A straightforward approach towards α-amino-β-keto esters via acylation of chelated amino acid ester enolates

Article abstract of DOI:10.1055/s-0031-1289674

Chelated enolates were found to be good nucleophiles for reactions with acyl halides affording -amino - keto esters. In most cases, the reactions are over after a few minutes and preparatively useful yields are obtained, independent of the protecting groups and halides used. Besides acyl halides, also the corresponding imidazolides can be used with similar success. With chloroformates as acylating agents different protected amino malonates become accessible. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289674

600
PAPER
A Straightforward Approach towards a-Amino-b-keto Esters via Acylation of
Chelated Amino Acid Ester Enolates
Katharina Schultz, Laura Stief, 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 November 2011; revised 19 December 2011
suitable for the synthesis of b-keto-a-amino acid esters via
Abstract: Chelated enolates were found to be good nucleophiles
nucleophilic attack on acyl halides or derivatives thereof.
for reactions with acyl halides affording a-amino-b-keto esters. In
most cases, the reactions are over after a few minutes and prepara-
tively useful yields are obtained, independent of the protecting
groups and halides used. Besides acyl halides, also the correspond-
ing imidazolides can be used with similar success. With chlorofor-
mates as acylating agents different protected amino malonates
become accessible.
Our investigations began with the N-tosylated tert-butyl
glycinate and benzoyl chloride as electrophile (Table 1).
The tosylated amino acid was chosen because of good re-
sults obtained previously in aldol additions.14 With three
equivalents of LDA as a base, the desired b-keto-a-amino
acid ester was obtained in acceptable yield (Table 1, entry
1). Increasing the amount of base to 3.8 equivalents result-
ed in an increase of the yield (entry 2), but also a higher
ratio of side products. A significant amount of N-benzoy-
lated product also was obtained, which could not be sepa-
rated easily. By lowering the amount of base to 2.5
equivalents (entry 3) the formation of the side products
could be suppressed, but the yield dropped significantly.
Therefore, we investigated also LHMDS (lithium hexa-
methyldisilazide) and LTMP (lithium tetramethylpiperid-
ide) as sterically demanding alternative bases (entries 4
Key words: acylation, acyl halides, amino acids, amino malonates,
chelated enolates, ketones
b-Keto-a-amino acids are not only important precursors
for the synthesis of b-hydroxy-a-amino acids,1 but are
also interesting building blocks for pharmaceuticals2 and
natural products, such as the miuraenamides.3 Therefore,
straightforward concepts towards their synthesis are high-
ly desired. Classical approaches are based on the diazota-
tion of the corresponding b-keto esters4 or on the ring
opening of oxazoles.5 Acylations of hippuric acid
derivatives6 and iminoglycinates7 were also reported, but
here the yields were moderate and varied significantly. An
interesting approach was reported by Hamada et al. start-
ing from acylimides of glycinates.8 Deprotonation with
strong bases such as LDA (lithium diisoproylamide) re-
sulted in an intramolecular N → C acyl shift and the for-
mation of the required protected b-keto amino acid.
Tanabe et al. described an interesting cross-Claisen con-
densation approach of titanium enolates and acyl imida-
zolides, formed in situ from the corresponding acyl
halides.9 In principle, this approach is also suitable for a-
amino-b-keto esters. The acyl halides could not be used
directly, because of decomposition under the reaction
conditions. But acyl halides can directly be used in acyla-
tions of a-amino malonic acid monoesters, providing the
b-keto esters after decarboxylation.10
Table 1 Benzoylation of Chelated Glycine Enolates
1) base
2) ZnCl2 (1.2 equiv)
O
PGHN
COOR
3) BzCl (1.1 equiv)
THF, –78 °C, 5 min
4) H3O+
PGHN
COOR
Entry
PG
R
Base
Equiv
Product Yield
(%)
1
2
Ts
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
LDA
LDA
LDA
3.0
3.8
2.5
1
1
1
1
1
2
3
4
4
4
5
6
7
54
61
31
59
59
53
50
48
60
62
67
79
83
Ts
3
Ts
4
Ts
LHMDS 3.8
5
Ts
LTMP
LDA
LDA
LDA
3.8
3.8
3.8
3.8
Our group is involved in amino acid synthesis since sev-
eral years, investigating reactions of chelated amino acid
ester enolates. These enolates show a higher thermal sta-
bility compared to nonchelated enolates and excellent ste-
reoselectivities in a wide range of reactions, such as
Claisen rearrangements,11 Michael additions,12 or transi-
tion-metal-catalyzed allylic alkylations.13 Therefore, we
were interested to find out if these enolates might also be
6
Ts
7
Ts
Bn
8
TFA
TFA
TFA
TFA
Boc
Boc
Bn
9
Bn
LHMDS 3.0
LTMP 3.0
LHMDS 3.0
10
11
12
13
Bn
t-Bu
Me
SYNTHESIS 2012, 44, 600–604
x
x
.x
x
.2
0
1
1
LDA
LDA
3.0
3.0
Advanced online publication: 24.01.2012
DOI: 10.1055/s-0031-1289674; Art ID: T110011SS
© Georg Thieme Verlag Stuttgart · New York
t-Bu

PAPER
Acylation of Chelated Enolates to a-Amino-b-keto Esters
601
and 5). The yields obtained were comparable to those of
the LDA reaction, but the side product formation could be
suppressed nearly completely, which made the workup
more convenient, because only the starting material had to
be removed.
Table 2 Acylation of Chelated Glycine Enolates
1) base
2) ZnCl2 (1.2 equiv)
O
R
PGHN
COOt-Bu
3) RCOCl (1.1 equiv)
THF, –78 °C
PGHN
COOt-Bu
4) H3O+
Next the influence of the protecting groups on the out-
come of the reaction was investigated. When the ester
functionality (entries 6 and 7) was changed the yield
dropped slightly, but obviously there is no great influence
from this protecting group. Therefore, we focused next on
the N-protecting group. Based on the good results ob-
tained in Michael additions12 and allylic alkylations,13 the
trifluoroacetyl protecting group (TFA) was investigated.
With the corresponding benzyl ester, a comparable yield
was obtained if LDA was used as a base (entry 8). In our
previous investigations of TFA enolates it was observed
that under certain conditions this protecting group can be
cleaved by the LDA used in excess, and that this problem
can be solved by applying sterically more demanding
bases such as LHMDS and LTMP. And indeed, by using
these bases, the yield could be increased to around 60%
Entry
PG
R
Base
Product Yield
(%)
1
2
3
4
5
6
7
8
Ts
4-PhC6H4
n-C5H11
t-Bu
LDA
LDA
LDA
8
9
54
47
68
93
61
62
67
87
Ts
Ts
10
11
12
13
14
15
TFA
TFA
TFA
TFA
TFA
t-Bu
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
i-Pr
n-Pr
Ada
c-C6H11
(entries 9 and 10). A further improvement brought the a Ad: 1-Adamantyl.
switch from the benzyl ester to the tert-butyl ester (entry
11), our standard nucleophile used in allylic alkylations,13
which also gave the best results here. As representatives
of the carbamate protecting groups, two Boc-protected es-
ters have been investigated as well, and they gave the best
yields so far (entries 12 and 13). Obviously, there are no
restrictions concerning the protecting groups that can be
used.
O
R
N
N
TFAHN
12 R = i-Pr 55%
13 R = n-Pr 56%
COOt-Bu
O
R
1) LHMDS
THF
TFAHN
COOt-Bu
We also proved the generality of the acyl halide compo-
nent in the reaction of the N-tosylated tert-butyl glycinate
(Table 2). With 4-phenylbenzoyl chloride, a slightly low-
er yield was obtained (Table 2, entry 1). But in contrast to
aromatic acyl halides, their aliphatic relatives are more
critical candidates, because under the basic reaction con-
ditions ketene formation might be an optional pathway,
resulting in the formation of various side products. For ex-
ample, the yield obtained with hexanoyl chloride was only
in the range of 50% (entry 2), probably because of ketene
formation. To eliminate this side reaction, pivaloyl chlo-
ride was used as the electrophile. And indeed, with this
sterically demanding acyl halide (without a-H) the yield
increased significantly (entry 3). Especially with the TFA
derivative an excellent yield was obtained (entry 4).
Therefore, the reaction was investigated with several ali-
phatic acyl halides with this nucleophile. Linear as well as
branched acyl chlorides provided the acylation products
in yields of 61–87% (entries 5–8).
–78 °C, 1 h
2) ZnCl2
(1.2 equiv)
O
OEt
TFAHN
COOt-Bu
16 78%
Scheme 1 Acylations using acyl imidazolides and chloroformates
To increase the generality of this approach chloroformates
were also subjected to our standard reaction conditions.
Although no b-keto esters are formed in this case, this ap-
proach gives direct access to differentially protected a-
amino malonates 16, which are also interesting building
blocks.
It should be mentioned, that the b-keto-a-amino acid es-
ters should be subjected to further modifications of the b-
keto group, before cleavage of the protecting group, be-
cause the N- and/or O-deprotected amino acids are not
stable. Cleavage of the ester functionality provides the
corresponding b-keto-a-amino acid, which undergoes fast
decarboxylation towards the corresponding a-amino ke-
tone, and cleavage of the N-protecting group results in the
formation of several side products (e.g., dimerization of
the free amino ketone).
As an alternative to acyl chlorides the corresponding
acylimidazolides were also investigated (Scheme 1).
These activated acyl derivatives can easily be generated in
situ from the corresponding carboxylic acid and carbonyl-
diimidazole.15 The yields obtained were slightly lower
compared to the acyl chlorides, but still in a preparatively
useful range. Therefore, the imidazolides might be an in-
teresting alternative in case the required acyl chlorides are
unstable or difficult to prepare.
In conclusion, we have shown that the direct acylation of
chelated enolates is a straightforward approach towards b-
keto-a-amino acid derivatives. Generally, preparatively
useful yields are obtained, nearly independent on the pro-
© Thieme Stuttgart · New York
Synthesis 2012, 44, 600–604

602
K. Schultz et al.
PAPER
chloride(115 mL, 141 mg, 1.00 mmol) to give 2, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a colorless solid;
yield: 176 mg (0.51 mmol, 53%); mp 102–103 °C.
1H NMR (400 MHz, CDCl3): d = 7.96 (d, J = 8.5 Hz, 2 H), 7.70 (d,
J = 8.2 Hz, 2 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.46 (dd, J = 8.3, 7.6 Hz,
2 H), 7.22 (d, J = 8.2 Hz, 2 H), 5.92 (d, J = 8.8 Hz, 1 H), 5.58 (d,
J = 8.8 Hz, 1 H), 3.51 (s, 3 H), 2.36 (s, 3 H).
tecting groups and the acyl halides used. Obviously, the
highly reactive chelated enolates can compete successful-
ly with undesired side reactions such as amide and ketene
formation. Applications of this approach in natural prod-
uct syntheses are currently under investigation.
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,
13C NMR (100 MHz, CDCl3): d = 189.9, 166.5, 149.0, 134.6, 130.2,
129.7, 129.3, 128.9, 128.5, 127.3, 60.6, 53.2, 21.4.
HRMS (CI): m/z calcd for C17H18NO5S [M + H]+:348.0906; found:
348.0905.
Anal. Calcd for C17H17NO5S (347.39): C, 58.78; H, 4.93; N, 4.03.
Found: C, 58.72; H, 5.10; N, 3.88.
1
KMnO4 solution, or I2. H and 13C NMR spectroscopic analyses
were performed on a Bruker Avance II 400 (400 MHz) spectrome-
ter. Chemical shifts are reported on the d (ppm) scale and the cou-
pling constant are given in Hz. High-resolution mass spectra were
recorded on a Finnigan MAT 95S mass spectrometer at the Institute
of Organic Chemistry, and on a Thermo LTQ-Orbitrap Hybrid-FT
mass spectrometer at the Institute of Pharmazeutical Biotechnology
at Saarland University. Elemental analyses were carried out at the
Department of Chemistry at Saarland University.
Benzyl 2-(Tosylamino)-3-oxo-3-phenylpropanoate (3)
According to the general procedure, Ts-Gly-OBn (263 mg, 0.82
mmol) and LDA (335 mg, 3.12 mmol) were reacted with benzoyl
chloride(105 mL, 128 mg, 0.91 mmol) to give 3, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a colorless solid;
yield: 174 mg (0.41 mmol, 50%); mp 80–82 °C.
1H NMR (400 MHz, CDCl3): d = 7.92 (dd, J = 8.4, 1.3 Hz, 2 H),
7.67 (d, J = 8.4 Hz, 2 H), 7.59 (tt, J = 7.5, 1.3 Hz, 1 H), 7.41 (dd,
J = 8.4, 7.5 Hz, 1 H), 7.45–7.22 (m, 3 H), 7.18 (d, J = 8.2 Hz, 2 H),
7.17 (m, 2 H), 5.95 (d, J = 8.8 Hz, 1 H), 5.61 (d, J = 8.8 Hz, 1 H),
4.93 (d, J = 12.4 Hz, 1 H), 4.89 (d, J = 12.0 Hz, 1 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 189.9, 166.0, 143.6, 136.5, 134.6,
134.3, 133.6, 129.9, 129.7, 129.0, 128.5, 128.1, 127.4, 127.3, 68.1,
60.9, 21.6.
HRMS (ESI): m/z calcd for C23H22NO5S [M + H]+: 424.1213;
found: 424.1192.
Acylation of Chelated Glycine Enolates; General Procedure
In a Schlenk tube, hexamethyldisilazane, diisopropylamine, or tet-
ramethylpiperidine (3.3 mmol, 3.3 equiv) was dissolved in anhyd
THF (5.0 mL). After cooling the solution to –78 °C, a 1.6 M solu-
tion of n-BuLi (1.88 mL, 3.00 mmol, 3.0 equiv) was added slowly.
The solution was stirred for 10 min before the cooling bath was re-
moved and the solution was stirred further for 10 min. In a second
Schlenk tube, ZnCl2 (164 mg, 1.2 mmol, 1.2 equiv) was dried with
a heat gun under vacuum. After cooling to r.t., protected glycine
(1.0 mmol, 1 equiv) and THF (5.0 mL) were added and the solution
was cooled to –78 °C before the above prepared base solution was
added slowly. The resulting solution was stirred for 30 min at
–78 °C. The corresponding acyl halide or imidazolide (1.1 equiv)
was added at –78 °C, and the reaction mixture was allowed to stir
for 5 min before it was hydrolyzed with aq 1 M KHSO4 (10 mL) and
extracted with Et2O (2 × 20 mL). The combined organic layers were
dried (Na2SO4), the solvent was evaporated in vacuo, and the crude
product was purified by flash chromatography (silica gel, hexanes–
EtOAc).
Benzyl 2-(Trifluoroacetamido)-3-oxo-3-phenylpropanoate (4)
According to the general procedure, TFA-Gly-OBn (261 mg, 1.00
mmol) and LHMDS (518 mg, 3.10 mmol) were reacted with ben-
zoyl chloride (130 mL, 155 mg, 1.10 mmol) to give 4, after flash
chromatography (silica gel, hexanes–EtOAc, 15:1), as a colorless
solid; yield: 220 mg (0.60 mmol, 60%); mp 60–61 °C.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J = 7.5 Hz, 2 H), 7.73 (br
s, 1 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.48 (m, 2 H), 7.30–7.22 (m, 3 H),
7.07 (d, J = 6.2 Hz, 2 H), 6.15 (d, J = 7.1 Hz, 1 H), 5.15 (d, J = 11.9
Hz, 1 H), 5.09 (d, J = 11.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 189.0, 164.5, 135.0, 134.1, 133.3,
tert-Butyl 2-(Tosylamino)-3-oxo-3-phenylpropanoate (1)
According to the general procedure, Ts-Gly-Ot-Bu (229 mg, 0.80
mmol) and LDA (326 mg, 3.04 mmol) were reacted with benzoyl
chloride(126 mL, 154 mg, 1.10 mmol) to give 1, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as colorless needles;
yield: 190 mg (0.488 mmol, 61%); mp 136–137 °C.
1H NMR (400 MHz, CDCl3): d = 7.96 (d, J = 7.3 Hz, 2 H), 7.71 (d,
J = 8.4 Hz, 2 H), 7.60 (t, J = 7.3 Hz, 1 H), 7.46 (dd, J = 7.3, 7.3 Hz,
2 H), 7.22 (d, J = 8.1 Hz, 2 H), 5.86 (d, J = 9.0 Hz, 1 H), 5.45 (d,
J = 9.0, 1 H), 2.36 (s, 3 H), 1.18 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 189.5, 165.9, 143.7, 134.7, 134.0,
130.7, 129.7, 128.9, 128.3, 127.3, 82.9, 61.5, 27.8, 21.5.
HRMS (ESI): m/z calcd for C20H24NO5S [M + H]+: 390.1375;
found: 390.1373.
129.8, 128.9, 128.7, 128.6, 128.1, 68.7, 58.3.
HRMS (ESI): m/z calcd for C18H15F3NO4 [M + H]+: 366.0953;
found: 366.0998.
tert-Butyl 2-(Trifluoroacetamido)-3-oxo-3-phenylpropanoate
(5)
According to the general procedure, TFA-Gly-Ot-Bu (682 mg, 3.00
mmol) and LHMDS (1.56 g, 9.30 mmol) were reacted with benzoyl
chloride(345 mL, 421 mg, 3.00 mmol) to give 5, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a colorless solid;
yield: 671 mg (2.02 mmol, 67%); mp 84–85 °C.
1H NMR (400 MHz, CDCl3): d = 8.09 (d, J = 7.5 Hz, 2 H), 7.66 (m,
2 H), 7.52 (dd, J = 7.5, 7.5 Hz, 2 H), 6.01 (d, J = 7.0 Hz, 1 H), 1.30
(s, 9 H).
13C NMR (100 MHz, CDCl3): d = 189.9, 163.4, 156.7 (q, J = 38.3
Hz), 134.8, 133.8, 129.7, 128.7, 115.6 (q, J = 287 Hz), 85.0, 59.1,
27.6.
Anal. Calcd for C20H23NO5S (389.47): C, 61.68; H, 5.95; N, 3.60.
Found: C, 61.57; H, 5.94; N, 3.56.
Methyl 2-(Tosylamino)-3-oxo-3-phenylpropanoate (2)
According to the general procedure, Ts-Gly-OMe (234 mg, 0.96
mmol) and LDA (391 mg, 3.65 mmol) were reacted with benzoyl
HRMS (ESI): m/z calcd for C15H17F3NO4 [M + H]+: 332.1104;
found: 332.1109.
Synthesis 2012, 44, 600–604
© Thieme Stuttgart · New York

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Acylation of Chelated Enolates to a-Amino-b-keto Esters
603
Methyl 2-(tert-Butoxycarbonylamino)-3-oxo-3-phenylpro-
panoate (6)
According to the general procedure, Boc-Gly-OMe (189 mg, 1.00
mmol) and LDA (332 mg, 3.10 mmol) were reacted with benzoyl
chloride(127 mL, 155 mg, 1.10 mmol) to give 6, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a colorless solid;
yield: 232 mg (0.79 mmol, 79%); mp 88–89 °C.
1H NMR (400 MHz, CDCl3): d = 8.09 (d, J = 7.2 Hz, 2 H), 7.61 (t,
J = 7.2 Hz, 1 H), 7.49 (m, 2 H), 5.95 (d, J = 8.0 Hz, 1 H), 5.87 (d,
J = 8.0 Hz, 1 H), 3.70 (s, 3 H), 1.44 (s, 9 H).
2.60 (dt, J = 17.6, 7.4 Hz, 1 H), 2.50 (dt, J = 17.6, 7.2 Hz, 1 H), 2.37
(s, 3 H), 1.51 (m, 2 H), 1.31 (s, 9 H), 1.28–1.16 (m, 4 H), 0.85 (t,
J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 200.9, 164.8, 143.9, 136.5, 129.7,
127.3, 84.1, 65.0, 39.9, 31.7, 27.7, 22.9, 22.5, 21.2, 14.0.
Enol Form (selected signals)
1H NMR (400 MHz, CDCl3): d = 12.7 (br s, 1 H), 7.67 (d, J = 8.2
Hz, 2 H), 5.40 (s, 1 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.1, 129.5, 127.8, 115.4, 82.6,
13.8.
HRMS (CI): m/z calcd for C19H30NO5S [M + H]+: 384.1845; found:
384.1887.
13C NMR (100 MHz, CDCl3): d = 191.0, 167.3, 157.2, 134.3, 133.3,
129.5, 128.8, 84.6, 63.2, 53.1, 28.2.
HRMS (CI): m/z calcd for C15H20NO5 [M + H]+: 294.1336; found:
294.1310.
tert-Butyl 2-(Tosylamino)-4,4-dimethyl-3-oxopentanoate (10)
According to the general procedure, Ts-Gly-Ot-Bu (229 mg, 0.80
mmol) and LDA (326 mg, 3.04 mmol) were reacted with pivaloyl
chloride (132 mL, 129 mg, 1.07 mmol) to give 10, after flash chro-
matography (silica gel, hexanes–EtOAc, 10:1), as a colorless solid;
yield: 180 mg (0.47 mmol, 47%); mp 120–121 °C.
1H NMR (400 MHz, CDCl3): d = 7.70 (d, J = 8.0 Hz, 2 H), 7.26 (d,
J = 8.0 Hz, 2 H), 5.59 (d, J = 10.0 Hz, 1 H), 4.94 (d, J = 10.0 Hz, 1
H), 2.37 (s, 3 H), 1.25 (s, 9 H), 1.14 (s, 9 H).
Anal. Calcd for C15H19NO5 (293.32): C, 61.42; H, 6.53; N, 4.78.
Found: C, 61.37; H, 6.44; N, 4.55.
tert-Butyl 2-(tert-Butoxycarbonylamino)-3-oxo-3-phenylpro-
panoate (7)
According to the general procedure, Boc-Gly-Ot-Bu (300 mg, 1.30
mmol) and LDA (431 mg, 4.00 mmol) were reacted with benzoyl
chloride(165 mL, 200 mg, 1.43 mmol) to give 7, after flash chroma-
tography (silica gel, hexanes–EtOAc, 15:1), as a colorless solid;
yield: 362 mg (1.08 mmol, 83%); mp 68–69 °C.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J = 7.5 Hz, 2 H), 7.59 (t,
J = 7.5 Hz, 1 H), 7.47 (dd, J = 7.5 Hz, 2 H), 5.87–5.80 (m, 2 H),
1.43 (s, 9 H), 1.29 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 192.7, 165.8, 155.0, 134.7, 133.9,
129.5, 128.5, 83.5, 80.4, 60.2, 28.3, 27.7.
HRMS (CI): m/z calcd for C18H26NO5 [M + H]+: 336.1805; found:
336.1797; m/z calcd for C18H27NO5 [M + 2 H]+: 337.1883; found:
337.1889.
13C NMR (100 MHz, CDCl3): d = 206.3, 165.2, 143.9, 136.7, 129.6,
127.4, 83.7, 58.9, 46.6, 27.6, 26.2, 21.5.
Anal. Calcd for C18H27NO5S (369.48): C, 58.51; H, 7.37; N, 3.79.
Found: C, 58.73; H, 7.15; N, 3.56.
tert-Butyl 2-(Trifluoroacetamido)-4,4-dimethyl-3-oxopen-
tanoate (11)
According to the general procedure, TFA-Gly-Ot-Bu (227 mg, 1.00
mmol) and LHMDS (518 mg, 3.10 mmol) were reacted with piv-
aloyl chloride (135 mL, 132 mg, 1.10 mmol) to give 11, after flash
chromatography (silica gel, hexanes–EtOAc, 10:1), as a colorless
solid; yield: 290 mg (0.93 mmol, 93%); mp 48–49 °C.
tert-Butyl2-(Tosylamino)-3-oxo-3-(4-phenyl)phenylpropanoate
(8)
According to the general procedure, Ts-Gly-Ot-Bu (229 mg, 0.80
mmol) and LDA (326 mg, 3.04 mmol) were reacted with 4-phenyl-
benzoyl chloride(217 mg, 1.00 mmol) to give 8, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as colorless needles;
yield: 200 mg (0.43 mmol, 54%); mp 135–136 °C.
1H NMR (400 MHz, CDCl3): d = 8.04 (d, J = 8.5 Hz, 2 H), 7.73 (d,
J = 8.5 Hz, 2 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.61 (m, 2 H), 7.47 (m,
2 H), 7.40 (m, 1 H), 7.23 (m, 2 H), 5.88 (d, J = 9.0 Hz, 1 H), 5.48
(d, J = 9.0 Hz, 1 H), 2.36 (s, 3 H), 1.21 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 190.3, 165.0, 147.0, 143.8, 139.4,
136.7, 132.4, 130.0, 129.7, 129.0, 128.6, 127.4, 127.3, 127.2, 84.0,
61.5, 27.5, 21.5.
HRMS (CI): m/z calcd for C26H28NO5S [M + H]+: 466.1688; found:
466.1682.
Besides the expected product 11, the enol forms were also observed
in the NMR spectra.
1H NMR (400 MHz, CDCl3): d = 7.27 (br s, 1 H), 5.57 (d, J = 7.9
Hz, 1 H), 1.45 (s, 9 H), 1.25 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 206.7, 164.2, 156.3 (q, J = 38.9
Hz), 115.5 (q, J = 287 Hz), 83.4, 56.5, 44.9, 27.8, 26.4.
Enol Forms (selected signals)
1H NMR (400 MHz, CDCl3): d = 7.27 (br s, 2 H), 1.47 (s, 9 H), 1.27
(s, 9 H), 1.24 (m, 18 H).
13C NMR (100 MHz, CDCl3): d = 175.5, 174.0, 161.5, 157.9, 118.0,
84.9, 39.5, 37.0, 28.2, 27.7, 27.1, 26.5.
HRMS (CI): m/z calcd for C13H21F3NO4 [M + H]+:312.1423; found:
312.1414.
Anal. Calcd for C24H27NO5S (465.56): C, 67.08; H, 5.85; N, 3.01.
Found: C, 66.88; H, 5.48; N, 2.72.
tert-Butyl 2-(Trifluoroacetamido)-4-methyl-3-oxopentanoate
(12)
tert-Butyl 2-(Tosylamino)-3-oxooctanoate (9)
According to the general procedure, TFA-Gly-Ot-Bu (227 mg, 1.00
mmol) and LHMDS (518 mg, 3.10 mmol) were reacted with isobu-
tyryl chloride (117 mg, 1.10 mmol) to give 12, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a yellow liquid;
yield: 182 mg (0.61 mmol, 61%).
1H NMR (400 MHz, CDCl3): d = 7.34 (br s, 1 H), 5.25 (d, J = 6.5
Hz, 1 H), 3.13 (qq, J = 6.9, 6.8 Hz, 1 H), 1.48 (s, 9 H), 1.23 (d,
J = 7.1 Hz, 3 H), 1.14 (d, J = 6.7 Hz, 3 H).
According to the general procedure, Ts-Gly-Ot-Bu (285 mg, 1.00
mmol) and LDA (332 mg, 3.10 mmol) were reacted with hexanoyl
chloride(152 mL, 144 mg, 1.08 mmol) to give 9, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a colorless solid;
yield: 180 mg (0.47 mmol, 47%); mp 75–76 °C.
Besides the expected product 9, the enol form was also observed in
the NMR spectra.
1H NMR (400 MHz, CDCl3): d = 7.71 (d, J = 8.2 Hz, 2 H), 7.28 (d,
J = 8.2 Hz, 2 H), 5.64 (d, J = 7.9 Hz, 1 H), 4.50 (d, J = 7.9 Hz, 1 H),
13C NMR (100 MHz, CDCl3): d = 203.5, 163.3, 156.5 (q, J = 38.6
Hz), 115.5 (q, J = 38.6 Hz), 85.1, 61.3, 38.9, 27.8, 18.8, 17.4.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 600–604

604
K. Schultz et al.
PAPER
HRMS (CI): m/z calcd for C12H19F3NO4 [M + H]+:298.1260; found:
198.1282.
13C NMR (100 MHz, CDCl3): d = 164.5, 163.0, 156.0 (q, J = 38.4
Hz), 114.9 (q, J = 38.9 Hz), 62.5, 56.4, 27.2, 13.5.
Anal. Calcd for C12H18F3NO4 (297.27): C, 48.48; H, 6.10; N, 4.71.
Found: C, 47.98; H, 5.93; N, 4.73.
HRMS (CI): m/z calcd for C7H7F3NO4 [M – t-BuO]+: 226.0322;
found: 226.0288.
tert-Butyl 2-(Trifluoroacetamido)-3-oxohexanoate (13)
According to the general procedure, TFA-Gly-Ot-Bu (227 mg, 1.00
mmol) and LHMDS (518 mg, 3.10 mmol) were reacted with butyryl
chloride (117 mg, 1.10 mmol) to give 13, after flash chromatogra-
phy (silica gel, hexanes–EtOAc 10:1), as a pale yellow liquid; yield:
185 mg (0.61 mmol, 62%).
Acknowledgment
Financial support from the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
1H NMR (400 MHz, CDCl3): d = 7.45 (br s, 1 H), 5.08 (d, J = 6.3
Hz, 1 H), 2.79 (t, J = 7.3 Hz, 1 H), 2.67 (t, J = 7.0 Hz, 1 H), 1.68 (tq,
J = 7.3, 7.3 Hz, 2 H), 1.49 (s, 9 H), 0.93 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 199.2, 163.1, 156.5, 115.4, 84.9,
62.9, 42.5, 27.6, 16.7, 13.3.
References
(1) (a) Genêt, J. P.; Pinel, C.; Mallart, S.; Juge, S.; Thorimbert,
S.; Laffitte, J. A. Tetrahedron: Asymmetry 1991, 2, 555.
(b) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y.
Tetrahedron: Asymmetry 2008, 19, 2816.
HRMS (CI): m/z calcd for C8H10F3NO4 [M – t-Bu + H]+:241.0556;
found: 241.0518.
(2) (a) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(b) Miossec, B.; Rudyk, H.; Toupet, L.; Danion-Bougot, R.;
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(c) Hernández, D.; Vilar, G.; Riego, E.; Caňedo, L. M.;
Cuevas, C.; Albericio, F.; Alvarez, M. Org. Lett. 2007, 9,
809.
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S.; Inukai, Y.; Ojika, M. J. Antibiot. 2006, 59, 385.
(b) Ojika, M.; Inukai, Y.; Kito, Y.; Hirata, M.; Iisuka, T.;
Fudou, R. Chem. Asian J. 2008, 3, 126.
(4) (a) Bolhofer, W. A. J. Am. Chem. Soc. 1952, 74, 5459.
(b) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J.
J. Chem. Soc., Perkin Trans. 1 1998, 591.
(5) Suzuki, M.; Iwasaki, T.; Miyashi, M.; Okumura, K.;
Matsumoto, K. J. Org. Chem. 1973, 33, 3571.
(6) (a) Harding, K. E.; Moreno, L. N.; Nace, V. M. J. Org.
Chem. 1981, 46, 2809. (b) Bosmans, J. P.; Van der Eycken,
J.; Vandewalle, M. Tetrahedron Lett. 1989, 30, 3877.
(c) Vishwakarma, R. A.; Balachandran, S.; Alanine, A. I. D.;
Stamford, N. P. J.; Kiuchi, F.; Leeper, F. J.; Battersby, A. R.
J. Chem. Soc., Perkin Trans. 1 1993, 2893.
Anal. Calcd for C12H18F3NO4 (297.27): C, 48.48; H, 6.10; N, 4.71.
Found: C, 48.53; H, 5.95; N, 4.79.
tert-Butyl 2-(Trifluoroacetamido)-3-adamantyl-3-oxopro-
panoate (14)
According to the general procedure, TFA-Gly-Ot-Bu (227 mg, 1.00
mmol) and LHMDS (518 mg, 3.10 mmol) were reacted with ada-
mantyl chloride(219 mg, 1.10 mmol) to give 14, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a colorless solid;
yield: 248 mg (0.68 mmol, 67%); mp 104–105 °C.
1H NMR (400 MHz, CDCl3): d = 7.27 (br s, 1 H), 5.56 (d, J = 7.9
Hz, 1 H), 2.07–2.08 (m, 3 H), 1.87–1.97 (m, 6 H), 1.68–1.77 (m, 6
H), 1.46 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 206.3, 164.5, 156.2 (q, J = 38.6
Hz), 115.2 (q, J = 286 Hz), 85.1, 56.1, 47.4, 38.1, 36.4, 27.9.
Anal. Calcd for C19H26F3NO4 (389.41): C, 58.60; H, 6.73; N, 3.60.
Found: C, 58.22; H, 6.62; N, 3.59.
(7) Singh, J.; Gordon, P. T. D.; Earley, W. G.; Morgan, B. A.
Tetrahedron Lett. 1993, 34, 211.
(8) Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39,
5537.
tert-Butyl 2-(Trifluoroacetamido)-3-cyclohexyl-3-oxopro-
panoate (15)
According to the general procedure, TFA-Gly-Ot-Bu (227 mg, 1.00
mmol) and LHMDS (518 mg, 3.10 mmol) were reacted with cyclo-
hexanecarbonyl chloride(161 mg, 1.10 mmol) to give 15, after flash
chromatography (silica gel, hexanes–EtOAc, 10:1), as a colorless
solid; yield: 248 mg (0.68 mmol, 67%); mp 69–70 °C.
(9) Misaki, T.; Nagase, R.; Matsumoto, K.; Tanabe, Y. J. Am.
Chem. Soc. 2005, 127, 2854.
(10) Schmidt, U.; Griesser, H.; Lieberknecht, A.; Schmidt, J.;
Gräther, T. Synthesis 1993, 765.
1H NMR (400 MHz, CDCl3): d = 7.43 (br s, 1 H), 5.22 (d, J = 6.5
Hz, 1 H), 2.87 (m, 1 H), 1.49 (s, 9 H), 1.58–2.06 (m, 6 H), 1.28–1.34
(m, 4 H).
13C NMR (100 MHz, CDCl3): d = 203.3, 164.1, 157.6 (q, J = 38.6
Hz), 112.6 (q, J = 284 Hz), 85.8, 62.4, 49.5, 30.1, 28.5, 26.3, 25.9.
HRMS (CI): m/z calcd for C11H13F3NO3 [M – t-BuO]+: 264.0842;
found: 264.0804.
(11) (a) Kazmaier, U. J. Org. Chem. 1996, 61, 3694.
(b) Kazmaier, U.; Maier, S. Tetrahedron 1996, 52, 941.
(c) Kazmaier, U.; Schneider, C. Synthesis 1998, 1321.
(d) Kazmaier, U.; Schneider, C. Tetrahedron Lett. 1998, 39,
817. (e) Krebs, A.; Kazmaier, U. Tetrahedron Lett. 1996, 37,
7945.
(12) (a) Pohlman, M.; Kazmaier, U. Org. Lett. 2003, 5, 2631.
(b) Mendler, B.; Kazmaier, U. Org. Lett. 2005, 7, 1715.
(c) Lukas, S.; Kazmaier, U. Synlett 2006, 255. (d) Schmidt,
C.; Kazmaier, U. Eur. J. Org. Chem. 2008, 887.
(13) (a) Kazmaier, U.; Lindner, T. Angew. Chem. Int. Ed. 2005,
44, 3303; Angew. Chem. 2005, 117, 3368. (b) Kazmaier, U.
Curr. Org. Chem. 2003, 7, 317. (c) Kazmaier, U.; Pohlman,
M. Synlett 2004, 623. (d) Kazmaier, U.; Stolz, D. Angew.
Chem. Int. Ed. 2006, 45, 3072; Angew. Chem. 2006, 118,
3143. (e) Bayer, A.; Kazmaier, U. Org. Lett. 2010, 12, 4960.
(14) Grandel, R.; Kazmaier, U.; Rominger, F. J. Org. Chem.
1998, 63, 4524.
Anal. Calcd for C15H22F3NO4 (337.33): C, 53.41; H, 6.57; N, 4.15.
Found: C, 53.33; H, 6.41; N, 4.15.
1-tert-Butyl 3-Ethyl 2-(Trifluoroacetamido)malonate (16)
According to the general procedure, TFA-Gly-Ot-Bu (227 mg, 1.00
mmol) and LHMDS (518 mg, 3.10 mmol) were reacted with ethyl
chloroformate (187 mg, 1.10 mmol) to give 16, after flash chroma-
tography (silica gel, hexanes–EtOAc, 10:1), as a pale yellow oil;
yield: 222 mg (0.78 mmol, 78%).
1H NMR (400 MHz, CDCl3): d = 7.26 (br s, 1 H), 5.01 (d, J = 6.8
Hz, 1 H), 4.35 (dq, J = 7.2, 7.2 Hz, 1 H), 4.26 (dq, J = 7.2, 7.2 Hz, 1
H), 1.49 (s, 9 H), 1.32 (t, J = 7.1 Hz, 3 H).
(15) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Laboroi, F.;
Mazzanti, G.; Ricci, A.; Varchi, G. J. Org. Chem. 1999, 64,
8008.
Synthesis 2012, 44, 600–604
© Thieme Stuttgart · New York