New asymmetric synthesis of protein farnesyltransferase inhibitors via palladium-catalyzed cross-coupling reactions of 2-iodo-imidazoles

Article abstract of DOI:10.1039/b902601k

Palladium catalyzed cross-coupling reactions of 2-iodoimidazole have been studied to synthesize imidazole-containing protein farnesyltransferase inhibitors. The Suzuki coupling reaction proved to be very efficient to introduce functionalized alkyl chains at the 2-position of the imidazole ring and a new synthesis of the required alkenylboronates was realised by a reaction of cross metathesis. Asymmetric synthesis of allyl succinic derivatives allowed us to synthesize chiral protein farnesyltransferase inhibitors through Suzuki coupling and to determine the influence of the stereochemistry of our inhibitors on the enzymatic activity.

Full text of DOI:10.1039/b902601k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
New asymmetric synthesis of protein farnesyltransferase inhibitors via
palladium-catalyzed cross-coupling reactions of 2-iodo-imidazoles†
Jennifer Kerherve´,a Candice Botuhab and Joe¨lle Dubois*a
Received 9th February 2009, Accepted 13th March 2009
First published as an Advance Article on the web 6th April 2009
DOI: 10.1039/b902601k
Palladium catalyzed cross-coupling reactions of 2-iodoimidazole have been studied to synthesize
imidazole-containing protein farnesyltransferase inhibitors. The Suzuki coupling reaction proved to be
very efficient to introduce functionalized alkyl chains at the 2-position of the imidazole ring and a new
synthesis of the required alkenylboronates was realised by a reaction of cross metathesis. Asymmetric
synthesis of allyl succinic derivatives allowed us to synthesize chiral protein farnesyltransferase
inhibitors through Suzuki coupling and to determine the influence of the stereochemistry of our
inhibitors on the enzymatic activity.
To achieve the asymmetric synthesis of the imidazole-containing
protein farnesyltransferase inhibitors 1 and 2 in enantiomerically
Protein farnesyltransferase (FTase) is a heterodimeric enzyme
pure form, we needed to find a straightforward synthesis to
Introduction
which catalyzes the post-translational modification of several cell
introduce each enantiomeric pure form of the 2-propylsuccinic
chain on both 4-((tert-butyldimethylsilyloxy)methyl)-1-methyl-
signaling proteins.1 It has emerged as a promising target in cancer
therapy2 and more recently in the anti-parasitic field.3 In the
1H-imidazole
3 and 5-((tert-butyldimethylsilyloxy)methyl)-1-
course of our search for new protein farnesyltransferase inhibitors
(FTI) we synthesized C-2,C-5 disubstituted imidazole derivatives
with encouraging activities (Fig. 1).4 Our best inhibitor 1 (n = 3)
bears a racemic 2-propylsuccinic chain and a tripeptide at the C-5
position. To examine both the influence of the stereochemistry
and the peptide functionality of the imidazole ring (4 or 5) on
the FTase inhibition we needed to synthesize the (R)-1 and (S)-1
enantiomers and their 4-substituted analogues 2 (Fig. 1).
methyl-1H-imidazole 4 (Scheme 1) and to develop an efficient
preparation of compound 3.
Scheme 1 Retrosynthetic pathway.
We present here a new palladium-catalyzed cross-coupling
reaction of 2-iodoimidazole derivatives as well as the synthesis of
the (R)- and (S)-allylsuccinic derivatives involved in the palladium-
catalyzed reaction. This article describes also a new synthesis
of 4-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-imidazole
3 and the formation and biological evaluation of compounds 1
and 2.
Fig. 1 Structure of imidazole-containing protein farnesyltransferase
inhibitors.
Results and discussion
1. Palladium-catalyzed cross-coupling of 2-iodoimidazole
derivatives
aInstitut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de
Recherche de Gif-sur-Yvette, Avenue de la Terrasse, 91198 Gif-sur-Yvette
cedex, France. E-mail: joelle.dubois@icsn.cnrs-gif.fr
Few examples of palladium-catalyzed cross-coupling reactions
between 2-iodoimidazole and alkene derivatives have been de-
scribed in the literature.5 A first example of a palladium-catalyzed
coupling at the C-2 position of the imidazole ring under the Heck
conditions has been reported with styrene olefins yielding only to
homocoupling product 5 (Fig. 2).6 No Heck coupling has been
successfully realized on 2-iodoimidazole derivatives yet. When we
tried this reaction on 2-iodo-1-trityl-1H-imidazole with methyl
acrylate and palladium acetate in the presence of a phosphine,
bUniversite´ Pierre et Marie Curie-Paris VI. IPCM, Laboratoire de Chimie
Organique, UMR 7201-Tour 44-45-Case 183, 4, Place Jussieu-75252, Paris
Cedex 05. E-mail: candice.botuha@upmc.fr
† Electronic supplementary information (ESI) available: Experimental
data for Heck cross-coupling reaction and for compounds 1a–b, 2b, 10a,
10b, 12, 14, 17a, 15–17b, 24b, 25a–b, 26b, 27a–b, 28b, 29a–b, 30b, 31a–b,
and crystallographic data for compound 19a. CCDC reference number
719966. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b902601k
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Fig. 2 Products of Heck cross-coupling assays.
5,5-diphenyl-5H-imidazo[2,1-a]isoindole 6 was surprisingly ob-
tained by an intramolecular arylation, a reaction occurring with
many 1-benzylimidazole derivatives (Fig. 2).7
To avoid the possibility of an intramolecular arylation process
during our study of the Heck reaction on 2-iodoimidazoles we
pursued our efforts on 1-methyl-2-iodoimidazole 7 with methyl
acrylate as alkylating agent (Scheme 2).8
Scheme 3 Reagents and conditions: a) NEt3, Pd(PPh3)4 5 mol%, CuI
10 mol%, for n = 1: RT, 3d, 44%, for n = 2: 40 ◦C, 18h, 26%, for 13: 40 ◦C,
18 h, 89%.
Negishi cross-coupling between 1-methyl-2-imidazole-zinc io-
dide and unsaturated iodides has been reported by Knochel in
good to excellent yields.8 However it would be more interesting for
the synthesis of our compounds to realize Negishi coupling with an
alkylzinc iodide as it has been described on the iodo derivative of
Boc-histidine.11 Unfortunately when we performed this reaction
on compound 11 only traces of the expected compound were
obtained.
Suzuki cross-coupling between iodoimidazole and a vinyl-
boronate has only been described at the C-4 position of the
imidazole ring but in a moderate yield.13 We explored this reaction
between commercially available pinacol vinyl boronate 13 and
compound 7. After optimization, 1-methyl-2-vinylimidazole 14
was obtained in excellent yield (Scheme 4).
Scheme 2 Heck cross-coupling reaction.
A range of conditions was examined for the Heck coupling
varying the catalyst, base, phosphine, solvent and temperature
and, unfortunately, none afforded the expected alkylated com-
pound 8.9 In most conditions we tried, the starting compound 7
was recovered. The use of a bulky and a more electron-enriched
phosphine (P(o-Tol)3), known to produce highly reactive catalysts,
did not improve the conversion. Increased temperature, longer
reaction time or a higher catalyst load afforded dehalogenated 1-
methylimidazole 9 or decomposition. When 5% mol. [Pd(PPh3)4]
was used with KOAc as base the homocoupling product 5 was
observed in low yield (5–15%). This side product, which can act as
a poison for Pd-catalyst, might be the reason for the low reactivity
of 2-iodo imidazole in this case. To increase the reactivity of our
system, we finally tried a reaction with bis(phosphinito) donor
palladium (II) complex as a catalyst which has been reported
to be a efficient and highly active catalyst for Heck reaction.10
Unfortunately, no conversion was observed which indicated a
possible degradation of the catalyst during the time of the reaction
that often occurs with this type of complex. Substitution of iodide
by bromide or of methyl by a Boc group on N-1 did not afford the
expected alkylation product under standard Heck conditions.
Therefore we next tried to employ the Sonogashira cross-
coupling as an alternative C–C bond forming reaction to func-
tionalize the C-2 position of the imidazole ring. This reaction
has been realized on several 2-iodoimidazole derivatives in vari-
able yields.6,11,12 Under the Kerwin conditions,12 with 5% mol
[Pd(PPh3)4], 10% mol. CuI and NEt3 as a base, we successfully
alkylated 1-methyl-2-iodoimidazole 7 with propargylic or homo-
propargylic alcohols with a total conversion albeit moderate yields
due to difficulties during the purification step. When the reaction
was performed on compound 11 (see below), the product 12 was
obtained in 89% yield (Scheme 3).
Scheme 4 Reagents and conditions: a) DMF, Na2CO3, Pd(PPh3)4 5 mol%,
130 ◦C, 3 h, 94%.
Stille cross-coupling at the C-2 position of the imidazole ring
with halo-olefins has only been realized with 2-(tributylstannyl)-
1H-imidazole.14 In our hands, cross-coupling of compound 7 with
commercially available vinyltributyltin afforded also 1-methyl-2-
vinylimidazole 14 in good yield.
Though the Sonogashira cross-coupling reaction was effective
with alcohol derivatives we were unable to apply this reaction
to ethyl propiolate or homopropiolate. Therefore a synthetic
pathway using this reaction would require many subsequent steps
to obtained the desired esters 1 and 2. Stille and Suzuki cross-
couplings were both effective to form C–C bond at the C-2
position of the imidazole ring. Because of tin toxicity we turned
to the Suzuki cross-coupling to synthesize 1 and 2 from 4(or 5)-
((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-imidazole 3 (or
4) and the enantiopure vinyl boronates 15. An enantioselective
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synthesis of 15 has been designed to obtain both (R) and (S)
isomers.
with a small amount of the Z-isomer in 6:1 and 5:1 ratios for
the (R) and (S) series respectively.19 Our results are similar to
those previously reported for the synthesis of functionalized vinyl
boronates by olefin cross-metathesis and thus enlarge the scope of
this methodology.20
2. Enantioselective synthesis of diethyl 2-allylsuccinate 16
The chiral vinyl boronates 15 have been obtained by cross
metathesis between the pinacol vinyl boronate 13 and the chiral
diethyl 2-allylsuccinates 16 synthesized by asymmetric alkylation
using Evans chiral auxiliary methodology (Scheme 5).15 Optically
pure (R)- and (S)-4-benzyl-2-oxazolidinone 17 were both obtained
in 3 steps from L- or D-phenylalanine respectively in 45% overall
yield. Phenylalanine was reduced into the corresponding alcohol
by sodium borohydride/iodine16 then the amine was protected by
a Boc group17 and the oxazolidinone was formed by addition of
tBuOK.18 The 4-benzyl-2-oxazolidinones 17 reacted with pent-4-
enoic acid through activation with pivaloyl chloride to yield the
desired chiral imides 18. The alkylation of (S)- and (R)-imides
18 with ethyl bromoacetate afforded 19a (74% yield, d.e. (S,R) >
98%) and 19b (85% yield, d.e. (R,S) = 65%) respectively. The 19b
diastereoisomers were easily separated by column chromatography
and the absolute configuration was confirmed by X-ray crystal-
lography of compound 19a. Removal of the chiral auxiliary and
esterification of the remaining acid provided (R)- and (S)-2-allyl
diethylsuccinate 16a and 16b. The vinyl boronates 15a–b were
easily obtained in excellent yield by a cross metathesis between
compounds 16a–b and pinacol vinyl boronate 13 using 10% mol. of
Grubbs I catalyst. The E-compound was mainly obtained together
3. Synthesis of 4-hydroxymethyl-1-methyl-1H-imidazole 20
Before applying the Suzuki cross-coupling reaction to get our
desired inhibitors 1 and 2, we needed a straightforward synthesis
of 1-methyl-4-hydroxymethyl imidazole 20. The N-methylation
of 4(5)hydroxymethyl-1-methyl-1H-imidazole represents the more
rapid way to synthesize this compound. However, this method
affords a mixture of both N-methylated products and C-4 and
C-5 isomers are hardly separable.21 Compound 20 has also
been synthesized from 2-amino-3-(methylamino)propanoic acid
through the formation of the imidazoline that was further oxidized
into imidazole.22 However the synthesis of the imidazoline and the
oxidation step were not reproducible in large scale and we looked
for another way to synthesize 20 in large amounts.
We took advantage of the ability of 1-substituted imidazole to
be alkylated at the N-3 position to afford imidazolium and of the
selective C-5 formylation according to Lipshutz methodology.23
The C-2 position of 1-SEM-imidazole24 was first deprotonated
and silylated then, a second deprotonation occurred exclusively at
the C-5 position allowing the selective C-5 formylation. Direct
methylation on compound 21 did not afford reproducibly the
imidazolium derivative. Therefore we reduced the aldehyde by
sodium borohydride and protected the resulting alcohol by a
p-methoxybenzyl (PMB) group. The PMB-protecting group was
chosen by the observation in preliminary experiments that bulky
protective group such as tert-butyldimethylsilyl (TBS) prevented
further alkylation of the imidazole ring and that the benzyl group
was difficult to remove after methylation. The PMB group had
the additional advantage to be concomitantly removed with the
SEM group. Methylation of compound 22 by methyl triflate
afforded the imidazolium derivative that was submitted without
purification to deprotection with TFA to yield the desired 1-
methyl-4-hydroxymethylimidazole 20. Protection of the alcohol
by a TBS group was realized on the crude product to facilitate
its purification. Compound 3 was obtained in five steps from
imidazole in 38% overall yield (Scheme 6).
Scheme 5 Reagents and conditions: a) i- NaBH4, I2, THF, reflux,
overnight, 75%; ii- Boc2O, H2O, 30–35 ◦C, 1 h; iii- tBuOK, THF, 0 ◦C,
2 h, 60% (2 steps); b) PivCl, Et3N, Et2O, 0 ◦C, 1 h, then -78 ◦C BuLi, 17,
-78 ◦C 15 min, 0 ◦C 1 h, (R): 94%, (S): 88%; c) NaHMDS, BrCH2CO2Et,
THF, -78 ◦C to RT, overnight, from 18-R: 85% d.e. (RS) = 65%, from
18-S: 74% d.e. (SR) > 98%; d) i- LiOH, H2O2, THF/H2O, 0 ◦C, 1 h; ii-
EtOH, HCl, reflux, overnight, (R)-16a 66%, (S)-16b 64%; e) 13, Grubbs
I catalyst 10 mol%, CH2Cl2, reflux, overnight, 15a 92% (E:Z = 6:1), 15b
90% (E:Z = 5:1).
Scheme 6 Reagents and conditions: a) nBuLi THF, -78 ◦C 45 min then
TMSCl, RT, 1 h 30 min; b) tBuLi, THF, -78 ◦C, 45 min then DMF, RT,
2 h, 76% (2 steps); c) NaBH4, MeOH, RT, 2 h, 93%; d) NaH, DMF, RT,
20 min then PMBCl, RT, overnight, 70%; e) TfOMe, toluene, 0 ◦C, 2 h; f)
TFA, 0 ◦C, 2 h; g) TBSCl, imidazole, DMF, RT, overnight, 82% (3 steps).
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Table 1 Activity on yeast and human FTases
4. Synthesis of protein farnesyltransferase inhibitors 1 and 2
As described above, the synthesis of our inhibitors 1 and 2 goes
through a Suzuki coupling reaction between boronates 15a–b
and the 2-iodo-4(or 5)-methylimidazole derivatives as a key step.
Iodination at the C-2 position of compounds 3 and 4 was carried
out according the reported procedure and provided 23 and 11
respectively.4 Suzuki cross coupling reaction of the E-isomer of
15a and 15b with respectively 23 and 11 afforded the expected
E-compounds 24a–b and 25a–b in 60% to 92% yield. Attachment
of the tripeptide VFM was realized as previously described using
a TBS-deprotection-oxidation sequence followed by a reductive
amination.4 A part of compounds 26a–b and 27a–b was saponified
to determine the influence of a more rigid alkyl chain at the
C-2 position of imidazole ring on the interaction with FTase.
The other part was hydrogenated to reduce the double bond
before saponification to afford compounds 1a–b and 2a–b in each
enantiomeric pure form (Scheme 7). This synthetic pathway is
more rapid and more efficient than our previous method: we have
synthesized 8 chiral compounds in 5 or 6 steps from the 1-methyl-
Double
bond
IC50 (mM)
human FTase
IC50 (mM)
Compound
Enantiomer
yeast FTase
1
R,S
R
S
R
S
R
S
R
S
no
E
E
no
no
E
E
no
no
—
80
5
29a
29b
1a
85
6
8
4
4
8
3
5
8
170 20
176 20
144
57
51
56
4
3
1b
58
28a
28b
2a
146
120
109
87
170 13
220 40
370 40
151 16
2b
4(5)-hydroxymethylimidazole 3 and 4 in 20–28% yield compared
to our first synthesis of racemic compound 1 achieved in 10 steps
from 1-methyl-5-hydroxymethyl imidazole in 17% overall yield.4
This method is also more convergent and allows the introduction
of a large variety of alkyl chains at the C-2 position of the imidazole
ring.
5. Biological evaluation
Compounds 1, 2, 28 and 29 in (R) or (S) configuration were
evaluated for their inhibitory activity against recombinant yeast25
and human26 FTases using a fluorescent-based assay27,28 adapted
to 96-well plate format. Results are reported in Table 1.
It should be pointed out that the presence of a double bond
in the propylsuccinic side chain is detrimental to the activity (29
versus 1 and 28 versus 2). The absolute configuration of this chain
seems to have very little influence on the inhibition of protein
farnesyltransferase (compounds a versus compounds b). Finally
our compounds are generally more active on human FTase and
the 5-substituted derivatives are better inhibitors than the 4-
substituted compounds.
Conclusions
The aim of this article was to determine whether the position
of the peptidic chain and the stereochemistry of the succinyl
moiety could have an influence on the inhibitory activity of
our imidazole-containing inhibitors 1 and 2. To address these
questions we have developed a more convenient synthesis of
1-methyl-4-hydroxymethylimidazole. We have also explored the
palladium-catalyzed cross-coupling reaction at the C-2 position
of the imidazole ring. Among the different C–C bond coupling
reactions we tried, the Suzuki cross-coupling conditions proved
to be the most efficient and represent the first example of Suzuki
cross-coupling on the C-2 position of imidazole derivatives with
aliphatic vinyl boronates which have been successfully synthesized
in enantiomerically pure form from the corresponding allylsuc-
cinates. The scope and limitations of this Suzuki cross-coupling
reaction are currently under investigation, especially with other
functionalized vinyl boronates or alkyl boranes, as well as the
olefin cross-metathesis with shorter acidic chains.
Scheme 7 Reagents and conditions: a) nBuLi, I2, THF, -78 ◦C to RT,
3 h, 83–87%; b) DMF, Na2CO3, Pd(PPh3)4 10 mol%, 15a–b, 130 ◦C, 3 h
30 min, 60–92%; c) TBAF, THF, 0 ◦C, 2 h, 81–96%; d) MnO2,CH2Cl2,
Biological evaluation of our compounds has shown the little
influence of the stereochemistry of the succinic moiety on the
FTase inhibition. The presence of a more rigid chain at the C-2
position of the imidazole ring is detrimental to the activity and
the position of the peptidic chain seems to be important for the
inhibition. Therefore, in the course of our search for new protein
˚
RT, overnight, 70–80%; e) NH2-VFM-OMe, MS 4A, CH2Cl2/MeOH, RT,
10 min then NaBH3CN in MeOH-1% AcOH, RT, overnight, 61–80%; f)
LiOH·H2O, THF/H2O (1/1), 0 ◦C→RT, overnight, quant.; g) H2, Pd/C
10%, EtOAc, 24 h, 57–75%.
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farnesyltransferase inhibitors, we are pursuing our investigations
into highly substituted imidazoles where the peptidic chain is
located at the C-5 position of the imidazole ring and with other
acidic chains.
atmosphere at 135 ◦C for 3 h 30 min. After the mixture had
been cooled down to room temperature, the solvent was removed
under reduced pressure and the residue was purified by flash
chromatography on silica gel.
General procedure C
Experimental
a—Removal of TBS group. A solution of tetrabutylammonium
fluoride (1 M in THF, 2 equiv.) was added to a THF solution
of compounds 24 or 25 at 0 ◦C. After stirring 2 h at 0 ◦C,
the reaction mixture was evaporated. The residue was purified
by column chromatography on silica gel to afford the required
primary alcohols.
General method
Unless otherwise indicated, all reactions were carried out with
magnetic stirring and in case of air- or moisture-sensitive com-
pounds reactions were carried out in oven-dried glassware under
argon. Syringes were used to transfer the reagents and the solvents
were purged with argon prior to use. Tetrahydrofuran (THF) was
distilled over sodium/benzophenone. Dichloromethane (CH2Cl2),
triethylamine (Et3N), diisopropylamine and toluene were dis-
tilled over calcium hydride. N,N¢-Dimethylformamide (DMF)
was dried over MgSO4 followed by distillation under reduced
pressure. Analytical thin-layer chromatography was carried out
on precoated silica gel glass plates (Merck TLC plates, silica gel
60F254). The silica gel (silicagel 60 (35–70 mm)) used for column
b—Oxidation of the primary alcohol. Manganese dioxide
(6.5 equiv.) was added to a CH2Cl2 solution of alcohols. The
mixture was refluxed overnight. The reaction was filtered through
a pad of celite (EtOAc) and concentrated. The residue was purified
by column chromatography to afford the required aldehydes.
c—Reductive amination. Tripeptide NH2-VFM-OMe4 in
MeOH/CH2Cl2 (3/1) was treated with molecular sieves powder
1
˚
chromatography was purchased from S.D.S. Company. H and
4 A and triethylamine (1 equiv.). After stirring for 20 min at
13C NMR spectra were recorded at Bruker Avance 300 MHz.
1H chemical shifts are reported in delta (d) units in parts per
million (ppm) relative to the singlet at 7.26 ppm for d-chloroform
(residual CHCl3) and the singlet (0.00 ppm) for TMS. 13C Chemical
shifts (d) are reported in ppm relative to the central line of
the triplet at 77.2 ppm for d-chloroform. Splitting patterns are
designated as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; and b, broad and combinations thereof. Coupling
constants J are reported in hertz (Hz). IR spectra were recorded
with an FTIR Perkin-Elmer Spectrum BX spectrometer. Low
and high resolution mass spectra were recorded by navigator
LC/MS (source AQA) for electron spray ionization (ESI—low
resolution) and electron ionization (EI—high resolution). Optical
rotations were measured with a JASCO 1010 polarimeter in a
1-dm cell and the sodium D line (589 nm) at the temperature,
solvent, and concentration indicated. X-ray structure was realized
at the X-Ray Crystallography Laboratory of the ICSN-Gif-sur-
Yvette and data were collected by a Enraf-Nonius KappaCCD
diffractometer with graphite-monochromated MoKa radiation
room temperature, a solution of the aldehyde in MeOH/CH2Cl2
(1/1) was added to the mixture. After 4 h, a solution of sodium
cyanoborohydride (1.5 equiv.) in MeOH/AcOH (1:0.1) was added
and the solution was stirred for 18 h at room temperature. Then,
the mixture was filtered through a pad of celite (CH2Cl2) and
concentrated. The mixture was taken into H2O and extracted
with CH2Cl2 (3¥). The combined organic layers were dried over
sodium sulfate, filtered and concentrated. The residue was purified
by column chromatography on silica gel to afford compound 26
or 27.
General procedure D. Saponification
To a solution of 26, 27, 30 or 31 in THF/MeOH/H2O 1:1:1
was added lithium hydroxide monohydrate (3–6 equiv.) at 0 ◦C.
After 1–2 h at this temperature and 1–16 h at room temperature,
Amberlite IRC 50 resin (H+) was added and the mixture was stirred
until pH = 7.0. Then, the reaction was filtered and the resin was
washed with MeOH (3¥). Evaporation of the solvents afforded the
target compounds 28, 29, 2 or 1.
˚
(l = 0.71069 A). Elemental analyses were performed by the
Microanalytical Laboratory of the ICSN-Gif-sur-Yvette.
4-(S)-Benzyl-3-pent-4-enoyloxazolidin-2-one (18a). To
a
cooled solution (-78 ◦C) of 4-pentenoic acid (1.09 ml, 10.7 mmol,
1 equiv.) and Et3N (1.7 ml, 11.9 mmol, 1.1 equiv.) in diethyl
ether (45 ml) was added pivaloyl chloride (1.32 ml, 10.7 mm◦ol,
1 equiv.). After 5 min, the reaction mixture was warmed to 0 C
and stirred for 1 h. In a separate flask, a solution of 17a (1.9 g,
10.7 mmol) in THF (13 ml) was cooled to -78 ◦C whereupon
nBuLi (1.6 M in hexane, 6.7 ml, 10.7 mmol, 1 equiv.) was added
General procedure A. Sonogashira cross-coupling
Under argon atmosphere, 1-methyl-2-iodo-1H-imidazole 7 was
added to a solution of Pd(PPh3)4 (5 mol%), CuI (10 mol%) in
NEt3 (2 ml). After addition of the alkyne alcohol, the mixture
was degassed and stirred. The reaction was followed by TLC
control and the reaction mixture was filtered on a pad of celite and
concentrated under vacuum after the time indicated in Scheme 4.
The residue was purified by chromatography on silica gel.
◦
slowly. The solution was stirred for 10 min at -78 C. The flask
containing the mixed anhydride was cooled to -78 ◦C, and the
lithiated oxazolidinone transferred via cannula ◦into the mixed
anhydride. After being stirred for 15 min at -78 C, the reaction
mixture was warmed to 0 ◦C and stirred for 1 h. The reaction was
quenched with water, the layers were separated and the aqueous
layer was extracted with diethyl ether (3 ¥ 25 ml). Combined
organic layers were washed with brine, dried over sodium
sulfate and concentrated. Purification by flash chromatography
General procedure B. Suzuki cross-coupling
To a solution of iodoimidazole derivative 11 or 23 in anhydrous
DMF under argon was added the palladium catalyst (10 mol%),
the alkenylboronate 15a or 15b (1.6 equiv.) as well as powdered
Na2CO3 (1.1 equiv.). The mixture was heated under an argon
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(heptane/EtOAc : 75/25) afforded pure 18a (2.5 g, 90%) as a
colorless oil. H NMR (300 MHz, CDCl3) d 2.43–2.51 (m, 2H),
was added pinacol vinylboronate 13 (1.17 ml, 6.9 mmol, 3 equiv.)
and Grubbs I catalyst (287 mg, 0.35 mmol, 0.15 equiv.). The
mixture was stirred at reflux for a night. The solution was
cooled to ambient temperature, diluted with dichloromethane and
filtrated over celite. After concentration and purification by flash
chromatography on silica gel (heptane/EtOAc: 9/1 to 8/2) pure
(E)-15a (633 mg, 79%) and (Z)-15a (111 mg, 14%) were obtained
as white amorphous solids. (E)-15a: 1H NMR (300 MHz, CDCl3)
d 1.26 (m, 18H), 2.38 (m, 1H), 2.47 (dd, J = 6.0, 16.0 Hz, 1H), 2.51
(m, 1H), 2.69 (dd, J = 9.5, 16.0 Hz, 1H), 2.97 (m, 1H), 4.15 (m,
4H), 5.50 (d, J = 18.0 Hz, 1H), 6.51 (dt, J = 13.0, 18.0 Hz, 1H).
13C NMR (75 MHz, CDCl3) d 14.1, 14.2, 24.7, 24.8, 24.9, 34.1,
35.1, 41.0, 60.5, 60.6, 83.1, 83.4, 149.9, 172.1, 174.3. MS (ESI+)
m/z 363 [M + Na]+.
1
2.77 (dd, J = 9.5, 13.0 Hz, 1H), 2.96–3.17 (m, 2H,), 3.39 (dd, J =
3.5, 13.0 Hz, 1H), 4.14–4.23 (m, 2H), 4.64–4.72 (m, 1H), 5.04 (dd,
J = 1.5, 10.0 Hz, 1H), 5.12 (dd, J = 1.5, 17.0 Hz, 1H), 5.89 (m,
1H), 7.20–7.37 (m, 5H). 13C NMR (75 MHz, CDCl3) d 20.1, 34.8,
37.9, 55.2, 66.2, 127.3, 128.9, 129.4, 135.3, 136.7, 153.5, 172.5.
MS (ESI+) m/z 282 [M + Na]+. [a]D = +60 (c 1.9 in CHCl3).
23
Ethyl 3-(R)-(4-(S)-benzyl-2-oxazolidine-3-carbonyl) hex-5-
enoate (19a). To a solution of compound 18a (2.35 g, 9.1 mmol)
in THF (90 ml) cooled to -78 ◦C was added 2M NaHMDS
in THF (5 ml, 10 mmol, 1.1 equiv.) over 10 min. The reacti◦on
mixture was allowed to stir for an additional 20 min. at -78 C
and ethyl bromoacetate (1.5 ml, 13.6 mmol, 1.5 equiv.) in THF
(9 ml) was added. The solution was stirred for 1 h at -78 ◦C
and then stirred for 4 h at room temperature. The reaction was
quenched with a saturated aqueous solution of NH4Cl and the
reaction mixture was concentrated. The residue was extracted
with dichloromethane (3 ¥ 50 ml) and organic layers were washed
with water and brine then dried over sodium sulfate. Purification
by flash chromatography on silica gel (heptane/EtOAc : 9/1
to 8/2) afforded pure (3R,4S)-19a (2.34 g, 74%) as a white
(Z)-15a. 1H NMR (300 MHz, CDCl3) d 1.27 (m, 18H), 2.45
(dd, J = 4.0, 16.0 Hz, 1H), 2.73 (m, 3H), 2.94 (m, 1H), 4.15 (m,
4H), 5.48 (d, J = 13.5 Hz, 1H), 6.36 (dt, J = 13.5, 14.5 Hz, 1H).
13C NMR (75 MHz, CDCl3) d 14.3, 14.4, 24.8, 24.9, 25.0, 34.3,
35.3, 41.2, 60.7, 60.8, 83.3, 83.6, 150.1, 172.3, 174.5. MS (ESI+)
m/z 363 [M + Na]+.
1-((2-(Trimethylsilyl)ethoxy)methyl)-5-formyl-1H -imidazole
(21). To a solution of 1-((2-(trimethylsilyl)et◦hoxy)methyl)-1H-
imidazole (1 g, 5 mmol)24 in THF (22 ml) at -78 C, n-butyllithium
(3.7 ml, 1.6 M in hexane, 5.9 mmol, 1.2 equiv.) was added slowly.
After stirring for 45 min at the same temperature, trimethylsilyl
chloride (0.77 ml, 6.02 mmol, 1.2 eq.) was added and the mixture
was stirred for 1 h 30 min at room temperature. The solution
was cooled to -78 ◦C and t-butyllithium (4.7 ml, 1.4 M in
hexane, 6.6 mmol, 1.3 equiv.) was added slowly. After stirring
for 45 min at -78 ◦C, dimethylformamide (2.8 ml, 36 mmol,
7.2 equiv.) was added and the mixture was stirred for 2 h at room
temperature. Water was added and the product was extracted
with ethyl acetate (3 ¥ 50 ml). Combined organic layers were
washed with water (3 ¥ 100 ml), brine (100 ml), dried over sodium
sulfate and concentrated. After flash chromatography on silica
gel (CH2Cl2/MeOH : 100/0 to 95/5) pure 21 (869 mg, 76%) was
1
amorphous solid. H NMR (300 MHz, CDCl3) d 1.25 (t, J =
7 Hz, 3H), 2.19–2.29 (m, 1H), 2.40–2.50 (m, 1H), 2.55 (dd, J =
4.0, 17.0 Hz, 1H), 2.76 (dd, J = 10.0, 13.0 Hz, 1H), 2.91 (dd, J =
11.0, 17.0 Hz, 1H), 3.36 (dd, J = 3.0, 13.0 Hz, 1H), 4.13 (q, J =
7.0 Hz, 2H), 4.16–4.21 (m, 2H), 4.26–4.35 (m, 1H), 4.63–4.71 (m,
1H), 5.07–5.15 (m, 2H), 5.72–5.87 (m, 1H), 7.25–7.37 (m, 5H).
13C NMR (75 MHz, CDCl3) d 14.2, 35.5, 36.3, 37.6, 38.9, 55.5,
60.7, 66.0, 118.0, 127.2, 128.9, 129.5, 134.3, 135.6, 136.7, 153.1,
171.9, 174.9. MS (ESI+) m/z 368 [M + Na]+. [a]D = +51 (c 1.5
23
in CHCl3).
Diethyl 2-(R)-allylsuccinate (16a). To a solution of compound
19a (1.5 g, 4.35 mmol) in THF/H2O (4:1, 40 ml) at 0 ◦C was
added H2O2 (30% aqueous, 2.5 ml, 22 mmol, 5 equiv.) followed
by aqueous LiOH solution (274 mg in 3 ml, 6.5 mmol, 1.5 equiv.).
The reaction mixture was stirred at 0 ◦C for 1 h and then an
aqueous solution of Na2SO3 (2.4 g in 17 ml, 19 mmol, 4.4 equiv.)
was added. After stirring for an additional 20 min, THF was
evaporated under reduced pressure and the residue was diluted
with CH2Cl2 and water. The organic layer that contained the
chiral auxiliary was separated. The aqueous layer was acidified
with 5 N aqueous HCl solution and was extracted with CH2Cl2.
The combined organic extracts were washed with water, brine and
dried over Na2SO4. After concentration in vacuum the product
was dissolved in ethanol (10 ml) and concentrated HCl (0.3 ml)
was added. After stirring for 20 h at reflux, the reaction was
concentrated and purified by flash chromatography on silica gel
(heptane/EtOAc: 75/25 to 50/50) to afford pure 16a (617 mg,
66%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) d 1.21 (m,
6H), 2.25 (m, 1H), 2.39 (m, 2H), 2.64 (m, 1H), 2.87 (m, 1H), 4.10
(m, 4H), 5.03 (m, 2H), 5.68 (m, 1H). 13C NMR (75 MHz, CDCl3)
d 14.2, 14.3, 35.3, 36.0, 40.9, 60.6, 60.7, 117.8, 134.6, 171.9, 174.2.
1
obtained as a yellow oil. H NMR (300 MHz, CDCl3) d 0.00 (s,
9H), 0.94 (t, J = 8.0 Hz, 1H), 3.61 (t, J = 8.0 Hz, 1H), 5.72 (s,
1H), 7.85 (s, 1H), 7.89 (s, 1H), 9.81 (s, 1H).
5-((4-Methoxybenzyloxy)methyl)-1-((2-(trimethylsilyl) ethoxy)-
methyl)-1H-imidazole (22). To a solution of compound 21
(1,28 g, 5.66 mmol) in methanol (15 ml) was added sodium
borohydride (310 mg, 9.2 mmol, 1.5 equiv.) and the solution
was stirred at room temperature for 2 h. When the reaction was
completed, saturated aqueous solution of ammonium chloride was
added. The product was extracted with ethyl acetate and combined
organic layers were washed with brine, dried over sodium sulfate,
filtrated and concentrated. To the crude product in DMF (15 ml)
was added sodium hydride (60% in oil, 280 mg, 7 mmol, 1.2 equiv.)
and the solution was stirred at room temperature for 20 min then
4-methoxybenzyl chloride (0.925 ml, 6.8 mmol, 1.2 equiv.) was
added. After stirring for 12 h at room temperature, the reaction
was quenched with water and the mixture was concentrated. Water
was added to the mixture and product was extracted with ethyl
acetate. The organic layers were washed with water, brine, dried
over sodium sulfate, filtrated and concentrated. Pure product 22
(1.29 g, 65%) was obtained after flash chromatography on silica gel
MS (ESI+) m/z 237 [M + Na]+. [a]D = +5.2 (c 2.2 in CHCl3).
23
Diethyl 2-(R)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
allyl)succinate (15a). To a solution of compound 16a (500 mg,
2.34 mmol) in dichloromethane (23 ml) under argon atmosphere
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Org. Biomol. Chem., 2009, 7, 2214–2222 | 2219
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(CH2Cl2/MeOH : 100/0 to 98/2) as a white amorphous solid. 1H
NMR (300 MHz, CDCl3) d 0.07 (s, 9H), 0.98 (t, 2H, J = 5.0 Hz),
3.56 (t, J = 5.0 Hz, 2H), 3.91 (s, 3H), 4.53 (s, 2H), 4.64 (s, 2H), 6.98
(d, J = 6.0 Hz, 2H), 7.13 (s, 1H), 7.33–7.36 (m, 2H), 7.70 (s, 1H).
13C NMR (75 MHz, CDCl3) d -2.3, 19.2, 56.7, 62.1, 67.6, 72.7,
75.9, 115.3, 129.1, 131.0, 131.2, 132.0, 140.5, 160.6. MS (ESI+)
m/z 349 [M + H] +, 371 [M + Na]+.
97.0 ◦C. 1H NMR (300 MHz, CDCl3) d 0.06 (s, 9H), 0.89 (s, 3H),
3.61 (s, 3H), 4.65 (s, 2H), 6.95 (s, 1H). 13C NMR (75 MHz, CDCl3)
d -5.2, 18.3, 25.9, 34.5, 55.7, 92.6, 130.9, 135.0. MS (ESI+, MeOH)
m/z 353 [M + H]+. Elemental analysis calcd (%) for C11H21IN2OSi:
C 37.50, H 6.01, N 7.95; found C 37.41, H 5.87, N 7.85.
(E)-Diethyl 2-(R)-(3-(4-((tert-butyldimethylsilyloxy) methyl)-1-
methyl-1H-imidazol-2-yl)allyl)succinate 24a. Prepared accord-
ing to general procedure B with 23 (528 mg, 1.5 mmol) in
DMF (6 ml) with (E)-15a (795 mg), Na2CO3 (172 mg) and
Pd(PPh3)4 (172 mg). After a classical work-up, purification by
flash chromatography on silicagel (heptane/EtOAc : 1/1) afforded
4-Hydroxymethyl-1-methyl-1H-imidazole (20). Compound 22
◦
(1.29 g, 3.7 mmol) was dissolved in toluene (18 ml) at 0 C and
methyl trifluoromethanesulfonate (0.49 ml, 4.5 mmol, 1.2 equiv.)
was added. After stirring for 2 h, the solution was concentrated.
The mixture was then dissolved in trifluoroacetic acid (9.8 ml) at
0 ◦C and a catalytic amount of water was added. The solution was
stirred for 2 h at 0 ◦C and concentrated. Diethyl ether was added
to help the evaporation of the trifluoroacetic acid. The residue was
dissolved in CH2Cl2/MeOH (2/1, 9 ml) and solid NaHCO3 was
added until pH of the solution was basic. The solution was filtered
and concentrated to afford crude 20. 1H NMR (300 MHz, CDCl3)
d 3.70 (s, 3H), 4.44 (bs, 1H), 4.62 (s, 2H), 6.88 (s, 1H), 7.55 (s, 1H).
1
pure 24a (566 mg, 86%) as a white amorphous solid. H NMR
(300 MHz, CDCl3) d 0.00 (s, 6H), 0,84 (s, 9H), 1.15–1.21 (m, 6H),
2.37–2.45 (m, 1H), 2.48 (dd, J = 3.0, 18.0 Hz, 1H), 2.56–2.65 (m,
1H), 2.68 (dd, J = 9.0, 18.0 Hz, 1H), 2.92–3.01 (m, 1H), 3.55 (s,
3H), 4.10 (q, J = 6 Hz, 2H), 4.12 (q, J = 6 Hz, 2H,), 4.51 (s, 2H),
6.25 (d, J = 15 Hz, 1H), 6.47–6.60 (m, 1H), 6.73 (s, 1H). 13C NMR
(75 MHz, CDCl3) d -5.1, 25.1, 26.0, 32.9, 35.2, 35.5, 41.1, 58.7,
60.8, 61.0, 118.6, 131.4, 141,4, 142.2, 171.9, 174.1. HRMS (ESI+)
calcd for C22H39N2O5Si [M + H]+: 439.2628 found: 439.2643. IR
4-((tert-Butyldimethylsilyloxy)methyl)-1-methyl-1H-imidazole
(3). To a solution of crude compound 20 in dimethylformamide
(41 ml) was added imidazole (620 mg, 9.1 mmol, 2.5 equiv.) and
tert-butyldimethylsilylchloride (760 mg, 5 mmol, 1.4 equiv.). After
stirring for 12 h at room temperature, the solution was quenched
with water and concentrated. Water was added to the mixture and
the product was extracted with ethyl acetate. Organic layers were
washed with water and brine, dried over sodium sulfate, filtered
and concentrated. Pure 3 (688 mg, 82%) was obtained after flash
chromatography on silica gel (EtOAc/MeOH : 99/1 to 90/10) as
1463, 1730 cm-1. [a]D = +4.0 (c 1.0 in CHCl3).
23
Compound 26a. Prepared according to general procedure C.
a- From 24a (566 mg, 1.3 mmol) in THF (5 ml) with TBAF (1M
in THF, 2.5 ml). Purification by flash chromatography on silicagel
(CH2Cl2/MeOH: 95/5) afforded the expected alcohol (418 mg,
quant.) as a white amorphous solid. 1H NMR (300 MHz, CDCl3)
d 1.15–1.21 (m, 6H), 2.37–2.45 (m, 1H), 2.48 (dd, J = 3.0, 18.0 Hz,
1H), 2.56–2.65 (m, 1H), 2.68 (dd, J = 9.0, 18.0 Hz, 1H), 2.92–3.01
(m, 1H), 3.55 (s, 3H), 4.10 (q, J = 6.0 Hz, 2H), 4.12 (q, J = 6.0 Hz,
2H,), 4.51 (s, 2H), 6.25 (d, J = 15.0 Hz, 1H), 6.47–6.60 (m, 1H),
6.73 (s, 1H). 13C NMR (75 MHz, CDCl3) d 25.1, 26.0, 32.9, 35.2,
35.5, 41.1, 58.7, 60.8, 61.0, 118.6, 131.4, 141,4, 142.2, 171.9, 174.1.
HRMS (ESI+) calcd for C16H25N2O5 [M + H]+: 325.1763 found:
1
a white amorphous solid. H NMR (300 MHz, CDCl3): d 0.08
(s, 6H), 0.90 (s, 9H), 3.62 (s, 3H), 4.65 (s, 2H), 6.77 (s, 1H), 7.33
(s, 1H). 13C NMR (75 MHz, CDCl3) -5.4, 18.4, 25.7, 33.2, 60.2,
117.1, 137.2, 143.1. MS (ESI+) m/z 227 [M + H] +. HRMS (ESI+)
calcd for C11H23N2OSi [M + H]+ 227.1561 found: 227.1580.
325.1769. IR 1464, 1729, 2978, 3409 cm-1. [a]D = +4.5 (c 1.0 in
23
CHCl3).
4-((tert-Butyldimethylsilyloxy)methyl)-2-iodo-1-methyl-1H-im-
idazole (23). To a solution of compound 3 (1.04 g, 4.6 mmol)
b- From the alcohol (418 mg) in CH2Cl2 (13 ml) with MnO2
(730 mg). Purification by flash chromatography on silicagel
(CH2Cl2/MeOH: 98/2) afforded the expected aldehyde (285 mg,
69%) as a white amorphous solid. 1H NMR (300 MHz, CDCl3) d
1.19 (t, J = 6.0 Hz, 3H), 1.20 (t, J = 6.0 Hz, 3H), 2.41–2.51 (m,
2H), 2.58–2.73 (m, 2H), 2.93–3.01 (m, 1H), 3.65 (s, 3H), 4.10 (q,
J = 6.0 Hz, 2H), 4.12 (q, J = 6.0 Hz, 2H), 6.27 (d, J = 15.0 Hz, 1H),
6.68–6.78 (m, 1H), 7.48 (s, 1H), 9.77 (s, 1H). 13C NMR (75 MHz,
CDCl3) d 14.3, 14.1, 33.7, 35.1, 35.6, 41.0, 60.9, 61.1, 117.7, 127.1,
134.9, 141.1, 147.0, 171.7, 173.9, 185.9. HRMS (ESI+) calcd for
C16H23N2O5 [M + H]+: 323.1607 found: 323.1601. IR 1447, 1537,
◦
in THF (11 ml) under argon atmosphere at -78 C was added a
1.6 M solution of n-butyllithium in THF (3.45 ml, 5.5 mmol,
1.2 equiv.). The solution was stirred for 45 min at the same
temperature and a solution of iodine (3.5 g, 13.8 mmol, 3 equiv.)
in THF (11 ml) was added dropwise at -78 ◦C. The solution was
warmed to ambient temperature and stirred for 3 h. The reaction
was quenched with ethanol and then concentrated. An aqueous
saturated solution of sodium thiosulfate (50 ml) was added and
the product was extracted with ethyl acetate (3 ¥ 50 ml), dried
over sodium sulfate, filtered and concentrated. Purification by
flash chromatography on silica gel (heptane/Et2O: 7/3) afforded
pure 4-((tert-butyldimethylsilyloxy)methyl)-2-iodo-1-methyl-1H-
imidazole 22 (1.41 g, 4.0 mmol, 87%) as an amorphous solid.
1H NMR (300 MHz, CDCl3) d 0.06 (s, 9H), 0.89 (s, 3H), 3.56 (s,
3H), 4.63 (s, 2H), 6.92 (s, 1H). 13C NMR (75 MHz, CDCl3) d -5.1,
18.6, 31.3, 36.9, 60.4, 90.1, 121.3, 146.5. HRMS (ESI+) calcd for
C11H22IN2ONaSi [M + Na]+: 375.0366 found: 375.0363.
23
1679, 1725, 2978 cm-1. [a]D = +7.0 (c 1.0 in CHCl3).
c- From NH2-VFM-OMe (360 mg, 0.88 mmol) in
MeOH/CH2Cl2 (3/1, 13.2 ml), and the aldehyde (285 mg,
0.88 mmol) in MeOH/CH2Cl2 (1/1, 2 ml) then sodium cyanoboro-
hydride (114 mg) in MeOH/AcOH (1/0.1, 2 ml). Purification by
flash chromatography on silicagel (CH2Cl2/MeOH: 98/2 to 95/5)
afforded the compound 26a (490 mg, 78%) as a white amorphous
1
solid. H NMR (300 MHz, CDCl3) d 0.64 (d, J = 6.0 Hz, 3H),
5-((tert-bButyldimethylsilyloxy)methyl)-2-iodo-1-methyl-1H-
imidazole (11). This compound was obtained under the same
conditions from compound 4.4 Further crystallization in heptane
afforded pure 11 (1.35 g, 83%) as pale yellow crystals. Mp 96.2–
0.75 (d, J = 6.0 Hz, 3H), 1.24 (t, J = 6.0 Hz, 3H), 1.25 (t, J =
6.0 Hz, 3H), 1.84–1.99 (m, 2H), 2.05 (s, 3H), 2.06–2.14 (m, 1H),
2.41 (t, J = 9.0 Hz, 1H), 2.43–2.56 (m, 2H), 2.56–2.70 (m, 1H),
2.73 (dd, J = 9.0, 15.0 Hz, 1H), 2.94 (d, J = 3.0 Hz, 1H), 2.97–3.14
2220 | Org. Biomol. Chem., 2009, 7, 2214–2222
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The Royal Society of Chemistry 2009
©

View Article Online
(m, 2H), 3.19 (dd, J = 6.0, 15.0 Hz, 1H), 3.47 (d, J = 12.0 Hz,
1H), 3.58 (d, J = 12.0 Hz, 1H), 3.59 (s, 3H), 3.72 (s, 3H), 4.13
(q, J = 6.0 Hz, 2H), 4.16 (q, J = 6.0 Hz, 2H), 4.59–4.72 (m, 2H),
6.29 (d, J = 18.0 Hz, 1H), 6.48–6.58 (m, 1H), 6.68 (s, 1H), 7.05
(d, J = 9.0 Hz, 1H), 7.18–7.30 (m, 5H), 8.01 (d, J = 9.0 Hz, 1H).
13C NMR (75 MHz, CDCl3) d 14.2, 14.2, 14.2, 15.6, 19.3, 29.8,
31.2, 31.5, 32.7, 35.1, 35.4, 37.3, 41.0, 45.9, 51.5, 52.4, 54.4, 60.6,
60.8, 67.5, 118.6, 118.9, 126.8, 128.6, 129.2, 131.3, 136.9, 139.2,
144.9, 171.2, 171.7, 171.8, 173.9, 174.5. HRMS (ESI+) calcd for
C36H54N5O8S [M + H]+: 716.3693 found: 716.3683. IR 1439, 1513,
(dd, J = 5.0, 14.0 Hz, 1H), 3.33 (d, J = 14.0 Hz, 1H), 3.48 (d,
J = 14.0 Hz, 1H), 4.31 (dd, J = 4.5, 7.0 Hz, 1H), 4.78 (dd, J =
4.5, 10.0 Hz, 1H), 6.79 (s, 1H), 7.12–7.33 (m, 5H). 13C NMR
(75 MHz, CD3OD) d 15.4, 18.9, 19.8, 26.6, 26.7 31.2, 32.5, 32.6,
33.6, 34.1, 36.8, 38.7, 40.4, 44.8, 45.0, 55.7, 55.8, 68.3, 121.0, 127.9,
129.7, 130.5, 135.6, 138.7, 149.7, 172.7, 175.5, 177.7, 179.5, 182.3.
HRMS (ESI-) calcd for C31H45N5O8NaS [M-H]-: 646.2911 found:
23
646.2897. [a]D = -14 (c 0.37 in MeOH).
FTase assays
1643, 1730, 2956, 3295 cm-1. [a]D = -41 (c 0.81 in CHCl3).
23
Assays were realized on 96-well plates, prepared with Biomek
NKMC and Biomek 3000 from Beckman Coulter and read on
Wallac Victor fluorimeter from Perkin-Elmer. Per well 20 mL
of farnesyl pyrophosphate (10 mM) was added to 180 mL of a
solution containing 2 mL of varied concentrations of 1a–b, 2a–b,
27a–b and 28a–b (dissolved in DMSO) and 178 mL of a solution
composed by 0.1 ml of partially purified recombinant yeast or
human FTase (2.2 mg/mL and 1.5mg/ml respectively) and 7.0 ml
of Dansyl-GCVLS peptide (in the following buffer: 5.8 mM DTT,
6 mM MgCl2, 12 mM ZnCl2, 0.09% (w/v) CHAPS for yeast
FTase or 0.18% (w/v) Octyl-D-glucopyranoside for human FTase,
53 mM Tris/HCl, pH 7.5). Then the fluorescence development was
recorded for 15 min (0.7 seconds per well, 20 repeats) at 30 ◦C with
an excitation filter at 340 nm and an emission filter at 486 nm. Each
measurement was realized twice as duplicate or triplicate.
Compound 30a. To a solution of compound 26a (120 mg,
0.17 mmol) in ethyl acetate (3 ml) was added palladium on
activated carbon 10% Pd (50% w/w), the mixture was purged
with hydrogen and stirred for 24 hours under hydrogen (1 atm.).
The mixture was filtered over celite, washed with ethyl acetate and
the filtrate was concentrated. Purification on by preparative TLC
silica gel (CH2Cl2/MeOH: 95/5, v/v) afforded pure 30a (75 mg,
1
62%) as a white amorphous solid. H NMR (300 MHz, CDCl3)
d 0.56 (d, J = 6.0 Hz, 3H), 0.66 (d, J = 6.0 Hz, 3H), 1.16 (t,
J = 6.0 Hz, 3H), 1.17 (t, J = 6.0 Hz, 3H), 1.48–1.57 (m, 1H),
1.59–1.72 (m, 3H), 1.78–1.94 (m, 2H), 1.97 (s, 3H), 2.00–2.05 (m,
1H), 2.32–2.40 (m, 3H), 2.56–2.67 (m, 3H), 2.73–2.81 (m, 1H),
2.84 (d, J = 3.0 Hz, 1H), 3.00 (dd, J = 6.0, 15.0 Hz, 1H), 3.12
(dd, J = 6.0, 15.0 Hz, 1H), 3.33 (d, J = 12.0 Hz, 1H), 3.45 (s, 3H),
3.49 (d, J = 12.0 Hz, 1H), 3.64 (s, 3H), 4.03 (q, J = 6.0 Hz, 2H),
4.07 (q, J = 6.0 Hz, 2H), 4.52–4.63 (m, 2H), 6.56 (s, 1H), 6.99 (d,
Acknowledgements
J = 9.0 Hz, 1H), 7.01–7.25 (m, 5H), 7.97 (d, J = 9.0 Hz, 1H). 13
C
NMR (75 MHz, CDCl3) d 14.3, 14.4, 15.6, 17.8,19.5, 25.7, 26.7,
30.0, 31.3, 31.7, 31.8, 32.7, 36.4, 37.4, 41.2, 45.9, 51.7, 52.6, 54.6,
60.8, 60.9, 67.4, 118.5, 127.0, 128.8, 129.4, 137.1, 148.1, 171.4,
172.0, 174.7. HRMS (ESI+) calcd for C36H55N5O8NaS [M + Na]+:
740.3669 found: 740.3636. IR 1439, 1454, 1504, 1537, 1644, 1650,
The authors thank Dr J. Ouazzani and P. Lopez for the production
and purification of recombinant yeast FTase, Dr P. Retailleau for
X-ray structure determination and CNRS for financial support.
Notes and references
1730, 2954, 3294 cm-1. [a]D = -39 (c 0.88 in CHCl3).
23
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Compound 28a. Prepared according to general procedure D
on 26a (54 mg, 0.075 mmol) in 1.5 ml solvent with LiOH·1H2O
(11 mg, 3.5 equiv.). Compound 28a (49 mg, quant.) was obtained
as a white amorphous solid. 1H NMR (300 MHz, CD3OD) d 0.64
(d, J = 6.0 Hz, 3H), 0.67 (d, J = 6.0 Hz, 3H), 1.66–1.77 (m, 1H),
1.78–1.93 (m, 1H), 1.95 (s, 3H), 1.96–2.10 (m, 1H), 2.32–2.40 (m,
4H), 2.41–2.57 (m, 2H), 2.69–2.76 (m, 1H), 2.80 (d, J = 6.0 Hz,
1H), 2.84 (dd, J = 6.0, 15.0 Hz, 1H), 3.13 (dd, J = 6.0, 15.0 Hz,
1H), 3.23 (d, J = 12.0 Hz, 1H), 3.36 (d, J = 12.0 Hz, 1H), 3.53 (s,
3H), 4.20 (dd, J = 3.0, 6.0 Hz, 1H), 4.67 (dd, J = 3.0, 9.0 Hz, 1H),
6.33 (d, J = 15.0 Hz, 1H), 6.44–6.54 (m, 1H), 6.69 (s, 1H), 7.01–
7.19 (m, 5H). 13C NMR (75 MHz, CD3OD) d 15.4, 18.8, 19.7, 31.3,
32.5, 33.6, 34.1, 36.8, 38.7, 39.3, 44.7, 45.4, 55.7, 55.8, 68.4, 118.1,
121.5, 127.9, 129.7, 130.5, 136.7, 137.4, 138.7, 146.5, 172.7, 175.3,
177.7, 178.9, 181.0. HRMS (ESI+) calcd for C31H43N5O8NaS [M +
12 A. K. Nadipuram, W. M. David, D. Kumar and S. M. Kerwin, Org.
23
Na]+: 668.2730 found: 668.2736. [a]D = -19 (c 0.32 in CHCl3).
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30a (60 mg, 0.0584 mmol) in 1.4 ml solvent with LiOH (13 mg,
6.4 equiv.). Compound 2a (48 mg, 88%) was obtained as a white
14 S. Sahli, B. Stump, T. Welti, W. B. Schweizer, F. Diederich, D. Blum-
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1
amorphous solid. H NMR (300 MHz, CD3OD) d 0.75 (d, J =
6.0 Hz, 6H), 0.67 (d, J = 6.0 Hz, 1H), 1.54–1.82 (m, 5H), 2.05
(s, 3H), 1.92–2.18 (m, 2H), 2.34–2.56 (m, 4H), 2.64–2.82 (m, 3H),
2.86 (d, J = 5.5 Hz, 1H), 2.97 (dd, J = 10.0, 14.0 Hz, 1H), 3.24
17 S. V. Chankeshwara and A. K. Chakraborti, Org. Lett., 2006, 8, 3259–
3262.
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