Straightforward asymmetric synthesis of Ala-Ψ[CF=CH]-pro, a proline-containing pseudodipeptide bearing a fluoroolefin as a peptide bond mimic

Article abstract of DOI:10.1039/c2nj40891k

From ethyl-2-oxocyclopentanecarboxylate, we developed an asymmetric synthesis of the fluorinated dipeptide Ala-Ψ[(Z)CFCH]-Pro analogue of the transoid parent dipeptide. The fluorinated pseudodipeptide could be incorporated into various peptides or proteins for conformational, structural studies and biological activity studies and could also play a relevant role as an enzyme inhibitor.

Full text of DOI:10.1039/c2nj40891k

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Straightforward asymmetric synthesis of
Ala-W[CFQCH]-Pro, a proline-containing pseudodipeptide
bearing a fluoroolefin as a peptide bond mimic†
Cite this: NewJ.Chem., 2013,
3
7, 1320
Guillaume Dutheuil, Camille Pierry, Emilie Villiers, Samuel Couve-Bonnaire* and
Xavier Pannecoucke*
Received (in Montpellier, France)
th October 2012,
5
From ethyl-2-oxocyclopentanecarboxylate, we developed an asymmetric synthesis of the fluorinated
dipeptide Ala-C[(Z)CFQCH]-Pro analogue of the transoid parent dipeptide. The fluorinated
pseudodipeptide could be incorporated into various peptides or proteins for conformational, structural
studies and biological activity studies and could also play a relevant role as an enzyme inhibitor.
Accepted 21st November 2012
DOI: 10.1039/c2nj40891k
www.rsc.org/njc
Proline is one of the most studied amino acids due to its
unique properties and its numerous implications in biological
1
processes. Proline is the only natural amino-acid with a con-
strained backbone (secondary cyclic amine) conferring it much
higher rigidity than other amino acids. When inserted in a
peptide, proline lacks hydrogen on the amide moiety and so
can only play a role as a hydrogen bond acceptor. It is well
known that the peptide bond is in equilibrium between trans-
oid and cisoid conformations. In dipeptides containing proline
residues, the probability to find the cis form is very high (0.1 to
Scheme 1 Cisoid and transoid conformers of dipeptide AA-Pro.
stabilities of the amino acid for specific applications like 4-fluoro-
3
3b
4
proline, 4,4-difluoroproline, 4,4-difluoro-3,3-dimethylproline,
4
5
6
-trifluoromethylproline, or a-trifluoromethylproline (Scheme 2).
0
.4) compared to other dipeptides for which this probability is
In addition, a fluorine atom can also be used as an efficient
À3
less than 10 ; both cis and trans forms in the AA-Pro unit
1
9
tool for structural study by F NMR spectroscopy thanks to the
high sensitivity of fluorine chemical shifts to its local environ-
(
where AA represents any amino acid) are very close energeti-
cally, explaining why proline is often implied in turns
Scheme 1). For all these reasons proline is of main interest
7
ment. For example, some fluorinated proline analogues have
(
1
9
been developed as F-labeled amino acids by Ulrich, Komarov
in peptide chemistry and having an analogue of a single
conformer, without any equilibrium, would be a relevant tool
for biological and structural studies.
8
and others for conformational study of peptides (Scheme 3).
Moreover, the incorporation of one or more fluorine atoms
in a molecule often changes significantly its properties
(
biological, physical, chemical and physiological) compared to
2
a non-fluorinated one. In this context numerous fluorinated
prolines bearing one or more fluorine atoms in various positions
have been studied to increase the conformational and biochemical
Scheme 2 Examples of fluorinated proline analogues.
Laboratoire COBRA (Chimie Organique Bio-organique R ´e activit ´e et Analyse), CNRS
UMR 6014 & FR 3038, Universit ´e et Institut National des Sciences Appliqu ´e es
(
INSA) de Rouen, Rue Tesni ´e re, 76130 Mont-Saint-Aignan, France.
E-mail: samuel.couve-bonnaire@insa-rouen.fr, xavier.pannecoucke@insa-rouen.fr;
Fax: +33 2 35 52 29 59; Tel: +33 2 35 52 29 20, +33 2 35 52 24 15
1
13
19
†
Electronic supplementary information (ESI) available: H, C and F NMR
spectra and a CIF file for compound (Z)-10. CCDC 872138. For ESI and crystal-
19
lographic data in CIF or other electronic format see DOI: 10.1039/c2nj40891k
Scheme 3
F-Labeled trifluoromethyl proline analogues.
1
320 New J. Chem., 2013, 37, 1320--1325
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Scheme 4 Dipeptide AA-C[CF=CH]-Pro analogues.
Nevertheless, very few reports have described the fluorinated
modification of the peptide bond of the dipeptide unit AA-Pro,
essentially due to synthetic difficulties. A goal of our group is
the development of new methodologies for the synthesis of
fluoropeptidomimetics bearing a fluoroolefin moiety as a peptide
bond mimic. Indeed, the fluoroolefin moiety has interesting
geometric and electronic similarities with a peptide bond and
Scheme 5 Retrosynthesis of Ala-C[(Z)CF=C]Pro 1.
9
could be considered as an efficient peptide bond mimic. We
wish to develop a new chiral constrained AA-Pro unit in stable
transoid or cisoid form, without an equilibrium between these
conformers (Scheme 4). Recently, Chang et al. synthesized a
fluorinated constrained Val-C[(Z)CFQCH]-Pro and used it to
10
design new efficient hepatitis C virus NS5A inhibitors.
Herein we present the first asymmetric synthesis of
Ala-C[(Z)CFQC]-Pro 1. Indeed, besides the fact that this dipeptide
unit can be found in numerous peptides and proteins, this
compound in the Z configuration is well known to be an effective
mimic of the native Ala-Pro unit. Moreover, this fluorinated
analogue is also very relevant as a pharmaceutical candidate
for the treatment of different diseases acting as an enzymatic
Scheme 6 Asymmetric synthesis of precursor 2.
an olefination reaction leading to 4 in 76% yield and a 60/40 Z/E
ratio. The Negishi reaction was then carried out from 4 furnishing
compound 3 in 66% yield and a slightly improved 68/32 Z/E ratio.
Indeed, partial isomerisation can occur during the hydrolysis
11
inhibitor of dipeptidyl peptidase.
For this purpose, the
Ala-C[(Z)CFQC]Pro unit has already been synthesised but not in
a straightforward and asymmetric manner. As a matter of fact,
Welch et al. have generated the fluoroolefin moiety by a Peterson
reaction and the racemic mixture of each diastereoisomer of the
final dipeptide analogue 1 was obtained after separation by
13b
step. The diastereoselective reductive amination of a-fluorenone
3
was performed with (S)-tert-butanesulfinamide as a chiral
auxiliary. Products 2 in both Z and E configuration were isolated
in moderate 32% and 28% yield, respectively, but with a very good
diastereomeric ratio of up to 96%. As previously reported in the
11f
column chromatography. Augustyns et al. have generated the
fluoroolefin moiety from a Horner–Wadsworth–Emmons reaction
11b
and finally obtained the racemic dipeptide unit 1.
Contrary to a previously reported study using the Boc sub-
12
literature, the attack of the hydride proceeded from the Re face
of sulfinyl imine allowing the same configuration as that of the
native peptide to be obtained. At this stage, it was relatively easy to
1
1
stituent as the protecting group, we decided to introduce the
Fmoc protecting group, commonly used in peptide solid phase
synthesis, at the N-terminal side of the dipeptide. Our retro-
synthetic strategy to reach compound 1 begins with the
chemical transformation of chiral allylamine 2 obtained by
separate both
chromatography.
Z
and
E
diastereoisomers by column
In order to obtain specifically the relevant transoid confor-
mer analogue, the major diastereoisomer (Z)-2 was submitted
to subsequent deprotection of tert-butane sulfoxide and silyl
groups, which afforded product (Z)-10 in quantitative yield. The
stereochemistry of this compound (Z)-10 was verified by X-ray
analysis which confirmed the reduction process.‡ Then the
compound (Z)-10 was subjected to Fmoc protection of the
primary amine, which gave the product (Z)-11 in 60% yield.
1
2
asymmetric reductive amination of a-fluoroketone 3.
Compound 3 could be obtained by a palladium mediated
Negishi cross-coupling between a-ethoxyvinylzinc chloride
1
3
and gem-bromofluoroolefin 4. This could be effected by
1
4
olefination reaction of ketone 5. This chiral ketone 5 could
be synthesised by a chemoenzymatic procedure from ethyl-
1
5
2
-oxocyclopentanecarboxylate 6 (Scheme 5).
As depicted in Scheme 6, we started the asymmetric synth-
esis using the chemoenzymatic procedure described by Buisson
‡
Crystal data for (Z)-10: C
9
H17ClFNO, M = 209.69, orthorhombic, a = 6.8983(6) Å,
3
a = 901, b = 12.0634(10) Å, b = 901, c = 12.5086(10) Å, g = 901, U = 1040.93(15) Å , T =
1
5b
and Azerad to synthesise the chiral ketone 5 in a pure form
293(2) K, space group P212121 (no. 19), Z = 48 336 reflections measured, 2137
with an overall yield of 40% in four steps; the first step
being the limiting step with 47% yield. Then we proceeded to wR(F ) = 0.07 (all data). Flack parameters = 0.03(5). CCDC 872138.
independent reflections (Rint = 0.0174). Final R values = 0.0272 (all data) and
2
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ionization (CI – 200 eV) or high-resolution MS experiments were
recorded on a JEOL AX 500 mass spectrometer using a mass
resolution of 5000 and with TOF as a mass analyzer for HRMS.
Elemental analyses were performed on a CE Instruments EA 110
CHNS-O instrument.
Ethyl-2-(S)-hydroxy-(R)-cyclopentane carboxylate (7). To a solu-
tion of ethyl 2-oxocyclopentanecarboxylate (16 g) in water at room
temperature Baker’s yeast (20 g) and glucose (8 g) were added
portionwise. The mixture was stirred for 4 days and then
extracted with Et
washed with water and dried over MgSO . After filtration and
2
O (3Â). The combined organic layers were
4
concentration under reduced pressure, the residue was purified
by chromatography on silica gel (eluent: cyclohexane/EtOAc: 80/20)
to afford the expected keto-alcohol as an orange oil in 47%
1
yield. R
CDCl
f
= 0.40 (cyclohexane/EtOAc: 50/50). H NMR (300 MHz,
3
3
): d 4.42–4.20 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.13 (brs,
H), 2.66 (dt, J = 4.2 Hz, J = 8.9 Hz, 1H), 2.02–1.57 (m, 6H),
.26 (t, J = 7.1 Hz, 3H). C NMR (75.4 MHz, CDCl ): d 175.2,
3
3
3
Scheme 7 Access to the fluorinated analogue Ala-C[(Z)CFQCH]-Pro 1.
1
1
7
3
13
3.8, 60.8, 49.6, 34.1, 26.6, 22.2, 14.4.
The final step, Jones oxidation of alcohol to acid, allowed the
fluorodipeptide analogue Fmoc-Ala-C[(Z)CFQC]-Pro 1 in a
pure form with 70% yield to be obtained (Scheme 7).
(
1S,2S)-2-Methanolhydroxycyclopentane (8). To a suspension
of LiAlH (2.6 g, 68.2 mmol, 1 equiv.) in dry THF (70 mL) at 0 1C
under argon was added dropwise a solution of ethyl-2-(S)-
hydroxy-(R)-cyclopentane carboxylate (10.79 g, 68.2 mmol,
4
We described here the first asymmetric synthesis of an
Ala-C[(Z)CFQC]-Pro unit. This dipeptide could have many
applications in structural study of peptide or protein as well
as a therapeutic agent such as a DPPIV or DPPII inhibitor. New
asymmetric synthetic methodologies are currently under investi-
gation to enlarge the scope of the synthesized dipeptide AA-Pro.
Indeed, we recently developed a new methodology based on
organometallic addition onto a-fluoroenimines generated from
1
equiv.) in THF (200 mL). The mixture was stirred at room
temperature overnight and then NaOH aq. (1 M, 23 mL, 0.3 equiv.)
was added slowly at À40 1C. The salts were filtered off on
MgSO and the filter cake was washed with Et O (at least 1.6 L).
Concentration under reduced pressure furnished quantitatively
crude 2-(S)-methanol-(S)-hydroxycyclopentane as a pale yellow
oil, which was pure enough to be used in the next step without
purification. R
300 MHz, CDCl
4
2
1
6
easily accessible a-fluoroacrylate derivatives. This methodology
will be applied soon to the proline residue in order to develop an
efficient access to a wide range of enantiopure AA-Pro dipeptides
both in transoid and cisoid conformations.
1
f
= 0.20 (cyclohexane/EtOAc: 80/20). H NMR
(
3
): d 4.30À4.26 (m, 1H), 3.92 (brs, 2H),
3
1
4
.69À3.62 (m, 2H), 2.01À1.89 (m, 1H), 1.83À1.70 (m, 2H),
13
.64À1.45 (m, 4H). C NMR (75.4 MHz, CDCl
3
): d 74.5, 62.4,
6.1, 34.9, 25.4, 22.1.
2
-(S)-(tert-Butyldiphenylsilyloxymethyl)-(S)-hydroxycyclopen-
Experimental section
General
tane (9). To a stirred solution of 2-(S)-methanol-(S)-hydroxy-
cyclopentane (7.73 g, 66.55 mmol, 1 equiv.) in dry DMF (770 mL)
All organometallic reagents were commercially available and was added at 0 1C imidazole (22.65 g, 333 mmol, 5 equiv.),
purchased from Aldrich or Acros. Reactions with organometallics followed by tert-butylchlorodiphenylsilane (20.7 mL, 79.86 mmol,
were carried out under an argon atmosphere. THF was distilled 1.2 equiv.). The mixture was allowed to warm to room tempera-
prior to use from sodium benzophenone ketyl under a nitrogen ture and stirred overnight. The mixture was shaken with a
atmosphere and dichloromethane from CaH2. TLC was saturated aqueous solution of NaHCO and extracted with EtOAc
3
performed on Merck 60F-250 silica gel plates, using UV light as (3Â). The combined organic layers were washed with brine and
a visualizing agent and an ethanolic solution of phosphomolybdic dried over MgSO . After filtration and concentration under
4
acid and heat as a developing agent. Flash column chromato- reduced pressure, the residue was purified by chromatography
graphy purifications were carried out using silica gel (70–230 mesh). on silica gel (eluent: cyclohexane/EtOAc: 90/10) to afford 2-
1
13
19
H NMR, C NMR and F NMR (CFCl
3
as internal reference) were (S)-(tert-butyldiphenylsilyloxymethyl)-(S)-hydroxycyclopentane as
= 0.70 (cyclohexane/EtOAc: 80/20).
): d 7.69À7.67 (m, 4H), 7.42À7.40 (m,
broad singlet, d: doublet, t: triplet, q: quadruplet, m: multiplet. J was 6H), 4.42 (m, 1H), 3.94À3.77 (m, 2H), 2.90 (brs, 1H), 1.81À1.91
recorded at 300.13, 75.47 and 282.40 MHz, respectively, on a Bruker a white solid in 98% yield. R
DXP 300. Abbreviations used for peak multiplicity are s: singlet, brs:
f
1
H NMR (300 MHz, CDCl
3
1
3
used to indicate coupling constant in Hertz. IR spectra were (m, 1H), 1.73À1.61 (m, 3H), 1.43À1.35 (m, 2H), 1.06 (s, 9H).
C
recorded on a Perkin-Elmer 500 FT-IR spectrometer. Absorption NMR (75.4 MHz, CDCl ): d 135.6, 133.2, 129.9, 127.7, 75.2, 64.4,
3
À1
bands are reported in cm . Electrospray ionization (ESI) mass 46.1, 34.7, 26.9, 25.5, 22.4, 19.2.
spectrometry (MS) experiments were performed on a Bruker-Esquire
2-(S)-(tert-Butyldiphenylsilyloxymethyl)cyclopentanone (5).
mass spectrometer. Electronic impact (EI – 70 eV), chemical To a mixture of pyridinium dichromate (64 g, 166 mmol, 2.5 equiv.)
1
322 New J. Chem., 2013, 37, 1320--1325
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and powdered molecular sieves (4 Å, 130 g) in CH
NJC
2
Cl
2
(500 mL) and (E) ((2-(bromofluoromethylene)cyclopentyl)-(R)-methoxy)-
under argon was added dropwise 2-(S)-(tert-butyldiphenylsilyloxy- tert-butyldiphenylsilane 4 (5.26 g, 11.7 5 mmol, 1 equiv.) in
methyl)-(S)-hydroxycyclopentane (23.6 g, 66.55 mmol, 1 equiv.) in anhydrous THF (115 mL) at 70 1C under argon. The mixture was
CH Cl (200 mL) at room temperature. The mixture was stirred at stirred for 1 h. After the reaction was completed, controlled by
2
2
1
9
room temperature for 2 h. After the reaction was completed, monitoring the F-NMR signal of the reaction mixture, HCl aq.
controlled by TLC, the mixture was diluted with Et O and filtered (1 M, 300 mL) was added and the mixture was stirred for 15 min
through silica gel. Evaporation of solvents gave pure 2-(S)-(tert- before being extracted with Et
butyldiphenyl silyloxymethyl)cyclopentanone as a white solid in organic layers were dried over MgSO
8% yield. R
2
2
O (3Â, 300 mL). The combined
4
and concentrated under
À1
9
f
= 0.30 (cyclohexane/EtOAc: 95/5). IR (neat, cm ): reduced pressure. The residue was then purified by chromato-
n 3417, 3070, 2956, 2932, 2858, 1741, 1428, 1111, 1080, 750, 505. graphy on silica gel (eluent: cyclohexane/EtOAc: 98/2), affording
1
H NMR (300 MHz, CDCl ): d 7.68À7.65 (m, 4H), 7.53À7.41 (m, 6H), the mixture of (Z) and (E) 1-(2-(R)-methoxy-tert-butyldiphenylsilane)-
3
2
3
2
3
.97 (dd, J = 4.5 Hz, J = 10.2 Hz, 1H), 3.78 (dd, J = 3.4 Hz, cyclopentylidene-1-fluoropropan-2-one (Z/E: 68/32) as a yellow oil in
3
J = 10.2 Hz, 1H), 2.30À2.01 (bm, 6H), 1.96À1.71 (m, 1H), 0.94 65% yield. R = 0.58 and 0.62 (cyclohexane/EtOAc: 95/5). IR
f
1
3
À1
3
(s, 9H). C NMR (75.4 MHz, CDCl ): d 220.2, 135.8, 134.9, 129.8, (neat, cm ): n 3072, 2968, 2930, 1702, 1638, 1477, 1428, 1382,
+
1
1
27.8, 62.8, 51.0, 39.3, 27.0, 26.6, 21.2, 19.4. MS (EI ): m/z = 199 1277, 1089, 1049, 881, 703, 505. H NMR (300 MHz, CDCl
3
):
Si: calcd: C, 74.95; d 7.68–7.60 (m, 4H), 7.43–7.34 (m, 6H), 3.77–3.50 (m, 2.6H),
3.15–3.13 (m, 0.6H), 2.72–2.67 (m, 1H), 2.50–2.44 (m, 1H), 2.21
+
[
M À 2Ph] . Elemental analysis for C22
28 2
H O
H, 8.01. Found: C, 74.76; H, 8.14%.
4
19
(
(2-(Bromofluoromethylene) cyclopentyl)-(R)-methoxy)-tert- (2d, J = 5.3 Hz, 3H), 1.97–1.65 (bm, 4H), 1.04 (s, 9H). F NMR
13
butyldiphenylsilane (4). To a solution of triphenylphosphine (282.5 MHz): d À119.2 (m, 0.4F ), À123.6 (m, 0.6F ). C NMR
E
Z
2
2
(28.59 g, 109.01 mmol, 7 equiv.), tribromofluoromethane (10.7 mL, (75.4 MHz, CDCl ): d 192.2 (d, J = 41 Hz), 191.7 (d, J = 40 Hz), 148.6
3
1
1
2
1
09.01 mmol, 7 equiv.), and 2-(S)-(tert-butyldiphenylsilyloxymethyl)- (d, J = 251 Hz), 148.5 (d, J = 251 Hz), 139.3 (d, J = 14 Hz), 138.5 (d,
2
cyclopentanone (5.49 g, 15.57 mmol, 1.0 equiv.) in anhydrous THF
200 mL) was added a solution of diethylzinc (109 mL of a 1 M 29.3, 28.7, 27.5, 26.3, 25.8, C15), 23.8, 21.7, 18.2. HRMS: calculated
solution in hexane, 109.01 mmol, 7 equiv.) dropwise via a syringe for C25 Si: 411.2135. Found: 411.2138.
pump over 30 min at room temperature under argon. The mixture N-{(1R)-2-[(2S)-2-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclo-
J = 13 Hz), 134.6, 132.6, 128.5, 126.6, 63.3, 62.8, 44.8, 43.3, 30.3,
(
H32FO
2
was stirred for 1 h and the resulting solution was then quenched pentylidene]-2-fluoro-1-methylethyl}-2-methyl-2-propanesulfina-
with methanol. After 15 min the mixture was concentrated under mide (2). A solution of Ti(OEt) (2.08 mL, 10.0 mmol, 5 equiv.)
4
reduced pressure and the residue then chromatographed on silica and ketone 3 (822.0 mg, 2.0 mmol, 1 equiv.) in dry THF (20 mL)
gel (eluent: 100% cyclohexane), affording the desired mixture of (Z) was prepared under argon. Then, (S)-tert-butanesulfinamide
and (E) ((2-(bromofluoromethylene)cyclopentyl)-(R)-methoxy)tert- (1.21 g, 10.0 mmol, 5 equiv.) was added and the mixture was
butyldiphenylsilane (Z/E: 60/40) as a pale yellow oil in 76% yield. heated to reflux for 8 h. The mixture was cooled down to À78 1C
À1
R
f
= 0.70 (cyclohexane/EtOAc: 98/2). IR (neat, neat cm ): n 3394, and NaBH
4
(302.8 mg, 8.0 mmol, 4 equiv.) was added. The
3
071, 2958, 2857, 1682, 1471, 1428, 1111, 1092, 823, 701, 504. mixture was stirred for 7 h at À78 1C and then allowed to warm
1
H NMR (300 MHz, CDCl
3
): d 7.61À7.56 (m, 4H), 7.31À7.24 (m, to room temperature. The resulting solution was poured into an
6
H), 3.64À3.61 (m, 1H), 3.50À3.41 (m, 1H), 3.03À2.95 (m, 0.4H ), equal volume of brine with rapid stirring. The resulting suspen-
Z
s
2
.72À2.61 (m, 0.6H ), 2.42À2.26 (m, 1.1H ), 2.24À2.12 (m, 0.9H ), sion was filtered through a plug of celite and the filter cake
E
E
Z
19
2.10À1.59 (bm, 4H), 0.97 (s, 9H). F NMR (282.5 MHz): d À74.0 (m, was washed with EtOAc. The aqueous layer was extracted with
13
0
.4F
Z
), À77.3 (m, 0.6F
E
). C NMR (75.4 MHz, CDCl
3
): d 142.9 (d, EtOAc (2Â) and the combined organic layers were dried over
SO , filtered and concentrated under reduced pressure. The
J = 10 Hz), 64.9, 64.2, 46.3, 45.3, 32.8, 31.3, 30.2, 29.8, 27.6, 26.7, crude mixture was purified by chromatography on silica gel
1
J = 249 Hz), 136.4, 135.2, 134.4, 131.0, 130.4, 128.7, 128.4, 125.3 (2d, Na
2
4
2
+
+
2
5.3, 24.7, 20.0. MS (EI ): m/z = 447 [M ]. Elemental analysis for (eluent: PE/EtOAc: 85/15-78/22) to afford the first desired (E)
28BrFOSi: C, 61.74; H, 6.31. Found: C, 61.57; H, 6.42%. diastereomer in 28% yield and then the desired (Z) diastereo-
Z) and (E) 1-(2-(R)-Methoxy-tert-butyldiphenylsilane)- mer 2 in 32% yield as colorless oil.
23
C H
(
cyclopentylidene-1-fluoropropan-2-one (3). To a solution of
potassium tert-butoxide (3.96 g, 35.26 mmol, 3 equiv.) in
anhydrous THF (175 mL) at À78 1C under argon was added
À1
f
Diastereomer (E)-2. R = 0.19 (PE/EtOAc: 85/15). IR (neat, cm ):
ethylvinylether (3.37 mL, 35.26 mmol, 3 equiv.) followed by n 3071, 2958, 1713, 1473, 1428, 1189, 1112, 1086, 702, 505.
1
addition of n-BuLi in hexane dropwise (14.1 mL of a 2.5 M
solution in hexane, 35.26 mmol, 3 equiv.). The mixture was (m, 6H), 3.78–3.51 (m, 3H), 3.20 (d, J = 8.3 Hz, 1H), 2.67–2.63
3
H NMR (300 MHz, CDCl ): d 7.68–7.66 (m, 4H), 7.42–7.26
3
3
stirred for 30 min at À78 1C and a solution of dry zinc chloride (m, 1H), 2.35–2.09 (m, 2H), 1.69–1.54 (m, 4H), 1.19 (d, J = 6.7 Hz,
1
9
3
(
9.61 g, 70.53 mmol, 6 equiv.) in THF (280 mL) was added 3H), 1.04 (s, 9H). F NMR (282.5 MHz): d À125.1 (dd, J = 27.8
4
13
1
dropwise. After 10 min, the cooling bath was removed and Hz, J = 3.3 Hz). C NMR (75.4 MHz, CDCl ): d 153.1 (d, J = 249.5
3
2
the solution was allowed to warm to room temperature for Hz), 135.7, 134.2, 133.8, 129.7, 127.7, 120.2 (d, J = 16.4), 64.9 (d,
4
2
3
30 min. The mixture was then added slowly to a solution
J = 4.4 Hz), 55.7, 50.9 (d, J = 28.0 Hz), 43.1 (d, J = 4.9 Hz), 29.4,
4
+
of palladium diacetate (132 mg, 0.59 mmol, 0.05 equiv.), 27.5 (d, J = 3.3 Hz), 27.1, 22.9, 22.4, 19.6, 19.4. MS (EI ):
triphenylphosphine (308 mg, 1.18 mmol, 0.1 equiv.) and (Z) m/z = 516.27 [M + H ]. Elemental analysis for C29H42FNO SSi:
2
+
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Paper
1
C, 67.53; H, 8.21; N, 2.72; S, 6.22. Found: C, 67.75; H, 8.43; N, d 155.6, 152.2 (d, J = 248.1 Hz), 143.9, 141.3, 127.7, 127.1, 125.1,
2
2
2
.75; 6.25%.
121.4 (d, J = 15.9 Hz), 120.2, 66.8, 64.1, 47.2, 46.2 (d, J = 27.5 Hz),
3
+
4
3.5, 29.4, 28.2 (d, J = 5.2 Hz), 24.8, 18.5. MS (EI ): m/z = 396
Diastereomer (Z)-2. R = 0.12 (PE/EtOAc: 85/15). IR (neat, [M + H ]. Elemental analysis for C H FNO : C, 72.89; H, 6.63; N,
cm ): n 3069, 2964, 2852, 1710, 1412, 1192, 1108, 1092, 700, 3.54; S. Found: C, 73.15; H, 6.91; N, 3.56%.
+
f
24 26
3
À1
1
5
(
1
1
9
(
13. H NMR (300 MHz, CDCl
m, 6H), 4.24–4.06 (m, 1H), 3.77–3.57 (m, 2H), 3.48 (d, J = 7.14 Hz, 1-fluoropropylidene)cyclopentanecarboxylic acid 1. To a solution
H), 3.11–3.08 (m, 1H), 2.49–2.22 (m, 2H), 1.90–1.81 (m, 2H), of N-protected amino alcohol (Z)-11 (110.9 mg, 0.28 mmol, 1
3
): d 7.68–7.65 (m, 4H), 7.41–7.37
(Z) (1S)-2-((Z,2R)-2-[{(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-
3
3
.76–1.66 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H), 1.20 (s, 9H), 1.04 (s, equiv.) in acetone (3 mL per mmol of alcohol) at 0 1C was added
19
3
13
H). F NMR (282.5 MHz): d À130.4 (d, J = 26.8 Hz). C NMR Jones reagent (2.74 N, 3 equiv.). The reaction mixture was stirred at
1
75.4 MHz, CDCl ): d 152.3 (d, J = 249.0 Hz), 135.7, 133.9, 129.5, 0 1C for 1 h and then quenched with isopropyl alcohol (10 equiv.)
3
2
4
1
27.6, 121.0 (d, J = 14.8 Hz), 64.6 (d, J = 3.8 Hz), 55.8, 50.8 (d, and water (13 mL per mmol of alcohol). The mixture was extracted
2
4
J = 28.0 Hz), 43.1, 29.4, 28.6 (d, J = 4.6 Hz), 26.8, 24.9, 22.6, 19.3, with AcOEt (3Â) and the combined organic layers were washed
+
+
1
C
6
9.01. MS (EI ): m/z = 516.27 [M + H ]. Elemental analysis for with a saturated aqueous solution of NaCl, dried over Na
42FNO SSi: C, 67.53; H, 8.21; N, 2.72; S, 6.22. Found: C, filtered and concentrated under reduced pressure. The crude
7.60; H, 8.28; N, 2.74; 6.24%. mixture was purified by column chromatography on silica gel
Z) (2R)-1-[(2S)-2-({[tert-Butyl(diphenyl)silyl]oxy}methyl)cyclo- (PE/EtOAc: 60/40 then 50/50 with 0.1% of acetic acid), affording 1
2 4
SO ,
29
H
2
(
2
0
pentylidene]-1-fluoro-2-propanaminium chloride ((Z)-10). To a as a colorless gum in 70% yield. [a]
D
= À44,3 (c 0.63, CHCl
3
). IR
À1
solution of (Z)-2 (213.0 mg, 0.41 mmol, 1 equiv.) in dry MeOH (neat, cm ): n 3328, 3066, 2960, 1707, 1522, 1450, 1300, 1249,
1
3
(
4
2 mL) was added 4 M HCl in dioxane (412 mL, 1.65 mmol, 1057, 759, 740, 621. H NMR (300 MHz, CDCl ): d 7.76 (d, J = 7.5
equiv.). The mixture was stirred at room temperature for 1h15 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.41–7.29 (m, 4H), 5.00 (d, J = 8.1
and then concentrated under reduced pressure to near dryness. Hz, 1H), 5.00–4.51 (m, 1H), 4.45–4.37 (m, 2H), 4.21 (t, J = 6.8 Hz,
2
The residue was then washed with Et O. The ether-insoluble 1H), 3.56 (brs, 1H), 2.62–2.42 (m, 2H), 2.10–1.72 (m, 4H), 1.35 (d, J
3
3
3
3
3
19
3
residue was concentrated under reduced pressure to afford pure = 6.8 Hz, 3H). F NMR (282.5 MHz): d À125.3 (d, J = 27.8 Hz).).
2
0
13
1
amine hydrochloride (Z)-10. [a]
D
2
= À39,7 (c 0.38, H O). IR (neat,
3
C NMR (75.4 MHz, CDCl ): d 175.2, 156.3, 153.9 (d, J = 251.1 Hz),
À1
2
cm ): n 3405, 3310, 2949, 2876, 1695, 1519, 1450, 1304, 1244, 144.9, 141.9, 128.4, 127.8, 126.0, 120.7, 119.1 (d, J = 15.4 Hz), 66.9,
046, 1016, 738, 707. H NMR (300 MHz, D O): d 4.28 (dq, 47.9, 46.6 (d, J = 26.9 Hz), 45.8 (d, J = 2.2 Hz), 32.2, 28.6 (d, J =
J = 27.2 Hz, J = 6.6 Hz, 1H), 3.65–3.60 (m, 1H), 3.48–3.42 (m, 4.4 Hz), 26.3, 17.6. MS (EI ): m/z = 410.0 [M + H ]. Elemental
H), 2.99 (brs, 1H), 2.30–2.28 (m, 2H), 1.76–1.70 (m, 4H), 1.42 (d, analysis for C H FNO : C, 70.40; H, 5.91; N, 3.42; S. Found: C,
J = 6.8 Hz, 3H). F NMR (282.5 MHz): d À132.5 (d, J = 26.9 Hz). 70.48; H, 6.00; N, 3.45%.
1
2
3
3
1
2
3
3
+
+
1
24
24
4
3
1
2
19
3
3
1
C NMR (75.4 MHz, CDCl
3
): d 151.3 (d, J = 245 7 Hz), 129.1 (d,
4
2
J = 13.2 Hz), 66.1 (d, J = 4.6 Hz), 49.9 (d, J = 28.7 Hz), 46.5, 32.6,
Acknowledgements
31.5, 27.9, 19.21. Elemental analysis for C
9
H17ClFNO: C, 51.5; H,
8.17; O, 7.63. Found: C, 51.23; H, 8.04; O, 7.44%.
This work has been financially promoted by the interregional
(
Z) 9H-Fluoren-9-ylmethyl (1R)-2-[(2S)-2-({[tert-butyl(diphenyl)- Norman chemistry network (CRUNCh) and the Ministry of
silyl]oxy}methyl)cyclopentylidene]-2-fluoro-1-methylethylcarbamate
Education and Research; the ‘‘R ´e gion Haute-Normandie’’ is
(
(Z)-11). To a solution of amine hydrochloride derivative (Z)-10 also gratefully thanked for its financial support.
86.034 mg, 0.41 mmol, 1 equiv.) in dioxane (4 mL per mmol of
amine hydrochloride) and water (4 mL per mmol of amine hydro-
chloride) was added NaHCO (104.1 mg, 1.24 mmol, 3 equiv.) at
1C, followed by Fmoc-OSu (167.2 mg, 0.49 mmol, 1 equiv.). The
(
Notes and references
3
0
1 (a) M. W. Macarthur and J. M. Thornton, J. Mol. Biol., 1991,
218, 397–412; (b) G. Vanhhof, F. Goossens, I. De Meester,
D. Hendriks and S. Scharp ´e , FASEB J., 1995, 9, 736–744;
(c) B. K. Kay, M. P. Williamson and M. Sudol, FASEB J., 2000,
14, 231–241.
reaction mixture was stirred at 0 1C for 2 h and at room temperature
overnight. The mixture was then poured into ice cold HCl (1 N, 8 mL
per mmol of amine hydrochloride) and extracted with AcOEt (3Â).
The combined organic layers were dried over Na SO , filtered and
2
4
concentrated under reduced pressure. The crude mixture was
purified by column chromatography on silica gel (PE/EtOAc: 88/
2 (a) J.-P. B ´e gu ´e and D. Bonnet-Delpon, in Bioorganic and
Medicinal Chemistry of Fluorine, Wiley, 2008; (b) Fluorine
and Health, ed. A. Tressaud and G. Haufe, Elsevier, 2008;
(c) Fluorine in Medicinal Chemistry and Chemical Biology, ed.
I. Ojima, Wiley-Blackwell, 2009; (d) A. M. Thayer, Chem. Eng.
News, 2006, 84, 15–33.
3 (a) M. Doi, Y. Nishi, N. Kiritoshi, T. Iwata, M. Nago,
H. Nakano, S. Uchiyama, T. Nakazawa, T. Wakamiya and
Y. Kobayashi, Tetrahedron, 2002, 58, 8453–8459;
(b) R. Golbik, C. Yu, E. Weyher-Stingl, R. Huber,
L. Moroder, N. Budisa and C. Schiene-Fischer, Biochemistry,
20
1
2-75/25), affording (Z)-11 in 60% yield as a colorless gum. [a]
À7,3 (c 0.62, CHCl ). R = 0.22 (cyclohexane/EtOAc: 50/50). IR (neat,
cm ): n 3406, 3320, 3065, 2952, 2874, 1702, 1534, 1450, 1247, 1054,
D
=
3
f
À1
1
3
759, 740. H NMR (300 MHz, CDCl ): d 7.76 (d, J = 7.5 Hz, 2H), 7.60
3
3
3
(d, J = 7.2 Hz, 2H), 7.43–7.28 (m, 4H), 5.23 (d, J = 8.5 Hz, 1H),
3
4.92–4.51 (m, 1H), 4.42–4.38 (m, 2H), 4.21 (t, J = 6.6 Hz, 1H),
3
.71–3.66 (m, 1H), 3.51–3.45 (m, 1H), 2.55–2.22 (m, 2H), 2.00 (brs,
3
19
1H), 1.81–1.55 (m, 4H), 1.33 (d, J = 6.9 Hz, 3H). F NMR
3
13
(282.5 MHz): d À130.1 (d, J = 28.9 Hz). C NMR (75.4 MHz, CDCl
3
):
1
324 New J. Chem., 2013, 37, 1320--1325
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View Article Online
Paper
NJC
2005, 44, 16026–16034; (c) B. C. Kim, K.-Y. Kim and H. Shin, 11 (a) S. D. Edmondson, L. Wei, J. Xu, J. Shang, S. Xu, J. Pang,
Org. Process Res. Dev., 2008, 12, 626–631.
(a) L. Chen, Y. M. Kim, D. J. Kucera, K. E. Harrisson,
S. Bahmanyar, J. M. Scott and D. Yazbeck, J. Org. Chem., 2006,
A. Chaudhary, D. C. Dean, H. He, B. Leiting, K. A. Lyons,
R. A. Patel, S. B. Patel, G. Scapin, J. K. Wu, M. G. Beconi,
N. A. Thornberry and A. E. Weber, Bioorg. Med. Chem. Lett.,
2008, 18, 2409–2413; (b) P. Van der Veken, K. Senten,
I. Kertesz, I. De Meester, A.-M. Lambeir, M.-B. Maes,
S. Scharp ´e , A. Haemers and K. Augustyns, J. Med.
Chem., 2005, 48, 1768–1780; (c) P. Van der Veken,
I. Kertesz, K. Senten, A. Haemers and K. Augustyns,
Tetrahedron Lett., 2003, 44, 6231–6234; (d) J. Lin,
P. J. Toscano and J. T. Welch, Proc. Natl. Acad. Sci.
U. S. A., 1998, 95, 14020–14024; (e) K. Zhao, D. S. Lim,
T. Funaki and J. T. Welch, Bioorg. Med. Chem., 2003, 11,
207–215; ( f ) J. T. Welch and J. Lin, Tetrahedron, 1996, 52,
291–304.
4
71, 5468–5473; (b) F. Rossi, F. Corcella, F. S. Caldarelli,
F. Heidempergher, C. Marchionni, M. Auguadro, M. Cattaneo,
L. Ceriani, G. Visentin, G. Ventrella, V. Pinciroli, D. Yazbeck and
D. J. Kucera, Org. Process Res. Dev., 2008, 12, 322–338.
5
6
(a) X.-L. Qiu and F.-L. Qing, J. Org. Chem., 2002, 67,
7162–7164; (b) J. R. Del Valle and M. Goodman, Angew.
Chem., Int. Ed., 2002, 41, 1600–1602.
(a) G. Chaume, M.-C. Van Severen, S. Marinkovic and
T. Brigaud, Org. Lett., 2006, 8, 6123–6126; (b) C. Caupene,
G. Chaume, L. Ricard and T. Brigaud, Org. Lett., 2009, 11,
209–212.
7
8
S. L. Cobb and C. D. Murphy, J. Fluorine Chem., 2009, 130, 12 G. Dutheuil, S. Couve-Bonnaire and X. Pannecoucke, Angew.
32–143 and references therein. Chem., Int. Ed., 2007, 46, 1290–1292.
P. K. Mykhailiuk, S. Afonin, G. V. Palamarchuk, 13 (a) G. Dutheuil, C. Paturel, X. Lei, S. Couve-Bonnaire and
1
O. V. Shishkin, A. S. Ulrich and I. Komarov, Angew. Chem.,
Int. Ed., 2008, 47, 5765–5767.
(a) R. J. Abraham, S. L. R. Ellison, P. Schonoholzer and
X. Pannecoucke, J. Org. Chem., 2006, 71, 4316–4319;
(b) G. Dutheuil, S. Couve-Bonnaire and X. Pannecoucke,
Tetrahedron, 2009, 65, 6034–6038.
9
W. A. Thomas, Tetrahedron, 1986, 42, 2101–2110; 14 (a) X. Lei, G. Dutheuil, X. Pannecoucke and J.-C. Quirion,
(
b) P. Cieplack, P. A. Kollman and J. P. Radomski, in Biomedical
Org. Lett., 2004, 6, 2101–2104; (b) L. Zoute, G. Dutheuil,
J.-C. Quirion, P. Jubault and X. Pannecoucke, Synthesis,
2006, 3409–3418.
frontiers of fluorine chemistry, ACS Symp. Ser 639, 1996,
pp. 143–156; (c) J. T. Welch, J. Lin, L. G. Boros, B. DeCorte,
K. Bergmann and R. Gimi, in Biomedical frontiers of fluorine 15 (a) B. S. Deol, D. D. Ridley and G. W. Simpson, Aust.
chemistry, ACS Symp. Ser 639, 1996, pp. 129–142.; (d) J. J. Urban,
B. G. Tillman and W. A. Cronin, J. Phys. Chem. A, 2006, 110,
J. Chem., 1976, 29, 2459–2467; (b) D. Buisson and
R. Azerad, Tetrahedron: Asymmetry, 1996, 7, 9–12;
(c) F. Theil and S. Ballschuh, Tetrahedron: Asymmetry,
1996, 7, 3565–3572.
11120–11129; (e) B. E. McKinney and J. J. Urban, J. Phys. Chem. A,
2010, 114, 1123–1133; ( f ) S. Couve-Bonnaire, D. Cahard and
X. Pannecoucke, Org. Biomol. Chem., 2007, 5, 1151–1157 and 16 (a) C. Pierry, L. Zoute, P. Jubault, E. Pfund, T. Lequeux,
references therein.
D. Cahard, S. Couve-Bonnaire and X. Pannecoucke, Tetra-
hedron Lett., 2009, 50, 264–266; (b) C. Pierry, D. Cahard,
S. Couve-Bonnaire and X. Pannecoucke, Org. Biomol. Chem.,
2011, 9, 2378–2386.
1
0 W. Chang, R. T. Mosley, S. Bansal, M. Keilman, A. M. Lam,
P. A. Furman, M. J. Otto and M. J. Sofia, Bioorg. Med. Chem.
Lett., 2012, 22, 2938–2942.
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2013
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