Asymmetric synthesis of γ-fluorinated α-amino acid derivatives

Article abstract of DOI:10.1002/ejoc.200400665

Asymmetric alkylation of (S)-Boc-BMI (1a, BMI = 2-tert-butyl-3- methylimidazolidin-4-one) and its α-methyl derivative 1b with 2-fluoroallyl tosylate, subsequent mild acidic deprotection of the products 2a and 2b, and basic hydrolysis of the thus formed N′-methylamides 4a and 4b gave (S)-2-amino-4-fluoropent-4-enoic acid (5a) and (S)-2-amino-4-fluoro-2- methylpent-4-enoic acid (5b). Basic hydrolysis of compound 4a was accompanied by partial racemization, which was overcome by applying a new stereoconservative deamidation procedure. The alkylated cis-configured product 2a formed under kinetic control epimerized on refluxing with 2 N NaOH to give the thermodynamically more stable trans isomer 9. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400665

FULL PAPER
Asymmetric Synthesis of γ-Fluorinated α-Amino Acid Derivatives
Deepak M. Shendage,[a,b] Roland Fröhlich,[a] Klaus Bergander,[a] and Günter Haufe*[a]
Keywords: Alkylation / Asymmetric synthesis / Fluorinated α-amino acids / 2-Fluoroallyl tosylate / Isomerization
Asymmetric alkylation of (S)-Boc-BMI (1a, BMI = 2-tert-bu-
tyl-3-methylimidazolidin-4-one) and its α-methyl derivative
1b with 2-fluoroallyl tosylate, subsequent mild acidic depro-
tection of the products 2a and 2b, and basic hydrolysis of the
thus formed NЈ-methylamides 4a and 4b gave (S)-2-amino-
4a was accompanied by partial racemization, which was
overcome by applying a new stereoconservative deamidation
procedure. The alkylated cis-configured product 2a formed
under kinetic control epimerized on refluxing with 2
N NaOH
to give the thermodynamically more stable trans isomer 9.
4-fluoropent-4-enoic acid (5a) and (S)-2-amino-4-fluoro-2- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
methylpent-4-enoic acid (5b). Basic hydrolysis of compound
Germany, 2005)
Introduction
Results and Discussion
In a recent synthetic program, we required optically pure
(S)-2-amino-4-fluoropent-4-enoic acid (5a) and (S)-2-
amino-4-fluoro-2-methylpent-4-enoic acid (5b) as isosteres
of asparagine (Asn) and its α-methyl derivative, respectively.
Amongst the methodologies developed for the preparation
of chiral α-amino acids (natural as well as unnatural) based
on asymmetric enolate alkylation of chiral glycine deriva-
tives, the “self-regeneration of stereocenters“ (SRS) in imid-
azolidinone derivatives is the most selective and efficient[33]
and has been used for the synthesis of various amino acids
of biological interest.[34–37] For our current synthetic plans,
we used Seebach’s commercially available enantiopure (S)-
Boc-BMI (1a, BMI = 2-tert-butyl-3-methylimidazolidin-4-
one).[33,38,39]
Fluorine is one of the most abundant elements on earth,
yet it occurs rarely in organic compounds as a result of its
low bioavailability. Hence procedures by which fluorine can
be introduced into organic molecules are well estab-
lished.[1–4] During the past few decades, the development of
methods for the synthesis of biologically active fluorinated
compounds,[5–7] particularly fluorinated amino acids, has
gained considerable attention[8–12] for various reasons.
Amongst these, the unique properties and effects of fluorine
as a substitute for hydrogen or hydroxy groups on the over-
all molecular and biological properties of a molecule have
been widely reviewed.[13–15] Owing to its extreme electrone-
gativity, fluorine is, for example, a weak hydrogen-bond ac-
ceptor.[16–19]
This paper reports the results of our efforts to synthesize
enantiopure γ-fluoro-α-amino acid derivatives and the cor-
responding α-methylated analogues by using enantiopure
(S)-Boc-BMI (1a) as a chiral glycine building block. 2-
Fluoroallyl tosylate, synthesized[40] in 90% yield from 2-
fluoroallyl alcohol[26] and tosyl chloride using NaOH/Et2O,
was used as the alkylating agent. By using a method similar
to that described in the literature,[33] the stereoselective al-
kylation of 1 was carried out by using LDA as a base in
dry THF in the presence of DMPU[41] as co-solvent under
argon at –50 °C. The use of MeI[34] or 2-fluoroallyl tosylate
as the electrophile for enolate alkylation leads selectively
to one diastereomer[42] in a smooth reaction that gave the
products 1b and 2a in 96 and 89% yields, respectively. Simi-
larly, compounds 2b–f were also prepared in good-to-excel-
lent yields (Scheme 1).
Recently, the growing interest in fluorinated amino acids
as protein residues has created a new challenge for synthetic
chemists.[20–22] Also α-substitution could lead to fluorinated
compounds with specific conformations and stronger resis-
tance to hydrolysis.[23] Our group has synthesized several
saturated and unsaturated γ-fluorinated amino acids.[24–26]
Fluoroolefins are well documented as isosteres of peptides
(or as peptidomimetics)[27–30] and are very important, par-
ticularly in protein design.[31] The importance and synthesis
of fluorinated α-amino acids have been recently re-
viewed.[32]
[a]
Organisch-Chemisches Institut, Universität Münster,
Corrensstr. 40, 48149 Münster, Germany
Fax: +49-251-8339772
E-mail: haufe@uni-muenster.de
[b]
NRW Graduate School of Chemistry, University of Münster,
The structures of these compounds were determined by
the usual spectroscopic methods and proved by X-ray crys-
tallography. Figure 1 shows the solid-state structure of com-
Corrensstr. 36, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2005, 719–727
DOI: 10.1002/ejoc.200400665
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D. M. Shendage, R. Fröhlich, K. Bergander, G. Haufe
FULL PAPER
Scheme 1. Stereoselective alkylations of (S)-Boc-BMI −reagents
and conditions: i. LDA, DMPU, THF, MeI, –50 °C, 3 h, 96%; ii.
LDA, DMPU, THF, CH2=CYCH2X, –50 °C, 3 h
Scheme 2. Deprotection reactions of the alkylation products − rea-
gents and conditions: i. HCl/MeOH, room temp., 1 h; ii. 1 n HCl,
MeOH/H2O, reflux, 3 h; iii. (a) 2 n KOH/H2O, reflux, 2 h; (b) pro-
pylene oxide, EtOH, reflux, 30 min
Figure 1. ORTEP diagram for tert-butyl (2S,5S)-2-tert-butyl-5-(2-
fluoroallyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (2a)
pound 2a (for the structures of 2b–f, see the Supporting
Information).
Hindered rotation around the carboxamide function of
1
compounds 2 was observed by H NMR spectroscopy at
various temperatures, but coalescence due to fluorine or
methyl substitution of the double bond was not observed,
even at temperatures as low as 193 K.[43]
Deprotection of the alkylation products 2 was achieved
in two steps. The alkylated derivatives 2a and 2b were de-
protected quantitatively to hydrochloride salts 3 with HCl/
MeOH[44] (Scheme 2). The hydrolysis of compounds 2 to
NЈ-methylamides 4 or free amino acids 5 without hydrolysis
of the acid-sensitive fluorovinyl group was explored under
Figure 2. X-ray crystal packing for (2S)-2-amino-4-fluoro-NЈ-
methylpent-4-enamide (4a)
different conditions, but the use of TFA/CH2Cl2 or HCl/ by treatment with propylene oxide in EtOH to give the cor-
MeOH at room temperature or at reflux (absolute condi- responding free amino acids in 63–66% yields (Scheme 2).
tions) always led to Boc-deprotection only. Refluxing com- Partial racemization of 5a occurred during basic amide hy-
pounds 2 in a 1:1 mixture of 1 n HCl/H2O in MeOH (aque- drolysis of 4a. Consequently, several lipases and esterases
ous conditions) resulted in the hydrolysis of the imidazolidi- were screened for enzymatic hydrolysis in order to overcome
none ring to NЈ-methylamides 4 in 43 and 63% yields the racemization of 4a to the corresponding free acids 5a,
(Scheme 2).
however without success.[45] Finally a nitrosative deamid-
The hydrochlorides 3 also gave NЈ-methylamides 4 by a ation of α-amino acid amides was developed.[46] The amino
similar aqueous acid hydrolysis. These reactions occurred group of NЈ-methylamide (S)-4a was completely protected
without racemization; no signals due to (R) enantiomers of by using phthalic anhydride (PhtA) in the presence of oxalyl
4 were observed in chiral GC and in NMR experiments chloride in CHCl3/MeOH at 65 °C to yield 89% of the im-
using [Eu(hfc)3] (30 mol-%) as a chiral shift reagent. No ide (S)-6 (Scheme 3). Then the deamidation reaction was
short intra- or intermolecular contact of fluorine with the carried out by thermal decomposition of the in situ gener-
NH bonds in crystal packing of compound 4a was detected ated NЈ-nitrosoamide in a stereoconservative reaction to
(Figure 2).
give the methyl ester (S)-7 in 91% yield.[46] In due course
Finally the NЈ-methylamides 4 were hydrolyzed by re- the enantiopure NЈ-methylamides 4a and 4b will be used in
fluxing the amides with 2 n aq. KOH for 1 hour followed peptide synthesis.[44]
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Asymmetric Synthesis of γ-Fluorinated α-Amino Acid Derivatives
FULL PAPER
We do not have an explanation for the formation of com-
pound 8 yet, and hence did not try to optimize the condi-
tions for its synthesis. However, this compound may be use-
ful in the selective synthesis of threonine analogues. These
investigations will be continued.
As mentioned above, a second alkylation reaction of 2a
was not possible under the applied conditions because de-
protonation of the α-position by LDA at –50 °C seems to
be hindered in this trans-2,5-disubstituted imidazolidinone
(Figure 1). The dynamics of the carbamoyl group, and
probably also that of the 2-fluoroallyl function, might be
the reason for the failure of the second alkylation of 2a. An
analogous failure of a similar imidazolidinone to undergo
a second alkylation reaction has been reported.[48] In this
case a trans-5-indolylmethyl group was not inverted into the
position cis to the tert-butyl group largely because of steric
hindrance. This suggestion is supported by the fact that sec-
ond alkylation reactions of trans-configured 1b proceed
smoothly to form compounds 2b, 2d, and 2f in high yields
(Scheme 1).
In the absence of an electrophile, compound 2a, formed
by alkylation under kinetic control under strong basic con-
ditions, isomerized mainly to the thermodynamically more
stable product 9 in a 1:9 ratio, respectively, by inversion of
the C-5 stereocenter (Scheme 5) Thus, in principle the syn-
thesis of both the enantiomers of 4a is possible by using the
same auxiliary.
Scheme 3. Stereoconservative deamidation of 4a − reagents and
conditions: i. PhtA, C2Cl2O2, CHCl3/MeOH, 0–65 °C, 7 h; ii. (a)
NaNO2, Ac2O/AcOH, 0–4 °C, 14–16 h; (b) dioxane, reflux, 5 h
The fluorovinyl group in compounds 2a and 2b was also
stable under stronger aqueous basic conditions but hydroly-
sis to 4-oxonorvalines occurred under stronger aqueous
acidic conditions.[24–26] Thus, the alkylation reagents, 2-
fluoroallylhalogenides and 2-fluoroallyl tosylate, can be
seen as acetonyl cation equivalents. 4-Oxo-l-norvaline has
been used as an important building block for protease inhi-
bition studies.[47] Investigations into the synthetic use of
compounds 2 are in progress and will be reported in due
course.
Attempts to synthesize the other diastereomer of 2b in-
aone-pot or step-by-step alkylation of compound 1a failed.
Under the conditions shown in Scheme 4, besides a 65%
isolated yield of compound 2a, compound 8 was isolated as
an enantiopure side-product in 20% yield (Scheme 4, Fig-
ure 3).
Scheme 5. Transformation of 2a to 9 − reagents and conditions:
2 n KOH/H2O, MeOH, reflux, 1 h
The assignment of the structures of 2a and 9 is supported
by investigations of the nuclear Overhauser effect (NOE).
By using the frequency of the tBu group at C-2, irradiation
increased the intensity of the signals of 5-Hb (as well as
those of Ha, and the Boc and N-methyl groups) for com-
pound 2a. On the other hand, the corresponding experi-
ment with compound 9 resulted in an increased intensity of
the signals of the 6-CH2 and 8-CH2 moieties (as well as
those of Ha, and the Boc and N-methyl groups). By com-
paring the results of the NOE experiments, compound 9
was assigned as the cis isomer with a (2S,5R) configuration
Scheme 4. Attempted one-pot dialkylation of (S)-Boc-BMI − rea-
gents and conditions: LDA, DMPU, THF, CH2=CFCH2OTs,
–50 °C, 3 h and then LDA, MeI, –50 °C, 3 h
Figure 3. OPTEP diagram for (5S,7aS)-5-tert-butyl-1,1,6-trimethyl-
dihydro-1H-imidazo[1,5-c][1,3]oxazole-3,7(7aH)-dione (8)
Figure 4. Significant NOE experiments for compounds 2a and 9 by
1H NMR (600 MHz) spectroscopy
Eur. J. Org. Chem. 2005, 719–727
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D. M. Shendage, R. Fröhlich, K. Bergander, G. Haufe
FULL PAPER
was extracted with Et2O (3×). The combined organic layers were
washed with 2 n citric acid, sat. aq. NaHCO3, water and dried
(MgSO4). Evaporation of the solvent under vacuum followed by
flash column (FC) chromatography[59] on silica gel (Et2O/cyclohex-
ane, 2:1) gave the respective product as a solid. Two sets of spectro-
scopic data corresponding to two rotamers were observed in most
the cases and were differentiated as major/minor rotamers by NMR
signal-to-signal integration.
(Figure 4). No dynamic effect was observed for compound
9 at room temperature.
Conclusions
We have reported herein a highly selective method, with
good overall yields, for the synthesis of γ-fluoro-α-amino
acid 5a and its α-methyl analogue 5b by using enantiopure
(S)-Boc-BMI (1a) as a chiral glycine equivalent. The race-
tert-Butyl (2S,5S)-2-tert-Butyl-3,5-dimethyl-4-oxoimidazolidine-1-
carboxylate (1b): Following general procedure A, (S)-Boc-BMI (1a)
mization of NЈ-methylamide 4a under basic conditions was (1.28 g, 5.0 mmol) and MeI (0.44 g, 7.0 mmol) yielded 1b as a pale
yellowish crystalline solid (1.3 g, 96%): m.p. 103 °C (Et2O/pentane).
[α]2D0 = –14.9 (c = 1.09, Et2O). The spectral data agree with those
reported previously.[38]
overcome by a new stereoconservative deamidation reac-
tion. The fluorinated α-amino acids, as isosteres of aspara-
gine and its α-methyl derivative, are of considerable interest
as peptidomimetics and will be studied further. This study
indicates that fluorine has a weak electronic effect on the
tert-Butyl (2S,5S)-2-tert-Butyl-5-(2-fluoroallyl)-3-methyl-4-oxoimid-
azolidine-1-carboxylate (2a): Following general procedure A, (S)-
overall properties of this type of molecule. Besides the dy- Boc-BMI (1a) (2.56 g, 10.0 mmol) and 2-fluoroallyl tosylate
(2.53 g, 11.0 mmol), prepared from 2-fluoroallyl alcohol[26] by tos-
namics of the carbamate group, no dynamic effect was ob-
served by solution NMR spectroscopy for the fluorovinyl
ylation, gave title compound 2a as a white crystalline solid (2.8 g,
89 %): m.p. 79 °C (Et2O/pentane). [α]2D0 = –16.5 (c = 0.515,
moiety in compounds 2a and 2b.
CH2Cl2). 1H NMR (300.14 MHz, CDCl3): δ = 0.98 (3 × s, 9 H,
CH-C(CH3)3), 1.48 (3 × s, 9 H, CO-C(CH3)3), 2.77–2.97 (m, 1 H,
CH-CH2-CF), 3.01 (s, 3 H, N-Me), 3.30–3.60 (m, 1 H, CH-CH2-
Experimental Section
3
2
CF), 4.12 (d, J(H,H) = 5.4 Hz, 1 H, CO-CH-N), 4.27 (dd, JH,H
= 2.1, 3JH,F = 50.0 Hz, 1 H, CF=CHZ), 4.57 (dd, 2JH,H = 2.1, 3JH,F
= 17.8 Hz, 1 H, CF=CHE), 4.95 ppm (br. s, 1 H, CH-C(CH3)3).
13C NMR (75.48 MHz, CDCl3): δ = 26.4 (3 × q, CH-C(CH3)3),
General Remarks:All air- and moisture-sensitive reactions were per-
formed under argon in flame-dried flasks using standard Schlenk-
line techniques. (S)-Boc-BMI (1a) was a gift of Degussa AG, Ger-
many. All other starting materials were obtained from Acros,
Merck or Fluka. Diisopropylamine was distilled from KOH,
DMPU was dried with molecular sieves (4 Å), and THF was dis-
tilled from sodium/benzophenone before use. The yields reported
are those obtained after purification. Melting points are uncor-
rected. Optical rotations were measured in the specified solvents at
20 °C. NMR spectra: 1H (300.14 and 598.98 MHz), 13C
(75.48 MHz), and 19F NMR (282.37 and 563.58 MHz). TMS (δ =
0 ppm) for 1H, CDCl3 (δ = 77.00 ppm) for 13C, and CFCl3 (δ =
0 ppm) for 19F were used as internal standards. The multiplicities
of the 13C NMR signals of the 13C–1H coupling were determined
by the DEPT (90 and 135°) method. Mass spectra: GC-MS-CI by
using NH3, GC-MS-EI coupling (70 eV), and MS-EI direct inlet.
Exact mass: Quattro LC method using nanospray and MicroTof
Bruker Daltonics using loop injection. Elemental analysis: Mikro-
analytisches Laboratorium, Organische Chemie, Universität
Münster. X-ray diffraction: Data sets were collected with Enraf–
Nonius CAD4 and Nonius-Kappa CCD diffractometers. Programs
used: data collection EXPRESS[49] and COLLECT,[50] data re-
duction MolEN[51] and Denzo-SMN,[52] absorption correction for
CCD data SORTAV,[53,54] structure solution SHELXS-97,[55] struc-
ture refinement SHELXL-97,[56] graphics DIAMOND[57]and
SCHAKAL.[58]
2
28.1 (3 × q, CO-C(CH3)3), 31.6 (ddd, JC,F = 26.9 Hz, H2C=CF),
32.0 (q, N-CH3), 40.8 (s, CH-C(CH3)3), 57.5 (d, N-CH-CO), 80.6
2
(s + d, CO-C(CH3)3 + CH-C(CH3)3), 93.6 (ddd, JC,F = 18.7 Hz,
1
CF-CH2), 152.6 (s, N-CO-OtBu), 162.3 (d, JC,F = 258.5 Hz,
CF=CH2), 171.1 ppm (s, H2C-CO-NMe). 19F NMR (282.37 MHz,
CDCl3) major rotamer: δ = –96.73 ppm (m, 1 F, CF=CH2); minor
rotamer: δ = –93.17 ppm (m, 1 F, CF=CH2). MS-ES: m/z = 315.3
[M + H]. GC-MS: m/z (%) = 257 (5) [M+ – C4H9], 241 (7) [M+
–
C4H10O], 201 (63), 181 (20), 157 (73), 131 (38), 110 (28), 88 (50),
69 (42), 57 (70), 42 (100). C16H27FN2O3 (314.4): calcd. C 61.12, H
8.66, N 8.91; found: C 61.14, H 8.91, N 9.01.
tert-Butyl
(2S,5S)-2-tert-Butyl-5-(2-fluoroallyl)-3,5-dimethyl-4-
oxoimidazolidine-1-carboxylate (2b): Following general procedure
A, slow addition of 2-fluoroallyl tosylate (0.97 g, 7 mmol) to (S)-
Boc-BMI-Me (1b) (1.35 g, 5.0 mmol) gave 2b as a white crystalline
solid (1.3 g, 84%): m.p. 68 °C (Et2O/pentane). [α]2D0 = –8.7 (c =1.09,
1
Et2O). H NMR (300.14 MHz, CDCl3) major rotamer: δ = 0.98 (3
× s, 9 H, CH-C(CH3)3), 1.51 (3 × s, 9 H, CO-C(CH3)3), 1.53 (s, 3
H, C*-Me), 2.97 (s, 3 H, N-Me), 2.98–3.20 (m, 1 H, CH-CH2-CF),
2
3
3.38–3.54 (m, 1 H, CH-CH2-CF), 4.25 (dd, JH,H = 2.7, JH,F
=
2
3
49.7 Hz, 1 H, CF=CHZ), 4.55 (dd, JH,H = 2.7, JH,F = 17.5 Hz, 1
H, CF=CHE), 5.00 ppm (s, 1 H, N-CH-NMe); minor rotamer: δ =
1.00 (3 × s, 9 H, CH-C(CH3)3), 1.48 (3 × s, 9 H, CO-C(CH3)3),
1.58 (s, 3 H, C*-Me), 2.45–2.73 (m, 2 H, CH-CH2-CF), 2.97 (s, 3
General Procedure A: A solution of lithium diisopropylamide was
prepared by addition of n-butyllithium (1.6 n solution in hexane)
(7.5 mL, 12.0 mmol) to a solution of diisopropylamine (1.7 mL,
12.0 mmol) in dry THF (7.5 mL) under argon at –50 °C. The mix-
ture was stirred for 15 min at this temperature. Then, DMPU
(3.6 mL, 30.0 mmol) and (S)-Boc-BMI (1a) or (S)-Boc-BMI-Me
2
3
H, N-Me), 4.29 (dd, JH,H = 2.5, JH,F = 49.8 Hz, 1 H, CF=CHZ),
2
3
4.53 (dd, JH,H = 2.4, JH,F = 17.3 Hz, 1 H, CF=CHE), 4.87 ppm
(s, 1 H, N-CH-NMe). 13C NMR (75.48 MHz, CDCl3) major rot-
amer: δ = 23.8 (s, C*-CH3), 26.9 (3 × q, CH-C(CH3)3), 28.3 (3 ×
q, CO-C(CH3)3), 31.7 (q, N-CH3), 38.7 (s, CH-C(CH3)3), 39.7
2
(1b) (10.0 mmol) in dry THF (7.5 mL) were added to the above (ddd, JC,F = 25.6 Hz, H2C-CF), 63.77 (s, N-C*-CO), 80.5 (d, N-
2
LDA solution at –50 °C. After 30 min, the corresponding elec-
trophile (11–13 mmol) in dry THF (3.0 mL) was added in one shot
at –50 °C. The resulting mixture was stirred for 2 h at this tempera-
ture and quenched with sat. aq. NH4Cl solution (5.0 mL) and then
Et2O (30 mL) was added. After phase separation, the aqueous layer
CH-N), 81.0 (s, CO-C(CH3)3), 93.7 (ddd, JC,F = 20.2 Hz,
1
CF=CH2), 153.1 (s, N-CO-OtBu), 163.0 (d, JC,F = 258.1 Hz,
CF=CH2), 172.8 ppm (s, CO-NMe); minor rotamer: δ = 23.6 (q,
C*-CH3), 27.2 (3 × q, CH-C(CH3)3), 28.1 (3 × q, CO-C(CH3)3),
2
31.9 (q, N-CH3), 38.2 (ddd, JC,F = 26.2 Hz, H2C-CF), 39.0 (s,
722
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Asymmetric Synthesis of γ-Fluorinated α-Amino Acid Derivatives
FULL PAPER
CH-C(CH3)3), 64.1 (s, N-C*-CO), 81.0 (d, N-CH-N), 81.1 (s, CO- CH-N). 13C NMR (75.48 MHz, CDCl3): δ = 23.7 (q, H2C=CH-
2
C(CH3)3), 94.1 (ddd, JC,F = 20.0 Hz, CF=CH2), 154.2 (s, N-CO- CH3), 26.5 (3 × q, CH-C(CH3)3), 28.1 (3 × q, CO-C(CH3)3), 32.0
1
OtBu), 162.6 (d, JC,F = 258.8 Hz, CF=CH2), 173.1 ppm (s, CO-
(q, N-Me), 35.6 (s, CH-C(CH3)3), 40.8 (dd, H2C-CCH3), 58.6 (d,
CO-CH-N), 80.7 (s, CO-C(CH3)3), 81.0 (d, N-CH-N), 112.8 (dd,
H2C=C-CH3), 140.4 (s, H2C=C-CH3), 152.9 (s, CO-OtBu),
172.0 ppm (s, CO-NMe). MS-ES: m/z = 311.3 [M + H]. GC-MS:
NMe). 19F NMR (282.37 MHz, CDCl3) major rotamer: δ = –
94.77 ppm (dddd, JH,F = 7.6, JH,F = 17.3, JH,F = 22.6, JH,F
3
3
3
3
=
49.6 Hz, 1 F, CF=CH2); minor rotamer: δ = –97.98 ppm (dddd,
3JH,F = 8.4, JH,F = 16.9, JH,F = 25.1, JH,F = 50.1 Hz, 1 F,
m/z (%) = 253 (5) [M+ – C4H9], 237 (2), 207 (7), 197 (71) [M+
–
3
3
3
CF=CH2). MS-ES: m/z = 329.2 [M + H]. GC-MS: m/z (%) = 271
C8H18], 179 (35), 167 (2), 153 (67), 134 (25), 127 (33), 110 (44), 94
(6) [M+ – C4H8], 255 (3) [M+ – C4H10O], 215 (84), 195 (2), 171 (82), 84 (76), 69 (94), 57 (94), 41 (100). C17H30N2O3 (310.4): calcd.
(43), 143 (3), 123 (2), 111 (35), 87 (5), 57 (100), 42 (58).
C17H29FN2O3 (328.4): calcd. C 62.17, H 8.90, N 8.53; found: C
62.23, H 8.93, N 8.40.
C 65.77, H 9.74, N 9.02; found: C 65.88, H 9.71, N 8.82.
tert-Butyl (2S,5S)-2-tert-Butyl-3,5-dimethyl-5-(2-methylallyl)-4-
oxoimidazolidine-1-carboxylate (2f): Following general procedure
A, the reaction of 1b (1.0 g, 3.7 mmol) with 2-methallyl chloride
(0.47 g, 5.2 mmol) gave compound 2f as a white crystalline solid
(1.02 g, 85%): m.p. 62 °C (Et2O/pentane). [α]2D0 = –34.4 (c= 1.01,
tert-Butyl (2S,5S)-5-Allyl-2-tert-butyl-3-methyl-4-oxoimidazolidine-
1-carboxylate (2c): Following general procedure A, the reaction of
1a (1.28 g, 5.0 mmol) with allyl bromide (0.85 g, 7.0 mmol) gave
compound 2c as a white crystalline solid (1.39 g, 94%): m.p. 63 °C
(Et2O/pentane). [α]2D0 = +1.2 (c = 1.005, Et2O). The spectral data
agree with those reported previously.[33]
1
Et2O). H NMR (300.14 MHz, CDCl3) major rotamer: δ = 0.99 (3
× s, 9 H, CH-C(CH3)3), 1.51 (3 × s, 9 H, CO-C(CH3)3), 1.52 (s, 3
2
H, C*-Me), 1.62 (s, 3 H, CH2=C-CH3), 2.43 (d, JH,H = 14.4 Hz,
1 H, CH-CH2-CMe), 2.94 (s, 3 H, N-Me), 2.95 (d, 2JH,H = 14.4 Hz,
tert-Butyl (2S,5S)-5-Allyl-2-tert-butyl-3,5-dimethyl-4-oxoimidazo-
lidine-1-carboxylate (2d): Following general procedure A, the
reaction of 1b (1.35 g, 5.0 mmol) with allyl bromide (0.85 g,
7.0 mmol) gave compound 2d as a white crystalline solid (1.4 g,
2
1 H, CH-CH2-CMe), 4.62 (d, JH,H = 10.6 Hz, 1 H, HZC=CMe),
4.79 (d, 2JH,H = 7.2 Hz, 1 H, HEC=CMe), 4.94 ppm (br. s, 1 H, N-
CH-N); minor rotamer: δ = 1.01 (3 × s, 9 H, CH-C(CH3)3), 1.47
(3 × s, 9 H, CO-C(CH3)3), 1.57 (s, 3 H, C*-Me), 1.59 (s, 3 H,
1
90%): m.p. 57 °C (Et2O-pentane). [α]2D0 = –15.2 (c = 1.0, Et2O). H
2
CH2=C-CH3), 2.40 (d, JH,H = 14.4 Hz, 1 H, CH-CH2-CMe), 2.95
NMR(300.14 MHz, CDCl3) major rotamer: δ = 0.97 (3 × s, 9 H,
CH-C(CH3)3), 1.51 (3 × s, 9 H, CO-C(CH3)3), 1.51 (s, 3 H, C*-
(s, 3 H, N-Me), 3.26 (d, 2JH,H = 14.4 Hz, 1 H, CH-CH2-CMe), 4.62
2
2
(d, JH,H = 10.6 Hz, 1 H, HZC=CMe), 4.79 (d, JH,H = 7.2 Hz, 1
H, HEC=CMe), 4.81 ppm (2 × br. s, 1 H, N-CH-N). 13C NMR
(75.48 MHz, CDCl3) major rotamer: δ = 23.7 (q, C*-CH3), 24.9 (q,
CH2-C-CH3), 27.0 (3 × q, CH-C(CH3)3), 28.3 (3 × q, CO-C(CH3)3),
31.5 (q, N-Me), 39.1 (s, CH-CMe3), 44.2 (dd, C-CH2-CMe), 64.3
(s, CO-C*-Me), 80.5 (d, N-CH-N), 80.7 (s, CO-OCMe3), 114.4 (dd,
H2C=CMe), 140.4 (s, H2C=CMe), 154.5 (s, CO-OtBu), 173.3 ppm
(s, CO-NMe);minor rotamer: δ = 23.2 (q, C*-CH3), 24.8 (q, CH2-
C-CH3), 27.3 (3 × q, CH-C(CH3)3), 28.1 (3 × q, CO-C(CH3)3),
31.5 (q, N-Me), 38.6 (s, CH-CMe3), 42.9 (dd, C-CH2-CMe), 64.8
(s, CO-C*-Me), 80.8 (s, CO-OCMe3), 80.9 (d, N-CH-N), 114.84
(dd, H2C=CMe), 140.7 (s, H2C=CMe), 152.7 (s, CO-OtBu),
173.6 ppm (s, CO-NMe). MS-ES: m/z = 325.3 [M + H]. GC-MS:
3
2
Me), 2.48 (dd, JH,H = 7.8, JH,H = 13.9 Hz, 1 H, CH2-CH=CH2),
2.90–3.00 (dd, overlapped, 1 H, CH2-CH=CH2), 2.95 (s, 3 H, N-
Me), 4.96 (br. s, 1 H, N-CH-N), 4.98–5.13 (m, 2 H, CH2-
CH=CH2), 5.26–5.48 ppm (m, 1 H, CH2-CH=CH2); minor rot-
amer: δ = 0.99 (3 × s, 9 H, CH-C(CH3)3), 1.48 (3 × s, 9 H, CO-
3
2
C(CH3)3), 1.57 (s, 3 H, C*-Me), 2.41 (dd, JH,H = 7.8, JH,H
=
13.9 Hz, 1 H, CH2-CH=CH2), 2.97 (2 × s, 3 H, N-Me), 3.26 (dd,
2
3JH,H = 8.4, JH,H = 13.9 Hz, 1 H, CH2-CH=CH2), 4.81 (br. s, 1
H, N-CH-N), 4.98–5.13 (m, 2 H, CH2-CH=CH2), 5.26–5.48 ppm
(m, 1 H, CH2-CH=CH2). 13C NMR (75.48 MHz, CDCl3) major
rotamer: δ = 23.6 (q, C*-CH3), 26.7 (3 × q, CH-C(CH3)3), 28.3 (3
× q, CO-C(CH3)3), 31.4 (q, N-Me), 38.9 (s, CH-C(CH3)3), 42.1 (dd,
CH2-CH=CH2), 65.0 (s, N-C*-Me), 80.6 (d, N-CH-N), 80.7 (s, CO-
C(CH3)3), 119.4 (dd, CH2-CH=CH2), 131.7 (d, CH2-CH=CH2),
155.0 (s, CO-C(CH3)3), 173.6 ppm (s, CO-NMe); minor rotamer: δ
= 23.5 (q, C*-CH3), 27.1 (3 × q, CH-C(CH3)3), 28.1 (3 × q, CO-
C(CH3)3), 31.4 (q, N-Me), 38.6 (s, CH-C(CH3)3), 40.3 (dd, CH2-
m/z (%) = 267 (3) [M+ – C4H9], 251 (1), 223 (1), 211 (64) [M+
C8H18], 193 (27), 167 (42), 151 (23), 112 (83), 108 (28), 98 (24), 82
(24), 69 (35), 57 (98), 41 (100). C18H32N2O3 (324.5): calcd. C 66.63,
H 9.94, N 8.63; found: C 66.37, H 10.04, N 8.60.
–
CH=CH2), 65.5 (s, N-C*-Me), 80.8 (s, CO-C(CH3)3), 81.0 (d, N- General Procedure B: The alkylation product 2 (5.0 mmol), dis-
CH-N), 119.4 (dd, CH2-CH=CH2), 132.2 (d, CH2-CH=CH2),
154.6 (s, CO-C(CH3)3), 173.7 ppm (s, CO-NMe). MS-ES: m/z =
311 [M + H]. GC-MS: m/z (%) = 253 (5) [M+ – C4H9], 197 (78)
[M+ – C8H18], 179 (30), 169 (43), 153 (45), 136 (10), 125 (15), 112
solved in anhydrous MeOH (5.0 mL), was treated with the anhy-
drous HCl/MeOH[44] (10.0 mL) and the mixture was stirred at
room temp. for 1 h. The solvent and excess reagent were removed
under vacuum and the residue was stirred in Et2O. The white pow-
(58), 94 (32), 84 (54), 69 (64), 57 (94), 42 (100). C17H30N2O3 der formed was isolated by filtration and washed with Et2O. The
(310.4): calcd. C 65.77; H 9.74, N 9.02; found: C 65.72; H 9.70, N
8.87.
solid was dried in vacuo and with P2O5 in a desiccator.
(2R,5S)-5-(2-Allyl)-2-tert-butyl-3-methylimidazolidin-4-one Hydro-
chloride (3a): Following general procedure B, starting from alky-
tert-Butyl (2S,5S)-2-tert-Butyl-3-methyl-5-(2-methylallyl)-4-oxoimid- lation product 2a (1.57 g, 5.0 mmol) the HCl salt of 3a was isolated
azolidine-1-carboxylate (2e): Following general procedure A, the re-
action of 1a (1.28 g, 15.0 mmol) with 2-methallyl chloride (0.63 g,
7.0 mmol) gave compound 2e as a white crystalline solid (1.41 g,
as a white powder (0.91 g, quant.): m.p. 130–135 °C (decomposi-
tion, Et2O/MeOH). [α]2D0 = –52.4 (c = 0.965, MeOH). 1H NMR
(300.14 MHz, CD3OD): δ = 1.16 (3 × s, 9 H, CH-C(CH3)3), 2.76–
91%): m.p. 82 °C (Et2O/pentane). [α]2D0 = –16.3 (c = 1.0, Et2O). H
3.12 (m, 2 H, CH-CH2-CF), 3.08 (s, 3 H, N-Me), 4.37 (dd, JH,H
1
2
3
NMR (300.14 MHz, CDCl3): δ = 0.98 (3 × s, 9 H, CH-C(CH3)3),
= 2.1, JH,H = 8.8 Hz, 1 H, CF=CHZ), 4.65–4.90 ppm (m, over-
1.47 (3 × s, 9 H, CO-C(CH3)3), 1.66 (s, 3 H, H2C=CH-CH3), 2.65 lapped for 5 H, CF=CHE, CO-CH-N, N-CH-N, CH-NH-CH). 13
C
(d, 2JH,H = 15.8 Hz, 1 H, CH-CH2-CMe), 3.00 (s, 3 H, N-Me), 3.13
NMR (75.48 MHz, CD3OD): δ = 25.3 (3 × q, CH-C(CH3)3), 32.6
4
2
2
(dd, JH,H = 4.9, JH,H = 15.7 Hz, 1 H, CH-CH2-CMe), 4.12 (dd,
(q, N-Me), 33.2 (ddd, JC,F = 27.9 Hz, CH-CH2-CF), 37.5 (s, CH-
3JH,H = 1.8, JH,H = 3.3 Hz, 1 H, CO-CH-CH2), 4.56 (d, 1 H,
C(CH3)3), 56.0 (d, NH-CH-CO), 82.7 (d, NH-CH-NMe), 95.5
3
MeC=CHZ), 4.78 (d, 1 H, MeC=CHE), 4.94 ppm (br. s, 1 H, N-
(ddd, 2JC,F = 18.0 Hz, CF=CH2), 161.4 (d, 1JC,F = 256.8 Hz, CH2-
Eur. J. Org. Chem. 2005, 719–727
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
723

D. M. Shendage, R. Fröhlich, K. Bergander, G. Haufe
FULL PAPER
CF=CH2), 169.2 ppm (s, CO-NMe). 19F NMR (282.37 MHz,
50.5 Hz, 1 F, CH2-CF=CH2). MS-ES: m/z = 147.2 [M + H]. GC-
CD3OD) major rotamer: δ = –97.73 ppm (dddd, 3JH,F = 15.5, 3JH,F MS: m/z (%) = 99 (2) [M+ – C2H3F], 88 (100) [M+ – C2H5NO], 69
3
3
= 16.0, JH,F = 20.0, JH,F = 51.4 Hz, 1 F, CH2-CF=CH2); minor
rotamer: δ = –96.25 ppm (m, 1 F, CH2-CF=CH2). MS-ES: m/z =
(12) [M+ – (HF + C2H5NO)], 61 (36), 58 (10), 41 (25), 39 (7).
C9H11FN2O (146.2): calcd. C 49.30, H 7.59, N 19.17; found: C
215.1 [M – Cl]. MS-EI: m/z (%) = 198 (5) [M+ – (Cl + CH3)], 171 49.19, H 7.62, N 19.15.
(89) [M+ – (Cl + CHF=CH2)], 157 (52) [M+ – (Cl + C4H8)], 88
(S)-2-Amino-4-fluoro-2-methylpent-4-enoicNЈ-Methylamide
(4b):
Following general procedure C, hydrolysis of 2b (4.36 g, 13.3 mmol)
gave compound 4b as a colorless oil (0.92 g, 43 %). [α]2D0 = –29.4 (c
= 1.32, CH2Cl2). 1H NMR (300.14 MHz, CDCl3): δ = 1.35 (s, 3 H,
(100), 57 (26). C11H20ClFN2O (250.7): calcd. C 52.69, H 8.04, N
11.17; found: C 52.14, H 8.08, N 11.08.
(2R,5S)-2-tert-Butyl-5-(2-fluoroallyl)-3,5-dimethylimidazolidin-4-
one Hydrochloride (3b): Following general procedure B, starting
from dialkylated product 2b (230 mg, 0.7 mmol) the HCl salt 3b
was isolated as a white powder (182 mg, quant.): m.p. 131–133 °C
(decomposition, Et2O/MeOH). [α]2D0 = –38.0 (c = 0.84, MeOH). 1H
NMR (300.14 MHz, CD3OD, major/minor): δ = 1.19/1.22 (2 × 3
× s, 9 H, CH-C(CH3)3), 1.67/1.57 (2 × s, 3 H, C*-Me), 2.88–2.93
(m, 1 H, CH-CH2-CF), 2.97–3.08 (m, 1 H, CH-CH2-CF), 3.05 (s,
3 H, N-Me), 4.65–4.92 ppm (m, overlapped for 4 H, CF=CHZ,
CF=CHE, N-CH-N, CH-NH-CH). 13C NMR (75.48 MHz,
CD3OD, major/minor): δ = 22.3 (q, C*-CH3), 25.4/25.7 (2 × 3 ×
q, CH-C(CH3)3), 32.1/31.4 (2 × q, N-Me), 36.0/35.5 (2 × s, CH-
C(CH3)3), 39.3 (ddd, 2JC,F = 28.7 Hz, CH2-CF=CH2), 64.5 (s, CO-
3
2
C*-Me), 1.61 (br. s, 2 H, C*-NH2), 2.46 (dd, JH,F = 8.4, JH,H
=
14.6 Hz, 1 H, CH-CH2-CF), 2.78 (dd, 3JH,F = 5.1, 2JH,H = 14.6 Hz,
3
3
1 H,), 2.79 (d, JH,H = 4.9 Hz, 3 H, NH-Me), 4.34 (dd, JH,F
=
50.0, 2JH,H = 2.7 Hz, 1 H, CF=CHZ), 4.66 (dd, 3JH,F = 17.3, JH,H
= 2.7 Hz, 1 H, CF=CHE), 7.69 ppm (br. s, 1 H, NH-Me). 13C
NMR (75.48 MHz, CDCl3): δ = 25.9 (q, C*-Me), 27.3 (q, N-Me),
2
2
3
42.9 (ddd, JC,F = 24.2 Hz, -C*-CH2-CF), 56.7 (d, JC,F = 1.8 Hz,
2
CO-C*-Me), 93.7 (ddd, JC,F = 19.5 Hz, CH2-CF=CH2), 163.5 (d,
1JC,F = 257.2 Hz, CH2-CF-CH2), 176.3 ppm (s, C*-CO-NHMe).
19F NMR (282.37 MHz, CDCl3): δ = –91.12 ppm (dddd, JH,F
=
3
4.5, 3JH,F = 7.9, 3JH,F = 19.1, JH,F = 49.9 Hz, 1 F, CH2-CF-CH2).
MS-ES: m/z = 161 [M + H]. MS-EI: m/z (%) = 140 (2) [M+ – HF],
123 (8) [140–CH3], 102 (72) [M+ – C2H5NO], 101 (15) [C3H4F], 94
(5), 86 (6), 80 (7), 66 (8), 61 (9), 59 (22), 55 (15), 42 (100). ES-EM
for [C7H13FN2O + H]: calcd. 161.1085; found: 161.1038.
3
2
C*-NH), 81.7 (d, N-CH-N), 97.2 (ddd, JC,F = 17.7 Hz, CH2-
1
CF=CH2), 161.3 (d, JC,F = 234.8 Hz, CH2-CF=CH2), 172.4 ppm
(s, MeN-CO-C*). 19F NMR (282.37 MHz, CD3OD) major rot-
3
3
3
amer: δ = –94.55 ppm (dddd, JH,F = 7.9, JH,F = 19.0, JH,F
=
General Procedure D: The respective NЈ-methylamide 4 (5 mmol)
was dissolved in 2 n KOH (20 mL) at room temp. and the solution
was then refluxed for 2 h. The pH of the solution was adjusted to
5–6 with stirring by using 2 n HCl at room temp. The water was
removed under vacuum, the residue diluted with anhydrous EtOH
(20 mL), and the precipitate (KCl) filtered. Propylene oxide
(10 mL) was added to the filtrate and the solution was refluxed for
30 min. After cooling in a freezer for 2 h the precipitated solid was
collected by filtration.
3
19.8, JH,F = 50.2 Hz, 1 F, CH2-CF=CH2); minor rotamer: δ = –
93.51 ppm (m, 1 F, CH2-CF=CH2). MS-ES: m/z = 229.1 [M – Cl].
MS-ES, daughters of 229.1: m/z (%) = 228 (7) [M+ – HCl], 168
(100) [M+ – (HCl + CH3F=CH2)], 150 (10) [M+ – (HCl + HF +
C4H8)], 143 (5) [M+ – (HCl + C5H11N)], 126 (10) [M+ – (HCl +
C7H13NO)], 112 (70) [M+ – (HCl + C4H8 + C2H3NO)], 108 (25),
101 (90), 99 (80), 101 (90); 85 (25), 68 (20), 157 (3), 42 (22).
C12H22ClFN2O (264.8): calcd. C 54.44, H 8.38, N 10.58; found: C
53.22, H 8.22, N 10.54.
(2S)-2-Amino-4-fluoropent-4-enoic Acid (5a): Following general
procedure D, starting from NЈ-methylamide 4a (702 mg, 4.8 mmol)
title compound 5a was isolated as a white powder (400 mg, 63%).
[α]2D0 = –5.3 (c = 1.03, H2O) [lit.[22] [α]2D0 = –18.0 (c = 1.78, H2O)].
The spectroscopic data for the racemate agree with previously pub-
lished values.[26]
General Procedure C: The alkylation product 2 (4.72 g, 15.0 mmol)
was dissolved in dry methanol (80 mL) and 1 n HCl solution
(80 mL) was added at room temp. and the mixture refluxed for 3 h.
The solvent was removed under vacuum and the residue was di-
luted with CH2Cl2 (100 mL). The pH of the aqueous phase was
adjusted to 7–8 with 2 n KOH solution. The organic layer was sep-
arated and the aqueous layer was extracted with CH2Cl2 (5×). The
combined organic layers were dried over Na2SO4 and the solvent
was evaporated in vacuo to give a dark oil. After purification by
column chromatography (CH2Cl2/MeOH, 9:1), NЈ-methylamides 4
were isolated as a single enantiomer (see Results and Discussion).
(2S)-2-Amino-4-fluoro-2-methylpent-4-enoic Acid (5b): Following
general procedure D, starting from NЈ-methylamide 4b (140 mg,
0.87 mmol) title compound 5b was isolated as a white powder
(85 mg, 66%). [α]2D0 = –3.7 (c = 1.04, H2O). The spectroscopic data
for the racemate agree with previously published values.[26]
(S)-4-Fluoro-2-(1,3-dioxaisoindolin-2-yl)pent-4-enoic N-Methylamide
(6):[46] Phthalic anhydride (3.6 mmol, freshly recrystallized from
CHCl3) was added to a solution of N-methylamide (S)-4a (438 mg,
3 mmol in CHCl3/MeOH (2:1, 30 mL) at 0 °C. After 10 min, oxalyl
chloride (4.5 mmol) was added dropwise at 0 °C. This solution was
refluxed for 5 h and then cooled to room temp. The solvent was
evaporated under vacuum and the residue was recrystallized from
(S)-2-Amino-4-fluoropent-4-enoicNЈ-Methylamide (4a): Following
general procedure C, alkylation product 2a (4.72 g, 15.0 mmol) af-
ter crystallization from CH2Cl2/pentane in a freezer gave pale yel-
lowish crystals of 4a (1.38 g, 63%): m.p. 39 °C (Et2O/pentane).
1
[α]D20 = –60.6 (c = 1.04, CH2Cl2). H NMR (300.14 MHz, CDCl3): δ
3
3
= 1.63 (br. s, 2 H, CH-NH2), 2.31 (ddd, JH,H = 5.4, JH,F = 9.9,
2JH,H = 15.3 Hz, 1 H, CH-CH2-CF), 2.82 (d, 3 H, JH,H = 5.0 Hz, CH2Cl2/pentane (2:1) in a freezer to give the title compound 6 as
N-Me), 2.88 (dddd, JH,H = 0.9, JH,H = 3.9, JH,F = 10.4, JH,H
3
4
3
3
2
=
white prisms (738 mg, 89%). In the X-ray structure determination,
15.3 Hz, 1 H, CH-CH2-CF), 3.57 (dd, 3JH,H = 3.9, JH,H = 9.5 Hz, 0.5 equiv. CH2Cl2 was used as the solvent of crystallization: m.p.
3
4
2
3
1 H, CO-CH-CH2), 4.37 (ddd, JH,H = 0.7, JH,H = 2.8, JH,F
=
=
169 °C (CH2Cl2/pentane). [α]D = –64.6 (c = 1.02, CH2Cl2). 1H
2
3
3
49.6 Hz, 1 H, CH2-CF=CHZ), 4.67 (dd, JH,H = 2.8, JH,F
NMR (300.14 MHz, CDCl3): δ = 2.78 (d, JH,H = 4.9 Hz, 3 H,
17.1 Hz, 1 H, CH2-CF=CHE), 7.46 ppm (br. s, 1 H, NH-Me). 13C
NH-Me), 3.03–3.14 (m, 1 H, CH-CH2-CF), 3.14–3.32 (m, 1 H,
2
NMR (75.48 MHz, CDCl3): δ = 25.7 (q, N-Me), 37.6 (ddd, JC,F
CH-CH2-CF), 4.28 (ddd, 4JH,H = 0.5, 3JH,F = 49.1, 2JH,H = 3.0 Hz,
3
2
= 27.6 Hz, CH-CH2-CF), 52.22 (d, CO-CH-CH2), 92.9 (ddd, 2JC,F 1 H, CH-CH2-CF), 4.50 (dd, JH,F = 16.8, JH,H = 3.0 Hz, 1 H,
1
= 20.2 Hz, CH2-CF=CH2), 163.3 (d, JC,F = 257.8 Hz, CH2-
CH2-CF=CHZ), 5.02 (dd, 3JH,H = 4.9, 3JH,H = 10.9 Hz, 1 H, CH2-
CF=CH2), 174.0 ppm (s, CO-NHMe). 19F NMR (282.37 MHz, CF=CHE), 6.32 (br. s, 1 H, NH-Me), 7.76 (2 × dd, JH,H = 3.0,
4
3
3
3
4
CDCl3): δ = –96.43 ppm (ddt, JH,F = 6.4, JH,F = 22.5, JH,F
=
3JH,H = 5.5 Hz, 2 H, CH-Armeta), 7.86 ppm (2 × dd, JH,H = 3.0,
724
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 719–727

Asymmetric Synthesis of γ-Fluorinated α-Amino Acid Derivatives
3JH,H = 5.5 Hz, 2 H, CH-Arortho). 13C NMR (75.48 MHz, CDCl3):
FULL PAPER
Me), 25.6 (3 × q, CH-C(CH3)3), 29.2 (q, C-Me), 31.1 (q, N-Me),
38.1 (s, CH-C(CH3)3), 66.3 (d, CO-CH-CMe2), 83.9 (s + d, CH-
CMe2, N-CH-N), 160.6 (s, N-CO-O), 169.1 ppm (s, CH-CO-NMe).
2
δ = 26.51 (q, N-Me), 31.42 (ddd, JC,F = 27.2 Hz, CH2-CF-CH2),
2
51.17 (d, CH-CH2-CF), 93.34 (ddd, JC,F = 19.4 Hz, CF=CH2),
123.58 (2 × d, CH-Arortho), 131.51 (2 × s, C-Ar), 134.40 (2 × d,
MS-ES: m/z = 263.4 [M + Na]. GC-MS: m/z (%) = 183 (27) [M+
–
CH-Armeta), 162.28 (d, 1JC,F = 258.0 Hz, CH2-CF=CH2), 167.67 (2 C4H8], 169 (2) [M+ – (C4H8 + CH3)], 153 (3) [M+ – (CO2 + C3H6)],
× s, C(Ar)-CO-N), 168.15 ppm (s, CH-CO-OMe). 19F NMR
139 (100) [M+ – (CO2 + C4H8)], 111 (5), 98 (5), 82 (78), 70 (18),
3
3
(282.41 MHz, CDCl3): δ = –98.13 ppm (dddd, JH,F = 12.1, JH,F 55 (28), 42 (75). C12H20N2O3 (240.3): calcd. C 59.98, H 8.39, N
= 16.8, 3JH,F = 17.0, 3JH,F = 49.1 Hz, 1 F, CH2-CF=CH2). MS-ES:
m/z = 277 [M + H], 299 [M + Na]. GC-MS-EI: m/z (%) = 276 (17)
[M+], 256 (15) [M+ – HF], 245 (7), 218 (65) [M+ – C2H4NO or
M+ – C3H4F], 198 (100) [218 – HF], 189 (10), 171 (13), 160 (41)
[218 – C2H4NO], 148 (12), 130 (41) [M+ – C8H4NO2], 104 (70)
[160 – C2H2NO], 76 (96), 58 (55), 50 (68), 42 (49). GC-HRMS for
[C14H12FN2O3]: calcd. 276.0910; found: 276.0915; for
[C14H12FN2O3 – HF]: calcd. 256.0848; found: 256.0856.
11.66; found: C 59.71, H 8.47, N 11.42.
tert-Butyl (2S,5R)-2-tert-Butyl-5-(2-fluoroallyl)-3-methyl-4-oxoimid-
azolidine-1-carboxylate (9): 2 n KOH (10 mL) was added to a solu-
tion of compound 2a (314 mg, 1.0 mmol) in MeOH (10 mL) at
room temp. The solution was refluxed for 2 h and MeOH was re-
moved under vacuum. The residual aqueous phase was neutralized
carefully with 2 n HCl solution at 0 °C and extracted with EtOAc
(3×). The combined organic layers were dried (MgSO4) and the
solvents evaporated under vacuum to give a colorless oil of 9 and
2a in a 9:1 ratio. The product cis-9 (90%) was separated from trans-
2a (10%) by column chromatography (cyclohexane/EtOAc, 4:1) to
give a colorless oil (277 mg, 88%). [α]2D0 = –25.6 (c = 1.1, CH2Cl2).
1H NMR (300.14 MHz, CDCl3): δ = 1.02 (3 × s, 9 H, CH-C(CH3)
Methyl (S)-4-Fluoro-2-(1,3-dioxaisoindolin-2-yl)pent-4-enoate (7):
Granular NaNO2 (1.53 g, 22 mmol) was added in portions over 2 h
to a solution of the N-phthaloyl NЈ-methylamide 6 (276 mg,
1 mmol) in a 2:1 mixture of Ac2O and AcOH (7.5 mL) at 0–4 °C.
Evolution of a brown gas occurred, the solution changed color, and
a solid precipitated. After 14–16 h, the mixture was warmed to
room temperature in less than 20 min, added to ice–water (10 mL),
and extracted with Et2O (3 × 20 mL). The combined organic layers
were washed (carefully!) with 5% Na2CO3 (3 × 20 mL) and then
H2O and dried (Na2SO4). Evaporation of the solvent gave a yellow-
ish liquid. GC shows complete conversion of the N-phthalimido-
NЈ-methylamide 6. Anhydrous 1,4-dioxane (10 mL) was added to
this residue, and the solution was refluxed. The yellowish color of
the solution disappeared in the first 1 h, but refluxing was contin-
ued for 5 h. Then, the solution was cooled to room temperature
and the solvent was removed under vacuum to give a colorless oil.
GC of the crude product as such shows high purity (252 mg, 91%):
3
3
3), 1.47 (3 × s, 9 H, CO-C(CH3)3), 2.51 (ddd, JH,H = 8.8, JH,F
=
22.7, 2JH,H = 14.7 Hz, 1 H, CH-CH2-CF), 2.78 (dddd, 4JH,H = 2.0,
3JH,H = 5.1, 3JH,F = 17.8, 2JH,H = 14.7 Hz, 1 H, CH-CH2-CF), 3.00
3
3
(s, 3 H, N-Me), 4.39 (dd, JH,H = 2.9, JH,F = 48.3 Hz, 1 H, CH2-
3
3
CF=CHE), 4.38 (dd, JH,H = 4.9, JH,H = 8.7 Hz, 1 H, CH-CH2-
2
3
CF), 4.61 (dd, JH,H = 2.9, JH,F = 16.5 Hz, 1 H, CH2-CF=CHZ),
4.99 ppm (br. s, 1 H, N-CH-N). 13C NMR (75.48 MHz, CDCl3): δ
= 26.6 (3 × q, CH-C(CH3)3), 28.0 (3 × q, CO-C(CH3)3), 31.31 (q,
2
N-Me), 36.3 (ddd, JC,F = 27.1 Hz, CH2-CF=CH2), 37.1 (s, CH-
C(CH3)3), 57.5 (d, CO-CH-CH2), 81.6 (s, CO-OC(CH3)3), 82.3 (d,
2
N-CH-N), 92.4 (ddd, JC,F = 19.6 Hz, CF=CH2), 155.8 (s, CO-
1
OtBu), 162.7 (d, JC,F = 258.8 Hz, CH2-CF-CH2), 170.7 ppm (s,
CH-CO-NMe). 19F NMR (282.37 MHz, CDCl3): δ = –94.67 ppm
1
[α]D = –67.9 (c = 1.1, CH2Cl2). H NMR (300.14 MHz, CDCl3): δ
3
3
3
3
(dddd, JH,F = 17.2, JH,F = 17.3, JH,F = 22.5, JH,F = 48.1 Hz, 1
F, CH2-CF=CH2). MS-ES: m/z = 315.3 [M + H]. GC-MS: m/z (%)
= 257 (5) [M+ – C4H8], 241 (7) [M+ – C4H10O], 201 (63), 181 (20),
157 (73), 131 (38), 110 (28), 88 (50), 69 (42), 57 (70), 42 (100). ES-
EM for [C16H26FN2O3 + H]: calcd. 315.2078; found: 315.2047.
= 3.04–3.24 (m, 2 H, CH2-CF=CH2), 3.68 (s, 3 H, CO-OMe), 4.22
3
2
(dd, JH,F = 49.2, JH,H = 3.0 Hz, 1 H, CH2-CF=CHZ), 4.45 (dd,
3JH,F = 16.8, JH,H = 3.1 Hz, 1 H, CH2-CF=CHE), 5.09 (dd, 3JH,H
2
3
4
= 5.7, JH,H = 10.3 Hz, 1 H, CO-CH-CH2), 7.67 (2 × dd, JH,H
=
=
3
4
3.1, JH,H = 5.5 Hz, 2 H, CH-Armeta), 7.79 ppm (2 × dd, JH,H
3
3.1, JH,H = 5.4 Hz, 2 H, CH-Arortho). 13C NMR (75.48 MHz,
X-ray Crystal Structure Analysis for 2a: Formula C16H27FN2O3, M
= 314.40, colorless crystal, 0.65 × 0.05 × 0.05 mm, a = 9.515(1), b
= 6.067(1), c = 16.305(1) Å, β = 106.19(1)°, V = 903.9(1) Å3, ρcalcd.
2
CDCl3): δ = 31.70 (ddd, JC,F = 27.7 Hz, CH-CH2-CF), 49.01 (q,
2
CO-OMe), 52.87 (d, CO-CH-CH2), 93.22 (ddd, JC,F = 20.2 Hz,
CF=CH2), 123.58 (2 × d, CH-Arortho), 131.66 (2 × s, C-Ar), 134.31 = 1.155 g cm–3, µ = 7.11 cm–1, empirical absorption correction
1
(2 × d, CH-Armeta), 161.87 (d, JC,F = 258.6 Hz, CH2-CF=CH2), 0.655 Յ T Յ 0.965, Z = 2, monoclinic, space group P21 (No. 4), λ
167.22 (2 × s, C(Ar)-CO-N), 168.64 ppm (s, CH-CO-OMe). 19F = 1.54178 Å, T = 223 K, ω and φ scans, 4229 reflections collected
3
NMR (282.37 MHz, CDCl3): δ = –98.26 ppm (dddd, JH,F = 12.9,
( h, k, l), [(sin θ)/λ] = 0.59 Å–1, 1855 independent (Rint = 0.038)
and 1252 observed reflections [I Ն 2σ(I)], 206 refined parameters,
R = 0.053, wR2 = 0.124, Flack parameter –0.6(5), max. residual
3JH,F = 15.9, JH,F = 16.6, JH,F = 49.2 Hz, 1 F, CH2-CF CH2).
3
3
MS-ES: m/z = 278 [M + H], 300 [M + Na]. GC-MS-EI: m/z (%) =
257 (1) [M+ – HF], 245 (3) [M+ – CH4O], 218 (45) [M+ – C2H4O2 electron density 0.19 (–0.14) e Å–3; hydrogen atoms were calculated
or M+ – C3H5F], 198 (100) [218 – HF], 190 (40) [218 – CH4O], 172
(7) [M+ – 104], 163 (9), 143 (5), 130 (100) [M+ – C8H5NO2], 115
(15), 104 (40) [M+ – C7H6O], 76 (47), 59 (20), 50 (51). ES-EM for
[C14H12FNO4+H]: calcd. 278.0823; found: 278.0801.
and all refined as riding atoms.
X-ray Crystal Structure Analysis for 4a: Formula C6H11FN2O, M
= 146.17, colorless crystal, 0.20 × 0.15 × 0.05 mm, a = 5.121(1), b
= 8.129(1), c = 9.538(1) Å, β = 99.50(1)°, V = 391.6(1) Å3, ρcalcd.
=
1.240 g cm–3, µ = 8.65 cm–1, empirical absorption correction 0.846
Յ T Յ 0.958, Z = 2, monoclinic, space group P21 (No. 4), λ =
1.54178 Å, T = 223 K, ω and φ scans, 1350 reflections collected
( h, k, l), [(sin θ)/λ] = 0.59 Å–1, 891 independent (Rint = 0.012)
and 763 observed reflections [I Ն 2σ(I)], 105 refined parameters, R
= 0.037, wR2 = 0.075, Flack parameter –0.1(4), max. residual elec-
tron density 0.14 (–0.17) e Å–3; hydrogen atoms bonded to nitrogen
atoms were obtained from difference Fourier calculations, others
were calculated and all refined as riding atoms.
(5S,7aS)-5-tert-Butyl-1,1,6-trimethyldihydro-1H-imidazo[1,5-c][1,3]-
oxazole-3,7(7aH)-dione (8): In a reaction similar to general pro-
cedure A, 1a, LDA (2 equiv.), DMPU (3 equiv.), 2-fluoroallyl tosyl-
ate (1.1 equiv.), and MeI (1.5 equiv.) gave a mixture of 2a (65%
yield) and 8 as a side-product (20% yield, see the Results and Dis-
cussion). The crude solid 8 was crystallized from Et2O/pentane in
a freezer to give white prisms: m.p. 144 °C (Et2O/pentane). [α]2D0
1
= –21.0 (c = 1.02, CH2Cl2). H NMR (300.14 MHz, CDCl3): δ =
1.04 (3 × s, 9 H, CH-C(CH3)3), 1.44 (s, 3 H, C-Me), 1.63 (s, 3 H,
C-Me), 3.00 (s, 3 H, N-Me), 3.96 (s, 1 H, CO-CH-CMe2), 4.71 ppm X-ray Crystal Structure Analysis for 8: Formula C12H20N2O3, M =
(s, 1 H, N-CH-N). 13C NMR (75.48 MHz, CDCl3): δ = 23.9 (q, C- 240.30, colorless crystal, 0.40 × 0.30 × 0.07 mm, a = 7.006(1), b =
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D. M. Shendage, R. Fröhlich, K. Bergander, G. Haufe
FULL PAPER
9.889(1), c = 19.362(1) Å, V = 1341.4(2) Å3, ρcalcd. = 1.190 g cm–3,
µ = 7.01 cm–1, empirical absorption correction 0.767 Յ T Յ 0.953,
Z = 4, orthorhombic, space group P212121 (No. 19), λ = 1.54178 Å,
T = 223 K, ω and φ scans, 5409 reflections collected ( h, k, l),
[(sin θ)/λ] = 0.58 Å–1, 2063 independent (Rint = 0.030) and 1670
observed reflections [I Ն 2σ(I)], 160 refined parameters, R = 0.038,
wR2 = 0.086, Flack parameter –0.1(4), max. residual electron den-
sity 0.12 (–0.10) e Å–3, hydrogen atoms were calculated and all re-
fined as riding atoms.
[19] I. Hyla-Kryspin, G. Haufe, S. Grimme, Chem. Eur. J. 2004, 10,
3411–3422.
[20] K. G. Grozinger, R. W. Kriwacki, S. F. Leonard, T. P. Pitner, J.
Org. Chem. 1993, 58, 709–713.
[21] D. Winkler, N. Sewald, K. Burger, N. N. Chung, P. W. Schiller,
J. Pept. Sci. 1998, 4, 496–501.
[22] K. W. Laue, S. Kröger, E. Wegelius, G. Haufe, Eur. J. Org.
Chem. 2000, 3737–3743.
[23] L. Zhang, J. M. Finn, J. Org. Chem. 1995, 60, 5719–5720 and
references cited therein.
[24] K. W. Laue, C. Mück-Lichtenfeld, G. Haufe, Tetrahedron 1999,
55, 10 413–10 424.
[25] G. Haufe, K. W. Laue, M. W. Triller, Y. Takeuchi, N. Shibata,
Tetrahedron 1998, 54, 5929–5938.
CCDC-246723 to -246730 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[26] K. W. Laue, G. Haufe, Synthesis 1998, 1453–1456.
[27] J. T. Welch, J. Lin, L. G. Boros, B. De Corte, K. Bogmann, R.
Gimi in Frontiers of Fluorine Chemistry (Eds.: I. Ojima, J. R.
McCarthy, J. T. Welch), ACS Symposium Series 639, American
Chemical Society, Washington, DC, 1996, pp. 129–142.
[28] T. Allmendinger, E. Felder, E. Hungerbühler, Tetrahedron Lett.
1990, 31, 7301–7304.
[29] L. G. Boros, B. De Corte, R. H. Gimi, J. T. Welch, Y. Wu, R. E.
Handschumacher, Tetrahedron Lett. 1994, 35, 6033–6036.
[30] R. J. Abraham, S. L. R. Ellison, P. Schonholzer, W. A. Thomas,
Tetrahedron1986, 42, 2101–2110.
Acknowledgments
This work was supported by the NRW Graduate School of Chemis-
try (GSC-MS), Münster, Germany. The kind donation of (S)-Boc-
BMI by Degussa AG, Germany, is gratefully acknowledged. We
thank Dr. C. M. Lichtenfeld for theoretical calculations and dis-
cussions.
[31] N. S. Yoder, K. Kumar, Chem. Soc. Rev. 2002, 31, 335–341.
[32] X.-L. Qui, W.-D. Meng, F.-L. Qing, Tetrahedron 2004, 60,
6711–6745 and references cited therein.
[1] G. A. Olah, R. D. Chambers, G. K. S. Prakash (Eds.), Syn-
thetic Fluorine Chemistry, Wiley Interscience, New York, 1992.
[2] J. Mann, Chem. Soc. Rev. 1987, 16, 381–436.
[3] B. Baasner, H. Hagemann, J. C. Tatlow (Eds.), Methods of Or-
ganic Chemistry (Houben-Weyl), 4th ed., George Thieme-Ver-
lag, Stuttgart and New York, 2000, vols. 10a–c.
[4] M. Hudlický, A. E. Pavlath (Eds.), Chemistry of Organic Fluor-
ine Compounds II. A Critical Review, ACS Monograph 187,
American Chemical Society, Washington, DC, 1995, chapter 3,
pp. 41–293.
[5] J. T. Welch (Ed.), Selective Fluorination in Organic and Bioor-
ganic Chemistry, ACS Symposium Series 456, American Chem-
ical Society, Washington, DC, 1991.
[6] R. Filler, Y. Kobayashi, L. M. Yagripolskii (Eds.), Organofluor-
ine Compounds in Medicinal Chemistry and Biomedical Applica-
tions, Elsevier, Amsterdam, 1993.
[7] K. L. Kirk, R. Filler in Biomedical Frontiers of Fluorine Chem-
istry (Eds.: I. Ojima, J. R. McCarthy, J. T. Welch), ACS Sympo-
sium Series 639, American Chemical Society, Washington, DC,
1996, pp. 1–24.
[8] J. T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemis-
try, John Wiley & Sons, New York, 1991, pp. 7–65.
[9] J. T. Welch, A. Gyenes, M. J. Jung in Fluorine-containing Amino
Acids: Synthesis and Properties (Eds.: V. P. KukharЈ, V. A. So-
loshonok), John Wiley & Sons, Chichester, 1995, pp. 311–331.
[10] K. L. Kirk in Fluorine-containing Amino Acids: Synthesis and
Properties (Eds.: V. P. Kukhar´, V. A. Soloshonok), John
Wiley & Sons, Chichester, 1995, pp. 343–401.
[11] V. Soloshonok in Biomedical Frontiers of Fluorine Chemistry
(Eds.: I. Ojima, J. R. McCarthy, J. T. Welch), ACS Symposium
Series 639, American Chemical Society, Washington, DC,
1996, pp. 26–41.
[33] R. Fitzi, D. Seebach, Tetrahedron 1988, 44, 5277–5292 and ref-
erences cited therein.
[34] M. J. Al-Darwich, A. Plenevaux, C. Lemaire, G. D. Fiore, L.
Christiaens, D. Comar, A. Luxen, J. Fluorine Chem. 1996, 80,
117–124.
[35] P. Damhaut, C. Lemaire, A. Plenevaux, C. Bihaye, L. Chris-
tiaens, D. Comar, Tetrahedron 1997, 53, 5785–5796.
[36] A. Mazón, C. Nájera, Tetrahedron: Asymmetry 1997, 8, 1855–
1859.
[37] H. Pajouhesh, M. Hosseini-Meresht, S. H. Pajonhesh, K.
Curry, Tetrahedron: Asymmetry 2000, 11, 4955–4958.
[38] D. Seebach, E. Dziadulewicz, L. Behrendt, S. Cantoreggi, R.
Fitzi, Liebigs Ann. Chem. 1989, 1215–1232.
[39] D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. 1996,
108, 2880–2921; Angew. Chem. Int. Ed. Engl. 1996, 35, 2708–
2748 and references cited therein.
[40] M. Lübke, Ph. D. Dissertation, Universität Münster, Germ-
nany, 2002.
[41] T. Mukhopadhyay, D. Seebach, Helv. Chim. Acta 1982, 65,
385–391.
[42] The diastereomeric purity of the crude products was checked
by GC and confirmed by 19F NMR spectroscopy.
[43] See the Supporting Information for dynamic NMR studies.
[44] The reagent HCl/MeOH was prepared by bubbling HCl gas
through cooled dry MeOH for 5 hours.
[45] In collaboration with Prof. Dr. A. Liese, Institute of Biochemis-
try, University of Münster, Germany, and Prof. Dr. F. P. J. T.
Rutjes, Department of Organic Chemistry, University of
Nijmegen, Nijmegen, The Netherlands.
[46] D. M. Shendage, R. Fröhlich, G. Haufe, Org. Lett. 2004, 6,
[12] K. Uneyama in Enantiocontrolled Synthesis of Fluoro-Organic
Compounds: Stereochemical Challenges and Biomedical Targets
(Ed.: V. A. Soloshonok), John Wiley & Sons, Chichester, 1999,
pp. 391–418.
3675–3678.
[47] R. Marshall, O. Shokek, J. T. Davis, J. Org. Chem. 1997, 62,
8243–82–46 and references cited therein.
[48] S. Mezengeza, T. K. Venkatachalam, M. Diksic, Amino Acids
2000, 18, 81–88.
[13] B. C. Smart, J. Fluorine Chem. 2001, 109, 3–11.
[14] D. O’Hagan, H. S. Rzepa, Chem. Commun. 1997, 645–652.
[15] M. Schlosser, D. Michel, Tetrahedron 1996, 52, 99–108.
[16] J. A. K. Howard, V. J. Hoy, D. O’Hagan, G. T. Smith, Tetrahe-
dron 1996, 52, 12 613–12 622.
[49] B. V. Nonius, EXPRESS, 1994.
[50]
[51]
[52]
B. V. Nonius, COLLECT, 1998.
K. Fair, B. V. Enraf–Nonius, MolEN, 1990.
Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276, 307–
326.
[17] I. Alkorta, I. Rozas, J. Elguero, J. Fluorine Chem. 2000, 101,
233–238.
[53]
[54]
R. H. Blessing, Acta Crystallogr. Sect. A 1995, 51, 33–37.
R. H. Blessing, J. Appl. Crystallogr. 1997, 30, 421–426.
[18] G. Haufe, T. C. Rosen, O. G. J. Meyer, R. Fröhlich, K. Ris-
sanen, J. Fluorine Chem. 2002, 114, 189–198.
726
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Asymmetric Synthesis of γ-Fluorinated α-Amino Acid Derivatives
FULL PAPER
[55] G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467–473.
[56] G. M. Sheldrick, SHELXL-97, University of Göttingen, 1997.
[57] K. Brandenburg, DIAMOND, University of Bonn, 1997.
[58] E. Keller, SCHAKAL, University of Freiburg, 1997.
[59] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923–
2925.
Received September 21, 2004
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