Synthesis of oligomers of trans-(4S,5R)-4-carboxybenzyl 5-methyl oxazolidin-2-one: An approach to new foldamers

Article abstract of DOI:10.1021/jo005583+

The synthesis of two oligomers containing three and four residues, respectively, of trans-(4S,5R)-4-carboxy 5-methyloxazolidin-2-ones is described. The monomer is obtained by starting from benzyl-N-Boc-(3R)-aminobutanoate, by cyclization into the corresponding trans-(2S,3R)-2-carboxybenzyl-3-methyl-N-Boc-aziridine and rearrangement of the product to trans-(4S,5R)-4-carboxybenzyl-5-methyloxazolidin-2-one, catalyzed by Sn(OTf)₂. The oligomers are synthesized by activating the carboxy group as its pentaflourophenyl ester. The trimer and the tetramer are obtained in good yield, and their ¹H NMR spectra suggest that these molecules fold in ordered structures, where the C-4 hydrogen of a ring is always close to the carbonyl of the next ring. This result shows that the 4-carboxy-5-substituted-oxazolidin-2-ones are a new class of pseudoprolines which fully control the formation of a Xaa_i-1-Pro_i peptide bond in the trans conformation and are complementary to the pseudoprolines obtained from cyclocondensation of cysteine, serine, or threonine and aldehydes or ketones, which strongly favor the Xaa_i-1-Pro_i peptide bond in the cis conformation.

Full text of DOI:10.1021/jo005583+

J . Org. Chem. 2001, 66, 727-732
727
Syn th esis of Oligom er s of tr a n s-(4S,5R)-4-Ca r boxyben zyl 5-Meth yl
Oxa zolid in -2-on e: An Ap p r oa ch to New F old a m er s
Simone Lucarini and Claudia Tomasini*
Dipartimento di Chimica “G.Ciamician” - Universita` degli Studi di Bologna,
Via F. Selmi 2, 40126 Bologna, Italy
tomasini@ciam.unibo.it
Received J uly 20, 2000
The synthesis of two oligomers containing three and four residues, respectively, of trans-(4S,5R)-
4-carboxy 5-methyloxazolidin-2-ones is described. The monomer is obtained by starting from benzyl-
N-Boc-(3R)-aminobutanoate, by cyclization into the corresponding trans-(2S,3R)-2-carboxybenzyl-
3-methyl-N-Boc-aziridine and rearrangement of the product to trans-(4S,5R)-4-carboxybenzyl-5-
methyloxazolidin-2-one, catalyzed by Sn(OTf)2. The oligomers are synthesized by activating the
carboxy group as its pentaflourophenyl ester. The trimer and the tetramer are obtained in good
yield, and their 1H NMR spectra suggest that these molecules fold in ordered structures, where
the C-4 hydrogen of a ring is always close to the carbonyl of the next ring. This result shows that
the 4-carboxy-5-substituted-oxazolidin-2-ones are a new class of pseudoprolines which fully control
the formation of a Xaai-1-Proi peptide bond in the trans conformation and are complementary to
the pseudoprolines obtained from cyclocondensation of cysteine, serine, or threonine and aldehydes
or ketones, which strongly favor the Xaai-1-Proi peptide bond in the cis conformation.
In tr od u ction
Gellman has suggested the term “foldamers” for novel
oligomers which have a tendency to adopt a specific
compact conformation.1 The main characteristics of a new
foldamer should be (i) the identification of new polymeric
backbones with suitable folding propensities; (ii) the
introduction of interesting chemical functions in the
foldamer; (iii) the discovery of an efficient synthetic
pathway, which generally includes preparation of the
monomers in enantiomerically pure form and optimiza-
tion of the polymer synthesis.
The first step in foldamer design must therefore be to
identify new backbones with well-defined secondary
structural preferences;2 for instance, conformationally
constrained amino acids provide access to short se-
quences of peptide mimetics with secondary structure.3
So as good monomers for the oligomerization reaction we
envisaged the trans-4-carboxymethyl-5-alkyl/aryl-oxazo-
lidin-2-ones, whose synthesis has been recently described,
starting from racemic â-amino acids.4 The key step for
the preparation of these heterocycles is the rearrange-
ment of 2-carboxymethyl-3-alkyl/aryl-tert-butyloxycar-
bonyl-aziridines to oxazolidin-2-ones, catalyzed by a
Lewis acid (Figure 1).5 The reaction proceeds with total
F igu r e 1. Mechanism for the rearrangement of trans-2-
carboxymethyl-3-alkyl/aryl-tert-butyloxycarbonyl-aziridines to
trans-4-carboxymethyl-5-alkyl/aryl-oxazolidin-2-ones.
regio- and stereoselectivity and can afford a wide range
of 5-carboxyoxazolidin-2-ones, simply by changing the
starting â-amino acid.
These heterocycles can be considered as new pseudopro-
lines (ΨPro).6 This term has recently been introduced to
indicate synthetic proline analogues which are usually
obtained by cyclocondensation of the amino acids cys-
teine, threonine, or serine with aldehydes or ketones. The
conformation concerning the ΨPro-preceding peptide has
been studied, because the propensity of the amino acid
proline for forming a Xaai-1-Proi cis peptide bond can
be strongly enhanced by the introduction of a pseudo-
proline residue.
Resu lts a n d Discu ssion
(1) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173 and references
therein.
(2) See for example: (a) Long, D. D.; Hungerford, N. L.; Smith, M.
D.; Brittain, D. E. A.; Marquess, D. G.; Claridge, T. D. W.; Fleet, G.
W. J . Tetrahedron Lett. 1999, 40, 2195. (b) Porter, E. A.; Wang, X.;
Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565. (c)
Huck, B. R.; Langenhan, J . M.; Gellman, S. H. Organic Lett. 1999, 1,
1717. (d) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.; Hinter-
mann, T.; J aun, B.; Matthews, J . L.; Schreiber, J . V.; Oberer, L.;
Hommel, U.; Widmer, H. Helv. Chim. Acta 1998, 81, 932. (e) Hinter-
mann, T.; Gademann, K.; J aun, B.; Seebach, D. Helv. Chim. Acta 1998,
81, 983.
We report here the synthesis of enantiomerically pure
trans-(4S,5R)-4-carboxybenzyl-5-methyl-N-Boc-oxazolidin-
2-one 6 (Scheme 1), whose oligomerization affords a
molecule which can be envisaged as a new foldamer with
(5) Ferraris, D.; Drudy, W. J ., III; Cox, C.; Lectka, T. J . Org. Chem.
1998, 63, 4568.
(6) (a) Wittelsberger, A.; Keller, M.; Scarpellino, L.; Patiny, L.; Acha-
Orbea, H.; Mutter, M. Angew. Chem., Int. Ed. 2000, 39, 1111. (b)
Mutter, M.; Haack, T. Tetrahedron Lett. 1992, 33, 1589. (c) Tam, J .
P.; Miao, Z. J . Am. Chem. Soc. 1999, 121, 9013.
(3) (a) Toniolo, C. J anssen Chim. Acta 1993, 11, 10. (b) Stigers, K.
D.; Soth, M. J .; Nowick, J . S. Curr. Opin. Chem. Biol. 1999, 3, 714.
(4) Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153.
10.1021/jo005583+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/11/2001

728 J . Org. Chem., Vol. 66, No. 3, 2001
Lucarini and Tomasini
Sch em e 1. Syn th esis of Ben zyl Ester 4 a n d N-Boc
reoselectivity (90:10 diastereomeric ratio from HPLC and
1H NMR analysis) and was obtained pure after flash
chromatography. The rearrangement to oxazolidin-2-one
was performed by reaction with a catalytic amount of
Sn(OTf)2 which resulted to be the chosen reagent. The
required oxazolidin-2-one 4 was obtained in quantitative
yield and with complete regio- and stereoselectivity and
can be used without any further purification.
Der iva tive 6 of th e Mon om er
To couple two molecules of (4S,5R)-4-carboxy-5-me-
thyloxazolidin-2-one, we had to introduce a protecting
group to the nitrogen and to activate the carboxy group.
Many attempts were made in order to introduce a
protecting group in quantitative yield, without damaging
the heterocycle. Owing to the low reactivity of the
nitrogen (which is a carbamate and not an amine), we
tried to form the corresponding anion by reaction with
LiHMDS at 0 °C and then to add some protecting
reagents, such as Boc2O, allyl bromide, and FMOC
chloride (Cbz chloride was avoided, because it is not
orthogonal with the benzyl ester). The results were poor
in all cases, and the protected compound was obtained
in 20-30% yield only by reaction with Boc2O. By replac-
ing LiHMDS with iPr2EtN (Hu¨nig’s base) and a catalytic
amount of DMAP and performing the reaction in DMF,
the desired N-Boc derivative 5 was obtained in quantita-
tive yield. After catalytic hydrogenation in ethyl acetate,
the N-protected acid 6 was obtained in 67% overall yield
from 2.
The introduction of an activating group on the carboxy
function required some study. Ciufolini and co-workers10
described the synthesis and the coupling of (4S,5R)-4-
chlorocarbonyl-5-methyl-N-acetyloxazolidin-2-one, de-
rived from threonine, by reaction of the carboxyl group
with oxalyl chloride and DMF. According to the authors,
the acid chloride is a reactive material and not easy to
purify. In our hands, with the Boc as protecting group,
the reaction afforded the desired acyl chloride in very
poor yield, owing to the acid-sensitive Boc group. Indeed,
in these conditions, deprotection occurs, and an unpro-
tected acyl chloride is obtained. As Ciufolini found, this
material is unstable and readily decomposes. So a pen-
taflourophenyl ester was synthesized, by reaction of the
acid with pentafluorophenyl trifloroacetate and pyridine
in DMF.11 The activated ester was obtained in quantita-
tive yield after working up with water but could not be
chromatographed (Scheme 2).
interesting properties. In particular, we will study the
role of the carbonyl of the heterocyclic ring, which in
principle should impart an ordered structure to the
oligomer.
The preparation of the monomer was carried out
starting from the enantiomerically pure (3R)-amino-
butanoic acid 1, obtained by enzymatic hydrolysis of the
corresponding racemic N-phenylacetyl amide with peni-
cyllin G acylase (PGA).7 Preferentially this enzyme
hydrolyzes the L (i.e., S) enantiomer, while the R is
successively hydrolyzed with 6 M HCl at reflux. The (3R)-
aminobutanoic acid is then transformed into 2 by protec-
tion of the amino group with Boc anhydride and sodium
carbonate and of the carboxy group with benzyl bromide
and triethylamine (Scheme 1). The benzyl was chosen as
the protecting group of the carboxy function because it
is removable by hydrogenolysis, which does not damage
the heterocyclic ring. An HPLC analysis of 2 has shown
that it was enantiomerically pure, and the result has
been confirmed by comparing of the [R]D with the data
reported in the literature.8
The coupling with the COOH-protected monomer 4 was
performed in dry DMF with iPr2EtN (2.2 equiv) and
DMAP at room temperature for 2 h. The yield is around
70%, but it is very sensitive to reaction conditions and
can drop to about 30%, if the reaction is not carefully
carried out. In any case we never isolated any byproduct,
due to the hydrolysis of an heterocyclic ring. Dimer 8 was
then obtained pure after flash chromatography.
The aziridine 3 was obtained by formation of the
dianion of 2 with LiHMDS in dry THF and cyclization
with iodine.9 The reaction proceeded with the intermedi-
ate formation of the anti 2-iodo derivative which was
immediately transformed into the heterocycle 3. The
trans aziridine was formed with high yield and diaste-
The 1H NMR spectrum of the dimer 8 showed an
interesting outcome. The chemical shift of the C-4
hydrogen of an heterocycle resonates at 5.49 ppm, while
the other resonates at 4.59 ppm, which is roughly the
(7) (a) Rossi, D.; Lucente, G.; Romeo, A. Experientia 1977, 33, 1557.
(b) Soloshonok, V. A.; Svedas, V. K.; Kukhlar, V. P.; Kirilenko, A. G.;
Rybakova, A. V.; Solodenko, V. A.; Fokina, N. A.; Kogut, O. V.; Galaev,
I. Y.; Kozlova, E. V.; Shishkina, I. P.; Galushko, S. V. Synlett 1993,
339. (c) Soloshonok, V. A.; Fokina, N. A.; Rybakova, A. V.; Shishkina,
I. P.; Galushko, S. V.; Sorochinsky, A. E.; Kukhlar, V. P.; Savchenko,
M. V.; Svedas, K. V. Tetrahedron: Asymmetry 1995, 7, 1601. (d)
Cardillo, G.; Tolomelli, A.; Tomasini, C. J . Org. Chem. 1996, 61, 8651.
For general reviews reporting the asymmetric synthesis of â-amino
acids, see: (e) Enantioselective Synthesis of â-Amino Acids; J uaristi,
E., Ed., Wiley-VCH: New York, 1997. (f) Cole, D. C. Tetrahedron 1989,
50, 9517. (g) J uaristi, E.; Quintana, D.; Escalante, J . Aldrichim. Acta
1994, 27, 3. (h) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25,
117.
(9) For general reviews reporting the synthesis of aziridines, see:
(a) Osborn, H. M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997, 8,
1693. (b) Zwanenburg, B.; Thjis, L. Pure Appl. Chem. 1196, 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; Weissberg, A., Ed.; Wiley-Interscience, New York, 1964; Part
1, p 524.
(8) Matthews, J . L.; Overhand, M.; Kuehnle, F. N. M.; Ciceri, P. E.;
Seebach, D. Liebigs Ann., Recl. 1997, 7, 1371.
(10) Xi, N.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 6595.
(11) Green, M.; Berman, J . Tetrahedron Lett. 1990, 31, 5851.

Oligomerization of 4-Carboxy-5-methyloxazolidin-2-ones
J . Org. Chem., Vol. 66, No. 3, 2001 729
F igu r e 2. The structure and the more representative chemi-
cal shift of dimer 9 is reported. The molecule comes from the
coupling of two racemates, so that a mixture of two diastere-
omers is obtained.
Sch em e 2. Syn th esis of th e Dim er 9
F igu r e 3. This conformation of 8 is in agreement with the
lower minimum obtained with AM1 calculations and accounts
for the anomalous chemical shift of C-4 hydrogen of ring A.
Sch em e 3. Syn th esis of th e Tr ioxa zolid in -2-on e
13 a n d of th e Tetr a oxa zolid in -2-on e 14
same chemical shift recorded for the monomers 4 (4.01
ppm), 5 (4.34 ppm), and 6 (4.42 ppm). To understand the
reason for this strong variation in chemical shift, we had
to understand whether the shifted doublet belonged to
ring A or to ring B. So we synthesized the racemic dimer
9, containing a methyl and an isopropyl residue (Figure
2). A mixture of two diastereomers was obtained, so two
doublets at 5.58 and 5.63 ppm and two doublets at 4.50
1
and 4.64 ppm were recorded. From H NMR decoupling
experiments, we could attribute the shifted doublets to
C-4 hydrogen of ring A.
This anomalous chemical shift may be attributed to a
rigid conformation assumed by the two oxazolidin-2-ones,
which are nearly orthogonal one to the other. In this
conformation, C-4 hydrogen of ring A results to be very
near to the carbonyl at C-2 of ring B, which causes its
strong deshielding. AM1 calculations performed on 8
confirm this prediction.12 Indeed, by rotating the two
bonds between ring A and ring B, four conformations of
8 corresponding to a minimum were found. Among them,
the most stable conformation13 is in agreement with our
hypothesis (Figure 3). This result shows that the 4-car-
boxy-5-substituted-oxazolidin-2-ones are a new class of
pseudoprolines which fully control the formation of a
Xaai-1-Proi peptide bond in the trans conformation and
are complementary to the pseudoprolines obtained from
cyclocondensation of cysteine, serine, or threonine and
tive yield, and no products obtained from the opening of
the heterocycles were isolated. On the other hand, by
reduction of the benzyl ester with hydrogen and pal-
ladium, the free acid 11 was obtained in quantitative
yield. Both compounds can be utilized without any
further purification. The acid was transformed in quan-
titative yield into the activated ester 12, which was stable
to workup, but could not be chromatographed. The
synthesis of the trimer 13 and of the tetramer 14 was
performed following the procedure that we had envisaged
for the synthesis of the dimer 8, in DMF in the presence
of iPr2EtN and DMAP. The trioxazolidin-2-one 13 and
the tetraoxazolidin-2-one 14 were obtained in 55% and
50% yield, respectively, after flash chromatography.
The 1H NMR spectra of 13 and 14 showed the expected
results (Figure 4): in the trimer 13, two of the three
doublets of C-4 hydrogens of rings A, B, C are strongly
aldehydes or ketones, which strongly favor the Xaai-1
-
Proi peptide bond in the cis conformation.6a
Bearing this result in mind, we felt that an oligomer
of n elements should have n - 1 shifted doublets to be a
foldamer. So we projected the synthesis of the corre-
sponding tri- and tetra-4-carboxyoxazolidin-2-one, to
verify if these oligomers had, respectively, two and three
shifted doublets (Scheme 3). Some dimer 8 was hydro-
lyzed with trifluoroacetic acid in order to remove the Boc
group. The reaction afforded the free NH 10 in quantita-
(12) The minimization was performed with semiempirical AM1
Hamiltonian using the integrated package MOPAC 2000.
(13) The most stable conformation of dimer 8 is reported in Figure
3 and is about 4 kcal/mol more stable than the closest alternative.

730 J . Org. Chem., Vol. 66, No. 3, 2001
Lucarini and Tomasini
F igu r e 4. 1H NMR of fully protected monomer 6 (a), dimer 8 (b), trimer 13 (c), and tetramer 14 (d). The areas regarding the ring
hydrogen are reported.
deshielded and all resonate between 5.4 and 5.7 ppm,
while the third resonates at 4.56 ppm. Following the
same behavior, three of the four doublets of C-4 hydro-
gens of the tetramer 14 resonate between 5.4 and 5.7
ppm, while the fourth resonates at 4.55 ppm. From this
outcome we can deduce that both the oligomers fold in
ordered structures, where the C-4 hydrogens of the first
rings are deshielded by the carbonyls of next rings, while
the C-4 hydrogen of C-terminal rings is not deshielded,
because it has no carbonyl groups nearby. Further
studies are in progress on this subject.
pure (4S,5R)-4-carboxybenzyl-5-methyloxazolidin-2-ones.
The method is quite general and can be utilized to obtain
a wide range of 4-carboxybenzyl-5-alkyl/aryl-oxazolidin-
2-ones. These compounds belong to the family of pseudo-
prolines, and their oligomerization was studied. So we
have shown an approach for the preparation of a trimer
and a tetramer of this heterocycle in good yield, avoiding
the ring hydrolysis at all stages. 1H NMR analysis of the
trimer 13 and of tetramer 14 shows that two and three
doublets respectively of the C-4 hydrogens are strongly
deshielded, while the doublet of the C-4 hydrogen of the
C-terminal ring is not: this effect can be attributed to
the deshielding effect of carbonyls of the adiacent ring,
which is always close to the hydrogen, thus showing that
these oligomers fold in ordered structures.
Con clu sion s
In this paper we have shown a straightforward syn-
thetic method for the preparation of enantiomerically

Oligomerization of 4-Carboxy-5-methyloxazolidin-2-ones
J . Org. Chem., Vol. 66, No. 3, 2001 731
84.5, 128.5, 128.6, 128.7, 134.5, 148.5, 167.3, 168.2. [R]D +10.8
(c 0.5, CH2Cl2) (lit.10 [R]D +7.7 (c 0.49, CH2Cl2). C12H13NO4
(235.2): calcd C 61.27, H 5.57, N 5.95; found C 61.32, H 5.53,
N 4.99.
Exp er im en ta l Section
Gen er a l. NMR spectra were recorded with spectrometers
at 300 or 200 MHz (1H NMR) and at 75 or 50 MHz (13C NMR).
Chemical shifts are reported in δ values relative to the solvent
peak of CHCl3, set at 7.27 ppm. Infrared spectra were recorded
with an FT-IR spectrometer. Melting points were determined
in open capillaries and are uncorrected. HPLC analysis was
performed on a liquid chromatograph equipped with a variable
wavelength UV detector (deuterium lamp 190-600 nm). HPLC
grade 2-propanol and hexane were used as the eluting solvents.
THF was distilled from sodium benzophenone ketyl.
(4S,5R)-N-Boc-4-Ca r boxyben zyl-5-m eth yloxa zolid in -2-
on e 5. To a stirred solution of oxazolidin-2-one 4 (1 mmol, 0.24
g) and Boc2O (1.25 mmol, 0.27 g) in dry DMF (1 mL) were
added iPr2EtN (1.1 mmol, 0.19 mL) and DMAP (0.1 mmol, 12
mg). The mixture was stirred 2 h under nitrogen at room
temperature, diluted with ethyl acetate (50 mL), washed with
0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous
NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concen-
trated in vacuo. The fully protected oxazolidin-2-one 5 was
obtained pure in 95% yield (0.32 g) as an oil after silica gel
chromatography (cyclohexane/ethyl acetate 9:1 as eluant). IR
Ben zyl N-Boc-(3R)-Am in obu ta n oa te 2. (3R)-Aminobu-
tanoic acid hydrochloride (5 mmol, 0.52 g) was dissolved in a
mixture of water (10 mL) and tert-butyl alcohol (15 mL),
sodium carbonate (15 mmol, 1.59 g) and Boc anhydride (7.5
mmol, 1.64 g) were added in one portion, and the mixture was
refluxed for 2 h. The mixture was cooled and acidified with
11 N HCl till pH ) 1, and then tert-butyl alcohol was removed
under vacuo and replaced with ethyl acetate. The organic layer
was separated, washed twice with water, and dried over
sodium sulfate, and the solvent was removed under reduced
pressure. The residue was dissolved in acetone (10 mL),
triethylamine (10 mmol, 1.4 mL) followed by benzyl bromide
(5.5 mmol, 0.70 mL) was added in one portion at room
temperature, and the mixture was stirred for 16 h. Water was
added, acetone was removed under vacuo and replaced with
ethyl acetate, the mixture was separated, and the organic layer
was dried over sodium sulfate and concentrated. The residue
was purified by silica gel chromatography (cyclohexane/ethyl
acetate 9:1 as eluant) and was obtained pure in 45% overall
yield (0.69 g). Mp ) 55-57 °C (lit.8 58-59 °C). IR (film): ν )
(Nujol): ν ) 1830, 1752, 1728 cm-1 1H NMR (CDCl3): δ )
.
1.45 (s, 9H), 1.52 (d, 3H, J ) 6.6 Hz), 4.34 (d, 1H, J ) 4.5 Hz),
4.45 (dq, 1H, J ) 4.5, 6.6 Hz), 5.22 (AB, 2H, J ) 12.3 Hz),
7.24-7.45 (m, 5H, Ph). 13C NMR (CDCl3): δ ) 21.1, 27.6, 62.7,
67.8, 72.2, 84.5, 128.5, 128.6, 128.7, 134.5, 148.5, 167.3. [R]D
-14.8 (c 1.2, CH2Cl2). C17H21NO6 (335.4): calcd C 60.89, H
6.31, N 4.18; found C 66.90, H 6.33, N 4.22.
(4S,5R)-N-Boc-4-Ca r boxy-5-m eth yloxa zolid in -2-on e 6.
To a solution of benzyl ester 5 (1 mmol, 0.34 g) in ethyl acetate
(10 mL) was added 10% palladium on charcoal (30 mg), and
the mixture was stirred in a Parr equipment with hydrogen
(3 atm) for 1 h. Then the catalyst was filtered on a Celite pad,
and the mixture was concentrated. The acid 6 was obtained
in quantitative yield (0.24 g) without any further purification.
Mp ) 114-116 °C. IR (Nujol): ν ) 3185, 1799, 1746, cm-1. 1H
NMR (CD3OD): δ ) 1.50 (s, 9H), 1.52 (d, 3H, J ) 6.2 Hz),
4.43 (d, 1H, J ) 4.4 Hz), 4.58 (dq, 1H, J ) 4.4, 6.2 Hz). 13C
NMR (CD3OD): δ ) 21.2, 28.0, 63.9, 74.5, 85.4, 150.2, 153.2,
171.7. [R]D -16.2 (c 0.8, methanol). C10H15NO6 (245.2): calcd
C 48.98, H 6.17, N 5.71; found C 49.02, H 6.21, N 5.74.
F u lly P r otected Dioxa zolid in -2-on e 8. To a stirred
solution of acid 6 (0.5 mmol, 123 mg) in dry DMF (1 mL) was
added pyridine (0.55 mmol, 50 µL) followed by pentafluorophe-
nyl triflouroacetate (0.63 mmol, 130 µL). The reaction was
allowed to stir for 45 min at room temperature, diluted with
ethyl acetate (50 mL), washed with 0.1 N aqueous HCl (2 ×
30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried
over sodium sulfate, and concentrated in vacuo. The penta-
flourophenyl ester 7 was obtained in quantitative yield (206
mg), but could not be purified by silica gel chromatography.
1H NMR (CDCl3): δ ) 1.51 (s, 9H), 1.62 (d, 3H, J ) 6.3 Hz),
4.65-4.71 (m, 2H). 13C NMR (CDCl3): δ ) 21.2, 27.6, 62.3,
72.1, 85.7, 136.2, 139.2, 139.6, 142.6, 148.1, 150.1, 164.8.
To a stirred solution of benzyl ester 5 (0.45 mmol, 106 mg),
iPr2EtN (0.9 mmol, 263 µL), and DMAP (0.05 mmol, 6 mg) in
dry DMF (1 mL) was added the pentaflourophenyl ester 7 (0.5
mmol, 206 mg) in dry DMF (1 mL) in one portion. The reaction
was allowed to stir for 2 h at room temperature, diluted with
ethyl acetate (50 mL), washed with 0.1 N aqueous HCl (2 ×
30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried
over sodium sulfate, and concentrated in vacuo. The dioxazo-
lidin-2-one 8 was obtained pure in 70% yield (146 mg) as a
waxy solid after silica gel chromatography (cyclohexane/ethyl
acetate 9:1 as eluant). IR (Nujol): ν ) 1826, 1795, 1750, 1718
1
3367, 1728, 1678 cm-1. H NMR (CDCl3): δ ) 1.22 (d, 3H, J
) 6.7 Hz), 1.44 (s, 9H, t-Bu), 2.48-2.64 (m, 2H), 3.92-4.18
(m, 1H), 4.90 (bs, 1H, NH), 5.12 (s, 2H), 7.22-7.51 (m, 5H).
13C NMR (CDCl3): δ ) 20.5, 28.4, 40.8, 43.5, 66.3, 128.1, 128.3,
128.5, 135.6, 154.9, 171.2. [R]D +17.3 (c 1, CH2Cl2) (lit.8 [R]D
+17.5 (c 1, CH2Cl2). C17H25NO4 (307.4): calcd C 66.43, H 8.20,
N 4.56; found C 66.38, H 8.22, N 4.58.
(2S,3R)-N-Boc-2-Ca r b oxyb en zyl-3-m et h yla zir id in e 3.
LiHMDS (5 mmol, 1 M soln in THF, 5 mL) was added to a
stirred solution of benzyl N-Boc-(3R)-aminobutanoate 2 (2.5
mmol, 0.77 g) in dry THF (10 mL) under nitrogen atmosphere
at -20 °C. The mixture was stirred 1 h and then was cooled
to -60 °C, and iodine was added (3 mmol, 0.76 g) in dry THF
(10 mL). The mixture was stirred 1 h, an aqueous saturated
solution of ammonium thiosulfate was added, and THF was
removed under reduced pressure and replaced with ethyl
acetate. The organic layer was separated, washed twice with
water, and dried over sodium sulfate, and the solvent was
removed under reduced pressure. The residue was obtained
pure in 79% yield (0.60 g) as an oil after silica gel chromatog-
raphy (cyclohexane/ethyl acetate 9:1 as eluant). IR (film): ν
) 1745, 1726 cm-1. 1H NMR (CDCl3): δ ) 1.31 (d, 3H, J ) 5.1
Hz), 1.41 (s, 9H), 2.78-2.89 (m, 2H), 5.17 (2H, AB J ) 12 Hz),
7.28-7.40 (m, 5H, Ph). 13C NMR (CDCl3): δ ) 20.9, 27.8, 39.6,
41.3, 67.1, 81.6, 128.2, 128.3, 128.4, 135.0, 158.7, 168.0. [R]D
+9.3 (c 0.5, CH2Cl2). C17H23NO4 (305.4): calcd C 66.86, H 7.59,
N 4.59; found C 66.90, H 7.62, N 4.57.
1
(4S,5R)-4-Ca r boxyben zyl-5-m eth yloxa zolid in -2-on e 4.
To a stirred solution of N-Boc-aziridine 3 (1 mmol, 0.31 g) in
dry methylene chloride (10 mL) was added Zn(OTf)2 (0.1 mmol,
42 mg). The mixture was stirred 4 h under nitrogen at room
temperature, additional methylene chloride and 5% aqueous
solution of NaHCO3 were added, the organic layer was
separated, and the aqueous layer was acidified with 0.1 N
aqueous HCl and extracted with methylene chloride. The
combined organic layers were dried over sodium sulfate and
concentrated in vacuo. The residue was obtained pure in 90%
yield (0.21 g) as an oil after silica gel chromatography
(cyclohexane/ethyl acetate 7:3 as eluant). IR (CH2Cl2): ν )
cm-1. H NMR (CDCl3): δ ) 1.52 (s, 9H), 1.55 (d, 3H, J ) 6.2
Hz), 1.59 (d, 3H, J ) 6.6 Hz), 4.45 (dq, 1H J ) 2.2, 6.2 Hz),
4.61 (d, 1H, J ) 3.5 Hz), 4.68 (dq, 1H, J ) 3.5, 6.6 Hz), 5.21
(AB, 2H, J ) 11.8 Hz), 5.51 (d, 1H, J ) 2.2 Hz), 7.22-7.49 (m,
5H). 13C NMR (CDCl3): δ ) 20.6, 21.2, 27.8, 61.1, 61.7, 68.6,
72.5, 74.7, 84.5, 128.5, 128.7, 128.9, 133.9, 149.2, 150.3, 151.8,
167.0, 168.0. [R]D -64.2 (c 0.7, CH2Cl2). C22H26N2O9 (462.5):
calcd C 57.14, H 5.67, N 6.06; found C 57.19, H 5.62, N 6.04.
Dioxa zolid in -2-on e NH 10. To a stirred solution of fully
protected dioxazolidin-2-one 8 (0.2 mmol, 92 mg) in dry
dichloromethane (10 mL) was added triflouroacetic acid (1.8
mmol, 0.45 mL). The reaction was allowed to stir for 3 h at
room temperature, washed with 5% aqueous NaHCO3 (2 × 10
mL), dried over sodium sulfate, and concentrated in vacuo. The
N-deprotected dioxazolidin-2-one 10 was obtained pure in 95%
yield (69 mg) as a waxy solid after silica gel chromatography
1
3453, 1777, 1748 cm-1. H NMR (CDCl3): δ ) 1.51 (d, 3H, J
) 6.3 Hz), 4.02 (d, 1H, J ) 5.1 Hz), 4.69 (dq, 1H, J ) 5.1, 6.3
Hz), 5.20 (AB, 2H, J ) 12.3 Hz), 6.73 (bs, 1H, NH), 7.24-7.33
(m, 5H, Ph). 13C NMR (CDCl3): δ ) 21.1, 27.6, 62.7, 67.8, 72.2,

732 J . Org. Chem., Vol. 66, No. 3, 2001
Lucarini and Tomasini
(cyclohexane/ethyl acetate 7:3 as eluant). IR (CH2Cl2): ν )
with 0.1 N aqueous HCl (2 × 30 mL), washed with 5% aqueous
NaHCO3 (1 × 30 mL), dried over sodium sulfate, and concen-
trated in vacuo. The trioxazolidin-2-one 13 was obtained pure
in 55% yield (29 mg) as a white solid after silica gel chroma-
tography (cyclohexane/ethyl acetate 9:1 as eluant). Mp ) 83-
85 °C (dec). IR (CH2Cl2): ν ) 1832, 1786, 1747, 1720 cm-1. 1H
NMR (CDCl3): δ ) 1.51 (s, 9H), 1.59 (d, 3H, J ) 6.6 Hz), 1.61
(d, 6H, J ) 6.6 Hz), 4.56 (d, 1H, J ) 3.6 Hz), 4.63-4.70 (m,
3H), 5.20 (AB, 2H, J ) 12.0 Hz), 5.47 (d, 1H, J ) 2.1 Hz), 5.63
(d, 1H, J ) 1.8 Hz), 7.24-7.51 (m, 5H). 13C NMR (CDCl3): δ
) 20.7, 21.3, 27.9, 61.0, 62.0, 68.8, 72.7, 75.2, 84.5, 128.6, 128.8,
129.1, 133.9, 148.6, 151.8, 152.2, 166.8, 168.4, 176.6. [R]D
-123.0 (c 0.6, CH2Cl2). C27H31N3O12 (589.6): calcd C 55.01, H
5.30, N 7.13; found C 55.08, H 5.33, N 7.08.
1
3431, 1784, 1772, 1714 cm-1. H NMR (CDCl3): δ ) 1.56 (d,
3H, J ) 6.4 Hz), 1.60 (d, 3H, J ) 6.4 Hz), 4.59 (d, 1H, J ) 4.2
Hz), 4.67 (dq, 1H, J ) 4.2, 6.4 Hz), 4.83 (dq, 1H, J ) 2.2, 6.4
Hz), 4.90 (d, 1H, J ) 2.2 Hz), 5.23 (AB, 2H, J ) 12.2 Hz), 5.81
(s, 1H, NH), 7.24-7.55 (m, 5H, Ph). 13C NMR (CDCl3): δ )
20.5, 21.2, 60.2, 61.5, 68.5, 74.8, 75.6, 128.5, 128.8, 128.9, 134.1,
144.4, 162.1, 167.1, 169.9. [R]D -23.0 (c 0.4, CH2Cl2). C17H18N2O7
(362.3): calcd C 56.35, H 5.01, N 7.73; found C 56.42, H 5.08,
N 7.69.
Dioxa zolid in -2-on e COOH 11. To a solution of fully
protected dioxazolidin-2-one 8 (0.2 mmol, 92 mg) in ethyl
acetate (10 mL) was added 10% palladium on charcoal (10 mg),
and the mixture was stirred in
a Parr equipment with
hydrogen (3 atm) for 1 h. Then the catalyst was filtered on a
Celite pad, and the mixture was concentrated. The acid 11
was obtained pure in quantitative yield (74 mg) without any
further purification. IR (CH2Cl2): ν ) 3437, 1827, 1807, 1722
cm-1. 1H NMR (CD3OD): δ ) 1.48 (s, 9H), 1.53 (d, 6H, J ) 6.6
Hz), 1.57 (d, 3H, J ) 6.3 Hz), 4.58 (d, 1H J ) 3.3 Hz), 4.74
(dq, 1H, J ) 2.5, 6.3 Hz), 4.82 (dq, 1H, J ) 3.3, 6.3 Hz), 5.59
(d, 1H, J ) 2.5 Hz), 13C NMR (CDCl3): δ ) 20.7, 21.3, 27.9,
61.1, 62.0, 73.0, 75.0, 84.9, 152.1, 168.1. [R]D -101.8 (c 0.2,
CH2Cl2). C15H20N2O9 (372.3): calcd C 48.39, H 5.41, N 7.52;
found C 48.38, H 5.44, N 7.55.
F u lly P r ot ect ed Tr ioxa zolid in -2-on e 13: To a stirred
solution of acid 11 (0.1 mmol, 37 mg) in dry DMF (1 mL) was
added pyridine (0.11 mmol, 11 µL) followed by pentafluorophe-
nyl triflouroacetate (0.13 mmol, 32 µL). The reaction was
allowed to stir for 45 min at room temperature, diluted with
ethyl acetate (30 mL), washed with 0.1 N aqueous HCl (2 ×
30 mL), washed with 5% aqueous NaHCO3 (1 × 30 mL), dried
over sodium sulfate, and concentrated in vacuo. The penta-
flourophenyl ester 12 was obtained in quantitative yield (54
mg), but could not be purified by silica gel chromatography.
1H NMR (CDCl3): δ ) 1.51 (s, 9H), 1.59 (d, 3H, J ) 6.3 Hz),
1.71 (d, 3H, J ) 6.0 Hz), 4.53 (dq, 1H, J ) 2.2, 6.3 Hz), 4.80-
4.95 (m, 2H), 5.51 (d, 1H, J ) 2.2 Hz). 13C NMR (CDCl3): δ )
20.6, 21.2, 27.8, 60.8, 61.8, 72.8, 74.6, 85.2, 136.4, 139.7, 142.5,
150.8, 151.3, 163.9, 168.0.
F u lly P r otected Tetr a oxa zolid in -2-on e 14. To a stirred
solution of dioxazolidin-2-one NH 10 (0.09 mmol, 33 mg), iPr2-
EtN (0.2 mmol, 57 µL), and DMAP (2 mg) in dry DMF (1 mL)
was added pentaflourophenyl ester 12 (0.1 mmol, 54 mg) in
dry DMF (1 mL) in one portion. The reaction was allowed to
stir for 3 h at room temperature, diluted with ethyl acetate
(50 mL), washed with 0.1 N aqueous HCl (2 × 30 mL), washed
with 5% aqueous NaHCO3 (1 × 30 mL), dried over sodium
sulfate, and concentrated in vacuo. The tetraoxazolidin-2-one
14 was obtained pure in 50% yield as a white solid after silica
gel chromatography (cyclohexane/ethyl acetate 9:1 as eluant).
Mp ) 94-97 °C (dec). IR (CH2Cl2): ν ) 1827, 1786, 1751, 1722,
1
1607 cm-1. H NMR (CDCl3): δ ) 1.52 (s, 9H), 1.59 (d, 6H, J
) 6.6 Hz), 1.63 (d, 3H, J ) 6.3 Hz), 1.67 (d, 3H, J ) 6.3 Hz),
4.55 (d, 1H, J ) 3.3 Hz), 4.58-4.73 (m, 3H), 4.87 (dq, 1H, J )
1.8, 6.3 Hz), 5.21 (AB, 2H, J ) 11.8 Hz), 5.47 (d, 1H, J ) 1.5
Hz), 5.57 (d, 1H, J ) 1.5 Hz), 5.64 (d, 1H, J ) 1.8 Hz), 7.22-
7.49 (m, 5H). 13C NMR (CDCl3): δ ) 20.7, 21.3, 28.0, 61.0,
61.1, 61.2, 62.0, 68.6, 72.6, 75.2, 75.4, 75.8, 84.5, 128.6, 128.8,
129.1, 133.9, 146.5, 156.5, 156.8, 166.7, 166.9, 167.2, 172.0,
177.7. [R]D -142.0 (c 0.7, CH2Cl2). C32H36N4O15 (716.7): calcd
C 53.63, H 5.06, N 7.82; found C 53.59, H 5.00, N 7.84.
Ack n ow led gm en t. This work was supported in part
by M.U.R.S.T. Cofin ’98 (Roma) and by University of
Bologna (funds for Selected Research Topics).
To a stirred solution of (4S,5R)-4-carboxybenzyl-5-methyl-
oxazolidin-2-one 4 (0.09 mmol, 21 mg), iPr2EtN (0.2 mmol, 57
µL), and DMAP (2 mg) in dry DMF (1 mL) was added
pentaflourophenyl ester 12 (0.1 mmol, 54 mg) in dry DMF (1
mL) in one portion. The reaction was allowed to stir for 3 h at
room temperature, diluted with ethyl acetate (50 mL), washed
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
monomer 5, and oligomers 8, 9, 13, and 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O005583+