A straightforward approach towards functionalized γ-hydroxy and heterocyclic amino acids

Article abstract of DOI:10.1055/s-0030-1260136

Regioselective ring opening of epoxides by chelated enolates in combination with Dess-Martin oxidation provides a straightforward approach towards -oxo amino acids, which are ideal substrates for carbonyl additions and the synthesis of heterocycles. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260136

3020
PAPER
A Straightforward Approach towards Functionalized g-Hydroxy and
Heterocyclic Amino Acids
Ameer F. Zahoor, Uli Kazmaier*
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 23 May 2011; revised 14 June 2011
Our group is involved in amino acid synthesis since al-
most two decades, investigating reactions of chelated ami-
no acid ester enolates.11 These enolates are excellent
nucleophiles for a wide range of reactions such as Claisen
rearrangements,12 transition-metal-catalyzed allylic
alkylations13 or epoxide openings.14 The last approach is
especially suitable for the synthesis of g-hydroxy amino
acids, and the substitution pattern depends on the structure
of the epoxide used. While aryl-substituted epoxides react
preferentially at the benzylic position giving rise to the
terminal primary alcohols,14b the corresponding alkyl-
substituted epoxides provide secondary alcohols 1 via nu-
cleophilic attack of the enolate at the sterically least hin-
dered position.14a
Abstract: Regioselective ring opening of epoxides by chelated
enolates in combination with Dess–Martin oxidation provides a
straightforward approach towards g-oxo amino acids, which are
ideal substrates for carbonyl additions and the synthesis of hetero-
cycles.
Key words: amino acids, chelated enolates, epoxides, epoxide
openings, g-hydroxy amino acids, g-oxo amino acids
Hydroxylated amino acids are important building blocks
found also in proteins, resulting from post-translational
modification. g-Hydroxyproline (Hyp) is widespread in
collagen and is involved in the stabilization of the col-
lagen triple helix.1 g-Hydroxyarginine occurs in proteins
forming adhesive plaques of marine mussels,2 and g-hy-
droxyvaline is incorporated in several conopeptides from
the venoms of Conus gladiator and Conus mus.3 Other g-
hydroxylated amino acids are found in natural products
such as biphenomycin4 und glidobactine.5 The occurrence
of these g-hydroxy acids in nature is not obvious, since the
g-hydroxy group can easily undergo lactonization, result-
ing in a cleavage of the peptide bond. For example, the
lactone of N-acetyl-g-hydroxyvaline was found in strepto-
mycetes in marine sediments.6 Not surprisingly, such g-
lactones form the C-terminus of natural products.7 The g-
hydroxy group can also be incorporated in heterocyclic
structures such as in dysiherbaine8 or lycoperdic acid,9
(Figure 1) glutamate-derived natural products with strong
agonist activity at the ionotropic glutamate receptors
(iGluRs) of the central nervous system.10 In these cases,
the g-hydroxy group is located at a quaternary center.
Therefore, straightforward synthetic protocols towards
these types of interesting g-hydroxy amino acids are high-
ly desirable.
These alcohols can easily be oxidized by Swern
oxidation15 or using the Dess–Martin periodinane
(DMP)16 to g-oxo amino acids (Table 1). In principle both
protocols are suitable for oxidation, but in general the
yields obtained were better with the Dess–Martin period-
Table 1 Synthesis of g-Keto Amino Acids 2
OH
1) LHMDS (2.5 equiv)
ZnCl2 (1.2 equiv)
R
TFAHN
COOt-Bu
O
2)
(1.5 equiv)
TFAHN
COOt-Bu
R
1
BF3•OEt2 (1.1.equiv)
THF, –78 °C to r.t., 16 h
O
R
oxidation
method A or B
TFAHN
COOt-Bu
2
1
R
Yield (%) of 1
2
Yield (%) of 2
Aa
Bb
91
89
90
93
82
84
87
H2N
1a
1b
1c
1d
1e
1f
Me
9214a
8614a
8214a
8614a
88
2a 78
2b 81
OH
O
O
O
HOOC
HOOC
Bu
O
CH2Cl
CH2OPh
2c
75
H2N
COOH
H2N
COOH
2d 76
dysiherbaine
lycoperdic acid
CH2O(C6H4Cl-4)
CH2O(C6H4CN-2)
CH2O(C6H4NO2-2)
2e
2f
72
76
Figure 1 Heterocyclic natural products derived from g-hydroxy
amino acids
85
1g
84
2g 75
SYNTHESIS 2011, No. 18, pp 3020–3026
x
x.
x
x
.
2
0
1
1
a Method A: Swern oxidation.
b Method B: DMP oxidation.
Advanced online publication: 28.07.2011
DOI: 10.1055/s-0030-1260136; Art ID: T54111SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Functionalized g-Hydroxy and Heterocyclic Amino Acids
3021
R
OH
inane (82–93%), while under Swern conditions the yields
were in the range of 75 3%.
1) Zn (1.1 equiv)
2) TMSCl (13 mol%)
COOMe
Br
COOMe
3) 2c or 2e
These g-oxo amino acids can be easily converted into a
wide range of highly functionalized quarternary g-hy-
droxy amino acids by simple carbonyl addition (Table 2).
In our first instance, we investigated Barbier reactions us-
ing allyl bromide as a nucleophile precursor (method A).
Interestingly, not the expected g-hydroxy amino acid ester
was formed, but directly the lactone, although the relative-
ly stable tert-butyl ester was used. Probably, the zinc(II)
bromide formed in situ acts as a strong Lewis acid, cata-
lyzing the lactonization process. Even with the chlorome-
thyl-substituted ketone 2c (Table 2, entry 3) only the
lactone was formed and no epoxide, which was actually
expected. The yields were acceptable and reproducible in
the range of 60–70%, but unfortunately no significant di-
astereoselectivity was observed. Similar results were ob-
tained in methylation reactions (method B) using
trimethylaluminum. In the presence of zinc(II) chloride,
the lactone was formed here also exclusively.
THF, – 5 °C to r.t.
TFAHN
COOt-Bu
R = CH2Cl
R = CH2O(4-ClC6H4)
4c 85%
4e 90%
Scheme 1 Synthesis of g-hydroxy homoglutamates 4
especially good candidates for this purpose. The benzofu-
ran derivative 5 was obtained from 2f by simple heating in
the presence of triethylamine.17 The nitro group in 2g
could be reduced by catalytic hydrogenation, which di-
rectly results in a reductive amination and the formation
of dihydrobenzoxazine amino acid 6 in almost quantita-
tive yield18 (Scheme 2).
NC
O
O
H2N
Et3N
Table 2 Synthesis of a-Amino-g-Butyrolactones 3
90 °C, 5 h
92%
O
O
R1
O
R2
TFAHN
COOt-Bu
TFAHN
COOt-Bu
R2M
R1
5
2f
O
method A or B
NO2
TFAHN
TFAHN
COOt-Bu
O
O
O
O
2
3
H2 (4 atm)
Pd/C (5 mol%)
R1
R2
Method
3
Yield (%)
N
H
Entry 2
MeOH, 6 h
98%
allyl Aa
allyl Aa
allyl Aa
allyl Aa
3a
3b
3c
3d
3e
3f
70
65
64
60
66
60
66
60
58
66
TFAHN
COOt-Bu
TFAHN
COOt-Bu
1
2
2a
2b
Me
2g
6
Bu
Scheme 2 Synthesis of heterocyclic amino acids
3
2c
2d
2e
2a
2c
2d
2e
2f
CH2Cl
CH2OPh
In conclusion we could show that g-oxo amino acids, re-
sulting from an epoxide opening/oxidation sequence, are
excellent starting materials for subsequent modifications.
Addition of organometallics allows the introduction of a
range of other functionalities, and intramolecular cycliza-
tions of functionalized aryl ethers are suitable for the syn-
thesis of heterocyclic amino acids. Further investigations
on the scope and limitations of this protocol and synthetic
applications are on the way.
4
5
CH2O(C6H4Cl-4) allyl Aa
6
Me
Me
Me
Me
Bb
Bb
Bb
Bb
Bb
7
CH2Cl
CH2OPh
3g
3h
3i
8
9
CH2O(C6H4Cl-4) Me
CH2O(C6H4CN-2) Me
10
3k
All reactions were carried out in oven-dried glassware (100 °C) un-
der N2. All solvents were dried before use. THF was distilled from
LiAlH4. The products were purified by flash chromatography on sil-
ica gel (0.063–0.2 mm). Mixtures of EtOAc and hexanes were gen-
erally used as eluents. Analysis by TLC was carried out on
commercially precoated Polygram SIL-G/UV 254 plates (Mach-
erey-Nagel, Düren). Visualization was accomplished with UV light,
a Method A: allyl bromide (1.0 equiv), Zn (2.0 equiv), THF, r.t., 1 h.
b Method B: Me3Al (2.0 equiv), ZnCl2 (1.3 equiv), THF, 0 °C to r.t.,
3 h.
Interestingly, no cyclization was observed in the corre-
sponding Reformatsky reactions. The reaction mixtures
were allowed to warm up to room temperature (from
–5 °C) overnight, and the required g-hydroxy homo-
glutamates 4 were obtained in high yields as 1:1 diaste-
reomeric mixtures (Scheme 1).
1
KMnO4 solution, or I2. H and 13C NMR spectroscopic analyses
were performed on a Bruker Avance II 400 MHz spectrometer.
Chemical shifts are reported on the d (ppm) scale and the coupling
constants are given in Hz. The epoxide openings and carbonyl addi-
tions proceed without significant diastereoselectivity and therefore
the relative configuration was not determined. Selected signals for
the minor isomers are extracted from the spectra of the isomeric
mixture and are those signals, which could be clearly assigned.
HRMS were measured with Finnigan MAT 95S mass spectrometer.
Finally, the use of g-keto amino acid derivatives 2 for the
synthesis of heterocyclic amino acids was investigated.
The cyano- and nitro-substituted derivatives 2f and 2g are
Synthesis 2011, No. 18, 3020–3026 © Thieme Stuttgart · New York

3022
A. F. Zahoor, U. Kazmaier
PAPER
Elemental analyses were carried out at the Department of Chemis-
try, Saarland University, Saarbrücken, Germany.
HRMS (CI): m/z [M + 1]+ calcd for C18H21F3N2O5: 403.1436;
found: 403.1482.
Epoxide Opening with Amino Acid Enolates; General Proce-
dure
tert-Butyl 4-Hydroxy-5-(2-nitrophenoxy)-2-(2,2,2-trifluoro-
acetamido)pentanoate (1g)
Colorless oil; yield: 390 mg (0.92 mmol, 84%); Rf = 0.31 (CH2Cl2–
In a Schlenk tube hexamethyldisilazane (497 mg, 3.08 mmol, 2.8
equiv) was dissolved in anhyd THF (5.0 mL). After cooling the so-
lution to –78 °C, a 1.6 M solution of n-BuLi (1.72 mL, 2.75 mmol,
2.5 equiv) was added slowly. The solution was stirred for 10 min be-
fore the cooling bath was removed and the solution was stirred for
a further 10 min. In a second Schlenk flask, ZnCl2 (180 mg, 1.32
mmol, 1.2 equiv) was dried with a heat gun under vacuum and dis-
solved in THF (5.0 mL). After cooling the solution to r.t., TFA-Gly-
Ot-Bu (250 mg, 1.1 mmol, 1 equiv) was added and cooled to –78 °C
before the LHMDS solution was added slowly. The resulting solu-
tion was stirred for 30 min at –78 °C. Then the epoxide (2.0 equiv)
was added followed by BF3·OEt2 (78.1 mg, 0.55 mmol, 0.5 equiv)
directly to the enolate at –78 °C. The reaction mixture was allowed
to warm to r.t. overnight before it was hydrolyzed with aq 1 M HCl
(15 mL) and extracted with EtOAc (3 × 20 mL). The combined or-
ganic layers were dried (Na2SO4), the solvent was evaporated in
vacuo, and the crude product was purified by flash chromatography
(silica gel, hexanes–EtOAc) (Table 1).
hexanes, 95:5).
1H NMR (400 MHz, CDCl3): d [major diastereomer (66%)] = 7.87
(dd, J = 8.5, 1.7 Hz, 1 H), 7.81 (d, J = 7.5 Hz, 1 H), 7.54 (m, 1 H),
7.01–7.06 (m, 2 H), 4.53 (q, J = 5.7 Hz, 1 H), 4.13–4.18 (m, 2 H),
4.03 (m, 1 H), 2.91 (d, J = 4.9 Hz, 1 H), 2.04–2.16 (m, 2 H), 1.49 (s,
9 H).
13C NMR (100 MHz, CDCl3):
d
[major diastereomer
(66%)] = 169.1, 157.4 (q, J = 37.4 Hz), 151.8, 139.8, 134.4, 125.9,
121.3, 115.7 (q, J = 285.6 Hz), 115.1, 83.5, 73.2, 67.1, 51.1, 34.2,
27.8.
1H NMR (400 MHz, CDCl3): d [minor diastereomer (34%), selected
signals] = 7.87 (dd, J = 8.1, 1.7 Hz, 1 H), 7.55 (m, 1 H), 7.81 (d,
J = 7.3 Hz, 1 H), 7.05–7.11 (m, 2 H), 4.72 (dt, J = 7.4, 4.2 Hz, 1 H),
4.11–4.18 (m, 2 H), 4.03 (m, 1 H), 3.52 (d, J = 2.5 Hz, 1 H), 2.30
(ddd, J = 14.5, 5.6, 2.9 Hz, 1 H), 2.10 (ddd, J = 14.6, 9.6, 5.4 Hz, 1
H), 1.51 (s, 9 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (34%), select-
ed signals] = 169.3, 151.9, 134.5, 126.0, 121.3, 115.0, 83.6, 73.2,
66.7, 51.4, 33.6, 27.8.
tert-Butyl 5-(4-Chlorophenoxy)-4-hydroxy-2-(2,2,2-trifluoro-
acetamido)pentanoate (1e)
Colorless oil; yield: 399 mg (0.97 mmol, 88%); Rf = 0.32 (CH2Cl2–
hexanes, 95:5).
HRMS (CI): m/z [M]+ calcd for C17H21F3N2O7: 423.1334; found:
423.1413.
1H NMR (400 MHz, CDCl3): d [major diastereomer (55%)] = 7.77
(d, J = 7.0 Hz, 1 H), 6.83–6.85 (m, 4 H), 4.73 (dt, J = 7.4, 4.5 Hz, 1
H), 4.10 (m, 1 H), 3.79–3.93 (m, 2 H), 3.11 (d, J = 3.3 Hz, 1 H),
2.03–2.13 (m, 2 H), 1.49 (s, 9 H).
Dess–Martin Oxidation; General Procedure
To a solution of the corresponding g-hydroxy amino acid ester 1
(1.32 mmol) in anhyd CH2Cl2 (5 mL) was added Dess–Martin per-
iodinane (721 mg, 1.7 mmol) at 0 °C under N2 and the mixture was
allowed to stir at r.t. for 3 h. After quenching the reaction with sat.
aq NaHCO3 containing Na2S2O3 (10 mL), the mixture was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were washed
with brine (10 mL), dried (Na2SO4), and the solvent removed in
vacuo. The corresponding g-keto amino acid ester 2 was obtained
after column chromatography (silica gel, EtOAc–hexanes)
(Table 1).
13C NMR (100 MHz, CDCl3):
(55%)] = 171.5, 157.4 (q, J = 37.4 Hz), 152.2, 130.0, 129.0, 115.7
(q, J = 285.6 Hz), 115.4, 114.9, 83.4, 72.6, 65.5, 55.8, 51.2, 27.9.
d
[major diastereomer
1H NMR (400 MHz, CDCl3): d [minor diastereomer (45%), selected
signals] = 7.44 (s, 1 H), 4.53 (q, J = 5.9 Hz, 1 H), 4.10 (m, 1 H), 2.22
(m, 1 H), 1.49 (s, 9 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (45%), select-
ed signals] = 171.3, 152.1, 129.9, 129.0, 115.5, 114.7, 83.4, 72.6,
65.5, 55.6, 51.2, 27.8.
tert-Butyl 4-Oxo-2-(2,2,2-trifluoroacetamido)pentanoate (2a)
Colorless oil; yield: 340 mg (1.20 mmol, 89%); Rf = 0.53 (hexanes–
EtOAc, 75:25).
HRMS (CI): m/z [M]+ calcd for C17H21ClF3NO5: 411.1060; found:
411.1075.
1H NMR (400 MHz, CDCl3): d = 7.37 (br s, 1 H), 4.59 (dt, J = 7.8,
3.8 Hz, 1 H), 3.22 (dd, J = 18.6, 4.0 Hz, 1 H), 3.97 (dd, J = 18.6, 4.0
Hz, 1 H), 2.10 (s, 3 H), 1.43 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 206.1, 168.0, 156.8 (q, J = 37.4
Hz), 115.5 (q, J = 285.6 Hz), 83.4, 49.0, 43.5, 29.7, 27.6.
HRMS (CI): m/z [M + 1]+ calcd for C11H16F3NO4: 284.1065; found:
284.1080.
tert-Butyl 5-(2-Cyanophenoxy)-4-hydroxy-2-(2,2,2-trifluoro-
acetamido)pentanoate (1f)
Colorless oil; yield: 376 mg (0.94 mmol, 85%); Rf = 0.31 (CH2Cl2–
hexanes, 95:5).
1H NMR (400 MHz, CDCl3): d [major diastereomer (57%)] = 7.68
(d, J = 7.5 Hz, 1 H), 7.52–7.58 (m, 2 H), 7.05 (t, J = 7.5 Hz, 1 H),
6.97 (m, 1 H), 4.74 (m, 1 H), 4.18–4.24 (m, 2 H), 3.99 (m, 1 H), 3.34
(d, J = 4.0 Hz, 1 H), 2.08–2.13 (m, 2 H), 1.50 (s, 9 H).
tert-Butyl 4-Oxo-2-(2,2,2-trifluoroacetamido)octanoate (2b)
Colorless oil; yield: 382 mg (1.17 mmol, 89%); Rf = 0.53 (hexanes–
EtOAc, 75:25)
1H NMR (400 MHz, CDCl3): d = 7.38 (br s, 1 H), 4.61 (dt, J = 7.9,
3.9 Hz, 1 H), 3.22 (dd, J = 18.4, 3.9 Hz, 1 H), 2.94 (dd, J = 18.4, 3.9
Hz, 1 H), 2.41 (dt, J = 7.4, 2.6 Hz, 2 H), 1.50–1.58 (m, 2 H), 1.43
(s, 9 H), 1.29 (sext, J = 7.3 Hz, 2 H), 0.89 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 208.9, 168.1, 156.8 (q, J = 37.4
Hz), 115.6 (q, J = 285.6 Hz), 83.3, 49.1, 42.9, 42.3, 27.7, 25.6, 22.1,
13.8.
13C NMR (100 MHz, CDCl3):
(57%)] = 168.0, 157.2 (q, J = 37.4 Hz), 134.4, 134.1, 122.2, 115.5
(q, J = 285.8 Hz), 114.8, 112.1, 102.6, 83.9, 72.7, 48.8, 40.3, 27.7.
d
[major diastereomer
1H NMR (400 MHz, CDCl3): d [minor diastereomer (43%), selected
signals] = 7.42 (d, J = 5.8 Hz, 1 H), 4.55 (dt, J = 5.7, 5.7 Hz, 1 H),
4.21–4.18 (m, 2 H), 2.66 (d, J = 4.5 Hz, 1 H), 2.32 (ddd, J = 14.5,
5.7, 3.2 Hz, 1 H), 2.18 (m, 1 H), 1.50 (s, 9 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (43%), select-
ed signals] = 168.5, 122.2, 114.8, 112.1, 102.6, 83.6, 72.7, 48.8,
40.4, 27.8.
HRMS (CI): m/z [M + 1]+ calcd for C14H22F3NO4: 325.1501; found:
325.1512.
Synthesis 2011, No. 18, 3020–3026 © Thieme Stuttgart · New York

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Functionalized g-Hydroxy and Heterocyclic Amino Acids
3023
tert-Butyl 5-Chloro-4-oxo-2-(2,2,2-trifluoroacetamido)pen-
tanoate (2c)
White solid; yield: 377 mg (1.18 mmol, 90%); mp 51–52 °C;
Rf = 0.50 (hexanes–EtOAc, 75:25).
1H NMR (400 MHz, CDCl3): d = 7.29 (br s, 1 H), 4.69 (dt, J = 8.0,
4.2 Hz, 1 H), 3.24 (dd, J = 18.6, 4.2 Hz, 1 H), 3.19 (dd, J = 18.8, 4.4
Hz, 1 H), 2.17 (d, J = 2.8 Hz, 2 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 200.7, 167.7, 157.1 (q, J = 37.7
Hz), 118.3 (q, J = 285.8 Hz), 84.0, 49.0, 47.4, 40.5, 27.7.
Hz, 1 H), 4.79 (dt, J = 7.8, 4.3 Hz, 1 H), 4.72 (d, J = 5.0 Hz, 2 H),
3.50 (dd, J = 18.8, 4.5 Hz, 1 H), 3.32 (dd, J = 18.8, 4.2 Hz, 1 H),
1.46 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 204.2, 168.0, 157.2 (q, J = 37.4
Hz), 150.7, 134.4, 126.2, 122.0, 115.5 (q, J = 285.8 Hz), 114.6,
83.9, 73.3, 48.8, 40.6, 27.7.
HRMS (CI): m/z [M]+ calcd for C17H19F3N2O7: 420.1144; found:
420.1156.
Allylation of 2; General Procedure
HRMS (CI): m/z [M]+calcd for C11H15ClF3NO4: 317.0642; found:
To a suspension of Zn dust (19.1 mg, 0.29 mmol) in anhyd THF (0.5
mL) at r.t. was added allyl bromide (18 mg, 0.15 mmol). After stir-
ring for 30 min, a solution of the corresponding g-keto amino acid
ester 2 (0.15 mmol) in THF (0.15 mL) was added dropwise and the
stirring was continued for 1 h. The reaction was quenched with aq
NH4Cl (1 mL), extracted with CH2Cl2 (2 × 5 mL), the combined or-
ganic extracts were dried (Na2SO4), and the solvent was removed
under vacuo. The crude product was purified by column chromatog-
raphy (silica gel, EtOAc–hexanes) (Table 2).
317.0764.
tert-Butyl 4-Oxo-5-phenoxy-2-(2,2,2-trifluoroacetamido)pen-
tanoate (2d)
White solid; yield: 461 mg (1.23 mmol, 93%); mp 57–58 °C;
Rf = 0.55 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 7.29–7.33 (m, 2 H), 7.02 (t,
J = 7.6 Hz, 1 H), 6.86–6.88 (m, 2 H), 4.73 (dt, J = 7.6, 4.3 Hz, 1 H),
4.57 (d, J = 1.2 Hz, 2 H), 3.21 (dd, J = 18.8, 4.4 Hz, 1 H), 3.42 (dd,
J = 18.8, 4.4 Hz, 1 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 205.9, 168.0, 157.3 157.2 (q,
J = 37.4 Hz), 129.7, 122.1, 115.5 (q, J = 289.0 Hz), 114.4, 83.7,
72.5, 48.7, 40.4, 27.7.
4-Allyl-4-methyl-2-(2,2,2-trifluoroacetamido)butyrolactone
(3a)
White solid; yield: 26 mg (0.11 mmol, 70%); mp 81–82 °C;
Rf = 0.44 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d [major diastereomer (55%)] = 6.80
(br s, 1 H), 5.75 (m, 1 H), 5.17–5.27 (m, 2 H), 4.81 (ddd, J = 11.6,
8.7, 5.7 Hz, 1 H), 2.69 (dd, J = 12.7, 8.8 Hz, 1 H), 2.43–2.57 (m, 2
H), 2.06 (t, J = 12.7 Hz, 1 H), 1.46 (s, 3 H).
HRMS (CI): m/z [M]+ calcd for C17H20F3NO5: 375.1294; found:
375.1289.
tert-Butyl 5-(4-Chlorophenoxy)-4-oxo-2-(2,2,2-trifluoroacet-
amido)pentanoate (2e)
Colorless oil; yield: 444 mg (1.08 mmol, 85%); Rf = 0.51 (hexanes–
EtOAc, 7:3).
13C NMR (100 MHz, CDCl3):
d
[major diastereomer
(55%)] = 172.5, 157.6 (q, J = 37.4 Hz), 130.8, 120.7, 115.6 (q,
J = 285.7 Hz), 84.8, 50.1, 45.6, 39.1, 23.6.
1H NMR (400 MHz, CDCl3): d = 7.32 (d, J = 7.3 Hz, 1 H), 7.22–
7.25 (m, 2 H), 6.77–6.81 (m, 2 H), 4.71 (dt, J = 8.0, 4.2 Hz, 1 H),
4.53 (d, J = 1.3 Hz, 2 H), 3.36 (dd, J = 18.8, 4.2 Hz, 1 H), 3.19 (dd,
J = 18.8, 4.2 Hz, 1 H), 1.43 (s, 9 H).
1H NMR (400 MHz, CDCl3): d [minor diastereomer (45%)] = 6.97
(br s, 1 H), 5.78 (m, 1 H), 5.22–5.27 (m, 2 H), 4.71 (ddd, J = 11.1,
9.4, 6.1 Hz, 1 H), 2.86 (dd, J = 13.0, 9.3 Hz, 1 H), 2.43–2.44 (m, 2
H), 2.06 (dd, J = 13.0, 11.3 Hz, 1 H), 1.51 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.1, 167.9, 157.2 (q, J = 37.4
Hz), 155.9, 129.6, 127.0, 115.7, 115.5 (q, J = 285.8 Hz), 114.0,
83.8, 72.6, 48.7, 40.3, 27.7.
HRMS (CI): m/z [M]+ calcd for C17H19ClF3NO5: 409.0904; found:
409.0883.
13C NMR (100 MHz, CDCl3): d [minor diastereomer (45%), select-
ed signals] = 173.0, 131.0, 121.0, 85.2, 50.5, 44.4, 39.0, 23.5.
HRMS (CI): m/z [M]+ calcd for C10H12F3NO3: 251.0769; found:
251.0789.
4-Allyl-4-butyl-2-(2,2,2-trifluoroacetamido)butyrolactone (3b)
White solid; yield: 29 mg (0.09 mmol, 65%); mp 79–81 °C;
Rf = 0.45 (hexanes–EtOAc, 8:2).
1H NMR (400 MHz, CDCl3): d [major diastereomer (58%)] = 6.90
(br s, 1 H), 5.77 (m, 1 H), 5.19–5.30 (m, 2 H), 4.65–4.72 (m, 1 H),
2.76–2.82 (m, 1 H), 2.44 (d, J = 7.0 Hz, 2 H), 1.99 (dd, J = 12.9,
11.3 Hz, 1 H), 1.69–1.78 (m, 2 H), 1.30–1.38 (m, 4 H), 0.89–0.94
(m, 3 H).
tert-Butyl 5-(2-Cyanophenoxy)-4-oxo-2-(2,2,2-trifluoroacet-
amido)pentanoate (2f)
White solid; yield: 444 mg (1.11 mmol, 84%); mp 71–72 °C;
Rf = 0.49 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 7.51–7.64 (m, 2 H), 7.28 (d,
J = 6.8 Hz, 1 H), 7.10 (t, J = 7.2 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H),
4.78 (dt, J = 7.6, 4.4 Hz, 1 H), 4.69 (d, J = 3.7 Hz, 2 H), 3.48 (dd,
J = 18.8, 4.4 Hz, 1 H), 3.28 (dd, J = 18.8, 4.3 Hz, 1 H), 1.43 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 204.1, 168.0, 157.2 (q, J = 37.4
Hz), 134.4, 134.1, 122.2, 115.5 (q, J = 285.8 Hz), 112.1, 102.6,
83.9, 72.7, 48.8, 40.3, 27.7.
13C NMR (100 MHz, CDCl3):
(58%)] = 172.8, 157.6 (q, J = 37.4 Hz), 130.8, 121.0, 115.6 (q,
J = 285.7 Hz), 87.5, 50.5, 42.3, 39.6, 37.5, 25.1, 22.7, 13.8.
d
[major diastereomer
1H NMR (400 MHz, CDCl3): d [minor diastereomer (42%), selected
signals] = 6.95 (br s, 1 H), 5.72 (m, 1 H), 5.16–5.29 (m, 2 H), 4.72
(dt, J = 10.0, 6.0 Hz, 1 H), 2.70 (dd, J = 12.8, 9.5 Hz, 1 H), 2.03 (dd,
J = 13.0, 11.3 Hz, 1 H), 1.66–1.73 (m, 2 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (42%), select-
ed signals] = 172.9, 130.8, 120.6, 87.3, 50.1, 43.2, 38.0, 37.3, 25.6,
22.7, 13.8.
HRMS (CI): m/z [M + 1]+ calcd for C18H19F3N2O5: 401.1280;
found: 401.1334.
tert-Butyl 5-(2-Nitrophenoxy)-4-oxo-2-(2,2,2-trifluoroacetami-
do)pentanoate (2g)
White solid; yield: 483 mg (1.15 mmol, 87%); mp 90–91 °C;
Rf = 0.49 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 7.93 (dd, J = 8.1, 1.7 Hz, 1 H),
7.55 (m, 1 H), 7.28 (br s, 1 H), 7.14 (m, 1 H), 6.96 (dd, J = 8.5, 1.0
HRMS (CI): m/z [M]+ calcd for C13H18F3NO3: 294.1272; found:
294.1292.
Synthesis 2011, No. 18, 3020–3026 © Thieme Stuttgart · New York

3024
A. F. Zahoor, U. Kazmaier
PAPER
4-Allyl-4-chloromethyl-2-(2,2,2-trifluoroacetamido)butyrolac-
tone (3c)
White solid; yield: 27 mg (0.09 mmol, 64%); mp 81–82 °C;
Rf = 0.52 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d [major diastereomer (55%)] = 7.33
(br s, 1 H), 5.76 (m, 1 H), 5.21–5.33 (m, 2 H), 4.81 (dt, J = 10.2, 6.6
Hz, 1 H), 3.61–3.74 (m, 2 H), 2.88 (t, J = 11.8 Hz, 1 H), 2.63 (d,
J = 7.3 Hz, 2 H), 2.29 (dd, J = 13.5, 10.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (42%), select-
ed signals] = 172.7, 156.2, 129.6, 121.4, 116.0, 84.7, 72.9, 50.8,
41.6, 36.1.
HRMS (CI): m/z [M]+ calcd for C16H15ClF3NO4: 377.0642; found:
377.0635.
Methylation of 2; General Procedure
To a solution of ZnCl2 (34 mg, 0.25 mmol) in anhyd THF (3.0 mL)
was added a solution of the corresponding g-keto amino acid ester
2 (0.19 mmol) in THF (2 mL) at r.t. and the mixture was allowed to
stir for 30 min. The resulting solution was transferred into a 2 M so-
lution of AlMe3 in toluene (0.19 mL, 27.8 mg, 0.38 mmol) at 0 °C
and warmed up to r.t. The reaction mixture was decomposed with
MeOH (5 mL) at 0 °C. The solvent was removed and diluted with
5% aq H2SO4. The aqueous layer was extracted with CH2Cl2 (2 × 10
mL), the combined organic layers were dried (Na2SO4), and the
crude product was purified by column chromatography (silica gel,
EtOAc–hexanes) (Table 2).
13C NMR (100 MHz, CDCl3):
(55%)] = 172.5, 157.6 (q, J = 37.4 Hz), 129.7, 122.3, 115.6 (q,
J = 285.7 Hz), 85.0, 50.4, 49.4, 42.9, 35.4.
d
[major diastereomer
1H NMR (400 MHz, CDCl3): d [minor diastereomer (45%), selected
signals] = 7.34 (br s, 1 H), 5.78 (m, 1 H), 5.22–5.27 (m, 2 H), 4.71
(dt, J = 10.2, 6.8 Hz, 1 H), 2.74 (dd, J = 13.2, 10.2 Hz, 1 H), 2.58
(d, J = 7.3 Hz, 2 H), 2.21 (dd, J = 14.5, 4.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (45%), select-
ed signals] = 172.1, 157.6 (q, J = 37.4 Hz), 129.5, 121.6, 84.7, 49.8,
49.2, 40.9, 34.9.
4,4-Dimethyl-2-(2,2,2-trifluoroacetamido)butyrolactone (3f)
White solid; yield: 26 mg (0.11 mmol, 60%); mp 88–90 °C;
Rf = 0.26 (hexanes–EtOAc, 8:2).
HRMS (CI): m/z [M + 1]+ calcd for C10H11ClF3NO3: 285.0380;
found: 285.0395.
1H NMR (400 MHz, CDCl3): d = 7.00 (br s, 1 H), 4.78 (ddd,
J = 11.8, 8.7, 6.1 Hz, 1 H), 2.79 (dd, J = 12.6, 8.7 Hz, 1 H), 2.79 (t,
J = 12.2 Hz, 1 H), 1.54 (s, 3 H), 1.48 (s, 3 H).
4-Allyl-4-phenoxymethyl-2-(2,2,2-trifluoroacetamido)butyro-
lactone (3d)
White solid; yield: 31 mg (0.09 mmol, 60%); mp 85–87 °C;
13C NMR (100 MHz, CDCl3): d = 172.2, 157.2 (q, J = 38.8 Hz),
115.5 (q, J = 285.8 Hz), 83.6, 50.5, 41.5, 28.8, 26.8.
HRMS (CI): m/z [M + 1]+ calcd for C8H10F3NO3: 226.0646; found:
Rf = 0.54 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d [major diastereomer (53%)] = 7.26–
7.32 (m, 3 H), 7.04 (m, 1H), 6.86–6.90 (m, 2 H), 5.81 (m, 1 H),
5.21–5.31 (m, 2 H), 4.81 (dt, J = 10.0, 6.5 Hz, 1 H), 4.09 (d, J = 10.0
Hz, 1 H), 4.00 (d, J = 10.1 Hz, 1 H), 2.95 (dd, J = 12.9, 9.6 Hz, 1 H),
2.56–2.65 (m, 2 H), 2.32 (dd, J = 13.7, 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3):
(53%)] = 173.1, 157.6 (q, J = 37.4Hz), 157.5, 129.9, 129.7, 122.0,
121.1, 115.6 (q, J = 285.7 Hz), 114.6, 84.8, 72.5, 50.8, 41.5, 36.0.
226.0673.
4-Chloromethyl-4-methyl-2-(2,2,2-trifluoroacetamido)butyro-
lactone (3g)
White solid; yield: 33 mg (0.13 mmol, 66%); mp 94–95 °C;
Rf = 0.28 (hexanes–EtOAc, 75:25).
d
[major diastereomer
1H NMR (400 MHz, CDCl3): d [major diastereomer (59%)] = 6.87
(br s, 1 H), 4.80 (m, 1 H), 3.73 (d, J = 11.8 Hz, 1 H), 3.62 (d,
J = 11.8 Hz, 1 H), 2.75 (dd, J = 13.0, 9.0 Hz, 1 H), 2.31 (dd,
J = 13.0, 11.1 Hz, 1 H), 1.59 (s, 3 H).
1H NMR (400 MHz, CDCl3): d [minor diastereomer (47%), selected
signals] = 6.97–7.04 (m, 2 H), 5.81 (m, 1 H), 5.22–5.28 (m, 2 H),
4.88 (m, 1 H), 4.09 (d, J = 10.7 Hz, 1 H), 3.98 (d, J = 10.3 Hz, 1 H),
2.77 (dd, J = 13.0, 10.3 Hz, 1 H), 2.55–2.66 (m, 2 H), 2.22 (dd,
J = 12.9, 10.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (47%), select-
ed signals] = 172.5, 156.8, 130.0, 129.8, 129.6, 122.2, 121.1, 114.8,
85.0, 72.2, 49.4, 40.6, 34.4.
13C NMR (100 MHz, CDCl3):
(59%)] = 172.2, 157.2 (q, J = 38.8 Hz), 115.5 (q, J = 285.8 Hz),
d
[major diastereomer
83.6, 50.5, 50.3, 37.7, 24.1.
1H NMR (400 MHz, CDCl3): d [minor diastereomer (41%), selected
signals] = 6.86 (br s, 1 H), 4.80 (m, 1 H), 3.00 (dd, J = 13.5, 10.0
Hz, 1 H), 2.31 (dd, J = 13.5, 10.3 Hz, 1 H), 1.59 (s, 3 H).
HRMS (CI): m/z [M]+ calcd for C16H16F3NO4: 343.1031; found:
343.1068.
13C NMR (100 MHz, CDCl3): d [minor diastereomer (41%), select-
4-Allyl-4-(4-chlorophenoxy)methyl-2-(2,2,2-trifluoroacetami-
do)butyrolactone (3e)
White solid; yield: 37 mg (0.10 mmol, 66%); mp 89– 90 °C;
Rf = 0.53 (hexanes–EtOAc, 8:2).
ed signals] = 172.2, 83.6, 50.5, 50.3, 37.7, 24.1.
HRMS (CI): m/z [M]+ calcd for C8H9ClF3NO3: 259.0223; found:
259.0182.
1H NMR (400 MHz, CDCl3): d [major diastereomer (58%)] = 7.23–
7.27 (m, 2 H), 6.96 (d, J = 5.0 Hz, 1 H), 6.80–6.84 (m, 2 H), 5.80
(m, 1 H), 5.27–5.32 (m, 2 H), 4.81 (q, J = 8.8 Hz, 1 H), 4.06 (d,
J = 10.1 Hz, 1 H), 3.96 (d, J = 10.1 Hz, 1 H), 2.79 (dd, J = 13.6,
10.2 Hz, 1 H), 2.53–2.63 (m, 2 H), 2.79 (dd, J = 13.6, 8.6 Hz, 1 H).
4-Methyl-4-phenoxymethyl-2-(2,2,2-trifluoroacetamido)buty-
rolactone (3h)
White solid; yield: 36 mg (0.11 mmol, 60%); mp 107–108 °C;
Rf = 0.28 (hexanes–EtOAc, 75:25).
1H NMR (400 MHz, CDCl3): d [major diastereomer (54%)] = 7.28–
7.33 (m, 4 H), 7.08 (d, J = 5.0 Hz, 1 H), 7.03 (m, 1 H), 4.78 (td,
J = 9.6, 7.0 Hz, 1 H), 4.10 (d, J = 10.1 Hz, 1 H), 3.98 (d, J = 10.1
Hz, 1 H), 2.71 (dd, J = 13.5, 9.9 Hz, 1 H), 2.40 (dd, J = 13.5, 8.2 Hz,
1 H), 1.58 (s, 3 H).
13C NMR (100 MHz, CDCl3):
(58%)] = 172.2, 156.8 (q, J = 37.4 Hz), 156.3, 129.7, 127.2, 122.0,
116.8, 116.2, 115.6 (q, J = 285.7 Hz), 84.9, 72.5, 49.6, 40.6, 34.3.
d
[major diastereomer
1H NMR (400 MHz, CDCl3): d [minor diastereomer (42%)] = 7.23–
7.27 (m, 2 H), 6.79–6.85 (m, 3 H), 5.81 (m, 1 H), 5.23–5.33 (m, 2
H), 5.02 (dt, J = 10.2, 5.8 Hz, 1 H), 4.08 (d, J = 10.0 Hz, 1 H), 3.98
(d, J = 10.0 Hz, 1 H), 2.99 (dd,J = 13.0, 9.5 Hz, 1 H), 2.55–2.66 (m,
2 H), 2.21 (dd, J = 13.0, 10.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3):
(54%)] = 172.3, 157.6, 157.2 (q, J = 38.8 Hz), 129.8, 122.3, 115.5
(q, J = 285.8 Hz), 114.8, 83.5, 73.1, 49.5, 36.9, 23.2.
d
[major diastereomer
1H NMR (400 MHz, CDCl3): d [minor diastereomer (46%), selected
signals] = 5.07 (m, 1 H), 4.09 (d, J = 10.1 Hz, 1 H), 3.96 (d, J = 10.1
Synthesis 2011, No. 18, 3020–3026 © Thieme Stuttgart · New York

PAPER
Functionalized g-Hydroxy and Heterocyclic Amino Acids
3025
Hz, 1 H), 3.11 (dd, J = 13.0, 9.5 Hz, 1 H), 2.40 (dd, J = 13.0, 10.7
Hz, 1 H), 1.54 (s, 3 H), 1.55 (s, 3 H).
tert-Butyl 6-Methyl 4-(chloromethyl)-4-hydroxy-2-(2,2,2-tri-
fluoroacetamido)hexanedioate (4c)
White solid; yield: 51 mg (0.13 mmol, 85%); mp 62–63 °C;
Rf = 0.46 (CH2Cl2–hexanes, 95:5).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (46%), select-
ed signals] = 173.0, 129.7, 122.0, 114.6, 83.5, 73.1, 51.3, 38.5, 24.1.
1H NMR (400 MHz, CDCl3): d = 7.28 (d, J = 6.0 Hz, 1 H), 4.69 (dt,
J = 8.6, 4.1 Hz, 1 H), 3.92 (d, J = 15.3 Hz, 1 H), 3.88 (d, J = 15.3
Hz, 1 H), 3.70 (s, 3 H), 2.80 (d, J = 16.2 Hz, 1 H), 2.67 (d, J = 9.2
Hz, 1 H), 2.27 (m, 1 H), 2.17 (dd, J = 14.9, 8.6 Hz, 1 H), 1.44 (s, 9
H).
13C NMR (100 MHz, CDCl3): d = 172.5, 169.1, 157.2 (q, J = 38.8
Hz), 115.5 (q, J = 285.8 Hz), 83.1, 72.5, 72.4, 52.1, 50.9, 39.4, 37.2,
27.7.
HRMS (CI): m/z [M]+ calcd for C14H14F3NO4: 317.0875; found:
317.0870.
4-(4-Chlorophenoxy)methyl-4-methyl-2-(2,2,2-trifluoroacet-
amido)butyrolactone (3i)
White solid; yield: 39 mg (0.11 mmol, 58%); mp 111–112 °C;
Rf = 0.50 (hexanes–EtOAc 75:25).
1H NMR (400 MHz, CDCl3): d [major diastereomer (55%)] = 7.23–
7.28 (m, 2 H), 6.90 (d, J = 5.0 Hz, 1 H), 6.79–6.85 (m, 2 H), 5.03
(dt, J = 10.1, 6.0 Hz, 1 H), 4.06 (d, J = 10.1 Hz, 1 H), 3.94 (d,
J = 10.1 Hz, 1 H), 3.09 (dd, J = 13.1, 9.5 Hz, 1 H), 2.40 (dd,
J = 13.0, 10.8 Hz, 1 H), 1.58 (s, 3 H).
HRMS (CI): m/z [M + 1]+ calcd for C14H21ClF3NO6: 392.1088;
found: 392.1071.
1-tert-Butyl 6-Methyl 4-[(4-chlorophenoxy)methyl]-4-hydroxy-
2-(2,2,2-trifluoroacetamido)hexanedioate (4e)
White solid; yield: 65 mg (0.14 mmol, 90%); mp 69–70 °C;
13C NMR (100 MHz, CDCl3):
(55%)] = 172.2, 157.2 (q, J = 38.8 Hz), 156.3, 129.6, 127.2, 116.1,
115.5 (q, J = 285.8 Hz), 83.3, 73.9, 51.2, 38.4, 24.1.
d
[major diastereomer
Rf = 0.25 (CH2Cl2–hexanes, 95:5).
1H NMR (400 MHz, CDCl3): d = 7.73 (d, J = 5.8 Hz, 1 H), 7.22–
7.25 (m, 2 H), 6.78–6.82 (m, 2 H), 4.50 (ddd, J = 8.6, 6.4, 4.4 Hz, 1
H), 3.92 (d, J = 9.2 Hz, 1 H), 3.88 (d, J = 9.2 Hz, 1 H), 3.70 (s, 3 H),
2.80 (d, J = 16.2 Hz, 1 H), 2.67 (d, J = 9.2 Hz, 1 H), 2.27 (m, 1 H),
2.17 (dd, J = 14.9, 8.6 Hz, 1 H), 1.44 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 172.5, 169.1, 157.2 (q, J = 38.8
Hz), 156.5, 129.4, 126.6, 115.8, 115.5 (q, J = 285.8 Hz), 83.1, 72.5,
72.4, 52.1, 50.9, 39.4, 37.2, 27.7.
1H NMR (400 MHz, CDCl3): d [minor diastereomer (45%)] = 7.23–
7.28 (m, 2 H), 7.01 (br s, 1 H), 6.79–6.85 (m, 2 H), 5.03 (dt, J = 9.4,
7.0 Hz, 1 H), 4.06 (d, J = 10.0 Hz, 1 H), 3.95 (d, J = 10.1 Hz, 1 H),
2.72 (dd, J = 13.3, 9.7 Hz, 1 H), 2.40 (dd, J = 13.0, 9.1 Hz, 1 H),
1.58 (s, 3 H).
13C NMR (100 MHz, CDCl3): d [minor diastereomer (45%), select-
ed signals] = 172.1, 129.6, 127.1, 115.5, 83.4, 73.2, 49.5, 38.6, 23.1.
HRMS (CI): m/z [M + 1]+ calcd for C14H13ClF3NO4: 353.0456;
found: 353.0419.
HRMS (CI): m/z [M + 1]+ calcd for C20H25ClF3NO7: 485.1242;
found: 485.1234.
4-(2-Cyanophenoxy)methyl-4-methyl-2-(2,2,2-trifluoroacet-
amido)butyrolactone (3k)
White solid; yield: 43 mg (0.13 mmol, 66%); mp 110–111 °C;
tert-Butyl 4-(3-Aminobenzofuran-2-yl)-4-oxo-2-(2,2,2-trifluo-
roacetamido)butanoate (5)
Ketone 2f (90 mg, 0.22 mmol) was refluxed in anhyd Et3N (2.5 mL)
under N2. After completion of the reaction, the Et3N was removed
in vacuo, and the crude product was purified by column chromatog-
raphy (silica gel, hexanes–EtOAc, 8:2) to afford 5 in 92% yield (81
mg, 0.20 mmol) as a colorless oil; Rf = 0.28 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d = 7.69 (d, J = 7.8 Hz, 1 H), 7.50–
7.59 (m, 2 H), 7.40 (m, 1 H), 7.25 (m, 1 H), 5.69 (br s, 2 H), 4.85
(dt, J = 8.3, 4.2 Hz, 1 H), 3.68 (dd, J = 17.6, 4.3 Hz, 1 H), 3.68 (dd,
J = 17.6, 4.3 Hz, 1 H), 1.49 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 187.4, 168.6, 157.2 (q, J = 38.8
Hz), 154.4, 140.0, 134.2, 130.2, 122.5, 120.7, 120.3, 115.5 (q,
J = 285.8 Hz), 112.7, 83.0, 49.3, 38.6, 27.7.
Rf = 0.26 (hexanes–EtOAc, 8:2).
1H NMR (400 MHz, CDCl3): d [major diastereomer (60%)] = 7.80
(d, J = 7.3 Hz, 1 H), 7.53–7.58 (m, 2 H), 7.08 (t, J = 7.6 Hz, 1 H),
6.96 (d, J = 8.2 Hz, 1 H), 5.09 (dt, J = 10.3, 7.9 Hz, 1 H), 4.27 (d,
J = 10.3 Hz, 1 H), 4.04 (d, J = 10.3 Hz, 1 H), 2.67 (d, J = 10.5 Hz,
2 H), 1.57 (s, 3 H).
13C NMR (100 MHz, CDCl3):
d
[major diastereomer
(60%)] = 171.9, 160.1, 157.2 (q, J = 38.8 Hz), 134.8, 133.0, 122.1,
117.0, 115.5 (q, J = 285.8 Hz), 113.2, 102.4, 82.6, 73.2, 51.5, 35.1,
23.2.
1H NMR (400 MHz, CDCl3): d [minor diastereomer (40%), selected
signals] = 7.53–7.58 (m, 2 H), 7.47 (br s, 1 H), 4.22 (d, J = 9.7 Hz,
1 H), 3.99 (d, J = 9.7 Hz, 1 H), 2.98 (dd, J = 12.9, 10.1 Hz, 1 H),
2.41 (dd, J = 13.0, 10.3 Hz, 1 H), 1.63 (s, 3 H).
HRMS (CI): m/z [M]+ calcd for C18H19F3N2O5: 400.1246; found:
400.1269.
13C NMR (100 MHz, CDCl3): d [minor diastereomer (40%), select-
ed signals] = 171.9, 159.6, 133.6, 113.2, 112.1, 101.9, 82.2, 74.1,
36.2, 23.9.
HRMS (CI): m/z [M]+ calcd for C15H13F3N2O4: 342.0827; found:
342.0867.
tert-Butyl 3-(3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)-2-
(2,2,2-trifluoroacetamido)propanoate (6)
To a solution of ketone 2g (50 mg, 0.12 mmol) in MeOH (15 mL)
was added 5% Pd/C (12.5 mg) and the solution was allowed to stir
under H2 (4 bar). After stirring for 6 h, the solution was filtered over
Celite, and the solvent was removed in vacuo. The crude product
was purified by column chromatography (silica gel, hexanes–
EtOAc, 8:2) to give 6 in ~100% yield (44 mg, 0.12 mmol) as a col-
orless solid; mp 63–64 °C; Rf = 0.46 (hexanes–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): d [major diastereomer (56%)] = 7.28
(d, J = 7.3 Hz, 1 H), 6.79–6.84 (m, 2 H), 6.65–6.69 (m, 2 H), 4.69
(ddd, J = 10.4, 8.0, 3.5 Hz, 1 H), 4.07 (dd, J = 10.7, 2.8 Hz, 1 H),
3.98 (dd, J = 10.7, 4.1 Hz, 1 H), 3.43 (m, 1 H), 2.19 (ddd, J = 14.3,
10.9, 3.5 Hz, 1 H), 2.19 (ddd, J = 14.0, 10.3, 3.0 Hz, 1 H), 1.48 (s,
9 H), NH was missing.
Reformatsky Reaction; General Procedure
To a solution of the corresponding g-keto amino acid ester 2 (0.15
mmol) in anhyd THF (0.5 mL) was added a freshly prepared 1.6 M
solution of zincbromo ester in THF (0.14 mL, 0.22 mmol) at –5 °C
and the mixture was allowed to warm to r.t. overnight. The reaction
mixture was quenched with aq 1 M HCl (2 mL) and extracted with
EtOAc (2 × 5 mL). The combined organic layers were washed with
brine (5 mL), dried (Na2SO4), and the solvent was removed in vac-
uo. The product was obtained after column chromatography (silica
gel, EtOAc–hexanes).
Synthesis 2011, No. 18, 3020–3026 © Thieme Stuttgart · New York

3026
A. F. Zahoor, U. Kazmaier
PAPER
13C NMR (100 MHz, CDCl3):
(56%)] = 170.0, 157.2 (q, J = 38.8 Hz), 143.5, 132.0, 122.0, 118.8,
116.7, 116.1, 115.5 (q, J = 285.8 Hz), 84.1, 68.2, 50.7, 46.7, 35.7,
27.9.
1H NMR (400 MHz, CDCl3): d [minor diastereomer (44%)] = 7.12
(d, J = 6.3 Hz, 1 H), 6.76–6.82 (m, 2 H), 6.57–6.70 (m, 2 H), 4.69
(q, J = 6.4 Hz, 1 H), 4.09 (dd, J = 10.7, 2.7 Hz, 1 H), 4.00 (dd,
J = 10.7, 4.9 Hz, 1 H), 3.57 (m, 1 H), 2.13 (ddd, J = 14.3, 6.1, 4.7
Hz, 1 H), 2.01 (m, 1 H), 1.45 (s, 9 H), NH was missing.
13C NMR (100 MHz, CDCl3): d [minor diastereomer (44%), select-
ed signals] = 169.7, 143.5, 131.8, 121.8, 119.1, 116.8, 116.1, 84.1,
68.0, 51.3, 47.4, 34.7, 27.8.
d
[major diastereomer
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HRMS (CI): m/z [M]+ calcd for C17H21F3N2O4: 374.1453; found:
374.1479.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
and by the Fonds der Chemischen Industrie. A. F. Zahoor thanks the
DAAD and HEC (Pakistan) for a Ph.D. fellowship.
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Synthesis 2011, No. 18, 3020–3026 © Thieme Stuttgart · New York