Synthesis and structure-activity relationships of new 1,3- disubstituted cyclohexanes as structurally rigid leukotriene B4 receptor antagonists

Article abstract of DOI:10.1021/jm9910573

A series of 1-hydroxy-3-[3-hydroxy-7-phenyl-1-hepten-1-yl] cyclohexane acetic acid derivatives was designed based on postulated active conformation of leukotriene B₄ (LTB₄) and evaluated as human cell surface LTB₄ receptor

Full text of DOI:10.1021/jm9910573

© Copyright 1999 by the American Chemical Society
Volume 42, Number 26
December 30, 1999
Articles
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of New 1,3-Disu bstitu ted
Cycloh exa n es a s Str u ctu r a lly Rigid Leu k otr ien e B4 Recep tor An ta gon ists
J ean-Marc Poudrel,† Pierre Hullot,† J ean-Pierre Vidal,† J ean-Pierre Girard,*,† J ean-Claude Rossi,†
Agne`s Muller,‡ Claude Bonne,‡ Vladimir Bezuglov,| Igor Serkov,| Pierre Renard,§ and Bruno Pfeiffer§
Laboratoire de Chimie Biomole´culaire et des Interactions Biologiques and Laboratoire de Physiologie cellulaire,
CNRS 5074, Faculte´ de Pharmacie, 34060 Montpellier, France, Shemyakin Orchinikov Institute of Bioorganic Chemistry,
Russian Academy of Science, Moscow, Russia, and Socie´te´ Servier-Adir, 1 rue Carle-He´bert, 92415 Courbevoie Cedex, France
Received April 12, 1999
A series of 1-hydroxy-3-[3-hydroxy-7-phenyl-1-hepten-1-yl] cyclohexane acetic acid derivatives
was designed based on postulated active conformation of leukotriene B4 (LTB4) and evaluated
as human cell surface LTB4 receptor (BLTR) antagonists. Binding was determined through
[3H]LTB4 displacement from human neutrophils and receptor antagonistic assays by in vitro
measurements of inhibition of leukocyte chemotaxis induced by LTB4. On the basis of these
assays, a structure-affinity relationship was investigated. Optimization of the acid chain length
and ω-substitution of a phenyl group on the lipophilic tail were shown to be critical for binding
activity. These modifications led to the discovery of compounds with submicromolar potency
and selective BLTR antagonism. The most potent compound 3bR (IC50 ) 250 nM) was found
to significantly inhibit oedema formation in a topical model of phorbolester-induced inflam-
mation. Substantial improvement of in vitro potency was achieved by modification of the
carboxylic acid function leading to the identification of the N,N-dimethylamide series. Compound
5bR, free of agonist activity, displayed higher potency in receptor binding with an IC50 of 40
nM. These results support the hypothesis that the spatial relationship between the carboxylic
acid and allylic hydroxyl functions is crucial for high binding affinity with BLTR.
In tr od u ction
Phe (fMLP). In addition, LTB4 production is upregulated
by many other inflammatory mediators.
Among the products of the 5-lipoxygenase-catalyzed
peroxidation of arachidonic acid (AA), leukotriene B4
(LTB4, Figure 1A) has been claimed to be the mediator
of a wide variety of human inflammatory diseases.1
LTB4 can stimulate neutrophil chemotaxis at submi-
cromolar concentrations,2a being equipotent in vitro to
other major chemokines including interleukin-8 (IL-8),
platelet activating factor (PAF), and formyl-Met-Leu-
Other pathophysiological responses of LTB4 include
promotion of polymorphonuclear leukocyte (PMNs) ag-
gregation and adherence to the vascular endothelium,2b
stimulation of the release of lysosomal enzymes and
superoxide radicals by PMNs,2c as well as an increase
in vascular permeability.2d The involvement of LTB4 in
human inflammatory diseases is also supported by
elevated concentrations of this mediator in psoriatic
lesional skin,3a,b colonic mucosa associated with inflam-
matory bowel diseases3c (ulcerative colitis and Crohn
disease), synovial fluid of patients with active rheuma-
toid arthritis,3d-f gouty effusions,3g sputum of cystic
† Laboratoire de Chimie Biomole´culaire et des Interactions Bio-
logiques, CNRS 5074.
‡ Laboratoire de Physiologie cellulaire, CNRS 5074.
| Russian Academy of Science.
§ Socie´te´ Servier-Adir.
10.1021/jm9910573 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/03/1999

5290 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
Ch a r t 1
F igu r e 1. Possible conformers of LTB4.
fibrosis3h,i and aggravation of patients suffering from
chronic bronchitis,3j asthma,3k or adult respiratory
distress syndrome3l. More recently, it has been reported
that LTB4 can activate the nuclear receptor PPARR,
raising the possibility that it may be involved in
feedback regulation of lipid metabolism.4
LTB4 is produced by mast cells, PMNs, monocytes,
alveolar macrophages, and keratinocytes. Its pharma-
cological effects are mediated through interaction with
specific cell surface receptors on inflammatory cells.5
These LTB4 receptor (BLTR) sites are widely distributed
and have been characterized on PMNs, monocytes,
U-937 cells, lymphocytes, mast cells, smooth muscle
cells, and endothelial cells, as well as on various tissues
such as spleen, lung, heart, brain, small intestine,
uterus, and kidney.1c An LTB4 receptor gene has re-
cently been cloned and encodes a protein of 352 amino
acids predicted to have seven membrane spanning
domains.6 The G proteins associated vary with the type
of cell expressing the LTB4 receptor, allowing diversity
in responses. The BLTR exists in interconvertible high
(Kd, 0.1-5 nM) and low (Kd, 15-500 nM) affinity states.7
Activation causes a rise in intracellular Ca2+ and
inositol-triphosphate concentrations and a fall in adenyl-
cyclase activity.
Since major proinflammatory activity of LTB4 in-
volves a receptor-mediated induction of the aggregation
and adhesion of inflammatory cells, potent and orally
active BLTR antagonists should be of benefit in the
treatment of chronic neutrophil-mediated disorders. For
this reason, research concerning the identification of
selective BLTR antagonists has received considerable
attention in the last 10 years.
The lack of direct information concerning the active
conformation of LTB4 in its receptor site, as well as the
high flexibility of the molecule8 in its free state, has
complicated the selection for representative conforma-
tions mimicking the receptor-bound conformation. How-
ever, a very popular strategy has initially focused on
the conformational restriction of the native ligand and
replacement of its unstable triene unit with a variety
of aromatic rings: benzene,9a-9c pyridine,9d-9g quinoline,9g
thiophene,9h furan,9h or dibenzofuran.9i These rigid and
stable analogues were shown to display good to excellent
affinity for BLTR but their activity was either purely
agonist9a,d,g or selectively antagonist for the low BLTR
affinity state that is associated with degranulation.9b,c,f
Since then, extensive structure-activity relationship
(SAR) studies have led to the identification of new
generations of BLTR antagonists that did not share any
obvious chemical similarity with the native ligand but
displayed high affinity for BLTR binding sites and
F igu r e 2. Structure of novel 1,3-disubstituted cyclohexane
LTB4 antagonists.
potent antagonist activity in functional assays.10a,b
Among them SC-53228,10c LY293111,10d-f SB 209247,10g
and CGS-25019C10a (Chart 1) were shown to be active
in animal or human models of inflammation.10h Some
of these orally active LTBR antagonists are currently
in clinical trials.
As part of our contribution toward the development
of new BLTR antagonists, we investigated the possibil-
ity of replacing the triene moiety instead of an aromatic
ring by a cyclohexylene moiety, using one of the ener-
getically allowed conformations of LTB4 as a template
(Figure 1). We selected the structure B (S-cis geometry
of the conjugated diene ∆6-7 and ∆8-9 and methylene
bridge joining C5-C9). This template also mimics a
collapsed conformation, as previously predicted on a
theoretical basis8a as being the most energetically
probable for a LTB4-calcium complex. It could be the
favored structure interacting with BLTR.
With this in mind, we designed the substituted
cyclohexane compounds 1-16 as mimics of the targeted
collapsed conformation of LTB4. This strategy led to the
identification of a novel series of 1,3-disubstituted
cyclohexane compounds (Figure 2) exhibiting high af-
finity for the receptor and competitive antagonist activ-
ity both in functional assays and in acute models of
inflammation. We must point out here the structurally
different 1,2-disubstituted cyclohexane compounds pre-
sented by Schering Company10i without biological data.

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5291
Sch em e 1a
a
Reagents: (a) n-BuLi, diethyl ether, -78 °C; (b) 3-methoxy-3-methyl-but-1-yne, n-BuLi, diethyl ether, -78 °C; (c) CuBr, Me2S, -20
°C; (d) 2-cyclohexen-1-one, THF, -78 °C, 88% from 17, 75% from 22; (e) DIBAL-H, toluene, -78 °C; (f) 26 or 27, HNA, THF, -40 °C, 86%
from 26, 90% from 27; (g) NaBH4, CeCl3, methanol, rt, 99% from 30, 92% from 33; (h) SiO2, H2SO4, CH2Cl2, rt, 77%; (i) TBDMSCl, DBU,
CH2Cl2, rt 94% from 32, 89% from 35.
We report here the synthesis and SAR study that led
to the development of this novel series of LTB4 antago-
nists.
with the cuprous acetylide at low temperature. In situ
addition of 2-cyclohexen-1-one on the thus obtained
mixed homocuprates afforded the 3-substituted cyclo-
hexanones 19 and 24 (Scheme 1).
Ch em istr y
These two compounds were key intermediates in our
synthetic strategy and have been used to introduce a
variety of substituents, thus affording 1,3-disubstituted
cyclohexanes with a number of different polar chains
(Scheme 2). Condensation of the lithio derivative of
1-(3-bromopropyl)-4-methyl-(2,6,7)-trioxabicyclo[2.2.2]-
octane14 on the 3-substituted cyclohexanone 19, followed
by OBO ortho ester hydrolysis provided the hydroxy acid
20, which was isolated as the corresponding lactone in
56% yield. A similar condensation of lithiated ethyl
acetate on both 19 and 24 provided the hydroxy esters
21 and 25, respectively, with a 92% yield in both cases.
Each compound displayed three stereogenic centers and
provided four racemic diastereoisomers (a , b, c, and d ).
The following general procedure was established as the
most efficient for the purification of the four diastereo-
isomers: (i) Column chromatography or HPLC separa-
tion of the silylated ethers allowed the separation of a
pair (a b) of trans isomers and a pair (cd ) of cis isomers
at the cyclohexyl ring (the trans isomers always being
eluted first on silica gel). (ii) After deprotection of the
alcohol by acidic hydrolysis, isolation of the four dia-
stereoisomers (a , b trans and c, d cis by order of elution
on normal phase) of compounds 1-3 could be achieved.
(iii) Each hydroxy ester diastereoisomer was converted
into its sodium salt by basic hydrolysis (NaOH/MeOH:
H2O) for further biological investigation. The two enan-
tiomers 3br and 3bâ from the racemic mixture 3b were
also separated for evaluation, using a chiral HPLC
column.
Two original synthetic pathways were developed to
prepare our 1,3-disubstituted cyclohexanes. All com-
pounds 1-16 were synthesized according to the proce-
dures outlined in Schemes 1-4. The two general routes
to 1,3-disubstituted cyclohexanes are exemplified for
compounds 1-9 in Schemes 1 and 2, while the prepara-
tion of analogues 10-16 is illustrated in Schemes 3 and
4 and resulted from slight modifications of the former
procedures.
In our initial synthesis of target compounds 1-3, the
lipophilic side chain was introduced on the cyclohexane
ring via the coupling of the mixed homocuprates,11a 18
and 23, with 2-cyclohexen-1-one (Scheme 1). A subse-
quent route involved the use of the Wadsworth-
Horner-Emmons reaction between the ylide of a
â-ketophosphonate11b-d (26 or 27) and cyclohexanecar-
boxaldehyde 29 (Scheme 1). Both methods were quite
flexible and allowed the introduction of a variety of
lipophilic and polar side chains on the cyclohexane ring.
In the initial approach, the iodovinyl precursors 17
and 22 of the mixed homocuprates 18 and 23 were
prepared as previously described from hexanoyl chlo-
ride12a and 5-phenylpentanoic acid,12b respectively. The
mixed homocuprates 18 and 23 were obtained using the
protected iodovinyl alcohols, 17 and 22 as transferable
moieties.13 This procedure involved formation of the
cuprous acetylide from 3-methoxy-3-methyl-but-1-yne,
halogen-metal exchange on the protected iodovinyl
alcohols, and treatment of these organolithium reagents

5292 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
Sch em e 2a
a
Reagents: (a) 20: Br(CH2)3OBO, t-BuLi, THF, -78 °C then 0.02N HCl, THF, 0 °C and LiOH, THF, rt, 56%; 21, 25, and 37: CH3CO2Et,
LDA, THF, -78 °C, 92, 92, and 87%, respectively; 38: CH3CONMe2, LDA, THF, -78 °C, 86%; 39: CH3CONMePh, LDA, THF, -78 °C,
82%; 40: CH3CON(n-Pr)2, LDA, THF, -78 °C, 87%. (b) Chromatoraphic separation. (c) 1 N HCl, THF, rt, 82-84%. (d) HPLC separation.
(e) 8a b: MnO2/C, CH2Cl2, rt, 60%. (f) 9b: H2, 10% Pd/C, 1% NaNO2, ethanol, rt, 87%. *Isolated as the lactone.
Sch em e 3a
a
Reagents: (a) 41: methyl diethylphosphonoacetate, HNa, THF, rt, 96%; 42: N,N-dimethylacetamide phosphonate, HNa, THF, rt,
91%. (b) HPLC separation, 41a b-41cd : 32/68; 42a b-42cd : 39/61. (c) 1N HCl, THF, rt, 92-96%. (d) HPLC separation (except for 10cd ).
(e) FeCl3-Ac2O, 12a b: 81%; 43a b: 18%. (f) H2, 10% Pd/C, 1% NaNO2, ethanol, rt, 85%.
The relative configuration of trans and cis isomers at
the 1,3-disubstituted cyclohexyl compounds was estab-
lished by 1H and two-dimensional NMR spectroscopy
using the silylated ether intermediates (e.g., 25 in Chart
2). First the equatorial position of the bulky lipophilic
chain was clearly established by the large coupling
constants between H3′ and both vicinal H2′ and H4′ (14.8
and 14.3 Hz, respectively), indicating an axial arrange-
ment of all three protons. The respective trans and cis
configurations could then be easily assigned, using the

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5293
Sch em e 4a
a
Reagents: (a) PPTS, acetone/H2O, reflux, 44: 96%; 46: 58%; 47: 14%. (b) CH3COOEt, LDA, THF, -78 °C, 87%. (c) HPLC separation.
(d) CH3Li, diethyl ether, -35 °C to rt, 94%. (e) TBDMSCl, DBU, CH2Cl2, rt, 48: 98%. (f) CH3CONMe2, LDA, THF, -78 °C, 15a -d : 85%;
16a -d : 84%. (g) MSTF, CH2Cl2, -50 °C, 49: 56%; 50: 26%.
Ch a r t 2
influence of the axial or equatorial position of the
quaternary hydroxyl substituent on the chemical shifts
of the axial protons on the cyclohexyl ring. The axial
protons H3′ and H5′ were more deshielded when the
hydroxyl function was locked in an axial position,
whereas H2′ and H6′ were more deshielded when the
hydroxyl function was in an equatorial position.
The first synthetic route described above provided the
target cyclohexanes 1-3 in reasonably good overall
yields. However this methodology suffered from several
drawbacks. First, it required the use of unstable inter-
mediates such as halogeno vinyl ketones. Second,
although the mixed homocuprate coupling was quite
efficient on a small scale, it was more difficult to handle
on the larger quantities required for SAR studies. This
prompted us to explore another synthetic route to the
key 3-substituted cyclohexanones 24 and 36.
This alternate approach (Scheme 1) involved the
Wadsworth-Horner-Emmons condensation15 of the
ylide of a â-ketophosphonate (26 or 27) on the carbox-
aldehyde 29. These â-ketophosphonates were obtained,
as previously16 described, by condensation of 5-phenyl-

5294 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
pentanoyl chloride (or nonanoyl chloride) on the orga-
nocopper derivative of diethyl methylphosphonate at low
temperature. The required ketal ester 28 was prepared
in three steps from methyl 3-hydroxybenzoate in 72%
yield as described elsewhere.17 Further reduction15a of
the methyl ester using DIBAL-H in toluene at -78 °C
afforded the protected 3-oxocyclohexane carboxyalde-
hyde 29. This aldehyde could be isolated and character-
ized but not stored more than several hours.11e For this
reason the reduction of the ester 28 had to be performed
concomitantly to the formation of the ylide of the
appropriate â-ketophosphonate (26 or 27) using sodium
hydride in THF at -40 °C. The resulting crude aldehyde
29 was added on the appropriate ylide as soon as traces
of alcohol were detected (after reduction of 29 for 30
min). According to this procedure, the corresponding
R,â-unsaturated ketones 30 and 33 were prepared in
86% and 90% yield, respectively. As expected, the
configuration of the double bond of these compounds,
of sodium nitrite was found to be necessary in order to
prevent the concomitant dehydroxylation of this com-
pound.
Unsaturated analogues 10 and 11 of â-hydroxyester
3 and â-hydroxyamide 5 were synthesized in excellent
yield by Wadsworth-Horner-Emmons condensation of
the ylide of the appropriate phosphonates (methyl
diethylphosphonoacetate20 and N,N-dimethylamide de-
rivative21) on the key 1,3-disubstituted cyclohexanone
24 (Scheme 3). HPLC separation of the silylated ethers
41 and 42 afforded, in each series, the Z (41-42a b) and
E (41-42cd ) isomers in a 32:68 and 39:61 ratio,
respectively. The stereochemistry of these compounds
was confirmed by NMR spectroscopy (Chart 2), the field
effect of the ester oxygen or amide nitrogen selectively
affecting the equatorial protons H2′e or H6′e in the Z or
E configurations. After acidic hydroxyl deprotection,
each racemic diastereoisomer could be isolated, except
for the mixture 10cd which could not be resolved. The
enantiomers 10br and 10bâ in 10b were further
separated by chiral HPLC for subsequent bioassays.
Acetylated derivatives 12a ,b of the ethylenic com-
pounds 11a ,b were prepared by O-acylation of the
silylated intermediate 42a b using ferric chloride in
acetic anhydride22 (Scheme 3). Besides the expected
acetylated compound 12a b obtained in 81% yield, 18%
of isomerized analogue 43a b could be detected. The
formation of the latter was explained by the generation
of an allylic carbocation intermediate which allowed the
migration of the double bond and attack of the acetate
anion on the carbon R to the cyclohexyl ring. Separation
of these two isomers and isolation of the two racemic
diastereoisomers 43a and 43b was performed by pre-
parative HPLC.
Fully saturated analogues of 10a b-10cd were ob-
tained by palladium catalyzed hydrogenation of 10cd
followed by HPLC separation of the cis and trans
diastereoisomeric mixtures 13a b and 13cd formed in a
72/28 ratio. The relative cis configuration of the major
isomer was established by NMR spectroscopy as previ-
ously described for the silylated â-hydroxyesters 1-3,
confirming that its formation was thermodynamically
favored, due to the equatorial position of both its chains.
Scheme 4 outlines the preparation of the diester
derivative 14 of â-hydroxyesters 3, as well as the
synthesis of methylated and dehydroxyfluorinated ana-
logues 15 and 16 of the â-hydroxyamide 5. Diester
derivatives 14a -d were obtained in two steps from the
dioxolane intermediate 30 after deprotection of the
cyclohexanone and condensation of the lithiated ethyl
acetate on both carbonyl functions of 44. The four
racemic diastereoisomers of 14 were isolated by pre-
parative HPLC, as described previously for 1-3. The
ratio of 14b was surprisingly low compared to 14a , 14c,
and 14d (3% instead of 38%, 31%, and 28%, respec-
tively), probably due to steric hindrance on one face of
the R,â-unsaturated ketone when the short polar chain
occupies the equatorial position.
as established by 1H NMR, proved to be E only (J trans
)
15.9 Hz), no trace of Z analogue being detected. The key
intermediates 24 and 36 were then obtained in three
steps from 30 and 33, by 1,2-reduction of the R,â-
unsaturated ketone using NaBH4 in the presence of
CeCl3 which avoids parallel 1,4-reduction,18 acidic depro-
tection of the carbonyl function using wet silica gel,19
and protection of the allylic alcohol as a tert-butyldi-
methylsilyl ether.
This alternative route to intermediates 24 and 36 via
â-ketophosphonates offered several advantages over the
original approach using homocuprates. Primarily, the
new route provided better overall yields (e.g., 45% for
24 from methyl 3-hydroxybenzoate15b instead of 14%
from 5-phenylpentanoic acid12b). Moreover it involved
stable intermediates that could be stored for a long time
and reproducible reactions that could be scaled more
easily. In addition, several of the intermediates gener-
ated in this procedure were used as starting materials
in the preparation of other modified cyclohexanes
required in our SAR study (cf. Schemes 3 and 4).
Condensation of the lithiated ethyl acetate on the
carbonyl function of 36 led to the â-hydroxyester 37 from
which were isolated four racemic diastereoisomers 4a -d
as previously described (Scheme 2). These isomers were
converted to their sodium salts for biological evaluation.
Similarly, a variety of lithiated acetamides were added
to the 3-substituted cyclohexanone 24 and provided the
â-hydroxyamides 38-40. N,N-dimethylacetamides 5a b
and 5cd , N-methyl-N-phenylacetamides 6a b and 6cd ,
and N,N-dipropylacetamide 7a b were isolated by HPLC
as mixtures of two racemic diastereoisomers each. Only
the individual racemic diastereoisomers 5a and 5b in
5a b were separated for further biological evaluation, as
were the enantiomers 5br and 5bâ in 5b.
Oxidation of the allylic alcohol of 3a was achieved
using manganese (IV) oxide on activated carbon and
provided the R,â-unsaturated ketone 8a b in 60% yield
only, although no side product or starting material could
be recovered (Scheme 2). This was probably due to
partial substrate adsorption onto the carbon, but no
yield enhancement was obtained by Soxhlet extraction.
Palladium catalyzed hydrogenation of 3b afforded the
saturated derivative 9b in 87% yield. A catalytic amount
Preparation of the methylated analogues 15 was
achieved in a five-step procedure starting from dioxolane
30. Introduction of the methyl substituent was per-
formed in high yield by condensation of methyllithium
on the R,â-unsaturated ketone of 30. The only problem-
atic step in this procedure was the acidic deprotection

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5295
Ta ble 1. Effect of the Nature of the Polar Chain and Lipophilic Tail Lengths
a
b
Carboxylic esters were tested into their sodium salts. Inhibition of [3H]LTB4 (1nM) specific binding to human PMNs, assay performed
as described in Experimental Section. c The IC50’s for 2b, 3b, 3bR 5b, and 5bR are the mean ( SEM of values obtained from at least
distinct three assays. TheIC50’s for 2d , 3d , 4b, 4c, and 4d were obtained from two distinct dose-response curves with less than 15%
variation. Inhibition of LTB4 induced chemotaxis of isolated human PMNs, assay performed as described in Experimental Section. pKB
d
were obtained from (n) various experiments.
of the carbonyl function of 45 which gave the expected
tertiary alcohol 46 in only 56% yield along with the
undesired isomerized compound 47 in 14% yield. Again,
this was explained by the generation of a tertiary allylic
carbocation after loss of H2O in acidic medium. How-
ever, no attempt was made to optimize the reaction
yield. The two isomers thus obtained could not be
separated by HPLC due to similar polarities. Advantage
was taken of their differences in reactivity toward a
hydroxyl-protecting agent such as TBDMSCl to purify
the mixture. Selective conversion of the secondary
alcohol 47 to the silylated ether 48 gave the unreacted
tertiary alcohol 46 in a straightforward manner. â-hy-
droxyamides 15a -d were obtained by condensation of
the lithiated N,N-dimethylacetamide on the carbonyl
function of 46, and subsequent HPLC purification as
previously described for the isolation of the four â-hy-
droxyester diastereoisomers 3a -d . In addition, chiral
HPLC separation of both enantiomers 15br and 15bâ
of racemic compound 15b was successfully achieved.
85% yield, to the â-hydroxyamides 16a -d , following the
procedure described for the preparation of 15a -d from
46.
Resu lts a n d Discu ssion
The LTB4 receptor affinities of the test compounds
were determined by evaluating their ability to compete
with the binding of [3H]LTB4 to receptors on intact
human PMNs, the primary target inflammatory cells
of interest. A few selected compounds were also tested
for their ability to compete with the binding of [3H]LTB4
to receptors on guinea pig lung membranes. Most of the
compounds were initially tested at 10 µM versus 1 nM
[3H]LTB4, and IC50 values were determined for the more
potent compounds. The BLTR binding data obtained
from these radioligand assays are summarized in Tables
1 and 2. Incubation of increasing concentrations of
unlabeled LTB4 resulted in a dose-dependent displace-
ment of [3H]LTB4 from its specific binding sites with
IC50 values of 8 nM and 2 nM, respectively, on human
PMNs and guinea pig lung membranes. In addition, the
LTB4 antagonist activity of the most active compounds
in the binding assays was established at the cellular
level in two different functional assays. These com-
pounds were evaluated for their ability to inhibit the
LTB4-induced chemotaxis of intact human PMNs in
Boyden-Keller chambers and the LTB4-induced guinea
pig lung parenchymal strip contraction.
Dehydroxyfluorinated analogues 16a -d were syn-
thesized in two steps from the 3-substituted cyclohex-
anone 32. Treatment of the allylic alcohol with mor-
pholinosulfurtrifluoride23 in dichloromethane at -50 °C
provided the expected allylic fluoro derivative 49 along
with its isomer 50 in an approximate 2:1 ratio. HPLC
separation of these two constitutional isomers provided
the required intermediate 49 which was converted, in

5296 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
Ta ble 2. Analogues with Variation at Allylic Hydroxyl
Our initial compound design utilized a structural
template based upon one of the possible conformations8
of LTB4, its unstable triene unit being replaced by a
cyclohexylene moiety that stabilizes the molecule and
restricts its conformational freedom. This approach led
to the synthesis of compound 1 (Scheme 2) possessing
most of the other features of the native ligand: two
hydroxyl groups in C5 and C12 (LTB4 numbering), a
carboxylic acid function, and a lipophilic tail. Only the
C14-C15 double bond of LTB4 was not included, as it
had previously been shown not to be critical for binding
or functional activity.24 As the initial compound 1b only
showed weak affinity for the LTB4 receptor (IC50 ) 70
µM), a SAR study was initiated in order to characterize
the structural features that could enhance the binding
to LTB4 receptors. This study involved the length and
chemical nature of the lipophilic tail and polar chains
substituting the cyclohexane ring (Table 1) and an
investigation of the relative importance on the binding
affinity of the cyclohexylic (C5) and allylic (C12) hy-
droxyls (Table 2).
(X-Y-Z) and C1 Hydroxyl Group Domains
Very early in this study, it was discovered that within
each series of dihydroxylated compounds 1-5, the more
polar trans diastereoisomers b were the most efficient
at inhibiting the binding of [3H]LTB4 to receptors on
human PMNs and guinea pig lung membranes. Inter-
estingly, a similar result was obtained with unsaturated
Z analogues 10b and 11b. This suggested that the
relative configuration of the allylic hydroxyl on the
lipophilic tail was a key feature for binding. This result
correlated with an earlier study that had established
that 12-epi-LTB4 was 6 times less potent than LTB4 in
binding studies and 25 times less potent in functional
assays.25 Similarly, when mixtures of two racemic
diastereoisomers were tested (a b or cd ), the trans
isomers (a b) were always more potent than the cis
isomers (cd ), indicating a receptor preference for the
trans configuration. All together, these results establish
the importance of the relative orientation of the allylic
hydroxyl and the polar side chain for binding affinity,
indicating that these two functions are strongly inter-
acting with the receptor.
Initial modulation of 1 focused on optimizing the
distance between the allylic hydroxyl and the carbox-
ylic acid moiety, two structural elements required in
the binding to the receptor. Shortening the polar chain
of 1b by two carbon units led to compound 2b which
displayed a higher affinity for the LTB4 receptor
(IC50 ) 8 µM). On the basis of these results, the distance
between the carboxylic acid and the allylic alcohol group
of our disubstituted cyclohexanes was estimated to be
an essential feature for receptor binding. For the first
time (in this series), an antagonist functional activity
was established at the cellular level on human PMNs
with compound 2b that blocks the LTB4-induced chemo-
taxis with a pKB value of 5.10. In vitro this compound
also inhibited the LTB4-induced contraction of guinea
pig lung parenchymal strips with an IC50 value of 0.3
µM.
a,b
See Table 1. c The IC50’s were obtained from two distinct
dose-response curves with less than 15% variation.
compound 2b in order to obtain a compound with a
lipophilicity similar to that of LTB4. This simple ho-
mologation provided compound 4b which, not surpris-
ingly, showed a 10-fold increase of the binding affinity
(IC50 ) 0.9 µM).
Several studies have described ω-oxidation as being
one of the major metabolic pathways of LTB4 leading
to loss of biological activity.27 It was anticipated that
the introduction of an aromatic ring at the end of the
lipidic tail of our compounds would thus enhance their
metabolic resistance by preventing ω-oxidation. The
effective in vivo activity would therefore be increased.
A similar aryl group substitution performed on pros-
taglandin analogues precluded metabolism and led to
derivatives with higher activity and selectivity.28 This
modification was achieved on compound 2 in order to
obtain an analogue of similar lipophilicity to compound
4. With IC50 values of 0.8 µM on human PMNs, the
Previous work had demonstrated that any modifica-
tion in the length of the lipophilic tail of the native LTB4
ligand correlated with a dramatic loss in binding affin-
ity.26 For this reason we thought it would be of interest
to elongate by four carbon units the lipidic tail of

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5297
phenyl-substituted compound 3b was equipotent in
comparison to its linear analogue 4b, indicating that
addition of an aromatic ring did not introduce any
negative interaction within the receptor. However, due
to its expected superior ability to resist metabolic
degradation in vivo, compound 3b was preferred to 4b
for further structural modifications.
One of the isolated enantiomers 3br displayed higher
receptor affinity than the previously tested racemic
compounds (IC50 ) 250 nM), whereas the other enan-
tiomer (3bâ) was not recognized by the LTB4 receptor.
This result clearly indicates the high stereospecificity
of our disubstituted cyclohexanes for the LTB4 receptor.
It is possible that the active enantiomer 3br has the
same R configuration at C12 as the native ligand, but
this needs to be determined.
The antagonist activity of compound 3b was demon-
strated at the cellular level on human PMNs in a LTB4-
induced chemotaxis assay. As expected, the gain in
affinity of 3b over 2b was accompanied by an enhance-
ment of antagonist activity (pKB ) 6.57). This compound
also inhibited the contractile effect of LTB4 on guinea
pig lung parenchymal strips (IC50 ) 40 nM). In a
phorbol-12-myristate-13-acetate (PMA)-induced ear oede-
ma test, 3b exhibited potent antiinflammatory activity
(56% of inhibition at 60 µg/ear vs 50% of inhibition at
10 µg/ear for dexamethasone) when applied topically 30
min prior to the application of PMA. This effect is
probably related to LTB4 antagonism, since 3b did not
show any ability to inhibit either the 5-lipoxygenase or
cyclooxygenase (COX1 and COX2) activities at concen-
trations up to 10 µM. Similarly 3b was inactive against
LTD4-induced guinea pig ileum contraction at up to 10
µM. Therefore compound 3b is characterized by a
specific LTB4 antagonist activity.
Subsequent efforts were directed toward examining
the effect on the binding affinity of modifying the
carboxylic acid moiety of our analogues with various
acetamide functions (Table 1). A previous study indi-
cated that such a replacement could be beneficial for
receptor binding, since the N-methyl-N-phenethylac-
etamide, moiety of the LTB4 antagonist RG14893 ap-
peared as a key feature for its high binding affinity.29
This observation prompted us to prepare the N,N-
dimethylacetamide, N-methyl-N-phenylacetamide and
N,N-dipropylacetamide derivatives of compound 3 (re-
spectively 5, 6, and 7).
chemotaxis assay where it displayed a pKB value of 7.50.
This clearly confirmed that our N,N-dimethylacetamide
derivatives could compete with the high affinity LTB4
binding sites in the receptor that are responsible for the
chemotactic response. In contrast, N,N-dimethylamide-
LTB4 was only shown to be a moderate antagonist of
the LTB4-induced degranulation of rabbit or rat PMNs,
displaying partial agonist activity at higher concentra-
tions and therefore possibly acting by a desensitization
mechanism.30,24a The other acetamide moieties investi-
gated here did not provide the same magnitude of
affinity increase over the carboxylic acid function.
Additional studies focused on determining the role of
the C1 hydroxyl element on receptor binding. It was
established in a previous study that the C5 hydroxyl
group of LTB4 was not a requirement for receptor
binding, since the 5-deoxy-LTB4 retains the high affinity
binding of the native ligand.25 Moreover, the 60 times
weaker binding affinity of 5-epi-LTB4 supported the
hypothesis that inversion of configuration at C5 could
introduce an unfavorable interaction with the receptor.
It was thus anticipated that a similar negative interac-
tion could be responsible for a loss in the affinity of our
dihydroxylated compounds. This led us to remove the
C1 hydroxyl from compounds 3 and 5 and synthesize
the unsaturated derivatives 10 and 11. Compound 10b
(Table 2) displayed a similar potency as its â-hydroxy-
acid analogue 3b, indicating that the C1 hydroxyl is not
required for binding to the receptor. This was confirmed
by the similar potency of the fully saturated derivative
tested as a mixture of two diastereoisomers 13a b, which
displayed higher binding affinity than the isolated
hydroxylated analogue isomer 9b. Again one of the
isolated enantiomers of 10b displayed higher receptor
affinity than the racemic, while the other one, 10bâ, was
not recognized by the receptor. However, in the N,N-
dimethylacetamide series, compound 11b did not retain
the high affinity of its dihydroxylated analogue 5b,
possibly because of the restricted orientation of the
amide function due to the presence of the exocyclic
double bond. Altogether, these results concerning com-
pounds 10 and 11 led to the conclusion that no negative
interaction was introduced by the presence of the C1
hydroxyl in our initial design (unless the observed
inferior binding affinity of cis diastereoisomers com-
pared to trans diastereoisomers was actually a reflection
of this negative interaction).
Replacement of the carboxylic acid moiety for an N,N-
dimethylacetamide function proved to be beneficial for
the binding affinity. With an IC50 value of 80 nM, the
isolated racemic diastereoisomer 5b displayed a 10-fold
enhancement of its affinity compared to that of the 3b
analogue. This increase in affinity was unexpected as
a similar modification of the native ligand provided the
N,N-dimethylamide-LTB4 which only competed for the
low affinity binding sites of LTB4.24b
Evaluation of both enantiomers of 5b provided one
high affinity compound 5br (IC50 ) 40 nM) while 5bâ
did not show any affinity for the LTB4 receptor. This
result correlated well with the one previously obtained
with the â-hydroxyester 3br, confirming the high ste-
reospecificity of these cyclohexane derivatives for the
LTB4 receptor. The antagonist activity of 5br was
further established in a LTB4-induced human PMN
Further efforts were aimed at confirming the key role
of the allylic hydroxyl moiety on receptor binding. To
this end several structural modifications of and around
this function were investigated (Table 2). Oxidation of
the alcohol in 3b provided the R,â-unsaturated ketone
8a b which did not retain any of the binding affinity of
its hydroxylated precursor. Similarly, saturation of the
double bond provided the derivative 9b which displayed
only one-fifth of the affinity observed with its unsatur-
ated analogue 3b, suggesting that an adjacent planar
structure is required for correct orientation of the
hydroxyl group. Taken together these results clearly
identified the allylic alcohol pharmacophore of our initial
design as an essential structural element. These results
were in agreement with earlier studies establishing the
presence of the C12 hydroxyl as a key feature for binding
to the receptor, due to the fact that 12-deoxy-LTB4 is

5298 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
more than 2 orders of magnitude less efficient in the
binding and chemotaxis assays.25 In addition, 10,11-
dehydro-LTB4 and 10,11-dehydro-12-oxo-LTB4 have been
identified in earlier studies as metabolites of LTB4 from
the reductase-dehydrogenase pathway with reduced or
no activity.31
Con clu sion
We have developed novel LTB4 receptor ligands based
on the introduction of a central cyclohexylene system
as a stable substitute for the triene unit of LTB4. To
our knowledge, this is the first time that high affinity
LTB4 antagonists have been developed upon introduc-
tion of a 1,3-disubstituted cyclohexane and not an
aromatic/heteroaromatic ring in place of the triene
moiety. Our SAR studies, based on in vitro receptor
binding assays, have established that the spatial rela-
tionship between the carboxylic acid and the allylic
hydroxyl functions is crucial for receptor binding. Com-
pounds 3br and 5br are stable analogues that display
high affinities for LTB4 receptors on human PMNs and
antagonist profiles with no detectable agonist activity.
They have been selected for further evaluation. This
series of 1,3-disubstituted cyclohexanes provides rigid
mimics of the natural ligand which should prove useful
as biological tools and may lead to significant advances
in our knowledge of the structural organization of the
receptor protein. The LTB4 receptor with the amino acid
sequence reported by Yokomino et al.6a has been ex-
pansed in Escherichia coli, and its interaction with the
antagonist 5br is being characterized at the structural
level.6b In addition it provides a framework for designing
novel leukotriene antagonists which may be useful for
a variety of inflammatory diseases.
O-Acylation of the allylic hydroxyl of the unsaturated
compound 11b led to derivative 12b with no affinity for
the LTB4 receptor, again indicating the necessity for a
hydrogen bond donor substituent or tight steric require-
ments of the binding site. However this result was
somewhat unexpected as the diacetyl-LTB4 had previ-
ously been described as a competitive inhibitor of LTB4-
induced chemotaxis of human PMNs at equimolar
concentrations with LTB4.32
Introduction of a second carboxylic acid function in
LTB4 antagonists has recently been the focus of several
studies.31d This structural modification provided ana-
logues with enhanced binding affinity, suggesting the
existence of two acid sites within the receptor protein.
With this in mind, we introduced a second carboxylic
acid group on C12 of compound 3, postulating that this
function would interact with the binding site usually
occupied by the allylic hydroxyl. The resulting derivative
14 did not show any affinity for the BLTR, clearly
indicating that the allylic hydroxyl could not be replaced
with a carboxylic function in this series.
Given the key role of the allylic hydroxyl in this series
of 1,3-disubstituted cyclohexanes, the last structural
modifications were aimed at enhancing their metabolic
stability toward the reductase-dehydrogenase pathway.
To this end, it was postulated that introduction of a
methyl group at C12 would prevent the oxidation of the
allylic hydroxyl, thus providing a metabolically stable
analogue of 5. Such a modification has previously been
used to provide 12(R)-methyl-LTB3 as a potent agonist
of LTB4 with a binding affinity similar to that of LTB3.33
Surprisingly, the methylated derivative 15b did not
retain the high affinity of its precursor 5b. Further
isolation of the enantiomer 15bâ did not provide any
affinity enhancement. This result suggested that the
newly introduced methyl substituent prevented the key
interaction of the allylic hydroxyl group with the recep-
tor protein.
Exp er im en ta l Section
Ch em ica l Meth od s. Melting points (uncorrected) were
measured in open capillary tubes on a Bu¨chi Tottoli melting
point apparatus. Mass spectra (MS) were recorded on a J EOL
DX-300 mass spectrometer or on a J EOL SX-102 mass spec-
trometer at Laboratoire de Mesures Physiques de l’Universite´
Montpellier II. Proton nuclear magnetic resonance (1H NMR)
spectra were obtained at room temperature on a Bruker AMX-
1
360 or AC-100 instrument with the solvents indicated. All H
NMR chemical shifts are reported in parts per million (δ)
relative to tetramethylsilane (TMS, δ 0.00) as the internal
standard. Assignments were made using 13C, homonuclear,
and heteronuclear bidimensional NMR. 31P NMR spectra were
recorded on a Bruker WP-200SY instrument using phosphoric
acid as internal standard. 19F NMR spectra were obtained on
a Bruker AC-250 instrument. Infrared (IR) spectra were
recorded on a Beckmann Acculab-2 spectrophotometer using
samples as liquid films on sodium chloride cells. Maximum
absorption frequencies are reported in cm-1. UV spectra were
obtained on a Varian Super Scan 2 spectrophotometer. Specific
rotation values were determined on a Perkin-Elmer 247
polarimeter at 589 nm. Elemental analyses were performed
by Service Central d’Analyses du CNRS (Vernaison, France)
and were within (0.40% of the calculated values. Analytical
thin-layer chromatography (TLC) was performed using Merck
silica gel 60F254 aluminum-backed plates. HPLC purifications
were performed on Waters HPLC equipment (Model 590 pump,
Model 481 LC spectrophotometer) at room temperature using
Rsil (10 µm, 22 × 250 mm), Inertsil (5 µm, 20 × 250 mm),
Nucleosil (10 µm, 10 × 250 mm) or Chiralcel-OD (5 µm, 10 ×
250 mm) columns with the solvents described. UV detection
was made at 260 nm. Chemicals used in this study were
obtained from Aldrich and solvents from SDS. Tetrahydrofu-
ran (THF) was fresly distilled from sodium-benzophenone,
methanol from sodium, cyclohexane from KOH, dichlo-
romethane from CaCl2 and then from CaH2, and ethyl acetate
from CaH2. All reactions were carried out under nitrogen, and
crude products were purified by chromatography using Ger-
udan SI 60 neutral silica gel (70-230 mesh) with the solvents
described. Nomenclature for the prepared compounds is given
following the IUPAC rules for the nomenclature of organic
In a further attempt to obtain an analogue with
increased metabolic stability toward the reductase-
dehydrogenases, the allylic hydroxyl was replaced with
a fluoro group in 16. Fluorinated derivatives are often
used to reduce the metabolism of hydroxylated com-
pounds as they are not subjected to oxidation.34 The
fluoro group is usually an excellent bioisostere for
hydroxyl functions as most of the physicochemical
parameters of oxygen and fluoro atoms are similar (bond
length, electronegativity). In addition, if steric effects
were here partly responsible for the reduced affinity of
12, 14, and 15, the smaller fluoro group may be
advantageous. When evaluated in receptor binding
assays, the fluoro analogues did exhibit some affinity
for the LTB4 receptor (IC50 ) 2 µM for 16a ), but did not
fully retain the potency of their hydroxylated analogues
5. Again, one possible explanation for this partial loss
of affinity could be the requirement for a hydrogen bond
donor substituent, in contrast to the fluoro group.

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5299
compounds. All tested compounds bearing an ester function
were tested as sodium salts after saponification.
diethyl ether: 65/35, 10 mL/min; 20a b: 26 min; and 20cd : 36
min) provided compounds 20a b (0.730 g, 1.789 mmol) and
20cd (0.890 g, 2.181 mmol).
3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-oct-1-en -1-yl]cyclo-
h exa n on e (19). A solution of compound 1712a (2.21 g, 6 mmol)
in dry diethyl ether (50 mL) was cooled to -78 °C and treated
with a 1.54 M solution of n-butyllithium in hexane (3.9 mL, 6
mmol). The mixture was stirred for 2 h at -78 °C. In parallel,
the cuprous acetylide was prepared10,13 from a stirred and
cooled to -50 °C solution of 3-methoxy-3-methyl-but-1-yne
(0.588 g, 6 mmol) in dry diethyl ether (25 mL), to which was
added dropwise n-butyllithium 1.54 M in hexane (3.9 mL, 6
mmol). At the end of the addition, the mixture was brought
back to -10 °C in 15 min and kept at this temperature for 15
min. Dry copper bromide-methyl sulfide complex (1.235 g, 6
mmol) was then added at -20 °C. A yellow coloration was
immediately observed, which rapidly turned to orange. After
30 min of stirring between -20 °C and -15 °C, the suspension
of copper salt had disappeared. The cuprous acetylide was
progressively added under nitrogen via a transfer needle to a
-78 °C solution of the silylated organolithium derivative. The
pale orange medium was brought back to -45 °C in 30 min
and kept at this temperature during 45 min to become pale
yellow. A solution of 2-cyclohexen-1-one (0.377 g, 3.3 mmol)
in dry THF (2 mL) was added dropwise to the -78 °C resulting
solution of the mixed cuprate 18. The golden yellowish medium
was brought back to -60 °C and became red-orange after 2 h
at this temperature. After a cold hydrolysis with saturated
NH4Cl, diethyl ether (50 mL) was added and the reaction
mixture was filtered through Celite. The aqueous layer was
extracted with diethyl ether, and the combined organic layers
were washed with distilled water and dried over anhydrous
sodium sulfate. After evaporation of the solvent, the residue
was chromatographed on silica gel. Elution with cyclohexane/
diethyl ether (90/10) afforded the title compound 19 (0.985 g,
(1S*,3S*)-3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-oct-1-en -
1-yl]-1-cycloh exa n e-6-sp ir o-δ-va ler ola ct on e (20a b ): 1H
NMR (360 MHz, CDCl3) δ 5.37 (m, 2H, H1′′ and H2′′), 3.96 (q,
J ) 6.4 Hz, 1H, H3′′), 2.52 (m, 1H, H3′), 2.45 (t, 2H, J ) 6.4 Hz,
H3), 1.95-0.90 (m, 20H, H4-H5, H2′, H4′-H6′ and H4′′-H7′′), 0.84
(m, 12H, Si-t-Bu and H8′′), 0.0 (d, 6H, Si-CH3); IR (film) 1730.
Anal. (C24H44O3Si) C, H, O.
(1R*,3S*)-3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-oct-1-en -
1-yl]-1-cycloh exa n e-6-sp ir o-δ-va ler ola ct on e (20cd ): 1H
NMR (360 MHz, CDCl3) δ 5.36 (m, 2H, H1′′ and H2′′), 3.95 (q,
J ) 6.4 Hz, 1H, H3′′), 2.46 (m, 2H, H3), 2.02 (m, 1H, H3′), 1.90-
0.95 (m, 20H, H4-H5, H2′, H4′-H6′ and H4′′-H7′′), 0.85 (m, 12H,
Si-t-Bu and H8′′), 0.0 (d, 6H, Si-CH3); IR (film) 1730. Anal.
(C24H44O3Si) C, H, O.
Eth yl 1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth ylsilyloxy-
oct-1-en -1-yl]-1-cycloh exa n e Aceta te (21). To a 1.59 M
solution of n-butyllithium in hexane (6.8 mL, 10 mmol) at -80
°C under nitrogen in a 1-L three-necked flask was added
dropwise in 30 min a solution of freshly distilled diisopropyl-
amine (1.165 g, 11.52 mmol) in dry THF (40 mL). The medium
was stirred for 40 min at -78 °C, and freshly distilled ethyl
acetate (0.996 g, 11.268 mmol) in dry THF (7 mL) was added
dropwise in 30 min. After 30 min of stirring at -78 °C,
compound 19 (2.106 g, 6.23 mmol) in dry THF (15 mL) was
added dropwise. The temperature was slowly allowed to rise
to room temperature during the 16 h of stirring after which
the mixture was hydrolyzed with ice-cold water (10 mL). The
aqueous layer was extracted with diethyl ether and the
combined organic layers were washed with distilled water
(2 × 50 mL) and dried over anhydrous sodium sulfate.
Evaporation of the solvent afforded an oily residue (2.7 g)
which was chromatographed on silica gel. Elution of cyclohex-
ane/diethyl ether (92/8) afforded separation of the two isomers
21a b (1.194 g, 2.80 mmol) and 21cd (1.220 g, 2.86 mmol) in
45% and 46% yield, respectively.
1
2.90 mmol) in 88% yield: H NMR (60 MHz, CCl4) δ 5.40 (m,
2H, H1′′ and H2′′), 4.05 (m, 1H, H3′′), 2.23-1.83 (m, 9H, H2′-
H6′), 1.3 (m, 8H, H4′′-H7′′), 0.91 (m, 12H, Si-t-Bu and H8′′), 0.0
(m, 6H, Si-CH3); IR (film) 1705; MS (IE, 20 eV) m/z 281 (M -
t-Bu). Anal. (C20H38O2Si) C, H, O.
Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth -
ylsilyloxy-oct-1-en -1-yl]-1-cycloh exa n e Aceta te (21a b): 1H
NMR (360 MHz, CDCl3) δ 5.41 (ABXY, 1H, J ) 15.9 Hz and
J ) 5.8 Hz, H1′′), 5.33 (ABXY, 1H, J ) 15.9 Hz and J ) 5.8
Hz, H2′′), 4.16 (q, J ) 7.2 Hz, 2H, CH2CH3), 3.97 (q, J ) 6.4
Hz, 1H, H3′′), 3.32 (m, 1H, OH), 2.40 (s, 2H, H2), 2.38 (m, 1H,
H3′), 1.80-0.90 (m, 16H, H2′, H4′-H6′ and H4′′-H7′′), 1.26 (t, 3H,
J ) 7.2 Hz, CH3), 0.86 (m, 12H, Si-t-Bu and H8′′), 0.0 (d, 6H,
Si-CH3); IR (film) 3500, 1720. Anal. (C24H46O4Si) C, H, O.
Eth yl (1R*,3S*)-1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth -
ylsilyloxy-oct -1-en -1-yl]-1-cycloh exa n e Acet a t e (21cd ):
1H NMR (360 MHz, CDCl3) δ 5.41 (ABXY, J ) 15.5 Hz and
J ) 6.1 Hz, 1H, H1′′), 5.33 (ABXY, J ) 15.5 Hz and J ) 6.1
Hz, 1H, H2′′), 4.22-4.12 (m, 2H, CH2CH3), 3.98 (q, J ) 6.4 Hz,
1H, H3′′), 3.79 (s, 1H, OH), 2.58 (d, J ) 15.0 Hz, 2H, H2), 2.02
(m, 1H, H3′), 1.80-0.95 (m, 16H, H2′, H4′-H6′ and H4′′-H7′′), 1.26
(t, 3H, J ) 7.2 Hz, CH3), 0.85 (m, 12H, Si-t-Bu and H8′′), 0.0
(d, 6H, Si-CH3); IR (film) 3500, 1720. Anal. (C24H46O4Si) C, H,
O.
3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-7-p h en yl-1-h ep ten -
1-yl]cycloh exa n on e (24). Procedure from 22 via the mixed
cuprate 23: Compound 24 was prepared from 2212b according
to the procedure described for 19. Purification by column
chromatography (eluent: cyclohexane/diethyl ether (96/4))
afforded the title compound 24 in 75% yield.
Procedure from 32: A stirred solution of tert-butyldimeth-
ylsilyl chloride (19.3 g, 128 mmol) and DBU (23.37 g, 153.5
mmol) in dry dichloromethane (160 mL) was cooled to 0 °C
under nitrogen. A solution of the compound 32 (30.5 g, 106.64
mmol) in dry dichloromethane (100 mL) was added dropwise,
and the mixture was stirred for 48 h at room temperature.
The reaction was hydrolyzed with distilled water and the
aqueous layer extracted with diethyl ether. The combined
organic layers were washed with 0.1 N HCl, saturated
NaHCO3, and distilled water and dried over anhydrous sodium
sulfate. After evaporation of the solvent, the residue was
3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-oct-1-en -1-yl]-1-cy-
cloh exa n e-6-sp ir o-δ-va ler ola cton e (20). To a stirred solu-
tion of (3-bromopropyl)-4-methyl(2,6,7)-trioxabicyclo[2.2.2]-
octane14 (2.1 g, 8.366 mmol) in dry THF (30 mL) under nitrogen
at -78 °C was added dropwise over 20 min a 1.8 M solution
of tert-butyllithium in pentane (9.3 mL, 16.7 mmol). The
reaction mixture was stirred for 30 min at -60 °C and then
cooled to -78 °C. A solution of 19 (2.38 g, 8.366 mmol) in dry
THF (10 mL) was added dropwise over 10 min, and the
temperature was slowly allowed to rise to room temperature
during the 4 h of stirring. The medium was hydrolyzed with
ice-cold water (10 mL), the aqueous layer was extracted with
diethyl ether, and the combined organic layers were washed
with distilled water and dried over anhydrous sodium sulfate.
Evaporation of the solvent afforded an oily residue (4.5 g)
which was chromatographed on silica gel pretreated with 10%
triethylamine in cyclohexane. Elution of diethyl ether contain-
ing 1% triethylamine afforded 2.810 g of the expected OBO
ortho ester which was dissolved in THF (50 mL). A 0.02 N
solution of HCl (12 mL, 0.24 mmol) was added dropwise at 0
°C for selective deprotection. After 40 min of stirring at room
temperature, the reaction was quenched with saturated Na2-
CO3. The reaction mixture was extracted with diethyl ether,
and the combined organic layers were dried over anhydrous
sodium sulfate. After evaporation of the solvent, the interme-
diate ester was dissolved in THF (100 mL) and a 0.1 N solution
of LiOH (60 mL) was added. Stirring was continued for 2 h,
and the medium was acidified with a 0.1 N solution of HCl.
After diethyl ether extraction, the combined organic layers
were washed with distilled water and dried over anhydrous
sodium sulfate. Evaporation of the solvent afforded a residue
which was chromatographed on silica gel. Elution of cyclohex-
ane/diethyl ether (70/30) afforded the title compound 20 (1.911
g, 4.685 mmol) in 56% yield. Further preparative HPLC
chromatography (10 µm Rsil, 22 × 250 mm, cyclohexane/

5300 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
purified by column chromatography (eluent: cyclohexane/
min and stirred for 16 h. The medium was hydrolyzed with
brine and stirred for 1 h 30. The reaction mixture was filtrated
over Celite and the cake washed with dichloromethane. The
combined organic layers were washed with brine and dried
over anhydrous sodium sulfate. After evaporation of the
solvent, a yellow oil (36.2 g) was obtained containing the title
compound 30 and a small amount of unreacted ester 28 (4%)
and unreacted â-ketophosphonate 26 (11.5%). The ester was
distilled off under reduced pressure (bp0.01 ) 60-70 °C). The
residue was then chromatographed on silica gel. Elution of
cyclohexane/diethyl ether (80/20) afforded the title compound
30 (29.5 g, 90 mmol) in 86% yield: 1H NMR (360 MHz, CDCl3)
δ 7.24 (m, 2H, H10′′), 7.14 (m, 3H, H9′′ and H11′′), 6.71 (ABX,
1H, J ) 16.0 Hz and J ) 6.8 Hz, H1′′), 6.02 (ABX, J ) 16.0 Hz
and J ) 1.2 Hz, 1H, H2′′), 3.91 and 3.92 (s, 4H, H1 and H2),
2.60 (t, J ) 7 Hz, 2H, H7′′), 2.52 (t, J ) 3.5 Hz, 2H, H4′′), 2.44
(m, 1H, H3′), 1.79 (m, 1H, H2′e), 1.77 (m, 1H, H5′e), 1.74 (m,
1H, H4′e), 1.73 (m, 1H, H6′e), 1.63 (m, 2H, H5′′), 1.63 (m, 2H,
diethyl ether, 97/3) to afford the title compound 24 (40.1 g,
1
100.2 mmol) in 94% yield: H NMR (360 MHz, CDCl3) δ 7.25
(m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′), 5.47 and 5.46 (ABXY,
J ) 15.5 Hz and J ) 6.0 Hz, 1H, H1′′), 5.38 (ABXY, J ) 15.5
Hz and J ) 6.1 Hz, 1H, H2′′), 3.99 (t, J ) 6.0 Hz, 1H, H3′′),
2.58 (t, J ) 7.7 Hz, 2H, H7′′), 2.45 (m, 1H, H3′), 2.40 (d, J )
13.6 Hz, 1H, H2′e), 2.35 (d, J ) 12.6 Hz, 1H, H6′e), 2.25 (td,
J ) 11.8 Hz and J ) 5.8 Hz, 1H, H6′a), 2.15 (t, J ) 12.7 Hz,
1H, H2′a), 2.03 (d, J ) 13.6 Hz, 1H, H5′e), 1.88 (d, J ) 13.6 Hz,
1H, H4′e), 1.67 (q, J ) 14.6 Hz, 1H, H5′a), 1.59 (quint, J ) 7.7
Hz, 2H, H6′′), 1.46 (qd, J ) 13.1 Hz and J ) 4.0 Hz, 1H, H4′a),
1.44 (m, 2H, H4′′), 1.31 (m, 2H, H5′′), 0.86 (s, 9H, Si-t-Bu), -0.01
and 0.00 (s, 6H, Si-CH3); IR (film) 1710; MS (FAB+): m/z 343
(M+ - t-Bu, 62). Anal. (C25H40O2Si) C, H.
Eth yl 1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth ylsilyloxy-7-
p h en yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te (25). Com-
pound 25 was prepared from 24 according to the procedure
described for 21. Elution on silica gel (cyclohexane/diethyl
ether: 92/8) afforded a first separation of the two isomers 25a b
and 25cd which were further purified by preparative HPLC
(5 µm Inertsil, 20 × 250 mm, cyclohexane/diethyl ether: 92/8,
12 mL/min; 25a b: 26 min; and 25cd : 36 min). After HPLC
chromatography, compounds 25a b (12.9 g, 26.39 mmol) and
25cd (15.0 g, 30.69 mmol) were isolated in, respectively, 42.5%
and 49.5% yield.
Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth -
ylsilyloxy-7-p h en yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te
(25a b): 1H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H, H10′′), 7.14
(m, 3H, H9′′ and H11′′), 5.41 and 5.42 (ABXY, 1H, J ) 15.9 Hz
and J ) 5.8 Hz, H1′′), 5.34 (ABXY, 1H, J ) 15.9 Hz and J )
5.8 Hz, H2′′), 4.17 (q, 2H, J ) 7.1 Hz, CH2CH3), 3.99 (q, 1H,
J ) 6.2 Hz, H3′′), 3.20 (s, 1H, OH), 2.58 (t, 2H, J ) 7.7 Hz,
H7′′), 2.42 (m, 1H, H3′), 2.41 (s, 2H, H2), 1.76 (d, 1H, J ) 13.4
Hz, H2′e), 1.74 (m, 1H, H5′a), 1.73 (d, 1H, J ) 13.4 Hz, H6′e),
1.73 (m, 1H, H4′e), 1.60 (m, 2H, H6′′), 1.56 (m, 1H, H5′e), 1.46
(m, 2H, H4′′), 1.33 (m, 2H, H5′′), 1.26 (t, 3H, J ) 7.1 Hz, CH3),
1.21 (td, 1H, J ) 14.4 Hz and J ) 4.3 Hz, H6′a), 1.04 (t, 1H,
J ) 14.8 Hz, H2′a), 0.94 (qd, 1H, J ) 14.3 Hz and J ) 3.7 Hz,
H
6′′), 1.49 (q, J ) 14.4 Hz, 1H, H5′a), 1.44 (td, J ) 13.2 Hz and
J ) 4.0 Hz, 1H, H6′a), 1.36 (t, J ) 12.6 Hz, 1H, H2′a), 1.08 (qd,
J ) 12.8 Hz and J ) 4.0 Hz, 1H, H4′a); IR (film) 1690, 1630,
970; MS (FAB+) m/z 329 (M + H+). Anal. (C21H28O3) C, H.
1,1-Eth ylen edioxy-3-[(E)-3-h ydr oxy-7-ph en yl-1-h ep ten -
1-yl]cycloh exa n e (31). To a stirred solution of compound 30
(40.05 g, 122.1 mmol) in distilled methanol (400 mL) in a 1 L
three-neck round-bottom flask was added cerium chloride
heptahydrate (45.5 g, 122.12 mmol). The reaction mixture was
stirred for 35 min during which the salt progressively dis-
solved. The medium was cooled to 9 °C, and sodium borohy-
dride (4.65 g, 123 mmol) was slowly added portionwise in 55
min. After the addition, the flask walls were rinsed with
methanol (70 mL) and the reaction mixture was allowed to
warm to room temperature and was stirred for 4 h. The
medium was cooled with an ice bath and hydrolyzed until
neutral pH with 2 N HCl, and brine (100 mL) was added. The
water layer was extracted with diethyl ether and the combined
organic layers washed with brine and dried over anhydrous
sodium sulfate. After evaporation of the solvent the title
compound 31 (40.12 g, 121.5 mmol) was obtained as a slightly
colored oil in 99.5% yield and could be used as such in the
following step: 1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′),
7.15 (m, 3H, H9′′ and H11′′), 5.54 (ABXY, J ) 15.4 Hz and J )
6.5 Hz, 1H, H1′′), 5.41 (ABXY, J ) 15.7 Hz and J ) 7.0 Hz,
1H, H2′′), 4.01 (q, J ) 6.5 Hz, 1H, H3′′), 3.93 and 3.95 (s, 4H,
H1 and H2), 2.59 (t, J ) 7.7 Hz, 2H, H7′′), 2.27 (m, 1H, H3′),
1.74 (m, 1H, H2′e), 1.73 (m, 1H, H5′e), 1.72 (m, 1H, H6′e), 1.70
(m, 1H, H4′e), 1.62 (m, 2H, H6′′), 1.50 (m, 2H, H4′′), 1.50 (m,
1H, H5′a), 1.41 (m 1H, H6′a), 1.35 (m, 2H, H5′′), 1.30 (t, J ) 12.6
Hz, 1H, H2′a), 1.0 (q, J ) 12.5 Hz, 1H, H4′a); IR (film) 3440,
1660, 960; MS (FAB+) m/z 313 (M + H+ - H2O). Anal.
(C21H30O3) C, H.
H
4′a), 0.87 (s, 9H, Si-t-Bu), 0.01 and -0.01 (s, 6H, Si-CH3); IR
(film) 3500, 1710; MS (FAB+) m/z 339 (M - H2O - OTBDMS).
Anal. (C29H48O4Si) C, H.
Eth yl (1R*,3S*)-1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth -
ylsilyloxy-7-p h en yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te
(25cd ): 1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15
(m, 3H, H9′′ and H11′′), 5.40 (ABXY, J ) 15.5 Hz and J ) 6.1
Hz, 1H, H1′′), 5.32 (ABXY, J ) 15.5 Hz and J ) 6.1 Hz, 1H,
H2′′), 4.17 (q, J ) 7.3 Hz, 2H, CH2CH3), 3.98 (q, J ) 5.6 Hz,
1H, H3′′), 3.79 (s, 1H, OH), 2.58 (t, J ) 7.2 Hz, 2H, H7′′), 2.58
(s, 2H, H2), 2.00 (m, 1H, H3′), 1.76 (d, J ) 13.7 Hz, 1H, H2′e),
1.76 (d, J ) 13.7 Hz, 1H, H6′e), 1.72 (m, 1H, H5′e), 1.65 (m, 1H,
H4′e), 1.60 (m, 2H, H6′′), 1.45 (m, 2H, H4′′), 1.39 (t, J ) 13.1 Hz,
1H, H6′a), 1.32 (m, 2H, H5′′), 1.31 (m, 1H, H5′a), 1.27 (t, J )
14.8 Hz, 1H, H2′a), 1.26 (t, J ) 7.3 Hz, 3H, CH3), 1.00 (qd, J )
14.3 Hz and J ) 3.7 Hz, 1H, H4′a), 0.85 (s, 9H, Si-t-Bu), 0.00
and -0.02 (s, 6H, Si-CH3); IR (film) 3500, 1710; MS (FAB+)
m/z 339 (M - H2O - OTBDMS). Anal. (C29H48O4Si) C, H, O.
1,1-Eth ylen ed ioxy-3-[(E)-3-oxo-7-p h en yl-1-h ep ten -1-yl]-
cycloh exa n e (30). A stirred solution of diethyl-2-oxo-6-
phenylhexylphosphonate 26 (36.4 g, 116.7 mmol) in dry THF
(420 mL) under nitrogen in a 2 L three-neck round-bottom
flask was treated portionwise with sodium hydride 50%
suspension in mineral oil (5.6 g, 116.7 mmol). Formation of
the ylide of the â-ketophosphonate was immediate as a yellow
coloration could be observed. In parallel, to a stirred solution
of ester 28 (21 g, 105 mmol) in dry toluene (420 mL) under
nitrogen at -80 °C in a 1 L three-neck round-bottom flask was
added dropwise in 1 h a 1 M solution DIBAL-H (105 mL, 105
mmol) in toluene. The formation of the aldehyde 29 was
followed by GC, and traces of overreduction could be detected
after 30 min. This solution of aldehyde at -78 °C was added
dropwise in 20 min via a transfer needle to the solution of ylide
cooled to -35 °C. The cooling bath was removed and the
reaction mixture allowed to warm to room temperature in 40
3-[(E)-3-Hyd r oxy-7-p h en yl-1-h ep t en -1-yl]cycloh exa n -
on e (32). To a stirred solution of silica gel (30 g) and a 15 wt
% solution of sulfuric acid (1.5 g) in dichloromethane (50 mL)
in a 250 mL three-neck round-bottom flask cooled with an ice
bath was added dropwise a solution of compound 31 (8.22 g,
24.9 mmol) in dichloromethane (35 mL). After the reaction
mixture was stirred for 16 h at room temperature, sodium
hydrogen carbonate was added and stirring was continued for
3 h. After filtration, silica gel was washed with dichlo-
romethane and the filtrate was washed with brine and dried
over anhydrous sodium sulfate. After evaporation of the
solvent, the residue (6.42 g) obtained as a yellow oil was
purified on silica gel. Elution with cyclohexane/diethyl ether
(65/35) afforded the title compound 32 (5.508 g, 19.25 mmol)
in 77.5% yield: 1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′),
7.15 (m, 3H, H9′′ and H11′′), 5.57 (ABXY, 1H, J ) 15.5 Hz and
J ) 6.5 Hz, H1′′), 5.44 (ABXY, 1H, J ) 15.5 Hz and J ) 6.2
Hz, H2′′), 4.03 (q, 1H, J ) 6.4 Hz, H3′′), 2.59 (t, 2H, J ) 7.6 Hz,
H
7′′), 2.45 (m, 1H, H3′), 2.41 (m, 1H, H2′e), 2.36 (m, 1H, H6′e),
2.25 (m, 1H, H6′a), 2.16 (m, 1H, H2′a), 2.03 (m, 1H, H5′e), 1.88
(m, 1H, H4′e), 1.67 (m, 1H, H5′a), 1.63 (m, 2H, H6′′), 1.52 (m,
2H, H4′′), 1.45 (m, 1H, H4′a), 1.36 (m, 2H, H5′′); IR (film) 3320,

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5301
1690, 960; MS (FAB+) m/z 269 (M - H2O + H+). Anal.
(C19H26O2) C, H.
HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/ethyl acetate:
83/17, 15 mL/min; 38a b: 36 min; and 38cd : 46 min). After
HPLC chromatography, compounds 38a b and 38cd were
isolated in, respectively, 50% and 32% yield.
1,1-Eth ylen ed ioxy-3-[(E)-3-oxo-u n d ec-1-en -1-yl]cyclo-
h exa n e (33). Compound 33 was prepared from diethyl-2-oxo-
decylphosphonate 27 according to the procedure described for
30. Purification by column chromatography (eluent: cyclohex-
ane/diethyl ether, 80/20) afforded the title compound 30 in 70%
(1S*,3S*)-1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-1-N,N-d im eth yl-a c-
eta m id e (38a b): 1H NMR (360 MHz, CDCl3) δ 7.23 (m, 2H,
1
yield: H NMR (60 MHz, CCl4) δ 6.62 (ABX, J ) 15.5 Hz and
H
10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.40 (ABXY, 1H, J ) 15.5
J ) 6.1 Hz, 1H, H1′), 5.95 (ABX, J ) 15.5 Hz, 1H, H2′′), 3.86 (s,
4H, H1 and H2), 2.8-2.1 (m, 3H, H3′ and H4′′), 2-1.05 (m, 20H,
H2′, H4′-H6′, H5′′-H10′′), 1.05-0.65 (m, 3H, H11′′); IR (film) 1680,
1620, 970; MS (IE, 20 eV) m/z 308 (M). Anal. (C19H32O3) C, H,
O.
Hz and J ) 6.5 Hz, H1′′), 5.33 (ABXY, 1H, J ) 15.5 Hz and
J ) 6.8 Hz, H2′′), 5.14 (s, 1H, OH), 3.97 (q, 1H, J ) 6.4 Hz,
H3′′), 2.96 (s, 3H, N-CH3), 2.92 (s, 3H, N-CH3), 2.58 (t, 2H, J )
7.6 Hz, H7′′), 2.45 (m, 1H, H3′), 2.33 (s, 2H, H2), 1.83 (d, 1H,
J ) 15.3 Hz, H2′e), 1.79 (d, 1H, J ) 15.3 Hz, H6′e), 1.76 (q, 1H,
J ) 14.9 Hz, H5′a), 1.71 (d, 1H, J ) 15.3 Hz, H4′e), 1.58 (quint,
2H, J ) 7.5 Hz, H6′′), 1.53 (d, 1H, J ) 16.3 Hz, H5′e), 1.41 (m,
2H, H4′′), 1.33 (m, 2H, H5′′), 1.09 (td, 1H, J ) 13.8 Hz and J )
4.0 Hz, H6′a), 0.94 (t, 1H, J ) 12.6 Hz, H2′a), 0.93 (qd, 1H, J )
14.9 Hz and J ) 3.2 Hz, H4′a), 0.86 (s, 9H, Si-t-Bu), -0.01 and
1,1-E t h ylen ed ioxy-3-[(E)-3-h yd r oxy-u n d ec-1-en -1-yl]-
cycloh exa n e (34). Compound 34 was prepared from 33
according to the procedure described for 31 (92% yield): 1H
NMR (60 MHz, CCl4) δ 5.43 (m, 2H, H1′′ and H2′′), 4.13-3.82
(m, 1H, H3′′), 3.86 (s, 4H, H1 and H2), 2.7-1.05 (m, 24H, H2′-
H6′, H4′′-H10′′ and OH), 1.05-0.65 (m, 3H, H11′′); IR (film) 3440,
1660, 960; MS (IE, 20 eV) m/z 292 (M - H2O, 14). Anal.
(C19H34O3) C, H, O.
0.00 (s, 6H, Si-CH3); IR (film) 3430, 1620, 1145. Anal. (C29H49
NO3Si) C, H, N, O.
-
(1R*,3S*)-1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-1-N,N-d im eth yl-a c-
eta m id e (38cd ): 1H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H,
3-[(E)-3-Hyd r oxy-u n d ec-1-en -1-yl]cycloh exa n on e (35).
Compound 35 was prepared from 34 according to the procedure
described for the preparation of 32. Purification by column
chromatography (eluent: cyclohexane/diethyl ether, 70/30)
afforded the title compound 35 in 76.5% yield: 1H NMR (60
MHz, CCl4) δ 5.53 (m, 2H, H1′′ and H2′′), 4.15-3.8 (m, 1H, H3′′),
2.8-1.1 (m, 24H, H2′-H6′, H4′′-H10′′ and OH), 1.1-0.65 (m, 3H,
H
10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.69 (d, 1H, J ) 5.0 Hz, OH),
5.40 (ABXY, 1H, J ) 15.4 Hz and J ) 6.1 Hz, H1′′), 5.32 (ABXY,
1H, J ) 6.1 Hz and J ) 15.4 Hz, H2′′), 3.97 (q, 1H, J ) 6.1 Hz,
H3′′), 3.02 (s, 3H, N-CH3), 2.94 (s, 3H, N-CH3), 2.57 (t, 2H, J )
7.2 Hz, H7′′), 2.51 (m, 2H, H2), 1.96 (m, 1H, H3′), 1.84 (m, 2H,
H6′e and H2′e), 1.70 (m, 1H, H5′e), 1.65 (m, 1H, H4′e), 1.58 (quint,
2H, J ) 7.5 Hz, H6′′), 1.43 (m, 2H, H4′′), 1.37 (m, 1H, H6′a),
1.29 (m, 3H, H5′′ and H5′a), 1.27 (m, 1H, H2′a), 1.01 (m, 1H, H4′a),
0.85 (m, 9H, Si-t-Bu), 0.01 (m, 6H, Si-CH3); IR (film) 3430,
1620, 1145. Anal. (C29H49NO3Si) C, H, N, O.
H
11′′); IR (film) 3400, 1695, 955; MS (IE, 20 eV) m/z 248 (M -
H2O). Anal. (C17H30O2) C, H, O.
3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-u n d ec-1-en -1-yl]cy-
cloh exa n on e (36). Compound 36 was prepared from 35
according to the procedure described for 24 from 32. Purifica-
tion by column chromatography (eluent: cyclohexane/diethyl
ether, 98.5/1.5) afforded the title compound 36 in 89% yield:
1H NMR (60 MHz, CCl4) δ 5.42 (m, 2H, H1′′ and H2′′), 4.3-3.8
(m, 1H, H3′′), 2.7-1.05 (m, 9H, H2′-H6′), 1.2 (m, 14H, H4′′-H10′′),
0.9 (m, 12H, Si-t-Bu and H11′′), 0.0 (m, 6H, Si-CH3); IR (film)
1705, 960, 825; MS (IE, 20 eV) m/z 323 (M - t-Bu). Anal.
(C23H44O2Si) C, H, O.
Eth yl 1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth ylsilyloxy-
u n d ec-1-en -1-yl]-1-cycloh exa n e Aceta te (37). Compound
37 was prepared from 36 according to the procedure described
for 25. Elution on silica gel afforded isomers 37a b (cyclohex-
ane/diethyl ether: 97/3) and 37cd (cyclohexane/diethyl ether:
96/4) in 42.5% and 44% yield, respectively.
Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth -
ylsilyloxy-u n d ec-1-en -1-yl]-1-cycloh exa n e Aceta te (37a b):
1H NMR (360 MHz, CDCl3) δ 5.38 (ABXY, J ) 15.5 Hz and
J ) 6.1 Hz, 1H, H1′′), 5.31 (ABXY, J ) 15.5 Hz and J ) 6.1
Hz, 1H, H2′′), 4.16 (q, J ) 7.2 Hz, 2H, CH2CH3), 3.96 (q, J )
6.4 Hz, 1H, H3′′), 3.37 (m, 1H, OH), 2.41 (m, 1H, H3′), 2.4 (s,
2H, H2), 1.8-1.11 (m, 23H, CH3, H4′-H6′ and H4′′-H10′′), 1.03
(m, 2H, H2′), 0.84 (m, 12H, Si-t-Bu and H11′′), 0.0 (d, 6H, Si-
CH3); IR (film) 3460, 1710, 960; MS (IE, 20 eV) m/z ) 411
(M - t-Bu). Anal. (C27H52O4Si) C, H, O.
1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth ylsilyloxy-7-p h en -
yl-1-h ep ten -1-yl]cycloh exa n e-1-N-m eth yl-N-p h en yl-a cet-
a m id e (39). Compound 39 was prepared by condensation of
N-methyl-N-phenylacetamide on 24 according to the procedure
described for 25. The residue obtained as an oil was purified
by column chromatography on silica gel (eluent: cyclohexane/
diethyl ether, 88/12) to afford a first separation of the two
isomers 39a b and 39cd which were further purified by
preparative HPLC (10 µm Rsil, 22 × 250 mm, cyclohexane/
diethyl ether: 60/40, 9 mL/min; 39a b: 23 min; and 39cd : 34
min). After HPLC chromatography, compounds 39a b and 39cd
were isolated in, respectively, 45% and 34% yield.
(1S*,3S*)-1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-1-N-m eth yl-N-p h en -
yl-a ceta m id e (39a b): 1H NMR (360 MHz, CDCl3) δ 7.44 (m,
2H, H4), 7.36 (m, 1H, H6), 7.22 (m, 2H, H10′′), 7.14 (m, 5H, H9′′
H11′′ and H5), 5.36 (ABXY, J ) 15.6 Hz and J ) 6.4 Hz, 1H,
1′′), 5.30 (ABXY, J ) 15.6 Hz and J ) 6.9 Hz, 1H, H2′′), 5.14
,
H
(s, 1H, OH), 3.97 (q, J ) 6.4 Hz, 1H, H3′′), 3.26 (s, 3H, N-CH3),
2.58 (t, J ) 7.7 Hz, 2H, H7′′), 2.43 (m, 1H, H3′), 2.12 (s, 2H,
H2), 1.75 (d, J ) 14.1 Hz, 1H, H2′e), 1.75 (q, J ) 15.1 Hz, 1H,
H
5′a), 1.70 (d, J ) 15.8 Hz, 1H, H6′e), 1.68 (d, J ) 16.8 Hz, 1H,
H4′e), 1.61 (quint, J ) 8.4 Hz, 2H, H6′′), 1.50 (d, J ) 15.1 Hz,
1H, H5′e), 1.46 (m, 2H, H4′′), 1.32 (m, 2H, H5′′), 0.91 (td, J )
16.0 Hz and J ) 4.2 Hz, 1H, H6′a), 0.87 (s, 9H, Si-t-Bu), 0.85
(qd, J ) 14.6 Hz and J ) 3.1 Hz, 1H, H4′a), 0.77 (t, J ) 14.3
Hz, 1H, H2′a), -0.01 and 0.00 (s, 6H, Si-CH3); IR (film) 3400,
1625, 1110, 960. Anal. (C34H51NO3Si) C, H, N, O.
Eth yl (1R*,3S*)-1-Hyd r oxy-3-[(E)-3-ter t-bu tyld im eth -
ylsilyloxy-u n d ec-1-en -1-yl]-1-cycloh exa n e Aceta te (37cd ):
1H NMR (360 MHz, CDCl3) δ 5.40 (ABXY, J ) 15.5 Hz and
J ) 6.1 Hz, 1H, H1′′), 5.32 (ABXY, J ) 15.5 Hz and J ) 6.1
Hz, 1H, H2′′), 4.17 (q, J ) 7.2 Hz, 2H, CH2CH3), 3.97 (q, J )
6.4 Hz, 1H, H3′′), 3.83 (m, 1H, OH), 2.57 (m, 2H, H2), 2.02 (m,
1H, H3′), 1.8-1.1 (m, 23H, CH3, H4′-H6′ and H4′′-H10′′), 1.02 (m,
2H, H2′), 0.85 (m, 12H, t-Bu and H11′′), 0.0 (d, 6H, Si-CH3); IR
(film) 3460, 1710, 960; MS (IE, 20 eV) m/z ) 319 (M -
OTBDMS - H2O). Anal. (C27H52O4Si) C, H, O.
(1R*,3S*)-1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-1-N-m eth yl-N-p h en -
yl-a ceta m id e (39cd ): 1H NMR (360 MHz, CDCl3) δ 7.44 (m,
2H, H4), 7.36 (m, 1H, H6), 7.22 (m, 2H, H10′′), 7.14 (m, 5H, H9′′
,
H11′′ and H5), 5.97 (d, 1H, OH), 5.40 (ABXY, 1H, J ) 15.4 Hz
and J ) 6.3 Hz, H1′′), 5.32 (ABXY, 1H, J ) 15.4 Hz and J )
6.7 Hz, H2′′), 3.97 (q, 1H, J ) 6.7 Hz, H3′′), 3.26 (s, 3H, N-CH3),
2.57 (t, 2H, J ) 7.2 Hz, H7′′), 2.26 and 2.32 (AB, 2H, J ) 15.8
Hz, H2), 1.90 (m, 1H, H3′), 1.82 (m, 1H, H2′e), 1.81 (m, 1H, H6′e),
1.72 (m, 1H, H5′e), 1.66 (m, 1H, H4′e), 1.57 (m, 2H, H6′′), 1.44
(m, 2H, H4′′), 1.37 (m, 1H, H6′a), 1.31 (m, 2H, H5′′), 1.26 (m,
1H, H2′a), 1.22 (m, 1H, H5′a), 1.00 (m, 1H, H4′a), 0.83 (s, 9H,
1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-7-ph en yl-
1-h epten -1-yl]cycloh exan e-1-N,N-dim eth yl-acetam ide (38).
Compound 38 was prepared by condensation of N,N-dimethyl-
acetamide on 24 according to the procedure described for 25.
The residue obtained as an oil was purified by column
chromatography on silica gel (eluent: cyclohexane/diethyl
ether, 65/35) to afford a first separation of the two isomers
38a b and 38cd which were further purified by preparative

5302 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
Si-t-Bu), 0.00 and 0.02 (s, 6H, Si-CH3); IR (film) 3400, 1625,
1110, 960. Anal. (C34H51NO3Si) C, H, N, O.
H2′′), 4.01 (q, J ) 6.0 Hz, 1H, H3′′), 3.67 (m, 1H, H2′e), 3.67 (s,
3H, OMe), 2.60 (t, J ) 7.7 Hz, 2H, H7′′), 2.25 (d, J ) 12.7 Hz,
1H, H6′e), 2.17 (m, 1H, H3′), 2.11 (td, J ) 12.7 Hz and J ) 4.6
Hz, 1H, H6′a), 1.91 (m, 1H, H5′e), 1.90 (m, 1H, H2′a), 1.82 (m,
1H, H4′e), 1.62 (m, 2H, H6′′), 1.50 (m, 2H, H4′′), 1.47 (m, 1H,
1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-7-ph en yl-
1-h epten -1-yl]cycloh exan e-1-N,N-dipr opyl-acetam ide (40).
Compound 40 was prepared by condensation of N,N-dipro-
pylacetamide on 24 according to the procedure described for
25. The residue obtained as an oil was purified by column
chromatography on silica gel (eluent: cyclohexane/diethyl
ether, 90/10) to afford a first separation of the two isomers
40a b and 40cd which were further purified by preparative
HPLC (10 µm Nucleosil, 10 × 250 mm, cyclohexane/diethyl
ether: 85/15, 4 mL/min; 40a b: 21 min; and 40cd : 29 min). After
HPLC chromatography, compounds 40a b and 40cd were
isolated in, respectively, 50% and 34.5% yield.
H
5′a), 1.38 (m, 2H, H5′′), 1.32 (m, 1H, H4′a), 0.88 (s, 9H, Si-t-
Bu), 0.02 (s, 6H, Si-CH3); IR (film) 1710, 1640, 960. Anal.
(C28H44O3Si) C, H, O.
Meth yl (E)-3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-7-p h en -
yl-1-h epten -1-yl]cycloh exyliden e Acetate (41cd): 1H NMR
(360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′ and
H11′′), 5.62 (s, 1H, H2), 5.44 (ABXY, J ) 15.5 Hz and J ) 6.5
Hz, 1H, H1′′), 5.36 (ABXY, J ) 6.5 Hz and J ) 15.5 Hz, 1H,
H
2′′), 4.00 (q, J ) 6.0 Hz, 1H, H3′′), 3.67 (s, 3H, OMe), 3.62 (d,
J ) 13.7 Hz, 1H, H6′e), 2.59 (t, J ) 7.7 Hz, 2H, H7′′), 2.26 (m,
1H, H2′e), 2.15 (m, 1H, H3′), 1.99 (m, 1H, H6′a), 1.97 (m, 1H,
H2′a), 1.89 (m, 1H, H5′e), 1.79 (m, 1H, H4′e), 1.60 (quint, J ) 7.5
Hz, 2H, H6′′), 1.49 (m, 2H, H4′′), 1.42 (m, 1H, H5′a), 1.35 (m,
2H, H5′′), 1.29 (m, 1H, H4′a), 0.87 (s, 9H, Si-t-Bu), 0.01 (s, 6H,
Si-CH3); IR (film) 1710, 1640, 960; MS (FAB+) m/z 399 (M -
t-Bu). Anal. (C28H44O3Si) C, H, O.
[3-((E)-3-ter t-Bu tyldim eth ylsilyloxy-7-ph en yl-1-h epten -
1-yl)cycloh exyliden e]-N,N-dim eth yl-acetam ide (42). Com-
pound 42 was prepared by condensation of diethyl N,N-
dimethylacetamidephosphonate to 24 according to the procedure
described for 41. The residue obtained as an oil was purified
by column chromatography on silica gel (eluent: cyclohexane/
diethyl ether, 55/45) to afford a first separation of the two
isomers 42a b and 42cd which were further purified by
preparative HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/
ethyl acetate: 85/15, 15 mL/min; 42a b: 30 min; and 42cd : 44
min). After HPLC chromatography, compounds 42a b and 42cd
were isolated in, respectively, 33.5% and 52.5% yield.
(1S*,3S*)-1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-1-N,N-d ip r op yl-a c-
eta m id e (40a b): 1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H,
H
10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.41 (m, 1H, H1′′), 5.38 (s,
1H, OH), 5.32 (m, 1H, H2′′), 3.96 (q, J ) 5.8 Hz, 1H, H3′′), 3.27
(q, J ) 9.7 Hz and J ) 7.2 Hz, 2H, H6), 3.16 (t, J ) 7.6 Hz,
2H, H3), 2.57 (t, J ) 7.6 Hz, 2H, H7′′), 2.45 (m, 1H, H3′), 2.33
(s, 2H, H2), 1.79 (d, J ) 15.0 Hz, 1H, H2′e), 1.77 (m, 1H, H5′a),
1.76 (d, J ) 13.5 Hz, 1H, H6′e), 1.71 (m, 1H, H4′e), 1.57 (m, 2H,
H4), 1.57 (m, 2H, H6′′), 1.55 (m, 2H, H7), 1.52 (m, 1H, H5′e),
1.43 (m, 2H, H4′′), 1.31 (m, 2H, H5′′), 1.08 (td, J ) 13.5 Hz and
J ) 4.3 Hz, 1H, H6′a), 0.91 (t, 1H, H2′a), 0.91 (m, 3H, H5), 0.89
(m, 1H, H4′a), 0.85 (m, 3H, H8), 0.84 (s, 9H, Si-t-Bu), 0.00 and
0.02 (s, 6H, Si-CH3); IR (film) 3380, 1605, 1120, 960. Anal.
(C33H57NO3Si) C, H, N, O.
(1R*,3S*)-1-Hydr oxy-3-[(E)-3-ter t-bu tyldim eth ylsilyloxy-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-1-N,N-d ip r op yl-a c-
eta m id e (40cd ): 1H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H,
H
10′′), 7.14 (m, 3H, H9′′, H11′′), 5.97 (d, 1H, OH), 5.40 (ABXY,
1H, J ) 15.4 Hz and J ) 6.3 Hz, H1′′), 5.32 (ABXY, 1H, J )
15.4 Hz and J ) 6.7 Hz, H2′′), 3.97 (q, 1H, J ) 6.7 Hz, H3′′),
3.31 and 3.22 (m, 2H, H6), 3.20 (m, 2H, H3), 2.57 (t, 2H, J )
7.2 Hz, H7′′), 2.47 and 2.54 (AB, 2H, J ) 15.8 Hz, H2), 1.90 (m,
1H, H3′), 1.82 (m, 1H, H2′e), 1.81 (m, 1H, H6′e), 1.72 (m, 1H,
[(Z)-3-((E)-3-ter t-Bu tyldim eth ylsilyloxy-7-ph en yl-1-h ep-
ten -1-yl)cycloh exyliden e]-N,N-dim eth yl-acetam ide (42ab):
1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H,
H9′′ and H11′′), 5.72 (s, 1H, H2), 5.46 (ABXY, J ) 15.5 Hz and
J ) 6.1 Hz, 1H, H1′′), 5.35 (ABXY, J ) 6.8 Hz and J ) 15.5
Hz, 1H, H2′′), 3.98 (q, J ) 6.0 Hz, 1H, H3′′), 3.00 (s, 3H, N-CH3),
2.95 (s, 3H, N-CH3), 2.88 (d, J ) 10.8 Hz, 1H, H2′e), 2.58 (t,
J ) 7.7 Hz, 2H, H7′′), 2.22 (m, J ) 12.7 Hz, 1H, H6′e), 2.09 (m,
1H, H3′), 2.04 (td, J ) 12.7 Hz and J ) 4.6 Hz, 1H, H6′a), 1.86
(m, 1H, H5′e), 1.77 (m, 1H, H4′e), 1.73 (t, J ) 10.8 Hz, 1H, H2′a),
1.58 (m, 2H, H6′′), 1.44 (m, 2H, H4′′), 1.41 (m, 1H, H5′a), 1.31
(m, 2H, H5′′), 1.22 (m, 1H, H4′a), 0.85 (s, 9H, Si-t-Bu), 0.00 (s,
6H, Si-CH3); IR (film) 1640, 1630, 1135, 960; MS (FAB+) m/z
338 (M - OTBDMS). Anal. (C29H47NO2Si) C, H, N, O.
[(E)-3-((E)-3-ter t-Bu tyldim eth ylsilyloxy-7-ph en yl-1-h ep-
ten -1-yl)cycloh exyliden e]-N,N-dim eth yl-acetam ide (42cd):
1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H,
H9′′ and H11′′), 5.72 (s, 1H, H2), 5.45 (ABXY, J ) 15.5 Hz and
J ) 6.5 Hz, 1H, H1′′), 5.35 (ABXY, J ) 15.5 Hz and J ) 6.5
Hz, 1H, H2′′), 3.98 (q, J ) 6.0 Hz, 1H, H3′′), 3.00 (s, 3H, N-CH3),
2.95 (s, 3H, N-CH3), 2.86 (d, J ) 12.6 Hz, 1H, H6′e), 2.58 (t,
J ) 7.2 Hz, 2H, H7′′), 2.23 (mt, J ) 12.6 Hz, 1H, H2′e), 2.11 (m,
1H, H3′), 1.91 (mt, J ) 12.6 Hz, 1H, H2′a), 1.86 (m, 1H, H6′a),
1.82 (m, 1H, H5′e), 1.74 (m, 1H, H4′e), 1.59 (quint, J ) 7.6 Hz,
2H, H6′′), 1.46 (m, 2H, H4′′), 1.38 (m, 1H, H5′a), 1.32 (m, 2H,
H
5′e), 1.66 (m, 1H, H4′e), 1.57 (m, 2H, H6′′), 1.56 (m, 2H, H4),
1.52 (m, 2H, H7), 1.44 (m, 2H, H4′′), 1.37 (m, 1H, H6′a), 1.31
(m, 2H, H5′′), 1.26 (m, 1H, H2′a), 1.22 (m, 1H, H5′a), 1.00 (m,
1H, H4′a), 0.93 (t, 3H, J ) 7.6 Hz, H5), 0.86 (m, 3H, H8), 0.83
(s, 9H, Si-t-Bu), 0.00 and 0.02 (s, 6H, Si-CH3); IR (film) 3380,
1605, 1120, 960. Anal. (C33H57NO3Si) C, H, N, O.
Meth yl 3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-7-p h en yl-1-
h ep ten -1-yl]cycloh exylid en e Aceta te (41). To a stirred
solution of sodium hydride 60% dispersion in mineral oil (0.259
g, 6.48 mmol) in freshly distilled THF (25 mL) under nitrogen
in a 100 mL three-neck round-bottom flask equipped with a
dropping funnel, a condenser, and a thermometer was added
dropwise a solution of diethyl methylphosphonoacetate (1.430
g, 6.80 mmol) in dry THF (10 mL). The reaction mixture was
stirred for 30 min at room temperature, and a solution of
compound 24 (1.300 g, 3.24 mmol) in dry THF (10 mL) was
added dropwise in 30 min. The colorless solution became
yellow. The reaction was heated at 60 °C for 1 h and became
orange. The medium was cooled with an ice bath, hydrolyzed
with ice cold water (30 mL), and extracted with diethyl ether
(3 × 100 mL). The combined organic layers were washed with
brine (2 × 10 mL) and dried over anhydrous sodium sulfate.
Evaporation of the solvent afforded an oily residue (1.607 g)
which was chromatographed on silica gel. Elution of cyclohex-
ane/diethyl ether (98/2) afforded a first separation of the two
isomers 41a b and 41cd which were further purified by
preparative HPLC (10 µm Rsil, 22 × 250 mm, cyclohexane/
diethyl ether: 98/2, 5 mL/min; 41a b: 39 min; and 41cd : 42 min
30 s). After HPLC chromatography, compounds 41a b (0.428
g, 0.94 mmol) and 41cd (0.919 g, 2.01 mmol) were isolated in,
respectively, 29% and 62% yield.
H
5′′), 1.22 (m, 1H, H4′a), 0.86 (s, 9H, Si-t-Bu), 0.00 (s, 6H,
Si-CH3); IR (film) 1640, 1630, 1135, 960; MS (FAB+) m/z 338
(M - OTBDMS). Anal. (C29H47NO2Si) C, H, N, O.
3-[(E)-3-Oxo-7-ph en yl-1-h epten -1-yl]cycloh exan on e (44).
To a stirred solution of compound 30 (1.50 g, 4.57 mmol) in
acetone/water: 95/5 (40 mL) was added portionwise pyridinium
p-toluenesulfonate (344 mg, 1.37 mmol). The reaction mixture
was refluxed for 4 h, and the solvent was evaporated under
reduced pressure. The resulting residue was taken up with
diethyl ether, washed with saturated NaHCO3 and with brine,
and dried over anhydrous sodium sulfate. After evaporation
of the solvent, the residue (1.320 g) obtained as an oil was
purified by column chromatography on silica gel (eluent:
cyclohexane/diethyl ether, 80/20) to afford the title compound
Meth yl (Z)-3-[(E)-3-ter t-Bu tyld im eth ylsilyloxy-7-p h en -
yl-1-h epten -1-yl]cycloh exyliden e Acetate (41ab): 1H NMR
(360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′ and
1
H
11′′), 5.64 (s, 1H, H2), 5.50 (ABXY, J ) 15.4 Hz and J ) 5.6
44 as a colorless oil in 96% yield: H NMR (360 MHz, CDCl3)
Hz, 1H, H1′′), 5.41 (ABXY, J ) 6.4 Hz and J ) 15.4 Hz, 1H,
δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′), 6.70 (ABX,

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5303
J ) 15.9 Hz and J ) 6.6 Hz, 1H, H1′′), 6.06 (ABX, J ) 15.9 Hz
and J ) 1.2 Hz, 1H, H2′′), 2.63 (m, 1H, H3′), 2.61 (t, J ) 7.0
Hz, 2H, H7′′), 2.53 (t, J ) 6.9 Hz, 2H, H4′′), 2.45 (d, J ) 14.0
Hz, 1H, H2′e), 2.39 (d, J ) 14.6 Hz, 1H, H6′e), 2.28 (td, J ) 11.9
Hz and J ) 6.0 Hz, 1H, H6′a), 2.23 (t, J ) 12.6 Hz, 1H, H2′a),
2.06 (d, J ) 14.6 Hz, 1H, H5′e), 1.96 (d, J ) 13.0 Hz, 1H, H4′e),
1.72 (q, J ) 15.1 Hz, 1H, H5′a), 1.63 (quint, J ) 3.6 Hz, 2H,
chromatography on silica gel to afford successively compounds
48 (eluent: cyclohexane/diethyl ether, 95/5) and 46 (eluent:
cyclohexane/diethyl ether, 50/50) in quantitative yields: 1H
NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′
and H11′′), 5.09 (d, J ) 8.3 Hz, 1H, H2′′), 4.19 (dd, J ) 5.0 Hz
and J ) 9.0 Hz, 1H, H1′′), 2.60 (t, J ) 7.7 Hz, 2H, H7′′), 2.46 (d,
J ) 14.4 Hz, 1H, H2′e), 2.33 (d, J ) 14.4 Hz, 1H, H6′e), 2.19 (td,
J ) 14.4 Hz and J ) 7.2 Hz, 1H, H6′a), 2.14 (t, J ) 14.4 Hz,
1H, H2′a), 2.04 (d, J ) 16.9 Hz, 1H, H5′e), 2.01 (t, J ) 7.2 Hz,
2H, H4′′), 1.79 (d, J ) 15.9 Hz, 1H, H4′e), 1.78 (m, 1H, H3′),
1.60 (quint, J ) 10.8 Hz, 2H, H6′′), 1.57 (m, 1H, H5′a), 1.44 (qd,
J ) 10.8 Hz and J ) 3.6 Hz, 1H, H4′a), 1.42 (quint, J ) 7.2 Hz,
2H, H5′′), 0.86 (s, 9H, Si-t-Bu), -0.04 and 0.00 (s, 6H, Si-CH3);
IR (film) 3410, 1690, 1650. Anal. (C26H42O2Si) C, H, O.
H
5′′), 1.63 (quint, J ) 3.6 Hz, 2H, H6′′), 1.56 (qd, J ) 11.6 Hz
and J ) 3.7 Hz, 1H, H4′a); IR (film) 1705, 1665, 1625, 970; MS
(FAB+) m/z 285 (M + H+). Anal. (C19H24O2) C, H, O.
1,1-E t h ylen ed ioxy-3-[(E)-3-h yd r oxy-3-m et h yl-7-p h en -
yl-1-h ep ten -1-yl]cycloh exa n e (45). To a stirred solution of
compound 30 (992 mg, 3.020 mmol) in dry diethyl ether (50
mL) under nitrogen in a 100 mL round-bottom flask was added
dropwise at -35 °C a 1.56 M solution of methyllithium (3.72
mL, 5.803 mmol) in diethyl ether. The reaction was exother-
mic, and the mixture became yellow. The reaction mixture was
allowed to warm to room temperature for 1 h. The medium
was hydrolyzed with ice cold water, and stirring was continued
for 20 min. The water layer was extracted with diethyl ether
(2 × 50 mL), and the combined organic layers were washed
with brine (2 × 10 mL) and dried over anhydrous sodium
sulfate. After evaporation of the solvent, the residue (1.103 g)
obtained as a yellow oil was purified by column chromatog-
raphy on silica gel (eluent: cyclohexane/diethyl ether, 85/15)
to afford the title compound 45 (976 mg, 2.833 mmol) as a
3-[(E )-3-F lu or o-7-p h e n yl-1-h e p t e n -1-yl]cycloh e xa n -
on e (49). To a stirred solution of compound 32 (100 mg, 0.349
mmol) in dry freshly distilled dichloromethane (2.5 mL) was
added under nitrogen at -80 °C morpholinosulfurtrifluoride
(50 µL, 0.410 mmol). The reaction mixture was stirred for 10
min at -75 °C and hydrolyzed with saturated NH4Cl (2 mL).
The resulting mixture was transferred to a separatory funnel
containing ethyl acetate (40 mL) and saturated NaHCO3 (10
mL). The organic layer was washed with distilled water (2 ×
10 mL) and brine (10 mL) and dried over anhydrous sodium
sulfate. After evaporation of the solvent, the residue (102 mg)
obtained as an oil was purified by column chromatography on
silica gel (eluent: cyclohexane/diethyl ether, 90/10) to afford
a mixture of isomers 49 and 50 in the ratio 68/32. Further
preparative HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/
ethyl acetate: 95/5, 15 mL/min; 50: 18 min and 49: 21 min)
afforded the separation of compounds 49 (56 mg, 0.195 mmol)
and 50 (26 mg, 0.090 mmol) which were isolated in, respec-
tively, 56% and 26% yield: 1H NMR (360 MHz, CDCl3) δ 7.26
(m, 2H, H10′′), 7.16 (m, 3H, H9′′ and H11′′), 5.67 (m, 1H, H1′′),
5.49 (m, 1H, H2′′), 4.80 (qd, J ) 48.7 Hz and J ) 6.4 Hz, 1H,
H3′′), 2.61 (t, J ) 7.6 Hz, 2H, H7′′), 2.50 (m, 1H, H3′), 2.43 (m,
1H, H2′e), 2.36 (d, J ) 15.2 Hz, 1H, H6′e), 2.28 (t, J ) 11.8 Hz,
1H, H6′a), 2.17 (t, J ) 13.5 Hz, 1H, H2′a), 2.05 (m, 1H, H5′e),
1.92 (m, 1H, H4′e), 1.68 (q, J ) 15.2 Hz, 1H, H5′a), 1.67 (m, 2H,
1
colorless oil in 94% yield: H NMR (360 MHz, CDCl3) δ 7.25
(m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′), 5.52 (ABX, J ) 15.8
Hz and J ) 5.8 Hz, 1H, H1′′), 5.45 (AB, J ) 15.8 Hz, 1H, H2′′),
3.93 (s, 4H, H1 and H2), 2.59 (t, J ) 7.5 Hz, 2H, H7′′), 2.26 (m,
1H, H3′), 1.75 (d, J ) 12.6 Hz, 1H, H2′e), 1.73 (m, 1H, H5′e),
1.72 (m, 1H, H6′e), 1.68 (m, 1H, H4′e), 1.60 (m, 2H, H6′′), 1.57
(m, 1H, H5′a), 1.52 (m, 2H, H4′′), 1.41 (td, J ) 13.3 Hz and J )
4.7 Hz, 1H, H6′a), 1.34 (m, 2H, H5′′), 1.30 (t, J ) 12.6 Hz, 1H,
H
2′a), 1.22 (s, 3H, CH3), 0.99 (qd, J ) 12.2 Hz and J ) 3.6 Hz,
1H, H4′a); IR (film) 3460, 960; MS (FAB+) m/z 327 (M + H+-
H2O). Anal. (C22H32O3) C, H, O.
3-[(E)-3-Hyd r oxy-3-m eth yl-7-p h en yl-1-h ep ten -1-yl]cy-
cloh exa n on e (46). Compound 46 was prepared from 45
according to the procedure described for 44. The residue was
purified by column chromatography on silica gel (eluent:
cyclohexane/diethyl ether, 80/20) to afford a mixture of isomers
46 and 47 in, respectively, 58% and 14% yield (ratio 80:20 as
determined by 1H NMR). As these compounds could not be
separated by HPLC, the mixture was submitted in the follow-
ing step to silylation conditions which derivatized selectively
compound 47.
H
4′′), 1.64 (quint, J ) 7.8 Hz, 2H, H6′′), 1.49 (q, J ) 14.1 Hz,
1H, H4′a), 1.41 (m, 2H, H5′′); 19F NMR (235 MHz, CDCl3)
δ -172.7 (m); IR (film) 1705, 960; MS (FAB+) m/z 269 (M -
HF + H+). Anal. (C19H25OF) C, H, O.
3-[(E )-1-F lu or o-7-p h e n ylh e p t -2-e n -1-yl]cycloh e xa n -
on e (50): 1H NMR (360 MHz, CDCl3) δ 7.26 (m, 2H, H10′′),
7.16 (m, 3H, H9′′ and H11′′), 5.75 (m, 1H, H3′′), 5.46 (m, 1H, H2′′),
4.67 and 4.61 (td, J ) 48.1 Hz and J ) 6.5 Hz, 1H, H1′′), 2.60
(t, J ) 7.6 Hz, 2H, H7′′), 2.38 (d, J ) 15.9 Hz, 1H, H6′e), 2.34
(d, J ) 15.9 Hz, 1H, H2′e), 2.26 (t, J ) 13.5 Hz, 1H, H6′a), 2.14
(t, J ) 13.5 Hz, 1H, H2′a), 2.11 (d, J ) 17.5 Hz, 1H, H5′e), 2.10
(m, 2H, H4′′), 2.06 (m, 1H, H3′), 2.04 (d, J ) 17.5 Hz, 1H, H4′e),
1.63 (quint, J ) 8.3 Hz, 2H, H6′′), 1.63 (q, J ) 14.7 Hz, 1H,
H5′a), 1.46 (q, J ) 13.7 Hz, 1H, H4′a), 1.44 (quint, J ) 7.9 Hz,
2H, H5′′); 19F NMR (235 MHz, CDCl3) δ -177.1 (md, J ) 48.0
Hz), -179.7 (md, J ) 47.7 Hz); IR (film) 1705, 960; MS (FAB+)
m/z 269 (M - HF + H+). Anal. (C19H25OF) C, H, O.
1
Compound 46: H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H,
10′′), 7.15 (m, 3H, H9′′ and H11′′), 5.56 (ABX, J ) 15.8 Hz and
H
J ) 5.8 Hz, 1H, H1′′), 5.47 (AB, J ) 15.8 Hz, 1H, H2′′), 2.59 (t,
J ) 7.6 Hz, 2H, H7′′), 2.47 (m, 1H, H3′), 2.40 (m, 1H, H2′e), 2.35
(m, 1H, H6′e), 2.25 (m, 1H, H6′a), 2.18 (m, 1H, H2′a), 2.04 (m,
1H, H5′e), 1.88 (m, 1H, H4′e), 1.68 (m, 1H, H5′a), 1.60 (m, J )
7.6 Hz, 2H, H6′′), 1.52 (m, 2H, H4′′), 1.48 (m, 1H, H4′a), 1.32 (m,
2H, H5′′), 1.23 (s, 3H, CH3); IR (film) 3440, 1705, 960; MS (IE,
70 eV) m/z 282 (M - H2O). Anal. (C20H28O2) C, H, O.
3-(1-H yd r oxy-3-m et h yl-7-p h en ylh ep t -2-en -1-yl)cyclo-
Met h yl (1S*,3S*)-1-H yd r oxy-3-[(3S*R*,E)-3-h yd r oxy-
oct-1-en -1-yl]-4-cycloh exa n e Bu ta n oa te (1a ) a n d Meth yl
(1S*,3S*)-1-H yd r oxy-3-[(3R*S*,E)-3-h yd r oxy-oct -1-en -1-
yl]-4-cycloh exa n e Bu ta n oa te (1b). To a stirred solution of
lactone 20a b (2 mmol) in distilled THF (25 mL) cooled to 0 °C
was added 1 N HCl (4 mL, 4 mmol). The reaction mixture was
stirred for 64 h at room temperature, and sodium hydrogen-
carbonate (0.336 g, 4 mmol) was added. The medium was
concentrated and then taken up with 50 mL of diethyl ether.
The aqueous layer was extracted with diethyl ether and the
combined organic layers were washed with distilled water
(2 × 10 mL) and dried over anhydrous sodium sulfate. After
evaporation of the solvent, the residue was purified by chro-
matography. The hydroxy lactone obtained was treated with
2 equiv of triethylamine in methanol at room temperature for
3 days. After evaporation of the solvent the crude methyl ester
was purified by preparative HPLC (10 µm Rsil, 22 × 250 mm,
cyclohexane/ethyl acetate: 90/10, 10 mL/min; 1a : 23 min and
h exa n on e (47): 1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H,
H
10′′), 7.15 (m, 3H, H9′′ and H11′′), 5.09 (d, J ) 8.3 Hz, 1H, H2′′),
4.19 (dd, J ) 5.0 Hz and J ) 9.0 Hz, 1H, H1′′), 2.60 (t, J ) 7.7
Hz, 2H, H7′′), 2.46 (d, J ) 14.4 Hz, 1H, H2′e), 2.33 (d, J ) 14.4
Hz, 1H, H6′e), 2.19 (td, J ) 14.4 Hz and J ) 7.2 Hz, 1H, H6′a),
2.14 (t, J ) 14.4 Hz, 1H, H2′a), 2.04 (d, J ) 16.9 Hz, 1H, H5′e),
2.01 (t, J ) 7.2 Hz, 2H, H4′′), 1.79 (d, J ) 15.9 Hz, 1H, H4′e),
1.78 (m, 1H, H3′), 1.60 (quint, J ) 10.8 Hz, 2H, H6′′), 1.57 (m,
1H, H5′a), 1.44 (qd, J ) 10.8 Hz and J ) 3.6 Hz, 1H, H4′a), 1.42
(quint, J ) 7.2 Hz, 2H, H5′′); IR (film) 3410, 1690, 1650. Anal.
(C20H28O2) C, H, O.
3-[(E)-1-ter t-Bu tyld im eth ylsilyloxy-3-m eth yl-7-p h en yl-
h ep t-2-en -1-yl]cycloh exa n on e (48). The mixture of com-
pounds 46 and 47 was submitted to silylation conditions
(procedure described for 24 from 32) in order to derivatize
selectively compound 47 which could then be easily separated
from the unchanged 46. The residue was purified by column

5304 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
1b: 27 min) which afforded isomers 1a and 1b in 43% and
42% yield, respectively: 1H NMR (360 MHz, CDCl3) δ 5.50
(ABXY, 1H, J ) 14.4 Hz and J ) 6.4 Hz, H1′′), 5.38 (ABXY,
1H, J ) 14.4 Hz and J ) 6.4 Hz, H2′′), 4.00 (q, J ) 6.4 Hz, 1H,
1H, J ) 14.4 Hz and J ) 6.4 Hz, H2′′), 4.16 (q, 2H, J ) 7.1 Hz,
CH2CH3), 3.99 (q, 1H, J ) 6.4 Hz, H3′′), 3.37 (s, 1H, OH), 2.58
(t, 2H, J ) 7.5 Hz, H7′′), 2.42 (m, 1H, H3′), 2.41 (s, 2H, H2),
1.77 (d, 1H, J ) 13.4 Hz, H2′e), 1.73 (d, 1H, J ) 14.4 Hz, H5′a),
1.72 (d, 1H, J ) 14.4 Hz, H6′e), 1.71 (d, 1H, J ) 12.6 Hz, H4′e),
1.61 (quint, 2H, J ) 7.8 Hz, H6′′), 1.55 (d, 1H, J ) 11.9 Hz,
H5′e), 1.50 (m, 2H, H4′′), 1.37 (m, 2H, H5′′), 1.26 (t, 3H, J )
7.1 Hz, CH3), 1.18 (td, 1H, J ) 13.5 Hz and J ) 4.0 Hz, H6′a),
1.03 (t, 1H, J ) 12.8 Hz, H2′a), 0.95 (qd, 1H, J ) 12.6 Hz and
J ) 4.0 Hz, H4′a); IR (film) 3410, 1720, 1185, 960; UV λmax
(cyclohexane) 262 (ꢀ ) 224); MS (FAB+) m/z ) 339 (M -
2H2O + H+); HRMS (FAB+, M + Na+) 397.33670 (397.23548
calcd for C23H34O4Na). Anal. (C23H34O4) C, H, O.
H
3′′), 3.65 (s, 3H, CH3), 2.36 (m, 1H, H3′), 2.28 (t, 2H, J ) 7.1
Hz, H2), 1.90-0.90 (m, 20H, H3-H4, H2′, H4′-H6′ and H4′′-H7′′),
0.86 (m, 3H, H8′′); IR (film) 3400, 1720, 1200, 960. Anal.
(C19H34O4) C, H, O.
Meth yl (1R*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-
oct-1-en -1-yl]-4-cycloh exa n e Bu ta n oa te (1c) a n d Meth yl
(1R*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-3-h yd r oxy-oct -1-en -1-
yl]-4-cycloh exa n e Bu ta n oa te (1d ). Compounds 1c and 1d
were prepared from the lactone 20cd according to the proce-
dure described for 1a and 1b. Preparative HPLC (10 µm Rsil,
22 × 250 mm, cyclohexane/ethyl acetate: 85/15, 10 mL/min;
1c: 20 min and 1d : 25 min) afforded isomers 1c and 1d in
Chiral HPLC separation (5 µm Chiralcel OD, 10.5 × 250
mm, heptane/2-propanol: 92.5/7.5, 1 mL/min, 34 °C; 3br: 15
min and 3b â: 24 min) from racemic diastereoisomer 3b
afforded enantiomers 3b r ([R]D ) -4.2°, CHCl3) and 3b â
([R]D ) +4.2°, CHCl3).
1
41% and 40% yield, respectively: H NMR (360 MHz, CDCl3)
δ 5.48 (ABXY, 1H, J ) 14.4 Hz and J ) 6.4 Hz, H1′′), 5.36
(ABXY, 1H, J ) 14.4 Hz and J ) 6.4 Hz, H2′′), 3.96 (q, J ) 6.4
Hz, 1H, H3′′), 3.63 (s, 3H, CH3), 2.33 (t, 2H, J ) 7.1 Hz, H2),
2.05 (m, 1H, H3′), 1.85-0.90 (m, 20H, H3-H4, H2′, H4′-H6′ and
H4′′-H7′′), 0.86 (m, 3H, H8′′); IR (film) 3400, 1720, 1200, 960.
Anal. (C19H34O4) C, H, O.
Eth yl (1R*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-7-
p h en yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te (3c) a n d
Eth yl (1R*,3S*)-1-Hydr oxy-3-[(3R*S*,E)-3-h ydr oxy-7-ph en -
yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te (3d ). Compounds
3c and 3d were prepared from 25cd according to the procedure
described for 3a and 3b. The crude residue obtained as an oil
was purified by column chromatography on silica gel (eluent:
cyclohexane/diethyl ether, 60/40) to afford a first separation
of the two isomers 3c and 3d which were further purified by
preparative HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/
ethyl acetate: 80/20, 15 mL/min; 3c: 42 min; and 3d : 52 min).
After HPLC chromatography, compounds 3c and 3d were
Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-oct-
1-en -1-yl]-1-cycloh exan e Acetate (2a) an d Eth yl (1S*,3S*)-
1-Hyd r oxy-3-[(3R*S*,E)-3-h yd r oxy-oct-1-en -1-yl]-1-cyclo-
h exa n e Aceta te (2b). To a stirred solution of compound 21a b
(0.730 g, 1.710 mmol) in distilled THF (20 mL) cooled to 0 °C
was added 1 N HCl (3.5 mL, 3.5 mmol). The reaction mixture
was stirred for 64 h at room temperature, and sodium
hydrogen carbonate (0.58 g, 7 mmol) was added. The medium
was concentrated and then taken up with 50 mL of diethyl
ether. The aqueous layer was extracted with diethyl ether, and
the combined organic layers were washed with distilled water
(2 × 10 mL) and dried over anhydrous sodium sulfate. After
evaporation of the solvent, the residue obtained as an oil was
purified by column chromatography on silica gel (eluent:
cyclohexane/diethyl ether, 60/40) to afford a first separation
of the two isomers 2a and 2b. Further preparative HPLC
purification (10 µm Rsil, 22 × 250 mm, cyclohexane/diethyl
ether: 80/20, 10 mL/min; 2a : 23 min; and 2b: 27 min) afforded
isomers 2a (0.229 g, 0.735 mmol) and 2b (0.213 g, 0.684 mmol)
in 43% and 40% yield, respectively: 1H NMR (360 MHz, CDCl3)
δ 5.52 (ABXY, 1H, J ) 14.4 Hz and J ) 6.4 Hz, H1′′), 5.40
(ABXY, 1H, J ) 14.4 Hz and J ) 6.4 Hz, H2′′), 4.17 (q, J ) 7.2
Hz, 2H, CH2CH3), 4.00 (q, J ) 6.4 Hz, 1H, H3′′), 2.45 (m, 1H,
H3′), 2.40 (s, 2H, H2), 1.80-0.90 (m, 19H, CH3, H2′, H4′-H6′ and
1
isolated in, respectively, 39% and 37.5% yield: H NMR (360
MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′),
5.53 (ABXY, 1H, J ) 15.5 Hz and J ) 6.5 Hz, H1′′), 5.40 (ABXY,
1H, J ) 15.5 Hz and J ) 6.8 Hz, H2′′), 4.17 (q, 2H, J ) 7.2 Hz,
CH2CH3), 4.00 (q, 1H, J ) 6.5 Hz, H3′′), 3.80 (s, 1H, OH), 2.59
(t, 2H, J ) 7.6 Hz, H7′′), 2.56 (s, 2H, H2), 2.04 (m, 1H, H3′),
1.79 (d, 1H, J ) 15.4 Hz, H2′e), 1.76 (d, 1H, J ) 15.4 Hz, H6′e),
1.74 (d, 1H, J ) 16.0 Hz, H5′e), 1.67 (d, 1H, J ) 12.4 Hz, H4′e),
1.61 (quint, 2H, J ) 7.7 Hz, H6′′), 1.52 (m, 2H, H4′′), 1.39 (t,
1H, J ) 14.5 Hz, H6′a), 1.38 (m, 2H, H5′′), 1.33 (q, 1H, J ) 15.1
Hz, H5′a), 1.28 (t, 1H, J ) 14.0 Hz, H2′a), 1.26 (t, 3H, J ) 7.2
Hz, CH3), 1.02 (qd, 1H, J ) 12.3 Hz and J ) 3.4 Hz, H4′a); IR
(film) 3410, 1720, 960; MS (FAB+) m/z 339 (M - 2H2O + H+).
Anal. (C23H34O4) C, H, O.
Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-u n -
d ec-1-en -1-yl]-1-cycloh exa n e Acet a t e (4a ) a n d E t h yl
(1S*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-3-Hyd r oxy-u n d ec-1-en -
1-yl]-1-cycloh exa n e Aceta te (4b). Compounds 4a and 4b
were prepared from 37a b according to the procedure described
for 2a and 2b. Preparative HPLC (10 µm Nucleosil, 10 × 250
mm, cyclohexane/diethyl ether: 85/15, 4 mL/min; 4a : 25 min;
and 4b: 29 min) afforded isomers 4a and 4b in 42% and 39.5%
H
4′′-H7′′), 0.86 (m, 3H, H8′′); IR (film) 3400, 1710. Anal.
(C18H32O4) C, H, O.
Eth yl (1R*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-oct-
1-en -1-yl]-1-cycloh exa n e a ceta te (2c) and Eth yl (1R*,3S*)-
1-Hyd r oxy-3-[(3R*S*,E)-3-h yd r oxy-oct-1-en -1-yl]-1-cyclo-
h exa n e Aceta te (2d ). Compounds 2c and 2d were prepared
from 21cd according to the procedure described for 2a and
2b. Preparative HPLC (10 µm Rsil, 22 × 250 mm, cyclohexane/
diethyl ether: 75/25, 10 mL/min; 2c: 20 min; and 2d : 25 min)
afforded isomers 2c and 2d in 40% and 42% yield, respectively:
1H NMR (360 MHz, CDCl3) δ 5.53 (ABXY, 1H, J ) 15.5 Hz
and J ) 6.5 Hz, H1′′), 5.40 (ABXY, 1H, J ) 15.5 Hz and J )
6.8 Hz, H2′′), 4.18 (q, J ) 7.2 Hz, 2H, CH2CH3), 4.00 (q, J )
6.4 Hz, 1H, H3′′), 2.58 (s, 2H, H2), 2.05 (m, 1H, H3′), 1.80-0.90
(m, 19H, CH3, H2′, H4′-H6′ and H4′′-H7′′), 0.87 (m, 3H, H8′′); IR
(film) 3400, 1715. Anal. (C18H32O4) C, H, O.
Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-7-
p h en yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te (3a ) a n d
E t h yl (1S*,3S*)-1-H yd r oxy-3-[(3 R*S*,E)-3-h yd r oxy-7-
p h en yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te (3b). Com-
pounds 3a and 3b were prepared from 25a b according to the
procedure described for 2a and 2b. Preparative HPLC (5 µm
Inertsil, 20 × 250 mm, cyclohexane/ethyl acetate: 87.5/12.5,
20 mL/min; 3a : 75 min; and 3b: 85 min) afforded isomers 3a
and 3b in 38% and 46% yield, respectively: 1H NMR (360 MHz,
CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′), 5.52
(ABXY, 1H, J ) 14.4 Hz and J ) 6.4 Hz, H1′′), 5.40 (ABXY,
1
yield respectively: H NMR (360 MHz, CDCl3) δ 5.52 (ABXY,
J ) 15.5 Hz and J ) 6.1 Hz, 1H, H1′′), 5.42 (ABXY, J ) 15.5
Hz and J ) 6.1 Hz, 1H, H2′′), 4.15 (q, J ) 7.2 Hz, 2H, CH2-
CH3), 3.99 (q, J ) 6.4 Hz, 1H, H3′′), 2.42 (m, 1H, H3′), 2.40 (s,
2H, H2), 1.83-1.16 (m, 23H, CH3, H4′-H6′ and H4′′-H10′′), 1.05
(m, 2H, H2′), 0.85 (m, 3H, H11′′); IR (film) 3400, 1710, 960; MS
(IE, 20 eV) m/z ) 318 (M - 2H2O). Anal. (C21H38O4) C, H, O.
Eth yl (1R*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-u n -
d ec-1-en -1-yl]-1-cycloh exa n e Acet a t e (4c) a n d E t h yl
(1R*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-3-h yd r oxy-u n d ec-1-en -
1-yl]-1-cycloh exa n e Aceta te (4d ). Compounds 4c and 4d
were prepared from 37cd according to the procedure described
for 2a and 2b. Preparative HPLC (10 µm Nucleosil, 10 × 250
mm, cyclohexane/diethyl ether: 80/20, 4 mL/min; 4c: 22 min;
and 4d : 27 min) afforded isomers 4c and 4d in 37% and 42.5%
yield, respectively: 1H NMR (360 MHz, CDCl3) δ 5.53 (ABXY,
1H, J ) 15.5 Hz and J ) 6.1 Hz, H1′′), 5.42 (ABXY, J ) 15.5
Hz and J ) 6.1 Hz, 1H, H2′′), 4.15 (m, J ) 7.2 Hz, 2H, CH2-
CH3), 4.0 (q, J ) 6.4 Hz, 1H, H3′′), 2.56 (m, 2H, H2), 2.02 (m,
1H, H3′), 1.8-1.2 (m, 23H, CH3, H4′-H6′ and H4′′-H10′′), 1.01 (m,
2H, H2′), 0.85 (t, 3H, H11′′); IR (film) 3400, 1720, 960; MS (IE,
20 eV) m/z ) 336 (M - H2O). Anal. (C21H38O4) C, H, O.

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5305
(1S*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-7-p h en yl-
1-h epten -1-yl]cycloh exan e-1-N,N-dim eth yl-acetam ide (5a)
an d (1S*,3S*)-1-Hydr oxy-3-[(3R*S*,E)-3-h ydr oxy-7-ph en yl-
1-h epten -1-yl]cycloh exan e-1-N,N-dim eth yl-acetam ide (5b).
Compounds 5a and 5b were prepared from 38a b according
to the procedure described for 2a and 2b. The residue obtained
as an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/ethyl acetate, 50/50) to afford a first
separation of the two isomers 5a and 5b which were further
purified by preparative HPLC (5 µm Inertsil, 20 × 250 mm,
cyclohexane/ethyl acetate: 48/52, 15 mL/min; 5a : 46 min; and
5b: 62 min). After HPLC chromatography, compounds 5a and
5b (white solid, mp ) 52 °C) were isolated in, respectively,
47% and 46% yield: 1H NMR (360 MHz, CDCl3) δ 7.23 (m, 2H,
(1R*,3S*)-1-Hyd r oxy-3-[(E)-3-h yd r oxy-7-p h en yl-1-h ep -
t en -1-yl]cycloh exa n e-1-N-m et h yl-N-p h en yl-a cet a m id e
(6cd ). Compound 6cd was prepared from 39cd according to
the procedure described for 2a and 2b. The residue obtained
as an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/diethyl ether, 50/50) to afford the dia-
stereomeric mixture 6cd which was further purified by
preparative HPLC (10 µm Rsil, 22 × 250 mm, ethyl acetate, 5
1
mL/min; 6c: 26 min, and 6d : 28 min) in 93% yield: H NMR
(360 MHz, CDCl3) δ 7.44 (m, 2H, H4), 7.36 (m, 1H, H6), 7.22
(m, 2H, H10′′), 7.14 (m, 5H, H9′′, H11′′ and H5), 6.00 (d, 1H, OH),
5.51 (ABXY, J ) 15.4 Hz and J ) 6.3 Hz, 1H, H1′′), 5.37 (ABXY,
J ) 15.4 Hz and J ) 6.7 Hz, 1H, H2′′), 3.99 (q, J ) 6.7 Hz, 1H,
H3′′), 3.26 (s, 3H, N-CH3), 2.59 (t, J ) 7.2 Hz, 2H, H7′′), 2.32
and 2.26 (AB, J ) 15.8 Hz, 2H, H2), 1.90 (m, 1H, H3′), 1.87 (m,
1H, H2′e), 1.81 (m, 1H, H6′e), 1.73 (m, 1H, H5′e), 1.66 (m, 1H,
H
10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.51 (ABXY, J ) 15.5 Hz
and J ) 6.5 Hz, 1H, H1′′), 5.38 (ABXY, J ) 15.5 Hz and J )
6.8 Hz, 1H, H2′′), 5.14 (s, 1H, OH), 3.97 (q, J ) 6.4 Hz, 1H,
H
4′e), 1.59 (m, 2H, H6′′), 1.52 (m, 2H, H4′′), 1.37 (m, 1H, H6′a),
1.36 (m, 2H, H5′′), 1.28 (m, 1H, H2′a), 1.22 (m, 1H, H5′a), 1.04
H
3′′), 2.96 (s, 3H, N-CH3), 2.92 (s, 3H, N-CH3), 2.58 (t, J ) 7.6
(m, 1H, H4′a); IR (film) 3400, 1625, 1110, 960. Anal. (C28H37
NO3) C, H, N, O.
-
Hz, 2H, H7′′), 2.45 (m, 1H, H3′), 2.33 (s, 2H, H2), 1.87 (d, J )
15.3 Hz, 1H, H2′e), 1.79 (d, J ) 15.3 Hz, 1H, H6′e), 1.76 (q, J )
14.9 Hz, 1H, H5′a), 1.71 (d, J ) 15.3 Hz, 1H, H4′e), 1.61 (quint,
J ) 7.5 Hz, 2H, H6′′), 1.53 (d, J ) 16.3 Hz, 1H, H5′e), 1.49 (m,
2H, H4′′), 1.38 (m, 2H, H5′′), 1.09 (td, J ) 13.8 Hz and J ) 4.0
Hz, 1H, H6′a), 0.94 (t, J ) 12.6 Hz, 1H, H2′a), 0.93 (qd, J ) 14.9
Hz and J ) 3.2 Hz, 1H, H4′a); IR (film) 3430, 1620, 1145, 960;
MS (FAB+) m/z ) 338 (M - 2H2O + H+). Anal. (C23H35NO3)
C, H, N, O.
(1S*,3S*)-1-Hyd r oxy-3-[(E)-3-h yd r oxy-7-p h en yl-1-h ep -
t en -1-yl]cycloh exa n e-1-N,N-d ip r op yl-a cet a m id e (7a b ).
Compound 7a b was prepared from 40a b according to the
procedure described for 2a and 2b. The residue obtained as
an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/diethyl ether, 60/40) to afford the dia-
stereomeric mixture 7a b which was further purified by
preparative HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/
ethyl acetate (75/25), 16 mL/min; 7a : 35 min; and 7b: 40 min)
in 93% yield: 1H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H, H10′′),
7.14 (m, 3H, H9′′, H11′′), 5.52 (ABXY, J ) 15.2 Hz and J ) 6.4
Hz, 1H, H1′′), 5.41 (s, 1H, OH), 5.37 (ABXY, J ) 15.2 Hz and
J ) 6.8 Hz, 1H, H2′′), 3.99 (q, J ) 6.5 Hz, 1H, H3′′), 3.28 and
3.25 (m, J ) 7.7 Hz, 3H, H6), 3.15 (m, J ) 7.7 Hz, 3H, H3),
2.59 (t, J ) 7.7 Hz, 2H, H7′′), 2.47 (m, 1H, H3′), 2.33 (s, 2H,
H2), 1.85 (d, J ) 14.2 Hz, 1H, H2′e), 1.78 (q, J ) 15.2 Hz, 1H,
H5′a), 1.77 (d, J ) 14.2 Hz, 1H, H6′e), 1.71 (d, J ) 15.5 Hz, 1H,
H4′e), 1.60 (quint, J ) 8.2 Hz, 2H, H6′′), 1.56 (sext, J ) 8.2 Hz,
3H, H4), 1.55 (sext, J ) 8.2 Hz, 3H, H7), 1.55 (d, J ) 15.1 Hz,
1H, H5′e), 1.51 (m, 2H, H4′′), 1.36 (m, 2H, H5′′), 1.09 (td, J )
13.3 Hz and J ) 4.4 Hz, 1H, H6′a), 0.94 (t, J ) 14.2 Hz, 1H,
H2′a), 0.94 (qd, J ) 15.2 Hz and J ) 3.2 Hz, 1H, H4′a), 0.90 (t,
J ) 7.4 Hz, 3H, H5), 0.87 (t, J ) 7.4 Hz, 3H, H8); IR (film)
3400, 1605, 1140, 960; MS (FAB+) m/z 394 (M - 2H2O + H+).
Anal. (C27H43NO3) C, H, N, O.
Chiral HPLC separation (5 µm Chiralcel OD, 10.5 × 250
mm, heptane/2-propanol: 80/20, 1.1 mL/min; 5br: 46 min 30
s; and 5bâ: 72 min) from racemic diastereoisomer 5b afforded
enantiomers 5br and 5bâ.
(1R*,3S*)-1-Hyd r oxy-3-[(E)-3-h yd r oxy-7-p h en yl-1-h ep -
t en -1-yl]cycloh exa n e-1-N,N-d im et h yl-a cet a m id e (5cd ).
Compound 5cd was prepared from 38cd according to the
procedure described for 2a and 2b. The residue obtained as
an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/ethyl acetate, 40/60) to afford the dia-
stereomeric mixture 5cd which was further purified by
preparative HPLC (10 µm Rsil, 22 × 250 mm, ethyl acetate,
12 mL/min, 5c: 22 min and 5d : 25 min) in 92% yield: 1H NMR
(360 MHz, CDCl3) δ 7.24 (m, 2H, H10′′), 7.14 (m, 3H, H9′′ and
H
11′′), 5.72 (d, J ) 5.0 Hz, 1H, OH), 5.51 (ABXY, J ) 15.4 Hz
and J ) 6.1 Hz, 1H, H1′′), 5.37 (ABXY, J ) 6.1 Hz and J )
15.4 Hz, 1H, H2′′), 4.00 (q, J ) 6.1 Hz, 1H, H3′′), 3.02 (s, 3H,
N-CH3), 2.94 (s, 3H, N-CH3), 2.59 (t, J ) 7.2 Hz, 2H, H7′′), 2.51
(m, 2H, H2), 1.98 (m, 1H, H3′), 1.90 (m, 1H, H2′e), 1.85 (m, 1H,
(1R*,3S*)-1-Hyd r oxy-3-[(E)-3-h yd r oxy-7-p h en yl-1-h ep -
t en -1-yl]cycloh exa n e-1-N,N-d ip r op yl-a cet a m id e (7cd ).
Compound 7cd was prepared from 40cd according to the
procedure described for 2a and 2b. The residue obtained as
an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/diethyl ether, 55/45) to afford the dia-
stereomeric mixture 7cd which was further purified by
preparative HPLC (10 µm Rsil, 22 × 250 mm, cyclohexane/
ethyl acetate (75/25), 5.4 mL/min; 7c: 44 min; and 7d : 55 min)
in 91% yield: 1H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H, H10′′),
7.14 (m, 3H, H9′′, H11′′), 6.00 (d, 1H, OH), 5.51 (ABXY, J ) 15.4
Hz and J ) 6.3 Hz, 1H, H1′′), 5.37 (ABXY, J ) 15.4 Hz and
J ) 6.7 Hz, 1H, H2′′), 4.00 (q, J ) 6.7 Hz, 1H, H3′′), 3.31 and
3.22 (m AB, 2H, H6), 3.19 (m, 2H, H3), 2.59 (t, J ) 7.2 Hz, 2H,
H
6′e), 1.73 (m, 1H, H5′e), 1.65 (m, 1H, H4′e), 1.61 (quint, J ) 7.5
Hz, 2H, H6′′), 1.51 (m, 2H, H4′′), 1.38 (m, 1H, H6′a), 1.34 (m,
2H, H5′′), 1.30 (m, 1H, H5′a), 1.30 (m, 1H, H2′a), 1.06 (m, 1H,
H
4′a); IR (film) 3430, 1620, 1145, 960; MS (FAB+) m/z 356
(M - H2O + H+). Anal. (C23H35NO3) C, H, N, O.
(1S*,3S*)-1-Hyd r oxy-3-[(E)-3-h yd r oxy-7-p h en yl-1-h ep -
t en -1-yl]cycloh exa n e-1-N-m et h yl-N-p h en yl-a cet a m id e
(6a b). Compound 6a b was prepared from 39a b according to
the procedure described for 2a and 2b. The residue obtained
as an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/diethyl ether, 55/45) to afford the dia-
stereomeric mixture 6a b which was further purified by
preparative HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/
ethyl acetate (75/25), 16 mL/min; 6a : 42 min; and 6b: 47 min)
H
7′′), 2.54 and 2.47 (AB, J ) 15.8 Hz, 2H, H2), 1.92 (m, 1H,
H3′), 1.88 (m, 1H, H2′e), 1.82 (m, 1H, H6′e), 1.75 (m, 1H, H5′e),
1.66 (m, 1H, H4′e), 1.60 (m, 2H, H6′′), 1.55 (m, 2H, H4), 1.52
(m, 2H, H7), 1.38 (m, 2H, H4′′), 1.38 (m, 1H, H6′a), 1.36 (m, 2H,
H5′′), 1.29 (m, 1H, H2′a), 1.23 (m, 1H, H5′a), 1.05 (m, 1H, H4′a),
0.92 (t, J ) 7.6 Hz, 3H, H5), 0.88 (m, 3H, H8); IR (film) 3400,
1605, 1140, 960. Anal. (C27H43NO3) C, H, N, O.
1
in 94% yield: H NMR (360 MHz, CDCl3) δ 7.44 (m, 2H, H4),
7.36 (m, 1H, H6), 7.22 (m, 2H, H10′′), 7.14 (m, 5H, H9′′, H11′′
and H5), 5.47 (ABXY, 1H, J ) 15.6 Hz and J ) 6.4 Hz, H1′′),
5.36 (ABXY, 1H, J ) 15.6 Hz and J ) 6.9 Hz, H2′′), 5.14 (s,
1H, OH), 3.97 (q, 1H, J ) 6.4 Hz, H3′′), 3.26 (s, 3H, N-CH3),
2.58 (t, 2H, J ) 7.7 Hz, H7′′), 2.43 (m, 1H, H3′), 2.12 (s, 2H,
H2), 1.75 (d, 1H, J ) 14.1 Hz, H2′e), 1.75 (q, 1H, J ) 15.1 Hz,
Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(E)-3-oxo-7-p h en yl-1-h ep -
ten -1-yl]-1-cycloh exa n e Aceta te (8a b). A solution of com-
pound 3a (120 mg, 0.320 mmol) in dichloromethane (10 mL)
and manganese(IV) oxide on activated carbon (840 mg, 4.83
mmol) was stirred for 16 h at room temperature. The reaction
mixture was filtrered on Celite and the cake washed with
dichloromethane. The filtrate was evaporated and the result-
ing residue (yellowish oil) purified by column chromatography
H
H
5′a), 1.70 (d, 1H, J ) 15.8 Hz, H6′e), 1.68 (d, 1H, J ) 16.8 Hz,
4′e), 1.61 (quint, 2H, J ) 8.4 Hz, H6′′), 1.50 (m, 2H, H4′′), 1.50
(d, 1H, J ) 15.1 Hz, H5′e), 1.36 (m, 2H, H5′′), 0.91 (td, 1H, J )
16.0 Hz and J ) 4.2 Hz, H6′a), 0.85 (qd, 1H, J ) 14.6 Hz and
J ) 3.1 Hz, H4′a), 0.77 (t, 1H, J ) 14.3 Hz, H2′a); IR (film) 3400,
1625, 1110, 960. Anal. (C28H37NO3) C, H, N, O.

5306 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
on silica gel. Elution with cyclohexane/diethyl ether (75/25)
gave the title compound 8a b as a colorless oil (72 mg, 60%).
Several attemps of continuous Soxhlet extraction (acetone,
methanol) were made in order to improve the yield but none
were successful: 1H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H,
H10′′), 7.14 (m, 3H, H9′′ and H11′′), 6.69 (ABX, J ) 16.0 Hz and
J ) 6.9 Hz, 1H, H1′′), 6.02 (ABX, J ) 1.2 Hz and J ) 16.0 Hz,
1H, H2′′), 4.16 (q, J ) 7.2 Hz, 2H, CH2CH3), 2.63 (m, 1H, H3′),
2.60 (m, 2H, H4′′), 2.51 (t, J ) 6.9 Hz, 2H, H7′′), 2.42 (s, 2H,
H2), 1.81 (m, 1H, H2′e), 1.78 (m, 2H, H4′e and H5′a), 1.75 (m,
1H, H6′e), 1.62 (m, 4H, H5′′ and H6′′), 1.60 (m, 1H, H5′e), 1.26 (t,
J ) 7.2, 3H, CH3), 1.20 (m, 1H, H6′a), 1.10 (t, J ) 12.7 Hz, 1H,
in 96% yield: 1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′),
7.15 (m, 3H, H9′′ and H11′′), 5.61 (s, 1H, H2), 5.54 (ABXY, J )
15.5 Hz and J ) 6.5 Hz, 1H, H1′′), 5.42 (ABXY, J ) 6.5 Hz and
J ) 15.5 Hz, 1H, H2′′), 4.01 (q, J ) 6.4 Hz, 1H, H3′′), 3.66 (s,
3H, OMe), 3.65 (d, J ) 13.7 Hz, 1H, H6′e), 2.59 (t, J ) 7.7 Hz,
2H, H7′′), 2.26 (m, 1H, H2′e), 2.15 (m, 1H, H3′), 1.99 (m, 1H,
H
6′a), 1.97 (m, 1H, H2′a), 1.89 (m, 1H, H5′e), 1.79 (m, 1H, H4′e),
1.60 (quint, J ) 7.5 Hz, 2H, H6′′), 1.49 (m, 2H, H4′′), 1.42 (m,
1H, H5′a), 1.35 (m, 2H, H5′′), 1.29 (m, 1H, H4′a); IR (film) 3400,
1710, 1640, 960; MS (FAB+) m/z 309 (M - H2O - Me). Anal.
(C22H30O3) C, H, O.
[(3S*R*,Z)-3-((3S*R*,E)-3-Hyd r oxy-7-p h en yl-1-h ep ten -
1-yl)cycloh exylid en e]-N,N-d im eth yl-a ceta m id e (11a ) a n d
[(3S*R*,Z)-3-((3R*S*,E)-3-Hyd r oxy-7-p h en yl-1-h ep ten -1-
yl)cycloh exylid en e]-N,N-d im eth yl-a ceta m id e (11b). Com-
pounds 11a and 11b were prepared from 42a b according to
the procedure described for 2a and 2b. The residue obtained
as an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/ethyl acetate, 50/50) to afford the dia-
stereomeric mixture 11a b in 92% yield. Further preparative
HPLC (5 µm Inertsil, 20 × 250 mm, diethyl ether/ethyl acetate:
85/15, 15 mL/min; 11a : 41 min 30 s; and 11b: 50 min 30 s)
afforded isomers 11a and 11b in 45% and 44% yield, respec-
H
2′a), 1.02 (m, 1H, H4′a); IR (film) 3410, 1720; MS (IE, 70 eV)
m/z 354 (M-H2O). Anal. (C23H32O4) C, H, O.
Eth yl (1S*,3S*)-1-Hydr oxy-3-[(3R*S*)-3-h ydr oxy-7-ph en -
ylh ep ta n -1-yl]-1-cycloh exa n e Aceta te (9b). To a solution
of compound 3b (72 mg, 0.191 mmol) in ethanol (5 mL) in a
25 mL round-bottom flask was added a 1% aqueous solution
of sodium nitrite (100 µL). After being stirred for 30 min, the
solution was treated with 10% palladium on activated carbon
(19 mg). The flask walls were rinsed with ethanol (2 mL), and
the reaction mixture was hydrogenated for 16 h at room
temperature. The medium was taken up with 3 mL of diethyl
ether which caused the catalyst to precipitate. After filtration
over Celite, the cake was rinsed with diethyl ether (3 × 10
mL) and the filtrate concentrated. The filtrate was evaporated,
and the resulting residue (80 mg) obtained as a colorless oil
was purified by column chromatography on silica gel. Elution
with cyclohexane/diethyl ether (65/35) afforded the title com-
pound 9b (61 mg, 0.162 mmol) as a white solid (mp ) 54 °C)
in 87% yield: 1H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H, H10′′),
7.14 (m, 3H, H9′′ and H11′′), 4.15 (q, J ) 7.1 Hz, 2H, CH2CH3),
3.52 (m, 1H, H3′′), 3.30 (s, 1H, OH), 2.60 (t, J ) 7.6 Hz, 2H,
1
tively: H NMR (360 MHz, CDCl3) δ 7.24 (m, 2H, H10′′), 7.14
(m, 3H, H9′′ and H11′′), 5.72 (s, 1H, H2), 5.57 (ABXY, J ) 15.5
Hz and J ) 6.5 Hz, 1H, H1′′), 5.42 (ABXY, J ) 6.8 Hz and J )
15.5 Hz, 1H, H2′′), 3.98 (q, J ) 6.5 Hz, 1H, H3′′), 2.98 (s, 3H,
N-CH3), 2.93 (s, 3H, N-CH3), 2.89 (d, J ) 13.2 Hz, 1H, H2′e),
2.58 (t, J ) 7.7 Hz, 2H, H7′′), 2.21 (d, J ) 13.9 Hz, 1H, H6′e),
2.14 (m, 1H, H3′), 2.05 (td, J ) 13.9 Hz and J ) 4.7 Hz, 1H,
H6′a), 1.84 (d, J ) 13.9 Hz, 1H, H5′e), 1.79 (t, J ) 13.2 Hz, 1H,
H2′a), 1.74 (d, J ) 8.5 Hz, 1H, H4′e), 1.61 (quint, J ) 8.0 Hz,
2H, H6′′), 1.49 (m, 2H, H4′′), 1.43 (m, J ) 13.9 Hz, 1H, H5′a),
1.35 (m, 2H, H5′′), 1.26 (mt, J ) 13.9 Hz, 1H, H4′a); IR (film)
3400, 1640, 1630, 1135, 960; MS (FAB+) m/z 338 (M - H2O +
H+). Anal. (C23H33NO2) C, H, N, O.
H
7′′), 2.39 (s, 2H, H2), 1.75 (d, J ) 15.9 Hz, 1H, H2′e), 1.73 (m,
1H, H3′), 1.73 (d, J ) 15.9 Hz, 1H, H4′e), 1.72 (d, J ) 15.9 Hz,
1H, H6′e), 1.68 (m, 1H, H5′a), 1.62 (m, 2H, H6′′), 1.53 (d, J )
13.3 Hz, 1H, H5′e), 1.42 (m, 2H, H4′′), 1.41 (m, 2H, H2′′), 1.39
(m, 2H, H5′′), 1.25 (t, J ) 7.1 Hz, 3H, CH3), 1.28 and 1.15 (m,
2H, H1′′), 1.18 (td, J ) 13.3 Hz and J ) 4.3 Hz, 1H, H6′a), 0.88
(t, J ) 12.4 Hz, 1H, H2′a), 0.77 (qd, J ) 11.8 Hz and J ) 3.6
Hz, 1H, H4′a); IR (film) 3410, 1720; MS (FAB+, NBA) m/z 341
(M - 2H2O + H+). Anal. (C23H36O4) C, H, O.
[(3S*R*,E)-3-((3S*R*,E)-3-Hyd r oxy-7-p h en yl-1-h ep ten -
1-yl)cycloh exylid en e]-N,N-d im eth yl-a ceta m id e (11c) a n d
[(3S*R*,E)-3-((3R*S*,E)-3-Hyd r oxy-7-p h en yl-1-h ep ten -1-
yl)cycloh exylid en e]-N,N-d im eth yl-a ceta m id e (11d ). Com-
pounds 11c and 11d were prepared from 42cd according to
the procedure described for 2a and 2b. The residue obtained
as an oil was purified by column chromatography on silica gel
(eluent: cyclohexane/ethyl acetate, 50/50) to afford the dia-
stereomeric mixture 11cd in 95% yield. Further preparative
HPLC (5 µm Inertsil, 20 × 250 mm, diethyl ether/ethyl acetate:
85/15, 15 mL/min; 11c: 43 min; and 11d : 52 min) afforded
Meth yl (3S*R*,Z)-3-[(3S*R*,E)-3-Hyd r oxy-7-p h en yl-1-
h ep ten -1-yl]cycloh exylid en e Aceta te (10a ) a n d Meth yl
(3S*R*,Z)-3-[(3R*S*,E)-3-Hydr oxy-7-ph en yl-1-h epten -1- yl]-
cycloh exylid en e Aceta te (10b). Compounds 10a and 10b
were prepared from 41a b according to the procedure described
for 2a and 2b. The residue obtained as an oil was purified by
column chromatography on silica gel (eluent: cyclohexane/
diethyl ether, 85/15) to afford the diastereomeric mixture 10a b
in 94% yield. Further preparative HPLC (5 µm Inertsil, 20 ×
250 mm, cyclohexane/ethyl acetate: 93/7, 15 mL/min; 10a : 64
min; and 10b: 71 min) afforded isomers 10a and 10b in 45%
and 44% yield, respectively: 1H NMR (360 MHz, CDCl3) δ 7.25
(m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′), 5.64 (s, 1H, H2), 5.60
(ABXY, 1H, J ) 15.5 Hz and J ) 6.6 Hz, H1′′), 5.47 (ABXY,
1H, J ) 6.8 Hz and J ) 15.5 Hz, H2′′), 4.02 (q, 1H, J ) 6.4 Hz,
1
isomers 11c and 11d in 46% and 45% yield, respectively: H
NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′
and H11′′), 5.71 (s, 1H, H2), 5.56 (ABXY, J ) 15.5 Hz and J )
6.5 Hz, 1H, H1′′), 5.42 (ABXY, J ) 6.5 Hz and J ) 15.5 Hz,
1H, H2′′), 4.02 (q, J ) 6.5 Hz, 1H, H3′′), 3.00 (s, 3H, N-CH3),
2.95 (s, 3H, N-CH3), 2.86 (d, J ) 12.6 Hz, 1H, H6′e), 2.60 (t,
J ) 7.6 Hz, 2H, H7′′), 2.24 (d, J ) 12.1 Hz, 1H, H2′e), 2.14 (m,
1H, H3′), 1.93 (t, J ) 12.1 Hz, 1H, H2′a), 1.86 (t, J ) 12.6 Hz,
1H, H6′a), 1.83 (m, 1H, H5′e), 1.78 (m, 1H, H4′e), 1.63 (quint,
J ) 7.6 Hz, 2H, H6′′), 1.49 (m, 2H, H4′′), 1.38 (q, J ) 12.6 Hz,
1H, H5′a), 1.33 (m, 2H, H5′′), 1.23 (qd, J ) 12.6 Hz and J ) 2.9
Hz, 1H, H4′a); IR (film) 3400, 1675, 1600, 960; MS (FAB+) m/z
338 (M - H2O + H+). Anal. (C23H33NO2) C, H, N, O.
[(3S*R*,Z)-3-((3S*R*,E)-3-[(E)-3-Acet oxy-7-p h en yl-1-
h ep t en -1-yl]cycloh exylid en e-N,N-d im et h yl-a cet a m id e
(12a) an d [(3S*R*,Z)-3-((3R*S*,E)-3-[(E)-3-Acetoxy-7-ph en -
yl-1-h ep t en -1-yl]cycloh exylid en e-N,N-d im et h yl-a cet a -
m id e (12b). To compound 42a b (100 mg, 0.213 mmol) stirred
in a 5 mL round-bottom flask were added under nitrogen at 0
°C acetic anhydride (0.9 mL, 9.5 mmol) and dry ferric chloride
(35 mg, 0.213 mmol). The flask walls were rinsed with acetic
anhydride (0.3 mL, 3.2 mmol), and the reaction mixture was
stirred for 15 min at 0 °C. The medium was hydrolyzed with
saturated NaHCO3 (3 mL), ethyl acetate (10 mL) was added,
and stirring was continued for 10 min. The water layer was
extracted with ethyl acetate (3 × 10 mL), and the combined
organic layers were washed with saturated NaHCO3 (3 mL)
H
3′′), 3.70 (m, 1H, H2′e), 3.67 (s, 3H, OMe), 2.60 (t, 2H, J ) 7.7
Hz, H7′′), 2.25 (d, 1H, J ) 12.7 Hz, H6′e), 2.17 (m, 1H, H3′), 2.11
(td, 1H, J ) 12.7 Hz and J ) 4.6 Hz, H6′a), 1.91 (m, 1H, H5′e),
1.90 (m, 1H, H2′a), 1.82 (m, 1H, H4′e), 1.62 (m, 2H, H6′′), 1.50
(m, 2H, H4′′), 1.47 (m, 1H, H5′a), 1.38 (m, 2H, H5′′), 1.32 (m,
1H, H4′a); IR (film) 3400, 1710, 1640, 960; MS (FAB+) m/z 325
(M - H2O + H+). Anal. (C22H30O3) C, H, O.
Chiral HPLC separation (5 µm Chiralcel OD, 10.5 × 250
mm, heptane/2-propanol: 90/10, 1.7 mL/min; 10br: 32 min; and
10bâ: 50 min) from the racemic diastereoisomer 10b afforded
enantiomers 10br and 10bâ.
Meth yl (E)-3-[(E)-3-Hyd r oxy-7-p h en yl-1-h ep ten -1-yl]-
cycloh exylid en e Aceta te (10cd ). Compound 10cd was
prepared from 41cd according to the procedure described for
2a and 2b. The residue obtained as an oil was purified by
column chromatography on silica gel (eluent: cyclohexane/
diethyl ether, 85/15) to afford the diastereomeric mixture 10cd

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5307
and with brine (3 mL) and dried over anhydrous sodium
sulfate. After evaporation of the solvent, the residue (110 mg)
obtained as an orange oil was purified by column chromatog-
raphy on silica gel (eluent: cyclohexane/diethyl ether, 60/40)
to afford a mixture of isomers 12a b and 43a b in the ratio 81:
19. Further preparative HPLC (5 µm Inertsil, 20 × 250 mm,
cyclohexane/ethyl acetate: 90/10, 15 mL/min; 12a : 35 min;
12b: 41 min; 43a : 50 min; and 43b: 62 min) afforded the
isolation of isomers in 81% for 12 and 18% for 43: 1H NMR
(400 MHz, CDCl3) δ 7.28 (m, 2H, H10′′), 7.19 (m, 3H, H9′′ and
ethyl acetate: 90/10, 15 mL/min; 14a : 51 min; and 14b: 54 min;
cyclohexane/ethyl acetate: 85/15, 15 mL/min; 14c: 36 min; and
14d : 43 min). After HPLC chromatography, compounds 14a ,
14b, 14c, and 14d were isolated in, respectively, 32%, 2.6%,
26%, and 23% yield.
Eth yl (1S*,3S*)-1-Hydr oxy-3-[(3S*R*,E)-3-eth yl Acetate-
3-h yd r oxy-7-p h en yl-1-h ep t en -1-yl]-1-cycloh exa n e Ac-
eta te (14a ) a n d Eth yl (1S*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-
3-eth yl Aceta te-3-h yd r oxy-7-p h en yl-1-h ep ten -1-yl]-1-cy-
cloh exa n e Aceta te (14b): 1H NMR (360 MHz, CDCl3) δ 7.24
(m, 2H, H10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.53 (ABX, J ) 15.8
Hz and J ) 6.8 Hz, 1H, H1′′), 5.35 (ABX, J ) 16.0 Hz, 1H,
H
11′′), 5.78 (s, 1H, H2), 5.66 (ABXY, J ) 15.5 Hz and J ) 6.3
Hz, 1H, H1′′), 5.39 (ABXY, J ) 7.2 Hz and J ) 15.5 Hz, 1H,
2′′), 5.19 (q, J ) 6.7 Hz, 1H, H3′′), 3.03 (s, 3H, N-CH3), 3.02
H
H
2′′), 4.15 (q, J ) 7.2 Hz, 2H, CH2), 4.10 (q, J ) 7.2 Hz, 2H,
(m, 1H, H2′e), 2.99 (s, 3H, N-CH3), 2.61 (t, J ) 7.7 Hz, 2H, H7′′),
2.26 (d, J ) 13.1 Hz, 1H, H6′e), 2.04 (s, 3H, CH3CO), 2.2-1.2
(m, 13H, H2′a, H3′-H5′, H6′a, H4′′-H6′′); IR (film) 1640, 1630, 1135,
960. Anal. (C25H35NO3) C, H, N, O.
CH2), 3.81 (s, 1H, OH), 3.38 (s, 1H, OH cycle), 2.58 (t, J ) 7.7
Hz, 2H, H7′′), 2.47 (s, 2H, H4), 2.42 (m, 1H, H3′), 2.40 (s, 2H,
H2), 1.73 (d, J ) 15.4 Hz, 1H, H2′e), 1.72 (d, J ) 15.4 Hz, 1H,
H6′e), 1.72 (d, J ) 15.4 Hz, 1H, H5′a), 1.66 (d, J ) 15.4 Hz, 1H,
(Z)-3-[(E)-1-Acetoxy-7-p h en ylh ep t-2-en -1-yl]cycloh ex-
ylid en e-N,N-d im eth yl-a ceta m id e (43a b): 1H NMR (360
MHz, CDCl3) 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′),
5.73 (s, 1H, H2), 5.67 (ABXY2, J ) 15.4 Hz and J ) 7.1 Hz,
1H, H3′′), 5.33 (ABXY2, J ) 8.0 Hz and J ) 15.4 Hz, 1H, H2′′),
5.04 (t, J ) 7.2 Hz, 1H, H1′′), 2.98 (s, 3H, N-CH3), 2.93 (s, 3H,
N-CH3), 2.85 (d, J ) 12.8 Hz, 1H, H2′e), 2.58 (t, J ) 7.7 Hz,
2H, H7′′), 2.22 (d, J ) 13.3 Hz, 1H, H6′e), 2.04 (q, J ) 7.0 Hz,
2H, H4′′), 2.03 (td, J ) 15.0 Hz and J ) 4.7 Hz, 1H, H6′a), 2.01
(s, 3H, CH3CO), 1.88 (d, J ) 16.8 Hz, 1H, H5′e), 1.79 (t, J )
14.1 Hz, 1H, H2′a), 1.74 (d, J ) 15.0 Hz, 1H, H4′e), 1.70 (m, 1H,
H3′), 1.60 (quint, J ) 7.8 Hz, 2H, H6′′), 1.40 (quint, J ) 7.5 Hz,
2H, H5′′), 1.38 (qt, J ) 11.3 Hz and J ) 3.2 Hz, 1H, H5′a), 1.19
(qd, J ) 10.7 Hz and J ) 3.2 Hz, 1H, H4′a); IR (film) 1640,
H4′e), 1.58 (m, 2H, H6′′), 1.55 (d, J ) 13.0 Hz, 1H, H5′e), 1.50
(m, 2H, H4′′), 1.36 (m, 2H, H5′′), 1.26 (t, J ) 7.1 Hz, 3H, CH3),
1.23 (t, J ) 7.1 Hz, 3H, CH3), 1.18 (td, J ) 13.7 Hz and J )
4.0 Hz, 1H, H6′a), 1.02 (t, J ) 12.9 Hz, 1H, H2′a), 0.92 (qd, J )
12.8 Hz and J ) 3.4 Hz, 1H, H4′a); IR (film) 3410, 1720, 960;
MS (FAB+) m/z 425 (M - 2H2O + H+). Anal. (C27H40O6) C, H,
O.
Eth yl (1R*,3S*)-1-Hydr oxy-3-[(3S*R*,E)-3-eth yl Acetate-
3-h yd r oxy-7-p h en yl-1-h ep t en -1-yl]-1-cycloh exa n e Ac-
eta te (14c) a n d Eth yl (1R*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-
3-eth yl Aceta te-3-h yd r oxy-7-p h en yl-1-h ep ten -1-yl]-1-cy-
cloh exa n e Aceta te (14d ): 1H NMR (360 MHz, CDCl3) δ 7.24
(m, 2H, H10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.56 (ABX, J ) 15.6
Hz and J ) 6.6 Hz, 1H, H1′′), 5.35 (ABX, J ) 16.2 Hz, 1H,
1630, 1135, 960; MS (FAB+) m/z 338 (M - OAc). Anal. (C25H35
NO3) C, H, N, O.
-
H
2′′), 4.16 (q, J ) 7.0 Hz, 2H, CH2), 4.11 (q, J ) 6.9 Hz, 2H,
CH2), 3.80 (s, 1H, OH), 3.75 (s, 1H, OH cycle), 2.57 (t, J ) 7.7
Hz, 2H, H7′′), 2.56 (s, 2H, H2), 2.47 (s, 2H, H4), 2.03 (m, 1H,
H3′), 1.75 (d, J ) 15.8 Hz, 1H, H6′e), 1.71 (d, J ) 18.4 Hz, 1H,
Meth yl 3-(3-Hydr oxy-7-ph en ylh eptan -1-yl)cycloh exan e-
1-Aceta te (13). Compound 13 was prepared from 10cd
according to the procedure described for 9b using twice the
proportion of palladium catalyst and sodium nitrite. The
residue obtained as a colorless oil was purified by column
chromatography on silica gel (eluent: cyclohexane/diethyl
ether, 80/20) to afford a first separation of the two isomers
13a b and 13cd which were further purified by preparative
HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/ethyl acetate:
94/6, 18 mL/min; 13cd : 62 and 63 min 30 s; and 13a b: 67.5
and 70 min). After HPLC chromatography, compounds 13cd
and 13a b were isolated in, respectively, 59% and 23% yield.
Meth yl (1R*,3S*)-3-(3-Hyd r oxy-7-p h en ylh ep ta n -1-yl)-
cycloh exa n e-1-Aceta te (13a b): 1H NMR (360 MHz, CDCl3)
δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H, H9′′ and H11′′), 3.64 (s, 3H,
OCH3), 3.52 (m, 1H, H3′′), 2.60 (t, J ) 7.7 Hz, 2H, H7′′), 2.17
(d, J ) 6.8 Hz, 2H, H2), 1.76 (m, 1H, H1′), 1.72 (d, J ) 15.1 Hz,
1H, H2′e), 1.72 (d, J ) 17.4 Hz, 1H, H5′e), 1.71 (d, J ) 15.1 Hz,
1H, H6′e), 1.70 (d, J ) 16.3 Hz, 1H, H4′e), 1.62 (m, 2H, H6′′),
1.43 (m, 2H, H4′′), 1.42 (m, 2H, H2′′), 1.41 (m, 2H, H5′′), 1.26 (q,
J ) 15.7 Hz, 1H, H5′a), 1.25 (m, 1H, H3′), 1.17 and 1.31 (m,
2H, H1′′), 1.18 (qd, J ) 11.9 Hz and J ) 3.6 Hz, 1H, H6′a), 0.77
(q, J ) 16.2 Hz, 1H, H4′a), 0.61 (q, J ) 11.6 Hz, 1H, H2′a); IR
(film) 3410, 1720; MS (FAB+) m/z 329 (M - H2O + H+). Anal.
(C22H34O3) C, H, O.
Meth yl (1S*,3S*)-3-(3-Hyd r oxy-7-p h en ylh ep ta n -1-yl)-
cycloh exa n e-1-Aceta te (13cd ): 1H NMR (360 MHz, CDCl3)
δ 7.24 (m, 2H, H10′′), 7.16 (m, 3H, H9′′ and H11′′), 3.64 (s, 3H,
OCH3), 3.55 (m, 1H, H3′′), 2.61 (t, J ) 7.7 Hz, 2H, H7′′), 2.25
(d, J ) 7.3 Hz, 2H, H2), 2.13 (m, 1H, H1′), 1.7-1.1 (m, 19H,
H2′-H6′, H1′′-H2′′ and H4′′-H6′′); IR (film) 3410, 1720; MS (FAB+)
m/z 329 (M - H2O + H+). Anal. (C22H34O3) C, H, O.
Eth yl 1-Hyd r oxy-3-[(E)-3-eth yl Aceta te-3-h yd r oxy-7-
p h en yl-1-h ep ten -1-yl]-1-cycloh exa n e Aceta te (14). Com-
pound 14 was prepared from 44 according to the procedure
described for 25 using 2.5 equiv of lithiated ethyl acetate. The
residue obtained as a colorless oil was purified by column
chromatography on silica gel (eluent: cyclohexane/diethyl
ether, 80/20) to afford a first separation of the four isomers
14a , 14b, 14c, and 14d which were further purified by
preparative HPLC (5 µm Inertsil, 20 × 250 mm, cyclohexane/
H
H
5′e), 1.71 (d, J ) 15.8 Hz, 1H, H2′e), 1.64 (d, J ) 15.8 Hz, 1H,
4′e), 1.57 (m, 2H, H6′′), 1.46 (m, 2H, H4′′), 1.39 (t, J ) 15.1 Hz,
1H, H6′a), 1.34 (m, 2H, H5′′), 1.29 (m, 1H, H5′a), 1.26 (t, J )
13.8 Hz, 1H, H2′a), 1.26 (t, J ) 7.0 Hz, 3H, CH3), 1.23 (t, J )
7.0 Hz, 3H, CH3), 0.98 (qd, J ) 12.2 Hz and J ) 3.6 Hz, 1H,
H
4′a); IR (film) 3410, 1720, 960; MS (FAB+) m/z 443 (M -
H2O + H+). Anal. (C27H40O6) C, H, O.
1-Hyd r oxy-3-[(E)-3-h yd r oxy-3-m eth yl-7-p h en yl-1-h ep -
ten -1-yl]cycloh exan e-1-N,N-dim eth yl-acetam ide (15). Com-
pound 15 was prepared by condensation of N,N-dimethylac-
etamide on 46 according to the procedure described for 25. The
residue obtained as an oil was purified by column chromatog-
raphy on silica gel (eluent: cyclohexane/diethyl ether, 60/40)
to afford a first separation of the four isomers 15a , 15b, 15c,
and 15d which were further purified by preparative HPLC (5
µm Inertsil, 20 × 250 mm, cyclohexane/ethyl acetate: 40/60,
15 mL/min, 15a : 24 min; 15b: 26 min; 15c: 38 min 30 s; and
15d : 42 min 30 s). After HPLC chromatography, compounds
15a , 15b, 15c, and 15d were isolated in, respectively, 25%,
26%, 15%, and 16% yield.
(1S*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-3-m eth yl-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-1-N,N-d im eth yl-a c-
eta m id e (15a ) a n d (1S*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-3-
h yd r oxy-3-m eth yl-7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-
1-N,N-d im eth yl-a ceta m id e (15b): 1H NMR (360 MHz,
CDCl3) δ 7.23 (m, 2H, H10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.47
(ABX, 1H, J ) 4.0 Hz, H1′′), 5.46 (AB, 1H, H2′′), 5.13 (s, 1H,
OH cycle), 2.98 (s, 3H, N-CH3), 2.94 (s, 3H, N-CH3), 2.58 (t,
2H, J ) 7.7 Hz, H7′′), 2.46 (m, 1H, H3′), 2.35 (s, 2H, H2), 1.86
(d, 1H, J ) 14.2 Hz, H2′e), 1.81 (d, 1H, J ) 14.2 Hz, H6′e), 1.79
(q, 1H, J ) 13.4 Hz, H5′a), 1.71 (d, 1H, J ) 13.4 Hz, H4′e), 1.56
(quint, 2H, J ) 7.7 Hz, H6′′), 1.54 (d, 1H, J ) 14.2 Hz, H5′e),
1.51 (m, 2H, H4′′), 1.38 (quint, 2H, J ) 7.7 Hz, H5′′), 1.21 (s,
3H, CH3), 1.09 (td, 1H, J ) 13.8 Hz and J ) 4.0 Hz, H6′a), 0.95
(t, 1H, J ) 12.6 Hz, H2′a), 0.93 (qd, 1H, J ) 13.2 Hz and J )
4.0 Hz, H4′a); IR (film) 3430, 1620, 1145, 970; MS (FAB+) m/z
370 (M - H2O+H+). Anal. (C24H37NO3) C, H, N, O.
Chiral HPLC separation (5 µm Chiralcel OD, 10.5 × 250
mm, heptane/2-propanol: 80/20, 1.125 mL/min; 15br: 42 min;

5308 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
and 15bâ: 47 min) from racemic diastereoisomer 15b afforded
enantiomers 15br and 15bâ.
ously described.36 Briefly, lungs were removed and washed in
phosphate buffer saline (PBS) without Ca2+ and Mg2+. Lungs
were minced and homogenized in 10 mM tris (HCl) buffer, pH
7.4, containing 250 mM sucrose, 100 µM phenylmethylsulfonyl
fluoride, and 2 mM dithioerythritol. The homogenate was
filtered through two layers of cheesecloth and centrifuged at
1000g for 10 min. The supernatant was centrifuged at 45000g
for 30 min, and the pellet was washed three times in 50 mM
tris (HCl) buffer, pH 7.4, containing 20 mM CaCl2. The pellet
was then resuspended in the same buffer and stored under
liquid nitrogen. The protein concentration was determined by
Lowry’s method.
(1R*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-h yd r oxy-3-m eth yl-
7-p h en yl-1-h ep ten -1-yl]cycloh exa n e-N,N-d im eth yl-a ceta -
m id e (15c) a n d (1R*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-3-h y-
dr oxy-3-m eth yl-7-ph en yl-1-h epten -1-yl]cycloh exan e-N,N-
d im eth yl-a ceta m id e (15d ): 1H NMR (360 MHz, CDCl3) δ
7.24 (m, 2H, H10′′), 7.14 (m, 3H, H9′′ and H11′′), 5.69 (s, 1H, OH),
5.51 (ABX, J ) 15.8 Hz and J ) 5.8 Hz, 1H, H1′′), 5.44 (AB,
J ) 15.8 Hz, 1H, H2′′), 3.01 (s, 3H, N-CH3), 2.94 (s, 3H, N-CH3),
2.58 (t, J ) 7.6 Hz, 2H, H7′′), 2.53 and 2.48 (AB, J ) 16.2 Hz,
2H, H2), 1.97 (m, 1H, H3′), 1.87 (m, 1H, H2′a), 1.83 (m, 1H, H6′a),
1.73 (m, 1H, H5′a), 1.67 (m, 1H, H4′e), 1.58 (m, 2H, H6′′), 1.50
(m, 2H, H4′′), 1.40 (m, 1H, H6′e), 1.32 (m, 2H, H5′′), 1.28 (m,
1H, H2′e), 1.24 (m, 1H, H5′e), 1.21 (s, 3H, CH3), 1.01 (qd, J )
11.9 Hz and J ) 3.6 Hz, 1H, H4′a); IR (film) 3430, 1620, 1145,
970; MS (FAB+) m/z 370 (M - H2O + H+). Anal. (C24H37NO3)
C, H, N, O.
1-H yd r oxy-3-[(E)-3-flu or o-7-p h en yl-1-h ep t en -1-yl]cy-
cloh exa n e-1-N,N-d im eth yl-a ceta m id e (16). Compound 16
was prepared by condensation of N,N-dimethylacetamide on
49 according to the procedure described for 25. The residue
obtained as an oil was purified by column chromatography on
silica gel. Elution of diethyl ether afforded a first separation
of the two isomers 16a b and 16cd which were further purified
by preparative HPLC (5 µM Inertsil, 20 × 250 mm, cyclohex-
ane/ethyl acetate: 75/25, 15 mL/min; 16a : 44 min; 16b: 48 min;
16c: 58 min; and 16d : 60 min). After HPLC chromatography,
compounds 16a , 16b, 16c, and 16d were isolated in, respec-
tively, 30, 28, 14, and 12% yield.
LTB4 Recep tor Bin d in g. Binding to PMNs was performed
in HBSS without Ca2+ and Mg2+ containing 5 mM HEPES
buffer. PMNs (106 cells) were incubated for 20 min at 4 °C
with 1 nM [3H] LTB4 (7.4 TBq/mmol) in the presence or
absence of competitors at various concentrations. Binding to
guinea pig lung membranes was performed in 50 mM tris
(HCl) buffer, pH 7.4, containing 20 mM CaCl2. Membranes (1
mg proteins/mL) were incubated for 30 min at 25 °C with 1
nM [3H] LTB4 in the presence or absence of competitors.
Binding was determined by filtration technique as previously
described.37
LTB4-In d u ced Ch em ota xis. PMNs prepared as described
above were used. The cells suspended in HBSS without Ca2+
and Mg2+ were labeled with 51Cr (1 µCi/106 cells) for 1 h at 37
°C and washed twice in HBSS. PMNs were finally resuspended
at 107 cells/mL in Hank’s buffer supplemented with 1% bovine
serum albumin. LTB4 and competitors in Hank’s buffer were
added to the bottom half of Boyden-Keller chambers, two 3
µm cellulose nitrate filters were placed over each well, and
the top part of the chambers was filled with cell suspension
as previously described.38 The chambers were incubated at 37
°C in 5% CO2/95% humidified air for 150 min. Radioactivity
on the lower filter was measured by liquid scintillation
spectrometry (Beckman LS 3801 counter). Results are ex-
pressed as percent of control.
(1S*,3R*)-1-Hyd r oxy-3-[(3S*R*,E)-3-flu or o-7-p h en yl-1-
h ep ten -1-yl]cycloh exa n e-N,N-d im eth yl-a ceta m id e (16a )
a n d (1S*,3R*)-1-Hyd r oxy-3-[(3R*S*,E)-3-flu or o-7-p h en yl-
1-h epten -1-yl]cycloh exan e-N,N-dim eth yl-acetam ide (16b):
1H NMR (360 MHz, CDCl3) δ 7.25 (m, 2H, H10′′), 7.15 (m, 3H,
H
9′′ and H11′′), 5.62 (m, 1H, H1′′), 5.45 (m, 1H, H2′′), 5.18 (s, 1H,
OH), 4.75 (qd, J ) 49.0 Hz and J ) 5.6 Hz, 1H, H3′′), 2.97 (s,
3H, N-CH3), 2.94 (s, 3H, N-CH3), 2.59 (t, J ) 7.7 Hz, 2H, H7′′),
2.50 (m, 1H, H3′), 2.35 (s, 2H, H2), 1.89 (d, J ) 13.8 Hz, 1H,
Gu in ea P ig Lu n g P a r en ch ym a l St r ip Con t r a ct ion .
Strips of Dunkin Hartley guinea pig lung parenchyma were
cut and placed in 10 mL organ baths containing oxygenated
(95% O2/5% CO2) Tyrode solution at 37 °C. Strips were
recorded on a polygraph with an isometric tension of 400 mg.
After a 1 h equilibration, mepyramine (1 µM) and atropine
(10 µM) were added to the Tyrode solution and competitors
were tested for their agonist activity. Contraction responses
were recorded for 5 min. The antagonist activities were tested
by adding the drugs to the bath 2 min before LTB4 (30 nM)
stimulation. The results are expressed as percent inhibition
of LTB4-induced contraction.
P MA-In du ced Mou se Ear In flam m ation Model.39 Twenty
microliters of Phorbol 12-myristate 13-acetate (5 mg in 20 mL
ethanol/water: 8/2) was applied topically to the anterior and
posterior surfaces of mice right ears, 30 min following similar
application of test substance or vehicle (2 × 20 µL at 5 min
intervals in absolute ethanol). Mice left ears were used as
control. Ear swelling was then measured by a Dyer model
micrometer gauge after 6 h as an index of inflammation. Five
mice (Iffa Credo, France male 25 ( 2 g) per dose level of test
substance were used. For all test procedures, percent inhibition
was calculated according to the equation: % ) [ Ic - It/Ic ] ×
100 where Ic and It represent the increase in ear thickness
(mm) in control and treated mice, respectively. Dexamethasone
was used as the positive reference agent in the control group.
H
H
2′e), 1.80 (d, J ) 13.8 Hz, 1H, H6′e), 1.79 (q, J ) 16.2 Hz, 1H,
5′a), 1.74 (d, J ) 13.8 Hz, 1H, H4′e), 1.64 (m, 2H, H4′′), 1.62
(m, 2H, H6′′), 1.54 (d, J ) 16.2 Hz, 1H, H5′e), 1.39 (m, 2H, H5′′),
1.09 (td, J ) 13.7 Hz and J ) 4.2 Hz, 1H, H6′a), 0.96 (t, J )
12.5 Hz, 1H, H2′a), 0.95 (q, J ) 15.4 Hz, 1H, H4′a); 19F NMR
(235 MHz, CDCl3) δ -169.8 (m); IR (film) 3430, 1620, 1145,
960; MS (FAB+) m/z 356 (M - HF + H+). Anal. (C23H34NO2F)
C, H, N, O.
(1R*,3S*)-1-Hyd r oxy-3-[(3S*R*,E)-3-flu or o-7-p h en yl-1-
h ep ten -1-yl]cycloh exa n e-N,N-d im eth yl-a ceta m id e (16c)
a n d (1R*,3S*)-1-Hyd r oxy-3-[(3R*S*,E)-3-flu or o-7-p h en yl-
1-h epten -1-yl]cycloh exan e-N,N-dim eth yl-acetam ide (16d):
1H NMR (100 MHz, CDCl3) δ 7.35-7.15 (m, 5H, H9′′-H11′′), 5.73
(s, 1H, OH), 5.57 (m, 2H, H2′′ and H1′′), 4.75 (qd, J ) 49.0 Hz
and J ) 5.6 Hz, 1H, H3′′), 3.01 (s, 3H, N-CH3), 2.95 (s, 3H,
N-CH3), 2.59 (t, J ) 7.7 Hz, 2H, H7′′), 2.51 (m, 2H, H2), 0.8-
2.2 (m, 15H, H2′-H6′ and H4′′-H6′′); 19F NMR (235 MHz, CDCl3)
δ -170.4 (md, J ) 48.9 Hz), -170.5 (md, J ) 49.2 Hz); IR
(film) 3430, 1620, 1145, 960. Anal. (C23H34NO2F) C, H, N, O.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Sod iu m
sa lts. To a 0.01 M solution of the pure ester in 1:1 MeOH/
H2O at 0 °C was added 1.5 equiv of 0.1 N NaOH, and the
solution was stirred at 25 °C for 16 h. TLC analysis indicated
all the starting ester was consumed.
Biologica l Eva lu a tion . Hu m a n Neu tr op h il P r ep a r a -
tion . Human PMNs were isolated from heparinized venous
blood of heatlthy donors by dextran T500 sedimentation as
previously described.35 Supernatant was centrifuged on Ficoll
Paque, and residual erythrocytes were removed by hypotonic
lysis. PMNs were washed in Hank’s balanced salt solution
(HBSS) without Ca2+ and Mg2+, and cell viability was assessed
by trypan blue exclusion.
Ack n ow led gm en t. This research has been sup-
ported by the Centre National de la Recherche Scien-
tifique (CNRS), Agence National de Valorisation de la
Recherche (ANVAR), and Servier-Adir Group. The
authors express gratitude to Professor C. Roussel and
Ms. C. Popescu (CNRS UMR 6516, Marseille) for
preliminary chiral chromatography tests.
Gu in ea P ig Lu n g Mem br a n e P r ep a r a tion . Adult male
Dunkin Hartley guinea pigs (350-500 g) were used, and all
lung membrane preparation was performed at 4 °C as previ-

Synthesis and SAR of 1,3-Disubstituted Cyclohexanes
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5309
(9) (a) Konno, M.; Nakae, T.; Sakuyama, S.; Nishizaki, M.; Odagaki,
Y.; Nakai, H.; Hamanaka, N. Synthesis of Structural Analogues
of Leukotriene B4 and their Receptor Binding Activity. Bioorg.
Med. Chem. 1997, 5, 1621-1647. (b) Tsai, B. S.; Keith, R. H.;
Villaniprice, D.; Haack, R. A.; Djuric, S. W. The Leukotriene B4
Receptor Agonist/Antagonist Activities of SC-45694 in Human
Neutrophils. J . Pharmacol. Exp. Ther. 1994, 268, 1493-1498.
(c) Djuric, S. W.; Haack, R. A.; Yu, S. S. Synthesis of (()-
Refer en ces
(1) (a) Bray, M. A. Leukotrienes in Inflammation. Agents Actions
1986, 19, 87-99. (b) Brain, S. D.; Williams, T. J . Leukotrienes
and Inflammation. Pharm. Ther. 1990, 46, 57-66. (b) Ford-
Hutchinson, A. W. Leukotriene B4 in Inflammation. Crit. Rev.
Immunol. 1990, 10, 1-12.
(2) (a) Palmblad, J .; Malmsten, C.; Uden, A.; Radmark, O.; Engstedt,
L.; Samuelsson, B. LTB4 is a Potent Stereospecific Stimulator
of Neutrophil Chemotaxis and Adherence. Blood 1981, 58, 658-
661. (b) Ringertz, B.; Palmblad, J .; Radmark, O.; Malmsten, C.
Leukotriene-Induced Neutrophil Aggregation In Vitro. FEBS
Lett. 1982, 147, 180-182. (c) Rae, S. A.; Smith, M. J . H. The
Stimulation of Lysosomal Enzyme Secretion from Human Poly-
morphonuclear Leucocytes by Leukotriene B4. J . Pharm. Phar-
macol. 1981, 33, 616-617. (d) Bjork, J .; Hedqvist, P.; Arfors, K.
E. Increase in Vascular Permeability Induced by Leukotriene
B4 and the Role of Polymorphonuclear Leukocytes. Inflammation
1982, 6, 189-199.
(3) (a) Brain, S. D.; Camp, R. D. R.; Cunningham, F. M.; Dowd, P.
M.; Greaves, M. W.; Kobza-Black, A. Leukotriene B4-Like
Material in Scale of Psoriatic Skin Lesions. Br. J . Pharmacol.
1984, 83, 313-317. (b) Fogh, K.; Herlin, T.; Kragballe, K.
Eicosanoids in Acute and Chronic Psoriatic Lesions: Leukotriene
B4 but not 12-Hydroxy-Eicosatetraenoic acid, is Present in
Biologically Active Amounts in Acute Guttate Lesions. J . Invest.
Dermatol. 1989, 92, 837-841. (c) Sharon, P.; Stenson, W. F.
Enhanced Synthesis of Leukotriene B4 by Colonic Mucosa in
Inflammatory Bowel Disease. Gastroenterology 1984, 86, 453-
460. (d) Klickstein, L. B.; Shapleigh, L.; Goetzl, E. Lipoxygen-
ation of Arachidonic Acid as a Source of Polymorphonuclear
Leukocyte Chemotactic Factors in Synovial Fluid and Tissue in
Rheumatoid Arthritis and Spondylosing Arthritis. J . Clin. Invest.
1980, 66, 1166-1170. (e) Davidson, E. M.; Rae, S. A.; Smith, M.
J . Leukotriene B4, a mediator of Inflammation present in
Synovial Fluid in Rheumatoid Arthritis. Ann. Rheum. Dis. 1983,
42, 677-679. (f) Ahmadzadeh, N.; Shingu, M.; Nobunaga, M.;
Tawara, T. Relationship Between Leukotriene B4 and Im-
munological Parameters in Rheumatoid Synovial Fluids. Inflam-
mation 1991, 15, 497-503. (g) Rae, S. A.; Davidson, E. M.;
Smith, M. J . H. Leukotriene B4, an Inflammatory Mediator in
Gout. Lancet 1982, 2, 1122-1124. (h) Lawrence, R.; Sorrell, T.
Eicosapentanoic Acid in Cystic Fibrosis: Evidence of a Patho-
genic Role for Leukotriene B4. Lancet 1993, 342, 465-469. (i)
Konstan, M. W.; Walenga, R. W.; Hilliard, K. A.; Hilliard, J . B.
Leukotriene B4 is Markedly Elevated in Epithelial Lining Fluid
of Patients with Cystic Fibrosis. Am. Rev. Respir. Dis. 1993, 48,
896-901. (j) Seggev, J . S.; Thornton, W. H.; Edes, T. E. Serum
Leukotriene B4 Levels in Patients with Obstructive Pulmonary
Disease. Chest 1991, 99, 289-291. (k) Wardlaw, A. J .; Hay, H.;
Cromwell, O.; Collins, J . V.; Kay, A. B. Leukotrienes, LTB4 and
LTC4 in Bronchoalveolar Lavage in Bronchial Asthma and Other
Respiratory Diseases. J . Allergy Clin. Immunol. 1989, 84, 19-
26. (l) Antonelli, M.; Buffi, M.; Deblasi, R. A.; Crimi, G.; Conti,
G.; Mattia, C.; Lombardi, D.; Dotta, A. Detection of Leukotrienes
B4, C4 and of their Isomers in Arterial, Mixed Venous Blood and
Bronchoalveolar Lavage Fluid of Patients with Cystic Fibrosis.
Intensive Care Med. 1989, 15, 296-301.
Benzoleukotriene B3:
a Novel Leukotriene B4 Analogue, J .
Chem. Soc., Perkin Trans. 1989, 2133-2134. (d) Ekerdt, R.;
Buchmann, B.; Fro¨hlich, W.; Giesen, C.; Heindl, J .; Skuballa,
W. The Role of Leukotriene B4 (LTB4) as an Inflammatory
Mediator in Skin and the Functional Characterisation of LTB4
Receptor Antagonists. In The 7th International Conference on
Prostaglandins and Related Compounds; Florence (Italy), 1990;
p 303. (e) Morris, J .; Wishka, D. G. Synthesis of Novel Antago-
nists of Leukotriene B4. Tetrahedron Lett. 1988, 29, 143-146.
(f) Taylor, B. M.; Crittenden, N. J .; Bruden, M. N.; Wishka, D.
G.; Morris, J .; Richards, I. M.; Sun, F. F. Biological Activity of
Leukotriene B4 Analogues: Inhibition of Guinea Pig Eosinophil
Migration In Vitro by the 2,6-Disubstituted Pyridine Analogues
U-75,302 and U-75,485. Prostaglandins 1991, 42, 211-224. (g)
Kingsbury, W. D.; Pendrak, I.; Leber, J . D.; Boehm, J . C.; Mallet,
B.; Sarau, H. M.; Foley, J . J .; Schmidt, D. B.; Daines, R. A.
Synthesis of Structural Analogues of Leukotriene B4 and their
Receptor Binding Activity. J . Med. Chem. 1993, 36, 3308-3320.
(h) Miyashiro, J . M.; Haack, R. A.; Djuric, S. W. In Abstracts of
Papers,198th National Meeting of the American Chemical
Society, Miami Beach, 1989; American Chemical Society: Wash-
ington, DC, 1989; MEDI 54. (i) Agrawal, D. K.; Numao, T.;
Shoupe, T. S.; Gale, D. A Novel LTB4 Receptor Antagonist and
its Effect on Neutrophil, Eosinophil and Monocyte Functions.
The American Academy of Allergy and Immunology, 48th
Annual Meeting, Orlando, Florida, March 6-11, 1992. In J .
Allergy Clin. Immunol. 1992, 89, 236.
(10) (a) Brooks, C. D. W.; Summers, J . B. Modulators of Leukotriene
Biosynthesis and Receptor Activation. J . Med. Chem. 1996, 39,
2629-2654. (b) Fretland, D. J .; Penning, T. D. Recent Advances
in Leukotriene B4 Receptor Antagonist Research. Exp. Opin.
Ther. Pat. 1996, 6, 21-28. (c) Higa, A.; Eto, T.; Nawa, Y.
Evaluation of the Role of Neutrophils in the Pathogenesis of
Acetic Acid-Induced Colitis in Mice. Scand. J . Gastroenterol.
1997, 32, 564-568. (d) Vanpelt, J .; Dejong, E.; Vanerp, P.;
Mitchell, M. I.; Marder, P.; Spaethe, S. M.; Vanhooijdonk, C.;
Kuijpers, A.; Vandekerkhof, P. The Regulation of CD11b Integrin
Levels on Human Blood Leukocytes and Leukotriene B4-
Stimulated Skin by a Specific Leukotriene B4 Receptor Antago-
nist (LY293111). Biochem. Pharmacol. 1997, 53, 1005-1012. (e)
Vanpelt, J .; Dejong, E.; Seijger, M.; Vanhooijdonk, C.; Debakker,
E.; Vanvlijmen, I.; Parker, G. L.; Vanerp, P.; Vandekerkhof, P.
Investigation on a Novel and Specific Leukotriene B4 Receptor
Antagonist in the Treatment of Stable Plaque Psoriasis. Br. J .
Dermatol. 1998, 139, 396-402. (f) Reiter, L. A.; Melvin, L. S.;
Crean, G. L.; Showell, H. J .; Koch, K.; Biggers, M. S.; Cheng, J .
B.; Breslow, R.; Conklyn, M. J .; Farrell, C. A.; Hada, W. A.; Laird,
E. R.; Martin, J . J .; Miller, G. T.; Pillar, J . S. 3-Substituted-4-
hydroxy-7-chromanylacetic Acid Derivatives as Antagonists of
the Leukotriene B4 (LTB4) Receptor. Bioorg. Med. Chem. Lett.
1997, 7, 2307-2312. (g) Daines, R. A.; Chambers, P. A.; Foley,
J . J .; Griswold, D. E.; Kingsbury, W. D.; Martin, L. D.; Schmidt,
D. B.; Sham, K. K. C.; Sarau, H. M. (E)-3-[6-[[(2,6-Dichlorophen-
yl)thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic Acid-a
High-Affinity Leukotriene B4 Receptor Antagonist with Oral
Antiinflammatory Activity. J . Med. Chem. 1996, 39, 3837-3841.
(h) Sawyer, J . S. Leukotriene B4 Receptor Antagonists: Recent
Clinical Developments, Expert. Opin. Invest. Drugs 1996, 5, 73-
77. (i) Skuballa, W.; Buchmann, B.; Heindl, J .; Froehlich, W.;
Ekerdt, R.; Giesen, C. Leukotriene B4 derivatives. Ger. Offen.
DE 4,227,790; 1994. (j) Skuballa, W.; Buchmann, B.; Heindl, J .;
Froehlich, W.; Ekerdt, R.; Giesen, C. New Leukotriene B4
derivatives, process for their preparation, and their use as drugs.
Ger. Offen. DE 4,236,540; 1994. (k) Skuballa, W.; Buchmann,
B.; Heindl, J .; Froehlich, W.; Ekerdt, R.; Giesen, C. Preparation
of leukotriene B4 derivatives as drugs. Ger. Offen. DE 4,242,-
390; 1994.
(4) Devchand, P. R.; Keller, H.; Peters, J . M.; Vazquez, M.; Gonzalez,
F. J .; Wahli, W. The PPARR-Leukotriene B4 Pathway to Inflam-
mation Control. Nature 1996, 384, 39-43.
(5) (a) Goldman, D. W.; Goetzl, E. J . Specific Binding of Leukotriene
B4 to Receptors on Human Polymorphonuclear Leukocytes. J .
Immunol. 1982, 129, 1600-1604. (b) Lin, A. H.; Ruppel, P. L.;
Gorman, R. R. Leukotriene B4 Binding to Human Neutrophils.
Prostaglandins 1984, 28, 837-849.
(6) Yokomizo, T.; Izumi, T.; Chang, K.; Takuwa, Y.; Shimizu, T. A
G-Protein-Coupled Receptor for Leukotriene B4 that Mediates
Chemotaxis. Nature 1997, 387, 620-624. (b) Parello, J .; Baneres,
J . L.; Durand, D.; Hullot, P.; Girard, J . P. Interactions of
Leukotriene B4 with its detergent-solubilized recombinant
receptor. 26th Meeting of the Federation of European Biochemical
Societies FEBS’99, Nice. Abstr. Biochimie 1999, Suppl 6, s143.
(7) Goldman, D. W.; Goetzl, E. J . Heterogeneity of Human Poly-
morphonuclear Leukocyte Receptors for Leukotriene B4. Iden-
tification of a Subset of High Affinity Receptors that Transduce
the Chemotactic Response. J . Exp. Med. 1984, 159, 1027-1041.
(8) Brasseur, R.; Deleers, M. Conformational analysis of 6-cis and
6-trans-leukotriene B4-calcium complexes. Proc. Natl. Acad. Sci.
U.S.A. 1984, 81, 3370-3374. (b) Sugiura, M.; Beierbeck, H.;
Belanger, P. C.; Kotovych, G. Conformational Analysis of Leu-
kotriene B4 in Solution Based on High-Field Nuclear Magnetic
Resonance Measurements. J . Am. Chem. Soc. 1984, 106, 4021-
4025. (c) Poudrel, J . M.; Hullot, P.; Vidal, J . P.; Girard, J . P.;
Rossi, J . C.; Muller, A.; Bonne, C. Synthesis and Pharmacological
Profile of New 1,3-Disubstituted Cyclohexanes as Leukotriene
B4 Receptor Antagonists. Bioorg. Med. Chem. Lett. 1996, 6,
2349-2354.
(11) (a) Corey, E. J .; Beames, D. J . Mixed Cuprate Reagents of Type
R1R2CuLi Which Allow Selective Group Transfer. J . Am. Chem.
Soc. 1972, 94, 7210-7211. (b) Corey, E. J .; Weinshenker, N. M.;
Schaff, T. K.; Huber, W. Stereo-Controlled Synthesis of Pros-
taglandins F2R and E2 (dl), J . Am. Chem. Soc. 1969, 91, 5675-
5677. (c) Corey, E. J .; Arnold, Z.; Hutton, J . Total Synthesis of
Prostaglandins F2R and E2 (dl) via a Tricarboxylic Intermediate,
Tetrahedron Lett. 1970, 307-310. (d) Schaaf, T. K.; Corey, E. J .
Total Synthesis of Prostaglandins F1R and E1. J . Org. Chem.
1972, 37, 2921-2922. (e) Cowherd, F. G.; Doria, M. C.; Galeazzi,
E.; Muchowski, J . M. N-Nitromethylphthalimide. A Formyl
Anion Equivalent. Can. J . Chem. 1977, 55, 2919-2929.

5310 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26
Poudrel et al.
(12) (a) Luo, F. T.; Negishi, E. I. A Selective Synthesis of a Mixture
of 15-Epimers of (()-11-Deoxyprostaglandin E2 Methyl Ester.
J . Org. Chem. 1985, 50, 4762-4766. (b) Hullot, P.; Poudrel, J .
M.; Muller, A.; Escale, R.; Rossi, J . C.; Girard, J . P.; Bonne, C.
Synthesis and Biochemical/Pharmacological Profile of the Novel
Leukotriene B4 Receptor Antagonist Sodium (1S*, 3S*)-1-
Hydroxy-3-[(3R*S*,E)-3-hydroxy-7-phenyl-1-hepten-1-yl]-1-cyclo-
hexane Acetate. Arzneim. Forsch./ Drug Res. 1997, 47, 51-58.
(13) Corey, E. J .; Floyd, D.; Lipshutz, B. H. (3-methyl-3-methoxy-1-
butynyl) copper, an Useful Reagent for the Generation of Mixed
Cuprates. J . Org. Chem. 1978, 43, 3418-3420.
(14) (a) Corey, E. J .; Raju, N. A New General Synthetic Route to
Bridged Ortho esters, Tetrahedron Lett. 1983, 24, 5571-5574.
(b) Bannai, K.; Tanaka, T.; Okamura, N.; Hazato, A.; Sugiura,
S.; Manabe, K.; Tomimori, K.; Kurozumi, S. Improved Synthesis
of Isocarbacyclin Using Regioselective Alkylation of Allylic
Alcohols. Tetrahedron Lett. 1986, 27, 6353-6356. (c) Kugel, C.;
Lellouche, J . P.; Beaucourt, J . P.; Niel, G.; Girard, J . P.; Rossi,
J . C. Stereospecific Total Synthesis of (5,6)-DiHETE isomers.
Tetrahedron Lett. 1989, 30, 4947-4950.
(15) Takacs, J . M.; Helle, M. A.; Seely, F. L. An Improved Procedure
for the Two Carbon Homologation of Esters to R,â-Unsaturated
Esters, Tetrahedron Lett. 1986, 27, 1257-1260
(16) (a) Savignac, P.; Mathey, F. Une Voie Simple et Efficace d’Acce´s
aux â-ce´tophosphonates. Tetrahedron Lett. 1976, 33, 2829-2832.
(b) Durand, T.; Savignac, P.; Girard, J .-P.; Escale, R.; Rossi, J .-
C. â-Ce´tophophonates: Pre´curseurs d’Analogues du LTB4. Tet-
rahedron Lett. 1990, 31, 4131-4134.
Lindgren, J . A.; Claesson, H. E.; Malmsten, C.; Samuelsson, B.
Stimulation of Human Leukocyte Degranulation by Leukotriene
B4 and its ω-Oxidized Metabolites. FEBS Lett. 1981, 136, 141-
144. (c) Shak, S.; Goldstein, I. M. ω-Oxidation Is the Major
Pathway for the Catabolism of Leukotriene B4 in Human
Polymorphonuclear Leukocytes, J . Biol. Chem. 1984, 259,
10181-10187.
(28) (a) Crossley, N. S. The Synthesis and Biological Activity of
Potent, Selective Luteolytic Prostaglandins. Prostaglandins
1975, 10, 5-18. (b) Resul, B.; Stjernschantz, J .; No, K.; Liljebris,
C.; Sele´n, G.; Astin, M.; Karlsson, M.; Bito, L. Z. Phenyl-
Substituted Prostaglandins: Potent and Selective Antiglaucoma
Agents. J . Med. Chem. 1993, 36, 243-248. (c) Liljebris, C.; Sele´n,
G.; Resul, B.; Stjernschantz, J .; Hacksell, U. Derivatives of 17-
phenyl-18,19,20-trinorprostaglandin F2R Isopropyl Ester: Po-
tential Antiglaucoma Agents. J . Med. Chem. 1995, 38, 289-304.
(29) Huang, F. C.; Chan, W. K.; Warus, J . D.; Morrissette, M. M.;
Moriarty, K. J .; Chang, M. N.; Travis, J . J .; Mitchell, L. S.; Nuss,
G. W.; Sutherland, C. A. 4-[2-(Methyl(2-phenethyl)amino]-2-
oxoethyl]-8-(phenylmethoxy)-2-naphthalenecarboxylic acid:
A
High Affinity, Competitive, Orally Active Leukotriene B4 Recep-
tor Antagonist. J . Med. Chem. 1992, 35, 4253-4255.
(30) Showell, H. J .; Otterness, I. G.; Marfat, A.; Corey, E. J . Inhibition
of Leukotriene B4-Induced Neutrophil Degranulation by Leu-
kotriene B4-Dimethylamide. Biochem. Biophys. Res. Commun.
1982, 106, 741-747.
(31) Powell, W. S.; Gravelle, F. Metabolism of Leukotriene B4 to
Dihydro and Dihydro-oxo Products by Porcine Leukocytes. J .
Biol. Chem. 1989, 264, 5364-5369. (b) Yokomizo, T.; Izumi, T.;
Takahashi, T.; Kasama, T.; Kobayashi, Y.; Sato, F.; Taketani,
Y.; Shimizu, T. Enzymatic Inactivation of Leukotriene B4 by a
Novel Enzyme found in the Porcine Kidney - Purification and
Properties of Leukotriene B4 12-Hydroxydehydrogenase. J . Biol.
Chem. 1993, 268, 18128-18135. (c) Yokomizo, T.; Ogawa, Y.;
Uozumi, N.; Kume, K.; Izumi, T.; Shimizu, T. cDNA Cloning,
Expression, and Mutagenesis Study of Leukotriene B4 12-
Hydroxydehydrogenase. J . Biol. Chem. 1996, 271, 2844-2850.
(d) Daines, R. A.; Chambers, P. A.; Eggleston, D. S.; Foley, J . J .;
Griswold, Don E.; Haltiwanger, R. C.: J akas, D. R.; Kingsbury,
W. D.; Martin, L. D.; Pendrak, I.; Schmidt, D. B.; Tzimas, M.
N.; Sarau, H. M. (E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4-methoxy-
phenyl)octyl]oxy]-2-pyridinyl]-methyl]thio]methyl]benzoic Acid
and related Compounds: High Affinity Leukotriene B4 Receptor
Antagonists. J . Med. Chem. 1994, 37, 3327-3336.
(32) Goetzl, E.; Pickett, W. C. Novel Structural Determinants of the
Human Neutrophil Chemotactic Activity of Leukotriene B. J .
Exp. Med. 1981, 153, 482-487.
(33) Shimazaki, T.; Kawajiri, K.; Kobayashi, Y.; Sato, F. 12(R)-
Methyl-Leukotriene B3: A Stable Leukotriene B4 Analogue
Toward the Reductase Metabolism. Prostaglandins 1993, 45,
335-345.
(34) Welch, J . T. Advances in the Preparation of Biologically Active
Organofluorine Compounds. Tetrahedron 1987, 43, 3123-3197.
(35) Boyum, A. Isolation of Mononuclear Cells and Granulocytes from
Human Blood. Isolation of Mononuclear Cells by One Centrifu-
gation, and of Granulocytes by Combining Centrifugation and
Sedimentation at 1 g. Scand. J . Clin. Lav. Invest. 1968, 21, 77-
89.
(36) Muller, A.; Rechencq, E.; Kugel, C.; Lellouche, J . P.; Beaucourt,
J . P.; Niel, G.; Girard, J . P.; Rossi, J . C.; Bonne, C. Comparative
Biological Activities of the four Synthetic (5,6)-DiHETE Isomers.
Prostaglandins 1989, 38, 635-644.
(17) (a) Maillard, J .; Delaunay, P.; Langlois, M.; Portevin, B.; Legeai,
J .; Benharkate, M. Synthe`se de De´rive´s Amine´s du Te´trahydro-
4,5,6,7 Benzotriazole. Eur. J . Med. Chem.-Chim. Ther. 1984,
19, 457-460. (b) House, H. O.; Latham, R. A.; Slater, C. D.
Preparation of 3-Isoprenylcyclohexanone. J . Org. Chem. 1966,
31, 2667-2669.
(18) Gemal, A. L.; Luche, J . L. Lanthanoids in Organic Synthesis. 6.
The Reduction of R-Enones by Sodium Borohydride in the
Presence of Lanthanoid Chlorides: Synthetic and Mechanistic
Aspects. J . Am. Chem. Soc. 1981, 103, 5454-5459.
(19) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J . M. Wet Silica
Gel; A convenient Reagent for Deacetalization. Synthesis 1978,
63-65,
(20) Wadsworth, W. S.; Emmons, W. D. Ethyl Cyclohexylideneac-
etate. Org. Synth. 1965, 45, 44-47.
(21) Tay, M. K.; About-J audet, E.; Collignon, N.; Savignac, P.
Phosphonates R-lithie´s, Agents de Transfert Fonctionnel. Pre´pa-
ration de Phosphonates R-Amides et d’Amides â-insature´s,
R-substitue´s, Tetrahedron 1989, 45, 4415-4430.
(22) Ganem, B.; Small, V. R. Ferric Chloride in Acetic Anhydride. A
Mild and Versatile Reagent for the Cleavage of Ethers. J . Org.
Chem. 1974, 39, 3728-3730.
(23) (a) Bezuglov, V. V.; Bergel’son, L. D. Synthesis of Prostaglandins.
I 11-Fluoro and 15-Fluoro Prostaglandins. Soviet J . Bioorg.
Chem. 1979, 5, 1137-1140. (b) Gerstenberger, M. R. C.; Hass,
A. Methods of Fluorination in Organic Chemistry. Angew. Chem.,
Int. Ed. Engl. 1981, 20, 647-667.
(24) (a) Shimazaki, T.; Kobayashi, Y.; Sato, F.; Iwama, T.; Shikada,
K. Some Newly Synthesized Leukotriene B4 Analogues Inhibit
LTB4-Induced Lysozyme Release from Rat Polymorphonuclear
Leukocytes. Prostaglandins 1990, 39, 459-467. (b) Soyombo, O.;
Spur, B. W.; Soh, C.; Lee, T. H. Structure Activity Relationship
of Leukotriene B4 and its Structural Analogues in Chemotactic,
Lysosomal-Enzyme Release and Receptor-Binding Assays. Eur.
J . Biochem. 1993, 218, 59-66.
(25) Leblanc, Y.; Fitzsimmons, B. J .; Charleson, S.; Alexander, P.;
Evans, J . F.; Rokach, J . Analogues of Leukotriene B4: Effects
of Modification of the Hydroxyl Groups on Leukocyte Aggrega-
tion and Binding to Leukocyte Leukotriene B4 Receptor. Pros-
taglandins 1987, 33, 617-625.
(26) Kobayashi, Y.; Shimazaki, T.; Kawajiri, K.; Sato, F.; Shimizu,
T.; Seyama, Y. Role of the C16-C20 Part of LTB4 on Binding
Activity to the LTB4 Receptor. In The 7th International Confer-
ence on Prostaglandins and Related Compounds; Florence (Italy),
1990; p 177.
(37) Muller, A.; Ghiglieri-Bertez, C.; Modat, G.; Bonne, C. Specific
Binding of Leukotriene C4 to Endothelial Cell Membranes.
Prostagland. Leuk. Med. 1987, 26, 233-240.
(38) Gallin, J . Chromium-51 Radioimmunoassay for Chemotaxis.
Methods Enzymol. 1988, 162, 59-64.
(39) Chang, J .; Blazek, E.; Skowtonek, M.; Marinari, L.; Carlson, R.
P. The Antiinflammatory Action of Guanabenz is Mediated
Through 5-Lipoxygenase and Cyclooxygenase Inhibition. Eur.
J . Pharmacol. 1987, 142, 197-205.
(27) (a) Hansson, G.; Lindgren, J . A.; Dahlen, S. E.; Hedquist, P.;
Samuelsson, B. Identification and Biological Activity of Novel
ω-Oxidized Metabolites of Leukotriene B4 from Human Leuko-
cytes. FEBS Lett. 1981, 130, 107-112. (b) Feinmark, S. J .;
J M9910573