Stereospecific beta-lithiation of oxazolinyloxiranes: synthesis of alpha,beta-epoxy-gamma-butyrolactones.

Article abstract of DOI:10.1021/ol025781i

[reaction: see text]. Stereospecific beta-lithiation of beta-aryl-substituted oxazolinyloxiranes is described. The trapping reaction of such reactive intermediates with carbonyl compounds gave alpha,beta-epoxy-gamma-butyrolactones after deblocking of the

Full text of DOI:10.1021/ol025781i

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1551-1554
Stereospecific â-Lithiation of
Oxazolinyloxiranes: Synthesis of
r,â-Epoxy-γ-butyrolactones
Vito Capriati, Leonardo Degennaro, Raffaele Favia, Saverio Florio,* and
Renzo Luisi
Istituto di Chimica dei Composti OrganoMetallici-ICCOM, Dipartimento
Farmaco-Chimico, UniVersita` di Bari, Via E.Orabona 4, I-70125 Bari, Italy
florio@farmchim.uniba.it
Received February 26, 2002
ABSTRACT
Stereospecific â-lithiation of â-aryl-substituted oxazolinyloxiranes is described. The trapping reaction of such reactive intermediates with
carbonyl compounds gave r,â-epoxy-γ-butyrolactones after deblocking of the oxazoline moiety. This methodology has been also extended
to the synthesis of optically active r,â-epoxy-γ-butyrolactones.
R,â-Epoxylactones are versatile intermediates in synthetic
organic chemistry. R,â-Epoxy-γ-butyrolactones, in particular,
intervene in synthetic routes to precursors of natural products
such as epolactaene, which has a potent neurite outgrowth
activity in a human neuroblastoma cell line SH-SYS5,1 of
(+)-cerulenine, a potent fungal inactivator of fatty acid
synthetase,2 and of R-methylenebis-γ-butyrolactones.3
Our continuing involvement in the chemistry of hetero-
cyclic systems as well as of oxiranyl anions4 led us to
consider the possibility that the chemistry of the oxazoline
system combined with the oxiranyl anion based methodology
might be exploited for the preparation of R,â-epoxy-γ-
butyrolactones according to the retrosynthetic approach
shown in Scheme 1. In this Letter we report the results of a
synthetic procedure based on such analysis.
Scheme 1
(1) Kuramochi, K.; Itaya, H.; Nagata, S.; Takao, K.; Kobayashi, S.
Tetrahedron Lett. 1999, 40, 7367-7370.
(2) Mani, N. S.; Townsend, C. A. J. Org. Chem. 1997, 62, 636-640.
(3) Lertvorachon, J.; Thebtaranonth, Y.; Thongpanchang, T.; Thonyoo,
P. J. Org. Chem. 2001, 66, 4692-4694.
(4) Abbotto, A.; Capriati, V.; Degennaro L.; Florio, S.; Luisi, R.; Pierrot,
M.; Salomone, A. J. Org. Chem. 2001, 66, 3049-3058 and references
therein.
(5) Relative configuration, distinguishing diastereoisomers, may be
denoted by the configurational descriptors R*,R* and R*,S* meaning,
respectively, that the two centres have identical or opposite configurations,
as reported in: IUPAC. Nomenclature of Organic Chemistry, Sections A-F
and H; Pergamon Press: Elmsford, NY, 1979; p 482, Rule E-4.10.
Our work started with the preparation of the needed
precursors. (1R*,2R*)- and (1R*,2S*)-1-methyl-1-oxazoli-
nyloxiranes 1a-d5 were prepared by the Darzens reaction
10.1021/ol025781i CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/03/2002

of lithiated 2-(1-chloroethyl)-2-oxazoline, as reported (Scheme
2).6 Once separated by column chromatography, the relative
proved the stability of aryl-substituted lithiated oxiranes.8
Lithium cation is probably coordinated by the aza group of
the oxazolinyl ring in lithiated species 2a,b. â-Lithiation in
substituted oxiranes has been recently reported.9 In all cases
the reaction of lithiated oxiranes 2a,b proceeded stereo-
specifically with complete retention of configuration, thus
proving the configurational stability of such lithiated spe-
cies.10 Interestingly, the reaction of lithiated oxiranes 2a,b
with symmetrical aliphatic and aromatic ketones afforded
quite good yields of spirocyclic compounds 4a-f (Table 1),
Scheme 2
Table 1. Spirocyclic Compounds 4 and Epoxylactones 5
spirocyclic
compound (% yield)a
epoxylactone
(% yield)a
Ar
R1
R2
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
Ph
p-tolyl
p-tolyl
Ph
Me
Et
-(CH2)4-
-(CH2)5-
Me
Et
4a (60)
4b (60)
4c (79)
4d (67)
4e (82)
4f (60)
4g (84)b
4h (94)c
4i (95)d
5a (>95)
5b (>95)
5c (>95)
5d (>95)
5e (>95)
5f (>95)
5g (>95)
5h (>95)
5i (>95)
configuration to 1a,b and 1c,d could be assigned on the basis
of the long-range 3JCH coupling constant between the methyl
group and the oxirane â-hydrogen.4,7
Lithiation of epoxides 1a,b (s-BuLi/TMEDA, Et2O, -98
°C) produced oxiranyllithiums 2a,b, which proved to be
stable at low temperature for several hours. Trapping of 2a
(R ) p-tolyl) with electrophiles (D2O, MeI, Me3SiCl, and
allyl chloride) afforded tetrasubstituted epoxides 3a-d in
good to excellent yields upon warming to room temperature
and conventional workup (Scheme 3).
Ph
Ph
Ph
H
H
H
Ph
Me
Ph
Ph
a Isolated yield. b Diastereomeric ratio 51/49 by GC analysis. c Diaste-
reomeric ratio 54/46 by GC analysis. d Diastereomeric ratio 67/33 by 1H
NMR analysis.
Scheme 3a
whose structure was established on the basis of spectroscopic
1
evidence (IR, H and 13C NMR). In all cases, in the FT-IR
spectrum we could see no C-N double bond stretching of
the oxazoline ring (typically at 1660 cm-1) and in the 13C
NMR a resonance at ca. 118 ppm, characteristic of an sp3
heterosubstituted carbon atom, was observed instead of the
Csp2 resonance of the C-N double bond of the oxazoline
ring (ca. 162 ppm).
The formation of spirocyclic compounds 4a-f could likely
be explained with the nucleophilic addition of the intermedi-
ate alkoxide on the C-N double bond of the oxazoline ring.
Such a cyclization took place diastereoselectively, furnishing
just one diastereomer. In a NOESY phase-sensitive experi-
ment carried out on the spirocyclic compound 4c, a dipolar
interaction between the NH group of the oxazolidine ring
and the methyl group of the oxirane ring testified a spatial
proximity relationship between the above groups. This seems
to indicate that the intermediate alkoxide, originated by the
stereospecific reaction of 2a,b with the ketone, attacks just
one of the diastereotopic faces (the re one) of the oxazoline
moiety (Scheme 3).
a (i) s-BuLi/TMEDA, Et2O, -98 °C; (ii) E+; (iii) R1R2CO; (iv)
H+; (v) 2% w/w aq (COOH)2.
It was nice to note that spirocyclic compounds 4a-f could
quantitatively be converted into epoxylactones 5a-f upon
treatment with 2% w/w oxalic acid (Table 1).
The stabilizing assistance to oxiranyllithiums 2a,b is likely
provided by both the oxazolinyl and the aryl groups. Indeed,
Eisch and Galle’s work on lithiated styreneoxides had amply
(8) Eisch, J. J.; Galle, J. E. J. Org. Chem. 1990, 55, 4835-4840.
(9) Lertvorachon, J.; Thebtaranonth, Y.; Thongpanchang, T.; Thongyoo,
P. J. Org. Chem. 2001, 66, 4692-4694.
(10) Generation and stereospecific alkylation of an optically active
R-trifluoromethyl oxiranyl anion has also been recently reported: Yamauchi,
Y.; Katagiri, T.; Uneyama, K. Org. Lett. 2002, 4, 173-176.
(6) Capriati, V.; Degennaro, L.; Florio S.; Luisi, R.; Tralli, C.; Troisi,
L. Synthesis 2001, 15, 2299-2306.
(7) Kingsbury, C. A.; Durham, D. L.; Hutton, R. J. Org. Chem. 1978,
43, 4696-4700.
1552
Org. Lett., Vol. 4, No. 9, 2002

The reaction of 2a,b with acetaldehyde and benzaldehyde
furnished a mixture of two spirocyclic diastereomers 4g-i
(dr 51/49, 54/46, 67/33, respectively), which could be
separated by flash chromatography and spectroscopically
characterized. Probably, the coupling reaction of 2a,b with
aldehydes is not stereoselective with reference to the newly
created stereogenic center, and as in the case of the addition
of 2a,b to ketones, the intermediate alkoxide attacks exclu-
sively the re face of the oxazoline ring thus generating only
two diastereomers. Deblocking of the masked carbonyl
function of 4g-i with oxalic acid yielded diastereomeric
epoxylactones 5g-i.
Scheme 5a
a (i) s-BuLi/TMEDA, Et2O, -98 °C; (ii) RR1CO; (iii) 2% w/w
aq (COOH)2.
reomer) that was quantitatively hydrolyzed with oxalic acid
to the corresponding epoxylactone 11a with very good er
value (Scheme 5, Table 2).
The present oxazolinyloxiranyl anion based methodology
to epoxylactones has been successfully extended to the
preparation of optically pure R,â-epoxy-γ-butyrolactones.
Optically pure (S,S,R)-oxazolinyl epoxide 9 (dr > 99:1
1
by H NMR) (Scheme 4) was prepared by the coupling
Table 2. Optically Active Spirocyclic Compounds 10a-c and
Epoxylactones 11a-c
spirocyclic
Scheme 4
R
R1
compound
epoxylactonea
er
Ph
H
Ph
Ph
H
10a (70)a
10b (50)b
10c (25)c
11a (>95)
11b (>95)
11c (>95)
98:2d
>99:1e
>99:1e
Ph
a Isolated yields (%). b Major isomer; yield determined by 1H NMR.
c Minor isomer; yield determined by 1H NMR. d Enantiomeric ratio by GC
analysis on chiraldex B-DM capillary column. e Enantiomeric ratio by HPLC
with OD-H column.
In the reaction of lithiated 9 with benzaldehyde, a
diastereomeric mixture (67/33 ratio) of the two spirocyclic
compounds 10b,c was detected by 1H NMR. Their purifica-
tion by flash chromatography led straightforwardly to a
mixture of the corresponding diastereomeric epoxylactones
11b,c. The latter could be quantitatively separated by
preparative HPLC and showed excellent er values (Table
2).14
reaction of the titanium azaenolate of (4S)-4-isopropyl-2-
chloromethyl-2-oxazoline11 6 with PhCHO, as similarly
reported for other chiral nonracemic R-chloroalkyl-2-oxazo-
lines.12
Compound 6 was first lithiated, transmetalated with Ti-
(i-PrO)4, and then reacted with benzaldehyde to furnish
(S,S,R)-epoxide 7 (dr trans/cis 90:10; er trans > 99:1), whose
In conclusion, we have shown how useful R,â-epoxy-γ-
butyrolactones can be conveniently prepared by combining
the chemistry of lithiated oxazolinyloxiranes with that of the
oxazoline system.
1
stereochemistry was assigned on the basis of H and 13C
NMR data and unequivocally confirmed by crystallographic
X-ray analysis.13 Treatment of 7 with s-BuLi/TMEDA in
THF at -98 °C afforded oxiranyllithium 8, which proved
to be configurationally stable and could be trapped with CH3I
to give, with complete retention of configuration, trisubsti-
tuted epoxide 9 (Scheme 4).
(14) The configuration at the new stereogenic center of 11b and 11c
was determined by a careful inspection of the 1H NMR chemical shifts.
Taking into consideration that in the most stable conformation of styrene
oxide derivatives a phenyl ring sets perpendicular to the plane of the oxirane
ring even when steric factors are at their minimum (Lazzeretti, P.; Moretti,
Z.; Taddei, F.; Torre, G. Org. Magn. Reson. 1973, 5, 385-389), the
pronounced shielding effect observed for the two aromatic ortho ring protons
(∆δ ) ca. 0.4 ppm for both) of 11c, should testify in favor of a cis
relationship of the two aromatic rings so that the above-mentioned protons
(probably those belonging to the γ-lactone phenyl ring) are forced to fall
in the anisotropic shielding ring current of the oxirane phenyl ring.
Moreover, the strong upfield shift observed (∆δ ) ca. 0.2 ppm) for the
γ-lactone proton could be analogously explained taking into account the
well-known anisotropic shielding effect exhibited by the oxirane ring on
the protons lying above and below its plane, expecially when the reference
molecular system is rigid (Hassner, A. In The Chemistry of Heterocyclic
Compounds: Small Ring Heterocycles Part 3; Weissberger, A., Taylor, E.
C., Eds.; John Wiley and Sons: 1985; pp 10-11). The latter consideration
also could be applied for the stereochemistry assignment to the diastereo-
meric spirocyclic compounds 4g (obtained from the reaction with CH3-
CHO) as well as of the corresponding epoxylactones 4g.
Lithiation of 9 and reaction with benzophenone gave
spirocyclic compound 10a in good yield (only one diaste-
(11) Florio, S.; Capriati, V.; Luisi, R. Eur. J. Org. Chem. 2001, 2035-
2038.
(12) Florio, S.; Capriati, V.; Luisi, R.; Abbotto, A.; Pippel, D. J.
Tetrahedron 2001, 57, 6775-6786.
(13) Crystallographic data for compound 7 have been deposited at the
Cambridge Crystallographic Data Centre (deposition no. CCDC-179557).
Copies of the data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, U.K. [fax: (int.) + 44-1223/336-
033; E-mail: deposit@ccdc.cam.ac.uk]. ORTEP view and CIF file for
compound 7 have been also reported as Supporting Information.
Org. Lett., Vol. 4, No. 9, 2002
1553

Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” supported by the
Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica (MURST, Rome) and by the University of Bari
and CNR (Rome). The authors are also indebted to Prof.
Marcel Pierrot of the Centre Scientifique Saint-Je´roˆme,
Marseille, France, for performing X-ray analysis of com-
pound 7.
Supporting Information Available: Full experimental
details and characterization data (1H and 13C NMR, physical
data) for compounds 3a-d, 4a-i, 5a-i, 7, 9, 10a, 11a-c;
ORTEP view (Fig. S1) and CIF file for compound 7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025781I
1554
Org. Lett., Vol. 4, No. 9, 2002