The fluoroalkene motif as a surrogate of the amide bond: Syntheses of AA-Ψ[(Z) and (E)-CFCH]-Pro pseudodipeptides and an Enalapril analogue

Article abstract of DOI:10.1016/j.tet.2015.06.093

This work describes the optimization process for the synthesis of pseudodipeptides featuring a proline bound to another amino acid through a fluoroalkene moiety that act as an amide bond surrogate. The synthetic methodology is extended to non-peptidic molecules as demonstrated in the design and synthesis of an Enalapril analogue.

Full text of DOI:10.1016/j.tet.2015.06.093

Tetrahedron 71 (2015) 7054e7062
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The fluoroalkene motif as a surrogate of the amide bond: syntheses
of AA-J[(Z) and (E)-CF]CH]-Pro pseudodipeptides and an Enalapril
analogue
*
Emilie Villiers, Samuel Couve-Bonnaire, Dominique Cahard, Xavier Pannecoucke
ꢀ
ꢁ
Normandie Universite, COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesniere, 76821 Mont Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2015
Received in revised form 24 June 2015
Accepted 25 June 2015
Available online 2 July 2015
This work describes the optimization process for the synthesis of pseudodipeptides featuring a proline
bound to another amino acid through a fluoroalkene moiety that act as an amide bond surrogate. The
synthetic methodology is extended to non-peptidic molecules as demonstrated in the design and syn-
thesis of an Enalapril analogue.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Fluoroalkene
Proline
Peptidomimetics
1. Introduction
the amide bond, allowing the use of the fluoroalkene as an effective
peptide bond mimic.
Of the proteinogenic amino acids, proline is unique owing to its
secondary amine function and a saturated ring causing a con-
Moreover, the fluoroalkene is more stable than a simple alkene
because isomerization and conjugation with an acid moiety is
disfavored by the fluorine atom. Compounds that contain fluo-
roalkene motifs are also more resistant to enzymatic degradation
compared to the peptidic bond.5 Pseudodipeptides that feature
a fluoroalkene moiety and a proline are rare in the literature. This
motif (Fig. 1) was constructed by Welch et al. via a Peterson fluo-
roolefination reaction.6 Augustyns et al. generated the fluoroolefin
moiety by a HornereWadswortheEmmons reaction,7 as also re-
strained
f dihedral angle. As a consequence, proline confers to
protein structures a higher conformational rigidity compared to
other amino acids.1e3 In return, proline lacks hydrogen on its ni-
trogen atom, meaning it can only play a role as a hydrogen bond
acceptor. Peptide bonds adopt the trans isomer conformation
(>99.9%) while the cis AA-Pro peptide bonds range from 10 to 40%
(AA stands for any amino acid). Indeed, in the case of AA-Pro, the
two isomers are nearly equal energetically because of similar steric
hindrance with the neighboring substituents. These properties
impact the secondary structure of proline-containing peptides
ported by Chang et al. in the synthesis of the dipeptide Val-
CF]CH]-Pro for the design of an efficient hepatitis C virus NS5A
inhibitor.8 Our group reported the synthesis of the dipeptide Ala-
J[(Z)-
J
through
a
-helices and
b
-sheets. Nevertheless, cis-trans isomeriza-
[CF]CH]-Pro with enhanced E:Z ratio as well as excellent diaster-
eoselectivity.9 However, a drawback of our synthetic sequence was
the way we introduced the R chain at the N-terminal side through
a Negishi reaction somehow limited the variety of substituents. We
tion still exists and a complete freeze of a conformation would be
highly desirable to define the direction of a peptide chain. In this
context, we have developed synthetic routes to pseudodipeptides
featuring a fluoroalkene motif as an amide bond replacement.4,5
Noteworthy, we have access to both E and Z diastereoisomers and
we control the configuration of the newly created stereogenic
carbons at C- and N-terminals of the pseudodipeptides. The fluo-
roalkene moiety possesses steric and electronic similarities with
* Corresponding author. Tel.: þ33 2 35 52 29 20; fax: þ33 2 35 52 29 59; e-mail
Fig. 1. AA-Pro isomers and fluorinated pseudodipeptide Fmoc-AA-J[(Z) and (E)-CF]
C]Pro analogues.
address: xavier.pannecoucke@insa-rouen.fr (X. Pannecoucke).
http://dx.doi.org/10.1016/j.tet.2015.06.093
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
7055
now report an improved synthetic sequence that allows for a wide
range of AA- [(Z) and (E)-CF]CH]-Pro pseudodipeptides. To fur-
ther illustrate the generality of the method in the construction of
non-peptidic molecules, we prepared an Enalapril analogue as
potential inhibitor of angiotensin-converting enzyme.
tert-butanesulfinamides for the straightforward preparation of b-
J
fluoroenimines 6 according to the well-established Ellman’s pro-
cedure (step h). The separation of the diastereomers of 3 and 4 was
difficult; however, the separation by chromatography was easier for
b-fluoroenimines 6. All the next steps could thus be realized on
each pure diastereoisomers. The relative configurations of the a,b-
unsaturated imine compounds 6 were easily determined by NOESY
NMR experiments. With the key intermediate fluoroenimines 6 in
hand, we added organometallic species (Grignard reagents or zin-
cate complexes) (step i), in order to get a diastereocontrol towards S
configuration of the newly created stereogenic centers at the N-
terminal side (as in the native peptide) (Table 1). Indeed, as pre-
viously reported in the literature,13,14 the efficiency of the organo-
metallic addition depends of the R group added to the chiral imine
and a reversal of the main diastereoisomer could be obtained
depending on the choice of the organometallic species. That is why
we proceeded with two methods because the stereoselectivity can
be planned by the choice of the appropriate couple organometallic
species/chiral auxiliaries. So in order to get the S configuration of
the chiral center at the N-terminal side, we used (R)-tert-butane-
sulfinamide with Grignard reagents and (S)-tert-butanesulfinamide
with zincate complexes.
2. Results and discussion
The synthetic sequence toward the target AA-J[CF]C]-Pro is
presented in Scheme 1. Compounds (E)-10 and (Z)-10 were Fmoc
protected at the N-terminal side of the dipeptide for direct use in
solid phase peptide synthesis. The sequence began with the
asymmetric installation of the stereogenic center at the C-terminal
side by a microorganism-driven dynamic kinetic resolution of the
b
-ketoester ethyl 2-oxocyclopentanecarboxylate 1 as described by
Buisson and Azerad (step a).10 The major cis (1R,2S)-
b-hydroxy ester
was obtained optically enriched (ee>95%) after separation by flash
chromatography (cis/trans ratio>9:1). Next, the ester moiety was
reduced (step b), the primary alcohol protected by a bulky silyl
group (step c), and the secondary alcohol oxidized (step d) to give 2.
At this stage, the fluoroolefination was investigated to install the
peptide bond mimic. Unfortunately, the laboratory conditions
In a first series of experiments, we conducted 1,2-additions of
Grignard reagents to imines 6 (RS) bearing the (R)-tert-butylsulfi-
namide auxiliary,15 E and Z diastereomers, independently (Table 1,
established for the synthesis of a-fluoro-a,b-unsaturated esters (a-
fluoroacrylates) from aldehydes or ketones with ethyl-
dibromofluoroacetate in presence of triphenylphosphine and
diethylzinc in dry THF failed in this case.11 Fortunately, a Hor-
nereWadswortheEmmons reaction was successful with ketone 2
entries 1e4). Precursors of pseudopeptides Ala-
CH]-Pro 7a were obtained in moderate yields and good diaster-
eoselectivities (Table 1, entries 1, 2) whereas only Ser- [(Z)-CF]
CH]-Pro (Z)-7b could be obtained (Table 1, entry 4). The synthesis of
the pseudodipeptide Ser- [CF]C]-Pro was achieved by the addi-
J[(Z) and (E)-CF]
J
and triethyl 2-fluoro-2-phosphonoacetate, affording
a nearly
enantiopure diastereomeric mixture of compounds 3 (step e).12
These esters 3 were reduced into the corresponding allylic alco-
hols 4 (step f), which were next submitted to the oxidation using
IBX (step g) in good yields and without epimerization. The in-
termediate aldehydes 5 were then reacted with either (R) or (S)-(ꢀ)
J
tion of a magnesium carbenoid prepared in situ from the corre-
sponding iodomethyl carboxylate with i-PrMgCl in THF/1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (5:1) at
Scheme 1. Synthesis of AA-
J
[CF]C]Pro pseudodipeptides.

7056
E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
Table 1
We have enlarged the scope of the asymmetric synthesis of
various AA- [(Z) and (E)-CF]CH]-Pro pseudodipeptides. These
Diastereoselective additions of Grignarda and organozincate reagentsb
J
Entry Substrate RM
Product Target
mimic
Yield d.r.d
(%)c
dipeptides are ready-to-use for solid-phase peptide synthesis and
could have applications in structural study of peptides or protein as
well as therapeutic agents. In addition, our synthetic methodology
was extended to non-peptidic molecules as demonstrated in the
design and synthesis of an Enalapril analogue (Fig. 3).24
1
2
3
4
5
6
7
8
(E)-6 (RS) MeMgBr
(Z)-6 (RS) MeMgBr
(E)-7a
(Z)-7a
(E)-7b
(Z)-7b
(E)-7c
(Z)-7c
(E)-7d
(Z)-7d
Ala-Pro
Ala-Pro
Ser-Pro
Ser-Pro
Leu-Pro
Leu-Pro
Val-Pro
Val-Pro
Phe-Pro
Phe-Pro
59
73
0
39
45
84
90
66
44
54
91:9
88:12
d
(E)-6 (RS) pivOCH2MgCl
(Z)-6 (RS) pivOCH2MgCl
(E)-6 (SS) i-BuMgBrþZnMe2
(Z)-6 (SS) i-BuMgBrþZnMe2
(E)-6 (SS) i-PrMgClþZnMe2
(Z)-6 (SS) i-PrMgClþZnMe2
33:67
92:8
99:1
96:4
92:8
95:5
93:7
65:35
85:15
9
(E)-6 (SS) PhCH2MgClþZnMe2 (E)-7e
(Z)-6 (SS) PhCH2MgClþZnMe2 (Z)-7e
10
11
12
(E)-6 (SS) vinylMgBrþZnMe2
(E)-7f
(Z)-7f
Thr-Proe 39
Thr-Proe 52
(Z)-6 (SS) vinylMgBrþZnMe2
a
Reaction conditions: Methyl Grignard reagent (3 equiv), toluene, 0 ꢁC or iodo-
methylpivalate, i-PrMgCl, ꢀ78 ꢁC, THF/DMPU (5:1), ꢀ78 to ꢀ50 ꢁC.
b
Reaction conditions: Grignard reagent (1.5 equiv)þZnMe2 (1.72 equiv), THF,
Fig. 3. Structure of Enalapril and fluoro analogue 12.
ꢀ78 ꢁC.
c
Yield of silica gel chromatographed analytically pure compounds.
Enalapril is an angiotensin-converting-enzyme inhibitor (or ACE
inhibitor) that is prescribed to reduce hypertension or to prevent
(or treat) heart failure.25 Some analogues of Enalapril have been
designed and synthesized. For example, Tinney et al. reported
a series of modified peptides in which various isosteric moieties (O,
S, SO, SO2) have been substituted for the amino group and in which
the proline residue has been replaced with various hydrophobic
amino acids.26 Greenlee et al. described analogues in which the
carbonyl of the scissile peptide bond was replaced by a CHCO2H
group; these inhibitors had inhibitory potency equal to that of the
parent compound.27 Bhagwat et al. synthesized dual inhibitors of
ACE and neutral endopeptidase (NEP) by incorporating a thiorphan
d
Diastereomeric ratios were determined by 19F NMR of the crude reaction
mixtures.
e
After hydration of the vinyl function.
ꢀ78 ꢁC.16 Separation of diastereomers by silica gel chromatography
provided enantiopure intermediates 7a and 7b for use in the next
synthetic steps.
Under these conditions that combine the (R)-tert-butylsulfina-
mide auxiliary and the use of a Grignard reagent, as previously
observed,13 we obtained the desired stereogenic center of (S) con-
figuration at the N-terminal side of 7a, identical to the configura-
tion of the corresponding natural dipeptide. The absolute
configuration of the new stereogenic center was ascribed by X-ray
crystallography of compound (E)-9a (Fig. 2).9,17 In the case of
compound 7b featuring a methylpivalate moiety, the presence of
the chelating carboxyl group clearly modifies the transition-state
intermediate and is responsible for the reversal of diastereo
selection.
unit at the b
-position of the proline ring of Enalapril.28 In order to
synthesize a fluoro analogue of Enalapril featuring the fluoroolefin
moiety in place of the amide bond between the Ala and Pro AAs, we
started from (Z)-10a, which was first deprotected to give (Z)-11 and
then directly submitted without purification to a reductive ami-
nation with ethyl 2-oxo-4-phenylbutanoate in the presence of hy-
drogen and palladium on carbon. Compound 12 was obtained as
a 9:1 mixture of diastereoisomers that were separated by pre-
parative HPLC (Scheme 2).
Fig. 2. X-ray structure of Fmoc-Ala-J[(E)-CF]CH]-Pro 9a.
The zincate complexes were generated from the Grignard in
presence of dimethylzinc and were reacted with the imines 6 at low
temperature in THF.14,18 The formed triorganozincate species
proved to be more reactive than Grignard species and less prone to
the
b
-hydride-transfer side-reaction.19e21 Reaction yields are
moderate to high and, in most cases, the diastereomeric ratios were
excellent except for the addition of the vinylzincate which only led
to moderate d.r. values (Table 1, entries 5e12). The synthetic se-
quence was continued with 7a and 7d by removal of the chiral
auxiliary and concomitant deprotection of the primary alcohol
under these acid conditions (step j), affording aminoalcohol 8. The
next step was the Fmoc protection of the primary amine (step k) to
get N-protected aminoalcohol 9. Finally, oxidation of the primary
alcohol function into a carboxylic acid22 allowed to get the target
pseudodipeptides 10 (step l). This last functional group in-
terconversion was carried out with Jones reagent to prepare both
Scheme 2. Synthesis of 12, a fluoro analogue of Enalapril.
3. Conclusion
We have described an optimized process toward the synthesis of
(E) and (Z) diastereoisomers of Val-
J
[CF]CH]-Pro 10d; however,
AA-
roalkene moiety that act as an amide bond surrogate. The new
route starting from -fluoroacrylates is amenable to wider
J[(Z) and (E)-CF]CH]-Pro pseudodipeptides featuring a fluo-
we could only obtain the Ala-J[(Z)-CF]CH]-Pro 10a, its (E) isomer
giving a messy reaction.23
a

E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
7057
structural modifications compared to our previous synthetic se-
quence. Overall, we could control the two stereogenic centers at the
C- and N-terminals with a definite geometry of the fluoroalkene.
The methodology was extended to a non-peptidic molecule as
demonstrated in the design and synthesis of an Enalapril analogue.
(CH2(Z)), 60.7 (CH2), 45.7 (CH(E)), 44.3 (CH(Z)), 31.0 (CH2(E)), 30.2
(CH2(E)), 29.7 (CH2(E)), 28.6 (CH2(Z)), 26.7 (CH3), 24.6 (CH2(E)), 22.7
(CH2(Z)), 19.1 (C), 14.0 (CH3) ppm MS (ESIþ): [MþH]þ¼441.07. Ele-
mental analysis for C26H33FOSi: calcd: C: 70.87; H: 7.55. Found: C:
70.82; H: 7.69.
4. Experimental section
4.1. General information
4.3. (R)-2-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopent-
ylidene)-2-fluoroethanol (4)
To a mixture of diastereomers (Z)-3 and (E)-3: 52/48 (288 mg,
0.65 mmol, 1 equiv) in dry THF (11 mL) at 0 ꢁC was added LiBH4
(100 mg, 4.55 mmol, 7 equiv). The reaction mixture was stirred for
20 min at 0 ꢁC and overnight at room temperature. The reaction
mixture was quenched carefully with a saturated aqueous solution
of NH4Cl and extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, filtered, and con-
centred under reduced pressure. The crude mixture was purified by
chromatography on silica gel (cyclohexane/EtOAc: 94/6) to afford
(E)-4 as a colorless oil (115.8 mg, 45%) and (Z)-4 as a colorless oil
(104.4 mg, 40%).
Experiments involving organometallics were carried out under
argon atmosphere. All moisture-sensitive reactants were handled
under argon atmosphere. Low temperature experiments were
carried out by cooling down the flasks with an acetone-dry ice bath.
All commercial solvents were distilled before use: THF was distilled
over sodium and benzophenone under nitrogen atmosphere, tol-
uene over sodium and DCM over CaH2. TLC were performed on
Merck 60F-250 silica gel plates, using UV light as a visualizing agent
and ethanolic solution of phosphomolybdic acid and heat as de-
veloping agents. Flash column chromatography purifications were
carried out using silica gel columns (particle size: 0.040e0.063 mm
(E)-4: Rf¼0.52 (cyclohexane/EtOAc: 9/1). IR (neat):
2958, 2925, 2846, 1717, 1427, 1390, 1251, 1111, 1080, 1007, 915, 823,
734, 703, 611 cmꢀ1. 1H NMR (300 MHz, CDCl3):
7.66e7.63 (m, 4H),
n 3407, 3065,
or 0.063e0.20 mm) or automatically on an SP1 Biotage. 1H NMR, 13
C
NMR and 19F NMR (CFCl3 as internal reference) were recorded at
300, 75.4, and 282.5 MHz, respectively on a Bruker DXP 300. COSY
and NOESY experiments were recorded at 300 MHz on a Bruker
DXP 300. Abbreviations used for peak multiplicity are s: singlet, d:
doublet, t: triplet, q: quadruplet, m: multiplet. J was used to in-
dicate coupling constants in Hertz. Optical rotations were mea-
d
7.47e7.37 (m, 6H), 4.14e3.94 (m, 2H), 3.51e3.45 (m, 1H), 3.39e3.34
(m, 1H), 2.91 (m, 1H), 2.47e2.23 (m, 2H), 1.76e1.49 (m, 5H), 1.06 (s,
9H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ115.0 (t, 3J¼19.8 Hz) ppm
13C NMR (75.4 MHz, CDCl3):
d
152.3 (d, C, 1J¼245.6 Hz), 135.6 (CH),
133.2 (CH), 129.8 (CH), 127.8 (CH), 122.9 (d, C, 2J¼16.3 Hz), 66.3
(CH2), 59.4 (d, CH2, 2J¼32.4 Hz), 42.69 (d, CH, 3J¼4.9 Hz), 29.7 (CH2),
28.6 (CH3), 27.0 (C), 23.2 (CH2), 19.2 (CH2) ppm MS (ESIþ):
sured on a PerkineElmer 341 polarimeter (
l
¼589 nm, 20 ꢁC,
concentrations used in cg.mLꢀ1). IR spectra were recorded on
a PerkineElmer 500 FT-IR spectrometer. Absorption bands are re-
ported in cmꢀ1. Electrospray ionization (ESI) mass spectrometry
(MS) experiments were performed on a Bruker-Esquire mass
spectrometer. Elemental analyses were performed on a CE In-
struments EA 110 CHNSeO. Compound 2 was synthesized accord-
ing to reported experimental procedure.9
[2MþNa]þ¼818.67. Elemental analysis for C24H31FNO2Si: calcd: C:
20
72.32; H: 7.84. Found: C: 72.25; H: 7.90. [
a
]
¼ꢀ26.4 (c 0.50, CHCl3).
D
(Z)-4: Rf¼0.42 (cyclohexane/EtOAc: 9/1). IR (neat):
n 3362, 3071,
2953, 2930, 2863, 2358, 1712, 1471, 1427, 1393, 1248, 1142, 1116,
1013, 935, 820, 740, 703, 614, 620 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
7.68e7.66 (m, 4H), 7.43e7.36 (m, 6H), 4.12 (dd, 2H, 2J¼3.0 Hz,
3J¼24.0 Hz), 3.85e3.80 (m, 1H), 3.57e3.51 (m, 1H), 3.07 (m, 1H),
4.2. (R)-Ethyl-2-(2-((tert-butyldiphenylsilyloxy)methyl)cyclo-
pentylidene)-2-fluoroacetate (3)
2.29e2.24 (m, 2H), 1.96e1.60 (m, 5H, OH), 1.06 (s, 9H) ppm 19F NMR
(282.5 MHz, CDCl3):
(75.4 MHz, CDCl3):
d
ꢀ120.2 (t, 3J¼19.8 Hz) ppm 13C NMR
d
151.3 (d, C, 1J¼245.6 Hz),135.6 (CH),133.9 (CH),
To a stirred suspension of sodium hydride (144 mg, 6 mmol,
1.5 equiv) in freshly distilled THF (43 mL) at ꢀ30 ꢁC was added
dropwise ethyl(diethylphosphono) (fluoro)acetate (1.2 mL, 6 mmol,
1.5 equiv). The yellowish suspension was then stirred for 30 min
until hydrogen evolution stopped. A solution of 2 (1.41 g, 4 mmol,
1 equiv) in 10 mL of distilled THF was added dropwise. The cooling
bath was removed and the mixture was stirred for an additional
1.5 h. The reaction mixture was quenched with a saturated aqueous
solution of NH4Cl. The aqueous layer was extracted with EtOAc, and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentred under reduced pressure. The crude
mixture was purified by chromatography on silica gel (cyclohex-
ane/EtOAc: 94/6) to afford a 52:48 mixture of (Z) and (E) isomers as
a colorless oil (1.46 g, 83%). Rf(E)¼0.54, Rf(Z)¼0.50 (cyclohexane/
129.8 (CH), 127.8 (CH), 123.2 (d, C, 2J¼14.8 Hz), 64.5 (CH2), 59.6 (d,
CH2, 2J¼30.5 Hz), 43.2 (CH), 29.7 (CH2), 28.5 (CH3), 27.0 (C), 24.8
(CH2), 19.2 (CH2) ppm MS (ESIþ): [2MþNa]þ¼818.67. Elemental
analysis for C24H31FNO2Si: calcd: C: 72.32; H: 7.84. Found: C: 71.97;
20
H: 7.75. [
a
]
¼ꢀ25.7 (c 0.75, CHCl3).
D
4.4. (R)-2-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopent-
ylidene)-2-fluoroacetaldehyde (5)
To a diastereomeric mixture of (Z)-4 and (E)-4 (61 mg,
0.14 mmol, 1 equiv) in dry EtOAc (2 mL) was added IBX (118 mg,
0.42 mmol, 3 equiv). The reaction mixture was heated at reflux for
3 h, filtered through a pad of Celite and then concentrated under
reduced pressure to afford a mixture of diastereomeric aldehydes
as a yellow oil (34 mg, 62%). Rf(E)¼0.43, Rf(Z)¼0.28 (cyclohexane/
EtOAc: 94/06). IR (neat):
n 3470, 2944, 1732, 1372, 1297, 1092, 704,
506 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d
7.75e7.63 (m, 4H),
EtOAc: 94/6). IR (neat): n 3069, 2954, 2937, 2856, 1691, 1478, 1426,
7.44e7.35 (m, 6H), 4.31e4.24 (q, 1H(Z)
,
3J¼6.9 Hz), 4.20e4.13 (dq,
1266, 1111, 1076, 1001, 817, 697, 605 cmꢀ1 1H NMR (300 MHz,
.
1H(E)
,
3J¼7.2 Hz), 3.84e3.70 (m, 1H(E)), 3.62e3.47 (m, 1.5H),
CDCl3):
d
9.49 (d, 0.42H(Z)
,
3J¼18.0 Hz), 9.38 (d, 0.58H(E)
,
3.25e3.17 (m, 0.5H(Z)), 2.74e2.67 (m, 1H(Z)), 2.57e2.51 (m, 1H(E)),
2.22e2.13 (m, 0.5H(E)), 2.06e1.96 (m, 0.5H(Z)), 1.86e1.66 (m, 3H),
1.31e1.35 (t, 1.5H(Z), 3J¼6.0 Hz), 1.26e1.22 (t, 1.5H(E), 3J¼6.0 Hz), 1.06
3J¼18.0 Hz), 7.70e7.60 (m, 4H), 7.47e7.37 (m, 6H), 3.84e3.70 (m,
1H), 3.64e3.42 (m, 1H), 3.38e3.36 (m, 0.58H(E)), 3.25e3.21 (m,
0.42H(Z)), 2.85e2.66 (m, 1H), 2.61e2.56 (m, 1H), 2.00e1.59 (m, 4H),
(m, 9H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ122.9 (E), -127.4 (Z)
1.03 (s, 9H) ppm 19F NMR (282.5 MHz, CDCl3):
d
(E): ꢀ129.2 (d,
ppm 13C NMR (75.4 MHz, CDCl3):
d
161.0 (d, C(E), 2J¼34.7 Hz), 160.4
3J¼16.9 Hz), (Z): ꢀ133.2 (d, 3J¼14.1 Hz) ppm 13C NMR (75.4 MHz,
(d, C(Z)
,
2J¼34.7 Hz), 142.5 (d, C(E)
,
1J¼247.3 Hz), 142.4 (d, C(Z)
,
CDCl3):
d
182.5 (d, CHO(E)
,
2J¼7.7 Hz), 182.2 (d, CHO(Z)
,
2J¼3.6 Hz),
1J¼248.1 Hz), 141.4 (d, C(E)
,
2J¼46.7 Hz), 141.2 (d, C(Z)
,
2J¼46.0 Hz),
151.0 (d, C(E), 1J¼249.0 Hz), 149.8 (d, C(Z), 1J¼247.5 Hz) 147.3 (C(E)),
135.4 (CH), 133.4 (CH), 129.5 (CH), 127.5 (CH), 64.5 (CH2(E)), 63.7
147.1 (C(Z)), 135.5 (CH), 133.3 (C(Z)), 132.8 (C(E)), 129.8 (CH), 127.8

7058
E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
(CH), 65.5 (d, CH2(E)
,
4J¼3.8 Hz), 63.8 (d, CH2(Z)
,
4J¼4.4 Hz), 45.6
(SS) (118.3 mg, 37%) and (Z)-6 (SS) (84.9 mg, 27%) both as a yellow
oil.
(CH(Z)), 42.7 (CH(E)), 29.5 (C(E)), 28.3 (C(Z)), 26.8 (CH3), 25.1 (CH2),
22.3 (CH2), 19.2 (CH2) ppm MS (ESIþ): [MþH]þ¼397.20;
(E)-6 (SS): Rf¼0.68 (cyclohexane/EtOAc: 8/2). IR (neat):
n 2857,
[MþNa]þ¼419.27. Elemental analysis for C24H29FO2Si: calcd: C:
1579, 1472, 1427, 1359, 1105, 1084, 1005, 998, 821, 738, 700, 689,
20
72.69; H: 7.37. Found: C: 72.98; H: 7.24. [
a
]
¼ꢀ57.3 (c 0.36, CHCl3).
613 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
8.22 (d, 1H, 3J¼21 Hz),
D
7.75e7.72 (m, 4H), 7.45e7.37 (m, 6H), 3.62e3.59 (m, 1H), 3.53e3.47
(m, 1H), 3.30 (m, 1H), 2.62e2.58 (m, 2H), 1.83e1.63 (m, 4H), 1.15 (s,
4.5. N-(2-((R)-2-((tert-butyldiphenylsilyloxy)methyl)cyclo-
pentylidene)-2-fluoroethylidene)-2-methylpropane-2-
sulfinamide (6 (RS))
9H), 1.09 (s, 9H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ122.0 (d,
3J¼22.6 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 152.4 (d, C,
2J¼23.4 Hz), 149.1 (d, C, 1J¼243.5 Hz), 142.6 (d, C, 2J¼15.1 Hz), 134.8
(CH), 133.1 (CH), 129.5 (CH), 127.7 (CH), 65.9 (d, CH2, 4J¼3.8 Hz),
43.4 (d, CH, 3J¼3.0 Hz), 29.2 (d, CH2, 4J¼1.5 Hz), 26.8 (C), 26.3 (CH3),
22.8 (CH2), 22.7 (CH3), 21.5 (C), 19.0 (CH2) ppm MS (ESIþ):
[MþH]þ¼500.13; [MþNa]þ¼522.20. Elemental analysis for
To a diastereomeric mixture of aldehyde (E)-5 and (Z)-5 (1.92 g,
4.84 mmol, 1 equiv) in dry THF (77 mL) were added Ti(OEt)4
(2.54 mL, 12.10 mmol, 2.5 equiv) and (R)-tert-butanesulfinamide
(1.47 g, 12.10 mmol, 2.5 equiv). The reaction mixture was heated at
reflux for 2 h and once cooled, poured into an equal volume of brine
with rapid stirring. The resulting suspension was filtered through
a pad of Celite and the filter cake was washed with EtOAc. The brine
layer was extracted with EtOAc. The combined organic portions
were dried over MgSO4, filtered and concentrated under reduced
pressure. The crude mixture was purified by chromatography on
silica gel (cyclohexane/EtOAc: 8/2) to afford (E)-6 (RS) as a yellow
oil (873 mg, 36%) and (Z)-6 (RS) as a yellow oil (1.05 g, 43%).
C
28H38FNO2SSi: calcd: C: 67.29; H: 7.66. Found: C: 67.25; H: 7.62.
20
[a
]
¼þ50.0 (c 0.50, CHCl3).
D
(Z)-6 (SS): Rf¼0.53 (cyclohexane/EtOAc: 8/2). IR (neat):
n 2958,
2930, 2857, 1661, 1578, 1472, 1427, 1362, 1278, 1106, 1083, 998, 821,
739, 700, 613, 503, 487 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 8.18 (d,
1H, 3J¼18.0 Hz), 7.67e7.62 (m, 4H), 7.44e7.40 (m, 6H), 3.89e3.85
(m, 1H), 3.71e3.65 (m, 1H), 3.24e3.23 (m, 1H), 2.69e2.59 (m, 2H),
2.05e1.70 (m, 4H), 1.23 (s, 9H), 1.05 (s, 9H) ppm 19F NMR
(282.5 MHz, CDCl3):
(75.4 MHz, CDCl3):
d
ꢀ125.4 (d, 3J¼19.8 Hz) ppm 13C NMR
(E)-6 (RS): Rf¼0.57 (cyclohexane/EtOAc: 8/2). IR (neat):
n 3395,
d
152.7 (d, C, 2J¼22.6 Hz),148.9 (d, C,
3070, 2957, 2930, 2856, 1581, 1472, 1428, 1078, 1107, 856, 821, 699,
1J¼243.5 Hz), 142.2 (d, C, 2J¼13.6 Hz), 135.5 (CH), 133.4 (CH), 129.6
(CH), 127.6 (CH), 64.0 (d, CH2, 4J¼4.5 Hz), 45.3 (CH), 29.7 (CH3), 29.5
(CH2), 26.8 (C), 24.9 (CH2), 22.1 (CH3), 22.0 (C), 19.7 (CH2) ppm MS
606, 502, 488 cmꢀ1 1H NMR (300 MHz, CDCl3):
. d 8.32 (d, 1H,
3J¼21.0 Hz), 7.68e7.63 (m, 4H), 7.42e7.37 (m, 6H), 3.63e3.58 (m,
1H), 3.51e3.46 (m, 1H), 3.35e3.31 (m, 1H), 2.63e2.53 (m, 2H),
1.83e1.57 (m, 4H), 1.24 (s, 9H), 1.05 (s, 9H) ppm 19F NMR
(ESIþ): [MþH]þ¼500.00. Elemental analysis for C28H38FNO2SSi:
20
calcd: C: 67.29; H: 7.66. Found: C: 67.24; H: 7.67. [
0.50, CHCl3).
a]
¼þ47.0 (c
D
(282.5 MHz, CDCl3):
(75.4 MHz, CDCl3):
d
ꢀ122.3 (d, 3J¼19.8 Hz) ppm 13C NMR
d
152.9 (d, C, 2J¼21.1 Hz), 149.6 (d, C,
1J¼243.5 Hz), 142.0 (d, C, 2J¼15.1 Hz), 135.4 (CH), 132.7 (CH), 129.5
(CH), 127.6 (CH), 65.4 (d, CH2, 4J¼3.8 Hz), 43.0 (CH), 29.2 (CH2), 28.6
(CH2), 26.7 (CH3), 22.6 (CH2), 22.7 (CH3), 22.3 (C), 18.8 (C) ppm MS
4.7. General procedure for the diastereocontrolled addition of
Grignard reagents to (R) or (S)-chiral N-(tert-butanesulfinyl)-
a-fluoroenimines 6
(ESIþ): [MþH]þ¼500.00. Elemental analysis for C28H38FNO2SSi:
20
calcd: C: 67.29; H: 7.66. Found: C: 67.25; H: 7.62. [
1.48, CHCl3).
a
]
¼ꢀ187.7 (c
D
To a solution of
b
-fluoroenimine 6 (1 equiv) in anhydrous tol-
uene (0.02 M) at 0 ꢁC under argon was slowly added the Grignard
reagent (3 equiv). The reaction mixture was stirred until the re-
action was completed as determined by TLC and then quenched
with a saturated aqueous solution of NH4Cl. The solution was
warmed to room temperature and the product was extracted with
EtOAc. The combined organic layers were washed with brine, dried
over Na2SO4, filtered and concentrated under reduced pressure.
The residue was checked by 19F NMR to determine the di-
astereomeric ratio (d.r.) and purified by chromatography on silica
gel.
(Z)-6 (RS): Rf¼0.43 (cyclohexane/EtOAc: 8/2). IR (neat):
n 3071,
2958, 2930, 2857, 1578, 1473, 1428, 1164, 1105, 1083, 818, 739, 700,
613, 503, 488 cmꢀ1 1H NMR (300 MHz, CDCl3):
. d 8.24 (d, 1H,
3J¼21 Hz), 7.68e7.63 (m, 4H), 7.46e7.35 (m, 6H), 3.84e3.72 (m, 2H),
3.26e3.23 (m, 1H), 2.69e2.62 (m, 2H), 1.97e1.87 (m, 4H), 1.23 (s,
9H), 1.04 (s, 9H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ126.2 (d,
3J¼19.8 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 152.6 (d, C,
2J¼22.6 Hz), 148.8 (d, C, 1J¼243.5 Hz), 142.2 (d, C, 2J¼13.6 Hz), 135.4
(CH),132.7 (CH),129.5 (CH),127.5 (CH), 64.0 (d, CH2, 4J¼4.5 Hz), 57.6
(CH2), 45.0 (CH), 28.9 (CH2), 26.6 (CH3), 24.8 (CH2), 22.3 (CH3), 22.3
(C), 19.1 (C) ppm MS (ESIþ): [MþNa]þ¼522.20. Elemental analysis
4.7.1. N-((S, E)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoropropan-2-yl)-2-methylpropane-2-sulfinamide
for C28H38FNO2SSi: calcd: C: 67.29; H: 7.66. Found: C: 67.32; H: 7.69.
20
[
a]
¼ꢀ153.3 (c 1.14, CHCl3).
D
((E)-7a). Yellow oil. Rf¼0.36 (cyclohexane/EtOAc: 7/3). IR (neat):
3070, 2931, 2859, 1428, 1365, 1106, 1072, 823, 737, 701, 611 cmꢀ1. 1H
NMR (300 MHz, CDCl3): 7.73e7.66 (m, 4H), 7.45e7.35 (m, 6H),
n
4.6. N-(2-((S)-2-((tert-butyldiphenylsilyloxy)methyl)cyclo-
pentylidene)-2-fluoroethylidene)-2-methylpropane-2-
sulfinamide (6 (SS))
d
3.81e3.62 (m, 1H), 3.60e3.48 (m, 1H), 3.39e3.32 (m, 1H), 3.15 (d,
1H, 3J¼8.7 Hz), 2.73e2.69 (m, 1H), 2.27e2.16 (m, 2H), 1.72e1.52 (m,
3
4H), 1.35 (d, 3H, J¼6.6 Hz), 1.03 (s, 9H), 0.92 (s, 9H) ppm 19F NMR
To a diastereomeric mixture of aldehyde (E)-5 and (Z)-5
(251 mg, 0.63 mmol, 1 equiv) in dry THF (10 mL) were added
Ti(OEt)4 (0.33 mL, 1.58 mmol, 2.5 equiv) and (S)-tert-butanesulfi-
namide (192 mg, 1.58 mmol, 2.5 equiv). The reaction mixture was
heated at reflux for 2 h and once cooled, poured into an equal
volume of brine with rapid stirring. The resulting suspension was
filtered through a pad of Celite and the filter cake was washed with
EtOAc. The brine layer was extracted with EtOAc. The combined
organic portions were dried over MgSO4, filtered and concentrated
under reduced pressure. The crude mixture was purified by chro-
matography on silica gel (cyclohexane/EtOAc: 8/2) to afford (E)-6
(282.5 MHz, CDCl3):
d
ꢀ125.3 (d, 3J¼28.8 Hz) ppm 13C NMR
(75.4 MHz, CDCl3):
d
152.9 (d, C, 1J¼248.3 Hz), 135.6 (CH), 133.7
(CH), 129.8 (CH), 127.7 (CH), 119.4 (d, C, 2J¼16.4 Hz), 64.5 (d, CH2,
4J¼4.7 Hz), 55.7 (C), 52.1 (d, CH, 2J¼27.3 Hz), 42.9 (d, CH,
3J¼14.2 Hz), 29.3 (CH2), 27.2 (d, CH2, 4J¼3.2 Hz), 26.8 (CH3), 22.8
(CH2), 22.5 (CH3), 20.9 (CH3), 19.9 (C) ppm MS (ESIþ):
[MþH]þ¼516.00; [MþNa]þ¼538.27. [
a
]
¼ꢀ7.3 (c 0.60, CHCl3).
20
D
4.7.2. N-((S, Z)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoropropan-2-yl)-2-methylpropane-2-sulfinamide
((Z)-7a). Yellow oil. Rf¼0.32 (cyclohexane/EtOAc: 7/3). IR (neat):
n

E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
7059
3068, 2962, 2927, 2861, 1711, 1468, 1433, 1367, 1246, 1165, 1104,
1048, 820, 740, 694, 507, 400 cmꢀ1. 1H NMR (300 MHz, CDCl3):
Elemental analysis for C32H48FNO2SSi: calcd: C: 68.89; H: 8.67; N:
20
2.51; S: 5.75 Found: C: 68.47; H: 8.54; N: 2.04; S: 5.06. [
(c 0.69, CHCl3).
a
]
D
¼þ36.1.
d
7.65 (m, 4H), 7.44e7.35 (m, 6H), 4.23e4.09 (m, 1H), 3.85e3.80 (m,
1H), 3.53e3.46 (m, 1H), 3.28 (d, 1H, 3J¼5.1 Hz), 3.03e3.02 (m, 1H),
2.37e2.19 (m, 2H), 1.93e1.82 (m, 4H), 1.32 (d, 3H, 3J¼6.9 Hz), 1.03 (s,
4.8.2. N-((S, Z)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoro-4-methylpentan-2-yl)-2-methylpropane-2-
sulfinamide ((Z)-7c). Colorless oil. Rf¼0.50 (cyclohexane/EtOAc: 7/
9H), 0.92 (s, 9H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ127.9 (d,
3J¼28.3 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 151.1 (d, C,
1J¼250.0 Hz), 135.6 (CH), 133.8 (CH), 129.5 (CH), 127.5 (CH), 122.1 (d,
C, 2J¼14.4 Hz), 64.5 (d, CH2, 4J¼3.6 Hz), 55.6 (C), 50.2 (d, CH,
2J¼27.1 Hz), 43.1 (CH2), 29.6 (d, CH2, 3J¼19.7 Hz), 28.6 (d, CH2,
4J¼5.0 Hz), 26.9 (CH3), 24.9 (CH2), 22.4 (CH3), 19.6 (CH3), 19.3 (C)
ppm MS (ESIþ): [MþH]þ¼516.00; [MþNa]þ¼538.33. Elemental
3). IR (neat): n 2956, 2931, 2858, 1468, 1429, 1365, 1107, 1072, 1007,
823, 739, 700, 612 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.60e7.57 (m,
4H), 7.32e7.30 (m, 6H), 4.06e3.83 (m, 1H), 3.67e3.62 (m, 1H),
3.57e3.50 (m, 1H), 3.32 (d, 1H, 3J¼9.0 Hz), 2.98e3.02 (m, 1H),
2.46e2.36 (m, 1H), 2.19e2.14 (m, 1H), 1.80e1.38 (m, 6H), 1.19e1.13
(m, 10H), 0.96 (s, 9H), 0.81e0.76 (m, 6H) ppm 19F NMR (282.5 MHz,
analysis for C29H42FNO2SSi: calcd: C: 67.53; H: 8.21. Found: C:
20
67.21; H: 8.20. [
a]
¼ꢀ0.30 (c 0.50, CHCl3).
CDCl3):
d
d
ꢀ130.6 (d, 3J¼28.2 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
D
152.3 (d, C, 1J¼248.8 Hz), 135.6 (CH), 133.8 (CH), 129.5 (CH), 127.6
4.7.3. (2R,
Z)-3-(R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
(CH), 121.0 (d, C, 2J¼15.1 Hz), 64.6 (d, CH2, 4J¼3.8 Hz), 50.8 (d, CH,
2J¼27.9 Hz), 43.2 (d, CH, 3J¼3.0 Hz), 42.2 (CH), 29.3 (CH2), 28.7
(CH2), 28.8 (CH2), 28.6 (CH3), 24.9 (CH2), 22.5 (CH3), 22.4 (C), 19.3
(CH3), 19.0 (C) ppm MS (ESIþ): [MþNa]þ¼580.27. Elemental anal-
p e n t y l i d e n e ) - 2 - ( 1,1 - d i m e t h y l e t h y l s u l fi n a m i d o ) - 3 -
fluoropropylpivalate ((Z)-7b). Colorless oil. Rf¼0.55 (cyclohexane/
EtOAc: 7/3). IR (neat):
n 2958, 2859, 1732, 1468, 1425, 1365, 1149,
1106, 1074, 822, 738, 700, 614 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
ysis for C32H48FNO2SSi: calcd: C: 68.89; H: 8.67; N: 2.51; S: 5.75.
20
d
7.60e7.58 (m, 4H), 7.36e7.28 (m, 6H), 4.30e4.14 (m, 1H),
Found: C: 68.77; H: 8.81; N: 2.54; S: 5.31. [
CHCl3).
a]
¼þ38.9 (c 0.9,
D
4.06e4.05 (m, 2H), 3.81e3.76 (m, 1H), 3.42e3.36 (m, 2H), 2.96 (m,
1H), 2.36e2.12 (m, 2H), 1.88e1.55 (m, 4H), 1.10 (s, 9H), 1.09 (s, 9H),
0.98 (s, 9H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ127.1 (d,
4.8.3. N-((S, E)-1-(R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoro-3-methylbutan-2-yl)-2-methylpropane-2-
sulfinamide ((E)-7d). Colorless oil. Rf¼0.37 (cyclohexane/EtOAc: 8/
3J¼25.4 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 178.1 (C), 149.2 (d, C,
1J¼248.1 Hz),135.6 (CH), 133.9 (CH), 129.5 (CH), 127.6 (CH), 123.9 (d,
C, 2J¼13.6 Hz), 63.9 (d, CH2, 4J¼24.1 Hz), 56.3 (C), 53.5 (d, CH,
2J¼27.1 Hz), 50.9 (CH2), 43.8 (CH), 38.7 (C), 29.6 (CH2), 28.4 (CH2),
27.1 (CH3), 26.9 (CH3), 24.3 (CH2), 22.5 (CH3), 19.3 (C) ppm MS
(ESIþ): [MþNa]þ¼638.40. Elemental analysis for C34H50FNO4SSi:
2). IR (neat): n 2957, 2929, 1472, 1427, 1111, 1073, 998, 822, 739, 700,
612 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.72e7.60 (m, 4H), 7.41e7.35
(m, 6H), 3.89e3.84 (m, 1H), 3.56e3.49 (m, 1H), 3.28 (d, NH,
3J¼9.0 Hz), 3.18e3.10 (m, 1H), 2.69e2.60 (m, 1H), 2.36e2.23 (m,
2H), 2.19e2.11 (m, 1H), 1.76e1.55 (m, 4H), 1.07 (s, 9H), 1.05 (s, 9H),
0.91 (d, 3H, 3J¼6.0 Hz), 0.80 (d, 3H, 3J¼6.0 Hz) ppm 19F NMR
calcd: C: 66.30; H: 8.18; N: 2.27; S: 5.21. Found: C: 66.29; H: 8.02; N:
20
2.01; S: 4.85. [
a
]
¼ꢀ47.4 (c 1.00, CHCl3).
D
(282.5 MHz, CDCl3):
(75.4 MHz, CDCl3):
d
ꢀ122.4 (d, 3J¼30.7 Hz) ppm 13C NMR
4.8. General procedure for the diastereocontrolled addition
of organozincate reagents to (S) or (R)-chiral N-(tert-butane-
sulfinyl)-a-fluoroenimines 6
d
152.3 (d, C, 1J¼247.3 Hz), 135.6 (CH), 133.2
(CH), 133.9 (CH), 127.8 (CH), 121.6 (d, C, 2J¼16.6 Hz), 64.3 (d, CH2,
4J¼4.5 Hz), 62.2 (d, CH, 2J¼27.1 Hz), 56.2 (CH3), 43.3 (d, CH,
3J¼5.3 Hz), 32.0 (CH2), 29.8 (CH2), 29.3 (CH), 27.1 (CH3), 26.5 (C),
26.7 (CH2), 22.5 (CH3), 19.4 (CH3) ppm MS (ESIþ): [MþH]þ¼544.85;
[MþNa]þ¼566.40. Elemental analysis for C31H46FNO2SSi: calcd: C:
To a solution of Grignard reagent (1.5 equiv) in dry THF (0.02 M)
was added under argon at room temperature Me2Zn (1.72 equiv)
and the mixture was stirred for 15 min. The resulting organozincate
solution was then transferred dropwise with a syringe to a solution
68.46; H: 8.53; N: 2.58; S: 5.90 Found: C: 68.24; H:8.47; N: 2.57; S:
20
5.44. [
a
]
¼þ35.5 (c 0.55, CHCl3).
D
of a
b-fluoroenimine (Z)-6 or (E)-6 in dry THF under argon at
ꢀ78 ꢁC. The reaction mixture was stirred until the reaction was
completed as determined by TLC then quenched with a saturated
aqueous solution of NH4Cl. The solution was warmed to room
temperature and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was checked by 19F NMR to determine the diastereomeric
ratio (d.r.) and purified by chromatography on silica gel.
4.8.4. N-((S, Z)-1-(R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoro-3-methylbutan-2-yl)-2-methylpropane-2-
sulfinamide ((Z)-7d). Colorless oil. Rf¼0.50 (cyclohexane/EtOAc: 7/
3). IR (neat): n 2957, 1740, 1428, 1105, 1076, 1008, 822, 739, 700, 613,
503, 489, 444, 427 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.68e7.65 (m,
4H), 7.41e7.35 (m, 6H), 3.80e3.76 (m, 1H), 3.62e3.56 (m, 1H),
3.51e3.48 (m, 1H), 3.49e3.47 (m, 1H), 3.15e3.12 (m, 1H), 2.50e2.40
(m, 2H), 2.27e2.19 (m, 1H), 1.73e1.64 (m, 4H), 1.22 (s, 9H), 1.04 (s,
9H), 0.98 (d, 3H, 3J¼6.0 Hz), 0.86 (d, 3H, 3J¼6.0 Hz) ppm 19F NMR
4.8.1. N-((S, E)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoro-4-methylpentan-2-yl)-2-methylpropane-2-
sulfinamide ((E)-7c). Colorless oil. Rf¼0.39 (cyclohexane/EtOAc: 7/
(282.5 MHz, CDCl3):
(75.4 MHz, CDCl3):
d
ꢀ127.5 (d, 3J¼27.8 Hz) ppm 13C NMR
d
151.1 (d, C, 1J¼247.2 Hz), 135.6 (CH), 133.2 (CH),
129.8 (CH), 127.8 (CH), 122.1 (d, C, 2J¼14.8 Hz), 64.6 (d, CH2,
4J¼3.6 Hz), 62.4 (d, CH, 2J¼26.5 Hz), 56.4 (C), 43.5 (d, CH,
3J¼19.1 Hz), 31.2 (CH2), 29.6 (CH2), 28.8 (CH), 26.8 (CH3), 24.8 (CH2),
22.9 (CH3), 22.6 (C), 19.3 (CH3) ppm MS (ESIþ): [MþH]þ¼544.20;
[MþNa]þ¼566.27. Elemental analysis for C31H46FNO2SSi: calcd: C:
3). IR (neat):
n 2930, 2860, 1478, 1429, 1358, 1107, 1070, 1007, 998,
823, 738, 700, 690 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.72e7.68 (m,
4H), 7.46e7.37 (m, 6H), 3.81e3.76 (m, 1H), 3.65e3.62 (m, 1H),
3.57e3.49 (m, 1H), 3.13 (d, 1H, 3J¼9.0 Hz), 2.68e2.66 (m, 1H),
2.34e2.27 (m, 2H), 2.19e2.12 (m, 2H), 1.71e1.54 (m, 4H), 1.49 (d,1H,
68.46; H: 8.53; N: 2.58; S: 5.90 Found: C: 68.31; H: 8.46; N: 1.93; S:
3J¼6.0 Hz), 1.10 (s, 9H), 1.06 (s, 9H), 0.88 (d, 6H, 3J¼6.0 Hz) ppm 19
F
5.42. [
a
]
¼þ39.0 (c 0.50, CHCl3).
20
D
NMR (282.5 MHz, CDCl3):
d
ꢀ124.1 (d, 3J¼31.1 Hz) ppm 13C NMR
(75.4 MHz, CDCl3):
d
152.3 (d, C, 1J¼248.1 Hz), 135.6 (CH), 133.8
4.8.5. N-((S, E)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoro-3-phenylpropan-2-yl)-2-methylpropane-2-
sulfinamide ((E)-7e). Colorless oil. Rf¼0.36 (cyclohexane/EtOAc: 7/
(CH), 129.6 (CH), 127.7 (CH), 121.1 (d, C, 2J¼16.6 Hz), 64.6 (d, CH2,
4J¼4.5 Hz), 55.9 (C), 54.2 (d, C, 2J¼21.1 Hz), 43.3 (d, CH, 3J¼5.3 Hz),
42.6 (CH2), 29.3 (CH2), 27.2 (CH2), 27.0 (CH3), 24.8 (CH), 22.7 (CH2),
22.4 (CH3), 22.3 (CH3), 19.9 (C) ppm MS (ESIþ): [MþNa]þ¼580.27.
3). IR (neat):
n 2956, 2930, 2858, 1472, 1427, 1107, 1064, 822, 739,
700, 612, 503 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.58e7.55 (m, 4H),

7060
E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
7.35e7.25 (m, 7H), 7.18e7.13 (m, 3H), 7.02e6.99 (m, 1H), 3.79e3.71
(m, 1H), 3.65e3.60 (m, 1H), 3.37e3.29 (m, 1H), 3.23 (d, 1H,
3J¼9.0 Hz), 2.86e2.71 (m, 2H), 2.23e2.17 (m, 1H), 2.12e2.02 (m,
2H), 1.57e1.36 (m, 4H), 0.98 (s, 9H), 0.94 (s, 9H) ppm 19F NMR
68.27; H: 8.02; N: 2.65; S: 6.08. Found: C: 68.10; H: 7.97; N: 2.62; S:
20
5.99. [
a
]
D
¼þ24.4 (c 0.80, CHCl3).
4.9. Synthesis of Ala-
J
[CF]CH]-Pro (Z)-10a
(282.5 MHz, CDCl3):
NMR (75.4 MHz, CDCl3):
d
ꢀ124.5 (dd, 3J¼31.1 Hz, 4J¼2.8 Hz) ppm 13C
d
150.1 (d, C, 1J¼247.3 Hz), 137.0 (C), 135.6
4.9.1. (S, Z)-1-fluoro-1-(R)-2-(hydromethyl)cyclopentylidene)-propan-
2-aminium chloride ((Z)-8a). To a solution of (Z)-7a (323 mg,
0.63 mmol, 1 equiv) in 2.50 mL of dry CH3OH was added 4 M HCl in
1,4-dioxane (4 equiv). The mixture was stirred at room temperature
for 75 min and then concentrated under reduced pressure to dry-
ness. The residue was then washed with Et2O. The ether-unsoluble
residue was concentrated under reduced pressure to afford pure
(Z)-8 as a white solid (132 mg, quantitative). The product was used
(CH), 134.0 (C, 4J¼8.2 Hz), 129.5 (CH), 129.3 (CH), 128.1 (CH), 127.6
(CH), 126.5 (CH), 122.4 (d, C, 2J¼14.3 Hz), 64.2 (d, CH2, 4J¼3.8 Hz),
57.3 (d, CH, 2J¼26.4 Hz), 56.1 (CH), 39.8 (CH2), 29.7 (C), 29.1 (CH2),
28.0 (CH2), 26.8 (CH3), 24.1 (CH2), 22.5 (CH3), 22.3 (C) ppm MS
(ESIþ): [MþNa]þ¼614.33. Elemental analysis for C35H46FNO2SSi:
calcd: C: 71.02; H: 7.83; N: 2.37; S: 5.42. Found: C: 70.68; H: 7.90; N:
20
2.35; S: 5.39. [
a
]
¼þ20.36 (c 0.83, CHCl3).
D
without further purification in the next step: IR (neat):
n
3310, 2949,
.
4.8.6. N-((S, Z)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluoro-3-phenylpropan-2-yl)-2-methylpropane-2-
sulfinamide ((Z)-7e). Colorless oil. Rf¼0.46 (cyclohexane/EtOAc: 7/
2876, 1695, 1519, 1450, 1244, 1047, 1017, 738, 707 cmꢀ1 1H NMR
(300 MHz, D2O):
d
4.24 (dq,1H, 3J¼27.0 Hz, 3J¼6.6 Hz), 3.64e3.59 (m,
1H), 3.49e3.43 (m, 1H), 2.97 (bs, 1H), 2.29e2.25 (m, 2H), 1.79e1.55
(m, 4H), 1.39 (d, 3H, 3J¼9.0 Hz) ppm 19F NMR (282.5 MHz, D2O):
3). IR (neat):
1069, 822, 739, 699, 612 cmꢀ1
7.70e7.66 (m, 4H), 7.44e7.38 (m, 7H), 7.03e7.01 (m, 4H),
n 2957, 2930, 2855, 1472, 1428, 1386, 1365, 1236, 1106,
.
1H NMR (300 MHz, CDCl3):
d
ꢀ132.1 (d, 3J¼27.1 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 151.3 (d,
d
C, 1J¼245.0 Hz), 129.1 (d, C, 2J¼12.1 Hz), 66.1 (d, CH2, 4J¼4.5 Hz), 49.9
4.19e4.00 (m, 1H), 3.70e3.69 (m, 1H), 3.55e3.52 (m, 1H), 3.07 (d,
1H, 3J¼9.0 Hz), 2.95e2.91 (m, 1H), 2.82e2.74 (m, 1H), 2.25e2.14 (m,
1H), 1.80e1.38 (m, 6H), 1.16 (s, 9H), 1.06 (s, 9H) ppm 19F NMR
(d, CH, 2J¼28.6 Hz), 46.5 (CH), 32.3 (CH2), 31.5 (CH2), 27.9 (CH2), 19.2
(CH3) ppm Elemental analysis for C9H17ClFNO: C: 51.50; H: 8.17; O:
20
7.63. Found: C: 51.23; H: 8.04; O: 7.44. [
a
]
¼ꢀ39.7 (c 0.38, H2O).
D
(282.5 MHz, CDCl3):
(75.4 MHz, CDCl3):
d
ꢀ129.6 (d, 3J¼28.2 Hz) ppm 13C NMR
d
150.5 (d, C, 1J¼248.1 Hz), 137.2 (C), 135.6 (CH),
4.9.2. (9H-fluoren-9-yl)methyl (S, Z)-1-fluoro-1-((R)-2-(hydrox-
ymethyl)cyclopentylidene)propan-2-ylcarbamate ((Z)-9a). To a solu-
tion of (Z)-8a (160 mg, 0.770 mmol, 1 equiv) in 1,4-dioxane (3 mL)
and water (3 mL) was added NaHCO3 (195 mg, 2.320 mmol, 3 equiv)
at 0 ꢁC, followed by Fmoc-OSu (260 mg, 0.770 mmol, 1 equiv). The
reaction mixture was stirred at 0 ꢁC for 2 h and at room tempera-
ture overnight. The mixture was then poured into ice cold 1N HCl
(6.16 mL) and extracted with EtOAc (ꢂ3). The combined organic
layers were dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude mixture was purified by column
chromatography on silica gel (cyclohexane/EtOAc: 98/2 to 75/25) to
afford (Z)-9a (252.6 mg, 83%): Rf¼0.70 (cyclohexane/EtOAc: 1/1). IR
134.2 (C), 129.6 (CH), 129.4 (CH), 128.2 (CH), 127.6 (CH), 126.6 (CH),
122.5 (d, C, 2J¼15.8 Hz), 64.5 (d, CH2, 4J¼5.3 Hz), 57.6 (d, CH,
2J¼27.1 Hz), 42.3 (d, CH, 3J¼4.5 Hz), 40.1 (CH2), 29.0 (CH2), 27.0
(CH3), 26.9 (C), 22.7 (CH2), 22.4 (C), 22.3 (CH3), 19.3 (CH2) ppm MS
(ESIþ): [MþH]þ¼592.13. Elemental analysis for C35H46FNO2SSi:
calcd: C: 71.02; H: 7.83; N: 2.37; S: 5.42. Found: C: 70.91; H: 8.06; N:
20
2.22; S: 4.91. [
a
]
¼þ44.0 (c 0.60, CHCl3).
D
4.8.7. N-((S, E)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluorobut-3-en-2-yl)-2-methylpropane-2-sulfinamide
((E)-7f). Colorless oil. Rf¼0.50 (cyclohexane/EtOAc: 7/3). IR (neat):
n
2962, 2932, 2860, 1468, 1429, 1105, 1074, 998, 822, 739, 700, 689,
(neat): n 3306, 2945, 2872, 1695, 1508, 1449, 1243, 1051, 1022, 755,
612 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
7.70e7.67 (m, 4H),
738, 621 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.76 (d, 2H), 7.61 (d,
7.45e7.36 (m, 6H), 5.81e5.70 (m, 1H), 5.23e5.17 (m, 2H), 4.25e4.12
(m, 1H), 3.80e3.75 (m, 1H), 3.57e3.50 (m, 1H), 3.31e3.28 (d, 1H,
3J¼9.0 Hz), 2.75e2.71 (m, 1H), 2.38e2.30 (m, 2H), 1.68e1.56 (m,
2H), 7.45e7.29 (m, 4H), 5.21 (d, 1H, 3J¼6.0 Hz), 4.90e4.52 (m, 1H),
4.42e4.38 (m, 2H), 4.20 (t, 1H, 3J¼7.0 Hz), 3.69 (m, 1H), 3.51e3.45
(m, 1H), 2.80 (m, 1H), 2.40 (m, 2H), 2.00 (br s, 1H), 1.64 (m, 4H), 1.33
4H), 1.10 (br s, 18H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ121.8 (d,
(d, 3H, 3J¼6.0 Hz) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ129.5 (d,
3J¼31.1 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d
150.6 (d, C,
3J¼28.2 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 155.6 (C),152.0 (d, C,
1J¼248.8 Hz), 135.7 (CH), 134.9 (C), 133.9 (d, CH, 3J¼87.7 Hz), 129.7
(CH), 127.7 (CH), 122.2 (d, C, 2J¼16.6 Hz), 117.3 (CH), 64.8 (CH2), 57.3
(d, CH, 2J¼26.4 Hz), 55.9 (C), 43.1 (CH), 29.3 (CH2), 28.4 (CH2), 27.0
(CH3), 22.8 (CH2), 22.4 (CH3), 19.3 (C) ppm MS (ESIþ):
[MþNa]þ¼550.27. Elemental analysis for C30H42FNO2SSi: calcd: C:
1J¼247.3 Hz), 143.9 (C), 141.3 (C), 127.7 (CH), 127.1 (CH), 125.1 (CH),
121.4 (d, C, 1J¼15.9 Hz), 120.2 (CH), 66.8 (CH2), 64.1 (CH2), 47.2 (CH),
46.2 (d, CH, 2J¼27.5 Hz), 43.5 (CH), 29.4 (CH2), 28.2 (d, CH2,
3J¼5.2 Hz), 24.8 (CH2), 18.5 (CH3) ppm MS (ESIþ): [MþH]þ¼396;
[MþNa]þ¼418.2. Elemental analysis for C24H26FNO3: C: 72.89; H:
20
68.27; H: 8.02; N: 2.65; S: 6.08. Found: C: 68.35; H: 7.99; N: 2.62; S:
6.63; N: 3.54. Found: C: 72.56; H: 6.61; N: 3.37. [
CHCl3).
a
]
¼ꢀ7.3 (c 0.62,
D
20
5.95. [
a
]
¼þ35.8 (c 0.59, CHCl3).
D
4.8.8. N-((S, Z)-1-((R)-2-((tert-butyldiphenylsilyloxy)methyl)-cyclo-
pentylidene)-1-fluorobut-3-en-2-yl)-2-methylpropane-2-sulfinamide
((Z)-7f). Colorless oil. Rf¼0.32 (cyclohexane/EtOAc: 7/3). IR (neat):
4.9.3. (R, Z)-2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl-amino)-
1-fluoropropylidene)-cyclopentanecarboxylic acid ((Z)-10a). To a so-
lution of (Z)-9a (159 mg, 0.403 mmol,1 equiv) in acetone (1.2 mL) at
n
2930, 2855,1665,1463,1428,1365,1244,1106,1080, 998, 822, 740,
0
ꢁC was added Jones’reagent (2.74 N, 5 equiv). The reaction mix-
701, 609 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d
7.70e7.67 (m, 4H),
ture was stirred at 0 ꢁC for 1 h and then quenched with isopropyl
alcohol (308 L, 4.03 mmol, 10 equiv) and water (5.2 mL, 13 mL/
7.45e7.36 (m, 6H), 5.81e5.70 (m, 1H), 5.23e5.17 (m, 2H), 4.25e4.12
(m, 1H), 3.80e3.75 (m, 1H), 3.57e3.50 (m, 1H), 3.31e3.28 (d, 1H,
3J¼9.0 Hz), 2.76e2.71 (m, 1H), 2.38e2.30 (m, 2H), 1.70e1.53 (m,
m
mmol of alcohol). The mixture was extracted with EtOAc and the
combined organic layers were washed with a saturated aqueous
solution of NaCl, dried over Na2SO4, filtered and concentrated un-
der reduced pressure. The crude mixture was purified by column
chromatography on silica gel (cyclohexane/EtOAc: 60/40 with 0.1%
of acetic acid) affording the carboxylic acid as a colorless gum. The
crude product was then purified by preparative HPLC with aceto-
nitrile/formic acid: 45/55 to afford (Z)-10a as a colorless gum
4H), 1.10 (br s, 18H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ127.2 (d,
3J¼25.4 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 150.0 (d, C,
1J¼249.6 Hz), 135.6 (CH), 134.6 (d, CH, 3J¼56.5 Hz), 133.8 (C), 129.5
(CH), 127.6 (CH), 122.7 (d, C, 2J¼7.2 Hz), 117.7 (CH), 64.6 (CH2), 57.3
(d, CH, 2J¼26.4 Hz), 56.1 (C), 43.3 (CH), 29.4 (CH2), 28.6 (CH2), 26.8
(CH3), 24.9 (CH2), 22.6 (CH3), 19.3 (C) ppm MS (ESIþ):
[MþNa]þ¼550.20. Elemental analysis for C30H42FNO2SSi: calcd: C:
(115.4 mg, 70%). Rf¼0.34 (cyclohexane/EtOAc: 6/4). IR (neat):
n

E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
7061
3328, 3066, 2960, 1707, 1522, 1450, 1300, 1249, 1057, 759, 740,
under reduced pressure. The crude mixture was purified by column
chromatography on silica gel (CH2Cl2/CH3OH: 100/0 to 90/10) to
afford (E)-9d as a white foam (115 mg, 79%): IR (neat): n 3059, 2958,
2868, 1670, 1512, 1450, 1269, 1219, 1022, 738, 654, 621, 542,
621 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
7.76 (m, 2H), 7.58 (m, 2H),
7.41e7.29 (m, 4H), 5.00 (d, 1H, 3J¼8.1 Hz), 5.00e4.51 (m, 1H),
4.45e4.37 (m, 2H), 4.21 (t, 1H, 3J¼6.8 Hz), 3.56 (m, 1H), 2.62e2.42
(m, 2H), 2.10e1.72 (m, 5H), 1.35 (d, 3H, 3J¼6.8 Hz) ppm 19F NMR
426 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
7.77 (d, 2H, 3J¼9.0 Hz), 7.59
(282.5 MHz, CDCl3):
(75.4 MHz, (CD3)2CO):
d
ꢀ125.3 (d, 3J¼27.8 Hz) ppm 13C NMR
(d, 2H, 3J¼9.0 Hz), 7.45e7.31 (m, 4H), 5.01 (d, 1H, NH, 3J¼9.6 Hz),
4.50e4.17 (m, 4H), 3.58 (d, 2H, 3J¼9.0 Hz), 2.83 (m, 1H), 2.54e2.31
(m, 2H), 1.93e1.81 (m, 1H), 1.78e1.63 (m, 4H), 1.03 (d, 3H,
3J¼9.0 Hz), 0.98 (d, 3H, 3J¼6.0 Hz). 19F NMR (282.5 MHz, CDCl3):
d
175.2 (C), 156.4 (C), 154.0 (d, C,
1J¼251.8 Hz), 144.9 (C), 142.1 (CH), 128.6 (C), 128.0 (CH), 126.1 (CH),
120.8 (CH), 119.3 (d, C, 2J¼15.1 Hz), 67.0 (CH2), 47.9 (CH), 46.8 (d, CH,
2J¼27.1 Hz), 46.0 (d, CH, 3J¼2.3 Hz), 32.4 (CH2), 28.7 (d, CH2,
3J¼28.7), 26.4 (CH2), 17.8 (CH3) ppm MS (ESIþ): [MþH]þ¼410;
d
ꢀ121.5 (d, 3J¼28.2 Hz). 13C NMR (75.4 MHz, CDCl3):
d 156.4 (C),
150.0 (d, C, 1J¼245.8 Hz), 143.7 (CAr), 141.2 (CAr), 127.6 (CAr), 127.0
(CAr),125.0 (CAr), 123.1 (d, C, 2J¼16.6 Hz),119.9 (CAr), 66.9 (CH2), 65.1
(CH2), 56.8 (d, CH, 2J¼26.4 Hz), 47.1 (CH), 43.4 (d, CH, 3J¼5.3 Hz),
30.9 (CH), 30.6 (CH2), 26.69 (d, CH2, 3J¼3.8 Hz), 23.4 (CH2), 19.3
(CH3), 19.0 (CH3). MS ESIþ: [MþH]þ¼423.93; [2MþNa]þ¼869.00.
[MþNa]þ¼432.2. Elemental analysis for C24H24FNO4: C: 70.40; H:
20
5.91; N: 3.42. Found: C: 70.48; H: 6.00; N: 3.45. [
a
]
¼ꢀ44.3 (c 0.
D
63, CHCl3).
4.10. Synthesis of Val-
J[CF]CH]-Pro (Z)-10d and (E)-10d
Anal. Calcd for C26H30FNO3: C: 73.73; H: 7.14; N: 3.31; Found: C:
20
73.40; H: 7.07; N: 3.45. [
a
]
¼ꢀ13.3 (c 0.55, CHCl3).
D
4.10.1. (S, E)-1-fluoro-1-((R)-2-(hydroxymethyl)-cyclopent-ylidene)-
3-methylbutan-2-aminium chloride ((E)-8d). To a solution of (E)-7d
(326 mg, 0.6 mmol, 1 equiv) in dry MeOH (3.2 mL) was added 4 M
HCl in 1,4-dioxane (0.6 mL, 2.4 mmol, 4 equiv). The mixture was
stirred at room temperature for 2 h and then concentrated under
reduced pressure to dryness to afford pure (E)-8d as a white
powder (144 mg, quantitative). The product was used without
4.10.4. (9H-fluoren-9-yl)methyl (S, Z)-1-fluoro-1-((R)-2-(hydrox-
ymethyl)cyclopentylidene)-3-methylbutan-2-ylcarbamate ((Z)-
9d). To a solution of (Z)-8d (82 mg, 0.23 mmol, 1 equiv) in 1,4-
dioxane (1 mL) and water (1 mL) was added NaHCO3 (57.4 mg,
0.684 mmol, 3 equiv) at 0 ꢁC, followed by Fmoc-OSu (76.9 mg,
0.228 mmol, 1 equiv). The mixture was stirred at 0 ꢁC for 2 h and at
room temperature overnight. The mixture was then poured into ice
cold HCl (1N, 1.6 mL) and extracted with EtOAc (ꢂ3). The combined
organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude mixture was purified by column
chromatography on silica gel (CH2Cl2/CH3OH: 90/10) to afford (Z)-
further purification in the next step: IR (neat):
n 3470, 3380, 3324,
3155, 2952, 2873, 1718, 1606, 1532, 1476, 1391, 1369, 1166, 1053,
1025, 991, 817, 732, 682, 552, 535 cmꢀ1. 1H NMR (300 MHz, CD3OD):
d
3.92 (dd, 1H, 3J¼30.0 Hz, 3J¼9.0 Hz), 3.60e3.54 (m, 1H), 3.36 (m,
1H), 2.88e2.80 (m, 1H), 2.53e2.40 (m, 2H), 2.21e2.07 (m, 1H),
1.85e1.59 (m, 4H), 1.09 (d, 3H, 3J¼6.0 Hz), 1.00 (d, 3H, 3J¼9.0 Hz)
9d as a yellow oil (92 mg, 95%): IR (neat): n 3070, 2958, 2868, 1791,
ppm 19F NMR (282.5 MHz, CD3OD):
d
ꢀ123.2 (d, 3J¼28.2 Hz) ppm
1740, 1700, 1515, 1450, 1259, 1216, 1022, 758, 737, 621, 540 cmꢀ1. 1H
13C NMR (75.4 MHz, CD3OD):
d
149.3 (d, C, 1J¼245.8 Hz), 129.5 (d, C,
NMR (300 MHz, CDCl3):
d
7.78 (d, 2H, 3J¼6.0 Hz), 7.60 (d, 2H,
2J¼14.3 Hz), 65.2 (d, CH2, 4J¼3.0 Hz), 58.2 (d, CH, 2J¼27.9 Hz), 44.3
(d, CH, 3J¼4.5 Hz), 30.6 (CH), 30.2 (CH2), 28.0 (CH2), 24.6 (CH2), 19.5
(CH3). MS ESIþ (TOF): [(M-Clꢀ)þHþ]¼202.16. HRMS (ESI)þ calcu-
3J¼9.0 Hz), 7.44e7.30 (m, 4H), 5.02 (d, 1H, NH, 3J¼9.0 Hz),
4.52e4.33 (m, 2H), 4.23 (t, 1H, 3J¼9.0 Hz), 4.20e4.07 (m, 1H),
3.74e3.51 (m, 2H), 3.03 (m, 1H), 2.57e2.23 (m, 2H), 1.91e1.81 (m,
1H), 1.79e1.63 (m, 4H), 1.00 (d, 3H, 3J¼6.0 Hz), 0.96 (d, 3H,
lated for [MþH]þ C11H21NOF: 202.1604, Found: 202.1607.
20
[
a
]
¼ꢀ9.60 (c 0.27, CH3OH).
3J¼6.0 Hz). 19F NMR (282.5 MHz, CDCl3):
d
ꢀ126.8 (d, 3J¼28.2 Hz).
D
13C NMR (75.4 MHz, CDCl3):
d
155.9 (C), 150.6 (d, C, 1J¼246.6 Hz),
4.10.2. (S, Z)-1-fluoro-1-((R)-2-(hydroxymethyl)-cyclopent-ylidene)-
3-methylbutan-2-aminium chloride ((Z)-8d). To a solution of (Z)-7d
(201 mg, 0.37 mmol, 1 equiv) in dry MeOH (2 mL) was added 4 M
HCl in 1,4-dioxane (0.37 mL, 1.48 mmol, 2 equiv). The mixture was
stirred at room temperature for 2 h and then concentrated under
reduced pressure to dryness to afford (Z)-8d as a white powder
(90 mg, quantitative). The product was used without further puri-
143.7 (CAr), 142.3 (CAr), 127.6 (CAr), 126.9 (CAr), 125.0 (CAr), 121.6 (d,
C, 2J¼14.3 Hz), 120.0 (CAr), 66.5 (CH2), 64.0 (CH2), 56.4 (d, CH,
2J¼24.9 Hz), 47.1 (CH), 43.5 (CH), 30.6 (CH), 29.3 (CH2), 28.4 (d, CH2,
3J¼5.3 Hz), 24.7 (CH2), 19.2 (CH3), 19.1 (CH3). MS (ESIþ): [MþHþ]¼
424.00; [MþH2O]¼440.87. Anal. Calcd for C26H30FNO3: C: 73.73; H:
20
7.14; N: 3.31; Found: C: 73.35; H: 7.05; N: 3.25. [
CHCl3).
a
]
¼ꢀ9.5 (c 0.65,
D
fication in the next step: IR (neat):
1622, 1525, 1380, 1177, 1022, 694, 542, 483, 433 cmꢀ1
(300 MHz, CD3OD): 3.85e3.70 (m, 2H), 3.38 (m, 1H), 3.06 (m, 1H),
n
3403, 3290, 2946, 2841, 2620,
.
1H NMR
4.10.5. (R, Z)-2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl-amino)-
1-fluoro-3-methylbutylidene) cyclopentanecarboxylic acid ((Z)-
10d). To a solution of (Z)-9d (96 mg, 0.227 mmol, 1 equiv) in ace-
tone (0.7 mL) at 0 ꢁC was added Jones’reagent (2.74 N, 5 equiv). The
reaction mixture was stirred at 0 ꢁC for 1 h and then quenched with
d
2.48e2.24 (m, 2H), 2.15 (m, 1H), 1.82e1.69 (m, 4H), 1.09 (d, 3H,
3J¼6.0 Hz), 1.01 (d, 3H, 3J¼6.0 Hz). 19F NMR (282.5 MHz, CD3OD):
d
ꢀ126.8 (d, 3J¼31.1 Hz). 13C NMR (75.4 MHz, CD3OD):
d 148.3 (d, C,
1J¼246.6 Hz), 128.2 (d, C, 2J¼12.8 Hz), 63.8 (CH2), 57.3 (d, CH,
2J¼25.6 Hz), 45.2 (CH), 31.1 (CH), 30.4 (CH2), 29.8 (CH2), 25.8 (CH2),
19.6 (CH3), 19.2 (CH3). MS ESIþ (TOF): [(M-Clꢀ)þHþ]¼202.16. HRMS
isopropyl alcohol (174 mL, 2.27 mmol, 10 equiv) and water (3 mL,
13 mL/mmol of alcohol). The mixture was extracted with EtOAc and
the combined organic layers were washed with a saturated aque-
ous solution of NaCl, dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude mixture was purified by column
chromatography on silica gel (100% dichloromethane) to afford
a mixture of diastereoisomers (80/20) as a colorless gum (53.0 mg,
53%). After this purification, the two diastereoisomers were not
separated. Rf¼0.22 (100% CH2Cl2). 1H NMR (300 MHz, CD3OD):
(ESI)þ calculated for [MþH]þ C11H21NOF: 202.1604, Found:
20
202.1607. [
a]
¼ꢀ26.0 (c 0.25, CH3OH).
D
4.10.3. (9H-fluoren-9-yl)methyl (S, E)-1-fluoro-1-((R)-2-(hydrox-
ymethyl)cyclopentylidene)-3-methylbutan-2-ylcarbamate ((E)-
9d). To a solution of (E)-8d (123 mg, 0.341 mmol, 1 equiv) in 1,4-
dioxane (1.4 mL) and water (1.4 mL) was added NaHCO3 (86 mg,
1.023 mmol, 3 equiv) at 0 ꢁC, followed by Fmoc-OSu (115 mg,
0.341 mmol, 1 equiv). The mixture was stirred at 0 ꢁC for 2 h and at
room temperature overnight. The mixture was then poured into ice
cold HCl (1 N, 2.8 mL) and extracted with EtOAc (ꢂ3). The combined
organic layers were dried over Na2SO4, filtered and concentrated
d
7.74 (d, 2H, 3J¼9.0 Hz), 7.60 (d, 2H, 3J¼6.0 Hz), 7.36ꢀ7.22 (m, 4H),
4.37ꢀ4.23 (m, 2H), 4.12 (t, 1H, 3J¼6.0 Hz), 4.01 (d, 1H, 3J¼9.0 Hz),
3.46e3.42 (m, 1H), 3.03 (t, 2H, 3J¼3.0 Hz), 2.62e2.51 (m, 2H),
2.05e1.60 (m, 3H), 0.95 (d, 6H, 3J¼6.0 Hz) ppm 19F NMR
(282.5 MHz, CD3OD):
d
ꢀ121.6 (d, 3J¼29.6 Hz), e121.5 (d,
3J¼30.7 Hz) ppm 13C NMR (75.4 MHz, CD3OD):
d 178.3 (C), 158.6 (C),

7062
E. Villiers et al. / Tetrahedron 71 (2015) 7054e7062
153.3 (d, C, 1J¼250.3 Hz), 145.4 (CAr), 142.7 (CAr), 129.2 (CAr), 128.9
(CAr), 128.2 (CAr), 126.3 (CAr), 121.6 (d, C, 2J¼15.8 Hz),121.0 (CAr), 67.9
(CH2), 58.3 (d, CH, 2J¼25.6 Hz), 46.9 (d, CH, 3J¼2.3 Hz), 33.0 (CH),
31.4 (CH2), 29.7 (CH2), 27.0 (CH2), 20.2 (CH3), 19.8 (CH3) ppm MS
(m, 2H), 1.22e1.18 (m, 6H) ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ124.4 (d, 3J¼28.2 Hz) ppm 13C NMR (75.4 MHz, CDCl3):
d 175.2
(C), 152.9 (d, C, 1J¼254.1 Hz), 141.1 (C), 128.5 (CH), 128.3 (CH), 125.9
(CH), 119.8 (d, C, 2J¼16.6 Hz), 60.8 (CH2), 58.1 (CH), 51.1 (CH), 50.8
(CH), 35.0 (CH2), 31.9 (CH2), 31.5 (CH2), 28.1 (CH2), 25.8 (CH2), 18.3
(CH3), 14.3 (CH3) ppm MS (ESIþ): [MþH]þ¼378.07. Elemental
ESIþ
(TOF):
[MþNH4]þ¼455.23;
[MþNa]þ¼460.19;
[MþK]þ¼476.16.; [MþH]þ¼438.21. HRMS (ESI): calcd for [MþH]þ
C26H29FNO4: 438.2081 found: 438.2093.
analysis for C21H28FNO4: calcd: C: 66.82; H: 7.48; N: 3.71 Found: C:
20
66.90; H: 7.52; N: 3.82. [
a
]
¼ꢀ35.7 (c 0.14, CHCl3).
D
4.10.6. (R, E)-2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl-amino)-
1-fluoro-3-methylbutylidene)cyclopentanecarboxylic
acid
((E)-
Acknowledgements
10d). To a solution of (E)-9d (103 mg, 0.245 mmol, 1 equiv) in ac-
etone (3 mL/mmol of alcohol) at 0 ꢁC was added Jones reagent
(2.74 N, 5 equiv). The reaction mixture was stirred at 0 ꢁC for 1 h
ꢀ
This work has been partially supported by Region Haute-Nor-
mandie (CRUNCh Network) and LABEX SYNORG (ANR-11-LABX-
0029).
and then quenched with isopropyl alcohol (187
mL, 2.45 mmol,
10 equiv) and water (3.2 mL, 13 mL/mmol of alcohol). The mixture
was extracted with EtOAc and the combined organic layers were
washed with a saturated aqueous solution of NaCl, dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude mixture was purified by column chromatography on silica gel
(100% dichloromethane) affording the carboxylic acid as a colorless
gum (54.6 mg, 51%). After this purification, the two diaster-
eoisomeres (88:12) were not separated. Rf¼0.26 (100% CH2Cl2). 1H
References and notes
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references therein.
ꢀ
€
€
NMR (300 MHz, CDCl3):
d
7.73 (d, 2H, 3J¼7 Hz), 7.56 (d, 2H,
3J¼6.0 Hz), 7.39e7.25 (m, 4H), 5.21 (m, 1H), 4.44e4.17 (m, 3H),
3.40e3.37 (m, 1H), 2.41 (m, 2H), 2.06e1.61 (m, 5H), 0.90 (m, 6H)
5. Pierry, C.; Couve-Bonnaire, S.; Guilhaudis, L.; Neveu, C.; Marotte, A.; Lefranc, B.;
ppm 19F NMR (282.5 MHz, CDCl3):
d
ꢀ115.6 (m), e119.0 (d,
ꢀ
Cahard, D.; Segalas-Milazzo, I.; Leprince, J.; Pannecoucke, X. ChemBioChem
3J¼28.6 Hz) ppm 13C NMR (75.4 MHz, CD3OD):
d
153.9 (d, C,
2013, 14, 1620.
1J¼249.6 Hz), 145.5 (d, C, 2J¼21.1 Hz), 142.7 (CH), 128.9 (CH), 128.3
(CH), 126.5 (CH), 121.0 (CH), 68.3 (CH2), 57.9 (d, CH, 2J¼26.4 Hz),
32.3 (CH), 28.9 (CH2), 25.9 (CH2), 19.7 (CH3) ppm MS ESIþ (TOF):
6. Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291.
7. Van der Veken, P.; Senten, K.; Kertesz, I.; De Meester, I.; Lambeir, A.-M.; Maes,
ꢀ
M.-B.; Scharpe, S.; Haemers, L. A.; Augustyns, K. J. Med. Chem. 2005, 48, 1768.
8. Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto,
M. J.; Sofia, M. J. Bioorg. Med. Chem. Lett. 2012, 22, 2938.
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10. Buisson, D.; Azerad, R. Tetrahedron: Asymmetry 1996, 7, 9.
11. Zoute, L.; Dutheuil, G.; Quirion, J.-C.; Jubault, P.; Pannecoucke, X. Synthesis 2006,
3409.
[MþNH4]þ¼455.23;
[MþNa]þ¼460.19;
[MþK]þ¼476.16;
[MþH]þ¼438.21. HRMS (ESI): calcd for [MþH]þ C26H29FNO4:
438.2081 found: 438.2086.
4.11. Synthesis of an Enalapril analogue
12. Van der Veken, P.; Kertesz, I.; Senten, K.; Haemers, A.; Augustyns, K. Tetrahedron
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4.11.1. (1R, Z)-2-((2S)-2-(1-ethoxy-1-oxo-4-phenylbutan-2-
ylamino)-1-fluoropropylidene)-cyclopentanecarboxylic acid (12).
Fmoc-Ala-J[CF]C]-Pro (Z)-10a (0.211 mmol, 1 equiv) in DMF
15. Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
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17. Atomic coordinates, anisotropic displacement parameters, bond lengths and
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23. Several oxidation methods were tested, but only the Jones reagent gave the
expected product. In the case of 10d a partial racemization occurred at the
Ceterminal stereocenter.
(2.7 mL) and morpholine (1.6 equiv) were stirred for 1 h at room
temperature. The crude mixture was then concentrated under re-
duced pressure and filtered on silica gel (dichloromethane/CH3OH:
8/2þ0.1% of acetic acid). The resulting Ala-
J[(Z)CF]C]-Pro (Z)-11
was pure enough to be engaged in the reductive amination with
ethyl 2-oxo-4-phenylbutanoate (2.3 equiv) in 2 mL of absolute
ꢂ
ethanol, 0.22 g of molecular sieves 4 A, and a catalytic amount of
10% Pd/C (0.22 equiv). The mixture was placed under H2 atmo-
sphere for 12 h at room temperature. Then, the reaction mixture
was filtered through Celite and the filtrate concentrated under re-
duced pressure to give a pale yellow oil, which was purified by
chromatography on silica gel (dichloromethane/CH3OH: 8/2þ0.1%
of acetic acid). The resulting mixture was purified by preparative
HPLC (MeOH/0.005M ammonium acetate: 45/55) to afford the
fluorinated analogue of Enalapril 12 (28.0 mg, 0.074 mmol, 35%).
24. For other examples of conformationally restricted peptidomimetics having
a fluoroolefin motif: Williams, D. R.; Fultz, M. W.; Christos, T. E.; Carter, J. S.
Tetrahedron Lett. 2010, 51, 121.
25. (a) Fang, J. C. Circulation 2005, 112, 2380; (b) Regulska, K.; Stanisz, B.; Regulski,
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R. D. Bioorg. Med. Chem. Lett. 1994, 4, 2673.
Rf¼0.14 (CH2Cl2/CH3OH: 8/2þ0.1% acetic acid). IR (neat):
n 2927,
1705, 1625, 1568, 1454, 1357, 1211, 1170, 1096, 862, 748, 699, 633,
577, 493 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.23e7.09 (m, 5H), 5.85
(bs, 1H), 4.11 (q, 2H, 3J¼9.0 Hz), 3.48e3.36 (m, 2H), 3.14 (t, 1H,
3J¼6.0 Hz), 2.62 (m, 2H), 2.22e2.09 (m, 2H), 1.92e1.75 (m, 4H), 1.50