A microwave-assisted synthesis of (S)-N-protected homoserine γ-lactones from l-aspartic acid

Article abstract of DOI:10.1021/jo2008093

A three-pot preparation of (S)-N-protected homoserine γ-lactones is presented. Conversion of N-protected l-aspartic acid to an oxazolidinone is followed by selective reduction/acid-catalyzed cyclization to deliver the lactones. Microwave irradiation proved valuable for improving the latter reaction steps in some cases.

Full text of DOI:10.1021/jo2008093

NOTE
pubs.acs.org/joc
A Microwave-Assisted Synthesis of (S)-N-Protected Homoserine
γ-Lactones from L-Aspartic Acid
Suneel P. Singh,† Alex Michaelides,† A. Rod Merrill,‡ and Adrian L. Schwan*,†
†Department of Chemistry and ‡Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario,
Canada N1G 2W1
S Supporting Information
b
ABSTRACT: A three-pot preparation of (S)-N-protected homoserine γ-lactones is
presented. Conversion of N-protected L-aspartic acid to an oxazolidinone is followed
by selective reduction/acid-catalyzed cyclization to deliver the lactones. Microwave
irradiation proved valuable for improving the latter reaction steps in some cases.
Scheme 1. Common Organic Reactions of (S)-N-Protected
Homoserine γ-Lactones
n response to fluctuations in cell-population density, many
bacteria regulate a diverse range of physiological actions by a
I
process called quorum sensing. Quorum sensing bacteria release
autoinducers to alter gene expression that leads to modification
of processes such as competence, conjugation, antibiotic pro-
duction, and biofilm formation. In general, Gram-negative bac-
teria (i.e., Pseudomonas aeruginosa) use N-acylated homoserine
γ-lactones (1, PG = acylated chain) as autoinducers.1,2 The study
of quorum sensing could find importance in the treatment
of several diseases such as cystic fibrosis (CF), which refers to
the distinctive fibrosis and cyst formation within the pancreas.
Although there is presently no cure for CF, most CF patients
survive into adulthood through the extensive use of antibiotics
and other medications. Because of the rise of antibiotic-resistant
strains of bacteria commonly found in the lungs of CF patients,
alternative methods are now sought for the treatment of lung
infections of CF patients and also for other diseases which rely on
the use of antibiotics.3 One such alternative therapy, which uses
chemicals that interrupt or destroy quorum sensing signals, is
called signal interference or quorum quenching. It has been reported
that the communication ability of bacteria can be interrupted and
thereby its ability to form colonies and to become pathogenic is
compromised. Thus, the bacteria can be naturally eliminated by
the body through normal immune system functions. It seems
plausible that the signal interference approach for the treatment
of bacterial infections would replace or complement the use of
antibiotics.4
the cost of racemic N-tert-butylcarbonylhomoserine γ-lactone
(1a) is about US $50/g.11 Other N-protected homoserine γ-lactones
(1) are not commercially available from any major chemical supplier.
Several procedures exist for the synthesis of lactones 1, but their
commercial scarcity may be caused by the lack of an attractive
or inexpensive synthetic protocol. Lactones 1 can be obtained
from the N-protection of homoserine γ-lactones (5) under basic
conditions9a,12 or from homoserine (6) via N-protection followed
by the cyclization to the lactone (Scheme 2).12a,13 The drawback
in these synthetic schemes is the high cost of L-homoserine γ-lactone
(5) and L-homoserine.11 Alternative methods use comparatively
less expensive starting materials such as L-methionine (7) and
L-aspartic acid (8).11 For example, (S)-N-protected homoserine
γ-lactones (1) can be synthesized by N-protection of L-methionine
(7) followed by refluxing with an alkyl iodide under acidic
conditions14a or by converting it to L-homoserine followed
N-Protected homoserine γ-lactones (1)5 have been used in
numerous biological studies6 and in the syntheses of several useful
organic compounds.7À10 They also serve as a precursor for a number
of synthetically important compounds such as homoserine deriva-
tives (2),8 2-amino-4-halobutanoic acid derivatives (3),9 and
vinylglycine derivatives (4) (Scheme 1).10
Despite their proven value, N-protected homoserine γ-lactones
(1) are very expensive or not available in their optically pure
form. For example, the cost of optically pure (S)-N- benzyloxy-
carbonylhomoserine γ-lactones (1b) is about US $100/g, while
Received: April 22, 2011
Published: July 19, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 2. Comparison of Possible Routes to Synthesize
N-Protected Homoserine γ-Lactones (1)
Scheme 4. Synthesis of (S)-3-(N-Protected)-5-oxo-4-oxazo-
lidineacetic Acid (11)*
* Key: (i) solvent, base, PG-Cl, or PG-anhydride (see detail in the
Experimental Section); (ii) solvent (toluene, benzene, or EtOAc/
Benzene), PTSA (catalytic amount), paraformaldehyde (2 equiv for
reflux/7.0 equiv for microwave heating conditions (MW)). a 14a,d were
commercially available.
Scheme 3. Synthetic Routes to Lactones 1 from L-Aspartic
Acid Based Compounds
γ-lactones (1) in a three-pot process from L-aspartic acids (8).
Our method involves N-protection of L-aspartic acid (8) under
basic conditions,20,23 followed by the acid-catalyzed condensa-
tion with paraformaldehyde to yield (S)-3-(N-protected)-5-oxo-
4-oxazolidineacetic acid (11) (Scheme 4).24 While some of the
compounds 11a,b,d could be synthesized in moderate to good
yields by refluxing a mixture of 14, paraformaldehyde, and
p-toluenesulfonic acid (p-TsOH) in toluene or benzene, such a
treatment resulted in a low yield of 11c or did not produce the
expected N-acetyl or N-nosyl-N-(2-nitrobenzenesulfonyl)oxazo-
lidinone compounds (11d, f) at all. Several attempts to obtain
11f by varying the equivalents of p-TsOH (0.06À1.1 equiv) and
paraformaldehyde (1À4 equiv), reaction time (1 h to overnight),
solvents (benzene, toluene, THF, DMF, acetic anhydride/acetic
acid), or temperature (60À100 °C or refluxing) under conven-
tional heating were unsuccessful. The 2-nitrobenzenesulfonyl
(nosyl) group, introduced by Fukuyama,25 is important because
it can be removed under very mild conditions with thiolates.
N-Fmoc protection is also important from a synthetic perspective,
whereas N-acyl-protected compounds are significant for biolo-
gical studies related to quorum sensing.
by N-protection and cyclization.14b While the synthesis from
L-methionine can generally be achieved in high yield and in
few steps, there is still a scope for improvement in the yield, cost,
and amino protecting group choices in these methods.15 Alter-
natively, lactones 1 can also be synthesized in a multistep pro-
cedure starting with selective esterification of L-aspartic acid (8)
followed by N-protection, precipitation of the dicyclohexylam-
monium salts, selective reduction with LiBH4, and cyclization to
the corresponding γ-lactones during isolation.16 Isolated examples
of syntheses of compounds 1 from L-aspartic acid based derivatives
(9À12) also exist in the literature; however, these reports did not
provide a collective study and appear to be protecting group
specific (Scheme 3, method A/B/C).17À19 For example, the
synthetic protocol from 12 to 1 proceeds only with selected pro-
tecting groups, whereas formation of lactone 13 occurs in other
situations.20 Most of these methods also require additional steps
and use of undesirable reagents (Scheme 3).19,21 For instance,
the synthetic protocol from 11 to 1 requires the use of thionyl
chloride, which is not only environmentally damaging but also
highly regulated and not easily available. In addition, use of
transition-metal catalysis in this protocol is undesirable in the late
stages of synthesis of pharmaceutically and biologically relevant
compounds.22
Following the lead of Tantry et al.,24c where an unmodified
domestic microwave was used for the synthesis of related oxazo-
lidinone derivatives, we attempted to use a microwave reactor for
the synthesis of the requisite oxazolidinones. Microwave treat-
ment (300 W, 80À105 °C, benzene or toluene) considerably
shortened the reaction time to 5À15 min and resulted in con-
sistently good yields of 11aÀf. The optimum reaction conditions
standardized for the synthesis of 11aÀf are described in the
Experimental Section. Oxazolidinones 11d and 11f represent
new compounds, while full characterization data has not been
previously reported for 11c and 11e. 1H and 13C NMR data for
11a also did not completely match with the reported data.
Considerable broadening was observed for the ÀCH2COOH
protons in the 1H NMR spectra of 11a and 11c, probably due to
the presence of rotamers.26a Structures of 11a and 11c were
confirmed by collecting 1H NMR spectra at higher temperatures
(see the Supporting Information). (S)-3-Acetyl-5-oxo-4-oxazo-
lidineacetic acid (11d) was obtained as a mixture of two rotamers
In light of the above-mentioned difficulties, we report an econom-
ical and facile way to synthesize the N-protected-L-homoserine
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NOTE
Scheme 5. Synthesis of (S)-N-Protected Homoserine
γ-Lactonesa
Scheme 6. Synthesis of Racemic (S)-N-Fmoc-homoserine
γ-Lactone (rac-1c)a
a Key: (i) 10% aq Na2CO3, dioxane, Fmoc-Cl (1.1 equiv); (ii) PTSA
(0.06 equiv), paraformaldehyde (7 equiv), toluene, MW (300 W, 105 °C,
6 min); (iii) (a) NMM (1.2 equiv)/IBCF (1.2 equiv) in THF, NaBH4
followed byMeOHand1 M acetic acid; (b) 0.5 Mcitricacid, MW, 300W,
10 min, 80 °C.
the cyclization step under conventional heating conditions. When
microwave irradiation (300 W, 80 °C) was applied to the crude
reaction mixture containing 16c in 1 M citric acid solution, there
was conversion to 1c within 10 min. Lactone 1c could be ob-
tained in 60% yield under MW conditions without workup or
purification at the reduction stage. Lactone 1d32 was similarly
obtained in 84% yield under MW conditions, whereas 1b and 1e,f
were obtained in moderate yields. Various acid conditions and
the MW treatment could not successfully bring about 1a; pre-
sumably the Boc group is too sensitive to the obligatory acid
treatment.
The configuration of the stereocenter of 1bÀf was assigned to
be S by using a variety of methods. Optical rotation values for 1b,
d,e correlated well with literature values (see the Supporting
Information).14a,18,32b,32c To confirm the optical purity of 1c,
racemic N-Fmoc-homoserine γ-lactone (rac-1c) was obtained
(Scheme 6). HLPC analysis of rac-1c on a CHIRACEL-OJ-H
chiral analytical column revealed two peaks at 51.7 and 55.3 min
(83/17 hexanes/2-propanol; 1.0 mL/min flow rate), while under
similar conditions, a single peak at 56.5 min was observed for 1c,
confirming the optical purity of 1c. The absolute configuration of
previously unknown 1f was determined to be S with the help of
single-crystal X-ray analysis.33
In summary, we have developed a new and facile method for
the synthesis of (S)-N-protected homoserine γ-lactones. This
method is an advancement of the previous methods and uses
inexpensive starting materials to produce (S)-N-protected homo-
serine γ-lactones of high enantiopurity in moderate to high yields,
but is not suitable when the Boc protecting group is used. The use
of MW conditions not only reduces the reaction time but also
saves significant quantities of organic solvents and the micro-
waves promote reactions that were unachievable under thermal
treatment only.
a Key: (i) NMM (1.2 equiv)/IBCF (1.2 equiv) in THF À10 to À15 °C,
NaBH4 followed by MeOH at 0 °C, quench with acid; (ii) 0.5À1 M
citric acid. Method A: refluxing for 2À4 h. Method B: microwave heating
(MW), 300 W, 5À15 min, 80À100 °C.
at room temperature as evidenced by 1H and 13C NMR spectro-
scopies which each exhibited two sets of peaks at 295 K. The
1H NMR spectrumof11d in pyridine-d5 was studiedfurtherunder
variable temperature conditions. The two sets ofpeaks (ratio1/2.5)
began tocoalesceasthetemperaturewasraisedandthepeaksmerged
completely at 67 °C (see the Supporting Information). This phe-
nomenon is consistent, with the presence of rotamers, as reported
previously for N-acyl-5-oxazolidinones.26b
It is known that the N-protected-L-aspartic acid derivatives
(14) can be selectively reduced;27 therefore, it was anticipated
that selective reduction of the COOH side chain of 11 can be
similarly achieved. (S)-3-(Benzyloxycarbonyl)-5-oxo-4-oxazoli-
dineacetic acid (11b) was chosen for initial experiments due to its
higher yields and stability. Treatment of 11b with N-methylmor-
pholine and methyl chloroformate in dry THF at À15 °C led to
the in situ formation of a mixed anhydride (15b, PG = Cbz) and
was subsequently reacted with NaBH4 and MeOH to reduce the
side chain for the formation of (S)-(N-Cbz)-4-(2-hydroxyethyl)-
5-oxo-3-oxazolidine (16b, PG = Cbz). The reaction was quenched
with an acid (dilute HCl or CH3COOH) to obtain 16b in 61%
yield.28 In an attempt to improve this yield, isobutyl chlorofor-
mate was used as an alternative to methyl chloroformate,29 which
raised the yield to 71% (Scheme 5). Compound 16b was further
treated with 1.0 M citric acid under refluxing conditions (1 h) to
afford 1b in 55% yield (Scheme 5). The yield could be increased
to 70% by subjecting 16b to the lactone-forming step without
workup and by extending the reaction time to 2À4 h. Additional
changes to reactions times and reagents did not bring about any
further improvements. (S)-N-Tosyl- and (S)-N-nosylhomoserine
γ-lactones (1e,f) were also obtained in 68% and 70% yield,
respectively, by using a similar two-step protocol.30 However, this
method failed to produce any significant quantities of 1a,c,d, pre-
sumably because of the acid sensitivity of the starting substrates
(11a,c,d) under refluxing temperatures.31
’ EXPERIMENTAL SECTION
General Methods. All air- and water-sensitive reactions were
carried out in oven-dried glassware under a nitrogen atmosphere using
syringeÀseptum cap techniques. All column chromatography purifica-
tions were performed under flash conditions using 200À450 mesh type
60 Å silica gel. Microwave reactions were carried out in a CEM Discover
S-class reactor. Microwave reactions were carried out in vessels equipped
witha Tefloncap. The temperature ofthereactionmixture was monitored
using a surface sensor. The dynamic method with maximum power 300 W,
250 psi setting for maximum pressure and without powermax option was
used (CAUTION! Cardiac pacemakers require magnets to control their
operation during checkout. Some danger exists if a pacemaker is posi-
tioned in close proximity to the instrument cavity.)
To determine at what stage the problem is occurring, the
reaction of 11c was stopped after the reduction step, and forma-
tion of 16c (PG = Fmoc) was observed in the reaction mixture by
1H NMR spectroscopy. However, 16c further decomposes during
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NOTE
General Procedure for N-Protected L-Aspartic Acids (14).
N-Protected L-aspartic acid derivatives (14a,d) were purchased from a
commercial supplier. Compound 14c was synthesized from the adaptation
of a reported method.23 Compounds 14b and 14e were synthesized using
reported protocols, and characterization data including optical rotation
for 14b and 14e matched literature values.20,23
added paraformaldehyde (7.0 equiv) and p-TsOH H2O (0.06 equiv). The
3
mixture was subjected to microwave irradiation (300 W) at 80 °C(for14a,b,
dÀf) or 105 °C (for 14c) for 5À15 min. The reaction mixture was concen-
trated in vacuo, and the corresponding oxazolidinones (11) were immediately
chromatographed using EtOAc/hexanes as the eluant.
(S)-3-(1,1-Dimethylethoxy)carbonyl)-5-oxo-4-oxazolidi-
neacetic Acid (11a) (Method A/B). To a solution of 14a (2.00 g for
method A or 200 mg for method B) in benzene/EtOAc (65.0/5.00 mL
for method A) or benzene (2 mL for method B) were added parafor-
maldehyde (2.0 equiv, 515 mg for method A or 7.0 equiv, 231 mg
Synthesis of N-Fmoc-L-aspartic Acid (14c). This protocol was
adapted from a previous method.23b To a solution of L-aspartic acid (1.00 g,
7.51 mmol, 1.0 equiv) in dioxane (10.0 mL) was added 10% aq Na2CO3
(20.5 mL) at rt, and the mixture was cooled to 0 °C with an ice bath.
Fmoc-Cl (1.1 equiv) in dioxane (20 mL) was added slowly, and the
mixture was stirred at 0 °C for 1 h. The ice bath was removed, and the mix-
ture stirred atrtfor 18 h. Waterwasadded tothe solution, and theaqueous
layer was washed with diethyl ether. The organic layer was extracted with
saturated NaHCO3, and the combined aqueous layers were then acid-
ified to pH 1 with 1 M HCl. The aqueous layer was then extracted with
EtOAc (3 Â 20 mL). The organic layers were then combined, dried over
Na2SO4, filtered, and concentrated. The resulting Fmoc-protected as-
partic acid (14c) was chromatographed using EtOAc/n-hexanes (1/1)
as the eluant: white solid; yield = 2.37 g (87%); mp 172À174 °C;
[R]D27 À4.0 (c = 1, MeOH); 1H NMR34 (MeOH-d4) δ 7.68 (d, J = 7.4
Hz, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.27 (t, J = 7.2 Hz, 2H), 7.19 (t, J = 7.3
Hz, 2H), 4.45 (t, J = 6.8 Hz, 1H), 4.27À4.21 (m, 2H), 4.17À4.10 (m,
1H), 2.73 (m, 2H); 13C NMR (MeOH-d4) δ 174.4, 174.1, 158.4, 145.2,
142.6, 128.8, 128.19, 126.31, 120.94, 68.23, 51.94, 48.35, 37.21; IR (neat,
ν max) 3308, 3033, 2990, 2951, 2894, 1708, 1684, 1526, 1451, 1410,
for method B) and p-TsOH H2O (0.06 equiv, 89 mg for method A or
3
0.06 equiv, 12 mg for method B). The mixture was either refluxed for 2 h
(method A) or subjected to microwave irradiation (300 W) at 65 °C
for 10 min. Compound 11a was obtained as white solid after workup as
reported earlier.24a Recrystallization from diethyl ether: yield = 1.47 g,
70% (method A), 126 mg, 60% (method B); mp 128À129 °C (lit.24a mp
132À134 °C); [R]D26.5 +151.3 (c = 1, CHCl3) (lit.24a[R]2D6.5 +153.1
(c = 1, CHCl3); 1H NMR(400 MHz, CDCl3) δ (at 328 K) 10.50 (s, 1
H), 5.43 (d, J = 2.0 Hz, 1H), 5.23 (d, J = 3.6 Hz, 1H), 4.32 (s, 1H), 3.19
(br d, J = ca. 17 Hz, 1H), 3.03 (dd, J = 17.9, 3.0 Hz, 1H), 1.49 (s, 9H); (at
293 K) 10.00À8.50 (br s, 1 H), 5.50À5.42 (br, 1H), 5.24 (d, J = 3.1 Hz,
1H), 4.31 (s, 1H), 3.25À3.02 (m, 2H), 1.49 (s, 9H); 13C NMR (100
MHz, CDCl3) δ (at 328 K) 174.2, 172.0, 152.2, 82.6, 78.5, 51.5, 34.5,
28.1; (at 293 K) 175.3, 172.0, 152.2, 82.6, 78.8, 51.7, 34.7, 28.2; IR (neat, ν
max) 3500À2800, 3064, 2980, 2933, 1804, 1712, 1499, 1478, 1398, 1370,
1313, 1290, 1265, 1169, 1141, 1100, 1052, 988 cmÀ1
.
1275, 1194, 1092, 1049, 1007, 906 cmÀ1
.
(S)-3-(Benzyloxycarbonyl)-5-oxo-4-oxazolidineacetic
Acid (11b) (Method A/B). To a solution of 14b (2.00 g for method A
or 200 mg for method B) in benzene (56.0 or 1 mL for method B) were
added paraformaldehyde (449 mg, 2 equiv for method A or 157 mg,
Synthesis of N-Nosyl-L-aspartic Acid (14f). To a solution of L-aspartic
acid (2.0 g, 15.0 mmol) in aq NaOH solution (16.0 mL, 1.20 g, 30.0 mmol)
at 0 °C were added Ns-Cl (3.66 g, 16.5 mmol), (i-Pr)2EtN (2.87 mL,
16.5 mmol), and acetone (16.0 mL). After being stirred for 10 min, the
mixture changed from cloudy to clear yellow and was allowed to stir at rt
for 18 h. The mixture was then diluted with water, and the aqueous layer
was washed with diethyl ether (3 Â 10 mL). The aqueous layer was acid-
ified to pH 1 with 1 M HCl and was extracted with EtOAc (3 Â 10 mL).
The organic layers were combined, dried over Na2SO4, filtered, and
concentrated. The nosyl-protected aspartic acid, 14f, (3.18 g, 83%) was
obtained as yellow oil after chromatography (70% EtOAc/n-hexane).
Recrystallization from EtOAc gave 14f as pale yellow crystals: mp 182À
184 °C; [R]2D7.5 À92.1 (c = 1, MeOH); 1H NMR (MeOH-d4) δ 8.13À
8.10 (m, 1H), 7.91À7.88 (m, 1H), 7.80À7.77 (m, 2H), 4.42 (t, J = 5.4 Hz,
1H), 2.85 (m, 2H); 13C NMR (MeOH-d4) δ 173.8, 173.2, 149.2, 135.4,
135.1, 133.9, 131.7, 126.2, 54.3, 38.5; IR (neat, ν max) 3293, 2990, 2933,
2879, 1706, 1541, 1415, 1404, 1358, 1341, 1298, 1228, 1195, 1160, 1124,
1068, 919 cmÀ1. Anal. Calcd for C10H10N2O8S: C, 37.74; H, 3.17.
Found: C, 38.00; H, 3.23.
7 equiv for method B) and p-TsOH H2O (77.0 mg, 0.06 equiv or 8 mg,
3
0.06 equiv for method B). The mixture was either refluxed for 2 h
(method A) or subjected to microwave irradiation (300 W) at 80 °C for
6 min (method B). Compound 11b was obtained as clear oil after
chromatography using EtOAc/hexanes (3/7) as the eluant. Recrystalli-
zation from EtOAc/n-hexane gave 11b as a clear crystal: yield = 1.90 g,
91% (method A), yield = 182 mg, 87% (method B); mp 82À84 °C
(lit.24b mp 85À87 °C); [R]D27.5 +124 (c = 3.53, MeOH) (lit.24b [R]D23
+
125.7 (c = 3.53, MeOH)); 1H NMR (CDCl3) δ 9.78 (br s, 1H), 7.34
(s, 5H), 5.48 (br s, 1H), 5.28 (d, J = 3.5 Hz, 1H), 5.21À5.11 (m, 2H),
4.34 (s, 1H), 3.30À3.02 (m, 2H); 13C NMR (CDCl3) δ 175.0, 171.7,
152.9, 135.2, 128.8, 128.4, 78.5, 68.3, 51.4, 34.0; IR (neat, ν max) 3500À
2600, 3030, 1802, 1721, 1422, 1360 cmÀ1
.
(S)-3-[(9H-Fluoren-9-ylmethoxy)carbonyl]-5-oxo-4-oxa-
zolidineacetic Acid (11c) (Method B). A mixture of 11c (300 mg),
paraformaldehyde (7.0 equiv, 177 mg), and p-TsOH H2O (0.06 equiv,
3
General Procedure for (S)-3-(N-Protected)-5-oxo-4-oxazo-
lidineacetic Acids (11). Method A. To a solution of 14 (1.0 equiv) in
EtOAc/benzene (10 mL/mmol (1/13) for 14a) or toluene (10 mL/mmol
9 mg) in toluene (1 mL) was subjected to microwave irradiation (300 W)
at 105 °C for 6 min. The reaction mixture was cooled to rt, and EtOAc
was added. The organic layer was washed with water and brine and dried
over MgSO4. The solution was filtered and concentrated. Recrystalliza-
tion from acetone/CH2Cl2/hexanes (2/1/3) or EtOAc/n-hexane gave
11c as a white solid. Alternatively, 11c can also be purified by chroma-
tography using EtOAc/hexanes (5/5) as the eluant: yield = 263 mg, 85%
(method B); mp 185À187 °C (lit.24c mp 175À177 °C); [R]D26.5 +103.4
(c = 1, MeOH); 1H NMR (acetone-d6, 318 K) δ 7.85 (d, J = 7.6 Hz, 2H),
7.66 (d, J = 7.3 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H),
5.41(d,J= 3.5 Hz, 1H), 5.19 (s, 1H), 4.62À4.53 (m, 2H), 4.33 (t, J=5.7Hz,
1H), 4.26 (m, 1H), 2.84 (br s, 2H); 13C NMR (DMSO-d6, 318 K)
δ 172.1, 171.3, 152.4, 143.6, 140.8, 127.7, 127.2, 127.1, 125.0, 120.1,
77.9, 67.1, 51.4, 46.6, 34.2; IR (neat, ν max) 3300, 3047, 2955, 2923,
1772, 1727, 1692, 1449, 1431, 1411, 1360, 1299, 1260, 1173, 1131, 1053,
for 14bÀe) were added paraformaldehyde (2.0 equiv) and p-TsOH
3
H2O (0.06 equiv). The mixture was heated to 60 °C (for 14a) or re-
fluxed (for 14bÀe) with removal of water using a DeanÀStark trap filled
with MgSO4, The reaction was stopped after disappearance of starting
material as judged by TLC analysis (approximately 1À2 h, 4 h for 14c).
The reaction mixture of 14a was cooled to rt, and EtOAc was added. The
organic layer was washed with aq K2CO3 (0.3 M, 2 mL) and brine and
dried over MgSO4. The solution was filtered and concentrated. Recrys-
tallization from diethyl ether provided 11a as a light yellow solid. For
14bÀe, after consumption of starting material the solvent was removed
under reduced pressure and the corresponding oxazolidinones (11b,c,e)
were immediately chromatographed using EtOAc/hexanes as the eluant.24
Compounds 11d and 11f could not be synthesized using this method.
Method B(Microwave-Assisted Method). To a solution of 14 (1.0 equiv)
in benzene (5 mL/g for 14a,b,dÀf) or toluene (5 mL/mmol for 14c) were
1131, 1053, 992 cmÀ1
.
(S)-3-[Acetyl]-5-oxo-4-oxazolidineacetic Acid (11d) (Method B).
A mixture of 14d (200 mg), paraformaldehyde (7.0 equiv, 231 mg), and
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The Journal of Organic Chemistry
NOTE
p-TsOH H2O (0.06 equiv, 12 mg) in benzene (1 mL) was subjected to
over MgSO4, filtered, and concentrated. The corresponding lac-
tones 1 were obtained after chromatography (hexanes/EtOAc).
3
microwave irradiation (300 W) at 80 °C for 15 min. The reaction mix-
ture was concentratedinvacuo, and11d was chromatographed using EtOAc/
hexanes (1/1) as the eluant. Compound 11d was dissolved in MeOH,
and hexanes/diethyl ether was added. This solution was triturated to
obtain a white solid after filtration: yield = 160 mg, 75% for two rotamers
(1/2.5) (method B); mp 132À133 °C; [R]2D3.5 +210.2 (c = 1.0, MeOH);
1H NMR (300 MHz, 295 K, MeOH-d4) δ 5.68 (d, J = 4.6 Hz, 1H*), 5.64
(d, J = 3.2 Hz, 1H), 5.50 (d, J = 3.1 Hz, 1H), 5.25 (d, J = 4.5 Hz, 1H*),
4.66 (d, J = 3.4 Hz, 1H*), 4.50 (t, J = 3.3 Hz, 1H), 3.14 (ABX, J = 18.2,
4.1, 2.3 Hz, 2H), 3.12 (d, J = 3.1 Hz, 2H*), 2.15 (s, 3H*), 2.07 (s, 3H)
*minor rotamer; 13C NMR (100 MHz, MeOH-d4) δ 174.3, 174.0, 173.5,
172.9, 171.7, 170.5, 80.1, 80.1, 53.7, 52.6, 36.6, 34.7, 21.6, 21.3; IR (neat,
νmax) 3500À2600, 2989, 2955, 2926, 2854, 1791, 1716, 1605, 1462,
1455, 1427, 1413, 1350, 1316, 1288, 1253, 1206, 1184, 1107, 1093, 1058,
1031, 994, 940 cmÀ1. Anal. Calcd for C7H9NO5: C, 44.92; H, 4.85.
Found: C, 45.11; H, 5.00.
Method B (Microwave-Assisted Method). To a dry THF (40.0 mL/g)
solution of 11 (1.0 equiv) at À10 to À15 °C were added N-methyl-
morpholine (1.2 equiv) and isobutyl chloroformate (1.2 equiv). The
mixture was left to stir under nitrogen for 15À30 min at À10 °C. NaBH4
(3.0 equiv) was added in one portion, and the reaction was allowed to
slowly warm while it stirred for 5À10 min. MeOH (50.0 mL/g) was added
dropwise, and the solution was stirred for an additional 10À15 min at
0 °C and then neutralized with 1 M acetic acid (∼ 8 mL/g) until the
solution became clear (pH ∼ 7). The reaction mixture was concentrated
in vacuo and transferred to a microwave vial with the help of additional
methanol and the solvent quickly evaporated in vacuo without exposing
it to heat (<40 °C). The reaction mixture was then added to 0.5À1 M
citric acid (∼ 4À6 mL/g) solution, and the mixture was exposed to the
microwave irradiation (300W) for 5À10 min at 80 °C. The mixture was
extracted with EtOAc (4Â). The organic layers were combined and
washed with water and brine, dried over MgSO4, filtered, and concen-
trated. The correspondinglactones1 were obtainedafter chromatography
(hexanes/EtOAc).
(S)-3-[(4-Methylphenyl)sulfonyl]-5-oxo-4-oxazolidine-
acetic Acid (11e) (Method A/B). A mixture of 14e (200 mg),
paraformaldehyde (2.0 equiv, 42 mg for method A; 7.0 equiv, 146 mg for
method B), and p-TsOH H2O (0.06 equiv, 7 mg) in toluene (6 mL for
(S)-N-Cbz-homoserine γ-Lactone (1b). A solution of 11b
(200 mg) in dry THF (8.0 mL) was treated with NMM (1.2 equiv, 94
μL) and IBCF (1.2 equiv, 113 μL), followed by the addition of NaBH4
(3.0 equiv, 80 mg), and then quenched with MeOH (10.0 mL) and 1 M
acetic acid (1.5 mL). The solvent was evaporated in vacuo, and 1 M citric
acid was added (4 mL for method A or 1 mL for method B). The reaction
mixture was either refluxed for 2 h (method A) or exposed to microwave
irradiation (300W) for 15 min at 80 °C. After the general workup pro-
cedure described, 1b was chromatographed using hexanes/EtOAc (7/3
to 1/1) as eluent. Recrystallization from EtOAc/n-hexane gave 11b as
white needles: yield = 118 mg, 70% (method A), 109 mg, 65% (method B);
mp 122À124 °C (lit.18 mp 126À127 °C); [R]2D7.5 À32.1 (c = 1.0,
3
method A and 1 mL for method B) was refluxed for 3 h or subjected to
microwave irradiation (300 W) at 100 °C for 5 min. The reaction
mixture was concentrated in vacuo, and 11e was chromatographed using
EtOAc/hexanes (7/3 to 3/7) as the eluant: sticky solid, yield = 137 mg,
66% (method A), 150 mg, 72% (method B); mp 117À118 °C (lit.24d
130À131 °C); [R]2D3.5 +252 (c = 1.0, acetone) (lit.24d +252 (c = 1.0,
acetone)); 1H NMR (300 MHz, CDCl3) δ 8.41 (br s, 1H), 7.93 (m, J =
8.2 Hz, 2H), 7.40 (m, J = 8.0 Hz, 2H), 5.38 (AB pattern, J = 5.1 Hz, 2H),
4.06 (t, J = 3.6 Hz, 1H), 3.16 (d, J = 3.7 Hz, 2H), 2.46 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 175.0, 170.9, 145.8, 132.0, 130.58, 127.7, 79.6,
52.9, 36.2, 21.6; IR (neat, νmax) 3500À2500, 3241, 3092, 3062, 2986,
2930, 1803, 1718, 1597, 1493, 1401, 1357, 1307, 1293, 1268, 1215, 1165,
1
MeOH) (lit.18 [R]2D5 À30.5 (c = 1.0, MeOH)); H NMR (400 MHz,
1105, 1045, 966 cmÀ1
.
CDCl3) δ 7.33 (s, 5H), 5.39 (br s, 1H), 5.11 (s, 2H), 4.44À4.35
(m, 2H), 4.24À4.17 (m, 1H), 2.78À2.70 (m, 1H), 2.26À2.11 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 175.1, 156.0, 135.8, 128.4, 128.1, 128.0,
67.1, 65.6, 50.2, 29.6; IR (neat, νmax) 3328, 3058, 3029, 2944, 1778,
(S)-3-[(2-Nitrophenyl)sulfonyl]-5-oxo-4-oxazolidineacetic
Acid (11f) (Method B). A mixture of 14f (200 mg), paraformaldehyde
(7.0 equiv, 132 mg), and p-TsOH H2O (0.06 equiv, 3.2 mg) in benzene
3
1695, 1542, 1385, 1298, 1265, 1225, 1180, 1073, 1013, 1007, 946 cmÀ1
;
(1 mL) was subjected to microwave irradiation (300 W) at 80 °C for 10
min. The reaction mixture was concentrated in vacuo, and 11f was
chromatographed using EtOAc/hexanes (1/1) and EtOAc as the eluant.
The solid was recrystallized with EtOAc/diethyl ether to yield a white
solid: yield = 178 mg, 86% (method B); mp 180À181 °C; [R]2D3.5 +232.4
(c = 1.0, MeOH); 1H NMR (400 MHz, MeOH-d4) δ 8.21À8.19
(m, 1H), 7.93À7.86 (m, 3H), 5.73 (d, J = 4.5 Hz, 1H), 5.43 (dd, J =
4.5 Hz, J= 0.7Hz, 1H), 4.61 (t, J =3.5 Hz, 1H), 3.04(ABX, J =18.1Hz, J=
4.2 Hz, J = 3.4 Hz, 2H); 13C NMR (400 MHz, MeOH-d4) δ 173.0, 149.8,
136.7, 133.8, 132.2, 131.4, 126.0, 80.7, 54.6, 36.6; IR (neat, νmax)
3500À2500, 3101, 3024, 2955, 2930, 2854, 1793, 1763, 1726, 1540, 1406,
GCÀMS (EI) m/z 235.1(M+, 1), 191.9 (59), 127.8 (100) .
(S)-N-Fmoc-homoserine γ-Lactone (1c). A solution of 11f
(200 mg) in dry THF (8.0 mL) was treated with NMM (1.2 equiv, 73
μL) and IBCF (1.2 equiv, 105 μL), followed by the addition of NaBH4
(3.0 equiv, 62 mg), and then quenched with MeOH (10.0 mL). The
solvent was quickly evaporated in vacuo, and 0.5 M citric acid (2 mL)
was added. The reaction mixture was exposed to the microwave irradia-
tion (300 W) for 10 min at 80 °C. After the general workup procedure,
1f was chromatographed using hexanes/EtOAc (1/1) as eluent followed
by recrystallization from 95% EtOH: white solid; yield = 105 mg, 60%
(method B); mp 208À209 °C (lit.9b mp 208À209 °C); [R]D22.0 +12.0
(c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.5 Hz,
2H), 7.58 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz,
2H), 5.39 (br s, 1H), 4.47À4.41 (m, 4H), 4.26À4.20 (m, 3H), 2.78
(m, 1H), 2.20 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.9, 156.1,
143.7, 143.6, 141.3, 127.8, 127.1, 125.0, 120.0, 67.3, 65.8, 50.5, 47.1,
30.5; IR (neat, νmax) 3328, 3061, 3017, 2948, 2918, 2851, 1789, 1686,
1534, 1461, 1384, 1243, 1285, 1263, 1222, 1187, 1161, 1103, 1081, 1017,
995, 971 cmÀ1; HPLC (17% iPrOH/hexanes, 1.0 mL/min flow rate, OJ-
H chiral analytical column: 250 mm (column length) Â 4.6 mm (internal
diameter). Packing composition: cellulose tris(4-methylbenzoate) coated
on5 μmsilica gel, 56.5 min (pure compound), 51.7and55.3min (racemic
mixture).
1372, 1330, 1301, 1223, 1201, 1170, 1127, 1101, 1050, 1041, 971, 852 cmÀ1
.
Anal. Calcd for C11H10N2O8S: C, 40.00; H, 3.05. Found: C, 40.19; H, 3.13.
General Procedure for the Preparation of (S)-N-Protected-
L-homoserine γ-Lactones (1). Method A. To a dry THF (40.0 mL/g)
solution of 11 (1.0 equiv) at À10 to À15 °C were added N-methylmorpho-
line (1.2 equiv) and isobutyl chloroformate (1.2 equiv). The mixture was al-
lowed to stir under nitrogen for 15À30 min at À15 °C. NaBH4 (3.0 equiv)
was then added in one portion, and the reaction was stirred for 5À10 min
followed by the dropwise addition of methanol (40.0 mL/g), and the
reaction mixture was further stirred for an additional 10À15 min at 0 °C and
then neutralized with 1 M acetic acid or citric acid until solution becomes
clear (pH = 5À7). The organic solvents were evaporated under reduced pre-
ssure while ensuring the water bath temperature did not exceed 35À40 °C.
To the concentrate was added 1.0 M citric acid (∼10 mL/g), and the mixture
was refluxed for 2À4 h, cooled to rt, and quickly extracted with EtOAc
(4Â). The organic layers were combined and washed with water, brine, dried
(S)-N-Acetylhomoserine γ-Lactone (1d). A solution of 11d
(200 mg) in dry THF (8.0 mL) was treated with NMM (1.2 equiv, 142
μL) and IBCF (1.2 equiv, 121 μL), followed by the addition of NaBH4
6829
dx.doi.org/10.1021/jo2008093 |J. Org. Chem. 2011, 76, 6825–6831

The Journal of Organic Chemistry
NOTE
(3.0 equiv, 121 mg), and then quenched with MeOH (10.0 mL) and 1 M
acetic acid (1.5 mL). The solvent was evaporated in vacuo, and 1 M citric
acid (1 mL) was added. The reaction mixture was exposed to the micro-
wave irradiation (300 W) for 15 min at 80 °C. The reaction mixture was
cooled to rt, and aq NaHCO3 was added to reach pH ∼7. The mixture
was extracted with EtOAc (4Â), and the combined organic layers were
washed with water and brine, dried over MgSO4, filtered, and concen-
trated. Compound 1d was chromatographed using EtOAc and EtOAc/
MeOH (95/5) as eluent followed by repeated recrystallization from
CH2Cl2/hexanes, spot detection in I2 chamber: white solid; yield = 137
(d, J = 11.2 Hz, 1H), 4.57À4.47 (m, 3H) 4.24À4.21 (m, 2H), 3.61 (br s,
1H), 2.49 (br s, 2H); 13C NMR (CDCl3) δ (mixture of rotational
isomers) 175.2, 174.7, 154.8, 135.6, 135.2, 128.4, 128.2, 128.1, 127.9,
72.3, 71.8, 68.1, 67.8, 65.9, 65.4, 56.0, 55.3, 27.4, 26.9; IR (neat, ν max)
3446 (br), 2956, 1779, 1705, 1482, 1436, 1355, 1258, 1184, 1024 cmÀ1
MS, ESI, m/z 288 ([M + Na]+, 100); HRMS, CI (+ve), m/z calcd for
C12H13NO4 [M À H2CO]+ 235.0845, found 235.0836.
’ ASSOCIATED CONTENT
mg, 84% (method B); mp 82À84 °C (lit.32a mp 82À84 °C); [R]2D7.5
À
Supporting Information. 1H and 13C NMR spectra for
S
b
51.0 (c = 1.0, DMF) (lit.32b [R]D27.5 À69.0 (c = 1.6, DMF), lit.32c À54.7,
DMF); 1H NMR (400 MHz, CDCl3)32d δ 6.13 (s, 1H), 4.61À
4.54 (m, 1H), 4.48 (m, 1H), 4.32À4.25 (m, 1H), 2.89À2.82 (m, 1H),
2.28À2.11 (m, 1H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8,
170.9, 66.0, 48.8, 29.4, 22.6; IR (neat, ν max) 3305, 3072, 2991, 2920,
compounds 14bÀc,eÀf, 11aÀf, 16b, and 1aÀf, a variable-
temperature 1H NMR spectrum of 11d in CDCl3 and d5-pyridine-d5,
ORTEP diagram, and X-ray data for the crystal of 1f (CIF) (CCDCno.
807944). This material is available free of charge via the Internet at
http://pubs.acs.org.
1777, 1656, 1542, 1450, 1431, 1379, 1300, 1221, 1180, 1154, 1020, 951 cmÀ1
;
GCÀMS (CI, MeOH), m/z 143.8 (M+, 100).
’ AUTHOR INFORMATION
(S)-N-Tosylhomoserine γ-Lactone (1e). A solution of 11f (250
mg) in dry THF (10.0 mL) was treated with NMM (1.2 equiv, 111 μL)
and IBCF (1.2 equiv, 134 μL), followed by the addition of NaBH4
(3.0 equiv, 95 mg), and then quenched with MeOH (12.5 mL) and 1 M
acetic acid (2 mL). The solvent was evaporated in vacuo, and 1 M citric
acid was added (5 mL for method A or 1.5 mL for method B). The
reaction mixture was either refluxed for 2 h (method A) or exposed to
microwave irradiation (300 W) for 10 min at 65 °C. After the general
workup procedure, 1f was chromatographed using hexanes/EtOAc (7/3
to 1/1) as eluent followed by recrystallization from CH2Cl2/hexanes, white
crystals: yield = 145 mg, 68% (method A), 100 mg, 46% (method B); mp
129À130 °C(lit.14a mp 130À133 °C); [R]D22.0 +8.0 (c= 1.0, MeOH) (lit.32c
[R]2D5 +8.0 (c = 1.0, MeOH); GCÀMS (CI) m/z 256.0 ((M + 1)+,100);
1H NMR, 13C NMR, and IR matched with the literature.30
(S)-N-Nosylhomoserine γ-Lactone (1f). A solution of 11f
(200 mg) in dry THF (8.0 mL) was treated with NMM (1.2 equiv, 81 μL)
and IBCF (1.2 equiv, 97 μL), followed by the addition of NaBH4 (3.0
equiv, 69 mg), MeOH (10.0 mL) and 1 M acetic acid (1.5 mL). The
solvent was evaporated in vacuo, and 1 M citric acid (4 mL for method A
or 1 mL for method B) was added. The reaction mixture was either re-
fluxed for 2 h (method A) or exposed to microwave irradiation (300 W)
for 5À10 min at 80 °C. After the general workup procedure, 1f was chro-
matographed using hexanes/EtOAc (1/1) as eluent followed by recrys-
tallization from CHCl3 to afford transparent crystals (121 mg, 70%,
method A), (73 mg, 42%, method B): mp 131À132 °C; [R]2D2.0 À350
(c = 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.16 (m, 1H), 7.97
(m, 1H), 7.80À7.75 (m, 2H), 6.16 (d, J = 5.7 Hz, 1H), 4.47 (d, J = 9.0
Hz, 1H), 4.30À4.23 (m, 2H), 2.77À2.83 (m, 1H), 2.34À2.45 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 173.8, 147.8, 134.1, 133.8, 133.2, 130.8,
125.9, 66.0, 52.7, 31.0; IR (neat, ν max) 3345, 3089, 2998, 2960, 2924,
2883, 1782, 1593, 1539, 1442, 1376, 1355, 1221, 1167, 1124, 1058, 1021,
999 cmÀ1. Anal. Calcd for C10H10N2O6S: C, 41.96; H, 3.52. Found: C,
41.89; H, 3.63.
Corresponding Author
*E-mail: schwan@uoguelph.ca.
’ ACKNOWLEDGMENT
We thank the Natural Sciences and Engineering Council of
Canada (NSERC) and Cystic Fibrosis Canada for funding this
research. We also thank Dr. Alan J. Lough at the University of
Toronto (Canada) for X-ray data collection and Mr. Joseph
Paquette for some initial experiments.
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3
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(33) Flack and Bernardinelli have suggested that one can use the
values of the Flack parameter (x) for deducing absolute configuration of
the chiral molecules forming a noncentrosymmetric crystal. The physi-
cally meaningful values of x are 0À1, but these values may be observed a
little outside of this range by a few standard uncertainties because of
statistical fluctuations and systematic errors. A crystal of an enantio-
merically pure compound in the correct absolute configuration has a
value of the Flack parameter of 0, while a value of the Flack parameter of
1 indicates the opposite absolute configuration. When the value of x is
between 0 and 1, i.e., x = 0.3, both types of enantiomers are present in the
crystal in a proportion of 70% of the proposed configuration and 30% of
the opposite configuration. The experimental value of the Flack param-
eter for 1f was found to be À0.10 (9). Flack, H. D.; Bernardinelli, G.
Chirality 2008, 20, 681.
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dx.doi.org/10.1021/jo2008093 |J. Org. Chem. 2011, 76, 6825–6831