Chiral succinate: A precursor for enantiomerically pure β2-amino acids

Article abstract of DOI:10.1055/s-2005-865362

Five suitably protected enantiomerically pure β²-amino acids, homologues of proteinogenic α-amino acids, were synthesized from the common chiral precursor, tert-butyl succinyloxazolidinone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865362

PAPER
1829
Chiral Succinate: A Precursor for Enantiomerically Pure b2-Amino Acids
C
hira
l
Succinate rvydas Stončius, Markus Nahrwold, Norbert Sewald*
Bielefeld University, Department of Chemistry, Universitätsstr. 25, 33615 Bielefeld, Germany
Fax +49(521)1068094; E-mail: norbert.sewald@uni-bielefeld.de
Received 26 October 2004; revised 15 February 2005
published later included the alkylation of lithium or sodi-
um enolates of chiral acyl-oxazolidinones with tert-butyl
bromoacetate. The second step involved the selective re-
moval of either imine or newly introduced ester function-
ality followed by Curtius degradation of the free carboxy
group. Thus, the substituted succinate formed serves as a
common precursor for b3-amino acids14 or b2-amino ac-
ids.11b In contrast, the synthesis published by Sibi15 is
based on the stereoselective and regioselective alkylation
of Na-enolates of tert-butyl succinyloxazolidinone as
chiral equivalent of b-alanine, followed by Curtius rear-
rangement of one of the carboxylic groups leading to a b2-
or b3-amino acid.
Abstract: Five suitably protected enantiomerically pure b2-amino
acids, homologues of proteinogenic a-amino acids, were synthe-
sized from the common chiral precursor, tert-butyl succinyloxazol-
idinone.
Key words: b-amino acids, rearrangements, regioselectivity, ring
closure, stereoselective synthesis
While it has been known for about five decades1 that b3-
amino acids can be obtained by various methods of simple
homologation of proteinogenic a-amino acids,2 methods
for the synthesis of b2-amino acids with proteinogenic
sidechains have been established only recently.3 Much of
the work regarding the stereoselective preparation of b2-
amino acids, their properties, and biological importance
has been reviewed.4
In spite of the relatively large number of published ‘gen-
eral’ methods for the synthesis of enantiopure b2-amino
acids, most of them are limited to rather simple alkyl-, ar-
yl- or benzyl-substituted amino acids. The first attempt to
synthesize a b2-amino acid with a functional group in the
sidechain, as a homologue of the corresponding proteino-
genic a-amino acid was published by Arvanitis.16 The
alkylation of the chiral oxazolidinones derived from vinyl
or dimethoxyphenyl substituted acids, equivalents of suc-
cinic acid, with bromoacetates and subsequent oxidation
provides enantiopure tricarballylic acid.17 After Curtius
degradation and cleavage of the chiral auxiliary, the N-
Cbz-protected b2-homo-aspartic acid was obtained.
Most of the methods known for the synthesis of a-substi-
tuted b-amino acids may be classified as two main ap-
proaches. The more straightforward one comprises the
stereoselective alkylation of a synthetic b-alanine equiva-
lent introducing the sidechain. The amino group in such a
b-alanine derivative is usually suitably protected5 or in-
cluded into a heterocycle,6 but may also be unprotected7
or masked as a nitro group.8
The stereoselective introduction of an amino or methyl-
amino group into a carboxylic acid equivalent bearing the
desired sidechain is the less straightforward method. In
each case a different precursor for each amino acid has to
be synthesized. Nevertheless, this is the most frequently
used approach to b2-amino acids.9 The key step of most of
these syntheses is the amidomethylation of Ti-enolates of
acylated chiral oxazolidinones first developed by Evans.10
The ease of cleavage of the chiral auxiliary leading to the
enantiomerically pure product was probably the main rea-
son for the success of this method. Later on, this method
underwent various modifications concerning the amido-
methylating reagent11 or the chiral auxiliary.12
Recently, Seebach presented the syntheses of suitably
protected b2-amino acids with 17 of the 20 proteinogenic
sidechains.3 The amino acids were prepared by diastereo-
selective reactions of Li-, B-, or Ti-enolates of the corre-
sponding 3-acyl-4-isopropyl-5,5-diphenyloxazolidin-2-
ones with appropriate electrophiles [amidomethylation,
hydroxyalkylation, (benzyloxycarbonyl)methylation] in
good yields and with diastereoselectivities of 80–97%.
We developed, independently from Seebach et al., a meth-
odology for the synthesis of some b2-amino acids with
proteinogenic sidechains.18 Among the various methods
described above, we found the concept of Sibi et al.15 to
be most suitable for our purposes. Thus, we tried to extend
their synthesis of methyl, allyl and benzyl substituted b2-
amino acids to derivatives with functionalized sidechains.
We focused our investigation on reactions of chiral succi-
nyloxazolidinones. The parent (4R)-4-benzyl-1,3-oxazo-
lidin-2-one was chosen as the source of chirality because
of its stability against common deprotecting reagents such
as TFA or H2, Pd/C (see ref.19) and better diastereoselec-
tion in some cases. Moreover, it is commercially available
or can be easily synthesized from phenylalanine.
Reactions of chiral N-acyl-oxazolidinones with the corre-
sponding acid derivatives in combination with Curtius re-
arrangement proved to be a highly effective method for
the introduction of an amino (carbamate) group in the syn-
thesis of amino acids. This method was for the first time
described by Evans and used for a synthesis of g-amino
acids.13 Most of the related syntheses of b-amino acids
SYNTHESIS 2005, No. 11, pp 1829–1837
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Advanced online publication: 02.05.2005
DOI: 10.1055/s-2005-865362; Art ID: T12704SS
© Georg Thieme Verlag Stuttgart · New York

1830
A. Stončius et al.
PAPER
Scheme 1 Reagents and conditions: a) THF, –78 °C–r.t.; b) CHCl3, t-BuOH, P2O5, see also ref.20; c) THF, NaHMDS, –78 °C; d) MeI, –78
°C to –50 °C; e) NaI, BrCH2CO2Bn, –95 °C to –78 °C; f) NaI, ClCH2OBn, –95 °C to –78 °C; g) CH2Cl2, TFA; h) EtOAc, H2, Pd/C (10%); i)
1. THF, ClCO2Et, Et3N, –15 °C to r.t.; 2. NaN3, H2O, 0 °C; 3. toluene, t-BuOH for 12, 13, 15, C6H5CH2OH for 14, reflux; j) THF, BH3·Me2S,
0 °C to r.t.; k) THF, H2O2, LiOH·H2O, 0 °C.
Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York

PAPER
Chiral Succinate
1831
In contrast to Sibi et al., we simplified the synthesis of the pure 6 in 60% yield after column chromatography and
chiral succinate 4. The Li imide of the chiral auxiliary 1 crystallization.
was almost quantitatively acylated with succinic anhy-
dride 2 (Scheme 1) and the resulting carboxylic acid 3 was
The reaction of the enolate of 4 with benzyl chloromethyl
ether (benzyloxymethyl chloride), which was converted
to benzyloxymethyl iodide in situ was carried out success-
subsequently converted to its tert-butyl ester using the
procedure described by Wright.20 Despite the moderate
fully. The benzyloxymethylated succinate 7 and its dia-
conversion (50%) and yield of 4, we preferred this method
over others because the ester 4 and unconverted starting
material 3 were easily separable and were obtained essen-
tially pure after the reaction. Thus, about 35% of uncon-
verted 3 can be recycled. This new procedure avoids the
additional synthesis of mono-tert-butyl succinate.
stereomer (in a ratio of about 4:1, according to 1H NMR)
were obtained as an inseparable mixture in 82% yield and
used as obtained in the next step.
The tert-butyl ester of the diastereomeric mixtures of both
succinates 5 and 7 was cleaved with TFA in CH2Cl2 in ex-
cellent yields. At this point the diastereomeric mixture of
the obtained intermediate acids could be easily separated
by column chromatography to provide the diastereomeri-
cally pure products 8 and 11. The tert-butyl ester of 6 was
cleaved using the same method as mentioned above. Al-
ternatively, the benzyl ester protection was removed by
hydrogenolysis to give carboxylic acid 10 quantitatively.
Subsequent Curtius rearrangement provided the imides of
protected b2-amino acids 12–15 in moderate yields.
In general, enolate reactions with iodomethane are the
least stereoselective processes and serve as a probe for the
method. It is also known that alkylations of Na enolates
are superior to analogous reactions of the corresponding
Li enolates.15,19,21 Therefore, firstly the chiral succinate 4
was treated with NaHMDS and allowed to react with io-
domethane. This reaction provided 5 as the single regio-
isomer with good diastereoselectivity (85% de, according
to 1H NMR spectra of the crude product). The mixture of
5 and its diastereomer (overall yield 79%) was inseparable
by column chromatography and used as obtained in the
next step. Relatively good results of this experiment en-
couraged us to examine the reactions of 4 with other elec-
trophiles. The enolate of 4 was treated with benzyl
bromoacetate. However, the first experiments were disap-
pointing not only due to moderate stereoselectivity and in-
complete regioselectivity but especially due to a low
reaction rate. It appeared that benzyl bromoacetate reacts
too slowly with the Na enolate of 4 at –50 °C and a detect-
able amount of starting material was present in the reac-
tion mixture even after 30 hours. The presence of
regioisomers and probably non-volatile benzyl bromoac-
etate in the crude product encumbered the determination
of diastereomeric purity. Up to seven partially overlap-
ping signals corresponding to a benzylic proton were ob-
served in the 1H NMR spectra.
The orthogonally protected tricarboxylic acid 6 is in fact
derived from the parent meso compound permitting the
selective synthesis of both enantiomers of the correspond-
ing protected b2-homo-aspartic acid 13 and 14. The re-
maining ester groups of 13 and 14 were cleaved as
described previously and the resulting acids 16 and 17
were subjected to further transformations, for example to
give a variety of homo-aspartate derivatives.25 In our at-
tempts to reduce the carboxylic group of intermediate ac-
ids 16 and 17 with a series of reduction agents, we found
out, that treatment with BH3·Me2S causes a ring closure
reaction, leading to the pyrrolidines 18 and 19 (see also
ref.26). This provided us with a relatively straightforward
method for the synthesis of both enantiomers of b-proline
(b2-isoproline). However, we were not able to obtain the
primary alcohols from any reduction reaction.
Thus, after cleavage of the chiral auxiliary with lithium
hydroperoxide according to a numerously employed pro-
cedure (see ref.15), five suitably protected b2-amino acids
20, 21, 22, 23 and 24 with proteinogenic sidechains were
synthesized in acceptable overall yields. Notably, all ami-
no acids were obtained starting from the single precursor
4. Moreover, some b2-amino acids were synthesized from
6, the product of one single diastereoselective reaction. As
the stereoselective creation of a new stereogenic center is
usually the most difficult procedure in the synthesis of
enantiomerically pure compounds, this feature of the syn-
thesis presented is of great value.
The reaction of 4 with benzyl bromoacetate in the pres-
ence of NaI proceeds much faster and only traces of start-
ing material 4 were detectable after 3 hours, even at low
temperatures (–100 °C to –78 °C; see also ref.22,23). Essen-
tially the same results were achieved, when benzyl io-
doacetate was prepared separately beforehand. However,
only moderate improvements of diastereoselectivity and
regioselectivity were observed in both cases. Six com-
pounds were present in the crude product in a ratio of
1
about 59:7:6:3:3:1 (according to H NMR spectra). The
lack of regioselectivity of this reaction was somehow as-
tonishing as the reaction with iodomethane was complete-
ly regioselective. A possible explanation may be that the
formed product 6 and its minor diastereomer in the reac-
tion mixture undergo partial trans-enolization of the ben-
zyl ester and react with a second molecule of benzyl
iodoacetate.24 It was not possible to completely overcome
this problem. Hence, the reaction conditions were opti-
mized to maximum conversion and minimum amounts of
by-products. This allows obtaining of diastereomerically
In summary, we have explored a highly versatile synthesis
of some proteinogenic b2-amino acids. A number of b2-
amino acids were synthesized from a single intermediate
using efficient procedures with a minimum of efforts for
stereoselection.
All chemicals were reagent grade and used as purchased, except for
succinic anhydride, which was sublimated and iodomethane, benzyl
bromoacetate and benzyl chloromethyl ether, which were distilled
Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York

1832
A. Stončius et al.
PAPER
prior to use. The solvents were purified by standard procedures. All
moisture-sensitive experiments were performed under anhydrous
conditions in flame-dried glassware under a dry Ar atmosphere, em-
ploying standard techniques for handling air-sensitive materials. 1H
NMR and 13C NMR spectra were recorded on the following instru-
ments: Bruker AC 250P (1H: 250 MHz, 13C: 62.9 MHz), Bruker
DRX 500 (1H: 500 MHz, 13C: 125.8 MHz) and Bruker Avance 600
(1H: 600 MHz). All chemical shifts are reported as ppm values (d)
relative to TMS or residual solvent. IR spectra were recorded on a
JASCO FT/IR-410 spectrophotometer, either using KBr discs or
films on NaCl plates. Optical rotations were measured on a Jasco
DIP-360 polarimeter at the sodium D-line (589 nm) (c in g/100 mL).
Mass spectral data were obtained either on a VG Autospec X (CI),
on a Bruker Esquire 3000 (ESI) or on a Bruker APEX III instrument
(ESI–FT–ICR, for HRMS). Melting points were determined in open
capillaries on a Büchi Melting Point apparatus B 540 and are uncor-
rected. Reactions were monitored by TLC on Merck silica gel 60
F254 plates, using a combination of UV- and chemical detection
(dipping the plate into a 5% ninhydrine solution in EtOH and sub-
sequent heating). Petroleum ether (PE) used had a boiling point
range of 30–60 °C.
over anhyd Na2SO4 and evaporated to dryness. The oily residue was
crystallized from a mixture of toluene (10 mL) and PE (1.5 mL),
thus recovering unreacted starting material 3 (2.48 g, 33%).
Mp 56.5–58 °C; [a]D22 –55.1 (c = 1.0, CHCl3).
IR (KBr): 3030, 3005, 2979, 2931, 1783, 1733, 1718, 1696, 1457,
1387, 1365, 1263, 1242, 1224, 1153, 996, 847, 761, 701 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.47 (s, 9 H), 2.59–2.65 (m, 2 H),
2.78 (dd, J = 13.5, 9.5 Hz, 1 H), 3.18–3.21 (m, 2 H), 3.29 (dd, J =
13.5, 3.2 Hz, 1 H), 4.14–4.25 (m, 2 H), 4.68 (m, 1 H), 7.19–7.37 (m,
5 H).
13C NMR (62.9 MHz, CDCl3): d = 28.1, 29.5, 31.0, 37.8, 55.1, 66.3,
80.7, 127.4, 129.0, 129.5, 135.3, 153.5, 171.6, 172.1.
MS (CI, NH3): m/z (%) = 178 (4), 195 (11), 278 (20), 295 (100), 334
(9) [M + H]+, 351 (29) [M + NH4]+.
tert-Butyl (3R)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-
methyl-4-oxobutanoate (5)
A solution of 4 (3.33 g, 9.99 mmol) in anhyd THF (100 mL) was
cooled to –78 °C and NaHMDS (12.00 mL of 1 M solution in THF,
12.00 mmol) was added dropwise. The mixture was stirred for 1 h
at the same temperature. A solution of MeI (3.12 mL, 7.11 g, 50.12
mmol) in THF (10 mL) was added dropwise. The mixture was
stirred at –78 °C for 5 h, then allowed to warm to –50 °C and stirred
overnight. The reaction was quenched with sat. aq NH4Cl (50 mL),
the mixture was allowed to warm to r.t. and THF was evaporated.
The resulting aq solution was extracted with CH2Cl2 (3 × 70 mL),
the combined organic extracts were washed successively with 5%
aq solutions of KHSO4, NaHCO3, Na2SO3 and brine, then dried
over anhyd Na2SO4, filtered and evaporated. The obtained oil con-
taining a mixture of the diastereomers 5 and epi-5 (85% de) (2.74 g,
79%) solidified upon a standing in a fridge. The mixture was insep-
arable by column chromatography and was used as such in the next
step.
1H NMR (250 MHz, CDCl3): d = 1.24 (d, J = 6.9 Hz, 3 H), 1.42 (s,
9 H), 2.35 (dd, J = 16.9, 4.4 Hz, 1 H), 2.80 (dd, J = 13.2, 9.4 Hz, 1
H), 2.85 (dd, J = 16.6, 10.4 Hz, 1 H), 3.23 (dd, J = 13.5, 3.5 Hz, 1
H), 4.06 (m, 1 H), 4.18 (dd, J = 9.1, 2.8 Hz, 1 H), 4.25 (m, 1 H), 4.71
(m, 1 H), 7.19–7.36 (m, 5 H).
13C NMR (62.9 MHz, CDCl3): d = 17.4, 28.1, 34.4, 38.0, 38.6, 55.2,
66.1, 80.7, 127.3, 128.9, 129.5, 135.2, 153.0, 171.2, 176.2.
4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoic
Acid (3)
A solution of (4R)-4-benzyl-1,3-oxazolidin-2-one (2; 2.00 g, 11.29
mmol) in anhyd THF (40 mL) was cooled to –78 °C and a solution
of n-BuLi (7.5 mL of 15% solution in hexane, 12.29 mmol) was
added dropwise. The obtained mixture was stirred for 30 min at –78
°C. A solution of succinic anhydride (1.35 g, 13.49 mmol) in anhyd
THF (90 mL) was slowly added at this point and the mixture was
stirred overnight allowing gradual warming to r.t. After the reac-
tion, water (90 mL) was added, THF was evaporated and sat. aq
NaHCO3 solution was added to adjust pH to 9. The basic aqueous
solution was washed with EtOAc (2 × 30 mL), then acidified with
concd HCl to adjust pH < 2 and extracted with CH2Cl2 (4 × 200
mL). The combined CH2Cl2 extracts were dried over anhyd
Na2SO4, filtered and evaporated to dryness. The oily residue was
crystallized from toluene–PE (25 mL, 7:1), affording 3 (3.01 g,
96%) as colorless crystals; mp 56 °C; [a]D24 –63.6 (c = 1.0, CHCl3).
IR (KBr): 3029, 1784, 1701, 1604, 1583, 1497, 1455, 1389, 1351,
1250, 1215, 1182, 1116, 990, 943, 845, 761, 730, 698 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.73–2.85 (m, 3 H), 3.22–3.30 (m,
3 H), 4.14–4.25 (m, 2 H), 4.67 (m, 1 H), 7.15–7.36 (m, 5 H).
1-Benzyl 5-tert-Butyl (3R)-3-{[(4R)-4-Benzyl-2-oxo-1,3-oxazoli-
din-3-yl]carbonyl}pentanedioate (6)
13C NMR (62.9 MHz, CDCl3): d = 28.1, 30.7, 37.8, 55.1, 66.4,
127.4, 129.0, 129.5, 135.1, 153.5, 171.7, 177.9.
A solution of 4 (3.00 g, 9.00 mmol) in anhyd THF (50 mL) was add-
ed to a solution of anhyd NaI (1.60 g, 10.67 mmol) in anhyd THF
(130 mL). The mixture was cooled to –78 °C (acetone–dry ice) and
NaHMDS (12.00 mL of 1 M solution in THF, 12.00 mmol) was
added dropwise. This mixture was stirred for 1 h at –78 °C, and then
cooled to –95 °C by addition of liquid N2 to the cooling bath. A so-
lution of benzyl bromoacetate (1.74 mL, 2.54 g, 11.44 mmol, 1.27
equiv) in anhyd THF (8 mL) was added within 2 h (syringe pump,
4 mL/h) and the reaction mixture was stirred for additional 4 h,
while it was allowed to warm to –75 °C. The reaction was quenched
by addition of sat. aq NH4Cl solution (80 mL), allowed to warm to
r.t. and THF was evaporated. The remaining aqueous mixture was
diluted with water (10 mL) and extracted with EtOAc (3 × 300 mL).
The combined organic extracts were washed successively with 5%
aq KHSO4, 5% aq NaHCO3 and brine (80 mL of each), dried over
anhyd Na2SO4 and evaporated to dryness. The crude yellow oil was
purified by flash column chromatography (CH2Cl2–Et2O, 40:1).
Crystallization of the obtained oil from Et2O–PE (50 mL, 1:1) gave
MS (CI, NH3): m/z (%) = 178 (37), 195 (100), 278 (23) [M + H]+,
295 (46) [M + NH4]+.
tert-Butyl 4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobu-
tanoate (4)
A solution of 3 (7.50 g, 27.05 mmol) in anhyd CHCl3 (100 mL) was
added to a suspension of P2O5 (4.20 g, 29.59 mmol) in anhyd CHCl3
(100 mL), followed by slow addition of anhyd t-BuOH (13.0 mL,
10.0 g, 135 mmol). The reaction mixture was stirred for 60 h at r.t.
in a tightly stoppered flask and subsequently poured into sat. aq
NaHCO3 solution (300 mL). After separation of the phases, the
aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The com-
bined organic extracts were washed with brine, dried over anhyd
Na2SO4 and evaporated to dryness. The obtained yellow oil was pu-
rified by flash chromatography (EtOAc–PE, 1:1), yielding 4 (4.48
g, 50%) as white crystals after recrystallization from Et2O–PE (16
mL, 1:1).
23
6 (2.60 g, 60%) as colorless crystals; mp 90–91 °C; [a]D –26.6
(c = 1.0, CHCl3).
The aqueous phase was acidified with concd HCl solution (pH 2)
and extracted with CH2Cl2 (4 ×). The combined extracts were dried
Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York

PAPER
Chiral Succinate
1833
IR (KBr): 3029, 2972, 2933, 1792, 1700, 1604, 1587, 1498, 1485,
1400, 1353, 1304, 1261, 1208, 1159, 1121, 1064, 1009, 958, 843,
729, 697 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.42 (s, 9 H), 2.48 (dd, J = 16.3,
5.6 Hz, 1 H), 2.57 (dd, J = 13.4, 10.0 Hz, 1 H), 2.65 (dd, J = 16.2,
5.9 Hz, 1 H), 2.74 (dd, J = 16.3, 8.3 Hz, 1 H), 2.89 (dd, J = 16.4, 8.1
Hz, 1 H), 3.25 (dd, J = 13.4, 3.3 Hz, 1 H), 4.11 (dd, J = 9.1, 3.0 Hz,
1 H), 4.19 (m, 1 H), 4.47 (m, 1 H), 4.64 (m, 1 H), 5.12 (s, 2 H), 7.17–
7.36 (m, 10 H).
(1.91 g, 88%) which was obtained as a colorless foam after co-evap-
oration with toluene and drying under high vacuum for 4 h.
IR (film): 3030, 2978, 2932, 1781, 1699, 1390, 1351, 1255, 1204,
1110, 979, 761, 747, 704 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.27 (d, J = 6.9 Hz, 3 H), 2.47 (dd,
J = 16.9, 4.4 Hz, 1 H), 2.79 (dd, J = 13.5, 9.1 Hz, 1 H), 2.97 (dd,
J = 17.6, 10.7 Hz, 1 H), 3.22 (dd, J = 13.2, 3.1 Hz, 1 H), 4.02–4.12
(m, 1 H), 4.18 (dd, J = 9.1, 2.8 Hz, 1 H), 4.26 (dd, J = 8.5, 8.5 Hz,
1 H), 4.72 (m, 1 H), 7.18–7.36 (m, 5 H), 10.3 (br, 1 H).
13C NMR (126 MHz, CDCl3): d = 17.4, 34.3, 37.0, 37.9, 55.1, 66.3,
127.4, 128.9, 129.5, 135.1, 153.1, 175.9, 178.0.
13C NMR (62.9 MHz, CDCl3): d = 28.4, 36.4, 36.7, 37.3, 38.0, 55.9,
66.6, 67.1, 81.5, 127.6, 128.7, 129.0, 129.3, 129.8, 136.0, 136.1,
153.5, 170.7, 171.3, 174.4.
MS (ESI): m/z = 292.0 [M + H]+, 313.9 [M + Na]+.
MS (ESI, negative mode): m/z = 290.0 [M – H]–, 325.9 [M + Cl]–.
MS (CI, NH3): m/z (%) = 178 (42), 195 (10), 266 (59), 334 (7), 426
(31), 443 (97), 482 (1) [M + H]+, 499 (27) [M + NH4]+.
HRMS (ESI): m/z [M + Na]+ calcd for C27H31NO7Na: 504.1991;
found: 504.1993.
(3S)-3-{[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-5-
(benzyloxy)-5-oxopentanoic Acid (9)
Compound 9 was obtained from 6 (2.00 g, 4.15 mol) following
GP1. Purification by flash column chromatography (PE–EtOAc,
2:3 + 0.5% AcOH) followed by co-evaporation with toluene and
drying under high vacuum afforded 9 (1.73 g, 98%) as a colorless
solid; mp 69–72 °C; [a]D22 –35.1 (c = 1.0, CHCl3).
tert-Butyl (3S)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-
[(benzyloxy)methyl]-4-oxobutanoate (7)
NaHMDS (5.40 mL of a 1 M solution in THF, 5.40 mmol) was add-
ed dropwise to a solution of 4 (1.50 g, 4.50 mmol) in anhyd THF (25
mL) at –78 °C and the solution was stirred for 1 h. At the same time
benzyl chloromethyl ether (0.77 mL, 0.85 g, 5.40 mmol) was added
separately to a solution of anhyd NaI (0.81 g, 5.40 mmol) in anhyd
THF (60 mL) and this mixture was stirred for 1 h at r.t. The resulting
slurry was added dropwise within 30 min to the solution of Na eno-
late of 4 which had been pre-cooled to –95 °C. After stirring the
mixture for 4 h at a temperature below –75 °C, the reaction was
quenched by addition of sat. aq NH4Cl (40 mL). THF was evaporat-
ed in vacuo, the aqueous residue was diluted with water (10 mL)
and extracted with EtOAc (4 × 200 mL). The combined organic ex-
tracts were washed successively with 5% aq solutions of KHSO4,
NaHCO3, Na2SO3 and with brine (50 mL of each), and finally dried
over anhyd Na2SO4, filtered and evaporated. The crude product was
chromatographed through a silica gel column (CH2Cl2–Et2O, 40:1).
An inseparable mixture of the diastereomers 7 and epi-7 (4:1) (1.67
g, 82%) was obtained as a colorless oil and was used in the next
step.
IR (KBr): 3064, 3031, 1781, 1734, 1700, 1605, 1498, 1456, 1391,
1352, 1212, 1004, 956, 751, 699 cm–1.
1H NMR (600 MHz, CDCl3): d = 2.57 (dd, J = 13.4, 9.8 Hz, 1 H),
2.61 (dd, J = 17.0, 5.6 Hz, 1 H), 2.68 (dd, J = 16.4, 6.2 Hz, 1 H),
2.88 (dd, J = 14.7, 7.2 Hz, 1 H), 2.89 (dd, J = 17.2, 8.9 Hz, 1 H),
3.22 (dd, J = 13.6, 3.4 Hz, 1 H), 4.11 (dd, J = 8.9, 2.8 Hz, 1 H), 4.18
(m, 1 H), 4.46 (m, 1 H), 4.65 (m, 1 H), 5.11 (s, 2 H), 7.18–7.34 (m,
10 H).
13C NMR (62.9 MHz, CDCl3): d = 35.2, 35.9, 36.1, 37.6, 55.4, 66.4,
66.9, 127.3, 128.4, 128.6, 128.9, 129.4, 135.4, 135.5, 153.2, 170.8,
173.6, 176.5.
MS (CI, isobutane): m/z (%) = 91 (97), 178 (100), 249 (4), 426 (0.1)
[M + H]+.
HRMS (ESI, negative mode): m/z [M+Cl]– calcd for C23H23NO7Cl:
460.1169; found: 460.1173.
1H NMR (250 MHz, CDCl3): d = 1.42 (s, 9 H), 2.51 (dd, J = 17.0,
4.3 Hz, 1 H), 2.67 (dd, J = 13.4, 9.3 Hz, 1 H), 2.93 (dd, J = 16.9,
10.4 Hz, 1 H), 3.20 (dd, J = 13.4, 3.3 Hz, 1 H), 3.58–3.66 (m, 2 H),
4.12 (dd, J = 9.1, 3.3 Hz, 1 H), 4.21 (m, 1 H), 4.48 (m, 1 H), 4.54 (s,
2 H), 4.72 (m, 1 H), 7.15–7.33 (m, 10 H).
13C NMR (62.9 MHz, CDCl3): d = 28.0, 34.5, 37.9, 40.3, 55.1, 66.0,
70.2, 73.0, 80.7, 127.2, 127.6, 128.3, 128.8, 129.4, 135.2, 137.9,
153.1, 171.0, 173.3.
(3S)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[(benzyl-
oxy)methyl]-4-oxobutanoic Acid (11)
Compound 11 was obtained from a mixture of 7 and epi-7 (4:1)
(1.40 g, 3.09 mmol) following GP1. The crude product was purified
by flash column chromatography (CH2Cl2–AcOH, 50:1 → 25:1), si-
multaneously resolving the mixture of diastereomers: epi-11 was
eluted first (0.25 g, 20%), followed by 11 (0.99 g, 80%). Both sub-
stances were obtained as colorless oils after co-evaporation with tol-
uene and drying under high vacuum.
MS (CI, isobutane): m/z (%) = 91 (41), 178 (30), 290 (28), 380 (20),
398 (100), 454 (13) [M + H]+, 488 (3) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H31NO6Na: 476.2044;
found: 476.2043.
Compound 11
[a]D22 –32.6 (c = 1.0, CHCl3).
IR (film): 3030, 2922, 2864, 1779, 1702, 1497, 1454, 1390, 1353,
1215, 1196, 1104, 743, 700 cm–1.
Cleavage of tert-Butyl Ester; General Procedure 1 (GP1)
TFA (2.4 mL, 31.0 mmol) was added dropwise to a solution of tert-
butyl ester 5–7 or 14 (3.1 mol) in anhyd CH2Cl2 (50 mL). The solu-
tion was stirred overnight at r.t., evaporated and subsequently co-
evaporated with toluene.
1H NMR (250 MHz, CDCl3): d = 2.64 (dd, J = 17.8, 4.3 Hz, 1 H),
2.67 (dd, J = 13.5, 9.2 Hz, 1 H), 3.07 (dd, J = 17.5, 10.3 Hz, 1 H),
3.18 (dd, J = 13.5, 3.4 Hz, 1 H), 3.70–3.72 (m, 2 H), 4.11 (m, 1 H),
4.21 (m, 1 H), 4.44 (m, 1 H), 4.54 (s, 2 H), 4.72 (m, 1 H), 7.13–7.32
(m, 10 H), 10.25 (br s, 1 H).
13C NMR (62.9 MHz, CDCl3): d = 33.1, 37.9, 40.3, 55.1, 66.3, 69.9,
73.1, 127.3, 127.7, 128.4, 128.9, 129.4, 135.2, 137.8, 153.3, 172.8,
177.7.
(3R)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-methyl-4-
oxobutanoic Acid (8)
Target compound 8 was obtained from a mixture of 5 and epi-5
(85% de) (2.60 g, 7.48 mmol) following GP1. The crude product
was purified by flash column chromatography (PE–EtOAc, 2:3 +
0.5% AcOH), simultaneously resolving the mixture of diastereo-
mers: the minor diastereomer epi-8 was eluted first, followed by 8
MS (CI, NH3): m/z (%) = 178 (37), 195 (100), 221 [M + H – Aux]+,
238 (16) [M + NH4 – Aux]+.
Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York

1834
A. Stončius et al.
PAPER
HRMS (ESI): m/z [M + Na]+ calcd for C22H23NO6Na: 420.1418;
evaporated. Purification by flash column chromatography afforded
found: 420.1420.
the corresponding urethane-protected amines 12–15.
Compound epi-11
tert-Butyl (2R)-3-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-
methyl-3-oxopropylcarbamate (12)
[a]D22 –62.5 (c = 1.0, CHCl3).
Compound 12 was obtained from 8 (1.91 g, 6.56 mmol) following
GP2, using t-BuOH. Flash chromatography (EtOAc–PE, 1:2) and
crystallization (Et2O–PE) afforded 12 (1.40 g, 59%) as a colorless
solid; mp 87–88.5 °C; [a]D25 –85.0 (c = 1.07, CHCl3).
IR (film): 3030, 2924, 2866, 1779, 1705, 1497, 1454, 1390, 1351,
1213, 1195, 1104, 742, 700 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.63 (dd, J = 17.6, 4.5 Hz, 1 H),
2.75 (dd, J = 13.6, 9.3 Hz, 1 H), 3.05 (dd, J = 17.5, 10.0 Hz, 1 H),
3.22 (dd, J = 13.5, 3.2 Hz, 1 H), 3.58–3.70 (m, 2 H), 4.00–4.12 (m,
2 H), 4.48 (s, 2 H), 4.50–4.60 (m, 2 H), 7.18–7.34 (m, 10 H), 9.20
(br s, 1 H).
13C NMR (62.9 MHz, CDCl3): d = 31.4, 35.6, 38.3, 53.8, 64.3, 68.0,
71.2, 125.5, 125.8, 126.6, 127.1, 127.7, 133.6, 136.1, 151.4, 171.2,
175.8.
IR (film): 3398, 2983, 2966, 2920, 1786, 1765, 1720, 1689, 1516,
1457, 1389, 1358, 1242, 1215, 1169, 1066, 1032, 972, 760, 746,
729, 717 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.24 (d, J = 6.9 Hz, 3 H), 1.43 (s,
9 H), 2.78 (dd, J = 13.2, 9.4 Hz, 1 H), 3.25 (dd, J = 13.2, 2.5 Hz, 1
H), 3.31 (m, 1 H), 3.46 (m, 1 H), 3.85 (m, 1 H), 4.18 (dd, J = 9.4,
2.5 Hz, 1 H), 4.25 (dd, J = 8.5, 8.5 Hz, 1 H), 4.67 (m, 1 H), 4.92 (br
m, 1 H), 7.16–7.38 (m, 5 H).
13C NMR (62.9 MHz, CDCl3): d = 14.9, 28.4, 37.9, 39.1, 42.7, 55.3,
66.3, 79.3, 127.4, 128.9, 129.3, 129.4, 135.2, 153.1, 155.9, 175.6.
HRMS (ESI): m/z [M + Na]+ calcd for C19H26N2O5Na: 385.1734;
MS (CI, NH3): m/z (%) = 108 (11), 178 (28), 195 (100), 221 (7)
[M + H – Aux]+, 238 (39) [M + NH4 – Aux]+.
(3R)-3-{[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-5-
tert-butoxy-5-oxopentanoic Acid (10)
Catalyst Pd/C (10% Pd) (10 mg) was added to a solution of 6 (1.30
g, 2.70 mmol) in EtOAc (15 mL). The suspension was deoxygenat-
ed and stirred overnight at r.t. under H2 atmosphere (1 atm). After
the reaction, the residual H2 was removed by bubbling of Ar through
the suspension. The reaction mixture was filtered through a Celite®
pad and evaporated. The yellow oily residue was purified by flash
column chromatography (EtOAc–PE, 2:3 + 0.5% AcOH). The frac-
tions were evaporated and co-evaporated with toluene. Drying un-
der high vacuum gave 10 (1.05 g, 100%) as a colorless semi-solid;
[a]D22 –50.1 (c = 1.0, CHCl3).
found: 385.1735.
Benzyl (3R)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-
{[(tert-butoxycarbonyl)amino]methyl}-4-oxobutanoate (13)
Target compound 13 was obtained from 9 (1.40 g, 3.29 mmol) fol-
lowing GP2, using t-BuOH. Flash column chromatography
(EtOAc–PE, 3:2) afforded 13 (0.91 g, 56%) as a yellowish oil;
[a]D22 –34.7 (c = 1.0, CHCl3).
IR (film): 3389, 2978, 1780, 1733, 1701, 1515, 1455, 1390, 1366,
1351, 1248, 1170, 1107, 753, 700 cm–1.
IR (film): 2979, 1781, 1708, 1392, 1368, 1351, 1208, 1154, 1006,
958, 912, 913, 762, 735, 704 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.41 (s, 9 H), 2.56 (dd, J = 13.2,
10.1 Hz, 1 H), 2.61 (dd, J = 17.0, 4.4 Hz, 1 H), 3.04 (dd, J = 16.4,
10.1 Hz, 1 H), 3.21 (dd, J = 13.2, 3.1 Hz, 1 H), 3.30 (m, 1 H), 3.58
(m, 1 H), 4.10 (dd, J = 8.8, 2.5 Hz, 1 H), 4.20 (m, 1 H), 4.34 (m, 1
H), 4.59 (br m, 1 H), 4.92 (br m, 1 H), 5.11 (s, 2 H), 7.19–7.36 (m,
10 H).
13C NMR (125.8 MHz, CDCl3): d = 28.3, 34.0, 37.5, 40.6, 41.5,
55.7, 66.3, 66.7, 79.5, 127.2, 128.3, 128.6, 128.9, 129.4, 135.6,
135.58, 153.63, 156.0, 171.5, 173.2.
1H NMR (250 MHz, CDCl3): d = 1.42 (s, 9 H), 2.50 (dd, J = 16.3,
5.8 Hz, 1 H), 2.62 (dd, J = 16.8, 6.3 Hz, 1 H), 2.73 (dd, J = 16.3, 8.2
Hz, 1 H), 2.75 (dd, J = 13.4, 9.6 Hz, 1 H), 2.88 (dd, J = 16.8, 7.8 Hz,
1 H), 3.28 (dd, J = 13.4, 3.3 Hz, 1 H), 4.17 (m, 1 H), 4.23 (m, 1 H),
4.41 (m, 1 H), 4.67 (m, 1 H), 7.19–7.36 (m, 5 H).
13C NMR (62.9 MHz, CDCl3): d = 28.1, 35.4, 36.2, 36.8, 37.6, 55.5,
66.3, 81.3, 127.3, 128.9, 129.5, 135.4, 153.2, 170.4, 177.2, 177.5.
MS (CI, NH3): m/z (%) = 178 (28), 195 (100), 232 (30), 409 (0.2)
MS (CI, isobutane): m/z (%) = 91 (53), 178 (22), 289 (100), 333
[M + NH4]+.
(17), 379 (10), 397 (37), 441 (26), 497 (5) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H25NO7Na: 414.1523;
HRMS (ESI): m/z [M + Na]+ calcd for C27H32N2O7Na: 519.2102;
found: 414.1523.
found: 519.2110.
Curtius Rearrangement; General Procedure 2 (GP2)
tert-Butyl (3S)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-
({[(benzyloxy)carbonyl]amino}methyl)-4-oxobutanoate (14)
Compound 14 was obtained from 10 (0.98 g, 2.50 mmol) following
GP2, using benzyl alcohol. Flash column chromatography (EtOAc–
PE, 2:3) afforded 14 (0.82 g, 66%) as a yellowish gum; [a]D22 –31.2
(c = 1.1, CHCl3).
A solution of the carboxylic acid 8–10 or 11 (3.29 mmol) in anhyd
THF (50 mL) was cooled to –15 °C and treated with Et3N (0.55 mL,
0.40 g, 3.95 mmol, 1.20 equiv). Ethyl chloroformate (0.34 mL, 0.39
g, 3.57 mmol, 1.09 equiv) was added dropwise and the mixture was
stirred for 15 min at –15 °C, then allowed to warm to r.t. and stirred
for an additional 15 min. The reaction mixture was then cooled to 0
°C, a solution of NaN3 (0.43 g, 6.61 mmol, 2.00 equiv) in water (8
mL) was added and the mixture was stirred at this temperature for 1
h. THF was evaporated without heating and the aq solution was ex-
tracted with Et2O (4 ×). The combined organic extracts were dried
over anhyd MgSO4. Evaporation to dryness (the bath below r.t.)
yielded a residue, which was dissolved in anhyd toluene (100 mL).
After heating to reflux, several mL of the solvent were distilled off
to remove traces of water, followed by addition of 120 equiv of t-
BuOH or 20 equiv of benzyl alcohol. The reaction mixture was re-
fluxed overnight. After cooling to r.t. the solvent was removed (ben-
zyl alcohol under high vacuum) and the residue was dissolved in
CH2Cl2 (30 mL). The solution was washed successively with 5% aq
KHSO4, 5% aq NaHCO3 and brine, dried over anhyd Na2SO4 and
IR (film): 3371, 2979, 1781, 1718, 1524, 1455, 1392, 1352, 1248,
1155, 1107, 1053, 1018, 912, 845, 735, 700 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.41 (s, 9 H), 2.45 (dd, J = 16.8,
4.5 Hz, 1 H), 2.67 (dd, J = 13.4, 9.7 Hz, 1 H), 2.86 (dd, J = 16.9,
10.0 Hz, 1 H), 3.23 (dd, J = 13.4, 3.3 Hz, 1 H), 3.41–3.60 (m, 2 H),
4.13 (dd, J = 9.1, 3.0 Hz, 1 H), 4.17–4.27 (m, 2 H), 4.66 (m, 1 H),
5.08 (s, 2 H), 5.17 (m, 1 H), 7.15–7.35 (m, 10 H).
13C NMR (62.9 MHz, CDCl3): d = 26.2, 33.4, 36.2, 38.4, 40.5, 53.7,
64.7, 65.0, 79.3, 125.5, 126.3, 126.7, 127.1, 127.6, 133.6, 134.7,
151.7, 154.6, 169.0, 171.6.
MS (CI, isobutane): m/z (%) = 91 (79), 178 (10), 289 (13), 333 (60),
397 (25), 441 (79), 497 (11) [M + H]+.
Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York

PAPER
Chiral Succinate
1835
HRMS (ESI): m/z [M + Na]+ calcd for C27H32N2O7Na: 519.2102;
found: 519.2104.
13C NMR (62.9 MHz, CDCl3): d = 33.5, 37.9, 40.2, 42.2, 55.4, 66.7,
66.9, 127.3, 128.0, 128.5, 128.9, 129.4, 135.4, 136.4, 153.6, 156.6,
173.1, 176.3.
tert-Butyl (2S)-3-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-
[(benzyloxy)methyl]-3-oxopropylcarbamate (15)
Target compound 15 was obtained from 11 (0.89 g, 2.24 mmol) fol-
lowing GP2 using t-BuOH. Flash chromatography (EtOAc–PE,
3:2) afforded 15 (0.62 g, 59%) as an off-white solid; mp 79–81 °C;
[a]D22 –54.4 (c = 1.0, CHCl3).
MS (CI, isobutane): m/z (%) = 91 (51), 178 (100), 192 (6), 264 (10),
441 (0.1) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H24N2O7Na: 463.1476;
found: 463.1482.
tert-Butyl (3R)-3-{[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-
yl]carbonyl}-1-pyrrolidinecarboxylate (18)
IR (film): 3385, 2976, 2928, 1779, 1702, 1508, 1454, 1390, 1365,
1249, 1212, 1171, 1106, 741, 700 cm–1.
BH3·Me2S (2.00 mL 2 M solution in THF, 4.00 mmol, 5.42 equiv)
was added to a solution of 16 (300 mg, 738 mmol) in anhyd THF (7
mL) and the mixture was stirred for 3 h at r.t. The reaction was
quenched by addition of MeOH (3 mL). After stirring for 20 min the
solvents were evaporated and the residue was purified by flash col-
umn chromatography (Et2O–PE, 3:1) to give 18 (208 mg, 75%) as
a colorless oil; [a]D23 –64.1 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): d = 1.41 (s, 9 H), 2.70 (dd, J = 13.5,
9.4 Hz, 1 H), 3.21 (dd, J = 13.7, 3.3 Hz, 1 H), 3.42–3.65 (m, 2 H),
3.77–3.79 (m, 2 H), 4.12 (dd, J = 8.9, 3.2 Hz, 1 H), 4.16–4.26 (m, 2
H), 4.54 (s, 2 H), 4.67 (br m, 1 H), 4.87 (br m, 1 H), 7.15–7.33 (m,
10 H).
13C NMR (62.9 MHz, CDCl3): d = 28.4, 37.9, 39.5, 44.9, 55.3, 66.2,
68.6, 73.3, 79.3, 127.3, 127.7, 128.4, 128.9, 129.4, 135.3, 137.9,
153.4, 156.0, 172.7.
IR (film): 2977, 2886, 1781, 1695, 1604, 1389, 1247, 1213, 1167,
1115, 881, 761, 703 cm–1.
MS (CI, NH3): m/z (%) = 91 (12), 108 (15), 178 (28), 195 (94), 261
(18), 351 (12), 369 (62), 395 (100), 412 (30), 430 (29), 469 (11)
[M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H32N2O6Na: 491.2153;
1H NMR (500 MHz, CD2Cl2): d = 1.45 (s, 9 H), 2.09–2.26 (m, 2 H),
2.86 (dd, J = 13.8, 9.4 Hz, 1 H), 3.21 (dd, J = 13.2, 3.1 Hz, 1 H),
3.37–3.46 (m, 2 H), 3.54–3.58 (m, 2 H), 4.11 (m, 1 H), 4.19 (m, 1
H), 4.25 (m, 1 H), 4.69 (m, 1 H), 7.20–7.35 (m, 5 H).
13C NMR [125.8 MHz, CD2Cl2, (cis/trans)]: d = 28.5, 28.7/29.2,
28.8, 38.0, 42.3/43.2, 45.5/45.8, 48.2, 55.5, 66.8, 79.3, 127.6, 129.2,
129.8, 135.7, 153.5, 154.4, 173.3.
found: 491.2153.
(3R)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-{[(tert-but-
oxycarbonyl)amino]methyl}-4-oxobutanoic Acid (16)
MS (CI, NH3): m/z (%) = 178 (5), 275 (100), 336 (43), 375 (4)
An oily yellow residue was obtained from 13 (0.88 g, 1.77 mmol)
following the procedure described for 10. This was purified by flash
column chromatography (EtOAc–PE, 3:2). After evaporation of the
fractions and drying under high vacuum, 16 (0.70 g, 97%) was ob-
tained as a solid foam; [a]D22 –66.4 (c = 1.0, CHCl3).
[M + H]+, 392 (1) [M + NH4]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H26N2O5Na: 397.1734;
found: 397.1734.
Benzyl (3S)-3-{[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]carbo-
nyl}-1-pyrrolidinecarboxylate (19)
Compound 19 was obtained from 17 (300 mg, 681 mmol) following
a procedure similar to the synthesis of 18. The raw product was pu-
rified by flash column chromatography (EtOAc–PE, 3:2) to give 19
(189 mg, 68%) as a colorless oil; [a]D22 –13.7 (c = 1.0, CHCl3).
IR (KBr): 3378, 2979, 2932, 1778, 1703, 1520, 1392, 1367, 1250,
1170, 1108, 1053, 1011, 968, 856, 760, 704 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.40 (s, 9 H), 2.57 (dd, J = 17.2,
4.9 Hz, 1 H), 2.76 (dd, J = 13.5, 9.4 Hz, 1 H), 2.98 (dd, J = 16.8, 9.3
Hz, 1 H), 3.21–3.34 (m, 2 H), 3.57 (m, 1 H), 4.14 (dd, J = 8.9, 2.9
Hz, 1 H), 4.19–4.33 (m, 2 H), 4.63 (br m, 1 H), 4.96 (br m, 1 H),
7.19–7.35 (m, 5 H), 9.20 (br s, 1 H).
13C NMR (62.9 MHz, CDCl3): d = 28.3, 33.7, 37.5, 40.5, 41.4, 55.6,
66.3, 79.8, 127.2, 128.9, 129.5, 135.5, 153.5, 156.2, 173.2, 176.6.
IR (film): 2954, 2886, 1778, 1699, 1420, 1389, 1450, 1247, 1212,
1112, 764, 700 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.09–2.26 (m, 2 H), 2.79 (dd, J =
13.3, 9.2 Hz, 1 H), 3.22 (br d, J = 13.4 Hz, 1 H), 3.46–3.83 (m, 4 H),
4.11 (dd, J = 14.1, 7.1 Hz, 1 H), 4.17–4.27 (m, 2 H), 4.68 (m, 1 H),
5.15 (s, 2 H), 7.15–7.39 (m, 10 H).
MS (CI, isobutane): m/z (%) = 178 (100), 289 (7), 351 (2), 407 (0.3)
[M + H]+.
HRMS (ESI, negative mode): m/z [M
C20H26N2O7Cl: 441.1434; found: 441.1439.
+
Cl]– calcd for
13C NMR [62.9 MHz, CDCl3, (cis/trans)]: d = 27.8/28.4, 37.9, 42.0/
42.9, 45.4/45.9, 48.3/49.0, 55.2, 66.5/66.9, 127.5, 128.0, 128.5,
129.0, 129.4, 135.0, 136.9, 153.2, 154.6, 172.8.
(3S)-4-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-({[(benzyl-
oxy)carbonyl]amino}methyl)-4-oxobutanoic Acid (17)
Compound 17 was obtained from 14 (0.46 g, 0.93 mol) following
GP1. The crude product was purified by flash column chromatogra-
phy (EtOAc–PE, 3:2 + 0.5% AcOH). Successive co-evaporation
with toluene, MeOH and MeCN followed by evacuation at the
pump afforded 17 (0.39 g, 96%) as a colorless solid; mp 78–83 °C;
[a]D22 –35.4 (c = 1.0, CHCl3).
MS (CI, isobutane): m/z (%) = 91 (45), 178 (13), 273 (29) [M + H –
Cbz]+, 317 (38), 365 (100), 409 (46) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C23H24N2O5Na: 431.1577;
found: 431.1578.
Cleavage of the Chiral Auxiliary; General Procedure 3 (GP3)
H2O2 (0.26 mL of 30% aq solution, 2.30 mmol, 4.30 equiv) was
added dropwise at 0 °C to a solution of the N-acylated oxazolidino-
ne 12, 14, 15, 18 or 19 (0.53 mmol) in THF (10 mL), followed by
dropwise addition of aq LiOH·H2O (49 mg, 1.17 mmol, 2.20 equiv
in 3 mL of water). The reaction mixture was stirred at 0 °C for 2.5
h. After addition of sat. aq Na2SO3 and sat. aq NaHCO3 (2.5 mL of
each), the mixture was stirred for an additional 20 min at r.t. THF
was evaporated, the aqueous residue was diluted with water (10
mL) and the basic solution (pH 10) was extracted with CH2Cl2 (4 ×).
This CH2Cl2 extract contained the cleaved chiral auxiliary. The re-
maining aqueous phase was acidified by addition of 5% aq KHSO4
IR (KBr): 3361, 3031, 1780, 1700, 1531, 1455, 1392, 1352, 1248,
1108, 1053, 1014, 739, 699 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.54 (dd, J = 17.4, 4.1 Hz, 1 H),
2.65 (dd, J = 13.3, 10.1 Hz, 1 H), 2.95 (dd, J = 17.2, 10.0 Hz, 1 H),
3.20 (br d, J = 13.1 Hz, 1 H), 3.40–3.65 (m, 2 H), 4.08 (dd, J = 9.0,
2.6 Hz, 1 H), 4.13–4.24 (m, 2 H), 4.64 (m, 1 H), 5.06 (s, 2 H), 5.31
(br m, 1 H), 7.12–7.35 (m, 10 H), 9.62 (br s, 1 H).
Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York

1836
A. Stončius et al.
PAPER
solution (ca. pH 2) and extracted with EtOAc (4 ×). The combined
EtOAc extracts were dried over anhyd Na2SO4, evaporated to dry-
ness and purified by flash column chromatography (short column,
EtOAc–PE, 3:2 + 0.5% AcOH). Co-evaporation with toluene,
MeOH and MeCN and drying under high vacuum afforded the pro-
tected b2-amino acid 20, 21, 22, 23 or 24, respectively.
MS (CI, NH3): m/z (%) = 91 (4), 106 (7), 210 (33), 254 (28), 271
(100), 310 (14) [M + H]+, 327 (6) [M + NH4]+.
HRMS (ESI, negative mode): m/z [M + Cl]– calcd for C16H23NO5Cl:
344.1270; found: 344.1268.
Acknowledgment
(2R)-3-[(tert-Butoxycarbonyl)amino]-2-methylpropanoic Acid
(20)
This research was supported through a European Community Marie
Curie Fellowship (individual fellowship for A.S., Contract No.
HPMF-CT-2000-00458) and by Deutsche Forschungsgemein-
schaft.
Compound 20 (0.47 g, 79%) was obtained as a colorless solid from
12 (1.07 g, 2.95 mmol) following GP3 after crystallization from
20
Et2O; mp 71–73 °C, (ref.5 mp 79–80 °C; ref.15 mp 72–73 °C); [a]D
26
–19.6 (c = 2.09, MeOH), {ref.5 [a] = –20 (c = 2, MeOH), ref.15 [a]D
–18.0 (c = 1.9, MeOH)}.
References
HRMS (ESI): m/z [M + H]+ calcd for C9H18NO4: 204.1230; found:
(1) Balenovic, K.; Cerar, D.; Fuks, Z. J. Chem. Soc. 1952, 3316.
(2) (a) Podlech, J.; Seebach, D. Liebigs Ann. 1995, 1217.
(b) Müller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837.
(3) (a) Seebach, D.; Schaeffer, L.; Gessier, F.; Bindschädler, P.;
Jäger, C.; Josien, D.; Kopp, S.; Lelais, G.; Mahajan, Y. R.;
Micuch, P.; Sebesta, R.; Schweizer, B. W. Helv. Chim. Acta
2003, 86, 1852. (b) Lelais, G.; Campo, M. A.; Kopp, S.;
Seebach, D. Helv. Chim. Acta 2004, 87, 1545. (c) Lelais,
G.; Micuch, P.; Josien-Lefebvre, D.; Rossi, F.; Seebach, D.
Helv. Chim. Acta 2004, 87, 3131.
204.1234.
(3R)-1-(tert-Butoxycarbonyl)-3-pyrrolidinecarboxylic Acid (21)
Compound 21 (106 mg, 89%) was obtained as a colorless crystal-
line solid from 18 (208 mg, 556 mmol) following GP3; mp 139–141
°C; [a]D –14.6 (c = 1.0, CHCl3), {ref.27 [a]D –8.0 (c = 0.5,
22
25
CHCl3)}.
HRMS (ESI, negative mode): m/z [M + Cl]– calcd for C10H17NO4Cl:
250.0852; found: 250.0851.
(4) (a) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206.
(b) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiv.
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Eur. J. Org. Chem. 2000, 83. (b) Gutierrez-Garcia, V. M.;
Lopez-Ruiz, H.; Reyes-Rangel, G.; Juaristi, E. Tetrahedron
2001, 57, 6487. (c) Gutierrez-Garcia, V. M.; Reyes-Rangel,
G.; Munoz-Muniz, O.; Juaristi, E. Helv. Chim. Acta 2002,
85, 4189. (d) Xue, C.-B.; He, X.; Roderick, J.; Corbett, R.
L.; Decicco, C. P. J. Org. Chem. 2002, 67, 865.
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Boog, A.; Schweizer, W. B. Eur. J. Org. Chem. 1999, 335.
(c) Munoz-Muniz, O.; Juaristi, E. Tetrahedron 2003, 59,
4223. (d) See also: Juaristi, E.; Seebach, D. In
(3S)-1-(Benzyloxycarbonyl)-3-pyrrolidinecarboxylic Acid (22)
Compound 22 (95 mg, 82%) was obtained as a colorless crystalline
solid from 19 (189 mg, 463 mmol) following GP3; mp 96–98 °C;
[a]D24 +16.5 (c = 0.9, CHCl3), {ref.28 [a]D25 +16.0 (c = 9.0, CHCl3)}.
HRMS (ESI, negative mode): m/z [M + Cl]– calcd for C13H15NO4Cl:
284.0695; found: 284.0694.
(2S)-2-{[(Benzyloxycarbonyl)amino]methyl}-4-tert-butoxy-4-
oxobutanoic Acid (23)
Compound 23 (178 mg, 94%) was synthesized as a colorless oil
22
from 14 (280 mg, 564 mmol) following GP3; [a]D –2.2 (c = 1.0,
CHCl3).
IR (film): 3341, 2978, 1732, 1538, 1456, 1368, 1259, 1152, 1020,
848, 738, 697 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.43 (s, 9 H), 2.51 (dd, J = 16.9,
5.7 Hz, 1 H), 2.63 (dd, J = 16.7, 7.5 Hz, 1 H), 3.00 (m, 1 H), 3.44–
3.49 (m, 2 H), 5.09 (s, 2 H), 5.34 (br m, 1 H), 7.28–7.38 (m, 5 H),
8.67 (br s, 1 H).
Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997, 261.
(7) Nagula, G.; Huber, V. J.; Lum, C.; Goodman, B. A. Org.
Lett. 2000, 2, 3527.
(8) (a) Rimkus, A.; Sewald, N. Org. Lett. 2003, 5, 79.
(b) Eilitz, U.; Lessmann, F.; Seidelmann, O.; Wendisch, V.
Tetrahedron: Asymmetry 2003, 14, 189. (c) Rimkus, A.;
Sewald, N. Synthesis 2004, 135.
(9) (a) Hintermann, T.; Seebach, D. Synlett 1997, 437.
(b) Seebach, D.; Abele, S.; Gademann, K.; Guichard, G.;
Hintermann, T.; Jaun, B.; Matthews, J. L.; Schreiber, J. V.;
Oberer, L.; Hommel, U.; Widmer, H. Helv. Chim. Acta
1998, 81, 932. (c) Coffey, P. E.; Drauz, K. H.; Roberts, S.
M.; Skidmore, J.; Smith, J. A. Chem. Commun. 2001, 2330.
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M. T. J. Am. Chem. Soc. 1990, 112, 8215.
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Ludwig (D’Souza), A. A.; Robinson, A. J.; Wyatt, P. B. J.
Chem. Soc., Perkin Trans. 1 1998, 521.
13C NMR (62.9 MHz, CDCl3): d = 27.0, 33.9, 40.6, 40.7, 66.0, 80.6,
127.1, 127.5, 135.3, 155.6, 169.8, 177.0.
MS (CI, isobutane): m/z (%) = 91 (65), 108 (126), 174 (39), 190 (5),
238 (35), 282 (100), 338 (6) [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H23NO6Na: 360.1418;
found: 360.1417.
(2S)-3-(Benzyloxy)-2-{[(tert-butoxycarbonyl)amino]meth-
yl}propanoic Acid (24)
Compound 24 (111 mg, 84%) was synthesized as a colorless oil
22
from 15 (200 mg, 427 mmol) following GP3; [a]D +8.4 (c = 1.0,
CHCl3).
IR (film): 3333, 2978, 2932, 2871, 1713, 1516, 1454, 1393, 1367,
1253, 1169, 1101, 739, 698 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.43 (s, 9 H), 2.88 (m, 1 H), 3.43–
3.47 (m, 2 H), 3.69–3.71 (m, 2 H), 4.51 (s, 2 H), 5.08 (br s, 1 H),
7.22–7.36 (m, 5 H), 10.30 (br s, 1 H).
13C NMR [62.9 MHz, CDCl3, (cis/trans)]: d = 28.4, 39.4/40.4, 46.0/
46.4, 68.6, 73.3, 79.6/81.2, 127.7, 128.4, 137.7, 156.1/157.7, 176.5/
177.3.
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Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.
Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York

PAPER
Chiral Succinate
1837
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and List of Participants; Hamburg University Press:
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product: signals corresponding to double alkylation products
were observed in MS (ESI).
(25) Manuscript in preparation.
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Synthesis 2005, No. 11, 1829–1837 © Thieme Stuttgart · New York