A Meldrum's Acid Based Multicomponent Synthesis of N-Fmoc-isoxazolidin-5-ones: Entry to N-Fmoc-β-amino Acids

Article abstract of DOI:10.1002/ejoc.201700472

A multicomponent Knoevenagel–aza-Michael cyclocondensation (KaMC) reaction starting from Meldrum's acid has been developed with base-sensitive N-Fmoc-hydroxylamine. The reaction takes place under very mild basic conditions, providing a straightforward synthetic route to various unprecedented N-Fmoc-isoxazolidin-5-ones. Subsequent chemoselective reductive cleavage of the N–O bond in the presence of Zn/AcOH allowed a short synthesis of the corresponding N-Fmoc-β-amino acids.

Full text of DOI:10.1002/ejoc.201700472

DOI: 10.1002/ejoc.201700472
Full Paper
Meldrum's Acid
A Meldrum's Acid Based Multicomponent Synthesis of N-Fmoc-
isoxazolidin-5-ones: Entry to N-Fmoc-ꢀ-amino Acids
Alexandra Le Foll Devaux,[a][‡] Emmanuel Deau,[a][‡] Emilie Corrot,[a] Laurent Bischoff,[a]
Vincent Levacher,[a] and Jean-François Brière*[a]
Abstract: A multicomponent Knoevenagel–aza-Michael cyclo- precedented N-Fmoc-isoxazolidin-5-ones. Subsequent chemo-
condensation (KaMC) reaction starting from Meldrum's acid has selective reductive cleavage of the N–O bond in the presence
been developed with base-sensitive N-Fmoc-hydroxylamine. of Zn/AcOH allowed a short synthesis of the corresponding
The reaction takes place under very mild basic conditions, N-Fmoc-ꢀ-amino acids.
providing a straightforward synthetic route to various un-
Introduction
The isoxazolidin-5-one structure is a motif that is present in
biologically active compounds (Scheme 1a),[1] but it has also
been used in building blocks for the synthesis of nucleoside
mimics and aminosugar architectures.[2,3] Most importantly, this
five-membered heterocycle has found significant application as
a readily available precursor of ꢀ-amino acid derivatives, after
the usually facile reductive cleavage of the N–O bond
(Scheme 1a).[4,5] Thus, owing to the importance of the ꢀ-amino
acid motif in naturally occurring molecules and ꢀ-peptides, and
in modern peptidomimetic strategies in medicinal chemistry,
the development of straightforward routes to new isoxazolidin-
5-ones is an appealing goal.[6]
Most synthetic approaches to date have led to the formation
of N-alkyl- (mainly benzyl-) or N-aryl-isoxazolidin-5-ones.[4,7]
Only a handful of examples have described the construction of
isoxazolidinones having an N-alkoxycarbonyl (R2 = CO2R) moi-
ety such as N-Boc or N-Cbz, despite the great utility of these
orthogonal protective functional groups.[4b,4d,8] Córdova, Bode,
Takemoto, and others have carried out one- or two-step synthe-
ses of N-Boc- (tert-butyloxycarbonyl-) or N-Cbz- (benzyloxy-
carbonyl-) -isoxazolidin-5-ones[4d,8] for subsequent transforma-
Scheme 1. Multicomponent KaMC reaction: new objectives and challenges.
tion into ꢀ-amino acid derivatives. On the other hand, Rinehart
achieved the multistep synthesis of an N-Boc-isoxazolidinone,
which was then transformed into ADDA [(2S,3S,4E,6E,8S,9S)-3-
amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoic
acid], a ꢀ-amino acid structure found in numerous cyanobacte-
rial toxins.[4b] In this context,[8b] we have recently described
an unprecedented multicomponent reaction (MCR) for the syn-
thesis of N-Boc- or N-Cbz-isoxazolidin-5-ones 6 and 7 from
the corresponding hydroxylamines
3 and 4, respectively
(Scheme 1b).[9] This approach is based on a Knoevenagel–aza-
Michael cyclocondensation (KaMC) sequence promoted by a
catalytic amount of DABCO (1,4-diazabicyclo[2.2.2]octane) or a
pyrrolidine as an organocatalyst. This MCR was successful with
both aromatic and aliphatic aldehydes 2, thanks to the transient
formation of the highly electrophilic alkylidene Meldrum's acid
intermediates 5, which may be seen as acrylate equivalents.[10]
Historically speaking, the aza-Michael addition reaction of
hydroxylamines to less reactive native acrylates was limited to
electron-rich N-alkyl derivatives (R2-NHOH, R2 = alkyl), which
[a] Normandie Université, INSA Rouen, Université de Rouen, CNRS, COBRA
(UMR 6014),
76000 Rouen, France
E-mail: jean-francois.briere@insa-rouen.fr
http://www.lab-cobra.fr/thematique/lorganocatalyse
[‡] These s contributed equally to this work.
Supporting information and ORCID(s) from the (s) for this article are avail-
able on the WWW under https://doi.org/10.1002/ejoc.201700472.
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led to the formation of the corresponding N-alkylisoxazol-
idinones.[4a,11]
The products 6 and 7, obtained by means of the multicom-
ponent KaMC reaction, were eventually used for the diastereo-
selective synthesis of ꢀ-amino acid derivatives, pyrrolizidines,
and a lactone.[9] At first glance, we hypothesized that this MCR
would be easily extrapolated to N-(9-fluorenylmethyloxy-
carbonyl)- (N-Fmoc-) -hydroxylamine (8), which would open up
a route to the corresponding N-Fmoc heterocycle 9, an N-func-
tionalized isoxazolidin-5-one that has not been reported before
(Scheme 1c). Then, reductive cleavage of the N–O bond would
open up a rapid route to highly valuable N-Fmoc-ꢀ-amino acids
10 with an orthogonal acid-stable protective group, which
could be used in peptide synthesis.[12] However, N-Fmoc deriva-
tives 8 and 9 proved to be tremendously labile to amine bases
and also to standard reductive conditions for N–O bond cleav-
age; this required the development of dedicated reaction condi-
tions. In this paper, we report an innovative development of
the multicomponent KaMC reaction with N-Fmoc-hydroxyl-
amine (8) for the synthesis of N-Fmoc-isoxazolidin-5-ones 9. The
reaction takes advantage of the unique acidity of Meldrum's
acid (pKa = 4.9 in water), which gives rise to the corresponding
soft conjugated base.[10] Furthermore, this work highlights Zn/
AcOH reagents, which allow remarkably chemoselective N–O
bond-cleavage reactions. This approach was compatible with
various functional groups, and this allowed the synthesis of a
range of N-Fmoc-ꢀ-amino acid derivatives, especially those hav-
ing the aliphatic side-chains found in the proteinogenic α-
amino acids.
Scheme 2. Limitations of the base-catalysed conditions with N-Fmoc-hydrox-
ylamine derivatives.
observed, already before the N–O-bond cleavage. The sensitiv-
ity of the N-Fmoc group to reductive conditions has been ob-
served previously,[12a] but this turned out to be a major issue
for isoxazolidinone 9a.
Preliminary investigations using Mo(CO)6 or SmI2 in THF did
not improve the outcome. In summary, the multicomponent
KaMC reaction with N-Fmoc-hydroxylamine (8) was demon-
strated, together with the subsequent reduction of the resulting
isoxazolidinone 9a into N-Fmoc-ꢀ-amino acid 10a. Neverthe-
less, the facile removal of the N-Fmoc group from isoxazol-
idinone 9a and precursor 8 under basic or reductive conditions
precludes any further development without a complete reinves-
tigation.
On this basis, we turned our attention to the optimization of
the KaMC sequence using a catalytic amount of a heterogene-
ous base, Cs2CO3 or K2CO3 (20 mol-%), hoping to minimize the
N-Fmoc deprotection side reaction (Table 1). Pleasingly, by us-
ing these carbonate bases together with a stoichiometric
amount of each component 1, 2a, and 8, the formation of isox-
azolidinone 9a, derived from dihydrocinnamaldehyde (2a), was
observed in good 72–74 % yields (by NMR spectroscopy) at
room temperature (Table 1, Entries 1 and 2). The reaction pro-
ceeded with complete conversion of aldehyde 2a in a relatively
Results and Discussion
Using our previously developed conditions for the synthesis of
N-Boc- and N-Cbz-isoxazolidinone derivatives 6 and 7,[9] Mel-
drum's acid (1), dihydrocinnamaldehyde (2a), and N-Fmoc-
hydroxylamine (8) were mixed in the presence of DABCO
(10 mol-%) at room temperature (Scheme 2). Although alde-
hyde 2a was rapidly consumed, a mixture of N-Fmoc-isoxazolid-
inone 9a and the corresponding NH counterpart 11 was
formed. The base-promoted N-Fmoc deprotection was shown
by the presence of a dibenzofulvene side-product 12, which
could be identified in the 1H NMR spectrum of the crude prod-
uct.
When an isolated sample of N-Fmoc-isoxazolidine 9a was clean fashion as deduced from the NMR spectrum of the crude
subjected to the reaction conditions, complete deprotection to product. When the reaction temperature was raised to 40 °C,
give product 11 took place within 4 h. Similarly, the N-Fmoc- conditions previously required to broaden the scope of the
hydroxylamine (8) underwent a loss of the Fmoc moiety to give multicomponent KaMC reaction with N-Boc-hydroxylamine 3,[9]
the corresponding hydroxylamine (72 % conversion after 4 h). this led to decreased yields of 66 and 47 % with K2CO3 and
Thus, it was clear that these derivatives were incompatible even Cs2CO3, respectively (Table 1, Entries 3 and 4). This is probably
with a soft base such as DABCO. The reductive cleavage of the due to some decomposition events. In the presence of sodium
N–O bond of 9a was also explored. Under standard conditions tert-butoxide (20 mol-%), a good 73 % yield was also obtained
(H2, Pd/C, 50 °C), the desired N-Fmoc-ꢀ-amino acid 10a was after 4 h, although a temperature of 40 °C was required (Table 1,
obtained in addition to the deprotected ꢀ-amino acid 13 Entries 5–7). We reasoned that K2CO3 and tBuOK simply gener-
(Scheme 2). When milder conditions were used (H2, Pd/C, room ated a significant amount of the potassium enolate of Mel-
temp., continuous flow with H-Cube), the incomplete but exclu- drum's acid 14a, which was required to trigger the subsequent
sive formation of NH-isoxazolidin-5-one 11 (9a/11, 50:50) was domino process (Table 1, Entry 8). Accordingly, we carried out
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the reaction with Meldrum's acid anions 14a or 14b (20 mol-
Having established these convenient conditions, we went on
%) at room temperature, and we observed the formation of to explore the scope and limitations of the multicomponent
isoxazolidinone 9a in 72 and 73 % yields, respectively (Table 1, KaMC reaction with various aldehydes 2 together with Mel-
Entries 9 and 10); thus, changing between the potassium and drum's acid (1) (Table 2). The model N-Fmoc substrate 9a was
sodium salts had minimal effect on the result. The same out- formed from dihydrocinnamaldehyde (2a) in 71 % isolated yield
come was observed at 40 °C, despite the presence of N-Fmoc after purification by silica gel column chromatography. By in-
as a base-sensitive functional group (Table 1, Entry 11); this creasing the amount of 1 and 2a from 1.0 to 1.3 equiv., the yield
demonstrates the mildness of these conditions. In our hands, was improved to 86 %. We then focussed on the construction
the addition of a quaternary ammonium salt as a phase-transfer of N-Fmoc-isoxazolidinones 9 with side-chains found in the pro-
catalyst did not result in any significant improvement (Table 1, teinogenic α-amino acids. Accordingly, products with alkyl
Entry 11). Although the dihydrocinnamaldehyde (2a) and Mel- chains 9b–9d (for phenylalanine-, valine-, and leucine-like de-
drum's acid (1) were completely consumed, the crude NMR rivatives, 64–79 % yields), together with those having various
spectrum revealed the presence of small amounts of N-Fmoc- functionalities such as ethers 9e and 9f (for serine-like com-
hydroxylamine (8). Consequently, a reaction was carried out us- pounds, 62–65 % yields), thioether 9g (for a methionine-like
ing 1.3 equiv. of both aldehyde 2a and Meldrum's acid (1), and compound, 52 % yield), a protected guanidine 9h (for an
this gave an improved 91 % yield determined by NMR spectro- arginine-like compound, 46 % yield), and an N-Boc-indole 9i
scopy; a similar outcome was not observed when Meldrum's (for a tryptophan-like compound, 50 % yield) were smoothly
acid (1; 1.3 equiv.) was used as the only component in excess synthesized in moderate to good yields (46–79 %). Interestingly,
(Table 1, Entry 12; 72 % yield by NMR spectroscopy). The MCR isoxazolidinone 9j, an analogue of N-Boc-protected lysine, was
was then evaluated with other solvents, including THF, aceto- easily obtained in 75 % yield from the corresponding piperidin-
nitrile, and toluene, but slightly lower yields were obtained 2-ol derivative 2j as a convenient aldehyde surrogate. Com-
(Table 1, Entries 13–15). Thus, the multicomponent KaMC reac-
tion allows the straightforward construction of N-Fmoc-isox-
azolidinone 9a simply in the presence of Meldrum's acid anion
14b (20 mol-%), very mild reaction conditions indeed.
Table 2. Scope of the multicomponent KaMC reaction with N-Fmoc-hydroxyl-
amine.[a,b]
Table 1. Optimization of the multicomponent KaMC reaction with N-Fmoc-
hydroxylamine.[a]
Entry
Base
Solvent
Temp.
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cs2CO3
K2CO3
Cs2CO3
K2CO3
tBuOK
tBuOK
tBuOK
–
14a
14b
14b
14b
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
THF
r.t.
r.t.
40 °C
40 °C
r.t.
r.t.
40 °C
r.t.
4
4
4
4
4
12
4
4
4
4
72
74
47
66
51
57
73
0
72
r.t.
r.t.
73 (71)[c]
73 (75)[d]
91[e] (72)[f]
67
40 °C
40 °C
40 °C
40 °C
40 °C
4
4
4
4
14b
14b
14b
MeCN
toluene
71
69
[a] Reaction carried out at a concentration of 0.25
M on a 0.5 mmol scale
4
with 1 equiv. of each component 1, 2, and 8, and 0.2 equiv. of the sodium
salt of Meldrum's acid 14b in EtOAc at 40 °C for 12–16 h. [b] Isolated yield
with respect to hydroxylamine 5 after silica gel column chromatography.
[c] Reaction carried out with 1.3 equiv. of aldehyde 2 and 1.3 equiv. of Mel-
drum's acid (1). [d] Reaction carried out with tert-butyl 2-hydroxypiperidine-
1-carboxylate 2j (1 equiv.). [e] Reaction carried out with 1.5 equiv. of alde-
hyde 2 and 1.5 equiv. of Meldrum's acid (1). [f] Reaction carried out for 4 h.
[a] Reaction carried out at a concentration of 0.25
M
on a 0.25 mmol scale
with 1 equiv. of each component and 20 mol-% of base. [b] Yield by NMR
spectroscopy, determined using an internal standard. [c] Isolated yield after
silica gel column chromatography. [d] In the presence of nBu4NBr (10 mol-
%). [e] With 1.3 equiv. of Meldrum's acid (1) and aldehyde 2a. [f] With
1.3 equiv. of Meldrum's acid (1).
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pound 9k, with a cyclopropyl substituent, was formed in 74 % acidic protocol, albeit in lower yield in the latter case, probably
yield. Moreover, a congener bearing a phenyl moiety 9l was due to precipitation issues.
also obtained in 60 % yield. Finally, a diastereoselective se-
Table 4. Scope of the Zn-promoted isoxazolidinone ring-opening reaction.[a,b]
quence was demonstrated starting from Ley's aldehyde 2m that
gave rise to the corresponding product 9m in 75 % yield with
a diastereoisomeric ratio of 85:15.
As mentioned above (Scheme 2), preliminary investigations
revealed that the N-Fmoc protective group on the isoxazolidin-
5-one ring 9 is markedly prone to elimination, even under mild
palladium-catalysed hydrogenolysis conditions. Pleasingly, we
found that zinc-promoted N–O bond cleavage occurred without
affecting the N-Fmoc moiety of the new structure 9a as a model
substrate (Table 3). Optimization of the conditions established
that THF is essential for the proper dissolution of the substrate
in the reaction mixture, leading to complete reaction within 4 h
(Table 3, Entries 1 and 2). Raising the amount of THF in the
solvent mixture to 80 % led to complete conversion of substrate
9a into the desired N-Fmoc-ꢀ-amino acid 10a in 88 % yield by
NMR spectroscopy (Table 3, Entry 3). In an attempt to optimize
the amount of metal by decreasing the amount of zinc to 20
or 10 equiv. resulted in higher degradation rates and decreased
yields of 68 and 75 %, respectively (Table 3, Entries 4 and 5).
Consequently, the conditions given in Table 3, Entry 3 were
used as the optimum conditions for the Zn-assisted reductive
isoxazolidinone ring opening.
Table 3. Optimization of the Zn-promoted N–O bond cleavage.[a,b]
[a] Reaction carried out at 0.05
M on a 0.4–0.5 mmol scale. [b] Isolated yield
with regard to hydroxylamine 5 after workup and precipitation. [c] Required
4.5 h reaction time. [d] Isolated yield after purification by column chromatog-
raphy on silica gel (n-pentane/EtOAc/AcOH, 1:1:0.1). [e] Required 80 equiv. of
activated Zn in a THF/H2O/AcOH (7.2:1:1.8) mixture at 40 °C for 4 h.
Entry
Zn
[equiv.]
Solvent
Temp. Time
Yield
[%][b]
Pleasingly, N-Fmoc-ꢀ-homoarginine 10h was conveniently
synthesized in 83 % yield, with retention of both Boc protective
groups; this demonstrates the mild conditions of the zinc-
assisted ring-opening reaction. Under the same conditions,
thioether 9g underwent a smooth N–O bond cleavage to yield
[°C]
[h]
1
2
3
4
5
40
40
40
20
10
AcOH/H2O (1:1)
40
40
40
40
40
4
4
4
4
4
49 (70)[c]
55 (92)[c]
88 (100)[c]
68 (97)[c]
75 (83)[c]
THF/AcOH/H2O (1:2:2)
THF/AcOH/H2O (8:1:1)
THF/AcOH/H2O (8:1:1)
THF/AcOH/H2O (8:1:1)
1
10g, as shown by H NMR spectroscopic analysis of the crude
[a] Reaction carried out at a concentration of 0.05
M on a 0.2 mmol scale.
product. Unfortunately, significant degradation (most likely
sulfoxide formation, as determined by MS analysis) occurred
before purification, and N-Fmoc-ꢀ-homomethionine 10g was
isolated in only a moderate 47 % yield. To our delight, this re-
ductive protocol could be successfully applied to N-Cbz-isox-
azolidinone 7a, allowing the formation of the corresponding N-
Cbz-ꢀ-amino acid 15 in 79 % yield (Table 4). Interestingly, this
chemoselective approach nicely complements the usual palla-
dium-promoted hydrogenolysis reaction, which would also
cleave the N-Cbz functional group.
[b] Yield by NMR spectroscopy, determined using an internal standard.
[c] Conversion determined by NMR spectroscopy using an internal standard,
based on remaining starting material.
Next, we explored a set of isoxazolidinone substrates 9 in
order to probe the functional-group compatibility of this zinc-
promoted transformation into ꢀ-amino acids 10 (Table 4). The
products were isolated after workup and purification on silica
gel, or a precipitation sequence, to give sufficiently pure com-
pounds. First of all, ꢀ-amino acids 10a–10c, bearing (CH2)2Ph,
benzyl, and phenyl side-chains, were easily synthesized in high
isolated yields ranging from 84 to 95 %. Compound 10d, bear-
ing a cyclopropyl moiety, was also formed in 89 % yield. In
Conclusions
terms of functional-group tolerance, we were pleased to find We have demonstrated that very mild and newly developed
that O-tert-butyldiphenylsilyl (TBDPS) precursor 9e was compat- conditions allow a multicomponent Knoevenagel-aza-Michael
ible with the Zn/AcOH conditions, and gave the corresponding cyclocondensation (KaMC) reaction between Meldrum's acid
ring-opened product 10e in 69 % yield. Importantly, N-Boc de- (1), aldehydes and N-Fmoc-hydroxylamine (8). This results in the
rivatives such as lysine homologue 10f (74 % yield) and trypto- straightforward construction of various N-Fmoc-isoxazolidin-5-
phan homologue 10i (46 % yield) were synthesized by this ones 9, heterocycles that were previously only known as their
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ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 166.1 (Cq), 99.9 (Cq), 62.5
(CH), 26.0 (CH3) ppm.
N-Boc or N-Cbz derivatives. A chemoselective reductive N–O
bond cleavage using Zn/AcOH provided a short route to the
corresponding ꢀ3-amino acids 10 and 15; a wide range of nitro-
gen- or oxygen-containing functional groups were unaffected.
This synthetic strategy involves a multicomponent approach,
and is expected to be useful for the formation of valuable N-
Fmoc-ꢀ3-amino acid derivatives 10. The development of enan-
tioselective variants of this multicomponent process is currently
under investigation.
General Procedure (GP2) for the Synthesis of N-Fmoc-
isoxazolidinones 9a–9m: At room temperature, 14b (16.6 mg,
100 μmol, 20 mol-%) was added in one portion to a stirred suspen-
sion of N-(9-fluorenylmethoxycarbonyloxy)hydroxylamine (8;
128 mg, 0.5 mmol, 1 equiv.), Meldrum's acid (72 mg, 0.5 mmol,
1 equiv.), and the appropriate aldehyde (1 equiv.) in freshly distilled
EtOAc (2 mL). The mixture was heated at 40 °C (preheated oil bath)
for the appropriate amount of time. The solution was warmed to
room temperature, diluted with EtOAc, and washed with a saturated
aqueous solution of sodium hydrogen carbonate. The aqueous layer
was extracted with EtOAc (2 ×). The combined organic layers were
dried with MgSO4, and concentrated in vacuo. The residue was puri-
fied by chromatography on silica gel to give the desired isoxazol-
idinone.
Experimental Section
General Information: Reactions were carried out using oven-dried
glassware under dry argon or nitrogen with freshly distilled or puri-
fied aldehydes. Unless otherwise noted, all reagent-grade chemicals
and solvents were obtained from commercial suppliers, and were
used as received. THF, toluene, MeCN and CH2Cl2 were dried with
an MBRAUN MB SPS-800 apparatus. EtOAc was freshly distilled from
K2CO3. Reactions were monitored by thin-layer chromatography on
silica gel 60 F254 precoated aluminium plates (0.25 mm). Visualiza-
tion was carried out under UV light, or by oxidation with phospho-
molybdic acid or KMnO4. Chromatographic purification of com-
pounds was carried out on silica gel 60 (40–63 μm).[13] Melting
points were measured with a WME Kofler hot-stage (Stuart SMP3).
Infrared spectra (IR) were recorded with a Perkin–Elmer Spectrum
100 Series FTIR spectrometer. Liquids and solids were applied onto
the single-reflection attenuated total reflectance (ATR) accessories.
( )-(9H-Fluoren-9-yl)methyl 5-Oxo-3-phenethylisoxazolidine-2-
carboxylate (9a): Isolated according to GP2 (petroleum ether/
CH2Cl2, 1:9 to 0:1) to give 9a (147 mg, 71 %) as a colourless solid.
M.p. 131–133 °C. 1H NMR (300 MHz, CDCl3): δ = 7.80–7.76 (app d,
J = 7.5 Hz, 2 H), 7.66–7.61 (app t, J = 7.5 Hz, 2 H), 7.46–7.16 (m, 9
H), 4.65 (dd, J = 10.5, 6.9 Hz, 1 H), 4.55 (dd, J = 10.5, 6.9 Hz, 1 H),
4.45 (tdd, J = 8.4, 5.4 Hz, 2.4 Hz, 1 H), 4.30 (app t, J = 6.6 Hz, 1 H),
2.84 (dd, J = 18, 9 Hz, 1 H), 2.77–2.52 (m, 2 H), 2.41 (dd, J = 17.7,
2.4 Hz, 1 H), 2.15–2.03 (m, 1 H), 1.85–1.73 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 173.0 (Cq), 157.4 (Cq), 143.3 (Cq), 143.1 (Cq),
141.5 (Cq), 140.4 (Cq), 128.7 (CH), 128.5 (CH), 128.1 (CH), 127.5 (CH),
127.4 (CH), 126.5 (CH), 125.3 (CH), 125.2 (CH), 120.2 (CH), 69.0 (CH2),
60.4 (CH), 47.0 (CH), 36.0 (CH2), 34.1 (CH2), 31.9 (CH2) ppm. IR (ATR):
Data are reported in cm–1 1H (300 MHz) and 13C (75 MHz) NMR
.
ν = 3024, 2953, 2926, 1802, 1722, 1448, 1314, 1126, 762 cm–1. HRMS:
spectra were recorded with a Bruker Avance 300 spectrometer.
Processing and analysis of the spectra were carried out with the
Topspin 3.5 software from Bruker using a PC workstation. Data are
reported in the following order: chemical shifts in ppm, which were
referenced to the internal solvent signal, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; dd, doublet of doublets, ddd, doublet
of doublets of doublets, dt, doublet of triplets; ddt, doublet of dou-
blets of triplets, td, triplet of doublets; tdd, triplet of doublets of
doublets; m, multiplet, ABq, AB system), coupling constant J in
Hertz, and number of protons. Note: NMR spectroscopic data ob-
tained in CDCl3 are consistent with literature data, but compounds
were also characterized in [D6]DMSO in order to minimize the ap-
pearance of interconverting rotamers. Accurate mass measurements
(HRMS) were carried out by the Mass Spectrometry Laboratory of
the University of Rouen, and were recorded with a Waters LCP 1er
XR spectrometer.
˜
calcd. for [M + NH4]+ C26H27N2O4 431.1964; found 431.1989.
( )-(9H-Fluoren-9-yl)methyl
3-Benzyl-5-oxoisoxazolidine-2-
carboxylate (9b): Isolated according to GP2 (petroleum ether/
CH2Cl2, 1:9 to 0:1) to give 9b (128 mg, 64 %) as a colourless solid.
M.p. 103–105 °C. 1H NMR (300 MHz, CDCl3): δ = 7.76 (app d, J =
7.4 Hz, 2 H), 7.62–7.57 (m, 2 H), 7.47–7.27 (m, 7 H), 7.15–7.06 (m, 2
H), 4.71–4.50 (m, 3 H), 4.27 (app t, J = 6.5 Hz, 1 H), 3.06 (dd, J =
13.8, 6.1 Hz, 1 H), 2.77 (dd, J = 13.8, 8.3 Hz, 1 H), 2.67 (dd, J = 17.9,
8.7 Hz, 1 H), 2.48 (dd, J = 17.9, 2.8 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 172.4 (Cq), 156.7 (Cq), 143.2 (Cq), 143.1 (Cq), 141.4 (Cq),
135.5 (Cq), 129.4 (CH), 128.9 (CH), 128.1 (CH), 127.5 (CH), 127.4 (CH),
127.3 (CH), 125.3 (CH), 125.1 (CH), 120.3 (CH), 120.2 (CH), 68.7 (CH2),
61.4 (CH), 47.0 (CH), 39.7 (CH2), 33.1 (CH2) ppm. IR (ATR): ν = 3064,
˜
3037, 2959, 2921, 2854, 1798, 1728, 1447, 1307, 1125, 763 cm–1
.
HRMS: calcd. for [M + NH4]+ C25H25N2O4 417.1809; found 417.1816.
General Procedure (GP1) for the Synthesis of 14a and 14b: A
freshly prepared solution of NaOEt or KOEt (2.02 mmol, 1.01 equiv.)
in EtOH (8 mL) was added dropwise to a stirred solution of Mel-
drum's acid (288 mg, 2 mmol, 1 equiv.) in EtOH (8 mL) at 0 °C. The
resulting mixture was stirred at 0 °C for 1 h, then it was warmed to
room temperature and stirred at room temperature for 1 h. The
solution was then concentrated in vacuo. The solid residue was
triturated with Et2O, then collected by filtration through a Büchner
funnel to give the desired compound in analytically pure form.
( )-(9H-Fluoren-9-yl)methyl 3-Isopropyl-5-oxoisoxazolidine-2-
carboxylate (9c): Isolated according to GP2 (petroleum ether/
CH2Cl2, 1:9 to 0:1) to give 9c (135 mg, 79 %) as a colourless solid.
M.p. 94–96 °C. 1H NMR (300 MHz, CDCl3): δ = 7.77 (app d, J = 7.5 Hz,
2 H), 7.62 (dd, J = 7.1, 4.1 Hz, 2 H), 7.42 (app t, J = 7.4 Hz, 2 H), 7.33
(app t, J = 7.4 Hz, 2 H), 4.66 (dd, J = 10.5, 6.5 Hz, 1 H), 4.52 (dd, J =
10.5, 6.7 Hz, 1 H), 4.29 (app t, J = 6.6 Hz, 1 H), 4.19–4.09 (m, 1 H),
2.74 (dd, J = 18.0, 9.4 Hz, 1 H), 2.49 (dd, J = 18.0, 2.2 Hz, 1 H), 1.95–
1.71 (m, 1 H), 0.91 (app d, J = 4.9 Hz, 3 H), 0.89 (app d, J = 4.9 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.3 (Cq), 157.5 (Cq), 143.4
(Cq), 143.2 (Cq), 141.5 (Cq), 128.1 (CH), 127.5 (CH), 127.4 (CH), 125.3
(CH), 125.2 (CH), 120.2 (CH), 68.8 (CH2), 65.7 (CH), 47.1 (CH), 31.9
Potassium 2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-olate (14a): Pre-
pared according to GP1 to give 14a (270 mg, 74 %) as an orange
1
solid. H NMR (300 MHz, [D6]DMSO): δ = 3.23 (br. s, 1 H), 1.43 (s, 6
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 165.9 (Cq), 99.6 (Cq), 62.3
(CH), 31.3 (CH2), 18.0 (CH), 17.9 (CH) ppm. IR (ATR): ν = 2966, 1804,
˜
1724, 1447, 1289, 1150, 758, 736 cm–1. HRMS: calcd. for [M + NH4]+
C24H23N2O4 403.1652; found 403.1651.
(CH), 26.0 (CH3) ppm.
Sodium 2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-olate (14b): Pre-
pared according to GP1 to give 14b (276 mg, 83 %) as a pale yellow
( )-(9H-Fluoren-9-yl)methyl
3-Isobutyl-5-oxoisoxazolidine-2-
1
solid. H NMR (300 MHz, [D6]DMSO): δ = 3.25 (s, 1 H), 1.43 (s, 6 H)
carboxylate (9d): Isolated according to GP2 (petroleum ether/
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CH2Cl2, 1:9 to 0:1) to give 9d (137 mg, 75 %) as a colourless solid. 4.43–4.33 (m, 1 H), 4.28 (app t, J = 6.5 Hz, 1 H), 3.51–3.25 (m, 2 H),
M.p. 80–82 °C. 1H NMR (300 MHz, CDCl3): δ = 7.77 (app d, J = 7.4 Hz,
2 H), 7.62 (dd, J = 7.3, 3.8 Hz, 2 H), 7.42 (app t, J = 7.3 Hz, 2 H), 7.33
(app t, J = 7.4 Hz, 2 H), 4.72 (dd, J = 10.6, 6.4 Hz, 1 H), 4.53 (dd, J =
10.6, 6.6 Hz, 1 H), 4.47–4.36 (m, 1 H), 4.28 (app t, J = 6.4 Hz, 1 H),
2.72 (dd, J = 17.6, 8.6 Hz, 1 H), 2.32 (dd, J = 17.6, 1.9 Hz, 1 H), 1.80–
1.58 (m, 2 H), 1.34–1.12 (m, 1 H), 0.89 (app d, J = 6.2 Hz, 3 H), 0.84
(app d, J = 6.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.5
(Cq), 157.6 (Cq), 143.3 (Cq), 143.2 (Cq), 141.5 (Cq), 141.4 (Cq), 128.3
(CH), 127.5 (CH), 127.4 (CH), 125.3 (CH), 125.1 (CH), 120.2 (CH), 120.2
(CH), 68.6 (CH2), 59.4 (CH), 47.1 (CH), 42.9 (CH2), 34.3 (CH2), 24.9
2.83 (dd, J = 17.8, 8.9 Hz, 1 H), 2.40 (dd, J = 17.8, 2.3 Hz, 1 H), 1.82–
1.55 (m, 4 H), 1.50 (s, 18 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
172.9 (Cq), 163.7 (Cq), 157.3 (Cq), 156.4 (Cq), 153.4 (Cq), 143.3 (Cq),
143.1 (Cq), 141.6 (Cq), 141.5 (Cq), 128.2 (CH), 128.1 (CH), 127.5 (CH),
125.3 (CH), 125.2 (CH), 120.3 (CH), 120.2 (CH), 83.4 (Cq), 79.5 (Cq),
68.8 (CH2), 60.4 (CH), 47.0 (CH), 40.0 (CH2), 34.1 (CH2), 31.6 (CH2),
28.5 (CH3), 28.2 (CH3), 25.5 (CH2) ppm. IR (ATR): ν = 3332, 2977,
˜
1807, 1718, 1636, 1614, 1325, 1130, 740 cm–1. HRMS: calcd. for [M
+ H]+ C32H41N4O8 609.2919; found 609.2927.
( )-(9H-Fluoren-9-yl)methyl 3-{[1-(tert-Butoxycarbonyl)-1H-ind-
ol-3-yl]methyl}-5-oxoisoxazolidine-2-carboxylate (9i): Isolated
according to GP2 (petroleum ether/CH2Cl2/EtOAc, 1:9:0 to 0:1:0 to
0:95:5) to give 9i (135 mg, 50 %) as a colourless solid. M.p. 156–
(CH), 22.7 (CH), 21.8 (CH) ppm. IR (ATR): ν = 2960, 1811, 1720, 1448,
˜
1323, 1126, 761 cm–1. HRMS: calcd. for [M + NH4]+ C22H27N2O4
383.1965; found 383.1974.
1
( )-(9H-Fluoren-9-yl)methyl
3-{[(tert-Butyldiphenylsilyl)oxy]-
158 °C. H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 8.0 Hz, 1 H), 7.74
methyl}-5-oxoisoxazolidine-2-carboxylate (9e): Isolated accord-
ing to GP2 (petroleum ether/CH2Cl2, 1:9 to 0:1) to give 9e (179 mg,
62 %) as a colourless solid. M.p. 59–61 °C. 1H NMR (300 MHz, CDCl3):
δ = 7.76 (dd, J = 7.5, 2.6 Hz, 2 H), 7.66–7.56 (m, 6 H), 7.37 (m, 10
H), 4.60–4.50 (m, 2 H), 4.49–4.39 (m, 1 H), 4.28 (app t, J = 7.0 Hz, 1
H), 3.88 (dd, J = 10.9, 3.7 Hz, 1 H), 3.66 (dd, J = 11.0, 3.1 Hz, 1 H),
2.99–2.73 (m, 2 H), 1.06 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
172.4 (Cq), 156.5 (Cq), 143.3 (Cq), 143.2 (Cq), 141.5 (Cq), 141.4 (Cq),
135.8 (CH), 135.7 (CH), 132.8 (Cq), 132.4 (Cq), 130.2 (CH), 130.1 (CH),
128.2 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.5 (CH), 127.4 (CH),
125.4 (CH), 125.3 (CH), 120.3 (CH), 120.2 (CH), 69.1 (CH2), 64.8 (CH2),
60.8 (CH), 46.9 (CH), 31.0 (CH2), 26.8 (CH3), 19.3 (Cq) ppm. IR (ATR):
(dd, J = 7.3, 2.3 Hz, 2 H), 7.59 (dd, J = 7.2, 2.5 Hz, 2 H), 7.50–7.20
(m, 8 H), 4.84–4.72 (m, 1 H), 4.63 (dd, J = 10.5, 6.8 Hz, 1 H), 4.53
(dd, J = 10.5, 6.9 Hz, 1 H), 4.26 (app t, J = 6.8 Hz, 1 H), 3.21 (dd, J =
14.7, 5.5 Hz, 1 H), 2.90 (dd, J = 14.6, 9.0 Hz, 1 H), 2.76 (dd, J = 17.9,
8.6 Hz, 1 H), 2.59 (dd, J = 17.9, 3.0 Hz, 1 H), 1.67 (s, 9 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 172.3 (Cq), 156.8 (Cq), 149.6 (Cq), 143.3
(Cq), 143.1 (Cq), 141.5 (Cq), 141.4 (Cq), 135.6 (Cq), 130.1 (CH), 128.2
(CH), 127.5 (CH), 127.4 (CH), 125.3 (CH), 125.2 (CH), 125.0 (CH), 124.3
(CH), 123.0 (CH), 120.2 (CH), 118.9 (CH), 115.6 (CH), 114.7 (Cq), 84.1
(CH), 69.0 (CH2), 60.1 (CH), 47.0 (CH), 33.6 (CH2), 29.6 (CH2), 28.4
(CH3) ppm. IR (ATR): ν = 3129, 3057, 2977, 2933, 1801, 1723, 1706,
˜
1450, 1393, 1347, 1141, 735 cm–1. HRMS: calcd. for [M + NH4]+
C32H34N3O6 556.2442; found 556.2460.
ν = 3077, 2926, 2857, 1807, 1722, 1316, 1149, 1105, 738, 700 cm–1
.
˜
HRMS: calcd. for [M + H]+ C35H39N2O5Si 595.2623; found 595.2645.
( )-(9H-Fluoren-9-yl)methyl 3-{4-[(tert-Butoxycarbonyl)amino]-
butyl}-5-oxoisoxazolidine-2-carboxylate (9j): Isolated according
( )-(9H-Fluoren-9-yl)methyl
3-[(Benzyloxy)methyl]-5-oxo-
isoxazolidine-2-carboxylate (9f): Isolated according to GP2 (pe- to GP2 (petroleum ether/CH2Cl2, 1:9 to 0:1) to give 9j (180 mg,
troleum ether/CH2Cl2, 1:9 to 0:1) to give 9f (140 mg, 65 %) as a
colourless solid. M.p. 110–112 °C. 1H NMR (300 MHz, CDCl3): δ =
7.77 (app d, J = 7.5 Hz, 2 H), 7.63 (dd, J = 7.2, 4.7 Hz, 2 H), 7.47–
7.27 (m, 9 H), 4.68–4.42 (m, 5 H), 4.29 (app t, J = 7.0 Hz, 1 H), 3.64
(dd, J = 10.0, 4.9 Hz, 1 H), 3.56 (dd, J = 10.1, 3.9 Hz, 1 H), 2.88 (dd,
J = 17.7, 9.0 Hz, 1 H), 2.77 (dd, J = 17.7, 3.2 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.2 (Cq), 156.6 (Cq), 143.3 (Cq), 143.2 (Cq),
141.5 (Cq), 141.4 (Cq), 137.4 (Cq), 128.7 (CH), 128.1 (CH), 127.8 (CH),
127.5 (CH), 127.4 (CH), 125.4 (CH), 125.3 (CH), 120.2 (CH), 73.7 (CH2),
75 %) as a colourless solid. M.p. 84–86 °C. 1H NMR (300 MHz, CDCl3):
δ = 7.77 (app d, J = 7.5 Hz, 2 H), 7.61 (app d, J = 7.2 Hz, 2 H), 7.42
(app t, J = 7.2 Hz, 2 H), 7.38–7.30 (m, 1 H), 4.69 (dd, J = 10.5, 6.4 Hz,
1 H), 4.58–4.43 (m, 2 H), 4.36–4.23 (m, 2 H), 3.13–3.02 (m, 2 H), 2.76
(dd, J = 17.9, 8.8 Hz, 1 H), 2.45–2.31 (m, 1 H), 1.80–1.63 (m, 1 H),
1.56–1.47 (m, 1 H), 1.44 (s, 9 H), 1.43–1.15 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 173.0 (Cq), 157.4 (Cq), 156.1 (Cq), 143.3 (Cq),
143.2 (Cq), 141.5 (Cq), 128.1 (CH), 127.5 (CH), 127.4 (CH), 125.3 (CH),
125.2 (CH), 120.2 (CH), 120.1 (CH), 79.4 (Cq), 68.7 (CH2), 60.5 (CH),
70.0 (CH2), 69.1 (CH2), 59.4 (CH), 46.9 (CH), 31.3 (CH2) ppm. IR (ATR): 47.1 (CH), 40.2 (CH2), 34.0 (CH2), 33.8 (CH2), 29.5 (CH2), 28.6 (CH3),
ν = 3031, 2867, 1805, 1721, 1450, 1318, 1140, 1119, 759, 737 cm–1
.
22.6 (CH2) ppm. IR (ATR): ν = 3380, 2932, 2861, 1805, 1740, 1684,
˜
˜
HRMS: calcd. for [M + NH4]+ C26H27N2O5 447.1914; found 447.1923. 1525, 1450, 1275, 1147, 738 cm–1. HRMS: calcd. for [M + H]+
C27H36N3O6 498.2599; found 498.2607.
( )-(9H-Fluoren-9-yl)methyl
3-[2-(Methylthio)ethyl]-5-oxo-
isoxazolidine-2-carboxylate (9g): Isolated according to GP2 (pe- ( )-(9H-Fluoren-9-yl)methyl 3-Cyclopropyl-5-oxoisoxazolidine-
troleum ether/CH2Cl2, 1:9 to 0:1) to give 9g (123 mg, 64 %) as a
colourless oil. 1H NMR (300 MHz, CDCl3): δ = 7.77 (app d, J = 7.5 Hz,
2 H), 7.62 (app d, J = 7.4 Hz, 2 H), 7.42 (app t, J = 7.4 Hz, 2 H), 7.34
(app t, J = 7.5 Hz, 2 H), 4.65 (dd, J = 10.5, 6.6 Hz, 1 H), 4.60–4.49
(m, 2 H), 4.28 (app t, J = 6.6 Hz, 1 H), 2.84 (dd, J = 17.8, 8.9 Hz, 1
H), 2.59–2.37 (m, 3 H), 2.08 (s, 3 H), 2.05–1.95 (m, 1 H), 1.82–1.66
2-carboxylate (9k): Isolated according to GP2 (petroleum ether/
CH2Cl2, 1:9 to 0:1) to give 9k (129 mg, 74 %) as a colourless solid.
M.p. 90–92 °C. 1H NMR (300 MHz, CDCl3): δ = 7.77 (app d, J = 7.5 Hz,
2 H), 7.62 (app d, J = 7.0 Hz, 2 H), 7.47–7.38 (m, 2 H), 7.38–7.29 (m,
2 H), 4.65 (dd, J = 10.5, 6.6 Hz, 1 H), 4.50 (dd, J = 10.5, 6.8 Hz, 1 H),
4.28 (app t, J = 6.6 Hz, 1 H), 4.04–3.90 (m, 1 H), 2.84 (dd, J = 17.7,
9.1 Hz, 1 H), 2.56 (dd, J = 17.8, 2.1 Hz, 1 H), 1.23–0.98 (m, 1 H), 0.65–
(m, 1 H) ppm. IR (ATR): ν = 3037, 3064, 2918, 2854, 1805, 1722,
˜
1449, 1139, 740 cm–1. HRMS: calcd. for [M + H]+ C21H22NO4S 0.49 (m, 2 H), 0.43–0.30 (m, 1 H), 0.30–0.15 (m, 1 H) ppm. 13C NMR
384.1264; found 384.1277.
(75 MHz, CDCl3): δ = 173.1 (Cq), 157.1 (Cq), 143.3 (Cq), 143.2 (Cq),
141.5 (Cq), 141.5 (CH), 128.1 (CH), 127.5 (CH), 127.4 (CH), 125.3 (CH),
125.2 (CH), 120.2 (CH), 68.8 (CH2), 63.9 (CH), 47.0 (CH), 34.3 (CH2),
( )-(9H-Fluoren-9-yl)methyl
3-{3-[2,3-Bis(tert-butoxycarbon-
yl)guanidino]propyl}-5-oxoisoxazolidine-2-carboxylate (9h): Iso-
lated according to GP2 (petroleum ether/CH2Cl2/EtOAc, 1:9:0 to
0:1:0 to 0:95:5) to give 9h (140 mg, 46 %) as a colourless solid. M.p.
80–82 °C. 1H NMR (300 MHz, CDCl3): δ = 11.49 (br. s, 1 H), 8.31 (t,
J = 5.7 Hz, 1 H), 7.78 (app d, J = 7.4 Hz, 2 H), 7.61 (dd, J = 7.2,
2.5 Hz, 2 H), 7.42 (app t, J = 7.4 Hz, 2 H), 7.33 (app t, J = 7.5 Hz, 2
H), 4.67 (dd, J = 10.5, 6.4 Hz, 1 H), 4.54 (dd, J = 10.5, 6.6 Hz, 1 H),
15.0 (CH), 3.5 (CH2), 2.5 (CH2) ppm. IR (ATR): ν = 2968, 1804, 1724,
˜
1448, 1384, 1289, 1150, 758, 736 cm–1. HRMS: calcd. for [M + NH4]+
C21H23N2O4 367.1652; found 367.1660.
( )-(9H-Fluoren-9-yl)methyl
5-Oxo-3-phenylisoxazolidine-2-
carboxylate (9l): Isolated according to GP2 (petroleum ether/
CH2Cl2, 1:9 to 0:1) to give 9l (116 mg, 60 %) as a colourless solid.
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1
M.p. 52–54 °C. H NMR (300 MHz, CDCl3): δ = 7.77 (d, J = 7.6 Hz, 2 (300 MHz, [D6]DMSO): δ = 12.05 (s, 1 H), 7.89 (d, J = 7.5 Hz, 2 H),
H), 7.55 (t, J = 7.1 Hz, 2 H), 7.46–7.27 (m, 10 H), 5.50 (dd, J = 9.5, 7.64 (d, J = 7.4 Hz, 2 H), 7.48–7.03 (m, 10 H), 4.29–4.08 (m, 3 H),
3.4 Hz, 1 H), 4.62 (dd, J = 10.5, 6.8 Hz, 1 H), 4.51 (dd, J = 10.5, 6.9 Hz,
1 H), 4.26 (t, J = 6.8 Hz, 1 H), 3.22 (dd, J = 17.8, 9.5 Hz, 1 H), 2.82
(dd, J = 17.8, 3.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.8
(Cq), 156.5 (Cq), 143.2 (Cq), 143.1 (Cq), 141.4 (Cq), 141.3 (Cq), 138.3
(Cq), 129.3 (CH), 128.7 (CH), 128.1 (CH), 128.0 (CH), 127.4 (CH), 127.3
(CH), 125.7 (CH), 125.3 (CH), 125.2 (CH), 120.2 (CH), 120.1 (CH), 69.0
4.07–3.86 (m, 1 H), 2.72 (d, J = 6.6 Hz, 2 H), 2.42–2.27 (m, 2 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 172.7 (Cq), 155.3 (Cq), 143.9 (Cq),
143.9 (Cq), 140.7 (Cq), 138.6 (Cq), 129.2 (CH), 128.2 (CH), 127.6 (CH),
127.1 (CH), 126.1 (CH), 125.2 (CH), 120.1 (CH), 65.2 (CH2), 49.7 (CH),
46.7 (CH), 39.7 (CH2), 38.9 (CH2) ppm. IR (ATR): ν = 3345, 3031, 2959,
˜
1722, 1687, 1529, 1228, 1084, 1044, 739 cm–1. HRMS: calcd. for [M
– H]– C25H22NO4 400.1554; found 400.1531.
(CH2), 63.0 (CH), 46.9 (CH), 37.0 (CH2) ppm. IR (ATR): ν = 2920, 1803,
˜
1722, 1449, 1283, 1165, 1124, 737 cm–1. HRMS: calcd. for [M + NH4]+
C24H23N2O4 403.1652; found 403.1651.
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-phenyl-
propanoic Acid (10c): Isolated according to GP3 (trituration with
n-pentane) to give 10c (184 mg, 95 %) as a colourless solid. Spectro-
scopic data are consistent with literature data.[15] M.p. 197–199 °C.
1H NMR (300 MHz, [D6]DMSO): δ = 12.21 (br. s, 1 H), 7.95 (app d,
( )-(9H-Fluoren-9-yl)methyl 3-[(2S,5R,6R)-5,6-Dimethoxy-5,6-di-
methyl-1,4-dioxan-2-yl]-5-oxoisoxazolidine-2-carboxylate (9m):
Isolated according to GP2 to give 9m (181 mg, 75 %) as a white
foam, a mixture of two diastereoisomers [dr 85:15; the diastereoiso- J = 8.6 Hz, 1 H), 7.88 (app d, J = 7.3 Hz, 2 H), 7.67 (app d, J = 7.2 Hz,
meric ratio was determined by integration of the signal for the mi- 2 H), 7.50–7.11 (m, 9 H), 4.93 (app q, J = 8.4, 7.8 Hz, 1 H), 4.42–4.03
nor diastereoisomer at δ = 2.97 ppm (dd) in the 1H NMR spectrum].
1H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 7.5 Hz, 2 H), 7.62 (t, J =
7.1 Hz, 2 H), 7.28–7.44 (m, 4 H), 4.68 (dd, J = 6.3, 10.5 Hz, 1 H), 4.52
(dd, J = 6.7, 10.5 Hz, 1 H), 4.34 (dt, J = 2.4, 10 Hz, 1 H), 4.28 (app t,
J = 6.4 Hz, 1 H), 3.87 (dt, J = 2.8, 11 Hz, 1 H), 3.67 (app t, J = 11.1 Hz,
1 H), 3.25 (m, 1 H), 3.23 (s, 3 H), 3.21 (s, 3 H), 2.78 (dd, J = 9.9,
(m, 3 H), 2.83–2.56 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
172.0 (Cq), 155.4 (Cq), 144.0 (Cq), 143.8 (Cq), 143.0 (Cq), 140.7 (Cq),
128.3 (CH), 127.6 (CH), 127.2 (CH), 127.1 (CH), 127.0 (CH), 126.4 (CH),
125.2 (CH), 125.2 (CH), 120.2 (CH), 65.4 (CH2), 51.7 (CH), 46.7 (CH),
41.2 (CH2) ppm. IR (ATR): ν = 3367, 3037, 2952, 1703, 1526, 1284,
˜
1227, 1026, 740 cm–1. HRMS: calcd. for [M – H]– C24H20NO4
17.6 Hz, 1 H), 2.64 (dd, J = 1.8, 17.6 Hz, 1 H), 1.26 (s, 6 H) ppm. 13C 386.1398; found 386.1395.
NMR (75 MHz, CDCl3): δ = 172.4 (Cq), 157.2 (Cq), 143.3 (CH), 143.0
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-cyclo-
(CH), 141.5 (CH), 128.2 (CH), 128.2 (CH), 127.5 (CH), 127.4 (CH), 127.3
(CH), 125.3 (CH), 125.1 (CH), 120.2 (CH), 120.2 (CH), 99.8 (Cq), 98.2
(Cq), 68.9 (CH2), 68.5 (CH2), 59.6 (CH), 59.5 (CH), 48.4 (CH3), 48.2
propylpropanoic Acid (10d): Isolated according to GP3 (trituration
with n-pentane/CH2Cl2, 1:1) to give 10d (155 mg, 89 %) as a colour-
less solid. M.p. 177–179 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 12.12
(br. s, 1 H), 7.89 (app d, J = 7.4 Hz, 2 H), 7.68 (app d, J = 7.2 Hz, 2
H), 7.41 (app t, J = 7.3 Hz, 2 H), 7.32 (app t, J = 7.8 Hz, 3 H), 4.38–
4.06 (m, 3 H), 3.44–3.33 (m, 1 H), 2.49–2.41 (m, 2 H), 0.97–0.80 (m,
1 H), 0.44–0.21 (m, 3 H), 0.14 (m, 1 H) ppm. 13C NMR (75 MHz,
(CH3), 47.0 (CH), 30.3 (CH2), 17.6 (2 × CH3) ppm. IR (ATR): ν = 2949,
˜
1807, 1723, 1450, 1375, 1309, 1143, 1117, 1035, 965, 875, 740 cm–1
.
HRMS: calcd. for [M + NH4]+ C26H33N2O8 501.2237; found 501.2221.
General Procedure (GP3) for the Zn-Assisted Isoxazolidinone
Ring-Opening (10a–10h): At room temperature, activated zinc DMSO): δ = 172.5 (Cq), 155.6 (Cq), 144.0 (Cq), 143.8 (Cq), 140.7 (Cq),
dust (1.308 g, 20 mmol, 40 equiv.) was added to a stirred solution 127.6 (CH), 127.1 (CH), 125.2 (CH), 120.1 (CH), 65.2 (CH2), 51.5 (CH),
of the appropriate isoxazolidinone (0.5 mmol, 1 equiv.) in a THF/
46.8 (CH), 40.1 (CH2), 16.0 (CH), 2.9 (CH2), 2.2 (CH2) ppm. IR (ATR):
˜
H2O/AcOH (8:1:1) mixture (10 mL). The heterogeneous solution was ν = 3333, 2958, 1806, 1698, 1449, 1255, 1105, 1051, 736 cm–1. HRMS:
stirred at 40 °C for 4 h. When the reaction was complete, the mix- calcd. for [M – H]– C21H20NO4 350.1398; found 350.1402.
ture was c to room temperature, and filtered through a pad of
diatomaceous earth. The pad was rinsed with THF. The filtrate was
partially concentrated in vacuo and diluted with H2O. The aqueous
layer was extracted with CH2Cl2 (3 ×). The combined organic layers
were washed with brine, dried with MgSO4, filtered, and concen-
trated in vacuo. The crude white residue was triturated or precipi-
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-4-[(tert-
butyldiphenylsilyl)oxy]butanoic Acid (10e): Isolated according to
GP3 (dissolved in Et2O and precipitated from n-pentane at 0 °C) to
give 10e (200 mg, 69 %) as a colourless solid. M.p. 82–84 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 12.22 (br. s, 1 H), 7.88 (app d, J =
7.5 Hz, 2 H), 7.68 (dd, J = 7.3, 3.4 Hz, 2 H), 7.64–7.57 (m, 4 H), 7.50–
tated from an appropriate solvent mixture (see details below) to
7.33 (m, 9 H), 7.32–7.22 (m, 2 H), 4.30–4.11 (m, 3 H), 4.10–3.96 (m,
give the desired ꢀ-amino acid in analytically pure form.
1 H), 3.64–3.47 (m, 2 H), 2.64–2.35 (m, 2 H), 0.98 (s, 9 H) ppm. 13C
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-5-phenyl-
pentanoic Acid (10a): Isolated according to GP3 (trituration with
n-pentane) to give 10a (179 mg, 86 %) as a colourless solid. M.p.
129–131 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 12.13 (br. s, 1 H),
NMR (75 MHz, [D6]DMSO): δ = 172.4 (Cq), 155.6 (Cq), 143.9 (Cq),
143.8 (Cq), 140.7 (Cq), 135.1 (CH), 132.9 (Cq), 132.8 (Cq), 129.9 (CH),
127.9 (CH), 127.8 (CH), 127.6 (CH), 127.0 (CH), 125.2 (CH), 120.1 (CH),
65.4 (CH2), 65.1 (CH2), 49.6 (CH), 46.7 (CH), 35.8 (CH2), 26.6 (CH2),
7.89 (app d, J = 7.5 Hz, 2 H), 7.77–7.67 (m, 2 H), 7.41 (app t, J = 18.8 (Cq) ppm. IR (ATR): ν = 3341, 3064, 2956, 2861, 1805, 1723,
˜
7.4 Hz, 2 H), 7.36–7.22 (m, 5 H), 7.22–7.11 (m, 3 H), 4.41–4.17 (m, 3 1697, 1449, 1278, 1112, 737 cm–1. HRMS: calcd. for [M + H]+
H), 3.81 (app q, J = 7.3 Hz, 1 H), 2.66–2.52 (m, 2 H), 2.43–2.25 (m, 2
H), 1.78–1.62 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 172.6
(Cq), 155.6 (Cq), 144.0 (Cq), 143.8 (Cq), 141.8 (Cq), 140.7 (Cq), 128.3
(CH), 128.2 (CH), 127.6 (CH), 127.1 (CH), 127.0 (CH), 125.7 (CH), 125.2
(CH), 120.1 (CH), 65.1 (CH2), 47.8 (CH), 46.9 (CH), 39.8 (CH2), 36.2
C35H38NO5Si 580.2514; found 580.2516.
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-7-[(tert-
butoxycarbonyl)amino]heptanoic Acid (10f): Isolated according
to GP3 (dissolved in Et2O and precipitated from n-pentane at 0 °C)
to give 10f (174 mg, 74 %) as a colourless solid. Spectroscopic data
are consistent with literature data.[14,16] M.p. 85–87 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 12.13 (br. s, 1 H), 7.89 (app d, J = 7.4 Hz,
2 H), 7.68 (app d, J = 7.1 Hz, 2 H), 7.41 (app t, J = 7.4 Hz, 2 H), 7.32
(CH2), 31.7 (CH2) ppm. IR (ATR): ν = 335, 3070, 3024, 2952, 1696,
˜
1538, 1296, 1250, 1046, 741 cm–1. HRMS: calcd. for [M + H]+
C26H26NO4 416.1856; found 416.1871.
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-4-phenyl- (app t, J = 7.3 Hz, 2 H), 7.20 (app d, J = 8.7 Hz, 1 H), 6.76 (app t, J =
butanoic Acid (10b):[14] Isolated according to GP3 (dissolved in
CH2Cl2 and precipitated with n-pentane at 0 °C) to give 10b
(169 mg, 84 %) as a colourless solid. M.p. 140–142 °C. 1H NMR
5.3 Hz, 1 H), 4.35–4.13 (m, 3 H), 3.74 (s, 1 H), 2.87 (app q, J = 5.6 Hz,
2 H), 2.41–2.15 (m, 2 H), 1.36 (s, 9 H), 1.33–1.05 (m, 6 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 172.5 (Cq), 155.5 (Cq), 155.5 (Cq),
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143.9 (Cq), 143.8 (Cq), 140.7 (Cq), 127.6 (CH), 127.0 (CH), 126.9 (CH),
125.2 (CH), 125.1 (CH), 120.1 (CH), 77.3 (Cq), 65.1 (CH2), 47.8 (CH),
H), 8.02 (app d, J = 8.3 Hz, 1 H), 7.88 (app d, J = 7.5 Hz, 2 H), 7.70
(app d, J = 7.6 Hz, 1 H), 7.65–7.56 (m, 2 H), 7.55–7.15 (m, 8 H), 4.28–
46.7 (CH), 39.6 (CH2), 39.4 (CH2), 33.9 (CH2), 29.3 (CH2), 28.2 (CH3), 3.99 (m, 4 H), 2.84 (d, J = 6.8 Hz, 2 H), 2.49–2.37 (m, 2 H), 1.55 (s, 9
22.7 (CH2) ppm. IR (ATR): ν = 3344, 2979, 2939, 1691, 1534, 1252,
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 172.7 (Cq), 155.5 (Cq),
1169, 739 cm–1. HRMS: calcd. for [M + NH4]+ C27H38N3O6 500.2755; 149.0 (Cq), 143.8 (Cq), 140.7 (Cq), 134.8 (Cq), 130.5 (Cq), 127.6 (CH),
˜
found 500.2762.
127.0 (CH), 125.2 (CH), 125.1 (CH), 124.3 (CH), 123.7 (CH), 122.5 (CH),
120.1 (CH), 119.3 (CH), 117.4 (CH), 114.7 (CH), 83.4 (Cq), 65.3 (CH2),
48.1 (CH), 46.7 (CH), 39.0 (CH2), 29.7 (CH2), 27.6 (CH3) ppm. IR (ATR):
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-5-(methyl-
thio)pentanoic Acid (10g): At room temperature, activated zinc
dust (1.046 g, 16 mmol, 40 equiv.) was added portionwise to a
stirred solution of isoxazolidinone 9g (153 mg, 0.4 mmol, 1 equiv.)
in a THF/H2O/AcOH (8:1:1) mixture (8 mL). The heterogeneous solu-
tion was stirred at 40 °C for 4 h. When the reaction was complete,
the mixture was cooled to room temperature, and filtered through
a pad of diatomaceous earth. The pad was rinsed with THF. The
filtrate was partially concentrated in vacuo and diluted with H2O.
The aqueous layer was extracted with CH2Cl2 (3 ×). The combined
organic layers were washed with brine, dried with MgSO4, filtered,
and concentrated in vacuo. The crude residue was purified by flash
chromatography on silica gel (n-pentane/EtOAc/AcOH, 1:1:0.1) to
give N-Fmoc-ꢀ3-homoMet-OH 10i (72 mg, 187 μmol, 47 %) as a
colourless solid. M.p. 129–131 °C. 1H NMR (300 MHz, [D6]DMSO):
δ = 12.18 (br. s, 1 H), 7.89 (app d, J = 7.5 Hz, 2 H), 7.68 (dd, J = 7.5,
3.6 Hz, 2 H), 7.41 (app t, J = 7.4 Hz, 2 H), 7.32 (app t, J = 7.5 Hz, 2
H), 7.27 (app d, J = 8.5 Hz, 1 H), 4.38–4.16 (m, 3 H), 3.95–3.81 (m, 1
H), 2.47–2.24 (m, 4 H), 2.01 (s, 3 H), 1.80–1.57 (m, 2 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 172.4 (Cq), 155.6 (Cq), 144.0 (Cq),
143.8 (Cq), 140.8 (Cq), 127.6 (CH), 127.1 (CH), 125.2 (CH), 120.1 (CH),
65.1 (CH2), 47.2 (CH), 46.8 (CH), 39.5 (CH2), 33.7 (CH2), 29.7 (CH2),
ν = 3339, 3044, 2979, 1729, 1691, 1532, 1452, 1367, 1250, 1159,
˜
1085, 732 cm–1. HRMS: calcd. for [M – H]– C21H20NO4 539.2188;
found 539.2196.
( )-3-{[(Benzyloxy)carbonyl]amino}-5-phenylpentanoic Acid
(15): Prepared according to GP3 using activated Zn dust (80 equiv.)
in a THF/H2O/AcOH (7.2:1:1.8) mixture (10 mL), and precipitated
from n-pentane at 0 °C after dissolution in CH2Cl2 to give 15
(129 mg, 79 %) as a colourless solid. Spectroscopic data are consist-
ent with literature data.[19] M.p. 148–150 °C. 1H NMR (300 MHz,
[D4]methanol): δ = 9.00–8.56 (m, 10 H), 6.72–6.49 (m, 2 H), 5.63–
5.37 (m, 1 H), 4.25–4.05 (m, 2 H), 4.06–3.86 (m, 2 H), 3.49–3.22 (m,
2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 176.4 (Cq), 155.6 (Cq),
142.1 (Cq), 137.4 (Cq), 128.4 (CH), 128.3 (CH), 127.8 (CH), 127.7 (CH),
125.6 (CH), 65.1 (CH2), 48.5 (CH), 41.6 (CH2), 35.9 (CH2), 31.9 (CH2)
ppm. IR (ATR): ν = 3388, 3034, 2944, 1693, 1568, 1414, 1252, 1050,
˜
697 cm–1. HRMS: calcd. for [M – H]– C19H20NO4 326.1398; found
326.1392.
Acknowledgments
This work has been partially supported by INSA Rouen, Rouen
University, the Centre National de la Recherche Scientifique
(CNRS), EFRD, and Labex SynOrg (ANR-11-LABX-0029), and by
Region Normandie (CRUNCh network). This work is part of
CrisOrg – LabCom V6 (ANR-14-LAB6-0002), Laboratoires com-
muns organismes de recherche publics – PME/ETI – 2014.
14.6 (CH3) ppm. IR (ATR): ν = 3311, 3070, 2917, 2887, 2854, 1694,
˜
1543, 1259, 1051, 735 cm–1. HRMS: calcd. for [M + NH4]+
C21H27N2O4S 403.1686; found 403.1689.
( )-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-6-[2,3-
bis(tert-butoxycarbonyl)guanidino]hexanoic Acid (10h): Freshly
activated zinc dust (2.615 g, 80 equiv.) was added portionwise to a
stirred solution of isoxazolidinone 9h (304 mg, 0.5 mmol) in a THF/
H2O/AcOH (7.2:1:1.8) mixture (10 mL). The heterogeneous solution
was stirred at 40 °C for 4 h. When the reaction was complete, the
mixture was brought back to room temperature, and filtered off on
a pad of diatomaceous earth. The pad was rinsed with THF and
CH2Cl2. The filtrate was concentrated in vacuo, and filtered through
a short pad of silica gel (n-pentane/EtOAc/AcOH, 1:1:0.1) to give
analytically pure N-Fmoc-ꢀ3-homoArg(N,N′-diBoc)-OH 10h (253 mg,
0.41 mmol, 83 %) as a colourless foamy solid. Spectroscopic data
are consistent with literature data.[17] M.p. 115–117 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 12.12 (br. s, 1 H), 11.50 (br. s, 1 H), 8.28
(app t, J = 5.7 Hz, 1 H), 7.88 (app d, J = 7.4 Hz, 2 H), 7.67 (dd, J =
7.1, 2.9 Hz, 2 H), 7.40 (app t, J = 7.4 Hz, 2 H), 7.31 (app t, J = 7.4 Hz,
2 H), 7.24 (app d, J = 8.6 Hz, 1 H), 4.39–4.13 (m, 3 H), 3.86–3.73 (m,
1 H), 3.30–3.15 (m, 2 H), 2.36 (app d, J = 6.8 Hz, 2 H), 1.42 (d, J =
24.4 Hz, 22 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 172.5 (Cq),
163.2 (Cq), 155.6 (Cq), 155.3 (Cq), 152.1 (Cq), 144.0 (Cq), 143.8 (Cq),
140.7 (Cq), 127.6 (CH), 127.0 (CH), 125.2 (CH), 120.1 (CH), 82.9 (Cq),
78.1 (Cq), 65.1 (CH2), 47.8 (CH), 46.8 (CH), 40.2 (CH2), 39.7 (CH2), 31.6
Keywords: Amino acids · Isoxazolidinones · Heterocycles ·
Meldrum's acid · Reduction · Multicomponent reactions
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solid. Spectroscopic data are consistent with literature data.[16,18]
1
M.p. 118–120 °C. H NMR (300 MHz, [D6]DMSO): δ = 12.26 (br. s, 1
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Received: April 5, 2017
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