Concise preparation of optically active heteroaryl α-(hydroxyamino) esters

Article abstract of DOI:10.1002/ejoc.201402322

A practical sequence for the synthesis of optically active heteroaryl α-(hydroxyamino) esters was explored. The highly diastereoselective addition of heteroaromatics to a cyclic chiral nitrone allowed access to a series of heteroaryl hydroxylamines. The scope of this reaction was evaluated on substrates possessing a pyrrole, an indole, or a furan core. The three-step sequence afforded the α-(hydroxyamino) esters in good overall yields (36-62-%) with good enantiomeric excess values (76 to ≥98-%). The highly diastereoselective addition of heteroaromatics to a cyclic chiral nitrone allows access to a series of heteroaryl hydroxylamines. The scope of this reaction is presented on substrates possessing a pyrrole, an indole, or a furan core. The three-step sequence affords α-(hydroxyamino) esters in good overall yields (36-62-%) with good enantiomeric excess values (76 to ≥98-%). Copyright

Full text of DOI:10.1002/ejoc.201402322

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402322
Concise Preparation of Optically Active Heteroaryl α-(Hydroxyamino) Esters
Marie Laure Murat-Onana,[a] Christophe Berini,[a] Jean-Noël Denis,[a]
Jean-François Poisson,[a] Frédéric Minassian,*[a] and Nadia Pelloux-Léon*[a]‡]
Keywords: Hydroxyamino esters / Nitrones / Heterocycles / Diastereoselectivity
A practical sequence for the synthesis of optically active het-
eroaryl α-(hydroxyamino) esters was explored. The highly
diastereoselective addition of heteroaromatics to a cyclic chi-
ral nitrone allowed access to a series of heteroaryl hydroxyl-
amines. The scope of this reaction was evaluated on sub-
strates possessing a pyrrole, an indole, or a furan core. The
three-step sequence afforded the α-(hydroxyamino) esters in
good overall yields (36–62%) with good enantiomeric excess
values (76 to Ն98%).
Introduction
Results and Discussion
The addition of pyrrole (1a) to cyclic chiral nitrone (R)-
2[13] was highly diastereoselective and led to the exclusive
formation of (3R,5R)-3a in 76% yield.[14] Compound 3a
was next converted into α-(hydroxyamino) ester 6a in only
a few steps (Scheme 1). Our synthetic plan for the prepara-
tion of α-(hydroxyamino) ester 6a implied the oxidative
cleavage of the β-alkoxy hydroxylamine moiety. Unfortu-
nately, this reaction proved to be unsuccessful starting from
cyclic 3a in the presence of lead tetraacetate. This derivative
was thus transformed into open-chain hydroxylamine 4a by
acid-catalyzed transesterification. In the presence of lead
tetraacetate,[15] the oxidative cleavage of 4a pleasingly gave
expected nitrone 5a as a unique regioisomer. The final
hydroxyaminolysis led to pyrrolyl hydroxyamino ester 6a in
60% yield. The overall yield could be improved by per-
α-(Hydroxyamino) acids are present in many natural
products[1] and pharmaceutical compounds.[2] Whereas the
synthesis of optically active α-amino acids is well estab-
lished,[3] only a few research groups have succeeded in the
preparation of the analogous α-(hydroxyamino) acids. This
may be impeded by the reported instability of these com-
pounds,[4] which therefore necessitates the protection of the
carboxylic acid function,[5] the hydroxylamine function,[2,6]
or both.[7] The enantioselective hydrolysis of amides con-
taining hydroxyamino acid moieties by l-selective amidases
has also been studied, but only for amides derived from
either racemic N-hydroxyphenylglycine[8a] or N-hydroxy-
phenylalanine.[8b]
In previous work, our group reported the nucleophilic
addition of pyrroles and indoles to the C=N bond of nitro-
nes to afford hydroxylamines in good yields.[9] In this con-
text, we decided to focus on the preparation of optically
active heteroaryl α-(hydroxyamino) esters.[10] The prepara-
tion of this class of compounds is a challenge for organic
chemists, taking into consideration the difficulty to obtain
enantiomerically enriched products. Indeed, owing to the
presence of the acidic α-methine proton, rapid epimeri-
zation can occur, which is similar to aryl and heteroaryl
amino esters.[11] Despite their relatively simple structures,
only a few examples of racemic N- or O-alkylated pyrrole
derivatives have previously been reported.[12]
forming the last two steps in
a one-pot sequence
[a] Univ. Grenoble Alpes, CNRS, DCM UMR 5250,
BP-53, 38041 Grenoble cedex 9, France
E-mail: frederic.minassian@ujf-grenoble.fr
http://dcm.ujf-grenoble.fr/
[‡] Dedicated to the memory of our colleague and friend Dr. Nadia
Pelloux-Léon who passed away on February 22, 2014
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402322.
Scheme 1. Synthetic pathway to hydroxyamino ester 6a.
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F. Minassian, N. Pelloux-Léon et al.
SHORT COMMUNICATION
(Scheme 1). Under these conditions, 6a was obtained in Table 1. Preparation of pyrrolyl hydroxylamines 3b–e.
80% enantiomeric excess (ee, measured by HPLC on a chi-
ral stationary phase).[16]
This synthetic route was next extended to a variety of
heteroaromatic compounds. Pyrroles 1b–e, indoles 1f–g,
and 2-methylfuran 1h (Figure 1) seemed to be a suitable
series for the starting materials. Indeed, these substrates co-
ver a representative range of π nucleophilicity, as previously
reported by Mayr and co-workers for other C–C bond-
forming processes.[17]
Entry Pyrrole Product
Conditions
Yield [%]
55
dr[a]
Figure 1. Starting heteroaryl substrates. TIPS = triisopropylsilyl.
1
2
3
4
5
1b[b]
1c[b]
1d
rac-3b –78 to –60 °C, 1 h
Ն98:2
rac-3c –78 to –60 °C, 1 h 64 (1:1)[c] Ն98:2
The reaction of pyrroles 1b–d with cyclic chiral nitrone
(R)-2 is presented in Table 1. In this series, only 1 equiv. of
hydrogen chloride was necessary to achieve good conver-
sions of the starting material. Starting from 2-methylpyrrole
(1b), corresponding cyclic hydroxylamine 3b was isolated in
55% yield as a unique regioisomer (Table 1, Entry 1). With
kryptopyrrole (1c), a mixture containing expected 3c to-
gether with corresponding ketimine 7 (see Table 4) was ob-
tained (Table 1, Entry 2). Our attempts to separate the two
compounds were unsuccessful. Owing to the lower reactiv-
ity of the C-3 position of the pyrrole ring, an increase in
the reaction temperature was suitable to obtain 3d in 86%
yield starting from pyrrole 1d (Table 1, Entries 3 and 4).
Hydroxylamine 3e was also obtained by using the pre-
viously described conditions.[14] As it was initially observed
with 3a, products 3b–e were all obtained as single diastereo-
isomers.
3d
3d
3e
–78 to –40 °C, 3 h
–20 to 0 °C, 3 h
see ref.[14]
59
Ն98:2
Ն98:2
Ն98:2
1d
86
[d]
1e
–
[a] Diastereomeric ratio of cyclic hydroxylamines 3b–e was deter-
1
mined by H NMR spectroscopy. [b] The reaction was performed
by starting from racemic nitrone rac-2. [c] The 3c/7c ratio (for the
structure, see Table 4), as determined by analysis of the crude reac-
tion mixture by 1H NMR spectroscopy, is given in parentheses.
[d] The yield of the isolated product after two steps is given in
Table 4.
Table 2. Preparation of indolyl hydroxylamines 3f and 3g.
In the indole series, the reaction of 1f with nitrone (R)-2
led to corresponding hydroxylamine 3f in 79% yield
(Table 2, Entry 1). Starting from 5-fluoroindole (1g), prod-
uct 3g was isolated in moderate yield, even after a longer
reaction time (Table 2, Entry 2). In this case, the best result
was then obtained if the reaction temperature was raised to
–20 °C (Table 2, Entry 3). At higher temperatures, corre-
sponding ketimine 7 (see Table 4) was formed in large
amounts (Table 2, Entry 4). Again, excellent levels of dia-
stereoselectivity were observed in all cases.
Entry Indole Product
Conditions
Yield [%]
dr[a]
1
2
3
4
1f
1g
1g
1g
3f
3g
3g
3g
–78 to –40 °C, 3 h
–78 to –40 °C, 6 h
–40 to –20 °C, 4 h
–20 to 0 °C, 4 h
79
49
Ն98:2
Ն98:2
Ն98:2
Ն98:2
64
49[b]
[a] Diastereomeric ratio was determined by analysis of the crude
reaction mixture by 1H NMR spectroscopy. [b] Ketimine 7g (for
the structure, see Table 4) was concomitantly isolated in 26% yield.
Furan is known to be less nucleophilic than pyrrole.[17]
It has also been shown that 2-methylfuran (1h) is 1000 times
more reactive than furan in trifluoroacetylation reac- Entry 5); the expected product was formed in 73% yield as
tions.[18] We therefore considered 1h as a suitable model. At a unique diastereoisomer.
0 °C, the conversion was low and desired product 3h was
With hydroxylamines 3a–h in hand, we next explored the
detected only in trace amounts (Table 3, Entry 1). By suc- oxidative sequence for the preparation of the corresponding
cessively increasing the reaction temperature and the rela- hydroxyamino esters. As a prerequisite to the subsequent
tive amount of reactant 1h, 3h was isolated in much better oxidation with lead tetraacetate, it was necessary to perform
yields (Table 3, Entries 2–4). The best result was finally ob- the transesterification step to convert cyclic hydroxylamines
tained if 5 equiv. of hydrogen chloride was used (Table 3, 3 into open-chain hydroxylamines 4. Upon treatment of ra-
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Optically Active Heteroaryl α-(Hydroxyamino) Esters
Table 3. Preparation of furyl hydroxylamine 3h.
Table 5. Preparation of heteroaryl α-(hydroxyamino) esters 6d–h
and 8e.
Entry 1h [equiv.] HCl [equiv.] Conditions Yield [%] dr[a]
1
2
3
4
5
1
1
5
10
10
1
1
1
1
5
0 °C, 12 h
r.t., 72 h
r.t., 36 h
r.t., 24 h
r.t., 10 h
trace
23
28
54
73
n.d.
Ն98:2
Ն98:2
Ն98:2
Ն98:2
[a] Diastereomeric ratio was determined by analysis of the crude
reaction mixture by 1H NMR spectroscopy; n.d. = not determined.
Entry
Hydroxylamine
Product
Yield [%]
ee[a] [%]
1
2
3
4
5
4d
4e
4f
4g
4h
6d
8e
6f
6g
6h
62
61[b]
85
73
78
90
90
80
76
Ն98
cemic 3b and 3c under acidic conditions in methanol at
–20 °C, the formation of expected hydroxylamines 4b and
4c was not observed, whereas the formation of cyclic ket-
imines 7b and 7c was predominant (Table 4, Entries 1 and
2). The 3c/7c ratio (for the structure, see Table 4) was deter-
mined by analysis of the crude reaction mixture by 1H
NMR spectroscopy. Other attempts to convert 3b and 3c
were performed at –40 °C or by using trifluoroacetic acid
as the acidic source, but these reactions gave lower conver-
sion ratios together with the formation of undesired ket-
imines 7b and 7c. However, under the initial conditions,
open-chain hydroxylamines 4d–h were obtained in good
yields (Table 4, Entries 3–7). Each hydroxylamine 4 was ob-
tained as a single diastereoisomer.
[a] Determined by integration of the 1H NMR signals by mixing
chiral amino ester 9 in the presence of Eu(hfc)3; hfc = 3-(hepta-
fluoropropylhydroxymethylene)-(+)-camphorate. [b] Yield of isolated
product over two steps.
All attempts to determine the enantiomeric excess values
of final α-(hydroxyamino) esters 6d–h either by HPLC tech-
niques or by H NMR spectroscopy in the presence of chi-
ral europium(III) complexes failed. To overcome this prob-
lem, the hydroxylamines were reduced into amines in the
presence of hydrogen by using Pearlman catalyst, and the
ee values of the obtained α-amino esters were then mea-
1
1
sured by H NMR spectroscopy in the presence of a chiral
Table 4. Preparation of open-chain hydroxylamines 4.
europium(III) salt (Scheme 2). As shown in Table 5, the ob-
served enantiomeric excess values were superior to 76%,
which is unprecedented for heteroaryl hydroxyamino esters.
In the case of the 2-furyl core, final compound 6h was ob-
tained as a single enantiomer (Table 5, Entry 6).
Entry Hydroxylamine
Product
Conditions
Yield [%]
1
2
3
4
5
6
7
3b[a]
3c[a]
3d
7b[a]
7c[a]
4d
–20 °C, 12 h
–20 °C, 24 h
–20 °C, 36 h
see ref.[9c,14]
–20 °C, 12 h
–20 °C, 24 h
–20 °C, 24 h
n.d.[b]
n.d.[b]
51
3e
4e
66[c]
92
3f
4f
3g
4g
78
77
3h
4h
[a] Racemic compounds. [b] n.d. = not determined. [c] Yield of iso-
lated product starting from 1e.
Scheme 2. Derivatization method for the determination of the en-
antiomeric excess values of 6d, 6f–h, and 8e.
In the next step, hydroxyamino esters 6d–h were obtained
through a one-pot sequence consisting in a regioselective
oxidation followed by hydroxyaminolysis (Table 5). Under
Conclusions
Concise access to optically active α-(hydroxyamino) es-
these conditions, 6d–h were obtained in good yield. In the ters was achieved through the highly diastereoselective ad-
case of the N-(triisopropylsilyl)pyrrole derivative, hydroxyl- dition of heteroaromatics to chiral cyclic nitrone (R)-2. A
amine 6e was converted into 8e by cleavage of the TIPS subsequent three-step sequence afforded the final products
group by using tetra-n-butylammonium fluoride (TBAF).
in good overall yields with good to excellent enantiomeric
Eur. J. Org. Chem. 2014, 3773–3776
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F. Minassian, N. Pelloux-Léon et al.
SHORT COMMUNICATION
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Experimental Section
General Procedure for the Preparation of Open-Chain Hydroxyl-
amines 4: To a stirred solution of cyclic hydroxylamine 3 (1 equiv.)
in MeOH (0.2–0.4 m) at –40 °C was added HCl (2 n in Et2O,
2 equiv.). The mixture was warmed at –20 °C and stirred for the
appropriate time. The reaction was stopped by the addition of a
saturated aqueous solution of NaHCO3 to pH = 8–9. The aqueous
layer was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried with anhydrous Na2SO4, and concen-
trated in vacuo. Obtained hydroxylamine 4 was purified by flash
chromatography on silica gel.
General Procedure for the Preparation of α-(Hydroxyamino) Esters
6 and 8e: To a stirred solution of hydroxylamine 4 (1 equiv.) in a
mixture of MeOH/CH2Cl2 (2:1) at 0 °C was added Pb(OAc)4
(1 equiv.). The mixture was stirred for 1 h, and then NH2OH·HCl
(5 equiv.) was added. The resulting mixture was stirred for an ad-
ditional 4 h. The mixture was then treated with a saturated aqueous
solution of NaHCO3 until pH = 8–9. The aqueous layer was ex-
tracted with CH2Cl2. The combined organic layers were washed
with brine, dried with anhydrous Na2SO4, and concentrated in
vacuo. Obtained α-(hydroxyamino) ester 6 was purified by flash
chromatography on silica gel. Unprotected 8e was obtained by re-
action of 4e with TBAF in anhydrous THF at room temperature
for 5 min.
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2009, 74, 1886–1896.
Supporting Information (see footnote on the first page of this arti-
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Acknowledgments
Financial support from the Centre National de la Recherche Sci-
entifique (CNRS) and the Université Joseph Fourier (UMR 5250,
ICMG FR-2607) as well as PhD fellowship awards from the French
Ministry of Education, Research and Technology (to M. L. M.-O.)
and from Cluster “Chimie durable et Chimie pour la santé” –
Région Rhônes-Alpes (to C. B.) are gratefully acknowledged.
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column. The eluent was a gradient system including 5–2% of
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Received: March 27, 2014
Published Online: May 13, 2014
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Eur. J. Org. Chem. 2014, 3773–3776