A straightforward approach towards isoxazoline amino acid esters by domino michael additions/nitrile oxide cycloadditions

Article abstract of DOI:10.1002/ejoc.201100233

The syntheses of new heterocyclic isoxazoline amino acids are described based on a domino Michael addition/nitrile oxide formation/[3+2] cycloaddition approach. Chelated amino acid ester enolates can be added to nitroalkenes, and the generated nitronates

Full text of DOI:10.1002/ejoc.201100233

FULL PAPER
DOI: 10.1002/ejoc.201100233
A Straightforward Approach towards Isoxazoline Amino Acid Esters by
Domino Michael Additions/Nitrile Oxide Cycloadditions
Lisa Wirtz[a] and Uli Kazmaier*[a]
Keywords: Amino acids / Chelated enolates / Cycloaddition / Isoxazolines / Michael addition / Nitrile oxides
The syntheses of new heterocyclic isoxazoline amino acids
are described based on a domino Michael addition/nitrile ox-
ide formation/[3+2] cycloaddition approach. Chelated amino
acid ester enolates can be added to nitroalkenes, and the
generated nitronates are directly converted into nitrile ox-
ides. These can be trapped intramolecularly by an alkene as
a dipolarophile. The alkene can be introduced either via the
nitroalkene or via the chelated enolate. Therefore, different
types of heterocyclic amino acids can be obtained in a simple
one-pot protocol.
Our group is involved in amino acid synthesis, investiga-
ting reactions of chelated amino acid ester enolates A.[16]
These enolates are easily obtained by double deprotonation
of amino acid esters in the presence of a metal salt such as
ZnCl2 or SnCl2 (Scheme 1).
Introduction
Isoxazolines are an interesting class of N,O-heterocycles
not only found as a core structure in a wide range of biolo-
gically active compounds, but also as synthetic intermedi-
ates.[1] Several 1,3-bifunctional compounds such as β-hy-
droxy ketones, α,β-unsaturated ketones or γ-amino acids
can be generated from these heterocycles.[2] According to
Huisgen et al., isoxazolines are easily available by 1,3-di-
polar cycloadditions of nitrile oxides to alkenes.[3] The ni-
trile oxides required are accessible either from oximes by
oxidation[4] or from nitro compounds by dehydration.[5]
They are highly reactive species, undergoing rapid additions
to alkenes, alkynes or carbonyl groups,[6] but the high reac-
tivity also results in the formation of a wide range of side
products.[7] Therefore, generation of nitrile oxides directly
in the presence of dipolarophiles is recommended, and the
dipolarophiles should also be used in excess. Not surpris-
ingly, sufficiently good results are obtained in intramolecu-
lar nitrile oxide cycloadditions (INOC), which makes this
approach interesting for natural-product and drug synthe-
sis.[8]
Nitroalkenes are especially interesting nitrile oxide pre-
cursors. The electron-poor double bond of nitroalkenes is
an excellent Michael acceptor, allowing the introduction of
a dipolarophile by Michael addition. The nitronate formed
in situ can be treated with dehydrating agents such as
phenyl isocyanate[9] or chloroformates[10] to generate the re-
active nitrile oxide, which undergoes an INOC.[11] Fre-
quently used nucleophiles are allyl alcohols,[12] allyl thi-
ols,[13] allylamine derivatives[14] as well as α-allylated malon-
ates.[15]
Scheme 1. Michael additions of chelated enolates to nitroalkenes.
They can undergo Claisen rearrangements when allylic
esters are used,[17] and they are suitable nucleophiles in al-
lylic alkylations[18] and Michael additions,[19] including
Michael-induced ring closing reactions (MIRC).[20] Nitro-
alkenes are excellent acceptors for these chelated enolates
A, and give access to a wide range of products, depending
on the reaction and workup conditions (Scheme 1). If the
nitronates B formed in situ are hydrolyzed, the expected
Michael addition products C are formed in good yields and
reasonably good diastereoselectivities (depending on the
metal salt used for chelation).[21] On the other hand, if ni-
[a] Institute for Organic Chemistry, Saarland University,
P. O. Box 151150, 66041 Saarbrücken, Germany
Fax: +49-681-302-2409
E-mail: u.kazmaier@mx.uni-saarland.de
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L. Wirtz, U. Kazmaier
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tronates B, obtained in the reaction of the zinc enolates, are
With this Michael acceptor in hand we first investigated
trapped with an excess of acyl halides or chloroformates, the Michael addition to optimize the initial step of the reac-
the deprotonated amides undergo cyclization with the tion. Under standard reaction conditions, with LHMDS as
iminooxazines D.[22] In contrast, if SnCl2 is used as a chelat- a base, the addition product 3 was obtained after 2 h at
ing metal salt, the formation of nitriles E is observed.[23] –78 °C in excellent yield (Scheme 3). Other amide bases
Shimizu reported, that nitronates can be converted into ni- such as LDA (89%) and lithium 2,2,4,4-tetramethylpiperid-
trile oxides by using chloroformates.[10] In our case, the ni- ide (LTMP, 94%) gave comparable results. Out of the four
trile oxide formed in situ is either reduced by Sn2+ or is possible stereoisomers, two were formed preferentially
intramolecularly attacked by the deprotonated TFA amide. (85%) as a 1:1 diastereomeric mixture. Based on our pre-
vious observations,[21] we assumed that the 85:15 ratio cor-
responded to the simple diastereoselectivity (syn/anti), and
that the induced diastereoselectivity could be neglected.
Results and Discussion
These observations inspired the idea to combine a che-
lated enolate Michael addition with an in situ nitrile oxide
formation/[3+2] cycloaddition to obtain access to isoxaz-
oline amino acids. To be able to generate different types of
amino acids, we decided to incorporate the dipolarophile in
both the nitroalkene and the chelated enolate. Therefore, we
synthesized nitroalkene 2 from O-allylated ethyl lactate[24]
by DIBALH reduction, Henry reaction and subsequent eli-
mination with MeSO2Cl/Hünig base (Scheme 2).[25]
Scheme 3. Michael addition to nitroalkene 2.
With these good results in hand, we directly investigated
the Michael addition/cycloaddition tandem process by add-
ing dehydrating agents (Table 1). As a first reagent we used
methyl chloroformate, which gave good results in the
Michael addition/iminooxazine formation.[22] In principle,
1 equiv. of chloroformate should be sufficient to generate
the nitrile oxide, but with 1.2 equiv. only 13% of the ex-
pected [3+2]-cycloaddition product 4 was formed (Entry 1).
The major product was the iminooxazine 5. With a larger
excess of chloroformate, 5 was formed exclusively, albeit in
moderate yield (Entry 2). This clearly indicates that an acyl-
ation of the nitrile oxide is faster than the [3+2] cycload-
dition, and a subsequent intramolecular nucleophilic attack
of the deprotonated amide results in the formation of het-
erocycle 5 according to Scheme 1.
Scheme 2. Synthesis of nitroalkene 2.
Table 1. Domino Michael addition/cycloaddition of nitroalkene 2.
Entry
1
Base
Dehydration agent
Reaction conditions[a]
Yield [%]
LHMDS
1.2 equiv.
ClCOOMe
3.0 equiv.
ClCOOMe
2.2 equiv.
PhNCO
3.0 equiv.
TCT
3.0 equiv.
TCT
3.0 equiv.
TCT
MA: –78 °C, 2 h
CA: –78 °C to r.t., 16 h
MA: –78 °C, 2 h
CA: –78 °C to r.t., 16 h
MA: –78 °C, 2 h
CA: –78 °C to r.t., 16 h
MA: –78 °C, 2 h
CA: –78 °C to r.t., 16 h
MA: –78 °C, 2 h
13 (4), 25 (5)
2
3
4
5
6
7
LHMDS
LHMDS
LHMDS
LHMDS
LDA
40 (5)
traces
72 (4)
69 (4)
91 (4)
94 (4)
CA: –78 °C, 3 h
MA: –78 °C, 2 h
CA: –78 °C, 3 h
MA: –78 °C, 2 h
LTMP
3.0 equiv.
TCT
CA: –78 °C, 3 h
[a] MA: Michael addition; CA: cycloaddition.
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Isoxazoline Amino Acid Esters
The application of phenyl isocyanate, a reagent intro- temperature at –78 °C (Entry 2). Here also, the usage of the
duced by Mukaiyama for nitrile oxide formation (Entry 3) corresponding zinc enolate proved to be superior (Entries 3
was also not satisfying.[26] So far the best results were ob- and 4). It should be mentioned that in the presence of other
tained by using cyanuric chloride (2,4,6-trichloro-1,3,5-tri- metal salts [SnCl2, Ti(OiPr)4] the yield dropped dramati-
azone, TCT). When the Michael addition was quenched with cally (Ͻ 20%), and LDA and LTMP also led to less
3 equiv. of TCT at –78 °C and the mixture was warmed up satisfying results (31–37% yield).
to room temperature overnight, the expected cycloadduct
was obtained in good yield (Entry 4). At least 3 equiv. of Table 2. Michael addition of N-allylated glycinate to nitrostyrene.
the dehydrating reagent are required; with less than 3 equiv.
the yield dropped dramatically. The nitrile oxide formation
and cycloaddition occur at very low temperature. A com-
parable yield was obtained after 3 h at –78 °C (Entry 5).
Under these conditions, the reaction proceeds without sig-
nificant formation of side products, which were observed at
temperatures above 0 °C. One of the side products results
from a reaction of the cyanuric chloride with the base
LHMDS. To suppress this side reaction, and based on the
good results obtained in the Michael addition with other
bases, we also investigated LDA and LTMP in the one-pot
protocol (Entries 6 and 7). With these bases, the yields
could be increased to above 90%.
Next, we investigated reactions where the dipolarophile
was introduced by the nucleophile, using allylated glycin-
ates. Two different options were considered: the N- and C-
allylglycinates. Both can easily be obtained from N-trifluo-
roacetylated glycinate by Pd-catalyzed allylic alkylation
(Scheme 4). When N-protected tert-butyl glycinate was
treated with allyl carbonate in the presence of allylpalla-
dium chloride/PPh3, the N-allylated product was obtained
in almost quantitative yield. During the π-allyl complex for-
mation methylate is liberated, which deprotonates the rather
acidic trifluoroamide, generating the actual nucleophile that
undergoes allylation.[27] On the other hand, if the TFA gly-
cinate was first converted into the chelated enolate A, the
corresponding C-allylation product was formed exclusively
in comparable yield. Here, chelation results in a protection
of the TFA amide, and allylation occurs only at the enol-
ate.[28]
Entry
(ZnCl2)
Reaction conditions
Yield [%]
1
2
3
4
–
–
–78 °C to r.t., 16 h
–78 °C, 2 h
–78 °C to r.t., 16 h
–78 °C, 2 h
43
50
68
65
ZnCl2
ZnCl2
Therefore, we focused our investigations of the domino
process on the lithium and zinc enolates, generated with
LHMDS as base (Table 3). Also, the use of chloroformate
here provided only traces of the cycloaddition product.
However, with TCT, both the lithium and the zinc enolates
gave rise to the required bicyclic amino acid derivative 7 in
acceptable yield. No significant influence of the reaction
temperature was observed, thus the yields obtained after
2 h at –78 °C were comparable to reactions, where the tem-
perature was allowed to rise to room temperature overnight.
Table 3. Domino Michael addition/cycloaddition of N-allylated
glycinate.
Entry
1
(ZnCl2)
–
Reaction conditions
Yield [%]
46
MA: –78 °C to r.t., 16 h
CA: –78 °C to r.t., 16 h
MA: –78 °C to r.t., 16 h
CA: –78 °C to r.t., 16 h
MA: –78 °C, 2 h
2
3
4
ZnCl2
–
41
48
44
CA: –78 °C, 2 h
MA: –78 °C, 2 h
ZnCl2
CA: –78 °C, 2 h
Next we examined the C-allylated glycine derivative
(Table 4). Deprotonation of amino acid esters other than
Scheme 4. Preparation of N- and C-allylated glycinates.
With these glycine esters in hand, we first investigated glycine esters can be a serious problem, especially with
the Michael addition using the N-allyl derivative (Table 2). LHMDS.[29] Therefore, we prolonged the enolate formation
With this pronucleophile no chelate complex formation time from 10 min to 2 h to obtain reasonable yields of the
should be possible, and therefore we first checked the reac- Michael addition product 8. The Li enolate (Entry 1) gave a
tion of the corresponding lithium enolate. The Michael ad- slightly better yield compared to the zinc enolate (Entry 2).
dition product 6 was obtained in moderate yield (Entry 1). Interestingly, no addition product was obtained with the
The yield could slightly be increased by keeping the reaction corresponding tin enolate. By using stronger bases such as
Eur. J. Org. Chem. 2011, 3467–3473
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L. Wirtz, U. Kazmaier
FULL PAPER
LDA or LTMP, the enolate formation time could be re-
duced to 10 min, and the yields, especially with the zinc
enolate, increased significantly (Entries 3, 4 and 5).
Experimental Section
General Remarks: Reactions with dry solvents were carried out in
oven-dried glassware (100 °C) under nitrogen. Solvents were dried
as follows: THF was distilled from LiAlH4 and CH2Cl2 from CaH2.
The products were purified by flash chromatography on silica gel
(0.063–0.2 mm). Mixtures of ethyl acetate (EtOAc) and hexanes
were generally used as eluents. Analysis by TLC was carried out
on commercially precoated Polygram SIL-G/UV 254 plates (Mach-
erey-Nagel, Dueren). Visualization was accomplished with UV
light or KMnO4 solution. 1H and 13C NMR spectra were obtained
at room temperature with a Bruker AV 400 spectrometer. Chemical
shifts are expressed in ppm relative to internal solvent. The dia-
stereomeric ratios were determined by 1H NMR spectra of the dia-
stereomeric mixture. Selected signals for the minor isomers were
extracted from the spectra of the isomeric mixture. Melting points
were determined with a MEL-TEMP II apparatus. High-resolution
mass spectra were recorded with a Finnigan MAT 95Q by using
the CI technique. Elemental analyses were performed with a Leco
CHN900.
Table 4. Michael addition of C-allylated glycinate to nitrostyrene.
Entry
Base
(ZnCl2) Reaction conditions Yield [%]
1
2
3
4
5
LHMDS[a]
LHMDS[a]
LDA
LDA
LTMP
–
–78 °C to r.t., 16 h
–78 °C to r.t., 16 h
–78 °C, 2 h
65
56
58
79
95
ZnCl2
–
ZnCl2
ZnCl2
–78 °C, 2 h
–78 °C, 2 h
[a] Enolate formation time: 2 h.
3-Allyloxy-1-nitrobutan-2-ol (1): A solution of DIBALH in hexane
(1 m, 7.50 mL, 7.50 mmol) was added dropwise at –78 °C to a solu-
tion of O-allylated ethyl lactate (1.08 g, 6.81 mmol) in dry dichloro-
methane (14 mL). After stirring the reaction mixture at –78 °C for
2 h, it was poured into a mixture of 10% aqueous tartaric acid
(33 mL) and dichloromethane (14 mL). After vigorous stirring for
30 min and separation of the layers, the aqueous layer was ex-
tracted three times with Et2O. The combined organic layers were
dried with Na2SO4 and concentrated. The crude product was dis-
solved in dry isopropyl alcohol (15 mL) and benzene (2 mL). Nitro-
methane (1.80 mL, 34.0 mmol) and potassium fluoride (67.0 mg,
34.0 mmol) were added, and the reaction mixture was stirred over-
night. After filtration through Celite, the solvent was removed in
vacuo, and the crude product was purified by flash chromatography
(hexane/EtOAc, 9:1) to yield 1 (1.05 g, 5.99 mmol, 88%) as a yellow
Under these optimized conditions, we investigated the
one-pot process using TCT as the dehydrating agent
(Table 5). With LHMDS, the yields obtained were in the
range of 40%, independent of whether the Li or Zn enolate
was used (Entries 1 and 2). With the use of stronger bases
the yield could be increased (Entries 3 and 4). In this case,
LDA gave the best results.
Table 5. Domino Michael addition/cycloaddition of C-allylated
glycinate.
1
oil. Rf = 0.17 (hexane/EtOAc, 8:2). H NMR (400 MHz, CDCl3):
3
δ = 1.22 (d, J4,3 = 6.3 Hz, 3 H, 4-H), 2.74 (br. s, 1 H, OH), 3.57
(m, 1 H, 3-H), 3.92 (m, 1 H, 5-H), 4.12 (m, 1 H, 5Ј-H), 4.23 (m, 1
H, 2-H), 4.50 (dd, 2J1,1Ј = 19.7, 3J1,2 = 9.6 Hz, 1 H, 1-H), 4.60 (dd,
3
3
2J1Ј,1 = 13.2, J1Ј,2 = 2.8 Hz, 1 H, 1Ј-H), 5.21 (ddt, J7E,6 = 10.3,
Entry
1
Base
LHMDS[a]
(ZnCl2) Reaction conditions Yield [%]
2J7E,7Z
=
4J7E,5 = 1.3 Hz, 1 H, 7-HE), 5.27 (ddt, J7Z,6 = 17.3,
3
2J7Z,7E = 4J7Z,5 = 1.3 Hz, 1 H, 7-HZ), 5.87 (m, 1 H, 6-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 15.5 (q, C-4), 69.9 (t, C-5), 71.6 (d,
C-2), 75.2 (d, C-3), 77.6 (t, C-1), 117.5 (t, C-7), 134.2 (d, C-6) ppm.
C7H13NO4 (175.18): calcd. C 47.99, H 7.48, N 8.00; found C 47.98,
H 7.41, N 7.60. HRMS (CI): calcd. for C7H13NO4 [M]+ 175.0845;
found 175.0857.
–
MA: –78 °C, 2 h
CA: –78 °C, 3 h
MA: –78 °C, 2 h
CA: –78 °C, 3 h
MA: –78 °C, 2 h
CA: –78 °C, 3 h
MA: –78 °C, 2 h
CA: –78 °C, 3 h
40
38
76
54
2
3
4
LHMDS[a]
LDA
ZnCl2
ZnCl2
ZnCl2
LTMP
3-Allyloxy-1-nitrobut-1-ene (2): Methanesulfonyl chloride (1.67 g,
14.6 mmol) was added at –78 °C to a solution of 1 (2.14 g,
12.2 mmol) in dry dichloromethane (120 mL). After stirring the re-
action mixture at –78 °C for 10 min, Hünig base (5.18 mL,
30.5 mmol) was added dropwise, and the mixture was warmed to
room temperature overnight. The reaction mixture was washed
with water, 2 n hydrochloric acid and saturated aqueous ammo-
nium chloride, dried with Na2SO4 and concentrated. The crude
product was purified by flash chromatography (hexane/EtOAc, 9:1)
[a] Enolate formation time: 2 h.
Conclusions
We have shown that the domino process Michael ad-
dition/nitrile oxide formation/intramolecular [3+2] cycload-
dition is a straightforward approach towards unusual cyclic
and bicyclic amino acids. The dipolarophile required for the
last step of the sequence can be introduced either via the
Michael acceptor or via the nucleophile, giving rise to dif-
ferent classes of heterocyclic amino acids, which might be
interesting scaffolds for drug-like molecules.
to yield 2 (1.08 g, 6.86 mmol, 58%) as a yellow oil. Rf = 0.50 (hex-
3
ane/EtOAc, 8:2). 1H NMR (400 MHz, CDCl3): δ = 1.36 (d, J4,3
=
3
6.6 Hz, 3 H, 4-H), 4.01 (d, J5,6 = 5.6 Hz, 2 H, 5-H), 4.23 (m, 1 H,
3-H), 5.21 (ddt, 3J7E,6 = 10.4, 2J7E,7Z = 4J7E,5 = 1.5 Hz, 1 H, 7-HE),
5.29 (ddt, J7Z,6 = 17.3, J7Z,7E = 4J7Z,5 = 1.5 Hz, 1 H, 7-HZ), 5.88
(m, 1 H, 6-H), 7.15 (m, 2 H, 1-H, 2-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.1 (q, C-4), 70.1 (t, C-5), 71.0 (d, C-3), 117.5 (t, C-
3
2
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Isoxazoline Amino Acid Esters
7), 134.0 (d, C-6), 139.4 (d, C-1), 143.0 (d, C-2) ppm. C7H11NO3 (m, 3 H, 15Ј-H, 5-H), 5.61 (m, 1 H, 4-H), 7.26 (m, 5 H, 12-H, 13-
(157.17): calcd. C 53.49, H 7.05, N 8.91; found C 53.19, H 6.78,
N 8.64. HRMS (CI): calcd. for C7H11NO3 [M]+ 157.0739; found
157.0748.
H, 14-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.8 (q, C-9),
42.7 (d, C-10), 52.7 (t, C-3), 61.7 (d, C-6), 77.8 (t, C-15), 83.7 (s,
C-8), 114.4 (s, C-1), 120.7 (t, C-5), 128.1 (d, C-12/C-13/C-14), 128.6
(d, C-12/C-13/C-14), 129.0 (d, C-12/C-13/C-14), 131.7 (d, C-4),
135.8 (s, C-11), C-2 signal not visible, 166.9 (s, C-7) ppm.
C19H23F3N2O5 (416.39): calcd. C 54.80, H 5.57, N 6.73; found C
55.13, H 5.58, N 7.11. HRMS (CI): calcd. for C15H16F3N2O5 [M –
tBu + H]+ 361.1011; found 361.1025.
General Procedure for the Michael Additions: In a Schlenk tube,
HMDS/TMP or DIPA (0.94 mmol, 3.13 equiv.) was dissolved in
dry THF (1 mL). After the solution had been cooled to –78 °C, n-
butyllithium in hexane (1.6 m, 0.75 mmol, 2.50 equiv.) was added
slowly. The cooling bath was removed, and the solution was stirred
for 10 min. In
a
second Schlenk flask, ZnCl2 (0.33 mmol,
tert-Butyl-2-(2-nitro-1-phenylethyl)-2-(2,2,2-trifluoroacetamido)-
pent-4-enoate (8): According to the general Michael addition pro-
cedure, C-Allyl-Tfa-Gly-OtBu (88.0 mg, 0.33 mmol, 1.10 equiv.)
and (E)-β-nitrostyrene (45.0 mg, 0.30 mmol, 1.00 equiv.) were al-
lowed to react in the presence of ZnCl2 (45.0 mg, 0.33 mmol,
1.10 equiv.) to give a pale yellow oil (101 mg, 0.29 mmol, 95%); Rf
= 0.10 (hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ = 1.60
(s, 9 H, 6-H), 2.75 (dd, 2J7,7Ј = 13.7, 3J7,8 = 6.8 Hz, 1 H, 7-H), 3.42
1.10 equiv.) was dried with a heat gun under vacuum before it was
dissolved in dry THF (1 mL). After the solution had been cooled
to room temperature, Tfa-Gly-OtBu (0.33 mmol, 1.10 equiv.) was
added. The freshly prepared LHMDS solution was cooled again to
–78 °C before the Tfa-Gly-OtBu/ZnCl2 solution was added drop-
wise. This solution was stirred at –78 °C for 30 min. At the same
time, a solution of the nitro olefin (0.30 mmol, 1 equiv.) was pre-
pared in THF (0.30 mL). The nitro olefin solution was added to
the enolate at –78 °C. The reaction mixture was stirred at –78 °C
for 2 h before it was diluted with ethyl acetate and hydrolyzed with
1 m aqueous potassium bisulfate. The layers were separated, and
the aqueous layer was extracted three times with ethyl acetate. The
combined organic layers were dried with Na2SO4, the solvent was
evaporated in vacuo, and the crude product was purified by flash
chromatography (silica gel, hexane/EtOAc).
2
3
3
(dd, J7,7Ј = 13.7, J7Ј,8 = 6.8 Hz, 1 H, 7Ј-H), 4.68 (dd, J10,11Ј
=
3
9.8, J10,11 = 5.4 Hz, 1 H, 10-H), 5.14 (m, 4 H, 9-H, 11-H), 5.48
(m, 1 H, 8-H), 7.01 (br. s, 1 H, NH), 7.23 (m, 5 H, 13-H, 14-H,
15-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.0 (q, C-6), 37.8
(t, C-7), 47.0 (d, C-10), 66.4 (s, C-3), 76.6 (t, C-11), 86.2 (s, C-5),
C-1 signal not visible, 121.8 (t, C-9), 128.9 (d, C-13/C-14/C-15),
128.9 (d, C-13/C-14/C-15), 129.0 (d, C-13/C-14/C-15), 129.5 (d, C-
8), 134.4 (s, C-12), 156.1 (s, C-2), 168.7 (s, C-4) ppm.
C
19H23F3N2O5 (416.39): calcd. C 54.80, H 5.57, N 6.73; found
tert-Butyl-4-(allyloxy)-3-(nitromethyl)-2-(2,2,2-trifluoroacet-
amido)pentanoate (3): According to the general Michael addition
procedure, Tfa-Gly-OtBu (75.0 mg, 0.33 mmol, 1.10 equiv.) and ni-
tro olefin 2 (47.0 mg, 0.30 mmol, 1.00 equiv.) were allowed to react
C 55.04, H 5.46, N 6.73. HRMS (CI): calcd. for C19H24F3N2O5 [M
+ H]+ 417.1638; found 417.1606.
General Procedure for the Domino Michael Additions/Cycload-
in the presence of ZnCl2 (45.0 mg, 0.33 mmol, 1.10 equiv.) to give ditions: The Michael addition product was generated as shown in
a pale yellow oil (108 mg, 0.28 mmol, 94%); Rf = 0.13 (hexane/ the general procedure for the Michael additions. After the Michael
EtOAc, 9:1). Major diastereomers (85 %): 1H NMR (400 MHz, addition was complete (–78 °C, 2 h), cyanuric chloride (0.90 mmol,
3
CDCl3): δ = 1.25 (d, J10,9 = 6.3 Hz, 3 H, 10-H), 1.48 (s, 9 H, 6-
3.00 equiv.) in dry THF (0.50 mL) was slowly added over 15 min.
The reaction mixture was stirred at –78 °C for 3 h before it was
diluted with ethyl acetate and hydrolyzed with 1 m aqueous potas-
H), 2.91 and 3.05 (m, 1 H, 9-H), 3.70 (m, 1 H, 8-H), 3.83 (ddt,
2J11,11Ј = 12.5, J11,12 = 6.4, J11,13 = 1.2 Hz, 1 H, 11-H), 4.01 and
3
4
2
3
4
4.10 (ddt, J11Ј,11 = 12.5, J11Ј,12 = 6.4, J11Ј,13 = 1.2 Hz, 1 H, 11Ј- sium bisulfate. The layers were separated, and the aqueous layer
H), 4.63 (m, 3 H, 8Ј-H, 3-H, 7-H), 5.21 (m, 1 H, 13-H), 5.83 (m, 1
H, 12-H), 7.32 and 7.69 (br. s, 1 H, NH) ppm; 13C NMR
(100 MHz, CDCl3): δ = 16.9 and 17.0 (q, C-10), 27.9 and 28.0 (q,
C-6), 44.4 and 44.7 (d, C-3/C-7), 53.4 and 54.6 (d, C-3/C-7), 69.7
and 70.1 (t, C-8), 72.4 (d, C-9/t, C-11), 72.5 (d, C-9/t, C-11), 84.1
and 84.7 (s, C-5), C-1 not visible, 118.0 and 119.1 (t, C-13), 133.3
and 133.8 (d, C-12), 157.2 (s, C-2), 167.5 and 167.9 (s, C-4) ppm.
was extracted three times with ethyl acetate. The combined organic
layers were dried with Na2SO4, the solvent was evaporated in
vacuo, and the crude product was purified by flash chromatography
(silica gel, hexane/EtOAc).
tert-Butyl 2-(6-Methyl-3a,4,6,7-tetrahydro-3-H-pyrano[4,3-c]-
isoxazol-7-yl)-2-(2,2,2-trifluoroacetamido)acetate (4): According to
the general Michael addition procedure, Tfa-Gly-OtBu (75.0 mg,
0.33 mmol, 1.10 equiv.) and nitro olefin 2 (47.0 mg, 0.30 mmol,
1.00 equiv.) were allowed to react in the presence of ZnCl2
(45.0 mg, 0.33 mmol, 1.10 equiv.). After the Michael addition, cya-
nuric chloride (166 mg, 0.90 mmol, 3.00 equiv.) was added to yield
a colorless solid (103 mg, 0.28 mmol, 94%); m.p. 94–98 °C; Rf =
1
Minor diastereomers (15%, selected signals): H NMR (400 MHz,
CDCl3): δ = 3.24 (m, 1 H, 9-H), 7.87 (br. s, 1 H, NH) ppm; 13C
NMR (100 MHz, CDCl3): δ = 16.8 (q, C-10), 27.8 (q, C-6), 42.8
(d, C-3/C-7), 52.9 (d, C-3/C-7), 69.6 (t, C-8), 83.8 (s, C-5), 117.9 (t,
C-13), 132.9 (d, C-12), 167.4 (s, C-4) ppm. C15H23F3N2O6 (384.35):
calcd. C 46.87, H 6.03, N 7.29; found C 46.96, H 6.05, N 7.47.
HRMS (CI): calcd. for C15H24F3N2O6 [M + H]+ 385.1586; found
385.1563.
0.43 (hexane/EtOAc, 8:2). Major diastereomers (77%): 1H NMR
2
(400 MHz, CDCl3): δ = 1.39 (m, 12 H, 6-H, 9-H), 3.10 (dd, J7,8
=
3
10.0, J7,3 = 2.9 Hz, 1 H, 7-H), 3.64 (m, 5 H, 10-H, 11-H, 12-H),
3
3
tert-Butyl-2-(N-allyl-2,2,2-trifluoroacetamido)-4-nitro-3-phenyl- 4.40 (m, 1 H, 8-H), 4.69 and 4.93 (dd, J3,NH = 9.7, J3,7 = 2.9 Hz,
butanoate (6): According to the general Michael addition pro- 1 H, 3-H), 7.29 and 7.64 (d, JNH,3 = 9.7 Hz, 1 H, NH) ppm; 13C
3
cedure, N-Allyl-Tfa-Gly-OtBu (88.0 mg, 0.33 mmol, 1.10 equiv.)
and (E)-β-nitrostyrene (45.0 mg, 0.30 mmol, 1.00 equiv.) were al-
lowed to react in the presence of ZnCl2 (45.0 mg, 0.33 mmol,
1.10 equiv.) to give a pale yellow oil (83 mg, 0.20 mmol, 65%); Rf
= 0.15 (hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ = 1.46
(s, 9 H, 9-H), 3.09 (dd, 3J3,3Ј = 16.0, 3J3,4 = 8.2 Hz, 1 H, 3-H), 3.88
NMR (100 MHz, CDCl3): δ = 17.7 and 19.4 (q, C-9), 27.7 and 27.8
(q, C-6), 46.0 (d, C-7), 48.2 (d, C-11), 50.5 (d, C-3), 69.7 (d, C-8),
71.5 (t, C-12), 76.2 (t, C10), 83.8 and 84.0 (s, C-5), C-1 signal not
visible, 152.9 (s, C-13), 157.3 (s, C-2), 167.1 and 168.0 (s, C-4) ppm.
1
Minor diastereomers (23%, selected signals): H NMR (400 MHz,
2
3
CDCl3): δ = 2.94 (dd, J7,8 = 10.0, J7,3 = 2.9 Hz, 1 H, 7-H), 4.87
3
3
3
3
3
3
(dd, J3,3Ј = 16.0, J3,4 = 8.2 Hz, 1 H, 3Ј-H), 4.01 (d, J6,10
=
(dd, J3,NH = 9.7, J3,7 = 2.9 Hz, 1 H, 3-H), 7.01 (d, JNH,3 =
3
3
10.4 Hz, 1 H, 6-H), 4.51 (dt, J10,6 = 10.4, J10,15 = 4.3 Hz, 1 H,
9.7 Hz, 1 H, NH) ppm; 13C NMR (100 MHz, CDCl3): δ = 17.4 (q,
3
3
10-H), 4.92 (dd, J15,15Ј = 13.2, J15,10 = 9.9 Hz, 1 H, 15-H), 5.28
C-9), 27.9 (q, C-6), 84.5 (s, C-5), 167.3 (s, C-4) ppm. C15H21F3N2O5
Eur. J. Org. Chem. 2011, 3467–3473
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3471

L. Wirtz, U. Kazmaier
FULL PAPER
(366.14): calcd. C 49.18, H 5.78, N 7.65; found C 49.16, H 5.78, N
7.80. HRMS (CI): calcd. for C15H22F3N2O5 [M + H]+ 367.1481;
found 367.1510.
and 118.0 (t, C-12), 133.7 and 133.8 (d, C-11), 143.2 and 143.5 (s,
C-2), 149.4 and 151.1 (s, C-13), 153.5 and 153.6 (s, C-14), 166.4
and 166.6 (s, C-4) ppm. Minor diastereomers (11%, selected sig-
1
3
nals): H NMR (400 MHz, CDCl3): δ = 1.23 (d, J9,8 = 6.2 Hz, 3
tert-Butyl
7-Phenyl-5-(2,2,2-trifluoroacetyl)-3,3a,4,5,6,7-hexahy-
3
H, 9-H), 1.49 and 1.52 (s, 9 H, 6-H), 2.82 and 2.88 (dd, J7,8 = 6.7,
droisoxazolo[4,3-c]pyridine-6-carboxylate (7): According to the ge-
neral Michael addition procedure, N-Allyl-Tfa-Gly-OtBu (88.0 mg,
0.33 mmol, 1.10 equiv.) and (E)-β-nitrostyrene (45.0 mg,
0.30 mmol, 1.00 equiv.) were allowed to react in the presence of
ZnCl2 (45.0 mg, 0.33 mmol, 1.10 equiv.). After the Michael ad-
dition, cyanuric chloride (166 mg, 0.90 mmol, 3.00 equiv.) was
added to yield a colorless solid (55 mg, 0.14 mmol, 48%); m.p. 108–
109 °C; Rf = 0.47 (hexane/EtOAc, 8:2). 1H NMR (400 MHz,
CDCl3): δ = 1.22 (s, 9 H, 6-H), 3.46 (m, 1 H, 14-H), 4.30 (m, 5 H,
3J7,3 = 1.2 Hz, 1 H, 7-H), 3.95 (s, 3 H, 15-H), 4. 51 (s, 1 H, 3-H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 27.9 and 28.0 (q, C-6),
43.4 (t, C-10), 52.5 (d, C-8), 54.7 (q, C-15), 56.0 (d, C-3), 69.4 and
71.5 (d, C-8), 73.3 (t, C-10), 82.2 and 83.8 (s, C-5), 108.0 (s, C-1),
117.2 (t, C-12) ppm. C17H23F3N2O7 (410.34): calcd. C 48.11, H
5.46, N 6.60; found C 48.45, H 5.95, N 6.78. HRMS (CI): calcd.
for C17H24F3N2O7 [M + H]+ 425.1536; found 425.1525.
3
7-H, 13-H, 15-H), 5.51 (d, J3,7 = 6.4 Hz, 1 H, 3-H), 7.43 (m, 5 H,
Acknowledgments
9-H, 10-H, 11-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.9 (q,
C-6), 40.8 (t, C-15), 43.6 (d, C-7), 47.8 (q, C-14), 57.1 (d, C-3), 71.0
(t, C-13), 84.4 (s, C-5), 117.6 (s, C-1), 126.5 (d, C-9/C-10/C-11),
127.9 (d, C-9/C-10/C-11), 129.3 (d, C-9/C-10/C-11), 135.4 (s, C-8),
155.7 (s, C-2), 157.3 (s, C-12), 166.5 (s, C-4) ppm. C19H21F3N2O4
(398.15): calcd. C 57.28, H 5.31, N 7.03; found C 57.49, H 5.59, N
6.69. HRMS (CI): calcd. for C19H22F3N2O4 [M + H]+ 399.1532;
found 399.1504.
Financial support by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
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6-Phenyl-5-(2,2,2-trifluoroacetamido)-3a,4,5,6-tetra-
hydro-3H-cylopenta[c]isoxazole-5-carboxylate (9): According to the
general Michael addition procedure, C-Allyl-Tfa-Gly-OtBu
(88.0 mg, 0.33 mmol, 1.10 equiv.) and (E)-β-nitrostyrene (45.0 mg,
0.30 mmol, 1.00 equiv.) were allowed to react in the presence of
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added to yield a colorless solid (91 mg, 0.23 mmol, 76%); m.p. 97–
101 °C; Rf = 0.45 (hexane/EtOAc, 8:2). 1H NMR (400 MHz,
3
3
CDCl3): δ = 1.30 (s, 9 H, 6-H), 2.20 (dd, J7,7Ј = 14.0, J7,8
=
3
3
7.3 Hz, 1 H, 7-H), 2.77 (dd, J7Ј,7 = 14.0, J7Ј,8 = 11.1 Hz, 1 H, 7Ј-
H), 3.94 (dd, J9,8 = 13.0, J9,9Ј = 7.8 Hz, 1 H, 9-H), 4.49 (m, 1 H,
3
3
3
3
8-H), 4.71 (dd, J9Ј,8 = 10.1, J9Ј,9 = 7.8 Hz, 1 H, 9Ј-H), 5.06 (s, 1
H, 11-H), 7.35 (m, 5 H, 13-H, 14-H, 15-H), 7.92 (br. s, 1 H, NH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 27.6 (q, C-6), 36.0 (t, C-
7), 45.9 (d, C-11), 51.3 (d, C-8), 72.3 (s, C-3), 75.3 (t, C-9), 85.7 (s,
C-5), C-1 not visible, 128.4 (d, C-13/C-14/C-15), 128.5 (d, C-13/C-
14/C-15), 129.1 (d, C-13/C-14/C-15), 131.8 (s, C-12), 155.7 (s, C-1),
166.5 (s, C-10), 169.7 (s, C-4) ppm. C19H21F3N2O4 (398.15): calcd.
C 57.28, H 5.31, N 7.03; found C 57.22, H 5.52, N 7.05. HRMS
(CI): calcd. for C15H13F3N2O4 [M – tBuH]+ 342.0827; found
342.0797.
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(400 MHz, CDCl3): δ = 1.27 and 1.30 (d, J9,8 = 6.2 Hz, 3 H, 9-
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