A new entry to polyfunctionalized 4,5-trans disubstituted oxazolidin-2-ones from L-aspartic acid

Article abstract of DOI:10.1055/s-2003-38733

A straightforward synthesis of enantiomerically pure (4R,5S)-5-oxazolidinecarboxylic acid, 2-oxo-4-[(t-butyldimethyl-silyloxy)methyl]-, benzyl ester and of (4S,5S)-4-oxazolidinecarboxylic acid, 2-oxo-5-[(t-butyldimethylsilyloxy)methyl]-, benzyl ester was envisaged starting from readily available L-aspartic acid. The key step is the diastereoselective addition of iodine with the introduction of a new stereogenic centre.

Full text of DOI:10.1055/s-2003-38733

LETTER
797
A New Entry to Polyfunctionalized 4,5-trans Disubstituted Oxazolidin-2-ones
from L-Aspartic Acid
P
olyfunctionalised
i
4,5-tra
a
ns
D
isubsti
n
tuted Oxazo
l
lidin-2-
u
ones igi Luppi, Claudia Tomasini*
Dipartimento di Chimica ‘G. Ciamician’, Alma Mater Studiorum, Università di Bologna, Via Selmi 2 – 40126 Bologna, Italy
E-mail: tomasini@ciam.unibo.it
Received 4 December 2002
The common reagent for the highly stereoselective syn-
Abstract: A straightforward synthesis of enantiomerically pure
thesis of the two compounds is the fully protected β-ami-
(4R,5S)-5-oxazolidinecarboxylic acid, 2-oxo-4-[(t-butyldimethyl-
silyloxy)methyl]-, benzyl ester and of (4S,5S)-4-oxazolidinecar-
boxylic acid, 2-oxo-5-[(t-butyldimethylsilyloxy)methyl]-, benzyl
no γ-hydroxy acid (S)-4a–c, which has been obtained in
five steps from commercially available Z-Asp-OH
ester was envisaged starting from readily available L-aspartic acid. (Z = carbobenzoxy) or Boc-L-Asp-OH (Boc = tert-butox-
The key step is the diastereoselective addition of iodine with the in-
troduction of a new stereogenic centre.
ycarbonyl). Alloc-L-Asp-OH (Alloc = allyloxycarbonyl)
was prepared from L-Asp-OH and AllocCl in DMF in the
Key words: L-aspartic acid, carboxyaziridines, oxazolidin-2-ones,
rearrangement, pseudopeptides
presence of DIEA (Scheme 1). Anhydrides 1a,b have
been obtained by reaction of Z-L-Asp-OH or Alloc-L-
Asp-OH with acetic anhydride (3 equiv) catalyzed by mi-
crowave irradiation, and the reactions are complete after 1
Molecules of a class of unnatural, synthetic oligomers minute in the absence of solvent. The N-Boc anhydride 1c
have been recently defined as foldamers.1 The essential was prepared from N-Boc-L-Asp-OH by reaction with di-
requirement of a foldamer is to possess a well-defined, re- isopropyl carbodiimmide in ethyl acetate in quantitative
petitive secondary structure, imparted by conformational yield in 2 hours.5 The previously described method,6 em-
restrictions of the monomeric unit. In this area of research ploying dicyclohexyl carbodiimide, afforded the desired
we have described a general method for the synthesis and product in high yield, but the purification step was more
the oligomerisation of 4-carboxy oxazolidin-2-ones.2 complex. Anhydrides 1a–c were then reduced to lactones
These compounds are common heterocycles, which can 2a–c with NaBH4 in anhyd THF.7 The transformation into
be easily obtained by reaction of vicinal amino alcohols the desired γ-hydroxy acids 3a–c proved to be more diffi-
with a synthetic equivalent of carbon dioxide,3 provided cult. Some authors have reported hydrolysis with K2CO3
that the amino alcohols are commercially available or can in refluxing water and acetone.8 In our hands this reaction
be easily synthesized.4
is very slow and, even after prolonged reaction times, af-
fords mixtures of lactone 2 and of hydroxy acid 3. In ad-
dition, hydrolysis with an aqueous solution of KOH
failed, leading to a complex mixture of compounds.8a In
contrast to these procedures, we found that the hydrolysis
proceeded smoothly in high yield in the presence of
Cs2CO3 in water and acetone at room temperature in 3
hours. The fully protected β-amino γ-hydroxy acids (S)-
4a–c were obtained by protection of the hydroxyl group
with t-BuMe2SiCl and imidazole and of the carboxyl
group with benzyl bromide and triethylamine.
As a part of this project, we report the synthesis of
(4R,5S)-5-oxazolidinecarboxylic acid, 2-oxo-4-[(t-bu-
tyldimethylsilyloxy)methyl]-, benzyl ester 1 and of
(4S,5S)-4-oxazolidinecarboxylic acid, 2-oxo-5-[(t-butyl-
dimethylsilyloxy)methyl]-, benzyl ester 2 from L-aspartic
acid (Figure 1).
O
TBMSO
TBMSO
OBn
OBn
O
HN
The introduction of the stereogenic centre at carbon 2 of
4a–c was achieved by formation of the corresponding lith-
ium salt and quenching with iodine, following a well es-
tablished protocol: by treatment with LiHMDS and iodine
at low temperature, these substrates undergo cyclization
with the formation of the corresponding aziridines.9 As
was previously observed by Seebach10 and by us,11 the re-
action of the lithium dianion of N-protected β-amino es-
ters with an electrophile affords the 2,3-anti adducts both
with high yields and high stereoselectivities. When the
electrophile is a good leaving group (as in the case of halo-
gens), the direct formation of the corresponding aziridine
is usually observed in THF, since the halogen is substitut-
ed by the neighbouring nitrogen. In a typical reaction pro-
cedure, a solution of LiHMDS (2.2 equiv) in dry THF was
OBn
O
TBMSO
L-Asp-OH
(4R,5S)-1
HNR
O
O
NH
O
O
(4S,5S)-2
Figure 1 Synthetic scheme for the preparation of oxazolidin-2-ones
1 and 2 from L-aspartic acid.
Synlett 2003, No. 6, Print: 05 05 2003.
Art Id.1437-2096,E;2003,0,06,0797,0800,ftx,en;D27702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

798
G. Luppi, C. Tomasini
O
LETTER
tained in quantitative yield, although: a drastic decrease of
yield was observed when the iodine was added at low tem-
perature (entry 3). Entries 7 and 8 report two experiments
where ZnCl2 was added to the lithium salt before the io-
dine. In both cases a decrease of yields and diastereoselec-
tivities was observed. On the contrary an excellent result
was observed, when switching the reaction solvent from
THF to toluene (entry 6).
NHCO2R
a: R = Bn
HO
i
OH
O
O
98%
O
NHCO2R
O
b: R = allyl
(S)-1a-b
O
NHBoc
HO
ii
OH
NHBoc
95%
O
O
O
O
(S)-1c
Moreover, while screening a suitable reaction solvent to
improve the diastereoselectivity, we found that the reac-
tion of 4a with LiHMDS and iodine in toluene resulted in
the exclusive formation of the anti α-iododerivative 7,12
which could be isolated as a single stereoisomer and trans-
formed into the trans oxazolidin-2-one 113 in quantitative
yield simply by treatment with microwave irradiation in
DMF (Scheme 2). The trans configuration was assigned
by analysis of the 1H NMR coupling constant of the het-
erocycle hydrogens (J = 4.4 Hz).14
NHR
OH
iii
78–82%
iv
HO
(S)-1a-c
80-85%
O
NHR O
O
(S)-2a-c
(S)-3a-c
OBn
O
a: R = Z
v, vi
65–70%
TBMSO
b: R = Alloc
c: R = Boc
HNR
(S)-4a-c
Scheme 1 (i) Ac2O (3 equiv), microwave, 1 min; (ii) DIC (1.1.
equiv), ethyl acetate, r.t., 2 h; (iii) NaBH4 (1.5 equiv), anhyd THF, r.t.,
16 h; (iv) Cs2CO3 (1.1 equiv), H2O–acetone, r.t., 3 h, then H3O+;
(v) imidazole (2 equiv), t-BuMe2SiCl (1.4 equiv), dry DMF, r.t., 16 h;
(vi) BnBr (1.1. equiv), Et3N (3 equiv), acetone, r.t. 16 h.
I
OBn
OBn
i, ii
TBMSO
TBMSO
93%
HNZ
O
HNZ
O
(S)-4a
(2R,3R)-7
O
added drop wise to a stirred solution of 4 in dry THF at
–20 °C. The mixture was stirred 45 minutes, then iodine
was added in the conditions reported in Table 1 and the
mixture was worked up as usual. The trans N-carboxy
aziridines 5a–c were obtained in high yield and good dia-
stereoselectivity.
TBMSO
OBn
iii
O
HN
85%
(4R,5S)-1
O
Scheme 2 (i) LiHMDS (2.2 equiv), anhyd toluene, –20 °C, 45 min;
(ii) I2 (1.1 equiv), anhyd toluene, –30 °C, 60 min; (iii) DMF, micro-
wave, 2 min.
Table 1 shows the chemical yields and the cis/trans ratios
obtained when the reaction conditions and the N-protect-
ing group are modified. Generally the aziridines are ob-
Table 1 Chemical Yields and Diastereomeric Product Ratios for the Synthesis of Aziridines 5a–c and 6a–c
O
O
OBn
TBMSO
TBMSO
OBn
TBMSO
OBn
+
N
R
N
R
HNR
R
O
(S)-4a–c
(2R,3S)-6a–c
(2S,3S)-5a–c
Entry
Reagent
Solvent
ZnCl2 (equiv)
t (min), T (°C)
I2 (1.1equiv)
Yield (%)
5:6 Ratioa
t (min), T (°C)
1
2
3
4
5
6
7
Z
Z
Z
4a
4a
4a
4b
4c
4c
4a
THF
THF
THF
THF
THF
toluene
THF
–
–
–
–
–
–
60 min, –20 °C
60 min, –30 °C
60 min, –60 °C
60 min, –30 °C
60 min, –30 °C
60 min, –30 °C
60 min, –20 °C to r.t.
95
90
0
75:25
83:17
–
Alloc
97
98
86b
30
56:44
68:32
98:2
Boc
Boc
Z
1.1 equiv,
70:30
45 min, –20 °C
8
Z
4a
THF
2.2 equiv,
60 min, –20 °C to r.t.
50
63:37
45 min, –20 °C
a Inseparable mixtures.
b The corresponding anti α-iododerivative was obtained in about 10% yield.
Synlett 2003, No. 6, 797–800 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Polyfunctionalised 4,5-trans Disubstituted Oxazolidin-2-ones
799
On the other hand, oxazolidin-2-one 2 was prepared by
ring expansion of the carboxyaziridines.15 The reaction is
catalyzed by Sn(OTf)2 in dry methylene chloride and is
totally regio- and diastereoselective. The presence of an
azaphilic Lewis acid, such as Sn(OTf)2, promotes the re-
arrangement which is enhanced and directed by the pres-
ence of the carboxy group nearby, while the t-butyl-
dimethylsilyloxy group does not affect the regioselectivi-
ty. Thus an inseparable mixture of N-Boc aziridines 5c
and 6c (98:2 ratio) was submitted to ring expansion
(Scheme 3) with a catalytic amount (20%) of Sn(OTf)2 in
anhyd dichloromethane and the oxazolidin-2-one 216 was
obtained in 80% yield after silica gel chromatography.
The regiochemical assignment of 2 was made by compar-
ison of its 1H NMR spectrum with the spectra of 1 and of
related molecules,17 and the stereochemical assignment
was made by analysis of the 1H NMR coupling constant of
the heterocycle hydrogens (J = 3.6 Hz).14 On the contrary,
if the N-Z aziridines 5a and 6a were treated with a catalyt-
ic amount of Sn(OTf)2, the reaction occurred much more
slowly and was complete in 70 hours, during which time
the partial cleavage of the silyloxy group occurred afford-
ing a mixture of 2-phenylmethoxy 5-oxazoles and oxazo-
lidin-2-ones.
Acknowledgment
This work was supported in part by MIUR (Cofin 2002 and 60% –
Roma) and by Alma Mater Studiorum – University of Bologna
(funds for Selected Research Topics).
References
(1) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (b) Hill,
D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. Rev. 2001, 101, 3893. (c) Cubberley, M. S.; Iverson,
B. L. Curr. Opin. Chem. Biol. 2001, 5, 650.
(2) (a) Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153.
(b) Lucarini, S.; Tomasini, C. J. Org. Chem. 2001, 66, 727.
(3) (a) Newman, S. M.; Kutner, A. J. Am. Chem. Soc. 1951, 73,
4199. (b) Hyne, J. B. J. Am. Chem. Soc. 1959, 81, 6058.
(b) Lubell, W. D.; Rapoport, H. J. Org. Chem. 1989, 54,
3824. (c) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835.
(4) Bergmeier, S. Tetrahedron 2000, 56, 2561.
(5) Acetic anhydride could not be employed, owing to the acid
sensitive Boc group.
(6) Munegumi, T.; Meng, Y.-Q.; Harada, K. Chem. Lett. 1988,
10, 1643.
(7) (a) McGarver, J.; Hiner, R. N.; Matsubara, Y.; Oh, T.
Tetrahedron Lett. 1983, 24, 2733. (b) McGarvey, G. J.;
Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. Am.
Chem. Soc. 1986, 108, 4943.
(8) (a) Nitta, H.; Ueda, I.; Hatanaka, M. J. Chem. Soc., Perkin
Trans. 1 1997, 1793. (b) Nitta, H.; Hatanaka, M.; Ueda, I. J.
Chem. Soc., Perkin Trans. 1 1990, 432.
(9) (a) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry
1997, 8, 1693. (b) Zwanenburg, B.; Thjis, L. Pure Appl.
Chem. 1996, 68, 735. (c) Tanner, D. Angew. Chem., Int. Ed.
Engl. 1994, 33, 599. (d) Fanta, P. E. In Heterocyclic
Compounds with Three- and Four-membered Rings, Part 1;
Weissberg, A., Ed.; Wiley Interscience: New York, 1964,
524.
O
O
TBMSO
OBn
i,ii
TBMSO
OBn
NH
O
N
80%
Boc
O
(2S,3S)-5c
(4S,5S)-2
O
TBMSO
OBn
(10) (a) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28,
3103. (b) Seebach, D.; Estermann, H. Helv. Chim. Acta
1988, 71, 1824.
iii
N
Z
(2S,3S)-5a
(11) (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C.
J. Org. Chem. 1998, 63, 2351. (b) Cardillo, G.; Tolomelli,
A.; Tomasini, C. Eur. J. Org. Chem. 1999, 155.
O
O
RO
OBn
RO
OBn
+
N
NH
O
O
(c) Nocioni, A. M.; Papa, C.; Tomasini, C. Tetrahedron Lett.
1999, 40, 8453. (d) Cardillo, G.; Gentilucci, L.; Tolomelli,
A.; Tomasini, C. Synlett 1999, 1727. (e) Papa, C.;
Tomasini, C. Eur. J. Org. Chem. 2000, 1569.
R = TBMS or H
OBn
O
Scheme 3 (i) Sn(OTf)2 (0.2 equiv), anhyd CH2Cl2, r.t., 20 h; (ii) si-
lica gel chromatography; (iii) Sn(OTf)2 (0.2 equiv), anhyd CH2Cl2,
r.t., 70 h.
(12) A similar behaviour in toluene has been recently described
by: Sim, T. B.; Kang, S. H.; Lee, K. S.; Lee, W. K.; Yun, H.;
Dong, Y.; Ha, H.-J. J. Org. Chem. 2003, 68, 104.
(13) Experimental Procedure: LiHMDS (2.2 mmol, 1 M soln.
in THF, 2.2 mL) was added to a stirred solution of (S)-4a (1
mmol, 0.42 g) in anhyd toluene (10 mL) under nitrogen
atmosphere at –20 °C. The mixture was stirred 45 min at
–20 °C, then iodine was added (1.5 mmol, 0.76 g) in anhyd
toluene (10 mL). The mixture was stirred 1 h, then an aq sat.
solution of Na2SO3 was added, and the organic layer was
separated, washed with H2O, dried over Na2SO4 and the
solvent was removed under reduced pressure. The
iododerivative 7 was obtained in 93% yield (0.51 g) without
any purification and dissolved in anhyd DMF (2 mL). The
mixture was stirred under a microwave irradiation (210 W
power, 2 min), then EtOAc was added (20 mL), and the
organic layer was washed twice with 1 N aq solution of HCl,
dried over Na2SO4 and the solvent was removed under
reduced pressure. The residue was purified by silica gel
In conclusion, we have demonstrated a new and conve-
nient synthesis of 4,5-trans disubstituted oxazolidin-2-
ones in enantiomerically pure form. This is a straightfor-
ward method, which leads to the desired compounds in a
small number of steps; furthermore the ready availability
of the starting Z-L-Asp-OH and Boc-L-Asp-OH proposes
these molecules as good candidates for several applica-
tions, for instance their introduction into oligopeptide
chains.
Synlett 2003, No. 6, 797–800 ISSN 0936-5214 © Thieme Stuttgart · New York

800
G. Luppi, C. Tomasini
LETTER
chromatography (cyclohexane–EtOAc 9:1 as eluant) and
obtained as a white solid in 83% yield (0.28 g): Mp = 55–
58 °C. IR(nujol): 3490, 3291, 1772, 1746, 1666 cm–1. 1H
NMR (200 MHz, CDCl3): δ = 0.09 (s, 6 H, Me2Si), 0.88 (s,
9 H, t-Bu), 2.68 (ABX, J = 4.4, 4.8, 12.2 Hz, 2 H, CH2OSi),
3.92 (q, J = 4.4 Hz, CHN), 4.82 (d, J = 4.4 Hz, CHO), 5.27
(AB, J = 12.6 Hz, OCH2Ph), 6.18 (br s, 1 H, NH), 7.25–7.42
(m, 5 H, Ph). 13C NMR (CDCl3): δ = –5.5, 25.7, 57.1, 64.1,
67.7, 74.6, 128.3, 128.6, 134.6, 158.0, 168.6. [α]D = +4.1
(c = 1.7 in CH2Cl2).
under nitrogen at r.t., then an aq sat. solution of Na2CO3 was
added, the organic layer was dried over Na2SO4 and the
solvent was removed under reduced pressure. The residue
was purified by silica gel chromatography (cyclohexane–
EtOAc 9:1 as eluant) and the product 2 was obtained in 80%
yield (88 mg) as a low melting solid. IR (CH2Cl2): 3443,
1772, 1746 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.09 (s,
6 H, Me2Si), 0.88 (s, 9 H, t-Bu), 3.79 (dd, 1 H, J = 3.0, 11.7
Hz, 1 H, CHHOSi), 3.91 (dd, J = 3.6, 11.4 Hz, 1 H,
CHHOSi), 4.43 (d, J = 5.1 Hz, CHN), 4.66–4.72 (m, 1 H,
CHO), 5.23 (AB, J = 11.8 Hz, OCH2Ph), 5.33 (br s, 1 H,
NH), 7.29–7.42 (m, 5 H, Ph). 13C NMR (CDCl3): δ = –5.3,
25.9, 54.9, 63.1, 68.1, 78.8, 128.8, 129.0, 129.1, 134.8,
157.9, 170.2. [α]D = +20.9 (c = 0.1 in CH2Cl2).
(14) Foglia, T. A.; Swern, D. J. Org. Chem. 1969, 34, 1680.
(15) Ferraris, D.; Drudy, W. J. III; Cox, C.; Lectka, T. J. Org.
Chem. 1998, 63, 4568.
(16) Experimental Procedure: To a stirred solution of a 98:2
mixture of N-Boc aziridines (2S,3S)-5c and (2R,3S)-6c (0.3
mmol, 0.13 g) in anhyd dicloromethane (10 mL) was added
Sn(OTf)2 (0.06 mmol, 25 mg). The mixture was stirred 20 h
(17) Scolastico, C.; Conca, E.; Prati, L.; Guanti, G.; Banfi, L.;
Berti, A.; Farina, P.; Valcavi, U. Synthesis 1985, 850.
Synlett 2003, No. 6, 797–800 ISSN 0936-5214 © Thieme Stuttgart · New York