Diastereoselective syntheses of new analogues of the farnesyltransferase inhibitor RPR 130401

Article abstract of DOI:10.1021/jo049037i

The access to several benzo[f]perhydroisoindolic analogues of farnesyltransferase inhibitors from a single dienic precursor is reported. An initial [4 + 2] cycloaddition between diphenylisobenzofuran 6 and pyrrolines 11, 14, and 15 led to either the syn o

Full text of DOI:10.1021/jo049037i

Dia ster eoselective Syn th eses of New An a logu es of th e
F a r n esyltr a n sfer a se In h ibitor RP R 130401
†
†
‡
,†
Nicolas Pichon, Anne Harrison-Marchand, Patrick Mailliet, and J acques Maddaluno*
Laboratoire des Fonctions Azot e´ es et Oxyg e´ n e´ es Complexes de l’IRCOF, UMR 6014 CNRS, INSA and
Universit e´ de Rouen, 76821 Mont St Aignan, France, and Aventis, Centre de Recherche de
Vitry-Alfortville, 13 Quai J ules Guesde, 94403 Vitry-sur-Seine Cedex, France
jmaddalu@crihan.fr
Received J une 8, 2004
The access to several benzo[f]perhydroisoindolic analogues of farnesyltransferase inhibitors from
a single dienic precursor is reported. An initial [4 + 2] cycloaddition between diphenylisobenzofuran
6
and pyrrolines 11, 14, and 15 led to either the syn or the anti isomers, depending on the mode
of activation of the cycloaddition. The syn diastereomers were isolated in 90% de under 12 kbar at
room temperature, while their anti counterparts were obtained with the same selectivity by warming
the reaction mixture to 110 °C in toluene at atmospheric pressure. Both syn and anti adducts were
separately N-deprotected, and the resulting amines reacted with an activated ester derived from
the acid (20) to afford the final targets (5). Two new analogues (5a and 5b) of the FT inhibitor RPR
1
6
30401 were thus synthesized in a mere three-step synthetic scheme with overall yields from 30 to
0%.
In tr od u ction
(FT), which prevents Ras-GDP from fixing on the cell
7
-10
wall, is the subject of numerous investigations
and
Ras proteins are small GTP1a binding proteins that
participate in many cellular functions, such as cell growth
and cellular differentiation. The regular cell division
has shown to be one of the most successful approaches
to date.
A major obstacle related to this strategy is the lack of
selectivity of inhibitors for FT over geranylgeranyltrans-
ferase (GGT). Among the numerous series of compounds
optimized toward an acceptable selectivity, the benzo[f]-
perhydroisoindole (BPHI) class (studied by Aventis) is
2
process first involves a farnesylation and the binding of
the Ras-GDP1b protein to the inner surface of the cell
membrane. After phosphorylation into Ras-GTP, a signal
cascade is triggered, leading to the translocation into the
nucleus and to the activation of gene transcription. The
reversibility of the transformation of Ras-GDP into Ras-
GTP ensures a normal and regular cell growth. The
mutation of the Ras protein prevents the hydrolysis of
the Ras-GTP into Ras-GDP, and a continuous cell pro-
liferation signal is then issued. Mutant Ras genes are
found in a wide range of human tumors, in particular,
11
one of the most efficient in vitro. Compounds such as
RPR 115135 (1; Figure 1) show acceptable cellular
potency with moderate in vivo activity. The optimization
(7) (a) Patel, D.; Schmidt, R.; Biller, S.; Gordon, E.; Robinson, S.;
Manne, V. J . Med. Chem. 1995, 38, 2606. (b) Gaon, I.; Turek, T.; Weller,
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(
c) Rawat, D. S.; Gibbs, R. A. Org. Lett. 2002, 4, 3027.
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in colon and pancreas cancers. Various biochemical
Beese, L. B. Science 1997, 275, 1800. (b) Long, S. B.; Casey, P. J .; Beese,
L. S. Biochemistry 1998, 37, 9612. (c) Burns, C. J .; Guitton, J . D.;
Baudoin, B.; Leli e` vre, Y.; Duschene, M.; Parker, F.; Fromage, N.;
Commer c¸ on, A. J . Med. Chem. 1997, 40, 1763. (d) Lee, H. Y.; Sohn, J .
H.; Kwon, B. M. Bioorg. Med. Chem. Lett. 2002, 12, 1599.
approaches have been used for understanding the con-
sequences of the presence of mutated Ras proteins,4
among which the inhibition of the farnesyltransferase
-6
(
9) (a) End, D. W.; Smets, G.; Todd, A. V.; Applegate, T. L.; Fuery,
†
Universit e´ de Rouen.
Aventis.
C. J .; Angibaud, P.; Venet, M.; Sanz, G.; Poignet, H.; Skrzat, S.; Devine,
A.; Wouters, W.; Bowden, C. Cancer Res. 2001, 61, 131. (b) Norman,
P. Curr. Opin. Invest. Drugs 2002, 3, 313. (c) Angibaud, P.; Bourdrez,
X.; Devine, A.; End, D. W.; Freyne, E.; Ligny, Y.; Muller, P.; Mannens,
G.; Pilatte, I.; Poncelet, V.; Skrzat, S.; Smets, G.; Van Dun, J .;
Remoortere, P. V.; Venet, M.; Wouters, W. Bioorg. Med. Chem. Lett.
2003, 13, 1543. (d) Lee, H.; Lee, J .; Lee, S.; Shin, Y.; J ung, W.; Kim, J .
H.; Park, K.; Kim, K.; Cho, H. S.; Ro, S.; Lee, S.; J eong, S.; Choi, T.;
Chung, H. H.; Koh, J . S. Bioorg. Med. Chem. Lett. 2001, 11, 3069. (e)
DeSolms, S. J .; Ciccarone, T. M.; MacTough, S. C.; Shaw, A. W.; Buser,
C. A.; Ellis-Hutchings, M.; Fernandes, C.; Hamilton, K. A.; Huber, H.
E.; Kohl, N. E.; Lobell, R. B.; Robinson, R. G.; Tsou, N. N.; Walsh, E.
S.; Graham, S. L.; Beese, L. S.; Taylor, J . S. J . Med. Chem. 2003, 46,
2973. (f) Nara, S.; Tanaka, R.; Eishima, J .; Hara, M.; Tanakashi, Y.;
Otaki, S.; Foglesong, R. J .; Hughes, P. F.; Turkington, S.; Kanda, Y.
J . Med. Chem. 2003, 46, 2647.
‡
(1) (a) GTP: guanosine triphosphate. (b) GDP: guanosine diphos-
phate.
(2) (a) Gibbs, J . G.; Graham, S. L.; Hartman, G. D.; Koblan, K. S.;
Kohl, N. E.; Omer, C. A.; Oliff, A. Biomed. Chem. 1997, 197. (b) Cox,
A. D.; Der, C. J . Biochim. Biophys. Acta 1997, 1333, F51.
3) Bos, J . L. Cancer Res. 1989, 49, 4682.
1
2
996, 39, 1352.
5) (a) Zhang, P.; Wang, Y.-Z.; Kagan, E.; Bonner, J . C. J . Biol. Chem.
000, 275, 22479. (b) Kato-Stankiewicz, J .; Hakimi, I.; Zhi, G.; Zhang,
(
J .; Serebriiskii, I.; Guo, L.; Edamatsu, H.; Koide, H.; Menon, S.; Eckl,
R.; Sakamuri, S.; Lu, Y.; Chen, Q.-Z.; Agarwal, S.; Baumach, W. R.;
Golemis, E. A.; Tamanoi, F.; Khazak, V. Proc. Natl. Acad. Sci. U.S.A.
2
002, 99, 14398.
6) Kato, K.; Cox, A.; Hisaka, M. M.; Graham, S. M.; Buss, J . E.;
Der, C. J . Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 6403.
(
(10) Lee, S. H.; Kim, H. K.; Seo, J . M.; Kang, H. M.; Kim, J . H.;
Son, K. H.; Lee, H.; Kwon, B. M. J . Org. Chem. 2002, 67, 7670.
1
0.1021/jo049037i CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/21/2004
7
220
J . Org. Chem. 2004, 69, 7220-7227

New Analogues of Farnesyltransferase Inhibitors
F IGURE 1. Farnesyltransferase inhibitors RPR 130401 and analogues (IC50 for Ki-Ras).
SCHEME 1
of this series afforded RPR 104213 and RPR 130401 (3
and 2, respectively; Figure 1), with the latter exhibiting
potent in vivo activity.
Our laboratory has been interested in the synthesis of
new BPHI analogues in which the ethylene bridge of 1,
diphenylisobenzofuran 6 (DPIB, at the origin of rings A
and B) and methyl propiolate (Scheme 1).
The Diels-Alder reaction between benzofuran 6 and
methyl propiolate was conducted under 12 kbar for 24 h
at room temperature. Biscycloadduct 8 was the sole
product isolated in a 90% yield. It results from a double
[4 + 2] cycloaddition of the diene on the acetylenic
dienophiles and was obtained even when less than 1
equiv of benzofuran was used. The stereoselectivity of
this process is assumed to be related to the concave
topology of tricyclic intermediate 7, which forces the
second equivalent of benzofuran 6 to approach along an
exo-type trajectory (Scheme 1) previously described by
Lautens et al. in a comparable reaction conducted under
thermal conditions.13 Rather than trying to stop the
reaction after the first cycloaddition by changing the
solvent14 or using a different dienophile, we chose to
explore the alternative route described below.
2
, and 3 was replaced by an oxo bridge, and the relative
position of the angular acid group was altered (Figure
1
2
1
). Thus, compounds 4a (syn isomer, RPR 225370) and
b (anti isomer, RPR 222490) have been synthesized
4
following either a [3 + 2]/[4 + 2] or a [4 + 2]/[3 + 2]
sequence of reactions. Biological activities are disappoint-
ing with these two substrates as 4a did not exhibit any
inhibition of farnesylation and 4b only retained moderate
potency (IC50 ) 7.5 µM). We considered that a trans
relationship between the acid group at position 11 and
an aromatic ring adjacent to the oxo bridge could be
necessary for preserving significant biological results.
Thus, access to the new BPHI derivatives 5a (syn isomer)
and 5b (anti isomer) featured in Figure 1 has been
studied. We present in this paper selective access to
either diastereomer through a single synthetic pathway.
15
This new strategy relied on pyrrolines 11, 14, and 15
containing the desired carboxyl group (Scheme 2). Pyr-
roline 11 was obtained following a [3 + 2] cycloaddition
described by Sakurai and Achiwa.1
2,16
Thus, in the
Resu lts a n d Discu ssion
presence of a catalytic amount of trifluoroacetic acid in
dichloromethane, amine 9 generates dipole 10, which
Our original synthetic approach to 5 (syn/anti) relied
on a step-by-step [4 + 2]/[3 + 2] sequence starting with
(13) (a) Lautens, M.; Fillion, E. J . Org. Chem. 1996, 61, 7994. (b)
Lautens, M.; Fillion, E. J . Org. Chem. 1997, 62, 4418.
(14) (a) Samuilov, Ya. D.; Nurullina, R. L.; Konovalov, A. I. Zh. Org.
Khim. 1982, 18, 2253. (b) Samuilov, Ya. D.; Nurullina, R. L.; Konovalov,
A. I. Zh. Org. Khim. 1983, 19, 1431. We thank one of the referees for
bringing these references (as well as those of ref 15) to our attention.
(15) (a) Berson, J . A. J . Am. Chem. Soc. 1953, 75, 1240. (b) Blitzke,
T.; Sicker, D.; Wilde, H. Synthesis 1995, 236.
(16) (a) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117.
(b) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull.
1985, 33, 2762.
(
11) Mailliet, P.; Laoui, A.; Bourzat, J . D.; Capet, M.; Chev e´ , M.;
Commer c¸ on, A.; Dereu, N.; Lebrun, A.; Martin, J . P.; Peyronel, J . F.;
Salagnad, C.; Thompson, F.; Zucco, M.; Guitton, J . D.; Pantel, G.;
Bissery, M. C.; Brealey, C.; Lavayre, J .; Leli e` vre, Y.; Riou, J .-F.;
Vrignaud, P.; Duschene, M.; Lavelle, F. Farnesyltransferase Inhibitors
in Cancer Therapy; Sebti, S. M., Hamilton, A. D., Eds.; Humana Press
Inc.: Totowa, NJ , 2001; p 115.
(
12) Martin, C.; Mailliet, P.; Maddaluno, J . J . Org. Chem. 2001, 66,
3
797.
J . Org. Chem, Vol. 69, No. 21, 2004 7221

Pichon et al.
SCHEME 2
TABLE 1. Cycloa d d ition Rea ction s betw een DP IB 6 a n d
P yr r olin es 11, 14, a n d 15 in 20 h u n d er Th er m a l or
Hyp er ba r ic Activa tion
syn/ conv
entry pyrroline solvent T (°C) P (kbar) adduct anti
%
3
1
2
3
4
5
6
7
8
9
0
1
11
CH2Cl2
THF
toluene 110
THF
THF
THF
CH2Cl2
THF
toluene 70
toluene 110
CH2Cl2
40
70
×10-
16
95/5 <5
60/40 93
5/95 80
95/5 92
62/38 72
95/5 77
93/7 95
86/14 97
80/20 80
rt
70
rt
40
70
12
-
3
3
14
15
×10
17
18
12
-
×10
1
1
a
a
rt
12
100/0 94
a
Decomposition.
interactions are likely to be due to the ester moiety, the
endo and exo transition states are associated to the anti
and syn isomers, respectively. The results summarized
in Table 1 show that this diastereoselectivity is highly
dependent upon the method of activation.
The syn diastereomers are the sole (entry 11 of Table
1
, 18a ) or main (entry 4, 16a , and entry 6, 17a ) products
isolated under high pressure at room temperature,
whatever the solvent. Thermal activation at atmospheric
pressure seems to privilege the syn isomers as the major
products when the temperature does not exceed 70-80
immediately reacts at room temperature with methyl
propiolate, yielding pyrroline 11 in 64% yield. Pyrroline
1
1
1 was then used as the precursor for pyrrolines 14 and
5. When a debenzylation procedure reported by Olofson
°
C (entries 1 and 2 for adduct 16, entries 7-9 for adduct
1
7
18). However, the proportion of the anti isomer increases
when going from 40 °C (entries 1 and 7) to 70 °C (entries
2, 8, and 9). It is also worth noting that the diastereo-
meric excess is hardly dependent on the solvent as both
toluene and tetrahydrofuran give a similar syn/anti ratio
at 70 °C (entries 8 and 9). By contrast, at a higher
temperature (110 °C), either a degradation of the starting
material (entry 10) or the almost exclusive formation of
the anti isomer (entry 3) is observed. The differences of
reactivity and selectivity observed among pyrrolines 11,
was adapted, treatment of 11 with 2 equiv of vinyl-
oxycarbonyl chloride 12 and allyloxycarbonyl chloride 13
in dichloromethane at room temperature for 24 h gave
pyrrolines 14 and 15 in 78 and 77% isolated yields,
respectively.
Diels-Alder cycloadditions have been conducted be-
tween DPIB 6 and pyrrolines 11, 14, and 15 in various
solvents with a thermal or hyperbaric activation (Scheme
3
).
SCHEME 3
1
4, and 15 also call for comment. N-benzylpyrroline 11
seems more sluggish than carbamates 14 and 15 (com-
pare entries 1 and 7). Also, the weaker preference for the
anti isomer under thermal conditions when using allyloxy
carbamate 18 (compare entries 2 and 8) can probably be
assigned to a competition between the latter function and
the ester appendage when it interacts with the π system
of DPIB.
Overall, this part of the study provides evidence that
the diastereoselectivity of the cycloaddition may be
controlled by simply changing the mode of activation
(
thermal vs high pressure). This observation is particu-
larly convincing for pyrroline 11, which leads to adduct
6a (12 kbar; entry 4) or 16b (110 °C; entry 3) in 90% de
1
and yields up to 76%. Each diastereomer has been
isolated separately by column chromatography.
As shown in Figure 2 for adduct 16, the hyperbaric
preference for the syn derivative, of which stereochem-
istry could be firmly established by a single-crystal X-ray
analysis, would be the consequence of the compactness
The syn and anti labels designate the relative positions
between the oxo bridge and the ester group in cyclo-
adducts 16-18. Considering that the main secondary
(despite its “exo” character) of the corresponding transi-
tion state with respect to that leading to the anti isomer.
This observation is in complete accordance with the well-
known preference of high pressure for compact transition
(
17) (a) Olofson, R. A.; Yamamoto, Y. S.; Wancowicz, D. J . Tetrahe-
dron Lett. 1977, 1563. (b) Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe,
J . P. Tetrahedron Lett. 1977, 1567.
7
222 J . Org. Chem., Vol. 69, No. 21, 2004

New Analogues of Farnesyltransferase Inhibitors
F IGURE 2. DPIB 6 by pyrroline 11 exo (top, compact) and endo (bottom, loose) approaches.
SCHEME 4
states,18 and 16a , 17a , and 18a 19 are certainly the main
compounds isolated in these conditions of activation.
Finally, to determine the kinetic and thermodynamic
nature of the product of the reaction, 16a was warmed
in toluene at 110 °C for 24 h. Conversion (80%) into 16b
has been observed, a result which indicates that the syn
diastereomer corresponds to the kinetic product while its
anti counterpart is the thermodynamic one.
in 96 and 58% yields, respectively. The good results
observed in the presence of acetic acid may be explained
by the fact that this cosolvent is known to allow for a
better recovery of amines.21
The N-deprotection of carbamates 17 and 18 has also
been studied. Unfortunately, the treatment of 17a and
1
2,15
17b by a hydrochloric acid solution in methanol
did
not give the desired amine 19. On the other hand,
N-carbamate 18a has been submitted to the action of a
catalytic amount of palladium acetate (10%) and tri-
phenylphosphine-3,3′,3′′-trisulfonic acid trisodium salt
The functionalization steps necessary for converting
each adduct (16-18a ,b) into their respective BPHI
analogues 5 proceed initially through an N-deprotection
(TPPTS, 20%) in the presence of 10 equiv of diethylamine
(Scheme 4). The first attempts to hydrogenolyze 16a and
2
in an acetonitrile/H O mixture, following Gen eˆ t’s proce-
1
6b in the presence of palladium hydroxide in methanol
dure.22 Thus, 19a was recovered in 92% yield after 30
min at room temperature. This route was not explored
further since amine 16 gave satisfactory results with the
simple debenzylation mentioned above.
2
0
(Pearlman’s conditions ) proved to be unsuccessful. In
contrast, the same catalyst used in a methanol/acetic acid
mixture leads to the expected free amines 19a and 19b
(
(
18) J enner, G. Tetrahedron 1997, 53, 2669.
19) On the basis of strong analogies between 1H NMR spectra (see
(21) (a) Lloyd-Williams, P.; J ou, G.; Albericio, F.; Giralt, E. Tetra-
hedron Lett. 1991, 32, 4207. (b) Kates, S. A.; Daniels, S. B.; Albericio,
F. Anal. Biochem. 1993, 212, 303.
experimental details).
20) Pearlman, W. M. Tetrahedron Lett. 1967, 1663.
(
J . Org. Chem, Vol. 69, No. 21, 2004 7223

Pichon et al.
The final coupling step between each isomer of 19 was
per million (ppm) and the coupling constants (J ) in hertz. The
solvent was deuteriochloroform. IR spectra were obtained by
transmission on an FTIR spectrometer. The mass spectra were
obtained either under electron impact conditions (EI) at 70
eV ionizing potential or under fast atom bombardment (FAB)
by a Xe beam accelerated under 4 kV (current threshold ) 10
mA) on a glycerol or 3-nitrobenzyl alcohol matrix. Melting
points were determined using a microscope apparatus. Thin-
layer chromatography (TLC) was carried out on fluorescent
carried out with pentafluorophenol ester 21, prepared
from R-(methoxyphenyl)acrylic acid 2023 and pentafluo-
rophenol in the presence of dicyclohexylcarbodiimide
(
DCC). The crude ester was immediately allowed to react
with amines 19a and 19b for 4 h in dichloromethane and
in the presence of diisopropylethylamine, giving target
compounds 5a and 5b in 72 and 62% isolated yields,
respectively, for this last step.
2
4
plates. The silica gel used for flash chromatography was
0
.040-0.063 mm. All reagents were of reagent grade and were
used as such or distilled prior to use. Due to the presence of
Con clu sion s
rotamers being noticed for compounds 16, 17, 9, 10, and 5,
1
13
some NMR signals ( H and C) may be doubled. In this case,
both chemical shifts have been indicated.
Two synthetic routes to new oxygen-bridged analogues
of BPHI FT inhibitors have been studied in this work.
Both approaches rely on a single, commercially available,
dienic precursor 6 and an initial [4 + 2] cycloaddition.
The first synthetic path, based on methylpropiolate as
the dienophile, led to the double addition of 6 in hyper-
baric conditions (12 kbar). The second strategy involved
a [4 + 2] cycloaddition between three different pyrrolines
and 6. Syn compounds 16-18a were obtained in diaster-
eomeric excesses up to 90% under high pressure (12 kbar)
at room temperature, while anti isomer 16b was recov-
ered as the major product (de > 90%) at 110 °C in toluene
at atmospheric pressure. All of these cycloadducts were
separately deprotected and coupled with an activated
ester to provide the final target of 5. Thus, 5a and 5b
were obtained from 6 in about 60 and 30% overall yields,
respectively, following two similar three-step pathways
that differ only by the mode of activation for the [4 + 2]
cycloaddition key step.
5
,12-6,11-Diep oxy-5,5a ,6,11,11a ,12-h exa h yd r o-5,6,11,12-
tetr a p h en yln a p h th a cen e-5a -ca r boxylic Acid Meth yl Es-
t er 8. A solution of diphenylisobenzofuran 6 (302 mg, 1.12
mmol, 1 equiv) and methyl propiolate (93 µL, 1.12 mmol, 1
equiv) in tetrahydrofuran (5 mL) was transferred via a syringe
into a glass cell. After 24 h under 12 kbar at room temperature,
the solvent was evaporated under reduced pressure. Purifica-
tion by flash chromatography on silica gel (eluent, heptane/
ethyl acetate 70:30) gave 8 as a white solid (315 mg, 90%):
mp 105 °C (heptane/ethyl acetate); IR (film, NaCl) ν 3059,
-
1 1
2
947, 1727, 1263, 1211 cm ; H NMR (300 MHz) δ 3.23 (3H,
13
s), 4.72 (1H, s), 6.74-8.00 (28H, m); C NMR (75 MHz) δ 51.6,
6
1
1
7.0, 78.7, 86.6, 88.2, 88.5, 90.8, 118.9, 121.2, 122.5, 122.9,
25.6, 126.3, 126.4, 126.5, 126.8, 127.1, 127.2, 127.3, 127.5,
27.6, 127.7, 128.0, 128.2, 128.3, 129.5, 134.3, 134.4, 136.0,
137.6, 144.6, 144.7, 146.9, 149.6, 171.2. Anal. Calcd for
: C, 84.59; H, 5.16. Found: C, 84.66; H, 4.87.
1-Ben zyl-2,5-d ih yd r op yr r ole-3-ca r boxylic Acid Meth yl
44 32 4
C H O
Ester 11.1
2,16
A solution of N-benzyl-N-(butyloxymethyl)-
trimethylsilylmethylamine 9 (10 g, 35.8 mmol, 1.2 equiv) in
dichloromethane (20 mL) was added under argon to a solution
of methyl propiolate (2.66 mL, 29.8 mmol, 1 equiv) in dichlo-
romethane (10 mL). A solution of trifluoroacetic acid (230 µL,
Biologica l Activities. Both new analogues 5a and 5b
of FT inhibitors, as well as the syn and anti isomers of
intermediates 16 and 18, have been evaluated but did
not exhibit any inhibition of a Kirsten-Ras4B related
peptide by FT (Table 2). A very small activity has only
been noticed for 5b (32% inhibition at 50 µM, entry 2).
These disappointing results are difficult to analyze in the
prospect of our original hypothesis on the respective
2
.98 mmol, 0.1 equiv) in dichloromethane (5 mL) was trans-
ferred via a syringe dropwise at 0 °C over a period of 5 min.
The resulting mixture was allowed to warm to room temper-
ature and then stirred for 3 h before being neutralized by
addition of a saturated solution of NaHCO
organic layer was washed with a saturated solution of NaCl
15 mL), then dried (MgSO ), filtered, and concentrated under
3
(20 mL). The
“trans” orientations of the ester and phenyl groups unless
(
4
the supplementary phenyl group on 5 and its precursors
jeopardize the expected fit between the receptor and the
ligand. Further works taking this hypothesis into account
are currently under way.
reduced pressure. Purification by flash chromatography on
silica gel (eluent, heptane/ethyl acetate 60:40) gave 11 as a
-1
yellow oil (4.15 g, 64%): IR (film) ν 1724, 1671, 1242 cm
;
+
+
+
EIMS (70 eV) m/z 217 (M , 46), 202 (M - Me, 16), 140 (M
-
+
1
C
6
H
5
, 15), 126 (M - C
6 5 2
H CH , 100); H NMR (200 MHz) δ
TABLE 2. In h ibition of Kir sten -Ra s4B F a r n esyla tion
Activity by Com p ou n d s 5, 16, a n d 18
3
.65 (2H, s), 3.72 (4H, s), 3.79 (3H, s), 6.73 (1H, s), 7.30 (5H,
m). The NMR spectrum is identical to the one described in
the literature.1
6b
entry
compound
IC50, µM (% at 50 µM)
1
2
3
4
5
6
5a
5b
16a
16b
18a
18b
>50 (0)
>50 (32)
>50 (0)
>50 (12)
>50 (2)
>50 (0)
2,5-Dih yd r op yr r ole-1,3-d ica r boxylic Acid 3-Meth yl Es-
ter 1-Vin yl Ester 14.17 Pyridine (47 µL, 0.583 mmol, 1.5
equiv) and vinyl chloroformate 12 (50 µL, 0.583 mmol, 1.5
equiv) were successively added at room temperature to a
solution of 1-benzyl-2,5-dihydropyrrole-3-carboxylic acid meth-
yl ester 11 (85 mg, 0.389 mmol, 1 equiv) in dichloromethane
(5 mL). The resulting mixture was stirred for 24 h before being
quenched by the addition of a saturated solution of NaHCO
3
Exp er im en ta l Section
(3 mL). The organic layer was washed with a saturated
4
solution of NaCl (3 mL), then dried (MgSO ), filtered, and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (eluent, heptane/ethyl acetate
Gen er a l Asp ects. NMR spectra were recorded at room
1
temperature on spectrometers operating at 300 or 200 MHz( H)
1
3
and 75 or 50 MHz ( C). Chemical shifts (δ) are given in parts
7
0:30) gave 16 as a white solid (60 mg, 78%): mp 81 °C
(
1
heptane/ethyl acetate 70:30); IR (neat) ν 1732, 1654, 1424,
(
22) (a) Gen eˆ t, J .-P.; Blart, E.; Savignac, M.; Lemeune, S.; Paris,
-
1
1
300 cm ; H NMR (200 MHz) δ 3.64 (3H, s), 4.24 (2H, m),
J .-M. Tetrahedron Lett. 1993, 34, 4189. (b) Lemaire-Audoire, S.;
Savignac, M.; Blart, E.; Pourcelot, G.; Gen eˆ t, J . P. Tetrahedron Lett.
4.26 (2H, m), 4.35 (1H, dd, J ) 1.4 and 6.2), 4.66 and 4.68
1
994, 35, 8783.
23) Giraud, E.; Luttmann, C.; Lavelle, F.; Riou, J . F.; Mailliet, P.;
Laoui, A. J . Med. Chem. 2000, 43, 1807.
(
(24) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
7
224 J . Org. Chem., Vol. 69, No. 21, 2004

New Analogues of Farnesyltransferase Inhibitors
(
(
1H, dd, J ) 1.5 and 14.0), 6.61 (1H, dd, J ) 1.6 and 5.7), 7.09
to room temperature, the reaction mixture was concentrated
under reduced pressure. Purification by flash chromatography
on silica gel (eluent, heptane/ethyl acetate 70;30) gave 17a (107
mg, 45%) and 17b (65 mg, 27%) as yellow oils. The syn/anti
ratio corresponds to 62:38.
1
3
1H, dd, J ) 6.3 and 14.0); C NMR (50 MHz) δ 51.7, 51.8
and 52.1, 53.6 and 54.0, 95.5, 131.5, 136.2, 142.0, 151.2 and
1
7
51.4, 162.6. Anal. Calcd for C
.10. Found: C, 54.82; H, 5.58; N, 6.78.
,5-Dih yd r op yr r ole-1,3-d ica r boxylic Acid 3-Meth yl Es-
9 4
H11NO : C, 54.82; H, 5.62; N,
2
Hyp er ba r ic Activa tion . A solution of diphenylisobenzo-
furan 6 (275 mg, 1.02 mmol, 1.02 equiv) and 2,5-dihydropyr-
role-1,3-dicarboxylic acid 3-methyl ester 1-vinyl ester 14 (200
mg, 1.02 mmol, 1 equiv) in THF (5 mL) was transferred via a
syringe into a glass cell. After 24 h under 12 kbar at room
temperature, the solvent was evaporated under reduced pres-
sure. Purification by flash chromatography on silica gel (eluent,
heptane/ethyl acetate 70:30) gave 17a (348 mg, 73%) and 17b
(19 mg, 4%) as yellow oils. The syn/anti ratio corresponds to
95:5. Data for 17a follow: IR (film, NaCl) ν 1724, 1646, 1424,
ter 1-Allyl Ester 15. Allyl chloroformate 13 (2.94 mL, 27.6
mmol, 3 equiv) was added at room temperature to a solution
of 1-benzyl-2,5-dihydropyrrole-3-carboxylic acid methyl ester
1
1 (2 g, 9.2 mmol, 1 equiv) in dichloromethane (5 mL). The
resulting mixture was stirred for 24 h before being quenched
by addition of a saturated solution of NaHCO (5 mL). The
organic layer was dried (MgSO ), filtered, and concentrated
3
4
under reduced pressure. Purification by flash chromatography
on silica gel (eluent, heptane/ethyl acetate 70:30) gave 15 as
a yellow solid (1.5 g, 77%): mp 34 °C (heptane/ethyl acetate
-
1 1
1225, 1151 cm ; H NMR (300 MHz) δ 3.24 and 3.25 (3H, s),
3.38 and 3.43 (1H, t, J ) 7.5), 3.50 and 3.77 (1H, dd, J ) 1.9
and 12.1), 3.71 and 3.81 (1H, t, J ) 12.6), 3.92 and 3.97 (1H,
dd, J ) 2.3 and 7.5), 4.29-4.35 (1H, m), 4.57-4.68 (1H, m),
6.73-6.81 (1H, m), 6.93-7.00 (1H, m), 7.13-7.62 (14H, m);
7
0:30); IR (neat) ν 1715, 1645, 1436, 1408, 1328, 1288 cm-1
;
1
H NMR (300 MHz) δ 3.73 (3H, s), 4.33 (4H, s), 4.57 (2H, d, J
5.64), 5.15-5.31 (2H, m), 5.83-5.96 (1H, m), 6.68-6.72 (1H,
)
1
3
m); C NMR (75 MHz) δ 51.7 and 52.2, 51.8, 53.5 and 54.0,
1
3
6
1
5.9, 117.4, 131.7 and 131.8, 132.7 and 132.8, 136.5 and 136.6,
54.2, 162.9.
C NMR (75 MHz) δ 46.0 and 46.2, 49.2 and 49.4, 52.2 and
52.25, 55.3 and 55.5, 67.2 and 67.9, 90.6 and 90.7, 93.4 and
93.45, 95.2 and 95.3, 120.2 and 120.7, 120.8 and 121.1, 125.3,
127.0 and 127.2, 127.3, 127.6, 127.8, 128.0 and 128.1, 128.15
and 128.2, 128.6 and 128.65, 135.2 and 135.3, 136.7 and
136.75, 142.0 and 142.05, 143.5 and 143.7, 145.2 and 145.25,
4
,9-E p oxy-4,9-d ip h en yl-2-p h en ylm et h yl-1,3,3a ,4,9,9a -
h exa h yd r oben zo[f]isoin d ole-3a -ca r boxylic Acid Meth yl
Ester 16. Th er m a l Activa tion . A solution of diphenylisoben-
zofuran 6 (500 mg, 1.85 mmol, 1 equiv) and 1-benzyl-2,5-
dihydropyrrole-3-carboxylic acid methyl ester 11 (441 mg, 2.03
mmol, 1.1 equiv) in toluene (15 mL) was heated at 110 °C for
150.0 and 150.2, 172.5 and 172.6. Anal. Calcd for C29
C, 74.50; H, 5.39; N, 3.00. Data for 17b follow: IR (film, NaCl)
5
H25NO :
-1 1
2
4 h. After the solution was cooled to room temperature, the
ν 1727, 1646, 1428, 1149 cm ; H NMR (300 MHz) δ 3.24 (1H,
dd, J ) 5.8 and 11.3), 3.50-3.55 (1H, m), 3.59 (3H, s), 3.73-
3.83 (1H, m), 3.93 (1H, dd, J ) 9.5 and 11.3), 4.22 (1H, d, J )
12.1), 4.45 (1H, dd, J ) 1.5 and 6.2), 4.72 and 4.80 (1H, s),
7.18-8.00 (15H, m); 13C NMR (75 MHz) δ 48.4 and 48.8, 51.9
and 52.3, 52.5, 56.7 and 57.8, 67.5 and 68.5, 90.4 and 90.7,
reaction mixture was concentrated under reduced pressure.
Purification by flash chromatography on silica gel (eluent,
heptane/ethyl acetate 70:30) gave 16a (36 mg, 4%) and 16b
(
684 mg, 76%) as pale yellow solids. The syn/anti ratio
corresponds to 5:95.
9
1
1
1
2.3 and 92.4, 95.4, 119.3, 121.0 and 121.2, 125.8, 127.0, 127.5,
28.0, 128.3 and 128.4, 128.8, 129.8, 133.0, 135.3 and 135.4,
36.1 and 136.2, 142.2, 144.8 and 145.0, 147.1 and 147.2, 151.2,
72.9 and 173.0.
Hyp er ba r ic Activa tion . A solution of diphenylisobenzo-
furan 6 (100 mg, 0.369 mmol, 1 equiv) and 1-benzyl-2,5-
dihydropyrrole-3-carboxylic acid methyl ester 11 (127 mg,
0
.585 mmol, 1.6 equiv) in tetrahydrofuran (5 mL) was trans-
ferred via a syringe into a glass cell. After 24 h under 12 kbar
at room temperature, the solvent was evaporated under
reduced pressure. Purification by flash chromatography on
silica gel (eluent, heptane/ethyl acetate 70:30) gave 16a (159
mg, 88%) and 16b (7 mg, 4%) as pale yellow solids. The syn/
anti ratio corresponds to 96:4. Data for 16a follow: mp 124
2-Allyloxyca r bon yl-4,9-ep oxy-4,9-d ip h en yl-1,3,3a ,4,9,-
9a-h exah ydr oben zo[f]isoin dole-3a-car boxylic Acid Meth -
yl Ester 18. A solution of diphenylisobenzofuran 6 (192 mg,
0.71 mmol, 1 equiv) and 2,5-dihydropyrrole-1,3-dicarboxylic
acid 3-methyl ester 1-allyl ester 15 (150 mg, 0.71 mmol, 1
equiv) in dichloromethane (10 mL) was refluxed for 24 h. After
the solution was cooled to room temperature, the reaction
mixture was concentrated under reduced pressure. Purification
by flash chromatography on silica gel (eluent, heptane/ethyl
acetate 70:30) gave 18a (303 mg, 88%) and 18b (23 mg, 7%)
as yellow solids. The syn/anti ratio corresponds to 93:7. Data
for 18a follow: mp 69 °C (heptane/ethyl acetate 70:30, retro-
°
C (heptane/ethyl acetate 70:30, retro-Diels-Alder); IR (neat)
-
1
+
ν 2784, 1726, 1454 cm ; FAB (Xe, glycerol) m/z 488 (MH ,
+
1
2
(
1
0), 270 (MH - C
1H, dd, J ) 2.9 and 9.5), 2.60-2.75 (1H, m), 2.69 (1H, d, J )
0.5), 2.99 (1H, d, J ) 10.2), 3.25 (2H, s), 3.26 (3H, s), 3.99
6 5 2
H CH , 42); H NMR (300 MHz) δ 2.55
1
3
(
1H, dd, J ) 2.9 and 7.3), 6.68-7.60 (19H, m); C NMR (75
-
1
MHz) δ 51.8, 54.3, 56.3, 57.5, 59.6, 68.5, 90.3, 92.7, 120.2,
Diels-Alder); IR (neat) ν 1698, 1434 cm ; FAB (Xe, 3-ni-
+
+
1
1
20.7, 125.4, 126.6, 126.7, 127.0, 127.6, 127.8, 127.9, 128.2,
28.3, 128.4, 128.8, 136.2, 138.0, 138.4, 145.8, 147.9, 173.8.
trobenzyl alcohol) m/z 482 (MH , 5), 270 (MH - C H13NO4,
1
0
1
100); H NMR (300 MHz) δ 3.19 and 3.21 (3H, s), 3.25-3.80
(4H, m), 3.87 and 3.92 (1H, dd, J ) 2.1 and 7.5), 4.10-4.25
(2H, m), 5.05-5.20 (2H, m), 5.60-5.80 (1H, m), 6.85-7.60
(14H, m); 13C NMR (75 MHz) δ 45.9 and 46.2, 49.1 and 49.5,
52.1 and 52.2, 55.5 and 55.9, 65.6, 67.3 and 68.1, 90.7, 93.5,
117.2, 120.2, 120.6 and 120.8, 121.1, 125.4, 126.9 and 127.0,
127.2, 127.5 and 127.7, 128.0 and 128.2, 128.6, 132.9, 135.4,
135.5, 136.9, 143.8 and 144.0, 145.4 and 145.5, 152.7 and 152.9,
172.7 and 172.8. Anal. Calcd for C H NO : C, 74.83; H, 5.65;
Anal. Calcd for C33
C, 81.12; H, 5.97; N, 2.84. Data for 16b follow: mp 94 °C
heptane/ethyl acetate 70:30); IR (neat) ν 2812, 1732, 1448
3
H29NO : C, 81.29; H, 5.99; N, 2.87. Found:
(
-
1
+
+
6 5
cm ; FAB (Xe, glycerol) m/z 488 (MH , 21), 270 (MH - C H -
1
CH
d, J ) 9.4), 3.00 (1H, t, J ) 8.8), 3.37 (3H, s), 3.40 (2H, s), 3.44
1H, d, J ) 9.5), 3.63 (1H, t, J ) 8.8), 6.90-7.82 (19H, m); 13
NMR (75 MHz) δ 52.1, 56.8, 57.6, 59.6, 60.4, 68.5, 90.1, 92.0,
2
, 40); H NMR (300 MHz) δ 1.92 (1H, t, J ) 8.7), 2.25 (1H,
(
C
3
0
27
5
1
1
1
19.3, 120.1, 126.0, 126.6, 126.7, 126.8, 127.3, 127.6, 127.9,
28.1, 128.2, 128.3, 128.5, 136.1, 137.0, 138.8, 145.7, 147.9,
N, 2.91. Found: C, 74.62; H, 5.72; N, 2.73. Data for 18b
follow: mp 60 °C (heptane/ethyl acetate 70:30); IR (neat) ν
73.9. Anal. Calcd for C33
H
29NO
3
: C, 81.29; H, 5.99; N, 2.87.
-1
1
(
724, 1448 cm ; FAB (Xe, 3-nitrobenzyl alcohol) m/z 482
Found: C, 81.12; H, 6.06; N, 2.97.
,9-Ep oxy-4,9-d ip h en yl-2-vin yloxyca r bon yl-1,3,3a ,4,9,-
a-h exah ydr oben zo[f]isoin dole-3a-car boxylic Acid Meth -
+
+
1
4
MH , 4), 270 (MH - C10H13NO , 100); H NMR (200 MHz) δ
4
3.09 (1H, dd, J ) 5.8 and 10.9), 3.41 (1H, d, J ) 12.4), 3.49
(3H, s), 3.62-3.71 (1H, m), 3.77-3.85 (1H, m), 4.09 (1H, d, J
) 12.1), 4.46 (2H, d, J ) 5.5), 5.08-5.22 (2H, m), 5.70-5.92
(1H, m), 6.90-7.92 (14H, m); 13C NMR (75 MHz) δ 48.3 and
48.7, 51.8 and 52.1, 52.3, 56.6 and 57.8, 65.7, 67.5 and 68.6,
90.4, 92.3, 117.1, 119.1, 120.9, 126.0, 126.2, 126.8 and 127.0,
127.3, 127.8 and 128.0, 128.1 and 128.2, 128.3, 128.5 and 128.7,
9
yl Ester 17. Th er m a l Activa tion . A solution of diphenyl-
isobenzofuran 6 (137 mg, 0.51 mmol, 1 equiv) and 2,5-
dihydropyrrole-1,3-dicarboxylic acid 3-methyl ester 1-vinyl
ester 14 (100 mg, 0.51 mmol, 1 equiv) in tetrahydrofuran (10
mL) was heated at 70 °C for 24 h. After the solution was cooled
J . Org. Chem, Vol. 69, No. 21, 2004 7225

Pichon et al.
1
32.9, 135.6, 136.2, 145.0, 147.3, 153.9, 173.1. Anal. Calcd for
: C, 74.83; H, 5.65; N, 2.91. Found: C, 74.96; H,
.71; N, 2.94.
,9-Ep oxy-4,9-d ip h en yl-1,3,3a ,4,9,9a -h exa h yd r oben zo-
f]isoin dole-3a-car boxylic Acid Meth yl Ester 19a. Meth od
173.9. Anal. Calcd for C26
Found: C, 78.73; H, 5.87; N, 3.44.
-(2-Meth oxyp h en yl)a cr ylic Acid P en ta flu or op h en yl
H
23NO
3
: C, 78.57; H, 5.83; N, 3.52.
30 5
C H27NO
5
2
4
Ester 21. A solution of 1,3-dicyclohexylcarbodiimide (DCC) in
tetrahydrofuran (5 mL) was added under argon and at room
temperature to a solution of 2-(2-methoxyphenyl)propen-2-oic
acid 20 (120 mg, 0.6226 mmol, 1 equiv) and pentafluorophenol
(128 mg, 0.6792 mmol, 1.2 equiv) in tetrahydrofuran (5 mL).
After 1 h at room temperature, the solution was filtered to
eliminate the dicyclohexylurea (DCU). The filtrate was diluted
four times with ether, filtered to remove the last traces of DCU,
and then concentrated. The crude ester (21) was used im-
mediately without any further purification.
[
A
%
2
0
w ith P d (OH)
2
/C. Palladium hydroxide on carbon (20 wt
Pd/C) (33 mg, 0.031 mmol, 0.1 equiv) was added to a solution
of 4,9-epoxy-4,9-diphenyl-2-phenylmethyl-1,3,3a,4,9,9a-hexahy-
drobenzo[f]isoindole-3a-carboxylic acid methyl ester 16a (150
mg, 0.307 mmol, 1 equiv) in a 1:1 (v/v) methanol/acetic acid
mixture (5 mL). The reaction mixture was placed under a
saturated atmosphere of hydrogen for 24 h and vigorously
stirred. After filtration, the palladium salts were washed with
a 1:1 (v/v) methanol/acetic acid mixture (10 mL) and the
4
,9-Ep oxy-2-[2,2-(m eth oxyp h en yl)p r op en -2-oyl]-4,9-d i-
3
filtrate was neutralized with NaHCO powder until a pH of 8
was obtained. The aqueous layer was extracted with ethyl
p h en yl-1,3,3a ,4,9,9a -h exa h yd r oben zo[f]isoin d ole-3a -ca r -
b oxylic Acid Met h yl E st er 5a . A solution of 4,9-epoxy-
acetate (3 × 5 mL), and the resulting organic layer was dried
4
,9-diphenyl-1,3,3a,4,9,9a-hexahydrobenzo[f]isoindole-3a-car-
4
(MgSO ), filtered, and concentrated. Purification of the residue
boxylic acid methyl ester 19a (225 mg, 0.566 mmol, 1 equiv)
and diisopropylethylamine (295 µL, 1.698 mmol, 3 equiv) in
tetrahydrofuran (5 mL) was added to a solution of 2-(2-
methoxyphenyl)acrylic acid pentafluorophenyl ester 21 (0.6226
mmol, 1 equiv) in tetrahydrofuran (5 mL). The reaction
mixture was stirred at room temperature for 4 h before being
quenched by the addition of a 0.5 M solution of NaOH (5 mL).
The organic layer was washed with a new 0.5 M solution of
NaOH (5 mL) and followed by a saturated solution of NaCl (2
by flash chromatography on silica gel (eluent, dichloromethane/
methanol 95:5) gave amine 19a as a white solid (118 mg, 96%).
Meth od B23 w ith P d (OAc)
/TP P TS/Dieth yla m in e. 2-Al-
2
lyloxycarbonyl-4,9-epoxy-4,9-diphenyl-1,3,3a,4,9,9a-hexahy-
drobenzo[f]isoindole-3a-carboxylic acid methyl ester 18a (1.04
g, 2.15 mmol, 1 equiv), palladium acetate (47.5% Pd, 100 mg,
0
.215 mmol, 0.1 equiv), and triphenylphosphine-3,3′,3′′-trisul-
fonic acid trisodium salt (244 mg, 0.43 mmol, 0.2 equiv) were
successively introduced into a 1:1 (v/v) water/acetonitrile
mixture (10 mL). After all of the solids were dissolved,
diethylamine (3 mL, 21.5 mmol, 10 equiv) was added and the
resulting reaction mixture was stirred at room temperature
for 2 h before being quenched with the addition of a saturated
solution of NaHCO
with dichloromethane (2 × 5 mL), and then the resulting
organic layer was dried (MgSO ), filtered, and concentrated.
× 5 mL) and then, after recovering, dried (MgSO
4
), filtered,
and concentrated. Purification of the residue by flash chro-
matography on silica gel (eluent, heptane/ethyl acetate 50:50)
gave 5a as a white solid (229 mg, 72%): mp 125 °C (heptane/
ethyl acetate 50:50, retro-Diels-Alder); IR (neat) ν 1723, 1639,
-
1
3
(5 mL). The aqueous layer was extracted
1431, 1278, 1236 cm ; FAB (Xe, 3-nitrobenzyl alcohol) m/z
+
+
558 (MH , 50), 270 (MH - C16
H
17NO
4
, 100); HRMS-FAB (m/
+
4
z) [MH ] found, M ) 558.2281, C36
H
32NO
5
requires 558.2280;
1
Purification of the residue by flash chromatography on silica
gel (eluent, dichloromethane/methanol 95:5) gave amine 19a
as a white solid (792 mg, 92%): mp 72 °C (dichloromethane/
H NMR (300 MHz) δ 3.30 (3H, s), 3.25-3.55 (2H, m), 3.68-
3.75 (1H, m), 3.78 (3H, s), 3.94-4.10 (2H, m), 5.05 and 5.13
(1H, dd, J ) 1.1 and 26.7), 5.55 (1H, s), 6.88-7.70 (18H, m);
-
1
13
methanol 95:5); IR (neat) ν 3341, 1723, 1452 cm ; FAB (Xe,
C NMR (75 MHz) δ 46.5 and 49.0, 49.8 and 52.6, 52.7 and
+
1
glycerol) m/z 398 (MH , 5); H NMR (300 MHz) δ 2.71 (1H, d,
J ) 12.8), 2.84 (1H, dd, J ) 7.2 and 13.2), 2.93 (1H, d, J )
52.75, 55.8 and 56.0, 56.1 and 56.9, 67.4 and 69.1, 91.1 and
91.4, 93.9, 111.4 and 111.5, 119.8 and 120.2, 120.7 and 121.0,
121.4 and 121.5, 121.7 and 122.1, 125.6 and 125.9, 126.5 and
126.7, 127.3 and 127.4, 127.7 and 128.0, 128.1 and 128.2, 128.4,
128.6 and 128.65, 129.0 and 129.1, 129.6 and 129.8, 130.1 and
130.2, 135.9 and 136.0, 137.4, 142.6, 144.8 and 145.2, 146.0
and 146.3, 156.6 and 156.7, 169.1 and 169.7, 173.3 and 173.5.
1
3.6), 3.14 (1H, d, J ) 13.9), 3.19 (3H, s), 3.84 (1H, dd, J ) 1.1
13
and 6.8), 6.90-7.60 (14H, m); C NMR (75 MHz) δ 48.6, 51.8,
5
1
Anal. Calcd for C26
C, 78.58; H, 6.09; N, 3.41.
,9-Ep oxy-4,9-d ip h en yl-1,3,3a ,4,9,9a -h exa h yd r oben zo-
2.1, 59.1, 71.0, 90.2, 92.6, 120.3, 120.4, 125.3, 127.1, 127.5,
27.8, 128.1, 128.4, 128.5, 135.9, 137.3, 144.3, 146.6, 173.8.
3
H23NO : C, 78.57; H, 5.83; N, 3.52. Found:
Anal. Calcd for C36
5
H31NO : C, 77.54; H, 5.60; N, 2.51. Found:
C, 77.48; H, 5.92; N, 2.46.
4
2
0
[
f]isoin d ole-3a -ca r boxylic Acid Meth yl Ester 19b. Pal-
4,9-Ep oxy-2-[2,2-(m eth oxyp h en yl)p r op en -2-oyl]-4,9-d i-
p h en yl-1,3,3a ,4,9,9a -h exa h yd r oben zo[f]isoin d ole-3a -ca r -
boxylic Acid Meth yl Ester 5b. The procedure reported above
for 5a was applied to synthesize 5b as a white solid (104 mg,
62%). A solution of 4,9-epoxy-4,9-diphenyl-1,3,3a,4,9,9a-
hexahydrobenzo[f]isoindole-3a-carboxylic acid methyl ester
19b (119 mg, 0.33 mmol, 1 equiv) in tetrahydrofuran (5 mL)
was added to a solution of 2-(2-methoxyphenyl)acrylic acid
pentafluorophenyl ester 21 (0.33 mmol, 1 equiv) in tetrahy-
drofuran (5 mL): mp 100 °C (heptane/ethyl acetate 50:50,
ladium hydroxide on carbon (20 wt % Pd/C) (65 mg, 0.061
mmol, 0.08 equiv) was added to a solution of 4,9-epoxy-4,9-
diphenyl-2-phenylmethyl-1,3,3a,4,9,9a-hexahydrobenzo[f]isoin-
dole-3a-carboxylic acid methyl ester 16b (360 mg, 0.740 mmol,
1
equiv) in a 1:1 (v/v) methanol/acetic acid mixture (10 mL).
The reaction mixture was placed under a saturated atmo-
sphere of hydrogen for 24 h and vigorously stirred. After
filtration, the palladium salts were washed with a 1:1 (v/v)
methanol/acetic acid mixture (10 mL) and the filtrate was
neutralized with NaHCO
The aqueous layer was extracted with ethyl acetate (3 × 5 mL),
and the resulting organic layer was dried (MgSO ), filtered,
-
1
3
powder until a pH of 8 was obtained.
retro-Diels-Alder); IR (neat) ν 1723, 1639, 1431 cm ; FAB
+
+
(Xe, 3-nitrobenzyl alcohol) m/z 558 (MH , 55), 270 (MH
C H17NO
16 4
-
, 80); 1H NMR (300 MHz) δ 2.99-3.10 (1H, m),
4
and concentrated. Purification of the residue by flash chro-
matography on silica gel (eluent, dichloromethane/methanol
3.30-3.37 and 3.42 (1H, m), 3.36 and 3.48 (3H, s), 3.56 and
3.59 (3H, 1s), 3.59-3.70 (1H, m), 4.05-4.15 (1H, m), 4.44 (1H,
d, J ) 13.6), 5.23 and 5.25 (1H, 1s), 5.47 and 5.52 (1H, 1s),
6.60-7.90 (18H, m); 13C NMR (75 MHz) δ 47.7 and 51.0, 51.1
and 54.3, 52.3 and 52.4, 55.4 and 55.5, 56.3 and 57.8, 67.4 and
68.7, 90.3 and 90.8, 92.4 and 92.7, 110.8 and 111.1, 118.6, 119.2
and 119.3, 120.7, 120.9 and 121.0, 125.8 and 125.9, 126.4 and
126.5, 126.9 and 127.0, 127.3, 127.4 and 127.5, 127.9 and 128.0,
128.2, 128.3 and 128.4, 128.7 and 128.8, 129.4 and 129.5, 129.7,
135.4 and 135.5, 136.2 and 136.3, 142.3 and 142.6, 144.8 and
145.2, 147.2 and 147.4, 156.3 and 156.4, 169.2 and 169.3, 173.0.
9
5:5) gave amine 19b as a white solid (170 mg, 58%): mp 70
°
1
C (dichloromethane/methanol 95:5); IR (neat) ν 3318, 1725,
-
1
+
3
453 cm ; FAB (Xe, glycerol) m/z 398 (MH , 5); CI (NH ) 398
+
1
(MH , 100); H NMR (300 MHz) δ 2.65 (1H, dd, J ) 5.6 and
1
3
2.4), 2.96 (1H, d, J ) 12.4), 3.01 (1H, dd, J ) 7.5 and 12.4),
.16 (1H, d, J ) 12.4), 3.38 (1H, dd, J ) 5.6 and 7.5), 3.44
1
3
(3H, s), 6.85-7.44 (14H, m); C NMR (75 MHz) δ 51.1, 52.0,
5
1
5.2, 60.6, 70.4, 90.5, 92.1, 118.9, 121.1, 125.9, 126.5, 127.0,
27.1, 127.7, 128.0, 128.2, 128.6, 136.0, 136.7, 146.2, 148.3,
7
226 J . Org. Chem., Vol. 69, No. 21, 2004

New Analogues of Farnesyltransferase Inhibitors
Anal. Calcd for C36
C, 77.48; H, 5.69; N, 2.43.
H
31NO
5
: C, 77.54; H, 5.60; N, 2.51. Found:
of Mr. Albert Marcual (IRCOF) with the FAB mass
spectra has been appreciated.
Ack n ow led gm en t. N.P. acknowledges the Minis-
t e` re de la Recherche et de la Technologie for a Ph.D.
grant. We also thank the Conseil R e´ gional de Haute-
Normandie for support of the IRCOF high-pressure
research program and Dr Lo ¨ı c Toupet (Universit e´ de
Rennes I) for the X-ray crystallography. The assistance
1
Su p p or tin g In for m a tion Ava ila ble: Copies of the IR, H
NMR, and/or 13C NMR spectra for compounds 5a , 8, 15, 17a ,
7b, and 19a . This material is available free of charge via the
1
Internet at http://pubs.acs.org.
J O049037I
J . Org. Chem, Vol. 69, No. 21, 2004 7227