Synthesis of oxa-bridged analogues of farnesyltransferase inhibitor RPR 115135

Article abstract of DOI:10.1021/jo0100188

Two synthetic routes to new oxygen-bridged analogues of farnesyltransferase inhibitors are described that follow either a [3 + 2]/[4 + 2] or a [4 + 2]/[3 + 2] sequence of reactions. The first approach has been achieved by reacting the in situ generated phenylisobenzofuran (PIBF) 4 with pyrroline 5a and has led stereoselectively to racemic 18, which was transformed in a few steps into the target molecule 2. The second pathway relies on a key intermediate 6, obtained either by condensation of PIBF with methyl acrylate, followed by a deprotonation/selenation and an oxidation/elimination sequence, or by cycloaddition between PIBF and α-phenylselenoacrylate 11, followed by the same oxidation/elimination sequence. The reaction of 6 with amino dipole 7 gives diastereoselective access to pyrrolidine 25, a precursor of the second target 3, an epimer of 2.

Full text of DOI:10.1021/jo0100188

J . Org. Chem. 2001, 66, 3797-3805
3797
Syn th esis of Oxa -Br id ged An a logu es of F a r n esyltr a n sfer a se
In h ibitor RP R 115135
Ce´line Martin,† Patrick Mailliet,‡ and J acques Maddaluno*,†
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes de l'IRCOF, UMR 6014 CNRS,
Universite´ de Rouen, 76821 Mont St Aignan, France, and Aventis-Pharma SA, Centre de Recherche de
Vitry-Alfortville, 13 quai J ules Guesde, 94403 Vitry-sur-Seine Cedex, France
jmaddalu@crihan.fr
Received J anuary 5, 2001
Two synthetic routes to new oxygen-bridged analogues of farnesyltransferase inhibitors are described
that follow either a [3 + 2]/[4 + 2] or a [4 + 2]/[3 + 2] sequence of reactions. The first approach has
been achieved by reacting the in situ generated phenylisobenzofuran (PIBF) 4 with pyrroline 5a
and has led stereoselectively to racemic 18, which was transformed in a few steps into the target
molecule 2. The second pathway relies on a key intermediate 6, obtained either by condensation of
PIBF with methyl acrylate, followed by a deprotonation/selenation and an oxidation/elimination
sequence, or by cycloaddition between PIBF and R-phenylselenoacrylate 11, followed by the same
oxidation/elimination sequence. The reaction of 6 with amino dipole 7 gives diastereoselective access
to pyrrolidine 25, a precursor of the second target 3, an epimer of 2.
In tr od u ction
The central role played by mutations of the Ras protein
in human cancerogenesis, especially in colon and pan-
creas tumors, has been well documented lately.1 Three
different mutation types, the so-called Harvey-Ras, Neu-
roblastoma-Ras, and Kirsten-Ras 4B, have been identi-
fied and are characterized by their C-terminal variations.
The early steps of the regular cell division process involve
the farnesylation and binding of the Ras-GDP protein to
the inner wall of the cell. This event, followed by a
phosphorylation into Ras-GTP, induces a signal cascade
ending with the translocation into the nucleus and the
gene transcription activation. Because it is unable to
switch back from the Ras-GTP to the Ras-GDP form, the
F igu r e 1. Farnesyl transferase inhibitor RPR 115135 and its
mutated protein keeps on firing a continuous cell prolif-
eration signal. Among the various biochemical strategies
studied to reverse this phenomenon, the inhibition of
farnesyl transferase (FT), which prevents the Ras-GDP
fixation on the cell wall, has turned out to be the most
efficient one and has opened promising new directions
in cancer therapy. There is, however, one major difficulty
associated with this approach, and that is the selective
inhibition of FT with respect to related enzymes such as
geranylgeranyltransferase (GGT), of which Ras is also a
substrate. Several classes of compounds have been
developed to reach an acceptable level of selectivity,
among which is the benzo[f]perhydroisoindole (BPHI)
class.
analogues.
presence of two aromatic rings, one on the lateral amide
chain and the other one at the 9 position.2 However,
several other important structural characteristics such
as the nature of the bridging element, or the position of
the angular acid group, have not been taken into account
yet. The possible role played by these fragments in the
drug-enzyme interaction led us to prepare the two new
analogues displayed in Figure 1, i.e., 2 (RPR 225,370)
and 3 (RPR 222,490). We present in this paper the
different synthetic pathways we have studied to access
these compounds.
Compounds such as RPR 115135 (1, Figure 1), which
combines a remarkably low GGT inhibition profile with
an elevated cellular potency and moderate in vivo activi-
ties,2 constitutes a particularly effective lead molecule in
this series. A large investigation on the structure-
activity relationship has already been achieved around
this skeleton and has revealed key features such as the
Resu lts a n d Discu ssion
The synthesis of the skeleton of 2 and 3 has been
tackled through the routes summarized in Figure 2,
(2) Mailliet, P.; Laoui, A.; Bourzat, J . D.; Capet, M.; Cheve´, M.;
Commerc¸on, A.; Dereu, N.; Le Brun, 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 .; Lelie`vre, Y.; Riou, J . F.;
Vrignaud, P.; Duchesne, M.; Lavelle, F. In Farnesyltransferase and
Geranylgeranyltransferase Inhibitors in Cancer and Cardiovascular
Therapy; Sebti, S., Ed.; Humana Press: Totowas, NJ , in press.
† Universite´ de Rouen.
‡ Rhoˆne-Poulenc Rorer, currently Aventis-Pharma SA.
(1) Bos, J . L. Cancer Res. 1989, 49, 4682.
10.1021/jo0100188 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

3798 J . Org. Chem., Vol. 66, No. 11, 2001
Martin et al.
F igu r e 2. Three retrosynthetic routes to analogue 2 and 3 skeleton.
Sch em e 1
Sch em e 2
corresponding to disconnections based on either a [3 +
2]/[4 + 2] or a [4 + 2]/[3 + 2] cycloaddition sequence. The
key step in route A relies on the reaction between
phenylisobenzofuran 4 and the pyroline 5. In route B,
the tetracyclic skeleton is obtained by addition of dipole
7 (derived from amine 9) on the double bond of 6. This
latter compound can be obtained from the corresponding
R-selenoester 8. Two possibilities open at that stage, the
first one (B1) relying on ester 10, obtained by reacting
PIBF 4 and an acrylate. The second path of the fork (B2)
is based on the direct reaction between 4 and the
R-selenoacrylate 11. We will see in the following that each
of these pathways A and B leads stereoselectively to
precursors of 2 and 3, respectively.
process and resorted to the method described by Tobia
and Rickborn,4c which relies on phthalane 17 (Scheme
2). This compound has been obtained following Rodrigo
and co-workers’ convenient procedure.5 Thus, acetaliza-
tion of o-bromobenzaldehyde 14 followed by bromine-
lithium exchange and benzaldehyde condensation pro-
vides alcohol 16, which cyclizes in methanol in the
presence of acidic Dowex 50W-X2. The phthalane 17
obtained presents a syn/anti ratio of 43:57. Addition of
n-butyllithium to 17 triggers a δ-elimination and affords,
the 1-phenylisoben-
zofuran (PIBF) 4. This diene has not been isolated or
purified and has been trapped in situ by pyrroline 5a
under mild thermal conditions (3 h 20 min at 55 °C in
THF). A single adduct 18 was recovered after flash
chromatography on silica gel in a mediocre 22% yield for
the two steps (Scheme 2).
Rou te A: Access to An a logu e 2
Let us first discuss the case of route A. The two
partners needed for this approach are relatively easy to
prepare. The pyroline skeleton of 5 is indeed accessible
through the [3 + 2] scheme proposed by Sakurai and
Achiwa (Scheme 1).3 The reaction of chloromethylbutyl
ether 12 with lithium amide 13 provides the tertiary
amine 9. The action of a catalytic amount of trifluoro-
acetic acid on the latter in methylene chloride generates
the dipole 7, which reacts in situ with methyl propiolate
at room temperature to yield pyroline 5a in 59% yield.
On the other hand, phenylisobenzofuran 4 is a well-
known compound of which synthesis have been described
under both acidic and basic conditions.4 An acidic me-
dium was anticipated to be hardly compatible with the
strained oxygen bridge in the expected adducts. We have
thus preferred to prepare the diene through a basic
after tert-butyl alcohol quenching,6
The NMR analysis indicates that the ring junction
proton H11 appears as a doublet, indicative of both the
regioselectivity and “exo” (with respect to the ester group)
selectivity of this reaction. The coupling between H11 and
H4 is indeed characteristic of the â-orientation of H11. The
(5) (a) Plaumann, H. P.; Smith, J . G.; Rodrigo, R. J . Chem. Soc.
Chem. Commun. 1980, 354. (b) Kuroda, T.; Takahashi, M.; Kondo, K.;
Iwasaki, T. J . Org. Chem. 1996, 61, 9560.
(6) Using methanol to quench this reaction leads to a double
conjugated addition of lithium methylate on methyl propiolate, provid-
ing to the known 2,2-dimethoxy methyl propionate. See, for instance:
(a) Walia, J . S.; Walia, A. S. J . Org. Chem. 1976, 41, 3765. (b) Bertz,
S. H.; Dabbagh, G.; Cotte, P. J . Org. Chem. 1982, 47, 2216. (c) Tietze,
L. F.; Meier, H.; Voss, E. Synthesis 1988, 274. (d) Hosokawa, T.; Aoki,
S.; Murahashi, S. I. Synthesis 1992, 558.
(3) (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.
(4) (a) Keay, B. A.; Plaumann, H. P.; Rajapaksa, D.; Rodrigo, R. Can.
J . Chem. 1983, 61, 1987. (b) Hayakawa, K.; Yamaguchi, Y.; Kane-
matsu, K. Tetrahedron Lett. 1985, 26, 2689. (c) Tobia, D.; Rickborn,
B. J . Org. Chem. 1986, 51, 3849. (d) Porsey, S. P.; Rajapaksa, D.;
Taylor, N. J .; Rodrigo, R. J . Org. Chem. 1989, 54, 4280.

Synthesis of Analogues of RPR 115135
J . Org. Chem., Vol. 66, No. 11, 2001 3799
Sch em e 4
F igu r e 3. Endo and exo approaches of phenylisobenzofuran
21 by pyroline 3a .
Sch em e 3
provides the expected tetracyclic adducts in modest yields
but in a fully diastereoselective way. The following func-
tionalization steps have been achieved to connect the
resulting adduct to the lateral chain determined from a
preliminary structure-activity relationship study.2 The
samples thus obtained have been evaluated for their in
vitro activities as farnesyltransferase inhibitors (see
below).10
Rou te B: Syn th esis of An a logu e 3
The most convergent B-type approach to the key-
synthon 6 requires methylpropiolate and PIBF 4 (Figure
4). Unfortunately, no reaction was observed between
these compounds (or propiolic acid and PIBF) at room
temperature, while a complex mixture of products, from
which no cycloadduct could be identified, was recovered
after 4 h 30 min at 100 °C in toluene. We have therefore
tried to prepare 6 through the oxidation of the corre-
sponding R-selenoesters 8, accessible through routes B1
or B2 (Figure 2).
latter, in the R-position, would correspond to a singlet,
due to the 90° dihedral angle between H11 and H4, as
evidenced below. This exo selectivity can be rationalized
by a putative π-π interaction taking place between the
benzylic part of 5a and the cyclohexadienic moiety of 4
(Figure 3).
The following functionalization steps to convert adduct
18 into analogue 2 first go through a debenzylation. All
attempts made to hydrogenolyze 18 in the presence of
palladium hydroxide (Pearlman’s catalyst) have re-
mained unsuccessful, despite several attempts to vary
the pressure, the solvent, and the temperature. The
N-dealkylation of tertiary amines is known to be possible
by the action of vinyl chloroformate (Voc-Cl).7 The addi-
tion of 2 equiv of vinylchloroformate to 18 in dichlo-
romethane in the presence of 2 equiv of pyridine provides
carbamate 19 in 49% yield (Scheme 3). The unprotected
pyrrolidine 20 is then obtained in 41% yield by refluxing
19 in a methanol solution of hydrochloric acid for 4 h.
The final coupling between 20 and the known8 R-(2-
methoxyphenyl)acrylic acid has been accomplished through
its chloride 21 in standard conditions.9 The low 26% yield
in the target amide 2 corresponds to an nonoptimized
reaction.
F igu r e 4. Routes between phenylisobenzofuran 21 and ester
22.
We first considered the B1 approach by reacting freshly
prepared 4 with methyl acrylate at room temperature for
3 h (Scheme 4). The adduct 23a is obtained as a mixture
of isomers in an overall 48% yield. Examples taken from
the literature suggest that a mixture of regioisomers was
to be expected, even if mainly the “ortho” substitution
pattern could be anticipated.11 A careful NMR analysis
led us to the conclusion that only the “ortho” regioisomer
23a represented had been obtained as a 38:62 mixture
of endo and exo isomers.
In conclusion, this study of route A indicates that the
[4 + 2] cycloaddition between PIBF 4 and pyrroline 5a
(7) (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.
(8) Giraud, E.; Luttmann, C.; Lavelle, F.; Riou, J . F.; Mailliet, P.;
Laoui, A. J . Med. Chem. 2000, 43, 1807.
(9) Only a slight excess of thionyl chloride is to be used to convert
the acid 25 into its chloride 26, since a conjugated addition of chloride
onto the acrylate double bond can occur.
(10) Martin, C.; Pichon, N.; Harrison-Marchand, A.; Maddaluno, J .;
Mailliet, P., to be published.

3800 J . Org. Chem., Vol. 66, No. 11, 2001
Martin et al.
coupling with H1, while the amplitude of its coupling
constant with H3 determines the syn or anti character
between H3 and H2â, thus the exo or endo character of
23a .
The possible influence of steric factors on both the
regio- and endo/exo selectivities of this reaction has been
considered. The access to other regioisomers of 3 was
indeed attractive to extend the structure/activity rela-
tionship study in this series, and reversing the regiose-
lectivity of the above cycloaddition seemed possible
considering the low differences between orbitalar coef-
ficients in the HOMO of 4 (Table 1). To increase the
dienophile bulkiness, we resorted to tert-butyl acrylate.
Its cycloaddition with PIBF takes place at reflux of
THF in 2 h and provides adduct 23b in 73% yield.14
The regioselectivity remains unaltered while the endo
selectivity is slightly enhanced (endo/exo ) 57:43, Scheme
4). Mellor and Webb have reported a comparable im-
provement of the endo preference with the increase of
the steric hindrance of the acrylates.15 The ease of
approach of the isobenzofuran nucleus has been also
modified replacing the phenyl group of 4 by an o-tolyl
appendage. The o-tolylisobenzofuran 22 has been pre-
pared following the procedure described above (Scheme
2). Its reaction with methyl acrylate takes place at room
temperature and provides adduct 24 in 49% yield after
3 h. The regioselectivity is once more unchanged and the
endo/exo ratio is 44:56 (Scheme 4). This set of experi-
ments tends to indicate that the regio- and the endose-
lectivity can hardly be influenced by the choice of the
partners.
The oxidation step needed to set the double bond in 6
has been achieved through deprotonation and selenation
of 23. As reported previously,16 KHMDS is well suited to
this task, provided diphenyl diselenide is added to the
medium before the deprotonation.17 The stereoconver-
gence observed in this reaction converts the two epimeric
esters 23 into a single (“endo”) R-phenylselenoester 8a
(Figure 4 and Scheme 5). The occurrence of a common
intermediate potassium enolate (except for the E(O)/Z(O)
ratio), of which only the convex face is accessible to the
electrophile, can explain this selectivity.16
F igu r e 5. AM1-optimized conformation of cycloadduct 24a .
Ta ble 1. AM1 Coefficien ts for th e HOMO a n d Atom ic
Ch a r ges of P h en ylisoben zofu r a n 4
HOMO coeff
atomic charges
C1: +0.40
C2: +0.03
C3: +0.20
C4: -0.39
C1: -0.09
C2: -0.11
C3: -0.01
C4: 0.00
A peculiar coupling pattern between their protons H2
and proton H1 is worth underlining. Molecular models
(as well as the AM1 optimization of 23a endo, Figure 5)
indeed show that the bridgehead proton H1 lies in a plane
more or less perpendicular to the H2 syn to the bridging
oxygen (H2â), leading to their almost null coupling
constant.12 This topological peculiarity can be confusing
since a superficial analysis of the NMR spectrum could
erroneously suggest that the “meta” regioisomer is ob-
tained selectively. The preferred “ortho” regioselectivity
can be qualitatively rationalized on the basis of the AM1
analysis of the HOMO coefficients of 4 (Table 1), albeit
only very small differences are obtained at this level of
calculation for the reagent alone and in its steady state.
Regarding the tendency to an exo-favored addition, it is
often reported for isobenzofurans13 but remains difficult
to explain. The attribution of the endo and exo structures
to the isomers is based on the analysis of the NMR
Interestingly, the route B2, viz. the thermal cycload-
dition between methyl R-phenylselenoacrylate 11 (easily
prepared from methyl acrylate and phenylselenium
chloride)18 and in situ generated PIBF 4, yields selec-
tively the opposite (“exo”)19 epimer 8b. Because they both
feature a proton syn to the selenium atom, the two
isomers can be smoothly oxidized by H2O2, separately or
together, in the same bridged unsaturated ester 6
(Scheme 5).
The crude reaction medium can then undergo a [3 +
2] dipolar cycloaddition with the ylid 7 prepared from
amine 9 according to Achiwa’s conditions as above. The
coupling constants. H2 is indeed identified through its
â
(11) (a) Faragher, R.; Gilchrist, T. L. J . Chem. Soc., Perkin Trans.
1 1976, 336. (b) Contreras, L.; McLean, D. Can. J . Chem. 1980, 58,
2573. (c) Smith, J . G.; Welankiwar, S. S.; Chu, N. G.; Lai, E, H.;
Sondheimer, S. J . J . Org. Chem. 1981, 46, 4658. (d) Rodrigo, R.; Knabe,
S. M.; Taylor, N. J .; Rajapaksa, D.; Chernishenko, M. J . J . Org. Chem.
1986, 51, 3973. (e) Sugahara, M.; Moritani, Y.; Terakawa, Y.; Ogiku,
T.; Ukita, T.; Iwasaki, T. Tetrahedron Lett. 1998, 39, 1377.
(12) For a comparable observation, see: J iang, D.; Herndon, J . W.
Org. Lett. 2000, 2, 1267.
(13) (a) Nozaki, H.; Yamaguti, T.; Ueda, S.; Kondo, K. Tetrahedron
1968, 24, 1445. (b) Hickmott, P. W.; Simpson, R. J . Chem. Soc. C 1972,
302. (c) Smith, J . G.; Welankiwar, S. S.; Shantz, B. S.; Lai, E. H.; Chu,
N. G. J . Org. Chem. 1980, 45, 1817. (d) Rodrigo, R.; Knabe, S. M. J .
Org. Chem. 1986, 51, 3973.
(14) Adduct 23 and 24 cannot be chromatographed on silica gel on
which they decompose. See the Experimental Section for details.
(15) Mellor, J . M.; Webb, C. F. J . Chem. Soc., Perkin Trans. 2 1974,
17.
(16) Martin, C.; Maillet, P.; Maddaluno, J . Org. Lett. 2000, 2, 923.
(17) Rodrigo and colleagues have shown that the electrophile is to
be added to PIBF adducts before the base to prevent the oxygen-bridge
opening: Keay, B.; Rajapaksa, D.; Rodrigo, R. Can. J . Chem. 1984,
62, 1093.
(18) Piettre, S.; J anousek, Z.; Merenyi, R.; Viehe, H. G. Tetrahedron
1985, 41, 2527.
(19) By contrast, R-phenylthioacrylate reacts with cyclopentadiene
under catalytic conditions to yield a major endo isomer: Aggarwal, V.
K.; J ones. D. E.; Martin-Castro, A. M. Eur. J . Org. Chem. 2000, 2939.

Synthesis of Analogues of RPR 115135
J . Org. Chem., Vol. 66, No. 11, 2001 3801
Sch em e 5
Sch em e 7
The late functionalization steps to convert 25 into 3
are identical to those presented above to transform 18
into 2. The reaction of 25 with Voc-Cl under the same
conditions as in Scheme 3 gives access to carbamate 26
in 53% yield. This compound is deprotected by the same
acidic treatment to afford pyrrolidine 27 (Scheme 7) in
70% yield after chromatography. The final coupling with
acid chloride 21 takes place in methylene chloride at
room temperature and affords the target-amide 3 in 47%
purified yield.
In conclusion to this part of the work, the [4 + 2]/[3 +
2] strategy offers a diastereoselective access to 3, another
analogue of farnesyltransferase inhibitor 1. The bending
of the tricyclic intermediate skeleton, due to the presence
of the bridging oxygen, is probably responsible for the
differentiation of the concave and convex faces toward
incoming dipole during the [3 + 2] step.
Con clu sion a n d Biologica l Activities
Several synthetic routes to new oxygen-bridged ana-
logues of farnesyltransferase inhibitors have been evalu-
ated in this work. The construction of their tetracyclic
core has been considered following either a [3 + 2]/[4 +
2] or a [4 + 2]/[3 + 2] sequence of reactions. The first
one (route A, Figure 2) has been studied by reacting in
situ generated PIBF with pyrroline 5a and has led
stereoselectively to 18, which has been converted in three
steps into 2. The second approach relies on a key
intermediate 6 that could not be prepared by direct
reaction between methyl propiolate and PIBF. Its syn-
thesis has been achieved through either: (1) the conden-
sation of PIBF with methyl acrylate, followed by a
deprotonation/selenation and an oxidation/elimination
sequence (route B1); or (2) the stereoselective cycloaddi-
tion between PIBF and R-phenylselenoacrylate 11, fol-
lowed by the same oxidation/elimination sequence (route
B2).
strong concavity of the bridged skeleton in 6 (Scheme 5)
explains why the addition takes place only on the “exo”
face,20 giving pyrrolidine 25 as a single isomer in 7-14%
yield from 17 (three to four steps).
The most important feature of this reaction is definitely
its total diastereoselectivity in favor of epimer 25,
indicating that the two B-type strategies (Figure 2)
are complementary to route A that provides only 18
(Scheme 6).
Sch em e 6
The reaction between 6 and amino dipole 7 gives a
diastereoselective access to 25, epimer of 18. The former
can be converted into analogue 3 through the same three-
step procedure used with 18.
Finally, these two independent routes have provided
two (racemic) stereoselective accesses to the two epimers
2 and 3, which have been evaluated in farnesyltrans-
ferase inhibition tests. New extensions are currently
brought to these strategies10 in an attempt to prepare a
larger set of compounds that could help to the detailed
mapping of the drug-enzyme active site interaction.
(20) Trost, B. M. Angew. Chem. Int. Ed. Engl. 1986, 25, 1.

3802 J . Org. Chem., Vol. 66, No. 11, 2001
Martin et al.
Ta ble 2. F a r n esyltr a n sfer a se In h ibitor y Activity of 1-3a
solution of NaHCO3. The organic phase was washed with 20
mL of a saturated solution of NaCl and then dried (MgSO4)
and evaporated under reduced pressure. Thus, 13.3 g of a
crude oil was recovered and purified by silica gel chromatog-
raphy eluting with petroleum ether/ethyl acetate 60/40 mix-
ture (yield ) 59%): IR (neat) 2950, 1724, 1671, 1242, 732
cm-1; EIMS (70 eV) m/z 217 (M+, 46), 202 (M+ - CH3, 16),
184 (M+ - MeOH - H, 14), 140 (M+ - Ph, 15), 126 (M -
CH2Ph, 100); 1H NMR (200 MHz, CDCl3) δ (ppm) 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.3b
compd
FT inhibition (IC50,b µM)
RPR 115135
(rac) RPR 115135-methyl ester
2
3
0.3
1.7
.10c
7.5
a
Purified human Ftase was incubated at 37 °C for 1 h with 50
nM of a Ki-Ras related peptide, Biot-(bA)3-S-K-D-G-(K)6-S-K-T-
K-C-V-I-M, 120 nM of FPP and various concentrations of inhibitor
in 100 µL final volume. Then 150 µL of a suspension of streptavidin
PVT beads was added at pH ) 4, thus blocking the farnesylation
reaction and giving, thanks to biotin/streptavidin interaction, a
2-Br om oben za ld eh yd em eth yl Keta l 15. In 8 mL of dry
methanol containing Dowex acidic resin (50W-8.50, 100 mesh)
was diluted 2-bromobenzaldehyde (1 g, 5.4 mmol, 1 equiv).
Trimethylorthoformate (1.80 mL, 3 equiv) was then added and
the medium warmed to reflux for 22 h. After filtration, the
organic phase was evaporated under reduced pressure. Thus,
1.13 g of a yellow oil was recovered, which did not need
purification (yield ) 91%): IR (neat) 2934, 1934, 1434, 1102,
754 cm-1; EIMS (70 eV) m/z 232-230 (M+, 17), 201-199 (M+
- OCH3, 100), 185-183 (M+ - OCH3 - CH3, 30), 157-155
b
scintillation that was measured on a scintillator. IC50 values as
means of two or more determinations. c 3 and 5% inhibition were
found at 10 µM in two separate determinations.
Using X-ray data of a truncated form of human FT
cocrystallized with benzo[f]perhydroisoindole (BPHI) de-
rivatives,21 docking experiments suggested that moving
the phenyl ring from position 9 to position 4, while
keeping the relative stereochemistry of the bridging
element and the carboxylate function at position 3a such
as in compound 3, could be easily accommodated in the
FPP-binding pocket of FT. On the other hand, similar
moving of the phenyl ring from position 9 to position 4,
without keeping the relative stereochemistry of the
bridge and the carboxylate, such as in compound 2,
should be prohibited. As expected, 2 does not exhibit any
inhibition of farnesylation of a Kirsten-Ras 4B related
peptide by FT (Table 2). More surprisingly, compound 3
only retains moderate potency (IC50 ) 7.5 µM). The FPP-
binding pocket of FT is highly hydrophobic and mainly
composed of aromatic residues in its deepest part.22 Since
the molecular shape of methyl ester 3 is likely to be
accommodated by FT (docking experiments not shown),
the drop in activity (4-5-fold) observed with 3, when
compared to methyl ester derivative of RPR 115135 1 is
suspectedly related to the less hydrophobic nature of oxa
bridge when compared to the ethano bridge.
1
(M+ - CH(OCH3)2, 18), 119 (M+ - Br - OCH3, 13); H NMR
(200 MHz, CDCl3) δ (ppm) 3.36 (6H, s), 5.54 (1H, s), 7.16 (1H,
dt, J ) 1.8, 7.6 Hz), 7.31 (1H, dt, J ) 1.2, 7.4 Hz), 7.56 (2H,
dd, J ) 1.2, 7.7 Hz); 13C NMR (50 MHz, CDCl3) δ (ppm) 53.79,
102.86, 122.87, 128.08, 128.23, 129.98, 132.79, 136.74.
Hyd r oxyben zyl-2-ben za ld eh yd e Meth yl Keta l 16. Un-
der argon was diluted 2-bromobenzaldehyde methyl ketal 15
(2.42 g, 10.47 mmol, 1 equiv) in 24 mL of dry ether. At -60 °C
was added a solution of n-butyllithium 2.4 M (4.8 mL, 1.1
equiv). After 1 h of stirring at the same temperature, a solution
of benzaldehyde (1.2 mL, 1.1 equiv) in 4 mL of dry ether that
had been previously sonicated for 10 min was added. The
medium was stirred at -60 °C for 1 h 30 min before being
quenched by addition of 7 mL of water at rt. The aqueous
phase was extracted twice with 20 mL of dichloromethane. The
combined organic phases were dried (MgSO4) and evaporated
under reduced pressure. Thus, 2.92 g of a colorless oil which
did not need any purification was recovered (yield ) 95%): IR
(neat) 3427, 2902, 1963, 1700, 1456, 1203, 1065 cm-1; GC/
EIMS (70 eV) m/z 256 (13), 241 (M+ - OH, 24), 225 (73), 209
(M+ - OMe - H2O, 100); 1H NMR (200 MHz, CDCl3) δ (ppm)
3.25 (3H, s), 3.30 (3H, s), 3.49 (1H, d, J ) 4.7 Hz), 5.40 (1H,
s), 6.21 (1H, d, 4.7 Hz), 7.23-7.56 (9H, m); 13C NMR (50 MHz,
CDCl3) δ (ppm) 53.31, 53.55, 72.41, 102.35, 126.44, 127.03,
128.11, 128.97, 135.18, 141.80-142.60.
Exp er im en ta l Section
Gen er a l Asp ects. 1H NMR spectra were recorded at 200
or 300 MHz and 13C NMR spectra at 50 MHz; chemical shifts
(δ) are given in parts per million (ppm) and the coupling
constants (J ) in hertz. The solvent was deuteriochloroform or
deuteriobenzene. IR spectra were realized by transmission.
Gas chromatography analyses were performed on a high-
resolution DB-1 type column (30 m, 0.25 mm DB-1). GC/MS
analyses were performed on an instrument equipped with the
same column. The mass spectra under electron impact condi-
tions (EI) were recorded at 70 eV ionizing potential; methane
(CH4), isobutane (t-BuH), or ammonia (NH3) were used for
chemical ionization (CI). The silica gel used for flash chroma-
tography was 0.040-0.063 mm. All reagents were of reagent
grade and were used as such or distilled prior to use.
1,3-Dih yd r o-1-m eth oxy-3-p h en ylisoben zofu r a n 17.5a
A
solution of hydroxybenzyl-2-benzaldehyde methyl ketal 28
(2.64 g, 10.23 mmol, 1 equiv) in 30 mL of dry methanol
containing Dowex acidic resin (50W-8.50, 100 mesh) was
warmed to reflux for 20 h. After filtration, the medium was
evaporated under reduced pressure. Thus, an orange oil that
did not need any purification was recovered. The product was
obtained as a cis/trans (43/57) mixture (yield ) 85%): IR (neat)
3040, 2893, 1677, 1475, 1272, 1000, 752 cm-1; EIMS (70 eV)
m/z 225 (M+ - H, 16), 194 (M+ - MeOH, 84), 165 (M+ - OMe
- OCH, 100); 1H NMR (200 MHz, CDCl3) δ (ppm) cis product
3.58 (3H, s), 6.11 (1H, s), 6.22 (1H, s), 7.02 (1H, m), 7.23-7.41
(8H, m), trans product 3.53 (3H, s), 6.27 (1H, d, J ) 2.0 Hz),
6.35 (1H, d, J ) 2.0 Hz), 7.02 (1H, m), 7.23-7.41 (8H, m); 13
C
N-Ben zyl-3-(m eth ylfor m a te)-2,5-d ih yd r op yr r ole 5a .3b
Under argon was diluted N-benzyl-N-(butyloxymethyl)tri-
methylsilylmethylamine 9 (16.74 g, 59.4 mmol, 1.2 equiv) in
100 mL of dry dichloromethane. Methyl propiolate (4.46
mL, 49.6 mmol, 1 equiv) was then added at 0 °C, followed,
dropwise, by a solution of trifluoroacetic acid (0.38 mL, 1.7
mmol, 0.03 equiv) in 5 mL of dichloromethane. The reaction
was exothermic. The medium was stirred at room tempera-
ture for 4 h before being neutralized by adding a saturated
NMR (50 MHz, CDCl3) δ(ppm) (cis/trans mixture) 55,10, 55.41,
85.06, 85.86, 107.16, 107.53, 122.14, 122.71, 122.83, 127.28,
127.58, 127.97, 128.27, 128.45, 128.57, 128.91, 129.67, 137.15,
137.52, 140.67, 141.61, 142.79, 143.17.
4,9-Epoxy-9-ph en yl-2-ph en ylm eth yl-1,3,4,9,1,11-h exah y-
d r oben zo[f]isoin d ole-10â-m eth ylca r boxyla te 18. Under
argon, to a solution of 1,3-dihydro-1-methoxy-3-(2-phenyl)-
isobenzofuran 17 (1.04 g, 4.60 mmol, 1 equiv) in 10 mL of dry
ether, was added, at rt, a solution of n-butyllithium (2.85 mL,
2.1 M, 5.6 mmol, 1.3 equiv). The medium became dark. After
15 min, a solution of tert-butyl alcohol (0.44 g, 5.6 mmol, 1.3
equiv) in 3 mL of dry THF was added, and the medium became
red. After 5 min, pyrroline 5a (1.02 g, 1 equiv) was added, the
reaction mixture was warmed to 55 °C for 3 h 20 min, and
(21) Laoui, A. Structure-aided approach for lead optimisation:
Application to farnesyltransferase inhibitors; oral communication #227
at the 221st ACS National Meeting, San Diego, April 1-5, 2001.
(22) Park, H.-W.; Bodoluri, S. R.; Moomaw, J . F.; Casey, P. J .; Beese,
L. S. Science 1997, 275, 1800.

Synthesis of Analogues of RPR 115135
J . Org. Chem., Vol. 66, No. 11, 2001 3803
then the reaction was quenched with 8 mL of water. The
aqueous phase was extracted three times with 10 mL of ether.
The combined organic phases were dried (MgSO4) and evapo-
rated under reduced pressure. Thus, 2.33 g of an oil was
recovered, which was purified by silica gel chromatography
eluting with heptane/ethyl acetate 90/10 then 80/20 mixture
(yield ) 22%). The product 18 could be recrystallized in ethyl
acetate (F ) 116 °C): IR (neat) 2782, 1723, 1456, 1267, 1207,
899, 733 cm-1; CIMS (t-BuH) m/z 412 (M + 1, 100); HRMS/CI
(t-BuH) calcd for C27H26O3N m/z 412.1913, found 412.1924; 1H
NMR (200 MHz, CDCl3) δ (ppm) 2.31 (1H, dd, J ) 6.9, 7.5
Hz), 2.62 (1H, d, J ) 10.5 Hz), 2.75 (1H, d, J ) 10.5 Hz), 3.14
(2H, s), 3.22 (3H, s), 3.69 (2H, m), 5.45 (1H, d, J ) 5.5 Hz),
6.77 (2H, m), 7.12-7.50 (12H, m); 13C NMR (50 MHz, CDCl3)
δ (ppm) 51.77, 52.53, 52.96, 56.91, 59.53, 66.05, 80.24, 94.22,
120.25, 120.31, 125.21, 126.48, 126.68, 126.93, 127.02, 127.59,
127.69, 127.90, 128.13, 128.40, 128.81, 136.03, 138.40, 144.85,
145.34, 173.90.
Meth yl 4,9-Ep oxy-2-vin ylfor m a te-9-p h en yl-1,3,4,9,1,11-
h exa h yd r oben zo[f]isoin d ole-10â-ca r boxyla te 19. P r oce-
d u r e A. To a solution of pyrrolidine 18 (145 mg, 0.36 mmol, 1
equiv) in 1.5 mL of dichloromethane were added, at rt, pyridine
(0.058 mL, 0.72 mmol, 2 equiv) and vinyl chloroformate (0.066
mL, 0.72 mmol, 2 equiv). After 5 h 20 min, the medium was
quenched with 1 mL of a saturated solution of NaHCO3. The
organic phase was washed with 1 mL of a saturated solution
of sodium chloride, dried (MgSO4), and evaporated under
reduced pressure. Thus, 151 mg of an oil was recovered, which
was purified by silica gel chromatography eluting with dichlo-
romethane/methanol 98/2. After purification, 70 mg of solid
19 was obtained (yield ) 49.5%).
P r oced u r e B. Under argon, to a solution of 1,3-dihydro-1-
methoxy-3-phenylisobenzofuran 17 (1.72 g, 7.61 mmol, 1 equiv)
in 17 mL of dry ether was added, at rt, a solution of
n-butyllithium (4.20 mL, 2.35 M, 9.9 mmol, 1.3 equiv). The
medium became dark. After 15 min, 0.13 mL of water was
added, and the medium became red. After 2 min, a solution of
pyrroline 5b (1.5 g, 1 equiv) in 17 mL of THF was added. The
medium was warmed at 55 °C for 3 h 30 min, and then the
reaction was quenched with 5 mL of water. The aqueous phase
was extracted twice with 20 mL of ether. The combined organic
phases were dried (MgSO4) and evaporated under reduced
pressure. Thus, 4 g of an oil was recovered, which was purified
by silica gel chromatography eluting with a dichloromethane/
methanol (98/2) mixture (yield ) 27%): F ) 118 °C; IR (neat)
2957, 1728, 1428, 1272, 1226, 1152, 733 cm-1; CIMS (n-BuH)
m/z 392 (M + 1, 56), 263 (26), 195 (M + 1 - 3b, 100); 1H NMR
(200 MHz, CDCl3) δ (ppm) (two rotamers) 3.12 (1H, m), 3.15
(1H, m), 3.21 (3H, s), 3.23 (3H, s), 3.27 (1H, d, J ) 8.8 Hz),
3.31 (1H, d, J ) 7.4 Hz), 3.55 (1H, d, J ) 12.7 Hz), 3.62 (1H,
d, J ) 12.8 Hz), 3.64 (1H, m), 3.70 (1H, d, J ) 10.7 Hz), 3.71
(1H, d, J ) 12.7 Hz), 4.31 (1H, dd, J ) 1.4, 6.2 Hz), 4.60 (1H,
dd, J ) 1.2, 14.0 Hz), 5.54 (1H, d, J ) 4.7 Hz), 6.71 (1H, dd, J
) 6.5, 14.0 Hz), 6.78 (1H, dd, J ) 6.4, 13.0 Hz), 7.14-7.54
(9H, m); 13C NMR (50 MHz, CDCl3) δ (ppm) (two rotamers)
44.83, 44.92, 48.96, 49.04, 51.78, 52.14, 64.92, 65.52, 80.28,
94.98, 95.21, 120.22, 120.41, 120.72, 121.02, 125.10, 126.97,
127.22, 127.58, 127.68, 128.02, 128.17, 135.06, 141.95, 142.02,
143.13, 143.27, 149.87, 150.04, 172.65.
13.6 Hz), 3.07 (1H, d, J ) 13.6 Hz), 3.19 (3H, s), 3.61 (1H, dd,
J ) 5.8, 6.0 Hz), 5.43 (1H, d, J ) 5.5 Hz), 7.17-7.51 (9H, m);
13C NMR (50 MHz, CDCl3) δ (ppm) 47.29, 51.73, 55.54, 68.65,
80.05, 94.25, 120.01, 120.54, 125.09, 127.42, 127.74, 128.05,
135.69, 143.46, 143.88, 173.84.
Meth yl-4,9-epoxy-2-[2-(2-m eth oxyph en yl)pr open -2-oyl]-
9-p h en yl-1,3,4,9,1,11-h exa h yd r ob en zo[f]isoin d ole-10â-
ca r boxyla te 2. Under argon, to a solution of 2-(2-methoxy-
phenyl)propen-2-oic acid (144 mg, 0.72 mmol, 1.9 equiv) in 1.5
mL of dichloromethane was added thionyl chloride (0.06 mL,
0.76 mL, 2 equiv). After 15 h at rt, the excess of thionyl chloride
was evaporated under reduced pressure. The 2-(2-methox-
yphenyl)propen-2-oyl chloride 21 left over was then diluted
directly in 1 mL of dichloromethane and added to a solution
of amine 20 (124 mg, 0.38 mmol, 1 equiv) in 4 mL of
dichloromethane and pyridine (0.064 mL, 0.79 mmol, 2.1 equiv)
at 0 °C and under argon. The medium was stirred at rt for 1
h 15 min before being quenched by 1 mL of a saturated
solution of NaHCO3. The organic phase was dried (MgSO4) and
evaporated under reduced pressure. After purification by silica
gel chromatography eluting with dichloromethane/methanol
95/5 mixture, 42 mg of 33 was recovered (two rotamers: 55/
45) (yield ) 26%): IR (neat) 2957, 1728, 1640, 1452, 1296,
1221, 927, 758 cm-1; CIMS (n-BuH) m/z 482 (M + 1, 24), 288
(33, 94), 251 (42), 195 (4 + 1, 100); HRMS/CI (n-BuH) calcd
for C30H28O5N m/z 482.1968, found 482.1985; 1H NMR (200
MHz, CDCl3) δ (ppm) (two rotamers) 2.90 (2H, m), 3.24 (3H,
s), 3.30 (1H, d, J ) 12.7 Hz), 3.40 (2H, m), 3.68 (3H, s), 3.70
(3H, s), 3.77 (1H, m), 3.84 (1H, m), 3.86 (1H, d, J ) 11.6 Hz),
4.88 (1H, s), 5.10 (1H, s), 5.43 (1H, s), 5.45 (1H, d, J ) 6.3
Hz), 5.48 (1H, s), 5.55 (1H, d, J ) 5.5 Hz), 6.77-7.54 (13H,
m); 13C NMR (50 MHz, CDCl3) δ (ppm) (2 rotamers) 44.70,
47.28, 48.95, 51.75, 51.66, 52.13, 52.49, 52.78, 55.50, 55.65,
64.48, 66.19, 80.28, 80.55, 95.12, 110.84, 110.96, 116.31,
120.11, 120.19, 120.39, 120.99, 121.30, 121.43, 124.94, 125.14,
127.24, 127.49, 127.67, 127.93, 128.14, 129.00, 129.22, 129.61,
135.16, 142.06, 142.31, 142.51, 143.18, 144.37, 156.07, 156.26,
168.14, 168.09, 172.94.
3-Meth ylcar boxylate-1,4-epoxy-4-ph en yl-1,2,3,4-tetr ah y-
d r on a p h th a len e 23a . Under argon, to a solution of 1,3-
dihydro-1-methoxy-3-(2-phenyl)isobenzofuran 17 (111 mg, 0.48
mmol, 1 equiv) in 2 mL of dry ether was added, at rt, a solution
of n-butyllithium (0.52 mL, 2.3 M, 2.5 equiv). The medium
became dark. After 15 min, tert-butyl alcohol (0.11 mL, 20.5
equiv) was added, and the medium became red. After 5 min,
methyl acrylate (0.086 mL, 2 equiv) was added. The medium
was stirred at rt for 1 h 30 min and quenched with 1 mL of
water. The aqueous phase was extracted with ether. The
combined organic phases were dried (MgSO4) and evaporated
under reduced pressure. Thus, the crude product was recov-
ered as an endo/exo mixture (endo/exo 38/62) that was purified
by silica gel chromatography eluting with petroleum ether/
ethyl acetate 95/5 then 90/10 mixture (yield ) 48%). The two
epimers could be separated by flash chromatography on silica
gel: IR (neat) 2950, 1732, 1460, 1170, 910, 732 cm-1; CIMS
(n-BuH) m/z 281 (M + 1, 100); HRMS/CI (n-BuH) calculated
for C18H17O3 m/z 281.1178, found: 281.1169; 1H NMR (200
MHz, CDCl3) δ (ppm) endo product 1.97 (1H, dd, J ) 3.9, 11.6
Hz), 2.65 (1H, m), 3.45 (3H, s), 3.64 (1H, dd, J ) 4.0, 10.4 Hz),
5.49 (1H, d, J ) 5.0 Hz), 7.00-7.74 (9H, m), exo product 1.94
(1H, dd, J ) 8.4, 11.4 Hz), 2.63 (1H, ddd, J ) 4.6, 5.2, 11.4
Hz), 3.05 (1H, dd, J ) 4.6, 8.4 Hz), 3.30 (3H, s), 5.66 (1H, d, J
) 5.2 Hz), 7.10-7.59 (9H, m); 13C NMR (50 MHz, CDCl3) δ
(ppm) endo product 34.78, 47.24, 51.67, 78.28, 91.70, 118.68,
121.32, 126.46, 127.24, 127.77, 128.19, 128.43, 135.61, 144.37,
145.98, 173.43, exo product 35.15, 49.17, 51.49, 78.06, 91.70,
118.54, 119.11, 125.64, 126.73, 127.10, 127.58, 128.09, 135.61,
145.60, 146.79, 173.48.
Meth yl 4,9-Ep oxy-9-p h en yl-1,3,4,9,1,11-h exa h yd r oben -
zo[f]isoin d ole-10â-ca r boxyla te 20. Carbamate 19 (389 mg,
0.99 mmol, 1 equiv) was diluted in 5 mL of a solution of
hydrochoric acid 1.5 M in methanol. The medium was warmed
at reflux for 3h45 then evaporated under reduced pressure.
The residue was diluted in 5 mL of dichloromethane and
neutralized with saturated NaHCO3. The organic phase was
washed with 1 mL of brine, dried (MgSO4), and evaporated
under reduced pressure. Thus, 239 mg of an oily compound
was recovered that was purified by silica gel chromatography
eluting with a dichloromethane/methanol (95/5) mixture (yield
) 41%): F ) 167 °C; IR (neat) 2948, 1728, 1461, 1323, 1267,
908, 738 cm-1; CIMS (n-BuH) m/z 322 (M + 1, 100); HRMS/
CI (n-BuH) calculated for C20H20O3N m/z 322.1443, found
3-Bu tylca r boxyla te-1,4-ep oxy-4-p h en yl-1,2,3,4-tetr a h y-
d r on a p h th a len e 23b. Under argon, to a solution of 1,3-
dihydro-1-methoxy-3-phenylisobenzofuran 17 (0.29 g, 1.28
mmol, 1 equiv) in 7 mL of dry ether was added, at rt, a solution
of n-butyllithium (1.15 mL, 2.25 M, 2 equiv). The medium
became dark. After 15 min, a solution of tert-butyl alcohol (0.19
g, 2.58 mmol, 2 equiv) in 2 mL of ether was added, and the
1
322.1445; H NMR (200 MHz, CDCl3) δ (ppm) 2.46 (1H, d, J
) 13.0 Hz), 2.58 (1H, dd, J ) 6.6, 13.0 Hz), 2.81 (1H, d, J )

3804 J . Org. Chem., Vol. 66, No. 11, 2001
Martin et al.
medium became red. After 5 min, a solution of tert-butyl
acrylate (0.37 mL, 2.58 mmol, 2 equiv) in 10 mL of dry THF
was added. The medium was warmed at reflux for 2 h 20 min
and then was quenched with 5 mL of water. The aqueous
phase was extracted twice with 10 mL of ethyl acetate. The
combined organic phases were dried (MgSO4) and evaporated
under reduced pressure. Thus, 0.46 g of an oil was recovered
that could not be purified by silica gel chromatography. The
product was obtained under an endo/exo (57/43) mixture. A
gummy precipitate appeared upon dilution into a petroleum
ether/ethyl acetate (90/10) mixture, that was discarded by
centrifugation. The remaining solution was then evaporated
under reduced pressure and compound 34 recovered as an
orange oil (yield ) 73%): CIMS (CH4) m/z 323 (M + 1, 47),
195 (M + 1 - CH2CHCO2-t-Bu, 100); 1H NMR (200 MHz,
CDCl3) δ (ppm) endo product 0.99 (9H, s), 1.96 (1H, dd,
J ) 4.0, 10.9 Hz), 2.56 (1H, ddd, J ) 5.5, 9.8, 10.9 Hz), 3.57
(1H, m), 5.46 (1H, d, J ) 5.0 Hz), 7.20-7.80 (9H, m), exo
product: 1.03 (9H, s), 1.86 (1H, dd, J ) 8.2, 11.7 Hz), 2.63
(1H, ddd, J ) 4.7, 4.0, 11.7 Hz), 2.88 (1H, dd, J ) 4.0, 8.4
Hz), 5.62 (1H, d, J ) 4.7 Hz), 7.20-7.80 (9H, m); 13C NMR
(50 MHz, CDCl3) δ (ppm) endo/exo mixture 27.70, 28.00,
34.42, 34.88, 48.07, 49.55, 77.59, 78.00, 80.45, 80.84, 118.60,
118.99, 121.45, 126.18, 126.51, 126.93, 127.18, 127.46, 127.96,
128.17, 128.35, 135.85, 136.70, 144.49, 145.95, 146.13, 170.57,
171.97.
3-Met h ylca r b oxyla t e-1,4-ep oxy-4-(o-t olyl)-1,2,3,4-t et -
r a h yd r on a p h th a len e 24. Under argon, to a solution of
2-bromobenzaldehyde methyl ketal 15 (2.03 g, 8.78 mmol, 1
equiv) in 10 mL of dry ether was added, at -55 °C, n-
butyllithium (3.85 mL, 2.5 M, 9.65 mmol, 1.1 equiv). After 1 h
of stirring at -60 °C, a solution of o-tolualdehyde (1.10 mL,
9.65 mmol, 1.1 equiv) in 4 mL of dry ether was added, which
had been previously sonicated for 10 min. The medium was
stirred at -60 °C for 1 h 30 min before being quenched by
adding 10 mL of water at rt. The aqueous phase was extracted
twice with 15 mL of dichloromethane. The combined organic
phases were dried (MgSO4) and evaporated under reduced
pressure. Thus, 2.17 g of a colorless oil corresponding to
hydroxybenzyl-2-o-tolualdehyde methyl ketal was recovered,
that cristallized later on (yield ) 91%): mp ) 63 °C; IR (neat)
3434, 2970, 1467, 1377, 1203 cm-1; CIMS (CH4) m/z 255 (M -
OH, 38), 209 (M + 1 - (OMe)2, 100);1H NMR (200 MHz, CDCl3)
δ (ppm) 2.06 (3H, s), 3.32 (3H, s), 3.39 (3H, s), 5.54 (1H, s),
6.42 (1H, s), 6.87-7.46 (8H, m); 13C NMR (50 MHz, CDCl3) δ
(ppm) 19.11, 53.10, 53.99, 68.48, 103.23, 125.75, 126.37, 127.09,
127.15, 127.38, 127.69, 128.94, 130.11, 135.15, 135.55, 140.59,
141.41.
A solution of hydroxybenzyl-2-o-tolualdehyde methyl ketal
prepared above (1.61 g, 5.91 mmol, 1 equiv) in 20 mL of dry
methanol containing Dowex acid resin (50W-8.50, 100 mesh)
was warmed for 13 h at reflux. After filtration, the medium
was evaporated under reduced pressure. Thus, 1.04 g of an
orange oil was recovered, which did not need any purification,
and the 1,3-dihydro-1-methoxy-3-(2-tolyl)isobenzofuran, pre-
cursor of 22, was obtained as a cis/trans (36/64) mixture (yield
) 73%): IR (neat) 2939, 1668, 1608, 1465, 1373, 1000, 756
cm-1; EIMS (70 eV) m/z 240 (M+, 6), 239 (M+ - H, 17), 208
(M+ - MeOH, 100), 194 (M+ - OMe - Me, 30); 1H NMR (200
MHz, CDCl3) δ (ppm) cis product 2.57 (3H, s), 3.54 (3H, s),
6.28 (1H, s), 6.49 (1H, s), 7.06-7.47 (8H, m), trans product:
2.43 (3H, s), 3.59 (3H, s), 6.36 (1H, d, J ) 1.8 Hz), 6.61 (1H,
bs), 7.06-7.47 (8H, m); 13C NMR (50 MHz, CDCl3) δ (ppm)
(cis/trans mixture) 19.27, 19.48, 55.18, 55.45, 82.18, 82.45,
107.05, 107.33, 122.11, 122.17, 122.85, 123.03, 126.24, 127.73,
127.88, 127.97, 128.24, 129.45, 130.34, 130.84, 135.58, 136.36,
137.76, 138.12, 139.34, 142.61, 142.89.
Under argon, to a solution of 1,3-dihydro-1-methoxy-3-(2-
tolyl)isobenzofuran prepared above (0.31 g, 1.29 mmol, 1 equiv)
in 8 mL of dry ether was added a solution of n-butyllithium
(1.15 mL, 2.25 M, 2 equiv) at rt. The medium became dark.
After 15 min, a solution of tert-butyl alcohol (0.19 g, 2.58 mmol,
2 equiv) in 2 mL of ether was added, and the medium became
red. After 10 min was added methyl acrylate (0.20 mL, 2.58
mmol, 2 equiv). The medium was stirred at rt for 3 h and then
was quenched by adding 3 mL of water. The aqueous phase
was extracted twice with 10 mL of ethyl acetate. The combined
organic phases were dried (MgSO4) and evaporated under
reduced pressure. Thus, 0.45 g of crude product was recovered
as an endo/exo (44/56) mixture, which was purified by silica
gel chromatography eluting with petroleum ether/ethyl acetate
90/10 mixture (yield ) 49%). During the flash chromatography,
the two epimers could be separated: IR (neat) 2948, 1732,
1461, 1267, 1166, 908, 756 cm-1; CIMS (t-BuH) m/z 295 (M +
1, 100); HRMS/CI (t-BuH) calcd for C19H19O3 m/z ) 295.1334,
found 295.1353; 1H NMR (200 MHz, CDCl3) δ (ppm) endo
product 1.92 (1H, dd, J ) 3.6, 11.5 Hz), 2.02 (3H, s), 2.58 (1H,
ddd, J ) 5.0, 11.5, 10.2 Hz), 3.44 (3H, s), 3.85 (1H, dd, J )
3.6, 10.2 Hz), 5.51 (1H, d, J ) 5.0 Hz), 6.84 (1H, d, J ) 7.1
Hz), 7.08-7.34 (6H, m), 7.93 (1H, m), exo product 1.02 (1H,
dd, J ) 8.6, 11.3 Hz), 2.57 (4H, m), 3.30 (1H, m), 3.37 (3H, s),
5.62 (1H, d, J ) 5.2 Hz), 7.06-7.60 (8H, m); 13C NMR (50 MHz,
CDCl3) δ(ppm) endo product 21.63, 34.43, 47.05, 51.68, 78.18,
92.22, 118.91, 121.09, 125.22, 126.39, 127.09, 128.73, 129.16,
131.82, 133.65, 139.67, 144.23, 144.55, 172.36, exo product
21.83, 35.35, 48.59, 51.59, 77.40, 92.55, 119.17, 120.07, 125.64,
126.4, 126.87, 127.07, 127.71, 131.74, 134.60, 146.04, 146.49,
173.82.
3r-Met h ylca r b oxyla t e-3â-p h en ylselen yl-1,4-ep oxy-4-
p h en yl-1,2,3,4-tetr a h yd r on a p h th a len e 8a . To a solution of
the endo isomer of 3-methylcarboxylate-1,4-epoxy-4-phenyl-
1,2,3,4-tetrahydronaphthalene 23a (59 mg, 0.21 mmol, 1 equiv)
in 1 mL of THF were added, under argon at rt, a solution of
diphenyldiselenide (0.13 g, 0.42 mL, 2 equiv) in 1.3 mL of THF
and a solution of KHMDS in THF (0.9 M, 0.46 mL, 0.42 mmol,
2 equiv). After 30 min, the solvent was evaporated under
reduced pressure before the addition of dichoromethane. The
medium was filtered. The liquid phase was evaporated under
reduced pressure. Thus, 0.19 g of an oil was recovered that
could be purified by silica gel chromatography eluting with a
petroleum ether/ethyl acetate (95/5) mixture (yield ) 34%).
This compound is difficult to purify and was thus generally
used as a crude mixture in the next step. When the mixture
of the two isomers of 23 was used as starting material, the
reaction time had to be increased from 30 min to 3 h: IR (neat)
3056, 2950, 1724, 1460, 1262 cm-1; CIMS (t-BuH) m/z 437 (M
+ 1, 45), 281 (M + 1-SePh, 100); HRMS/CI (t-BuH) calcd for
C
24H21O3Se m/z 437.0656, found 437.0662 for 80Se, 435.0613
for 78Se; H NMR (200 MHz, CDCl3) δ (ppm) 2.51 (1H, d, J )
12.8 Hz), 2.73 (H, dd, J ) 5.1, 12.8 Hz), 3.41 (3H, s), 5.50 (1H,
d, J ) 5.1 Hz), 7.10-8.15 (14H, m); 13C NMR (50 MHz, CDCl3)
δ (ppm) 43.62, 51.91, 59.90, 77.73, 119.07, 121.58, 125.77,
126.63, 127.34, 127.82, 128.15, 128.59, 128.93, 135.67, 137.12,
143.82, 145.63, 172.02.
1
3-Meth ylca r boxyla te-1,4-ep oxy-4-p h en yl-1,4-d ih yd r o-
n a p h th a len e 6. To a solution of crude 3R-methylcarboxylate-
3â-phenylselenyl-1,4-epoxy-4-phenyl-1,2,3,4-tetrahydronaph-
thalene 8a (1.01 g) in 8 mL of dichloromethane was added a
35% solution of H2O2 (0.42 mL) at -40 °C. The medium was
stirred for 1 h at -40 °C. The organic phase was washed with
a saturated solution of sodium sulfite until negative peroxide
test. The organic phase was dried (MgSO4) and evaporated
under reduced pressure. Thus, 0.46 g of a yellow oil was
recovered. Compound 22 could not be purified by flash chro-
matography and was therefore used as such in the next step.
The procedure was the same when using 3â-methylcarboxy-
late-3R-phenylselenyl-1,4-epoxy-4-phenyl-1,2,3,4-tetrahydro-
naphthalene 8b as starting material: 1H NMR (200 MHz,
CDCl3) δ (ppm) 3.62 (3H, s), 5.86 (1H, d, J ) 1.8 Hz), 7.00-
7.75 (H, m), 7.80 (1H, d, J ) 1.8 Hz).
Meth yl r-P h en ylselen oa cr yla te 11.17 A solution of phen-
ylselenium chloride (0.46 g, 2.40 mmol, 1 equiv) in 5 mL of
dichloromethane was added on dry ZnCl2 (0.32 g, 1 equiv)
under argon. The medium was stirred for 45 min at rt and
then was added dropwise methyl acrylate (0.21 mL, 1 equiv);
the solution became colorless. After addition of triethylamine
(0.50 mL, 1,5 equiv) and 10 mL of toluene, the reaction was
brought to reflux for 13 h. Water (8 mL) was then added after
the mixture returned to rt. The aqueous phase was extracted
with ethyl acetate. The combined organic phases were dried

Synthesis of Analogues of RPR 115135
J . Org. Chem., Vol. 66, No. 11, 2001 3805
(MgSO4) and evaporated under reduced pressure. Thus, 0.47
g of a dark oil was recovered (yield ) 82%): 1H NMR (200
MHz, CDCl3) δ (ppm) 3.80 (3H, s), 5.31 (1H, s), 6.64 (1H, s),
7.10-7.60 (5H, m). This NMR spectrum is identical to that
described in the literature.17
CDCl3) δ (ppm) (two rotamers) 3.15 (1H, m), 3.45 (3H, s), 3.47
(1H, d, J ) 12.2 Hz), 3.60 (1H, dd, J ) 5.2, 13.6 Hz), 4.02 (2H,
m), 4.39 (2H, m), 4.67 (1H, d, J ) 14.0 Hz), 4.77 (1H, d, J )
14.0 Hz), 5.28 (1H, s), 7.11-7.73 (10H, m); 13C NMR (50 MHz,
CDCl3) δ (ppm) (two rotamers) 50.29, 50.61, 51.49, 52.07,
52.31, 54.23, 65.12, 66.17, 82.66, 93.49, 95.32, 95.46, 119.15,
121.35, 121.57, 126.80, 127.43, 128.20, 128.37, 135.33, 142.10,
144.53, 144.82, 151.04, 151.30, 172.84.
3â-Met h ylca r b oxyla t e-3r-p h en ylselen yl-1,4-ep oxy-4-
p h en yl-1,2,3,4-tetr a h yd r on a p h th a len e 8b. Under argon, to
a solution of 1,3-dihydro-1-methoxy-3-phenylisobenzofuran 17
(2.57 g, 11.39 mmol, 1 equiv) in 35 mL of dry ether was added,
at rt, a solution of n-butyllithium (7.70 mL, 2.22 M, 1.5 equiv).
The medium became dark. After 15 min, tert-butyl alcohol
(1.60 mL, 1.5 equiv) was added, and the medium became red.
After 5 min, a solution of methyl R-phenylselenoacrylate 11
(3.31 g, 1.2 equiv) in 30 mL of dry toluene was added. The
medium was warmed at 80 °C for 2 h and then was quenched
with 20 mL of water. The aqueous phase was extracted twice
with 40 mL of ethyl acetate. The combined organic phases were
dried (MgSO4) and evaporated under reduced pressure. Thus,
5.82 g of a dark oil was recovered. The purification by silica
gel chromatography (petroleum ether/ethyl acetate 95/5 mix-
ture) was inefficient, and 23b was obtained in less than 25%
yield. Therefore, compound 23b was generally used in the next
step as a crude mixture: IR (neat) 2995, 2858, 1726, 1444,
1385, 1237, 1120 cm-1; CIMS (CH4) m/z 437 (M + 1, 15), 279
(M + 1 - SePh - H2, 100); 1H NMR (200 MHz, CDCl3) δ (ppm)
1.83 (1H, d, J ) 12.4 Hz), 3.08 (3H, s), 3.52 (H, dd, J ) 5.4,
12.4 Hz), 5.53 (1H, d, J ) 5.4 Hz), 7.03-7.95 (14H, m); 13C
NMR (50 MHz, CDCl3) δ (ppm) 41.76, 52.16, 59.21, 77.67,
94.38, 119.08, 125.79, 126.64, 127.39, 127,74, 127.82, 128.17,
128.35, 128.63, 128.95, 135.70, 136.40, 137.13, 144.22, 143.92,
146.15, 171.54.
Meth yl 4,9-Ep oxy-9-p h en yl-1,3,4,9,1,11-h exa h yd r oben -
zo[f]isoin d ole-10r-ca r boxyla te 27. Carbamate 26 (97.5 mg,
0.25 mmol, 1 equiv) was diluted in 1.5 mL of a solution of
hydrochloric acid 1.5 M in methanol. The medium was warmed
at reflux temperature for 6 h 30 min, and then methanol was
evaporated under reduced pressure. The residue was diluted
in dichloromethane and neutralized with saturated NaHCO3.
The organic phase was washed with brine (1 mL), dried
(MgSO4), and evaporated under reduced pressure. Thus, 56.2
mg of an oily compound was recovered, that was purified by
silica gel chromatography eluting with a dichloromethane/
methanol (92/8) mixture (yield ) 57%): IR (neat) 2930, 1728,
1461, 1277, 1207, 908, 738 cm-1; CIMS (t-BuH) m/z 322 (M +
1, 100); HRMS/CI (t-BuH) calcd for C20H20O3N m/z 322.1443,
1
found 322.1438; H NMR (200 MHz, C6D6) δ (ppm) 2.80 (2H,
m), 3.02 (3H, s), 3.10 (1H, m), 3.15 (1H, d, J ) 12.5 Hz), 3.32
(1H, d, J ) 12.5 Hz), 4.75 (1H, s), 6.80-7.30 (7H, m), 8.11
(2H, d, J ) 7.5 Hz); 13C NMR (50 MHz, C6D6) δ (ppm) 51.01,
53.00, 55.26, 58.51, 66.67, 82.04, 93.10, 118.66, 121.68, 126.21,
126.58, 127.20, 127.68, 136.73, 146.07, 146.99, 173.71.
Met h yl 4,9-E p oxy-2-[2-(2-m et h oxyp h en yl)p r op en -2-
oyl]-9-p h en yl-1,3,4,9,1,11-h exa h yd r ob en zo[f]isoin d ole-
10r-ca r boxyla te 3. To a solution of amine 27 (87 mg, 0.27
mmol, 1 equiv) in 3 mL of dichloromethane was added pyridine
(0.021 mL, 0.27 mmol, 1 equiv), under argon and at 0 °C, and
the solution of the acyl chloride 21 previously prepared. The
medium was stirred at rt for 1 h 30 min before being quenched
with 2 mL of saturated NaHCO3. The organic phase was dried
(MgSO4) and evaporated under reduced pressure. After silica
gel chromatography eluting with a dichloromethane/methanol
(92/8) mixture, 61 mg of 3 (two rotamers 50/50) was recovered
as a white solid (yield ) 47%): F ) 170 °C; IR (neat) 2957,
1742, 1627, 1433, 1295, 1320, 908, 738 cm-1; CIMS (t-BuH)
m/z 482 (M + 1, 10), 288 (M + 1 - 21, 100); HRMS/CI (t-BuH)
Meth yl 4,9-Ep oxy-9-p h en yl-2-p h en ylm eth yl-1,3,4,9,1,-
11-h exa h yd r oben zo[f]isoin d ole-10R-ca r boxyla te 25. To
crude 3-methylcarboxylate-1,4-epoxy-4-phenylnaphthalene 6
in 20 mL of dichloromethane and under argon was added
amine 9 (4.29 g, 1 equiv with respect to starting 1,3-dihydro-
1-methoxy-3-phenylisobenzofuran 17) in 5 mL of dichlo-
romethane. At rt, trifluoroacetic acid (0.10 mL, 0.1 equiv) was
added dropwise. After 3 h 15 min, the medium was neutralized
by a saturated solution of sodium bicarbonate. The organic
phase was washed with 5 mL of saturated solution of sodium
chloride, dried (MgSO4), and evaporated under reduced pres-
sure. An oily compound (4.79 g) was thus recovered, which
was purified by silica gel chromatography eluting with a
petroleum ether/ethyl acetate (90/10) mixture (yield ) 3-14%
for three steps): IR (neat) 2951, 2783, 1713, 1456, 1258, 1212,
901 cm-1; CIMS (t-BuH) m/z 412 (M + 1, 100); HRMS/CI (t-
1
calcd for C30H28O5N m/z 482.1968, found 482.1981; H NMR
(200 MHz, CDCl3) δ (ppm) (two rotamers) 3.15 (2H, dd, J )
5.7 Hz, J ) 9.2 Hz), 3.38 (3H, s), 3.38 (1H, d, J ) 12.1 Hz),
3.41 (1H, m), 3.50 (3H, s), 3.50 (1H, m), 3.60 (1H, m), 3.64
(3H, s), 3.73 (3H, s), 4.00 (1H, d, J ) 12.3 Hz), 4.07 (1H, dd, J
) 7.1, 10.8 Hz), 4.32 (1H, dd, J ) 9.4, 12.1 Hz), 4.35 (1H, d, J
) 12.2 Hz), 5.14 (1H, s), 5.31 (1H, s), 5.36 (1H, s), 5.48 (1H, s),
5.56 (1H, s), 5.69 (1H, s), 6.72-7.75 (13H, m); 13C NMR (50
MHz, CDCl3) δ (ppm) (two rotamers) 49.39, 50.92, 52.16, 52.27,
52.67, 53.37, 53.93, 55.46, 55.66, 64.95, 66.36, 82.10, 82.66,
93.69, 110.96, 118.79, 118.92, 119.01, 119.21, 120.87, 120.94,
121.10, 121.53, 126.69, 127.06, 127.42, 128.06, 128.25, 129.39,
129.60, 129.75, 135.32, 142.44, 143.11, 144.39, 144.61, 144.89,
145.23, 156.34, 168.97, 169.34, 172.95.
1
BuH) calcd for C27H26O3N m/z 412.1913, found 412.1913; H
NMR (200 MHz, CDCl3) δ (ppm) 2.27 (1H, d, J ) 9.6 Hz), 2.35
(1H, t, J ) 8.1 Hz), 3.20 (1H, t, J ) 7.9 Hz), 3.34 (1H, d, J )
7.9 Hz), 3.40 (3H, s), 3.48 (1H, d, J ) 9.5 Hz), 3.56 (2H, s),
5.22 (1H, s), 6.94-7.77 (14H, m); 13C NMR (50 MHz, CDCl3) δ
(ppm) 52.02, 54.82, 58.28, 59.71, 59.91, 66.27, 81.06, 92.94,
119.29, 120.43, 126.57, 126.84, 127.06, 127.22, 127.87, 128.15,
128.38, 136.00, 138.63, 144.87, 145.83, 173.83.
Meth yl 4,9-Ep oxy-2-vin ylfor m a te-9-p h en yl-1,3,4,9,1,11-
h exa h yd r oben zo[f]isoin d ole-10r-ca r boxyla te 26. To a
solution of compound 25 (195 mg, 0.47 mmol, 1 equiv) in 2
mL of dichloromethane were added, at rt, pyridine (0.08 mL,
2 equiv) and vinyl chloroformate (0.09 mL, 2 equiv). After 4
h, the medium was quenched with 1 mL of a saturated solution
of NaHCO3. The organic phase was washed with 1 mL of a
saturated solution of sodium chloride, dried (MgSO4), and
evaporated under reduced pressure. Thus, 195 mg of an oil
was recovered, which was purified by silica gel chromatogra-
phy, eluting with a dichloromethane/methanol (99.5/0.5) mix-
ture (yield ) 53%): IR (neat) 2948, 1719, 1410, 1221, 1152,
908, 756 cm-1; CIMS (t-BuH) m/z 392 (M + 1, 38), 374 (M +
1 - H2O, 7), 263 (100); HRMS/CI (t-BuH) calculated for
Ackn owledgm en t. C.M. thanks Rhoˆne-Poulenc Ror-
er and the Conseil Re´gional de Haute-Normandie for a
PhD grant. The high-pressure device used in this work
was purchased thanks to a FIACIR joint grant of the
Conseil Re´gional de Haute-Normandie and the DRRT
to J .M.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR and 13C spectra for compounds 2, 3, 6, 8, 15-20, and
22-27. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
23H22O5N m/z 392.1498, found 392.1496; 1H NMR (200 MHz,
J O0100188