (KBr) 1784 cm-1; H NMR (CDCl3) δ
1
1.05 (s, 18 H, 2 × C(CH3)3), 2.20 (distorted t, 2 H, H-4a,b), 2.65
(distorted t, 2 H, H-3a,b), 3.70 (AB q, J ) 10.9 Hz, 4 H, CH2-
OSi), 7.30-7.70 (m, 10 H, Ph); 13C NMR (CDCl3) δ 19.19, 25.69,
26.73, 29.41, 66.46, 88.23, 127.72, 127.82, 129.88, 132.52,
132.77, 135.55, 135.61, 177.14. Anal. (C38H46O4Si2) C, H.
as an oil: IR (neat) 1740 cm-1
;
1H NMR (CDCl3) δ 0.90
5-Bis(h yd r oxym et h yl)t et r a h yd r o-2-fu r a n on e (3a ). A
(distorted t, 3 H, CH3), 1.10 (s, 9 H, C(CH3)3), 1.20-1.40 (m,
20 H, CH3(CH2)10CH2CH2CO), 1.65 (m, 2 H, CH3(CH2)10CH2-
CH2CO), 2.40 (t, J ) 7.5 Hz, 2 H, CH3(CH2)10CH2CH2CO), 4.25
(s, 2 H, CH2OSi), 5.02 (s, 2 H, CH2OCO), 7.45-7.65 (m, 10 H,
Ph); 13C NMR (CDCl3) δ 14.10, 19.17, 22.67, 24.85, 26.71, 29.07,
29.25, 29.33, 29.43, 29.59, 29.63, 29.65, 31.90, 33.82, 66.76,
68.78, 127.99, 130.16, 132.04, 135.44, 173.07, 203.31. Anal.
(C33H50O4Si) C, H.
2-Hyd r oxy-2-[[(ter t-bu tyld ip h en ylsilyl)oxy]m eth yl]-1-
[(ter t-bu t yld ip h en ylsilyl)oxy]-4-p en t en e (2c). A stirred
solution of 1c (1.0 g, 1.76 mmol) in THF (12 mL) at 0 °C was
treated with a solution of allylmagnesium bromide (2 M, 1.76
mL), which was added dropwise over a period of 5 min. The
reaction mixture was stirred at 0 °C for 1 h, the reaction was
quenched with 1 N HCl (5 mL), and the mixture was
concentrated under reduced pressure. The residue was ex-
tracted with EtOAc (2 × 20 mL), and the organic extract was
washed with water (10 mL), dried (NaSO4), and concentrated
under vacuum. The residue obtained was purified by flash
column chromatography using silica gel and hexane/EtOAc
(98:2) to give the title compound 2c (0.99 g, 93%) as a colorless
solution of 3c (0.62 g, 1 mmol) and ammonium fluoride (0.37
g, 10 mmol) in MeOH (30 mL) was stirred at room temperature
for 4 days. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by flash column
chromatography on silica gel using EtOAc/MeOH (95:5) as
eluant to give the title compound 3a (0.058 g, 40%) as a clear
liquid: IR (neat) 3415.9, 1760.1 cm-1; 1H NMR (CDCl3) δ 2.15
(distorted t, 2 H, H-4a,b), 2.65 (m, 4 H, H-3a,b, 2 × OH), 3.65
(dd, J ) 12.1, 6.0 Hz, 2 H, CH2OH), 3.80 (dd, J ) 12.1, 6.2 Hz,
2 H, CH2OH); 13C NMR (CDCl3) δ 25.10, 29.17, 65.24, 88.48,
177.57. Anal. (C6H10O4) C, H.
5-[[(ter t-Bu t yld ip h en ylsilyl)oxy]m et h yl]-5-[(t et r a d e-
ca n oyloxy)m eth yl]tetr a h yd r o-2-fu r a n on e (3d ). A stirred
solution of 2d (1.04 g, 1.8 mmol) in dry THF (35 mL) at -78
°C was treated dropwise with a THF solution of BH3‚SMe2 (2
M, 1.8 mL) while being maintained under a blanket of argon.
The reaction mixture was allowed to reach room temperature
during the course of 3 h and was stirred further for 12 h.
Evaporation of the solvent under reduced pressure gave a
residue that was dissolved in dry CH2Cl2 (100 mL) and treated
with pyridinium chlorochromate (PCC, 15 g, 69.5 mmol). The

24 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Sharma et al.
dark reaction mixture was stirred at room temperature for 3
days and was diluted with dry ether (500 mL) before being
filtered through a short silica gel column. The solution
obtained was dried (Na2SO4) and reduced to dryness. The
residue was purified by flash column chromatography over
silica gel using 10% EtOAc in hexane as eluant to give 3d
ambient conditions. The layers were separated, and the
aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic extract was washed with water (15 mL) and
dried (Na2SO4). The solvent was evaporated, and the residue
was purified by flash column chromatography over silica gel
using hexane/EtOAc (95:5) as eluant to give the corresponding
â-hydroxy lactone intermediate (0.641 g, 70%) as a clear
(0.758 g, 71%) as a pale yellow oil: IR (neat) 1785, 1743 cm-1
;
1H NMR (CDCl3) δ 0.87 (distorted t, 3 H, CH3), 1.05 (s, 9 H,
C(CH3)3), 1.25 (m, 20 H, CH3(CH2)10CH2CH2CO), 1.55 (m, 2
liquid: IR (neat) 3510, 1752 cm-1 1H NMR (CDCl3) δ 0.90
;
(distorted t, 3 H, CH3), 1.10 (s, 18 H, 2 × C(CH3)3), 1.20-1.50
(m, 24 H, (CH2)12CH3), 1.90 (distorted t, 1 H, H-4a), 2.20 (dd,
J ) 12.7, 10.1 Hz, 1 H, H-4b), 2.85 (dd, J ) 19.5, 10.1 Hz, 1 H,
H-3), 3.60-3.80 (m, 4 H, CH2OSi), 4.00 (s, 1 H, CHOH), 7.30-
7.70 (m, 20 H, Ph); 13C NMR (CDCl3) δ 14.13, 19.15, 19.21,
22.69, 24.86, 26.56, 26.73, 26.77, 28.99, 29.36, 29.66, 29.69,
31.92, 34.83, 45.87, 65.76, 66.40, 72.16, 86.84, 127.70, 127.80,
127.90, 129.62, 129.90, 129.99, 132.24, 132.54, 132.62, 132.68,
134.79, 135.52, 135.57, 135.61, 179.56. Anal. (C52H74O5Si2)
C, H.
H, CH3(CH2)10CH2CH2CO), 2.00-2.40 (m,
4 H, H-4a,b,
CH3(CH2)10CH2CH2CO), 2.60 (m, 2 H, H-3a,b), 3.70 (AB q, J )
10.8 Hz, 2 H, CH2OSi), 4.20 (AB q, J ) 12.0 Hz, 2 H, CH2-
OCO), 7.30-7.70 (m, 10 H, Ph); 13C NMR (CDCl3) δ 14.10,
19.17, 22.67, 24.78, 25.91, 26.72, 28.87, 29.08, 29.20, 29.33,
29.41, 29.57, 29.62, 31.90, 34.03, 65.64, 66.15, 85.77, 127.88,
130.01, 132.25, 132.50, 135.52, 135.59, 173.15, 176.28. Anal.
(C36H54O5Si) C, H.
5-[(Tetr a d eca n oyloxy)m eth yl]-5-(h yd r oxym eth yl)tet-
r a h yd r o-2-fu r a n on e (3e). A solution of 3d (0.118 g, 0.2
mmol) in THF (3 mL) at room temperature was stirred with a
solution of n-tetrabutylammonium fluoride in THF (1 M, 0.3
mL) for 40 min. The solution was evaporated under vacuum,
dissolved in EtOAc (20 mL), dried (Na2SO4), and concentrated.
The residue obtained was purified by flash column chroma-
tography over silica gel using hexane/EtOAc (7:3) as eluant
to give 3e (0.051 g, 72%) as a white solid: mp 65-66 °C
A solution of this compound (0.583 g, 0.68 mmol) and
triethylamine (0.343 g, 3.4 mmol) in dry CH2Cl2 (12 mL) was
treated with methanesulfonyl chloride (0.196 g, 1.7 mmol), and
the resulting mixture was stirred for 75 min. The reaction
mixture was cooled to 0 °C, treated with 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU, 0.624 g, 4 mmol), and allowed to reach
room temperature. Stirring continued for a total of 4 h. The
volatiles were removed under vacuum, and the residue was
treated with 1 N HCl (10 mL) and extracted with EtOAc (3 ×
10 mL). The combined organic extract was washed with 1 N
HCl (2 × 20 mL) and water (5 mL) and dried (Na2SO4). The
residue was purified by flash column chromatography over
silica gel using hexane/EtOAc (98:2) to give 10a (0.172 g, 30%)
as the less polar compound, followed by 11a (0.345 g, 60.5%).
Both compounds were isolated as oils. 10a : IR (neat) 1759,
(EtOAc/hexane); IR (KBr) 3448, 1763, 1728 cm-1 1H NMR
;
(CDCl3) δ 0.88 (distorted t, 3 H, CH3), 1.30 (m, 20 H,
CH3(CH2)10CH2CH2CO), 1.60 (m, 2 H, CH3(CH2)10CH2CH2CO),
2.00-2.12 (m, 1 H, H-4a), 2.20-2.30 (m, 1 H, H-4b), 2.33 (t, J
) 7.6 Hz, 2 H, CH3(CH2)10CH2CH2CO), 2.45 (t, J ) 6.4 Hz, 1
H, OH), 2.65 (m, 2 H, H-3a,b), 3.60 (dd, J ) 12.1, 5.9 Hz, 1 H,
CHHOH), 3.75 (dd, J ) 12.1, 6.1 Hz, CHHOH), 4.10 (d, J )
12.0 Hz, 1 H, CHHOCO), 4.30 (d, J ) 12.0 Hz, 1 H, CHHOCO);
13C NMR (CDCl3) δ 14.09, 22.65, 24.81, 25.47, 28.79, 29.07,
29.19, 29.32, 29.41, 29.56, 29.60, 31.89, 34.03, 64.82, 65.45,
86.02, 173.48, 176.47; FAB MS (m/ z, relative intensity) 357
(MH+, 100), 211 (C13H27CO+, 35). Anal. (C20H36O5) C, H.
5-{[(Z)-9-Octadecen oyloxy]m eth yl}-5-(h ydr oxym eth yl)-
tetr a h yd r o-2-fu r a n on e (3f). A stirred solution of 3a (0.025
g, 0.17 mmol), dry pyridine (68 mg), and DMAP (2 mg) in dry
CH2Cl2 (5 mL) at 0 °C was treated with oleoyl chloride (0.051
g, 0.17 mmol). After 1 h, the reaction was quenched with
water (3 mL), and the resulting layers were separated. The
aqueous layer was extracted with CH2Cl2 (1 × 5 mL), and the
combined organic extract was washed with 1 N HCl (5 mL)
and water (5 mL) and dried (Na2SO4). The solvent was
evaporated, and the residue obtained was purified by flash
column chromatography over silica gel using hexane/EtOAc
(65:35) as eluant to give the title compound 3f (0.046 g, 66%)
as a white solid: mp 38.5-39.5 °C (EtOAc/hexane); IR (KBr)
3447, 1780, 1738 cm-1; 1H NMR (CDCl3) δ 0.86 (distorted t, 3
H, CH3), 1.30 (m, 20 H, CH3(CH2)6CH2CHdCHCH2(CH2)4CH2-
CH2CO), 1.60 (m, 2 H, CH3(CH2)6CH2CHdCHCH2(CH2)4CH2-
CH2CO),1.90-2.10 (m, 5 H, CH2CHdCHCH2, H-4a), 2.20-2.40
(m, 3 H, CH3(CH2)6CH2CHdCHCH2(CH2)4CH2CH2CO, H-4b),
2.65 (m, 2 H, H-3a,b), 3.61 (d, J ) 12.1 Hz, 1 H, CHHOH), 3.75
(d, J ) 12.1 Hz, CHHOH), 4.12 (d, J ) 12.0 Hz, 1 H,
CHHOCO), 4.30 (d, J ) 12.0 Hz, 1 H, CHHOCO), 5.32 (m, 2
H, CHdCH); 13C NMR (CDCl3) δ 14.09, 22.65, 24.80, 25.48,
27.13, 27.19, 28.76, 29.05, 29.10, 29.29, 29.50, 29.66, 29.73,
31.87, 34.02, 64.82, 65.44, 85.93, 129.67, 130.01, 173.45,
176.36; FAB MS (m/ z, relative intensity) 411 (MH+, 37), 265
(C17H33CO+, 11). Anal. (C24H42O5) C, H.
1670 cm-1 1H NMR (CDCl3) δ 0.85 (distorted t, 3 H, CH3),
;
1.05 (s, 18 H, 2 × C(CH3)3), 1.20-1.60 (m, 22 H, (CH2)11CH3),
2.70 (m, 2 H, dCHCH2), 2.80 (br s, 2 H, H-4a,b), 3.70 (AB q, J
) 10.7 Hz, 2 H, CH2OSi), 6.10 (distorted t, 1 H, dCH), 7.30-
7.70 (m, 20 H, Ph); 13C NMR (CDCl3) δ 14.12, 19.22, 22.68,
26.68, 27.01, 29.18, 29.34, 29.51, 29.59, 29.66, 31.91, 33.15,
66.05, 84.37, 125.34, 127.75, 129.78, 132.70, 132.89, 135.57,
135.61, 143.35, 169.35. Anal. (C52H72O4Si2) C, H.
11a : IR (neat) 1763 and 1681 cm-1; 1H NMR (CDCl3) δ 0.85
(distorted t, 3 H, CH3), 1.00 (s, 18 H, 2 × C(CH3)3), 1.30-1.50
(m, 22 H, (CH2)11CH3), 2.15 (m, 2 H, dCHCH2), 2.75 (s, 2 H,
H-4a,b), 3.70 (AB q, J ) 10.7 Hz, 2 H, CH2OSi), 6.70 (m, 1 H,
dCH), 7.30-7.60 (m, 20 H, Ph); 13C NMR δ 14.12, 19.20, 22.68,
26.67, 28.14, 29.35, 29.41, 29.46, 29.53, 29.66, 30.18, 31.91,
66.16, 85.22, 127.47, 127.76, 129.81, 132.62, 132.87, 135.56,
135.61, 139.79, 170.60. Anal. (C52H72O4Si2) C, H.
(Z)-5-Bis[[(ter t-bu tyld ip h en ylsilyl)oxy]m eth yl]-3-[(Z)-
9-octadecen yliden e]tetr ah ydr o-2-fu r an on e (10b) an d (E)-
5-Bis[[(ter t-b u t yld ip h en ylsilyl)oxy]m et h yl]-3-[(Z)-9-oc-
t a d ecen ylid en e]t et r a h yd r o-2-fu r a n on e (11b ). These
compounds were obtained as oils in a fashion similar to 10a
and 11a starting from 3c and oleyl aldehyde.
â-Hydroxy lactone intermediate (74%): IR (neat) 3510, 1750,
1589 cm-1 1H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3),
;
1.00 and 1.05 (singlets, 18 H, C(CH3)3), 1.20-1.50 (m, 24 H,
CHOH(CH2)6CH2CHdCHCH2(CH2)6CH3), 1.90 (dd, J ) 12.6,
10.9 Hz, 1 H, H-4a), 2.00 (m, 4 H, CH2CHdCHCH2), 2.20 (dd,
J ) 12.6, 10.1 Hz, 1 H, H-4b), 2.80 (m, 1 H, H-3), 3.50-3.80
(m, 4 H, CH2OSi), 3.97 (s, 1 H, CHOH), 5.45 (m, 2 H, CHdCH),
7.30-7.60 (m, 20 H, Ph); 13C NMR (CDCl3) δ 14.10, 19.14,
19.20, 22.67, 24.88, 26.71, 26.75, 27.21, 28.97, 29.30, 29.51,
29.56, 29.60, 29.76, 31.88, 34.84, 45.87, 65.72, 66.38, 72.14,
86.82, 127.79, 127.88, 129.80, 129.89, 129.94, 129.98, 132.21,
132.51, 132.61, 132.65, 135.51, 135.55, 135.59, 179.54. Anal.
(C56H80O5Si2) C, H.
(Z)-5-Bis[[(ter t-b u t yld ip h en ylsilyl)oxy]m et h yl]-3-t et -
r a d eca n ylid en etetr a h yd r o-2-fu r a n on e (10a ) a n d (E)-5-
Bis[[(ter t-bu tyld ip h en ylsilyl)oxy]m eth yl]-3-tetr a d eca n -
ylid en et et r a h yd r o-2-fu r a n on e (11a ). A solution of 3c
(0.685 g, 1.10 mmol) in anhydrous THF (10 mL) at -78 °C
was treated with lithium diisopropylamide (2 M in heptane/
THF/ethylbenzene, 1.37 mL) and stirred for 1 h. A solution
of ZnCl2 (0.5 M in THF, 2.3 mL) was added, and after 5 min
a solution of 1-tetradecanal (0.280 g, 1.32 mmol) in THF (9
mL) was introduced into the reaction mixture dropwise. After
1.3 h, the reaction was quenched with a saturated NH4Cl
solution (10 mL), and the temperature was allowed to reach
10b (32%): IR (neat) 1759 and 1670 cm-1; 1H NMR (CDCl3)
δ 0.86 (distorted t, 3 H, CH3), 1.00 (s, 18 H, 2 × C(CH3)3), 1.20-
1.50 (m, 22 H, CH2(CH2)5CH2CHdCHCH2(CH2)6CH3), 2.00 (m,
4 H, CH2CHdCHCH2), 2.65 (m, 2 H, >CdCHCH2), 2.80 (br s,
2 H, H-4a,b), 3.70 (AB q, J ) 10.7 Hz, 2 H, CH2OSi), 5.35 (m,
2 H, CHdCH), 6.10 (distorted t, 1 H, >CdCH), 7.30-7.70 (m,
20 H, Ph); 13C NMR (CDCl3) δ 14.11, 19.21, 22.67, 26.68, 27.21,
27.59, 29.17, 29.23, 29.30, 29.41, 29.51, 29.76, 31.89, 33.15,

Conformationally Constrained Analogues of Diacylglycerol. 10
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 25
66.05, 84.37, 125.37, 127.74, 129.77, 129.82, 129.91, 132.69,
132.88, 135.56, 135.60, 143.27, 169.36. Anal. (C56H78O4Si2)
C, H.
chromatography over silica gel using 25-30% EtOAc in
hexane. The compounds were isolated as colorless oils or
solids:
11b (60%): IR (neat) 1763 and 1683 cm-1; 1H NMR (CDCl3)
δ 0.90 (distorted t, 3 H, CH3), 1.03 (s, 18 H, 2 × C(CH3)3), 1.20-
1.50 (m, 22 H, CH2(CH2)5CH2CHdCHCH2(CH2)6CH3), 2.00 (m,
4 H, CH2CHdCHCH2), 2.15 (m, 2 H, >CdCHCH2), 2.75 (br s,
2 H, H-4a,b), 3.70 (AB q, J ) 10.7 Hz, 2 H, CH2OSi), 5.35 (m,
2 H, CHdCH), 6.70 (m, 1 H, >CdCH), 7.30-7.65 (m, 20 H,
Ph); 13C NMR (CDCl3) δ 14.13, 19.22, 22.69, 26.69, 27.19, 27.23,
28.16, 29.18, 29.33, 29.39, 29.53, 29.69, 29.76, 30.18, 31.91,
66.19, 85.23, 127.52, 127.78, 129.73, 129.83, 130.02, 132.62,
132.88, 135.58, 135.62, 139.72, 170.59. Anal. (C56H78O4Si2)
C, H.
Gen er a l Desilyla tion P r oced u r e for th e Syn th esis of
10c,d a n d 11c,d . A stirred solution of 10a ,b/11a ,b (0.28
mmol) in THF (8 mL) at room temperature was treated with
a THF solution of tetrabutylammonium fluoride (1 M, 0.85 mL)
for the course of 1 h. After the volatiles were removed under
reduced pressure, the residue was partitioned between EtOAc
(20 mL) and water (10 mL). The organic layer was separated
and dried (Na2SO4). After evaporation of the solvent, the
residue obtained was purified by flash column chromatography
over silica gel using a 0%-25% gradient of EtOAc in hexane
as eluant. The compounds were isolated as colorless oils or
solids:
r a c-(Z)-5-[(Acetyloxy)m eth yl]-5-(h yd r oxym eth yl)-3-tet-
r a d eca n ylid en etetr a h yd r o-2-fu r a n on e (10e): solid (67%
yield from 10c): mp 58-59 °C (EtOAc/hexane); IR (KBr) 3387,
1
1728.0, 1676 cm-1; H NMR (CDCl3) δ 0.86 (distorted t, 3 H,
CH3), 1.20-1.50 (m, 22 H, (CH2)11CH3), 2.05 (s, 3 H, CH3CO),
2.34 (br s, 1 H, OH), 2.65 (m, 3 H, H-4a, dCHCH2), 2.88 (m, 1
H, H-4b), 3.62 (br AB q, J ) 12.1 Hz, 2 H, CH2OH), 4.20 (AB
q, J ) 11.8 Hz, 2 H, CH2OAc), 6.20 (m, 1 H, dCH); 13C NMR
(CDCl3) δ 14.09, 20.65, 22.65, 27.73, 29.05, 29.26, 29.32, 29.42,
29.53, 29.62, 29.64, 31.89, 33.05, 64.53, 65.28, 82.22, 123.58,
145.77, 168.65, 170.81; FAB MS (m/ z, relative intensity) 383
(MH+, 100). Anal. (C22H38O5) C, H.
r a c-(Z)-5-[(Acetyloxy)m eth yl]-5-(h ydr oxym eth yl)-3-[(Z)-
9-octa d ecen ylid en e]tetr a h yd r o-2-fu r a n on e (10f): semi-
solid gum (62% yield from 10d ): IR (neat) 3433, 1747, 1650
1
cm-1; H NMR (CDCl3) δ 0.88 (distorted t, 3 H, CH3), 1.20-
1.50 (m, 22 H, CH2(CH2)5CH2CHdCHCH2(CH2)6CH3), 2.00 (m,
4 H, CH2CHdCHCH2), 2.10 (s, 3 H, CH3CO), 2.70 (m, 3 H,
H-4a, >CdCHCH2), 2.88 (m, 1 H, H-4b), 3.62 (m, 2 H, CH2-
OH), 4.20 (AB q, J ) 11.8 Hz, 2 H, CH2OAc), 5.32 (m, 2 H,
CHdCH), 6.22 (m, 1 H, >CdCH); 13C NMR (CDCl3) δ 14.09,
20.66, 22.66, 27.19, 27.72, 29.04, 29.18, 29.23, 29.30, 29.50,
29.71, 29.74, 31.88, 33.08, 64.56, 65.23, 82.11, 123.52, 129.76,
129.96, 145.80, 168.50, 170.80; FAB MS (m/ z, relative inten-
sity) 437 (MH+, 36). Anal. (C26H44O5) C, H.
(Z)-5-Bis(h ydr oxym eth yl)-3-tetr a deca n yliden etetr a h y-
d r o-2-fu r a n on e (10c): solid (80% yield from 10a ): mp 63-
64 °C (EtOAc/hexane); IR (KBr) 3316, 1750, and 1676 cm-1
;
r a c-(E)-5-[(Acetyloxy)m eth yl]-5-(h ydr oxym eth yl)-3-tet-
r a d eca n ylid en etetr a h yd r o-2-fu r a n on e (11e): solid (54%
yield from 11c): mp 77.5-78.5 °C: IR (KBr) 3384, 1733, 1680
1H NMR (CDCl3) δ 0.85 (distorted t, 3 H, CH3), 1.10-1.50 (m,
22 H, (CH2)11CH3), 2.65 (m, 2 H, >CdCHCH2), 2.75 (br s, 2 H,
H-4a,b), 3.00 (t, J ) 6.2 Hz, 2 H, OH), 3.70 (m, 2 H, CH2OH),
6.20 (m, 1 H, >CdCH); 13C NMR (CDCl3) δ 14.09, 22.67, 27.78,
29.05, 29.28, 29.33, 29.45, 29.56, 29.63, 29.66, 31.90, 32.66,
64.92, 84.49, 124.09, 145.84, 169.58. Anal. (C20H36O4) C, H.
(Z)-5-Bis(h yd r oxym eth yl)-3-[(Z)-9-octa d ecen ylid en e]-
tetr a h yd r o-2-fu r a n on e (10d ): oil (81% yield from 10b); IR
1
cm-1; H NMR (CDCl3) δ 0.85 (distorted t, 3 H, CH3), 1.20-
1.50 (m, 22 H, (CH2)11CH3), 2.05 (s, 3 H, CH3CO), 2.15 (m, 2
H, dCHCH2), 2.40 (t, J ) 6.7 Hz, 1 H, OH), 2.60 (dd, J ) 17.1,
2.6 Hz, 1 H, H-4a), 2.80 (dd, J ) 17.1, 2.8 Hz, H-4b), 3.65 (m,
2 H, CH2OH), 4.20 (AB q, J ) 11.8 Hz, 2 H, CH2OAc), 6.72
(m, 1 H, dCH); 13C NMR (CDCl3) δ 14.09, 20.63, 22.66, 28.05,
29.32, 29.37, 29.50, 29.61, 29.79, 30.28, 31.89, 64.71, 65.43,
82.90, 125.64, 142.22, 169.89, 170.77; FAB MS (m/ z, relative
intensity) 383 (MH+, 100). Anal. (C22H38O5) C, H.
(neat) 3416, 1759, 1660 cm-1 1H NMR (CDCl3) δ 0.86
;
(distorted t, 3 H, CH3), 1.20-1.50 (m, 22 H, CH2(CH2)5CH2-
CHdCHCH2(CH2)6CH3), 2.00 (m, 4 H, CH2CHdCHCH2), 2.15
(t, J ) 6.5 Hz, 2 H, OH), 2.68 (m, 2 H, >CdCHCH2), 2.80 (br
s, 2 H, H-4a,b), 3.70 (m, 2 H, CH2OH), 5.35 (m, 2 H, CHdCH),
6.22 (m, 1 H, >CdCH); 13C NMR (CDCl3) δ 14.09, 22.65, 27.19,
27.76, 29.04, 29.19, 29.25, 29.29, 29.35, 29.49, 29.63, 29.73,
31.87, 32.67, 64.82, 84.60, 124.16, 129.77, 129.94, 145.74,
169.71. Anal. (C24H42O4) C, H.
r a c-(E)-5-[(Acetyloxy)m eth yl]-5-(h ydr oxym eth yl)-3-[(Z)-
9-octa d eca en ylid en e]tetr a h yd r o-2-fu r a n on e (11f): solid
(62% yield from 11d ): mp 45.5-46.5 °C: IR (KBr) 3383, 1732,
1680 cm-1 1H NMR (CDCl3) δ 0.85 (distorted t, 3 H, CH3),
;
1.20-1.50 (m, 22 H, CH2(CH2)5CH2CHdCHCH2(CH2)6CH3),
2.00 (m, 4 H, CH2CHdCHCH2), 2.10 (s, 3 H, CH3CO), 2.15
(m, 2 H, >CdCHCH2), 2.35 (t, J ) 6.8 Hz, 1 H, OH), 2.62 (dd,
J ) 17.1, 2.6 Hz, 1 H, H-4a), 2.80 (dd, J ) 17.1, 2.8 Hz, 1 H,
H-4b), 3.61 (m, 2 H, CH2OH), 4.26 (AB q, J ) 11.8 Hz, 2 H,
(E)-5-Bis(h ydr oxym eth yl)-3-tetr a deca n yliden etetr a h y-
d r o-2-fu r a n on e (11c): solid (80% yield from 11a ): mp 76.5-
1
77.5 °C (EtOAc/hexane); IR (KBr) 3414, 1715, 1684 cm-1; H
CH2OAc), 5.32 (m, 2 H, CHdCH), 6.75 (m, 1 H, >CdCH); 13
C
NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.10-1.50 (m, 22
H, (CH2)11CH3), 2.15 (m, 2 H, dCHCH2), 2.68 (br s, 2 H, H-4a,b),
3.05 (br, 2 H, OH), 3.70 (AB q, J ) 12.1 Hz, 2 H, CH2OH),
6.70 (m, 1 H, dCH); 13C NMR (CDCl3) δ 14.09, 22.66, 28.05,
29.34, 29.36, 29.38, 29.52, 29.62, 30.29, 31.89, 64.93, 85.55,
126.29, 142.20, 171.03. Anal. (C20H36O4) C, H.
NMR (CDCl3) δ 14.09, 20.63, 22.65, 27.12, 27.19, 28.05, 29.13,
29.29, 29.49, 29.68, 29.73, 29.78, 30.27, 31.87, 64.70, 65.42,
82.89, 125.66, 129.64, 130.04, 142.17, 169.80, 170.77; FAB MS
(m/ z, relative intensity) 437 (MH+, 68). Anal. (C26H44O5) C,
H.
5-[(Acetyloxy)m eth yl]-5-(h yd r oxym eth yl)-3-tetr a d eca -
n yltetr a h yd r o-2-fu r a n on e (Mixtu r e of Dia ster eoisom er s,
12). A solution of 11e (0.006 g) in EtOAc (5 mL) was
hydrogenated in the presence of 10% Pd/C (0.003 g) at 45 psi
for 1.3 h. The reaction mixture was filtered through a small
pad of silica gel which was washed with additonal EtOAc (10
mL). The collected filtrate was concentrated under vaccum
to give the title compound as a white solid in nearly quantita-
tive yield: mp 79-81 °C (EtOAc/hexane); IR (KBr) 3415, 1741
cm-1; FAB MS (m/ z, relative intensity) 385 (MH+, 100). Anal.
(C22H40O5) C, H.
(E)-5-Bis(h yd r oxym eth yl)-3-[(Z)-9-octa d ecen ylid en e]-
tetr a h yd r o-2-fu r a n on e (11d ): oil (76% yield from 11b); IR
(neat) 3411, 1714, 1683 cm-1 1H NMR (CDCl3) δ 0.88
;
(distorted t, 3 H, CH3), 1.20-1.50 (m, 22 H, CH2(CH2)5CH2-
CHdCHCH2(CH2)6CH3), 2.00 (m, 4 H, CH2CHdCHCH2), 2.15
(m, 2 H, >CdCHCH2), 2.70 (br s, 2 H, H-4a,b), 2.85 (br s, 2 H,
OH, D2O exchanged), 3.70 (AB q, J ) 12.0 Hz, 2 H, CH2OH),
5.35 (m, 2 H, CHdCH), 6.72 (m, 1 H, >CdCH); 13C NMR
(CDCl3) δ 14.09, 22.65, 27.14, 27.20, 28.03, 29.14, 29.29, 29.34,
29.50, 29.69, 29.73, 30.27, 31.88, 65.05, 85.33, 126.23, 129.68,
130.01, 142.20, 170.78. Anal. (C24H42O4) C, H.
1,3-Bis-O-(ter t-bu tyldim eth ylsilyl)-1,3-dih ydr oxy-2-pr o-
p a n on e (4a ). This compound was prepared in the same
fashion as 1c according to the method of Kinder et al.24
Met h yl 3,3-Bis[(ter t-b u t yld im et h ylsiloxy)m et h yl]a c-
r yla te (5a ). A solution of 4a (12.74 g, 40 mmol) in benzene
(200 mL) was treated with methyl (triphenylphosphoranylide-
ne)acetate (16.05 g, 48 mmol) and refluxed for 8 h. The
reaction mixture was cooled and concentrated under reduced
pressure. The residue was dissolved in hexane and filtered,
and the filtrate was concentrated. The residue was purified
Gen er a l P r oced u r e for th e Mon oa cetyla tion of Diols
10c,d a n d 11c,d . Syn th eses of 10e,f a n d 11e,f. A stirred
solution of diol 10c,d /11c,d (0.14 mmol), pyridine (0.7 mmol),
and DMAP (1 mg) in dry CH2Cl2 (4 mL) at 0 °C was treated
with acetic anhydride (0.14 mmol) for 1 h. The reaction was
quenched by the addition of water (2 mL), and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (5
mL), and the combined organic extract was washed with 1 N
HCl (5 mL) and water (5 mL) and dried (Na2SO4). The residue
obtained after evaporation was purified by flash column

26 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Sharma et al.
by flash column chromatography over silica gel with hexane/
EtOAc (19:1) as eluant to give the title compound 5a (13.48 g,
90%) as an oil: IR (neat) 1719, 1654 cm-1; 1H NMR (CDCl3) δ
0.04 and 0.06 (s, 6 H, Si(CH3)2), 0.87 and 0.91 (s, 9 H, C(CH3)3),
3.67 (s, 3 H, CO2CH3), 4.42 (m, 2 H, CH2OSi), 4.85 (m, 2 H,
CH2OSi), 5.98 (m, 1 H, dCH); 13C NMR (CDCl3) δ -2.14, 18.15,
18.37, 25.76, 25.88, 50.99, 61.55, 63.17, 111.33, 162.07, 166.96.
Anal. (C18H38O4Si2) C, H.
29.53, 29.56, 31.81, 33.93, 36.57, 45.76, 66.63, 73.60, 116.63,
136.81, 173.27, 175.03. Anal. (C21H36O4) C, H.
4-(Hyd r oxym eth yl)-4-[(tetr a d eca n oyloxy)m eth yl]-4-vi-
n yltetr a h yd r o-2-fu r a n on e (9c). A stirring solution of 8c
(0.49 g, 1.4 mmol) in aqueous acetone (1:1, 20 mL) was treated
with 4-methylmorpholine N-oxide (0.33 g, 2.8 mmol), sodium
metaperiodate (0.6 g, 2.8 mmol), and osmium tetroxide (2.5
wt % solution in tert-butyl alcohol, 1.75 mL, 0.14 mmol) for
20 h at room temperature. The reaction mixture was quenched
with saturated sodium thiosulfate solution (10 mL), stirred
for 10 min, and extracted with EtOAc. The combined organic
3,3-Bis[(ter t-bu tyld im eth ylsiloxy)m eth yl]-2-p r op en -1-
ol (6a ). A solution of 5a (11.24 g, 30 mmol) in CH2Cl2 (100
mL) was cooled to -60 °C and treated dropwise with a solution
of diisobutylaluminum hydride in CH2Cl2 (1.0 M, 40 mL). The
reaction was quenched with saturated potassium sodium
tartrate tetrahydrate, and the mixture was warmed to room
temperature. The aqueous layer was extracted with CH2Cl2,
and the combined organic layer was washed with water and
brine. The organic layer was dried (NaSO4) and concentrated.
The residue was purified by flash column chromatography over
silica gel with hexane/EtOAc (5:1) as eluant to give the title
compound 6a (9.77 g, 94%) as an oil: IR (neat) 3357, 1471
layer was washed with water, dried (Na2
SO4), and concen-
trated. The residue was purified by flash column chromatog-
raphy over silica gel with EtOAc/hexane (1:1) as eluant to give
the corresponding aldehyde (0.432 g, 88%) as a white solid:
mp 63 °C; IR (KBr) 1784, 1767, and 1735 cm-1
(CdO); 1H NMR
(CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.25 (m, 20 H,
CH3(CH2)10CH2CH2CO), 1.60 (m, 2 H, CH3(CH2)10CH2CH2CO),
2.30 (t, J ) 7.4 Hz, 2 H, CH3(CH2)10CH2CH2CO), 2.54 (d of
AB, J ) 17.9 Hz, 1 H, H-3a), 2.92 (d of AB, J ) 17.9 Hz, 1 H,
H-3b), 4.21 (d of AB, J ) 9.9 Hz, 1 H, H-5a), 4.38 (AB q, J )
11.65 Hz, 2 H, CH2OCOC13H27 ), 4.55 (d of AB, J ) 9.9 Hz, 1
H, H-5b), 9.66 (s, 1 H, CHO); 13C NMR (CDCl3) δ 14.05, 22.62,
24.67, 28.98, 29.12, 29.28, 29.36, 29.51, 29.56, 31.84, 32.11,
33.76, 54.27, 63.49, 68.66, 173.10, 173.30, 196.71, 196.86.
cm-1 1H NMR (CDCl3) δ 0.05 and 0.06 (s, 12 H, Si(CH3)2),
;
0.88 and 0.89 (s,18 H, C(CH3)3), 1.86 (br s, 1 H, OH), 4.14 (br
s, 2 H, CH2OH), 4.20 (m, 4 H, 2 × CH2OSi), 5.80 (m, 1 H,
dCH); 13C NMR (CDCl3) δ -1.95, 18.19, 18.33, 25.62, 25.79,
25.88, 58.50, 59.24, 64.75, 125.47, 140.81. Anal. (C17H38O3-
Si2) C, H.
Anal. (C20
H34O5) C, H. This aldehyde (0.425 g, 1.2 mmol) was
dissolved in MeOH (15 mL), cooled to -10 °C, and treated with
sodium borohydride (0.09 g, 2.4 mmol). After stirring for 30
min, the reaction mixture was quenched by the slow addition
of a phosphate buffer solution (pH 4, 5 mL) and extracted with
ether. The organic layer was washed with water, dried (Na2-
SO4), and concentrated. The residue was purified by flash
column chromatography over silica gel with EtOAc/hexane (1:
1) as eluant to give the title compound 9c (0.35 g, 82%) as a
white solid: mp 50 °C; IR (KBr) 3461 (OH), 1764, and 1739
Eth yl 3,3-Bis[(ter t-bu tyld im eth ylsiloxy)m eth yl]-4-p en -
ten oa te (7a ). A mixture of 6a (9.36 g, 27 mmol), triethyl
orthoacetate (34.75 mL, 189 mmol), and propionic acid (0.2
mL, 2.7 mmol) was heated at 138 °C for 20 h with removal of
ethanol. The reaction mixture was cooled and concentrated
under vacuum, and the residue was purified by flash column
chromatography over silica gel with hexane/EtOAc (19:1) as
eluant to give the title compound 7a (8.77 g, 78%) as an oil:
1
IR (neat) 1737, 1471 cm-1; H NMR (CDCl3) δ 0.01 (br s, 12
1
cm-1 (CdO); H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3),
H, 2 × Si(CH3)2), 0.85 (br s, 18 H, 2 × C(CH3)3), 1.21 (t, 3 H,
CH3CH2), 2.42 (s, 2 H, CH2COEt), 3.61 (AB q, J ) 9.3 Hz, 4
H, 2 × CH2OSi), 4.06 (q, 2 H, CH2CH3), 5.06 (m, 2 H,
CHdCH2), 5.84 (dd, J ) 19.9, 11.3, 1 H, CHdCH2); 13C NMR
(CDCl3) δ -5.58, 14.24, 18.23, 25.84, 36.81, 45.97, 59.84, 64.63,
114.47, 139.73, 171.87. Anal. (C21H44O4Si2) C, H.
1.25 (m, 20 H, CH3(CH2)10CH2CH2CO), 1.60 (m,
2 H,
CH3(CH2)10CH2CH2CO), 2.33 (t, J ) 7.4 Hz, 2 H, CH3(CH2)10-
CH2CH2CO), 2.50 (AB q, J ) 17.8 Hz, 2 H, H-3 a,b), 3.58 (bs, 2
H, CH2OH), 4.15 (AB q, J ) 9.6 Hz, 2 H, H-5a,b), 4.17 (s, 2 H,
CH2OCOC13H27); 13C NMR (CDCl3) δ 13.99, 22.56, 24.73, 29.00,
29.10, 29.22, 29.33, 29.48, 29.52, 29.54, 31.79, 33.94, 34.04,
45.17, 63.47, 64.78, 72.05, 173.93, 176.19; FAB MS m/ z
(relative intensitiy) 357 (MH+, 59), 211 (C13H27CO+, 55). Anal.
(C20H36O5) C, H.
4-(Hyd r oxym eth yl)-4-vin yltetr a h yd r o-2-fu r a n on e (8b).
A solution of 7a (8.34 g, 20 mmol) in aqueous THF (60 mL,
1:1) was treated with concentrated H2SO4 (10 mL) and stirred
at room temperature for 24 h. The mixture was concentrated
under vacuum and diluted with water, and the aqueous layer
was extracted with CHCl3. The combined organic layer was
washed with H2O, dried (NaSO4), and concentrated. The
residue was purified by flash column chromatography over
silica gel with EtOAc/hexane (2:1) as eluant to give the title
compound 8b (2.50 g, 88%) as an oil: IR (neat) 3452 (OH),
1777 (CdO), 1641 cm-1; 1H NMR (CDCl3) δ 2.51 (d of AB, J )
17.4 Hz, 1 H, H-3a), 2.63 (d of AB, J ) 17.4 Hz, 1 H, H-3b),
3.62 (s, 2 H, CH2OH), 4.16 (d of AB, J ) 9.2 Hz, 1 H, H-5a),
4.32 (d of AB, J ) 9.2 Hz, 1 H, H-5b), 5.19 (d, J ) 17.5 Hz, 1
H, CHdCHH), 5.29 (d, J ) 10.8 Hz, 1 H, CHdCHH), 5.85 (dd,
J ) 17.5, 10.8 Hz, 1 H, CHdCH2); 13C NMR (CDCl3) δ 35.94,
47.61, 65.56, 73.33, 116.18, 137.55, 176.97. Anal. (C7H10O3)
C, H.
4-[(Ben zyloxy)m et h yl]-4-[(ter t-b u t yld im et h ylsiloxy)-
m eth yl]tetr a h yd r o-2-fu r a n on e (13). A solution of 8b (1.28
g, 9.0 mmol) in THF (60 mL) was cooled to 0 °C, treated with
sodium hydride (60% dispersion in mineral oil, 0.72 g, 18
mmol), and stirred for 30 min. The reaction mixture was
warmed to room temperature and treated with benzyl bromide
(1.6 mL, 13.5 mmol) followed by tetrabutylammonium iodide
(0.33 g, 0.9 mmol). The reaction mixture was stirred for 8 h
at room temperature, cooled with an ice bath, and quenched
with acetic acid (1 mL). The mixture was filtered through a
short pad of silica gel, and the filtrate was concentrated. The
residue was purified by flash column chromatography over
silica gel with hexane/EtOAc (2:1) as eluant to give the
corresponding benzyl ether (2.0 g, 96%) as an oil: IR (neat)
1780 (CdO) and 1641 cm-1 (CdC); 1H NMR (CDCl3) δ 2.49 (d
of AB, J ) 17.3 Hz, 1 H, H-3a), 2.65 (d of AB, J ) 17.3 Hz, 1
H, H-3b), 3.42 (s, 2 H, CH2OCH2Ph), 4.14 (d of AB, J ) 9.05
Hz, 1 H, H-5a), 4.32 (d of AB, J ) 9.05 Hz, 1 H, H-5b), 4.54 (s,
2 H, CH2OCH2Ph), 5.16 (d, J ) 17.6 Hz, 1 H, CHdCHH), 5.22
(d, J ) 10.8 Hz, CHdCHH), 5.87 (dd, J ) 17.6, 10.9 Hz, 1 H,
CHdCH2), 7.20-7.40 (m, 5 H, Ph); 13C NMR (CDCl3) δ 36.50,
46.55, 73.03, 73.35, 73.87, 115.71, 127.49, 127.79, 128.41,
137.45, 137.99, 175.91. Anal. (C14H16O3) C, H.
4-[(Tet r a d eca n oyloxy)m et h yl]-4-vin ylt et r a h yd r o-2-
fu r a n on e (8c). A solution of 8b (0.2 g, 1.4 mmol) in CH2Cl2
(20 mL) was treated with pyridine (0.45 mL, 5.6 mmol),
(dimethylamino)pyridine (0.034 g, 0.28 mmol), and tetrade-
canoyl chloride (0.76 mL, 2.8 mmol). After stirring for 2 h at
room temperature, the reaction mixture was concentrated, and
the residue was purified by flash column chromatography over
silica gel with hexane/EtOAc (3:1) as eluant to give the title
compound 8c (0.49 g, 99%) as an oil: IR (neat) 1788 and 1741
1
cm-1 (CdO); H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3),
The above compound (2.0 g, 8.6 mmol) was dissolved in
aqueous acetone (1:1, 80 mL) and treated with 4-methylmor-
pholine N-oxide (2.02 g, 17.22 mmol), sodium metaperiodate
(3.68 g, 17.22 mmol), and osmium tetroxide (2.5 wt % in tert-
butyl alcohol, 2.16 mL, 0.17 mmol). After stirring for 20 h at
room temperature, the reaction mixture was quenched with a
saturated sodium thiosulfate solution (40 mL), stirred for 10
min, and extracted with EtOAc. The organic layer was washed
1.25 (m, 20 H, CH3(CH2)10CH2CH2CO), 1.60 (m,
2 H,
CH3(CH2)10CH2CH2CO), 2.31 (t, J ) 7.4 Hz, 2 H, CH3(CH2)10-
CH2CH2CO), 2.60 (s, 2 H, H-3a,b), 4.12 (AB q, J ) 11.3 Hz, 2
H, CH2OCOC13H27), 4.20 (AB q, J ) 9.3 Hz, 2 H, H-5a,b), 5.19
(d, J ) 17.6 Hz, 1 H, CHdCHH), 5.28 (d, J ) 10.9 Hz, 1 H,
CHdCHH), 5.84 (dd, J ) 10.9, 17.6 Hz, CHdCH2); 13C NMR
(CDCl3) δ 14.02, 22.58, 24.69, 28.99, 29.11, 29.24, 29.34, 29.48,

Conformationally Constrained Analogues of Diacylglycerol. 10
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 27
with water, dried (Na2SO4), and concentrated. The residue
was purified by flash column chromatography over silica gel
with EtOAc/hexane (2:1) as eluant to give the corresponding
aldehyde (1.90 g, 94%) as an oil: IR (neat) 1781 and 1728 cm-1
(m, 2 H, dCHCH2), 3.41 (d of AB, J ) 8.8 Hz, 1 H, CHHOSi),
3.49 (d of AB, J ) 8.8 Hz, 1 H, CHHOSi), 3.60 (s, 2 H, CH2-
OCH2Ph), 4.13 (AB q, J ) 9.5 Hz, 2 H, H-5), 4.50 (AB q, J )
12.2 Hz, 2 H, CH2OCH2Ph), 6.22 (t, J ) 7.6 Hz, 1 H, dCH),
7.20-7.40 (m, 5 H, Ph); 13C NMR (CDCl3) δ -5.65, -5.57,
14.11, 18.15, 22.67, 25.74, 27.53, 29.16, 29.23, 29.34, 29.45,
29.54, 29.64, 29.66, 31.90, 48.24, 65.04, 70.37, 71.62, 73.46,
127.24, 127.51, 127.71, 128.39, 137.85, 146.55, 170.28. Anal.
(C33H56O4Si) C, H.
Compound 15a : oil; IR (neat) 1760 (CdO) and 1672 cm-1
(CdC); 1H NMR (CDCl3) δ 0.02 (s, 6 H, Si(CH3)2), 0.85 (m, 12
H, C(CH3)3, (CH2)12CH3), 1.10-1.50 (m, 22 H, dCHCH2(CH2)11-
CH3), 2.25 (m, 2 H, dCHCH2), 3.60 (AB q, J ) 8.8 Hz, CH2-
OSi), 3.70 (d of AB, J ) 9.7 Hz, 1 H, CHHOCH2Ph), 3.80 (d of
AB, J ) 9.7 Hz, 1 H, CHHOCH2Ph), 4.13 (AB q, J ) 9.4 Hz,
2 H, H-5), 4.50 (AB q, J ) 12.0 Hz, 2 H, CH2OCH2Ph), 6.83 (t,
J ) 7.8 Hz, 1 H, dCH), 7.20-7.40 (m, 5 H, Ph); 13C NMR
(CDCl3) δ -5.62, -5.59, 14.11, 18.18, 22.67, 25.74, 28.93, 28.99,
29.35, 29.42, 29.53, 29.64, 31.90, 49.20, 64.65, 70.94, 71.03,
73.55, 127.47, 127.43, 127.79, 128.40, 137.62, 144.79, 171.85.
Anal. (C33H56O4Si) C, H.
(Z )-4-(Ac e t o x y m e t h y l)-4-[(B e n z y lo x y )m e t h y l]-3-
tetr a d eca n ylid en etetr a h yd r o-2-fu r a n on e (14b). A solu-
tion of 14a (0.80 g, 1.47 mmol) in THF (20 mL) was cooled to
0 °C, treated dropwise with tetrabutylammonium fluoride (1.0
M, 3.0 mL, 3 mmol), and stirred for 30 min. The reaction
mixture was diluted with ether, and the organic phase was
washed with water. The organic layer was dried (Na2SO4) and
concentrated. The residue was purified by flash chromatog-
raphy over silica gel with hexane/EtOA (2:1) as eluant to give
the intermediate alcohol (0.63 g, 99.6%) as an oil: IR (neat)
3447 (OH), 1754 (CdO) and 1662 cm-1 (CdC); 1H NMR (CDCl3)
1
(CdO); H NMR (CDCl3) δ 2.51 (d of AB, J ) 17.9 Hz, 1 H,
H-3a), 2.84 (d of AB, J ) 17.9 Hz, 1 H, H-3b), 3.69 (AB m, 2 H,
CH2OCH2Ph), 4.23 (d of AB, J ) 9.8 Hz, 1 H, H-5a), 4.51 (d of
AB, J ) 9.8 Hz, 1 H, H-5b), 4.54 (s, 2 H, CH2OCH2Ph), 7.20-
7.40 (m, 5 H, Ph), 9.67 (s, 1 Η, CHO); 13C NMR (CDCl3) δ 32.05,
54.75, 69.14, 69.95, 73.49, 127.62, 128.03, 128.47, 136.73,
174.08, 198.66, 198.82. Anal. (C13H14O4) C, H.
The above aldehyde (1.08 g, 4.6 mmol) was dissolved in
aqueous THF (1:9, 100 mL) and cooled to -15 °C. The solution
was treated with sodium borohydride (0.348 g, 9.2 mmol) and
stirred for 30 min. The reaction mixture was acidified with 1
N HCl solution to pH 2-3 and concentrated to small volume.
The mixture was diluted with water and extracted with ether.
The organic layer was washed with water, dried (Na2SO4), and
concentrated. The residue was purified by flash column
chromatography over silica gel with EtOAc/hexane (3:2) as
eluant to give the corresponding alcohol (1.07 g, 98%) as an
1
oil: IR (neat) 3456 (OH), 1775 cm-1 (CdO); H NMR (CDCl3)
δ 2.14 (bs, 1 H, OH), 2.45 (AB q, J ) 17.9 Hz, 2 H, H-3a,b),
3.51 (s, 2 H, CH2OH), 3.68 (AB m, 2 H, CH2OCH2Ph), 4.16 (d
of AB, J ) 9.45 Hz, 1 H, H-5a), 4.22 (d of AB, J ) 9.45 Hz, 1
H, H-5b), 4.52 (s, 2 H, CH2OCH2Ph), 7.20-7.40 (m, 5 H, Ph);
13C NMR (CDCl3) δ 34.23, 45.54, 64.96, 72.17, 72.37, 73.48,
127.57, 127.94, 128.49, 137.29, 176.69. Anal. (C13H16O4) C,
O.
The above alcohol (1.07 g, 4.5 mmol) was dissolved in DMF
(20 mL) and treated with tert-butyldimethylsilyl chloride (1.02
g, 6.75 mmol) and imidazole (1.23 g, 18 mmol). The reaction
mixture was stirred for 14 h and then diluted with water. The
aqueous phase was extracted with CH2Cl2, and the organic
layer was washed with water and brine. The organic phase
was then dried (Na2SO4) and concentrated. The residue was
purified by flash column chromatography over silica gel with
hexane/EtOAc (5:1) as eluant to give the title compound 13
δ
0.86 (distorted t, 3 H, CH3), 1.10-1.50 (m, 22 H,
dCHCH2(CH2)11CH3), 2.10 (br s, OH), 2.70 (m, 2 H, dCHCH2),
3.51 (AB q, J ) 9.0 Hz, 2 H, CH2OH), 3.64 (d of AB, J ) 11.0
Hz, 1 H, CHHOCH2Ph), 3.74 (d of AB, J ) 11.0 Hz, 1 H,
CHHOCH2Ph), 4.18 (d of AB, J ) 9.5 Hz, H-5a), 4.27 (d of AB,
J ) 9.5 Hz, 1 H, H-5b), 4.51 (AB q, J ) 12.1 Hz, 1 H, CH2-
OCH2Ph), 6.16 (t, J ) 7.6 Hz, 1 H, dCH), 7.20-7.40 (m, 5 H,
Ph); 13C NMR (CDCl3) δ 14.10, 22.67, 27.54, 29.09, 29.23, 29.34,
29.41, 29.53, 29.63, 29.65, 31.90, 47.98, 66.50, 70.44, 73.69,
73.91, 126.84, 127.63, 128.04, 128.57, 137.27, 146.65, 169.93.
Anal. (C27H42O4) C, H. This compound (0.63 g, 1.46 mmol)
was dissolved in CH2Cl2 (30 mL) and treated with pyridine
(0.5 mL, 6.2 mmol) and acetic anhydride (0.3 mL, 3.2 mmol).
After stirring for 1 h at room temperature, the reaction
mixture was concentrated and the residue was purified by
flash column chromatography over silica gel with hexane/
EtOAc (3:1) as eluant to give the title compound 14b (0.684 g,
99%) as an oil: IR (neat) 1750 (CdO) and 1662 cm-1 (CdC);
1H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.10-1.50 (m,
22 H, dCHCH2(CH2)11CH3), 1.99 (s, 3 H, CH3CO), 2.72 (m, 2
H, dCHCH2), 3.42 (s, 2 H, CH2OCH2Ph), 4.10-4.24 (m, 4 H,
CH2OAc, H-5), 4.51 (AB q, J ) 12.2 Hz, 2 H, CH2OCH2Ph),
6.22 (t, 1 H, J ) 7.6 Hz, 1 H, dCH), 7.20-7.40 (m, 5 H, Ph);
13C NMR (CDCl3) δ 14.10, 20.64, 22.67, 27.47, 29.00, 29.16,
29.33, 29.40, 29.53, 29.62, 31.90, 46.51, 65.78, 70.15, 72.02,
73.45, 126.19, 127.57, 127.88, 128.45, 137.43, 147.23, 169.48,
170.51. Anal. (C29H44O5) C, H.
1
(1.51 g, 96%) as an oil: IR (neat) 1781 cm-1 (CdO); H NMR
(CDCl3) δ 0.03 (s, 6 H, Si(CH3)2), 0.85 (s, 9 H, C(CH3)3), 2.44
(s, 2 H, H-3a,b), 3.41 (s, 2 H, CH2OSi), 3.57 (s, 2 H, CH2OCH2-
Ph), 4.13 (s, 2 H, H-5a,b), 4.49 (s, 2 H, CH2OCH2Ph), 7.20-
7.40 (m, 5 H, Ph); 13C NMR (CDCl3) δ -5.66, 18.09, 25.68,
34.05, 46.07, 64.35, 71.08, 72.32, 73.42, 127.55, 127.80, 128.43,
137.60, 176.56. Anal. (C19H30O4Si) C, H.
(Z)-4-[(Ben zyloxy)m eth yl]-4-[(ter t-bu tyldim eth ylsiloxy)-
m eth yl]-3-tetr adecan yliden etetr ah ydr o-2-fu r an on e (14a)
a n d (E)-4-[(Ben zyloxy)m et h yl]-4-[(ter t-b u t yld im et h yl-
siloxy)m e t h yl]-3-t e t r a d e ca n ylid e n e t e t r a h yd r o-2-fu r -
a n on e (15a ). A solution of 13 (1.563 g, 4.46 mmol) in THF (9
mL) was cooled to -78 °C, treated with sodium bis(trimeth-
ylsilyl) amide (1.0 M in tetrahydrofuran, 5.35 mL, 5.35 mmol),
and stirred for 1 h. A mixture of tetradecyl aldehyde (80%,
1.42 g, 5.35 mmol) and hexamethylphosphoramide (0.96 g, 5.35
mmol) was added, and the reaction mixture was stirred at -78
°C for 1 h and at -48 °C for another hour. The mixture was
quenched with a saturated NH4Cl solution and diluted with
ether. The organic layer was washed with water, dried (Na2-
SO4), and concentrated. The residue was purified by flash
column chromatography over silica gel with hexane/EtOAc
(from 10:1 to 5:1) as eluant to give the â-hydroxy lactone
intermediate. This compound was dissolved in CH2Cl2 (100
mL), cooled to 0 °C, and stirred with triethylamine (3.0 mL,
21.5 mmol) and methanesulfonyl chloride (0.66 mL, 8.53 mmol)
for 30 min. The reaction mixture was warmed to room
temperature, stirred for 30 min extra, and additional triethy-
lamine (12.0 mL, 86 mmol) was added. After stirring for 24 h
at room temperature, the mixture was concentrated and
diluted with ether. The ethereal solution was filtered, and the
filtrate was concentrated. The residue was purified by flash
column chromatography over silica gel with hexane/EtOAc (19:
1) as eluant to give the Z-isomer 14a (1.26 g, 52%) as the first
fraction, followed by the E-isomer 15a (0.63 g, 26%). Com-
(E )-4-(Ac e t o x y m e t h y l)-4-[(B e n z y lo x y )m e t h y l]-3-
tetr a d eca n ylid en etetr a h yd r o-2-fu r a n on e (15b). Starting
with 15a , the same procedure described for the synthesis of
14b afforded the corresponding intermediate alcohol in 99%
yield: oil; IR (neat) 3446 (OH), 1757 (CdO) and 1676 (CdC)
1
cm-1; H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3), 1.10-
1.50 (m, 22 H, dCHCH2(CH2)11CH3), 2.23 (m, 2 H, dCHCH2),
3.57 (d of AB, J ) 9.0 Hz, 1 H, CHHOH), 3.72 (d of AB, J )
11.0 Hz, 1 H, CHHOCH2Ph), 3.76 (d of AB, J )9.0 Hz, 1 H,
CHHOH), 4.01 (d of AB, J ) 11.0 Hz, 1 H, CHHOCH2Ph), 4.25
(d of AB, J ) 9.5 Hz, 1 H, H-5a), 4.34 (d of AB, J ) 9.5 Hz, 1
H, H-5b), 4.51 (AB q, J ) 11.9 Hz, 2 H, CH2OCH2Ph), 6.83 (t,
J ) 8.0 Hz, 1 H, dCH), 7.20-7.40 (m, 5 H, Ph); 13C NMR
(CDCl3) δ 14.10, 22.67, 28.78, 29.00, 29.16, 29.34, 29.39, 29.50,
29.63, 31.90, 32.26, 32.31, 48.63, 50.55, 63.36, 65.82, 70.96,
72.94, 73.89, 127.68, 127.75, 128.15, 128.50, 128.60, 135.02,
145.45, 171.32. Anal. (C27H42O4) C, H. This compound was
1
pound 14a : oil; IR (neat) 1757 (CdO), 1658 cm-1 (CdC); H
NMR (CDCl3) δ 0.01 (s, 6 H, Si(CH3)2), 0.85 (m, 12 H, C(CH3)3,
(CH2)12CH3), 1.10-1.50 (m, 22 H, dCHCH2(CH2)11CH3), 2.72

28 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Sharma et al.
(9) Wilkinson, S. E.; Hallam, T. J . Protein Kinase C: Is It Pivotal
Role in Cellular Activation Over-stated? Trends Pharmacol. Sci.
1994, 15, 53-57.
(10) Ahmed, S.; Lee, J .; Kozma, R.; Best, A.; Monfries, C.; Lim, L. A
Novel Functional Target for Tumor-promoting Phorbol Esters
and Lysophosphatic Acid. J . Biol. Chem. 1993, 268, 10709-
10712.
(11) Teng, K.; Marquez, V. E.; Milne, G. W. A.; Barchi, J . J ., J r.;
Kazanietz, M. G.; Lewin, N. E.; Blumberg, P. M.; Abushanab,
E. Conformationally Constrained Analogues of Diacylglycerol.
Interaction of γ-Lactones with the Phorbol Ester Receptor of
Protein Kinase C. J . Am. Chem. Soc. 1992, 114, 1059-1070.
(12) Wang, S.; Milne, G. W. A.; Nicklaus, M. C.; Marquez, V. E.; Lee,
J .; Blumberg, P. M. Protein Kinase C. Modeling of the Binding
Site and Prediction of Binding Constants. J . Med. Chem. 1994,
4, 1326-1338.
(13) Lee, J .; Sharma, R.; Teng, K.; Lewin, N. E.; Blumberg, P. M.;
Marquez, V. E. Conformationally Constrained Analogues of
DAG. 8. Changes in PK-C Binding Affinity Produced by Isosteric
Groups of the 3-O-Acyl Function in 2-Deoxy-L-Ribonolactones.
BioMed. Chem. Lett. 1994, 4, 1369-1374.
(14) Lee, J .; Marquez, V. E.; Lewin, N. E.; Bahador, A.; Kazanietz,
M. G.; Blumberg, P. M. Conformationally Constrained Analogues
of Diacylglycerol (DAG). 4. Interaction of R-Alkylidene-γ-Lac-
tones with Protein Kinase C (PK-C). BioMed. Chem. Lett. 1993,
3, 1107-1110.
(15) Hosomi, A.; Sakurai, H. Synthesis of γ,δ-Unsaturated Alcohols
from Allylsilanes and Carbonyl Compounds in the Presence of
Titanium Tetrachloride. Tetrahedron Lett. 1976, 1295-1298.
(16) Mandal, A. K.; Mahajan, S. W. A One-pot Synthesis of Racemic
and Enantiomeric γ-Butyrolactones. Synthesis 1991, 311-313.
(17) Zhang, W.; Robins, M. J . Removal of Silyl Protecting Groups from
Hydroxyl Functions with Ammonium Fluoride in Methnol.
Tetrahedron Lett. 1992, 33, 1177-1180.
(18) Marquez, V. E.; Lee, J .; Sharma, R.; Teng, K.; Wang, S.; Lewin,
N. E.; Bahador, A.; Kazanietz, M. G.; Blumberg, P. M. Confor-
mationally Constrained Analogues of Diacylglycerol. 6. Changes
in PK-C Binding Affinity for 3-O-Acyl-2-Deoxy-L-Ribonolactones
Bearing Different Acyl Chains. BioMed. Chem. Lett. 1994, 4,
355-360.
acetylated as described for the synthesis of 14b to afford the
E-isomer 15b in 99% yield: oil; IR (neat) 1750 (CdO) and 1672
1
cm-1 (CdC); H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3),
1.10-1.50 (m, 22 H, dCHCH2(CH2)11CH3), 2.00 (s, 3 H, CH3-
CO), 2.24 (m, 2 H, dCHCH2), 3.53 (d of AB, J ) 9.0 Hz, 1H,
CHHOCH2Ph), 3.63 (d of AB, J ) 9.0 Hz, 1 H, CHHOCH2Ph),
4.15 (d of AB, J ) 9.5 Hz, 1 H, CHHOAc), 4.23 (d of AB, J )
9.5 Hz, 1 H, CHHOAc), 4.30 (AB q, J ) 11.2 Hz, 2 H, H-5a,b),
4.50 (AB q, J ) 12.0 Hz, 2 H, CH2OCH2Ph), 6.88 (t, J ) 7.9
Hz, 1 H, dCH), 7.20-7.40 (m, 5 H, Ph); 13C NMR (CDCl3) δ
14.10, 20.70, 22.67, 28.86, 29.17, 29.33, 29.36, 29.42, 29.51,
29.63, 31.90, 46.86, 65.26, 70.73, 71.18, 73.57, 126.20, 127.68,
127.97, 128.48, 137.23, 145.94, 170.57, 171.08. Anal. (C29H44O5)
C, H.
(Z)-4-(Ac e t oxym e t h yl)-4-(h yd r oxym e t h yl)-3-t e t r a -
d eca n ylid en etetr a h yd r o-2-fu r a n on e (14c). A solution of
14b (0.324 g, 0.685 mmol) in CH2Cl2 (20 mL) was cooled to
-78 °C, treated with boron trichloride (1.0 M in dichlo-
romethane, 2.74 mL, 2.74 mmol) and stirred for 1 h at that
temperature. The reaction mixture was quenched with satu-
rated NaHCO3 solution (3.0 mL) and immediately partitioned
between chloroform and a pH 7 phosphate buffer solution. The
organic layer was washed with water, dried (Na2SO4), and
concentrated. The residue was purified by flash column
chromatography over silica gel with EtOAc/hexane (1:1) as
eluant to give the title compound 14c (0.252 g, 96%) as a white
solid: mp 48 °C; IR (KBr) 3489 (OH), 1735 (CdO), and 1667
1
cm-1 (CdC); H NMR (CDCl3) δ 0.86 (distorted t, 3 H, CH3),
1.10-1.50 (m, 22 H, dCHCH2(CH2)11CH3), 2.08 (s, 3 H, CH3-
CO), 2.60-2.90 (m, 2 H, dCHCH2), 3.59 (AB m, 2 H, CH2OH),
4.18 (2 AB multiplets, 4 H, H-5a,b, CH2OAc), 6.28 (t, 1 H, J )
7.6 Hz, 1 H, dCH); 13C NMR (CDCl3) δ 14.11, 20.72, 22.68,
27.61, 29.06, 29.24, 29.35, 29.41, 29.55, 29.64, 31.91, 47.58,
64.42, 65.34, 69.86, 126.06, 147.72, 169.69, 171.19; FAB MS
m/ z 383 (MH+, 100). Anal. (C22H38O5) C, H.
(19) Kazanietz, M. G.; Areres, L. B.; Bahador, A.; Mischak, H.;
Goodnight, J .; Mushinski, J . F.; Blumberg, P. M. Characteriza-
tion of Ligand and Substrate Specificity for the Calcium-
Dependent and Calcium-Independent Protein Kinase C Isozymes.
Mol. Pharmacol. 1993, 44, 298-307.
(E )-4-(Ace t oxym e t h yl)-4-(h yd r oxym e t h yl)-3-t e t r a -
d eca n ylid en etetr a h yd r o-2-fu r a n on e (15c). The identical
deblocking procedure described for the preparation of 14c was
applied to 15b to yield the title compound 15c in 96% yield:
solid; mp 52 °C; IR (neat) 3545 (OH), 1757 and 1724 (CdO),
(20) Based on the 10-fold difference in Ki values between compound
10f and OAG, the following equation
1
and 1672 cm-1 (CdC); H NMR (CDCl3) δ 0.86 (distorted t, 3
H, CH3), 1.10-1.50 (m, 22 H, dCHCH2(CH2)11CH3), 1.90 (br
s, 1 H, OH), 2.07 (s, 3 H, CH3CO), 2.32 (m, 2 H, dCHCH2),
3.75 (d of AB, J ) 11.1 Hz, 1 H, CHHOH), 3.82 (d of AB, J )
11.1 Hz, 1H, CHHOH), 4.15 (d of AB, J ) 9.6 Hz, 1 H, H-5a),
4.25 (d of AB, J ) 9.6 Hz, 1 H, H-5b), 4.37 (AB q, J ) 11.3 Hz,
2 H, CH2OAc), 6.94 (t, 1 H, J ) 7.9 Hz, 1 H, dCH); 13C NMR
(CDCl3) δ 14.10, 20.73, 22.67, 28.95, 29.01, 29.34, 29.44, 29.52,
29.63, 31.90, 48.16, 63.94, 65.03, 70.51, 126.18, 146.37, 170.97,
171.51; FAB MS m/ z 383 (MH+, 100). Anal. (C22H38O5) C,
H.
-2.303RT∆(log Ki)OAG-10f ) ∆(∆G)OAG-10f
)
∆(∆H)OAG-10f - ∆(T∆S)OAG-10f
helps us calculate what the entropic advantage is for the binding
of 10f relative to OAG. ∆(log Ki)OAG-10f is the binding affinity
difference between OAG and 10f in a log scale; ∆(∆G)OAG-10f is
the difference in free energy change between OAG and 10f
associated with the binding process; ∆(∆H)OAG-10f is the differ-
ence in the enthalpic energy change between OAG and 10f
associated with the binding process; and ∆(T∆S)OAG-10f is the
difference in the entropic energy change between OAG and 10f
associated with the binding process. The enthalpic energy
associated with the binding of OAG and 10f should be the same,
thus ∆(∆H)OAG-10f becomes zero. Therefore, the above equation
is reduced to
Refer en ces
(1) Lee, J .; Lewin, N. E.; Blumberg, P. M.; Marquez, V. E. Confor-
mationally Constrained Analogues of Diacylglycerol. 9. The
Effect of Side-Chain Orientation on the Protein Kinase C (PK-
C) Binding Affinity of δ-Lactones. BioMed. Chem. Lett. 1994, 4,
2405-2410.
(2) For a review, see: Protein Kinase C. Current Concepts and
Future Perspectives; Lester, D. S., Epand, R. M., Eds.; Ellis
Horwood: New York, 1992.
(3) Hug, H.; Saare, T. F. Protein Kinase C Isoenzymes. Divergence
in Signal Transduction. Biochem. J . 1993, 291, 329-343.
(4) Leach, K. L.; J ames, M. L.; Blumberg, P. M. Characterization
of a Specific Phorbol Ester Aporeceptor in Mouse Brain Cytosol.
Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 4208-4212.
(5) Castagna, M.; Takai, Y.; Kaibuchi, K.; Sano, K.; Kikkawa, U.;
Nishizuka, Y. Direct Activation of Calcium-activated, Phospho-
lipid-dependent Protein Kinase by Tumor-promoting Phorbol
Esters. J . Biol. Chem. 1982, 257, 7847-7851.
(6) Ashendel, C. L.; Staller, J . M.; Boutwell, R. K. Protein Kinase
Activity Associated with a Phorbol Ester Receptor Purified from
Mouse Brain. Cancer Res. 1983, 43, 4333-4337.
(7) Sando, J . J .; Young, M. C. Identification of High-affinity Phorbol
Ester Receptor in Cytosol of EL4 Thymoma Cells: Requirement
for Calcium, Magnesium, and Phospholipids. Proc. Natl. Acad.
Sci. U.S.A. 1983, 80, 2642-2646.
(8) Sharkey, N. E.; Leach, K. L.; Blumberg, P. M. Competitive
Inhibition by Diacylglycerol of Specific Phorbol Ester Binding.
Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 607-610.
∆(T∆S)OAG-10f ) 2.303RT∆(log Ki)OAG-10f
Since ∆(log Ki) equals one, the corresponding entropic advantage
for the binding of 10f at 25 °C is 5.70 kJ /mol or 1.36 kcal/mol.
For additional details, see ref 12.
(21) Rando, R. R.; Young, N. The Stereospecific Activation of Protein
Kinase C. Biochem. Biophys. Res. Commun. 1984, 122, 818-
823.
(22) Allen, F. H.; Bellard, S.; Brice, M. D.; Cartwright, B. A.;
Doubleday, A.; Higgs, H.; Hummelink, T.; Hummelink-Peters,
B. G.; Kennard, O.; Motherwell, W. D. S.; Rodgers, J . R.; Watson,
D. G. Acta Crystallogr. 1979, B35, 905. Structures with core
template I: BAHREH, PERBGUY, SOFFIC, and VEFFUH.
Structures with core template II: PARBUG, SIVVAU, and
VEKZUG.
(23) Zhang, G. G.; Kazanietz, M. G.; Blumberg, P. M.; Hurley, J . H.
Crystal structure of the cys2 activator-binding domain of protein
kinase C delta in complex with phorbol ester. Cell 1995, 81, 917-
924.
(24) Kinder, F. R.; Tang, Y. S.; Sunay, U. B. Synthesis of Carbon-14
and Tritium Analogues of the Phospholipid Antitumor Agent
SDZ 62-834zi. J . Labelled Compd. Radiopharm. 1992, 31,
829-835.
J M950276V