Stereoselective synthesis of novel 4,5-epoxy-1,2-oxazin-6-ones and α,β-epoxy-γ-amino acids from β-lithiated oxazolinyloxiranes and nitrones

Article abstract of DOI:10.1021/ol0618609

(Chemical Equation Presented) A stereoselective synthesis of 9,10-epoxy-1,6-dioxa-4,7-diazaspiro[4,5]decanes has been developed on the basis of the addition of β-lithiated oxazolinyloxiranes to nitrones. Conversion of these spirocyclic derivatives into 4,

Full text of DOI:10.1021/ol0618609

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4803-4806
Stereoselective Synthesis of Novel
4,5-Epoxy-1,2-oxazin-6-ones and
r
,
â
-Epoxy-
γ-amino Acids from
â
-Lithiated Oxazolinyloxiranes and
Nitrones
Vito Capriati, Leonardo Degennaro, Saverio Florio,* Renzo Luisi, and
Pasqualina Punzi
Dipartimento Farmaco-Chimico, UniVersita` di Bari, C.N.R; Istituto di Chimica dei
Composti OrganoMetallici “ICCOM”, Sezione di Bari, Via E.Orabona 4,
I-70125 Bari, Italy
florio@farmchim.uniba.it
Received July 27, 2006
ABSTRACT
A stereoselective synthesis of 9,10-epoxy-1,6-dioxa-4,7-diazaspiro[4,5]decanes has been developed on the basis of the addition of
oxazolinyloxiranes to nitrones. Conversion of these spirocyclic derivatives into 4,5-epoxy-1,2-oxazin-6-ones and successively into
-amino acids, -hydroxy- -amino acids, and -butyrolactams is described.
â
-lithiated
r,â-epoxy-
γ
r
γ
γ
Unnatural, structurally complex amino acids have recently
been attracting a great deal of interest in medicinal chemistry
due to the growing belief that structural modifications of
amino acids in peptide strands may result in a greater control
over related chemical and conformational properties.1 There-
fore, the development of synthetic procedures for the
construction of conformationally constrained â- and γ-amino
acids2,3 is challenging. A three-component synthesis of R,â-
cyclopropyl-γ-amino acids has been recently reported:4 due
to the presence of the cyclopropane ring, these amino acids
possess the structural rigidity which is paramount to the
conformational mimicry of the peptide strand. In this context,
we reasoned that a somewhat comparable rigidity could be
introduced in a peptide strand by an oxirane ring of an R,â-
epoxy-γ-amino acid.
Recent efforts in our group have focused on the use of
lithiated oxazolinyloxiranes for the preparation of target
molecules.5,6 Here, we wish to report the synthesis of 4,5-
epoxy-1,2-oxazin-6-ones and R,â-epoxy-γ-amino acids based
on the reaction of â-lithiated oxazolinyloxiranes with ni-
(3) (a) Woll, M. G.; Lay, J. R.; Guzei, I. A.; Taylor, S. J. C.; Smith, M.
E.; Gellman, S. J. Am. Chem. Soc. 2001, 123, 11077-11078. (b) Martin-
Vila`, M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.; Branchadell, V.;
Minguillo`n, C.; Giralt, E.; Ortuno, R. M. Tetrahedron: Asymmetry, 2000,
11, 3569-3584. (c) Aravinda, S.; Ananda, K.; Shamala, N.; Balaram, P.
Chem. Eur. J. 2003, 9, 4789-4795. (d) Gnad, F.; Reiser, O. Chem. ReV.
2003, 103, 1603-1623.
(4) (a) Wipf, P.; Stephenson, C. R. J. Org. Lett. 2005, 7, 1137-1140.
(b) Esposito, A.; Piras, P. P.; Ramazzotti, D.; Taddei, M. Org. Lett. 2001,
3, 3273-3275.
(1) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219-3232. (b) Hill, D. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893-4012.
(2) (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiV. 2004,
1, 1111-1239. (b) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.;
Moore, J. S. Chem. ReV. 2001, 101, 3893-4011.
10.1021/ol0618609 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/20/2006

trones. Our interest for this kind of amino acids stems from
the literature verification that they are rare and potentially
useful for elaboration to other substances.7 (1R*,2S*)-1-
Methyl-1-oxazolinyloxirane 2a was prepared by the Darzens
reaction of lithiated 2-(1-chloroethyl)-2-oxazoline with Ph-
CHO, as reported.5a When â-lithiated oxazolinyloxirane 3a,
generated from 2a (s-BuLi/TMEDA, THF, -78 °C), was
reacted with (Z)-N-tert-butylphenylnitrone 1a, the perfectly
stable 9,10-epoxy-1,6-dioxa-4,7-diazaspiro[4.5]decane 4a
formed in a good yield and diastereoselectively (dr > 98/
2)8 (Scheme 1, Table 1). Similarly, 3a reacted with nitrones
Table 1. Reaction of â-Lithiated Oxazolinyloxirane 3a with
Nitrones 1a-m: Preparation of Spirocyclic Compounds 4 and
Isoxazinones 6
4 (yield,
6 (yield,
nitrone 1
R1
R
%)a,b
%)a,b
1a
1b
1c
1d
1e
1f
t-Bu
C6H5
4a (71)
4b (62)
4c (55)
4d (61)
4e (64)c
4f (42)d
4g (51)d
4h (78)
4i (62)
6a (80)
6b (71)
6c (71)
6d (94)
6e (71)
6f (64)
6g (40)
6h (71)
6i (88)
6j (52)
6k (87)
6l (67)
6m (10)e
′′
p-MeOC6H4
p-CF3C6H4
p-ClC6H4
PhCHdCH
C6H11
′′
′′
′′
′′
1g
1h
1i
′′
C7H15
C6H5
p-MeOC6H4
p-ClC6H4
2-furyl
5-(3-CF3C6H4)-2-furyl
C6H11
cumyl
′′
′′
′′
′′
′′
1j
4j (60)
1k
1l
4k (72)
4l (77)
Scheme 1
1m
4m (52)d
a Isolated yields. b The diastereomeric ratio (dr > 98:2) was established
1
from the analysis of the H NMR spectra of the crude reaction mixture of
6 (see ref 8). c Partial hydrolysis takes place on silica gel to afford a small
amount of 4,5-epoxy-1,2-oxazin-6-one 6e. d These derivatives are mainly
present as the hydroxylamino forms 5. e In this case, compound 8 (Scheme
1) was isolated as the main product (see ref 21).
with the hydroxylamino forms 5a-g and diast 4a-g,11 the
position of the equilibrium being dependent upon the nature
of the nitrone: the hydroxylamino form 5 is favored with
aliphatic nitrones, whereas the spirocyclic form 4 prevails
with aromatic ones.12,13 For R ) cyclohexyl, the hydroxyl-
amine 5f crystallizes from hexane, and its structure was
confirmed by single-crystal X-ray analysis.14
Trifluoroacetic acid (TFA) catalyzed hydrolysis of com-
pounds 4a-g, carried out in dioxane/H2O, afforded in good
yields and diastereoselectivity (dr > 98/2)8 4,5-epoxy-1,2-
oxazin-6-ones 6a-g (Scheme 1) (see the Supporting Infor-
mation). The intermediacy of the epoxyhydroxyamides 7 in
the transformation of 4 to 6 was proved by quenching the
reaction mixture at shorter reaction times (16 h).15 Com-
pounds 7a,b,d,f were isolated and, upon hydrolysis, trans-
formed quantitatively into the corresponding epoxy-1,2-
oxazinones 6a,b,d,f (see the Supporting Information). For
6d, the structure and relative configuration were confirmed
by X-ray analysis.16
1b-g furnishing compounds 4b-g, the spirocyclic structure
of which was spectroscopically established (1H and 13C NMR
and FT-IR) and secured by an X-ray analysis in the case of
4b.9,10 In CDCl3 solution, as well as in THF-d8 which is the
reaction solvent, spirocyclic compounds 4a-g equilibrate
Reduction of N-tert-butylepoxy-1,2-oxazinones 6f,g (R )
alkyl) (H2, 1 atm, Pd/C, 5 mol %, MeOH) gave the R,â-
(11) Luisi, R.; Capriati, V.; Degennaro, L.; Florio, S. Tetrahedron 2003,
59, 9713-9718.
(12) 13C NMR data give strong evidence of such an equilibration between
4 and 5 occurring in CDCl3 as well as in THF-d8; indeed, 13C resonances
at 111-113 ppm and at ca. 164 ppm are diagnostic of two spirocyclic carbon
atoms and of an oxazoline CdN group, respectively. On the other hand, in
the solid state, only the spirocyclic skeleton of 4 was detected by means of
an IR investigation (KBr); indeed, a diagnostic NH stretching band appeared
at ca. 3360 cm-1, whereas no oxazoline CdN bond stretching was observed
at ca. 1668 cm-1 which is the typical stretching frequency.
(13) In the case of aromatic-substituted derivatives, spirocyclic com-
pounds 4 are the main forms present in freshly prepared CDCl3 solution,
as checked by 1H NMR; over time, the signals of the hydroxylamino forms
5 tend to increase. Under the same conditions, the alkyl-substituted
derivatives are mainly present, from the beginning, as hydroxylamino forms.
(14) CCDC 606447 contains the supplementary crystallographic data for
compound 5f. These data can be obtained, free of charge, from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(5) (a) Capriati, V.; Degennaro L.; Favia, R.; Florio, S.; Luisi, R. Org.
Lett. 2002, 4, 1551-1554. (b) Luisi, R.; Capriati, V.; Degennaro, L.; Florio,
S. Org. Lett. 2003, 5, 2723-2726.
(6) Capriati, V.; Florio, S.; Luisi, R. Synlett 2005, 9, 1359-1369.
(7) Scholz, D.; Billich, A.; Charpiot, B.; Ettmayer, P.; Lehr, P.;
Rosenwirth, B.; Schreiner, E.; Gstach, H. J. Med. Chem. 1994, 37, 3079-
3089.
(8) The diastereomeric ratio of 4, with reference to the newly created
1
stereocenter at carbon 8, was ascertained by H NMR analysis performed
on the crude deblocked 1,2-oxazin-6-ones 6 (see text).
(9) For a stereoselective synthesis of optically active 5-isoxazolidin-5-
ones and â-amino acids, see: (a) Capriati, V.; Degennaro, L.; Florio, S.;
Luisi, R. Eur. J. Org. Chem. 2002, 2961-2969. (b) Luisi, R.; Capriati, V.;
Florio, S.; Vista, T. J. Org. Chem. 2003, 68, 9861-9864.
(10) CCDC 606445 contains the supplementary crystallographic data for
compound 4b. These data can be obtained, free of charge, from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(15) Such epoxyhydroxyamides are the main products when the reaction
is performed with an excess of TFA.
4804
Org. Lett., Vol. 8, No. 21, 2006

epoxy-γ-amino acids 10a,b with good yields, whereas N-tert-
butylepoxy-1,2-oxazinones 6a-c (R ) aryl) under different
conditions [H2, 20 atm, Pd(OH)2/C, 10 mol %, MeOH]
furnished the R-hydroxy-γ-amino acids 11a-c as the main
products17 (Scheme 2). The structure of 11a was confirmed
Scheme 3
Scheme 2
with very good yields. Reduction, instead, of epoxy-1,2-
oxazinones 9a,b,d (Scheme 3) gave the R,â-epoxy-γ-
butyrolactams 13a,b.23
Next, we evaluated the possibility of performing an asym-
metric synthesis of such epoxy-1,2-oxazinones, simply
by an X-ray analysis.18
The N-tert-butyl substituent of 6 and 10 or 11 could not
be removed. Therefore, we turned our attention to cumyl
nitrones in view of the fact that the cumyl group can be easily
removed under mild conditions.19,20 As expected, 4,5-epoxy-
1,2-oxazinones 6h-m could be prepared by hydrolysis of
compounds 4h-m, which in turn had been obtained by the
addition of 3a to N-cumylnitrones 1h-m (Scheme 1 and
Table 1).8,21 Reduction [H2, 1 atm, Pd/C (5 mol %)] of
N-cumylepoxy-1,2-oxazinones 6h,i,k provided the R,â-
epoxy-γ-amino acid 12a-c in good yields with the free
amino group (Scheme 3). Moreover, treatment of 12a-c with
Me3SiCHN2 in dry MeOH gave R,â-epoxy-γ-butyrolactams
13a-c quantitatively.22 N-Cumylepoxy-1,2-oxazinones 6h-j
too could be selectively N-deprotected under acidic condi-
tions (TFA, CH2Cl2) giving epoxy-1,2-oxazinones 9a,b,d
Table 2. Reaction of Chiral Nonracemic â-Lithiated
Oxazolinyloxirane 3b with Nitrones 1a,g,h: Preparation of
Optically Active Spirocyclic Compounds 4 and
4,5-Epoxy-1,2-oxazinones 6
(16) CCDC 606446 contains the supplementary crystallographic data for
compound 6d. These data can be obtained, free of charge, from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(17) It is worth noting that in the case of 6f,g reduction even under 20
atm on Pd(OH)2/C did not cause any oxirane ring-opening reaction leading,
instead, to R,â-epoxy-γ-amino acids 10a,b as the main products.
(18) CCDC 606448 contains the supplementary crystallographic for
compound 11a. These data can be obtained, free of charge, from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(19) For some examples concerning the easy deprotection of the cumyl
group, see: (a) Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett. 2000,
2, 4229-4232. (b) Clayden, J.; Tchabanenko, K.; Yasin, S. A.; Turnbull,
M. D. Synlett 2001, 302-304.
(20) N-Benzyl nitrones are not useful because of the pronounced acidity
of the benzylic hydrogens, which is able to protonate the starting lithiated
oxirane.
nitrone 1
R1
R
4 (% yield)a,b
6 (% yield)a,b
erc
1a
1g
1h
t-Bu
′′
cumyl
C6H5
C7H15
C6H5
(-)-4n (61)
(-)-4o (51)
(-)-4p (65)
(-)-6a (50)
(-)-6 g (60)
(-)-6h (61)
98:2
′′
′′
a Isolated yields. b The diastereomeric ratio (dr > 98:2) was established
1
from the analysis of the H NMR spectra of the crude reaction mixture of
6 (see ref 8). c The enantiomeric ratio was determined via HPLC (Diacel
OD-H) or chiral gas chromatography on epoxy-1,2-oxazinones 6 in
comparison with racemic samples.
(21) Hydrolysis of 4m furnished the expected epoxy-1,2-oxazinone 6m
only in a low yield, the main product being the hydroxyamide 8 (Scheme
1). The formation of this compound, which is currently under investigation,
could be explained with a concerted cumene hydroperoxide-type rearrange-
ment involving a reactive delocalized phenonium ion as the intermediate
further to an electrophilic aromatic substitution promoted by the π-electrons
on the nitrogen atom linked to the cumyl group. See also: Hamann, H.-Y.;
Liebscher, Y. J. Org. Chem. 2000, 65, 1873-1876.
starting from optically active oxazolinyloxiranes. Lithiation
of the optically active oxazolinyloxirane 2b (er ) 98/2),5a
followed by the coupling of the corresponding lithiated inter-
mediate 3b with N-tert-butylnitrones 1a,g and N-cumylni-
Org. Lett., Vol. 8, No. 21, 2006
4805

trone 1h, gave spirocyclic compounds 4n-p (Table 2) with
complete diastereo- and enantioselectivity.24 Hydrolysis
(TFA) of 4n-p furnished highly enantioenriched N-tert-
butylepoxy-1,2-oxazinones (S,S,S)-(-)-6a, (S,S,S)-(-)-6g,
and N-cumylepoxy-1,2-oxazinones (S,S,S)-(-)-6h, respec-
tively, which are amenable to the corresponding R,â-epoxy-
γ-amino acids, as in the case of (-)-12a (Table 2).
In conclusion, we have reported a highly stereoselective
synthesis of novel epoxy-1,2-oxazin-6-ones that can be easily
transformed into R,â-epoxy-γ-amino acids and the corre-
sponding R,â-epoxy-γ-butyrolactams. To date, these are rare
examples of R,â-epoxy-γ-amino acids to be reported. The
constraints of the oxirane ring in the backbone of these
γ-amino acids could make this new derivatives very attractive
for study in the field of new peptides and peptidomimetics.
An added value to these kinds of amino acids is given by
the presence of the oxirane ring that could be manipulated
for synthetic purposes.7 More work is underway in our
laboratory to this end.
Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” and the FIRB
Project “Progettazione, preparazione e valutazione biologica
e farmacologica di nuove molecole organiche quali potenziali
farmaci innovativi” MIUR (Rome), by the University of Bari
and by the Consortium CINMPIS. We also thank Dr. Michel
Giorgi of the Centre Scientifique Saint-Jerome, Marseille,
France, for X-ray analysis of compounds 4b, 5f, 6d, and
11a.
(22) R,â-Epoxy-γ-amino acids 12 convert spontaneously into R,â-epoxy-
γ-butyrolactams 13 simply by keeping them in CDCl3 for at least 24-36
h.
(23) Under reduction conditions, a dehalogenation of 9d (R ) p-ClC6H4)
occurred; see also: (a) Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 91-
95. (b) Luisi, R.; Capriati, V.; Florio, S.; Vista, T. J. Org. Chem. 2003, 68,
9861-9864.
(24) In these cases, in contrast to that observed with spirocyclic
compounds 4a-m, there was no equilibration with the corresponding
hydroxylamino forms.
Supporting Information Available: Experimental pro-
cedures and compound characterizations. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0618609
4806
Org. Lett., Vol. 8, No. 21, 2006