Organocatalytic asymmetric 5-hydroxyisoxazolidine synthesis: A highly enantioselective route to β-amino acids

Article abstract of DOI:10.1039/b613410f

The highly chemo- and enantioselective organocatalytic tandem reaction between N-protected hydroxyl amines and α,β-unsaturated aldehydes is presented; the reaction provides access to 5-hydroxyisoxazolidines and β-amino acids in high yields and with 90-99% ee. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613410f

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Organocatalytic asymmetric 5-hydroxyisoxazolidine synthesis: A
highly enantioselective route to b-amino acids{
Ismail Ibrahem, Ramon Rios, Jan Vesely, Gui-Ling Zhao and Armando Co´rdova*
Received (in Cambridge, UK) 14th September 2006, Accepted 1st November 2006
First published as an Advance Article on the web 23rd November 2006
DOI: 10.1039/b613410f
The highly chemo- and enantioselective organocatalytic tandem
reaction between N-protected hydroxyl amines and a,b-unsa-
turated aldehydes is presented; the reaction provides access to
5-hydroxyisoxazolidines and b-amino acids in high yields and
with 90–99% ee.
5-Hydroxyisoxazolidines and 5-isoxazolidinones are important
chiral building blocks1 that are readily converted into the
corresponding amino alcohols and b-amino acids.2 Thus, asym-
metric methods have been developed for their preparation.1 For
instance, optically active 5-acetoxyisoxazolines can be converted in
two steps to the corresponding isoxazolidinones.1d–e Moreover,
utilization of chiral auxiliaries enables the asymmetric synthesis of
5-isoxazolidinones.1e–f Recently, 5-isoxazolidinones were prepared
by the Lewis acid-catalyzed enantioselective conjugate addition of
hydroxyl amines to a,b-unsaturated amide derivatives.1b–c,3
In the field of organocatalysis, amine-catalyzed reactions that
involve catalytic domino, tandem or cascade reaction pathways
Scheme 1 A plausible reaction pathway for a chiral amine-catalyzed
have recently been developed.4–6 In this context, we most recently
enantioselective formation of 5-hydroxyisoxazolidines.
found that chiral pyrrolidines catalyze the formation of 1,2-
dihydroquinoline derivatives via an asymmetric domino amine-
ee), which are converted in one-pot to 5-isoxazolidinones (up to
conjugate/aldol reaction pathway between 2-aminobenzaldehyde
and enals (eqn. (1)).7
99% ee) or in two steps to b-amino acids (up to 99% ee).
In an initial catalyst screen for the reaction between N-Boc-
protected hydroxylamine 1a (0.30 mmol) and cinnamic aldehyde
ð1Þ
Table 1 Catalyst screen for the reaction between 1a and 2a
Despite all the chemoselectivity issues that could arise in the
amine conjugate addition step, such as non-productive imine
formation and racemic background reactions, the subsequent
intramolecular aldol addition kinetically controls the desired
reaction pathway and pushes the equilibrium towards product
formation. Based on these lessons and retrosynthetic analysis, we
envisioned that the chiral amine-catalyzed reaction between
Entry
Catalyst
Solvent
Time/h
Yield (%)a
ee (%)b
N-protected hydroxylamines and enals would be a simple
asymmetric entry route to 5-hydroxyisoxazolidines, where sub-
sequent tandem intramolecular hemiacetal formation is an
important driving force for product formation (Scheme 1).8
Herein, we present a highly enantioselective catalytic route to
the synthesis of 5-hydroxyisoxazolidines (75–94% yield, 90–99%
1
2
3
4
5
6
7
8
9
4
5
6
7
8
9
9
9
9
9
9
DMF
DMF
13
14
13
13
13
3
3
3
3
3
0
0
—
—
240
9
10
99
99
84
89
77
97
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
DMF
39
26
70
90
88
85
60
70
71
b
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, 10691 Stockholm, Sweden.
E-mail: acordova1a@netscape.net; acordova@organ.su.se;
Fax: +46 8154908; Tel: +46 8162479
{ Electronic supplementary information (ESI) available: Experimental
procedures. See DOI: 10.1039/b613410f
10
11
EtOH
Toluene
3
a
Isolated yield of the pure product compound 3a. Determined by
chiral-phase HPLC analyses.
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2a (0.25 mmol), we found that simple chiral pyrrolidines such as
Table 2 Scope of the organocatalytic tandem reaction
6–9 catalyzed the chemoselective formation of 5-hydroxyisoxazo-
lidine 3a (Table 1). However, (S)-proline was not a catalyst for this
transformation. To our delight, protected diarylprolinol 99
catalyzed the formation of 3a with high efficiency and selectivity
under various reaction conditions (Table 1, entries 6–11). The
highest enantioselectivity was achieved when CHCl3 and toluene
were used as the solvent.
Yield ee
Time/h (%)a (%)b
Entry
1
R
R1
Product
Ph
Boc
3
80
99
Thus, we decided to investigate the scope of the catalytic
asymmetric tandem reaction using CHCl3 as the solvent (Table 2).
The organocatalytic enantioselective tandem reactions were
highly chemo- and enantioselective at 4 uC, and the corresponding
5-hydroxyisoxazolidines 3 were isolated in 75–94% yield with a 90–
99% ee. Moreover, the reactions with N-Cbz-protected hydro-
xylamine 1b gave the corresponding products 3 in 85–94% yield
and in 95–99% ee (Table 2, entries 2, 8 and 11). The tandem
reactions with a,b-unsaturated aliphatic acceptor aldehydes 2
(Table 2, entries 9–11) were slower compared to the aryl
substituted enals 2 (Table 2, entries 1–7). In addition, the
organocatalytic reaction was readily scaled up, giving access to a
variety of 5-hydroxyisoxazolidines. Next, a one-pot protocol for
the asymmetric synthesis of 5-oxazolidinones 10 was developed
(Scheme 2).
2
3
Ph
Cbz
3
94
99
4-ClC6H4 Boc
4-BrC6H4 Boc
4-CNC6H4 Boc
4-NO2C6H4 Boc
3
3
3
3
89
80
90
75
90
97
97
98
4
5
6
Thus, in situ oxidation of 5-hydroxyisoxazilidones 3 with
NaClO2 gave the corresponding N-protected 5-oxazilidinones 10
in high overall yield with 95–99% ee. Moreover, in situ reduction
with NaBH4 gave direct access to c-amino alcohols 12. Notably,
hydrogenolysis of the isolated oxazolidinones 10b and 10c with
10% Pd/C led to efficient N–O bond cleavage and removal of the
Cbz group to quantitatively give the corresponding b-amino acids
11. Comparison with the literature revealed that the absolute
configuration of 11b at C3 was S ([a]2D5 = 26.9 (c 1 in H2O); lit.
[a]2D5 = 26.9 (c 0.8 in H2O)10). Thus, efficient shielding of the Si-
face of the chiral iminium intermediate by the bulky aryl groups of
9 leads to stereoselective Re-facial nucleophilic conjugate attack on
the b-carbon by the amino group of 1. Next, the released
N-hydroxy-b-aminoaldehyde intermediate undergoes a favored
hemiacetal formation to give 5-hydroxyisoxazolidine 3. The
importance of hemiacetal formation in pushing the equilibrium
towards product formation in the presence of catalyst 9 was
established by the fact that O-protected hydroxylamines 1 did not
form any conjugate addition products with the cinnamic aldehydes
2 under our reaction conditions.
7
Naphthyl Boc
3
77
95
8
9
CO2Et
Cbz
Boc
16
16
85
94
97
91
n-Bu
In summary, we report a highly chemo- and enantioselective
organocatalytic synthesis of 5-hydroxyisoxazolidines and 5-oxazo-
lidinones, which are formed in high yield with 90–99% ee.
Moreover, the organocatalytic tandem reaction represents a
10
11
a
n-Pr
n-Pr
Boc
Cbz
16
16
93
92
91
95
Isolated yield of the pure product
3
Determined by chiral-phase HPLC or GC
after silica-gel
b
chromatography.
analyses.
Scheme 2 One-pot organocatalytic enantioselective syntheses of 5-oxa-
zolidinones 10, amino alcohol 12a and b-amino acids 11.
850 | Chem. Commun., 2007, 849–851
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versatile asymmetric entry point to different b-amino acid and
c-amino alcohol derivatives. Mechanistic studies and synthetic
applications of this transformation, as well as the development of
other enantioselective tandem reactions, are ongoing in our
laboratory.
We gratefully acknowledge the Swedish National Research
Council and the Carl Trygger Foundation for financial support.
5 For selected examples, see: (a) N. Halland, P. S. Aburell and
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Chem. Commun., 2007, 849–851 | 851