Synthesis of fluorinated cyclopropyl amino acid analogues: Toward the synthesis of original fluorinated peptidomimetics.

Article abstract of DOI:10.1021/jo302222n

A straightforward, easy, and practical access to various amino acid analogues (methionine, leucine, lysine, and arginine) from a unique fluorinated cyclopropane scaffold is described. Moreover, the synthesis, for the first time, of one tripeptide incorporating a fluorinated cyclopropane amino acid (FCAA) analogue is reported.

Full text of DOI:10.1021/jo302222n

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pubs.acs.org/joc
Synthesis of Fluorinated Cyclopropyl Amino Acid Analogues: Toward
the Synthesis of Original Fluorinated Peptidomimetics.
Gaelle Milanole,† Samuel Couve-Bonnaire,† Jean-Franco
̧
is Bonfanti,‡ Philippe Jubault,*,†
̈
and Xavier Pannecoucke†
†INSA de Rouen, UMR 6014 & FR 3038, COBRA Universite
́ ̀
de Rouen, 1 rue Tesniere, 76131 Mont-Saint-Aignan Cedex, France
‡Janssen Research & Development, Medicinal Chemistry Infectious Diseases, Centre de Recherche Janssen Cilag, Campus de
Maigremont, BP 615, 27106 Val de Reuil Cedex, France
S
* Supporting Information
ABSTRACT: A straightforward, easy, and practical access to various amino acid analogues (methionine, leucine, lysine, and
arginine) from a unique fluorinated cyclopropane scaffold is described. Moreover, the synthesis, for the first time, of one
tripeptide incorporating a fluorinated cyclopropane amino acid (FCAA) analogue is reported.
compounds.5 For example, fluorinated amino acids (trifluor-
INTRODUCTION
■
oleucine and trifluoromethionine, in particular) have recently
Of the numerous emerging fields in organic chemistry, the
emerged as valuable building blocks for designing hyperstable
synthesis of organofluorine compounds has attracted great
proteins folds as well as directing highly specific protein−protein
interest in recent years due to the anomalous physical properties
interactions.6 Moreover, the design of small rigid molecules, such
of the fluorine atom as well as restricted synthetic access to these
as cyclopropane peptidomimetics, that replicate the essential
compounds.1 Indeed, the introduction of one or several fluorine
features of oligopeptide secondary structure is a central goal in
atoms on a compound alters its chemical, physical, and
efforts to identify peptide-like ligands having high affinity for
biochemical properties such as solubility, lipophilicity, con-
biological targets.7 The incorporation of cyclopropyl amino acids
formation, metabolic stability, and even intrinsic structure.2
has already been reported in the literature showing interesting
From a more fundamental point of view, the extraordinary
results in terms of biological activity and conformational
potential of hydrogen or oxygen substitution by fluorine, to
modify and/or increase in some cases the pharmacological (in
particular metabolic stability) properties of organic molecules,
induction.7b,d,l,m To our knowledge, the synthesis of peptidomi-
metics incorporating within their structure a fluorinated
cyclopropyl amino acid analogue has never been reported in
led to the development of original and innovative programs
the literature. Herein, we report our recent success in tackling
dedicated to new synthetic strategies toward fluorinated
biomolecules. In addition to the fluorine atom, the cyclopropane
this very interesting issue by using a straightforward strategy from
a unique fluorinated cyclopropane scaffold ( )-1. This latter
ring has several relevant properties and is present in many natural
allowed the synthesis of methionine, leucine, arginine, and lysine
products and biological molecules.3 The cyclopropane has a
unique structural feature and can be used to constrain the
analogues which could be further used in peptide synthesis.
skeleton of a molecule, having an impact in molecule’s properties.
Combining the remarkable properties of the fluorine atom to
RESULTS AND DISCUSSION
■
In the past decades, many syntheses of highly valuable
fluorinated scaffolds from commercially available ethyl dibromo-
fluoroacetate have been developed.8 Among them, we recently
reported a general one-step synthesis of highly functionalized
monofluorinated cyclopropanes from electron-deficient alkene-
s.9a Other alternative approaches toward the synthesis of such
fluorinated cyclopropanes have been reported. Interestingly, our
the structural constraint provided by the cyclopropane seemed
very useful to lead to fluorinated cyclopropanes as new powerful
scaffolds which could be of great interest for many applications in
the agrochemical or pharmaceutical domains.4
Among this general family, fluorinated cyclopropanes bearing
an amino acid moiety can be considered as highly valuable
precursors for the synthesis of fluorinated constrained amino
acids. This type of amino acid analogues may be incorporated in
peptide analogues to imply new highly localized features that may
be used in structural and biological studies of bioactive
Received: October 16, 2012
© XXXX American Chemical Society
A
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method was successfully applied to the synthesis of the
fluorinated amino acid ( )-1 on a 0.1 mol scale (30 g of Michael
acceptor) with 93% yield (Scheme 1).
Scheme 3. Synthesis of Racemic Analogues of Methionine
( )-Z-5 and ( )-E-5
a
Scheme 1. Cyclopropanation Process Using Zn/LiCl
Combination
a
Reagents and conditions: (a) thioacetic acid, DIAD, Ph3P, THF, 0 °C
Remarkably, the cyclopropane diester ( )-1 can be diastereo-
selectively saponified using lithium hydroxide at 0 °C,8b,10 thus
giving after acid−basic extraction the corresponding Z isomer of
carboxylic acid ( )-2 and the E isomer of diester 1 as highly
enriched diastereisomers. Then, diester ( )-E-1 can be
saponified regioselectively using lithium hydroxide at room
temperature leading to ( )-E-2 in 86% yield. In order to build
efficiently the lateral chain of the four envisioned amino acid
mimics (methionine, leucine, lysine and arginine), the two
isomeric alcohols ( )-E-3 and ( )-Z-3 were synthesized using
mixed anhydride formation and subsequent reduction strategy
from corresponding substrates ( )-2 (Scheme 2).
to rt, 2 h, (( )-Z-4: 83%, ( )-E-4: 66%); (b) NaOMe, MeOH, 0 °C,
30 min; (c) CH3I, 0 °C to rt, 90 min, (( )-Z-5: 74%, ( )-E-5: 61%).
a
Scheme 4. Synthesis of racemic Analogue of Leucine ( )-Z-9
From these two ( )-Z-3 and ( )-E-3 building blocks, we
investigated the synthesis of both isomers of methionine as
outlined in Scheme 3. For that purpose, reaction of ( )-Z-3
alcohol and thioacetic acid in the presence of triphenylphosphine
and diisopropyl azodicarboxylate led to the corresponding
thioacetate ( )-Z-4 via a Mitsunobu reaction in 83% yield.
Subsequent deprotection and in situ methylation afforded the
expected ( )-Z-5 analogue of methionine.11 A similar strategy
was further applied to ( )-E-3 leading in a more moderate
overall yield to the corresponding ( )-E-5 isomer. For this first
amino acid analogue, both isomers of fully protected methionine
analogue ( )-Z-5 and ( )-E-5 were obtained, respectively, in
32% and 19% overall yield from ( )-1.
The next goal was to achieve the synthesis of leucine analogue
bearing an isopropyl group on the lateral chain. The following
sequence was carried out (Scheme 4). Oxidation of primary
alcohol ( )-Z-3 with IBX in refluxing ethyl acetate afforded the
corresponding aldehyde ( )-Z-6 in quantitative yield.12 Treat-
ment with methylmagnesium bromide at low temperature,13
followed by subsequent oxidation of the corresponding
secondary alcohol with IBX, led to the corresponding ketone
( )-Z-7 in 55% yield over two steps. Formation of the double
bond via a Wittig reaction was achieved using triphenylmethyl-
phosphonium bromide to give alkene ( )-Z-8 in 79% yield.
a
Reagents and conditions: (a) 2-iodoxybenzoic acid, EtOAc, reflux, 5
h, 99%; (b) CH3MgBr, THF, −10 °C, 30 min, 79%; (c) 2-
iodoxybenzoic acid, EtOAc, reflux, 9 h, 69%; (d) Ph3PCH3Br,
KHMDS, Et2O, 0 °C to RT, 2 h, 79%; (e) H2, (Ph3P)3RhCl, toluene,
20 bar, rt, overnight, 89%.
Finally, hydrogenation of the alkene moiety was achieved using
Wilkinson’s catalyst14 under hydrogen pressure leading to the
expected target ( )-Z-9 (overall yield: 20% from 1). The
stereochemistry of this leucine analogue ( )-Z-9 was confirmed
by X-ray analysis (Figure 1).15
A slightly modified procedure was applied for the synthesis of
( )-E-9 from ( )-E-2. Indeed, all attempts to oxidize the
secondary alcohol ( )-E-3 failed. As an alternative, carboxylic
acid ( )-E-2 was efficiently converted to the corresponding
Weinreb amide which was then treated with methyl lithium at
low temperature to generate the expected ketone ( )-E-7. The
same final steps (Wittig reaction and hydrogenation using
Wilkinson’s catalyst) were then applied leading to the expected
a
Scheme 2. Preparation of Racemic Alcohols ( )-Z-3 and ( )-E-3
a
Reagents and conditions: (a) 1 M LiOH, THF/water (10:1), 0 °C, 1 h, 85%; (a′) 1 M LiOH, THF/water (5:2), rt, overnight, 86%; (b) ethyl
chloroformate, Et3N, THF, 10−0 °C, 45 min; (c) NaBH4, MeOH, 0 °C, 1 h, 68% in two steps for ( )-Z-3, 60% in two steps for ( )-E-3.
B
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Scheme 6. Partial and Complete Deprotection Steps for
a
( )-Z-9 and Synthesis of N-Fmoc ( )-Z-23
Figure 1. X-ray structure of (1R,2S)-Z-9.
a
Reagents and conditions: (a) HCl 4 N in dioxane, MeOH, rt, 4 h,
quant; (b) Yb(OTf)3, CH3CN, 0 °C to rt, 1 h, 93%; (c) LiOH,
MeOH/H2O, reflux, 4 h, 76%; (d) CH3CO2H/HCl 12 N (1:1), reflux,
30 h, 88%; (e) K2CO3, Fmoc-OSu, dioxane/water (1/1), 0 °C, 1 h
then 40 °C, 3 h, 68%.
leucine analogue ( )-E-9 (Scheme 5; overall yield: 14% from
( )-1).
Scheme 5. Synthesis of Racemic Analogue of Leucine ( )-E-
a
9
Wadsworth−Emmons reaction of ( )-Z-6 using diethyl
cyanomethylphosphonate was performed giving the correspond-
ing α,β-unsaturated nitrile ( )-Z-14 in 70% yield. Catalytic
hydrogenation of ( )-Z-14 in the presence of PtO2 (10 bar H2)
afforded the expected scaffold ( )-Z-15 in high yield (overall
yield: 32% from ( )-1).17 Concerning the E analogue, oxidation
of the primary alcohol ( )-E-3 with IBX afforded ( )-E-6, and a
similar procedure was performed for the first step of the sequence
leading to α,β-unsaturated nitrile ( )-E-14 but in a lower yield
(36%) probably because of the cis relationship between the
aldehyde and the dicarbamate functions. However, the direct
conversion of ( )-E-14 to ( )-E-15, using previously reported
conditions, did not occur properly. For that purpose, a two-step
procedure was developed leading to the expected ( )-E-15 in
82% yield (Scheme 7, overall yield: 10% from ( )-1).
a
Reagents and conditions: (a) HBTU, DIEA, DMF, 0 °C, 1 h then
MeO(Me)NH.HCl, DMF, rt, 16 h, 62%; (b) CH3Li, −78 °C, 40 min;
57% (c) Ph3PCH3Br, KHMDS, Et2O, 0 °C to rt, 16 h, 65%; (d) H2,
(Ph3P)3RhCl, toluene, 20 bar, rt, 15 h, 78%.
Finally, we developed the synthesis of the lateral chain of
arginine which was obtained efficiently as described in Scheme 8.
Treatment of aldehyde ( )-Z-6 with nitromethane in the
presence of catalytic amount of 1,1,3,3-tetramethylguanidine via
the Henry reaction, followed by subsequent crotonisation
afforded the corresponding α,β-unsaturated compound ( )-Z-
16 in 71% yield.18 The E configuration of the alkene bond was
To demonstrate the high value of our present synthesis, we
envisioned carrying out a selective (ester deprotection or
carbamate deprotection) and full deprotection of ( )-Z-9. The
N,N-(di-tert-butyloxycarbonyl) protection could be removed
very efficiently using HCl 4 M in dioxane leading to
hydrochloride salt ( )-Z-10 in quantitative yield. Attempts to
selectively saponify the methyl ester function from ( )-Z-9 with
lithium hydroxide under reflux did not provide the expected
carboxylic derivative. We assumed that this lack of reactivity was
probably due to the steric hindrance of the two N-tert-
butyloxycarbonyl groups, impeding the saponification process
to occur. Thus, as an alternative approach, treatment of fully
protected amino acid ( )-Z-9 with ytterbium(III) triflate16 led
to the corresponding mono-N-Boc-protected amine compound
( )-Z-11 which can be hydrolyzed with lithium hydroxide to
give carboxylic acid ( )-Z-12. Both protecting groups of ( )-Z-
9 were removed simultaneously in acidic conditions
(CH3CO2H/HCl 12 N) under reflux to generate the fully
deprotected fluorocyclopropane analogue of leucine ( )-Z-13.
Finally, in order to demonstrate the remarkable potency of the
fluorinated cyclopropane amino acid analogues for the synthesis
of peptidomimetics and its possible application in peptide solid-
phase synthesis using Fmoc strategy, ( )-Z-23 was prepared
from ( )-Z-9 (Scheme 6).
1
assigned from H NMR data. The saturated nitro compound
( )-Z-17 was obtained by reduction of ( )-Z-16 using sodium
borohydride and was then converted to the amine ( )-( )-Z-18
by catalytic hydrogenation.19 Finally, guanidinylation of ( )-Z-
20 was achieved in moderate yield using N,N′-Di-Cbz-N″-
trifluoromethane sulfonyl guanidine,20 leading to the expected Z
N-Cbz protected analogue of arginine ( )-Z-19.
Having in hand these four amino acid analogues, we focused
on standard peptide-coupling reactions to generate a tripeptide
incorporating one fluorinated cyclopropane (( )-Z-9) as
described in Scheme 9. The leucine analog ( )-Z-9 was treated
with ytterbium(III) triflate to remove efficiently one N-tert-
butyloxycarbonyl group, allowing the subsequent hydrolysis of
the methyl ester. The resulting acid ( )-Z-12 was coupled with
the natural amino-acid H-Ala-OMe in the presence of HATU
and DIEA to afford the dipeptide Z-20 as a mixture of
diastereoisomers.21 Subsequent N-protecting group removal
under standard acidic conditions led to the amine Z-21. The
resulting hydrochloride was coupled with N-Cbz protected
alanine (HATU/NMM) to afford the final fluorinated cyclo-
propyl tripeptide Z-22 in very good yield (76%).22 These two
We then turned our attention toward the synthesis of the
lateral chain of lysine which was synthesized efficiently following
the procedure depicted in Scheme 7. Indeed, Horner−
C
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a
Scheme 7. Synthesis of Racemic Analogues ( )-Z-15 and ( )-E-15 of Lysine
a
Reagents and conditions: (a) diethyl cyanomethylphosphonate, Et3N, THF, rt, 16 h, 70% from ( )-Z-6, 39% from ( )-E-6; (b) H2, PtO2, CHCl3,
10 bar, rt, overnight, 89%. (c) H2, Pd−C, EtOH, 1 bar, rt, overnight, 94%; (d) H2, PtO2, CHCl3, 20 bar, rt, overnight, 87%.
a
Scheme 8. Synthesis of Racemic Z-Analogue of Arginine ( )-Z-19
a
Reagents and conditions: (a) nitromethane, 1,1,3,3-tetramethylguanidine, toluene, 0 °C, 1 h; (b) MsCl, Et3N, 0 °C to rt, 1 h, 71% in two steps; (c)
NaBH4, EtOH, 0 °C to rt, 1 h, 92%; (d) H2, Pd−C, MeOH, 10 bar, rt, overnight, 86%; (e) N,N′-di-Cbz-N″-trifluoromethanesulfonyl guanidine,
Et3N, CH2Cl2, rt, overnight, 24%.
a
Scheme 9. Synthesis of Fluorinated Cyclopropyl Tripeptide Z-22
a
Reagents and conditions: (a) HATU, DIEA, DMF, 0 °C, 1 h; (b) H-Ala-OMe·HCl, DMAP, DBU, DMF, rt, overnight, 57% in two steps; (c) 4 N
HCl in dioxane, MeOH, rt, 4 h, quant; (d) Z-Ala-OH, HATU, NMM, DMF, 0 °C, 1 h; (e) Z-21, DMF, rt, overnight, 76% in two steps.
diastereoisomers can be efficiently purified and separated by
supercritical fluid chromatography (SFC).23
acid analogues (methionine, leucine, lysine and arginine) was
reported. The synthesis, for the first time, of one tripeptide
incorporating a fluorinated cyclopropane amino-acid analogue
was also described. All these new fluorinated scaffolds can be
considered as very useful intermediates for the peptidomimetics
building. From these analogues, because of the constrained
CONCLUSION
■
In conclusion, from a unique fluorinated cyclopropane scaffold, a
straightforward, easy, and practical access to new various amino-
D
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165.4 (JCF = 25.3 Hz), 151.1, 151.0, 83.4, 83.3, 81.5 (JCF = 248.0 Hz),
feature of the cyclopropane moiety and the presence of fluorine
atom, modified conformations, physical−chemical properties,
and/or biological activity can be expected compared to the native
peptides. These aspects, as well as the incorporation of these
amino acid analogues in more complex structures, are currently
underway in our laboratory.
62.4, 53.2, 48.2 (JCF = 13.7 Hz), 27.9, 27.7, 26.8 (JCF = 8.9 Hz), 13.9. 19
NMR (282.4 MHz, CDCl3): −195.0 (dd, JFH = 10.7, 17.5 Hz).
F
2-(N,N-(Di-tert-butyloxycarbonyl)amino)-1-fluoro-2-methox-
ycarbonylcyclopropylmethanoic Acid (( )-Z-2). In a 500 mL,
three-necked, round-bottom flask equipped with magnetic stirrer was
dissolved ( )-1 (19.83 g, 48.9 mmol, 1 equiv) in a mixture of THF/
water 10:1 (300 mL) and cooled to 0 °C. Subsequently, a molar solution
of lithium hydroxide (73 mL, 73 mmol, 1.5 equiv) was added dropwise
via a dropping funnel. The solution was stirred at 0 °C until complete
consumption of ( )-Z-1 was observed (monitored by 19F NMR). Upon
completion, 1 M KHSO4 solution was added until pH 2, and aqueous
layer was extracted with Et2O (3 × 200 mL). The combined organic
layers were concentrated in vacuo. The oily residue was dissolved in
Et2O, and the desired acid ( )-Z-2 was extracted with 1 M NaHCO3
solution (3 × 50 mL) in its sodium salt form. The organic layer was
washed with brine, dried over anhydrous MgSO4, and concentrated in
vacuo to afford ( )-E-1 (contaminated by 7% ( )-Z-1) as a yellow oil
(7.05 g, 87%). The aqueous layer was acidified to pH 2 by addition of 1
M KHSO4 solution and extracted with Et2O (4 × 100 mL). The
combined organic layers were dried over anhydrous MgSO4 and
concentrated in vacuo to afford ( )-Z-2 (contaminated by 8% of ( )-E-
2) as a yellow syrup (9.26 g, 85%). Analytical TLC (silica gel 60): (20%
cyclohexane in ethyl acetate) Rf = 0.21. 1H NMR (300.1 MHz, CDCl3):
9.52 (bs, 1H), 3.72 (s, 3H, CH3), 2.63 (dd, 1H, JHH = 9.2 Hz, JHF = 16.9
Hz), 1.95 (dd, 1H, JHH = 9.2 Hz, JHF = 20.8 Hz), 1.48 (2s, 18H). 13C
NMR (75.4 MHz, CDCl3): 167.9, 166.5 (JCF = 26.4 Hz), 151.4, 151.0,
84.2, 83.7, 80.9 (JCF = 241.4 Hz), 53.2, 46.5 (JCF = 10.0 Hz), 27.8, 27.7,
EXPERIMENTAL SECTION
■
General Information. All reactions were conducted in oven-dried
glassware 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 bath frozen by dry
ice. The flasks were equipped with septum caps. All commercial solvents
were distilled prior to use: THF and Et2O were distilled over sodium/
benzophenone under nitrogen atmosphere, CH2Cl2 over CaH2, and
toluene over sodium. Analytical thin-layer chromatography was
performed on precoated 250 μm layer thickness silica gel 60 F254 plates.
Visualization was performed by ultraviolet light and staining with a
solution of phosphomolybdic acid. Flash column chromatography was
performed using 40−63 μm or 70−200 μm silica gel using compressed
air or automated equipment with prepacked silica cartridges. 1H NMR,
13C NMR, and 19F NMR were recorded at 300, 75.4, and 282.5 MHz,
respectively, on a 300 MHz spectrometer. The following abbreviations
were used to explain the multiplicities: s: singlet, d: doublet, t: triplet, q:
quadruplet, m: multiplet, bs: broad singlet, bm: broad multiplet. J was
used to indicate coupling constants in hertz (Hz). IR spectra were
recorded on a FT-IR spectrometer. Mass spectra were obtained on a
quadripole ion trap instrument equipped with an electrospray ionization
(ESI) source. High-resolution electrospray mass spectra (HR-ESI MS)
were recorded on a QTOF-MS instrument.
26.4 (JCF = 8.4 Hz). 19F NMR (282.4 MHz, CDCl3): −183.3 (dd, JFH
=
17.0, 21.0 Hz). MS (ESI negative mode): m/z 376.07 [M − H]−. IR
(neat): 3500, 2981, 2927, 1748, 1371, 1283, 1156, 1112, 852, 772 cm−1.
Anal. Calcd for C16H24FNO8: C, 50.92; H, 6.41; N, 3.71. Found: C,
51.13; H, 6.65; N, 3.76.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-ethoxy-
carbonyl-2-fluorocyclopropylcarboxylate (( )-1). Lithium chlor-
ide (10.6 mg, 0.25 mol, 2.5 equiv) and zinc (16.4 g, 0.25 mol, 2.5 equiv)
were placed into a 1 L round-bottom flask equipped with septum and
magnetic stirrer, dried at 170 °C (10−1 mbar) for 60 min, and then
flushed with argon. Subsequently, 400 mL of freshly distilled THF, 800
μL of DMSO, and 1.6 mL of TMSCl were added, and the mixture was
stirred vigorously at 50 °C for 15 min. Then, 10 drops of ethyl
dibromofluoroacetate were added, the mixture was immediately cooled
to −5 °C, and Boc-ΔAla(N-Boc)-OMe (30.1 g, 1 mmol, 1 equiv)
previously dissolved in 50 mL of THF under an argon atmosphere was
added. Finally, ethyl dibromofluoroacetate (22 mL, 0.16 mol, 1.6 equiv)
was added dropwise over 30 min via a syringe pump, and the resulting
mixture was stirred for an additional 10 min at −5 to 0 °C until complete
disappearance of starting material (monitored by TLC). Upon
completion, the mixture was poured into a mixture of EtOAc (400
mL) and aqueous HCl (0.5 M, 200 mL). Then, the aqueous layer was
extracted with EtOAc (100 mL). The combined organic layers were
washed with brine (15 mL), dried over anhydrous MgSO4, and
concentrated in vacuo. The resulting crude product was purified by
column chromatography on silica gel to afford ( )-1 as a pale yellow oil
(37.7 g, 93%) as a mixture of Z and E stereoisomers (dr 59:41 by 19F
NMR). Analytical TLC (silica gel 60): (30% ethyl acetate in
cyclohexane) Rf = 0.51. MS (ESI positive mode): m/z 428.20 [M +
Na]+, 833.20 [2M + Na]+. IR (neat): 3445, 1799, 1748, 1371, 1278,
1255, 1159, 1122, 1101, 1027, 855, 785 cm−1. Anal. Calcd for
C18H28FNO8: C, 53.33; H, 6.96; N, 3.45. Found: C, 52.95; H, 6.64;
N, 3.71.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-fluoro-2-
(hydroxymethyl)cyclopropyl Carboxylate (( )-3). General Pro-
cedure for the Synthesis of ( )-Z- and ( )-E-3. In a 250 mL round-
bottom flask equipped with septum and magnetic stirrer under an argon
atmosphere was dissolved ( )-2 (2.74 g, 7.26 mmol, 1 equiv) in THF
(50 mL) and the mixture cooled to −10 °C. Triethylamine (1.08 mL,
7.99 mmol, 1.1 equiv) and ethyl chloroformate (1.11 mL, 11.62 mmol,
1.6 equiv) were added slowly, and the reaction mixture was stirred for 45
min at −10 °C until complete disappearance of starting material
(monitored by TLC). The mixture was taken up in Et2O, stirred for 10
min, and filtered through a pad of Celite, and the filtrate was
concentrated in vacuo. After being cooled to −10 °C, the residue was
dissolved in MeOH (50 mL), and sodium borohydride (549 mg, 14.52
mmol, 2 equiv) was added portionwise. The reaction mixture was stirred
for 1 h at 0 °C until complete disappearance of starting material
(monitored by TLC). Upon completion, the mixture was quenched with
saturated NH4Cl solution (40 mL), and extracted with CH2Cl2 (3 × 25
mL). The combined organic layers were washed with saturated
NaHCO3 solution (40 mL), dried over anhydrous MgSO4, and
concentrated in vacuo. The resulting yellow residue was purified by
column chromatography on silica gel to afford the expected product.
( )-Z-3. Compound ( )-Z-3 was obtained as a yellow oil in 68%
yield. Analytical TLC (silica gel 60): (40% ethyl acetate in cyclohexane)
Rf = 0.29. 1H NMR (300.1 MHz, CDCl3): 4.27 (ddd, 1H, JHH = 5.7, 12.8
Hz, JHF = 15.6 Hz), 4.08 (ddd, 1H, JHH = 5.4, 12.0 Hz, JHF = 30.6 Hz),
3.75 (s, 3H), 3.02 (t, 1H, JHH = 5.7 Hz), 2.20 (dd, 1H, JHH = 8.7 Hz, JHF
=
Major Isomer (( )-Z-1). 1H NMR (300.1 MHz, CDCl3): 4.22 (q, 2H,
JHH = 7.1 Hz), 3.66 (s, 3H), 2.55 (dd, 1H, JHH = 9.0 Hz, JHF = 15.9 Hz),
1.84 (dd, 1H, JHH = 8.9 Hz, JHF = 20.7 Hz), 1.42 (2s, 18H), 1.26 (t, 3H,
JHH = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): 167.7 (JCF = 2.6 Hz),
164.1 (JCF = 25.7 Hz), 151.1, 151.0, 83.4, 81.2 (JCF = 241.8 Hz), 62.3,
52.8, 46.5 (JCF = 10.2 Hz), 28.0, 27.9, 26.5 (JCF = 8.2 Hz), 13.9. 19F NMR
(282.4 MHz, CDCl3): −185.5 (dd, JFH = 16.1, 20.9 Hz).
17.4 Hz), 1.80 (dd, 1H, JHH = 8.7 Hz, JHF = 22.2 Hz), 1.48 (2s, 18H,
CH3-9). 13C NMR (75.4 MHz, CDCl3): 169.8 (JCF = 2.3 Hz), 152.8,
151.8, 86.1 (JCF = 233.2 Hz), 83.6, 83.2, 60.9 (JCF = 23.1 Hz), 52.9, 44.4
(JCF = 9.3 Hz), 27.9, 27.8, 26.8 (JCF = 9.3 Hz). 19F NMR (282.4 MHz,
CDCl3): −177.4 (dddd, JFH = 15.8, 17.4, 22.0, 30.5 Hz). MS (ESI
positive mode): m/z 385.93 [M + Na]+, 748.93 [2M + Na]+. IR (neat):
3436, 2924, 2854, 1736, 1456, 1370, 1281, 1157, 1121, 1042, 762 cm−1.
HRMS (ESI positive mode): calcd for C16H26FNO7Na 386.1591, found
386.1599.
Minor Isomer (( )-E-1). 1H NMR (300.1 MHz, CDCl3): 4.22 (q, 2H,
JHH = 7.2 Hz), 3.76 (s, 3H), 2.77 (dd, 1H, JHH = 8.4 Hz, JHF = 17.7 Hz),
2.04 (dd, 1H, JHH = 8.4 Hz, JHF = 10.8 Hz), 1.46 (2s, 18H), 1.30 (t, 3H,
JHH = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): 166.2 (JCF = 2.3 Hz),
( )-E-3. Compound ( )-E-3 was obtained as a white solid in 68%
yield. Mp: 66−69 °C. Analytical TLC (silica gel 60): (30% ethyl acetate
E
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in cyclohexane) Rf = 0.24. 1H NMR (300.1 MHz, CDCl3): 4.08 (dd, 1H,
JHH = 11.6 Hz, JHF = 25.0 Hz), 3.78 (s, 3H), 3.68 (ddd, 1H, JHH = 1.7,
13.8 Hz, JHF = 24.2 Hz), 2.50 (dd, 1H, JHH = 8.7 Hz, JHF = 20.4 Hz), 1.52
MgSO4 and concentrated in vacuo to afford a yellow oil. The resulting
yellow residue was purified by column chromatography on silica gel to
give the desired product.
(s, 9H), 1.45 (s, 9H), 1.11 (dd, 1H, JHH = 8.7 Hz, JHF = 11.1 Hz). 13
C
( )-Z-5. Compound ( )-Z-5 was obtained as a white solid in 74%
yield. Mp: 60−62 °C. Analytical TLC (silica gel 60): (30% ethyl acetate
in cyclohexane) Rf = 0.50. 1H NMR (300.1 MHz, CDCl3): 3.74 (s, 3H),
3.23 (dd, 1H, JHH = 14.9 Hz, JHF = 33.8 Hz), 3.17 (dd, 1H, JHH = 1.5, 14.9
Hz), 2.22 (s, 3H), 2.10 (dd, 1H, JHH = 8.6 Hz, JHF = 18.1 Hz), 1.76 (ddd,
1H, JHH = 1.4, 8.5 Hz, JHF = 21.1 Hz), 1.48 (d, 18H). 13C NMR (75.4
MHz, CDCl3): 169.7 (JCF = 2.2 Hz), 151.7, 151.6, 86.5 (JCF = 232.5 Hz),
83.0, 82.8, 52.8, 46.2 (JCF = 9.5 Hz), 33.5 (JCF = 22.1 Hz), 28.0, 27.9, 27.8
NMR (75.4 MHz, CDCl3): 167.6, 154.1, 151.8, 86.3 (JCF = 240.5 Hz),
84.4, 83.8, 62.4 (JCF = 21.2 Hz), 53.0, 47.2 (JCF = 14.9 Hz), 27.9, 27.8,
23.5 (JCF = 9.9 Hz). 19F NMR (282.4 MHz, CDCl3): −191.1 (dddd, JFH
= 11.9, 20.3, 24.3, 27.4 Hz). MS (ESI positive mode): m/z 386.07 [M +
Na]+, 749.00 [2M + Na]+. IR (neat): 3418, 2930, 2359, 1746, 1435,
1370, 1248, 1157, 1123, 1046, 849, 762 cm−1. Anal. Calcd for
C16H26FNO7: C, 52.88; H, 7.21; N, 3.85. Found: C, 52.84; H, 7.38;
N, 3.84.
Methionine Analogue. Methyl 1-(N,N-(Di-tert-butyloxy-
carbonyl)amino)-2-((acetylthio)methyl)-2-fluorocyclopropyl-
carboxylate (( )-4). General Procedure for the Synthesis of ( )-Z-
and ( )-E-4. In a 50 mL round-bottom flask equipped with septum and
magnetic stirrer under an argon atmosphere was dissolved triphenyl-
phosphine (1.44 g, 5.49 mmol, 2 equiv) in THF (15 mL) and the
mixture cooled to 0 °C. Subsequently, diisopropyl azodicarboxylate
(1.08 mL, 5.49 mmol, 2 equiv) was added slowly, and the reaction
mixture was stirred for 30 min at 0 °C until a precipitate was observed.
Then, ( )-3 (1 g, 2.75 mmol, 1 equiv) and thioacetic acid (0.394 mL,
5.49 mmol, 2 equiv) were added. The reaction mixture was stirred for 1 h
at 0 °C and allowed to warm to room temperature for 1 h until complete
disappearance of starting material (monitored by TLC and 19F NMR).
The reaction mixture was concentrated in vacuo, taken up in a mixture of
Et2O/cyclohexane (1:1), and stirred for 30 min. The precipitate was
filtered off, and the filtrate was concentrated in vacuo to afford an orange
oil. The crude product was purified by column chromatography on silica
gel to afford the expected product as a yellow oil.
(JCF = 7.9 Hz), 16.6. 19F NMR (282.4 MHz, CDCl3): −170.4 (ddd, JFH
=
18.4, 22.0, 33.7 Hz). MS (ESI positive mode): m/z 416.07 [M + Na]+,
809.00 [2M + Na]+. IR (neat): 3105, 2930, 1717, 1335, 1279, 1250,
1155, 1110, 1083, 857, 785, 762, 599 cm−1. Anal. Calcd for
C17H28FNO6S: C, 51.89; H, 7.17; N, 3.56; S, 8.15. Found: C, 51.81;
H, 7.25; N, 3.57; S, 8.02.
( )-E-5. Compound ( )-E-5 was obtained as a white solid in 61%
yield. Mp: 65−67 °C. Analytical TLC (silica gel 60): (20% ethyl acetate
in cyclohexane) Rf = 0.39. 1H NMR (300.1 MHz, CDCl3): 3.77 (s, 3H),
3.42 (ddd, 1H, JHH = 2.4, 15.1 Hz, JHF = 11.0 Hz), 2.61 (ddd, 1H, JHH
=
2.2, 8.7 Hz, JHF = 19.2 Hz), 2.54 (dd, 1H, JHH = 15.3 Hz, JHF = 36.4 Hz),
2.26 (s, 3H), 1.49 (d, 18H), 1.30 (dd, 1H, JHH = 8.7 Hz, JHF = 12.3 Hz).
13C NMR (75.4 MHz, CDCl3): 167.5, 151.7, 151.5, 88.4 (JCF = 238.6
Hz), 82.9, 82.6, 52.7, 48.8 (JCF = 14.3 Hz), 36.7 (JCF = 23.4 Hz), 27.6,
27.5, 26.1 (JCF = 10.1 Hz), 16.3 (JCF = 2.4 Hz). 19F NMR (282.4 MHz,
CDCl3): −179.8 (dddd, JFH = 11.0, 11.9, 19.5, 31.1 Hz). MS (ESI
positive mode): m/z 416.13 [M + Na]+. IR (neat): 3111, 2925, 1734,
1367, 1271, 1163, 1129, 1071, 783, 766, 459 cm−1. Anal. Calcd for
C17H28FNO6S: C, 51.89; H, 7.17; N, 3.56; S, 8.15. Found: C, 51.85; H,
7.18; N, 3.53; S, 8.06.
Leucine Analogue. Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)-
amino)-2-fluoro-2-(oxomethyl)cyclopropylcarboxylate (( )-6).
General Procedure for the Synthesis of ( )-Z- and ( )-E-6. In a 100
mL round-bottom flask equipped with septum, magnetic stirrer, and
reflux condenser under an argon atmosphere were dissolved 3 (1.78 g,
4.90 mmol, 1 equiv) and 2-iodoxybenzoic acid (4.11 g, 14.69 mmol, 3
equiv) in dry EtOAc (50 mL). The resulting suspension was stirred for 5
h under reflux (85 °C) until complete disappearance of starting material
(monitored by TLC). Upon completion, the reaction mixture was
cooled to room temperature and filtered through a pad of Celite, and the
filtrate was concentrated in vacuo to afford ( )-6. No further
purification was needed.
( )-Z-6. Compound ( )-Z-6 was obtained as a colorless oil in 99%
yield. Analytical TLC (silica gel 60): (20% ethyl acetate in cyclohexane)
Rf = 0.34. 1H NMR (300.1 MHz, CDCl3): 9.90 (d, 1H, JHF = 14.4 Hz),
3.78 (s, 3H), 2.73 (dd, 1H, JHH = 9.1 Hz, JHF = 15.7 Hz), 2.12 (dd, 1H,
JHH = 9.3 Hz, JHF = 19.7 Hz), 1.47 (2s, 18H). 13C NMR (75.4 MHz,
CDCl3): 190.7 (JCF = 17.0 Hz), 168.8 (JCF = 2.6 Hz), 151.0, 150.2, 84.6
(JCF = 242.9 Hz), 83.7, 53.0, 48.3 (JCF = 9.3 Hz), 28.1 (JCF = 7.4 Hz),
27.8, 27.7. 19F NMR (282.4 MHz, CDCl3): −192.9 (ddd, JFH = 14.9,
15.6, 19.7 Hz). MS (ESI positive mode): m/z 383.93 [M + Na]+, 745.00
[2M + Na]+. IR (neat): 3426, 1799, 1736, 1458, 1369, 1276, 1254, 1156,
1121, 829, 784 cm−1. Anal. Calcd for C16H24FNO7: C, 53.18; H, 6.69; N,
3.88. Found: C, 53.19; H, 6.68; N, 3.64.
( )-Z-4. Compound ( )-Z-4 was obtained as a yellow oil in 83%
yield. Analytical TLC (silica gel 60): (20% ethyl acetate in cyclohexane)
Rf = 0.32. 1H NMR (300.1 MHz, CDCl3): 3.89 (dd, 1H, JHH = 14.7 Hz,
JHF = 35.4 Hz), 3.79 (s, 3H), 3.56 (ddd, 1H, JHH = 1.6, 13.9 Hz, JHF = 11.9
Hz), 2.41 (s, 3H), 2.11 (dd, 1H, JHH = 8.6 Hz, JHF = 17.5 Hz), 1.72 (ddd,
1H, JHH = 1.5, 8.5 Hz, JHF = 21.0 Hz), 1.51 (d, 18H). 13C NMR (75.4
MHz, CDCl3): 193.9, 169.3 (JCF = 2.5 Hz), 151.4, 151.2, 84.4 (JCF
=
225.3 Hz), 83.0, 82.9, 52.8, 46.4 (JCF = 9.3 Hz), 30.2, 29.5 (JCF = 21.5
Hz), 27.8, 27.7, 21.7 (JCF = 7.6 Hz). 19F NMR (282.4 MHz, CDCl3):
−172.2 (dddd, JFH = 11.9, 17.5, 20.9, 35.0 Hz). MS (ESI positive mode):
m/z 444.20 [M + Na]+, 865.00 [2M + Na]+. IR (neat): 3446, 3110,
2981, 1799, 1731, 1480, 1430, 1366, 1268, 1117, 1022, 966, 919, 854,
790, 729, 622 cm−1. Anal. Calcd for C18H28FNO7S: C, 51.29; H, 6.70; N,
3.32; S, 7.61. Found: C, 51.27; H, 6.71; N, 3.19; S, 7.22.
( )-E-4. Compound ( )-E-4 was obtained as a yellow oil in 66%
yield. Analytical TLC (silica gel 60): (20% ethyl acetate in cyclohexane)
Rf = 0.36. 1H NMR (300.1 MHz, CDCl3): 3.74 (s, 3H), 3.62 (ddd, 1H,
JHH = 2.1, 14.7 Hz, JHF = 9.9 Hz), 3.26 (dd, 1H, JHH = 14.7 Hz, JHF = 36.3
Hz), 2.46 (ddd, 1H, JHH = 2.1, 8.7 Hz, JHF = 19.1 Hz), 2.36 (s, 3H), 1.50
(d, 18H), 1.31 (dd, 1H, JHH = 8.7 Hz, JHF = 11.9 Hz). 13C NMR (75.4
MHz, CDCl3): 194.4, 168.6, 151.8, 151.5, 86.5 (JCF = 238.3 Hz), 83.4,
83.2, 52.8, 48.7 (JCF = 14.0 Hz), 32.2 (JCF = 22.8 Hz), 30.3, 28.2, 28.1,
25.9 (JCF = 9.9 Hz). 19F NMR (282.4 MHz, CDCl3): −182.0 (dddd, JFH
= 9.9, 11.3, 18.9, 36.2 Hz). MS (ESI positive mode): m/z 444.07 [M +
Na]+, 864.87 [2M + Na]+. IR (neat): 3442, 3090, 2985, 1711, 1702,
1363, 1325, 1249, 1168, 1123, 1025, 858, 618 cm−1. Anal. Calcd for
C18H28FNO7S: C, 51.29; H, 6.70; N, 3.32; S, 7.61. Found: C, 51.28; H,
6.69; N, 3.36; S, 7.53.
( )-E-6. Compound ( )-E-6 was obtained as a white solid in 65%
yield. Mp: 75−77 °C. Analytical TLC (silica gel 60): (20% ethyl acetate
in cyclohexane) Rf = 0.40. 1H NMR (300.1 MHz, CDCl3): 9.57 (d, 1H,
JHF = 4.5 Hz), 3.77 (s, 3H), 2.78 (dd, 1H, JHH = 8.5 Hz, JHF = 17.5 Hz),
1.98 (dd, 1H, JHH = 8.6 Hz, JHF = 11.2 Hz), 1.46 (d, 18H). 13C NMR
(75.4 MHz, CDCl3): 190.9 (JCF = 35.9 Hz), 167.9, 151.5, 151.3, 86.4
(JCF = 245.7 Hz), 84.1, 83.8, 53.3, 49.0 (JCF = 13.2 Hz), 28.0, 27.9, 25.4
(JCF = 9.2 Hz). 19F NMR (282.4 MHz, CDCl3): −203.2 (ddd, JFH = 4.5,
11.3, 16.7 Hz). MS (ESI positive mode): m/z 383.93 [M + Na]+, 745.00
[2M + Na]+. IR (neat): 3393, 2980, 1737, 1439, 1370, 1253, 1254, 1159,
1123, 850, 773 cm−1. Anal. Calcd for C16H24FNO7: C, 53.18; H, 6.69; N,
3.88. Found: C, 53.20; H, 6.73; N, 3.52.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-fluoro-2-
((methylthio)methyl)cyclopropylcarboxylate ((
)-5). General
Procedure for the Synthesis of ( )-Z- and ( )-E-5. In a 50 mL round-
bottom flask equipped with septum and magnetic stirrer under an argon
atmosphere was dissolved ( )-4 (500 mg, 1.19 mmol, 1 equiv) in
MeOH (10 mL) and the mixture cooled to 0 °C. Subsequently, a freshly
prepared solution of NaOMe (161 mg, 2.98 mmol, 2.5 equiv) in MeOH
(1 mL) was added dropwise. The reaction mixture was then stirred for
30 min before methyl iodide (185 μL, 2.98 mmol, 2.5 equiv) was added
dropwise at 0 °C. After being stirred at room temperature for 1 h, the
reaction mixture was poured into cold water and extracted with Et2O (3
× 15 mL). The combined organic layers were dried over anhydrous
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-(1-hy-
droxyethyl)-2-fluorocyclopropylcarboxylate. In a 25 mL round-
bottom flask equipped with septum and magnetic stirrer under an argon
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atmosphere was dissolved ( )-Z-6 (200 mg, 0.553 mmol, 1 equiv) in
THF (6 mL) and the mixture cooled to −20 °C. After the mixture was
stirred for 10 min at −20 °C, methylmagnesium bromide 1 M in THF
(0.830 mL, 0.830 mmol, 1.5 equiv) was added dropwise. The mixture
was stirred for 30 min at −20 °C until complete disappearance of
starting material (monitored by 19F NMR). Then, the reaction mixture
was quenched by saturated NH4Cl solution and stirred for 10 min. The
layers were separated, and the aqueous layer was extracted with EtOAc
(3 × 5 mL). The combined organic layers were washed with brine (10
mL), dried over anhydrous MgSO4, and concentrated in vacuo. The
resulting yellow oil was purified by column chromatography on silica gel
to give the desired product (165 mg, 79%) as a colorless oil. Analytical
(bs). MS (ESI positive mode): m/z 443.13 [M + Na]+, 459.20 [M + K]+,
863.07 [2M + Na]+, 878.87 [2M + K]+. IR (neat): 2983, 1734, 1708,
1655, 1364, 1168, 1125, 1004, 845, 781, 755, 548, 448 cm−1. Anal. Calcd
for C18H29FN2O8: C, 51.42; H, 6.95; N, 6.66. Found: C, 50.98; H, 6.89;
N, 6.71.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-acetyl-2-
fluorocyclopropylcarboxylate (( )-E-7). In a 50 mL round-bottom
flask equipped with septum and magnetic stirrer under an argon
atmosphere was dissolved ( )-E-2a (545 mg, 1.30 mmol, 1 equiv) in
THF (20 mL). The resulting solution was cooled to −78 °C, and
methyllithium 1.5 M in Et2O (1.73 mL, 2.6 mmol, 2 equiv) was added
dropwise. The reaction mixture was stirred for 45 min at −78 °C until
complete disappearance of starting material (monitored by TLC). Then
the reaction mixture was quenched with saturated NH4Cl solution (10
mL) and extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with brine (5 mL), dried over anhydrous MgSO4,
and concentrated in vacuo to afford ( )-E-7 (278 mg, 57%). Analytical
1
TLC (silica gel 60): (40% ethyl acetate in cyclohexane) Rf = 0.48. H
NMR (300.1 MHz, CDCl3): 4.20 (ddd, 1H, JHH = 2.9, 6.6 Hz, JHF = 28.1
Hz), 3.75 (s, 3H), 3.63 (d, 1H, JHH = 2.9 Hz), 2.12 (dd, 1H, JHH = 8.6 Hz,
JHF = 18.9 Hz), 1.74 (dd, 1H, JHH = 8.6 Hz, JHF = 22.6 Hz), 1.49 (2s,
18H), 1.38 (d, 3H, JHH = 6.6 Hz). 13C NMR (75.4 MHz, CDCl3): 169.2
1
TLC (silica gel 60): (20% ethyl acetate in cyclohexane) Rf = 0.33. H
(JCF = 2.2 Hz), 153.7, 151.6, 87.3 (JCF = 237.5 Hz), 84.1, 83.2, 65.0 (JCF
=
NMR (300.1 MHz, CDCl3): 3.76 (s, 3H), 2.65 (dd, 1H, JHH = 8.1 Hz,
JHF = 17.9 Hz), 2.42 (d, 3H, JHF = 5.2 Hz), 2.05 (dd, 1H, JHH = 8.1 Hz,
JHF = 12.0 Hz), 1.46 (s, 9H), 1.44 (s, 9H). 13C NMR (75.4 MHz,
CDCl3): 200.0 (JCF = 28.9 Hz), 166.3 (JCF = 1.1 Hz), 152.7, 151.2, 87.1
(JCF = 252.1 Hz), 83.6, 83.2, 53.2, 49.5 (JCF = 13.2 Hz), 27.7, 26.6, 26.3
(JCF = 8.7 Hz). 19F NMR (282.4 MHz, CDCl3): −193.3 (ddd, JFH = 5.3,
11.9, 17.5 Hz). MS (ESI positive mode): m/z 398.07 [M + Na]+, 773.00
[2M + Na]+. IR (neat): 2984, 1723, 1708, 1366, 1276, 1245, 1216, 1115,
1044, 778, 543 cm−1. Anal. Calcd for C17H26FNO7: C, 54.39; H, 6.98; N,
3.73. Found: C, 54.64; H, 6.95; N, 3.97.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-fluoro-2-
(prop-1-en-2-yl)cyclopropylcarboxylate (( )-8). General Proce-
dure for the Synthesis of ( )-Z- and ( )-E-8. In a 100 mL round-
bottom flask equipped with septum and magnetic stirrer under an argon
atmosphere was added methyltriphenylphosphonium bromide (1.59 g,
4.46 mmol, 2.5 equiv) in Et2O (30 mL). The resulting suspension was
cooled to 0 °C and the mixture stirred for 10 min. Then potassium
bis(trimethylsilyl)amide 0.5 M in toluene (8.92 mL, 4.46 mmol, 2.5
equiv) was added, and the yellow solution was stirred for 10 min at 0 °C.
Subsequently, ( )-7 (670 mg, 1.78 mmol, 1 equiv), previously dissolved
in Et2O (10 mL), was added slowly at 0 °C, and the resulting orange
solution was allowed to warm to room temperature and stirred for 1 h
until complete disappearance of starting material (monitored by TLC
and 19F NMR). Then the reaction mixture was quenched with water,
and the organic layer was separated. The aqueous layer was extracted
with EtOAc (3 × 10 mL), and the combined organic layers were washed
with brine (10 mL), dried over anhydrous MgSO4, and concentrated in
vacuo to afford a brownish oil. The resulting crude oil was purified by
column chromatography on silica gel to afford ( )-8
20.5 Hz), 53.0, 45.0 (JCF = 9.1 Hz), 27.8, 27.6, 26.5 (JCF = 9.4 Hz), 17.8
(JCF = 4.1 Hz). 19F NMR (282.4 MHz, CDCl3): −190.5 (ddd, JFH = 18.1,
22.6, 28.4 Hz). MS (ESI positive mode): m/z 400.07 [M + Na]+, 776.93
[2M + Na]+. IR (neat): 2981, 1733, 1367, 1273, 1248, 1157, 1117, 1053,
868, 852, 836, 785 cm−1. Anal. Calcd for C17H28FNO7: C, 54.10; H,
7.48; N, 3.71. Found: C, 53.93; H, 7.65; N, 3.89.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-acetyl-2-
fluorocyclopropylcarboxylate (( )-Z-7). In a 100 mL round-
bottom flask equipped with septum, magnetic stirrer, and reflux
condenser under an argon atmosphere were dissolved the secondary
alcohol (1.31 g, 3.47 mmol, 1 equiv) and 2-iodoxybenzoic acid (2.91 g,
10.41 mmol, 3 equiv) in dry EtOAc (50 mL). The resulting suspension
was stirred for 7 h under reflux (85 °C) until complete disappearance of
starting material (monitored by 19F NMR). Then, the reaction mixture
was cooled to room temperature and filtered through a pad of Celite,
and the filtrate was concentrated in vacuo. The resulting crude oil was
purified by column chromatography on silica gel to afford ( )-Z-7 as a
yellow oil (677 mg, 69%). Analytical TLC (silica gel 60): (20% ethyl
acetate in cyclohexane) Rf = 0.35. 1H NMR (300.1 MHz, CDCl3): 3.67
(s, 3H), 2.62 (dd, 1H, JHH = 8.8 Hz, JHF = 17.8 Hz), 2.41 (d, 3H, JHF = 3.5
Hz), 1.87 (dd, 1H, JHH = 8.8 Hz, JHF = 20.8 Hz), 1.49 (s, 18H). 13C NMR
(75.4 MHz, CDCl3): 197.7 (JCF = 27.1 Hz), 167.5 (JCF = 2.6 Hz), 153.4,
153.0, 85.6 (JCF = 244.1 Hz), 83.3, 83.2, 52.9, 47.4 (JCF = 9.9 Hz), 27.6,
27.4, 26.6 (JCF = 1.6 Hz), 24.8 (JCF = 8.1 Hz). 19F NMR (282.4 MHz,
CDCl3): −183.9 (tdd, JFH = 3.1, 17.6, 20.6 Hz). MS (ESI positive
mode): m/z 398.07 [M + Na]+, 773.00 [2M + Na]+. IR (neat): 2978,
1733, 1715, 1367, 1272, 1251, 1155, 1115, 1089, 865, 852, 785 cm−1.
Anal. Calcd for C17H26FNO7: C, 54.39; H, 6.98; N, 3.73. Found: C,
54.26; H, 7.11; N, 3.86.
( )-Z-8. Compound ( )-Z-8 was obtained as a white solid in 79%
yield. Mp: 79−81 °C. Analytical TLC (silica gel 60): (10% ethyl acetate
in cyclohexane) Rf = 0.31. 1H NMR (300.1 MHz, CDCl3): 5.32 (dd, 1H,
JHH = Jgem = 1.4 Hz, JHF = 4.6 Hz), 5.24 (d, 1H, JHH = Jgem = 1.4 Hz), 3.71
(s, 3H), 2.29 (dd, 1H, JHH = 8.3 Hz, JHF = 16.9 Hz), 1.93 (s, 3H), 1.76
(dd, 1H, JHH = 8.3 Hz, JHF = 21.3 Hz), 1.51 (s, 18H). 13C NMR (75.4
MHz, CDCl3): 168.9 (JCF = 2.3 Hz), 152.8, 152.2, 136.5 (JCF = 18.5 Hz),
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-(N,O-di-
methylhydroxylaminocarbonyl)-2-fluorocyclopropylcarboxy-
late (( )-E-2a). In a 50 mL round-bottom flask equipped with septum
and magnetic stirrer under an argon atmosphere was dissolved ( )-E-2
(100 mg, 0.27 mmol, 1 equiv) in anhydrous DMF (4 mL), and the
resulting solution was cooled to 0 °C. Subsequently, HBTU (120.6 mg,
0.32 mmol, 1.2 equiv) and DIEA (0.231 mL, 1.33 mmol, 5 equiv) were
added, and the reaction mixture was stirred at 0 °C for 1 h and allowed to
warm to room temperature for 5 min. Then, a solution of N,O-
dimethylhydroxylamine hydrochloride (52 mg, 0.53 mmol, 2 equiv) in
anhydrous DMF (1.5 mL) was added dropwise, and the resulting orange
solution was stirred at room temperature overnight. Upon completion,
the reaction mixture was dissolved with EtOAc (10 mL). The organic
layer was washed with 1 M NaHCO3 solution (2 × 5 mL), water (5 mL),
and brine (5 mL), dried over anhydrous MgSO4, and concentrated in
vacuo. The resulting crude oil was purified by column chromatography
on silica gel to afford ( )-E-2a as a white solid (70 mg, 62%). Mp: 103−
105 °C. Analytical TLC (silica gel 60): (30% ethyl acetate in
cyclohexane) Rf = 0.46. 1H NMR (300.1 MHz, CDCl3): 3.76 (s, 3H),
3.71 (s, 3H), 3.27 (bs, 3H), 2.56 (dd, 1H, JHH = 8.1 Hz, JHF = 20.0 Hz),
2.28 (bm, 1H), 1.46 (s, 18H). 13C NMR (75.4 MHz, CDCl3): 166.5,
152.2, 151.3, 84.2 (JCF = 259.1 Hz), 82.7, 60.7, 53.0, 48.1 (JCF = 13.1
Hz), 27.8, 26.0. 19F NMR (282.4 MHz, CDCl3): −187.2 and −193.2
119.4 (JCF = 7.5 Hz), 87.0 (JCF = 228.1 Hz), 83.0, 82.8, 52.5, 46.2 (JCF
=
10.9 Hz), 28.0, 27.7, 26.3 (JCF = 9.8 Hz), 19.3. 19F NMR (282.4 MHz,
CDCl3): −166.6 (ddd, JFH = 4.5, 16.7, 21.2 Hz). MS (ESI positive
mode): m/z 396.20 [M + Na]+, 769.13 [2M + Na]+. IR (neat): 2980,
1735, 1360, 1269, 1241, 1128, 1092, 916, 876 cm−1. Anal. Calcd for
C18H28FNO6: C, 57.90; H, 7.56; N, 3.75. Found: C, 57.89; H, 7.47; N,
3.61.
( )-E-8. Compound ( )-E-8 was obtained as a white solid in 65%
yield. Mp: 75−77 °C. Analytical TLC (silica gel 60): (10% ethyl acetate
in cyclohexane) Rf = 0.30. 1H NMR (300.1 MHz, CDCl3): 5.00 (dd, 1H,
JHH = Jgem = 1.3 Hz, JHF = 2.7 Hz), 4.79 (d, 1H, JHH = Jgem = 1.3 Hz), 3.75
(s, 3H), 2.58 (dd, 1H, JHH = 8.9 Hz, JHF = 21.4 Hz), 1.88 (s, 3H), 1.72
(dd, 1H, JHH = 8.9 Hz, JHF = 13.5 Hz), 1.45 (s, 18H). 13C NMR (75.4
MHz, CDCl3): 168.0, 151.9, 151.7, 138.2 (JCF = 23.5 Hz), 113.5 (JCF
=
8.1 Hz), 86.5 (JCF = 232.8 Hz), 83.0, 82.8, 52.8, 48.6 (JCF = 15.8 Hz),
27.9, 27.8, 25.8 (JCF = 9.7 Hz), 19.7 (JCF = 6.3 Hz). 19F NMR (282.4
G
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MHz, CDCl3): −181.6 (ddd, JFH = 2.3, 13.6, 20.6 Hz). MS (ESI positive
mode): m/z 396.07 [M + Na]+, 769.00 [2M + Na]+. IR (neat): 2979,
1744, 1714, 1363, 1243, 1162, 1122, 1062, 904, 851, 835, 749 cm−1.
HRMS (ESI positive mode) calcd for C18H28FNO6Na 396.1798, found
396.1794.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-fluoro-2-
isopropylcyclopropylcarboxylate (( )-9). General Procedure for
the Synthesis of ( )-Z- and ( )-E-9. A solution of ( )-8 (207.2 mg,
0.555 mmol, 1 equiv) and tris(triphenylphosphine)rhodium chloride
(51.3 mg, 0.055 mmol, 10 mol %) in toluene (20 mL) was stirred under
a pressure of hydrogen at 20 bar for 24 h, until complete disappearance
of starting material (monitored by TLC). After evaporation of the
solvent in vacuo, the resulting orange crude oil was purified by column
chromatography on silica gel to afford ( )-9.
acetate in cyclohexane) Rf = 0.23. 1H NMR (300.1 MHz, CDCl3): 6.40
(dd, 1H, JHH = Jtrans = 16.2 Hz, JHF = 22.2 Hz), 5.69 (d, 1H, JHH = Jtrans
=
16.2 Hz), 3.78 (s, 3H), 2.79 (dd, 1H, JHH = 8.7 Hz, JHF = 18.9 Hz), 1.57
(dd, 1H, JHH = 9.0 Hz, JHF = 11.1 Hz), 1.48 (2s, 18H). 13C NMR (75.4
MHz, CDCl3): 166.4, 151.2, 150.9, 149.1 (JCF = 17.8 Hz), 116.5, 99.7
(JCF = 12.1 Hz), 84.4 (JCF = 242.5 Hz), 84.1, 83.9, 53.2, 49.3 (JCF = 13.0
Hz), 28.1 (JCF = 9.6 Hz), 27.9, 27.8. 19F NMR (282.4 MHz, CDCl3):
−191.8 (ddd, JFH = 11.3, 19.2, 22.3 Hz). MS (ESI positive mode): m/z
407.13 [M + Na]+. IR (neat): 3439, 2983, 2243, 1733, 1709, 1364, 1235,
1164, 1127, 979, 966, 844, 776 cm−1. Anal. Calcd for C18H25FN2O6: C,
56.24; H, 6.56; N, 7.29. Found: C, 56.26; H, 6.52; N, 7.27.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-(2-cya-
noethyl)-2-fluorocyclopropylcarboxylate (( )-E-14a). In a 50
mL round-bottom flask equipped with septum and magnetic stirrer was
dissolved ( )-E-14 (72 mg, 0.187 mmol, 1 equiv) in EtOAc (2.5 mL).
Subsequently, palladium 10% on dry carbon (19.9 mg, 0.019 mmol, 10
mol %) was added, and the resulting suspension was stirred overnight
under an atmospheric pressure of hydrogen at room temperature until
complete disappearance of starting material (monitored by TLC). The
reaction mixture was filtered through a pad of Celite, and the filtrate was
concentrated in vacuo to afford the expected product as a white solid (68
mg, 94%). No further purification was needed. Mp: 102−104 °C.
Analytical TLC (silica gel 60): (30% ethyl acetate in cyclohexane) Rf =
0.40. 1H NMR (300.1 MHz, CDCl3): 3.73 (s, 3H), 2.64 (m, 2H), 2.51
( )-Z-9. Compound ( )-Z-9 was obtained as a white solid in 89%
yield. Mp: 69−72 °C. Analytical TLC (silica gel 60): (10% ethyl acetate
in cyclohexane) Rf = 0.34. 1H NMR (300.1 MHz, CDCl3): 3.71 (s, 3H),
2.22 (m, 1H), 1.86 (dd, 1H, JHH = 7.8 Hz, JHF = 17.1 Hz), 1.65 (dd, 1H,
JHH = 7.8 Hz, JHF = 21.6 Hz), 1.47 (2s, 18H), 1.11 (d, 3H, JHH = 7.2 Hz),
1.02 (d, 3H, JHH = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): 170.0 (JCF
2.3 Hz), 152.8, 152.3, 89.5 (JCF = 237.4 Hz), 82.3, 82.2, 52.5, 45.8 (JCF
=
=
9.6 Hz), 28.6, 28.2 (JCF = 8.8 Hz), 27.9, 27.8, 18.1, 17.3. 19F NMR (282.4
MHz, CDCl3): −189.9 (ddd, JFH = 17.2, 22.0, 33.6 Hz). MS (ESI
positive mode): m/z 398.13 [M + Na]+, 772.80 [2M + Na]+. IR (neat):
2890, 1753, 1736, 1726, 1366, 1310, 1292, 1276, 1156, 1112, 1089,
1048, 872, 863 cm−1. Anal. Calcd for C18H30FNO6: C, 57.58; H, 8.05; N,
3.73. Found: C, 57.96; H, 8.32; N, 3.67.
(m, 2H), 1.82 (m, 1H), 1.49 (s, 9H), 1.47 (s, 9H), 1.29 (dd, 1H, JHH
=
8.7 Hz, JHF = 12.3 Hz). 13C NMR (75.4 MHz, CDCl3): 170.7, 152.0,
151.6, 118.7, 85.5 (JCF = 257.6 Hz), 83.6, 83.5, 52.5, 46.7 (JCF = 13.9
Hz), 28.5 (JCF = 21.9 Hz), 28.0, 25.7 (JCF = 10.5 Hz), 13.5. 19F NMR
(282.4 MHz, CDCl3): −186.0 (m). MS (ESI positive mode): m/z
409.40 [M + Na]+, 794.87 [2M + Na]+ . IR (neat): 2981, 2249, 1739,
1716, 1438, 1368, 1273, 1252, 1220, 1151, 1118, 1100, 956, 853, 784,
760, 462 cm−1. Anal. Calcd for C18H27FN2O6: C, 55.95; H, 7.04; N, 7.25.
Found: C, 55.94; H, 7.09; N, 7.26.
( )-E-9. Compound ( )-E-9 was obtained as a white solid in 78%
yield. Mp: 64−66 °C. Analytical TLC (silica gel 60): (20% ethyl acetate
in cyclohexane) Rf = 0.38. 1H NMR (300.1 MHz, CDCl3): 3.74 (s, 3H),
2.38 (dd, 1H, JHH = 8.5 Hz, JHF = 21.2 Hz), 1.85 (m, 1H), 1.49 (s, 18H),
1.18 (d, 3H, JHH = 6.9 Hz), 1.17 (m, 1H), 1.06 (d, 3H, JHH = 6.9 Hz). 13
C
NMR (75.4 MHz, CDCl3): 168.7, 152.7, 152.6, 89.7 (JCF = 241.1 Hz),
83.2, 52.6, 48.4 (JCF = 15.2 Hz), 30.2 (JCF = 21.4 Hz), 28.0, 25.8 (JCF
=
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-(3-amino-
propyl)-2-fluorocyclopropylcarboxylate Hydrochloride
(( )-15). General Procedure for the Synthesis of ( )-Z- and ( )-E-
1. A solution of ( )-Z-14 or ( )-E-14a (0.399 mmol, 1 equiv),
chloroform (0.270 mL, 0.399 mmol, 1 equiv), and platinum oxide (13.6
mg, 0.06 mmol, 15 mol %) in EtOH (12 mL) was stirred under a
pressure of hydrogen at 20 bar for 24 h until complete disappearance of
starting material (monitored by TLC). Upon completion, the reaction
mixture was filtered through a pad of Celite, and the filtrate was
concentrated in vacuo to afford ( )-15. No further purification was
needed.
( )-Z-15. Compound ( )-Z-15 was obtained as a pale yellow oil in
89% yield. 1H NMR (300.1 MHz, CD3OD): 3.73 (s, 3H), 2.98 (m, 2H),
2.03 (m, 2H), 1.69 (m, 2H), 1.51 (s, 18H), 1.46 (m, 2H). 13C NMR
(75.4 MHz, CD3OD): 172.7, 153.6, 87.1 (JCF = 231.3 Hz), 84.8, 59.4,
52.8, 40.7, 30.8, 28.9, 28.8, 26.7 (JCF = 15.6 Hz). 19F NMR (282.4 MHz,
CD3OD): −172.5 (bs). MS (ESI positive mode): m/z 391.13 [M + H]+.
IR (neat): 2976, 1744, 1694, 1367, 1279, 1251, 1124, 851, 763, 462
cm−1. HRMS (ESI positive mode): calcd for C18H32FN2O6 391.2244,
found 391.2245
( )-E-15. Compound ( )-E-15 was obtained as a colorless oil in 87%
yield. 1H NMR (300.1 MHz, CD3OD): 3.76 (s, 3H), 3.06 (m, 2H), 2.44
(m, 2H), 2.03 (s, 2H), 1.60−1.48 (m, 20H). 13C NMR (75.4 MHz,
CD3OD): 169.8, 153.4, 153.0, 88.4 (JCF = 237.5 Hz), 84.8, 84.7, 53.3,
40.3, 30.5 (JCF = 21.9 Hz), 28.7, 28.1, 27.0 (JCF = 10.0 Hz), 24.9. 19F
NMR (282.4 MHz, CD3OD): −184.2 (m). MS (ESI positive mode):
m/z 391.07 [M + H]+, 780.80 [2M + H]+. IR (neat): 2984, 1739, 1369,
1154, 1105, 851, 787 cm−1. HRMS (ESI positive mode) calcd for
C18H32FN2O6 391.2244, found 391.2249.
Arginine Analogue. Methyl 1-(N,N-(Di-tert-butyloxy-
carbonyl)amino)-2-(2-nitrovinyl)-2-fluorocyclopropylcarboxy-
late (( )-Z-16). In a 50 mL round-bottom flask equipped with septum
and magnetic stirrer under an argon atmosphere was dissolved ( )-Z-6
(1 g, 2.77 mmol, 1 equiv) in toluene (12 mL) and the mixture cooled to
0 °C. Subsequently, 1,1,3,3-tetramethylguanidine (35 μL, 0.28 mmol, 10
mol %) and nitromethane (1.49 mL, 27.67 mmol, 10 equiv) were added
slowly, and the reaction mixture was stirred for 3 h at 0 °C until complete
10.4 Hz), 20.0, 17.9 (JCF = 7.6 Hz). 19F NMR (282.4 MHz, CDCl3):
−192.1 (ddd, JFH = 14.7, 22.0, 35.6 Hz). MS (ESI positive mode): m/z
398.07 [M + Na]+. IR (neat): 2974, 1745, 1714, 1437, 1355, 1237, 1158,
1122, 1057, 1025, 850, 795, 778, 752 cm−1. Anal. Calcd for
C18H30FNO6: C, 57.58; H, 8.05; N, 3.73. Found: C, 57.24; H, 8.02;
N, 3.72.
Lysine Analogue. Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)-
amino)-2-(2-cyanovinyl)-2-fluorocyclopropylcarboxylate
(( )-14). General Procedure for the Synthesis of ( )-Z- and ( )-E-14.
In a 100 mL round-bottom flask equipped with septum and magnetic
stirrer under an argon atmosphere was dissolved ( )-6 (1.38 g, 3.81
mmol, 1 equiv) in THF (25 mL). Subsequently, diethyl cyanomethyl-
phosphonate (1.23 mL, 7.61 mmol, 2 equiv) and triethylamine (1.07
mL, 7.61 mmol, 2 equiv) were successively added. The resulting
suspension was stirred overnight at room temperature until complete
disappearance of starting material (monitored by TLC). The reaction
mixture was filtered through a pad of Celite, and the filtrate was
concentrated in vacuo. The resulting orange crude oil was purified by
column chromatography on silica gel to afford the expected product as a
white solid.
( )-Z-14. Compound ( )-Z-14 was obtained as a white solid in 78%
yield. Mp: 105−107 °C. Analytical TLC (silica gel 60): (20% ethyl
acetate in cyclohexane) Rf = 0.27. 1H NMR (300.1 MHz, CDCl3): 7.08
(dd, 1H, JHH = Jtrans = 16.3 Hz, JHF = 23.9 Hz), 5.76 (d, 1H, JHH = Jtrans
=
16.3 Hz), 3.79 (s, 3H), 2.39 (dd, 1H, JHH = 8.7 Hz, JHF = 17.0 Hz), 2.04
(dd, 1H, JHH = 8.7 Hz, JHF = 21.5 Hz), 1.51 (s, 18H). 13C NMR (75.4
MHz, CDCl3): 168.7 (JCF = 2.5 Hz), 151.3, 150.9, 145.6 (JCF = 16.1 Hz),
116.4, 100.6 (JCF = 12.6 Hz), 83.8, 83.4, 83.1 (JCF = 237.3 Hz), 53.4, 48.2
(JCF = 9.1 Hz), 29.8 (JCF = 8.5 Hz), 28.2, 28.1. 19F NMR (282.4 MHz,
CDCl3): −182.2 (ddd, JFH = 17.2, 21.5, 24.0 Hz). MS (ESI positive
mode): m/z 407.07 [M + Na]+, 791.00 [2M + Na]+. IR (neat): 3441,
2981, 2236, 1789, 1737, 1458, 1377, 1276, 1156, 1100, 966, 854, 787
cm−1. Anal. Calcd for C18H25FN2O6: C, 56.24; H, 6.56; N, 7.29. Found:
C, 55.97; H, 6.51; N, 7.32.
( )-E-14. Compound ( )-E-14 was obtained as a white solid in 39%
yield. Mp: 123−125 °C. Analytical TLC (silica gel 60): (20% ethyl
H
dx.doi.org/10.1021/jo302222n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
disappearance of starting material (monitored by TLC and 19F NMR).
Triethylamine (0.974 mL, 6.93 mmol, 2.5 equiv) and methanesulfonyl
chloride (0.322 mL, 4.16 mmol, 1.5 equiv) were added, and the reaction
mixture was stirred for 2 h at 0 °C. Upon completion, the reaction
mixture was diluted with EtOAc (30 mL) and washed with saturated
NaHCO3 solution (20 mL). The aqueous layer was extracted with
EtOAc (3 × 10 mL), and the combined organic layers were dried over
anhydrous MgSO4 and concentrated in vacuo to afford the desired
( )-Z-16 as a white solid (796 mg, 71%). The crude product was
directly engaged in the next step. Mp: 106−107 °C. Analytical TLC
(silica gel 60): (30% ethyl acetate in cyclohexane) Rf = 0.57. 1H NMR
(300.1 MHz, CDCl3): 7.67 (dd, 1H, JHH = Jtrans = 13.2 Hz, JHF = 26.1
mmol, 1 equiv) and ( )-Z-18 (80 mg, 0.213 mmol, 1 equiv) were
added. The reaction mixture was stirred overnight at room temperature
until complete disappearance of starting material (monitored by TLC
and 19F NMR). Then, the mixture was quenched with saturated
NaHCO3 solution, and the aqueous layer was extracted with CH2Cl2 (2
× 1 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. The resulting crude product was
purified by column chromatography on silica gel to afford ( )-Z-19 as a
pale yellow oil (35 mg, 24%). Analytical TLC (silica gel 60): (30% ethyl
acetate in cyclohexane) Rf = 0.50. 1H NMR (300.1 MHz, CDCl3): 11.64
(s, 1H), 8.59 (t, 1H, JHH = 5.4 Hz), 7.35−7.18 (10H), 5.08 (s, 2H), 5.05
(s, 2H), 3.63 (m, 2H), 3.57 (s, 3H), 2.33 (dq, 2H, JHH = 5.9 Hz, JHF
25.4 Hz), 1.92 (dd, 1H, JHH = 8.4 Hz, JHF = 18.2 Hz), 1.59 (dd, 1H, JHH
=
=
Hz), 7.30 (d, 1H, JHH = Jtrans = 13.2 Hz), 3.79 (s, 3H), 2.47 (dd, 1H, JHH
=
8.7 Hz, JHF = 16.8 Hz), 2.12 (dd, 1H, JHH = 8.7 Hz, JHF = 21.3 Hz), 1.48
8.3 Hz, JHF = 22.1 Hz), 1.42 (d, 18H). 13C NMR (75.4 MHz, CDCl3):
169.6 (JCF = 2.3 Hz), 163.7, 155.7, 153.4, 152.2, 152.0, 136.9, 134.8,
128.8, 128.7, 128.6, 128.5, 128.2, 127.9, 84.8 (JCF = 231.6 Hz), 83.1, 83.0,
68.0, 67.1, 52.7, 44.7 (JCF = 9.3 Hz), 37.5, 28.9 (JCF = 19.8 Hz), 28.1,
28.0, 27.6 (JCF = 9.7 Hz). 19F NMR (282.4 MHz, CDCl3): −172.6 (m).
MS (ESI positive mode): m/z 687.27 [M + H]+, 709.00 [M + Na]+.
Anal. Calcd for C34H43FN4O10: C, 59.47; H, 6.31; N, 8.16. Found: C,
59.78; H, 6.38; N, 7.93.
(d, 18H). 13C NMR (75.4 MHz, CDCl3): 167.5 (JCF = 2.6 Hz), 150.3,
150.0, 139.1 (JCF = 9.0 Hz), 133.9 (JCF = 14.9 Hz), 82.9, 82.5, 81.2 (JCF
=
F
234.1 Hz), 52.4, 47.2 (JCF = 9.1 Hz), 30.1 (JCF = 9.1 Hz), 29.0, 28.7. 19
NMR (282.4 MHz, CDCl3): −179.1 (ddd, JFH = 16.6, 21.4, 25.9 Hz).
MS (ESI positive mode): m/z 427.07 [M + Na]+, 830.87 [2M + Na]+. IR
(neat): 3446, 2981, 2936, 1796, 1732, 1536, 1463, 1435, 1371, 1276,
1256, 1156, 1097, 1119, 972, 854, 784 cm−1. HRMS (ESI positive
mode): calcd for C17H25FN2O8Na 427.1493, found 427.1485.
Selective Deprotection and Peptide Coupling. Methyl 1-
((tert-Butyloxycarbonyl)amino)-2-fluoro-2-isopropylcyclopro-
pylcarboxylate (( )-Z-11). In a 25 mL round-bottom flask equipped
with septum and magnetic stirrer under an argon atmosphere was
dissolved ( )-Z-9 (150 mg, 0.40 mmol, 1 equiv) in CH3CN (5 mL).
The resulting solution was cooled to 0 °C, ytterbium(III) trifluor-
omethanesulfonate (248 mg, 0.40 mmol, 1 equiv) was added, and the
solution was stirred for 1 h at room temperature until complete
disappearance of starting material (monitored by TLC). Then, the
reaction mixture was dissolved with EtOAc (30 mL), and the organic
layer was washed with water (15 mL). The aqueous layer was extracted
with EtOAc (3 × 10 mL), and the combined organic layers were washed
with saturated NaHCO3 solution (15 mL) and brine (15 mL), dried
over anhydrous MgSO4, and concentrated in vacuo to afford a pale
yellow solid. The resulting crude product was purified by column
chromatography on silica gel to afford ( )-Z-11 as a colorless oil (102
mg, 93%). Analytical TLC (silica gel 60): (30% ethyl acetate in
cyclohexane) Rf = 0.50. 1H NMR (300.1 MHz, CDCl3): 5.30 and 5.06
(bs, 1H), 3.71, 1.85 (m, 2H), 1.52 (dd, 1H, JHH = 7.8 Hz, JHF = 21.4 Hz),
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-(2-nitro-
ethyl)-2-fluorocyclopropylcarboxylate (( )-Z-17). In a 100 mL
round-bottom flask equipped with septum and magnetic stirrer under an
argon atmosphere was dissolved ( )-Z-16 (780 mg, 1.93 mmol, 1
equiv) in EtOH (40 mL) and the mixture cooled to 0 °C. Sodium
borohydride (365 mg, 9.65 mmol, 5 equiv) was added portionwise. After
being stirred at room temperature for 1 h, the reaction mixture was
evaporated. The resulting residue was dissolved in EtOAc and quenched
with saturated NH4Cl solution (20 mL), and the aqueous layer was
extracted by EtOAc (3 × 10 mL). The combined organic layers were
washed with saturated NaHCO3 solution (15 mL) and brine (15 mL),
dried over anhydrous MgSO4, and concentrated in vacuo to afford
( )-Z-17 as a white solid (720 mg, 92%). Mp: 80−82 °C. Analytical
1
TLC (silica gel 60): (30% ethyl acetate in cyclohexane) Rf = 0.33. H
NMR (300.1 MHz, CDCl3): 4.65 (m, 2H), 3.77 (s, 3H), 2.91 (m, 2H),
2.03 (dd, 1H, JHH = 8.7 Hz, JHF = 17.9 Hz), 1.79 (dd, 1H, JHH = 8.7 Hz,
JHF = 15.7 Hz), 1.51 (2s, 18H). 13C NMR (75.4 MHz, CDCl3): 169.5
(JCF = 2.4 Hz), 152.5, 151.7, 83.3, 83.2, 83.0 (JCF = 232.3 Hz), 71.2, 53.1,
44.5 (JCF = 9.4 Hz), 27.9 (JCF = 8.9 Hz), 27.8, 27.7, 27.4 (JCF = 27.3 Hz).
19F NMR (282.4 MHz, CDCl3): −175.2 (dddd, JFH = 15.5, 17.5, 21.5,
1.42 (s, 9H), 1.10 (d, 3H, JHH = 6.9 Hz), 0.92 (d, 3H, JHH = 6.9 Hz). 13
C
NMR (75.4 MHz, CDCl3): 170.2, 155.6, 88.2 (JCF = 236.7 Hz), 80.2,
52.7, 41.4 (JCF = 9.2 Hz), 28.9 (JCF = 20.4 Hz), 28.3, 25.9 (JCF = 7.6 Hz),
17.6 (JCF = 2.1 Hz), 17.3 (JCF = 1.8 Hz). 19F NMR (282.4 MHz, CDCl3):
−195.2 (ddd, JFH = 16.1, 21.2, 35.9 Hz), −195.6 (m). MS (ESI positive
mode): m/z 275.73 [M + H]+, 298.20 [M + Na]+. IR (neat): 3255, 2976,
1710, 1360, 1326, 1254, 1200, 1155, 1047, 1027, 857, 706, 642, 442
cm−1. Anal. Calcd for C13H22FNO4: C, 56.71; H, 8.05; N, 5.09. Found:
C, 56.66; H, 8.07; N, 5.19.
1-((tert-Butyloxycarbonyl)amino)-2-fluoro-2-isopropylcyclo-
propylcarboxylic Acid (( )-Z-12). In a 25 mL round-bottom flask
equipped with septum and magnetic stirrer was dissolved ( )-Z-11
(186 mg, 0.68 mmol, 1 equiv) in a mixture of MeOH/water 2:3 (8.5
mL) and the mixture cooled to 0 °C. Subsequently, lithium hydroxide
(81 mg, 3.38 mmol, 5 equiv) was added slowly, and the solution was
stirred under reflux until complete disappearance of starting material
(monitored by TLC). Upon completion, the reaction mixture was
dissolved with EtOAc (10 mL), and 1 M KHSO4 solution was added
until pH 2. The aqueous layer was extracted with EtOAc (3 × 10 mL),
and the combined organic layers were washed with brine (15 mL), dried
over anhydrous MgSO4, and concentrated in vacuo to afford ( )-Z-12
as a white solid (134.1 mg, 76%). No further purification was needed.
Mp: 161−163 °C. Analytical TLC (silica gel 60): (50% ethyl acetate in
cyclohexane) Rf = 0.17. 1H NMR (300.1 MHz, CD3OD): 5.00 (bs, 1H),
2.07 (dq, 1H, JHH = 6.9 Hz, JHF = 33.2 Hz), 1.80 (dd, 1H, JHH = 7.5 Hz,
JHF = 15.9 Hz), 1.45 (s, 9H), 1.43 (dd, 1H, JHH = 7.6 Hz, JHF = 20.9 Hz),
1.14 (d, 3H, JHH = 7.0 Hz), 1.04 (d, 3H, JHH = 6.9 Hz). 13C NMR (75.4
24.6 Hz). MS (ESI positive mode): m/z 428.93 [M + Na]+. IR (neat):
3441, 2976, 2931, 1740, 1556, 1435, 1368, 1276, 1248, 1159, 1123,
1097, 854, 790 cm−1. HRMS (ESI positive mode): calcd for
C17H27FN2O8Na 429.1649, found 429.1635.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-(2-amino-
ethyl)-2-fluorocyclopropylcarboxylate (( )-Z-18). A solution of
( )-Z-17 (272 mg, 0.670 mmol, 1 equiv) and palladium 10% on dry
carbon in MeOH (6 mL) was stirred under a pressure of hydrogen at 10
bar for 16 h, until complete disappearance of starting material
(monitored by TLC). Upon completion, the reaction mixture was
filtered through a pad of Celite, and the filtrate was concentrated in
vacuo to afford the desired product (217 mg, 86%). No further
purification was needed. 1H NMR (300.1 MHz, CDCl3): 4.20 (bs, 2H),
3.75 (s, 3H), 3.07 (m, 2H), 2.53 (m, 2H), 1.99 (dd, 1H, JHH = 8.3 Hz, JHF
= 13.1 Hz), 1.67 (dd, 1H, JHH = 7.9 Hz, JHF = 21.8 Hz), 1.48 (d, 18H).
13C NMR (75.4 MHz, CDCl3): 169.5, 153.0, 151.8, 84.8 (JCF = 219.2
Hz), 83.7, 83.2, 53.1, 44.8 (JCF = 9.4 Hz), 37.6, 30.9 (JCF = 19.9 Hz),
28.2, 27.7 (JCF = 9.5 Hz). 19F NMR (282.4 MHz, CDCl3): −172.4
(dddd, JFH = 14.6, 17.4, 22.6, 33.6 Hz). MS (ESI positive mode): m/z
377.00 [M + H]+. IR (neat): 1699, 1225, 1158, 1105, 1086, 1031, 1011,
846, 782 cm−1. HRMS (ESI positive mode): calcd for C17H30FN2O6
377.2088, found 377.2092.
Methyl 1-(N,N-(Di-tert-butyloxycarbonyl)amino)-2-(2-(2,3-
bis((benzyloxy)carbonyl)guanidine)ethyl)-2-fluorocyclopro-
pylcarboxylate (( )-Z-19). In a 10 mL round-bottom flask equipped
with septum and magnetic stirrer under an argon atmosphere was
dissolved N,N′-di-Cbz-N″-trifluoromethanesulfonylguanidine (95 mg,
0.213 mmol, 1 equiv) in CH2Cl2 (1 mL). Triethylamine (28 μL, 0.213
MHz, CD3OD): 176.2, 161.1, 91.9 (JCF = 235.0 Hz), 83.2, 45.0 (JCF
=
9.2 Hz), 31.1 (JCF = 20.2 Hz), 29.4, 26.3 (JCF = 8.2 Hz), 18.0 (JCF = 2.3
Hz), 17.8 (JCF = 1.8 Hz). 19F NMR (282.4 MHz, CD3OD): −191.9
I
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Featured Article
(ddd, JFH = 16.1, 20.9, 33.9 Hz), −192.5 (ddd, JFH = 16.1, 20.3, 34.7 Hz).
MS (ESI positive mode): m/z 259.93 [M-H]−. IR (neat): 3246, 3089,
2977, 1691, 1646, 1408, 1367, 1165, 1084, 861, 795, 785, 618 cm−1.
Anal. Calcd for C12H20FNO4: C, 55.16; H, 7.72; N, 5.36. Found: C,
55.08; H, 7.96; N, 5.51.
634 cm−1. HRMS (ESI positive mode): calcd for C16H28FN2O5
347.1982, found 347.1993.
Methyl 2-(1-Amino-2-fluoro-2-isopropylcyclopropylcarbox-
amido)propanoate Hydrochloride (Z-21). The same procedure as
described for the synthesis of ( )-Z-10 was applied to Z-20 to generate
1
Z-21 as a brownish oil in a quantitative yield. H NMR (300.1 MHz,
Methyl 1-Amino-2-fluoro-2-isopropylcyclopropylcarboxy-
late Hydrochloride (( )-Z-10). In a 25 mL round-bottom flask
equipped with septum and magnetic stirrer was dissolved ( )-Z-9 (700
mg, 1.87 mmol, 1 equiv) in MeOH (5 mL). A solution of HCl 4 M in
dioxane (3.5 mL) was added slowly, and the solution was stirred at room
temperature until complete disappearance of starting material
(monitored by TLC). Then, the reaction mixture was concentrated in
vacuo to afford ( )-Z-10 as a pale yellow solid (395 mg, quant.). No
CD3OD): 4.47 (bm, 1H), 3.69 (s, 3H), 3.57 (s, 2H), 2.18 (bm, 1H),
1.79 (bm, 2H), 1.41 (s, 3H), 1.20 (s, 3H), 1.08 (s, 3H). 13C NMR (75.4
MHz, CD3OD): 173.3, 165.8, 85.8 (JCF = 236.1 Hz), 53.4, 43.8, 42.2,
30.1 (JCF = 19.3 Hz), 20.1 (JCF = 13.1 Hz), 17.8, 17.1, 17.0. 19F NMR
(282.4 MHz, CD3OD): −197.9 (bs). MS (ESI positive mode): m/z
247.11 [M − HCl], 492.80 [2M − HCl]. HRMS (ESI positive mode):
calcd for C11H20FN2O3 247.1458, found 247.1456.
1
further purification was needed. Mp: 192−194 °C. H NMR (300.1
Methyl 2-(1-(2-(((Benzyloxy)carbonyl)amino)propanamido)-
2-fluoro-2-isopropylcyclopropylcarboxamido)propanoate (Z-
22). In a 10 mL round-bottom flask equipped with septum and
magnetic stirrer under an argon atmosphere was dissolved N-
(benzyloxycarbonyl)-L-alanine (47 mg, 0.21 mmol, 3 equiv) was
dissolved in anhydrous DMF (1 mL), and the resulting solution was
cooled to 0 °C. Subsequently, HATU (81 mg, 0.21 mmol, 3 equiv) and
N-methylmorpholine (39 μL, 0.36 mmol, 5 equiv) were added, and the
reaction mixture was stirred at 0 °C for 30 min and allowed to warm to
room temperature for 30 min. Then, a solution of Z-21 (20 mg, 0.07
mmol, 1 equiv) in anhydrous DMF (0.5 mL) was added dropwise, and
the resulting brownish solution was stirred at room temperature
overnight. Upon completion, the reaction mixture was dissolved with
EtOAc (10 mL). The organic layer was washed with 1 M NaHCO3
solution (2 × 5 mL), water (5 mL), and brine (5 mL), dried over
anhydrous MgSO4, and concentrated in vacuo. The resulting crude oil
was purified by column chromatography on silica gel to afford Z-22 as a
mixture of diastereomers (overall yield 76%) which can be easily
separated by SFC (CHIRALPAK column IA 250 × 20 mm, mobile
phase CO2 85% MeOH 15%, flow rate 60 mL/min, T = 35 °C, P outlet
100bet, 220 nm). Analytical TLC (silica gel 60): (40% cyclohexane in
ethyl acetate) Rf = 0.35. MS (ESI positive mode): m/z 475.27 [M +
Na]+. IR (neat): 3269, 3040, 2970, 2880, 1744, 1656, 1624, 1523, 1450,
1317, 1384, 1359, 1072, 1011, 885, 755 cm−1. Anal. Calcd for
C22H30FN3O6: C, 58.53; H, 6.70; N, 9.31. Found: C, 58.87; H, 6.76;
N, 9.31.
MHz, CD3OD): 3.91 (s, 3H), 2.08 (dq, 1H, JHH = 6.9 Hz, JHF = 34.3
Hz), 1.97 (m, 2H), 1.22 (d, 3H, JHH = 7.0 Hz), 1.07 (d, 3H, JHH = 6.9
Hz). 13C NMR (75.4 MHz, CD3OD): 167.6, 87.6 (JCF = 235.5 Hz),
54.6, 41.1 (JCF = 9.5 Hz), 29.7 (JCF = 20.1 Hz), 23.2 (JCF = 9.3 Hz), 17.8
(JCF = 1.8 Hz). 19F NMR (282.4 MHz, CD3OD): −196.6 (m). GCMS:
m/z 175 [M − HCl]. IR (neat): 2981, 2879, 2671, 2165, 1995, 1741,
1525, 1339, 1316, 1257, 1197, 1165, 889, 865, 784, 688, 539 cm−1. Anal.
Calcd for C8H15ClFNO2: C, 45.40; H, 7.14; N, 6.62. Found: C, 45.53;
H, 7.41; N, 6.60.
1-Amino-2-fluoro-2-isopropylcyclopropylcarboxylic Acid
Hydrochloride (( )-Z-13). In a 100 mL round-bottom flask equipped
with septum, magnetic stirrer, and reflux condenser was dissolved
( )-Z-9 (366 mg, 0.975 mmol) in a solution of AcOH/HCl 12 N (1:1)
(50 mL). The solution was stirred under reflux for 30 h until complete
disappearance of starting material (monitored by 19F NMR). Then, the
reaction mixture was concentrated in vacuo. The residue was dissolved
in 1 M HCl solution, and the aqueous phase was washed with CH2Cl2
(10 mL) and Et2O (10 mL). Subsequently, the aqueous phase was
lyophilized to afford ( )-Z-13 as a pale brownish solid (354 mg, 88%).
Mp: 204−207 °C. 1H NMR (300.1 MHz, CD3OD): 5.93 (bs, 2H), 1.98
(bm, 3H), 1.14−1.04 (bm, 6H). 13C NMR (75.4 MHz, CD3OD): 169.8,
87.8 (JCF = 233.9 Hz), 41.9, 29.9 (JCF = 17.6 Hz), 23.6, 18.2. 19F NMR
(282.4 MHz, CD3OD): −197.1 (bs). MS (ESI negative mode): m/z
160.08 [M − H − HCl]−. IR (neat): 2971, 2878, 1717, 1579, 1488,
1427, 1192, 1136, 1054, 889, 859, 677, 629, 551, 516 cm−1. HRMS (ESI
negative mode): calcd for C7H11FNO2 160.0774, found 160.0771.
Methyl 2-(1-((tert-Butyloxycarbonyl)amino)-2-fluoro-2-
isopropylcyclopropylcarboxamido)propanoate (Z-20). In a 100
mL round-bottom flask equipped with septum and magnetic stirrer
under an argon atmosphere was dissolved ( )-Z-12 (258 mg, 0.99
mmol, 1 equiv) in anhydrous DMF (15 mL), and the resulting solution
was cooled to 0 °C. Subsequently, HATU (451 mg, 1.19 mmol, 1.2
equiv) and DIEA (895 μL, 5.14 mmol, 5.2 equiv) were added, and the
reaction mixture was stirred at 0 °C for 30 min and allowed to warm to
room temperature for 30 min. Then, a solution of alanine methyl ester
hydrochloride (579 mg, 4.15 mmol, 4.2 equiv), DBU (621 μL, 4.15
mmol, 4.2 equiv), and DMAP (507 mg, 4.15 mmol, 4.2 equiv) in
anhydrous DMF (15 mL) was added dropwise, and the resulting yellow
solution was stirred at room temperature overnight. Upon completion,
the reaction mixture was dissolved with EtOAc (50 mL). The organic
layer was washed with 1 M NaHCO3 solution (3 × 15 mL) and brine (15
mL), dried over anhydrous MgSO4, and concentrated in vacuo. The
resulting crude oil was purified by column chromatography on silica gel
to afford Z-20 (276 mg, 57%) as a mixture of diastereomers (1:1) as a
yellowish oil. Analytical TLC (silica gel 60): (30% ethyl acetate in
cyclohexane) Rf = 0.36. 1H NMR (300.1 MHz, CDCl3): 7.48, 7.18 (bs,
1H), 5.23, 5.20 (bs, 1H), 4.55 (q, 1H, JHH = 7.2 Hz), 3.73−3.71 (s, 3H),
1.96 (dd, 1H, JHH = 7.7 Hz, JHF = 16.7 Hz), 1.95 (m, 1H), 1.45−1.44 (s,
9H), 1.37 (d, 3H, JHH = 7.2 Hz), 1.28 (dd, 1H, JHH = 7.7 Hz, JHF = 21.8
Hz), 1.10−1.08 (d, 3H, JHH = 7.0 Hz), 0.98−0.96 (d, 3H, JHH = 7.0 Hz).
13C NMR (75.4 MHz, CDCl3): 173.2, 168.3, 168.1, 156.1, 156.0, 88.6
Diastereoisomer 1. White solid. Mp: 173−175 °C. [α]20D = −92.8
(0.25, CHCl3). 1H NMR (300.1 MHz, CDCl3): 7.45 (d, 1H, JHH = 7.5
Hz), 7.32 (s, 5H), 6.73 (bs, 1H), 5.29 (d, 1H, JHH = 5.1 Hz), 5.10 (2d,
2H), 4.47 (q, 1H, JHH = 7.2 Hz), 4.05 (q, 1H, JHH = 6.4 Hz), 3.69 (s, 3H),
2.06 (m, 1H), 1.98 (dd, 1H, JHH = 7.8 Hz, JHF = 17.1 Hz), 1.36 (m, 6H),
1.26 (m, 1H), 1.10 (d, 3H, JHH = 7.0 Hz), 1.03 (d, 3H, JHH = 6.9 Hz). 13
C
NMR (75.4 MHz, CDCl3): 173.8, 173.2, 167.5, 156.4, 135.8, 128.6−
128.0, 88.2 (JCF = 234.9 Hz), 67.3, 52.2, 51.1, 48.6, 41.3 (JCF = 8.7 Hz),
28.1 (JCF = 20.1 Hz), 24.2 (JCF = 8.4 Hz), 17.8, 17.0. 19F NMR (282.4
MHz, CDCl3): −194.07 (ddd, JFH = 17.2 Hz, 21.7 Hz, 35.3 Hz).
Diastereoisomer 2. White solid. Mp: 136−139 °C. [α]20 = +34.4
D
(0.25, CHCl3). 1H NMR (300.1 MHz, CDCl3): 7.58 (d, 1H, JHH = 6.9
Hz), 7.34 (s, 5H), 6.96 (bs, 1H), 5.40 (d, 1H, JHH = 5.6 Hz), 5.11 (s,
2H), 4.50 (q, 1H, JHH = 7.1 Hz), 4.20 (q, 1H, JHH = 6.7 Hz), 3.70 (s, 3H),
2.00 (m, 1H), 1.93 (dd, 1H, JHH = 7.7 Hz, JHF = 16.7 Hz), 1.41 (t, 6H, JHH
= 7.0 Hz), 1.27 (m, 1H), 1.11 (d, 3H, JHH = 7.0 Hz), 1.05 (d, 3H, JHH
=
6.9 Hz). 13C NMR (75.4 MHz, CDCl3): 174.2, 173.2, 167.4, 156.4,
135.9, 128.6−128.1, 87.7 (JCF = 235.9 Hz), 67.2, 52.4, 50.9, 48.6, 41.8
(JCF = 9.0 Hz), 28.4 (JCF = 20.3 Hz), 23.7 (JCF = 9.3 Hz), 17.9, 17.4. 19
NMR (282.4 MHz, CDCl3): −194.09 (m).
F
1-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-fluoro-2-
isopropylcyclopropylcarboxylic Acid (( )-Z-23). In a 10 mL
round-bottom flask equipped with septum and magnetic stirrer was
dissolved ( )-Z-13 (20 mg, 0.101 mmol, 1 equiv) in dioxane (0.6 mL)
and water (0.6 mL), and the resulting solution was cooled to 0 °C.
Subsequently, K2CO3 (55.8 mg, 0.404 mmol, 4 equiv) was added,
followed by 9-fluorenylmethyl succinimidyl carbonate (37.4 mg, 0.111
mmol, 1.1 equiv) previously dissolved in dioxane (0.175 mL). The
reaction mixture was stirred at 0 °C for 1 h and at 40 °C for 3 h. Upon
completion, the reaction mixture was dissolved with EtOAc (5 mL). The
desired acid was extracted with 1 M NaHCO3 solution (2 × 5 mL) in its
(JCF = 235.2 Hz), 81.2, 52.6, 52.5, 48.6, 48.5, 42.5, 28.5 (JCF = 7.2 Hz),
28.3, 28.2, 27.0, 24.2, 18.7, 18.3, 17.5, 17.4. 19F NMR (282.4 MHz,
CDCl3): −194.4 (m), −195.1 (m). MS (ESI positive mode): m/z
369.13 [M + Na]+, 714.80 [2M + Na]+. IR (neat): 3293, 2971, 1755,
1694, 1647, 1507, 1367, 1275, 1249, 1207, 1160, 1059, 1041, 982, 853,
J
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The Journal of Organic Chemistry
Featured Article
sodium salt form. Then, the combined aqueous layers were acidified to
pH 1 by addition of 1 M HCl solution and extracted with EtOAc (3 × 5
mL). The combined organic layers were washed with brine (5 mL),
dried over anhydrous MgSO4, and concentrated in vacuo to afford
( )-Z-23 (26.5 mg, 68%) as a white solid. No further purification was
needed. Mp: 180−182 °C. Analytical TLC (silica gel 60): (5% methanol
in dichloromethane) Rf = 0.19. 1H NMR (300.1 MHz, CD3OD): 8.01
(bs, 1H), 7.80 (d, 2H, JHH = 8.1 Hz), 7.69 (d, 2H, JHH = 7.4 Hz), 7.35 (dt,
4H, JHH = 7.4 Hz, JHH = 24.7 Hz), 4.28 (m, 3H), 2.17 (dq, 1H, JHH = 7.1
Hz, JHF = 33.3 Hz), 1.84 (dd, 1H, JHH = 7.5 Hz, JHF = 16.0 Hz), 1.52 (dd,
1H, JHH = 7.5 Hz, JHF = 21.2 Hz), 1.18 (d, 3H, JHH = 7.0 Hz), 1.11 (d, 3H,
JHH = 6.9 Hz). 13C NMR (75.4 MHz, CD3OD): 173.6, 159.2, 145.3,
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M.; Twining, L. A. Tetrahedron 2005, 61, 11488−11500. (l) Wipf, P.;
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66, 1657−1671.
142.6, 128.8, 128.2, 126.4, 120.9, 89.4 (JCF = 235.0 Hz), 68.2, 42.6 (JCF
=
9.1 Hz), 30.0 (JCF = 20.5 Hz), 26.4 (JCF = 8.6 Hz), 18.1, 17.9. 19F NMR
(282.4 MHz, CDCl3): −193.0 (m). MS (ESI negative mode): m/z
381.80 [M − H]−, 764.87 [2M − H]−. HRMS (ESI negative mode):
calcd for C22H21FNO4 382.1455, found 382.1451.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of spectra for the new compounds; crystallographic
information (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) (a) Lemonnier, G.; Zoute, L.; Quirion, J.-C.; Jubault, P. J. Org.
Chem. 2009, 74, 4124−4131. (b) Lemonnier, G.; Zoute, L.; Quirion, J.-
C.; Jubault, P. Org. Lett. 2010, 12, 844−846. (c) Lemonnier, G.; Lion,
C.; Quirion, J.-C.; Pin, J.-P.; Goudet, C.; Jubault, P. Bioorg. Med. Chem.
2012, 20, 4716−4726. (d) Tarui, A.; Kawashima, N.; Sato, K.; Omote,
M.; Ando, A.; Kumadaki, I. Tetrahedron Lett. 2010, 51, 2000−2003.
(e) Tarui, A.; Kawashima, N.; Sato, K.; Omote, M.; Ando, A.
Tetrahedron Lett. 2010, 51, 4246−4249.
AUTHOR INFORMATION
Corresponding Author
*E-mail: philippe.jubault@insa-rouen.fr.
■
Notes
(9) (a) Ivashkin, P.; Couve-Bonnaire, S.; Jubault, P.; Pannecoucke, X.
Org. Lett. 2012, 14, 2270−2273. For alternative approaches toward the
synthesis of monofluorinated cyclopropanes, see: (b) Shen, X.; Zhang,
W.; Zhang, L.; Luo, T.; Wan, X.; Gu, Y.; Hu, J. Angew. Chem., Int. Ed.
2012, 51, 6966−6970. (c) Seyferth, D.; Woodruff, R. A. J. Org. Chem.
1973, 38, 4031−4039. (d) Tamura, O.; Hashimoto, M.; Kobayashi, Y.;
Katoh, T.; Nakatani, K.; Kamada, M.; Hayakawa, I.; Akiba, T.;
Tereshima, S. Tetrahedron Lett. 1992, 33, 3483−3486. (e) Meyer, O.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We warmly thank Janssen for financial support (Ph.D. grant to
■
G.M.). This work was supported by MESR (Minister
̀
e de
ieur et de la Recherche), FEDER 32819
(European fund for Regional development), the Region Haute-
l′Enseignement Super
́
́
Normandie (CRUNCH program), CNRS, University of Rouen,
and INSA of Rouen.
G. J.; Frohlich, R.; Haufe, G. Synthesis 2000, 1479−1490. (f) Hruschka,
̈
S.; Frohlich, R.; Kirsch, P.; Haufe, G. Eur. J. Org. Chem. 2007, 141−148.
̈
(g) Tamura, O.; Hashimoto, M.; Kobayashi, Y.; Katoh, T.; Nakatani, K.;
Kamada, M.; Hayakawa, I.; Akiba, T.; Tereshima, S. Tetrahedron Lett.
1992, 33, 3487−3490.
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