New Synthesis of Optically Active 5-Isoxazolidinones and β-Amino Acids

Article abstract of DOI:10.1021/jo035356i

A new simple and stereoselective synthesis of 5-isoxazolidinones based on the reaction of lithiated 2-isopropyl-2-oxazolines with nitrones is described. A chiral version of such a methodology allows the preparation of highly enantioenriched 5-isoxazolidinones which are useful precursors for the synthesis of β-amino acids.

Full text of DOI:10.1021/jo035356i

SCHEME 1
New Syn th esis of Op tica lly Active
5-Isoxa zolid in on es a n d â-Am in o Acid s
Renzo Luisi, Vito Capriati, Saverio Florio,* and
Teresa Vista
Dipartimento Farmaco-Chimico, Universita` degli Studi di
Bari, Via E. Orabona 4, I-70126 Bari, Italy, and C.N.R.,
Istituto di Chimica dei Composti Organometallici “ICCOM”,
Sezione di Bari, Italy
SCHEME 2a
florio@farmchim.uniba.it
Received September 15, 2003
Abstr a ct: A new simple and stereoselective synthesis of
5-isoxazolidinones based on the reaction of lithiated 2-iso-
propyl-2-oxazolines with nitrones is described. A chiral
version of such a methodology allows the preparation of
highly enantioenriched 5-isoxazolidinones which are useful
precursors for the synthesis of â-amino acids
Isoxazolidinones are well-established building blocks
in synthetic organic chemistry. Synthetic routes to them
are numerous, including the enantioselective conjugate
addition of hydroxylamines to pyrazolidinone acryla-
mides,1 propenoates,2 crotonic acid esters,3 and R,â-
unsaturated-δ-lactones.4 The 1,3-dipolar cycloaddition of
nitrones with ynolates to give isoxazolidinones has been
developed quite recently.5
One of the reasons the isoxazolidinones, particularly
5-isoxazolidinones, are of considerable interest to organic
chemists is that they are good precursors to unnatural
â-amino acids: these are, indeed, unmasked forms of
5-isoxazolidinones.
a
Key: (i) (a) LDA, -78 °C, THF, (b) CH3I; (ii) s-BuLi/TMEDA,
-78 °C, THF, 1 h; (iii) H+.
Lithiation (s-BuLi/TMEDA, THF, -78 °C) of 2-isopro-
pyl-4,4-dimethyl-2-oxazoline 2, simply prepared from
2-ethyl-4,4-dimethyl-2-oxazoline 1 by the deprotonation-
methylation sequence, furnished lithiated oxazoline 3; the
addition of nitrone 4a after 1 h and workup with
saturated aqueous NH4Cl yielded the spiro[4,4]-1,6-dioxa-
2,9-diazanonane 5a highly diastereoselectively (dr > 98/
2) (Scheme 2).
In a research project focused on the development of
new methodologies based on the use of metalated 2-alkyl-
2-oxazolines we envisaged that 5-isoxazolidinones could
be achieved from 2-alkyl-2-oxazolines according to the
retrosynthetic approach shown in Scheme 1, where the
5-isoxazolidinone system A is seen as obtainable by
hydrolysis of the spirocyclic oxazolidinylisoxazolidine B
which derives from the reaction of the nitrone C with
2-alkyl-2-oxazoline D (Scheme 1).
In this paper, we report a novel and stereoselective
synthesis of 5-isoxazolidinones based on the reaction of
2-isopropyl-2-oxazolines with nitrones. In previous pa-
pers, concerned with the reaction of lithiated 2-alkyl-2-
oxazolines with nitrones we demonstrated that spirocyclic
oxazolidinylisoxazolidines are stable intermediates that
can be isolated and eventually transformed into 2-alken-
yl-2-oxazolines, oxazolinyl[1,2]oxazetidines, or 5-isoxazo-
lidinones depending upon the experimental conditions.6
The formation of 5a can be accounted for by assuming
a nucleophilic addition of lithiated oxazoline 3 to the
nitrone 4a followed by a stereoselective addition of the
resulting lithiated hydroxylamine to the C-N double
bond of the oxazoline ring. The spirocyclic structure of
5a was established by NMR and IR spectroscopy: the
13C NMR spectrum showed the presence of the diagnostic
resonance of the spiro carbon atom at 120 ppm and the
absence of the CdN carbon of the oxazoline ring at 160
ppm. Moreover, the FT-IR analysis revealed a sharp
absorption band at 3350 cm-1 (NH stretching) and the
absence of the 1650 cm-1 band which is diagnostic for
the oxazoline CdN bond. Equally highly stereoselective
were the reactions with aryl nitrones 4b and 4c (Table
1) which afforded in good yields spirocyclic compounds
5b and 5c, respectively. Lower chemical yields of spiro-
cyclic compounds 5d and 5e were obtained when we used
aliphatic nitrones 4d and 4e: the diastereoselectivity
was, however, once more very high.7 To our satisfaction,
the acidic hydrolysis of all the spirocyclic compounds
5a -e with oxalic acid or trifluoroacetic acid (see the
Supporting Information) furnished high to quantitative
* To whom correspondence should be addressed. Phone: +39-080-
5442749. Fax: +39-080-5442251.
(1) Sibi, M. P.; Liu, M. Org. Lett. 2001, 3, 4181-4184.
(2) Baldwin, J . E.; Harwood, L. M.; Lombard, M. J . Tetrahedron
1984, 40, 4363-4370.
(3) Ishikawa, T.; Nagai, K.; Senzaki, M.; Tatsukawa, A.; Saito, S.
Tetrahedron 1998, 54, 2433-2448.
(4) Panfil, I.; Maciejewski, S.; Belzecki, C.; Chmielewski, M. Tetra-
hedron Lett. 1989, 30, 1527-1528.
(6) (a) Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R. Tetrahedron
Lett. 2001, 42, 9183-9186. (b) Capriati, V.; Degennaro, L.; Florio, S.;
Luisi, R. Eur. J . Org. Chem. 2002, 2961-2969.
(5) Shindo, M.; Itoh, K.; Tsuchiya, C.; Shishido, K. Org. Lett. 2002,
4, 3119-3121.
10.1021/jo035356i CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/15/2003
J . Org. Chem. 2003, 68, 9861-9864
9861

SCHEME 3a
TABLE 1. P r ep a r a tion of Sp ir ocyclic Com p ou n d s
5,5-isoxa zolid in on es 6 a n d â-Am in o Acid s 7
spirocyclic 5-isoxazol-
compd 5 idinone
(% yield)a,b 6 (% yield)a
â-amino
nitrone
acid
a
Key: (i) (a) C2H5C(OEt)3, (CH2)2Cl2, 70 °C; (ii) (a) LDA, -78
R
4
7 (% yield)
°C, THF, (b) CH3I; (iii) (a) s-BuLi/TMEDA, -78 °C, THF, 1 h, (b)
4a ; (iv) (COOH)2, THF/H2O (4/1 v/v).
Ph
4a
4b
4c
4d
4e
5a (70)
5b (74)
5c (72)
5d (38)d
5e (35)d
6a (78)
6b (>98)
6c (34)
6d (80)
6e (>98)
7a (>98)
p-ClC6H4
p-MeOC6H4
Cy
7a ‚HCl (>98)c
7b (>98)
SCHEME 4a
7c (>98)
7d (>98)
CH3(CH2)6
a
b
Isolated yields after column chromatography. For all spiro-
cyclic compounds 5 dr > 98/2. c The chlorine atom was lost in the
course of reduction of 6b and amino acid 7a was obtained as a
d
hydrochloride salt. The spirocyclic compounds 5d ,e in solution
equilibrate to the corresponding hydroxylamino forms (see ref 7).
yields of isoxazolidin-5-ones 6a -e (with the exception of
6c), which are likely candidates for the elaboration to R-
and â-substituted â-amino acids upon the N-O bond
reduction. Indeed, treatment of 6a -e with H2 and Pd/C
gave a quantitative yield of the â-amino acids 7a -d .8
The asymmetric version of the above reaction starting
from a chiral oxazoline came to our mind most obviously.
The (4R)-2-ethyl-4-benzyl-2-oxazoline 8 was prepared
from (R)-(+)-2-amino-3-phenyl-1-propanol and triethyl
orthopropionate.9 Lithiation of 8 with LDA followed by
trapping with MeI produced a 75% yield of (4R)-(+)-2-
isopropyl-4-benzyl-2-oxazoline 9. Lithiation of (+)-9 (s-
BuLi/TMEDA, -78 °C, THF) followed after 1 h by the
addition of nitrone 4a gave the hydroxylamine (R,R)-10
(71%) highly diastereoselectively (dr 90/10), as ascer-
a
Key: (i) (a) C2H5C(OEt)3, (CH2)2Cl2, 70 °C, (b) LDA, -78 °C,
THF, (c) CH3I; (ii) (a) s-BuLi/TMEDA, -78 °C, THF, (b) 4a ,b.
compound (R,R,R)-12a (R ) Ph), in good yield (79%) and
very high diastereoselectivity (dr 95/5), rapidly equili-
brating in solution (CDCl3) with its open hydroxylamino
1
form (R,R)-13a (Scheme 4), as clearly indicated by an H
and 13C NMR examination (see the Supporting Informa-
tion). By crystallization from hexane only compound
(R,R,R)-12a was found to be present in the solid state,
as ascertained by the FT-IR spectrum run in KBr
showing the absence of the CdN absorption band at 1660
1
tained by H NMR analysis. Treatment of (R,R)-10 with
oxalic acid gave the 5-isoxazolidinone (-)-6a (78% yield)
with only an acceptable optical purity (er 89/11) (Scheme
3).10
So we decided to turn to another chiral oxazoline. The
(4R)-2,4-diisopropyl-2-oxazoline (+)-11 was synthesized
from D-valinol using the same procedure followed for the
preparation of oxazolines 2 and (+)-9. Lithiation of (+)-
11 and trapping with nitrone 4a afforded the spirocyclic
cm-1 but the presence of the NH stretching at 3370 cm-1
;
on the contrary, the FT-IR spectrum run in solution
displayed the characteristic CdN absorption band of the
oxazoline system together with the OH and NH stretch-
ing bands. The absolute configuration of (R,R,R)-12a was
also unambiguously determined by means of a single-
crystal X-ray analysis.11
We did not care too much, however, about this equili-
bration simply because two of three stereogenic centers
of (R,R,R)-12a were going to be lost in its hydrolysis to
the corresponding 5-isoxazolidinone. Indeed, hydrolysis
of (R,R,R)-12a in acidic conditions (CF3COOH, dioxane/
H2O) furnished the isoxazolidinone (-)-6a highly enan-
tioselectively (er 95/5) (Scheme 5).12 This proves that the
spirocyclic species are involved in the reaction leading
to the 5-isoxazolidinone. Similarly, 5-isoxazolidinone (-)-
(7) The presence of the spirocyclic compounds 5d ,e, which equili-
brate to the corresponding hydroxylamino forms in solution, was
ascertained by NMR spectroscopy. 13C NMR, indeed, showed two
diagnostic signals: the spiro carbon at around 120 ppm and the CdN
carbon at around 165 ppm; two species were revealed by 1H NMR
spectra as well (see the Supporting Information).
(8) In the course of the reduction of 6b the chlorine atom was lost
and 7a was the only isolated product. There are other cases concerning
the loss of a halogen atom under reduction conditions, see: McQuillin,
F. J .; Ord, W. O. J . Am. Chem. Soc. 1959, 81, 9-3172.
(9) Kamata, K.; Agata, I., Meyers, A. I. J . Org. Chem. 1998, 63,
3113-3116.
(10) Hydroxylamine (R,R)-10 was isolated and characterized after
column chromatography by FT-IR analysis (bands at 3373 cm-1, OH,
and 1690 cm-1, CdN) and 13C NMR (see the Supporting Information).
Compound (R,R)-10 was found to equilibrate in CDCl3 or acidic solution
to the corresponding spirocyclic form whose hydrolysis gave the
5-isoxazolidinone (-)-6a (er determinated by chiral GC, see the
Supporting Information).
(11) The X-ray analysis of (R,R,R)-12a allowed the determination
of the absolute configuration at the newly created stereogenic centers.
CCDC-213766 contain the supplementary crystallographic data for
compound (R,R,R)-12a . These data can be obtained free of charge at
www.ccdc.ac.uk/conts/retrieving.html or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
Fax: (int) +44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk.
9862 J . Org. Chem., Vol. 68, No. 25, 2003

SCHEME 5a
SCHEME 7a
a
Key: (i) CF3COOH, 1,4-dioxane/H2O (4/1 v/v).
SCHEME 6a
a
Key: (a) s-BuLi/TMEDA, -78 °C, THF, (b) 4d ; (ii) (COOH)2,
THF/H2O (4/1 v/v).
TABLE 2. P r ep a r a tion of â-Am in o Acid s 7
5-isoxazolidinone (+)-6
R
â-amino acid 7 (% yield)a
(+)-6a
(+)-6b
(+)-6d
Ph
p-ClC6H4
Cy
(+)-7a (>98)
(-)-7a ‚HCl (>98)b
(-)-7c (>98)
a
b
Isolated yields after column chromatography. The chlorine
atom was lost in the reduction of (+)-6b, and the amino acid 7a
was obtained as a hydrochloride salt.
a
Key: (i) (a) s-BuLi/TMEDA, -78 °C, THF, (b) 4a ,b; (ii)
CF3COOH, 1,4-dioxane/H2O (4/1 v/v).
the spirocyclic compound which forms in the reaction of
the lithiated oxazoline with nitrone equilibrates to the
open hydroxylamino form depending upon the substitu-
ents which are present in the oxazoline ring and on the
nitrone. What is useful, however, is that subsequent
acidic treatment leads to the desired 5-isoxazolidinone.
6b (er 95/5) was obtained (>98% yield) by hydrolysis of
the spirocyclic compound (R,R,R)-12b (R ) p-ClC6H4)
which in turn was prepared from oxazoline (+)-11 and
nitrone 4b (Scheme 5).13
To our gratification and as expected, 5-isoxazolidinones
of opposite configuration with respect to (-)-6a ,b were
obtained starting from (4S)-2,4-diisopropyl-2-oxazoline
(-)-11, which was prepared from L-valinol following the
procedure adopted for the synthesis of oxazolines 2, (+)-
9, and (+)-11. Indeed, compound (-)-11, once lithiated,
reacted with nitrones 4a ,b to give spirocyclic compounds
(S,S,S)-12a ,b and then, after hydrolysis, 5-isoxazolidi-
nones (+)-6a ,b [(+)-6a , 78% yield; (+)-6b, >98% yield]
all highly enantiomerically enriched (er 97/3) (Scheme
6).
The reaction of lithiated oxazoline (-)-11 with cyclo-
hexylnitrone 4d afforded the hydroxylamino derivative
(S,S)-14 (40% yield) after flash chromatography highly
diastereoselectively. The structure of (S,S)-14 was proved
by IR and 13C NMR analysis.14 Its hydrolysis with oxalic
acid furnished the 5-isoxazolidinone (+)-6d highly enan-
tioenriched (er 98/2) (Scheme 7) through the correspond-
ing spirocyclic form (S,S,S)-15.15 It seems, therefore, as
Subsequently, we decide to convert the optically active
5-isoxazolidinones into the corresponding â-amino acids
by the N-O reduction. The results are summarized in
Table 2. It is worth pointing out that the reduction of
5-isoxazolidinone (+)-6b afforded the same â-amino acid
7a (as a hydrochloride salt) obtained in the reduction of
(+)-6a as a consequence of a loss of the p-chlorine atom
in (+)-6b under the reaction conditions.16 Other methods
of preparation of chiral â-amino acids have been re-
ported.17 Our methodology, at least when aromatic ni-
trones are used, compares rather well.
In conclusion, this paper reports a new simple stereo-
selective and enantioselective synthesis of 5-isoxazolidi-
nones which are precursors of â-amino acids, which are
important targets in organic synthesis, by using the
chemistry of lithiated 2-alkyl-2-oxazolines with nitrones.
(14) The presence of two bands at 3272 (OH stretching) and at 1697
cm-1 (CdN stretching) in the FT-IR spectrum and a carbon at 168
ppm in the 13C NMR spectrum are diagnostic of the presence of the
hydroxylamino form (S,S)-14.
(15) The absolute configuration of (+)-6d was assigned by analogy
with those of (+)-6a ,b.
(12) The er value of 5-isoxazolidinones (-)-6a ,b were determined
by chiral GC on a â-cyclodextrin capillary column. The retention time
of (-)-6a was the same observed in the case of the 5-isoxazolidinone
derived from the hydrolysis of (R,R)-10, thus confirming its absolute
configuration (R) at C-3.
(13) 5-Isoxazolidinone (-)-6b was tentatively assigned the R con-
figuration by comparison of its GC retention time (first eluted) and
the sign of its optical rotation with those of the known (-)-6a (see the
Supporting Information).
(16) As a prove of the formation of (-)-7a ‚HCl in the reduction of
(+)-6b, a hydrochloride salt was generated from the â-amino acid (+)-
7a derived from (+)-6a . These two salts showed similar 1H, 13C NMR,
FT-IR, and [R]D (see the Supporting Information).
J . Org. Chem, Vol. 68, No. 25, 2003 9863

Highly enantiomerically enriched 5-isoxazolidinones and
â-amino acids of opposite configuration can be prepared
simply by changing the chirality of the starting 2-iso-
propyl-2-oxazoline. Limitations of the above methodology
reside in the nitrone tert-butyl N-protection and the low
yields of the reactions that use alkyl nitrones. More
interesting results are expected from the coupling reac-
tion of lithiated 2-alkyl-2-oxazolines carrying an R-ster-
eocenter that should lead to R,R′-disubstituted â-amino
acids. Work is in progress to this end, and results will
be reported in due course.
in Sintesi Organica, Metodologie ed Applicazioni” and
the FIRB Project “Progettazione, preparazione e valuta-
zione biologica e farmacologica di nuove molecole
organiche quali potenziali farmaci innovativi” supported
by the Ministero dell’Istruzione, dell’Universita` e della
Ricerca (MIUR, Rome) and by the University of Bari
and CNR (Rome). We are also grateful to Prof. Marcel
Pierrot of the Centre Scientifique Saint-J erome,
Marseille, France, for performing X-ray analysis on
compound (R,R,R)-12a .
Ack n ow led gm en t. This work was carried out under
the framework of the National Project “Stereoselezione
Su p p or tin g In for m a tion Ava ila ble: General procedures
for the preparation of 2-isopropyl-2-oxazolines 2, (+)-9 and (+)/
(-)-11 (S2), of spirocyclic compounds 5 (S2), of 5-isoxazolidi-
nones 6 (S9), and of â-amino acids 7 (S12). Spectroscopic and
physical data for compounds 5a -e (S3-S5), 6a -e (S9-S12),
7a -d (S12,S13), 10 (S6), 12a ,b (S7,S8), 13a ,b (S7,S8), and
14 (S9) and an ORTEP view of the spirocyclic compound
(R,R,R)-12a (Figure S1, S12). This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) For reviews on the synthesis of â-amino acids, see: (a) Enan-
tioselective Synthesis of â-amino acids; J uaristi, E., Ed.; Wiley-VCH:
New York, 1997. (b) J uaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem.
1999, 6, 983. For the preparation of â-peptide foldamers, see: (a)
Seebach, D.; Overhand, M.; Kuhnle, F. N. M.; Martinoni, B.; Oberer,
L.; Hommel, U.; Widmer, H. Helv. Chim. Acta 1996, 79, 913. (b)
Hintermann, T.; Seebach, D. Synlett 1997, 437. For biologically active
â-peptides, see: (c) Werder, M.; Hausre, H.; Abele, S.; Seebach, D. Helv.
Chim. Acta 1999, 82, 1774. (d) Porter, E. A.; Wang, X.; Lee, H.-S.;
Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565.
J O035356I
9864 J . Org. Chem., Vol. 68, No. 25, 2003