A novel synthesis of 9-cis-retinoic acid and tagretin analogues via the Pauson-Khand or Heck reaction

Article abstract of DOI:10.1016/S0040-4020(01)00655-X

The synthesis of a selection of compounds related to 9-cis-retinoic acid and tagretin is outlined. The methodology utilises the Pauson-Khand and Heck reaction as the key steps to prepare the intermediate aryl cyclopentenone regioisomers.

Full text of DOI:10.1016/S0040-4020(01)00655-X

TETRAHEDRON
Pergamon
Tetrahedron 57 12001) 7383±7390
A novel synthesis of 9-cis-retinoic acid and tagretin analogues via
the Pauson±Khand or Heck reaction
Anthony Murray,p John Bondo Hansen and Birgitte V. Christensen
Ê
Department of Medicinal Chemistry, Novo Nordisk A/S, Novo Nordisk Park, 2760 Malùv, Denmark
Received 3 August 2000; revised 30 May 2001; accepted 14June 2001
AbstractÐThe synthesis of a selection of compounds related to 9-cis-retinoic acid and tagretin is outlined. The methodology utilises the
Pauson±Khand and Heck reaction as the key steps to prepare the intermediate aryl cyclopentenone regioisomers. q 2001 Elsevier Science
Ltd. All rights reserved.
The retinoids are analogues of vitamin A, and are respon-
sible for a variety of biological effects via activation of the
retinoid family of receptors.1 The retinoid receptors can be
divided into two sub-families, the retinoic acid receptor
1RAR), and the retinoid X receptor 1RXR), with further
sub-types 1a, b, g) also being found. As shown on Fig. 1
the endogenous ligands for these two receptor families are
all-trans-retinoic acid 1active on RAR) and 9-cis-retinoic
acid 1active on both RXR and RAR).
selective either for RXR 1rexinoids) or PPARg 1e.g. rosi-
glitazone) can independently activate this heterodimer and
that, when they are used together, a synergistic response can
be obtained.2 This has increased the interest in RXR selec-
tive ligands, since it may provide a new or improved route to
the treatment of diabetes.
During a research program in this area we were interested in
preparing compounds that were both active and selective for
the RXR, and ultimately the PPAR:RXR heterodimeric
receptor complex. Compounds of the type shown below
have been shown to bind selectively to RXR with only
weak binding at RAR,3,4 and in the case of LG 1069
1Tagretin), in vivo data has indicated anti-diabetic activity
in ob/ob 1obese) and db/db 1diabetic) mice2 1Fig. 2).
This paper deals with the preparation of a selection of
compounds which combine in a novel way some of the
structural features outlined above. The importance of the
cyclopropyl or cyclopentyl ring as a potential bioisostere
for the 8,9 double bond in 9-cis-retinoic acid has been
demonstrated,3,4 and our strategy relied on a route to the
novel cyclopentenones 1 and 2 to provide suitable and
versatile intermediates for further elaboration towards a
series of analogues 1Fig. 3). The route to these ring systems
Figure 1.
Retinoid X receptors can form heterodimers with a variety
of other nuclear receptors, including the peroxisome pro-
liferator activated receptor 1PPAR), the thyroid receptor
and the orphan receptor LXR. The RXR:PPARg hetero-
dimer is a target in the search for compounds affecting
glucose metabolism. It has been shown in vitro that ligands
Figure 2.
Keywords: retinoic acid; retinoic acid receptor; Pauson±Khand reaction.
Corresponding author. Tel.: 144-44434806; fax: 144-44434547; e-mail: amur@novonordisk.com
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020101) 00655-X

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A. Murray et al. / Tetrahedron 57 (2001) 7383±7390
1no coupling between these protons) in quantitative yield
in a ratio of about 6:4. The isomers could be separated
easily by ¯ash chromatography and conversion of 4a via
Mitsunobo reaction with methyl 4-hydroxybenzoate
1simpli®ed coupling pattern of the proton at the tertiary
centre consistent with inversion) and hydrolysis using
potassium hydroxide gave the carboxylic acid 5. The
corresponding trans-isomer 4b can be converted in a similar
fashion.
Figure 3.
utilised Pauson±Khand and organopalladium coupling reac-
tions, respectively, thus providing a convenient route to
either regioisomer.
The unsaturated analogue could be accessed via Luche
reduction of 1, providing the allylic alcohol 6, which
could again be coupled with methyl 4-hydroxybenzoate
under Mitsunobo conditions to give the corresponding
ester, which was further hydrolysed to give 7.
The aryl alkyne 3, which could be prepared according to the
literature procedure,5 was treated with dicobalt octacarbonyl
in petroleum ether to form the corresponding dicobalt
hexacarbonyl±alkyne complex. This complex underwent
intermolecular Pauson±Khand6 reaction with ethylene
using triethylamine-N-oxide dihydrate as the oxidative
source.7 In accordance with reactions of this type the
more bulky group 1the aryl moiety) is located alpha to the
carbonyl moiety in the product giving cyclopentenone 1 as
the sole regioisomer 1Scheme 1).
Cyclopropanation of the alkene moiety of 1 was also
investigated, and initially an attempt was made using
dimethylsulphoxonium methyl ylide8 but the enone was
completely unreactive under these conditions. After exten-
sive investigation it was found necessary to ®rst prepare the
allylic alcohol 6, where the proximal alcohol moiety could
then assist the cyclopropanation and counteract the detri-
mental presence of the bulky aryl group. It was found that
upon reaction with diethylzinc and chloroiodomethane9 the
cyclopropyl alcohol could be prepared in moderate yield,
and PCC oxidation of the resultant product gave the desired
cyclopropyl ketone 8. Horner±Emmons reaction using
either para or meta diethyl-carbomethoxybenzyl phospho-
nate was found in each case to give a single isomeric
product, which presumably due to steric constraints
imposed by the methyl substituent on the aromatic ring
completely favours formation of the E-isomer. In each
case a small amount of transesteri®cation of the methyl
ester to an ethyl ester was observed, and this was generally
It should be noted that the synthesis of 1 via Heck, Negishi
or Stille coupling of the respective aryl-metal with 2-iodo-
cyclopent-2-enone was also investigated. However, in
each case the yields were poor 1,20%) and the reactions
generally not as clean.
The approach to the saturated cyclopentane required hydro-
genation of enone 1 using platinum oxide, and reduction of
the product with sodium borohydride gave the cis- alcohol
4a 1proton coupling observed between the benzylic
hydrogen and the vicinal proton on hydroxy containing
carbon) together with the corresponding trans-alcohol 4b
Scheme 1. Reagents: 1a) i. Co21CO)8, ii. ethylene, Me3NO 142% over two steps); 1b) 40 psi H2, PtO2 178%); 1c) NaBH4 158% cis, 4 2%trans);
1d) HOC6H4CO2CH3, DEAD, Ph3P 170%); 1e) KOH, MeOH 179%); 1f) NaBH4, CeCl3 199%); 1g) as for d 126%); 1h) as for e 140%); 1j) Et2Zn, CH2ICl
131%); 1k) PCC 199%); 1l) MeO2CC6H4CH2P1O)1OEt)2, NaH, 15-crown-5 1para60%, meta 75%); 1m) as for d 1para 80%, meta 51%).

A. Murray et al. / Tetrahedron 57 (2001) 7383±7390
7385
Scheme 2. Reagents: 1a) i. PdCl21PPh3)2, NaOAc, 1-chlorocyclopent-1-en-3-one 165%); 1b) NaBH4, CeCl3 163%); 1c) Et2Zn, CHICl 149%); 1d) PCC 197%);
1e) MeO2CC6H4CH2P1O)1OEt)2, NaH, 15-crown-5 1para 99%, meta 87%); 1f) KOH, MeOH 1para 75%, meta 57%); 1g) HOC6H4CO2CH3, DEAD, Ph3P
154%); 1h) as for f 113%); 1i) 40 psi H2, PtO2, KOAc 179%); 1j) as for e 1para 93%, meta 93%); 1k) as for f 1para 41%, meta 54%).
observed for the Horner±Emmons reactions described in
this paper 1see Section 2 for details), and may be due to
some ethanol traces in the starting phosphonate 1derived
from an Arbuzov reaction). This was however only a tran-
sient problem since ester hydrolysis afforded the respective
para- and meta- acids 9 and 10.
complete consumption of starting material gave, together
with 17, substantial amounts of a less polar by-product,
resulting in poor and irreproducible reaction yields. It was
thought that there could be some reduction of the ketone
moiety occurring under the reaction conditions, and that the
resultant allylic alcohol could be unstable especially in the
presence of trace amounts of acid. We thought that base may
inhibit this side reaction and it was found that by carrying
out the hydrogenation in the presence of potassium acetate
the desired ketone could be accessed in good yield. Finally
the Horner±Emmons hydrolysis sequence as described
above gave the meta- or para- carboxylic acids 18 and 19
as an E/Z mixture. The product also contained traces of
two cyclopentene regioisomers formed via double bond
migration into the 5-membered ring.
The route to the regioisomeric cyclopentenone is shown in
Scheme 2, and was achieved via Heck coupling of boronic
acid 11 with 1-chlorocyclopent-1-en-3-one, providing 2 in
65% yield. A small amount of isomerisation of the double
bond in 2 was also observed, however, the non-conjugated
cyclopentenone could be readily reconverted to 2 simply by
re¯uxing in benzene or toluene. Luche reduction gave the
corresponding allylic alcohol, which was further converted
to the cyclopropyl alcohol 12 1relative stereochemistry
shown).
1. Conclusion
PCC oxidation of alcohol 12 to the corresponding cyclo-
propyl ketone 13 and Horner±Emmons hydrolysis as
shown in Scheme 2 gave the respective para- or meta-
E/Z aryl alkenes 14 and 15. It proved very dif®cult to
separate and thus de®ne the stereochemistry of the respec-
tive E and Z compound mixtures in 14 or 15, and only in the
case of 14 a small amount of pure isomer 1absolute stereo-
chemistry not determined) could be obtained via recrystal-
lisation. Alternatively, Mitsunobo coupling of 12 with
methyl 4-hydroxybenzoate followed by ester hydrolysis
gave the benzyl ether 16.
In summary, we have developed a new route to analogues of
9-cis retinoic acid and tagretin as potential ligands for the
retinoid X receptor. The novel cyclopentenones 1 and 2 can
be derivatised to provide compounds for comparison that
incorporate single, double, or cyclopropyl moieties in the
central ®ve membered ring. Biological activity of these
and additional compounds will be reported in a future
communication.
2. Experimental
2.1. General methods
Initial attempts to hydrogenate the enone double bond of 2
were unsuccessful, and surprisingly, conversion of this
substrate was not as straightforward as anticipated. It was
found that normal catalytic hydrogenation whilst providing
Melting points were determined with a BuÈchi melting point

7386
A. Murray et al. / Tetrahedron 57 (2001) 7383±7390
apparatus B-545. IR spectra were recorded on a Perkin±
Elmer Spectrum One FT-IR Spectrometer. H NMR was
stirred for 4h. Dilute HCl was added and the reaction
partially concentrated. Water was added and the aqueous
layer extracted with ether, dried and concentrated under
reduced pressure. Chromatography 1hexane/ethyl acetate
3:1) gave 14a) 1288 mg, 58%) as a gum eluting ®rst,
followed by 14b) 1210 mg, 42%) as a white solid mp 78±
798C. 14a) IR 1KBr) 3468, 3023, 2960, 1502, 1455,
1362 cm21; dH 1CDCl3) 1.18±1.31 112H, m, 2CMe2), 1.62
14H, s, CH2CH2), 1.73±2.25 16H, m, CH2CH2CH2), 2.29
13H, s, ArMe), 3.16 11H, ddd, Jˆ11.1, 7.3, 3.8 Hz,
CHCHOH), 4.20±4.26 11H, m, CHOH), 7.08 11H, s,
ArH), 7.21 11H, s, ArH). dC 1CDCl3) 143.4, 142.8, 134.6,
134.3, 128.9, 126.0, 73.5, 48.7, 35.6, 35.5, 34.4, 34.3, 34.2,
32.5, 32.3, 32.2, 32.1, 28.3, 22.8, 20.0. HRMS calcd for
C20H30O 286.2297; found: 286.2288. 14b) IR 1KBr) 3369,
3019, 2957, 1500, 1452, 1361 cm21; dH 1CDCl3) 1.22 112H,
s, 2CMe2), 1.62 14H, s, CH2CH2), 1.58±1.99 14H, m,
CH2CH2), 2.02±2.25 12H, m, CH2), 2.32 13H, s, ArMe),
3.12 11H, dd, Jˆ13.9, 7.6 Hz, CHCHOH), 4.24±4.34 11H,
m, CHOH), 7.05 11H, s, ArH), 7.10 11H, s, ArH). dC
1CDCl3) 142.4, 142.2, 138.5, 133.5, 128.0, 123.2, 79.9,
49.7, 35.1, 35.0, 33.9, 33.8, 33.7, 31.9, 31.8, 31.8, 31.7,
29.6, 22.0, 19.6. HRMS calcd for C20H30O 286.2297;
found: 286.2289.
1
recorded at 300 MHz and 13C NMR at 75 MHz on a Bruker
DRX 300 spectrometer. Chemical shifts are given in ppm
1d) relative to tetramethylsilane. Mass spectra were
recorded on a Varian MAT 311A mass spectrometer using
the peak matching method, or on a Finnigan MAT TSQ 70
mass spectrometer with electron impact 1EI) ionization,
Elemental analysis was performed on a Fisons EA1108
elemental analyser by Novo Nordisk Microanalytical
Laboratory, Denmark. Column chromatography was
performed on Macherey±Nagel Kieselgel 60 1230±
440 mesh).
2.1.1. 2--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)cyclopent-2-enone -1). To a stirred suspension
of cobalt carbonyl 19.1 g, 27 mmol) in petroleum ether
1300 mL) under nitrogen was added alkyne 13) 15.5 g,
24mmol) and petroleum ether 125 mL), and the reaction
stirred for 3 h at room temperature. The reaction mixture
was then ®ltered through a pad of Celite and concentrated
under reduced pressure. The crude cobalt alkyne complex
was redissolved in benzene 175 mL) and exposed to an
ethylene atmosphere using an ethylene ®lled balloon. A
solution of trimethylamine-N-oxide dihydrate 114.4 g,
192 mmol) in methanol 175 mL) was added over 2.5 h and
the reaction was stirred for 16 h. The reaction mixture was
then ®ltered through a pad of Celite and concentrated under
reduced pressure. Chromatography 1hexane/ethyl acetate
2:1) gave 11) 12.88 g, 42%) as an off white solid mp 138±
1398C. IR 1KBr) 2954, 2920, 2880, 1690 1CO), 1502, 1457,
1388, 1361, 1315 cm21; dH 1CDCl3) 1.26 16H, s, CMe2),
1.27 16H, s, CMe2), 1.65 14H, s, CH2CH2), 2.1413H, s,
ArMe), 2.53±2.62 12H, m, CH2), 2.72±2.81 12H, m,
COCH2), 7.0411H, s, Ar H), 7.12 11H, s, ArH), 7.55±7.60
11H, m, CvCH). dC 1CDCl3) 208.2, 161.2, 147.0, 145.3,
142.5, 133.5, 129.6, 128.7, 127.9, 35.5, 35.3, 34.4, 34.3,
32.3, 32.2, 27.2, 20.4. HRMS calcd for C20H26O:
282.1984; found: 282.1969.
2.1.3. trans-4-[2--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)cyclopentyloxy]benzoic acid -5). To
solution of 14) 1190 mg, 0.66 mmol), triphenyl phosphine
1174mg, 0.66 mmol) and 4-carbomethoxyphenol 1121 mg,
0.79 mmol) in THF was added, dropwise, diethylazodi-
carboxylate 1DEAD), 1110 mg, 0.66 mmol) in THF 10.4
mL) and the solution stirred for 4h, whereupon a further
0.33 mmol of triphenyl phosphine, 4-carbomethoxyphenol
and DEAD was added and the reaction stirred for 12 h.
Concentration under reduced pressure and chromatography
1hexane/ethyl acetate 6:1) gave the methyl ester of 15)
1194mg, 70%). IR 1KBr) 3022, 2956, 1713 1CO), 1604,
1277, 1251, 1176 cm21; dH 1CDCl3) 1.20±1.32 112H, m,
2CMe2), 1.55±2.33 16H, m, CH2CH2CH2), 1.62 14H, s,
CH2CH2), 2.29 13H, s, ArMe), 3.46 11H, dt, Jˆ7.7,
5.3 Hz, CHCHOAr), 3.70 13H, s, CO2Me), 4.70±4.80 11H,
m, CHOAr), 6.75 12H, d, Jˆ8.4Hz, 2Ar H), 7.02 11H, s,
ArH), 7.05 11H, s, ArH) 7.93 12H, d, Jˆ8.4Hz, 2Ar H).
dC 1CDCl3) 166.8, 162.0, 142.6, 142.6, 138.8, 132.2,
131.4, 128.7, 126.0, 123.5, 115.1, 86.0, 51.7, 47.8, 35.2,
34.0, 33.9, 32.9, 32.7, 32.0, 32.0, 31.9, 31.8, 24.1, 19.7.
HRMS calcd for C28H36O3: 420.2665; found: 420.2662.
2.1.2. cis- and trans-2--3,5,5,8,8-Pentamethyl-5,6,7,8-
tetrahydronaphthalen-2-yl)cyclopentanol -4). A mixture
of 11) 12.0 g, 7 mmol) and platinum oxide 1200 mg) in ethyl
acetate 130 mL) was hydrogenated at 40 psi for three days.
The catalyst was removed by ®ltration through a Celite pad
and the solution concentrated under reduced pressure.
Chromatography 1hexane/ethyl actetate 5:1) gave 2-13,5,
5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclo-
pentanone 11.56 g, 78%), mp 86±86.58C. IR 1KBr) 3019,
2959, 1732 1CO), 1503, 1451, 1361 cm21; dH 1CDCl3) 1.20
16H, s, CMe2), 1.22 13H, s, CMe), 1.23 13H, s, CMe), 1.63
14H, s, CH2CH2), 1.80±2.50 16H, m, CH2CH2CH2), 2.20
13H, s, ArMe), 3.45 11H, dd, Jˆ13.9, 8.3 Hz, COCH),
6.88 11H, s, ArH), 7.05 11H, s, ArH). dC 1CDCl3) 219.1,
143.2, 142.6, 134.4, 133.5, 128.6, 125.6, 53.4, 38.7, 35.2,
35.1, 33.9, 33.7, 32.0, 31.9, 31.8, 31.7, 31.6, 21.0, 19.7.
Anal. calcd for C20H28O; C 84.45, H 9.92. Found C 84.31,
H 9.92. HRMS calcd for C20H28O: 284.2140; found:
284.2133.
The product from the previous step 1140 mg, 0.48 mmol)
and aqueous potassium hydroxide 11 mL of 6 M) in
methanol 18 mL) was heated at re¯ux for 2 h. Water was
added and the aqueous layer extracted with dichloro-
methane, dried and concentrated under reduced pressure.
Chromatography 1dichloromethane/methanol 20:1) gave
15) 1107 mg, 79%) as a white solid mp 1988C. IR 1KBr)
3020, 2961, 1675 1CO), 1605, 1294, 1250, 1172 cm21; dH
1CDCl3) 1.20±1.32 112H, m, 2CMe2), 1.55±2.33 16H, m,
CH2CH2CH2), 1.62 14H, s, CH2CH2), 2.29 13H, s, ArMe),
3.46 11H, dt, Jˆ7.7, 5.3 Hz, CHCHOAr), 4.70±4.80 11H, m,
CHOAr), 6.78 12H, d, Jˆ8.4Hz, 2Ar H), 7.02 11H, s, ArMe),
7.05 11H, s, ArMe), 7.93 12H, d, Jˆ8.4Hz, 2Ar H). dC
1CDCl3) 171.0, 162.7, 142.6, 142.6, 138.8, 133.2, 132.1,
128.2, 123.5, 120.9, 115.2, 86.1, 47.8, 35.2, 34.0, 33.8,
To the product from the previous step 1500 mg, 1.76 mmol)
in ethanol 15 mL) and dichloromethane 10.5 mL) was added
sodium borohydride 180 mg, 2.1 mmol) and the reaction

A. Murray et al. / Tetrahedron 57 (2001) 7383±7390
7387
32.9, 32.7, 32.0, 31.8, 24.1, 19.7. Anal. calcd for C27H34O3;
C 79.76, H 8.43. Found C 79.32, H 8.53. HRMS calcd for
C27H34O3: 406.2508; found: 406.2498
2.1.6.
naphthalen-2-yl)bicyclo[3.1.0]hexan-2-one -8). To
E-1--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
a
stirred solution of diethylzinc 10.36 mL, 3.5 mmol) dichloro-
ethane 14mL) in an ice bath was added, dropwise, chloro-
iodoethane 10.5 mL, 7 mmol) forming a white suspension.
After 10 min compound 16) 1500 mg, 1.8 mmol) in dichloro-
ethane 11 mL) was added and the reaction stirred at this
temperature for 5 min, then heated at 508C for 15 min. The
reaction mixture was diluted with diethyl ether and saturated
ammonium chloride 18 mL) was added. The ether phase was
washed with water, dried and concentrated under reduced
pressure. Chromatography 1hexane/ethyl acetate 4:1) gave
1-13,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-
bicyclo[3.1.0]hexan-2-ol 1164mg, 31%) as a white solid mp
127±127.58C. IR 1KBr) 3415, 2958, 2920, 2863, 1501,
1457, 1361, 1049 cm21. dH 1CDCl3) 0.73 11H, dd, Jˆ7.3,
4.9 Hz, cyclopropCHaHb), 1.10 11H, t, Jˆ4.9 Hz, cyclo-
propCHaHb), 1.26 112H, s, 2CMe2), 1.40±1.50 11H, m,
cyclopropCH), 1.58 11H, s, OH), 1.61 14H, s, CH2CH2),
1.79±2.10 14H, m, CH2CH2), 2.30 13H, s, ArMe), 4.50
11H, t, Jˆ7.3 Hz, CHOH), 7.03 11H, s, ArH), 7.18 11H, s,
ArH). dC 1CDCl3) 143.7, 142.8, 137.6, 135.2, 129.9, 128.6,
126.3, 78.9, 37.5, 35.6, 35.6, 34.3, 32.4, 32.3, 32.2, 29.6,
25.5, 25.3, 19.5, 11.0. HRMS calcd for C21H30O: 298.2297;
found: 298.2283.
2.1.4. 2--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)cyclopent-2-enol -6). To a stirred solution of
11) 1190 mg, 0.67 mmol) in methanol 15 mL) in an ice
bath was added cerium chloride heptahydrate 1320 mg,
0.87 mmol) and the mixture stirred for 5 min. Sodium boro-
hydride 135 mg, 0.92 mmol) was then added in one portion
and the reaction stirred for 15 min. Diethyl ether 115 mL)
and a mixture of brine 15 mL) and dilute HCl 11 mL) was
added and the organic phase recovered. The aqueous layer
was extracted with diethyl ether and the combined organic
layers dried and concentrated under reduced pressure.
Chromatography 1hexane/ethyl acetate 3:1) gave 16)
1190 mg, 99%) as an oil 1deteriorates on storage). IR
1KBr) 3418, 2959, 1498, 1458, 1362 cm21. dH 1CDCl3)
1.26 112H, s, 2CMe2), 1.65 14H, s, CH2CH2), 1.81±1.98
11H, m, CHaHbCH2), 2.1413H, s, Ar Me), 2.42±2.50 12H,
m, CHaHbCH2), 2.52±2.69 11H, m, CHaHb), 5.10±5.19 11H,
m, CHOH), 5.87 11H, m, CvCH), 7.10 11H, s, ArH), 7.21
11H, s, ArH). dC 1CDCl3) 146.6, 144.6, 143.0, 134.0, 133.6,
132.8, 129.4, 127.6, 80.1, 61.3, 36.0, 34.8, 34.7, 34.2, 32.8,
32.7, 32.6, 31.5, 21.5, 15.0. HRMS calcd for C20H30O
284.2069; found: 284.2139.
The product from the previous step 140 mg, 0.13 mmol),
pyridinium chlorochromate 160 mg, 0.28 mmol) and
dichloromethane 13 mL) was stirred for 2 h at room
temperature. Removal of solvent under reduced pressure
and chromatography 1eluant hexane/ethyl acetate 4:1)
gave 18) 140 mg, 99%) as a white solid mp 152.5±
153.58C. IR 1KBr) 3023, 2962, 2921, 1717 1CO), 1499,
1454, 1360 cm21; dH 1CDCl3) 1.21 13H, s, CMe), 1.23
19H, s, 3CMe), 1.59 11H, t, Jˆ4.8 Hz, cyclopropCHaHb),
1.60 11H, dd, Jˆ7.3, 4.8 Hz, cyclopropCHaHb), 1.63 14H,
s, CH2CH2), 2.02±2.41 15H, m, CH2CH2CH), 2.29 13H, s,
ArMe), 7.02 11H, s, ArH), 7.08 11H, s, ArH). dC 1CDCl3)
213.9, 144.5, 142.4, 135.8, 132.4, 128.8, 128.5, 126.3, 41.7,
35.6, 34.3, 32.8, 32.4, 32.3, 32.2, 29.9, 22.3, 20.3, 19.8.
HRMS calcd for C21H28O: 296.2140; found: 296.2146.
2.1.5.
4-[2--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)cyclopent-2-enyloxy]benzoic acid -7).
To solution of 16) 1400 mg, 1.4 mmol), triphenyl phosphine
1400 mg, 1.5 mmol) and 4-carbomethoxyphenol 1240 mg,
1.5 mmol) in THF was added, dropwise, diethylazodi-
carboxylate 1DEAD), 166 mg, 1.5 mmol) in THF 11 mL)
and the solution stirred for 1.5 h. Work up as for 15) afforded
the methyl ester of 17) 1130 mg, 26%). IR 1KBr) 3020, 2959,
1717 1CO), 1604, 1508, 1434, 1290, 1247 cm21; dH
1CDCl3) 1.12 13H, s, CMe), 1.18 13H, s, CMe), 1.28 16H,
s, CMe2), 1.62 14H, s, CH2CH2), 2.03±2.1411H, m,
CHaHbCH2), 2.29 13H, s, ArMe), 2.36±2.83 13H, m,
CHaHbCH2), 3.82 13H, s, CO2Me), 5.50±5.59 11H, m,
CHOAr), 6.11 11H, s, CvCH), 6.85 12H, d, Jˆ8.1 Hz,
2ArH), 7.05 11H, s, ArH), 7.18 11H, s, ArH), 7.93 12H, d,
Jˆ8.1 Hz, 2ArH). dC 1CDCl3) 167.3, 162.7, 144.2, 142.3,
141.9, 135.4, 133.2, 133.1, 131.9, 128.6, 127.2, 122.5,
115.5, 86.0, 52.1, 35.5, 34.3, 34.2, 32.2, 32.1, 32.0, 31.7,
30.9, 23.0, 21.3, 14.5. HRMS calcd for C28H34O3: 418.2508;
found: 418.2514.
2.1.7. E-4-[1--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)bicyclo[3.1.0]hex-2-ylidenemethyl]ben-
zoic acid -9). To a stirred suspension of sodium hydride
160 mg of 60% in mineral oil, 1.4mmol) in THF 12 mL)
under nitrogen was added 4-1diethoxyphosphorylmethyl)-
benzoic acid methyl ester 10.4g, 1.4mmol) in THF
11 mL) and the mixture stirred for 20 min. A mixture of
18) 170 mg, 0.23 mmol) and 15-crown-5 10.28 mL, 1.4
mmol) was added and the reaction stirred for 16 h at room
temperature. Water was added and the aqueous phase
extracted with diethyl ether, the combined organic layers
were dried and concentrated under reduced pressure.
Chromatography 1hexane/ethyl acetate 4:1) gave a mixture
of the methyl and ethyl ester of 19) 164mg, 60%), which was
used directly in the next step.
The product from the previous step 160 mg, 0.14mmol) and
aqueous potassium hydroxide 10.8 mL of 6 M) in methanol
15 mL) was heated at re¯ux for 2 h. Work up as for 15) gave
17) 123 mg, 40%) as a solid mp 87.5±88.58C. IR 1KBr)
3440, 2959, 1683 1CO), 1509, 1424, 1246, 1168 cm21; dH
1CDCl3) 1.12 13H, s, CMe), 1.18 13H, s, CMe), 1.28 16H, s,
CMe2), 1.62 14H, s, CH2CH2), 2.03±2.1411H, m,
CHaHbCH2), 2.29 13H, s, ArMe), 2.36±2.83 13H, m,
CHaHbCH2), 5.50±5.59 11H, m, CHOAr), 6.11 11H, s,
CvCH), 6.85 12H, d, Jˆ8.1 Hz, 2ArH), 7.05 11H, s,
ArH), 7.18 11H, s, ArH), 7.93 12H, d, Jˆ8.1 Hz, 2ArH).
dC 1CDCl3) 171.2, 162.9, 143.8, 142.0, 141.5, 135.1,
132.8, 132.7, 132.1, 128.3, 126.9, 122.1, 115.2, 85.7, 35.1,
35.1, 33.9, 33.8, 31.8, 31.8, 31.3, 30.5, 20.8. HRMS calcd
for C27H32O3: 404.2352; found: 404.2334.
The product from the previous step 150 mg, 0.12 mmol) and
aqueous potassium hydroxide 10.2 mL of 6 M) in methanol
13 mL) was heated at re¯ux for 2 h. Dilute HCl was added
and the solvent removed under reduced pressure. Work up
as for compound 15) gave 19) 142 mg, 80%) as a white solid

7388
A. Murray et al. / Tetrahedron 57 (2001) 7383±7390
mp 274.5±275.28C. IR 1KBr) 3560, 2955, 1682 1CO), 1604,
1412, 1316, 1289 cm21; dH 1CDCl3) 1.00±1.78 14H, m,
cyclopropCHaHbCHc, CHdHeCH2), 1.20±1.30 112H, m,
2CMe2), 1.63 14H, s, CH2CH2), 2.00±2.42 12H, m,
CHdHeCH2), 2.15 13H, s, ArMe), 2.71±2.85 11H, m,
CHdHe), 5.7411H, s, C vCH), 7.10 11H, s, ArH), 7.22
12H, d, Jˆ8.2 Hz, 2ArH), 7.26 11H, s, ArH), 7.97 12H, d,
Jˆ8.2 Hz, 2ArH). dC 1CDCl3) 171.8, 153.7, 144.3, 143.4,
142.1, 135.9, 135.4, 129.9, 129.7, 128.2, 128.0, 125.9,
119.6, 40.2, 35.2, 34.0, 32.0, 31.9, 27.1, 26.9, 26.7, 19.5,
18.2. Anal. calcd for C29H34O2 C 84.02, H 8.33. Found C
84.28, H 8.27. HRMS calcd for C29H34O2: 414.2559; found:
414.2557.
thalen-2-yl)bicyclo[3.1.0]hexan-2-ol -12). In an identical
manner to compound 16), compound 12) 16.5 g, 23 mmol)
in methanol 1175 mL), cerium chloride heptahydrate
112.3 g, 33 mmol) and sodium borohydride 11.3 g, 33
mmol) gave 3-13,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)cyclopent-2-enol 14.1 g, 63%) as an off
white solid mp 86±878C 1deteriorates on storage). IR
1KBr) 3257, 2956, 1455, 1361 cm21. dH 1CDCl3) 1.25
16H, s, CMe2), 1.26 16H, s, CMe2), 1.55 11H, s, OH), 1.62
14H, s, CH2CH2), 1.65±1.89 11H, m, CHaHbCvCH), 2.39
13H, s, ArMe), 2.32±2.48 11H, m, CHaHb), 2.51±2.70 11H,
m, CHcHdCHOH), 2.83±2.95 11H, m, CHcHd), 4.99 11H, br
s, CHOH), 5.82 11H, m, CvCH), 7.10 11H, s, ArH), 7.13
11H, s, ArH). dC 1CDCl3) 147.8, 144.5, 142.5, 134.5, 132.9,
131.2, 129.0, 126.5, 78.7, 36.5, 35.3, 34.4, 34.3, 34.2, 32.3,
32.1, 21.4. HRMS calcd for C20H30O 284.2069; found:
286.2130.
2.1.8. E-3-[1--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)bicyclo[3.1.0]hex-2-ylidenemethyl]ben-
zoic acid -10). Using the same procedure as described for
compound 19), sodium hydride 188 mg of 60% in mineral
oil, 2.2 mmol), 3-1diethoxyphosphorylmethyl)benzoic acid
methyl ester 1600 mg, 2.2 mmol) and 18) 1130 mg, 0.43
mmol) in THF 12 mL) gave a mixture of the methyl and
ethyl ester of 110) 1146 mg, 75%) which was used directly
in the next step.
To a stirred solution of diethylzinc 10.59 mL, 5.2 mmol) in
dichloroethane 115 mL) in an ice bath was added, dropwise,
chloroiodoethane 10.76 mL, 10.4mmol) forming a white
suspension. After 10 min 3-13,5,5,8,8-pentamethyl-5,6,
7,8-tetrahydronaphthalen-2-yl)cyclopent-2-enol 11.0 g, 3.5
mmol) in dichloroethane 15 mL) was added and the reaction
stirred at this temperature for 5 min. Work up as described
for compound 18) gave 112) 1510 mg, 49%) as a white solid
mp 119±1208. IR 1KBr) 3240, 2955, 1502, 1457, 1361,
1061 cm21. dH 1CDCl3) 0.73 11H, dd, Jˆ7.3, 5.2 Hz, cyclo-
propCHaHb), 1.12 11H, t, Jˆ5.3 Hz, cyclopropCHaHb), 1.26
112H, s, 2CMe2), 1.6414H, s, C H2CH2), 1.69±2.10 16H, m,
CH2CH2CHOHCH), 2.32 13H, s, ArMe), 4.72±4.85 11H, m,
CHOH), 7.02 11H, s, ArH), 7.15 11H, s, ArH). dC 1CDCl3)
144.5, 143.6, 140.2, 136.1, 129.5, 129.1, 75.8, 36.6, 35.3,
35.2, 33.6, 33.4, 33.3, 33.3, 33.2, 33.0, 32.9, 31.7, 31.2,
20.4, 12.4. HRMS calcd for C21H30O: 298.2297; found:
298.2292.
The product from the previous step 1140 mg, 0.48 mmol)
and aqueous potassium hydroxide 10.5 mL of 6 M) in
methanol 15 mL) was heated at re¯ux for 2 h. Work up as
for 19) and recrystallisation from hexane/ethyl acetate gave
110) 170 mg, 51%) as a white solid mp 240±2418C. IR 1KBr)
3448, 2961, 1678 1CO), 1600, 1450, 1409, 1276 cm21; dH
1CDCl3) 1.00±1.80 14H, m, cyclopropCHaHbCHc,
CHdHeCH2) 1.20±1.31 112H, m, 2CMe2), 1.65 14H, s,
CH2CH2), 2.00±2.47 12H, m, CHdHeCH2), 2.12 13H, s,
ArMe), 2.65±2.82 11H, m, CHdHe), 5.72 11H, s, CvCH),
7.10 11H, s, ArH), 7.2411H, s, Ar H), 7.30±7.45 12H, m,
2ArH), 7.80±7.90 12H, m, 2ArH). dC 1CDCl3) 172.7,
151.5,143.3, 143.1, 142.0, 139.0, 136.1, 135.5, 135.4,
133.4, 129.9, 129.7, 127.7, 127.2, 119.1, 39.8, 35.3, 35.1,
33.9, 33.8, 32.0, 31.9, 29.7, 26.8, 26.4, 19.7, 18.7. HRMS
calcd for C29H34O2: 414.2559; found: 414.2559.
2.1.11. 5--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)bicyclo[3.1.0]hexan-2-one -13). In an identical
manner to compound 18), a mixture of 112) 1610 mg,
2 mmol), pyridinium chlorochromate 1880 mg, 4mmol)
and dichloromethane 140 mL) gave 113) 1590 mg, 97%) as
a white solid mp 128.5±1298C. IR 1KBr) 2955, 1729 1CO),
1615, 1502, 1457, 1361 cm21. dH 1CDCl3) 1.21 16H, s,
CMe2), 1.22 16H, s, CMe2), 1.47 11H, t, Jˆ5.0 Hz, cyclo-
propCHaHb), 1.50±1.53 11H, m, cyclopropCHaHb), 1.65
14H, s, CH2CH2), 2.03 11H, dd, Jˆ8.4, 3.5 Hz, cyclo-
propCHc), 2.10±2.40 14H, m, CH2CH2), 2.33 13H, s,
ArMe), 7.07 11H, s, ArH), 7.11 11H, s, ArH). dC 1CDCl3)
214.8, 144.3, 142.8, 136.8, 134.6, 128.6, 127.6, 37.7,
35.2, 35.2, 34.1, 34.0, 34.0, 33.7, 32.0, 32.0, 31.9, 29.7,
20.6, 19.1. HRMS calcd for C21H28O: 296.2140; found:
296.2135.
2.1.9. 3--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)cyclopent-2-enone -2). To
a mixture of
dichlorobis1triphenylphosphine)palladium1II) 1220 mg, 0.3
mmol), sodium acetate 12.1 g, 15 mmol) and 3-chloro-
cyclopentpent-2-enone 11.2 g, 10.3 mmol) in methanol
135 mL) at room temperature under nitrogen was added
5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene-
boronic acid 111) 12.7 g, 11 mmol) and the mixture heated at
re¯ux for 3 h, cooled to room temperature and ®ltered
through a plug of Celite. Concentration under reduced
pressure and chromatography 1hexane/ethyl acetate 2:1)
gave 12) 12.0 g, 65%) as a white solid mp 87±888C. IR
1KBr) 2959, 1677 1CO), 1610, 1584, 1454 cm21. dH
1CDCl3) 1.27 112H, s, 2CMe2), 1.65 14H, s, CH2CH2),
2.47 13H, s, ArMe), 2.52±2.59 12H, m, CH2CH2CO),
3.01±3.10 12H, m, CH2CO), 6.32 11H, s, CvCH), 7.18
11H, s, ArH), 7.42 11H, s, ArH). dC 1CDCl3) 209.9, 175.7,
147.1, 142.8, 133.3, 132.5, 131.6, 129.6, 125.6, 34.9, 34.9,
34.2, 34.0, 31.9, 31.8, 31.6, 21.6. HRMS calcd for C20H26O:
282.1984; found: 282.1988.
2.1.12. 4-[5--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)bicyclo[3.1.0]hex-2-ylidenemethyl]-
benzoic acid -14). In an identical manner to compound 18),
sodium hydride 1180 mg of 60% in mineral oil, 4.5 mmol)
in THF 15 mL), 3-1diethoxyphosphorylmethyl)benzoic acid
methyl ester 11.3 g, 4.5 mmol) in THF 13 mL), 113)
1270 mg, 0.9 mmol) and 15-crown-5 10.9 mL, 4.5 mmol)
gave a mixture of the methyl and ethyl ester of 114)
1390 mg, 99%) which were used directly in the next step.
2.1.10. 5--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaph-

A. Murray et al. / Tetrahedron 57 (2001) 7383±7390
7389
In an identical manner to compound 18), the product from
the previous step 1390 mg) and aqueous potassium hydrox-
ide 11 mL of 6 M) in methanol 15 mL) gave 114) 1280 mg,
75%). A pure sample 140 mg of a gum) of one of the isomers
was obtained by recrystallisation from methanol. IR 1KBr)
3432, 2954, 1692 1CO), 1362, 1272 cm21; dH 1CDCl3)
0.82±0.92 11H, m, cyclopropCHaHb), 1.13 11H, t, Jˆ
5.0 Hz, cyclopropCHaHb), 1.15±1.32 112H, m, 2CMe2),
1.40±1.46 11H, m, cyclopropCHc), 1.61 14H, s, CH2CH2),
1.90±2.10 12H, m, CH2), 2.21 13H, s, ArMe), 2.30±2.61
12H, m, CH2), 6.35 11H, s, CvCH), 6.99 11H, s, ArH),
7.12 11H, s, ArH), 7.39 11H, t, Jˆ7.0 Hz, ArH), 7.63 11H,
d, Jˆ7.3 Hz, ArH), 7.89 11H, d, Jˆ7.3 Hz, ArH), 8.16 11H,
s, ArH). HRMS calcd for C29H34O2: 414.2559; found:
414.2546. Assignable peaks of other isomer from E/Z
mixture. dH 1CDCl3) 2.28 1s, ArMe), 6.58 1s, CvCH),
7.05 11H, s, ArH), 7.20 11H, s, ArH), 7.43 11H, t, Jˆ
7.0 Hz, ArH), 7.50 11H, d, Jˆ7.3 Hz, ArH), 7.83±7.99
11H, m, ArH), 8.01 11H, s, ArH).
ArH), 8.01 12H, d, Jˆ8.4Hz, 2Ar H). dC 1CDCl3) 167.4,
162.1, 143.5, 142.5, 138.4, 135.4, 132.0, 128.8, 128.4,
127.4, 115.5, 81.3, 52.2, 35.5, 34.3, 34.2, 33.5, 32.4, 32.3,
32.2, 29.4, 29.0, 19.2, 14.3. HRMS calcd for C29H36O3:
432.2665; found: 432.2656.
The product from the previous step 1150 mg, 0.34mmol)
and aqueous potassium hydroxide 11 mL of 5 M) in
methanol 13 mL) was heated at re¯ux for 2 h. Work as
described for 15) and chromatography 1dichloromethane/
methanol 20:1) gave 116) 119 mg, 13%), as a white solid
mp 221±2228C. IR 1KBr) 3420, 2959, 1684 1CO), 1604,
1509, 1250 cm21. dH 1CDCl3) 0.75 11H, t, Jˆ4.3 Hz, cyclo-
propCHaHb), 0.92 11H, dd, Jˆ7.6, 4.3 Hz, cycloprop-
CHaHb), 1.20 112H, m, 2CMe2), 1.62 14H, s, CH2CH2),
1.70±1.85 11H, m, cyclopropCHc), 1.85±2.30 15H, m,
CH2CH2CHOH), 2.20 13H, s, ArMe), 4.95 11H, d, Jˆ
5.3 Hz, CHOAr), 6.97±7.05 13H, m, 3ArH), 7.18 11H, s,
ArH), 8.13 12H, d, Jˆ8.4Hz, 2Ar H). dC 1CDCl3) 172.1,
162.9, 143.5, 142.6, 138.4, 135.4, 132.8, 128.8, 128.4,
115.6, 81.5, 35.6, 34.3, 34.2, 33.5, 32.3, 32.2, 29.4, 29.0,
19.2, 14.3. HRMS calcd for C28H34O2: 418.2508; found:
418.2485.
2.1.13. 3-[5--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)bicyclo[3.1.0]hex-2-ylidenemethyl]ben-
zoic acid -15). In an identical manner to compound 18),
sodium hydride 1180 mg of 60% in mineral oil, 4.3 mmol)
in THF 15 mL), 4-1diethoxyphosphorylmethyl)benzoic acid
methyl ester 10.1 g, 4.3 mmol) in THF 11 mL), compound
113) 1260 mg, 0.87 mmol) and 15-crown-5 10.09 mL, 4.3
mmol) in THF 15 mL) gave a mixture of the methyl and
ethyl ester of 115) 1320 mg, 87%) which was used directly
in the next step.
2.1.15. 3--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaph-
thalen-2-yl)cyclopentanone -17). Compound 12) 1950 mg,
3.3 mmol), potassium acetate 160 mg) and platinum oxide
140 mg) in ethyl acetate 125 mL) was hydrogenated at 3 atm
for 24h. Work up as described for compound 1 4) gave 117)
1650 mg, 68%) as a white solid mp 97±98oC. IR 1KBr)
3027, 2957, 2931, 1742 1CO), 1502, 1455, 1360 cm21. dH
1CDCl3) 1.22 112H, m, 2CMe2), 1.6414H, s, C H2CH2),
1.91±2.10 11H, m, CHaHb), 2.20±2.50 14H, m, CHaHbCH2-
COCHcHd), 2.30 13H, s, ArMe), 2.52±2.65 11H, dd, Jˆ14.0,
7.0 Hz, CHcHd), 3.47±3.61 11H, m, ArCH), 7.03 11H, s,
ArH), 7.12 11H, s, ArH). dC 1CDCl3) 219.8, 143.8, 143.2,
138.8, 133.8, 129.3, 123.6, 46.4, 39.5, 39.1, 36.0, 35.9, 34.9,
34.6, 32.8, 32.7, 32.6, 32.5, 31.0, 20.2. HRMS calcd for
C20H28O: 284.2140; found: 284.2143.
In an identical manner to compound 18), the product from
the previous step 1310 mg, 0.7 mmol) and aqueous
potassium hydroxide 11 mL of 6 M) in methanol 15 mL)
gave 115) 1170 mg, 57%) as a mixture of E and Z isomers
in a ratio of approx. 6:4. IR 1KBr) 3450, 2954, 1680 1CO),
1605, 1422, 1286 cm21; dH assignable as E and Z mixture
1CDCl3) 0.79±0.91 1cyclopropCHaHb), 1.05±1.18 1t, Jˆ
5.2 Hz, cyclopropCHaHb), 1.20±1.30 1m, 2CMe2), 1.38±
1.50 1cyclopropCHc), 1.61 and 1.63 1s, CH2CH2), 2.20 and
2.30 1s, ArMe), 1.90±2.60 1m, CH2CH2), 6.32 and 6.61 1s,
CvCH), 6.98 and 7.05 1s, ArH), 7.12 and 7.20 1ArH), 7.30±
7.55 1m, 2ArH), 7.92±8.10 1m, 2ArH). HRMS calcd for
C29H34O2: 414.2559; found: 414.2553.
2.1.16. 4-[3--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)cyclopentylidenemethyl]benzoic acid
-18). In an identical manner to compound 18), sodium
hydride 1190 mg of 60% in mineral oil, 4.1 mmol) in THF
15 mL), 4-1diethoxyphosphorylmethyl)benzoic acid methyl
ester 11.18 g, 4.1 mmol) in THF 11 mL), compound 117)
1235 mg, 0.82 mmol) and 15-crown-5 10.82 mL, 4.1
mmol) gave the methyl and ethyl ester of 118) 1315 mg,
93%) as a mixture of E and Z isomers 1dH of CvCH at
6.43 and 6.49), contaminated with a trace amount of two
cyclopentenes 1dH of CvCH at 5.41 and 5.45), which was
used directly in the next step.
2.1.14. 4-[5--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)bicyclo[3.1.0]hex-2-yloxy]benzoic acid
-16). To solution of 112) 1190 mg, 0.63 mmol), triphenyl-
phosphine 1200 mg, 0.76 mmol) and 4-carbomethoxy-
phenol 1170 mg, 1.1 mmol) in THF 12 mL) at ice bath
temperature was added, dropwise, diethylazodicarboxylate
1DEAD), 1130 mg, 0.76 mmol) in THF 11 mL) and the
solution stirred for 1.5 h and a further 16 h at room tempera-
ture. Concentration under reduced pressure and chroma-
tography afforded the methyl ester of 116) 1110 mg, 54%).
IR 1KBr) 2957, 2864, 1719 1CO), 1605, 1507, 1434, 1278,
1249 cm21. dH 1CDCl3) 0.75 11H, t,Jˆ4.2 Hz, cycloprop-
CHaHb), 0.92 11H, dd,Jˆ7.6, 4.3 Hz, cyclopropCHaHb),
1.15 13H, s, CMe), 1.25 19H, s, 3CMe), 1.62 14H, s,
CH2CH2), 1.76 11H, dd, Jˆ8.4, 4.3 Hz, cyclopropCHc),
1.80±2.20 14H, m, CH2CH2), 2.32 13H, s, ArMe), 3.90
13H, s, CO2Me), 4.91 11H, d, Jˆ5.2 Hz, CHOAr), 6.98
12H, d, Jˆ8.4Hz, 2Ar H), 7.0411H, s, Ar H), 7.18 11H, s,
In an identical manner to compound 18), the product from
the previous step 1315 mg, 0.7 mmol) and aqueous potas-
sium hydroxide 12 mL of 5 M) in methanol 14mL) gave
118) 1120 mg, 41%) as a mixture of E and Z isomers,
contaminated with a trace amount of two cyclopentenes.
IR 1KBr) 2960, 1688 1CO), 1600, 1453, 1282 cm21; dH
assigned as E and Z mixture 1CDCl3) 1CDCl3) assignable
1.15±1.35 112H, m, 2CMe2), 1.62 and 1.65 14H, s,
CH2CH2), 1.80±3.20 16H, m, CH2CH2CHCH2), 2.30 and
2.32 13H, s, ArMe), 3.24±3.42 11H, m, CH2CHCH2), 6.46

7390
A. Murray et al. / Tetrahedron 57 (2001) 7383±7390
and 6.48 11H, s, CˆCH), 7.00±7.26 12H, m, 2ArH), 7.34±
7.58 12H, m, 2ArH), 7.80±8.05 12H, m, 2ArH), 11.70 11H,
br s, CO2H). HRMS calcd for C28H34O2: 402.2559; found:
402.2561.
References
1. Sporn, M. B.; Roberts, A. B.; Goodman D. S. The Retinoids:
Biology, Chemistry and Medicine, 2nd ed.
2. Mukherjee, R.; Davies, P. J. A.; Crombie, D. L.; Bischoff, E. D.;
Cesario, R. M.; Jow, L.; Hamann, L. G.; Boehm, M. F.;
Mondon, C. E.; Nadzan, A. M.; Paterniti, J. R.; Heyman,
R. A. Nature 1997, 386, 407.
2.1.17. 3-[3--3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-
naphthalen-2-yl)cyclopentylidenemethyl]benzoic acid
-19). In an identical manner to compound 18), sodium
hydride 1190 mg of 60% in mineral oil, 4.1 mmol) in THF
15 mL), 3-1diethoxyphosphorylmethyl)benzoic acid methyl
ester 11.18 g, 4.1 mmol) in THF 11 mL), compound 117)
1235 mg, 0.82 mmol) and 15-crown-5 11.6 mL, 8.2 mmol)
gave the methyl and ethyl ester of 119) 1315 mg, 93%) as a
mixture of E and Z isomers 1dH of CvCH at 6.44 and 6.50),
contaminated with a trace amount of two cyclopentenes 1dH
of CvCH at 5.42 and 5.49) which was used directly in the
next step.
3. Farmer, L. J.; Jeong, S.; Kallel, E. A.; Koch, S. S. C.; Croston,
G. E.; Flatten, K. S.; Heyman, R. A.; Nadzan, A. M. Bioorg.
Med. Chem. Lett. 1997, 7, 2393.
4. Vuligonda, V.; Lin, Y.; Chandraratna, R. A. S. Bioorg. Med.
Chem. Lett. 1996, 6, 213.
5. Beard, R. L.; Chandraratna, R. A. S.; Colon, D. F.; Gillett, S. J.;
Henry, E.; Marler, D. K.; Song, T.; Denys, L.; Garst, M. E.;
Taghreed, A.; Klein, E.; Gil, D. W.; Wheeler, L.; Kochhar,
D. M.; Davies, P. J. A. J. Med. Chem. 1995, 38, 2820.
6. For reviews of this reaction see: 1a) Schore, N. E. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, pp. 1037±1064. 1b) Pauson,
P. L. Tetrahedron 1985, 41, 5855. 1c) Chung, Y. K. Coord.
Chem. Rev. 1999, 188, 297. 1d) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263.
In an identical manner to compound 18), the product from
the previous step 1310 mg, 0.7 mmol) and aqueous potas-
sium hydroxide 12 mL of 5 M) in methanol 13 mL) gave
compound 119) 1160 mg, 54%) as a mixture of E and Z
isomers contaminated with trace amounts of two cyclo-
pentenes. IR 1KBr) 2958, 1682 1CO), 1605, 1421, 1317,
1288 cm21; dH assigned as E and Z mixture 1CDCl3)
1.12±1.31 112H, m, 2CMe2), 1.62 14H, s, CH2CH2),
2.25 and 2.32 13H, s, ArMe), 1.60±3.12 16H, m,
CH2CH2CHCH2), 3.25±3.48 11H, m, CH2CHCH2), 6.45
and 6.47 11H, s, CvCH), 6.98±7.23 12H, m, 2ArH),
7.26±7.45 12H, m, 2ArH), 7.80±8.01 12H, m, 2ArH),
11.80 11H, br s, CO2H). HRMS calcd for C28H34O2:
402.2559; found: 402.2542.
7. 1a) Gordon, A. R.; Johnstone, C.; Kerr, W. J. Synlett 1995, 1083.
1b) Donkervoort, J. G.; Gordon, A. R.; Johnstone, C.; Kerr,
W. J.; Lange, U. Tetrahedron 1996, 52, 7391.
8. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 1355.
9. Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974.
Acknowledgements
We thank Jùrgen Mùller and Ole Sùrensen 1University of
Odense) for mass spectra determination.