Selective synthesis of new fluorinated alicyclic β-amino ester stereoisomers

Article abstract of DOI:10.1002/ejoc.201100583

New fluorinated alicyclic β-amino ester stereoisomers with a cyclohexene or cyclohexane skeleton were prepared from cis- or trans-2-aminocyclohex-3-enecarboxylic acids in five or six steps through a regio- and stereoselective hydroxylation and hydroxy-fluorine exchange. Fluorinated aminoester enantiomers were synthesized from enantiopure cis- or trans-2-aminocyclohexenecarboxylic acid (prepared byenzymatic resolution of the racemic substances). New fluorinated alicyclic β-amino ester stereoisomers with a cyclohexene or cyclohexane skeleton were prepared from cis-or trans-2-aminocyclohex-3-enecarboxylicacids in five or six steps. Copyright

Full text of DOI:10.1002/ejoc.201100583

FULL PAPER
DOI: 10.1002/ejoc.201100583
Selective Synthesis of New Fluorinated Alicyclic β-Amino Ester Stereoisomers
Loránd Kiss,[a] Eniko˝ Forró,[a] Santos Fustero,[b,c] and Ferenc Fülöp*[a,d]
Keywords: Amino acids / Hydroxylation / Fluorine / Regioselectivity / Diastereoselectivity
New fluorinated alicyclic β-amino ester stereoisomers with a
cyclohexene or cyclohexane skeleton were prepared from
cis- or trans-2-aminocyclohex-3-enecarboxylic acids in five
or six steps through a regio- and stereoselective hydroxyl-
ation and hydroxy–fluorine exchange. Fluorinated amino
ester enantiomers were synthesized from enantiopure cis- or
trans-2-aminocyclohexenecarboxylic acid (prepared by
enzymatic resolution of the racemic substances).
have been reported, among either α-amino acids[3a,5] or γ-
amino acids.[3a,6] Despite their importance in pharmaceuti-
cal and peptide chemistry and the fact that cyclic β-amino
acids have undergone intensive research in recent years,[1]
only a small number of fluorinated derivatives have been
synthesized so far.[3f,7,8]
Introduction
Conformationally rigid cyclic β-amino acids are consid-
ered of high importance for synthetic and medicinal chem-
istry, and particularly for the synthesis of new bioactive mo-
lecules. These compounds are key elements in natural prod-
ucts and precursors to bioactive β-lactams. A number of β-
amino acids, such as cispentacin, oxetin, oryzoxymicin, and
icofungipen, are important antifungal or antibacterial
agents. The alicyclic or heterocyclic conformationally re-
stricted β-amino acids are building blocks in the synthesis
of new biologically active peptides.[1]
As a consequence of fluorine being present in many im-
portant pharmacological compounds, organic chemistry in-
volving fluorinated drugs and agrochemicals has undergone
enormous developments in the past 20 years. However, al-
though fluorine is not present in biologically active natural
compounds, an increasing number of drugs on the market
contain at least one fluorine atom. It is noteworthy that the
replacement of one or more atoms or functional groups by
fluorine in biologically active molecules can lead to pro-
found changes in their physical, chemical, and especially
biological properties.[2]
Results and Discussion
Herein, we report on the regio- and stereoselective syn-
theses of new mono- and difluorinated cyclohexane β-
amino acids. The stereo- and regioselective introduction of
a fluorine atom to the cyclohexane skeleton was ac-
complished by a hydroxy–fluorine exchange approach. As
in our earlier experiments, the racemic N-Boc-protected
(tert-butoxycarbonyl) starting materials cis- and trans-2-
aminocyclohex-3-enecarboxylic acid (1 and 16, respectively)
were first regio- and stereoselectively hydroxylated by iodol-
actonization and lactone-opening procedures, as key steps
resulting in the hydroxylated amino ester stereoisomers 2,
10, and 17.[9] The C–C double bond of all-cis-hydroxylated
cyclohexene β-amino ester 2 derived from amino acid 1
(Scheme 1) was saturated first to give ethyl 5-hydroxy-2-
aminocyclohexanecarboxylate 3. Amino ester 3 was then
subjected to hydroxy–fluorine exchange by using different
fluorinated organic reagents. Fluorination with bis(2-
methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) in
CH2Cl2 at 20 °C for 15 h resulted in the inversion of config-
uration to give the 5-fluorinated amino ester 4 (Scheme 1),
which was easily separated from the small amount of elimi-
nation side products by chromatography. A similar result
was obtained using diethylaminosulfur trifluoride (DAST).
An interesting and somewhat surprising experimental result
was observed when cis-hydroxylated cyclohexene β-amino
ester 2 was subjected to fluorination. Upon treatment with
either Deoxo-Fluor or DAST, amino ester 2, with a C–C
double bond in the ring, furnished a mixture of two fluori-
nated products in approximately a 1:1 ratio (the ratio of the
mixture of T6 and T7 was determined by analysis of the
Accordingly, an increasing number of fluorinated deriva-
tives of natural products and other bioactive compounds
have been prepared. Fluorinated amino acids[3] and pept-
ides[4] are recognized as valuable biomolecules in medicinal
chemistry and biochemistry, as antibiotics, enzyme inhibi-
tors, or antitumor agents.
Although the cyclic amino acids exhibit high pharmaceu-
tical potential, relatively few cyclic fluorinated derivatives
[a] Institute of Pharmaceutical Chemistry, University of Szeged,
Eötvös u. 6, 6720 Szeged, Hungary
[b] Departamento de Química Orgánica, Facultad de Farmacia,
Universidad de Valencia,
46100 Burjassot, Valencia, Spain
[c] Laboratorio de Moléculas Orgánica, Centro de Investigación
Príncipe Felipe,
46012 Valencia, Spain
[d] Research Group of Stereochemistry of the Hungarian Academy
of Sciences, University of Szeged,
Eötvös u. 6, 6720 Szeged, Hungary
Eur. J. Org. Chem. 2011, 4993–5001
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4993

L. Kiss, E. Forró, S. Fustero, F. Fülöp
FULL PAPER
Scheme 1. Synthesis of fluorinated β-amino acids 4 and 5 by fluorination of all-cis-hydroxylated amino ester 2. Reagents and conditions:
(i) HCOONH4, 10% Pd/C, EtOH, 70 °C, 1 h, 87%; (ii) Deoxo-Fluor, CH2Cl2, 20 °C, 15 h, 40%; (iii) 1.5 equiv. Deoxo-Fluor, CH2Cl2,
20 °C, 13 h, 63%, (T6/T7, 1:1); (iv) 1.3 equiv. DAST, CH2Cl2, 20 °C, 13 h, 55%, (T6/T7, 1:1); (v) H2, 10% Pd/C, EtOH, 20 °C, 1 h, 82%;
(vi) H2, 10% Pd/C, EtOAc, 20 °C, 1 h, 4 (22% from 2), 5 (22% from 2); (vii) FLUOLEAD, CH2Cl2, 20 °C, 15 h, 78%.
NMR spectroscopic data for the crude mixture), which (Scheme 2). This desired fluorinated derivative was easily
could not be separated by either crystallization or separated from a relatively small quantity of elimination
chromatography. To separate and characterize the two fluo- side products by chromatography.
rinated amino esters, hydrogenation of the ring double bond
The fluorination of amino ester 10 gave the expected in-
was effected. Hydrogenation in the presence of 10% Pd/C version product 13 (an SN2 product, see Figure 1) as the
in EtOH, resulted in saturation and removal of the fluorine minor product and 3-fluorinated derivative 14 as the major
to give amino ester 8 (Scheme 1). When the mixture of T6 product, identified by 2D NMR analysis. To determine of
and T7 was hydrogenated in the presence of the Pd/C cata- the stereochemistry of 14, a chemical correlation approach
lyst in EtOAc, the corresponding saturated derivatives was applied. Ethyl (1S*,2R*,3R*)-2-(tert-butoxycarbonyl-
could be separated by chromatography, affording β-amino amino)-3-fluorocyclohexanecarboxylate, where the amino
esters 4 and 5, each consisting of the 5-fluorocyclohexane moiety and fluorine atom are trans to each other, was pre-
skeleton (Scheme 1). This experimental result indicated pared earlier by our group.[8] Hydrogenation of 14 produced
that, in contrast to fluorination occurring by an SN2 pro- ethyl (1S*,2R*,3S*)-2-(tert-butoxycarbonylamino)-3-fluo-
cess leading to inversion at the hydroxyl site of cyclohexane rocyclohexanecarboxylate, where the amino group and flu-
amino ester 3, fluorination of hydroxylated cyclohexene orine atom are cis to each other, a diastereomer of the pre-
amino ester 2 proceeded by an SN1 mechanism. Com- viously synthesized ethyl (1S*,2R*,3R*)-2-(tert-butoxy-
pounds 4 and 5 were synthesized earlier under similar con- carbonylamino)-3-fluorocyclohexanecarboxylate.
ditions from all-cis-ethyl-2-(tert-butoxycarbonylamino)-3-
A possible mechanistic route to 13 and 14 is proposed in
Figure 2. Treatment of hydroxylated amino ester 10 with
hydroxycyclohex-4-enecarboxylate.[8]
Although the synthesis of the fluorinated cyclohexane DAST probably involves synchronized processes. A new
amino esters could be achieved, preparation of their unsatu- oxygen–sulfur bond is formed while simultaneously break-
rated counterparts remained unresolved. Since the fluorin- ing a sulfur–fluorine bond (S1), which is then followed by
ation of 2 with either Deoxo-Fluor or DAST furnished an an intramolecular attack of the fluoride anion on the sp2
inseparable mixture, we attempted the reaction with a new carbon atom (S2) to afford 14 as the major product (Fig-
fluorinating agent, 2,4,6-trimethylbenzenesulfur trifluoride ure 2, path a). Although less favorable, an alternate compet-
(FLUOLEAD). Unfortunately no fluorinated product re- itive process involving an intramolecular equatorial fluoride
sulted, but oxazolinone derivative 9 was obtained in good attack results in inversion to give the substitution product
yield, involving an intramolecular nucleophilic attack of the 13 as the minor isomer.
carbamate’s oxygen atom on C-3 by an SN2Ј process
Compounds 13 and 14 were readily separated by flash
(Scheme 1).
chromatography (Scheme 2). In view of our earlier results,
Next, the fluorination of amino ester 10, the C-1 epimer formation of 14 by an SN2Ј mechanism was predictable
of 2 which is derived from cis-amino acid 1, was investi- (Figure 3), and the fluorination of unsaturated cyclic hy-
gated. Saturation of the C–C double bond in 10 gave 11, droxylated amino esters furnished such products.[8] Oxazol-
which then yielded 5-fluoro β-aminocarboxylate 12 inone derivative 15 was obtained as the sole product in
4994
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4993–5001

Selective Synthesis of Fluorinated Alicyclic β-Amino Ester Stereoisomers
Scheme 2. Synthesis of fluorinated β-amino acids 12, 13, and 14 from hydroxylated amino ester 10. Reagents and conditions:
(i) HCOONH4, 10% Pd/C, EtOH, 70 °C, 1 h, 84%; (ii) Deoxo-Fluor (1.5 equiv.), CH2Cl2, 20 °C, 15 h, 53%; (iii) Deoxo-Fluor (1.5 equiv.),
CH2Cl2, 20 °C, 13 h, 13 (27%), 14 (41%); (iv) DAST (1.3 equiv.), CH2Cl2, 20 °C, 13 h, 13 (31%), 14 (42%); (v) FLUOLEAD, CH2Cl2,
20 °C, 15 h, 69%.
Figure 3. Formation of fluorinated amino esters 13 and 14 and
oxazolinone derivative 15.
Figure 1. ORTEP diagram of 13.
Figure 2. Proposed routes for the formation of 13 and 14.
Eur. J. Org. Chem. 2011, 4993–5001
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4995

L. Kiss, E. Forró, S. Fustero, F. Fülöp
FULL PAPER
Scheme 3. Synthesis of fluorinated amino esters 19, 14, and 20. Reagents and conditions: (i) HCOONH4, 10% Pd/C, EtOH, 70 °C, 1 h,
86%; (ii) 1. Deoxo-Fluor (5 equiv.), CH2Cl2, 20 °C, 15 h, 60%; (iii) Deoxo-Fluor (4.0 equiv.), CH2Cl2, 20 °C, 13 h, 20 (58%), 14 (5%);
(iv) DAST (1.3 equiv.), CH2Cl2, 20 °C, 13 h, 20 (57%), 14 (5%); (v) FLUOLEAD, CH2Cl2, 20 °C, 15 h, 66%. (vi) H2, 10% Pd/C, EtOH,
20 °C, 1 h, 78%; (vii) H2, 10% Pd/C, EtOAc, 20 °C, 1 h, 82%.
moderate yield from 10 upon treatment with FLUOLEAD
Compound 20 was synthesized earlier by an alternate
(Scheme 2, Figure 3). To prepare other new fluorinated 2- route, as an SN2Ј product from ethyl (1S*,2R*,3S*)-6-(tert-
aminocarboxylate stereoisomers, hydroxylated β-amino es- butoxycarbonylamino)-3-hydroxycyclohex-4-enecarboxyl-
ter stereoisomer 17 (derived from trans-β-amino acid 16) ate.[8] The formation of 20 was also confirmed by hydrogen-
was first reduced to give 18. Fluorination of 18 with Deoxo-
Fluor afforded the corresponding 5-fluoro-amino ester 19
in 60% yield (Scheme 3).
Direct fluorination of 17 by treatment with Deoxo-Fluor
or DAST resulted, analogously as in the case of its stereo-
isomer 10, in both 5- and 3-fluorinated derivatives 20 (SN2
product) and 14 (SN2Ј product), respectively. However,
somewhat surprising and in contrast with the fluorination
of 10, the major product in this transformation was the 5-
fluorinated derivative 20 (Scheme 3).
The difference in the reactivity between 10 and 17 and
the product ratio (14/20) may be explained by considering
the processes illustrated in Figure 4. Again, a synchronized
process is probably responsible for the ratio of the fluori-
nated products. In intermediate S3, the two competing pro-
cesses are an intramolecular fluoride attack on the sp2 C
atom (path b, leading to 14 as the minor isomer) and an
intramolecular substitution with inversion by an “axial at-
tack” (path a, affording 20 as the major product).
Scheme 4. Enzymatic resolution of racemic azetidinone 22. Rea-
gents and conditions: (i) CAL-B (Lipase B from Candida antarc-
tica), H2O (0.5 equiv.), iPr2O, 60 °C; (ii) Boc2O, 10% NaOH, H2O/
THF, 0 °C to 20 °C, 12 h, 76%. (iii) KI, I2, NaHCO3, H2O/CH2Cl2,
20 °C, 16 h, 79%; (iv) DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene),
THF (tetrahydrofuran), 65 °C, 4 h, 69%.
Figure 4. Proposed routes for the formation of 14 and 20.
4996
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4993–5001

Selective Synthesis of Fluorinated Alicyclic β-Amino Ester Stereoisomers
Scheme 5. Synthesis of enantiomerically pure fluorinated amino esters (–)-4 and (+)-12. Reagents and conditions: (i) NaOEt, EtOH, 0 °C,
1 h, 70%; (ii) NaOEt, EtOH, 20 °C, 10 h, 66%. (iii) HCOONH4, Pd/C, EtOH, 70 °C, 1 h, (–)-3 (83%), (+)-11 (81%); (iv) DAST, CH2Cl2,
20 °C, 7 h, (–)-4 (43%), (+)-12 (45%).
ation in EtOAc which led to saturated product 19, whereas trans-β-amino ester 26, in iPr2O at 60 °C.[12] By following a
hydrogenation in EtOH was accompanied by removal of the similar reaction pathway as that for the racemic substance,
fluorine to give amino ester 21 (Scheme 3).
transformation of the enantiopure trans-β-amino acid (+)-
The synthetic route presented offered a possibility for the 27 afforded fluorinated amino ester enantiomer (+)-19
preparation of enantiomeric substances. Enantiomerically (94%ee, Scheme 6).
pure β-amino acid (–)-23 (Ͼ 98%ee)[10] was prepared by
New geminal difluorinated cyclohexane β-amino esters
the Lipolase-catalyzed (Lipase B from Candida antarctica) were synthesized by selective hydroxylation through the cor-
enantioselective ring cleavage of unsaturated racemic β-lac- responding keto-aminocarboxylates. Hydroxylated amino
tam 22.[11] High enantioselectivity (E Ͼ 200) was observed esters 3 and 18 were converted with a sulfur trioxide–pyr-
when the reaction was performed with 0.5 equiv. of H2O in
iPr2O at 60 °C. Enantiopure (–)-23 was further transformed
under the earlier experimental conditions to lactone (–)-25
(Scheme 4), from which the hydroxylated amino esters (+)-
2 and (+)-10 were prepared in optically pure form.
Hydrogenation of (+)-2 and (+)-10 to (–)-3 and (+)-11,
respectively, followed by fluorination furnished the corre-
sponding
fluorinated
aminocyclohexanecarboxylate
enantiomers (–)-4 and (+)-12 (98%ee, Scheme 5). Enantio-
mer (–)-4 was prepared earlier through an alternate route.[8]
Enantiopure (Ͼ 98%ee) trans-β-amino acid (+)-27[10]
was obtained through the Lipolase-catalyzed enantioselec- Scheme 7. Synthesis of difluorinated amino esters 32 and 33. Rea-
gents and conditions: (i) Py–SO3, DMSO, Et3N CH2Cl2, 20 °C,
20 h, 30: 76%, 31: 73%. (ii) Deoxo-Fluor, CH2Cl2, 1 drop of EtOH,
0 °C, 8 h, 32 (36%), 33 (37%).
tive (E Ͼ 100) hydrolysis (0.5 equiv. of H2O) of racemic
Scheme 6. Synthesis of enantiomerically pure fluorinated amino es-
ter (+)-19. Reagents and conditions: (i) Lipase PS, H2O, Et2O.
(ii) Boc2O, 10% NaOH, H2O/THF, 0 °C to 20 °C, 12 h, 79%.
(iii) I2, KI, NaHCO3, H2O, CH2Cl2, 20 °C, 14 h, 86%. (iv) DBU,
THF, 65 °C, 4 h, 69%. (v) NaOEt, EtOH, 20 °C, 7 h, 68%;
(vi) HCOONH4, Pd/C, EtOH, 70 °C, 1 h, 79%. (vii) DAST,
CH2Cl2, 20 °C, 6 h, 41%.
Figure 5. ORTEP diagram of 32.
Eur. J. Org. Chem. 2011, 4993–5001
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4997

L. Kiss, E. Forró, S. Fustero, F. Fülöp
General Procedure for Fluorination
FULL PAPER
idine complex in the presence of Et3N and DMSO (di-
methyl sulfoxide) to the corresponding 5-keto-2-amino es-
ters 30 and 31, respectively. (Scheme 7). Upon treatment
with Deoxo-Fluor and one drop of EtOH in CH2Cl2, the
oxocarboxylates led to difluorinated amino esters 32 and 33
(Scheme 7, Figure 5).
Method A: To a solution of hydroxy amino ester 2, 3, 10, 11, 17,
or 18 (0.55 mmol) in CH2Cl2 (5 mL) under an Ar atmosphere was
added Deoxo-Fluor (50%) in toluene (1.5 equiv.), and the solution
was stirred at 20 °C for 13 h. The solution was then diluted with
CH2Cl2 (20 mL), and the organic layer was washed with a saturated
aqueous NaHCO3 solution (2ϫ15 mL). The organic layer was
dried with Na2SO4 and concentrated. The crude product was puri-
fied by column chromatography on silica gel (n-hexane/EtOAc,
9:1).
Conclusions
A simple diastereo- and regioselective method has been
applied for the synthesis of new mono- or difluorinated cy-
clohexane or cyclohexene β-amino esters through selective
hydroxylation and hydroxy–fluorine exchange. The syn-
thetic procedure was also extended to the preparation of
these derivatives in enantiomerically pure form.
Method B: To a solution of hydroxy amino ester 2, 10, or 17)
(0.55 mmol) in CH2Cl2 (5 mL) under an Ar atmosphere was added
DAST (1.3 equiv.), and the solution was stirred at 20 °C for 13 h.
The solution was then diluted with CH2Cl2 (20 mL), and the or-
ganic layer was washed with saturated aqueous NaHCO3 solution
(2ϫ15 mL). The organic layer was dried with Na2SO4 and concen-
trated. The crude product was purified by column chromatography
on silica gel (n-hexane/EtOAc, 9:1).
Experimental Section
General Procedure for Reduction of 2, 10, and 17: To a solution of
hydroxy amino ester 2, 10, or 17 (1.65 mmol) in EtOH (20 mL) was
added HCOONH4 (8.25 mmol, 5 equiv.) and Pd/C (10%, 90 mg).
The mixture was stirred at 75 °C. After 1 h, the solids were filtered,
and the filtrate was concentrated and purified by chromatography
on silica gel (n-hexane/EtOAc, 1:1).
Ethyl (1R*,2S*,5S*)-2-(tert-Butoxycarbonylamino)-5-fluorocyclo-
hexanecarboxylate (4): Yield 22%, see ref.[8]
Ethyl (1R*,2S*,5R*)-2-(tert-Butoxycarbonylamino)-5-fluorocyclo-
hexanecarboxylate (5): Yield 22%, see ref.[8]
Ethyl (1S*,2S*,5S*)-2-(tert-Butoxycarbonylamino)-5-fluorocyclo-
hexanecarboxylate (12): A white solid (53%), m.p. 73–75 °C (n-hex-
ane). Rf = 0.7 (n-hexane/EtOAc, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 1.20 (t, J = 7.15 Hz, 3 H, CH3), 1.31 (s, 9 H, tBu),
1.49–1.62 (m, 2 H, CH2), 1.77–1.82 (m, 1 H, CH2), 1.99–2.15 (m,
2 H, CH2), 2.20–2.28 (m, 1 H, CH2), 2.27–2.33 (m, 1 H, 1-H), 3.58–
3.67 (m, 1 H, 2-H), 4.10–4.17 (m, 2 H, OCH2), 4.30–4.57 (m, 2 H,
5-H and NH) ppm. 13C NMR (400 MHz, CDCl3): δ = 14.5, 28.7,
30.0, 31.3, 34.4, 47.6, 50.9, 61.4, 80.0, 89.0, 91.3, 155.3, 172.6 ppm.
C14H24FNO4 (289.35): calcd. C 58.11, H 8.36, N 4.84; found C
57.83, H 8.00, N 4.54. HRMS: calcd. for C14H24FNO4 [M]+
289.1689; found 289.1699.
General Procedure for Reduction of T6, T7, and 20: To a solution
of a mixture of fluorinated amino esters T6, T7, and 20 (1.5 mmol)
in EtOAc (15 mL) was added Pd/C (10%, 70 mg) The mixture was
stirred under a H2 atmosphere for 2 h, and the solids were then
filtered through Celite. The filtrate was concentrated, and the crude
product was separated and purified by column chromatography on
silica gel (n-hexane/EtOAc, 9:1).
Ethyl (1R*,2S*,5R*)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclo-
hexanecarboxylate (3): A colorless oil (87%). Rf = 0.45 (n-hexane/
EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.10 Hz,
3 H, CH3), 1.43 (s, 9 H, tBu), 1.52–1.79 (m, 3 H, CH2), 1.89–2.10
(m, 3 H, CH2), 2.76–2.82 (m, 1 H, 1-H), 3.80–3.85 (m, 1 H, 2-H),
3.90–3.99 (m, 1 H, 5-H), 4.11–4.20 (m, 2 H, OCH2), 5.20 (br. s, 1
H, NH) ppm. 13C NMR (400 MHz, CDCl3): δ = 14.6, 26.4, 28.7,
31.4, 33.5, 43.2, 48.3, 61.1, 67.1, 79.7, 155.6, 174.5 ppm.
C14H25NO5 (287.36): calcd. C 58.52, H 8.77, N 4.87; found C
58.19, H 8.55, N 4.48.
Ethyl (1S*,2S*,5R*)-2-(tert-Butoxycarbonylamino)-5-fluorocyclo-
hex-3-enecarboxylate (13): A white solid (Method A, 27%; Method
B, 31%), m.p. 113–115 °C (hexane). Rf = 0.65 (n-hexane/EtOAc,
1
3:1). H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.15 Hz, 3 H,
CH3), 1.46 (s, 9 H, tBu), 2.01–2.17 (m, 1 H, CH2), 2.34–2.42 (m, 1
H, CH2), 2.56–2.68 (m, 1 H, 1-H), 4–18–2.29 (m, 2 H, OCH2),
4.44–4.53 (m, 1 H, 2-H), 4.60 (br. s, 1 H, NH), 5.10–5.28 (m, 1 H,
5-H), 5.70–5.97 (m, 2 H, 3-H and 4-H) ppm. 13C NMR (400 MHz,
CDCl3): δ = 14.5, 28.7, 31.8, 32.1, 45.5, 61.5, 85.7, 87.9, 128.7,
133.0, 155.3, 172.6 ppm. C14H22FNO4 (287.33): calcd. C 58.52, H
7.72, N 4.87; found C 58.16, H 7.56, N 4.50. HRMS: calcd. for
C14H24FNO4 [M + Na]+ 310.1431; found 310.1423.
Ethyl (1S*,2S*,5R*)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclo-
hexanecarboxylate (11): A colorless oil (84%). Rf = 0.4 (n-hexane/
EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.10 Hz,
3 H, CH3), 1.42 (s, 9 H, tBu), 1.57–2.00 (m, 6 H, CH2), 2.68–2.79
(m, 1 H, 1-H), 3.68–3.80 (m, 1 H, 2-H), 4.07–4.20 (m, 3 H, OCH2
and 5-H), 4.61 (br. s, 1 H, NH) ppm. 13C NMR (400 MHz, CDCl3):
δ = 14.6, 27.2, 28.7, 31.3, 31.6, 35.1, 44.6, 50.9, 61.0, 65.0, 79.7,
155.4, 174.3 ppm. C14H25NO5 (287.36): calcd. C 58.52, H 8.77, N
4.87; found C 58.22, H 8.42, N 4.50.
Ethyl (1S*,2R*,3S*)-2-(tert-Butoxycarbonylamino)-3-fluorocyclo-
hex-4-enecarboxylate (14): A colorless oil (Method A, 41%;
Method B, 42%). Rf = 0.68 (n-hexane/EtOAc, 3:1). 1H NMR
(400 MHz, CDCl3): δ = 1.19 (t, J = 7.15 Hz, 3 H, CH3), 1.38 (s, 9
H, tBu), 2.30–2.43 (m, 1 H, CH2), 2.62–2.73 (m, 1 H, 1-H), 4.01–
Ethyl (1S*,2S*,5S*)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclo-
hexanecarboxylate (18): A white solid (86%), m.p. 125–128 °C. Rf
= 0.4 (n-hexane/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ =
1.23 (t, J = 7.10 Hz, 3 H, CH3), 1.41 (s, 9 H, tBu), 1.36–1.43 (m, 4.16 (m, 3 H, OCH2 and 2-H), 4.63–4.85 (m, 1 H, 3-H), 4.86 (br.
1 H, CH2), 1.66–1.71 (m, 1 H, CH2), 1.83–2.21 (m, 4 H, CH2),
2.36–2.42 (m, 1 H, 1-H), 3.58–3.77 (m, 2 H, 2-H and 5-H), 4.15–
s, 1 H, NH), 5.78–5.83 (m, 1 H, 5-H), 5.92–6.00 (m, 1 H, 4-H) ppm.
13C NMR (400 MHz, CDCl3): δ = 14.1, 28.3, 28.5, 41.1, 51.1, 60.9,
4.20 (m, 2 H, OCH2), 4.51–4.61 (br. s, 1 H, NH) ppm. 13C NMR 82.4, 84.6, 86.0, 122.9, 133.5, 154.9, 172.8 ppm. C14H22FNO4
(400 MHz, CDCl3): δ = 14.5, 28.7, 31.0, 34.0, 37.1, 48.4, 51.2, 61.2,
69.1, 79.8, 155.4, 173.9 ppm. C14H25NO5 (287.36): calcd. C 58.52,
H 8.77, N 4.87; found C 58.17, H 8.51, N 4.49.
(287.33): calcd. C 58.52, H 7.72, N 4.87; found C 58.14, H 8.00, N
4.53. HRMS: calcd. for C14H24FNO4 [M + Na]+ 310.1431; found
310.1425.
4998
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4993–5001

Selective Synthesis of Fluorinated Alicyclic β-Amino Ester Stereoisomers
Ethyl (1S*,2S*,5R*)-2-(tert-Butoxycarbonylamino)-5-fluorocyclo-
Ethyl (1R*,2S*)-2-(tert-Butoxycarbonylamino)-5-oxocyclohexane-
hexanecarboxylate (19): A white solid (60%), m.p. 81–83 °C (n-hex- carboxylate (30): A white solid (76%), m.p. 134–137 °C. Rf = 0.45
1
ane). Rf = 0.7, (n-hexane/EtOAc, 3:1). 1H NMR (400 MHz,
(n-hexane/EtOAc, 4:1). H NMR (400 MHz, CDCl3): δ = 1.29 (t,
CDCl3): δ = 1.19 (t, J = 7.15 Hz, 3 H, CH3), 1.37 (s, 9 H, tBu), J = 7.15 Hz, 3 H, CH3), 1.44 (s, 9 H, tBu), 2.05–2.14 (m, 2 H,
1.42–2.19 (m, 6 H, CH2), 2.51–2.62 (m, 1 H, 1-H), 3.61–3.71 (m, 1 CH2), 2.40–2.60 (m, 3 H, CH2), 2.72–2.79 (m, 1 H, CH2), 3.19–
H, 2-H), 4.05–4.13 (m, 2 H, OCH2), 5.50 (br. s, 1 H, NH), 4.65–
4.91 (m, 1 H, 5-H) ppm. 13C NMR (400 MHz, CDCl3): δ = 14.6,
27.6, 28.7, 29.9, 31.3, 33.3, 44.9, 61.2, 77.7, 86.2, 88.5, 156.0,
173.4 ppm. C14H24FNO4 (289.35): calcd. C 58.11, H 8.36, N 4.84;
found C 57.86, H 8.02, N 4.53.
3.26 (m, 1 H, 1-H), 4.19–4.30 (m, 3 H, OCH2, 2-H), 5.20 (br. s, 1
H, NH) ppm. 13C NMR (400 MHz, CDCl3): δ = 15.0, 28.7, 29.1,
38.5, 41.1, 45.6, 48.5, 61.7, 80.3, 155.5, 172.6, 207.6 ppm.
C14H23NO5 (285.34): calcd. C 58.93, H 8.12, N 4.91; found C
58.61, H 7.76, N 4.60.
Ethyl
(1S*,2S*,5S*)-2-(tert-Butoxycarbonyl)-5-fluorocyclohex-3-
Ethyl (1S*,2S*)-2-(tert-Butoxycarbonylamino)-5-oxocyclohexane-
carboxylate (31): A white solid (73%), m.p. 117–120 °C. Rf = 0.40
(n-hexane/EtOAc, 4:1). H NMR (400 MHz, CDCl3): δ = 1.25 (t,
enecarboxylate (20): Yield 63%, see ref.[8]
1
Ethyl (3aR*,4R*,7aS*)-2-Oxo-2,3,3a,4,5,7a-hexahydrobenzo[d]ox-
azole-4-carboxylate (9): A white solid (78%), m.p. 98–100 °C (n-
hexane/EtOAc). Rf = 0.35 (n-hexane/EtOAc, 1:2). 1H NMR
(400 MHz, CDCl3): δ = 1.28 (t, J = 7.10 Hz, 3 H, CH3), 2.39–2.47
(m, 2 H, CH2), 2.68–2.80 (m, 1 H, 4-H), 4.19–4.28 (m, 2 H, OCH2),
4.48–4.51 (m, 1 H, 3a-H), 5.08–5.11 (m, 1 H, 7a-H), 5.55 (br. s, 1
H, NH), 5.74–5.78 (m, 1 H, 6-H), 6.09–6.15 (m, 1 H, 7-H) ppm.
13C NMR (400 MHz, CDCl3): δ = 14.7, 22.8, 42.1, 52.0, 61.9, 73.4,
123.8, 132.4, 158.7, 173.9 ppm. C10H13NO4 (211.22): calcd. C
56.86, H 6.20, N 6.63; found C 56.60, H 5.86, N 6.41.
J = 7.15 Hz, 3 H, CH3), 1.45 (s, 9 H, tBu), 1.70–1.81 (m, 1 H,
CH2), 2.26–2.60 (m, 4 H, CH2), 2.70–2.79 (m, 2 H, CH2, 1-H),
4.08–4.24 (m, 3 H, OCH2, 2-H), 4.70 (br. s, 1 H, NH) ppm. 13C
NMR (400 MHz, CDCl3): δ = 14.5, 28.7, 31.5, 39.2, 41.7, 48.8,
50.2, 61.7, 80.5, 155.3, 172.1, 207.8 ppm. C14H23NO5 (285.34):
calcd. C 58.93, H 8.12, N 4.91; found C 58.60, H 7.79, N 4.63.
General Procedure for Fluorination of Keto-Amino Esters 26 and 27:
To a solution of amino ester 26 or 27 (1.5 mmol) in CH2Cl2
(12 mL) was added Deoxo-Fluor (50% in toluene, 1.5 equiv.) and
one drop of EtOH at 0 °C. Stirring was continued at this tempera-
ture for 8 h. The mixture was then diluted with CH2Cl2 (25 mL),
and the organic phase was washed with an aqueous solution of
NaHCO3. The organic layer was dried with Na2SO4 and concen-
trated, and the crude product was purified by column chromatog-
raphy on silica gel (n-hexane/EtOAc, 4:1).
Ethyl (3aR*,4S*,7aS*)-2-Oxo-2,3,3a,4,5,7a-hexahydrobenzo[d]ox-
azole-4-carboxylate (15): A white solid [69% (66%)], m.p. 115–
118 °C (n-hexane/EtOAc). Rf = 0.40 (n-hexane/EtOAc, 1:2). 1H
NMR (400 MHz, CDCl3): δ = 1.33 (t, J = 7.10 Hz, 3 H, CH3),
2.08–2.17 (m, 1 H, CH2), 2.56–2.65 (m, 2 H, 4-H and CH2), 3.92–
4.00 (m, 1 H, 3a-H), 4.20–4.29 (m, 2 H, OCH2), 4.92–5.03 (m, 1
H, 7a-H), 5.96 (br. s, 1 H, NH), 5.98–6.02 (m, 1 H, 6-H), 6.18–6.21
(m, 1 H, 7-H) ppm. 13C NMR (400 MHz, CDCl3): δ = 14.6, 25.5,
43.4, 53.2, 61.8, 72.6, 123.7, 132.3, 158.8, 173.2 ppm. C10H13NO4
(211.22): calcd. C 56.86, H 6.20, N 6.63; found C 56.99, H 6.53, N
6.44. HRMS: calcd. for C10H13NO4 [M]+ 211.0845; found
211.0853.
Ethyl
(1R*,2S*)-2-(tert-Butoxycarbonylamino)-5,5-difluorocyclo-
hexanecarboxylate (32): A white solid (36%), m.p. 98–100 °C. Rf =
0.65 (n-hexane/EtOAc, 4:1). 1H NMR (400 MHz, CDCl3): δ = 1.23
(t, J = 7.20 Hz, 3 H, CH3), 1.43 (s, 9 H, tBu), 1.79–1.88 (m, 1 H,
CH2), 1.90–2.08 (m, 2 H, CH2), 2.10–2.21 (m, 2 H, CH2), 2.31–
2.44 (m, 1 H, CH2), 2.94–2.99 (m, 1 H, 1-H), 4.03–4.10 (m, 1 H,
2-H), 4.16–4.24 (m, 2 H, OCH2), 5.23 (br. s, 1 H, NH) ppm. 13C
NMR (400 MHz, CDCl3): δ = 14.4, 26.8, 28.7, 31.1, 33.9, 42.9,
47.5, 61.4, 80.1, 122.6, 155.6, 172.0 ppm. C14H23F2NO4 (307.34):
calcd. C 54.71, H 7.54, N 4.56; found C 55.06, H 7.20, N 4.23.
Ethyl (1R*,2S*)-2-(tert-Butoxycarbonylamino)cyclohexanecarboxyl-
ate (8): A white solid (82%), m.p. 54–57 °C (n-hexane). Rf = 0.45
1
(n-hexane/EtOAc, 9:1). H NMR (400 MHz, CDCl3): δ = 1.26 (t,
J = 7.15 Hz, 3 H), 1.48 (s, 9 H, tBu), 1.55–2.12 (m, 8 H, CH2),
2.74–2.78 (m, 1 H, 1-H), 3.77–3.86 (m, 1 H, 2-H), 4.13–4.25 (m, 2
H, OCH2), 5.28 (br. s, 1 H, NH) ppm. 13C NMR (400 MHz,
CDCl3): δ = 14.6, 22.9, 24.1, 27.3, 28.7, 30.2, 45.2, 49.5, 60.7, 79.5,
155.6, 174.3 ppm. C14H25NO4 (271.36): calcd. C 61.97, H 9.29, N
5.16; found C 61.65, H 8.96, N 4.90.
Ethyl (1S*,2S*)-2-(tert-Butoxycarbonylamino)-5,5-difluorocyclohex-
anecarboxylate (33): A white solid (37%), m.p. 97–99 °C. Rf = 0.60
1
(n-hexane/EtOAc, 4:1). H NMR (400 MHz, CDCl3): δ = 1.23 (t,
J = 7.20 Hz, 3 H, CH3), 1.41 (s, 9 H, tBu), 1.50–1.61 (m, 1 H,
CH2), 1.79–1.96 (m, 1 H, CH2), 2.06–2.17 (m, 3 H, CH2), 2.22–
2.31 (m, 1 H, CH2), 2.56–2.62 (m, 1 H, 1-H), 3.70–3.81 (m, 1 H,
2-H), 4.13–4.20 (2 H, OCH2), 4.47 (br. s, 1 H, NH) ppm. 13C NMR
(400 MHz, CDCl3): δ = 14.5, 22.5, 28.7, 32.6, 35.6, 46.0, 49.6, 61.6,
80.5, 119.4, 155.2, 172.5 ppm. C14H23F2NO4 (307.34): calcd. C
54.71, H 7.54, N 4.56; found C 54.40, H 7.21, N 4.79.
Ethyl (1S*,2S*)-2-(tert-Butoxycarbonylamino)cyclohexanecarboxyl-
ate (21): A white solid (78%), m.p. 65–67 °C (n-hexane). Rf = 0.45
(n-hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ = 1.12–1.26
(m, 1 H, CH2), 1.24 (t, J = 7.15 Hz, 3 H), 1.48 (s, 9 H, tBu), 1.53–
2.20 (m, 7 H, CH2), 2.20–2.26 (m, 1 H, 1-H), 3.62–3.74 (m, 1 H,
2-H), 4.12–4.22 (m, 2 H, OCH2), 4.51 (br. s, 1 H, NH) ppm. 13C
NMR (400 MHz, CDCl3): δ = 14.7, 22.9, 24.6, 27.8, 29.5, 30.9,
45.1, 49.8, 61.0, 79.8, 155.2, 174.7 ppm. C14H25NO4 (271.36): calcd.
C 61.97, H 9.29, N 5.16; found C 61.60, H 8.98, N 4.88.
Characterization of the Enantiomers: The 1H NMR spectroscopic
data of the enantiomeric compounds were the same as those of the
racemic compounds.
General Procedure for Oxidation of 3 or 18: To a solution of amino
ester 3 or 18 (3 mmol) in CH2Cl2 (25 mL) was added Et3N
(4.0 equiv.), sulfur trioxide–pyridine complex (3.0 equiv.), and
DMSO (2.5 mL) at 0 °C, and the mixture was stirred for 10 h at
20 °C. The reaction mixture was diluted with CH2Cl2 (25 mL) and
(1R,6S)-6-(tert-Butoxycarbonylamino)cyclohex-3-enecarboxylic
Acid [(–)-1]: A white solid (76%), m.p. 75–78 °C (n-hexane). [α]2D5
= –22.6 (c = 4.8, CHCl3).
tert-Butyl (1R,2S,4S,5S)-4-Iodo-7-oxo-6-oxabicyclo[3.2.1]octan-2-
washed with H2O (3ϫ25 mL). The organic layer was then dried ylcarbamate [(–)-24]: A white solid (79%; for the racemic com-
with Na2SO4 and concentrated. The crude product was purified by
pound, see ref.[9]), m.p. 179–180 °C (n-hexane). [α]2D5 = –58.1 (c =
column chromatography on silica gel (n-hexane/EtOAc, 3:1).
1.7, CHCl3).
Eur. J. Org. Chem. 2011, 4993–5001
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4999

L. Kiss, E. Forró, S. Fustero, F. Fülöp
FULL PAPER
3666; d) E. Torres, C. Acosta-Silva, F. Rua, A. Alvarez-Larena,
T. Parella, V. Branchadell, R. M. Ortuno, Tetrahedron 2009,
65, 5669–5675; e) D. Fernandez, E. Torres, F. X. Aviles, R. M.
Ortuno, J. Vendrell, Bioorg. Med. Chem. 2009, 17, 3824–3828;
f) C. Fernandes, E. Pereira, S. Faure, D. J. Aitken, J. Org.
Chem. 2009, 74, 3217–3220; g) F. Fülöp, T. A. Martinek, G. K.
Tóth, Chem. Soc. Rev. 2006, 35, 323–334; h) L. Kiss, E. Forró,
R. Sillanpää, F. Fülöp, J. Org. Chem. 2007, 72, 8786–8790; i)
L. Kiss, E. Forró, T. A. Martinek, G. Bernáth, N. De Kimpe,
F. Fülöp, Tetrahedron 2008, 64, 5036–5043; j) E. A. Porter, B.
Weisblum, S. H. Gellman, J. Am. Chem. Soc. 2005, 127, 11516–
11529; k) O. Roy, S. Faure, D. J. Aitken, Tetrahedron Lett. 2006,
47, 5981–5984; l) F. Rua, S. Boussert, T. Parella, I. Diez-Perez,
V. Branchadell, E. Giralt, R. M. Ortuno, Org. Lett. 2007, 9,
3643–3645; m) V. DЈElia, H. Zwicknagl, O. Reiser, J. Org.
Chem. 2008, 73, 3262–3265; n) C. Fernandes, S. Faure, E. Per-
eira, V. V. Declerck, R. Guillot, D. J. Aitken, Org. Lett. 2010,
12, 3606–3609.
a) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K.
Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637–
643; b) P. Jeschke, ChemBioChem 2004, 5, 570–589; c) C. Is-
anbor, D. J. O’Hagan, J. Fluorine Chem. 2006, 127, 303–319; d)
S. Fustero, J. F. Sanz-Cervera, J. L. Acena, M. Sanchez-Ro-
sello, Synlett 2009, 525–549; e) J. P. Bégué, D. Bonnet-Delpon,
J. Fluorine Chem. 2006, 127, 992–1012; f) K. L. Kirk, J. Fluor-
ine Chem. 2006, 127, 1013–1029; g) X.-L. Qiu, X.-H. Xu, F.-
L. Qing, Tetrahedron 2010, 66, 789–843; h) S. Purser, P. R.
Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37,
320–330; i) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359–
4369; j) S. Bresciani, A. M. Z. Slawin, D. O’Hagan, J. Fluorine
Chem. 2009, 130, 537–543.
tert-Butyl (1R,2S,5S)-7-Oxo-6-oxabicyclo[3.2.1]oct-3-en-2-ylcarba-
mate [(–)-25]: A white solid (69%; for the racemic compound, see
ref.[9]), m.p. 144–146 °C (n-hexane). [α]2D5 = –35.4 (c = 1.45, CHCl3).
Ethyl (1R,2S,5S)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclohex-
3-enecarboxylate [(+)-2]: (see also ref.[9]) A white solid (70%), m.p.
86–88 °C (n-hexane). [α]2D5 = +53.5 (c = 0.9, CHCl3).
Ethyl (1S,2S,5S)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclohex-
3-enecarboxylate [(+)-10]: (see also ref.[9]) A white solid (66%), m.p.
106–108 °C (n-hexane). [α]2D5 = +31.3 (c = 1, CHCl3).
Ethyl (1R,2S,5R)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclohex-
anecarboxylate [(–)-3]: A colorless oil (83%). [α]2D5 = –11.2 (c = 0.55,
CHCl3).
Ethyl (1S,2S,5R)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclohex-
anecarboxylate [(+)-11]: A colorless oil (81%). [α]2D5 = +11.1 (c =
0.75, CHCl3).
[2]
Ethyl (1R,2S,5S)-2-(tert-Butoxycarbonylamino)-5-fluorocyclohex-
anecarboxylate [(–)-4]:[8] A white solid (43%, 98%ee), m.p. 60–
63 °C (n-hexane). [α]2D5 = –2.0 (c = 0.465, CHCl3).
Ethyl (1S,2S,5S)-2-(tert-Butoxycarbonylamino)-5-fluorocyclohex-
anecarboxylate [(+)-12]: A white solid (45%, 98%ee) m.p. 69–72 °C
(n-hexane). [α]2D5 = +11.4 (c = 1.735, CHCl3).
(1S,2S)-2-(tert-Butoxycarbonylamino)cyclohex-3-enecarboxylic Acid
[(+)-16]: A white solid (79%), m.p. 125–126 °C (n-hexane/EtOAc).
[α]2D5 = +22.7 (c = 0.55, EtOH).
[3]
[4]
a) A. Sutherland, C. L. Willis, Nat. Prod. Rep. 2000, 17, 621–
631; b) X.-L. Qiu, W.-D. Meng, F.-L. Qing, Tetrahedron 2004,
60, 6711–6745; c) R. Smits, C. D. Cadicamo, K. Burger, B.
Koksch, Chem. Soc. Rev. 2008, 37, 1727–1739; d) A. E. Soroch-
insky, V. A. Soloshonok, J. Fluorine Chem. 2010, 131, 127–139;
e) Y. Pan, Y. Zhao, T. Ma, Y. Yang, H. Liu, Z. Jiang, C.-H.
Tan, Chem. Eur. J. 2010, 16, 779–782; f) J. L. Acena, A. Simon-
Fuentes, S. Fustero, Curr. Med. Chem. 2010, 14, 928–949.
a) N. C. Yoder, K. Kumar, Chem. Soc. Rev. 2002, 31, 335–341;
b) D. F. Hook, F. Gessier, C. Noti, P. Kast, D. Seebach, Chem-
BioChem 2004, 5, 691–706; c) C. Jäckel, W. Seufert, S. Thust,
B. Koksch, ChemBioChem 2004, 5, 717–720; d) C. Jäckel, B.
Koksch, Eur. J. Org. Chem. 2005, 4483–4503; e) R. I. Mathad,
B. Jaun, O. Flögel, J. Gardiner, M. Löweneck, J. D. C. Codée,
P. H. Seeberger, D. Seebach, M. K. Edmonds, F. H. M.
Graichen, A. D. Abell, Helv. Chim. Acta 2007, 90, 2251–2273;
f) S. Capone, I. Kieltsch, O. Flögel, G. Lelais, A. Togni, D.
Seebach, Helv. Chim. Acta 2008, 91, 2035–2056; g) D. Seebach,
J. Gardiner, Acc. Chem. Res. 2008, 41, 1366; h) D. Seebach,
Angew. Chem. Int. Ed. 2011, 50, 96.
tert-Butyl (1S,2S,4R,5R)-4-Iodo-7-oxo-6-oxabicyclo[3.2.1]octan-2-
ylcarbamate [(+)-28]: A white solid (86%), m.p. 159–161 °C (n-hex-
ane/EtOAc). [α]2D5 = +20.2 (c = 0.75, EtOH).
tert-Butyl (1S,2S,5R)-7-Oxo-6-oxabicyclo[3.2.1]oct-3-en-2-ylcarb-
amate [(+)-29]: A white solid (69%), m.p. 146–149 °C (n-hexane/
EtOAc). [α]2D5 = +177.2 (c = 0.325, EtOH).
Ethyl (1S,2S,5R)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclohex-
3-enecarboxylate [(+)-17]: (see also ref.[9]). A white solid (68%),
m.p. 140–143 °C (n-hexane/EtOAc). [α]2D5 = +118.3 (c = 0.5, EtOH).
Ethyl (1S,2S,5S)-2-(tert-Butoxycarbonylamino)-5-hydroxycyclohex-
anecarboxylate [(+)-18]: A white solid (79%), m.p. 126–129 °C (n-
hexane/EtOAc). [α]2D5 = +3.6 (c = 0.675, EtOH).
Ethyl
(1S,2S,5R)-2-(tert-butoxycarbonylamino)-5-fluorocyclohex-
anecarboxylate [(+)-19]: A white solid (41%, 94%ee), m.p. 80–
82 °C (n-hexane/EtOAc). [α]2D5 = +8.2 (c = 0.6, EtOH).
[5]
[6]
[7]
a) S. Fustero, M. Sánchez-Roselló, V. Rodrigo, J. F. Sanz-Cerv-
era, J. Piera, A. Simón-Fuentes, C. del Pozo, Chem. Eur. J.
2008, 14, 7019–7029; b) S. Fustero, M. Sánchez-Roselló, V. Ro-
drigo, C. del Pozo, J. F. Sanz-Cervera, A. Simón, Org. Lett.
2006, 8, 4129–4132; c) P. K. Mykhailiuk, D. S. Radchenko, I. V.
Komarov, J. Fluorine Chem. 2010, 131, 221–223.
a) Y. Pan, K. Calvert, R. B. Silverman, Bioorg. Med. Chem.
2004, 12, 5719–5725; b) A. Yasuhara, K. Sakagami, R. Yoshi-
kawa, S. Chaki, M. Nakamura, A. Nakazato, Bioorg. Med.
Chem. 2006, 14, 3405–3420; c) Z. Wang, R. B. Silverman, Bi-
oorg. Med. Chem. 2006, 14, 2242–2252; d) H. Lu, R. B. Sil-
verman, J. Med. Chem. 2006, 49, 7404–7412.
a) S. Fustero, J. F. Sanz-Cervera, J. Piera, M. Sánchez-Roselló,
G. Chiva, A. Simón-Fuentes, J. Fluorine Chem. 2004, 125, 621–
627; b) S. Fustero, M. Sánchez-Roselló, J. L. Acena, B. Fernan-
dez, A. Asensio, J. F. Sanz-Cervera, C. del Pozo, J. Org. Chem.
2009, 74, 3414–3423; c) S. Fustero, M. Sánchez-Roselló, J. F.
Sanz-Cervera, J. F. Acena, C. del Pozo, B. Fernández, A. Bar-
tolomé, A. Asensio, Org. Lett. 2006, 8, 4633–4636; d) J. Mitten-
Acknowledgments
We are grateful to the Hungarian Research Foundation (OTKA
No. T81371) for financial support and acknowledge the receipt of
Bolyai János Fellowships for L. K. and E. F. We would also like to
thank MICINN (CTQ2010-19774) of Spain and Generalitat Valen-
ciana (PROMETEO/2010/061) for financial support. We acknow-
ledge the support from European Cost Action: Functional peptido-
mimetic foldamers: from unnatural amino acids to self-assembling
nanomaterials (COST-CM0803).
[1] a) L. Kiss, E. Forró, F. Fülöp, “Synthesis of Carbocyclic β-
Amino Acids” in Amino Acids, Peptides and Proteins in Organic
Chemistry (Ed.: A. B. Hughes), Wiley, Weinheim, 2009, vol. 1,
pp. 367–409; b) L. Kiss, F. Fülöp, Synlett 2010, 1302–1314; c)
T. A. Martinek, F. Fülöp, Eur. J. Biochem. 2003, 270, 3657–
5000
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4993–5001

Selective Synthesis of Fluorinated Alicyclic β-Amino Ester Stereoisomers
dorf, F. Kunisch, F. M. Matzke, H.-C. Militzer, A. Schmidt, W. [10] E. Forró, J. Chromatogr., A 2009, 1216, 1025–1029.
Schonfeld, Bioorg. Med. Chem. Lett. 2003, 13, 433–436.
[8] L. Kiss, E. Forró, S. Fustero, F. Fülöp, Org. Biomol. Chem.,
accepted for publication.
[9] E. Forró, L. Schönstein, L. Kiss, A. Vega-Peñaloza, E. Juaristi,
F. Fülöp, Molecules 2010, 15, 3998–4010.
[11] E. Forró, F. Fülöp, Tetrahedron: Asymmetry 2004, 15, 2875–
2880.
[12] E. Forró, F. Fülöp, Chem. Eur. J. 2007, 13, 6397–6401.
Received: April 26, 2011
Published Online: June 29, 2011
Eur. J. Org. Chem. 2011, 4993–5001
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5001