Biaryl diacid inhibitors of human s-PLA2 with anti-inflammatory activity

Bioorganic & Medicinal Chemistry 8 (2000) 1087±1109

Biaryl Diacid Inhibitors of Human s-PLA₂with

Anti-In¯ammatory Activity

Dane M. Springer, ^a,* Bing-Yu Luh, ^aJoanne J. Bronson, ^aKatharine E. McElhone, ^a

Muzammil M. Mansuri, ^aKurt R. Gregor, ^bDavid O. Nettleton, ^bPaul L. Stanley ^b

and Kenneth M. Tramposch ^b

^aCentral Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, PO Box 5100,

Wallingford, CT 06492, USA

^bDermatology Discovery Research, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 Forest Avenue,

Bualo, NY 14213, USA

Received 9 August 1999; accepted 13 January 2000

AbstractÐTwenty-four hydrophobic dicarboxylic acids are described which were evaluated as inhibitors of 14 kDa human platelet

phospholipase A₂(HP-PLA₂). In general, biarylacetic acid derivatives were found to be more active than biaryl acids or biaryl-

propanoic acids. More potent inhibitors were obtained when hydrophobic groups were attached to the biaryl acid nucleus using an

ole®n linkage as compared to an ether linkage. Compounds with larger hydrophobic groups were usually more potent inhibitors

of HP-PLA₂. Five of the compounds disclosed in this report (2, 4, 28, 36b and 36i) were found to possess signi®cant anti-

in¯ammatory activity in a phorbol ester induced mouse ear edema model of chronic in¯ammation. # 2000 Elsevier Science Ltd. All

rights reserved.

Introduction

calcium-independent 40 kDa protein isolated from

myocardium, a 14 kDa pancreatic enzyme, and a non-

pancreatic 14 kDa PLA₂isolated from platelets and

rheumatoid synovial ¯uid.^{17 20}Two groups have suc-

cessfully crystallized the human non-pancreatic PLA₂

found in synovial ¯uid and determined its X-ray struc-

ture.^21,22The interfacial mechanism of action of PLA₂

presents a challenge for kinetic analysis in this class of

enzymes, and has sparked interest in the conformational

changes which take place when these soluble enzymes

bind to an organized phospholipid surface.^21,23

Phospholipases A₂have been implicated as the causal or

aggravating agent in the pathogenesis of various

in¯ammatory diseases. These enzymes cleave fatty acids

from the sn-2 position of glycerophospholipids. The

resultant lysophospholipid products of this hydrolysis

can be converted to platelet-activating factor (PAF), a

potent mediator of in¯ammation. Arachidonic acid

release from phospholipids by the action of PLA₂is

proin¯ammatory by virtue of the subsequent enzymatic

transformations of this fatty acid into prostaglandins

and leukotrienes.¹PLA₂activity has been linked to a

variety of errant processes such as asthma, arthritis,

psoriasis, pancreatitis, demyelinating diseases, hypoten-

sion during septic shock, and tissue injury during myo-

cardial ischemia.^{2 8}The normal physiological functions

of PLA₂s are equally diverse, and are likely to include

roles in membrane homeostasis, signal transduction, cell

proliferation, dierentiation, fertilization, bacterial

defense, and aging.^{9 16}

By virtue of the occurrence of the non-pancreatic 14

kDa enzyme in in¯ammatory lesions, we decided to

target this enzyme in a program to develop inhibitors of

PLA₂as anti-in¯ammatory agents. Our initial clinical

goal was to develop a PLA₂inhibitor as a topical agent

for treatment of psoriasis.

Strategy

There are four predominant PLA₂s that are isolable

from human sources; a cytosolic 85 kDa protein, a

Many classes of compounds have been recently descri-

bed as inhibitors of human non-pancreatic PLA₂.²⁴

During a broad screen of proprietary compounds, we

found the diacid BMS-181162 to be a good inhibitor of

*Corresponding author.

PII: S0968-0896(00)00047-X

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D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

14 kDa human platelet PLA₂(HP-PLA₂).^24dBMS-

181162 displayed an IC₅₀=40 mM against HP-PLA₂,

and an ED₅₀=160 mg/ear for reduction of mouse ear

edema in a phorbol ester induced acute in¯ammation

assay. BMS-181162 was found to not signi®cantly inhi-

bit many other enzymes involved in the in¯ammatory

response such as: PLA₁, PI-PLC, PLD, sphingomyelin-

ase, acetyl-CoA synthetase, cyclooxygenase-1, elastase,

LTA₄hydrolase, LTC₄synthetase, lipid peroxidase, 5-

LPO, 15-LPO, and protein kinase C. BMS-181162 has

also exhibited active-site directed competitive inhibition

of HP-PLA₂in a `scooting-mode' assay.²⁵

Table 1. Biological activity of diacids 1±4, and BMS-181162

% Inhibition

of human

a

platelet PLA₂

c

Compd

R

n

100 mM 10 mM IC₅₀ED₅₀

(mM)^b(mg/per dose)

1

0

80

96

22

46

26

10

Ð

We wished to develop an anti-in¯ammatory program

around BMS-181162, and de®ned its pharmacophore to

be a hydrophobic tail linked to a polar, diacid head

group. The chemical and photostability of the polyene

unit of 181162 was a concern to us at the outset of our

synthetic program. Therefore we decided to replace the

b-ionone type tail with a group of similar size, yet one

that is inherently more chemically stable. The tetra-

methyl-tetrahydronaphthalene group, well known in the

retinoid literature, was chosen for this purpose. We also

decided to incorporate additional atoms of the polyene

chain of 181162 into an extra aryl ring to further

improve the stability of our analogues. The inclusion of

the extra aryl ring into the general structure would also

simplify the synthesis of this class of molecules, as well

as provide an opportunity to optionally substitute this

ring. With these simpli®cations in mind, we decided to

target biaryl diacids 1 and 2 as synthetic analogues of

BMS-181162.

2

1

116

3

4

t-styryl

1

28

93

16

38

Ð

18

Ð

79

BMS-181162

77^d

12^d

45

180

^aValues reported are the mean of two samples at each concentration.

^bHP-PLA₂: values reported are the mean of three separate experi-

ments.

^cPhorbol ester induced mouse ear chronic in¯ammation assay. For

details see ref 30.

^dExtrapolated from the dose±response curve used in the IC₅₀determi-

nation.

Chemistry

o-vanillin (5) was converted to aryl tri¯ate 6. This

tri¯ate was then coupled to (3-carboethoxy)phenyl-

tributylstannane (7) to provide biaryl aldehyde 8. The

aldehyde was oxidized to the acid, which was esteri®ed

to produce diester 9. Demethylation of 9 to alcohol 10

was followed by the conversion of 10 to biaryl tri¯ate

11. For the n=1 series (Scheme 2), intermediate biaryl

aldehyde 8 was homologated via Wittig chemistry to

aldehyde 12, which was converted as above to diester

Our general synthetic approach²⁶to molecules of type

1±4 (Table 1) is summarized by eq (1). Palladium-cata-

lyzed coupling of a vinyl stannane and a biaryl tri¯ate

aords a product that can be hydrolyzed to deliver the

desired biaryl diacid targets.(1)

The syntheses of the required tri¯ates are illustrated in

Schemes 1 and 2. For the case where n=0 in eq (1),

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1089

Scheme 1. Reaction conditions: (a) Tf₂O, DMAP, CH₂Cl₂; (b) PdCl₂(PPh₃)₂, LiCl, DMF, 150 ^ꢀC; (c) NaClO₂, H₂NSO₃H, THF, H₂O; (d) HCl,

EtOH, re¯ux; (e) Me₂BBr, ClCH₂CH₂Cl.

Scheme 2. Reaction conditions: (a) Ph₃PCH₂OCH₃+Cl , t-BuOK, toluene, THF; (b) 1 N HCl, THF, re¯ux; (c) NaClO₂, H₂NSO₃H, THF, H₂O;

(d) HCl, EtOH, re¯ux; (e) (CH₃)₂BBr, ClCH₂CH₂Cl; (f) Tf₂O, DMAP, CH₂Cl₂.

13. Demethylation of 13, and tri¯ation of the resultant

alcohol 14 yielded aryl tri¯ate 15.

hydrophobic tail. This approach obviates the successful

yet cumbersome stannane/tri¯ate coupling of these two

components, allowing more facile synthesis of analo-

gues. The ether-linked compounds prepared in the

biaryl carboxylic acid (n=0), and biaryl acetic acid

(n=1) series are illustrated in Table 2. The synthetic

routes that were utilized for these ethers are summarized

in Schemes 5 and 6.

The syntheses of targets 1 and 2 are depicted in Scheme

3. Commercially available ketone 16 was converted to

stannane 17 by a two-step sequence involving Wittig

reaction to a bromo ole®n, followed by metal±halogen

exchange and trapping of the intermediate vinyl anion

with tributyltin chloride. Palladium catalyzed cross

coupling of stannane 17 with tri¯ate 11 then aorded

diester 18, which was hydrolyzed to diacid 1. The same

sequence when applied to tri¯ate 15 provided diacid 2.

Ether-linked compounds that contain a tetramethyl-

tetrahydronaphthalene as the hydrophobic tail were

synthesized starting from 2,3-dihydroxybenzaldehyde 24

(Scheme 5). The dianion of 2,3-dihydroxybenzaldehyde

reacted regioselectively at C-3²⁷with commercially

available 2-chloromethyl-5,5,8,8-tetramethyl-tetrahydro-

naphthalene to yield salicylaldehyde 25. Following con-

version to tri¯ate 26, reaction with stannane 7 provided

biaryl ether 27. Oxidation of 27 to the acid, followed by

hydrolysis of the ester, aorded diacid 28. Intermediate

aldehyde 27 was additionally homologated to 29, which

was converted to diacid 30. Tri¯ate 26 was coupled to

stannane 31 to yield aldehyde 32, which was then

transformed to diacid 33.

Two additional targets, 3 and 4, containing a smaller

and larger hydrophobic tail respectively, were synthe-

sized by this general approach (Scheme 4). Commer-

cially available stannane 20, when coupled to tri¯ate 15,

yielded diester 21. Hydrolysis of 21 then aorded diacid

3. The same process utilizing stannane 22 gave rise to

diacid 4.

We next synthesized analogues bearing an ether linkage

between the biaryl portion of the molecule and the

1090

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

Scheme 3. Reaction conditions: (a) Ph₃PCH₂Br+Br , t-BuOK, THF, 0 ^ꢀC; (b) t-BuLi, THF, 78 ^ꢀC, then n-Bu₃SnCl; (c) PdCl₂(PPh₃)₂, LiCl,

DMF, 125 ^ꢀC; (d) 2 N NaOH, CH₃OH, THF, re¯ux, then 1 N HCl.

Scheme 4. Reaction conditions: (a) PdCl₂(PPh₃)₂, LiCl, DMF, 110 ^ꢀC; (b) 2 N NaOH, CH₃OH, THF, re¯ux, then 1 N HCl.

The remaining members of Table 2 were synthesized by

the two general approaches outlined in Scheme 6. Sui-

tably functionalized benzyl alcohols of type 34 were

linked to biaryl phenols 10 or 14 using diisopropyl-

azodicarboxylate to produce ethers 35. Hydrolysis of

the ester groups yielded acids 36. Alternatively, benzyl

iodides 37 could be used to alkylate the phenoxide

derived from 10 or 14 to yield the desired ether inter-

mediates 35.

and DIAD yielded diesters of type 39. Hydrolysis of

these diesters then gave the target diacids 40. Unsatu-

rated diacids 43 were also synthesized from biaryl alde-

hyde 8. Demethylation of 8, followed by etheri®cation,

delivered aldehydes 41. Wadsworth±Emmons ole®na-

tion of 41, followed by hydrolysis, yielded the target

diacids 43.²⁸

The synthesis of the ethyl- and ethylene-linked diacids

45 and 46, containing the tetramethyl tetrahydro-

naphthalene hydrophobic group, began with the Wittig

ole®nation of aldehyde 27 to mixed diester 44. Hydro-

genation of 44, followed by hydrolysis, delivered the

saturated diacid 45. Direct hydrolysis of 44 yielded the

unsaturated diacid 46.

We additionally synthesized some biaryl diacid deriva-

tives which incorporated a two carbon link between the

biaryl nucleus and one of the carboxyl substituents. The

compounds synthesized in this class are shown in Table

3. These derivatives were synthesized according to the

methods illustrated in Schemes 7 and 8.

The synthesis of saturated compounds of type 40 begins

with the ole®nation of biaryl aldehyde 8 using methyl

diethylphosphonoacetate and sodium methoxide. The

resulting unsaturated diester is hydrogenated, and then

demethylated to aord phenol 38. Etheri®cation as

described in Scheme 6 with appropriate benzyl alcohols

Biology

The in vitro activity of new compounds was determined

as previously described.^24dPhospholipase A₂from

human platelets (puri®ed 3000-fold) was pre-incubated

at 37 ^ꢀC with test compound for 7 min. [1-¹⁴C] oleic acid

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

Table 2. Biological activity of ether-linked diacids

1091

a

% Inhibition of human platelet PLA₂

Compd

R

n

m

100 mM

10 mM

IC₅₀(mM)^b

ED₅₀^c(mg/ear per dose)

28

30

33

3,4-C(CH₃)₂CH₂CH₂(CH₃)₂C-

3,4-bis(n-C₅H₁₁O-)

0

1

0

1

0

1

0

1

0

1

0

1

0

54

80

72

53

96

20

73

79

62

97

99

22

32

9

27

35

7

29

14

24

52

84

77

>100

24

Ð

>100

8

Ð

80

Ð

15

2

147

Ð

32

Ð

73

36a

36b

36c

36d

36e

36f

36g

36h

36i

3,4-bis(n-C₅H₁₁O-)

3,4-bis((CH₃)₂CCHCH₂O-)

3,4-bis(c-C₅H₉O-)

3-CH₃O-;4-(1-adamantyl)

3,4-bis(n-C₁₀H₂₁O-)

4-(n-C₁₀H₂₁O-)

4

^aValues reported are the mean of two samples at each concentration.

^bHP-PLA₂: values reported are the mean of three separate experiments.

^cPhorbol ester induced mouse ear chronic in¯ammation assay. For details see ref 30.

Scheme 5. Reaction conditions: (a) NaH (2.5 equiv), DMSO, 2-chloromethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene; (b) Tf₂O, DMAP,

CH₂Cl₂; (c) PdCl₂(PPh₃)₂, LiCl, DMF, 125 ^ꢀC; (d) NaClO₂, H₂NSO₃H, THF, H₂O; (e) 2 N NaOH, CH₃OH, THF, re¯ux, then 1 N HCl; (f)

Ph₃PCH₂OCH₃+Cl , t-BuOK, toluene, THF; (g) 1 N HCl, THF, re¯ux.

labeled, autoclaved Escherichia coli membrane substrate

was then added, and the reaction quenched after 30 min.

The released, labeled oleic acid was quantitated by

liquid scintillation counting and reported as percent

inhibition relative to a vehicle control. Enzyme inhibi-

tion data determined at inhibitor concentrations of 100

and 10 mM were obtained in a high throughput screen

and are the mean of two samples at each concentration.

Reported IC₅₀values were determined by regression

analysis of a dose response curve and are the mean of

three separate experiments. For reference purposes, the

IC₅₀of manoalide (a potent PLA₂inhibitor) against

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D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

Scheme 6. Reaction conditions: (a) DlAD, PPh₃, THF, 0 ^ꢀC; (b) K₂CO₃, MlBK, re¯ux; (c) 2 N NaOH, CH₃OH, THF, re¯ux, then 1 N HCl.

Table 3. Biological activity of biaryl propionic and propenoic acids

a

% Inhibition of human platelet PLA₂

Compd

R

Type

100 mM

10 mM

IC₅₀(mM)^b

40a

43a

40b

43b

40c

43c

45

3,4-bis(n-C₅H₁₁O-)

3,4-bis((CH₃)₂CCHCH₂O-)

3,4-bis(c-C₅H₉O-)

3,4-C(CH₃)₂CH₂CH₂(CH₃)₂C-

Saturated

Unsaturated

Saturated

Unsaturated

Saturated

Unsaturated

Saturated

Unsaturated

59

55

73

51

86

54

72

6

22

6

16

4

24

7

20

57

40

Ð

>100

88

Ð

46

Ð

^aValues reported are the mean of two samples at each concentration.

^bHP-PLA₂: values reported are the mean of three separate experiments.

HP-PLA₂was found to be 6 mM under our assay con-

purposes, the ED₅₀of lonapalene (a known 5-lipoxy-

genase inhibitor and antipsoriasis agent) in this chronic

assay is 1000 mg/ear.^30a

ditions.²⁹

The ED₅₀values obtained in the phorbol ester induced

mouse ear chronic in¯ammation assay (reported in

Tables 1 and 2) were determined as previously repor-

ted.³⁰The application of irritant alone to the mouse ear

over the ®rst 7 days of this 10-day assay invokes a

chronic state of in¯ammation. During the ®nal 3 days of

the assay the test compound is dosed with continued

application of the phorbol ester. On day 10, in¯amma-

tion can be assayed by measuring epidermal thickness,

or myeloperoxidase content (MPO activity is a marker

for polymorphonuclear (PMN) leukocyte in®ltration³¹),

relative to vehicle control samples. The reported ED₅₀

values in the tables are the dose concentration of test

compound necessary to inhibit half the MPO activity

relative to control samples.³²This stringent assay is a

measure of a compound's ability to reduce edema in an

established in¯ammatory condition. For comparison

Discussion

Some structure±activity relationships (SAR) pertaining

to the diacid portion of these molecules can be deduced

from the data presented in the tables. In general, com-

pounds in the n=1 series are more active than the cor-

responding derivatives from the n=0 or n=2 series.

This eect is ®rst observed by comparing the data for

diacids 1 and 2. Subsequent derivatives in the ether-

linked series, as exempli®ed by the data in Tables 2 and

3, further support the general trend that n=1 deriva-

tives are the more potent inhibitors of HP-PLA₂.

Another generality is that in the n=2 series, the unsa-

turated compounds are more active than the corre-

sponding saturated diacids (Table 3). A trend can be

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1093

Scheme 7. Reaction conditions: (a) (EtO)₂P(O)CH₂CO₂Me (1.33 equiv), NaOCH₃(2.5 equiv) in CH₃OH, toluene; (b) 10% Pd/C, H₂(50 psi),

EtOH; (c) Me₂BBr, ClCH₂CH₂Cl; (d) ArCH₂OH, DlAD, PPh₃, THF, 0 ^ꢀC; (e) 2 N NaOH, CH₃OH, THF, re¯ux, then 1 N HCl.

Scheme 8. Reaction conditions: (a) Ph₃PCHCO₂CH₃(4.4 equiv), CH₂Cl₂; (b) 10% Pd/C, H₂(1 atm), EtOAc; (c) 2 N NaOH, CH₃OH, THF,

re¯ux, then 1 N HCl.

observed concerning SAR in the middle section of these

molecules. The ole®n-linked molecules 1 and 2 are both

more potent than their analogous ether-linked deriva-

tives 28 and 30.

activity yields mixed conclusions. In one class of com-

pounds, the n=2 unsaturated series of Table 3, we

observed an increase in potency by molecules containing

the more entropically constrained (rigid) unsaturated

pentyl derivatives relative to the n-pentyl analogues. In

contrast, the data obtained from these pentyl derivatives

in the n=0, n=1, and n=2 saturated series indicates

that there is little or no eect of rigidity on activity.

Thus, subtle changes in the structure of the hydrophobic

group may have a profound eect on activity in some

series of compounds but not in others.

SARs in the hydrophobic portion of the molecule are

more dicult to discern. PLA₂enzymes have a large

active site, capable of hosting geometrically diverse

structures. However, it can be observed that the enzyme

displays a very clear preference for molecules with larger

hydrophobic groups. For example, the small styryl di-

acid 3 is less active than either the tetrahydronaphthalene

2 or the tetrahydroanthracene 4. The bis-pentyloxy

compound 36a shows diminished potency relative to the

bis-decyloxy molecule 36h. The data obtained for com-

pounds 36h and 36i indicates that the enzyme may pre-

fer hydrophobic groups which resemble the large, and

¯exible alkyl chains of the fatty esters present in the

natural substrate. These compounds were found to be

the most active biaryl inhibitors of HP-PLA₂.

Five of these biaryl diacid compounds (2, 4, 28, 36b and

36i) were evaluated in a phorbol ester induced mouse

ear chronic edema assay (see Tables 1 and 2).³³All ®ve

compounds were found to reduce mouse ear edema in

this in vivo model. These derivatives displayed ED₅₀

values ranging between 32 and 147 mg/ear per dose.

Thus, these compounds were found to be up to ®ve

times more eective as anti-in¯ammatory agents in this

model than the lead compound BMS-181162 (ED₅₀=

180 mg/ear per dose) and up to thirty times more eec-

tive than lonapalene (ED₅₀=1000 mg/ear per dose).

However, an analysis of the eect of molecular shape of

certain variants of the hydrophobic group on inhibitory

1094

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

A comparison of the in vitro (human enzyme) and in

vivo (mouse ear) data for diacids 2, 4, 28, 36b and 36i,

indicates there is no direct correlation between these

parameters. There are many possible explanations for

this discrepancy. These compounds may display dier-

ential inhibitory activity between human platelet PLA₂

and the corresponding mouse PLA₂. Pharmacological

factors, such as bioavailability and metabolism, may

also be aecting the in vivo ecacy of these compounds.

Additionally, these compounds may aect the activity

of other enzymes (such as cyclooxygenases, lipoxy-

genases, etc.) involved in mediating in¯ammatory pro-

cesses. However, we believe this latter explanation to be

less likely since these compounds are so closely related

in structure to BMS-181162, a compound determined to

be an insigni®cant inhibitor of many enzymes involved

in the in¯ammatory response.^30a

shifts are reported in d (ppm) units relative to tetra-

methylsilane (TMS) and interproton coupling constants

are reported in Hertz (Hz). Infrared spectra were deter-

mined on a Perkin±Elmer 1800 FT-IR spectrometer

1

from 4000 to 400 cm ¹, calibrated to the 1601 cm

absorption of a polystyrene ®lm, and are reported in

reciprocal centimeters (cm ¹). Mass spectra were recor-

ded on a Kratos MS-50 or a Finnegan 4500 instrument

utilizing direct chemical ionization (DCI, isobutene) or

fast atom bombardment (FAB). Ultraviolet spectra

were determined on a Hewlett Packard 8452 diode array

spectrophometer in the solvent indicated.

General procedure A. Synthesis of aryl tri¯ates: 2-tri-

¯uoromethylsulphonyloxy-3-methoxybenzaldehyde (6).

o-Vanillin (4.00 g, 26.3 mmol) was dissolved in 115 mL

of dry methylene chloride. 4-Dimethylaminopyridine

(11.7 g, 95.8 mmol) was added, and the ¯ask cooled

to 0 ^ꢀC. Tri¯uoromethanesulfonylanhydride (5.09 mL,

30.3 mmol) was added dropwise via syringe over 5 min.

The mixture was stirred for 30 min at 0 ^ꢀC, and then

poured into 1 N HCl. The organic layer was washed

twice with 1 N HCl, once with water, and then brine.

The organic phase was dried (MgSO₄), and then con-

centrated in vacuo, yielding a crude solid. Chromato-

graphy on silica gel using 25 then 50% methylene

chloride:hexane aorded 6 (5.52 g, 19.4 mmol, 74%

yield) as a white crystalline solid, analytically identical to

the known material:³⁴mp=29.5±31.5 ^ꢀC; UV_max(CHCl₃)

244 nM (E=8641), 314 nM (E=3139); ¹H NMR

(300 MHz, CDCl₃) d 10.23 (s, 1H, CHO), 7.51 (dd,

J=2, 8 Hz, 1H, ArH), 7.44 (dd, J=8, 8 Hz, 1H, ArH),

Conclusions

A number of biaryl dicarboxylic acids were synthesized

which inhibit human platelet PLA₂. In general, for this

collection of biaryl inhibitors, three trends in SAR were

observed. Derivatives in the n=1 series were more

active than the corresponding analogues in the n=0 or

n=2 series. There was a slight increase in potency for

compounds bearing ole®n-linked hydrophobic groups

when compared with the relevant ether-linked deriva-

tives. It was clear that compounds with larger hydro-

phobic groups were better inhibitors of HP-PLA₂.

The most active compound in vitro, 36h, was greater

than 20 times more active than the lead compound

BMS-181162 (IC₅₀=2 mM versus 45 mM). Five of the

compounds reported here (2, 4, 28, 36b and 36i)

demonstrated anti-in¯ammatory eects in a phorbol

ester induced mouse model of chronic ear edema. The

most active compound in vivo, 36b, was found to be

more than ®ve times as eective as BMS-181162, and

more than thirty times more eective than lonapalene

in reducing in¯ammation. These compounds remain

interesting leads for the development of novel, anti-

in¯ammatory PLA₂inhibitors.

7.28 (dd, J=2, 8 Hz, 1H, ArH), 3.95 (s, 3H, OCH₃); ¹³

C

NMR (75 MHz, CDCl₃) d 186.69 (CO), 151.68,

129.53, 129.08, 121.13, 120.79, 118.59, 116.54, 56.58,

(OCH₃); IR (KBr) 1706, 1608, 1580, 1482, 1422, 1294,

1230, 1210, 1132, 946, 888 cm ¹; MS (DCI) m/e 285

(MH⁺). Anal. (C₉H₇F₃O₅S) C, H.

Synthesis of 3-carboethoxyphenyltributylstannane (7).

Ethyl 3-bromobenzoate (13.8 mL, 86.2 mmol) and bis-

(tributyl)tin (100 g, 172 mmol) were dissolved under

argon in 380 mL of toluene. Tetrakis(triphenylphos-

phine)-palladium(0) (5.00 g, 4.33 mmol) was added, and

the mixture heated to re¯ux overnight (ca. 16 h). The

reaction was allowed to cool to room temperature, and

was then ®ltered through Celite. The ®ltrate was con-

centrated in vacuo, and the residue was chromato-

graphed on silica gel using hexane, then 10% methylene

chloride:hexane as the eluent. Stannane 7 was obtained

Experimental

General

1

Unless otherwise indicated all reactions were performed

under a nitrogen atmosphere and all solvents were of

reagent grade. Analytical thin-layer chromatography

(TLC) was carried out on silica gel plates (60F-254) and

visualized using UV light, iodine vapors, and/or staining

by heating with ethanolic phosphomolybdic acid.

`Chromatography' or `Chromatography on silica gel'

refers to ¯ash column chromatography using E-Merck

silica gel 60 (230±400 mesh) unless otherwise noted.

as a clear oil (21.1 g, 48.1 mmol, 56%, 95% purity): H

NMR (300 MHz, CDCl₃) d 8.15 (s, 1H, ArH), 7.97

(ddd, J=2, 2, 8 Hz, 1H, ArH), 7.62 (ddd, J=2, 2, 8 Hz,

1H, ArH), 7.39 (dd, J=8, 8 Hz, 1H, ArH), 4.37 (q,

J=8 Hz, 2H, CO₂CH₂), 1.54 (m, 6H, 3ÂSnCH₂), 1.37

(m, 9H, 3ÂSnCH₂CH₂and CO₂CH₂CH₃), 1.10 (m, 6H,

3ÂSnCH₂CH₂CH₂), 0.94 (t, J=8 Hz, 9H, 3ÂCH₃).

General procedure B. Coupling of aryl tri¯ates with stan-

nanes: synthesis of 2-methoxy-3⁰-carboethoxy-[1,1⁰-biphen-

yl]-6-carboxaldehyde (8). Stannane 7 (4.25 g, 9.68 mmol)

and tri¯ate 6 (1.80 g, 6.44 mmol) were suspended

in 17 mL of DMF. Bis(triphenylphosphine)palladium

Proton and carbon-13 nuclear magnetic resonance (¹H

and ¹³C NMR) spectra were recorded on a Bruker AM-

300 or a Varian Gemini 300 spectrometer. Chemical

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1095

dichloride (0.68 g, 0.969 mmol) and LiCl (0.82 g,

19.3 mmol) were added and the mixture was heated to

150 ^ꢀC. After 45 min, more bis(triphenylphosphine)-

palladium dichloride (0.2 g, 0.285 mmol), more LiCl

NMR (300 MHz, CDCl₃) d 8.01 (m, 1H, ArH), 7.92 (m,

1H, ArH), 7.47±7.40 (m, 3H, ArH), 7.39 (dd, J=8,

8 Hz, 1H, ArH), 7.09 (dd, J=2, 8 Hz, 1H, ArH), 4.34 (q,

J=7 Hz, 2H, CO₂CH₂), 3.98 (q, J=7 Hz, 2H, CO₂

CH₂), 3.73 (s, 3H, OCH₃), 1.35 (t, J=7 Hz, 3H,

CH₂CH₃), 0.91 (t, J=7 Hz, 3H, CH₂CH₃); ¹³C NMR

(75 MHz, CDCl₃) d 168.04 (CO), 166.65 (CO),

156.92, 137.28, 134.11, 133.22, 130.73, 130.07, 129.98,

128.78, 128.22, 127.63, 121.63, 113.87, 60.88, 56.02,

14.34, 13.65; IR (®lm) 2982, 1718, 1466, 1366, 1298,

1260, 1234, 1110, 1060 cm ¹; MS (DCI) m/e 329

(MH⁺), 283 (M C₂H₅O). Anal. (C₁₉H₂₀O₅) C, H.

(0.4 g, 9.42 mmol), and more stannane

7 (0.8 g,

1.82 mmol) were added, and heating was continued for

2 h. (The reaction generally turned from yellow±brown

to black when complete.) The mixture was allowed to

cool to room temperature, and 15 mL of aqueous satu-

rated KF and 10 mL of ether were added. The mixture

was stirred for 30 min, and then ®ltered through Celite

to remove the tin salts. The ®lter cake was washed with

EtOAc and ether, and the combined ®ltrates were

washed with water, followed by 3% aqueous ammonia

solution and then brine. The organic phase was dried

(MgSO₄) and then concentrated in vacuo. Chromato-

graphy on silica gel using 25, 50 then 75% methylene

chloride:hexane aorded aldehyde 8 (1.72 g, 6.06 mmol,

94%) as a slightly yellow oil which crystallized on

standing: mp=67±69 ^ꢀC; UV_max(CHCl₃) 242 nM

(E=15,819), 324 nM (E=3953); ¹H NMR (300 MHz,

CDCl₃) d 9.70 (s, 1H, CHO), 8.09 (ddd, J=2, 2, 7 Hz,

1H, ArH), 7.99 (s, 1H, ArH), 7.62 (dd, J=2, 8 Hz, 1H,

ArH), 7.49 (m, 3H, ArH), 7.19 (dd, J=2, 8 Hz, 1H,

ArH), 4.37 (q, J=7 Hz, 2H, CO₂CH₂), 3.76 (s, 3H,

OCH₃), 1.34 (t, J=7 Hz, 3H, CO₂CH₂CH₃); ¹³C NMR

(75 MHz, CDCl₃) d 191.93 (CO), 166.31 (CO),

156.98, 135.27, 133.73, 133.57, 131.92, 130.42, 129.17,

129.09, 128.09, 119.30, 115.95, 61.14, 56.06, 14.32; IR

(®lm) 2980, 2940, 2838, 1718, 1694, 1468, 1294, 1260,

1234, 1110, 794 cm ¹; MS (DCI) m/e 285 (MH⁺), 239

General procedure D. Demethylation of aryl methyl

ethers: synthesis of 2-hydroxy-3⁰-carboethoxy-(1,1⁰-biphen-

yl)-6-carboxylic acid, ethyl ester (10). Diester 9 (0.968 g,

2.95 mmol) was dissolved under argon in 9.8 mL of

1,2-dichloroethane. Dimethylboron bromide (1.16 mL,

11.9 mmol) was added, the ¯ask was sealed and the

mixture allowed to stir for 21 h at ambient temperature.

Another 1.16 mL of dimethylboron bromide was added,

and the mixture stirred, sealed under argon, for 3 days.

The ¯ask was cooled to 0 ^ꢀC, and 20 mL of saturated

NaHCO₃was added with caution. The mixture was

poured into 1 N HCl, and extracted thrice with EtOAc.

The combined extracts were washed with brine, dried

(MgSO₄), and evaporated. Chromatography using 10%

EtOAc:hexane yielded 10 (0.659 g, 2.10 mmol, 71%) as a

yellow oil: UV_max(CHCl₃) 242 nM (E=10,155), 296 nM

(E=4591); ¹H NMR (300 MHz, CDCl₃) d 8.09 (dd,

J=2, 8 Hz, 1H, ArH), 7.96 (dd, J=2, 2 Hz, 1H, ArH),

7.57±7.45 (m, 3H, ArH), 7.33 (dd, J=8, 8 Hz, 1H,

ArH), 7.14 (dd, J=2, 8 Hz, 1H, ArH), 4.98 (br, 1H,

OH), 4.35 (q, J=7 Hz, 2H, CO₂CH₂), 3.99 (q, J=7 Hz,

2H, CO₂CH₂), 1.36 (t, J=7 Hz, 3H, CH₂CH₃), 0.95 (t,

J=7 Hz, 3H, CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃) d

167.18 (CO), 166.13 (CO), 153.18, 135.46, 134.13,

131.76, 131.25, 130.67, 129.42, 129.16, 129.03, 127.32,

122.42, 119.19, 61.21, 60.85, 14.30, 13.70; IR (®lm)

3406, 2982, 1718, 1296, 1236, 758 cm ¹; MS (DCI) m/e

315 (MH⁺), 269 (M-C₂H₅O). HRMS (FAB) m/e

337.1044 [(M+Na)⁺calcd for C₁₈H₁₈O₅Na: 337.1052].

.

(M C₂H₅O). Anal. (C₁₇H₁₆O₄0.25 H₂O) C, H.

General procedure C. Conversion of aldehydes to esters:

synthesis of 2-methoxy-3⁰-carboethoxy-[1,1⁰-biphenyl]-6-

carboxylic acid, ethyl ester (9). Aldehyde 8 (0.512 g,

1.80 mmol) was dissolved in 17 mL of THF and 13 mL

of H₂O. The solution was cooled to 0 ^ꢀC. Sulfamic acid

(0.525 g, 5.41 mmol) was then added, followed by a

solution of sodium chlorite (80% tech, 0.612 g,

5.41 mmol) in 4 mL of H₂O. The mixture was stirred for

15 min at 0 ^ꢀC, and then poured into EtOAc and water.

The aqueous layer was extracted thrice with EtOAc, and

the combined organic phase was washed with brine. The

organic phase was dried (MgSO₄) and then con-

centrated in vacuo to aord 2-methoxy-3⁰-carboethoxy-

[1,1⁰-biphenyl]-6-carboxylic acid as a pale yellow oil

(0.583 g, 1.80 mmol, 100%): ¹H NMR (300 MHz,

CDCl₃) d 10.17 (br, 1H, CO₂H), 8.02 (ddd, J=2, 2,

8 Hz, 1H, ArH), 7.94 (s, 1H, ArH), 7.56 (d, J=8 Hz,

1H, ArH), 7.41 (m, 3H, ArH), 7.15 (d, J=8 Hz, 1H,

ArH), 4.19 (q, J=7 Hz, 2H, CO₂CH₂), 3.73 (s, 3H,

OCH₃), 1.39 (t, J=7 Hz, 3H, CH₂CH₃).

Synthesis of 3⁰-carboethoxy-6-carboethoxy [1,1⁰-biphen-

yl] 2-tri¯uoromethanesulphonate (11). General proce-

dure A was applied to phenol 10 (0.375 g, 1.19 mmol) to

aord 11 (0.438 g, 0.982 mmol, 83%): chromatographed

on silica using CH₂Cl₂:hexane; ¹H NMR (300 MHz,

CDCl₃) d 8.09 (ddd, J=2, 2, 7 Hz, 1H, ArH), 7.92 (m,

2H, ArH), 7.57±7.43 (m, 4H, ArH), 4.35 (q, J=7 Hz,

2H, CO₂CH₂), 4.03 (q, J=7 Hz, 2H, CO₂CH₂), 1.03 (t,

J=7 Hz, 3H, CO₂CH₂CH₃), 0.94 (t, J=7 Hz, 3H,

CO₂CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃) d 166.18

(CO), 166.09 (CO), 147.21, 135.05, 134.36, 134.05,

133.82, 130.54, 130.37, 129.77, 129.52, 129.40, 128.07,

124.67, 120.29, 61.51, 61.13, 14.27, 13.61; IR (®lm)

3074, 2986, 1722, 1426, 1368, 1296, 1240, 1214, 1140,

950, 850 cm ¹; MS (DCI) m/e 447 (MH⁺), 401

(M C₂H₅O). Anal. (C₁₉H₁₇F₃O₇S) C, H.

The above acid (0.583 g, 1.90 mmol) was dissolved in

12 mL of absolute EtOH. Concentrated HCl (0.6 mL)

was added, and the mixture heated to re¯ux for 24 h.

The mixture was then partitioned between EtOAc and

water. The organic phase was washed with brine, dried

(MgSO₄), and concentrated in vacuo. Chromatography

on silica gel using 5%, then 10% EtOAc:hexane yielded

9 (0.432 g, 1.32 mmol, 73%) as a clear oil: UV_max

(CHCl₃) 242 nM (E=12,036), 296 nM (E=4724); ¹H

General procedure E. Wittig homologation of aldehydes:

synthesis of 3⁰-carboethoxy-2-methoxy-1,1⁰-biphenyl-6-

acetaldehyde (12). A solution of (methoxymethyl)-

1096

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

triphenylphosphonium chloride (3.88 g, 11.3 mmol) in

15 mL of toluene and 50 mL of THF was cooled to 0 ^ꢀC.

Potassium t-butoxide (95%, 1.53 g, 12.9 mmol) was then

added, and the mixture allowed to stir at 0 ^ꢀC for

30 min. A solution of 8 (3.05 g, 10.7 mmol) in 15 mL of

THF was then added rapidly dropwise, and the mixture

allowed to stir for 5 min at 0 ^ꢀC. The ice-bath was

removed, and stirring continued for another 2 h at room

temperature. The reaction mixture was partitioned

between ether and water, and the organic phase washed

with brine, dried (MgSO₄), and concentrated. Pentane

was added to precipitate Ph₃PO, which was removed by

®ltration. The ®ltrate was concentrated to aord an oil.

The crude material was chromatographed on silica gel

using methylene chloride:hexane as the eluent to aord

a mixture of (E) and (Z) 3⁰-carboethoxy-2-methoxy-6-

[(1-methoxy)-2-ethenyl]-1,1⁰-biphenyl (3.27 g, 10.5 mmol,

98%) as a clear oil (ꢁ2:1 mixture of E:Z isomers): data

(EtOH) 206 nM (E=28,222), 282 nM (E=817); ¹H

NMR (300 MHz, CDCl₃) d 8.06 (dd, J=2, 8 Hz, 1H,

ArH), 7.91 (s, 1H, ArH), 7.56±7.31 (m, 3H, ArH), 6.98

(d, J=8 Hz, 1H, ArH), 6.90 (d, J=8 Hz, 1H, ArH), 4.67

(s, 1H, OH), 4.37 (q, J=7 Hz, 2H, CO₂CH₂), 4.02 (q,

J=7 Hz, 2H, CO₂CH₂), 3.68 (s, 3H, OCH₃), 3.35 (s, 2H,

ArCH₂CO₂), 1.37 (t, J=7 Hz, 3H, CO2CH₂CH₃), 1.13

(t, J=7 Hz, 3H, CO₂CH₂CH₃); ¹³C NMR (75 MHz,

CDCl₃) d 171.52 (CO), 166.60 (CO), 157.05, 137.03,

134.76, 134.07, 131.22, 130.42, 128.74, 128.38, 128.12,

122.44, 109.69, 60.92, 60.74, 55.75, 39.17, 14.33, 14.06;

IR (KBr) 2990, 1735, 1718, 1580, 1470, 1300, 1255,

1235 cm ¹; MS (DCI) m/e 343 (MH⁺). Anal. (C₂₀H₂₂

.

O₅0.10 hexane) C, H.

Synthesis of 3⁰-carboethoxy-2-hydroxy-1,1⁰-biphenyl-6-

acetic acid, ethyl ester (14). Diester 13 (2.77g, 8.10mmol)

was converted via general procedure D to phenol 14

(2.40 g, 7.32 mmol, 90%): chromatographed on silica gel

using EtOAc:hexane; ¹H NMR (300 MHz, CDCl₃) d

8.12 (d, J=8 Hz, 1H, ArH), 7.96 (s, 1H, ArH), 7.56 (dd,

J=8, 8 Hz, 1H, ArH), 7.50 (d, J=8 Hz, 1H, ArH), 7.24

(d, J=8 Hz, 1H, ArH), 6.92 (d, J=8 Hz, 1H, ArH), 6.90

(d, J=8 Hz, 1H, ArH), 4.67 (s, 1H, OH), 4.37 (q,

J=7 Hz, 2H, CO₂CH₂), 4.02 (q, J=7 Hz, 2H, CO₂

CH₂), 3.35 (s, 2H, ArCH₂CO₂), 1.37 (t, J=7 Hz, 3H,

CO₂CH₂CH₃), 1.13 (t, J=7 Hz, 3H, CO₂CH₂CH₃); ¹³C

NMR (75 MHz, CDCl₃) d 171.35 (CO), 152.99,

135.00, 134.87, 133.74, 131.49, 129.66, 129.40, 129.24,

122.39, 114.44, 61.24, 60.81, 39.27, 14.30, 14.05; MS

(DCI) m/e 329 (MH⁺).

1

for E isomer: H NMR (300 MHz, CDCl₃) d 8.04 (d,

J=8 Hz, 1H, ArH), 7.95 (s, 1H, ArH), 7.50±7.27 (m,

3H, ArH), 7.19 (d, J=8 Hz, 1H, ArH), 6.90 (d, J=

12 Hz, 1H, CCH), 6.81 (d, J=8 Hz, 1H, ArH), 5.41 (d,

J=12 Hz, 1H, CCH), 4.38 (q, J=7 Hz, 2H, CO₂CH₂),

3.71 (s, 3H, OCH₃), 3.45 (s, 3H, OCH₃), 1.36 (t,

J=7 Hz, 3H, CO₂CH₂CH₃).

The above mixture of Z and E enol ether isomers was

dissolved in 31 mL of THF and 31 mL of 1 N HCl. The

mixture was heated to re¯ux for 24 h, and then parti-

tioned between ethyl acetate and water. The organic

phase was washed with brine, dried (MgSO₄), and con-

centrated. Crude 12 was obtained as a yellow oil

(3.30 g), which was of suitable purity for use in sub-

Synthesis of 3⁰-carboethoxy-2-tri¯uoromethylsulphonyl-

oxy-1,1⁰-biphenyl-6-acetic acid, ethyl ester (15). Phenol

14 (1.13 g, 3.45 mmol) was converted by general proce-

dure A to tri¯ate 15 (1.21 g, 2.63 mmol, 76%): chroma-

1

sequent reactions: H NMR (300 MHz, CDCl₃) d 9.55

(s, 1H, CHO), 8.03 (d, J=8 Hz, 1H, ArH), 7.49±7.34

(m, 4H, ArH), 6.93 (d, J=8 Hz, 1H, ArH), 6.88 (d,

J=8 Hz, 1H, ArH), 4.36 (q, J=7 Hz, 2H, CO₂CH₂),

3.72 (s, 3H, OCH₃), 3.49 (s, 2H, ArCH₂CHO), 1.38 (t,

J=7 Hz, 3H, CO₂CH₂CH₃); ¹³C NMR (75 MHz,

CDCl₃) d 199.08 (CO), 166.45 (CO), 157.34, 136.86,

134.60, 132.03, 131.09, 130.71, 130.63, 129.11, 128.54,

128.38, 122.61, 109.99, 61.02, 55.74, 48.32, 14.32.

1

tographed on silica gel using CH₂Cl₂:hexane; H NMR

(300 MHz, CDCl₃) d 8.17 (ddd, J=2, 2, 8 Hz, 1H, ArH),

7.94 (dd, J=2, 2 Hz, 1H, ArH), 7.54 (dd, J=8, 8 Hz,

1H, ArH), 7.44 (m, 3H, ArH), 7.33 (dd, J=2, 8 Hz, 1H,

ArH), 4.39 (q, J=7 Hz, 2H, CO₂CH₂), 4.05 (q, J=7 Hz,

2H, CO₂CH₂), 3.48 (s, 2H, ArCH₂), 1.39 (t, J=7 Hz,

3H, CO₂CH₂CH₃), 1.15 (t, J=7 Hz, 3H, CO₂CH₂CH₃).

Synthesis of 3⁰-carboethoxy-2-methoxy-1,1⁰-biphenyl-6-

acetic acid, ethyl ester (13). Aldehyde 12 (3.30 g crude)

was oxidized following general procedure C to aord

crude 3⁰-carboethoxy-2-methoxy-1,1⁰-biphenyl-6-acetic

acid (3.78 g), which was of suitable purity for use in

subsequent reactions: ¹H NMR (300 MHz, CDCl₃) d

8.05 (d, J=7 Hz, 1H, ArH), 7.90 (s, 1H, ArH), 7.55±

7.31 (m, 3H, ArH), 6.95 (d, J=7 Hz, 1H, ArH), 6.85 (d,

J=7 Hz, 1H, ArH), 4.35 (q, J=7 Hz, 2H, CO₂CH₂),

3.70 (s, 3H, OCH₃), 3.40 (s, 2H, ArCH₂CO₂), 1.33 (t,

J=7 Hz, 3H, CO₂CH₂CH₃); ¹³C NMR (75 MHz,

CDCl₃) d 177.40 (CO), 166.72 (CO), 157.08, 136.89,

134.81, 133.36, 131.26, 130.50, 130.41, 128.87, 128.50,

128.31, 122.49, 109.91, 61.07, 55.73, 38.72, 14.28.

Synthesis of (E)-2-[5,6,7,8-tetrahydro-5,5,8,8-tetrameth-

yl-2-naphthalenyl]-1-propenyltributylstannane

(17).

Bromomethyltriphenylphosphonium bromide (6.07 g,

13.9 mmol) was suspended in 28 mL of dry toluene. The

suspension was cooled to 40 ^ꢀC. Potassium tert-but-

oxide (95%, 1.57 g, 13.3 mmol) was added and the ¯ask

allowed to warm to 20^ꢀC over 30min. The mixture was

re-cooled to 40 ^ꢀC, and 2-acetyl (5,6,7,8-tetrahydro-

5,5,8,8-tetramethylnaphthalene) 16 (3.05 g, 13.3 mmol)

dissolved in 10 mL of toluene was added dropwise. The

¯ask was allowed to warm to 30 ^ꢀC and stir for 2 h.

The mixture was poured into half-saturated ammonium

chloride solution, and extracted with EtOAc and ether.

The organic phase was washed with brine, dried

(MgSO₄) and then concentrated in vacuo. Chromato-

graphy on silica gel using hexane as the eluent aorded

(E)-2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthal-

enyl]-1-bromopropene (1.70 g, 5.54 mmol, 42%) as a

17:1 mixture of E:Z ole®n isomers: Data for E isomer:

The acid from above (3.78 g crude) was then converted

to the diethyl ester to aord 13 (2.77 g, 8.10 mmol, 77%

overall yield from (E) and (Z) 3⁰-carboethoxy-2-meth-

oxy-6-[(1-methoxy)-2-ethenyl]-1,1⁰-biphenyl): chromato-

graphed on silica gel using EtOAc:hexane; UV_max

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1097

¹H NMR (300 MHz, CDCl₃) d 7.29 (d, J=8 Hz, 1H,

ArH), 7.27 (d, J=2 Hz, 1H, ArH), 7.11 (dd, J=2, 8 Hz,

1H, ArH), 6.40 (q, J=1 Hz, 1H, CCHBr), 2.23 (d,

J=1 Hz, 3H, CCCH₃), 1.70 (s, 4H, CH₂CH₂), 1.31 (s,

6H, 2ÂCH₃), 1.29 (s, 6H, 2ÂCH₃).

90% MeOH:H₂O as eluent aorded diacid 1 (0.149 g,

0.318 mmol, 88%) as a white solid: UV_max(EtOH)

212 nM (E=29,622), 276 nM (E=12,314); ¹H NMR

(300 MHz, CD₃OD) d 8.02 (ddd, J=2, 2, 8 Hz, 1H,

ArH), 7.89 (s, 1H, ArH), 7.79 (d, J=8 Hz, 1H, ArH),

7.59 (d, J=8 Hz, 1H, ArH), 7.49 (m, 2H, ArH), 7.42

(ddd, J=2, 2, 8 Hz, 1H, ArH), 7.18 (d, J=8 Hz, 1H,

ArH), 6.95 (m, 2H, ArH), 6.20 (s, 1H, CCH), 2.08 (s,

3H, CH₃), 1.64 (s, 4H, CH₂CH₂), 1.22 (s, 6H, 2ÂCH₃),

1.14 (s, 6H, 2ÂCH₃); ¹³C NMR (75 MHz, CD₃OD) d

169.78 (CO), 145.57, 144.93, 141.99, 141.88, 141.78,

139.76, 139.23, 135.11, 133.84, 131.96, 131.50, 129.42,

128.98, 128.36, 127.33, 126.82, 124.90, 124.33, 36.28,

36.18, 35.13, 34.95, 32.25, 32.16, 17.56; IR (KBr) 3510,

2956, 2924, 1694, 1408, 1300, 1250, 758 cm ¹; MS (DCI)

m/e 469 (MH⁺), 451 (M OH). Anal. (C₃₁H₃₂O₄) C, H.

(E)-2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl)-2-naph-

thalenyl]-1-bromopropene (0.680 g, 2.20 mmol) was dis-

solved in 6.8 mL of dry THF. The solution was cooled

to 78 ^ꢀC and t-BuLi (1.7 M in hexane, 2.74 mL,

4.62 mmol) was added dropwise. After stirring for

30 min at

78 ^ꢀC, tri(n-butyl)tin chloride (0.60 mL,

2.2 mmol) was added. The mixture was stirred at 78 ^ꢀC

for 15 min and the cooling bath was removed. After

15 min, the solution was poured into water, and extrac-

ted with ether. The ether extracts were washed with

brine, dried (MgSO₄) and then concentrated in vacuo.

The yield of crude stannane 17 was 1.50 g. This material

was suitable for use in subsequent reactions without

Synthesis of 3⁰-carboethoxy-(E)-2-[(5,6,7,8-tetrahydro-

5,5,8,8,-tetramethyl-2-naphthalenyl)-1-propenyl]-[1,1⁰-bi-

phenyl]-6-acetic acid, ethyl ester (19). Stannane 17

(0.860g, 1.66mmol) and tri¯ate 15 (0.302 g, 0.657 mmol)

were coupled using general procedure B. After heating

at 110 ^ꢀC for 15 min the reaction was incomplete as

judged by thin-layer chromatography. The bath tem-

perature was raised to 130 ^ꢀC, and heating was con-

tinued for another 10 min to complete the reaction.

Diester 19 (0.309 g, 0.574 mmol, 87%) was obtained as a

clear oil: chromatographed on silica gel using EtOAc:

hexane; UV_max(EtOH) 208 nM (E=30,099), 276 nM

1

puri®cation: H NMR (300 MHz, CDCl₃) d 7.40 (bs,

1H, ArH), 7.28 (m, 2H, ArH), 6.23 (m, 1H, CCH),

2.21 (s, 3H, CCCH₃), 1.69 (s, 4H, CH₂CH₂), 1.60 (m,

6H, 3ÂSnCH₂), 1.35 (m, 12H, 3ÂSnCH₂CH₂CH₂), 1.32

(s, 6H, 2ÂCH₃), 1.30 (s, 6H, 2ÂCH₃), 0.95 (m, 9H,

3ÂCH₃).

Synthesis of 6-carboethoxy-2-[(E)-2-[5,6,7,8-tetrahydro-

5,5,8,8-tetramethyl-2-naphthalenyl]-1-propenyl]-3⁰-carbo-

ethoxy-[1,1⁰-biphenyl] (18). Stannane 17 (0.840 g,

1.62 mmol) and tri¯ate 11 (0.238 g, 0.530 mmol) were

coupled at 130 ^ꢀC using general procedure B to aord

diester 18 (0.233 g, 0.445 mmol, 84%): chromato-

graphed on silica gel using EtOAc:hexane; UV_max

(EtOH) 212 nm (E=30,865), 278 nM (E=11,586); ¹H

NMR (300 MHz, CDCl₃) d 8.03 (ddd, J=2, 2, 8 Hz, 1H,

ArH), 7.90 (s, 1H, ArH), 7.78 (dd, J=2, 8 Hz, 1H,

ArH), 7.52 (dd, J=2, 8 Hz, 1H, ArH), 7.44 (dd, J=8,

8 Hz, 1H, ArH), 7.39 (m, 2H, ArH), 7.16 (d, J=8 Hz,

1H, ArH), 7.00 (d, J=2 Hz, 1H, ArH), 6.95 (dd, J=2,

8 Hz, 1H, ArH), 6.28 (s, 1H, CCH), 4.31 (q, J=7 Hz,

2H, CO₂CH₂), 4.01 (q, J=7 Hz, 2H, CO₂CH₂), 2.08 (s,

3H, CCCH₃), 1.62 (s, 4H, CH₂CH₂), 1.32 (t, J=7 Hz,

3H, CH₂CH₃), 1.22 (s, 6H, 2ÂCH₃), 1.16 (s, 6H,

2ÂCH₃), 0.94 (t, J=7 Hz, 3H, CH₂CH₃); ¹³C NMR

(75 MHz, CDCl₃) d 168.20 (CO), 166.47 (CO),

144.46, 144.06, 140.44, 140.37, 140.26, 138.53, 137.53,

133.82, 132.92, 131.82, 130.32, 130.02, 128.24, 128.04,

127.75, 127.21, 126.30, 125.73, 123.91, 123.11, 60.91,

1

(E=13,855); H NMR (300 MHz, CDCl₃) d 8.04 (ddd,

J=2, 2, 8 Hz, 1H, ArH), 7.87 (dd, J=2, 2 Hz, 1H,

ArH), 7.46 (dd, J=8, 8 Hz, 1H, ArH), 7.37 (m, 3H,

ArH), 7.26 (dd, J=2, 8 Hz, 1H, ArH), 7.15 (d, J=8 Hz,

1H, ArH), 6.96 (d, J=2 Hz, 1H, ArH), 6.92 (dd, J=2,

8 Hz, 1H, ArH), 6.26 (s, 1H, CCH), 4.33 (q, J=7 Hz,

2H, CO₂CH₂), 4.02 (q, J=7 Hz, 2H, CO₂CH₂), 3.43 (s,

2H, ArCH₂), 2.11 (s, 3H, CH₃), 1.61 (s, 4H, CH₂CH₂),

1.34 (t, J=7 Hz, 3H, CO₂CH₂CH₃), 1.22 (s, 6H,

2ÂCH₃), 1.15 (m, 9H, CO₂CH₂CH₃and 2ÂCH₃); ¹³C

NMR (75 MHz, CDCl₃) d 171.68 (CO), 166.44

(CO), 144.46, 143.85, 140.83, 140.57, 139.90, 137.92,

136.78, 134.47, 132.50, 130.78, 130.45, 128.62, 128.49,

128.44, 128.26, 127.41, 126.51, 126.24, 123.94, 123.12,

60.97, 60.76, 39.49, 35.10, 34.99, 34.18, 34.01, 31.74,

17.24, 14.29, 14.09; IR (®lm) 2960, 2928, 1722, 1462,

1366, 1298, 1240, 1158, 1110, 1034, 752 cm ¹; MS (DCI)

m/e 539 (MH⁺), 493 (M C₂H₅O). Anal. (C₃₆H₄₂

.

O₄1.25 H₂O) C, H.

60.85, 35.11, 34.99, 34.20, 34.04, 31.73, 17.23, 14.27,

1

13.70; IR (®lm) 2960, 2926, 1722, 1292, 1234, 1136cm

MS (DCI) m/e 525 (MH⁺), 479 (M C₂H₅O).

;

Synthesis of 3⁰-carboxy-(E)-2-[(5,6,7,8-tetrahydro-5,5,

8,8,-tetramethyl-2-naphthalenyl)-1-propenyl]-[1,1⁰-biphen-

yl]-6-acetic acid (2). Diester 19 (0.476 g, 0.885 mmol)

was hydrolyzed according to general procedure F to

yield diacid 2 (0.380 g, 0.788 mmol, 89%): crystallized

from CH₂Cl₂:pentane; mp=253.5±255.5 ^ꢀC; UV_max

(EtOH) 210 nM (E=38,336), 276 nM (E=15,928); ¹H

NMR (300 MHz, DMSO-d₆) d 7.95 (d, J=8 Hz, 1H,

ArH), 7.70 (s, 1H, ArH), 7.56 (dd, J=8, 8 Hz, 1H,

ArH), 7.43±7.29 (m, 4H, ArH), 7.17 (d, J=8 Hz, 1H,

ArH), 6.91 (d, J=8 Hz, 1H, ArH), 6.85 (d, J=2 Hz, 1H,

ArH), 6.15 (s, 1H, CCH), 3.36 (s, 2H, ArCH₂), 2.06 (s,

3H, CH₃), 1.56 (s, 4H, CH₂CH₂), 1.16 (s, 6H, 2ÂCH₃),

General procedure F. Hydrolysis of esters: synthesis of

(E)-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthal-

enyl)-1-propenyl]-[1,1⁰-biphenyl]-6,3⁰-dicarboxylic acid

(1). Diester 18 (0.189 g, 0.361 mmol) was dissolved in

3.1 mL of MeOH, 3.1 mL of 2 N NaOH, and 4 mL of

THF. The mixture was heated to re¯ux for 2 h. The

solution was allowed to cool to room temperature, and

then acidi®ed to pH 2 with 1 N HCl. The material was

extracted thrice with chloroform, and the extracts were

washed with brine, dried (MgSO₄), and evaporated.

Reverse-phase chromatography on C-18 silica gel with

3

1.08 (s, 6H, 2ÂCH₃); C NMR (75 MHz, DMSO-d₆) d

1098

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

172.46 (CO), 167.09 (CO), 144.01, 143.48, 140.57,

140.23, 139.53, 136.69, 136.30, 133.92, 133.15, 130.66,

130.52, 129.13, 128.56, 128.14, 127.87, 127.25, 126.22,

125.98, 123.32, 122.95, 34.58, 34.48, 33.74, 33.67, 31.47,

17.00; IR (KBr) 3422, 2964, 2926, 1698, 1460, 1432,

1406, 1292, 1258, 748 cm ¹; MS (DCI) m/e 483 (MH⁺),

78 ^ꢀC, and then tri(n-butyl)tin chloride (1.74 mL,

6.42 mmol) was added. The mixture was stirred at

78 ^ꢀC for 15 min, and then the cooling bath was

removed. After another 15 min, the solution was poured

into water, and extracted with ether. The ether extracts

were washed with brine, dried (MgSO₄) and then con-

centrated in vacuo. Chromatography on silica gel using

hexane, then CH₂Cl₂:hexane as solvent yielded stannane

22 (3.28 g, 6.22mmol, 97%) as a clear oil; ¹H NMR

(300MHz, CDCl₃) d 7.82 (s, 1H, ArH), 7.74 (s, 2H, ArH),

7.67 (d, J=8Hz, 1H, ArH), 7.41 (d, J=8 Hz, 1H, ArH),

1.76 (s, 4H, CH₂CH₂), 1.57 (m, 6H, butyl), 1.35 (m,

18H, 4ÂCH₃and butyl), 1.09 (m, 6H, butyl), 0.88 (m,

9H, butyl); ¹³C NMR (75 MHz, CDCl₃) d 144.18,

144.10, 138.24, 135.81, 132.28, 131.77, 131.63, 125.99,

124.79, 124.54, 35.15, 34.60, 34.57, 32.57, 30.83, 29.45,

29.03, 27.73, 27.43, 13.74, 9.60, 7.88; IR (®lm) 2956,

2926, 2870, 2854, 1462, 1376, 1362 cm ¹; MS (DCI) m/e

529 (MH⁺).

.

465 (M OH). Anal. (C₃₄H₃₄O₄0.25 H₂O) C,H.

Synthesis of (E) and (Z)-3⁰-carboethoxy-2-styryl-[1,1⁰-bi-

phenyl]-6-acetic acid, ethyl ester (21). Tributyl(styryl)-

stannane 20 (0.332 g, 0.845 mmol; ca. 10:1 mixture of

E:Z) was coupled with tri¯ate 15 (0.259 g, 0.563 mmol)

via heating at 110 ^ꢀC for 20 minutes following General

procedure B to aord (after chromatography on silica

gel using 20% EtOAc:hexane) a 10:1 mixture of (E) and

(Z) 21 (0.221 g, 0.534 mmol, 95%). A second chromato-

graphic puri®cation utilizing a gradient elution of EtOAc:

hexane was necessary to separate the isomers: Data for E-

1

27a: H NMR (300MHz, CDCl₃) d 8.12 (ddd, J=2, 2,

8 Hz, 1H, ArH), 7.91 (dd, J=2, 2 Hz, 1H, ArH), 7.72 (d,

J=8Hz, 1H, ArH), 7.52 (dd, J=8, 8 Hz, 1H, ArH), 7.40

(m, 2H, ArH), 7.29 (dd, J=2, 8 Hz, 1H, ArH), 7.23 (m,

5H, ArH), 6.99 (d, J=17 Hz, 1H, CHC), 6.66 (d,

J=17 Hz, 1H, CHC), 4.39 (q, J=7Hz, 2H, CO₂CH₂),

4.04 (q, J=7 Hz, 2H, CO₂CH₂), 3.40 (s, 2H, ArCH₂), 1.37

(t, J=7 Hz, 3H, CO₂CH₂CH₃), 1.15 (t, J=7Hz, 3H,

CO₂CH₂CH₃). Data for Z-27a: ¹H NMR (300 MHz,

CDCl₃) d 8.03 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.86 (dd,

J=2, 2 Hz, 1H, ArH), 7.43 (dd, J=8, 8 Hz, 1H, ArH),

7.37 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.24±7.15 (m, 8H,

ArH), 6.34 (d, J=12 Hz, 1H, CHC), 6.16 (d,

J=12 Hz, 1H, CHC), 4.37 (q, J=7 Hz, 2H, CO₂CH₂),

4.04 (q, J=7 Hz, 2H, CO₂CH₂), 3.42 (s, 2H, ArCH₂),

1.35 (t, J=7 Hz, 3H, CO₂CH₂CH₃), 1.16 (t, J=7 Hz,

3H, CO₂CH₂CH₃).

Synthesis of 3⁰-carboethoxy-2-[(1,2,3,4-tetrahydro-1,1,4,4-

tetramethyl)-7-anthracenyl]-[1,1⁰-biphenyl]-6-acetic acid,

ethyl ester (23). Stannane 22 (0.775 g, 1.47 mmol) was

coupled to tri¯ate 15 (0.451 g, 0.980 mmol) using general

procedure B to aord diester 23 (0.355 g, 0.650 mmol,

66%) as a clear oil: chromatographed on silica gel using

EtOAc:hexane; UV_max(CHCl₃) 244 nM (E=37,190); ¹H

NMR (300 MHz, CDCl₃) d 7.86 (d, J=2 Hz, 1H, ArH),

7.84 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.65 (s, 1H, ArH),

7.62 (s, 1H, ArH), 7.57 (s, 1H, ArH), 7.38 (m, 4H, ArH),

7.22 (m, 2H, ArH), 6.88 (dd, J=2, 8 Hz, 1H, ArH), 4.28

(m, 2H, CO₂CH₂), 4.03 (q, J=7 Hz, 2H, CO₂CH₂), 3.51

(d, J=16 Hz, 1H, ArCH₂CO₂), 3.43 (d, J=16 Hz, 1H,

ArCH₂CO₂), 1.73 (s, 4H, CH₂CH₂), 1.36 (s, 3H, CH₃), 1.35

(s, 3H, CH₃), 1.33 (s, 6H, 2ÂCH₃), 1.29 (t, J=7 Hz, 3H,

CO₂CH₂CH₃), 1.15 (t, J=7 Hz, 3H, CO₂CH₂CH₃); ¹³C

NMR (75 MHz, CDCl₃) d 171.72 (CO), 166.48 (CO),

144.36, 144.29, 142.22, 139.81, 139.64, 138.24, 135.12,

133.06, 131.49, 130.26, 129.99, 129.73, 129.48, 128.01,

127.88, 127.82, 127.36, 126.00, 124.95, 124.53, 60.89,

60.81, 39.73, 35.06, 34.54, 32.49, 14.24, 14.10; IR (®lm)

2960, 2926, 2860, 1734, 1720, 1462, 1298, 1232,

1110cm ¹; MS (DCI) m/e 549 (MH⁺), 503 (M C₂H₅O).

Synthesis of (E)-3⁰-carboxy-2-styryl-[1,1⁰-biphenyl]-6-ace-

tic acid (3). Diester 21 (0.123 g, 0.297 mmol) was hydro-

lyzed according to general procedure F to yield diacid 3

(0.091g, 0.254 mmol, 86%): chromatographed on reverse-

phase C-18 silica gel using water:methanol as eluent, then

crystallized from CH₂Cl₂:pentane; UV_max(EtOH)

206 nM (E=27,755), 228 nM (E=26,398), 302 nM

1

(E=22,153); H NMR (300MHz, CD₃OD) d 8.09 (d,

J=8Hz, 1H, ArH), 7.87 (s, 1H, ArH), 7.74 (d, J=8Hz,

1H, ArH), 7.58 (dd, J=8, 8 Hz, 1H, ArH), 7.39 (m, 2H,

ArH), 7.29 (d, J=8 Hz, 1H, ArH), 7.17 (m, 5H, ArH),

7.00 (d, J=16 Hz, 1H, C=CH), 6.65 (d, J=16 Hz, 1H,

CCH), 3.39 (s, 2H, ArCH₂); ¹³C NMR (75 MHz,

CD₃OD) d 175.39 (CO), 169.62 (CO), 141.62,

140.87, 138.73, 137.68, 135.89, 134.75, 132.35, 130.99,

130.93, 129.89, 129.70, 129.64, 129.15, 128.64, 128.05,

127.36, 125.19, 40.13; IR (KBr) 3422, 2922, 1700, 1410,

Synthesis of 3⁰-carboxy-2-[(1,2,3,4-tetrahydro-1,1,4,4-

tetramethyl)-7-anthracenyl]-[1,1⁰-biphenyl]-6-acetic acid (4).

Diester 23 was hydrolyzed using general procedure F to

aord diacid 4 (0.113 g, 0.230 mmol, 57%) as a white

solid: crystallized from CH₂Cl₂:pentane; mp=235±

240 ^ꢀC; UV_max(CHCl₃) 242 nM (E=39,630); H NMR

1

(300MHz, CDCl₃) d 7.86 (ddd, J=2, 2, 8 Hz, 1H, ArH),

7.81 (s, 1H, ArH), 7.64 (s, 1H, ArH), 7.63 (s, 1H, ArH),

7.56 (s, 1H, ArH), 7.46±7.33 (m, 6H, ArH), 7.02 (dd, J=2,

8 Hz, 1H, ArH), 3.54 (d, J=16 Hz, 1H, ArCH₂CO₂), 3.47

(d, J=16 Hz, 1H, ArCH₂CO₂), 1.73 (s, 4H, CH₂CH₂),

1.36 (s, 3H, CH₃), 1.34 (s, 6H, 2ÂCH₃), 1.26 (s, 3H, CH₃);

¹³C NMR (75 MHz, CDCl₃) d 178.87 (CO), 172.12

(CO), 144.46, 144.38, 142.18, 140.04, 139.58, 137.66,

135.03, 132.95, 132.67, 131.39, 130.31, 130.00, 128.90,

128.35, 128.12, 127.23, 126.15, 124.98, 124.51, 40.90,

35.04, 34.53, 32.49, 29.71; IR (KBr) 3420, 2960, 2926,

1704, 1298, 1248, 750 cm ¹; MS (DCI) m/e 493 (MH⁺),

1306, 1258, 744 cm ¹; MS (DCI) m/e 359 (MH⁺), 358

+

.

(M ), 341 (M OH). Anal. (C₂₃H₁₈O₄0.25 H₂O) C, H.

Synthesis of 2-tributylstannyl-5,6,7,8-tetrahydro-5,5,8,8-

tetramethylanthracene (22). 2-Bromo-5,6,7,8-tetrahydro-

5,5,8,8-tetramethylanthracene (2.03 g, 6.42 mmol) (for a

synthesis of this bromide see ref 35) was dissolved in

20 mL THF. The solution was cooled to 78 ^ꢀC, and

tert-butyl lithium (1.7 M in hexane, 7.93 mL, 13.5 mmol)

was added. The mixture was allowed to stir 30 min at

.

475 (M OH). Anal. (C₃₃H₃₂O₄0.75 H₂O) C, H.

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1099

Synthesis of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

naphthalenyl)methoxy-salicylaldehyde (25). Sodium

hydride (2.54 g, 0.106 mol; 80% dispersion, unwashed)

was suspended in 75 mL of DMSO. A solution of 2,3-

dihydroxybenzaldehyde (5.84 g, 42.3 mmol) in 30 mL of

DMSO was added dropwise with water bath cooling,

and the mixture allowed to stir 1 h at room temperature.

A solution of 2-chloromethyl-5,5,8,8-tetramethyl-5,6,7,

8-tetrahydronaphthalene (10 g, 42.3 mmol) in 30 mL of

DMSO was added and the mixture was allowed to stir

overnight at room temperature. The mixture was then

poured into half-saturated ammonium chloride solu-

tion, and extracted with EtOAc. The aqueous phase was

saturated with sodium chloride, and then extracted

twice with EtOAc. The combined organic phase was

washed with brine, dried (MgSO₄), and evaporated.

Chromatography on silica gel using 50% CH₂Cl₂:hexane

aorded aldehyde 25 as a yellow oil (6.02 g, 17.8 mmol,

44%) which occasionally crystallizes upon standing:

UV_max(CHCl₃) 268 nM (E=9894), 240 nM (E=6181),

7.27 (dd, J=2, 8 Hz, 1H, ArH), 7.19 (d, J=8Hz, 1H,

ArH), 7.04 (d, J=2Hz, 1H, ArH), 6.92 (dd, J=2, 8 Hz,

1H, ArH), 5.00 (s, 2H, ArCH₂O), 4.36 (q, J=7Hz, 2H,

CO₂CH₂), 1.62 (s, 4H, CH₂CH₂), 1.36 (t, J=7Hz, 3H,

CO₂CH₂CH₃), 1.22 (s, 6H, 2ÂCH₃), 1.12 (s, 6H, 2ÂCH₃);

¹³C NMR (75 MHz, CDCl₃) d 191.91 (CO), 166.26

(CO), 156.18, 144.99, 144.44, 135.36, 135.30, 134.43,

133.74, 133.25, 131.94, 130.40, 129.15, 128.77, 128.13,

126.57, 124.59, 123.79, 119.61, 117.86, 70.57, 61.12, 34.96,

34.18, 34.07, 31.80, 31.70, 14.33; IR (®lm) 2960, 2928,

2860, 1720, 1692, 1458, 1294, 1260, 1234, 1110,

756 cm ¹; MS (DCI) m/e 471 (MH⁺), 425 (M C₂H₅O),

201 (C₁₅H⁺₂₁). HRMS (FAB) m/e 493.2349 [(M+Na)⁺

calcd for C₃₁H₃₄O₄Na: 493.2355].

Synthesis of 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

naphthalenyl)methoxy - [1,1⁰- biphenyl] - 6,3⁰- dicarboxylic

acid (28). General procedure C was used to convert

aldehyde 27 (1.80 g, 3.83 mmol) to the corresponding

monocarboxylic acid (1.44 g, 2.97 mmol, 78%): recrys-

tallized from CH₂Cl₂:pentane; UV_max(CHCl₃) 242 nM

(E=11,785), 298 nM (E=3885); ¹H NMR (300 MHz,

CDCl₃) d 8.02 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.98 (s,

1H, ArH), 7.56 (dd, J=1, 8 Hz, 1H, ArH), 7.44 (m, 2H,

ArH), 7.38 (t, J=8 Hz, 1H, ArH), 7.20 (dd, J=1, 8 Hz,

1H, ArH), 7.16 (d, J=8 Hz, 1H, ArH), 6.98 (d, J=2 Hz,

1H, ArH), 6.88 (dd, J=2, 8 Hz, 1H, ArH), 4.94 (s, 2H,

ArCH₂O), 4.33 (q, J=7 Hz, 2H, CO₂CH₂), 1.60 (s, 4H,

CH₂CH₂), 1.34 (t, J=7 Hz, 3H, CH₂CH₃), 1.21 (s, 6H,

2ÂCH₃), 1.10 (s, 6H, 2ÂCH₃); ¹³C NMR (75 MHz,

CDCl₃) d 171.22 (CO), 166.63 (CO), 156.32, 144.94,

144.29, 136.94, 134.06, 133.34, 131.93, 130.96, 130.63,

129.98, 128.74, 128.44, 127.75, 126.45, 124.52, 123.72,

122.84, 116.84, 70.52, 60.86, 34.96, 34.15, 34.06, 31.79,

31.67, 14.33, 11.17; IR (KBr) 3260, 3100, 2960, 2926,

1718, 1698, 1576, 1456, 1298, 1262, 1234, 758 cm ¹; MS

(DCI) m/e 487 (MH⁺), 469 (M OH), 201 (C₁₅H₂⁺₁).

1

350 nM (E=2513); H NMR (300 MHz, CDCl₃) d 11.01

(s, 1H, OH), 9.91 (s, 1H, CHO), 7.33 (d, J=2Hz, 1H,

ArH), 7.29 (d, J=8Hz, 1H, ArH), 7.21±7.13 (m, 3H,

ArH), 6.90 (dd, J=8, 8 Hz, 1H, ArH), 5.10 (s, 2H,

ArCH₂O), 1.66 (s, 4H, CH₂CH₂), 1.25 (s, 12H, 4ÂCH₃);

¹³C NMR (75 MHz, CDCl₃) d 196.45 (CO), 152.31,

147.46, 145.07, 144.86, 133.33, 126.93, 125.90, 125.12,

125.01, 121.06, 120.97, 119.46, 71.78, 35.03, 35.00, 34.26,

34.16, 31.83; IR (®lm) 2960, 2926, 2860, 1658, 1456, 1388,

1364, 1276, 1252, 1216, 750, 736 cm ¹; MS (DCI) m/e 339

+

.

(MH ), 201 (C₁₅H₂₁). Anal. (C₂₂H₂₆O₃0.4 H₂O) C,H.

Synthesis of 2-tri¯uoromethylsulphonyloxy-3-(5,6,7,8-tet-

rahydro - 5,5,8,8 - tetramethyl - 2 - naphthalenyl)methoxy -

benzaldehyde (26). General procedure A was used to

convert aldehyde 25 (2.316 g, 6.85 mmol) to tri¯ate 26

(1.47 g., 3.13 mmol, 47%): chromatographed on silica gel

using CH₂Cl₂:hexane, clear oil; UV_max(CHCl₃) 250 nM

(E=8852), 314 nM (E=3184); ¹H NMR (300 MHz,

CDCl₃) d 10.24 (s, 1H, CHO), 7.51 (dd, J=2, 8 Hz, 1H,

ArH), 7.40 (dd, J=8, 8 Hz, 1H, ArH), 7.38±7.30 (m, 3H,

ArH), 7.16 (dd, J=2, 8 Hz, 1H, ArH), 5.15 (s, 2H,

ArCH₂O), 1.67 (s, 4H, CH₂CH₂), 1.27 (s, 6H, 2ÂCH₃),

1.25 (s, 6H, 2ÂCH₃); ¹³C NMR (75 MHz, CDCl₃) d

186.68 (CO), 151.07, 145.41, 145.29, 139.61, 131.81,

129.55, 128.97, 126.90, 125.79, 124.70, 121.09, 120.73,

120.13, 72.00, 35.03, 34.97, 34.31, 34.21, 31.83, 31.71;

IR (®lm) 3028, 2962, 2930, 2866, 1704, 1580, 1478, 1460,

1426, 1282, 1250, 1208, 1140, 880, 782 cm ¹; MS (DCI)

m/e 471 (MH⁺), 401 (M CF₃), 201 (C₁₅H₂⁺₁). Anal.

(C₂₃H₂₅F₃O₅S) C, H.

.

Anal. (C₃₁H₃₄O₅0.5 H₂O) C,H.

The above acid (0.139g, 0.286 mmol) was then hydrolyzed

using general procedure F to aord diacid 28 (0.097g,

0.212 mmol, 74%): chromatographed on C-18 silica gel

using MeOH:water, then recrystallized from CHCl₃:pen-

tane; mp=239±242^ꢀC; UV_max(EtOH) 214 nM

(E=44,121), 290 nM (E=3263); ¹H NMR (300MHz,

CD₃OD) d 7.98 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.96 (dd,

J=2, 2 Hz, 1H, ArH), 7.49±7.38 (m, 4H, ArH), 7.31 (dd,

J=2, 8 Hz, 1H, ArH), 7.18 (d, J=8Hz, 1H, ArH), 7.04 (d,

J=2Hz, 1H, ArH), 6.92 (dd, J=2, 8 Hz, 1H, ArH), 4.98

(s, 2H, ArCH₂O), 1.63 (s, 4H, CH₂CH₂), 1.21 (s, 6H,

2ÂCH₃), 1.11 (s, 6H, 2ÂCH₃); ¹³C NMR (75 MHz,

CD₃OD) d 171.48 (CO), 169.98 (CO), 157.45, 145.88,

145.17, 139.00, 135.59, 135.09, 132.35, 131.96, 131.34,

129.92, 129.34, 128.77, 127.45, 125.83, 125.15, 122.77,

117.09, 71.49, 36.20, 36.17, 35.12, 34.98, 32.24; IR (KBr)

3422, 2956, 2922, 1690, 1598, 1576, 1452, 1412, 1312,

Synthesis of 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

naphthalenyl)methoxy-[1,1⁰-biphenyl]-3⁰-carboethoxy-6-

carboxaldehyde (27). General procedure B was used to

couple stannane 7 (1.96 g, 4.47mmol) with tri¯ate 26

(1.47 g, 3.13mmol) to aord aldehyde 27 (1.13 g,

2.40mmol, 77%): chromatographed on silica gel using

CH₂Cl₂:hexane; UV_max(CHCl₃) 242 nm (E=13,370),

322 nM (E=2203); ¹H NMR (300MHz, CDCl₃) d 9.73 (s,

1H, CHO), 8.10 (ddd, J=2, 2, 8 Hz, 1H, ArH), 8.06 (dd,

J=2, 2 Hz, 1H, ArH), 7.64 (dd, J=2, 8 Hz, 1H, ArH),

7.53 (m, 2H, ArH), 7.47 (ddd, J=2, 8, 8 Hz, 1H, ArH),

1284, 1262, 1064cm ¹; MS (DCI) m/e 459 (MH⁺), 441

+

.

(M-OH), 201 (C₁₅H₂₁). Anal. (C₂₉H₃₀O₅0.75 H₂O) C, H.

Synthesis of 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

naphthalenyl)methoxy-3⁰-carboethoxy-1,1⁰-biphenyl-6-

acetaldehyde (29). General procedure E was used to

convert aldehyde 27 (0.521 g, 1.11 mmol) to a mixture of

1100

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

enol ethers (0.506 g, 1.02 mmol, 91%): chromatographed

on silica gel using 20% EtOAc:hexane to aord a white

solid (ꢁ2:1 mixture of E:Z isomers); ¹H NMR (300 MHz,

CDCl₃) d 8.35 (ddd, J=2, 2, 8 Hz, 1H, ArH from Z iso-

mer), 8.08 (m, ArH from E and Z), 7.82 (ddd, J=2, 2,

8 Hz, 1H, ArH from E isomer), 7.59±7.49 (m, ArH from

E and Z), 7.37±7.20 (m, ArH from E and Z), 7.11 (d,

J=8 Hz, 1H, ArH from E isomer), 7.07 (m, ArH, from E

and Z), 6.94 (m, ArH, from E and Z), 6.03 (d, J=8 Hz,

CHC from Z isomer), 5.49 (d, J=14 Hz, CHC from E

isomer), 4.99 (s, 2H, ArCH₂O from E isomer), 4.98 (s,

2H, ArCH₂O from Z isomer), 4.89 (d, J=8 Hz, CHC

from Z isomer), 4.41 (m, 2H, CO₂CH₂from E and Z),

3.75 (s, 3H, OCH₃from Z isomer), 3.49 (s, 3H, OCH₃

from E isomer), 1.45 (t, J=7 Hz, 3H, CO₂CH₂CH₃from

Z isomer), 1.41 (t, J=7 Hz, 3H, CO₂CH₂CH₃from E

isomer), 1.25 (s, 6H, 2ÂCH₃), 1.15 (s, 6H, 2ÂCH₃).

8 Hz, 1H, ArH), 4.94 (m, 2H, ArCH₂O), 3.47 (s, 2H,

ArCH₂CO₂), 1.57 (s, 4H, CH₂CH₂), 1.18 (s, 6H,

2ÂCH₃), 1.05 (s, 3H, CH₃), 1.03 (s, 3H, CH₃); ¹³C NMR

(75 MHz, CDCl₃) d 178.77 (CO), 172.37 (CO),

156.30, 144.88, 144.13, 137.24, 134.77, 133.91, 133.76,

132.76, 131.08, 129.19, 129.11, 128.66, 126.38, 124.56,

123.65, 123.21, 69.94, 40.22, 34.95, 34.11, 34.02, 31.77,

31.60; IR (KBr) 3422, 2960, 2926, 1702, 1456, 1412, 1300,

1258 cm ¹; MS (DCI) m/e 473 (MH⁺), 455 (M OH),

+

.

201 (C₁₅H₂₁). Anal. (C₃₀H₃₂O₅0.33 H₂O) C, H.

Synthesis of (3-carboethoxymethyl)phenyl-tributylstan-

nane (31). tert-Butyllithium (1.77

M in pentane,

9.08 mL, 15.8 mmol) was added dropwise to a cooled

( 5 ^ꢀC) solution of diisopropylamine (1.60 g,

15.8 mmol) in 60 mL of THF. The mixture was stirred

5 min, and then cooled to 78 ^ꢀC. A solution of 3-

bromophenylacetic acid, ethyl ester (3.49 g, 14.4 mmol)

dissolved in 12 mL THF was added dropwise, and the

solution was allowed to stir for 20 min at 78 ^ꢀC. tert-

Butyllithium (1.77 M in pentane, 16.5 mL, 28.7 mmol)

was added, and the bright yellow solution was stirred

for 55 min at 78 ^ꢀC. Tri(n-butyl)tin chloride (5.14 g,

15.8 mmol) was added, and the mixture allowed to warm

to 10 ^ꢀC over 1.5 h. The solution was partitioned

between saturated NH₄⁺Cl , and ether. The aqueous

layer was extracted with ether, and the combined

organic phase was washed with brine, dried (MgSO4),

and evaporated. The residue was chromatographed on

silica using EtOAc:hexane to aord stannane 31 (2.89 g,

The above mixture of enol ethers was hydrolyzed to

aord aldehyde 29 (0.458 g, 0.945 mmol, 93%) of sui-

1

table purity for use in subsequent reactions: H NMR

(300 MHz, CDCl₃) d 9.61 (bs, 1H, CHO), 8.10 (m, 2H,

ArH), 7.60±7.49 (m, 2H, ArH), 7.39 (dd, J=8, 8 Hz,

1H, ArH), 7.22 (d, J=8 Hz, 1H, ArH), 7.08 (m, 2H,

ArH), 6.96 (m, 2H, ArH), 5.01 (s, 2H, ArCH₂O), 4.43

(q, J=7 Hz, 2H, CO₂CH₂), 3.56 (bs, 2H, ArCH₂CHO),

1.58 (s, 4H, CH₂CH₂), 1.39 (t, J=7 Hz, CO₂CH₂CH₃),

1.29 (s, 6H, 2ÂCH₃), 1.17 (s, 6H, 2ÂCH₃).

Synthesis of 3⁰-carboxy-2-(5,6,7,8-tetrahydro-5,5,8,8-

tetramethyl-2-naphthalenyl)methoxy-[1,1⁰-biphenyl]-6-acetic

acid (30). General procedure C was used to oxidize

aldehyde 29 (0.458 g, 0.945 mmol) to the corresponding

monocarboxylic acid (0.244 g, 0.490 mmol, 48% from

the mixture of enol ethers obtained in the synthesis of

29): chromatographed on silica gel using 35% EtOAc:

hexane; UV_max(CHCl₃) 242 nM (E=8586), 278 nM

1

6.38 mmol, 44%): H NMR (300 MHz, CDCl₃) d 7.36

(s, 1H, ArH), 7.31±7.20 (m, 3H, ArH), 4.16 (q, J=7 Hz,

2H, CO₂CH₂), 3.59 (s, 2H, ArCH₂CO₂), 1.72±1.44 (m,

6H, 3ÂSnCH₂), 1.42±1.22 (m, 15H, 3ÂSnCH₂CH₂CH₂

and CO₂CH₂CH₃), 0.94 (m, 9H, 3ÂCH₃).

Synthesis of 6-carboxy-2-[5,6,7,8-tetrahydro-5,5,8,8-

tetramethyl-2-naphthalenyl]methoxy-[1,1⁰-biphenyl]-3⁰-acetic

acid (33). Tri¯ate 26 (0.826 g, 1.76 mmol) was coupled

to stannane 31 (1.19 g, 2.63 mmol) via the method of

general procedure B to yield ester 32 (0.410 g): chroma-

tographed on silica gel using 5% EtOAc:hexane to

aord a yellow oil as a 3:1 mixture of 32 and tri¯ate 26.

1

(E=3144); H NMR (300 MHz, CDCl₃) d 8.04 (m, 1H,

ArH), 7.96 (s, 1H, ArH), 7.46 (m, 2H, ArH), 7.32 (dd,

J=8, 8 Hz, 1H, ArH), 7.16 (d, J=8 Hz, 1H, ArH), 6.98

(m, 3H, ArH), 6.87 (dd, J=2, 8 Hz, 1H, ArH), 4.92 (s,

2H, ArCH₂O), 4.31 (q, J=7 Hz, 2H, CO₂CH₂), 3.44 (s,

2H, ArCH₂CO₂), 1.60 (s, 4H, CH₂CH₂), 1.32 (t,

J=7 Hz, 3H, CO₂CH₂CH₃), 1.20 (s, 6H, 2ÂCH₃), 1.08

(s, 6H, 2ÂCH₃); ¹³C NMR (75 MHz, CDCl₃) d 176.98

(CO), 166.53 (CO), 156.30, 144.83, 144.09, 136.92,

134.77, 133.81, 133.26, 131.20, 130.45, 128.83, 128.56,

128.27, 126.39, 124.47, 123.65, 122.63, 111.62, 70.02,

60.93, 38.54, 34.99, 34.14, 34.04, 31.80, 31.66, 14.27; IR

(®lm) 3240, 2960, 2926, 1716, 1456, 1298, 1258, 1232,

758 cm ¹; MS (DCI) m/e 501 (MH⁺), 483 (M OH),

455 (M C₂H₅O), 201 (C₁₅H⁺₂₁).

The mixture obtained above was oxidized via the

method of general procedure C to yield the corre-

sponding carboxylic acid (0.210 g, 0.43 mmol, 25%

overall from tri¯ate 26): chromatographed on silica gel

1

using methanol:CH₂Cl₂to aord a yellow oil; H NMR

(300MHz, CDCl₃) d 7.49 (d, J=8Hz, 1H, ArH), 7.33 (m,

2H, ArH), 7.26±7.15 (m, 5H, ArH), 7.05 (d, J=2Hz, 1H,

ArH), 6.89 (dd, J=2, 8 Hz, 1H, ArH), 4.94 (s, 2H,

ArCH₂O), 4.05 (q, J=7Hz, 2H, CO₂CH₂), 3.59 (s, 2H,

ArCH₂CO₂), 1.63 (s, 4H, CH₂CH₂), 1.22 (s, 6H, 2ÂCH₃),

1.15 (s, 6H, 2ÂCH₃), 1.15 (t, J=7Hz, 3H, CO₂CH₂CH₃);

¹³C NMR (75 MHz, CDCl₃) d 171.68 (CO), 171.64

(CO), 156.21, 144.87, 144.23, 136.72, 133.58, 133.44,

132.16, 130.56, 128.42, 128.37, 128.01, 127.89, 126.55,

124.67, 123.89, 122.57, 116.76, 70.69, 60.80, 41.43,

35.03, 34.19, 34.07, 31.82, 31.74, 14.12; IR (®lm) 2960,

2926, 1734, 1700, 1456, 1364, 1300, 1260, 1152,

758 cm ¹; MS (DCI) m/e 501 (MH⁺), 483 (M OH),

201 (C₁₅H⁺₂₁).

The acid obtained above (0.207 g, 0.414 mmol) was

hydrolyzed via general procedure F to yield diacid 30

(0.167 g, 0.354 mmol, 85%) as a white foam: chromato-

graphed on reverse-phase C-18 silica gel using metha-

nol; UV_max(CHCl₃) 242 nM (E=9965), 278 nM

1

(E=3435); H NMR (300 MHz, CDCl₃) d 8.02 (m, 2H,

ArH), 7.51 (dd, J=8, 8 Hz, 1H, ArH), 7.46 (ddd, J=2,

2, 8 Hz, 1H, ArH), 7.33 (dd, J=8, 8 Hz, 1H, ArH), 7.14

(d, J=8 Hz, 1H, ArH), 7.02 (d, J=8 Hz, 1H, ArH), 6.96

(d, J=8 Hz, 1H, ArH), 6.93 (s, 1H, ArH), 6.85 (dd, J=2,

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1101

The acid obtained above (0.199 g, 0.41mmol) was hydro-

lyzed via the method of general procedure F to aord

diacid 33 (0.169 g, 0.37mmol, 90%) as a yellow solid:

UV_max(MeOH) 208 nM (E=42,683), 292 nM (E=3412);

¹H NMR (300MHz, CD₃OD) d 7.39±7.17 (m, 8H, ArH),

7.10 (d, J=2 Hz, 1H, ArH), 6.93 (dd, J=2, 8 Hz, 1H,

ArH), 4.96 (s, 2H, ArCH₂O), 3.59 (s, 2H, ArCH₂CO₂),

1.65 (s, 4H, CH₂CH₂), 1.22 (s, 6H, 2ÂCH₃), 1.15 (s, 6H,

2ÂCH₃); ¹³C NMR (75 MHz, CD₃OD) d 175.49 (CO),

172.19 (CO), 157.42, 145.81, 145.16, 138.56, 135.60,

135.25, 135.19, 132.46, 131.86, 129.65, 129.50, 128.92,

128.73, 127.54, 126.02, 125.32, 122.37, 117.06, 71.56,

42.09, 36.21, 35.17, 35.00, 32.29, 32.25; IR (KBr) 3430,

2960, 2926, 1706, 1456, 1298, 1260 cm ¹; MS (DCI) m/e

473 (MH⁺), 472 (M⁺), 455 (M-OH), 201 (C₁₅H₂⁺₁).

156.11, 149.19, 148.37, 137.26, 134.90, 134.14, 131.32,

131.12, 130.36, 129.71, 128.76, 128.28, 128.03, 122.85,

118.82, 113.55, 111.93, 111.75, 70.80, 69.31, 68.83, 60.92,

60.73, 39.21, 29.01, 28.96, 28.31, 22.53, 14.33, 14.08; IR

(KBr) 2930, 2955, 1720 (CO), 1585, 1510, 1465, 1260,

1230 cm ¹; MS (DCI) m/e 591 (MH⁺), 525, 263. Anal.

.

(C₃₆H₄₆O₇0.1 CH₂Cl₂) C; H: calcd, 7.80; found, 8.25.

2-[3,4-Bis(3-methyl-2-butenyloxy)phenyl]methoxy-[1,1⁰-

biphenyl]-6,3⁰-dicarboxylic acid, diethyl ester (35c). Iso-

lated as a white solid (68% yield): chromatographed on

silica gel using EtOAc:hexane; mp=85.5±87.5 ^ꢀC;

UV_max(CHCl₃) 242 nM (E=19,498), 286 nM (E=6685);

¹H NMR (300 MHz, CDCl₃) d 8.00 (ddd, J=2, 2, 8 Hz,

1H, ArH), 7.96 (dd, J=2, 2 Hz, 1H, ArH), 7.49±7.39

(m, 3H, ArH), 7.35 (dd, J=8, 8 Hz, 1H, ArH), 7.13 (dd,

J=2, 8 Hz, 1H, ArH), 6.74 (d, J=8 Hz, 1H, ArH), 6.67

(dd, J=2, 8 Hz, 1H, ArH), 6.63 (d, J=2 Hz, 1H, ArH),

5.44 (m, 2H, CCH), 4.92 (s, 2H, ArCH₂O), 4.51 (d,

J=6 Hz, 2H, RCH₂O), 4.36 (d, J=6 Hz, 2H, RCH₂O),

4.32 (q, J=7 Hz, 2H, CO₂CH₂), 3.98 (q, J=7 Hz, 2H,

CO₂CH₂), 1.73 (s, 6H, 2ÂCH₃), 1.67 (s, 3H, CH₃), 1.66 (s,

3H, CH₃), 1.34 (t, J=7Hz, 3H, CO₂CH₂CH₃), 0.91 (t,

J=7Hz, 3H, CO₂CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃)

d 168.01 (CO), 166.54 (CO), 155.98, 148.89, 148.31,

137.52, 137.44, 137.07, 134.18, 133.22, 130.93, 130.78,

129.94, 129.17, 128.71, 128.16, 127.53, 122.15, 120.26,

119.92, 119.14, 116.29, 113.73, 112.40, 70.65, 66.05, 65.72,

60.88, 25.80, 25.77, 18.20, 14.30, 13.66; IR (KBr) 2982,

2930, 1714, 1574, 1512, 1290, 1252, 1232, 1038, 852,

766 cm ¹; MS (DCI) m/e 573 (MH⁺). Anal. (C₃₅H₄₀O₇)

C, H.

.

Anal. (C₃₀H₃₂O₅0.5 H₂O) C, H.

General procedure G. Mitsunobu etheri®cation of phenols

with benzyl alcohols: synthesis of 2-[(3,4-bispentyloxy)phe-

nyl]methoxy-[1,1⁰-biphenyl]-6,3⁰-dicarboxylic acid, diethyl

ester (35a). Phenol 10 (0.200 g, 0.637 mmol) was dis-

solved in 3.2 mL dry THF. Triphenylphosphine (0.200g,

0.764 mmol) was added and the solution was cooled to

0 ^ꢀC. Diisopropylazodicarboxylate (0.15 mL, 0.764 mmol)

was added, and then a solution of (3,4-bispentyl-

oxy)benzyl alcohol (0.178 g, 0.637 mmol; for a synthesis

of this and all other benzyl alcohols used in the Mitsu-

nobu coupling see ref 26) in 1.5 mL dry THF was added

dropwise. The mixture was stirred at 0 ^ꢀC for 4 h, and

then poured into water and EtOAc. The aqueous layer

was extracted with EtOAc, and the organic phase was

washed with brine, dried (MgSO₄) and evaporated.

Chromatography on silica gel using EtOAc:hexane

aorded as a clear oil diester 35a (0.200 g, 0.350 mmol,

2-[(3,4-Biscyclopentyloxy)phenyl]methoxy-[1,1⁰-biphenyl]

- 6,3⁰- dicarboxylic acid, 3⁰- ethyl ester, 6 - methyl ester

(35d). From 2-(3⁰-carboethoxyphenyl)-3-carbomethox-

yphenol and (3,4-biscyclopentyloxy)benzyl alcohol (69%

yield): chromatographed on silica gel using EtOAc:hex-

1

55%): H NMR (300 MHz, CDCl₃) d 8.09 (ddd, J=2,

2, 8 Hz, 1H, ArH), 8.01 (s, 1H, ArH), 7.51±7.40 (m, 3H,

ArH), 7.38 (dd, J=8, 8 Hz, 1H, ArH), 7.17 (d, J=8 Hz,

1H, ArH), 6.76 (d, J=8 Hz, 1H, ArH), 6.67 (dd, J=2,

8 Hz, 1H, ArH), 6.61 (d, J=2 Hz, 1H, ArH), 4.94 (s,

2H, ArCH₂O), 4.36 (q, J=7 Hz, 2H, CO₂CH₂), 4.01 (q,

J=7 Hz, 2H, CO₂CH₂), 3.95 (t, J=7 Hz, 2H, RCH₂O),

3.76 (t, J=7 Hz, 2H, RCH₂O), 1.79 (m, 4H,

RCH₂CH₂O), 1.40 (m, 8H, pentyl), 1.39 (t, J=7 Hz,

3H, CO₂CH₂CH₃), 0.91 (m, 9H, 2xRCH₃and

CO₂CH₂CH₃).

1

ane; H NMR (300 MHz, CDCl₃) d 8.00 (ddd, J=2, 2,

8 Hz, 1H, ArH), 7.96 (dd, J=2, 2 Hz, 1H, ArH), 7.45 (m,

3H, ArH), 7.35 (dd, J=7, 7 Hz, 1H, ArH), 7.15 (dd,

J=2, 8 Hz, 1H, ArH), 6.74 (d, J=8 Hz, 1H, ArH), 6.65

(dd, J=2, 8 Hz, 1H, ArH), 6.60 (d, J=2 Hz, 1H, ArH),

4.91 (s, 2H, ArCH₂O), 4.66 (m, 1H, R₂CHOR), 4.50 (m,

1H, R₂CHOR), 4.33 (q, J=7 Hz, 2H, CO₂CH₂), 3.54 (s,

3H, CO₂CH₃), 1.85±1.63 (m, 10H, cycloalkyl), 1.54 (m,

6H, cycloalkyl), 1.36 (t, J=7 Hz, 3H, CO₂CH₂CH₃);

¹³C NMR (75 MHz, CDCl₃) d 168.19 (CO), 166.40

(CO), 159.04, 148.93, 137.28, 134.12, 132.71, 130.65,

129.94, 129.34, 128.71, 128.18, 127.55, 122.10, 119.32,

116.58, 116.31, 115.24, 81.13, 80.84, 70.54, 60.87, 51.94,

32.76, 32.71, 23.87, 23.83, 14.32; IR (®lm) 2958, 1720,

1508, 1296, 1262, 1234, 1166, 758 cm ¹; MS (DCI) m/e

559 (MH⁺).

Also obtained in this fashion were the following:

2-[(3,4-Bispentyloxy)phenyl]-methoxy-3⁰-carboethoxy-

[1,1⁰-biphenyl]-6-acetic acid, ethyl ester (35b). Isolated as

a clear oil (46% yield): chromatographed on silica gel using

CH₂Cl₂:hexane; UV_max(EtOH) 208 nM (E=53,224),

1

280 nM (E=6773); H NMR (300 MHz, CDCl₃) d 8.05

(dd, J=2, 8 Hz, 1H, ArH), 7.97 (s, 1H, ArH), 7.46 (m,

2H, ArH), 7.32 (dd, J=8, 8 Hz, 1H, ArH), 7.03 (d,

J=8 Hz, 1H, ArH), 6.97 (d, J=8 Hz, 1H, ArH), 6.75 (d,

J=8 Hz, 1H, ArH), 6.68 (dd, J=2, 8 Hz, 1H, ArH),

6.60 (s, 1H, ArH), 4.93 (s, 2H, ArCH₂O), 4.37 (q,

J=7 Hz, 2H, CO₂CH₂), 4.06 (q, J=7 Hz, 2H,

CO₂CH₂), 3.93 (t, J=6 Hz, 2H, OCH₂R), 3.76 (t,

J=6 Hz, 2H, OCH₂R), 3.42 (s, 2H, ArCH₂CO₂), 1.82±

0.93 (m, 24 H, pentyl and 2ÂCO₂CH₂CH₃); ¹³C NMR

(75 MHz, CDCl₃) d 171.45 (CO), 166.45 (CO),

2-[(3,4-Biscyclopentyloxy)phenyl]methoxy-3⁰-carboethoxy-

[1,1⁰-biphenyl]-6-acetic acid, ethyl ester (35e). 57% yield:

chromatographed on silica gel using CH₂Cl₂:hexane;

UV_max(EtOH) 208 nM (E=56,239), 282 nM (E=6164);

¹H NMR (300 MHz, CDCl₃) d 8.04 (dd, J=2, 5 Hz, 1H,

ArH), 7.96 (s, 1H, ArH), 7.48 (d, J=5 Hz, 2H, ArH),

7.31 (dd, J=8, 8 Hz, 1H, ArH), 7.02 (d, J=8 Hz, 1H,

ArH), 6.96 (d, J=8 Hz, 1H, ArH), 6.78 (d, J=8 Hz, 1H,

1102

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

ArH), 6.67 (d, J=8 Hz, 1H, ArH), 6.60 (s, 1H, ArH),

4.91 (s, 2H, ArCH₂O), 4.69±4.40 (m, 2H, 2ÂR₂CHOR),

4.35 (q, J=7 Hz, 2H, CO₂CH₂), 4.05 (q, J=7 Hz, 2H,

CO₂CH₂), 3.41 (s, 2H, ArCH₂CO₂), 1.96±1.52 (m, 16H,

cyclopentyl), 1.35 (t, J=7 Hz, 3H, CO₂CH₂CH₃); 1.15

(t, J=7 Hz, 3H, CO₂CH₂CH₃); ¹³C NMR (75 MHz,

CDCl₃) d 171.51 (CO), 166.51 (CO), 156.10, 148.88,

148.20, 137.18, 134.92, 134.12, 131.23, 131.06, 130.31,

129.87, 128.71, 128.27, 128.01, 122.78, 119.13, 116.61,

115.07, 111.71, 81.14, 81.08, 70.08, 60.91, 60.74, 39.20,

32.76, 32.71, 23.89, 23.83, 14.31, 14.06; IR (KBr) 2960,

1730 (CO), 1720 (CO), 1580, 1505, 1425, 1260,

1230 cm ¹; MS (DCI) m/e 587 (MH⁺), 586 (M), 519,

128.81, 128.70, 128.35, 128.18, 128.06, 122.82, 114.25,

111.90, 70.12, 67.93, 60.76, 39.22, 31.92, 29.59, 29.42,

29.36, 29.28, 22.72, 14.38, 14.18, 14.10.

Synthesis of 3⁰-carboethoxy-2-[4-(1-adamantyl)-3-methoxy-

phenyl]-methoxy-[1,1⁰-biphenyl]-6-acetic acid, ethyl ester

(35g). Phenol 14 (0.656 g, 2.00 mmol) was dissolved in

15 mL of methyl isobutyl ketone. 4-[1-Adamantyl]-3-

methoxybenzyl iodide (0.766 g, 2.00 mmol; for a synth-

esis of this iodide see ref 26) and potassium carbonate

(1.00 g, 7.2 mmol) were added and the mixture was

heated to re¯ux for 5 h. The solvents were evaporated

and the residue was dissolved in methylene chloride. This

solution was washed with water and brine, then dried

(MgSO₄), and concentrated. The crude material was

chromatographed on silica gel using 50% CH₂Cl₂:hex-

.

259. Anal. (C₃₆H₄₂O₇0.1 H₂O) C; H: calcd, 7.10; found,

6.69.

2-[4-(1-Adamantyl)-3-methoxyphenyl]methoxy-[1,1⁰-bi-

phenyl]-6,3⁰-dicarboxylic acid, diethyl ester (35f). 62%

yield: chromatographed on silica gel using CH₂Cl₂:hex-

ane; ¹H NMR (300 MHz, CDCl₃) d 8.05 (d, J=8 Hz, 1H,

ArH), 8.02 (s, 1H, ArH), 7.49±7.39 (m, 4H, ArH), 7.26

(d, J=8 Hz, 1H, ArH), 7.09 (d, J=8 Hz, 1H, ArH), 6.74

(d, J=8 Hz, 1H, ArH), 6.59 (s, 1H, ArH), 5.00 (s, 2H,

ArCH₂O), 4.38 (q, J=7 Hz, 2H, CO₂CH₂), 4.02 (q,

J=7 Hz, 2H, CO₂CH₂), 3.62 (s, 3H, CH₃O), 2.04 (s, 9H,

adamantyl), 1.75 (s, 6H, adamantyl), 1.40 (t, J=7 Hz,

3H, CO₂CH₂CH₃), 0.97 (t, J=7 Hz, 3H, CO₂CH₂CH₃);

¹³C NMR (75 MHz, CDCl₃) d 167.89 (CO), 166.60

(CO), 158.89, 156.02, 137.81, 137.64, 135.27, 134.25,

133.16, 130.81, 129.99, 128.85, 127.66, 126.36, 122.12,

118.21, 115.88, 109.57, 70.16, 60.94, 54.86, 40.53, 37.12,

36.82, 29.07, 14.38, 13.71.

ane to aord diester 35g (0.725 g, 1.24 mmol, 62%): H

1

NMR (300 MHz, CDCl₃) d 8.06 (dd, J=2, 8 Hz, 1H,

ArH), 7.98 (s, 1H, ArH), 7.50±7.47 (m, 2H, ArH), 7.33±

6.97 (m, 4H, ArH), 6.69 (dd, J=2, 8 Hz, 1H, ArH), 6.57

(d, J=2 Hz, 1H, ArH), 4.97 (s, 2H, ArCH₂O), 4.38 (q,

J=7 Hz, 2H, CO₂CH₂), 4.03 (q, J=7 Hz, 2H,

CO₂CH₂), 3.59 (s, 3H, CH₃O), 3.41 (s, 2H, ArCH₂CO₂),

2.03 (s, 9H, adamantyl), 1.75 (s, 6H, adamantyl), 1.40 (t,

J=7 Hz, 3H, CO₂CH₂CH₃), 1.16 (t, J=7 Hz, 3Hz,

CO₂CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃) d 171.48

(CO), 166.54 (CO), 158.84, 156.13, 137.62, 137.33,

135.74, 134.91, 134.21, 131.31, 131.05, 130.44, 128.82,

128.33, 128.14, 126.27, 122.82, 118.09, 111.49, 109.54,

69.75, 60.97, 60.77, 54.82, 40.55, 39.23, 37.13, 36.80,

29.09, 14.38, 14.12.

Synthesis of 2-[(3,4-bispentyloxy)phenyl]methoxy-[1,1⁰-

biphenyl]-6,3⁰-dicarboxylic acid (36a). Diester 35a

(0.200 g, 0.35 mmol) was hydrolyzed using general pro-

cedure F to aord diacid 36a (0.105 g, 0.200 mmol,

57%): recrystallized from CH₂Cl₂:pentane; mp=202±

203 ^ꢀC (dec.); UV_max(EtOH) 208 nM (E=35722), 284

2-[(3,4-Bisdecyloxy)phenyl]methoxy-[1,1⁰-biphenyl]-6,3⁰-

dicarboxylic acid, diethyl ester (35h). Isolated as a clear

oil which crystallized on standing (44% yield): chroma-

tographed using 25±50±75% CH₂Cl₂:hexane; mp=59.5±

60.5 ^ꢀC; ¹H NMR (300 MHz, CDCl₃) d 8.03 (ddd, J=2,

2, 8 Hz, 1H, ArH), 7.99 (d, J=2 Hz, 1H, ArH), 7.50±

7.40 (m, 3H, ArH), 7.37 (dd, J=8, 8 Hz, 1H, ArH), 7.17

(d, J=8 Hz, 1H, ArH), 6.77 (d, J=8 Hz, 1H, ArH), 6.67

(dd, J=2, 8 Hz, 1H, ArH), 6.61 (d, J=2 Hz, 1H, ArH),

4.94 (s, 2H, ArCH₂O), 4.36 (q, J=7 Hz, 2H, CO₂CH₂),

4.02 (q, J=7 Hz, 2H, CO₂CH₂), 3.94 (t, J=7 Hz, 2H,

RCH₂O), 3.77 (t, J=7 Hz, 2H, RCH₂O), 1.78 (m, 4H,

RCH₂CH₂O), 1.43 (m, 4H, decyl), 1.36 (t, J=7 Hz, 3H,

CO₂CH₂CH₃), 1.29 (m, 24H, decyl), 0.95 (t, J=7 Hz,

3H, CO₂CH₂CH₃), 0.89 (t, 6H, 2ÂCH₃).

1

nm (E=5099); H NMR (300 MHz, CDCl₃) d 8.01 (d,

J=8 Hz, 1H, ArH), 7.90 (s, 1H, ArH), 7.59 (m, 2H,

ArH), 7.43 (dd, J=8, 8 Hz, 1H, ArH), 7.37 (dd, J=8,

8 Hz, 1H, ArH), 7.17 (d, J=8 Hz, 1H, ArH), 6.73 (d,

J=8 Hz, 1H, ArH), 6.62 (dd, J=2, 8 Hz, 1H, ArH),

6.56 (d, J=2 Hz, 1H, ArH), 4.90 (s, 2H, ArCH₂O), 3.91

(t, J=7 Hz, 2H, RCH₂O), 3.74 (t, J=7 Hz, 2H,

RCH₂O), 1.74 (m, 4H, RCH₂CH₂O), 1.48±1.28 (m, 8H,

pentyl), 0.89 (m, 6H, 2ÂCH₃); ¹³C NMR (75 MHz,

CDCl₃) d 173.47 (CO), 172.40 (CO), 156.20, 149.35,

148.70, 137.35, 135.55, 131.77, 131.07, 129.14, 128.93,

127.76, 123.15, 119.16, 117.33, 113.63, 112.17, 70.77,

69.42, 69.08, 29.07, 29.03, 28.35, 28.30, 22.58, 14.15; IR

(KBr) 3400, 2956, 2932, 2870, 1692, 1516, 1468, 1432,

1302, 1262, 1170, 1136, 1108, 1080, 758, 694 cm ¹; MS

(DCI) m/e 521 (MH⁺), 503 (M OH). Anal.

3⁰-Carboethoxy-2-[4-decyloxyphenyl]methoxy-[1,1⁰-biphen-

yl]-6-acetic acid, ethyl ester (35i). 44% yield: chromato-

1

graphed on silica gel using CH₂Cl₂:hexane; H NMR

(300 MHz, CDCl₃) d 8.07 (dd, J=2, 8 Hz, 1H, ArH), 7.98

(s, 1H, ArH), 7.49±7.47 (m, 2H, ArH), 7.31 (dd, J=8,

8 Hz, 1H, ArH), 7.08±6.80 (m, 4H, ArH), 6.77 (d,

J=8 Hz, 2H, ArH), 4.94 (s, 2H, ArCH₂O), 4.38 (q,

J=7 Hz, 2H, CO₂CH₂), 4.07 (q, J=7 Hz, 2H, CO₂CH₂),

3.94 (t, J=Hz, 2H, OCH₂R), 3.43 (s, 2H, ArCH₂CO₂),

1.76 (m, 2H, OCH₂CH₂R), 1.38 (t, J=7 Hz, 2H,

CO₂CH₂CH₃), 1.28 (s, 14 H, R(CH₂)₇CH₃), 1.20 (t,

J=7 Hz, 3H, CO₂CH₂CH₃), 0.90 (t, J=7 Hz, 3H,

RCH₃); ¹³C NMR (75 MHz, CDCl₃) d 171.54 (CO),

158.61, 156.12, 137.03, 134.87, 134.08, 131.39, 130.25,

.

(C₃₁H₃₆O₇0.4 H₂O) C, H.

Also obtained in this fashion were the following:

2-[(3,4-Bispentyloxy)phenyl]methoxy-3⁰-carboxy-[1,1⁰-bi-

phenyl]-6-acetic acid (36b). Isolated as a white solid

(49% yield): chromatographed on reverse-phase C-18

silica gel using methanol; mp=105±106 ^ꢀC; UV_max

(EtOH) 208 nM (E=52,348), 280 nM (E=6237); ¹H

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1103

NMR (300 MHz, CDCl₃) d 8.03 (d, J=2 Hz, 1H, ArH),

8.01 (s, 1H, ArH), 7.52±7.46 (m, 2H, ArH), 7.34 (dd,

J=8, 8 Hz, 1H, ArH), 7.04 (d, J=8 Hz, 1H, ArH), 6.98

(d, J=8 Hz, 1H, ArH), 6.70 (d, J=8 Hz, 1H, ArH), 6.63

(dd, J=2, 8 Hz, 1H, ArH), 6.59 (s, 1H, ArH), 4.94 (s,

2H, ArCH₂O), 3.95±3.69 (m, 4H, 2ÂRCH₂O), 3.48 (s,

2H, ArCH₂CO₂H), 1.79±0.88 (m, 18H, pentyl); ¹³C

NMR (75 MHz, CDCl₃) d 178.72 (CO), 172.28

(CO), 156.11, 149.22, 148.36, 137.28, 134.84, 133.90,

132.71, 131.07, 129.54, 129.10, 128.61, 123.34, 118.84,

113.54, 112.30, 111.82, 70.05, 69.33, 68.77, 40.24, 28.89,

28.18, 22.46, 14.03; IR (KBr) 3550 (OH), 2950, 2925,

1700 (C0), 1570, 1530, 1250 cm ¹; MS (DCI) m/e 535

(MH⁺), 517 (M OH), 273, 263, 255. Anal.

(EtOH) 206 nM (E=61,550), 282 nM (E=5781); ¹H

NMR (300 MHz, CDCl₃) d 8.04 (d, J=8 Hz, 1H, ArH),

8.01 (s, 1H, ArH), 7.54±7.45 (m, 2H, ArH), 7.34 (dd,

J=8, 8 Hz, 1H, ArH), 7.03 (d, J=8 Hz, 1H, ArH), 6.98

(d, J=8 Hz, 1H, ArH), 6.76 (d, J=8 Hz, 1H, ArH), 6.66

(d, J=8 Hz, 1H, ArH), 6.61 (s, 1H, ArH), 4.94 (s, 2H,

ArCH₂O), 4.67±4.48 (m, 2H, 2ÂR₂CHOR), 3.47 (s,

ArCH₂CO₂), 1.80±1.54 (m, 16H, cyclopentyl); ¹³C

NMR (75 MHz, CDCl₃) d 178.71 (CO), 172.26

(CO), 156.11, 148.88, 148.23, 137.26, 134.85, 130.90,

132.64, 131.04, 129.71, 129.12, 129.10, 128.60, 123.31,

119.16, 116.57, 114.97, 112.27, 111.47, 81.13, 80.56,

70.02, 40.21, 32.69, 23.87; IR (KBr) 3400 (OH), 2950,

2840, 1690 (CO), 1580, 1510, 1260 cm ¹; MS (DCI) m/

e 531 (MH⁺), 530 (M⁺), 509, 445 (M-C₅H₉O), 395,

.

(C₃₂H₃₈O₇0.75 H₂0) C, H.

.

273, 255. Anal. (C₃₂H₃₄O₇1.5 H₂O) C, H.

2-[3,4-Bis(3-methyl-2-butenyloxy)phenyl]methoxy-[1,1⁰-

biphenyl] - 6,3⁰- dicarboxylic acid (36c). Isolated as a

white solid (76% yield): chromatographed on C-18

silica gel using MeOH:water; mp=145 ^ꢀC (dec.); UV_max

(CHCl₃) 242 nM (E=20,264), 286 nM (E=6689); ¹H

NMR (300 MHz, CDCl₃) d 8.02 (ddd, J=2, 2, 8 Hz, 1H,

ArH), 7.89 (dd, J=2, 2 Hz, 1H, ArH), 7.59 (m, 2H,

ArH), 7.44 (dd, J=8, 8 Hz, 1H, ArH), 7.37 (dd, J=8,

8 Hz, 1H, ArH), 7.18 (dd, J=2, 8 Hz, 1H, ArH), 6.74 (d,

J=8 Hz, 1H, ArH), 6.43 (dd, J=2, 8 Hz, 1H, ArH),

6.00 (bs, 1H, ArH), 5.44 (m, 2H, CCH), 4.91 (s, 2H,

ArCH₂O), 4.50 (d, J=7 Hz, 2H, CCHCH₂O), 4.34 (d,

J=7 Hz, 2H, CCHCH₂O), 1.72 (s, 6H, 2ÂCH₃), 1.66

(s, 3H, CH₃), 1.65 (s, 3H, CH₃); ¹³C NMR (75 MHz,

CDCl₃) d 173.41 (CO), 172.29 (CO), 156.09, 148.90,

148.32, 137.61, 132.19, 137.09, 134.44, 131.62, 131.42,

130.94, 129.00, 128.92, 128.82, 127.66, 123.06, 120.25,

119.79, 119.09, 117.26, 113.67, 112.24, 70.71, 66.03,

65.70, 25.80, 18.20, 18.17; IR (KBr) 3400, 1690, 1510,

2-[4-(1-Adamantyl)-3-methoxyphenyl]methoxy-[1,1⁰-bi-

phenyl]-6,3⁰-dicarboxylic acid (36f). Isolated as a white

solid (51% yield): recrystallized from ether:CH₂Cl₂;

mp=245±250 ^ꢀC; UV_max(EtOH) 206 nM (E=49,943),

1

282 nM (E=5808); H NMR (300 MHz, CDCl₃) d 7.53

(d, J=8 Hz, 1H, ArH), 7.38±7.27 (m, 5H, ArH), 7.16 (d,

J=8 Hz, 1H, ArH), 7.07 (d, J=8 Hz, 1H, ArH), 6.67 (d,

J=8 Hz, 1H, ArH), 6.58 (s, 1H, ArH), 4.96 (s, 2H,

ArCH₂O), 3.91 (s, 3H, CH₃O), 2.02 (s, 9H, adamantyl),

1.73 (s, 6H, adamantyl); ¹³C NMR (75 MHz, CDCl₃) d

158.90 (CO), 156.15 (CO), 137.79, 136.58, 135.34,

132.61, 129.58, 128.41, 127.71, 127.07, 126.30, 122.66,

118.11, 116.77, 109.64, 70.28, 54.95, 40.51, 37.09, 36.70,

29.04; IR (KBr) 3420 (OH), 2905, 1690 (CO), 1585,

1410, 1268 cm ¹; MS (DCI) m/e 513 (MH⁺), 512 (M⁺),

495 (M OH), 255. Anal. (C₃₂H₃₂O₆) C, H.

3⁰-Carboxy-2-[4-(1-adamantyl)-3-methoxyphenyl]me-

thoxy-[1,1⁰-biphenyl]-6-acetic acid (36g). Isolated as a

white solid (81% yield): chromatographed on silica gel

using 10% MeOH:CH₂Cl₂; mp=240±242 ^ꢀC; UV_max

(EtOH) 206 nM (E=47,130), 280 nM (E=3760); ¹H

NMR (300 MHz, CDCl₃) d 8.03 (d, J=8 Hz, 1H, ArH),

8.01 (s, 1H, ArH), 7.55±7.45 (m, 2H, ArH), 7.34 (dd,

J=8, 8 Hz, 1H, ArH), 7.05 (d, J=8 Hz, 1H, ArH), 7.00

(d, J=8 Hz, 1H, ArH), 6.94 (d, J=8 Hz, 1H, ArH), 6.65

(d, J=8 Hz, 1H, ArH), 6.56 (s, 1H, ArH), 4.99 (s, 2H,

ArCH₂O), 3.55 (s, 3H, CH₃O), 3.47 (s, 2H, ArCH₂CO₂),

1.99 (s, 9H, adamantyl), 1.71 (s, 6H, adamantyl); ¹³C

NMR (75 MHz, CDCl₃) d 173.73 (CO), 168.55

(CO), 158.76, 155.95, 137.44, 137.20, 135.73, 134.69,

134.46, 131.57, 130.66, 128.61, 128.43, 127.99, 126.14,

122.88, 118.01, 111.25, 109.48, 69.62, 54.83, 40.45,

40.23, 39.95, 39.67, 38.88, 37.03, 36.68, 28.96; IR (KBr)

3400 (OH), 2920, 1720 (CO), 1680 (CO), 1560, 1523,

1250 cm ¹; MS (DCI) m/e 527 (M⁺), 255. Anal.

1430, 1300, 1255, 1220, 1130, 1000, 755 cm ¹; MS (DCI)

+

.

m/e 517 (MH ), 431 (M C₅H₉O). Anal. (C₃₁H₃₂O₇0.8

H₂O) C, H.

2-[(3,4-Biscyclopentyloxy)phenyl]methoxy-[1,1⁰-biphenyl]

-6,3⁰-dicarboxylic acid (36d). Isolated as a white solid

(48% yield): recrystallized from CH₂Cl₂:pentane;

mp=178±180 ^ꢀC; UV_max(CHCl₃) 242 nM (E=48,261),

284 nM (E=16,536); ¹H NMR (300 MHz, CDCl₃) d 8.01

(ddd, J=2, 2, 8 Hz, 1H, ArH), 7.90 (dd, J=2, 2 Hz, 1H,

ArH), 7.59 (m, 2H, ArH), 7.44 (dd, J=8, 8 Hz, 1H,

ArH), 7.38 (dd, J=8, 8 Hz, 1H, ArH), 7.18 (d, J=8 Hz,

1H, ArH), 6.74 (d, J=8 Hz, 1H, ArH), 6.63 (dd, J=2,

8 Hz, 1H, ArH), 6.58 (d, J=2 Hz, 1H, ArH), 4.90 (s,

2H, ArCH₂O), 4.66 (m, 1H, R₂CHOR), 4.50 (m, 1H,

R₂CHOR), 1.80±1.50 (m, 16H, cycloalkyl); ¹³C NMR

(75 MHz, CDCl₃) d 173.37 (CO), 172.25 (CO), 156.08,

148.96, 148.45, 137.20, 135.46, 131.48, 131.44, 130.94,

129.18, 128.98, 128.87, 126.68, 122.95, 119.37, 117.13,

116.52, 115.18, 81.12, 80.86, 70.62, 32.76, 32.71, 23.89,

23.84; IR (KBr) 3422, 2962, 2872, 1690, 1508, 1304,

1262cm ¹; MS (DCI) m/e 517 (MH⁺), 499 (M OH).

Anal. (C₃₁H₃₂O₇) C, H.

.

(C₃₃H₃₄O₆1.33 H₂O) C; H: calcd, 6.70; found, 6.29.

2-[(3,4-Bisdecyloxy)phenyl]methoxy-[1,1⁰-biphenyl]-6,3⁰-

dicarboxylic acid (36h). Isolated as a white solid (54%

yield): recrystallized from CHCl₃:pentane; mp=102±

104 ^ꢀC; UV_max(CHCl₃) 242 nM (E=19060), 286 nM

(E=6543); ¹H NMR (300 MHz, CDCl₃) d 8.02 (ddd,

J=2, 2, 8 Hz, 1H, ArH), 7.90 (dd, J=2, 2 Hz, 1H,

ArH), 7.60 (m, 2H, ArH), 7.44 (dd, J=8, 8 Hz, 1H,

ArH), 7.38 (dd, J=8, 8 Hz, 1H, ArH), 7.18 (d, J=8 Hz,

2-[(3,4-Biscyclopentyloxy)phenyl]methoxy -3⁰-carboxy-

[1,1⁰-biphenyl]-6-acetic acid (36e). Isolated as a white

solid (65% yield): chromatographed on reverse-phase

C-18 silica gel using methanol; mp=146±148 ^ꢀC; UV_max

1104

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1H, ArH), 6.73 (d, J=8Hz, 1H, ArH), 6.62 (dd, J=2,

8 Hz, 1H, ArH), 6.56 (d, J=2Hz, 1H, ArH), 4.90 (s, 2H,

ArCH₂O), 3.91 (t, J=7Hz, 2H, RCH₂O), 3.74 (t,

J=7Hz, 2H, RCH₂O), 1.74 (m, 4H, RCH₂CH₂O), 1.41

(m, 4H, decyl), 1.24 (m, 20H, decyl), 0.85 (m, 6H,

2ÂCH₃); ¹³C NMR (75 MHz, CDCl₃) d 173.40 (CO),

172.29 (CO), 156.09, 149.23, 148.59, 139.40, 137.23,

135.90, 131.47, 131.37, 130.92, 129.01, 128.98, 128.00,

123.50, 119.01, 117.21, 113.53, 112.05, 70.65, 69.33, 68.97,

>10:1 mixture of E:Z isomers) was dissolved in 50 mL

of ethanol, and 10% palladium on carbon (0.360 g,

0.338 mmol) was added. The suspension was hydro-

genated at 50 psi for 4 h. An aliquot was taken, and the

reaction judged to be only 30% complete by NMR

analysis. More catalyst (0.180 g, 0.169 mmol) was

added, and hydrogenation continued for another 18 h.

The analysis of an aliquot at this time indicated the

reaction was only 75% complete, and another portion

of catalyst (0.200 g, 0.188 mmol) was added. After a

further 5 h of hydrogenation, the reduction was com-

plete. The suspension was ®ltered through Celite, and

the ®lter cake washed with ethanol. The ®ltrate was

evaporated to dryness, and the residue ®ltered through a

pad of silica gel using CH₂Cl₂to aord the saturated

diester (2.10 g, 6.14 mmol, 87%): UV_max(EtOH) 206 nm

(E=32,090), 280 nM (E=3164); ¹H NMR (300 MHz,

CDCl₃) d 8.09 (d, J=8 Hz, 1H, ArH), 7.97 (s, 1H,

ArH), 7.57±7.50 (m, 2H, ArH), 7.18 (d, J=8 Hz, 1H,

ArH), 6.80 (m, 2H, ArH), 3.95 (s, 3H, CO₂CH₃), 3.70 (s,

3H, CO₂CH₃), 3.60 (s, 3H, OCH₃), 2.91 (t, J=7 Hz, 2H,

ArCH₂CH₂), 2.37 (t, J=7 Hz, 2H, CH₂CH₂CO₂); ¹³C

NMR (75 MHz, CDCl₃) d 173.12 (CO), 167.13

(CO), 156.97, 139.94, 137.30, 131.22, 131.13, 130.13,

129.73, 128.79, 128.27, 121.14, 108.87, 55.71, 52.09,

51.54, 34.94, 28.37; IR (KBr) 2950, 1740, 1720, 1589,

1470, 1300, 1260, 1235 cm ¹; MS (DCI) m/e 329

(MH⁺), 311 (M OH). Anal. (C₁₉H₂₀O₅) C, H.

31.91, 29.62, 29.47, 29.43, 29.37, 29.28, 26.08, 26.01, 22.69,

1

14.11; IR (®lm) 2924, 2854, 1694, 1514, 1468, 1262cm

MS (FAB) m/e 683 (MNa⁺). Anal. (C₄₁H₅₆O₇) C, H.

;

3⁰-Carboxy-2-[4-decyloxyphenyl]methoxy-[1,1⁰-biphenyl]-

6-acetic acid (36i). Isolated as a white solid (69% yield):

chromatographed on silica gel using CH₂Cl_2,then 10%

methanol:CH₂Cl₂; mp=130±131 ^ꢀC; UV_max(EtOH)

204 nM (E=39,538), 224 nM (E=31,401), 280 nm

(E=4138); ¹H NMR (300 MHz, CDCl₃) d 8.03 (d,

J=8 Hz, 1H, ArH), 8.00 (s, 1H, ArH), 7.55±7.45 (m, 2H,

ArH), 7.34 (dd, J=8, 8 Hz, 1H, ArH), 7.05 (d, J=8 Hz,

1H, ArH), 7.02±6.94 (m, 3H, ArH), 6.67 (d, J=8 Hz,

1H, ArH), 6.57 (s, 1H, ArH), 4.98 (s, 2H, ArCH₂O),

3.90 (t, J=7 Hz, 2H, ArOCH₂R), 3.36 (s, 2H,

ArCH₂CO₂), 1.80-1.67 (m, 2H, OCH₂CH₂R), 1.51±1.20

(m, 14H, R(CH₂)₇CH₃), 0.90 (t, J=7 Hz, 3H, CH₃C);

¹³C NMR (75 MHz, CDCl₃) d 178.20 (CO), 172.19

(CO), 158.66, 156.21, 137.10, 134.80, 133.90, 132.72,

131.26, 129.20, 129.06, 128.98, 128.84, 128.71, 128.59,

128.19, 123.32, 114.55, 114.33, 112.51, 70.20, 65.09,

40.09, 31.88, 29.55, 29.39, 29.31, 29.24, 26.16, 22.67,

14.11; IR (KBr) 3400 (OH), 2950, 2850, 1710 (CO),

1690 (CO), 1580, 1510, 1250 cm ¹; MS (DCI) m/e 510

The above saturated diester (2.90 g, 8.48 mmol) was

demethylated using general procedure D to aord phe-

nolic diester 38 as a white solid (2.10 g, 6.40 mmol, 76%):

chromatographed on silica gel using CH₂Cl₂:hexane,

then CH₂Cl₂, then 10% EtOAc:CH₂Cl₂; mp=98±99 ^ꢀC;

UV_max(EtOH) 206 nM (E=30,901), 284 nM (E=3178);

¹H NMR (300 MHz, CDCl₃) d 8.10±6.80 (m, 7H, ArH),

4.77 (s, 1H, OH), 3.90 (s, 3H, CO₂CH₃), 3.56 (s, 3H,

CO₂CH₃), 2.67 (t, J=8 Hz, 2H, ArCH₂CH₂), 2.36 (t,

J=8 Hz, 2H, CH₂CH₂CO₂); ¹³C NMR (75 MHz,

CDCl₃) d 173.08 (CO), 166.62 (CO), 152.95, 139.61,

135.31, 134.94, 131.45, 131.26, 129.51, 129.25, 127.04,

120.86, 113.60, 52.31, 51.58, 34.84, 28.43; IR (KBr) 3410,

1750, 1700, 1580, 1465, 1320, 1280, 1270 cm ¹; MS

(DCI) m/e 329 (MH⁺), 315, 283. Anal. (C₁₈H₁₈O₅) C, H.

+

.

(M ), 273, 255, 247. Anal. (C₃₂H₃₈O₆H₂O) C, H.

General procedure H. Wadsworth±Emmons ole®nation

of aldehydes: synthesis of 2-hydroxy-6-[methyl(3-pro-

panoate)]-1,1⁰-biphenyl-3⁰-carboxylic acid, methyl ester

(38). Aldehyde 8 (0.852g, 3.00mmol) was dissolved in

10mL of toluene, and methyl diethylphosphonoacetate

(0.840g, 4.00mmol) was added. A solution of 25% by

weight sodium methoxide in methanol (1.62 g, 7.50mmol)

was added and the mixture stirred at room temperature

for 18 h. The mixture was partitioned between saturated

aqueous ammonium chloride solution and ethyl acetate.

The aqueous phase was extracted twice with ethyl acetate,

and the combined extracts were washed with water and

brine. The organic phase was dried (MgSO₄), and evapo-

rated. The crude material was chromatographed on silica

gel using CH₂Cl₂:hexane to aord (E) and (Z) 2-methoxy-

6-[methyl(3-propenoate)]-1,1⁰-biphenyl-3⁰-carboxylic acid,

methyl ester (0.650 g, 2.01 mmol, 67%) as a >10:1 mix-

ture of E:Z isomers: Data for E isomer: ¹H NMR

(300 MHz, CDCl₃) d 8.05 (m, 1H, ArH), 7.93 (s, 1H,

ArH), 7.51±7.32 (m, 5H, ArH and CCH), 7.00 (d,

J=8 Hz, 1H, ArH), 6.31 (d, J=16 Hz, 1H, CCH),

3.90 (s, 3H, OCH₃), 3.71 (s, 3H, CO₂CH₃), 3.68 (s, 3H,

CO₂CH₃); ¹³C NMR (75 MHz, CDCl₃) d 167.01 (CO),

157.04, 143.06, 135.81, 135.23, 134.53, 131.83, 130.81,

129.99, 128.92, 128.71, 128.16, 119.46, 118.66, 112.06,

55.86, 52.05, 51.59.

Synthesis of 2-[3,4-bis(pentyloxy)phenyl]methoxy-3⁰-car-

bomethoxy-[1,1⁰-biphenyl]-6-propanoic acid, methyl ester

(39a). General procedure G was used to couple phenol

38 with (3,4-bispentyloxy)benzyl alcohol to aord di-

ester 39a (66% yield): chromatographed on silica gel

using CH₂Cl₂:hexane to aord a clear oil; UV_max

(EtOH) 206 nm (E=52,865), 280 nM (E=4838); ¹H

NMR (300 MHz, CDCl₃) d 8.06 (ddd, J=2, 2, 8 Hz, 1H,

ArH), 7.94 (d, J=2 Hz, 1H, ArH), 7.45±6.90 (m, 5H,

ArH), 6.70 (dd, J=2, 8 Hz, 1H, ArH), 6.62 (dd, J=2,

8 Hz, 1H, ArH), 6.55 (d, J=2 Hz, 1H, ArH), 4.87 (s,

2H, ArCH₂O), 3.95 (t, J=7 Hz, 2H, ArOCH₂R), 3.70

(t, J=7 Hz, 2H, ArOCH₂R), 3.90 (s, 3H, CO₂CH₃), 3.57

(s, 3H, CO₂CH₃), 2.72 (t, J=7 Hz, 2H, ArCH₂CH₂),

2.34 (t, J=7 Hz, 2H, CH₂CO₂CH₃), 1.80±0.87 (m, 18H,

pentyl); ¹³C NMR (75 MHz, CDCl₃) d 173.09 (CO),

166.99 (CO), 155.98, 149.13, 148.32, 139.98, 137.51,

134.80, 131.25, 130.49, 130.05, 129.71, 128.77, 128.17,

A mixture of the above diester (2.40 g, 7.06 mmol;

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1105

121.51, 118.79, 113.50, 111.91, 110.96, 70.04, 69.31,

68.84, 52.06, 51.55, 34.92, 28.98, 28.93, 28.39, 28.28,

22.51, 14.08; IR (KBr) 2950, 1740 (CO), 1730 (CO),

1580, 1530, 1425, 1250, 1235 cm ¹; MS (DCI) m/e 577

(MH⁺), 576 (M), 575, 263. Anal. (C₃₅H₄₄O₇) C, H.

(m, 5H, ArH), 4.88 (s, 2H, ArCH₂O), 3.90 (t, J=6 Hz,

2H, ArOCH₂), 3.72, (t, J=6 Hz, 2H, ArOCH₂), 2.71 (m,

2H, ArCH₂CH₂), 2.49 (m, 2H, ArCH₂CH₂CO₂), 1.80±

0.86 (m, 18H, pentyl); ¹³C NMR (75 MHz, CDCl₃) d

179.33 (C0), 172.33 (C0), 155.98, 149.18, 148.35,

139.75, 137.53, 135.81, 132.07, 130.45, 129.68, 129.14,

128.91, 128.77, 128.19, 121.31, 118.84, 113.57, 111.93,

110.94, 70.05, 69.34, 68.86, 35.15, 28.97, 28.91, 28.25,

28.18, 27.85, 22.46, 14.03; IR (KBr) 3450 (OH), 2950,

2860, 1700 (C0), 1270cm ¹; MS (DCI) m/e (M⁺-17),

Also obtained in this fashion were the following:

2-[3,4-Bis(3-methyl-2-butenyloxy)phenyl]methoxy-3⁰-car-

bomethoxy-[1,1⁰-biphenyl]-6-propanoic acid, methyl ester

(39b). 51% yield: chromatographed on silica gel using

CH₂Cl₂:hexane, then CH₂Cl₂to aord a clear oil;

UV_max(EtOH) 208 nM (E=59,871), 280 nM (E=4832);

¹H NMR (300MHz, CDCl₃) d 8.01 (ddd, J=2, 2, 8 Hz,

1H, ArH), 7.93 (d, J=2Hz, 1H, ArH), 7.49 (d, J=8Hz,

1H, ArH), 7.44 (s, 1H, ArH), 7.24 (d, J=8Hz, 1H, ArH),

6.95 (d, J=8 Hz, 1H, ArH), 6.86 (d, J=8Hz, 1H, ArH),

6.70 (d, J=8 Hz, 1H, ArH), 6.60 (m, 2H, ArH), 5.44 (m,

2H, 2ÂCCH), 4.87 (s, 2H, ArCH₂O), 4.51 (d, 2H,

J=7Hz, OCH₂R), 4.33 (d, 2H, J=7Hz, OCH₂R), 3.87 (s,

3H, CO₂CH₃), 3.56 (s, 3H, CO₂CH₃), 2.72 (t, 2H,

ArCH₂CH₂₎, 2.36 (t, 2H, CH₂CO₂CH₃), 1.74 (s, 3H, CH₃),

.

531, 269, 263. Anal. (C₃₃H₄₀O₇0.25 H₂O) C, H.

Also obtained in this fashion were the following:

2-[3,4-Bis(3-methyl-2-butenyloxy)phenyl]methoxy-3⁰-car-

boxy-[1,1⁰-biphenyl]-6-propanoic acid (37a). 83% yield:

chromatographed on reverse-phase C-18 silica gel using

methanol to aord a white solid; mp=142±143 ^ꢀC;

UV_max(EtOH) 208 nM (E=58,708), 280 nM (E=4999);

¹H NMR (300 MHz, CDCl₃) d 8.02 (m, 2H, ArH), 7.48

(m, 2H, ArH), 7.28 (d, J=8 Hz, 1H, ArH), 6.95 (d,

J=8 Hz, 1H, ArH), 6.92 (d, J=8Hz, 1H, ArH), 6.75 (d,

J=8Hz, 1H, ArH), 6.65 (m, 2H, ArH), 5.41 (m, 2H,

OCH₂CHC), 4.88 (s, 2H, ArCH₂O), 4.51 (d, J=6 Hz,

2H, O-CH₂C=C), 4.33 (d, J=6Hz, 2H, O-CH₂CC),

2.71 (m, 2H, ArCH₂CH₂) 2.45 (m, 2H, ArCH₂CO₂), 1.71

(s, 6H, 2ÂCH₃), 1.66 (s, 6H, 2ÂCH₃). ¹³C NMR

(75 MHz, CDCl₃) d 179.29 (CO), 172.29 (CO), 156.02,

148.86, 148.12, 139.75, 137.64, 137.49, 137.03, 135.79,

131.97, 130.45, 129.67, 129.19, 128.91, 128.83, 128.21,

121.36, 120.31, 119.83, 118.97, 113.75, 112.22, 111.06,

70.18, 66.06, 65.61, 35.12, 27.92, 25.79, 25.75, 18.18; IR

(KBr) 3430 (OH), 3540 (OH), 2900, 1680, (CO), 1580,

1510, 1260cm ¹; MS (DCI) m/e 545 (MH⁺), 537, 527,

1.72 (s, 3H, CH₃), 1.67 (s, 3H, CH₃), 1.64 (s, 3H, CH₃); ¹³

C

NMR (75 MHz, CDCl₃) d 173.07 (CO), 166.98 (CO),

156.00, 148.83, 148.10, 139.98, 137.54, 137.46, 136.99,

134.78, 131.25, 130.50, 130.06, 129.70, 128.76, 128.16,

121.54, 120.33, 119.94, 118.95, 113.67, 112.20, 111.04,

96.10, 70.15, 66.02, 65.67, 52.04, 51.53, 34.92, 28.40,

25.78, 18.20; IR (KBr) 2920, 1740 (CO), 1725 (CO),

1580, 1510, 1440, 1260, 1230 cm ¹; MS (DCI) m/e 573

(MH⁺), 572 (M), 315, 259. Anal. (C₃₅H₄₀O₇) C, H.

2-[3,4 - Bis(cyclopentyloxy)phenyl]methoxy-3⁰- carbome-

thoxy - [1,1⁰- biphenyl] - 6 - propanoic acid, methyl ester

(39c). 53% yield: chromatographed on silica gel using

CH₂Cl₂:hexane, then CH₂Cl₂to aord a clear oil;

UV_max(EtOH) 208 nm (E=55,184), 282 nM (E=4919);

¹H NMR (300 MHz, CDCl₃) d 8.04 (d, 1H, J=8 Hz,

ArH), 7.98 (s, 1H, ArH), 7.51 (d, J=8 Hz, 1H, ArH),

7.46 (s, 1H, ArH), 7.27 (d, J=8 Hz, 1H, ArH), 6.89 (d,

J=8 Hz, 1H, ArH), 6.86 (d, J=8 Hz, 1H, ArH), 6.77 (d,

J=8 Hz, 1H, ArH), 6.64 (d, J=8 Hz, 1H, ArH), 6.60 (s,

1H, ArH), 4.90 (s, 2H, ArCH₂O), 4.69 (m, 1H,

R₂CHOR), 4.45 (m, 1H, R₂CHOR), 3.91 (s, 3H,

CO₂CH₃), 3.59 (s, 3H, CO₂CH₃), 1.81±1.58 (m, 16H,

cyclopentyl), 2.75 (t, J=8 Hz, 2H, ArCH₂CH₂), 2.39 (t,

J=8 Hz, 2H, CH₂CO₂CH₃); ¹³C NMR (75 MHz,

CDCl₃) d 173.03 (CO), 166.96 (CO), 155.99, 148.86,

148.20, 139.98, 137.53, 134.85, 131.23, 130.42, 129.90,

128.78, 128.18, 121.47, 119.14, 116.2, 115.03, 110.88,

81.06, 80.67, 69.98, 52.04, 51.50, 34.92, 32.89, 28.41,

24.06; IR (KBr) 2960, 1740 (CO), 1725 (CO), 1580,

1508, 1435, 1260, 1220 cm ¹; MS (DCI) m/e 573

(MH⁺), 572 (M), 517, 505, 259. Anal. (C₃₅H₄₀O₇) C, H.

.

289, 269, 259. Anal. (C₃₃H₃₆O₇H₂O) C, H.

2- [3,4- Bis(cyclopentyloxy)phenyl]methoxy- 3⁰- carboxy -

[1,1⁰-biphenyl]-6-propanoic acid (40c). 90% yield: chro-

matographed on reverse-phase C-18 silica gel using

methanol to aord a white solid; mp=148±150 ^ꢀC;

UV_max(EtOH) 208 nM (E=55,091), 280 nM (E=4755);

¹H NMR (300 MHz, CDCl₃) d 8.03 (m, 2H, ArH), 7.46±

7.27 (m, 3H, ArH), 6.90 (d, J=8 Hz, 1H, ArH), 6.87 (d,

J=8 Hz, 1H, ArH), 6.74 (d, J=6 Hz, 1H, ArH), 6.25 (dd,

J=2, 8 Hz, 1H, ArH), 6.57 (d, J=2 Hz, 1H, ArH), 4.87

(s, 2H, ArCH₂O), 4.65±4.48 (m, 2H, 2ÂR₂CHOAr), 2.75

(m, 2H, ArCH₂CH₂), 2.46 (m, 2H, ArCH₂CH₂CO₂),

1.78±1.54 (m, 16H, cyclopentyl); ¹³C NMR (75 MHz,

CDCl₃) d 179.44 (CO), 172.46 (CO), 156.13, 149.02,

148.35, 139.88, 137.65, 135.96, 132.13, 130.51, 129.99,

129.27, 129.03, 128.91, 128.35, 121.40, 119.32, 116.72,

115.20, 111.03, 81.28, 80.89, 70.17, 35.23, 32.89, 28.02,

24.02, 23.96; IR (KBr) 3450 (OH), 2960, 1700 (CO),

1430, 1265 cm ¹; MS (DCI) m/e 545 (MH⁺), 544 (M⁺),

.

527 (M H₂O), 269, 259. Anal. (C₃₃H₃₆O₇0.10 H₂O) C, H.

Synthesis of 2-[3,4-bis(pentyloxy)phenyl]methoxy-3⁰-car-

boxy-[1,1⁰-biphenyl]-6-propanoic acid (40a). Diester 39a

was hydrolyzed using general procedure F to aord diacid

40a (66% yield): chromatographed on reverse-phase C-18

silica gel using methanol to aord a white solid; mp=145±

146 ^ꢀC; UV_max(EtOH) 206 nM (E=59,315), 280 nM

Synthesis of 2-[(3,4-bispentyloxy)phenyl]methoxy-3⁰-car-

boethoxy-[1,1⁰-biphenyl]-6-carboxaldehyde (41a). Alde-

hyde 8 was demethylated using general procedure D to

aord the corresponding phenol (75% yield): chroma-

tographed on silica gel using EtOAc:CH₂Cl₂; mp=185±

192 ^ꢀC; UV_max(EtOH) 222 nM (E=22,861), 328 nM

1

(E=4818); H NMR (300 MHz, CDCl₃) d 8.02 (m, 2H,

ArH), 7.50 (m, 2H, ArH), 7.27 (m, 1H, ArH), 6.95±6.55

1

(E=2822); H NMR (300 MHz, CDCl₃) d 9.72 (s, 1H,

1106

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

CHO), 8.20 (dd, J=2, 8 Hz, 1H, ArH), 8.06 (d, J=2 Hz,

1H, ArH), 7.67±7.25 (m, 5H, ArH), 5.04 (s, 1H, OH),

4.41 (q, J=7 Hz, 2H, CO₂CH₂), 1.38 (t, J=7 Hz, 3H,

CO₂CH₂CH₃); ¹³C NMR (75 MHz, CDCl₃) d 191.43

(CO), 165.86 (CO), 153.24, 135.06, 134.89, 132.15,

131.62, 130.01, 129.58, 129.42, 121.25, 120.57, 61.45,

14.29; IR (KBr) 3200, 1720, 1670, 1580, 1290,

1240 cm ¹; MS (DCI) m/e 271 (MH⁺), 253, 225.

¹³C NMR (300 MHz, CDCl₃) d 167.02 (CO), 166.88

(CO), 156.10, 149.20, 149.04, 143.01, 136.05, 134.60,

132.46, 131.02, 131.59, 130.17, 129.96, 129.30, 128.91,

128.65, 128.09, 119.46, 119.07, 114.82, 113.76, 112.10,

70.34, 69.29, 68.92, 52.09, 51.59, 29.07, 28.99, 28.27,

28.22, 22.51, 22.48, 14.07; IR (KBr) 2960, 2870, 1750,

1690, 1510, 1280, 1200 cm ¹; MS (DCI) m/e 575 (MH⁺),

.

543, 295, 263. Anal. (C₃₅H₄₂O₇0.25 H₂O) C, H.

The above phenolic aldehyde was coupled to (3,4-bis-

pentyloxy)benzyl alcohol using general procedure G to

aord aldehyde 41a (49% yield): chromatographed on

silica gel using CH₂Cl₂:hexane to aord an oil: ¹H NMR

(300 MHz, CDCl₃) d 9.75 (s, 1H, CHO), 8.13-8.10 (m,

1H, ArH), 8.09 (s, 1H, ArH), 7.65 (dd, J=2, 8 Hz, 1H,

ArH), 7.55±7.40 (m, 3H, ArH), 7.27 (dd, J=2, 8 Hz, 1H,

ArH), 6.80±6.65 (m, 3H, ArH), 4.98 (s, 2H, ArCH₂O),

4.39 (q, J=7 Hz, 2H, CO₂CH₂), 3.92 (t, J=6 Hz, 2H,

OCH₂CH₂R), 3.79 (t, J=6 Hz, 2H, OCH₂CH₂R), 1.82±

1.75 (m, 4H, OCH₂CH₂R), 1.45±1.36 (m, 11H,

2ÂRCH₂CH₂CH₃and CO₂CH₂CH₃), 0.94 (m, 6H,

2ÂCH₃); ¹³C NMR (75 MHz, CDCl₃) d 191.83 (CO),

166.19 (CO), 149.22, 148.50, 135.31, 134.44, 133.76,

132.01, 130.36, 129.13, 129.08, 129.00, 128.92, 127.99,

119.79, 119.18, 118.23, 113.56, 112.27, 70.66, 69.30,

69.01, 61.14, 28.98, 28.19, 22.47, 14.30, 14.03.

Also obtained in this fashion were the following:

(E)-2-[3,4-Bis(3-methyl-2-butenyloxy)phenyl]methoxy-6-

[methyl(3-propenoate)]-1,1⁰-biphenyl-3⁰-carboxylic acid,

methyl ester (42b). 36% yield: chromatographed on

silica gel using CH₂Cl₂:hexane to aord an oil; UV_max

(EtOH) 206 nM (E=64,456), 232 nM (E=38,475),

284 nM (E=19,713); ¹H NMR (300 MHz, CDCl₃) d 8.05

(d, J=8 Hz, 1H, ArH), 8.00 (s, 1H, ArH), 7.51±7.06 (m,

5H, ArH and CCH), 6.79 (d, J=8 Hz, 1H, ArH), 6.70±

6.60 (m, 3H, ArH), 6.37 (d, J=16 Hz, 1H, CCH), 5.49

(m, 2H, 2ÂOCH₂CHC), 4.92 (s, 2H, ArCH₂O), 4.55 (d,

J=6 Hz, 2H, OCH₂CHC), 4.39 (d, J=6 Hz, 2H,

OCH₂CHC), 3.90 (s, 3H, CO₂CH₃), 3.69 (s, 3H,

CO₂CH₃), 1.75 (s, 6H, 2ÂCH₃), 1.66 (s, 6H, 2ÂCH₃);

¹³C NMR (75 MHz, CDCl₃) d 167.02 (CO), 166.87

(CO), 156.09, 148.86, 148.27, 143.02, 137.56, 137.09,

136.00, 135.51, 134.56, 131.93, 131.55, 129.95, 129.29,

128.92, 128.66, 128.08, 120.27, 119.92, 119.45, 119.15,

119.08, 114.34, 113.66, 112.34, 70.28, 65.93, 65.64,

52.09, 51.59, 25.77, 18.19; IR (KBr) 2900, 1730 (CO),

1663 (CO), 1510, 1430, 1255, 1230 cm ¹; MS (DCI) m/

e 571 (MH⁺), 539, 503, 471, 449, 435, 313, 259. Anal.

Also obtained in this fashion were the following:

2-[3,4-Bis(3-methyl-2-butenyloxy)phenyl]methoxy-3⁰-car-

boethoxy-[1,1⁰-biphenyl]-6-carboxaldehyde (41b). 49%

yield: chromatographed on silica gel using CH₂Cl₂:hex-

ane to aord an oil; ¹H NMR (300 MHz, CDCl₃) d 9.75

(s, 1H, CHO), 8.15±8.05 (m, 2H, ArH), 7.76±7.25 (m,

5H, ArH), 6.81±6.60 (m, 3H, ArH), 5.48 (m, 2H,

2ÂCCH), 4.99 (s, 2H, ArCH₂O), 4.54 (q, J=7 Hz, 2H,

CO₂CH₂), 4.39 (m, 4H, 2ÂOCH₂CC), 1.70 (s, 6H,

2ÂCH₃), 1.69 (s, 3H, CH₃), 1.66 (s, 3H, CH₃), 1.38 (t,

J=7 Hz, 3H, CO₂CH₂CH₃).

.

(C₃₅H₃₆O₇0.1 CH₂Cl₂) C, H.

(E)-2-[(3,4-Biscyclopentyloxy)phenyl]methoxy-6-[methyl(3-

propenoate)]-1,1⁰-biphenyl-3⁰-carboxylic acid, methyl ester

(42c). 57% yield: chromatographed on silica gel using

1

CH₂Cl₂:hexane to aord an oil; H NMR (300 MHz,

CDCl₃) d 8.09 (d, J=8 Hz, 1H, ArH), 7.99 (s, 1H, ArH),

7.46±7.04 (m, 6H, ArH and CCH), 6.79 (d, J=8 Hz,

1H, ArH), 6.68 (d, J=8 Hz, 1H, ArH), 6.63 (s, 1H, ArH),

6.37 (d, J=13 Hz, 1H, CCH), 3.93 (s, 2H, ArCH₂O),

4.69±4.52 (m, 2H, 2ÂR₂CHOR), 3.90 (s, 3H, CO₂CH₃),

3.70 (s, 3H, CO₂CH₃), 1.82-1.58 (m, 16H, cyclopentyl);

¹³C NMR (75 MHz, CDCl₃) d 167.03 (CO), 166.88

(CO), 156.91, 148.86, 148.36, 143.04, 136.03, 135.34,

134.59, 131.89, 131.52, 129.94, 129.47, 128.91, 128.64,

128.09, 119.44, 119.33, 119.03, 116.49, 115.18, 114.22,

81.06, 80.79, 70.29, 52.09, 51.59, 32.77, 23.90.

2-[(3,4-Biscyclopentyloxy)phenyl]methoxy-3⁰-carboethoxy-

[1,1⁰-biphenyl]-6-carboxaldehyde (41c). 41% yield: chro-

matographed on silica gel using CH₂Cl₂:hexane, then

1

CH₂Cl₂, then 5% EtOAc:CH₂Cl₂to aord an oil; H

NMR (300 MHz, CDCl₃) d 9.74 (s, 1H, CHO), 8.15±7.66

(m, 10H, ArH), 4.98 (s, 2H, ArCH₂O), 4.70 (b, 2H,

2ÂR₂CHOR), 4.35 (q, J=7 Hz, 2H, CO₂CH₂), 1.82±1.58

(m, 16H, cyclopentyl), 1.38 (t, J=7Hz, 3H, CO₂CH₂

CH₃).

Synthesis of (E)-2-[(3,4-bispentyloxy)phenyl]methoxy-6-

[methyl(3-propenoate)]-1,1⁰-biphenyl-3⁰-carboxylic acid,

methyl ester (42a). Aldehyde 41a was converted to di-

ester 42a using general procedure H (63% yield): chro-

matographed on silica gel using CH₂Cl₂:hexane to aord

an oil; UV_max(EtOH) 208 nM (E=47,562), 232 nm

Synthesis of 2-[(3,4-bis(pentyloxy)phenyl]methoxy-3⁰-car-

boxy-[1,1⁰-biphenyl]-6-[(E)-3-propenoic acid] (43a). Di-

ester 42a was hydrolyzed using general procedure F to

aord diacid 43a (73% yield): recrystallized using ether:

hexane; mp=191±193 ^ꢀC; UV_max(EtOH) 206 nM

(E=49,197), 232 nm (E=36,853), 282 nM (E=20,355); ¹H

NMR (300MHz, CDCl₃) d 8.00 (ddd, J=2, 2, 8 Hz, 1H,

ArH), 7.91 (dd, J=2, 2 Hz, 1H, ArH), 7.43±7.27 (m, 5H,

ArH and CHCHCO₂H), 7.01 (dd, J=4, 8 Hz, 1H,

ArH), 6.69 (d, J=8 Hz, 1H, ArH), 6.61 (dd, J=2, 8 Hz,

1H, ArH), 6.55 (d, J=2 Hz, 1H, ArH), 6.22 (d, J=16 Hz,

1H, CHCHCO₂H), 4.87 (s, 2H, ArCH₂O), 3.93±3.66

(m, 4H, 2ÂRCH₂O), 1.76±0.82 (m, 18H, pentyl); ¹³C

1

(E=36,190), 284 nM (E=19,436); H NMR (300 MHz,

CDCl₃) d 8.08 (d, J=8 Hz, 1H, ArH), 7.98 (s, 1H, ArH),

7.51±7.34 (m, 6H, ArH and CCH), 7.06 (dd, J=5, 5 Hz,

1H, ArH), 6.61 (s, 1H, ArH), 6.37 (d, J=16 Hz, 1H,

CCH), 4.94 (s, 2H, ArCH₂O), 3.97 (t, J=7Hz, 2H,

OCH₂R), 3.95 (s, 3H, OCH₃), 3.77 (t, J=7Hz, 2H,

OCH₂R), 3.70 (s, 3H, OCH₃), 1.81±0.90 (m, 18 H, pentyl);

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1107

NMR (75 MHz, CDCl₃) d 169.11 (CO), 168.92 (CO),

155.98, 149.05, 148.37, 143.69, 135.91, 135.43, 134.52,

132.26, 131.53, 130.05, 129.39, 128.87, 127.96, 119.74,

119.16, 119.09, 118.75, 114.35, 113.60, 112.15, 70.31,

69.35, 68.99, 28.87, 28.81, 28.16, 28.10, 22.40, 13.93; IR

(KBr) 3400 (OH), 2950, 1685 (C0), 1625, 1513, 1257,

1140 cm ¹; MS (DCI) m/e 547 (MH⁺), 529 (M OH),

another 20 h. The mixture was poured into water and

EtOAc, and the aqueous phase was extracted with

EtOAc. The combined extracts were washed with brine,

dried (MgSO₄), and concentrated. The crude material

was chromatographed using EtOAc:hexane (5%±10%±

20%) to aord diester 44 (0.694 g, 1.32 mmol, 64%) as a

clear oil: UV_max(CHCl₃) 242 nM (E=31,760), 286 nM

(E=23,380), 656 nM (E=4992); ¹H NMR (300 MHz,

CDCl₃) d 8.06 (ddd, J=2, 2, 8 Hz, 1H, ArH), 7.98 (dd,

J=2, 2 Hz, 1H, ArH), 7.50 (dd, J=8, 8 Hz, 1H, ArH),

7.43 (m, 1H, ArH), 7.41 (d, J=16 Hz, 1H, CCH), 7.33

(m, 2H, ArH), 7.17 (d, J=8Hz, 1H, ArH), 7.06 (dd, J=2,

8 Hz, 1H, ArH), 7.00 (d, J=2Hz, 1H, ArH), 6.90 (dd,

J=2, 8 Hz, 1H, ArH), 6.32 (d, J=16 Hz, 1H, CCH),

4.95 (s, 2H, ArCH₂O), 4.34 (q, J=7Hz, 2H, CO₂CH₂),

3.68 (s, 3H, CO₂CH₃), 1.61 (s, 4H, CH₂CH₂), 1.35 (t,

J=7Hz, 3H, CO₂CH₂CH₃), 1.21 (s, 6H, 2ÂCH₃), 1.10 (s,

6H, 2ÂCH₃); ¹³C NMR (75 MHz, CDCl₃) d 167.07

(CO), 166.48 (CO), 156.27, 144.89, 144.23, 143.37,

143.09, 135.93, 135.15, 134.66, 133.58, 131.79, 131.63,

130.35, 128.89, 128.78, 128.16, 126.47, 124.52, 123.73,

119.44, 118.95, 113.90, 70.28, 60.94, 51.61, 34.98, 34.16,

34.06, 31.80, 31.68, 14.33; IR (®lm) 2958, 2928, 1720,

1636, 1570, 1460, 1294, 1258, 1230, 1170 cm ¹; MS

(DCI) m/e 527 (MH⁺), 495 (M CH₃O), 481

(M C₂H₅O), 201 (C₁₅H₂⁺₁). HRMS (FAB) m/e 549.2611

[(M+Na)⁺calcd for C₃₄H₃₈O₅Na: 549.2617].

.

299, 281, 267. Anal. (C₃₃H₃₈O₇0.5 H₂O) C, H.

Also obtained in this fashion were the following:

2-[3,4-Bis(3-methyl-2-butenyloxy)phenyl]methoxy-3⁰-car-

boxy-[1,1⁰-biphenyl]-6-[(E)-3-propenoic acid] (43b). 70%

yield: recrystallized using CH₂Cl₂:hexane; mp=175±

179 ^ꢀC; UV_max(EtOH) 208 nM (E=55,237), 232 nM

1

(E=36,495), 282 nM (E=18,975); H NMR (300 MHz,

CDCl₃) d 7.96 (d, J=8 Hz, 1H, ArH), 7.83 (s, 1H,

ArH), 7.44 (dd, J=8, 8 Hz, 1H, ArH), 7.35±7.24 (m,

4H, ArH and CHCHCO₂H), 7.07 (d, J=8 Hz, 1H,

ArH), 6.74±6.61 (m, 3H, ArH), 6.26 (d, J=16 Hz, 1H,

CCHCO₂H), 5.33 (m, 2H, 2ÂOCH₂CHC), 4.86 (s,

2H, ArCH₂O), 4.47 (d, J=6 Hz, 2H, OCH₂CHC), 4.34

(d, J=6 Hz, 2H, OCH₂CHC), 1.66 (s, 6H, 2ÂCH₃),

1.61 (s, 6H, 2ÂCH₃); ¹³C NMR (75 MHz, CDCl₃) d

169.82, (CO), 169.51 (CO), 156.68, 149.36, 148.70,

143.85, 138.52, 138.14, 136.76, 135.85, 132.79, 131.26,

130.46, 129.56, 129.33, 128.53, 120.68, 120.58, 120.25,

120.08, 119.74, 115.11, 114.77, 113.31, 70.91, 66.72,

66.36, 25.94, 25.92, 18.34, 18.30; IR (KBr) 3240 (OH),

2900, 1680 (CO), 1630, 1510, 1250 cm ¹; MS (DCI) m/

Synthesis of 3⁰-carboxy-2-[5,6,7,8-tetrahydro-5,5,8,8-

tetramethyl-2-naphthalenyl]methoxy-[1,1⁰-biphenyl]-6-

propanoic acid (45). Diester 44 (0.629 g, 1.20 mmol) was

dissolved in 10mL of EtOAc, and 10% palladium on

carbon (0.100g, 0.094 mmol) was added. The suspension

was hydrogenated using a balloon of hydrogen for 3.5 h.

The mixture was ®ltered through a pad of Florisil, eluting

with ether and ethyl acetate. The ®ltrate was evaporated,

and the crude material was chromatographed on silica gel

using 5% EtOAc:hexane to yield 3⁰-carboethoxy-2-

[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]

methoxy-[1,1⁰-biphenyl]-6-[3-propanoic acid], methyl ester

(0.608 g, 1.15 mmol, 96%) as a clear oil: UV_max(CHCl₃)

242 nM (E=9776), 278 nM (E=3210); ¹H NMR

(300 MHz, CDCl₃) d 8.04 (ddd, J=2, 2, 8 Hz, 1H, ArH),

7.97 (dd, J=2, 2 Hz, 1H, ArH), 7.45 (m, 2H, ArH), 7.28

(dd, J=8, 8 Hz, 1H, ArH), 7.16 (d, J=8 Hz, 1H, ArH),

6.97 (d, J=2 Hz, 1H, ArH), 6.93 (d, J=3 Hz, 1H, ArH),

6.90 (d, J=3 Hz, 1H, ArH), 6.86 (dd, J=2, 8 Hz, 1H,

ArH), 4.91 (s, 2H, ArCH₂O), 4.35 (q, J=7 Hz, 2H,

CO₂CH₂), 3.57 (s, 3H, CO₂CH₃), 2.73 (dd, J=8, 8 Hz,

2H, ArCH₂CH₂CO₂), 2.39 (dd, J=8, 8 Hz, 2H, ArCH_2-

CH₂CO₂), 1.61 (s, 4H, CH₂CH₂), 1.36 (t, J=7 Hz, 3H,

CO₂CH₂CH₃), 1.21 (s, 6H, 2ÂCH₃), 1.09 (s, 6H,

2ÂCH₃); ¹³C NMR (75 MHz, CDCl₃) d 173.15 (CO),

166.60 (CO), 156.16, 144.81, 144.03, 140.06, 137.40,

134.67, 133.95, 131.14, 130.54, 130.47, 128.77, 128.34,

128.25, 126.36, 124.43, 123.63, 121.41, 110.60, 69.97,

60.92, 51.55, 34.99, 34.15, 34.03, 31.80, 31.66, 28.42,

14.33; IR (®lm) 2958, 2928, 1738, 1718, 1580, 1456,

1364, 1296, 1258, 1230, 1080, 758 cm ¹; MS (DCI) m/e

529 (MH⁺), 483 (M C₂H₅O), 201 (C₁₅H₂⁺₁). Anal.

(C₃₄H₄₀O₅) C, H.

.

e 517, 267, 259. Anal. (C₃₃H₃₄O₇0.75 H₂O) C, H.

2-[(3,4-Bis(cyclopentyloxy)phenyl]methoxy-3⁰-carboxy-

[1,1⁰-biphenyl]-6-[(E)-3-propenoic acid] (43c). 75% yield:

recrystallized using ether:hexane; mp=215±216 ^ꢀC;

UV_max(EtOH) 208 nM (E=47,271), 232 nm (E=35,149),

282 nM (E=18,855); ¹H NMR (300 MHz, CDCl₃) d 8.05

(ddd, J=2, 2, 8 Hz, 1H, ArH), 7.91 (dd, J=2, 2 Hz, 1H,

ArH), 7.51±7.31 (m, 5H, ArH and CHCHCO₂H), 7.14

(dd, J=2, 8 Hz, 1H, ArH), 6.79 (d, J=6 Hz, 1H, ArH),

6.68 (dd, J=2, 6 Hz, 1H, ArH), 6.61 (d, J=2 Hz, 1H,

ArH), 6.35 (d, J=16 Hz, 1H, CCHCO₂H), 4.92 (s,

2H, ArCH₂O), 4.70±4.68 (m, 1H, R₂CHOAr) 4.52±4.49

(m, 1H, R₂CHOAr) 1.77±1.56 (m, 16H, cyclopentyl);

¹³C NMR (75 MHz, CDCl₃) d 172.70 (CO), 172.33

(CO), 159.92, 152.48, 151.80, 146.90, 140.24, 139.09,

138.22, 135.73, 135.35, 134.43, 133.94, 132.80, 132.33,

131.78, 123.57, 123.24, 122.65, 120.27, 118.65, 118.11,

84.95, 84.47, 73.72, 36.18, 27.42, 27.31; IR (KBr) 3420,

2960, 1685, 1630, 1250 cm ¹; MS (DCI) m/e 543

(MH⁺), 457 (M C₄H₈O), 281, 267, 259. Anal.

.

(C₃₃H₃₄O₇0.75 H₂O) H; C, calcd, 71.46; found, 71.04.

Synthesis of 3⁰-carboethoxy-2-[5,6,7,8-tetrahydro-5,5,8,8

-tetramethyl-2-naphthalenyl]methoxy-[1,1⁰-biphenyl]-6-

[(E)-3-propenoic acid], methyl ester (44). Aldehyde 27

(0.965 , 2.05 mmol) was dissolved in 15.6 mL of CH₂Cl₂,

and methyl(triphenylphosphoranylidene)acetate (2.74 g,

8.20mmol) is added. The mixture was stirred at room

temperature for 24h. Thin-layer chromatographic analy-

sis at this time indicated the reaction was incomplete. More

methyl(triphenylphosphoranylidene)acetate (0.246g,

0.736 mmol) was added and stirring continued for

The above saturated diester (0.548 g, 1.04 mmol) was

1108

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

hydrolyzed using general procedure F to aord diacid

45 (0.306 g, 0.630 mmol, 61%) as a white solid: recrys-

tallized from CH₂Cl₂:pentane; mp=160±161 ^ꢀC; UV_max

(CHCl₃) 242 nM (E=11,222), 278 nM (E=3474); ¹H

NMR (300 MHz, CDCl₃) d 8.04 (m, 2H, ArH), 7.49 (m,

2H, ArH), 7.29 (dd, J=8, 8 Hz, 1H, ArH), 7.15 (d,

J=8 Hz, 1H, ArH), 6.98 (d, J=2 Hz, 1H, ArH), 6.93 (d,

J=8 Hz, 1H, ArH), 6.91 (d, J=8 Hz, 1H, ArH), 6.85 (dd,

J=2, 8 Hz, 1H, ArH), 4.91 (s, 2H, ArCH₂O), 2.72 (m,

2H, ArCH₂CH₂CO₂), 2.49 (m, 2H, ArCH₂CH₂CO₂),

1.59 (s, 4H, CH₂CH₂), 1.20 (s, 6H, 2ÂCH₃), 1.08 (s, 6H,

2xCH₃); ¹³C NMR (75 MHz, CDCl₃) d 179.38 (CO),

172.41 (CO), 156.14, 145.85, 144.85, 144.05, 139.77,

137.49, 135.78, 133.87, 132.05, 130.40, 129.23, 128.90,

128.30, 126.37, 124.46, 123.66, 121.19, 110.61, 70.00,

176. (d) Pruzanski, W.; Vadas, P. Immunology Today 1991, 12,

143. (e) Vadas, P.; Pruzanski, W. Lab. Invest. 1986, 55, 391.

2. Henderson, Jr., W. R. Am. Rev. Respir. Dis. 1991, 143, S86.

3. Pruzanski, W.; Vadas, P. J. Rheumatol 1988, 15, 1601.

4. Forster, S.; Ilderton, E.; Norris, J. F.; Summerly, R.;

Yardley, H. J. Br. J. Dermatol 1985, 112, 135.

5. ; Nevalainen, T. Scand. J. Gastroenterol 1980, 15, 641.

6. (a) Gregson, N. A. Biochem. Soc. Trans. 1989, 17, 280. (b)

Trotter, J.; Smith, M. A. Clin. Biol. Res. 1984, 146, 55.

7. Vadas, P. J. Lab. Clin. Med. 1984, 104, 873±881.

8. Ford, D. A.; Hazen, S. L.; Satz, J. E.; Gross, R. W. J.

Clin. Invest. 1991, 88, 331.

9. Van den Bosch, H. Biochim. Biophys. Acta 1980, 604, 191.

10. Axelrod, J. Chem. Senses 1989, 1, 1; Brand, J. G. Ed.;

Dekker: New York.

11. Di Marzo, V.; Galadari, S. H. I.; Tippins, J. R.; Morris, H.

R. Life Sci. 1991, 49, 247.

35.13, 34.99, 34.13, 34.03, 31.79, 31.65, 27.87; IR (KBr)

1

12. Arita, H.; Hanasaka, K.; Nakano, T.; Oka, S.; Teroka, H.;

Matsumoto, K. J. Biol. Chem. 1991, 266, 19139.

13. Gupta, C. Proc. Soc. Exp. Biol. Med. 1988, 188, 489.

14. Fry, M. R.; Ghosh, S. S.; East, J. M.; Franson, R. C.

Biology Of Reproduction 1992, 47, 751.

3414, 2960, 2928, 1704, 1580, 1458, 1260, 1078 cm

;

MS (DCI) m/e 487 (MH⁺), 469 (M OH), 201 (C₁₅H₂⁺₁).

.

Anal. (C₃₁H₃₄O₅0.7 H₂O) C, H.

Synthesis of 3⁰-carboxy-2-[5,6,7,8-tetrahydro-5,5,8,8-

tetramethyl-2-naphthalenyl]methoxy-[1,1⁰-biphenyl]-6-[(E)-

3-propenoic acid] (46). Diester 44 (0.246 g, 0.467 mmol)

was hydrolyzed using general procedure F to aord di-

acid 46 (0.194 g, 0.401 mmol, 86%) as a white solid:

recrystallized from EtOAc:hexane; mp=247±249 ^ꢀC;

UV_max(EtOH) 204 nM (E=34,000), 220 nM (E=30,186),

15. Elsbach, P.; Weiss, J. Biochem. Biophys. Acta 1988, 947,

29.

16. Regelson, W.; Franson, R. Ann. N.Y. Acad. Sci. 1991, 621,

262.

17. (a) Clark, J. D.; Milona, N.; Knopf, J. L. Proc. Natl. Acad.

Sci. USA 1990, 87, 7708. (b) Kramer, R. M.; Roberts, E. F.;

Manetta, J.; Putnam, J. E. J. Biol. Chem. 1991, 266, 5268. (c)

Clark, J. D.; Lin, L.-L.; Kriz, R. W.; Ramesha, C. S.; Sultz-

man, L. A.; Lin, A. Y.; Milona, N.; Knopf, J. L. Cell 1991, 65,

1043. (d) Sharp, J. D.; White, D. L.; Chiou, X. G.; Goodson,

T.; Gamboa, G. C.; McClure, D.; Burgett, S.; Hoskins, J.;

Skatrud, P. L.; Sportsman, J. R.; Becker, G. W.; Kang, L.H.;

Roberts, E. F.; Kramer, R. M. J. Biol. Chem. 1991, 266,

14850.

18. (a) Hazen, S. L.; Hall, C. R.; Ford, D. A.; Gross, R. W. J.

Clin. Invest. 1993, 91, 2513. (b) Hazen, S. L.; Gross, R. W.

Biochem. J. 1991, 280, 581.

19. Nishijima, J.; Okamoto, M.; Ogawa, M.; Kosaki, G.;

Yamano, T. J. Biochem. 1983, 94, 137.

20. (a) Hara, S.; Kudo, I.; Chang, H. W.; Matsuta, K.;

Miyamoto, T.; Inoue, K. J. Biochem. 1989, 105, 395. (b) Seil-

hamer, J. J.; Pruzanski, W.; Vadas, P.; Plant, S.; Miller, J. A.;

Kloss, J.; Johnson, L. K. J. Biol. Chem. 1989, 264, 5335. (c)

Kramer, R. M.; Hession, C.; Johansen, B.; Hayes, G.;

McGray, P.; Chow, E. P.; Tizard, R.; Pepinsky, R. B. J. Biol.

Chem. 1989, 264, 5768.

1

280 nM (E=15,343); H NMR (300 MHz, DMSO-d₆) d

12.70 (b, 2H, 2ÂCO₂H), 7.97 (bd, J=8 Hz, 1H, ArH),

7.79 (s, 1H, ArH), 7.61±7.40 (m, 4H, ArH), 7.27 (d,

J=8 Hz, 1H, ArH), 7.19 (d, J=8 Hz, 1H, ArH), 7.15 (d,

J=16 Hz, 1H, CCH), 7.03 (s, 1H, ArH), 6.94 (d,

J=8 Hz, 1H, ArH), 6.42 (d, J=16 Hz, 1H, CCH),

5.00 (s, 2H, ArCH₂O), 1.56 (s, 4H, CH₂CH₂), 1.16 (s,

6H, 2ÂCH₃), 1.06 (s, 6H, 2ÂCH₃); ¹³C NMR (75 MHz,

DMSO-d₆) d 167.26 (CO), 167.14 (CO), 155.67,

144.20, 143.55, 141.43, 135.90, 134.94, 133.73, 133.65,

131.23, 130.70, 129.25, 128.48, 128.40, 126.15, 124.49,

124.12, 120.61, 118.81, 114.16, 69.43, 34.51, 33.74, 33.70,

31.56, 31.46; IR (KBr) 3422, 2962, 2926, 1688, 1626, 1570,

1464, 1310, 1254cm ¹; MS (DCI) m/e 467 (M OH), 201

+

.

(C₁₅H₂₁). Anal. (C₃₁H₃₂O₅0.75 H₂O) C, H.

21. (a) Wery, J.-P.; Schevitz, R. W.; Clawson, D. K.; Bobbitt,

J. L.; Dow, E. R.; Gamboa, G.; Goodson, Jr., T.; Hermann,

H. B.; Kramer, R. M.; McClure, D. B.; Mihelich, E. D.; Put-

nam, J. E.; Sharp, J. D.; Stark, D. H.; Teater, C.; Warrick, M.

W.; Jones, N. D. Nature 1991, 352, 79. (b) Scott, D. L.; White,

S. P.; Browning, J. L.; Rosa, J. J.; Gelb, M. H.; Sigler, P. B.

Science 1991, 254, 1007.

Acknowledgement

We thank the Department of Analytical Research in

Wallingford, CT for analytical data in support of this

work.

22. A group at Lilly has recently reported the elegant use of

related structural information in the design of indole-based

PLA₂inhibitors; see: Schevitz, R. W.; Bach, N. J.; Carlson, D.

G.; Chirgadze, N. Y.; Clawson, D. K.; Dillard, R. D.; Dra-

heim, S. E.; Hartley, R. W.; Jones, N. D.; Mihelich, E. D.;

Olkowski, J. L.; Snyder, D. W.; Sommers, C.; Wery, J.-P.

Nature Structural Biology 1995, 2, 458.

23. (a) Jain, M. K.; Ghomaschi, F.; Yu, B.-Z.; Bayburt, T.;

Murphy, D.; Houck, D.; Brownell, J.; Reid, J. C.; Solowiej,

J. E.; Wong, S.-M.; Mocek, U.; Jarrell, R.; Sasser, M.; Gelb,

M. H. J. Med. Chem. 1992, 35, 3584. (b) Gelb, M. H.; Jain,

M. K.; Berg, O. Bioorg. Med. Chem. Lett. 1992, 2, 1335. (c)

Yu, L.; Dennis, E. A. Bioorg. Med. Chem. Lett. 1992, 2,

1343. (d) For general comments regarding lipase interactions

References

1. (a) Davies, P.; MacIntyre, D. E. In In¯ammation: Basic

Principles and Clinical Correlates, 2nd ed.; Gallin, J. I.; Gold-

stein, I. M.; Snyderman, R., Eds.; Raven Press: New York,

1992; pp 123±138. (b) Lam, B. K.; Austen, K. F. In In¯am-

mation: Basic Principles and Clinical Correlates, 2nd ed.; Gal-

lin, J. I.; Goldstein, I. M.; Snyderman, R., Eds.; Raven Press:

New York, 1992; pp 139±148. (c) Zimmerman, G. A.; Pre-

scott, S. M., McIntyre, T. M. In In¯ammation: Basic Principles

and Clinical Correlates, 2nd ed.; Gallin, J. I.; Goldstein, I. M.;

Snyderman, R., Eds.; Raven Press: New York, 1992; pp 149±

D. M. Springer et al. / Bioorg. Med. Chem. 8 (2000) 1087±1109

1109

with organized lipid surfaces see: Blow, D. Nature 1991, 351,

444.

products containing a ¯uorene nucleus, but this has not been

rigorously determined.)

24. For examples see: (a) Musser, J. H.; Kreft, A. F.; Failli, A.

A.; Demerson, C. A.; Shah, U. S.; Nelson, J. A. International

Patent Publication 1991, WO91/06537. (b) Failli, A. A.; Kreft,

A. F.; Musser, J. H.; Banker, A. L.; Nelson, J. A.; Shah, U. S.

US Patent 1991, 5,071,988. (c) Djuric, S. W.; Haack, R. A.;

Miyashiro, J. M. International Patent Publication, 1992,

WO92/21644. (d) Tramposch, K. M.; Steiner, S. A.; Stanley,

P. L.; Nettleton, D. O.; Franson, R. C.; Lewin, A. H.; Carroll,

F. I. Biochem. Biophys. Res. Commun. 1992, 189, 272. (e)

Kohler, T.; Heinisch, M.; Kirchner, M.; Peinhardt, G.; Hir-

schelmann, R.; Nuhn, P. Biochemical Pharmacology 1992, 44,

805. (f) LeMahieu, R. A.; Carson, M.; Han, R.-J.; Madison,

V. S.; Hope, W. C.; Chen, T.; Morgan, D. W.; Hendrickson,

H. S. J. Med. Chem. 1993, 36, 3029. (g) Beaton, H. G.; Ben-

nion, C.; Connolly, S.; Cook, A. R.; Gensmantel, N. P.; Hal-

lam, C.; Hardy, K.; Hitchin, B.; Jackson, C. G.; Robinson, D.

H. J. Med. Chem. 1994, 37, 557. (h) Carson, M.; Han, R.-J.;

LeMahieu, R. A.; Madison, V. S. US Patent 1994, 5,298,652.

(i) Pisabarro, M. T.; Ortiz, A. R.; Palomer, A.; Cabre, F.;

Garcia, L.; Wade, R. C.; Gago, F.; Mauleon, D.; Carganico,

G. J. Med. Chem. 1994, 37, 337. (j) Wheeler, T. N.; Blanchard,

S. G.; Andrews, R. C.; Fang, F.; Gray-Nunez, Y.; Harris, C.

O.; Lambert, M. H.; Mehrotra, M. M.; Parks, D. J.; Ray, J.

A.; Smalley, Jr., T. L. J. Med. Chem. 1994, 37, 4118. (k) Potts,

B. C. M.; Faulkner, D. J. J. Nat. Prod. 1992, 55, 1701. (l)

Tanaka, K.; Matsutani, S.; Kanda, A.; Kato, T.; Yoshida, T.

J. Antibiotics 1994, 47, 631. (m) Barnette, M. S.; Rush, J.;

Marshall, L. A.; Foley, J. J.; Schmidt, D. B.; Sarau, H. M.

Biochem. Pharmacol. 1994, 47, 1661. (n) Carganico, G.;

Mauelon, D.; Garcia, M. L. International Patent Publication

1993, WO93/21211. (o) Marki, F.; Breitenstein, W.; Beriger,

E.; Bernasconi, R.; Caravatti, G.; Francis, J. E.; Paioni, R.;

Wehrli, H. U.; Wiederkehr, R. Agents Actions 1993, 38, 202.

(p) Pruzanski, W.; Greenwald, R. A.; Street, I. P.; Laliberte,

F.; Stefanski, E.; Vadas, P. Biochem. Pharmacol. 1992, 44,

1165. (q) Garst, M. E. Curr. Opin. Ther. Pat. 1992, 400. (r)

Schiehser, G. A.; Von Burg, G. F. US Patent 1991, 5,070207.

(s) Marshall, L. A.; Steiner, K. E.; Schiehser, G. A. US Patent

1990, 4,933,365.

29. For comparison purposes, the IC₅₀of manoalide has been

determined to be 20 nM against the non-pancreatic 14 kDa

PLA₂isolated from human synovial ¯uid; Marshall, L. A.;

Bauer, J.; Sung, M. L.; Chang, J. Y. J. Rheumatol. 1991, 18,

59), and 3.2 mM against the non-pancreatic enzyme isolated

from human polymorphonuclear leukocytes (Marki, F.;

Breitenstein, W.; Beriger, E.; Bernasconi, R.; Caravatti, G.;

Francis, J. E.; Paioni, R.; Wehrli, H. U.; Wiederkehr, R.

Agents Actions 1993, 38, 202.

30. (a) Tramposch, K. M.; Chilton, F. H.; Stanley, P. L.;

Franson, R. C.; Havens, M. B.; Nettleton, D. O.; Davern, L.

D.; Darling, I. M.; Bonney, R. J. J. Pharmacol. Expt. Ther-

apeut. 1994, 271, 852. (b) Stanley, P. L.; Steiner, S.; Havens,

M.; Tramposch, K. M. Skin Pharmacol. 1991, 4, 262.

31. Bradley, P. P.; Priebat, D. A.; Christensen, R. D.; Roth-

stein, G. J. Invest. Derm 1982, 78, 206.

32. The compounds tested in the chronic in¯ammation in vivo

assay (2, 4, 28, 36b, 36i) were not evaluated as potential inhi-

bitors of MPO in a control experiment. Thus, the possibility

exists that some (or all) of the in vivo activity reported for

these compounds in the tables is a consequence of direct inhi-

bition of the enzyme marker MPO rather than a re¯ection of

reduced in¯ux of neutrophils (PMNs). However, animals

treated with compound 28 had signi®cant, dose-dependent ear

weight reductions that paralleled the measured reduction of

myeloperoxidase activity. This implies that the drug is redu-

cing general hyperplasia (and in¯ammation), and that it is not

acting simply as a MPO inhibitor. Many other structurally

similar (but non-biaryl) compounds were evaluated in the

chronic assay for both ear weight reduction and inhibition of

MPO activity. The compounds tested almost always displayed

ear weight reductions that paralleled the measured reduction

of myeloperoxidase activity.

33. In general, compounds with IC₅₀s against the human

enzyme <20 mM were resynthesized for evaluation in the

chronic in vivo assay. However, since compound 28 was one

of the ®rst compounds synthesized from this general biaryl

structural class, and it was easy to synthesize on the 250 mg

scale required for evaluation of a compound in the 10-day

chronic assay, it was tested despite the poor IC₅₀against the

human enzyme. Compound 36h, the most active derivative in

vitro reported here (IC₅₀=2 mM), was not evaluated in vivo in

the chronic assay due to its erratic behavior in a whole-cell

assay that measured arachidonic acid release from PMNs sti-

mulated with ionophore A23187 (calcimycin). (For details

regarding this assay see ref 30. The erratic behavior (non-dose

response) of 36h in this assay was attributed to possible toxi-

city due to surfactant eects on the PMN cell membranes.)

Many compounds were tested in the PMN arachidonic acid

release assay from dierent structural series, but only four

compounds from the biaryl diacid class were tested. The IC₅₀

for 36h could not be determined, but the remaining IC₅₀s are

as follows: 2=4 mM; 36i=2 mM; and 36b=20 mM. Activity in

this assay can be viewed as evidence for cellular penetration of

the test compounds, and inhibitory activity towards the

desired enzymatic target (PLA₂), although other explanations

are possible.

25. (a) Burke, J. R.; Gregor, K. R.; Tramposch, K. M. J. Biol.

Chem. 1995, 270, 274. (b) For a complete discussion of the

`scooting-mode' assay see: Gelb, M. H.; Berg, O.; Jain, M. K.

Curr. Opin. Struct. Biol. 1991, 1, 836.

26. Springer, D. M.; Luh, B.-Y.; Greene, K. M.; Bronson, J.

J.; Mansuri, M. M. Biaryl Phospholipase A₂Inhibitors. US

Patent 1995, 5,391,817.

27. Kessar, S. V.; Gupta, Y. P.; Mohammad, T.; Khurana, A.;

Sawal, K. K. Heterocycles 1984, 22, 2723.

28. We initially attempted a more concise strategy for the

synthesis of compounds in the n=2 unsaturated series illu-

strated by 43. Wittig reaction of aldehyde 8 provided the

expected unsaturated diester (an intermediate in the synthesis of

38). It was hoped that demethylation of this intermediate would

provide a phenol suitable for Mitsunobu coupling to a variety of

alcohols. Unfortunately, treatment of the above Wittig product

with Me₂BBr resulted in the loss of the ole®n, with retention of

the methoxy group. (It is possible that intramolecular Friedel±

Crafts cyclization of the unsaturated ester occurred to give

34. Saa, J. M. J. Org. Chem. 1992, 57, 678.

35. Dawson, M. I.; Hobbs, P. D.; Dorsky, A.; Morimoto, H.

J. Labelled Compounds and Radiopharmaceuticals 1990, 28, 89.

Article Doi

Biaryl diacid inhibitors of human s-PLA2 with anti-inflammatory activity

DOI: 10.1016/S0968-0896(00)00047-X

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