Synthesis of α,ω-polyfluorinated α-amino acid derivatives and δ,δ-difluoronorvaline

Article abstract of DOI:10.1039/c6ob00131a

Intending to synthesize ω,ω-difluoroalkyl amino acid derivatives by oxidative desulfurization-fluorination reactions of suitable arylthio-2-phthalimido butanoates and pentanoates, in addition to small amounts of the target products, mainly α,ω-polyfluorinated amino acid derivatives were formed by additional sulfur-assisted α-fluorination. This novel structural motif was verified spectroscopically as well as by X-ray analysis. A plausible mechanism of formation is suggested. Using a different approach, δ,δ-difluoronorvaline hydrochloride was synthesized with at least 36% enantiomeric excess via deoxofluorination of the corresponding aldehyde.

Full text of DOI:10.1039/c6ob00131a

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Synthesis of α,ω-polyfluorinated α-amino acid
derivatives and δ,δ-difluoronorvaline†
Cite this: DOI: 10.1039/c6ob00131a
Dirk Ulbrich,a,b Constantin G. Daniliuca and Günter Haufe*a,b
Intending to synthesize ω,ω-difluoroalkyl amino acid derivatives by oxidative desulfurization–fluorination
reactions of suitable arylthio-2-phthalimido butanoates and pentanoates, in addition to small amounts of
the target products, mainly α,ω-polyfluorinated amino acid derivatives were formed by additional sulfur-
assisted α-fluorination. This novel structural motif was verified spectroscopically as well as by X-ray ana-
lysis. A plausible mechanism of formation is suggested. Using a different approach, δ,δ-difluoronorvaline
hydrochloride was synthesized with at least 36% enantiomeric excess via deoxofluorination of the corres-
ponding aldehyde.
Received 15th January 2016,
Accepted 29th January 2016
DOI: 10.1039/c6ob00131a
www.rsc.org/obc
valuable improvements in industrial as well as medicinal
applications.24–26 In this publication we present the syntheses
Introduction
Fluorinated organic molecules play equally important roles in of α,δ-polyfluorinated amino acid derivatives by oxidative
industry1 as well as for medical2–5 and agricultural desulfurization–fluorination as well as the first synthesis of
applications.6–8 For industrial uses especially polyfluorinated 2-amino-5,5-difluoropentanoic acid (δ,δ-difluoronorvaline).
materials are of great interest whereas for medicinal or pestici-
dal purposes interest lies mainly in molecules containing
single fluorine substituents or small fluorinated groups. Due
Results and discussion
to the characteristics of the fluorine substituent, particularly
its strong electronegativity and low polarizability, the physical–
In the course of our research it was our aim to synthesize the
chemical and pharmacokinetic properties of the respective
previously unknown 2-amino-5,5-difluoropentanoic acid
molecules can be directly influenced. These include the com-
(δ,δ-difluoronorvaline). To achieve this, we thought oxidative
pounds’ chemical reactivity, polarity, solubility, etc. Addition-
desulfurization–difluorination was a promising method.27 As
ally, fluorine substitution in strategic positions can increase
the metabolic stability of pharmaceuticals e.g. by preventing
cytochrome mediated oxidation of the oxidation prone sites of
the corresponding molecules.
previously reported,28,29 this kind of reaction can be employed
to convert alkyl aryl thioethers like 1 to the corresponding
ω,ω-difluoromethyl compounds such as 2 (Scheme 1).
For the synthesis of FAAs by oxidative desulfurization–
difluorination first of all suitable starting materials had to be
Amino acids are omnipresent in all organisms. They are not
only found as monomers, but mostly in the polymerized form
prepared. The alkylation of Schiff bases 3 using sodium hexa-
as peptides and proteins.9 The enzymes formed from these
methyl
disilazide
(NaHMDS)
and
3-bromoprop-1-yl-
polymers are crucial for every living organism as they catalyse
chemical reactions inside and outside of cells. Fluorinated
amino acids (FAAs)10–13 can be used to stabilize certain pep-
tides or enzymes and sometimes even increase enzymatic
activity.14–23 Thus the inclusion of FAAs in enzymes can cause
arylthioethers 4 was generally possible (Scheme 2, condition A).
However, alkylation with potassium tert-butoxide in DMSO as
a base, which is already known to be very effective for synthe-
sizing α-amino acid derivatives bearing aliphatic side chains,30
provided simpler access to the required 5-arylthio amino
pentanoic acid derivatives 5 (Scheme 2, condition B).
aOrganisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstraße
40, D-48149 Münster, Germany. E-mail: haufe@uni-muenster.de
bCells-in-Motion Cluster of Excellence, Westfälische Wilhelms-Universität,
Waldeyerstraße 15, D-48149 Münster, Germany
†Electronic supplementary information (ESI) available: Copies of NMR spectra
of compounds 5–10, 12–15, 21, 26–29, 36–41, and spectroscopic data of new
starting materials. CCDC 1429375 and 1429376. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c6ob00131a
Scheme 1 Conversion of alkyl aryl thioethers to difluorides by oxidative
desulfurization–fluorination.
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Although the α-fluorinated products 13b and 13c of the
reaction of 9a could not be separated by column chromato-
graphy, the obtained mixture was extensively investigated by
NMR spectroscopy. The FH-HETCOR NMR spectrum clearly
shows two fluorine signals with shifts of δ = −123.7 ppm and
δ
= −116.8/−117.6 ppm that couple with the C-3 and
Scheme 2 Alkylation of Schiff bases 3a and 3b.
C-4 methylene moieties respectively. While the first is split
into a doublet of doublets of triplets (3JF,H = 26.0, 11.2 Hz,
5JF,F = 1.5 Hz, 1 F, 2-CF), the latter is an AB signal (2JF,F
=
=
281.9 Hz, JF,H = 56.4 Hz, JF,H = 16.2 Hz, JF,F = 1.3 Hz/2JF,F
2
3
5
Due to the possible hydrolysis on silica gel, the products
were not subjected to chromatography. In the following steps,
a nitrogen protection group that is sufficiently stable under the
highly acidic conditions of the fluorination step had to be
introduced. In previous experiments, the phthalimide group
had already proved to be a good choice in this respect. There-
fore, after acidic hydrolysis of the diphenylmethylene imines
5a, 5b and 6b, the obtained free amino acids 7 and 8 were con-
densed with phthalic anhydride to yield thioethers 9 and 10 in
moderate overall yields after three steps from diphenylmethyl-
ene imines 3 (Scheme 3).
2
3
5
281.9 Hz, JF,H = 56.2 Hz, JF,H = 18.7, 16.6 Hz, JF,F = 1.7 Hz,
2 F, 5-CF2H), which shows a distinctive roof effect. While the
long range coupling of the fluorine atoms in the H coupled
1
19F NMR spectrum can only be surmised based on the rela-
tively broad signals, they can clearly be seen in the 1H
decoupled fluorine spectrum. Further proof for the proposed
structures was obtained from the 13C NMR spectrum which
clearly shows coupling of the side chain methylene units with
a monofluoro as well as a difluoro group (see ESI†).
Looking at the ESI-MS spectrum, in addition to the
expected sodium adduct peaks we also noticed a peak that has
to be assigned to the sodium adduct of the α-methoxy com-
pound 17, which originates from the reaction of trifluoride 13c
with methanol (Scheme 6) in a fashion first described by Hud-
homme and Duguay.41 We later recognized that the formation
of such products under ESI conditions is characteristic for all
of the obtained α-fluorinated α-amino acid derivatives. No
reaction, however, was observed when 13c was dissolved in
methanol and maintained at room temperature for 24 hours.
The oxidative desulfurization–fluorination of thioether 10b
leads to similar results. After chromatography, a mixture of
products 14a–c was isolated (Scheme 5). The traces of the
δ,δ-difluoride 14a could subsequently be removed by crystalli-
zation. Although we were not able to separate the two α-fluori-
nated products 14b and 14c from each other
chromatographically, the crystallization yielded single crystals
of methyl 2,5,5-trifluoro-2-phthalimidopentanoate (14c), which
The lower homologue 12 of thioether 10b was accessible
from methyl 4-bromo-2-phthalimidobutanoate31,32 by the sub-
stitution of bromide against phenyl thiolate (Scheme 4).
The subsequent reaction of the aforementioned thioethers
9a and 10b with 1,3-dibromo-5,5-dimethylhydantoin (DBH)
and Olah’s reagent yielded only a small amount of the target
ω,ω-polyfluoroamino acid derivatives. Quite surprisingly, we pri-
marily observed the formation of trifluorides 13c, 14c and 15c as
the major products (Scheme 5). Thus, we found a method to sim-
ultaneously introduce fluorine atoms on two remote C-atoms
separated by one or two methylene groups creating a new struc-
tural motif. It is noteworthy that in contrast to previous reports
of β-hydrogen containing α-FAAs,33–40 our example represents the
first method employing a nucleophilic fluorine source.
Scheme 3 Introduction of the phthalimide protecting group.
Scheme 4 Synthesis of methyl 4-phenylthio-2-phthalimido-butanoate
(12).
Scheme 5 Reaction of thioethers 9, 10 and 12 with DBH and Olah’s
reagent.
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γ,γ-difluoride 15b (19F NMR), which could not be separated
chromatographically from the α-fluorides 15a (49%) and 15c
(48%) (Scheme 5).
To the best of our knowledge, this type of reaction has
never been reported before. We anticipate that the products
13a–c are formed according to the mechanism depicted in
Scheme 7 that is based on postulations by Hugenberg.29,42
Notably, compound 13c can be formed either via pathway A –
first introduction of the α-fluorine atom (IV) and afterwards
oxidative desulfurization fluorination in the δ-position – or via
pathway B, which starts with δ-monofluorination (VII) followed
by α-fluorination (X) and finally introduction of the second
δ-fluorine atom.
Scheme 6 Reaction of 13c with methanol during ESI-MS.
To further elucidate the proposed mechanism, several
control experiments (Scheme 8) were conducted. Simple
addition of pyridine polyhydrofluoride to substrate 9a proved
the stability of the starting material under acidic conditions in
the absence of an electrophile and thus the involvement of a
bromonium species in δ- as well as in α-fluorination. Exposure
of the protected leucine 18 to DBH and Olah’s reagent also did
not lead to any reaction so that the initial bromination in the
α-position followed by substitution with fluoride could be
ruled out. To prove the importance of the sulfur atom for the
α-fluorination, an ether analogue 19 of thioether 9a was syn-
thesized and subjected to standard conditions for oxidative desul-
furization–fluorination. Instead of fluorination, however, only
bromination of the aromatic system resulting in the formation of
20 occurred. To check the probability of the two suggested path-
ways, following a procedure by Robins and Wnuk43 we further-
more synthesized a 5-fluoro derivative 21 of thioether 9 and
subsequently applied our fluorination protocol. Among the
products were δ,δ-difluoride 13a as well as α,δ,δ-trifluoride
were analyzed by X-ray diffraction (Fig. 1). Thus, we gained
definite proof of the constitution of the unexpectedly obtained
polyfluorides.
The application of oxidative desulfurization–fluorination
conditions to thioether 12 also yielded only 3% of the target
Fig. 1 X-ray crystal structure of 14c (CCDC 1429376).
Scheme 7 Proposed mechanisms leading to fluorides 13a–c.
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Scheme 9 Synthesis of aldehyde 26.
Scheme 8 Control experiments to confirm the proposed mechanism.
13c, whereas expectedly the α,δ-difluoride 13b was not
observed. This shows that the generation of 13c via pathway B
is probable, although pathway A cannot be definitely excluded.
Based on the difficulties experienced in selectively synthe-
sizing ω,ω-difluorinated amino acids by oxidative desulfuriza-
tion–difluorination reactions of thioethers, we looked for
alternative routes to our initial target molecules. As deoxo-
fluorination reactions are commonly used to generate difluoro-
methyl moieties from aldehydes,44 we aimed at employing this
convenient methodology for our purposes. At first we planned
to test the applicability of the method with our system by
synthesizing protected rac-2-amino-5-oxopentanoic acid and
reacting it with the deoxofluorinating agents diethyl-
aminosulfur trifluoride (DAST), morpholinosulfur trifluoride
(MOST) and bis-(2-methoxyethyl)aminosulfur trifluoride
(Deoxo-Fluor). The aldehyde 26 was synthesized in a similar
fashion as used for thioethers 9 and 10. Beginning with Schiff
base 3a, rac-methyl 5-oxo-2-phthalimido-pentanoate (26) was
synthesized in 5 steps that included alkylation of 3a, hydrolysis
of the formed imine 23, phthalimide protection of the free
amino group to form 24, hydrogenation of the benzyl ester to
25 and finally oxidation of the terminal hydroxy functionality
to aldehyde 26 (Scheme 9).
Scheme 10 Fluorination of 26 and deprotection of 27.
pKa(COOH) = 2.3 (ref. 46)), and almost one magnitude more
acidic than norvaline (pKa(NH2) = 9.81, pKa(COOH) = 2.32
(ref. 47)), the corresponding value of the carboxy moiety of
2.23 was slightly lower than expected.
One could also imagine a direct route to the analogous
monofluoride 30 by reacting the alcohol 25 with Deoxo-Fluor
and subsequent deprotection. Although the fluorination step to
form 29 was indeed successful, the deprotection step using the
above mentioned method led to a complex mixture of un-
identified, partly defluorinated products (Scheme 11). Thus, the
original procedure to prepare 30 is the only option to date.46
Now that we had proven the general applicability of our
method for synthesizing δ,δ-difluoronorvaline, we approached
the asymmetric synthesis of the target molecule. To make this
happen, the alkylation step had to be carried out in a stereo-
selective manner, for which the assignment of the hydroxy-
pinanone auxiliary seemed promising.48–52 Consequently,
In the following step, aldehyde 26 was reacted with
different deoxofluorinating agents, namely DAST, MOST and
Deoxo-Fluor to yield difluoride 27 (Scheme 10). The reaction
was feasible with all of these reagents, although the yields of
25, 35 and 38% were rather low in all cases.
Having the protected δ,δ-difluorinated amino acid ester 27
in hand, we adapted a method by Griesbeck and Hirt45 to
obtain the free racemic amino acid in the form of the hydro-
chloride salt 28 in 89% yield after solid phase extraction (SPE).
While the pKa value of the amino function was determined to
be 9.01, similar to that of δ-fluoronorvaline (pKa(NH2) = 8.8,
Scheme 11 Failed synthesis of δ-fluoronorvaline 30.
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Scheme 12 Synthesis of (R)-tert-butyl 5-oxo-2-phthalimido-pentanoate (36).
Conclusions
The attempt to synthesize ω,ω-difluorinated α-amino acids
from thioethers by oxidative desulfurization difluorination
only yielded traces of the desired products. Surprisingly,
Scheme 13 Deoxofluorination of (R)-tert-butyl 5-oxo-2-phthalimido- α,ω-polyfluorinated amino acid derivatives 13b,c, 14b,c and
pentanoate (36).
15c, respectively, were formed predominantly. The structure of
compound 14c was verified by X-ray crystallography. The
structures of the other products were determined by NMR
(R)-tert-butyl 5-oxo-2-phthalimidopentanoate was synthesized
from (1S,2S,5S)-(−)-2-hydroxypinane-3-one (31) and tert-butyl
glycine in six steps (Scheme 12).
investigations. A plausible mechanism for these remarkable
and yet unknown reactions by the neighbouring group partici-
pation of the thioether function was proposed and elucidated
by several control experiments. Subsequently, the first syn-
thesis of previously unreported δ,δ-difluoronorvaline was
achieved by the deoxofluorination of a suitable aldehyde
In contrast to the reaction of the racemic aldehyde 26, treat-
ment of 36 with Deoxo-Fluor besides the desired difluoride
37 (34%) also yielded one dominating diastereomer of the
fluorinated lactone 38 (28%) (Scheme 13) that was presumably
formed from the difluoride by lactonization after loss of the
tert-butyl group by acidic hydrolysis due to traces of hydrogen
fluoride in the reaction mixture. Attempts to carry out the
fluorination reaction in a non-acidic environment by addition
of substoichiometric amounts of triethyl amine only yielded
the product in small amounts of up to 9%, although cycliza-
tion was not observed in these cases.
precursor.
Additionally,
enantiomerically
enriched
(R)-δ,δ-difluoronorvaline was obtained by making use of the
hydroxypinanone auxiliary. The pKa value of the target mole-
cule’s amino function was determined to be 9.01 showing the
remarkable influence of the fluorine in the δ-position. The
respective value of the carboxy function was measured to be
2.23 indicating no effect of fluorine on this group.
Subsequent deprotection analogous to the already men-
tioned method45 delivered δ,δ-difluoronorvaline hydrochloride
(39) in 96% yield. For the determination of the enantiomeric
excess a derivatization with (S)-2-chloropropionic acid chloride
(40) (Scheme 14)50,53–55 was necessary, after which an ee value
of 36% was calculated from the 19F NMR signal integrals of
the diastereoisomers.
Experimental section
General methods
Column chromatography was performed on Merck silica gel 60
(40–63 µm). NMR spectra were recorded on Bruker AV300 and
Bruker DPX300 (1H NMR, 300 MHz, 13C NMR, 75 MHz,
19F NMR, 282 MHz), Bruker AV400 (1H NMR, 400 MHz,
13C NMR, 101 MHz) and Agilent DD2 600 (1H NMR: 600 MHz,
13C NMR: 151 MHz, 19F NMR: 564 MHz) spectrometers. TMS
(1H), CDCl3 (13C) and CFCl3 (19F) were used as internal stan-
dards. Mass spectra were recorded on Waters-Micromass Tri-
plequad Quattro Micro GC (EI), Waters-Micromass Quattro
LCZ (ESI), and Bruker Daltonics MicroTof (ESI) instruments.
All air and moisture-sensitive reactions were performed under
an argon atmosphere. Solvents were purified and dried by lit-
erature methods where necessary. Enantiomeric excesses were
determined by using a chiral GC (HP 5890 Series II (FID) with
integrator HP 3396A; Beta-Dex™ 120, 30 m, 0.25 mm, 0.25 μm,
Supelco Co.) or chiral HPLC (for details see ESI†). pKa
Scheme 14 Deprotection of 37 and derivatization of 39 with (S)-
2-chloropropionic acid chloride (40).
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measurements were conducted using the titrator SI Analytics (ESI): [M + H]+ calcd for C26H26ClNO2SH+: 452.1446; found:
TitroLine® 7000 with the dosing unit WA 20 mL. The values 452.1449. Exact mass (ESI): [M
Na]+ calcd for
were calculated by using the TitriSoft 3.0 software. For the C26H26ClNO2SNa+: 474.1265; found: 474.1271.
titration app. 189.65 mg substance were dissolved in 0.1 M Methyl 5-(4-chlorophenyl)thio-2-(diphenylmethylene)amino-
hydrochloric acid (10 mL) and titrated against 1 M NaOH pentanoate (6b). Compound 6b was synthesised according to
+
1
solution.
method A described above for 5a. H NMR (400 MHz, CDCl3,
TMS) δ = 1.49–1.71 (m, 2 H, SCH2CH2), 1.99–2.10 (m, 2 H,
Synthesis of N,O-protected thioether containing amino acids
CHCH2), 2.79 (t, 3JH,H = 7.3 Hz, 2 H, SCH2), 3.70 (s, 3 H, OCH3),
3
Ethyl 5-phenylthio-2-(diphenylmethylene)aminopentanoate 4.07 (dd, JH,H = 7.5, 5.5 Hz, 1 H, CH), 7.11–7.14 (m, 2 H, 2 ×
(5a). Method A: ethyl N-(diphenylmethylene)glycinate (2.673 g, Ph–CH), 7.19 (s, 4 H, C6H4Cl), 7.30–7.35 (m, 2 H, 2 × Ph–CH),
10.0 mmol) was dissolved in abs. THF (20 mL) under an argon 7.38–7.43 (m, 4 H, 4 × Ph–CH), 7.57–7.62 (m, 2 H, 2 × Ph–CH).
atmosphere and the solution was cooled to −40 °C before 13C NMR (101 MHz, CDCl3) δ = 25.3 (SCH2CH2), 32.6 (CHCH2),
adding a 2 M solution of NaHMDS (0.55 mL, 11 mmol) and 33.6 (SCH2), 52.2 (OCH3), 64.7 (CH), 127.8 (Ph–CH), 128.1 (Ph–
stirring for 30 min. Subsequently, a solution of 1-bromo-3- CH), 128.6 (Ph–CH), 128.7 (Ph–C), 128.8 (Ph–CH), 128.9 (2 ×
phenylthiopropane (2.543 g, 11.0 mmol) in abs. THF (11 mL) CHCCl), 130.5 (Ph–CH), 130.7 (2 × SCCH), 131.9 (CCl), 134.9
was added dropwise. After stirring for 2 h at −40 °C and at r.t. (SCCH), 136.2 (Ph–C), 139.2 (Ph–C), 170.8 (NvC), 172.5
overnight, the reaction was quenched with half concentrated (CvO). Exact mass (ESI): [M
+
H]+ calcd for
NaCl solution and the mixture was extracted with Et2O (2 × C25H2435ClNO2SH+: 438.1289; found: 438.1287. Exact mass
15 mL). The organic phase was washed with H2O (15 mL) and (ESI): [M + Na]+ calcd for C25H2435ClNO2SNa+: 460.1108; found:
sat. NaCl solution (15 mL) and dried over MgSO4. Evaporation 460.1107.
of the solvent delivered the product as an orange oil (4.393 g).
The crude product was used in the following step without A:45 after acidic hydrolysis (2 M HCl(aq.), r.t., 24 h) of the Schiff
purification. base, the free amine was mixed with phthalic anhydride and
Ethyl 5-phenylthio-2-phthalimidopentanoate (9a). Method
Method B:30 ethyl N-(diphenylmethylene)glycinate (1.951 g, heated to 140 °C in an open vessel in a microwave at 165 W for
7.3 mmol) was dissolved in DMSO (15 mL) and reacted with 7 min. Column chromatography (CyH/EtOAc 5 : 1) yielded a
KOtBu (819 mg, 7.3 mmol) for 20 min. 1-Bromo-3-phenylthio- yellow oil (527 mg, 1.4 mmol, 18% over 3 steps from ethyl
propane (1.699 g, 7.4 mmol) was added and the mixture was N-(diphenylmethylene)glycinate).
stirred overnight. The reaction was quenched with half concen-
Method B: after acidic hydrolysis the amine was mixed with
trated NaCl solution (20 mL) and the mixture was extracted finely powdered phthalic anhydride and stirred in a pre-heated
with Et2O (30 mL). After washing with H2O and sat. NaCl solu- oil bath at 145 °C for 1 h. Chromatographic purification gave
tion (2 × 30 mL each) the organic phase was dried over MgSO4 the product as a yellow oil (675 mg, 1.8 mmol, 24% over
1
and the solvent was evaporated. The product was obtained as a 3 steps from 5a). H NMR (400 MHz, CDCl3, TMS) δ = 1.22 (t,
yellow oil (2.622 g) that was used in the next step without 3JH,H = 7.1 Hz, 3 H, OCH2CH3), 1.55–1.75 (m, 2 H, SCH2CH2),
purification.
2.35–2.43 (m, 2 H, CHCH2), 2.93 (m, 2 H, SCH2), 4.20 (m, 2 H,
3
3
1H NMR (400 MHz, CDCl3, TMS) δ = 1.24 (t, JH,H = 7.1 Hz, OCH2), 4.82 (dd, JH,H = 8.6, 7.1 Hz, 1 H, CH), 7.08–7.14 (m,
3 H, OCH2CH3), 1.48–1.77 (m, 2 H, SCH2CH2), 2.00–2.12 (m, 2 1 H, para-CH), 7.16–7.23 (m, 2 H, meta-CH), 7.25–7.30 (m, 2 H,
H, CHCH2), 2.83 (t, 3JH,H = 7.3 Hz, 2 H, SCH2), 4.04 (dd, 3JH,H
=
ortho-CH), 7.72–7.78 (m, 2 H, 2 × Phth–CCHCH), 7.83–7.89 (m,
7.3, 5.7 Hz, 1 H, CH), 4.09–4.23 (m, 2 H, OCH2), 7.09–7.66 (m, 2 H, 2 × Phth–CCH). 13C NMR (101 MHz, CDCl3) δ = 14.1
15 H, 15 × Ph–CH). 13C NMR (101 MHz, CDCl3) δ = 14.2 (CH3), (OCH2CH3), 25.9 (SCH2CH2), 27.8 (CHCH2), 33.0 (SCH2), 51.8
25.6 (SCH2CH2), 32.6 (CHCH2), 33.4 (SCH2), 60.9 (OCH2), 64.8 (CH), 61.9 (OCH2), 123.6 (2 × Phth–CCH), 126.0 (C-para), 128.8
(CH), 125.8 (Ph–CH), 127.8 (Ph–CH), 128.0 (Ph–CH), 128.3 (2 × C-meta), 129.5 (2 × C-ortho), 131.7 (Phth–C), 134.2 (Phth–
(Ph–CH), 128.5 (Ph–CH), 128.8 (Ph–CH), 128.8 (Ph–CH), 129.3 CCHCH), 136.0 (C-ipso), 167.7 (Phth–CvO), 169.0 (CO2Et).
(Ph–CH), 130.1 (Ph–CH), 130.4 (Ph–C), 136.3 (Ph–C), 136.4 Exact mass (ESI): [M + H]+ calcd for C21H21NO4SH+: 384.1264;
(Ph–C), 170.7 (NvC), 172.1 (CvO). Exact mass (ESI): [M + H]+ found: 384.1256. Exact mass (ESI): [M + Na]+ calcd for
calcd for C26H27NO2SH+: 418.1835; found: 418.1837. Exact C21H21NO4SNa+: 406.1083; found: 406.1077.
mass (ESI): [M + Na]+ calcd for C26H27NO2SNa+: 440.1655;
found: 440.1657.
Ethyl 5-(4-chlorophenyl)thio-2-phthalimidopentanoate (9b).
Compound 9b (2.950 g, 7.3 mmol, 43% (3 steps from ethyl
Ethyl 5-(4-chlorophenyl)thio-2-(diphenylmethylene)amino- N-(diphenylmethylene)glycinate)) was synthesised according to
1
pentanoate (5b). Compound 5b was synthesised according to method B described above for 9a. H NMR (300 MHz, CDCl3,
1
3
method B described above for 5a. H NMR (300 MHz, CDCl3, TMS) δ = 1.22 (t, JH,H = 8.5 Hz, 3 H, OCH2CH3), 1.52–1.72 (m,
3
TMS) δ = 1.24 (t, JH,H = 7.1 Hz, 3 H, OCH2CH3), 1.46–1.72 (m, 2 H, SCH2CH2), 2.32–2.45 (m, 2 H, CHCH2), 2.79–3.01 (m, 2 H,
2 H, SCH2CH2), 1.95–2.16 (m, 2 H, CHCH2), 2.80 (t, JH,H = 7.4 SCH2), 4.20 (m, 2 H, OCH2), 4.77–4.84 (m, 1 H, CH), 7.12–7.23
3
3
Hz, 2 H, SCH2), 4.03 (dd, JH,H = 7.5, 5.5 Hz, 1 H, CH), (m, 4 H, C6H4Cl), 7.72–7.79 (m, 2 H, 2 × Phth–CCHCH),
4.07–4.24 (m, 2 H, OCH2), 7.09–7.16 (m, 2 H, 2 × Ph–CH), 7.19 7.82–7.89 (m, 2 H, 2 × Phth–CCH). 13C NMR (75 MHz, CDCl3)
(s, 4 H, C6H4Cl), 7.29–7.39 (m, 2 H, 2 × Ph–CH), 7.39–7.47 (m, δ = 14.1 (OCH2CH3), 25.7 (SCH2CH2), 27.6 (CHCH2), 33.2
4 H, 4 × Ph–CH), 7.58–7.63 (m, 2 H, 2 × Ph–CH). Exact mass (SCH2), 51.6 (CH), 62.0 (OCH2), 123.5 (2 × Phth–CCH), 128.9
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(2 × C-meta), 130.9 (2 × C-ortho), 131.6 (Phth–C), 132.0 (C-para), solution was stirred for 30 min at 0 °C and overnight at r.t.
134.3 (Phth–CCHCH), 134.4 (C-ipso), 167.6 (Phth–CvO), 168.9 The mixture was neutralized with ice/sat. NaHCO3 solution
(CO2Et). Exact mass (ESI): [M
C21H2035ClNO4SH+: 418.0874; found: 418.0870. Exact mass layers were washed with 0.1 M HCl solution and 5% NaHCO3
(ESI): [M
Na]+ calcd for C21H20ClNO4SNa+: 440.0694/ solution before the solvent was evaporated. After chromato-
442.0666; found: 440.0687/442.0665. graphy (CyH/EtOAc, 5 : 1) a product mixture (29 mg) that
Methyl
5-(4-chlorophenyl)thio-2-phthalimidopentanoate according to 19F NMR spectroscopy consisted of ethyl 2,5,5-tri-
+
H]+ calcd for and extracted with Et2O (3 × 20 mL). The combined organic
+
(10b). Compound 10b (1.120 g, 2.8 mmol, 72% (3 steps from fluoro-2-phthalimidopentanoate (88%) and ethyl 2,5-difluoro-
methyl N-(diphenylmethylene)glycinate)) was synthesised 2-phthalimidopentanoate (12%) was obtained.
according to method A described above for 9a. 1H NMR
Ethyl 2,5,5-trifluoro-2-phthalimidopentanoate (13c). Identi-
(400 MHz, CDCl3, TMS) δ = 1.52–1.72 (m, 2 H, SCH2CH2), fied out of the mixture received from the above reaction. 1H
3
2.34–2.42 (m, 2 H, CHCH2), 2.80–3.00 (m, 2 H, SCH2), 3.73 (s, NMR (600 MHz, CDCl3, TMS) δ = 1.36 (t, JH,H = 7.2 Hz, 3 H,
3
3 H, OCH3), 4.83 (dd, JH,H = 8.5, 7.2 Hz, 1 H, CH), 7.13–7.22 OCH2CH3), 1.87–2.00 (m, 1 H, CF2HCHa), 2.08–2.22 (m, 1 H,
(m, 4 H, C6H4Cl), 7.73–7.79 (m, 2 H, 2 × Phth–CCHCH), CF2HCHb), 2.57–2.69 (m, 1 H, CFCHa), 3.16–3.24 (m, 1 H,
7.82–7.88 (m, 2 H, 2 × Phth–CCH). 13C NMR (101 MHz, CDCl3) CFCHb), 4.34–4.45 (m, 2 H, OCH2), 5.94 (tt, JH,F = 56.5 Hz,
2
δ = 25.6 (SCH2CH2), 27.6 (CHCH2), 33.2 (SCH2), 51.4 (CH), 3JH,H = 4.3 Hz, 1 H, CF2H), 7.79–7.83 (m, 2 H, Phth–CCHCH),
123.6 (2 × Phth–CCH), 128.9 (2 × C-meta), 130.9 (2 × C-ortho), 7.88–7.92 (m, 2 H, Phth–CCH). 13C NMR (151 MHz, CDCl3) δ =
2
3
131.6 (Phth–C), 132.0 (C-para), 134.3 (Phth–CCHCH), 134.4 14.0 (OCH2CH3), 26.9 (dt, JC,F = 25.4 Hz, JC,F = 6.2 Hz,
(C-ipso), 167.6 (Phth–CvO), 169.5 (CO2Et). Exact mass (ESI): CFCH2), 28.6 (td, 2JC,F = 22.3 Hz, 3JC,F = 3.7 Hz, CF2HCH2), 63.1
[M + H]+ calcd for C20H1835ClNO4SH+: 404.0718; found: 404.0724. (OCH2), 96.4 (d, JC,F = 219.8 Hz), 116.1 (t, JC,F = 239.6 Hz,
1
1
Exact mass (ESI): [M + Na]+ calcd for C20H18ClNO4SNa+: CF2H), 124.1 (Phth–CCH), 131.1 (Phth–C), 135.0 (Phth–
2
3
426.0537/428.0509; found: 426.0537/428.0512.
CCHCH), 165.7 (d, JC,F = 32.0 Hz, CO2Et), 166.6 (d, JC,F
=
Methyl 4-phenylthio-2-phthalimidobutanoate (12). To
a
1.8 Hz, Phth–CvO). 19F NMR (564 MHz, CDCl3, CFCl3) δ =
2
2
solution of thiophenol (0.11 mL, 1.1 mmol) in DMF (3 mL) −116.8/−117.6 (AB signal, JF,F = 281.9 Hz, JF,H = 56.4 Hz,
was added ethyldiisopropylamine (0.18 mL, 1.1 mmol) and 3JF,H = 16.2 Hz, JF,F = 1.3 Hz/2JF,F = 281.9 Hz, JF,H = 56.2 Hz,
5
2
stirred at r.t. for 10 min. Methyl 4-bromo-2-phthalimidobu- 3JF,H = 18.7, 16.6 Hz, JF,F = 1.7 Hz, 2 F, CF2H), −123.7 (ddt,
5
tanoate31 (341 mg, 1.05 mmol) in DMF (3 mL) was added and 3JF,H = 26.0, 11.2 Hz, JF,F = 1.5 Hz, 1 F, CF). Exact mass (ESI):
5
after stirring for 4 h at r.t. the reaction was quenched with 1 M [M
+
Na]+ calcd for C15H14F3NO4Na+: 352.0767; found:
HCl solution. Then the mixture was extracted with CH2Cl2 (2 × 352.0764. Exact mass (ESI): [M − F− + MeO− + MeOH + Na]+
15 mL) and the combined organic phases were washed with calcd for C17H21F2NO6Na+: 396.1229; found: 396.1226.
water and sat. NaCl solution (2 × 25 mL each), dried over
Ethyl 2,5-difluoro-2-phthalimidopentanoate (13b). Identi-
MgSO4 and the solvent evaporated. Column chromatography fied out of the mixture received from the above reaction of 9a.
3
delivered the product as a yellow oil that gradually solidified to 19F NMR (282 MHz, CDCl3, CFCl3) δ = −123.9 (ddd, JF,H
=
=
5
2
a yellow solid (335 mg, 0.94 mmol, 90%); mp 80–81 °C. 28.0, 11.3 Hz, JF,F = 1.3 Hz, 1 F, 2-CF), −219.9 (tddd, JF,H
3
3
5
1H NMR (300 MHz, CDCl3, TMS) δ = 2.43–2.64 (m, 2 H, 47.0 Hz, JF,H = 26.9 Hz, JF,H = 23.3 Hz, JF,F = 1.3 Hz, 1 F,
CHCH2), 2.81–3.08 (m, 2 H, SCH2), 3.72 (s, 3 H, OCH3), 5.13 CFH2). Exact mass (ESI): [M + Na]+ calcd for C15H15F2NO4Na+:
(dd, JH,H = 9.2, 5.8 Hz, 1 H, CH), 7.13–7.22 (m, 1 H, para-CH), 334.0861; found: 334.0856. Exact mass (ESI): [M − F−
+
3
7.22–7.30 (m, 2 H, meta-CH), 7.30–7.36 (m, 2 H, ortho-CH), MeO− + MeOH + Na]+ calcd for C17H21F2NO6Na+: 378.1320;
7.72–7.78 (m, 2 H, Phth–CCHCH), 7.84–7.90 (m, 2 H, Phth– found: 378.1323.
CCH). 13C NMR (75 MHz, CDCl3) δ = 28.5 (CHCH2), 30.9
Oxidative desulfurization–fluorination of methyl 5-(4-chloro-
(SCH2), 50.8 (CH), 52.9 (OCH3), 123.6 (Phth–CCH), 126.4 phenyl)thio-2-phthalimidopentanoate
(C-para), 129.0 (C-meta), 129.9 (C-ortho), 131.7 (Phth–C), 134.3 chlorophenyl)thio-2-phthalimidopentanoate
(10b). Methyl
(503
5-(4-
mg,
(Phth–CCHCH), 135.3 (C-ipso), 167.6 (2 × Phth–CvO), 169.4 1.25 mmol) was dissolved in CH2Cl2 (8 mL), the solution
(CO2Me). Exact mass (ESI): [M
+
Na]+ calcd for cooled to 0 °C and treated with Olah’s reagent (1.7 mL,
C19H17NO4SNa+: 378.0770; found: 378.0771. Exact mass (ESI): 7.5 mmol, 6 eq.) and DBH (1.430 g, 5.0 mmol, 4 eq.). The red
[M + MeOH + Na]+ calcd for C19H17NO4SCH3OHNa+: 410.1033; solution was stirred for 30 min at 0 °C and overnight at r.t.
found: 410.1033. The structure was confirmed by X-ray diffrac- The mixture was neutralized with ice/sat. NaHCO3 solution
tion (CCDC 1429375).
and extracted with Et2O (3 × 50 mL). The combined organic
layers were washed with 10% aqueous Na2S2O3, 0.1 M HCl and
5% aqueous NaHCO3. The solution was dried over MgSO4
Oxidative desulfurization–fluorination reactions
Oxidative desulfurization–fluorination of ethyl 5-phenylthio- before the solvent was evaporated. Chromatography (CyH/
2-phthalimidopentanoate (9a). Ethyl 5-phenylthio-2-phthali- EtOAc, 5 : 1) yielded a 81 : 14 : 5 (19F NMR) mixture (140 mg) of
midopentanoate (97 mg, 0.25 mmol) was dissolved in CH2Cl2 methyl 2,5,5-trifluoro-2-phthalimidopentanoate (14c) (29%
(2 mL), the solution was cooled to 0 °C and treated with Olah’s yield calcd from 19F NMR ratio), methyl 2,5-difluoro-2-phthali-
reagent (0.28 mL, 1.2 mmol, 4.8 eq.) and 1,3-dibromo-5,5-di- midopentanoate (14b) (5%) and methyl 5,5-difluoro-2-phthali-
methylhydantoin (DBH) (214 mg, 0.75 mmol, 3.0 eq.). The red midopentanoate (14a) (2%). Recrystallization led to isolation
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of a mixture of 14c and 14b (85 : 15) that was subjected to X-ray ice/sat. NaHCO3 solution and extracted with Et2O (2 × 15 mL).
analysis.
The combined organic layers were washed with 1 M aqueous
Methyl
2,5,5-trifluoro-2-phthalimidopentanoate
(14c). HCl, 10% aqueous Na2S2O3, and 5% aqueous NaHCO3. The
Identified out of the mixture received from the above reaction solution was dried over MgSO4 before the solvent was evapo-
of 10b. 1H NMR (600 MHz, CDCl3, TMS) δ = 1.87–1.99 (m, 1 H, rated. Chromatography (CyH/EtOAc, 5 : 1) yielded a mixture of
CF2HCHa), 2.07–2.21 (m, 1 H, CF2HCHb), 2.55–2.70 (m, 1 H, methyl 4-fluoro-2-phthalimidobutanoate (49%, 19F NMR),
CFCHa), 3.14–3.27 (m, 1 H, CFCHb), 3.91 (s, 3 H, OCH3), 5.94 methyl 2,4-difluoro-2-phthalimidobutanoate (48%) and methyl
2
3
(tt, JH,F = 56.4 Hz, JH,H = 4.3 Hz, 1 H, CF2H), 7.78–7.84 (m, 4,4-difluoro-2-phthalimidobutanoate (3%).
2 H, Phth–CCHCH), 7.88–7.93 (m, 2 H, Phth–CCH). 13C NMR
Methyl 4-fluoro-2-phthalimidobutanoate (15a). Identified
2
3
(151 MHz, CDCl3) δ = 27.0 (dt, JC,F = 25.5 Hz, JC,F = 6.2 Hz, out of the mixture received from the above reaction of 12. Only
CFCH2), 28.8 (td, 2JC,F = 22.3 Hz, 3JC,F = 3.6 Hz, CF2HCH2), 53.7 identified signals are listed. 19F NMR (282 MHz, CDCl3, CFCl3)
2
3
(OCH3), 96.5 (d, 1JC,F = 219.8 Hz, CF), 116.2 (t, 1JC,F = 239.6 Hz, δ = −222.5 (tdd, JH,F = 47.2 Hz, JH,F = 24.0, 30.3 Hz, 1 F,
CF2H), 124.3 (Phth–CCH), 131.2 (Phth–C), 135.2 (Phth– CH2F). Exact mass (ESI): [M + Na]+ calcd for C13H12FNO4Na+:
2
3
CCHCH), 166.4 (d, JC,F = 32.1 Hz, CO2Et), 166.7 (d, JC,F
=
288.0643; found: 288.0639.
Methyl 4,4-difluoro-2-phthalimidobutanoate (15b). Identi-
1.9 Hz, Phth–CvO). 19F NMR (564 MHz, CDCl3, CFCl3) δ =
2
2
−117.1/−117.5 (AB signal, JF,F = 281.9 Hz, JF,H = 56.5 Hz, fied out of the mixture received from the above reaction of 12.
3JF,H = 16.7 Hz, JF,F = 1.7 Hz/2JF,F = 281.9 Hz, JF,H = 56.5 Hz, Only identified signals are listed. 19F NMR (282 MHz, CDCl3,
5
2
5
3
2
2
3JF,H = 16.7 Hz, JF,F = 1.9 Hz, 2 F, CF2H), −123.6 (ddt, JF,H
=
CFCl3) δ = −116.2/−119.1 (AB signal, JF,F = 287.8 Hz, JH,F
=
=
26.1, 10.9 Hz, JF,F = 1.5 Hz, 1 F, CF). Exact mass (ESI): 55.7 Hz, JH,F = 16.4 Hz/2JF,F = 287.8 Hz, JH,F = 55.8 Hz, JH,F
5
3
2
3
[M
338.0614. Exact mass (ESI): [M − F− + MeO− + MeOH + Na]+ C13H11F2NO4Na+: 306.0548; found: 306.0538. [M − F− + MeO−
calcd for C16H19F2NO6Na+: 382.1073; found: 382.1075. + MeOH + Na]+ calcd for C13H11F2NO4Na+: 350.1010; found:
Methyl 2,5-difluoro-2-phthalimidopentanoate (13b). Identi- 350.1015.
+
Na]+ calcd for C14H12F3NO4Na+: 338.0611; found: 18.3, 15.9 Hz, 2 F, CF2H). Exact mass (ESI): [M + Na]+ calcd for
fied out of the mixture received from the above reaction of
Methyl 2,4-difluoro-2-phthalimidobutanoate (15c). Identi-
10b. Only identified signals are listed. 1H NMR (600 MHz, fied out of the mixture received from the above reaction of 12.
CDCl3, TMS) δ = 4.54 (dm, 2JH,F = 47.0 Hz, 2 H, CH2F. 13C NMR Only identified signals are listed. 19F NMR (282 MHz, CDCl3,
2
3
(151 MHz, CDCl3) δ = 24.9 (dd, JC,F = 20.3 Hz, JC,F = 3.1 Hz, CFCl3) δ = −124.7 (ddd, 3JH,F = 28.3, 10.4 Hz, 4JF,F = 2.1 Hz, 1 F,
2
3
2
3
4
CFCH2), 24.9 (dd, JC,F = 24.9 Hz, JC,F = 5.8 Hz, CF2HCH2), CF), −220.4 (tddd, JH,F = 46.7 Hz, JH,F = 33.3, 19.3 Hz, JF,F
=
53.5 (OCH3), 83.1 (d, 1JC,F = 166.5 Hz, CF), 97.1 (d, 1JC,F = 219.5 2.1 Hz, 1 F, CH2F). The ESI results are already listed for mole-
Hz, CF2H), 124.2 (Phth–CCH), 131.3 (Phth–C), 135.1 (Phth– cule 15b with the same molecular weight above.
2
3
CCHCH), 166.7 (d, JC,F = 32.4 Hz, CO2Et), 166.8 (ds, JC,F
=
2.0 Hz, Phth–CvO). 19F NMR (564 MHz, CDCl3, CFCl3) δ =
3
5
Synthesis of racemic δ,δ-difluoronorvaline
−123.8 (ddd, JF,H = 27.9, 11.0 Hz, JF,F = 1.2 Hz, 1 F, CF),
2
3
3
−220.0 (tddd, JF,H = 47.1 Hz, JF,H = 26.9 Hz, JH,F = 23.0 Hz,
Ethyl 5-benzyloxy-2-(diphenylmethylene)aminopentanoate
5JF,F = 1.2 Hz, 1 F, CH2F). Exact mass (ESI): [M + Na]+ calcd for (23). Ethyl
N-(diphenylmethylene)glycinate
(2.760
g,
C14H13F2NO4Na+: 320.0705; found: 320.0709. Exact mass (ESI): 10.3 mmol) was dissolved in DMSO (10 mL) and according to
[M − F− + MeO− + MeOH + Na]+ calcd for C16H20FNO6Na+: method B described for the synthesis of 5a reacted with KOtBu
364.1167; found: 364.1172.
(1.268 g, 11.3 mmol, 1.1 eq.) and O-tosyl-3-benzyloxy-1-propa-
Methyl 5,5-difluoro-2-phthalimidopentanoate (13a). Identi- nol (3.308 g, 10.3 mmol). The product (3.947 g) was used in
fied in the mixture obtained by the above reaction of 10b. Only the following step without purification. 1H NMR (400 MHz,
1
3
identified signals are listed. H NMR (300 MHz, CDCl3, TMS) CDCl3, TMS) δ = 1.25 (t, JH,H = 7.1 Hz, 3 H, CO2CH2CH3),
δ = 5.85 (tt, 2JH,F = 56.2 Hz, 3JH,F = 4.1 Hz, 2 H, CF2H). 19F NMR 1.45–1.73 (m, 2 H, CH2CH2OBn), 1.91–2.11 (m, 2 H, CHCH2),
(282 MHz, CDCl3, CFCl3) δ = −116.8/−116.8 (AB signal*, 3JF,H
=
3.41 (t, JH,H = 6.6 Hz, 2 H, CH2OBn), 4.06 (dd, JH,H = 7.9,
3
3
2
17.3 Hz, 2 F, 5-CF2H). *The JF,H coupling could not be deter- 5.3 Hz, 1 H CH), 4.10–4.31 (m, 2 H, CO2CH2), 4.44 (s, 2 H,
mined because the signal was partially covered by the ana- OCH2Ph), 7.09–7.20 (m, 2 H, 2 × Ph–CH), 7.21–7.38 (m, 8 H,
2
logous signal of 13c. The JF,F coupling was not possible to 5 × Bn–CH, 3 × Ph–CH), 7.38–7.45 (m, 3 H, 3 × Ph–CH),
determine due to the small outer signals. The ESI results are 7.60–7.66 (m, 2 H, 2 × Ph–CH). 13C NMR (101 MHz, CDCl3) δ =
already listed above for molecule 13b with the same molecular 14.2 (CO2CH2CH3), 26.3 (CH2CH2OBn), 30.3 (CHCH2), 60.8
weight.
(CO2CH2), 65.2 (CH), 70.0 (CH2OBn), 72.8 (OCH2Ph), 127.6 (2 ×
Oxidative desulfurization–fluorination of methyl 4-phe- Bn–CH-ortho), 127.8 (2 × Ph–CH), 128.0 (2 × Bn–CH-meta),
nylthio-2-phthalimidobutanoate (12). Methyl 4-phenylthio- 128.3 (2 × Ph–CH), 128.3 (Bn–CH-para), 128.5 (2 × Ph–CH),
2-phthalimidobutanoate (355 mg, 1.0 mmol) was dissolved in 128.6 (Ph–CH), 128.8 (2 × Ph–CH), 130.3 (Ph–CH), 136.4 (Ph–
CH2Cl2 (3 mL) and treated with Olah’s reagent (1.4 mL, C), 138.5 (Bn–C), 139.5 (Ph–C), 170.5 (CvN), 172.2 (CO2Et).
6.0 mmol, 6 eq.) and cooled to 0 °C. After addition of DBH Exact mass (ESI): [M + H]+ calcd for C27H29NO3H+: 416.2220;
(858 mg, 3.0 mmol, 3 eq.) the solution was stirred for 30 min found: 416.2220. Exact mass (ESI): [M + Na]+ calcd for
at 0 °C and overnight at r.t. The mixture was neutralized with C27H29NO3Na+: 438.2040; found: 438.2037.
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Ethyl
5-benzyloxy-2-phthalimidopentanoate
(24). Ethyl (427 mg, 1.5 mmol, 75%). 1H NMR (400 MHz, CDCl3, TMS) δ =
3
5-benzyloxy-2-(diphenylmethylene)aminopentanoate
(23) 1.24 (t, JH,H = 7.1 Hz, 3 H, CO2CH2CH3), 2.38–2.71 (m, 4 H,
(3.947 g, crude from reaction above) was dissolved in EtOH CH2CHO and CHCH2), 4.22 (m, 2 H, CO2CH2), 4.87 (dd, 3JH,H
=
(40 mL) and treated with 1 M aqueous HCl (40 mL) for 2 h at 10.4, 5.4 Hz, 1 H, CH), 7.71–7.82 (m, 2 H, 2 × Phth–CCHCH),
3
r.t. The mixture was washed with Et2O (50 mL) and the ethe- 7.83–7.92 (m, 2 H, 2 × Phth–CCH), 9.74 (t, JH,H = 1.0 Hz, 1 H,
real phase extracted with 1 M aqueous HCl (20 mL). The com- CHO). 13C NMR (101 MHz, CDCl3) δ = 14.1 (CO2CH2CH3), 21.7
bined aqueous phases were then neutralized with NaHCO3 (CHCH2), 40.5 (CH2CHO), 51.4 (CH), 62.1 (CO2CH2), 123.7
and extracted with Et2O (2 × 50 mL). The combined organic (Phth–CCH), 131.7 (Phth–C), 134.4 (PhthCCHCH), 167.6 (2 ×
phases were washed with sat. aqueous NaHCO3 (30 mL), dried Phth–CvO), 168.6 (CO2Et), 200.4 (CHO). Exact mass (ESI):
over MgSO4 and the solvent evaporated. The residue (1.675 g) [M + H]+ calcd for C15H15NO5H+: 290.1023; found: 290.1024.
and finely mortared phthalic anhydride (992 mg, 6.7 mmol) Exact mass (ESI): [M + Na]+ calcd for C15H15NO5Na+: 312.0842;
were mixed and stirred at 145 °C in a pre-heated oil bath for found: 312.0842.
30 min. The crude product was dissolved in CH2Cl2 and the
Ethyl 5,5-difluoro-2-phthalimidopentanoate (27). A solution
solution dried over MgSO4. After evaporation of the solvent the of ethyl 5-oxo-2-phthalimidopentanoate (26) (595 mg,
product (836 mg, 2.2 mmol, 21% over 3 steps from ethyl 2.1 mmol) in abs. CH2Cl2 (5 mL) was treated with Deoxo-Fluor
N-(diphenylmethylene)glycinate) was purified chromatographi- (2.7 M in PhMe, 1.0 mL, 2.7 mL, 1.3 eq.) and the now
cally (CyH/EtOAc, 5 : 1). 1H NMR (400 MHz, CDCl3, TMS) δ = yellow solution was stirred for 4 h at r.t. After neutralization
3
1.23 (t, JH,H = 7.1 Hz, 3 H, CO2CH2CH3), 1.54–1.74 (m, 2 H, with sat. aqueous NaHCO3, the phases were separated and the
3
CH2CH2OBn), 2.25–2.43 (m, 2 H, CHCH2), 3.48 (t, JH,H
=
aqueous phase extracted with CH2Cl2 (2 × 10 mL). The com-
6.4 Hz, 2 H, CH2OBn), 4.20 (m, 2 H, CO2CH2), 4.47 (s, 2 H, bined organic phases were dried over MgSO4 and the solvent
3
OCH2Ph), 4.85 (dd, JH,H = 10.4, 5.4 Hz, 1 H, CH), 7.22–7.35 evaporated. Chromatographic purification (CH/EtOAc, 5 : 1)
(m, 5 H, 5 × Ph–CH), 7.70–7.78 (m, 2 H, 2 × Phth–CCHCH), yielded the product as a yellow, viscous oil (245 mg, 0.8 mmol,
3
7.83–7.89 (m, 2 H, 2 × Phth–CCH). 13C NMR (101 MHz, CDCl3) 38%). 1H NMR (400 MHz, CDCl3, TMS) δ = 1.24 (t, JH,H
=
δ = 14.1 (CO2CH2CH3), 25.6 (CHCH2), 26.6 (CH2CH2OBn), 52.1 7.1 Hz, 3 H, CO2CH2CH3), 1.75–2.05 (m, 2 H, CH2CF2H),
(CH), 61.8 (CO2CH2), 69.3 (CH2OBn), 73.0 (OCH2Ph), 123.5 2.27–2.54 (m, 2 H, CHCH2), 4.22 (m, 2 H, CO2CH2), 4.85 (dd,
2
3
(Phth–CCH), 127.5 (C-para), 127.6 (C-ortho), 128.3 (C-meta), 3JH,H = 10.2, 5.3 Hz, 1 H, CH), 5.85 (tt, JH,F = 56.4, JH,H
=
131.8 (Phth–C), 134.2 (PhthCCHCH), 138.3 (C-ipso), 167.7 (2 × 4.3 Hz, 1 H, CHF2), 7.72–7.82 (m, 2 H, 2 × Phth–CCHCH),
Phth–CvO), 169.2 (CO2Et). Exact mass (ESI): [M + H]+ calcd 7.85–7.94 (m, 2 H, 2 × Phth–CCH). 13C NMR (101 MHz, CDCl3)
3
for C22H23NO5H+: 382.1649; found: 382.1656. Exact mass (ESI): δ = 14.1 (CO2CH2CH3), 21.9 (t, JC,F = 5.8 Hz, CHCH2), 31.1 (t,
[M + Na]+ calcd for C22H23NO5Na+: 404.1468; found: 404.1473.
2JC,F = 21.7 Hz, CH2CF2H), 51.5 (CH), 62.1 (CO2CH2), 116.4 (t,
Ethyl 5-hydroxy-2-phthalimidopentanoate (25). To a solu- 1JC,F = 239.5 Hz, CHF2), 123.7 (Phth–CCH), 131.6 (Phth–C),
tion of Ethyl 5-benzyloxy-2-phthalimidopentanoate (24) in abs. 134.4 (Phth–CCHCH), 167.6 (2 × Phth–CvO), 168.5 (CO2Et).
EtOH (10 mL) was added Pd/C (10% w/w, 100 mg) and the sus- 19F NMR (282 MHz, CDCl3) δ = −116.78/−116.81 (AB signal,
pension was stirred for 4 h at r.t. under a 2 bar atmosphere of 2JF,F = 281.6 Hz, JF,H = 56.5 Hz, JF,H = 17.3 Hz, 2 F, CF2H).
H2. The catalyst was removed by filtration over celite and the Exact mass (ESI): [M + Na]+ calcd for C15H15F2NO4Na+:
solvent evaporated which yielded the product as a yellowish oil 334.0861; found: 334.0853. Exact mass (ESI): [M + MeOH +
(560 mg, 1.9 mmol, 86%). 1H NMR (400 MHz, CDCl3, TMS) δ = Na]+ calcd for C15H15F2NO4CH3OHNa+: 366.1124; found:
2
3
3
1.23 (t, JH,H = 7.2 Hz, 3 H, CO2CH2CH3), 1.48–1.69 (m, 2 H, 366.1124.
3
CH2CH2OH), 2.21–2.43 (m, 2 H, CHCH2), 3.67 (t, JH,H = 6.5
2-Amino-5,5-difluoropentanoic
acid
hydrochloride
Hz, 2 H, CH2OH), 4.20 (m, 2 H, CO2CH2), 4.88 (dd, 3JH,H = 10.4, (28). Similar to a literature procedure,45 ethyl 5,5-difluoro-2-
5.4 Hz, 1 CH), 7.72–7.80 (m, 2 H, 2 × Phth–CCHCH), 7.82–7.92 phthalimidopentanoate (27) (299 mg, 0.96 mmol) was stirred
(m, 2 H, 2 × Phth–CCH). 13C NMR (101 MHz, CDCl3) δ = 14.1 with 6 N aqueous HCl (5 mL) and HOAc (0.5 mL) in a pressure
(CO2CH2CH3), 25.3 (CHCH2), 29.3 (CH2CH2OH), 52.1 (CH), tube at 130 °C for 16 h. The volatile components were evapo-
61.9 (CO2CH2 and CH2OH), 123.6 (Phth–CCH), 131.8 (Phth–C), rated and the brown residue was dissolved in ice-cold water
134.3 (PhthCCHCH), 167.8 (2 × Phth–CvO), 169.3 (CO2Et). (3 mL). Solid-phase extraction (Chromabond C-18 ec, 500 mg)
Exact mass (ESI): [M + H]+ calcd for C15H17NO5H+: 292.1179; with ice-cold water as an eluent yielded the product as a white
found: 292.1183. Exact mass (ESI): [M + Na]+ calcd for solid (162 mg, 0.85 mmol, 89%). If necessary, residues of
C15H17NO5Na+: 314.0999; found: 314.1002.
phthalic anhydride can be removed by repeated washing with
Ethyl 5-oxo-2-phthalimidopentanoate (26). Ethyl 5-hydroxy- hot Et2O. Mp 209–210 °C (dec.); 1H NMR (400 MHz, CD3OD,
2-phthalimidopentanoate (25) (595 mg, 2.0 mmol) was dis- TMS) δ = 1.89–2.21 (m, 4 H, CHCH2 and CH2CF2H), 4.07 (t,
solved in CH2Cl2 (5 mL) and reacted with Dess–Martin-periodi- 3JH,H = 5.8 Hz, 1 H, CH), 6.00 (tt, JH,F = 56.3, JH,H = 3.6 Hz,
nane (1.038 g, 2.5 mmol, 1.2 eq.) for 2 h at r.t. The reaction 1 H, CHF2). H NMR (300 MHz, (CD3)2SO, TMS) δ = 1.72–2.23
2
3
1
3
was quenched with sat. aqueous NaHCO3 and sat. aqueous (m, 4 H, CHCH2 and CH2CF2H), 3.96 (t, JH,H = 5.3 Hz, CH),
2
3
Na2SO3. After phase separation, the aqueous phase was 6.16 (tt, JH,F = 57.0, JH,H = 3.5 Hz, 1 H, CHF2), 8.60 (br s, 3 H,
extracted with CH2Cl2 (2 × 10 mL) and the solvent evaporated. NH3 ). 13C NMR (101 MHz, CD3OD) δ = 24.1 (t, JC,F = 6.2 Hz,
Filtration over silica yielded the product as a colorless oil CHCH2), 30.9 (t, 2JC,F = 21.9 Hz, CH2CF2H), 53.2 (CH), 117.8 (t,
+
3
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1JC,F = 238.0 Hz, CHF2), 168.5 (CO2H). 19F NMR (282 MHz, organic solvent was evaporated and the aqueous residue was
2
3
CD3OD) δ = −117.2 (dt, JF,H = 56.5 Hz, JF,H = 16.7 Hz, 2 F, washed with n-pentane (3 × 5 mL). Then NaHCO3 was added
CF2H). Exact mass (ESI): [M + H]+ calcd for C5H9F2NO2H+: to the aqueous phase until it reached pH > 7. The solution was
154.0674; found: 154.0670. Exact mass (ESI): [M + Na]+ calcd extracted with Et2O (4 × 5 mL) and the combined organic
for C5H9F2NO2Na+: 176.0494; found: 176.0493. Exact mass phases dried over MgSO4. After evaporation of the solvent the
(ESI): [M + Na]+ calcd for C5H8F2NO2−: 152.0529; found: product (145 mg, 0.52 mmol, 80%) could be used without
152.0530. Elemental analysis: calcd for C5H10ClF2NO2: further purification. [α]2D0 = 2.2 (c = 1.20, CHCl3); 1H NMR
C 31.68%, H 5.32%, N 7.39%; found: C 31.76%, H 5.29%, (400 MHz, CDCl3, TMS) δ = 1.46 (s, 9 H, CO2C(CH3)3),
N 7.49%.
1.56–1.83 (m, 4 H, CO2CHCH2 and CH2CH2OBn), 3.32 (dd,
(R)-tert-Butyl 5-benzyloxy-2-{[(1S,2S,5S,E)-2-hydroxy-2,6,6-tri- 3JH,H = 7.4, 5.2 Hz, 1 H, CH), 3.50 (t, JH,H = 6.1 Hz, 2 H,
methylbicyclo[3.1.1]-heptan-3-ylidene]amino}pentanoate (33). CH2OBn), 4.50 (s, 2 H, OCH2Ph), 7.24–7.31 (m, 1 H, para-CH),
A solution of diisopropylamine (0.28 mL, 2.0 mmol, 2.0 eq.) in 7.31–7.36 (m, 4 H, 2 × ortho-CH and 2 × meta-CH). 13C NMR
abs. THF (2 mL) was cooled to −78 °C and dropwise treated (101 MHz, CDCl3) δ = 25.9 (CH2CH2OBn), 28.0 (CO2C(CH3)3),
with n-butyllithium (1.6 N in hexane, 1.25 mL, 2.0 mmol, 31.8 (CO2CHCH2), 54.8 (CO2CH), 69.9 (CH2OBn), 72.8
2.0 eq.). The solution was stirred at r.t. for 15 min and then (OCH2Ph), 80.9 (C(CH3)3), 127.5 (C-para), 127.6 (2 × C-ortho),
3
t
again cooled to −78 °C. Subsequently a solution of tert-butyl 128.3 (2 × C-meta), 138.5 (C-ipso), 175.4 (CO2 Bu). Exact mass
2-{[(1R,2S,5R,E)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]-heptane- (ESI): [M + H]+ calcd for C16H25NO3H+: 280.1907; found:
3-ylidene]amino}acetate (32) (281 mg, 1.0 mmol) in abs. THF 280.1904. Exact mass (ESI): [M + Na]+ calcd for C16H25NO3Na+:
(1 mL) was added dropwise and the solution was stirred for 302.1727; found: 302.1724.
90 min at the same temperature. After that O-tosyl-3-benzyloxy-
(R)-tert-Butyl 5-benzyloxy-2-phthalimidopentanoate (34).
1-propanol (22) (352 mg, 1.1 mmol, 1.1 eq.) in THF (1.1 mL) (R)-tert-Butyl 2-amino-5-benzyloxypentanoate (42) (559 mg,
was added and the mixture was stirred for 2 h at −78 °C and 2.0 mmol) and finely mortared phthalic anhydride (296 mg,
overnight at r.t. The reaction was quenched by addition of half 2.0 mmol) were mixed and in a pre-heated oil bath stirred at
conc. aqueous NaCl (2.5 mL), the organic phase separated and 145 °C for 1 h. The cold residue was purified chromatographi-
the aqueous phase extracted with Et2O (4 × 8 mL). The com- cally (CyH/EtOAc, 5 : 1) which gave a colorless oil (433 mg,
bined organic phases were washed with H2O and sat. aqueous 1.06 mmol, 53%, 94% ee, determined by chiral HPLC). [α]D20
=
NaCl (2 × 20 mL each) and dried over MgSO4. After evaporation 1.2 (c = 1.20, CHCl3); 1H NMR (300 MHz, CDCl3, TMS) δ = 1.43
of the solvent the crude product was obtained as a yellow wax. (s, 9 H, CO2C(CH3)3), 1.56–1.71 (m, 2 H, CH2CH2OBn),
3
Purification by column chromatography (CyH/EtOAc, 10 : 1 → 2.23–2.38 (m, 2 H, CO2CHCH2), 3.48 (t, JH,H = 6.5 Hz, 2 H,
3
1 : 1) gave a yellow oil (279 mg, 0.65 mmol, 65%). It was also CH2OBn), 4.47 (s, 2 H, OCH2Ph), 4.77 (dd, JH,H = 9.7, 6.2 Hz,
possible to use the crude product for the following reaction. 1 H, CH), 7.22–7.28 (m, 1 H, para-CH), 7.28–7.35 (m, 4 H, 2 ×
[α]2D0 = −25.6 (c = 1.06, CHCl3); 1H NMR (400 MHz, CDCl3, ortho-CH and 2 × meta-CH), 7.68–7.75 (m, 2 H, 2 × Phth–
TMS) δ = 0.88 (s, 3 H, CH3), 1.32 (s, 3 H, CH3), 1.43 (s, 9 H, CCHCH), 7.81–7.88 (m, 2 H, 2 × Phth–CCH). 13C NMR
3
OC(CH3)3), 1.50 (d, JH,H = 8.2 Hz, 1 H, CHaCHCH2), 1.50 (s, 3 (75 MHz, CDCl3) δ = 25.6 (CO2CHCH2), 26.8 (CH2CH2OBn),
H, C(OH)CH3), 1.56–1.69 (m, 2 H, CH2CH2OBn), 1.83–1.94 (m, 27.9 (CO2C(CH3)3), 52.9 (CO2CH), 69.3 (CH2OBn), 72.9
1 H, CO2CHCHa), 1.94–2.07 (m, 2 H, CO2CHCHb, CH2CHCH2), (OCH2Ph), 82.4 (C(CH3)3), 123.4 (2
2.07 (t, JH,H = 5.9 Hz, CH2CHC(OH)CH3), 2.32 (m, 1 H, (C-para), 127.6 (2 × C-ortho), 128.3 (2 × C-meta), 131.8 (2 ×
× Phth–CCH), 127.5
3
3
CHbCHCH2), 2.49–2.52 (m, 2 H, CHCH2CN), 3.49 (t, JH,H
=
Phth–C), 134.1 (2 × Phth–CCHCH), 138.4 (C-ipso), 167.8 (2 ×
6.4 Hz, 2 H, CH2OBn), 4.07 (dd, JH,H = 8.2, 5.1 Hz, 1 H, Phth–CvO), 168.2 (CO2 Bu). Exact mass (ESI): [M + Na]+ calcd
CHCO2), 4.50 (s, 2 H, OCH2Ph), 7.25–7.30 (m, 1 H, para-CH), for C24H27NO5Na+: 432.1781; found: 432.1782.
3
t
7.31–7.37 (m, 4 H, 2 × ortho-CH and 2 × meta-CH). 13C NMR
(R)-tert-Butyl 5-hydroxy-2-phthalimidopentanoate (35). To a
(101 MHz, CDCl3) δ = 23.0 (CH3), 26.2 (CH2CH2OBn), 27.3 solution of (R)-tert-butyl 5-benzyloxy-2-phthalimido-pentanoate
(CH3), 28.0 (CHCH2CH and CO2C(CH3)3), 28.4 (C(OH)CH3), (34) (524 mg, 1.3 mmol) in EtOAc (6 mL) was added Pd/C (10%
29.8 (CO2CHCH2), 33.5 (CHCH2CN), 38.4 (CH2CHCH2), 38.5 w/w, 50 mg) and the suspension was stirred under a 2 bar
(CH3CCH3), 50.0 (CHC(OH)CH3), 62.9 (CO2CH), 70.1 atmosphere of H2 for 3 h at r.t. After filtration over celite the
(CH2OBn), 72.9 (OCH2Ph), 76.7 (C(OH)CH3), 81.0 (C(CH3)3), product was obtained as a colorless oil (360 mg, 1.1 mmol,
127.5 (C-para), 127.7 (2 × C-ortho), 128.3 (2 × C-meta), 138.5 88%, 43% ee, determined by chiral HPLC). [α]2D0 = 1.4 (c = 0.97,
t
(C-ipso), 170.8 (CO2 Bu), 178.4 (CvN). Exact mass (ESI): CHCl3); 1H NMR (300 MHz, CDCl3, TMS) δ = 1.43 (s, 9 H,
[M + H]+ calcd for C26H39NO4H+: 430.2952; found: 430.2948. CO2C(CH3)3), 1.50–1.66 (m, 2 H, CH2CH2OH), 2.22–2.37 (m,
3
Exact mass (ESI): [M + Na]+ calcd for C26H39NO4Na+: 452.2771; 2 H, CO2CHCH2), 3.67 (t, JH,H = 6.4 Hz, 2 H, CH2OH), 4.80
3
found: 452.2766.
(dd, JH,H = 9.1, 6.6 Hz, 1 H, CH), 7.70–7.79 (m, 2 H, 2 × Phth–
(R)-tert-Butyl 2-amino-5-benzyloxypentanoate (42). (R)-tert- CCHCH), 7.81–7.91 (m, 2 H, 2 × Phth–CCH). 13C NMR
Butyl
5-benzyloxy-2-{[(1S,2S,5S,E)-2-hydroxy-2,6,6-trimethyl- (75 MHz, CDCl3) δ = 25.3 (CO2CHCH2), 27.9 (CO2C(CH3)3), 52.9
bicyclo[3.1.1]heptan-3-ylidene]amino}pentanoate (33) (279 mg, (CO2CH), 62.1 (CH2OH), 82.6 (C(CH3)3), 123.5 (Phth–CCH),
0.65 mmol) was dissolved in THF (1.2 mL) and treated with 131.8 (2 × Phth–C), 134.2 (Phth–CCHCH), 167.9 (2 × Phth–
15% citric acid (1.2 mL) at 0 °C. After stirring at r.t. for 3 d, the CvO), 168.2 (CO2 Bu). Exact mass (ESI): [M + Na]+ calcd for
t
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C17H21NO5Na+: 342.1312; found: 342.1318. Exact mass (ESI): Hz, 3JH,H = 1.8, 1.8 Hz, 1 H, CHF), 7.72–7.80 (m, 2 H, 2 × Phth–
[M + MeOH + Na]+ calcd for C17H21NO5CH3OHNa+: 374.1574; CCHCH), 7.84–7.92 (m, 2 H, 2 × Phth–CCH). 13C NMR (CDCl3,
3
found: 374.1576.
101 MHz): δ = 20.3 (dt, JC,F = 2.4 Hz, CHNCH2), 27.6 (dt,
(R)-tert-Butyl 5-oxo-2-phthalimidopentanoate (36). (R)-tert- 2JC,F = 23.3 Hz, CHFCH2), 48.4 (d, CHN), 106.9 (dd, JC,F
=
1
Butyl 5-hydroxy-2-phthalimidopentanoate (35) (335 mg, 228.4 Hz, CHF), 123.8 (d, 2 × Phth–CCH), 131.7 (s, 2 × Phth–C),
3
1.1 mmol) was dissolved in CH2Cl2 and treated with Dess– 134.5 (d, 2 × Phth–CCHCH), 165.0 (d, JC,F = 1.7 Hz, CO2),
Martin periodinane (534 mg, 1.3 mmol, 1.2 eq.). The mixture 166.9 (s, 2 × Phth–CvO). 19F NMR (CDCl3, 282 MHz): δ =
2
3
was stirred for 1.5 h at r.t. before being quenched with sat. −119.4 (ddd, JH,F = 53.4 Hz, JH,F = 36.3, 6.7 Hz, 1 F, CFH).
aqueous Na2SO3 and sat. aqueous NaHCO3. After extraction Exact mass (ESI): [M
+
Na]+ calcd for C13H10FNO4Na+:
with CH2Cl2 (3 × 10 mL) the combined organic phases were 286.0486; found: 286.0486; [M + MeOH + Na]+, calcd for
dried over MgSO4 and the solvent evaporated. Chromato- C13H10FNO4CH3OHNa+: 318.0748; found: 318.0740.
graphic purification (CyH/EtOAc 2 : 1) led to a yellow, viscous
(R)-2-Amino-5,5-difluoropentanoic
acid
hydrochloride
oil (203 mg, 0.64 mmol, 61%, 34% ee, determined by chiral (39). In a pressure tube (R)-tert-butyl 5,5-difluoro-2-phthali-
HPLC). [α]2D0 = −0.3 (c = 1.19, CHCl3); 1H NMR (400 MHz, mido-pentanoate (37) (93 mg, 0.27 mmol) was dissolved in
CDCl3, TMS) δ = 1.43 (s, 9 H, CO2C(CH3)3), 2.38–2.66 (m, 4 H, HOAc (0.5 mL) and 6 N aqueous HCl (5 mL) and the solution
CH2CHO and CO2CHCH2), 4.75–4.86 (m, 1 H, CH), 7.72–7.80 heated to 130 °C for 15 h. The volatile components were evapo-
(m, 2 H, 2 × Phth-CCHCH), 7.84–7.91 (m, 2 H, 2 × Phth–CCH), rated and the residue was purified by SPE (Chromabond C18ec,
3
9.74 (t, JH,H = 0.9 Hz, 1 H, CHO). 13C NMR (101 MHz, CDCl3) 500 mg, 3 mL ice-cold H2O) which gave the product as a white
δ = 21.7 (CO2CHCH2), 27.8 (CO2C(CH3)3), 40.7 (CH2CHO), 52.1 solid (50 mg, 0.26 mmol, 96%, 36% ee, determined by 19F NMR
(CO2CH), 82.9 (C(CH3)3), 123.5 (Phth–CCH), 131.7 (2 × Phth– of the (S)-2-chloropropionyl amide). Mp 214–215 °C (dec.);
C), 134.3 (Phth–CCH), 167.5 (CO2 Bu), 167.7 (2 × Phth–CvO), [α]2D0 = 3.5 (c = 1.00, 1 M HCl(aq.)). The spectroscopic and spectro-
t
200.5 (CHO). Exact mass (ESI): [M
+
Na]+ calcd for metric data are consistent with those already listed for 28.
C17H19NO5Na+: 340.1155; found: 340.1153. Exact mass (ESI):
[M + MeOH + Na]+ calcd for C17H19NO5CH3OHNa+: 372.1418;
found: 372.1415.
Crystallographic data
(R)-tert-Butyl 5,5-difluoro-2-phthalimidopentanoate (37).
X-Ray diffraction. Data sets were collected with a Nonius
Under an argon atmosphere a solution of (R)-tert-butyl 5-oxo-2- KappaCCD diffractometer. Programs used: data collection,
phthalimidopentanoate (36) (252 mg, 0.79 mmol) in CH2Cl2 COLLECT (R. W. W. Hooft, Bruker AXS, 2008, Delft, The
(7 mL) was reacted with Deoxo-Fluor (2.7 M in PhMe, Netherlands); data reduction, Denzo-SMN;56 absorption correc-
0.44 mL, 1.19 mmol, 1.5 eq.) for 3 h at r.t. The reaction was tion, Denzo;57 structure solution, SHELXS-97;58 structure
quenched with sat. aqueous NaHCO3 and the mixture refinement, SHELXL-97.59 R-Values are given for observed
extracted with CH2Cl2 (3 × 10 mL). The combined organic reflections, and wR2 values are given for all reflections.
phases were dried over MgSO4, the solvent was evaporated and
X-ray
crystal
structure
analysis
of
12
(CCDC
the residue was purified by column chromatography (CyH/ 1429375). Formula C19H17NO4S, M = 355.40, colourless crystal,
EtOAc, 2 : 1) to give a yellow oil (93 mg, 0.27 mmol, 34%), 0.15 × 0.07 × 0.05 mm, a = 7.6727(2), b = 8.5813(3), c =
1
[α]2D0 = 1.1 (c = 1.14, CHCl3); H NMR (300 MHz, CDCl3, TMS) 14.3778(6) Å, α = 82.996(1)°, β = 79.762(1)°, γ = 67.718(2)°, V =
δ = 1.43 (s, 9 H, CO2C(CH3)3), 1.71–2.06 (m, 2 H, CH2CF2H), 860.5(1) Å3, ρcalc = 1.372 g cm−3, μ = 0.212 mm−1, empirical
3
2.25–2.48 (m, 2 H, CO2CHCH2), 4.77 (dd, JH,H = 9.7, 5.8 Hz, absorption correction (0.968 ≤ T ≤ 0.989), Z = 2, triclinic,
2
3
ˉ
1 H, CH), 5.84 (tt, JH,F = 56.5 Hz, JH,H = 4.4 Hz, 1 H, CF2H), space group P1 (no. 2), λ = 0.71073 Å, T = 223(2) K, ω and
7.73–7.80 (m, 2 H, 2 × Phth–CCHCH), 7.85–7.92 (m, 2 H, 2 × φ scans, 7846 reflections collected ( h, k, l), 3456 indepen-
Phth–CCH). 13C NMR (75 MHz, CDCl3) δ = 21.9 (t, JC,F = 5.8 dent (Rint = 0.035) and 2985 observed reflections [I > 2σ(I)], 227
3
Hz, CO2CHCH2), 27.8 (CO2C(CH3)3), 31.2 (t, JC,F = 21.6 Hz, refined parameters, R = 0.049, wR2 = 0.107, max. (min.)
2
CH2CF2H), 52.2 (CO2CH), 83.0 (C(CH3)3), 116.5 (t, JC,F = 239.4 residual electron density 0.29 (−0.29) e Å−3; hydrogen atoms
1
Hz, CF2H), 123.6 (Phth–CCH), 131.7 (2 × Phth–C), 134.3 (Phth– were calculated and refined as riding atoms.
t
CCHCH), 167.5 (CO2 Bu), 167.7 (2 × Phth–CvO). 19F NMR
X-ray crystal structure analysis of 14c (CCDC
2
(282 MHz, CD3OD) δ = −116.7/−116.8 (AB signal, JF,F = 281.5 1429376). Formula C14H12F3NO4,
M = 315.25, colourless
Hz, JF,H = 56.5 Hz, JF,H = 17.2 Hz/2JF,F = 281.5 Hz, JF,H = 56.5 crystal, 0.36 × 0.22 × 0.04 mm, a = 13.6630(1), b = 7.8244(1), c =
2
3
2
Hz, JF,H = 17.3 Hz, 2 F, CF2H). Exact mass (ESI): [M + Na]+ 13.7079(1) Å, β = 109.783(1)°, V = 1378.9(1) Å3, ρcalc
=
3
calcd for C17H19F2NO4Na+: 362.1174; found: 362.1172.
1.518 g cm−3, μ = 1.204 mm−1, empirical absorption correction
2-[(3R)-6-Fluoro-2-oxotetrahydro-2H-pyran-3-yl]isoindoline- (0.671 ≤ T ≤ 0.953), Z = 4, monoclinic, space group P21/c (no.
1,3-dione (38). Isolated as a white solid product in addition to 14), λ = 1.54178 Å, T = 223(2) K, ω and φ scans, 9087 reflections
37. Yield: 58 mg (0.22 mmol, 28%), mp 172–173 °C, [α]D20
=
collected ( h, k, l), 2376 independent (Rint = 0.038) and 2161
−0.7 (c = 1.08, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = observed reflections [I > 2σ(I)], 200 refined parameters, R =
2.01–2.11 (m, 1 H, CHNCHa), 2.12–2.32 (m, 2 H, CHFCHa), 0.049, wR2 = 0.139, max. (min.) residual electron density
2.34–2.44 (m, 1 H, CHFCHb), 2.88–3.06 (m, 1 H, CHNCHb), 0.22 (−0.24) e Å−3. The hydrogen at N1 atom was refined freely;
4.96 (dd, 3JH,H = 12.7, 6.6 Hz, 1 H, CHN), 6.14 (ddd, 2JH,F = 53.7 others were calculated and refined as riding atoms.
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22 P. Baker and J. Montclare, ChemBioChem, 2011, 12, 1845–
Acknowledgements
1848.
Financial support of this work by the Cells-in-Motion Cluster 23 U. I. M. Gerling, M. Salwiczek, C. D. Cadikamo,
of Excellence (CiM) is gratefully acknowledged. We would like
to thank Martina Prekel from Professor Studer’s research
group for measuring the ee values of compounds 36 and 43.
H. Erdbrink, S. L. Grage, P. Wadwani, A. S. Ulrich,
M. Behrends, G. Haufe, C. Czekelius and B. Koksch, Chem.
Sci., 2014, 5, 819–830.
24 B. Davis and V. Boyer, Nat. Prod. Rep., 2001, 18, 618–640.
25 D. P. McGregor, Curr. Opin. Pharmacol., 2008, 8, 616–619.
26 P. C. Michels, Y. L. Khmelnitsky, J. S. Dordick and
D. S. Clark, Trends Biotechnol., 1998, 16, 210–215.
27 M. Shimizu and T. Hiyama, Angew. Chem., Int. Ed., 2005,
44, 214–231.
Notes and references
1 Organofluorine Chemistry: Principles and Commercial Appli-
cations, ed. R. E. Banks, B. E. Smart and J. C. Tatlow, 28 V. Hugenberg, R. Fröhlich and G. Haufe, Org. Biomol.
Plenum Press, New York, 1994. Chem., 2010, 8, 5682–5691.
2 P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reac- 29 V. Hugenberg and G. Haufe, J. Fluorine Chem., 2010, 131,
tivity, Applications, Wiley-VCH, Weinheim, 2013. 942–950.
3 Fluorine and Health Molecular Imaging, Biomedical 30 G. Haufe, K. W. Laue, M. U. Triller, Y. Takeuchi and
-
Materials and Pharmaceuticals, ed. A. Tressaud and
N. Shibata, Tetrahedron, 1998, 54, 5929–5938.
G. Haufe, Elsevier, Amsterdam, 2008.
31 E. W. Logusch, Tetrahedron Lett., 1986, 27, 5935–5938.
4 Fluorine in Medicinal Chemistry and Chemical Biology, ed. 32 G. Talbot, R. Gaudry and L. Berlinguet, Can. J. Chem., 1958,
I. Ojima, John Wiley & Sons Ltd, Chichester, 2009. 36, 593–596.
5 J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal 33 A. Tarui, N. Kawashima, K. Sato, M. Omote and A. Ando,
Chemistry of Fluorine, Imperial College Press, Hoboken,
2008.
Tetrahedron Lett., 2010, 51, 4246–4249.
34 A. Tarui, N. Kawashima, K. Sato, M. Omote, Y. Miwa,
6 G. Theodoridis, in Advances in Fluorine Science, ed. A. Tres-
saud, Elsevier, Amsterdam, 2006, pp. 121–175.
7 P. Jeschke, ChemBioChem, 2004, 5, 570–589.
8 T. Pitterna, M. Böger and P. Maienfisch, Chimia, 2004, 58,
108–116.
H. Minami and A. Ando, Tetrahedron Lett., 2010, 51, 2000–
2003.
35 S. C. Kim and F. M. Raushel, J. Enzyme Inhib., 1988, 2, 153–
161.
36 D. Baba and T. Fuchigami, Tetrahedron Lett., 2002, 43,
9 N. Sewald and H.-D. Jakubke, Peptides: Chemistry and
Biology, Wiley-VCH, Weinheim, 2003.
10 Fluorine-containing Amino Acids - Synthesis and Properties,
4805–4808.
37 J. Kwiatkowski and Y. Lu, Org. Biomol. Chem., 2015, 13,
2350–2359.
ed. V. P. Kukhar and V. A. Soloshonok, John Wiley & Sons, 38 P.-F. Zheng, Q. Ouyang, S.-L. Niu, L. Shuai, Y. Yuan,
Chichester, 1994.
11 A. Sutherland and C. L. Willis, Nat. Prod. Rep., 2000, 17,
K. Jiang, T.-Y. Liu and Y.-C. Chen, J. Am. Chem. Soc., 2015,
137, 9390–9399.
621–631.
39 L. Hu, C. Che, Z. Tan and G. Zhu, Chem. Commun., 2015,
51, 16641–16644.
12 X.-L. Qiu, W.-D. Meng and F.-L. Qing, Tetrahedron, 2004,
60, 6711–6745.
40 A. M. Paloyan, L. A. Stepanyan, S. A. Dadayan,
A. A. Hambardzumyan, G. P. Halebyan and A. S. Saghiyan,
Appl. Biochem. Microbiol., 2013, 49, 106–112.
13 X.-L. Qiu and F.-L. Qing, Eur. J. Org. Chem., 2011, 3261–
3273.
14 V. Asante, J. Mortier, G. Wolber and B. Koksch, Amino 41 P. Hudhomme and G. Duguay, Tetrahedron, 1990, 46, 5263–
Acids, 2014, 46, 2733–2744. 5272.
15 B. Koksch, N. Sewald, H.-J. Hofmann and K. Burger, J. Pept. 42 V. Hugenberg, S. Wagner, K. Kopka, O. Schober,
Sci., 1997, 3, 157–167.
M. Schäfers and G. Haufe, J. Org. Chem., 2010, 75, 6086–
16 H. Biava and N. Budisa, Eng. Life Sci., 2014, 14, 340–351.
6095.
17 Enzyme Catalysis in Organic Synthesis, ed. K. Drauz, H. 43 M. J. Robins and S. F. Wnuk, J. Org. Chem., 1993, 58, 3800–
Gröger and O. May, Wiley-VCH, Weinheim, 2012. 3801.
18 C. Jäckel, M. Salwiczek and B. Koksch, Angew. Chem., Int. 44 W. Dmowski, in Organo-Fluorine Compounds, ed. B.
Ed., 2006, 45, 4198–4203.
19 Y. Tang, G. Ghirlanda, W. A. Petka, T. Nakajima,
Baasner, H. Hagemann and J. C. Tatlow, Houben-Weyl,
Stuttgart, 2000.
W. F. DeGrado and D. A. Tirrell, Angew. Chem., Int. Ed., 45 A. G. Griesbeck and J. Hirt, Liebigs Ann. Chem., 1995, 11,
2001, 40, 1494–1496. 1957–1961.
20 E. Pourabed, F. G. Golmohamadi, S. M. Monfared, 46 S. Kröger and G. Haufe, Amino Acids, 1996, 11, 409–424.
S. M. Ravazi and Z.-S. Shobbar, Mol. Biotechnol., 2015, 57, 47 Data for Biomedical Research, ed. R. M. C. Dawson,
12–26.
D. C. Elliott, W. H. Elliott and K. M. Jones, Oxford Univer-
sity Press, London, 1974.
21 E. N. G. Marsh, Acc. Chem. Res., 2014, 47, 2878–2886.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Paper
48 N. Minowa, M. Hirayama and S. Fukatsu, Tetrahedron Lett., 54 S. Kröger and G. Haufe, Liebigs Ann./Recl., 1997, 1201–1206.
1984, 25, 1147–1150.
49 N. Minowa, M. Hirayama and S. Fukatsu, Bull. Chem. Soc.
Jpn., 1987, 60, 1761–1766.
50 K. W. Laue, S. Kröger, E. Wegelius and G. Haufe,
Eur. J. Org. Chem., 2000, 3737–3743.
51 R. G. Carlson and J. K. Pierce, J. Org. Chem., 1971, 36,
2319–2324.
55 K. Watabe, S.-C. Chang, E. Gil-Av and B. Koppenhoefer,
Synthesis, 1987, 225–228.
56 Z. Otwinowski and W. Minor, Methods Enzymol., 1997, 276,
307–326.
57 Z. Otwinowski, D. Borek, W. Majewski and W. Minor,
Acta Crystallogr., Sect. A: Fundam. Crystallogr., 2003, 59,
228–234.
52 K. W. Laue, PhD thesis, University of Münster, 1998.
53 W. Kruizinga, J. Bolster, R. M. Kellogg, J. Kamphuis,
58 G. M. Sheldrick, Acta Crystallogr., Sect. A: Fundam. Crystal-
logr., 1990, 46, 467–473.
W. H. J. Boesten, E. M. Meijer and H. E. Shoemaker, J. Org. 59 G. M. Sheldrick, Acta Crystallogr., Sect. A: Fundam. Crystal-
Chem., 1988, 53, 1826–1827.
logr., 2008, 64, 112–122.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.