Use of the transannular Diels-Alder (TADA) reaction to probe biological receptors: Rational design and synthesis of tricyclic TADA adducts capable of rigidly holding pharmacophore parts

Article abstract of DOI:10.1139/v02-064

Transannular Diels-Alder (TADA) adducts constitute a collection of rigid structures, whose conformational diversity is rich. It is possible to design such specifically functionalized molecules capable of binding to known biological targets by molecular modelling MCSS-HOOK (multiple copy simultaneous search). Here we show that such carefully designed compounds can be easily built from small synthons. TADA adducts are very interesting due to their huge conformational diversity, their rigidity (biological interest), and their ease of synthesis (chemical interest).

Full text of DOI:10.1139/v02-064

875
Use of the transannular Diels–Alder (TADA)
reaction to probe biological receptors: Rational
design and synthesis of tricyclic TADA adducts
capable of rigidly holding pharmacophore parts
Yves A. Chantigny, Yves L. Dory, András Toró, and Pierre Deslongchamps
Abstract: Transannular Diels–Alder (TADA) adducts constitute a collection of rigid structures, whose conformational
diversity is rich. It is possible to design such specifically functionalized molecules capable of binding to known biolog-
ical targets by molecular modelling MCSS–HOOK (multiple copy simultaneous search). Here we show that such care-
fully designed compounds can be easily built from small synthons. TADA adducts are very interesting due to their
huge conformational diversity, their rigidity (biological interest), and their ease of synthesis (chemical interest).
Key words: tricycles, synthesis, transannular Diels–Alder, macrocyclization, conformation, diversity.
Résumé : Les adduits de la réaction Diels–Alder transannulaire (DATA) constituent une banque de structures rigides
dont la diversité conformationnelle est riche. Il est possible de concevoir de telles molécules spécifiques
fonctionnalisées capables de se lier à des cibles biologiques connues, par modélisation moléculaire MCSS–HOOK.
Nous montrons ici que de tels composés soigneusement sélectionnés peuvent être aisément assemblées à partir de petits
synthons. L’intérêt de telles molécules se situe donc à trois niveaux : leur diversité conformationnelle étendue, leur
rigidité (intérêt biologique), et leur relative facilité de synthèse (intérêt chimique).
Mots clés : tricycles, synthèse, Diels–Alder transannulaire, macrocyclisation, conformation, diversité. Chantigny et al.
884
Introduction
realistic potential for the creation of molecular diversity and
for the synthesis of original structures.
Generating molecular diversity constitutes an important
tool for pharmaceutical chemists to discover new drug leads
and to study biological targets (1). To date, nature is still one
of the most important sources of original structures, al-
though chemists have devised numerous ways to generate
the sought-after diversity (2). We too have added milestones
to this continuous and general synthetic effort by preparing
libraries of macrocycles (3–7). By incorporating a diene and
a dienophile within a macrocycle, a transannular Diels–Alder
(TADA) reaction can occur (8–10). We have already made a
thorough investigation of this reaction and showed that it is a
powerful method in organic synthesis. In this work, we want
to further demonstrate that the TADA reaction also offers a
Molecular modelling design of our targets
The TADA macrocyclic precursors can be easily prepared
from building blocks, and each of these macrocycles can be
divided into four regions (Fig. 1). The reacting part includes
two regions: the dienophile, which can be either cis (C) or
trans (T), and the diene, which can be TT, TC, or CT, but
not CC since no TADA adducts have ever been obtained
from that particular diene geometry (11). The other two re-
gions are the tethers, which define the size and shape of the
resulting A and C rings of the TADA adducts. Our previous
studies indicated that TADA adducts can reasonably be ex-
pected for five- to seven-membered rings for A and C (12).
According to these limitations, there are 54 TADA
macrocyclic precursors that can be prepared, which yield
144 tricycles after the reaction. The adducts are more nu-
merous than the macrocyclic trienes because each TT diene
can give rise to two products and because the enantiomers
must also be included. It is obvious that many positions of
these 54 bare macrocycles can be substituted so that the di-
versity expands accordingly. Such huge diversity can, in
principle, be exploited in combinatorial libraries.
Received 11 December 2001. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 3 July 2002.
In memory of Professor Raymond U. Lemieux.
Y.A. Chantigny and A. Toró. Laboratoire de synthèse
organique, Département de chimie, Institut de pharmacologie
de Sherbrooke, Université de Sherbrooke, 3001, 12e avenue
Nord, Sherbrooke, QC J1H 5N4, Canada.
Y.L. Dory and P. Deslongchamps.l Laboratoire de
modélisation moléculaire, Département de chimie, Institut de
pharmacologie de Sherbrooke, Université de Sherbrooke,
3001, 12e avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
Another important aspect of the TADA approach resides
in the rigidity of the resulting tricyclic frameworks. The 144
tricycles are sufficiently different from each other, so that
conformational diversity arises as well. This important
aspect can be fruitfully used when carrying out computa-
1Corresponding author (e-mail:
pierre.deslongchamps@courrier.usherb.ca).
Can. J. Chem. 80: 875–884 (2002)
DOI: 10.1139/V02-064
© 2002 NRC Canada

876
Can. J. Chem. Vol. 80, 2002
Fig. 1. Diversity generated by means of the TADA reaction.
Scheme 1.
C or T
OTBDPS
c)
TADA
X
m
n
OTBDPS
OTHP
3 X = OH
RO
a)
b)
OTHP
e)
O
4 X = OMs
TT or TC or CT
n
5
m
7 and 5
7
7 R = H (92%)
d)
5 X = I (99%)
54 macrocycles
144 tricycles
6
8 R = MOM (97%)
f)
Fig. 2. Use of TADA tricyclic adducts to hold parts pharma-
cophores.
X
OTBDPS
X
OTHP
MOMO
g)
MOMO
g)
H
OC
HO
H
5
.5
9 X = OH (95%)
10 X = OH (95%)
t
o
NHR
X
HO
6
Å
OC
OC
NHR
NHR
12 X = Cl (90%)
13 X = Cl (91%)
e)
OH
h)
h)
CO2Me
CO2Me
X
X
X
X
1 R = npentyl
2 R =
RO
CO2Me
MOMO
MOMO
MOMO
CO2Me
16 X = OTBDPS (89%)
18 X = OH (81%)
20 X = Cl (99%)
j)
dienophile: C
diene: TC
m = 6; n = 5
15 X = OTHP (71%)
17 X = OH (82%)
19 X = Cl (94%)
f)
e)
g)
11 X = OH (97%)
14 X = Cl (75%)
k)
i)
g)
tional drug design, in particular by means of MCSS–HOOK
(multiple copy simultaneous search) (13–15). A search on
the stain P1/Mahomey of the polyovirus by means of the
MCSS method yielded valuable information about the posi-
tions, where simple molecules such as water, methanol,
amines, and amides, could best interfere with the virus (16).
Given the positions and orientations of the suitable func-
tional sites (Fig. 2), HOOK then systematically searched a
database of our tricyclic adducts for skeletons that logically
connected these binding sites in the presence of the virus.
Two structures (1 and 2), having a trans-syn-cis (TSC) ge-
ometry, were obtained as result of that protocol. Both com-
pounds differ only by the nature of their amine moiety;
therefore, they can be prepared from the same adequately
protected 13-membered tricycle bearing a cis (C) dienophile
and a trans–cis (TC) diene, as previously shown in our
model studies (17).
j)
CO2Me
CO2Me
CN
CO2Me
MOMO
MOMO
22
21
(79%)
(43% from 19)
(50% from 20)
a) MsCl, Et3N, CH2Cl2, 0ºC. b) NaI, acetone, reflux. c) t-BuLi, THF, -78ºC. d) KHMDS,
MOMCl, THF, 0ºC to 70ºC. e) TBAF, THF, rt. f) PPTS, i-PrOH, reflux.g) Ph P, HCA,
CH2Cl2, 0ºC. h) CH2(CO2Me)2, NaH, NaI, THF 0ºC to 70ºC. i) Ph3P, HCA, CH2Cl2, -20ºC.
j) Cs2CO3, CsI, MeCN, 70ºC, slow addition. k) NCCH2CO2Me, Cs2CO3, THF:DMF (2:1),
80ºC, slow addition.
3
The remaining allylic ether was then cleaved with PPTS to
yield alcohol 17 (82%), which was transformed as before
into its corresponding allylic chloride 19 (94%). The other
macrocyclization precursor (20), which would lead to the
same macrocycle (21), was prepared from the same triether
(8) by a very similar pathway, with an overall yield of 62%
for the five-step sequence. Alternatively, alcohol 10 (ob-
tained from 8 with a yield of 95%) en route to 20, was trans-
formed into diol 11 by means of TBAF (97% yield).
Dichloride 14 was then prepared in 75% yield by means of
HCA and Ph3P as before, but at lower temperature. All three
allylic chlorides (19, 20, and 22) were then subjected to
high-dilution macrocyclization conditions. Isomeric chlo-
rides 19 and 20 yielded the same racemic macrocycle (21)
with similar yields (43 and 50%, respectively) when slowly
injected into a mixture of cesium carbonate in acetonitrile. A
much better yield of 79% was obtained for the synthesis of
macrocycle 22 (mixture of racemic diastereoisomers) when
a mixture of methyl cyanoacetate and dichloride 14 in THF
was added slowly to a suspension of cesium carbonate in
THF and DMF (21). In summary, 21 was obtained from 3,
via 19 and 20, with overall yields of 18 and 27%, respec-
tively; the yield for 22, however, was as high as 51%. Con-
sequently, it proved easier to prepare substantial quantities of
macrocycle 22 to carry on with the synthesis of 1 and 2.
Both macrocycles 21 and 22 were heated at 140°C to pro-
voke the TADA reaction (Scheme 2) — the expected TSC
Synthesis
In terms of ease of synthesis, the macrocyclic trienes 21
and 22 (Scheme 1) were identified as being the most suitable
TADA precursors. They were prepared in 10 and eight steps,
respectively, from the same starting materials 3 and 6 (18,
19). Alcohol 3 was activated as its corresponding mesylate
4, and subsequently treated with sodium iodide in acetone
without purification. Resulting iodide 5 was obtained in 99%
yield for the two steps. Upon treatment with tert-
butyllithium at –78°C, iodide 5 was transformed into its cor-
responding anion. Addition of aldehyde 6 to the reaction
mixture led to alcohol 7 as a mixture of diastereoisomers
with a yield of 92%. The alcohol functionality was protected
as methoxymethyl ether 8 in 97% yield. The silyl ether was
then cleaved with tetrabutyl ammonium fluoride (TBAF) to
yield allylic alcohol 9 (95% yield). Allylic chloride 12 was
obtained from the preceding alcohol by means of
hexachloroacetone (HCA) and triphenylphosphine (Ph3P)
(90%) (20). SN2 nucleophilic attack of sodium dimethyl
malonate onto the allylic iodide (formed in situ by sodium
iodide) led to monosubstituted malonate 15 in 71% yield.
© 2002 NRC Canada

Chantigny et al.
877
Scheme 2.
Scheme 3.
H
H
H
H
H
CN
CN
CN
)
H
RO
H
H
H
+
E
H
b)
H
H
H
O
O
CO2Me
MOMO
a)
26 R = MOM
28 (48%)
29 (32%)
b) E = CO2Me
c) E = CN
a)
21 E = CO2Me
22 E = CN
27 R = H (99%)
H
H
CO2H
e)
c)
OH
I
E
H
H
H
E
H
H
CN
CO2Me
H
c) E = CN
H
H
H
HO
H
RO
f)
O
H
O
31 (90%)
d)
32
H
H
MOMO
MOMO
25 E = CO2Me
(90% from 21) (89% from 22)
(97% from 24)
H
23 E = CO2Me (100%)
24 E = CN (78%)
26 E = CN
30 R = H (85%)
H
CO2H
d)
H
33 R = TIPS (99%)
H
H
TIPSO
a) xylenes, 140ºC, 4h. b) NaCl, DMSO, 160ºC. c) NaCN, DMSO, 160ºC.
O
34 (83%)
H
NH
h)
H
g)
O
O
H
H
tricycles 23 and 24 were obtained with good yields of 100
and 78%, respectively. Tricycle 23 was produced as a 2:1
mixture (ꢀ or ꢁ at C4) of two racemic diastereoisomers,
whereas 24 was obtained as a mixture of racemic diastereo-
isomers at C4 and C12. Demethoxycarbonylation of 24 was
then performed at 160°C in dimethyl sulfoxide with sodium
cyanide (97% yield) (22). Since demethoxycarbonylation oc-
curs at high temperature, we tried successfully to induce
both demethoxycarbonylation and TADA together by treat-
ing macrocycles 21 and 22 under demethoxycarbonylation
conditions. Thus, 21 led to tricycle 25 (90%), when heated
at 160°C in DMSO that contained sodium chloride (22); 22
gave 26 in 89% yield when it was treated under identical
conditions previously used to prepare 26 from 24. This con-
firmed our choice of selecting cyanide 26 (rather than
methyl ester 25) for further work, since it is obtained from 3
with an overall yield of 45%.
NH
NH
RO
+
H
H
H
H
H
H
35 R = TIPS (80%)
1 R = H (81%)
H
i)
H
RO
RO
i)
+
+
37 R = TIPS (73%)
36
2
38 R = H (84%)
a) 6N HCl, MeOH, rt. b) Dess-Martin, CH2Cl2, rt. c) i Li tri-ibutylborohydride, THF,
-78ºC; ii NaOH, H2O2, rt. d) NaOH, H2O2, MeOH, reflux. e) Na2CO3, I2, H2O, THF, rt.
f) TIPS-triflate, 2,6-lutidine, CH2Cl2, rt. g) i (COCl)2, DMF, CH2Cl2, rt.; ii amylamine,
Et3N, CH2Cl2, rt. h) i (COCl)2, DMF, CH2Cl2, rt.; ii (S)-(+)-1-aminoindane, Et3N,
CH2Cl2, rt. i) 6N HCl, MeOH, reflux
could not be separated from its diastereoisomer 38 (yield of
84%).
All that remained to be done were functional-group ma-
nipulations to introduce the amides at the nitrile position and
to address the stereochemistry of the amide and the alcohol.
To do this, methoxymethyl (MOM) ether 26 was cleaved by
means of concentrated HCl to yield alcohol 27 (99% yield)
(Scheme 3). Dess–Martin oxidation of this alcohol gave a
separable mixture of two racemic ketones 28 (48% yield)
and 29 (32% yield). To identify the relative stereochemistry
of the nitrile, the major ketone (28) was first reduced with a
bulky borohydride (lithium triisobutylborohydride) to give
exclusively ꢁ-OH TSC tricycle 30 (85%) in which the sec-
ondary alcohol exists in the axial orientation. The nitrile was
then hydrolyzed under basic conditions to corresponding
acid 31 (90%), which could undergo iodolactonization to
generate lactone 32. The identities of nitriles 28 and 29 were
inferred from that latter experiment, because no lactone can
be obtained from the carboxylic acid derived from nitrile 29.
Alcohol 30 was protected as its triisopropyl silyl (TIPS)
ether (33), with a yield of 99%, by means of TIPS triflate
and 2,6-lutidine as a base. Hydrolysis of the nitrile, as be-
fore, yielded acid 34 in 83% yield. The acid group was acti-
vated as its acid chloride with oxalyl chloride (23).
Amylamine was added to the crude acid chloride, and
racemic amide-ether 35 was obtained in 80% yield. Alterna-
tively, addition of (S)-(+)-1-aminoindane to the acid chloride
provided the corresponding amide-ether as an inseparable
mixture of racemic diastereoisomers 36 and 37 (73%).
Finally, strong acidic conditions (6 N HCl) had to be used to
cleave the silyl ethers to afford desired amide-alcohol 1, to-
gether with its enantiomer (81%). The other target (2) was
prepared in a similar manner from a mixture of 36 and 37; it
Conclusion
Compounds 1 and 2 proved not to have a significant affin-
ity for the target virus, at least no better than the threshold of
the assay, which was set in the sub-micromolar range. Nev-
ertheless, our main goal during this preliminary work was
first to demonstrate the chemical utility of TADA adducts
for drug design. Thus, TADA tricycles could be used in
combinatorial libraries, but the lack of mobility of the
tricyclic framework is usually so severe that they should be
more useful at the lead optimization stage. Rigidity, how-
ever, can be an asset when the shape of the target is pre-
cisely known from different theoretical sources (molecular
docking or other computational techniques like MCSS–
HOOK). In the latter case, rigid skeletons are necessary to
hold binding sites (functional groups) uncovered by the the-
oretical protocol. A collection of reasonably rigid TADA-
adduct tricyclic cores can easily provide the diversity neces-
sary to ensure that any combination of two or three binding
functional groups can be successfully held in the desired
spatial arrangement (within the limits of the span of tricy-
cles). In this work we have proven that, from MCSS–HOOK
calculations, adequate tricycles capable of holding binding
sites can be selected from a theoretical library of TADA-
adduct structures. The resulting chemical targets can be
synthesized in a reasonable number of steps, so that the
suggested targets can be rapidly tested. In summary, TADA
adducts are structurally attractive because their various geo-
metries can cover a large conformational space; they are also
chemically attractive because they come from macrocycles
easily assembled from smaller pieces.
© 2002 NRC Canada

878
Can. J. Chem. Vol. 80, 2002
washed with brine, dried over MgSO4, filtered, and
concentrated under vacuo. The residue was purified by flash
chromatography (hexanes–ether, 1:1) to yield the title com-
pound as an oil (14.2 g, 92%). IR (cm–1): 3444 (br), 2934,
2858, 1428, 1113, 1077, 1024, 823, 703, 614. 1H NMR
(CDCl3) ꢃ: 7.70 and 7.40 (2m, 10H, 2 phenyl), 6.49 (dd, J =
15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2), 6.10 (t, J =
11.0 Hz, 1H, CH=CHCH=CHCH2), 5.72–5.55 (m, 3H,
CH=CHCH2OSi and CH=CHCH=CH), 5.39 (m, 1H,
CH=CHCH2OSi), 4.64 (t, J = 4.0 Hz, 1H, OCHO), 4.36 (dd,
J = 6.5 Hz, 1H, CHHOTHP), 4.23 (d, J = 5.5 Hz, 2H,
CH2OSi), 4.21ꢂ4.08 (m, 2H, CHHOTHP and CHOH), 3.90
(m, 1H, OCHH of THP), 3.52 (m, 1H, OCHH of THP), 1.88
(q, J = 7.0 Hz, 2H, CH2CH2CH=CH), 1.84–1.25 (m, 10H,
other CH2), 1.06 (s, 9H, SiC(CH3)3). 13C NMR (CDCl3) ꢃ:
135.6, 133.8, 130.7, 129.5, 129.4, 127.6, 97.7, 72.2, 72.1,
62.7, 62.1, 60.2, 36.6, 30.5, 27.3, 26.7, 25.9, 25.2, 19.3, 19.0.
MS m/z: 552 ([M + NH4]+), 517 ([M – OH]+). Exact mass ([M
+ NH4]+) calcd.: 552.3509; found: 552.3500.
Experimental
The infrared (IR) spectra were taken on a PerkinElmer
1600 series FT-IR. The NMR spectra were recorded on a
Brüker AC 300 instrument. The mass spectra (MS) were ob-
tained on a ZAB-IF spectrometer. Flash chromatography
was performed on silica gel Merck 60, 230ꢂ400 mesh.
Synthesis
Methanesulfonic acid 6-(tert-butyl-diphenyl-silanyloxy)hex-
(4Z)-enyl ester (4)
To a solution of alcohol 3 (11.6 g, 32.6 mmol) and
triethylamine (6.82 mL, 48.9 mmol) in dichloromethane
(150 mL) at 0°C, was added methanesulfonyle chloride
(2.78 mL, 35.9 mmol). The mixture was stirred for 1 h and a
HCl 1 N solution (100 mL) was added. The mixture was ex-
tracted with dichloromethane (3 × 100 mL). The combined
organics were dried over MgSO4, filtered, and concentrated
under vacuo to yield the crude title compound as an oil
(used as is in the next step). IR (cm–1): 3021, 2936, 2859,
tert-Butyl-[7-methoxymethoxy-12-(tetrahydropyran-2-
yloxy)dodeca-(2Z,8E,10Z)-trienyloxy]diphenyl silane (8)
(diastereoisomers)
1
1469, 1428, 1356, 1175, 1109, 936, 823, 704, 613. H NMR
(CDCl3) ꢃ: 7.70 and 7.40 (2m, 10H, 2 phenyl), 5.65 (m, 1H,
CH=CHCH2OSi), 5.45 (m, 1H, CH=CHCH2OSi), 4.26 (d,
J = 6.5 Hz, 2H, CH2OSi), 4.12 (t, J = 7.0 Hz, 2H,
CH2OMs), 2.92 (s, 3H, SO3CH3), 2.00 (q, J = 7.0 Hz, 2H,
To a solution of alcohol 7 (1.294 g, 2.42 mmol) in THF
(25 mL) at –78°C, was added a solution of potassium
bis(trimethylsilyl) amide 0.5 M (5.81 mL, 2.9 mmol). After
15 min, methyl-methylether chloride (552 L, 7.26 mmol)
was added. After stirring for 2 h, a saturated NH4Cl solution
(30 mL) was added and the mixture was extracted with hex-
anes (3 × 20 mL). The combined organics were washed with
brine, dried over MgSO4, filtered, and concentrated under
vacuo. The residue was purified by flash chromatography
(hexanes–ether, 3:1) to yield the title compound as an oil
(1.35 g, 97%). IR (cm–1): 2940, 2858, 1428, 1113, 1078,
CH2CH2CH=CH), 1.71 (quintet,
J
=
6.5 Hz, 2H,
CH2CH2CH=CH), 1.06 (s, 9H, SiC(CH3)3). 13C NMR
(CDCl3) ꢃ: 135.4, 133.6, 130.7, 129.6, 128.6, 128.5, 69.0,
60.0, 37.1, 28.7, 26.7, 23.2, 19.0. MS m/z: 375 ([M – C4H9]+).
Exact mass (M – C4H9) calcd.: 375.1086; found: 375.1091.
tert-Butyl-(6-iodo-hex-(2Z)-enyloxy)diphenyl silane (5)
A solution of crude mesylate 4 (11.6 g, 32.6 mmol) and
sodium iodide (48.9 g, 326 mmol) in acetone (250 mL) was
heated to reflux for 1.5 h. The cooled mixture was concen-
trated under vacuo until saturation, diluted with water
(150 mL), and extracted with hexanes (3 × 150 mL). The
combined organics were washed with brine, dried over
MgSO4, filtered on Florisil, and concentrated under vacuo to
yield the title compound as an oil (15.14 g, 99% 2 steps). IR
(cm–1): 3069, 3017, 2933, 2857, 1467, 1428, 1108, 822, 703,
1
1032, 822, 741, 703, 614, 503. H NMR (CDCl3) ꢃ: 7.70
and 7.40 (2m, 10H, 2 phenyl), 6.44 (dd, J = 15.0, 11.0 Hz,
1H, CH=CHCH=CHCH2), 6.10 (t, J = 11.0 Hz, 1H,
CH=CHCH=CHCH2), 5.72–5.55 (m, 3H, CH=CHCH2OSi and
CH=CHCH=CH), 5.39 (m, 1H, CH=CHCH2OSi), 4.65 and
4.48 (2d, J = 7.0 Hz, 2 × 1H, OCH2O), 4.63 (t, J= 4.0 Hz,
1H, OCHO), 4.36 (m, 1H, CHHOTHP), 4.18 (m, 1H, CHHOTHP),
4.23 (d, J = 5.5 Hz, 2H, CH2OSi), 3.99 (q, J = 5.5 Hz, 1H,
CHOMOM), 3.87 (m, 1H, OCHH of THP), 3.52 (m, 1H,
OCHH of THP), 3.33 (s, 3H, OCH3), 1.88 (q, J = 7.0 Hz,
2H, CH2CH2CH=CH), 1.84–1.25 (m, 10H, other CH2), 1.06
(s, 9H, SiC(CH3)3). 13C NMR (CDCl3) ꢃ: 135.5, 135.2, 133.8,
130.5, 130.4, 130.3, 129.5, 129.3, 127.6, 127.5, 127.2, 98.1,
97.8, 93.6, 76.1, 62.9, 62.8, 62.2, 62.1, 60.1, 55.3, 35.1,
30.6, 27.3, 26.7, 25.4, 25.3, 19.5, 19.4, 19.1. MS m/z: 596
([M + NH4]+), 419 ([M – C4H9 – THPO]+). Exact mass
([M + NH4]+) calcd.: 596.3771; found: 596.3763.
1
612, 504. H NMR (CDCl3) ꢃ: 7.70 and 7.40 (2m, 10H,
2 phenyl), 5.65 (m, 1H, CH=CHCH2OSi), 5.45 (m, 1H,
CH=CHCH2OSi), 4.26 (d, J = 6.5 Hz, 2H, CH2OSi), 3.15
(t, J = 7.0 Hz, 2H, CH2I), 2.00 (q, J = 7.0 Hz, 2H,
CH2CH2CH=CH), 1.78 (quintet, J = 6.5 Hz, 2H, CH2CH2I),
1.06 (s, 9H, SiC(CH3)3). 13C NMR (CDCl3) ꢃ: 135.5, 133.7,
130.6, 129.6, 128.6, 128.5, 60.2, 33.1, 28.3, 26.8, 19.1, 6.9.
MS m/z: 407 ([M – C4H9]+).
12-(tert-Butyl-diphenyl-silanyloxy)-1-(tetrahydropyran-2-
yloxy)dodeca-(2Z,4E,10Z)-trien-6-ol (7) (diastereoisomers)
To a solution of tert-butyllithium 1.5 M (40 mL,
60 mmol) in ether (100 mL) at –78°C, was added dropwise
over 10 min a solution of iodide 5 (14.82 g, 32 mmol) in
ether (20 mL). After stirring for 10 min, a solution of alde-
hyde 6 (5.0 g, 25 mmol) in ether (20 mL) was added
dropwise over 10 min. The mixture was allowed to warm to
room temperature for 15 min, then cooled to –78°C, and a
saturated NH4Cl solution (40 mL) was added. The mixture
was extracted with hexanes (3 × 20 mL). The organics were
7-Methoxymethoxy-12-(tetrahydropyran-2-yloxy)-dodeca-
(2Z,8E,10Z)-trien-1-ol (9) (diastereoisomers)
A solution of methoxymethyl ether 8 (1.3 g, 2.33 mmol)
and tetrabutylammonium fluoride (1 M, 4.76 mL, 4.66 mmol)
in THF (20 mL) was stirred at –20°C overnight. The mixture
was diluted with water (100 mL) and extracted with di-
chloromethane (3 × 100 mL). The combined organics were
dried over MgSO4, filtered, and concentrated under vacuo.
The residue was purified by flash chromatography (hexanes–
ether, 1:1 to 3:7) to yield the title compound as an oil
© 2002 NRC Canada

Chantigny et al.
879
(744 mg, 95%). IR (cm–1): 3460, 2941, 2882, 1455, 1387,
1349, 1205, 1120, 1031, 912. H NMR (CDCl3) ꢃ: 6.44 (dd,
4.15 (d, J = 6.0 Hz, 2H, CH2CH=CHCH2OH), 4.05 (q, J =
7.0 Hz, 1H, CHOMOM), 3.35 (s, 3H, OCH3), 2.10 (q, J =
7.0 Hz, 2H, CH2CH2CH=CH), 1.70–1.30 (m, 4H, other
CH2). 13C NMR (CDCl3) ꢃ: 135.2, 132.4, 130.3, 129.7,
128.8, 127.1, 93.6, 16.2, 58.6, 58.4, 55.4, 64.8, 27.1, 25.2.
MS m/z: 225 ([M – OMe]+), 211 ([M – MOM]+). Exact
mass ([M – OMe]+) calcd.: 225.1491; found: 225.1485;
([M – C2H5O]+) calcd.: 211.1334; found: 211.1340.
1
J = 15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2), 6.10 (t, J =
11.0 Hz, 1H, CH=CHCH=CHCH2), 5.68–5.50 (m, 4H,
CH=CH and CH=CHCH=CH), 4.67 and 4.51 (2d, J =
7.0 Hz, 2 × 1H, OCH2O), 4.65 (t, J = 4.0 Hz, 1H, OCHO),
4.42ꢂ4.20 (m, 2H, CH2OTHP), 4.18 (d, J = 6.5 Hz, 2H,
CH2OH), 4.07 (q, J = 5.5 Hz, 1H, CHOMOM), 3.87 (m, 1H,
OCHH of THP), 3.52 (m, 1H, OCHH of THP), 3.38 (s, 3H,
OCH3), 2.13 (q, J = 7.0 Hz, 2H, CH2CH2CH=CH), 1.90–
1.35 (m, 10H, other CH2). 13C NMR (CDCl3) ꢃ: 134.8,
134.6, 128.9, 128.7, 127.0, 123.53, 123.5, 119.2, 98.7, 95.6,
92.0, 91.8, 91.3, 91.1, 77.9, 60.4, 56.3, 55.9, 26.8, 26.4,
25.0, 23.8, 23.6, 22.0, 19.0.
2-(12-Chloro-6-methoxymethoxy-dodeca-(2Z,4E,10Z)-
trienyloxy)-tetrahydro-pyran (12) (diastereoisomers)
To a solution of alcohol 9 (420 mg, 1.25 mmol) and
hexachloroacetone (228 L, 1.5 mmol) in dichloromethane
(10 mL) at 0°C was added triphenylphosphine (492 mg,
1.9 mmol). The mixture was allowed to warm to room tem-
perature and stirred 45 min. The mixture was concentrated
under vacuo and purified by flash chromatography
(hexanes–ether, 9:1) to yield the title compound as an oil
(397 mg, 90%). IR (cm–1): 2942, 1454, 1032. 1H NMR
(CDCl3) ꢃ: 6.44 (dd, J = 15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2),
6.10 (t, J = 11.0 Hz, 1H, CH=CHCH=CHCH2), 5.68–5.50
(m, 4H, CH=CH and CH=CHCH=CH), 4.67 and 4.51 (2d,
J = 7.0 Hz, 2 × 1H, OCH2O), 4.65 (t, J = 4.0 Hz, 1H, OCHO),
4.42ꢂ4.20 (m, 2H, CH2OTHP), 4.07 (d, J = 7.0 Hz, 2H,
CH2Cl), 4.07 (q, J = 5.5 Hz, 1H, CHOMOM), 3.87 (m, 1H,
OCHH of THP), 3.52 (m, 1H, OCHH of THP), 3.38 (s, 3H,
OCH3), 2.14 (q, J = 7.0 Hz, 2H, CH2CH2CH=CH), 1.90–
1.35 (m, 10H, other CH2). 13C NMR (CDCl3) ꢃ: 135.0,
134.9, 130.4, 127.8, 127.4, 125.5, 98.1, 97.9, 93.7, 76.1,
62.9, 62.8, 62.3, 62.2, 55.4, 39.4, 35.0, 30.6, 26.9, 25.4,
25.0, 19.5, 19.4.
12-(tert-Butyl-diphenyl-silanyloxy)-6-methoxymethoxy-
dodeca-(2Z,4E,10Z)-trien-1-ol (10)
A solution of silylether 8 (1.57g, 2.72 mmol) and
pyridinium p-toluenesulfonate (171 mg, 681 mol) in
isopropanol (50 mL) was stirred at reflux for 1 h. The solu-
tion was allowed to cool to room temperature and sodium
bicarbonate (57.2 g, 681 mol) was added. The mixture was
concentrated under vacuo, water (50 mL) was added, and the
mixture extracted with dichloromethane (3 × 50 mL). The
combined organics were dried over MgSO4, filtered, and
concentrated under vacuo. The residue was purified by flash
chromatography (hexanes–ether, 3:1) to yield the title com-
pound as an oil (1.09 g, 81%). IR (cm–1): 3422, 2932, 2858,
1473, 1429, 1149, 1111, 1031, 824, 741, 702. 1H NMR
(CDCl3) ꢃ: 7.70 and 7.40 (2m, 10H, 2 phenyl), 6.42 (dd, J
= 15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2), 6.05 (t, J =
11.0 Hz, 1H, CH=CHCH=CHCH2), 5.72–5.55 (m, 3H,
CH=CHCH2OSi and CH=CHCH=CH), 5.46–5.35 (m, 1H,
CH=CHCH2OSi), 4.65 and 4.49 (2d, J = 7.0 Hz, 2 × 1H,
OCH2O), 4.30 (dd, J = 7.0, 1.0 Hz, 2H, CH2OH), 4.24
(dd, J = 6.0, 1.0 Hz, 2H, CH2OSi), 3.99 (q, J = 5.5 Hz, 1H,
CHOMOM), 3.33 (s, 3H, OCH3), 1.90 (q, J = 7.0 Hz, 2H,
CH2CH2CH=CH), 1.60–1.25 (m, 4H, other CH2), 1.04 (s,
9H, SiC(CH3)3). 13C NMR (CDCl3) ꢃ: 135.615, 135.527,
135.414, 133.979, 130.536, 130.109, 129.667, 129.527,
129.402, 127.590, 126.916, 93.597, 76.188, 60.176, 58.661,
55.345, 35.045, 27.344, 26.756, 25.308, 19.092. MS m/z:
512 ([M + NH4]+). Exact mass ([M + NH4]+) calcd.:
512.3196; found: 512.3197.
tert-Butyl-(12-chloro-7-methoxymethoxy-dodeca-
(2Z,8E,10Z)-trienyloxy)diphenyl silane (13)
Prepared similar to chloride 12 (91%). IR (cm–1): 3016,
2932, 2858, 1472, 1428, 1149, 1112, 1031, 824, 703, 614.
1H NMR (CDCl3) ꢃ: 7.70 and 7.40 (2m, 10H, 2 phenyls),
6.43 (dd, J = 15.0, 11.5 Hz, 1H, CH=CHCH=CHCH2), 6.12
(t, J = 11.0 Hz, 1H, CH=CHCH=CHCH2), 5.66–5.55 (m,
3H, CH=CHCH2OSi and CH=CHCH=CH), 5.45–5.34 (m,
1H, CH=CHCH2OSi), 4.65 and 4.50 (2d, J = 7.0 Hz, 2 ×
1H, OCH2O), 4.22 (d, J = 6.5 Hz, 2H, CH2OSi), 4.19 (d, J =
8.5 Hz, 2H, CH2Cl), 4.03 (q, J = 5.5 Hz, 1H, CHOMOM),
3.34 (s, 3H, OCH3), 1.89 (q,
J = 7.0 Hz, 2H,
CH2CH2CH=CH), 1.60–1.24 (m, 4H, other CH2), 1.06 (s,
9H, SiC(CH3)3). 13C NMR (CDCl3) ꢃ: 137.1, 135.6, 135.5,
134.7, 133.8, 131.8, 130.5, 129.5, 129.4, 127.6, 125.9,
125.6, 93.7, 76.0, 60.1, 55.3, 39.3, 34.9, 27.3, 26.7, 26.5,
25.2, 19.1. MS m/z: 477 ([M – Cl]+), 455 ([M – C4H9]+),
451 ([M – CH3OCH2O]+). Exact mass ([M – C4H9]+) calcd.:
455.1809; found: 455.1812.
6-Methoxymethoxy-dodeca-(2Z,4E,10Z)-triene-1,12-diol (11)
To a solution of alcohol 10 (1.19 g, 2.41 mmol) in THF
(35 mL) at 0°C was added a solution of tetrabutylammonium
fluoride (1 M in THF, 4.81 mL, 4.81 mmol). The mixture
was allowed to warm to room temperature and stirred for
1.25 h. A saturated NH4Cl solution (50 mL) was added and
the mixture was extracted with dichloromethane (3 × 30 mL).
The combined organics were dried over MgSO4, filtered, and
concentrated under vacuo. The residue was purified by flash
chromatography (ethyl acetate) to yield the title compound
as an oil (599 mg, 97%). IR (cm–1): 3372, 2944, 1460, 1440,
1,12-Dichloro-6-methoxymethoxy-dodeca-(2Z,4E,10Z)-
triene (14)
To a solution of diol 11 (599 mg, 2.34 mmol) and
triphenylphosphine (1.72 g, 6.55 mmol) in dichloromethane
(35 mL) at 0°C was added hexachloroacetone (426 L,
2.81 mol). The solution was allowed to warm to room tem-
perature and stirred for 20 min. The mixture was concen-
trated under vacuo and purified by flash chromatography
(100% hexanes then 95:5 hexanes–ether) to yield the title
compound as an oil (514 mg, 75%). IR (cm–1): 2931, 1453,
1
1150, 1095, 1029, 855. H NMR (CDCl3) ꢃ: 6.45 (dd, J =
15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2), 6.06 (t, J =
11.0 Hz, 1H, CH=CHCH=CHCH2), 5.66–5.45 (m, 4H,
CH=CH, CH=CHCH=CH), 4.66 and 4.49 (2d, J = 7.0 Hz, 2 ×
1H, OCH2O), 4.30 (d, J = 7.0 Hz, 2H, CH=CHCH=CHCH2OH),
© 2002 NRC Canada

880
Can. J. Chem. Vol. 80, 2002
1
1251, 1031, 762. H NMR (CDCl3) ꢃ: 6.47 (dd, J = 15.0,
11.0 Hz, 1H, CH=CHCH=CHCH2), 6.15 (t, J = 11.0 Hz,
1H, CH=CHCH=CHCH2), 5.7–5.58 (m, 4H, CH=CH and
CH=CHCH=CH), 4.69 and 4.51 (2d, J = 7.0 Hz, 2 × 1H, OCH2O),
4.20 (dd, J = 8.0, 2.5 Hz, 2H, CH=CHCH=CHCH2Cl), 4.10
(d, J = 7.0 Hz, 2H, CH=CHCH2Cl), 4.15ꢂ4.00 (m, 1H,
CHOMOM), 3.38 (s, 3H, OCH3), 2.15 (q, J = 7.0 Hz, 2H,
CH2CH2CH=CH), 1.70–1.40 (m, 4H, other CH2). 13C NMR
(CDCl3) ꢃ: 136.9, 134.7, 131.7, 126.0, 125.7, 125.5, 93.8,
75.8, 55.4, 39.3, 34.9, 26.7, 24.9. MS m/z: 310 ([M +
NH4]+). Exact mass ([M + NH4]+) calcd.: 310.1340; found:
310.1333.
26.7, 25.3, 19.0. MS m/z: 551 ([M – C4H9]+). Exact mass
([M – C4H9]+) calcd.: 551.2465; found: 551.2456.
2-(12-Hydroxy-7-methoxymethoxy-dodeca-(2Z,8E,10Z)-
trienyl)malonic acid dimethyl ester (17)
A solution of malonate 15 (693 mg, 1.54 mmol) and pyri-
dinium p-toluenesulfonate (77 mg, 0.31 mmol) in methanol
(8 mL) was heated to reflux for 3 h. The mixture was cooled
to room temperature, sodium bicarbonate (26 mg) was
added, and the mixture was concentrated under vacuo. The
residue was purified by flash chromatography (hexanes–
ether, 1:3) to yield the title compound as an oil (401 mg,
73%). IR (cm–1): 3393, 2932, 1733, 1649, 1628, 1430, 1030.
1H NMR (CDCl3) ꢃ: 6.45 (dd, J = 15.0, 11.0 Hz, 1H,
CH=CHCH=CHCH2), 6.08 (t, J = 11.0 Hz, 1H, CH=
CHCH=CHCH2), 5.68–5.40 (m, 3H, CH=CHCH2CH and
CH=CHCH=CH), 5.30 (m, 1H, CH=CHCH2CH), 4.67 and
4.51 (2d, J = 6.5 Hz, 2 × 1H, OCH2O), 4.32 (d, J = 7.0 Hz,
2H, CH2OH), 4.07 (q, J = 5.5 Hz, 1H, CHOMOM), 3.73 (s,
6H, CO2CH3), 3.40 (t, J = 4.0 Hz, 1H, CH(CO2Me)2),
3.38 (s, 3H, OCH2OCH3), 2.64 (t, J = 7.5 Hz, 2H,
CH2CH(CO2Me)2), 2.09 (q, J = 7.0 Hz, 2H, CH2CH2CH=CH),
1.70–1.35 (m, 4H, other CH2). 13C NMR (CDCl3) ꢃ: 169.3,
135.0, 132.6, 130.4, 129.3, 127.1, 124.7, 93.4, 76.1, 58.4,
55.3, 52.4, 51.5, 34.9, 26.9, 26.6, 25.4.
2-[7-Methoxymethoxy-12-(tetrahydropyran-2-yloxy)-
dodeca-(2Z,8E,10Z)-trienyl]malonic acid dimethyl ester
(15) (diastereoisomers)
To a suspension of sodium hydride 60% (200 mg,
5 mmol) in a DMF–THF solution (2:1, 15 mL) at 0°C, was
added dropwise dimethylmalonate (640 L, 5.6 mmol). The
mixture was allowed to warm to room temperature and
stirred 30 min. This solution was added to a solution of
chloride 12 (397 mg, 1.12 mmol) and sodium iodide
(168 mg, 1.12 mmol) in THF (10 mL) and heated to 70°C
for 2 h. A saturated NH4Cl solution (40 mL) was added to
the cooled mixture and extracted with hexanes (3 × 20 mL).
The combined organics were washed with brine, dried over
MgSO4, filtered, and concentrated under vacuo. The residue
was purified by flash chromatography (hexanes–ether, 9:1)
to yield the title compound as an oil (358 mg, 71%). IR (cm–1):
2-(12-Hydroxy-6-methoxymethoxy-dodeca-(2Z,4E,10Z)-
trienyl)malonic acid dimethyl ester (18)
Compound 18 was prepared similar to alcohol 9 (81%).
IR (cm–1): 3448, 3012, 2951, 1738, 1437, 1344, 1275, 1233,
1
2949, 1738, 1437, 1343, 1272, 1234, 1201, 1150, 1030. H
1
1150, 1096, 1032, 919, 738. H NMR (CDCl3) ꢃ: 6.45 (dd,
NMR (CDCl3) ꢃ: 6.44 (dd, J = 15.0, 11.1 Hz, 1H, CH=CH-
CH=CHCH2), 6.10 (t, J = 11.0 Hz, 1H, CH=CHHC=
CHCH2), 5.65–5.40 (m, 3H, CH=CHCH2CH and CH=
CHCH=CH), 5.30 (m, 1H, CH=CHCH2CH), 4.67 and 4.51
(2d, J = 6.5 Hz, 2 × 1H, OCH2O), 4.65 (t, J = 3.0 Hz, 1H,
OCHO), 4.42ꢂ4.15 (m, 2H, CH2OTHP), 4.07 (q, J = 5.6 Hz,
1H, CHOMOM), 3.87 (m, 1H, OCHH of THP), 3.52 (m,
1H, OCHH of THP), 3.76 (s, 6H, CO2CH3), 3.40 (t, J =
4.0 Hz, 1H, CH(CO2Me)2), 3.36 (s, 3H, OCH2OCH3), 2.64
(t, J = 7.5 Hz, 2H, CH2CH(CO2Me)2), 2.09 (q, J = 7.0 Hz,
2H, CH2CH2CH=CH), 1.90–1.40 (m, 10H, other CH2). 13C
NMR (CDCl3) ꢃ: 169.3, 135.1, 132.7, 130.3, 127.6, 127.1,
124.6, 98.0, 97.8, 93.5, 76.1, 62.8, 62.7, 62.2, 62.1, 55.3,
52.4, 51.5, 35.0, 30.5, 26.9, 26.6, 25.3, 25.2, 19.4.
J = 15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2), 6.06 (t, J =
11.0 Hz, 1H, CH=CHCH=CHCH2), 5.7–5.48 (m, 3H,
CH=CHCH2OH and CH=CHCH=CH), 5.36 (dq, J = 11.0,
3.0 Hz, 1H, CH=CHCH2OH), 4.68 and 4.52 (2d, J = 6.5 Hz,
2 × 1H, OCH2O), 4.19 (d, J = 6.5 Hz, 2H, CH2OH), 4.07
(q, J = 6.5 Hz, 1H, CHOMOM), 3.73 (s, 3H, CO2Me), 3.72
(s, 3H, CO2Me), 3.43 (t, J = 7.5 Hz, 1H, CH(CO2Me)2),
3.37 (s, 3H, OCH2OCH3), 2.78 (t, J = 7.5 Hz, 2H,
CH2CH(CO2Me)2), 2.12 (q, J = 7.0 Hz, 2H, CH2CH2CH=
CH), 1.70–1.40 (m, 4H, other CH2). 13C NMR (CDCl3) ꢃ:
169.1, 134.8, 134.5, 130.4, 127.2, 126.6, 125.4, 93.4, 76.1,
74.5, 55.3, 52.5, 51.3, 39.3, 34.9, 27.0, 26.7, 25.0. MS m/z:
308 ([M – MOMOH]+), 325 ([M – MOM]+), 338 ([M –
CH3OH]+). Exact mass ([M – CH3OH]+) calcd.: 338.1729;
found: 338.1737.
2-[12-(tert-Butyl-diphenyl-silanyloxy)-6-methoxymethoxy-
dodeca-(2Z,4E,10Z)-trienyl]malonic acid dimethyl ester (16)
Preparation was similar to malonate 15 (89%). IR (cm–1):
3014, 2953, 2859, 1739, 1429, 1344, 1150, 1033, 824, 703.
1H NMR (CDCl3) ꢃ: 7.66 and 7.40 (2m, 10H, 2 phenyl),
6.43 (dd, J = 15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2), 6.04
(t, J = 11.0 Hz, 1H, CH=CHCH=CHCH2), 5.67–5.29 (m,
4H, CH=CHCH2OSi and CH=CHCH=CH), 4.66 and 4.49
(2d, J = 7.0 Hz, 2 × 1H, OCH2O), 4.24 (d, J = 6.5 Hz, 2H,
CH2OSi), 4.00 (q, J = 7.0 Hz, 1H, CHOMOM), 3.72 (s, 3H,
CO2Me), 3.73 (s, 3H, CO2Me), 3.42 (t, J = 7.5 Hz, 1H,
CH(CO2Me)2), 3.34 (s, 3H, OCH2OCH3), 2.77 (dt, J = 7.5,
1.0 Hz, 2H, CH2CH(CO2Me)2), 1.89 (q, J = 7.0 Hz, 2H,
CH2CH2CH=CH), 1.60–1.20 (m, 4H, other CH2), 1.06 (s,
9H, SiC(CH3)3). 13C NMR (CDCl3) ꢃ: 169.0, 135.5, 135.4,
134.8, 133.7, 130.5, 129.5, 129.4, 129.3, 127.5, 126.9,
126.5, 93.5, 76.1, 60.1, 55.2, 52.3, 51.4, 35.1, 27.3, 27.0,
2-(12-Chloro-7-methoxymethoxy-dodeca-(2Z,8E,10Z)-
trienyl)malonic acid dimethyl ester (19)
To a solution of alcohol 17 (294 mg, 80 mmol) and
hexachloroacetone (155 L, 1 mmol) in dichloromethane
(10 mL) at 0°C, was added triphenylphosphine (334 mg,
1.28 mmol). After stirring for 1 h at room temperature, the
mixture was concentrated under vacuo. The residue was pu-
rified by flash chromatography (hexanes–ether, 9:1 to 3:1) to
yield the title compound as an oil (288 mg, 94%). IR (cm–1):
2946, 1748, 1735, 1433, 1234, 1145, 1029. 1H NMR
(CDCl3) ꢃ: 6.45 (dd, J = 15.0, 11.0 Hz, 1H, CH=CHCH=
CHCH2), 6.08 (t, J = 11.0 Hz, 1H, CH=CHCH=CHCH2),
5.68–5.40 (m, 3H, CH=CHCH2CH and CH=CHCH=CH),
5.30 (m, 1H, CH=CHCH2CH), 4.67 and 4.51 (2d, J =
6.5 Hz, 2 × 1H, OCH2O), 4.20 (dd, J = 7.0, 2.0 Hz, 2H,
© 2002 NRC Canada

Chantigny et al.
881
CH2Cl), 4.07 (q, J = 5.5 Hz, 1H, CHOMOM), 3.73 (s, 6H,
CO2CH3), 3.40 (t, J = 4.0 Hz, 1H, CH(CO2Me)2), 3.38 (s,
3H, OCH2OCH3), 2.64 (t, J = 7.5 Hz, 2H, CH2CH(CO2Me)2),
2.09 (q, J = 7.0 Hz, 2H, CH2CH2CH=CH), 1.70–1.35 (m,
4H, other CH2). 13C NMR (CDCl3) ꢃ: 169.3, 137.0, 132.6,
131.7, 126.9, 126.7, 124.7, 93.7, 76.0, 55.3, 52.4, 51.6, 39.3,
34.9, 26.9, 26.7, 25.1.
cesium carbonate (11.0 g, 33.8 mmol) in a THF–DMF
solution (2:1, 800 mL) at 80°C. The DMF was purged with
nitrogen for 1 h before use. One hour after the final addition,
the solution was cooled to room temperature, filtered, and
concentrated under vacuo. The residue was purified by flash
chromatography (hexanes–ether, 8:2) to yield the title com-
pound as an oil (568 mg, 79 %). IR (cm–1): 2934, 2249,
1
1748, 1440, 1219. H NMR (CDCl3) ꢃ: 6.47–6.26 (m, 2H,
2-(12-Chloro-6-methoxymethoxy-dodeca-(2Z,4E,10Z)-
trienyl)malonic acid dimethyl ester (20)
CH=CHCH=CHCH2), 5.90 (dt, J = 15.0, 6.0 Hz, 1H,
CH=CHCH=CHCH2), 5.62–5.50 (m, 1H, CH2CH2CH=CH),
5.38 (q, J = 9.0 Hz, 1H, CH=CHCH2C), 5.24 (m, 1H,
CH=CHCH=CHCH2), 4.62 (m, 2H, OCH2O), 4.18 (q, J =
8.0 Hz, 1H, CHOMOM), 3.86 (s, 3H, CO2CH3), 3.37 (s, 3H,
OCH2OCH3), 2.80–2.43 (m, 4H, CH=CHCH2C), 2.22–1.30
(m, 6H, other CH2). 13C NMR (CDCl3) ꢃ: 168.7, 137.8,
137.4, 136.7, 134.8, 134.7, 126.8, 126.4, 123.6, 123.1,
122.8, 119.4, 95.1, 77.0, 76.7, 56.0, 54.2, 46.8, 42.9, 46.8,
42.9, 32.1, 31.6, 30.5, 30.2, 29.8, 26.8, 25.2, 24.9. MS m/z:
319 (M+). Exact mass (M+) calcd.: 319.1783; found:
319.1789.
Compound 20 was prepared similar to chloride 19 (99 %).
IR (cm–1): 3016, 2951, 1754, 1738, 1435, 1345, 1233, 1149,
1
1031, 666. H NMR (CDCl3) ꢃ: 6.46 (dd, J = 15.0, 11.0 Hz,
1H, CH=CHCH=CHCH2), 6.06 (t, J = 11.0 Hz, 1H,
CH=CHCH=CHCH2), 5.7–5.56 (m, 2H, CH=CHCH=CHCH2
and CH=CHCH2Cl), 5.53 (dd, J = 15.0, 8.0 Hz, 1H,
CH=CHCH=CHCH2), 5.36 (dq, J = 10.5, 3.0 Hz, 1H,
CH=CHCH2Cl), 4.69 and 4.52 (2d, J = 6.5 Hz, 2 × 1H,
OCH2O), 4.09 (d, J = 5.0 Hz, 2H, CH2Cl), 4.05 (m, 1H,
CHOMOM), 3.73 (s, 3H, CO2Me), 3.72 (s, 3H, CO2Me),
3.43 (t, J = 7.5 Hz, 1H, CH(CO2Me)2), 3.37 (s, 3H, OCH2OCH3),
2.78 (dt, J = 7.5, 0.5 Hz, 2H, CH2CH(CO2Me)2), 2.13 (q, J =
7.0 Hz, 2H, CH2CH2CH=CH), 1.70–1.30 (m, 4H, other CH2).
13C NMR (CDCl3) ꢃ: 169.1, 134.8, 134.5, 130.4, 127.2,
126.6, 125.4, 93.4, 76.1, 74.5, 55.3, 52.5, 51.3, 39.3, 39.3,
34.9, 27.0, 26.7, 25.0. MS m/z: 353 ([M – Cl]+), 358 ([M –
CH3OH]+). Exact mass (M+) calcd.: 388.1653; found:
388.1647.
6-Methoxymethoxy-1,3,3a,5a,6,7,8,9,9a,9b-decahydro-
cyclopenta[a]naphthalene-2,2-dicarboxylic acid dimethyl
ester (23) (diastereoisomers)
A solution of macrocycle 21 (61 mg, 173 mol) in
xylenes (1 mL) was stirred at 140°C for 4 h. The crude was
purified by flash chromatography (hexanes–ether, 8:2) to
yield the title compound as an oil (61 mg, 100%, OMOM,
1
ꢀ:ꢁ = 2:1). H NMR (CDCl3) ꢃ: 5.83 (d, J = 10.0 Hz, 1H,
7-Methoxymethoxy-cyclotrideca-(3Z,5E,11Z)-triene-1,1-
dicarboxylic acid (21)
CH=CH), 5.48 (dt, J = 10.0, 3.0 Hz, 1H, CH=CH), 4.77 (d,
J = 7.0 Hz, 0.66H, OCH2OMe alpha), 4.70 (d, J = 7.0 Hz,
0.33H, OCH2OMe beta), 4.63 (d, J = 7.0 Hz, 0.66H,
OCH2OMe alpha), 4.60 (d, J = 7.0 Hz, 0.33H, OCH2OMe
beta), 3.90 (m, 0.33H, CHOMOM beta), 3.72 (s, 3H,
CO2Me), 3.68 (s, 3H, CO2Me), 3.39 (s, 2H, OCH2OMe),
3.37 (s, 1H, OCH2OMe), 3.20 (td, J = 10.5, 4.5Hz, 0.66H,
CHOMOM alpha), 2.75 (m, 1H, CHCH=CH), 2.51 (m, 1H,
CHCH=CH), 2.30–1.05 (m, 12H, other CH2 and CH).
13C NMR (CDCl3) ꢃ: 170.0, 129.2, 126.2, 95.6, 79.5, 76.5,
56.0, 53.01, 53.0, 41.9, 41.2, 39.4, 39.2, 33.3, 32.9, 31.0,
30.7, 30.1, 29.7, 24.3.
A solution of chloride 19 (or 20) (280 mg, 0.72 mmol) in
acetonitrile (10 mL) was added over 12 h via a syringe
pump, to a solution of cesium carbonate (2.4 g, 7.5 mmol)
and cesium iodide (390 mg, 1.5 mmol) in acetonitrile
(600 mL) at 70°C (final concentration = 1 mM). Three hours
after the final addition, the mixture was cooled to room tem-
perature, filtered on florisil, and concentrated under vacuo.
Water (20 mL) was added to the residue and the mixture was
extracted with a 1:1 ether–hexanes solution (3 × 20 mL).
The combined organics were washed with brine, dried over
MgSO4, filtered, and concentrated under vacuo. The residue
was purified by flash chromatography (hexanes–ether, 9:1)
to yield the final compound as an oil (113 mg, 43%). IR
2-Cyano-6-methoxymethoxy-2,3,3a,5a,6,7,8,9,9a,9b-
decahydro-1H-cyclopenta[a]naphthalene-2-carboxylic acid
methyl ester (24) (diastereoisomers)
1
(cm–1): 2951, 1737, 1437, 1208, 1037. H NMR (CDCl3) ꢃ:
A solution of macrocycle 22 (67 mg, 208 mol) in
xylenes (500 L) was stirred at 140°C for 8 h. The crude
was purified by flash chromatography (hexanes–ether, 8:2)
to yield the title compound as an oil (52 mg, 78%). 1H NMR
(CDCl3) ꢃ: 5.92 (dd, J = 15.0, 6.5 Hz, 1H, CH=CH), 5.57
(m, 1H, CH=CH), 4.79 (d, J = 7.0 Hz, 0.66H, OCH2OMe al-
pha), 4.71 (d, J = 7.0 Hz, 0.33H, OCH2OMe beta), 4.63 (d,
J = 7.0 Hz, 0.66H, OCH2OMe alpha), 4.60 (d, J = 7.0 Hz,
0.33H, OCH2OMe beta), 3.92 (m, 0.33H, CHOMOM beta),
3.82 (s, 1H, CO2Me), 3.81 (s, 1H, CO2Me), 3.80 (s, 1H,
CO2Me), 3.39 (s, 2H, OCH2OMe), 3.38 (s, 1H, OCH2OMe),
3.21 (td, J = 10.5, 4.5 Hz, 0.66H, CHOMOM alpha), 2.93
(m, 1H, CHCH=CH), 2.65–1.00 (m, 13H, other CH2 and
CH). 13C NMR (CDCl3) ꢃ: 170.4, 169.4, 169.2, 130.0,
129.9, 129.6, 129.0, 127.5, 126.2, 95.4, 95.0, 79.0, 78.9,
74.9, 55.4, 55.2, 53.6, 53.4, 46.8, 46.6, 42.4, 42.3, 42.1,
41.0, 40.8, 40.7, 40.4, 39.3, 38.8, 38.6, 37.8, 36.4, 36.3,
6.42 (dd, J = 15.0, 11.0 Hz, 1H, CH=CHCH=CHCH2), 6.21
(t, J = 11.0 Hz, 1H, CH=CHCH=CHCH2), 5.82 (dd, J =
16.0, 5.5, 1H, CH=CHCH=CHCH2), 5.45 (m, 1H,
CH=CHCH2C), 5.10ꢂ4.95 (m, 2H, CH=CHCH2C and
CH=CHCH=CHCH2), 4.62 and 4.67 (2d, J = 7.0 Hz, 2 ×
1H, OCH2O), 4.13 (m, 1H, CHOMOM), 3.75 (s, 6H,
CO2CH3), 3.38 (s, 3H, OCH2OCH3), 2.69 (d, J = 8.5 Hz,
2H, CH=CHCH=CHCH2), 2.51 (d, J = 7.0 Hz, 2H,
CH=CHCH2C), 2.20–1.30 (m, 6H, other CH2). 13C NMR
(CDCl3) ꢃ: 171.3, 171.2, 135.6, 135.0, 133.0, 126.5, 124.7,
123.8, 94.4, 76.5, 56.9, 55.3, 52.6, 30.0, 29.2, 29.0, 25.9, 24.8.
1-Cyano-7-methoxymethoxy-cyclotrideca-(3Z,5E,11Z)-
trienecarboxylic acid methyl ester (22) (diastereoisomers)
A solution of bischloride 14 (720 mg, 2.25 mmol) and
methyl cyanoacetate (298 L, 3.38 mmol) in THF (20 mL)
was added over 10 h using a syringe pump, to a solution of
© 2002 NRC Canada

882
Can. J. Chem. Vol. 80, 2002
36.0, 33.5, 32.8, 32.6, 30.8, 30.6, 30.3, 29.7, 24.1, 24.0,
20.7.
to yield the title compound as an oil (1.06 g, 100%). IR (cm–1):
3426, 2928, 2860, 2239, 1449, 1348, 1281, 1059, 1028.
1H NMR (CDCl3) ꢃ: 6.05–5.40 (m, 2H, CH=CH), 4.10ꢂ4.07
(m, 0.33H, CHOMOM, Hax), 3.37–3.22 (m, 0.66H,
CHOMOM, Heq), 2.90–2.60 (m, 2H, CHCH=CHCH), 2.5–
2.3 (m, 1H, CHCN), 2.15–1.00 (m, 13H, other CH2 and
CH). 13C NMR (CDCl3) ꢃ: 133.3, 130.8, 130.4, 130.0,
128.4, 128.2, 126.0, 123.5, 73.5, 69.7, 43.3, 43.0, 42.5, 41.4,
41.1, 40.3, 40.0, 39.8, 38.9, 38.7, 36.7, 36.3, 33.0, 32.9,
32.7, 31.2, 31.1, 30.8, 30.7, 30.4, 29.6, 29.2, 26.3, 24.4,
24.3, 20.6, 20.5. MS m/z: 216 ([M – H]+). Exact mass
([M – H]+) calcd.: 216.1388; found: 216.1392.
6-Methoxymethoxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-
cyclopenta[a]naphthalene-2-carboxylic acid methyl ester
(25) (diastereoisomers)
A solution of macrocycle 21 (92 mg, 261 mol), sodium
chloride (39 mg, 653 mol), and water (10 L) in DMSO
(1 mL) was stirred at 160°C for 7 h. Water (10 mL) was
added to the cooled solution and the mixture was extracted
with a hexanes–ether solution (1:1, 3 × 10 mL). The com-
bined organics were washed with brine, dried over MgSO4,
filtered, and concentrated under vacuo to yield the title com-
1
6-Oxo-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-cyclo-
penta[a]naphthalene-2-carbonitrile (28) and (29)
pound as an oil (66 mg, 90%). H NMR (DMSO-d6) ꢃ: 5.75
(d, J = 6.5 Hz, 1H, CH=CH), 5.41 (m, 1H, CH=CH),
4.71ꢂ4.50 (m, 2H, OCH2O), 3.82 (m, 0.33H, CHOMOM, H
alpha), 3.65 (s, 2H, CO2Me), 3.60 (s, 1H, CO2Me), 3.28 (s,
2H, OCH2OMe), 3.23 (s, 1H, OCH2OMe), 3.10 (m, 0.66H,
CHOMOM, H beta), 2.70 (m, 1H, CHCH=CH), 2.53–2.38
(m, 2H, CHCH=CH and CHCO2), 2.20–1.00 (m, 12H, other
CH2 and CH).
To a solution of alcohol 27 (145 mg, 671 mol) in di-
chloromethane (22 mL) at 0°C, was added Dess–Martin
periodinane (370 mg, 872 mol). The solution was allowed
to warm to room temperature and stirred for 30 min. A satu-
rated NaHCO3 solution (30 mL) and sodium thiosulfate
(477 mg, 1.92 mmol) were added and stirred 30 min. The
mixture was extracted with dichloromethane (3 × 30 mL).
The combined organics were dried over MgSO4, filtered, and
concentrated under vacuo. The residue was purified by flash
chromatography (hexanes–ether, 9:1) to yield two racemic
diastereoisomeres as oils (ꢀ-nitrile 66 mg and ꢁ-nitrile
50 mg, total yield: 80%).
6-Methoxymethoxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-
cyclopenta[a]naphthalene-2-carbonitrile (26)
(diastereoisomers)
A solution of macrocycle 22 (1.7 g, 5.43 mmol) and so-
dium cyanide (293 mg, 6 mmol) in DMSO (25 mL) was
stirred at 160°C for 8 h. Water (100 mL) was added to the
cooled solution and the mixture was extracted with a hex-
anes–ether solution (1:1, 3 × 100 mL). The combined
organics were washed with brine, dried over MgSO4, fil-
tered, and concentrated under vacuo to yield the title com-
pound as an oil (1.27 g, 89%, OMOM, ꢀ:ꢁ = 2:1).
Alternatively, a solution of tricycle 24 (50 mg, 157 mol)
and sodium cyanide (9.6 mg, 195.6 mol) in DMSO
(500 L) was stirred at 160°C for 8 h. The mixture was di-
luted with water (15 mL) and extracted with a hexanes–ether
solution (1:1, 3 × 15 mL). The combined organics were
washed with brine, dried over MgSO4, filtered, and concen-
trated under vacuo to yield the title compound as an oil
(40 mg, 97%). IR (cm–1): 2927, 2237, 1446, 1149, 1099,
1040. 1H NMR (CDCl3) ꢃ: 5.92–5.88 (m, 1H, CH=CH),
5.60–5.42 (m, 1H, CH=CH), 4.80ꢂ4.57 (m, 2H, OCH2O),
3.98–3.90 (m, 0.33H, CHOMOM, Hax), 3.40 (s, 1H,
OCH2OMe), 3.39 (s, 1H, OCH2OMe), 3.36 (s, 0.5H,
OCH2OMe), 3.35 (s, 0.5H, OCH2OMe), 3.25–3.10 (m,
0.66H, CHOMOM, Heq), 2.90–2.60 (m, 2H, CHCH=
CHCH), 2.9–0.5 (m, 13H, other CH2 and CH). 13C NMR
(CDCl3) ꢃ: 131.3, 131.0, 130.6, 130.1, 129.9, 128.6, 126.2,
123.4, 95.6, 95.1, 79.3, 75.2, 55.5, 55.3, 43.3, 43.2, 41.5,
41.2, 41.0, 40.6, 39.9, 39.6, 39.2, 39.1, 38.6, 36.7, 36.3,
33.7, 32.8, 31.1, 31.0, 30.7, 30.6, 30.3, 29.9, 29.6, 29.5,
27.3, 26.3, 24.3, 24.1, 21.0, 20.8. MS m/z: 261 (M+), 246
([M – CH3]+), 229 ([M – CH3OH]+), 216 ([M – MOM]+).
Exact mass (M+) calcd.: 261.1729; found: 261.1733.
Ketone 28 (ꢀ-nitrile). IR (cm–1): 2928, 2850, 2335, 1709,
1
1450, 1360, 1240, 1145. H NMR (CDCl3) ꢃ: 6.03 (d, J =
10.0 Hz, 1H, O=CCHCH=CH), 5.63 (dt, J = 10.0, 2.5 Hz,
1H, CH=CH), 2.82–2.70 (m, 3H, CHCH=CHCH and
CHCN), 2.48–1.52 (m, 12H, other CH2 and CH). 13C NMR
(CDCl3) ꢃ: 209.95, 131.54, 122.61, 121.91, 47.31, 42.91,
41.87, 41.22, 40.18, 38.31, 36.05, 30.41, 26.50, 26.28. MS
m/z: 215 (M+). Exact mass (M+) calcd.: 215.1310; found:
215.1315.
1
Ketone 29 (ꢁ-nitrile). H NMR (CDCl3) ꢃ: 6.07 (d, J =
10.0 Hz, 1H, O=CCHCH=CH), 5.51 (dt, J = 10.0, 3.0 Hz,
1H, CH=CH), 2.90–2.70 (m, 2H, CHCH=CHCH), 2.55 (qd,
J = 9.0, 3.5 Hz, 1H, CHCN), 2.49–1.50 (m, 12H, other CH2
and CH). 13C NMR (CDCl3) ꢃ: 209.84, 130.75, 124.10,
123.0, 46.78, 41.80, 41.14, 39.54, 36.30, 30.22, 29.58,
28.91, 26.34, 26.15.
6-Hydroxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-cyclo-
penta[a]naphthalene-2-carbonitrile (30)
To a solution of ketone 28 (213 mg, 995 mmol) in THF
(15 mL) at –78°C, was added lithium triisobutylborohydride
(0.5 M, 2.8 mL, 1.4 mmol). After 3.5 h, NaOH (10%,
2.4 mL, 6 mmol) and H2O2 (35%, 583 L, 6 mmol) were
added and the mixture was stirred for 3 h at room temperature.
A sodium thiosulfate solution (1 M) was then added and
stirred for 30 min. The mixture was extracted with dichloro-
methane (3 × 50 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuo.
The residue was purified by flash chromatography (100%
ether) to yield the title compound as an oil (171 mg, 80%).
IR (cm–1): 3312, 2930, 2845, 2232, 1445, 1322, 1064.
1H NMR (CDCl3) ꢃ: 5.63 (dt, J = 10.0, 2.5 Hz, 1H,
OCHCHCH=CH), 5.52 (d, J = 10.0 Hz, 1H, OCHCHCH=
CH), 4.10 (s, 1H, CHOH), 2.85–2.65 (m, 2H, CHCH=
CHCH), 2.35 (dt, J = 13.5, 9.0 Hz, 1H, CHCN), 2.15–1.08
6-Hydroxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-cyclo-
penta[a]naphthalene-2-carbonitrile (27) (diastereoisomers)
A solution of tricycle 26 (1.27 g, 4.85 mol) and HCl 6 N
(750 L) in methanol (125 mL) was heated to reflux for 8 h.
The solution was concentrated under vacuo and purified by
flash chromatography (hexanes–ether, 40% to 100% ether)
© 2002 NRC Canada

Chantigny et al.
883
(m, 12H, other CH2 and CH). 13C NMR (CDCl3) ꢃ: 133.2,
128.1, 123.1, 69.7, 43.2, 40.3, 38.9, 36.1, 32.9, 32.7, 31.2,
30.4, 26.2, 20.6. MS m/z: 217 (M+). Exact mass (M+) calcd.:
217.1467; found: 217.1469.
CH2), 1.20–0.95 (m, 21H, OTIPS). 13C NMR (CDCl3) ꢃ:
130.6, 130.1, 123.4, 70.8, 43.6, 41.5, 39.0, 36.2, 34.2, 32.6,
31.5, 30.3, 26.2, 20.8, 18.2, 13.3, 12.8, 12.4. MS m/z : 330
([M – C3H7]+). Exact mass ([M – C3H7]+) calcd.: 330.2253;
found: 330.2255.
6-Hydroxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-cyclo-
penta[a]naphthalene-2-carboxylic acid (31)
6-Triisopropylsilanyloxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-
1H-cyclopenta[a]naphthalene-2-carboxylic acid (34)
To a solution of alcohol 30 (12.5 mg, 58 mol) in metha-
nol (2 mL) was added an NaOH solution (25%, 416 L,
2.6 mmol) and a H2O2 solution (30%, 600 L, 12% v/v).
The mixture was stirred at 65°C for 24 h and concentrated
under vacuo to -1 mL. The mixture was diluted with water
(15 mL), the pH was adjusted to 2 with 1 N HCl, and the
mixture extracted with dichloromethane (3 × 15 mL). The
combined organics were dried over MgSO4 and concentrated
under vacuo. The residue was purified by flash chromatogra-
phy (acetone–hexanes, 6:1) to yield the title compound as
white crystals (12.4 mg, 90%). IR (cm–1): 3400–2300, 3392,
To a solution of silyl ether 33 (67 mg, 180 mmol) in
methanol (20 mL) was added NaOH (10%, 3.2 mL) and
H2O2 (35%, 9 mL). The solution was heated to reflux for
24 h. The cooled solution was concentrated under vacuo to
-10 mL and acidified to pH 2 with HCl (1 N, 25 mL). The
solution was extracted with dichloromethane (3 × 30 mL).
The combined organics were dried over MgSO4, filtered, and
concentrated under vacuo. The residue was purified by flash
chromatography (hexanes–ethyl acetate, 6:4) to yield the ti-
tle compound as an oil (58 mg, 83%). IR (cm–1): 3450–
2400, 2929, 2866, 1704, 1463, 1238, 1118, 1066, 882.
1
2921, 2851, 1704, 1651, 1463, 1221. H NMR (MeOD-d4)
ꢃ: 5.54 (dt, J = 10.0, 2.5 Hz, 1H, OCHCHCH=CH), 5.42 (d,
J = 10.0 Hz, 1H, OCHCHCH=CH), 3.99 (s, 1H, CHOH),
2.8–2.6 (m, 2H, CHCH=CHCH), 2.25 (dt, J = 13.5, 9.0 Hz,
1H, CHCO2H), 2.15–1.12 (m, 12H, other CH2 and CH).
1H NMR (CDCl3) ꢃ: 5.53 (d,
OCHCHCH=CH), 5.34 (dt,
J
=
10.0 Hz, 1H,
J
= 10.0, 2.5 Hz, 1H,
OCHCHCH=CH), 4.22 (m, 1H, CHOTIPS), 2.89–2.60 (m,
2H, CHCH=CHCH), 2.45–2.15 (m, 1H, CHCO2H), 2.44–
0.80 (m, 33H, other CH, CH2 and CH3). 13C NMR (CDCl3)
ꢃ: 182.3, 131.6, 129.1, 70.9, 43.8, 42.6, 41.5, 38.8, 34.7,
34.3, 32.9, 31.6, 29.7, 28.9, 20.9, 18.3, 18.2, 12.8. MS m/z:
349 ([M – C3H7]+). Exact mass ([M – C3H7]+) calcd.:
349.2199; found: 349.2194.
Iodolactone 32
To a solution of acid 31 (1.5 mg, 3.8 mol) in THF
(0.5 mL) was added one crystal of iodide, one drop of water,
and sodium bicarbonate (1 mg, 7.5 mol). The solution was
stirred 3 days at room temperature, then diluted with water
(10 mL), and the pH adjusted to 2 with 1 N HCl. The mix-
ture was extracted with dichlorometane (3 × 15 mL). The
combined organic layers were dried over MgSO4, filtered,
and concentrated under vacuo to yield the title compound as
a red oil (2 mg) (excess iodide). IR (cm–1): 3557, 3006,
2956, 2880, 1743, 1601, 1454, 1365, 1244, 1163, 1066,
1002. 1H NMR (CDCl3) ꢃ: 4.68 (t, J = 3.5 Hz, 1H,
CHOC=O), 4.44 (t, J = 3.0 Hz, 1H, CHI), 4.02 (m, 1H,
CHOH), 3.05 (q, J = 6.5 Hz, 1H, CH2CHCHOC=O), 2.88
(dd, J = 7.5, 6.5 Hz, 1H, CHCO2), 2.35–1.12 (m, 13H, other
CH and CH2). 13C NMR (CDCl3) ꢃ: 174.0, 84.5, 69.2, 40.4,
39.8, 35.1, 34.9, 34.5, 34.3, 32.4, 30.8, 30.6, 29.9, 29.7,
18.4. MS m/z: 362 (M+), 235 ([M – I]+). Exact mass (M+)
calcd.: 362.0379; found: 362.0387; ([M – I]+) calcd.:
235.1334; found: 235.1339.
6-Triisopropylsilanyloxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-
1H-cyclopenta[a]naphthalene-2-carboxylic acid
pentylamide (35)
To a solution of acid 34 (22 mg, 56 mol) in dichloro-
methane (3 mL) at 0°C was added oxalyle chloride (8 L,
88 mol) and DMF (1 L, 11 mol). The solution was
warmed to room temperature. After 1.5 h, triethylamine
(9 L, 67 mol) and amylamine (13 L, 112 mol) were
added and stirred 24 h. The mixture was concentrated under
vacuo and purified by flash chromatography (hexanes–ace-
tone, 7:3) to yield the title compound as an oil (22 mg,
80%). IR (cm–1): 3300, 2927, 2864, 1643, 1462, 1065.
1H NMR (CDCl3) ꢃ: 5.5–5.3 (m, 3H, CH=CH and NH), 4.22
(br s, 1H, CHOTIPS), 3.21 (qd, J = 7.0, 1.0 Hz, 2H,
CH2NH), 2.73–2.46 (m, 2H, CHCH=CHCH), 2.20 (dt, J =
13.5, 9.5 Hz, 1H, CHCONH) 2.13–0.99 (m, 39H, other CH,
CH2 and CH3) 0.89 (t, J = 7.0 Hz, 3H, CH2CH3). 13C NMR
and DEPT-135 (CDCl3) ꢃ: 175.6 (s), 132.0 (d), 128.8 (d),
71.0 (d), 45.1 (d), 44.0 (d), 41.5 (d), 39.4 (t), 38.7 (d), 35.6
(t), 34.3 (t), 32.9 (d), 31.6 (t), 29.9 (t), 29.7 (t), 29.3 (t), 29.1
(t), 22.3 (t), 20.9 (t), 18.3 (q), 14.0 (q), 12.8 (d). MS m/z:
461 (M+), 418 ([M – C3H7]+). Exact mass (M+) calcd.:
461.3689; found: 461.3680.
6-Triisopropylsilanyloxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-
1H-cyclopenta[a]naphthalene-2-carbonitrile (33)
To a solution of alcohol 30 (55 mg, 254 mol) and 2,6-
lutidine (89 L, 762 mol) in dichloromethane (4 mL) at
0°C, was added slowly triisopropylsilane triflate (102 L,
381 mol). After 1 h at room temperature, a saturated
NH4Cl solution (30 mL) was added and the mixture ex-
tracted with dichloromethane (3 × 30 mL). The combined
organics were dried over MgSO4, filtered, and concentrated
under vacuo. The residue was purified by flash chromatogra-
phy (hexanes–ether, 95:5) to give the title compound as an
oil (96 mg, 100%). IR (cm–1): 2929, 2237, 1448, 1363,
6-Triisopropylsilanyloxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-
1H-cyclopenta[a]naphthalene-2-carboxylic acid indan-
(1S)-ylamide (36) and (37) (diastereoisomers)
Same procedure as for amide 35, using (S)-(+)-1-
aminoindane instead of amylamine. The title compound was
obtained as an oil (18 mg, 73%) and recovered acid 34
(2 mg). IR (cm–1): 3281, 2936, 2865, 1643, 1539, 1461,
1
1278, 1217, 1149, 1097, 1041, 917. H NMR (CDCl3) ꢃ:
5.52 (d, J = 10.0 Hz, 1H, OCHCHCH=CH), 5.44 (dt, J =
10.0, 2.5 Hz, 1H, OCHCHCH=CH), 4.25 (br s, 1H, CH-
OTIPS), 2.80–2.66 (m, 2H, CHCH=CHCH), 2.30 (dt, J =
13.5, 9.5 Hz, 2H, CHCN), 2.20–1.38 (m, 12H, CH and
1
1384, 1243, 1066, 881, 745, 674. H NMR (CDCl3) ꢃ: 7.30–
7.15 (m, 4H, H-aryl), 5.72–5.33 (m, 3H, CH=CH and
© 2002 NRC Canada

884
Can. J. Chem. Vol. 80, 2002
CONH), 4.22 (br s, 1H, CHOTIPS), 3.07–0.80 (m, 40H,
other CH, CH2 and CH3). 13C NMR (CDCl3) ꢃ: 175.4, 143.4,
131.9, 128.9, 127.8, 126.7, 124.7, 123.9, 71.0, 54.5, 45.1,
44.0, 41.5, 38.7, 35.7, 35.5, 34.2, 32.9, 31.6, 30.2, 30.0,
29.8, 20.9, 18.3, 12.8. MS m/z: 507 (M+). Exact mass (M+)
calcd.: 507.3532; found: 507.3541.
Chercheurs et l’Aide à la Recherche (FCAR). We thank
Dr. Diane Joseph-McCarthy from Harvard University for the
theoretical design of the target molecules and for running
the biological assays.
References
6-Hydroxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-
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cyclopenta[a]naphthalene-2-carboxylic acid pentylamide (1)
A solution of amide 35 (18 mg, 39 mol) and HCl (6 N,
0.3 mL) in methanol (5 mL) was heated to reflux for 24 h.
The cooled solution was concentrated under vacuo and puri-
fied by flash chromatography (hexanes–acetone, 7:3) to
yield the title compound as an oil (7 mg, 81%). IR (cm–1):
1
3300, 2927, 2860, 1647, 1548, 1456, 1372, 1249. H NMR
(CDCl3) ꢃ: 5.66 (dt, J = 10.0, 2.5 Hz, 1H, CH=CH), 5.49–
5.37 (m, 2H, CH=CH and CONH), 4.06 (br s, 1H, CHOH),
3.21 (qd, J = 7.0, 1.0 Hz, 2H, CH2NH), 2.80–2.65 (m, 1H,
CHCH=CH), 2.63–2.45 (m, 1H, CHCH=CH), 2.22 (td, J =
13.5 Hz, 1H, CHCONH), 2.15–1.00 (m, 18H, other CH and
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175.2, 134.8, 126.6, 69.9, 45.0, 43.5, 40.3, 39.5, 38.6, 35.5,
33.3, 32.7, 31.3, 29.8, 29.7, 29.3, 29.1, 22.3, 20.7, 14.0. MS
m/z: 305 (M+). Exact mass (M+) calcd.: 305.2355; found:
305.2359.
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6-Hydroxy-2,3,3a,5a,6,7,8,9,9a,9b-decahydro-1H-
cyclopenta[a]naphthalene-2-carboxylic acid indan-(1S)-
ylamide (2) and (38) (diastereoisomers)
Same procedure as for alcohol 1 but using a mixture of
amides 36 and 37 instead of amide 35. The title compounds
were obtained as an oil (18 mg, 84%). IR (cm–1): 3289,
3012, 2930, 2864, 1645, 1538, 1455, 1231, 1056, 988, 909,
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(2000).
1
732. H NMR (CDCl3) ꢃ: 7.30–7.17 (m, 4H, H-aryl), 5.71–
5.41 (m, 3H, CH=CH, CONH), 4.08 (br s, 1H, CHOH),
3.05–2.50 (m, 5H, CH2ArCHNH and CHCH=CHCH), 2.25–
0.80 (m, 15H, other CH and CH2). 13C NMR (CDCl3) ꢃ:
175.1, 143.4, 134.8, 134.2, 129.7, 128.0, 126.7, 124.9,
123.9, 70.0, 54.5, 45.0, 43.7, 40.4, 38.7, 35.4, 34.2, 33.6,
33.4, 32.7, 31.3, 30.2, 29.9, 29.7, 20.8. MS m/z: 351 (M+).
Exact mass (M+) calcd.: 351.2198; found: 351.2200.
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22. A.P. Krapcho and J.F. Wemaster. J. Org. Chem. 45, 4105 (1980).
23. G. Martin and M. Martin. Bull. Soc. Chim. Fr. 1637 (1963).
Acknowledgments
This work was supported financially by the Natural Sci-
ences and Engineering Research Council of Canada
(NSERC) and by the Fonds pour la Formation de
© 2002 NRC Canada